Original Article
Comparison of Atovaquone (566C80) with Trimethoprim-Sulfamethoxazole to Treat Pneumocystis carinii Pneumonia in Patients with AIDS
N Engl J Med 1993; 328:1521-1527May 27, 1993
- Abstract
Background
Both trimethoprim-sulfamethoxazole and pentamidine are effective as treatments for Pneumocystis carinii pneumonia, but adverse effects frequently limit their use. Atovaquone (566C80) is a new hydroxynaphthoquinone with activity against P. carinii.
Methods
We conducted a double-blind, multicenter study in patients with the acquired immunodeficiency syndrome and mild or moderately severe P. carinii pneumonia. They were randomly assigned to 21 days of orally administered treatment three times daily with either atovaquone (750 mg) or trimethoprim (320 mg) plus sulfamethoxazole (1600 mg).
Results
Of the 322 patients with histologically confirmed P. carinii pneumonia, 160 received atovaquone and 162 received trimethoprim-sulfamethoxazole. Of those who could be evaluated for therapeutic efficacy, 28 of 138 patients given atovaquone (20 percent) and 10 of 146 patients given trimethoprim-sulfamethoxazole (7 percent) did not respond (P = 0.002). Treatment-limiting adverse effects required a change of therapy in 11 patients in the atovaquone group (7 percent) and 33 patients in the trimethoprim-sulfamethoxazole group (20 percent) (P = 0.001). Therapy involving only the initial drug was successful and free of adverse effects in 62 percent of those assigned to atovaquone and 64 percent of those assigned to trimethoprim-sulfamethoxazole.
Within four weeks of the completion of treatment, there were 11 deaths in the atovaquone group (4 due to P. carinii pneumonia) and 1 death in the trimethoprim-sulfamethoxazole group (P = 0.003). Diarrhea at entry was associated with lower plasma drug concentrations (P = 0.009), therapeutic failure (P<0.001), and death (P<0.001) in the atovaquone group but not in the trimethoprim-sulfamethoxazole group.
Conclusions
For the treatment of P. carinii pneumonia, atovaquone is less effective than trimethoprim-sulfamethoxazole, but it has fewer treatment-limiting adverse effects.
Media in This Article
Figure 1
Distribution of Patients Enrolled in the Study.Table 1
Characteristics of All Patients with Histologically Documented P. carinii Pneumonia (PCP) at Entry into the Study.Article Activity
- Article
More than half of patients with the acquired immunodeficiency syndrome (AIDS) have adverse effects when they are treated with either pentamidine or trimethoprim-sulfamethoxazole1. In laboratory animals a 1,4-hydroxynaphthoquinone designated as 566C80, or atovaquone, is at least as effective as trimethoprim-sulfamethoxazole in the prevention and treatment of murine Pneumocystis carinii pneumonia,2 although the mechanism of action has not been determined. In Plasmodium falciparum, hydroxynaphthoquinones interfere with the electron-transport chain, indirectly inhibit the activity of dihydroorotate dehydrogenase, and stop the de novo synthesis of pyrimidines3-5.
Because initial clinical studies6,7 showed atovaquone to be effective and well-tolerated by patients with AIDS, we conducted a prospective study comparing atovaquone and trimethoprim-sulfamethoxazole for the treatment of P. carinii pneumonia in such patients. Trimethoprim-sulfamethoxazole was chosen for comparison because it is one of the two drugs approved by the Food and Drug Administration to treat this infection and is at least equal to pentamidine in therapeutic efficacy1-8.
Methods
Study Design
This study was a randomized, double-blind, controlled trial comparing the efficacy and safety of atovaquone with those of trimethoprim-sulfamethoxazole to treat mild (alveolar-arterial oxygen gradient, <35 mm Hg) and moderately severe (alveolar-arterial oxygen gradient, 35 to 45 mm Hg) P. carinii pneumonia in adults with AIDS. The patients were stratified before enrollment on the basis of the severity of their disease. The end point chosen to determine the sample size was the proportion of subjects with mild disease in whom therapy was considered successful. The sample was calculated with the objective of establishing that atovaquone was no less successful therapeutically than trimethoprim-sulfamethoxazole9. A clinically important difference was defined as an arithmetic difference of 0.15 in success rates.
Patients received either trimethoprim-sulfamethoxazole or atovaquone for 21 days, unless there was no response or drug toxicity was encountered. Surviving patients were evaluated by chest radiography at four weeks and by clinical history at eight weeks after the completion of therapy. Patients were categorized according to end points defined as follows.
Definitions of End Points
Therapeutic Failure Due to Lack of Efficacy
Four definitions of therapeutic failure due to lack of efficacy were used: (1) deterioration after the first 3 days of therapy and a requirement for mechanical ventilation; (2) deterioration after 7 days of therapy, defined by the presence of any two of three conditions: worsening gas exchange (i.e., an increase in the alveolar-arterial oxygen gradient by 20 mm Hg or more over the base-line value, with an absolute value greater than 30 mm Hg), worsening findings on chest radiography, and worsening clinical symptoms; (3) lack of improvement in alveolar-arterial oxygen gradient, chest radiograph, or clinical symptoms after 10 days of therapy; and (4) a requirement for alternative therapy within 4 weeks of the discontinuation of the study medication, although no patient was considered to have had a therapeutic failure according to this criterion.
Treatment-Limiting Adverse Effects
The discontinuation of treatment resulting from suspected toxicity of the study drug and necessitating alternative therapy was considered a treatment-limiting adverse effect. Adverse reactions requiring the discontinuation of therapy included neutropenia ( ≤ 500 cells per cubic millimeter); thrombocytopenia ( ≤ 25,000 cells per cubic millimeter); hepatotoxicity, as defined by aspartate aminotransferase or alanine aminotransferase levels increased to more than 5 times the base-line value or more than 10 times the upper limit of normal, or a bilirubin level increased to more than 5 times the upper limit of normal; nephrotoxicity (a creatinine level more than 2.5 times the upper limit of normal, or a calculated reduction in creatinine clearance of more than 40 percent from base line); a hemoglobin level less than 6.5 g per deciliter despite transfusion; a prothrombin time twice the upper limit of normal, or 1.5 times the upper limit of normal with a platelet count of less than 40,000 per cubic millimeter; pancreatic toxicity (amylase level more than 5 times the upper limit of normal); vomiting for more than two consecutive days despite antiemetic therapy; the Stevens-Johnson syndrome; urticaria with systemic symptoms; and serious exfoliative dermatitis.
Successful Therapy
A successful course free of adverse effects was defined as therapy with sustained improvement in clinical and respiratory measures at least four weeks after the cessation of the study medication and without discontinuation of the initial study drug due to treatment failure or adverse effects.
Survival
Patients who remained alive without ventilatory support for at least four weeks after the termination of therapy were considered survivors.
Patients Who Could Not Be Evaluated
Any patient whose therapy was discontinued for any reason other than lack of response or a treatment-limiting adverse effect (e.g., noncompliance or loss to follow-up) was considered unable to be evaluated.
Patients
To be eligible for the study, patients were required to have AIDS and untreated P. carinii pneumonia as documented by the histologic demonstration of pulmonary P. carinii infection, plus fever, symptoms of respiratory disease, or radiographic evidence of pneumonitis. Enrollment was limited to patients with alveolar-arterial oxygen gradients ≤ 45 mm Hg measured with the patient breathing room air and with partial pressures of oxygen ≥ 60 mm Hg.
Clinical and Laboratory Assessment
Patients were monitored for therapeutic efficacy and signs of drug toxicity by chest radiography, arterial-blood gas measurements, complete blood counts with differential count and platelet count, urinalysis, and measurements of the prothrombin time, creatinine, creatinine clearance, aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, amylase, albumin, total protein, bilirubin, and electrolytes. A scoring system was used to measure the extent of dyspnea, cough, and chest pain or tightness (Table 1Table 1
Characteristics of All Patients with Histologically Documented P. carinii Pneumonia (PCP) at Entry into the Study.). The patients were evaluated initially and on days 2, 4, 7, 10, 14, 17, and 21 of therapy and at 4 and 8 weeks after therapy.Blood samples were collected at enrollment and on days 4, 7, 14, and 21 of therapy to determine the concentrations of atovaquone (each such sample was obtained within 24 hours of the previous dose) or trimethoprim-sulfamethoxazole (each sample was obtained within 8 hours of the previous dose). The plasma concentrations of atovaquone determined on or after day 7 and within 24 hours of the previous dose were averaged to determine the mean steady-state concentration. Concentrations of trimethoprim and sulfamethoxazole in plasma samples obtained on or after day 4 and within eight hours of the previous dose were included to determine the mean concentration of these agents. Radiographs of the chest were evaluated at study entry and determined to be normal or abnormal. Before the study code was broken, the radiographs obtained on days 7 and 21 were interpreted by the radiologist at the site with respect to the type and extent of pneumonia. Each radiograph was classified according to whether the patient's condition appeared resolved, improved, stable, or deteriorated in comparison to the radiograph obtained before treatment.
Medication, Dosage, and Duration
The patients were randomly assigned to one of two treatment groups: 750 mg of atovaquone (three 250-mg tablets) three times daily or 320 mg of trimethoprim plus 1600 mg of sulfamethoxazole (two Septra DS [Burroughs Wellcome] or Septrin forte [Wellcome Research Laboratories] tablets) three times daily for 21 days. The study involved two placebos, with one group randomly assigned to receive oral atovaquone and tablets of placebo resembling trimethoprim-sulfamethoxazole and the other group assigned to receive trimethoprim-sulfamethoxazole and tablets of placebo resembling atovaquone.
After an amendment to the protocol in February 1991, while the study was ongoing, all the patients in the United States and Canada who were in the moderate-disease stratum (alveolar-arterial oxygen gradient, 35 to 45 mm Hg) were required to receive oral prednisone as recommended in a consensus report10.
Prophylaxis against P. carinii pneumonia was recommended for all patients who completed treatment successfully. The choice of the drug used for prophylaxis was left to the discretion of the patient's physician.
Statistical Analysis
The primary analyses of therapeutic-response end points and other measures were performed with the intention-to-treat rule -- i.e., excluding only patients who did not have confirmed P. carinii pneumonia. Patients who could not be evaluated for therapeutic efficacy were excluded from the intention-to-treat analysis if the supply of data corresponding to them had ended before the first therapeutic failure in this assessment. Subgroup analyses were also made of all patients who could be evaluated and were confirmed to have P. carinii pneumonia.
The combined-stratum analyses of the proportions of patients reporting adverse effects were based on the odds ratio, with adjustment for differences between strata11,12. For cells containing five patients or more, the Mantel-Haenszel estimate and the related test-based confidence interval are given (for this analysis we used SAS PROC FREQ software). Otherwise, Fisher's exact test and the 95 percent confidence interval for the estimated common odds ratio are used (STAT Xact. Cytel software).
Fisher's exact test was used to compare end points of therapeutic efficacy within each stratum, and confidence intervals for the differences between treatments were estimated with the large-sample normal approximation. The Cochran-Mantel-Haenszel test was used in the analyses of the combined strata, and the test-related 95 percent confidence interval for the relative risk was also calculated.
Medians were used to summarize the measured values and changes from base line. Differences between medians were examined by the Wilcoxon rank-sum test and the associated 95 percent confidence intervals. Logistic-regression analysis was used to predict the probability of a therapeutic response as a function of the steady-state plasma concentration of atovaquone. After the adequacy of the model was confirmed, an approximate 95 percent confidence interval around the plasma concentration needed to achieve a 90 percent rate of therapeutic success was calculated with SAS PROC PROBIT and PROC LOGISTIC software13.
An explanatory analysis of factors that might have affected survival was done. The patients were classified according to whether they remained alive at the end of follow-up, and comparisons within treatment groups were made by Fisher's exact test for categorical variables and by the Wilcoxon rank-sum test for continuous variables. The analysis of time-to-event data was done by Kaplan-Meier survival analysis and the log-rank test.
Results
Four hundred eight patients were enrolled at 37 clinical-trial sites from August 10, 1990, through August 16, 1991. Of these patients, 322 were found to have histologically confirmed P. carinii pneumonia and were then qualified for the trial (Figure 1Figure 1
Distribution of Patients Enrolled in the Study.).The base-line clinical and demographic characteristics of the 322 patients are summarized in Table 1. The initial clinical features of P. carinii pneumonia in the patients in the atovaquone and trimethoprim-sulfamethoxazole groups were not significantly different.
Therapeutic Failure Due to Lack of Efficacy
The analysis of the 322 patients is shown in Table 2Table 2
Intention-to-Treat Analysis of End Points on Day 49, Four Weeks after the End of Therapy.. The proportion who did not respond because of lack of efficacy of treatment excludes 38 patients who could not be evaluated and for whom data were censored before the first episode in which there was treatment failure, leaving 138 and 146 patients in the atovaquone and trimethoprim-sulfamethoxazole groups, respectively. By day 7 of treatment, lack of therapeutic efficacy was noted in six patients treated with atovaquone (4 percent) and four patients treated with trimethoprim-sulfamethoxazole (3 percent). By day 21, the last day of study-drug administration, the lack of efficacy was evident in 25 patients treated with atovaquone (18 percent) and 9 patients treated with trimethoprim-sulfamethoxazole (6 percent). By day 49, one month after therapy, lack of therapeutic efficacy was evident in 28 of the 138 patients treated with atovaquone (20 percent) and 10 of the 146 treated with trimethoprim-sulfamethoxazole (7 percent) (P = 0.002).The intention-to-treat and subgroup analyses showed no significant differences between the treatment groups in the pattern of radiographic response in either the mild or the moderate disease stratum.
Adverse Effects
Adverse effects were assessed in the 408 patients enrolled in the study and given one of the study treatments (Table 3Table 3
Treatment-Limiting Adverse Effects Reported Most Frequently among All Patients Enrolled in the Study.). The episodes of treatment-limiting adverse effects in the 322 patients with documented P. carinii pneumonia are shown in Table 2. When all such experiences were considered, significantly higher rates (P<0.05) were reported in the trimethoprim-sulfamethoxazole group than in the atovaquone group for nausea (44 percent vs. 20 percent), vomiting (35 percent vs. 14 percent), constipation (17 percent vs. 3 percent), dizziness (8 percent vs. 3 percent), fever (25 percent vs. 14 percent), and rash (34 percent vs. 23 percent). Diarrhea occurred more frequently during treatment with atovaquone (19 percent) than during treatment with trimethoprim-sulfamethoxazole (7 percent) (P<0.05), but it was not associated with lack of efficacy or treatment-limiting adverse effects. The cause of diarrhea was not systematically investigated.Screening for glucose-6-phosphate dehydrogenase deficiency revealed that 7 of 185 patients receiving atovaquone and 5 of 192 patients receiving trimethoprim-sulfamethoxazole were deficient in this enzyme. There were no indications of hemolytic anemia or other adverse effects related to glucose-6-phosphate dehydrogenase deficiency despite the continuation of therapy. With atovaquone, a significantly smaller proportion of patients were unable to tolerate the drug for the full duration of therapy than were their counterparts taking trimethoprim-sulfamethoxazole (7 percent vs. 20 percent) (P = 0.001) (Table 2).
Alternative Therapy Required
The proportion of patients requiring an alternative therapy was similar in both study groups in both the mild and the moderate categories of disease (Table 2). In the stratum with mild disease, the mean period before an alternative therapy began was 17.4 ±14.8 days in the atovaquone group and 10.0 ±6.7 days in the trimethoprim-sulfamethoxazole group. Differences between treatments were tested by the Kaplan-Meier product-limit method and the log-rank test, with data on patients censored when they did not require alternative therapy by the last day of the observation period. The difference between the treatments in the mild stratum was not statistically significant (P = 0.485). Similar results were observed in the stratum with moderate disease; 16.7 ±16.6 days passed before the start of an alternative treatment in the atovaquone group, as compared with 7.2 ±5.1 days in the trimethoprim-sulfamethoxazole group (P = 0.644). When data on patients who had therapeutic failures due to adverse effects were excluded from the analysis, the mean number of days to alternative therapy was 24 in the atovaquone group and 11 in the trimethoprim-sulfamethoxazole group.
Successful Therapy
The number of successful courses of therapy (i.e., recovery without adverse effects) was similar in the two study groups in both the mild and moderate categories (Table 2). A similarity in the clinical response was also found when individual measures of alveolar-arterial oxygen gradient, temperature, and serum lactate dehydrogenase activity were compared in patients who received the study medication for at least 19 days.
Survival
Among the 322 patients with confirmed P. carinii pneumonia, 12 patients died, including 11 of the 160 patients assigned to atovaquone (7 percent) and 1 of the 162 patients assigned to trimethoprim-sulfamethoxazole (0.6 percent) (P = 0.003), all of whom died during the period extending for four weeks after the end of therapy (Table 2). The patient treated with trimethoprim-sulfamethoxazole died of the AIDS wasting syndrome. No deaths due to P. carinii pneumonia occurred in either of the groups with mild disease; in the groups with moderate disease, however, deaths from P. carinii pneumonia occurred in four of the atovaquone-treated patients between days 8 and 37 of treatment. Other causes of death in the atovaquone group included Streptococcus pneumoniae infection (three patients), cryptococcal meningitis (one), Pseudomonas aeruginosa and Staphylococcus aureus pneumonia (one), renal and pulmonary failure with bacterial pneumonia (one), and klebsiella and pseudomonas infection with the adult respiratory distress syndrome (one).
Plasma Concentrations of Atovaquone and Trimethoprim-Sulfamethoxazole
Mean steady-state plasma concentrations of atovaquone were calculated for 133 patients (97 with mild disease and 36 with moderate disease). The mean steady-state level for the entire group was 13.9 ±6.9 μg per milliliter. Similar concentrations were found in the groups with mild (14.0 ±6.8 μg per milliliter) and moderate (13.7 ±7.1 μg per milliliter) disease. The values ranged from 0.39 to 36.3 μg per milliliter.
Logistic-regression analyses were made with data on the patients with P. carinii pneumonia who received atovaquone therapy and did not have treatment-limiting drug toxicity, in order to predict the probability of a therapeutic response (i.e., the efficacy) from steady-state plasma con centrations of the drug. The probability of a therapeutic response was strongly associated with steady-state plasma concentrations of atovaquone (P<0.001 on the basis of a likelihood-ratio test in which the null and final models were compared) (Table 4Table 4
Probability of a Therapeutic Response (Efficacy), According to Steady-State Plasma Concentrations of Atovaquone, on the Basis of a Logistic-Regression Model for All Patients Who Could Be Evaluated, Excluding Those in Whom Treatment Failed Because of Toxicity.). There was no relation between the plasma concentration of the drug and treatment-limiting adverse effects.Plasma concentrations of trimethoprim and sulfamethoxazole were determined for 120 patients in samples obtained within eight hours of a dose. The overall mean trimethoprim concentration was 6.9 ±3.25 μg per milliliter (range, 0.33 to 21.8). The mean sulfamethoxazole concentration was 175.9 ±59.9 μg per milliliter (range, 2.2 to 392.2). Therapeutic success and the incidence of treatment-limiting adverse effects were not related to plasma concentrations of trimethoprim-sulfamethoxazole.
Correlations of Survival with Clinical, Demographic, and Physical Factors
Data obtained for all patients at entry into the study were used to seek factors related to survival. These variables included the use of antiretroviral drugs, previous prophylaxis, previous episodes of P. carinii pneumonia, fungal infections (diagnosed clinically or microbiologically), bacterial infections (diagnosed microbiologically), weight, temperature, duration of symptoms, alveolar-arterial oxygen gradient, dyspnea score, partial pressure of oxygen, and diarrhea within seven days before enrollment. Only preexisting diarrhea was associated with increased mortality, and only in the atovaquone group. Among the 160 atovaquone-treated patients, significantly lower rates of survival (P<0.001), rates of successful response without adverse effects (P<0.001), and plasma concentrations (P = 0.009) occurred in those with preexisting diarrhea than in those without such diarrhea. Diarrhea had no association with either survival or therapeutic success in the group treated with trimethoprim-sulfamethoxazole.
Discussion
In this randomized, double-blind trial of treatment of P. carinii pneumonia in AIDS, patients treated with atovaquone more often had no response to treatment than those treated with trimethoprim-sulfamethoxazole (20 percent vs. 7 percent, P = 0.002). However, adverse effects of sufficient magnitude to require a change to an alternative therapy were significantly more common in the trimethoprim-sulfamethoxazole group (20 percent) than in the atovaquone group (7 percent) (P = 0.001). Rates of successful therapy, the need for alternative therapy, and resolution of abnormal blood gas values, chest radiographs, and clinical signs and symptoms were similar in the two groups. The mortality rates four weeks after therapy were significantly higher (7 percent) in the atovaquone group than the trimethoprim-sulfamethoxazole group (0.6 percent) (P = 0.003). There were four deaths due to P. carinii pneumonia in the atovaquone group. Two of these four patients had received only one day of atovaquone therapy, and a third also had an infection of the lung with Mycobacterium avium complex. The trend toward a higher rate of S. pneumoniae infection among the patients who died in the atovaquone group may be related to that drug's lack of antibacterial effect as compared with trimethoprim-sulfamethoxazole.
The plasma concentration of atovaquone is an important determinant of therapeutic outcome in P. carinii pneumonia, and maximal plasma concentrations are needed. Of major importance in the bioavailability of atovaquone is its administration with food. Work in progress toward a new, improved oral formulation appears promising, as does work on an intravenous preparation of atovaquone that may achieve higher plasma concentrations. Our patients with diarrhea at entry into the study had low plasma concentrations of atovaquone and poorer therapeutic responses, indicating that the drug should be avoided in patients with underlying conditions that interfere with absorption.
On the basis of the dosage and formulation used in this trial, atovaquone, a hydroxynaphthoquinone compound demonstrated to have activity against P. carinii, offers a useful alternative to trimethoprim-sulfamethoxazole for patients with AIDS who cannot tolerate that treatment or who fail to respond to it.
Supported in part by the AIDS Clinical Trials Group of the National Institute of Allergy and Infectious Diseases, the California Collaborative Treatment Group of the California Universitywide AIDS Research Program, Burroughs Wellcome, and the Wellcome Foundation.
We are indebted to Nathaniel Brown, M.D., Lynn Dix, Ph.D., and Janna Harris, M.S., M.P.H., of the Burroughs Wellcome Company; to Neil Garbett, M.D., and Steve Hobigger, M.D., of the Wellcome Foundation; and to Carol Trapnell, M.D., of Georgetown Medical Center, for their assistance in the design of the study and the management and analysis of data.
Source Information
From the Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, Tenn. (W.H.); the Department of Medicine, Davies Medical Center, San Francisco (G.L.); Los Angeles County Hospital and the University of Southern California, Los Angeles (F.K., F.S.); the University of California, San Diego (S.A.B.); the University of Cincinnati, Cincinnati (P.F.); St. Pierre University Hospital, Brussels, Belgium (N.C.); the Department of Critical Care Medicine, National Institutes of Health, Bethesda, Md. (H.M., J. Falloon); the Department of Medicine, the Regional Medical Center, University of Tennessee, Memphis (D.L.); the Wellesley Hospital, Toronto (C.C.); Georgetown University Medical Center, Washington, D.β(J.L.); San Francisco General Hospital and the University of California, San Francisco (S.S.); the Infectious Diseases Research Consortium of Georgia, Atlanta (J.R.); the Johns Hopkins Hospital, Baltimore (J. Feinberg); the Department of Infectious Diseases and Immunology, Burroughs Wellcome Co., Research Triangle Park, N.β(S.L., M.R.); and the California Clinical Trials Group and AIDS Clinical Trials Group, Division of AIDS, National Institute of Allergy and Infectious Diseases, National Institutes of Health.
Address reprint requests to Dr. Hughes at the Department of Infectious Diseases, St. Jude Children's Research Hospital, 332 North Lauderdale, Memphis, TN 38105.
Additional clinical investigators and study centers are listed in the Appendix.
Appendix
In addition to the authors, the following institutions and principal clinical investigators participated in the study.
R.M. Buckley, Pennsylvania Hospital, Philadelphia; M. Conant, San Francisco; W. El-Sadr, Harlem Hospital, New York; J. Falutz, Montreal General Hospital, Montreal; M. Dohn, University of Cincinnati College of Medicine, Cincinnati; S. Greenberg, Baylor College of Medicine, Houston; D. Haghighat, University of California, Irvine; D. Hardy, UCLA Center for Health Sciences, Los Angeles; D. Hawkins, St. Stephens Hospital, London; P. Joseph, Merritt Peralta Hospital, Oakland, Calif.; A. Labriola, Washington Veterans Affairs Hospital, Washington, D.C.; M. L'Age, Auguste-Viktoria-Krankenhaus, Berlin, Germany; S. Matheron, Claude-Bernard Hospital, Paris; R.D. Meyer, Cedars Sinai Medical Center, UCLA, Los Angeles; D. Mildvan, Beth Israel Medical Center, New York; J. Montaner, St. Paul's Hospital, Vancouver, B.C.; P. Pappas, University of Alabama at Birmingham Medical Center, Birmingham; W.G. Powderly, Washington University School of Medicine, St. Louis; P. Reiss, Academic Medical Center, Amsterdam; J. Stansell, San Francisco General Hospital and University of California, San Francisco; J. Sampson, the Research and Education Group of Portland, Portland, Oreg.; P. Sax, D. Allan, and M. Hirsch, Harvard AIDS Clinical Trials Group, Boston; J. Spotkov, Los Angeles Kaiser Permanente, Los Angeles; R. Torres, St. Vincent Hospital, New York; H. Waskin, Duke University Medical Center, Durham, N.C.; and J. Weber, St. Mary's Hospital, London.
- References
References
1
Sattler FR ,Cowan R ,Nielsen DM ,Ruskin J . Trimethoprim-sulfamethoxazole compared with pentamidine for treatment of Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome: a prospective, noncrossover study. Ann Intern Med 1988;109:280-287
Web of Science | Medline2
Hughes WT ,Gray VL ,Gutteridge WE ,Latter VS ,Pudney M . Efficacy of a hydroxynaphthoquinone, 566C80, in experimental Pneumocystis carinii pneumonitis. Antimicrob Agents Chemother 1990;34:225-228
Web of Science | Medline3
Fry M ,Hudson AT ,Randall AW ,Williams RB . Potent and selective hydroxynaphthoquinone inhibitors of mitochondrial electron transport in Eimeria tenella (Apicomplexa: Coccidia). Biochem Pharmacol 1984;33:2115-2122
CrossRef | Web of Science | Medline4
Hudson AT ,Randall AW ,Fry M , et al. Novel anti-malarial hydroxynaphthoquinones with potent broad spectrum anti-protozoal activity. Parasitology 1985;90:45-55
CrossRef | Web of Science | Medline5
Hammond DJ ,Burchell JR ,Pudney M . Inhibition of pyrimidine biosynthesis de novo in Plasmodium falciparum by 2-(4-t-butylcyclohexyl)-3-hydroxy-1,4-naphthoquinone in vitro. Mol Biochem Parasitol 1985;14:97-109
CrossRef | Web of Science | Medline6
Hughes WT ,Kennedy W ,Shenep JL , et al. Safety and pharmacokinetics of 566C80, a hydroxynaphthoquinone with anti-Pneumocystis carinii activity: a phase I study in human immunodeficiency virus (HIV)-infected men. J Infect Dis 1991;163:843-848
CrossRef | Web of Science | Medline7
Falloon J ,Kovacs J ,Hughes W , et al. A preliminary evaluation of 566C80 for the treatment of pneumocystis pneumonia in patients with the acquired immunodeficiency syndrome. N Engl J Med 1991;325:1534-1538
Full Text | Web of Science | Medline8
Hughes WT ,Feldman S ,Chaudhary SC , et al. Comparison of pentamidine isethionate and trimethoprim-sulfamethoxazole in the treatment of Pneumocystis carinii pneumonia. J Pediatr 1978;92:285-291
CrossRef | Web of Science | Medline9
Makuch R ,Simon R . Sample size requirements for evaluating a conservative therapy. Cancer Treat Rep 1978;62:1037-1040
Medline10
The National Institutes of Health-University of California Expert Panel for Corticosteroids as Adjunctive Therapy for Pneumocystis Pneumonia
Full Text | Web of Science | Medline11
Geller NL ,Pocock SJ . Interim analysis in randomized clinical trials: ramifications and guidelines for practitioners. Biometrics 1987;43:213-223
CrossRef | Web of Science | Medline12
Fleiss JL. Statistical methods for rates and proportions. 2nd ed. New York: John Wiley, 1973:29.
13
SAS/STAT user's guide: version 6. 4th ed. Vol. 2. Cary, N.C.: SAS Institute, 1989.
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Sadhna M Shankar, Joseph J Nania. (2007) Management of Pneumocystis jiroveci Pneumonia in Children Receiving Chemotherapy. Pediatric Drugs 9:5, 301-309
CrossRef15
Carola Lütgendorf, Chaiporn Rojanawatsirivet, Gunther Wernsdorfer, Jeeraphat Sirichaisinthop, Herwig Kollaritsch, Walther H. Wernsdorfer. (2006) Pharmacodynamic interaction between atovaquone and other antimalarial compounds against Plasmodium falciparum in vitro. Wiener klinische Wochenschrift 118:S3, 70-76
CrossRef16
D Lin, WK Li, MJ Rieder, Michael Rieder. 2006. Cotrimoxazole for prophylaxis or treatment of opportunistic infections of HIV/AIDS in patients with previous history of hypersensitivity to cotrimoxazole. .
CrossRef17
C. A. Benson, J. E. Kaplan, H. Masur, A. Pau, K. K. Holmes. (2005) Treating Opportunistic Infections among HIV-Infected Adults and Adolescents: Recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association/Infectious Diseases Society of America. Clinical Infectious Diseases 40:Supplement 3, S131-S235
CrossRef18
Norma Hernández-Trejo, Oliver Kayser, Hartwig Steckel, Rainer H. Müller. (2005) Characterization of nebulized buparvaquone nanosuspensions—effect of nebulization technology. Journal of Drug Targeting 13:8-9, 499-507
CrossRef19
W. T. Hughes, W. M. Dankner, R. Yogev, S. Huang, M. E. Paul, M. A. Flores, M. W. Kline, L.-J. Wei, . (2005) Comparison of Atovaquone and Azithromycin with Trimethoprim-Sulfamethoxazole for the Prevention of Serious Bacterial Infections in Children with HIV Infection. Clinical Infectious Diseases 40:1, 136-145
CrossRef20
Lauren A. Trepanier, Andrea R. Yoder, Sunil Bajad, Michelle D. Beckwith, Jennifer L. Bellehumeur, Frank M. Graziano. (2004) Plasma Ascorbate Deficiency Is Associated With Impaired Reduction of Sulfamethoxazole-Nitroso in HIV Infection. JAIDS Journal of Acquired Immune Deficiency Syndromes 36:5, 1041-1050
CrossRef21
Naimish Patel, Henry Koziel. (2004) Pneumocystis jiroveci Pneumonia in Adult Patients with AIDS. Treatments in Respiratory Medicine 3:6, 381-397
CrossRef22
Jean T. Santamauro, Rashmi Nisha Aurora, Diane E. Stover. (2002) Pneumocystis carinii pneumonia in patients with and without HIV infection. Comprehensive Therapy 28:2, 96-108
CrossRef23
Rafik Samuel, Robert L. Bettiker, Byungse Suh. (2002) AIDS related opportunistic infections, going but not gone. Archives of Pharmacal Research 25:3, 215-228
CrossRef24
Keith Chirgwin, Richard Hafner, Catherine Leport, Jack Remington, Janet Andersen, Elizabeth M. Bosler, Clemente Roque, Natasa Rajicic, Vincent McAuliffe, Philippe Morlat, D. T. Jayaweera, Jean‐Louis Vilde, Benjamin J. Luft, . (2002) Randomized Phase II Trial of Atovaquone with Pyrimethamine or Sulfadiazine for Treatment of Toxoplasmic Encephalitis in Patients with Acquired Immunodeficiency Syndrome: ACTG 237/ANRS 039 Study. Clinical Infectious Diseases 34:9, 1243-1250
CrossRef25
Jay Alan Fishman. (2001) Prevention of Infection Caused by Pneumocystis carinii in Transplant Recipients. Clinical Infectious Diseases 33:8, 1397-1405
CrossRef26
Daniel M. Rosenberg, William McCarthy, Joseph Slavinsky, Charles K. N. Chan, Julio Montaner, James Braun, Michael N. Dohn, Paul T. Caldwell. (2001) Atovaquone suspension for treatment of Pneumocystis carinii pneumonia in HIV-infected patients. AIDS 15:2, 211-214
CrossRef27
James P. Souza, Michael Boeckh, Ted A. Gooley, Mary E. D. Flowers, Stephen W. Crawford. (1999) High Rates of Pneumocystis carinii Pneumonia in Allogeneic Blood and Marrow Transplant Recipients Receiving Dapsone Prophylaxis. Clinical Infectious Diseases 29:6, 1467-1471
CrossRef28
Tony W. Cheung. (1999) Overdose of atovaquone in a patient with AIDS. AIDS 13:14, 1984
CrossRef29
Judith Falloon, Susie Sargent, Stephen C. Piscitelli, Christine Bechtel, Stephen W. LaFon, Brian Sadler, Robert E. Walker, Joseph A. Kovacs, Michael A. Polis, Richard T. Davey, H. Clifford Lane, Henry Masur. (1999) Atovaquone Suspension in HIV-Infected Volunteers: Pharmacokinetics, Pharmacodynamics, and TMP-SMX Interaction Study. Pharmacotherapy 19:9, 1050-1056
CrossRef30
Indresh K. Srivastava, Joanne M. Morrisey, Elisabeth Darrouzet, Fevzi Daldal, Akhil B. Vaidya. (1999) Resistance mutations reveal the atovaquone-binding domain of cytochrome b in malaria parasites. Molecular Microbiology 33:4, 704-711
CrossRef31
Vilar, Khoo, Walley. (1999) The management of Pneumocystis carinii pneumonia. British Journal of Clinical Pharmacology 47:6, 605-609
CrossRef32
Brent G. Petty, John R. Black, Craig W. Hendrix, Lionel D. Lewis, Yiannis Basiakos, Judith Feinberg, David G. Pattison, Richard Hafner. (1999) Escalating Multiple-Dose Safety and Tolerance Study of Oral WR 6026 in HIV-Infected Subjects: AIDS Clinical Trials Group 173. JAIDS: Journal of Acquired Immune Deficiency Syndromes 21:1, 26-32
CrossRef33
El-Sadr, Wafaa M., Murphy, Robert L., Yurik, Teresa McCabe, Luskin-Hawk, Roberta, Cheung, Tony W., Balfour, Henry H. Jr., Eng, Robert, Hooton, Thomas M., Kerkering, Thomas M., Schutz, Malte, van der Horst, Charles, Hafner, Richard, . (1998) Atovaquone Compared with Dapsone for the Prevention of Pneumocystis carinii Pneumonia in Patients with HIV Infection Who Cannot Tolerate Trimethoprim, Sulfonamides, or Both. New England Journal of Medicine 339:26, 1889-1895
Full Text34
Matthew K. Wynia, John P.A. Ioannidis, Joseph Lau. (1998) Analysis of life-long strategies to prevent Pneumocystis carinii pneumonia in patients with variable HIV progression rates. AIDS 12:11, 1317-1325
CrossRef35
Bertrand Lell, Doris Luckner, Maryse Ndjavé, Trevor Scott, Peter G Kremsner. (1998) Randomised placebo-controlled study of atovaquone plus proguanil for malaria prophylaxis in children. The Lancet 351:9104, 709-713
CrossRef36
C DECKER, H MASUR. (1998) PNEUMONIA IN AIDS PATIENTS IN THE CRITICAL CARE UNIT. Critical Care Clinics 14:1, 135-157
CrossRef37
John P.A. Ioannidis, Joseph Lau. (1997) The impact of high-risk patients on the results of clinical trials. Journal of Clinical Epidemiology 50:10, 1089-1098
CrossRef38
Roger W. Jelliffe, Pilar Gomis, Babak Tahani, Joel Ruskin, Fred R. Sattler. (1997) A Population Pharmacokinetic Model of Trimethoprim in Patients With Pneumocystis Pneumonia, Made With Parametric and Nonparametric Methods. Therapeutic Drug Monitoring 19:4, 450-459
CrossRef39
M COWAN, J SHELHAMER, S LEVINE. (1997) ACUTE RESPIRATORY FAILURE IN THE HIV-SEROPOSITIVE PATIENT. Critical Care Clinics 13:3, 523-552
CrossRef40
Ziad Hussein, Jane Eaves, David B. Hutchinson, Craig J. Canfield. (1997) Population pharmacokinetics of atovaquone in patients with acute malaria caused by Plasmodium falciparum*. Clinical Pharmacology & Therapeutics 61:5, 518-530
CrossRef41
Stewart J. Levine. (1996) PNEUMOCYSTIS CARINII. Clinics in Chest Medicine 17:4, 665-695
CrossRef42
Laurence Huang, John D. Stansell. (1996) AIDS AND THE LUNG. Medical Clinics of North America 80:4, 775-801
CrossRef43
G.P. Rizzardi, A. Lazzarin, M. Musicco, D. Frigerio, M. Maillard, M. Lucchini, M. Moroni. (1996) Risks and benefits of aerosolized pentamidine and cotrimoxazole in primary prophylaxis of Pneumocystis carinii pneumonia in HIV-1-infected patients: a two-year Italian multicentric randomized controlled trial. Journal of Infection 32:2, 123-131
CrossRef44
P Morlat, C Bartou, J.M. Ragnaud, L Dequae, D Lacoste, M Buisson, N Bernard, P Mercié, B Couprie, J Beylot, J Aubertin. (1996) La pneumocystose pulmonaire au cours du sida: analyse rétrospective de 80 cas documentés (1985–1993). La Revue de Médecine Interne 17:1, 25-33
CrossRef45
Belle L. Lee, Martin G. Täuber, Brian Sadler, Donna Goldstein, Henry F. Chambers. (1996) Atovaquone inhibits the glucuronidation and increases the plasma concentrations of zidovudine*. Clinical Pharmacology & Therapeutics 59:1, 14-21
CrossRef46
S.D. Studenberg, J.D. Long, J.H. Woolf, C.J. Bruner, D. Wilson, J.L. Woolley. (1995) A robotics-based liquid chromatographic assay for the measurement of atovaquone in plasma. Journal of Pharmaceutical and Biomedical Analysis 13:11, 1383-1393
CrossRef47
Pankaj Gupta, Randolph W. Hurley, Peter H. Helseth, Jesse L. Goodman, Dale E. Hammerschmidt. (1995) Pancytopenia due to hemophagocytic syndrome as the presenting manifestation of babesiosis. American Journal of Hematology 50:1, 60-62
CrossRef48
A. E. Jolley, J. G. M. Hastings. (1995) Therapeutic progress IV: Treatment and prophylaxis of Pneumocystis carinii infection. Journal of Clinical Pharmacy and Therapeutics 20:3, 121-130
CrossRef49
Andre Rosowsky, Clara E. Mota, Sherry F. Queener. (1995) Synthesis and antifolate activity of 2,4-diamino-5,6,7,8-tetrahydropyrido[4,3- d ]pyrimidine analogues of trimetrexate and piritrexim. Journal of Heterocyclic Chemistry 32:1, 335-340
CrossRef50
T.J. Blanchard, D.C.W. Mabey, A. Hunt-Cooke, G. Edwards, D.B.A. Hutchinson, S. Benjamin, P.L. Chiodini. (1994) Multiresistant falciparum malaria cured using atovaquone and proguanil. Transactions of the Royal Society of Tropical Medicine and Hygiene 88:6, 693
CrossRef51
Tamiko Kimura, Toshio Okano, Naoko Tsugawa, Yoshitaka Okamura, Tadashi Kobayashi. (1994) Effects of dietary supplementation of calcium and vitamin don bone growth in growing male rats. Journal of Bone and Mineral Metabolism 12:S1, S7-S11
CrossRef52
M.J. Fisher, B.G. Gazzard, D.A. Hawkins, M.R. Nelson. (1994) Atovaquone as prophylaxis against Pneumocystis carinii pneumonia. Journal of Infection 28:1, 103-104
CrossRef
