dMultidrug-resistant tuberculosis (MDR-TB) threatens global TB control. The lengthy treatment includes one of the injectable drugs kanamycin, amikacin, and capreomycin, usually for the first 6 months. These drugs have potentially serious toxicities, and when given as intramuscular injections, dosing can be painful. Advances in particulate drug delivery have led to the formulation of capreomycin as the first antituberculosis drug available as a microparticle dry powder for inhalation and clinical study. Delivery by aerosol may result in successful treatment with lower doses. Here we report a phase I, single-dose, dose-escalating study aimed at demonstrating safety and tolerability in healthy subjects and measuring pharmacokinetic (PK) parameters. Twenty healthy adults (n ‫؍‬ 5 per group) were recruited to self-administer a single dose of inhaled dry powder capreomycin (25-mg, 75-mg, 150-mg, or 300-mg nominal dose) using a simple, handheld delivery device. Inhalations were well tolerated by all subjects. The most common adverse event was mild to moderate transient cough, in five subjects. There were no changes in lung function, audiometry, or laboratory parameters. Capreomycin was rapidly absorbed after inhalation. Systemic concentrations were detected in each dose group within 20 min. Peak and mean plasma concentrations of capreomycin were dose proportional. Serum concentrations exceeded 2 g/ml (MIC for Mycobacterium tuberculosis) following the highest dose; the half-life (t 1/2 ) was 4.8 ؎ 1.0 h. A novel inhaled microparticle dry powder formulation of capreomycin was well tolerated. A single 300-mg dose rapidly achieved serum drug concentrations above the MIC for Mycobacterium tuberculosis, suggesting the potential of inhaled therapy as part of an MDR-TB treatment regimen. M ultidrug-resistant tuberculosis (MDR-TB) is difficult to treat and readily spread and threatens global tuberculosis control, especially where HIV coinfection is common. According to the WHO, an estimated 440,000 new cases of MDR-TB occur each year (1, 2), but only a small fraction are receiving qualityassured treatment (1). In most public health treatment programs, 18 to 24 months of therapy with four or more second-line drugs are required. Second-line drugs are less efficacious, more toxic, and associated with treatment success rates of only 40 to 80% (1, 3-6). According to current WHO MDR-TB treatment guidelines, at least one injectable antibiotic (kanamycin, amikacin, or capreomycin) is an essential part of the 6-month intensive phase of treatment. These 3-to 7-times-per-week injections are painful for patients, especially for children and those with little muscle mass. Injections require skilled health care staff and place them at risk of needle stick injuries and infections (3). Treatment with injectable drugs is associated with systemic toxicity, including nephrotoxicity, which is typically mild and reversible, and ototoxicity, which can be significant and irreversible. Dosing must also be adjusted in individuals with preexisting renal...

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