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PubMed1998

Treatment of obstetric and gynecologic infections with meropenem: comparison with imipenem/cilastatin.

The aim of this study was to compare the clinical and bacteriologic efficacy of meropenem with imipenem/cilastatin in the treatment of obstetric and gynecologic infections. This was a controlled, multicenter, randomized study with two parallel groups and a follow-up period of up to 4 weeks. A total of 105 hospital in-patients requiring antibacterial parenteral therapy were enrolled, 52 in the meropenem group and 53 in the imipenem/cilastatin group. Both drugs were administered at 0.5 g every 8 hours, by slow intravenous infusion over 20-30 minutes; for meropenem the administration by intravenous bolus injection (over approximately 5 minutes) was allowed. The mean duration of therapy was 5 days for both treatments. At the end of treatment, all 46 evaluable patients in the meropenem treatment group had a satisfactory clinical response, while in the imipenem/cilastatin group 5/49 patients were clinical failures. The difference between the treatment groups in clinical response was statistically significant (100% vs 89.8%; p=.026). A similar result was seen in the intention-to-treat analysis (98% vs 84.6%; p=0.017). Both treatments were well tolerated, but fewer meropenem patients experienced treatment-related adverse events in comparison with imipenem/cilastatin (11.5% vs 15.1%).

Adolescent↗

PubMed2004

Pharmacokinetics and pharmacodynamics of meropenem in febrile neutropenic patients with bacteremia.

BACKGROUND: Pharmacodynamic investigations with antimicrobials define the relationship between the infecting organism and achievable drug concentrations with clinical outcome. OBJECTIVE: To examine this relationship for meropenem in a population of patients who are at high risk of infection-related morbidity and mortality. METHODS: The study was a retrospective analysis of a multicenter, randomized, blinded clinical trial. A population-based predictive model was created using data from adults with febrile neutropenia and the nonparametric modeling program, NPEM. Patient age, body weight, and serum creatinine level were covariates in the model used to predict unbound concentrations for each patient. Pathogen susceptibility was estimated using product literature minimum inhibitory concentrations for effectiveness against 50% of microorganisms (MIC50) for specific organisms. The pharmacodynamic index of percent time above MIC (% T>MIC) was analyzed for its association with clinical outcome. RESULTS: A 2-compartment pharmacokinetic model using patient covariates of body weight and renal function best described the pharmacokinetics of meropenem in febrile neutropenic patients. Sixty patients with confirmed gram-positive or -negative bacteremia were studied. An average of 83% T>MIC was identified for the 42 clinical responders compared with 59% T>MIC for the 18 nonresponders (p = 0.04). An 80% clinical response rate was evident when the % T>MIC for meropenem exceeded 75% of the dosing interval (p = 0.01). CONCLUSIONS: To our knowledge, this is the first published report of a relationship between a pharmacodynamic index and clinical outcome in a febrile neutropenic population. Based on this relationship, dosing with intravenous meropenem 500 mg every 6 hours is predicted to be comparable to the currently recommended 1 g every 8 hours for serious infections. Our model provides further justification for a prospective clinical trial to evaluate a pharmacodynamically targeted meropenem dosing schedule as to its ability to improve clinical outcome in these patients.

Adult↗

PubMed2006

Pharmacodynamic evaluation of meropenem and cefotaxime for pediatric meningitis: a report from the OPTAMA program.

OBJECTIVE: To determine the probability of meropenem (Merrem, AstraZeneca Pharmaceuticals L.P., Wilmington, DE, USA) and cefotaxime (Claforan, Aventis Pharmaceuticals Inc., Bridgewater, NJ, USA) achieving bactericidal exposures in the cerebrospinal fluid against Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae. METHODS: A 5,000-patient Monte Carlo simulation in a population of 10-year-old children with meningitis was conducted. Pediatric pharmacokinetic data were derived from the literature. Pathogen minimum inhibitory concentrations (MICs) were obtained from common bacteria that had caused meningitis collected during pediatric clinical trials. Time above the MIC exposures in the cerebrospinal fluid was calculated. Bactericidal exposure or probability of target attainment was defined as 40% and 50% time above the MIC for meropenem and cefotaxime, respectively. High cumulative fractions of responses were defined as >90% probability of target attainment against the populations of bacteria. RESULTS: Meropenem was calculated to achieve 94.7%, 94.3%, and 96.1% cumulative fractions of response against S. pneumoniae, H. influenzae, and N. meningitidis, respectively. Cefotaxime only achieved a high likelihood of bactericidal attainment against N. meningitidis (91.6%). Against S. pneumoniae and H. influenzae, cefotaxime was only calculated to achieve 84.3% and 84.8% cumulative fractions of response, respectively. CONCLUSION: In a simulated population of 10-year-old children, meropenem had a high likelihood of attaining bactericidal exposures in the cerebrospinal fluid. Cefotaxime had a >90% cumulative fraction of response against only N. meningitidis. Therefore, at the doses simulated, meropenem may be a more appropriate empiric choice for the treatment of bacterial meningitis in pediatric patients presumed to be caused by these pathogens until culture and susceptibility data are available.

Anti-Bacterial Agents↗

PubMed1993

The disposition and metabolic fate of 14C-meropenem in man.

1. The metabolism and pharmacokinetics of 14C-meropenem were studied in five volunteers who received 0.5 g (40 microCi) of the radiolabelled drug by i.v. infusion. 2. The maximum concentration of drug in plasma was 27 +/- 2 micrograms/ml (70 microM) corresponding to 98% of plasma radioactivity at the end of a 30 min infusion. The elimination half-life for meropenem in plasma was 1 h and meropenem remained the major radioactive component up to 6 h, but represented a decreasing proportion of the plasma radioactivity with time. One metabolite (the ring-open lactam) accounted for most of the remaining plasma radioactivity. The maximum concentration of metabolite was 1 +/- 0.1 micrograms/ml and the concentration of total radioactivity decreased to 2% of the peak value by 8 h. 3. Over the 5 days of the study, urinary excretion of radioactivity accounted for 99 +/- 0.5% dose, most of which was recovered in the first 8 h. There was negligible excretion in faeces. 4. Structural confirmation of the drug-related components in urine was accomplished by h.p.l.c.-mass spectrometry. Meropenem accounted for 71 +/- 2% dose of 14C and the ring-open lactam metabolite for most of the remainder, no other metabolites were detected. 5. Meropenem was the major radioactive component in urine up to 8 h after dosing and is therefore remarkably stable to human renal dehydropeptidase (DHP-1) compared with other carbapenems in clinical use.

Adult↗

PubMed2004

Therapeutic efficacy of meropenem for treatment of experimental penicillin-resistant pneumococcal meningitis.

With the widespread emergence of antimicrobial resistance, combination regimens of ceftriaxone and vancomycin (C+V) or ceftriaxone and rifampin (C+R) are recommended for empirical treatment of pneumococcal meningitis. To evaluate the therapeutic efficacy of meropenem (M), we compared various treatment regimens in a rabbit model of meningitis caused by penicillin-resistant Streptococcus pneumoniae (PRSP). Therapeutic efficacy was also evaluated by the final bacterial concentration in the cerebrospinal fluid (CSF) at 24 hr. Each group consisted of six rabbits. C+V cleared the CSF at 10 hr, but regrowth was noted in 3 rabbits at 24 hr. Meropenem monotherapy resulted in sterilization at 10 hr, but regrowth was observed in all 6 rabbits at 24 hr. M+V also resulted in sterilization at 10 hr, but regrowth was observed in 2 rabbits at 24 hr. M+V was superior to the meropenem monotherapy at 24 hr (reduction of 4.8 vs. 1.8 log10 cfu/mL, respectively; p=0.003). The therapeutic efficacy of M+V was comparable to that of C+V (reduction of 4.8 vs. 4.0 log10 cfu/mL, respectively; p=0.054). The meropenem monotherapy may not be a suitable choice for PRSP meningitis, while combination of meropenem and vancomycin could be a possible alternative in the treatment of PRSP meningitis.

Animals↗

PubMed1999

Effects of imipenem and meropenem on purine content of endothelial cells.

UNLABELLED: Intravenous compatibility of antibacterial agents has been tested in animal models. Use of human umbilical venous endothelial cells (HUVEC) to test antibiotic solutions for intravenous tolerance provides a valuable alternate model. OBJECTIVE: Evaluation of the effect of imipenem and meropenem on intracellular purines reflecting viability, energy production, signal transduction, and DNA/RNA synthesis of these cells. MATERIALS AND METHODS: Levels of intracellular adenosine 5' triphosphate (ATP), adenosine 5' diphosphate (ADP), guanosine 5' triphosphate (GTP) and guanosine 5' diphosphate (GDP) were measured by means of high performance liquid chromatography (HPLC). RESULTS: The total amount of ATP after incubation of cells with 10.0 mg/ml imipenem and meropenem for 20 minutes (12.93 +/- 0.93 nmol/million cells and 13.27 +/- 0.89 nmol/million cells, respectively) did not result in a decrease compared to controls (12.34 +/- 0.87 nmol/million cells). In addition, ATP levels were maintained or actually increased after 60 minutes. Incubation of cells with 5.0 mg/ml and 2.5 mg/ml of imipenem or meropenem for 20 and 60 minutes showed similar results. Purine nucleotide profiles of ADP, GTP, GDP following exposure of 10.0 mg/ml, 5.0 mg/ml and 2.5 mg/ml of imipenem and meropenem did not differ markedly. CONCLUSIONS: These in vitro data show an excellent endothelial compatibility of imipenem and meropenem even in high concentrations.

Adenosine Diphosphate↗

PubMed1999

Pharmacodynamic parameters and hydrophobicity changes induced by meropenem in Acinetobacter baumannii.

The suppression of bacterial growth of four Acinetobacter baumannii strains after 60 min exposure to meropenem at supra-inhibitory concentrations (postantibiotic effect; PAE) or at supra-subinhibitory concentrations (postantibiotic-sub-MIC effect; PA SME) was studied. The duration of the PAE was dependent on antibiotic concentration and on the strain. Meropenem at 2x or 4x the minimum inhibitory concentration (MIC), with the exception of one strain treated with 4x MIC, did not provoke suppression of bacterial growth compared with untreated controls. The highest concentration of meropenem (8x MIC) induced PAE for the strains tested in the range of 0.6-6.9 h. The effect of supra-subinhibitory concentrations of meropenem (2x, 4x or 8x MIC + 0.2x MIC) on bacterial growth was more efficient compared with supra-inhibitory concentrations alone. Two out of the four strains treated did not renew their growth. Bacterial suspensions exposed to meropenem showed reduced surface hydrophobicity. Decreases in hydrophobicity were associated with longer PAE and PA SME depending on the strain.

Acinetobacter↗

PubMed2000

MYSTIC (Meropenem Yearly Susceptibility Test Information Collection) results from the Americas: resistance implications in the treatment of serious infections. MYSTIC Study Group (Americas).

The Meropenem Yearly Susceptibility Test Information Collection (MYSTIC) programme aims to provide in vitro surveillance data for geographically diverse institutions where meropenem is available for use. The in vitro activity of meropenem and eight comparator antimicrobial agents against 2340 significant pathogens obtained in 1999 was assessed and compared in 14 study centres in Brazil, Mexico and the USA. Isolates were further characterized for production of extended-spectrum beta-lactamases (ESBLs), AmpC beta-lactamases and carbapenemases. Carbapenems demonstrated their broad spectrum and potency, inhibiting > or = 95% of all isolates irrespective of the geographical region or centre type. The overall order of activity of the nine agents tested against all pathogens in 1999 was meropenem (96%) > imipenem (95%) > cefepime (92%) > gentamicin (89%) > piperacillin/tazobactam (88%) > ceftazidime = tobramycin (86%) > cefotaxime (84%) > ciprofloxacin (83%). Thus far, the results from the Americas indicate that meropenem has excellent potency and spectrum of activity despite being prescribed for the treatment of seriously ill patients. In contrast, other ESBLs, fluoroquinolones and aminoglycosides have lost activity in many institutions as a result of the selection of strains producing ESBLs or having AmpC and other resistance determinants. Carbapenem resistance was observed rarely and at a prevalence similar to those reported in earlier studies. Carbapenems appear to be a continuing reliable option for the treatment of serious nosocomial infection.

Americas↗

PubMed2002

Comparison of meropenem with ceftazidime as monotherapy of cancer patients with chemotherapy induced febrile neutropenia.

BACKGROUND: Ceftazidime is commonly used as monotherapy of cancer patients with fever and neutropenia. Concern, however, has been raised regarding potential for drug resistance due to its widespread use. Meropenem is a new carbapenem with more extended antibacterial spectrum including anaerobes. It provides better coverage against gram positives. Hence, it may offer an advantage over ceftazidime. PATIENTS AND METHODS: We prospectively treated 49 patients hospitalized for fever (> 38 degrees C) and neutropenia (ANC < or = 500/cmm) with meropenem. We compared their outcome with 50 patients who consecutively received ceftazidime in the immediate past for the same indication. RESULTS: Comparison of demographic features between the 2 groups revealed no differences in age, gender, type of neoplasm, number of patients with prior antibiotic use, number of days since chemotherapy, absolute neutrophil count and number of patients previously or already hospitalized. Duration of fever, duration of neutropenia and number of patients with pyrexia of undetermined origin were also similar. Therapeutic outcome was same between the two groups. Eighty four percent of patients receiving meropenem and 79% receiving ceftazidime required no modification of the initially assigned therapeutic regimen. Two patients receiving meropenem died. Toxicity was minimal. CONCLUSION: We conclude that meropenem offers no significant advantage over ceftazidime in the management of neutropenic febrile patients.

Adult↗

PubMed1994

In vitro activity of meropenem compared with imipenem, metronidazole, ampicillin, and ampicillin/sulbactam against anaerobes.

The aim of the present study was to compare the in vitro activity of meropenem (ICI 194660, CAS 96036-03-2) with imipenem, metronidazole, clindamycin, ampicillin and ampicillin/sulbactam against a variety of anaerobic bacteria using an agar dilution method. 423 clinical isolates were tested belonging to 70 species of 15 anaerobic genera. They included Bacteroides fragilis (n = 62), Bacteroides thetaiotaomicron (n = 45), Prevotella bivia (n = 11), Fusobacterium nucleatum (n = 12), Clostridium perfringens (n = 15) and several rarely isolated species and genera, e.g. Selenomonas sputigena and Clostridium symbiosum. Bacteroides species were inhibited by meropenem at < or = 2.0 micrograms/ml, Clostridium species, including C. difficile, at < or = 4.0 micrograms/ml and all the other anaerobes at < or = 0.5 microgram/ml. Meropenem and imipenem were the most active substances, but often equal to, or only slightly better than, metronidazole, clindamycin or ampicillin/sulbactam, dependent on species. Meropenem was especially active against Bacteroides gracilis (MIC90 0.015 microgram/ml), Prevotella disiens (MIC90 0.03 microgram/ml), Fusobacterium nucleatum (MIC90 0.015 microgram/ml), Clostridium perfringens (MIC90 0.015 microgram/ml) and Veillonella parvula (MIC90 0.03 microgram/ml). The results obtained indicate that meropenem might be a useful adjunct to chemotherapy of anaerobic and mixed aerobic and anaerobic infections.

Ampicillin↗

PubMed1996

Meropenem in cystic fibrosis patients infected with resistant Pseudomonas aeruginosa or Burkholderia cepacia and with hypersensitivity to beta-lactam antibiotics.

OBJECTIVE: To assess the efficacy and safety of meropenem, administered on a compassionate basis to 62 cystic fibrosis (CF) patients (age: 24plus minus6 years) with hypersensitivity reactions to beta-lactam antibiotics and/or infection by bacteria resistant to other antibiotics. METHODS: Fifty-seven patients were chronically infected with Pseudomonas aeruginosa and 5 with Burkholderia cepacia. In total, 124 courses (1 to 6/patient) of meropenem, 2 g three times a day by intravenous infusion (10 to 15 min) for 14 days, were administered. RESULTS: During treatment for P. aeruginosa the mean increase in pulmonary function (as a percentage of the predictive values) was 5.6% for FEV1 (forced expiratory volume in the first second) and 8.6% for FVC (forced vital capacity). C-reactive protein and erythrocyte sedimentation rate (ESR) and leukocyte count decreased significantly. In courses administered for chronic infection with B. cepacia the post treatment FEV1 and FVC values were higher than the pre-treatment values, and all the inflammatory parameters decreased. The geometric means of minimal inhibitory concentration (MICs) (microg/mL) for P. aeruginosa (B. cepacia) were: tobramycin 6 (59), ciprofloxacin 1.2 (9.7), piperacillin 49 (16.3), ceftazidime 26 (23), aztreonam 26 (35), imipenem 6.4 (not determined) and meropenem 5.1 (4.8). No statistically significant increase in the MICs of meropenem for either pathogen occurred during therapy. Of the 124 courses, 115 were tolerated without any clinical complaint. The following side effects were observed: nausea (0.8%), itching (4%), rash (3.2%), drug fever (1.6%). CONCLUSIONS: Meropenem proved to be a valuable drug in the treatment of CF patients with chronic pulmonary infection with multiresistant P. aeruginosa and B. cepacia and with hypersensitivity reactions to other beta-lactam drugs.

Journal Article↗

PubMed1998

Pharmacokinetics in vivo and pharmacodynamics ex vivo/in vitro of meropenem and cefpirome in the Yucatan micropig model: continuous infusion versus intermittent injection.

OBJECTIVE: To investigate the pharmacodynamic disposition of two recently developed beta-lactam antibiotics, meropenem and cefpirome, in the Yucatan micropig model, and to compare the bactericidal activity of these drugs against bacteria in this in vitro/ex vivo micropig model after administration by both intermittent injection and continuous infusion. METHODS: Cefpirome (1 g) was given to the micropig over a 12-h period by direct intravenous injection and 6-h continuous infusion (500 mg). Meropenem (250 mg) was administered either by 30-min intravenous and 8-h continuous infusion. The two drugs were assayed by HPLC. The pharmacodynamics of these drugs were evaluated by means of (1) serum killing curve against Klebsiella pneumoniae producing extended-spectrum beta-lactamase, stably derepressed Enterobacter cloacae and methicillin-susceptible penicillinase-producing Staphylococcus aureus, and (2) calculations of index of surviving bacteria (ISB). RESULTS: The bactericidal activity of meropenem against K. pneumoniae and E. cloacae in this in vitro/ex vivo model was excellent, with a 4 log decrease at peak concentrations. Meropenem produced a mixed concentration- and time-dependent, killing effect against E. cloacae and K. pneumoniae. The ISB value ranged from 25% to 30% for E. cloacae. With concentrations above MIC for S. aureus (1 mg/L), cefpirome has a time-dependent bactericidal activity, as shown by the ISB ranging from 20% to 80% after 4 h and between 20% and 40% after an 8-h drug exposure. For both antibiotics, the higher concentrations obtained just after intermittent injection had a rapid and strong killing effect against the strains tested, but the trough levels had no bactericidal activity. The continuous infusions produce consistent concentrations of antibiotic that can be maintained above the MIC, and the bactericidal activity of which ranges from 2 to 4 log10 decrease of inoculum. CONCLUSIONS: In the present study the micropig has been shown to be an adequate model for the pharmacodynamic investigation of cefpirome and meropenem. In general, continuous infusion appears to optimize the pharmacodynamic profile of the two tested beta-lactam antibiotics. However, against Gram-negative bacilli, the administration of a loading dose prior to continuous infusion of beta-lactams would eliminate the only potential pharmacokinetic disadvantage of continuous infusion and ensure the rapid onset of antimicrobial activity.

Journal Article↗

PubMed2000

MYSTIC (Meropenem Yearly Susceptibility Test Information Collection) results from the Americas: resistance implications in the treatment of serious infections.

The Meropenem Yearly Susceptibility Test Information Collection (MYSTIC) programme aims to provide in vitro surveillance data for geographically diverse institutions where meropenem is available for use. The in vitro activity of meropenem and eight comparator antimicrobial agents against 2340 significant pathogens obtained in 1999 was assessed and compared in 14 study centres in Brazil, Mexico and the USA. Isolates were further characterized for production of extended-spectrum beta-lactamases (ESBLs), AmpC beta-lactamases and carbapenemases. Carbapenems demonstrated their broad spectrum and potency, inhibiting >/=95% of all isolates irrespective of the geographical region or centre type. The overall order of activity of the nine agents tested against all pathogens in 1999 was meropenem (96%) > imipenem (95%) > cefepime (92%) > gentamicin (89%) > piperacillin/tazobactam (88%) > ceftazidime = tobramycin (86%) > cefotaxime (84%) > ciprofloxacin (83%). Thus far, the results from the Americas indicate that meropenem has excellent potency and spectrum of activity despite being prescribed for the treatment of seriously ill patients. In contrast, other ESBLs, fluoroquinolones and aminoglycosides have lost activity in many institutions as a result of the selection of strains producing ESBLs or having AmpC and other resistance determinants. Carbapenem resistance was observed rarely and at a prevalence similar to those reported in earlier studies. Carbapenems appear to be a continuing reliable option for the treatment of serious nosocomial infection.

Journal Article↗

PubMed1997

A compilation of studies assessing the in vitro activity of meropenem and comparators in 84 laboratories throughout Europe.

OBJECTIVE: To compile the results of investigations conducted in 84 centers throughout Europe of the in vitro activity of meropenem and a standard set of comparators against some 12 000 Gram-positive, Gram-negative, aerobic and anaerobic bacteria. METHODS: Recent clinical isolates from 84 European countries were tested using Mueller---Hinton broth or agar (aerobes and nutritionally fastidious species) or Wilkins---Chalgren medium (anaerobes) for susceptibility to meropenem, imipenem, cefotaxime, ceftazidime, piperacillin, ciprofloxacin and gentamicin (aerobes) or meropenem, imipenem, clindamycin and metronidazole (anaerobes). RESULTS: Whether compared across studies or across countries, meropenem and imipenem were the only compounds that produced uniform and predictable activity. The activity of ceftazidime and cefotaxime was compromized because of instability to both chromosomally mediated and new plasmid-mediated (transferable) beta-lactamases. This effect was even more pronounced with piperacillin. Resistance to gentamicin was commonplace, although variable between countries; strains resistant to ciprofloxacin occurred in many genera of Enterobacteriaceae and amongst the pseudomonads. Metronidazole was uniformly active against anaerobes but there were many clindamycin-resistant strains. Resistance, or diminished susceptibility, amongst Streptococcus pneumoniae was found frequently, but of the beta-lactams tested, only ceftazidime and piperacillin produced minimum inhibitory concentration values that could compromize therapeutic efficacy outside the central nervous system. CONCLUSIONS: These data provide further evidence of the high incidence of antibiotic resistance in Europe, notably in France, Spain and Italy. Fortunately, the carbapenems are highly stable to the enzymes that hydrolyze cephalosporins and penicillins. Hence, they retain an essentially unaltered and exceptional antimicrobial spectrum, embracing the vast majority of strains resistant to the other comparators, although meropenem was more reliable than imipenem against Pseudomonas aeruginosa.

Journal Article↗

PubMed1997

Meropenem: laboratory and clinical data.

The usefulness of many beta-lactams, including the third-generation cephalosporins, has been threatened in recent years by the dissemination of beta-lactamase-mediated resistance. The carbapenems, meropenem and imipenem/cilastatin, demonstrate ultra-broad spectra of antibacterial activity which encompass the majority of clinically significant Gram-positive and Gram-negative aerobic and anaerobic pathogens. Due to the unique arrangement of the moieties around the carbapenem beta-lactam ring, these agents possess unrivaled stability to almost all serine beta-lactamases, including the mutant extended-spectrum types produced by Enterobacteriaceae which hydrolyze third-generation cephalosporins. Meropenem has a number of additional structural features which confer advantages over imipenem, notably stability to metabolism by dehydropeptidase-I and enhanced activity against Gram-negative organisms, including Pseudomonas aeruginosa. In the treatment of nosocomial respiratory tract infections, meropenem monotherapy has compared favorably with ceftazidime plus aminoglycoside combination regimens or imipenem/cilastatin, producing rates of clinical efficacy of > 75%. Likewise, in patients with intra-abdominal infections, meropenem has proved to be as efficacious as clindamycin plus tobramycin, cefotaxime plus metronidazole and equivalent dosages of imipenem/cilastatin. Meropenem is well tolerated by the central nervous system and, unlike imipenem/cilastatin, is approved for the treatment of meningitis.

Journal Article↗

PubMed2001

A rapid, sensitive high performance liquid chromatographic method for the determination of meropenem in pharmaceutical dosage form, human serum and urine.

A new, simple, precise and rapid high performance liquid chromatographic method was developed for the determination of meropenem in human serum, urine and pharmaceutical dosage forms. Chromatography was carried out on an LC(18) column using a mixture of 15 mM KH(2)PO(4):acetonitrile:methanol (84:12:4; v/v/v), adjusted to pH 2.8 with H(3)PO(4). The proposed method was conducted using a reversed-phase technique, UV monitoring at 307.6 nm and cefepime as an internal standard. The retention times were 5.98 and 7.47 min for cefepime and meropenem, respectively. The detector response was linear over the concentration range of 50-10,000 ng/mL. The detection limit of the procedure was found to be 22 ng/mL. The detection limit for meropenem in human plasma was 108.4 ng/mL and the corresponding value in human urine was 179.3 ng/mL. No interference from endogenous substances in human serum, urine and pharmaceutical preparation was observed. The proposed method is sufficiently sensitive for determination of the concentrations of meropenem and may have clinical application for its monitoring in patients receiving the drug.

Carbapenems↗

PubMed2001

Crystal structures of the class D beta-lactamase OXA-13 in the native form and in complex with meropenem.

The therapeutic problems posed by class D beta-lactamases, a family of serine enzymes that hydrolyse beta-lactam antibiotics following an acylation-deacylation mechanism, are increased by the very low level of sensitivity of these enzymes to beta-lactamase inhibitors. To gain structural and mechanistic insights to aid the design of new inhibitors, we have determined the crystal structure of OXA-13 from Pseudomonas aeruginosa in the apo form and in complex with the carbapenem meropenem. The native form consisted of a dimer displaying an overall organisation similar to that found in the closely related enzyme OXA-10. In the acyl-enzyme complex, the positioning of the antibiotic appeared to be ensured mainly by (i) the covalent acyl bond and (ii) a strong salt-bridge involving the carboxylate moiety of the drug. Comparison of the structures of OXA-13 in the apo form and in complex with meropenem revealed an unsuspected flexibility in the region of the essential serine 115 residue, with possible consequences for the catalytic properties of the enzyme. In the apo form, the Ser115 side-chain is oriented outside the active site, whereas the general base Lys70 adopts a conformation that seems to be incompatible with the activation of the catalytic water molecule required for the deacylation step. In the OXA-13:meropenem complex, a 3.5 A movement of the backbone of the 114-116 loop towards the side-chain of Lys70 was observed, which seems to be driven by a displacement of the neighbouring 91-104 loop and which results in the repositioning of the side-chain hydroxyl group of Ser115 toward the catalytic centre. Concomitantly, the side-chain of Lys70 is forced to curve in the direction of the deacylating water molecule, which is then strongly bound and activated by this residue. However, a distance of ca 5 A separates the catalytic water molecule from the acyl carbonyl group of meropenem, a structural feature that accounts for the inhibition of OXA-13 by this drug. Finally, the low level of penicillinase activity revealed by the kinetic analysis of OXA-13 could be related to the specific presence in position 73 of a serine residue located close to the general base Lys70, which results in a decrease of the number of hydrogen-bonding interactions stabilising the catalytic water molecule.

Amino Acid Sequence↗

PubMed1997

Pharmacokinetics of meropenem in febrile neutropenic patients. Swedish study group.

To determine the impact of neutropenia on the pharmacokinetics of meropenem, 14 patients with fever and neutropenia were given 1 g of meropenem i.v. every 8 h as an infusion over 30 min. The volume of distribution (16.2 l/1.73 m2) and the nonrenal clearance [75 ml/(min x 1.73 m2)] in this group were significantly increased compared to healthy subjects studied previously with identical techniques. The kinetic study was repeated when the patients had a normal temperature and a raised neutrophil count; most kinetic variables did not differ from the findings on the first day of treatment. The pharmacokinetic profile of meropenem in febrile neutropenic patients differs from earlier findings in healthy subjects. Considering these data and known minimum inhibitory concentration values for common pathogens, meropenem administered every 6 to 8 h seems an appropriate regimen in patients with febrile neutropenia. The shorter time interval may be used for treatment of Pseudomonas infection.

Adult↗