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Pneumocystis Pneumonia
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Epidemiology

Pneumocystis pneumonia (PCP) is caused by Pneumocystis jirovecii, a ubiquitous organism that is classified as a fungus but that also shares biologic characteristics with protozoa. The taxonomy of the organism has been changed; Pneumocystis carinii now refers only to the pneumocystis that infects rodents, and Pneumocystis jirovecii refers to the distinct species that infects humans. The abbreviation PCP is still used to designate Pneumocystis pneumonia. Initial infection with P. jirovecii usually occurs in early childhood; two thirds of healthy children have antibody to P. jirovecii by age 2-4 years (81Pifer LL, Hughes WT, Stagno S, Woods D. Pneumocystis carinii infection: evidence for high prevalence in normal and immunosuppressed children. Pediatrics 1978;61:35-41.). Rodent studies and case clusters among immunosuppressed patients suggest that Pneumocystis spreads by the airborne route. Disease probably occurs by new acquisition of infection and by reactivation of latent infection (82Keely SP, Stringer JR, Baughman RP, et al. Genetic variation among Pneumocystis carinii hominis isolates in recurrent pneumocystosis. J Infect Dis 1995;172:595-8., 83Helweg-Larsen J, Tsolaki AG, Miller RF, Lundgren B, Wakefield AE. Clusters of Pneumocystis carinii pneumonia: analysis of person-to-person transmission by genotyping. Qjm 1998;91:813-20., 84Huang LM, Huang SY, Chen MY, et al. Geographical differences in human herpesvirus 8 seroepidemiology: a survey of 1,201 individuals in Asia. J Med Virol 2000;60:290-3.). Before the widespread use of primary PCP prophylaxis and ART, PCP occurred in 70%-80% of patients with AIDS (85Phair J, Munoz A, Detels R, et al. The risk of Pneumocystis carinii pneumonia among men infected with human immunodeficiency virus type 1. Multicenter AIDS Cohort Study Group. N Engl J Med 1990;322:161-5.); the course of treated PCP was associated with a mortality of 20%-40% in persons with profound immunosuppression. Approximately 90% of cases occurred among patients with CD4+ counts of <200 cells/µL. Other factors associated with a higher risk for PCP included CD4+ cell percentage <14%, previous episodes of PCP, oral thrush, recurrent bacterial pneumonia, unintentional weight loss, and higher plasma HIV RNA (86Kaplan JE, Hanson DL, Navin TR, Jones JL. Risk factors for primary Pneumocystis carinii pneumonia in human immunodeficiency virus-infected adolescents and adults in the United States: reassessment of indications for chemoprophylaxis. J Infect Dis 1998;178:1126-32., 87Kaplan JE, Hanson DL, Jones JL, Dworkin MS. Viral load as an independent risk factor for opportunistic infections in HIV-infected adults and adolescents. AIDS 2001;15:1831-6.).

Incidence of PCP has declined substantially with widespread use of prophylaxis and ART; recent incidence among patients with AIDS in Western Europe and the United States is 2-3 cases per 100 person-years (88Furrer H, Egger M, Opravil M, et al. Discontinuation of primary prophylaxis against Pneumocystis carinii pneumonia in HIV-1-infected adults treated with combination antiretroviral therapy. Swiss HIV Cohort Study. N Engl J Med 1999;340:1301-6.). The majority of cases occur among patients who are unaware of their HIV infection or are not receiving ongoing HIV care (89Lundberg BE, Davidson AJ, Burman WJ. Epidemiology of Pneumocystis carinii pneumonia in an era of effective prophylaxis: the relative contribution of non-adherence and drug failure. AIDS 2000;14:2559-66.) or among those with advanced immunosuppression (CD4+ counts <100 cells/µL) (90Wolff AJ, O'Donnell AE. Pulmonary manifestations of HIV infection in the era of highly active antiretroviral therapy. Chest 2001;120:1888-93.).

Clinical Manifestations

The most common manifestations of PCP among HIV-infected persons are the subacute onset of progressive dyspnea, fever, nonproductive cough, and chest discomfort that worsens within days to weeks. The fulminant pneumonia observed among non-HIV-infected patients is less common (91Kovacs JA, Hiemenz JW, Macher AM, et al. Pneumocystis carinii pneumonia: a comparison between patients with the acquired immunodeficiency syndrome and patients with other immunodeficiencies. Ann Intern Med 1984;100:663-71., 92Selwyn PA, Pumerantz AS, Durante A, et al. Clinical predictors of Pneumocystis carinii pneumonia, bacterial pneumonia and tuberculosis in HIV-infected patients. AIDS 1998;12:885-93.).

In mild cases, pulmonary examination is usually normal at rest. With exertion, tachypnea, tachycardia, and diffuse dry ("cellophane") rales might be observed (92Selwyn PA, Pumerantz AS, Durante A, et al. Clinical predictors of Pneumocystis carinii pneumonia, bacterial pneumonia and tuberculosis in HIV-infected patients. AIDS 1998;12:885-93.). Oral thrush is a common coinfection. Fever is apparent in the majority of cases and might be the predominant symptom among some patients. Extrapulmonary disease is rare but can occur in any organ and has been associated with use of aerosolized pentamidine prophylaxis.

Hypoxemia, the most characteristic laboratory abnormality, might range from mild (room air arterial oxygen [pO2] of ≥70 mm Hg or alveolar-arterial O2 difference, [A-a] DO2 <35 mm Hg) to moderate ([A-a] DO2 >35 and <45 mm Hg) to severe levels ([A-a] DO2 >45 mm Hg). Oxygen desaturation with exercise is indicative of an abnormal A-a gradient but is nonspecific (93Smith DE, McLuckie A, Wyatt J, Gazzard B. Severe exercise hypoxaemia with normal or near normal X-rays: a feature of Pneumocystis carinii infection. Lancet 1988; 2:1049-51.). Elevation of lactate dehydrogenase levels to >500 mg/dL is common but nonspecific (94Zaman MK, White DA. Serum lactate dehydrogenase levels and Pneumocystis carinii pneumonia: diagnostic and prognostic significance. Am Rev Respir Dis 1988;137:796-800.). The chest radiograph typically demonstrates diffuse, bilateral, symmetrical interstitial infiltrates emanating from the hila in a butterfly pattern (92Selwyn PA, Pumerantz AS, Durante A, et al. Clinical predictors of Pneumocystis carinii pneumonia, bacterial pneumonia and tuberculosis in HIV-infected patients. AIDS 1998;12:885-93.); however, patients with early disease might have a normal chest radiograph (95Opravil M, Marincek B, Fuchs WA, et al. Shortcomings of chest radiography in detecting Pneumocystis carinii pneumonia. J Acquir Immune Defic Syndr 1994;7:39-45.). In addition, atypical presentations with nodules, blebs and cysts, asymmetric disease, upper lobe localization, and pneumothorax occur. Pneumothorax in a patient with HIV infection should raise the suspicion of PCP (96Metersky ML, Colt HG, Olson LK, Shanks TG. AIDS-related spontaneous pneumothorax: risk factors and treatment. Chest 1995;108:946-51., 97Sepkowitz KA, Telzak EE, Gold JW, et al. Pneumothorax in AIDS. Ann Intern Med 1991;114:455-9.). Cavitation, intrathoracic adenopathy, and pleural effusion are uncommon in the absence of other pulmonary pathogens or malignancy, and their presence might indicate an alternative diagnosis. Approximately 13%-18% of patients with documented PCP have another concurrent cause of pulmonary dysfunction (e.g., TB, KS, or bacterial pneumonia) (98Baughman RP, Dohn MN, Frame PT. The continuing utility of bronchoalveolar lavage to diagnose opportunistic infection in AIDS patients. Am J Med 1994;97:515-22., 99Stover DE, Zaman MB, Hajdu SI, et al. Bronchoalveolar lavage in the diagnosis of diffuse pulmonary infiltrates in the immunosuppressed host. Ann Intern Med 1984;101:1-7.).

Thin-section computerized tomography (CT) demonstrating patchy ground-glass attenuation (100Gruden JF, Huang L, Turner J, et al. High-resolution CT in the evaluation of clinically suspected Pneumocystis carinii pneumonia in AIDS patients with normal, equivocal, or nonspecific radiographic findings. Am J Roentgenol 1997;169:967-75., 101Hidalgo A, Falco V, Mauleon S, et al. Accuracy of high-resolution CT in distinguishing between Pneumocystis carinii pneumonia and non-Pneumocystis carinii pneumonia in AIDS patients. Eur Radiol 2003;13:1179-84.) or a gallium scan indicating increased pulmonary uptake (102Rosso J, Guillon JM, Parrot A, et al. Technetium-99m-DTPA aerosol and gallium-67 scanning in pulmonary complications of human immunodeficiency virus infection. J Nucl Med 1992;33:81-7.) increases the likelihood that a diagnostic study such as bronchoscopy would demonstrate PCP in patients with mild-to-moderate symptoms and a normal chest radiograph and might be useful as adjunctive studies.

Diagnosis

Because the clinical presentation, blood tests, or chest radiographs are not pathognomonic for PCP and the organism cannot be cultivated routinely, histopathologic demonstration of organisms in tissue, bronchoalveolar lavage fluid, or induced sputum samples (98Baughman RP, Dohn MN, Frame PT. The continuing utility of bronchoalveolar lavage to diagnose opportunistic infection in AIDS patients. Am J Med 1994;97:515-22., 99Stover DE, Zaman MB, Hajdu SI, et al. Bronchoalveolar lavage in the diagnosis of diffuse pulmonary infiltrates in the immunosuppressed host. Ann Intern Med 1984;101:1-7., 103Kovacs JA, Ng VL, Masur H, et al. Diagnosis of Pneumocystis carinii pneumonia: improved detection in sputum with use of monoclonal antibodies. N Engl J Med 1988;318:589-93., 104Roger PM, Vandenbos F, Pugliese P, et al. Persistence of Pneumocystis carinii after effective treatment of P. carinii pneumonia is not related to relapse or survival among patients infected with human immunodeficiency virus. Clin Infect Dis 1998;26:509-10.) are required for a definitive diagnosis. Spontaneously expectorated sputum has low sensitivity and should not be submitted to the laboratory to diagnose PCP. Giemsa, Diff-Quik, and Wright stains detect both the cyst and trophozoite forms but do not stain the cyst wall; Gomori methenamine silver, Gram-Weigert, cresyl violet, and toluidine blue stain the cyst wall. Certain laboratories prefer direct immunofluorescent staining. Nucleic acid tests have greater sensitivity but less specificity than colorimetric or immunologic stains and can be combined with noninvasive samples such as induced sputum or oral wash samples; however, their availability is limited (105Larsen HH, Masur H, Kovacs JA, et al. Development and evaluation of a quantitative, touch-down, real-time PCR assay for diagnosing Pneumocystis carinii pneumonia. J Clin Microbiol 2002;40:490-4., 106Torres J, Goldman M, Wheat LJ, et al. Diagnosis of Pneumocystis carinii pneumonia in human immunodeficiency virus-infected patients with polymerase chain reaction: a blinded comparison to standard methods. Clin Infect Dis 2000;30:141-5., 107Larsen HH, Huang L, Kovacs JA, et al. A prospective, blinded study of quantitative touch-down polymerase chain reaction using oral-wash samples for diagnosis of Pneumocystis pneumonia in HIV-infected patients. J Infect Dis 2004;189:1679-83.). (1→3)ß-D-glucan (a component of fungal cell walls) might be elevated in patients with PCP, but the sensitivity and specificity of this assay to establish a diagnosis of PCP has not been adequately evaluated. (108Pisculli M, Sax P. Use of a Serum b-Glucan Assay for Diagnosis of HIV-related Pneumocystis jiroveci pneumonia in patients with negative microscopic examination results. Clin Infect Dis 2008 (in press).).

Previous studies of stained respiratory tract samples obtained by various methods indicate the following relative diagnostic sensitivities: induced sputum <50%->90% (the sensitivity and specificity depend on the quality of the specimens and the experience of the microbiologist or pathologist), bronchoscopy with bronchoalveolar lavage 90%-99%, transbronchial biopsy 95%-100%, and open lung biopsy 95%-100%.

Because of the potential for certain processes to have similar clinical manifestations, a specific diagnosis of PCP should be sought rather than relying on a presumptive diagnosis, especially in patients with moderate-to-severe disease. Treatment can be initiated before making a definitive diagnosis because organisms persist in clinical specimens for days or weeks after effective therapy is initiated (104Roger PM, Vandenbos F, Pugliese P, et al. Persistence of Pneumocystis carinii after effective treatment of P. carinii pneumonia is not related to relapse or survival among patients infected with human immunodeficiency virus. Clin Infect Dis 1998;26:509-10.).

Preventing Exposure

Certain authorities might recommend that persons who are at risk for PCP not share a hospital room with a patient who has PCP, a recommendations based on animal studies and anecdotal human experience. Data are insufficient to support this recommendation as standard practice (CIII).

Preventing Disease
Initiating Primary Prophylaxis

HIV-infected adults and adolescents, including pregnant women and those on ART, should receive chemoprophylaxis against PCP if they have a CD4+ count of <200 cells/µL (AI) or a history of oropharyngeal candidiasis (AII) (32CDC. Guidelines for prophylaxis against Pneumocystis carinii pneumonia for persons infected with human immunodeficiency virus. MMWR 1989;38:1-9., 85Phair J, Munoz A, Detels R, et al. The risk of Pneumocystis carinii pneumonia among men infected with human immunodeficiency virus type 1. Multicenter AIDS Cohort Study Group. N Engl J Med 1990;322:161-5., 86Kaplan JE, Hanson DL, Navin TR, Jones JL. Risk factors for primary Pneumocystis carinii pneumonia in human immunodeficiency virus-infected adolescents and adults in the United States: reassessment of indications for chemoprophylaxis. J Infect Dis 1998;178:1126-32.). Persons who have a CD4+ cell percentage of <14% or a history of an AIDS-defining illness, but do not otherwise qualify, should be considered for prophylaxis (BII) (32,85,86). When monitoring CD4+ counts frequently (e.g., every 1-3 months) is not possible, initiating chemoprophylaxis at a CD4+ count of >200, but <250 cells/µL, also should be considered (BII) (86Kaplan JE, Hanson DL, Navin TR, Jones JL. Risk factors for primary Pneumocystis carinii pneumonia in human immunodeficiency virus-infected adolescents and adults in the United States: reassessment of indications for chemoprophylaxis. J Infect Dis 1998;178:1126-32.).

TMP-SMX is the recommended prophylactic agent (AI) (32CDC. Guidelines for prophylaxis against Pneumocystis carinii pneumonia for persons infected with human immunodeficiency virus. MMWR 1989;38:1-9., 109Bozzette SA, Finkelstein DM, Spector SA, et al. A randomized trial of three antipneumocystis agents in patients with advanced human immunodeficiency virus infection. N Engl J Med 1995;332:693-9., 110Schneider MM, Hoepelman AI, Eeftinck Schattenkerk JK, et al. A controlled trial of aerosolized pentamidine or trimethoprim-sulfamethoxazole as primary prophylaxis against Pneumocystis carinii pneumonia in patients with human immunodeficiency virus infection. N Engl J Med 1992;327:1836-41., 111Schneider MM, Nielsen TL, Nelsing S, et al. Efficacy and toxicity of two doses of trimethoprim-sulfamethoxazole as primary prophylaxis against Pneumocystis carinii pneumonia in patients with human immunodeficiency virus. J Infect Dis 1995;171:1632-6.). One double-strength tablet daily is the preferred regimen (AI). However, one single-strength tablet daily (111Schneider MM, Nielsen TL, Nelsing S, et al. Efficacy and toxicity of two doses of trimethoprim-sulfamethoxazole as primary prophylaxis against Pneumocystis carinii pneumonia in patients with human immunodeficiency virus. J Infect Dis 1995;171:1632-6.) also is effective and might be better tolerated than one double-strength tablet daily (AI). One double-strength tablet three times weekly also is effective (BI) (112El-Sadr WM, Luskin-Hawk R, Yurik TM, et al. A randomized trial of daily and thrice-weekly trimethoprim-sulfamethoxazole for the prevention of Pneumocystis carinii pneumonia in human immunodeficiency virus-infected persons. Clin Infect Dis 1999;29:775-83.). TMP-SMX at a dose of one double-strength tablet daily confers cross-protection against toxoplasmosis (113Carr A, Tindall B, Brew BJ, et al. Low-dose trimethoprim-sulfamethoxazole prophylaxis for toxoplasmic encephalitis in patients with AIDS. Ann Intern Med 1992; 117:106-11.) and selected common respiratory bacterial infections (109Bozzette SA, Finkelstein DM, Spector SA, et al. A randomized trial of three antipneumocystis agents in patients with advanced human immunodeficiency virus infection. N Engl J Med 1995;332:693-9., 114Hardy WD, Feinberg J, Finkelstein DM, et al. A controlled trial of trimethoprim-sulfamethoxazole or aerosolized pentamidine for secondary prophylaxis of Pneumocystis carinii pneumonia in patients with the acquired immunodeficiency syndrome. N Engl J Med 1992;327:1842-8.). Lower doses of TMP-SMX also likely confer such protection. For patients who have an adverse reaction that is not life threatening, chemoprophylaxis with TMP-SMX should be continued if clinically feasible; for those who have discontinued such therapy because of an adverse reaction, reinstituting TMP-SMX should be strongly considered after the adverse event has resolved (AII). Patients who have experienced adverse events, including fever and rash, might better tolerate reintroduction of the drug with a gradual increase in dose (i.e., desensitization), according to published regimens (BI) (115Para MF, Finkelstein D, Becker S, et al. Reduced toxicity with gradual initiation of trimethoprim-sulfamethoxazole as primary prophylaxis for Pneumocystis carinii pneumonia. J Acquir Immune Defic Syndr 2000;24:337-43., 116Leoung GS, Stanford JF, Giordano MF, et al. Trimethoprim-sulfamethoxazole (TMP-SMZ) dose escalation versus direct rechallenge for Pneumocystis carinii pneumonia prophylaxis in human immunodeficiency virus-infected patients with previous adverse reaction to TMP-SMZ. J Infe ct Dis 2001;184:992-7.) or reintroduction of TMP-SMX at a reduced dose or frequency (CIII); as many as 70% of patients can tolerate such reinstitution of therapy (114Hardy WD, Feinberg J, Finkelstein DM, et al. A controlled trial of trimethoprim-sulfamethoxazole or aerosolized pentamidine for secondary prophylaxis of Pneumocystis carinii pneumonia in patients with the acquired immunodeficiency syndrome. N Engl J Med 1992;327:1842-8.).

If TMP-SMX cannot be tolerated, alternative prophylactic regimens include dapsone (BI) (109Bozzette SA, Finkelstein DM, Spector SA, et al. A randomized trial of three antipneumocystis agents in patients with advanced human immunodeficiency virus infection. N Engl J Med 1995;332:693-9.), dapsone plus pyrimethamine plus leucovorin (BI) (117Podzamczer D, Salazar A, Jimenez J, et al. Intermittent trimethoprim-sulfamethoxazole compared with dapsone-pyrimethamine for the simultaneous primary prophylaxis of Pneumocystis pneumonia and toxoplasmosis in patients infected with HIV. Ann Intern Med 1995;122:755-61., 118Opravil M, Hirschel B, Lazzarin A, et al. Once-weekly administration of dapsone/pyrimethamine vs. aerosolized pentamidine as combined prophylaxis for Pneumocystis carinii pneumonia and toxoplasmic encephalitis in human immunodeficiency virus-infected patients. Clin Infect Dis 1995;20:531-41., 119Girard PM, Landman R, Gaudebout C, et al. Dapsone-pyrimethamine compared with aerosolized pentamidine as primary prophylaxis against Pneumocystis carinii pneumonia and toxoplasmosis in HIV infection. N Engl J Med 1993;328:1514-20.), aerosolized pentamidine administered by the Respirgard II nebulizer (manufactured by Marquest, Englewood, Colorado) (BI) (110Schneider MM, Hoepelman AI, Eeftinck Schattenkerk JK, et al. A controlled trial of aerosolized pentamidine or trimethoprim-sulfamethoxazole as primary prophylaxis against Pneumocystis carinii pneumonia in patients with human immunodeficiency virus infection. N Engl J Med 1992;327:1836-41.), and atovaquone (BI) (120Chan C, Montaner J, Lefebvre EA, et al. Atovaquone suspension compared with aerosolized pentamidine for prevention of Pneumocystis carinii pneumonia in human immunodeficiency virus-infected subjects intolerant of trimethoprim or sulfonamides. J Infect Dis 1999;180:369-76., 121El-Sadr WM, Murphy RL, Yurik TM, et al. Atovaquone compared with dapsone for the prevention of Pneumocystis carinii pneumonia in patients with HIV infection who cannot tolerate trimethoprim, sulfonamides, or both. N Engl J Med 1998;339:1889-95.). Atovaquone is as effective as aerosolized pentamidine (120Chan C, Montaner J, Lefebvre EA, et al. Atovaquone suspension compared with aerosolized pentamidine for prevention of Pneumocystis carinii pneumonia in human immunodeficiency virus-infected subjects intolerant of trimethoprim or sulfonamides. J Infect Dis 1999;180:369-76.) or dapsone (BI) (121El-Sadr WM, Murphy RL, Yurik TM, et al. Atovaquone compared with dapsone for the prevention of Pneumocystis carinii pneumonia in patients with HIV infection who cannot tolerate trimethoprim, sulfonamides, or both. N Engl J Med 1998;339:1889-95.) but is substantially more expensive than the other regimens. For patients seropositive for Toxoplasma gondii who cannot tolerate TMP-SMX, recommended alternatives to TMP-SMX for prophylaxis against both PCP and toxoplasmosis include dapsone plus pyrimethamine plus leucovorin (BI) (117Podzamczer D, Salazar A, Jimenez J, et al. Intermittent trimethoprim-sulfamethoxazole compared with dapsone-pyrimethamine for the simultaneous primary prophylaxis of Pneumocystis pneumonia and toxoplasmosis in patients infected with HIV. Ann Intern Med 1995;122:755-61., 118Opravil M, Hirschel B, Lazzarin A, et al. Once-weekly administration of dapsone/pyrimethamine vs. aerosolized pentamidine as combined prophylaxis for Pneumocystis carinii pneumonia and toxoplasmic encephalitis in human immunodeficiency virus-infected patients. Clin Infect Dis 1995;20:531-41., 119Girard PM, Landman R, Gaudebout C, et al. Dapsone-pyrimethamine compared with aerosolized pentamidine as primary prophylaxis against Pneumocystis carinii pneumonia and toxoplasmosis in HIV infection. N Engl J Med 1993;328:1514-20.) or atovaquone with or without pyrimethamine plus leucovorin (CIII).

Oral pyrimethamine plus sulfadoxine also has activity in preventing PCP (CIII) (122Payen MC, De Wit S, Sommereijns B, Clumeck N. A controlled trial of dapsone versus pyrimethamine-sulfadoxine for primary prophylaxis of Pneumocystis carinii pneumonia and toxoplasmosis in patients with AIDS. Biomed Pharmacother 1997;51:439-45., 123Schurmann D, Bergmann F, Albrecht H, et al. Twice-weekly pyrimethamine-sulfadoxine effectively prevents Pneumocystis carinii pneumonia relapse and toxoplasmic encephalitis in patients with AIDS. J Infect Dis 2001;42:8-15., 124Schurmann D, Bergmann F, Albrecht H, et al. Effectiveness of twice-weekly pyrimethamine-sulfadoxine as primary prophylaxis of Pneumocystis carinii pneumonia and toxoplasmic encephalitis in patients with advanced HIV infection. Eur J Clin Microbiol Infect Dis 2002;21:353-6 1). This combination should not be used in patients with hypersensitivity to sulfonamides. Pyrimethamine plus sulfadoxine has an increased risk for severe cutaneous reactions, including Stevens-Johnson syndrome (125Navin TR, Miller KD, Satriale RF, Lobel HO. Adverse reactions associated with pyrimethamine-sulfadoxine prophylaxis for Pneumocystis carinii infections in AIDS. Lancet 1985;1:1332.), and the long half-life of both pyrimethamine and sulfadoxine will result in a delayed clearance when the drug is stopped. Largely because TMP-SMX has superior safety, widespread availability, and is low cost, oral pyrimethamine plus sulfadoxine should be used rarely in the United States (CIII).

The following regimens cannot be recommended as alternatives because data regarding their efficacy for PCP prophylaxis are insufficient:

transparent gifgrey bulletAerosolized pentamidine administered by other nebulization devices
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transparent gifgrey bulletIntermittently administered parenteral pentamidine
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transparent gifgrey bulletOral clindamycin plus primaquine.
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However, clinicians might consider using these agents in unusual situations in which the recommended agents cannot be administered (CIII).

Discontinuing Primary Prophylaxis

Primary pneumocystis prophylaxis should be discontinued for adult and adolescent patients who have responded to ART with an increase in CD4+ counts to >200 cells/µL for >3 months (AI). In observational and randomized studies supporting this recommendation, the majority of patients were taking antiretroviral regimens that included a protease inhibitor (PI), and the majority had a CD4+ count of >200 cells/µL for >3 months before discontinuing PCP prophylaxis (88Furrer H, Egger M, Opravil M, et al. Discontinuation of primary prophylaxis against Pneumocystis carinii pneumonia in HIV-1-infected adults treated with combination antiretroviral therapy. Swiss HIV Cohort Study. N Engl J Med 1999;340:1301-6., 126Dworkin MS, Hanson DL, Kaplan JE, Jones JL, Ward JW. Risk for preventable opportunistic infections in persons with AIDS after antiretroviral therapy increases CD4+ T lymphocyte counts above prophylaxis thresholds. J Infect Dis 2000;182:611-5., 127Mussini C, Pezzotti P, Govoni A, et al. Discontinuation of primary prophylaxis for Pneumocystis carinii pneumonia and toxoplasmic encephalitis in human immunodeficiency virus type I-infected patients: the changes in opportunistic prophylaxis study. J Infect Dis 2000;181:1 635-42., 128Schneider MM, Borleffs JC, Stolk RP, Jaspers CA, Hoepelman AI. Discontinuation of prophylaxis for Pneumocystis carinii pneumonia in HIV-1-infected patients treated with highly active antiretroviral therapy. Lancet 1999;353:201-3., 129Weverling GJ, Mocroft A, Ledergerber B, et al. Discontinuation of Pneumocystis carinii pneumonia prophylaxis after start of highly active antiretroviral therapy in HIV-1 infection. Lancet 1999;353:1293-8., 130Yangco BG, Von Bargen JC, Moorman AC, Holmberg SD. Discontinuation of chemoprophylaxis against Pneumocystis carinii pneumonia in patients with HIV infection. Ann Intern Med 2000;132:201-5., 131Furrer H, Opravil M, Rossi M, et al. Discontinuation of primary prophylaxis in HIV-infected patients at high risk of Pneumocystis carinii pneumonia: prospective multicentre study. AIDS 2001;15:501-7., 132Kirk O, Lundgren JD, Pedersen C, Nielsen H, Gerstoft J. Can chemoprophylaxis against opportunistic infections be discontinued after an increase in CD4 cells induced by highly active antiretroviral therapy? AIDS 1999;13:1647-51., 133Lopez Bernaldo de Quiros JC, Miro JM, et al. A randomized trial of the discontinuation of primary and secondary prophylaxis against Pneumocystis carinii pneumonia after highly active antiretroviral therapy in patients with HIV infection. N Engl J Med 2001;344:159-67., 124Schurmann D, Bergmann F, Albrecht H, et al. Effectiveness of twice-weekly pyrimethamine-sulfadoxine as primary prophylaxis of Pneumocystis carinii pneumonia and toxoplasmic encephalitis in patients with advanced HIV infection. Eur J Clin Microbiol Infect Dis 2002;21:353-6 1). The median CD4+ count at the time prophylaxis was discontinued was >300 cells/µL, most had a CD4+ cell percentage of ≥14 %, and many patients had a sustained suppression of HIV plasma RNA levels below detection limits of the assay employed. Median follow-up was 6-19 months.

Discontinuing primary prophylaxis among these patients is recommended because prophylaxis adds limited disease prevention (i.e., for PCP, toxoplasmosis, or bacterial infections) (127Mussini C, Pezzotti P, Govoni A, et al. Discontinuation of primary prophylaxis for Pneumocystis carinii pneumonia and toxoplasmic encephalitis in human immunodeficiency virus type I-infected patients: the changes in opportunistic prophylaxis study. J Infect Dis 2000;181:1 635-42., 133Lopez Bernaldo de Quiros JC, Miro JM, et al. A randomized trial of the discontinuation of primary and secondary prophylaxis against Pneumocystis carinii pneumonia after highly active antiretroviral therapy in patients with HIV infection. N Engl J Med 2001;344:159-67.) and because discontinuing drugs reduces pill burden, potential for drug toxicity, drug interactions, selection of drug-resistant pathogens, and cost.

Prophylaxis should be reintroduced if the CD4+ count decreases to <200 cells/µL (AIII).

Treatment of Disease

TMP-SMX is the treatment of choice (AI) (135Hughes W, Leoung G, Kramer F, et al. Comparison of atovaquone (566C80) with trimethoprim-sulfamethoxazole to treat Pneumocystis carinii pneumonia in patients with AIDS. N Engl J Med 1993;328:1521-7., 136Safrin S, Finkelstein DM, Feinberg 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;124:792-802.). The dose must be adjusted for abnormal renal function. Multiple randomized clinical trials indicate that TMP-SMX is as effective as parenteral pentamidine and more effective than other regimens. Adding leucovorin to prevent myelosuppression during acute treatment is not recommended because of questionable efficacy and some evidence for a higher failure rate (DII) (137Safrin S, Lee BL, Sande MA. Adjunctive folinic acid with trimethoprim-sulfamethoxazole for Pneumocystis carinii pneumonia in AIDS patients is associated with an increased risk of therapeutic failure and death. J Infect Dis 1994;170:912-7.). Oral outpatient therapy of TMP-SMX is highly effective among patients with mild-to-moderate disease (AI) (136Safrin S, Finkelstein DM, Feinberg 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;124:792-802.).

Mutations associated with resistance to sulfa drugs have been documented, but their effect on clinical outcome is uncertain (138Crothers K, Beard CB, Turner J, et al. Severity and outcome of HIV-associated Pneumocystis pneumonia containing Pneumocystis jirovecii dihydropteroate synthase gene mutations. AIDS 2005;19:801-5., 139Huang L, Crothers K, Atzori C, et al. Dihydropteroate synthase gene mutations in Pneumocystis and sulfa resistance. Emerg Infect Dis 2004;10:1721-8., 140Stein CR, Poole C, Kazanjian P, Meshnick SR. Sulfa use, dihydropteroate synthase mutations, and Pneumocystis jirovecii pneumonia. Emerg Infect Dis 2004;10:1760-5.). Patients who have PCP despite TMP-SMX prophylaxis are usually effectively treated with standard doses of TMP-SMX (BIII).

Patients with documented or suspected PCP and moderate-to-severe disease, as defined by room air pO2 <70 mm Hg or arterial-alveolar O2 gradient >35 mm Hg, should receive adjunctive corticosteroids as early as possible, and certainly within 72 hours after starting specific PCP therapy (AI) (141Nielsen TL, Eeftinck Schattenkerk JK, Jensen BN, et al. Adjunctive corticosteroid therapy for Pneumocystis carinii pneumonia in AIDS: a randomized European multicenter open label study. J Acquir Immune Defic Syndr 1992;5:726-31., 142Bozzette SA, Sattler FR, Chiu J, et al. A controlled trial of early adjunctive treatment with corticosteroids for Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome. N Engl J Med 1990;323:1451-7., 143National Institutes of Health. Consensus statement on the use of corticosteroids as adjunctive therapy for Pneumocystis pneumonia in the acquired immunodeficiency syndrome. N Engl J Med 1990;323:1500-4., 144Montaner JS, Lawson LM, Levitt N, et al. Corticosteroids prevent early deterioration in patients with moderately severe Pneumocystis carinii pneumonia and the acquired immunodeficiency syndrome (AIDS). Ann Intern Med 1990;113:14-20., 145Gallant JE, Chaisson RE, Moore RD. The effect of adjunctive corticosteroids for the treatment of Pneumocystis carinii pneumonia on mortality and subsequent complications. Chest 1998;114:1258-63., 146Briel M, Bucher HC, Boscacci R, Furrer H. Adjunctive corticosteroids for Pneumocystis jiroveci pneumonia in patients with HIV-infection. Cochrane Database Syst Rev 2006:3:CD006150.). If steroids are started at a later time, their benefits are unclear, although the majority of clinicians would use them in such circumstances for patients with moderate-to-severe disease (BIII). Methylprednisolone at 75% of the respective prednisone dose can be used if parenteral administration is necessary.

Alternative therapeutic regimens for mild-to-moderate disease include 1) dapsone and TMP (BI) (136Safrin S, Finkelstein DM, Feinberg 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;124:792-802., 147Medina I, Mills J, Leoung G, et al. 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;323:776-82.) (this regimen might have similar efficacy and fewer side effects than TMP-SMX but is less convenient because of the number of pills), 2) primaquine plus clindamycin (BI) (148Black JR, Feinberg J, Murphy RL, et al. Clindamycin and primaquine therapy for mild-to-moderate episodes of Pneumocystis carinii pneumonia in patients with AIDS. Clin Infect Dis 1994;18:905-13., 149Toma E, Thorne A, Singer J, et al. 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. Clin Infect Dis 1998;27:524-30., 150Smego RA, Jr., Nagar S, Maloba B, Popara M. A meta-analysis of salvage therapy for Pneumocystis carinii pneumonia. Arch Intern Med 2001;161:1529-33.) (the clindamycin component can be administered intravenously for more severe cases; however, primaquine is only available orally), and 3) atovaquone suspension (BI) (135Hughes W, Leoung G, Kramer F, et al. Comparison of atovaquone (566C80) with trimethoprim-sulfamethoxazole to treat Pneumocystis carinii pneumonia in patients with AIDS. N Engl J Med 1993;328:1521-7., 151Dohn MN, Weinberg WG, Torres RA, et al. Oral atovaquone compared with intravenous pentamidine for Pneumocystis carinii pneumonia in patients with AIDS. Ann Intern Med 1994;121:174-80.) (this is less effective than TMP-SMX for mild-to-moderate disease but has fewer side effects). Patients should be tested for G6PD deficiency whenever possible before administration of primaquine. Alternative therapeutic regimens for patients with moderate-to-severe disease include clindamycin-primaquine or intravenous (IV) pentamidine (AI) (150Smego RA, Jr., Nagar S, Maloba B, Popara M. A meta-analysis of salvage therapy for Pneumocystis carinii pneumonia. Arch Intern Med 2001;161:1529-33., 152Conte JE, Jr., Chernoff D, Feigal DW, Jr., et al. Intravenous or inhaled pentamidine for treating Pneumocystis carinii pneumonia in AIDS: a randomized trial. Ann Intern Med 1990;113:203-9., 153Wharton JM, Coleman DL, Wofsy CB, et al. Trimethoprim-sulfamethoxazole or pentamidine for Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome: a prospective randomized trial. Ann Intern Med 1986;105:37-44.) (usually the drug of second choice for severe disease). Certain clinicians prefer IV pentamidine because of convincing data regarding its high degree of efficacy. Other clinicians prefer clindamycin-primaquine because this combination is better tolerated than pentamidine, although data regarding efficacy are not as robust as the data supporting pentamidine. Aerosolized pentamidine should not be used for the treatment of PCP because of limited efficacy and more frequent relapse (DI) (152Conte JE, Jr., Chernoff D, Feigal DW, Jr., et al. Intravenous or inhaled pentamidine for treating Pneumocystis carinii pneumonia in AIDS: a randomized trial. Ann Intern Med 1990;113:203-9., 154Soo Hoo GW, Mohsenifar Z, Meyer RD. Inhaled or intravenous pentamidine therapy for Pneumocystis carinii pneumonia in AIDS: a randomized trial. Ann Intern Med 1990;113:195-202., 155Montgomery AB, Feigal DW, Jr., Sattler F, et al. Pentamidine aerosol versus trimethoprim-sulfamethoxazole for Pneumocystis carinii in acquired immune deficiency syndrome. Am J Respir Crit Care Med 1995;151:1068-74.). Trimetrexate is no longer available commercially.

The recommended duration of therapy for PCP is 21 days (AII) (91Kovacs JA, Hiemenz JW, Macher AM, et al. Pneumocystis carinii pneumonia: a comparison between patients with the acquired immunodeficiency syndrome and patients with other immunodeficiencies. Ann Intern Med 1984;100:663-71.). The probability and rate of response to therapy depend on the agent used, number of previous PCP episodes, severity of illness, degree of immunodeficiency, and timing of initiation of therapy.

Although the overall prognosis of patients whose degree of hypoxemia requires intensive care unit (ICU) admission or mechanical ventilation remains poor, survival in up to 50% of patients requiring ventilatory support has been reported in recent years (156Randall Curtis J, Yarnold PR, Schwartz DN, Weinstein RA, Bennett CL. Improvements in outcomes of acute respiratory failure for patients with human immunodeficiency virus-related Pneumocystis carinii pneumonia. Am J Respir Crit Care Med 2000;162:393-8., 157Dworkin MS, Hanson DL, Navin TR. Survival of patients with AIDS, after diagnosis of Pneumocystis carinii pneumonia, in the United States. J Infect Dis 2001;183:1409-12., 158Morris A, Wachter RM, Luce J, Turner J, Huang L. Improved survival with highly active antiretroviral therapy in HIV-infected patients with severe Pneumocystis carinii pneumonia. AIDS 2003;17:73-80.). Because long-term survival is possible for patients in whom ART is effective, certain patients with AIDS and severe PCP should be offered intensive care unit (ICU) admission or mechanical ventilation when appropriate (e.g., when they have reasonable functional status) (AII).

Because of the potential for additive or synergistic toxicities associated with anti-PCP and antiretroviral therapies, certain health-care providers delay initiation of ART until after the completion of anti-PCP therapy, or until at least 2 weeks after initiating anti-PCP therapy, despite some suggestion of potential benefit of early ART in the treatment of PCP (CIII) (157Dworkin MS, Hanson DL, Navin TR. Survival of patients with AIDS, after diagnosis of Pneumocystis carinii pneumonia, in the United States. J Infect Dis 2001;183:1409-12., 159Huang L, Quartin A, Jones D, Havlir DV. Intensive care of patients with HIV infection. N Engl J Med 2006; 355:173-81.).

Monitoring and Adverse Events, Including Immune Reconstitution Inflammatory Syndrome (IRIS)

Careful monitoring during therapy is important to evaluate response to treatment and to detect toxicity as soon as possible. Follow-up after therapy includes assessment for early relapse, especially when therapy has been with an agent other than TMP-SMX or was shortened for toxicity. PCP prophylaxis should be initiated immediately upon completion of therapy and maintained until the CD4+ count is >200 cells/µL.

Adverse reaction rates among patients with AIDS are high for TMP-SMX (20%-85%) (135Hughes W, Leoung G, Kramer F, et al. Comparison of atovaquone (566C80) with trimethoprim-sulfamethoxazole to treat Pneumocystis carinii pneumonia in patients with AIDS. N Engl J Med 1993;328:1521-7., 136Safrin S, Finkelstein DM, Feinberg 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;124:792-802., 147Medina I, Mills J, Leoung G, et al. 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;323:776-82., 149Toma E, Thorne A, Singer J, et al. 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. Clin Infect Dis 1998;27:524-30., 153Wharton JM, Coleman DL, Wofsy CB, et al. Trimethoprim-sulfamethoxazole or pentamidine for Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome: a prospective randomized trial. Ann Intern Med 1986;105:37-44., 161Eeftinck Schattenkerk JK, Lange JM, van Steenwijk RP, Danner SA. Can the course of high dose cotrimoxazole for Pneumocystis carinii pneumonia in AIDS be shorter? A possible solution to the problem of cotrimoxazole toxicity. J Intern Med 1990;227:359-62., 162Gordin FM, Simon GL, Wofsy CB, Mills J. Adverse reactions to trimethoprim-sulfamethoxazole in patients with the acquired immunodeficiency syndrome. Ann Intern Med 1984;100:495-9., 163Hughes WT, LaFon SW, Scott JD, Masur H. Adverse events associated with trimethoprim-sulfamethoxazole and atovaquone during the treatment of AIDS-related Pneumocystis carinii pneumonia. J Infect Dis 1995;171:1295-301., 164Klein NC, Duncanson FP, Lenox TH, et al. Trimethoprim-sulfamethoxazole versus pentamidine for Pneumocystis carinii pneumonia in AIDS patients: results of a large prospective randomized treatment trial. AIDS 1992;6:301-5., 165Sattler FR, Frame P, Davis R, et al. Trimetrexate with leucovorin 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;170:165-72.). Common adverse effects are rash (30%-55%) (including Stevens-Johnson syndrome), fever (30%-40%), leukopenia (30%-40%), thrombocytopenia (15%), azotemia (1%-5%), hepatitis (20%), and hyperkalemia. Supportive care for common adverse effects should be attempted before discontinuing TMP-SMX (AIII). Rashes can often be "treated through" with antihistamines, nausea can be controlled with antiemetics, and fever can be managed with antipyretics.

The most common adverse effects of alternative therapies include methemoglobinemia and hemolysis with dapsone or primaquine (especially in those with G6PD deficiency); rash and fever with dapsone (136Safrin S, Finkelstein DM, Feinberg 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;124:792-802., 147Medina I, Mills J, Leoung G, et al. 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;323:776-82.); azotemia, pancreatitis, hypo- or hyperglycemia, leukopenia, electrolyte abnormalities, and cardiac dysrhythmia with pentamidine (151Dohn MN, Weinberg WG, Torres RA, et al. Oral atovaquone compared with intravenous pentamidine for Pneumocystis carinii pneumonia in patients with AIDS. Ann Intern Med 1994;121:174-80., 152Conte JE, Jr., Chernoff D, Feigal DW, Jr., et al. Intravenous or inhaled pentamidine for treating Pneumocystis carinii pneumonia in AIDS: a randomized trial. Ann Intern Med 1990;113:203-9., 153Wharton JM, Coleman DL, Wofsy CB, et al. Trimethoprim-sulfamethoxazole or pentamidine for Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome: a prospective randomized trial. Ann Intern Med 1986;105:37-44., 164Klein NC, Duncanson FP, Lenox TH, et al. Trimethoprim-sulfamethoxazole versus pentamidine for Pneumocystis carinii pneumonia in AIDS patients: results of a large prospective randomized treatment trial. AIDS 1992;6:301-5.); anemia, rash, fever, and diarrhea with primaquine and clindamycin (136Safrin S, Finkelstein DM, Feinberg 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;124:792-802., 148Black JR, Feinberg J, Murphy RL, et al. Clindamycin and primaquine therapy for mild-to-moderate episodes of Pneumocystis carinii pneumonia in patients with AIDS. Clin Infect Dis 1994;18:905-13., 149Toma E, Thorne A, Singer J, et al. 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. Clin Infect Dis 1998;27:524-30.); and headache, nausea, diarrhea, rash, and transaminase elevations with atovaquone (135Hughes W, Leoung G, Kramer F, et al. Comparison of atovaquone (566C80) with trimethoprim-sulfamethoxazole to treat Pneumocystis carinii pneumonia in patients with AIDS. N Engl J Med 1993;328:1521-7., 163Hughes WT, LaFon SW, Scott JD, Masur H. Adverse events associated with trimethoprim-sulfamethoxazole and atovaquone during the treatment of AIDS-related Pneumocystis carinii pneumonia. J Infect Dis 1995;171:1295-301.).

IRIS has been reported following PCP. Most cases have occurred within weeks of the episode of PCP. Reported cases are not sufficient to provide guidance on the optimal time to start ART following a mild or severe case of PCP (160Wislez M, Bergot E, Antoine M, et al. Acute respiratory failure following HAART introduction in patients treated for Pneumocystis carinii pneumonia. Am J Respir Crit Care Med 2001;164:847-51., 166Koval C, Gigliotti FN, Demeter, LM. Immune reconstitution syndrome after successful treatment of Pneumocystis carinii pneumonia in a man with human immunodeficiency virus type 1 infection. Clin Infect Dis 2002;35:491-3.).

Management of Treatment Failure

Clinical failure is defined as lack of improvement or worsening of respiratory function documented by arterial blood gases (ABGs) after at least 4-8 days of anti-PCP treatment. Treatment failure attributed to treatment-limiting toxicities occurs in up to one third of patients (136Safrin S, Finkelstein DM, Feinberg 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;124:792-802.). Switching to another regimen is the appropriate management for treatment-related toxicity (BII). Failure attributed to lack of drug efficacy occurs in approximately 10% of those with mild-to-moderate disease. No convincing clinical trials exist on which to base recommendations for the management of treatment failure attributed to lack of drug efficacy. Clinicians should wait at least 4-8 days before switching therapy for lack of clinical improvement (BIII). In the absence of corticosteroid therapy, early and reversible deterioration within the first 3-5 days of therapy is typical, probably because of the inflammatory response caused by antibiotic-induced lysis of organisms in the lung. Other concomitant infections must be excluded as a cause for clinical failure (98Baughman RP, Dohn MN, Frame PT. The continuing utility of bronchoalveolar lavage to diagnose opportunistic infection in AIDS patients. Am J Med 1994;97:515-22., 99Stover DE, Zaman MB, Hajdu SI, et al. Bronchoalveolar lavage in the diagnosis of diffuse pulmonary infiltrates in the immunosuppressed host. Ann Intern Med 1984;101:1-7.); bronchoscopy with bronchoalveolar lavage should be strongly considered to evaluate for this possibility, even if it was conducted before initiating therapy.

If TMP-SMX has failed or must be avoided for toxicity in moderate-to-severe disease, the common practice is to use parenteral pentamidine or primaquine combined with clindamycin (BII) (149Toma E, Thorne A, Singer J, et al. 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. Clin Infect Dis 1998;27:524-30., 153Wharton JM, Coleman DL, Wofsy CB, et al. Trimethoprim-sulfamethoxazole or pentamidine for Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome: a prospective randomized trial. Ann Intern Med 1986;105:37-44., 165Sattler FR, Frame P, Davis R, et al. Trimetrexate with leucovorin 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;170:165-72.). As noted above, trimetrexate is no longer available commercially. For mild disease, atovaquone is a reasonable alternative (BII). Although one meta-analysis concluded that the combination of clindamycin and primaquine might be the most effective regimen for salvage therapy (150Smego RA, Jr., Nagar S, Maloba B, Popara M. A meta-analysis of salvage therapy for Pneumocystis carinii pneumonia. Arch Intern Med 2001;161:1529-33.), no prospective clinical trials have evaluated the optimal approach to patients who experience a therapy failure with TMP-SMX.

Preventing Recurrence

Patients who have a history of PCP should be administered chemoprophylaxis for life (i.e., secondary prophylaxis or chronic maintenance therapy) with TMP-SMX unless immune reconstitution occurs as a result of ART (167Masur H, Kaplan JE, Holmes KK. Guidelines for preventing opportunistic infections among HIV-infected persons-2002: Recommendations of the U.S. Public Health Service and the Infectious Diseases Society of America. Ann Intern Med 2002;137:435-78.) (AI). For patients who are intolerant of TMP-SMX, alternatives are dapsone, dapsone combined with pyrimethamine, atovaquone, or aerosolized pentamidine.

Discontinuing Secondary Prophylaxis (Chronic Maintenance Therapy)

Secondary prophylaxis should be discontinued for adult and adolescent patients whose CD4+ count has increased from <200 cells/µL to >200 cells/µL for >3 months as a result of ART (BII). Reports from observational studies (126Dworkin MS, Hanson DL, Kaplan JE, Jones JL, Ward JW. Risk for preventable opportunistic infections in persons with AIDS after antiretroviral therapy increases CD4+ T lymphocyte counts above prophylaxis thresholds. J Infect Dis 2000;182:611-5., 132Kirk O, Lundgren JD, Pedersen C, Nielsen H, Gerstoft J. Can chemoprophylaxis against opportunistic infections be discontinued after an increase in CD4 cells induced by highly active antiretroviral therapy? AIDS 1999;13:1647-51., 168Soriano V, Dona C, Rodriguez-Rosado R, Barreiro P, Gonzalez-Lahoz J. Discontinuation of secondary prophylaxis for opportunistic infections in HIV-infected patients receiving highly active antiretroviral therapy. AIDS 2000;14:383-6., 169Zellweger C, Opravil M, Bernasconi E, et al. Long-term safety of discontinuation of secondary prophylaxis against Pneumocystis pneumonia: prospective multicentre study. AIDS 2004;18:2047-53.) and from two randomized trials (133,170) and a combined analysis of eight European cohorts being followed prospectively (171) support this recommendation. In these studies, patients had responded to ART with an increase in CD4+ counts to ≥200 cells/µL for >3 months. The majority of patients were taking PI-containing regimens. The median CD4+ count at the time prophylaxis was discontinued was >300 cells/µL and most had a CD4+ cell percentage of >14%. The majority of patients had sustained suppression of plasma HIV RNA levels below the detection limits of the assay employed; the longest follow-up was 40 months. If the episode of PCP occurred at a CD4+ count of >200 cells/µL, continuing PCP prophylaxis for life, regardless of how high the CD4+ count rises as a consequence of ART, would be prudent (CIII); however, data regarding the most appropriate approach in this setting are limited.

Discontinuing secondary prophylaxis for patients is recommended because prophylaxis adds limited disease prevention (i.e., for PCP, toxoplasmosis, or bacterial infections) and because discontinuing drugs reduces pill burden, potential for drug toxicity, drug interactions, selection of drug-resistant pathogens, and cost.

Prophylaxis should be reintroduced if the CD4+ count decreases to <200 cells/µL (AIII). If PCP recurs at a CD4+ count of >200 cells/µL, lifelong prophylaxis should be administered (CIII).

Special Considerations During Pregnancy

PCP diagnostic considerations for pregnant women are the same as for nonpregnant women. Indications for therapy are the same as for nonpregnant women. The preferred initial therapy during pregnancy is TMP-SMX, although alternate therapies can be used if patients are unable to tolerate or are unresponsive to TMP-SMX (172Connelly RT, Lourwood DL. Pneumocystis carinii pneumonia prophylaxis during pregnancy. Pharmacotherapy 1994;14:424-9.) (AI). In case-control studies, trimethoprim has been associated with an increased risk for neural tube defects and cardiovascular, urinary tract, and multiple anomalies after first-trimester exposure (173Czeizel AE, Rockenbauer M, Sorensen HT, Olsen J. The teratogenic risk of trimethoprim-sulfonamides: a population based case-control study. Reprod Toxicol 2001;15:637-46., 174Hernandez-Diaz S, Werler MM, Walker AM, Mitchell AA. Folic acid antagonists during pregnancy and the risk of birth defects. N Engl J Med 2000;343:1608-14., 175Hernandez-Diaz S, Werler MM, Walker AM. Neural tube defects in relation to use of folic acid antagonists during pregnancy. Am J Epidemiol 2001;153:961-8.). Epidemiologic data suggest that folic acid supplementation might reduce this risk (174Hernandez-Diaz S, Werler MM, Walker AM, Mitchell AA. Folic acid antagonists during pregnancy and the risk of birth defects. N Engl J Med 2000;343:1608-14., 175Hernandez-Diaz S, Werler MM, Walker AM. Neural tube defects in relation to use of folic acid antagonists during pregnancy. Am J Epidemiol 2001;153:961-8.), but no controlled studies have been done. In a small study, an increased risk for birth defects among infants born to women receiving antiretrovirals and folate antagonists, primarily trimethoprim, was reported, whereas no increase was observed among those with either antiretroviral or folate antagonist exposure alone (176Jungmann EM, Mercey D, DeRuiter A, et al. Is first trimester exposure to the combination of antiretroviral therapy and folate antagonists a risk factor for congenital abnormalities? Sex Transm Infect 2001;77:441-3.). Although first-trimester exposure to trimethoprim might be related to a small increased risk for birth defects, pregnant women in their first trimester with PCP should be treated with TMP-SMX (AIII). Although folic acid supplementation of 0.4 mg/day is routinely recommended for all pregnant women (177CDC. Recommendations for the use of folic acid to reduce the number of cases of spina bifida and other neural tube defects. MMWR 1992;41(No. RR-14).), data do not indicate if higher levels of supplementation, such as the 4 mg/day recommended for pregnant women with a previous infant with a neural tube defect, would provide added benefit in this situation. Follow-up ultrasound to assess fetal anatomy at 18-20 weeks is recommended (BIII).

Neonatal-care providers should be informed of maternal sulfa or dapsone therapy if used near the delivery date because of the theoretical increased risk for hyperbilirubinemia and kernicterus (178Andersen DH, Blanc WA, Crozier DN, Silverman WA. A difference in mortality rate and incidence of kernicterus among premature infants allotted to two prophylactic antibacterial regimens. Pediatrics 1956;18:614-25.).

Pentamidine is embryotoxic but not teratogenic among rats and rabbits (179Harstad TW, Little BB, Bawdon RE, et al. Embryofetal effects of pentamidine isethionate administered to pregnant Sprague-Dawley rats. Am J Obstet Gynecol 1990;163:912-6.). Adjunctive corticosteroid therapy should be used as indicated in nonpregnant adults (180Albino JA, Shapiro JM. Respiratory failure in pregnancy due to Pneumocystis carinii: report a successful outcome. Obstet Gynecol 1994;83:823-4., 181Madinger NE, Greenspoon JS, Ellrodt AG. Pneumonia during pregnancy: has modern technology improved maternal and fetal outcome? Am J Obstet Gynecol 1989;161:657-62., 182Koonin LM, Ellerbrock TV, Atrash HK, et al. Pregnancy-associated deaths due to AIDS in the United States. JAMA 1989;261:1306-9., 183Benedetti TJ, Valle R, Ledger WJ. Antepartum pneumonia in pregnancy. Am J Obstet Gynecol 1982;144:413-7.) (AIII). Maternal fasting and postprandial glucose levels should be monitored closely when corticosteroids are used in the third trimester because the risk for glucose intolerance is increased.

Rates of preterm labor and preterm delivery are increased with pneumonia during pregnancy. Pregnant women with pneumonia after 20 weeks of gestation should be monitored for evidence of contractions (BII).

Chemoprophylaxis for PCP should be administered to pregnant women the same as for other adults and adolescents (AIII). TMP-SMX is the recommended prophylactic agent; dapsone is an alternative. Because of theoretical concerns regarding possible teratogenicity associated with drug exposures during the first trimester, health-care providers might withhold prophylaxis during the first trimester. In such cases, aerosolized pentamidine can be considered because of its lack of systemic absorption and the resultant lack of exposure of the developing embryo to the drug (CIII).

Prophylaxis to prevent first episode of opportunistic disease: Pneumocystis pneumonia (PCP)
IndicationFirst choiceAlternative
Excerpted from Table 1
Abbreviations: DS = double strength; SS = single strength

CD4+ count <200 cells/µL (AI) or oropharyngeal candidiasis (AII)

CD4+ <14% or history of AIDS-defining illness (BII)

CD4+ count >200 but <250 cells/µL if monitoring CD4+ count every 1-3 months is not possible (BII)

Trimethoprim-sulfamethoxazole (TMP-SMX), 1 DS PO daily (AI); or 1 SS daily (AI)

transparent gifgrey bulletTMP-SMX 1 DS PO tiw (BI); or
transparent gif
transparent gifgrey bulletDapsone 100 mg PO daily or 50 mg PO bid (BI); or
transparent gif
transparent gifgrey bulletDapsone 50 mg PO daily + pyrimethamine - 50 mg PO weekly + leucovorin 25 mg PO weekly (BI); or
transparent gif
transparent gifgrey bulletAerosolized pentamidine 300 mg via Respigard II™ nebulizer every month (BI); or
transparent gif
transparent gifgrey bulletAtovaquone 1,500 mg PO daily (BI); or
transparent gif
transparent gifgrey bulletAtovaquone 1,500 mg + pyrimethamine 25 mg + leucovorin 10 mg PO daily (CIII)
transparent gif
Drug therapy for treatment and chronic maintenance therapy of AIDS-associated opportunistic infections in adults and adolescents: Pneumocystis pneumonia (PCP)
Preferred therapy, duration of therapy, chronic maintenanceAlternative therapyOther options/issues
Excerpted from Table 2
Preferred treatment for moderate to severe PCPAlternative therapy for moderate to severe PCPIndications for corticosteroids (AI)
transparent gifgrey bulletTrimethoprim-sulfamethoxazole (TMP-SMX): [15-20 mg TMP and 75-100 mg SMX]/kg/day IV administered q6h or q8h (AI), may switch to PO after clinical improvement (AI)
transparent gif
transparent gifgrey bulletDuration of therapy: 21 days (AII)
transparent gif
transparent gifgrey bulletPentamidine 4 mg/kg IV daily infused over ≥60 minutes (AI), certain specialists reduce dose to 3 mg/kg IV daily because of toxicities (BI); or
transparent gif
transparent gifgrey bulletPrimaquine 15-30 mg (base) PO daily plus clindamycin 600-900 mg IV q6h to q8h or clindamycin 300-450 mg PO q6h to q8h (AI)
transparent gif
transparent gifgrey bulletPaO2 >70 mmHg at room air or alveolar-arterial O2 gradient >35 mmHg
transparent gif
transparent gifgrey bulletPrednisone doses (beginning as early as possible and within 72 hours of PCP therapy) (AI):
Days 1-5 -- 40 mg PO bid
Days 6-10 -- 40 mg PO daily
Days 11-21 -- 20 mg PO daily
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transparent gifgrey bullet IV methylprednisolone can be administered as 75% of prednisone dose
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transparent gifgrey bulletBenefits of corticosteroid if started after 72 hours of treatment is unknown, but a majority of clinicians will use it in patients with moderate to severe PCP (BIII)
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transparent gifgrey bulletWhenever possible, patients should be tested for G6PD deficiency before use of primaquine
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Preferred treatment for mild to moderate PCPAlternative therapy for mild-to-moderate PCP
transparent gifgrey bulletSame daily dose of TMP-SMX as above, administered PO in 3 divided doses (AI); or
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transparent gifgrey bulletTMP-SMX (160 mg/800 mg or DS) 2 tablets tid (AI)
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transparent gifgrey bulletDuration of therapy: 21 days (AII)
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transparent gifgrey bulletDapsone 100 mg PO daily and TMP 15 mg/kg/day PO (3 divided doses) (BI); or
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transparent gifgrey bulletPrimaquine 15-30 mg (base) PO daily plus clindamycin 300-450 mg PO q6h to q8h (BI); or
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transparent gifgrey bulletAtovaquone 750 mg PO bid with food (BI)
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Preferred secondary prophylaxisAlternative secondary prophylaxis
transparent gifgrey bulletTMP-SMX (160 mg/800 mg or DS) tablet PO daily (AI); or
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transparent gifgrey bulletTMP-SMX (80 mg/400 mg or SS) tablet PO daily (AI)
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transparent gifgrey bulletTMP-SMX (160 mg/800 mg or DS) PO tiw (BI)
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transparent gifgrey bulletDapsone 50 mg PO bid or 100 mg PO daily (BI); or
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transparent gifgrey bulletDapsone 50 mg PO daily plus pyrimethamine 50 mg PO weekly plus leucovorin 25 mg PO weekly (BI); or
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transparent gifgrey bulletDapsone 200 mg PO plus pyrimethamine 75 mg PO plus leucovorin 25 mg PO weekly (BI); or
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transparent gifgrey bulletAerosolized pentamidine 300 mg every month via Respirgard II™ nebulizer (BI); or
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transparent gifgrey bulletAtovaquone 1,500 mg PO daily (BI); or
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transparent gifgrey bulletAtovaquone 1,500 mg + pyrimethamine 25 mg + leucovorin 10 mg PO daily (CIII)
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