Ototoxicity of artemether/lumefantrine in the treatment of falciparum malaria: a randomized trial.
BACKGROUND
Due to increasing drug resistance, artemisinin-based combination chemotherapy (ACT) has become the first-line treatment of falciparum malaria in many endemic countries. However, irreversible ototoxicity associated with artemether/lumefantrine (AL) has been reported recently and suggested to be a serious limitation in the use of ACT. The aim of the study was to compare ototoxicity, tolerability, and efficacy of ACT with that of quinine and atovaquone/proguanil in the treatment of uncomplicated falciparum malaria.


METHODS
Ninety-seven patients in south-west Ethiopia with slide-confirmed malaria were randomly assigned to receive either artemether/lumefantrine or quinine or atovaquone/proguanil and followed-up for 90 days. Comprehensive audiovestibular testing by pure tone audiometry (PTA), transitory evoked (TE) and distortion product (DP) otoacoustic emissions (OAE) and brain stem evoked response audiometry (BERA) was done before enrolment and after seven, 28 and 90 days.


RESULTS
PTA and DP-OAE levels revealed transient significant cochlear hearing loss in patients treated with quinine but not in those treated with artemether/lumefantrine or atovaquone/proguanil. TE-OAE could be elicited in all examinations, except for three patients in the Q group on day 7, who suffered a transient hearing loss greater than 30 dB. There was no evidence of drug-induced brain stem lesions by BERA measurements.


CONCLUSIONS
There was no detrimental effect of a standard oral regimen of artemether/lumefantrine on peripheral hearing or brainstem auditory pathways in patients with uncomplicated falciparum malaria. In contrast, transient hearing loss is common after quinine therapy and due to temporary outer hair cell dysfunction.
Gürkov
Robert
R
Department of Otorhinolaryngology Head and Neck Surgery, Ludwig Maximilians University, Munich, Germany. robert.guerkov@med.uni-muenchen.de
Eshetu
Teferi
T
Miranda
Isabel Barreto
IB
Berens-Riha
Nicole
N
Mamo
Yoseph
Y
Girma
Tsinuel
T
Krause
Eike
E
Schmidt
Michael
M
Hempel
John-Martin
JM
Löscher
Thomas
T
D000293:Adolescent; D000328:Adult; D000077549:Artemether; D037621:Artemisinins / Q000009:adverse effects* / Q000627:therapeutic use; D053626:Atovaquone / Q000009:adverse effects / Q000627:therapeutic use; D001299:Audiometry; D002648:Child; D004983:Ethanolamines / Q000009:adverse effects* / Q000627:therapeutic use; D005002:Ethiopia; D005260:Female; D005449:Fluorenes / Q000009:adverse effects* / Q000627:therapeutic use; D006319:Hearing Loss, Sensorineural / Q000139:chemically induced*; D006801:Humans; D000078102:Lumefantrine; D016778:Malaria, Falciparum / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D002727:Proguanil / Q000009:adverse effects / Q000627:therapeutic use; D011803:Quinine / Q000009:adverse effects / Q000627:therapeutic use
D037621:Artemisinins; D004983:Ethanolamines; D005449:Fluorenes; D011803:Quinine; D000077549:Artemether; D000078102:Lumefantrine; D002727:Proguanil; D053626:Atovaquone
Clin Rheumatol. 2007 Nov;26(11):1809-10
17594118
Am J Trop Med Hyg. 2000 Jan;62(1):65-9
10761725
Clin Infect Dis. 1999 Jun;28(6):1330-1
10451183
Travel Med Infect Dis. 2006 Mar;4(2):71-6
16887727
Arch Neurol. 1988 Jul;45(7):737-9
3390028
Am J Trop Med Hyg. 1999 Apr;60(4):547-55
10348227
N Engl J Med. 1997 May 1;336(18):1328
9132599
J Clin Microbiol. 1991 Jun;29(6):1171-4
1864936
Antimicrob Agents Chemother. 2002 Mar;46(3):821-7
11850267
Toxicol Lett. 2004 Mar 1;147(2):99-107
14757313
Trans R Soc Trop Med Hyg. 2004 May;98(5):261-7; discussion 268-9
15109547
J Acoust Soc Am. 2002 Apr;111(4):1810-8
12002865
Exp Parasitol. 1994 Sep;79(2):106-16
7914494
Z Med Phys. 2003;13(2):93-8
12868334
Rinsho Byori. 1990 Dec;38(12):1383-6
2082039
Parasitol Today. 1998 Nov;14(11):462-7
17040849
Laryngoscope. 1952 Apr;62(4):333-51
14928708
Am J Trop Med Hyg. 2006 Feb;74(2):211-4
16474072
Trans R Soc Trop Med Hyg. 2000 Apr;94 Suppl 1:S1-90
11103309
Am J Trop Med Hyg. 2000 Jul-Aug;63(1-2):48-55
11357994
Clin Ter. 1999 Sep-Oct;150(5):379-82
10687269
Trop Med Int Health. 2006 Sep;11(9):1350-9
16930256
Trans R Soc Trop Med Hyg. 2006 Dec;100(12):1098-104
16808940
Toxicol Lett. 2006 Oct 10;166(2):95-104
16828992
Lancet. 2003 Jul 26;362(9380):295-6
12892962
Mol Biochem Parasitol. 1993 Oct;61(2):315-20
8264734
Clin Otolaryngol Allied Sci. 1991 Apr;16(2):138-41
2070528