Antiplatelet and direct antithrombin agents may be useful in the prophylaxis of IE in humans. In particular, the potential dual benefit of dabigatran etexilate might be reconsidered for patients with prosthetic valves, who require life-long anticoagulation and in whom S. aureus IE is associated with high mortality.

The new 8-methoxyquinolone moxifloxacin was tested against two ciprofloxacin-susceptible Staphylococcus aureus strains (strains P8 and COL) and two ciprofloxacin-resistant derivatives of strain P8 carrying a single grlA mutation (strain P8-4) and double grlA and gyrA mutations (strain P8-128). All strains were resistant to methicillin. The MICs of ciprofloxacin and moxifloxacin were 0.5 and 0.125 mg/liter, respectively, for P8; 0.25 and 0.125 mg/liter, respectively, for COL; 8 and 0.25 mg/liter, respectively, for P8-4; and >128 and 2 mg/liter, respectively, for P8-128. In vitro, the rate of spontaneous resistance of P8 and COL was 10 ؊7 on agar plates containing ciprofloxacin at two times the MIC, whereas it was <10 ؊10 on agar plates containing moxifloxacin at two times the MIC. Rats with experimental aortic endocarditis were treated with doses of drugs that simulate the kinetics in humans: moxifloxacin, 400 mg orally once a day; ciprofloxacin, 750 mg orally twice a day; or vancomycin, 1 g intravenously twice a day. Treatment was started either 12 or 24 h after infection and lasted for 3 days. Moxifloxacin treatment resulted in culture-negative vegetations in a total of 20 of 21 (95%) rats infected with P8, 10 of 11 (91%) rats infected with COL, and 19 of 24 (79%) rats infected with P8-4 (P < 0.05 compared to the results for the controls). In contrast, ciprofloxacin treatment sterilized zero of nine (0%) vegetations infected with first-level resistant mutant P8-4. Vancomycin sterilized only 8 of 15 (53%), 6 of 11 (54%), and 12 of 23 (52%) of the vegetations, respectively. No moxifloxacin-resistant derivative emerged among these organisms. However, moxifloxacin treatment of highly ciprofloxacin-resistant mutant P8-128 failed and selected for variants for which the MIC increased two times in 2 of 10 animals. Thus, while oral moxifloxacin might deserve consideration as treatment for staphylococcal infections in humans, caution related to its use against strains for which MICs are borderline is warranted.

Progress in modern medicine has led to a worldwide increase in the incidence of Candida infections (2, 25). Amphotericin B, a fungicidal agent, has been the standard treatment for these infections for decades, but the toxicity of its conventional form and the costs of its lipid forms limit its use. Other antifungal agents, such as azoles, have excellent efficacy-toxicity profiles and play an important role in the treatment of candidal infections in nonneutropenic patients, although they have mostly fungistatic activities (13,18,19). However, the treatment of candidiasis during neutropenia and the emergence of azole-resistant Candida species continue to represent major challenges (1,17,19,(25)(26)(27). Thus, new therapeutic strategies need to be developed. In Candida albicans, efflux pumps play a major role in azole susceptibility and may represent a new therapeutic target (22). Promising results were reported in studies in which efflux of cytotoxic agents was inhibited in multiresistant human cancer cells (10, 24). As mammalian and fungal multidrug efflux transporters (METs) have strong structural homologies, human efflux pump inhibitors were screened in vitro to determine whether they have synergistic activities with fluconazole (FLC) against C. albicans. We found that the combination of FLC and cyclosporine (CY) is fungicidal against FLC-susceptible C. albicans strains (13). This powerful synergism was confirmed in experimental endocarditis. The association of FLC and CY was fungicidal against infection in aortic valve vegetations, a model of localized neutropenia, as well as in the kidney, an organ with a neutrophil-phagocytic host response (11). Although this phenomenon was discovered during the screening of inhibitors of efflux pumps in cancer cells, the mechanism of the synergism of FLC and CY in C. albicans is unknown. CY has several cellular targets including the cell membrane, METs, and the cyclophilin-calmodulin-calcineurin pathway. Thus, its interaction with FLC might intervene at different sites (9). The objective of the present work was to investigate the involvement of METs encoded by the CDR1, CDR2, CaMDR1, and FLU1 genes, which have been found to mediate FLC efflux in C. albicans. We postulated that their deletion would result in the loss of the fungicidal synergism of FLC-CY. For this purpose, the in vitro and in vivo activities of the combination of FLC and CY were compared against FLC-susceptible parent strain C. albicans CAF2-1 and FLC-hypersusceptible mutant C. albicans DSY1024, obtained by targeted deletion of the MET genes CDR1, CDR2, CaMDR1, and FLU1 (3,21).

Transient high-grade bacteremia following invasive procedures carries a risk of infective endocarditis (IE).This is supported by experimental endocarditis. On the other hand, case-control studies showed that IE could be caused by cumulative exposure to low-grade bacteremia occurring during daily activities. However, no experimental demonstration of this latter possibility exists. This study investigated the infectivity in animals of continuous low-grade bacteremia compared to that of brief high-grade bacteremia. Rats with aortic vegetations were inoculated with Streptococcus intermedius, Streptococcus gordonii or Staphylococcus aureus (strains Newman and P8). Animals were challenged with 10 3 to 10 6 CFU. Identical bacterial numbers were given by bolus (1 ml in 1 min) or continuous infusion (0.0017 ml/min over 10 h). Bacteremia was 50 to 1,000 times greater after bolus than during continuous inoculation. Streptococcal bolus inoculation of 10 5 CFU infected 63 to 100% vegetations compared to 30 to 71% infection after continuous infusion (P > 0.05). When increasing the inoculum to 10 6 CFU, bolus inoculation infected 100% vegetations and continuous infusion 70 to 100% (P > 0.05). S. aureus bolus injection of 10 3 CFU infected 46 to 57% valves. This was similar to the 53 to 57% infection rates produced by continuous infusion (P > 0.05). Inoculation of 10 4 CFU of S. aureus infected 80 to 100% vegetations after bolus and 60 to 75% after continuous infusion (P > 0.05). These results show that high-level bacteremia is not required to induce experimental endocarditis and support the hypothesis that cumulative exposure to low-grade bacteremia represents a genuine risk of IE in humans.

Levofloxacin is the L isomer of ofloxacin, a racemic mixture in which the L stereochemical form carries the antimicrobial activity. Levofloxacin is more active than former quinolones against gram-positive bacteria, making it potentially useful against such pathogens. In this study, levofloxacin was compared to ciprofloxacin, flucloxacillin, and vancomycin for the treatment of experimental endocarditis due to two methicillin-susceptible Staphylococcus aureus (MSSA) and two methicillin-resistant S. aureus (MRSA) isolates. The four test organisms were susceptible to ciprofloxacin, the levofloxacin MICs for the organisms were low (0.12 to 0.25 mg/liter), and the organisms were killed in vitro by drug concentrations simulating both the peak and trough levels achieved in human serum (5 and 0.5 mg/liter, respectively) during levofloxacin therapy. Rats with aortic endocarditis were treated for 3 days. Antibiotics were injected with a programmable pump to simulate the kinetics of either levofloxacin (350 mg orally once a day), ciprofloxacin (750 mg orally twice a day), flucloxacillin (2 g intravenously four times a day), or vancomycin (1 g intravenously twice a day). Levofloxacin tended to be superior to ciprofloxacin in therapeutic experiments (P = 0.08). More importantly, levofloxacin did not select for resistance in the animals, in contrast to ciprofloxacin. The lower propensity of levofloxacin than ciprofloxacin to select for quinolone resistance was also clearly demonstrated in vitro. Finally, the effectiveness of this simulation of oral levofloxacin therapy was at least equivalent to that of standard treatment for MSSA or MRSA endocarditis with either flucloxacillin or vancomycin. This is noteworthy, because oral antibiotics are not expected to succeed in the treatment of severe staphylococcal infections. These good results obtained with animals suggest that levofloxacin might deserve consideration for further study in the treatment of infections due to ciprofloxacin-susceptible staphylococci in humans.