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CP-65,207 is a new broad-spectrum penem antimicrobial agent that is a 1:1 mixture of two stereoisomers. Five minutes after a 10-min intravenous infusion of 1 g of CP-65,207 to volunteers, mean concentrations in serum were 33 micrograms of the R isomer per ml and 29 micrograms of the S isomer per ml. Following rapid distribution, half-lives of the isomers were 53 and 55 min, respectively. Concentrations in urine exceeded 800 micrograms of each isomer per ml. Recovery of the S isomer in urine (46%) was much greater than recovery of the R isomer (26%). The serum kinetics of the S isomer (volume of distribution, 319 ml/kg; total clearance, 315 ml/min; elimination rate constant, 0.80 h-1 were similar when it was given alone and when it was contained in CP-65,207, demonstrating that the presence of the R isomer has little effect on the serum kinetics of the S isomer. However, when the S isomer was given alone, the urinary recovery of intact S isomer (36%) was substantially lower than that when it was given with the R isomer as CP-65,207 (57%). Administration of the S isomer alone did not produce the unpleasant sulfurous odor in urine that was observed following administration of CP-65,207. Oral doses of a prodrug, which contained 1 g of CP-65,207, produced peak concentrations in serum of 1.6 micrograms of the R isomer per ml and 1.8 micrograms of the S isomer per ml. Approximately 36% of the S-isomer component was absorbed, and 20% of this isomer was recovered in urine. A 1-g oral dose of the prodrug of the single S isomer provides concentrations in serum above 1.0 microgram/ml (the MIC for 90% of over 1,000 hospital pathogens) for 3.5 h, suggesting that the drug given orally will prove to be efficacious against many infections.

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Fluconazole therapy was evaluated prospectively in patients with serious fungal infections who failed to respond to or could not tolerate conventional antifungal therapy. Patients were enrolled if they had a life-threatening fungal infection and conventional therapy had failed to eradicate the infection, had caused serious toxic reactions, or was contraindicated. Patients were treated with 200 mg/day, a dosage that could be increased to 400 mg/d if the initial response was not satisfactory. AIDS was the underlying risk factor in 65% of 232 patients evaluated in the study and in 85% of 151 patients with cryptococcal infection. Fifty-eight patients had active cryptococcal infection; 74% had a satisfactory clinical response, and 75% of 44 patients became culture-negative. Patients with inactive infection had a relapse rate of 4.5/1,000 patient-weeks. Twenty-three of 30 patients with coccidioidal infection and 10 of 14 patients with candidiasis or another mycosis were clinically improved. Five patients (2%) discontinued fluconazole therapy because of adverse effects possibly attributable to therapy. Fluconazole may be effective in the treatment of serious fungal infections in patients who cannot continue conventional antifungal therapy.

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Sultamicillin at an adult dose of 375-750 mg twice daily or a pediatric dose of 50 mg/kg/d provides effective outpatient/office therapy for community-acquired infections of the upper and lower respiratory tract, urinary tract, and skin/soft tissue structures. Given the incidence of Haemophilus influenzae and Branhamella catarrhalis in otitis media and the frequent occurrence of beta-lactamase-producing strains, it is particularly appropriate for the therapy of otitis media in infants and children. The increasing prevalence of beta-lactamase-producing pathogens in these infections, coupled with the fact that diagnostic bacteriology is often not available or practical in office practice, suggests that the broad use of sultamicillin might be desirable. Several factors support such usage: 1) the superiority of sultamicillin compared with the ampicillin commercial dosage form as a delivery system for ampicillin; 2) the possible occurrence at the infection site of beta-lactamase-producing organisms, not themselves pathogens, which nevertheless impair the activity of the beta-lactam antibiotic against sensitive pathogens; 3) the complementary binding of penicillin-binding proteins by ampicillin and sulbactam in ampicillin-sensitive organisms; 4) the lack of resistance development following repeated exposure of strains sensitive to sulbactam/ampicillin suggested by in vitro studies; and 5) the inability of sulbactam to induce beta-lactamase production. In addition to broad use in community-acquired infections, oral therapy with sultamicillin should also provide convenient outpatient follow-up for initial parenteral sulbactam/ampicillin therapy. Extensive testing of various laboratory parameters has revealed no evidence of systemic toxicity with sultamicillin. The only significant side effect of sultamicillin is diarrhea/loose stools, which, although a frequent complaint in some studies, is of mild to moderate severity and results in a low discontinuation rate.

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Infusions of 50 mg of sulbactam per kg per day and 400 mg of ampicillin per kg per day in divided doses to infants and children with bacterial meningitis produced levels in cerebrospinal fluid approximately one-third those in serum. Concentrations in cerebrospinal fluid of 5.5 micrograms of sulbactam per ml and 16.0 micrograms of ampicillin per ml declined within a few days of therapy to 1.9 microgram of sulbactam per ml and 5.2 micrograms of ampicillin per ml.

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The efficacy and safety of sulbactam/ampicillin has been evaluated in 39 studies of therapeutic use and six studies of prophylaxis. Studies of therapy were conducted in 899 patients: 751 seriously ill, many of whom had multiple concurrent diseases, and 148 with gonorrhea. Overall clinical and bacteriologic success was achieved in 92% of assessable cases; 88% of 768 pathogens in these patients were eradicated. Of these pathogens, 43% were resistant to ampicillin; eradication rates of 91% and 85% were achieved in ampicillin-resistant and ampicillin-sensitive organisms, respectively. In 388 patients who received prophylactic sulbactam/ampicillin, efficacy was similar to that of comparative agents and better than that of a placebo in preventing wound infections after appendiceal, biliary, upper-gastrointestinal, or gynecologic surgery. Adverse reactions were infrequent with the exception of injection-site pain, which occurred mainly after intramuscular injection and was reduced in incidence by concurrent administration of lidocaine.

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We gave intravenous infusions of sulbactam, a beta-lactamase inhibitor, in combination with ampicillin or cephalothin to women 2 days after cesarean section delivery. The elimination t1/2 was 1.0 hours, the volume of distribution at steady state was 268 ml/kg, and renal clearance was 295 ml/min. These values are similar to those in normal young men and in surgical patients and suggest that dose regimens of sulbactam will not need adjustment in the postpartum period. Sulbactam concentrations in breast milk averaged 0.5 micrograms/ml, a value similar to that of several beta-lactam antibiotics.

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The kinetics of co-administered ampicillin plus sulbactam were examined at doses being used in clinical trials of this combination of a beta-lactam antibiotic (ampicillin) and a beta-lactamase inhibitor (sulbactam). Following 15-min infusion of 2 g ampicillin plus 1 g sulbactam, peak serum concentrations of 120 micrograms/ml ampicillin and 60 micrograms/ml sulbactam were observed. The half-life was approximately one hour for both drugs. Approximately 75% of the dose of sulbactam and ampicillin was recovered in urine. The data fit a two-compartment pharmacokinetic model. Intramuscular administration of 1 g ampicillin plus 0.5 g sulbactam produced mean peak concentrations of 18 micrograms/ml ampicillin plus 13 micrograms/ml sulbactam. Estimates of variability of the data in normal male subjects are provided to serve as references for clinical trials.

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