No abstract

To measure the magnitude of risk reduction within a cohort of homosexual men, questionnaire responses in April 1984-March 1985 were compared to those in October 1986-September 1987. A total of 361 subjects were eligible (231 seronegative, 130 seropositive). The annual number of sex partners declined significantly from a median of 8.0 to 5.0 with no difference between the serologic groups. The number of subjects reporting no receptive anal intercourse increased as did condom use during anal receptive intercourse. More seronegatives than seropositives subjects report- IntroductionIn the absence of an effective vaccine against human immunodeficiency virus (HIV), primary prevention efforts must center on modifying behaviors associated with its transmission. Thus, community groups and public health agencies have concentrated their efforts to varying degrees on promoting both reductions in the number of sex partners and in the frequency of anal intercourse, as well as increases in the use of condoms and in the practice of other safe sexual activities. The degree to which such changes have occurred has only recently been assessed and the effect of knowledge of HIV serologic status on risk reduction remains unclear. We report here on changes in sexual practices and condom use in our ongoing cohort study of homosexual men.

Fosfomycin is the only expoxide antimicrobial and is currently under development in the United States as an intravenously administered product. We were interested in identifying the exposure indices most closely linked to its ability to kill bacterial cells and to suppress amplification of less susceptible subpopulations. We employed the hollow fiber infection model for this investigation and studied wild-type strain PAO1. Because of anticipated rapid resistance emergence, we shortened the study duration to 24 h but sampled the system more intensively. Doses of 12 and 18 g/day and schedules of daily administration, administration every 8 h, and administration by continuous infusion for each daily dose were studied. We measured fosfomycin concentrations (by liquid chromatography-tandem mass spectrometry), the total bacterial burden, and the burden of less susceptible isolates. We applied a mathematical model to all the data simultaneously. There was a rapid emergence of resistance with all doses and schedules. Prior to resistance emergence, an initial kill of 2 to 3 log(CFU/ml) was observed. The model demonstrated that the area under the concentration-time curve/MIC ratio was linked to total bacterial kill, while the time that the concentration remained above the MIC (or, equivalently, the minimum concentration/MIC ratio) was linked to resistance suppression. These findings were also seen in other investigations with ( systems) and (murine system). We conclude that for serious infections with high bacterial burdens, fosfomycin may be of value as a new therapeutic and may be optimized by administering the agent as a continuous or prolonged infusion or by use of a short dosing interval. For indications such as ventilator-associated bacterial pneumonia, it may be prudent to administer fosfomycin as part of a combination regimen.

Treating high-density bacterial infections is a challenging clinical problem. We have a paucity of new agents that can address this problem. Pseudomonas aeruginosa is a particularly difficult pathogen to treat effectively because of the plethora of resistance mechanisms it carries. Fosfomycin is an agent discovered circa 40 years ago. Recently, it has been resurrected in the United States and studied for intravenous therapy. We hypothesized that, to maximize its utility, it would require combination chemotherapy when used in a clinical circumstance in high-bacterial-burden infections. We chose to examine the combination of meropenem plus fosfomycin. These agents were studied in the hollow-fiber infection model. We utilized a fully factorial study design, looking at 2 doses of meropenem alone (1 and 2 g 8-hourly) and two doses of fosfomycin alone (6 and 8 g 8-hourly), as well as all possible combinations plus a no-treatment control. We used a high-dimensional model of 5 inhomogeneous differential equations with 5 system outputs to analyze all data simultaneously. Combination therapy outperformed all monotherapy regimens, with all combinations driving >6 log10 CFU/ml of bacterial killing. Combination therapy was able to counterselect resistance emergence (meropenem mutants being killed by the combination, as well as fosfomycin mutants being killed by the combination) in all regimens studied. The analysis demonstrated that the combination was significantly synergistic for bacterial cell killing and resistance suppression. Meropenem plus fosfomycin is a promising combination for therapy of high-burden Pseudomonas aeruginosa infections and requires further study.