A Meta-Analysis of Salvage Therapy for Pneumocystis Carinii Pneumonia

ORIGINAL INVESTIGATION A Meta-analysis of Salvage Therapy for Pneumocystis carinii Pneumonia

Raymond A. Smego, Jr, MD, MPH, DTM&H; Shashi Nagar, BSc; Bonnie Maloba, MBBCh; Mirjana Popara, MBBCh

Objective: To determine the relative efficacies of alter- (63 patients), trimethoprim-sulfamethoxazole and/or native antipneumocystis agents in human immunodefi- pentamidine (258 patients), aerosolized pentamidine (6 ciency virus (HIV)–infected patients with Pneumocystis patients), atovaquone (3 patients), dapsone (3 pa- carinii pneumonia unresponsive to primary drug treat- tients), a combination product of trimethoprim and dap- ment with a combination product of trimethoprim and sone (2 patients), and trimethoprim-sulfamethoxazole fol- sulfamethoxazole or parenteral pentamidine. lowed by a combination of clindamycin and primaquine phosphate (2 patients). Efficacies of salvage regimens were Methods: Meta-analysis of 27 published clinical drug tri- as follows: clindamycin-primaquine (42 to 44 [88%- als, case series, and case reports involving P carinii pneu- 92%] of 48 patients; PϽ10−8), atovaquone (4 [80%] of monia. Data extracted included underlying disease, pri- 5), eflornithine hydrochloride (40 [57%] of 70; PϽ.01), mary antipneumocystis treatment, days of failed primary trimethoprim-sulfamethoxazole (27 [53%] of 51; PϽ.08), treatment, salvage regimen, use of systemic corticoste- pentamidine (64 [39%] of 164), and trimetrexate (47 roids and antiretroviral drugs, and clinical outcome. [30%] of 159).

Results: In 497 patients with microbiologically con- Conclusion: The combination of clindamycin plus pri- firmed P carinii pneumonia (456 with HIV or acquired maquine appears to be the most effective alternative treat- immunodeficiency syndrome), initial antipneumocys- ment for patients with P carinii pneumonia who are un- tis treatment failed and they therefore required alterna- responsive to conventional antipneumocystis agents. tive drug therapy. Failed regimens included trimethoprim- sulfamethoxazole (160 patients), intravenous pentamidine Arch Intern Med. 2001;161:1529-1533

OR PATIENTS with Pneumo- efficacy of “salvage” therapy for patients cystis carinii pneumonia, a unresponsive to conventional treatment combination product of tri- with trimethoprim-sulfamethoxazole or methoprim and sulfa- pentamidine. Agents available for treat- methoxazole and paren- ing first-episode and unresponsive P ca- teralF pentamidine are first-line therapeutic rinii pneumonia include trimetrexate, agents and have been shown to have com- atovaquone, and a combination of clinda- parable clinical efficacy.1-4 Trimethoprim- mycin and primaquine phosphate, but no sulfamethoxazole is considered the drug comparative trials using these drugs as sal- of choice because of its excellent tissue vage regimens have been conducted. We penetration and oral bioavailability, more conducted a literature review and meta- rapid in vivo activity, and relatively lower analysis of drug treatment studies and case cost and wide availability. Intolerance to series or reports to determine the relative both trimethoprim-sulfamethoxazole and efficacies of alternative antipneumocys- pentamidine is not uncommon, espe- tis agents in patients with unresponsive cially in patients with human immunode- P carinii pneumonia. ficiency virus/acquired immunodefi- From the Department of ciency syndrome (HIV/AIDS), and may RESULTS Clinical Microbiology and require a change in therapy in up to 50% Infectious Diseases, University 3,5 of the Witwatersrand/South to 60% of treated patients. For these in- Clinical and treatment features for pa- African Institute for Medical dividuals, substitution of pentamidine for tients treated with salvage drug regimens Research, and the Sizwe trimethoprim-sulfamethoxazole or vice for P carinii pneumonia are shown in Tropical Diseases Hospital, versa is generally effective.2,6 However, Table 1. Four hundred ninety-seven pa- Johannesburg, South Africa. there is a paucity of published data on the tients were identified in our systematic lit-

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Downloaded From: https://jamanetwork.com/ on 10/01/2021 PATIENTS AND METHODS 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 pre- From January 1975 through August 1999, a comprehen- cise duration of initial antipneumocystis treatment was not sive analysis of the English-language literature was con- given; these included a National Institutes of Health study ducted on the basis of a MEDLINE computerized search, pe- (37 patients) and a Centers for Disease Control multi- rusal of Index Medicus and Current Contents, and review of center trial (14 patients). bibliographies of articles and major infectious diseases text- In the studies reviewed, a positive response to sal- books to identify clinical trials or case series or reports in vage treatment was variably defined but included 1 of the which alternative agents were used for patients with P cari- following: (1) amelioration or resolution of baseline signs nii pneumonia and conventional treatment failure. Key words and symptoms (eg, fever, cough, dyspnea, pulse, and res- included P carinii, HIV/AIDS, salvage therapy, trimethoprim- piratory rate), chest radiograph, and arterial blood gases; sulfamethoxazole, pentamidine, trimetrexate, atovaquone, and (2) sustained clinical improvement for at least 2 to 4 weeks clindamycin-primaquine. Twenty-seven clinical studies were after cessation of antipneumocystis therapy with no alter- identified that reported sufficient details of drug treatment nate treatment given during that time; (3) patient dis- failure and alternative therapy for P carinii pneumonia, in- charged alive from the hospital; or (4) patient alive 30 days cluding clinical outcome, and were included in this review. after confirmation of the diagnosis. Salvage therapy was con- Only cases of pneumonia that were microbiologically considered a failure when the above criteria for positive re- firmed by lung biopsy, bronchoalveolar lavage, or sputum sponse were not met. smear to be due to P carinii infection were included in the Systemic corticosteroids were not administered with analysis. Data extracted included underlying disease, pri- salvage agents for most study patients. Six studies indi- mary antipneumocystis treatment, days of failed primary treat- cated that steroids had been used for some patients (a maxi- ment, salvage regimen, use of systemic corticosteroids and mum of 38 patients, or 7.6% of the study cohort) with mod- antiretroviral drugs, and clinical outcome. erately severe P carinii pneumonia, usually at the discretion Failure of primary antipneumocystis treatment was of the attending physician, but few details were given. There generally defined as clinical deterioration occurring dur- were no statistically significant differences in the inci- ing the first 4 to 5 days of therapy or lack of improvement dences of adjuvant corticosteroid or antiretroviral drug use in the patient’s condition after 7 or more days of treat- between the salvage regimens examined. ment. We included patients from 3 studies in which pa- Statistical interpretation of data was performed using tients were switched to alternate drug therapy after only 3 a computer software package (Epi Info; Centers for Dis- or more days of treatment because of the stringent criteria ease Control and Prevention, Atlanta, Ga) and the ␹2 test that were used: (1) progressive clinical deterioration as dem- with Yates correction factor or Fisher exact test, as appro- onstrated by the inability to maintain a stable arterial PaO2 priate. For all tests, PϽ.05 was considered statistically sig- despite an increase in the fraction of inspired oxygen (FIO2), nificant. Confidence intervals were determined assuming and (2) progressive deterioration of vital signs (pulse rate, a binomial distribution of values.

erature review and included in the data analysis. Most COMMENT 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 For HIV-related P carinii pneumonia, treatment with tri- therapy. Drugs used in failed treatment regimens in- methoprim-sulfamethoxazole or parenteral pentami- cluded trimethoprim-sulfamethoxazole (160 patients), dine is effective in about 75% to 95% of cases1-3,5,6,15; im- parenteral pentamidine (63 patients), inhaled pentami- provement generally occurs within 4 to 8 days of dine (6 patients), atovaquone (3 patients), dapsone (3 treatment, and some patients appear to respond within patients), a combination product of trimethoprim and dap- 24 hours. However, the optimal clinical approach for pa- sone (2 patients), and trimethoprim-sulfamethoxazole tients whose condition does not improve or continues followed by clindamycin-primaquine (2 patients). For to deteriorate despite 4 to 10 days of primary drug treat- 258 patients, failure was reported for conventional therapy ment is not certain. Switching therapy from trimethoprim- (ie, trimethoprim-sulfamethoxazole and/or pentami- sulfamethoxazole to pentamidine or vice versa or to agents dine; when patients received both drugs, they were gen- such as trimetrexate, atovaquone, or clindamycin- erally given sequentially). Duration of failed primary primaquine is typically the recommended strategy,1,3 but therapy was 3 days or more (33 patients), 4 days or more there are few useful data available that detail the likeli- (20 patients), 6 days (25 patients), or 5 to 7 days or more hood of success with these substitutions. (358 patients); the length of failed treatment was not stated In most settings, trimethoprim-sulfamethoxazole is the for 61 patients. Salvage treatment included trimetrexate agent of first choice for P carinii pneumonia, and when in- (159 patients), pentamidine (164 patients), eflorni- tolerance or unresponsiveness to treatment occurs, pen- thine hydrochloride (70 patients), clindamycin- tamidine is usually the alternative drug used. For many years primaquine (48 patients), trimethoprim-sulfamethoxa- it has been observed that patients with P carinii pneumo- zole (51 patients), and atovaquone (5 patients). nia who are switched to pentamidine because of adverse Comparable efficacies of these salvage regimens are shown effects due to trimethoprim-sulfamethoxazole, such as fe- in Table 2. ver, rash, hepatitis, leukopenia, or azotemia, respond much

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Downloaded From: https://jamanetwork.com/ on 10/01/2021 Table 1. Clinical Drug Studies and Case Reports of Salvage Therapy for Pneumocystis carinii Pneumonia*

No. of Days of Failed Source, y Patients Underlying Condition Treatment Failure Therapy Salvage Therapy Response, No. (%) Hughes et al,7 1976 6 Children TMP-SMX Ն3 Pentamidine 2/6 (33) 6 Children Pentamidine TMP-SMX 3/6 (50) Hughes et al,8 1978 9 Children TMP-SMX Ն3 Pentamidine 3/9 (33) 9 Children Pentamidine TMP-SMX 4/9 (44) Winston et al,9 1980 2 Hodgkin disease, TMP-SMX Ն4 Pentamidine 1/2 (50) erythema multiforme Mitsuyasu et al,10 1982 1 Acute leukemia TMP-SMX 14 Pentamidine 1/1 (100) Follansbee et al,11 1982 1 Homosexual TMP-SMX 6 Pentamidine 0/1 (0) Golden et al,12 1984 2 HIV/AIDS Pentamidine 8 and 6, Eflornithine 2/2 (100) respectively 1 HIV/AIDS TMP-SMX 14 Eflornithine 1/1 (100) Siegel et al,13 1984 1 Cancer TMP-SMX Ն3 Pentamidine 1/1 (100) 2 Cancer Pentamidine . . . TMP-SMX 1/2 (50) Murray et al,14 1987 37 HIV/AIDS TMP-SMX NS Pentamidine 4/37 (11) Haverkos,15 1984 14 HIV/AIDS TMP-SMX NS Pentamidine 5/14 (36) Small et al,16 1995 13 HIV/AIDS TMP-SMX 9† Pentamidine 4/13 (31) Wharton et al,17 1986 2 HIV/AIDS TMP-SMX 8 Pentamidine 0/2 (0) Montgomery et al,18 1987 2 HIV/AIDS Inhaled pentamidine 4 TMP-SMX 1/1 (50) Allegra et al,19 1987 16 HIV/AIDS TMP-SMX and/or Ն7 Trimetrexate 11/16 (69) pentamidine Franson et al,20 1987 4 Renal transplant TMP-SMX NS Pentamidine, then 1/4 (25) eflornithine (2 patients) Gilman et al,21 1986 9 HIV/AIDS TMP-SMX and/or 4-14 Eflornithine 3/9 (33) pentamidine Mills et al,22 1988 2 HIV/AIDS Dapsone 4 Pentamidine 0/2 (0) 1 HIV/AIDS Dapsone 5 TMP-SMX 0/1 (0) 1 HIV/AIDS TMP-SMX 9 Pentamidine 0/1 (0) Efferen et al,23 1989 22 HIV/AIDS TMP-SMX Ն5 Pentamidine 15/22 (68) Toma et al,24 1989 14 HIV/AIDS TMP-SMX and/or Ն7 Clindamycin-primaquine 12/14 (86) pentamidine 14/14 (100)‡ Medina et al,25 1990 3 HIV/AIDS TMP-SMX Ն4 Pentamidine 2/3 (67) 2 HIV/AIDS TMP-dapsone Pentamidine 2/2 (100) Hoo et al,26 1990 5 HIV/AIDS Inhaled pentamidine Ն5 TMP-SMX 3/5 (60) Kay and DuBois,27 1990 2 HIV/AIDS TMP-SMX NS Clindamycin-primaquine 2/2 (100) 4 HIV/AIDS Pentamidine NS Clindamycin-primaquine 4/4 (100) Smith et al,28 1990 31 HIV/AIDS TMP-SMX and/or 6-8§ Eflornithine 21/31 (68) pentamidine Feinberg et al,29 1992 143 HIV/AIDS TMP-SMX 14 Trimetrexate 36/143 (25) Klein et al,2 1992 39 HIV/AIDS TMP-SMX 5 Pentamidine 18/39 (46) 27 HIV/AIDS Pentamidine 5 TMP-SMX 18/27 (67) Noskin et al,30 1992 28 HIV/AIDS TMP-SMX and/or 9࿣ Clindamycin-primaquine 24/28 (86) pentamidine 2 HIV/AIDS TMP-SMX; clindamycin- 7 and 3, Pentamidine 2/2 (100) primaquine respectively Paulson et al,31 1992 2 HIV/AIDS TMP-SMX Ն5 Eflornithine 0/2 (0) 8 HIV/AIDS Pentamidine Eflornithine 5/8 (63) 15 HIV/AIDS TMP-SMX and/or Eflornithine 8/15 (53) pentamidine Dohn et al,32 1994 5 HIV/AIDS Pentamidine 7 Atovaquone 4/5 (80) 3 HIV/AIDS Atovaquone 7 Pentamidine 3/3 (100)

*TMP-SMX indicates a combination product of trimethoprim and sulfamethoxazole; HIV/AIDS, human immunodeficiency virus/acquired immunodeficiency syndrome; NS, not stated; TMP-dapsone, a combination of trimethoprim and dapsone; and clindamycin-primaquine, a combination of clindamycin and primaquine phosphate. †Mean of 9 days (range, 2-15 days). ‡Study patients were those unresponsive (14 patients) or intolerant to conventional treatment; all but 2 responded to a combination of clindamycin and primaquine but it was not stated whether these patients were from the refractory or intolerant group. §Mean of 6 days for TMP-SMX (range, 3-15 days); mean of 8 days for pentamidine (range, 3-15 days). ࿣Mean of 9 days (range, 3-17 days).

better than when pentamidine is used because of clinical persons requiring a change in therapy (to either drug) be- disease refractory to trimethoprim-sulfamethoxazole.2,5,6 In cause of failure to respond were 46% for the trimethoprim- a large prospective comparative trial of trimethoprim- sulfamethoxazole group and 56% for the pentamidine sulfamethoxazole vs pentamidine for P carinii pneumo- group. When a change in therapy was made because of toxic nia, Klein and colleagues2 showed that survival rates for effects, survival rates were 97% and 94% for these 2 drugs,

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Downloaded From: https://jamanetwork.com/ on 10/01/2021 metrexate does not appear to be a useful salvage agent for Table 2. Efficacies of Salvage Drug Regimens Used in 497 patients with HIV-related P carinii pneumonia that is clini- Patients With Pneumocystis carinii Pneumonia* cally resistant to conventional therapy. Atovaquone is a 1,4-hydroxynaphthoquinone that Salvage Regimen Response to (Failed Regimen) Treatment, No. (%) P has clinical activity against P carinii, and it is a useful oral therapeutic option for patients with mild to moderate Pentamidine 64/164 (39) . . . (TMP-SMX) 57/155 (37) . . . P carinii pneumonia. Like trimetrexate, atovaquone has (TMP-dapsone) 2/2 (100) NS been found to be less effective than trimethoprim- (TMP-SMX followed by 2/2 (100) NS sulfamethoxazole for the initial treatment of P carinii clindamycin-primaquine) pneumonia, but it has fewer treatment-limiting adverse (Atovaquone) 3/3 (100) NS effects.35-37 The drug offers an alternative for persons who (Dapsone) 0/2 (0) NS cannot tolerate trimethoprim-sulfamethoxazole, but there TMP-SMX 27/51 (53) Ͻ.08 (Pentamidine) 23/44 (52) Ͻ.06 is insufficient experience with atovaquone as a salvage (Inhaled pentamidine) 4/6 (67) NS therapy agent to allow practical comments about its use (Dapsone) 0/1 (0) NS in cases of unresponsive P carinii pneumonia. Clindamycin-primaquine 42-44/48 (88-92) Ͻ10−8† Of all the salvage agents examined, the combina- (TMP-SMX and/or pentamidine) 36-38/42 (86-90) Ͻ10−7‡ tion of clindamycin-primaquine was the most success- (TMP-SMX) 2/2 (100) NS ful regimen for patients in whom conventional antipneu- (Pentamidine) 4/4 (100) NS mocystis treatment failed. Approximately 90% (PϽ10−8) Trimetrexate 47/159 (30) NS (TMP-SMX and/or pentamidine) 47/159 (30) NS of patients with P carinii pneumonia refractory to tri- Eflornithine 40/70 (57) Ͻ.01 methoprim-sulfamethoxazole or pentamidine or both had (TMP-SMX) 1/3 (33) NS a good clinical response to clindamycin-primaquine. This (Pentamidine) 7/10 (70) Ͻ.05 dual combination is effective as primary treatment of mild (TMP-SMX and pentamidine) 11/26 (42) NS to moderately severe AIDS-related P carinii pneumonia (TMP-SMX and/or pentamidine) 21/31 (68) Ͻ.02 and perhaps has fewer adverse effects compared with tri- Atovaquone 4/5 (80) NS 38-45 (Pentamidine) 4/5 (80) Ͻ.07 methoprim-sulfamethoxazole. The reason(s) for the significantly better response rate for clindamycin- *TMP-SMX indicates a combination product of trimethoprim and primaquine compared with other salvage regimens is not sulfamethoxazole; TMP-dapsone, a combination of trimethoprim and clear; variables such as the duration of failed primary treat- dapsone; clindamycin-primaquine, a combination of clindamycin and ment, severity of pneumonia or clinical presentation, or primaquine phosphate; ellipses, all salvage regimens are compared with pentamidine substituted for TMP-SMX; and NS, not significant. type of underlying disease do not appear to account for †Odds ratio, 12 to 19. these differences. It is possible that combination treat- ‡Odds ratio, 10 to 16. ment provides a synergistic antipneumocystis effect not afforded by monotherapy, although the present diffi- respectively. In the present meta-analysis, pentamidine was culty in culturing this organism in vitro precludes sus- successful in only 37% of patients in whom trimethoprim- ceptibility testing and proof of such a hypothesis. The sulfamethoxazole treatment had failed, and conversely tri- most serious toxic effects of clindamycin-primaquine are methoprim-sulfamethoxazole appeared little more effec- hematologic (eg, neutropenia, anemia, thrombocytope- tive (53%) when used because of unresponsiveness to nia, and methemoglobinemia).44 The optimal role for clin- pentamidine. Eflornithine, an antiprotozoan drug that re- damycin-primaquine may, in fact, be as a salvage regi- duces polyamine synthesis via irreversible inhibition of or- men for patients unresponsive to or unable to tolerate nithine decarboxylase, has been investigated during the past trimethoprim-sulfamethoxazole or pentamidine. 15 years as a possible therapeutic option for primary P ca- It may be very difficult to determine whether a lack rinii pneumonia and for treatment failures with first-line of response for an individual patient with P carinii pneu- agents.12,20,21,28,30 The cumulative data summarized herein monia to conventional treatment is due to drug resis- suggest that eflornithine has efficacy (40 [57%] of 70 pa- tance, immunologic dysfunction, concurrent pulmonary tients; PϽ.01) as a salvage drug for unresponsive P carinii infection, or another factor. Sequencing of resistance genes pneumonia. in P carinii can identify a molecular basis for trimethoprim- Trimetrexate is a lipid-soluble analogue of metho- sulfamethoxazole resistance, but this technology is not trexate and a much more potent inhibitor of protozoan di- widely available commercially and remains largely a re- hydrofolate reductase than either trimethoprim or pyri- search tool. Although there are some patients who do bet- methamine.19,32-34 The drug is currently available only in ter when taking one antipneumocystis agent compared with intravenous form and is administered in combination with another, it is much more common to recognize a second leukovorin (folinic acid) to prevent adverse hematologic process (eg, concurrent pulmonary infection, tumor, al- effects. In comparison with trimethoprim-sulfamethoxa- lergy, acute respiratory distress syndrome) as a cause for zole as primary treatment for moderately severe P carinii unresponsiveness to treatment.14,46-48 Bronchoscopic stud- pneumonia, trimetrexate was better tolerated than trimeth- ies of unresolving HIV-related pneumonia have docu- oprim-sulfamethoxazole but was associated with a lower mented a secondary pulmonary infection in 8.9% to 39% response rate and a higher incidence of relapse than tri- of cases.46,49,50 Concurrent pathogens may include vi- methoprim-sulfamethoxazole therapy.32-34 In this review, ruses (especially cytomegalovirus), mycobacteria, fungi, trimetrexate was effective in only 30% of trimethoprim- and bacteria.46,49,50 Noninfectious pathologic conditions sulfamethoxazole and pentamidine treatment failures.19 Tri- such as Kaposi sarcoma or non-Hodgkin lymphoma may

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Downloaded From: https://jamanetwork.com/ on 10/01/2021 also occur concurrently with P carinii pneumonia. Ac- ciency syndrome: a different perspective. Am J Med. 1989;87:401-404. 24. Toma E, Fournier S, Poisson M, et al. Clindamycin with primaquine for Pneu- cordingly, bronchoalveolar lavage with or without lung mocystis carinii pneumonia. Lancet. 1989;1:1046-1048. biopsy should be strongly considered for any patient with 25. Medina I, Mills J, Leoung G, et al. Oral therapy for Pneumocystis carinii pneu- presumptive or documented P carinii pneumonia who is monia in the acquired immunodeficiency syndrome: a controlled trial of trimethoprim-sulfamethoxazole vs trimethoprim-dapsone. N Engl J Med. 1990;323: not responding to antipneumocystis treatment to detect 776-782. alternative or coexisting lung pathologic conditions.46-50 26. Hoo GWS, Mohsenifar Z, Meyers RD. Inhaled or intravenous pentamidine therapy When salvage therapy is indicated, clindamycin- for Pneumocystis carinii pneumonia in AIDS: a randomized trial. Ann Intern Med. 1990;113:195-202. primaquine appears to be the most effective alternative form 27. Kay R, DuBois RE. Clindamycin/primaquine therapy and secondary prophylaxis of drug therapy. against Pneumocystis carinii pneumonia in patients with AIDS. South Med J. 1990; 83:403-404. 28. Smith D, Davies S, Nelson M, et al. Pneumocystis carinii pneumonia treated with Accepted for publication December 6, 2000. eflornithine in AIDS patients resistant to conventional therapy. AIDS. 1990;4: Corresponding author: Raymond A. Smego, Jr, MD, 1019-1021. 29. Feinberg J, McDermott C, Nutter J. Trimetrexate (TMTX) salvage therapy for PCP MPH, DTM&H, Department of Medicine, The Aga Khan in AIDS patients with limited therapeutic options. 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