Interventions for Tuberculosis Control and Elimination 2002

Based on evidence that the addition of pyrazinamide hastened sputum conversion,
a series of studies was designed by the British Medical Research
Council. In 1970, it was demonstrated for the first time that the inclusion
of rifampicin and pyrazinamide in a regimen of isoniazid and streptomycin
substantially reduced the subsequent risk of relapse. 122
A multitude of clinical trials was designed and carried out by the
British Medical Research Council with regimens containing, as a minimum,
isoniazid, rifampicin, and pyrazinamide in the intensive phase, virtually
always supplemented by streptomycin during this period. 122 Two studies
in East Africa were critical for future research into this combination. 507,508
In these trials it was observed that regimens containing pyrazinamide but
not rifampicin were almost as effective as those containing rifampicin.
Furthermore, there was later evidence that both drugs given in the regimen
were more effective than one alone. 122 These studies laid the basis for
modern treatment.
The consistent finding in these studies was that the four drugs were
optimally given for a two-month intensive phase, followed either by four
months of rifampicin plus isoniazid or six months of a combination of drugs
not containing rifampicin (the continuation phase).
The role of the fourth drug (streptomycin or ethambutol) is unclear as
few studies have evaluated it, 491,509 but most likely it has a minor role in
patients with a strain that is fully susceptible at the outset. 122 A recommendation
to drop the fourth drug in patients with sputum smear-negative
tuberculosis seems to have no evidence base. Patients with paucibacillary
disease may require a shorter duration of treatment (see below); however,
dropping the fourth drug in the intensive phase may not be justified as it
may lead to functional monotherapy with rifampicin in lesions with a low
pH among patients with a strain that is initially resistant to isoniazid (pyrazinamide
not being active in such lesions).
Rifampicin-containing continuation phase
A regimen consisting of a two-month intensive phase with isoniazid,
rifampicin, pyrazinamide, and streptomycin, followed by a four-month continuation
phase with isoniazid plus rifampicin, all given daily, was first
evaluated in Singapore. 510-512 The high efficacy of this regimen was confirmed
in the United Kingdom, and was equally effective if streptomycin
was replaced by ethambutol. 513-515 It has become the standard regimen for
patients with fully susceptible organisms in most industrialized countries.
Shorter durations have been put on trial, 516,517 but the frequency of relapse
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