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.

Sequential parenteral and oral ciprofloxacin regimen versus parenteral therapy for bacteremia: a pharmacoeconomic analysis.

OBJECTIVE: To compare, in patients with gram-negative bacteremia, a course of parenteral antibiotic therapy alone with initial parenteral therapy followed by oral ciprofloxacin in terms of the length of hospitalization, clinical effectiveness, toxicity, and cost. DESIGN: A prospective, controlled, randomized, open trial in select hospitalized patients. SETTING: Large metropolitan teaching hospital. PATIENTS: Fifty hospitalized patients with proven gram-negative bacteremia were randomized to receive either oral ciprofloxacin (group 1) following a 72-hour initial intravenous antibiotic regimen or to continue parenteral therapy alone (group 2). To compare the length of hospitalization, an additional group of 50 hospitalized patients with bacteremia (not enrolled in the study, group 3) were analyzed. INTERVENTION: Parenteral antibiotics for 72 hours followed by continuation of a parenteral regimen or oral ciprofloxacin 750 mg bid. MAIN OUTCOME MEASURES: Clinical response, toxicity, and length of hospitalization. RESULTS: Clinical resolution was comparable in the 24 group 1 patients receiving intravenous antibiotics followed by oral ciprofloxacin (83%), the 26 group 2 patients receiving parenteral therapy alone (77%), and the 50 comparison patients (76%). There was little toxicity noted in any group, and the initial parenteral antibiotic regimens were similar. The mean numbers of hospital days on antibiotics were 9.1, 11.2, and 10.6 days in groups 1,2, and 3, respectively (p < 0.05 for group 1 vs. group 2 or 3), and the lengths of hospitalization were 9.8, 15.7, and 12.1 days, respectively (p < 0.05 for group 1 vs. group 2 or 3). Shortening the length of hospitalization and days of antibiotic therapy was associated with a cost savings of up to $78 000 for group 1 patients. CONCLUSIONS: Parenteral therapy for 72 hours followed by oral ciprofloxacin significantly shortened both the number of hospital days taking antibiotics and the length of stay compared with parenteral therapy alone. Both regimens were equally effective and safe in the therapy of gram-negative bacteremia, and initial parenteral therapy followed by oral ciprofloxacin was cost-effective.

Some effects of signal bandwidth and spectral density on the acoustic-reflex threshold in the elderly.

The acoustic-reflex thresholds (ART) for multicomponent tonal complexes of varying bandwidth and spectral density were obtained from 20 normal-hearing (air-conduction thresholds less than or equal to 20 dB HL at 250-8000 Hz) young adults ranging in age from 20-30 years and 20 normal-hearing, old subjects ranging in age from 60-71 years. The results revealed that the ART decreased with spectral density, plateauing after seven components in the young group and after five components in the old group; the decrease in the acoustic-reflex threshold as a result of the increase in spectral density was less in the old than in the young group. The bandwidth effect (when bandwidth was plotted in hertz or octaves) on the acoustic-reflex threshold was present in the young adults, but substantially reduced in the elderly, as evidenced by the statistically significant interaction between subject group and signal bandwidth. The spectral density results are discussed in terms of their theoretic implications for the energy summation capacity and frequency resolution of the auditory system. The bandwidth results are discussed in terms of their theoretic implications for the frequency-resolving power of the auditory system.

Ocular toxicity of high-dose intravenous desferrioxamine.

Desferrioxamine was given intravenously, at higher doses than previously reported, to counter the effects of transfusion-induced iron overload in four patients with beta thalassaemia major. In two of them retinal abnormalities developed, presenting with night blindness and field defects, which improved on withdrawal of the drug.

The acoustic reflex threshold in aging ears.

This study investigates the controversy regarding the influence of age on the acoustic reflex threshold for broadband noise, 500-, 1000-, 2000-, and 4000-Hz activators between Jerger et al. [Mono. Contemp. Audiol. 1 (1978)] and Jerger [J. Acoust. Soc. Am. 66 (1979)] on the one hand and Silman [J. Acoust. Soc. Am. 66 (1979)] and others on the other. The acoustic reflex thresholds for broadband noise, 500-, 1000-, 2000-, and 4000-Hz activators were evaluated under two measurement conditions. Seventy-two normal-hearing ears were drawn from 72 subjects ranging in age from 20-69 years. The results revealed that age was correlated with the acoustic reflex threshold for BBN activator but not for any of the tonal activators; the correlation was stronger under the 1-dB than under the 5-dB measurement condition. Also, the mean acoustic reflex thresholds for broadband noise activator were essentially similar to those reported by Jerger et al. (1978) but differed from those obtained in this study under the 1-dB measurement condition.

Double-blind randomised controlled trial of folate treatment before conception to prevent recurrence of neural-tube defects.

A randomized controlled double-blind trial was undertaken in south Wales to prevent the recurrence of neural-tube defects in women who had had one child with a neural-tube defect. Sixty women were allocated before conception to take 4 mg of folic acid a day before and during early pregnancy and 44 complied with these instructions. Fifty-one women were allocated to placebo treatment. There were no recurrences among the compliant mothers but two among the non-compliers and four among the women in the placebo group. Thus there were no recurrences among those who received supplementation and six among those who did not; this difference is significant (p = 0.04). It is concluded that folic acid supplementation might be a cheap, safe, and effective method of primary prevention of neural-tube defects but that this must be confirmed in a large, multicentre trial.

Air contrast colon examination in patients with colostomies.

A readily feasible technique for producing an excellent air contrast examination of the colon in patients with colostomies is described. The technique employes no special equipment and is easily tolerated by patients. Indications for the examination include a symptomatic patient with a negative conventional enema or suspicious single column examination. The surprisingly high incidence of both benign and malignant coexisting colonic neoplasms is reviewed.

Angiographic spectrum in Crohn's disease of the small intestine and colon.

Barium and angiographic examinations of the small intestine and colon were performed in 34 patients with histopathologically verified Crohn's disease. The spectrum of angiographic findings varied from hypervascularity with no morphologic changes of the vasa recta to complete obstruction of the vasa recta resulting in hypovascularity of the diseased intestine. A distinctive angiographic pattern was present in the distal part of the small intestine in those patients with advanced narrowing of the intestinal lumen as demonstrated on barium examination.