ProMED-mail |

Published Date: 2007-02-05 18:00:04
Subject: PRO/EDR> Tuberculosis, XDR - worldwide
Archive Number: 20070205.0456

TUBERCULOSIS, XDR - WORLDWIDE
*****************************
A ProMED-mail post
<http://www.promedmail.org>
ProMED-mail, a program of the
International Society for Infectious Diseases
<http://www.isid.org>
Date: Mon, 5 Feb 2007
From: ProMED-mail <promed@promedmail.org>
Source: Emerging Infectious Diseases, in press [edited]
<http://www.cdc.gov/eid/content/13/3/06-1400.htm>
[This paper on XDR-TB, Shah NS, Wright A, Bai G-H, et al: Worldwide
emergence of extensively drug-resistant tuberculosis. Emerg Infect
Dis, in press, is posted in edited form. - Mod.LL]

Multidrug-resistant tuberculosis (MDR TB) has been documented in
nearly 90 countries and regions worldwide (1); 424 203 cases of MDR
TB were estimated to have occurred in 2004, which is 4.3 percent of
all new and previously treated TB cases (2). Treatment for MDR TB
patients requires use of 2nd line drugs (SLDs) for more than 24
months. These drugs are more costly, toxic, and less effective than
1st-line drugs used for routine treatment of TB (3-6). As with other
diseases, resistance to TB drugs results primarily from nonadherence
by patients, incorrect drug prescribing by providers, poor quality
drugs, or erratic supply of drugs (7).
To facilitate treatment of MDR TB in resource-limited countries,
where most TB cases occur (1,2), the WHO and its partners developed
the Green Light Committee, which helps ensure proper use of SLDs, to
prevent further drug resistance (8). Nonetheless, the Green Light
Committee encountered numerous anecdotal reports of MDR TB cases with
resistance to most SLDs. Once a strain has developed resistance to
SLDs, these new TB strains are even more difficult to treat with
existing drugs. Untreated or inadequately treated patients are at
increased risk of spreading their disease in the community, which
could lead to outbreaks in vulnerable populations and widespread
emergence of a lethal, costly epidemic of drug-resistant TB,
reminiscent of the MDR TB outbreaks in the early 1990s (9-13).
Therefore, to determine whether these anecdotal reports were isolated
events, early evidence of an emerging epidemic, or the occurrence of
virtually untreatable forms of drug-resistant TB that had not been
described previously in different parts of the world, we
characterized and quantified the frequency of SLD resistance in
several geographic regions.
We sought to determine the extent to which highly resistant _M.
tuberculosis_ strains have been identified by the international
laboratories that participate in the Network of Supranational
Reference Laboratories (SRLs). The SRL Network consists of 25 highly
proficient TB laboratories on 6 continents. These laboratories
collaborate with national reference laboratories to strengthen
culture and drug-susceptibility testing capacity and to provide
quality control for the WHO/International Union Against Tuberculosis
and Lung Diseases Global Project on Anti-TB Drug Resistance (14).
Methods: From November 2004 through November 2005, we surveyed the
global SRL Network. All SRL directors were invited to participate
during the 2004 annual SRL directors meeting, by individual mailings,
and by personal phone calls. Drug-susceptibility testing results were
requested for _M. tuberculosis_ isolates that had been tested for
resistance to 1st-line drugs and SLDs during 2000-2004. Two SRLs were
not eligible because they did not test for SLDs or tested for less
than 3 classes of SLDs.
The 14 SRLs that provided data for this study support 112 TB
laboratories in 80 countries worldwide (Fig. 1 [for figures and
tables, see original URL - Mod.LL]). SRLs serve as international
reference laboratories to a wide geographic area, performing
drug-susceptibility testing that may not be available in a country
(e.g., for SLDs) and providing quality assurance for 1st-line drug
testing. Most SRLs also serve as the national reference laboratory
for the country in which they are located; they receive varying
proportions of isolates from their own and other countries for
surveillance, clinical diagnosis, and quality assurance. First-line
drug susceptibility testing is performed on all isolates; SLD
susceptibility testing is usually limited to isolates from patients
known or suspected to have drug-resistant TB. Of the 14 participating
SRLs, not all tested for all 6 classes of SLDs, and 4 did not submit
data for the entire survey period.
To best compare data for the study samples with data from the Global
Drug Resistance Survey and other population-based drug-resistance
surveillance, we analyzed 1st-line drug resistance patterns according
to standard methods used in anti-TB-drug resistance surveys (1).
These patterns included any drug resistance, monoresistance
(resistance to only the one specified drug), polyresistance
(resistance to more than 2 1st-line drugs, but which drugs not
specified), and multidrug resistance (resistance to at least
isoniazid (INH) and rifampin (RIF), with or without other drugs).
We defined 6 classes of SLDs as follows: aminoglycosides other than
streptomycin (eg, kanamycin and amikacin), cyclic polypeptides (eg,
capreomycin), fluoroquinolones (eg, ofloxacin, ciprofloxacin,
levofloxacin, and moxifloxacin), thioamides (eg, prothionamide and
ethionamide), serine analogs (eg, cycloserine and terizidone), and
salicylic acid derivatives (eg, para-aminosalicyclic acid).
For this survey we created a consensus definition that incorporates
SLD susceptibility results and is based on international guidelines
for management of drug-resistant TB (15). The mainstay of an MDR TB
treatment regimen consists of one injectible drug (eg, aminoglycoside
or cyclic polypeptide) and a fluoroquinolone; additional drugs from
the remaining classes are added until the total reaches 4-6 drugs to
which the organism is susceptible. If the infecting organism is
resistant to 3 or more SLD classes, designing a treatment regimen
with sufficient drugs that are known to be effective against TB is
difficult. Thus, we defined extensively drug-resistant TB (XDR TB)
isolates as those meeting the criteria established for MDR TB plus
resistance to 3 or more of the 6 classes of SLDs.
SLD resistance patterns were analyzed by geographic region from which
the isolate was submitted to the SRL. Regions were grouped into
epidemiologically meaningful categories on the basis of prevalence of
TB and MDR TB (1,16). This retrospective survey was evaluated and
approved as public health surveillance by the CDC.
Results: We received data for 18 462 patients from 14 (61 percent) of
23 eligible SRLs. We excluded those patients tested before 2000
(n=223), tested after 2004 (n = 14), or tested for resistance to less
than 3 classes of SLDs (n = 535). Our final study sample consisted of
17 690 patients whose isolates were tested for resistance to 3 or
more SLDs during 2000-2004 (Figure 2). Of these, 11 939 (67.5
percent) patients were from the Republic of Korea and 5751 (32.5
percent) were from the remaining SRLs.
[Data on resistance patterns for other than XDR TB can be found in
the original URL. - Mod.LL]
Among patients from the 13 SRLs, resistance to aminoglycosides was
detected in 489 (8.7 percent) isolates and to fluoroquinolones in 298
(5.3 percent) (Table 2). Among isolates from Republic of Korea
patients, resistance was most commonly seen to fluoroquinolones (n
=524, 4.4 percent) and thioamides (n = 259, 2.2 percent).
From all SRLs, isolates that were resistant to at least INH and RIF
(ie, MDR TB; n = 3520) and tested for susceptibility to 3 or more
SLDs were combined for analysis of SLD resistance patterns.
Resistance to one or more class of SLD was present in 1542 (43.8
percent) MDR TB patients (Table 3). The most commonly observed
patterns were resistance to aminoglycosides (n = 630, 18.3 percent),
fluoroquinolones (n = 673, 19.3 percent), and thioamides (n = 605,
19.3 percent).
MDR TB patients whose isolates had further resistance to 3 or more
classes of SLDs were classified as XDR TB (Table 3). A total of 347
(9.9 percent) MDR TB patients met criteria for XDR TB. According to
the revised Global XDR TB Task Force definition
(<http://www.who.int/mediacentre/news/notes/2006/np29/en/index.html>),
234 (6.6 percent) isolates met criteria for XDR TB. Among XDR TB
patients, combination drug-resistance patterns included 90 (3.4
percent) with resistance to aminoglycosides, capreomycin and
fluoroquinolones; 102 (3.4 percent) with resistance to
aminoglycosides, fluoroquinolones, and thioamides; and 94 (3.8
percent) with resistance to fluoroquinolones, thioamides, and
para-aminosalicyclic acid. Nearly half (n = 167, 48.1 percent) of all
XDR TB isolates were resistant to all 4 1st-line drugs, bringing the
total to 7 or more drugs to which the isolate was resistant.
The proportion of XDR TB patients by region is shown in Table 4.
Among the group of industrialized nations, 53 (6.5 percent) MDR TB
patients met criteria for XDR TB. Among patients from Russia and
Eastern Europe, 55 (13.6 percent) MDR TB patients met criteria for
XDR TB. Among patients from the Republic of Korea, 200 (15.4 percent)
MDR TB patients, who accounted for 1.7 percent of all _M.
tuberculosis_ isolates tested, met criteria for XDR TB.
In evaluating the accuracy of SLD susceptibility testing, we found
that 7 (0.1 percent) of 11 426 patients fully susceptible to all
1st-line drugs were resistant to 2 SLDs, and 109 (1 percent) were
resistant to 1 STD. Most of these patients were resistant to fluoroquinolones.
Discussion: This study represents the first assessment of the
widespread occurrence of _M. tuberculosis_ with such extensive drug
resistance as to be nearly untreatable with currently available
drugs, according to international guidelines. We provide data on SLD
resistance for the largest sample of patients to date, including more
than 5000 patients from 47 countries, apart from the Republic of
Korea. The definition of XDR TB in this survey is based on WHO
guidelines for the programmatic management of drug-resistant TB; the
guidelines recommend treatment with 4 or more drugs known to be
effective (15). Therefore, with 3 or less remaining classes of SLDs
to which the infecting organism is susceptible, treatment of these
patients cannot meet international standards. XDR TB has been
detected in all regions of the world. XDR TB strains in this study
also have high rates of resistance to pyrazinamide and ethambutol,
thereby severely limiting the treatment options available.
Analysis of combination SLD resistance patterns is critical for
clinicians and policymakers who design treatment regimens for these
patients. Although limited data exist in the literature about SLD
resistance patterns among MDR TB patients, data from patients
undergoing retreatment for TB in Hong Kong showed that 30 (17
percent) MDR TB isolates were resistant to 3 or more SLDs (17),
thereby meeting criteria for XDR TB. A drug-resistance survey of 447
culture-positive new patients and patients undergoing retreatment in
Abkhazia, Republic of Georgia, found that of 63 MDR TB patients, 2 (3
percent) had additional resistance to 3 or more SLD classes,
consistent with XDR TB (18). More recently, clusters of XDR TB have
been reported in South Africa and Iran (19,20) and have been
associated with HIV infection and rapid and high death rates.
The emergence of new strains of TB that are resistant to SLDs,
especially in settings where TB control programs have become unable
to adequately monitor treatment regimens for MDR TB, is cause for
concern. After the resurgence of TB in industrialized countries
during the 1980s and increased awareness of this global problem,
implementation of strong TB control programs based on the principles
of the global directly observed treatment strategy, short course
(DOTS) improved treatment outcomes and reduced TB and MDR TB
incidence in several countries. This framework for DOTS, promulgated
by WHO, and the pilot MDR TB management projects (DOTS-Plus projects)
became the basis for programmatic management of MDR TB, which has
demonstrated feasibility and effectiveness in low- and middle-income
countries (5,15). However, 2nd-line drugs are available worldwide
outside of well-organized TB-control programs (WHO, unpub. data).
Improper treatment of drug-resistant TB, such as using too few drugs,
relying on poor-quality SLDs, and failing to ensure adherence to
treatment, will likely lead to increases in XDR TB. Strengthening
basic TB programs and infection control measures is crucial for
preventing the selective pressure and environments in which resistant
strains are transmitted from person to person. Additionally, MDR TB
programs that rely on quality-assured and internationally recommended
treatment regimens according to WHO guidelines must be scaled up and
strengthened to stem further SLD resistance and spread of XDR TB. The
Green Light Committee provides a global mechanism to help affected
countries achieve these steps. A commentary published in 2000
predicted that "failure to institute [the] entire DOTS-Plus package
is likely to destroy the last tools available to combat [TB], and may
ultimately result in the victory of the tubercle bacillus over
mankind" (21). XDR TB is an indirect indicator of program failure to
adequately diagnose, prevent, and treat MDR TB.
Documenting the emergence of XDR TB requires a laboratory-based
diagnosis that relies on 1st- and SLD susceptibility testing. A
limitation to accurate detection of XDR TB is that existing tests for
resistance to SLDs are not yet standardized and are less reproducible
than tests for resistance to INH and RIF. Lack of international
recommendations for use, as well as lack of standardization and the
historical unavailability of MDR TB treatment in the public sector,
has limited use of SLD susceptibility testing on a wider scale. As
access to treatment with SLDs increases, standardized methods,
improved diagnostics, and quality assurance for SLD susceptibility
testing are urgently needed to enable reliable testing and design of
appropriate treatment regimens. Although internationally accepted
methods were used by all laboratories, the precise methods and drug
concentrations used varied among participating SRLs (22). Because
these SRLs represent some of the most highly performing laboratories
on 6 continents, results of drug-susceptibility testing are credible
within the context of stated limitations. Initial studies that
standardized different methods for SLD susceptibility testing have
been completed (23-26), but more are needed.
Our study has other limitations. The numbers reported for XDR TB
probably represent an underestimate of the true number of cases
because not all labs and not all national reference laboratories test
for all 6 classes of SLDs. In the absence of test results for all 6
classes of SLDs, we speculate, on the basis of a patient's TB
treatment history and known patterns of drug cross-resistance, that
many other unidentified patients are likely to have had and died from
XDR TB. For example, an MDR TB isolate that is also resistant to an
aminoglycoside and a fluoroquinolone but that has not been tested for
the other SLD classes is very likely to be resistant to an additional
SLD class for the following reasons: INH and ethionamide have a 15-20
percent rate of cross-resistance (27); kanamycin and capreomycin
cross-resistance is common, ranging from 20-60 percent (CDC, unpub.
data) (28,29); and in this study, isolates that were resistant to all
4 1st line drugs as well as an aminoglycoside and a fluoroquinolone
were 70-80 percent likely to be resistant to at least one additional
class of SLD.
Lastly, we had limited clinical information about each patient
because information submitted to each SRL varied and was not reliably
available for inclusion in the analysis. Data about TB treatment
history, patient age and sex, or HIV status are not routinely
collected by all laboratories. Genotyping data were not available to
confirm whether XDR TB isolates are related to W variant of the
Beijing strain, a highly drug-resistant strain of _M. tuberculosis_
responsible for large nosocomial outbreaks in New York in the early 1990s (30).
Despite these limitations, our survey provides the 1st documentation
of the emergence of XDR TB as a serious worldwide public health
threat. XDR TB was identified on 6 continents and is significantly
associated with worse treatment outcomes than MDR TB (31,32). The
emergence of XDR TB, coupled with the increased use of SLDs, suggests
that urgent measures are needed to improve rational use of
quality-assured SLDs. In addition, population-based surveillance for
SLD susceptibility testing is needed to better describe the magnitude
of XDR TB worldwide, track trends, and plan a public health response.
Indeed, the convergence of XDR TB with the HIV epidemic may undermine
gains in HIV prevention and treatment programs and requires urgent
interventions. These interventions include ensuring adherence to
recommended international standards of care aimed at promptly and
reliably diagnosing TB, ensuring adherence to recommended treatment
regimens with demonstrated efficacy, implementing infection control
precautions where patients congregate, and improving laboratories'
capacity to accurately and rapidly detect drug-resistant _M.
tuberculosis_ isolates so that patients can receive effective
treatment (33). Other unmet needs include further development of
international standards for SLD susceptibility testing, new anti-TB
drug regimens, and better diagnostic tests for TB and MDR TB. Such
measures are crucial if future generations are to be protected from
potentially untreatable TB.
--
ProMED-mail
<promed@promedmail.org>
[Reference citations are available at the original URL.
The future epidemiology of these frighteningly drug resistant (FDR is
not used as yet) strains of _M. tuberculosis_, especially in the
HIV-infected cohort in the developing world may put XDR TB much
higher up on the list of emerging diseases in the near future.
XDR TB, in the latest WHO publications, is now defined slightly
differently as mentioned above (an isolate resistant to INH and
rifampin that was also resistant to a fluoroquinolone and to one or
more of the following 3 injectable anti-tuberculosis drugs:
capreomycin, kanamycin and amikacin)
According to the WHO meeting in Oct 2006
(<http://www.who.int/tb/xdr/news_release_17oct06/en/index.html>), a
number of considerations were used in revising the definition, including:
- technical feasibility and reproducibility of testing for SLDs
- efficacy and availability of SLDs
- the need for a definition with significant worse treatment outcome
than MDR-TB alone. - Mod.LL]

See Also