Prevention of Infection Caused by Pneumocystis carinii in Transplant Recipients
- David R. Snydman, Section Editor
- Infectious Disease Division and Transplantation Unit, Massachusetts General Hospital, Harvard Medical School, Boston
- Reprints or correspondence: Dr. Jay A. Fishman, Infectious Disease Division, Massachusetts General Hospital, 55 Fruit St., Boston, MA 02114 (Jfishman{at}partners.org).
Abstract
Pneumocystis carinii remains an important pathogen in patients who undergo solid-organ and hematopoietic transplantation. Infection results from reactivation of latent infection and via de novo acquisition of infection from environmental sources. The risk of infection depends on the intensity and duration of immunosuppression and underlying immune deficits. The risk is greatest after lung transplants, in individuals with invasive cytomegalovirus disease, during intensive immunosuppression for allograft rejection, and during periods of neutropenia. Prophylaxis with trimethoprim-sulfamethoxazole (TMP-SMZ) prevents many opportunistic infections, including infection with P. carinii, Toxoplasma gondii, and community-acquired respiratory, gastrointestinal, and urinary tract pathogens. Intolerance of TMP-SMZ is common; desensitization is useful less often in transplant patients than in patients with AIDS. Alternative agents provide a narrower spectrum of protection than does TMP-SMZ and less adequate protection against Pneumocystis species. Clinically, the diagnosis of breakthrough Pneumocystis pneumonia often requires invasive procedures. Strategies for the prevention of Pneumocystis infection must be individualized on the basis of a stratification of risk for each patient.
Pneumocystis carinii remains an important pathogen in immunocompromised individuals despite the variety of effective antimicrobial strategies. Prophylactic strategies should reflect the nature of predisposing immune deficits, the ability of patients to tolerate specific agents, geography, and the medical institution. Studies of the microbial pathogenesis, antimicrobial susceptibility, and molecular biology of Pneumocystis species provide a basis for the development of additional therapies.
Targets For Antimicrobial Development
Some features of the life cycle of Pneumocystis species are relevant to consideration of the antimicrobial agents used in prophylaxis and therapy (table 1). Three forms of the organism have been identified: trophozoite, cyst, and sporozoite (or “intracystic body”). In the alveolus, Pneumocystis species are embedded in glycoproteins derived from the organism and host, including immunoglobulins, albumin, surfactant, laminin, and fibronectin. This coating may interfere with antibody-mediated lysis, opsonization, and phagocytosis. The cell wall contains cholesterol but no ergosterol. Pneumocystis species do not seem to synthesize sterols de novo, which accounts for the lack of susceptibility to most antifungal agents [1]. The presence of chitin in the cell wall is controversial. The surface of P. carinii is carbohydrate rich, with glucose, mannose, and β-1,3-glucan [2, 3]. The echinocandin and papulocandin antifungal agents inhibit β-1,3,glucan synthase and block Pneumocystis cyst formation [4–8]. These agents used for prophylaxis produce trophozoite-only infection via asexual replication. The neutral lipid fraction of P. carinii includes a variety of phytosterols also found in plants and fungi, including Physarum species [9].
Table 1
Potential targets for antimicrobial agents in Pneumocystis carinii.
Subspecies of P. carinii have been described on the basis of relative host species specificity, geography, antigens, enzymes, and genes [10–13]. Such strains may differ in susceptibility to antimicrobial agents (reviewed by Stringer [14] and Stringer and Cushion [15]). Molecular phylogenetic data, the presence of separate genes encoding the thymidylate synthase and dihydrofolate reductase, a cyst wall rich in β-glucan, poorly developed mitochondria, and the airborne spread of infection support taxonomic assignment with the fungi [16–18]. However, the thick-walled cyst with internal “sporozoites” and amoeboid trophozoites, the absence of ergosterol, apparent haploidy of trophozoites, the low copy number of ribosomal RNA genes, susceptibility to antiprotozoal agents, and the existence of antigenic variation lend credence to identification with the protozoa. Unique cell wall components (glucans and phytosterols), synthetic pathways (e.g., topoisomerases), and self-splicing group I intron mRNAs may provide targets for the development of antimicrobial agents [9, 19–24].
Antimicrobial Susceptibility: In Vivo and In Vitro Cultivation
Continuous cultivation of P. carinii in vitro for use in antimicrobial susceptibility testing has not been consistently achieved [19, 25–27]. In vitro studies demonstrate differences between the activity of compounds against isolated target enzymes and against intact organisms (e.g., dihydrofolate reductase [28]). Rodent models have been used to mimic the effects of various immune deficiencies and to confirm in vitro data [29–32].
The emergence of resistance by P. carinii to antimicrobial agents has not been clearly demonstrated for human-derived organisms associated with therapeutic failures [33–35]. The slow replication rate of the organism (7–10 days) might predict that antimicrobial resistance of P. carinii would emerge slowly. However, prolonged survival of immunocompromised hosts receiving anti-Pneumocystis prophylaxis may, ultimately, contribute to the development of resistant strains. For example, polymorphisms in dihydropteroate synthase (DHPS) genes of P. carinii recovered from patients receiving trimethoprim-sulfamethoxazole (TMP-SMZ) are consistent with the evolution of DHPS genes under selective pressure from sulfa drugs [34].
Pathogenesis of Infection
In rodent models, protein-calorie malnutrition and immunosuppression result in the development of P. carinii pneumonitis. This observation suggested that Pneumocystis pneumonitis is the result of the emergence of latent infection during immunosuppression [36, 37]. These data are consistent with serologic evidence of exposure by the age of 4 years in most individuals [38–40]. However, organisms are identified in 0%–8% of autopsies. This carrier state can be eradicated in infected animals with TMP-SMZ; subsequent immunosuppression does not result in the reemergence of infection in animals maintained in respiratory isolation [41]. Eradication of carriage in humans after pneumonia has not been achieved. Aerosol transmission of the organism has been demonstrated in the animal model by Hughes and coworkers [29, 30]. Relatively few organisms (10–100 cysts) are needed to cause infection in immunocompromised animals [42]. Epidemiologic studies and reports of clusters of infection in oncology centers and in renal transplant recipients support the acquisition of infection from environmental or human sources [43–47]. Molecular studies in animals and humans, using a variety of genetic probes, have suggested that both reinfection and reactivation of latent infection are significant factors in disease incidence [48, 49]. Thus, it is reasonable to isolate patients with known Pneumocystis pneumonia from other immunocompromised individuals. However, immunocompromised individuals receiving effective prophylaxis should not be considered at risk for the spread or acquisition of infection.
T lymphocyte deficiencies are important to the pathogenesis of P. carinii infection [32, 50, 51]. Passive transfer of immune T lymphocytes is protective against P. carinii pneumonia in mice, whereas transfer of Ig is only partially protective [52]. Mice with defects in macrophage function are also susceptible to Pneumocystis pneumonia. In patients with AIDS, the risk of infection increases with the decrease of the CD4+ lymphocyte count to <300 cells/mm3 and increases to <200 cells/mm3, or to <20% of the total lymphocyte pool. The rate of infection nearly doubles with a decrease in CD4+ lymphocyte counts, from 100–200 cells/mm3 to <100 cells/mm3. Treatment of HIV infection with highly active antiretroviral therapy (HAART) with reversal of immunodeficiency seems to eliminate the risk of Pneumocystis pneumonia (studied up to 2 years) in patients with AIDS, with and without prior Pneumocystis pneumonia [53–56]. Few data exist on the incidence of Pneumocystis pneumonia in solid-organ transplant recipients in the era of calcineurin inhibitors, mycophenolate mofetil, and sirolimus. In patients with less intensive immunosuppression (e.g., Wegener's granulomatosis) but often with lung injury, prophylaxis with TMP-SMZ is cost-effective and life prolonging for the duration of immunosuppression [57].
Patients Requiring Prophylaxis
The spectrum of patients requiring anti-Pneumocystis prophylaxis has changed with evolving immunosuppressive regimens for organ transplantation, graft-versus-host disease and connective tissue diseases, intensive chemotherapeutic regimens for malignancy, and, conversely, the decreasing incidence of opportunistic infections in patients with AIDS (table 2). In most immunocompromised patients who do not have AIDS, the risk of disease is of the order of 5%–15%, depending on the nature and duration of the immunosuppression. Routine anti-Pneumocystis prophylaxis has been reserved, in general, for centers or patient groups that are known to have a fixed high incidence of disease (i.e., on the order of 3%–5% of susceptible hosts) or for individuals with recurrent Pneumocystis disease.
Table 2
Conditions associated with Pneumocystis carinii pneumonia.
The relative risk of infection with Pneumocystis is greatest during the first 6 months after solid-organ transplantation; in patients receiving prolonged courses of corticosteroid therapy; in patients with prolonged neutropenia; and in patients with acutely increased immunosuppression for graft rejection, graft-versus-host disease, or flares of autoimmune diseases [58]. The rate of Pneumocystis infection seems to have increased during the past 10 years, but this observation may be an artifact of improved diagnostic capabilities [59–61]. At our center, 14% of nonprophylaxed renal transplant recipients develop Pneumocystis pneumonia. In solid-organ transplant recipients, bolus corticosteroids and the calcineurin inhibitors contribute to the risk of Pneumocystis pneumonia [62–64]. Although mycophenolate mofetil may have some intrinsic anti-Pneumocystis activity [65], this does not seem to be protective in vivo. Patients who have undergone transplantation during or shortly after a course of corticosteroids (e.g., for chronic obstructive pulmonary disease or autoimmune hepatitis) are at increased risk of P. carinii pneumonia in the first weeks after transplantation, rather than 1–6 months after surgery. These individuals should receive prophylaxis before or immediately after transplantation. In single-lung transplant recipients, prophylactic failures have been observed in the residual (native) lung despite successful protection of the allograft.
Invasive infection with cytomegalovirus (CMV), but not mucosal secretion of the virus, seems to enhance the virulence of Pneumocystis [66]. In vitro, infection of a feeder cell layer of pulmonary fibroblasts with murine CMV increases the adhesion of murine Pneumocystis and increases the replication of organisms by 5–10-fold over 5 days (author's unpublished data). The mechanism for this change is unknown. However, minimization of immunosuppression and prevention and treatment of invasive CMV disease (as opposed to viral secretion) are useful in the prevention of Pneumocystis pneumonia.
Even with these observations, there are few clear rules regarding patients who “should” be receiving prophylaxis. However, experience dictates that these rules might include the following: (1) Patients with AIDS who have CD4+ lymphocyte counts <200 cells/mm3 blood or <20% of total CD4+ lymphocytes, increasing HIV loads, persistent CMV infection, or recurrent opportunistic infections suggestive of persistent T cell defects despite HAART therapy. Transplant patients with CD4+ lymphopenia are expected to be at increased risk. (2) Individuals receiving anti–T cell therapies or corticosteroids with >20 mg/day of prednisone for a period of >2–3 weeks (an arbitrary duration consistent with the life cycle of the organism and clinical observations). (3) Solid-organ transplant recipients, depending on the incidence of infection in the institution (>5%–10% without prophylaxis), but up to lifelong for heart, liver, and lung recipients and 6 months to a year after the transplant for kidney recipients. These recommendations are based on the periods of greatest risk due to the intensity of immunosuppression. Any transplant recipient with a history of Pneumocystis pneumonia or frequent opportunistic infections, who is receiving prophylaxis or therapy for CMV infection, or who is treated for acute allograft rejection merits consideration for Pneumocystis prophylaxis. Individuals with chronic graft dysfunction and those who receive greater than usual levels of immunosuppression merit prophylaxis. In transplant centers without a high incidence of Pneumocystis infection, prophylaxis may be reserved for the highest-risk individuals. If immunosuppression cannot be reduced after a course of treatment for Pneumocystis pneumonia, prophylaxis should be maintained indefinitely. (4) Use in patients with neutropenic cancer is beneficial but challenging, given the marrow suppression that may result from TMP-SMZ. Failure of marrow reconstitution may mitigate to prophylaxis with alternative agents.
Breakthrough Infection
The use of appropriate prophylaxis will generally prevent Pneumocystis pneumonia [60, 67–71]. Breakthrough infection rarely occurs in patients taking TMP-SMZ routinely with adequate systemic absorption [72]. Breakthrough Pneumocystis infections in patients taking non–TMP-SMZ drugs are often atypical in appearance. In these patients, bronchoalveolar lavage samples are often negative for P. carinii, and lung biopsy is often required for diagnosis. The occurrence of infection while receiving prophylaxis reflects (1) inadequate treatment before initiating secondary prophylaxis; (2) noncompliance; (3) inadequate dosing because of malabsorption, infection occurring before adequate tissue levels are achieved (e.g., pneumonia before the third dose of pentamidine for primary prophylaxis), or rapid metabolism; (4) acute immunosuppression (antilymphocyte therapy) with use of a second line prophylactic agent; (5) high-level exposure in the community, which is a theoretical concern suggested by the clustering of cases; and (6) antimicrobial agent resistance, which has not been fully documented. One example of inadequate dosing reflects the pharmacokinetics of a specific agent; for example, extrapulmonary pneumocystosis while the patient is taking aerosolized pentamidine (AP). Inadequate blood levels of active (unconjugated) sulfa drugs may reflect rapid hepatic metabolism (acetylation) in some individuals. The amount of unconjugated sulfa drug in serum varies among individuals from 15% to 70%.
Specific Agents
TMP-SMZ. TMP-SMZ (cotrimoxazole) is the agent of choice for the prevention of Pneumocystis infection in patients who tolerate this agent [70–76]. At a dosage of 1 single-strength tablet per day (80 mg of trimethoprim and 160 mg of sulfamethoxazole) or 1 double-strength tablet per day, a wide variety of opportunistic infections are generally prevented, including infection with P. carinii, most Toxoplasma gondii, and many community-acquired respiratory, gastrointestinal, and urinary tract pathogens. In addition, TMP-SMZ will suppress Isospora belli (on the basis of experience with patients who have AIDS) and most Nocardia asteroides (on the basis of susceptibility data) [77–80]. However, infections caused by Nocardia species (including Nocardia nova) have been observed in both bone marrow and solid-organ transplant recipients who have received TMP-SMZ. Although protection against T. gondii is incomplete in patients with AIDS (80%–90% effective), breakthrough toxoplasmosis is rare in extracardiac transplant recipients.
Studies of low- and high-dose regimens (single- or double-strength TMP-SMZ tablets) for prophylaxis in patients with AIDS suggest no mortality advantage with the higher dose (12% incidence vs. 15% in the lower-dose group) and earlier occurrence of toxicity in the high-dose group [74, 81]. Although no Pneumocystis infection was observed in compliant individuals in either group at 1 year of treatment, 63 of 156 patients dropped out because of toxicity. For Pneumocystis prevention, it is equally effective to administer the antimicrobial agents (single or double strength) 3 days per week [74, 82–84].
Drug toxicity is common even with low-dose regimens, especially as mild hematopoietic suppression. Such toxicity is notable in combination with other marrow-suppressive agents (e.g., azathioprine, ganciclovir, cyclophosphamide, and allopurinol), malnutrition, or infection (CMV and hepatitis C virus). Significant toxicities generally evolve within the first month of therapy unless they are masked by immunosuppression. Anemia, neutropenia, and azotemia have been related to trimethoprim levels in patients with AIDS [85]. Rash and hepatotoxicity have been related to serum sulfa levels. Some patients will not tolerate any dose of sulfa drugs because of significant rash, Stevens-Johnson syndrome, hepatitis (particularly in patients with liver allografts), eosinophilic nephritis, or neutropenia. Hyperkalemia may be observed in the setting of baseline renal function as a result of interference by trimethoprim with the secretion of potassium at the renal distal tubule. This is reversible and more common during full-dose (iv) therapy than with prophylaxis. Treatment of TMP-SMZ–induced neutropenia with folinic acid has been associated with treatment failure in some individuals [86–88]. Patients with AIDS who have mild intolerance of TMP-SMZ will often tolerate the reintroduction of the drugs at a reduced dose after the resolution of acute toxicities (generally rash). In contrast, whereas marrow suppression may be tolerable, interstitial nephritis, hepatitis, and severe skin reactions will generally recur in solid-organ and hematopoietic transplant recipients. Toxicity to transplanted organs may occur at any level of drug and, once established, rarely resolves without discontinuation of the agent. Thus, whereas oral and iv desensitization regimens allow the use of TMP-SMZ in many patients with AIDS who are otherwise intolerant of TMP-SMZ, alternative agents should be used for prophylaxis in bone marrow and organ transplant recipients with similar, mild, drug-related toxicities (marrow suppression, nephritis, nausea, or hepatitis), at least until graft function and immunosuppressive regimens are stable.
Alternative prophylactic regimens are available for the patient who is intolerant of TMP-SMZ. Unfortunately, all other prophylactic agents should be considered second line, in part because of diminished activities of most alternative regimens against pathogens other than P. carinii.
Pentamidine. Aerosolized pentamidine (AP) isethionate (300 mg every 3–4 weeks) was pioneered for primary and secondary prophylaxis in patients with AIDS and is also well tolerated in solid-organ and hematopoietic transplant recipients [69, 89, 90]. AP prophylaxis is most effective when administered by experienced personnel with a nebulizer that produces droplets in the 1–3-μm range. Up to 600 mg/month, accumulation of pentamidine in plasma does not occur. However, pulmonary pentamidine concentrations continue to increase for the first 6 months of aerosolized therapy. The benefit of adjusting patient positioning during inhalation is unclear. Breakthrough infection is seen in 10%–23% of patients with AIDS who are compliant with AP regimens for 1 year, with disease occurring in the most heavily immunosuppressed patients. Breakthrough infection is often in the upper lobes, either because the aerosolized drug may not reach the upper lobes or because the growth of Pneumocystis species may be favored in this region. Pneumothorax is a complication of Pneumocystis infection of the upper lobes, but a unique relationship with AP therapy has not been demonstrated. Chest radiographs are often unrevealing, and chest CT scans reveal diffuse interstitial disease. Either iv pentamidine or AP (300 mg every 3–4 weeks) has been successful in prophylaxis of a small series of transplant patients [69, 89, 91]. However, in our experience, breakthrough infection exceeds 10% with pentamidine (iv or aerosol) in solid-organ transplant recipients, making this a less than optimal agent. Breakthroughs are generally in patients who have not yet received ⩾2 doses of pentamidine (i.e., in the first 8 weeks of prophylaxis), in individuals with tissue-invasive CMV infection, in secondary prophylaxis after incomplete clearance of infections, during chemotherapy for hepatoma or posttransplantation lymphoproliferative disorder, and in those who are receiving antilymphocyte globulins or high-dose steroids for graft rejection.
Cough and bronchospasm are the common side effects of AP therapy and are generally reversible with bronchodilator therapy. Hypoglycemia or hyperglycemia have been observed, and these are particularly worrisome in pancreas transplant recipients. Transient, mild hypoglycemia and nausea are more common after iv administration. The use of pentamidine prophylaxis requires the simultaneous administration of a second antimicrobial agent (e.g., quinolone) for antibacterial prophylaxis; this is not generally required in patients receiving TMP-SMZ.
Dapsone. Dapsone (diaminodiphenylsulfone), with or without trimethoprim or pyrimethamine, is widely used for prophylaxis in a variety of combinations. Whereas low serum levels of sulfone are attained in vivo, therapeutic levels are maintained in alveolar fluids. Dapsone has equivalent activity to sulfamethoxazole and sulfadiazine in in vitro assays of activity against the enzyme DHPS at equivalent concentrations [92]. Because of a long serum half-life, dapsone may be administered in dosages from 50–100 mg/day to 100 mg/week. Breakthrough infection has been observed in patients who have undergone transplantation at dosages up to 50 mg/day; toxicity begins to be limiting at 100 mg/day, reducing the utility of the drug as a single agent for prophylaxis or therapy. Therefore, pyrimethamine may be administered weekly (25 or 50 mg) to supplement dapsone (50–100 mg/day). TMP-SMZ and dapsone have equal anti-Toxoplasma efficacy [74]. Trials of dapsone at dosages of 100 mg given 2 or 3 times per week show equivalence to pentamidine therapy; dosages of 50–100 mg per day are equivalent to TMP-SMZ therapy. Trimethoprim (100–200 mg/day) may replace pyrimethamine in this regimen in patients with creatinine clearances of >15 mL/min.
Intolerance of dapsone (i.e., from mild side effects, including anemia or rash, to anaphylaxis) is roughly equivalent to that of TMP-SMZ. In the transplant recipient, intolerance to TMP-SMZ generally predicts intolerance to dapsone. On the basis of experience with AIDS, up to 40% of patients who discontinue prophylactic therapy with either of these agents because of toxicity will not be able to tolerate the other drug [93]. Switching from TMP-SMZ to dapsone cannot be recommended for individuals who have experienced severe side effects due to either agent, including desquamation, neutropenia, severe nephritis or hepatitis, and documented G6PD deficiency. Toxicities observed with dapsone are long lived and may limit utility, especially in liver transplant recipients [94–96]. Dapsone is metabolized via the hepatic P450 system (CYP3A). This predicts interference with cyclosporine and tacrolimus metabolism and increased serum dapsone levels in the presence of azole antifungal agents.
Atovaquone. Atovaquone has been approved by the Food and Drug Administration for the treatment of mild to moderate P. carinii infections, but it may be most useful for prophylaxis [97–100]. Atovaquone is a hydroxynapthoquinone and an inhibitor of mitochondrial electron transport. Failure of atovaquone prophylaxis for Pneumocystis species has been attributed to mutations in a ubiquinone-binding site on cytochrome b [35, 101]. Atovaquone undergoes enterohepatic circulation without metabolism and has a long serum half-life (>70 h). Atovaquone also has the potential unique advantage of activity against the bradyzoites (intracystic bodies) of T. gondii, a cause of encephalitis in patients with AIDS and of carditis in cardiac transplant recipients. Absorption is enhanced by fatty foods and decreased by diarrhea, by malabsorption, and in patients with AIDS. Bioavailability has been improved via reformulation as a liquid suspension. Rash, nausea, and increased liver transaminases are occasionally documented. The incidence of rash correlates with the serum concentration. Experience suggests that bioavailability in patients with AIDS is one-half to one-third that of other compromised hosts. Thus, in transplant recipients or patients with cancer, serum levels achieved with prophylactic doses in the range of 1000–1500 mg/day of liquid drug exceed the MIC of atovaquone for rodent-derived P. carinii. Some patients complain about the flavor and color of atovaquone liquid (which stains clothes), but most find it preferable to AP.
In an attempt to develop alternate prophylactic regimens, we have performed 3 institutional review board–approved trials of atovaquone suspension for prophylaxis in patients who are not immunocompromised by AIDS. In a phase I trial, serum atovaquone levels were obtained from 5 renal transplant recipients taking stable triple immunosuppressive regimens (prednisone [<10 mg/day], cyclosporine, and azathioprine) and who received 1000 mg q.d. given orally for 4 weeks. For 3 weekly determinations, the mean serum level with this regimen was 15.46 μg/mL (range, 8.31–23.91 μg/mL). No interaction of atovaquone with cyclosporine was documented, and no drug-related toxicity was encountered.
Subsequently, 25 renal, 14 hepatic, and 5 cardiac transplant recipients who were intolerant of TMP-SMZ received prophylaxis with atovaquone (1000 mg/day) and ofloxacin (400 mg/day) for 6 months. Of these 44 patients, 39 completed 6 months of therapy without complications. In these 39 patients, no infection caused by Pneumocystis species or ofloxacin-susceptible bacteria was observed. No rash was observed. Of the 5 patients who did not complete 6 months of therapy, 1 renal and 1 hepatic transplant recipient discontinued atovaquone because of gastrointestinal intolerance, and these patients were switched to iv pentamidine. In addition, 3 liver transplant recipients developed Pneumocystis pneumonia. One of these patients developed Pneumocystis pneumonia 5 days after transplantation for autoimmune hepatitis (3 days after starting atovaquone). This patient had received prednisone (30 mg orally [po] q.d.) for 5 months before transplantation, suggesting prior asymptomatic infection with P. carinii. Infection resolved with iv pentamidine. The second patient developed Pneumocystis pneumonia during adriamycin therapy for hepatocellular carcinoma in the setting of active hepatitis C and CMV infections and chemotherapy-induced neutropenia. This patient was ultimately cured of infection with atovaquone (1500 mg b.i.d.) after intolerance of multiple other agents. This observation suggests that resistance to atovaquone was not the etiology of this infection. The third patient developed Pneumocystis pneumonia during therapy with OKT3 antibody for acute rejection. His course was complicated by accelerated hepatitis C infection, oral thrush, and herpes simplex infection, with a markedly decreased CD4+ lymphocyte count (<9%). He ultimately died of respiratory failure despite pentamidine therapy. In each of these patients, the diagnosis of Pneumocystis pneumonia was made by means of lung biopsy after induced sputum and bronchoalveolar lavage samples were unrevealing.
In a subsequent randomized, prospective toxicity trial of atovaquone (1500 mg po q.d.) with ofloxacin (400 mg po q.d.) versus TMP-SMZ (single strength po q.d.) in 40 allogeneic bone marrow transplant recipients, 20 patients tolerated atovaquone without complications, and 8 of 20 patients discontinued TMP-SMZ because of toxicity (rash or marrow intolerance) [102]. No Pneumocystis infection occurred in either group. These data suggest that atovaquone (1500 mg po q.d.) is effective as an alternative agent in TMP-SMZ–intolerant transplant recipients.
Clindamycin and pyrimethamine. Both treatment and prophylaxis with the combination of clindamycin and pyrimethamine are effective as alternatives to TMP-SMZ [103]. However, although small, prospective trials have indicated some efficacy for prophylaxis, clinical trials of the combination of clindamycin and primaquine for the prevention of pneumocystosis have been complicated by a high incidence of Clostridium difficile colitis and anemia (especially in G6PD-deficient hosts).
Patients receiving prophylaxis for toxoplasmosis (sulfadiazine, triple sulfa, atovaquone, clindamycin with pyrimethamine, or primaquine) have also been protected against P. carinii. Patients receiving quinolone antimicrobial agents (e.g., for urinary prophylaxis after renal transplantation) will be at the same risk for Pneumocystis pneumonia as is the general population. Trials by Hughes et al. suggest that the macrolides in combination with the sulfonamides may work synergistically against Pneumocystis but that these agents do not seem to have significant activity as single agents for this purpose.
Vaccine Development
Patients with P. carinii pneumonia generally carry both antibodies and T lymphocytes directed against Pneumocystis antigens at the time of presentation; this suggests that such immunities are not protective in the setting of immunosuppression. This may reflect changes in the major surface antigens of P. carinii or impairment in the coordination of immune function (e.g., control of alveolar macrophage function) [52, 104–111]. The development of vaccines for the prevention of Pneumocystis pneumonia has been hindered by the inability to define invariant antigens of the organism that generate protective immunity, especially in immunocompromised individuals.
Conclusion
Pneumocystis infection remains an important consideration in the care of transplant patients and other immunocompromised hosts. The risk for infection can be assessed for each patient on the basis of the nature, intensity, and duration of immunosuppression and additional patient-specific risk factors. The risk of infection seems to increase with chronic corticosteroid therapy, with higher maintenance levels of immunosuppression, in lung transplant recipients, in individuals with invasive CMV disease, during treatment of allograft rejection and graft-versus-host disease, and during periods of neutropenia. In my experience, the inability to tolerate prophylaxis with TMP-SMZ is a risk factor for P. carinii as well as other opportunistic infections. Alternative regimens must be adapted to the needs of individual patients.
Footnotes
-
Conflict of interest: Dr. Fishman has been a consultant to Fujisawa Healthcare, Inc., Gilead Sciences, Novartis, BioTransplant, Inc., Genzyme, Inc., and Glaxo-Wellcome, Inc. and is a member of the Speaker's Bureau for Pharmacia & Upjohn, Hoffman-LaRoche, and Fujisawa Healthcare. No support for this work was received from any corporate entity.
- Received March 1, 2001.
- Revision received June 5, 2001.
- © 2001 by the Infectious Diseases Society of America
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