Imipenem (formerly N-formimidoyl thienamycin) and ceftazidime were investigated for their postantibiotic effect on Pseudomonas aeruginosa. Four strains of P. aeruginosa in the logarithmic phase of growth were exposed for 1 and 2 h to concentrations of antibiotics achievable in human serum. Recovery periods of test cultures were evaluated after dilution or addition of j-lactamase. A consistent postantibiotic effect against all strains was obtained with imipenem but not with ceftazidime. Although ceftazidime did not have a postantibiotic effect, it did suppress the growth of the organisms at concentrations equivalent to one-third of the MIC. The clinical implications of these effects need further evaluation.Early studies demonstrated that staphylococci exposed to lethal concentrations of penicillin did not immediately resume growth after the drug was removed (11,12). Eagle and Musselman (5) later showed that this effect was not peculiar to staphylococci but could also be observed with other species.More recent studies have characterized the postantibiotic effect (PAE) for gram-positive and gram-negative aerobic organisms (3,4,9,15). Of interest, inhibitors of protein and RNA syntheses have produced the longest PAE for most species (4). 13-Lactam antibiotics produce a consistent PAE against gram-positive cocci when used at concentrations near the MIC, but none or a minimal effect was seen against gram-negative bacilli (3). The duration of the PAE of ampicillin for Escherichia coli was less than 0.5 h despite exposing these organisms to concentrations 100 times their MIC (15).Pseudomonas aeruginosa, a significant pathogen for the cancer patient who is granulocytopenic, exhibited a PAE when exposed to gentamicin; but no or a negative PAE was demonstrated when the organism was exposed to ticarcillin, cefoperazone, or moxalactam (4 dilutions of the antibiotic in 0.05 ml were made with an automated microdiluter. After the addition of 0.05 ml of Mueller-Hinton broth to each well, the inoculum was added with a microdiluter inoculator (Dynatech Laboratories, Inc., Alexandria, Va.). The MIC was the lowest concentration which prevented visible growth after overnight incubation.Determination of PAE. At time zero, 2 ml of the inoculum was added to 50-ml flasks containing 18 ml of MuellerHinton broth with or without test antibiotic. Antibiotic concentrations were 20 ,ug/ml for imipenem and amikacin, 65,ug/ml for ceftazidime, and 100 jxg/ml for moxalactam. These concentrations were chosen to approximate those achieved at 1 h postinfusion in the serum of normal human volunteers who were given intravenous doses of imipenem (1 g), ceftazidime and moxalactam (2 g), and amikacin (7.5 mg/kg). The inoculum was a 2-ml aliquot of a 1:10 dilution of a faintly turbid broth culture in the logarithmic phase of growth, producing a final concentration of inoculum in the test flask of approximately 105 organisms per ml. After incubation for 1 h in a 37°C shaking water bath, antibiotics were removed by diluting the contents of the flask by 10-2 ...

We characterized the pharmacokinetic profile of imipenem-cilastatin administered intravenously to six normal volunteers in a dose of 1,000 mg of each drug every 6 h for 40 doses. The plasma concentrations of imipenem and cilastatin 1 h after the end of a 30-min infusion were 18.7 (± 2.1) and 19.1 (± 4.6), 20.0 (± 3.2) and 17.8 (± 4.8), and 23.4 (± 2.3) and 19.1 (± 3.5) ,ug/ml in the 1st, 17th, and 37th dosing intervals, respectively. The central compartment volumes of distribution for imipenem and cilastatin were 0.16 (± 0.05) and 0.14 (± 0.03) liter/kg, respectively. Elimination half-lives were short: 0.93 (± 0.09) h for imipenem and 0.84 (± 0.11) h for cilastatin. Plasma clearances were 12.1 (± 0.06) liters/h per 1.73 m2 for imipenem and 12.4 (± 1.1) liters/h per 1.73 m2 for cilastatin. Renal clearance accounted for 54% of the plasma clearance of imipenem and 69% of the plasma clearance of cilastatin. Sample acquisition and assay. Blood samples from all volunteers were collected during the 1st, 17th, and 37th dosing intervals before the dose, at the termination of the half-hour infusion, and at 0.25, 0.5, 0.75, 1, 1.5, 2.5, 3.5, 4.5, and 5.5 h thereafter. Plasma was promptly separated in a refrigerated centrifuge (2 to 5°C), stabilized by the addition of an equal volume of a 1:1 mixture of 1 M morpholinoethane-sulfonate buffer (pH 6) 80 [Lg/ml; the coefficient of variation was 0.28% at 96.1 ,ug/ ml, 5.2% at 53.8 pLg/ml, and 4.7% at 2.6 ,ug/ml. Cilastatin was assayed by the high-pressure liquid chromatographic technique described by Demetriadis et al. (personal communication). The plasma assay was linear over a range from 0.75 to 75 ,ug/ml; the coefficient of variation was 3.7% at 75 pLg/ml, 3.0% at 50 Fg/ml, 2.6% at 20 jLg/ml, 2.2% at 10 [ig/ml, 2.5% at 5 ,ug/ml, 2.6% at 2 [ig/ml, 10.5% at 1 p.g/ml, and 10% at 0.75 p.g/ml.Urine for the drug assay was collected from 0 to 2, 2 to 4, and 4 to 6 h during the 1st, 17th, and 37th dosing intervals.

Potentially fatal Candida infections are commonplace in seriously ill hospitalized patients. The infectious disease physician is challenged to develop expertise in using the newly introduced antifungal agents, applying evidence-based guidelines developed from quality randomized clinical trials. The infectious disease specialist is called to play a multidisciplinary role formulating infection control policies, developing drug formularies, educating the staff and treating the sickest patients. Infection surveillance in local communities coupled with available antifungal agents may improve our management of Candida infections.