Novel non-nucleoside inhibitors of cytomegaloviruses (BAY 38-4766): in vitro and in vivo antiviral activity and mechanism of action.

For two decades it has been impossible to develop drugs with novel mechanisms of action against herpesviruses, and treatment has been confined largely to the use of inhibitors of viral DNA polymerase. As a representative of a novel inhibitory approach, the non-nucleosidic BAY 38-4766 was identified as a highly selective inhibitor of human cytomegalovirus (HCMV). The compound selectively inhibits not only HCMV strains, including ganciclovir-resistant, ganciclovir/foscarnet and ganciclovir/cidofovir double-resistant clinical isolates, but also a number of monkey and rodent cytomegaloviruses. In a murine cytomegalovirus (MCMV) pathogenicity model in mice, antiviral efficacy and excellent tolerability were demonstrated. BAY 38-4766-resistant HCMV and MCMV strains are not cross-resistant to the nucleoside analogues ganciclovir and cidofovir or the pyrophosphate analogue foscarnet, indicating a different mode of action. Mechanistic studies demonstrated that the high selectivity of this drug class is most likely due to the inhibition of a late stage of the viral replication cycle. Sequence analyses of resistant HCMV and MCMV strains revealed mutations in UL89 and UL104, proteins known to be involved in viral DNA cleavage and packaging. Consequently, the drug is highly specific for the viral as opposed to cellular functions, since UL89 is related to a bacteriophage terminase and no human equivalent exists. In addition, because some of the genes of the viral DNA cleavage and packaging complex are highly conserved among herpesviruses, development of broad-spectrum agents covering additional human herpesviruses might be possible using this approach.

Risk factor assessment for the acquisition of fluoroquinolone-resistant isolates of Pseudomonas aeruginosa in a community-based hospital.

A case-control study was performed in a community-based nonteaching hospital to assess patient risk factors for the acquisition of fluoroquinolone-resistant isolates of Pseudomonas aeruginosa. Fifty-five patients who were hospitalized between July 1, 1993 and December 31, 1993 and who had P. aeruginosa recovered from a clinical specimen were included in the analysis. Two patient populations were designated based on the fluoroquinolone susceptibility of their P. aeruginosa isolates. Statistical evaluation using univariate analysis of demographic and clinical data from the 42 patients with quinolone-susceptible P. aeruginosa and the 13 patients with quinolone-resistant P. aeruginosa demonstrated that prior receipt of a fluoroquinolone was the only significant risk factor for the subsequent emergence of fluoroquinolone resistance among P. aeruginosa isolated from patients hospitalized in this small community-based institution (p = 0.0196). Multivariate analysis supported the finding that prior receipt of a fluoroquinolone was the major risk factor for the isolation of fluoroquinolone-resistant P. aeruginosa (p = 0.0004); isolation of this Gram-negative bacillus from sputum (p = 0.0306) and a history of recent surgery (p = 0.0058) were also significantly associated as risk factors for resistance.

Epidemiologic analysis and genotypic characterization of a nosocomial outbreak of vancomycin-resistant enterococci.

We are reporting on a nosocomial outbreak of 213 cases of vancomycin-resistant enterococcus infection involving 2,812 enterococcal isolates from patients over a period of 36 months. In 1990, the Enterococcus faecium vancomycin susceptibility rate was found to be 85.7% (36 of 42 cases), and an incidence of 10.9% (42 of 383) was noted. The 1991 data showed E. faecium with a vancomycin susceptibility rate of 61.8% (110 of 178) and an incidence of 26.0% (178 of 684). Subsequently, in 1992, the incidence of E. faecium increased to 34.0% (599 of 1,745), with a decreased vancomycin susceptibility rate of 25.8% (155 of 599). The E. faecalis vancomycin susceptibility rate remained near 97% (1,768 of 1,823) over the 36-month period. Of 115 vancomycin-resistant enterococcus (VRE) clinical isolates identified by the MicroScan MIC Combo-6 panels (Baxter Healthcare, Sacramento, Calif.), the agar dilution method indicated the resistance rate to be 92.3% (106 of 115) (high level), 3.5% (4 of 115) midlevel, and 3.5% (4 of 115) (low level). Genotypic characterization of 32 different VRE isolates by field-inversion gel electrophoresis demonstrated 19 dissimilar restriction endonuclease patterns, with 9 patterns associated with VRE quinolone resistance. Statistical analysis of case-control data for 32 patients with VRE infections indicated a positive association with intrabdominal surgical procedures (odds ratio, 24.12), multidrug therapy (odds ratio, 37.80), preexposure to vancomycin (odds ratio, 20.21), and death (odds ratio, 17.50).