Beverly A. Tatem

Postantibiotic effect of imipenem on Pseudomonas aeruginosa.

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 beta-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.

Multiple-dose pharmacokinetics of imipenem-cilastatin.

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) micrograms/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. The concentrations of imipenem in plasma and urine remained above the MICs of the vast majority of pathogens throughout the dosing interval.

Comparative Activity of Tobramycin, Amikacin, and Gentamicin Alone and with Carbenicillin Against Pseudomonas aeruginosa

The effect of gentamicin against 130 clinical isolates of Pseudomonas aeruginosa was compared with that of two investigational aminoglycoside antibiotics, tobramycin and amikacin. Minimal inhibitory concentration data indicated that, on a weight basis, tobramycin was two to four times as active as gentamicin against most isolates. However, 14 of 18 organisms highly resistant to gentamicin (≥80 μg/ml) were also highly resistant to tobramycin. Amikacin was the least active aminoglycoside on a weight basis, but none of the isolates were highly resistant to this antibiotic. When therapeutically achievable concentrations were used, adding carbenicillin to gentamicin or to tobramycin enhanced inhibitory activity against those isolates susceptible (≤5 μg/ml) or moderately resistant (10 to 40 μg/ml) to the aminoglycoside. Such synergy was seldom demonstrated for isolates highly resistant to gentamicin or tobramycin. The combination of carbenicillin and amikacin enhanced inhibition against all but two of the isolates. Both tobramycin and amikacin offer in vitro advantages over gentamicin against P. aeruginosa.

Comparison of the pharmacokinetics of ceftazidime and moxalactam and their microbiological correlates in volunteers.

We compared ceftazidime with moxalactam, a commonly utilized, currently available drug. The microbiological activities of ceftazidime and moxalactam were studied. In addition, single-dose pharmacokinetics and serum bactericidal activity 1 and 6 h after a 2.0-g, 30-min infusion of each drug were determined in a crossover study in human volunteers. In vitro, both drugs had MICs for 90% of the isolates of less than 1.0 microgram/ml against the common members of the family Enterobacteriaceae and of 8.0 micrograms/ml against Staphylococcus aureus. Against Pseudomonas aeruginosa ceftazidime was more active than moxalactam, the respective MICs for 90% of the isolates being 8 and 128 micrograms/ml. Mean half-lives were 1.75 (+/- 0.21) h for ceftazidime and 2.5 (+/- 0.38) h for moxalactam. The serum bactericidal titers for both compounds against Escherichia coli and Klebsiella pneumoniae were high. Titers against S. aureus 6 h after infusion were negative. The mean (geometric) serum bactericidal titer of ceftazidime against 31 strains of P. aeruginosa (1:44) was higher than that of moxalactam (1:3.4).

BL-P1654, Ticarcillin, and Carbenicillin: In Vitro Comparison Alone and in Combination with Gentamicin Against Pseudomonas aeruginosa

Minimum inhibitory concentrations of carbenicillin, ticarcillin, and BL-P1654 were determined for 89 clinical isolates of Pseudomonas aeruginosa. Ticarcillin was generally twice as active and BL-P1654 eight to 16 times as active as carbenicillin. Usually carbenicillin and ticarcillin killed at the same concentration or twice the concentration needed to inhibit, whereas 400 μg of BL-P1654 per ml was not bactericidal for the majority of isolates tested. The inhibitory effect of all three drugs varied markedly with the size of bacterial inoculum. When therapeutically achievable concentrations were used, adding gentamicin enhanced the inhibitory and bactericidal activity of all three penicillin derivatives for the majority of isolates. However, inhibition of isolates highly resistant to gentamicin was not improved by combining the semisynthetic penicillins with gentamicin.

Bactericidal activity of ceftazidime in serum compared with that of ticarcillin combined with amikacin.

We compared the bactericidal activity of serum attained 1 and 6 h after the termination of infusions of either ceftazidime (2 g) or ticarcillin plus amikacin (5 g and 7.5 mg/kg, respectively) in 6 volunteers against a panel of the most common pathogens found in the blood of febrile granulocytopenic cancer patients. Ceftazidime consistently produced significantly higher serum bactericidal titers at both 1 and 6 h against all species of gram-negative bacilli. Its performance against Pseudomonas aeruginosa was especially impressive. The geometric mean titer against this organism was 1:41 at 1 h, contrasted with 1:12 for ticarcillin plus amikacin (P = 0.025). However, for Staphylococcus aureus, the geometric mean serum bactericidal titer of ceftazidime was 1:3.6 at 1 h and undetectable at 6 h. Ceftazidime shows promise as single-agent therapy for serious gram-negative bacillary infections. Whether this promise is fulfilled and whether the observed antistaphylococcal activity is adequate for empiric therapy in infected granulocytopenic patients need further investigation.

Imipenem coadministered with cilastatin compared with moxalactam: integration of serum pharmacokinetics and microbiologic activity following single-dose administration to normal volunteers.

We administered 1 g of imipenem along with equal amounts of cilastatin (a dehydropeptidase I inhibitor) or 2 g of moxalactam intravenously over a period of 30 min to six volunteers in a crossover manner 1 week apart. The antibiotic concentrations and pharmacokinetics for each drug were determined and integrated with the microbiologic activity by measuring the duration of time that the free drug concentrations remained above the MICs for 90% of 581 clinical isolates and by measuring serum bactericidal activities against organisms which commonly infect granulocytopenic cancer patients. Moxalactam produced serum levels at 1 h after infusion of 99.9 micrograms/ml; these levels were four times greater than the plasma levels of imipenem (22.8 micrograms/ml). The trough (5.5-h) moxalactam serum levels were 10 times greater than those of imipenem (18.5 and 1.7 micrograms/ml, respectively). Essentially all of the imipenem was unbound to protein, whereas 36 to 42% of the moxalactam was unbound. Moxalactam produced free antibiotic concentrations that were above the MIC for 90% of the strains tested for more than 6 h against all of the species tested except Staphylococcus aureus (5.3 h), Enterobacter hafnia (1.6 h), and Pseudomonas aeruginosa (0 h). The imipenem concentrations were above the MIC for 90% of the strains tested for 5.6 h or more against all of the bacteria tested except Proteus spp. and Pseudomonas aeruginosa (4.5 h). The geometric mean peak bactericidal titers from volunteers receiving imipenem were more than 1:8 against all bacteria and were significantly higher than the titers from volunteers receiving moxalactam against S. aureus (1:7.3) and Pseudomonas aeruginosa (1:4.5). These data, in addition to information obtained from animal models, indicate that imipenem is a promising new candidate for carefully controlled clinical trials as a single agent for therapy of serious infections, including empiric therapy for fever in granulocytopenic cancer patients.

The plasma pharmacokinetics of high dose (1 g) imipenem coadministered with 1 g cilastatin in six normal volunteers

The plasma pharmacokinetics of imipenem, a beta-lactam antibiotic of the new class of carbapenems, was evaluated by administering 1 g imipenem plus 1 g of the dehydropeptidase inhibitor cilastatin to six healthy male volunteers over 30 min. Subsequently intensive plasma sampling was done for 5.5 h. The volume of distribution of the central compartment was 0.16±0.04 1/kg; the volume of distribution (area) was 0.28±0.07 1/kg; the volume of distribution (steady state) was 0.23±0.03 1/kg. The mean plasma clearance was 10.1±1.0 l/h/1.73 m2. Model-independent analysis showed excellent agreement with these values. The terminal excretion half-life was short (1.3±0.4 h). For approximately 6 h after administration, the observed plasma levels were above those required to inhibit most nosocomial pathogens in vitro.

Correlation of predicted serum bactericidal activities and values measured in volunteers

A method was devised for predicting the serum bactericidal activity of new drugs. Six healthy volunteers received 2 g moxalactam, cefoperazone and cefotaxime, respectively, as 30-min infusions in a crossover manner at one-week intervals. The pharmacokinetics of each drug was characterized and the bactericidal activity of the serum 1 h after infusion was measured against panels of six strains ofPseudomonas aeruginosa,six strains ofEscherichia coli,six strains ofStaphylococcus aureus,and four strains ofKlebsiella pneumoniae.The minimum bactericidal concentration of each antibiotic was determined for each organism by the standard NCCLS reference method and the method of Stratton and Reller. On the basis of these values and a serum concentration-time curve constructed from individual patient pharmacokinetic parameters, the bactericidal activity of the serum 1 h after infusion was predicted. These predictions showed a 90% agreement with measured values calculated according to the method of Stratton and Reller, whereas an agreement of 74 % was obtained with the reference method. This difference was statistically significant (p<0.001).

Comparison of Serum Bactericidal Activity Among Three Antimicrobial Combinations

Three antimicrobial combinations, ticarcillin plus cephalothin (T+C), ticarcillin plus gentamicin (T+G), and cephalothin plus gentamicin (C+G), were administered to 105 febrile granulocytopenic cancer patients at the Baltimore Cancer Research Center as part of a multi-institutional prospective randomized antibiotic trial. The sera from 32 of these patients (T+C−10 patients, T+G−10 patients, and C+G−12 patients) obtained 1 h post-antibiotic administration were examined for bactericidal activity against 11 strains each of the most common pathogens infecting the granulocytopenic host: Pseudomonas aeruginosa, Klebsiella pneumoniae, Escherichia coli, and Staphylococcus aureus. Each of the three antibiotic regimens produced a high degree of bactericidal activity in these sera against S. aureus and E. coli. P. aeruginosa was equally, although poorly, killed by sera containing ticarcillin (T+G, T+C), whereas C+G produced no measurable serocidal activity (P < 0.05). Sera with C+G killed K. pneumoniae more effectively than T+G; T+C produced the least killing effect of the three regimens against this organism (P < 0.05). The bactericidal activity of the serum from these 32 patients supplements the overall clinical results of the multi-institutional antibiotic trial and suggests that T+G is a useful initial regimen for empiric therapy of febrile episodes in granulocytopenic cancer patients.