Original Article
Oral Therapy for Pneumocystis carinii Pneumonia in the Acquired Immunodeficiency Syndrome — A Controlled Trial of Trimethoprim—Sulfamethoxazole versus Trimethoprim—Dapsone
N Engl J Med 1990; 323:776-782September 20, 1990
- Abstract
- Abstract
Background.
Antimicrobial drugs that can be taken orally are needed for the treatment of Pneumocystis carinii pneumonia in patients with the acquired immunodeficiency syndrome (AIDS). Preliminary data indicate that dapsone with trimethoprim may be an effective alternative to trimethoprim–sulfamethoxazole, which is frequently toxic.
Methods.
In a double-blind trial, 60 patients with AIDS and mild-to-moderately-severe first episodes of P. carinii pneumonia (partial pressure of oxygen in arterial blood, >60 mm Hg while breathing room air) were randomly assigned to 21 days of treatment with either trimethoprim–sulfamethoxazole (20 and 100 mg per kilogram of body weight per day, respectively) or trimethoprim-dapsone (20 mg per kilogram per day and 100 mg per day).
Results.
The orally administered treatment failed because of progressive pneumonitis in 3 of the 30 patients assigned to trimethoprim–sulfamethoxazole and in 2 of the 30 assigned to trimethoprim-dapsone (P>0.3). Major toxic effects required a switch to intravenous pentamidine for 17 patients (57 percent) in the trimethoprim–sulfamethoxazole group, as compared with 9 (30 percent) in the trimethoprim-dapsone group (P<0.025). With trimethoprim–sulfamethoxazole, there were more instances of severe chemical hepatitis (six, as compared with one in the trimethoprim-dapsone group) and marked neutropenia (five vs. one). Intolerable rash (three in each treatment group) and severe nausea and vomiting (two in each group) occurred with equal frequency with both drug combinations. Methemoglobinemia occurred in most of the patients treated with trimethoprim-dapsone, but it was asymptomatic and the level exceeded 20 percent in only one patient. Mild hyperkalemia (serum potassium level, 5.1 to 6.1 mmol per liter) also occurred in 53 percent of the patients treated with trimethoprim-dapsone.
Conclusions.
In patients with AIDS, oral therapy with trimethoprim–sulfamethoxazole and with trimethoprimdapsone are equally effective for mild-to-moderate first episodes of P. carinii pneumonia, but with trimethoprimdapsone there are fewer serious adverse reactions than with trimethoprim–sulfamethoxazole. (N Engl J Med 1990; 323:776–82.)
Media in This Article
Figure 1
Cumulative Months of Survival in Patients Treated with Trimethoprim—Dapsone (Dashed Line) or Trimethoprim–Sulfamethoxazole (Solid Line).Figure 2
Cumulative Monthly Proportion of Patients with P. carinii Pneumonia Who Were Free of Relapse after Treatment with Trimethoprim—Dapsone (Dashed Line) or Trimethoprim–Sulfamethoxazole (Solid Line).Article Activity
- Article
Pneumocystis carinii pneumonia is the most common opportunistic infection in patients with the acquired immunodeficiency syndrome (AIDS), as well as the most common index diagnosis.1 2 3 4 Although both trimethoprim–sulfamethoxazole and pentamidine are effective, they have failure rates of 5 to 20 percent and cause severe adverse reactions in up to 60 percent of patients with AIDS.5 6 7 8 9 New regimens are needed, especially oral regimens that can be used for outpatient treatment.
In 1984, Hughes and Smith10 demonstrated in the rat model of pneumocystis that dapsone alone (25 mg per kilogram of body weight per day) or dapsone (5 mg per kilogram per day) with trimethoprim (60 mg per kilogram per day) was at least as effective as trimethoprim–sulfamethoxazole. Open trials of dapsone (100 mg per day) plus trimethoprim (20 mg per kilogram per day) in patients with AIDS and mild-to-moderate first episodes of P. carinii pneumonia11 , 12 found this combination to be at least as effective and probably better tolerated than intravenous therapy with either pentamidine or trimethoprim–sulfamethoxazole.9 In 1985, oral dapsone alone (100 mg per day) was tested in 18 patients with mild-to-moderate first episodes of P. carinii pneumonia and had an unacceptably high failure rate of 39 percent.13 We therefore conducted a randomized, double-blind trial of oral therapy with either trimethoprim-dapsone or trimethoprim–sulfamethoxazole for first episodes of P. carinii pneumonia in patients with AIDS. Oral trimethoprim–sulfamethoxazole has been used effectively in the treatment of pneumocystosis and was recently evaluated prospectively in patients with AIDS and P. carinii pneumonia.14 , 15
Methods
Between March 17, 1986, and January 23, 1987, all patients 18 years of age or older with AIDS and their first episode of histologically confirmed P. carinii pneumonia were evaluated for entry into this study. All patients underwent sputum induction.16 Those with negative findings for P. carinii had a diagnosis established by bronchoscopic evaluation (bronchoalveolar lavage with or withoul transbronchial biopsy).17 All specimens were processed for p. carinii in the standard manner and cultured lor bacteria, mycobacteria, legionella, fungi, and viruses.18
Patients were excluded from this study if they had partial pressure of oxygen in arterial blood lower than 60 mm Hg while breathing room air; a history of allergy to dapsone, trimethoprim, or sulfaconlaining drugs; a below-normal activity of glucose-6-phosphate dehydrogenase in erythrocytes; a serum creatinine level above 2 mg per deciliter; a total neutrophil count below 1000 per microliter; a platelet count below 100,000 per microliler; more than 48 hours of other therapy for P. carinii pneumonia; enrollment in another investigational study; or a predicted survival of less than one week without therapy. These same criteria for exclusion were applied in our previous noncomparative studies of dapsone alone13 and trimethoprim—dapsone.11 The study protocol and consent form were approved by the Committee on Human Research of the University of California, San Francisco, and an institutional review board constituted according to the guidelines of the Food and Drug Administration.
After informed consent had been given, one of the investigators obtained an initial history and performed a physical examination of each patient, pertinent components of which were repeated daily. As in previous studies, clinical determinations of improvement or deterioration were based on dyspnea scores, frequency of cough, respiratory rates, and body temperatures.9 , 11 , 13 Laboratory studies, including a complete blood count, platelet count, and serum analysis (levels of electrolytes and glucose, tests of kidney and liver function, and lactate dehydrogenase activity), were performed every three days. Urinalysis and chest roentgenography were carried out on admission and at least weekly thereafter. Immune studies and CD4-cell counts were not performed. Serum specimens for the measurement of drug concentrations were obtained on days 3, 7, 14, and 21; the measurements were made after the completion of the trial and are reported elsewhere.19
A gallium citrate lung scan was performed at the beginning and end of therapy and was scored by established criteria.20 All scans and chest roentgenograms were interpreted after the completion of the study by a reader who had no knowledge of the patient's treatment or clinical condition. Pulmonary-function tests, including tests of vital capacity, total lung capacity, and single-breath diffusing capacity for carbon monoxide, were performed before or within three days of the start of therapy and repeated at the end of the study. Arterial blood gas and pH measurements (with the patient breathing room air) were performed at the beginning and end of therapy, and at other times at the discretion of the attending physicians.
As in previous studies,9 , 11 , 13 failure to respond to treatment was defined as profound deterioration within the first four days of therapy, as documented by multiple clinical radiographic or laboratory markers, or lack of improvement after one week of therapy. The records of patients whose condition was deemed to be worsening were reviewed by two study physicians and the attending physician, who determined collectively whether the study drug would be withdrawn.
Major adverse reactions were defined as a neutrophil count below 750 per microliter; a decrease in the hematocrit by more than 25 percent of the base-line level; a platelet count below 40,000 per microliter; an increase in the serum creatinine level to more than 180 μmol per liter (2 mg per deciliter); a serum activity of alanine aminotransferase, aspartate aminotransferase, or alkaline phosphatase more than five times the upper limit of normal in the absence of another cause for such elevation; a methemoglobin level above 20 percent; and the development of a skin rash that was intolerable to the patient, persisted unabated for 48 hours or more, or had bullae or mucous-membrane involvement. These adverse reactions were the same as those studied previously at this hospital.9 , 11 , 13 All adverse reactions, major or minor, were evaluated by one of the investigators. Therapy was changed to intravenous pentamidine isethionate (4 mg per kilogram per day) if treatment with the study drug was unsuccessful or if major adverse reactions were encountered.
In order for us to ensure compliance, assess response, observe adverse reactions, and comply with the standard of care at the time of the study, the patients remained in the hospital for the first two weeks of therapy. They were evaluated each day, however, to determine whether outpatient management would have been appropriate had hospitalization not been required by the study protocol, Patients who were stable or improving after 14 days were discharged; they received the third week of therapy as outpatients. Patients who survived the entire period of treatment were followed monthly for at least three months or until death.
Randomization and Drug Regimens
With use of a computer-generated, blocked, unstratified, 1:1 random-number sequence, 60 patients with a first episode of P. carinii pneumonia were assigned in equal numbers to one of two orally administered treatments: trimethoprim-dapsone or trimethoprim–sulfamethoxazole. Dapsone was given as a single dose of 100 mg per day; trimethoprim was given as 20 mg per kilogram per day in four divided doses; and sulfamethoxazole was given as 100 mg per kilogram per day in four divided doses. These doses had been evaluated and found to be effective in published trials and were considered conventional therapy at the start of the trial.9 , 11 , 13 No patient received concomitant folinic acid. Dapsone and identical-appearing placebo were supplied by Jacobus Pharmaceuticals; trimethoprim, sulfamethoxazole, and placebos for both drugs were supplied by Burroughs Wellcome.
All drugs and the placebo counterparts were given orally throughout the 21 days of therapy. A clinical pharmacist assembled the identical-appearing treatment packets and maintained the code in a locked cabinet. The patients, primary physicians, and investigators were blinded with regard to treatment group. In the hospital the drugs were administered under direct observation. To assess compliance, pill counts were performed during the third week of outpatient therapy.
Statistical Analysis
The code was not broken until the completion of therapy, except in the case of two patients who were switched to treatment with intravenous pentamidine during the study period. The patients were grouped according to the drug to which they were originally assigned. The significance of differences in data obtained at various intervals was determined by a two-tailed t-test. Nominal-scale data were compared by a chi-square analysis, with Fisher's exact test when appropriate. A P value of <0.05 was considered significant. For the life tables, generalized Wilcoxon (Breslow) and generalized average (Mantel–Cox) tests were used. Plus-minus values are means ±SD.
Results
During the study period, 60 of the 79 patients with AIDS who were given a diagnosis of a first episode of P. carinii pneumonia met the study criteria. Nineteen patients were excluded for the following reasons: more than 48 hours of previous treatment (11 patients), expected survival of less than one week (4), enrollment in another experimental study (2), neutrophil count under 1000 (1), or a decision not to participate (1). There were no statistically significant differences between the two study groups with respect to demographic, clinical, or laboratory variables (Table 1Table 1
Base-Line Characteristics of the Patients, According to Treatment Group.*).Failure to Respond to Treatment
Five patients (8 percent) (two receiving trimethoprim-dapsone and three receiving trimethoprim–sulfamethoxazole; P>0.3) had severe and progressive pulmonary deterioration during the first four days of therapy and were changed to treatment with intravenous pentamidine for a total of 21 days of therapy or until death (Table 2Table 2
Outcome of Treatment and Major Adverse Drug Reactions Requiring Discontinuation of Study Drugs.*). One of the five patients died, for an overall mortality of 1 in 60 (2 percent; 95 percent confidence interval, 0 to 10.4 percent). The death occurred in a patient treated with trimethoprim–sulfamethoxazole who was switched to pentamidine on day 4 and died of respiratory failure on day 13 despite the initiation of steroid treatment on day 6. No other opportunistic infection was identified. The patient declined mechanical ventilation, and no postmortem examination was performed.Adverse Reactions
The patients treated with trimethoprim–sulfamethoxazole had nearly twice as many major adverse reactions as those treated with trimethoprim—dapsone (17 vs. 9, respectively; P = 0.025) (Table 2). The mean length of time to the development of adverse drug reactions was 10.3 days for those treated with trimethoprim—dapsone and 12.5 days for those treated with trimethoprim–sulfamethoxazole.
Severe chemical hepatitis and neutropenia requiring the discontinuation of the study drug occurred nearly exclusively in the patients treated with trimethoprim–sulfamethoxazole rather than trimethoprim—dapsone (P<0.05 for hepatitis; P<0.08 for neutropenia); mild hepatitis and neutropenia were also more frequent in the trimethoprim–sulfamethoxazole group than in the trimethoprim—dapsone group (P = 0.05 and 0.03, respectively) (Table 3Table 3
Minor Adverse Reactions to Study Drugs.*). The mean peak aminotransferase levels were higher in the trimethoprim–sulfamethoxazole group (aspartate aminotransferase, 173 IU per liter [range, 18 to 1362]; alanine aminotransferase, 216 IU per liter [range, 22 to 2010) than in the trimethoprim—dapsone group (aspartate aminotransferase, 51 IU per liter [range, 13 to 146]; alanine aminotransferase, 60 IU per liter [range, 18 to 200]; P<0.001). Other causes of elevated aminotransferase levels were excluded before it was concluded thai an adverse drug reaction had occurred.Rash without mucous-membrane involvement but with associated fever occurred with nearly equal frequency in both groups: 12 (40 percent) of the patients treated with trimethoprim—dapsone had rash and fever, as compared with 14 (47 percent) of those treated with trimethoprim–sulfamethoxazole; however, therapy was continued without an alteration of the dose in all but 6 patients who had intolerable pruritus (3 in each group). The rash and fever appeared after a mean of 9 days (range, 5 to 11), reached maximum intensity 1 to 2 days later, and disappeared after another 3 to 4 days even when therapy was maintained.
Minor adverse reactions occurred in nearly all the patients (in 97 percent of those taking trimethoprim–sulfamethoxazole and 93 percent of those taking trimethoprim—dapsone), with a frequency of 2.7 reactions per patient (Table 3). The incidence of gastrointestinal symptoms was about the same in both groups (Tables 2 and 3), but the nausea was judged more severe in the trimethoprim–sulfamethoxazole group.
Two patients (one per group) had thrombocytopenia (<40,000 platelets per microliler) during the second week of treatment. The patient treated with trimethoprim–sulfamethoxazole had a drop in the platelet count from 223,000 per microliter at base line to 30,000 per microliter on day 12 of therapy. Pentamidine therapy was substituted, and the platelets were within normal limits three days later. The patient treated with trimethoprim—dapsone had a precipitous drop in the platelet count from 146,000 per microliler to 5000 per microliter on day 9 of therapy, with associated petechiae but no bleeding. Dapsone treatment was discontinued, the patient received five units of platelets, and three days later his platelet count was 30,000 per microliter. When he began taking pentamidine, the platelet count gradually returned to the pretreatment value.
Methemoglobinemia, a known side effect of dapsone, occurred in fwo thirds of the patients in the trimethoprim—dapsone group (Table 3).21 22 23 24 25 26 27 All were asymptomatic. Therapy was discontinued in only one, whose methemoglobin level rose to 21 percent on day 9. Pentamidine was substituted, and the patient was treated with methylene blue (2 mg per kilogram given once intravenously as a 1 percent solution, in accordance with the study protocol); 24 hours later, the methemoglobin concentration was 5 percent. The methemoglobinemia appeared during the second week of treatment, and in all affected patients who were maintained on trimethoprim—dapsone the methemoglobin level decreased to 10 percent or less during the third week.
Decreases in the hematocrit occurred frequently and exceeded 10 percent in nine patients treated with trimethoprim—dapsone and five treated with trimethoprim–sulfamethoxazole (P>0.30). In one patient in the trimethoprim—dapsone group, the hematocrit dropped from 33 percent to 22 percent during the second week of treatment, and the patient received two units of packed erythrocytes. Trimethoprim—dapsone treatment was stopped at the request of the attending physician because of the patient's anemia, mild hepatitis, rash, and fever.
Mild hyperkalemia (potassium level, 5.1 to 6.1 mmol per liter) was observed in 53 percent of the patients taking trimethoprim—dapsone, as compared with 20 percent of those taking trimethoprim–sulfamethoxazole (P<0.001 by Fisher's exact test). None of the patients were symptomatic, no electrocardiographic abnormalities were observed, and the potassium levels became normal with no change in therapy. One patient in the trimethoprim—dapsone group (potassium, 5.9 mmol per liter) and one in the trimethoprim–sulfamethoxazole group (potassium, 6.1 mmol per liter) were each treated with a single dose of sodium polystyrene sulfonate (Kayexalate), with resulting stabilization of the potassium level at less than 5.5 mmol per liter. Therapy was stopped only in the second patient (trimethoprim–sulfamethoxazole), because of intractable nausea and vomiting with dehydration.
Outcome
The initial mean uptake scores on the gallium scan were equivalent in the two treatment groups and fell substantially by the end of therapy (Table 4Table 4
Clinical and Laboratory Indexes of Severity of Illness before and after Treatment.*).Dyspnea scores, respiratory rates, partial pressure of oxygen while breathing room air, single-breath diffusing capacity for carbon monoxide, and serum lactate dehydrogenase levels did not differ significantly between groups before or after treatment. The mean length of time to the initial improvement in both groups was five days (range, three to seven). Chest radiographs showed some worsening infiltration during the first six days of treatment in all but three patients, a phenomenon described previously in intravenous-treatment trials, but all the patients improved by the third week of therapy.9
Of the 60 patients, 39 (65 percent; 22 assigned to receive trimethoprim—dapsone and 17 assigned to receive trimethoprim–sulfamethoxazole) were determined on subjective assessment to have P. carinii pneumonia of a severity that would have required an initial hospitalization under any circumstance. Although the study design dictated that the patients remain in the hospital for the first two weeks, a daily assessment was made to ascertain whether hospitalization was medically necessary. This assessment indicated that 85 percent of the patients could have been discharged after the first week. Obligatory hospitalization because of respiratory status continued for the same period in each group (trimethoprim—dapsone, 7.3±1.7 days; trimethoprim–sulfamethoxazole, 7.7±3.1 days).
Patients who survived the period of treatment were evaluated at monthly intervals for at least three months thereafter or until death (Fig. 1Figure 1
Cumulative Months of Survival in Patients Treated with Trimethoprim—Dapsone (Dashed Line) or Trimethoprim–Sulfamethoxazole (Solid Line). and 2Figure 2Cumulative Monthly Proportion of Patients with P. carinii Pneumonia Who Were Free of Relapse after Treatment with Trimethoprim—Dapsone (Dashed Line) or Trimethoprim–Sulfamethoxazole (Solid Line).). There was no significant difference between the two treatment groups with respect to overall survival or relapse rates. None of the patients received prophylaxis for P. carinii during the first three months after the completion of therapy, and none of them had a relapse during this interval. No patients received zidovudine during therapy, but nine patients in each group received it after treatment was completed. There were no differences in survival or relapse rates between the patients who received zidovudine and those who did not (data not shown).Discussion
This study demonstrates that oral therapy with either trimethoprim—dapsone or trimethoprim–sulfamethoxazole is effective for the treatment of mild-tomoderate first episodes of P. carinii pneumonia in patients with AIDS. The overall therapeutic response rate of 92 percent and the overall mortality of only 2 percent are equal to or better than those in patients with AIDS treated previously with parenteral trimethoprim–sulfamethoxazole or pentamidine.3 , 5 , 9 , 14 All other measures of efficacy that we studied (such as the length of time to improvement and the end-of-thcrapy gallium-uptake scores) were similar in the two treatment groups.
Although the treatments were equally effective, there were significantly fewer major adverse reactions requiring the discontinuation of therapy with trimethoprim—dapsone than with trimethoprim–sulfamethoxazole (30 percent vs. 57 percent, respectively). As in previous studies, hepatitis and neutropenia accounted for most of the major adverse reactions to trimethoprim–sulfamethoxazole, and the majority of these side effects occurred during the second week of treatment.5 , 7 8 9 , 13 The incidence of minor side effects (such as mild neutropenia or increased aminotransferase levels) was also higher in the trimethoprim–sulfamethoxazole group. Although Sattler and associates15 have shown that with appropriate dose adjustment, oral therapy with trimethoprim–sulfamethoxazole can be continued successfully even when moderate neutropenia or chemical hepatitis occurs, the unavailability of assays to measure serum drug levels, the difficulty of monitoring daily blood levels in outpatients, and reports of occasional severe hepatitis and neutropenia7 , 9 have led us to change to alternative drugs when severe adverse reactions develop. The appearance of a generalized maculopapular rash and fever, however, did not by itself mandate the cessation of therapy. In a majority of participants in both groups (Table 3), rash and fever resolved within two to three days while treatment continued at the full dose. Therapy should be discontinued if the rash is subjectively intolerable or if there is desquamation or involvement of mucous membranes.
Anemia is a well-recognized and poorly explained complication of prolonged dapsone therapy even in the absence of a glucose-6-phosphate dehydrogenase deficiency.21 22 23 24 However, the overall drop of 4 to 6 percent in the hematocrit was comparable in the two groups. Nine patients (30 percent) in the trimethoprim—dapsone group and five patients (17 percent) in the trimethoprim–sulfamethoxazole group had a decrease in the hematocrit of more than 10 percent but less than 25 percent (P>0.30) during the second week of treatment. Only one patient (treated with trimethoprim—dapsone) required blood transfusion, and he was asymptomatic. Methemoglobinemia is also recognized as a complication of dapsone therapy in other populations of patients26 27 28; it occurred in 67 percent of the patients treated with trimethoprim—dapsone but in none of those treated with trimethoprim–sulfamethoxazole. All the patients were asymptomatic, however, and only one had a methemoglobin level above 20 percent, which responded well to treatment. The frequency of anemia and methemoglobinemia and the known likelihood of hemolysis in the presence of a glucose-6-phosphate dehydrogenasc deficiency highlight the necessity of screening for this deficiency before dapsone therapy is instituted. Hemoglobin concentrations and hematocrits should be determined at regular intervals, and monitoring for signs of methemoglobinemia should be continued throughout the 21 days of therapy.
Thrombocytopenia has been described in patients with AIDS who were treated with trimethoprim–sulfamethoxazole,5 , 7 , 9 but it has not been previously described with dapsone. One patient in the trimethoprim—dapsone group had a precipitous decrease in the platelet count, which could have been due to an idiosyncratic reaction.
As compared with treatment with oral dapsone alone (100 mg per day) as described previously in a study of 18 patients with AIDS and a first episode of P. carinii pneumonia, the trimethoprim—dapsone combination was much more effective, but it induced a higher incidence of methemoglobinemia (67 percent vs. 11 percent) and hyperkalemia (53 percent vs. 0 percent).13 Dapsone levels were 40 percent higher in the patients who received combination therapy in this study than in the 18 patients previously treated with dapsone only.19 Because this drug is eliminated from the body by acetylation and oxidative metabolism and because trimethoprim has been shown to inhibit the oxidative metabolism of other drugs, it is likely that inhibition of dapsone metabolism caused the higher dapsone levels found in the trimethoprim—dapsone group.19 Higher dapsone levels resulting from this possible drug interaction may have contributed to the toxic effects noted in the trimethoprim—dapsone group, particularly the methemoglobinemia, anemia, and hyperkalemia, but they may also have accounted for the greater efficacy of the combination therapy as compared with dapsone alone.13 In fact, there is probably a double interaction, in that dapsone may alter the metabolism of trimethoprim. The patients receiving trimethoprim—dapsone had a 49 percent higher concentration of trimethoprim than the patients receiving trimethoprim–sulfamethoxazole. The implications of these drug interactions are described elsewhere.19
The incidence of adverse reactions with oral trimethoprim–sulfamethoxazole was qualitatively and quantitatively similar to that seen with intravenous therapy and in other studies of oral administration.5 , 7 , 14 , 15 Although 65 percent of these patients were sick enough to require initial hospitalization, fully 85 percent could have been discharged within one week of beginning medications. Because adverse reactions appear most commonly during the second week of treatment, however, outpatients require close follow-up. Survival rates were identical in the two groups. Relapse rates were similar to those of historical controls, with no relapses in the first three months after the completion of therapy in either group. No patients received P. carinii prophylaxis during that period.
At our institution, we now hospitalize severely ill patients and those with a first episode of P. carinii pneumonia who are not incorporated into the health care system. These patients generally remain in the hospital for four to seven days for stabilization of respiratory symptoms, education about the disease, and evaluation of other AIDS-related problems. Patients who are already receiving medical care and are less ill, especially those with a second or subsequent episode of mild-to-moderate P. carinii pneumonia, are treated with oral therapy as outpatients. Patients are advised which anticipated adverse reactions they should report, and they are evaluated with a complete blood count, platelet count, analysis of blood chemistry, and measurements of lactate dehydrogenase activity two times a week. Candidates for dapsone therapy are tested for glucose-6-phosphate dehydrogenase before being given the drug, and methemoglobin concentrations are obtained when indicated. Drug levels are not used for routine clinical management.
We have shown that oral therapy is highly satisfactory for mildly to moderately ill patients with AIDS and P. carinii pneumonia and that trimethoprim—dapsone and trimethoprim–sulfamethoxazole are equally effective treatments. Because trimethoprim–sulfamethoxazole induced a higher incidence of major toxic effects (including neutropenia and hepatitis), we believe that trimethoprim—dapsone is preferable for oral therapy for ambulatory or mildly ill patients, and we now use it as our initial therapy for outpatients with mild-to-moderate P. carinii pneumonia. However, the trimethoprim—dapsone combination was associated with other adverse reactions (methemoglobinemia and hyperkalemia) that are probably dose-related, and further trials with this combination are needed to study the interactions between trimethoprim and dapsone in order to define optimal doses that will decrease toxicity without altering efficacy.
Supported in part by grants from the Food and Drug Administration (FDR000137–01–1), the State of California Universitywide Task Force on AIDS (2–534996–19900), and the AIDS Clinical Study Center of the University of California, San Francisco.
We are indebted to Dr. Walter Hughes for many helpful discussions; to Iris Gartner, L.T., for exceptional knowledge of the field of parasitology; to W. Keith Hadley, M.D., Ph.D., for microbiologic assistance; to Zachary Weingart for conscientious assistance in data recording; to the house staff at San Francisco General Hospital, who cared for the patients and provided invaluable assistance in the Conduct of this study; and to Sam Broyles for skillful assistance in the preparation of the manuscript.
Source Information
From the Medical Service, San Francisco General Hospital, and the Department of Medicine, University of California, San Francisco (I.M., J.M., G.L., P.C.H., B.L., G.M., N.B., C.B.W.), and the Department of Microbiology, University of California, San Francisco (J.M.). Address reprint requests to Dr. Wofsy at Ward 95, Bldg. 90, San Francisco General Hospital. 995 Potrero Ave., San Francisco, CA 94110.
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