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At least 19 recordsLinked to original sources
PubMed1988

Effect of imipenem treatment versus imipenem surgical prophylaxis on the intestinal microflora.

The impact of imipenem treatment versus imipenem surgical prophylaxis on the intestinal microflora was investigated in 40 patients. Ten patients received 0.5 g imipenem four times a day and ten patients 1.0 g imipenem four times a day for four to 11 days for treatment of different infections. The imipenem treatment was associated with minor to moderate changes in the intestinal flora. There was a decrease in the numbers of enterobacteria, anaerobic cocci and bacteroides during treatment, but afterwards the microflora was normalized in all patients. No new colonization with imipenem-resistant bacteria was seen. No concentrations of imipenem in faeces were observed. Twenty patients undergoing elective colorectal surgery participated in the imipenem surgical prophylaxis group. To ten patients, imipenem was given in a dose of 0.5 g at induction of anaesthesia followed by subsequent doses of 0.5 g at 6 h intervals for 48 h. The other ten patients received 1 g imipenem at 6 h intervals for 48 h. The aerobic bacteria - staphylococci, streptococci, enterococci and enterobacteria - were suppressed significantly during the prophylaxis period. Among the anaerobic bacteria, cocci, bifidobacteria, eubacteria, lactobacilli, clostridia, fusobacteria and bacteroides decreased markedly during the same period. The microflora was normalized after two weeks. The imipenem concentrations in the intestinal mucosa varied between 0.1-3.6 mg/kg for the dose of 0.5 g and 3.2-13.4 mg/kg for the dose of 1.0 g, and the concentrations in the faecal samples were between 0.1-5.0 mg/kg and 0.7-11.3 mg/kg respectively.

Adolescent↗
PubMed1986

Serum bactericidal activity and killing rate for volunteers receiving imipenem, imipenem plus amikacin, and ceftazidime plus amikacin against Pseudomonas aeruginosa.

Serum bactericidal activity against 20 strains of Pseudomonas aeruginosa was studied in 10 volunteers after administration of imipenem (25 mg/kg), imipenem (25 mg/kg) plus amikacin (7.5 mg/kg), and ceftazidime (25 mg/kg) plus amikacin (7.5 mg/kg). Eight strains were susceptible and 12 were resistant to ticarcillin. Serum levels were measured microbiologically after 30 and 60 min and were, respectively, 97 and 46 micrograms/ml for imipenem given alone and 79 and 45 micrograms/ml for imipenem given with amikacin. Despite the very large dose of imipenem used, imipenem and imipenem plus amikacin appeared slightly less active than ceftazidime plus amikacin (P less than or equal to 0.1; Wilcoxon matched-pairs test), with respective median titers at 30 min of 1:128, 1:128, and 1:256 against ticarcillin-susceptible strains and 1:32, 1:32, and 1:64 against ticarcillin-resistant strains; however, more than 90% of the serum determinations, regardless of the regimen, had a serum bactericidal activity greater than or equal to 1:8. Amikacin significantly increased the rate of killing in serum of P. aeruginosa by imipenem. Imipenem plus amikacin appeared as effective as ceftazidime plus amikacin in reducing the viable counts of P. aeruginosa after 24 h of incubation.

Amikacin↗
PubMed2001

Mechanisms of resistance to imipenem in imipenem-resistant, ampicillin-sensitive Enterococcus faecium.

Enterococcus faecium has six penicillin-binding proteins (PBP), where PBP5 seems to be the main target for beta-lactam antibiotics. The PBP profiles of three imipenem-resistant, ampicillin-sensitive E. faecium strains, isolated from the same patient, were studied using biotinylated ampicillin and chemiluminescence detection. Imipenem resistance in these strains was found to be associated with hyperproduction of PBP5 compared to the ampicillin- and imipenem-susceptible strain ATCC 19434. PBP5 in the imipenem-resistant strains (S1, B2) exhibited a selectively decreased affinity for imipenem. An 854 bp DNA fragment, corresponding to the penicillin-binding domain of pbp5fm, was studied in the resistant strains and the reference strain. Four amino acid substitutions were observed in the resistant strains compared to the susceptible one. The contribution of these substitutions to the increased production of PBP5 in these strains is unclear since the substitution was observed also in a strain without increased production of PBP5. Our results suggest that the moderate imipenem resistance observed in these strains is associated with increased production of PBP5 with relatively decreased affinity for imipenem, and that evolution of imipenem resistance in E. faecium is dinstinct from that of the other beta-lactams such as ampicillin.

Ampicillin↗
PubMedDate not supplied

[Actinomycetoma and Nocardia sp. Report of five cases treated with imipenem or imipenem plus amikacin].

INTRODUCTION: Dapsone with trimethoprim-sulfamethoxazol is currently the standard treatment for actinomycetoma. In select cases, amikacin, streptomycin, kanamycin, amoxicillin/clavulanic acid or phosphomycin may be also added. Imipenem has shown to be effective both in vitro and in vivo against some actinomycetes. Amikacin with Imipenem has a synergistic effect. OBJECTIVES: To report our preliminary findings using imipenem alone or with amikacin for severe or multi-resistant mycetomas due to Nocardia sp. MATERIAL AND METHODS: We present 5 cases of chronic mycetoma infection previously treated with anti-bacterial multidrug regimens. All patients were hospitalized and treated with imipenem 500 mg IV, three times a day for three weeks. Three patients received in addition amikacin. RESULTS: We included 3 male and 2 female patients. The average length of disease duration was 7.4 years. In 3 cases mycetoma was located on the back; one of them involved the rib and the lung. One case was localized in the abdominal wall, and another one involved the posterior side of the cervical region. Two patients achieved clinical and bacteriological cure one year after treatment with Imipenem, and the remaining three displayed clinical improvement, even though grains were observed, cultures where negative. None of the 5 patients studied showed clinical evidence of adverse reactions to Imipenem. CONCLUSIONS: Imipenem is a strong antibiotic and constitutes an important treatment alternative for severe or multi-resistant mycetoma especially for cases with bone and visceral involvement.

Adult↗
PubMed1990

Mechanism of imipenem resistance acquired by three Pseudomonas aeruginosa strains during imipenem therapy.

Imipenem sensitive pretherapy isolates (MICs 1-2 mg/l) and the corresponding resistant posttherapy isolates (MICs 16 mg/l) of Pseudomonas aeruginosa from three patients undergoing imipenem treatment were analyzed to establish the resistance mechanism. The identity of pyocin types, serotypes, DNA restriction endonuclease profiles and plasmid profiles strongly suggested isogenicity of pre- and posttherapy isolates. The imipenem resistant posttherapy isolates showed cross-resistance only to another carbapenem, meropenem. There were neither qualitative nor quantitative differences between pre- and posttherapy isolates in beta-lactamase production. Affinity of the penicillin-binding proteins 1A, 1B, 2, 3, 4,4' and 5 for [14C]imipenem was the same in pre- and posttherapy isolates. One-dimensional and two-dimensional gel electrophoresis of outer membrane protein preparations showed diminished expression of an outer membrane protein of about 46.5 and 47.5 kilodaltons, respectively, in the posttherapy isolates. This protein had an apparent isoelectric point of about pH 5.2 in two-dimensional gel electrophoresis. Growth in proteose peptone no. 2 broth did not reduce expression of this outer membrane protein, which spoke against its identity with the outer membrane protein D1. The permeability of the outer membrane for imipenem was reduced in the posttherapy isolates, since addition of 0.5 or 0.25 of the MIC of the permeabilizing agent ethylene-diaminetetraacetate reduced the MICs of imipenem for all isolates from each patient to the same (susceptible) level. The diminished expression of one of the outer membrane proteins might be the reason for this reduced permeability.

Bacterial Outer Membrane Proteins↗
PubMed1987

Synergism of the combinations of imipenem plus ciprofloxacin and imipenem plus amikacin against Pseudomonas aeruginosa and other bacterial pathogens.

The combinations of imipenem plus ciprofloxacin and imipenem plus amikacin were investigated for their activity against Pseudomonas aeruginosa and other bacterial pathogens. For imipenem-susceptible P. aeruginosa, synergy of imipenem plus ciprofloxacin and imipenem plus amikacin was observed against 36 and 45% of the strains, respectively. The incidence of synergy against imipenem-resistant isolates of P. aeruginosa was 10% for both combinations. Antagonism was not observed with either combination.

Amikacin↗
PubMed1994

Prospective randomized comparison of imipenem monotherapy with imipenem plus netilmicin for treatment of severe infections in nonneutropenic patients.

Nosocomial pneumonia and sepsis, as well as severe diffuse peritonitis, must be treated early in order to prevent complications such as septic shock and organ dysfunctions. With the availability of new broad-spectrum and highly bactericidal antibiotics, the need of combining beta-lactams with aminoglycosides for the treatment of severe infections should be reassessed. A prospective randomized controlled study was performed to compare imipenem monotherapy with a combination of imipenem plus netilmicin in the empiric treatment of nosocomial pneumonia, nosocomial sepsis, and severe diffuse peritonitis. A total of 313 patients were enrolled, and 280 were assessable. The antibiotic treatment was successful in 113 of 142 patients (80%) given the monotherapy and in 119 of 138 patients (86%) given the combination (P = 0.19). The failure rates for the most important type of infection, i.e., pneumonia, were similar in the two groups, as well as the number of superinfections. While creatinine increase was associated with factors not related to antibiotic therapy for all eight patients of the monotherapy group, no factor other than the antibiotics could be found for 6 of the 14 cases of nephrotoxicity observed in the combination group (P = 0.014). Finally, the emergence of Pseudomonas aeruginosa resistant to imipenem occurred in 8 monotherapy patients and in 13 combination therapy patients. In conclusion, imipenem monotherapy appeared as effective as the combination of imipenem plus netilmicin for the treatment of severe infection. The addition of netilmicin increased nephrotoxicity, and it did not prevent the emergence of P. aeruginosa resistant to imipenem.

Adult↗
PubMed2026

Molecular determinants associated with resistance to imipenem and imipenem-relebactam in clinical Pseudomonas aeruginosa isolates.

BACKGROUND: Pseudomonas aeruginosa accounts for 10-20% of hospital-acquired infections and is a major pathogen in immunocompromised patients. Combination therapies with beta-lactam antibiotics and beta-lactamase inhibitors, such as imipenem-relebactam have improved treatment options, yet resistant strains have already emerged, with mechanisms still not fully elucidated. RESULTS: We sequenced and analyzed 10 clinical P. aeruginosa isolates resistant to imipenem-relebactam (IMI/REL) and compared them with publicly available genomes of imipenem-resistant (IMI-R) and imipenem-susceptible (IMI-S) strains. Resistance genes were identified using the RGI CARD database, while amino acid variations in core-genome proteins were evaluated through Gene Ontology overrepresentation analysis (GO), followed by GWAS. In total, 15,758 ARGs were detected, 25.85% associated with carbapenem resistance, but only 568 classified as beta-lactamases. Among IMI/REL isolates, 36.36% carried Ambler class A and 54.54% class B beta-lactamases, contrasting with much lower frequencies in IMI-R (5.4% and 3.6%) and IMI-S (0% and 0.73%). Core-genome analysis revealed 1,106 proteins with resistance-associated variations. Comparative analyzes identified 1,618 proteins differing between IMI/REL and IMI-R genomes, and 1,015 differing between IMI/REL and all other strains. GWAS highlighted candidate genes with strong statistical associations, including those involved in metal ion transport (e.g., tonB, foxA, phuR, pfeA) and efflux pumps (e.g., czcB), as well as regulators such as mexT and biofilm-related proteins. CONCLUSIONS: These findings suggest that, beyond classical beta-lactamases, resistance may be associated with multifactorial contributions from periplasmic and outer membrane proteins, metal ion homeostasis, efflux regulation, and biofilm-associated pathways. Our results expand current knowledge of P. aeruginosa resistome and highlight novel genomic signatures potentially driving resistance to imipenem-relebactam.

Imipenem↗
PubMed1999

Impaired imipenem uptake associated with alterations in outer membrane proteins and lipopolysaccharides in imipenem-resistant Shigella dysenteriae.

Three imipenem-resistant mutants were obtained from a clinical isolate (C152) of Shigella dysenteriae by selection with increasing concentrations of imipenem. Resistance to imipenem was associated with resistance to several other beta-lactam antibiotics. The penicillin-binding protein (PBP) patterns of the resistant and the wild-type strains were comparable. The permeability of the outer membrane proteins (OMPs) of the most resistant mutant, IM16, was lower than that of the parent strain C152 when imipenem and arabinose were used as test solutes. This mutant had lower levels of both the major OMPs of M(r) 43,000 and 38,000. There were also differences in the patterns of lipopolysaccharide (LPS) of the mutants and the wild-type strain. The mutant IM16 had less short-chain LPS than the parent C152. Increasing imipenem resistance was also associated with a concomitant decrease in the level of 2-keto-3-deoxyoctonate, a component of the core region of LPS.

Anti-Bacterial Agents↗
PubMed1984

Subinhibitory concentrations of imipenem induce increased resistance to methicillin and imipenem in vitro in methicillin-resistant Staphylococcus aureus.

Methicillin-resistant (MR) Staphylococcus aureus that was susceptible to less than 0.75 micrograms of imipenem per ml demonstrated inducible resistance. MR S. aureus preincubated with 0.05 microgram of imipenem per ml grew in medium with an imipenem concentration of 32 micrograms/ml, and methicillin MICs increased 20-fold. Non-MR S. aureus exhibited no induction. Preincubation with methicillin produced no effect. Induction appeared to be a unique interaction of imipenem with MR S. aureus.

Enzyme Induction↗
PubMed1998

Failure of quality control measures to prevent reporting of false resistance to imipenem, resulting in a pseudo-outbreak of imipenem-resistant Pseudomonas aeruginosa.

False results showing an outbreak of Pseudomonas aeruginosa with resistance to imipenem were traced to a defective lot of microdilution MIC testing panels. These panels contained two- to threefold lower concentrations of imipenem than expected and resulted in artifactual two- to fourfold increases in MICs of imipenem. The quality-control MIC results for Pseudomonas aeruginosa ATCC 27853 were 4 microg/ml, the highest value within the range recommended by the National Committee for Clinical Laboratory Standards. We recommend that this value be considered out of the quality-control range.

Case-Control Studies↗
PubMed1991

[Susceptibilities of clinical bacterial isolates to antimicrobial agents, 1989. A study mainly focused on imipenem. The Research Group for Testing Imipenem Susceptibilities of Clinical Isolates].

We investigated susceptibilities of clinical bacterial isolates to imipenem (IPM) and other antimicrobial agents at hospital laboratories throughout Japan from September to December of 1989. The susceptibility testing was carried out according to the 1-dilution or 3-dilution disc technique in which susceptibilities are classified into 4 grades: (+++), (++), (+) and (-). IPM showed markedly high in vitro activities against Streptococcus pneumoniae, Neisseria gonorrhoeae, Moraxella catarrhalis, Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Citrobacter freundii, Acinetobacter calcoaceticus, Bacteroides fragilis and had rather strong activities against Enterococcus faecalis, Haemophilus influenzae, Serratia marcescens, Proteus mirabilis, Morganella morganii, Pseudomonas aeruginosa and Achromobacter xylosoxidans, but was less active to Staphylococcus aureus, coagulase-negative staphylococci and Xanthomonas maltophilia. IPM has been found to have activities superior to those of other antibiotics tested against E. faecalis, E. cloacae, C. freundii, S. marcescens, P. aeruginosa and B. fragilis. No antibiotics tested showed good activities against MRSA except minocycline.

Bacteria↗
PubMed1990

[Susceptibilities of clinical bacterial isolates to antimicrobial agents. A study mainly focused on imipenem. Research Group for Testing Imipenem Susceptibility on Clinical Isolates].

We investigated susceptibilities of clinical bacterial isolates to imipenem (IPM) and other antimicrobial agents at 459 hospital laboratories throughout Japan from September to December of 1988. In this study, identification and susceptibility testing were performed at each hospital laboratory and the tests were carried out according to the 1-dilution or 3-dilution disc technique in which susceptibilities are classified into 4 grades: , ++, + and -. IPM had significantly high activity against Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus agalactiae, Neisseria gonorrhoeae, Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca, Enterobacter aerogenes, Enterobacter cloacae, Salmonella spp., Citrobacter freundii, Proteus mirabilis, Providencia rettgeri, Acinetobacter calcoaceticus, Moraxella catarrhalis, Alcaligenes spp., Peptococcus spp./Peptostreptococcus spp., Bacteroides fragilis and Bacteroides spp. and should slightly lower activities on coagulase-negative staphylococci (CNS), Enterococcus faecalis, Haemophilus influenzae, Serratia marcescens, Proteus vulgaris, Providencia stuartii and Pseudomonas aeruginosa than on the above mentioned bacteria. In a comparative study on activities of IPM against bacteria from different clinical sources, no remarkable differences were found due to different sources among S. pneumoniae, E. faecalis, H. influenzae, E. coli, K. pneumoniae, E. cloacae, C. freundii, P. mirabilis or A. calcoaceticus, whereas slight differences were found among Staphylococcus aureus, CNS, S. marcescens and P. aeruginosa.

Anti-Bacterial Agents↗
PubMed1990

[Susceptibilities of clinical bacterial isolates to antimicrobial agents. A study mainly focused on imipenem. Reported by the Research Group for Testing Imipenem Susceptibility on Clinical Isolates].

This study was conducted to investigate susceptibilities of clinical bacterial isolates to imipenem (IPM) and other antibacterial agents at 64 hospital laboratories throughout Japan from September to December of 1988. In this study, identification and susceptibility testing were carried out at each laboratory and the tests were performed according to the disk dilution method recommended by NCCLS in which susceptibilities are classified into "S", "MS", "I" and "R". IPM showed markedly high in vitro activities against Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus agalactiae, Enterococcus faecalis, Haemophilus influenzae, Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca, Enterobacter aerogenes, Enterobacter cloacae, Serratia marcescens, Salmonella spp., Citrobacter freundii, Proteus mirabilis, Proteus vulgaris, Morganella morganii, Providencia rettgeri, Providencia stuartii, Acinetobacter calcoaceticus, Moraxella (Branhamella) catarrhalis, Alcaligenes spp., Peptococcus spp./Peptostreptococcus spp., Bacteroides fragilis and Bacteroides spp. IPM also had strong activities against Achromobacter xylosoxidans and Pseudomonas aeruginosa, but less active against Flavobacterium spp., E. faecium, coagulase-negative staphylococci (CNS), Staphylococcus aureus and Pseudomonas cepacia. In a study in which activities of IPM against bacteria isolated from different clinical sources were compared, differences in susceptibilities were observed among S. aureus, CNS, A. calcoaceticus and P. aeruginosa, but such differences were not apparent among S. pneumoniae, E. faecalis, H. influenzae, E. coli, K. pneumoniae, E. cloacae, C. freundii, S. marcescens or P. mirabilis.

Bacteria↗
PubMed1998

Piperacillin/tazobactam versus imipenem: a double-blind, randomized formulary feasibility study at a major teaching hospital.

With the introduction of piperacillin/tazobactam to the North American market, hospitals have been faced with the task of making a decision regarding its formulary role. In view of its broad spectrum of activity, piperacillin/tazobactam could be considered as a formulary alternative to imipenem. To evaluate the formulary feasibility of substituting piperacillin/tazobactam for imipenem, a comparative assessment of these agents in the empiric treatment of serious bacterial infections was undertaken at this tertiary care hospital. This trial was conducted as a randomized, double-blind, single-center study. Consenting adult patients (>16 years of age) who were prescribed imipenem were randomized to receive either 4 g of i.v. piperacillin/tazobactam or imipenem 500 mg of i.v. Q6H with or without concurrent antibiotics. Doses were adjusted according to renal function. There were no restrictions regarding the use of nonstudy antibiotics before and during the study period. Patients with beta-lactam allergies or meningitis or who had received greater than 72 h of previous imipenem therapy were excluded. Patients were evaluated at the end of treatment, at discharge, and at 30 days postdischarge. Endpoints included both clinical and microbiologic efficacy as well as drug toxicity. Over the 433-day study period, 360 imipenem treatment courses were initiated. Of these, 150 treatment courses (75 piperacillin/tazobactam courses and 75 imipenem courses) met study criteria and were subsequently randomized. The distribution of prescriber services for enrolled patients was similar to that for all patients receiving imipenem during the study period (p = 0.15). Also, there were no statistically significant differences in demographic parameters between enrolled and excluded patients. For those patients enrolled in the study, demographic characteristics, treatment course indication(s), and accompanying antibiotics were similar across treatment arms. The mean duration of study drug therapy was 7.7 days (SD, 6.2) for imipenem and 7.5 days (SD, 6.7)for piperacillin/tazobactam (p = 0.84). In the majority of cases, treatment discontinuation occurred as a result of a favorable treatment course outcome, stepdown to a narrower spectrum parenteral agent, or stepdown to an oral agent and did not differ between study drugs (p = 0.73). Clinical and microbiologic treatment course outcomes were also similar across treatment arms. Clinical outcome was deemed successful or improved for 68% of imipenem and 70% of the piperacillin/tazobactam treatment courses (p = 0.54). Fifty-three percent of treatment courses were microbiologically confirmed. Of the 58 courses that were assessed for microbiological outcome, 93% demonstrated successful eradication of the causative pathogens. There was no difference between study drugs (96% imipenem; 90% piperacillin/tazobactam; p = 0.61). The proportion of treatment courses with at least one adverse event was similar between the study drugs (p = 1.0). Nausea and/or vomiting were/was observed more commonly in the imipenem arm (p = 0.03). Discontinuation of therapy due to drug toxicity occurred in 16% of imipenem and 5% of piperacillin/tazobactam treatment courses (p = 0.06). There was no statistically significant difference between the mean treatment course cost for imipenem ($762; range, $55-$3192) versus piperacillin/tazobactam ($696; range, $79-$2967; p = 0.59). In summary, piperacillin/tazobactam seems to represent a suitable alternative to imipenem for several clinical indications including intraabdominal infections, pneumonia, febrile neutropenia, and skin/soft tissue infections in which the causative pathogens are susceptible. However, in view of the prevalence of multiresistant Gram-negative aerobic pathogens at this institution, we do not believe that imipenem can be removed from the drug formulary. In addition, at the currently studied dosing regimen, there seems to be no evidence of a direct cost advantage associated with

Adolescent↗
PubMed1986

Imipenem-cilastatin sodium, a broad-spectrum carbapenem antibiotic combination.

The chemistry, antimicrobial spectrum, mechanism of action, pharmacology and pharmacokinetics, clinical use, adverse effects, dosage and administration, place in therapy, cost-effectiveness, and formulary considerations of imipenem-cilastatin sodium are reviewed. Imipenem is the first carbapenem antibiotic of the thienamycin class to be used clinically. Imipenem has the widest spectrum of antimicrobial activity of currently available beta-lactam agents and, in contrast to other beta-lactam antibiotics, lacks cross resistance with recently introduced extended-spectrum penicillins and third-generation cephalosporins. Against gram-positive and gram-negative aerobic and anaerobic organisms, imipenem demonstrates excellent activity. Pseudomonas maltophilia, some strains of Pseudomonas cepacia, and Streptococcus faecium are resistant. Strains of methicillin-resistant staphylococci should also be considered resistant to imipenem. For clinical use imipenem is coadministered in equal parts with cilastatin. Cilastatin is a renal dehydropeptidase inhibitor that inhibits the metabolism of imipenem by renal brush-border enzymes, thus increasing imipenem concentrations in urine. Imipenem-cilastatin is administered by the intravenous route only. The adverse reaction profile of imipenem-cilastatin is similar to t that of other beta-lactam antibiotics. Recommended dosage reductions appropriate for renal impairment should be guided by periodic assessments of renal function, with close adherence to recommended dosage schedules, particularly among patients who are predisposed to seizures or receiving anticonvulsant medication. Imipenem-cilastatin performed well in both comparative and noncomparative trials of clinical efficacy and safety. For infections with multiple organisms (e.g., pelvic, intra-abdominal, or soft-tissue infections), imipenem-cilastatin may be a cost-effective and less toxic single-agent alternative to "standard" combination (e.g., aminoglycoside-penicillin plus an antianaerobic agent) therapy. However, in patients with serious pseudomonal infections (e.g., pneumonia), isolates may rapidly acquire resistance to imipenem or be replaced by resistant strains of Ps. aeruginosa when imipenem is used alone. Therefore, when the recovery of Ps. aeruginosa is anticipated or documented, treatment with imipenem-cilastatin should include an aminoglycoside to reduce the likelihood of the emergency of resistant organisms during therapy.

Anti-Bacterial Agents↗
PubMed1983

Pharmacokinetics of imipenem in healthy volunteers.

The pharmacokinetics of imipenem were evaluated in four studies involving 49 healthy men, several of whom participated in more than one study. Within a dose-range of 150 to 1000 mg, imipenem was found to give high plasma concentrations, proportional to the size of the dose. The half life in the beta-phase was about 1 h in 48 subjects with normal renal function and about 80 min in one subject with a glomerular filtration rate (GFR) of about 50 ml/min/1 X 73 m2. The volume of distribution in the central compartment was about 101. Co-administration of imipenem with probenecid resulted in a slight but significant increase of the plasma half life and a corresponding increase of the area under the plasma concentration curve (AUC). The renal excretion of imipenem was characterized by low urinary recovery (UR) of imipenem. That was in agreement with findings by others that in animals, imipenem undergoes renal metabolism by a dipeptidase, dehydropeptidase I, located to the brush border of the proximal tubular cells. There was a very high degree of between-subject variability of the UR with values varying from about 5% to more than 40% of the dose. Comparing the results obtained after several administrations of imipenem to the same subjects, a small within-subject variability was found. Co-administration of imipenem with inhibitors of the dehydropeptidase MK0789 or MK0791 (cilastatin), resulted in a uniform increase of the imipenem UR to about 70% of the dose irrespective of the degree of metabolism when imipenem was given alone. The effects of the inhibitors on the plasma kinetics of imipenem were an increase of the AUC by about 20% and a proportional decrease of the plasma clearance (VClp) while the plasma half life remained unaffected. Testing various ratios of imipenem and the inhibitors and using incremental data, it could be demonstrated that an increase of the imipenem/cilastatin ratio resulted in a prolonged inhibition of the renal metabolism. Optimal inhibition seemed to be achieved at a ratio of 1:1 between imipenem and cilastatin. A practical consequence of the inhibition of renal metabolism by cilastatin was that high urine concentrations were maintained for longer periods when the combination was given than when imipenem was administered alone. In all subjects, imipenem and the inhibitors were well tolerated and the only adverse reaction observed was nausea during infusion, observed in one subject.

Adolescent↗