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Cubicin Monograph V2.1:Cubicin Monograph 1-4.qxd 19/12/07 08:23

Figure 1.1

European Antimicrobial Resistance Surveillance System(EARSS)

Table 1.3

Lawrence Eron, Journal of Antimicrobial Chemotherapy(52 (Suppl S1)) pp. i3–i17

Copyright © 2003 by The British Society forAntimicrobial ChemotherapyReprinted by permission of Oxford University Press

Table 2.2

Ronan J Murray, In: Internal Medicine Journal BlackwellPublishing, 2005;35:S25–S44

Table 2.3

Jennifer Li et al., Clinical Infectious Diseases (30) pp. 633–638

Copyright © 2000 by the Infectious Diseases Society ofAmericaReprinted by permission of The University of ChicagoPress

Table 3.9

Judith N Steenbergen, Journal of AntimicrobialChemotherapy (55) pp. 283–288

Copyright © 2005 by The British Society forAntimicrobial ChemotherapyReprinted by permission of Oxford University Press

Figure 4.4

Winifred V Kern, International Journal of Clinical Practice(60: (3)) pp. 370–378

Copyright © 2006 by Blackwell PublishingReprinted by permission of Blackwell Publishing

Figure 4.5

Grace M Thorne, Clinical Microbiology Newsletter (24(5))pp. 33–40

Copyright © 2002 by Elsevier ScienceReprinted by permission of Elsevier Science

Figure 4.6

Kerry L LaPlante, Antimicrobial Agents and

Chemotherapy (48(12)) pp. 4665–4672

Copyright © 2004 by American Society for MicrobiologyReprinted by permission of SAGE Publications, Inc.

Figure 4.7

Barry H Dvorchik, Antimicrobial Agents andChemotherapy (47(4)) pp. 1318–1323


Figure 4.8

Mark Benvenuto, Antimicrobial Agents andChemotherapy (50(10)) pp. 3245–3249


Figure 4.9

Barry H Dvorchik, Journal of Clinical Pharmacology (44)pp. 715–722

Copyright © 2004 by American College of ClinicalPharmacologyReprinted by permission of SAGE Publications, Inc.

Figure 4.10

Barry H Dvorchik, Journal of Clinical Pharmacology (45)pp. 48–56

Copyright © 2005 by American College of ClinicalPharmacologyReprinted by permission of SAGE Publications, Inc.

Figure 5.1 and Tables 5.2, 5.3, 5.4 and 5.5

Robert D Arbeit, Clinical Infectious Diseases (38) pp. 1673–1681

Copyright © 2004 by the Infectious Diseases Society ofAmericaReprinted by permission University of Chicago Press

Tables 5.9 and 5.10

Vance G Fowler, Clinical Infectious Diseases (355) pp. 653–665

Copyright © 2006 by the Massachusetts MedicalSociety. All rights reserved.

AcknowledgementsWe gratefully acknowledge the publishers and individuals who allowed us to reproducethe following illustrations:

CUBICIN is a trademark of Cubist Pharmaceuticals, Inc. (“Cubist”) and is registered in the United States and otherjurisdictions. Novartis markets CUBICIN under licence from Cubist.

© 2007 Novartis AG, 4002 Basel, Switzerland.

Distributed as a service to medicine by Novartis AG, 4002 Basel, Switzerland.

All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted inany form by any means, electronic, mechanical, photocopying, recording, or otherwise, without the prior writtenpermission of the publisher.

Although great care is taken to ensure accuracy, the publishers will not be liable for any errors or omissions in thispublication. Any product mentioned in this publication should be used in accordance with the prescribinginformation prepared by the manufacturers.

Prepared for publication by Chameleon Communications International Ltd, London, UK.

Printed November 2007.

PAGE 2


Contents

Introduction 4

1. Skin and soft tissue infections 5

2. Staphylococcus aureus bacteraemia and infective endocarditis 19

3. Cubicin history and development 29

4. Cubicin product profile 31

5. Cubicin in cSSTI clinical trials 47

6. Summary of product characteristics 63

7. References 71

PAGE 3PAGE 3


IntroductionComplicated skin and soft tissue infections (cSSTIs) are a growing problem worldwide. InEurope, it is estimated that ~10% of hospital admissions for infections are for cSSTIs,1 ofwhich an increasing proportion is caused by Gram-positive bacteria.2 In several Europeancountries, it has been found that around 40% of Gram-positive cSSTIs are caused byStaphylococcus aureus,2 and approximately 40% of these infections are caused bymethicillin-resistant S. aureus (MRSA).3 The emergence and evolution of resistance tomany currently used antibiotics,4 combined with the increasing incidence of community-acquired infections, provides challenges in anti-infective treatment.5

Staphylococcus aureus is a leading cause of bacteraemia and infective endocarditis (IE) inmany parts of the world,6-8 with the prevalence of methicillin-resistant strains at an all-time high in some institutions.9 Staphylococcus aureus bacteraemia (SAB) and IE are bothassociated with a poor outcome, with mortality rates for SAB and IE reported as high as29% and 29.4%, respectively.7,10 The prevalence of SAB and IE is increasing11 – this hasbeen attributed to the increased use of invasive procedures, prosthetic devices andintravascular catheters.11

The current management of cSSTIs, SAB and IE is based on the correct selection of anappropriate therapy to rapidly clear the infection. Many currently used antibiotics arevery effective against particular pathogens;12 however, laboratory tests are usuallyrequired for identification, which can take several days and may delay the initiation oftreatment. Delayed or inappropriate therapy of these infections may increase the risk ofmortality13 and lead to further complications.14

Cubicin is the first in a new class of antibiotics called the cyclic lipopeptides, and has anovel mode of action that is advantageous in terms of its efficacy against antibiotic-resistant strains. It has been shown to be effective in vitro against infections caused byGram-positive bacteria, including both methicillin-susceptible S. aureus (MSSA) andMRSA.15 Phase III clinical trials have determined the efficacy and safety of Cubicin relativeto comparator agents,16,17 resulting in approval of Cubicin for the initial treatment ofcSSTIs, SAB and IE in several countries worldwide. Cubicin is an intravenous antibioticapproved in the US and the EU for the treatment of cSSTIs, right-sided infectiveendocarditis (RIE) caused by S. aureus and S. aureus bacteraemia when associated withcSSTI or RIE.

Cubicin has several advantages over current comparator anti-infective agents. It israpidly bactericidal15 with negligible cell lysis,18 which could potentially minimize the riskof release of harmful bacterial toxins into the circulation upon cell death. Furthermore,the prolonged post-antibiotic effect of Cubicin19 delays bacterial regrowth and enablescontinued bacterial suppression in the period following drug exposure, potentiallyallowing for increased duration between doses. Once-daily administration of Cubicinallows for potential outpatient therapy.

PAGE 4


1. Skin and soft tissue infections 1.1 Introduction to skin and soft tissue infections1.1.1 Summary

1.2 Skin and soft tissue infectionsSkin and soft tissue infections (SSTIs) are defined as microbial infections of theepidermis, dermis or subcutaneous tissue that induce a host response.22,23 They areamong the most common human bacterial infections and are one of the mainreasons why individuals seek medical advice.22 Therefore, they represent one of themost common reasons for initiating antimicrobial therapy.22

SSTIs may be caused by numerous different pathogens, and can present with a widevariety of clinical signs and symptoms, which range in severity from mild skin ulcersto serious necrotizing infections.21 Although there are several classification systems,the division into uncomplicated and complicated SSTIs (cSSTIs) draws the distinctionbetween those that can usually be managed in the community and those thatrequire hospitalization with possibly both surgical and antibiotic treatment.24

The majority of SSTIs are treated on an outpatient basis.25 SSTIs account for up to10% of all hospital admissions in North America21 and Europe.1 The most common iscellulitis (28% of all SSTI hospital admissions), followed by surgical-site infection(20%), and diabetic foot infections (14%).26

Surgical-site infections are the third most common type of nosocomial infection,occurring in approximately 500,000 of the ~27 million patients in the US whoundergo surgery annually.27 These patients account for 25% of the ~2 millionnosocomial infections that occur annually in US hospitals.28

1.3 Principal Gram-positive pathogens isolated from cSSTIsGram-positive cocci – most notably Staphylococcus aureus – and Gram-negative rodsare the most common bacteria isolated from patients who are hospitalized withcSSTIs.29 According to the SENTRY Antimicrobial Surveillance Program, S. aureus is themajor pathogen in SSTIs, present in approximately 40% of all clinical isolates fromEurope in 2004.2

SSTIs are highly prevalent in both community and hospital settings,and range from mild skin ulcers to serious necrotizing infections20

SSTIs can be categorized as either uncomplicated or complicated. Thelatter are more problematic and may require hospitalization21

The majority of SSTIs are caused by the two main genera of Gram-positive bacteria: staphylococci and streptococci. Enterococci areoccasional isolates. At least 40% of cases are caused by a singlepathogen: S. aureus2

The epidemiology of S. aureus infections is changing, with an increasein both hospital-acquired MRSA and community-acquired MRSA5

PAGE 5

SECTION 1

SKIN AND SOFT TISSUEINFECTIONS

PAGE 5

cSSTIs are seriousconditions that

may requirehospitalization


Different pathogens may predominate in certain SSTIs and/or in certain patientsubpopulations, and this may reflect differences in infection type, environmentalsource, risk factors and comorbidities. Often, more than one pathogen can beisolated from cSSTIs; for example, 75% of diabetic foot infections in hospitalizedpatients involve multiple bacterial pathogens.30

There are three major, clinically important types of Gram-positive bacteria in isolatesfrom patients with cSSTIs: staphylococci, streptococci and enterococci.2 The primarydefence against infecting organisms is the innate immune system; however, bacteriaexpress a wide array of secreted and cell surface virulence factors that enable themto overcome the immune response.31 Some of the virulence factors for thesebacterial species are given in Table 1.1.

Table 1.1. Summary of Gram-positive bacterial virulence factors

1.3.1 StaphylococciStaphylococci are ubiquitous colonizers of the skin and mucosal surfaces, and cancause a variety of infections if they enter the body via skin wounds (due tointravenous [i.v.] drug abuse, accidental trauma, or animal bites) or invasive medicalprocedures.32 Staphylococcus aureus is the most virulent staphylococcal species inhumans,5 and the main cause of cSSTIs.2 As noted previously, it is estimated that S. aureus is the causative pathogen in up to 40% of SSTIs.2

Staphylococcus aureus infections are particularly problematic for treating physicians.Over 90% of S. aureus isolates have an outer polysaccharide capsule, which protectsthe bacteria from ingestion by host immune cells and may also increase virulence.35

Interactions between S. aureus cell surface proteins and mucin enable this pathogento successfully colonize the mucous membranes of the nares.32 This could create achronic carrier state, which may be a source of infection in others, especially if thecarrier is involved in healthcare delivery or food handling.

SECTION 1


ESP, extracellular surface protein; MSCRAMMs, microbial surface components recognizing adhesive matrix molecules

Virulence factor Mechanism of action

Staphylococci Adhesion factors: MSCRAMMs32

Fibronectin-binding protein33

Toxins:Panton–Valentine leukocidin toxin34

α-toxin34

Pyrogenic T-cell superantigentoxin32

Polysaccharide capsule28

Protein A25

Adhesion to host tissue and devicesurfaces

Host cell damage

Inhibits phagocytosisAnti-phagocytic surface protein

Streptococci Adhesion factors:M protein36

Lipoteichoic acid37

Fibronectin-binding protein37

Haemolysins38

Streptokinase39

DNase40

Peptidases41,42

Streptococcal pyrogenic exotoxins43– 45

Hyaluronic acid capsule

Mediates adhesion to host tissueand other surfaces

Lysis of red blood cells andimmune cellsHost cell damage

Inhibits phagocytosis

Enterococci Adhesion factors:ESP46

Aggregation substance47

Serine proteases47

Gelatinases47

Haemolysins46

Bacterial aggregation, adhesion tohost tissue and other surfaces

Lysis of red blood cells andimmune cells

Staphylococcus aureusis the causativepathogen in up to 40%of SSTIs

Staphylococcus aureusis the most virulent staphylococcal speciesin humans


Staphylococcus aureus is also often the cause of deep-seated infections, such asinfective endocarditis (IE).32 This is due to its unique ability to adhere to, and formvegetations on, normal heart valves.32 It also has the ability to adhere to foreign orprosthetic materials, such as intravenous catheters coated with serum proteins (e.g.fibrinogen and fibronectin) and form biofilms, via ‘microbial surface componentsrecognizing adhesive matrix molecules’.32 Consequently, medical devices, includingintravenous catheters, are commonly associated with S. aureus infection.

Upon entry into the bloodstream through a skin lesion, S. aureus adheres to, and isphagocytosed by, endothelial cells.32 Once inside the endothelial cell, it is protectedfrom the host immune response and from bactericidal drugs in the hostbloodstream.32 Subsequently, secretion of proteases by S. aureus lyses the endothelialcell, facilitating dissemination within the bloodstream and spread of infection toadjoining tissues.32 When in the bloodstream, S. aureus may also evade the antibody-mediated host immune response by the expression of anti-phagocytic surfaceproteins (e.g. protein A).32

Staphylococcus aureus produces several toxins (Table 1.1), such as α-toxin (a 33 kDaprotein) and pyrogenic T-cell superantigen toxins (e.g. toxic shock syndrome toxin 1),which lead to host cell damage and life-threatening complications (e.g. septicshock).32 An increasing proportion of S. aureus strains produce the Panton–Valentineleukocidin (PVL) toxin, which can combine with γ-haemolysin and attack white bloodcells.34 Furthermore, S. aureus abrogates the effects of penicillin by producing β-lactamase.32

Around 20% of healthy individuals are carriers of S. aureus, and up to 60% areintermittent carriers.33 In addition to the skin, sites typically colonized by S. aureus arethe anterior nares, axillae and the perianal area.32

1.3.2 Streptococci

The Streptococcus genus is a large and diverse group of bacteria, ranging in virulencefrom harmless, normal flora to major human pathogens. In addition to streptococcalthroat infections (strep throat), streptococci are responsible for many cases ofmeningitis, bacterial pneumonia, endocarditis and necrotizing fasciitis.48

Streptococci generally possess the same types of virulence factors as other Gram-positive bacteria (Table 1.1). However, some streptococci produce additional virulencefactors, including specific enzymes and toxins that are unique to the species andmay vary between serotypes of the same species (Table 1.1). For example, virulencefactors produced by Streptococcus pyogenes include:

M protein – which mediates skin adherence via binding to glycosaminoglycans,36

and prevents phagocytosis by host immune cells36

Lipoteichoic acid and fibronectin-binding protein37 – which aid adhesion toepithelial cells

Haemolysins38 – which damage the host tissue and immune cells

Enzymes – which contribute to tissue invasion and destruction (e.g.streptokinase,39 DNAse40 and peptidases41,42

)

Streptococcal pyrogenic exotoxins – which are a family of superantigensassociated with streptococcal toxic shock syndrome,43 necrotizing fasciitis44 andscarlet fever45

The presence of a hyaluronic acid capsule – which inhibits phagocytosis by host cells49

SECTION 1


Medical devices,including intravenous

catheters, arecommonly associated

with S. aureusinfection

Streptococci areresponsible for many

cases of meningitis,bacterial pneumonia,

endocarditis andnecrotizing

fasciitis


1.3.3 Enterococci

Enterococci are normally found in soil, food and water and form part of the normalbacterial flora of humans, particularly in the gut.47 Only two species of Enterococcusare commonly implicated in human disease: Enterococcus faecalis and Enterococcusfaecium.50 Until recently, E. faecalis was estimated to account for 80–90% of clinicalenterococcal isolates, and E. faecium for 5–10%, but there is evidence that E. faeciumis becoming more common, especially in hospital-acquired SSTIs.50 Enterococci arefrequently isolated from nosocomial SSTIs,2,51 and are often found in mixed infectionsinvolving multiple pathogens.52 These are more likely to occur in patients withserious underlying disease,53 or those who have had an invasive medical procedure.27

In addition, enterococci are commonly found in urinary tract infections, bacterialendocarditis and bacteraemia.50 Enterococci are not as virulent as S. aureus; however,they do possess adhesion factors, including the extracellular surface protein46 and‘aggregation substance’,47 to promote bacterial aggregation and adherence to hosttissues and other surfaces.47 They also produce enzymes, including serine proteasesand gelatinases, which may enhance enterococcal virulence by aiding bacterialdissemination.47 In addition, some E. faecalis strains produce haemolysins (Table 1.1).46

1.4 The spectre of resistance1.4.1 The emergence of resistant strains Since the introduction of penicillin in the 1940s, bacteria have developed resistanceto antimicrobial agents through natural selection of random mutations andhorizontal transmission.54,55 The prevalence of antibiotic resistance has increaseddramatically over the past 2 decades, particularly in staphylococci and enterococci.4

Common mechanisms of resistance include drug inactivation or modification, such as:

Inactivation of penicillin by production of β-lactamase54

Alteration of the antibiotic binding site54

Alteration of metabolic pathways55

Reduced drug accumulation, by decreasing drug permeability and/or increasingdrug efflux54

Resistant species of bacteria are difficult to treat and have serious morbidity andmortality implications for infected patients, which are associated with increasedhealthcare costs and treatment failures.54

1.4.2 The emergence of MRSAOf particular note among the resistant bacteria commonly encountered is methicillin-resistant S. aureus (MRSA), which is causing a significant clinical challengein many countries.54 MRSA now accounts for some 50% or more of all S. aureusinfections in some areas of Europe,3 the Far East, including Japan, China and Taiwan,56

and the US.57 However, MRSA rates do vary widely between countries and regions;currently, the European countries with the highest rates of MRSA are Romania (61.4%),Cyprus (55.6%), Malta (55.1%), Portugal (46.6%), and the UK (43.6%) (Figure 1.1).3

1.4.3 Hospital-acquired MRSAMRSA colonization of healthy carriers varies with age, underlying disease andoccupation. For example, MRSA carrier rates are 11–32% among healthy adults, and25% among hospital staff.58 Higher carrier rates are also found in individuals at highrisk of S. aureus infection, including intravenous drug users, patients with insulin-dependent diabetes mellitus, patients with long-term indwelling catheters, andthose living or working in closed communities (Table 1.2).58PAGE 8

SECTION 1


Enterococci are amajor cause ofnosocomialinfections

The incidence ofMRSA is risingrapidly across the EU


Table 1.2. Individuals with an increased risk of cSSTIs caused by MRSA

1.4.4 Community-acquired MRSAThe first community-acquired-MRSA (CA-MRSA) isolates were identified in WesternAustralia in the early 1990s.62 These initial strains were of low virulence and typicallyassociated with mild-to-moderate infections.62 Since the late 1990s, MRSA hasreplaced methicillin-susceptible S. aureus (MSSA) as a major cause of community-acquired infections in several locations, including the US (59% of S. aureus SSTIs) andWestern Australia (77.5% of MRSA isolates).5,62 In fact, CA-MRSA has been described asreaching epidemic proportions in the US.5

CA-MRSA has also shifted in genotype since the late 1990s, acquiring mobile geneticelements that have conferred increasing virulence (e.g. PVL genes).5,62 The PVL toxincauses tissue necrosis and leukocyte destruction.62,63 Consequently, CA-MRSA is nowassociated with a more severe pattern of infection (e.g. necrotizing pneumonia,necrotizing fasciitis, severe sepsis and Waterhouse–Friderichsen syndrome), and canaffect previously healthy individuals with few or no traditional healthcare-associatedrisk factors for MRSA (Table 1.2).5,64 PAGE 9

SECTION 1


Figure 1.1. Proportion of S. aureus isolates that were methicillin resistant acrossEurope in 2005

3

No Data<1%

1 – 5%

5 – 10%

10 – 25%

25 – 50%

>50%

At-risk groups Predisposing factors

Hospital-acquired MRSA

Immunosuppressed patients23 (e.g.chemotherapy recipients, transplantrecipients, persons infected withHIV)Patients with diabetes mellitus23

Renal haemodialysis patients23

Patients undergoing surgicalprocedures, including implants andother hardware (e.g. catheters)23

ICU patients59

Advanced age23

Asplenia23

Underlying disease (e.g. chronic renalor liver disease)23

Alcohol abuse23

Recent antimicrobial therapy23

Community-acquired MRSA

Prison inmates60

Sports teams61

Homosexual men60

Military personnel61

Children at daycare centres60

Close physical contact61

Intravenous drug use60

Recent hospitalization23


Currently, although more prevalent outside Europe, small numbers of cases of thesehighly virulent strains of CA-MRSA have been identified in France, Scotland, TheNetherlands, Switzerland and Greece,64,65 and are anticipated to become more prevalent.

Analysis of the genetic backgrounds of these strains suggests that CA-MRSA did notemerge from hospital-acquired MRSA, and may have co-evolved simultaneously inthree separate continents.66 This changing pattern of patient susceptibilities andpathogen genotypes has implications for the control and treatment of S. aureuscSSTIs.

1.4.5 The impact of MRSA infectionsInfections due to S. aureus, especially MRSA, represent a major burden on healthcaresystems.67 For example, the estimated cost of a 2-year outbreak of MRSA in Kettering,UK, was £400,000, not including the cost of additional length of hospital stay,68

which, in a separate study, was found to be 5 (median) additional days’hospitalization for patients with MRSA infections compared with patients with MSSAinfections.69 In the US, a study of 479 patients with surgical-site infections revealedthat patients with MRSA had a 1.19-fold increase in hospital charges, equating to anextra $13,901 per infection, compared with patients with MSSA.69 Staphylococcusaureus infections are associated with high mortality rates,70 which are probably dueto the high rates of MRSA strains. Compared with MSSA infections, MRSA infectionsare associated with increased incidence of bacteraemia,10 septic shock,71

amputation72 and mortality (Figure 1.2).73,74,75

In addition, patients with MRSA have been reported to have a significantly longerlength of stay in hospital than those with MSSA (P=0.016),76 and thereby incursignificantly higher costs.76,69 Three studies have shown that MRSA infections are morecostly to manage than other types of infection, and that the length of stay in thehospital is a major determinant of the total cost of an episode of infection.70,77,78

1.4.6 Glycopeptide resistance in S. aureusA consequence of the rising prevalence of MRSA is the increasing use of glycopeptideantibiotics against these infections, which may result in the emergence of higherrates of glycopeptide resistance.79 Another factor causing the emergence ofvancomycin resistance has been the increased use of oral vancomycin to treatClostridium difficile gastroenteritis,80 with the result of increased incidence ofvancomycin-resistant enterococci (VRE) in hospitals that has the potential to spreadresistance elements into more-pathogenic bacteria, including S. aureus.81 This hasresulted in resistance or lack of success when using vancomycin to treat systemicinfection in hospitals where the above-treatment protocol has been frequently usedto manage pseudomembranous colitis. PAGE 10

SECTION 1


Figure 1.2. Mortality rates in patients with MRSA and MSSA bloodstream infections,from a meta-analysis of studies from 1980 to 2000

75

0

5

Mor

talit

y (%

)

1980–2000

N=3963

MRSA MSSA

15

10

20

25

30

35

4036.4

23.4


The first staphylococci with reduced vancomycin susceptibility was isolated in Japanin 1997.82 Vancomycin-intermediate strains of S. aureus (VISA), with minimuminhibitory concentrations (MICs) of 8 μg/ml, are still quite rare;83 more common areheteroresistant strains (hVISA), accounting for 26% of MRSA infections in fourJapanese hospitals.84 However, prevalence is still low in Europe, between 0–5%;85 forexample, Belgian hospitals report an incidence of 0.7%.86 The MICs of hVISA strainsare within the susceptible range, but subpopulations with reduced susceptibility arepresent that may have the potential to develop into VISA strains. Treatment-failurerates of strains susceptible to vancomycin are still relatively high, with 55.6% ofpatients treated successfully when the MIC is ≤0.5 μg/ml, and only 9.5% treatedsuccessfully when the MIC is 1–2 μg/ml.87 Vancomycin-resistant strains of S. aureus(VRSA), with MIC values ≥32 μg/ml, have now been reported in the US.88 Treatmentguidelines suggest the cautious use of vancomycin,89 and that it should not be usedfor known MSSA infections unless there is a β-lactam allergy.90,91

1.4.7 Vancomycin-resistant enterococciVRE were reported in Europe by 1986 and in the US by 1987.92 By 2002, the prevalenceof VRE in ICUs in the US had reached 27.5%.57 VRE have a major impact on mortality,estimated at 76% (overall mortality rate) for bacteraemia caused by VRE comparedwith 41% for patients with vancomycin-susceptible enterococcal bacteraemia,93 aswell as increased duration of treatment and associated hospital costs.93 Resistance isconferred by the acquisition of VanA–VanE92 and VanG resistance genes;94 VanA andVanB are inducibly resistant with high MIC values,81 VanC and VanE show low-levelresistance with MICs of 4–32 μg/ml and ≥16 μg/ml, respectively.81 VanG confers MICvalues of 12–16 μg/ml.81 The potential exists for the spread of vancomycin resistancefrom enterococci to other pathogens through the transfer of genetic material, suchas plasmids and transposons.81 Enterococcal vancomycin-resistance genes have notyet been isolated from VISA;92 however, the VanA gene has been found in a strain ofVRSA.94

PAGE 11

SECTION 1



1.5 Clinical characteristics of SSTIs1.5.1 Summary

1.6 Characteristics of SSTIs

1.6.1 ClassificationThe classification of SSTIs is not straightforward. In an attempt to improve thedesign of clinical trials of antimicrobial agents, the FDA redefined ‘skin and softtissue infections’ as ‘skin and skin structure infections’, and introduced two broadcategories: uncomplicated and complicated. However, SSTIs may also be defined bycausative organism, depth and location of the infection, the presence of toxicsymptoms and the presence and stability of comorbidities (Table 1.3).23,95

Table 1.3. Classification of SSTIs23

Uncomplicated SSTIs include class 1 infections, such as boils, simple abscesses,furuncles and impetigo, which present with local symptoms that are not usuallyserious (Table 1.3). These infections can often be treated by oral or topical antibiotics,surgical incision, wound care and drainage, and do not generally requirehospitalization.90

Complicated SSTIs (cSSTIs) are, or have the potential to be, serious and limb- or life-threatening. They include class 2, 3 and 4 infections, such as infected burns,secondary infections of diseased skin, surgical-site infections, acute wound infections(traumatic, post-operative or bite-related), chronic wound infections (such as diabeticfoot infections, venous stasis ulcers, pressure sores) and perianal cellulitis (with orwithout abscess).21 cSSTIs – especially those involving S. aureus – may be associatedwith a high incidence of bloodstream infections (bacteraemia),96 which may lead tothe formation of secondary foci of infection (e.g. infective endocarditis [IE]).97

PAGE 12

SECTION 1


Class Criteria

1 Afebrile and healthy, other than cellulitis

2 Febrile and ill appearing, but no unstable comorbidities

3 Toxic appearance, or at least one unstable comorbidity, or a limb-threateninginfection

4 Sepsis syndrome or life-threatening infection, e.g. necrotizing fasciitis

SSTIs are caused by numerous different pathogens and may presentwith a wide variety of physical symptoms

Diagnosis of SSTIs can usually be made on visual inspection

Inappropriate or failed treatment of SSTIs increases the risk of seriouscomplications, including bacteraemia, nephritis and carditis14

Patients with MRSA infections usually require a longer duration ofhospitalization than those with MSSA

MRSA infections usually result in a greater economic burden than MSSA

MRSA infections are associated with increased mortality rates75

Increasing prevalence of MRSA necessitates the use of drugs that areeffective against both MSSA and MRSA

cSSTIs may bepotentially limb- orlife-threateninginfections


1.6.2 Symptoms of SSTIsSSTIs cover a wide variety of clinical signs and symptoms, some of which are given inTable 1.4.

Table 1.4. Symptoms of uncomplicated and complicated SSTIs21,23,90

1.7 SSTIs – clinical overviewAs described in Section 1.3, SSTIs are caused by numerous different pathogens, andmay present with a wide variety of physical symptoms. Correct diagnosis isimportant for the correct choice of therapy, and the differences in visual presentationand the results of laboratory tests can be used in combination to aid in theidentification of the infection (Table 1.5).

For example, blood cultures, skin swabs and tissue cultures are rarely positive forcellulitis, and diagnosis relies more heavily on physical examination.98 The borders ofcellulitis may not be clearly defined, and the extent of inflammation may be greaterthan for more-superficial infections.98

Diagnosis of abscesses, surgical-site infections, trauma wounds and ulcers is usuallyby visual inspection, although imaging studies may help diagnose or better definediabetic foot ulcers and eliminate the possibility of osteomyelitis.99 Visual inspectioncan also identify necrotizing fasciitis, because the fascia will appear swollen and grey,with areas of fat necrosis, and pressure on the area can produce a thin, brown fluidrather than pus.

PAGE 13

SECTION 1


Uncomplicated SSTIs Complicated SSTIs

Localsymptoms

Induration (hardening)RednessWarmthPainTenderness

As for uncomplicated SSTIs, plus:Violaceous bullaePain disproportionate to physicalfindingsCutaneous haemorrhageSkin sloughingSkin anaesthesiaRapid progressionGas in the tissueCrepitusFluctuance

Systemicsymptoms

FeverChillsMalaiseHypotensionTachycardiaConfusionHypothermia


Table 1.5. Clinical characteristics of SSTIs21,100

PAGE 14

SECTION 1


Infection type Common bacteria Description

Cellulitis Streptococci: Group A; occasionallyGroups B, C and GS. aureusHaemophilus influenzae

Can be simple anduncomplicated, or acute andcomplicated with the infectionspenetrating into thesubcutaneous layer of the skin

Abscesses S. aureus (MSSA and MRSA); anaerobicenterococci, often associated withaerobic bacteria

Cavities in the deeper layers ofskin, which contain pus anddisintegrated tissue

Necrotizingfasciitis

Streptococci: Groups A, C and GClostridiaPolymicrobial; mix of aerobes andanaerobes

Rare, rapidly spreading andpotentially fatal infection of thesubcutaneous fat and fascia

Surgical-siteinfections Incisional

Superficial

Deep infections

Organ and organspace

Not involving surgery of thegastrointestinal or female genital tract:S. aureusStreptococci: Group AEnterobacteriaceae

Involving surgery of thegastrointestinal or female genital tract:S. aureusStreptococci: Groups A, B and CEnterobacteriaceaeBacteroides spp. and other anaerobesEnterococci

Bacterial infections along theline of the incision associatedwith surgical procedures

Infections of the skin andsubcutaneous tissueInfections of the deep softtissue, muscle and fascia

Bacterial infections caused bysurgical procedures, whichintroduce bacteria into organsor surrounding areas

Ulcers, includingdecubitus anddiabetic footulcers

Decubitus ulcers: Polymicrobial; mix of Streptococcuspyogenes (Groups A, C and G),enterococci, anaerobic streptococci,Enterobacteriaceae, Pseudomonas spp.,Bacteroides spp., S. aureus

Diabetic foot ulcers: S. aureusAerobic Gram-positive cocciAerobic Gram-negative bacilliEnterococci

A hollowed-out area of the skinthat becomes colonized bybacteria

Wounds fromtrauma and bites

Trauma wounds: Mix of S. aureus, streptococci (Group Aand anaerobic), Enterobacteriaceae,Clostridium perfringens, Clostridiumtetani

Bite wounds: Cat: Pasteurella multocida, S. aureusDog: Pasteurella multocida, S. aureus,Bacteroides spp., Fusobacterium spp.Human: Viridans streptococci,Staphylococcus epidermidis,Corynebacterium spp., S. aureus,Eikenella spp., Bacteroides spp., Peptostreptococcus spp.

Infections of the skin and deepertissues caused by physical injuryor human or animal bites


1.8 Current management of cSSTIsTraditionally, individuals with an increased risk of developing a cSSTI included thosewho are seriously ill or have underlying disease processes resulting in reduced ordelayed wound healing, such as:

Reduced arterial perfusion

Neuropathy

Chronic venous insufficiency

Diabetes

Obesity

Malnutrition

An impaired immune response (e.g. due to chemotherapy, post-transplantimmunosuppressant treatment or HIV)23

However, the increasing incidence of CA-MRSA in certain regions of the world hasexpanded the at-risk population to include those who live and/or work in closedcommunities, including prison inmates, military recruits and sports teams.61

1.8.1 cSSTI preventionPreventative measures to help reduce the incidence of cSSTIs include meticulousattention to basic hygiene and frequent hand washing, which are encouraged toprevent transmission to at-risk patients.26 Decubitus ulcers occur frequently inpatients who are immobile, and can be prevented by regular turning and inspection ofthe skin for redness or irritation, particularly at pressure points.101 Prevention ofdiabetic foot ulcers relies on frequent inspection of the feet and careful attention tominor cuts and abrasions.102

Surgical-site infections may be prevented through the administration of prophylacticantibiotics prior to surgery.103 An antibiotic should be chosen based on its efficacyagainst the type of pathogens most likely to be associated with the surgicalprocedure, but routine prophylaxis with vancomycin is discouraged because of the riskof development of resistance.104

1.8.2 cSSTI diagnosisDiagnosis of SSTIs is primarily by physical examination of the lesion andconsideration of apparent symptoms, both local and systemic. The patient’s medicaland social history may be taken into account in the overall assessment if this revealspredisposing factors.90

In addition to the visual and physical signs and symptoms, laboratory testing isuseful for the identification of causative organisms. This involves the examinationand culture of blood samples or tissue and fluid samples from the wound, usingnumerous techniques for pathogen identification (Figure 1.3), including:

Gram staining26

Catalase testing to differentiate between staphyococci (positive) and streptococciand enterococci (negative)105

Coagulase testing to differentiate between S. aureus (positive) and coagulase-negative staphylococci (CoNS)106

Growing cultures at 45°C or in 6.5% NaCl to differentiate between streptococciand enterococci107,108

Computerized tomography or magnetic resonance imaging to determine thedepth of infection or the presence of foreign bodies21,109

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1.8.3 Current guidelines for cSSTIsComplicated SSTIs often require hospitalization and treatment, including surgicalintervention (debridement) and systemic antimicrobial therapy.23 Although diagnosisis primarily visual, diagnostic algorithms are available to help clinicians accuratelyand quickly differentiate and diagnose cSSTIs, including the Laboratory Risk Indicatorfor Necrotizing Fasciitis (LRINEC).110 This scoring system combines several predictiveclinical laboratory factors (total white blood cell count and haemoglobin, sodium,glucose, serum creatinine, and C-reactive protein levels) in a multiple logisticregression model to obtain a LRINEC score.110 Scores ≥6 are highly predictive (92%) ofnecrotizing fasciitis.110

Guidelines for the diagnosis and management of SSTIs were developed andpublished by the Infectious Diseases Society of America in 2005 (Table 1.6).90

Table 1.6. Infectious Diseases Society of America (IDSA) recommendations forpatients with SSTIs that present with signs suggestive of systemic toxicity90

Patients with signs and symptoms of cSSTIs require immediate therapy to ensure thebest possible outcome,26 because delayed or inappropriate treatment of cSSTIs canincrease the risk of serious complications, including bacteraemia, nephritis andcarditis.14 Mortality rates due to cSSTIs vary. Cellulitis is generally a localized infectionand is associated with low mortality (5%).111 However, it can progress to more-severeconditions, such as erysipelas,112 and necrotizing soft tissue infections, which aresevere and associated with high mortality rates (up to 76%).113

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Signs and symptoms IDSA recommended course of action

Fever or hypothermiaTachycardia (heart rate >100 beats/minute)Hypotension (systolic blood pressure <90 mmHg, or 20 mmHg below baseline)

Hypotension and/or elevated creatinine

Low serum bicarbonateElevated creatine phosphokinase (2–3* upper limit of normal)

C-reactive protein level >13 μg/ml

Draw blood for:Blood cultureSusceptibility testsComplete blood cell count with differentialmeasurement of creatinine, bicarbonate,creatine phosphokinase and C-reactiveprotein levels

Consider hospitalization

Aggressively pursue diagnosis by:Gram staining and culture of needleaspiration or punch biopsy specimen

Request surgical consultation for:Inspection, aspiration or drainage

Figure 1.3. Flow chart describing the laboratory tests commonly used for pathogenidentification of Gram-positive bacteria

Gram-positive

StaphylcococciStreptococciEnterococci

Catalase-negative

StreptococciEnterococci

Catalase-positive

Staphylcococci

Coagulase-positive

S. aureus

Does not grow at 45°C or in 6.5% NaCI

Streptococci

Coagulase-negative

CoNS

Grows at 45°C or in 6.5% NaCI

Enterococci


Treatment should begin with supportive wound care and empiric antibiotic therapy,which can be adjusted if necessary according to the results of laboratory tests.26

Empiric approaches to therapy are based on the physician’s knowledge of the likelyinfecting pathogens and their susceptibilities, together with factors concerning thepatient (e.g. age, renal and hepatic function and previous antibiotic therapy).26

Antibiotic classes commonly used in the empiric treatment of Gram-positive cSSTIsinclude the β-lactams, glycopeptides, oxazolidinones and streptogramins.26

Treatment is normally administered parenterally for at least the first 24 hours.90

However, the increasing prevalence of MRSA is driving the treatment paradigm forcSSTIs to the earlier use of drugs that are effective against both MRSA and MSSA.90

1.9 Antibiotic treatment for Gram-positive cSSTIs whereMRSA is suspected or confirmed

1.9.1 VancomycinVancomycin is the ‘gold standard’ treatment for MRSA.24 Originally launched by EliLilly in the 1950s, this glycopeptide antibiotic has been available in generic form formany years. It is a ‘tried and trusted’ drug with 50 years of experience in patienttreatment. It has a slowly bactericidal mode of action15 and is active against mostGram-positive bacteria, including MRSA.12 However, its disadvantages include:

Tendency to become weakly bactericidal or bacteriostatic against difficult-to-treatbacteria (high inocula)15

Inferior potency against MSSA compared with semisynthetic penicillins12

Poor patient tolerability compared with teicoplanin114

Increasing reports of emerging resistance in staphylococci and enterococci2

Inconvenient dosing schedule (twice-daily i.v.)90

Monitoring of serum concentrations is required114

Increased reliance on vancomycin as a frontline therapy against methicillin-resistantbacteria is likely to be a contributing factor in the emergence of VRSA strains.88

Although VRSA strains remain rare,85 VISA (and hVISA) strains are more common. VREmay also be a cause of cSSTIs.115

1.9.2 TeicoplaninTeicoplanin is also a glycopeptide antibiotic, with a similar structure to vancomycinand a better safety profile.116 Among its advantages are good tolerability, long half-life, suitability for a wide variety of indications and once-daily i.v. or intramuscularadministration.117 Its disadvantages include incompatibility with aminoglycosides,and a complicated dosing schedule for more-severe infections that involves loadingand maintenance dosing, which is adjusted according to the severity of theinfection.117 There are also reports of emerging resistance to the drug.118 Teicoplaninwill usually demonstrate bacteriostatic activity in the presence of a high inoculum ofthe bacterial pathogen.119,120

1.9.3 LinezolidLinezolid is from the oxazolidinone family of antibiotics, and may be used in cases ofvancomycin resistance.121 It is indicated for use against Gram-positive cSSTIs as wellas Gram-positive nosocomial or community-acquired pneumonia.122 Its advantagesinclude administration by either i.v. or oral routes,121 allowing for cost-effectiveoutpatient therapy. Its disadvantages include its high drug cost relative tovancomycin, and twice-daily schedule of i.v. administration.121 Linezolid has beenassociated with side-effects, including thrombocytopenia, anaemia and neutropenia, PAGE 17

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and should not be taken by patients with certain comorbidities, includinguncontrolled hypertension and bipolar disorder, or those taking adrenergic orserotonergic medications.121,123 A recent clinical study found that patients with Gram-negative infections, mixed infections with both Gram-negative and Gram-positivebacteria, or no infection had increased risk of death when treated with linezolid.124

Prolonged duration of treatment beyond 28 days has not been investigated. Inaddition, it shows bacteriostatic action against both low- and high-inoculumcultures.15 This means that bacterial colonies may not be cleared and could resumegrowth after treatment is withdrawn, increasing the risk of recurrence of infection.125

1.10 Future of cSSTI managementSerious infections caused by Gram-positive bacteria are increasingly difficult to treatwith standard-of-care therapy because of pathogens such as MRSA, VISA, hVISA andVRE.126 The spread of resistance has compromised conventional treatment optionsfor cSSTIs, and reports of resistance to newer antibiotics such as linezolid andquinupristin/dalfopristin are also emerging.126 Many current treatment options arealso associated with complex administration or monitoring regimens, orunfavourable toxicity profiles. Therefore, there is an urgent clinical need for newantibiotics that have suitable pharmacokinetic properties and safety profiles, andactivity against resistant Gram-positive pathogens.126

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2.2 Staphylococcus aureus bacteraemia and infectiveendocarditis

Staphylococcus aureus can colonize and infect both immunologically competent andimmunologically compromised patients, both in the hospital and in the communitysetting.135 Invasion of deeper structures by S. aureus can lead to metastatic infectionas the bacterium spreads through the bloodstream to other organs.135

Staphylococcus aureus is one of the most frequent causes of bacteraemia127 and canresult in life-threatening endocarditis and septicaemia.135

IE refers to an infection of the heart valves or lining of the heart resulting frombacterial or (less commonly) fungal infection.136 IE is believed to develop as a resultof a sequence of events beginning with the formation of nonbacterial thromboticendocarditis (NBTE) on the surface of a heart valve or elsewhere, followed byendothelial damage, bacteraemia, adherence of blood-borne bacteria to the NBTEand bacterial proliferation within a vegetation.137 The host immune response to theinfecting organism is responsible for many of the clinical manifestations of IE.137 IEcan affect the aortic or mitral valves (left-sided) or the tricuspid or pulmonary valves(right-sided),138 although simultaneous infection of both sides of the heart can occur.Right-sided IE is the predominant form of infection in intravenous drug users,whereas left-sided IE predominates in patients with no intravenous drug use.139

2.2.1 DefinitionsBacteraemia is defined as the presence of cultivable bacteria in the bloodstream.140

Sepsis is defined as the presence of clinical symptoms of infection in addition to thepresence of bacteria in the bloodstream.6 Therefore, sepsis is a condition that arisesfrom bacteraemia. Severe sepsis is the term used to describe sepsis that is alsoassociated with hypotension, hypoperfusion or dysfunction of organs distant fromthe site of infection.140

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STAPHYLOCOCCUSAUREUS BACTERAEMIA

AND INFECTIVEENDOCARDITIS

2. Staphylococcus aureus bacteraemia andinfective endocarditis

2.1 Introduction to Staphylococcus aureus bacteraemia andinfective endocarditis

2.1.1 Summary

Staphylococcus aureus is a leading cause of bacteraemia and IE inmany parts of the world6-8,127

MRSA accounts for up to 42% of SAB infections,128 and almost 40% ofIE caused by S. aureus7 in some regions

SAB and IE are associated with high mortality rates7,10,129-131

The clinical features of both SAB and IE are commonly non-specific,132,133 and bacteraemia may be asymptomatic132

Antibiotic prophylaxis for medical procedures with a risk ofbacteraemia is recommended for the prevention of SAB/IE134


2.2.2 EpidemiologyStaphylococcus aureus is a leading cause of bacteraemia in the US and across Europe.In the US, S. aureus was the most frequent cause of bacteraemia during the period1992–1993,6 and the second-most frequent cause of nosocomial bacteraemia duringthe period 1995–2002.127 In Europe, S. aureus was the second-most prevalent cause ofbacteraemia during the period 1997–1998.8 Furthermore, S. aureus is the mostcommon causative pathogen of IE in many parts of the developed world.7

Dramatic changes in antibiotic susceptibility have been reported for the majorcausative organisms of S. aureus bacteraemia (SAB)/IE, with methicillin-resistance inS. aureus isolates at an all-time high in some institutions.9 Of the cases of SAB inEngland and Wales from 1990 to 2000, the annual rate of MRSA being isolatedincreased from 2% to 42%.

128 At the end of 2003, MRSA was reported to account for29% and 40% of the IE caused by S. aureus in the US and Europe, respectively.7

Staphylococcus aureus isolates that are partially and fully resistant to vancomycin havealso been reported, and are an added complication to the treatment of S. aureus IE.9

Community-acquired SAB has a high complication and mortality rate, and isconsidered to be a more serious issue than nosocomial infections.96 The incidence ofIE following community-acquired SAB is high and is associated with a poor outcome(mortality of approximately 68%).96 The predominance of community- or hospital-acquired IE varies according to geographic region: in 2003, community-acquired IEwas the predominant form in Australia, New Zealand, Europe and the Middle East,whereas hospital-acquired IE was predominant in the US and Brazil.7 Overall,however, the majority of IE cases are community-acquired, where cases notassociated with intravenous drug use are predominant over those associated withintravenous drug use.7

Rates of SAB and IE are increasing.11 From 1980 to 1989, SAB was reported to haveincreased by 283% in non-teaching hospitals and 176% in large teaching hospitals inthe US.141 A major contributing factor to the increased frequency of SAB is thought tobe the increased use of invasive procedures, prosthetic devices and intravascularcatheters.11 Nosocomial IE, previously considered to be uncommon, is also becomingmore prevalent142 – probably owing to the increased use of interventional proceduresand implantable devices.11

2.2.3 Predisposing factorsNasal colonization by S. aureus is a predisposing factor for SAB, because a substantialproportion of cases of SAB originate from organisms carried in the patient's ownnasal mucosa.143 There are numerous medical procedures, both diagnostic andtherapeutic, that have been identified as possible causes of bacteraemia, including:134

Bronchoscopy with a rigid instrumentCystoscopy during urinary tract infectionBiopsy of urinary tract lesions or prostateDental procedures with the risk of gingival/mucosal traumaTonsillectomy and adenoidectomyOesophageal dilation/sclerotherapy

In addition, there are several factors associated with an increased risk of developingSAB that have been identified, including:

Previous MRSA infection or colonization144

Urinary catheter insertion145

Skin ulcers or cellulitis at hospital admission144

Intravenous drug use (in HIV-infected patients)146PAGE 20

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STAPHYLOCOCCUSAUREUS BACTERAEMIAAND INFECTIVEENDOCARDITIS


Presence of central venous catheters144

Surgical-site infection145

The risk of death among individuals with SAB is heightened by several factors,including presence of human immunodeficiency virus (HIV) viraemia and high AcutePhysiology and Chronic Health Evaluation (APACHE) III score.147 Mortality ratesamong individuals with SAB are also higher in the elderly (>65 years) than in youngerindividuals.148 SAB is also a frequent cause of death in neutropenic patients withcancer,149 and is an independent risk factor for mortality after liver transplantation.150

The predisposing factors associated with the development of IE are listed in Table 2.1,including both cardiac and non-cardiac, patient-related conditions.134

Table 2.1. Predisposing factors for the development of IE134

2.2.4 Impact of SAB/IEIt is consistently reported that SAB, in particular that caused by MRSA, is associatedwith a longer median length of hospital stay, higher median total treatment cost,and greater risk of mortality than bacteraemia due to any other bacterialpathogen.76,151 In one study carried out in a tertiary-care teaching hospital in the US,the median length of hospitalization after SAB for patients who survived, and themedian hospital charges after SAB, were significantly increased in MRSA patients (7 vs 9 days, P=0.045; $19,212 vs $26,424, P=0.008).76 In a study in community-dwellinghaemodialysis patients, MRSA bacteraemia was associated with significantly highertreatment costs than MSSA bacteraemia, at initial hospitalization ($21,251 vs $13,978;P=0.012) and after 12 weeks in hospital ($25,518 vs $17,354; P=0.015).151

SAB and IE are both associated with a high mortality rate. In five studies published in2005–2006, overall SAB mortality rates were in the range of 20–29%.10,129-131 SABmortality rates are also high among elderly patients. In one study, the mortality ratein patients >65 years of age was approximately 16% within 7 days of SAB onset;152 inanother study, mortality was 28% within 15 days of hospital admission.153 Mortalityrates of SAB caused by methicillin-resistant strains are generally higher than thosefor SAB caused by methicillin-susceptible strains.74,75 In a large study of 1779 patients,IE mortality rates due to S. aureus were 29.4% for patients whose infections werehospital-acquired, 27.7% for those fitted with cardiac devices, and 29.8% for thosewith MRSA.7 The mortality rate associated with IE due to MSSA was lower (23.3%).7 PAGE 21

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Cardiac conditions

High riskPrevious history of IEProsthetic heart valves or other foreign materialSurgically created conduitsComplex cyanotic congenital abnormalities

Moderate riskAcquired valvular heart diseasesMitral valve prolapse with valvular regurgitation or severe valve thickeningNon-cyanotic congenital heart diseases (except for secundum-type atrial septal defect),including bicuspid aortic valvesHypertrophic cardiomyopathy

Non-cardiac, patient-related conditions

Old ageConditions promoting non-bacterial thrombotic vegetationConditions compromising host defenceConditions compromising local non-immune defence mechanismsIncreased risk, frequency and/or amount of bacteraemia


If the initial choice of empiric antibiotic therapy for SAB is inappropriate, this willhave an effect on the outcome, and add to the cost of treatment.154,155 In one study,the impact of initial antibiotic choice (β-lactams vs vancomycin) on the outcome ofSAB (50.9% MRSA) was evaluated in 342 patients.154 Mortality was higher withinappropriate therapy (35.0% vs 20.9%; P=0.02),154 and initial suboptimal treatmentof methicillin-susceptible SAB with vancomycin was associated with a higherincidence of delayed clearance (≥3 days) of bacteraemia (56.3% vs 37.0%; P=0.03).154 Inanother study, delayed treatment was found to be an independent predictor ofinfection-related mortality (odds ratio, 3.8; 95% confidence interval, 1.3–11.0; P=0.01)and was associated with a longer hospital stay.155

2.3 Staphylococcus aureus bacteraemia2.3.1 Clinical features of SABThe clinical features of SAB can be non-specific, and low-grade bacteraemia, whichcan lead to seeding of the heart valves or other sites, can be completelyasymptomatic.132 In symptomatic cases, fever and severe myalgias are often presentand septic shock may develop. An infected cannula site or other skin/soft tissuesource might be found upon physical examination. Approximately 25% of SAB casesdevelop concurrent bacteriuria. Therefore, the development of bacteriuria, in theabsence of urinary tract pathology or recent urinary tract instrumentation, shouldprompt a clinical evaluation for deep-seated infection.132

2.3.2 Current management of SABPreventionA large number of cases of SAB originate from colonies in the nasal mucosa.143

Therefore, elimination of nasal carriage – by locally applied or systemic antibiotics,and by bacterial interference156 – has been suggested as a strategy for preventingSAB.143 Of the commonly used nasal ointments, mupirocin (pseudomonic acid)ointment has been shown to be 97% effective in reducing S. aureus nasal carriage.156

Where a patient undergoes certain medical procedures that are known to oftenresult in bacteraemia (listed in Section 2.2.3), antibiotic prophylaxis therapy is usuallygiven.134 This is discussed further in Section 2.4.2.

DiagnosisSAB is characterized by a positive blood culture for S. aureus.132 Approximately 95% ofbacteraemia cases can be detected by collection and culture of two or three bloodsamples.6 Despite the possibility of contamination of the blood culture duringcollection, even a single culture positive for S. aureus from multiple sets of bloodcultures is considered significant, and patients should be assumed to havebacteraemia and be managed accordingly.132

Current guidelines for SABAggressive antibiotic therapy and removal of intravascular devices are central to theoptimal management of SAB. The appropriate therapy for SAB is determined byseveral factors, namely:132

Susceptibility testing of the infecting organism

The source of infection

The presence of endocarditis and/or other metastatic sites of infection

Patient factors (underlying disease and antibiotic allergy)

Empiric therapy is critical in the treatment of SAB because delaying the antibiotictreatment of SAB, even by only 45 hours, has been shown to increase the risk ofPAGE 22

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infection-related mortality and increase the duration of hospitalization.155 On theother hand, the use of an inappropriate empiric treatment regimen can also havedetrimental effects, and is associated with higher in-hospital mortality.154 On thebasis of assessment of the local prevalence of MRSA and the patients’ history,selection of empiric regimens for suspected SAB may be guided by the probabilitythat MRSA is the cause.132 Oral therapy is inappropriate for the initial therapy of SAB,but may be used following i.v. therapy to treat residual deep-seated infection.132

Penicillinase-resistant penicillins (flucloxacillin or dicloxacillin) are currently thepreferred treatment option for bacteraemia due to penicillin-resistant MSSA.132

Vancomycin and first-generation cephalosporins provide alternative treatmentoptions for patients who are allergic to or intolerant of penicillinase-resistantpenicillins. However, these agents are inferior to the penicillins in SAB therapy157 andshould not be used without good cause.132 Aminoglycosides can be used incombination with penicillinase-resistant penicillins in the treatment of bacteraemiacaused by MSSA, especially in patients with endocarditis.132 These combinations leadto more-rapid clearing of bacteraemia, but do not appear to increase overall curerates.132

Vancomycin is currently the first-line option for SAB caused by MRSA.132 Otherpossible antibiotic options for management of MRSA bacteraemia includeclindamycin, linezolid and quinupristin/dalfopristin.132 Clindamycin is being usedextensively in infections caused by SAB, but animal models have shown this drug tobe inferior to penicillins and vancomycin.132 Linezolid has been used as salvagetherapy in patients on whom other therapies have failed, whereas quinupristin/dalfopristin can be considered for patients who do not respond to or are intolerant ofvancomycin.132 However, both linezolid and quinupristin/dalfopristin are limited byunfavourable adverse-effect profiles and high cost, and are recommended for use inhighly selected cases only.132

Failure of antimicrobial therapy for SAB should be suspected when there is persistentfever (≥72 hours after appropriate antibiotics), persistent positive blood cultures orongoing signs of sepsis (e.g. persistent hypotension).132 In such cases, the followingoptions should be considered:132

Undertake appropriate imaging to look for endocarditis or other metastaticinfection

Optimize antibiotic doses

Consider surgery (valve replacement in endocarditis, drainage of abscesses)

Modify underlying conditions (e.g. reduce immunosuppressive therapy)

Consider adding an additional agent, such as rifampicin to flucloxacillin orvancomycin

For MRSA with a poor response to apparently optimal vancomycin therapy, requestlaboratory tests for isolates with reduced glycopeptide susceptibility

For suspected hVISA infection or in selected cases where therapy is failing,consider switching to linezolid with quinupristin/dalfopristin as an alternative

2.4 Staphylococcus aureus infective endocarditis2.4.1 Clinical features of IEThe common symptoms of IE are shown in Table 2.2.138 Highly specific symptoms ofIE are rare, whereas non-specific symptoms are common and ubiquitous in thepopulation.133 Fever is the most common symptom, but may be absent or minimal inpatients with congestive heart failure, severe debility, chronic renal or liver failureand previous use of antimicrobial drugs or infection with less-virulent organisms. PAGE 23

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Although rare, peripheral manifestations – such as splinter haemorrhages, Osler’snodes, Roth’s spots and Janeway’s lesions – are considered an excellent clue in thediagnosis of IE.133,138

Table 2.2. Symptoms and signs of S. aureus IE138

Endocardial vegetation is a typical cardiac manifestation of IE, and consists ofaggregates of platelets, fibrin and organisms that adhere to heart valves or to theendocardium.138 Progression of infection can result in acute valvular dysfunction,which is a common cause of death from IE. Perivalvular abscesses or fistulae mayalso develop and, without surgery, are associated with a high mortality rate.138

2.4.2 Current management of IEPreventionAntibiotic prophylaxis for medical procedures with a risk of bacteraemia isrecommended for the prevention of IE, particularly for patients with a prostheticcardiac valve, previous IE, congenital heart disease, cardiac transplantation recipientswho develop cardiac valvulopathy, or patients who undergo any medical procedurethat might lead to bacteraemia (listed in Section 2.2.2).134 Antibiotic prophylaxisshould be administered in a single dose before the procedure, but may beadministered up to 2 hours after the procedure.137 Generally, amoxicillin isrecommended as a prophylactic antibiotic, given orally in a single dose, butclindamycin can be given in patents with penicillin allergy.158

Antibiotic prophylaxis is not the only preventative measure against IE. Guidelines forthe prevention of IE, set by the Working Party of the British Society for AntimicrobialChemotherapy, emphasize vigilance in patients at risk of IE who are receivingmedical care. Infections that could lead to bacteraemia should be adequatelytreated, colonized intravascular devices should be promptly removed and conditionsthat can lead to chronic or repeated infections should be managed effectively.158

Diagnosis Diagnosis of IE is simple in patients displaying obvious manifestations, such asbacteraemia, active valvulitis, peripheral emboli and immunological vascularphenomena;9 however, in many cases, some or all of these classic features areabsent.9 The rapid development of acute IE may also result in an absence of theimmunological vascular phenomena that generally characterize subacute IE.9 Inaddition, valve lesions in acute right-sided IE are not usually associated with thePAGE 24

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Involvement Symptoms Signs

Either left-sided orright-sided

FeverRigorsMyalgiasArthralgias

Inflammation/pus at entry siteTachycardiaHypotensionMetastatic infection (bone, joint,visceral)

Left-sided DyspnoeaCentral nervous systemsymptoms

Heart blockOslerian manifestations: Osler’s nodes,Janeway’s lesions, splinterhaemorrhages, Roth’s spotsAortic or mitral valve regurgitationManifestation of arterial emboli(cerebral, limb, visceral)

Right-sided DyspnoeaPleuritic chest painCough with sputumHaemoptysis

Tricuspid or pulmonary regurgitationLung consolidationEffusion


peripheral emboli and immunological vascular phenomena typical of left-sidedvalvular involvement. However, right-sided IE might lead to septic pulmonary emboli.9

The Duke criteria provide a method of diagnosing IE on the basis of the presence orabsence of several major or minor criteria (Table 2.3).9 Echocardiography is afundamental technique in the diagnosis of IE and should be performed in all cases ofsuspected IE.9 Echocardiographic evidence of an oscillating intracardiac mass orvegetation, annular abscess, prosthetic valve partial dehiscence, and new valvularregurgitation are major criteria in the diagnosis of IE.9

Trans-oesophageal echocardiography (TOE; also called TEE) and trans-thoracicechocardiography (TTE) are used in the diagnosis of IE. The type of echocardiographythat should be performed depends on the clinical scenario. TOE is the preferredtechnique because it uses higher ultrasonic frequencies,138 which produce higherquality images of the heart, and is recommended for patients with:132

Community-acquired SAB

Prosthetic valves or permanent pacemakers

Clinical features typical of IE

Persistent fever, signs of sepsis, positive blood culture for S. aureus after 72 hours ofappropriate antistaphylococcal therapy

No primary focus of infection who have other metastatic complications

TTE, which is less invasive, widely available and easier and cheaper to perform,132,138

may be performed initially in:9

Patients at low risk for IE

Children

When TOE is not available or clinically possible

Table 2.3. The Duke criteria for diagnosis of IE9

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Major criteriaBlood culture positive for IE

Typical microorganisms, consistent with those known to cause IE, isolated from twoseparate blood cultures: viridans streptococci, Streptococcus bovis, HACEK group*, S. aureus;community-acquired enterococci in the absence of primary focusMicroorganisms consistent with IE from persistently positive blood cultures are defined as follows: at least two positive cultures of blood samples drawn >12 hours apart; or, all of 3 separate cultures or a majority of ≥4 separate cultures of blood (with first and lastsample drawn at least 1 hour apart) testing positiveSingle positive blood culture for Coxiella burnetii or anti-phase 1 IgG antibody titer >1:800

Evidence of endocardial involvement: echocardiogram positive for IEOscillating intracardiac mass on valve or supporting structures, in the path of regurgitantjets, or on implanted material in the absence of an alternative anatomic explanation;abscess; new partial dehiscence of prosthetic valve; or new valvular regurgitation(worsening or changing or pre-existing murmur not sufficient)

Minor criteria

Predisposition, predisposing heart condition or intravenous drug useFever (temperature >38°C)Vascular phenomena, major arterial emboli, septic pulmonary infarcts, mycotic aneurysm,intracranial haemorrhage, conjunctival haemorrhages and Janeway’s lesionsImmunological phenomena: glomerulonephritis, Osler’s nodes, Roth’s spots and rheumatoidfactorMicrobiological evidence: positive blood culture that does not meet a major criterion orserological evidence of active infection with organism consistent with IE

*HACEK group: Haemophilus parainfluenzae, Haemophilus aphrophilus, Haemophilus paraphrophilus,Haemophilus influenzae, Actinobacillus actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens,Kingella kingae, and Kingella denitrificans


The Duke criteria state that IE can be positively diagnosed if either two majorcriteria, one major and three minor criteria, or five minor criteria are met.9 Possible IEis defined as meeting one major and one minor criterion or three minor criteria. Adiagnosis of IE can be rejected if these criteria are not met or if there is a firmalternative diagnosis explaining evidence of IE, resolution of IE with antibiotictherapy for less than 4 days, or no pathological evidence of IE at surgery or autopsyfollowing antibiotic therapy of less than 4 days.9

Current guidelines for IE caused by S. aureusThe optimal antimicrobial options for S. aureus IE remain unclear, although currentevidence supports the use of at least 2 weeks of antimicrobial therapy for right-sidedinfections, and at least 4 weeks for uncomplicated left-sided infections.138

Complicated left-sided and prosthetic valve infections should be treated withantimicrobial therapy for at least 6 weeks.138 Rapid identification and susceptibilitytesting are essential for selection of appropriate antimicrobial therapy.138 Bactericidalantibiotic agents are crucial in the treatment of IE.159,160 Bacteria in cardiacvegetations are present at very high densities, at which their susceptibility to active agents may be reduced. Therefore, prolonged therapy with high doses of abactericidal agent is generally required for true sterilization of the vegetation.160

Consistent with guidelines for management of SAB, penicillins should be consideredas the first-line option for S. aureus IE in patients with susceptible isolates.138 Thefirst-generation cephalosporins (cephalothin and cephazolin) are often used to treatS. aureus IE in patients with hypersensitivity to penicillins, despite a lack of evidencefrom clinical trials.138 The third-generation cephalosporin ceftriaxone has been usedfor the treatment of staphylococcal IE, but is not recommended for use in S. aureus IE because of a high incidence of clinical failures.138

Vancomycin is currently regarded by many experts as the first choice for treatmentof IE caused by MRSA, and in a small number of patients with intolerance of orsevere hypersensitivity to β-lactam agents.138 However, close observation is requiredduring vancomycin treatment,138 and its use is associated with several adverse eventsor allergic reactions, such as nephrotoxicity, rash, red-man syndrome and drugfever.114 The antibacterial activity of vancomycin is significantly slower than β-lactamagents, and treatment failure in IE has been associated with reduced susceptibility of S. aureus while on vancomycin therapy.138

Teicoplanin is a glycopeptide antibiotic with a similar structure and antibacterialspectrum to vancomycin.114 Its advantages over vancomycin include a lower incidenceof side-effects and no requirement for routine monitoring.114 However, teicoplaninpenetrates poorly into vegetations and has been associated with high failure rates inS. aureus IE and a high incidence of adverse events such as rash and fever.138

Resistance to teicoplanin has also been documented during treatment of S. aureus IE.Consequently, teicoplanin should only be used in rare cases where patients areintolerant of both β-lactam agents and vancomycin.138

Clindamycin, fluoroquinolones and rifampicin monotherapy are not recommendedfor the treatment of S. aureus IE, and there is currently insufficient evidence todetermine the efficacy of co-trimoxazole.138 Quinupristin/dalfopristin is not currentlyrecommended as a first-line option for S. aureus IE, but could be considered for thetreatment of IE caused by MRSA in patients who cannot tolerate vancomycin, or whohave persistent bacteraemia despite appropriate first-line therapy, as well as in thosewith IE caused by S. aureus with reduced vancomycin susceptibility, VISA or VRSAstrains.138

Because there are no randomized, controlled clinical trials of linezolid in S. aureus IE,there is currently insufficient evidence to recommend the use of linezolid as a first-PAGE 26

SECTION 2



line option for the management of S. aureus IE.138 Despite the ability of linezolid tosterilize vegetations as effectively as vancomycin in some animal model studies,there have been reports of linezolid treatment failure in S. aureus IE and developmentof resistance during treatment of serious MRSA infection.138 However, linezolid maybe considered in patients with IE due to MRSA who are refractory to, or intolerant of,vancomycin, as well as in IE due to S. aureus with reduced vancomycin susceptibility,VISA or VRSA strains.138

2.5 Future of SAB/IE managementSAB and IE are becoming increasingly difficult to treat with standard therapybecause of the increased prevalence of S. aureus strains – such as MRSA, VISA andVRSA – which have reduced susceptibility to the recommended antibiotics. The useof newer antimicrobials such as linezolid and quinupristin/dalfopristin is currentlylimited by unfavourable adverse effect profiles and high cost.132 There isconsequently a need for the development of new antibiotic therapies, withfavourable safety and tolerability profiles and potent activity against multidrug-resistant S. aureus for the management of SAB/IE.

Vaccines could play a role in the future management of S. aureus infections.11

StaphVAX is an investigational vaccine designed to prevent severe infections causedby S. aureus. StaphVAX targets S. aureus types 5 and 8,

161 which are responsible forapproximately 87% of S. aureus infections.162 StaphVAX has been shown to preventpost-operative bacteraemia in patients vaccinated prior to orthopaedic procedures.163

PAGE 27

SECTION 2




3.2 IntroductionLY146032 (daptomycin) was identified as a promising compound in the treatment ofGram-positive infections in the 1980s; however, twice-daily dosing studies revealedadverse effect issues relating to muscle toxicity, leading to termination of thedevelopment programme by Eli Lilly at that time. Over the intervening years, it has beenre-evaluated and thoroughly investigated in clinical studies using once-daily dosing. It isnow licensed as Cubicin in the EU for the treatment of cSSTIs, right-sided infectiveendocarditis (RIE) due to S. aureus, and SAB associated with RIE or cSSTI.164 Thedevelopmental history of Cubicin is shown in Table 3.1.

3.3 TimelineTable 3.1. Key dates in the development of Cubicin

3. Cubicin history and development3.1 Summary

Cubicin is an i.v. antibiotic that is indicated in the treatment of cSSTIsin the European Union164

Cubicin is further approved in the treatment of S. aureus bacteraemiawhen associated with right-sided endocarditis or cSSTIs and right-sided infective endocarditis due to S. aureus in the European Union164

Date Development

1980s LY146032 (daptomycin) discovered by Eli Lilly & CoNineteen phase I and II clinical studies, involving more than 370 subjects,conducted in the 1980s and early 1990s

1990s Lilly ceased development in the early 1990s due to difficulties with optimizationof dosing regimens

1997 Cubist Pharmaceuticals acquired worldwide rights

1999 US and EU trials conducted by Cubist commenced in 1999

FDA fast-track status

2001 Completion of phase III clinical trials on the efficacy and safety of daptomycin inthe treatment of cSSTIs

2003 Cubicin (daptomycin) 4 mg/kg approved in the US by the FDA for the treatmentof complicated skin and skin structure infections (cSSSIs) Cubist and Chiron (now Novartis) signed a development and commercializationagreement for European marketing rights

2004 Completion of phase III clinical trials on the efficacy and safety of Cubicin in thetreatment of endocarditis and bacteraemia caused by S. aureus

2005 Cubist submitted a supplemental NDA to the FDA for use of Cubicin in S. aureus bacteraemia with known or suspected right-sided infective endocarditis

2006 Cubicin 4 mg/kg approved for the treatment of cSSTIs in Europe by theEuropean Commission Cubicin 6 mg/kg approved for the treatment of SAB and RIE in the US by the FDA

2007 Cubicin 6 mg/kg approved for the treatment of SAB in SwitzerlandCubicin 6 mg/kg approved in the EU for the treatment of cSSTIs, RIE due to S. aureus, and SAB associated with RIE or cSSTI164

SECTION 3

CUBICIN HISTORYAND DEVELOPMENT


3.4 Current indicationsCubicin is currently approved in the EU and US at 4 mg/kg for the treatment ofcSSTIs (synonymous with cSSSIs) caused by susceptible Gram-positive bacteria,including S. aureus.164 It is licenced in the the US at 6 mg/kg for the treatment of SABand RIE, and in the EU for RIE due to S. aureus, and SAB when associated with RIE orcSSTI164 (SAB/RIE; Table 3.2). Cubicin is also approved in Israel and Argentina for cSSTIsand is undergoing regulatory review in several other countries.

Table 3.2. Current indications in Europe and the US

*Note: Cubicin is approved in the EU for RIE due to S. aureus and S. aureus bacteraemia when associated withcSSTIs or RIE

Cubicin is an i.v.antibiotic approvedfor the treatment of cSSTIs, based onthe results ofprospective,randomized,controlled clinicaltrials

PAGE 30

Europe US

cSSTIs January 2006

(Approved in Switzerland in 2007)November 2003

SAB/IE* September 2007

(Approved in Switzerland for SAB only in 2007)May 2006

SECTION 3

CUBICIN HISTORYAND DEVELOPMENT


4. Cubicin product profile 4.1 Product characteristics4.1.1 Summary

4.2 Isolation and characterizationDaptomycin was first isolated from Streptomyces roseosporus, a soil-dwellingbacterium,174 and was found to have in vitro activity against Gram-positive strains ofbacteria.175 Further investigation determined activity against Gram-positive bacterialisolates from European and Latin American patients.176

4.3 Chemical description Cubicin is the first in a new class of antibiotics, the cyclic lipopeptides. Daptomycin(the active ingredient) is composed of a 13-member amino acid water-soluble(hydrophilic) core and a lipid soluble (lipophilic) 10-carbon tail (Figure 4.1). Thechemical name is N-decanoyl-L-tryptophyl-D-asparaginyl-L-aspartyl-L-threonylglycyl-L-ornithyl-L-aspartyl-D-alanyl-L-aspartylglycyl-D-seryl-threo-3-methyl-L-glutamyl-3-anthraniloyl-L-alanine ε

1-lactone. The empirical formula is C

72H

101N

17O

26and it has a

molecular weight of 1620.67.177

Cubicin:

First of a new class of antibiotics, the cyclic lipopeptides165

A novel mode of action that may minimize the risk of pre-existingmechanisms of resistance in bacterial populations165

Rapidly bactericidal with negligible bacterial cell lysis18

Active in vitro against Gram-positive bacteria, including MRSA, MSSAand VRE166

Achieves a 3 log10

reduction in viable S. aureus organisms, includingMRSA, in less than 2 hours167

Active against growing and stationary-phase bacteria15,168

Shows little or no drug–drug interactions, but synergistic interactionswith other antibiotics have been observed169-173

PAGE 31Figure 4.1. Daptomycin chemical structure

Lipophilic tail

CONH2

(CH2),CH

3

CO2H

NH2

HO2C

HO2C

HO2C

NH2

O O

NH

NH

NH

NHNH

NH

HN

HN

HN

HO

HN

HN

HN

HN

NH

O

O

O

OO

O

O

OO

O

O

OOO

SECTION 4

CUBICIN PRODUCTPROFILE


4.4 Pharmaceutical formCubicin powder is soluble in water and yields a yellow to light-brown solution.178

Stress stability studies have shown that it can degrade when exposed to direct light,heat or oxygen, and to extremes of pH in solution.178 The pH of Cubicin reconstitutedin 0.9% sodium chloride according to the prescribing information is between 4.0

and 5.0.

4.5 Novel mechanism of actionDaptomycin possesses a novel mechanism of action that is conferred by its novelchemical structure. Although the precise mechanism of action has yet to bedetermined, studies suggest that daptomycin acts by binding to bacterial cellmembranes in such a way that results in membrane depolarization and celldeath.18,179 This bactericidal activity results in cell death with negligible cell lysis (see Section 4.6.3).18

The antibacterial activity of daptomycin is known to be calcium dependent.180

Interaction with extracellular calcium appears to induce a structural change thatallows the daptomycin molecule to interact with the bacterial cell membrane. Thelipophilic tail of daptomycin inserts itself into the cytoplasmic membrane of Gram-positive bacteria. It is proposed that the oligomerization of multiple daptomycinmolecules results in the formation of transmembrane channels that allow the effluxof potassium ions from the cell (depicted in Figure 4.2).18 This results in rapiddepolarization of the cell membrane,181 leading to inhibition of protein, DNA and RNAsynthesis, and is a possible cause of bacterial cell death.167 The proposed mechanismof action is summarized in Table 4.1.

Table 4.1. Proposed mechanism of action of daptomycin18

PAGE 32

SECTION 4


Cubicin has a novelmode of action

Step 1 Calcium binding to daptomycin induces a structural change in the drug,180

allowing it to interact with the bacterial membrane182

Step 2 The lipophilic tail of daptomycin inserts itself into the cytoplasmic membraneof susceptible Gram-positive bacteria

Step 3 Formation of ion channels through the membrane by oligomerization ofdaptomycin molecules183

Step 4 Efflux of potassium ions from the cell and depolarization of the cellmembrane181

Step 5 Inhibition of protein, DNA and RNA synthesis within the cell

Step 6 Rapid cell death without lysis


4.6 Benefits conferred by the mechanism of action The efficacy and safety of daptomycin are due to its unique mechanism of action;these are explained in detail in Sections 5.2 and 5.3, respectively.

4.6.1 ResistanceDaptomycin, being the first in a new class of antibiotics, is unlikely to have beenencountered previously by infecting pathogens. It is speculated that this may reducethe likelihood of pre-existing mechanisms of resistance to daptomycin being presentin the bacterial population, due to the absence of encounters with antibiotics thatuse a similar mechanism of action.184,185

It has proven difficult to generate resistance to daptomycin in the laboratory usingthree methods: spontaneous resistance, serial passage in the presence of increasingdrug concentrations, and chemical mutagenesis.186 No transferable elements

Cubicin is the firstof a new class of

cyclic lipopeptideantibiotics

PAGE 33

Figure 4.2. Daptomycin mechanism of action Steps 2–4. Step 2: Daptomycin insertsits lipophilic tail into the bacterial cell membrane. Step 3: Formation of ion channelsin cell membrane. Step 4: Efflux of potassium ions and membrane depolarization18

SECTION 4

CUBICIN PRODUCTPROFILEStep 2

Step 3

Step 4


conferring daptomycin resistance have been isolated,187 suggesting resistance maybe slow to evolve. In support of these laboratory studies, the emergence of resistanceto daptomycin among S. aureus strains was found to be only 0.1% in a worldwidestudy of Gram-positive clinical isolates collected from centres in Europe, NorthAmerica and South America,166 and less than 0.2% across the entire set of phase IIand III clinical trials, involving over 1000 Cubicin-treated participants.177 Strains withdecreased susceptibility to daptomycin have been reported during the treatment ofpatients with difficult-to-treat infections and/or following administration forprolonged periods, including seven patients in a clinical trial for endocarditis andcomplicated bacteraemia.17,164

Because the mechanism of action is unique, it was predicted that daptomycin wouldnot exhibit cross-resistance with other classes of antibiotics. However, recent studieshave suggested that reduced susceptibility to daptomycin may be associated withreduced susceptibility to vancomycin.187 There was a strong positive correlationbetween reduced daptomycin susceptibility and vancomycin resistance in VISA.187

Thickening of the cell wall is a common characteristic of vancomycin resistance, andthis acts as a physical barrier resulting in reduced drug penetration.188 Increased cellwall thickness is also correlated with reduced daptomycin susceptibility, and it issuspected that this may impede daptomycin penetration through the cell wall,reducing daptomycin accessibility to the bacterial cell membrane.187 Daptomycin hasshown good susceptibility against VRSA, but VRSA resistance is conferred by thevanA gene transposon rather than cell wall thickening,187 and therefore does notcontradict the cross-resistance results with VISA.

4.6.2 Synergistic activityDaptomycin is the only antibiotic currently available from the cyclic lipopeptide classof antibiotics,165 and offers the potential for synergistic action with antibiotics fromother drug classes that have different mechanisms of action.184 Studies have foundthat daptomycin combined with β-lactams (e.g. ampicillins and ceftriaxone)169 orgentamicin against VRE and MRSA,189 and with rifampicin against VRE169 and E. faecium170 showed synergistic activity in the clearance of bacterial isolates.169-171

Concentrations below the MIC of daptomycin and gentamicin in combinationresulted in synergy against 68% of tested S. aureus strains172 and >70% of MRSAstrains.173 Antagonistic effects of antibiotic combinations have not been observedwith daptomycin.172 This may increase the effectiveness of drug therapy, especially inthe treatment of mixed infections, by enabling the targeting of different bacterialpathways or processes.

4.6.3 Cidality The rapid bactericidal activity of daptomycin offers potentially important advantagesover bacteriostatic drugs (Figure 4.3; see also Section 4.7.7). Bacteriostatic antibioticsact through inhibition of bacterial growth; however, these drugs do not kill thebacteria,159 and bacterial vegetations may remain present in the system. Cidalitycould reduce the risk of recurrence of an infection after treatment cessation bypreventing regrowth of static bacterial colonies.125 A rapid bactericidal effect that isindependent of the host immune response may also help the potential suppressionof resistance emergence and selection.159,190

4.6.4 Bacterial cell lysisDaptomycin treatment results in negligible cell lysis because the cell wall of bacteriakilled by daptomycin remains intact.18,178,191 In contrast, some antibiotics, mostnotably β-lactams, are bactericidal and cause lysis. This can theoretically be harmful,because it may cause the release of bacterial toxins and other inflammation-inducing cell components into the circulation and thereby trigger, or exacerbate,PAGE 34

SECTION 4


Emergence ofresistance to Cubicinamong S. aureusstrains is rare, basedon a worldwidestudy of Gram-positiveclinical isolates


septic shock and multiple organ failure in patients with serious infections.159,192

Staphylococcus aureus secretes the cell wall components lipoteichoic acid andpeptidoglycan, as well as toxins and other harmful agents into the bloodstream,which can induce the production of pro-inflammatory cytokines by monocytes.193 Anincreasing proportion of S. aureus strains, particularly community-acquired S. aureusinfections, produce the PVL toxin, which can attack white blood cells and compromisethe immune response.34 β-lactam antibiotic therapy dramatically increases the serumconcentration of these factors.194 Daptomycin is thought to resolve bacterialinfections without rupturing the bacterial cells.18 This suggests that daptomycin maybe able to reduce the risk of potential complications and inflammatory reactions thatare known to be caused by toxin release upon bacterial cell lysis.159,195

4.7 In vitro activity4.7.1 Spectrum of activityRecent studies have confirmed that daptomycin is active in vitro against most Gram-positive bacteria, including staphylococci, streptococci, enterococci and, importantly,against Gram-positive strains that are resistant to multiple first-line antibiotics.196,197

4.7.2 StaphylococciAlmost all (>99.9%) staphylococci were susceptible to ≤1 μg/ml daptomycin from atotal of 6737 clinical Gram-positive isolates collected from infected patients in over70 centres in Europe, North America and South America (Table 4.2).166 Resistance toother antibiotics does not appear to influence the activity of daptomycin, which issimilarly active against MSSA and MRSA, with a reported MIC that inhibits 50% ofthe strains (MIC

50) of 0.25 μg/ml against both and MIC

90of 0.25 and 0.5 μg/ml,

respectively.12,198 These values indicate susceptibility according to the EuropeanCommittee on Antimicrobial Susceptibility Testing (EUCAST) breakpoint ofSusceptible <1 μg/ml and Resistant >1 μg/ml.199

Table 4.2. In vitro activity of daptomycin against staphylococcal clinical isolates166

Cubicin has abactericidal action,with negligible cell

lysis

PAGE 35

SECTION 4


Cubicin is activeagainst a broad

spectrum ofclinically relevant

Gram-positivebacteria

Figure 4.3. Cidality and cell lysis (Figure interpreted from Finberg et al. 2004)159

Organism N MIC range(μg/ml)

MIC50

(μg/ml)MIC

90

(μg/ml)

Staphylococcus aureusMethicillin-susceptibleMethicillin-resistant

1955

1247

≤0.12–2.0

≤0.12–1.0

0.25

0.25

0.5

0.5

Coagulase-negative staphylococciMethicillin-susceptibleMethicillin-resistant

169

669

≤0.12–2.0

≤0.12–1.0

0.25

0.25

0.5

0.5


4.7.3 StreptococciStreptococcus species included in the surveillance programme166 were all susceptibleto daptomycin, with MIC

90≤1 μg/ml, including strains that are resistant to other

antibiotics (Table 4.3). This is below the breakpoint value indicating susceptibility todaptomycin issued by the FDA, the United States Clinical and Laboratory StandardsInstitute (CLSI; formerly known as the National Committee for Clinical LaboratoryStandards [NCCLS]), which refer to susceptible, intermediate and resistant strains,and EUCAST, which refer to susceptible and resistant strains only, which is ≤1 μg/mlfor S. pyogenes,177 Streptococcus groups A, B, C and G,199 S. agalactiae and S. dysgalactiae subsp. equisimilis.177

Table 4.3. In vitro activity of daptomycin against streptococcal clinical isolates166

4.7.4 EnterococciEnterococcus faecalis has greater susceptibility to daptomycin in vitro (MIC

90: 1 μg/ml)

than E. faecium, which has a relatively high MIC90

value of 4 μg/ml (Table 4.4).166 This iswithin the CLSI established breakpoint of ≤4 μg/ml for Enterococcus species177 and issimilar to, or better than, some antibiotics against resistant E. faecium infections (seeSection 4.7.5). There are currently no defined breakpoints for enterococci in Europe.Enterococcus species show susceptibility to daptomycin, with an MIC

90 of ≤2 μg/ml

(Table 4.4).166 There is currently insufficient evidence to draw firm conclusions aboutthe clinical efficacy of daptomycin against E. faecalis and E. faecium.164

Table 4.4. In vitro activity of daptomycin against enterococcal clinical isolates166

PAGE 36

SECTION 4


aEnterococcus species include E. avium (4 strains), E. casseliflavus (3 strains), E. durans (3 strains), E. gallinarum (4 strains), E. raffinosus (1 strain) and Enterococcus non-speciated (6 strains)Note: Cubicin is not approved in enterococcal infections

Note: It has been demonstrated in clinical studies that Cubicin is not effective in the treatment of pneumonia164


MIC50

(μg/ml)MIC

90

(μg/ml)

Enterococcus faecalisVancomycin-susceptibleVancomycin-resistant

626

20

≤0.12–4.0

0.25–1.0

1.0

1.0

1.0

1.0

Enterococcus faeciumVancomycin-susceptibleVancomycin-resistant

97

55

≤0.12–8.0

0.25–4.0

2.0

1.0

4.0

4.0

Enterococcus spp.a 21 0.5–4.0 1.0 2.0


MIC50

(μg/ml)MIC

90

(μg/ml)

β-haemolytic streptococci 247 ≤0.12–0.5 ≤0.12 0.25

Viridans group streptococciPenicillin-susceptiblePenicillin-resistant

118

31

≤0.12–1.0

≤0.12–1.0

0.25

0.25

0.5

1.0

Streptococcus pneumoniaePenicillin-susceptiblePenicillin-resistant

1018

406

≤0.12–1.0

≤0.12–1.0

≤0.12

≤0.12

0.25

0.25

Streptococcus bovis 16 ≤0.12 ≤0.12 ≤0.12


4.7.5 Resistant pathogensIn a study comparing a wide variety of anti-infective agents against 2759 Gram-positive clinical isolates, including antibiotic-resistant organisms, from patients inNorth America, daptomycin was the most active antibiotic tested (Table 4.5).198 Allisolates examined in this study (including oxacillin-susceptible S. aureus [1090

strains], oxacillin-resistant S. aureus [773 strains], vancomycin-susceptible E. faecalis[674 strains], Group A β-haemolytic streptococci [84 strains], and Group B β-haemolytic streptococci [138 strains]) were susceptible to daptomycin according toCLSI and FDA breakpoints.198

Table 4.5. Comparison of MIC90

of different antibiotics against common Gram-positive pathogens12,200,201

Daptomycin is active in vitro against drug-resistant isolates, not only MRSA and VRE,but also vancomycin-intermediate staphylococci and teicoplanin-non-susceptibleCoNS.202 Daptomycin is also active against pathogens resistant to newer anti-Gram-positive antibiotics, namely quinupristin/dalfopristin-resistant staphylococci and E. faecium, and linezolid-resistant Gram-positive cocci (Table 4.6).202

Table 4.6. In vitro activity of daptomycin against drug-resistant Gram-positiveisolates collected in Europe, North America and South America in 2001–2002

202

Results of studies have found little or no variation in the in vitro activity ofdaptomycin against antibiotic resistant pathogens, MRSA and VRE, regardless of thelocal prevalence of these organisms.185 Prevalence of antibiotic resistance has beenfound to differ considerably between countries; for example, MRSA incidence in 2005

in Europe varied between 0.9% in The Netherlands and 43.6% in the UK.3 PAGE 37

SECTION 4


MRSE, methicillin-resistant Staphylococcus epidermidis; MSSE, methicillin-susceptible S. epidermidis; VAN-R,vancomycin resistant

MIC90

(μg/ml)

Daptomycin Vancomycin Linezolid Teicoplanin

MSSA 0.25 1 4 0.5

MRSA 0.5 1 4 1

MSSE 0.5 1 1 2

MRSE 0.25 2 2 4

Enterococcus faecalis 1 2 2 0.12

Enterococcus faecalis (VAN-R) 1 >256 2 >64

Enterococcus faecium 4 1 2 0.5

Enterococcus faecium (VAN-R) 4 >256 2 >64


MIC50

(μg/ml)MIC

90

(μg/ml)

Vancomycin-intermediatestaphylococci

13 0.5–1.0 0.5 1.0

Quinupristin/dalfopristin-resistant staphylococci

11 0.25–1.0 0.5 1.0

Teicoplanin-non-susceptibleCoNS

20 ≤0.12–0.5 0.25 0.5

Quinupristin/dalfopristin-resistant Enterococcus faecium

41 ≤0.12–8.0 2.0 4.0

Linezolid-resistant Gram-positivecocci

14 ≤0.12–4.0 1.0 2.0

Cubicin is activeagainst growing and

stationary-phasebacteria


4.7.6 Other Gram-positive pathogensDaptomycin shows in vitro activity against a variety of unusual aerobic bacteria andanaerobic Gram-positive pathogens, with MIC

90≤2 μg/ml (Table 4.7).203,204

Table 4.7. In vitro activity of daptomycin against other clinical isolates166,203,204

4.7.7 Rapid bactericidal activityDaptomycin has been shown to possess rapid,205 concentration-dependentbactericidal activity against susceptible Gram-positive organisms in vitro.206 Whencompared with vancomycin, linezolid and nafcillin at 4� MIC in time–kill studies,daptomycin demonstrated equivalent or faster bactericidal activity against MSSA(Figure 4.4),165 MRSA, VISA, methicillin-resistant S. epidermidis and VRE, reducing thenumber of viable bacteria by 99.9% within 8 hours.165,200 In vitro, daptomycin canachieve a 3 log

10reduction in viable bacteria in less than 2 hours against S. aureus,

including MRSA, at concentrations 2–4� the MIC (Figure 4.5),167 and results instatistically faster kill rates than vancomycin against high-inoculum MRSA atsimulated therapeutic dosing regimens (Figure 4.6),15 which may lead to fasterresolution of infection. Daptomycin retains bactericidal activity against stationary-phase bacteria, whereas both vancomycin and linezolid were found to bebacteriostatic against high-inoculum cultures.15

A rapid time-to-clearance of bacterial infection may offer treatment advantages,because SSTIs have the potential to be the focal infection site or initiating site forserious complications – including bacteraemia, nephritis and carditis – if treatment isdelayed or inadequate.14 The potential associated reduction in treatment times mayresult in lower healthcare and hospitalization costs.207 Rapid bactericidal activity canalso reduce the length of time that bacteria are exposed to an antibiotic, which mayhave the effect of minimizing the potential for the emergence of resistance.

4.7.8 Post-antibiotic effectCubicin produced a longer, dose-dependent post-antibiotic effect against E. faecalis,MSSA and MRSA than standard antibiotic treatment regimens, includingvancomycin, nafcillin, penicillin and gentamicin.19 Post-antibiotic effect may helpdelay bacterial regrowth when the antibiotic plasma concentration falls below the MIC.

PAGE 38

SECTION 4



MIC50

(μg/ml)MIC

90

(μg/ml)

Bacillus spp.166 10 ≤0.12–8.0 1.0 2.0

Corynebacterium spp.166 14 ≤0.12–1.0 ≤0.12 0.25

Listeria spp.166 18 ≤0.25–4.0 2.0 2.0

Clostridium perfringens203 12 0.25–1.0 1.0 1.0

Clostridium difficile204 102 0.125–2.0 0.5 1.0

Eubacterium spp.a,203 13 0.06–8.0 0.5 0.5

Propionibacterium acnes204 117 0.25–1.0 0.5 1.0

Finegoldia magna204 101 ≤0.015–2.0 0.5 1.0

a Includes Eubacterium contortum (n=2), Eubacterium moiliforme (n=1), Eubacterium tenue (n=2),Pseudoramibacter alactolyticus (n=7) and other Eubacterium spp. (n=1)

Cubicin is rapidlybactericical and kills99.9% of growingor stationary-phaseS. aureus within 24 hours


SECTION 4


Figure 4.4. Activity of daptomycin (D) against high-inoculum MSSA, compared withgrowth control (GC), nafcillin (N), vancomycin (V) and linezolid (L). Error bars indicatestandard deviation. (CFU, colony forming units)165

GC

N

VL

D

12

10

8

6

4

2

0

0 12 24 36 48 60 72

Activ

ity (l

og10

CFU

/g)

Time (hours)

Figure 4.5. Bactericidal activity of daptomycin against S. aureus at 2, 4 and 8 timesthe MIC167

Control2* MIC4* MIC8* MIC

103

104

105

106

107

108

300 60 90

Activ

ity (l

og10

CFU

/ml)

Time (minutes)

Figure 4.6. Time–kill curves of daptomycin and vancomycin against high-inoculumMRSA. Error bars indicate standard deviation15

Growth controlGentamicin

DaptomycinDaptomycin/gentamicin

Vancomycin/gentamicin

Vancomycin

LinezolidLinezolid/gentamicin

1

12

11

10

9

8

7

6

5

4

3

2

328 16 240 64 72564840

Activ

ity (l

og10

CFU

/g)

Time (hours)


4.8 Pharmacology profile4.8.1 Summary

4.9 Pharmacokinetics and pharmacodynamics4.9.1 Plasma level profileDaptomycin (the active ingredient of Cubicin), has demonstrated a linear,predictable, and dose-proportional pharmacokinetic profile in preclinicalinvestigations at doses between 4–12 mg/kg.208-210,216 The drug has a relatively longplasma half-life (t

V; approximately 9 hours)211 and showed minor (20%) accumulation

that was not statistically significant when administered once daily at doses between4–8 mg/kg in healthy volunteers (Figure 4.7).211 Cubicin administered at higher dosesbetween 6 and 12 mg/kg has also been found to result in linear, dose-proportionalpharmacokinetics (Figure 4.8),209 indicating that the pharmacokinetics of higherdoses of Cubicin can be predicted with some confidence.

PAGE 40

SECTION 4


Cubicin has a predictable, dose-proportional pharmacokineticprofile208-210

No clinically significant accumulation has been observed211

Cubicin achieves tissue penetration that results in therapeuticconcentrations sufficient to resolve infections208,212

Cubicin is eliminated primarily by the kidney213

Cubicin has low potential for drug interactions214

No routine monitoring of Cubicin serum levels is required215

Figure 4.7. Mean plasma drug concentrations of daptomycin versus time plots foronce-daily dosing of Cubicin on day 1 (A) and day 7 (B) in healthy subjects (n=24).Error bars indicate standard deviation211

Day 1: 4 mg/kgDay 1: 6 mg/kgDay 1: 8 mg/kg

0

20

40

60

80

100

120A

B

84 120 16 20 24

Mea

n da

ptom

ycin

plas

ma

conc

entr

atio

n (μ

g/m

l)

Time (hours)

Day 7: 4 mg/kgDay 7: 6 mg/kgDay 7: 8 mg/kg

0

20

40

60

80

100

140

120

84 120 16 20 24

Mea

n da

ptom

ycin

plas

ma

conc

entr

atio

n (μ

g/m

l)

Time (hours)


4.9.2 Plasma protein bindingA large proportion of administered daptomycin has been shown to bind reversibly tohuman plasma proteins, primarily albumin (91–95% at 6 mg/kg dose),217 in aconcentration-independent manner.218 However, daptomycin binds weakly and reversiblyto albumin (dissociation constant 90.3 μM),125 whereas binding to the membranes ofsusceptible Gram-positive bacteria appears to be very strong, or even irreversible.210,219

This is demonstrated by the small effect that serum proteins have on antibacterialactivity; daptomycin MICs typically increased 2-fold in the presence of 4% humanalbumin (approximately 75% effective protein binding; Table 4.8).178 Arithmetic meanMICs in 95% solutions of human and mouse sera, in 5% human albumin solution and inbroth, showed that daptomycin was 2–4-fold more active than would be predicted fromcalculations of concentrations of free drug.220 Thus, the assumption that only 10% ofdaptomycin is unbound and active may be an underestimate.178 This could be explainedby the formation of a reservoir of albumin-bound daptomycin. As the drug is used up atthe site of the infection, the resultant osmotic tissue pressure gradient allowsdaptomycin to separate from the albumin, providing a prolonged supply of daptomycinto the site of infection.

Table 4.8. Daptomycin MIC in the presence of albumin and serum compared withbroth alone220

4.9.3 DistributionDaptomycin has a low volume of distribution (~0.1 l/kg),211 with a distribution mostlylimited to serum and the extracellular space.221 Studies in animals have shown thatdaptomycin preferentially penetrates into highly vascularized tissues.212 It has minimalpenetration across the blood–brain barrier into the cerebrospinal fluid of non-inflamedrabbit meninges;222 however, a 5% penetration (relative to serum) across theblood–brain barrier has been found in rabbits with experimental S. aureus meningitis,which resulted in clearance of the infection.222 Daptomycin penetrates well into blisterinflammatory fluid; in healthy subjects (n=7), a single i.v. dose of Cubicin 4 mg/kgproduced a mean Cmax in blister inflammatory fluid of 27.6 μg/ml at a mean time of 3.7 hours (Table 4.9), which corresponds to 68.4% of plasma levels relative to serumconcentration.208 These data indicate that daptomycin achieves tissue penetrationresulting in therapeutic concentrations that are sufficient to resolve infections. PAGE 41

SECTION 4


Figure 4.8. Daptomycin has linear, dose-proportional pharmacokinetics at dosesbetween 6 and 12 mg/kg209

1

100

10

1000

Day 1 Day 4

0 302010

Mea

n pl

asm

aco

ncen

trat

ion

(μg/

ml)

Time (hours)

A

1

100

10

1000

0 302010

Mea

n pl

asm

aco

ncen

trat

ion

(μg/

ml)

Time (hours)

B6 mg/kg8 mg/kg10 mg/kg12 mg/kg

Cubicin achievesexcellent tissue

penetration

Mean MIC (μg/ml)Broth 5% albumins or 95% serum

Staphylococcus aureus 0.44 0.85–2.33

Enterococcus faecalis 2.33 4.67–8.25

Streptococcus pneumoniae 0.22 0.50–1.13


Table 4.9. Tissue penetration data for daptomycin212

4.9.4 Metabolism and excretionDaptomycin is eliminated primarily by the kidney.214 In humans, 86% of aradiolabelled daptomycin dose given to healthy individuals was recovered: 78% inurine, 5% in faeces and 3% in breath.164,178 Of the 78% excreted in the urine, 52%remained microbiologically active.178 The remainder appeared in the urine as abiologically undetectable 14C entity that may represent peptide fragments producedafter renal excretion. Four minor metabolites were detected in urine, two of whichare Phase I oxidative metabolites present in low concentrations.164 Thepharmacokinetics of daptomycin are unaffected by the co-administration ofprobenecid,164 suggesting that daptomycin is excreted primarily by glomerularfiltration with insignificant tubular secretion. Analysis of plasma samples fromsubjects who received a 6 mg/kg dose of Cubicin did not show any trace of serummetabolites, suggesting little or no systemic metabolism.164

4.9.5 Determination of dosing periodCubicin has been determined to be safe and effective at 4 mg/kg once daily for thetreatment of cSSTIs from studies in dogs,223 human volunteers,211 and clinical trials,16

and at 6 mg/kg once daily for the treatment of RIE caused by S. aureus and fortreatment of SAB when associated with RIE or cSSTIs on the basis ofpharmacokinetic data and trials in human volunteers.17,164 Skeletal muscle toxicitypredicted by elevated creatine phosphokinase (CPK) levels associated with Cubicintherapy has been reported, and experience in dogs and patients indicate that this islinked to the period between doses rather than the amount of each dose. Muscletoxicity in dogs was greater with fractionated rather than once-daily administrationof the same total daily dose.223 The relatively long half-life of 8–9 hours,211 combinedwith a prolonged post-antibiotic effect, allows for effective therapy of bacterialinfections with once-daily dosing.224 Cubicin is delivered by 30-minute i.v. infusion,which is convenient for patients and allows for potential outpatient delivery.225

4.9.6 Drug–drug interactionsPlasma levels of daptomycin may be increased when co-administered with drugsthat reduce renal filtration, such as non-steroidal anti-inflammatory drugs and COX-2 inhibitors.164 Daptomycin has also been found to interfere with a reagent(recombinant thromboplastin) used in some prothrombin time/internationalnormalized ratio assays,164 although most marketed tests show no reaction. This testmeasures blood clotting capacity, and interference between daptomycin and a testreagent may give false results, suggesting poor blood clotting. In vitro studies usinghuman hepatocytes showed no inhibition or induction of clinically significantPAGE 42

SECTION 4


Tissue Species Maximumconcentration

(μg/ml)

Concentrationrelative to

serum level (%)

Blister fluid Human 27.6 68.4

Blood clot tissue Rat, rabbit 3.5 72.7

Peritoneal tissue chamber Rat 11.8 35.1

Bronchoalveolar lavage epithelial lining fluid* Mouse, rat,sheep

1.0 2.0

Cerebrospinal fluid Rabbit 5.2 6.0

Cubicin has asimple, once-dailydosing regimen

Cubicin has a lowpotential for CYP450-related drug interactions

*Note: it has been demonstrated in clinical studies that Cubicin is not effective in the treatment ofpneumonia164


cytochrome P450 (CYP450) isoenzymes by daptomycin.213 Hence, no drug interactionsare to be expected with drugs that are metabolized or induced by this system.164

Synergistic activity may be experienced with other antibiotics (see Section 4.6.2).

4.10 Susceptibility testingThe choice of antibiotic used in the non-empiric treatment of an infection dependslargely on the susceptibility of the pathogens to antibacterial drugs and localguidance.226

Daptomycin has two characteristics that affect the reliability of susceptibility testingmethods: molecular weight and its requirement of calcium ions for activity. Antibioticswith a large molecular weight (>700 Da), such as daptomycin, have poor diffusionfrom paper disks onto surface agar,227 making it difficult to distinguish betweensusceptible and resistant organisms using the disk diffusion method.228 Results of aninvestigation into susceptibility testing methods for daptomycin, published in 2000,229

against 844 strains of Gram-positive bacteria in growth medium containing threedifferent concentrations of calcium showed that daptomycin activity increases withincreasing concentrations of calcium,229 which has implications for laboratorysusceptibility testing. A calcium concentration of 50 μg/ml (1.1 mM) in the growthmedia has been found to be optimal for determination of MIC and correlates withphysiological levels of free calcium in human serum (1.15–1.31 mM).230

Two methods of susceptibility testing are currently recommended for daptomycin:the Etest strip and broth microdilution (BMD) methods. The daptomycin Etest strip(AB Biodisk, Sweden) contains a constant concentration of calcium across adaptomycin concentration gradient, and is suitable for use with Mueller-Hintonagar228 and Iso-Sensitest agar.231 The BMD method is recommended for thedetermination of MIC and susceptibility of pathogens to daptomycin.177

4.11 Special populations4.11.1 Renal insufficiencyFollowing administration of a single 4 mg/kg dose of Cubicin to subjects with variousdegrees of renal insufficiency, Cubicin clearance was reduced and systemic exposure(area under curve [AUC]) was increased.164 Exposure and elimination half-life wereincreased between 2- and 3-fold in subjects with severe renal insufficiency (creatinineclearance <30 ml/min) and end-stage renal disease, relative to healthy subjects.

Because of limited clinical experience, Cubicin should only be used in patients withrenal insufficiency where it is considered that the clinical benefit would outweighany risk. The response to treatment and renal function should be monitored in allpatients with some degree of renal insufficiency (creatinine clearance <80 ml/min).No dose adjustment is required in patients with creatinine clearance ≥30 ml/min (4 mg/kg in patients with cSSTI without SAB) or ≥50 ml/min (6 mg/kg in patientswith RIE or cSSTI associated with SAB).164 The dose should be reduced to 4 mg/kg,administered as a single dose once every 48 hours, for cSSTI patients without SABwith creatinine clearance <30 ml/min and those on haemodialysis or continuousambulatory peritoneal dialysis.232 When possible, Cubicin should be administeredfollowing the completion of dialysis on dialysis days. There is insufficient evidence tosupport a dose recommendation for patients with RIE or cSSTIs associated with SABwho have a creatinine clearance of <50 ml/min.164

PAGE 43

SECTION 4



4.11.2 Hepatic insufficiency

The pharmacokinetics of daptomycin are not altered in subjects with moderatehepatic insufficiency (Child–Pugh classification of cirrhosis) compared with healthyvolunteers matched for gender, age and weight following a single 4 mg/kg dose(Figure 4.9).164,214 No dosage adjustment is necessary when administering Cubicin inpatients with moderate hepatic insufficiency. The pharmacokinetics of daptomycin inpatients with severe hepatic insufficiency (Child–Pugh C classification) have not beenevaluated.164

4.11.3 ElderlyA study showed an increase in drug accumulation and a decrease in systemic andrenal clearance in elderly patients compared with younger patients.221 There was nosignificant difference in the Cmax or volume of distribution between the two patientgroups, indicating that differences in renal clearance may be attributed more to ahigher incidence of renal dysfunction in the elderly.221 There is no need for doseadjustment in elderly patients with Cubicin;221 however, there are limited dataavailable on administration of Cubicin to patients aged >65 years, and caution needsto be exercised in such patients where comorbidities may be present.164

4.11.4 Children and adolescentsThe pharmacokinetics of Cubicin following a single 4 mg/kg dose in adolescentsaged 12–17 were found to be similar to those of healthy adults, although with trendstowards lower exposure (AUC and Cmax): exposure and elimination half-life werereduced compared with those of children in younger age groups (2–6 years and 7–11 years). Due to the lack of safety and efficacy data, Cubicin is not recommendedfor use in children and adolescents (<18 years of age).164

4.11.5 ObesityThe absolute renal clearance and plasma profile of Cubicin, including plasma half-life, was found to be unchanged in obese patients compared with matched non-obese controls (Figure 4.10).234 However, the volume of distribution and plasmaclearance were higher in obese patients, with a rate of change associated withincreased body mass index (BMI). Relative to non-obese subjects, systemic exposureof Cubicin measured by AUC increased by about 30% in obese subjects (BMI of>25–40 kg/m2) but remained within the pre-determined safe range, and there is norequirement for adjustment of dosing in these patient groups.234 PAGE 44

SECTION 4


Figure 4.9. Moderate liver impairment has no effect on the plasmaconcentration–time profile of daptomycin233

ControlHepatic impairment

1

100

10

1000

0 8 16 24

Plas

ma

conc

entr

atio

n (μ

g/m

l)

Time (hours)


4.11.6 Pregnancy and lactation

There are no clinical data available documenting the use of Cubicin in pregnancy orlactation, but animal studies indicate that harmful effects are unlikely. It is unknownif Cubicin is excreted in human milk; therefore, breastfeeding should be discontinuedduring the course of treatment. Cubicin should be used in pregnancy and lactationonly where benefits outweigh the risks.164

4.12 ToxicityCubicin has been linked with elevations in plasma CPK and myopathies that areassociated with muscle pain and weakness.164 However, muscle degeneration wasfound to be fully reversible, with no fibrosis on regeneration in a study in dogs.223

This study also indicated that muscle toxicity effects are related more closely to theinterval between doses than the concentration of the dose given, with greaterincreases in serum CPK levels and myopathy observed with doses of 25 mg/kg every8 hours than with doses of 75 mg/kg every 24 hours.223

Muscle toxicity can be minimized by once-daily dosing and regular (at least onceweekly) monitoring of CPK levels in all patients, with dose adjustment ordiscontinuation as necessary.164 More-frequent monitoring of CPK levels should becarried out in patients at risk of developing myopathies, such as those receivingother medication (e.g. statins) that may trigger myopathies. Combination of Cubicinwith high-risk medicines should only be considered where the benefits outweigh therisks. Cases of myositis, myoglobinaemia and rhabdomyolysis, although rare, havebeen reported in patients undergoing Cubicin therapy.164

Cubicin appears to have low potential for immunotoxicity and exhibited lowimmunogenicity upon repeat administration.178 Tests to evaluate the long-termcarcinogenic potential of daptomycin have not been conducted, although nomutagenic potential has been found in an array of genotoxicity tests.

Animal studies were performed to investigate the toxic potential of Cubicintreatment. Administration did not affect the fertility or reproductive performance ofmale or female rats when exposed to nine times the estimated human exposurelevels based on AUCs.15 In adult animals, effects on peripheral nerves, includingdegeneration and pain, were only observed at concentrations higher than thoseassociated with skeletal muscle degeneration.164

PAGE 45

SECTION 4


Figure 4.10. Obesity has no significant effect on the plasma concentration–timeprofile of daptomycin234

1

10

100

80 4 1612 20 24

Plas

ma

conc

entr

atio

n (μ

g/m

l)

Time (hours)

Moderately obese

Morbidly obese

Matched control formoderately obese

Matched control for morbidly obese


5.1.2 Efficacy in clinical trials in cSSTITwo pivotal phase III clinical trials (9801 and 9901) demonstrated the efficacy andtolerability of Cubicin compared with comparator antibiotic therapy in the treatmentof Gram-positive cSSTIs.16 Study 9801 was conducted in the US and South Africa, andstudy 9901 in Europe, South Africa, Australia and Israel.

Study designEligible patients were aged 18–85 years (18–65 years in South Africa) with Gram-positive cSSTIs requiring hospitalization (Table 5.1). Patients with confirmedbacteraemia at baseline were excluded, but those diagnosed with bacteraemiaduring the course of the study were allowed to continue.

Table 5.1. Inclusion and exclusion criteria for the selection of patients to studies 9801

and 990116,178

PAGE 47

SECTION 5

CUBICIN INCLINICAL TRIALS

5. Cubicin in clinical trials5.1 Cubicin in cSSTI clinical trials5.1.1 Summary

Cubicin:

Evaluated for efficacy and safety in the treatment of cSSTIs in two majorphase III clinical trials16

Demonstrates non-inferiority to comparator antibiotics in thetreatment of Gram-positive cSSTIs

– Has a safety and tolerability profile similar to that of conventionalantibiotics

Effective in treatment of cSSTIs caused by both MSSA and MRSA16

Significantly more patients were treated successfully with Cubicinwithin 4–7 days than with comparator therapy, including vancomycin16

Entry criteria 9801 9901

Inclusion:Diagnosis of cSSTIs known to be due to Gram-positive bacteria Wound infections (surgical, trauma and bites)Major abscesses, diabetic ulcers, other ulcersCarbunculosisInfections involving deeper tissues, fascia or muscleRequired hospitalization with parenteral antimicrobial therapy forat least 96 hours

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Exclusion:Minor or superficial infections (e.g. simple abscess, impetigo,uncomplicated cellulitis)Perirectal abscessGangreneMultiple infected ulcers at distant sitesBacteraemia at time of enrolmentRequired curative surgery (e.g. amputation)Concomitant infection at another site (e.g. endocarditis,osteomyelitis, septic arthritis)Infections of third degree burns

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After performing the baseline evaluation, the investigator at each site assigned acomparator regimen (semisynthetic penicillin [cloxacillin, nafcillin, oxacillin,flucloxacillin] 4–12 g i.v. per day in equally divided doses, or vancomycin 1 g i.v. twicedaily by 60-minute infusion) to be administered if the patient was randomized tocomparator treatment. Patients were then randomized in a 1:1 ratio to Cubicin orcomparator treatment groups to receive treatment for 7–14 days with either Cubicin(4 mg/kg, once daily by 30-minute i.v. infusion) or a comparator antibiotic regimen(Figure 5.1).

The patient populationAcross both studies, 1092 patients were enrolled and received ≥1 dose of studymedication. At baseline, the types of SSTI most commonly diagnosed were woundinfections, major abscesses and ulcers (Figure 5.2).

Baseline demographics, including patient demographics (sex, age and ethnicity), andclinical characteristics were similar between both treatment groups (Table 5.2).16 Itwas found that 88% (study 9801) and 97% (study 9901) of patients in the Cubicingroups and 89% (9801) and 97% (9901) of patients in the comparator groups had fiveor more signs or symptoms of infection, indicating the presence of cSSTI infections.178

PAGE 48

SECTION 5


Figure 5.1. Design of studies 9801 and 990116

(SSP, semisynthetic penicillins; VAN,vancomycin)

Investigator assigns comparator agent

Randomization to treatment groupp

SSPS

Comparator(VAN)

Comparator(SSP)

CubicinCubicin

VANA

Figure 5.2. Pooled baseline primary diagnoses of patients with cSSTIs in studies 9801

and 990116

Wound infections Major abscessesDiabetic ulcersOther ulcersOther infections

24%

12%

13%

7%

44%


Table 5.2. Patients’ demographics, and baseline clinical characteristics of the ITTpopulation16

aCloxacillin, flucloxacillin, nafcillin, oxacillin or vancomycinSIRS, systemic inflammatory response syndrome; ITT, intention-to-treat (all randomized patients with a cSSTIwho received ≥1 dose of study medication)

Infections caused by Gram-positive organisms were identified in 80% and 84% ofCubicin and comparator-treated patients, respectively. Staphylococcus aureus was themost frequently isolated pathogen in both treatment groups, with approximately70% of patients overall with confirmed S. aureus infection. Of these, approximately10% had MRSA (Table 5.3). The types of infecting pathogen were similarly representedbetween Cubicin and comparator groups (Table 5.3).

OutcomesOutcomes were based primarily on clinical and microbiological assessment prior toadministration of the first dose of study drug, and at test of cure (6–20 days afterreceipt of the last dose). Patients were considered to show clinical success if they hadresolution or improvement of signs and symptoms such that no further antibiotictherapy was required. Patients were considered to have failed treatment if theyshowed inadequate response to therapy at any point during the study.16

Pooled analysis from studies 9801 and 9901 demonstrated clinical success rates of83.4% for patients treated with Cubicin and 84.2% for patients treated withcomparator antibiotics (clinically evaluable [CE] population) (Figure 5.3), confirmingnon-inferiority of Cubicin to comparators.16 Cubicin was also as effective asindividual comparator antibiotics, with clinical success rates of 69% (Cubicin) and67% (vancomycin) when pre-assigned to vancomycin treatment; and 84% (Cubicin)and 82% (semisynthetic penicillins, modified intention-to-treat [MITT] population)when pre-assigned to semisynthetic penicillin treatment (Figure 5.4).178

PAGE 49

SECTION 5

CUBICIN INCLINICAL TRIALSCharacteristic Cubicin group

number (%)(n=534)

Comparator groupa

number (%)(n=558)

SexMaleFemale

293 (55)

241 (45)

308 (55)

250 (45)

AgeMean years (range)≥65 years

51.5 (18–91)

145 (27)

51.9 (17–94)

139 (25)

RaceWhiteBlackOther

313 (59)

145 (27)

76 (14)

313 (56)

151 (27)

94 (17)

Comorbid conditionsDiabetes mellitusPeripheral vascular diseaseImmunocompromised

160 (30)

103 (19)

18 (3)

194 (35)

128 (23)

19 (3)

Baseline diagnosisWound infectionMajor abscessInfected diabetic ulcerInfected ulcer, not diabeticOther infection

224 (42)

138 (26)

61 (11)

70 (13)

41 (8)

254 (46)

124 (22)

72 (13)

75 (13)

33 (6)

Bacteraemia 14 (3) 12 (2)

SIRS 190 (36) 213 (38)

Cubicin hasdemonstrated

non-inferiority tocurrent standard

of care


Table 5.3. Infecting Gram-positive organisms at baseline in studies 9801 and 9901

(MITT population)16

aCloxacillin, flucloxacillin, nafcillin, oxacillin or vancomycinMITT, modified intention-to-treat (all patients in the ITT population with an infecting Gram-positiveorganism isolated at baseline)Note: species that are represented by <10 patients per treatment group are not shown. Totals add to >100%because 227 subjects in the MITT population had >1 Gram-positive organism at baseline

PAGE 50

SECTION 5


Number (%) of patientsOrganism Cubicin group

(n=428)

Comparator groupa

(n=471)

Staphylococcus aureusAllMSSAMRSA

305 (71.3)

231 (54.0)

40 (9.3)

323 (68.6)

239 (50.7)

47 (10.0)

Streptococcus pyogenes 92 (21.5) 103 (21.9)

Streptococcus agalactiae 30 (7.0) 41 (9.7)

Streptococcus dysgalactiae subsp. equisimilis 12 (2.8) 15 (3.2)

Viridans streptococci 26 (6.1) 38 (8.1)

Enterococcus faecalis 45 (10.5) 61 (13.0)

Figure 5.3. Clinical success rates in clinically evaluable patients pooled from studies9801 and 9901

16

0

10

Clin

ical

succ

ess (

%)

Cubicin (n=446) Comparator (n=456)

30

20

40

50

60

70

80

90

100

95% CI, -4.0 to 5.6

83.4 84.2

Note: 95% CI (confidence interval) for the difference in success rate between the Cubicin and comparator group

Figure 5.4. Clinical success rates in the MITT population in studies 9801 and 9901 ofCubicin compared with vancomycin and semisynthetic penicillins178

0

10

Clin

ical

succ

ess (

%)

Cubicin(n=112)

Pre-assignment: vancomycin Pre-assignment: SSP

Vancomycin(n=187)

Cubicin(n=268)

SSP(n=280)

30

20

40

50

60

70

80

90

100

69

848295% CI, -12.3 to 9.5

95% CI, -8.4 to 4.1

67



Separate analysis of the individual studies (9801 and 9901) confirmed the non-inferiority of Cubicin compared with the pooled comparator antibiotic group,with clinical success rates of 75% (Cubicin) and 75% (comparator) in study 9801, and88.6% (Cubicin) and 89.7% (comparator) in study 9901 (CE populations) (Figure 5.5).178

Cubicin was also effective in the treatment of patients with systemic inflammatoryresponse syndrome (SIRS). The slight decrease in clinical success in patients with SIRS(Figure 5.6) compared with patients with no evidence of SIRS was observed in bothCubicin and comparator groups.

Cubicin achieved a comparable clinical success rate to that of comparator antibioticsin treating cSSTIs in patients with infections caused by MRSA, 75% for Cubicin versus69.4% for the comparator arm (Figure 5.7).16 In both treatment groups, clinicalsuccess rates for MRSA infections were lower than those for MSSA infections. This isprobably due to comorbidities that commonly occur in patients with MRSAinfections16 (e.g. renal impairment74 or diabetes mellitus69).

The efficacy of Cubicin was comparable with that of the comparator antibiotics intreating a wide range of cSSTIs, namely wound infection, major abscess, and infecteddiabetic and non-diabetic ulcer (Figure 5.8). Cubicin was also equally effective againsta wide variety of infecting Gram-positive organisms (Table 5.4). PAGE 51

SECTION 5


Figure 5.5. Clinical success rates in clinically evaluable patients in studies 9801 and9901

178

0

10

Clin

ical

succ

ess (

%)

Cubicin(n=223)

Study 9801 Study 9901

Comparator(n=222)

Cubicin(n=238)

Comparator(n=250)

30

20

40

50

60

70

80

9088.6 89.7

100


74.8 74.8

95% CI, -8.2 to 8.0

95% CI, -4.3 to 6.5

Figure 5.6. Clinical success rates in patients with or without systemic inflammatoryresponse syndrome (SIRS; MITT population)178

0

10

Clin

ical

succ

ess (

%)

Cubicin(n=89)

SIRSStudy 9901Study 9801

Comparator(n=97)

30

20

40

50

60

70

90

80

100

62

Cubicin(n=120)

No SIRS

Comparator(n=115)

6871

Cubicin(n=71)

SIRS

Comparator(n=82)

8081

Cubicin(n=142)

No SIRS

Comparator(n=173)


65

87 86

95% CI, -8.8 to 14.7

95% CI, -17.1 to 10.5

95% CI, -12.4 to 12.8

95% CI, -8.7 to 6.6


Table 5.4. Clinical success rates in patients with cSSTIs and confirmed Gram-positiveinfections in studies 9801 and 9901 (microbiologically evaluable population)16

aCloxacillin, flucloxacillin, nafcillin, oxacillin or vancomycinbEnterococci are not considered to be pathogenic in cSSTIs and are therefore not listed in the Summary ofProduct Characteristics95% CI, confidence interval for the difference in success rate between the Cubicin and comparator groups; n, number of patients successfully treated in each treatment group; N, total number of patients in eachtreatment group

PAGE 52

SECTION 5


Organism Cubicin groupn/N (%)

Comparatorgroupa

n/N (%)

Difference(95% CI)

Staphylococcus aureusMSSAMRSA

170/198 (85.9)

21/28 (75.0)

180/207 (87.0)

25/36 (69.4)

1.1 (–5.6 to 7.8)

5.6 (–28.5 to 17.4)

Streptococcus pyogenes 79/84 (94.0) 80/88 (90.9) 3.1 (–11.1 to 4.9)

Streptococcus agalactiae 23/27 (85.2) 22/29 (75.9) 9.3 (–30.9 to 12.2)

Streptococcus dysgalactiae 8/8 (100) 9/11 (81.8) 18.2 (–48.6 to 12.2)

Enterococcus faecalisb 27/37 (73.0) 40/53 (75.5) 2.5 (–16.3 to 21.3)

Figure 5.7. Clinical success rates in patients with MRSA (ME population)16

0

10

Clin

ical

succ

ess (

%)


30

20

40

50

60

70

80

90

100

69.4

75.0

P=NS

Figure 5.8. Clinical success rates in patients with various types of cSSTIs (CEpopulation)16

0

10

Clin

ical

succ

ess (

%)

Cubicin(n=169)

Wound infection Major abscess

Comparator(n=180)

30

20

40

50

60

70

90

80

100

84 87

Cubicin(n=102)

Comparator(n=92)

9288

Cubicin(n=47)

Infected diabetic ulcer

Comparator(n=56)

66

70

Cubicin(n=47)

Infected other ulcer

Comparator(n=58)

79

83

95% CI, -4.8 to 10.195% CI, -12.6 to 4.3

95% CI, -14.4 to 21.8

95% CI, -11.2 to 19.3



The duration of hospitalization is the main driver of direct healthcare costs associatedwith the treatment of serious infections such as cSSTIs, and the need for i.v. antibiotictherapy has a major impact on the duration of hospitalization. Significantly morepatients in the Cubicin arm (63%) were successfully treated within 4–7 days with i.v.therapy only, compared with the comparator arm (33%; P<0.0001) (Figure 5.9).16

5.1.3 Safety in clinical trials in cSSTIIn the >1400 patients receiving Cubicin in clinical studies, a safety and tolerabilityprofile similar to that of comparator therapies has been demonstrated.178 Of 1221

people receiving a daily dose of 4 mg/kg Cubicin, 1108 were patients and 113 werehealthy volunteers.164 In studies 9801 and 9901, safety was evaluated in all patientswho received one or more doses of study treatment.

Adverse eventsIn the 9801 and 9901 studies, adverse events were monitored daily and graded as mild,moderate or severe on the basis of the World Health Organization Toxicity GradingScale. A serious adverse event was defined as any that was fatal, life-threatening,required prolonged hospitalization, caused persistent or significant disability, was acongenital abnormality, or was an otherwise important medical event.16

Most adverse events in both treatment groups were mild to moderate, and thepattern of events was very similar in the Cubicin and comparator treatment groups(Table 5.5).16 In patients who received Cubicin, the adverse events most frequentlyreported were: constipation (6.2%), nausea (5.8%), injection-site reaction (5.8%) andheadache (5.4%). The same four events were also the most commonly reportedadverse events in the comparator group, with nausea being the most common, in9.5% of patients (Table 5.5).16 CPK elevations, with no associated clinical myopathy,were observed in 2.1% of patients in the Cubicin group compared with 1.4% in thecomparator group. These data indicate that there was no significant differencebetween Cubicin and comparator groups in the incidence of adverse events.16

Of the total reported adverse events, 11% were characterized as severe in the Cubicingroup, compared with 9% for patients treated with comparator. In the Cubicin andcomparator groups, 10.9% and 8.8% of patients, respectively, showed evidence ofmore than one severe adverse event; however, no single type of severe adverse eventwas reported in more than 2% of patients in the study. The only severe adverse event PAGE 53

SECTION 5


Cubicin resolvesmore cSSTIs within

4–7 days thancomparatorantibiotics,

includingvancomycin

Figure 5.9. Proportion of patients successfully treated with i.v. therapy alone (Cubicinor comparator antibiotics) requiring only 4 –7 days of treatment16

0

10

Patie

nts (

%)


30

20

40

50

60

70

80

90

100

63

33

P<0.0001


to be reported in more than 1% of patients was cellulitis (1.3% in the Cubicin group,0% in the comparator group). Treatment was discontinued in 2.8% of patients fromeach group due to adverse events. Eight patients from each treatment group died;however, no deaths were considered to be due to treatment.16 These data indicate nosignificant difference between Cubicin and comparator groups in the incidence ofsevere adverse events.

Table 5.5. Adverse events that occurred in ≥2% of patients in either treatment group16

aCloxacillin, flucloxacillin, nafcillin, oxacillin or vancomycinCPK, creatine phosphokinase

PAGE 54

SECTION 5


Adverse event Number (%) of patients

Cubicin group(n=534)

Comparator groupa

(n=558)

Constipation 33 (6.2) 38 (6.8)

Nausea 31 (5.8) 53 (9.5)

Injection-site reaction 31 (5.8) 43 (7.7)

Headache 29 (5.4) 30 (5.4)

Diarrhoea 28 (5.2) 24 (4.3)

Insomnia 24 (4.5) 30 (5.4)

Rash 23 (4.3) 21 (3.8)

Vomiting 17 (3.2) 21 (3.8)

Abnormal liver function test results 16 (3.0) 9 (1.6)

Pruritus 15 (2.8) 21 (3.8)

Elevated serum CPK level 15 (2.8) 10 (1.8)

Fungal infection 14 (2.6) 18 (3.2)

Hypotension 13 (2.4) 8 (1.4)

Urinary tract infection 13 (2.4) 3 (0.5)

Renal failure 12 (2.2) 15 (2.7)

Dizziness 12 (2.2) 11 (2.0)

Anaemia 11 (2.1) 13 (2.3)

Dyspnoea 11 (2.1) 9 (1.6)

Fever 10 (1.9) 14 (2.5)

Limb pain 8 (1.5) 11 (2.0)

Hypotension 6 (1.1) 11 (2.0)

Dyspepsia 5 (0.9) 14 (2.5)

Arthralgia 5 (0.9) 12 (2.2)


Adverse reactionsAdverse events in the 9801 and 9901 studies that were considered to be possibly,probably or definitely related to treatment are termed adverse reactions, and werereported in 18% of patients treated with Cubicin and 21% of patients treated withcomparator antibiotics when data were combined for studies 9801 and 9901. Thiscompares with adverse reactions reported in 20% of patients treated with Cubicinand 19% of patients on comparator regimens, across all clinical studies (Figure 5.10).178

The same three symptoms – nausea, elevated liver function tests and diarrhoea –were the most commonly reported adverse reactions in both the Cubicin andcomparator groups (Table 5.6).235

Table 5.6. Adverse reactions in the pooled analysis from 9801 and 9901 studiesoccurring in ≥1% of patients treated with Cubicin or comparator antibiotics235

aCloxacillin, flucloxacillin, nafcillin, oxacillin or vancomycinCPK, creatine phosphokinase

Safety profile since launch in the USOver 325,000 patients have been treated with Cubicin since November 2003.236

Adverse reactions, possibly or probably related to treatment, were reported veryrarely during post-marketing experience and included hypersensitivity, anaphylaxis,infusion reaction and rhabdomyolysis.164 PAGE 55

SECTION 5


Figure 5.10. Frequency of adverse reactions across all patients in studies 9801 and9901, compared with patients across all clinical studies16,178

0

5

Subj

ects

(%)

Cubicin(n=550)

cSSTIs All studies

Comparator(n=558)

Cubicin(n=1474)

Comparator(n=1222)

15

10

20

25

21

20

1819

Adverse reaction Number (%) of patients (ITT population)Cubicin group

(n=550)

Comparator groupa

(n=558)

Diarrhoea 13 (2.4) 16 (2.9)

Nausea 14 (2.5) 20 (3.6)

V0miting 10 (1.8) 9 (1.6)

Injection-site reaction 8 (1.5) 12 (2.2)

Fungal infections and infestations 8 (1.5) 10 (1.8)

Abnormal liver function test results 25 (4.5) 16 (2.9)

Elevated serum CPK level 12 (2.2) 8 (1.4)

Headache 4 (0.7) 4 (0.7)

Rash 7 (1.3) 12 (2.2)

Pruritus 3 (0.5) 8 (1.4)

Clinical experiencewith 325,000

patients over 4 years has

confirmed theexcellent safety and

tolerability profileof Cubicin


5.2.2 Efficacy in clinical trials in SAB/RIEThe efficacy and tolerability of Cubicin in the treatment of bacteraemia and RIEcaused by S. aureus were demonstrated in an open-label, randomized phase IIIclinical trial conducted between 28 August 2002 and 16 February 2005.

17

Study designEligible patients were 18 years of age or older, with one or more blood culturespositive for S. aureus within 2 days before initiating study medication. Studyexclusion criteria are listed in Table 5.7.

17 Patients with left-sided endocarditis wereexcluded until April 2004, after which patients with a high likelihood of left-sidedendocarditis at the time of enrolment were randomized centrally using a separateschedule, with stratification by investigative site.237

Table 5.7. Exclusion criteria for selection of patients17,237

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SECTION 5


5.2 Cubicin in SAB/IE clinical trials5.2.1 Summary

Cubicin:

Evaluated for efficacy and safety in the treatment of bacteraemia andright-sided endocarditis caused by S. aureus in a phase III clinical trial17

Demonstrates non-inferiority to comparator antibiotics in thetreatment of SAB and RIE17

– Has a safety and tolerability profile similar to that of comparatorantibiotics

Effective in treatment of SAB and RIE, caused by both MSSA and MRSA,respectively17

Exclusion criteria

Renal failure with creatinine clearance <30 ml/minInitial S. aureus blood culture outside the two-day window periodPresence of intravascular material (excluding cardiac stents) not intended to be removedwithin 4 daysReceipt of non-study antibiotics potentially effective against S. aureusHigh likelihood of death or valve replacement surgery in the first 3 days followingrandomizationRefractory shockSignificant hepatic insufficiencySevere leucopeniaOsteomyelitisPneumoniaPolymicrobial bacteraemiaWeight <50 kg or >150 kgAllergy to vancomycin or penicillinInfection with S. aureus with reduced susceptibility to vancomycin (MIC >4 μg/ml)Inability to provide consent or unlikely to comply with study-related procedures


Patients were randomized in a 1:1 ratio to receive either Cubicin (6 mg/kg, once dailyby 30-minute i.v. infusion) or comparator treatments (either vancomycin or anantistaphylococcal penicillin, depending on the susceptibility of the causative strainto methicillin). Patients with left-sided endocarditis who were assigned to theCubicin treatment group, and all patients assigned to comparator treatment, werescheduled to receive gentamicin (1 mg/kg, every 8 hours by i.v. infusion) for the first 4 days.17

The duration of therapy was determined on the basis of the working diagnosis:patients with uncomplicated bacteraemia received medication for 10–14 days;patients with uncomplicated MSSA RIE received medication for 14–28 days; patientswith complicated bacteraemia or complicated right-sided or left-sided endocarditisreceived medication for 28–48 days.17 The definitions of the above infections aregiven in Table 5.8.17

Table 5.8. The definitions used to diagnose the different types of bacteraemia and RIE17

The patient populationOf the 246 patients who were randomized in the study, 236 received ≥1 dose of studymedication. Patient demographics (sex, age and ethnicity) at baseline and finaldiagnoses were similar in both treatment groups (Table 5.9).17 Nineteen of 120 patients treated with Cubicin met the criteria for RIE, of which 11 were infectedwith MSSA, and eight with MRSA. The overall infection rate with MRSA was 45% and44% for the Cubicin and the comparator treatment groups, respectively.

PAGE 57

SECTION 5


Diagnosis Definition

Uncomplicated bacteraemia Isolation of S. aureus once from enrolment bloodcultures in patients without evidence ofhaematogenous spread

Complicated bacteraemia Isolation of S. aureus from blood cultures on at least 2 days of the study up to day 5, the spread of infection,or infection involving prostheses not removed within 4 days

Uncomplicated RIE Definite or possible MSSA endocarditis in the absence ofpredisposing abnormalities or active infection of themitral or aortic valve in a patient with active injection-drug use, a serum creatinine level <2.5 mg/dl, and noevidence of extrapulmonary sites of infection

Complicated RIE Definite or possible endocarditis in the absence ofpredisposing abnormalities or active infection of themitral or aortic valve, with extrapulmonary sites ofinfection, a serum creatinine level ≥2.5 mg/dl, MRSAbacteraemia, or the absence of infection-drug use


Table 5.9. Characteristics of patients in the MITTa population17

PAGE 58

SECTION 5

CUBICIN INCLINICAL TRIALS Characteristic Cubicin group

number (%)(n=120)

Comparator groupnumberb (%)

(n=115)

AgeMean yearsc (range) 50.5 (21–87) 55.0 (25–91)

SexMaleFemale

70 (58.3)

50 (41.7)

71 (61.7)

44 (38.3)

Race or ethnic groupWhiteBlackHispanicAsianOther

75 (62.5)

32 (26.7)

8 (6.7)

1 (0.8)

4 (3.3)

81 (70.4)

23 (20.0)

5 (4.3)

2 (1.7)

4 (3.5)

Body mass indexd

Median (range) 26.9 (17.6–49.7) 25.7 (17.0–44.0)

Creatinine clearance, ml/minMedian (range)Creatinine clearance <50 ml/min

86.4 (28.0–246.9)

19 (15.8)

83.6 (17.9–277.0)

22 (19.1)

Risk factorDiabetes mellitusSystemic inflammatory responsesyndromeInjection-drug usePre-existing valvular heart diseaseSurgery within previous 30 daysExtravascular foreign materialSeptic pulmonary embolismHIV-positivee

44 (36.7)

89 (74.2)

25 (20.8)

16 (13.3)

49 (40.8)

28 (23.3)

10 (8.3)

8 (6.7)

42 (36.5)

87 (75.7)

25 (21.7)

9 (7.8)

36 (31.3)

29 (25.2)

13 (11.3)

1 (0.9)

Baseline pathogenInfection with MRSA 45 (37.5) 44 (38.3)

Diagnosis according to adjudicationcommittee

Baseline diagnosisDefinite endocarditisPossible endocarditisNot endocarditisFinal diagnosisUncomplicated bacteraemiaComplicated bacteraemiaUncomplicated right-sidedendocarditisComplicated right-sidedendocarditisLeft-sided endocarditis

17 (14.2)

73 (60.8)

30 (20.5)

32 (26.7)

60 (50.0)

6 (5.0)

13 (10.8)

9 (7.5)

20 (17.4)

71 (61.7)

24 (20.9)

29 (25.2)

61 (53.0)

4 (3.5)

12 (10.4)

9 (7.8)

aMITT, modified intention-to-treat (all patients in the study population who received ≥1 dose of study drugwith no known left-sided endocarditis prior to left-sided endocarditis protocol amendment)bThe comparator group included 62 patients who received antistaphylococcal penicillins (50 with nafcillin,nine with flucloxacillin and three with oxacillin) and 53 patients who received vancomycincP=0.07 for the comparison between groupsdThe body mass index is the weight in kilograms divided by the square of the height in metreseP=0.04 for the comparison between groups


OutcomesThe primary outcome of the study was the clinical success rate in the MITTpopulation of the two treatment groups at test of cure (42 days after the end oftherapy). Patients were considered to have clinical failure if they had no response tothe study drug on the basis of ongoing signs and symptoms of infection. Patientswere considered to have microbiological failure if they had persistent or relapsing S. aureus infection.17

Failure at test of cure was defined as: clinical failure, microbiological failure, death,failure to obtain blood culture, receipt of potentially effective non-study antibiotics, orpremature discontinuation of study medication because of clinical failure,microbiological failure or adverse event.17

Clinical success rates as determined by the Independent External AdjudicationCommittee, documented 42 days after the end of therapy, were 44.2% for patientstreated with Cubicin and 41.7% for patients treated with comparator antibiotics (MITTpopulation) (Figure 5.11), confirming non-inferiority of Cubicin to standard therapy.17 Atthe end of therapy, the clinical success rates were 61.7% for patients treated withCubicin and 60.9% for patients in the comparator therapy group (MITT population).17

Figure 5.12 shows that, in patients with MRSA infection, the clinical success rate washigher for those who received Cubicin treatment (44.4%) than for those whoreceived comparator therapy (31.8%) (MITT analysis). In patients with MSSA infection,Cubicin treatment achieved a comparable success rate to that of comparatorantibiotics (44.6% for Cubicin versus 48.6% for comparator therapy; Figure 5.12).Remarkably, in the Cubicin group, the success rate for patients with MRSA was verysimilar to that for patients with MSSA (44.4% and 44.6%). As shown in Figure 5.13,subgroup analyses of patients by final diagnosis were based upon smaller numbersof patients, but these results were consistent with the results of the whole studypopulation (MITT analysis).17

The median length of time to clearance of bacteraemia (MRSA and MSSA) did notdiffer significantly between the Cubicin and comparator therapy groups: MSSAbacteraemia was cleared in 3 or 4 days (P=0.28), whereas MRSA bacteraemia wascleared in 8 or 9 days (P=0.25) by Cubicin or standard therapy, respectively.17

PAGE 59

SECTION 5


Cubicin hasdemonstrated non-

inferiority to currentstandard of care

Figure 5.11. Clinical success rates in the MITT population17

0

10

Clin

ical

succ

ess (

%)


30

20

40

50

60

70

80

90

100

44.241.7

95% CI, –10.2 to 15.1



5.2.3 Safety in clinical trials in SAB/IEThe population used in the safety analyses were all patients in the study populationwho received ≥1 dose of study drug; there were 236 of these patients: 120 wereassigned to Cubicin and 116 were assigned to the comparator therapy group. In thissafety population, a similar safety and tolerability profile was demonstrated for bothtreatment groups.17

Adverse eventsMost adverse events in both treatment groups were mild to moderate in severity,and considered to be unrelated to study treatment; the overall incidence of adverseevents in the two treatment groups was similar (Table 5.10).17 In patients whoreceived Cubicin, the adverse events most frequently reported were: anaemia (12.5%),diarrhoea (11.7%), vomiting (11.7%), constipation (10.8%) and nausea (10.0%). Thesewere among the most commonly reported adverse events in the comparator group,with nausea being the most common, in 19.8% of patients.17

CPK elevations were significantly more common in the Cubicin group (6.7%) than thecomparator group (0.9%). CPK elevation led to discontinuation of treatment in threeout of 120 patients treated with Cubicin, but for 20 of the 24 patients receivingCubicin and who had increased CPK levels, these levels returned to normal eitherduring or after treatment.17PAGE 60

SECTION 5


Figure 5.13. Clinical success rates according to final diagnosis (MITT population)17

0

10

Clin

ical

succ

ess (

%)

Cubicin(n=32)

Uncomplicatedbacteraemia

Complicatedbacteraemia

Comparator(n=29)

30

20

40

50

60

70

90

80

100

56.2 55.2

Cubicin(n=60)

Comparator(n=61)

43.3

37.7

Cubicin(n=6)

Uncomplicated right-sided endocarditis

Complicated right-sided endocarditis

Comparator(n=4)

50.0

25.0

Cubicin(n=13)

Comparator(n=12)

38.5

50.0

95% CI, -23.9 to 26.0

95% CI, -11.8 to 23.1

95% CI, -33.3 to 83.395% CI, -45.2 to 22.9


Figure 5.12. Clinical success rates in patients with MRSA or MSSA (MITT population)17

0

10

Clin

ical

succ

ess (

%)

Cubicin(n=45)

MRSA MSSA

Comparator(n=44)

Cubicin(n=74)

Comparator(n=70)

30

20

40

50

60

70

80

90

31.8

44.6

100


95% CI, -7.4 to 32.695% CI, -20.3 to 12.3

44.4

48.6


Renal impairment was significantly more common in the comparator group (18.1%)than in the Cubicin group (6.7%),17 and resulted in the discontinuation of treatmentin five of 116 of patients (4.3%) receiving comparator therapy compared with one of120 patients (0.8%) receiving Cubicin.17

Of the patients who received Cubicin, 51.7% had a serious adverse event, as did 44.8%of the patients who received comparator therapy.17 Of the serious adverse events,infections and infestations occurred in 31.7% of patients receiving Cubicin and 19.8%of patients receiving comparator therapy. This difference was accounted for by thelower incidence of Gram-negative infection in comparator-treated patients, whichcould be partially related to the use of gentamicin in these patients.237

Table 5.10. Common adverse events and serious adverse events for both treatmentgroups17

PAGE 61

SECTION 5


Adverse event Number (%) of patients (ITT population)

Cubicin group(n=120)

Comparator groupa

(n=116)

Most common adverse events (≥10% incidence in either group)

Anaemia 15 (12.5) 18 (15.5)

Diarrhoea 14 (11.7) 21 (18.1)

Vomiting 14 (11.7) 15 (12.9)

Constipation 13 (10.8) 14 (12.1)

Nausea 12 (10.0) 23 (19.8)

Hypokalaemia 11 (9.2) 15 (12.9)

Renal impairment 8 (6.7) 21 (18.1)

Headache 8 (6.7) 12 (10.3)

Peripheral 0edema 8 (6.7) 16 (13.8)

Arthralgia 4 (3.3) 13 (11.2)

Serious adverse events according to system organ class

Blood and lymphatic disorders 1 (0.8) 3 (2.6)

Cardiac disorders 9 (7.5) 8 (6.9)

Gastrointestinal disorders 2 (1.7) 6 (5.2)

General disorders and conditions at theinjection site 3 (2.5) 4 (3.4)

Infections and infestations 38 (31.7) 23 (19.8)

Injury, poisoning and procedural complaints 2 (1.7) 3 (2.6)

Laboratory abnormalities 3 (2.5) 0

Metabolism and nutrition disorders 2 (1.7) 5 (4.3)

Benign and malignant neoplasms 1 (0.8) 3 (2.6)

Nervous system disorders 4 (3.3) 5 (4.3)

Psychiatric disorders 4 (3.3) 1 (0.9)

Renal and urinary disorders 1 (0.8) 9 (7.8)

Respiratory, thoracic and mediastinaldisorders 8 (6.7) 5 (4.3)

Vascular disorders 2 (1.7) 2 (1.7)


5.3 Current clinical trials Several clinical trials have been completed recently, and more are in progress. Thesetrials are designed to augment the existing knowledge on the use of Cubicin for itscurrent indications, as well as to investigate the potential role of Cubicin for otherindications.

A phase I, open-label, non-randomized, non-comparative study has been initiated toassess the pharmacokinetic profile, and safety and tolerability of multiple doses of 6 mg/kg Cubicin in non-infected adults with end-stage renal disease.238

A randomized phase II trial is underway that is comparing the efficacy and safety ofhigh-dose, short-duration Cubicin therapy (10 mg/kg every 24 hours for 4 days) withconventional therapy (vancomycin ± semisynthetic penicillin for 7–14 days) inpatients with cSSTIs due to Gram-positive bacteria.238 In addition, there is arandomized, open-label, active-control trial to investigate the efficacy, safety andpharmacokinetics of 6 mg/kg and 8 mg/kg Cubicin in the treatment of patientsundergoing surgery for osteomyelitis associated with an infected prosthetic jointcaused by MRSA and/or CoNS.238

A phase IV, randomized, double-blind trial is in progress to evaluate the efficacy andsafety of Cubicin versus either vancomycin or teicoplanin for the treatment ofcSSTIs.238

There are currently several investigator-initiated trials underway, including patientswith the following conditions: catheter-related S. aureus bloodstream infections,febrile neutropenia, cSSTI caused by MRSA and enterococcal native valveendocarditis.

PAGE 62

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6. Summary of product characteristics1. NAME OF THE MEDICINAL PRODUCTCubicin, 350 mg powder for concentrate for solution for infusion

2. QUALITATIVE AND QUANTITATIVE COMPOSITIONEach vial contains 350 mg daptomycin.

One ml provides 50 mg of daptomycin after reconstitution with 7 ml of sodium chloride 9 mg/ml (0.9%)solution or water for injections.

For excipient, see section 6.1.

3. PHARMACEUTICAL FORM

Powder for concentrate for solution for infusion.

A pale yellow to light-brown lyophilized powder.

4. CLINICAL PARTICULARS

4.1 Therapeutic indicationsCubicin is indicated for the treatment of the following infections in adults (see sections 4.4 and 5.1).

Complicated skin and soft-tissue infections (cSSTI).Right-sided infective endocarditis (RIE) due to Staphylococcus aureus. It is recommended that thedecision to use daptomycin should take into account the antibacterial susceptibility of the organismand should be based on expert advice. See sections 4.4 and 5.1.Staphylococcus aureus bacteraemia (SAB) when associated with RIE or with cSSTI.

Daptomycin is active against Gram positive bacteria only (see section 5.1). In mixed infections where Gramnegative and/or certain types of anaerobic bacteria are suspected, Cubicin should be co-administered withappropriate antibacterial agent(s).

Consideration should be given to official guidance on the appropriate use of antibacterial agents.

4.2 Posology and method of administrationPosology

cSSTI without concurrent Staphylococcus aureus bacteraemia: The recommended dose is 4 mg/kgadministered once every 24 hours for 7-14 days or until the infection is resolved (see section 5.1).

cSSTI with concurrent Staphylococcus aureus bacteraemia: The recommended dose is 6 mg/kgadministered once every 24 hours. See below for dose adjustments in patients with renal insufficiency.The duration of therapy may need to be longer than 14 days in accordance with the perceived risk ofcomplications in the individual patient.

Known or suspected right-sided infective endocarditis due to Staphylococcus aureus: The recommendeddose is 6 mg/kg administered once every 24 hours. See below for dose adjustments in patients withrenal insufficiency. The duration of therapy should be in accordance with available officialrecommendations.

Renal insufficiency

Daptomycin is eliminated primarily by the kidney.

Due to limited clinical experience (see table and footnotes below), Cubicin should only be used in patientswith any degree of renal insufficiency (Cr Cl < 80 ml/min) when it is considered that the expected clinicalbenefit outweighs the potential risk. The response to treatment and renal function should be closelymonitored in all patients with some degree of renal insufficiency) (see also sections 4.4 and 5.2).

Dose adjustments in patients with renal insufficiency by indication and creatinine clearance

(1) The safety and efficacy of the dose interval adjustment has not been clinically evaluated and the recommendation is based onpharmacokinetic modelling data (see sections 4.4 and 5.2).

(2) The same dose adjustments, which are also based solely on modelling are recommended for patients on haemodialysis or continuousambulatory peritoneal dialysis (CAPD). Whenever possible, Cubicin should be administered following the completion of dialysis on dialysisdays (see section 5.2).

(3) There are insufficient data to support a dose recommendation for patients with RIE or cSSTI associated with Staphylococcus aureusbacteraemia who have a creatinine clearance < 50 ml/min. There are no data available to support the efficacy of 4 mg/kg daily in patientswith RIE or cSSTI associated with Staphylococcus aureus bacteraemia whose creatinine clearance is between 30-49 ml/min or to supportthe use of 4 mg/kg every 48 hours in such patients whose creatinine clearance is < 30 ml/min. PAGE 63

SECTION 6

SUMMARY OF PRODUCTCHARACTERISTICS

Indication for use (1) Creatinineclearance (1)

Doserecommendation (1)

Comments

cSSTI without S. aureus bacteraemia

≥ 30 ml/min 4 mg/kg once daily See section 5.1

< 30 ml/min 4 mg/kg every48 hours

(1, 2)

RIE or cSSTI associatedwith S. aureusbacteraemia

≥ 50 ml/min 6 mg/kg once daily (3)


Hepatic insufficiency

No dose adjustment is necessary when administering Cubicin to patients with mild or moderate hepaticinsufficiency (Child-Pugh Class B) (see section 5.2). No data are available in patients with severe hepaticinsufficiency (Child-Pugh Class C). Therefore, caution should be exercised if Cubicin is given to suchpatients.

Elderly patients

The recommended doses should be used in elderly patients except those with severe renal insufficiency(see above and section 4.4). However, there are limited data on the safety and efficacy of daptomycin inpatients aged > 65 years and caution should be exercised if Cubicin is given to such patients.

Children and adolescents (< 18 years old)

Due to the lack of data on safety and efficacy, Cubicin is not recommended for use in children andadolescents (< 18 years of age). See also section 5.2.

Method of administration

Cubicin is given by intravenous infusion (see section 6.6) and administered over a 30-minute period.

4.3 ContraindicationsHypersensitivity to the active substance or excipient.

4.4 Special warnings and precautions for useIf a focus of Staphylococcus aureus infection other than cSSTI or RIE is identified after initiation of Cubicintherapy, consideration should be given to instituting alternative antibacterial therapy that has beendemonstrated to be efficacious in the treatment of the specific type of infection(s) present.

It has been demonstrated in clinical studies that Cubicin is not effective in the treatment of pneumonia.

Clinical data on the use of Cubicin to treat RIE due to Staphylococcus aureus are limited to 19 patients (see“Information from clinical trials” in section 5.1).

The efficacy of Cubicin in patients with prosthetic valve infections or with left-sided infective endocarditisdue to Staphylococcus aureus has not been demonstrated.

Patients with deep-seated infections should receive any required surgical interventions (e.g. debridement,removal of prosthetic devices, valve replacement surgery) without delay.

Creatine phosphokinase and myopathy

Increases in plasma creatine phosphokinase (CPK; MM isoenzyme) levels associated with muscular painsand/or weakness and cases of myositis, myoglobinaemia and rhabdomyolysis have been reported duringtherapy with Cubicin (see also sections 4.5, 4.8 and 5.3). In clinical studies, marked increases in plasma CPKto > 5x Upper Limit of Normal (ULN) without muscle symptoms occurred more commonly in Cubicin-treated patients (1.9%) than in those that received comparators (0.5%). Therefore, it is recommended that:

Plasma CPK should be measured at baseline and at regular intervals (at least once weekly) duringtherapy in all patients.

It cannot be ruled out that those patients with CPK greater than 5 times upper limit of normal atbaseline may be at increased risk of further increases during daptomycin therapy. This should be takeninto account when initiating daptomycin therapy and, if daptomycin is given, these patients should bemonitored more frequently than once weekly.

CPK should be measured more frequently than once weekly in patients who are at higher risk ofdeveloping myopathy. These patients include those with severe renal insufficiency (creatinine clearance< 30 ml/min; see also section 4.2) and patients taking other medications known to be associated withmyopathy (e.g. HMG-CoA reductase inhibitors, fibrates and ciclosporin).

Cubicin should not be administered to patients who are taking other medications associated withmyopathy unless it is considered that the benefit to the patient outweighs the risk.

Patients should be reviewed regularly while on therapy for any signs or symptoms that might representmyopathy.

Any patient that develops unexplained muscle pain, tenderness, weakness or cramps should have CPKlevels monitored every 2 days. Cubicin should be discontinued in the presence of unexplained musclesymptoms if the CPK level reaches greater than 5 times upper limit of normal.

Peripheral Neuropathy

Patients who develop signs or symptoms that might represent a peripheral neuropathy during therapywith Cubicin should be investigated and consideration should be given to discontinuation of daptomycin(see sections 4.8 and 5.3).

Renal Insufficiency

Renal insufficiency has been reported during treatment with Cubicin, although the relationship todaptomycin remains unclear. Severe renal insufficiency may in itself also pre-dispose to elevations indaptomycin levels which may increase the risk of development of myopathy (see above).

Dose adjustment is needed for patients with cSSTI without bacteraemia whose creatinine clearance is < 30 ml/min (see sections 4.2 and 5.2). The safety and efficacy of the dose interval adjustment guidelinesprovided in section 4.2 are based on pharmacokinetic modelling and have not been clinically evaluated. InPAGE 64

SECTION 6



addition there are no data to support the use of 6 mg/kg daptomycin once daily in patients with RIE orwith cSSTI associated with bacteraemia whose creatinine clearance is < 50 ml/min. Cubicin should only beused in such patients when it is considered that the expected clinical benefit outweighs the potential risk.

Caution is advised when administering Cubicin to patients who already have some degree of renalinsufficiency (creatinine clearance < 80 ml/min) before commencing therapy with Cubicin. Regularmonitoring of renal function is advised (see also section 5.2).

In addition, regular monitoring of renal function is advised during concomitant administration ofpotentially nephrotoxic agents, regardless of the patient’s pre-existing renal function (see also section 4.5).

In obese subjects with Body Mass Index (BMI) > 40 kg/m2 but with creatinine clearance > 70 ml/min, theAUC

0-∞ daptomycin was significantly increased (mean 42% higher) compared with non-obese matchedcontrols. There is limited information on the safety and efficacy of daptomycin in the very obese and socaution is recommended. However, there is currently no evidence that a dose reduction is required (seesection 5.2).

The use of antibiotics may promote the overgrowth of non-susceptible micro-organisms. If superinfectionoccurs during therapy, appropriate measures should be taken.

Antibiotic-associated colitis and pseudomembranous colitis have been reported with nearly allantibacterial agents and may range in severity from mild to life-threatening. Therefore, it is important toconsider this diagnosis in patients who present with diarrhoea during or shortly following treatment.

4.5 Interaction with other medicinal products and other forms of interactionDaptomycin undergoes little to no Cytochrome P450 (CYP450) mediated metabolism. In vitro studies havedetermined that daptomycin does not inhibit or induce the activities of clinically significant human CYPisoforms (1A2, 2A6, 2C9, 2C19, 2D6, 2E1, 3A4). Therefore, no CYP450-related drug interactions are to beexpected.

There is limited experience regarding concomitant administration of daptomycin with other medicinalproducts that may trigger myopathy. However, some cases of marked rises in CPK levels and cases ofrhabdomyolysis occurred in patients taking one of these medications at the same time as Cubicin. It isrecommended that other medications associated with myopathy should if possible be temporarilydiscontinued during treatment with Cubicin unless the benefits of concomitant administration outweighthe risk. If co-administration cannot be avoided, CPK levels should be measured more frequently than onceweekly and patients should be closely monitored for any signs or symptoms that might representmyopathy. See sections 4.4, 4.8 and 5.3.

Daptomycin is primarily cleared by renal filtration and so plasma levels may be increased during co-administration with medicinal products that reduce renal filtration (e.g. NSAIDs and COX-2 inhibitors). Inaddition, there is a potential for a pharmacodynamic interaction to occur during co-administration due toadditive renal effects. Therefore, caution is advised when daptomycin is co-administered with any othermedicinal product known to reduce renal filtration.

During post–marketing surveillance, cases of interference between daptomycin and a particular reagentused in some assays of Prothrombin Time/International Normalised Ratio (PT/INR) have been reported.This interference led to an apparent prolongation of PT and elevation of INR. If unexplained abnormalitiesof PT/INR are observed in patients taking daptomycin, consideration should be given to a possible in vitrointeraction with the laboratory test. The possibility of erroneous results may be minimised by drawingsamples for PT or INR testing near the time of trough plasma concentrations of daptomycin.

4.6 Pregnancy and lactationNo clinical data on pregnancies are available for daptomycin. Animal studies do not indicate direct orindirect harmful effects with respect to fertility, pregnancy, embryonal/fetal development, parturition orpostnatal development (see section 5.3).

Cubicin should not be used during pregnancy unless clearly necessary, i.e. only if the potential benefitoutweighs the possible risk.

It is not known whether daptomycin is excreted in human milk. Therefore, breastfeeding should bediscontinued during treatment with Cubicin.

4.7 Effects on ability to drive and use machinesNo studies on the effects on the ability to drive and use machines have been performed.

On the basis of reported adverse drug reactions, Cubicin is presumed to be unlikely to produce an effecton the ability to drive or use machinery

4.8 Undesirable effectsClinical Studies

In clinical studies, 2,011 subjects received Cubicin. Within these trials, 1,221 subjects received a daily dose of4 mg/kg, of whom 1,108 were patients and 113 were healthy volunteers; 460 subjects received a daily doseof 6 mg/kg, of whom 304 were patients and 156 were healthy volunteers. Adverse reactions (i.e. consideredby the investigator to be possibly, probably, or definitely related to the medicinal product) were reported atsimilar frequencies for Cubicin and comparator regimens.

For subjects who received Cubicin, the adverse reactions that were most frequently reported duringtherapy plus follow-up were: headache, nausea, vomiting, diarrhoea, fungal infections, rash, infusion sitereaction, increased Creatine phosphokinase (CPK) and abnormal liver enzymes; Alanine aminotransferase PAGE 65

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(ALT), Aspartate aminotransferase (AST), Alkaline phosphatase.

The following adverse reactions were reported during therapy and during follow-up with frequenciescorresponding to Common = ≥ 1/100, < 1/10; Uncommon = > 1/1,000, < 1/100; Rare = > 1/10,000, < 1/1,000,

Very rare = ≤ 1/10,000:

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.Infections and InfestationsCommon: Fungal infectionsUncommon: Urinary tract infectionBlood and lymphatic system disordersUncommon: Thrombocythaemia, anaemia, eosinophiliaMetabolism and nutrition disordersUncommon: Anorexia, hyperglycaemiaPsychiatric disordersUncommon: Anxiety, insomniaNervous system disordersCommon: HeadacheUncommon: Dizziness, paraesthesiae, taste disorderCardiac disordersUncommon: Supraventricular tachycardia, extrasystoleVascular disordersUncommon: Flushes, hypertension, hypotensionGastrointestinal disordersCommon: Nausea, vomiting, diarrhoeaUncommon: Constipation, abdominal pain, dyspepsia, glossitisHepatobiliary disordersUncommon: JaundiceSkin and subcutaneous tissue disordersCommon: RashUncommon: Pruritis, urticariaMusculoskeletal, connective tissue and bone disordersUncommon: Myositis, muscle weakness, muscle pain, arthralgiaRenal and urinary disordersUncommon: Renal insufficiencyReproductive system and breast disordersUncommon: VaginitisGeneral disorders and administration site conditionsCommon: Infusion site reactionsUncommon: Pyrexia, weakness, fatigue, painInvestigationsCommon: Liver function tests abnormal (increased AST, ALT and alkaline phosphatase), increased CPKUncommon: Electrolyte imbalance, increased serum creatinine, increased myoglobin, Lacticdehydrogenase (LDH) increased

Post-Marketing

Adverse reactions that have been reported Post-Marketing that are not listed above are:

Immune system disordersVery rare: Hypersensitivity, manifested by isolated spontaneous reports including, but not limited to;pulmonary eosinophilia, vesicobullous rash with mucous membrane involvement and sensation oforopharyngeal swelling.

Very rare: Anaphylaxis

Very rare: There have been isolated cases of infusion reactions including the following symptoms:tachycardia, wheezing, pyrexia, rigors, systemic flushing, vertigo, syncope and metallic taste.

Musculoskeletal, connective tissue and bone disordersVery rare: RhabdomyolysisIsolated cases of rhabdomyolysis have been reported; when clinical information on the patients wasavailable to make a judgement, approximately 50% of the cases occurred in patients with pre-existingrenal insufficiency, or in those receiving concomitant medications known to cause rhabdomyolysis.

Investigations

In some cases of myopathy involving raised CPK and muscle symptoms, the patients also presented withelevated transaminases. These transaminase increases were likely to be related to the skeletal muscleeffects. The majority of transaminase elevations were of Grade 1-3 toxicity and resolved upondiscontinuation of treatment.

4.9 OverdoseIn the event of overdose, supportive care is advised. Daptomycin is slowly cleared from the body byhaemodialysis (approximately 15% of the administered dose is removed over 4 hours) or by peritonealdialysis (approximately 11% of the administered dose is removed over 48 hours).PAGE 66

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5. PHARMACOLOGICAL PROPERTIES5.1 Pharmacodynamic propertiesPharmacotherapeutic group: Antibacterials for systemic use, Other antibacterials, ATC code: J01XX09

Mode of action

Daptomycin is a cyclic lipopeptide natural product that is active against Gram positive bacteria only.

The mechanism of action involves binding (in the presence of calcium ions) to bacterial membranes ofboth growing and stationary phase cells causing depolarisation and leading to a rapid inhibition ofprotein, DNA, and RNA synthesis. This results in bacterial cell death with negligible cell lysis.

PK/PD relationship

Daptomycin exhibits rapid, concentration dependent bactericidal activity against sensitive Gram positiveorganisms in vitro. In animal models AUC/MIC and Cmax/MIC correlate with efficacy and predictedbacterial kill in vivo at single doses equivalent to human doses of 4 mg/kg and 6 mg/kg once daily.

Mechanisms of resistance

Strains with decreased susceptibility to daptomycin have been reported during the treatment of patientswith difficult to treat infections and/or following administration for prolonged periods. In a clinical trial inwhich daptomycin was used for the treatment of endocarditis and complicated bacteraemia, there weresix patients in whom the observed decrease in susceptibility to daptomycin may have contributed to theirfailure to respond to therapy.

The mechanism of resistance to daptomycin has not yet been identified.

Breakpoints

Minimum inhibitory concentration (MIC) breakpoint established by the European Committee onAntimicrobial Susceptibility Testing (EUCAST) for Staphylococci and Streptococci (except S. pneumoniae)are Susceptible ≤ 1 mg/l and Resistant > 1 mg/l.

Susceptibility

The prevalence of resistance may vary geographically and over time for selected species and localinformation on resistance is desirable, particularly when treating severe infections. As necessary, expertadvice should be sought when the local prevalence of resistance is such that the utility of the agent in atleast some types of infections is questionable.

Information from clinical trials

In two clinical trials in complicated skin and soft tissues infections, 36% of patients treated with Cubicinmet the criteria for systemic inflammatory response syndrome (SIRS). The most common type of infectiontreated was wound infection (38% of patients), while 21% had major abscesses. These limitations of thepatients population treated should be taken into account when deciding to use Cubicin.

There is insufficient evidence to be able to draw any conclusions regarding the possible clinical efficacy ofCubicin against Enterococcus faecalis and Enterococcus faecium.

In a randomised controlled open-label study in 235 patients with Staphylococcus aureus bacteraemia (i.e.at least one positive blood culture of Staphylococcus aureus prior to receiving the first dose) 19 of 120

patients treated with Cubicin met the criteria for RIE. Of these 19 patients, 11 were infected withmethicillin-susceptible and 8 with methicillin-resistant Staphylococcus aureus. The success rates in RIEpatients are shown in the table below.

Failure of treatment due to persisting or relapsing Staphylococcus aureus infections was observed in19/120 (15.8%) patients treated with Cubicin, 9/53 (16.7%) patients treated with vancomycin and 2/62

(3.2%) patients treated with an anti-staphylococcal semi-synthetic penicillin. Among these failures sixpatients treated with Cubicin and one patient treated with vancomycin were infected with Staphylococcusaureus that developed increasing MICs of daptomycin on or following therapy (see “Mechanisms of PAGE 67

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Commonly susceptible species

Staphylococcus aureus*Staphylococcus haemolyticusCoagulase-negative staphylococci Streptococcus agalactiae*Streptococcus dysgalactiae subsp. equisimilis*Streptococcus pyogenes*Group G streptococciClostridium perfringensPeptostreptococcus spp.

Inherently resistant organisms

Gram-negative organisms

* denotes species against which it is considered that activity has been satisfactorily demonstrated in clinical studies.


resistance” above). Most patients who failed due to persisting or relapsing Staphylococcus aureus infectionhad deep-seated infection and did not receive necessary surgical intervention.

5.2 Pharmacokinetic propertiesDaptomycin pharmacokinetics are generally linear and time-independent at doses of 4 to 12 mg/kgadministered as a single daily dose for up to 14 days in healthy volunteers. Steady-state concentrations areachieved by the third daily dose.

Animal studies showed that daptomycin is not absorbed to any significant extent after oraladministration.

Distribution

The steady state volume of distribution of daptomycin was approximately 0.1 l/kg in healthy adultvolunteers, consistent with distribution primarily within the extracellular space. Tissue distribution studiesin animals have shown that daptomycin preferentially distributes into highly vascularised tissues and to alesser degree penetrates the blood brain barrier and the placental barrier following single and multipledoses.

Daptomycin is reversibly bound to human plasma proteins in a concentration independent manner. Inhealthy volunteers and patients treated with daptomycin, protein binding averaged about 90% includingsubjects with renal insufficiency.

Metabolism

In vitro studies have demonstrated that there is no or limited liver microsomal mediated metabolism ofdaptomycin in humans and that CYP450 involvement in daptomycin metabolism is minimal. Analysis ofplasma samples from subjects who received a 6 mg/kg dose of daptomycin did not show any trace ofmetabolism, suggesting little to no systemic metabolism.

Furthermore, no metabolites have been observed in plasma following administration of radiolabeled drugto humans based on total radiolabel and microbiologically active concentrations. Of the four minormetabolites detected in urine, two are Phase I oxidative metabolites present in low concentrations.

Elimination

Daptomycin is excreted primarily by the kidneys. Concomitant administration of probenecid anddaptomycin has no effect on daptomycin pharmacokinetics in humans suggesting minimal to no activetubular secretion of daptomycin.

Following intravenous administration, plasma clearance of daptomycin is approximately 7 to 9 ml/h/kgand its renal clearance is 4 to 7 ml/h/kg.

In a mass balance study using radiolabelled material, 78% of the administered dose was recovered fromthe urine based on total radioactivity, whilst urinary recovery of unchanged daptomycin wasapproximately 50% of the dose. About 5% of the administered radiolabel was excreted in the faeces.

Special populations

ElderlyNo dose adjustment is necessary based on age alone. However, renal function should be assessed and thedose should be reduced if there is evidence of severe renal insufficiency.

Children and adolescents (< 18 years of age)Pharmacokinetic profiles were obtained following single intravenous administration of daptomycin 4 mg/kg in paediatric patients with proven or suspected Gram-positive infection, divided into three agegroups (2-6 years, 7-11 years and 12-17 years). The pharmacokinetics of daptomycin following a single 4 mg/kg dose in adolescents aged 12-17 years are generally similar to those of healthy adult subjects withnormal renal function with trends towards lower AUC and Cmax in adolescents. In the younger age groups(2-6 years and 7-11 years), exposure (Cmax and AUC) and elimination half-life for the same mg/kg dose werereduced compared with adolescents.

ObesityRelative to non-obese subjects daptomycin systemic exposure measured by AUC is increased by about28% in moderately obese subjects (Body Mass Index of 25-40 kg/m2) and by 42% in extremely obesesubjects (Body Mass Index of > 40 kg/m2). However, no dose adjustment is considered to be necessarybased on obesity alone.PAGE 68

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Population Daptomycinn/N (%)

Comparatorn/N (%)

Differences in successrates (95% CI)

ITT Population:RIE 8/19 (42.1%) 7/16 (43.8%) -1.6% (-34.6, 31.3)

PP Population:RIE 6/12 (50.0%) 4/8 (50.0%) 0.0% (-44.7, 44.7)


GenderNo clinically significant gender-related differences in daptomycin pharmacokinetics have been observed.

Renal insufficiencyFollowing administration of a single 4 mg/kg or 6 mg/kg dose of daptomycin to subjects with variousdegrees of renal insufficiency, daptomycin clearance (CL) was reduced and systemic exposure (AUC) wasincreased. In subjects with severe renal insufficiency (CLcr < 30 ml/min) and end stage renal disease,exposure (AUC) and elimination half life were increased between 2-3 fold relative to healthy subjects. Seesection 4.2 regarding the need for dose adjustment.

Hepatic insufficiencyThe pharmacokinetics of daptomycin is not altered in subjects with moderate hepatic insufficiency (ChildPugh B classification of cirrhosis) compared with healthy volunteers matched for gender, age and weightfollowing a single 4 mg/kg dose. No dosage adjustment is necessary when administering daptomycin inpatients with moderate hepatic insufficiency. The pharmacokinetics of daptomycin in patients with severehepatic insufficiency (Child Pugh C classification) have not been evaluated.

5.3 Preclinical safety dataIn studies of clinically-relevant duration (14-28 days), daptomycin administration was associated withminimal to mild degenerative/regenerative changes in skeletal muscle in the rat and dog. Microscopicchanges in skeletal muscle were minimal (approximately 0.05% of myofibres affected) and at the higherdoses were accompanied by elevations in CPK. No fibrosis or rhabdomyolysis was observed. Depending onthe study duration, all muscle effects, including microscopic changes, were fully reversible within 1-3 months following cessation of dosing. No functional or pathological changes in smooth or cardiacmuscle were observed.

The lowest observable effect level (LOEL) for myopathy in rats and dogs occurred at exposure levels of 0.8 to 2.3-fold the human therapeutic levels at 6 mg/kg for patients with normal renal function. A study indogs demonstrated that skeletal myopathy was reduced upon once daily administration as compared tofractionated dosing at same total daily dose, suggesting that myopathic effects in animals were primarilyrelated to time between doses.

Effects on peripheral nerves were observed at higher doses than those associated with skeletal muscleeffects in adult rats and dogs, and were primarily related to plasma Cmax. Peripheral nerve changes werecharacterised by minimal to slight axonal degeneration and were frequently accompanied by functionalchanges. Reversal of both the microscopic and functional effects was complete within 6 months post-dose. Safety margins for peripheral nerve effects in rats and dogs are 8- and 6-fold, respectively, based oncomparison of Cmax values at the No Observed Effect Level (NOEL) with the Cmax achieved on dosing with 6 mg/kg once daily in patients with normal renal function.

In contrast to adult dogs, juvenile dogs appeared to be more sensitive to peripheral nerve lesions ascompared to skeletal myopathy. Juvenile dogs developed peripheral and spinal nerve lesions at doseslower than those associated with skeletal muscle toxicity.

Reproductive toxicity testing showed no evidence of effects on fertility, embryofetal, or postnataldevelopment. However, daptomycin can cross the placenta in pregnant rats (see section 5.2). Excretion ofdaptomycin into milk of lactating animals has not been studied.

Long-term carcinogenicity studies in rodents were not conducted. Daptomycin was not mutagenic orclastogenic in a battery of in vivo and in vitro genotoxicity tests.

6. PHARMACEUTICAL PARTICULARS6.1 List of excipientsSodium hydroxide.

6.2 IncompatibilitiesCubicin is not physically or chemically compatible with glucose-containing solutions. This medicinalproduct must not be mixed with other medicinal products except those mentioned in section 6.6.

6.3 Shelf life3 years

After reconstitution: Chemical and physical in-use stability of the reconstituted solution in the vial hasbeen demonstrated for 12 hours at 25°C and up to 48 hours at 2°C – 8°C. Chemical and physical stability ofthe diluted solution in infusion bags is established as 12 hours at 25°C or 24 hours at 2°C – 8°C. Thecombined storage time (reconstituted solution in vial and diluted solution in infusion bag; see section 6.6)at 25°C should not exceed 12 hours (or 24 at 2°C – 8°C).

From a microbiological point of view the product should be used immediately. If not used immediately, in-use storage times are the responsibility of the user and would not normally be longer than 24 hours at2 to 8°C, unless reconstitution/dilution has taken place in controlled and validated aseptic conditions.

6.4 Special precautions for storageStore in a refrigerator at 2°C – 8°C.

For storage conditions of the reconstituted diluted medicinal product see section 6.3. PAGE 69

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6.5 Nature and contents of containerSingle use 10 ml type 1 clear glass vials with type 1 rubber stoppers and aluminium closures with yellowplastic flip off caps.

6.6 Instructions for use and handling (and disposal)A 50 mg/ml concentration is obtained by reconstituting with 7 ml of sodium chloride 9 mg/ml (0.9%)solution for injection, or water for injections.

A septic technique should be used to reconstitute lyophilised Cubicin. The polypropylene flip off capshould be removed to expose the central portions of the rubber stopper. 7 ml of either sodium chloride 9 mg/ml solution for injection or water for injections should be slowly injected through the centre of therubber stopper into the vial pointing the needle towards the wall of the vial. The vial should be gentlyrotated to ensure complete wetting of the product and then allowed to stand for 10 minutes. Finally thevial should be gently rotated/swirled for a few minutes as needed to obtain a clear reconstituted solution.Vigorous shaking/agitation should be avoided to prevent foaming of the product. Reconstitution istypically complete within 15 minutes.

The reconstituted solution should be checked carefully to ensure that the product is in solution andvisually inspected for the absence of particulates prior to use.

Reconstituted solutions of Cubicin range in colour from pale yellow to light brown.

The reconstituted solution should then be diluted with sodium chloride intravenous infusion (typicalvolume 50 ml) and infused over 30 minutes as directed in section 4.2.

The following have been shown to be compatible when added to Cubicin containing infusion solutions:aztreonam, ceftazidime, ceftriaxone, gentamicin, fluconazole, levofloxacin, dopamine, heparin andlidocaine.

Cubicin vials are for single-use only.

Any unused product or waste material should be disposed of in accordance with local requirements.

7. MARKETING AUTHORISATION HOLDERNovartis Europharm LimitedWimblehurst RoadHorshamWest Sussex, RH12 5AB

United Kingdom

8. MARKETING AUTHORISATION NUMBER(S)EU/1/05/328/001

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION19 January 2006

10. DATE OF REVISION OF THE TEXTSeptember 2006

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