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Treatment of Severe Sepsis with Artemether-Lumefantrine Is Associated with Decreased Mortality in Ugandan Patients without Malaria

We enrolled 382 patients at two hospitals in Uganda in a prospective observational study of severe sepsis. Because artemisinins improve survival in murine sepsis models, we performed a post hoc analysis of the association between the use of artemether-lumefantrine (A-L) and mortality in patients with or without malaria. In patients with negative malaria smears (N = 328 of 379), Kaplan–Meier curves revealed decreased combined inpatient and 30-day mortality among patients receiving A-L versus those who did not (20.6%, SE = 10.6 versus 48.8%, SE = 3.2; Log rank ² = 3.93, P = 0.048). The decrease in mortality associated with A-L was maintained in the most clinically ill patients determined by Karnofsky Performance Scores 50 (16.7%, SE = 15.2 versus 58.3%, SE = 3.7; Log rank ² 3.94, P = 0.041). Research into the properties of A-L is needed to improve treatment of sepsis without compromising malarial susceptibility.

Received June 6, 2008. Accepted for publication January 22, 2009.

Acknowledgments: We thank the nurses and staff of Mulago Accident and Emergency Department and Masaka Regional Referral Hospital for their assistance in the enrollment of patients for the study and overall dedication to the care of patients. In addition, we are especially grateful to members of the PRISM-U Study Team [Mulago site: Rebecca Burke, Cheryl Lynn Horton, Cassim Kalisa, Kasozi Kimuli, Angelo Nganizi, and Samson Omongot; and Masaka site: Patrick Ddikusoka, Sr. Scholastica Sekayiba, and Francis Ssali] for their dedication and hard work during the study. We also thank Richard D. Pearson for his critical review of the manuscript.

Financial support: Christopher C. Moore and Shevin T. Jacob received fellowships from the Pfizer Initiative in International Health at the University of Virginia to support this work. This Initiative was conceived to fund exchange programs of post-doctoral fellows and students between the University of Virginia and several international partners to conduct research on global health issues. The major purpose of this program is to foster and enhance bidirectional research training. An independent board at the University of Virginia determines which research proposals are funded. Pfizer provided funds to promote the Initiative, but has no role in the planning or execution of research protocols including the study described in our manuscript. This work was also supported in part by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health.

^* Address correspondence to Christopher C. Moore, Division of Infectious Diseases and International Health, Department of Medicine, University of Virginia, 409 Lane Road, MR-4 Building, Room 2111, Charlottesville, VA 22908. E-mail: ccm5u{at}virginia.edu

Authors’ addresses: Christopher C. Moore, Relana Pinkerton, and W. Michael Scheld, Division of Infectious Diseases and International Health, Department of Medicine, University of Virginia, 409 Lane Road, MR-4 Building, Room 2111, Charlottesville, VA 22908, Tel: +1 (434) 924-5991, Fax: +1 (434) 924-2885, E-mails: ccm5u{at}virginia.edu, rcp3w{at}virginia.edu, and wms{at}virginia.edu. Shevin T. Jacob, Division of Allergy and Infectious Diseases, University of Washington, 1959 NE Pacific Street, Box 355330, Seattle, WA 98195, Tel: +1 (206) 446-7075, E-mail: sjacob{at}post.harvard.edu. Patrick Banura, Masaka Regional Referral Hospital, PO Box 18, Masaka, Uganda, Tel: +256-48-120018, E-mail: banura2003{at}yahoo.com. David B. Meya and Harriet Mayanja-Kizza, Faculty of Medicine, Makerere University, Mulago Hospital Complex, PO Box 22418, Kampala, Uganda, Tel: +256-41-307000 or +256-31-307200, Fax: +256-41-307290, E-mails: david.meya{at}gmail.com and hmk{at}mucwru.or.ug. Steven J. Reynolds, NIAID/NIH, 2190 Kampala Place, Washington, DC 20521, Tel: +256-414-323-255, Fax: +256-414-323-252, E-mail: sjr{at}jhmi.edu. Nathan Kenya-Mugisha, Ministry of Health, Republic of Uganda, Plot 6 Lourdel Rd, Wandegeya, Box 7272, Kampala, Uganda, Tel: +256-41-340884, Fax: 256-41-340887, E-mail: nkmugisha{at}yahoo.com.

Reprint requests: Christopher C. Moore, Division of Infectious Diseases and International Health, Department of Medicine, University of Virginia, 409 Lane Road, MR-4 Building, Room 2111, Charlottesville, VA 22908, Tel: +1 (434) 924-5991, Fax: +1 (434) 924-2885, E-mail: ccm5u{at}virginia.edu.