Research articles

Multidrug-resistant tuberculosis in Uzbekistan: results

of a nationwide survey, 2010 to 2011
D J Ulmasova1, G Uzakova2, M N Tillyashayhov3, L Turaev4 , W van Gemert5, H Hoffmann6, M Zignol5, K Kremer 7, T Gombogaram8,
J Gadoev8, P du Cros9, N Muslimova4 , A Jalolov2, A Dadu7, P de Colombani7, O Telnov10, A Slizkiy10, B Kholikulov1, M Dara7,
D Falzon (falzond@who.int)5
1. Republican DOTS Centre, Tashkent, Uzbekistan
2. Programme Implementation Unit, The Global Fund to Fight AIDS, TB and Malaria (TGF), Tashkent, Uzbekistan
3. National Institute of TB and Pulmonology, Tashkent, Uzbekistan
4. National Reference Laboratory (NRL), Tashkent, Uzbekistan
5. World Health Organization, Global TB Programme, Geneva, Switzerland
6. Supranational TB Reference Laboratory (SRL Gauting), IML red GmbH, synlab Bayern, Asklepios Fachkliniken München-
Gauting, Germany
7. World Health Organization Regional Office for Europe, Copenhagen, Denmark
8. World Health Organization Country Office, Tashkent, Uzbekistan
9. Médecins Sans Frontières (MSF), London, United Kingdom
10. Médecins Sans Frontières (MSF), Tashkent/Nukus, Uzbekistan

Citation style for this article:

Ulmasova DJ, Uzakova G, Tillyashayhov MN, Turaev L, van Gemert W, Hoffmann H, Zignol M, Kremer K, Gombogaram T, Gadoev J, du Cros P, Muslimova N, Jalolov A,
Dadu A, de Colombani P, Telnov O, Slizkiy A, Kholikulov B, Dara M, Falzon D. Multidrug-resistant tuberculosis in Uzbekistan: results of a nationwide survey, 2010 to
2011. Euro Surveill. 2013;18(42):pii=20609. Available online: http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=20609

Article submitted on 30 January 2013 / published on 17 October 2013

Multidrug-resistant tuberculosis (MDR-TB; resistance more, employing drugs which are difficult to procure
to at least rifampicin and isoniazid) is a global public and more toxic and expensive than those used to treat
health concern. In 2010–2011, Uzbekistan, in central drug-susceptible forms of the disease [2-4].
Asia, conducted its first countrywide survey to deter-
mine the prevalence of MDR-TB among TB patients. Over the last decade, countries of the former Soviet
The proportion of MDR-TB among new and previously Union have reported the highest levels of MDR-TB infec-
treated TB patients throughout the country was meas- tion among TB patients [5,6]. In one of these countries,
ured and risk factors for MDR-TB explored. A total of Uzbekistan, in central Asia, two sub-national studies
1,037 patients were included. MDR-TB was detected in performed since 2001 have detected MDR-TB in 13–15%
165 treatment-naïve (23.2%; 95% confidence interval of new TB patients and in 40–60% of previously treated
(CI) 17.8%–29.5%) and 207 previously treated (62.0%; patients [7,8]. In 2011 Uzbekistan had a population of
95% CI: 52.5%–70.7%) patients. In 5.3% (95% CI: 29 million inhabitants and a Gross National Income of
3.1%–8.4%) of MDR-TB cases, resistance to fluoroqui- EUR 1,137 per capita, making it a lower middle income
nolones and second-line injectable drugs (extensively country [9]. The state Republican DOTS Centre (RDC)
drug resistant TB; XDR-TB) was detected. MDR-TB in the capital city Tashkent is responsible for the TB
was significantly associated with age under 45 years control services in all of the country’s 14 administra-
(adjusted odds ratio: 2.24; 95% CI: 1.45–3.45), impris- tive divisions, including the Autonomous Republic of
onment (1.93; 95% CI: 1.01–3.70), previous treat- Karakalpakstan. In 2011, Uzbekistan reported 15,913
ment (4.45; 95% CI: 2.66–7.43), and not owning a TB cases, 28% of whom were culture-confirmed and
home (1.79; 95% CI: 1.01–3.16). MDR-TB estimates for 50% of these also had results for drug-susceptibility
Uzbekistan are among the highest reported in former testing (DST) to both isoniazid and rifampicin [10].
Soviet Union countries. Efforts to diagnose, treat and
prevent spread of MDR-TB need scaling up. As estimates from subnational surveys may not nec-
essarily be generalisable to a whole country, the RDC
Introduction conducted the first nationally-representative study of
Tuberculosis (TB) remains a major challenge to pub- anti-TB drug resistance based on a countrywide sam-
lic health worldwide. In 2011, the World Health ple of TB patients in Uzbekistan. The estimate from
Organization (WHO) estimated that there were about this study would enable the national TB control pro-
12 million prevalent TB cases globally of whom about gramme and its partners, particularly Médecins Sans
630,000 were infected with strains resistant to at Frontières (MSF) and the Global Fund against AIDS, TB
least both rifampicin and isoniazid (multidrug-resist- and Malaria (TGF), to better target their efforts and
ant TB; MDR-TB) [1]. Inadequate use of anti-TB drugs resources and understand the different risk factors
to treat drug-susceptible TB favours the emergence associated with MDR-TB, including co-infection with
of drug resistance. MDR-TB patients require combina- human immunodeficiency virus (HIV). In this article
tion treatment which commonly lasts 20 months or we describe the main outcomes of the survey and we

www.eurosurveillance.org 1
discuss their implications for the continued surveil- region was reached. Cases were excluded if they were
lance, prevention, diagnosis, treatment and scale-up sputum smear-positive at the end of a re-treatment
of MDR-TB programme management in the country. We regimen, or if sputum was collected 10 days or more
believe the findings of this study are relevant beyond into the current course of treatment, or if they did not
the country’s borders as they add to the current knowl- or could not consent, or if they were not smear-posi-
edge base about the burden of MDR-TB in eastern tive, or were later found to be infected with strains
Europe [11], a phenomenon that has a sizeable impact other than Mycobacterium tuberculosis complex. All
upon the epidemiology of TB in European Union coun- patients were offered HIV testing and counselling. A
tries as a result of migration and population move- standardised information form was used to collect data
ments [12]. (Figure 1). Information was cross-checked with patient
records when available and then transferred from the
Methods completed forms onto two electronic registers housed
at the National TB Reference Laboratory (NRL) and the
Sampling, recruitment and statistical analysis RDC and then merged.
The objectives of the study were to estimate (i) the
proportion of new (TB treatment-naïve) and previously The proportions used to describe the first-line drug
treated (four weeks of treatment or more) TB cases resistance patterns among new and previously treated
infected with MDR-TB strains; (ii) the proportion of cases tested were weighted by the TB cases notified
MDR-TB cases infected with strains additionally resist- in each administrative region in 2011. Univariate analy-
ant to fluoroquinolones and second-line injectable sis was used to study relationships between risk fac-
drugs (extensively drug-resistant TB; XDR-TB [13]); and tors and MDR-TB, and associations with p<0.10 were
(iii) the magnitude of association between risk factors further analysed using multivariable logistic regres-
and infection with MDR-TB strains. Definitions used sion. Effects were expressed as crude and adjusted
for previous treatment history and resistance patterns odds ratios and p<0.05 was considered statistically
were as recommended by WHO [14]. A detailed sur- significant. The associations were further explored by
vey protocol including associated costs was prepared imputing missing values and by using random-effects
according to these WHO guidelines and approved by modelling. Statistical analysis was performed using
the National Ethics Committee of the Ministry of Health. STATA SE/12.1 (StataCorp LP, TX, USA) and the ggplot2
package running in the R environment (R 3.0.1; [15])
The survey was carried out using non-invasive tech- was used to produce all graphics.
niques employed in the course of regular investiga-
tion of any patient with presumptive TB. Patients were Laboratory procedures
asked to sign their informed consent for participation. The country is covered by a network of over 320 lab-
Confidentiality was respected during collection and oratories which perform direct microscopy of spu-
storage of clinical data. tum at primary healthcare level. Two laboratories
in the country can perform both culture and DST for
The sampling frame consisted of pulmonary TB first- and second-line anti-TB drugs reliably: the NRL
patients diagnosed at public healthcare facilities in in Tashkent and the laboratory at the TB hospital in
all administrative regions of Uzbekistan. All patients Nukus, Karakalpakstan. Both laboratories perform DST
diagnosed with positive sputum smear on microscopy on solid and liquid media, line-probe assay (LPA) and
were eligible for inclusion. The sample size was cal- participate in quality assurance programmes with the
culated on the basis of new sputum-smear TB cases WHO supranational TB reference laboratories (SRL) in
notified in the country in 2008 (n=5,234), an expected Borstel and Gauting, Germany. Laboratory capacity
prevalence of 15% MDR-TB among new cases (based to detect drug-resistance has increased substantially
on the most recent survey in Tashkent) [8], an absolute in Uzbekistan since 2008 and more than a thousand
precision of 2.5% of the expected prevalence, and a MDR-TB cases are now detected each year in the coun-
95% confidence level. A total of 818 new cases were try [1].
thus required, inclusive of a 20% margin to cover for
expected losses. As all previously treated sputum- For the purposes of the survey, 3 to 5 ml of sputum were
smear positive TB cases presenting to healthcare facili- collected from each study participant. If inspection of
ties during the survey period were also to be recruited, the specimen showed saliva or insufficient quantity,
1,174 study subjects were targeted in total. the patient was asked to provide a morning sputum the
following day. Patients whose sputum was found to be
The survey was carried out over the 12 months until smear–positive at the district or regional level labo-
June 2011 using 100% sampling. The national sample ratories using bright-field microscopy after hot Ziehl-
was split among the different regions (Oblasts) accord- Neelsen staining, were requested to provide a second
ing to the TB notification patterns from 2008. During sputum specimen. The second specimens were stored
the study period, eligible patients were referred from between 4°C and 12°C for a maximum of six days
the districts to the regional-level TB dispensaries for before shipment to the NRL in Tashkent where they
enrolment, collection of sputa for the study and inter- were rechecked using fluorescence microscopy after
viewing until the expected number of cases from each Auramine O staining. Specimens from Karakalpakstan

2 www.eurosurveillance.org
Figure 1
Clinical Information Forma, nationwide study on drug-resistant tuberculosis, Uzbekistan, 2010–2011

1. DRS code
2. Region
3. District
4. Patient surname
Part 1. Details of
5. Patient name
the TB patient
6. Date of birth day/month/year
7. Sex male/female
8. Date of registration in the TB register day/month/year
9. HIV status
No (if not, ask questions 11-16)
10. Have you ever been treated for TB previously?
Yes (if yes, go to question 17)
11. How long have you been sick?
12. Did you have the same symptoms prior to this episode?
Did you have other symptoms of lung disease prior to
13.
Part 2. Clinical this episode (haemoptysis, chest pain, cough)?
information 14. Did you have sputum examination prior to this episode?
Did you ever take anti-TB drugs for more than one
15.
month?
16. Did you ever have injections for more than one month?
Did the patient remember previous treatment for TB
17.
after these questions?
After checking through the available medical files have No
18. you discovered that the patient was registered for TB Yes
treatment before? (If yes, number in the TB03 register)
Final decision taking into consideration the answers
No (go to question 21)
Part 3. Medical of the patient on the standardised clinical history: Has
19. Yes (go to question 20)
records and the the patient been previously treated for TB for more
Unknown
final decision on than one month?
previous anti-TB Cured/treatment completed
treatment Failed new patient regimen using first-line drugs only
Failed retreatment regimen using first line drugs only
20. If yes, what was the outcome of previous treatment?
Failed regimen including second-line drugs
Defaulted
Other
Uzbekistan
21. Country of birth?
Abroad (specify the country)
Higher (University)
Middle special (Technical college)
22. Your education (completed)?
Secondary
Primary or lower
House (apartment) owned
House (apartment) rented
23. Your housing conditions?
Dormitory
Homeless
24. How many people share your house? Specify the number of persons
student
unemployed / looking for a job
25. Your occupation? invalid
retired
occupation (specify)
Part 4. Social No
26. Have you been in prison in the last 10 years?
determinants Yes (specify the number of years)
No
27. Have you travelled abroad for work in the last 2 years?
Yes (specify the country)
never
rarely
28. How often do you take alcohol?
sometimes
often
No
29. Have you been smoking daily during the past 5 years?
Yes
No
30. Have you taken any illicit drugs during the last month? Yes
If yes, which drug:
No
Yes
31. Have you been in hospital in the last 10 years?
If yes,
i. for how many weeks
ii. which hospital

Name of the responsible officer

__________________________

Date of completion ___/___/_____

a
Translated from Russian.

www.eurosurveillance.org 3
Figure 2
Flowchart of patients included in the nationwide study on drug-resistant tuberculosis, Uzbekistan, 2010–2011

Cases recruited in the

survey (n=1,295)
Ineligible (n=148):
54 smear negative/unknown
49 tested during treatment
30 ‘chronics’
13 culture negative
2 not Mycobacterium tuberculosis

Eligible survey population

(n=1,147)

No DST results available (n=110):

95 LPA result positive; no DSTa
15 no LPA or DSTa results

Eligible survey population

with DSTa data available
(n=1,037)

Unknown previous treatment history

(n=0)

DST: drug-susceptibility testing; LPA: line-probe assay.

a
For isoniazid and rifampicin (phenotypic).

and Khorezm were processed identically at the Nukus M. tuberculosis complex and detection of resistance-
laboratory. Patients were considered smear-positive conferring mutations to isoniazid and rifampicin. Each
if at least one of two sputum specimens examined isolate, for which the results of genetic and pheno-
yielded ≥ 1 acid fast bacillus per 100 high power fields typic DST assays differed, was transferred to the SRL
[16]. All specimens were processed using a modified for determination of the final susceptibility pattern. If
Petroff-method or NALC-NaOH procedures and inocu- genetic mutations known to be associated with drug
lated in both Löwenstein-Jensen medium and myco- resistance were identified using Genotype MTBDRplus,
bacteria growth indicator tube (MGIT) liquid medium the isolate was considered resistant to the respective
(Becton-Dickinson, New Jersey, United States). DST drug. If no mutation was identified, the SRL repeated
was performed using the method of proportion [17] and the DST in liquid medium and this result was consid-
the MGIT system. Susceptibility patterns to isoniazid, ered definitive.
rifampicin, ethambutol and streptomycin were deter-
mined for all cases. If the growth of isolates allowed, Quality control of DST was provided through (i) inter-
MDR-TB strains were additionally tested for ofloxacin, nal control according to EN DIN 58943-8:2009-04,
a second-line aminoglycoside (amikacin and/or kana- (ii) four monitoring visits by an expert from the SRL
mycin) and capreomycin. Positive cultures were tested München-Gauting (co-author H.H.), (iii) annual exter-
using Genotype MTBDRplus (1st generation, Hain nal quality assessment by testing a panel of 30 WHO
Lifescience, Nehren, Germany) for identification of control strains (provided by the Institute of Tropical

4 www.eurosurveillance.org
Table 1A
Characteristics of the study population, completeness of drug-susceptibility testing data and associations with multidrug-
resistant tuberculosis in the nationwide study on drug-resistant tuberculosis, Uzbekistan, 2010–2011 (n=1,037)

Missing
data for Adjusted
Association Odds ratios
Previously DSTa to odds ratios
New Total with for MDR-TB,
treated isoniazid MDR-TB, for MDR-TB,
Characteristic missingness, univariate
and % multivariable
Chi-square, analysis
rifampicin regression
P-value (95%CIs)
(95%CIs)
n % n % n %b n %
Sex
Female 364 72 141 28 505 44 53 10 35 Reference NA
0.85, P=0.36
Male 418 65 224 35 642 56 57 9 36 1.06 (0.82-1.36) NA
Age
>44 years 332 72 130 28 462 40 43 9 26 Reference Reference
0.07, P=0.79
<45 years 450 66 235 34 685 60 67 10 43 2.11 (1.61-2.76) 2.24 (1.45-3.45)
Administrative region/city
Andijan 81 82 18 18 99 9 2 2 30 Reference Reference
Bukhara 22 55 18 45 40 3 0 0 40 1.56 (0.73-3.37) 1.27 (1.10-1.46)
Djizak 26 62 16 38 42 4 1 2 37 1.35 (0.63-2.92) 1.05 (0.80-1.39)
Fergana 109 87 16 13 125 11 16 13 28 0.89 (0.49-1.63) 1.07 (0.91-1.27)
Karakalpakstan 61 46 71 54 132 12 19 14 62 3.82 (2.14-6.80) 2.33 (1.85-2.94)
Kashkadarya 59 70 25 30 84 7 35 42 51 2.44 (1.20-4.96) 2.17 (1.60-2.95)
Khorezm 31 65 17 35 48 4 6 13 185.9, 33 1.17 (0.54-2.54) 0.73 (0.60-0.89)
Namangan 63 73 23 27 86 7 9 10 P=0.00 32 1.13 (0.59-2.15) 1.08 (0.87-1.33)
Navoiy 17 44 22 56 39 3 1 3 42 1.71 (0.78-3.71) 0.71 (0.52-0.97)
Samarkand 96 77 28 23 124 11 1 1 20 0.57 (0.30-1.06) 0.46 (0.35-0.61)
Surhadarya 43 81 10 19 53 5 17 32 17 0.47 (0.18-1.25) 0.44 (0.34-0.56)
Syrdarya 32 68 15 32 47 4 0 0 36 1.33 (0.64-2.78) 1.68 (1.39-2.04)
Tashkent city 67 54 57 46 124 11 3 2 38 1.44 (0.81-2.54) 0.93 (0.79-1.09)
Tashkent region 75 72 29 28 104 9 0 0 38 1.41 (0.78-2.53) 1.19 (0.95-1.50)
Origin
Uzbek 764 68 360 32 1124 98 108 10 36 Reference NA
0.02, P=0.88
Foreign 18 78 5 22 23 2 2 9 29 0.71 (0.27-1.85) NA
Education
Higher 242 66 125 34 367 32 24 7 38 Reference NA
5.79, P=0.02
Up to secondary 540 69 240 31 780 68 86 11 35 0.85 (0.65-1.10) NA
Home-owner
No 102 63 59 37 161 14 22 14 43 Reference Reference
3.58, P=0.06
Yes 680 69 306 31 986 86 88 9 35 0.70 (0.49-1.01) 0.56 (0.32-0.99)
Occupation
Not employed 565 66 295 34 860 75 86 10 38 Reference Reference
Employed/ 0.67, P=0.41
217 76 70 24 287 25 24 8 30 0.72 (0.53-0.97) 0.67 (0.37-1.22)
Student
In prison in the previous 10 years
No 759 70 319 30 1078 94 106 10 34 Reference Reference
1.22, P=0.27
Yes 23 33 46 67 69 6 4 6 60 2.88 (1.72-4.81) 1.93 (1.01-3.70)
Hospitalised in the last 10 years
No 594 91 61 9 655 57 58 9 26 Reference Reference
0.95, P=0.33
Yes 188 38 304 62 492 43 52 11 49 2.77 (2.14-3.60) 1.29 (0.78-2.15)

CI: confidence interval; DST: drug-susceptibility testing; MDR-TB: multidrug-resistant tuberculosis; NA: not applicable.
a
For isoniazid and rifampicin.
b
For the column.

www.eurosurveillance.org 5
Table 1B
Characteristics of the study population, completeness of drug-susceptibility testing data and associations with multidrug-
resistant tuberculosis in the nationwide study on drug-resistant tuberculosis, Uzbekistan, 2010–2011 (n=1,037)

Missing
data for Adjusted
Association Odds ratios
Previously DSTa to odds ratios
New Total with for MDR-TB,
treated isoniazid MDR-TB, for MDR-TB,
Characteristic missingness, univariate
and % multivariable
Chi-square, analysis
rifampicin regression
P-value (95%CIs)
(95%CIs)
n % n % n %b n %
Worked abroad in the last 2 years
No 705 68 328 32 1033 90 95 9 36 Reference NA
1.86, P=0.17
Yes 77 68 37 32 114 10 15 13 37 1.07 (0.70-1.65) NA
Uses alcohol
Never 480 70 206 30 686 60 67 10 36 Reference NA
0.06, P=0.80
Yes 302 66 159 34 461 40 43 9 36 1.00 (0.77-1.30) NA
Regular smoker
No 640 71 268 29 908 79 99 11 35 Reference NA
8.65, P=0.00
Yes 142 59 97 41 239 21 11 5 38 1.13 (0.84-1.54) NA
HIV infection
No 707 68 334 32 1041 91 106 10 32 Reference NA
Yes 18 55 15 45 33 3 2 6 42 1.45 (0.71-2.99) NA
4.85, P=0.09
Unknown 57 78 16 22 73 6 2 3 27 0.69 (0.41-1.18) NA
Previously treated for TB
No 782 68 77 10 23 Reference Reference
0.19, P=0.66
Yes 365 32 33 9 62 5.42 (4.09-7.19) 4.45 (2.66-7.43)

CI: confidence interval; DST: drug-susceptibility testing; HIV: human immunodeficiency virus; MDR-TB: multidrug-resistant tuberculosis;
NA: not applicable.
a
For isoniazid and rifampicin.
b
For the column.

Medicine in Antwerp, Belgium), and (iv) re-checking by 60%), native Uzbeks (1,124; 98%) and had not been
the SRL of a randomly-selected sample of all isolates previously treated (782; 68%). Thirty-two percent of
collected for the survey. A total of 90 MDR-TB isolates, cases (367) had attended university or a technical col-
104 fully susceptible ones, 102 isoniazid-resistant lege, 86% (986) lived in a home they owned, 25% (287)
and rifampicin-susceptible ones, and two isoniazid- were employed or studying, 6% (69) had a history of
susceptible and rifampicin-resistant were rechecked imprisonment and 43% (492) had been hospitalised in
using WHO-recommended sampling parameters (14). the previous 10 years. Intake of alcohol in the previ-
This control revealed 7/298 (2.3%) errors for isonia- ous month was reported to be ‘sometimes’ or ’often’
zid, 3/298 (1.0%) for rifampicin, 0/90 (0%) for ofloxa- by 40% of patients (461), and 21% (239) had smoked
cin, 6/90 (6.7%), 4/90 (4.4%) for kanamycin, and 5/90 regularly in the previous five years. HIV-infection was
(5.6%) for capreomycin. detected in 3% of cases (33).

Results Of the 1,147 cases, 1,037 (90%) had DST results for all
A total of 1,147 eligible culture-positive cases remained the four first-line drugs tested (isoniazid, rifampicin,
in the study, after exclusion of ineligible cases ethambutol and streptomycin). Most cases with miss-
included in the original dataset (Figure 2). The distri- ing DST had a positive LPA test (95/110; 86%), while in
bution of cases recruited in each of the administrative the rest no DST result could be traced. The availability
divisions in the country ranged from 3 to 12% of the of DST results did not differ significantly by the patient
total (Table 1). The ratio of new cases enrolled in the characteristics studied (Table 1).
survey to those actually notified in each administra-
tive region also varied, from 11.6% in Karakalpakstan Resistance patterns by treatment history
to 28.3% in Syrdarya (Figure 3). The majority of cases Table 2 shows the distribution of resistance to the
were male (642; 56%), under 45 years of age (685; four first-line drugs among new and previously treated

6 www.eurosurveillance.org
patients for all 1,037 patients with DST results (per- injectable drugs only. The prevalence of second-line
centages weighted for variations in notifications). Any drug resistance was comparable between new and
resistance to one or more drugs was observed in 47% previously treated cases. In 15 of 17 XDR-TB cases
of new cases and 82% of previously treated, most resistance was observed to all three second-line inject-
often for isoniazid (42% in new and 79% in previously able drugs tested. None of the XDR-TB cases were
treated) or streptomycin (40% and 77% respectively). HIV-infected.
Most cases with rifampicin resistance were also resist-
ant to the other three drugs (251/382) or to isoniazid
and streptomycin (112), with only few cases (7) being Risk factors associated with
mono-resistant to rifampicin. MDR-TB was detected in infection with MDR-TB strains
372 cases (23% of new and 62% of previously treated At univariate analysis, significant positive associa-
cases). The percentage MDR-TB in both new and previ- tions with MDR-TB were observed with cases reported
ously treated cases did not vary significantly when the from Karakalpakstan and Kashkadarya (referenced to
analysis was repeated after imputing data for the 110 Andijan), age under 45 years, history of imprisonment
cases with missing DST results. A total of 14 MDR-TB or hospitalisation in the previous 10 years, and previous
cases (3.8%) were HIV-infected. exposure to anti-TB treatment (Table 1). The percentage
of MDR-TB was significantly higher in Karakalpakstan
There were 319 MDR-TB cases (86%) with DST results compared to Samarkand and Surhadarya, for new
for at least one fluoroquinolone and one second-line cases, and to Namangan for those previously treated
injectable drug (Table 3). Of these, 17 (5.3%; 95% CI (Figure 4).
3.1%-8.4%) were resistant to both and thus XDR-TB. In
addition, 23 cases (7.2%) were resistant only to fluo- When multivariable logistic regression was performed,
roquinolones and another 63 (19.7%) to second-line MDR-TB was positively associated with age under 45

Figure 3
Ratio of new sputum-smear positive tuberculosis cases recruited in the survey (n=782) to those notified in 2011, by
administrative region, in the nationwide study on drug-resistant tuberculosis, Uzbekistan, 2010–2011

Kazakhstan
Georgia

Turkey
Armenia
Uzbekistan
Kyrgyzstan
Lebanon Syria Turkmenistan
Israel
Azerbaijan Tajikistan
Iraq
Jordan
Iran Afghanistan

Karakalpakstan Kuwait
Saudi Arabia Pakistan
Qatar

U.A.E.
Oman
Recruited to Navoiy Tashkent city India
notified
Khorezm Yemen Tashkent Namangan
<12% Djizak
Andijan
Fergana
12−13.9% Syrdarya

14−15.9% Bukhara
Samarkand
16−17.9%
18−18.9%
19−19.9% Kashkadarya
20−20.9% Sri Lanka

21−21.9% Surkhandarya

22−28%

Countrywide value: 18.6%.

www.eurosurveillance.org 7
Table 2
Drug-susceptibility results to first-line anti-tuberculosis drugs in the nationwide study on drug-resistant tuberculosis,
Uzbekistan, 2010–2011 (n=1,037)

Treatment historya
Resistance pattern New cases (n=705) Previously treated cases (n=332)
%b 95% CIsb %b 95% CIsb
Any resistance to isoniazid (H) 41.9 (36.2-47.8) 78.9 (70.4- 85.5 )
Any resistance to rifampicin (R) 24.2 (18.6-30.8 ) 62.5 (53.0-71.1)
Any resistance to ethambutol (E) 20.1 (15.6-25.5) 47.6 (39.9-55.4)
Any resistance to streptomycin (S) 40.0 (33.1-47.4) 76.8 (65.9-85.0)
Total any resistance 47.4 (41.9-52.9) 82.0 (71.6-89.1)

Resistance to H only 5.5 (3.3- 8.9) 3.4 (2.0-5.7)

Resistance to R only 0.9 (0.4-1.7) 0.2 (0.0-1.6)
Resistance to E only 0.0 NA 0.2 (0.0-2.0)
Resistance to S only 4.4 (2.5- 7.5) 2.0 (0.9-4.7)
Total mono-resistance 10.0 (7.3-15.5) 5.8 (3.9-8.5)

H+R 0.2 (0.0-1.4) 0.9 (0.2-3.4)

H+R+E 0.3 (0.1-1.1) 0.3 (0.1-2.3)
H+R+S 6.9 (4.7-10.2) 17.2 (11.4-25.1)
H+R+E+S 15.8 (12.1-20.4) 43.6 (36.4-51.2)
Total multidrug resistance (MDR) 23.2 (17.8-29.5) 62.0 (52.5-70.7)

H+E 0.6 (0.1-2.4) 0.2 (0.0-1.9)

H+S 9.3 (7.1-12.1) 10.6 (8.5-13.2)
H+E+S 3.4 (2.1-5.4) 2.7 (1.1-6.4)
R+E 0.0 NA 0.0 NA
R+S 0.2 (0.0-1.6) 0.2 (0.0-1.5)
R+E+S 0.0 NA 0.2 (0.0-2.0)
E+S 0.1 (0.0-1.1) 0.3 (0.1-2.1)
Total poly-resistance other than MDR 13.5 (10.6-17.1) 14.2 (11.6-17.1)

Total susceptible 52.6 (47.1-58.1) 18.0 (10.9-28.4)

CI: confidence linterval; DRS: drug-resistance survey; E: ethambutol; H: isoniazid; MDR: multidrug resistance; NA: not applicable;
R: rifampicin; S: streptomycin.

a
Previous treatment history was known for all cases.
b
Percentages have been weighted by the number of sputum-smear positive TB cases notified in each region in 2011.

years, not living in an owned home, history of impris- in the capital city Tashkent in 2005 [8] but higher than
onment and previous anti-TB treatment. Regional vari- that in Karakalpakstan in 2001-2002 [7].
ations in risk were also observed (Table 1).
The proportion of MDR-TB among TB patients in
Discussion Uzbekistan is among the highest being reported by for-
This is the first nationwide, representative anti-TB mer Soviet Union countries in recent years [11]. More
drug resistance survey of patients presenting for than two-thirds of MDR-TB cases were resistant to eth-
treatment in Uzbekistan. The proportion of new cases ambutol and therefore it is likely that in a majority of
with MDR-TB calculated from this survey is higher cases this drug will not be effective if it is added to a
than that found in other studies performed in parts second-line drug regimen. HIV infection, which augurs
of Uzbekistan since 2001. The estimate for MDR-TB in badly for the prognosis in MDR-TB unless managed
previously treated cases is similar to the one observed adequately, was infrequent. It is noteworthy that 44%

8 www.eurosurveillance.org
Table 3
Drug-susceptibility results to second-line anti-tuberculosis drugs, in the nationwide study on drug-resistant tuberculosis,
Uzbekistan, 2010–2011 (n=319)

Treatment historya
Resistance pattern New MDR-TB cases Previously treated MDR-TB cases
n % 95% CIs n % 95% CIs
MDR-TB cases with DST results for any fluoroquinolone
144 NA NA 175 NA NA
and any second-line injectable drug b
MDR-TB cases susceptible to both fluoroquinolones
99 68.8 60.5-76.2 117 66.9 59.4-73.8
and second-line injectable drugs
MDR-TB cases with any resistance to fluoroquinolones 11 7.6 3.9-13.3 12 6.9 3.6-11.7
MDR-TB cases with any resistance
26 18.1 12.1-25.3 37 21.1 15.3-27.9
to a second-line injectable drug
MDR-TB cases resistant to both a fluoroquinolone
8 5.6 2.4-10.7 9 5.1 2.4-9.5
and a second-line injectable drug (XDR-TB)

CI: confidence interval; MDR-TB: multidrug-resistant tuberculosis; NA: not applicable; XDR-TB: extensively drug-resistant tuberculosis.

a
Previous treatment history was known in all cases
b
Cases tested for fluoroquinolones (one or more from ciprofloxacin, ofloxacin or moxifloxacin) and second-line injectable drugs (amikacin
and/or kanamycin plus capreomycin; three cases had a test result for either amikacin/kanamycin or capreomycin only).

of MDR-TB cases detected in this survey were not pre- Two social factors remained significantly associated
viously exposed to anti-TB drugs and such cases were with MDR-TB after adjustment: imprisonment and lack
reported from all administrative regions. Two-fifths of of home-ownership. Incarceration has been associated
new MDR-TB cases were in individuals aged between 13 with MDR-TB elsewhere in the former Soviet Union [20].
and 30 years, with a male to female ratio of 1.2:1. Drug- This study has now documented this risk in a central
resistance in cases not previously exposed to anti-TB Asian setting as well. Individuals who do not possess
drugs generally indicates primary infection with resist- their house may be more prone to develop MDR-TB as a
ant strains and points to shortfalls in prevention. Its result of increased mobility and poor treatment adher-
widespread occurrence in our study across regions, ence. In a subset analysis (data not shown), crude
ages and sexes implies that transmission probably odds for MDR-TB were 1.5 times higher in unemployed
occurs in different settings, such as hospitals, prisons, patients when compared to those employed. Given
and households. that long-standing illness may reduce the chances of
employment, this association may be in part an effect
Representative surveillance data from a number of of MDR-TB rather than its cause.
settings in the world indicate that on average 9.0% of
MDR-TB cases (95% CI: 6.7–11.2) have XDR-TB strains Notifications of new sputum-positive TB cases in
[1]. Among MDR-TB patients in Uzbekistan, the propor- Uzbekistan have declined each year since 2006, from
tion of XDR-TB was lower (5.3%; 95% CI: 3.1%–8.4%) 7,211 that year to 4,198 in 2012 [1]. There is concern
although the confidence interval overlaps with those however, that this apparently promising trend may
of the global estimates. Nonetheless, two additional be accompanied by an increase in the prevalence of
observations about the XDR-TB cases in this study drug-resistant cases among the residual TB patients.
have important inferences. Firstly, unlike the case with In Uzbekistan, both drug-susceptible and drug-resist-
MDR-TB, the frequency of infection with XDR-TB strains ant TB patients have been treated in accordance with
was not different between new and previously treated WHO-recommended guidelines for a number of years.
MDR-TB patients. This indicates direct transmission DOTS first-line treatment regimens were piloted in the
of XDR-TB. Secondly, next to all XDR-TB patients were late 1990s and expanded to reach nationwide coverage
resistant to both classes of second-line injectable by 2005. Since then, treatment success for new spu-
drugs, the aminoglycosides and the polypeptide capre- tum-smear positive cases has been reported consist-
omycin. This was higher than was found in a recent ently at around 80%, but is lower in previously treated
review [18]: it means that treatment options for XDR-TB cases [1].
patients are substantially compromised given that the
injectable drugs – considered a mainstay of XDR-TB All patients with MDR-TB detected in this survey were
regimens [19] - are likely to be ineffective in most referred for treatment. In some sites, treatment could
XDR-TB patients in the country. only be started when second-line drugs became availa-
ble. Second-line drug treatment for MDR-TB patients is
known to comply with international recommendations in

www.eurosurveillance.org 9
Figure 4
Percentage of multidrug-resistance among new (left) and previously treated (right) tuberculosis cases by region/city in the
nationwide study on drug-resistant tuberculosis, Uzbekistan, 2010–2011 (n=1,037)

new previously treated

Tashkent Region ●

Tashkent City ●

Syrdarya ●

Surhadarya ●

Samarkand ●

Navoiy ●

Namangan ●

Khorezm ●

Kashkadarya ●

Karakalpakstan ●

Fergana ●

Djizak ●

Bukhara ●

Andijan ●

0 25 50 75 100 0 25 50 75 100

% multidrug-resistant tuberculosis

two treatment sites in Uzbekistan. In 2003, MSF started this reason, the study estimates were weighted by the
to support the treatment of drug-resistant TB patients TB cases actually notified during the second year of the
in public healthcare facilities in a project approved study (differences between weighted and unweighted
by the Green Light Committee in Karakalpakstan [21]. values were small). The study was designed to esti-
Over 2,300 patients had started treatment by the mate the proportion of MDR-TB among a nationwide
end of April 2012 of whom over 900 were supported sample of new TB cases and was not powered to detect
by funding from TGF. Among the 710 MDR-TB patients differences between other patient subgroups or the
enrolled between 2003 and 2008, 62% finished their administrative divisions in Uzbekistan. Thus, statisti-
treatment successfully [22]. In Tashkent, the RDC staff cally significant differences could only be discerned
have been treating drug-resistant TB patients since between regions with extreme values. The proportion
2006 through the support of TGF and UNITAID. By mid- of MDR-TB among previously treated TB cases as esti-
2012, 1,490 MDR-TB patients had started treatment mated in this survey is expected to be conservative
and treatment success for the 446 patients enrolled given that previously treated patients who experienced
in 2009 was 61%. Treatment with second-line drugs is a treatment failure in a year prior to the one of the sur-
also available for imprisoned patients. In 2011, a total vey were not included.
of 1,385 MDR-TB cases were detected in Uzbekistan,
and 855 were enrolled on treatment. If the estimates The validity of data collected by patient interview alone
observed in this survey are applied to the number of on problem use of alcohol and narcotics was open to
new and previously treated pulmonary TB cases noti- question and so these data were not used in the final
fied in the country in 2011, about 3,000 MDR-TB cases analysis. This precluded the investigation of associa-
(range: 2,700-3,400) would be expected each year if tions with these potential risks. The missing data on
DST were to be performed on all notified TB cases [1]. HIV status in 6% of patients may also have been the rea-
About 80% of these cases would be expected to occur son why no significant relationship was found between
among new TB patients. These numbers do not include HIV infection and MDR-TB, an association which has
prevalent MDR-TB cases surviving from previous years been noted elsewhere in countries of the former Soviet
and who would likewise be eligible for treatment. Union [8]. Although data on DST were missing for 110
eligible cases, when the estimates were recalculated
This study had some limitations. While the overall num- after imputation of missing values only slight differ-
ber of cases enrolled in the survey approached the tar- ences were noted. The ‘missingness’ of DST data was
get aimed for at the design stage, the number of cases therefore considered to be at random. Finally, as the
recruited into the survey as a proportion of cases noti- study was limited to sputum-smear positive TB cases,
fied varied between the administrative regions. This it is possible that the patterns of resistance in children
may have under- or over-represented the contribution of and in sputum-smear negative disease may differ from
cases from certain centres to the overall estimate. For the ones described in this study.

10 www.eurosurveillance.org
 coverage of DST in Uzbekistan, including the previ-
This survey has identified some useful leads for future ously untreated TB patients who, as in many other
study. Geographic disparities in MDR-TB levels may countries, harbour a substantial part of the MDR-TB
reflect confounding by social variables but also dif- caseload [34]. If coupled with an efficient electronic
ferences in programme performance and variations in system of data capture this would also enable the use
the pattern of circulating strains. The lack of associa- of data from routine diagnostic testing for drug resist-
tion with some of the risk factors measured may be in ance surveillance in the near future. Finally, given that
part due to problems with validity of data and also the international migration is expected to keep increasing
relatively small number of observations. These require in the future, greater efforts to reinforce surveillance
further study, particularly migration which has been and response to the challenge of drug-resistant TB in
linked to TB in recent reports in central Asia [23,24]. countries such as Uzbekistan are expected to benefit
Migration from countries of the former Soviet Union to public health beyond the confines of this country’s
several European Union countries in the last decade border.
has been marked [25], and studies such as the cur-
rent one underline the importance of continued sur-
veillance for drug-resistance in the western Europe Acknowledgments
[12,26]. Biochemical tests and expert interviewers We thank Christopher Fitzpatrick of WHO for his support to
may be needed to elicit valid answers to questions the analysis of data.
of a sensitive nature such as problem use of alcohol
and narcotic drugs, lifestyles which have been asso- The study was made possible by a grant of the TGF (Round
8), financial backing from WHO’s Global TB Programme, and
ciated with drug-resistant TB elsewhere in the former the time of staff from the Ministry of Health of Uzbekistan
Soviet Union countries [27,28]. Genotyping studies and WHO SRL Gauting. A Dadu, M Dara, P de Colombani, D
may be required to identify any linked clusters of HIV- Falzon, J Gadoev, K Kremer, G Tsogt, W van Gemert and M
associated MDR-TB. Meta-analysis combining individ- Zignol are all staff members of WHO and they alone are re-
ual patient data from similar studies in other countries sponsible for the views expressed in this publication and
they do not necessarily represent the decisions or policies
could usefully increase the power to detect associa- of WHO.
tions and could add to the current evidence-base on
the influence of specific drugs on successful outcome
in MDR-TB and XDR-TB patients [18,29]. Authors’ contributions
The survey was undertaken under the supervision of
In conclusion, the findings of this survey have an DJ Ulmasova, G Uzakova, H Hoffmann, L Turaev, MN
important bearing on the capacity of the national pro- Tillyashayhov, B Kholikulov, A Jalolov, N Muslimova, and J
gramme staff and their technical and financing part- Gadoev. Technical advice on the study design and protocol
ners to achieve universal access to adequate care for were provided by W van Gemert, D Falzon, and M Zignol. P du
MDR-TB patients [30]. The implications are broad and Cros, K Kremer, A Dadu, P de Colombani, O.Telnov, A Slizkiy,
M Dara and G Tsogt also contributed to the analysis of the
point towards a need to expand ambulatory and in- data. The writing of the manuscript was coordinated by D
patient facilities, the supply of second-line drugs, and Falzon and all the other co-authors provided substantive
safeguarding the quality of drugs [31]. Based on the contributions to the content and format. All authors agree
findings of this study, and in line with Consolidated with the inferences and conclusions drawn.
Action Plan to Prevent and Combat M/XDR-TB in WHO
European Region 2011-2015 [32], Uzbekistan is imple-
menting a national action plan to prevent and combat Conflicts of interest
M/XDR-TB. Patient adherence to first-line drug treat- We declare that we have no conflicts of interest.
ment may need strengthening. Early detection of drug-
resistant TB and institution of second-line treatment
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