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GUIDANCE ON TREATMENT OF

CARBAPENAMASE PRODUCING

ENTEROBACTERIACEAE

June 2016

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UKCPA Pharmacy Infection Network Carbapenamase producing Enterobacteriaceae (CPE) treatment guidance

Acknowledgements

This document has been developed on behalf of the UK Clinical Pharmacy Association by a Working Group comprising the following members:

Kelly Alexander Mark Gilchrist Laura Whitney Jacqueline Sneddon Hani Habayeb

Other members of the Pharmacy Infection Network Committee provided feedback.

Definitions

Enterobacteriaceae are commensal bacteria of the gut of humans and animals. However, these organisms are some of the most common causes of opportunistic urinary tract infections, intra-abdominal and bloodstream infections. Enterobacteriaceae include species such as Escherichia coli, Klebsiella spp. and Enterobacter spp. Carbapenems are a structurally related and similar group (class) of antibiotics normally reserved for serious infections caused by drug-resistant Gram-negative bacteria (including Enterobacteriaceae). They include meropenem, ertapenem and imipenem. The carbapenem class of antibiotics are commonly regarded as “last line” treatment for the most serious of infections. Antimicrobial resistance (AMR) is resistance of a microorganism to an antimicrobial drug that was originally effective for treatment of infections caused by it. Several mechanisms exist by which bacteria can display resistance to carbapenem antibiotics. A full discussion on the mechanisms of resistance is beyond the scope of this guidance. Carbapenemases are enzymes that destroy carbapenem antibiotics, conferring resistance. They are produced by a small but growing number of Enterobacteriaceae strains. The presence of a carbapenemase does not always result in high level resistance to carbapenems in vitro. There are different types of carbapenemases, of which KPC, OXA-48, NDM and VIM enzymes are currently the most common. 1 Carbapenemases include enzymes from beta-lactamases classes A, C and D (Ambler classification). The main classes of acquired carbapenemases are listed below

Beta-lactamase class Variant(s)

Class A (Serine) KPC

Class B (Zinc)

Metallo-beta-lactamases

NDM, VIM, IMP

Class D (Serine) OXA

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Scope

The aim of this guideline is to support the guidance outlined in the Public Health England Acute trust toolkit for the early detection, management and control of carbapenemase-producing Enterobacteriaceae (CPE). A key recommendation of this guidance was that “Treatment of the patient with an infection caused by CPE should be undertaken under the advice of the microbiologist”. It is hoped that this document will support Trust antimicrobial committees, microbiology and pharmacy teams in developing the most effective strategies to treat these highly resistant infections. This guidance was developed following a review of the published literature to propose a series of treatment principles, review the place in therapy of antibiotic treatments that may be effective and provide information on dose optimisation to maximise response for treatment. Information is provided on unlicensed doses and methods of administration that have been used in the literature or theoretically have potential to maximise effect. It is the responsibility of Healthcare organisations to review the suitability of these options on an individual patient basis. Clinicians and patients must be made aware of the unlicensed status when using doses outside of the UK marketing authorisation. There are a number of drugs in development that may have activity against some CPE. These have not been included and are outside of the scope of this document. This guideline refers principally to treatment of acquired carbapenemases in

Enterobacteriaceae, specifically NDM, VIM, IMP, KPC, OXA-48 (as defined by UK Standards for Microbiology Investigations. Laboratory Detection and Reporting of Bacteria with Carbapenem-Hydrolysing β-lactamases (Carbapenemases). Public Health England May 2014). Other bacteria such as multi-drug resistant Acinetobacter and Pseudomonas may host several mechanisms conferring resistance to carbapenems including carbapenemases (class D, class B), reduced porin channels and multi-drug efflux pumps. An attempt has been made to include information relating to these organisms where possible. The recommendations assume treatment of infection rather than colonisation. Data in children is extremely limited and information relating to drug dosing in children has not been included.

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Treatment Principles and Recommendations

General principles The statements below are based on best practice for management of infection and national guidance.

Treatment of the patient with an infection caused by CPE should be undertaken under the advice of the microbiologist

Start treatment promptly

Treatment should be guided by susceptibility results. These may vary between strains, including samples obtained from a single patient during a single infection.

Only treat if patient has symptoms of infection. Patients may be colonised with CPE. Usually identified by a rectal swab or stool sample but may also be colonised at other sites.

Review treatment daily to confirm effectiveness and check for adverse effects.

Specific principles From a review of the available literature the working group recommend the following principles be used in managing infections caused by CPE. All recommendations relating to treatment assume that the organism is susceptible on testing (below MIC breakpoint) unless specified. Combination verses monotherapy Recommendations relating to combination therapy are based on clinical outcomes of published cases / retrospective reviews. There is currently no data to inform whether combination therapy prevents or promotes emergence of resistance in this setting. There are no studies that compare the efficacy of different combination of antibiotics against infections caused by CPE. The following combinations have been quoted in the literature as being successful in some cases. A review from 2012 describes mortality outcomes in relation to each antibiotic regime but numbers are too small to draw conclusions.

Recommendations and Supporting Evidence

For bacteraemias and severe infection, including respiratory tract infections, use a minimum of 2 antibiotics to which the organism is susceptible. There is insufficient evidence to conclude which combinations are most effective.

In a review of 105 cases with a variety of KPC infections, significantly more treatment failures were seen with monotherapy (49% vs. 25% p= 0.01). 2 Higher rates of treatment failure with monotherapy for respiratory tract infections were observed (67% vs. 29% p=0.03). A systematic review of antibiotic treatment of infections caused by carbapenemase producing Enterbacteriaceae3 found that the majority of studies did not show statistically

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significant differences in mortality or treatment failures between combination and monotherapy. However 3 studies reviewed including a total of 194 patients with bacteraemia demonstrated a significantly lower mortality with combination therapy. colistin/polymyxin B or tigecycline combined with a carbapenem. The mortality in this group was 12.5% (1/8). Despite in vitro susceptibility, patients who received monotherapy with colistin/polymyxin B or tigecycline had a higher mortality of 66.7% (8/12) than those patients receiving combination therapy.1 In 125 patients from 3 centres with KPC blood stream infections 30 day mortality was 54.3% vs. 34.1% in those who received monotherapy vs. combined drug therapy, respectively; P =0.02.4 In another study of 35 patients with KPC blood stream infections, appropriate antibiotics (defined as in-vitro susceptibility) were administered for at least 48 hours. All 20 patients that received combination therapy had favourable infection outcome; in contrast, seven of 15 patients given appropriate monotherapy died (p = 0.001). The study found that appropriate antimicrobial therapy was the only modifiable predictor of infection outcome.5 The optimal number of agents has not been established; one study noted a survival benefit with the addition of a carbapenem to tigecycline and colistin therapy.5

Carbapenems may be used in combination with other agents. Outcomes are likely to be improved if the organism appears susceptible on in vitro testing (meropenem and imipenem MIC < 1µg/mL, ertapenem < 0.5µg/mL) or is close to the breakpoint. There is limited data to support the addition of meropenem to other agents if the MIC is ≤4µg/mL leading to improved outcomes.

Several studies1,4,5 demonstrate that combination therapy involving a carbapenem may be effective. In a review of 105 cases of KPC infection, treatment failure was higher with carbapenem monotherapy compared to carbapenem-based combination therapy (60% vs. 26%).2 In an Italian multicentre study of 125 patients with KPC producing K. pneumoniae bacteraemia combination therapy with tigecycline, colistin and meropenem (2g eight hourly infused over an extended period of 3 hours) was associated with lower mortality (OR 0.11, p=0.01).4 It is unknown whether this benefit translates to traditional meropenem dosing and administration. 36 patients were treated with this combination, in 17 patients the meropenem MIC was >16mg/L. Survival in this group was 64%. Survival was 100% for patients treated with the combination were meropenem MIC was <2mg/L (n=5). Numbers are too small to draw any firm conclusions, but may be suggestive of a survival benefit. The authors concluded that addition of meropenem may be helpful if the MIC < 4µg/mL.

Colistin is not recommended as monotherapy for systemic infections In a review of 105 cases of KPC infection, polymyxin monotherapy was associated with higher rates of treatment failure compared to polymyxin based combination therapy (73% vs. 29%; 8/11 vs. 10/34; p=0.02).2 This review did not give details of the doses of polymyxin used. It has been hypothesised by Lee et al. that combination therapy may prevent the development of resistance to polymyxin B whilst on therapy.6

Where tigecycline is used for treatment of respiratory tract infections it should be used in combination with a second agent.

The Summary of Product Characteristics for Tigecycline (Tygacil) states it is only licensed for complicated skin and soft tissue infections, excluding diabetic foot infections, and complicated intra-abdominal infections and that “Tygacil should be used only in situations where other alternative antibiotics are not suitable.”

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In clinical studies in complicated skin and soft tissue infections (cSSTI), complicated intra-abdominal infections (cIAI), diabetic foot infections, nosocomial pneumonia and studies in resistant pathogens, a numerically higher mortality rate among tigecycline treated patients has been observed as compared to the comparator treatment. The causes of these findings remain unknown, but poorer efficacy and safety than the study comparators cannot be ruled out.7 The European Medicines Agency Committee for Medicinal Products for Human Use (CHMP) has recommended that tigecycline should only be used within its licensed indications as a pooled analysis of clinical studies showed an increased mortality associated with tigecycline versus comparator agents.8 A similar communication from the Food and Drug Administration noted that the greatest increase in risk of mortality in the tigecycline arm was seen in ventilator associated pneumonia (19.1% vs. 12.3%).9 However in a single review of a small number of CPE cases there was no difference in failure rates between tigecycline monotherapy and combination therapy (29% vs. 37% p=0.4) (n=2/7 and 7/19 respectively.9 Treatment failures included patients treated for urosepsis and pneumonia with empyema.

Fosfomycin should be used in combination with other agents when used for systemic therapy, due to its vulnerability to acquired resistance.

The Summary of Product Characteristics states that Fosfomycin should be used only when conventional therapy is considered inappropriate. It has been demonstrated that resistance to intravenous fosfomycin can develop rapidly when it is used for monotherapy.10 An in vitro study investigating the synergistic effect and impact on development of resistance of fosfomycin with colistin, meropenem or gentamicin found that all combinations showed improved bactericidal activity compared to fosfomycin alone and prevented the development of resistance in the majority of fosfomycin-susceptible isolates.11 In a small case series of critical care patients with carbapenem resistant Klebsiella pneumoniae intravenous fosfomycin (4g every 6 hours adjusted for renal impairment) was administered as combination therapy with colistin (n=6), gentamicin (n=3) and piperacillin/tazobactam (n=1). All-cause mortality was 18.1% but no patient developed a relapse of infection.12

• Temocillin and aztreonam may be used in combination with non-beta-lactams if organisms appear to be susceptible.

These agents must not be used as monotherapy. Temocillin is not active against most CPE but remains effective against KPC-producing Enterobacteriaceae in in vitro studies. Urinary tract infections

Urinary tract infections may be treated with a single agent that is known to concentrate in the urine and which the isolate is susceptible to.

The review by Lee and Burgess found an 81% success rate (9/11) in patients treated for urinary tract infections, with 8 of these cases treated with monotherapy.2

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Aminoglycoside antibiotics should be considered for treatment of urinary tract infections where sensitivities allow

Aminoglycoside therapy resulted in a significantly higher rate of microbiologic clearance of carbapenem resistant K. pneumoniae in the urine compared to polymyxin B or tigecycline in one study.13 There was no difference in failure rates between aminoglycoside monotherapy and combination therapy (0/6 and 4/24 respectively, p=0.6) in the study by Lee et al above.2

Patients successfully treated with monotherapy included blood stream infections (n=3) and urinary tract infections (n=2).

Tigecycline is not recommended for treatment of urinary tract infections Low levels of tigecycline are excreted into the urine.

Limitations

Due to the lack of randomised controlled trials the recommendations in this guide are based on limited or low quality evidence. However it is intended as a practical guide based on the best information available. Meta-analyses show there is lack of consistency in outcome data. Due to the heterogeneity and low patient numbers in the studies it is not possible to compare the outcomes of different combination therapies. When well conducted meta-analyses / review papers collating data on outcomes from individual studies were available there were used in preference. The majority of the studies report on KPC carbapenemase producing Klebsiella pneumoniae as the most common CPE mechanism.

UK Guidance and supporting references

Acute trust toolkit for the early detection, management and control of carbapenemase-producing Enterobacteriaceae. Public Health England. December 2013 https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/329227/Acute_trust_toolkit_for_the_early_detection.pdf UK Standards for Microbiology Investigations. Laboratory Detection and Reporting of Bacteria with Carbapenem-Hydrolysing β-lactamases (Carbapenemases). Public Health England and NHS England May 2014 https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/344071/P_8i1.1.pdf

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References 1. Qureshi ZA, Paterson DL, Potoski BA et al. Treatment outcome of bacteremia due to KPC-

producing Klebsiella pneumoniae: superiority of combination antimicrobial regimens. Antimicrob. Agents Chemother. 2012 56: 2108-2113

2. Lee, Burgess. Treatment of Klebsiella Pneumoniae Carbapenemase (KPC) infections: a review of published case series and case reports. Annals of clinical Microbiology and Antimicrobials 2012; 11; 32

3. Falagas ME, Lourida P, Poulikakos P et al. Antibiotic treatment of Infections due to Carbapenem-resistant Enterbacteriaceae: Systematic Evaluation of the Available Evidence. Antimicrob. Agents Chemother 2014, 58(2): 654-663

4. Tumbarello M, Viale P, Viscoli C et al. Predictors of mortality in bloodstream infections caused by Klebsiella pneumoniae carbapenemase producing K. pneumoniae: importance of combination therapy. Clin. Infect.Dis.2012. 55:943–950.

5. Zarkotou O, Pournaras S, Tselioti P et al. 2011. Predictors of mortality in patients with bloodstream infections caused by KPCproducing Klebsiella pneumoniae and impact of appropriate antimicrobial treatment. Clin. Microbiol. Infect. 17:1798–1803

6. Lee J et al. Decreased susceptibility to polymyxin B during treatment for carbapenem-resistant Klebsiella Pneumoniae. J Clin Microbiol 2009; 47 (5): 1611-12

7. Summary of Product Characteristics Tygacil last updated on the eMC: 25/04.2016. Accessed on 11/05/16 via http://www.medicines.org.uk/emc/

8. European Medicines Agency. Questions and answers on the review of Tygacil (tigecycline) Outcome of a renewal procedure. February 2011 Accessed 16/05/16 via http://www.ema.europa.eu/docs/en_GB/document_library/Medicine_QA/human/000644/WC500102228.pdf

9. FDA Drug Safety Communication: FDA warns of increased risk of death with IV antibacterial Tygacil (tigecycline) and approves new Boxed Warning. September 2013. Accessed on 16/05/16 via http://www.fda.gov/Drugs/DrugSafety/ucm369580.htm

10. Ellington MJ, Livermore DM, Pitt TL et al. Mutators among CTX-M beta-lactamase producing Escherichia coli and risk of emergence of fosfomycin resistance. J Antimicrob Chemother 2006; 58:848-52

11. Souli M, Galani I, Boukovalas S et al. In vitro interactions of antimicrobial combinations with fosomycin against KPC-2 producing Klebsiella pneumoniae and protection of resistance development. Antimicrobial agents and Chemotherapy 2011: 55 (5): 2395-97

12. Michalopoulos A, Virtzili S, Rafailidis P et al. Intravenous fosfomycin for the treatment of nosocomial infections caused by carbapenem-resistant Klebsiella pneumoniae in critically ill patients: a prospective evaluation. Clin. Microbiol. Infect 2010; 16:184–186.

13. Satlin MJ, Kubin CJ, Blumenthal JS et al. Comparative effectiveness of aminoglycosides, polymyxin B and tigecycline for clearance of carbapenem-resistant Klebsiella pneumoniae from the urine. Antimicrob Agents Chemother 2011; 55; 5893-5899

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APPENDIX

Drug dosing information

Optimising dosing strategies to give the highest drug exposure according to pharmacokinetic and pharmacodynamic parameters is recommended. The tables below provide information on how this can be achieved. Please note that some recommendations reflect dosing strategies not covered by the product license. For details of side effects and interactions please refer to Summary of Product characteristics http://www.medicines.org.uk/emc/ and the current British National Formulary https://www.evidence.nhs.uk/ .

Aminoglycosides

Place in therapy Resistance to aminoglycosides is variable between strains. NDM-1 producing organisms frequently carry resistance to aminoglycosides. Case reports most frequently cite amikacin as a treatment option.

Optimal administration and dosing

The working group recommends standard optimal once daily regimens based on optimal pharmacokinetic parameters: Gentamicin 5-7mg/kg daily Amikacin 15mg/kg daily

Cautions associated with high dose regimens

Caution should be applied to patients with pre-existing renal insufficiency, or pre-existing hearing or vestibular damage. Amikacin must not be used in patients with Myasthenia Gravis. Aminoglycosides should be used with caution in patients with muscular disorders such as parkinsonism, since these drugs may aggravate muscle weakness because of their potential curare-like effect on the neuromuscular junction.

Local experience / practical issues

Ototoxicity is more common with amikacin, baseline audiology recommended if course is likely to be prolonged (> 2 weeks).

References Falagas ME, Lourida P, Poulikakos P et al. Antibiotic Treatment of Infections Due to Carbapenem-Resistant Enterobacteriaceae: Systematic Evaluation of the Available Evidence Antimicrob. Agents Chemother. 2014, 58(2):654

Aztreonam

Place in therapy May be a treatment option for metallo-betalactamases. Not active against KPC.

Optimal administration and dosing

There is a paucity of evidence regarding use of aztreonam in CPE therefore dosing information has been extrapolated from information on carbapenem-resistant pseudomonas where 2g IV every 8 hours is advised. The dosing interval can be reduced to 6 hours for severe systemic or life-threatening infections.

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Extended infusions of beta-lactams are advocated in difficult to treat infections because their activity is time-dependent and a positive correlation exists between their efficacy and the amount of time the drug concentration exceeds the MIC value during the dosing interval. There is one published case report of successful treatment of an MDR P. aeruginosa infection in an immunocompromised patient with a continuous of infusion of aztreonam (8.4g/day) in combination with tobramycin, ciprofloxacin, vancomycin, polymixin B, azithromycin and nebulized colistin.

Cautions associated with high dose regimens

Neurotoxicity is one of the most serious potential side effects of beta-lactam antibiotics and may include confusion, disorientation, somnolence, twitching, myoclonus, and seizures. Risk factors for neurotoxicity include high dosages, history of seizures, other CNS disorders, renal failure, and concomitant drugs that lower the seizure threshold. If aminoglycosides are used concurrently with aztreonam, particularly in high doses or prolonged duration there is potential for nephrotoxicity and ototoxicity.

Clinical pharmacokinetics

Absorption: negligible oral bioavailability (<1%), completely absorbed after intramuscular injection Distribution: Vdss after intravenous or intramuscular injection is approx 0.16 L/kg (0.42 L/kg for the free drug). Dose – concentration relationship: Over a large dosage range plasma concentrations increase linearly with dose. No accumulation occurs after multiple dosing. Plasma binding: 56% in healthy subjects, not concentration dependent. Diffusion into tissues is generally slow, and dependent upon tissue type. In inflamed meninges, penetration of aztreonam into CSF is more rapid than with uninflamed meninges. Diffusion through the placenta is poor, as is diffusion into breast milk. Metabolism occurs to a very limited extent. Elimination: primarily renal by active tubular excretion. Extra-renal clearance is probably due to excretion by the liver. Total plasma clearance in healthy adults is about 140 ml/min (8.4 L/h) or 2 ml/min/kg (0.12 L/h/kg), and terminal half-life is 1.7 hours.

References Souha S, Kanj MD and Kanafani ZA, MD Current Concepts in Antimicrobial Therapy Against Resistant Gram-Negative Organisms: Extended-Spectrum β-Lactamase–Producing Enterobacteriaceae, Carbapenem-Resistant Enterobacteriaceae, and Multidrug-Resistant Pseudomonas aeruginosa Mayo Clin Proc. 2011 Mar; 86(3): 250–259.

Moriyama B, Henning SA, Childs R, et al. High-dose continuous infusion β-lactam antibiotics for the treatment of resistant Pseudomonas aeruginosa infections in immunocompromised patients. Ann Pharmacother. 2010;44:929-935

Mattie H, Clinical pharmacokinetics of aztreonam. Clin Pharmacokinet. 1988 Mar;14(3):148-55.

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Carbapenems

Place in therapy Carbapenems may be used in combination with other agents. In practice meropenem is the most commonly used carbapenem in the UK. Outcomes are likely to be improved if the organism appears susceptible on in vitro testing (meropenem, imipenem MIC < 1µg/mL, ertapenem < 0.5µg/mL) or close to the breakpoint. There is limited data to support the addition of meropenem to other agents if the MIC is < 4µg/mL leading to improved outcomes.

Optimal administration and dosing

Because the killing activity of beta-lactams is time-dependent, a positive correlation exists between their efficacy and the amount of time the drug concentration exceeds the MIC value during the dosing interval. To optimize dosing strategies to achieve better bacterial killing, studies have evaluated the role of administering beta-lactams in extended infusions with encouraging results. Evidence suggests that using a high dose extended infusion has a lower mortality rate compared to short-term infusions. However, the data are based on case reports with small numbers and heterogeneity, and well-designed RCT are warranted to confirm these findings. Meropenem 1 – 2g tds Imipenem 500mg qds or 1g tds Ertapenem 1g od It is important to note that, before adopting high-dose and extended-infusion regimens, consideration should be given to the safety and stability of the compounds used. For example, imipenem is not likely to be considered for this therapeutic strategy, in view of its lower stability at elevated room temperatures and its lower tolerability when administered in higher dosages. Case reports suggest the following infusion regimen: Meropenem 3 hour infusion or 8 hour infusion.

Cautions associated with high dose regimens

Care with high dose imipenem – increased risk of neurotoxicity

Clinical pharmacokinetics

Monte Carlo simulation models of different dosing regimens of carbapenems indicate that prolonging the infusion time from 30 min to 3 h increases the probability of bactericidal target attainment at each MIC value. The probabilities of attaining T > MIC targets for at least 50% of the dosing intervals for an MIC of 4 mg/L were 69%, 93% and 100% for the 1 g prolonged infusion (PI) every 8 h, 1 g PI every 8 h and 2 g PI every 8 h dosing regimens, respectively.

For an MIC of 8 mg/L, only the high-dose/prolonged-infusion regimen displayed a relatively high probability (85%) of bactericidal target attainment.

Considering these observations in combination with the MIC distributions of CPKP isolates, the high-dose/prolonged-infusion regimen of meropenem achieves the bactericidal PK/PD targets with a high degree of certainty for CPE with MICs of <4 mg/L.

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References Falagas ME, Lourida P, Poulikakos P et al. Antibiotic Treatment of Infections Due to Carbapenem-Resistant Enterobacteriaceae: Systematic Evaluation of the Available Evidence Antimicrob. Agents Chemother. 2014, 58(2):654.

Abbott I, Cerqueira GM, Bhuiyan S and Peleg AY. Carbapenem resistance in Acinetobacter baumannii: laboratory challenges, mechanistic insights and therapeutic strategies Expert Rev. Anti Infect. Ther. 11(4), 395–409 (2013)

Daikos GL and Markogiannakis A. Carbapenemase-producing Klebsiella pneumoniae: (when) might we still consider treating with carbapenems? Clin Microbiol Infect 2011; 17: 1135–1141

Pankey GA, Ashcraft DS. Detection of synergy using the combination of polymyxin B with either meropenem or rifampin against carbapenemase-producing Klebsiella pneumoniae Diagnostic Microbiology and Infectious Disease 70 (2011) 561–564.

Tripodi MF, Durante-Mangoni E, Fortunato R, Utili R, Zarrilli R. Comparative activities of colistin, rifampicin, imipenem and sulbactam/ampicillin alone or in combination against epidemic multidrug-resistant Acinetobacter baumannii isolates producing OXA-58 carbapenemases. International Journal of Antimicrobial Agents 30 (2007) 537–540.

Carmeli Y, Akova M, Cornaglia G et al. Controlling the spread of carbapenemase-producing Gram-negatives: therapeutic approach and infection control. Clin Microbiol Infect 2010; 16: 102–111

Giamarellou H, Galani L, Baziaka F, Karaiskos I. Effectiveness of a Double-Carbapenem Regimen for Infections in Humans Due to Carbapenemase-Producing Pandrug-Resistant Klebsiella pneumonia AAC 2013; 57(5): 2388–2390.

Falagas ME, Tansarli GS, Ikawa K, Vardakas KZ. Clinical Outcomes With Extended or Continuous Versus Short-term Intravenous Infusion of Carbapenems and Piperacillin/Tazobactam: A Systematic Review and Meta-analysis. CID 2013:56 (15 January): 272-282.

Ho VP, Jenkins SG, Afaneh CI et al. Use of Meropenem by Continuous Infusion to Treat a Patient with a Blakpc-2-Positive Klebsiella pneumoniae Blood Stream Infection. Surgical Infections 2011; 12 (4): 325-327.

Rogers BA, Sidjabat HE, Silvey A et al. Treatment Options for New Delhi Metallo-Beta-Lactamase-Harboring Enterobacteriaceae.. Microbial Drug Resistance 2013; 19 (2): 100-103.

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Colistin

Place in therapy The treatment of multi drug resistant organisms including CPE. Colistin therapy should be used in combination with another agent.

Optimal administration and dosing

The use of intravenous high dose colistin for the treatment of multi drug resistant organisms has been reported in the literature since 2011. Since then experience in adults has grown however, its use has been predominantly confined to critical care settings. Many studies have reported work on pharmacokinetics to ascertain optimum dosage for effective treatment with minimal adverse effects. In 2014 the European Medicine agency released guidance on standardising adult dosing of colistin given the threat of Gram negative resistance. In 2015, UK manufacturers updated their colistin monographs and licenses. For adults, the recommended dosing schedule is now a two-step process comprising of a loading dose and maintenance dose. In general the loading dose is between 7-9 million units and given as a stat dose (depending on weight). This is followed by a maintenance dose of 4.5 million units BD or 3 million units TDS tailored to renal function. In the case of a confirmed or suspected bacteraemia consideration should be given to using up to 12 million units as a total daily dose. Therapeutic drug monitoring is advised to ensure the patient is eliminating colistin. Trough levels of 2-4 mg/L are advised. In respiratory infections additional colistin may also be administered as nebules. In the USA a different preparation is used therefore dosing strategies also vary.

Cautions associated with high dose regimens

Use with extreme caution in patients with porphyria or those receiving neuromuscular blocking properties and ether. Use with caution in existing renal impairment.

Clinical pharmacokinetics

Colistimethate sodium (CMS) is a prodrug that is hydrolyzed after intravenous administration to produce several derivatives, including the active drug colistin. Colistin is tightly bound to membrane lipids of cells of many body tissues, including the liver, lung, kidney, brain, heart, and muscles. Data on the pharmacokinetics of intravenous CMS are sparse, but CMS has a half-life of 124 minutes, whereas colistin (base) has a half-life of 251 minutes. CMS is excreted in the urine, and colistin is non-renally excreted. No biliary excretion has been reported in humans. The distribution of colistin to the pleural cavity, lung parenchyma, bones, and cerebrospinal fluid (CSF) is relatively poor. Colistin CSF penetration is low (CSF-to-serum ratio of 5 percent) and bactericidal concentrations are inadequate.

Local experience / practical issues

Imperial College Healthcare NHS Trust has undertaken a review of colistin dosing within adults, paediatrics and neonates. Their policy is available by contacting Mark Gilchrist (Consultant Pharmacist ID).

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References Michalopoulos A, Falagas ME. Colistin: recent data on pharmacodynamics properties and clinical efficacy in critically ill patients.Annals of Intensive Care 2011. 1. 30

Spapen H,Jacobs R, Van Gorp V et al. Renal and neurological side-effects of colistin in critically ill patients. Annals of Intensive Care 2011. 1. 14

Li J, Nation RL, Turnidge JD et al. Colistin: the re-merging antibiotic for multidrug-resistant Gram-negative bacterial infections. Lancet Infect Dis 2006;6:589-601

Dalfino L, Puntillo F, Mosca A et al. High dose, Extended-interval colistin administration in critically ill patients; is this the right dosing strategy? A Preliminary Study. Clinical Infect Dis. 2012;54(12):1720-6

Falagas ME, Rafailidis PI, Ioannidou E, et al. Colistin therapy for microbiologically documented multidrug-resistant gram-negative bacterial infections: a retrospective cohort study of 258 patients. International Journal of Antimicrobial Agents.2010; 35: 194-199

Michalopoulos A, Tsiodras S, Rellos K et al. Colistin treatment in patients with ICU-acquired infections caused by multidrug resistant Gram-negative bacteria: the renaissance of an old antibiotic. Clin Microbiol Infect 2005;11:115-21

Markou N, Apostolakos H, Koumoudiou C et at. Intravenous colistin in the treatment of sepsis from multidrug resistant Gram-negative bacilli in critically ill patients. Crit Care 2003;7:878-83

Mezzatesta ML, Gona F, Caio C et al. Outbreak of KPC-3-producing, and colistin-resistant, Klebsiella pneumoniae infections in two Sicilian hospitals. Clin Microbiol Infect 2011;17(9):1444-7

Toth A, Damjanova I, Puskas E et al. Emergence of a colistin-resistant KPC-2-producing Klebsiella pneumoniae ST 258 clone in Hungary. Eur J Clin Microbiol Infect Dis. 2010;29(7):765-9

Roberts JA, Lipman J. Closing the loop – A colistin clinical study to confirm dosing recommendations from PK/PD modelling. Clin Infect Dis. 2012;54(12):1727-9

Plachouras D, Karvanen M, Friberg LE et al. Population Pharmacokinetic Analysis of Colistin Methansulfonate and colistin after intrevenous administration in critically ill patients with infections caused by Gram-negative bacteria. Antimicrob. Agents Chemother. 2009;53(8):3430-3436

Kasiako SK, Michalopoulos A, Soterides ES et al. Combination therapy with intravenous colistin for management of infections due to multidrug-resistant Gram-negative bacteria in patients without Cystic Fibrosis. Antimicrob. Agents Chemother. 2005;49:3136-46

Garonzik SM, Li j, Thamlikitkul V et al. Population Pharmacokinetics of Colistin Methanesulfonate and Formed Colistin in Critically Ill Patients from a Multicenter Study Provide Dosing Suggestions for Various Categories of Patients. Antimicrob. Agents Chemother. 2011;55(7):3284-94

Guideline for Intravenous Colistimethate Sodium Dosing and Monitoring in Critically Ill Patients at Tallaght Hospital, September 2012.

Critical Care Guideline for intravenous colistimethate sodium (Colistin). Guy’s and St Thomas’ NHS Foundation Trust, June 2014.

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Michalopoulos A, Falagas ME. Colistin: recent data on pharmacodynamics properties and clinical efficacy in critically ill patients. Annals of Intensive Care 2011. 1. 30

Summary of Product Characteristics, Colistimethate sodium injection (Profile Pharma). http://www.medicines.org.uk/emc/medicine/13531 Accessed 06/06/2016.

Karvanen M Plachouris D, Friberg LE et al. Colistin Methanesulfonate and colistin Pharmacokinetics in critically ill patients receiving continous venovenous hemodialfiltration. Antimicrob. Agents Chemother. 2013;57 (1); 668-671

Visser Kift E, Maartens G, Bamford C. Systematic review of the evidence for rational dosing of colistin. SAMJ; 2014; 104 (3); 183-186

Marchand S, Frat J, Petitpas F et al. Removal of colistin during intermittent haemodialysis in two critically ill patients; J Antimicrob Chemother 2010: 1836-1837

Alfahad W, Omrani AS. Update on colistin in clinical practice. Saudi Med J 2014; 35 (1); 9-19

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Fosfomycin

Place in therapy Drug distribution, data from clinical studies and licensed indications in Germany support use in combination with other therapy in the following infections: Generalised sepsis Respiratory tract infections including pulmonary abscesses Skin and soft tissue infections Biliary tract infections Central nervous system (CNS) infection Osteomyelitis Ophthalmic infections For treatment of urinary tract infections fosfomycin is routinely given as monotherapy. The SPC clearly states fosfomycin should be used only when it is considered inappropriate to use antibacterial agents that are commonly recommended for the initial treatment of the infections listed above, or when these alternatives antibacterial agents have failed to demonstrate efficacy.

Optimal administration and dosing

Doses in the literature recommend 8 to 16g daily depending on the site and severity of infection. The working group recommend IV fosfomycin for treatment of severe infections with multi-resistant organisms at a dose of 16g daily (divided doses 4g four times daily). Oral therapy for UTI Complex UTI or other indication: 3g PO every 48 hours for up to 2 weeks. Usual duration = 3 doses

Dosing in renal impairment

IV preparation: Reduce dose in renal impairment GFR 20-50ml/min: 4g every 8 hr GFR 10-20ml/min : 4g every 12-hr GFR <10ml/min: 4g every 24 hr HD/HDF: 4g every 12 hr , CVVH: Dose as normal kidney function Oral preparation GFR <50ml/min: Complex UTI or other indication: 3g every 72 hr for up to 14 days HD: 3g at the end of the haemodialysis.

Clinical pharmacokinetics

The concentrations in serum are higher when oral doses are administered before food intake. Pharmacokinetic parameters indicate oral absorption is significantly reduced after food intake. Fifty-eight per cent of the administered dose is found in the urine within 24 hours. Urinary concentrations are high and may exceed 2000 mg/L after administration of a single dose. Urinary levels remain high for a prolonged period (over 24 hours).

Local experience / practical issues

Experience from Manchester suggests that resistance may rapidly develop in patients treated for urinary tract infection and hence they recommend a prolonged course of oral therapy.

References Raz R, Fosfomycin: an old—new antibiotic. Clin Microbiol Infect 2012; 18:4–7

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Fluoroquinolones

Place in therapy The review was unable to locate any clinical outcome data relating to treatment of CPE infections with fluoroquinolone agents. CPE isolates may be sensitive in vitro. Where isolates demonstrate in vitro sensitivity the working group recommends that fluoroquinolones may be included within therapy regimes as they have been proven to be effective treatments in numerous clinical settings where carbapenemase producing enzymes are not present.

Optimal administration and dosing

Ciprofloxacin Standard doses for ciprofloxacin: Oral 500mg every 12 hours Intravenous infusion 400mg every 12 hours Maximal licensed and recommended doses of ciprofloxacin in adults are 750mg every 12 hours orally and 400mg every 8 hours via the intravenous route. For severe and deep seated infections maximal licensed doses should be used.

Clinical pharmacokinetics

Ciprofloxacin For optimal efficacy the AUC:MIC ratio of unbound drug should be greater than 125 for fluoroquinolones. BSAC breakpoint MIC Enterbacteriacae: <0.5mg/L

Based on the published pharmacokinetic data values close to the optimal AUC:MIC ratios are only likely to be achieved for organisms with an MIC of less than 0.25mg/L. However this does not take into account the degree of distribution into tissues Pharmacokinetic data

Drug Route Regime Fraction unbound

Mean AUC mg/h/L

Ciprofloxacin IV 400mg 12h 70% 22.8

Ciprofloxacin Po 750mg 12h 70% 40

A 60-minute infusion of 400 mg ciprofloxacin every 8 hours is equivalent with respect to AUC to 750 mg oral regimen given every 12 hours.

Protein binding of ciprofloxacin is low (20-30%). Ciprofloxacin is present in plasma largely in a non-ionised form and has a large steady state distribution volume of 2-3 L/kg body weight. Ciprofloxacin reaches high concentrations in a variety of tissues such as lung (epithelial fluid, alveolar macrophages, biopsy tissue), sinuses, inflamed lesions (cantharides blister fluid), and the urogenital tract (urine, prostate, endometrium) where total concentrations exceeding those of plasma concentrations are reached.

Local experience / practical issues

Experience from Manchester suggests that ciprofloxacin used at standard doses can achieve clinical cure where the MIC < 0.5mg/L. Local experience includes treatment of urinary tract infections. For other infections use combination therapy where possible

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References Drusano GL. Prevention of resistance: A goal for dose selection for antimicrobial agents. Clin Infect Dis.2003;36(Suppl 1):S42-S50.

Bristish Society for Antimicrobial Chemotherapy Susceptability Testing, Version 14, 2015 http://bsac.org.uk/wp-content/uploads/2012/02/BSAC-Susceptibility-testing-version-14.pdf (Accessed 06/06/2016)

Moczygemba LR, Frei CR, Burgess DS. Pharmacodynamic modelling of carbapenems and fluoroquinolones against bacteria that produce extended spectrum beta-lactamases. Clinical Therapeutics 2004; 26(11): 1800-1807

Wispelwey B. Clinical implications of pharmacokinetics and pharmacodynamics of fluoroquinolones.CID 2005;41(suppl 2): S127-S135

Rifampicin

Place in therapy Rifampicin has been shown to have synergistic activity with meropenem and colistin, and may be considered for combination therapy.

Optimal administration and dosing

Very little data in literature of doses used. One case report where rifampicin used in combination with colistin. Rifampicin 300mg bd.

References Pankey GA, Ashcraft DS. Detection of synergy using the combination of polymyxin B with either meropenem or rifampin against carbapenemase-producing Klebsiella pneumoniae Diagnostic Microbiology and Infectious Disease 70 (2011) 561–564.

Tripodi MF, Durante-Mangoni E, Fortunato R et al. Comparative activities of colistin, rifampicin, imipenem and sulbactam/ampicillin alone or in combination against epidemic multidrug-resistant Acinetobacter baumannii isolates producing OXA-58 carbapenemases. International Journal of Antimicrobial Agents 30 (2007) 537–540.

Rogers BA, Sidjabat HE, Silvey A et al. Treatment Options for New Delhi Metallo-Beta-Lactamase-Harboring Enterobacteriaceae. Microbial Drug Resistance 2013; 19 (2): 100-103.

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Temocillin

Place in therapy In vitro data shows that KPC-producing Enterobacteriaceae are often susceptible to temocillin. The most recent and largest dataset is from the ARHAI Reference Unit, Public Health England where susceptibility rates of 51% and of 94% were observed using, the systemic (8 mg/L) and the urinary (16 mg/L) breakpoints, respectively. Temocillin is not a treatment option for organisms producing other carbapenemases (e.g. VIM, OXA). The review was unable to locate any clinical outcome data relating to treatment of CPE infections with temocillin.

Optimal administration and dosing

Maximal licensed and recommended dose in adults is 2g every 12 via the intravenous route. Higher doses of temocillin (2g IV TDS) may be recommended in severely septic patients hospitalised in intensive care, although this regimen is not licensed. Although not licensed, temocillin (4g/day or 6g/day) is suitable for continuous infusion which allows reaching better PK/PD target. In this case, a loading dose of 2g is required.

Cautions associated with high dose regimens

No specific side effects have been reported with both the maximal recommended dose (2g BD) and the high dose (6g/day) in critically ill patients but as with most beta-lactams, caution is required in regards to a potential neurotoxicity.

Clinical pharmacokinetics

There are no EUCAST or CLSI breakpoints for temocillin. Breakpoints following the BSAC method for Enterobacteriaceae are as follows: Susceptible organisms: MIC ≤ 8 mg/L Resistant organisms: MIC > 8 mg/L Uncomplicated urinary tract infections: Susceptible organisms: MIC ≤ 32 mg/L Resistant organisms: MIC > 32 mg/L PK/PD of IV temocillin using Monte Carlo simulation5

Regimen Mean fT>MIC in % of free temocillin

MIC of 8 mg/L MIC of 32 mg/L

2g 24h 37% 2%

2g 12h 80% 9%

2g 8h 100% 27%

fT>MIC = Proportion of time that free temocillin above MIC Studies indicate 24h continuous infusion provides longer fT>MIC. The protein serum binding rate is 85% in healthy volunteers and temocillin is excreted unchanged mainly in the kidney (up to 80% of the dose is found in the urine after 24 hours). In patients with renal impairment, the dose must be adapted.

Creatinine clearance (mL/min)

Regimen

4g 6g

More than 60 2g BD 2g TDS

60 to 30 1g BD 1g TDS

10 to 30 1g OD 1.5g OD

Less than 10 1g/48h or 500mg OD 750 mg OD

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Local experience / practical issues

Some local treatment experience in Manchester for treating KPC-producing Enterobacteriaceae, most frequently for urinary tract infections. Minimum dose 2g BD. Monitor for development of resistance whilst on therapy or in recurrent infections.

References Woodford N, Pike R, Meunier Det al. In vitro activity of temocillin against multidrug-resistant clinical isolates of Escherichia coli, Klebsiella spp. and Enterobacter spp., and evaluation of high-level temocillin resistance as a diagnostic marker for OXA-48 carbapenemase. J Antimicrob Chemother. 2014;69(2):564-7

Adams-Haduch JM, Potoski BA, Sidjabat HE et al. Activity of temocillin against KPC-producing Klebsiella pneumoniae and Escherichia coli. Antimicrob Agents Chemother. 2009;53(6):2700-1

Balakrishnan I, Awad-El-Kariem FM, Aali A et al. Temocillin use in England: clinical and microbiological efficacies in infections caused by extended-spectrum and/or derepressed AmpC β-lactamase-producing Enterobacteriaceae. J Antimicrob Chemother. 2011;66(11):2628-31

Laterre PF., Wittebole X., Van de Velde S et al. Temocillin 6g daily in critically ill patients : continuous infusion vs. conventional administration. J. Antimicrob. Chemother. Publication has just been accepted.

De Jongh R, Hens R, Basma V et al. Continuous versus intermittent infusion of temocillin, a directed spectrum penicillin for intensive care patients with nosocomial pneumonia: stability, compatibility, population pharmacokinetic studies and breakpoint selection. J Antimicrob Chemother. 2008;61(2):382-8

Tigecycline

Place in therapy Evidence for use particularly in combination with other agents.

Optimal administration and dosing

Standard dosing (100mg loading dose followed by 50mg BD) and high dose regimen of 100mg BD have been used for treatment of CPE infections with success in critical care. Evidence evaluating outcomes comparing these regimens is scarce. These patient groups may benefit from high dose regimen:

Cultures with intermediate sensitivity to tigecycline

Patients with ventilator associated pneumonia

Cautions associated with high dose regimens

Increased incidence of side-effects

Nausea, vomiting and diarrhoea

Increased transaminases

Thrombocytopenia

Local experience / practical issues

Owing to the increased adverse effects associated with unlicensed high doses the following are recommended:

Prescription of anti-emetic medication

Weekly monitoring of LFTs

Weekly monitoring of platelets

References Falagas ME, Lourida P, Poulikakos P et al. Antibiotic Treatment of Infections Due to Carbapenem-Resistant Enterobacteriaceae: Systematic Evaluation of the Available Evidence Antimicrob. Agents Chemother. 2014, 58(2):654