Published Date: 2007-04-03 23:00:03
Subject: PRO/EDR> Tuberculosis, XDR, 2003-2006 - Europe (Germany, Italy)
Archive Number: 20070403.1132

TUBERCULOSIS, XDR, 2003-2006 - EUROPE (GERMANY, ITALY)
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Date: Tue 3 Apr 2007
From: ProMED-mail <promed@promedmail.org>
Source: Emerging Infectious Diseases 2007; 13(5) (in press) [edited]
<http://www.cdc.gov/EID/content/13/5/07-0200.htm>

Twenty-three countries have reported one or more
cases of extensively drug-resistant tuberculosis
(XDR TB) (1); however, information about XDR TB
is still incomplete. In particular, the response
of XDR TB to treatment in countries with low
incidence is not known. We compared mortality
rates from XDR TB with those from
multidrug-resistant (MDR) TB.
We analyzed data from all culture-confirmed TB
cases diagnosed during 2003-2006 by the TB
clinical reference centers in Italy (Sondalo,
Milan, Rome) and Germany (Borstel, Grosshansdorf,
Bad-Lippspringe) and reviewed original clinical
records. Drug susceptibility testing for 1st and
2nd line anti-TB drugs was performed according to
World Health Organization (WHO) recommendations
by quality-assured laboratories and retested at
WHO Supranational Reference Laboratories
(Rome/Milan; Borstel) (2-4).
XDR TB was defined as resistance to at least
rifampin and isoniazid (MDR TB definition) in
addition to any fluoroquinolone and one or more
of 3 injectable anti-TB drugs (capreomycin,
kanamycin, amikacin) (3). Characteristics of MDR
TB and XDR TB cases were compared by chi-square
test (categorical variables), Student t test
(admission days), and Kaplan-Maier curve (sputum
smear, culture conversion), where appropriate.
Of 2888 culture-positive TB cases analyzed (Italy
2140, Germany 748), 126 (4.4 percent) were MDR
(Italy 83, Germany 43) and 11 (0.4 percent) were
XDR (Italy 8, Germany 3). We estimate that the TB
cases analyzed represent 24 percent of
culture-positive cases reported in Italy (69.7
percent of MDR) and 4.2 percent of those reported
in Germany (12.6 percent of MDR). XDR TB was
diagnosed in each year of the study. All 11 XDR
TB patients were receiving retreatment, and of
the 126 MDR TB patients, 74 (58.7 percent) were
receiving retreatment. All XDR TB patients were
HIV seronegative; and of 109 MDR TB patients
tested for HIV, 10 (9.2 percent) were HIV
seropositive. Details about previous treatment
regimens, drug resistance, and duration of
treatment of XDR TB patients are summarized in
the Appendix Table [see original URL - Mod.LL].
XDR TB patients were significantly more likely
than MDR TB patients to be resistant to all
1st-line drugs (8/11 vs. 36/126, p less then
0.005); 2 of these patients were resistant to all
tested drugs (Appendix Table).
In Germany, non-nationals accounted for 95.3
percent (41/43) of MDR TB cases and 100 percent
(3 of 3) of XDR TB cases (all from the former
Soviet Union); in Italy, they accounted for 72.3
percent (60/83) and 50 percent (4/8),
respectively (p less than 0.001). Of 126 patients
with MDR, 8 (6.3 percent) died, 45 (35.7 percent)
were treated successfully, 67 (53.2 percent) were
still receiving treatment (after achieving
bacteriologic conversion, radiologic and clinical
improvement, or both) and 6 defaulted (4.8
percent). Of 11 patients with XDR, 4 (36.4
percent) died and 7 (63.6 percent) were still
receiving treatment. Compared with MDR TB
patients, XDR TB patients had a 5-fold higher
risk for death (relative risk 5.45; 95 percent
confidence interval 1.95-15.27; p less than 0.01)
and required longer hospitalization (mean � SD
241.2 � 177.0 vs. 99.1 � 85.9 days; p less than
0.001) and longer treatment durations (30.3 �
29.4 vs. 15.0 � 23.8 months; p less than 0.05).
Smear and culture conversions were observed for 4
XDR TB patients compared with 102 MDR TB patients
(smear median 110 vs. 41 days; culture median
97.5 vs. 58 days, respectively); time to smear
and culture conversion significantly differed
between the 2 groups (p less than 0.01). A
higher percentage of XDR TB than MDR TB patients
had received previous anti-TB treatment (100
percent [11/11] vs. 59 percent [74/126],
respectively, p<0.01) and were >45 years of age
(64 percent [7/11] and 23 percent [29/126],
respectively, p<0.01). Radiologic patterns of the
thorax did not differ between XDR TB and MDR TB
patients. In the overall sample, the only
variable significantly associated with death
(other than XDR TB status) was immigrant status
(p less than 0.01). The association between XDR
TB status and risk for death remained significant
after stratification by immigrant status (p less
than 0.05).
Our findings suggest that mismanagement of TB
cases plays a major role in emergence of the
problem in Europe (along with suboptimal
infection control in congregate settings) (5),
while in high HIV-prevalence settings (such as
South Africa) XDR TB was mainly observed in
patients never treated previously (6). Mortality
rates among MDR TB patients treated in reference
centers (6.3 percent) were lower than the rate
observed in a previous study in general hospitals
in Italy (8.7 percent) (5), although a proportion
of our MDR TB patients are still completing
treatment. This difference in rates is probably
due to better management of MDR in the reference
centers. Because of the high proportion of XDR TB
patients still receiving treatment, further
follow-up is necessary to assess potential for
cure. The clinical relevance of resistance to all
1st-line drugs or other factors (such as, delayed
or inadequate treatment, or suboptimal
observation of drug intake) as major determinants
of death needs further evaluation. The appearance
of XDR TB in western Europe confirms that poor
management and poor infection control in
congregate settings exist and that new rapid
diagnostic tests and new drugs are urgently
needed.
References:
1. Migliori GB, Loddenkemper R, Blasi F,
Raviglione MC: 125 years after Robert Koch's
discovery of the tubercle bacillus: the new
XDR-TB threat. Is "science" enough to tackle the
epidemic? Eur Respir J. 2007;29: 423-7.
2. Laszlo A, Rahman M, Espinal M, et al: Quality
assurance programme for drug susceptibility
testing of _Mycobacterium tuberculosis_ in the
WHO/IUATLD Supranational Laboratory Network: five
rounds of proficiency testing 1994-1998. Int J
Tuberc Lung Dis. 2002;6: 748-56.
3. World Health Organization: Extensively
drug-resistant tuberculosis (XDR TB):
recommendations for prevention and control. Wkly
Epidemiol Rec. 2006;81: 430-2.
4. Shah NS, Wright A, Bai G-H, et al: Worldwide
emergence of extensively drug-resistant
tuberculosis. Emerg Infect Dis. 2007;13: 380-7.
5. Ferrara G, Richeldi L, Bugiani M, et al:
Management of multidrug-resistant tuberculosis in
Italy. Int J Tuberc Lung Dis. 2005;9: 507-13.
6. Gandhi NR, Moll A, Sturm AW, et al:
Extensively drug-resistant tuberculosis as a
cause of death in patients co-infected with
tuberculosis and HIV in a rural area of South
Africa. Lancet. 2006;368: 1575-80.
[Byline: Migliori GB, Ortmann J, Girardi E, et al]
--
ProMED-mail
<promed@promedmail.org>
[As noted in this posting, the XDR tuberculosis
cases found were related to inadequate previous
therapy, not from primary transmission of the XDR
strain. - Mod.LL]

See Also

Tuberculosis, XDR - South Africa (07): Eastern Cape 20070326.1044
Tuberculosis, XDR, 1993-2006 - USA 20070322.1005
Tuberculosis, XDR, 1991-2003 - Spain 20070302.0738
Tuberculosis, XDR - worldwide 20070205.0456
Tuberculosis, XDR - South Africa: interventions 20070126.0349
Tuberculosis, extensively drug-resistant - Canada (ON) (02) 20070125.0340
Tuberculosis, extensively drug-resistant - Canada (ON) 20070124.0318
2006
----
Tuberculosis, multiresistant - Hungary 20061110.3233
Tuberculosis, multiresistant - South Africa (KN) (04): nationwide 20061019.3003
Tuberculosis, multi-drug resistant - South Africa (KN) 20060904.2514
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