Effect of coadministration of moxifloxacin and rifampin on Mycobacterium tuberculosis in a murine aerosol infection model.

Coadministration of moxifloxacin and rifampin was evaluated in a murine model of Mycobacterium tuberculosis pulmonary infection to determine whether the finding of antagonism documented in a hollow-fiber infection model could be recapitulated in vivo. Colony counts were followed in a no-treatment control group, groups administered moxifloxacin or rifampin monotherapy, and a group administered a combination of the two agents. Following 18 days of once-daily oral administration to mice infected with M. tuberculosis, there was a reduction in the plasma exposure to rifampin that decreased further when rifampin was coadministered with moxifloxacin. Pharmacodynamic analysis demonstrated a mild antagonistic interaction between moxifloxacin and rifampin with respect to cell kill in the mouse model for tuberculosis (TB). No emergence of resistance was noted over 28 days of therapy, even with monotherapy. This was true even though one of the agents in the combination (moxifloxacin) induces error-prone replication. The previously noted antagonism with respect to cell kill shown in the hollow-fiber infection model was recapitulated in the murine TB lung model, although to a lesser extent.

Impact of short-course quinolone therapy on susceptible and resistant populations of Staphylococcus aureus.

We previously demonstrated that therapy duration has a differential impact on susceptible and resistant subpopulations of Staphylococcus aureus. What our previous investigation did not address was what would transpire after stopping therapy and whether these events would be different in susceptible and resistant subpopulations. We used the regimen previously demonstrated to amplify resistant subpopulation at day 4-5 (area under the concentration-time curve/minimum inhibitory concentration ratio, 100). Therapy was started in our hollow-fiber infection model on day 0; garenoxacin was administered in 4, 5, or 6 doses (days 3-5). The system was observed until day 13. Four drug doses kept the susceptible population dominant, but with the resistant subpopulation amplifying. Five and 6 doses caused the resistant population to exceed the susceptible population at the end of therapy and for a variable time thereafter. Ultimately, the susceptible population became dominant by day 13. Modeling demonstrated that the resistant isolates grew more slowly and had a higher natural death rate.

Impact of drug-exposure intensity and duration of therapy on the emergence of Staphylococcus aureus resistance to a quinolone antimicrobial.

We have shown previously in animal model and in vitro systems that antimicrobial therapy intensity has a profound influence on subpopulations of resistant organisms. Little attention has been paid to the effect of therapy duration on resistant subpopulations. We examined the influence of therapy intensity (area under the concentration/time curve for 24 h:minimum inhibitory concentration [AUC24:MIC] ratio) and therapy duration on resistance emergence using an in vitro model of Staphylococcus aureus infection. AUC24:MIC ratios of>or=100 were necessary to kill a substantial portion of the total population. Importantly, we demonstrated that therapy duration is a critical parameter. As the duration increased beyond 5 days, the intensity needed to suppress the antibiotic-resistant subpopulations increased, even when the initial bacterial kill was>4 log10 (cfu/mL). These findings were prospectively validated in an independent experiment in which exposures were calculated from the results of fitting a large mathematical model to all data simultaneously. All of the prospectively determined predictions were fulfilled in this validation experiment.

Impact of the order of initiation of fluconazole and amphotericin B in sequential or combination therapy on killing of Candida albicans in vitro and in a rabbit model of endocarditis and pyelonephritis.

In vitro time-kill studies and a rabbit model of endocarditis and pyelonephritis were used to define the impact that the order of exposure of Candida albicans to fluconazole (FLC) and amphotericin B (AMB), as sequential and combination therapies, had on the susceptibility of C. albicans to AMB and on the outcome. The contribution of FLC-induced resistance to AMB for C. albicans also was assessed. In vitro, AMB monotherapy rapidly killed each of four C. albicans strains; FLC alone was fungistatic. Preincubation of these fungi with FLC for 18 h prior to exposure to AMB decreased their susceptibilities to AMB for 8 to >40 h. Induced resistance to AMB was transient, but the duration of resistance increased with the length of FLC preincubation. Yeast sequentially incubated with FLC followed by AMB plus FLC (FLC-->AMB+FLC) showed fungistatic growth kinetics similar to that of fungi that were exposed to FLC alone. This antagonistic effect persisted for at least 24 h. Simultaneous exposure of C. albicans to AMB and FLC [AMB+FLC(simult)] demonstrated activity similar to that with AMB alone for AMB concentrations of > or =1 microg/ml; antagonism was seen using an AMB concentration of 0.5 microg/ml. The in vitro findings accurately predicted outcomes in our rabbit infection model. In vivo, AMB monotherapy and treatment with AMB for 24 h followed by AMB plus FLC (AMB-->AMB+FLC) rapidly sterilized kidneys and cardiac vegetations. AMB+FLC(simult) and FLC-->AMB treatments were slower in clearing fungi from infected tissues. FLC monotherapy and FLC-->AMB+FLC were both fungistatic and were the least active regimens. No adverse interaction was observed between AMB and FLC for the AMB-->FLC regimen. However, FLC-->AMB treatment was slower than AMB alone in clearing fungi from tissues. Thus, our in vitro and in vivo studies both demonstrate that preexposure of C. albicans to FLC reduces fungal susceptibility to AMB. The length of FLC preexposure and whether AMB is subsequently used alone or in combination with FLC determine the duration of induced resistance to AMB.

Efficacies of high-dose fluconazole plus amphotericin B and high-dose fluconazole plus 5-fluorocytosine versus amphotericin B, fluconazole, and 5-fluorocytosine monotherapies in treatment of experimental endocarditis, endophthalmitis, and pyelonephritis due to Candida albicans.

We compared the efficacies of fluconazole (Flu), amphotericin B (AmB), and 5-fluorocytosine (5FC) monotherapies with the combination of Flu plus 5FC and Flu plus AmB in a rabbit model of Candida albicans endocarditis, endophthalmitis, and pyelonephritis. The dose of Flu used was that which resulted in an area under the concentration-time curve in rabbits equivalent to that seen in humans who receive Flu at 1,600 mg/day, the highest dose not associated with central nervous system toxicity in humans. Quantitative cultures of heart valve vegetations, the choroid-retina, vitreous humor, and kidney were conducted after 1, 5, 14, and 21 days of therapy. All untreated controls died within 6 days of infection; animals treated with 5FC monotherapy all died within 18 days. In contrast, 93% of animals in the other treatment groups appeared well and survived until they were sacrificed. At day 5, the relative decreases in CFU per gram in the vitreous humor were greater in groups that received Flu alone and in combination with 5FC or AmB than in groups receiving AmB or 5FC monotherapies (P < 0. 005) but were similar thereafter. In the choroid-retina, 5FC was the least-active drug. However, there were no differences in choroidal fungal densities between the other treatment groups. On days 5 and 14 of therapy, fungal densities in kidneys of AmB recipients were lower than those resulting from the other therapies (P < 0.001 and P < or = 0.038, respectively) and AmB-plus-Flu therapy was antagonistic; however, all therapies for fungal pyelonephritis were similar by treatment day 21. While fungal counts in cardiac valves of Flu recipients were similar to those of controls on day 5 of therapy and did not change from days 1 to 21, AmB therapy significantly decreased valvular CFUs versus Flu at days 5, 14, and 21 (P < 0.005 at each time point). 5FC plus Flu demonstrated enhanced killing in cardiac vegetations compared with Flu or 5FC as monotherapies (P < 0. 03). Similarly, the combination of AmB and Flu was more active than Flu in reducing the fungal density in cardiac vegetations (P < 0.03). However, as in the kidney, AmB plus Flu demonstrated antagonism versus AmB monotherapy in the treatment of C. albicans endocarditis (P < 0.05, P = 0.036, and P < 0.008 on days 5, 14, and 21, respectively).

Interaction between fluconazole and amphotericin B in mice with systemic infection due to fluconazole-susceptible or -resistant strains of Candida albicans.

The interaction between fluconazole (Flu) and amphotericin B (AmB) was evaluated in a murine model of systemic candidiasis for one Flu-susceptible strain (MIC, 0.5 microg/ml), two strains with intermediate Flu resistance (Flu mid-resistant strains) (MIC, 64 and 128 microg/ml), and one highly Flu-resistant strain (MIC, 512 microg/ml) of Candida albicans. Differences in fungal densities in kidneys of infected mice after 24 h of therapy and in survival rates at 62 days of mice treated with an antifungal drug or a combination of antifungal drugs for 4 days were compared. For the Flu-susceptible and Flu mid-resistant strains, the combination of Flu and AmB was antagonistic, as shown by both quantitative culture results and survival. The interaction was additive for the highly Flu-resistant strain. These results suggest that the combination of Flu and AmB should be used with caution in infections due to fungi that are usually susceptible to both antifungal agents and as empirical antifungal drug therapy.

Surgical resection following interleukin 2 therapy for metastatic renal cell carcinoma prolongs remission.

Records of 399 patients with metastatic renal cell carcinoma treated with interleukin 2 with or without lymphokine-activated killer cell immunotherapy enrolled in 14 separate clinical trials from multiple institutions were reviewed to determine whether patients with a partial response to interleukin 2 therapy would benefit from surgical resection of residual tumor. Sixty-two patients demonstrated objective responses (15.5%), 18 (4.5%) complete and 44 (11.0%) partial. Eleven patients underwent resection of residual tumor in the lung, kidney, retroperitoneum, or pelvis so that they had "surgically no evidence of disease" (SNED). Of these, 10 had partial responses, and one patient with progressive disease had a complete response. Comparison of response duration showed no difference between the complete response and SNED groups, but there was a significant difference between each of these groups and the partial response group. At this writing, all 11 patients in the SNED group remained alive without evidence of disease (median follow-up, 21 months). In contrast, only 14 patients (76%) with complete responses and 15 patients (35%) with partial responses remained free of disease progression. Enhanced survival of the complete response and SNED groups compared with the partial response group borders on significance and awaits longer follow-up. These data suggest that surgical resection, if technically feasible, may benefit patients who show a partial response to interleukin 2 treatment for metastatic renal cell carcinoma.

Comparative in-vitro susceptibilities of Pseudomonas aeruginosa, Xanthomonas maltophilia, and Pseudomonas spp. to sparfloxacin (CI-978, AT-4140, PD131501) and reference antimicrobial agents.

The susceptibility of sparfloxacin, a new broad spectrum fluoroquinolone, was determined for 72 clinical isolates of Pseudomonas aeruginosa, 15 Xanthomonas maltophilia, and 19 Pseudomonas spp. The activity of sparfloxacin was compared with that of ciprofloxacin and other reference antibiotics. Sparfloxacin was the most active antibiotic tested against X. maltophilia (MIC90 1 mg/l) and the most active quinolone against P. cepacia and P. putrifaciens. Ciprofloxacin, however, demonstrated greater activity than sparfloxacin against P. fluorescens and P. stutzeri. P. aeruginosa was most susceptible to ciprofloxacin with an MIC90 of 2 mg/l, compared with an MIC90 of 8 mg/l for sparfloxacin and ofloxacin. Although cross-resistance between quinolones was noted, cross-resistance between antibiotic classes was not seen. Aminoglycoside-resistant and aminoglycoside-susceptible P. aeruginosa strains were equally susceptible to sparfloxacin. Kill curves showed sparfloxacin to be rapidly bactericidal against P. aeruginosa at 1 x MIC. Sparfloxacin demonstrated greater bactericidal activity than ciprofloxacin at 1 x and 2 x their MICs. Unlike ciprofloxacin and gentamicin, sparfloxacin showed sustained bactericidal activity at greater than or equal to 1 MIC for 24 h.

Current trends and prospects in surgical adjuvant trials.

New concepts and treatments currently available for adjuvant studies are illustrated by a review of ongoing studies sponsored by the National Cancer Institute. More thorough information is needed on immunotherapeutic agents to allow more rationale in the use of these agents. Solid bases to properly select drugs or drug combinations for adjuvant purposes are being established. However, dose-schedule and duration of treatment are still to be defined. Strategies directed at prolonging the benefit of surgical adjuvant chemotherapy remain to be planned. Progress continuously achieved with immunotherapy and chemotherapy should rapidly broaden the spectrum of tumour types to be included in adjuvant studies.