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Reduced-Dose Trimethoprim-Sulfamethoxazole Effective in Treating Mild to Moderate Pneumocystis jirovecii Pneumonia

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Contagion, Contagion, September 2022 (Vol. 07, No. 4),

Here is a review of using this therapy in this patient population.

Pneumocystis jirovecii is a ubiquitous fungus that can cause severe respiratory infection in the immunocompromised host. Patients at risk for Pneumocystis jirovecii pneumonia (PJP) include those on immunosuppressive therapies or those living with HIV/AIDS, organ transplantation, or hematologic malignancy.1 In areas with a low prevalence of uncontrolled HIV/AIDS, patients with hematologic malignancies constitute the largest group at risk of PJP.2

Trimethoprim-sulfamethoxazole (TMP-SMX) is recommended for PJP prophylaxis in many patients with hematologic malignancy.3 TMP-SMX is also the treatment of choice for mild, moderate, and severe PJP.3 The CDC guidelines recommend a standard dose of 15 to 20 mg/kg daily of the TMP component for adults with PJP, but this recommendation is based on weak data extrapolated from pediatric literature.4,5 Moreover, adverse events from TMP-SMX are dose dependent, thus the standard doses of TMP-SMX typically used in PJP are frequently associated with significant adverse effects.6

A recent meta-analysis of more than 300 patients compared reduced dose (10 mg/kg/d or less of TMP) with the standard dose (15-20 mg/kg/d of TMP) of TMP-SMX in the treatment of mild to severe PJP and revealed no statistically significant difference in mortality (absolute risk difference, –9%; 95%, CI, –27% to 8%) but a significant reduction in adverse events with the reduced dose (absolute risk reduction of 18%; 95% CI, –31% to –5%).7 However, as this analysis included only 63 (14%) patients with hematologic malignancies, the results may not be generalizable to this population.7 Thus, questions remain regarding the ideal dosing of TMP-SMX in the treatment of PJP among patients with hematologic malignancies.

Hammarström et al examined this issue in their recent manuscript “Treatment With Reduced Dose Trimethoprim- Sulfamethoxazole Is Effective in Mild to Moderate Pneumocystis jirovecii Pneumonia in Patients with Hematologic Malignancies.”8 The authors completed a retrospective study of adult patients with hematologic malignancies who were treated for probable or proven PJP with TMP-SMX at 6 Swedish university hospitals between 2013 and 2017. Patients were included if they had (1) a hematologic malignancy or prior allogeneic hematologic stem cell transplant, (2) positive immunofluorescence or polymerase chain reaction for Pneumocystis jirovecii in a sputum or bronchoalveolar lavage sample, (3) both typical radiograph findings (ie, diffuse interstitial infiltrates or ground glass opacity) and respiratory symptoms (ie dyspnea, cough, or hypoxia < 95% oxygen saturation of arterial blood without oxygen therapy), and (4) were treated with TMP-SMX, with an initial dose of 7.5 to 20 mg/kg/day of the TMP component. The reduced-dose cohort was defined as those who received 7.5 to 15 mg/kg/d of the TMP component, and the standard-dose cohort as those who received more than 15 to 20 mg/kg/d of the same, with doses adjusted for renal function. The primary outcome assessed a change in objective respiratory function, measured as the difference in partial pressure arterial oxygen and fraction of inspired oxygen ratio (PaO₂/FiO₂) between baseline and day 8 of TMP-SMX treatment. The secondary outcomes included clinical failure ( failure to improve or worsening respiratory status as determined by clinical judgement) or death at day 8, 30-day mortality, and the frequency of adverse events.8

A total of 113 patients were included in the study, with 80 patients in the reduced-dose cohort and 33 patients in the standard-dose cohort. Of the 33 patients receiving standard-dose TMP-SMX, 19 (53%) were transitioned to reduced-dose therapy between days 3 and 7 of treatment. The study population was predominantly men (80/113, 71%), older (median age 68 years, range 22-88), had normal or mildly reduced renal function (106/113, 95%) with a creatinine clearance of greater than 50, and hypoalbuminemia less than 30 g/L (77/113, 83%). The 2 study groups were comparable, aside from the standard-dose group having an ECOG performance status of greater than 3 in 27% (9/33) compared with 10% (8/80) in the reduced-dose group (P = .04).8

For the primary outcome, the change in PaO₂/FiO₂ by day 8 was a mean (SD) of +70.2 (± 104.2) mm Hg in the reduced-dose group compared with a mean (SD) of +83.8 (± 107.5) mm Hg in the standard-dose group, which was not a statistically significant difference (P = .5). The secondary outcomes also did not reveal a statistically significant difference between the reduced-dose and standard-dose groups regarding clinical failure or death at day 8 (18% vs 21%, P = .8), overall 30-day mortality (14% vs 15%, P > .9), or adverse events (25% vs 33%, P = .4).8

The study had several limitations, including a small sample size and its retrospective nature. Although there were no significant differences in mortality between the 2 treatment groups regarding severe PJP, the authors advise caution that a relevant difference cannot be ruled out. There is also concern for selection bias, as patients with a worse baseline prognosis were more likely to have standard-dose TMP-SMX.8

Despite the limitations, this study included a well-defined cohort of patients from numerous institutions and was the first of its kind to analyze reduced-dose TMP-SMX for treatment of PJP in patients with hematologic malignancies. The authors demonstrated that reduced-dose TMP-SMX can be effective in mild to moderate PJP within the study population. Ultimately, this important study revealed the need for prospective, randomized investigations to establish updated guidelines for the treatment of PJP.

Highlighted Study

Hammarström H, Krifors A, Athlin S, et al. Treatment with reduced dose trimethoprim-sulfamethoxazole is effective in mild to moderate Pneumocystis jirovecii pneumonia in patients with hematologic malignancies. Clin Infect Dis. 2022;ciac386. doi:10.1093/cid/ciac386

References

1. Thomas CF Jr, Limper AH. Pneumocystis pneumonia. N Engl J Med. 2004;350(24):2487-2498. doi:10.1056/NEJMra032588

2. Grønseth S, Rogne T, Hannula R, Åsvold BO, Afset JE, Damås JK. Epidemiological and clinical characteristics of immunocompromised patients infected with Pneumocystis jirovecii in a twelve-year retrospective study from Norway. BMC Infect Dis. 2021;21(1):659. doi:10.1186/s12879-021-06144-1

3. Cooley L, Dendle C, Wolf J, et al. Consensus guidelines for diagnosis, prophylaxis and management of Pneumocystis jirovecii pneumonia in patients with haematological and solid malignancies, 2014. Intern Med J. 2014;44(12b):1350-1363. Published correction appears in Intern Med J. 2014;45(4):469.

4. Masur H, Brooks JT, Benson CA, et al. Prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: updated guidelines from the Centers for Disease Control and Prevention, National Institutes of Health, and HIV Medicine Association of the Infectious Diseases Society of America. Clin Infect Dis. 2014;58(9):1308-1311. doi:10.1093/cid/ciu094

5. McDonald EG, Butler-Laporte G, Del Corpo O, et al. On the treatment of Pneumocystis jirovecii pneumonia: current practice based on outdated evidence. Open Forum Infect Dis. 2021;8(12):ofab545. doi:10.1093/ofid/ofab545

6. Chang HM, Tsai HC, Lee SS, et al. High daily doses of trimethoprim/sulfamethoxazole are an independent risk factor for adverse reactions in patients with pneumocystis pneumonia and AIDS. J Chin Med Assoc. 2016;79(6):314-319. doi:10.1016/j.jcma.2016.01.007

7. Butler-Laporte G, Smyth E, Amar-Zifkin A, Cheng MP, McDonald EG, Lee TC. Low-dose TMP-SMX in the treatment of Pneumocystis jirovecii pneumonia: a systematic review and meta-analysis. Open Forum Infect Dis. 2020;7(5):ofaa112. doi:10.1093/ofid/ofaa112

8. Hammarström H, Krifors A, Athlin S, et al. Treatment with reduced dose trimethoprim-sulfamethoxazole is effective in mild to moderate Pneumocystis jirovecii pneumonia in patients with hematologic malignancies. Clin Infect Dis. Published online May 20, 2022. doi:10.1093/cid/ciac386