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Intravenous Artesunate for the Treatment of Severe and Complicated Malaria in the United States: Clinical Use Under an Investigational New Drug ProtocolIntravenous Artesunate for Severe Malaria

Patrick S. Twomey, MD; Bryan L. Smith, MD; Cathy McDermott, RN, MPH; Anne Novitt-Moreno, MD; William McCarthy, PhD; S. Patrick Kachur, MD; and Paul M. Arguin, MD
[+] Article, Author, and Disclosure Information

This article was published online first at www.annals.org on 25 August 2015.


From U.S. Army Medical Materiel Development Activity, Fort Detrick; Fast-Track Drugs and Biologics, North Potomac; and Centers for Disease Control and Prevention, Bethesda, Maryland.

Disclaimer: The views expressed in the article are that of the authors and do not necessarily represent the views of the U.S. Army or the Centers for Disease Control and Prevention.

Acknowledgment: The authors thank Aarti Agarwal, Veronica Baechler, Melissa Briggs, John T. Brooks, Cristina Cardemil, Kevin R. Clarke, Gregory Deye, Tarayn A. Fairlie, Nan Guo, Julie Gutman, Keren Z. Landman, Sheryl Lyss, Monica E. Parise, Janet Ransom, Alexander Rowe, Isaac See, Katherine Tan, and Andrew Terranella.

Disclosures: Dr. Smith is a full-time U.S. Army product manager responsible for the development of intravenous artesunate. Dr. Novitt-Moreno reports an army contract with the U.S. Army Medical Research and Materiel Command. Authors not named here have disclosed no conflicts of interest. Disclosures can also be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M15-0910.

Editors' Disclosures: Christine Laine, MD, MPH, Editor in Chief, reports that she has no financial relationships or interests to disclose. Darren B. Taichman, MD, PhD, Executive Deputy Editor, reports that he has no financial relationships or interests to disclose. Cynthia D. Mulrow, MD, MSc, Senior Deputy Editor, reports that she has no relationships or interests to disclose. Deborah Cotton, MD, MPH, Deputy Editor, reports that she has no financial relationships or interest to disclose. Jaya K. Rao, MD, MHS, Deputy Editor, reports that she has stock holdings/options in Eli Lilly and Pfizer. Sankey V. Williams, MD, Deputy Editor, reports that he has no financial relationships or interests to disclose. Catharine B. Stack, PhD, MS, Deputy Editor for Statistics, reports that she has stock holdings in Pfizer.

Reproducible Research Statement:Study protocol: Available at www.cdc.gov/malaria/artesunate.html. Statistical code and data set: Not available.

Requests for Single Reprints: Patrick S. Twomey, MD, U.S. Army Medical Materiel Development Activity, 1430 Veterans Drive, Fort Detrick, MD 21702; e-mail, patrick.s.twomey.mil@mail.mil.

Current Author Addresses: Drs. Twomey, Smith, and McCarthy; and Ms. McDermott: U.S. Army Medical Materiel Development Activity, 1430 Veterans Drive, Fort Detrick, MD 21702.

Dr. Novitt-Moreno: Fast-Track Drugs and Biologics, 5 Paramus Court, North Potomac, MD 20878.

Drs. Kachur and Arguin: Centers for Disease Control and Prevention, 1600 Clifton Road, Atlanta, GA 30333.

Author Contributions: Conception and design: P.S. Twomey, B.L. Smith, C. McDermott, A. Novitt-Moreno, W. McCarthy, S.P. Kachur, P.M. Arguin.

Analysis and interpretation of the data: P.S. Twomey, B.L. Smith, C. McDermott, A. Novitt-Moreno, S.P. Kachur, P.M. Arguin.

Drafting of the article: P.S. Twomey, C. McDermott, A. Novitt-Moreno, P.M. Arguin.

Critical revision of the article for important intellectual content: P.S. Twomey, B.L. Smith, C. McDermott, S.P. Kachur, P.M. Arguin.

Final approval of the article: P.S. Twomey, B.L. Smith, C. McDermott, S.P. Kachur, P.M. Arguin.

Provision of study materials or patients: B.L. Smith.

Statistical expertise: W. McCarthy.

Obtaining of funding: B.L. Smith.

Administrative, technical, or logistic support: B.L. Smith, C. McDermott, S.P. Kachur.

Collection and assembly of data: P.S. Twomey, B.L. Smith, C. McDermott, S.P. Kachur, P.M. Arguin.


Ann Intern Med. 2015;163(7):498-506. doi:10.7326/M15-0910
Text Size: A A A

Background: Quinidine gluconate, the only U.S. Food and Drug Administration–approved treatment for life-threatening malaria in the United States, has a problematic safety profile and is often unavailable in hospitals.

Objective: To assess the safety and clinical benefit of intravenous artesunate as an alternative to quinidine.

Design: Retrospective case series.

Setting: U.S. hospitals.

Patients: 102 patients aged 1 to 72 years (90% adults; 61% men) with severe and complicated malaria. Patients received 4 weight-based doses of intravenous artesunate (2.4 mg/kg) under a treatment protocol implemented by the Centers for Disease Control and Prevention between January 2007 and December 2010. At baseline, 35% had evidence of cerebral malaria, and 17% had severe hepatic impairment. Eligibility required the presence of microscopically confirmed malaria, need for intravenous treatment, and an impediment to quinidine.

Measurements: Clinical and laboratory data from each patient's hospital records were abstracted retrospectively, including information from baseline through a maximum 7-day follow-up, and presented before a physician committee to evaluate safety and clinical benefit outcomes.

Results: 7 patients died (mortality rate, 6.9%). The most frequent adverse events were anemia (65%) and elevated hepatic enzyme levels (49%). All deaths and most adverse events were attributed to the severity of malaria. Patients' symptoms generally improved or resolved within 3 days, and the median time to discharge from the intensive care unit was 4 days, even for patients with severe liver disease or cerebral malaria. More than 100 concomitant medications were used, with no documented drug–drug interactions.

Limitation: Potential late-presenting safety issues might occur outside the 7-day follow-up.

Conclusion: Artesunate was a safe and clinically beneficial alternative to quinidine.

Primary Funding Source: Office of the Surgeon General, Department of the U.S. Army.

Figures

Grahic Jump Location
Figure 1.

Time to negative parasitemia in evaluable patients who received artesunate plus concomitant antimalarial medications versus those who received artesunate alone.

Kaplan–Meier survival analysis of the 87 evaluable patients.

Grahic Jump Location
Grahic Jump Location
Figure 2.

Time to negative parasitemia in evaluable patients with quinidine exposure versus those with no exposure.

Kaplan–Meier survival analysis of the 87 evaluable patients.

Grahic Jump Location

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Intravenous artesunate for the treatment of severe malaria in Western countries : is it the drug, the patient’s age or the ICU stay that impact on mortality?
Posted on October 21, 2015
Spinello Antinori, Salvatore Sollima, Laura Milazzo, Mario Corbellino
Department of Biomedical and Clinical Sciences L Sacco, University of Milano, Italy
Conflict of Interest: None Declared
In their paper about the three-year (2007-10) cumulative US experience on the use of intravenous artesunate for severe and complicated malaria, Twomey (1) discuss the 6.9% observed case fatality rate (CFR) and positively compare it with the cumulative 15% CFR of the TropNet Europe study (2) and the 10.5% CFR observed by Bruneel et al. (3) in what is the largest cohort of critically ill adult patients with imported severe malaria published so far. In both studies age had an impressive impact on the outcome of patients: 32% mortality was reported the age group 50-89 years vs 0.9% among those 10-49 years in the former (2) whereas in the latter, older age was one of the three variables independently associated with hospital death at admission in the ICU (per 10-year increment, odds ratio 1.72,CI 95% 1.28-2.32, p=0.0004) (3). The importance of age is also evident in the UK cohort of more than 25,000 patients with imported P. falciparum malaria where the adjusted OR of death was 4.6 for those >50-65 years and 10.68 for those > 65 years (4).
On the other hand, if we look at the published European experience on the use of artesunate for the treatment of severe falciparum malaria, the reported CFR rates are: zero in UK (0/24), 1.4% (1/70) in the TropNet severe malaria study, 3.6% (2/55) in Belgium and the Netherlands and 4.9 % in France (6/117) (5-8). The overall CFR for patients treated with artesunate was 3.4 % (9/266). However, this mortality rate is comparable to what was observed in two of these studies (5,6) that included patients who received intravenous quinine: 1.7 % (2/115) in the study by Kurth et al. (6) and 3.5% (5/143) in the study by Eder et al. (5) with a cumulative CFR of 2.7 (7/258).
Due to the low number of cases and the low mortality rate observed in the most recent studies which may be ascribed to high quality intensive care with optimal treatment of organ failure, it seems difficult that in western countries a superiority of artesunate vs quinine will ever be demonstrated.
However the more rapid parasite clearance from blood (5,6) and a reduced length of stay in intensive care unit (6) reported in patients treated with artesunate might impact favorably on the outcome of patients by decreasing the risk of nosocomial infections . In fact, as observed in the study of Bruneel et al. at least one third of patient died of infectious complications and had a longer stay in the ICU (median: 11 days, range 2-173 days) (3). In conclusion, intravenous artesunate will be a welcome drug once registered in Western countries, but the impressive results obtained in South-East Asia and sub-Saharan Africa will be difficult to replicate in high-income, non-endemic countries, as previously suggested (9).
REFERENCES
1. Twomey PS, Smith BL, McDermott C, et al. Intravenous artesunate for the treatment of severe and complicated malaria in the United States: clinical use under an investigational new drug protocol. Ann Intern Med 2015;163:498-506.
2. Muhlberger N, Jelinek T, Beherens RH, et al. Age as a risk factor for severe manifestations and fatal outcome of falciparum malaria in European patients: observations from TropNetEurop and SIMPID surveillance data. Clin Infect Dis 2003;36:990-5
3. Bruneel F, Tubach F, Corne P, et al. Severe imported falciparum malaria: a cohort study in 400 critically ill adults. Plos one 2010;5:e13236.
4. Checkley AM, Smith A, Smith V, Blaze M, Bradley D, Chiodini P, et al. Risk factors for mortality from imported falciparum malaria in the United Kingdom over 20 years: an observational study. BMJ 2012; 344:e2116.
5. Eder M, Farne H, Cargill T, Abbara A, Davidson RN. Intravenous artesunate versus intravenous quinine in the treatment of severe falciparum malaria: a retrospective evaluation from a UK centre. Pathogen Glob health 2012; 106:181-7.
6. Kurth F, Develoux M, Mechain M, Clerinx J, Antinori S, Gjorup IE, et al. Intravenous artesunate reduces parasite clearance time, duration of intensive care, and hospital treatment in patients with severe malaria in Europe : the TropNet severe malaria study. Clin Infect Dis 2015; 61:1441-4.
7. Kreeftmeijer-Vegter AR, van Genderen PJ, Visser LG, Bierman W, Clerinx J, van Veldhuizen C, et al. Treatment outcome of intravenous artesunate in patients with severe malaria in the Netherlands and Belgium. Malaria J 2012;11:102.
8. Jaureguiberry S, Thellier M, Ndour PA, Roussel C, Sonneville R, Mayaux J, et al. Delayed-onset haemolytic anemia in patients with travel-associated severe malaria treated with artesunate, France, 2011-2013. Emerg Infect Dis 2015,21:804-12.
9. Cramer JP, Lopez-Velez R, Bruchard GD, Grobusch MP, de Vries PJ. Treatment of imported severe malaria with artesunate instead of quinine- more evidence needed? Malaria J 2011;10:256.
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