Interventions for Tuberculosis Control and Elimination 2002

drugs with a high therapeutic margin such as isoniazid, as the effective
half-life at sub-inhibitory concentrations would persist longer than that of
other drugs. 471 The difference in pharmacokinetics of the drugs given
together (in a combination tablet or in separate preparations) may be such
that after several hours only one of the drugs is still active, leading to functional
monotherapy. Sub-inhibitory concentrations of one or more drugs
may be observed in patients with impaired gastrointestinal absorption.
Differences in post-antibiotic effect (lag phase)
When drugs are stopped, the length of time it takes bacilli to restart growth
(post-antibiotic lag phase) differs for different anti-tuberculosis medications
(figure 40). 472 Thus, for example, mutants resistant to drug A (with a long
lag phase) are killed by drug B (with a short lag phase). Mutants resistant
to drug A will thus start re-growth earlier when both drugs are stopped and
obtain a selective advantage at the end of the cycle (figure 41). 464
Clinical trials in the treatment of pulmonary tuberculosis
Since the discovery of streptomycin, clinical trials with anti-tuberculosis
medications in various combinations have been carried out throughout the
world to ascertain the shortest possible and best tolerated efficacious treatment
regimens. The standard approach for studying a new drug or drug
Rifampicin
Ethambutol
Isoniazid
0 1 2 3 4 5 6 7 8 9 10
Lag after 24 hr exposure to drug (days)
59
Streptomycin
Figure 40. Post-antibiotic effects with M. tuberculosis lag periods before recommencement
of growth after exposure in 7H10 medium. 472