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T-borlr and taint DUnu (1993) 7S. 121-323
O 1994 Longman Group l-ld

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Laboratory Chemicals

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Tubercle and
Lung Disease

Apparatus Products

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Editorial

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Microscopy Stains

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Electrophoresis Reagents

BDH

HPLC Solvents

H. L. Rieder

Tuberculosis Section of the International Union Against Tuberculosis and Lung Disease, Paris. France

Analytical Reagents

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FOR ALL YOUR LABORATORY NFFPq
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BDH Laboratory Supplies. Poole, Doi
trset. BH15 I T D. England. Fax: +44 202 666856: Tel: +44 202 660444. Telex: 41186

The KSCV. a Dutch
non-governmental
orgundation.
encourages research,
promotes expertise,
provides technical
support and
disseminates
knowledge in the field
of tuberculosis

In cooperation with
national and
international
organisations.
KNCV supports
national tuberculosis
programmes in
Tan:ania. Malawi,
Benin. Vietnam,
Kenya. Indonesia
I he Gambia and
Mali,

Royal Netherlands Tuberculosis Association

f KNCV

Due to the increasing workload in international activities,
the KNCV is looking for a candidate for the position of

SENIOR CONSULTANT
Responsibilities

Conditions

- review and monitoring of national
tuberculosis programmes;
- preparation of development plans and
progress reports (including budgets);
- preparation of manuals and guidelines;
- ordering of drugs and other supplies;
- participation in KNCV meetings on technical
and management issues.

- position and salary according to Dutch
regulations:
the successful candidate w ill be based in
Tile Hague. The Netherlands.

Requirements
- MD degree as well as a Public Health degree;
- at least 5 years experience in low-income
countries, preferably in tuberculosis control
and/or management of infectious disease
control programmes;
- communicative skills;
- proficiency in English, and preferably.
French and Spanish as well;
- ability to work in a team.

Drug-resistant tuberculosis: issues in epidemiology and challenges for public
health

The position requires extensive travelling.
Letters ot application including a curriculum
vitae, as well as a date of availability should be
addressed to the Director of KNCV w ithin four
weeks after publication of this advertisement.

For more detailed information
please contact:

J F Brockmans. Director
Phone: + 31 70 354 3K 43
Fax:
+3I7O35X4OO4

KNCV
PO Box 146
2501 CC The Hague
The Netherlands

30 years ago, Canetti warned implicitly
.. Since
optimal chemotherapy of tuberculosis produced by wild
strains reduces the frequency of emergence of resistance
drastically, the general feeling tends to prevail that
resistance has slipped into history ..The medical
community has subsequently learned the hard way. from
experience in the USA2"* and elsewhere.'"6 that Canetti
really meant optimal chemotherapy and not availability

that such 3-drug regimens were able to cure tuberculosis
patients who had had no previous treatment in l(X)% of
cases without creating drug resistance.'1 These warnings
and insights, however, apparently went unheeded, and
isoniazid resistance became a major problem in many
areas of the world.1" Fortunately, the introduction of
rifampicin plus pyrazinamide-containing treatment re­
gimens helped to overcome and successfully treat even
those patients with strains initially resistant to isoniazid
in a very large proportion of cases." The third and most
recent chapter in complacency over well-established
principles has resulted in the emergence of combined
isoniazid-rifampicin resistance, a pattern that currently
marks the irreversible end-point of effective tuberculosis
control in many parts of the world.
Because the risk of tuberculosis following infection
remains lifelong, a crude cross-sectional appraisal of the
prevalence of drug resistance carries little information
on the susceptibility patterns of currently circulating
strains. In the same way that tuberculosis in children is
a sentinel event for tuberculosis transmission in the
community,1’ so the frequency of drug-resistant tuber­
culosis in children reflects a precise evaluation of the
current situation. Susceptibility patterns from cultures
obtained from children with tuberculosis under the age
of 5 years should thus be the most informative source
of knowledge about susceptibility patterns of currently
circulating strains. Unfortunately, such cultures tend to
be the most difficult to obtain. In a recent survey in the
United States, the crude prevalence of any resistance
was 14.2%.* Age-specific resistance adjusted for demo­
graphic characteristics was highest in children below
the age of 15 (21.6%) and decreased with increasing age
to 9.4% among patients aged 65 years and older. This
strongly suggests that the frequency of any resistance
has been increasing dangerously over time in the USA.
In contrast, the crude prevalence of rifampicin-isoniazid
resistance was 3.5%. but lowest (2.0%) in children under
the age of 15 and highest in the 25- to 44-year-old
age group, indicating that the circulation of strains with
combined resistance might still be limited in the USA.

of optimal drugs.
T he British Medical Research Council's streptomycin
trial’ revealed early on what is now abundantly clear:
in each wild strain of tubercle bacilli, approximately 1
out of every 1-10 000 000 organisms is spontaneously
resistant to at least 1 of the known drugs.8 Because
patients with cavitary pulmonary lesions may harbor
10 (XX) (XX)-1 (XX) 000 (XX) tubercle bacilli.' any patient
treated with only a single effective drug has a very high
probability that the drug-resistant mutants are preferen­
tially selected while the susceptible ones are killed
off. Conversely, a patient continuously treated with 2
or more drugs, in concentrations to which the strain is
susceptible, has a very high probability of escaping the
fate of incurable drug-resistant tuberculosis. The role
of chemotherapy is paramount in the production of all
clinically important drug resistance.
Three phases in the development of antituberculosis
chemotherapy might be distinguished. They are charac11 terized by increasing knowledge about principles of
treatment, accompanied by neglect of that knowledge
, by large segments of the medical community. The first
' phase began with the discovery of streptomycin and the
early observation of the iatrogenic creation of strep­
tomycin resistance in clinical trials. An insight into the
harm inflicted by monotherapy was gained in this
period, in the second phase, it was shown that strep­
tomycin resistance could be largely overcome with the
addition of para-aminosalicylic acid and isoniazid, and

Correspondence to: Or Hans L. Rieder MD. MPH. Chief.
Tuberculosis Section of the IUATLD. Reichenbachstr 15. 3004
Bern. Switzerland.

321

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Drug-resistant tuberculosis: issues in epidemiology and challenges for public health

$22 Tubercle and Lung Disease

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To elicit a proper history on previous treatment
among patients with tuberculosis is of crucial impor­
tance, not only to decide on the correct initial regimen
for the individual patient (which should be different
for cases with and cases without a history of previous
treatment), but also to gain better knowledge about
the current circulation of drug-resistant strains. Patients
who claim never to have been treated for tuberculosis
before, but who are found to have drug-resistant tubercle
bacilli, are said to have an initially resistant strain;
patients with a history of previous treatment found to
have a resistant strain are defined as having acquired
resistance? That treatment histories are not always
adequate is indicated in the article by Tahaoglu and
collaborators in this issue of Tubercle and Lung Disease.''
Although the authors do not provide the relevant infor­
mation. it is likely that rifampicin has not been available
on a wide scale for more than 25 years in their country;
yet halt of their patients with any rifampicin resistance
who claimed no previous treatment were over 30 years
of age; almost 30% were over 50. and thus had a high
likelihood of having acquired their infection before
the introduction of rifampicin. Unless one is willing to
postulate an increasing role of exogenous reinfection
tuberculosis with strains resistant to rifampicin, the
only other conclusion must be that history of previous
treatment was inadequately obtained in a considerable
proportion ol patients. Initial resistance represents, to a
varying degree, a contamination of primary resistance
(the result of infection with a resistant strain that pro­
gressed to clinical tuberculosis) with acquired resistance
resulting from undisclosed previous inadequate treatment.
The challenge to the evaluation of a patient's history
lies in minimizing this contamination. Structured, and
perhaps repeat, interviews combined with a thorough
review of all available records enhance the probability
that the difference between initial and primary resistance
becomes sufficiently small to allow meaningful interpre­
tation of the epidemiologic situation of drug resistance
in the community.
A single survey on initial and acquired drug resistance
may help to give an idea of the magnitude of the
problem in the community and may have important
repercussions on the designing of the best regimen for
new cases with tuberculosis and the appropriate regimen
for patients in need of retreatment." Repeat surveys
or a regular surveillance system for initial and acquired
drug resistance on the other hand are an essential public
health management tool, allowing the observation of
deficiencies or improvements in tuberculosis control
over time. The Korean Institute of Tuberculosis and the
Korean National Tuberculosis Association, for example,
have demonstrated with repeat surveys that the level of
both initial and acquired resistance can be reduced with
a properly structured program, encompassing standardized
treatment regimens of high efficacy.14 Very similar
observations have been made in Algeria.15
The World Health Organization has taken up the
gauntlet, declared war on tuberculosis, and developed

a new strategy with two clearly defined objectives, the
first being to attain a large cure ratio among diagnosed
tuberculosis patients, the second to subsequently expand
case-finding.16 These two objectives must take their
place under the hierarchically higher principle which is
to avoid at all costs the introduction of drug resistance
into the community by inadequate intervention, be it
through faulty prescriptions or through failure to gua­
rantee patients' adherence. Situations such as have been
reported, from New York City,2-4 the Philippines,5 or as
are apparently in the making in some areas in Turkey,6
reflect gross negligence on the part of the medical
profession toward the community. Patients have numerous
reasons for becoming non-adherent with treatment,
particularly if the system fails them from the outset.17
and the blame for failure must rest with the health
care system, not the individual patient.
Adequate chemotherapy can clearly prevent the emer­
gence of drug-resistant tubercle bacilli, it is not possible
to assess changes in drug-susceptibility patterns rapidly,
because once a new drug is introduced, it will take
considerable time for drug resistance to manifest itself
in a crude sample of patients. Despite the rapid increase
in Tanzania of tuberculosis associated with the epidemic
of human immunodeficiency virus, the level of initial
isoniazid resistance has not increased over the 15 years
of the existing national program.,s and initial rifampicin
resistance is at present below 1%.1''Antituberculosis
drug resistance is a man-made problem and is thus
amenable to corrective action. A combination of the
best available drugs must be given for patients with
the largest bacterial population (sputum smear-positive
cases), i.e. isoniazid, rifampicin, pyrazinamide plus a
fourth drug (ethambutol or streptomycin), given under
direct observation for the first 2 months or until they
are sputum smear-negative, if they have not converted
by 2 months. Such treatment will overcome even initial
isoniazid resistance in most cases and lower the bacterial
population to such an extent that a self-administered
continuation phase with a fixed 2-drug combination
coupled with regular bacteriological controls will pre­
vent the introduction of drug-resistant strains into the
community and continue to cure most tuberculosis
patients in the world. The potential of introducing drug
resistance, resulting from a failure to adhere to these
principles, will never be overcome, even by the develop­
ment of new drugs.

References
1. Canetti G. The J. Bums Amberson lecture. Present aspects of
bacterial resistance in tuberculosis. Am Rev Respir Dis 1965;
92; 687-703.
2. Frieden T R. Sterling T. Pablos-Mendez A. Kilburn J O. Cauthen
G M. Dooley S W. The emergence of drug-resistant tuberculosis
in New York City. N Engl J Med 1993; 328: 521-526.
3 Iseman M D. Treatment of multidrug-resislanl tuberculosis. N
Engl J Med 1993; 329: 784-791.
4. Bloch A B. Caulhen G M. Onorato I M et al. Nationwide survey
of drug-resistant tuberculosis in the United States. JAMA 1994
271:665-671.

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5. Manalo F. Tan F. Sbarbarr J A. ’seman M D. Community-based
short-course treatment of pulmonary tuberculosis in a developing
nation. Initial report of an eight-month, largely intermittent
regimen in a population with a high prevalence of drug
resistance. Am Rev Respir Dis 1990; 1301-1305.
6. Tahaoglu K, Kizkin O, Karagoz T, Tor M. Partal M. Sadoglu T.
High initial and acquired drug resistance in pulmonary
tuberculosis in Turkey. Tubercle Lung Dis 1994; 75: XXX-Y.
7. British Medical Research Council. Streptomycin treatment of
pulmonary tuberculosis. BMJ 1948; 2: 769-782.
8. Mitchison D A. Drug resistance in mycobacteria. Br Med Bull
1984; 40: 84-90.
9. Crofton J W. Chemotherapy of pulmonary tuberculosis. BMJ
1957; 1: 1610-1614.
10. Kleebcrg H H. Olivier MSA world atlas of initial drug
resistance. 2nd ed. Atlanta: US Depanment of Health and Human
Services. Centers for Disease Control. 1984.
11. Mitchison D A, Nunn A J. Influence of initial drug resistance <on
the response to shon-coursc chemotherapy of pulmonary
tuberculosis. Am Rev Respir Dis 1986; 133.423-430.
12. Bloch A B. Snider D E Jr. How much tuberculosis in children
must we accept? (editorial) Am J Public Health 1986: 76: 14-15.
13. Tuberculosis Programme World Health Organization/

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International Union Against Tuberculosis and Lung Disease.
Guidelines for surveillance of drug resisunce in mberculosis.
Document WHO/TB/94. 178, Geneva: World Health
Organization, 1994.
14. Hong Y P. Kim S J, Kwon D W. Chang S C. Lew W J. Han
Y C. The sixth nationwide tuberculosis prevalence survey in
Korea. 1990. Tubercle Lung Dis 1993: 74: 323-331.
15. Boulahbal F. Khaled S. Tazir M. The interest of follow-up of
resistance of the tubercle bacillus in the evaluation of a
programme. Bull Int Union Tuberc Lung Dis 1989: 64: 23-25.
16. Kochi A. The global tuberculosis situation and the new control
strategy of the World Health Organization (leading article).
Tubercle 1991; 72: 1-6.
17. Brudney K. Dobkin J. Resurgent tuberculosis in New York City.
Human immunodeficiency virus, homelessness, and the decline
of tuberculosis programs. Am Rev Respir Dis 1992;
144: 745-749.
18. Chonde T M. The role of bacteriological services in the National
Tuberculosis and Leprosy Programme in Tanzania. Bull Int
Union Tuberc Lung Dis 1989; 64: 37-39.
19. International Union Against Tuberculosis and Lung Disease. The
Tanzania National Tuberculosis/Leprosy Programme. Progress
report no. 31. Paris. April 1994.
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