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PubMed1992

Activity of meropenem against imipenem-resistant bacteria and selection in vitro of carbapenem-resistant Enterobacteriaceae.

The activity of meropenem against 106 imipenem-resistant (MIC > or = 8 mg/l) clinical isolates, and the frequency of resistance to meropenem and imipenem among 24 Enterobacteriaceae was determined. Both agents selected colonies on agar but 20-80% were susceptible after one subculture and 72% of the mutants reverted to susceptibility 1 to 6 months after selection. All isolates and stable mutants were inhibited by > 1 mg/l meropenem, although the MIC of imipenem was 4-16 mg/l. Three of six Xanthomonas maltophilia isolates were susceptible to meropenem (MICs 2-4 mg/l). Pseudomonas aeruginosa lacking outer membrane protein D2 were resistant to meropenem, although isolates with substantially reduced expression of this protein were susceptible. None of the imipenem-resistant gram-positive bacteria were susceptible to meropenem. There was no clear correlation between altered outer membrane protein expression and decreased susceptibility to carbapenems, and there was no apparent involvement of plasmid or chromosomal beta-lactamase.

Bacteria↗

PubMed1991

Pharmacokinetics of meropenem compared to imipenem-cilastatin in young, healthy males.

Imipenem combined with cilastatin and meropenem was given as intravenous infusions of 1 g to eight young, healthy males on two separate occasions. Blood and urine samples were collected for up to 12 h. The terminal half-lives in plasma were 0.98 h and 1.11 h for meropenem and imipenem, respectively. The volume of distribution was smaller for meropenem than for imipenem (12.5 l and 14.4 l, respectively). The plasma clearance for meropenem was 188 (SD 31) ml/min and for imipenem 183 (SD 25) ml/min. Renal clearance was on average 139 (SD 24) ml/min and 135 (SD 11) ml/min, respectively. About 75% of the administered dose of both compounds was eliminated unchanged in urine. Non-renal clearance accounted for approximately 25% of the total clearance for both drugs. The kinetics of meropenem are very similar to those of imipenem given with cilastatin, and meropenem is as stable against renal metabolic degradation as imipenem combined with cilastatin.

Adult↗

PubMed2001

Meropenem in neonatal severe infections due to multiresistant gram-negative bacteria.

Recently, new broad spectrum carbapenem has been investigated on a world-wide scale for the treatment of moderate to severe infections. In the neonatal intensive care units the extensive use of third generation cephalosporins for therapy of neonatal sepsis may lead to rapid emergence of multiresistant gram-negative organisms. We report the use of meropenem in 35 infants with severe infections due to Acinetobacter baumanii and Klebsiella pneumoniae. All gram negative bacteria were resistant to ampicillin, amoxicillin, ticarcilin, cefazoline, cefotaxime, ceftazidime, ceftriaxone and aminoglycosides. Eighty two percent of the cases (29/35) were born prematurely. Assisted ventilation was needed in 85.7% (30/35). All infants deteriorated during their conventional treatment and were changed to meropenem monotherapy. Six percent (2/35) died. The incidence of drug-related adverse events (mostly a slight increase in liver enzymes) was 8.5%. No adverse effects such as diarrhea, vomiting, rash, glossitis, oral or diaper area moniliasis, thrombocytosis, thrombocytopenia, eosinophilia and seizures were observed. At the end of therapy, overall satisfactory clinical and bacterial response was obtained in 33/35 (94.3%) of the newborns treated with meropenem. Clinical and bacterial response rates for meropenem were 100% for sepsis and 87.5% for nosocomial pneumonia. This report suggests that meropenem may be a useful antimicrobial agent in neonatal infections caused by multiresistant gram negative bacilli. Further studies are needed to confirm these results: Meropenem, newborn, sepsis and nosocomial infection.

Acinetobacter Infections↗

PubMed1998

Meropenem monotherapy versus combination therapy with ceftazidime and amikacin for empirical treatment of febrile neutropenic patients.

Infections remain the major cause of morbidity and mortality among neutropenic cancer patients. The current study addresses the question whether monotherapy with the new broad-spectrum carbapenem meropenem exhibits efficacy comparable to that of the standard combination therapy with ceftazidime and amikacin for empirical treatment of febrile neutropenic patients. Seventy-one patients with hematological malignancies (55%) or solid tumors (45%), neutropenia < 500/microliter, and fever > 38.5 degrees C were randomly assigned to either meropenem (1 g every 8 h) or ceftazidime (2 g every 8 h) and amikacin (15 mg/kg/day) intravenously. Meropenem (n = 34) and ceftazidime/amikacin (n = 37) were equivalent with respect to the clinical response at 72 h (62% versus 68%) (p > 0.05) and at the end of unmodified therapy (59% versus 62%). Gram-positive bacteremia responded poorly in the meropenem and ceftazidime/amikacin group (29% versus 25%), whereas all gram-negative bacteremias responded except for one in the meropenem group caused by Pseudomonas aeruginosa. All patients survived to 72 h. One patient in each group died of gram-positive sepsis resistant to study medication. No significant side effects occurred in any regimen. This study suggests that meropenem monotherapy might be as effective as combination therapy with ceftazidime and amikacin for the empirical treatment of febrile neutropenic patients.

Adolescent↗

PubMed2000

Meropenem versus ceftazidime as empirical monotherapy for febrile neutropenic cancer patients.

A total of 101 cancer patients with 121 febrile neutropenia episodes were randomised to receive empirical treatment with i.v. meropenem (1g/8 h) or ceftazidime (2 g/8 h). After 3 days, 89% of patients were on unmodified therapy in the meropenem group, compared with 83% in the ceftazidime group. Of the evaluable episodes (n = 106), the success rate with unmodified empirical therapy until the end of the treatment course was slightly higher with meropenem than with ceftazidime (48% vs 38%, P=0.39). Furthermore, initial success with further infections was observed in 22% of episodes treated with meropenem and in 13% of episodes treated with ceftazidime. Glycopeptides were used as first modification in 28% and 39% of meropenem and ceftazidime recipients, respectively. Both treatments were well tolerated and there were no reports of drug-related nausea/vomiting or seizures. No significant differences in response rate or in tolerability were observed when analysing only the first febrile episodes. In conclusion, meropenem seems to be as efficacious and well tolerated as ceftazidime and may be associated with a lesser requirement for the addition of glycopeptides.

Adolescent↗

PubMed2006

Cost-utility analysis comparing meropenem with imipenem plus cilastatin in the treatment of severe infections in intensive care.

This study compared the cost-effectiveness of meropenem with that of imipenem plus cilastatin in the treatment of severe infections in hospital intensive care in the UK. A Markov model was constructed to model lifetime costs and quality-adjusted life years (QALYs) of using meropenem and imipenem plus cilastatin for the treatment of severe infections in intensive care. Estimates of effectiveness, utility weights and costs were obtained from the published literature. Probabilistic sensitivity analysis was conducted to assess the robustness of the results. Estimated treatment costs for the patient cohort were pound 14,938 with meropenem and pound 15,585 with imipenem plus cilastatin. QALYs gained were 7,495 with meropenem and 7,413 with imipenem plus cilastatin. Probabilistic sensitivity analysis showed meropenem to be significantly less costly (-pound 636.47, 95% CI -pound 132.33 to -pound 1,140.62) and more effective (0.084, 95% CI 0.023 to 0.144). Meropenem thus appears significantly more effective and less expensive than imipenem plus cilastatin and should therefore be considered the dominant treatment strategy.

Aged↗

PubMedDate not supplied

In vitro activity of meropenem (SM-7338), imipenem, and five other antibiotics against anaerobic clinical isolates.

The in vitro susceptibility of 513 recent anaerobic clinical isolates was evaluated against meropenem (SM-7338), a new carbapenem, and six other antibiotics. Virtually all Gram-positive and Gram-negative anaerobic bacteria tested were susceptible to meropenem (defined as MICs less than or equal to 8 micrograms/ml) with 99.8% of the isolates inhibited by less than or equal to 4 micrograms/ml. The activity of meropenem was comparable to imipenem for most clinical isolates. Minor differences were observed for Clostridium and Veillonella (meropenem more active) and other Gram-positive bacilli (imipenem more active). Meropenem inhibited all anaerobes resistant to clindamycin and metronidazole. Bactericidal tests performed with meropenem demonstrated killing activity against all isolates except Clostridium and Lactobacillus.

Anti-Bacterial Agents↗

PubMed2006

A post hoc subgroup analysis of meropenem versus imipenem/cilastatin in a multicenter, double-blind, randomized study of complicated skin and skin-structure infections in patients with diabetes mellitus.

BACKGROUND: In a multicenter, international, double-blind, randomized clinical trial involving hospitalized patients with complicated skin and skin-structure infections (cSSSIs), meropenem and imipenem/cilastatin (both administered 500 mg intravenously every 8 hours) were not significantly different in their efficacy and safety profiles. OBJECTIVE: The objective of the post hoc subgroup analysis discussed in the current article was to report the efficacy and tolerability of meropenem and imipenem/cilastatin for the treatment of cSSSIs in patients with or without underlying diabetes mellitus (DM). METHODS: Hospitalized patients aged > or =13 years with evidence of cSSSIs were eligible for inclusion. Patients were randomized to receive meropenem or imipenem/cilastatin, each 500 mg intravenously every 8 hours, for at least 3 days and up to a maximum of 14 days. Patients were analyzed according to the presence or absence of DM and by the pathogen(s) isolated from wound cultures at baseline, end of N treatment, and test-of-cure visits. The primary efficacy end point was clinical outcome at the posttreatment follow-up (test-of-cure) visit in the clinically evaluable and modified intent-to-treat (intent-to-treat [ITT] subjects who met all eligibility criteria) populations; this was defined as 7 to 14 days after final administration of antibiotics. The secondary efficacy end points included clinical response at the test-of-cure visit in the ITT population (ie, those who received >1 dose of study drug) and at the end of N treatment visit in the clinically evaluable and fully evaluable populations. At baseline, the end of N treatment, and the test-of-cure visits, specimens were obtained from the most extensive site of skin and skin-structure infection and were cultured for bacteria. Adverse events were monitored daily during treatment and for 30 days after the completion of all antibiotic treatment. RESULTS: Of the 1076 patients enrolled in the original study, 398 had DM. The mean ages of patients with and without DM were 55 and 45 years, respectively; 17.3% of patients with DM and 6.1% of patients without DM had impaired renal function at study entry. Complex abscess was the most common infection diagnosis in both groups (patients with DM, 30.0%; patients without DM, 48.8%). The other top infections per group (patients with and without DM, respectively) were as follows: cellulitis, 24.6% and 12.4%; and ischemic/diabetic ulcers, 20.9% and 1.9%. Gram-negative aerobic and anaerobic pathogens accounted for >40% of bacterial isolates from both groups, with polymicrobial infections reported in 44.2% of patients with DM and 34.0% of patients without DM. In the clinically evaluable population, the satisfactory clinical response rate was 85.6% for patients with DM receiving meropenem and 72.4% for those receiving imipenem/cilastatin; for patients without DM, those rates were 86.6% and 89.0%, respectively. Meropenem and imipenem/cilastatin were generally well tolerated. Reported adverse events were similar between groups. CONCLUSION: This subgroup analysis found that 500 mg every 8 hours intravenously of meropenem or imipenem/cilastatin appeared efficacious and well tolerated for the treatment of cSSSIs among these patients with and without DM.

Adolescent↗

PubMed2004

Microbiological assay for the determination of meropenem in pharmaceutical dosage form.

Meropenem is a highly active carbapenem antibiotic used in the treatment of a wide range of serious infections. The present work reports a microbiological assay, applying the cylinder-plate method, for the determination of meropenem in powder for injection. The validation method yielded good results and included linearity, precision, accuracy and specificity. The assay is based on the inhibitory effect of meropenem upon the strain of Micrococcus luteus ATCC 9341 used as the test microorganism. The results of assay were treated statistically by analysis of variance (ANOVA) and were found to be linear (r=0.9999) in the range of 1.5-6.0 microg ml(-1), precise (intra-assay: R.S.D.=0.29; inter-assay: R.S.D.=0.94) and accurate. A preliminary stability study of meropenem was performed to show that the microbiological assay is specific for the determination of meropenem in the presence of its degradation products. The degraded samples were also analysed by the HPLC method. The proposed method allows the quantitation of meropenem in pharmaceutical dosage form and can be used for the drug analysis in routine quality control.

Analysis of Variance↗

PubMed2004

Meropenem decreases serum level of valproic acid.

Concomitant administration of meropenem has been reported to decrease serum level of valproic acid both in humans and in animals. This report describes three children who required simultaneous administration of valproic acid and meropenem. Meropenem rapidly decreased serum valproic acid concentration to subtherapeutic levels in all three children, and serum valproic acid levels were returned to therapeutic levels in a short time after discontinuing simultaneous meropenem therapy. Valproic acid was not changed to another antiepileptic agent, because no seizure activity was observed. To our knowledge, this is the first case report on the simultaneous administration of meropenem and valproic acid in childhood. In conclusion, it is clear that concomitant meropenem administration decreases serum valproic acid concentration, and we believe that there may be no need to change the antiepileptic drug during this period, provided that the patient has no seizure. More detailed studies are required.

Adolescent↗

PubMed1999

Pharmacokinetics of meropenem in critically ill patients with acute renal failure undergoing continuous venovenous hemofiltration.

OBJECTIVE: Meropenem is a broad-spectrum antibiotic used for severe infections. In patients with chronic end-stage renal failure, meropenem clearance is reduced and doses must be adjusted according to the creatinine clearance. The aim of this study was to assess pharmacokinetic data of meropenem in patients with acute renal failure and to determine the amount of drug removed by continuous venovenous hemofiltration, an often-used renal replacement therapy in patients with acute renal failure. METHODS: Nine critically ill anuric patients with acute renal failure undergoing continuous venovenous hemofiltration received 500 mg meropenem 2 or 3 times daily. Plasma and hemofiltrate concentrations were determined during 1 dosing interval at steady state. Pharmacokinetic parameters were calculated for a 2-compartment open model and dose requirements were calculated. RESULTS: The total meropenem clearance was 52.0 +/- 8.4 mL/min, with a hemofiltration clearance of 22.0 +/- 4.7 mL/min and a nonrenal-nonhemofiltration clearance of 29.9 +/- 5.4 mL/min; 235.9 +/- 88.6 mg, or 47.2% +/- 17.7%, of the dose were removed through continuous venovenous hemofiltration. The terminal elimination half-life was 8.7 +/- 3.5 hours and the volume of distribution at steady state was 12.4 +/- 1.8 L. Peak and trough concentrations for a dosing interval of 12 hours were 38.9 +/- 9.7 mg/L and 7.3 +/- 1.3 mg/L, respectively. The corresponding concentrations for a dosing interval of 8 hours were 44.7 +/- 10.4 mg/L and 11.9 +/- 0.7 mg/L, respectively. CONCLUSION: Pharmacokinetic data of anuric patients with acute renal failure were similar to those of patients with end-stage renal failure. Because hemofiltration contributes significantly to meropenem elimination, the recommended dose for critically ill anuric patients receiving continuous venovenous hemofiltration should be increased by 100% to avoid potential underdosing.

Acute Kidney Injury↗

PubMed1998

In vitro activity of meropenem against common pathogenic bacteria isolated in Taiwan.

The in vitro antimicrobial activity of meropenem, in comparison with nine other antimicrobial agents, against 12 different common pathogenic bacteria were evaluated to know the susceptibility of common bacteria to meropenem in Taiwan. Meropenem was active against most Gram-positive, Gram-negative, and anaerobic bacteria, including methicillin-sensitive Staphylococcus aureus, Streptococcus pyogenes, Enterococcus faecalis, Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Pseudomonas aeruginosa, Burkholderia cepacia, Acinetobacter baumannii, Haemophilus influenzae, and Bacteroides fragilis. For many of them, meropenem was the most active one in comparison with other broad-spectrum cephalosporins, aztreonam, imipenem, and ciprofloxacin. It is concluded that meropenem is a very active agent against most common pathogenic bacteria. It is uncommon for these common bacteria, except MRSA and Stenotrophomonas maltophilia, to be resistant to meropenem in Taiwan, where a high prevalence of resistance to other antimicrobial agents was found in many of the common bacteria.

Anti-Bacterial Agents↗

PubMed1998

Meropenem in elderly and renally impaired patients.

The safety profile of meropenem in the elderly (aged > 65 years, n=843) and/or renally impaired (creatinine clearance < 51 ml/min, n=436) was assessed by evaluating data from 26 phase III studies which compared the use of meropenem (0.5 or 1.0 g, i.v. every 8 h) with other antimicrobial agents in patients with bacterial infections. The overall pattern and frequency of adverse events following meropenem therapy in the elderly and/or renally impaired were similar to those in younger and/or non-renally impaired cohorts and to imipenem/cilastatin and injectable third generation cephalosporins. Both dosages of meropenem (0.5 and 1.0 g, i.v. every 8 h) were generally well tolerated. There was no clinically significant mean change in indicators of renal flux between baseline and the end of treatment in any patient sub-group. Importantly, meropenem-related seizures were rare (0.1%), even in patients with renal impairment. In summary, meropenem has an excellent safety profile and is therefore suitable for use in elderly and/or renally impaired patients.

Aged↗

PubMed1999

Meropenem in elderly and renally impaired patients.

The safety profile of meropenem in the elderly (aged > 65 years, n = 843) and/or renally impaired (creatinine clearance < 51 ml/min, n = 436) was assessed by evaluating data from 26 phase III studies which compared the use of meropenem (0.5 or 1.0 g, i.v. every 8 h) with other antimicrobial agents in patients with bacterial infections. The overall pattern and frequency of adverse events following meropenem therapy in the elderly and/or renally impaired were similar to those in younger and/or non-renally impaired cohorts and to imipenem/cilastatin and injectable third generation cephalosporins. Both dosages of meropenem (0.5 and 1.0 g, i.v. every 8 h) were generally well tolerated. There was no clinically significant mean change in indicators of renal flux between baseline and the end of treatment in any patient sub-group. Importantly, meropenem-related seizures were rare (0.1%), even in patients with renal impairment. In summary, meropenem has an excellent safety profile and is therefore suitable for use in elderly and/or renally impaired patients.

Aged↗

PubMed2000

Lipase activity of Acinetobacter baumannii after treatment with meropenem.

The effects of meropenem (CAS 96036-03-2) at subinhibitory concentrations (sub-MICs; 1/4, 1/8 or 1/16 of the minimal inhibitory concentrations) on the lipase activity of 15 strains of Acinetobacter baumannii were evaluated in vitro. The lipolytic activity was demonstrated by hydrolysis of the substrate Tween 20. Meropenem at the concentrations tested affected the production of bacterial lipase. The degree of induced changes was strain and antibiotic concentration dependent. Eight strains showed an increased lipolytic activity after treatment with meropenem at all three sub-MICs tested; four strains after exposure to two concentrations, and two strains after the treatment with meropenem at one of the concentrations tested. Meropenem at all concentrations reduced the lipase activity only in one strain. In six strains the enzyme activity was decreased only after treatment with some antibiotic concentrations. The possible relevance of increased lipolytic activity in most A. baumannii strains after the effect with meropenem at subinhibitory concentrations has to be clarified by additional studies.

Acinetobacter↗

PubMed2006

Renal handling of CS-023 (RO4908463), a novel parenteral carbapenem antibiotic, in rabbits in comparison with meropenem.

The plasma half-life of CS-023 (RO4908463), a novel parenteral carbapenem antibiotic, is longer than that of meropenem in animals and humans. To address this issue, renal clearance studies were conducted in rabbits. A constant rate infusion of CS-023 and meropenem was conducted in male Japanese White rabbits. Concentrations in the plasma, urine and renal cortex were measured to evaluate renal clearance and renal tissue uptake. CS-023 showed a clearance ratio (renal clearance/glomerular filtration rate) of around 1, which was not affected by co-administration of probenecid or p-aminohippurate. On the other hand, meropenem exhibited a clearance ratio of around 3, which was significantly decreased to 1 by co-administration of probenecid. p-Aminohippurate, in contrast, had no effect. The renal cortex/plasma concentration ratio of CS-023 was around 0.6 with or without probenecid co-administration. This ratio of meropenem was around 3, which was decreased significantly by co-administration of probenecid to around 0.6. These data suggest that meropenem is secreted in the renal tubules via organic anion transporters, but CS-023 is not. The present findings in rabbits would indicate that a lack of renal tubular secretion of CS-023 is a reason for the long plasma half-life compared with meropenem.

Animals↗

PubMed2005

Transfer of meropenem in the ex vivo human placenta perfusion model.

OBJECTIVES: To determine maternal-fetal transplacental passage of meropenem in the ex vivo human perfusion model. STUDY DESIGN: Term placentae (n = 6) were collected immediately after delivery. A single cotyledon was localized, perfused and stabilized with physiologic Eagles minimal essential medium containing 3% bovine albumin and heparin as described by Chalier (Chalier JC. Criteria for evaluating perfusion experiments and presentation results. Contrib Gynecol Obstet 1985; 13:32 - 39). Meropenem was added to the maternal medium in concentrations similar to maternal serum peak and trough levels, then perfused through the maternal circulation of the cotyledon. To assess transfer and accumulation, fluid aliquots from both the maternal and fetal compartments were collected over an hour at defined intervals in an open and closed system. Antipyrine 14C was added to the medium in order to calculate the transport fraction and clearance indexes. Meropenem and antipyrine 14C concentrations were determined by High-pressure Liquid Chromatography and liquid scintillation, respectively. RESULTS: Mean antipyrine transport fraction was 2.33 + 0.25. Maternal and fetal mean meropenem peak concentrations were 54.3 + 3.3 microg/ml and 2.2 + 0.18 microg/ml, respectively. Whereas, maternal and fetal mean trough concentrations were 12.7 + 1.3 microg/ml and 0.41 + 0.10 microg/ml, respectively. Mean peak clearance index was 0.077 + 0.007 and the mean trough was 0.052 + 0.015. Mean accumulation for the peak and trough concentrations of meropenem were 0.9 and 2.95 microg/ml, respectively. CONCLUSIONS: Transplacental passage of meropenem was incomplete in the ex vivo human placental perfusion model. Accumulation was also noted in the fetal compartment.

Anti-Infective Agents↗

PubMed2003

Economic benefit of a meropenem dosage strategy based on pharmacodynamic concepts.

The economic benefit of a meropenem dosage strategy based on pharmacodynamic concepts is described. The pharmacodynamics of novel meropenem dosing regimens were compared with FDA-approved regimens by using Monte Carlo simulation with 5000 subjects. Using the meropenem NCCLS-susceptibility breakpoint of 4 micrograms/mL, the percentage of the dosing interval that drug concentration remained above the minimum inhibitory concentration (%t > MIC) was calculated for each regimen. Probability distributions for half-life and volume of distribution using previously published pharmacokinetic data from healthy volunteers were developed. Cost-minimization analysis was performed from the institution's perspective using both drug acquisition and supply costs. Daily costs for the lower dosage regimens were calculated using 2001 average wholesale prices. The mean %t > MIC for meropenem 500 mg administered every six hours (43.91% [95% confidence interval (CI), 36.77-51.46%]) was similar to that of 1000 mg every eight hours (45.77% [95% CI, 40.06-50.69%]). The mean %t > MIC for meropenem 1000 mg administered every six hours (61.02% [95% CI, 54.71-67.43%]) was similar to the regimen of 2000 mg every eight hours (57.77% [95% CI, 51.84-63.76%]). The 500-mg regimen reduced drug costs by $38.64 per day compared with the standard regimen of 1000 mg administered every eight hours. A pharmacodynamically influenced dosage strategy for meropenem resulted in %t > MIC exposure similar to standard regimens and required a lesser amount of the drug, thereby reducing costs without compromising efficacy.

Anti-Infective Agents↗