Recent advances in the diagnosis, treatment, and prevention of Pneumocystis carinii pneumonia

Davey, Richard T.; Masur, Henry

doi:10.1128/aac.34.4.499

Cited by 58 publications

(30 citation statements)

References 45 publications

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“…Initial studies of Diff-Quik-stained scid mouse lung homogenates revealed stained bodies with morphologies and sizes comparable to previously published observations describing P. carinii in rat and human samples (see Masur et al, 1989;Davey & Masur, 1990;Smulian & Walzer, 1992). That the scid mice bred by us were indeed positive for P. carinii was confirmed by the demonstration that bodies of the size and morphology of P. carinii were present in Giemsa-stained histological lung sections (not presented).…”

Section: Validation Of Cyst Enumeration Methodssupporting

confidence: 58%

“…That the scid mice bred by us were indeed positive for P. carinii was confirmed by the demonstration that bodies of the size and morphology of P. carinii were present in Giemsa-stained histological lung sections (not presented). Furthermore, as presented below, animals treated with trimethoprim/sulphamethoxazole, an agent known to be effective against P. carinii (see Masur et al, 1989;Davey & Masur, 1990;Smulian & Walzer, 1992), did not contain such bodies.…”

Section: Validation Of Cyst Enumeration Methodsmentioning

confidence: 99%

“…Although both experimental and clinical research has demonstrated both trimethoprim/sulphamethoxazole and aerosol pentamidine to be effective agents (Masur et al, 1989;Davey & Masur, 1990;Sraulian & Walzer, 1992), particularly in primary or secondary prophylaxis, the incidence of failures, development of infections refractory to treatment (especially after inadequate secondary phophylaxis), and severe side-effects, clearly indicate the need for novel therapeutic approaches. Furthermore, recent clinical experience has demonstrated P. carinii to be present in extra-pulmonary sites, including patients that had received aerosol pentamidine prophylaxis (Dembinski et al, 1990;Telak et al, 1990), and suggests the possibility that this route of pentamidine administration is incapable of suppressing the growth of this organism at distal sites, thus rendering this form of prophylaxis potentially ineffectual in the long term.…”

Section: Introductionmentioning

confidence: 99%

“…The usual in-vivo model for experimental P. carinii research is the dexamethasone immunosuppressed rat, which relies on chemical immunosuppression to allow either the growth of endogenous P. carinii (Hughes et al, 1974;Kovacs et al, 1988;Masur et al, 1989;Davey & Masur, 1990), or exogenous P. carinii following intratracheal infection (Bartlett et al, 1990;Boylan & Current, 1992). Cortisone-immunosuppressed mice have also been used (Walzer, Powell & Yoneda, 1979a;Powles et al, 1992).…”

Section: Introductionmentioning

confidence: 99%

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The scid mouse as an experimental model for the evaluation of anti-Pneumocystis carinii therapy

Kunz¹,

Junker²,

Blaser³

et al. 1995

J Antimicrob Chemother

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The usefulness of scid mice bearing endogenous Pneumocystis carinii infection as a model for experimental chemotherapy was examined using standard compounds known to be effective against P. carinii. Trimethoprim/sulphamethoxazole was able to reduce pulmonary P. carinii cysts in a dose-dependent manner within the dose range studied (10/50 to 100/500 TMP/SMX mg/kg/d, bd, po, 5 days per week for 30 treatments). However, alterations in associated symptoms of infection (reduced body weight, increased lung weight, increased blood leucocytes and erythrocytes), was apparently not linearly dose-dependent. Blood and lung lavage fluid levels of sulphamethoxazole one hour post administration of trimethoprim/sulphamethoxazole was dose-dependent, but not linear with dose, and was apparently correlated to cyst reduction; trimethoprim was below the limit of detection at this time. Treatment of mice with 100/500 mg/kg/day trimethoprim/ sulphamethoxazole required 2 weeks (bd for 10 days of treatment) before changes in indices of infection became significant. Pentamidine (20 mg/kg, sc, three times per week for 3 weeks) was nearly as effective as high-dose trimethoprim/ sulphamethoxazole in reducing cysts, whereas lower doses were ineffective. Despite being unable to reduce pulmonary P. carinii infection, even low doses of pentamidine (6 or 2 mg/kg, sc, three times per week for 3 weeks) were able to reduce lung weights and blood leucocyte levels. This model of pulmonary P. carinii infections is amenable to chemotherapeutic intervention in an apparently dose-dependent fashion, and can be used to evaluate the capacity of compounds to eradicate P. carinii and resolve signs of infection.

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Section: Validation Of Cyst Enumeration Methodssupporting

confidence: 58%

Section: Validation Of Cyst Enumeration Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

The scid mouse as an experimental model for the evaluation of anti-Pneumocystis carinii therapy

Kunz¹,

Junker²,

Blaser³

et al. 1995

J Antimicrob Chemother

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“…Although the standard agents for treatment, pentamidine and a combination of trimethoprim and sulfamethoxazole (TMP-SMZ), have high response rates, they often produce severe side effects which necessitate cessation of therapy in more than 60% of AIDS patients (5). Better-tolerated modes of treatment are needed.…”

mentioning

confidence: 99%

Response of rat model of Pneumocystis carinii pneumonia to continuous infusion of deferoxamine

Merali

Chin

Grady

et al. 1995

Antimicrob Agents Chemother

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The iron-chelating drug deferoxamine mesylate (DFO) is active against Pneumocystis carinii in vitro and in rat and mouse models of P. carinii pneumonia. Because DFO has a short half-life, daily divided or continuous dosage was expected to improve the dose response, as is the case with DFO treatment of malaria. Therefore, results of single daily intraperitoneal injections were compared with results of an evenly divided four-timesdaily dosage and the efficacy of delivery with implanted infusion pumps. The highest bolus dosage (1,000 mg kg ؊1 of body weight day ؊1) was as effective as the standard combination of trimethoprim with sulfamethoxazole. Unexpectedly, very little improvement was observed with the divided or continuous dosage, and several mechanisms that could account for this are discussed.Pneumocystis carinii is a fungus that causes P. carinii pneumonia (PCP), an opportunistic infection of considerable importance for AIDS and other immunosuppressive conditions (9). Although the standard agents for treatment, pentamidine and a combination of trimethoprim and sulfamethoxazole (TMP-SMZ), have high response rates, they often produce severe side effects which necessitate cessation of therapy in more than 60% of AIDS patients (5). Better-tolerated modes of treatment are needed. Deferoxamine mesylate (DFO) is a very potent hexadentate iron chelator used routinely since the 1960s to treat iron overload in ␤-thalassemia patients (12). It is also used to remove aluminum from kidney dialysis patients (3). In both of these types of patients DFO has been well tolerated for prolonged periods. DFO is also active against P. carinii in vitro (17) and is therapeutic in animal models of PCP, although very high dosages, i.e., up to 1,000 and 400 mg kg Ϫ1 of body weight day Ϫ1, are required for rats (4) and mice (17), respectively. In contrast, the usual clinical dose ranges from 40 to 60 mg kg Ϫ1. Since the half-life (t 1/2 ) of DFO is about 10 to 20 min (10, 15) and the daily bolus dosage was used in the previous studies, administration by divided doses or by continuous infusion was expected to improve markedly the dose response, as has been observed for treatment of malaria (13, 18). MATERIALS AND METHODS Materials.The following materials were used: DFO, available as Desferal, Ciba Pharmaceuticals Co., Summit, N.J.; a pediatric suspension of TMP-SMZ, Barre-National, Baltimore, Md.; a water-soluble preparation of dexamethasone sodium phosphate for injection (10 mg ml Preparation of immunosuppressed rats. Specific-pathogen-free Sprague-Dawley rats were acquired from Taconic Farms (Germantown, N.Y.), placed in a barrier colony, and given multiple antibiotics to avoid other opportunistic infections as previously described (14) except that on arrival the rats were also given a single injection of penicillin G (6,000 IU) plus procaine. The animals were immunosuppressed by the addition of dexamethasone to the drinking water (1.5 mg liter Ϫ1 ), a regimen which was continued for all animals throughout the experiment.Induction of P...

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Critical Care of Patients With AIDS

Wachter

Luce²,

Hopewell³

1992

JAMA

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The provision of critical care for PCP and respiratory failure specifically or AIDS generally cannot be considered futile. Therefore, decisions about the use of critical care should be guided by the particular clinical situation and the patient's preferences. More research is needed to elucidate the reasons for the improving survival for patients with PCP and respiratory failure and the predictors of such survival.

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Recent advances in the diagnosis, treatment, and prevention of Pneumocystis carinii pneumonia

Cited by 58 publications

References 45 publications

The scid mouse as an experimental model for the evaluation of anti-Pneumocystis carinii therapy

The scid mouse as an experimental model for the evaluation of anti-Pneumocystis carinii therapy

Response of rat model of Pneumocystis carinii pneumonia to continuous infusion of deferoxamine

Critical Care of Patients With AIDS

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