SYNERGISTIC COMBINATIONS OF RO 11-8958 AND OTHER DIHYDROFOLATE-REDUCTASE INHIBITORS WITH SULFAMETHOXAZOLE AND DAPSONE FOR THERAPY OF EXPERIMENTAL PNEUMOCYSTOSIS
Pd. Walzer et al., SYNERGISTIC COMBINATIONS OF RO 11-8958 AND OTHER DIHYDROFOLATE-REDUCTASE INHIBITORS WITH SULFAMETHOXAZOLE AND DAPSONE FOR THERAPY OF EXPERIMENTAL PNEUMOCYSTOSIS, Antimicrobial agents and chemotherapy, 37(7), 1993, pp. 1436-1443
We compared Ro 11-8958, an analog of trimethoprim (TMP) with improved
antimicrobial and pharmacokinetic properties, other dihydrofolate redu
ctase (DHFR) inhibitors, sulfamethoxazole (SMX), and dapsone (DAP) in
the treatment of Pneumocystis carinii pneumonia in an immunosuppressed
rat model. In contrast to previous reports, high dosages of the DHFR
inhibitors were used in combination with fixed, low dosages of SMX (3
mg/kg of body weight per day) or DAP (25 mg/kg/day). When administered
alone at these dosages, SMX and DAP reduced the median P. carinii cys
t count about 5- to 15-fold. Ro 11-8958, TMP, and diaveridine used at
a dosage of 20 mg/kg/day with SMX were only slightly more effective th
an SMX used alone. However, administration of these DHFR inhibitors at
a dosage of 100 mg/kg/day with SMX lowered the cyst count about 500-
to 1,000-fold, indicating a synergistic effect. Little or no synergism
was found when other DHFR inhibitors (pyrimethamine, cycloguanil, and
tetroxoprim) were combined with SMX. Regimens of Ro 11-8958 at a dosa
ge of 20 mg/kg/day with DAP and of TMP or diaveridine used at a dosage
of 100 mg/kg/day with DAP showed comparable anti-P. carinii activity,
lowering the cyst count 100- to 200-fold. By contrast, Ro 11-8958 adm
inistered at a dosage of 100 mg/kg/day with DAP reduced the cyst count
>1,000-fold. Thus, the experimental approach used here enables the ra
t model of pneumocystosis to be used to compare synergistic combinatio
ns of antifolate drugs. The favorable results achieved with Ro 11-8958
indicate that it should be considered for clinical trials.