Antitubercular Antibiotics

ANTITUBERCULAR  ANTIBIOTICS     

The antibiotics used for the treatment of tuberculosis belong to a variety of chemical classes, but it is convenient to consider them together in the same section for two reasons: first, most of them are used exclusively for tuberculosis, and second, therapy extends over several months, during which time resistance development is a significant possibility. This risk is minimized by the use of two or three antibiotics in combination, so it is appropriate to consider them together because that represents their normal pattern of use.

Streptomycin, introduced in the late 1940s, was the first effective treatment for tuberculosis, but its use in isolation was short lived because of the ease with which the bacteria became resistant to a single antibiotic. Isoniazid, which became available about 5 years later, was used first in combination with streptomycin then with rifampicin after the latter was introduced in 1967. The combination of isoniazid and rifampicin has been the mainstay of tuberculosis therapy from that time until the present day, although other drugs like pyrizinamide and ethambutol have been added to the combination, and multidrug-resistant tuberculosis has become an increasing problem in recent years; this is, by definition, simultaneous resistance to isoniazid and rifampicin.

Tuberculosis may be caused by any one of three Mycobacterium species, but all three characteristically grow slowly in the body and may persist for long periods in a near dormant state. Because the course of therapy is normally 4–6 months, antibiotics that are orally effective are much preferred; this is because unsupervised patients are more likely to take oral medicines, and in many countries where patients may have difficulty travelling to clinics the daily administration of injectable antibiotics is not feasible. The ideal antitubercular drug should also have the potential to kill rather than merely inhibit the growth of the infecting organism. Because mycobacteria can survive, and even reproduce, within macrophages, relying on the immune system to eradicate an infection following the use of a bacteristatic drug is unlikely to be an effective strategy. Rifampicin kills dormant bacteria, while pyrizinamide is active against bacteria that are slowly reproducing in acidic environments; isoniazid is most useful against more rapidly growing cells.

The current approach is to treat tuberculosis in two phases: an initial phase of 2 months using isoniazid, rifampicin and pyrizinamide (with or without ethambutol), and a 4 month continuation phase with isoniazid and rifampicin. If, however, the infecting organism is resistant to any of the above, second-line drugs may be used and the duration of treatment possibly extended. The status of streptomycin is equivocal; it is now rarely used in the UK and is not a first-choice treatment recommendation of the European Respiratory Society either, but it is more commonly used in front-line therapy in the USA. Second-line drugs available for infections caused by resistant organisms, or when first-line drugs cause unacceptable side effects, include amikacin, capreomycin, cycloserine, newer macrolides (e.g. azithromycin and clarithromycin) and moxifloxacin. Drug regimens are often indicated using a shorthand notation with single letters to indicate the drugs employed, initial numbers indicating months of therapy and following numbers (which may be in parentheses or subscripts) indicating days per week. For example, 2RHZ(E)/4HR(3) or 2RHZ(E)/4HR₃ would mean 2 months of rifampicin, isoniazid and pyrizinamide (with the possible addition of ethambutol) followed by 4 months of isoniazid and rifampicin three times per week. Several of the antitubercular drugs have specific contraindications or require monitoring during use; some of these requirements and cautions are shown in Table 11.6.

Rifampicin is the only one of the common antitubercular drugs that is used in the treatment of non-mycobacterial infections. It is active against Gram-positive bacteria and some Gram-negative species, but not Enterobacteriaceae or pseudomonads. Rifampicin possesses significant bactericidal activity at very low concentrations against staphylococci. Unfortunately, resistant mutants may arise very rapidly, both in vitro and in vivo, so it has been recommended that rifampicin should be combined with another antibiotic, e.g. vancomycin, in the treatment of staphylococcal infections. Rifabutin, a semisynthetic rifamycin, may be used in the prophylaxis of M. avium complex infections in immuno-compromised patients and in the treatment, with other drugs, of pulmonary tuberculosis and non-tuberculous mycobacterial infections.