In Vitro Activities of Pentamidine, Pyrimethamine, Trimethoprim, and Sulfonamides against Aspergillus Species

Abstract

The susceptibilities of 70 strains of Aspergillus species were tested against seven different sulfa drugs and pentamidine by a microdilution method with RPMI 1640 and yeast nitrogen base media. Sulfamethoxazole, sulfadiazine, and pentamidine were active in vitro. The MICs obtained with RPMI 1640 were significantly higher than those with yeast nitrogen base. More studies are needed to further elucidate the action of these drugs.Invasive aspergillosis is now one of the most common invasive fungal infections in immunocompromised patients and carries high mortality rates (6). Invasive aspergillosis is a rare complication of end-stage AIDS despite the immunocompromised status of the host. Although invasive aspergillosis in AIDS is associated with neutropenia and corticosteroid therapy, other factors might contribute to the low incidence. Sulfonamides, especially trimethoprim-sulfamethoxazole (SXT), are antimicrobial agents frequently employed for prophylaxis in AIDS patients to prevent Pneumocystis carinii pneumonia. Sulfa drugs are active against Paracoccidioides brasiliensis (16,17), and pentamidine (PNT) has some activity against yeast (2,5,13). We have recently shown that sulfamethoxazole (SMX) is active in vitro against Aspergillus fumigatus and therefore might help to prevent invasive aspergillosis in AIDS patients receiving SXT prophylaxis (1). The aim of this study was to further evaluate the in vitro activities of seven different sulfa compounds and PNT against Aspergillus isolates comprising six different species in two different media.Seventy clinical isolates of Aspergillus were tested: 20 isolates of A. fumigatus and 10 isolates each of the following species: A. flavus, A. niger, A. nidulans, A. ustus, and A. terreus. Isolates were passaged twice in PDA at an interval of 5 to 7 days at 37°C. All isolates were tested in duplicate on 2 different days. A broth microdilution method was performed according to National Committee for Clinical Laboratory Standards (NCCLS) guidelines (M38-P) (14). The drugs used in this study were trimethoprim (TMP), SMX, SXT, pyrimethamine (PMT), dapsone (DAP), sulfamethizole (SMT), sulfisoxazole (SSX), sulfadiazine (SDZ), sulfamethoxypyridazine (SMP), and PNT. All drugs were obtained as standard powders from Sigma-Aldrich Chemie GmbH, Steinheim, Germany. The final concentrations of the drugs ranged from 16 to 0.01 g/ml for TMP and DAP, 320 to 0.31 g/ml for SMX, and 16/320 to 0.01/0.31 g/ml for SXT (1:20 dilution ratio), 4 to 0.004 g/ml for PMT, 500 to 0.4 g/ml for SMT, 128 to 0.12 g/ml for PNT, and 400 to 0.3 g/ml for SSX, SDZ, and SMP. Dimethyl sulfoxide was used to dissolve all drugs except for PNT, which was dissolved in water.The drug dilutions were made in RPMI 1640 medium (with L-glutamine, without bicarbonate) (GIBCO BRL, Life Technologies, Woerden, The Netherlands) and in yeast nitrogen base (YNB) (Difco Laboratories, Sparks, Md.) and were prepared according to the manufacturer's instructions. Both media were buffered to pH 7.0 with 0.165 M morpholinepropanesulfonic aci...

In Vitro Effect of Sulfamethoxazole-Trimethoprim against Histoplasma capsulatum var. capsulatum

“…Previous studies have described the effect of sulfamethoxazole or SMX-TMP against other pathogenic fungi, such as Cryptococcus neoformans (8) and Aspergillus fumigatus (1). The results of this study demonstrated for the first time the inhibitory effect of SMX-TMP against H. capsulatum.…”

Pentamidine Is Active In Vitro againstFusariumSpecies

“…Nevertheless, PNT had significantly enhanced activities against all of the isolates in YNB medium. A similar discrepancy in the efficacies of several drugs (including PNT) in the rich YNB medium was described previously (2). It has been postulated that the YNB medium facilitates fungal growth, with resultant higher levels of metabolic activity and better drug penetration into the intracellular site of action (18).…”

“…Administration of PNT is a well-established approach used for prophylaxis and treatment of pneumonia caused by Pneumocystis carinii, a microorganism that was recently classified taxonomically to be a fungus (21). PNT has also been shown to have in vitro activities against a variety of fungal pathogens, such as Candida albicans, Cryptococcus neoformans, Scedosporium prolificans, and Aspergillus terreus (1,2,5,20). Therefore, in this study, we evaluated the in vitro activities of PNT against 10 clinical isolates of Fusarium spp.…”

Combination Treatment of Invasive Fungal Infections

“…The aromatic diamidine pentamidine (PN) displays multiples effects against protozoa, bacteria and fungi (17, 53, 58, 132, 137, 217a, 237). Among the fungi, its effect has been mostly studied against Pneumocystis carinii (95,228), C. neoformans (10), C. albicans (150,162), and A. fumigatus (3). The in vitro effect of PN-plus-ITRA and PN-plus-KETO combinations on 11 C. albicans strains (including one azole-resistant isolate) has also been studied (217a).…”