What is the role of dual treatment of Pneumocystis jirovecii pneumonia (PJP) in immunocompromised Bone Marrow Transplant (BMT) patients?

From the Guidelines

Dual therapy with trimethoprim-sulfamethoxazole (TMP-SMX) plus corticosteroids is strongly recommended for moderate to severe Pneumocystis jirovecii pneumonia (PJP) in immunocompromised bone marrow transplant (BMT) patients. The standard regimen consists of TMP-SMX at 15-20 mg/kg/day (based on trimethoprim component) divided into 3-4 doses for 21 days, plus prednisone 40 mg twice daily for 5 days, followed by 40 mg daily for 5 days, then 20 mg daily until treatment completion, as suggested by the NCCN guidelines 1.

Key Considerations

• Corticosteroids should be initiated within 72 hours of PJP treatment for maximum benefit, as they reduce the inflammatory response to dying organisms, preventing respiratory deterioration and decreasing mortality by approximately 50% in moderate to severe cases (PaO2 <70 mmHg or A-a gradient >35 mmHg) 1.
• For patients unable to tolerate TMP-SMX, alternative antimicrobial options include intravenous pentamidine (4 mg/kg daily), clindamycin (600 mg IV every 8 hours) plus primaquine (30 mg daily), or atovaquone (750 mg twice daily), though these should be combined with corticosteroids in moderate to severe disease 1.
• Prophylaxis with TMP-SMX (one double-strength tablet three times weekly) should be continued for at least 6 months post-transplant or longer if immunosuppression persists, as BMT patients remain at high risk for PJP due to impaired T-cell immunity 1.

Patient Selection

• Allogeneic HCT recipients, patients receiving CAR T-cell therapy, and those with ALL should receive PJP prophylaxis for at least 6 months and while receiving immunosuppressive therapy (IST) 1.
• Patients receiving select phosphatidylinositol-3-kinase inhibitors, intensive corticosteroid treatment, or temozolomide should also receive PJP prophylaxis at least through active treatment 1.
• The decision to use dual therapy should be based on the individual patient's risk factors, including the underlying malignancy, disease status, and intensity of immunosuppression 1.

From the FDA Drug Label

Atovaquone oral suspension is indicated for the prevention of Pneumocystis jirovecii pneumonia (PCP) in adults and adolescents (aged 13 years and older) who cannot tolerate trimethoprim-sulfamethoxazole (TMP-SMX). The recommended oral dosage is 1,500 mg (10 mL) once daily administered with food. Atovaquone oral suspension is indicated for the acute oral treatment of mild-to-moderate PCP in adults and adolescents (aged 13 years and older) who cannot tolerate TMP-SMX. The recommended oral dosage is 750 mg (5 mL) twice daily (total daily dose = 1,500 mg) administered with food for 21 days.

The role of dual treatment of PJP in immunocompromised BMT patients is not directly addressed in the provided drug labels.

• No direct information is available regarding the use of dual treatment with atovaquone and sulfamethoxazole for PJP in immunocompromised BMT patients.
• The labels provide information on the use of atovaquone and sulfamethoxazole as individual treatments for PJP, but do not discuss combination therapy 2, 3.

From the Research

Dual Treatment of PJP in Immunocompromised BMT Patients

• The role of dual treatment of Pneumocystis jirovecii pneumonia (PJP) in immunocompromised bone marrow transplant (BMT) patients is a critical aspect of their care, as PJP remains a common and highly morbid infection in this population 4.
• Trimethoprim-sulfamethoxazole (TMP-SMX) is the antimicrobial treatment of choice for PJP, but it can lead to significant dose-dependent renal and hematologic adverse events 4, 5.
• Reduced doses of TMP-SMX (≤10 mg/kg/d of trimethoprim) have been shown to be effective in treating PJP with a lower risk of adverse events, including nausea and hyponatremia 6, 7.
• A systematic review and meta-analysis found that low-dose TMP-SMX was associated with similar rates of mortality and a significant reduction in adverse events compared to conventional-dose TMP-SMX 4, 7.
• Another study found that low-dose TMP-SMX was associated with reduced adverse events and similar survival rates compared to conventional-dose TMP-SMX in patients with non-HIV PJP 6.
• The use of alternative treatments, such as clindamycin/primaquine, may be considered in patients who fail or develop toxicity to first-line therapy with TMP-SMX 8.
• A phase III randomized, placebo-controlled trial is currently underway to directly compare the efficacy and safety of low-dose TMP-SMX with the standard of care (15 mg/kg/d of TMP) in patients with PJP 5.

Key Findings

• Reduced doses of TMP-SMX are effective in treating PJP with a lower risk of adverse events.
• Low-dose TMP-SMX is associated with similar rates of mortality and a significant reduction in adverse events compared to conventional-dose TMP-SMX.
• Alternative treatments, such as clindamycin/primaquine, may be considered in patients who fail or develop toxicity to first-line therapy with TMP-SMX.

Treatment Considerations

• The choice of treatment for PJP in immunocompromised BMT patients should be individualized based on the patient's underlying condition, renal function, and potential for adverse events.
• Reduced doses of TMP-SMX may be considered as a viable option for the treatment of PJP in this population, particularly in patients who are at high risk of adverse events 4, 7.