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Published in: Drugs 6/2008

01-04-2008 | Adis Drug Evaluation

Meropenem

A Review of its Use in the Treatment of Serious Bacterial Infections

Authors: Claudine M. Baldwin, Katherine A. Lyseng-Williamson, Susan J. Keam

Published in: Drugs | Issue 6/2008

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Summary

Abstract

Meropenem (Merrem®, Meronem®) is a broad-spectrum antibacterial agent of the carbapenem family, indicated as empirical therapy prior to the identification of causative organisms, or for disease caused by single or multiple susceptible bacteria in both adults and children with a broad range of serious infections.
Meropenem is approved for use in complicated intra-abdominal infection (cIAI), complicated skin and skin structure infection (cSSSI) and bacterial meningitis (in paediatric patients aged ≥3 months) in the US, and in most other countries for nosocomial pneumonia, cIAI, septicaemia, febrile neutropenia, cSSSI, bacterial meningitis, complicated urinary tract infection (UTI), obstetric and gynaecological infections, in cystic fibrosis patients with pulmonary exacerbations, and for the treatment of severe community-acquired pneumonia (CAP).
Meropenem has a broad spectrum of in vitro activity against Gram-positive and Gram-negative pathogens, including extended-spectrum β-lactamase (ESBL)-and AmpC-producing Enterobacteriaceae. It has similar efficacy to comparator antibacterial agents, including: imipenem/cilastatin in cIAI, cSSSI, febrile neutropenia, complicated UTI, obstetric or gynaecological infections and severe CAP; clindamycin plus tobramycin or gentamicin in cIAI or obstetric/ gynaecological infections; cefotaxime plus metronidazole in cIAI; cefepime and ceftazidime plus amikacin in septicaemia or febrile neutropenia; and ceftazidime, clarithromycin plus ceftriaxone or amikacin in severe CAP. Meropenem has also shown similar efficacy to cefotaxime in paediatric and adult patients with bacterial meningitis, and to ceftazidime when both agents were administered with or without tobramycin in patients with cystic fibrosis experiencing acute pulmonary exacerbations. Meropenem showed greater efficacy than ceftazidime or piperacillin/tazobactam in febrile neutropenia, and greater efficacy than ceftazidime plus amikacin or tobramycin in patients with nosocomial pneumonia. Meropenem is well tolerated and has the advantage of being suitable for administration as an intravenous bolus or infusion. Its low propensity for inducing seizures means that it is suitable for treating bacterial meningitis and is the only carbapenem approved in this indication. Thus, meropenem continues to be an important option for the empirical treatment of serious bacterial infections in hospitalized patients.

Pharmacological Properties

Meropenem demonstrated good in vitro activity against clinically relevant Enterobacteriaceae (Citrobacter freundii, C. koseri, Enterobacter aerogenes, E. cloaceae, Escherichia coli, Klebsiella pneumoniae, K. oxytoca, Morganella morganii, Proteus mirabilis, P. vulgaris and Serratia marcescens). The minimum concentration inhibiting 90% of strains (MIC90) was ≤0.25 mg/L and susceptibility rates were 98–100%. Meropenem was active against ESBL-and AmpC-producing Enterobacteriaceae, with little or no change in MIC90 values compared with non-ESBL-and non-AmpC-producing strains. Meropenem also demonstrated good activity against Haemophilus influenzae and Neisseria meningitidis (MIC90 0.25 mg/L; susceptibility rates of 99–100%). Against Pseudomonas aeruginosa, Acinetobacter baumannii and Burkholderia cepacia, MIC90 values were 16–64 mg/L and susceptibility rates were 71.5–76.4%. Meropenem demonstrated good in vitro activity against Gram-positive pathogens, including Staphylococcus aureus (methicillin/oxacillin-susceptible isolates), S. epidermidis (oxacillin-susceptible isolates), Streptococcus pneumoniae (including penicillin-resistant strains) and viridans group streptococci (MIC90 of 0.25–2 mg/L; susceptibility rates of 95–100%), but had poor activity against Enterococcus faecalis. Meropenem lacked activity against methicillin/oxacillin-resistant staphylococci and E. faecium. Meropenem demonstrated good in vitro activity against a range of anaerobes, including Clostridium difficile, C. perfringens, and Peptostreptococcus spp. and Prevotella spp. (MIC90 0.125–4 mg/L; susceptibility rates 100%). Against Bacteroides fragilis, meropenem had an MIC90 of 8 mg/L with a susceptibility rate of 89%.
A mathematical model has estimated that meropenem is likely to achieve an optimal bactericidal pharmacodynamic target attainment against E. coli and K. pneumoniae, but a lower attainment against P. aeruginosa and A. baumannii. Meropenem is also estimated to achieve an optimal bactericidal pharmacodynamic target attainment against most pathogens associated with nosocomial pneumonia, cIAI, nosocomial blood infection, cSSSI and paediatric meningitis.
Meropenem has rapid, time-dependent bactericidal activity and a minimal inoculum effect. Meropenem shows stability against hydrolysis by most β-lactamases, including ESBLs and AmpC β-lactamases, but may be affected by carbapenemases such as metallo-β-lactamases, serine carbapenemases and oxacil-linases with carbapenemase activity (such as OXA-23, OXA-24 and OXA-58). Except for the production of carbapenemases, it appears that two or more resistance mechanisms, such as reduced permeability or overexpression of multidrug efflux pumps, are required for significant carbapenem resistance to emerge. Meropenem appears to have a low potential for selecting resistant strains in vitro.
Meropenem did not accumulate at steady state after intravenous administration. Plasma protein binding is low (≈2%) and meropenem achieves good penetration into a wide range of tissues, including lung, skin blister fluid, interstitial fluid, intra-abdominal tissues, peritoneal fluid and cerebrospinal fluid. Meropenem is mainly eliminated via the kidneys and clinically significant alterations to the pharmacokinetics of the drug are seen in patients with advanced or end-stage renal failure. Meropenem has a short plasma elimination half-life of ≈1 hour.

Clinical Efficacy

The efficacy of meropenem in adult and paediatric patients with serious bacterial infections has been examined in numerous well designed trials.
Meropenem showed greater efficacy than the combinations of ceftazidime plus amikacin or tobramycin in patients with nosocomial pneumonia, with end of treatment (EOT) clinical response rates of 83% and 89% vs 66% and 72%, and bacteriological response rates of 75% and 89% vs 53% and 67%.
Meropenem was as effective as imipenem/cilastatin in four trials in patients with cIAI, with clinical cure rates at EOT or follow-up of 90–98% and 88–98% for the respective treatments, and bacteriological cure rates of 84–98% and 79–96%. In one trial, clinical cure rates were 84% and 85% with meropenem or doripenem, and the respective bacteriological cure rates were 85% and 84%. In a comparison between meropenem and tobramycin plus clindamycin, clinical and bacteriological response rates were each 96% with meropenem and 93% with tobramycin plus clindamycin. In two trials comparing the efficacy of meropenem and cefotaxime plus metronidazole, results were mixed.
In patients with septicaemiae secondary to a serious bacterial infection, meropenem was as effective as ceftazidime with or without amikacin, with clinical response rates at EOT of 92% and 94% for the respective treatments.
Meropenem was as effective as imipenem/cilastatin, cefepime, ceftazidime with or without amikacin or piperacillin/tazobactam in numerous trials in patients with febrile neutropenia, with initial response rates to unmodified treatment regimens at 72 hours of 56–88% and 40–80% of episodes. Response rates to meropenem were significantly greater than ceftazidime (56% vs 40%; p = 0.003) and piperacillin/tazobactam (64% vs 50%; p < 0.05). Treatment success at EOT, regardless of regimen modification, was seen in 44–100% of episodes treated with meropenem and 41–100% of those treated with comparators; meropenem was more effective than ceftazidime in one trial (54% vs 44%; p < 0.05).
Meropenem efficacy was noninferior to that of imipenem/cilastatin in patients with cSSSI in one trial, with clinical response rates of 86% and 83%, respectively, at the follow-up visit. In another trial, there were no significant differences between meropenem and imipenem/cilastatin in terms of clinical response (98% vs 95%) or bacteriological response (94% vs 91%) at EOT assessment.
The proportion of patients achieving cure with no sequelae with meropenem in two trials in paediatric patients with bacterial meningitis did not differ from that with cefotaxime at EOT (46% vs 56%) and/or follow-up (54% vs 58% and 72% vs 81%). In adult patients with meningitis, clinical cure (with or without sequelae) occurred in 100% of clinically evaluable meropenem recipients compared with 77% of cephalosporin (cefotaxime or ceftriaxone) recipients.
Meropenem was an effective alternative therapy to imipenem/cilastatin in patients with complicated UTI, evidenced by clinical responses of 99% in either treatment group and bacteriological responses in 90% of meropenem and 87% of imipenem/cilastatin recipients.
In women with obstetric or gynaecological infections, meropenem achieved similar clinical or bacteriological response rates at EOT and follow-up to clindamycin plus gentamycin (88–98% vs 86–100%). In another trial, meropenem achieved a significantly higher clinical cure rate than imipenem/cilastatin at EOT (100% vs 90%; p = 0.026), but not at follow-up (98% vs 97%).
In two trials in patients with cystic fibrosis, meropenem plus tobramycin improved pulmonary function at EOT in patients with acute exacerbations of infection to the same extent as ceftazidime plus tobramycin (absolute change from baseline in percentage predicted forced expiratory volume in one second of 5.1–13.8% and 6.1–11.1%), confirming results of an earlier trial of meropenem versus ceftazidime monotherapy in which 98% of meropenem and 90% of ceftazidime recipients were classed as responders. Both combination therapy regimens decreased sputum bacterial burden.
In patients with severe CAP, meropenem achieved clinical response rates of 87–91 % at EOT and 96–100% at follow-up, which were similar to those seen with imipenem/cilastatin (86–91% and 100%), ceftazidime (90% and not reported), clarithromycin plus ceftriaxone (69% and 92%) or clarithromycin plus amikacin (86% and 96%). Bacteriological response rates with meropenem, imipenem/cilastatin or ceftazidime at EOT or follow-up were 95–100%, 93% and 100%, and 92% for the respective treatments.
Pharmacoeconomic analyses of meropenem from a health payer perspective in the UK, US and Russia predicted that meropenem is a cost-effective therapy relative to other antibacterials, including imipenem/cilastatin or conventional combination antibacterial treatments in the treatment of serious bacterial infections in intensive care units. In the UK cost-utility analysis, meropenem dominated imipenem/cilastatin with regard to cost per quality-adjusted life-year gained, and was predicted to be more cost-effective than imipenem/cilastatin in the treatment of P. aeruginosa infections in the US and conventional combination antibacterial treatments in high-risk nosocomial infections in Russia.

Tolerability

Intravenous meropenem was generally well tolerated in adult and paediatric patients with serious bacterial infections, and most adverse events were mild to moderate in severity. The most commonly reported drug-related adverse events in patients treated with meropenem included diarrhoea, rash, and/or nausea and vomiting; in paediatric patients, diarrhoea and rash were most common. The most commonly reported laboratory adverse events included increased levels of ALT and AST and thrombocytosis. Meropenem had good CNS tolerability with an incidence of drug-related seizures in patients with infections other than meningitis of 0.07%. No seizures were considered to be related to meropenem in a trial in paediatric patients with bacterial meningitis.
Footnotes
1
The use of trade names is for product identification purposes only and does not imply endorsement.
 
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Metadata
Title
Meropenem
A Review of its Use in the Treatment of Serious Bacterial Infections
Authors
Claudine M. Baldwin
Katherine A. Lyseng-Williamson
Susan J. Keam
Publication date
01-04-2008
Publisher
Springer International Publishing
Published in
Drugs / Issue 6/2008
Print ISSN: 0012-6667
Electronic ISSN: 1179-1950
DOI
https://doi.org/10.2165/00003495-200868060-00006

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