Moxalactam - Antimicrobial Agents and Chemotherapy

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May 13, 1982 - 24.1 liters, respectively), to the terminal half-life (1.6 versus 2.0 h), and to urinary recovery of the active compound (96 versus 79%). Ceftazidime ...
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Aug. 1982, p. 237-241 0066-4804/82/080237-05$02.00/0

Vol. 22, No. 2

Comparative Pharmacokinetics of Ceftazidime and Moxalactam T. B. TJANDRAMAGA,1 A. VAN HECKEN,' A. MULLIE,1 R. VERBESSELT,' P. J. DE SCHEPPER,1 AND L. VERBIST2* Division of Clinical Pharmacology' and Diagnostic Microbiology Laboratory,2 St. Rafael, Academic Hospital

Catholic University of Leuven B-3000 Leuven, Belgium

Received 29 January 1982/Accepted 13 May 1982

The pharmacokinetics of ceftazidime and moxalactam were compared after intravenous and intramuscular administration of single 1-g doses to eight healthy volunteers in a crossover study. The bioavailability of the antibiotics after administration by either route was almost complete. Both drugs had similar areas under the serum curves. Significant differences between ceftazidime and moxalactam were observed with respect to the apparent volume of distribution (18.4 and 24.1 liters, respectively), to the terminal half-life (1.6 versus 2.0 h), and to urinary recovery of the active compound (96 versus 79%). Ceftazidime was almost completely eliminated by renal excretion (>96%), whereas about 20% of the moxalactam was eliminated by nonrenal mechanisms. The concentrations of ceftazidime and moxalactam in serum after a 1-g dose exceeded the concentrations required to inhibit 90% of the Enterobacteriaceae for about 8 and 10 h, respectively. The levels of ceftazidime and moxalactam in serum exceeded the 90% minimal inhibitory concentration of Pseudomonas aeruginosa for about 6 and 1 h, respectively. The novel ,-lactam antibiotics ceftazidime and moxalactam combine a high stability to 1Blactamases with an enhanced potency against gram-negative species. In studies using clinical isolates of a wide range of species, both antibiotics were very active against all species of Enterobacteriaceae (1, 6, 7, 11-15). Moxalactam exhibits moderate antipseudomonal activity, whereas the newly developed ceftazidime has significantly higher activity against Pseudomonas aeruginosa and other Pseudomonas species (7, 13, 14). In this study, we compared the pharmacokinetic properties of the two antibiotics after their administration in 1-g doses intravenously (i.v.) and intramuscularly (i.m.) in healthy adult volunteers. MATERIALS AND METHODS Subjects and study design. Eight healthy male volunteers participated in this study after providing informed consent. They ranged from 22 to 24 years of age and were 72.6 ± 4.8 kg in weight and 1.9 ± 0.1 m2 in surface area; creatinine clearance was 120.5 ± 18.8 ml/min. They had no significant medical history, no allergy to 1-lactam antibiotics, and normal renal and liver function tests. There were four parts to this study. In the first, each volunteer was given a 1-g dose of moxalactam by i.m. injection into the buttock. In the second, performed at least 7 days later, the subjects were given a 1-g dose of the same antibiotic by the i.v. route through a slow (3

min) bolus injection. In the third part, the same subjects were given a 1-g dose of ceftazidime by the i.m. route, and in the fourth part, at least 1 week later, the same dose was given by the i.v. route. Subjects fasted overnight and up to 2 h after drug administration in each segment of the study. On the day of drug administration, 400 ml of fluid was given orally in the morning to ensure adequate diuresis, followed by additional volumes to make up for urine eliminated during the 24-h collection periods. Breakfast was allowed 2 h after the antibiotic morning dosing. Ceftazidime (Glaxo Laboratories) as the monosodium salt and moxalactam (Eli Lilly & Co.) in 1-g amounts were dissolved in 3 ml of sterile water for i.m. injections and in 10 ml of water for i.v. injections. Each i.v. dose was injected over a period of 3 min into an antecubital vein. An i.v. cannula with a butterfly needle was inserted into the contralateral arm vein and maintained patent by a minimum flushing dose of heparin-saline solution (100 IU/ml). Blood and urine collections. After discarding the first 1 to 2 ml, 4-ml samples of blood were collected before drug administration (blank sample) at 0 h (at end of i.v. injection) and at 3, 6, 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, 100, and 110 min and at 2, 3, 4, 5, 6, 8, 10, 12, and 24 h after drug administration. Serum was separated as soon as possible and stored at -20°C until assayed. Urine was collected before drug administration and at 0 to 2, 2 to 4, 4 to 6, 6 to 8, 8 to 12, and 12 to 24 h after injection of the antibiotic. The volumes were measured, and 10-ml samples were stored at -20°C until assayed. Preliminary assays showed that moxalactam was stable for at least 2 weeks in both serum and urine

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samples stored at -20°C. Ceftazidime was also stable in urine for 2 weeks at -20°C; however, in serum, especially at the lower concentrations, there was a small loss ( 0.05. Calculated based on an F-value of 0.910 for ceftazidine and 0.991 for moxalactam.

DISCUSSION Our results on the pharmacokinetics of moxalactam correspond well with those obtained by Srinivasan et al. (9) after i.v. and i.m. administration and with those of Scheld et al. (8) after i.m. administration, but they are different from those of Wise et al. (17). In our volunteers, the AUCs were substantially lower, whereas the renal clearances and the urinary recovery were substantially higher in our subjects, resulting in a shorter half-life. Our pharmacokinetic results of ceftazidime were very similar to those reported by others (4, 16; R. Liithi, J. Blaser, A. Bonetti, H. Simmen, R. Wise, and W. Siegenthaler, J. Antimicrob. Chemother. 8(Suppl.): 273-276, 1981), but again renal and total body clearance, as well as urinary recovery, were somewhat higher, and consequently the half-life was somewhat shorter in our volunteers. An obvious explanation is that our subjects constituted a very young and homogenous age group (between 20 and 24 years) with maximal excretion capacities; and furthermore, during the test, a special effort was made to ensure adequate hydration. Some pharmacokinetic parameters of ceftazidime and moxalactam were significantly different, but most of these differences are probably unimportant in the clinical situation. However, if the higher nonrenal clearance of moxalactam (20% of total clearance versus 3.5% for ceftazidime) is mainly due to biliary excretion, an important influence of moxalactam on the fecal flora may be expected. Most important, however, is the relationship between the serum levels obtained and the MICs of the antibiotics against potential pathogens. The relationship between these serum levels and the in vitro activity of both drugs is demonstrat-

ed by plotting the concentrations to inhibit 90% (MIC90) of 136 P. aeruginosa strains and 565 cephalosporin-resistant Enterobacteriaceae (13) against the serum curves of ceftazidime and moxalactam (Fig. 1 and 2). The MIC90 against the Enterobacteriaceae was exceeded by the serum levels of ceftazidime, after a 1,000-mg dose, for about 8 h and by the serum levels of moxalactam for about 10 h. From the clinical viewpoint, this slight difference is probably irrelevant. However, the MIC90 against P. aeruginosa was exceeded by serum levels of ceftazidime for about 6 h and for only 1 h by moxalactam. This difference could make ceftazidime the better choice to start an empiric treatment of patients with severe infection by gram-negative species in environmental circumstances where P. aeruginosa infections may be expected. ACKNOWLEDGMENTS This study was supported by a grant from Glaxo Research Laboratories, which also supplied the ceftazidime. The moxalactam used in the study was a gift from Eli Lilly & Co. LITERATURE CITED 1. Barza, M., F. P. Tally, N. V. Jacobus, and S. L. Gorbach. 1979. In vitro activity of LY 127935. Antimicrob. Agents Chemother. 16:287-292. 2. Gibaldi, M., and D. Perrier. 1975. Pharmacokinetics. Marcel Dekker, Inc., New York. 3. Greenblatt, D. J., and J. Koch-Weser. 1975. Clinical pharmacokinetics. N. Engl. J. Med. 293:702-705, 9f4-970. 4. Harding, S. M., A. J. Munro, J. E. Thornton, J. Ayrton, and M. I. J. Hogg. 1981. The comparative pharmacokinetics of ceftazidime and cefotaxime in healthy volunteers. J.

Antimicrob. Chemother. 8(Suppl. B):263-272. 5. Loo, J. C. K., and S. Riegelman. 1970. Assessment of pharmacokinetic constants from post-infusion blood curves obtained after I.V. infusion. J. Pharm. Sci. 59:5354. 6. Neu, H. C., N. Aswapokee, K. P. Fu, and P. Aswapokee. 1979. Antibacterial activity of a new 1-oxacephalosporin compared with that of other ,-lactam compounds. Antimicrob. Agents Chemother. 16:141-149.

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CEFTAZIDIME-MOXALACTAM PHARMACOKINETICS

7. O'Callaghan, C. H., P. Acred, P. B. Harper, D. M. Ryan, S. M. Kirby, and S. M. Harding. 1980. GR 20263, a new broad-spectrum cephalosporin with anti-pseudomonal activity. Antimicrob. Agents Chemother. 17:876-883. 8. Scheld, W. M., D. A. Spyker, G. R. Donowitz, W. Kline Bolton, and M. A. Sande. 1981. Moxalactam and cefazolin: comparative pharmacokinetics in normal subjects. Antimicrob. Agents Chemother. 19:613-619. 9. Srinivasan, S., K. P. Fu, and H. C. Neu. 1981. Pharmacokinetics of moxalactam and cefazolin compared in normal volunteers. Antimicrob. Agents Chemother. 19:302-305. 10. Tjandramaga, T. B., A. Mullie, R. Verbesselt, P. J. De Schepper, and L. Verbist. 1978. Piperacillin: human pharmacokinetics after intravenous and intramuscular administration. Antimicrob. Agents Chemother. 14:829-837. 11. Trager, G. M., G. W. White, V. M. Zimelis, and A. P. Panwalker. 1979. LY 127935, a novel betalactam antibiotic, with unusual antibacterial activity. Antimicrob. Agents Chemother. 16:297-300. 12. Verbist, L. 1981. Comparison of in vitro activities of eight P-lactamase-stable cephalosporins against f3-lactamase-

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producing gram-negative bacilli. Antimicrob. Agents Chemother. 19:407-413. Verbist, L., and J. Verhaegen. 1980. GR 20263, a new aminothiazolyl cephalosporin with high activity against Pseudomonas and Enterobacteriaceae. Antimicrob. Agents Chemother. 17:807-812. Wise, R., J. M. Andrews, and K. A. Bedford. 1979. LY 127935, a novel oxa-p-lactam: an in vitro comparison with other P-lactam antibiotics. Antimicrob. Agents Chemother. 16:341-345. Wise, R., J. M. Andrews, and K. A. Bedford. 1980. Comparison of in vitro activity of GR 20263, a novel cephalosporin derivative, with activities of other betalactam compounds. Antimicrob. Agents Chemother. 17:876-883. Wise, R., G. C. Armstrong, R. M. Brown, and J. M. Andrews. 1981. The pharmacokinetics and tissue penetration of ceftazidime and cefamandole in healthy volunteers. J. Antimicrob. Chemother. 8(Suppl. B):277-282. Wise, R., S. Baker, and R. Livingston. 1980. Comparison of cefotaxime and moxalactam pharmacokinetics and tissue levels. Antimicrob. Agents Chemother. 18:369-371.