Meropenem

Abstract

Meropenem is a carbapenem antibacterial agent that has antimicrobial activity against Gram-negative, Gram-positive and anaerobic micro-organisms. In vitro studies involving isolates from patients in intensive care units (ICUs) indicate that meropenem is more active against most Gram-negative pathogens than other comparators (including imipenem), although, compared with imipenem, meropenem is less active against most Gram-positive organisms. Resistance to meropenem is uncommon in most bacteria. Treatment with meropenem as initial empirical monotherapy was effective in a range of serious infections in adult and paediatric ICU patients. Meropenem monotherapy was as effective as imipenem/cilastatin in 4 comparative trials in terms of satisfactory clinical and bacteriological responses. Meropenem monotherapy was significantly more effective than ceftazidime-based combination treatments in 2 trials in patients with nosocomial lower respiratory tract infections (LRTIs) in terms of both clinical and bacteriological responses. Meropenem was also more active than ceftazidime-based treatments against both Gram-positive and Gram-negative organisms. However, 2 studies in patients with a range of serious infections found no significant differences between meropenem and cephalosporin-based treatments in terms of clinical or bacteriological response. Meropenem was also as effective as cephalosporin-based treatments in comparative trials in children with serious infections. Meropenem is well tolerated as either a bolus or an infusion, and clinical trials have shown similar incidences of adverse events to those observed with cephalosporin-based treatments. It is well tolerated by the CNS, with seizures reported infrequently, and can therefore be used at high doses and in patients with meningitis. The incidence of drug-related nausea and vomiting is low and, in contrast to imipenem/cilastatin, does not increase with dose or speed of administration. Conclusions: Meropenem is a well tolerated broad spectrum antibacterial agent that, when used as initial empirical monotherapy, is as effective as imipenem/cilastatin in the treatment of a range of serious infections (including nosocomial) in adults and children in ICUs. Compared with cephalosporin-based combination treatments, meropenem monotherapy may be more effective in the treatment of nosocomial LRTIs and can be used as monotherapy. Meropenem has an important role in the empirical treatment of serious infections in adults and children in ICUs. Meropenem has a broad spectrum of activity against most common intensive care unit (ICU) pathogens in in vitro studies, and, in particular, was more active than most other agents (including imipenem) against Enterobacteriaceae. A survey of 14 857 isolates (not all from ICUs) found that values for the minimum drug concentration required to inhibit the growth of 90% of bacterial strains (MIC90) with meropenem were 4- to 16-fold lower than those with imipenem (≤0.06 to 0.5 mg/L and 0.25 to 8 mg/L, respectively). All Enterobacteriaceae isolated from 13 ICUs were highly susceptible to meropenem, with MIC₉₀ values ranging from 0.13 to 1 mg/L; values for imipenem ranged from 1 to 4 mg/L. Haemophilus influenzae and Neisseria meningitidis were also highly susceptible to meropenem (MIC₉₀ ≤1 mg/L); data from North American centres indicated that meropenem was more active than imipenem against H. influenzae (99.4 and 85.3% of isolates were susceptible, respectively). Isolates of Pseudomonas aeruginosa from ICU patients were of intermediate susceptibility to meropenem and resistant to all other agents tested, including imipenem. Stenotrophomonas maltophilia was resistant to both carbapenems. Gram-positive bacteria susceptible (MIC₉₀ ≤4 mg/L) to meropenem include methicillin-sensitive Staphylococcus aureus and S. epidermidis, and Streptococcus pneumoniae. Meropenem is less active than imipenem against Enterococcus faecalis. Methicillin-resistant staphylococci and E. faecium are resistant to meropenem. Meropenem is highly active against most anaerobic bacteria, with 1 review finding that 99.1% of 2257 isolates were susceptible. Meropenem, like imipenem, is highly resistant to hydrolysis by most of the serine-based β-lactamases produced by Gram-negative bacteria; however, both drugs are susceptible to the metallo-β-lactamases and clavulanic acid-inhibited carbapenemases produced by S. maltophilia and some Flavobacterium spp. Hyperproduction of β-lactamases by some bacteria is also associated with decreased susceptibility when expressed in conjunction with certain porin deficiencies. Alterations in penicillin-binding proteins account for the inherent resistance of E. faecium and methicillin-resistant S. aureus. Meropenem has demonstrated additive or synergistic activity when used in combination with a range of antibacterial agents in in vitro studies. Like imipenem, meropenem has a postantibiotic effect on Gram-negative bacilli. Meropenem may cause less release of endotoxin from Gram-negative bacteria than other agents such as the cephalosporins, although results are inconsistent. Meropenem has linear pharmacokinetics and distributes into a wide range of body fluids and tissues. Mean values for peak plasma concentrations (C_max) in healthy volunteers were 54.8 to 61.6 mg/L after single dose meropenem 1g; these values were similar 1 hour after either bolus or infusion administration. Mean values for elimination half-life (t½) were 1.0 to 1.4 hours, and volume of distribution was 12.5 to 23L. Meropenem is largely excreted renally, with 54 to 79% of a 1g dosage excreted unchanged in the urine and 19 to 27% excreted as an inactive metabolite. Unlike imipenem, meropenem is stable to human renal dehydropeptidase-1. Data relating to the effects of...