A Meta-analysis of Salvage Therapy for Pneumocystis carinii Pneumonia | Fungal Infections | JAMA Internal Medicine | JAMA Network
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Table 1. 
Clinical Drug Studies and Case Reports of Salvage Therapy for Pneumocystis carinii Pneumonia*
Clinical Drug Studies and Case Reports of Salvage Therapy for Pneumocystis carinii Pneumonia*
Table 2. 
Efficacies of Salvage Drug Regimens Used in 497 Patients With Pneumocystis carinii Pneumonia*
Efficacies of Salvage Drug Regimens Used in 497 Patients With Pneumocystis carinii Pneumonia*
1.
Masur  H Prevention and treatment of Pneumocystis pneumonia.  N Engl J Med. 1992;3271853- 1860Google ScholarCrossref
2.
Klein  NCDuncanson  FPLenox  TH  et al.  Trimethoprim-sulfamethoxazole vs pentamidine for Pneumocystis carinii pneumonia in AIDS patients: results of a large prospective randomized treatment trial.  AIDS. 1992;6301- 305Google ScholarCrossref
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Fishman  JA Treatment of infection due to Pneumocystis carinii Antimicrob Agents Chemother. 1998;421309- 1314Google Scholar
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Glatt  AEChirgwin  K Pneumocystis carinii pneumonia in human immunodeficiency virus-infected patients.  Arch Intern Med. 1990;150271- 279Google ScholarCrossref
5.
Wofsy  CB Use of trimethoprim-sulfamethoxazole in the treatment of Pneumocystis carinii pneumonitis in patients with acquired immunodeficiency syndrome.  Rev Infect Dis. 1987;9 ((suppl)) S184- S191Google ScholarCrossref
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Not Available, Treatment for Pneumocystis carinii pneumonia.  Med Lett Drug Ther. 1987;29103- 104Google Scholar
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Hughes  WTFeldman  SChaudhury  S  et al.  Comparison of trimethoprim-sulfamethoxazole (TMP-SMZ) and pentamidine (PNT) in the treatment of Pneumocystis carinii pneumonia (PCP).  Pediatr Res. 1976;10399- 403Google Scholar
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Hughes  WTFeldman  SChaudhary  SC  et al.  Comparison of pentamidine isethionate and trimethoprim-sulfamethoxazole in the treatment of Pneumocystis carinii pneumonia.  J Pediatr. 1978;92285- 291Google ScholarCrossref
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Winston  DJLau  WKGale  RPYoung  LS Trimethoprim-sulfamethoxazole for the treatment of Pneumocystis carinii pneumonia.  Ann Intern Med. 1980;92762- 769Google ScholarCrossref
10.
Mitsuyasu  RTCorwin  HLHarris  AA  et al.  Failure of trimethoprim-sulfamethoxazole in the therapy of recurrent Pneumocystis carinii pneumonia.  Am Rev Respir Dis. 1982;125762- 765Google Scholar
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Follansbee  SEBusch  DFWofsy  CB  et al.  An outbreak of Pneumocystis carinii pneumonia in homosexual men.  Ann Intern Med. 1982;96705- 713Google ScholarCrossref
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Golden  JASjoerdsma  ASanti  DV Pneumocystis carinii pneumonia treated with α-difluoromethylornithine.  West J Med. 1984;141613- 623Google Scholar
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Siegel  SEWolff  LJBaehner  RLHammond  D Treatment of Pneumocystis carinii pneumonitis.  AJDC. 1984;1381051- 1054Google Scholar
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Murray  JFGaray  SMHopewell  PC  et al.  Pulmonary complications of the acquired immunodeficiency syndrome—an update: report of the Second National Heart, Lung, and Blood Institute Workshop.  Am Rev Respir Dis. 1987;32504- 509Google Scholar
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Small  CBHarris  CAFriedland  GHKlein  RS The treatment of Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome.  Arch Intern Med. 1995;145837- 840Google ScholarCrossref
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Wharton  JMColeman  DLWofsy  CB  et al.  Trimethoprim-sulfamethoxazole or pentamidine for Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome.  Ann Intern Med. 1986;10537- 44Google ScholarCrossref
18.
Montgomery  ABDebs  RJLuce  JM  et al.  Aerosolized pentamidine as sole therapy for Pneumocystis carinii pneumonia in patients with acquired immune deficiency syndrome.  Lancet. 1987;2480- 483Google ScholarCrossref
19.
Allegra  CJChabner  BATuazon  CU  et al.  Trimetrexate for the treatment of Pneumocystis carinii pneumonia in patients with AIDS.  N Engl J Med. 1987;317978- 985Google ScholarCrossref
20.
Franson  TRKauffman  HMAdams  MB  et al.  Cyclosporine therapy and refractory Pneumocystis carinii pneumonia.  Arch Surg. 1987;1221034- 1036Google ScholarCrossref
21.
Gilman  TMPaulson  YJBoylen  YJ  et al.  Pentamidine treatment of Pneumocystis carinii pneumonia in AIDS.  JAMA. 1986;2562197- 2198Google ScholarCrossref
22.
Mills  JLeoung  GMedina  I  et al.  Dapsone treatment of Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome.  Antimicrob Agents Chemother. 1988;321057- 1060Google ScholarCrossref
23.
Efferen  LSNadarajah  DPalat  DS Survival following mechanical ventilation for Pneumocystis carinii pneumonia in patients with the acquired immunodeficiency syndrome: a different perspective.  Am J Med. 1989;87401- 404Google ScholarCrossref
24.
Toma  EFournier  SPoisson  M  et al.  Clindamycin with primaquine for Pneumocystis carinii pneumonia.  Lancet. 1989;11046- 1048Google ScholarCrossref
25.
Medina  IMills  JLeoung  G  et al.  Oral therapy for Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome: a controlled trial of trimethoprim-sulfamethoxazole vs trimethoprim-dapsone.  N Engl J Med. 1990;323776- 782Google ScholarCrossref
26.
Hoo  GWSMohsenifar  ZMeyers  RD Inhaled or intravenous pentamidine therapy for Pneumocystis carinii pneumonia in AIDS: a randomized trial.  Ann Intern Med. 1990;113195- 202Google ScholarCrossref
27.
Kay  RDuBois  RE Clindamycin/primaquine therapy and secondary prophylaxis against Pneumocystis carinii pneumonia in patients with AIDS.  South Med J. 1990;83403- 404Google ScholarCrossref
28.
Smith  DDavies  SNelson  M  et al.  Pneumocystis carinii pneumonia treated with eflornithine in AIDS patients resistant to conventional therapy.  AIDS. 1990;41019- 1021Google ScholarCrossref
29.
Feinberg  JMcDermott  CNutter  J Trimetrexate (TMTX) salvage therapy for PCP in AIDS patients with limited therapeutic options.  Program and abstracts of the Fifth International Conference on AIDS 1992 Amsterdam, the NetherlandsAbstract PoB 3297
30.
Noskin  GAMurphy  RlBlack  JR Salvage therapy with clindamycin/primaquine for Pneumocystis carinii pneumonia.  Clin Infect Dis. 1992;14183- 188Google ScholarCrossref
31.
Paulson  YJGilman  TMHeseltine  PNRSharma  OPBoylen  CT Eflornithine treatment of refractory Pneumocystis carinii pneumonia in patients with AIDS.  Chest. 1992;10167- 74Google ScholarCrossref
32.
Dohn  MNWeinberg  WGTorres  RA  et al.  Oral atovaquone compared with intravenous pentamidine for Pneumocystis carinii pneumonia in patients with AIDS.  Ann Intern Med. 1994;121174- 180Google ScholarCrossref
33.
Sattler  FRAllegra  CJVerdegen  TD  et al.  Trimetrexate-leukovorin dosage evaluation study for treatment of Pneumocystis carinii pneumonia.  J Infect Dis. 1990;16191- 96Google ScholarCrossref
34.
Sattler  FRFrame  PDavis  RNichols  LShelton  B Trimetrexate with leukovorin versus trimethoprim-sulfamethoxazole for moderate-to-severe episodes of Pneumocystis carinii pneumonia in patients with AIDS: a prospective, controlled multicenter investigation of the AIDS Clinical Trials Group Protocol 029/031.  J Infect Dis. 1994;170165- 172Google ScholarCrossref
35.
Hughes  WTLeoung  GKramer  F  et al.  Comparison of atovaquone (566C80) with trimethoprim-sulfamethoxazole to treat Pneumocystis carinii pneumonia in patients with AIDS.  N Engl J Med. 1993;3281521- 1527Google ScholarCrossref
36.
Not Available, Atovaquone for Pneumocystis carinii pneumonia.  Med Lett Drug Ther. 1993;3528- 29Google Scholar
37.
Falloon  JKovacs  JHughes  W  et al.  A preliminary evaluation of 566C80 for the treatment of Pneumocystis carinii pneumonia in patients with the acquired immunodeficiency syndrome.  N Engl J Med. 1991;3251534- 1538Google ScholarCrossref
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Ruf  BPohle  HD Clindamycin/primaquine for Pneumocystis carinii pneumonia.  Lancet. 1989;2626- 627Google ScholarCrossref
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Ruf  BRohde  IPohle  HD Efficacy of clindamycin/primaquine versus trimethoprim-sulfamethoxazole in primary treatment of Pneumocystis carinii pneumonia.  Eur J Clin Microbiol Infect Dis. 1991;10207- 210Google ScholarCrossref
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Toma  E Clindamycin/primaquine for treatment of Pneumocystis carinii pneumonia in patients with AIDS.  Eur J Clin Microbiol Infect Dis. 1991;10210- 213Google ScholarCrossref
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Toma  EFournier  SDumont  MBolduc  PDeschamps  H Clindamycin/primaquine versus trimethoprim-sulfamethoxazole as primary therapy for Pneumocystis carinii pneumonia in AIDS: a randomized, double-blind pilot trial.  Clin Infect Dis. 1993;17178- 184Google ScholarCrossref
42.
Black  JRFeinberg  JMurphy  RL  et al.  Clindamycin and primaquine as primary treatment for mild and moderately severe Pneumocystis carinii pneumonia in patients with AIDS.  Eur J Clin Microbiol Infect Dis. 1991;10204- 207Google ScholarCrossref
43.
Black  JRFeinberg  JMurphy  RL  et al.  Clindamycin and primaquine therapy for mild-to-moderate episodes of Pneumocystis carinii pneumonia in patients with AIDS: AIDS Clinical Trials Group 044.  Clin Infect Dis. 1994;18905- 913Google ScholarCrossref
44.
Safrin  SFinkelstein  DMFeinberg  J  et al.  Comparison of three regimens for treatment of mild to moderate Pneumocystis carinii pneumonia in patients with AIDS: a double-blind, randomized trial of oral trimethoprim-sulfamethoxazole, dapsone-trimethoprim, and clindamycin-primaquine.  Ann Intern Med. 1996;124792- 802Google ScholarCrossref
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Toma  EThorne  ASinger  J  et al. CTN-PCP Study Group, Clindamycin with primaquine vs. trimethoprim-sulfamethoxazole therapy for mild and moderately severe Pneumocystis carinii pneumonia in patients with AIDS: a multicenter, double-blind, randomized trial (CTN 004).  Clin Infect Dis. 1998;27524- 530Google ScholarCrossref
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Shelhamer  JHToews  GBMasur  HHenderson  DK Respiratory disease in the immunosuppressed patient.  Ann Intern Med. 1992;117415- 431Google ScholarCrossref
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Meduri  GUStein  DS Pulmonary manifestations of acquired immunodeficiency syndrome.  Clin Infect Dis. 1992;1498- 113Google ScholarCrossref
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Baughman  RPDohn  MNFrame  PT The continuing utility of bronchoalveolar lavage to diagnose opportunistic infection in AIDS patients.  Am J Med. 1994;97515- 522Google ScholarCrossref
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Orlovic  DKularatne  RFerraz  VSmego Jr  RA Dual pulmonary infection with Mycobacterium tuberculosis and Pneumocystis carinii in HIV-infected patients.  Clin Infect Dis. 2001;32289- 294Google ScholarCrossref
Original Investigation
June 25, 2001

A Meta-analysis of Salvage Therapy for Pneumocystis carinii Pneumonia

Author Affiliations

From the Department of Clinical Microbiology and Infectious Diseases, University of the Witwatersrand/South African Institute for Medical Research, and the Sizwe Tropical Diseases Hospital, Johannesburg, South Africa.

Arch Intern Med. 2001;161(12):1529-1533. doi:10.1001/archinte.161.12.1529
Abstract

Objective  To determine the relative efficacies of alternative antipneumocystis agents in human immunodeficiency virus (HIV)–infected patients with Pneumocystis carinii pneumonia unresponsive to primary drug treatment with a combination product of trimethoprim and sulfamethoxazole or parenteral pentamidine.

Methods  Meta-analysis of 27 published clinical drug trials, case series, and case reports involving P carinii pneumonia. Data extracted included underlying disease, primary antipneumocystis treatment, days of failed primary treatment, salvage regimen, use of systemic corticosteroids and antiretroviral drugs, and clinical outcome.

Results  In 497 patients with microbiologically confirmed P carinii pneumonia (456 with HIV or acquired immunodeficiency syndrome), initial antipneumocystis treatment failed and they therefore required alternative drug therapy. Failed regimens included trimethoprim-sulfamethoxazole (160 patients), intravenous pentamidine (63 patients), trimethoprim-sulfamethoxazole and/or pentamidine (258 patients), aerosolized pentamidine (6 patients), atovaquone (3 patients), dapsone (3 patients), a combination product of trimethoprim and dapsone (2 patients), and trimethoprim-sulfamethoxazole followed by a combination of clindamycin and primaquine phosphate (2 patients). Efficacies of salvage regimens were as follows: clindamycin-primaquine (42 to 44 [88%-92%] of 48 patients; P<10−8), atovaquone (4 [80%] of 5), eflornithine hydrochloride (40 [57%] of 70; P<.01), trimethoprim-sulfamethoxazole (27 [53%] of 51; P<.08), pentamidine (64 [39%] of 164), and trimetrexate (47 [30%] of 159).

Conclusion  The combination of clindamycin plus primaquine appears to be the most effective alternative treatment for patients with P carinii pneumonia who are unresponsive to conventional antipneumocystis agents.

FOR PATIENTS with Pneumocystis carinii pneumonia, a combination product of trimethoprim and sulfamethoxazole and parenteral pentamidine are first-line therapeutic agents and have been shown to have comparable clinical efficacy.1-4 Trimethoprim-sulfamethoxazole is considered the drug of choice because of its excellent tissue penetration and oral bioavailability, more rapid in vivo activity, and relatively lower cost and wide availability. Intolerance to both trimethoprim-sulfamethoxazole and pentamidine is not uncommon, especially in patients with human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS), and may require a change in therapy in up to 50% to 60% of treated patients.3,5 For these individuals, substitution of pentamidine for trimethoprim-sulfamethoxazole or vice versa is generally effective.2,6 However, there is a paucity of published data on the efficacy of "salvage" therapy for patients unresponsive to conventional treatment with trimethoprim-sulfamethoxazole or pentamidine. Agents available for treating first-episode and unresponsive P carinii pneumonia include trimetrexate, atovaquone, and a combination of clindamycin and primaquine phosphate, but no comparative trials using these drugs as salvage regimens have been conducted. We conducted a literature review and meta-analysis of drug treatment studies and case series or reports to determine the relative efficacies of alternative antipneumocystis agents in patients with unresponsive P carinii pneumonia.

Patients and methods

From January 1975 through August 1999, a comprehensive analysis of the English-language literature was conducted on the basis of a MEDLINE computerized search, perusal of Index Medicus and Current Contents, and review of bibliographies of articles and major infectious diseases textbooks to identify clinical trials or case series or reports in which alternative agents were used for patients with P carinii pneumonia and conventional treatment failure. Key words included P carinii, HIV/AIDS, salvage therapy, trimethoprim-sulfamethoxazole, pentamidine, trimetrexate, atovaquone, and clindamycin-primaquine. Twenty-seven clinical studies were identified that reported sufficient details of drug treatment failure and alternative therapy for P carinii pneumonia, including clinical outcome, and were included in this review. Only cases of pneumonia that were microbiologically confirmed by lung biopsy, bronchoalveolar lavage, or sputum smear to be due to P carinii infection were included in the analysis. Data extracted included underlying disease, primary antipneumocystis treatment, days of failed primary treatment, salvage regimen, use of systemic corticosteroids and antiretroviral drugs, and clinical outcome.

Failure of primary antipneumocystis treatment was generally defined as clinical deterioration occurring during the first 4 to 5 days of therapy or lack of improvement in the patient's condition after 7 or more days of treatment. We included patients from 3 studies in which patients were switched to alternate drug therapy after only 3 or more days of treatment because of the stringent criteria that were used: (1) progressive clinical deterioration as demonstrated by the inability to maintain a stable arterial PaO2 despite an increase in the fraction of inspired oxygen (FIO2), and (2) progressive deterioration of vital signs (pulse rate, blood pressure, and respiratory rate) with a requirement for increased FIO2. Four studies (with a total of 51 patients) were also included in the analysis even though a precise duration of initial antipneumocystis treatment was not given; these included a National Institutes of Health study (37 patients) and a Centers for Disease Control multicenter trial (14 patients).

In the studies reviewed, a positive response to salvage treatment was variably defined but included 1 of the following: (1) amelioration or resolution of baseline signs and symptoms (eg, fever, cough, dyspnea, pulse, and respiratory rate), chest radiograph, and arterial blood gases; (2) sustained clinical improvement for at least 2 to 4 weeks after cessation of antipneumocystis therapy with no alternate treatment given during that time; (3) patient discharged alive from the hospital; or (4) patient alive 30 days after confirmation of the diagnosis. Salvage therapy was considered a failure when the above criteria for positive response were not met.

Systemic corticosteroids were not administered with salvage agents for most study patients. Six studies indicated that steroids had been used for some patients (a maximum of 38 patients, or 7.6% of the study cohort) with moderately severe P carinii pneumonia, usually at the discretion of the attending physician, but few details were given. There were no statistically significant differences in the incidences of adjuvant corticosteroid or antiretroviral drug use between the salvage regimens examined.

Statistical interpretation of data was performed using a computer software package (Epi Info; Centers for Disease Control and Prevention, Atlanta, Ga) and the χ2 test with Yates correction factor or Fisher exact test, as appropriate. For all tests, P<.05 was considered statistically significant. Confidence intervals were determined assuming a binomial distribution of values.

Results

Clinical and treatment features for patients treated with salvage drug regimens for P carinii pneumonia are shown in Table 1. Four hundred ninety-seven patients were identified in our systematic literature review and included in the data analysis. Most patients were adults (467 of 497 patients). In the study population, HIV/AIDS was the major underlying disease, accounting for 92% of cases treated with salvage therapy. Drugs used in failed treatment regimens included trimethoprim-sulfamethoxazole (160 patients), parenteral pentamidine (63 patients), inhaled pentamidine (6 patients), atovaquone (3 patients), dapsone (3 patients), a combination product of trimethoprim and dapsone (2 patients), and trimethoprim-sulfamethoxazole followed by clindamycin-primaquine (2 patients). For 258 patients, failure was reported for conventional therapy (ie, trimethoprim-sulfamethoxazole and/or pentamidine; when patients received both drugs, they were generally given sequentially). Duration of failed primary therapy was 3 days or more (33 patients), 4 days or more (20 patients), 6 days (25 patients), or 5 to 7 days or more (358 patients); the length of failed treatment was not stated for 61 patients. Salvage treatment included trimetrexate (159 patients), pentamidine (164 patients), eflornithine hydrochloride (70 patients), clindamycin-primaquine (48 patients), trimethoprim-sulfamethoxazole (51 patients), and atovaquone (5 patients). Comparable efficacies of these salvage regimens are shown in Table 2.

Comment

For HIV-related P carinii pneumonia, treatment with trimethoprim-sulfamethoxazole or parenteral pentamidine is effective in about 75% to 95% of cases1-3,5,6,15; improvement generally occurs within 4 to 8 days of treatment, and some patients appear to respond within 24 hours. However, the optimal clinical approach for patients whose condition does not improve or continues to deteriorate despite 4 to 10 days of primary drug treatment is not certain. Switching therapy from trimethoprim-sulfamethoxazole to pentamidine or vice versa or to agents such as trimetrexate, atovaquone, or clindamycin-primaquine is typically the recommended strategy,1,3 but there are few useful data available that detail the likelihood of success with these substitutions.

In most settings, trimethoprim-sulfamethoxazole is the agent of first choice for P carinii pneumonia, and when intolerance or unresponsiveness to treatment occurs, pentamidine is usually the alternative drug used. For many years it has been observed that patients with P carinii pneumonia who are switched to pentamidine because of adverse effects due to trimethoprim-sulfamethoxazole, such as fever, rash, hepatitis, leukopenia, or azotemia, respond much better than when pentamidine is used because of clinical disease refractory to trimethoprim-sulfamethoxazole.2,5,6 In a large prospective comparative trial of trimethoprim-sulfamethoxazole vs pentamidine for P carinii pneumonia, Klein and colleagues2 showed that survival rates for persons requiring a change in therapy (to either drug) because of failure to respond were 46% for the trimethoprim-sulfamethoxazole group and 56% for the pentamidine group. When a change in therapy was made because of toxic effects, survival rates were 97% and 94% for these 2 drugs, respectively. In the present meta-analysis, pentamidine was successful in only 37% of patients in whom trimethoprim-sulfamethoxazole treatment had failed, and conversely trimethoprim-sulfamethoxazole appeared little more effective (53%) when used because of unresponsiveness to pentamidine. Eflornithine, an antiprotozoan drug that reduces polyamine synthesis via irreversible inhibition of ornithine decarboxylase, has been investigated during the past 15 years as a possible therapeutic option for primary P carinii pneumonia and for treatment failures with first-line agents.12,20,21,28,30 The cumulative data summarized herein suggest that eflornithine has efficacy (40 [57%] of 70 patients; P<.01) as a salvage drug for unresponsive P carinii pneumonia.

Trimetrexate is a lipid-soluble analogue of methotrexate and a much more potent inhibitor of protozoan dihydrofolate reductase than either trimethoprim or pyrimethamine.19,32-34 The drug is currently available only in intravenous form and is administered in combination with leukovorin (folinic acid) to prevent adverse hematologic effects. In comparison with trimethoprim-sulfamethoxazole as primary treatment for moderately severe P carinii pneumonia, trimetrexate was better tolerated than trimethoprim-sulfamethoxazole but was associated with a lower response rate and a higher incidence of relapse than trimethoprim-sulfamethoxazole therapy.32-34 In this review, trimetrexate was effective in only 30% of trimethoprim-sulfamethoxazole and pentamidine treatment failures.19 Trimetrexate does not appear to be a useful salvage agent for patients with HIV-related P carinii pneumonia that is clinically resistant to conventional therapy.

Atovaquone is a 1,4-hydroxynaphthoquinone that has clinical activity against P carinii, and it is a useful oral therapeutic option for patients with mild to moderate P carinii pneumonia. Like trimetrexate, atovaquone has been found to be less effective than trimethoprim-sulfamethoxazole for the initial treatment of P carinii pneumonia, but it has fewer treatment-limiting adverse effects.35-37 The drug offers an alternative for persons who cannot tolerate trimethoprim-sulfamethoxazole, but there is insufficient experience with atovaquone as a salvage therapy agent to allow practical comments about its use in cases of unresponsive P carinii pneumonia.

Of all the salvage agents examined, the combination of clindamycin-primaquine was the most successful regimen for patients in whom conventional antipneumocystis treatment failed. Approximately 90% (P<10−8) of patients with P carinii pneumonia refractory to trimethoprim-sulfamethoxazole or pentamidine or both had a good clinical response to clindamycin-primaquine. This dual combination is effective as primary treatment of mild to moderately severe AIDS-related P carinii pneumonia and perhaps has fewer adverse effects compared with trimethoprim-sulfamethoxazole.38-45 The reason(s) for the significantly better response rate for clindamycin-primaquine compared with other salvage regimens is not clear; variables such as the duration of failed primary treatment, severity of pneumonia or clinical presentation, or type of underlying disease do not appear to account for these differences. It is possible that combination treatment provides a synergistic antipneumocystis effect not afforded by monotherapy, although the present difficulty in culturing this organism in vitro precludes susceptibility testing and proof of such a hypothesis. The most serious toxic effects of clindamycin-primaquine are hematologic (eg, neutropenia, anemia, thrombocytopenia, and methemoglobinemia).44 The optimal role for clindamycin-primaquine may, in fact, be as a salvage regimen for patients unresponsive to or unable to tolerate trimethoprim-sulfamethoxazole or pentamidine.

It may be very difficult to determine whether a lack of response for an individual patient with P carinii pneumonia to conventional treatment is due to drug resistance, immunologic dysfunction, concurrent pulmonary infection, or another factor. Sequencing of resistance genes in P carinii can identify a molecular basis for trimethoprim-sulfamethoxazole resistance, but this technology is not widely available commercially and remains largely a research tool. Although there are some patients who do better when taking one antipneumocystis agent compared with another, it is much more common to recognize a second process (eg, concurrent pulmonary infection, tumor, allergy, acute respiratory distress syndrome) as a cause for unresponsiveness to treatment.14,46-48 Bronchoscopic studies of unresolving HIV-related pneumonia have documented a secondary pulmonary infection in 8.9% to 39% of cases.46,49,50 Concurrent pathogens may include viruses (especially cytomegalovirus), mycobacteria, fungi, and bacteria.46,49,50 Noninfectious pathologic conditions such as Kaposi sarcoma or non-Hodgkin lymphoma may also occur concurrently with P carinii pneumonia. Accordingly, bronchoalveolar lavage with or without lung biopsy should be strongly considered for any patient with presumptive or documented P carinii pneumonia who is not responding to antipneumocystis treatment to detect alternative or coexisting lung pathologic conditions.46-50 When salvage therapy is indicated, clindamycin-primaquine appears to be the most effective alternative form of drug therapy.

Accepted for publication December 6, 2000.

Corresponding author: Raymond A. Smego, Jr, MD, MPH, DTM&H, Department of Medicine, The Aga Khan University Medical College, Stadium Road, PO Box 3500, Karachi 74800, Pakistan.

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Wofsy  CB Use of trimethoprim-sulfamethoxazole in the treatment of Pneumocystis carinii pneumonitis in patients with acquired immunodeficiency syndrome.  Rev Infect Dis. 1987;9 ((suppl)) S184- S191Google ScholarCrossref
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Hughes  WTFeldman  SChaudhury  S  et al.  Comparison of trimethoprim-sulfamethoxazole (TMP-SMZ) and pentamidine (PNT) in the treatment of Pneumocystis carinii pneumonia (PCP).  Pediatr Res. 1976;10399- 403Google Scholar
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