In the Journals

Cutting TB drug dosage in half reduces hearing loss, maintains efficacy

Second-line tuberculosis treatments with aminoglycosides have been associated with hearing loss, but researchers in the Netherlands have discovered that carefully reducing the recommended dose by half could spare patients this side effect without sacrificing the regimen’s efficacy.

“The dosage applied in our study is two-fold lower than the 15 mg/kg recommended by the World Health Organization, yet outcome was favorable in the vast majority of patients, and in those with unfavorable outcome, aminoglycoside dosage appeared unrelated to those outcomes, Jan-Willem C. Alffenaar, PhD, PharmD, associate professor in the department of clinical pharmacy and pharmacology at the University of Groningen, and colleagues wrote in Antimicrobial Agents and Chemotherapy.

The aminoglycosides amikacin and kanamycin — two second-line injectable drugs for the treatment of multidrug-resistant (MDR)-TB — have both been associated with “profound and permanent” toxicity, with 8% to 37% of patients experiencing hearing loss and nephrotoxicity after taking them for any period of time, according to researchers. Prolonged treatment with the drugs and at higher doses may compound these problems.

At their TB Center in the Netherlands, Alffenaar and colleagues monitor concentrations of aminoglycosides in patients’ blood, making adjustments based on a prespecified maximum concentration to mean inhibitory concentration ratio. This allows them to maintain the efficacy of a patient’s regimen while reducing its toxicity at lower doses. In the study, drug susceptibility testing was conducted for all patients.

“If the bacteria are more susceptible to the antibiotic than normal, we can use a lower dose,” Alffenaar said in a press release.

The researchers retrospectively evaluated medical records of 80 MDR-TB or extensively drug-resistant TB patients aged at least 17 years who were treated with amikacin or kanamycin from 2000 through 2012. Audiometry data were available for 70 of these patients (87.5%), and results showed that 11.3% suffered hearing loss, “predominantly at higher frequencies,” they said.

All but three patients completed their therapy and were discharged — demonstrating that the treatment was effective at lower doses — and among those with unfavorable outcomes, nephrotoxicity and ototoxicity were not significantly correlated with the aminoglycoside dose, the researchers said. Among those who completed treatment and were followed up, 67.3% had successful outcomes.

According to Alffenaar and colleagues, the success of their individualized treatment approach demonstrates that “a new MDR-TB dosing strategy can be designed to improve efficacy while toxicity may be reduced.”

In some cases, the researchers reduced the recommended dosage by as much as two-thirds. However, these results should be confirmed in a prospective, randomized controlled trial, they said.  by John Schoen

Disclosure: The researchers report no relevant financial disclosures.

Second-line tuberculosis treatments with aminoglycosides have been associated with hearing loss, but researchers in the Netherlands have discovered that carefully reducing the recommended dose by half could spare patients this side effect without sacrificing the regimen’s efficacy.

“The dosage applied in our study is two-fold lower than the 15 mg/kg recommended by the World Health Organization, yet outcome was favorable in the vast majority of patients, and in those with unfavorable outcome, aminoglycoside dosage appeared unrelated to those outcomes, Jan-Willem C. Alffenaar, PhD, PharmD, associate professor in the department of clinical pharmacy and pharmacology at the University of Groningen, and colleagues wrote in Antimicrobial Agents and Chemotherapy.

The aminoglycosides amikacin and kanamycin — two second-line injectable drugs for the treatment of multidrug-resistant (MDR)-TB — have both been associated with “profound and permanent” toxicity, with 8% to 37% of patients experiencing hearing loss and nephrotoxicity after taking them for any period of time, according to researchers. Prolonged treatment with the drugs and at higher doses may compound these problems.

At their TB Center in the Netherlands, Alffenaar and colleagues monitor concentrations of aminoglycosides in patients’ blood, making adjustments based on a prespecified maximum concentration to mean inhibitory concentration ratio. This allows them to maintain the efficacy of a patient’s regimen while reducing its toxicity at lower doses. In the study, drug susceptibility testing was conducted for all patients.

“If the bacteria are more susceptible to the antibiotic than normal, we can use a lower dose,” Alffenaar said in a press release.

The researchers retrospectively evaluated medical records of 80 MDR-TB or extensively drug-resistant TB patients aged at least 17 years who were treated with amikacin or kanamycin from 2000 through 2012. Audiometry data were available for 70 of these patients (87.5%), and results showed that 11.3% suffered hearing loss, “predominantly at higher frequencies,” they said.

All but three patients completed their therapy and were discharged — demonstrating that the treatment was effective at lower doses — and among those with unfavorable outcomes, nephrotoxicity and ototoxicity were not significantly correlated with the aminoglycoside dose, the researchers said. Among those who completed treatment and were followed up, 67.3% had successful outcomes.

According to Alffenaar and colleagues, the success of their individualized treatment approach demonstrates that “a new MDR-TB dosing strategy can be designed to improve efficacy while toxicity may be reduced.”

In some cases, the researchers reduced the recommended dosage by as much as two-thirds. However, these results should be confirmed in a prospective, randomized controlled trial, they said.  by John Schoen

Disclosure: The researchers report no relevant financial disclosures.