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PubMed2006

Comparative in vivo efficacy of meropenem, imipenem, and cefepime against Pseudomonas aeruginosa expressing MexA-MexB-OprM efflux pumps.

To identify the optimal pharmacodynamic exposures of meropenem, imipenem, and cefepime, and the emergence of resistance in vivo for Pseudomonas aeruginosa overexpressing MexA-MexB-OprM efflux pumps, we used the murine thigh model. Mice were challenged with P. aeruginosa isolates: PAO1 (K767 wild type), K767+ (MexA-MexB-OprM efflux mutant), and DeltaK767 (knockout strain). Efficacy (Delta log colony-forming unit [CFU]) was determined at various exposures of %T > MIC at both standard (10(5) CFU/thigh) and high (10(7) CFU/thigh) inoculums. At 10(5) CFU/thigh, meropenem and imipenem produced a maximal activity against PAO1 (-2.82, -1.88) and K767+ (-2.24, -2.68) at 40%T > MIC; cefepime at 70%T > MIC produced a comparable kill (-2.74 and -2.19, respectively). Similar magnitudes of kill were observed at the 10(7) inocula. Except for DeltaK767 with cefepime, no development of resistance emerged at various %T > MIC. All agents exhibited reduced activity against DeltaK767. DeltaK767 cefepime-resistant strains were isolated up to 100%T > MIC. The overexpression of MexA-MexB-OprM efflux pumps did not result in the loss of efficacy of the antibiotics tested regardless of the amount of bacterial inocula; however, their presence also did not lead to increased selection for resistance. The effects of efflux mechanisms on beta-lactam agents in vivo warrant further research.

Animals↗

PubMed2005

Novel IMP-1 metallo-beta-lactamase inhibitors can reverse meropenem resistance in Escherichia coli expressing IMP-1.

IMP-1 metallo-beta-lactamase is a zinc metalloenzyme that confers antibiotic resistance to bacteria through the hydrolysis of beta-lactam antibiotics. Pathogens that express the enzyme show reduced susceptibility to carbapenems, such as meropenem and imipenem. In order to identify novel IMP-1 inhibitors, the National Cancer Institute (NCI) chemical diversity set was screened using 96-well high throughput screening format. The collection yielded several novel succinic acid derivatives that exhibited mixed inhibition of IMP-1 with compound 20707 having the highest affinity with a Ki value of 3.3 microM+/-1.7. The compounds are moderately potent inhibitors of IMP-1 with IC50 values ranging from 5.0 to 17 microM. An original chemical class of IMP-1 inhibitor, 2-((E)-(1,3-dihydroxy-2-methylpropan-2-ylimino)methyl)-4,6-diiodophenol, was discovered and was the most potent with an IC50 of 1.2 microM. NCI compounds, 20707, 140905 and 9746 sensitized a carbapenem-resistant laboratory strain of Escherichia coli to clinically achievable levels of meropenem.

Anti-Bacterial Agents↗

PubMed2006

Comparison of probability of target attainment calculated by Monte Carlo simulation with meropenem clinical and microbiological response for the treatment of complicated skin and skin structure infections.

Monte Carlo simulation is often used to predict the cumulative fraction of response (CFR) for antibiotics, but the relevance of these predictions to outcomes in humans has not been well studied. We compared the CFR for meropenem 500 mg every 8h against pathogens causing complicated skin and skin structure infections from a randomised, multicentre clinical trial with clinical response (CR) and microbiological response (MR). A population pharmacokinetic model was utilised to estimate pharmacokinetic parameters for 96 clinically evaluable patients with pathogen and minimum inhibitory concentration (MIC) data available. A 1000-subject Monte Carlo simulation was performed to estimate bacteriostatic (20% of time serum concentration above the MIC (T>MIC)) and bactericidal (40% T>MIC) exposures for comparison. Only the bactericidal CFR versus the CR was not statistically different (92% CR versus 91.9% CFR; 95% confidence interval of the difference, -7.7% to 4.2%), whilst bacteriostatic CFRs overestimated actual CR and MR. This study demonstrates that the use of Monte Carlo simulation to predict the CR of meropenem in complicated skin and skin structures is accurate.

Anti-Infective Agents↗

PubMed2006

Pharmacodynamic profiling of imipenem, meropenem and ertapenem against clinical isolates of extended-spectrum beta-lactamase-producing Escherichia coli and Klebsiella spp. from Brazil.

The pharmacodynamic potency of imipenem, meropenem and ertapenem against extended-spectrum beta-lactamase (ESBL)-producing isolates was investigated. Minimal inhibitory concentration (MIC) determination, confirmation of ESBLs by Etest and the disk approximation test were performed for 133 ESBL-producing isolates of Escherichia coli and Klebsiella spp. Pharmacodynamic exposure, measured as percent of the dosing interval during which free drug was above the MIC (% fT>MIC), was modelled via a 5000-subject Monte Carlo simulation. Bactericidal cumulative fraction of response (CFR), defined as 40% fT>MIC, was calculated against each bacterial population. All agents achieved high bactericidal CFR against all ESBL isolates as a group, but ertapenem (96.26%) was slightly less effective than imipenem (99.96%) and meropenem (99.90%) (P<0.05). Similar results were observed against Klebsiella spp. only (P<0.05). Against E. coli, CFRs were close to 100%. Ertapenem is probably an effective agent against ESBL-producing bacteria, although its ability to achieve bactericidal pharmacodynamic exposures will depend on the bacterial susceptibility.

Brazil↗

PubMed2005

Serratia marcescens prosthesis infection successfully treated with meropenem after imipenem failure.

A 78-year-old woman developed an early knee-prosthesis infection due to multiresistant Serratia marcescens that was successfully treated with high-dose meropenem, after failure of a long-term therapy combining imipenem and multiple surgical interventions. Because of its lower neurotoxicity, meropenem might be preferred to imipenem/cilastatin for the treatment of osteo-articular infections due to multiresistant Gram-negative bacilli in the elderly.

Aged↗

PubMed1998

Determination of meropenem in serum by high-performance liquid chromatography with column switching.

A rapid, accurate and sensitive liquid chromatographic assay with on-line solid-phase extraction for determination of meropenem in serum is described. Sample was directly injected onto the extraction column for sample clean-up and extraction. Thereafter, using an on-line column-switching system the drug was quantitatively transferred and separated on a C18 analytical column. Ultraviolet absorption at 298 nm was used for detection. The assay was linear from 1 to 100 micrograms/ml. Recovery was 98.5%. Based on a 20-microliters sample volume (serum- water, 1:1, v/v), detection limit was 0.1 microgram/ml. An application of the method to study the pharmacokinetics of meropenem is given.

Chromatography, High Pressure Liquid↗

PubMed1997

Comparative in vitro interactions of ceftazidime, meropenem, and imipenem with amikacin on multiresistant Pseudomonas aeruginosa.

To evaluate the possibility of an enhanced killing effect by ceftazidime, meropenem, or imipenem with amikacin 26 multiresistant Pseudomonas aeruginosa isolates, to nine anti-pseudomonal antimicrobials of diverse chemical classes were studied. A modified time-kill curve procedure was used with a 16 micrograms/ml concentration of each antimicrobial, i.e. within the range of their serum level; a total of 248 killing-curves were performed. Any > or = 2 log10 decrease of viable cell counts by a combination compared to the most active single agent was considered an adequate enhanced killing effect. The latter was found to be mainly expressed at 24 h of growth and involved 30-50% of the tested isolates. The above findings were independent of the MIC level to any individual beta-lactam or to amikacin. It is concluded that there is no difference between the activity of the ceftazidime and amikacin combination and those of meropenem or imipenem with amikacin on multiresistant P. aeruginosa.

Amikacin↗

PubMed2001

In vitro activity of mezlocillin, meropenem, aztreonam, vancomycin, teicoplanin, ribostamycin and fusidic acid against Borrelia burgdorferi.

The in vitro susceptibility profile of Borrelia burgdorferi is not yet well defined for several antibiotics. Our study explored the in vitro susceptibility of B. burgdorferi to mezlocillin, meropenem, aztreonam, vancomycin, teicoplanin, ribostamycin and fusidic acid. Minimal inhibitory concentrations (MICs) and minimal borreliacidal concentrations (MBCs) were measured using a standardised colorimetric microdilution method and conventional subculture experiments. MIC values were lowest for mezlocillin (MIC(90), < or =0.06 mg/l) and meropenem (MIC(90), 0.33 mg/l). Vancomycin (MIC(90), 0.83 mg/l) was less effective in vitro. Borreliae proved to be resistant to aztreonam (MIC(90), >32 mg/l), teicoplanin (MIC(90), 6.6 mg/l), ribostamycin (MIC(90), 32 mg/l), and fusidic acid (MIC(90), >4 mg/l). The mean MBCs resulting in 100% killing of the final inoculum after 72 h of incubation were lowest for mezlocillin (MBC, 0.83 mg/l). This study gathered further data on the in vitro susceptibility patterns of the B. burgdorferi complex. The excellent in vitro effectiveness of acylamino-penicillin derivatives and their suitability for the therapy of Lyme disease is emphasised.

Anti-Bacterial Agents↗

PubMed1998

Comparative in vitro activity of meropenem versus other routinely used antimicrobials against 18632 aerobic bacteria tested in 92 German centers.

The in vitro antibacterial activity of meropenem and up to 26 other antibiotics was compared under routine conditions at 92 German centers from March to June 1995 with use of the agar diffusion method against 18632 recent isolates from ICU--hemato-oncology--and pediatric patients. Overall, meropenem was the most active drug exhibiting a higher activity against gram-negative aerobes than imipenem, but somewhat less active against staphylococci and enterocooci. The overall resistance rates of most antibiotics tested was higher compared to the recently published surveillance data of the Paul-Ehrlich-Society in Germany. The main reason for this discrepancy is the higher percentage of test strains which were recovered from intensive care unit patients in the present study. These data confirm similar results from the USA and underscore the pressing need for the implementation of a nationwide antimicrobial surveillance system which is risk-stratified by hospital size, ICU- versus non-ICU-patients, and body site from which the isolates are recovered.

Anti-Bacterial Agents↗

PubMed1998

Susceptibility of the anaerobic gram-negative non-sporulating rod, Bilophila wadsworthia to beta-lactams, beta-lactamase inhibitors, meropenem, metronidazole, clindamycin and quinolones.

The susceptibility of eighty-seven strain of Bilophila wadsworthia to five beta-lactams, two beta-lactamase inhibitors, meropenem, metronidazole, clindamycin and two quinolones was determined. Tests were performed by the modified reference agar dilution technique using triphenyltetrazolium chloride for endpoint reading. The test strains showed a reduced susceptibility to the beta-lactams, penicillin G (MIC90 4 micrograms/ml), ampicillin (MIC90 32 micrograms/ml), piperacillin (MIC90 64 micrograms/ml), cephalothin (MIC90 2 micrograms/ml and cefotaxim (MIC90 4 micrograms/ml). The activity of ampicillin was increased by addition of the beta-lactamase inhibitor, sulbactam (MIC90 2 micrograms/ml), as was the activity of piperacillin by the addition of tazobactam (MIC90 4 micrograms/ml) 90.8% of the strains were found to produce beta-lactamase by the nitrocefin tube method. All strains were shown to be highly susceptible to meropenem, metronidazole and clindamycin (MICs < or = 1 microgram/ml). Sparfloxacin (MIC90 1 microgram/ml) and ciprofloxacin (MIC90 0.5 microgram/ml) were found to be active against most of the strains tested.

Anti-Bacterial Agents↗

PubMed1998

Meropenem exists in equilibrium with a carbon dioxide adduct in bicarbonate solution.

Evidence is provided for the existence of a second discrete chemical form of meropenem at clinically relevant concentrations prepared from the marketed formulation of the drug. Proton and carbon-13 NMR spectra in D2O, coupled with tandem mass spectroscopy (MS/MS) and cross polarization/magic angle spinning (CP-MAS) NMR experiments, allow structural assignment of the compound as a covalent carbon dioxide adduct of meropenem. This carbon dioxide adduct exists in equilibrium with the free drug in solution and can be observed in the solid state following lyophilization. The equilibrium constant of formation of the adduct (Keq = 20 +/- 8 M-1) was estimated in D2O at 25 degreesC.

Bicarbonates↗

PubMed2000

PCR-based DNA fingerprinting (REP-PCR, AP-PCR) and pulsed-field gel electrophoresis characterization of a nosocomial outbreak caused by imipenem- and meropenem-resistant Acinetobacter baumannii.

OBJECTIVE: To demonstrate the usefulness of REP-PCR and AP-PCR on molecular typing of A. baumannii isolates. METHOD: From February to November 1997, 29 inpatients at Ramón y Cajal Hospital, Madrid-23 in five intensive care units (ICUs) and six at two different medical departments-were either colonized or infected with imipenem- and meropenem-resistant Acinetobacter baumannii (IMRAB) strains (MICs of 64-256 mg/L). A wide antibiotic multiresistance profile was observed with IMRAB strains, and only tobramycin, sulbactam and colistin displayed valuable activity. For typing IMRAB isolates, repetitive extragenic palindromic sequence-based polymerase chain reaction (REP-PCR) and arbitrary primer sequence-based polymerase chain reaction (AP-PCR) methods were used and compared with pulsed-field gel electrophoresis (PFGE) as reference technique. For comparative purposes, 30 imipenem- and meropenem-susceptible A. baumannii (IMSAB) strains isolated before, during and after the outbreak were included in this study. RESULTS: The molecular typing results showed that the outbreak was caused by a single IMRAB strain (genotype 1). On the other hand, seven different genotypes were observed in the pre-, at- and post-outbreak strains tested by REP-PCR. Regarding AP-PCR, three of four at-outbreak IMSAB strains were indistinguishable from the IMRAB profile. Thus, with AP-PCR, only six genotypes were obtained, apart from the IMRAB genotype. CONCLUSION: Under our experimental conditions, REP-PCR had a higher discriminatory power than AP-PCR, with PFGE as reference technique. The REP-PCR technique is a useful and expeditious method for the epidemiologic characterization of A. baumannii nosocomial outbreaks, the results being comparable to those obtained with the PFGE technique.

Acinetobacter↗

PubMed1991

In-vitro activity of meropenem, a new carbapenem, against imipenem-resistant Pseudomonas aeruginosa and Xanthomonas maltophilia.

The activity of meropenem, a new carbapenem, as well as imipenem, ceftazidime, aztreonam, tobramycin, amikacin and ciprofloxacin against 18 strains of Xanthomonas maltophilia and 23 strains of Pseudomonas aeruginosa resistant to imipenem was tested. All strains of X. maltophilia were resistant to both penems. Ceftazidime, tobramycin and ciprofloxacin were the most active antimicrobial agents against this specie. 17% of imipenem-resistant strains of P. aeruginosa were sensitive to meropenem. Ciprofloxacin, amikacin and aztreonam were the most effective agents against these strains.

Anti-Bacterial Agents↗

PubMed1999

Successful treatment of ceftazidime-resistant Klebsiella pneumoniae ventriculitis with intravenous meropenem and intraventricular polymyxin B: case report and review.

Increasing prevalence of multidrug-resistant gram-negative organisms has led to a rise in clinically significant infections with these organisms and an increasing therapeutic dilemma. We present a case of a neurosurgical patient who developed ventriculoperitoneal shunt-associated ventriculitis due to ceftazidime-resistant Klebsiella pneumoniae susceptible to cefepime, imipenem, meropenem, and polymyxin B only. Successful management was accomplished by removal of the shunt and therapy with systemic meropenem and intraventricular polymyxin B. Rapid cerebrospinal fluid (CSF) sterilization occurred, with CSF bactericidal titers of 1:32 to 1:128. Polymyxin B should be considered as adjunctive therapy for life-threatening multidrug-resistant gram-negative infections. Prior literature on use of intrathecal polymyxin B in therapy for meningitis supports its potential efficacy.

Anti-Bacterial Agents↗

PubMed1989

In-vitro activity of meropenem against Neisseria gonorrhoeae, Haemophilus influenzae and H. ducreyi from Canada and Kenya.

Meropenem, a new parenteral carbapenem demonstrated increased activity as compared to imipenem against 336 strains of Neisseria gonorrhoeae, 119 strains of Haemophilus influenzae, and 110 strains of H. ducreyi. Neither carbapenem was affected by the beta-lactamase activity of the organisms tested. Ceftriaxone and ciprofloxacin demonstrated activity superior to that of both carbapenems while the activity of ceftazidime was similar to that of meropenem.

Anti-Bacterial Agents↗

PubMed1989

Bactericidal activity of meropenem and interactions with other antibiotics.

MICs of meropenem for selected clinical isolates of bacteria were determined. Killing curves were performed on strains of methicillin-sensitive Staphylococcus aureus, methicillin-resistant Staph. aureus (MRSA), methicillin-resistant Staph, epidermidis, Escherichia coli, Klebsiella spp., Enterobacter cloacae, Pseudomonas aeruginosa, Citrobacter freundii and Acinetobacter spp. A reduction of greater than or equal to 3 x log10 in viable cells was observed at 4 and 6 h of exposure to 4 and 8 x MIC, and this was usually maintained at 24 h (with a few exceptions for methicillin-resistant Staph, epidermidis and Ent. cloacae). At the MIC and twice the MIC regrowth tended to occur at 24 h although this varied from strain to strain. The interaction with other antibiotics was determined by the chequerboard technique. Usually an additive or synergistic effect was observed when meropenem or imipenem was used in combination with an aminoglycoside against Gram-negative species, while in a few cases antagonism occurred in combination with beta-lactams. Against Staph, aureus, MRSA and Staph, epidermidis synergism was usually obtained with combinations with teicoplanin or vancomycin and either synergism or addition with combinations with rifampicin, co-trimoxazole or ciprofloxacin.

Anti-Bacterial Agents↗

PubMed1989

Interaction of meropenem with humoral and phagocytic defences.

Meropenem and imipenem were compared for their capacity to kill intracellular Staphylococcus aureus, to alter the pattern of lysis of serum-sensitive or resistant Escherichia coli, and to affect the uptake and intracellular killing of opsonized S. aureus by human neutrophils and mouse peritoneal macrophages. Meropenem killed intracellular S. aureus at concentrations equal to eight times the MBC while imipenem did not. Neither antibiotic had any significant effect on any of the other interactions studied.

Antibody Formation↗

PubMed1989

Meropenem: evidence of lack of proconvulsive tendency in mice.

The proconvulsive tendency of the novel carbapenem, meropenem was compared to that of imipenem, alone and in combination with cilastatin. The potentiation of metrazole-induced convulsions in mice was measured. Both imipenem and imipenem/cilastatin caused significant potentiation of metrazole-induced convulsions at a dose of 200 mg/kg, i.v. In contrast, meropenem (50-400 mg/kg, iv) failed to exhibit any significant potentiation of metrazole-induced seizures.

Animals↗