BACKGROUND: Vascular pythiosis, caused by Pythium insidiosum, is a life-threatening disease with high mortality rate in patients with residual disease post-surgery. This study evaluated the effectiveness of a combination therapy of surgery, azithromycin, doxycycline, and itraconazole. METHODS: In this open-label, Phase II multicenter trial, 51 patients were enrolled. Patients were categorized based on residual disease post-surgery (unresectable lesions, incomplete resection, or persistent symptoms). Patients with residual disease received azithromycin (500 mg daily), doxycycline (100 mg twice daily), and itraconazole (200 mg thrice daily) until beta-d-glucan (BDG) levels were negative (<
80 pg/ml) for three months. Those without residual disease received the same regimen for six months. Outcomes included all-cause mortality at six months, adverse events, changes in BDG levels over time, and factors associated with residual disease and mortality. RESULTS: At six months, the all-cause mortality rate was 15.7%. Mortality in patients with residual disease was 31.5% compared to 6.25% for those without (p=0.04). Lesions above the popliteal artery were a significant predictor of residual disease (incidence rate ratio [IRR] 3.20, 95% confidence interval [CI] 1.08-11.70). BDG levels decreased over time (odds ratio [OR] 0.82, 95%CI 0.77-0.88 per week, p<
0.001), but remained higher in the residual disease group (OR 4.29, 95% CI 1.55-11.92). CONCLUSIONS: The combination therapy of surgery, azithromycin, doxycycline, and itraconazole improves survival in patients with vascular pythiosis, including those with residual disease. This regimen is well-tolerated and should be considered a standard of care, with further research needed for long-term outcomes.