E-DRUG: XDR-TB: Lancet and BMJ editorials, 7 point plan
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[Both BMJ and Lancet have editorials about the recent XDR-TB outbreak in
South Africa; as a third item, the 7-point plan that WHO and Southern
African countries agreed to on 8 Sept. However, there are no easy
solutions, and the plan is unlikely to have shortterm impact in a health
care system that is already stressed by the HIV pandemic. Looks like XDR-TB
is not treatable (only 3 drugs are sensitive, we should have 4 for a
treatment, and they are not easy to get, and not nice to take). Health
workers might also be at risk, especially if HIV+. Time to put mouth
protection gear on the essential supplies list? Copied as fair use, and
thanks to Andy for spotting. WB]
http://bmj.bmjjournals.com/cgi/content/full/333/7568/559
BMJ 2006;333:559-560 (16 September), doi:10.1136/bmj.38971.587222.AB
Editorial
Extensively drug resistant tuberculosis
A serious wake-up call for global health
Tuberculosis outbreaks in the developed world are newsworthy.1 However, in
the developing world, where deaths from tuberculosis are common, it takes
something exceptional for an outbreak to attract much attention. In
response to a recent report at the 16th international AIDS conference2 and
to increasing South African media reports, the World Health Organization
last week expressed concern about extensively drug resistant tuberculosis
(also referred to as "XDR tuberculosis").3
Among 536 culture confirmed cases of tuberculosis at a rural hospital in
South Africa, 41% were multidrug resistant,2 defined as resistance to
rifampicin and isoniazid (two key first line drugs). This is cause enough
for concern as multidrug resistant tuberculosis has a worse outcome and its
management is very difficult even in high resource settings.4 Even more
alarming was that 53 (24%) of the isolates from multidrug resistant
tuberculosis fulfilled the definition of extensively drug resistant
tuberculosis2-namely, multidrug resistant tuberculosis that is also
resistant to at least three of the six classes of second line agents. Such
tuberculosis is virtually untreatable.
All patients in this outbreak who were tested were HIV infected, and 52 of
the 53 died after a median of just 25 days.2 In 90% of the isolates the
same genetic fingerprint was present, indicating extensive recent
transmission. Fifty six per cent of patients had previously been admitted
to hospital, raising the likelihood of nosocomial transmission.
Outbreaks of infectious diseases are always more newsworthy if their
implications extend beyond the local context, which is the case with
extensively drug resistant tuberculosis. For some years, such strains have
been known to exist in Asia, North and South America, and Europe. In March
this year, the Centers for Disease Control and Prevention and WHO reported
a survey of over 17 000 tuberculosis isolates collected from around the
world between 2000 and 2004.5 Overall, 2% of multidrug resistant strains
were also extensively drug resistant, being most frequently found in
eastern Europe, western Asia, and South Korea. Population based data from
the United States, Latvia, and South Korea showed that 4%, 19%, and 15%
respectively of multidrug resistant strains could be defined as extensively
drug resistant.
The epidemiology and the limited genotypic data currently available2 6
indicate that this is not a single strain, but that extensively drug
resistant strains are likely to have emerged in many different places and
on multiple occasions. Paradoxically, this is both reassuring and alarming.
It is reassuring in that the emergence of extensively drug resistant
tuberculosis in more than one strain suggests that the mutations
responsible are specific for drug resistance rather than reflecting a
fundamental change in behaviour of the organism. This is nevertheless
alarming because it also suggests that extensively drug resistant
tuberculosis probably arises fairly regularly and is already disseminated.
Drug resistance to tuberculosis results largely from poorly managed care
and control of the disease. Poor prescribing practices, low drug quality
(or erratic supply), and suboptimal adherence can all contribute to this.
Bacilli are subject to intense drug selection, and exposure to mono-therapy
predisposes to an accumulation of mutations that confer resistance. Hence
optimal treatment includes four drugs to which the organism is sensitive,
and a single drug should never be added to a failing regimen. In much of
the world, routine culture and sensitivity testing is not available. Thus,
where multidrug resistant tuberculosis emerges, inappropriate treatment
regimens may lead to serial acquisition of resistance mutations, with
potential for emergence of extensively drug resistant tuberculosis.
Widespread use of second line tuberculosis drugs (such as quinolones for
respiratory tract infections) may also contribute to the development of
resistance. Thus, the emergence of extensively drug resistant tuberculosis
should come as no surprise-it was entirely predictable in the context of
poor control practices.
The havoc that institutional transmission of multidrug resistant
tuberculosis can wreak amongst HIV infected people was evident in the US in
the early 1990s.7 The very modest actual rise in the incidence of
tuberculosis that coincided with these outbreaks has now been reversed,8
albeit with extraordinary effort and cost. However, the huge potential for
extensively drug resistant tuberculosis to further undermine control
practices in communities in South Africa and elsewhere in the region is
self evident and would be much more difficult to control. In some
communities with an antenatal prevalence of HIV of 30%, annual notification
rates for tuberculosis have already increased uncontrollably over the past
10 years, reaching 1500/100 000-a rate more than 250 times higher than
rates in the US.9 Extensively drug resistant tuberculosis must now serve as
a serious wake-up call. Although the potential consequences may be most
grave in settings with a high prevalence of tuberculosis and HIV,
extensively drug resistant tuberculosis is nevertheless already a very
serious development in many other parts of the world too.5
What response is needed? The global scale and molecular epidemiology of
extensively drug resistant tuberculosis require urgent assessment, and
laboratory capacity needs to be greatly increased within a network of
sentinel sites. Control practices must be rigorously and effectively
implemented. Increasing cure rates for tuberculosis through directly
observed treatment short course (DOTS) is crucial. Detection rates for
cases of tuberculosis need to be improved, highlighting the need for a new
diagnostic test. Technologies that can determine the presence of drug
resistance at the point of care are needed, as are new drug treatments. The
DOTS-Plus strategy10 for treatment of multidrug resistant tuberculosis
needs to be further developed for areas where the disease is established.
Nosocomial transmission of tuberculosis is probably commonplace in the
developing world, and simple, effective strategies to reduce such
transmission need to be urgently implemented. More fundamentally, the
emergence of extensively drug resistant tuberculosis is a reminder that
tuberculosis needs massive broader commitment: the incompletely funded
Global Plan to Stop TB11 demands political will and financial action.
Stephen D Lawn, senior lecturer in infectious and tropical diseases
Desmond Tutu HIV Centre, Institute of Infectious Disease and Molecular
Medicine, Faculty of Health Sciences, University of Cape Town, Anzio Road,
Observatory 7925, Cape Town, South Africa
(stevelawn@yahoo.co.uk)
Robert Wilkinson, Wellcome Trust senior fellow in clinical tropical
medicine
Institute of Infectious Disease and Molecular Medicine, University of Cape
Town
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Competing interests: None declared.
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