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PubMed2002

A comparison of the antimicrobial activity of meropenem and selected broad-spectrum antimicrobials tested against multi-drug resistant Gram-negative bacilli including bacteraemic Salmonella spp.: initial studies for the MYSTIC programme in India.

The evolution in India of multi-drug resistant pathogens possessing extended-spectrum beta-lactamases (ESBLs) threatens to compromise the clinical utility of third-generation cephalosporins and monobactams. Using selected resistant strains from a recent Indian 10 centre surveillance study that measured the prevailing incidence of resistance to beta-lactam antibiotics, the potential clinical utility of meropenem was assessed against nine other antimicrobial agents. A total of 212 Gram-negative bacilli were tested, of which 125 were confirmed by reference methods to be ESBL-producers. Meropenem was the most active of the test antimicrobials against these strains and the rank order of susceptibility was meropenem (99.1% susceptible) > piperacillin/tazobactam (76.9%) > ciprofloxacin (42.5%) > aminoglycosides (34.4-39.6%) = other beta-lactams (30.0-39.6%). Of the tested strains only two (Acinetobacter spp. and Pseudomonas putida) showed an intermediate susceptibility (8 mg/l) to meropenem. Of the 57 tested strains of Salmonella spp., three had an ESBL phenotype, confirmed two of the strains. This study confirms the high levels of resistance to beta-lactams agents in India reported elsewhere and also demonstrates, for Escherichia coli and Klebsiella spp., high levels of co-resistance between the tested beta-lactam agents and ciprofloxacin and the aminoglycosides, gentamicin and tobramycin. However, carbapenems such as meropenem, remain a therapeutic option.

Anti-Bacterial Agents↗

PubMed1992

Antibacterial in vitro-activity of meropenem against 200 clinical isolates in comparison to 11 selected antibiotics.

The antimicrobial activity of meropenem, a new parenteral carbapenem, was tested in vitro by an agar dilution method against 200 clinical isolates (gram-negative/positive aerobes and anaerobes). Meropenem was compared with imipenem, ceftazidime, cefotaxime, piperacillin, ciprofloxacin, gentamicin; and metronidazole, cefoxitin, chloramphenicol, clindamycin, vancomycin when appropriate. Meropenem and imipenem exhibited an extended spectrum of activity with low minimal inhibitory concentrations (MICs). Only one strain each of Enterococcus faecium and Pseudomonas (Xanthomonas) maltophilia were resistant. Of the carbapenems, imipenem was slightly more active against Enterococcus faecalis, Streptococcus agalactiae, and staphylococci, but meropenem was obviously more active against enterobacteriaceae and Clostridium perfringens. Both, meropenem and imipenem had similar activities towards Pseudomonas aeruginosa, Acinetobacter calcoaceticus, Streptococcus pyogenes and Bacteroides sp. All other antibiotics tested were less potent than the carbapenems with the exception of ciprofloxacin which generally exhibited similar antibacterial activities, except for anaerob microorganisms.

Anti-Bacterial Agents↗

PubMed2004

Antibiotic prophylaxis with meropenem after allogeneic stem cell transplantation.

In the present study, we analyze the efficacy of prophylaxis with meropenem in patients receiving a matched related donor allogeneic transplant. In total, 38 patients were sequentially treated with meropenem starting on the day of the first febrile episode (n=17, group A) vs prophylactic meropenem starting on the first day with <500/mm(3) granulocytes (n=21, group B), and maintained until resolution of fever or after granulocyte count >500/mm(3). Of these, 16 (94%) patients in group A developed fever as compared to 16 (76%) in group B (P=0.02). While only one patient in group A did not require first-line antibiotherapy, there were seven (33%) in group B who did not require it (P=0.01) since fever lasted less than 72 h. In addition, 52% patients in group B did not require second-line antibiotics as compared to 11% among patients in group A (P=0.04). In multivariate analysis prophylaxis with meropenem (HR=2.83, 95% CI (1-8.02); P=0.04) and disease status at transplant (HR for early stage=0.15, 95% CI (0.04-0.62); P=0.04) significantly influenced the development of fever. In conclusion, the current pilot study suggests that the use of prophylaxis with meropenem during the period of neutropenia in patients undergoing allogeneic transplantation favorably affects the morbidity of the procedure by reducing febrile episodes.

Acute Disease↗

PubMed2001

Investigation of synergism of meropenem and ciprofloxacin against Pseudomonas aeruginosa and Acinetobacter strains isolated from intensive care unit infections.

The aim of this study was to determine synergistic effects of meropenem and ciprofloxacin against Pseudomonas aeruginosa and Acinetobacter strains isolated from intensive care unit (ICU) infections. A total of 18 P. aeruginosa and 17 Acinetobacter strains were tested. MICs were determined using the broth microdilution method. The synergy of meropenem and ciprofloxacin was investigated in glass tubes using time-kill methodology. The synergistic effect of meropenem and ciprofloxacin in combination was found to be 22% at 0.5 x the MIC and 61% at 1 x the MIC in P. aeruginosa strains. Two strains (11%) showed synergy at both 0.5 and 1 x the MIC. Of the 18 P. aeruginosa strains, 1 strain (6%) did not show a synergistic effect at either 0.5 or 1 x the MIC. In Acinetobacter strains, the synergistic effect of meropenem and ciprofloxacin in combination was found to be 29% at 0.5 x the MIC and 18% at 1 x the MIC. One strain (6%) showed synergy at both 0.5 and 1 x the MIC. Of the 17 Acinetobacter strains, 8 strains (47%) did not show a synergistic effect at either 0.5 or 1 x the MIC. According to the results of this study, the combination of meropenem and ciprofloxacin is more effective than either antibiotic alone in ICU infections due to P. aeruginosa strains.

Acinetobacter↗

PubMed1998

Empiric monotherapy for febrile neutropenia--a randomized study comparing meropenem with ceftazidime.

In this Swedish multicentre study we compared the efficacy of meropenem with ceftazidime for treatment of febrile neutropenia. 192 patients were randomized and the number of evaluable patients was 92 in the meropenem group and 95 in the ceftazidime group. 40 (43%) patients in the meropenem arm and 49 (52%) in the ceftazidime arm had acute leukaemia. 56 (61%) and 52 (55%) patients respectively had a neutrophil count of < 0.1 x 10(9)/l at randomization and the median duration of neutropenia was 6.5 and 8 d, respectively. Thirty-one (34%) and 28 (29%) patients had a microbiologically defined infection, 14 (15%) and 17 (18%) a clinically defined infection and the remaining 47 (51%) and 50 (53%) had unexplained fever. After 72 h of treatment, 46 (50%) patients in the meropenem arm and 53 (56%) patients in the ceftazidime arm were alive on unmodified monotherapy. 42 (46%) and 47 (49%) of these completed the study on monotherapy alone. Only 2 patients (2%) in each arm had to stop treatment owing to allergic reactions. None of the observed differences were statistically significant and we therefore conclude that meropenem was an effective and safe alternative to ceftazidime for empiric treatment of fever during neutropenia.

Adolescent↗

PubMed1997

Penetration of meropenem in plasma and abdominal tissues from patients undergoing intraabdominal surgery.

We assessed the penetration of a new carbapenem antibiotic, meropenem, into abdominal tissues. A single 1,000-mg intravenous dose was administered to 66 patients undergoing elective intraabdominal surgery. Plasma, body fluid (peritoneal fluid and bile), and tissue samples (colon, gallbladder, omentum, stomach, fascia, muscle, and skin) were taken at various times up to 8 hours after administration of the dose. Meropenem concentrations were determined by means of validated bioassay techniques. Peak meropenem concentrations in most tissue specimens and one body fluid occurred within approximately 1 hour; the exceptions were bile and muscle specimens, in which peak concentrations were present in approximately 2 to approximately 4 hours. The bile concentration increased with time, thus indicating active excretion of drug into bile. Only one adverse event (mild nausea) was attributable to meropenem. Our results show that meropenem achieves adequate tissue concentrations for the treatment of intraabdominal infections due to susceptible bacteria.

Anti-Bacterial Agents↗

PubMed1997

The pharmacology of meropenem, a new carbapenem antibiotic.

Meropenem, a new carbapenem antibiotic, is more active against gram-negative bacilli and less active against gram-positive cocci than is imipenem, and there are several important structural differences between meropenem and the older carbapenem. These differences may be responsible for the lower potential for the induction of epileptogenic activity observed with meropenem as well as for its increased stability to degradation by dehydropeptidase-I. The pharmacokinetics of meropenem are typical of those of a parenteral beta-lactam antibiotic with low protein binding and predominantly renal excretion. Dosage reduction is required in patients with reduced renal function; no dosage adjustment is required for patients with hepatic impairment. Meropenem has excellent penetration in abdominal tissues, bile, blister fluid, inflammatory exudate, cerebrospinal fluid (in the presence of inflammation), gynecologic tissues, respiratory tract tissues, and urinary tract tissues; tissue levels are generally equal to or above the levels needed for the treatment of patients with susceptible pathogens.

Adult↗

PubMed1989

Comparative in-vitro activity of meropenem against clinical isolates including Enterobacteriaceae with expanded-spectrum beta-lactamases.

Meropenem, a new parenteral carbapenem, was tested in vitro by an agar-dilution method against 373 standard strains (aerobes and anaerobes) and against nine expanded-spectrum beta-lactamase-producing strains and their transconjugants (5 CTX-1, 2 CAZ-1, 2 CAZ-2). Meropenem was compared with methicillin, imipenem, piperacillin, cefoxitin, cefotaxime, ceftazidime, gentamicin, chloramphenicol, clindamycin, ciprofloxacin, vancomycin and metronidazole. Meropenem and imipenem exhibited an extended spectrum of activity, with low MICs. Only methicillin-resistant staphylococci, and Pseudomonas (Xanthomonas) maltophilia were resistant. Of the carbapenems, imipenem was more active against methicillin-susceptible staphylococci, streptococci and Enterococcus faecalis, but meropenem was markedly more active against all the Enterobacteriaceae and some pseudomonads. Both had similar activity against Ps. aeruginosa, Acinetobacter spp. and anaerobes. The carbapenem MICs were very low for Enterol acteriaceae producing the expanded-spectrum beta-lactamases. Against CTX-1-producing strains resistant to cefotaxime and ceftazidime and against CAZ-1 or CAZ-2-producers highly resistant to ceftazidime meropenem was the most active, with MICs lower (0.03-0.12 mg/l) than those of imipenem (0.06-0.5 mg/l), for wild type producers and their transconjugants.

Bacteria↗

PubMed1989

Comparative activity of meropenem against Pseudomonas aeruginosa strains with well-characterized resistance mechanisms.

Four major mechanisms cause resistance to beta-lactams in Pseudomonas aeruginosa: (i) cell wall impermeability gives broad-spectrum intrinsic resistance to all beta-lactams except imipenem, (i) loss of D-group outer membrane proteins correlates with narrow spectrum imipenem resistance, (iii) plasmid mediated beta-lactamases compromise antipseudomonal penicillins, cefoperazone and cefsulodin, and (iv) chromosomal beta-lactamase hyper-production compromises most beta-lactams except carbenicillin and imipenem. Meropenem was tested in vitro against P. aeruginosa isolates, mutants and transconjugants with these mechanisms. Meropenem had impaired activity (MIC 1-2 mg/l compared to 0.25 mg/l for sensitive isolates) for organisms with broad-spectrum intrinsic resistance. MICs of meropenem also were elevated (to 1-2 mg/l) for mutants with D2-protein-deficiency-associated imipenem resistance. Most plasmids encoding TEM, OXA or PSE beta-lactamases did not increase the MIC (0.12 mg/l) of meropenem for P. aeruginosa PU21. Decreased susceptibility (MIC 4 mg/l), however, was observed when plasmids coding the uncommon NPS-1, PSE-2 and OXA-3 enzymes were present in this strain. MICs of meropenem remained identical for chromosomal beta-lactamase-inducible P. aeruginosa strains and their enzyme-derepressed and basal mutants, indicating that the chromosomal beta-lactamase could not protect against the new carbapenem, regardless of its mode of expression.

Bacterial Outer Membrane Proteins↗

PubMed1989

In-vitro susceptibility of Haemophilus influenzae to meropenem compared with imipenem, five other beta-lactams, chloramphenicol and ciprofloxacin.

The in-vitro activity of the new carbapenem, meropenem, was compared with that of imipenem, five other beta-lactams, chloramphenicol and ciprofloxacin against 223 isolates of Haemophilus influenzae. This number included 115 ampicillin-susceptible, and 56 beta-lactamase positive isolates and 52 beta-lactamase negative isolates with reduced susceptibility to ampicillin. The activities of chloramphenicol and ciprofloxacin did not vary between groups of isolates delineated by their susceptibility to ampicillin. In contrast with ampicillin and piperacillin, the two carbapenems and three cephalosporins tested showed no reduction in activity against beta-lactamase producing isolates. beta-Lactam concentrations required for inhibition of 50% and 90% of beta-lactamase negative isolates with reduced susceptibility to ampicillin (MIC greater than or equal to 1 mg/l) were increased in comparison with similar concentrations required for the ampicillin-susceptible group. The differences in meropenem and imipenem activities between these two groups were much smaller than those observed for each of the other beta-lactams. MICs of meropenem were consistently the lower of the two carbapenems for all isolates. In addition, there were no notable increases in the concentrations of meropenem required for inhibition of the isolates least susceptible to imipenem (MIC greater than or equal to 4 mg/l), suggesting that differences in penetration and/or target-binding properties exist not only between the carbapenems and other beta-lactams, but also between meropenem and imipenem.

Ampicillin↗

PubMed1989

The antibacterial activity of meropenem in combination with gentamicin or vancomycin.

The kinetics of bacterial killing by meropenem alone and in combination with gentamicin (for Pseudomonas aeruginosa) and vancomycin (for Staphylococcus aureus) were studied for two strains of each species. Against the two strains of P. aeruginosa, meropenem at concentrations up to 4 x MIC was rapidly bactericidal--but regrowth occurred by 24 h. The addition of half the MIC of gentamicin to the MIC of meropenem led to a more rapid decline of the colony count and to the prevention of regrowth of the strain which was gentamicin-susceptible. Similar results were obtained for a methicillin-susceptible strain of S. aureus when vancomycin was added at a concentration of half the MIC. A methicillin-resistant strain also was killed by a combination of vancomycin at half the MIC plus meropenem at the MIC. The study showed that the killing action of meropenem against P. aeruginosa and staphylococci is enhanced by the addition of gentamicin or vancomycin respectively.

Carbapenems↗

PubMed1989

The pharmacokinetics of meropenem in volunteers.

Two human volunteer studies were performed with meropenem: a dose proportionality study of 0.25, 0.5 and 1.0 g and a probenecid interaction study. Six volunteers took part in each study. Meropenem was generally well tolerated: One volunteer was withdrawn from the dose proportionality study because of looseness of stool and abdominal pain after a dose of 1.0 g. The plasma concentrations of meropenem were linearly related to dose. The half-life of meropenem was approximately 1 h and the urinary recovery of unchanged drug was 79%. In the presence of probenecid the plasma half-life of meropenem was increased by 33% but the urinary recovery was unaffected.

Adult↗

PubMed1989

In-vitro activity of meropenem against clinical isolates in a multicentre study in Italy.

A multicentre in-vitro study was undertaken to evaluate the susceptibility of bacterial pathogens isolated in different Italian hospitals to meropenem. A total of 1399 aerobic and 452 anaerobic strains was analysed. Comparative agents were imipenem, cefotaxime, ceftazidime, ceftriaxone, piperacillin, ciprofloxacin, gentamicin, amikacin, plus vancomycin when appropriate. The MIC ranges (mg/l) of meropenem were: 0.015-2 for Klebsiella spp., Proteus spp., Morganella morganii and Providencia spp.; less than 0.008-1 for Escherichia coli; 0.016-32 for Serratia spp.; 0.03-2 for Enterobacter spp. and Citrobacter spp.; 0.03- greater than 128 for Acinetobacter anitratus; 0.03-32 for Pseudomonas spp.; less than 0.008-0.5 for Haemophilus spp. and Neisseria spp.; 0.015-64 for Staphylococcus spp.; 0.06- greater than 128 for Enterococcus spp.; less than 0.008-0.25 for Streptococcus spp.; 0.016-8 for Fusobacterium spp.; 0.03-8 for Bacteroides spp.; less than 0.06-0.5 for anaerobic Gram-positive cocci; 0.08-2 for Clostridium spp. Meropenem exhibited superior antibacterial activity against the aerobic and anaerobic strains tested when compared to the other beta-lactam drugs. The new carbapenem was as active as ciprofloxacin and more active than imipenem and the aminoglycosides against Enterobacteriaceae and Ps. aeruginosa. It was also more active than ciprofloxacin against most strains of Gram-positive cocci. Meropenem was slightly less potent than imipenem against staphylococci and enterococci, with the exception of oxacillin-susceptible Staph. aureus against which meropenem and imipenem exhibited similar antibacterial activity.

Aminoglycosides↗

PubMed1994

In-vitro activity of biapenem, compared with imipenem and meropenem, against Pseudomonas aeruginosa strains and mutants with known resistance mechanisms.

The activity of biapenem (L-627, LJC-10627), a new carbapenem, was investigated against Pseudomonas aeruginosa strains, mutants and isolates with known resistance mechanisms to other beta-lactams. The behaviour of biapenem closely resembled that of imipenem, although it showed minor differences compared with meropenem, Inducible (i.e. normal) or derepressed chromosomal beta-lactamase expression gave slight protection against biapenem and imipenem, but insufficient to raise the MICs above clinically significant limits. This behaviour correlated with the slight lability of these compounds to the purified enzyme and with their strong capacity to induce beta-lactamase synthesis. Inducible or derepressed enzyme gave no protection against meropenem, possibly reflecting this compound's particular ability to deactivate the enzyme. Biapenem also has some ability to reversibly deactivate the enzyme. None of several plasmid-mediated beta-lactamases (TEM-2, PSE-1, -3 or -4; OXA-3,-6,-10,-11; NPS-1 or LCR-1) introduced into a P. aeruginosa PU21 recipient strain reduced susceptibility to biapenem or other carbapenems. Amongst permeability mutants, those lacking the D2 'carbapenem-specific' porin had reduced susceptibility to biapenem as well as to imipenem and meropenem. Biapenem and imipenem insusceptibility in these D2 porin-deficient mutants required continued expression of the chromosomal beta-lactamase, although this did not apply to meropenem. P. aeruginosa isolates and mutants with broad-spectrum insusceptibility ('intrinsic resistance') to penicillins, cephalosporins and unrelated drugs remained fully susceptible to biapenem and imipenem, whilst showing slightly reduced susceptibility to meropenem. Overall, these findings suggest that biapenem, like the earlier carbapenems, should prove to be a useful antipseudomonal agent, overcoming the mechanisms that commonly confer resistance to other classes of antipseudomonal beta-lactams.

Carbenicillin↗

PubMed1995

Potent activity of meropenem against Escherichia coli arising from its simultaneous binding to penicillin-binding proteins 2 and 3.

A mutant strain of Escherichia coli with reduced susceptibility to imipenem, designated TL2740, was selected following serial passage of the parent strain, E. coli C600, in broth containing increasing concentrations of the carbapenem; the MIC of imipenem for TL2740 was eight-fold greater than that of the parent strain. The mutant also exhibited reduced susceptibilities to panipenem and biapenem and high-level resistance to mecillinam, but was as susceptible to meropenem, ceftazidime, piperacillin and the other beta-lactams tested as strain C600. The affinity of penicillin-binding protein (PBP) 2 of TL2740 for imipenem and meropenem was ten-fold less than that of C600, thereby providing an explanation for the mutant's reduced susceptibility to some carbapenems and mecillinam. However, this theory was confounded by the observation that the in-vitro activities of meropenem against both parent and mutant strains were virtually the same and by the fact that PBP 2 is the principal target of the antibiotic. Imipenem and aztreonam, which bind to PBP 2 and PBP 3 respectively, demonstrated synergic activity when tested in combination against both C600 and TL2740. These results suggest that the potent activity of meropenem against the mutant strain might also be due to a synergic effect resulting from simultaneous binding to both PBP 2 and PBP 3 and that the variable activities of the carbapenems against TL2740 were related to their different PBP binding profiles. Compared with C600, TL2740 appeared shorter on electron microscopy and had a longer generation time, discrepancies which are compatible with defective PBP 2 activities in the mutant strain. We also identified three clinical isolates of E. coli with beta-lactam susceptibility profiles which resembled that of TL2740 i.e. high-level resistance to mecillinam and low-level resistance to carbapenems, with the exception of meropenem to which these strains were susceptible; in common with TL2740, the combination of imipenem and aztreonam was synergic against these isolates. The genetic basis of resistance in all of the mecillinam-resistant strains, including TL2740, mapped close to lip at 15' on the E. coli chromosome with transductional analysis. The results strongly suggest that the reduced susceptibilities of the clinical isolates to carbapenems were due to mutations in the genes encoding the PBP 2s of these strains which affected their affinities for beta-lactam antibiotics.

Bacterial Outer Membrane Proteins↗

PubMed1995

Penetration of meropenem into heart valve tissue.

Thirty-three patients requiring cardiac valve surgery were administered meropenem 1000 mg by a 5 to 10 min iv injection. Samples of blood, cardiac valve and atrial muscle tissue were removed at valvectomy and analysed for meropenem by high performance liquid chromatography (HPLC) with UV detection. The plasma concentrations observed in the samples from these patients were higher than those reported when meropenem 1000 mg was administered to healthy volunteers by 5 min iv injection. No clinical adverse events attributable to meropenem were reported and the single 1000 mg dose was well tolerated. The penetration of meropenem into cardiac muscle and valve tissue was rapid and in excess of that expected solely on the basis of distribution into extracellular fluid. The concentrations achieved in the tissues were in excess of the MICs of the pathogens commonly causing endocarditis.

Aortic Valve↗

PubMed1995

Efficacy of meropenem in experimental meningitis.

Meropenem and comparator antibiotics, including ceftriaxone, ceftazidime, benzyl penicillin and a combination of ampicillin plus gentamicin, were evaluated in a model of bacterial meningitis in the guinea-pig. The model is an acute infection in which challenge with each organism, if untreated, causes an increase in numbers of white blood cells, elevation of protein concentrations and 6-8 log10 cfu/mL of bacteria in the CSF. Infections caused by Haemophilus influenzae, Neisseria meningitidis, three strains of Streptococcus pneumoniae (two penicillin-resistant), Escherichia coli, Pseudomonas aeruginosa and Listeria monocytogenes all responded to meropenem, which was as active as the comparator agents in all studies, and was more active in most. Of particular note were the results seen against S. pneumoniae (penicillin-resistant) infections, in which meropenem was significantly more effective than ceftriaxone. Also notable were results from the P. aeruginosa infection where meropenem, at low doses, was more effective than ceftazidime. Activity against L. monocytogenes was equivalent to that produced by treatment with the combination of ampicillin plus gentamicin, even when treatment was delayed. These results show that, in an animal model, meropenem penetrates into CSF in concentrations sufficient to produce significant reductions in the numbers of common and less common pathogens.

Ampicillin↗

PubMed1996

Clinical pharmacokinetics of meropenem after the first and tenth intramuscular administration.

We investigated the pharmacokinetics of meropenem after the first and tenth i.m. administration in patients with respiratory tract infections. Ten patients (mean age 63.8 +/- 5.2 years) received meropenem 500 mg tds for at least ten doses, and plasma and urine antibiotic concentrations were determined by microbiological assay. After the first injection a mean peak plasma concentration of 7.93 +/- 1.29 mg/L was observed at 1 h. Trough levels at 8 h (0.29 +/- 0.16 mg/L) were detectable in five of ten treated patients. The mean terminal half-life was 1.08 +/- 0.2 h with an area under the curve (AUC) value of 23.8 +/- 4.59 mg/L.h, and a cumulative urinary recovery at 8 h of 48.43 +/- 3.12%. There was no evidence of change in the pharmacokinetics of meropenem after repeated i.m. administration, though the mean peak plasma concentration and AUC value were slightly increased. The accumulation ratio (assessed using AUC values) was 1.18 +/- 0.19 after multiple doses and was considered to be of little kinetic and clinical importance. Moreover, many of the trough concentrations of meropenem were below the limit of detection of the assay. After i.m. administration meropenem concentrations exceeded 0.5 mg/L for longer than previously described following i.v. infusion. No adverse events were reported.

Aged↗