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Antituberculosis drug resistance, whose extent in
Europe is not well documented, is a serious threat to tuberculosis
control. The aim of the recent European recommendations on
antituberculosis drug resistance surveillance, issued by a working group
composed by representatives of WHO, IUATLD and of 35 countries of the WHO
European Region, is to enhance standardisation of definitions and methods.
These recommendations emphasise quality assurance and linkage of
laboratory reports of drug susceptibility tests with clinical notification
data. Antituberculosis drug resistance surveillance should become an
integral component of tuberculosis surveillance.
Antituberculosis drug resistance, and in particular
multi-drug resistance (MDR, defined as resistance to isoniazid and
rifampicin with or without resistance to other drugs), is a serious threat
to tuberculosis control. Treatment of MDR tuberculosis patients is long
and costly and its outcome is generally poor. The prolonged contagiousness
of MDR tuberculosis patients may cause outbreaks, particularly among
people with HIV infection. Since drug resistance results from the
selection of resistant mutant bacilli following inadequate treatment, its
presence in a community is an indicator of past or present misuse of
antituberculosis drugs.
In recent years, outbreaks of MDR tuberculosis were
reported in western Europe (1-3) and high levels of drug resistance were
reported in some eastern European countries (4). The extent of
antituberculosis drug resistance in Europe is, however, not well
documented.
A working group consisting of representatives of the
World Health Organization (WHO), of the International Union Against
Tuberculosis and Lung Disease (IUATLD), and of 35 countries of the WHO
European Region, was set up in 1998 to adapt recently published WHO/IUATLD
international recommendations (5) to the European context. The complete
report of the recommendations with the list of all members of the working
group was recently published (6)
Review of existing antituberculosis drug resistance
surveillance systems in Europe
A mail survey was conducted in 1998 among the
coordinators for tuberculosis surveillance in the 51 countries of the WHO
European Region. A total of 47 countries responded. In 32 countries, drug
susceptibility tests (DST) were routinely performed in all tuberculosis
patients. The number of laboratories (public or private) offering DST per
million inhabitants varied widely by country, from 0.1 in the United
Kingdom to 3.2 in Belarus. Most countries (35) had an established national
reference laboratory for mycobacteria, with various responsibilities
including expertise, training, research and quality assurance programmes.
The majority of these laboratories (22) participated in an international
proficiency testing programme, but only a few (11) organised proficiency
testing for other laboratories in their own country.
A total of 39 countries reported having conducted
antituberculosis drug resistance surveillance in the period 1992-1997. In
24 countries, one or more ongoing national systems were organised: 22
systems based on the reporting of susceptibility results to first line
drugs or of drug resistant isolates, and four (in Belgium, Denmark, France
and Portugal) based on the reporting of MDR isolates only. Laboratory
reports were linked with data of the tuberculosis notification in only a
few countries. National surveys were conducted in four countries and
systems not covering the entire country were also organised in 15
countries.
These data, including the general practice of DST in
many European countries, indicate that surveillance of antituberculosis
drug resistance is feasible. There is, however, a need to improve the
standardisation.
Objectives of antituberculosis drug resistance
surveillance
National aims are to evaluate the quality of tuberculosis treatment in
the country, to identify populations at high risk of drug resistance and,
secondarily, to provide indications on the transmission of drug resistant
tuberculosis. Results should help improve tuberculosis treatments and
target interventions for preventing the development and transmission of
drug resistant tuberculosis.
At the European level, drug resistance levels and trends should be
compared across countries and high risk population groups should be
identified, in order to help coordinate tuberculosis control efforts
Methods
In countries where resources allow, laboratories should report drug
susceptibility test (DST) results on all isolates of Mycobacterium
tuberculosis complex. Laboratory reporting of M. tuberculosis
isolates already forms an essential part of the European recommendations
on tuberculosis surveillance (7,8).
Where such a system cannot be organised, representative surveys based
on a suitable sampling scheme, or sentinel surveillance based on a
non-random selection of laboratories or diagnostic centres, are possible
alternatives.
First line drugs tested are isoniazid, rifampicin, ethambutol and
streptomycin. DST should be performed using one of the following methods:
- the proportion method on Löwenstein-Jensen or Middlebrook 7H10
medium
- the radiometric proportion method
- the resistance ratio method
- the absolute concentration method.
Whatever method is adopted, quality assurance (9) is essential,
including an internal quality control, and in countries where several
laboratories are performing DST, a national proficiency testing programme
consisting of periodical exchange of panels of coded strains between
laboratories for blind re-testing. Moreover, an international proficiency
testing programme should be organised between the national reference
laboratory and an external (supranational) laboratory. A European network
of supranational reference laboratories has been established for this
purpose by the WHO and the IUATLD.
Linkage of laboratory reports with clinical data of the notification
should be performed as early as possible, at the local or national level,
based on the date at which the specimen was taken (to identify the
specimen taken at the start of treatment), and the patient’s name or
other identifier (depending on the country’s legal requirements).
Data analysis
The proportion of tuberculosis cases whose bacilli are resistant to a
drug or a combination of drugs at the start of treatment, particularly the
proportion of resistance to isoniazid, to rifampicin or to both drugs
(MDR), are the major indicators of interest. These proportions should be
calculated among all definite cases, i.e., culture-positive, notified over
a calendar year, separately among :
- patients previously treated (by one month or more of curative
treatment with combined antituberculosis drugs, excluding preventive
chemotherapy), providing an indicator for acquired resistance;
- patients never treated (as defined above), providing an indicator
for primary resistance.
Results should be presented by calendar year and analysed by age, sex,
site of disease and sputum smear results. In European countries reporting
high levels of drug resistance in immigrants, results should be analysed
separately according to patient’s geographic origin (place of birth).
Trends in age-specific proportions of resistance among patients never
treated born in the country of diagnosis may provide indications on the
development of drug resistance over time in the country.
MDR surveillance
The surveillance of drug resistance at start of treatment captures only
a subset of MDR tuberculosis cases, since MDR can develop during the
course of treatment (and thus not be present at the time of notification)
and since MDR tuberculosis patients may remain infectious for a long
period without being repeatedly notified. It is, however, possible to
establish a specific surveillance system for MDR tuberculosis, provided
drug susceptibility is tested at least once a year in such patients.
Reporting of MDR isolates may prove feasible, even in countries where
reporting of full DST results cannot yet be organised.
The number of patients with at least one MDR isolate within the
calendar year is used to estimate the annual prevalence of MDR
tuberculosis in the country. In addition to age, sex, birthplace, history
of previous tuberculosis, site of disease and sputum smear results,
additional information on treatment, treatment outcome and HIV status may
be collected. This information should be obtained at least once a year
through linkage with the tuberculosis notification or through a separate
questionnaire
Conclusion
In all countries where resources are available,
antituberculosis drug resistance surveillance should become an integral
component of tuberculosis surveillance. The recently organised European
network of supranational laboratories is expected to facilitate the
implementation of quality assurance. Linkage of laboratory reports on DST
results with clinical data of the notification is a key element for
obtaining valid and representative information on drug resistance. This
will be best achieved by incorporating laboratories into the notification
scheme as recommended.
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