Anti–Human Immunodeficiency Virus Drugs Are Ineffective againstPneumocystis cariniiIn Vitro and In Vivo

Abstract

Human immunodeficiency virus (HIV) protease inhibitors (PIs) recently have been reported to be active against Pneumocystis carinii in cell culture. Twelve anti-HIV drugs were analyzed for their effects against rat P. carinii by an ATP cytotoxicity assay. Indinavir and saquinavir exhibited slight anti-P. carinii activity at concentrations above those that can be clinically achieved in serum; other PIs and nucleoside and nonnucleoside reverse-transcriptase inhibitors were inactive against the organism. Anti-HIV drugs, alone or in combination, did not materially reduce the organism count in the treatment of P. carinii pneumonia in immunosuppressed mice. Thus, anti-HIV drugs have little or no activity against P. carinii in these in vitro and in vivo systems. Caution should be used when interpreting reports of the susceptibility of P. carinii to anti-HIV drugs on the basis of in vitro testing only.

Use of Terbinafine in Mouse and Rat Models ofPneumocystis cariniiPneumonia

“…Although this concentration indicates moderate activity on our rating scale (7, 28), it exceeds levels of terbinafine in serum that can be achieved in humans (1 to 2 g/ml) or rodents (2 to 2.5 g/ml) with oral administration of the drug (9,13,15,18,19,20). Here we have analyzed the efficacy of terbinafine in our mouse and rat models of pneumocystosis.Adult C3H/HeN mice and Lewis rats (Charles River) were housed under barrier conditions with infected mice and rats, respectively, and administered corticosteroids to induce the development of pneumocystosis as previously described (25,26,27,28). After 6 to 7 weeks of immunosuppression, when the infection reached moderate intensity, the animals were randomly divided into treatment and control groups.…”

“…The ␣ value was set at 0.05. Drug activity was also analyzed by a scoring system ranging from no activity (Ͻ5-fold reduction in organism counts) to very marked activity (Ն1,000-fold reduction) (25,26,27,28).The first experiment was performed with mice. Terbinafine was administered at doses of 20 to 150 mg/kg/day, which were similar to those used by other investigators to treat mouse systemic fungal and protozoal infections (8,11,15,19,21,22,23,30) (Fig.…”

“…Adult C3H/HeN mice and Lewis rats (Charles River) were housed under barrier conditions with infected mice and rats, respectively, and administered corticosteroids to induce the development of pneumocystosis as previously described (25,26,27,28). After 6 to 7 weeks of immunosuppression, when the infection reached moderate intensity, the animals were randomly divided into treatment and control groups.…”

“…Control animals on steroids (C/S animals) were given a placebo or received no treatment. In our model, drug effectiveness is based on organism burden rather than survival because the animals sometimes die from causes (e.g., other opportunistic infections) other than P. carinii (25,26,27,28). The animals have to receive the terbinafine for at least 7 days to be included in the data analysis, because it usually takes this long to see an effect.…”

“…The ␣ value was set at 0.05. Drug activity was also analyzed by a scoring system ranging from no activity (Ͻ5-fold reduction in organism counts) to very marked activity (Ն1,000-fold reduction) (25,26,27,28).…”