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 regimens for penicillin in the treatment of enterococcal infections, when bactericidal synergism cannot be achieved with penicillin-aminoglycoside combinations.

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.

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. 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 ,ug/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 Iymphocyte counts or p24 antigen levels in serum.CD4 is a surface glycoprotein of a subset of mature T lymphocytes and serves as the primary receptor for human immunodeficiency virus (HIV) (10,21,25,26) and class II major histocompatibility complex antigen in humans (7, 14,22). Infection of CD4-bearing cells by diverse strains of HIV type 1 (HIV-1), and by the closely related lentiviruses HIV-2 and simian immunodeficiency virus is mediated by the binding of a viral envelope glycoprotein, gp120, to cellular CD4 (27). The subsequent destruction of CD4 lymphocytes by direct viral cytopathicity, or possibly by immune mechanisms which may not distinguish between infected cells and uninfected cells with free viral gpl20 on the surface, is important in the pathogenesis of AIDS (23).Recombinant soluble CD4 (rCD4), like native CD4, binds viral gpl20 with high affinity (11, 13, 18,29,30). The antiviral effects of rCD4 have been demonstrated in vitro by the measurement of decreases in both HIV-induced syncytium formation and reverse transcriptase activity (4, 11, 13, 18,29,30). In addition, in vivo evidence of rCD4 antiviral activity against simian immunodeficiency virus in rhesus monkeys has been reported (33). Phase 1 clinical trials with patie...

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.

These results demonstrate that biweekly administration of 60 mg or 120 mg of aerosol pentamidine significantly decreases PCP recurrence when compared with a 5-mg regimen or findings in historic controls and is generally well tolerated. There is no significant difference in effect or safety between these two dosing regimens in patients followed for at least 52 weeks of therapy.