British Medical Bulletin 2005 73-74(1):17-24; doi:10.1093/bmb/ldh047
Published online 14 June 2005
© The Author 2005. Published by Oxford University Press on behalf of The British Council. All rights reserved. For permissions, please e-mail: journals.permissions@oupjournals.org
Multidrug-resistant tuberculosis (MDR-TB): epidemiology, prevention and treatment
L. P. Ormerod
Chest Clinic, Blackburn Royal Infirmary, Blackburn, Lancs BB2 3LR, and Postgraduate School of Medicine and Health, University of Central Lancashire, Preston, Lancs PR1 2HE, UK
Correspondence to: Professor L. P. Ormerod, Chest Clinic, Blackburn Royal Infirmary, Blackburn, Lancs BB2 3LR, UK. E-mail: Peter.Ormerod{at}mail.bhrv.nwest.nhs.uk
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Abstract
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Multidrug-resistant tuberculosis (MDR-TB) is an increasing global
problem, with most cases arising from a mixture of physician
error and patient non-compliance during treatment of susceptible
TB. The extent and burden of MDR-TB varies significantly from
country to country and region to region. As with TB itself,
the overwhelming burden of MDR-TB is in high-burden resource-poor
countries. The diagnosis depends on confirming the drug susceptibility
pattern of isolated organisms, which is often only possible
in resource-rich settings. There should be a strong suspicion
of drug resistance, including MDR-TB, in persons with a history
of prior treatment or in treatment failure cases. Treatment
in developed countries is expensive and involves an individualized
regimen based on drug susceptibility data and use of reserve
drugs. In resource-poor settings a WHO retreatment regimen may
be used, but increasingly the move is to a directly observed
treatment based ‘DOTS-plus’ regimen in a supported
national TB programme. However, even where such treatment is
given, the outcome for patients is significantly worse than
that for fully susceptible TB and has a much higher cost.
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Introduction
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Multidrug-resistant tuberculosis (MDR-TB) is tuberculosis due
to organisms which show high-level resistance to both isoniazid
and rifampicin, with or without resistance to other anti-TB
drugs. The molecular basis of resistance to isoniazid and rifampicin
(and some other drugs) is now largely understood (Table
1).
Resistance to isoniazid is due to mutations at one of two main
sites, in either the
katG or
inhA genes.
1,2 Resistance to rifampicin
is nearly always due to point mutations in the
rpo gene in the
beta subunit of DNA-dependent RNA polymerase.
3 These mutations
are not directly connected, and so separate mutations are required
for organisms to change from a drug-susceptible isolate to MDR-TB.
The accurate diagnosis of MDR-TB requires a positive culture
of
Mycobacterium tuberculosis and drug susceptibility testing.
However, genetic probes which detect drug resistance to rifampicin
with >95% accuracy are very suggestive of MDR-TB; <10%
of rifampicin resistance is monoresistant, and so rifampicin
resistance is a marker for MDR-TB in >90% of cases.
4 Because
of its increasing prevalence MDR-TB is now subdivided into ‘basic’
MDR-TB, with resistance only to rifampicin and isoniazid, and
‘MDR-TB-plus’, with a similar resistance pattern
but with resistance to one or more additional first- and/or
second-line drugs.
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The global extent of the problem
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The extent of the problem of MDR-TB has been examined by the
World Health Organization (WHO) in cross-sectional surveys of
drug resistance in either clinical series or whole-country cohorts.
5 Cross-sectional surveys almost certainly underestimate the burden
and number of cases of MDR-TB because they do not take into
account the numerical burden of TB in the high-burden countries.
When the exercise is repeated with a mathematical modelling
design using drug-resistance estimates and the number of cases
of TB, a more accurate picture of the global MDR-TB burden is
claimed
6 (Table
2).
However, even this has been criticized as underestimating the global burden for the following reason. The stated number of cases per year from a country often includes up to 20% of cases which are actually on ‘retreatment’, i.e. have had a previous course of first-line drugs. The prevalence of MDR-TB in retreatment cases is between 30% and 80% depending on the country. In Gujerat, for example, where there are about 400 000 ‘new’cases annually, if it is assumed that 20% are being ‘retreated’ and there is an MDR-TB rate of 30–80% in retreatment cases, this would include 24 000–64 000 cases of MDR-TB [i.e. (400 000 x 0.2 x (0.3–0.8)]. The estimate of the global burden obtained by modelling could be wrong by a factor of 2–4.
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Why is MDR-TB such a matter of concern?
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Understanding the scientific basis of short-course 6 month chemotherapy
for tuberculosis helps to explain why the loss of sensitivity
to both isoniazid and rifampicin, even without resistance to
additional drugs, has such major effects on outcome. Numerous
controlled trials have shown that a 6 month regimen of rifampicin
and isoniazid, supplemented by pyrazinamide and streptomycin
or ethambutol for the first 2 months, will provide a cure in
>95% of cases if the medication is taken correctly. Such
a regimen also renders infectious cases non-infectious in 2
weeks.
7 Each drug varies in its ability to kill tubercle bacilli
(bactericidal ability), to deal with persistent organisms which
are only occasionally metabolically active (sterilizing ability)
and to prevent the emergence of drug resistance.
7 Isoniazid
is the best bactericidal drug and if monoresistance to this
occurs, treatment with rifampicin and ethambutol has to be extended
for 9–12 months, in addition to 2 months initial pyrazinamide.
8 Rifampicin is the best sterilizing drug, and monoresistance
to this drug requires treatment with isoniazid and ethambutol
for 18 months, with 2 months initial pyrazinamide.
8 Therefore
loss of response to both the main bactericidal drug and the
main sterilizing drug means that patients remain infectious
for much longer, both in the community and in hospital, that
treatment is required for at least 12 and possibly more than
24 months, and that less effective and more toxic second-line
drugs have to be used
8 (Table
3).
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How do we stop creating new cases (prevention)?
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Although some individuals who have not had previous TB treatment
are infected by MDR-TB, this is not the case for most patients.
Many new cases of MDR-TB are created each year by a combination
of physician error and poor patient compliance with treatment,
which turn fully susceptible organisms, or those with less complex
resistance patterns, into MDR-TB. Professor Michael Iseman,
the US ‘guru’ of MDR-TB, has shown that two to four
errors are needed to turn a fully susceptible organism into
a case of MDR-TB.
9 He has ten commandments for physicians: the
first is never to add a single drug to a failing regimen, and
the other nine are for the physician to repeat the first commandment
nine times to make sure that the message is understood!
Support and funding of national TB programmes, in which treatment is given as directly observed therapy (DOT), is essential for all persons with TB if at all possible. Physicians should always use evidence-based treatment guidelines and drugs of proven bio-availability. The WHO recommend a 6 month initial treatment regimen of rifampicin, isoniazid, pyrazinamide and ethambutol for 2 months, followed by rifampicin and isoniazid for 4 months (2RHZE–4RH). If the patient fails treatment (positive cultures or sputum smears in months 5 or 6 of treatment) or relapses, an 8 month retreatment regimen is recommended. This consists of streptomycin, rifampicin, isoniazid, pyrazinamide and ethambutol for 2 months, followed by rifampicin, isoniazid, pyrazinamide and ethambutol for 1 month, followed by rifampicin, isoniazid and ethambutol for 5 months (2SRHZE–1RHZE–5HRE).10
This retreatment schedule is now being re-evaluated, as it may be amplifying the problem. Since patients who fail on or relapse after the initial treatment outlined above have a 10–15-fold increased risk of having MDR-TB,11 the retreatment regimen 2SRHZE–1RHZE–5RHE, which, for 7 of the 8 months, adds only one drug to the previous treatment regimen of 2RHZE–4RH, can be said to be failing the first commandment (see above).
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Treatment and management of cases in developed (resource-rich) settings
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Previous drug treatment is the largest single risk factor for
the presence of MDR-TB. In an international comparative study,
the rates of resistance in England and Wales in 1995 and 1997
were 6.9–7.2% for isoniazid resistance and 0.9–1.1%
for MDR-TB for all patients, but 22–33% and 13–17%,
respectively, for those patients with a history of prior treatment.
5 Therefore physicians should suspect that any patient with a
prior treatment history, or failure during treatment (defined
earlier), could have acquired resistance. Urgent gene probes
for rifampicin resistance should be carried out on material
which is either microscopy or culture positive. The suspicion
of MDR-TB, and the appropriate isolation of suspected cases
until they are either effectively treated or MDR-TB is disproved,
is also important because of the potential for nosocomial outbreaks
if there is inadequate isolation and/or immunocompromised (mainly
HIV-positive) patients are exposed. In the USA, HIV-positive
MDR-TB cases initially had a 100% mortality,
12 but with greater
awareness and earlier diagnosis an improvement in initial survival
rates to up to 50% has been reported.
13 HIV-negative cases in
the USA have had better response rates of between 56%
14 and
69%
15. Nosocomial outbreaks, often in an HIV setting, are well
documented in other countries as well as the USA. An outbreak
in Spain between 1991 and 1995 killed 47 of 48 patients infected,
16 and in two outbreaks in London (Chelsea and Westminster Hospital
and St Thomas’s Hospital
17) the mortality was over 50%
in HIV-positive patients. Algorithms for correct isolation,
which make use of sputum microscopy, a suspicion of MDR-TB and
whether immunocompromised patients are on the same ward, are
available.
18
Principles for managing cases of MDR-TB in developed countries have been set out. Those recommended by the British Thoracic Society8 are similar to those recommended by the European and American Thoracic Societies and the WHO with the International Union Against Tuberculosis and Lung Disease (IUATLD).10 The main features are as follows.
- Such cases should only be treated by physicians experienced in treating complex cases with drug-resistant organisms.
- Infectious cases should only be treated as inpatients and in facilities with full negative pressure ventilation.
- Cases should be managed in close collaboration with national/regional mycobacteriology services utilizing drug susceptibility data.
The drug regimens used will have to be individualized to the patient’s drug resistance profile and will include reserve drugs, as well as any remaining first-line drugs to which the organism remains susceptible (Table 3). A minimum of five drugs (preferably including one injectable form) to which the patient is known, or thought likely, to be susceptible should be used until cultures are negative. After cultures become negative, a minimum of three drugs should be continued for a minimum of a further 9 months.8 The cost per case of such treatment is very high, and has ben conservatively estimated at a minimum of £50000–70000 ($85 000–120 000) in the UK.19
Specialized centres in the USA have suggested that surgical resection under drug cover is an option in selected cases,14 particularly those with unilateral disease. Their experience with this approach, coupled with the availablity and use of fluoroquinolones, particularly moxifloxacin and levofloxacin, in the drug regimen, has improved the survival in such patients.20 The long-term success rate was increased from 56% in the prior cohort14 to 75%, and the TB death rate fell from 22% to 12% as quinolones and surgery were used increasingly. However, these outcomes are still significantly worse than for unselected tuberculosis, which is largely fully drug susceptible and for which death rates of 5% and cure/completion rates of 89% for respiratory disease and 94.4% for all forms of disease in programme conditions are reported.21
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Treatment and management of cases in resource-poor settings
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There have been concerns that the WHO retreatment regimen could
be exacerbating the MDR-TB problem, particularly where there
are failures in the national TB programme (see above). Therefore
the WHO has considered a strategy of supervised treatment of
MDR-TB cases, the so-called ‘DOTS-plus’ programme,
to try to contain the problem. This approach requires a sustainable
and functioning national TB programme, drug availability at
a reasonable cost via the Global TB Alliance and some support
for drug-resistance monitoring either within the country, or
provided outside the country via a partnership with a resource-rich
country. This strategy has been tested in settings with a moderate
MDR-TB problem, but with a good TB programme, wide DOT provision
and a good infrastructure for monitoring and delivery of treatment.
For example, 298 patients in Peru were treated for MDR-TB with a fixed regimen of kanamycin for 3 months, and pyrazinamide, ethambutol, ethionamide and ciprofloxacin for 18 months.22 Twelve per cent died, 48% were cured, 12% defaulted and 28% did not respond. The total cost was $600 000, which was 8% of the cost of the whole national programme. The cost per patient completing treatment was $2381 and the cost per death-adjusted life year (DALY) was $211. Peru is a middle-income country, with a strong TB programme and little HIV at present. Such results and costs may only be applicable if these conditions are met. Where there is a poor TB control programme, even such modest results may not be possible.
Treatment modified by drug susceptibility tests may improve the outcome in such DOTS programmes, provided that there is drug availability and continuity at affordable prices. The WHO is carefully vetting DOTS-plus applications and monitoring them where they are implemented. By amplifying drug resistance without improving outcome, poor treatment can be worse than no treatment.
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What is the future?
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As with all TB, 99% of MDR-TB occurs in high-burden resource-poor
countries. However, increasing globalization and population
mobility will mean an increase in MDR-TB cases in developed
countries. It is clear that without both political will and
money, the number of cases of MDR-TB in both developed and developing
countries will continue to rise. It is also clear that, in the
long term, the costs of inaction are likely to be greater than
those of action.
In the early 1980s TB case numbers were dropping in the USA, including in New York. Therefore regular drug susceptibility testing was stopped and much of the TB control infrastructure was dismantled as a ‘health economy measure’. By 1985 case numbers were starting to rise again, and by 1990 19% of patients had MDR-TB, and in some parts of New York as few as 10% of patients were completing treatment. An expensive and extensive effort was made, which has reduced the incidence of MDR-TB to <5% and has also significantly reduced case numbers, but at a cost of $1 billion in New York alone.
In 1995 the WHO declared tuberculosis to be a global emergency, and in 1998 the Group of Seven signed up to the Amsterdam Declaration to fund the fight against the ‘big three’ infectious killers: TB, HIV and malaria. So far action and money lag well behind the promises. Continuing pressure and resources will be needed to ensure that the DOTS-plus strategy is funded and monitored, but only introduced into national programmes when these are robust.
Accepted for publication May 11, 2005.
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Abstract
Introduction