Therapy For Pneumocystis Carinii Pneumonia Research Articles

Crystallographic analysis reveals a novel second binding site for trimethoprim in active site double mutants of human dihydrofolate reductase

In order to produce a more potent replacement for trimethoprim (TMP) used as a therapy for Pneumocystis pneumonia and targets dihydrofolate reductase from Pneumocystis jirovecii (pjDHFR), it is necessary to understand the determinants of potency and selectivity against DHFR from the mammalian host and fungal pathogen cells. To this end, active site residues in human (h) DHFR were replaced with those from pjDHFR. Structural data are reported for two complexes of TMP with the double mutants Gln35Ser/Asn64Phe (Q35S/N64F) and Gln35Lys/Asn64Phe (Q35K/N64F) of hDHFR that unexpectedly show evidence for the binding of two molecules of TMP: one molecule that binds in the normal folate binding site and the second molecule that binds in a novel subpocket site such that the mutated residue Phe64 is involved in van der Waals contacts to the trimethoxyphenyl ring of the second TMP molecule. Kinetic data for the binding of TMP to hDHFR and pjDHFR reveal an 84-fold selectivity of TMP against pjDHFR (K(i) 49 nM) compared to hDHFR (K(i) 4093 nM). Two mutants that contain one substitution from pj--and one from the closely related Pneumocystis carinii DHFR (pcDHFR) (Q35K/N64F and Q35S/N64F) show K(i) values of 593 and 617 nM, respectively; these K(i) values are well above both the K(i) for pjDHFR and are similar to pcDHFR (Q35K/N64F and Q35S/N64F) (305nM). These results suggest that active site residues 35 and 64 play key roles in determining selectivity for pneumocystis DHFR, but that other residues contribute to the unique binding of inhibitors to these enzymes.

Trimethoprim-Sulfamethoxazole–Induced Methemoglobinemia in an HIV-Infected Patient

Trimethoprim-Sulfamethoxazole–Induced Methemoglobinemia in an HIV-Infected Patient

Marginal Structural Models to Estimate the Joint Causal Effect of Nonrandomized Treatments

Even in the absence of unmeasured confounding factors or model misspecification, standard methods for estimating the causal effect of time-varying treatments on survival are biased when (a) there exists a time-dependent risk factor for survival that also predicts subsequent treatment, and (b) past treatment history predicts subsequent risk factor level. In contrast, methods based on marginal structural models (MSMs) can provide consistent estimates of causal effects when unmeasured confounding and model misspecification are absent. MSMs are a new class of causal models whose parameters are estimated using a new class of estimators—inverse-probability-of-treatment weighted estimators. We use a marginal structural Cox proportional hazards model to estimate the joint effect of zidovudine (AZT) and prophylaxis therapy for Pneumocystis carinii pneumonia on the survival of HIV-positive men in the Multicenter AIDS Cohort Study, an observational study of homosexual men. We obtained an estimated causal mortality rate (hazard) ratio of .67 (conservative 95% confidence interval .46-.98) for AZT and of 1.14 (.79, 1.64) for prophylaxis therapy. These estimates will be consistent for the true causal rate ratios when the functional forms chosen for our models are correct and data have been obtained on all time-independent and time-dependent covariates that predict both subsequent treatment and mortality.

Complications during clinical courses of Pneumocystis carinii pneumonia in patients with acquired immunodeficiency syndrome.

To describe the incidence of complications before and during therapy of Pneumocystis carinii pneumonia (PCP) in patients with acquired immunodeficiency syndrome (AIDS). A retrospective review of the patient's medical records. A total of 29 patients with AIDS and PCP who were admitted to the AIDS Clinical Center, International Medical Center of Japan from July 1996 to November 1999. Adverse effects were found in 24 (88.9%) of 27 patients treated with trimethoprim/sulfamethoxazole (T/S), 6 (46.1%) of 13 treated with parenteral pentamidine, and 2 (20%) of 10 treated with inhaled pentamidine. Infectious and/or non-infectious complications were found in 25 (86.2%) of 29 study patients. Regarding infectious complications, 16 (55.2%) were found on admission and 10 cases (34.5%) with infectious complications were identified during admission; including oral candidiasis (37.9% and 17.2%, respectively) and genital herpes (3.4% and 6.9%, respectively). Cytomegalovirus antigenemia was detected in 4 cases (13.8%) on admission and 12 cases (41.4%) during admission. Non-infectious complications affected 11 cases (37.9%) on admission, and 6 cases (20.7%) during admission, the latter included heart failure (10.3%) and pneumothorax (6.9%). PCP was successfully treated in all but one patient who suffered from repeated pneumothorax. Treatment of PCP can be problematic and it is important to be aware of the high incidence of various complications that can occur during the treatment of PCP.

A 5-year retrospective review of adverse drug reactions and their risk factors in human immunodeficiency virus-infected patients who were receiving intravenous pentamidine therapy for Pneumocystis carinii pneumonia.

The incidence and severity of adverse drug reactions (ADRs) in human immunodeficiency virus-infected persons receiving intravenous pentamidine for Pneumocystis carinii pneumonia during a 5-year period were reviewed retrospectively. Predisposing risk factors for ADRs were identified. ADRs were included if they occurred during or within 1 week following the discontinuation of pentamidine treatment. Nephrotoxicity, dysglycemia, hepatotoxicity, hyperkalemia, and hyperamylasemia accounted for 80% of ADRs (n = 174) that occurred in 76 (71.7%) of 106 patients during 84 treatment courses of pentamidine. A significant relationship between hypoglycemia and nephrotoxicity was observed (P = .002). Four factors were significantly associated with occurrence of an ADR: number of concomitant medications (odds ratio [OR] = 1.36, P = .005), nonwhite ethnicity (OR = 5.00, P = .017), cumulative dosage of pentamidine (OR = 1.03, P = .030), and concurrent use of other nephrotoxic drugs (OR = 2.34, P = .047). Two factors, daily dosage and history of intravenous drug use, approached significance. Knowledge of and avoidance of potential risk factors might allow safer use of pentamidine and reduce the prevalence of ADRs.

VANCOMYCIN, TRIMETHOPRIMSULFAMETHOXAZOLE, AND RIFAMPIN

Vancomycin is a safe, effective antibiotic for a variety of serious gram-positive infections. Because of emerging vancomycin-resistant enterococci and the threat of spread of vancomycin-resistant genes to other gram-positive organisms, judicious use of vancomycin should be promoted. Trimethoprim-sulfamethoxazole, a broad-spectrum synergistic combination, continues to find widespread use in gram-negative bacterial infections, especially involving the urinary tract. It has enjoyed enormous success in prophylaxis and therapy of Pneumocystis carinii pneumonia. Rifampin remains of paramount significance as a cidal agent against Mycobacterium tuberculosis; however, increasing reports of strains of MDR-tuberculosis are of great concern.

Indium-111 labelled pooled human immunoglobulin imaging to monitor the efficacy of specific therapy for Pneumocystis carinii pneumonia.

Functional imaging is ideally suited to monitoring the effect of specific therapy on disease processes. In this pilot study five patients with AIDS and Pneumocystis carinii pneumonia (PCP) were imaged with Indium-111 labelled pooled human immunoglobulin (111In-HIG) during infection and after therapy for PCP. The lung activity of 111In-HIG, measured as a lung/heart ratio, was calculated in a study performed during infection with PCP and after therapy. In all five patients the lung/heart ratio of 111In-HIG was reduced after treatment. The mean reduction in heart/lung ratio was 27% (range 12%-53%). If these results are confirmed by a larger study, 111In-HIG will be useful in monitoring the response of PCP to therapy in patients with AIDS.

Adjusting for Differential Rates of Prophylaxis Therapy for PCP in High-Versus Low-Dose AZT Treatment Arms in an AIDS Randomized Trial

Abstract In the AIDS Clinical Trial Group randomized trial 002 comparing the effect of high-dose versus low-dose 3-azido-3-deoxythymidine (AZT) on the survival of acquired immunodeficiency syndrome (AIDS) patients, the median survival in the low-dose arm exceeded that in the high-dose arm. But subjects in the low-dose AZT arm received significantly more prophylaxis therapy for pneumocystis carinii pneumonia (PCP), a nonrandomized treatment, than those in the high-dose AZT arm. Thus the improved median survival in the low-dose arm might represent either the benefits associated with avoiding the toxicity of high-dose AZT therapy or the benefits of receiving prophylaxis therapy. The authors use structural nested failure time (SNFT) models to estimate the survival curves that would have been observed if the PCP prophylaxis experience in the high-dose and low-dose treatment arms had been similar. Our simplest models relate a subject's observed time of death and observed prophylaxis therapy to the time that the...

Adjusting for Differential Rates of Prophylaxis Therapy for PCP in High-Versus Low-Dose AZT Treatment Arms in an AIDS Randomized Trial

Abstract In the AIDS Clinical Trial Group randomized trial 002 comparing the effect of high-dose versus low-dose 3-azido-3-deoxythymidine (AZT) on the survival of acquired immunodeficiency syndrome (AIDS) patients, the median survival in the low-dose arm exceeded that in the high-dose arm. But subjects in the low-dose AZT arm received significantly more prophylaxis therapy for pneumocystis carinii pneumonia (PCP), a nonrandomized treatment, than those in the high-dose AZT arm. Thus the improved median survival in the low-dose arm might represent either the benefits associated with avoiding the toxicity of high-dose AZT therapy or the benefits of receiving prophylaxis therapy. The authors use structural nested failure time (SNFT) models to estimate the survival curves that would have been observed if the PCP prophylaxis experience in the high-dose and low-dose treatment arms had been similar. Our simplest models relate a subject's observed time of death and observed prophylaxis therapy to the time that the subject would have died if prophylaxis therapy had been withheld. Conditional on certain assumptions and our model, we infer that survival in the low-dose arm would have still exceeded that in the high-dose arm even if the two arms had been given identical amounts of prophylaxis. Under the same assumptions, we also find the data are consistent with continuous prophylaxis therapy increasing survival by 16% or decreasing survival by 18% at the 95% confidence level (p = .85).

Disseminated Cryptococcal Disease Complicating Steroid Therapy for Pneumocystis carinii Pneumonia in a Patient With AIDS

Recent studies have suggested that steroid therapy may reduce the morbidity and mortality of HIV-associated Pneumocystis carinii pneumonia (PCP) in a select population of patients. However, the risks of steroid therapy for this group have not been well defined. We describe the case of a patient admitted with severe PCP whose treatment included high-dose steroids. During his hospitalization, overwhelming cryptococcal disease developed, contributing to his death. We postulate that the rapidity of progression was due, in part, to the steroid therapy. We have also reviewed the literature. We recommend screening for cryptococcal infection before beginning steroid therapy.

Racial Differences in the Use of Drug Therapy for HIV Disease in an Urban Community

Guidelines for drug therapy in human immunodeficiency virus (HIV) disease are based primarily on the stage of the disease. To determine whether sociodemographic characteristics of patients influence drug therapy in practice, we analyzed the use of antiretroviral therapy and prophylactic therapy for Pneumocystis carinii pneumonia (PCP) in an urban population infected with HIV. All patients presenting for the first time to our HIV clinic from March 1990 through December 1992 were enrolled. Data on sociodemographic and clinical variables and on drug use were collected at the time of presentation and after six months. We asked whether patients with CD4+ cell counts of 500 or less per cubic millimeter were receiving antiretroviral therapy at the time of presentation, and whether patients with CD4+ cell counts of 200 or less per cubic millimeter were receiving PCP prophylaxis. Among the 838 patients enrolled, 656 (79 percent) were blacks, 167 (20 percent) were non-Hispanic whites, and 15 (2 percent) were Asian or Hispanic descent or were not racially classified. There were no racial differences in the stage of HIV disease at the time of presentation. However, there were racial disparities in the receipt of antiretroviral therapy: 63 percent of eligible whites but only 48 percent of eligible blacks received such therapy (P = 0.003). PCP prophylaxis was received by 82 percent of eligible whites but only 58 percent of eligible blacks (P < 0.001). There were no significant differences in the receipt of drug therapy with respect to age, sex, mode of HIV transmission, type of insurance, income, education, or place of residence. In a logistic-regression analysis, race was the feature most strongly associated with the receipt of drug therapy. When blacks were compared with whites, the adjusted relative odds were 0.59 (95 percent confidence interval, 0.38 to 0.93) for the receipt of an antiretroviral agent and 0.27 (95 percent confidence interval, 0.13 to 0.56) for the receipt of PCP prophylaxis. Among patients infected with HIV, blacks were significantly less likely than whites to have received antiretroviral therapy or PCP prophylaxis when they were first referred to an HIV clinic. This disparity suggests a need for culturally specific interventions to ensure uniform access to care, including drug therapy, and uniform standards of care.

FDA approves trimetrexate as second-line therapy for Pneumocystis carinii pneumonia

Journal Article FDA approves trimetrexate as second-line therapy for Pneumocystis carinii pneumonia Get access Nancy Tarleton Landis Nancy Tarleton Landis Search for other works by this author on: Oxford Academic Google Scholar American Journal of Hospital Pharmacy, Volume 51, Issue 5, 1 March 1994, Pages 591–592, https://doi.org/10.1093/ajhp/51.5.591 Published: 01 March 1994

Interaction of Pneumocystis carinii dihydropteroate synthase with sulfonamides and diaminodiphenyl sulfone (dapsone).

Dihydropteroate synthase is the target enzyme for the sulfonamide compounds, which are the mainstay of therapy for Pneumocystis carinii pneumonia, a common infection in patients with impaired immunity. The stability of this enzyme, its kinetic constants with respect to substrates, and the 50% inhibitory concentration (IC50) of several sulfonamides and the sulfone dapsone have been characterized using both cell-free and intact organism assay systems. Stability of the enzyme is dependent on storage temperature, reducing reagents, and to a lesser extent, protease inhibitors. The sulfonamides sulfadiazine and sulfamethoxazole were found to be highly potent inhibitors of P. carinii dihydropteroate synthase with IC50s of 0.42 and 0.71 microM, respectively. Dapsone had equivalent potency when compared with the most potent sulfonamides tested in both assay systems. Data suggest that sulfamethoxazole, sulfadiazine and dapsone may represent equivalent choices as P. carinii dihydropteroate synthase inhibitors, assuming an equivalent in vivo drug exposure can be achieved.

Aerosolized pentamidine for prophylaxis of Pneumocystis carinii pneumonia in infants with human immunodeficiency virus infection.

Aerosolized pentamidine is widely used in adult patients with human immunodeficiency virus as both prophylaxis and therapy for Pneumocystis carinii pneumonia. The aim of this study was to evaluate the safety of a monthly regimen of aerosolized pentamidine in human immunodeficiency virus-infected infants. Seven human immunodeficiency virus-infected infants, ages 3.5 to 11 months, were given a total of 45 monthly treatments of aerosolized pentamidine. The infant's dose of pentamidine was based on an adult dosage of 300 to 600 mg/month, adjusted for minute ventilation and weight. There were no discernible clinical side effects in 62% (28 of 45) of the treatments. Observed toxicity included mild to moderate coughing, mild wheeze and transient arterial desaturation as measured by pulse oximetry. Pulmonary function data revealed an increased tidal volume (P < 0.005) and an increased pulmonary resistance (P < 0.02) post-pentamidine treatment. Urinary pentamidine concentrations were obtained and pentamidine was detected in all tested samples suggesting pulmonary deposition and systemic absorption. In conclusion aerosolized pentamidine appears to be a relatively safe, well-tolerated treatment in infants, with side effects similar to those seen in adults.

Hyperkalemia With High-Dose Trimethoprim-Sulfamethoxazole Therapy

In a patient with the acquired immunodeficiency syndrome, a progressive increase in the serum potassium concentration occurred with high-dose trimethoprim-sulfamethoxazole (TMP-SMX) therapy for Pneumocystis carinii pneumonia. In this patient, factors known to alter transcellular potassium shifts to induce hyperkalemia were not present. There was no evidence of glucocorticoid or mineralocorticoid insufficiency at the time of hyperkalemia, while the transtubular potassium gradient decreased. The hyperkalemia resolved spontaneously on discontinuation of TMP-SMX therapy, suggesting that this electrolyte abnormality is related to altered renal tubular secretion of potassium as a consequence of the high-dose TMP-SMX therapy.

Adjuvant corticosteroid therapy for Pneumocystis carinii pneumonia in AIDS patients.

To review published abstracts, case reports, and journal articles and evaluate data examining the use of systemic corticosteroids as adjuvant treatment for Pneumocystis carinii pneumonia (PCP) in patients with AIDS. Computerized online databases, peer-reviewed journals from January 1986 through September 1991, and personal communication with a National Institutes of Health correspondent. The authors identified 13 reports pertinent to this review. By author consensus, five studies were selected for analysis based on sample size, controlled study design, and clinical outcome measures. Recommendations of an expert panel from the National Institutes of Health and the University of California also are discussed. Data are presented based on the methodologic strength of the studies reviewed. Studies are assessed on sample size, inclusion criteria, comparative cohort populations, specific patient outcome measures, and statistical analysis. Results of the study analysis support the use of systemic corticosteroids as early adjunctive therapy for AIDS patients with moderate-to-severe PCP who have an initial arterial oxygen partial pressure of less than 70 mm Hg or an alveolar-arterial gradient greater than 35 mm Hg on room air. Improved outcomes included decreased mortality, respiratory failure, and deterioration of oxygenation. Data evaluated have shown that adjuvant corticosteroid therapy is most effective when initiated within 72 hours of beginning specific antipneumocystis therapy. A small, but sometimes significant, increased rate of infection in steroid-treated patients was noted. Based on the literature reviewed, early systemic adjuvant corticosteroid therapy can benefit patients with moderate-to-severe AIDS-related PCP. The steroid regimen used in the largest controlled trial and recommended by the expert panel is prednisone 40 mg bid (days 1-5), then 40 mg/d (days 6-10), then 20 mg/d (days 1-21).

Efficacy of intermittent dosage of 8-aminoquinolines for therapy or prophylaxis of Pneumocystis pneumonia in rats.

Experimental 8-aminoquinolines from Walter Reed Army Institute for Research are effective for prophylaxis or therapy of Pneumocystis carinii pneumonia in rat models. In the present study, primaquine, WR6026, and WR238605 were tested in prophylaxis and treatment models of P. carinii pneumonia to compare the effectiveness of continuous versus intermittent dosing. For treatment of P. carinii pneumonia, the drugs showed detectable effects when given once every 4 days (primaquine and WR6026 at doses greater than 8 mg/kg; WR238605 at doses greater than 2 mg/kg). For prophylaxis, WR6026 and WR238605 were effective given alone daily (WR6026 at doses greater than 0.25 mg/kg; WR238605 at doses greater than 0.57 mg/kg). WR6026 and WR238605 at 4 mg/kg given once every 4 days for prophylaxis were as effective as daily trimethoprim-sulfamethoxazole. These studies suggest that higher doses of 8-aminoquinolines administered at appropriate intervals may be as effective as continuous dosing for prophylaxis of P. carinii pneumonia.

Antiparasitic Agents

In recent years, introduction of new and more effective agents has improved the overall therapy for parasitic infections. This field, however, is still plagued by numerous problems, including the development of resistance to antimicrobial agents (especially with malaria), unavailability of agents in the United States or lack of approval by the Food and Drug Administration, and major toxicities or lack of experience in pregnant women and children, which limits use in these groups of patients. Widespread resistance of Plasmodium falciparum to chloroquine and other agents has complicated the treatment and prophylaxis of this type of malaria. A combination of quinine and Fansidar is usually effective oral therapy for falciparum malaria; quinidine may be administered if intravenous therapy is needed. Mefloquine, which is currently recommended for prophylaxis against chloroquine-resistant P. falciparum, is also effective for single-dose oral treatment, although this regimen has not yet been approved by the Food and Drug Administration. Metronidazole has been widely used for treatment of gastroenteritis due to Entamoeba histolytica and Giardia lamblia (not approved by the Food and Drug Administration for the latter) and is considered safe and effective. A new macrolide, azithromycin, has been reported to be effective for cryptosporidiosis in experimental animals; currently, no effective therapy is available for human infections. Combinations of sulfonamides with other antifolates, trimethoprim or pyrimethamine, are recommended therapy for Pneumocystis carinii pneumonia or toxoplasmosis, respectively. Therapies for the various types of leishmaniasis and trypanosomiasis are complex, often toxic, and often of limited efficacy. The benzimidazoles are effective for roundworm infections, although thiabendazole has severe toxic effects. The recent introduction of ivermectin has revolutionized the treatment and control of onchocerciasis. Another relatively new agent, praziquantel, is a true broad-spectrum anthelmintic agent that is effective against most trematodes, many adult cestodes, and larval cestodes as well (especially cysticerci of Taenia solium).

Aspergillosis in the Acquired Immunodeficiency Syndrome

The role of Aspergillus species as a pathogen in acquired immunodeficiency syndrome (AIDS) has not been clearly defined. From 1984 to 1989, more than 2,000 AIDS patients were seen at Beth Israel Medical Center, New York. Aspergillus was isolated in ten patients; seven had invasive disease and three had noninvasive disease. Invasive pulmonary aspergillosis (IPA) was diagnosed in six patients and invasive renal aspergillosis was found in one patient. Five were homosexual men and two were intravenous drug users. At presentation, all ten had fever, seven had cough, eight had dyspnea, and five had pleuritic chest pain. Chest roentgenograms revealed focal infiltrates in six patients, bilateral interstitial infiltrates in two patients, and bilateral pneumothoraces in one patient. Predisposing conditions included corticosteroid therapy in four, granulocytopenia (less than 1,000/cu m) in two, and broad-spectrum antibiotic therapy in five. Three of the four patients receiving corticosteroids received them as adjuvant therapy for Pneumocystis carinii pneumonia (PCP). Aspergillus was identified antemortem in eight patients, in bronchoalveolar lavage (BAL) fluid in six, in transbronchial biopsy specimen in three, in open lung biopsy specimen in one, and postmortem in one patient. Six of seven patients had at least one concomitant pulmonary process. Six underwent necropsy and findings showed IPA in three, disseminated aspergillosis in two, and PCP in one. Invasive aspergillosis, although significant, is uncommon in AIDS. When Aspergillus is isolated in the setting of corticosteroid therapy, antibiotics, or granulocytopenia, one must suspect invasive disease.

Incidence of QT interval prolongation during pentamidine therapy of Pneumocystis carinii pneumonia

Pentamidine isethionate, a first-line drug for the therapy of Pneumocystis carinii pneumonia, has been linked with QT interval prolongation and ventricular tachyarrhythmias in patients with the acquired immunodeficiency syndrome, 1–6 but strategies for preventing, detecting and treating pentamidine-associated QT prolongation require a better understanding of its rate of occurrence and its complications. To estimate the incidence of QT prolongation during pentamidine therapy and the incidence of serious cardiac arrhythmias among patients with QT prolongation, and to identify patients at risk for QT prolongation, we reviewed all patients treated with intravenous pentamidine at our institution over a 6-month period.