Meropenem

Meropenem is a carbapenem antibacterial agent with a broad spectrum of activity which encompasses Gram-negative, Gram-positive and anaerobic bacteria. Like other carbapenems, meropenem is stable against chromosomal and extended-spectrum β-lactamases.

In patients with moderate to severe intra-abdominal infections, empirical mono therapy with meropenem achieved clinical response rates ranging from 91 to 100% in 7 randomised comparative trials. Efficacy rates were similar to those of imipenem/cilastatin (94 to 97%), clindamycin plus tobramycin (93%) and, overall, to cefotaxime plus metronidazole (75 to 100%), although there were differences between trials versus this combination regimen. According to limited data, meropenem also achieved clinical response rates of over 80% in patients with severe intra-abdominal infections.

Meropenem is well tolerated, the most common adverse events being diarrhoea, rash, nausea/vomiting and inflammation at the injection site which are reported in <2.5% of patients each. Meropenem also has an improved CNS tolerability profile compared with imipenem/cilastatin.

Conclusions: Extensive comparative clinical data demonstrate that meropenem can be used effectively as empirical monotherapy in moderate to severe intra-abdominal infections. It also shows potential in the most severe forms of infection, although experience in this infection type remains limited. Compared with standard combination regimens, meropenem offers the benefits of ease of administration without the need for monitoring. It also offers improved CNS tolerability compared with imipenem/cilastatin with the option of a higher maximum dosage, which may be a particular advantage in patients with severe intra-abdominal infections.

Meropenem has consistently strong activity against Enterobacteriaceae; over 98% of European and North American isolates in a large in vitro study were susceptible to the drug. Imipenem showed 4- to 32-fold less activity against the same pathogens. According to the same survey, 91% of Pseudomonas aeruginosa are susceptible to meropenem [minimum concentration required to inhibit 90% of isolates (MIC90) 4 mg/L] and meropenem exhibited good activity against Acinetobacter baumannii (MIC90 values of 1 or 2 mg/L), although infrequent isolates with decreased susceptibility or resistance to the carbapenems have been documented worldwide.

Meropenem has good activity (MIC₉₀ ≤1 mg/L) against Gram-positive bacteria relevant to intra-abdominal infections including viridans streptococci, methicillin-susceptible Staphylococcus epidermidis and S. aureus. 71 and 79% of Enterococcus faecalis isolated from Europe and North America, respectively, were susceptible to meropenem. Imipenem had slightly more activity (up to 4-fold) than meropenem against Gram-positive bacteria.

Stenotrophomonas maltophilia, E. faecium and methicillin-resistant S. aureus are inherently resistant to the carbapenems.

Meropenem produces only minor alterations in the intestinal microflora of healthy volunteers; numbers of streptococci, enterobacteria, bacteroides, veillonella/acidaminococci and clostridia decreased and those of enterococci increased during a 7-day course of intravenous meropenem 1.5 g/day but all gut flora returned to normal within 2 weeks of completing treatment.

Meropenem, like other β-lactams, does exhibit an inoculum effect in vitro. However, MIC values reported at an inoculum of ⁈10⁷ colony forming units (cfu)/spot did not exceed 4 mg/L for any organism including Enterobacteriaceae expressing chromosomal or plasmid-mediated β-lactamases.

Meropenem has a postantibiotic effect against both Gram-negative and Gram-positive bacteria.

Meropenem has linear pharmacokinetics over the dose range 0.25 to 2g. Mean peak plasma concentrations (C_max) of meropenem following a single intravenous lg dose ranged from 54.8 to 61.6 mg/L in healthy volunteers.

Meropenem is distributed in the extracellular (interstitial) fluid. Typically, meropenem concentrations achieved in the abdominal tissues are in the range of 2 to 4 mg/L, although concentrations in the bile are higher and range from 7 to 15 mg/L. In patients with intra-abdominal infections, the volume of distribution (Vd) tends to be up to approximately 2-fold higher compared with values observed in healthy volunteers.

Meropenem is cleared predominantly in the kidney by both glomerular filtration and tubular secretion. Excretion is rapid and over 95% of an administered dose is excreted within 8 hours. Biliary excretion of meropenem is therefore limited; 2.1% of a drug dose is recovered in the faeces.

Meropenem has a single open-ring metabolite formed by hydrolysis which is pharmacologicallyinactive.Theeliminationhalf-life(t12) of meropenem is approximately 1 hour.

In patients with renal impairment, the clearance of meropenem is decreased and t12 prolonged. Dosage adjustment is therefore required based on creatinine clearance (CL_CR). Meropenem is cleared by haemodialysis and continuous veno-venous haemofiltration, and dosage adjustment may be required in these patients. The pharmacokinetics of meropenem are, however, unaltered in patients with hepatic impairment.

In intra-abdominal infections of moderate severity, meropenem 1.5 g/day achieved a satisfactory clinical response in 92 and 98% of patients compared with rates of 94 and 96% with imipenem/cilastatin 1.5 or 2 g/day in 2 multicentre, randomised trials.

In patients with moderate to severe infections, meropenem 3 g/day achieved clinical response rates ranging from 91 to 100% in 7 randomised trials. Efficacy rates were similar to those of imipenem/cilastatin (94 to 97%) and clindamycin plus tobramycin (93%). Compared with cefotaxime plus metronidazole in 3 trials, the regimens were similar in one trial (satisfactory clinical response in 93 vs 92%) but significantly different in the remaining 2 trials (95 with meropenem vs 75% with the combination regimen in one trial and 91 vs 100% in the other). Slight differences in bacteriological outcome were observed between regimens on a per pathogen basis, but statistical analyses were not performed.

The efficacy of meropenem appeared to be unaffected by the site of intra-abdominal infection according to a retrospective analysis of 4 clinical trials; meropenem consistently achieved a satisfactory response in over 89% of patients which was similar to that of comparator regimens.

In 2 comparative trials which recruited patients with severe infections, clinical response rates were 82 and 96% with meropenem 3 g/day versus 81 and 77% with imipenem/cilastatin 3 g/day in those patients with severe intra-abdominal infections (>50 patients per study).

In patients with intra-abdominal infections who failed therapy (4 to 16%), the most common persistent organisms following failure of meropenem therapy included Escherichia coli, other Enterobacteriaceae, enterococci, Streptococcus spp. and P. aeruginosa. Superinfections developed in similar numbers of patients receiving meropenem and comparator regimens.

In the 2 cost analyses that compared delivery methods of meropenem, bolus administration was associated with delivery cost savings of approximately 30% in an Australian study and 45% in a UK study compared with an infusion of the drug.

A recent overview of clinical trial data involving 9514 patients found that the overall incidence of adverse events, drug-related adverse events, adverse events leading to withdrawal and mortality were similar between meropenem, imipenem/cilastatin and combination regimens. Drug-related events most frequently associated with meropenem are diarrhoea (2.3%), rash (1.4%), nausea/vomiting (1.4%) and local inflammation at the injection site (1.1%). A concern with imipenem/cilastatin is that the incidence of gastrointestinal events is linked to the rate of administration and dosage of the drug, although these events can be managed by slowing the rate of infusion of the drug. Meropenem can, however, can be administered without regard to the rate of infusion or dose.

A tolerability concern with β-lactam agents is their potential to cause CNS toxicity and seizures. With regard to the CNS, meropenem appears to be well tolerated, whereas imipenem/cilastatin is associated with a risk of seizures, particularly in those with predisposing factors such as renal dysfunction, underlying CNS pathology or advanced age. In an overview of 46 clinical trials, which excluded patients with meningitis and a history of CNS disorders, the incidence of meropenem-related seizures was 0.08% of treatment exposures compared with 0.28% with imipenem/cilastatin, 0.05% with cephalosporin-based regimens and 0% with clindamycin plus an aminoglycoside.

Laboratory events most commonly associated with meropenem included thrombocytosis (1.6%) and increases in ALT (4.3%), AST (3.4%) and alkaline phosphatase (1.5%).

Meropenem is indicated as monotherapy for the treatment of intra-abdominal infections. According to the manufacturer’s recommendations, meropenem should be administered at a dosage of 1.5 to 3 g/day in 3 divided doses depending on the type and severity of infection, the susceptibility of the pathogen(s) and the condition of the patient. This dosage range may, however, differ from that recommended on a national level. Meropenem can be administered as an intravenous bolus injection or infusion.

Dosage adjustment is required in patients with renal impairment (CL_CR ≤3 L/h) but not in the elderly (CL_CR >3 L/h) or in patients with impaired hepatic function.