Major adverse effects of PZA include hepatotoxicity (in 1–5% of patients), nausea, vomiting, drug fever, photosensitivity, and hyperuricemia. The latter occurs uniformly and is not a reason to halt therapy if patients are asymptomatic.
The alternative drugs listed below are usually considered only (1) in case of resistance to first-line agents; (2) in case of failure of clinical response to conventional therapy; and (3) in case of serious treatment-limiting adverse drug reactions. Expert guidance  is desirable in dealing with the toxic effects of these second-line drugs. For many drugs listed in the following text, the dosage, emergence of resistance, and long-term toxicity have not been fully established.
The mechanism of action and other pharmacologic features of streptomycin, an aminoglycoside, are discussed in Chapter 45. The typical adult dosage is 1 g/d (15 mg/kg/d). If the creatinine clearance is less than 30 mL/min or the patient is on hemodialysis, the dosage is 15 mg/kg two or three times per week. Most tubercle bacilli are inhibited by streptomycin, 1–10 mcg/mL, in vitro. Nontuberculous species of mycobacteria other than Mycobacterium avium complex (MAC) and Mycobacterium kansasii are resistant. All large populations of tubercle bacilli contain some streptomycin-resistant mutants. On average, 1 in 108 tubercle bacilli can be expected to be resistant to streptomycin at levels of 10–100 mcg/mL. Resistance may be due to a point mutation in either the rpsL gene encoding the S12 ribosomal protein or the rrs gene encoding 16S ribosomal RNA, which alters the ribosomal binding site.
Streptomycin penetrates into cells poorly and is active mainly against extracellular tubercle bacilli. The drug crosses the blood-brain barrier and achieves therapeutic concentrations with inflamed meninges.
Streptomycin sulfate is used when an injectable drug is needed or desirable and in the treatment of infections resistant to other drugs. The usual dosage is 15 mg/kg/d intramuscularly or intravenously daily for adults (20–40 mg/kg/d for children, not to exceed 1 g) for several weeks, followed by 15 mg/kg two or three times weekly for several months. Serum concentrations of approximately 40 mcg/mL are achieved 30–60 minutes after intramuscular injection of a 15 mg/kg dose. Other drugs are always given in combination to prevent emergence of resistance.
Streptomycin is ototoxic and nephrotoxic. Vertigo and hearing loss are the most common adverse effects and may be permanent. Toxicity is dose-related, and the risk is increased in the elderly. As with all aminoglycosides, the dose must be adjusted according to renal function (see Chapter 45). Toxicity can be reduced by limiting therapy to no more than 6 months whenever possible.
Ethionamide is chemically related to isoniazid and similarly blocks the synthesis of mycolic acids. It is poorly water soluble and available only for oral use. It is metabolized by the liver.
Most tubercle bacilli are inhibited in vitro by ethionamide, 2.5 mcg/mL or less. Some other species of mycobacteria also are inhibited by ethionamide, 10 mcg/mL. Serum concentrations in plasma and tissues of approximately 1-5 mcg/mL are achieved by a dosage of 1 g/d. Cerebrospinal fluid concentrations are equal to those in serum.