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Antimicrobial Agents and Chemotherapy, December 1999, p. 2831-2840, Vol. 43, No. 12
Divisions of Infectious
Diseases1 and Clinical
Pharmacology,2 Albany Medical College, Albany,
New York 12208, and Department of Ophthalmology, Montefiore
Medical Center-Albert Einstein College of Medicine, Bronx, New York
100173
Received 10 July 1998/Returned for modification 8 November
1998/Accepted 30 July 1999
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
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Copyright © 1999, American Society for Microbiology. All rights reserved.
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
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).
*
Corresponding author. Mailing address: Division of
Infectious Diseases, Mail Code-49, Albany Medical College, 47 New
Scotland Ave., Albany, NY 12208. Phone: (518) 262-6548. Fax: (518)
262-6727. E-mail:
arnold_louie_at_amc01-3{at}ccgateway.amc.edu.
Antimicrobial Agents and Chemotherapy, December 1999, p. 2831-2840, Vol. 43, No. 12
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
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