524

Clindamycin with vs. Trimethoprim-Sulfamethoxazole Therapy for Mild and Moderately Severe Pneumocystis carinii Pneumonia in Patients with AIDS: A Multicenter, Double-Blind, Randomized Trial (CTN 004)

Emil Toma, Anona Thorne, Joel Singer, Janet Raboud, From the Department of Microbiology and Infectious Diseases, Centre Claude Lemieux, Sylvie Trottier, Michel G. Bergeron, Hospitalier de l’Universite´ de Montre´al, the Immunodeficiency Chris Tsoukas, Julian Falutz, Richard Lalonde, Treatment Centre (IDTC), Montreal General Hospital, and the Royal Victoria Hospital, Montreal, and Centre Hospitalier de l’Universite´ du Christiane Gaudreau, Rachel Therrien, and the Que´bec, Quebec, Quebec; and the Canadian HIV Trials Network, CTN-PCP Study Group* Vancouver, British Columbia, Canada

This double-blind, randomized, multicenter trial compared /primaquine (Cm/Prq) Downloaded from https://academic.oup.com/cid/article/27/3/524/280761 by guest on 25 September 2021 with trimethoprim-sulfamethoxazole (TMP-SMZ) as therapy for AIDS-related Pneumocystis carinii pneumonia (PCP). Forty-five patients received clindamycin (450 mg four times daily [q.i.d.]) and primaquine (15 mg of base/d); 42 received TMP-SMZ (320 mg/1,600 mg q.i.d. if weight of §60 kg or 240 mg/1,200 mg q.i.d. if weight of õ60 kg) plus placebo primaquine. Overall, the efficacy of Cm/Prq was similar to that of TMP-SMZ (success rate, 76% vs. 79%, respectively); Cm/Prq was associated with fewer adverse events (P Å .04), less steroid use (P Å .18), and more rashes

(P Å .07). These differences were even greater for patients with PaO2 of ú70 mm Hg (P Å .02,

P Å .04, and P Å .02, respectively). For patients with PaO2 of £70 mm Hg (23 Cm/Prq recipients and 21 TMP-SMZ recipients), the efficacy of Cm/Prq was similar to that of TMP-SMZ (success rate, 74% vs. 76%, respectively); Cm/Prq was associated with similar adverse events (P Å .57), steroid use (P Å .74), and rashes (P Å .78). This trial confirms that Cm/Prq is a reasonable alternative therapy for mild and moderately severe PCP.

The implementation of effective prophylaxis for Pneumo- have been evaluated in open, noncontrolled [11–13], retrospec- cystis carinii pneumonia (PCP) as well as earlier diagnosis and tive [14, 15], prospective, noncomparative [16], and double- treatment of HIV have contributed to a decline in its blind, randomized trials [17, 18]. No statistically significant incidence [1–3]. Nonetheless, PCP remains the most frequent differences in therapeutic efficacy, survival, or rates of dose- AIDS-defining disease, and severe forms are still encountered limiting toxicities have been detected. [1–4]. Patients experiencing adverse events associated with The initial aim of this prospective, double-blind, randomized conventional agents during prophylaxis or therapy for PCP as trial was to assess the safety and efficacy of Cm/Prq in compari- well as those for whom standard therapeutic regimens fail re- son with trimethoprim-sulfamethoxazole (TMP-SMZ) as ther- quire alternative therapy, such as dapsone/trimethoprim or ato- apy for mild but also moderately severe forms of AIDS-related vaquone for mild-to-moderate PCP and trimetrexate with PCP. for moderately severe PCP [4–9]. The action of clindamycin/primaquine (Cm/Prq) against P. carinii was first proven in 1987 in tissue cultures and in an Patients and Methods experimental rat model [10]. Since then, its safety and efficacy Study Design and Treatment Regimens

This was a double-blind, randomized study conducted Received 7 November 1997; revised 29 April 1998. through the Canadian HIV Trials Network (CTN) in 15 univer- This work was presented in part at the 35th Interscience Conference on sity-affiliated hospitals (see list under CTN-PCP Study Group Antimicrobial Agents and Chemotherapy held on 17–20 September 1995 in San Francisco. Members at the end of the text). An independent data safety Written informed consent was obtained from the patients, and the study was and monitoring board that periodically evaluated the conduct approved by the Canadian HIV Trials Network Safety and Efficacy Review of the study recommended its termination 2 years after initia- Committee and by the institutional ethics committees at the participating cen- ters. tion (2 March 1992) because of slow accrual of patients and Financial support: This work was supported by National Health Research a lower-than-expected incidence of clinical end points. and Development Programme (NHRDP)-Health and Welfare Canada (grant Primaquine and an identical placebo were supplied by 6605-3720 AIDS), the Canadian HIV Trials Network, Sanofi-Winthrop (USA), Upjohn (Canada), and Burroughs Wellcome (Canada). Sanofi-Winthrop (New York). Clindamycin was provided by * Members of the CTN-PCP Study Group are listed at the end of the text. Upjohn (Mississauga, Ontario, Canada), and TMP-SMZ was Reprints or correspondence: Dr. Emil Toma, Hoˆtel-Dieu de Montreal, 3840 obtained from Burroughs Wellcome (Kirkland, Quebec, Can- St-Urbain, Montreal, Quebec H2W 1T8, Canada. ada). The preparation of intravenous in similar Clinical Infectious Diseases 1998;27:524–30 packages was done by local pharmacies following a central ᭧ 1998 by the Infectious Diseases Society of America. All rights reserved. 1058–4838/98/2703–0019$03.00 protocol. Oral clindamycin and TMP-SMZ were packaged in

/ 9c55$$se20 08-17-98 22:29:49 cidal UC: CID CID 1998;27 (September) Treatment of AIDS-Related PCP 525 similar-looking capsules by Dr. N. McMullen at the Faculty £70 mm Hg at study entry or at any time during the course of Pharmacy, University of Montreal, Montreal. of therapy was decided by the patient’s physician [19–21]. To ensure a balanced distribution, randomization was stra- Secondary prophylaxis was recommended to begin 2 weeks tified according to PaO2 measured when patients were breathing after study termination. room air: ú70 mm Hg and 50 to 70 mm Hg. Inclusion criteria were as follows: age of older than 16 years, proven or presump- Clinical and Laboratory Assessments tive HIV-related PCP, PaO2 of ú50 mm Hg, and body weight of ú45 kg. Individuals with allergy or intolerance to the study At baseline, each patient underwent a physical examination, , known glucose-6-phosphate dehydrogenase defi- a detailed medical history and chest radiographs were obtained, ciency, grade 3 or more diarrhea or vomiting, or a history and arterial blood gas tension and pH were measured while of pseudomembranous colitis in the previous 2 months were the patient was breathing room air. A complete blood cell count excluded from enrollment. Other exclusion criteria were preg- with differential blood cell counts, blood chemistry analysis, Downloaded from https://academic.oup.com/cid/article/27/3/524/280761 by guest on 25 September 2021 nancy or lactation; active intravenous drug use; inability to urinalysis, lymphocyte immunophenotyping, tests for glucose- attend follow-up visits; administration of more than two doses 6-phosphate dehydrogenase deficiency (as needed), blood cul- of TMP-SMZ, pentamidine, dapsone/trimethoprim, atova- tures, toxoplasma serology (optional), and a test for serum quone, or Cm/Prq within 3 days preceding initiation of study cryptococcal antigen were performed. Sputum or bronchoal- drug therapy; or concomitant chemotherapy or therapy with veolar lavage fluid specimens were processed for the presence systemic corticosteroids, colony-stimulating factors, amphoter- of mycobacteria, fungi, and cytomegalovirus in addition to icin B, ganciclovir, or cyclosporine. Laboratory exclusion crite- P. carinii. The Karnofsky score was assessed, and PCP scores ria were as follows: granulocyte count, õ1,000/dL (1 1 109/L); for body temperature, respiratory rate, cough, chest tightness, hemoglobin level, õ9.0 g/dL (90 g/L); platelet count, dyspnea, need for supplemental O2, and chest radiograph find- õ75,000/dL (75 1 109/L); serum creatinine level, ú1.25 times ings were calculated on the basis of a modification of that the upper limit of normal; and results of liver function tests, ú5 proposed by Nichols et al. [22] and Vanhems and Toma [23]. times the upper limit of normal. During the study period, clinical evaluations and routine The diagnosis of PCP was confirmed by identification of laboratory investigations (complete blood cell counts and blood P. carinii in specimens of induced or expectorated sputum or chemistry analyses) were performed at days 3, 7, 10, 14, and bronchoalveolar lavage fluid. Patients with presumptive PCP 21 of therapy. Repeated chest radiographs were obtained at were withdrawn from the trial if the diagnosis of PCP was not days 7, 14, and 21 of treatment. These assessments were re- proven within 5 days of study entry. The most appropriate peated 2 weeks and 1, 2, 3, and 6 months after termination of treatment was decided by the treating physicians. Attending study treatment or until there was a PCP relapse or the patient physicians, patients, and investigators were blinded to each died, if earlier. Lymphocyte immunophenotyping was repeated patient’s study treatment. 2 weeks after termination of study treatment. The first regimen was TMP-SMZ (intravenous or oral) at a dose of 320 mg/1,600 mg (or four capsules if given orally) Evaluation of Safety and Efficacy every 6 hours for patients weighing §60 kg and 240 mg/ 1,200 mg (or three capsules if given orally) every 6 hours for Symptoms and signs of toxicity and abnormal laboratory test individuals weighing õ60 kg; in addition, one capsule of pla- results were graded (1 to 4) according to criteria set by the cebo primaquine was given daily. The second regimen con- AIDS Clinical Trials Group of the National Institute of Allergy sisted of clindamycin (intravenous or oral) at a dose of and Infectious Diseases. Grade 3 or 4 toxicity represented an 450 mg every 6 hours and primaquine (oral) at a daily dose indication to discontinue the study treatment, but the final deci- of 15 mg of base. The daily dose of oral clindamycin was sion was left to the treating physician. packaged, divided, and administered in the same manner as Success of treatment was defined as a decrease of at least that of TMP-SMZ. two points in the PCP score accompanied by PCP scores for The standard course of therapy was 21 days unless there all items that were lower than those at baseline. Treatment that were treatment-limiting adverse events, deterioration of clinical lasted ú14 days but õ21 days was also considered to be a status, or lack of improvement within 7 days that led to discon- success if there was objective evidence of improvement without tinuation of the initial regimen. In the case of discontinuation administration of alternative medication. The primary indica- of the study treatment, alternative regimens were intravenous tion of efficacy was success of treatment, with no ventilator pentamidine, dapsone/trimethoprim, or , as thought use or switch to alternate therapy before improvement and no to be more appropriate for the patient by their other physician. steroid use after day 4 of therapy and before improvement. No crossover to the alternative study drug regimen was al- Survival for at least 35 days after the onset of therapy and the lowed. The initial and subsequent routes of administration (in- relapse rate within the following 6 months were also examined. travenous or oral) were decided by the treating physician. Relapse was defined as a recurrence of clinical signs and symp- Antiretroviral therapy was interrupted during the study treat- toms and/or radiographic changes suggestive of PCP and the ment period. Corticosteroid therapy for patients with PaO2 of identification of P. carinii.

/ 9c55$$se20 08-17-98 22:29:49 cidal UC: CID 526 Toma et al. CID 1998;27 (September)

Statistical Analysis summarized in table 3. The rates of success for TMP-SMZ and Cm/Prq treatments were 76% and 74%, respectively (95% CI The initial sample size of 180 was based on the ability to for the difference, 2% { 25%). There were no statistically detect a difference in occurrence of adverse events of 85% vs. significant differences between the treatment regimens with 65% with a power of 0.8 and a two-sided a value of .05. After respect to dyspnea scores, PCP scores, and lactate dehydroge- only 116 patients were enrolled in the study after almost 2 nase values at any time. These markers of severity indicated years, the trial was stopped on the basis of the recommendation improvements in both groups of patients in a similar manner. of the data safety and monitoring board. Two deaths due to PCP occurred during the 21-day study The distribution of categorical variables was compared be- period in each treatment arm. Two other Cm/Prq recipients tween treatment groups by means of the x2 test or Fisher’s exact died between day 21 and day 35: one who had PCP and Myco- test. The distribution of continuous variables was compared by bacterium avium complex bacteremia died following the using the two-sample t test if the data were normally distributed

change to alternate therapy, and one with bilateral pneumotho- Downloaded from https://academic.oup.com/cid/article/27/3/524/280761 by guest on 25 September 2021 and the Wilcoxon rank-sum test otherwise. A P value of õ.05 rax died after the initiation of support with mechanical ventila- was considered statistically significant, and all P values were tion. There were no significant differences in the mortality rates two-sided. between the treatment groups in the 35 days following the All patients who received at least two doses of the study beginning of study therapies (P Å .33). medication were eligible for the assessment of adverse events. There was no difference between treatment groups with re- Analysis of time to discontinuation of the study medication spect to the use of steroids (12 patients per group; P Å .74). due to adverse events, time to first corticosteroid use during In contrast, among less severely ill patients (i.e., those with therapy for PCP, and the comparison of survival between treat- PaO of ú70 mm Hg), a significantly higher number of TMP- ment groups was done by using the Kaplan-Meier survival 2 SMZ recipients than of Cm/Prq recipients received steroid ther- method. apy (six vs. one, respectively; P Å .04) (table 4). Four patients required support with mechanical ventilation Results during the study period (two patients per group; P Å .92). There was no significant difference in the rate of PCP recur- Study Population and Severity of Disease rence between the two treatment arms (P Å .99). In total, 116 patients were enrolled in the trial. PCP in 25 patients was not confirmed, and incomplete information was Tolerance and Adverse Events available for four individuals. Thus, the primary analysis was based on data for 87 patients, 42 TMP-SMZ recipients and 45 The major (grades 3 and 4) adverse reactions that occurred Cm/Prq recipients. A separate analysis of evaluable patients during study treatment are shown in table 5. In total, 21 differ- with moderately severe PCP (PaO2, £70 mm Hg), 21 ent grades 3 and 4 adverse events or reactions occurred in 19 TMP-SMZ recipients and 23 Cm/Prq recipients, was per- patients, 10 TMP-SMZ recipients and nine Cm/Prq recipients formed. (P Å .57) (tables 4 and 5). However, there was a statistically The demographic and clinical characteristics of evaluable significant difference in the incidence of major adverse events patients are presented in table 1. Most enrolled patients were in those patients with mild disease (P Å .02). Adverse events experiencing their first episode of PCP. Less than 50% of pa- resulted in discontinuation of study therapy for seven patients tients had received antiretroviral therapy, and õ25% had re- in each arm (P Å .77; logrank test). ceived prophylaxis for PCP. The main baseline laboratory find- Rash was the most frequent clinical event. All rashes in ings are shown in table 2. There were no statistically significant Cm/Prq recipients were of grade 1 or 2; in three patients, rash differences between treatment groups with respect to any of was the reason for discontinuation of study therapy. The num- the baseline values shown, risk factors, or clinical severity of ber of Cm/Prq recipients and TMP-SMZ recipients with rashes

PCP at study entry (according to PaO2, the Karnofsky score, was similar (7 vs. 5, respectively; P Å .78), but among patients and PCP scores). with mild PCP, significantly more Cm/Prq recipients than TMP-SMZ recipients had rashes (15 vs. 7, respectively; P Å .02). No cases of pseudomembranous colitis or clinically Outcome of Therapy significant methemoglobinemia were encountered during the The presentation of results given herein and in the next study period. section focuses on the subgroup of patients with PaO2 of £70 mm Hg (23 Cm/Prq recipients and 21 TMP-SMZ recipi- Discussion ents). Data for all patients are presented in the tables. Of the 44 patients, 59% completed the 21-day course of Several points should be considered when interpreting the therapy without any changes. There was no significant differ- findings of this study. The design of this trial was adapted to ence in the duration of therapy between treatment groups conform with routine clinical practice during 1992–1994. The (P Å .68). Therapeutic outcomes and reasons for failure are patient’s treating physician determined the initial route of ther-

/ 9c55$$se20 08-17-98 22:29:49 cidal UC: CID CID 1998;27 (September) Treatment of AIDS-Related PCP 527

Table 1. Baseline demographic characteristics and clinical profile of patients with AIDS who received TMP-SMZ or Cm/Prq as therapy for PCP.

Patients with PaO2 of £70 mm Hg All patients

Characteristic Cm/Prq TMP-SMZ Cm/Prq TMP-SMZ

No. of evaluable patients 23 21 45 42 Mean age { SD (y) 40.2 { 9.1 37.8 { 6.5 38.8 { 8.7 36.7 { 9.3 Male 23 (100) 20 (95) 45 (100) 40 (95) Caucasian 19 (83) 19 (90) 39 (87) 39 (93) Homosexual or bisexual 20 (87) 16 (76) 39 (87) 32 (76) Mean weight { SD (kg) 63 { 8.9 59 { 9.6 63 { 7.6 62 { 9.4 Downloaded from https://academic.oup.com/cid/article/27/3/524/280761 by guest on 25 September 2021 First episode of PCP 22 (96) 19 (90) 44 (98) 39 (93) Prior therapy for HIV infection 10 (43) 6 (29) 20 (44) 21 (50) Prior prophylaxis for PCP 5 (22) 3 (14) 10 (22) 8 (19) Prior AIDS-defining diagnosis 14 (61) 12 (57) 27 (60) 27 (64) Median Karnofsky score (range) 60 (30–80) 60 (20–90) 70 (30–100) 70 (20–90) Median PCP score (range) 25 (13–22) 24 (11–34) 17 (8–32) 18 (9–34)

NOTE. Unless stated otherwise, data are no. (%) of patients. Cm/Prq Å clindamycin/primaquine; PCP Å Pneumo- cystis carinii pneumonia; TMP-SMZ Å trimethoprim-sulfamethoxazole.

apy (intravenous or oral), as well as the need for steroid use ity of clindamycin in patients with AIDS [24] and the low or changes in treatment regimen or route of administration. tolerance of single oral doses of clindamycin of ú450 mg Nonetheless, the blinded nature of the trial and the evaluation [25–27]. The daily primaquine dose (15 mg of base) used in of secondary outcome measures minimized possible biases in this and other trials conducted in Canada [11, 14, 17, 28, 29] assessment. was one-half the dose used by other researchers [12, 13, 15, The dosing regimens for both clindamycin and primaquine 16, 18, 25, 27]. A dose of 15–30 mg of primaquine base were different from those used in other studies. The total clinda- was recommended at an international meeting [28] in 1992. mycin daily dose was 1,800 mg given as 450 mg every 6 hours Furthermore, the 15-mg dose is also recommended by The both intravenously and orally, because of the high bioavailabil- Sanford Guide to HIV/AIDS Therapy [30]; in addition, our

Table 2. Main baseline laboratory findings for patients with AIDS who received TMP-SMZ or Cm/Prq as therapy for PCP.

Median value (range)

Patients with PaO2 of £70 mm Hg All patients

Cm/Prq TMP-SMZ Cm/Prq TMP-SMZ Laboratory evaluation (n Å 23) (n Å 21) (n Å 45) (n Å 42)

CD4/ cell count (/mm3) 35 (7–208) 30 (4–462) 35 (3–265) 41 (4–462) Percent of CD4/ cells 4 (1–13) 4 (2–22) 5 (1–15) 6 (1–27)

PaO2* (mm Hg) 63 (50–70) 59 (50–70) 70 (50–99) 71 (50–99) LDH level (U/L) 484 (140–1,126) 376 (221–954) 338 (108–1,126) 379 (145–954) WBC count (1109/L) 4.6 (1.1–10) 4.7 (2.7–10.8) 4.8 (1.1–10) 4.7 (1.4–11.8) Hemoglobin level (g/L) 117 (92–147) 119 (81–151) 120 (92–147) 118 (81–152) Platelet count (1109/L) 213 (91–431) 216 (103–448) 221 (85–485) 220 (103–448) Albumin level (g/L) 32 (20–40) 30 (18–39) 32 (20–43) 33 (18–45)

NOTE. Cm/Prq Å clindamycin/primaquine; LDH Å lactate dehydrogenase; PCP Å Pneumocystis carinii pneumo- nia; TMP-SMZ Å trimethoprim-sulfamethoxazole. * Measured while patients were breathing room air.

/ 9c55$$se20 08-17-98 22:29:49 cidal UC: CID 528 Toma et al. CID 1998;27 (September)

Table 3. Treatment outcome for patients with AIDS who received Table 5. Major (grades 3 and 4) adverse events in patients with TMP-SMZ or Cm/Prq as therapy for PCP. AIDS who received TMP-SMZ or Cm/Prq as therapy for PCP.

Patients with PaO2 of No. of patients £70 mm Hg All patients

Patients with PaO2 of Outcome Cm/Prq TMP-SMZ Cm/Prq TMP-SMZ £70 mm Hg All patients

No. of patients 23 21 45 42 Adverse event or Cm/Prq* TMP-SMZ Cm/Prq TMP-SMZ No. (%) for whom therapy toxic effect (n Å 23) (n Å 21) (n Å 45) (n Å 42) was a success 17 (74) 16 (76) 34 (76) 33 (79) No. for whom therapy LFT elevation 0 1 0 3 failed 6 5 11 9 Hematotoxic effect 8 5 11 13 Death during therapy 1 1 1 2 Anemia 1 1 1 1 Downloaded from https://academic.oup.com/cid/article/27/3/524/280761 by guest on 25 September 2021 Death within 35 days 2 0 2 0 Leukopenia 6 4 9 11 Intubation 1 2 1 3 Neutropenia 1 2 3 5 Alternate therapy 1 2 4 4 Thrombocytopenia 1 0 1 1 Recurrence 1 0 3 0 Clinical event 1 3 3 5 Delirium 0 0 0 1 NOTE. Cm/Prq Å clindamycin/primaquine; PCP Å Pneumocystis carinii Hallucinations 0 0 0 1 pneumonia; TMP-SMZ Å trimethoprim-sulfamethoxazole. Neurotoxic effect 0 1 0 1 Nausea or vomiting 1 1 1 2 Diarrhea 0 0 1 0 Fever 0 0 1 1 experience suggests that primaquine retains its efficacy and Rash 0 1 0 1 may be better tolerated at daily doses of 15 mg [29]. Any toxic effect 9 10* 13 21† Despite the fact that 62% of patients had a prior AIDS- defining diagnosis, most participants in this trial had never NOTE. Cm/Prq Å clindamycin/primaquine; LFT Å liver function test; PCP Å Pneumocystis carinii pneumonia; TMP-SMZ Å trimethoprim-sulfa- received prophylaxis for PCP. This alarming phenomenon was methoxazole. also reported in the AIDS Clinical Trials Group (ACTG) study * P Å .57. † comparing three oral regimens for treatment of PCP [18]. More P Å .04. should be done to enhance the use of effective preventive strategies in addition to optimal therapy for HIV infection. manner. With Cm/Prq, there was a more rapid decrease in the The rates of success were similar among the two treatment dyspnea score by day 3 of therapy without the use of steroids, groups, and the results compare favorably with previously re- as we noted in a previous pilot trial [17]; among TMP-SMZ ported data [5, 6, 11–18, 31, 32]. The markers of severity recipients with mild PCP, there was greater steroid use in the (dyspnea score, PCP scores, and lactate dehydrogenase values) first 4 days of therapy. These results agree with those from the revealed improvement in both groups of patients in a similar ACTG 108 trial, where the conditions of patients receiving oral Cm/Prq apparently improved more rapidly, as indicated by assessment of quality of life at day 7 of therapy [18, 33]. Table 4. Summary of data on adverse events, rash, and use of Among all patients as well as the subgroup with mild disease, steroids for patients with AIDS who received TMP-SMZ or Cm/Prq there was a higher incidence of grades 3 and 4 adverse events as therapy for PCP. in TMP-SMZ recipients (P Å .04 and P Å .02, respectively), No. of patients but no statistical difference was found for patients with moder- ately severe PCP (P Å .57). The higher incidence of adverse Clinical parameter, patient group Cm/Prq TMP-SMZ P value events in TMP-SMZ recipients with mild PCP contrasts with that reported by Safrin et al. [18] and may be due to the lower Adverse events (grades 3 and 4) All patients 13 21 .04 dose of primaquine and the higher dose of TMP-SMZ that

Patients with PaO2, £70 mm Hg 9 10 .57 were used in our trial.

Patients with PaO2, ú70 mm Hg 4 11 .02 Rash was the most frequent clinical adverse event, as has Rash (all grades) been reported in all previous studies with these treatments [5, All patients 22 12 .07 6, 11–18, 31, 32]. In the report by Safrin et al. [18], the severity Patients with PaO , £70 mm Hg 7 5 .78 2 of rash was higher in the Cm/Prq group, whereas in our Patients with PaO2, ú70 mm Hg 15 7 .02 Steroid use study, the only severe (grade 3) rash occurred in a patient All patients 13 18 .18 receiving TMP-SMZ. It is possible that the primaquine dose Patients with PaO2, £70 mm Hg 12 12 .74 may increase the severity but not the incidence of rash in these Patients with PaO2, ú70 mm Hg 1 6 .04 patients. Since antihistamines [34] do not affect the incidence NOTE. Cm/Prq Å clindamycin/primaquine; PCP Å Pneumocystis carinii of rash due to Cm/Prq, we suspect that rash is primarily due pneumonia; TMP-SMZ Å trimethoprim-sulfamethoxazole. to primaquine’s metabolites, specifically carboxyprimaquine,

/ 9c55$$se20 08-17-98 22:29:49 cidal UC: CID CID 1998;27 (September) Treatment of AIDS-Related PCP 529 and its severity is probably dose-dependent [35]. Among pa- References tients with mild PCP, there was a significantly higher incidence 1. Montaner JSG, Le T, Hogg R, et al. The changing spectrum of AIDS of rashes in Cm/Prq recipients (P Å .02), but the incidence of index diseases in Canada. AIDS 1994;8:693–6. 2. Katz MH, Hessol NA, Buchbinder SP, Hirozawa A, O’Malley P, Holmberg TMP-SMZ-associated rash was lower than reported elsewhere SD. Temporal trends of opportunistic and malignancies in [5, 6, 31, 32, 36–38]. This finding may be due to the increased homosexual men with AIDS. J Infect Dis 1994;170:198–202. use of systemic corticosteroids among those patients [21, 38]. 3. Hoover DR, Saah AJ, Bacellar H, et al. Clinical manifestations of AIDS There was no severe diarrhea reported by patients with mod- in the era of Pneumocystis prophylaxis. N Engl J Med 1993;329: erately severe PCP in this study. Moreover, no pseudomembra- 1922–6. 4. Sepkowitz KA, Armstrong D. Treatment of opportunistic infections in nous colitis was documented. In other studies, Clostridium dif- AIDS. Lancet 1995;346:588–9. ficile colitis was described in a limited number of patients [16, 5. Hughes W, Leoung G, Kramer F, et al. Comparison of atovaquone (566 18, 27]. C80) with trimethoprim-sulfamethoxazole to treat Pneumocystis carinii

Methemoglobinemia has been observed during treatment of pneumonia in patients with AIDS. N Engl J Med 1993;328:1521–7. Downloaded from https://academic.oup.com/cid/article/27/3/524/280761 by guest on 25 September 2021 PCP with clindamycin in association with 30 mg of primaquine 6. Medina I, Mills J, Leoung G, et al. Oral therapy for Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome: a controlled base/d [12, 13, 15, 16, 18]. Although we have not yet encoun- trial of trimethoprim-sulfamethoxazole versus trimethoprim-dapsone. N tered a clinically relevant case of methemoglobinemia with the Engl J Med 1990;323:776–82. 15-mg daily dose of primaquine, we recommend caution and 7. Sattler FR, Frame P, Davis R, et al. Trimetrexate with leucovorin versus close monitoring. trimethoprim-sulfamethoxazole for moderate to severe episodes of In summary, our data demonstrate that Cm/Prq is a valuable Pneumocystis carinii pneumonia in patients with AIDS: a prospective, controlled, multicenter investigation of the AIDS Clinical Trials Group option for the treatment of mild and moderately severe AIDS- Protocol 029/031. J Infect Dis 1994;170:165–72. related PCP. This finding is in keeping with our previous expe- 8. Feinberg J, McDermott C, Nuter J. Trimetrexate (TMTX) salvage therapy rience when we showed that Cm/Prq could be used as salvage for PCP in AIDS patients with limited therapeutic options [abstract no therapy for patients with severe PCP [29]. Overall, therapeutic PoB 3297]. In: Program and abstracts of the 8th International Confer- success and the incidence of severe adverse events were compa- ence on AIDS (Amsterdam). Vol 2. Amsterdam: CONGREX Holland BV, 1992:B136. rable with those shown for TMP-SMZ therapy. For patients 9. Dohn MN, Weinberg WG, Torres RA, et al. Oral atovaquone compared with moderately severe PCP, the two regimens were similar in with intravenous pentamidine for Pneumocystis carinii pneumonia in terms of safety and efficacy. The incidence of rash among patients with AIDS. Ann Intern Med 1994;121:171–80. 10. Queener SF, Bartlett MS, Richardson JD, Durkin MM, Jay MA, Smith Cm/Prq recipients with mild disease (PaO2, ú70 mm Hg) was higher than that among TMP-SMZ recipients with mild disease; JW. Activity of clindamycin with primaquine against Pneumocystis carinii in vitro and in vivo. Antimicrob Agents Chemother 1988;32: however, the incidence of severe adverse events in Cm/Prq 807–13. recipients was lower, and those patients used less steroids. 11. Toma E, Fournier S, Poisson M, Morisset R, Phaneuf D, Vega C. Clinda- mycin with primaquine for Pneumocystis carinii pneumonia. 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University of Alberta, Edmonton, Alberta; Fred Aoki, Health Sci- 15. Noskin GA, Murphy RL, Black JR, Phair JP. Salvage therapy with clinda- ences Centre, Winnipeg, Manitoba; John Gill, South Alberta HIV mycin/primaquine for Pneumocystis carinii pneumonia. Clin Infect Dis Clinic, Calgary, Alberta; Christian Sinave, Memorial University, 1992;14:183–8. St. John’s, Newfoundland (currently at the University of Sher- 16. Black JR, Feinberg J, Murphy RL, et al. Clindamycin and primaquine brooke, Sherbrooke, Quebec); Lyne Johnston, Victoria General therapy for mild-to-moderate episodes of Pneumocystic carinii pneumo- Hospital, Halifax, Nova Scotia; and William Cameron, Ottawa nia in patients with AIDS: AIDS Clinical Trials Group 044. Clin Infect General Hospital, Ottawa, Ontario, Canada. Dis 1994;18:905–13. 17. Toma E, Fournier S, Dumont M, Bolduc P, Deschamps H. Clindamycin/ primaquine vs. trimethoprim-sulfamethoxazole as primary therapy for Pneumocystis carinii pneumonia in AIDS: a randomized, double-blind, Acknowledgments pilot trial. Clin Infect Dis 1993;17:178–84. 18. Safrin S, Finkelstein DM, Feinberg J, et al. Comparison of three regimens The authors are indebted to the participating patients and their for treatment of mild to moderate Pneumocystis carinii pneumonia in patients with AIDS. Ann Intern Med 1996;124:792–802. treating physicians, research nurses, and pharmacists at local sites. 19. The National Institutes of Health–University of California Expert Panel They thank Dr. Julio Montaner for his helpful study and data for Corticosteroids as Adjunctive Therapy for . analysis suggestions and for a careful review of the manuscript, Consensus statement on the use of corticosteroids as adjunctive therapy and Dr. Donald Zarowny for his continuous support and help for Pneumocystis pneumonia in the acquired immunodeficiency syn- during this trial. drome. N Engl J Med 1990;323:1500–4.

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