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PubMed1991

Pharmacokinetics of meropenem in serum and suction blister fluid during continuous and intermittent infusion.

The pharmacokinetics and penetration into suction blister fluid of meropenem was investigated after intermittent (10 mg/kg/6 h) and during continuous infusion (10 mg/kg/6 h) in eight healthy male volunteers in a crossover fashion. Concentrations in serum, urine and blister fluid were determined by a HPLC method. The pharmacokinetic parameters in serum (+/- S.D.) T1/2 beta, AUC and clearance after the third dose of intermittent infusion were 62.7 (11.4) min, 43.5 (7.1) mg.h/L and 292.1 (36.8) mL/min respectively. The penetration in blister fluid was rapid and good, with a AUC ratio blister fluid/serum of 84.7 (11.4)%. During continuous infusion, from 12 to 18 h after the start of the infusion, the mean concentration in serum was 6.3 (0.7, S.D.) mg/L and in blister fluid 5.4 (0.7, S.D.) mg/L. The clearance was 338.3 (45.6) mL/min for serum. Urinary recovery was 61.6 (8.7)% after intermittent and 61.9 (6.9)% after continuous infusion.

Adult↗
PubMed2002

Meropenem stability to beta-lactamase hydrolysis and comparative in vitro activity against several beta-lactamase-producing Gram-negative strains.

The interaction between meropenem and class A, B, C and D beta-lactamases was studied by a spectrophotometric method. Class A, C and D beta-lactamases were unable to confer in vitro resistance to carbapenems. Surprisingly, several class B metallo-beta-lactamases expressed in Escherichia coli failed to confer resistance when a conventional inoculum (105 cfu/mL) was used.

Enzyme Activation↗
PubMed2003

The role of inducible nitric oxide synthase inhibitor, meropenem, and taurine in experimental acute necrotizing pancreatitis.

INTRODUCTION: Translocation of bacteria from the gut is one of the most important factors in the development of septic complications and mortality in acute pancreatitis. AIMS: To investigate whether S-methylisothiourea (SMT), taurine (TAU), and meropenem (MER) could effect bacterial translocation and the course of acute necrotizing pancreatitis. METHODOLOGY: Seventy male Sprague-Dawley rats were studied. Rats were randomly allocated into seven groups. Acute pancreatitis was induced in group II (MER), group III (TAU), group IV (TAU + MER), group V (TAU + SMT), group VI (TAU + MER + SMT), and group VII (positive control) by retrograde injection of taurocholate into the common biliopancreatic duct. Group I rats (sham) received normal saline infusion into the common biliopancreatic duct as negative control. Rats were treated with drug combinations intraperitoneally for 48 hours after induction of pancreatitis. At the 48th hour of induction, all animals were killed, and specimens were collected. RESULTS: Bacterial translocation to peritoneum and pancreas in groups treated with MER were lower than in the other groups. Pancreatic tissue GSHpx and SOD levels were higher in all groups in comparison with levels in group VII. Pancreatic tissue MDA levels were also lower in all treatment groups except group II. The most favorable results were obtained in group VI (TAU + MER + SMT). Also, the lowest pathologic score between the groups in which acute pancreatitis developed was obtained in group VI. CONCLUSIONS: Addition of TAU and SMT to the treatment protocol for acute pancreatitis seems to improve the pathologic score and oxidative stress parameters. Also, antibiotherapy with MER decreases the risk of bacterial translocation.

Animals↗
PubMed2004

The effect of combination therapy of hyperbaric oxygen, meropenem, and selective nitric oxide synthase inhibitor in experimental acute pancreatitis.

Despite the new diagnostic and therapeutic advancements, acute pancreatitis has still high rate of morbidity and mortality. We aimed to evaluate the effects of hyperbaric oxygen (HBO) therapy alone or combined with S-methylisothiourea (SMT), and meropenem (MER) therapy in an experimental rat model of acute necrotizing pancreatitis. Rats were randomly divided into 8 groups, and acute pancreatitis was induced in all groups except group 1. Treatment protocols were saline for group 2, SMT for group 3, SMT + MER for group 4, SMT + HBO for group 5, HBO for group 6, HBO + MER for group 7, and MER for group 8. All surviving animals were killed 48 hours after the induction of pancreatitis, and specimens were collected. Oxidative stress parameters, histopathologic scores and amylase levels were better in treatment groups than in the positive control group (group 2). The most favorable results were obtained in HBO treatment groups, especially in HBO + MER group (group 7). Our results indicate that adding HBO therapy to the antibiotic therapy will decrease oxidative stress parameters, serum amylase levels, and histopathological score. We suggest that adding the HBO therapy as an adjunctive to the treatment protocol of acute necrotizing pancreatitis may yield improvement in the morbidity and mortality of the disease.

Animals↗
PubMed2006

Timing of antibiotic prophylaxis in acute pancreatitis: a controlled randomized study with meropenem.

OBJECTIVES: Antibiotic prophylaxis improves the outcome of acute pancreatitis. Since bacterial translocation from the gut occurs in the first h of disease, early therapy is likely to achieve the maximal effect. The study compares early antibiotic treatment with treatment started after the demonstration of pancreatic necrosis. METHODS: Two hundred fifteen patients with pancreatitis were randomized to either group A (N=108), who started antibiotic therapy (meropenem 500 mg t.i.d.) at admission, or group B (N=107), who received antibiotics after the demonstration of necrosis at computed tomography (CT). CT was performed in both groups after at least 48 hr of hospitalization. The clinical course of disease was compared in the two groups. RESULTS: Thirty patients in group A and 29 in B showed necrosis on CT. The two groups were similar in demographics and characteristics of disease. Antibiotic treatment was started after 4.56+/-1.2 days from hospitalization in group B and after 1.07+/-0.6 days in A. Pancreatic infection occurred in four patients in group A (13.3%) and in nine in B (31%) (p=0.1). Extrapancreatic infection occurred in 16.6% of patients in group A and in 44.8% in B (p<0.05). Need for surgery and length of hospitalization were also higher in group B. Mortality rates were similar in the two groups, but, 3 of 4 patients with infected necrosis in group A and only 2 of 9 in group B died. CONCLUSIONS: Early antibiotic treatment is associated with a significant improvement in the prognosis of necrotizing acute pancreatitis (AP), because of a reduction in the occurrence of septic complications.

Adult↗
PubMed2006

Mutant prevention concentrations of levofloxacin alone and in combination with azithromycin, ceftazidime, colistin (Polymyxin E), meropenem, piperacillin-tazobactam, and tobramycin against Pseudomonas aeruginosa.

The mutant prevention concentrations (MPCs) of levofloxacin alone and in combination with ceftazidime, colistin (polymyxin E), meropenem, piperacillin-tazobactam, and tobramycin were established against Pseudomonas aeruginosa. Antibiotic combinations using levofloxacin with any antibiotic with individual activity against P. aeruginosa resulted in synergistic lowering (an at-least-fourfold reduction) of the isolate's MPC.

Anti-Bacterial Agents↗
PubMed1997

Pharmacokinetic and pharmacodynamic models of the antistaphylococcal effects of meropenem and cloxacillin in vitro and in experimental infection.

The efficacies of meropenem (MPM) and cloxacillin (CLC) against two Staphylococcus aureus strains were established in vitro. A pharmacodynamic model equation, based on the concept that the killing rate depends on concentration and time, was fitted to the numbers of CFU. The parameters of the equation are maximum killing rate, time point of maximum killing, and 50% effective concentration (EC50). The EC50s for the two strains were 0.047 and 0.040 mg/liter, respectively, for MPM and 0.105 and 0.121 mg/liter, respectively, for CLC. Calculated values of the parameters were used to predict the numbers of CFU at exponentially decreasing concentrations in vitro as well as in an experimental infection model. The prediction for in vitro conditions gave a satisfactory fit (R2, between 0.862 and 0.894). In vivo the numbers were predicted with the assumption that killing rate in vivo is proportional to that in vitro (R2, between 0.731 and 0.973). The proportionality factor ranged between 0.23 and 0.42; this variation was due mainly to covariation with growth rates in control animals, without other significant differences between antibiotics or strains.

Animals↗
PubMed2005

An evaluation of an optimal sampling strategy for meropenem in febrile neutropenics.

Optimal sampling design with nonparametric population modeling offers the opportunity to determine pharmacokinetic parameters for patients in whom blood sampling is restricted. This approach was compared to a standard individualized modeling method for meropenem pharmacokinetics in febrile neutropenic patients. The population modeling program, nonparametric approach of expectation maximization (NPEM), with a full data set was compared to a sparse data set selected by D-optimal sampling design. The authors demonstrated that the D-optimal sampling strategy, when applied to this clinical population, provided good pharmacokinetic parameter estimates along with their variability. Four individualized and optimally selected sampling time points provided the same parameter estimates as more intensive sampling regimens using traditional and population modeling techniques. The different modeling methods were considerably consistent, except for the estimation of CL(d) with sparse sampling. The findings suggest that D-optimal sparse sampling is a reasonable approach to population pharmacokinetic/pharmacodynamic studies during drug development when limited sampling is necessary.

Anti-Bacterial Agents↗
PubMed2004

Meropenem +/- granulocyte colony stimulating factor in the treatment of febrile neutropenic patients with cancer: prospective randomized study.

The purpose of this study was to evaluate the impact of granulocyte-colony stimulating factor (G-CSF) on the therapy for febrile neutropenia (FN). Our patient population differed significantly from those of previous studies as no patients received antimicrobial or CSF prophylaxis before randomization and all were solid tumor patients. When the diagnosis of FN was established, patients were started on intravenous meropenem 1 g every 8 hours and randomly assigned to receive G-CSF (5 microg/kg body weight per day subcutaneously) or not. Twenty-eight patients with 30 FN episodes received G-CSF and 25 patients with 30 FN episodes did not receive G-CSF according to randomization. The time to resolution of fever, recovery of neutrophil count over 1000/mm3, duration of hospitalization, need for erythrocyte and platelet transfusion and mortality rate were similar in both study groups. Side effects of therapy were mild. These results provide preliminary evidence that G-CSF administration, in addition to effective antibiotic therapy as treatment of febrile neutropenic patients with solid tumor, does not help improve infection-related morbidity and mortality.

Adolescent↗
PubMed2005

The efficacy and safety of meropenem and tobramycin vs ceftazidime and tobramycin in the treatment of acute pulmonary exacerbations in patients with cystic fibrosis.

BACKGROUND: Cystic fibrosis (CF) is characterized by chronic pulmonary infection with acute pulmonary exacerbations (APEs) requiring IV antibiotic treatment. We report on a blinded comparative trial of IV meropenem (40 mg/kg to 2 g q8h) or ceftazidime (5 mg/kg to 2 g q8h), each of which was administered with IV tobramycin (at a serum peak of > or = 8 microg/mL and a trough of < 2 microg/mL), as treatment for CF patients with APEs. METHODS: Patients who were > or = 5 years of age who were infected with ceftazidime-susceptible Pseudomonas aeruginosa were stratified by lung function and randomized to treatment with meropenem/tobramycin or ceftazidime/tobramycin. Patients infected with Burkholderia cepacia complex or ceftazidime-resistant P aeruginosa were assigned to receive open-label meropenem/tobramycin. Clinical response was assessed by spirometry to determine the change in percent predicted FEV1 and by a clinical acute change score (ACS). RESULTS: One hundred two patients were randomized to meropenem/tobramycin (n = 50) or ceftazidime/tobramycin (n = 52). Nineteen patients received open-label meropenem/tobramycin. FEV1 was improved at the end of treatment (EOT) with meropenem/tobramycin (mean [+/- SD] increase, 38.8 +/- 52.3%) and with ceftazidime/tobramycin (mean increase, 29.4 +/- 35.1%; p < 0.0001 vs baseline values). The proportion of patients with > or = 15% relative increase from baseline FEV1 (satisfactory response) at day 7 was 62% for the meropenem/tobramycin group and 44% for the ceftazidime/tobramycin group (p = 0.04). The median time to FEV1 response was 4 days for meropenem/tobramycin therapy vs 6 days for ceftazidime/tobramycin therapy. Similarly, FEV1 improved in the open-label group (mean increase, 12.5 +/- 25.7%; p = 0.05). ACS improved in all three groups at EOT (p < 0.0001 vs baseline values). CONCLUSIONS: Therapy with both meropenem/tobramycin and ceftazidime/tobramycin improved pulmonary and clinical status and reduced sputum bacterial burden in CF patients with APEs. A larger proportion of patients receiving meropenem/tobramycin therapy demonstrated a satisfactory FEV1 response at day 7. Resistant P aeruginosa emerged infrequently during treatment with both regimens.

Adolescent↗
PubMed1999

Nephrotoxic and peroxidative potential of meropenem and imipenem/cilastatin in rat and human renal cortical slices and microsomes.

BACKGROUND: Carbapenems are a relatively new class of beta-lactam antibiotics characterized by a broad spectrum of antibacterial activity. Meropenem (MER), a new carbapenem has shown a lower nephrotoxic potential compared to imipenem (IMI). IMI is used in a fixed one-to-one combination with the nephroprotective agent cilastatin (CIL). The present studies examined whether MER and IMI/CIL produce peroxidative and nephrotoxic alterations including oxidative changes in rat and human renal cortical slices and microsomes. MATERIALS AND METHODS: Untreated slices and microsomes were incubated in vitro for various periods of time in phosphate-buffered media containing various concentrations of MER, IMI/CIL or for comparison cephaloridine (CPH). Lipid peroxidation was monitored by the determination of malondialdehyde (MDA) in incubation media and slices in the presence or absence of antioxidants. Total glutathione, oxidized glutathione (GSSG), pyruvate-stimulated gluconeogenesis and paraaminohippurate (PAH) accumulation were measured in slices. RESULTS: In rat renal cortical slices, MER, IMI/CIL and CPH induced a time- and concentration-dependent MDA production (content in incubation media plus slices). 5 mM MER, 5 mM IMI/CIL and 3 mM CPH were the lowest concentrations which caused a significant MDA production after 3 hs compared to control (control 61.5+/-15.3 nmol MDA/g tissue, MER 75.4+/-10.9, p<0.001; control 48.0+/-8.7, IMI/CIL 65.1+/-11.7, p<0.001; control 61.5+/-15.3, CPH 113.0+/-28.2, p<0.001). 20 mM MER, 20 mM IMI/CIL and 12 mM CPH revealed marked MDA production after 3 hs in human renal cortical slices (control 29.8+/-4.2 nmol MDA/g tissue, MER 49.4+/-8.7, p<0.01; control 27.6+/-7.0, IMI/CIL 68.3+/-9.9, p<0.001; control 32.5+/-7.7, CPH 93.8+/-31.6, p<0.001) and in human renal microsomes (control 1.0+/-0.9 nmol MDA/mg protein, MER 2.9+/-1.0, p<0.05; IMI/CIL 6.8+/-2.2, p<0.001; CPH 8.4+/-2.2, p<0.001), respectively. The corresponding MDA production was about 2-fold higher in rat renal cortical slices and almost the same in rat renal microsomes. Antioxidants reduced the MER-induced increase in MDA content in rat renal cortical slices by 48% (alpha-tocopherol, 10(-4) M), 72% ((+)-cyanidanol-3, 10(-5) M) and 100% (DPPD, N, N'-diphenyl-p-phenylendiamine, 10(-6) M). In rat renal cortical slices, MER and IMI/CIL induced an increase up to 50% in the content of GSSG and a corresponding %-decrease in reduced glutathione (GSH). In rat renal cortical slices, MER and IMI/CIL induced a time- and concentration-dependent decrease in PAH accumulation and gluconeogenesis. PAH accumulation was already reduced by 5 mM MER after 1 h (control slice to medium ratio 18.3+/-6.8, MER 10.7+/-1.9, p<0.05) and by 10 mM IMI/CIL after 3 h (control 16.9+/-5.6, IMI/CIL 5.5+/-1.3, p<0.001). Pyruvate-stimulated gluconeogenesis after 3 hs was already reduced by 2.5 mM MER (control 5.7+/-2.1 micromol glucose/g tissue/h, MER 3.9+/-1.1, p<0.05) and by 10 mM IMI/CIL (control 5.7+/-2.1, IMI/CIL 2.8+/-1.0, p<0.001). CONCLUSION: Thus, MER and IMI/CIL (at concentrations more than 10-fold higher as peak plasma concentrations achieved in humans) revealed an oxidative change (depletion of GSH, production of GSSG), a peroxidative potential (production of MDA) and a nephrotoxic potential (reduction in pyruvate-stimulated gluconeogenesis and PAH accumulation). Human kidney seems to be less susceptible to beta-lactam antibiotic-induced lipid peroxidation than rat kidney.

Animals↗
PubMed1999

[Antimicrobial activities of meropenem against clinically isolated strains in 1997].

In order to evaluate antimicrobial activity of meropenem (MEPM), minimum inhibitory concentrations (MICs) of MEPM and control drugs were determined against clinical isolates in 1997. The results were as follows; 1. Antimicrobial activities of MEPM against Gram-positive bacteria were stronger than those of cephems (CEPs) and were approximately equal to those of imipenem (IPM) and panipenem (PAPM). 2. Carbapenems showed strong antimicrobial activities against Enterobacteriaceae, Glucose non-fermentative Gram-negative rods and Bacteroides fragilis group that were multiple drug resistant including the third generation CEPs. Antimicrobial activities of MEPM against these organisms were stronger than those of IPM and PAPM. By comparing antimicrobial activities of MEPM against Gram-negative bacteria in 1997 with those obtained in 1993, increase of resistance was not observed. 3. MIC-ranges of MEPM were low against the resistant strains of Pseudomonas aeruginosa to IPM and PAPM. It was considered that these resistant strains were not expressing oprD products (D2 porin protein), forming main outer membrane porin channels of carbapenems and basic amino acids.

Bacteria↗
PubMed2001

[Clinical effects of meropenem on infectious diseases in obstetrics and gynecology].

The efficacy and the safety of meropenem (MEPM) were examined in obstetric and gynecological infections and the results shown below were obtained. 1. The subjects were patients with infectious diseases during a non-pregnant period (n = 14), a pregnant period (n = 13) and a puerperal period (n = 11). After intravenous drip infusion of MEPM at 1-2 g/day, the response rate was 38/39 (97.4%) (Excellent: 13/39 (33.3%), Effective: 25/39 (64.1%)). 2. The response rates in a group receiving 1 g/day, a group receiving 2 g/day and a group receiving a combination of both were, respectively, 25/26 (96.2%), 9/9 (100%) and 4/4 (100%). 3. In cases that did not respond to previous treatments, the response rate to MEPM was 20/20 (100%). 4. In clinical efficacy classified by causative organisms, the rate of Excellent was 10/23 (43.5%) and the rate of Effective was 13/23 (56.5%), and the bacterial eradication rate was 21/23 (91.3%). 5. No subjective and objective adverse reactions or abnormalities in clinical laboratory tests due to administration of MEPM were observed.

Adult↗
PubMed2001

[Antimicrobial activities of meropenem against clinically isolated strains in 1999].

We determined the antibacterial activity of meropenem (MEPM) and control drugs against clinical isolates of 310 strains of Gram-positive bacteria (14 species), 590 strains of Gram-positive bacteria (21 species), and 120 strains of anaerobic bacteria (10 species) in 1999. We compared the results thus obtained with those in 1993 and 1997. The results were as follows; 1. MEPM showed excellent antibacterial activities against most of the species tested, except for MRSA, E. faecium, E. avium, and methicillin-resistant S. epidermidis (MRSE). 2. MEPM had much higher activity than IPM and PAPM against Gram-negative bacteria including S. marcescens and P. aeruginosa, part of which have been reported to produce metallo-beta-lactamase. 3. There was little difference in the susceptibility of clinical isolates to MEPM between 1993 and 1999. Thus MEPM was shown to retain its potent and broad antibacterial activity now at the same level as before available for use in 1995.

Bacteria, Anaerobic↗
PubMed2002

[Pharmacokinetic study of penetration of meropenem into pleural effusion in patients with pleurisy].

Complication by secondary infection is observed in not only bacterial pleurisy but also other pleurisy, and the appropriate administration of antibacterial agents is necessary. It is very important to secure a smooth penetration of systemically administered antibacterial agents to pleural effusion in infection therapy. In this study, we investigated the pharmacokinetics of a carbapenem antibiotic, meropenem (MEPM), in blood and pleural effusion in patients with an accumulation of pleural effusion caused by pleurisy, who underwent placement of an indwelling thoracic drain and received intravenous drip administration of MEPM for pneumonia or other respiratory tract infection. The blood pharmacokinetic parameters of MEPM after an intravenous drip administration of 0.5 g MEPM in six patients were: area under the blood concentration-time curve (AUCx), 37.9 +/- 6.2 (hr.mg/L); volume of distribution (Vd), 27.3 +/- 4.4 (L); total clearance (CLtotal), 13.4 +/- 1.8 (L/hr); elimination half life (t1/2), 0.50 +/- 0.08 (hr-1); and elimination rate constant (kel), 1.42 +/- 0.22 (hr). The pharmacokinetic parameters in pleural effusion were: AUCx, 35.7 +/- 7.1 (hr.mg/L); mean retention time (MRT), 5.00 +/- 3.25 (hr); variance of retention time (VRT), 29.9 +/- 44.6 (hr2); kel, 0.34 +/- 0.27 (hr-1); and t1/2, 3.14 +/- 2.36 (hr). The penetration rate calculated from the ratio of pleural concentration to blood concentration in each patient was 46.5 +/- 26.1%, showing good penetration comparable or superior to those of other antibacterial agents previously reported. From these results, it was suggested that MEPM was rapidly penetrated to the pleural effusion and was retained for a more prolonged time in the pleural effusion than in the blood of patients with accumulated pleural effusion, and it suggested the usefulness of MEPM in antibacterial therapy for patients with pleurisy causing accumulation of pleural effusion.

Aged↗
PubMed2002

[Meropenem was effective to the bacterial meningitis due to beta-lactamase negative ampicillin-resistant Haemophilus influenzae; case report].

We experienced a case in the infant of the bacterial meningitis due to beta-lactamase negative ampicillin-resistant Haemophilus influenzae (BLNAR) which has increased in recent years. In the present condition, the sensitivity of the bacteria to the antibacterial-drug used as the initial treatment for the bacterial meningitis is sometimes inadequate. If it takes into consideration that BLNAR participates in H. influenzae meningitis, it will be one of the choice to use meropenem with other antibacterial-drug concomitantly.

Ampicillin Resistance↗