Empirical ANtibiotic THErapy in Adults Hospitalised With Malaria

The study's participants will be adults hospitalized with malaria at four tertiary referral hospitals in Myanmar. The study will be a collaboration between clinicians at Insein General Hospital North Okkalapa General Hospital and Thingangyun General Hospital in Yangon and Naypyidaw General Hospital in Naypyidaw, Myanmar and the Department of Global Health at Menzies School of Health Research.

The study's participants will be cared for by local doctors and nurses according to current WHO guidelines for the management of severe malaria. Management will include a systematic screen for bacterial infection with a detailed history, examination, radiological and laboratory studies, including the collection of blood cultures in all patients (this is recommended in WHO guidelines, but rarely performed in the resource poor setting). The only difference to the current WHO guidelines for the management of severe malaria will be the administration of empirical antibacterial therapy to all participants with falciparum malaria on admission. Participants with vivax malaria - who have a much lower incidence of complicated disease - would be managed according to the existing WHO guidelines, which suggest that antibacterial therapy should only be commenced in the presence of convincing evidence of severe bacterial co-infection.

After informed consent is obtained, artesunate is administered and a detailed work up for bacterial co-infection is performed, all participants with falciparum malaria will receive empiric levofloxacin. This will continue until 48 hours when, if the patient is improving and the work up for infection is negative, antibiotics will be ceased. Conversely if cultures are positive, targeted antibacterial therapy will be commenced as soon as sensitivity data are available. In the setting of convincing clinical evidence of bacterial infection when cultures are negative (a patient with a chest x-ray consistent with pneumonia but in whom cultures are negative for example), appropriate antibacterial will be continued. Participants who deteriorate in the first 48 hours will have their antibacterial therapy escalated to vancomycin and meropenem (based on microbiological findings in our pilot study).

Participants hospitalized with vivax malaria will also receive parenteral antimalarial therapy and have a detailed work up for infection, but empirical antibacterial therapy will not be commenced. Study clinicians may start antibacterial therapy in the setting of positive cultures or unequivocal evidence of bacterial infection if cultures are negative.

The subsequent clinical course of the participants and the frequency of confirmed bacterial co-infection would be compared to historical controls at the study sites to determine the utility of empirical antibacterial therapy in adults hospitalized with malaria in Myanmar. These data would be generalizable to other low transmission settings potentially.

The plan is to continue the study for 3 years; we expect that this will allow sufficient time to enrol enough patients to answer the study questions. The data will be analysed annually by independent safety monitors (from the University of Medicine 2, Myanmar and The Kirby Institute, Australia) and the study terminated if clear benefit or harm is identified. Independent safety monitors will also follow the study locally, review all deaths and be available to address any concerns of the participants and their families.