Version July 2025
| Indication | Agent | Duration |
| Initial therapy | ||
| Classic Whipple's disease or chronic localized non-CNS infection | Doxycycline 100 mg PO twice daily plus Hydroxychloroquine 200 mg PO twice daily | 12 months |
| Endocarditis | Initial phase* Penicillin G 2 million units IV every 4 hours or Ceftriaxone 2 g IV once daily | 4 weeks |
| Maintenance phase Trimethoprim-sulfamethoxazole one DS tablet twice daily | 12 months | |
| CNS disease¶ | Initial phase* Ceftriaxone 2 g IV once daily or Penicillin G 4 million units IV every 4 hours | 2 to 4 weeks |
| Maintenance phase Trimethoprim-sulfamethoxazole one DS tablet twice daily | 12 months | |
| Therapy for relapse | ||
| Initial phase* | Penicillin G 4 million units IV every 4 hours or Ceftriaxone 2 g IV twice daily | 4 weeks |
| Maintenance phase | Doxycycline 100 mg PO twice daily plus hydroxychloroquine 200 mg PO twice daily or Trimethoprim-sulfamethoxazole one DS tablet twice daily | 12 months |
CNS: central nervous system; CSF: cerebrospinal fluid; DS: double-strength (one double-strength tablet is equivalent to 160 mg trimethoprim and 800 mg sulfamethoxazole); IM: intramuscularly; IV: intravenously; PCR: polymerase chain reaction; PO: orally.
* The initial phase is followed by the maintenance phase. If the patient cannot take ceftriaxone or penicillin, meropenem 1 g intravenously every 8 hours is an alternative.
¶ Central nervous system disease includes neurologically asymptomatic patients with a positive CSF PCR test for Tropheryma whipplei as well as patients with Whipple's disease and neurologic symptoms despite a negative CSF PCR test.
