The pharmacokinetics of imipenem, a new carbapenem antibiotic, and cilastatin, a metabolic inhibitor, were evaluated in 17 patients with cystic fibrosis. Imipenem and cilastatin were combined in a ratio of 1:1 in the infusion solution, and patients intravenously received 30, 60, or 90 mg of imipenem per kg of body weight per day, divided into four equal doses. Pharmacokinetic evaluation after the first dose and again under steady-state conditions revealed biodisposition characteristics which were similar and independent of the daily dose administered. Cilastatin concentrations in serum paralleled those of imipenem. A linear relationship between dose and area under the serum concentration-time curve for both compounds was observed, suggesting a first-order pharmacokinetic process. A total of 50 and 78% of the doses of imipenem and cilastatin, respectively, were recovered unchanged in the urine. The renal clearances of imipenem and cilastatin averaged 54 and 88%, respectively, of the serum clearance. These data suggest that an extrarenal mechanism may be involved in the overall elimination of imipenem. No patient experienced any clinical or biochemical abnormalities during drug therapy.

Ceftazidime, a new beta-lactam antibiotic, was used to treat 60 children with suspected bacterial infections occurring outside the central nervous system. The patients ranged in age from 0.1 to 21 years and received 30 mg of ceftazidime per kg up to a total single dose of 1 g administered every 8 h. Fifty-three pathogens were isolated from 43 children before the initiation of therapy. All children responded clinically, although one child failed bacteriologically and five children were considered colonized at the end of ceftazidime therapy. Adverse reactions associated with ceftazidime administration were primarily alterations in laboratory parameters and were clinically insignificant. Ceftazidime administered on an 8-h dosing regimen is effective monotherapy for the treatment of childhood infections.

Eighty-five patients with cystic fibrosis who were experiencing an acute infectious exacerbation of their disease were randomized in double-blind fashion to receive either 50 or 75 mg of ceftazidime per kg (body weight) per dose administered intravenously every 8 h for 14 days. Three patients were dropped from the study within 4 days of enrollment for reasons unrelated to drug administration. The total daily dose of ceftazidime administered was restricted by protocol design and was independent of the body weight of the patient. Thus, for datum analysis, patients were separated into three ceftazidime dosage groups (denoted as range of milligrams per kilogram per dose): group 1, 22 to 44.5; group 2, 46.3 to 56.6; and group 3, 66.7 to 80.6. Ceftazidime monotherapy had no effect on sputum colony counts for any Pseudomonas cepacia isolate. In contrast, a substantial reduction in Pseudomonas aeruginosa sputum colony counts was observed, and from 19 to 31% of isolates were suppressed _i10 CFU/mi after 14 days of therapy. Bacterial resistance in vitro was not observed, although a trend for increasing ceftazidime MICs was observed for group 1 patients (P < 0.05). Overall, clinical response appeared independent of drug dose, and no relationship could be identified between the reduction in P. aeruginosa sputum colony counts and clinical outcome. Adverse effects of ceftazidime were mild and transient, necessitating drug discontinuation in one patient. These data suggest that the clinical response to ceftazidime in patients with cystic fibrosis may be maximal with 50 mg/kg per dose (150 mg/kg per day) up to a total daily dose of 6 g.Ceftazidime, an aminothiazolyl expanded-spectrum cephalosporin, demonstrates potent in vitro activity against Pseudomonas aeruginosa and Pseudomonas cepacia sputum isolates obtained from patients with cystic fibrosis (CF) (1, 7). Pharmacologic evaluations of ceftazidime in these patients have demonstrated altered biodisposition characteristics (8) similar to those observed for other antimicrobial agents in patients with CF (9, 12, 16). Our previous experience assessing the sputum penetration characteristics of ceftazidime in patients with CF revealed sputum drug concentrations which equalled or only marginally exceeded the MIC for pseudomonal isolates (2). Despite these potential pharmacologic limitations, numerous studies have documented the clinical efficacy of ceftazidime monotherapy in the treatment of acute pulmonary exacerbations experienced by patients with CF (2, 3, 6, 11). These data combined suggest that an increased total daily dose of ceftazidime might improve bacteriologic or patient clinical response. To evaluate this hypothesis, we undertook a randomized double-blind evaluation of the efficacy and tolerability of ceftazidime monotherapy administered in varying dosages to patients with CF who were experiencing an acute pulmonary exacerbation of their disease.(Portions of this work were presented at the 25th Interscience Conference on Antimicrobial Agents and Chemotherapy, Minneapoli...

Ceftriaxone is a new cephalosporin with a broad spectrum of antibacterial activity and unique serum and CSF pharmacokinetics. The drug was compared in a randomized fashion with ampicillin and chloramphenicol in the treatment of 19 children with Haemophilus influenzae type b meningitis. Ceftriaxone was also administered non-randomly to six other patients including three children with Gram-negative meningitis. Among the children with H. influenzae meningitis, no deaths were noted and the outcomes of the study and the control groups were similar. Ninety per cent of the isolates of H. influenzae were inhibited by 0.0625, 1 and 1 mg/l of ceftriaxone, ampicillin and chloramphenicol respectively. One child with pneumococcal meningitis and two children with meningococcal meningitis recovered rapidly and without incident during ceftriaxone therapy. Three children with Gram-negative meningitis caused by multiply-drug resistant organisms were bacteriologically cured within five days of the onset of therapy. Persistent pleocytosis and neurological disabilities were noted in two at the conclusion of therapy. Ceftriaxone, as a single agent, was comparable in efficacy with traditional antimicrobial therapy usually employed in childhood meningitis.