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PubMed1992

[Pharmacokinetic and clinical studies with meropenem in the pediatric field. Pediatric Study Group of Meropenem].

Pharmacokinetic and clinical evaluations in pediatrics were made on meropenem (SM-7338, MEPM), a new parenteral dehydropeptidase-1 stable carbapenem used without any inhibitors, at 33 medical institutions. The results are summarized as follows. 1. Pharmacokinetic studies. MEPM at a dose of 10, 20, or 40 mg/kg was administered to 53 children by 30-minute drip infusion. Peak plasma concentrations (Cmax's) and plasma half-lives (T1/2's) of these doses were 28.5, 47.2 and 130.0 micrograms/ml, and 0.80, 0.93 and 0.94 hours, respectively. A clear dose response was observed in Cmax's and T1/2 values were quite similar to those observed in adults. In the first 6 hours after administration, 54.4 to 68.1% of the administered drug was recovered in urine. The cerebrospinal fluid (CSF) levels of MEPM in patients with purulent meningitis were 0.13 microgram/ml at a dose of 6 mg/kg, and 0.64 to 4.22 micrograms/ml at a dose of 29 to 44 mg/kg within day 4 of onset. The penetration rate of MEPM showed an intermediate value among those for other cephalosporin antibiotics. 2. Clinical study. Clinical efficacies of MEPM were evaluated in 389 cases. The most common doses used were 10 to 20 mg/kg/once, 2 to 3 times a day. The maximum dose was 173 mg/kg/day q.i.d. MEPM gave "excellent" or "good" responses in 242 (97.6%) out of 248 cases in which causative organisms were documented and in 134 (95.0%) out of 141 cases in which causative organisms were not identified. Clinical efficacy rates were 100% in 11 patients with purulent meningitis, 85.7% in 7 with septicemia, 98.8% in 173 with pneumonia, and 100% in 65 with UTI. Bacteriologically, 260 strains (96.7%) out of 269 strains were eradicated by MEPM treatment. Eradication rates were 89.2% for Staphylococcus aureus (37 strains) and 100% for Streptococcus pneumoniae (35 strains). The overall eradication rate for Gram-positive bacteria was 94.6%. Among Gram-negative bacteria, 98.3% out of 172 strains were eradicated. The eradication rate of Haemophilus influenzae (73 strains) was 98.6% and Pseudomonas aeruginosa (11 strains) was 90.9%, and all of Branhamella catarrhalis (15 strains), Escherichia coli (42 strains), and Klebsiella pneumoniae (6 strains) were eradicated. Out of 84 cases for which previous antibiotic therapies of 3 days or longer were not successful, MEPM gave "excellent" or "good" responses in 77 cases (91.7%) and excellent bacteriological responses (95.7%).(ABSTRACT TRUNCATED AT 400 WORDS)

Bacterial Infections↗

PubMed1992

Beta-lactamase stability and inhibitory activity of meropenem combined with a potent antibacterial activity.

The affinity of meropenem for various known types of beta-lactamases and its stability to them were tested in comparison with other beta-lactams, including imipenem. Meropenem exhibited a marked stability to all beta-lactamases tested and was only hydrolyzed by Xanthomonas maltophilia beta-lactamase, as were other beta-lactams. This was responsible for the potent antibacterial activities of meropenem against beta-lactamase-producing strains. Meropenem and imipenem had almost the same, relatively high affinity for beta-lactamases; however, they had a lower affinity than clavulanic acid for penicillin beta-lactamases and cefoxitin for cephalosporin beta-lactamases. Meropenem also had higher beta-lactamase inhibitory activity than imipenem. Meropenem inhibited type III (TEM-1), Ia Citrobacter freundii and Ic Proteus vulgaris beta-lactamases in a progressive manner. Meropenem was thought to be a potent inhibitor of various beta-lactamase because of its ability to form stable enzyme-meropenem acyl-complexes. Meropenem generally exhibited a lower induction potential than imipenem against five clinical isolates of C. freundii, Enterobacter cloacae and Pseudomonas aeruginosa, but its induction potential was higher than that of ceftazidime. Meropenem induced beta-lactamases at concentrations above the MIC.

Bacteria↗

PubMed1992

Pharmacokinetics of meropenem (ICI 194,660) and its metabolite (ICI 213,689) in healthy subjects and in patients with renal impairment.

The pharmacokinetics of meropenem (ICI 194,660) and its open-ring metabolite (ICI 213,689) were studied in 6 healthy volunteers and 16 patients with moderate to severe renal impairment after a single intravenous dose of 500 mg given as a 30-min infusion. Concentrations of unchanged meropenem in plasma and urine were measured by both microbiological and high-pressure liquid chromatographic (HPLC) assays. A good correlation was found between the two techniques. Pharmacokinetic parameters of unchanged meropenem were determined by using the HPLC data. The terminal half-life of unchanged meropenem increased in relation to the degree of renal impairment, being 1.2 h in subjects with normal renal function and 10 h in patients with end-stage renal failure. Total body clearance and renal clearance of unchanged meropenem are linearly related to creatinine clearance. The concentrations of the metabolite in plasma, which are very low in healthy subjects, significantly increased in uremic patients. The apparent half-life of ICI 213,689 increased in uremic patients and was about 35 h in patients with severe renal insufficiency. Meropenem and its metabolite are effectively removed by hemodialysis. The dialysis clearance of the unchanged drug was 81 +/- 22 ml/min. Dosage adjustments of meropenem will be necessary in patients with severe renal impairment.

Adult↗

PubMed1992

Cross-resistance to meropenem, cephems, and quinolones in Pseudomonas aeruginosa.

Multiple-drug-resistant mutants were isolated from Pseudomonas aeruginosa PAO1 on agar plates containing ofloxacin and cefsulodin. These mutants were four to eight times more resistant to meropenem, cephems, carbenicillin, quinolones, tetracycline, and chloramphenicol than the parent strain was. In contrast, these mutants showed no significant changes in their susceptibilities to all carbapenems except meropenem. In these mutants, the amounts of an outer membrane protein with an apparent molecular weight of 49,000 (designated OprM) were increased compared with the amount in PAO1. Multiple-drug-resistant mutants of this type were also isolated from PAO1 on agar plates containing meropenem. Approximately 5% of clinical isolates showed cross-resistance to meropenem, cephems, and quinolones, concomitant with overproduction of OprM. Moreover, these two phenotypes, i.e., multiple-drug resistance and overproduction of OprM, were cotransferable by transduction. These data suggest that overproduction of OprM is associated with cross-resistance to meropenem, cephems, and quinolones in P. aeruginosa. The ofloxacin-cefsulodin-resistant mutant required higher concentrations of meropenem to induce beta-lactamase than PAO1 did, indicating the possibility that this mutation involves decreased outer membrane permeability to meropenem.

Anti-Bacterial Agents↗

PubMed1992

Diffusion of meropenem and imipenem through the outer membrane of Escherichia coli K-12 and correlation with their antibacterial activities.

The outer membrane permeability to meropenem and imipenem in Escherichia coli K-12 was investigated, and its porin-deficient mutants were transformed with a constructed vector carrying the carbapenem-hydrolyzing CphA metallo-beta-lactamase gene. By using the method of Zimmermann and Rosselet, meropenem was shown to penetrate through the outer membrane of E. coli K-12 five times faster than cephaloridine but twice as slowly as imipenem. Lack of one or both porins significantly reduced the penetration of both carbapenems. No evidence of specific porin pathways of the type described in Pseudomonas aeruginosa was found. Despite its slower penetration, meropenem was two to eight times more active than imipenem against both parent and porin-defective mutants, whether harbouring CphA beta-lactamase or not. Meropenem was also more active than imipenem against E. coli DC2, a strain with a breakdown in the outer membrane permeability which made periplasmic concentrations of beta-lactams similar to the external concentrations. In this strain, meropenem caused a more than 50% reduction in cell number increase at a concentration very close to the 50% inhibitory concentration for penicillin-binding protein type 2 (PBP 2), whereas imipenem, at the same concentration, did not significantly inhibit cell growth. This result was explained by the higher affinity of meropenem for PBP 3 compared with imipenem and supports the conclusion that synergistic inhibition of both PBPs was the main mechanism in the better antibacterial activity of meropenem.

Bacteria↗

PubMed1992

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

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

Bacteria↗

PubMed1992

Pharmacokinetics of meropenem and its metabolite in young and elderly healthy men.

The pharmacokinetics of meropenem and its ring-opened metabolite (ICI 213,689) were investigated with eight young (20- to 34-year-old) and eight elderly (67- to 80-year-old) healthy male volunteers given single 30-min intravenous infusions of 500 mg of meropenem. All subjects had normal age-correlated glomerular function. The mean terminal half-life of meropenem was 1.27 h in the elderly subjects versus 0.81 h in the younger subjects (P less than 0.001). This and similar increases in mean residence time and area under the concentration-time curve were explained by a reduction in total [139 versus 203 ml/(min.1.73 m2); P less than 0.001], renal, and nonrenal clearances in subjects at advanced ages. The apparent volume of distribution and urinary recovery over 8 h were not significantly altered. With the metabolite, prolonged serum half-life and mean residence time, enlarged area under the concentration-time curve, and lower renal clearance but no significant changes in peak plasma concentration or urinary recovery were found in the elderly. The reduction in the renal excretion rate of meropenem and its metabolite corresponds to the age-associated physiological decline in renal function. The capacity to metabolize meropenem may also be slightly impaired in people at advanced ages. Dose reduction of meropenem should be considered for elderly patients.

Adult↗

PubMed1992

Pharmacokinetics of meropenem in subjects with various degrees of renal impairment.

Five healthy volunteers and 18 patients with various degrees of renal impairment received 500 mg of meropenem intravenously as a 30-min infusion. Five dialysis patients were dosed 2 h prior to hemodialysis, and four of them were also dosed between hemodialysis treatments. Plasma and urine samples were collected for up to 48 h and 12 h, respectively. Concentrations of meropenem and its open ring metabolite ICI 213,689 were determined by high-performance liquid chromatography and radioimmunoassay, respectively. The subjects were divided into four groups with glomerular filtration rates (GFR) of greater than 80, 30 to 80, 5 to 29, or less than 5 ml/min. There were linear correlations between the GFR and the rates for total plasma clearance as well as renal clearance of meropenem (group mean values for total clearance of 186, 74, 53, and 19 ml/min/1.73 m2, respectively). In subjects with normal renal function, nonrenal clearance accounted for approximately 20% of total elimination, increasing to about 50% in patients with GFR between 5 and 29 ml/min/1.73 m2. The terminal half-life of meropenem increased from 0.9 h in the healthy volunteers to 6.8 h in patients with end-stage renal disease. The half-life of ICI 213,689 was 2.31 h in the healthy volunteers and increased to 23.6 h in patients with GFR of 5 to 29 ml/min. In patients with end-stage renal disease, half-lives could not be measured, as concentrations were hardly declining during the 48-h observation period. The area under the concentration-time curve for meropenem increased more than 10-fold. Both meropenem and its open ring metabolite were readily dialyzable, with dialysis clearances of 79 and 81 ml/min/1.73 m2, respectively.

Adult↗

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↗

PubMed1992

In-vitro activity of new carbapenem antibiotics: comparative studies with meropenem, L-627 and imipenem against pathogenic Nocardia spp.

MICs of two new carbapenems, meropenem and L-627, and imipenem were determined against 98 strains of the Nocardia asteroides group (i.e. N. asteroides sensu stricto, Nocardia farcinica and Nocardia nova), 46 strains of Nocardia brasiliensis and 17 strains of Nocardia otitidiscaviarum. Meropenem and L-627 were less active against the N. asteroides group than imipenem. Among the three species of the N. asteroides group, N. nova was the most sensitive to all the carbapenems. Meropenem was more active than imipenem against both N. brasiliensis and N. otitidiscaviarum with MIC50 values of 28.3-53.3 mg/L. L-627 was less active than meropenem.

Carbapenems↗

PubMed2026

Empirical Meropenem Versus Piperacillin/Tazobactam for Critically Ill Adults With Sepsis: Feasibility of a Randomised Trial.

BACKGROUND: Meropenem and piperacillin/tazobactam are commonly used empirical antibiotics in critically ill adults with sepsis, but whether one is superior to the other is uncertain. METHODS: The Empirical Meropenem versus Piperacillin/Tazobactam for Adult Patients with Sepsis (EMPRESS) trial is an ongoing investigator-initiated, randomised, open-label, adaptive clinical trial with an integrated feasibility phase comparing empirical treatment with meropenem versus piperacillin/tazobactam in critically ill adults with sepsis. The integrated feasibility phase enrolled 200 participants across 10 intensive care units (ICUs) in Denmark between 28 June and 12 December 2025. Five pre-specified feasibility criteria were evaluated; if all feasibility criteria were met, the trial would proceed unaltered, whereas failure to meet one or more criteria would require intervention and re-evaluation. RESULTS: We randomised 200 of 284 screened patients (70.4%). The median age was 70 years (interquartile range (IQR): 60-77), 65.5% were males. At randomisation, 80.0% received vasopressors or inotropes, and 43.5% were on invasive mechanical ventilation. Four of five pre-specified feasibility criteria were met: time to completion of the feasibility phase (5.5 months vs. threshold < 12.0 months), recruitment proportion (70.4% vs. threshold ≥ 50.0%), proportion of participants without consent to the continued collection of data (2.5% vs. threshold < 5.0%) and protocol adherence (81.0% vs. threshold ≥ 75.0%). The proportion of participants with timely primary outcome data availability (30-day mortality) within 45 days was 85.5% and below the pre-specified threshold of ≥ 95.0%. The proportions were low in the first 3 months (33.3%, 22.2% and 30.8%, respectively), increasing to 95.8% in the last month of the feasibility phase. All-cause mortality at 30 days was 30.5%, and specific serious adverse reactions occurred in 4.0% of participants. CONCLUSIONS: In this integrated feasibility evaluation of the EMPRESS trial comparing empirical meropenem versus piperacillin/tazobactam in critically ill adults with sepsis, four of five pre-specified feasibility criteria were met. The unmet criterion, timely primary outcome data availability, improved substantially during the feasibility phase. We consider the trial feasible and will proceed without modifications. EDITORIAL COMMENT: This feasibility study assessed recruitment, randomised allocation and data collection for the multicentre EMPRESS trial. For adaptive trials on trial platforms, careful interim checking of trial design functions is an important and necessary process. TRIAL REGISTRATION: Clinical Trials Information System EUCT number: 2023-509703-33-00; ClinicalTrials.gov identifier: NCT06184659; Universal Trial Number: U1111-1301-6379.

Humans↗

PubMed1992

Stability of meropenem and effect of 1 beta-methyl substitution on its stability in the presence of renal dehydropeptidase I.

The stability of meropenem in the presence of renal dehydropeptidase I (DHP-I) varied extremely with the animal source of the enzyme. Meropenem, compared with imipenem, was rather easily hydrolyzed by DHP-Is from mice, rabbits, and monkeys, while it showed a higher resistance to guinea pig and beagle dog DHP-Is. In addition, meropenem was four times more resistant than imipenem to human DHP-I. The 1 beta-methyl substituent on carbapenems, i.e., meropenem and 1 beta-methyl imipenem, made them considerably more resistant to mouse and swine DHP-Is than the 1-unsubstituted derivatives are.

Animals↗

PubMed2026

Evaluation of sequential phage-antibiotic therapy reveals enhanced biofilm control with meropenem and colistin in clinical MDR hypervirulent Klebsiella pneumoniae strain.

AIMS: The convergence of multidrug resistance and hypervirulence in Klebsiella pneumoniae (MDR-HvKp) has narrowed treatment options. Despite growing interest in phage-antibiotic synergy, this study evaluates the underexplored combinatorial effects of phage and antibiotics, including drug-specific interactions and sequence dependency, against the biofilm-forming MDR-HvKp clinical strain. METHODS AND RESULTS: A T5-like Klebsiella bacteriophage, Round, within the genus Webervirus, was therapeutically and genomically characterized. A biofilm-forming clinical strain, Kleb_134, was used to evaluate in vitro phage-antibiotic interactions with meropenem, colistin, and tigecycline in planktonic and biofilm models.In planktonic assays, phage combinations with meropenem and colistin resulted in a multi-log CFU reduction compared to monotherapies, whereas reduced efficacy was observed with tigecycline. In biofilm assays, pre-phage treatment followed by antibiotic exposure demonstrated the strongest biofilm reduction. Drug-specific and sequence-dependent effects were evident. Meropenem-phage combinations reduced biofilm biomass by 2.85-fold (high phage titre) and 3.8-fold (low phage titre), while colistin-phage combinations achieved reductions of 8.4-fold (high phage titre) and 2.8-fold (low phage titre). CONCLUSIONS: Sequential phage-antibiotic treatment was effective against MDR-HvKp biofilms, with pre-phage exposure enhancing antibiotic access through biofilm disruption. The bacteriostatic nature of tigecycline reduced efficacy by affecting phage replication. These findings highlight the importance of treatment sequence and antibiotic selection, and extend existing knowledge in optimizing therapeutic outcomes in MDR-HvKp infections.

Biofilms↗

PubMed1992

In vitro activity of meropenem and other agents against oral bacteria.

The susceptibility of 106 oral bacteria to meropenem, a new carbapenem antimicrobial, penicillin V, tetracycline and metronidazole was assessed by an agar dilution method. Meropenem was the most effective of the antimicrobials, with all strains tested being inhibited at < or = 1 mg/l. A number of strains were resistant to penicillin V, particularly Bacteroides gracilis, and tetracycline resistance was widespread amongst the streptococci tested. Metronidazole was extremely effective against obligate anaerobes. The results of this study suggest that meropenem has potential for use in the treatment of serious head and neck infections.

Anti-Bacterial Agents↗

PubMed1992

Interpretive criteria and quality control guidelines for lomefloxacin and meropenem in susceptibility tests of Haemophilus influenzae using Haemophilus test medium.

Lomefloxacin and meropenem were tested in a multilaboratory study to establish susceptibility testing interpretive criteria and quality control (QC) guidelines for Haemophilus influenzae using Haemophilus test medium (HTM). Interpretive criteria were established by using triplicate testing of 102 representative H. influenzae strains. Only a susceptible category was proposed for lomefloxacin (greater than or equal to 22 mm and less than or equal to 2 micrograms/ml) and meropenem (greater than or equal to 13 mm and less than or equal to 4 micrograms/ml) due to the lack of resistant isolates. QC range for H. Influenzae ATCC 49247 were established using multiple HTM agar and broth base lots, three disk lots for each drug, and a number of test replicates consistent with the National Committee for Clinical Laboratory Standards M23-T guideline.

Anti-Infective Agents↗

PubMed1992

A study of the penetration of meropenem into bile using endoscopic retrograde cholangiography.

One gram of meropenem was administered as prophylaxis to patients undergoing endoscopic retrograde cholangiography (ERC) in a study of the bile pharmacokinetics of this agent. Twenty-four patients were evaluated and a single bile sample was collected from each one during ERC at different time intervals following intravenous infusion. Bile concentrations after the dose ranged from 0.7 to 25.7 mg/L (mean 11.1) and exceeded the MIC90s for the pathogens most commonly associated with biliary tract infections for up to 203 mins. The bile concentrations of 13 patients with biliary tree obstruction were compared with those of 11 patients without obstruction. Bile concentrations in excess of the MIC90s for the predominant pathogens were achieved in both groups; a positive correlation between meropenem bile concentration and the time of dose administration was demonstrable only for the obstructed group. ERC may be a useful technique for biliary pharmacokinetic studies.

Adult↗

PubMed1992

In vitro activity of meropenem and imipenem against mycobacteria: development of a daily antibiotic dosing schedule.

The activity of two carbapenem antibiotics, meropenem and imipenem, against Mycobacterium species was assessed by means of the Bactec 460 radiometric apparatus. This system allowed a result to be read in 4-10 days. The instability of imipenem, particularly, in the test system necessitated the development of a regimen of daily addition of antibiotic to permit a more accurate assessment of antibiotic activity to be made. When antibiotic-containing media are incubated for long periods, as is the case when determining antimycobacterial activity, the stability of test antibiotics is an important factor that must be considered.

Culture Media↗

PubMed2026

Meropenem-Colistin Combination Mitigates Porin-Associated Carbapenem Resistance Development in Ertapenem-Mono-Resistant Enterobacterales.

BACKGROUND: Non-carbapenemase-producing Enterobacterales with isolated ertapenem resistance (ETP-mono-R) may represent an early stage in the evolution toward broader carbapenem resistance, but whether further resistance induction occurs and its underlying mechanisms remain poorly understood. METHODS: Resistance induction was assessed in three Escherichia coli, four Klebsiella pneumoniae, and two Enterobacter cloacae isolates through serial exposure to subinhibitory concentrations of meropenem (MEM), imipenem, ceftazidime-avibactam, or colistin (COL), with antibiotic-free passaging for reversion. Resistance induction under MEM+COL was evaluated separately. Whole-genome sequencing (WGS), targeted porin-gene Sanger sequencing, and transcriptional analysis were used to characterize resistance mechanisms across induction stages. RESULTS: Subinhibitory MEM exposure rapidly selected for carbapenem resistance through porin-associated alterations in a species-specific manner. E. coli accumulated loop-region mutations in ompC, while K. pneumoniae predominantly developed disruptive mutations in ompK36, both accompanied by marked transcriptional downregulation. In contrast, E. cloacae retained wild-type porins but showed increased MEM MICs, suggesting a non-porin-mediated mechanism. Subinhibitory exposure to COL alone rapidly induced colistin resistance but was associated with decreased carbapenem MICs. Co-exposure to MEM and COL significantly delayed resistance development and reduced MIC increases (all P < 0.05). Targeted sequencing of 26 non-carbapenemase-producing K. pneumoniae isolates resistant to all carbapenems revealed widespread disruptive ompK36 alterations, including the S337P substitution identified experimentally, consistent with a shared permeability-loss pathway. CONCLUSIONS: In ETP-mono-R Enterobacterales, subinhibitory carbapenem exposure promotes carbapenem resistance, with porin-associated mechanisms predominating in E. coli and K. pneumoniae. Co-exposure to COL attenuates this process, suggesting a potential strategy to delay the emergence of carbapenem resistance.

Enterobacterales↗