Short-Course Chemotherapy for Pulmonary Tuberculosis
Item
- Title
-
Short-Course Chemotherapy for
Pulmonary Tuberculosis - extracted text
-
State of the Art
r^'thmat-
s of pul
results.
that airicator of
than cx<on<1ucit is untlose realso pos] airways
large airan effect
?f inhaled
drug. I’1
-be a valid
=nd believe
?d to prourentent is
Short-Course Chemotherapy for
Pulmonary Tuberculosis’ ’
I
WALLACE FOX anci D. A. MITCHISON
I
Introduction
There have been several major landmarks in
our understanding of the chemotherapy ofI tuthc .......
introduction
of
berculosis. 'Die first was t..~
-
::rz“t;“y'in. The
second was the finding that
streptomycin.
-------------combined chemotherapy with streptomycin plus
para-aminosalicylic acid (PAS) prevented the
of —
the 2
emergence of strains resistant ■to» either
c------ —
the ......
introduction
of isoniadrugs. The third was t...........
zid (INH), leading; to the development of uni
formly successful primary chemotherapy. 1 he
fourth was the demonstration that ambulatory,
domiciliary treatment was highly effective and
i
ry and treatMcd, 1973,
hiringcr, G.:
•ta2-reccptort) in patients
nary disease.
Howes. J. N„
ilin, L.
and
•diorcspiratory
;iol in patients
)70.1.65.
. W.t Clinical
rs delivered by
iparativc effects
fly resistance in
] Med Sd.
, Begin, R-.
■nc« to 3 bronir Dis, 1974. 109.
*
i
not only of our own groups, but of large num
bers of colleagues who collaborated in the pro
gram of the East African Tuberculosis Investi
gation Centre (Director: Dr. 1’. W. Kent) and
the research program of the Hong Kong 1 uberculosis Services (Coordinator: Dr. W. G. L. Al
lan), and from one vital observation on inter
mittent chemotherapy made in a study, with
which we were both also closely associated, in
the Tuberculosis Chemotherapy Centre, Madras
(Director at the time: Dr. N. K. Menon).
Standard Regimens and Their Limitations
Standard regimens of chemotherapy, as exem
plified by streptomycin plus INI I plus PAS
(or ethambutol), followed by IN 11 plus PAS
(or ethambutol), are given for a minimum of
18 months to 2 years, and some physicians pre
scribe them for even longer. Adverse reactions
arc common, especially to .streptomycin and
mark.
PAS (1. 2), and even when the reactions arc
Wo wish to emphasize that we arc presenting
minor, patients are expected to tolerate a lack
findings that resulted from the joint activities
of well-being for many mon'hs. It is psychologic
ally undesirable for even a symptom-free patient
1 From the Medical Research Council Tuberculo
to feel that he is suffering from, and receiving
sis and Chest Diseases Unit, Bromptnn Hospital,
therapy for, a disease for such a long period of
Fulham Road, London, SW5 RHP. and the Medical
time. In practice, many patients discontinue
Research Council Unit for Laboratory Studies of
treatment prematurely, either ceasing to take
Tuberculosis, Royal Postgraduate Medical School,
drugs, although continuing to attend the treat
Ducane Road. London, WI2 OHS England.
ment services, or else stopping attending alto
2 This article is based on the Waring Lecture de
livered by W. Fox al the University of Colorado
gether. This happens often enough in the tech
School of Medicine on October 7, 1974. and at the
nically advanced countries, where middle-aged,
Stanford University School of Medicine, Palo Al
vagrant men arc a particularly difficult patient
to, California on October 14, 1974, and a paper given
group of increasing importance, and it becomes
by D. A. Mitchison at the XII International Con
a problem of major dimensions in developing
gress on Diseases of the Chest in London on July
countries. Indeed, the very high failure rate (as
11,1974.
that it did not expose close family contacts to
appreciable risk of infection. The fifth was the
introduction of fully supervised, intermittent
chemotherapy with its consequent control over
drug ingestion. We consider that short-course
chemotherapy is beyond question the latest land
i
l
i
AMERICAN REVIEW OF RESPIRATORY niSEASE. VOLUME 111. 1975
-A
325
*
326
I OX AND MITCHISON
an effective therapeutic combination (46-48);
addition of pyrazinamide enhanced the effec
tiveness of a standard triple regimen (49); it
has been argued that streptomycin plus pyra
zinamide together form a single bactericidal
drug, with streptomycin active in tissues with
an alkaline pH and pyrazinamide, in those with
an acid pH (50); pyrazinamide is much cheap
er than rifampin. If both rifampin and pyraziuamide regimens were highly effective, it would
be important to know whether ihiacrt.uouv (not
available in the United States) would be a suit
able third drug. 'I'hiacetazone, a standard drug
in East Africa, is widely used because it is effec
tive with INII and is very cheap, costing approx
imately one-threehundredth of the price of ri
fampin. If all 3 3-drug combinations were effec
The First East African Study
It was clear that the first study would have to tive, it would be uncertain whether a third drug
investigate the problems in depth, and with this was necessary at all. For this reason, the 2-drug
in view, a large-scale, cooperative, controlled, combination of INH plus streptomycin was al
clinical trial was established in East Africa and so studied as a control regimen. Finally, to re
Zambia in association with the East African 1 u- late the efficacies of the 6-month regimens to
berculosis Investigation Centre (42-44). More that of traditional chemotherapy, the standard
than 1,100 patients with newly diagnosed, ex 18-month regimen for treatment of tuberculosis
tensive, smear-positive, cavitary disease were ad in East Africa, consisting of streptomycin plus
mitted. Four 6-monlh regimens were compared, INH plus thiacetazone daily for 2 months, fol
by random allocation, with a standard 18-month lowed by INH plus thiacetazone for 16 months
regimen (table 1). The first was streptomycin (51, 52), was included. In this study, all drugs
were given daily and in standard dosage: 1 g
plus INII plus rifampin daily for 6 months. We
of streptomycin; 300 mg of isoniazid; 450 or
reasoned that, if this regimen were not effective,
600 mg of rifampin, depending on body weight;
then a 3-drug, G-month regimen did not exist
2 g of pyrazinamide, 150 mg of thiacetazone.
among the currently available drugs; if, how
The 30-month results of this study have been
ever, it proved to be effective, the extent to
published (42-44) and need only be summa
which the rifampin had contributed to its suc
rized briefly. It is convenient, in the light of
cess would be uncertain. Hence, in the second
the findings, not to refer to the standard 18regimen, pyrazinamide was chosen as the third
month regimen, although its results are given
drug for several reasons: INH plus pyrazina
in the relevant tables.
mide has been one of the most effective steriliz
ing lombinations lor mouse tuberculosis (45);
I’aiirnls with <li ugsus< eftlible pre treat me nl
there was clinical evidence that these drugs form
strains.
The results obtained during chemotherapy
TABLE 1
were the following. (/) There were early
REGIMENS STUDIED IN THE FIRST
deaths from tuberculosis on all regimens. The
EAST AFRICAN/BHITISH MEDICAL
fact that desperately ill patients may die before
RESEARCH COUNCIL SHORT-COURSE
even the most potent antibacterial combinations
CHEMOTHERAPY STUDY
can have an effect represents a limitation of all tu
Duration
berculosis chemotherapy and underlines the im
(months)
Regimen
Drugs
portance of earlier case finding and diagnosis^
6
Streptomycin + INH + rifampin
SHR
(2)
The rifampin and pyrazinamide regimens pro
6
Streptomycin + INH + pyrazinamide
SHZ
duced more rapid culture negativity in the first
6
Streptomycin + INH + thiacetazone
SHT
6
3 months (figure 1), i.e., they killed susceptible
Streptomycin + INH
SH
2
Al. tuberculosis more effectively than did thiaSTH/TH Streptomycin + INH + thiacetazone;
16
then INH + thiacetazone
cetazone or the 2-drug combination. (3) All four
high as 50 per cent) of standard chemotherapy
in program conditions in the developing
countries stems directly from the difficulty of
persuading patients to remain under treatment
for a long enough period of time (3, 4).
Committee Report (38) and which was, inci
dentally, reiterated recently in its Ninth Report
(39). Finally, when rifampin was introduced,
tome workers questioned whether it was be
cause ol its obvious potency, a unique drug
with spcdal binirricidaI iictivity that would
pci mil effective, shot l-ioursc chemotherapy (40,
41). To us, rifampin provided the linal justifi
cation to reinvestigate 6-month regimens that
previously had been studied so incompletely.
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327
SHORT-COURSE CHEMOTHERAPY FOR PULMONARY TUBERCULOSIS
100
-48);
ifTec-
); n
0)
o
u
lyra-
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with
with
icapazinould
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to re■ns to
ndard
ulosis
I plus
IS. follonths
drugs
e: 1 g
450 or
veight:
te.
e been
ummaight of
ard 18• given
•u/mrnf
therapy
? early
ns. The
c before
inations
of all tu. the imiagnosis.
icns prothe first
sceptiblc
lid thiaAH four
80
o
Q»
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bn
<u
G
60
tn
5
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I 40
f
o
SHR--------SHZ
--------SHT
--------
4>
bn
c
S
20
J'
0>
cu
0
V
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SH
...........
STH/TH ---------
1
2
3
Months
4
5
6
Fig. I. Monthly culture results of single specimens of sputum for the 5 regimens in
the first East African/British Medical Research Council short-course chemotherapy
study. S = streptomycin; H = isoniazid; R = rifampin; 7. = pyrazinamide; for drug
schedules, see table 1.
6-month regimens were uniformly and very high
ly effective. In fact, among 690 patients assessed
at 6 months, there was only 1 bactcriologic fail
ure with a drug-resistant strain, striking con/ finnation of the efficacy of the combination of
INH plus streptomycin, whether alone or sup
plemented by a third drug.
After stopping short-course chemotherapy, the
bactcriologic relapse rates between 7 and 30
months showed important differences (table 2).
The thiacctazonc and the 2-drug regimens had
high relapse rates (22 per cent and 29 per cent,
respectively, with the difference not significant).
Thus, it is uncertain whether the thiacctazonc
conferred any therapeutic benefit when added
We in the British Medical Research Council
(BMRC) have been concerned with this prob
lem for many years, because we have fated it
in very sharp terms ever since we became in
volved, in the 1950s, in the organization of
chemotherapy for patients in East Africa and in
Madras in South India. Indeed, much of our
program has been directed toward ensuring the
cooperation of patients in treatment. Two ap
proaches with which we have been deeply in
volved arc of particular relevance: entirely su
pervised, intermittent t hemothernpy, our re
search into which dates back to 1960; and the
—mu ■■ www
-A r .
more recent approach of substantially shortened
duration of chemotherapy.
At first, these approaches may appear to be
alternative and mutually exclusive; however, we
have had reason to believe that it should be poss
ible to combine them (see later section). In fact,
our target, formulated several years ago, has
been to try to find a short-course regimen, given,
perhaps, for as short as 6 months, but for not
longer than 9 months, in which the chemother
apy is given intermittently for at least much of
the time, possibly twice per week, but conceiv
ably even once per week (5). In this article, we
review the progress we have made.
Background of Short-Course Chemotherapy
First, we summarize the steps that led us to ex
plore short-(outsc chemotherapy In depth, after
recalling important points in the history of the
development of tuberculosis chemotherapy.
When chemotherapy was first introduced, pa
tients were usually treated with single drugs for
short periods, 6 weeks to 3 months, the latter be
ing sufficiently long to produce a high rate of
drug resistance in patients who remained bacteriologically positive (6). When it became pos
sible to prevent the emergence of drug resls
tancc by using combined chemotherapy (7-9),
I’
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'f
I
FOX AND MITCH1SON
328
I
I
I
and with the introduction of INH, courses soon
this regimen raised the P^Wii^ that i^mc-
hecame much ionger, a year being the minimal
- might.^
6
duration; 2 years, usual; indeed, some physicians
, months, i.e., that the INH in the continuation
advocated indefinitely prolonged chemotherapy
chemotherapy for life (14)1
phase might have contributed nothing. At ap
(10-13) and even <
proximately this time, it had also become clear
There was a clear need to compare, in a con
to us that the fully supervised, intermittent che
trolled, clinical trial, courses of intermediate
motherapy tried in program conditions was of
and longer durations. In the mid-1950s, the
ten organizationally disappointing in develop
1JMRC, aware of this need, undertook what we
ing countries, and that alternative approaches
believe was the only controlled clinical trial in
were needed. This led us to consider the value
which 6-month chemotherapy was compared
of concentrating organizational resources and
with therapy of longer durations, namely 12 and
facilities on a period of chemotherapy shorter
24 months (1). This study showed that INH plus
than the minimum of 1 year, which we had long
PAS for 6 months, even if supplemented by
advocated as the principal priority of chemo
streptomycin for the first 6 weeks, was followed
therapy (37), which had been recommended in
by an unacceptably high rate of relapse, often
the Eighth World Health Organization Expert
with fully drug-susceptible organisms. Further
to the 2-drug combination. In contrast, the iimore, the rales of relapse after the end of cours
iainpin and pyrazinamide regimens were strik
es of chemotherapy lasting 1 year were broadly
ingly and significantly superior (table 2). In a
similar, whether the regimen contained INH
more precise comparison of these 2 regimens
alone, or 2 drugs given daily (1, 15-22) or in
made on a larger population of patients, the
termittently (18, 19). There appeared to be
rifampin regimen had a 3 per cem relapse rate
little piospect of .substantially shortening the
in 152 patients, and the pyrazinamide regimen,
duration of chemotherapy.
an 8 per cent relapse rate in 153 patients; the
The next step in our thinking was concerned
difference was significant (P = 9.05). I bus, these
with preventing the emergence of drug resis
latter 2 regimens, particularly the rifampin icgitance during chemotherapy. In the mid-1960s,
mcn, clearly were highly effective even in the
the efficacy of the combination of INH phis
severe disease studied.
streptomycin, given daily, was reviewed (23).
Two important points concerning bacterio
It was evident that the combination was much
logic relapse emerged (table 2): (I) Most remore effective than INH plus PAS and that it
’lapses; in this study occurred between 6 and 12
rendered practically all patients culture negamonths,
live (24-30, and Russell, W. F., Jr.: Personal
1 i.e., in the first 6 months after stopping
chemotherapy; of these, most occurred between
communication). In fact, it lived up to pre
6 and 9 months. After 12 months, there were
dictions based on studies of the large numbers
very few relapses on any regimen, and it was
of bacilli in tuberculous cavities in the lungs,
particularly noteworthy that between 18 and 30
and the small likelihood that doubly resistant
months, there was not a single relapse on either
mutants to INH and streptomycin would be
the rifampin or the pyrazinamide regimen. (2)
present at the start of treatment in previously
In nearly all patients whose disease relapsed, the
untreated patients (31-34).
organisms were fully susceptible to both strep
We obtained further information on this com
tomycin and INH (table 2), so that bacterio
bination in the course of a controlled clinical
logic relapse was due to the reappearance of sus
trial in Singapore (35), where the local physi
ceptible bacilli in the sputum, not to the emer
cians were particularly eager to study a regimen
gence of drug-resistant strains during chemo
consisting of streptomycin plus IN 11 daily for
therapy and their subsequent appearance in the
6 months, followed by INH alone for a further
12 or 18 months. They hoped that this regi sputum.
These findings suggest that the rifampin and
men, which was particularly suitable for local
pyrazinamide regimens were more effective be
operational reasons, would be both effective
cause of their ability to eliminate susceptible
and nontoxic. Among 114 patients so treated,
bacilli, which they did sooner (figure 1) and
only 1 case was a bacteriologic failure at 12
;
more permanently than the other regimens (ta
months; a recent report of these patients has
ble 2). In terms of the Jawetz concept of syner
shown no further bacteriologic failure in a 3-yeat
gistic bactericidal activity of drug combinations
follow-up period (36). The high efficacy of
1
I
*
I
SJIORT.COURSE CHEMO THERAPY
FOR PULMONARY TUBERCULOSIS
329
(53, 54), INH and rifampin can be considered
"complete” bactericidal drugs that are active
against the entire bacterial population, but
streptomycin, effective only at an alkaline pl ,
fntt be Hitnideted as "otic-half" a drug. 1 bus
the rifampin regimen contained 2.5 bactcricldal
drugs, INH and rifampin, and, in addition,
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streptomycin; the pyrazinamide regimen con
tained 2 bactericidal drugs, INH as one, and
streptomycin and pyrazinamide acting together
as the other. In contrast, the 2 unsatisfactory
regimens contained only 1.5 bactericidal drugs,
INH and streptomycin. We planned the subse
quent program of research reported in this pa
per bearing in mind the importance of testing
the working hypothesis that the effectiveness of
short-course regimens is related to the number
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of bactericidal drugs, at least 2 being necessary.
The reason for the undoubted superiority of
the rifampin regimen over the pyrazinamide
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third drug). It has already been suggested that
the pyrazinamide regimen contained, in bac
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tericidal terms, no third drug, because at no
point in the pH scale would both streptomycin
and pyrazinamide be acting together on the same
organisms. (2) There might, in fact, be a pH
gap between approximately pH G and pH 7.
with the alkaline range covered by the strepto
mycin, the acid range covered by pyrazinamide,
but neither drug effective at intermediate pH
values. (5) It is possible that rifampin might
he especially bactericidal either on normal met
abolizing organisms or on dormant organisms,
or on both.
These explanations based1 on the Jawetz conimplifications. Rifampin
ccpt arc probably oversim,
is not appreciably more bactericidal than is INH
against rapidly growing or dormant organisms
(55, 56, and Awaness, A. M., Dickinson, J. M.,
and Mitchison. D. A.: Unpublished data). Fur
thermore, there is early bactericidal antagon
ism between INH and pyrazinamide in the
mouse (57), and no synergism between IN 11
and rifampin in vitro (55. and Awaness, A.M.,
Dickinson, J. M., and Mitchison. D. A.: Unpub
lished data). On the other hand, bactericidal
synergism between streptomycin and INH docs
occur (58, 59). These issues arc considered more
fully later.
I
--------- ------------------------------------------- —r. -- ■
FOX AND MITCH ISON
330
I
Patients with drug-resistant M. tuberculosis
pre treatment
Most patients with initial drug resistance to
INH alone, to streptomycin alone, and to both
INH and streptomycin responded to both ri
fampin and pyrazinamide regimens;..relapse
rates were low, although with neither regimen
was the response as satisfactory as in patients
with fully susceptible organisms.
I
pie, rifampin (SHR) regimen of the first study
as a control, several important questions were
posed. The second (HR) regimen. INH plus
rifampin, was introduced to investigate wheth
er or not the streptomycin had contributed to
the therapeutic success of the triple-drug regi
men. The other 2 regimens explored whether the
duration of daily rifampin could be reduced to 2
months without loss of therapeutic effectiveness,
if followed in the continuation phase by a stan
dard regimen of thiacetazone plus INH daily
for 4 months (SHRZ/TH), or by a twice-week
ly, intermittent, 3-drug regimen (SHRZ/SaHaZa).
Drug toxicity
Drug toxicity was uncommon in this relative
ly young African patient population, and al
Background of the Use of Intermittent
though 5zPer cent of 225 patients who started
Short-Course Chemotherapy
treatment with rifampin had toxic reactions, as
'Ihe
background
of the use ol intermittent,
did 7 per tent ol 232 patients receiving pyrazinshorl-iouise i hemolhenipy dates back to a study
amidc, 9 per cent of 227 receiving thiacclazouc,
in the Chemotherapy Centre. Madias (61). with
and 3 per cent ol 227 receiving 2 drugs, only 2
patients receiving rifampin, 4 receiving pyrazin which the BMRC was closely associated. In
this study, 4 regimens were compared: strepto
amide.
amide, and 7 receiving thiacetazone had 1 or
mycin
plus high-dosage INH twice per week
more drugs stopped.
(S2H.,); the same combination given only once
When this first study was designed, we were
fully aware that none of the regimens was of per week (S^Ij); a second, once-weekly regi
immediate practical importance, because all in men (SjH^!), in which an attempt was made
volved a daily injection of streptomycin for 6 to strengthen the streptomycin and INH com
months. It was, however, essential to begin by bination by adding a third drug, pyrazinamide;
studying the principles and establishing decisive a regimen of streptomycin plus INH in stan
ly whether or not 6-month regimens were feasi dard dosage daily for 4 weeks, followed by once
ble. Our further aims in
i developing the pro- weeTtiy combination of streptomycin plus high.
dosage
(S7H7/S1H1)- The 12-month re
gram have been to move toward widely
applicINH
able. practical regimens suitable for program sults of single-culture examinations of sputum
conditions. The selection of the regimensi for are shown for the 4 regimens in figure 2. Despite
views of
the widely varying dosage schedules of strepto
study, however, has been based on our v.~..
mycin plus INH (once per week, twice per
the underlying mechanisms.
week, or daily for 4 weeks and then once per
week), the 4 regimens produced culture nega
The Second East African Study
tivity at an identical rate in the early months,_
In the second study in East Africa (60), 4 regi
i.e., they eliminated susceptible M. tubercu(table 3). Using the tii- i
mens were investigated
i
TABLE 3
RPCIMFNS STUDIED IN THE SECOND EAST AFRICAN/BRITISH MEDICAL
RESEARCH COUNCIL SHORT-COURSE CHEMOTHERAPY STUDY_--------------- ---
Bactericidal Drug*
Regimen
Drugs
Streptomycin + INH + rifampin dally tor 6 months
SHR
HR
SHRZ/TH
SHRZ/S2H2Z2
.P.r.oth.„.
INH + rifampin dally for 6 months
Streptomycin + INH + rifampin + pyrazinamide
daily for 2 months, then thiacetazone + INH dally
for 4 months
Streptomycin + INH + rifampin + pyrazinamide
daily for 2 months, than streptomycin + INH +
pyrazinamide twice per week for 4 months____
.•». I.. compl...
d,uB.
No.
Drugs
2.5
2
3, then 1
H + R +(SI*
H + R
H + R + SZ.
than H
3, th«n 2
Intermittently
H ♦ R + SZ.
then H + SZ
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331
SHORT-COURSE CHEMOTHERAPY FOR PULMONARY TUBERCULOSIS
100 r
S2H2
96^
S7H7/S1H]
91%
I
78%
80 -
SiHjZj
72%
t
01
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bD
II
40
20
t,
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th
■In
ock
//
_____I____
10
0 *
6
8
Months after start of chemotherapy
0
12
Fig. 2. Culture negativity of single collection specimens of sputum for the 4 regimens
investigated in the Madras study of once wcekly regimens of chemotherapy. S ~ streptomycin: Il = isoniazid; Z = pyrazinamide; the regimens arc defined on page 330.
ICC
R'de
>mde;
annce
ighrc'tum
.pitc
pro
per
per
II'''
60 -
losis equally effectively. Only when drug resis
tance began to emerge did differences in the
therapeutic efficacy of the 4 regimens become
manifest. Because the effectiveness of short
course chemotherapy in patients with fully sus
ceptible organisms depends on the effective elim
ination of susceptible bacilli, these observa
tions raised the possibility that intermittent reg
imens could also be effective in short-course che
motherapy. This is why the regimen with inter
mittent chemotherapy after 2 months of daily
I
1CRA-
nibs,
crcu-
chemotherapy was introduced into the second
East African study.
The 1-ycar results suggested several main con
clusions.
Patients with (Iru(’-suscef)tiblc strains
pretreatment
Bacteriologic responses during chemotherapy
were as follows. (/) In the first 2 months, the
SHRZ regimens eliminated susceptible Af. tuber
culosis more rapidly; the proportion of patients
TABLE 4
BACTERIOLOGIC RELAPSES FROM 6 TO 12 MONTHS, THEIR TIMING, AND DRUG
I
SUSCEPTIBILITY OF THE ORGANISMS IN THE SECOND EAST AFRICAN/BRITISH
MEDICAL RESEARCH COUNCIL SHORT-COURSE CHEMOTHERAPY STUDY’
Rnlapia with
Organisms
No. of
«
Bacterlologlc
Relapses
Relapse In Month
INH
Streptomycin,
Bactericidal
Patients
H
♦ sz,
< 4 SZ
No. of
Assessed
(no.)
(%)
7-9
10-11
and R Ifampln
Drugs*
SHR
HR
SHRZ/TH
166
170
4
8
11
3
5
8
4
180
2
5
6
4
9
3
11
SHRZ/S}H3Z j
161
7
4
6
1
7
2.5
2
3. then 1
daily
3, then 2
Intermittently
Regimen
•• (S) •
♦ SZ.
Susceptible to
Bacterlologlc
•Excluding 1 HR and 2 SHRZ/SiHjZj patlnnts classified as treatment failures at 6 months.
tThe bactericidal drugs are tabulated In the last column of table 3.
i
> .r
- > ¥“
HMMhlir
4
I
I,
t
i
I
332
FOX AND MITCH ISON
findings with the 2 SHRZ regimens suggest that
with negative- cultures in these 2 regimens was H2
an initial intensive phase with 3 complete bac
per cent, compared with 70 per cent lor the tuple
tericidal drugs for 2 months, whether followed
(SHR) regimen (P = 0.006), and 64 per cent
i, by a single bactericidal drug (H) daily or by 2
for the 2-drug (HR) regimen. By 3 months,
complete bactericidal drugs (SHZ) twice per
however, all regimens had similar rates of cul
week, are effective regimens. It is uncertain
ture negativity. (2) Of more than 700 patients
whether 2.5 bactericidal drugs (SHR) in the
assessed at 6 months, only 3 had an unfavorable
first 2 months, or 2 (HR) would have been
bacteriologic response, 1 in the HR series and
equally effective. It seems unlikely that the 2
2 in the intermittent (SHRZ/S2H2Z2) series.
complete bactericidal drugs (SHZ) would have
Drug-resistant bacilli (resistant to INH) were ob
been equally effective in the first 2 months, be
tained only for the HR patient, and the other 2
cause in the first East African study they were
were probably late converters.
not, even when given daily for 6 months in the
(?) 1 he baiteriologic relapse rate alter stopping
SHZ regimen (12-41). It is not clear wheth
chemotherapy was low on all 4 regimens (table 4).
er thiacetazone contributed at all to the efficacy
The triple SHR regimen had a very low relapse
of the SHRZ/TH regimen, or whether INI I
rate, 4 of 166 patients (2 per cent), just as in the
alone in the continuation phase might have
first study. There was a suggestion that this regi
been equally effective in patients with fully sus
men was marginally superior to the HR regimen, ceptible organisms. Further, it is uncertain from
in which the relapse rate was 5 per cent of 170 pa
this study whether, for an intermittent regimen
tients; if this is confirmed in longer follow-up,
to be successful in short-course chemotherapy,
streptomycin may, in fact, have contributed to
it is necessary that it be preceded by an initial
the therapeutic success in a small number of pa intensive phase; this question is being investi
tients.
(•/) After an initial 4-drug (SHRZ) phase of months, effective regimens resulted, whether the
continuation chemotherapy was with the stan
dard daily (TH) regimen (relapse rate: 6 per
cent of 180 patients), or with the twice-weekly,
fully intermittent (S2H2Z2) regimen (relapse rate:
4 percent of 161 patients).
Despite the short follow-up, it is evident that
the pattern of bacteriologic relapse observed in
'I
I
I
1
gated in a study in Hong Kong (Hong Kong
Tuberculosis Treatment Services/BMRC: Un
published data).
Patients with drug-resistant strains pretreatment
Responses during treatment were as follows.
Nearly all patients with initial drug resistance
to INII alone had a favorable response to their
regimen at 6 months, as did all 20 patients with
streptomycin resistance. Although the number
' ..... t strains was
.......... ...
lapses occurred
small,
their
response
was
less
satisfactoiy.
: occurred with
Although the relapse rate in patients with
. strains. Thus, 22 of 31 relapsinitial resistance to INH alone was clearly high
es had occurred by 9 months, and only 9 oc
oc-
er than that in patients with fully susceptible
culted in the next 2 months. In all but 1 patient,
' > susceptible to, organisms, it was still relatively low; so far, none
relapse occurred with strains
of the patients with initial resistance to streptoand rifampin, confirming
streptomycin, INII, «...
.
mycin alone has relapsed.
that relapse was due to the failure of the regiThe likely level of therapeutic success ob
nuns to eliminate susceptible M. tuberculosis,
tained by the effective regimens in the presence
£nd was not a consequence of emergence of
of initial drug resistance was best assessed by
drug-resistant bacilli during chemotherapy.
amalgamating the findings of the rifampin and
In bactericidal terms (table 4), the findings
pyrazinamide regimens in the first East African
for the patients with susceptible organisms can
study with those of all 4 regimens in the second
be interpreted as follows. (/) Streptomycin
investigation (table 5). The estimated failure
might have contributed to the bactericidal ac
rates in the last column of the table were derive
tion of the SHR regimen. We would expect this
by adding the number of failures in the 6
contribution, if it exists, to be small, because
months while the patients were on chemo
streptomycin contributes only "one-half" a drug
therapy and the number of relapses in the b
tollie 2 complete drugs, IN 11 and rifampin. In
months after stopping chemotherapy,
practical terms, addition of streptomycin ap
inion the assumption that all patients with
v...........
pears unnecessary in most patients. (2) 1 he
♦
I
I
1!**^*'
SHORT-COURSE CHEMOTHERAPY FOR
333
PULMONARY TUBERCULOSIS
TABLE 5
ONE YEAR RESULTS IN PATIENTS WITH PRETREATMENT DRUG RESISTANCE
0NE’Y,n THE 2 east afr.can/british medical research council
SHORT-COURSE CHEMOTHERAPY STUDIES
Estimated
Failure
Regimen
r
Drug
Reilrtance
e
-n
2
•e
erc
INH Blone
:h
Streptomycin
alone
ive
.nsom
ten
•py.
tial
estiong
Un
SHR
HR
TH
24
9
10
10
12
65
No. of patients
Unfavorable status
0
1
0
1
0
2
at 6 months
No. assessed for relapse
23
8
4
3
5
0
8
2
52
10
Relapses 7-12 months
8
1
6
6
5
2
19
No. of patients
Unfavorable status,
0
0
0
1
1
5
0
2
i
0
o
14
0
19
mrnl
No. assessed for relapse
Relapses 7-1 2 months
6
0
5
8
2
0
4
No. of patients
Unfavorable status,
2
3
2
0
1
8
3
0
12
2
No. assessed for relapse
Relapses 7-1 2 months
3
0
5
1
1
1
0
0
Rate
(%)
22
51
521
.
-------------- —, not resistance to a relevant drug,
•On this regimen, streptomycin reslstance was
25 observations.
tThls percentage Is based on fewer than
------- —
I
lows.
tancc
their
with
imber
s was
, with
- high•ptiblc
, none
trcptocss obrcscncc
sscd by
■>in and
African
: second
failure
derived
i the 6
chemon the 6
adjusted
A-ith ini-
at 6 months
at 6 months
INH and
streptomycin
All
Regimens
Ai«nm»nt
ie
hcy
SHZ
SHRZ/
S2H3Z2
SHRZ/
i
I
I
cncc might also have been due to a greater fre
tial drug resistance had been followed for 1 year.
quency of true primary resistance in patients
The rates were 22 per cent of 65 patients with
with resistance to INH alone (62. 63). because
resistance to INH alone, 5 per cent of 19 pa
some response to treatment with INH alone is
tients with resistance to streptomycin alone, and
common (64). although it is very unlikely to
52 per cent of 19 patients with resistance to the
occur in those with undisclosed acquired re
2 drugs. Furthermore, the 80-month evidence
sistance (65, 66).
from the first East African study (42-44) sug
It should be noted that in the patients with
gests that these estimated failure rates were
initial
resistance to INH alone, the response at
unlikely to become much higher when all pa
6 months was almost uniformly favorable, but
tients had completed longer follow-up. It seems
the relapse rate was substantial. It is probable,
safe to conclude that streptomycin resistance
alone had very little over-all influence on the re however, that had chemotherapy been prolonged
for a relatively short period, c.g.. to a total of 9
sults of therapy with the regimens containing ri
months
or less, the relapse rate might well have
fampin (the number of observations on the SHZ
been
appreciably
less, as was the case in the
regimen was too small to draw conclusions about
Hong
Kong
short-course
study (Hong Kong
this regimen). In contrast, resistance to INH
Tuberculosis Treatment Services/BMRC Invcs
alone had a definite cITcct observable in all the
tigation: Unpublished data).
regimens, and resistance to both drugs carricd a
bad prognosis. These findings suggest that strep
Drug toxicity
tomycin contributes less than INH to the bac
Adverse reactions to the drugs were uncom
tericidal action of the regimens under consider
mon. Of 913 patients (237. SHR: 237. HR: 239.
ation. That it has some activity is probable from
fn patient; with double- SHRZ/TH: 230. SHRZ/S2Ha) who started
the higher failure rate in a
treatment, only 3 had 1 or more drugs termi
drug resistance, confirming the conclusions on
nated; all 3 drugs in an SHR patient, and thiadrug activity drawn from the patients with ini
daily susceptible organisms; however, the differ- cetazone plus INH in 2 SHRZ/1 H patients.
,v...
-A r
-w
FOX AND M1TCHISON
831
■
fl
I
The Hong Kong Study
A study in Hong Kong was undertaken as part
of a cooperative research program by the Hong
Kong Tuberculosis Treatment Services and the
BMRC (Unpublished data). In this study, the
potential of the pyrazinamide (SHZ) regimen,
which was effective in the first East African study,
was explored in depth. Background factois in
this study were that (/) Hong Kong could not
afford a daily rifampin regimen for 6 months as
standard primary chemotherapy; (2) treatment
services in Hong Kong are geared to provide
entiiely supervised regimens of chemoiherapy.on
a large scale, even when chemotherapy is given
daily to outpatients, although streptomycin
plus high-dosage INH twice per week is now the
standard outpatient continuation regimen used
for most Hong Kong patients (67). The Hong
Kong Tuberculosis Services were, therefore, ea
ger to search for a short-course, intermittent reg
imen that could readily be given under superoulpatiHUs. Rjfa.npin is an excepuonvision to <
al drug (68) in that it produces adverse reac^
lions more frequently when given intermittent
ly than when given daily (69, 70); most of these
I—reactions are immunologic. There is good evi
dence, however, that large, intermittent doses
of pyrazinamide not only have low toxicity (61,
71), but are also somewhat more effective,
weight for weight, when so given than when
given daily (72, 73). For these reasons, 3 sched
ules of administration of streptomycin plus INH
plus pyrazinamide were studied by random al
location (table 6): daily (SHZ), 3 times per
week (S3H3Z3), and twice per week (S2H2Z2).
It was also decided to study by random alloca
tion both the 6-month duration and a longer
course, 9 months, because of the possibility that
chemotherapy prolonged beyond 6 months might
substantially reduce the relapse rate or elimi-
naie all relapses. In terms of bactericidal drugs,
the study was a comparison of 2 complete bac
tericidal drugs given daily, 3 times per week, or
twice a week.
The main analysis concerned 137 SHZ pa
tients; 141, S3H3Z3, and 120, S2H2Z2.
Patients with drug-susceptible strains
pretreatment
Responses during chemotherapy were as fol
lows. Although there was evidence that the pro
portion of patients with negative cultures was
lower in the S2II2Z2 regimen than in the other
2 regimens, the difference was accounted for by
patients whose treatment failed because of
emergence of drug-resistant organisms. I here
was, however, no evidence of any difference be
tween the regimens in the rate at which they
eliminated susceptible organisms. At 6 months
(table 7), it was noteworthy that the SoHoZo
regimen had 5 failures among 126 patients (4
per rent), compared with 2 of 1 11 (1 per cent)
SoH.Zq patients and 0 of 13/ patients on the
daily regimen. Although the inferiority of the
twice-weekly regimen was only marginal, we
nevertheless consider it axiomatic that (/) at
the end of a short-course treatment, the regimen
should be practically uniformly successful in pa
tients with pretreatment drug-susceptible strains
and (2) this failure rate, although low is unac
ceptable for countries that achieve very high
levels of success under program conditions with
primary regimens of standard durations.
All failures in patients receiving chemother
apy, even in the 9-month series, occurred in the
first 6 months (table 7), with the exception x>f
1 S2H2Z2 patient.
The relapse rates in the first 6 months after
stopping chemotherapy in patients on all 3 regi
mens in the 6-month series were relatively high:
I
I
TABLE 6
THREE REGIMENS OF STREPTOMYCIN PLUS ISONIAZID (INH) PLUS P^^INAMIOE
STUDIED IN THE HONG KONG/BRITISH MEDICAL RESEARCH COUNOL
SHORT-COURSE CHEMOTHERAPY STUDY_______________________
No. of
Bactericidal
Drug*
Regimen
Dosage
Schedule
SHZ
2
Dally’
SjHaZs
2
Three time* per week
SjH^Zj
2
Twice per week
• Between 6 and 9 months, the 9-month
1
Duration
Comparison
Streptomycin
INH
Pyrazlnamide
6 month*
0.75 - 1-0 g
300 mg
1.5- 2.0 g
■nd
0.75- 1.0 g
1 5 mg/kg
2.0 - 2.5 g
9 months
0.75 -1.0 g
16 mg/kg
3.0- 3.5 g
series received the 3 times per week (S3H3Z3) schedule.
1
335
SHORT-COURSE CHEMOTHERAPY FOR PULMONARY TUBERCULOSIS
TABLE 7
-------------- , |N THE H0NG kong/british
BACTERIOLOGIC RESPONSE DURING CHEr^2THE^Y
RESEARCH COUNCIL SHORT-COURSE CHEMOTHERAPY STUDY
MEDICAL
---- - ------Duration of
Chemotherapy
(months)
Patient*
No. assessed at 6 months
6*
Unfavorable response
Favorable response at 6 months
9
s3h3z3
SHZ
Relapsed between 6 and 9 months
(no.)
SjHjZj
?noj
(%)
T%)
(no.)
(%)
137
0
0
2
1
5
4
70
0
0
67
0
0
74
1
1
126
141
•Including patients treated for 9 months.
ii
the very start of treatment. Clearly, the East
13 per cent of 63, 16 per cent of 69, and 18 per
cent of 38, respectively (table 8), between 6 African and Hong Kong studies suggest that
further exploration of intermittent, short-course
and 12 months. In contrast, when given for 9
regimens
should become a major objective of fur
months, all 3 regimens clearly had lower relapse
rates in the 6 months after stopping chemother ther research.
The Hong Kong study demonstrated that 2
apy (9 to 15 months): 3, 4, and 4 per cent, re
complete
bactericidal drugs, given daily or in
spectively. of groups of over 50 patients.
termittently, can be highly effective; but when
All strains from patients in both the 6- and 9month series whose disease relapsed had organ the intermittent schedule is altered from 3 to 2
times per week, the effectiveness during the ac
isms fully susceptible to streptomycin and INH.
Thus, although the 6-month regimens had un tual period of chemotherapy becomes marginal
satisfactorily high relapse rates, the 9-month ly less, owing to emergence of drug resistance.
SHZ and S3H3Z3 regimens were not only effec Further, the superiority of the 9-month regi
tive while patients were on them, but, so far, mens over the 6-month regimens demonstrated
have low relapse rates. Apart from the failure that chemotherapeutic activity on the bacterial
of a small proportion of patients during che population continued beyond 6 months with all
motherapy with the S2H2Z2 regimen, the 9- 3 regimens.
In comparing this study with the first African
month regimen with this combination was also
study,
the relapse rate after 6 months of chemo
highly effective. Thus, the hypothesis deduced
from the Madras study data (61), that inter- therapy with the regimen containing daily strep
miticnt doses and short-course chemotherapy tomycin. INH. and pyrazinamidc was higher in
could be effectively combined, was confirmed the Hong Kong patients. I he disease in Hong
in the Hong Kong study; unlike the intermit Kong was less acute, as assessed radiograph
tency in the continuation phase in the second ically, and it was our impression that it was
study in East Africa, it was intermittency from also less extensive and had less cavitation.
i
/
s
)
2
4
0
iC
te
.-c
at
I
?n
>ans
acKh
ith
icr-
I
I
I
the
of
[ter
egiigh:
TABLE 8
BACTERIOLOGIC RELAPSE IN FIRST 6 MONTHS AFTER STOPPING CHEMOTHERAPY IN HONG
KONG/BRITISH MEDICAL RESEARCH COUNCIL SHORT-COURSE CHEMOTHERAPY STUDY__
I
I
Duration
of Chemo
therapy
(mnnths)
at End of
Chemotherapy
Regimen
amide
2.0 g
6
2.5 g
3.5 g
9
Relapse*
Patl"nt« with
Favorable Statu*
SHZ
S3H3Z3
SsHjZj
63
69
SHZ
s3h3z3
62
67
SjHjZ^
52
38
•All strains were susceptible to streptomycin and INH.
<
Total*
First
Second
(no.)
(%)
3 Months
3 Months
8
13
16
18
5
11
7
9
6
3
2
2
3
2
3
4
4
2
2
1
1
0
1
1
FOX AND M1TCH1SON
336
TABLE 9
Chemotherapy
(months)
SiHaZ;
S3H3Z3
SHZ
Duration of
(no.)
(%)'
37
36
14
39
(9)
11
2
(18)
(no.)
Patients
33
6*
Assessed at 6 months
Unfavorable response
9
Favorable response at 6 months
Relapse between 6 and 9 months
30
10
41
15
11
14
0
(0)
1
»
I
•including patients treated for 9 months.
obsarvations
tPercentage. In parentheses are based on fewer than 25 observer!
These observations, which suggest differences in
lhe host./patusite relationship between Airman
and Hong Kong patients, will be the subject o
a further communication. Attention has alreac y
been drawn to this possibility in another con
text (71).
favorable response by 6 months, compared with
8 of 18 such patients on the S;iH:iZa, and 7 o
Ki on the SJI2Z,. regimen. Finally, allhough
lhe numbers are small, the lindings so far avail
able suggest that the 9-monlh regimens may
well have lower relapse rates alter stopping themotherapy than the 6-month regimens (table 10).
Patients with dru^csistant strains prclreatment
/hug toxicity
The numbers of patients with drug-resistant
Although possible adverse reactions were re
strains were relatively small, but the findings
corded in a substantial proportion of patients,
(table 9) suggested that approximately one
the proportions in whom either one of the drugs
third of the patients with strains resistant to
or the whole regimen were actually terminated
INII, to streptomycin, or to both drugs had an
were low in all 3 regimens (table 11). Pyrazmaunfavorable response by 6 months, 'l he only lur
mide was not particularly troublesome, as might
iher failures encountered between 6 and J
have been feared.
months in the 9-month series occurred in pa
It merits comment that the earlier literature
tients on the intermittent regimens. There was
on pyrazinamide toxicity in primary chemother
also an important difference between the SHZ
apy concerned daily regimens and. usual y.
and the 2 intermittent regimens. Streptomycin
higher dosages of the drug than were used m the
resistance alone (data not tabulated) had hltle
Hong Kong study. Injailure regimen chemo
influence on the response to treatment with the
therapy, in which most clinicians have obtained
SHZ regimen; only I of 15 patients had an un
I
I
I
TABLE 10
qactfrIOLOGIC
RELAPSES IN THE FIRST 6 MONTHS AFTER
stopping chemotherapy !N pat.ents with Resistant
STRAINS PRETREATMENT IN THE HONG KON55/BR'TISH
MEDICAL RESEARCH COUNCIL SHORT-COURSE
CHEMOTHERAPY STUDY
Favorable Response
Duration of
Chemotherapy
(months)
6
9
Relapses_______
at End of
Chemotherapy
(no.)
2
1
2
(29)
(7)
(20)
SjHiZj
7
14
10
SHZ
S3H3Z3
S^H^Zj
11
9
7
0
(0)
(0)
(14)
Regimen
SHZ
S3H3Z3
•Parentheses Indicate percentages based on
0
1
fewer than 25 observations.
*
I
rjpw*.:
jMMW.*^*^**'* ' *** '
SHORT.COURSE CHEMOTHERAPY FOR
337
PULMONARY TUBERCULOSIS
TABLE 11
REACTIONS IN THE FIRST
‘ --------- 1 MEDICAL RESEARCH COUNCIL
x™.”
STUDY
SHORT-COURSE CHEMOTHERAPY
C------- --------------
One Drug Terminated
INH
Streptomycin
Regimen
SHZ
S3H3Z3
s2h2z2
No. of
Patients
194
207
182
7noJ
Pyrazlnnm Ide
(%)
7%F
3
2°
2
0
1
o0
11
0
1
Regimen
Terminated
(%)
(no.)
(%)
(no.)
(%)
0
0
1
6
4
3
3
2
2
4
3
5
2
1
3
)
h
;h
nav
-0).
reits.
I
ugs
ted
inaight
tUTC
iherlally.
i the
emolined
I
I
I
I
I
An Alternative Approach tn Bactericidal
their experience of pyrazinam.de, it was com
Mechanisms
bined with the toxic drugs ethionamide and/or The concept of bactericidal synergism, which
cycloserine. Further, it was usually given to vul we have used as a working hypothesis m plannerable groups, middle-aged and elderly pa
ning clinical studies and in explaining their re
tients. in whom primary chemotherapy had al sults, has. as mentioned previously, certain de
ready failed because of drug toxicity or nonco- fects. In particular, despite the high efficacy of
operation. In these circumstances, it is dilhculi
INH and rifampin in short-course chemotherto identify, even in a general way, the level of
apy, no bactericidal synergism has been demon
adverse reactions to or toxicity of pyrazinamidc.
strated between these drugs in vitro. Bactcru u a
Moreover, interpretations of abnormal hepatic
'
function tests have added to the confusion, and activity may. perhaps, be
cred under 2 headings: (/) thejniuaU^
many of the reports of hepatic toxicity in the
tively growing bacilli: (2) the "sterilizing act.vliterature rested solely on such tests.
iV on persisting bacilli. That bacterial persis
We have been involved in a number of stud tence is of particular importance is indicated by
ies in developing countries in which pyrazina- the much longer time taken for reduction of v.amide in moderate dosage (20 to 30 mg per kg
blcTounts in the sputum of patients than in m
of body weight) was used daily and in combina
vitro experiments, in which bacilli in the otion with streptomycin (72. 75) or streptomycin
garithmic phase of growth' arc exposed to rcalisplus PAS (76) and in intermittent chemother(’ “
in"omhinaUon wkh “repiomycin (72) and tic drug concentrations
apy i*. - ------.
It is well established that drugs do not kill ba
with streptomycin plus INI! (61) in dosages
cilli when their growth (metabolic activtty) has
that were increased with the interval between
doses, reaching 90 mg per kg of body weight been completely prevented by low temperature,
anaerobic conditions, certain types of niitrtin a oncc-wcckly regimen (71 and Hong Kong/
tional deficiency, or when they are in the sta
BMRC study, unpublished data). We have been
tionary phase of growth (56. 77-80). The stnv
impressed by the convenience and low toxicity
plcst explanation of bacterial persistence dunng
of pyrazinamidc: the main complaint was ar chemotherapy is, therefore, that a proportion of .
thralgia, and this was less common on intermit the bacterial population is tn a nonmultip ytent regimens. We believe that it is now ncccs- —
) state. An alternative explana
sar)'
physicians in the technically advanced mg, (dormant)
tion is that bacilli are in sites to which drugs do
countries to obtain practical experience with
not penetrate in adequate concentration. 1 his
the use of regimens containing pyrazinamidc.
probably does not apply to INH, rifampin, or
especially regimens that arc intermittent from pyrazinamidc, because they all readily cross bmthe start or after a short daily phase, in new y logic membranes, including the normal blood
diagnosed, previously untreated patients. Such
brain barrier; their intralcsional concentrations
an appraisal, if carefully conducted with suit approximate those in blood, and they appear to
able control regimetn. would establish the ren
hr active iigaltnl iniratrlhdar bacilli (R1-M).
levels of toxicity of regimens < onlnlnlng pyi a/ln
On the other hand, streptomyrin (ails to pmr
amide. One such investigation is currently in
tratc many cell membranes and is much less acprogress in Hong Kong.
-A r
if
-------------
338
f----
1
FOX AND M1TCH1SON
live aguiiui imraadluhu- than extracellular baolli (82,8'J, 90).
.
Afomz and man. In examining the bacteri
cidal activity of the drugs in detail, evidence
obtained from tuberculosis experimentally induced in mice has been of greatest value. We
have drav^HTspecially on the pioneering work
done at Cornell University and on the extensive
studies at the Pasteur Institute.
Certain features of the murine model are par
ticularly important. (/) Histologic examina
tion of the organs suggests that mostjjacilli a^e
intracellular, except in advanced pulmonary lesFo’ns' (2) Although direct measurements of the
pH of the environment of bacilli have not been
made, the bactericidal activity of pyrazinamidc
in the mouse shows that it must be less than
approximately pH 5.6 for most bacilli, because
the drug is inactive at a more alkaline pH m
vitro (91). (3) In chronic murine tuberculosis,
can
yet, account for the remarkable sterilizing actioiTof INH plus pynuinumidv or of INH plus
'
rifampin.
Man develops a much higher degree of hyper
sensitivity to antigens of Af. tuberculosis than
:
does the mouse. In consequence, few bacilli are
found intracellularly; most occur in well-aer
ated cavity walls, at least in the patients usually
studied in controlled clinical trials. The_pH_of_
resected tissue and caseous material has been
found to be 6.94, on average (range for 95 per
cent of observations: 6.8 to 7.2), using glass
viable counts in the lungs remain constant, not
because there is a balance between growth and
death ol bacilli, but because the immune mecha
nism is essentially bacteriostatic (92, 93). Al
though the mice used in experimental chemo
therapy have either had acute disease or were
changing hum aculc lo clironii disease, it is
reasonable to suppose that at least a proportion
of the bacilli are held static by the immune pro
cess.
..
These conclusions suggest that bacdli_usuany
ivnoinmu.i
grow within the macrophage in an env“011u‘tl“
rt tteir
"wliere acidity and perhaps low Po2 llm
1--mSication, as originally suggested by Dubos (94). Streptomycin would be of low efficacy,
partly because of the intracellular site, and part
ly because of the acid reaction. Isoma/id and
in i
tain
mid
base
dos;
usei
T
chai
lion
size
font
sion
rifa
eral
dos.
leri
of
cid;
by
tan
con
mil
Fin
an
tra(=
electrodes (97). Thus, most bacilli, lying extracellularly and at a neutral pH, should be sus
ceptible to streptomycin in relatively low con
centrations. Little is known concerning the fac
tors causing dormancy of bacilli in human le
sions. That there are dormant organisms is
shown by the long periods of conventional che
motherapy necessary to achieve low ultimate re
lapse rates and, indeed, by the early observa
tions on endogenous reactivation of tuberculo
sis. We may surmise that dormant bacilli sur
vive either within the macrophage (endothelioid cell) or within areas of caseation that do
not communicate with a bronchus and there
fore have a decreased Poa. Thai_POj is iu» im
portant factor limiting growth is shown by the
small numbers of bacilli found in the closed le
sions of spinal tuberculosis (98, 99).
Initial bactericidal activity of drugs. In table
12 are summarized the early bactericidal ac-
I
t
iyt ha
ini<
act
act
giv
an<
it
I
r
uvity in Vitro (58. 59. WO, 101 and, D>du.»o
J. M., and Mitchison, D. A.: Personal comand in
munication), in the mouse (102-104),
x
the guinea pig (105, 106, and Dickinson, J.
I
gu
cid
no
M„ and Mitchison, D. A.: Personal communication) of the 4 most important drugs used in
rifampin, whose activities are unallected by pH.
short-course chemotherapy, 'the comparisons
would kill growing organisms. In advanced pul
monary lesions, the accumulation of bacilli (and
TABLE 12
therefore their antigens) within an individua
SHort-term BACTERICIDAL ACTIVITY OF
macrophage would destroy the cell (95), and
main chemotherapeutic drugs used
the bacilli would be liberated to the extracellu
IN SHORT-COURSE chemotherapy
lar environment, where streptomycin would be
Bactericidal Activity_______
more effective (96). Finally, after a period of
In guinea
chemotherapy, the bacterial load would be re
Plfl
in mouse
In vitro
Drug
duced, so that the bacilli would no longer de
stroy their macrophages, but would remain more
or less dormant within them. Under these cir
cumstances, the bactericidal activity of the drugs,
and particularly that of streptomycin, would be
greatly reduced. This model can explain many
of the findings in experimental chemotherapy
of murine tuberculosis, although it does notr as.
1
INH
Rifampin
Streptomycin
Pyrazlnamido
2+
2+
3+
2+t
•Drug given in a dosage
that used In man.
tpH: 5.2 to 5.6 units.
2+
2+
2+’
2+
2+
2+
0*
considerably higher than
I
I
I
is
in;
co
ca
en
is
Pi
de
ni«
pe
la
tu
ai
by
ro
SHORT-COURSE CHEMOTHERAPY
I
I
I
c
♦
1e
n,
Ti-
in
.1-
I
jlnea
-g
2*
2+
2+
0*
than
339
I
fcctive in preventing the emergence of 1NHonly be approximate, because the effective I
can
resistant organisms when patients are
- treated
in vivo concentration of each drug is not ccr- iwith INH and streptomycin. On the other hand,
tain; but except for streptomycin and pyrazina pyrazinamide is of only moderate efficacy m pre
mide in the mouse, the estimates of activity arc venting resistance to another drug. 1 hese find
based on experiments using concentrations or ings arc compatible with the view that the range
dosages likely to approximate those obtainec or of environmental pH is greater in man than in
used in man.
,
.
cither the mouse or the guinea pig. but that
The bactericidal activity of INH m v.lro is most bacilli arc in a more alkaline (extracellu
changed only to a small extent by large altera lar) environment than that in the mouse. Evr
tions in drug concentration (59). Likewise, t ic dence that cannot be reviewed here in dcta.l on
size or rhythm of INH dosage in man was not
the virulence in man of various types of atten
found to influence speed of sputum conver uated bacilli, including JNII-resistant and
sion (107-109). The bactericidal activity of South Indian strains, also suggests that the im_rifampin alone is, however, affected to a consid munc process in man is intermediate between
erable extent by changes of concentration or
that of the mouse and the guinea pig. but is
dosage, so that the drug is only slowly baccloser to that of the mouse.
tcriri.lal at low dosage. The concentrauon
■ We con, thmrorc. expect that streptomycin
of streptomycin profoundly influence* bacteri would be a more important bactericidal drug in
cidal activity in vitro. Here we can be gu.ded
human disease than in the disease of mice. In
by well-established observations on drug resis the early stage of killing of actively growing batance, which indicate that the effective in vivo cilli. pyrazinamide would be considerably less
concentration in man is only 4 to 8 times the
effective than it is in the mouse. These expecta
minimal inhibitory concentration (119. 111). tions are illustrated diagrammatically in figure 3.
Finally, pyrazinamide is bactericidal in vitro at
an acid pH; the relationship between concen
ACID
pH 7 0
ALKALINE
tration and activity will be discussed subsequent-
»
niin
ms
FOR PULMONARY TUBERCULOSIS
I
I
I
The broad conclusion emerges from table 12
that, although INH, rifampin, and pyrazina
mide have fairly similar, moderate bactericidal
activities in vitro, streptomycin has the highest
activity. In contrast, streptomycin at the dosage
given in man is virtually inactive in the mouse,
and. even when the dosage is increased 10-fo d,
it is less active than INII or rifampin. In the
guinea pig. streptomycin is moderately bacteri
cidal at the same dosage and scrum concentra
tion used in man. Pyrazinamide in high dosage
is bactericidal in the mouse, but appears to be
inactive in the guinea pig. These apparently
contradictory findings in mouse and guinea pig
can be explained on 2 grounds: (/) that (he
environmental pH of a< lively growing bacilli
is more acid in the mouse than in the guinea
pig; (2) that the immune system in the mouse
1 °
n
.1 _ .1:...
depends on low Po
I A2 and acidity, whereas other
' : on pH (such as
mechanisms, less dependent
greater imporperoxide production), arc of
'
tancc in the guinea pig.
When we attempt to a pply these findings in
tuberculosis experimentally induced in mice
and guinea pigs to man, we can only be guided
by broad generalizations. With regard to envi
ronmental pH, streptomycin is known to be ef-
MOUSE
to
1'!'
HR [3
[S]HR
■11V
MAN
y.?-
mycin, on extracellular organisms m an alkaline
medium. The broad arrows indicate the principal
sites of bacillary multiplication, intracellular m the
mouse and extracellular in man. H - isoniazid, R
rifampicin; Z = pyrazinamide; S - streptomycin.
- > yt
tA
I i
1
FOX AND MH CH ISON
340
TABLE 13
I
sterilizing activity of drug combinations IN MURINE tuberculosis
------------------ TDrugs
Duration^
Treatment
(months)
Lung/Spleen
4-6
3+
4 0
a•
i+*
INH 4 ethambutol
IHH t tirapiuniycln
Streptomycin ' rifampin
INH ♦ rifampin 1
4
4 6
Culture
Ro,aPse
After
<
Chemotherapy
!
Grombach (112)
Grombach st al. (113)
la Llriln d »•»)
La Llrzln (114)
1*
0
Study
Grombach (101)
Grombach at al. (113) (110)
La Lirzin (114)
Batten (115)
Kradolfer and Schnell (117)
INH + rifampin + streptomycin
INH + streptomycin
INH + pyrazinarnide
INH + pyrazinarnide
Streptomycin + pyrazinarnide________
4—6
0
1+
16-18
1+
2+
01
2+
6
0
0
3
0T
3
Grombach et al. (114)
Grumbach et al. (114)
McCone et al. (45)
Grumbach (103)
McCune et al. (118)
McCune et al. (45)
•Two of 8 lungs each yielded 1 colony
and from 1
Oof 77 mica after INH plus pyrazinarnide.
TPositive cultures of spleen from C -- .
8 mica after strepto-
I
mycin plus pyrazinarnide.
1
tain, because the experimental conditions were
■ agents
—> responsible for the eatly
Thus, the main
different. Conclusions that can tentative y e
ould be INH, rifampin, and streptomycin,
drawn include the following. (7) Isoniazid m
kill wot.— -- streptomycin affecting only part of the
combination with ethambutol was the least bac
with s..-r— ,
.1— :.j jjQ demonpopulation. As noted earlier, there is
tericidal regimen, an expected finding m view
srtrable"carly bactericidal synergism between
of the essentially bacteriostatic action of et iam;
INH and rifampin, but some synergism exists
butol in the dosage used in mice and m immbetween INI! and streptomycin. Furthermore,
(2\ Isoniazid plus rifampin was the most elec
INH and pyrazinarnide were found to be an tive verilizing combination. Because streptomy
tagonistic in the early stages of treatment in
cin plus rifampin reduced lung counts to a sub
the mouse. It can be concluded that giving a
stantially lower level than did INH plus strepto
multiplicity of drugs at the start of treatment
mycin, rifampin appears to be the main agent
should be of relatively little extra benefit in
responsible for the sterilizing activity. 1 hat ukilling actively growing, drug susceptible orga fampin has a special role in sterilizing was also
nisms, although the results are probably unite
shown by the experiment of ^‘adoller and
different for such combinations considered in
Schnell (117), who treated mice with INH plus
their capacity as sterilizing drugs.
rifampin for various periods, followed by rifamSterilizinf' activity of drugs. Some ol the find
pin INH, or streptomycin alone; rifampin was
ings in the chemotherapy of murine tuberculo the’only drug capable of sterilizing the lungs
sis that are of particular relevance to the stenlizand preventing ultimate relapse. Nevertheless,
ing .activity
.Z of short-course
of short-course
regimens
regimens are sumrifampin was only effective when given in a dos
marked in'table 13. In these experiments,
age that produced serum concentrations approx
for long periods with drug com- imately 3 times higher than those usually
were treated
1.—
„ and when culture of (he lung yielded achieved in man. Streptomycin plus r*faniP£
binations,
■“i at the end of che- (table 13) was a little less effective than INH
no apparently viable 'bacilli
for relapse
motherapy, survivors were-> observed
c
the plus rifampin, demonstrating that there is some
for several months. Comparisons between t
synergism between INH and rifampin. 1 he low
top one half of the
t— table, derived mainly from efficacy of streptomycin in the murine model is
..v .Pasteur Institute, and the bottom shown by this comparison and also by the tin
work at the
derived mainly from the earlier stud- sing that the addition of streptomycin to the
one half, <----- Cornell
are somewhat uncer- >
ies at t-~--—- University,
-
1
I
I
~v*i •*<
'•» '---«•• «*T*»*» ■
341
SHORT-COURSE CHEMOTHERAPY FOR PULMONARY TUBERCULOSIS
)
I
: 11 e)
117)
1
I
1
rep to-
were
ly be
'id in
t bacvicw
thamman.
eflec>tomya subreptoagent
bat ri
as also
r and
T plus
I
4
i
combination of INH plus rifampin produced
no additional benefit. (3) Pyrazinamide in very
high dosage was of exceptional value as a steril
izing drug. The absence of any relapses after G
months of INH plus pyrazinamide, compared
with their occurrence after the same duration
of INH plus rifampin, together with the slight
superiority of streptomycin plus pyrazinamide
over streptomycin plus rifampin, suggests that
pyrazinamide may be superior to rifampin in
the mouse.
It is of interest to note that the Cornell group
found that 4 weeks of INH followed by 8 weeks
of pyrazinamide were as effective as 12 weeks
of both drugs together from the start of chemo
therapy. This finding emphasizes the sharp dis
tinction between the initial kill and the steriliz
ing period that was so beautifully demonstrated
in their murine model. A clear temporal distinc
tion between these 2 phases Is much less likely
to be true for the more heterogenous conditions
in human lesions. Thus, the sterilizing activity
of drugs may be more important in the early
stages of chemotherapy in man than in the
mouse. It should also be noted that obtaining a
negative culture from patients, which often oc
curred at 1 or 2 months, may well involve ster
ilizing activity as well as early kill, again sug
gesting that absence of a well-demarcated biphas
ic response.
When the conclusions drawn from the murine
model are applied to human short-course che
motherapy, it is clear that the 3 key drugs arc
INH. rifampin, and pyrazinamide. Pyrazinamide
should be relatively less effective in man than in
the mouse. On the other hand, streptomycin, of
very limited value in the mouse, should provide
slight additional benefit in man.
I
I
TABLE 14
i il.un
in was
lungs
holes*,
a dos-
pproxjsually
ampin
< INH
s some
he low
odcl is
e findto the
Special roles of rifampin and pyrazinamide.
There are reasons, derived from experiments on
pulsed exposures of Af. tuberculosis to drugs, to
suggest that rifampin and pyrazinamide have
especially important, but different, bactericidal
activities against bacilli that arc nearly dor
mant. In these experiments, cultures in the lo
garithmic phase of growth were exposed to puls
es lasting 6 hours, 24 hours, or longer (106, 119,
120). Bactericidal activity was accompanied by
a period after the pulse during which growth did
not occur (lag period). The results of experi
ments with bactericidal drugs are summarized
in table 14. Isoniazid was only bactericidal after
exposures of 24 hours or more, although the
effects of several shorter exposures were cumu
lative (121). The duration of the lag period
after an exposure was also long.
Streptomycin, rifampin, and pyrazinamide
were the only drugs (apablr ol indiiritig lag
after an exposure ol only 6 hours. In the case of
streptomycin, induction of lag by a short expo
sure was subsequently found to be highly de
pendent on the ionic strength of the medium
used to wash the bacilli after exposure to the
drug; it is, therefore, uncertain whether the in
vitro experimental conditions truly represent
those in lesions. Rifampin appears to be unique
among the remaining drugs in the speed with
which its bactericidal activity starts. Thus, re
duction in ribonucleic acid formation was evi
dent within 20 minutes of exposure to a realis
tic concentration (56). Although rifampin is no
more effective against slowly growing organisms
than is INH (55, and Awancss, A. M., Dickin
son, J. M., and Mitchison, D. A.: Unpublished
data), we can imagine that it is particularly le
thal to bacilli in human lesions that have resist-
LAG PERIODS AFTER PULSED EXPOSURES TO
BACTERICIDAL DRUGS (106, 119, 120)
I
I
Drug
Drug
Concentration
(ug/ml)
INH
Streptomycin
■I
■
Rifampin
Pyrazlnamlde
Ethionamide
Cycloserine
Ethambutol
Capreomycln
•Dependent on pH of medium.
1
5
0.2
50
5
100
10
10
Lag period (days) after exposure for
6 hours
24 hours
0
8-10
2-3
5-40*
0
0
0
5
6-9
8-10
2-3
> 40*
10
4-8
4-5
6
i
I
V-.
r
342
I
EOX AND MITCH ISON
ed drug action because they are dormant and
then start to grow for a short period of, per
haps, a few hours, loo short a time for them to
be killed by INH. It should, however, be noted
that rifampin is only bactericidal al high con
centrations, and that recovery from an expo
sure is also very rapid (56, 106). Thus, rifampin
may only be bactericidal in patients receiving
therapy during certain periods of the day, when
tissue concentrations arc at their peak.
In the case of pyrazinamide, the bactericidal
activity and the length of the subsequent lag
period increase as the growth rate of bacilli is
progressively slowed by increasing acidity of the
culture medium (table 15) (122). It is remarkTABLE 15
LAG PERIODS AFTER PULSED EXPOSURES TO
50 gg OF PYRAZINAMIDE PER ML (122)
Lag Period (days)
After Exposure for
pH of
Medium
(units}
Rate of Growth
(Logxo
viable units/day)
6 hours
6.2
5.8
5.6
0.36
0.27
0.14
0
0
40
96 hours
9
72
> 76
1 I
S’
able how even a brief exposure inhibited for
long periods the subsequent growth of bacilli
that could only just multiply in drug-free acid
medium. Hence, it might be a particularly ef
fective drug against organisms that grow very
slowly, and are therefore relatively immune to
the bactericidal activity of other drugs.
In summary, rifampin and pyrazinamide may
have special activity against nearly dormant or
ganisms, rifampin against those going through a
temporary period of active metabolism at the
time that high intralesional drug concentrations
are attained; pyrazinamide, against those with
more persistent, but very slow, growth due to
acid inhibition. Isoniazid would provide a
"back-stop” for organisms that grow slowly but
continuously, irrespective of the environmental
pH. Because the bacilli concerned would be dif
ferent, strong synergism would be expected be
tween these 3 drugs to provide the most effec
tive elements of a sterilizing regimen. Because
conditions of pH, O2 supply, and, indeed, the
basic immune process are likely to be more het
erogenous in man than in any conventional ani
mal model, this synergism should be more ap
parent in clinical trials than in experimental
murine tuberculosis. The relevant experiments
4>
’’
have not been done in animals, but the results of
the second East African study certainly suggest
that the combination of INH, rifampin, pyrazinamide, and streptomycin is of remarkably high
efficacy. We have yet to see whether streptomy
cin contributes an element of any real impor
tance to this combination. It should also be no
ted that the suggested synergism is effective
against physiologic heterogeneity in the bacil
lary population arising from their environment,
whereas the type of synergy conventionally as
sociated with combined chemotherapy is effec
tive against genetic heterogeneity (presence of
resistant mutants) in the population.
In this section we have presented a series of hy
potheses in an attempt to unify the findings of
many workers in the field of experimental chemo
therapy. These hypotheses will stand or fall ac
cording to whether they are supported by addi
tional experimental work and whether they lead
to predictions validated by the results of further
clinical trials. They emphasize the importance of
studies on the immune process in experimental
animals and in man, particularly on how the
growth of bacilli is controlled. For instance, is
the environmental pH really as decisive as it
seems to be in murine tuberculosis, and what is
the mechanism, probably different, that oper
ates in the guinea pig and in man? Is the physio
logic state of bacilli in man as heterogenous as
has been suggested? Predictions that might be
tested in clinical trials include the following.
(7) The dose of rifampin may be of considerable
importance, because a larger dose would lead to
higher and more prolonged peak concentrations,
which could kill a larger proportion of the or
ganisms in a semidormant state. (2) Given
quantities of rifampin and pyrazinamide may
be at least as effective if given after the initial
kill than if given from the start of chemother
apy. (3) It should be possible to develop short
course regimens that are effective in preventing
relapse when given for periods even shorter than
G months. The rational planning of further clin
ical trials must, in any case, be supported by
theory, and it is this that we have attempted to
provide.
Other Workers' Findings
In 1973, Poppe de Figueiredo and associates
(123) studied the combination of INH plus ri
fampin plus etliambutol for 6 months, with one
half of the patients in hospital for the full 6
months, one half, for 2 months, followed by 4
I
I
I
I
i
f
i
1
t
t
c
r
c
SHORT-COURSE CHEMOTHERAPY FOR PULMONARY TUBERCULOSIS
tits of
iKgest
Tazin• high
uomymporbe noTectivc
bacilnment.
ally ass cffec?nce of
es of hylings of
1 chemo
fall ac
hy adclihey lead
f further
rtance of
irimental
how the
stance, is
sive as it
,d what is
hat opcrhe physioigcnous as
might be
following,
msidcrable
old lead to
■entrations,
, of the or(2) Given
amide may
the initial
chemothervelop short
preventing
shorter than
further clin.ipported by
ittempted to
V
id associates
INH phis riths. with one
or the full 6
ollowcd by 4
1
I
>
I
I
1
I
1
I
4
I
i
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I
i
343
the findings will be especially interesting, be
months of self-administered, ambulatory chemo
cause they will provide a direct comparison of
therapy. After 24-month follow-up, there were c3
the relative effectiveness of INH alone and
with
bacteriologic relapses among 89 patients
rifampin alone when used in the continuation
fully susceptible organisms and 1 among 13 pa
phase of short-course chemotherapy of 6-month
tients with INH-resistant organisms pretreat
duration.
ment. Although the intensity of bacteriologic
investigation was low, the findings nevertheless
Other Possible Combinations for Shortconfirm those from East Africa, both for suscep
Course Chemotherapy
tible and resistant infections.
The
question
arises, what drugs would it be
Brouet and Roussel (124), in a cooperative
fruitful
to
investigate
in short-course regimens
investigation involving 13 centers in France,
other
than
those
based
on INH plus streptomy
studied rifampin plus INH for 6, 9, and 12
cin
plus
rifampin,
or
INH plus streptomy
months, supplemented in the first 3 months, at
cin
plus
pyrazinamide?
There is. of course,
the choice of the physician in charge, by either
particular interest in regimens that do not in
streptomycin daily or ethambutol daily. Two
volve rifampin because of the yet unsolved prob
years after the start of chemotherapy, there
lem of adverse reactions to this drug when given
was only one certain bacteriologic relapse in the
'in
intermittent regimens, and because of its cost.
18-month follow-up among 59 patients in the
6-month series, none of 62 in the. 15-month fol A study in Hong Kong is relevant (127, 128) be
cause it is informative concerning PAS as the
low-up of the 9-month series, and none of 49 in
third drug when combined with streptomycin
the 12-month follow-up of the 12-month series.
plus INH. Patients were allocated this triple
Thus, all the regimens were effective.
Although these reports confirm the effective regimen either for 3 or for 6 months daily; every
dose of the oral medicament was given tinder
ness of short-course chemotherapy in 2 other
supervision for the 6 months, followed by self
areas of the world, they contribute relatively
administered INH plus PAS for 18 or 24 months.
little to our understanding of the underlying
Among 184 3-month, triple-regimen patients,
mechanisms. The assumption has widely been
there was a 5 per cent bacteriologic relapse
made that because rifampin may be a uniquely
rate during chemotherapy, and a 3 per cent re
bactericidal drug, it must therefore not only be
lapse rate after stopping in patients who had
included in all short-course regimens, but it
fully susceptible strains on admission (unpub
must also be given for the full duration of
lished data). The corresponding relapse rates
chemotherapy. It is clear from the studies in East
in 186 patients on the 6-month triple regimen
Africa and Hong Kong that adherence to this
initially were 5 per cent and 2 per cent, respec
assumption is no longer tenable, and also that it
tively. Also, there was goorl evidence from mon
narrows the exploration of possible approaches
itoring the drug intake by urine testing that re
to short-course chemotherapy.
A British Thoracic and Tuberculosis Associa lapses while the patients were still on the regi
men resulted from irregularity in self-adminis
tion study (125) is investigating rifampin plus
INH for 6 or 12 months, supplemented by strep tration of the 2-drug oral regimen in the contin
uation phase. Hence, it can safely be assumed
tomycin or ethambutol for the first 8 weeks in
that a 6-month, short-course regimen of strepto
patients with pretreatment cavitation less than
mycin
plus INH plus PAS would have had an
2 cm in diameter; 9-month and 18-month dura
tions are being compared for patients with more even higher relapse rate. Thus, it seems wisest
to regard this triple combination daily for 6
extensive cavitation.
months
as likely to have a relatively unsatisfac
A study by Leston and co-workers (126) is of
tory
relapse
rate when compared with the tri
particular interest in relation to the bactericid
al hypothesis we have put forward. They report ple-drug regimen containing rifampin (SHR) of
the 2 East African studies.
ed preliminary findings of a study in which all
A point of special interest arises in relation
the patients are being treated for 2 months with
to
the continuation phase of the SHRZ/TH
daily INH plus rifampin plus ethambutol. then
regimen,
in which phase only one bactericidal
one-half, by random allocation, with 10 mg of
drug, INH, was used and which, nevertheless,
rifampin per kg alone daily for -1 months and
appeared reasonably effective. It is likely that
one-half, with 8 mg of INH per kg alone daily.
the combination of PAS plus INH daily (also
Although it is too early to report relapse rates,
•A r *
FOX AND MITCHISON
344
The Influence of Initial Drug Resistance on
containing the same single bactericidal drug),
Short-Course Chemotherapy
or even INH alone would be as good in the
In
conventional
chemotherapy, there are 2 teacontinuation phase. There is, furthermore, evi
sons for giving an initial intensive phase of
dence that when high-dosage INH plus PAS is
treatment with 3 drugs. (/) In patients with
given twice per week, the rate of sputum con
initially susceptible organisms, the likelihood of
version is as rapid as when the combination is
the emergence of drug resistance is decreased
given daily in standard dosage, and it is less tox
(23), especially when it is proposed to give INH
ic (129). It is tempting to speculate whether
with a weak drug in the continuation phase.
the twice-weekly regimen of INH and 1’AS, con
(2) It also improves the chances of eliminating
taining, as it does, the single bactericidal drug,
resistant bacilli present at the start of treatment.
INH, in high dosage, but intermittently, would
A triple-drug regimen is usually ellective against
be as effective as the low daily dosage of the
strains resistant to only one drug because the
same bactericidal drug. It is already established
bacilli will still be acted on by 2 drugs, whose
that the S2H2Z2 intermittent continuation regi
effects are unimpaired. It may also be effective
men, the twice-weekly 2-bactericidal drug regi
because only a proportion of the bacilli in the
men, is effective. A further possible oral 2-drug
strain are resistant to 2 or all 3 drugs. If the
regimen is INH plus pyrazinamide, which might
hypothesis that 2 bactericidal drugs are impor
well be better than INH plus thiacetazone or
tant to the effectiveness of short-course chemo
INH plus PAS.
therapy is coriecl, it is evident that in the pres
Ethambutol has been used with INH and
ence of pretreannent drug resistance, the oirifampin in short-course studies. There is some
ganisms would not usually be exposed to 2 bac
justification for its use to prevent the emergence
tericidal drugs, unless at least 3 bactericidal
of rifampin-resistant organisms in patients with
drugs are included in a short-course regimen.
strains initially resistant to INH; however, in
Rifampin or pyrazinamide or both drugs must
the currently used dosage of 12 to 25 mg per
clearly be included in view of their special ster
kg, experimental studies in the mouse (112), and
ilizing activity in animals and in man. Luckily,
in the guinea pig (120) suggest that it is only bac
primary resistance to either of these drugs is
teriostatic, and in combination with INH does
still very rare. These considerations must be
not increase the speed with which viable bacilli
borne in mind when planning studies of regi
are eliminated from the lungs. When larger doses
mens for use in areas with high prevalence of
of ethambutol (45 to 90 mg per kg) were given
initial drug resistance, especially if intermit
twice weekly or once weekly with INH for 1 year
tent regimens are under consideration.
to patients at the Chemotherapy Centre, Madras,
In organizing chemotherapy programs with
the subsequent relapse rates were much higher
regimens of conventional duration, there aie
than those encountered after courses of standard
2 main alternative approaches to initial drug
chemotherapy of the same duration, showing
resistance. One is to adjust the regimen of che
that even if larger doses; are used (albeit inter motherapy for the individual patient on the ba
ba-
mittently), ethambutol iremains a bacteriostatic
sis of pretreatment susceptibility tests. The oth
drug (130).
er is to ignore the pretreannent susceptibility
Experimental work in the mouse suggests that
of the strains and give a regimen of chemother
ethionamide plus rifampin is as effective a ster
apy known to be able to achieve quiescence
ilizing combination as INH plus rifampin (101).
of the disease in at least a proportion of pa
Because of the high rale of adverse reactions to
tients with resistance to one or more relevant
ethionamide, this finding has, in practice, no
drugs; retreatment with a reserve regimen is
immediate application in primary chemother
started when patients remain consistently bacapy. It might, however, be relevant in some cir>
teriologically positive (127, 128). In technical
cumstances in retreatment regimens for patients
ly advanced countries, it is common to find
with organisms initially resistant to INH.
that undisclosed acquired resistance is virtual
The importance of pyrazinamide as one of
ly nonexistent and that the prevalence of pri
the 2 drugs with a special sterilizing activity
mary resistance is low (often less than 5 pei
suggests that further experimental work should
cent). It has been pointed out (23) that the
be done to search for other drugs with similar
benefit from routine pretreatment susceptibility
properties (131) and to explore the mechanism
testing under such circumstances is very limited.
of action of pyrazinamide itself.
1
t
I
I
I
I
II
I
•net•WBwnre
SHORT-COURSE CHEMOTHERAPY FOR PULMONARY TUBERCULOSIS
At least 95 of each 100 patients will have fully
susceptible organisms, and the tests will there
fore in no way alter or improve their chemo
therapy. More than three fifths of the remain
ing 5 per cent of patients will have resistance
to a single drug, and it has long been recognized
that this has very little influence on prognosis
with standard triple regimens of long term che
motherapy, for example, streptomycin plus INH
plus PAS. Less than 2 per cent of all patients will
have strains resistant to 2 or all 3 drugs. Thus,
only in this latter, very small proportion of pa
tients is there potential benefit from pretreat
ment susceptibility tests. It has been estimated
on a sound basis (127, 128) that in Britain, only
1 of each 200 bacteriologically positive patients
would benefit from the routine use of accurate
pretreatnient susceptibility tests if the regimen
being prescribed is the standard regimen de
scribed. The benefit to this patient would he
that a reserve regimen would be introduced
sooner, leading to the more rapid achievement
of quiescent disease. The same considerations
apply to North America, where the prevalence
of initial drug resistance is similar (132—141).
It has also been demonstrated (127, 128) that
even in an area where there is a high level of
initial resistance (i.e., both primary and con
cealed ac(|uirc<l), the contribution it makes to
failure may still be relatively small in compari
son with the proportion of failures that result
from patients with fully susceptible organisms
who attend regularly, but become irregular in
self-administering their oral drugs. Moreover,
stopping attending for treatment altogether can
be an even greater threat (3, 142).
Consider now short-course chemotherapy
against this background. If the traditional prac
a>(
h
•d
H
e.
>
ig
it.
ist
-he
>sc
ve
he
he
orno•csor»acdal
en.
I
lUSt
ter.ily,
s is
be
egi’ of
mit-
with
arc
drug
chcc baothjility
ttherrcncc
( papvant
cn is
• bacnicalfind
rtual.( pvi
5 per
u the
ibility
mited.
i
I
!
345
tice of the technically advanced countries of
starting chemotherapy and adjusting the regi
men in the light of susceptibility tests is fol
lowed, there is no reason why the results should
be any worse in short-course chemotherapy than
with regimens of standard duration; however,
for patients on short-course regimens whose che
motherapy is changed, the retreatment regimen
may have to be given for the usual longer pe
riod.
If, in fact, the rate of initial resistance is low,
it would be rational and operationally much
simpler to ignore such tests and to wait until
patients fail to respond to their short-course reg
imen. then retreat them with a regimen of con
ventional duration. The evidence already avail
able suggests that a substantial proportion of
patients with resistant strains will respond sat
isfactorily to short-course regimens.
Given a standard level of efficiency of organ
ization of programs, however, the over-all suc
cess achieved by the currently available short
course regimens, without pretreatment suscep
tibility testing, is potentially lower in areas
where the prevalence of resistance to INH.
whether alone or with other drugs, is high. The
important need for areas with high rates of ini
tial drug resistance is the development of regi
mens that will still prove effective without ref
erence to the pretreatment susceptibility of the
strain in the individual patient. This is especial
ly so because it is in the developing countries
that not only may high rates of initial resistance
be present, including high rates to 2 (table 16)
and even 3 standard drugs, but susceptibility
testing may not be available at all or be unreli
able, or, at best, reliable testing may be limited
to 1 or 2 laboratories. Hence, finding suitable
TABLE 16
i
LEVELS OF INITIAL DRUG RESISTANCE IN HONG KONG, EAST AFRICA, AND BRITAIN IN
RECENT STUDIES; TESTS WERE DONE IN BRITISH MEDICAL RESEARCH
COUNCIL OR ASSOCIATED REFERENCE LABORATORIES
Hong Kong
Short Course
(1974)
(%)
Drug
First (1972)
Second (1974)
Chemotherapy
Study In
Britain (1973)
(%)
(%)
(%)
East African Short Course
Streptomycin alone
INH alone
Both driig*
9
5
8
i
7
1
5
1
2.1
1.5
0.4
Total r*»l«tnnna
21
n
0
4.1
No. of patients In study
with susceptibility tests
586
1,073
883
-A - .
3
467
't9
* - Y•
346
FOX ANO MITCH ISON
as many as 30 per cent of patients stop attend
ing completely. Il is argued that this is just as
likely to happen with a 6-month regimen as
with a 12- or 18-month regimen. This view, how
ever, represents a failure to appreciate the full
implications of short-course chemotherapy. Cur
rently, a patient on standard chemotherapy in
the technically advanced countries is expected
to remain under treatment for at least 18 months
and, in developing countries, for at least 12
months. When, as is almost always the case, a pa
The Implications of Short-Course Chemotherapy
tient feels well and has, within a month or two
What are the implications of short-course che
of
starting treatment, lost all symptoms ot his
motherapy under program conditions, assuming
disease, he faces the prospect of having to con
that we can expect to cure almost all patients
tinue to cooperate in treatment, not only by
within a period of 9 months or less? (/) 1 he
attending
the treatment services, but also by
total delivery of health services in terms of pa
ingesting
his
medicament regularly for many
tient attendance, supervision of the actual inges
months
to
come,
medicament which he may find
tion of drugs, routine investigation of the pa
is unpleasant or produces minor side elfects.
tients, are all curtailed. Less total quantity of
drug is used, and so the cost is lowered. In tech The demands made on a symptom-free patient
are much less if he knows that to be cured re
nically advanced countries, the total demands
quires cooperation for only a few more months.
made on the resources of the health service
should be substantially reduced. In the devel There can be little doubt that adequate explan
ation of the new type of therapy, its short dura
oping countries, limited resources can be put to
tion, and the certainly of success, combined
better use.
with the improved organization that will result
(2) It is self-evident that there will be less
from concentrating the available resources on
chronic drug toxicity. Although much of the
a short-course regimen, could well lead to a dra
drug toxicity to standard regimens occurs in the
matic improvement in cooperation under pro
early months and even weeks of treatment, par
gram conditions. Adequate explanation would
ticularly the hypersensitivity reactions, adverse
be necessary at the start of treatment and would
reactions continue to arise for the first time even
need to be repeated if and when the patient
in the later months of long-term chemotherapy
hlmwrd signs of iricgularily in attendamv, m
(143), A ahoiienlng ol the total durulion would
failure to ingest his medhameut regularly, it
therelore reduce the incidence ol drug toxicity.
it is to be self-administered.
(3) Early default from treatment is less haz
(5) Routine follow up after the end of che
ardous to the patient. This is because the pa
motherapy can be drastically curtailed, or aban
tients who discontinue their treatment in the
doned altogether. We have followed with great
early months are more likely to be culture neg
interest recent articles and correspondence
ative and remain permanently so than similar
(144-150) in the American Review of Respira
patients on standard chemotherapy; however,
tory Disease concerning the duration of follow
to obtain more precise facts on this point, it is
up of patients who have completed their treat
important when undertaking research into short
ment. Also, early in this year, the U. S. Public
course chemotherapy to make every effort to ob
Health Service Center for Disease Control (151)
tain a bacteriologic follow-up for patients who
recommended discharging patients with tuber
discontinue their regimen prematurely.
culosis who complete adequate drug therapy
(•/) More effort can be concentrated on en
from medical care, and Dr. Reichman moderat
suring that the patients continue to attend and
ed a panel discussion on the topic at the May
actually remain on their chemotherapy for the
1974 meeting of the American Thoracic Society
full period prescribed.
in Cincinnati (152). The same point has recent
It is already being stated in some circles that
ly been made in a survey of patients treated in
short-course chemotherapy is of little impor
Scotland (153). Regular long-term follow-up, as
tance in developing countries, because it cannot
undertaken in the prechemotherapy and early
appreciably influence the common finding that
years of the chemotherapy era, was practiced
within the first 2 or 3 months of chemotherapy.
regimens that can be effective without resort
to routine susceptibility testing is of special
importance. In all research into short-course
chemotherapy, in developing countries and in
technically advanced countries also, it is impor
tant to study the response of patients with pre
treatment resistant strains, for without such
knowledge, only a partial evaluation of a regi
men will be obtained.
I
i
(j
‘I
I
I
-
I
I
I
I
I
i
I
I
I
SHORT-COURSE CHEMOTHERAPY FOR PULMONARY TUBERCULOSIS
because it was undoubtedly necessary, for re
lapse was common. We have, however, pointed
out for some years (19) that, because the re
lapse rate is very low when good regimens of
chemotherapy are given for an adequate period
of time and under good supervision, long-term
follow up is illogical.
The prospect now is that with short-course
chemotherapy, it will be even easier to ensure
that a patient really does complete a full course
of excellent chemotherapy. Hence, the likeli
hood of relapse will be even less than in the
past. Because a high proportion of relapses arise
within 6 months of stopping chemotherapy, and
most of them within 3 months, the maximal fol
4
4
s
2
o
is
’Y
>y
II
I
low-up that even the greatest caution would in
dicate might be 6 months; however, with in
creasing experience and confidence in short
course chemotherapy, even such a short follow
up would be likely to be abandoned, always
provided that the supervision of chemotherapy
remains efficient. The prospect that we visualize
is that at the end of short-course chemotherapy,
it will be possible to discharge the patient with
advice to present himself again for diagnosis if
respiratory symptoms recur. If it is found that
the cause is a relapse of tuberculosis (or a rein
fection), he can be treated with an appropriate
regimen.
iy
id
.5.
nt
is.
n■3-
ed
ill
on
raroild
ild
?nt
or
if
heaneat
ncc
iraoweatblic
151)
bcrrapy
May
ciety
rent
'd in
p, as
early
tired
I
iI
1
I
I
I
I
I
I
I
|
Conclusion
From the evidence reviewed in this report, there
can he no doubt that it is just a matter of time
before the standard durations of rhcinothcrnpy
in general use, both in the technically advanced
anti developing countries, will be short. Al
though in the light of current knowledge this
is already practicable, there are many prob
lems still to be solved, especially for the devel
oping countries. These include the need to find
regimens that can be applied with uniform suc
cess in areas with a high prevalence of initial
drug resistance, without reference to suscepti
bility tests. There is much to discover concern
ing the role of an initial intensive phase and of
regimens of chemotherapy both intermittent
front the start and in the contimiation phase. Il
Is important to discover how little rifampin Is
needed in short-course chemotherapy and
how best to use that little amount, and to ex
plore alternative regimens that do not include
rifampin at all for use in the many developing
countries where the cost of drug is, and is likely
to remain, an important consideration for many
347
years to come. There remains much to learn
concerning the role of pyrazinamide. The ex
tension of the principle of short-course chemo
therapy to failure regimen chemotherapy also
merits consideration. I he desirability of plan
ning studies on a sound scientific basis, rather
than selecting regimens empirically and with
out consideration of the possible underlying
mechanisms, cannot be overstressed.
Finally, the practical problems involved in
the application of short-course chemotherapy
under program conditions, particularly in de
veloping countries, is a subject of outstanding
importance.
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I
<
i
!
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i
1
1
i
It
nn MOX ARV VVM'KVVUW
short-coursf. cuf.motherapv
stttdy of supervised
' 30.; Menon, N. K.: Madras
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