Treating Mycobacterial Infections

Mycobacteria are responsible for two diseases tuberculosis, mostly caused by M. tuberculosis, and leprosy due to M. leprae. The therapeutic principle applicable to both is combined treatment with two or more drugs. Combination therapy prevents the emergence of resistant mycobacteria Because the antibacterial effects of the individual substances are additive, correspondingly smaller doses are sufficient Therefore, the risk of individual adverse effects is lowered. Most drugs are active against only one of the two diseases. 

Drugs of choice are isoniazid, rifampin, ethambutol, along with streptomycin and pyrazinamide. Less well tolerated, second-line agents include p-aminosal-icylic acid, cycloserine, viomycin, ka-namycin, amikacin, capreomycin, ethionamide. 

Isoniazid is bactericidal against growing M. tuberculosis. Its mechanism of action remains unclear. (In the bacterium it is converted to isonicotinic acid, which is membrane impermeable, hence likely to accumulate intracellu-larly.) Isoniazid is rapidly absorbed after oral administration. In the liver, it is inactivated by acetylation, the rate of which is genetically controlled and shows a characteristic distribution in different ethnic groups (fast vs. slow acetylators). Notable adverse effects are peripheral neuropathy, optic neuritis preventable by administration of vitamin Be (pyridoxine) hepatitis, jaundice. 

Rifampin. Source, antibacterial activity, and routes of administration are described on p. 274. Albeit mostly well tolerated, this drug may cause several adverse effects including hepatic damage, hypersensitivity with flu-like symptoms, disconcerting but harmless red/orange discoloration of body fluids, and enzyme induction (failure of oral Liillmann, Color Atlas of Pharmacology 

EthambutoL The cause of its specific antitubercular action is unknown. Ethambutol is given orally. It is generally well tolerated, but may cause dose-dependent damage to the optic nerve with disturbances of vision (red/green blindness, visual field defects). 

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Summary of drugs used to treat mycobacterial infections. 

Ciprofloxacin and levofloxacin are no longer recommended for the treatment of gonococcal infection in the USA as resistance is now common. However, both drugs are effective in treating chlamydial urethritis or cervicitis. Ciprofloxacin, levofloxacin, or moxifloxacin is occasionally used for treatment of tuberculosis and atypical mycobacterial infections. These agents may be suitable for eradication of meningococci from carriers or for prophylaxis of infection in neutropenic patients. 

Thus, though mycobacterial infections are difficult to treat under even the best of circumstances using currently available drugs, novel antibiotics targeting the biosynthesis of the unique mycobacterial cell wall structures show promise for clinical development. Further characterization of the enzymes involved in the biosynthesis of cell wall structures will facilitate the development of such antibiotics. Furthermore, studies of the cell wall biosynthetic pathways will likely uncover new potential targets for drug design efforts. 

Fig. 12.1 Schematic diagram of a typical bacterial cell showing the sites of action of the major classes of antibiotics and antimicrobial agents used to treat infections. Agents listed without brackets are used to treat bacterial infections. Agents used against mycobacterial, fungal or protozoal infections are indicated by theuseofQ, [] and brackets, respectively.

Atypical (nontuberculous) mycobacteria Nontuberculous cervical lymphadenopathy (scrofula) occurs in children infected with M. scrofidaceum or M. kansasii. Patients may demonstrate a weakly positive PPD, but diagnosis often requires biopsy. Mycobacterial infections of the skin are usually due to M. marinum. M. avium-intracellulare infects patients with chronic pulmonary disease and may become fulminant in AIDS patients. Atypical mycobacteria are treated with combination chemotherapy or in some cases, surgery. Because drug resistance is more common in nontuberculous mycobacterial infections than in TB, the susceptibility of the infectious agent must be determined early in the course of treatment. 

Infection risk Patients receiving infliximab are more susceptible to serious infections, including mycobacterial infections [128 ] and pneumonia [129 ]. Concomitant treatment with glucocorticoids was the only independent susceptibility factor for infections in patients with inflammatory bowel disease treated with infliximab [130. ... 

Aerosolised amikacin was used to treat pulmonary nontuberculous mycobacterial infection at a dose of 300 mg twice per day via a nebuliser. A cumulative dose of 35,000mg was administered over the trial period. No significant effects on nephro- or ototoxicity were seen. A hoarse voice and a bitter taste reported by one subject required a dose reduction to lOOmg [5 ]. Although a small cohort, this study supports the safety of nebulised amikacin in these patients. 

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