Postantibiotic effect of imipenem on Pseudomonas aeruginosa

Abstract

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 ...

Postantibiotic effect of beta-lactam antibiotics on Escherichia coli evaluated by bioluminescence assay of bacterial ATP

“…Similar results with differences in the PAEs for P-lactam antibiotics on gram-positive cocci and gramnegative bacteria have also been observed by other investigators (1,4,16). The only reported exception to the absence of PAE when 1-lactam antibiotics and gram-negative bacteria are combined is imipenem (2,3,10,13).…”

“…P-Lactam antibiotics have consistently shown PAEs against various gram-positive cocci (1,(3)(4)(5). In contrast to gram-positive cocci, there are marked differences in PAE caused by P-lactam antibiotics on gram-negative bacteria (2,3,5,13,16). Gudmunsson and Craig did not see any PAE and frequently noted a negative PAE when Escherichia coli and Pseudomonas aeruginosa were exposed to p-lactam antibiotics (3).…”

Activity of the carbapenem panipenem and role of the OprD (D2) protein in its diffusion through the Pseudomonas aeruginosa outer membrane

“…Imipenem and panipenem show a significant postantibiotic effect against gram-negative bacilli, including P. aeruginosa, but other P-lactams do not (1,11,17). They show stronger rapid killing activity of P. aeruginosa than do other 3-lactams (1,8,15,17). These features also may give carbapenems stronger antipseudomonal activity in vivo.…”

“…The apparent permeability coefficient (P) was calculated by the method of Nikaido et al (16), by using the modifications of Yoshimura and Nikaido (23). The flux of solutes (v) through a nonspecific channel is described by Fick's first law of diffusion, v = PA(Co -CQ) (1) where A, Co, and Ci denote the area of the membrane, the solute concentration outside, and the solute concentration inside, respectively. If diffusion occurs through a symmetrical channel with one ligand binding site inside the channel, this formula is modified to the following: V = VmaA(Co -C)I(Co + Ci + Km) ( was necessary to detect the radioactivity in the cells.…”

Isolation and in-vitro and in-vivo characterisation of a mutant of Pseudomonas aeruginosa PAO1 that exhibited a reduced postantibiotic effect in response to imipenem

“…widely reported to induce PAEs in Gram-negative bacteria in vitro (Bustamante et al, 1984;Manek, Andrews & Wise, 1986;Chin & Neu, 1989;Nadler, Pitkin & Sheikh, 1989) and to a lesser extent, in vivo (Gudmundsson, Vogelman & Craig, 1986;Renneberg & Walder, 1989;Jabes, Rossi & Delia Bruna, 1992). In theory at least, such PAEs may be of clinical value, allowing dosage intervals to be extended.…”