Tubercle bacilli are usually inhibited in vitro by aminosalicylic acid, 1–5 mcg/mL. The granule formulation of aminosalicylic acid results in improved absorption from the gastrointestinal tract. Peak serum levels are expected to be 20–60 mcg/mL 6 hours after a 4 g oral dose. The dosage is 8–12 g/d orally for adults and 300 mg/kg/d for children, administered in two or three divided doses. The drug is widely distributed in tissues and body fluids except the cerebrospinal fluid. Aminosalicylic acid is rapidly excreted in the urine, in part as active PAS and in part as the acetylated compound and other metabolic products. To avoid accumulation in renal impairment, the maximum dose is 4 g twice daily when creatinine clearance is less than 30 mL/min. Very high concentrations of aminosalicylic acid are reached in the urine, which can result in crystalluria.
Aminosalicylic acid is used infrequently in the USA because other oral drugs are better tolerated. Gastrointestinal symptoms are common but occur less frequently with the delayed-release granules; they may be diminished by giving the drug with meals and with antacids. Peptic ulceration and hemorrhage may occur. Hypersensitivity reactions manifested by fever, joint pains, skin rashes, hepatosplenomegaly, hepatitis, adenopathy, and granulocytopenia often occur after 3–8 weeks of PAS therapy, making it necessary to stop administration temporarily or permanently.
The aminoglycoside antibiotics are discussed in Chapter 45. Kanamycin had been used for treatment of tuberculosis caused by streptomycin-resistant strains, but it is no longer available in the USA, and less toxic alternatives (eg, capreomycin and amikacin) have taken its place.
Amikacin is playing a greater role in the treatment of tuberculosis due to the prevalence of multidrug-resistant strains. Prevalence of amikacin-resistant strains is low (<5%), and most multidrugresistant strains remain amikacin-susceptible. M tuberculosis is inhibited at concentrations of 1 mcg/mL or less. Amikacin is also active against atypical mycobacteria. There is no cross-resistance between streptomycin and amikacin, but kanamycin resistance often indicates resistance to amikacin as well. Peak serum concentrations of 30–45 mcg/mL are achieved 30–60 minutes after a 15-mg/kg intravenous infusion or intramuscular injection. Amikacin is indicated for treatment of tuberculosis suspected or known to be caused by streptomycin-resistant or multidrugresistant strains. This drug must be used in combination with at least one and preferably two or three other drugs to which the isolate is susceptible for treatment of drug-resistant cases. The recommended dosage is 15 mg/kg once daily initially, followed by intermittent dosing two or three times per week.
In addition to their activity against many Gram-positive and Gram-negative bacteria (discussed in Chapter 46), ciprofloxacin, levofloxacin, gatifloxacin, and moxifloxacin inhibit strains of M tuberculosis at concentrations less than 2 mcg/mL. They are also active against atypical mycobacteria. Moxifloxacin is the most active against M tuberculosis in vitro. Levofloxacin tends to be slightly more active than ciprofloxacin against M tuberculosis, whereas ciprofloxacin is slightly more active against atypical mycobacteria.