Aspirin to Prevent Gentamicin-Induced Hearing Loss
http://www.100md.com
《新英格兰医药杂志》
To the Editor: The use of aminoglycosides as powerful broad-spectrum, bactericidal, and nonallergenic antibiotics is limited by serious side effects, including irreversible hearing loss. Nevertheless, the drugs are commonly prescribed in some situations, including as part of the regimen against multidrug-resistant tuberculosis recommended by the World Health Organization.1 The incidence of gentamicin-induced hearing loss averages 8 percent for a short course of therapy2 but may be higher in developing countries, where aminoglycosides are frequently the only affordable antibiotics and are sold over the counter. No therapy presently exists to prevent ototoxicity. Animal models suggest that ototoxicity is caused by reactive oxygen species and is attenuated by antioxidants.3 Salicylate is a clinically promising antidote4 that can be administered as aspirin.
In cooperation with the Department of Otolaryngology at the Fourth Military Medical University in Xi'an, China, we conducted a prospective, randomized, double-blind trial at Xijing Hospital and Airforce Chengdu Hospital from 1999 to 2003. The study was approved by the institutional review boards at the Xi'an facility and at the University of Michigan Medical School and complied with the provisions of the Declaration of Helsinki. Our study was supported by the George and Christine Strumbos Foundation and the Kent and Carol Landsberg Foundation.
Volunteers were recruited among inpatients with acute infections who were scheduled for treatment with gentamicin. Patients between the ages of 18 and 65 years were eligible. Patients were excluded if they had a preexisting hearing loss of more than 30 dB at any frequency, if they had been treated with aminoglycosides within the preceding year, if they were scheduled for surgery during the treatment period, if they had ulcers or reported other gastric problems, if they had a history of renal or hepatic problems, if they were pregnant, if they were mentally incompetent to give informed consent, and if they were receiving concurrent antioxidant supplements. All patients provided written informed consent.
A total of 195 patients completed the study. They received 80 to 160 mg of gentamicin twice daily by intravenous infusion (generally for 5 to 7 days) and were randomly assigned to receive 14 days of supplementation either with 3 g of aspirin per day, divided into three doses (89 patients), or with placebo (106 patients). Ototoxicity was defined as a shift from baseline of 15 dB or more at both 6 and 8 kHz, either unilaterally or bilaterally, as assessed five to seven weeks after treatment.
The groups were similar in all characteristics tested (Table 1). Audiologic data at baseline were also similar. Gentamicin-induced hearing loss was mostly moderate in its effect. The incidence of hearing loss in the placebo group was within the anticipated range (13 percent) but was significantly lower in the aspirin group (3 percent). The efficacy of the gentamicin therapy was not affected by the administration of aspirin. Serum levels of creatinine, urea nitrogen, and carbon dioxide were normal in both groups. However, gastric symptoms were more common in the aspirin group. Three patients were removed from the study because of gastric bleeding.
Table 1. Characteristics of the Patients in the Study Groups.
The results demonstrate the principle of antioxidant protection against ototoxicity. A "safe aminoglycoside" may reduce health care costs and increase the armamentarium against drug-resistant bacteria. Although other antioxidants can be explored as alternatives, prophylactic treatment with aspirin may appeal to practitioners in developing countries because of its simplicity and low cost.
Su-Hua Sha, M.D.
University of Michigan Medical School
Ann Arbor, MI 48109-0506
Jian-Hua Qiu, M.D.
Fourth Military Medical University Xi'an 710032, China
Ann Arbor, MI 48109-0506
Jochen Schacht, Ph.D.
University of Michigan Medical School
Ann Arbor, MI 48109-0506
schacht@umich.edu
References
Global tuberculosis control -- surveillance, planning, financing. WHO report 2005. Geneva: World Health Organization, 2005. (WHO/HTM/2005.349.)
Govaerts PJ, Claes J, van de Heyning PH, Jorens PG, Marquet J, De Broe ME. Aminoglycoside-induced ototoxicity. Toxicol Lett 1990;52:227-251.
Forge A, Schacht J. Aminoglycoside antibiotics. Audiol Neurootol 2000;5:3-22.
Sha S-H, Schacht J. Salicylate attenuates gentamicin-induced ototoxicity. Lab Invest 1999;79:807-813.
In cooperation with the Department of Otolaryngology at the Fourth Military Medical University in Xi'an, China, we conducted a prospective, randomized, double-blind trial at Xijing Hospital and Airforce Chengdu Hospital from 1999 to 2003. The study was approved by the institutional review boards at the Xi'an facility and at the University of Michigan Medical School and complied with the provisions of the Declaration of Helsinki. Our study was supported by the George and Christine Strumbos Foundation and the Kent and Carol Landsberg Foundation.
Volunteers were recruited among inpatients with acute infections who were scheduled for treatment with gentamicin. Patients between the ages of 18 and 65 years were eligible. Patients were excluded if they had a preexisting hearing loss of more than 30 dB at any frequency, if they had been treated with aminoglycosides within the preceding year, if they were scheduled for surgery during the treatment period, if they had ulcers or reported other gastric problems, if they had a history of renal or hepatic problems, if they were pregnant, if they were mentally incompetent to give informed consent, and if they were receiving concurrent antioxidant supplements. All patients provided written informed consent.
A total of 195 patients completed the study. They received 80 to 160 mg of gentamicin twice daily by intravenous infusion (generally for 5 to 7 days) and were randomly assigned to receive 14 days of supplementation either with 3 g of aspirin per day, divided into three doses (89 patients), or with placebo (106 patients). Ototoxicity was defined as a shift from baseline of 15 dB or more at both 6 and 8 kHz, either unilaterally or bilaterally, as assessed five to seven weeks after treatment.
The groups were similar in all characteristics tested (Table 1). Audiologic data at baseline were also similar. Gentamicin-induced hearing loss was mostly moderate in its effect. The incidence of hearing loss in the placebo group was within the anticipated range (13 percent) but was significantly lower in the aspirin group (3 percent). The efficacy of the gentamicin therapy was not affected by the administration of aspirin. Serum levels of creatinine, urea nitrogen, and carbon dioxide were normal in both groups. However, gastric symptoms were more common in the aspirin group. Three patients were removed from the study because of gastric bleeding.
Table 1. Characteristics of the Patients in the Study Groups.
The results demonstrate the principle of antioxidant protection against ototoxicity. A "safe aminoglycoside" may reduce health care costs and increase the armamentarium against drug-resistant bacteria. Although other antioxidants can be explored as alternatives, prophylactic treatment with aspirin may appeal to practitioners in developing countries because of its simplicity and low cost.
Su-Hua Sha, M.D.
University of Michigan Medical School
Ann Arbor, MI 48109-0506
Jian-Hua Qiu, M.D.
Fourth Military Medical University Xi'an 710032, China
Ann Arbor, MI 48109-0506
Jochen Schacht, Ph.D.
University of Michigan Medical School
Ann Arbor, MI 48109-0506
schacht@umich.edu
References
Global tuberculosis control -- surveillance, planning, financing. WHO report 2005. Geneva: World Health Organization, 2005. (WHO/HTM/2005.349.)
Govaerts PJ, Claes J, van de Heyning PH, Jorens PG, Marquet J, De Broe ME. Aminoglycoside-induced ototoxicity. Toxicol Lett 1990;52:227-251.
Forge A, Schacht J. Aminoglycoside antibiotics. Audiol Neurootol 2000;5:3-22.
Sha S-H, Schacht J. Salicylate attenuates gentamicin-induced ototoxicity. Lab Invest 1999;79:807-813.