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.
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.
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.
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.
KeywordsCystic Fibrosis Febrile Neutropenia Ceftazidime Tobramycin Meropenem
- 3.Merrem/MeronemTM (IV, 500mg, 1g): core data sheet. Astra-Zeneca, 2006 SepGoogle Scholar
- 8.MerremRM IV (meropenem for injection): US Prescribing Information. AstraZeneca, 2007 FebGoogle Scholar
- 9.Electronic medicines compendium. Meronem IV 500mg & 1g, summary of product characteristics from the electronic medicines compendium [online]. Available from URL: http://www.emc.medicines.org.uk/ [Accessed 2008 Mar 17]
- 11.Clinical and Laboratory Standards Institute. Performance standards for antimicrobial susceptibility testing; 18th informational supplement. 2008 JanGoogle Scholar
- 12.Clinical and Laboratory Standards Institute. Methods for antimicrobial susceptibility testing of anaerobic bacteria; approved standard —seventh edition. 2008 JanGoogle Scholar
- 13.Data on File. AstraZeneca, 2008Google Scholar
- 17.Jones RN, Sader HS, Beach ML. Contemporary in vitro spectrum of activity summary for antimicrobial agents tested against 18 569 strains of non-fermentative gram-negative bacilli isolated in the SENTRY antimicrobial surveillance program (1997–2001). Int J Antimicrob Agents 2003; 22(6): 551–6PubMedCrossRefGoogle Scholar
- 22.Rhomberg PR, Deshpande LM, Kirby JT, et al. Activity of meropenem as serine carbapenemases evolve in US medical centers: monitoring report from the MYSTIC Program (2006). Diagn Microbiol Infect Dis 2007 Jul 25Google Scholar
- 23.Deshpande LM, Rhomberg PR, Sader HS, et al. Emergence of serine carbapenemases (KPC and SME) among clinical strains of Enterobacteriaceae isolated in the United States Medical Centers: report from the MYSTIC Program (1999–2005). Diagn Microbiol Infect Dis 2006 Dec; 56(4): 367–72PubMedCrossRefGoogle Scholar
- 24.European Committee on Antimicrobial Susceptibility Testing. European Committee on Antimicrobial Susceptibility Testing guidelines [online]. Available from URL: http://www.escmid.org/ [Accessed 2008 Jan 1]
- 26.Clinical and Laboratory Standards Institute. Performance standards for antimicrobial susceptibility testing of anaerobic bacteria; informational supplement. 2003 JanGoogle Scholar
- 36.Carryn S, Van Bambeke F, Mingeot-Leclercq M-P, et al. Comparative intracellular (THP-1 macrophage) and extracellular activities of beta-lactams, azithromycin, gentamicin, and fluor-oquinolones against Listeria monocytogenes at clinically relevant concentrations. Antimicrob Agents Chemother 2002; 46(7): 2095–103PubMedCrossRefGoogle Scholar
- 41.Kiffer CR, Mendes C, Kuti JL, et al. Pharmacodynamic comparisons of antimicrobials against nosocomial isolates of Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii and Pseudomonas aeruginosa from the MYSTIC surveillance program: the OPTAMA Program, South America 2002. Diagn Microbiol Infect Dis 2004 Jun; 49(2): 109–16PubMedCrossRefGoogle Scholar
- 59.Bearden DT, Earle SB, McConnell DB, et al. Pharmacokinetics of meropenem in extreme obesity [abstract no. A-10 plus poster]. 45th Interscience Conference on Antimicrobial Agents and Chemotherapy; 2005 Dec 1; Washington DC, 2Google Scholar
- 69.Hou F, Li JT, Wu GP, et al. A randomized, controlled clinical trial on meropenem versus imipenem/cilastatin for the treatment of bacterial infections. Chin Med J (Engl) 2002 Dec; 115: 1849–54Google Scholar
- 73.Yakovlev S, Beloborodov V, Sidorenko S, et al. Adequacy and efficacy of initial empiric antibiotic treatments in severe nosocomial infections in ICU departments: results of multicentre randomised study [abstract no. P835 plus poster]. 17th European Congress of Clinical Microbiology and Infectious Diseases and the 25th International Congress of Chemotherapy; 2007 Mar 31; MunichGoogle Scholar
- 77.Odio CM, Puig JR, Feris JM, et al. Prospective, randomized, investigator-blinded study of the efficacy and safety of meropenem vs. cefotaxime therapy in bacterial meningitis in children. Pediatr Infect Dis J 1999 Jul; 18: 581–90Google Scholar
- 79.Solomkin JS, Umeh O, Jiang J, et al. Doripenem vs. meropenem with an option for oral step-down therapy in the treatment of complicated intra-abdominal infections [abstract no. L-487]. 47th Interscience Conference on Antimicrobial Agents and Chemotherapy; 2007 Sep 17; Chicago (IL)Google Scholar
- 80.Lucasti C, Jasovich A, Umeh O, et al. Treatment of complicated intra-abdominal infections: doripenem versus meropenem. 17th European Congress of Clinical Microbiology and Infectious Diseases and the 25th International Congress of Chemotherapy 2007 Mar 31; (abstract no. P834 plus poster (Munich, Germany))Google Scholar
- 81.Malafaia O, Umeh O, Jiang J. Doripenem versus meropenem for the treatment of complicated intra-abdominal infections. 46th Interscience Conference on Antimicrobial Agents and Chemotherapy: Final Program 2006 Sep 27; 188 (abstract no. L-1564b plus poster (California, USA))Google Scholar
- 91.Kutluk T, Kurne O, Akyuz C, et al. Cefepime vs. meropenem as empirical therapy for neutropenic fever in children with lymphoma and solid tumours. Pediatr Blood Cancer 2004; 42(3): 284–6Google Scholar
- 96.Cometta A, Calandra T, Gaya H, et al. Monotherapy with meropenem versus combination therapy with ceftazidime plus amikacin as empiric therapy for fever in granulocytopenic patients with cancer: The International Antimicrobial Therapy Cooperative Group of the European Organization for Research and Treatment of Cancer and the Gruppo Italiano Malattie Ematologiche Maligne dell’Adulto Infection Program. Antimicrob Agents Chemother 1996 May; 40(5): 1108–15PubMedGoogle Scholar
- 105.Byrne S, Maddison J, Connor P, et al. Clinical evaluation of meropenem versus ceftazidime for the treatment of Pseudomonas spp. infections in cystic fibrosis patients. J Antimicrob Chemother 1995 Jul; 36 (Suppl. A): 135–43Google Scholar
- 107.Fabian TC, File TM, Embil JM, et al. Meropenem versus imipenem-cilastatin for the treatment of hospitalized patients with complicated skin and skin structure infections: results of a multicenter, randomized, double-blind comparative study. Surg Infect (Larchmt) 2005; 6(3): 269–82CrossRefGoogle Scholar
- 108.Wilson SE. Results of a randomized, multicenter trial of meropenem versus clindamycin/tobramycin for the treatment of intra-abdominal infections. Clin Infect Dis 1997 Feb; 24 Suppl. 2: S197-206Google Scholar
- 111.Sieger B, Berman SJ, Geckler RW, et al. Empiric treatment of hospital-acquired lower respiratory tract infections with meropenem or ceftazidime with tobramycin: a randomized study. Meropenem Lower Respiratory Infection Group. Crit Care Med 1997 Oct; 25(10): 1663–70Google Scholar
- 113.Heyland DK, Dodek P, Muscedere J, et al. Randomized trial of combination versus monotherapy for the empiric treatment of suspected ventilator-associated pneumonia. Crit Care Med 2008; 36(2): 1–8Google Scholar
- 123.PrimaxinRM I.V. (Imipenem and cilastatin for injection): US prescribing information. Merck & Co, 2007 OctGoogle Scholar
- 127.DeRyke CA, Kuti JL, Nicolau DP. Pharmacodynamic target attainment as a surrogate marker for antibiotic efficacy in cost-effectiveness analyses [abstract no. O-1465 plus poster]. 46th Interscience Conference on Antimicrobial Agents and Chemotherapy; 2006 Sep 17–20; San Francisco (CA), 444Google Scholar
- 130.Tumbarello M, Sanguinetti M, Montuori E, et al. Predictors of mortality in patients with bloodstream infections caused by extended-spectrum-beta-lactamase-producing Enterobacteriaceae: importance of inadequate initial antimicrobial treatment. Antimicrob Agents Chemother 2007 Jun; 51(6): 1987–94PubMedCrossRefGoogle Scholar
- 132.Kollef MH. Inadequate antimicrobial treatment: an important determinant of outcome for hospitalized patients. Clin Infect Dis 2000 Sep; 31 Suppl. 4: S131-8Google Scholar
- 138.Ortho-McNeil Pharmaceutical I. DoribaxTM (doripenem for injection) for intravenous infusion: US prescribing information. 2007 OctGoogle Scholar
- 147.Naber KG, Bishop MC, Bjerklund-Johansen TE, et al. Guidelines on the management of urinary and male genital tract infections [online]. Available from URL: http://www.uroweb.org/professional-resources/guidelines/ [Accessed 2008 Feb 18]