Pneumocystis jiroveci pneumonia is a life-threatening infection that occurs after allo-SCT. Without prophylaxis, 5–16% of patients develop pneumocystis pneumonia with a median onset at 9 weeks after transplantation and a mortality rate of 76%.1 Risk factors for pneumocystis pneumonia after allo-SCT include immunosuppressive therapy, chronic GVHD, relapse of primary disease or low CD4+ T cell count (<200 cells per μL).2, 3, 4 As the introduction of trimethoprim–sulfamethoxazole as prophylaxis against pneumocystis, the incidence of pneumocystis pneumonia after allo-SCT has decreased to less than 5%, and most cases of the disease develop after discontinuation of the drug at more than 6 months after transplantation.1, 2, 3, 5 Alternative drugs include aerosolized pentamidine, dapsone and atovaquone;6 however, they are less effective than trimethoprim–sulfamethoxazole.5, 7, 8 Moreover, compared with prophylaxis with trimethoprim–sulfamethoxazole, that with aerosolized pentamidine is associated with increased mortality at 1 year after allo-SCT.8
Although trimethoprim–sulfamethoxazole is the most effective prophylactic drug for pneumocystis, its adverse effects, such as rash, marrow suppression, fever, and renal, gastrointestinal and liver dysfunction, are frequently observed and sometimes require discontinuation of the drug. One double-strength trimethoprim–sulfamethoxazole tablet (trimethoprim 160 mg per sulfamethoxazole 800 mg) daily, one single-strength tablet (80 mg per 400 mg) daily or one double-strength tablet q.d. thrice per week are recommended for pneumocystis prophylaxis following allo-SCT;9 however, the optimal dosage remains to be defined. Several attempts were made at lowering the dose of the drug without increasing the incidence of pneumocystis pneumonia, but considerable rates of discontinuation of the drug were still reported.8, 10
We originally planned a low-dose trimethoprim–sulfamethoxazole prophylactic regimen that included administration of two single-strength tablets twice a week for patients undergoing allo-SCT. Here, we report on the safety and efficacy of this regimen for pneumocystis prophylaxis after allo-SCT.
Between January 1998 and July 2009, 185 patients underwent allo-SCT at Chiba University Hospital. Of these, 13 patients who died within 30 days after transplantation and 16 patients who did not receive trimethoprim–sulfamethoxazole because of their general condition or previous adverse events were excluded from the analysis. The remaining 156 patients were analyzed.
Low-dose prophylaxis against pneumocystis involved administration of one single-strength tablet b.i.d. twice a week from the beginning of the previous chemotherapy or 1 month before transplantation until the beginning of the conditioning regimen. The drug was resumed after engraftment and continued until 6 months or more if patients were receiving immunosuppressive treatments. For patients who could not start or tolerate the drug, aerosolized pentamidine (300 mg) was administered every 3–4 weeks. Diagnosis of pneumocystis pneumonia was confirmed by identification of P. jiroveci with Grocott staining, or PCR of induced sputum, bronchoalveolar lavage fluid or transbronchial biopsy specimens. Pneumocystis pneumonia cases that occurred within the first 6 months after transplantation was defined as early onset and cases that occurred after 6 months were defined as late onset. Patients diagnosed with pneumocystis pneumonia were treated with oral or i.v. trimethoprim–sulfamethoxazole (trimethoprim: 15–20 mg/kg, sulfamethoxazole: 75–100 mg/kg).4
The characteristics of the 156 patients are shown in Table 1. The median age was 42 (range, 16–62). A total of 60 patients (38.5%) underwent allo-SCT from related donors and 79 (50.6%) from unrelated donors, and 17 (10.9%) underwent cord blood transplantation. In total, 117 (75.0%) and 39 (25.0%) patients received myeloablative and reduced-intensity conditioning, respectively. The median follow-up period was 1006 days after allo-SCT (range, 37–4424). The median day of restarting trimethoprim–sulfamethoxazole was day 28 after transplantation (range, 14–122) and the median period for receiving the drug was 243 days (range, 1–2303 days).
Trimethoprim–sulfamethoxazole was well tolerated and only two patients (1.3%) discontinued the drug, one because of neutropenia at day 64 and one because of liver dysfunction at day 50 after allo-SCT (Table 2). These two patients didn’t receive further prophylaxis for pneumocystis. Aerosolized pentamidine was administered in one patient who could not start trimethoprim–sulfamethoxazole after engraftment because of acute GVHD and the patient started the drug on day 61. Among 138 patients who survived over 6 months after transplantation, 56 patients discontinued the drug within 6 months, but 82 patients (59.4%) continued the drug beyond 6 months because of chronic GVHD or immunosuppressive drugs and their median period for receiving the drug was 549 days (range, 190–2303 days).
None of the 156 patients developed early-onset pneumocystis pneumonia and only one patient with AML (0.6%), who had a leukemia relapse on day 68, developed late-onset pneumocystis pneumonia at 194 days after discontinuation of trimethoprim–sulfamethoxazole (461 days after allo-SCT). This patient was treated with six single-strength tablets b.i.d. and steroid pulse therapy; however, she died because of respiratory failure 473 days after transplantation.
Souza et al.5 reported that the incidence of adverse reaction to trimethoprim–sulfamethoxazole in allo-SCT was 5–15%. Vasoconcelles et al.8 reported that 35.4% of patients who received one double-strength tablet b.i.d. thrice per week after auto- or allo-SCT discontinued the drug because of any toxicity, including marrow suppression or rash. El-Sadr et al.10 prospectively compared the efficacy and safety of one double-strength tablet daily and thrice per week in HIV-infected patients for pneumocystis prophylaxis. Marrow suppression, hypersensitivity and the overall toxicity rate requiring discontinuation of trimethoprim–sulfamethoxazole in the two groups per 100 person-years were 13.9 vs 6.3 (P<0.001), 6.8 vs 4.3 (P=0.002) and 13.9 vs 6.3 (P<0.001), respectively. These reports indicate that lowering the dose of trimethoprim–sulfamethoxazole for pneumocystis prophylaxis after allo-SCT may decrease the rate of discontinuation because of adverse events. In this study, administration of one single-strength tablet b.i.d. twice a week was well tolerated and demonstrated lower rates of discontinuation than previous reports.8, 10 All except two patients (1.3%), who discontinued the drug because of neutropenia or liver dysfunction, could continue the drug, and only one patient developed late-onset pneumocystis pneumonia at 194 days after discontinuation of trimethoprim–sulfamethoxazole. The safety of our regimen may enable more patients to continue prophylaxis.
In our case series, 137 patients (87.8%) received pre-transplant prophylaxis with low-dose trimethoprim–sulfamethoxazole and none developed early-onset pneumocystis pneumonia. Trimethoprim–sulfamethoxazole is usually avoided during the neutropenic period because of its myelotoxicity,6 but even after engraftment, continuous administration of the drug is sometimes difficult because of neutropenia, renal dysfunction or nausea. Thus, pre-transplant trimethoprim–sulfamethoxazole administration is important for preventing early-onset pneumocystis pneumonia. Our experience suggests that pre-transplant administration of low-dose trimethoprim–sulfamethoxazole is effective against early-onset pneumocystis pneumonia with minimal toxicity.
In this study, the median period for receiving post-transplant trimethoprim–sulfamethoxazole was 8 months. However, among patients who survived over 6 months after transplantation, 60% of them continued the drug over 6 months with the median period for receiving the drug of 1.5 years. Patients with severe chronic GVHD had to continue the drug for years, but none of them discontinued the drug because of adverse events and the prophylaxis for pneumocystis was successful. These results suggest that this regimen is safe and effective not only for patients within 6 months after transplantation but also for patients with severe chronic GVHD who receive immune-suppressive drugs for a long time.
In conclusion, administration of low-dose trimethoprim–sulfamethoxazole, one single-strength tablet b.i.d. twice a week, is an effective and well-tolerated regimen to prevent pneumocystis pneumonia after allo-SCT, and might be an optimal pneumocystis prophylaxis regimen. Low-dose trimethoprim–sulfamethoxazole should be continued until 6 months after transplantation or longer if patients have a risk factor for developing pneumocystis pneumonia.
Meyers JD, Pifer LL, Sale GE, Thomas ED . The value of Pneumocystis carinii antibody and antigen detection for diagnosis of Pneumocystis carinii pneumonia after marrow transplantation. Am Rev Respir Dis 1979; 120: 1283–1287.
Wingard JR, Mellits ED, Sostrin MB, Chen DY, Burns WH, Santos GW et al. Interstitial pneumonitis after allogeneic bone marrow transplantation. Nine-year experience at a single institution. Medicine (Baltimore) 1988; 67: 175–186.
Tuan IZ, Dennison D, Weisdorf DJ . Pneumocystis carinii pneumonitis following bone marrow transplantation. Bone Marrow Transplant 1992; 10: 267–272.
Thomas Jr CF, Limper AH . Pneumocystis pneumonia. N Engl J Med 2004; 350: 2487–2498.
Souza JP, Boeckh M, Gooley TA, Flowers ME, Crawford SW . High rates of Pneumocystis carinii pneumonia in allogeneic blood and marrow transplant recipients receiving dapsone prophylaxis. Clin Infect Dis 1999; 29: 1467–1471.
Gea-Banacloche J, Masur H, Arns da Cunha C, Chiller T, Kirchhoff LV, Shaw P et al. Regionally limited or rare infections: prevention after hematopoietic cell transplantation. Bone Marrow Transplant 2009; 44: 489–494.
Green H, Paul M, Vidal L, Leibovici L . Prophylaxis for Pneumocystis pneumonia (PCP) in non-HIV immunocompromised patients. Cochrane Database Syst Rev 2007; Issue 3: CD005590.
Vasconcelles MJ, Bernardo MV, King C, Weller EA, Antin JH . Aerosolized pentamidine as pneumocystis prophylaxis after bone marrow transplantation is inferior to other regimens and is associated with decreased survival and an increased risk of other infections. Biol Blood Marrow Transplant 2000; 6: 35–43.
Center for International Blood, Marrow Transplant Research (CIBMTR); National Marrow Donor Program (NMDP); European Blood, Marrow Transplant Group (EBMT); American Society of Blood, Marrow Transplantation (ASBMT); Canadian Blood, Marrow Transplant Group (CBMTG); Infectious Disease Society of America (IDSA); Society for Healthcare Epidemiology of America (SHEA); Association of Medical Microbiology, Infectious Diseases Canada (AMMI); Centers for Disease Control Prevention (CDC). Guidelines for preventing infectious complications among hematopoietic cell transplant recipients: a global perspective. Bone Marrow Transplant 2009; 44: 453–558.
El-Sadr WM, Luskin-Hawk R, Yurik TM, Walker J, Abrams D, John SL 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. Terry Beirn Community Programs for Clinical Research on AIDS (CPCRA). Clin Infect Dis 1999; 29: 775–783.
The authors declare no conflict of interest.
About this article
Cite this article
Muto, T., Takeuchi, M., Kawaguchi, T. et al. Low-dose trimethoprim–sulfamethoxazole for Pneumocystis jiroveci pneumonia prophylaxis after allogeneic hematopoietic SCT. Bone Marrow Transplant 46, 1573–1575 (2011). https://doi.org/10.1038/bmt.2010.335
Journal of Infection and Chemotherapy (2016)
Consensus guidelines for diagnosis, prophylaxis and management ofPneumocystis jiroveciipneumonia in patients with haematological and solid malignancies, 2014
Internal Medicine Journal (2014)
Delayed opportunistic infections in hematopoietic stem cell transplantation patients: a surmountable challenge