zavicefta product monograph - pfizer pro · 1.1 summary antimicrobial resistance is a growing...

PRODUCT MONOGRAPH

COVER PAGE

INSIDE PAGE

Index

EXECUTIVE SUMMARY

1. Antibiotics – key issues and unmet needs 1.1 Summary

1.2 The growing threat of antimicrobial resistance

1.3 Unmet needs in the management of serious Gram-negative infections

1.3.1 cIAI

1.3.2 cUTI

1.3.3 HAP, including VAP

1.3.4 Serious infections due to MDR Gram-negative pathogens

1.4 Lack of treatment options for resistant infections

1.5 The impact of treatment failure

2. Ceftazidime-avibactam – an anti-pseudomonal, third-generation cephalosporin combined with a novel non-ß-lactam, ß-lactamase inhibitor 2.1 Summary

2.2 Mechanism of action

2.2.1 Mechanism of action of ceftazidime

2.2.2 Mechanism of action of avibactam

2.3 Antimicrobial activity

2.3.1 In vitro activity – aerobic Gram-negative bacteria

2.3.1.1 Activity against Enterobacteriaceae

2.3.1.2 Activity against Pseudomonas aeruginosa

2.3.2 In vitro activity – aerobic Gram-positive bacteria and anaerobic organisms

2.4 Avibactam compared with other ß-lactamase inhibitors

2.5 Penetration studies (against experimental infections)

2.5.1 Renal infection model

2.5.2 Thigh infection model

2.5.3 Sepsis model

2.5.4 Neutropenic pneumonia model

2.6 Surveillance data

2.7 Propensity for resistance

2.8 Dosage and administration

2.9 Contraindications

01

02

02

02

05

05

05

06

07

07

09

10

10

10

11

11

13

13

16

17

18

19

20

20

20

21

21

22

25

26

26

INSIDE PAGE

2.10 Special warnings and precautions of use

2.10.1 Hypersensitivity reactions

2.10.2 Clostridium difficile-associated diarrhea

2.10.3 Patients with renal impairment

2.10.4 Non-susceptible organisms

2.10.5 Non-drug interference

2.10.6 Direct antiglobulin test (DAGT or Coombs test) seroconversion and potential risk of hemolytic anemia

2.10.7 Controlled sodium diet

3. Pharmacology and pharmacokinetics of ceftazidime-avibactam 3.1 Summary

3.2 Ceftazidime-avibactam: pharmacokinetic/pharmacodynamic relationship

3.3 Pharmacokinetics of ceftazidime-avibactam

3.3.1 Distribution

3.3.2 Metabolism

3.3.3 Elimination

3.3.4 Use in special populations

3.3.4.1 Renal impairment

3.3.4.2 Hepatic impairment

3.3.4.3 Elderly patients (≥65 years)

3.3.4.4 Paediatric patients

3.3.4.5 Gender

3.3.4.6 Ethnicity

3.3.5 Drug interactions

4. Clinical and safety profile of ceftazidime-avibactam in complicated intra-abdominal infections (cIAI) 4.1 Summary

4.2 Clinical development programme – RECLAIM and REPRISE

4.3 RECLAIM 1 and 2

4.3.1 Baseline characteristics

4.3.2 Clinical efficacy

4.3.2.1 Clinical cure rates

4.3.2.2 Clinical response by baseline pathogen

4.3.3 Safety and tolerability

4.3.4 Impact of treatment failure on healthcare resource utilization in the RECLAIM program

4.3.5 Conclusions

4.4 RECLAIM: Indian subset analysis




4.4.2.2 Clinical response by baseline pathogen


4.4.4 Conclusions

4.5 REPRISE

5. Clinical and safety profile of ceftazidime-avibactam in complicated urinary tract infections (cUTI) including pyelonephritis 5.1 Summary

5.2 Clinical development programme – RECAPTURE and REPRISE

5.3 RECAPTURE


5.3.2 Treatment switching



5.3.5 Conclusions

5.4 REPRISE




5.4.4 Conclusions

6. Clinical and safety profile of ceftazidime-avibactam in hospital-acquired pneumonia including ventilator-associated pneumonia 6.1 Summary

6.2 REPROVE





6.2.4 Conclusions

27

27

27

27

27

28

28

28

29

29

29

32

32

34

34

34

34

34

35

35

35

35

35

36

36

36

37

39

42

43

44

45

47

47

48

48

52

53

54

56

58

58

59

59

59

61

63

64

65

67

68

68

70

72

73

73

74

74

74

76

78

79

81

81

01

INSIDE PAGE

Ceftazidime-avibactam is approved for the treatment of adults with complicated intra-abdominal infections (cIAI), complicated urinary tract infections (cUTI) including pyelonephritis, hospital-acquired pneumonia (HAP), including ventilator-associated pneumonia (VAP).1

Ceftazidime-avibactam combines a third-generation cephalosporin that has a well- established ecacy and safety prole, with a novel non-ß-lactam, ß-lactamase inhibitor that restores the activity of ceftazidime against most clinically important Gram-negative pathogens which are resistant to standard of care, including ceftazidime.2

Treatment with ceftazidime-avibactam plus metronidazole was shown to be non-inferior to meropenem in hospitalized patients with cIAI.3 Ceftazidime-avibactam has also been demonstrated to be eective for the empiric treatment of cUTI. In the rst randomized controlled trial to demonstrate non-inferiority of a new antimicrobial therapy versus a carbapenem targeting Gram-negative pathogens in nosocomial pneumonia, ceftazidime- avibactam was non-inferior to meropenem in patients with HAP/VAP.4,5 In patients with serious ceftazidime-resistant Gram-negative bacterial infections (cUTI and cIAI), the ecacy prole of ceftazidime-avibactam was similar to best available therapy (BAT) with similar clinical cure rates and numerically higher per-patient favorable microbiological response rates.6 e majority (97%) of patients in the BAT group received a carbapenem and most of these (96%) received a carbapenem as monotherapy.6 e safety and tolerability prole of ceftazidime-avibactam was found to be consistent with ceftazidime and comparable with carbapenem comparators.3, 5, 6

Executive summary

See summary of prescribing information on last page

6.3 REPROVE: Indian Subset Analysis





6.3.4 Conclusions

7. Conclusions

8. Prescribing information

9. Abbreviations and References

82

82

85

86

89

90

91

92

94

1.1 SummaryAntimicrobial resistance is a growing threat, which is making currently available antibiotics unreliable7 and the treatment of a variety of infections more dicult and more expensive with increased morbidity and mortality.8

In particular, the management of serious multidrug resistant (MDR) Gram-negative infections, including cIAI, cUTI and HAP, including VAP, is increasingly challenging due to bacterial diversity and the continued and well-documented emergence of resistance.9-13 Increased antibiotic resistance and decreased drug development is making antimicrobial treatment, especially that of resistant bacteria, dicult.14,15

1.2 e growing threat of antimicrobial resistanceIn recent decades, high-level antimicrobial resistance (AMR) and MDR, have rendered entire classes of antibiotics unreliable.7 Gram-negative bacteria such as Escherichia coli and Klebsiella pneumoniae, which are commensals (living in close association with another organism of a dierent species with neither having an obvious eect on the other) and pathogens for humans and animals, have become increasingly resistant to third-generation cephalosporins and, in many countries, they are becoming increasingly resistant to carbapenems.13

Resistance is intrinsic in some bacteria but can also be due to spontaneous mutations.16 Once bacteria are resistant, they are selected via appropriate and inappropriate use of antibiotics after which they spread.13 Inappropriate use of antibiotics is of limited and/or no benet and should be curtailed.13 Despite hand hygiene measures, resistant bacteria have a survival advantage that allows them to cause outbreaks and to travel globally.13

In general, AMR makes the treatment of a variety of infections more dicult and more expensive. Some Gram-negative bacilli have developed resistance to nearly all currently available antibiotics, making them nearly untreatable.13,17,18 Four of the six microorganisms classied as ESKAPE (or ESCAPE; Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacteriaceae) pathogens are Gram-negative bacilli (Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter spp.), which often harbour MDR mechanisms, and are of utmost concern.19,21,22 ese are capable of ‘escaping’ the action of antibiotics and are said to represent new paradigms in pathogenesis, transmission, and resistance.20

e ESKAPE pathogens are particularly prominent in the aetiology of cIAI, cUTI, and HAP.7,13,21,22

02 03

1. Antibiotics – key issues and unmet needs

INSIDE PAGE

ESBL: Extended-spectrum ß-lactamase. KPCs: Klebsiella pneumoniae carbapenemases. OXA: Oxacillinase.

e three major types of MDR Gram-negative pathogens19 include: Extended-spectrum ß-lactamase (ESBL)-producing Enterobacteriaceae Carbapenemase-producing Enterobacteriaceae MDR P. aeruginosa.Production of ß-lactamases is the most common resistance mechanism to ß-lactam antibiotics19 and these enzymes are classied based on their molecular structure by ‘Ambler’ class:23 Class A, which includes the ESBLs, and Klebsiella pneumoniae carbapenemases (KPCs); Class B, the metallo-ß-lactamases (MBLs); Class C, AmpC; and Class D, the oxacillinases (OXAs).

Figure 1.1: Clinically important ß-lactamases according to Ambler class2,23

Older TEM & SHV,ESBLs: new TEM,

SHV, CTX-M

Class A Class C Class D Class B

Amp C OXA IMP, NDM-1 VIM-1

KPCs

B-lactamases

Serine enzymes Metallo-enzymes


Prevalence, %

Europe Asia PacificUSA

ESBLs

AmpC

MDR Pseudomonas spp.

KPCs

2–8 24

4.0–8.5 26

22.0 31

38 33

35.8–42.2 25

14.8–20.4 29, 30

29.8 25

‘Endemic’ 35

6–16 24

0.6–2.6 27, 28

33.3 32

15.2–49.0 34

e prevalence of resistance in Gram-negative bacilli is growing around the world(Table 1.1).13

Table 1.1: Global prevalence of resistance in isolates of Gram-negative pathogens.

ESBL: Extended-spectrum-lactamase. KPCs: Klebsiella pneumoniae carbapenemases. MDR: Multidrug-resistant.

e most common treatment of ESBL-producing Enterobacteriaceae, such as E. coli and K. pneumoniae,36 has been carbapenems until the recent development of Enterobacteriaceae-producing carbapenemases that are resistant to most ß-lactam antibiotics, including those in the carbapenem class. Data from 13,086 patients across 10 tertiary care hospitals in India showed highest mortality rates in patients infected with Gram-negative bacteria (17.7%), as opposed to those caused by Gram-positive bacteria (10.8%), particularly in the ICU, where 26.9% of patients with Gram-negative MDR infections died.37 With the ongoing use of carbapenems with the resulting selection of resistant pathogens, has resulted in increasing prevalence. Further, these pathogens often have multiple mechanisms of resistance causing resistance to many other classes of antibiotics,36 contributing to their association with a number of serious infections and considerable mortality.17 In the study by Gandara, et al. (2018) to understand the relationship between MDR pathogens and mortality in India, for non-MDR K. pneumoniae, the odds of mortality were 2.29 (95% CI 1.45–3.62) times higher for XDR K. pneumoniae.37 In addition, patients tested for colistin-resistance indicated 9 (0.8%) E. coli cases and 38 (4.6%) K. pneumoniae cases as non-susceptible, with 2 and 10 deaths reported among them, respectively.37

With the increasing importance of ESBL-producing and ciprooxacin-resistant Enterobacteriaceae in serious hospital infections, resistance is being noted in patients with E. coli infections, particularly resistant to multiple drug classes, including ß-lactam ß-lactamase inhibitors. A cross-sectional study in the ICUs of KIMS, Bhubaneshwar showed 61.1% of 1038 isolates were ESBL-producing E. coli and 452 isolates were resistant to third generation cephalosporins.38 Another study in an NICU in northern India revealed increasing resistance due to a long-term outbreak of ESBL-producing K. pneumoniae in neonates treated with third generation cephalosporins, warranting judicial use of antibiotics.39

04 05

INSIDE PAGE

1.3 Unmet needs in the management of serious Gram-negative infections

1.3.1 cIAIcIAIs, which include a wide range of sub-conditions from appendicitis to fecal peritonitis, represent the second most common cause of infectious mortality in intensive care units (ICUs) in the USA.9 Complicated intra-abdominal infections (cIAIs) are local or systemic infections that occur as a result of a perforation in the gastrointestinal tract or by a necrotic gut wall spilling bacteria into the peritoneal space, leading to abscess formation and/or generalized peritonitis. ese infections require operative intervention or percutaneous drainage in conjunction with broad-spectrum antibacterial therapy. e Complicated Intra-Abdominal infection Observational (CIAO) Study, which included 2,152 patients with cIAI from 68 centers in Europe, found that the overall mortality rate was 7.6%, and that 24.2% of the patients were admitted to ICUs in the early recovery phase after surgery.40 In addition, results from the Study for Monitoring Antimicrobial Resistance Trends (SMART) have indicated that the susceptibility of causative Gram-negative pathogens to frequently used antimicrobials continues to decrease in patients with cIAI.29, 41 A study by Veeraraghavan, et al. (2018) the rate of ESBL-positive isolates ranging from 66%–77% in E. coli to 61%–72% in K. pneumoniae, respectively.42 e IDSA Guideline 2010 on intra-abdominal infections emphasizes the need to factor in local antimicrobial susceptibility patterns when opting for an appropriate empiric regimen.43

In summary, the management of cIAI is increasingly challenging due to bacterial diversity, the severity of the infection and the well-documented, continued emergence of resistance.9,44

1.3.2 cUTIcUTIs are often associated with structural or functional urinary tract abnormalities, including calculi, catheters, obstruction, immunosuppression, renal failure, renal transplantation or pregnancy.45 Catheter-associated bacteriuria is the most common healthcare-associated infection worldwide and accounts for up to 40% of hospital-acquired infections in US hospitals each year.10 Signicant healthcare resources are expended in eorts to prevent and treat catheter-associated urinary tract infections (CA-UTIs). Given the high frequency of urinary catheter-associated infections in the USA results in as much as US$500 million added to annual healthcare costs.10 Healthcare-associated UTIs often involve a large reservoir of highly AMR organisms, particularly in critical care units, which can be the source of cross-infection.10,11 In addition, the bacterial aetiology diers markedly between infections.11,46 A wide range of Gram-negative and Gram-positive species are involved in hospital- and community-acquired cUTIs, with the spectrum generally greater in hospital-acquired cUTIs. Further, the spectrum of pathogens involved in cUTIs is generally broader than those involved in uUTIs. CA-UTI is a subset of all cUTIs, but can be hospital- or community-acquired.11,46


Enterobacteriaceae are the predominant pathogens in cUTI, with E. coli being the most common. However, non-fermenters (e.g. P. aeruginosa) and Gram-positive cocci (e.g. Staphylococci and Enterococci) may also play an important role, depending on the underlying conditions.46

In summary, antibiotics with an enlarged antibacterial spectrum are necessary for initial empiric treatment of cUTI.11 Local resistance patterns need to be considered, which may result in dierent antibiotic recommendations.46

1.3.3 HAP, including VAPHAP, including VAP, is responsible for up to 25% of all ICU infections and for more than 50% of antibiotic prescriptions.47 Although many critically ill patients with HAP die of their underlying disease rather than pneumonia, HAP remains an important cause of morbidity and mortality as 33–50% of deaths in such patients remain attributable to HAP despite advances in antimicrobial therapy and better supportive care modalities.47 e development of HAP increases the duration of hospitalization by an average of 7–9 days per patient, resulting in an excess cost of >US$40,000 per patient.47 Results from the SENTRY Antimicrobial Surveillance Program (2009–2012) showed high rates of AMR among the most frequently isolated Gram-negative pathogens from hospitalized patients with pneumonia (mostly HAP) in the US and the European/Mediterranean region.12

e ICUs in India and Asia particularly, constitute a greater proportion of Gram-negative isolates such as extended spectrum ß-lactamase (ESBLs), AmpCs, and carbapenemases,48 with the EPIC-2 study indicating the lungs as the most common site of infection (approximately 64% of infections).49 Patients who have been mechanically ventilated for more than 48h are at an increased risk of ventilator acquired pneumonia (VAP), and this risk can range from 6-52%.50 A study conducted by Khurana, et al. (2017) over a 5-year period in a Level-1 Trauma Care Center in north India revealed a high rate of multi-drug resistant (MDR) infections, with ESBL, AmpC and carbapenemase genes isolated among 433 episodes of VAP.51 Another study of 2,731 clinical specimens from seven hospitals across India revealed a rate of ESBL-positive isolates ranging from 66–77% in E. coli to 61–72% in K. pneumoniae, respectively.42

In summary, guidelines recommend initial intravenous (i.v.) antibiotic treatment to improve clinical outcomes, reduce costs and reduce the length of hospital stay,52 but failure to initiate therapy active against the causative pathogen promptly in patients with HAP is consistently associated with an increase in mortality.47 us, it is imperative that initial, empiric therapy is active against organisms likely to cause HAP. Because very few agents remain broadly active against the most frequently isolated MDR Gram-negative organisms, the treatment of patients with pneumonia in medical centers has become increasing dicult.12

06 07

INSIDE PAGE

1.3.4 Serious infections due to MDR Gram-negative pathogensRates of antibiotic-resistant Gram-negative infections are continuing to rise worldwide in community and hospital settings.13 MDR pathogens, in particular, are associated with high morbidity and mortality, inappropriate empiric therapy and greatly increased hospital costs and productivity losses.13,53,54 Eective treatments for MDR Gram-negative infections are severely limited and new treatment options and combinations are required.53

1.4 Lack of treatment options for resistant infectionse research and development of new antibiotics has slowed in recent years with very few compounds in development that may have activity against MDR Gram-negative pathogens.55

e number of new antibacterial agents approved by the US Food and Drug Administration (FDA) is illustrative of the decline in the development of new agents (Figure 1.2). e new government and government-private initiatives have reversed this worrisome trend to some degree, but greater unmet needs remain.

Figure 1.2: Antibiotic approvals from 1983–2015 *56,57

e issue of AMR therefore demands a novel, broad and systemic approach, taking into account the various contributing factors inuencing this matter. e World Health Organization (WHO) has provided an example of one such systemic plan in its core Global Action Plan (GAP) for AMR,58 focussing on the following to address AMR: Improve awareness and understanding of antimicrobial resistance Strengthen knowledge through surveillance and research Reduce the incidence of infection

*Antibiotics approved since 2014: Dalbavancin, oritavancin, tedizolid, ceftazidime-avibactam and ceftolozane-tazobactam.57

01983-1987

App

rova

ls fo

r new

ant

ibac

teria

l age

nts

1988-1992 1993-1997 1998-2002 2003-2007 2008-2012 2013-2015

2

4

6

8

10

12

14

16

18


Optimize the use of antimicrobial agents Develop the economic case for sustainable investment that takes into account the needs of all countries, and increase investment in new medicines, diagnostic tools, vaccines and other interventions.Declaring 2016 as the year for action for AMR, the WHO aimed to action various stakeholders to address AMR on a global scale. In order to address the lack of new agents in development, several important initiatives have been introduced in Europe and the USA to combat the decline in new antibiotic approvals. ese include: New Drugs 4 Bad Bugs (ND4BB) is part of the Innovative Medicines Initiative (IMI)

action plan against the rising threat from AMR adopted by the European Commission. The aim is to create innovative public-private collaborative partnerships that will positively impact research into and development of novel new antibacterial agents. In particular, the ND4BB aims to boost research focused on improving the uptake (and decreasing the efflux) of antibiotics into Gram-negative bacteria.59

The Generating Antibiotics Incentives Now (GAIN) Act (2011) — a US Government initiative, is designed to provide incentives to encourage the development of products for antibiotic resistant infections. The Act grants an additional five years of patent protection for new ‘Qualified Infectious Disease Products’.60

The 10x20 initiative is an initiative from the Infectious Diseases Society of America (IDSA), in collaboration with numerous organizations in the USA and Europe. The goal is to create an environment where development of 10 new, systemic, safe and effective antibacterial drugs by the year 2020 is possible through the discovery of newer classes of antibacterials or through modification of existing classes of medications.61

DRIVE-AB (Driving reinvestment in research and development and responsible antibiotic use) is a project composed of 16 public and 7 private partners from 12 countries that is funded by the Innovative Medicines Initiative (IMI). IMI is a joint undertaking between the European Union (EU) and the European Federation of Pharmaceutical Industries and Associations (EFPIA). It aims to reduce AMR through responsible antibiotic use and to identify how to incentivize the discovery and development of new novel antibiotics for use now and in the future.62

From an industry point of view, the reinvention of the business model used for the discovery and development of new antibiotics, focussing on the de-linkage of profitability associated with an antibiotic and volumes sold, is vital.58 Such de-linkage will enable and enhance antibiotic research and discovery to make treatment options available in the face of severe AMR. The reinvention of the business model for antibiotic discovery and development will also bring much needed change to what was a laborious and complicated process.

1.5 e impact of treatment failureRates of AMR infections are increasing globally and are associated with poor clinical outcomes, including prolonged illness, longer stay in hospitals and greater risk of death.63 For example, the Centers for Disease Control (CDC), USA, estimate that there are 610 deaths per year, due to carbapenem-resistant Enterobacteriaceae, 1,700 deaths per year due to infections with ESBL Enterobacteriaceae and 440 cases per year due to MDR P. aeruginosa (CDC 2013). In Europe, preliminary estimates of the number of deaths directly attributable to hospital-acquired infections due to the most common major MDR bacteria suggest that they are responsible for one-third to one-half of the deaths,18 with approximately 25,000 deaths attributable to resistant infections each year.64 In particular, an analysis of mortality associated with P. aeruginosa in hospitalized patients has demonstrated a greater than 2-fold increased risk of mortality with MDR P. aeruginosa (relative risk [RR] 2.34, 95% condence interval [CI] 1.53, 3.57) compared with susceptible P. aeruginosa.53

08 09

INSIDE PAGE


2.1 SummaryCeftazidime-avibactam combines a third-generation cephalosporin with well-established ecacy and safety prole, with a novel non-ß-lactam, ß-lactamase inhibitor that restores the activity of ceftazidime against most clinically important Gram-negative pathogens which are resistant to standard of care,2 including ceftazidime.In particular, avibactam restores the activity of ceftazidime against most strains of Enterobacteriaceae and P. aeruginosa, including against some ESBL-, AmpC- or KPC-producing Enterobacteriaceae and MDR P. aeruginosa in vitro.65

Results obtained from penetration studies in in vivo animal models have demonstrated that ceftazidime-avibactam is eective against: a variety of ß-lactamase-producing organisms in a renal infection model;66 P. aeruginosa67 and two strains of KPC-producing K. pneumoniae in a thigh infection model;68 as well as in models of sepsis68 and neutropenic pneumonia.69

2.2 Mechanism of actionCeftazidime-avibactam combines a third-generation cephalosporin with a well-established ecacy and safety prole, with a novel non-ß-lactam, ß-lactamase inhibitor (Figure 2.1). is combination restores the activity of ceftazidime against most clinically important Gram-negative pathogens that are resistant to standard of care as a result of the production of Ambler class A, class C and certain class D enzymes.2

Figure 2.1: Chemical structures of a) ceftazidime and b) avibactam.2

2.2.1 Mechanism of action of ceftazidimeCeftazidime, like other ß-lactam antibiotics, inhibits multiple penicillin-binding proteins (PBPs) in the bacterial cell (Figure 2.2). is disrupts peptidoglycan synthesis in the cell wall and ultimately leads to lysis and death.2, 70, 71

Figure 2.2: Inhibition of penicillin-binding proteins by ceftazidime.

2.2.2 Mechanism of action of avibactamAvibactam is a novel, rst-in-class, non-ß-lactam ß-lactamase inhibitor that diers from currently available ß-lactamase inhibitors, in that it does not have a ß-lactam skeleton nor induce ß-lactamase production. It is from a new chemical class, known as diazabicyclooctanes.72,73 Avibactam restores the activity of ceftazidime by preventing its hydrolysis by forming a covalent adduct with ß-lactamases causing their inactivation (Figure 2.3).73 It inhibits both Ambler class A and class C ß-lactamases and some class D enzymes, including ESBLs (CTX-M-15), KPC and OXA-48 carbapenemases, and AmpC enzymes.1, 73 Avibactam does not inhibit class B enzymes (metallo-ß-lactamases) and is not able to inhibit many class D enzymes.1

10 11

2. Ceftazidime-avibactam – an anti-pseudomonal, third-generation cephalosporin combined with a novel non-ß-lactam, ß-lactamase inhibitor

INSIDE PAGE

Ceftazidime

Bacterium

Cell wall synthesis

PBP

Porin

LYSISPBP: Penicillin-binding protein.

H2N

H3C

CH3

S

N

N

S

N+

2 2

3

3

1

14

4

5

67

N

NH

a)

H H

OH

O

7

5

68

O

O

O

O O–

b)

O

N

NS

O

O

OO

O–

H2N


In contrast, older ß-lactamase inhibitors, bind to ß-lactamases in a one-way irreversible reaction. While structurally related to ß-lactams, all are ineective against Ambler class C and D enzymes and may induce ß-lactamase production.73 e acylation reaction of avibactam with ß-lactamases has been shown to be slowly reversible (Figure 2.3). is deacylation does not occur in the older ß-lactam-based inhibitors due to the high ring strain of the 4-membered ß-lactam ring.74 e potency of avibactam against ß-lactamases is 10 to >100 times that of the currently available therapeutic inhibitors-clavulanic acid and tazobactam, and it provides a broader spectrum of ß-lactamase inhibition.2

2.3 Antimicrobial activityAntimicrobial breakpoints are minimum inhibitory concentrations (MICs) that categorise pathogens as susceptible (i.e. treatable), intermediate (higher doses of drugs can be used as possible treatment) and resistant (cannot be treated). In vitro susceptibility breakpoints for ceftazidime against the Enterobacteriaceae and P. aeruginosa as dened by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) and Clinical Laboratory Standards Institute (CLSI) are given in Table 2.1.75,76,77,78

Table 2.1: MIC breakpoints for ceftazidime from CLSI,75 EUCAST76 and FDA.77, 78

2.3.1 In vitro activity – aerobic Gram-negative bacteriaAvibactam restores the activity of ceftazidime against most strains of Enterobacteriaceae and P. aeruginosa (including against some ESBLs, AmpC- or KPC -producing Enterobacteriaceae and MDR P. aeruginosa, in vitro). However, avibactam does not improve the activity of ceftazidime against Acinetobacter spp., Burkholderia spp. or most anaerobic Gram-negative rods in vitro.65

Results from several published studies of the in vitro activity of ceftazidime-avibactam against Gram-negative pathogens are given in Table 2.2.

CLSI: (US) Clinical and Laboratory Standards Institute. EUCAST: European Committee on Antimicrobial Susceptibility Testing. I.V.: Intravenous. MIC: Minimum inhibitory concentration. NA: Not available. FDA: (US) Food and Drug Administration.

Figure 2.3: Mechanism of action of avibactam; acylation results in ß-lactamase inhibition and deacylation reverses the inhibition and results in the regeneration of active avibactam.73

12 13

INSIDE PAGE

P. aeruginosa

Ceftazidime (1000 mg every 6 h or 2000 mg i.v. every 8 h)

Ceftazidime-Avibactam (30 mg ceftazidime + 20 mg avibactam)

≤8

NA

≥32

NA

≤83

≤83

>83

>83

≤8

≤8/4

≥16

≥16/4

EUCAST76 FDA77, 78CLSI75

MIC, mg/L Susceptible Resistant Susceptible Resistant Susceptible Resistant

Enterobacteriaceae

Ceftazidime (1000 mg every 8 h)

Ceftazidime-Avibactam (30 mg ceftazidime + 20 mg avibactam)

≤4

NA

≥16

NA

≤1

≤83

>4

>83

≤4

≤8/4

≥16

≥16/4

O O

O

O OO

OH

H2N

HN

H2N

N N

NOSO3 OSO3

OH

O

O HN

H2N

N

OSO3

ß-lactamase(active)

ß-lactamase(active)

ß-lactamase(inhibited)

acylation

deacylation

hydrolysis


14 15

INSIDE PAGE

Notes: MICs were measured in mg/L. Susceptibility rates for ceftazidime, ceftriaxone, and cefepime were determined by (US) Clinical and Laboratory Standards Institute (CLSI) breakpoints. Susceptibility breakpoints for ceftazidime were applied to ceftazidime-avibactam. %S: Per cent of isolates susceptible to antimicrobial agents. ESBL: Extended-spectrum ß-lactamase. KPC: Klebsiella pneumoniae carbapenemase. MIC: Minimum inhibitory concentration. MIC50: MIC that inhibits 50% of isolates. MIC90: MIC that inhibits 90% of isolates. NA: Not available.

Cestazidime-avibactamOrganism Cestazidime

Citrobacter freundii

Enterobacter aerogenes

Enterobacter cloacae

Escherichia coli

ESBL-producing

AmpC-hyperproducing

Klebsiella oxytoca

Klebsiella pneumoniae

ESBL-producing

OXA-48-producing

KPC-producing

Carbapenem-non-susceptible

Morganella morganii

Proteus mirabilis

Proteus vulgaris

Salmonella enterica

Serratia marcescens

Burkholderia cepacia

Pseudomonas aeruginosa

Multidrug-resistant

AmpC-derepressed

Acinetobacter baumannii

Carbapenem-resistant

Haemophilus inuenzae

0.125/0.5

0.25/0.5

0.25/1

0.12/0.25

0.12/0.25

0.12/0.5

0.12/2

0.12/0.5

0.5/1

0.25/0.5

0.25/1

0.5/2

≤0.06/0.12

≤0.06/0.12

0.06/0.25

0.25/0.5

0.25/0.5

8/>128

2/8

8/>16

4/8

8/>16

32/>32

≤0.06/≤0.06

≤0.06–2

≤0.06–16

≤0.06–16

≤0.06–4

≤0.06–1

≤0.06–2

≤0.06–2

≤0.06–8

≤0.06–2

<0.008–1

≤0.06–1

≤0.03–32

≤0.06–0.5

≤0.06–0.25

≤0.03–2

≤0.03–0.5

≤0.06–2

≤1–>128

≤0.06–>16

4–>16

≤1–64

0.5–>16

0.25–>32

≤0.06-0.1

100

98.5

99.5

100

100

100

100

99.9

100

100

100

NA

100

100

100

100

100

NA

94.7

60.0

96.2

60.3

NA

100

0.5/>32

0.5/>32

0.5/>32

≤0.25/1

16/>32

16/>32

≤0.25/0.5

≤0.25/1

32/>32

256/512

>256/>256

>32/>32

≤0.25/8

≤0.25/≤0.25

0.12/8

0.25/0.5

≤0.25/1

64/>128

4/32

>16/>16

64/>126

8/>32

>32/>32

NA

≤0.25–>32

≤0.25–>32

≤0.25–>32

≤0.25–>32

1–>32

1–>32

≤0.25–>32

≤0.25–>32

4–64

≤0.12–512

32–>256

NA

≤0.25–16

≤0.25–32

NA

NA

≤0.25–16

8–>128

≤0.25–>32

4–>16

8–>128

NA

NA

NA

78.2

76.9

78.7

94.9

34.8

41.4

99.3

98.5

66.7

NA

0

NA

89.7

99.6

NA

NA

99.6

NA

82.8

4.

3.8

78.2

NA

NA

MIC50/90 MIC range %S MIC50/90 MIC range %S

Table 2.2: In vitro activity of ceftazidime alone and ceftazidime-avibactam againstGram-negative aerobic and facultative pathogens.2,67,79-87 Adapted from.65

MIC: Minimum inhibitory concentration. MIC50: MIC that inhibits 50% of isolates. MIC90: MIC that inhibits 90% of isolates.

Avibactam concentration(mg/L)

0

0.016

0.031

0.063

0.125

0.25

0.5

1

2

4

8

16

32

64

32

32

32

32

32

32

16

8

4

4

2

2

1

1

128

128

128

128

128

128

64

32

16

16

8

8

4

4

32

8

4

2

2

2

2

1

1

0.5

≤0.031

≤0.031

≥512

128

64

16

16

8

8

4

2

1

0.25

≤0.031

32

2

1

1

1

1

0.5

0.5

0.5

0.25

≤0.031

≤0.031

64

16

8

2

2

2

2

1

1

0.5

0.063

≤0.031

128

32

16

8

8

4

2

1

1

0.5

≤0.031

≤0.031

>512

128

128

128

64

64

8

4

2

2

0.25

≤0.031

Pseudomonasaeruginosa

(n=18)

AllEnterobacteriaceae

(n=51)

Klebsiellapneumoniae

(n=29)

Escherichiacoli

(n=18)

MIC50,mg/L

MIC90,mg/L

MIC50,mg/L

MIC90,mg/L

MIC50,mg/L

MIC90,mg/L

MIC50,mg/L

MIC90,mg/L

Results from a single study using in vitro checkerboard assays for 81 clinical strains with known resistance to ceftazidime (69 with phenotypically ceftazidime-resistant strains) are given in Table 2.3. For most strains, the tested addition of avibactam 4 mg/L restored the antibacterial activity of ceftazidime to a level comparable to that of wild-type strains, indicating full inhibition, with strains becoming susceptible according to the EUCAST and CLSI criteria.88

Table 2.3: MIC50 and MIC90 values for ceftazidime at increasing concentrations of avibactam.88


16 17

INSIDE PAGE

MIC: Minimum inhibitory concentration. ^Overproducer

a MIC50/90. b Imipenem MICs vs. 25 clinical isolates carrying blaOXA-48 and various other ß-lactamase genes.MIC: Minimum inhibitory concentration. MIC50: MIC that inhibits 50% of isolates. MIC90: MIC that inhibits 90% of isolates.

MIC, mg/LEnzymeStrain / lab #Species Cestazidime-

avibactamCestazidime Piperacillin-

tazobactam

2.3.1.1 Activity against Enterobacteriaceaee in vitro activity of ceftazidime and ceftazidime-avibactam against Enterobacteriaceae from several studies is collated in Tables 2.4 and 2.5. ese studies evaluated susceptibility against well-characterised Gram-negative strains from all molecular classes, and compared the activity of ceftazidime-avibactam with the companion ß-lactams alone, and with meropenem and piperacillin-tazobactam (agents that might be used in similar clinical settings).89,90

Table 2.4: MICs for ceftazidime, ceftazidime-avibactam and piperacillin-tazobactam against characterised Enterobacteriaceae clinical isolates.89, 90

0.25

1

2

0.5

≤0.06

0.5

128

>128

128

>128

16

128

TEM-28

TEM-10, TEM-12

SHV-52

SHV-18

CTX-M-15, OXA-1

CTX-M-55

6043

4103

1980

MCV37

IU-339

11444

8

>128

8

8

32

16

ESBLs

Escherichia coli 89

Klebsiella pneumoniae 89

E. coli 90

K. pneumoniae 89

E. coli 89

E. coli 90

1

≤0.06

0.5

1

0.5

>128

64

64

64

16

AmpC ↑^

AmpC ↑

CMY-24

MOX-1

MIR-1, TEM-1

NUH10

1507

3433

1382

4074

>128

128

8

64

128

Enterobacter cloacae 2, 90

Citrobacter freundii 90

E. coli 90

K. pneumoniae 90

K. pneumoniae 89

Class C / AmpC ß-lactamases

MIC, mg/LEnzymeStrainSpecies Cestazidime-

avibactamCestazidime Piperacillin-

tazobactam

Table 2.5: MICs against characterised clinical and laboratory isolates of carbapenemase-producing organisms.79, 89, 91

Meropenem

1

1

0.12

0.5

0.5

0.25

4

0.25/0.5a

>128

>128

0.25

32

32

32

>128

256/512a

KPC-2, TEM-type

KPC-3, SHV-11, TEM-1

Parent strain

KPC-5

KPC-6

KPC-7

KPC-8

OXA-48

KPC-2

IU-1108

Isogenic

Isogenic

Isogenic

Isogenic

Isogenic

>128

>128

1–2

64

64

128

128

-

16

16

≤0.015–0.03

0.12

0.12

0.5

0.5

8/256a,b

Klebsiellaoxytoca 89

K. pneumoniae 89

Escherichia coli 91

E. coli 91

E. coli 91

E. coli 91

E. coli 91

K. pneumoniae 79

Eux pump

OprDimipenem/

meropenem

Otherchannel(s)

ceftazidime

External phase Outer membrane

Cytoplasmicmembrane PBP: Penicillin-binding protein.

2.3.1.2 Activity against Pseudomonas aeruginosaP. aeruginosa represents a greater challenge to treat because it is inherently less permeable than Enterobacteriaceae and is better able to remove toxic molecules via eux pumps84, 92 as illustrated in Figure 2.4.

Figure 2.4: Mechanism of resistance to antibacterial treatment in Pseudomonas aeruginosa.


2.3.2 In vitro activity – aerobic Gram-positive bacteria and anaerobic organismsCeftazidime-avibactam has no clinically relevant activity against the Gram-positive microbial species.1

For infections involving anaerobic bacteria, co-administration of ceftazidime-avibactam with the anti-anaerobe antibiotic metronidazole is required for ecacy against anaerobic species, in vitro.93

2.4 Avibactam compared with other ß-lactamase inhibitorsAvibactam has a broader spectrum of ß-lactamase inhibition than currently available ß-lactamase inhibitors. Table 2.7 outlines results from several studies highlighting comparative half maximal inhibitory concentration (IC50) values for avibactam, clavulanic acid and tazobactam. Overall, avibactam has activity similar to that of clavulanic acid against SHV-4 and similar to that of both clavulanic acid and tazobactam against CTX-M-15, but shows greater activity than comparator inhibitors in all other cases, particularly against the carbapenemase KPC-2 and the class C ß-lactamases.2

18 19

INSIDE PAGE

MIC: Minimum inhibitory concentration.

IC50: Half-maximal inhibitory concentration. KPC: Klebsiella pneumoniae carbapenemase.

MIC, mg/LOprDAmpCStrain Cestazidime-

avibactamCestazidime Meropenem

In a study designed to test the eects of ceftazidime-avibactam in non-fermenting bacteria, avibactam appeared to overcome most AmpC-mediated resistance in P. aeruginosa, reducing ceftazidime MICs to the current EUCAST / British Society for Antimicrobial Chemotherapy (BSAC) susceptibility breakpoint of ≤8 mg/L, even when expression of this enzyme was completely depressed, for example, in the 1405-con strain.84 e results suggested that avibactam can cross the bacterial outer membrane and accumulate in eective concentrations in the periplasm.84 e activity of ceftazidime- avibactam against P. aeruginosa AmpC mutants is shown in Table 2.6. However, avibactam did not reverse eux-mediated ceftazidime resistance in P. aeruginosa, in vitro.84

Table 2.6: In vitro activity of ceftazidime-avibactam against Pseudomonas aeruginosa AmpC mutants.84

2

8

8

4

128

128

Basal

Basal

Deleted

Basal

Depressed

Depressed

0.25

0.5

16

1405-def

1405-con

1405-con D2

ß-lactamases typesAvibactam Clavulanic acid Tazobactam

IC50 for inhibition of ß-lactamase activity, nM

Table 2.7: Comparative activity of avibactam versus clavulanic acid and tazobactam determined after 5 min of incubation with dierent ß-lactamases, in vitro.94-99 Adapted from.2

Class A ß-lactamases

TEM-1 94

TEM-1 99

SHV-4 97

SHV-4 99

KPC-2 98

KPC-2 96

KPC-2 99

CTX-M-15 96

CTX-M-15 95

CTX-M-15 99

Class C ß-lactamases

P99 94

P99 99

AmpC 99

8

8

1.5

3

38

37.5 ± 2.6

170

4.5 ± 0.9

5

5

80

100

128

130

58

5

4

6500

6500 ± 400

>100,000

12.5 ± 2.8

12

12

1 X 106

>100,000

>100,000

40

32

120

55

80,000

9200 ± 4100

50,000

5.8 ± 2.7

6

6

5000

1300

4600


20 21

INSIDE PAGE

2.5 Penetration studies (against experimental infections)Penetration into the target tissue and subsequent microbiological activity of an antibacterial in experimental infections in animal models gives insights into the likely eects in humans. Ceftazidime-avibactam has been evaluated in penetration studies in several experimental infection models in animals. e selection of dosage regimens for these studies was intended to simulate plasma exposures that would normally be observed with standard doses used in humans, i.e. ceftazidime 2000 mg plus avibactam 500 mg every 8 h, administered as a 2-h infusion.67,69

2.5.1 Renal infection modelIn a murine kidney infection model, mice were infected with approximately 104 colony-forming units (CFU) of one of six ceftazidime-resistant strains (E. coli expressing SHV-4, E. coli expressing AmpC, Enterobacter cloacae expressing AmpC, K. pneumoniae expressing AmpC and SHV-11, Morganella morganii expressing AmpC, or Citrobacter freundii expressing AmpC).66 Infected mice were treated at 4, 8, 24 and 32 h after infection with ceftazidime-avibactam or ceftazidime alone. Bacterial load in the kidney in mice receiving ceftazidime-avibactam was 2.6–4.5 log10 lower than the bacterial load in mice receiving ceftazidime alone,66 indicating that ceftazidime-avibactam was eective against a variety of ß-lactamase-producing organisms.

2.5.2 igh infection modelIn a neutropenic murine thigh infection model, mice were infected with two strains of KPC-producing K. pneumoniae (VA-361 and VA-406) introduced via intramuscular injection. Mice were treated 1.5 h after infection with a single subcutaneous dose of ceftazidime-avibactam (4:1 ratio) or ceftazidime.68 Reductions in CFUs were achieved with ceftazidime-avibactam at doses of ≥256:64 mg/kg against the VA-361 strain, whereas for VA-406, reductions in CFUs were achieved at doses of ≥128:32 mg/kg. e static doses were determined to be 216:54 mg/kg for VA-361 and 116:29 mg/kg for VA-406. Dosages of ≤64:16 mg/kg were unable to reduce the CFU count for both KPC-producing K. pneumoniae isolates compared with ceftazidime alone at doses of ≥1024 mg/kg.68

In another murine thigh infection model, neutropenic and immunocompetent mice were infected with one of 27 strains of P. aeruginosa.67 Ceftazidime-avibactam MICs ranged from 4–32 mg/L; all isolates (except one) were non-susceptible to ceftazidime, with MICs ranging from 8– >128 mg/L.67 In neutropenic animals, ceftazidime decreased bacterial densities by >0.5 log unit for 10 of 27 isolates, while ceftazidime-avibactam did so for 22 of 27 isolates.67 In immunocompetent animals, ceftazidime achieved reductions of >0.3 log unit for 10 of 15 isolates, whereas ceftazidime-avibactam did so against all 15 isolates; no resistant isolates were detected, in vivo.67

2.5.3 Sepsis modelIn a neutropenic murine septicemia infection model, mice were infected with two strains of KPC-producing K. pneumoniae (VA-361 and VA-406) via intraperitoneal injection. Mice were treated 30 minutes after infection with a single subcutaneous dose of ceftazidime- avibactam or ceftazidime; doses for the septicaemia model were in ratios of 2:1, 4:1, 8:1 and 16:1.68 Ceftazidime alone exhibited median eective dose (ED50) values of 1,578 and 709 mg/kg, for VA-361 and VA-406 respectively, versus 15.1 and 3.8 mg/kg, respectively, for ceftazidime-avabactam, indicating that the addition of avibactam restored the ecacy of ceftazidime against these two ß-lactamase-producing K. pneumoniae isolates (Table 2.8).68

Table 2.8: Murine sepsis model with KPC-producing Klebsiella pneumoniae.68

2.5.4 Neutropenic pneumonia modelIn a neutropenic murine pneumonia model, ceftazidime-avibactam and cefazidime were tested for penetration into the epithelial lining uid (ELF) and their microbiological eects against 28 isolates of P. aeruginosa were measured.69 Ceftazidime-avibactam demonstrated substantial activity against P. aeruginosa with ceftazidime-avibactam MICs up to 32 mg/L. Serum-free drug concentrations in serum remained above the MIC for 32% of the dosing interval. Moreover, serum-free drug concentrations in the ELF remained above the MIC for ≥19% of the dosing interval, suggesting the potential utility of ceftazidime-avibactam for the treatment of lung infections caused by P. aeruginosa.69

a VA-361: meropenem MIC = 4 mg/L. b VA-406: meropenem MIC = 256 mg/L.ED50: Median eective dose. MIC: Minimum inhibitory concentration.

MIC, mg/L ED50, mg/kgEnzymesOrganism Cestazidime-

avibactamCestazidime

0.25

≤0.06

256

≥512

Cestazidime-avibactam

Cestazidime

15.1

3.8

1578

709

KPC-2, TEM-1, SHV-11

KPC-2, TEM-1, SHV-11, SHV-12

K. pneumoniae VA-361a

K. pneumoniae VA-406b


22 23

INSIDE PAGE

2.6 Surveillance datae International Network For Optimal Resistance Monitoring (INFORM) Global Surveillance Study of the in vitro activity of ceftazidime-avibactam against resistant Klebsiella spp. from hospitalized patients has shown restoration of susceptibility to ceftazidime. Avibactam inhibited the most common ß-lactamases that caused ceftazidime resistance in MDR K. pneumoniae and K. oxytoca (Figure 2.5).100

Figure 2.5: Cumulative proportion of 948 MDR Klebsiella spp. inhibited by ceftazidime and ceftazidime-avibactam.100

e activity of ceftazidime combined with avibactam has been evaluated against a large collection of aerobic Gram-negative clinical isolates recovered from patients in hospitals in the USA during 2012–2013. e antimicrobial susceptibility patterns of organisms isolated from patients in ICUs, as well as those from patients with ventilator-associated pneumonia (VAP), were also assessed and compared with those from non-ICU patients at the same hospitals during the same time period.101 Ceftazidime-avibactam was active against 99.8/100.0% of Enterobacteriaceae (MIC90, 0.25/0.25 mg/L) from ICU/non-ICU patients, respectively; this included activity against isolates from patients with VAP (99.1%), MDR strains (99.3%), extensively drug-resistant (XDR) strains (96.5%) and meropenem- non-susceptible strains (98.0%), at MICs of ≤8 mg/L. Ceftazidime-avibactam also inhibited 95.6/97.5% of P. aeruginosa isolates from ICU/non-ICU patients, respectively; 97.3% of isolates from patients with VAP, 80.7% of ceftazidime-non-susceptible and 80.7% of MDR isolates at MIC ≤8 mg/L.101

A European surveillance programme has tested the activity of ceftazidime-avibactam against a collection of isolates from 26 centres in Belgium, France, Germany, Ireland, Italy, Poland, Portugal, Spain, Sweden, Switzerland, Turkey and the UK. It was found that avibactam restored the ceftazidime MIC90 values for Gram-negative bacteria to the EUCAST MIC frequency distributions and epidemiological cut-o values (ECOFFs) for ceftazidime (Figure 2.6).102

Figure 2.6: Comparison of the cumulative MIC frequency distributions for ceftazidime and ceftazidime-avibactam from a 2009 European surveillance programme when compared with the MIC distribution on the EUCAST website (http://www.eucast.org/mic distributions/Accessed 25 April 2012) for a) P. aeruginosa (n=439, EUCAST MIC distribution n=31,953); b) E. coli (n=1175, EUCAST MIC distribution n=15,162); c) Klebsiella spp. (n=442, EUCAST MIC distribution n=1128); d) Enterobacter spp. (n=242, EUCAST MIC distribution n=8323); e) Proteus mirabilis (n=108, EUCAST MIC distribution n=1311); and f) Serratia spp. (n=106, EUCAST MIC distribution n=291). Adapted from.102

MDR: Multidrug-resistant. MIC: Minimum inhibitory concentration. PD: Pharmacodynamic. PK: Pharmacokinetic.

90

80

70

60

50

40

30

20

10

02 4 8≤0.03 0.12 0.25 0.5 1 16 32 >32 0.06

MIC (µg/mL)

ECOFF100

% o

f iso

late

s

A

90

80

70

60

50

40

30

20

10

02 4 8≤0.03 0.12 0.25 0.5 1 16 32 >32 0.06

MIC (µg/mL)

ECOFF100

% o

f iso

late

s

B

90

80

70

60

50

40

30

20

10

02 4 8≤0.03 0.12 0.25 0.5 1 16 32 >32 0.06

MIC (µg/mL)

ECOFF100

% o

f iso

late

s

C

90

80

70

60

50

40

30

20

10

02 4 8≤0.03 0.12 0.25 0.5 1 16 32 >32 0.06

MIC (µg/mL)

ECOFF*100

% o

f iso

late

s

D

Ceftazidime (Europe 2009)Ceftazidime-avibactam (Europe 2009) EUCAST Ceftazidime MIC distribution

90

80

70

60

50

40

30

20

10

02 4 8≤0.004 0.015 0.03 0.06 0.12 0.25 0.5 1 16 32 64 >64 0.008

MIC (µg/mL)

97% MIC≤8 mg/L

(PK/PD cut o)

100

Cum

ulat

ive

perc

ent i

nhib

ited

Ceftazidime Ceftazidime-avibactam


e results showed high activity of ceftazidime-avibactam against Enterobacteriaceae (MIC, 1 mg/L) and P. aeruginosa (MIC, 8 mg/L) isolated from patients with HAP and VAP, including many ceftazidime- or meropenem-resistant isolates, and those with an ESBL phenotype (Table 2.9).102

Table 2.9: Activity of ceftazidime and ceftazidime-avibactam against Gram-negative bacteria (2512 strains) from Europe (2009). Adapted from.102

1 Criteria as published by the CLSI and EUCAST. CLSI interpretive criteria for ceftazidime (susceptible [S]/resistant [R]): Enterobacteriaceae (≤4/≥16 mg/L) and P. aeruginosa (≤8/≥32 mg/L); EUCAST interpretive criteria for ceftazidime (S/R): Enterobacteriaceae (≤1/≥4 mg/L) and P. aeruginosa (≤8/>8 mg/L).2 Includes Klebsiella oxytoca (105 strains), K. ozaenae (1 strain), and K. pneumoniae (336 strains).3 Includes Enterobacter aerogenes (54 strains), E. amnigenus (2 strains), E. cloacae (185 strains), and E. sakazakii (1 strain).4 Includes Serratia liquefaciens (5 strains) and S. marcescens (101 strains).CLSI: (US) Clinical and Laboratory Standards Institute. ESBL: Extended-spectrum ß-lactamase. EUCAST: European Committee on Antimicrobial Susceptibility Testing. MIC: Minimum inhibitory concentration.

24 25

INSIDE PAGE

Organisms/antimicrobialagent, (no. tested)

Pseudomonas aeruginosa (439)

Ceftazidime-avibactam

Ceftazidime

Escherichia coli (1175)


Ceftazidime

ESBL phenotype (154)


Ceftazidime

MIC50

2

2

0.12

0.25

0.12

4

MIC90

8

>32

0.25

2

0.5

32

Range

0.25–>32

0.25–>32

≤0.03–1

0.06–>32

≤0.03–1

0.06–>32

MIC, mg/L

-/-

72.7/27.3

-/-

87.5/6.6

-/-

8.4/50.0

EUCAST1 %S/%R

-/-

72.7/21.0

-/-

93.4/4.3

-/-

50.0/33.1

CLSI1 %S/%R

Organisms/antimicrobialagent, (no. tested)

Klebsiella spp.2 (422)


Ceftazidime

ESBL phenotype (108)


Ceftazidime

Enterobacter spp.3 (242)


Ceftazidime

Proteus mirabilis (108)


Ceftazidime

Serratia spp.4 (106)


Ceftazidime

MIC50

0.12

0.25

0.5

32

0.25

0.25

0.06

0.06

0.25

0.12

MIC90

0.5

32

2

>32

1

>32

0.06

0.5

0.5

1

Range

≤0.03–32

0.03–>32

≤0.03–32

0.12–>32

≤0.03–>32

0.06–>32

≤0.03–0.25

0.03–32

0.06–8

0.03–32

MIC, mg/L

-/-

76.2/19.7

-/-

10.2/80.6

-/-

64.3/30.3

-/-

90.7/2.8

-/-

91.5/5.7

EUCAST1

%S/%R

-/-

80.3/17.4

-/-

19.4/71.3

-/-

69.7/28.2

-/-

97.2/2.8

-/-

94.3/5.7

CLSI1 %S/%R

2.7 Propensity for resistancee propensity for the development of resistance to ceftazidime-avibactam has been evaluated in three P. aeruginosa strains carrying the derepressed AmpC alleles. e frequency of spontaneous resistance to ceftazidime-avibactam in the three strains was low; the resistant variants that were isolated had MIC values ranging from 64 to 256 mg/L. All of the mutants exhibited changes in the chromosomal AmpC gene, the majority of which were deletions of various sizes in the Ω-loop region of AmpC that impacted both ceftazidime hydrolysis and avibactam inhibition.103

*ere is no EUCAST ECOFF available for Enterobacter spp; the ECOFF for E. aerogenes and E. cloacae is shown here for represen-tatives purposes. EUCAST: European Committee on Antimicrobial Susceptibility Testing. MIC: Minimum inhibitory concentration.

Ceftazidime (Europe 2009)Ceftazidime-avibactam (Europe 2009) EUCAST Ceftazidime MIC distribution

90

80

70

60

50

40

30

20

10

02 4 8≤0.03 0.12 0.25 0.5 1 16 32 >320.06

MIC (µg/mL)

100

% o

f iso

late

s

ECOFFE

90

80

70

60

50

40

30

20

10

02 4 8≤0.03 0.12 0.25 0.5 1 16 32 >320.06

MIC (µg/mL)

100

% o

f iso

late

s

ECOFFF


Table 2.11: Recommended doses of ceftazidime-avibactam in patients with renal impairment (based on pharmacokinetic modelling). Adapted from.1

1 For complicated urinary tract infections including pyelonephritis, the total duration of treatment can be increased to 14 days for patients with bacteraemia.

1 Creatinine clearance (CrCl) calculated using the Cockcroft-Gault formula.2 Ceftazidime and avibactam are removed by haemodialysis and should be administered after haemodialysis on haemodialysis day. ESRD: End-stage renal disease.

Indication Treatment duration, days

Complicated intra-abdominal infections [used in combination with metronidazole]

Complicated urinary tract infections, including pyelonephritis

Hospital-acquired pneumonia, including ventilator-associated pneumonia

Estimated CrCl (mL/min)1 Frequency of dosingInfusion time, h

5–14

5–101

7–14 (Torres et al)

26 27

INSIDE PAGE

2.8 Dosage and administratione recommended dosage of ceftazidime-avibactam is ceftazidime 2000 mg and avibactam 500 mg administered every 8 h by i.v. infusion over 2 h in patients aged ≥18 years. For the treatment of cIAIs, metronidazole (required for ecacy against anaerobic species) should be given concurrently. e recommendations for treatment duration by indication or condition are outlined in Table 2.10 and the dosage recommendations for patients with renal impairment are outlined Table 2.11.1

Table 2.10: Recommendations for ceftazidime-avibactam treatment duration by indication or condition. Adapted from.1

2.10 Special warnings and precautions of use

2.10.1 Hypersensitivity reactionsAs with all ß-lactam antibacterial agents, serious and occasionally fatal hypersensitivity reactions have been reported. In case of severe hypersensitivity reactions, treatment with ceftazidime-avibactam must be discontinued immediately and adequate emergency measures initiated.Before beginning treatment, it should be established whether the patient has a history of severe hypersensitivity reactions to ceftazidime, to other cephalosporins or to any other type of ß-lactam agent. Caution should be used if ceftazidime-avibactam is given to patients with a history of non-severe hypersensitivity to other ß-lactam agents.1

2.10.2 Clostridium dicile-associated diarrheaAntibacterial agent-associated colitis and pseudo-membranous colitis have been reported with nearly all antibacterial agents, including ceftazidime-avibactam, and may range in severity from mild to life-threatening. erefore, it is important to consider this diagnosis in patients who present with diarrhea during or subsequent to the administration of ceftazidime-avibactam. Discontinuation of therapy with ceftazidime-avibactam and the administration of specic treatment for Clostridium dicile should be considered. Medicinal products that inhibit peristalsis should not be given.1

2.10.3 Patients with renal impairmentCeftazidime and avibactam are both eliminated via the kidneys, therefore, the dose should be reduced according to the degree of renal impairment. Patients with renal impairment should be closely monitored for both safety and ecacy. Neurological sequelae, including tremor, myoclonus, non-convulsive status epilepticus, convulsion, encephalopathy and coma, have occasionally been reported with ceftazidime when the dose has not been reduced in patients with renal impairment.Concurrent treatment with high doses of cephalosporins and nephrotoxic medicinal products such as aminoglycosides or potent diuretics (e.g. furosemide) may adversely aect renal function.1

2.10.4 Non-susceptible organismsProlonged use of antibiotics may result in the overgrowth of non-susceptible organisms (e.g. Enterococci, fungi), which may require interruption of treatment or other appropriate measures.1

2.9 Contraindications Ceftazidime-avibactam is contraindicated in patients with known hypersensitivity to ceftazidime or avibactam, the excipient sodium carbonate, or other members of the cephalosporin class and in patients with immediate and severe hypersensitivity (e.g. anaphylactic reaction) to any other type of ß-lactam antibacterial agent (e.g. penicillins, monobactams or carbapenems)1

Recommended dosageregimen cestazidime/

avibactam, mg

50–31

30–16

15–6

ESRD including on haemodialysis2

Every 8 h

Every 12 h

Every 24 h

Every 48 h

2

2

2

2

1000/250

750/187.5

750/187.5

750/187.5


28 29

INSIDE PAGE

2.10.5 Non-drug interferenceCeftazidime does not interfere with enzyme-based tests for glycosuria, but slight interference (false-positive) may occur with copper reduction methods (Benedict's, Fehling's, Clinitest).1

Ceftazidime does not interfere in the alkaline picrate assay for creatinine.104

2.10.6 Direct antiglobulin test (DAGT or Coombs test) seroconversion and potential risk of hemolytic anemiaCephalosporin use may cause development of a positive direct antiglobulin test (DAGT, or Coombs test), which may interfere with the cross-matching of blood and/or cause drug-induced immune hemolytic anemia. While DAGT seroconversion in patients receiving ceftazidime-avibactam was frequent in clinical studies, there was no evidence of hemolysis in patients who developed a positive DAGT on treatment. However, the possibility that hemolytic anemia could occur in association with ceftazidime-avibactam treatment cannot be ruled out. Patients experiencing anemia during or after treatment with ceftazidime- avibactam should be investigated for this possibility.1

2.10.7 Controlled sodium dietFor patients who are on a controlled sodium diet, the following important information about the ingredients of ceftazidime and avibactam should be considered: Ceftazidime 2000 mg powder for solution for infusion contains 4.52 mmol of sodium

per vial; and Avibactam 500 mg powder for solution for infusion contains 1.92 mmol of sodium per

vial.104

3.1 Summarye pharmacokinetics of ceftazidime and avibactam are complementary, with similar volumes of distribution (V), terminal half-lives (t1/2) and clearance (CL). e administration of avibactam does not impact on the pharmacokinetics of ceftazidime and vice versa.105-107

Ceftazidime-avibactam penetrates into human bronchial ELF with drug concentrations of approximately 30% of those in plasma.108

Ceftazidime and avibactam both undergo renal elimination (~100% excreted unchanged in urine).106

Ceftazidime-avibactam dose adjustments are necessary in patients with moderate-to- severe renal impairment and end-stage renal disease (ESRD), including patients on hemodialysis. However, dose adjustments are simple due to the linear pharmacokinetic proles of both drugs.1, 107, 109, 110

No dose adjustments are required for adult patients based on age or gender.1

e pharmacokinetic/pharmacodynamics target for ceftazidime-avibactam is a joint target comprising ceftazidime at 50% free drug time above the MIC (50% ƒT>MIC) for ceftazidime and 50% ƒT>CT, the critical threshold concentration of avibactam at 1 mg/L. e probability of attaining this joint pharmacokinetic/pharmacodynamics target is greater with a 2 h (vs 0.5 or 1 h) infusion of ceftazidime-avibactam.111

3.2 Ceftazidime-avibactam: pharmacokinetic/pharmacodynamic relationshipAs with all ß-lactam antimicrobial agents, the maintenance of free drug concentrations above the MIC of the infecting organism for a given proportion of the dosing interval is necessary for the ecacy of ceftazidime-avibactam.1 A study of exposure-response relationships of ceftazidime and avibactam in a mouse neutropenic thigh model in vivo has demonstrated that the eect of avibactam was primarily dependent on %ƒT>CT 1 mg/L and that relatively higher exposures of avibactam were required at lower doses of ceftazidime.112

3. Pharmacology and pharmacokinetics ofceftazidime-avibactam


e dose of ceftazidime 2000 mg plus avibactam 500 mg every 8 h by 2-h i.v. infusion for patients with creatinine clearance (CrCl) >50 mL was selected for the ceftazidime- avibactam phase 3 clinical trial programme on the basis of eectiveness demonstrated against ceftazidime-resistant P. aeruginosa in a neutropenic mouse thigh infection model (where the pharmacokinetics of both agents were linear and dose proportional).67,88

With FDA-approved doses of ceftazidime-avibactam, achievement of the joint pharmacokinetic/ pharmacodynamics target was predicted to be >95% for patients with cIAI, cUTI or HAP and normal or mild renal impairment, and ~70% with dose adjustments for patients with cIAI, cUTI or HAP if renal function improved rapidly.114 Further, Monte Carlo simulations based on preclinical pharmacokinetic/pharmacodynamic data and clinical pharmacokinetic data supported the use of the selected dose in HAP and VAP.115,116

30 31

INSIDE PAGE

ESRD: End-stage renal disease. MIC: Minimum inhibitory concentration. %ƒT>CT: Percent free drug time above critical threshold. %ƒT >MIC: Percent free drug time above minimum inhibitory concentration.

CT1=0.5 mg/L, MIC=8 mg/L CT2=1.0 mg/L, MIC=8 mg/LCestazidime/

avibactam dose (mg)Renal function 50% ƒT>CT1

50% ƒT>MIC40% ƒT>CT1

40% ƒT>MIC50% ƒT>CT2 50% ƒT>MIC

40% ƒT>CT2 40% ƒT>MIC

2-h i.v. infusion

Normal

Mild

Moderate

Severe 1

Severe 2

ESRD

2000/500, q8h

2000/500, q8h

1000/250, q12h

1000/250, q24h

500/125, q24h

500/125, q48h

99.0

99.6

99.4

96.5

96.2

98.2

96.0

98.5

97.4

88.0

90.4

94.6

92.1

97 6

89.1

75.4

89.6

94.6

98.9

99.5

96.8

92.4

96.1

98.2

1-h i.v. infusion

Normal

Mild

Moderate

Severe 1

Severe 2

ESRD

2000/500, q8h

2000/500, q8h

1000/250, q12h

1000/250, q24h

500/125, q24h

500/125, q48h

97.8

99.2

99.1

96.3

95.9

98.0

93.2

97.9

96.2

86.8

90.2

94.6

84.1

94.3

85.7

73.8

89.2

94.6

96.8

99.0

95.4

91.5

95.8

98.0

e probability of attaining the pharmacokinetic/pharmacodynamic target (PTA) of 50% ƒT>MIC for ceftazidime and avibactam ≥1 mg/L vs. P. aeruginosa in patients with dierent levels of renal function is outlined in Table 3.1.111

Table 3.1: Predicted joint probability of pharmacokinetic/pharmacodynamic target attainment for ceftazidime-avibactam to achieve 40% or 50% ƒT>MIC for ceftazidime and 40% or 50% ƒT>CT for avibactam for simulations of 1000 patients with ceftazidime/avibactam dosed in dierent durations of i.v. infusion for dierent renal function groups.111

CT1=0.5 mg/L, MIC=8 mg/L CT2=1.0 mg/L, MIC=8 mg/LCestazidime/

avibactam dose (mg)Renal function 50% ƒT>CT1

50% ƒT>MIC40% ƒT>CT1

40% ƒT>MIC50% ƒT>CT2 50% ƒT>MIC

40% ƒT>CT2 40% ƒT>MIC

0.5-h i.v. infusion

Normal

Mild

Moderate

Severe 1

Severe 2

ESRD

2000/500, q8h

2000/500, q8h

1000/250, q12h

1000/250, q24h

500/125, q24h

500/125, q48h

97.0

99.2

98.7

96.2

95.6

97.6

90.3

97.2

95.5

85.8

90.2

94.7

78.8

91.9

84.1

72.7

90.2

94.7

94.5

98.8

94.7

90.9

95.6

97.6


Unless otherwise stated values are geometric mean (CV%).* Median (range). ** Arithmetic mean (SD).AUC: Area under the plasma concentration-time curve. AUClast: AUC from time zero to time of last measurable plasma concentration. AUC0-∞: AUC from time zero to innity on day 1. CL: Plasma clearance. CLR: Renal clearance. Cmax: Maximum observed plasma concentration. CV%: Percentage coecient of variation. i.v.: Intravenous. SD: Standard deviation. t1/2: Terminal half-life. tmax: Time to maximum plasma concentration. Vss: Apparent volume of distribution at steady state.

Cmax, mg/L

tmax, h*

AUClast, h·mg/L

AUC0-∞, h·mg/L

t1/2, h**

Vss, L

CL, L/h

CLR, L/h

93.17 (31)

0.50 (0.50–1.00)

195.94 (25)

198.59 (26)

3.07 (66)

28.23 (33)

10.07 (23)

9.70 (26)

23.33 (26)

0.50 (0.50–0.67)

37.15 (22)

37.41 (22)

2.16 (53)

25.43 (26)

13.36 (19)

12.71 (22)

33

INSIDE PAGE

3.3 Pharmacokinetics of ceftazidime-avibactamAvibactam exposure is dose-related and avibactam pharmacokinetics are linear and not aected by ceftazidime.107 Similarly, ceftazidime exposure is dose-related, with linear pharmacokinetics,117 which are also unaected by co-administration with avibactam (Table 3.2).107 No appreciable accumulation of ceftazidime or avibactam was observed following multiple i.v. infusions of ceftazidime-avibactam 2000 mg/500 mg administered every 8 h for up to 11 days in healthy adults with normal renal function.1

Table 3.2: Summary of the pharmacokinetic properties of ceftazidime-avibactam after a single i.v. infusion in healthy subjects. Adapted from.107

In general, the pharmacokinetic parameters of avibactam were similar between young male and female subjects (aged 18–45 years). Although there were trends for some dierences in pharmacokinetic parameters between the young and elderly subjects (aged ≥65 years) and between the elderly male and female subjects, these were not considered sucient to warrant dose adjustment in clinical practice.118

3.3.1 DistributionAntibiotics must penetrate the area of infection to adequately control pathogens involved in infection. e extent of protein binding for an antimicrobial agent has a signicant eect on the time taken to achieve MIC in target tissues. Lower protein binding may result in earlier build-up of the antimicrobial to therapeutic concentrations. us, low levels of protein binding found for ceftazidime (10–17%) may promote faster penetration into the site of infection.109,110 Ceftazidime is widely distributed into body tissues and uids.109,110 Avibactam has a similar low level of protein binding (~8%) and similar steady-state volume of distribution to ceftazidime in healthy subjects (Table 3.2).65,107

Pharmacokineticparameters

Cestazidime 2000 mgi.v. infusion (n=8)

Avibactam 500 mgi.v. infusion (n=8)

32

ELF: Epithelial lining uid. SD: Standard deviation.

A phase 1 open-label study in 43 healthy male subjects who were enrolled in two cohorts (Cohort A ceftazidime 2000 mg plus avibactam 500 mg [n=22] and Cohort B ceftazidime 3000 mg plus avibactam 1000 mg [n=21] every 8 h for 3 days) has demonstrated that ceftazidime and avibactam penetrate into human bronchial ELF to the same extent, with concentrations of approximately 30% of those attained in plasma. Concentration time proles were similar between ELF and plasma for both drugs (Figure 3.1).119

Figure 3.1: Plasma and ELF concentration-time proles (geometric mean [SD] plasma and median ELF concentrations [semi-log scale]) in a phase 1 study in healthy subjects.108,119

Ceftazidime and avibactam plasma exposure were comparable across patients with dierent indications, cIAI, cUTI and HAP.1

e penetration of ceftazidime across the intact blood-brain barrier is poor, resulting in low levels of ceftazidime in cerebrospinal uid (CSF) in the absence of inammation. However, concentrations of 4–20 mg/L or more are achieved in the CSF when the meninges are inamed.117

100

10

1

0.1

0.010 4 8 12 16 20 24

Time after start of infusion (h)

1000

Conc

entra

tion

(mg/

L)

Cohort A: Avibactam 500 mg + Ceftazidime 2000 mg

100

10

1

0.1

0.010 4 8 12 16 20 24


1000

Conc

entra

tion

(mg/

L)

100

10

1

0.1

0.010 4 8 12 16 20 24


1000

Conc

entra

tion

(mg/

L)

Cohort B: Avibactam 1000 mg + Ceftazidime 3000 mg

100

10

1

0.1

0.010 4 8 12 16 20 24


1000

Conc

entra

tion

(mg/

L)

Plasma geometric mean concentration (n= 22)ELF median concentration (n=5)

Individual ELF data

Plasma geometric mean concentration (n=22)ELF median concentration (n=5)

Individual ELF data


Individual ELF data


Individual ELF data


Individual ELF data

Cef

tazid

ime

Avib

acta

m


35

INSIDE PAGE

e penetration of avibactam through the blood-brain barrier has not been studied clinically, but in rabbits with inamed meninges, CSF exposures of ceftazidime and avibactam were 43% and 38% of plasma area under the concentration-time curve (AUC), respectively.1 For ceftazidime, concentrations in excess of the MIC for common pathogens can be achieved in tissues such as bone, heart, bile, sputum, aqueous humour, synovial, pleural and peritoneal uids. Ceftazidime crosses the placenta readily, and is excreted in breast milk.117

3.3.2 MetabolismNo metabolites of ceftazidime109 or avibactam106 have been identied.

3.3.3 Eliminatione terminal elimination half-life (t1/2) of both ceftazidime and avibactam is approximately 2 h after i.v. infusion.107, 109, 110, 118 e primary route of elimination of ceftazidime is via the kidneys, almost exclusively (>95%) by glomerular ltration as unchanged drug.109,120

Avibactam is also predominantly excreted unchanged via the kidneys, with a mean of 91% and 86% of the dose recovered in urine within 24 h of administration in young male and female cohorts (18–45 years), respectively. Urinary excretion in the rst 24 h after dosing was lower in the elderly (≥65 years) cohorts (68% in elderly men and 60% in elderly women), possibly reecting age-related dierences in renal function.118 Less than 1% of ceftazidime is excreted via the bile and <0.25% of avibactam is excreted into faeces.1

3.3.4 Use in special populations3.3.4.1 Renal impairmentElimination of ceftazidime and avibactam is decreased in patients with moderate or severe renal impairment and ESRD, including patients undergoing hemodialysis. e dose should be reduced in patients with CrCl ≤50 mL/min (see Table 2.11 in Section 2).1

Because the exposure of both ceftazidime and avibactam is highly dependent on renal function, regular monitoring of estimated CrCl is advised in patients with impaired renal function. is is because in some patients, especially early in the course of their infection, the CrCl estimated from serum creatinine can change rapidly.1

3.3.4.2 Hepatic impairmentMild-to-moderate hepatic impairment had no eect on the pharmacokinetics of ceftazidime in individuals who received 2000 mg i.v. every 8 h for 5 days, provided renal function was not impaired. e pharmacokinetics of ceftazidime in patients with severe hepatic impairment has not been established and the pharmacokinetics of avibactam in patients with any degree of hepatic impairment has not been studied. As ceftazidime and avibactam do not appear to undergo signicant hepatic metabolism, the systemic clearance of either drug is not expected to be signicantly altered by hepatic impairment and no dosage adjustment of ceftazidime-avibactam is recommended for patients with hepatic impairment.1

3.3.4.3 Elderly patients (≥65 years)e reduced clearance of ceftazidime observed in elderly patients was primarily due to age-related decreases in renal clearance. e mean t1/2 of ceftazidime ranged from 3.5–4 h following single or repeated doses (every 12 h for 7 days) of 2000 mg i.v. bolus injections in elderly patients aged ≥80 years. Following single dose administration of avibactam 500 mg as a 30-minute i.v. infusion, elderly patients had a slower t1/2 of avibactam, which may be attributed to age-related decrease in renal clearance. Dosage adjustment for ceftazidime-avibactam is not required in elderly subjects (aged ≥65 years) with CrCl >50 mL/min.1

3.3.4.4 Pediatric patientse safety and ecacy of ceftazidime-avibactam in pediatric patients (aged <18 years) have not been established.1

3.3.4.5 Gendere pharmacokinetic parameters of ceftazidime-avibactam were similar between males and females. No dose adjustment is required based on gender.1

3.3.4.6 EthnicityBased on a population pharmacokinetic analysis, no dose adjustment of ceftazidime- avibactam is required based on race.1

3.3.5 Drug interactionsConcurrent treatment with high doses of cephalosporins and nephrotoxic medicinal products such as aminoglycosides or potent diuretics (e.g. furosemide) may adversely aect renal function and thus reduce clearance of ceftazidime and avibactam.1

Chloramphenicol is antagonistic in vitro with ceftazidime and other cephalosporins. e clinical relevance of this nding is unknown, but due to the possibility of antagonism in vivo this drug combination should be avoided.1

Avibactam showed no signicant inhibition of cytochrome P450 enzymes. Avibactam and ceftazidime showed no in vitro cytochrome P450 induction in the clinically relevant exposure range. Avibactam and ceftazidime do not inhibit the major renal or hepatic transporters in the clinically relevant exposure range, therefore, the drug–drug interaction potential via these mechanisms is considered low.1

In vitro, avibactam is a substrate of organic anion transporter OAT1 and OAT3 which might contribute to the active uptake from the blood compartment and, thereby its excretion. Probenecid (a potent OAT inhibitor) inhibits this uptake by 56–70% in vitro and, therefore, has the potential to alter the elimination of avibactam when co-administered.1, 106 Since a clinical interaction study of avibactam and probenecid has not been conducted, co-administration of avibactam with probenecid is not recommended.1

34 See summary of prescribing information on last page

37

INSIDE PAGE

36

4.1 Summary

e RECLAIM programme of three prospective, multicenter, randomized, double-blind, comparative phase 3 studies was designed to compare the ecacy and safety of ceftazidime-avibactam plus metronidazole vs. meropenem in hospitalized adults with a diagnosis of cIAI.3

In the RECLAIM 1 and 2 studies, treatment with ceftazidime-avibactam plus metronidazole was shown to be non-inferior to meropenem in hospitalized patients with cIAI.3

High response rates were noted against key Gram-negative pathogens (E. coli and P. aeruginosa), and ceftazidime-avibactam plus metronidazole was also eective against ceftazidime-resistant Gram-negative pathogens.3

e safety and tolerability prole of ceftazidime-avibactam plus metronidazole was found to be broadly similar to those of ceftazidime and metronidazole alone.3

4.2 Clinical development programme – RECLAIM and REPRISEe ecacy, safety and tolerability of ceftazidime 2000 mg-avibactam 500 mg plus metronidazole 500 mg i.v. vs. meropenem 1000 mg plus placebo i.v. every 8 h for 5–14 days was initially evaluated in a phase 2, prospective, randomized, double-blind, active-controlled trial in 204 hospitalized adults with cIAI (ClinicalTrials.gov identier: NCT00752219).121 e primary ecacy endpoint was the clinical response in microbiologically evaluable (ME) patients at the test-of-cure (TOC) visit 2 weeks after the last dose of study therapy.121

e median duration of treatment was similar in both groups (6.0 and 6.5 days in the ceftazidime-avibactam plus metronidazole and meropenem groups, respectively).121 A favourable clinical response (dened as complete resolution or signicant improvement of signs/symptoms of infection with no requirement for additional antibiotics or surgery) in the ME population at the TOC visit was observed in 91.2% (62/68) and 93.4% (71/76) of patients in the ceftazidime-avibactam plus metronidazole and meropenem groups, respectively. e estimated dierence in response rate was -2.2% (95% CI -20.4, 12.2).121

A favorable microbiological response was seen in >90% of patients in both treatment groups, including most patients with E. coli isolates at the TOC visit. Most patients with Gram-positive or anaerobic isolates had favourable microbiological responses, as did all patients with bacteremia at baseline.121

e incidence of treatment-emergent adverse events (TEAEs) was similar for ceftazidime- avibactam plus metronidazole (64.4%) and meropenem (57.8%).121

Although this phase 2 study was limited in size, and included a high proportion of less severely ill patients, the results provided a positive indication that ceftazidime-avibactam plus metronidazole may be an eective treatment in patients with cIAI, including in some patients with ceftazidime-non-susceptible pathogens.121

e RECLAIM programme of three prospective, multicenter, randomised, double-blind, comparative phase 3 studies was initiated to report on the ecacy and safety of ceftazidime-avibactam plus metronidazole vs. meropenem in hospitalized adults (18–90 years) with a diagnosis of cIAI.e REPRISE prospective, international, randomized, open-label phase 3 study was initiated to report on the ecacy and safety of ceftazidime-avibactam in patients with serious ceftazidime-resistant Gram-negative bacterial infections (cUTI and cIAI) (discussed in detail in Section 5).

4.3 RECLAIM 1 and 2RECLAIM 1 (NCT01499290) and RECLAIM 2 (NCT01500239) are two identically designed studies that have been analysed as a single pooled dataset (Figure 4.1). e primary objective was to assess non-inferiority of ceftazidime-avibactam plus metronidazole compared with meropenem on clinical cure rate (dened as resolution or signicant improvement of signs and symptoms so that no further treatment is required) at TOC visit in patients with ≥1 identied pathogen in the microbiological modied-intention-to-treat (mMITT) population.3

Figure 4.1: RECLAIM 1 and 2 (phase 3 study design)3

4. Clinical and safety prole ofceftazidime-avibactam in complicatedintra-abdominal infections (cIAI)

RECLAIM 1: NCT1499290. RECLAIM 2: NCT01500239. *Stratied by baseline severity of disease (Acute Physiology and Chronic Health Evaluation [APACHE] II score) and region. cIAI: Complicated intra-abdominal infection. FDA: (US) Food and Drug Administration. I.V.: Intravenous. NI: Non-inferiority.

1:1 randomization*EOT (end-of-treatment)

within 24 h last i.v. infusion

(5-14 days of therapy)

Meropenem1000 mg, 30 min i.v. infusion, q8h

12.5% NI margin(powered for 10.0% NI margin

as required by FDA)

28-35 daysafter

randomization

42-49 daysafter

randomization

TOC(test-of-cure)

LFU(late follow-up)

Hospitalizedpatients aged ≥18 years withcIAI requiring hospitalization

from 136 centresacross

30 countriesworldwide

Ceftazidime-avibactam(2000-500 mg, 2 h i.v. infusion)

+ metronidazole(500 mg, 60 min i.v. infusion)

every 8 h (q8h)


4.3.1 Baseline characteristicsPatient characteristics, including type and site of cIAI, were comparable between the ceftazidime-avibactam plus metronidazole and meropenem groups at baseline (Table 4.2). Approximately 41% of patients had a primary diagnosis of appendiceal perforation or peri-appendiceal abscess. Moderate renal impairment with CrCl between >30 and ≤50 mL/min was observed in 8% of patients and the majority of patients had Acute Physiology and Chronic Health Evaluation II (APACHE II) scores ≤1.3

39

INSIDE PAGE

38

Patients were enrolled in the studies based on the inclusion and exclusion criteria summarized in Table 4.1.

Table 4.1: Key inclusion and exclusion criteria for the RECLAIM 1 and 2 trials.3

APACHE: Acute physiology and chronic health evaluation. cIAI: Complicated intra-abdominal infection. MRSA: Methicillin-resistant Staphylococcus aureus.

Inclusion criteria Exclusion criteria

Age 18–90 years (18–65 years in India)

Presumed or denitive diagnosis of cIAI

Intra-operative/ post-operative enrolment with visual conrmation

Pre-operative enrolment with conrmation of infection by surgical intervention within 24 h of study entry

APACHE II score >30

Patient needed eective concomitant systemic antibacterials or antifungals in addition to those designated in the two study groups

With the exception of vancomycin, linezolid or daptomycin if started for known or suspected MRSA or Enterococcus spp.

Hemodialysis or peritoneal dialysis

Traumatic bowel perforation undergoing surgery within 12 h or perforation of gastroduodenal ulcers undergoing surgery within 24 h

Abdominal wall abscess or bowel obstruction without perforation or ischemic bowel without perforation

Simple cholecystitis or gangrenous cholecystitis without rupture, or simple appendicitis, or acute suppurative cholangitis; or infected necrotising pancreatitis or pancreatic abscess

Surgery which included staged abdominal repair, or ‘open abdomen’ technique, or marsupialization

Known Clostridium dicile-associated diarrhoea

Perinephric infections

Indwelling peritoneal dialysis catheter

Suspected intra-abdominal infections due to fungus, parasites (e.g. amoebic liver abscess), virus or tuberculosis

Table 4.2: RECLAIM 1 and 2 – key patient characteristics at baseline (MITT population).3

APACHE II: Acute physiology and chronic health evaluation II. cIAI: Complicated intra-abdominal infection. CrCl: Creatinine clearance. MITT: Modied intention-to-treat. mMITT: Microbiological modied intention-to-treat. SD: Standard deviation.

Age (years), mean (SD)

Gender, male, n (%)

Renal status-moderate impairment (CrCl >30–≤50 mL/min)

APACHE II score, n (%)

≤10

>10–≤30

>30

Primary diagnosis, n (%)

Cholecystitis

Diverticular disease

Appendiceal perforation or peri-appendiceal abscess

Acute gastric and duodenal perforations

Traumatic perforations

Secondary peritonitis

Intra-abdominal abscess

Single abscess

Multiple abscess

cIAI not conrmed at surgery

Bacteremia, n (%)

Disease characteristics (mMITT population)

Ceftazidime-resistant, n (%)

ParameterCestazidime-avibactam

plus metronidazole (n=520)Meropenem

(n=523)

49.8 (17.5)

326 (62.7)

41 (7.9)

437 (84.0)

78 (15.0)

1 (0.2)

87 (16.7)

35 (6.7)

218 (41.9)

96 (18.5)

9 (1.7)

36 (6.9)

39 (7.5)

32 (6.2)

7 (1.3)

0

22 (4.2)

n=413

47 (11.4)

50.3 (18.3)

332 (63.5)

43 (8.2)

434 (83.0)

80 (15.3)

0

77 (14.7)

52 (9.9)

213 (40.7)

99 (18.9)

8 (1.5)

33 (6.3)

41 (7.8)

35 (6.7)

6 (1.1)

0

14 (2.7)

n=410

64 (15.6)


41

INSIDE PAGE

40

Pathogens isolated from the abdominal site or blood were similar in both treatment groups at baseline, and were as would be expected in patients with cIAI (Table 4.3).3 E. coli was the most prevalent pathogen present in 65.6% of patients in the ceftazidime-avibactam plus metronidazole group, and 69.5% of patients in the meropenem group. In total, 13.5% (n=111) of all patients had a ceftazidime-resistant aerobic Gram-negative pathogen (CLSI-breakpoint-dened resistant and intermediate categories, i.e. MIC ≥8 mg/L for Enterobacteriaceae and ≥16 mg/L for P. aeruginosa), the majority of which were either E. coli or K. pneumoniae. Isolates that were non-susceptible to meropenem or potentially non-susceptible to ceftazidime-avibactam were evenly distributed between the two treatment groups, with the exception of P. aeruginosa non-susceptible to ceftazidime-avibactam, which all occurred in the meropenem group.3

Table 4.3: RECLAIM 1 and 2 – microbiological characteristics at baseline (mMITT population).3

Figure 4.2: RECLAIM 1 and 2 – MIC frequency distributions for ceftazidime and ceftazidime-avibactam against E. coli, K. pneumoniae and P. aeruginosa and all ceftazidime-resistant Enterobacteriaceae at baseline (mMITT population).122

a A patient could have had ≥1 pathogen. Multiple isolates of the same species from the same patient are counted only once,regardless of source.b ere was an additional Citrobacter freundii pathogen in the meropenem group that was not coded to C. freundii complex.mMITT: Microbiological modied intention-to-treat.

Enterobacteriaceae

Escherichia coli


Klebsiella oxytoca

Citrobacter freundii complexb


Proteus mirabilis


Other Gram-negative pathogens


Gram-positive aerobes

Anaerobes

Common pathogens identified at baseline (combined frequency of ≥10)a

Cestazidime-avibactamplus metronidazole (n=413)

Meropenem (n=410)

334 (80.9)

271 (65.6)

51 (12.3)

18 (4.4)

18 (4.4)

13 (3.1)

8 (1.9)

5 (1.2)

42 (10.2)

35 (8.5)

157 (38.0)

134 (32.4)

353 (86.1)

285 (69.5)

49 (12.0)

15 (3.7)

12 (2.9)

19 (4.6)

9 (2.2)

5 (1.2)

51 (12.4)

36 (8.8)

156 (38.0)

126 (30.7)

e activity of ceftazidime and ceftazidime-avibactam against the three most prevalent baseline pathogens (E. coli, K. pneumoniae and P. aeruginosa) and against all ceftazidime-resistant Enterobacteriaceae is shown in Figure 4.2, which demonstrates that avibactam successfully restored the activity of ceftazidime.3,122

60

50

40

30

20

10

0

MIC (mg/mL)

% Is

olat

es a

t eac

h M

IC

≤0.008 0.015 0.03 0.06 0.12 0.25 0.5 1 2 4 8 16 32 >32

60

50

40

30

20

10

0

MIC (mg/mL)

% Is

olat

es a

t eac

h M

IC

≤0.008 0.015 0.03 0.06 0.12 0.25 0.5 1 2 4 8 16 32 >32

60

50

40

30

20

10

0

MIC (mg/mL)

% Is

olat

es a

t eac

h M

IC

≤0.008 0.015 0.03 0.06 0.12 0.25 0.5 1 2 4 8 16 32 >32

Escherichia coli n=543

Pseudomonas aeruginosa n=69

Klebsiella pneumoniae n=99

Ceftazidime Ceftazidime-avibactam

60

50

40

30

20

10

0

MIC (mg/mL)

% Is

olat

es a

t eac

h M

IC

≤0.008 0.015 0.03 0.06 0.12 0.25 0.5 1 2 4 8 16 32 >32

All ceftazidime-resistant Enterobacteriaceae n=108

MIC: Minimum inhibitory concentration. mMITT: Microbiological modied intention-to-treat.


Solid line represents the pre-specied NI margin of -12.5% for the lower limit of the 95% CI. Dashed line represents FDA requirement of -10%. CI: Condence interval. CE: Clinically evaluable. EMA: European Medicines Agency. FDA: (US) Food and Drug Administration. MITT: Modied intention-to-treat. mMITT: Microbiological modied intention-to-treat. NI: Non-inferiority. TOC: Test-of-cure.

43

INSIDE PAGE

42

4.3.2.1 Clinical cure ratesFor the primary endpoint of clinical cure at the TOC visit, the lower limit of the 95% CI for the between group dierence was >-10% across all analysis populations demonstrating non-inferiority of ceftazidime-avibactam plus metronidazole vs. meropenem in hospitalized patients with cIAIs (Figure 4.4).3

Figure 4.4: RECLAIM 1 and 2 primary ecacy results – clinical cure at TOC visit.3

Subgroup analyses of ecacy at TOC visit indicated no clinically meaningful trends when results were stratied by patient and disease characteristics, with the exception of patients with moderate renal impairment at baseline. In this subgroup, there was a treatment response in favor of meropenem, possibly due to under-dosing of ceftazidime-avibactam plus metronidazole.3

Renal function is known to aect the pharmacokinetics and pharmacodynamics of ceftazidime, avibactam and meropenem. In the RECLAIM 1 and 2 studies, dose adjustments were made for all patients with moderate renal impairment (CrCl >30 to ≤50 mL/min) at baseline to account for this (dose adjustment: ceftazidime 1000 mg / avibactam 250 mg as a 2-h i.v. infusion every 12 h, or meropenem 1000 mg as a 3-min infusion every 12 h). No adjustment was made for metronidazole.3 Post-hoc review of serum creatinine and dosing data indicated that some of the patients with moderate renal impairment at baseline had a rapid improvement of renal function after enrolment. Although plasma exposure at day 3 was broadly comparable with those seen previously, improvements in renal function and appropriate increase in study drug dosing had already occurred by this time.

Clinical cure rate n/N(%)

Ceftazidime-avibactam+

metronidazolen

1043 429/520(82.5)

444/523(84.9)

Analysis population

MITT(EMA Co-primaryanalysis population)

CE at TOC(EMA co-primaryanalysis population)

mMITT(FDA primaryanalysis population)

826 376/410(91.7)

385/416(92.5)

823337/413

(81.6)349/410

(85.1)

% dierence in clinical cure rate (95% CI)

-30 -20 -10 0 10

- 2.4 (-6.90, 2.10)

- 0.8 (-4.61, 2.89)

- 3.5 (-8.64, 1.58)

Meropenem

Between groupdierence, %

(95% CI)

* Evaluable assessment; no protocol deviations aecting assessment of ecacy; received therapy for ≥48 h with ≥80% of schedules drug administered; received no prior or concomitant antibiotics other than protocol-allowed; adequate initial infection source control. CE: Clinically evaluable. MITT: Modied intention-to-treat. mMITT: Microbiological modied intention-to-treat. TOC: Test-of-cure.

4.3.2 Clinical ecacye analysis population dened in the RECLAIM 1 and 2 trials included the modied intention-to-treat (MITT) population, the mMITT population and the CE population at TOC (Figure 4.3). e MITT population comprised patients who met clinical disease criteria and received study drug and the CE population was a subset of the MITT population who met all evaluability criteria. e mMITT population comprised patients who met clinical disease criteria and had ≥1 pathogen identied at study entry.3

Figure 4.3: Disposition of patients in the RECLAIM 1 and 2 trials.3

Co-primary analysis:MITT and CE populations

EUROPEAN MEDICINES AGENCY FDA

Primary analysis:mMITT population

mMITT populationMet clinical disease criteria

and ≥1 pathogenidentied at study entry

823 patientsCeftazidime-avibactam+ metronidazole n=413

Meropenem n=410

CE at TOC populationMet all evaluability criteria*

826 patientsCeftazidime-avibactam + metronidazole n=410

Meropenem n=416

MITT populationMet clinical disease criteria and

received study drug1043 patients

Ceftazidime-avibactam+ metronidazole n=520

Meropenem n=523

1066 patients randomized

Safety population 1058 patients


45

INSIDE PAGE

44

erefore, it is plausible that some patients with moderate renal impairment at baseline may have been under-dosed during the critical early treatment period. Dose adjustment was greater in the ceftazidime-avibactam plus metronidazole group (-66%) than in the meropenem group (-33%) and, therefore, the risk of under-dosing in the former group was more severe and this may explain the trend in favor of meropenem seen by this stratication. Pharmacokinetic/pharmacodynamic modelling work, undertaken since these studies were completed, has been used to provide revised dose adjustments to ensure optimal plasma exposure for target attainment is achieved, thereby minimizing the risk of under-exposure in the event of rapid improvements in renal function.3

4.3.2.2 Clinical response by baseline pathogene clinical responses at TOC visit by baseline pathogen between the two treatment groups were comparable in the mMITT population. Response rates of >80% were observed for patients with E. coli infections and >85% for those with P. aeruginosa infections (Table 4.4).3

Table 4.4: RECLAIM 1 and 2 – clinical response at TOC by baseline pathogen. Baseline Gram-negative pathogens with ≥10 isolates from both treatment groups (mMITT population).3

In Gram-negative pathogens resistant to ceftazidime, ceftazidime-avibactam plus metronidazole resulted in a similar clinical cure rate to meropenem and similar clinical cure rate to ceftazidime-susceptible pathogens, which indicated that avibactam successfully restored the activity of ceftazidime against ceftazidime-resistant infections (Table 4.5).3

Table 4.5: RECLAIM 1 and 2 – clinical response at TOC against Gram-negative ceftazidime-resistant pathogens (mMITT population).3

4.3.3 Safety and tolerabilitySimilar proportions of patients in the ceftazidime-avibactam plus metronidazole and meropenem groups reported adverse events (AEs: 45.9% vs. 42.9%, respectively). e most frequently reported AEs in the ceftazidime-avibactam plus metronidazole group were diarrhea (7.6%), nausea (6.8%), vomiting (4.5%) and pyrexia (4.5%) and in the meropenem group were hypertension (4.5%), nausea (4.5%), pyrexia (4.5%) and constipation (3.8%). e majority of AEs were of mild or moderate intensity and similar proportions of patients in the ceftazidime-avibactam plus metronidazole and meropenem groups reported serious AEs (SAEs: 7.9% vs. 7.6%, respectively). In addition, the incidence of AEs leading to discontinuation was similar in both treatment groups (Figure 4.5).3

One conrmed case of C. dicile enterocolitis occurred in each treatment group, both were considered non-serious and moderate in intensity.3

In the ceftazidime-avibactam plus metronidazole group, 12 patients had AEs that fell under the safety topic of ‘renal disorder’.3 None of the AEs that resulted in death were considered related to the study drug.3 No meaningful trends were observed in any other laboratory values, vital signs or electrocardiograms and no new, signicant or unexpected safety concerns were identied.3, 122

CI: Condence interval. mMITT: Microbiologically modied intention-to-treat. TOC: Test-of-cure.

Cestazidime-avibactam plus

metronidazole (n=413)

Meropenem (n=410)

Clinical cure, n (%)

272 (81.4)

218 (80.4)

40 (78.4)

14 (77.8)

14 (77.8)

11 (84.6)

5 (62.5)

4 (80.0)

36 (85.7)

30 (85.7)


305 (86.4)

248 (87.0)

37 (75.5)

12 (80.0)

9 (75.0)

16 (84.2)

7 (77.8)

5 (100.0)

49 (96.1)

34 (94.4)

n

353

285

49

15

12

19

9

5

51

36

n

334

271

51

18

18

13

8

5

42

35

Comparisonbetween groups

Dierence, % (95% CI)

–5.0 (–10.53, 0.53)

–6.6 (–12.80, –0.45)

2.9 (–13.77, 19.68)

–2.2 (–30.32, 27.76)

2.8 (–27.17, 35.88)

0.4 (–29.80, 26.38)

–15.3 (–55.12, 28.64)

–20.0 (–64.27, 31.61)

–10.4 (–24.58, 1.30)

–8.7 (–24.88, 6.16)

Enterobacteriaceae

Escherichia coli


Klebsiella oxytoca

Citrobacter freundii complex


Proteus mirabilis


Non-Enterobacteriaceae


CI: Condence interval. mMITT: Microbiologically modied intention-to-treat. TOC: Test-of-cure.

Cestazidime-avibactam plus

metronidazole (n=413)

Meropenem (n=410)


39 (83.0)

237 (82.0)


55 (85.9)

256 (87.7)

n

64

292

n

47

289

Comparisonbetween groups

Dierence, % (95% CI)

–3.0 (–17.89, 10.60)

–5.7 (–11.57, 0.17)

All ceftazidime-resistant

All ceftazidime-susceptible


Pathogen

Pathogen

47

INSIDE PAGE

Figure 4.5: Incidence of TEAEs leading to discontinuation (safety population at LFU).122 4.3.4 Impact of treatment failure on healthcare resource utilisation in the RECLAIM programmeTreatment success was achieved in 83.7% of the RECLAIM study population (82.3% in the ceftazidime-avibactam plus metronidazole group and 85.1% in the meropenem group).123

Patients who were dened as treatment successes spent on average 10.3 fewer days (95% CI 5.3, 14.3) in hospital than those who were treatment failures. is was composed of 3.5 fewer days (95% CI 1.0, 6.5) in the ICU and 6.8 fewer days (95% CI 2.6, 10.1) in general hospital wards.123 e length of time spent in hospital was greater in treatment failures as opposed to treatment successes irrespective of treatment (Figure 4.6). In total, 44.2% of treatment failures spent time in the ICU as opposed to 40.8% of treatment successes and 97% of all patients spent fewer than 20 days in the ICU. Treatment failures had a mean (SD) duration of i.v. therapy of 8.36 (2.94) days compared with treatment successes who had a mean duration of 7.11 (3.86) days, with no substantive dierences between the two treatment groups.123

Figure 4.6: Hospital stay by treatment and response in the RECLAIM study.123

4.3.5 ConclusionsOverall, ceftazidime-avibactam plus metronidazole therapy was non-inferior to meropenem in hospitalized patients with cIAI in the RECLAIM study programme. High response rates against key pathogens were noted and ceftazidime-avibactam plus metronidazole was eective against ceftazidime-resistant pathogens. It should be noted that recommendations for ceftazidime-avibactam dose adjustment for renal impairment at baseline have been modied since this study was completed, based on pharmacokinetic/pharmacodynamic modelling data. e safety and tolerability prole of ceftazidime-avibactam plus metronidazole was broadly similar to the known proles of ceftazidime and metronidazole alone.3

46

LFU: Late follow-up. TEAE: Treatment-emergent adverse event.

ICU: Intensive care unit.

Transaminases increased

Pyrexia

Impaired healing

Renal failure

Rash pruritic

Rash

Drug eruption

Ileal perforation

Diarrhoea

Pulmonary congestion

shock

Right ventricular failure

Cardiac failure

Headache

Delirium tremens

Hypersensitivity

rombocytopenia

Anaemia

Urinary tract infection

Respiratory tract infection

Candida sepsis

Bronchopneumonia

Any TIME

Incidence of TEAE (%) 0 1 2 3

0.20.0

0.20.0

0.20.0

0.20.0

0.20.0

0.20.2

0.00.2

0.00.2

0.00.2

0.00.2

0.00.2

0.00.2

0.00.2

0.00.2

0.00.2

0.00.2

0.00.2

0.00.2

0.00.2

1.32.6

0.20.0

0.20.0

0.00.2

Meropenem (n=529)

Ceftazidime-avibactamplus metronidazole (n=529)

Day

s in

hos

pita

l

20

15

10

5

0Ceftazidime-avibactam

Success

Days in general ward Days in ICU

Ceftazidime-avibactam failure

MeropenemSuccess

Meropenemfailure


49

INSIDE PAGE

4.4 RECLAIM: Indian Subset AnalysisA qualitative analysis was carried out to assess the ecacy and safety of Ceftazidime- Avibactam (CAZ-AVI and metronidazole in comparison with meropenem for the treatment of complicated intra-abdominal infections, in the Indian population cohort of the RECLAIM trial participants. In the global RECLAIM, a total of 1066 patients were enrolled from 136 centers in 23 countries, out of which 142 patients were enrolled from 8 centers in India.124 e aim of this subgroup analysis was to assess whether the results in the subgroup (Indian population) are in line with the results of the overall RECLAIM study125 (overall population) and therefore the conclusions made for the overall study could be considered as applicable to the Indian population.

4.4.1 Baseline characteristicsA total of 142 Indian patients with cIAI were enrolled across eight centres in India, 125 of which were randomized to one of the two study treatment arms randomized (62 to CAZ-AVI + metronidazole and 63 to meropenem). Baseline demographic and patient characteristics were generally well balanced between treatment groups for both overall and Indian population.124

e mean age of subjects in the Indian population (36.6 years, range: 18 years to 64 years) was lower than the overall population (mean-50.0 years) and most patients were 18 to 45 years of age; in contrast to the global population, no patients above 65 years of age were enrolled in India (per local requirements). e mean age and range of age was lower in the Indian population, as compared with the overall population.124

e mean BMI (22.03 kg/m2) was lower in the Indian population with only 1 patient (0.9%) having a BMI >30 kg/m2 compared to 219 (21.0%) in the overall population. e Indian subpopulation did not include any patients with APACHE II score >20 or with severe renal impairment. Disease characteristics were generally balanced between treatment arms for both the Indian and the overall populations; cIAI diagnoses were adequately represented. e proportion of patients with appendicitis in the Indian population (41.7%) was similar to that of the overall population (41.3%) (Table 4.6).124

48

Table 4.6: Disease Characteristics of Indian Patients at Baseline (MITT Analysis Set).124

Total(N=115)

Meropenem(N=59)

CAZ-AVI + Metronidazole

(N=56)

115

6.0

3.89

5.0

0

20

105 (91.3)

10 (8.7)

115 (100)

102 (88.7)

13 (11.3)

115 (100)

5 (4.3)

110 (95.7)

115 (100)

50 (43.5)

47 (40.9)

3 (2.6)

65 (56.5)

115 (100)

1 (0.9)

114 (99.1)

115 (100)

59

5.6

3.52

5.0

0

14

54 (91.5)

5 (8.5)

59 (100)

51 (86.4)

8 (13.6)

59 (100)

2 (3.4)

57 (96.6)

59 (100)

27 (45.8)

26 (44.1)

1 (1.7)

32 (54.2)

59 (100)

0

59 (100)

59 (100)

56

6.3

4.24

5.0

0

20

51 (91.1)

5 (8.9)

56 (100)

51 (91.1)

5 (8.9)

56 (100)

3 (5.4)

53 (94.6)

56 (100)

23 (41.1)

21 (37.5)

2 (3.6)

33 (58.9)

56 (100)

1 (1.8)

55 (98.2)

56 (100)

n

Mean

SD

Median

Minimum

Maximum

≤10

>10 to ≤30

Total

≤10

>10 to ≤30

Total

Yes

No

Total

Yes

≤24 hours

≥24 hours

No

Total

Yes

No

Total

APACHE II Score (from eCRF)a

APACHE II (from eCRF) n (%)

APACHE II (from IVRS)b n (%)

Prior treatment failure n (%)

Prior systemic antibiotics use in the previous 72 hours before randomization n (%)

Complication of a previous abdominal surgeryc n (%)


51

INSIDE PAGE

50

Total(N=115)

Meropenem(N=59)


(N=56)

114

93.0

28.81

93.6

31

169

105 (91.3)

9 (7.8)

1 (0.9)

115 (100)

44 (38.3)

71 (61.7)

115 (100)

6 (5.2)

109 (94.8)

115 (100)

7 (6.1)

1 (0.9)

48 (41.7)

42 (36.5)

3 (2.6)

9 (7.8)

59

90.0

27.63

93.8

32

169

54 (91.5)

5 (8.5)

0

59 (100)

24 (40.7)

35 (59.3)

59 (100)

2 (3.4)

57 (96.6)

59 (100)

3 (5.1)

0

25 (42.4)

22 (37.3)

2 (3.4)

6 (10.2)

55

96.2

29.95

93.4

31

160

51 (91.1)

4 (7.1)

1 (1.8)

56 (100)

20 (35.7)

36 (64.3)

56 (100)

4 (7.1)

52 (92.9)

56 (100)

4 (7.1)

1 (1.8)

23 (41.1)

20 (35.7)

1 (1.8)

3 (5.4)

n

Mean

SD

Median

Minimum

Maximum

Normal renal function/mildimpairment (CrCl >50 ml/min)

Moderate impairment (CrCl ≥30 to ≤50 ml/min)

Missing

Total

Pre-operative

Post-operative/ Intra-operative

Total

Yes

No

Total

Cholecystitis



Acute gastric and duodenal perforations

Traumatic perforation


Estimated CrCl (ml/min)d

Renal status n (%)

Timing of enrollment n (%)

Bacteremia n (%)

Primary diagnosis n (%)

Total(N=115)

Meropenem(N=59)


(N=56)

5 (4.3)

4 (3.5)

1 (0.9)

0

115 (100)

27 (23.5)

2 (1.7)

0

7 (6.1)

29 (25.2)

4 (3.5)

0

49 (42.6)

33 (28.7)

45 (39.1)

24 (20.9)

16 (13.9)

6 (5.2)

0

2 (1.7)

46 (40.0)

115 (100)

1 (1.7)

1 (1.7)

0

0

59 (100)

15 (25.4)

0

0

3 (5.1)

15 (25.4)

2 (3.4)

0

25 (42.4)

19 (32.2)

24 (40.7)

13 (22.0)

9 (15.3)

3 (5.1)

0

1 (1.7)

22 (37.3)

59 (100)

4 (7.1)

3 (5.4)

1 (1.8)

0

56 (100)

12 (21.4)

2 (3.6)

0

4 (7.1)

14 (25.0)

2 (3.6)

0

24 (42.9)

14 (25.0)

21 (37.5)

11 (19.6)

7 (12.5)

3 (5.4)

0

1 (1.8)

24 (42.9)

56 (100)

Intra-abdominal abscess

Single abscess

Multiple abscess

cIAI not conrmed at surgery

Total

Stomach

Liver

Pancreas

Gall bladder

Small intestine

Large intestine

Spleen

Appendix

Other

Monomicrobial

Polymicrobial

2 pathogens

3 pathogens

4 pathogens

≥5 pathogens

No study qualifying pathogen identied

Total

Anatomic location of infectione n (%)

Infection type n (%)


Percentages were based on the total number of patients in the treatment group (N).APACHE II: Acute Physiology and Chronic Health Evaluation II. CAZ-AVI: Ceftazidime-avibactam. cIAI: Complicated intra-abdominal infection. CrCl: Creatinine clearance. eCRF: Electronic case report form. IVRS: Interactive voice response system. MITT: Modied intent-to-treat. N: Total number of patients in the treatment group. n: Number of patients in category or analysis. SD: Standard deviation. aAPACHE II score was calculated programmatically using data obtained at the site and reported in the eCRF. bAs reported by the site in IVRS at enrollment. cQualifying infection was a complication of a previous abdominal surgery. dAs reported by the site using the Cockcroft Gault method 1976 method based on local lab data. ePatients with >1 diagnosis at the same location were counted only once for that location.

e baseline microbiology in the overall study population showed that 67.6% patients were infected with E. coli, 12.2% were infected with K. pneumoniae and 8.6% were infected with P. aeruginosa; within the India subset, the baseline microbiology was similar to that of the overall population, with 80.0% of patients infected with E. coli, 16.9% infected with K. pneumoniae and 10.8% infected with P. aeruginosa.124

4.4.2 Clinical ecacy124

Clinical responses were determined by investigators at the end-of-treatment, test-of-cure and late-follow-up visits as cure, failure, or indeterminate. Clinical cure was dened as complete resolution or signicant improvement of signs and symptoms of the index infection such that no further antibacterial therapy, drainage, or surgical intervention was necessary.124

Due to dierent regulatory requirements for the statistical analysis of this study, the primary ecacy outcome for US FDA analyses was the proportion of patients with clinical cure at the test-of-cure (TOC) visit (28-35 days after randomization) in the microbiologically modied intention-to-treat population (mMITT) analysis set dened as ‘all patients who met the disease denition of cIAI and had ≥1 baseline pathogen.124 e aim of this subgroup analysis was to assess whether the results in the Indian population subgroup are in line with the results of the overall study and therefore the conclusions made for the overall study could be considered also applicable to the Indian subset. Although there are inherent limitations to this analysis due to the subgroup size, it provides information on clinical ecacy and safety relevant for the intended use of CAZ-AVI in Indian patients.124

4.4.2.1 Clinical cure ratesIn the overall study, non-inferiority of CAZ-AVI compared to meropenem was demonstrated in relation to clinical response at the TOC using the pre-dened non-inferiority margin of 12.5% in both the US FDA primary analysis set and ROW (Rest-of-the-World) co-primary analysis sets.125 e secondary end points in the RECLAIM study included clinical response at end-of treatment (EOT) (up to 24 hours after last infusion) and at late follow up visit (LFU) (42–49 days after randomization), microbiological response at TOC, EOT, LFU visits and the ecacy of ceftazidime-avibactam plus metronidazole or meropenem against ceftazidime-resistant pathogens.e majority (~90%) of patients randomized in India completed study treatment, consistent with the proportion of patients who completed the study in the overall population. In the overall population, for all Enterobacteriaceae isolated at baseline (mMITT analysis set), the ceftazidime MIC90 was 8 µg/mL and the CAZ-AVI MIC90 was 0.25 µg/mL, a 32-fold reduction.125 In the Indian population, for all Enterobacteriaceae isolated at baseline (mMITT analysis set), the ceftazidime MIC90 was >64 µg/mL and the CAZ-AVI MIC90 was 2 µg/mL, a reduction of at least 32-fold.124 is reduction in MIC90 demonstrates the impact of avibactam on the antimicrobial activity of ceftazidime.In the RECLAIM study, the overall objective was met; clinical and microbiological response rates at TOC were high and comparable across the treatment groups, demonstrating the non-inferiority of CAZ-AVI plus metronidazole to meropenem in the treatment of cIAI (against 12.5% NI margin and also 10% NI margin).125 Consistent results were seen across all primary and secondary analysis sets (MITT, CE, mMITT, ME, extended ME). e primary ecacy outcome measure (USFDA analysis) was the clinical cure rate at TOC. e overall population cure rates seen were 81.6% in CAZ-AVI plus metronidazole group and 85.1%, in the meropenem group (dierence -3.5%; 95% CI -8.64, 1.58) which fullled the pre-dened non-inferiority margin of 12.5%.125 e clinical cure rate at TOC for the mMITT analysis set of the Indian population, for CAZ-AVI plus metronidazole group and in the meropenem group were 83.3% and 77.1%, respectively (dierence: 6.2%; 95% CI -14.31, 25.65).124

53

INSIDE PAGE

52

Total(N=115)

Meropenem(N=59)


(N=56)

99 (86.1)

0

2 (1.7)

14 (12.2)

0

115 (100)

52 (88.1)

0

1 (1.7)

6 (10.2)

0

59 (100)

47 (83.9)

0

1 (1.8)

8 (14.3)

0

56 (100)

Laparotomy with fascial and skin closure

Laparotomy with fascial closure but without skin closure

Percutaneous drainage

Laparoscopic surgery

Other

Total

Study qualifying procedure n (%)


e non-inferiority of CAZ-AVI plus metronidazole compared to meropenem was also demonstrated in both of the ROW primary analysis sets in the overall RECLAIM study using the pre-dened 12.5% non-inferiority margins. For the MITT analysis set, the clinical cure rates at TOC in the CAZ-AVI plus metronidazole group and in the meropenem group were 82.5% and 84.9%, respectively (dierence -2.4%; 95% CI -6.90, 2.10). In the CE analysis set, the clinical cure rates at TOC in the CAZ-AVI plus metronidazole group and in the meropenem group were 91.7% and 92.5%, respectively (dierence -0.8%; 95% CI -4.61, 2.89). In the Indian sub-group, for the MITT analysis set, the clinical cure rates at TOC in the CAZ-AVI plus metronidazole group and in the meropenem group were 89.3% and 84.7%, respectively (dierence 4.5%; 95% CI -8.41, 17.50). In the CE at TOC analysis set, clinical cure rates at TOC in the CAZ-AVI plus metronidazole group and in the meropenem group were 97.8% and 95.5%, respectively (dierence 2.4%; 95% CI -7.41, 13.33). e results in Indian subset were thus consistent with the overall RECLAIM study ndings.124

For the Indian population, the observed dierence in cure rates between the CAZ-AVI and meropenem treatment groups at EOT ranged from -4.8% (95% CI -22.63, 11.52) in the mMITT analysis set to 1.6% (95% CI -7.50, 10.62) in the CE analysis set at EOT. e numerically lower cure rate in the meropenem group in the India subset appeared to be driven mainly by a higher proportion of indeterminate responses in the Indian meropenem group (20%) vs. the India CAZ-AVI plus metronidazole group (6.7%) and the overall population, meropenem group (7.6%).

4.4.2.2 Clinical response by baseline pathogenClinical cure rates by pathogen in the CAZ-AVI treatment group in the India subset (mMITT analysis set) were similar to those observed in the overall population for the most common Enterobacteriaceae isolates (E. coli and K. pneumoniae) as well as for P. aeruginosa (Table 4.10). Per-pathogen favorable microbiological response rates were similar to the clinical response rates by pathogen in both the India subset and the overall population.124 In both the overall population as well as the India subset, CAZ-AVI demonstrated ecacy at TOC against ceftazidime-resistant Enterobacteriaceae and Gram-negative pathogens other than Enterobacteriaceae, although the small numbers in the India subset limit interpretation (Table 4.11).124

Table 4.10: Clinical Response at TOC by baseline Pathogen (mMITT Analysis Set) – Indian Patients.124

A patient can have >1 pathogen. Multiple isolates of the same species in the same patient were counted only once regardless of source (intra-abdominal or blood) using the isolate with the highest MIC to study drug received. Clinical cure rate for the mMITT analysis set was dened as the number of patients with a clinical response of clinical cure at the TOC visit divided by the number of patients with clinical cure + clinical failure + indeterminate. Clinical response was based on surgical review evaluation if it was dierent from the investigator's assessment.Percentages were based on the total number of patients in the subgroup (n).CAZ-AVI: Ceftazidime-avibactam. CI: Condence interval. MIC: Minimum inhibitory concentration. mMITT: Microbiologically modied intent-to-treat. N: Total number of patients in the treatment group. n: Number of patients in category or analysis. TOC: Test-of-cure.a Dierence: dierence in clinical cure rates (CAZ-AVI + metronidazole group minus meropenem group).b CIs for group dierences were calculated using the unstratied Miettinen and Nurminen method.

55

INSIDE PAGE

54

6.2

6.4

-33.3

-1.2

75.0

0.0

0.0

(-14.31, 25.65)

(-15.23, 26.79)

(-82.73, 66.94)

(-22.65, 19.67)

(5.57, 93.24)

(-59.41, 46.75)

(-59.90, 52.84)

27

25

0

1

1

1

23

0

0

5

1

4

77.1

75.8

100

100

33.3

85.2

0.0

100

100

100

35

33

0

1

1

3

27

3

0

5

1

4

25

23

1

0

0

0

21

6

0

3

0

3

83.3

82.1

100

0.0

84.0

75.0

0.0

100

100

All

Enterobacteriaceae

Citrobacter freundii complex


Enterobacter asburiae


Escherichia coli


Proteus vulgaris group

Gram-negative pathogens other than Enterobacteriaceae

Comamonas testosteroni


30

28

1

0

0

1

25

8

1

3

0

3

ComparisonBetween Groups

Number of Patients

Pathogen 95% CIb for %

Difference

Differencea

(%)Number

ofClinicalCures

CureRate(%)

nNumberof

ClinicalCures

CureRate(%)

n

Meropenem(N=35)

CAZ-AVI + Metronidazole(N=30)


Table 4.11: Clinical Response at TOC for Patients Infected by Ceftazidime-Resistant Gram-Negative Pathogen (mMITT Analysis Set) – Indian Patients.124

ere were no emergent infections reported in the India subset. One patient in the CAZ-AVI plus metronidazole group (mMITT analysis set) was a clinical failure due to persistence (incomplete clinical resolution) at the EOT visit; at the TOC and LFU visits, there were no cases of clinical failure due to persistence. No cases of emergent infection or persistence were reported in the MITT or CE at TOC analysis sets.

4.4.3 Safety and tolerabilityBased on the data of Indian population enrolled in the RECLAIM study, a descriptive analysis of the safety and ecacy results in the Indian population sub-group was carried out and results were compared with the overall results in the global trial. In addition, the study also analysed the safety of CAZ-AVI with metronidazole in comparison with meropenem in the Indian patients by monitoring the number and severity of adverse events (AEs) during the study up to and including LFU visit.e safety analysis set included 125 Indian patients. In the overall population, the rate of AEs, including AEs with a fatal outcome, SAEs, and DAEs (Discontinuation of investigational product due to an AE) was similar across the 2 treatment groups.125 In Indian population, a comparable percentage of patients in both treatment groups experienced atleast 1 AE upto the EOT visit (76.7% and 55.6% in CAZ-AVI plus metronidazole groups respectively).

Overall, the percentage of patients who had at least 1 AE reported in the Indian population was higher compared to the overall population (67.7% and 55.6% in the CAZ-AVI plus metronidazole and meropenem groups, respectively) in the Indian subset compared to (42.0% and 36.9% in the CAZ-AVI plus metronidazole and meropenem groups, respectively) the overall population (Table 4.12).124 However, it is not possible to conclude that this is a true nding or is reective of a smaller denominator in the Indian population. e safety evaluation showed no new safety concerns in the Indian population; the safety ndings were in line with the previous known eects of ceftazidime and cephalosporins in general, and conrmed that the safety prole of CAZ-AVI is similar to that of ceftazidime.

Included patients infected by at least 1 ceftazidime-resistant Gram-negative pathogen. Clinical cure rate for the mMITT analysis set was dened as the number of patients with a clinical response of clinical cure at the TOC visit divided by the number of patients with clinical cure + clinical failure + indeterminate. Clinical response was based on surgical review evaluation if it was dierent from the investigator's assessment. Ceftazidime resistance included both the CLSI (M100-S22) breakpoint-dened resistant and intermediate categories. Percentages were based on the total number of patients in the subgroup (n).CAZ-AVI: Ceftazidime-avibactam. CI: Condence interval. CLSI: Clinical and Laboratory Standards Institute. mMITT: Microbiologically modied intent-to-treat. N: Total number of patients in the treatment group. n: Number of patients in category or analysis; TOC: Test of cure.a Dierence: dierence in clinical cure rates (CAZ-AVI + metronidazole group minus meropenem group).b CIs for group dierences were calculated using the unstratied Miettinen and Nurminen method.

Percentages were based on the total number of patients in the treatment group (N).AEs: Adverse events. CAZ-AVI: Ceftazidime-avibactam. CSR: Clinical study report. IP: Investigational product. EOT: End of treatment. LFU: Late follow-up. N: Number of patients in the treatment group. PT: Preferred term. SAE: Serious adverse events. SOC: System organ class.a Patients with multiple AEs were counted once for each SOC and/or PT.b Deaths due to disease progression were not presented here.c Action taken, IP permanently stopped. Included AEs and SAEs with an onset date and time on or after the date and time of rst dose and up to and including the EOT/LFU visit.

57

INSIDE PAGE

56

ComparisonBetween Groups

Number of Patients

Pathogen 95% CIb for %

Difference

Differencea

(%)Number

ofClinicalCures

CureRate(%)

nNumberof

ClinicalCures

CureRate(%)

n

Meropenem(N=35)

CAZ-AVI + Metronidazole(N=30)

-5.2

-9.3

0

(-36.20, 27.15)

(-41.98, 24.41)

11

11

78.6

78.6

2

14

14

0

11

9

100

73.3

69.2

All

Enterobacteriaceae


15

13

2

AE CategoryOverall patients

Number (%) of patientsa

Indian patients

CAZ-AVI +Metronidazole

(N=529)

Meropenem(N=529)

CAZ-AVI +Metronidazole

(N=62)

Meropenem(N=63)

EOT Visit

LFU Visit

35 (55.6)

0

1 (1.6)

2 (3.2)

1 (1.6)

35 (55.6)

0

1 (1.6)

2 (3.2)

1 (1.6)

42 (67.7)

1 (1.6)

1 (1.6)

1 (1.6)

1 (1.6)

44 (71.0)

1 (1.6)

1 (1.6)

1 (1.6)

1 (1.6)

195 (36.9)

1 (0.2)

20 (3.8)

7 (1.3)

25 (4.7)

227 (42.9)

5 (0.9)

40 (7.6)

7 (1.3)

36 (6.8)

222 (42.0)

4 (0.8)

26 (4.9)

14 (2.6)

19 (3.6)

243 (45.9)

8 (1.5)

42 (7.9)

14 (2.6)

30 (5.7)

Any AE

Any AE with outcome = deathb

Any SAE

Any AE leading to discontinuation of IPc

Any AE of severe intensity

Any AE

Any AE with outcome = deathb

Any SAE

Any AE leading to discontinuation of IPc

Any AE of severe intensity


Table 4.12: Adverse Event up to EOT and LFU Visit in Any Category (Safety Analysis Set).124

59

INSIDE PAGE

e percentage of patients who had at least 1 AE reported in the Indian population was higher compared to the overall population. is increase was not attributable to increases in frequency of individual events but distributed across SOCs (system organ class) with no obvious trend or pattern. e denominator of the Indian study population is too small to robustly demonstrate that this change in frequency is a true safety nding and these observations are assessed as unlikely to be due to a true treatment eect.e extended duration of treatment in the Indian population might also, in part, explain the increased frequency of AEs observed in the Indian population compared to the overall population. Overall, longer treatment duration was observed in the Indian patients than in the overall population: the majority of patients in the Indian population were treated for 11 to 14 days compared to 5 to 10 days in the overall population.

4.4.4 ConclusionsRECLAIM is the rst phase III study of ceftazidime-avibactam in adults with complicated intra-abdominal infections.125 Results of this study show non-inferiority versus meropenem for the treatment of complicated intra-abdominal infections caused by ceftazidime non-susceptible or ceftazidime-susceptible Gram-negative aerobic pathogens.e safety and ecacy outcomes in Indian population treated with CAZ-AVI as part of the RECLAIM study were in line with the global RECLAIM trial.124 Although there are inherent limitations to this analysis due to the subgroup size, it provides information on clinical ecacy and safety relevant for the intended use of CAZ-AVI in Indian patients. CAZ-AVI proved to be an eective option for critically patients with cIAI and may be considered an alternative to carbapenem in the ICU setting for the treatment of resistant pathogens.

4.5 REPRISEe ecacy and safety of ceftazidime-avibactam in patients with serious ceftazidime-resistant Gram-negative bacterial infections, including a small number with cIAI, have been evaluated in REPRISE, a prospective, international, randomized, open-label phase 3 study (NCT01644643) (discussed in detail in Section 5).6

58

5.1 Summary

e RECAPTURE programme of two prospective, multi-centre, randomised, double-blind, comparative phase 3 studies was designed to compare the ecacy and safety of ceftazidime-avibactam vs. doripenem plus placebo in adults with cUTI (including acute pyelonephritis).4

e REPRISE prospective, international, randomised, open-label phase 3 study was initiated to report on the ecacy and safety of ceftazidime-avibactam vs. best available therapy (BAT) in patients with serious ceftazidime-resistant Gram-negative bacterial infections (cUTI and cIAI). e ecacy prole of ceftazidime-avibactam was similar to BAT with similar clinical cure rates and numerically higher per-patient favorable microbiological response rates. e safety and tolerability prole of ceftazidime-avibactam reported here is broadly similar to the recognised prole of ceftazidime alone.6

5.2 Clinical development programme – RECAPTURE and REPRISEe ecacy, safety and tolerability of ceftazidime 500 mg-avibactam 125 mg i.v. every 8 h compared with imipenem-cilastatin 500 mg i.v. every 6 h for 7–14 days was initially evaluated in a phase 2, prospective, randomised, investigator-blind, active-controlled trial in 135 hospitalised adults with cUTI (NCT00690378).126 e primary ecacy endpoint was a favorable microbiological response at the TOC visit, 5–9 days after the last dose of the study therapy, in the ME population.126

In this phase 2 study, the predominant uropathogen isolated was E. coli, which was recovered in 92.6% (25/27) of patients in the ceftazidime-avibactam group and 94.3% (33/35) of patients in the imipenem-cilastatin group.126 e median duration of i.v. therapy was 5 and 6 days in the ceftazidime-avibactam and imipenem-cilastatin treatment groups, respectively, and the median duration of i.v. plus oral therapy was 11 and 12 days, respectively.126 A favorable microbiological response in the ME population at the TOC visit was observed in 70.4% (19/27) of patients in the ceftazidime-avibactam group and 71.4% (25/35) of patients in the imipenem-cilastatin group (observed dierence -1.1% [95% CI -27.2, 25.0]) (Figure 5.1).126 Among patients with ceftazidime-resistant uropathogens, a favorable microbiological response at the TOC visit was achieved in 85.7% (6/7) and 81.8% (9/11) of patients in the ceftazidime-avibactam and imipenem-cilastatin groups, respectively.126

5. Clinical and safety prole of ceftazidime-avibactam in complicated urinary tractinfections (cUTI) including pyelonephritis


61

INSIDE PAGE

Figure 5.1: Proportion (95% CI) of cUTI patients with favorable microbiological response (ME population) from a phase 2 study of ceftazidime-avibactam versus imipenem-cilastatin.126

60

CI: Condence interval. cUTI: Complicated urinary tract infection. I.V.: Intravenous. LFU: Late follow-up. ME: Microbiologically evaluable. TOC: Test-of-cure.

e incidence of AEs over the course of the study was lower in the ceftazidime-avibactam group (67.6% [46/68] of patients) compared with the imipenem-cilastatin group (76.1% [51/67] of patients). e most common AEs in both groups included: constipation, diarrhea, abdominal pain, headache, anxiety and injection/infusion site reactions.126

Although this phase 2 study was limited in size, included only a relatively small proportion of patients with a pathogen isolated at baseline in the ME population in each treatment arm and a small number of patients with ceftazidime-resistant or P. aeruginosa infections, the results provided promising evidence that ceftazidime-avibactam may be eective in patients with cUTI.126 e REPRISE prospective, international, randomized, open-label phase 3 study was initiated to report on the ecacy and safety of ceftazidime-avibactam in patients with serious ceftazidime-resistant Gram-negative bacterial infections (cUTI and cIAI).6

5.3 RECAPTURERECAPTURE 1 (NCT01595438) and RECAPTURE 2 (NCT01599806) are two identically designed studies that have been analysed as a single pooled dataset (Figure 5.2).4

e primary objective of these studies was to assess the non-inferiority of ceftazidime-avibactam compared with doripenem plus placebo on co-primary endpoints (FDA) (Proportion of patients with resolution of UTI specic symptoms, proportion of patients with resolution/improvement of ank pain) in the mMITT population. e EMA primary endpoint was the proportion of patients with a favorable per-patient microbiological response (ie, eradication) at TOC in the mMITT population.4

Resp

onse

rate

(%)

100

90

80

70

60

50

40

30

20

10

0End i.v.

96.2

(80.

4, 9

9.9)

100.

0 (8

9.7,

100

.0)

70.4

(49.

8, 8

6.2)

71.4

(53.

7, 8

5.4)

57.7

(36.

9, 7

6.6)

60.0

(60.

0, 7

7.3)

Ceftazidime-avibactam (n=27) Imipenem-cilastatin (n=35)

TOC visit LFU visit

Figure 5.2: RECAPTURE 1 and 2 – phase 3 study design.4

EOT: End-of-treatment. I.V.: Intravenous. LFU: Late follow-up. TOC: Test-of-cure.

Qualifying patients may switch to oral ciprooxacin orsulfamethoxazole-trimethoprim for those with

a uoroquinolone-resistant pathogen after at least 5 full days of iv. study therapy

iv., q8 hoursWithin 24 h of

the last dose of the iv.study therapy

Duration of antibiotic treatment is 10 days unless the patient is bacteremic at study entry.erapy may be extended to 14 days in bacteremic patients.

21-25 days afterrandomization

45-52 days afterrandomization

Day 1Randomization

(Baseline)


2000/500 mg

Doripenem500 mg

Day - 1 to 0Eligibility/screening

EOT (i.v.)End-of-Treatment

TOCTest-of-Cure

LFULate Follow-Up


63

Dose modications were made for patients with renal impairment as following: CrCl (mL/min) 50–31 ceftazidime-avibactam 1000-250 mg every 12 hours; CrCl 30–16 ceftazidime-avibactam 1000-250 mg every 24 hours; CrCl 15–10 ceftazidime-avibactam 500-125 mg every 24 hours.127

Co-primary endpoints dened for the FDA were: (1) the proportion of patients with resolution of UTI-specic symptoms, except ank pain, with resolution or improvement in ank pain from baseline at day 5 (patient-assessed); (2) the proportion of patients with both microbiological eradication and resolution of UTI-specic at TOC (21–25 days post-randomisation) in the mMITT population. e primary endpoint dened for the European Medicines Agency (EMA) was the proportion of patients with per patient microbiological response eradication at TOC in the mMITT population.4

Secondary endpoints included (1) per-patient microbiological response at end of i.v. study treatment (EOT[IV]) and late follow-up (LFU; 45–52 days post-randomisation); per-patient and per-pathogen microbiological response at TOC and LFU in patients with ≥1 ceftazidime- resistant or only ceftazidime-susceptible pathogens isolated at baseline; investigator- determined clinical cure at EOT(IV), TOC, and LFU; sustained clinical cure at LFU; and safety.4

Ceftazidime resistance was dened as a central microbiology reference laboratory MIC ≥ 8 µg/mL for Enterobacteriaceae or ≥16 µg/mL for Pseudomonas aeruginosa, or local laboratory disk diusion diameter (from a 30 µg ceftazidime disk) of ≤20 mm for Enterobacteriaceae and ≤17 mm for P. aeruginosa.4

5.3.1 Baseline characteristicsA total of 1,033 patients were enrolled and randomly allocated to receive either ceftazidime-avibactam (n=516) or doripenem (n=517) and 1,020 received ≥1 dose of study drug (ceftazidime-avibactam, n=511; doripenem, n=509).4 e mMITT population comprised of 810 patients.Patients’ demographic, clinical and disease characteristics at baseline were generally similar between the treatment groups (Tables 5.2 and 5.3).4 Of the 810 patients in the mMITT population, 227 (28.0%) had cUTI without pyelonephritis and 583 (72.0%) had acute pyelonephritis (Table 5.3).Most patients (801/810 [98.9%]) had a single baseline uropathogen; nine patients each had two pathogens.4 e majority of patients were infected with Enterobacteriaceae; E. coli was the most frequently isolated pathogen from urine and blood.4

62

1 Black or African American, Asian, American Indian, Alaska native or other.cUTI: Complicated urinary tract infection. mMITT: Microbiologically modied intention-to-treat. SD: Standard deviation.

Table 5.2: RECAPTURE – key patient characteristics at baseline (mMITT population)4

Cestazidime-avibactam(n=393)

Doripenem (n=417)

53.3 (18.6)

293 (70.3)

351 (84.2)

66 (15.8)

26.3 (5.6)

379 (90.9)

35 (8.4)

3 (0.7)

51.4 (20.2)

272 (69.2)

321 (81.7)

72 (18.3)

26.2 (5.9)

350 (89.1)

42 (10.7)

1 (0.3)


Female, n (%)

Race, n (%)

White

Other1

Body mass index (kg/m2), mean (SD)

Renal status, creatinine clearance (mL/min), n (%)

>50

31–50

<31

INSIDE PAGE


Patients were enrolled in the studies based on the inclusion and exclusion criteria summarized in Table 5.1.

Table 5.1: Key inclusion and exclusion criteria for the RECAPTURE 1 and 2 trials.4, 127

CFU: Colony-forming unit. I.V.: Intravenous. UTI: Urinary tract infection. WBC: White blood cells.


Age 18–90 years

Pyuria with ≥10 WBCs and a positive urine culture within 48 h of enrolment containing ≥105 CFU/mL of a recognised uropathogen known to be susceptible to i.v. study therapy (ceftazidime-avibactam and doripenem)

Demonstrates either acute pyelonephritis or complicated lower UTI without pyelonephritis

Urine pathogen is a Gram-positive pathogen or a uropathogen resistant to ceftazidime-avibactam or doripenem

Urine culture at study entry isolates ≥2 microorganisms regardless of colony count or patient has a conrmed fungal UTI

Haemodialysis or peritoneal dialysis or renal transplant

Immunocompromised

Considered unlikely to survive the 6- to 8-week study period or has a rapidly progressive or terminal illness including septic shock which is associated with a high risk of mortality

Complete obstruction of any portion of the urinary tract, perinephric or intrarenal abscess, or prostatitis; UTI symptoms potentially attributable to another process; urinary diversion or vesicoureteral reux; creatinine clearance (CrCl) ≤30 mL/minute (including patients on dialysis)

a Includes pathogens reported with a combined frequency of ≥10 patients. Patients could have >1 pathogen. Multiple isolates of the same species from the same patient are counted only once. Other pathogens isolated in <10 patients were Citrobacter freundii complex (n=6 overall), Citrobacter koseri (n=2), Enterobacter aerogenes (n=2), Klebsiella oxytoca (n=7), Morganella morganii (n=4), Serratia marcescens (n=3), Proteus vulgaris group (n=2), Providencia rettgeri (n=2), and Burkholderia cepacia complex (n=1). cUTI: Complicated urinary tract infection. ESBL: Extended-spectrum ß-lactamase. mMITT: Microbiologically modied intention-to-treat.

Table 5.3: RECAPTURE– disease characteristics at baseline (mMITT population).4

5.3.2 Treatment switchingIn the mMITT population, 468 (57.7%) patients switched to oral antibiotics after day 5; 188 and 207 ceftazidime-avibactam and doripenem patients, respectively, switched to ciprooxacin, 23 and 33 switched to sulfamethoxazole-trimethoprim, and 10 and 7 received alternative antibiotics.4

5.3.3 Clinical ecacye proportions of patients with patient-assessed symptom resolution at day 5 (FDA co-primary endpoint 1) was 70.2% and 66.2% [4.0 (95% CI −2.39, 10.42)], and the proportion of patients with both patient-assessed symptom resolution and microbiological eradication at TOC (FDA co-primary endpoint 2) was 71.2% and 64.5%, in the ceftazidime-avibactam group and doripenem group, respectively [6.7 (95% CI 0.30, 13.12)] (Table 5.4).4 e proportion of patients with microbiological eradication at TOC (EMA primary endpoint) was 77.4% and 71.0%, in the ceftazidime-avibactam group and doripenem group, respectively (6.4 [95% CI 0.33, 12.36]).4

Based on pre-specied lower limits for 85% CI, non-inferiority of ceftazidime-avibactam vs. doripenem was demonstrated for the FDA co-primary endpoints and the EMA primary endpoint.4 e lower limit of the 2-sided 95% CI for the treatment dierence for the EMA primary endpoint was also >0%, indicating a statistically signicant dierence of ceftazidime-avibactam at the 5% signicance level.4

Across treatment groups, fewer patients with cUTI without pyelonephritis achieved the primary endpoints compared with those with acute pyelonephritis.4

Subgroup analyses of the primary endpoints were largely consistent across various baseline patient characteristics, with the point estimates for treatment dierence generally favoring ceftazidime-avibactam.4 Exceptions where the point estimates favoured doripenem were: bacteraemia for FDA co-primary endpoint 1 and moderate renal impairment (CrCl 30–50 mL/minute) for FDA co-primary endpoint 2 and the EMA primary endpoint, dierence in symptomatic resolution rate at day 5 (65.8% and 72.7%, in the ceftazidime-avibactam group and doripenem group, respectively, for patients with bacteraemia; 70.7% and 65.6%, in the ceftazidime-avibactam group and doripenem group, respectively, for patients without bacteraemia);4 and moderate renal impairment (CrCl 30–50 mL/min) for FDA co-primary endpoint 2, dierence in favorable combined symptomatic and microbiological response rates at TOC (66.7% and 71.4%, in the ceftazidime-avibactam group and doripenem group, respectively)4 and the EMA primary endpoint, dierence in per-patient favorable microbiological response rate at TOC (69.0% and 77.1%, in the ceftazidime- avibactam group and doripenem group, respectively).4, 127

e higher microbiological eradication rate at TOC with ceftazidime-avibactam vs. doripenem (EMA primary endpoint) was maintained at LFU.4 Among patients with ceftazidime non-susceptible pathogens, eradication rates were similar for ceftazidime- avibactam and doripenem at TOC, and numerically higher for ceftazidime-avibactam at LFU; for ceftazidime susceptible pathogens, eradication rates at TOC and LFU were numerically higher with ceftazidime-avibactam4 than those treated with doripenem.Investigator-determined clinical cure rates were high and similar across treatment groups (Table 5.4).4 Clinical cure rates for patients with ceftazidime-resistant E. coli and K. pneumoniae were numerically higher for ceftazidime-avibactam than for doripenem; those for ceftazidime-resistant E. cloacae and P. aeruginosa were numerically higher for doripenem.4

6564


Doripenem (n=417)

121 (29.0)

296 (71.0)

39 (9.4)

31 (7.4)

33 (7.9)

27 (6.5)

396 (95.0)

306 (73.4)

56 (13.4)

13 (3.1)

13 (3.1)

82 (19.7)

21 (5.0)

20 (4.8)

106 (27.0)

287 (73.0)

41 (10.4)

33 (8.4)

38 (9.7)

28 (7.1)

376(95.7)

292 (74.3)

44 (11.2)

17 (4.3)

11 (2.8)

73 (18.6)

18 (4.6)

18 (4.6)

Diagnosis, n (%)

cUTI without pyelonephritis

Pyelonephritis

With ≥1 complicating factor

Meeting symptom criteria for cUTI

Bacteraemia, yes, n (%)

Prior systemic antibiotic use, n (%)

Baseline pathogen in urine, n (%)a

Enterobacteriaceae

Escherichia coli


Proteus mirabilis


ESBL-positive Enterobacteriaceae

Other Gram-negative bacteria


INSIDE PAGE


a Symptomatic resolution of symptoms of frequency, urgency, dysuria, and suprapubic pain with resolution or improvement in ank pain, based on the patient-reported symptom assessment questionnaire (PSAQ). b Co-primary endpoints for the FDA. Non-inferiority concluded if the lower limit of the 95% CI at TOC was greater than −12.5%. e FDA non-inferiority margin was a lower limit of the 95% CI greater than −10.0%. c Symptomatic resolution of all symptoms (frequency, urgency, dysuria, suprapubic pain, and ank pain) based on the PSAQ. d Primary endpoint for the EMA. Non-inferiority concluded if the lower limit of the 95% CI at TOC was greater than −12.5%. e Ceftazidime resistance was dened as a central microbiology reference laboratory minimum inhibitory concentration ≥8 µg/mL for Enterobacteriaceae or ≥16 µg/mL for Pseudomonas aeruginosa, or local laboratory disk diusion diameter (from a 30 µg ceftazidime disk) of ≤20 mm for Enterobacteriaceae and ≤17 mm for P. aeruginosa. Nine patients were not included in either subset (ceftazidime-resistant or ceftazidime-susceptible) because no susceptibility tests were performed (6 patients) or baseline blood or urine susceptibility results were missing (3 bacteraemic patients). f One patient in the doripenem group had 2 ceftazidime-resistant pathogens isolated at baseline. CI: Condence interval. EMA: European Medicines Agency. EOT(IV): End of intravenous treatment. FDA: (US) Food and Drug Administration. LFU: Late follow–up (45–52 days after randomisation). mMITT: Microbiologically modied intention-to-treat. TOC: Test-of-cure (21–25 days after randomisation).

Table 5.4: RECAPTURE– primary and secondary ecacy endpoints (mMITT population).4

6766

Difference,% (95% CI)

276 (70.2)

280(71.2)

304 (77.4)

332 (84.5)

304 (77.4)

374 (95.2)

268 (68.2)

47/75 (61.3)

46/75 (61.3)

256/316 (81.0)

221/316 (69.9)

Doripenem(n=417)


(n=393)

FDA co-primary endpoints

Patient-assessed symptomatic resolutiona at day 5b

Combined symptomatic resolutiona and favorable per-patient microbiological response at TOCb

Per-patient favourable microbiological response at TOC

Patient-reported symptomatic resolution at TOC

EMA primary endpoint

Per-patient favorable microbiological response at TOCd

Secondary endpoints

Microbiological

Per-patient favorable microbiological response at EOT (IV)

Per-patient favorable microbiological response at LFU

Per-patient favorable microbiological response at TOC in patients with a ceftazidime-resistant pathogene

Per-patient favorable microbiological response at LFU in patients with a ceftazidime-resistant pathogene

Per-patient favorable microbiological response at TOC in patients with a ceftazidime-susceptible pathogene

Per-patient favorable microbiological response at LFU in patients with a ceftazidime-susceptible pathogene

INSIDE PAGE

Patients, n (%)

4.0 (–2.39, 10.42)

6.7 (0.30, 13.12)

6.4 (0.33, 12.36)

–1.9 (–6.78, 3.02)

6.4 (0.33, 12.36)

0.4 (–2.7, 3.56)

7.3 (0.68, 13.81)

2.0 (–13.18, 16.89)

16.1 (0.50, 30.89)

8.0 (1.5, 14.48)

5.8 (–1.46, 13.05)

276 (66.2)

269 (64.5)

296 (71.0)

360 (86.3)

296 (71.0)

395 (94.7)

254 (60.9)

51/84f (60/7)

38/84 (45.2)

238/326 (73.0)

209/326 (64.1)

Difference,% (95% CI)

378 (96.2)

355 (90.3)

335 (85.2)

330/355 (93.0)

287/316 (90.8)

67/75 (89.3)

Doripenem(n=417)


(n=393)

Clinical

Investigator-determined clinical cure

EOT(IV)

TOC

LFU

Sustained clinical cure at LFU in patients who were cured at TOC

Investigator-determined clinical cure at TOC in patients with a ceftazidime-susceptible pathogene

Investigator-determined clinical cure at TOC in patients with a ceftazidime-resistant pathogene

Patients, n (%)

–1.4 (–4.07, 1.02)

–0.1 (–4.23, 4.03)

1.3 (–3.71, 6.30)

–0.6 (–3.5, 2.3)

0.3 (–4.3, 4.9)

0.0 (–10.4, 10.1)

407 (97.6)

377 (90.4)

350 (83.9)

345/377 (91.5)

295/326 (90.5)

75/84f

(89.3)

5.3.4 Safety and tolerabilityMedian durations of i.v. therapy (safety population) were 7 and 8 days for ceftazidime- avibactam and doripenem, respectively; 992 of 1,020 (97.3%) patients received 5-14 days of i.v. treatment.4 Up to LFU, 185 of 511 (36.2%) and 158 of 509 (31.0%) ceftazidime- avibactam and doripenem recipients, respectively, had experienced at least 1 AE.4

AEs were predominantly mild or moderate in intensity, and generally balanced across groups.4 21 (4.1%) and 12 (2.4%) patients treated with ceftazidime-avibactam and doripenem, respectively, had ≥1 SAE, of which most occurred after the last dose of i.v. treatment.4 Only 7 (1.4%) and 6 (1.2%) patients discontinued the study drug due to AEs, and no deaths occurred.4 3 AEs of Clostridium difcile colitis occurred in 2 (0.4%) ceftazidime- avibactam-treated patients; none were reported for doripenem.4

No new safety concerns were identied and no clinically meaningful trends in laboratory values, electrocardiographic parameters, physical examination, or vital signs were identied.4


cIAI: Complicated intra-abdominal infection. cUTI: Complicated urinary tract infection. I.V.: Intravenous. TOC: Test-of-cure.

APACHE II: Acute Physiology and Chronic Health Evaluation II. CFU: Colony-forming units. cIAI: Complicated intra-abdominal infection. CLSI: (US) Clinical and Laboratory Standards Institute. cUTI: Complicated urinary tract infection. EUCAST: European Committee on Antimicrobial Susceptibility Testing. LFT: Liver function test.

Dose modications were made for patients with renal impairment as following: CrCl (mL/min) 50–31 ceftazidime-avibactam 1000-250 mg every 12 h; CrCl 30–16 ceftazidime-avibactam 1000-250 mg every 24 h; CrCl 15–6 ceftazidime-avibactam 500-125 mg every 24 h. Patients with cIAI who were randomly allocated to ceftazidime-avibactam also received i.v. metronidazole 500 mg administered as a 60-min infusion every 8 h, immediately after the ceftazidime-avibactam infusion, for anaerobe coverage.6, 129

Ceftazidime-resistant Enterobacteriaceae and P. aeruginosa were dened as having ceftazidime MIC values of ≥8 mg/L and ≥16 mg/L, respectively.6

e primary endpoint was assessment of clinical response at TOC visit 7–10 days after last infusion of study therapy in the mMITT population. Secondary endpoints included the proportions of patients with clinical cure in the mMITT and CE populations.6

5.3.5 ConclusionsIn the RECAPTURE study, non-inferiority was demonstrated for ceftazidime-avibactam vs. doripenem for the treatment of hospitalized patients with cUTI or acute pyelonephritis based on FDA- and EMA-dened endpoints. e CI around the treatment dierence for microbiological eradication at TOC (EMA primary endpoint) also demonstrated a statistically signicant dierence in ceftazidime-avibactam treatment over doripenem at the 5% signicance level.4 Eradication rates in both groups were lower among patients with ceftazidime-resistant pathogens compared with the overall population. Investigator- determined clinical cure rates at TOC were approximately 90% across groups, and similar for patients with ceftazidime-resistant and ceftazidime-susceptible pathogens.4 e safety prole of ceftazidime-avibactam was consistent with that of ceftazidime alone.6

5.4 REPRISEe ecacy and safety of ceftazidime-avibactam in patients with serious ceftazidime- resistant Gram-negative bacterial infections (cUTI and cIAI) have been evaluated in REPRISE, a pathogen-directed prospective, international, randomized, open-label phase 3 study (NCT01644643) (Figure 5.3).6

e primary objective of REPRISE was to estimate the clinical response to ceftazidime- avibactam and BAT at TOC in the treatment of selected serious infections caused by ceftazidime-resistant Gram-negative pathogens.6

Figure 5.3: REPRISE – phase 3 study design.6

Patients were enrolled in the study based on the inclusion and exclusion criteria summarised in Table 5.5.

Table 5.5: Key inclusion and exclusion criteria for the REPRISE trial.6, 128

6968

INSIDE PAGE


Age 18–90 years Patient had a ceftazidime-resistant Gram-negative causative pathogen that was

isolated from an appropriate culture within 5 days prior to study entry (susceptibility results are intermediate or resistant using CLSI methodology and isolates that are resistant using EUCAST methodology)

Patient who had received appropriate prior empiric antibacterial therapy was to meet at least one of the following criteria:

Worsening of objective symptoms or signs of infection after at least 48 h of appropriate therapy

Lack of improvement of objective symptoms or signs of infection after at least 72 h of appropriate therapy

cUTI Pathogen was to be obtained from a positive urine culture at ≥105 CFU/mL Patient had pyuria in the 5 days prior to screening Patient demonstrated either acute pyelonephritis or complicated lower UTI

without pyelonephritis cIAI Pathogen was to be isolated from an abdominal source obtained during a

surgical intervention Patient to have at least one of eight specied IAI diagnoses during surgical

intervention Patient had specied signs or symptoms of cIAI

APACHE II score >30 (patients with cIAI only)

Infection due to Gram-negative bacterial species that was unlikely to respond to ceftazidime- avibactam treatment

Unlikely to respond to 5–21 days of study treatment

Haemodialysis or peritoneal dialysis

Estimated creatinine clearance <6 mL/min

Acute hepatitis in the prior 6 months or hepatic failure

Specied LFT abnormalities Neutrophil count

<500/mm3

1:1 randomisationEOT (end-of-treatment)

within 24 h last i.v. infusion

Follow-up 1 Follow-up 2

Follow-up 1

7-10 days after last infusion

21-25 daysafter randomization



cUTI:

cIAI:

(5-21 days of i.v. therapy)

TOCHospitalizedpatients aged≥18 years with

cIAI or cUTIcaused by aceftazidime-

resistantGram-negative

pathogen

Ceftazidime-avibactam(+metronidazole if cIAI)

(2000 mg ceftazidime-500 mg avibactam

+500 mg metronidazole)

Best available therapy(as specied and documented

before randomization)


71

INSIDE PAGE

5.4.1 Baseline characteristicsA total of 333 patients were enrolled and randomly allocated to receive either ceftazidime-avibactam (n=165 [153 with cUTI and 12 with cIAI]) or BAT (n=168 [153 with cUTI and 15 with cIAI]). Most of the patients in the BAT group (97%) received a carbapenem antibiotic and the majority (96%) received this as monotherapy.6

Patients’ demographic, clinical and disease characteristics at baseline were generally similar between the treatment groups in cUTI, and also broadly similar in cIAI (although patient numbers were small) (Tables 5.6 and 5.7).6 e majority of patients were infected with Enterobacteriaceae, most commonly K. pneumoniae and E. coli. In 9 of the 10 patients with cUTI and bacteremia, the isolates were E. coli or K. pneumoniae (the same pathogens as were isolated in their urine).6

Table 5.6: REPRISE – key patient characteristics at baseline (mMITT population).6

70

1 Black or African American, Asian or other.BAT: Best available therapy. cIAI: Complicated intra-abdominal infection. cUTI: Complicated urinary tract infection. mMITT: Microbiologically modied intention-to-treat. SD: Standard deviation.

a Pathogens identied in blood were Klebsiella pneumoniae, Escherichia coli, Bacteroides fragilis and Clostridium ramosum. b Other pathogens identied in urine were: Citrobacter freundii complex, Enterobacter aerogenes, Klebsiella oxytoca, Klebsiella ozaenae, Morganella morganii, Proteus mirabilis, Proteus rettgeri, Providencia stuartii, Raoultella terrigena, Serratia marcescens and Ochrobactrum anthropi. Other pathogens identied in intra-abdominal site were: C. freundii, Gram-positive aerobes and anaerobes. BAT: Best available therapy. cIAI: Complicated intra-abdominal infection. cUTI: Complicated urinary tract infection. mMITT: Microbiologically modied intention-to-treat. NA: Not applicable.

BAT(n=11)

cIAIcUTI

Cestazidime-avibactam plusmetronidazole

(n=10)

BAT(n=137)


(n=144)

68.4 (11.1)

4 (36)

11 (100.0)

0

28.6 (4.6)

6 (55)

3 (27)

2 (18)

0

49.9 (16.1)

6 (60.0)

9 (90.0)

1 (10.0)

25.2 (6.3)

10 (100)

0

0

0

61.3 (15.3)

63 (46.0)

131 (96)

6 (4)

28.0 (5.8)

113 (82)

18 (13)

5 (4)

1 (1)

64.3 (14.6)

64 (44)

136 (94)

8 (6)

28.1 (5.5)

118 (82)

19 (13)

4 (3)

3 (2)


Female, n (%)

Race, n (%)

White

Other1


>50

31–50

16–30

6–15

Renal status, creatinine clearance (mL/min), n (%)

Table 5.7: REPRISE – disease characteristics at baseline (mMITT population).6

BAT(n=11)

cIAIcUTI

Cestazidime-avibactam plusmetronidazole

(n=10)

BAT(n=137)


(n=144)

NA

NA

4 (36)

1 (9)

0

2 (12)

4 (36)

0

4 (36)

5 (45)

2 (18)

11 (100)

11 (100)

6 (55)

3 (27)

1 (9)

1 (9)

NA

NA

2 (20)

1 (10)

2 (20)

3 (30)

2 (20)

0

4 (40)

4 (40)

2 (20)

10 (100)

9 (90)

4 (40)

5 (50)

3 (30)

1 (10)

70 (51)

67 (49)

NA

NA

NA

NA

NA

6 (4)

131 (96)

6 (4)

0

63 (46)

132 (96)

57 (42)

65 (47)

6 (4)

5 (4)

57 (40)

87 (60)

NA

NA

NA

NA

NA

4 (3)

139 (97)

4 (3)

1 (1)

72 (50)

131 (91)

59 (41)

55 (38)

8 (6)

14 (10)

Diagnosis cUTI, n (%)

Acute pyelonephritis

cUTI without pyelonephritis

Diagnosis cIAI, n (%)

Cholecystitis




Intra-abdominal abscess (≥1)

Bacteraemia, yes, n (%)a

Infection type, n (%)

Monomicrobial

Polymicrobial (2 pathogens)

Polymicrobial (≥3 pathogens)

Prior antibiotic use, n (%)

Enterobacteriaceae

Escherichia coli




Baseline pathogen in urine (cUTI) or intra-abdominal site (cIAI), n (%)b


INSIDE PAGE

BAT: Best available therapy. CI: Condence interval. cIAI: Complicated intra-abdominal infection. cUTI: Complicated urinary tract infection. mMITT: Microbiologically modied intention-to-treat. TOC: Test-of-cure.

BAT: Best available therapy. CI: Condence interval. cIAI: Complicated intra-abdominal infection. cUTI: Complicated urinary tract infection. mMITT: Microbiologically modied intention-to-treat. TOC: Test-of-cure.

73

5.4.2 Clinical ecacyOverall clinical cure rates at TOC in the mMITT population (cUTI and cIAI combined) were 91% (140/154; 95% CI 85.6, 94.7) for ceftazidime-avibactam and 91% (135/148; 95% CI 85.9, 95.0) for BAT, respectively.6

e proportions of patients with cIAI with clinical cure at TOC were 80% (8/10; 95% CI 47.9, 95.6) in the ceftazidime-avibactam plus metronidazole group and 55% (6/11; 95% CI 27.0, 80.0) in the BAT group (Figure 5.4). Per-patient microbiological outcomes for patients with cIAI were presumed from clinical response (Figure 5.5). However, the CIs were very wide due to the small number of patients with cIAI enrolled.6

Clinical cure rates at TOC were similar between the two treatment groups in patients with cUTI (ceftazidime-avibactam, 92% [132/144; 95% CI 86.3, 95.4] and BAT 94% [129/137; 95% CI 89.3, 97.2]) (Figure 5.4).6 e proportion of patients with a favorable microbiological response at TOC in the cUTI population were higher with ceftazidime-avibactam (82% [118/144; 95% CI 75.1, 87.6]) than with BAT (64% [88/137; 95% CI 56.0, 71.9]), with the 95% CIs in each treatment group not overlapping (Figure 5.5).6 In terms of later time points, clinical cure rates decreased over time in both treatment groups, but remained ≥85% with ceftazidime-avibactam, generally achieving similar clinical cure rates to BAT at each visit.6 In line with the natural history of cUTI, the microbiological response was lower at subsequent visits after TOC. However, at each subsequent visit, the microbiological response rates were consistently higher for ceftazidime-avibactam than for BAT.6

Figure 5.4: Clinical response rate (95% CI) at TOC (mMITT population).6, 130

5.4.3 Safety and tolerabilitye median duration of ceftazidime-avibactam and BAT exposure was 10.5 and 12 days in patients with cIAI and 10 and 10 days in patients with cUTI, respectively.130 By the time of the last follow-up visit (28–35 days post-randomisation), 31% (51/164) of patients in the ceftazidime-avibactam group and 39% (66/168) of patients in the BAT group had experienced AEs, with SAEs in 5.5% and 6.0%, respectively.6, 130 Gastrointestinal disorders were the most frequently reported AEs with both ceftazidime-avibactam (13%) and BAT (18%). ree AEs leading to discontinuation of study drug occurred in one (1%) patient in the ceftazidime-avibactam group and two (1%) patients in the BAT group. Seven patients experienced an AE with an outcome of death, three in the ceftazidime-avibactam group and four in the BAT group, none of which were considered related to study drug by the investigators. e incidence of AEs considered related to study drug by the investigator was low in both treatment groups (9% for ceftazidime-avibactam and 7% for BAT). No new safety concerns were identied for ceftazidime-avibactam.6

5.4.4 ConclusionsIn the REPRISE study, the treatment of serious ceftazidime-resistant Gram-negative cUTIs with ceftazidime-avibactam produced similar clinical cure rates to treatment with BAT and numerically higher per-patient favorable microbiological response rates. In cIAI, clinical and microbiological response rates were also high for ceftazidime-avibactam and in line with those observed with BAT although the number of patients with cIAI in the REPRISE study was small. Overall, the safety and tolerability prole of ceftazidime-avibactam was broadly similar to ceftazidime alone.6

Figure 5.5: Per-patient favorable microbiological response rate (95% CI) at TOC (mMITT population).6, 130

72

Ceftazidime-avibactam : BAT

(140/154) 91% vs 91% (135/148)

(132/144) 92% vs 94% (129/137)

Clinical response rate (%)

0 10 20 30 40 50 60 70 80 90 100

cUTI+clAI

cIAI

cUTI

(8/10) 80% vs 55% (6/11)

Ceftazidime-avibactam : BAT

(126/154) 82% vs 64% (94/148)

(118/144) 82% vs 64% (88/137)

Microbiological response rate (%)

0 10 20 30 40 50 60 70 80 90 100

cUTI+clAI

cIAI

cUTI

(8/10) 80% vs 55% (6/11)


75

INSIDE PAGE

6.1 Summary

e REPROVE prospective, international, randomised, multi-center, parallel-group, double-blind, double-dummy, non-inferiority, phase 3 study reports on the ecacy and safety of ceftazidime-avibactam vs. meropenem, in patients with HAP/VAP. e ecacy prole of ceftazidime-avibactam was non-inferior to meropenem. e safety prole of ceftazidime-avibactam was consistent with that previously noted with ceftazidime alone and with the known prole of ceftazidime-avibactam in patients with complicated intra-abdominal or urinary tract infections.5

6.2 REPROVE5

REPROVE (NCT01808092) investigated the non-inferiority of ceftazidime 2000 mg-avibactam 500 mg i.v. for 2 hours every 8 hours, to meropenem, 1000 mg i.v. for 30 min every 8 hours for 7–14 days, in 817 adults with HAP/VAP. HAP was dened as acquired pneumonia with onset 48 h or longer after admission or less than 7 days after discharge from inpatient care. VAP was dened as parenchymal lung infection with onset 48 h or longer after endotracheal intubation and mechanical ventilation. e primary ecacy endpoint was the proportion of patients in the cMITT and CE co-primary populations who were clinically cured at the TOC visit, 21–25 days after randomisation. For primary ecacy endpoints, ceftazidime-avibactam was considered non-inferior if the lower limit of the two-sided 95% CI for treatment dierences was greater than -12.5%.

Figure 6.1: REPROVE – phase 3 study design5

Patients were enrolled in the study based on the inclusion and exclusion criteria summarised in Table 6.1.e REPROVE protocol was amended to increase the ceftazidime-avibactam dose in patients with moderate or severe renal impairment based on the outcomes of RECLAIM 1 and 2, which suggested that the original dosing regimen could have been an underdose in those patients.5 In patients with CrCl > 50 mL/min, the unadjusted dose (ceftazidime- avibactam 2000-500 mg and meropenem 1000 mg) was used throughout the infusion schedule. In patients with CrCL <50 mL/min, ceftazidime-avibactam dose was 1000-250 mg and meropenem dose was 1000 mg; in patients with CrCl <30 mL/min ceftazidime- avibactam dose was 750-187.5 mg and meropenem dose was 1000 mg and in CrCl <25 ceftazidime-avibactam dose was 750-187.5 mg and meropenem dose was 500 mg.132

Table 6.1: Key inclusion and exclusion criteria for the REPROVE trial.5, 132

6. Clinical and safety prole of ceftazidime-avibactam in hospital-acquired pneumonia including ventilator-associated pneumonia


18-90 years of age

For female patients, at least one of the following criteria were met:

Surgically sterilised

Age ≥50 and postmenopausal1

Age <50 and postmenopausal2

Negative pregnancy test and avoidance of pregnancy3

Onset of symptoms ≥ 48 h after admission or <7 days after discharge from an inpatient acute or chronic care facility

New/worsening inltrate on chest X-ray obtained with 48 h prior to randomisation

At least one of the following systemic signs:

Temperature >38°C or <35°C

WBC count >10,000 cells/mm3 or <4500 cells/mm3, or >15% band forms

At least 2 of the following respiratory signs/symptoms:

New onset or worsening of cough

Purulent sputum production or endotracheal secretions

Pneumonia/pulmonary consolidation on auscultation

Dyspnoea, tachypnoea, hypoxaemia

Need for mechanical ventilation or requirement for changes in ventilator to enhance oxygenation

• HAP caused by S. aureus and/or S. pneumoniae without concomitant Gram-negative infection; with a Gram-negative infection not expected to respond to study drugs; or with a carbapenem-resistant Gram-negative infection

• Presence of Gram-positive pathogens without Gram-negative pathogens in BAL4

• Total duration of antibiotic exposure for antibiotics whose administration begun in the 48 hours prior to randomisation, was longer than 24 hours, unless the pathogen(s) identied was non-susceptible to the antimicrobial agent received (based on local laboratory results) and the patient had shown objective signs of worsening despite therapy

• History of serious allergy, hypersensitivity or serious reaction to carbapenem, cephalosporin, other β-lactam antibiotics

• Serious reaction to both vancomycin and linezolid

• Concurrent infection that prevented accurate assessment on treatment eects

• Pulmonary disease that precluded evaluation of therapeutic response

• Lung abscess, pleural empyema or postobstructive pneumonia

• Heart/lung transplant recipient

• Immunocompromised due to HIV, chemotherapy ≤6 wk prior to randomisation, immunosuppressants, neutrophil count <500/mm3

• HAP treatment course expected to exceed 14 days

• APACHE II score > 30 or <10

• High likelihood of death within the study period despite adequate treatment delivery

Randomised 1:1

Hospitalised adult patients≥18 years old with HAP/VAP*N= 817)

2000 mg ceftazidime/500 mg avibactam i.v.

every 8 hours

1000 mg meropenem i.v. every 8 hours*

End of treatment

7-14 days of iv. therapy21-25 days

after randomisation28-32 days

after randomisation

Final protocol follow-upTest-of-cure

REPROVE: NCT01808092. *e carbapenem arm regimen used the standard dosing of meropenem as per the IDSA guidelines.131

HAP: Hospital-acquired pneumonia. VAP: Ventilator-associated pneumonia. I.V.: Intravenous.


1 Amenorrhea for ≥12 months following cessation of hormonal treatments. 2 LH and FSH levels in postmenopausal range AND amenorrhea for ≥12 months following cessation of hormonal treatments. 3 Oral contraceptives were not to be used as the sole method of birth control because the eect of ceftazidime-avibactam on the ecacy of oral contraceptives has not yet been established. 4 Gram stain showing no organisms did not preclude enrolment. LH: Luteinising hormone. FSH: Follicle-stimulating hormone. WBC: White blood cell. BAL: Bronchoalveolar lavage. APACHE II: Acute Physiology and Chronic Health Evaluation II. CrCl: Creatine clearance. DNR: Do not resuscitate.

HAP: Hospital-acquired pneumonia.

77

INSIDE PAGE

76

6.2.1 Baseline characteristicsPatients’ baseline demographic, clinical and disease characteristics were broadly similar between the treatment groups in the cMITT population (Tables 6.2 and 6.3).5

Table 6.2: REPROVE – key patient characteristics at baseline (cMITT population).5

e most frequently isolated pathogens at baseline in the mMITT population were Enterobacteriaceae, primarily K. pneumoniae 130/355 (36.6%), with similar frequencies in both groups.132

62.1 (16.6)

268 (75%)

150 (42%)

1 (<1%)

201 (56%)

4 (1%)

23.97 (6.11)

102.6 (67.5)

286 (80%)

18 (5%)

50 (14%)

Meropenem(n=370)



Male, n (%)

Race, n (%)

White

Black or African American

Asian

Other


Renal status

Estimated creatinine clearance (mL/min)

Normal renal function or mild impairment (51-150 mL/min)

Moderate or severe impairment (16-50 mL/min)

Augmented (> 151 mL/min)

61.9 (17.4)

274 (74%)

163 (44%)

2 (1%)

199 (54%)

6 (2%)

23.94 (5.17)

100.1 (53.1)

292 (79%)

18 (5%)

58 (16%)

Table 6.3: REPROVE – disease characteristics at baseline (cMITT population)5

118 (33%)

29 (8%)

89 (25%)

238 (67%)

19 (5%)

104 (29%)

69 (19%)

183 (51%)

122 (34%)

185 (52%)

49 (14%)

72 (20%)

199 (56%)

85 (24%)

154 (43%)

202 (57%)

Meropenem(n=370)


Type of HAP

Ventilator-associated pneumonia

Early

Late

Non-ventilator-associated pneumonia

Bacteraemia, yes, n (%)

Infection type

Monomicrobial

Polymicrobial

No study-qualifying pathogen found

Prior systemic antibiotic use, n (%)

None

≤24 h

>24 to ≤48 h

Concomitant aminoglycoside use

None

>0 to ≤72 h

>72 h

Mechanical ventilation at baseline

Ventilated

Not ventilated

128 (35%)

47 (13%)

81 (22%)

242 (65%)

15 (4%)

105 (28%)

83 (22%)

182 (49%)

117 (32%)

209 (56%)

44 (12%)

68 (18%)

225 (61%)

77 (21%)

159 (43%)

211 (57%)



Gram stain and culture results available within 48 h prior to randomisation and after the onset of HAP symptoms

• Estimated CrCl <16mL/min or expected haemodialysis or renal support during study

• Recent history of acute hepatitis, cirrhosis, acute hepatic failure, or acute decompensation of chronic hepatic failure

• Presence of DNR order

• Prior exposure to ceftazidime-avibactam or enrolment in the study

• History of epilepsy

79

INSIDE PAGE

78

6.2.2 Clinical ecacye analysis populations dened in the REPROVE study included the MITT, cMITT and CE populations (Figure 6.2). e cMITT population comprised all patients who were included in the MITT population (all randomized patients who met minimum disease requirements and received any amount of study therapy) and one of either of the following criteria:5, 132

Patients whose baseline respiratory cultures demonstrated Gram-negative respiratory pathogens with or without concomitant Gram-positive pathogens (excluding patients with Gram-negative pathogens not expected to respond to either study drug [i.e. patients with only the following monomicrobial Gram-negative infections: any of the Acinetobacter spp, or any Legionella spp; or Stenotrophomonas maltophilia; or Elizabethkingia meningoseptica) OR

Patients in whom no aetiologic pathogens were identied.e CE population comprised all patients in the cMITT population who met the following criteria.5, 132

Patients received an adequate course of treatment as dened below Received therapy for ≥48 h, with ≥80% of the scheduled drug administered over

the number of days administered, OR Received therapy <48 h before discontinuing treatment due to an adverse event Had a clinical response of success or failure (i.e. excluding indeterminates) within the protocolled visit window, for the respective EOT and TOC visits Had no important protocol deviations that would aect assessment of ecacy Did not receive prior antibiotics other than those outlined as acceptable in the exclusion criteria between the time of randomization and the time of the respective EOT and TOC visits Did not receive concomitant antibiotic therapy with potential activity against the

baseline pathogen, except for protocol allowed antibiotics. If no baseline pathogen was identied, receipt of any concomitant antibiotic other than those outlined in the protocol would exclude the patient from the CE population

6.2.2.1 Clinical cure rates.5

e proportion of patients who were clinically cured at TOC were similar in both treatment groups in both the cMITT and CE populations. In the cMITT population 245/356 people in the ceftazidime-avibactam group and 270/370 in the meropenem group were clinically cured at TOC (Figure 6.3). Subgroup analysis of the primary ecacy endpoint showed no association between clinical cure and various patient factors, including renal status, previous systemic antibiotic use, type of infection and APACHE II score category.Per-pathogen clinical cure rates at the TOC visit were similar between treatment groups; numerical dierences among individual bacterial species had wide CIs (Table 6.4). With both the ceftazidime-resistant and ceftazidime-non-resistant pathogens, per-pathogen clinical rates at the TOC visit were similar between treatment groups in the CE population.Per-patient favorable microbiological response rates at TOC visit were lower than clinical cure rates overall, but proportions were similar between treatment groups and consistent across the mMITT (55.6% vs. 64.1%), eME (64% vs. 67.9%) and ME (65.4% vs. 70.3%) populations.

Figure 6.2: Disposition of patients in the REPROVE study.5

*One patient in the meropenem group completed the test-of-cure visit (which was out of window) and the nal protocol follow-up visit on the same day, and was treated as having neither completed nor discontinued the study.

FPFU: Final protocol follow up

62 patients with moderate or severe renal impairment at baseline excluded

408 randomised to meropenem

5 did not receive study treatment 1 eligibility criteria not fullled 1 died 3 for other reasons

403 received meropenem

39 discontinued the study* 4 patient decision 27 died 7 lost to follow-up 1 for other reasons

Safety (n=403)cMITT (n=370)CE (n=270)eME (n=131)

363 completed study (FPFU visit)355 completed study (FPFU vist)

50 discontinued the study 8 patient decision 37 died 3 lost to folloW-up 2 for other reasons

Safety (n=405)cMITT (n=356)CE (n=257)eME (n=125)

405 received ceftazidime-avibactam

4 did not receive study treatment 1 patient decision 2 died 1 for other reasons

409 randomized to ceftazidime-avibactam

879 patients randomised


CE: Clinically evaluable. CI: Condence interval. cMITT: Clinically modied intention-to-treat.

Data are patients with clinical cure/number of patients in subgroup (%) and % dierenceBaseline pathogens were eradicated or presumed eradicated in the favorable microbiological response analysis. TOC: Test-of-cure. CE: Clinically evaluable.

Meropenem(n=270)


Difference

81

INSIDE PAGE

80

Figure 6.3: Proportion (95% CI) of HAP/VAP patients (CE and cMITT population) with favorable clinical response at test-of-cure.5

6.2.3 Safety and tolerabilitye safety prole of ceftazidime-avibactam in this trial was similar to that of ceftazidime alone and consistent with the prole of ceftazidime-avibactam. No new safety concerns were identied. Treatment-related AEs occurred in 66/405 (16%) patients in the ceftazidime-avibactam group and 54/403 (13%) patients in the meropenem group. e most common AEs in both groups included diarrhoea, hypokalaemia, constipation and vomiting and few AEs resulted in discontinuation of drugs. Overall, 302/405 patients in the ceftazidime-avibactam and 299/403 patients in the meropenem group experienced at least one AE.5

Serious AEs occurred in 75/405 (19%) patients in the ceftazidime-avibactam group and 54/403 (13%) patients in the meropenem group. e most common serious AEs were in the system organ classes of infections and infestations; respiratory, thoracic, and mediastinal disorders; and cardiac disorders. ere was a numerical dierence in the incidence of serious AEs in the ceftazidime-avibactam group compared with the meropenem group but most of these AEs were not related to study treatment. Four patients (1%) in the ceftazidime- avibactam group and none in the meropenem group had a serious AE that was considered by investigators to be related to the study drug.5

All-cause mortality in the safety population was 38/405 (9%) in the ceftazidime-avibactam and 30/403 (7%) in the meropenem group but this may have been partly due to the exclusion of patients with concurrent morbidities that prevented accurate analysis and patients likely to die within the study period.5

6.2.4 ConclusionsIn REPROVE, the rst phase 3 study of ceftazidime-avibactam in adults with HAP/VAP, non-inferiority of ceftazidime-avibactam to meropenem in the treatment of HAP/VAP caused by Gram-negative pathogens was shown.5

Clinical cure rates were comparable in patients with VAP and non-VAP HAP and were similar regardless of renal function status. Per-pathogen microbiological response rates were similar between the treatment groups, demonstrating clinical ecacy against Gram-negative pathogens most commonly associated with HAP/VAP. e safety prole of ceftazidime- avibactam in this trial was consistent with the proles of ceftazidime- avibactam and ceftazidime alone.5 e results from the REPROVE study support a role for ceftazidime- avibactam as a potential alternative to carbapenems in patients with nosocomial pneumonia (including ventilator-associated pneumonia) caused by Gram-negative pathogens.

Table 6.4: Per-pathogen clinical cure rates at TOC visit (CE population).5

83.8 %

95.2 %

72.7 %

100.0 %

83.3 %

66.7 %

64.3%

90.9%

Enterobacteriaceae



Escherichia coli

Proteus mirabilis

Serratia marcescens




Haemophilus inuenzae

79.6 %

63.6 %

77.8 %

87.5 %

100.0 %

40.0 %

77.1 %

84.6 %

4.2 (-13.49, 20.50)

31.6 (4.79, 61.30)

- 5.1 (-39.26, 25.79)

12.5 (-16.54, 48.07)

- 16.7 (-45.58, 19.48)

26.7 (-31.92, 70.73)

- 12.8 (-32.25, 8.01)

6.3 (-26.19, 36.09)

Ceftazidime-avibactam Meropenem

Clinical cure rate at test of cure

Patie

nts

with

favo

urab

le

clin

ical

resp

onse

(%)

100

80

60

40

20

0–0·7% [95% CI –7·9, 6·4]

(n=199/257) (n=211/270)

–4·2% [95% CI –10·8, 2·5]

(n=245/356) (n=270/370)

CE population

77.4 78.1

68.8 73.0

cMITT population


83

INSIDE PAGE

6.3 REPROVE: Indian Subset AnalysisAn analysis was carried out to assess the ecacy and safety of ceftazidime-avibactam (CAZ-AVI in comparison with meropenem for the treatment of nosocomial pneumonia, including ventilator-associated pneumonia, in the Indian population cohort of the REPROVE trial participants. A total of 879 patients were enrolled across 136 centres in23 countries as part of this study, which included 90 patients across 4 centres from India.133 e aim of the study was to assess whether the results in the Indian subgroup are in line with the overall results of the REPROVE trial,134 and therefore the conclusions made for the overall study could be considered also applicable to the India subset.

6.3.1 Baseline characteristicsA total of 90 Indian patients with HAP were enrolled across 4 centres in India, 78 of which were randomly assigned to CAZ-AVI (n=36) or meropenem (n=42). e patient disposition, demographics, baseline patient characteristics, and concomitant antibiotics used were comparable between the two groups (Table 6.5, 6.6).133, 134 In the Indian population there were no patients with VAP compared to 35% in the overall population.134

Table 6.5: Disease Characteristics of Indian Patients at Baseline (Safety Analysis Set).133

82

Total(N=78)

Meropenem(N=42)

CAZ-AVI(N=36)

78

14.6

2.44

14.0

10

21

0

74 (94.9)

4 (5.1)

78 (100)

63 (80.8)

63 (80.8)

0

15 (19.2)

78 (100)

42

15.0

2.32

15.0

11

21

0

40 (95.2)

2 (4.8)

42 (100)

34 (81.0)

34 (81.0)

0

8 (19.0)

42 (100)

36

14.2

2.54

14.0

10

21

0

34 (94.4)

2 (5.6)

36 (100)

29 (80.6)

29 (80.6)

0

7 (19.4)

36 (100)

n

Mean

SD

Median

Minimum

Maximum

<10

10-19

20-30

Total

Yes

≤24 hours

≥24 hours

No

Total

APACHE II Score

APACHE II n (%)

Prior systemic antibiotics used in the previous 48 hours before randomization n (%)

Total(N=78)

Meropenem(N=42)

CAZ-AVI(N=36)

0

78 (100)

0

78 (100)

78

78.9

29.85

72.5

35

199

0

78 (100)

78 (100)

2 (2.6)

74 (94.9)

2 (2.6)

78 (100)

0

78 (100)

78 (100)

0

78 (100)

78 (100)

4 (5.1)

74 (94.9)

78 (100)

0

42 (100)

0

42 (100)

42

80.5

34.82

72.4

35

199

0

42 (100)

42 (100)

2 (4.8)

38 (90.5)

2 (4.8)

42 (100)

0

42 (100)

42 (100)

0

42 (100)

42 (100)

2 (4.8)

40 (95.2)

42 (100)

0

36 (100)

0

36 (100)

36

77.1

23.09

72.6

52

149

0

36 (100)

36 (100)

0

36 (100)

0

36 (100)

0

36 (100)

36 (100)

0

36 (100)

36 (100)

2 (5.6)

34 (94.4)

36 (100)

Yes

No

Other

Total

n

Mean

SD

Median

Minimum

Maximum

Ventilated

Non-ventilated

Total

Moderate or severe impairment (CrCl 16 to 50 ml/min)

Normal renal function/mild impairment (CrCl 51 to 150 ml/min)

Augmented (CrCl >150 ml/min)

Total

VAP

Non-VAP

Total

VAP

Non-VAP

Total

Yes

No

Total

Failure of prior antibiotics used n (%)a

Estimated CrCl (ml/min)b

Ventilated or non-ventilated at baseline

Renal status n (%)

NP subtype (from eCRF)c n (%)

NP subtype (from IVRS)d n (%)

Bacteremic n (%)


Table 6.6: Common Pathogens Identied at Baseline – Respiratory Site or Blood (mMITT Analysis Set) – Indian Population.133

6.3.2 Clinical ecacyClinical outcomes at the end-of-treatment (EOT) (i.e., within 24 hours of the last dose of study treatment) and test-of-cure visits (TOC) (21–25 days after randomization) were classied by investigators as cure (dened at the test-of-cure visit as resolution of all signs and symptoms of pneumonia such that no antibacterial therapy for nosocomial pneumonia was taken between the end-of-treatment and test-of-cure visits, inclusive), indeterminate, or treatment failure. e primary ecacy outcome measure in the REPROVE study was clinical cure rate of CAZ-AVI compared with that of meropenem at TOC in clinically modied intent-to-treat (cMITT) dened as ‘all patients in the modied intent-to-treat (MITT) analysis set who had either ≥1 baseline Gram-negative pathogen or no baseline pathogen’ and clinically evaluable (CE) analysis sets dened as ‘Patients in the cMITT analysis set who received an adequate course of treatment, had an evaluable assessment, no protocol deviations that aected the assessment of ecacy, and no unacceptable prior or concomitant antibiotics’. Non-inferiority was concluded if the lower limit of the two-sided 95% CI for the treatment dierence was greater than –12·5% in the co-primary clinically modied intention-to-treat and clinically evaluable populations.5

e secondary ecacy outcome measures included clinical cure at EOT in pre-dened analysis sets including cMITT, CE as well as mMITT i.e. Microbiologically Modied intent-to-treat population dened as ‘Patients who were included in the MITT populations and had a properly obtained respiratory culture demonstrating Gram-negative pathogens’, ME and Extended ME analysis sets dened as ‘Patients in the CE analysis set with a baseline pathogen susceptible to both study treatments (ME) or regardless of susceptibility (Extended-ME).5, 132

85

INSIDE PAGE

84

Total(N=78)

Meropenem(N=42)

CAZ-AVI(N=36)

27 (34.6)

3 (3.8)

47 (60.3)

77 (98.7)

76 (97.4)

2 (2.6)

78 (100)

18 (23.1)

0

0

0

0

0

60 (76.9)

78 (100)

0

0

0

15 (35.7)

1 (2.4)

25 (59.5)

41 (97.6)

41 (97.6)

1 (2.4)

42 (100)

9 (21.4)

0

0

0

0

0

33 (78.6)

42 (100)

0

0

0

12 (33.3)

2 (5.6)

22 (61.1)

36 (100)

35 (97.2)

1 (2.8)

36 (100)

9 (25.0)

0

0

0

0

0

27 (75.0)

36 (100)

0

0

0

G+ alone

G- alone

G-mixed (both + and -)

Total

Acute care facility

Other care facility

Total

Mono-microbial

Poly-microbial

2 pathogens

3 pathogens

4 pathogens

≥5 pathogens

No study qualifying pathogen identied

Total

Early-VAP

Late-VAP

Total

Gram stain n (%)

Hospital care n (%)

Infection type n (%)

Type of infection (VAP patients only) n (%)

Total(N=13)

Meropenem(N=8)

CAZ-AVI(N=5)

Baseline Pathogen

6 (46.2)

2 (15.4)

3 (23.1)

1 (7.7)

7 (53.8)

7 (53.8)

5 (62.5)

1 (12.5)

3 (37.5)

1 (12.5)

3 (37.5)

3 (37.5)

1 (20.0)

1 (20.0)

0

0

4 (80.0)

4 (80.0)

-

Escherichia coli


Proteus vulgaris group

-


Enterobacteriaceae

Gram negative pathogens other than Enterobacteriaceae

NOTES: Percentages were based on the total number of patients in the treatment group. APACHE II: Acute Physiology and Chronic Health Evaluation II.CAZ-AVI: Ceftazidime-avibactam. CrCl: Creatinine clearance. CPIS: Clinical pulmonary infection score. eCRF: Electronic case report form. IVRS: Interactive voice-response system. N: Number of patients in treatment group. n: Number of patients in category or analysis. NP: Nosocomial pneumonia. SD: Standard deviation. VAP: Ventilator-associated pneumonia. a Other included patients with >24 hours of prior antibiotic therapy that did not meet the criteria for failure of prior antibiotic therapy following manual review. b As reported by the site using the Cockcroft Gault method based on local laboratory data. c Using data obtained at the site and reported in the eCRF. d As reported by the site in IVRS at enrollment. e CPIS total score is derived using the method of Luna and was only required for patients who are on ventilator at screening.

NOTES: Pathogens included in this table were collected from respiratory site or blood. A patient could have had >1 pathogen. Multiple isolates of the same species from the same patient were counted only once, regardless of source (respiratory or blood). Percentages were based on the total number of patients in the treatment group. CAZ-AVI: Ceftazidime-avibactam. mMITT: Microbiologically modied intent-to-treat. N: Number of patients in the treatment group.


ResponseAnalysis Set

Comparison Between GroupsNumber (%) of patients

Differencea (%) (95% CIb) for Percent Difference

-

8.9 (-12.09, 28.27)

-

-

-

10.9 (-10.39, 29.77)

-

-

Clinical cure

Clinical failure

Indeterminate

-

Clinical cure

Clinical failure

cMITT

CE at TOC

NOTES: Percentages were based on the total number of patients in the treatment group for each analysis set. CAZ-AVI: Ceftazidime-avibactam. CE: Clinically evaluable. cMITT: Clinically modied intent-to-treat. N: Number of patients in the treatment group. TOC: Test of cure.a Dierence=Dierence in clinical cure rates (CAZ-AVI treatment group minus meropenem treatment group).b e condence interval (CI) for the dierence was calculated using the unstratied Miettinen and Nurminen method.

TOC: Test-of-cure. cMITT: Clinically modied intent-to-treat. CAZ-AVI: Ceftazidime-avibactam. CE: Clinically evaluable. mMITT: Microbiologically modied intent-to-treat.

87

INSIDE PAGE

86

CAZ-AVI Meropenem

e aim of this subgroup analysis was to assess whether the results in the subgroup are in line with the results of the overall study and therefore the conclusions made for the overall study could be considered also applicable to the Indian subset. Although there are inherent limitations to this analysis due to the subgroup size, it provides information on clinical ecacy and safety relevant for the intended use of CAZ-AVI in Indian patients. e study also evaluated the safety and tolerability prole of CAZ-AVI compared with meropenem in the safety analysis population.

6.3.2.1 Clinical cure ratese clinical cure rate at TOC in Indian sub-group was 80.6% (n=25/31) in patients on CAZ-AVI vs. 71.8% (n=28/39) in the meropenem group (8.9% [95% CI -12.09,28.27] (Table 6.6). e clinical cure rates were consistent with those observed in the overall population of 68.8% with CAZ-AVI and 73% with meropenem (–4·2% [95% CI –10·8, 2·5]) (Table 6.7). In the clinically evaluable analysis set (CE) of Indian population, clinical cure rate was 88.0% with CAZ-AVI (n=22/31) and 77.1% with meropenem (n=27/39), (10.9 [95% CI -10.39, 29.77) (Table 6.6), which was also consistent with the overall results with CAZ-AVI of 77·4% cure rate (n=199/257) compared with 78.1% (n=211/270) in the meropenem group (-0.7%, [95% CI: -7.86, 6.39] p<0.001) (Table 6.7). In addition, dierences in the clinical cure rates of patients at EOT across all analysis sets in Indian cohort were consistent with primary ecacy analysis for mMITT, eME, ME as seen in the overall population. (Table 6.8).134

Table 6.6: Clinical Response at TOC (cMITT and CE at TOC Analysis Sets) – Indian Population.133

Table 6.7: Primary Ecacy Evaluations in the Overall Population versus Indian Population.133

(N=31)

25 (80.6)

3 (9.7)

3 (9.7)

(N=25)

22 (88.0)

3 (12.0)

(N=39)

28 (71.8)

8 (20.5)

3 (7.7)

(N=35)

27 (77.1)

8 (22.9)

Proportion of Patients With Clinical Cure at TOC Visit

Proportion of Patients with Clinical Cure

cMITT and CE Analysis Sets

Indian Population (%)Analysis Set CAZ-AVI Meropenem

80.6

88.0

71.8

77.1

Overall Population (%)

CAZ-AVI Meropenem

68.6

77.4

73.0

78.1

cMITT

CE

mMITT, ME and Extended-ME Analysis Sets

Indian Population (%)Analysis Set CAZ-AVI Meropenem

Overall Population (%)

CAZ-AVI Meropenem

100.0

100.0

100.0

50.0

66.7

57.1

70.2

79.4

76.8

75.0

79.7

78.6

mMITT

ME

Extended-ME


Dierence=Dierence in clinical cure rates (CAZ-AVI treatment group minus meropenem treatment group).CAZ-AVI: Ceftazidime-avibactam. CI: Condence interval. ME: Microbiologically evaluable. mMITT: Microbiologically modied intent-to-treat. N: Number of patients in the treatment group. EOT: End of treatment. a Condence intervals for group dierences were calculated using the unstratied Miettinen and Nurminen method. b Percentages are based on the total number of patients in the treatment group (N). c Percentages are based on the total number of patients in the ME set at the particular visit in each treatment group (N). d Percentages are based on the total number of patients in the extended ME set at the particular visit in each treatment group (N).

89

INSIDE PAGE

88

Table 6.8: Clinical Response at EOT by mMITT, ME and Extended-ME Analysis Sets – Indian Population.133

Although best eorts were made within the context of the global study to ensure that at least 25% of the overall population enrolled had a VAP diagnosis, the Indian subgroup did not include any patients with VAP (compared to 34.7% in the overall population). However, the clinical cure rates observed at the TOC visit for the overall population were similar in VAP and non-VAP patients and it is therefore expected that the response rates for VAP patients in India would also be similar to those observed in non-VAP patients. e number of patients with pathogens isolated at baseline in the India was lower than that of the overall population. Although the rate of isolation was low compared to the overall population, the pathogens identied at baseline were consistent with the overall population. A comparison between the proportion of favorable per-pathogen microbiologic responses at TOC between the overall and Indian populations is limited by the small patient numbers in the Indian subgroup. While the rate of pathogen isolation was low for the India population as compared to the overall population, there were no specic reasons identied within the study to explain this dierence. ere were no cases of persistence with increasing MIC in the mMITT analysis set at EOT or TOC.

11 patients were classied as clinical failure at the TOC visit, of which 10 were classied as clinical failure at EOT (3 in the CAZ-AVI and 7 in the meropenem group), and 1 patient in the meropenem group was classied as clinical failure due to unresolved nosocomial pneumonia (NP). At the TOC visit, the number of patients in the CE analysis set who were classied as clinical failure was 3 (12.0%) patients in the CAZ-AVI group and 7 (20.0%) patients in the meropenem group.133

ResponseAnalysis Set

Comparison Between GroupsNumber (%) of patients

Differencea (%) (95% CIb) for Percent Difference

CAZ-AVI Meropenem

-

37.5 (-15.37, 70.42)

-

-

-

33.3 (-20.47, 71.30)

-

-

42.9 (-11.68, 75.93)

-

-

Clinical cure

Clinical failure

Indeterminate

-

Clinical cure

Clinical failure

-

Clinical cure

Clinical failure

mMITTb

MEc

Extended-MEd

(N=5)

5 (100)

0

0

(N=5)

5 (100)

0

(N=5)

5 (100)

0

(N=8)

5 (62.5)

3 (37.5)

0

(N=6)

4 (66.7)

2 (33.3)

(N=7)

4 (57.1)

3 (42.9)


Table includes AEs with an onset date and time on or after the date and time of rst dose and up to and including the EOT and FPFU visits. Percentages are based on the total number of patients in the treatment group (N). CAZ-AVI: Ceftazidime-avibactam. EOT: End of treatment. FPFU: Final protocol follow-up. AE: Adverse event.

Number (%) of Patients (Patient with any AE)

Indian PatientsVisit

CAZ-AVI(N=36)

Meropenem(N=42)

Overall Patients

CAZ-AVI(N=405)

Meropenem(N=403)

23 (63.9)

23 (63.9)

33 (78.6)

33 (78.6)

267 (65.9)

302 (74.6)

267 (66.3)

299 (74.2)

EOT

FPFU

6.3.3 Safety and tolerabilitye safety analysis set including 78 Indian patients (36 on CAZ-AVI and 38 on meropenem) showed that CAZ-AVI treatment was well-tolerated. No patient reported any AE with a fatal outcome, SAE, AE of severe intensity or AE leading to discontinuation of study treatment. 64% patients (n=23/36) in the CAZ-AVI group and 78% (n=33/42) patients in the meropenem group reported at least 1 AE up to end of therapy (EOT) and the nal protocol follow-up (FPFU) visits (Table 6.9). e most common AEs in the CAZ-AVI group versus meropenem group, were: vomiting (25.0% of patients versus 19% of patients), diarrhea (8.3% of patients versus 23.8% of patients), nausea (8.3% of patients versus 11.9% of patients), and pruritus generalized (13.9% of patients versus 4.8% of patients).

Table 6.9: Adverse events up to EOT and FPFU visit.133

In the overall population, the most common AEs in the CAZ-AVI group vs. meropenem group, with an incidence of >5%, were: diarrhea (15.1% of patients vs. 15.4% of patients), hypokalaemia (10.6% of patients vs. 8.2% of patients), constipation (6.2% of patients vs. 7.7% of patients), anaemia (6.2% of patients vs. 4.5% of patients), and vomiting (5.7% of patients vs. 5.5% of patients).134 In the Indian population the most common AEs in the CAZ-AVI group vs. meropenem group, were: vomiting (25.0% of patients vs. 19% of patients), diarrhea (8.3% of patients vs. 23.8% of patients), nausea (8.3% of patients vs. 11.9% of patients), and pruritus generalized (13.9% of patients vs. 4.8% of patients). No dierences were identied up to FPFU compared with EOT comparing the overall and Indian sub-populations.133 CAZ-AVI was well tolerated in the India subset. ere were no deaths, SAEs and discontinuations due to AEs in the India subset.

91

INSIDE PAGE

90

6.3.4 ConclusionsREPROVE is the rst phase III study of ceftazidime-avibactam in adults with nosocomial pneumonia (including ventilator-associated pneumonia).134 Results of this study show non-inferiority for the treatment of nosocomial pneumonia caused by ceftazidime non-susceptible or ceftazidime-susceptible Gram-negative aerobic pathogens.e safety and ecacy outcomes in Indian population treated with CAZ-AVI as part of the REPROVE study were consistent with the global REPROVE trial.133 Although there are inherent limitations to this analysis due to the subgroup size, it provides information on clinical ecacy and safety relevant for the intended use of CAZ-AVI in Indian patients. e ecacy of CAZ-AVI for the treatment of nosocomial pneumonia in Indian patients, including pathogens resistant to ceftazidime is supported. CAZ-AVI was well tolerated in the Indian subset. ere were no deaths, SAEs and discontinuations due to AEs in the Indian subset.


In four Phase 3 clinical studies, ceftazidime-avibactam was non-inferior to a carbapenem for the treatment of cIAI, cUTI and HAP/VAP.3-6 In the REPRISE study, the clinical ecacy of ceftazidime-avibactam was proven for the treatment of cUTIs and cIAIs caused by ceftazidime-resistant Gram-negative pathogens,6 conrming its potential clinical benet in ceftazidime-resistant infections. e potential clinical utility of ceftazidime-avibactam for the treatment of HAP/VAP was initially investigated, and conrmed, in a Phase 1 study that demonstrated penetration of both agents into the ELF of healthy volunteers.108 e clinical utility was conrmed in the Phase 3 REPROVE trial that showed non-inferiority of ceftazidime-avibactam to meropenem in patients with nosocomial pneumonia.5 e clinical evidence for ceftazidime-avibactam conrms its role as an alternative to a carbapenem in the treatment of cIAI, cUTI and HAP/VAP infections caused by aerobic Gram-negative pathogens.3-6

7. Conclusions

93

INSIDE PAGE

92

For the use only of Registered Medical Practitioners, or a Hospital or a Laboratory.

COMPOSITION: Contents: Each vial contains ceftazidime pentahydrate equivalent to 2 g ceftazidime and avibactam sodium equivalent to 0.5 g avibactam. Each vial contains 6.44 mmol of sodium (approximately 148 mg).

INDICATIONS: ZAVICEFTA is indicated in adults in Complicated intra abdominal infection (cIAI), Complicated urinary tract infection (cUTI), including pyelonephritis, and Hospital-acquired pneumonia (HAP), including ventilator-associated pneumonia (VAP).

CONTRA-INDICATIONS: Hypersensitivity to the active substances or to any of the excipients (anhydrous sodium carbonate), or to any cephalosporin antibacterial agent. Severe hypersensitivity (e.g. anaphylactic reaction, severe skin reaction) to any other type of ß-lactam antibacterial agent (e.g. penicillins, monobactams or carbapenems).

ADVERSE REACTIONS: e most common adverse reactions occurring in ≥5% of patients treated with ZAVICEFTA were positive results in a direct Coombs test, nausea, and diarrhea. Nausea and diarrhea were usually mild or moderate in intensity. e other common ADRs are candidiasis (including vulvovaginal candidiasis and oral candidiasis), eosinophilia, thrombocytosis, thrombocytopenia, headache, dizziness, abdominal pain, increase in hepatic enzymes, maculo - papular rash, urticaria, pruritus, infusion site thrombosis, infusion site phlebitis, and pyrexia. Uncommon adverse reactions are Clostridium dicile colitis, pseudomembranous colitis, neutropenia, leucopenia, lymphocytosis, paresthesia, dysgeusia, increased blood creatinine, increased blood urea, and acute kidney injury. Tubulointerstitial nephritis is rare. e frequency is unknown for agranulocytosis, hemolytic anemia, anaphylactic reaction, jaundice, toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, angioedema, and Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS). Healthcare professionals are asked to report any suspected adverse reactions.

SPECIAL WARNINGS AND PRECAUTIONS: Serious and occasionally fatal hypersensitivity reactions are possible. In case of hypersensitivity reactions, treatment with ZAVICEFTA must be discontinued immediately and adequate emergency measures must be initiated. Clostridium dicile-associated diarrhea has been reported with ceftazidime/avibactam, and can range in severity from mild to life-threatening. Neurological sequelae, including tremor, myoclonus, non-convulsive status epilepticus, convulsion, encephalopathy and coma, have occasionally been reported with ceftazidime when the dose has not been reduced in patients with renal impairment. In patients with renal impairment, close monitoring of estimated creatinine clearance is advised. In some patients, the creatinine clearance estimated from serum creatinine can change quickly, especially early in the course of treatment for the infection. Concurrent treatment with high doses of cephalosporins and

8. Summary of full prescribing information


nephrotoxic medicinal products such as aminoglycosides or potentdiuretics (e.g. furosemide) may adversely aect renal function. Ceftazidime/avibactam use may cause development of a positive direct antiglobulin test (DAGT, or Coombs test), which may interfere with the cross-matching of blood and/or may cause drug-induced immune hemolytic anemia. Patients experiencing anemia during or after treatment with ZAVICEFTA should be investigated or this possibility.

DOSAGE AND ADMINISTRATION: e recommended intravenous dose for patients with estimated creatinine clearance (CrCL) ≥ 51 mL/min is:

Infection Type Dose (CEFT/AVI) Frequency Infusion Time Duration of Treatment

cIAI1,2

cUTI2

HAP2

2 g/0.5 g

2 g/0.5 g

2 g/0.5 g

Every 8 hours

Every 8 hours

Every 8 hours

2 hours

2 hours

2 hours

5-14 days

5-10 days

7-14 days

3

1. To be used in combination with metronidazole when anaerobic pathogens are known or suspected to be contributing to the infectious process. 2. To be used in combination with an antibacterial agent active against Gram-positive pathogens when these are known or suspected to be contributing to the infectious process. 3. e total duration shown may include intravenous Zavicefta followed by appropriate oral therapy.

No dosage adjustment is required in elderly patients. No dosage adjustment is required in patients with hepatic impairment.

e recommended intravenous doses for patients with estimated CrCL ≤ 50 mL/min are:

Dose (CEFT/AVI)

1 g/0.25 g

0.75 g/0.1875 g

0.75 g/0.1875 g

0.75 g/0.1875 g

Frequency

Every 8 hours

Every 12 hours

Every 24 hours

Every 48 hours

Infusion time

2 hours

2 hours

2 hours

2 hours

Estimated CrCL (mL/min)

31-50

16-30

6-15

ESRD including on haemodialysis

Ceftazidime and avibactam are removed by hemodialysis. Dosing of Zavicefta on hemodialysis days should occur after completion of hemodialysis. Safety and ecacy in children and adolescents below 18 years of age have not yet been established. No data are available.

METHOD OF ADMINISTRATION: ZAVICEFTA is administered by intravenous infusion over 120 minutes in an infusion volume of 100 mL.

Refer to full prescribing information for further details.

Adapted from Local Product Document of ZAVICEFTA LPDZAVIC122017.TM Trademark Proprietor: Pzer Ireland Pharmaceuticals. Licensed User: Pzer Limited, India.

95

INSIDE PAGE

94

%fT>CT: Per cent free drug time above critical threshold

%fT >MIC: Per cent free drug time above minimal inhibitory concentration

AE: Adverse event

APACHE II: Acute Physiology and Chronic Health Evaluation II

AMR: Antimicrobial resistance

AUC: Area under the concentration-time curve

AUClast: Area under the concentration-time curve from time zero to time of last measurable plasma concentration

AUC0-: Area under the concentration-time curve from time 0 to infinity

BAT: Best available therapy

BSAC: British Society for Antimicrobial Chemotherapy

CA-UTI: Catheter-associated urinary tract infection

CDC (US): Centers for Disease Control

CIAO: Complicated Intra-Abdominal infection Observational (study)

CE: Clinically evaluable

CFU: Colony-forming units

CI: Confidence interval

cIAI: Complicated intra-abdominal infections

CL: Plasma clearance

CLR: Renal clearance

CLSI (US): Clinical and Laboratory Standards Institute

Cmax: Maximum plasma concentration

cMITT: Clinical modified intention-to-treat

CrCl: Creatinine clearance

CSF: Cerebrospinal fluid

(c)UTI: (Complicated) urinary tract infections

CV%: Percentage coefficient of variation

DAGT: Direct antiglobulin test

DRIVE-AB: Driving reinvestment in research and development and responsible antibiotic use

9. Abbreviations and References


ECDC: European Centre for Disease Prevention and Control

ECOFFs: EUCAST MIC frequency distributions and epidemiological cut-off values

ED50: Median effective dose

EFPIA: European Federation of Pharmaceutical Industries and Associations

ELF: Epithelial lining fluid

EMA: European Medicines Agency

EME: Extended microbiologically evaluable

EOT: End-of-treatment

ESBL: Extended-spectrum ß-lactamase

ESKAPE: Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacteriaceae

ESRD: End-stage renal disease

EU: European Union

EUCAST: European Committee on Antimicrobial Susceptibility Testing

FDA (US): Food and Drug Administration

FPFU: Final protocol follow-up

GAIN: Generating Antibiotics Incentives Now, a US government initiative to increase research in anti-infectives

GAP: Global Action Plan

HAP: Hospital-acquired pneumonia

IDSA: Infectious Diseases Society of America

IMI: Innovative Medicines Initiative, an EU partnership between government and the pharmaceutical industry to increase funding for anti-infective research

INFORM: International Network For Optimal Resistance Monitoring, an AstraZeneca surveillance program

I.V. Intravenous

IC50: Half-maximal inhibitory concentration

ICU: Intensive care unit

KPC: Klebsiella pneumoniae carbapenemase

LFU: Late follow-up

MBL: Metallo-ß-lactamase

97

INSIDE PAGE

96

MDR: Multidrug resistant

ME: Microbiologically evaluable

MIC: Minimum inhibitory concentration

MITT: Modified intention-to-treat

cMITT: Clinically modified intention-to-treat

mMITT: Microbiological modified intention-to-treat

MRSA: Methicillin-resistant Staphylococcus aureus

NA: Not available

ND4BB: New Drugs 4 Bad Bugs, an IMI initiative

OAT: Organic anion transporter

OXA: Oxacillinase

PBP: Penicillin-binding protein

PD: Pharmacodynamic

PK: Pharmacokinetic

PTA: PK/PD target attainment

R: Resistant

RR: Relative risk

S: Susceptible

SAE: Serious adverse event

SD: Standard deviation

SMART: Study for Monitoring Antimicrobial Resistance Trends

t1/2: Terminal elimination half-life

TEAE: Treatment-emergent adverse event

TOC: Test-of-cure

tmax: Time to reach maximum plasma concentration

VAP: Ventilator-associated pneumonia, a subset of HAP often evaluated separately in clinical studies

Vss: Apparent volume of distribution at steady state

WBC: White blood cells

WHO: World Health Organization

XDR: Extensively drug-resistant


REFERENCES

1. ZAVICEFTA Local Product Document LPDZAVIC122017.

2. Zhanel GG, et al. Ceftazidime-avibactam: a novel cephalosporin/beta-lactamase inhibitor combination. Drugs. 2013;73(2):159-77.

3. Mazuski JE, et al. Efficacy and Safety of Ceftazidime-Avibactam Plus Metronidazole Versus Meropenem in the Treatment of Complicated Intra-abdominal Infection: Results From a Randomized, Controlled, Double-Blind, Phase 3 Program. Clin Infect Dis. 2016;62(11):1380-9.

4. Wagenlehner FM, et al. Ceftazidime-avibactam Versus Doripenem for the Treatment of Complicated Urinary Tract Infections, Including Acute Pyelonephritis: RECAPTURE, a Phase 3Randomized Trial Program. Clin Infect Dis. 2016;63(6):754-62.

5. Torres A, et al. Ceftazidime-avibactam versus meropenem in nosocomial pneumonia, including ventilator-associated pneumonia (REPROVE): a randomised, double-blind, phase 3 non-inferiority trial. Lancet Infect Dis. 2018;18(3):285-295.

6. Carmeli Y, et al. Ceftazidime-avibactam or best available therapy in patients with ceftazidime-resistant Enterobacteriaceae and Pseudomonas aeruginosa complicated urinary tract infections orcomplicated intra-abdominal infections (REPRISE): a randomized, pathogen-directed, phase 3 study. Lancet Infect Dis. 2016;16(6):661-73.

7. Pendleton JN, Gorman SP and Gilmore BF. Clinical relevance of the ESKAPE pathogens. Expert RevAnti Infect Ther. 2013;11(3):297-308.

8. World Health Organization. The evolving threat of antimicrobial resistance-options for action, 2012.[Accessed on 23/03/2019]; Available from: http://whqlibdoc.who.int/publications/2012/ 9789241503181_eng.pdf.

9. Solomkin JS, et al. Diagnosis and management of complicated intra-abdominal infection in adults and children: guidelines by the Surgical Infection Society and the Infectious Diseases Society of America. Clin Infect Dis. 2010;50(2):133-64.

10. Hooton TM, et al. Diagnosis, prevention, and treatment of catheter-associated urinary tract infection in adults: 2009 International Clinical Practice Guidelines from the Infectious Diseases Society of America. Clin Infect Dis. 2010;50(5):625-63.

11. Wagenlehner FM, et al. Epidemiology, treatment and prevention of healthcare-associated urinarytract infections. World J Urol. 2012;30(1):59-67.

12. Sader HS, et al. Antimicrobial susceptibility of Gram-negative organisms isolated from patientshospitalised with pneumonia in US and European hospitals: results from the SENTRY AntimicrobialSurveillance Program, 2009-2012. Int J Antimicrob Agents. 2014;43(4):328-34.

13. Carlet J, et al. Ready for a world without antibiotics? The Pensieres Antibiotic Resistance Call toAction. Antimicrob Resist Infect Control. 2012;1(1):11.

14. Fair RJ and Tor Y. Antibiotics and bacterial resistance in the 21st century. Perspectives in medicinalchemistry. 2014;6:25-64.

15. Ventola CL. The antibiotic resistance crisis: part 1: causes and threats. P & T : a peer-reviewed journal for formulary management. 2015;40(4):277-83.

16. Woodford N and Ellington MJ. The emergence of antibiotic resistance by mutation. Clinical Microbiology and infection: the official publication of the European Society of Clinical Microbiology and Infectious Diseases. 2007;13(1):5-18.

17. Morrill HJ, et al. Treatment Options for Carbapenem-Resistant Enterobacteriaceae Infections. Open Forum Infect Dis. 2015;2(2):v050.

18. CDC. Antibiotic resistance threats in the United States, 2013. [Accessed on 23/03/2019]; Available from: http://www.cdc.gov/drugresistance/pdf/ar-threats-2013-508.pdf.

19. Kanj SS and Kanafani ZA. Current concepts in antimicrobial therapy against resistant gram- negative organisms: extended-spectrum beta-lactamase-producing Enterobacteriaceae, carbapenem-resistant Enterobacteriaceae, and multidrug-resistant Pseudomonas aeruginosa. Mayo Clin Proc. 2011;86(3):250-9.

20. Rice LB. Federal funding for the study of antimicrobial resistance in nosocomial pathogens: no ESKAPE. J Infect Dis. 2008;197(8):1079-81.

21. Boucher HW, et al. Bad Bugs, No Drugs: No ESKAPE! An Update from the Infectious Diseases Society of America. Clin Infect Dis. 2009;48(1):1-12.

22. Rice LB. Progress and challenges in implementing the research on ESKAPE pathogens. Infect Control Hosp Epidemiol. 2010;31(1):S7-10.

23. Amble, RP. The structure of beta-lactamases. Philos Trans R Soc Lond B Biol Sci. 1980; 289(1036):321-31.

24. Guzman-Blanco M, et al. Extended spectrum beta-lactamase producers among nosocomial Enterobacteriaceae in Latin America. Braz J Infect Dis. 2014;18(4):421-33.

25. Kang CI and Song JH. Antimicrobial resistance in Asia: current epidemiology and clinical implications. Infect Chemother. 2013;45(1):22-31.

26. Alvarez M, et al. Epidemiology of conjugative plasmid-mediated AmpC beta-lactamases in the United States. Antimicrob Agents Chemother. 2004;48(2):533-7.

27. Miro E, et al. Prevalence and molecular epidemiology of acquired AmpC beta-lactamases and carbapenemases in Enterobacteriaceae isolates from 35 hospitals in Spain. Eur J Clin Microbiol Infect Dis. 2013;32(2):253-9.

28. Reuland EA, et al. Detection and occurrence of plasmid-mediated AmpC in highly resistant gram-negative rods. PLoS One. 2014;9(3):e91396.

99

INSIDE PAGE


29. Sheng WH, et al. Distribution of extended-spectrum beta-lactamases, AmpC beta-lactamases, and carbapenemases among Enterobacteriaceae isolates causing intra-abdominal infections in the Asia-Pacific region: results of the study for Monitoring Antimicrobial Resistance Trends (SMART). Antimicrob Agents Chemother. 2013;57(7):2981-8.

30. Grover N, Sahni AK, and Bhattacharya S. Therapeutic challenges of ESBLS and AmpC beta-lactamase producers in a tertiary care center. Med J Armed Forces India. 2013;69(1):4-10.

31. Zilberberg MD and Shorr AF. Prevalence of multidrug-resistant Pseudomonas aeruginosa and carbapenem-resistant Enterobacteriaceae among specimens from hospitalized patients with pneumonia and bloodstream infections in the United States from 2000 to 2009. J Hosp Med. 2013;8(10):559-63.

32. Morales E, et al. Hospital costs of nosocomial multi-drug resistant Pseudomonas aeruginosa acquisition. BMC Health Serv Res. 2012;12:122.

33. Arnold RS, et al., Emergence of Klebsiella pneumoniae carbapenemase-producing bacteria. South Med J. 2011;104(1):40-5.

34. Chen LF, Anderson DJ and Paterson DL. Overview of the epidemiology and the threat of Klebsiella pneumoniae carbapenemases (KPC) resistance. Infect Drug Resist. 2012;5:133-41.

35. Munoz-Price LS, et al. Clinical epidemiology of the global expansion of Klebsiella pneumoniae carbapenemases. Lancet Infect Dis. 2013;13(9):785-796.

36. Livermore DM, et al. Activities of NXL104 combinations with ceftazidime and aztreonam against carbapenemase-producing Enterobacteriaceae. Antimicrob Agents Chemother. 2011;55(1):390-4.

37. Gandra S, et al. The mortality burden of multidrug-resistant pathogens in India: a retrospective observational study. Clin Infect Dis. 2018. doi: 10.1093/cid/ciy955.

38. Singh N, et al. Prevalence of ESBL in Escherichia Coli isolates among ICU patients in a tertiary care hospital. J Clin Diag Res. 2016;10(9):DC19.

39. Banerjee T, et al. Long-term outbreak of Klebsiella pneumoniae & third generation cephalosporin use in a neonatal intensive care unit in north India. Ind J Med Res. 2016;144(4):622.

40. Sartelli M, et al. Complicated intra-abdominal infections in Europe: a comprehensive review of the CIAO study. World J Emerg Surg. 2012;7(1):36.

41. Hoban DJ, et al. Susceptibility of gram-negative pathogens isolated from patients with complicated intra-abdominal infections in the United States, 2007-2008: results of the Study for Monitoring Antimicrobial Resistance Trends (SMART). Antimicrob Agents Chemother. 2010;54(7):3031-4.

42. Veeraraghavan B, et al. Antimicrobial susceptibility profiles of gram-negative bacteria causing infections collected across India during 2014–2016: Study for monitoring antimicrobial resistance trend report. Ind J Med Microbiol. 2018;36(1):32.

43. Solomkin JS, et al. Diagnosis and management of complicated intra-abdominal infection in adults and children: guidelines by the Surgical Infection Society and the Infectious Diseases Society of America. Surg Infect. 2010;11(1):79-109.

44. Eckmann C, et al. Antimicrobial treatment of "complicated" intra-abdominal infections and the new IDSA guidelines ? a commentary and an alternative European approach according to clinical

definitions. Eur J Med Res. 2011;16(3):115-26.

45. Pallett A, Hand K. Complicated urinary tract infections: practical solutions for the treatment ofmultiresistant Gram-negative bacteria. J Antimicrob Chemother. 2010;65(3):iii25-33.

46. Grabe M, et al. Guidelines on urological infections. 2015 [Accessed on 23/03/2019]; Available from:http://uroweb.org/wp-content/uploads/EAU-Guidelines-Urological-Infections-v2.pdf.

47. American Thoracic, S. and Infectious Diseases Society of America, Guidelines for the managementof adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia. Am JRespir Crit Care Med. 2005;171(4):388-416.

48. Chaudhry D, Prajapat B. Intensive care unit bugs in India: How do they differ from the westernworld&#63. J Assoc Chest Phys. 2017;5(1):10-17.

49. Vincent J-L, et al. International study of the prevalence and outcomes of infection in intensive careunits. JAMA. 2009;302(21):2323-2329.

50. Gadani H, Vyas A, Kar AK. A study of ventilator-associated pneumonia: Incidence, outcome, riskfactors and measures to be taken for prevention. Ind J Anaesth. 2010;54(6):535.

51. Khurana S, et al. Incidence of ventilator-associated pneumonia and impact of multidrug-resistantinfections on patient's outcome: Experience at an Apex Trauma Centre in North India. Ind J MedMicrobiol. 2017;35(4):504.

52. Wilke M, Grube R. Update on management options in the treatment of nosocomial and ventilatorassisted pneumonia: review of actual guidelines and economic aspects of therapy. Infect DrugResist. 2013;7:1-7.

53. Nathwani D, et al. Clinical and economic consequences of hospital-acquired resistant andmultidrug-resistant Pseudomonas aeruginosa infections: a systematic review and meta-analysis.Antimicrob Resist Infect Control. 2014;3(1):32.

54. Giske CG, et al. Clinical and economic impact of common multidrug-resistant gram-negative bacilli.Antimicrob Agents Chemother. 2008;52(3):813-21.

55. European Centre for Disease Prevention and Control (ECDC). Antimicrobial resistance: Factsheetfor experts. 2015 [Accessed on 23/03/2019]; Available from:http://ecdc.europa.eu/en/ healthtopics/antimicrobial_resistance/basic_facts/Pages/factsheet_experts.aspx.

101

INSIDE PAGE


56. Boucher HW, et al. 10 x '20 Progress--development of new drugs active against gram-negativebacilli: an update from the Infectious Diseases Society of America. Clin Infect Dis.2013;56(12):1685-94.

57. Theuretzbacher U. Recent FDA antibiotic approvals: Good news and bad news. 2015 [Accessed on 23/03/2019]; Available from:http://cddep.org/blog/posts/recent_fda_antibiotic_approvals_good_ news_and_bad_news#sthash.449V4guE.3xVLym3B.dpbs.

58. World Health Organization. Global action plan on antimicrobial resistence 2015 [Accessed on 23/03/2019]; Available from:http://www.wpro.who.int/entity/drug_resistance/resources/global_action_plan_eng.pdf.

59. New Drugs 4 Bad Bugs (ND4BB). Problem statement: Antimicrobial resistance. 2015 [Accessed on 23/03/2019]; Available from: http://www.nd4bb.eu/index.php/project.

60. Congress.gov. H.R.2182 - Generating Antibiotic Incentives Now Act of 2011. [Accessed on 23/03/2019]; Available from: https://www.congress.gov/bill/112th-congress/house-bill/2182.

61. Infectious Diseases Society of America. Antibiotic Development: The 10 x '20 Initiative. 2015 [Accessed on 23/03/2019]; Available from: http://www.idsociety.org/10x20/.

62. DRIVE-AB. Driving reinvestment in R&D for antibiotics and advocating their responsible use. [Accessed on 23/03/2019]; Available from: http://drive-ab.eu/about/.

63. Thabit AK, Crandon JL, Nicolau DP. Antimicrobial resistance: impact on clinical and economic outcomes and the need for new antimicrobials. Expert Opin Pharmacother. 2015;16(2):159-77.

64. World Health Organization Regional Office for Europe. Antimicrobial resistance. 2015 [Accessed on 23/03/2019]; Available from: http://www.euro.who.int/en/health-topics/disease-prevention/ antimicrobial-resistance/antimicrobial-resistance.

65. Lagace-Wiens P, Walkty A, Karlowsky JA. Ceftazidime-avibactam: an evidence-based review of its pharmacology and potential use in the treatment of Gram-negative bacterial infections. Core Evid. 2014;9:13-25.

66. Borgonovi M, Miossec C, Lowther J. The efficacy of ceftazidime combined with NXL104, a novel ß-lactamase inhibitor, in a mouse model of kidney infections induced by ß-lactamase producing Enterobacteriaceae [abstract no. P794]. Clin Microbiol Infect. 2007;13(2):S199-200.

67. Crandon JL, et al. Comparative in vitro and in vivo efficacies of human simulated doses of ceftazidime and ceftazidime-avibactam against Pseudomonas aeruginosa. Antimicrob Agents Chemother. 2012;56(12):6137-46.

68. Endimiani A, et al. Evaluation of ceftazidime and NXL104 in two murine models of infection due to KPC-producing Klebsiella pneumoniae. Antimicrob Agents Chemother. 2011;55(1):82-5.

103

INSIDE PAGE

102

69. Housman ST, et al. Efficacies of ceftazidime-avibactam and ceftazidime against Pseudomonas aeruginosa in a murine lung infection model. Antimicrob Agents Chemother. 2014;58(3):1365-71.

70. Hayes MV, Orr DC, Mode of action of ceftazidime: affinity for the penicillin-binding proteins of Escherichia coli K12, Pseudomonas aeruginosa and Staphylococcus aureus. J Antimicrob Chemother. 1983;12(2):119-26.

71. Davies TA, et al. Binding of ceftobiprole and comparators to the penicillin-binding proteins of Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, and Streptococcus pneumoniae. Antimicrob Agents Chemother. 2007;51(7):2621-4.

72. Coleman K. Diazabicyclooctanes (DBOs): a potent new class of non-beta-lactam beta-lactamase inhibitors. Curr Opin Microbiol. 2011;14(5):550-5.

73. Lahiri SD, et al. Structural insight into potent broad-spectrum inhibition with reversible recyclization mechanism: avibactam in complex with CTX-M-15 and Pseudomonas aeruginosa AmpC beta-lactamases. Antimicrob Agents Chemother. 2013;57(6):2496-505.

74. Ehmann DE, et al. Avibactam is a covalent, reversible, non-beta-lactam beta-lactamase inhibitor. Proc Natl Acad Sci. USA. 2012;109(29):11663-8.

75. Dudley MN, et al. Background and rationale for revised clinical and laboratory standards institute interpretive criteria (Breakpoints) for Enterobacteriaceae and Pseudomonas aeruginosa: I. Cephalosporins and Aztreonam. Clin Infect Dis. 2013;56(9):1301-9.

76. EUCAST. The European Committee on Antimicrobial Susceptibility Testing. Breakpoint tables for interpretation of MICs and zone diameters. Version 7.0. 2017 [Accessed on 23/03/2019]; Available from: http://www.eucast.org/fileadmin/src/media/PDFs/EUCAST_files/Breakpoint_tables/v_7.0_ Breakpoint_Tables.pdf.

77. Pharmaceuticals, S. Ceftazidime PI. 2014 [Accessed on 23/03/2019]; Available from: http://www.sagentpharma.com/wp-content/uploads/2015/04/Ceftazidime-for-Injection-USP-6-g-PI.pdf.

78. Allergan USA Inc. Avycaz US Prescribing Information. 2017 [Accessed on 23/03/2019]; Available from: https://www.allergan.com/assets/pdf/avycaz_pi.

79. Aktas, Z, Kayacan C, Oncul O. In vitro activity of avibactam (NXL104) in combination with beta-lactams against Gram-negative bacteria, including OXA-48 beta-lactamase-producing Klebsiella pneumoniae. Int J Antimicrob Agents. 2012;39(1):86-9.

80. Stachyra T, et al. In vitro activity of the beta-lactamase inhibitor NXL104 against KPC-2 carbapenemase and Enterobacteriaceae expressing KPC carbapenemases. J Antimicrob Chemother. 2009;64(2):326-9.

81. Levasseur P, et al. In vitro antibacterial activity of the ceftazidime-avibactam (NXL104) combination against Pseudomonas aeruginosa clinical isolates. Antimicrob Agents Chemother. 2012;56(3):1606-8.


82. Curcio D. Activity of a novel combination against multidrug-resistant nonfermenters: ceftazidime plus NXL104. Expert Rev Anti Infect Ther. 2011;9(2):173-6.

83. Walkty A, et al. In vitro activity of ceftazidime combined with NXL104 versus Pseudomonas aeruginosa isolates obtained from patients in Canadian hospitals (CANWARD 2009 study). Antimicrob Agents Chemother. 2011;55(6):2992-4.

84. Mushtaq S,Warner M, Livermore DM. In vitro activity of ceftazidime+NXL104 against Pseudomonas aeruginosa and other non-fermenters. J Antimicrob Chemother. 2010;65(11):2376-81.

85. Lagace-Wiens PR, et al. Activity of NXL104 in combination with beta-lactams against genetically characterized Escherichia coli and Klebsiella pneumoniae isolates producing class A extended-spectrum beta-lactamases and class C beta-lactamases. Antimicrob Agents Chemother. 2011;55(5):2434-7.

86. Endimiani A, Choudhary Y and Bonomo RA. In vitro activity of NXL104 in combination with beta-lactams against Klebsiella pneumoniae isolates producing KPC carbapenemases. Antimicrob Agents Chemother. 2009;53(8):3599-601.

87. Karlowsky JA, et al. In vitro activity of ceftaroline-avibactam against gram-negative and gram-positive pathogens isolated from patients in Canadian hospitals from 2010 to 2012: results from the CANWARD surveillance study. Antimicrob Agents Chemother. 2013;57(11):5600-11.

88. Berkhout J, et al. Pharmacokinetics and penetration of ceftazidime and avibactam into epithelial lining fluid in thigh- and lung-infected mice. Antimicrob Agents Chemother. 2015;59(4):2299-304.

89. Li H, et al. In vitro susceptibility of characterized beta-lactamase-producing strains tested with avibactam combinations. Antimicrob Agents Chemother. 2015;59(3):1789-93.

90. Yoshizumi A, et al. In vitro susceptibility of characterized beta-lactamase-producing Gram-negative bacteria isolated in Japan to ceftazidime-,ceftaroline-, and aztreonam-avibactam combinations. J Infect Chemother. 2015;21(2):148-51.

91. Papp-Wallace KM, et al. Activities of ceftazidime, ceftaroline, and aztreonam alone and combined with avibactam against isogenic Escherichia coli strains expressing selected single beta-lactamases. Diagn Microbiol Infect Dis. 2015;82(1):65-9.

92. Livermore DM. Multiple mechanisms of antimicrobial resistance in Pseudomonas aeruginosa: our worst nightmare? Clin Infect Dis. 2002;34(5):634-40.

93. Dubreuil LJ, et al. Anti-anaerobic activity of a new beta-lactamase inhibitor NXL104 in combination with beta-lactams and metronidazole. Int J Antimicrob Agents. 2012;39(6):500-4.

94. Bonnefoy A, et al. In vitro activity of AVE1330A, an innovative broad-spectrum non-beta-lactam beta-lactamase inhibitor. J Antimicrob Chemother. 2004;54(2):410-7.

105

INSIDE PAGE

104

95. Docquier J, et al. High resolution crystal structure of CTX-M-15 in complex with the new ß –lactamase inhibitor NXL104 [abstract no. C1-1098 plus oral presentation], in 49th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy. 2009: San Francisco (CA).

96. Pechereau M, et al. Activite in vitro de NXL104 sur CTX-M-15 et KPC-2: un nouvel inhibiteur de ß-lactamases a spectre etendu (BLSE) et de carbapenemases de classe A [abstract no. 468 plus poster], in 28eme Reunion Interdisciplinaire de Chimiotherapie Anti-infectieuse. 2008: Paris.

97. Pechereau M, et al. Activite in vitro de NXL104 sur SHV-4: un nouvel inhibiteur des ß-lactamases a spectre etendu [abstract no. 382 plus poster] in 26eme Reunion Interdisciplinaire de Chimiotherapie Anti-infectieuse. 2006: Paris.

98. Stachyra T, et al. Activity of the new ß-lactamase inhibitor NXL104 against KPC ß-lactamases [abstract no. F1-320 plus poster], in 47th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy. 2007: Chicago [IL].

99. Stachyra T, et al. Mechanistic studies of the inactivation of TEM-1 and P99 by NXL104, a novel non-beta-lactam beta-lactamase inhibitor. Antimicrob Agents Chemother. 2010;54(12):5132-8.

100. Hackel M, et al. A global assessment of the in vitro activity of ceftazidime-avibactam against multi-drug-resistant Klebsiella spp. - INFORM Surveillance Program 2012. Poster E-1685, in 53rd

ICAAC. 2013: Denver CO.

101. Sader HS, et al. Ceftazidime/avibactam tested against Gram-negative bacteria from intensive care unit (ICU) and non-ICU patients, including those with ventilator-associated pneumonia. Int J Antimicrob Agents. 2015;46(1):53-9.

102. Flamm RK, et al. Avibactam reverts the ceftazidime MIC90 of European Gram-negative bacterial clinical isolates to the epidemiological cut-off value. J Chemother. 2014;26(6):333-8.

103. Lahiri SD, et al. Selection and molecular characterization of ceftazidime/avibactam-resistant mutants in Pseudomonas aeruginosa strains containing derepressed AmpC. J Antimicrob Chemother. 2015;70(6):1650-8.

104. AstraZeneca(A). Core Data Sheet Zavicefta (ceftazidime-avibactam), powder for solution for infusion, 2 g + 0.5 g. 2015 [13 February 2015 15 September 2015].

105. Das S, et al. Randomized pharmacokinetic and drug-drug interaction studies of ceftazidime, avibactam, and metronidazole in healthy subjects. Pharmacol Res Perspect. 2015;3(5):e00172.

106. Vishwanathan K, et al. Assessment of the mass balance recovery and metabolite profile of avibactam in humans and in vitro drug-drug interaction potential. Drug Metab Dispos. 2014; 42(5):932-42.

107. Merdjan H, Rangaraju M, Tarral A. Safety and pharmacokinetics of single and multiple ascending doses of avibactam alone and in combination with ceftazidime in healthy male volunteers: results of two randomized, placebo-controlled studies. Clin Drug Investig. 2015;35(5):307-17.


108. Nicolau DP, et al. Phase 1 study assessing the steady-state concentration of ceftazidime and avibactam in plasma and epithelial lining fluid following two dosing regimens. J Antimicrob Chemother. 2015;70(10):2862-9.

109. Rains CP, Bryson HM, Peters DH. Ceftazidime. An update of its antibacterial activity, pharmacokinetic properties and therapeutic efficacy. Drugs. 1995;49(4):577-617.

110. Richards DM. Brogden RN. Ceftazidime. A review of its antibacterial activity, pharmacokinetic properties and therapeutic use. Drugs. 1985;29(2):105-61.

111. Li J, et al. Population pharmacokinetic modeling of ceftazidime (CAZ) and avibactam (AVI) in healthy volunteers and patients with complicated intra-abdominal infec tion (cIAI) (Poster A-634), in 52nd Annual Interscience Conference on Antimicrobial Agents and Chemotherapy. 2012: San Francisco (CA).

112. Berkhout J, et al. Exposure response relationships of ceftazidime and avibactam in a neutropenic thigh model (Poster A-1023), in 53rd lnterscience Conference on Antimicrobial Agents and Chemotherapy. 2013: Denver (CO).

113. Coleman K, et al. Activities of ceftazidime and avibactam against beta-lactamase-producing Enterobacteriaceae in a hollow-fiber pharmacodynamic model. Antimicrob Agents Chemother. 2014;58(6):3366-72.

114. LI J, et al. PK/PD Target Attainment Analyses and Assessment of Dose Adjustments for Renal Insufficiency for Ceftazidime-Avibactam (CAZ-AVI) in Patients with Complicated Intra-abdominal Infection (cIAI), Complicated Urinary Tract Infection (cUTI) or Nosocomial Pneumonia (NP), in American Association of Pharmaceutical Scientists Annual Meeting and Exposition 2015. 2015: Orlando, Florida, USA.

115. Das S, Nichols WW, Li J. Dose selection of ceftazidime-avibactam in patients with nosocomial pneumonia, including ventilator-associated pneumonia, based on preclinical efficacy, preclinical pharmacokinetic/pharmacodynamic and clinical pharmacokinetic data (Poster P1288), in 25th European Congress of Clinical Microbiology and Infectious Diseases. 2015: Copenhagen.

116. Li J, et al. Population pharmacokinetic modelling of ceftazidime and avibactam and probability of target attainment to support the dosing regimen in patients with nosocomial pneumonia including ventilator-associated pneumonia (Poster P1289), in 25th European Congress of Clinical Microbiology and Infectious Diseases. 2015: Copenhagen.

117. Wockhardt. Ceftazidime Summary of Product Characteristics. 2015 [Accessed on 23/03/2019]; Available from: https://www.medicines.org.uk/emc/medicine/21129.

118. Tarral A and Merdjan H. Effect of age and sex on the pharmacokinetics and safety of avibactam in healthy volunteers. Clin Ther. 2015;37(4):877-86.

107

INSIDE PAGE

106

119. Nicolau DP, et al. Concentration of avibactam (AVI) and ceftazidime (CAZ) in plasma and epithelial lining fluid (ELF) in healthy volunteers (Poster A-1027), in 53rd International Conference on Antimicrobial Agents and Chemotherapy. 2013: Denver (CO).

120. Verhagen CA, Mattie H, van Strijen E. The renal clearance of cefuroxime and ceftazidime and the effect of probenecid on their tubular excretion. Br J Clin Pharmacol. 1994;37(2):193-7.

121. Lucasti C, et al. Comparative study of the efficacy and safety of ceftazidime/avibactam plus metronidazole versus meropenem in the treatment of complicated intra-abdominal infections in hospitalized adults: results of a randomized, double-blind, Phase II trial. J Antimicrob Chemother. 2013;68(5):1183-92.

122. Mazuski JE, et al. Efficacy and safety of ceftazidime-avibactam plus metronidazole versus meropenem in the treatment of complicated intra-abdominal infection – results from a Phase III program (RECLAIM) (Oral 0191), in 25th European Congress of Clinical Microbiology and Infectious Diseases. 2015: Copenhagen.

123. Lawson R and Ryan K. Investigating the impact of treatment failure on healthcare resource utilization from the RECLAIM trial (ePoster EV0360), in 25th European Congress of Clinical Microbiology and Infectious Diseases. 2015: Copenhagen.

124. India Subset analysis based on study: A Phase III, Randomized, Multicenter, Double-Blind, Double-Dummy, Parallel-Group, Comparative Study toDetermine the Efficacy, Safety, and Tolerability of Ceftazidime-Avibactam (CAZ-AVI) Plus Metronidazole Versus Meropenem in the Treatment of Complicated Intra-Abdominal Infections (cIAIs) in Hospitalized Adults_Data on File; Protocol D4280C00001/5 (C3591015/08). January 2018, AstraZeneca AB-Pfizer Ltd.

125. Mazuski JE, et al. Efficacy and safety of ceftazidime-avibactam plus metronidazole versus meropenem in the treatment of complicated intra-abdominal infection: results from a randomized, controlled, double-blind, phase 3 program. Clin Infect Dis. 2016; 62(11):1380-1389.

126. Vazquez JA, et al. Efficacy and safety of ceftazidime-avibactam versus imipenem-cilastatin in the treatment of complicated urinary tract infections, including acute pyelonephritis, in hospitalized adults: results of a prospective, investigator-blinded, randomized study. Curr Med Res Opin. 2012;28(12):1921-31.

127. Wagenlehner FM, et al. Ceftazidime-avibactam Versus Doripenem for the Treatment of Complicated Urinary Tract Infections, Including Acute Pyelonephritis: RECAPTURE, a Phase 3 Randomized Trial Program. Clin Infect Dis. 2016;63(6):754-762.

128. AstraZeneca(B), Data on file: Ceftazidime-Avibactam (CAZ-AVI) REPRISE top-level results. 2015.

129. Carmeli Y, et al. Ceftazidime-avibactam or best available therapy in patients with ceftazidime-resistant Enterobacteriaceae and Pseudomonas aeruginosa complicated urinary tract infections or complicated intra-abdominal infections (REPRISE): a randomised, pathogen-directed, phase 3 study. Lancet Infect Dis. 2016;16(6):661-673.

130. Carmeli Y, et al. Efficacy and safety of ceftazidime-avibactam and best available therapy in the treatment of ceftazidime-resistant infections – results from a Phase III study (REPRISE) (ePoster LBEV0061b), in 25th European Congress of Clinical Microbiology and Infectious Diseases. 2015: Copenhagen.

131. Kalil AC, et al. Executive Summary: Management of Adults With Hospital-acquired and Ventilator-associated Pneumonia: 2016 Clinical Practice Guidelines by the Infectious Diseases Society of America and the American Thoracic Society. Clin Infect Dis. 2016;63(5):575-82.


133. India Subset Analysis based on study: Phase III, Randomized, Multicentre, Double-blind, Double-dummy, Parallel-group Comparative Study to Determine the Efficacy, Safety and Tolerability of Ceftazidime-Avibactam (CAZ-AVI) Versus Meropenem in the Treatment of Nosocomial Pneumonia (NP) Including Ventilator-Associated Pneumonia (VAP) in Hospitalised Adults_Data on File; Protocol D4281C00001 (C3591006). January 2018.



Pfizer Limited, The Capital - A Wing, 1802, 18th Floor, Plot No. C-70, G Block, Bandra-Kurla Complex, Bandra (East), Mumbai 400 051, India.

PP-Z

VA-I

ND

-000

4 1

2th J

une

2019

For the use only of Registered Medical Practitioners, or a Hospital or a Laboratory.

zavicefta product monograph - pfizer pro · 1.1 summary antimicrobial resistance is a growing...

Documents