Preclinical pharmacokinetics/pharmacodynamics studies defining the role of ethambutol in <i>Mycobacterium kansasii</i> lung disease

Rifampin, isoniazid, and ethambutol are the backbone of the regimen used to treat <i>Mycobacterium kansasii-</i>complex (MKC) lung disease. However, ethambutol pharmacokinetics/pharmacodynamics (PK/PD) studies to inform on optimal exposure target and clinical dose for MKC are lacking. We performed studies to determine ethambutol minimum inhibitory concentration (MIC), mutation frequency (3× MIC), a PK/PD study using the hollow fiber system model of MKC (HFS-MKC) using the reference ATCC#12478 strain, and Monte Carlo simulation experiments for clinical dose selection and susceptibility breakpoint. We also performed a literature search to generate ethambutol MIC distribution for MKC. First, nine studies were identified with MIC of 587 isolates, and MIC₅₀ and MIC₉₀ identified as 4 and 16 mg/L, respectively. Second, the ethambutol MIC of the ATCC strain was 8 mg/L, and the mutation frequency was 4.23 × 10^-2 CFU/mL. Third, in the HFS-MKC, ethambutol failed to kill <i>M. kansasii</i> below stasis (<i>B</i>₀), and resistance emerged rapidly. The target exposure was an AUC_0-24/MIC of 5.47 (95% confidence interval: 1.17-9.77). Fourth, Monte Carlo experiments of 10,000 virtual subjects identified doses of 1,200 and 3,000 mg to achieve or exceed target exposure in 18.21% and 58.57% of patients; and PK/PD MIC susceptibility breakpoints were determined as 2 and 4 mg/L, respectively. Doses >1,200 mg/day may have a higher likelihood of ocular toxicity. The risk of toxicity versus no microbial kill benefit in HFS-MKC suggests the need for better drugs compared to ethambutol in the treatment of MKC lung disease.