Meropenem

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Abstract
The parenteral carbapenem mewpenem is relatively stable to inactivation by human renal dehydropeptidase (DHP-1) and does not require concomitant administration of a DHP-1 inhibitor such as cilastatin. It has a broad spectrum of antibacterial activity in vitro, the majority of Gram-negative, Gram-positive and anaerobic pathogens being highly susceptible to the drug. Meropenem has shown clinical and bacteriological efficacy in the treatment of a wide range of serious infections in adults and children which is at least comparable with that of currently available treatment options. Its clinical and bacteriological efficacy is similar to that of imipenem/cilastatin, clindamycin plus tobramycin and cefotaxime plus metronidazole in the treatment of intra-abdominal infections; cefotaxime or ceftriaxone in the treatment of meningitis; imipenem/cilastatin, and ceftazidime with or without an aminoglycoside, in lower respiratory tract infections; and imipenem/cilastatin or ceftazidime in the treatment of urinary tract infections. Satisfactory clinical and bacteriological response rates have also been achieved in patients with skin and skin structure infections, obstetric and gynaecological infections or septicaemia, and in immunocompromised patients with febrile episodes. Preliminary findings also indicate efficacy in the treatment of respiratory tract infections in patients with cystic fibrosis. The tolerability profile of mewpenem is generally similar to that of comparator agents, although it is associated with a lower incidence of adverse gastrointestinal effects (nausea and vomiting) than imipenem/cilastatin. Importantly, the incidence of seizures in patients with meningitis is not increased following administration of meropenem. Thus, mewpenem is an effective broad spectrum antibacterial drug for the treatment of a wide range of infections including polymicrobial infections in both adults and children, with comparable efficacy to imipenem/cilastatin and various other treatment regimens. Mewpenem is likely to be of greatest value as empiric monotherapy in the treatment of serious infections or those caused by multiply-resistant pathogens. Further clinical experience is necessary, however, to ultimately define its place in therapy. Meropenem causes bacterial cell death by binding covalently to penicillin binding proteins involved in cell wall synthesis. For a wide range of aerobic and anaerobic bacteria, the ratio of the minimum bactericidal activity (MBC) to minimum inhibitory concentration (MIC) was 1 or 2. Unlike other β-lactam antibacterial agents, carbapenems induce a postantibiotic effect against Gram-negative bacilli, and that produced by meropenem was often longer than that produced by imipenem in the same bacteria. The drug is generally more active in vitro than imipenem against Enterobacteriaceae, including nosocomial clinical isolates resistant to ceftazidime, cefotaxime, ceftriaxone, piperacillin and gentamicin, with over 90% of isolates generally inhibited by meropenem 0.008 to 0.5 mg/L. In most studies, the MIC of meropenem for 90% (MIC90) of Pseudomonas aeruginosa isolates was ≤4 mg/L. All tested strains of Haemophilus influenzae and Neisseria gonorrhoeae were susceptible to meropenem. The drug is also active against Staphylococcus aureus, as well as S. epidermidis, S. saprophyticus and other coagulase-negative staphylococci, but is generally less active than imipenem against these Gram-positive organisms. Combinations of meropenem with several other antibacterial agents have shown a synergistic antibacterial activity against methicillin-resistant S. aureus. Streptococcus pyogenes, S. agalactiae and S. pneumoniae, including penicillin-resistant strains, are inhibited by low concentrations of meropenem, and most strains of Enterococcus faecalis are susceptible or moderately susceptible. E. faecium strains are resistant to meropenem. Meropenem 0.06 to 4 mg/L inhibits the growth of virtually all tested strains of Bacteroides fragilis, B. fragilis group, and Fusobacterium spp., and is also active against non-B. fragilis group Bacteroides spp., Prevotella and Porphyromonas species. Meropenem is more active than imipenem against clinical isolates of Clostridium perfringens, C. difficile, Veillonella spp. and Peptococcus species. Carbapenems appear to be highly resistant to hydrolysis by all of the TEM and SHV β-lactamases (Richmond Sykes Class III), and meropenem appears to be stable to all β-lactamases belonging to Richmond Sykes Class I including those with an extended spectrum against third-generation cephalosporins. Altered penicillin binding proteins account for resistance among E. faecium and methicillin-resistant S. aureus. Impermeability resistance is a clinical problem with Gram-negative bacilli, but these organisms are rarely resistant to meropenem. A similar type of resistance mechanism occurs in P. aeruginosa, and meropenem-resistant strains lack the D2 outer membrane protein. There is considerable cross-resistance between monobactams, second- and third-generation cephalosporins and ureidopenicillins, but very little between these drugs and meropenem. Meropenem exhibits approximately linear kinetics, with plasma concentrations increasing with dose (reaching higher levels after a bolus injection than after a 30 minute infusion in the first hour). Other pharmacokinetic parameters are unchanged after bolus injection compared with infusion. The mean peak plasma concentration after a single 30 minute infusion of meropenem 1g ranges between 53.1 and 61.6 mg/L. Meropenem is widely distributed into body tissues and fluids, including cerebrospinal fluid. The elimination half-life is approximately 1 hour after intravenous doses of 0.5 to 1g in healthy volunteers, and is increased in neonates, infants and patients with impaired renal function. Renal clearance occurs mainly via glomerular filtration but tubular secretion also plays a part. 54 to 79% of the original dose of meropenem is recovered unchanged in the urine, indicating stability of the molecule to the human renal dehydropeptidase enzyme (DHP-1); about 2% is recovered in the faeces, and the remainder appears to be excreted in the urine as the inactive metabolite. The pharmacokinetic profile of meropenem is similar to that of imipenem administered as imipenem/cilastatin. Meropenem has shown clinical efficacy at least equal to that of comparator agents in the treatment of a wide range of infections in adults and children in randomised, generally nonblinded, clinical trials. Intravenous meropenem 0.5 or 1g every 8 hours showed clinical and bacteriological efficacy similar to that of imipenem/cilastatin, clindamycin plus tobramycin and cefotaxime plus metronidazole in patients with intra-abdominal infections. Clinical responses (cure or improvement) were achieved in 91 to 100% of patients following treatment with meropenem, and the bacteriological response rate ranged between 84 and 95%. Preliminary findings have shown the efficacy of intravenous meropenem 1g every 8 hours to be similar to that of ceftazidime 2g every 8 hours as initial empiric monotherapy for the treatment of febrile episodes in patients with neutropenia. 44% of febrile episodes responded to treatment with meropenem versus 41% with ceftazidime. Intravenous meropenem 120 mg/kg/day (up to 6 g/day in adults and children weighing ≥ 50kg) has shown clinical and bacteriological efficacy similar to that of the cephalosporins cefotaxime and ceftriaxone in adults and children with bacterial meningitis caused predominantly by S. pneumoniae, N. meningitidis or H. influenzae. Clinical responses were achieved in 98% of meropenem recipients and the bacteriological eradication rate was 100% in one study. Comparative studies with imipenem/cilastatin are not available as this drug combination is not licensed for bacterial meningitis due to an associated increased incidence of seizures. Case studies have reported efficacy of meropenem in the treatment of cephalosporin-resistant pseudomonal infections; however, data on the drug’s clinical value against infections caused by other pathogens resistant to current treatment regimens are not available. The clinical efficacy of intravenous or intramuscular meropenem 0.5 to 3 g/day was similar to that of imipenem/cilastatin and ceftazidime with or without an aminoglycoside in patients with lower respiratory tract infections. The clinical response rate in patients with nosocomially-acquired infections was 98% in one study, and ranged between 93 and 100% in patients with community-acquired infections. Bacteriological eradication rates were 88% and 91 to 100%, respectively. Clinical and bacteriological responses were achieved in 81 and.71% of patients with severe nosocomial infection and in 93% and 91 to 100% of patients with severe community-acquired infections. The clinical value of meropenem against infections in patients with cystic fibrosis remains to be established. However, studies in small numbers of patients have demonstrated efficacy in reducing pulmonary sepsis similar to that shown by ceftazidime. Intravenous or intramuscular meropenem 0.5 to 1.5 g/day was also effective in the treatment of uncomplicated and complicated urinary tract infections, producing clinical responses in 79 to 97% of patients and bacteriological eradication in 56 to 92%. Randomised trials indicated an efficacy generally similar to that of imipenem/cilastatin or ceftazidime, although one study reported a significantly greater clinical response rate in meropenem compared with imipenem/cilastatin recipients (97 versus 90%; p < 0.05). Clinical and bacteriological response rates in patients with skin and skin structure infections were 98 and 94%, respectively, (similar to those achieved with imipenem/cilastatin), and were 88 to 100% and 88 to 90% in patients with obstetric and gynaecological infections (similar to those achieved with combination therapy of intravenous clindamycin and gentamicin). Preliminary studies have shown meropenem to be as effective as ceftazidime in the treatment of septicaemia (clinical response rate 92 versus 94%). The mean response rate to meropenem in clinical trials of the drug in children with a range of infections was 98% and bacteria were eradicated from between 89 and 97% of patients. The tolerability profile of intravenous (as an infusion or bolus injection) or intramuscular meropenem 1.5 to 6 g/day is similar to that of other β-lactam antibacterials with which it has been compared. It is similar in children, adults and the elderly and is not altered in patients with renal impairment. Nausea and vomiting (in ≤3.6% of patients), diarrhoea (≤4.3%) and transient changes in hepatic biochemistry (increased ALT and AST in 7 and 5.6%, respectively) occur most often. However, nausea and vomiting and inflammation at the injection site appear to occur less frequently in patients receiving meropenem than in those receiving imipenem/cilastatin. Seizures appear to occur at a similar rate in meropenem recipients to that seen in patients receiving other antibacterial drugs (0.38% in one large analysis). Unlike imipenem/cilastatin, however, meropenem has not induced seizures in patients with meningitis. The recommended intravenous dosage of meropenem in adults with normal renal function is 0.5 to 1g every 8 hours, and 1g every 8 hours in patients with neutropenia. Children should receive 10 to 20 mg/kg every 8 hours. The dosage is increased in patients with meningitis (adults: 2g every 8 hours; children: 40 mg/kg every 8 hours), and decreased in patients with renal impairment. Meropenem may be administered by intravenous bolus injection over approximately 5 minutes or by intravenous infusion over 15 to 30 minutes.
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