By Sydney Hyder, MD, MS
Division of Pulmonary and Critical Care Medicine, Stroger Hospital of Cook County, Chicago
SYNOPSIS: In patients without human immunodeficiency virus who were diagnosed with Pneumocystis jirovecii pneumonia, mortality rates were similar between the low-dose vs. conventional-dose trimethoprim-sulfamethoxazole (TMP-SMX) groups, while low-dose TMP-SMX was associated with fewer adverse events.
SOURCE: Nagai T, Matsui H, Fujioka H, et al. Low-dose vs conventional-dose trimethoprim-sulfamethoxazole treatment for Pneumocystis pneumonia in patients not infected with HIV: A multicenter, retrospective observational cohort study. Chest 2024;165:58-67.
Pneumocystis jirovecii pneumonia (PCP) is a well-known opportunistic fungal infection that is transmitted through the inhalation of airborne particles and results in 400,000 cases yearly worldwide. Although initially associated with acquired immunodeficiency syndrome (AIDS) in the 1980s, antiretroviral therapy has reduced the incidence of PCP in individuals with human immunodeficiency virus (HIV). As PCP in the HIV population declines, the proportion of cases in the non-HIV population is increasing because of the implementation of novel anti-cancer drugs, immunosuppressive treatments, and an increasing number of organ transplants. Current guidelines recommend trimethoprim-sulfamethoxazole (TMP-SMX) with doses of 15 mg/kg/day to 20 mg/kg/day of TMP and 75 mg/kg/day to 100 mg/kg/day of SMX as first-line treatment for PCP in both HIV and non-HIV patients. However, TMP-SMX has a toxic side effect profile that includes drug rash in addition to the risk of blood, renal, gastrointestinal, and liver injury.
Initial studies looking at the efficacy of TMP-SMX were conducted in the 1980s in young men (< 40 years old) with HIV, while the current non-HIV PCP population is older and more likely to be female.1 This discrepancy is relevant because the current non-HIV PCP population has more comorbidities and organ dysfunction, which can increase the risk of toxicity from conventionally dosed TMP-SMX. As the population of PCP patients has evolved, recent research efforts have started to guide the evolution of its treatment. Nagai and colleagues hoped to address this issue by evaluating the efficacy of low-dose TMP-SMX compared to conventional-dose TMP-SMX in patients with non-HIV PCP with various underlying comorbidities.
The investigation was conducted in Japan in a multicenter, retrospective, observational cohort study that included patients with non-HIV PCP treated with TMP-SMX. Patients were enrolled between January 2006 and March 2021 at three different hospitals. Patients enrolled met all three defined criteria for PCP: an immunocompromised state other than HIV, clinical criteria of clinical symptoms and radiographic findings, and meeting microbial criteria through testing. Exclusion criteria included patients who did not receive treatment, patients who were treated initially with a medication other than TMP-SMX, and those receiving > 20 mg/kg of TMP. The patients were divided into a low-dose group (TMP < 12.5 mg/kg/day) and a conventional-dose group (TMP 12.5 mg/kg/day to 20 mg/kg/day). The attending physician during the study period was given the responsibility of deciding whether a patient received low dosing or conventional dosing based on patient characteristics. During analysis, risk-adjusted cohorts were created using the overlap weighting method with propensity scores. The primary endpoint was 30-day mortality. Secondary endpoints were 180-day mortality, incidence of adverse events, and initial treatment completion rates defined as administration of TMP-SMX for 14 to 21 days.
A total of 136 immunocompromised non-HIV patients diagnosed with PCP met the inclusion criteria, with 81 patients included in the conventional-dose group and 55 in the low-dose group. The average dose of TMP-SMX in the low-dose group was 8.71 mg/kg/day vs. 17.78 mg/kg/day in the conventional-dose group. When patient background characteristics were adjusted, the low-dose and conventional-dose groups did not have a significant difference in 30-day mortality (6.7% vs. 18.4%, respectively; P = 0.080). There also was no difference in 180-day mortality (14.6% vs. 26.1%, respectively; P = 0.141) when cohorts were adjusted for patient background characteristics. The incidence of adverse events was significantly lower in the low-dose compared to the conventional-dose group (29.8% vs. 59.0%, respectively; P = 0.005). Hyponatremia and nausea were the two adverse effects that were found to have lower rates of occurrence in the low-dose group, while there were no significant differences in incidence of skin rashes, cytopenias, hyperkalemia, and alanine aminotransferase elevation between the two groups. Lastly, initial treatment completion rates were 43.3% in the low-dose group vs. 29.6% in the conventional-dose group (P = 0.158).
COMMENTARY
Nagai et al conducted a multicenter, retrospective, observational study that evaluated outcomes in non-HIV PCP patients treated with low-dose vs. conventional-dose TMP-SMX with cohorts adjusted for patient demographics and clinical characteristics. The authors successfully completed the first and largest multicenter study to show similar survival rates between low and conventional doses, with reduced adverse effects in the low-dose group. Previous studies have shown similar results, but without adjustment for patient characteristics.2,3
The authors noted that the results may be attributed to the concept that tissue and blood may be able to obtain sufficient minimum inhibitory concentration (MIC) for P. jirovecii even at low doses. The conventional dose of TMP-SMX is based on historical practice and stems from an underpowered study of 20 children with leukemia in 1975 but has never been analyzed further through randomized controlled trials studying various doses and their adverse side effect profiles on more current patient populations.4 Healthcare professionals continue the tradition of conventional dosing of TMP-SMX because of the lack of powered research and limited research on the susceptibility of P. jirovecii to antimicrobial agents.
Limitations in this study include immortal time bias and residual confounding because of its design as a retrospective observational study. Moreover, TMP-SMX blood levels were not measured, making it difficult to correlate actual blood levels, treatment response, and adverse events, especially if the authors are concerned about studying sufficient MIC levels at low doses. Lastly, the patient population analyzed was not only small, but it also included a small number of patients with severe respiratory failure (i.e., requiring mechanical ventilation); the dose response of these critically ill patients to TMP-SMX remains unknown.
Nagai and his colleagues contribute to a growing body of observational data that continues to show that low-dose TMP-SMX is a safe and effective treatment for non-HIV patients diagnosed with PCP. The current dosing guidelines for TMP-SMX are not based on evidence-based research. Future work should aim to define a standardized low dose of TMP-SMX and evaluate it within a larger, sufficiently powered randomized controlled trial.
REFERENCES
- 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:ofab545.
- Butler-Laporte G, Smyth E, Amar-Zifkin A, et al. Low-dose TMP-SMX in the treatment of Pneumocystis jirovecii pneumonia: A systematic review and meta-analysis. Open Forum Infect Dis 2020;7:ofaa112.
- 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 2023;76:e1252-e1260.
- Hughes WT, Feldman S, Sanyal SK. Treatment of Pneumocystis carinii pneumonitis with trimethoprim-sulfamethoxazole. Can Med Assoc J 1975;112:47-50.
