Antimicrobial susceptibility changes in Enterococcus faecalis following various penicillin exposure regimens.

Penicillin-"virgin" strains of Enterococcus faecalis collected from a population of individuals with no previous antibiotic exposure were subjected in vitro to penicillin delivered as repeated pulses, stepwise increasing concentrations, or sustained levels of a single concentration. Changes in resistance to penicillin were assessed by determination of MICs, and time-kill studies were performed to evaluate changes in tolerance to the bactericidal effects of penicillin. Isogenic clones, derived from various exposure regimens, which exhibited changes in either resistance or tolerance were further examined for changes in penicillin-binding proteins. Exposure to repeated pulses of penicillin resulted in the development of tolerance to penicillin without changes in the level of resistance. Clones derived from a regimen of stepwise increases in the penicillin concentration acquired both increased penicillin resistance and tolerance. Clones selected after prolonged continuous exposure to a fixed concentration of penicillin displayed minimally increased resistance to penicillin, but they retained the lytic, nontolerant response to the bactericidal effect of penicillin. Clones which acquired tolerance to the bactericidal effect of penicillin without changes in penicillin resistance exhibited a penicillin-binding protein pattern identical to that of the parental strain. Increased labeling of several penicillin-binding proteins accompanied the development of increased penicillin resistance in both penicillin-tolerant and nontolerant strains. Exposure of E. faecalis to penicillin in repeated pulses of brief duration, for prolonged periods at a constant concentration, or in stepwise graded concentrations can result in the selection of clones with increased resistance to the inhibitory or bactericidal effects of penicillin, or both. These observations may be relevant to the selection of dosing regimes for penicillin in the treatment of enterococcal infections, when bactericidal synergism cannot be achieved with penicillin-aminoglycoside combinations.

Phase 1 study of recombinant human CD4-immunoglobulin G therapy of patients with AIDS and AIDS-related complex.

The safety and pharmacokinetics of recombinant CD4-immunoglobulin G (rCD4-IgG) were evaluated in a phase 1 study with dose escalation. A total of 16 patients, 6 with AIDS and 10 with AIDS-related complex, were evaluated at two university-affiliated hospital clinics. rCD4-IgG was administered once weekly for 12 weeks to four patients each at doses of 0.03, 0.1, 0.3, and 1.0 mg/kg of body weight. Dosing was intravenous for two patients in the 1.0-mg/kg dose group and intramuscular for the remaining patients. Dosing was intravenous for two patients in the 1.0-mg/kg dose group and intramuscular for the remaining patients. Pharmacokinetic, toxicity, and immunologic variables were monitored with all patients. Administration of rCD4-IgG was well tolerated, with no important clinical or immunologic toxicities noted. No subjects required dose reduction or discontinuation of therapy due to toxicity. No consistent changes were seen in human immunodeficiency virus antigen levels in serum or CD4 lymphocyte populations. The volume of distribution was small, and compared with that of rCD4, the half-life of the hybrid molecule was markedly prolonged following intramuscular or intravenous administration. The rate and extent of absorption following intramuscular dosing were variable. Intramuscular administration of rCD4-IgG appears to be inferior to intravenous dosing from a pharmacokinetic standpoint, with lower peak concentrations and variable absorption. After intravenous administration, peak concentrations of rCD4-IgG in serum (20 to 24 micrograms/ml) that have shown antiviral activity in vitro against more sensitive clinical isolates of human immunodeficiency virus were achieved. The peak concentrations in serum after intramuscular administration were below these levels. Treatment with rCD4-IgG was well tolerated at the doses administered to patients in this study but did not result in significant changes in CD4 lymphocyte counts or p24 antigen levels in serum.

In vitro activity of BAY v 3522, a new cephalosporin for oral administration.

The activity of BAY v 3522 was tested against over 500 clinical bacterial isolates and compared with the activities of ampicillin, amoxicillin-clavulanate, cefaclor, cefixime, cefuroxime, cephalexin, and/or ciprofloxacin, erythromycin, and metronidazole. BAY v 3522 activity against staphylococci and streptococci equaled or exceeded those of the other agents. BAY v 3522 exhibited no significant advantage over cefaclor, cefuroxime, or cephalexin against gram-negative bacilli.

The safety and pharmacokinetics of recombinant soluble CD4 (rCD4) in subjects with the acquired immunodeficiency syndrome (AIDS) and AIDS-related complex. A phase 1 study.

STUDY OBJECTIVE: To evaluate the safety and pharmacokinetics of recombinant, soluble human CD4 (rCD4) in subjects with the acquired immunodeficiency syndrome (AIDS) and AIDS-related complex. The protein rCD4 binds to envelope protein, gp120, of the human immunodeficiency virus (HIV) and blocks HIV infection of CD4 lymphocytes in vitro. DESIGN: Phase 1 trial with dose escalation. SETTING: Two university-affiliated hospital clinics. SUBJECTS: Of 42 subjects enrolled, 29 had AIDS and 13 had AIDS-related complex. INTERVENTIONS: The rCD4 was administered by rapid intravenous infusion on day 1, followed by a 3-day washout, then once a day for 10 days, followed by a 7-day washout, and then three times a week for 8 weeks. Doses of 1, 10, 30, 100, and 300 micrograms/kg body weight per day of rCD4 were administered intravenously to 6 subjects at each dose level. Twelve additional patients received 300 micrograms/kg.d of rCD4: 6 by intramuscular and 6 by subcutaneous injection. All subjects were monitored for toxicity. Immunologic and virologic variables were also monitored. MEASUREMENTS AND MAIN RESULTS: Administration of rCD4 was not associated with important toxicity as determined by clinical monitoring or by serum chemistry, hematologic, or immunologic variables. No subjects required dose reduction or discontinuation of therapy due to rCD4-related toxicity. No consistent or sustained changes in CD4 lymphocyte populations or HIV antigen levels were observed. The volume of distribution of rCD4 was small, and clearance remained constant over the dose range studied. The bioavailability of intramuscular injection and subcutaneous injection was 51% and 45%, respectively. CONCLUSIONS: At the dose levels used in this study, rCD4 appears safe and well tolerated. Serum concentrations of rCD4 were achieved that were comparable to concentrations shown to have antiviral activity in vitro. Further studies are indicated to determine whether rCD4 or related molecules will be useful in treating HIV infection.