Should Bactrim (trimethoprim/sulfamethoxazole) be given to patients induced with two doses of Rituxan (rituximab) and then receiving Rituxan (rituximab) every 6 months for 3 years?

Pneumocystis Pneumonia Prophylaxis for Patients on Rituximab Maintenance Therapy

Patients receiving rituximab induction (two doses) followed by maintenance therapy every 6 months for 3 years should receive trimethoprim-sulfamethoxazole (TMP-SMX) prophylaxis for Pneumocystis jirovecii pneumonia (PJP) for at least 6 months after rituximab induction and throughout the maintenance period, especially for those with risk factors.

Evidence-Based Rationale

Guideline Recommendations

The 2024 KDIGO clinical practice guideline for ANCA-associated vasculitis explicitly recommends:

• "Low-dose trimethoprim-sulfamethoxazole (TMP-SMX), or alternative, is advised for pneumocystis pneumonia prophylaxis for the duration of the cyclophosphamide course or for 6 months following rituximab induction."
• "Longer-term use may be considered in those receiving repeated rituximab infusions, those with structural lung disease, and those requiring ongoing immunosuppressive or glucocorticoid therapy." 1

The 2021 American College of Rheumatology/Vasculitis Foundation guideline similarly states:

• "For patients with GPA/MPA who are receiving rituximab or cyclophosphamide, we conditionally recommend prophylaxis to prevent P jirovecii pneumonia." 1

Risk Assessment and Monitoring

Risk Factors That Warrant Prophylaxis

• Receiving repeated rituximab infusions (as in maintenance therapy)
• Concomitant use of high-dose glucocorticoids (≥30 mg/day prednisone or equivalent)
• Structural lung disease
• Low IgG levels (<3 g/L)
• Previous history of PJP infection

Monitoring During Rituximab Therapy

• IgG levels should be measured at baseline and every 6 months for patients treated with rituximab 1
• Low baseline IgG (<3 g/L) may predict greater risk of secondary immunodeficiency with rituximab 1

Prophylaxis Regimen

Recommended Approach:

1. First-line prophylaxis: TMP-SMX at low dose (80/400 mg three times weekly or single-strength tablet three times weekly)
2. Alternative options (if TMP-SMX is not tolerated):
   • Atovaquone
   • Dapsone
   • Pentamidine (inhaled)

Duration:

• Minimum: 6 months following rituximab induction
• Extended: Throughout the 3-year maintenance period, especially for patients with risk factors

Risk-Benefit Analysis

Benefits of Prophylaxis

• Significant reduction in PJP incidence with TMP-SMX prophylaxis (adjusted HR 0.20,95% CI 0.10-0.42) 2
• PJP carries high mortality (27.2-63.6%) when it occurs in immunocompromised patients 2, 3

Risks of Prophylaxis

• Adverse events with TMP-SMX include:
  • Leukopenia (HR 3.1; 95% CI 1.1-8.6)
  • Rash (HR 1.9; 95% CI 1.0-3.6)
  • Nephropathy (HR 2.6; 95% CI 1.3-5.1) 4
• Lower-dose regimens (80/400 mg three times weekly) show fewer adverse events compared to higher-dose regimens 5

Special Considerations

• For patients with hypogammaglobulinemia (IgG <3 g/L) and recurrent infections, consider immunoglobulin supplementation 1, 6
• Potential drug interaction between methotrexate and TMP-SMX at higher doses, but prophylactic doses are generally tolerated 1

Recent Evidence on PJP Risk

A 2024 study found lower rates of PJP in patients with ANCA-associated vasculitis than previously observed:

• During induction: 15.0 cases per 1,000 patient-years
• During rituximab maintenance: 2.1 cases per 1,000 person-years 4

However, the risk-benefit analysis still favors prophylaxis, particularly in high-risk patients receiving concomitant high-dose glucocorticoids, where the number needed to treat (NNT) to prevent one PJP case was 20 compared to a number needed to harm (NNH) of 86 for severe adverse events 3.

Practical Implementation

1. Start TMP-SMX prophylaxis at initiation of rituximab therapy
2. Continue for at least 6 months after rituximab induction
3. For patients receiving maintenance rituximab every 6 months for 3 years, continue prophylaxis throughout this period
4. Monitor for adverse effects and adjust or switch prophylaxis regimen if necessary
5. Check IgG levels every 6 months and consider immunoglobulin supplementation if levels fall below 3 g/L with recurrent infections

By following these evidence-based recommendations, clinicians can effectively reduce the risk of PJP in patients receiving rituximab induction and maintenance therapy while minimizing potential adverse effects from prophylaxis.