Interventions for Tuberculosis Control and Elimination 2002

Council, streptomycin monotherapy, para-aminosalicylic acid monotherapy
and chemotherapy with both drugs combined was carried out. 494,495 It was
demonstrated unequivocally, and for the first time, that combined chemotherapy
reduced the risk of acquisition of resistance. Similarly, a clinical trial
in Denver, Colorado, USA showed that the combination of streptomycin
and para-aminosalicylic acid overcame the emergence of resistance, in contrast
to monotherapy with either one (figure 43). 493
Per cent with resistant strains
80
60
40
20
0
0 28 42 60 75 90 120
Day of treatment
62
Streptomycin
alone
PAS
alone
Streptomycin
and PAS
Figure 43. Emergence of resistance to streptomycin and/or para-aminosalicylic
acid given alone or in combination. Reproduced from 493 by the permission of the
publisher American Thoracic Society at the American Lung Association.
Streptomycin plus para-aminosalicylic acid plus isoniazid
It appears that the logical step following the introduction of isoniazid, namely
to compare the efficacy of streptomycin, para-aminosalicylic acid, and isoniazid
with a control arm of streptomycin plus para-aminosalicylic acid,
was never subjected to a formal randomized clinical trial, either by the US
Public Health Service or by the British Medical Research Council. This
is particularly astonishing, as this triple combination therapy must be
considered the breakthrough in tuberculosis treatment because it introduced
the certainty of consistently curing tuberculosis patients with an initially
fully susceptible strain.
It is furthermore a curiosity in the history of medicine that the curative
results of this combination therapy were not even accorded a full-length