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PubMed1992

Pharmacokinetics of meropenem in subjects with renal insufficiency.

The pharmacokinetics of IV meropenem (500 mg over 30 min) has been studied in 6 healthy volunteers and 26 patients with various degrees of renal impairment. Blood samples were taken at different times over 24 h in healthy subjects and 36 to 48 h in uraemic patients, and four or five urine samples were collected over 24 or 48 h. Meropenem concentrations in plasma and urine were measured by a microbiological assay. The mean peak plasma concentration of meropenem ranged from 28 to 40 micrograms.ml-1 and was not affected by the degree of renal impairment. The terminal half-life of meropenem was approximately 1 h in subjects with normal kidney function and it was proportionately increased as renal function decreased. A significant linear relationship between total body clearance and creatinine clearance as well as between renal clearance and creatinine clearance was observed. The mean apparent volume of distribution at steady state was not significantly altered in uraemic patients. The mean cumulative urinary recovery of meropenem in healthy volunteers was 77% of the administered dose and it was significantly decreased in patients with renal impairment. Haemodialysis shortened the elimination half-life, from 9.7 h during the predialysis period to 1.4 h during the dialysis period. The dose of meropenem should be reduced in relation to the decrease in creatinine clearance.

Adult↗

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↗

PubMed1991

Pharmacokinetics of meropenem compared to imipenem-cilastatin in young, healthy males.

Imipenem combined with cilastatin and meropenem was given as intravenous infusions of 1 g to eight young, healthy males on two separate occasions. Blood and urine samples were collected for up to 12 h. The terminal half-lives in plasma were 0.98 h and 1.11 h for meropenem and imipenem, respectively. The volume of distribution was smaller for meropenem than for imipenem (12.5 l and 14.4 l, respectively). The plasma clearance for meropenem was 188 (SD 31) ml/min and for imipenem 183 (SD 25) ml/min. Renal clearance was on average 139 (SD 24) ml/min and 135 (SD 11) ml/min, respectively. About 75% of the administered dose of both compounds was eliminated unchanged in urine. Non-renal clearance accounted for approximately 25% of the total clearance for both drugs. The kinetics of meropenem are very similar to those of imipenem given with cilastatin, and meropenem is as stable against renal metabolic degradation as imipenem combined with cilastatin.

Adult↗

PubMedDate not supplied

In vitro activity of meropenem (SM-7338), imipenem, and five other antibiotics against anaerobic clinical isolates.

The in vitro susceptibility of 513 recent anaerobic clinical isolates was evaluated against meropenem (SM-7338), a new carbapenem, and six other antibiotics. Virtually all Gram-positive and Gram-negative anaerobic bacteria tested were susceptible to meropenem (defined as MICs less than or equal to 8 micrograms/ml) with 99.8% of the isolates inhibited by less than or equal to 4 micrograms/ml. The activity of meropenem was comparable to imipenem for most clinical isolates. Minor differences were observed for Clostridium and Veillonella (meropenem more active) and other Gram-positive bacilli (imipenem more active). Meropenem inhibited all anaerobes resistant to clindamycin and metronidazole. Bactericidal tests performed with meropenem demonstrated killing activity against all isolates except Clostridium and Lactobacillus.

Anti-Bacterial Agents↗

PubMed1989

Antibacterial properties of meropenem towards clinical isolates, beta-lactamase producers and laboratory mutants.

Clinical isolates (1017) obtained from a multicentre study were examined. The activity of meropenem was better than that of imipenem against Enterobacteriaceae and Pseudomonas aeruginosa. Meropenem was slightly less active against staphylococci than was imipenem. Meropenem had little activity against enterococci (MIC90, 16 mg/l). Mutants selected with imipenem or meropenem remained more sensitive to meropenem but MICs increased for both drugs. Other resistance mechanisms such as beta-lactamases or aminoglycoside modifying enzymes did not influence meropenem activity with the exception of beta-lactamase from Ps. cepacia.

Bacteria↗

PubMed1989

The postantibiotic effect of meropenem and imipenem on selected bacteria.

Controlled experiments were conducted to determine the in-vitro postantibiotic effect (PAE) of meropenem and imipenem on ten selected bacteria representative of medically important species: Staphylococcus aureus (2). Pseudomonas aeruginosa (4), Escherichia coli (1), Serratia marcescens (1), Morganella morganii (1), and Providencia stuartii (1). The PAE was determined by comparing serial colony counts of cultures recovering from exposure to drug concentrations at 4 x MIC for 1.5 h with the counts of drug-free controls. A PAE was observed with both meropenem and imipenem when tested against four strains of Ps. aeruginosa (meropenem PAE = 0.8-2 h; imipenem PAE = 1.2-2.5 h) and two strains of Staph. aureus (meropenem PAE = 0.7, 1.7 h; imipenem PAE = 1.7, 1.8 h). In addition, a PAE was observed with meropenem on two of four Enterobacteriaceae, E. coli ATCC 25922 (0.8 h) and Prov. stuartii (1.2 h), but not with one strain each of M. morganii and Ser. marcescens. A PAE was not observed when imipenem was tested against the four Enterobacteriaceae. Studies are suggested to investigate further the PAE of meropenem on additional strains of Enterobacteriaceae.

Bacteria↗

PubMed1989

Comparative in-vitro activity of meropenem on clinical isolates from the United Kingdom.

MICs of meropenem were determined for a wide range of common bacteria of clinical importance. For Enterobacteriaceae, Aeromonas spp., Haemophilus influenzae, Branhamella catarrhalis, Neisseria gonorrhoeae, Gardnerella vaginalis, Campylobacter coli/jejuni, beta-haemolytic streptococci and anaerobes other than Clostridium difficile, MICs were almost always within the range 0.002-0.5 mg/l. The activity of meropenem for these organisms was always greater than that of imipenem and piperacillin, and was similar to that of ceftazidime and cefotaxime except that strains resistant to these latter, and to piperacillin, were usually sensitive to imipenem and meropenem. Meropenem was also active against most non-fermentative Gram-negative bacilli, with MICs in the range 0.12-4 mg/l but Pseudomonas (Xanthomonas) maltophilia was often resistant, as it was to all the other drugs tested. Staphylococci, Strreptococcus pneumoniae and other alpha-haemolytic streptococci were usually more sensitive to imipenem than to meropenem, but even methicillin-resistant staphylococci were sensitive to both drugs (MICs less than 4 mg/l). Enterococci were also less sensitive to meropenem than to imipenem, and Enterococcus faecium was invariably highly resistant to all the drugs tested except ciprofloxacin, which had marginal activity. Results for Ps. maltophilia and Haem. influenzae were affected by media used for sensitivity testing.

Bacteria↗

PubMed1989

In-vitro activity of meropenem against clinical isolates obtained in Canada.

The in-vitro activity of meropenem, a new parenteral carbapenem, was compared with that of imipenem, ceftazidime, cefotaxime, piperacillin, gentamicin and, where appropriate, other antibiotics against recent clinical isolates and characterized beta-lactamase producers. MICs were determined by a standard agar dilution procedure and two inocula (10(4) and 10(6) cfu) were used throughout. Meropenem inhibited 90% of isolates of Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, indole-positive Proteus spp., Enterobacter spp., Serratia marcescens and Providencia stuartii at less than or equal to 0.25 mg/l and was four- to 16-fold more active than imipenem against these species. Against the enteric pathogens Salmonella typhi, Shigella sonnei, Yersinia enterocolitica and Campylobacter jejuni, meropenem was four- to eight-fold more active than imipenem, inhibiting all isolates at less than or equal to 0.03 mg/l. Meropenem was also more active than imipenem against Haemophilus influenzae (MIC90 0.06 mg/l) but had similar activity against the Bacteroides fragilis group (MIC90 0.25 mg/l), against Pseudomonas aeruginosa (MIC90 2 mg/l) and against streptococci. Imipenem was four-fold more active than meropenem against Acinetobacter spp. and two- to eight-fold more active against all species of staphylococci tested. Both meropenem and imipenem were inactive against Ps. (Xanthomonas) maltophilia.

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↗

PubMed1989

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

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

Bacteria↗

PubMed1989

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

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

Bacterial Outer Membrane Proteins↗

PubMed1989

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

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

Ampicillin↗

PubMed1989

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

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

Carbapenems↗

PubMed1989

The pharmacokinetics of meropenem in volunteers.

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

Adult↗

PubMed1989

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

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

Aminoglycosides↗

PubMed1991

Effect of meropenem on the intestinal microflora.

Ten healthy volunteers were given 500 mg of meropenem by intravenous infusion over 30 min three times daily for seven days. Stool specimens were collected before, during and after meropenem administration. The numbers of enterobacteria and streptococci decreased during the administration period, while the numbers of enterococci increased. There was a decrease in the numbers of clostridia, bacteroides and gram-negative cocci, while the numbers of gram-positive cocci and rods were not changed by the administration of meropenem. The intestinal flora returned to normal in all volunteers within two weeks after the termination of meropenem administration.

Adult↗