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Case 1: Discussion

Pneumocystis pneumonia (PCP) remains an important opportunistic infection among HIV-infected persons who have advanced immunosuppression. The causative agent, Pneumocystis jiroveci (formerly Pneumocystis carinii), was renamed in honor of Otto Jirovec, the Czech pathologist, who first identified this organism as the cause of outbreaks of interstitial pneumonia in premature and malnourished infants in Europe in the 1930s and 1940s[1,2]. Based on DNA sequence analysis, P. jiroveci is now classified as a fungus, although unlike other fungi, it lacks ergosterol and is extraordinarily difficult to grow in culture. This organism shares some biologic characteristics with protozoa.

Transmission of Pneumocystis jiroveci

Airborne transmission of P. jiroveci has been demonstrated in animal studies and transmission in humans most likely also occurs via the airborne route. Based on serologic testing, nearly 100% of children acquire infection with P. jiroveci by age 2[3]. Earlier expert opinion suggested Pneumocystis pneumonia was due to reactivation of latent infection, but subsequent reports identified clustered cases of Pneumocystis pneumonia among immunocompromised groups, suggesting that acute disease can develop due to person-to-person spread of P. jiroveci[2]. In addition, in recent studies, investigators detected P. jiroveci in air samples surrounding hospitalized patients with Pneumocystis pneumonia[4] and they documented regional clustering of drug-resistant strains[5], thus suggesting inter-human transmission. Furthermore, molecular analyses of P. jiroveci strains refute the hypothesis that disease predominantly results from reactivation of dormant organisms acquired in childhood[1].

Risk of Developing Pneumocystis Pneumonia

Among HIV-infected patients in the pre-HAART era, the risk of ever developing Pneumocystis pneumonia without preventive therapy was approximately 80%, and the likelihood of relapse without secondary prophylaxis was 70 to 80%[6]. Formerly, Pneumocystis pneumonia was the most common AIDS-defining opportunistic infection and was responsible for almost 30% of all cases of community-acquired pneumonia in HIV-infected patients. The incidence of HIV-associated Pneumocystis pneumonia in the United States peaked in 1990 (20,000 cases/year) and then initially declined due to widespread use of Pneumocystis pneumonia prophylaxis. Subsequently, a more prominent decline resulted from the widespread use of effective antiretroviral therapy (Figure 1)[2,7]. Further decline in the number of cases of Pneumocystis pneumonia in HIV-infected persons has occurred in recent years (Figure 2)[8].

Recommendations for Preventing Exposure to P. jiroveci

According to the 2009 Guidelines for the Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents, published by the CDC, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America (IDSA), no specific measures are recommended as standard practice for preventing exposure to P. jiroveci[9]. Some experts recommend that HIV-infected persons at risk for Pneumocystis pneumonia should not share a hospital room with another patient who has acute Pneumocystis pneumonia, but insufficient data exist to routinely recommend this practice.

Recommendations for Initiating Primary Prophylaxis

Prophylaxis for Pneumocystis pneumonia is classified as either primary prophylaxis (preventing first episode of Pneumocystis pneumonia) or secondary prophylaxis (preventing recurrence of Pneumocystis pneumonia). Among asymptomatic HIV-infected patients, a CD4 count less than 200 cells/mm3 is the strongest identified risk factor for developing Pneumocystis pneumonia (RR 4.9 compared with patients who have a CD4 count greater than 200 cells/mm3)[10]. Other independent risk factors for developing Pneumocystis pneumonia include a history of oral candidiasis, a CD4 percentage less than 14, or a history of an AIDS-defining illness[10,11]. The 2009 U.S. opportunistic infections guidelines strongly recommend initiating primary prophylaxis for Pneumocystis pneumonia for patients who have an absolute CD4 count less than 200 cells/mm3 or a history of oral candidiasis (Figure 3); these guidelines include a rating scheme indicating the strength of the recommendation (A-E) and the quality of evidence supporting the recommendation (I-III) (Figure 4)[9]. These guidelines also recommend considering prophylaxis for patients who have a CD4 percentage less than 14 or a history of an AIDS-defining illness. Further, prophylaxis for Pneumocystis pneumonia should be considered for patients who have a CD4 count between 200 and 250 cells/mm3 if regular monitoring of the CD4 cell count is not possible.

Recommended First Choice Prophylaxis Regimens

Trimethoprim-sulfamethoxazole (Bactrim, Septra) provides the most effective primary and secondary prophylaxis against Pneumocystis pneumonia[12,13]. Use of trimethoprim-sulfamethoxazole has the added benefit of providing protection against Toxoplasma encephalitis[25], isosporiasis[24], and some community-acquired bacterial pathogens[26]. The 2009 opportunistic infection guidelines recommends trimethoprim-sulfamethoxazole at a dose of one double-strength or one single strength tablet daily as the preferred prophylaxis regimen (Figure 3)[9]. Common adverse effects due to trimethoprim-sulfamethoxazole include rash and fever that may occur in up to 50 to 60% of patients. Less common side effects include leukopenia, hepatitis, hyperkalemia, nephritis and, rarely, aseptic meningitis.

Recommended Alternative Prophylaxis Regimens

Alternative regimens exist for Pneumocystis pneumonia prophylaxis in patients unable to take trimethoprim-sulfamethoxazole daily, including trimethoprim-sulfamethoxazole dosed at one double-strength tablet three times weekly (which is associated with fewer adverse effects than with daily dosing)[14], dapsone, aerosolized pentamidine (NebuPent, Pentam), and atovaquone (Mepron). Dapsone (or dapsone plus pyrimethamine plus leucovorin) is an effective alternative, but some who are intolerant of trimethoprim-sulfamethoxazole will also develop intolerance to dapsone. Moreover, dapsone can cause hemolytic anemia, particularly in glucose-6-phosphate dehydrogenase (G6PD)-deficient persons, and methemoglobinemia regardless of G6PD status. If dapsone is used for Pneumocystis pneumonia prophylaxis and Toxoplasma encephalitis prophylaxis is also required, pyrimethamine and leucovorin should be added. Monthly, aerosolized pentamidine is moderately effective, but inferior to trimethoprim-sulfamethoxazole[13]. Distribution of aerosolized pentamidine throughout the lung is not uniform and patients may develop Pneumocystis pneumonia in the lung periphery and upper lobes[15]. In addition, aerosolized pentamidine does not provide protect against extra-pulmonary P. jiroveci infection. The major adverse effect of aerosolized pentamidine is bronchial airway constriction, which can be overcome or prevented with inhaled bronchodilators. Atovaquone causes few adverse effects and is equivalent to dapsone for the prevention of Pneumocystis pneumonia, but is very expensive[16].

Resistance to Trimethoprim-Sulfamethoxazole

The antimicrobial effect of trimethoprim-sulfamethoxazole results from its inhibition of enzymes that catalyze successive steps in folate synthesis. Sulfamethoxazole (and dapsone) inhibit the enzyme dihydropteroate synthase (DHPS) and trimethoprim inhibits dihydrofolate reductase (DHFR) (Figure 5). Standard testing for bacterial resistance to trimethoprim-sulfamethoxazole is performed using in vitro susceptibility testing (growth of the bacteria in the presence of drug). Since P. jiroveci cannot be easily grown in vitro, P. jiroveci resistance testing requires sequence analysis of the genes for DHPS and DHFR. Several studies have investigated the prevalence of DHPS and DHFR mutations in patients with P. jiroveci and detected DHPS mutations in 77% of patients who had received sulfamethoxazole prophylaxis versus 20% of patients who had not received sulfamethoxazole prophylaxis[2]. The presence of these mutations in sulfa-exposed patients has not correlated well with trimethoprim-sulfamethoxazole treatment failure or decreased survival, making the clinical significance of these mutations uncertain[18]. Mutations in DHFR, the target of trimethoprim, have not been observed with P. jiroveci, suggesting that trimethoprim provides no selective pressure (and possibly no treatment effect) on P. jiroveci[19]. More recently, a retrospective European study has reported that interhuman spread of resistant strains accounts for a significant proportion of the (DHPS) resistance found in HIV-infected patients[5].

Desensitization to Trimethoprim-Sulfamethoxazole

Adverse reactions to trimethoprim-sulfamethoxazole and dapsone are common among HIV-infected patients, with a mean onset at day 10 to 14[6]. Unfortunately, patients who are intolerant of trimethoprim-sulfamethoxazole have approximately a 40% chance of having an adverse reaction to dapsone. For patients who develop a rash due to trimethoprim-sulfamethoxazole, desensitization to trimethoprim-sulfamethoxazole is ultimately successful in 37 to 70% (less success with longer follow-up) and should be attempted if the rash is not severe. Gradual desensitization to trimethoprim-sulfamethoxazole can be accomplished in the outpatient setting using a liquid suspension of trimethoprim-sulfamethoxazole (Figure 6)[20]. The patient should not be rechallenged with trimethoprim-sulfamethoxazole if the prior reaction included hepatitis, aseptic meningitis, or a a severe hypersensitivity reaction (marked by high fever, severe rash, or mucosal involvement suggestive of Stevens-Johnson syndrome)[6].

Recommendations for Discontinuing Primary Prophylaxis

Multiple studies have shown that HIV-infected persons receiving effective antiretroviral therapy who have a CD4 count that increases above 200 cells/mm3 (for at least 3 months) have an extremely low risk of developing Pneumocystis pneumonia[9,21,22]. In these studies, patients generally had sustained excellent responses to antiretroviral therapy. Accordingly, the 2009 opportunistic infections guidelines recommend that patients should discontinue primary Pneumocystis pneumonia prophylaxis if they have responded to effective combination antiretroviral therapy and their CD4 counts have increased to greater than 200 cells/mm3 for at least 3 months. Discontinuing prophylaxis can reduce pill burden, cost, the potential for drug toxicity, and the risk of developing resistant infectious pathogens. If a patient's CD4 count subsequently decreases to less than 200 cells/mm3, the patient should restart Pneumocystis prophylaxis[9]. Notably, a recent study reported that patients on antiretroviral therapy with suppressed HIV (less than 400 copies/ml), CD4 counts between 100 and 200 cells/mm3, and not taking Pneumocystis pneumonia prophylaxis had rates of Pneumocystis pneumonia, similar to those on prophylaxis, suggesting it may be safe to discontinue prophylaxis in these individuals[23]. These findings, however, need to be confirmed in other studies before such a recommendation should be adopted into practice.

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    Figure 1. Trends for Pneumocystis Pneumonia in United States, 1992-1998

    The data is obtained via the Adult and Adolescent Spectrum of Disease Project during the years 1992-1998. The data represent the number of cases of Pneumocystis pneumonia per 100 person-years. The graph shows a major decline in cases of Pneumocystis pneumonia in the era of highly active antiretroviral therapy (HAART). The figure is adapted from Kaplan JE, Hanson D, Dworkin MS, et al. Epidemiology of human immunodeficiency virus-associated opportunistic infections in the United States in the era of highly active antiretroviral therapy. Clin Infect Dis. 2000;30 Suppl 1:S5-14. This figure is adapted from and reproduced with permission from the University of Chicago Press. Copyright © 2000 by the Infectious Diseases Society of America. All rights reserved.


    Figure 1
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    Figure 2. Incidence of <em>Pneumocystis</em> Pneumonia in United States: The HIV Outpatient Study, 1994-1997

    From: Buchacz K, Baker RK, Palella FJ Jr, et al. AIDS-defining opportunistic illnesses in U.S. patients, 1994-2007: a cohort study. AIDS. 2010;24:1549-59.


    Figure 2
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    Figure 3. Primary Prophylaxis for <em>Pneumocystis</em> Pneumonia

    Abbreviations: TMP-SMX = trimethoprim-sulfamethoxazole; DS = double strength; SS = single strength; qd = once daily; bid = twice daily; qwk = once weekly; 3x/wk = three times per week. Therapy is oral unless otherwise noted. From Kaplan JE, Benson C, Holmes KK, et al. Guidelines for prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. MMWR Recomm Rep. 2009;58(RR-4):1-207.


    Figure 3
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    Figure 4. Rating Scheme for the Opportunistic Infections Prevention and Treatment Recommendations

    From: Kaplan JE, Benson C, Holmes KK, et al. Guidelines for prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. MMWR Recomm Rep. 2009;58(RR-4):1-207.


    Figure 4
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    Figure 5. Mechanism of Action of Sulfamethoxazole, Dapsone, and Trimethoprim

    Sulfamethoxazole and dapsone exert their antimicrobial effect by competitively inhibiting the incorporation of para-aminobenzoic acid into dihydropteroic acid. Trimethoprim exerts its effect by inhibiting dihydrofolate reductase and this effect is at least 10,000 times more active in microorganisms than in humans. Inhibiting the synthesis of tetrahydrofolic acid is critical since it is the physiologically active form of folic acid, an essential factor in DNA synthesis. Humans do not synthesize folic acid, but they do acquire it via food intake.


    Figure 5
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    Figure 6. Protocol for Trimethoprim-Sulfamethoxazole Desensitization*

    *Liquid suspension: 5 ml = 40 mg trimethoprim plus 200 mg sulfamethoxazole. Abbreviations: SS = single strength; DS = double strength. Adapted from: Para MF, Finkelstein D, Becker S, Dohn M, Walawander A, Black JR. Reduced toxicity with gradual initiation of trimethoprim-sulfamethoxazole as primary prophylaxis for Pneumocystis carinii pneumonia: AIDS Clinical Trials Group 268. J Acquir Immune Defic Syndr. 2000;24:337-43.


    Figure 6