Skip to main content
Log in

Efficacy and safety of atovaquone-proguanil compared with mefloquine in the treatment of nonimmune patients with uncomplicated P. falciparum malaria in Japan

  • ORIGINAL ARTICLE
  • Published:
Journal of Infection and Chemotherapy

Abstract

Malaria treatment is becoming increasingly difficult due to the widespread drug resistance of Plasmodium falciparum. In Japan, only three antimalarials are approved for treatment: oral quinine, sulfadoxine-pyrimethamine, and mefloquine. Recently, however, the Research Group on Chemotherapy of Tropical Diseases introduced atovaquone-proguanil for treating drug-resistant P. falciparum malaria. This research group had also introduced mefloquine before it was licensed nationally. Using data obtained from the research group, we analyzed the efficacy and safety of atovaquone-proguanil, as compared with mefloquine, in nonimmune patients with uncomplicated P. falciparum malaria. Cures were attained in all (100%) of 20 atovaquone-proguanil-treated and 49 (98%) of 50 mefloquine-treated adults. The mean fever clearance time (FCT) and parasite clearance time (PCT) appeared to be longer in the atovaquone-proguanil group than in the mefloquine group, but the differences were not statistically significant. Three (15%) of the 20 atovaquone-proguanil-treated adults had adverse events (AEs), all of which were transient elevations of liver enzymes, while 19 (38%) of the 50 mefloquine-treated adults had AEs, including dizziness in 8 (16%) and nausea/vomiting in 7 (14%). All 3 children treated with atovaquone-proguanil were cured without developing AEs. Despite the limitations of this study in not being a formal clinical trial, atovaquone-proguanil seemed to be at least equal to, or even better than, mefloquine for the treatment of uncomplicated P. falciparum malaria in nonimmune patients, including children. Its marketing in Japan could be beneficial in offering an alternative therapeutic option. However, vigilance should be maintained on the possible occurrence of rare but severe AEs, and also of the possible spread of drug resistance.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. HO Lobel PE Kozarsky (1997) ArticleTitleUpdate on prevention of malaria for travelers JAMA 278 1767–71 Occurrence Handle9388154 Occurrence Handle1:STN:280:DyaK1c%2FkslentQ%3D%3D Occurrence Handle10.1001/jama.278.21.1767

    Article  PubMed  CAS  Google Scholar 

  2. P Muentener P Schlagenhauf R Steffen (1999) ArticleTitleImported malaria (1985–1995): trends and perspectives Bull World Health Organ 77 560–6 Occurrence Handle10444879 Occurrence Handle1:STN:280:DyaK1Mzntl2jtw%3D%3D

    PubMed  CAS  Google Scholar 

  3. GD Shanks (2001) Drugs used in malaria chemoprophylaxis. Atovaquone/proguanil P Schlagenhauf (Eds) Travelers' malaria BC Decker Hamilton 227–46

    Google Scholar 

  4. S Looareesuwan P Wilairatana K Chalermarut Y Rattanapong CJ Canfield DBA Hutchinson (1999) ArticleTitleEfficacy and safety of atovaquone/proguanil compared with mefloquine for treatment of acute Plasmodium falciparum malaria in Thailand Am J Trop Med Hyg 60 526–32 Occurrence Handle10348224 Occurrence Handle1:CAS:528:DyaK1MXjs1arsbw%3D

    PubMed  CAS  Google Scholar 

  5. DG Bustos CJ Canfield E Canete-Miguel DBA Hutchinson (1999) ArticleTitleAtovaquone-proguanil compared with chloroquine and chloroquine–sulfadoxine-pyrimethamine for treatment of acute Plasmodium falciparum malaria in the Philippines J Infect Dis 179 1587–90 Occurrence Handle10228090 Occurrence Handle1:CAS:528:DyaK1MXjvFeltLw%3D Occurrence Handle10.1086/314770

    Article  PubMed  CAS  Google Scholar 

  6. FEC de Alencar C Cerutti SuffixJr RR Durlacher M Boulos FP Alves W Milhous et al. (1997) ArticleTitleAtovaquone and proguanil for the treatment of malaria in Brazil J Infect Dis 175 1544–7 Occurrence Handle9180204 Occurrence Handle1:CAS:528:DyaK2sXjsl2jtrc%3D Occurrence Handle10.1086/516497

    Article  PubMed  CAS  Google Scholar 

  7. PD Radloff J Philipps M Nkeyi D Hutchinson PG Kremsner (1996) ArticleTitleAtovaquone and proguanil for Plasmodium falciparum malaria Lancet 347 1511–4 Occurrence Handle8684102 Occurrence Handle1:CAS:528:DyaK28XjvVyrurY%3D Occurrence Handle10.1016/S0140-6736(96)90671-6

    Article  PubMed  CAS  Google Scholar 

  8. M Mulenga TY Sukwa CJ Canfield DBA Hutchinson (1999) ArticleTitleAtovaquone and proguanil versus pyrimethamine/sulfadoxine for the treatment of acute falciparum malaria in Zambia Clin Ther 21 841–52 Occurrence Handle10397379 Occurrence Handle1:CAS:528:DyaK1MXkt1CksLs%3D Occurrence Handle10.1016/S0149-2918(99)80006-X

    Article  PubMed  CAS  Google Scholar 

  9. O Bouchaud E Monlun K Muanza R Fontanet T Scott A Goetschel et al. (2000) ArticleTitleAtovaquone plus proguanil versus halofantrine for the treatment of imported acute uncomplicated Plasmodium falciparum malaria in non-immune adults: a randomized comparative trial Am J Trop Med Hyg 63 274–9 Occurrence Handle11421377 Occurrence Handle1:CAS:528:DC%2BD3MXkvFeitbo%3D

    PubMed  CAS  Google Scholar 

  10. S Thybo I Gjorup AM Ronn D Meyrowitsch IC Bygberg (2004) ArticleTitleAtovaquone-proguanil (Malarone): an effective treatment for uncomplicated Plasmodium falciparum malaria in travelers from Denmark J Travel Med 11 220–4 Occurrence Handle15541224 Occurrence Handle10.2310/7060.2004.19005

    Article  PubMed  Google Scholar 

  11. D Malvy F Djossou R Vatan Th Pistone G Etienne M Longy-Boursier et al. (2002) ArticleTitleAtovaquone plus proguanil for treatment of uncomplicated Plasmodium falciparum malaria: a 112 case series Med Trop (Mars) 62 229–31 Occurrence Handle1:STN:280:DC%2BD38votlWluw%3D%3D

    CAS  Google Scholar 

  12. M Kimura A Suzaki Y Matsumoto K Nakajima Y Wataya H Ohtomo (2003) ArticleTitleEpidemiological and clinical aspects of malaria in Japan J Travel Med 10 122–7 Occurrence Handle12650657 Occurrence Handle10.2310/7060.2003.31775

    Article  PubMed  Google Scholar 

  13. InstitutionalAuthorNameAnonymous (2005) ArticleTitleMalaria: April 1999–December 2004 Infect Dis Wkly Rep Jpn 7 IssueID34 14–8

    Google Scholar 

  14. WRJ Taylor NJ White (2004) ArticleTitleAntimalarial drug toxicity: a review Drug Saf 27 25–61 Occurrence Handle14720085 Occurrence Handle1:CAS:528:DC%2BD2cXhsl2lu7g%3D Occurrence Handle10.2165/00002018-200427010-00003

    Article  PubMed  CAS  Google Scholar 

  15. InstitutionalAuthorNameWorld Health Organization (2000) ArticleTitleSevere falciparum malaria Trans R Soc Trop Med Hyg 94 IssueIDSuppl 1 S1/1–S1/90

    Google Scholar 

  16. F Marra JR Salzman MHH Ensom (2003) ArticleTitleAtovaquone-proguanil for prophylaxis and treatment of malaria Ann Pharmacother 37 1266–75 Occurrence Handle12921511 Occurrence Handle1:CAS:528:DC%2BD3sXnsFCms7w%3D Occurrence Handle10.1345/aph.1C473

    Article  PubMed  CAS  Google Scholar 

  17. D Overbosch H Schilthuis U Bienzle RH Behrens KC Kain PD Clarke et al. (2001) ArticleTitleAtovaquone-proguanil versus mefloquine for malaria prophylaxis in nonimmune travelers: results from a randomized, double-blind study Clin Infect Dis 33 1015–21 Occurrence Handle11528574 Occurrence Handle1:CAS:528:DC%2BD3MXnsFWitrc%3D Occurrence Handle10.1086/322694

    Article  PubMed  CAS  Google Scholar 

  18. P Schlagenhauf A Tschopp R Johnson HD Nothdurft B Beck E Schwartz et al. (2003) ArticleTitleTolerability of malaria chemoprophylaxis in non-immune travellers to sub-Saharan Africa: multicentre, randomised, double blind, four arm study BMJ 327 1078–81 Occurrence Handle14604928 Occurrence Handle10.1136/bmj.327.7423.1078

    Article  PubMed  Google Scholar 

  19. M Grieshaber J Lämmli L Marcus (2005) ArticleTitleAcute hepatitis and atovaquone/proguanil J Travel Med 12 289–90 Occurrence Handle16256055 Occurrence Handle10.2310/7060.2005.12510

    Article  PubMed  Google Scholar 

  20. RK Gupta M van Vugt L Paiphun T Slight S Looareesuwan NJ White et al. (2005) ArticleTitleNo evidence of cardiotoxicity of atovaquone-proguanil alone or in combination with artesunate Am J Trop Med Hyg 73 267–8 Occurrence Handle16103586 Occurrence Handle1:CAS:528:DC%2BD2MXhtVWru7nP

    PubMed  CAS  Google Scholar 

  21. W Stauffer PR Fischer (2003) ArticleTitleDiagnosis and treatment of malaria in children Clin Infect Dis 37 1340–8 Occurrence Handle14583868 Occurrence Handle10.1086/379074

    Article  PubMed  Google Scholar 

  22. Y Mizuno N Sato E Hayakawa T Matsushita M Saegusa S Kuboshima (2006) ArticleTitleThree pediatric patients with falciparum malaria treated with atovaquone-proguanil J Jpn Pediatr Soc 110 442–6

    Google Scholar 

  23. Borrmann S, Faucher JF, Binder RK, Miller GB, Lell B, Kremsner PG. Atovaquone and proguanil versus amodiaquine in the treatment of uncomplicated Plasmodium falciparum malaria in children weighing ≥5 and <11 kg in Gabon [poster 813]. Program and Abstracts of the 50th Annual Meeting of the American Society of Tropical Medicine and Hygiene (Atlanta). Northbrook, IL. American Society of Tropical Medicine and Hygiene 2001:432

  24. QL Fivelman GA Butcher IS Adagu DC Warhurst G Pasvol (2002) ArticleTitleMalarone treatment failure and in vitro confirmation of resistance of Plasmodium falciparum isolate from Lagos Nigeria Malar J 1 1 Occurrence Handle12057021 Occurrence Handle10.1186/1475-2875-1-1

    Article  PubMed  Google Scholar 

  25. E Schwartz S Bujanover KC Kain (2003) ArticleTitleGenetic confirmation of atovaquone-proguanil-resistant Plasmodium falciparum malaria acquired by a nonimmune traveler to East Africa Clin Infect Dis 37 450–1 Occurrence Handle12884171 Occurrence Handle10.1086/375599

    Article  PubMed  Google Scholar 

  26. KP David M Alifrangis A Salanti LS Vestergaard A Rønn I Bygbjerg (2003) ArticleTitleAtovaquone/proguanil resistance in Africa: a case report Scand J Infect Dis 35 897–8 Occurrence Handle14723376 Occurrence Handle10.1080/00365540310016862

    Article  PubMed  Google Scholar 

  27. A Färnert J Lindberg P Gil G Swedberg Y Berqvist MM Thapar et al. (2003) ArticleTitleEvidence of Plasmodium falciparum malaria resistant to atovaquone and proguanil hydrochloride: case reports BMJ 326 628–9 Occurrence Handle12649236 Occurrence Handle10.1136/bmj.326.7390.628

    Article  PubMed  Google Scholar 

  28. S Kuhn MJ Gill KC Kain (2005) ArticleTitleEmergence of atovaquone-proguanil resistance during treatment of Plasmodium falciparum malaria acquired by a non-immune North American traveller to West Africa Am J Trop Med Hyg 72 407–9 Occurrence Handle15827276

    PubMed  Google Scholar 

  29. O Wichmann M Muehlen H Gruss FP Mockenhaupt N Suttorp T Jelinek (2004) ArticleTitleMalarone treatment failure not associated with previously described mutations in the cytochrome b gene Malar J 3 14 Occurrence Handle15186499 Occurrence Handle10.1186/1475-2875-3-14

    Article  PubMed  Google Scholar 

  30. O Wichmann N Muehlberger T Jelinek M Alifrangis G Peyerl-Hoffmann M Mühlen et al. (2004) ArticleTitleScreening for mutations related to atovaquone/proguanil resistance in treatment failures and other imported isolates of Plasmodium falciparum in Europe J Infect Dis 190 1541–6 Occurrence Handle15478057 Occurrence Handle1:CAS:528:DC%2BD2cXhtVWltLjK Occurrence Handle10.1086/424469

    Article  PubMed  CAS  Google Scholar 

  31. MD Edstein BM Kotecka KL Anderson DJ Pombo DE Kyle KH Rieckmann et al. (2005) ArticleTitleLengthy antimalarial activity of atovaquone in human plasma following atovaquone-proguanil administration Antimicrob Agents Chemother 49 4421–2 Occurrence Handle16189139 Occurrence Handle1:CAS:528:DC%2BD2MXhtV2gurzE Occurrence Handle10.1128/AAC.49.10.4421-4422.2005

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Mikio Kimura.

About this article

Cite this article

Hitani, A., Nakamura, T., Ohtomo, H. et al. Efficacy and safety of atovaquone-proguanil compared with mefloquine in the treatment of nonimmune patients with uncomplicated P. falciparum malaria in Japan. J Infect Chemother 12, 277–282 (2006). https://doi.org/10.1007/s10156-006-0465-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10156-006-0465-8

Key words

Navigation