Atovaquone

The Cochrane Abstract below is a summary of a review from the Cochrane Library. It is accompanied by an interpretation that will help clinicians put evidence into practice. William E. Cayley, Jr., M.D., presents a clinical scenario and question based on the Cochrane Abstract, along with the evidence-based answer and a full critique of the abstract.

This clinical content conforms to AAFP criteria for evidence-based continuing medical education (EB CME). EB CME is clinical content presented with practice recommendations supported by evidence that has been systematically reviewed by an AAFP-approved source. The practice recommendations in this activity are available online at http://www.cochrane.org/ cochrane/revabstr/AB000138.htm.

Clinical Scenario

A 54-year-old woman preparing for a mission trip to Mexico asks what she should do to prevent malaria.

Clinical Question

Should we prescribe mefloquine for the prevention of malaria in nonimmune adult travelers?

Evidence-Based Answer

Mefloquine prevents malaria in military personnel, but its effectiveness in a heterogeneous population of civilian travelers is poorly studied. Evidence of side effects is based on spontaneous reports and may underestimate their frequency.

Practice Pointers

Residents of countries with endemic malaria have some protection from severe disease because of partial immunity. Although mefloquine is commonly recommended for preventing malaria in the 70 million nonimmune civilian travelers visiting such areas annually, (2) reports of adverse effects have led to public concern. (3) The U.S. Food and Drug Administration recently issued a Safety Alert indicating potential side effects ranging from depression to psychosis and suicidal ideation. (4)

This review sought documentation of the efficacy, tolerability, and safety of mefloquine in civilian travelers, but the authors found only field trials in military populations and tolerability trials in nonexposed civilians. One study found that mefloquine and doxycycline were equally effective (one case of malaria prevented for every two people treated), but the study did not include enough patients to detect a clinically meaningful difference between the medications. Four trials found more withdrawals from mefloquine than placebo (of every 30 patients given mefloquine, one stopped treatment), but six trials found no difference between mefloquine and other medications in the rates of withdrawal from therapy. The only side effects consistently specific to mefloquine in the controlled trials were insomnia and fatigue, but the review found 516 additional published case reports of adverse effects.

Although the reviewed studies suggest that mefloquine may be just as safe and effective as other malaria prevention medications, it is unclear if the efficacy information derived from military populations can be generalized to the civilian traveling population. Because 63 percent of the 516 adverse-event case reports were from business or tourist travelers, it is possible that civilian populations may have more difficulties with mefloquine and lower tolerance for its adverse effects, and may be less likely to continue therapy than persons in a more structured military setting. (5)

Since this review was published, one study in nonimmune civilian travelers found that atovaquone plus proguanil is just as effective as mefloquine, with fewer neuropsychiatric side effects and fewer withdrawals from prophylaxis. (6) Another study comparing four prophylactic regimens in civilian travelers found that overall tolerability was the same among mefloquine, doxycycline, chloroquine plus proguanil, and atovaquone plus proguanil. (7) Patients taking mefloquine had higher rates of severe neuropsychiatric side effects, and patients taking chloroquine plus proguanil had higher rates of adverse skin reactions. (7) A third study has shown that nearly one third of malaria cases in returning travelers is late-onset illness, most often caused by Plasmodium vivax and Plasmodium ovale, which have a liver phase that is not susceptible to mefloquine. (8)

Although mefloquine is the most commonly recommended agent for malaria prophylaxis, no study has adequately assessed its safety and efficacy in the general civilian population. Although mefloquine prevents malaria, doxycycline may work just as well, and atovaquone plus proguanil may work better with fewer side effects. Selection of an antimalarial agent should be guided by the patient's health status and travel plans.

Research is needed to clarify the most appropriate regimen for prevention and terminal prophylaxis against liver-stage P. ovale and P. vivax. Recommendations from the Centers for Disease Control and Prevention are available online at http://www.cdc.gov/travel.

REFERENCES

(1.) Croft AM, Garner P. Mefloquine for preventing malaria in non-immune adult travellers. Cochrane Database Syst Rev 2000: CD000138.

(2.) Lo Re V 3d, Gluckman SJ. Prevention of malaria in travelers. Am Fam Physician 2003;68:509-14.

(3.) Croft AM, Garner P, Squire SB. Malaria prevention for travelers. JAMA 1998;279:990.

(4.) U.S. Food and Drug Administration. 2002 safety alert-Lariam (mefloquine hydrochloride). Accessed November, 2003 at: http://www.fda.gov/medwatch/SAFETY/2002/lariam_deardoc.htm.

(5.) Croft A, Garner P. Mefloquine to prevent malaria: a systematic review of trials. BMJ 1997;315:1412-6.

(6.) Overbosch D, Schilthuis H, Bienzle U, Behrens RH, Kain KC, Clarke PD, et al. Malarone International Study Team. Atovaquone-proguanil versus mefloquine for malaria prophylaxis in nonimmune travelers: results from a randomized, double-blind study. Clin Infect Dis 2001;33:1015-21.

(7.) Schlagenhauf P, Tschopp A, Johnson R, Nothdurft HD, Beck B, Schwartz E, et al. Tolerability of malaria chemoprophylaxis in non-immune travellers to sub-Saharan Africa: multicentre, randomised, double blind, four arm study. BMJ 2003;327:1078.

(8.) Schwartz E, Parise M, Kozarsky P, Cetron M. Delayed onset of malaria-implications for chemoprophylaxis in travelers. N Engl J Med 2003;349:1510-6.

RELATED ARTICLE: Cochrane abstract.

Background. Mefloquine is commonly prescribed to prevent malaria in travelers and has replaced other drugs because Plasmodium falciparum is commonly resistant to them. However, mefloquine may be associated with harmful neuropsychiatric effects.

Objectives. To assess the effects of mefloquine in adult travelers compared with other regimens in relation to episodes of malaria, withdrawal from prophylaxis, and adverse events.

Search Strategy. The authors1 searched the Cochrane Infectious Diseases Group specialized trials register (September 2002), the Cochrane Central Register of Controlled Trials (the Cochrane Library, Issue 3, 2002), MEDLINE (1966 to September 2000), EMBASE (1980 to September 2002), LILACS (September 2002), Science Citation Index (1981 to September 2002), and bibliographies in retrieved papers and standard textbooks. They contacted pharmaceutical companies and researchers in the subject of malaria chemoprophylaxis.

Selection Criteria. Randomized trials comparing mefloquine with other standard prophylaxis or placebo in nonimmune adult travelers and nontraveling volunteers were selected. For adverse events, any published case reports were collected.

Data Collection and Analysis. The authors independently assessed trial quality and extracted data. Adverse events from observational studies were categorized by the study type. Study authors also were contacted.

Primary Results. Ten trials involving 2,750 nonimmune adult participants were included. Five were field trials, and of these, all involved primarily male soldiers. One trial comparing mefloquine with placebo showed that mefloquine prevented malaria episodes in an area of drug resistance (Peto odds ratio [OR], 0.04; 95 percent confidence interval [CI], 0.02 to 0.08). Withdrawals in the mefloquine group were consistently higher in four placebo controlled trials (OR, 3.56; 95 percent CI, 1.67 to 7.60). In five trials comparing mefloquine with other chemoprophylaxis, no difference in tolerability was detected. The authors found 516 published case reports of mefloquine adverse effects; 63 percent involved tourists and business travelers. Four fatalities were attributed to mefloquine.

Reviewers' Conclusions. Mefloquine prevents malaria but has adverse effects that limit its acceptability. There is evidence from nonrandomized studies that mefloquine has potentially harmful effects in tourists and business travelers, and its use needs to be carefully balanced against this potential risk. Trials of comparative effects of anti-malarial prophylaxis should include episodes of malaria and withdrawal from prophylaxis as outcomes.

William E. Cayley, Jr., M.D., is assistant professor at the University of Wisconsin Eau Claire Family Practice Residency Program.

Address correspondence to William E. Cayley, Jr., M.D., University of Wisconsin Eau Claire Family Practice Residency, 807 S. Farwell, Eau Claire, WI 54701 (e-mail: bcayley@yahoo.com). Reprints are not available from the author.

COPYRIGHT 2004 American Academy of Family Physicians
COPYRIGHT 2004 Gale Group