Low-dose amikacin with appropriate dose adjustment based on adequate monitoring demonstrated limited toxicity with positive outcomes as a treatment option for multidrug-resistant tuberculosis (MDR-TB), according to the findings of a retrospective cohort study published in BMC Infectious Diseases.

MDR-TB is defined as resistance to both rifampin and isoniazid and has become a global epidemic for which the World Health Organization has created guidelines for recommended regimens. The updated guidelines have classified amikacin as a Group C drug because of its significant toxicity; however, there is evidence to support the use of low-dose aminoglycoside therapy for MDR-TB.

Investigators examined 49 patients with MDR-TB who received amikacin 8 mg/kg to 10 mg/kg from 2010 to 2016 at a TB referral hospital in Toronto, Canada. Dose adjustment was performed according to therapeutic drug monitoring, using 30-minute postdose levels that targeted a maximum concentration to minimum inhibitory concentration ratio of 25:35.


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The median starting dose of daily amikacin was 8.9 mg/kg (interquartile range [IQR], 8-10). The target therapeutic drug levels with daily treatment were achieved at a median of 12 days (IQR, 5-26).

The researchers monitored for amikacin-associated ototoxicity (hearing loss), which was defined as a 20-decibel or more decline in hearing threshold from baseline at any frequency in either ear. Severe hearing loss was defined as a 70-decibel or more decline in hearing threshold from baseline in either ear. Of all 49 patients, 6 (12.2%) experienced audiometry-confirmed hearing loss. Of those 6 patients, 5 (83.3%) experienced hearing loss in the high-frequency range (>2000 Hertz). No patients experienced severe hearing loss.

Nephrotoxicity was defined as a 50% or greater increase in serum creatinine from baseline at any point during therapy with amikacin. The investigators observed that 10 (23%) patients had nephrotoxicity to a median peak creatinine of 90 (IQR, 76-106). However, it was noted that the described nephrotoxicity was subclinical, and only 5 patients had a glomerular filtration rate less than 60 mL/min/m2 at the end of treatment. The study authors found that 86% of the patients who did not receive other nephrotoxic medications were more likely to recover renal function compared with 40% of patients who received nephrotoxic medications plus amikacin (P =.043).

The median time to sputum culture conversion was 1 month (IQR, 1-2) among those patients with pulmonary disease. End-of-treatment outcomes were defined according to the World Health Organization and included treatment success (41 [84%] patients), treatment failure (1 [2%] patient), death during treatment (1 [2%] patient), and loss to follow-up/not evaluated (6 [12%] patients).

Limitations of this study included the inability to evaluate treatment efficacy due to lack of a control group, the study’s modest sample size, and underestimation of achieved maximum concentration to minimum inhibitory concentration ratios.

“When an adequate regimen cannot be constructed with Group A and B drugs, we believe that low-dose amikacin should be considered as a component of a multidrug treatment regimen, as long as adequate resources for monitoring are in place,” the study authors concluded.

Reference

Sabur NF, Brar MS, Wu L, Brode SK. Low-dose amikacin in the treatment of multidrug-resistant tuberculosis (MDR-TB). BMC Infect Dis. Published online March 10, 2021. doi:10.1186/s12879-021-05947-6