Accepted Manuscript

Title: Trends and Characteristics of Drug-resistantTuberculosis in Rural Shandong, China

Authors: Ning-ning Tao, Xiao-chun He, Xian-xin Zhang, YaoLiu, Chun-bao Yu, Huai-chen Li

PII: S1201-9712(17)30243-6DOI: https://doi.org/10.1016/j.ijid.2017.09.019Reference: IJID 3042

To appear in: International Journal of Infectious Diseases

Received date: 25-5-2017Revised date: 17-9-2017Accepted date: 18-9-2017

Please cite this article as: Tao Ning-ning, He Xiao-chun, Zhang Xian-xin, LiuYao, Yu Chun-bao, Li Huai-chen.Trends and Characteristics of Drug-resistantTuberculosis in Rural Shandong, China.International Journal of Infectious Diseaseshttps://doi.org/10.1016/j.ijid.2017.09.019

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Trends and Characteristics of Drug-resistant Tuberculosis in Rural

Shandong, China

Ning-ning Taoa#, Xiao-chun Heb, Xian-xin Zhangc, Yao Liua, Chun-bao

Yud, and Huai-chen Lia*

a.Department of Respiratory Medicine, Shandong Provincial Hospital

Affiliated to Shandong University, Jinan;

b.Department of Respiratory Medicine, Baoji Central Hospital, Baoji,

Shaanxi, China;

c.Department of Respiratory Medicine, Shandong Provincial Chest

Hospital, Jinan, China;

d.Katharine Hsu International Research Center of Human Infectious

Diseases, Shandong Provincial Chest Hospital, Jinan, China;

#This author is first author on this work.

*Correspondence and requests for materials should be addressed to

Huai-chen Li. Mailing Address: Shandong Provincial Hospital Affiliated

to Shandong University, 324 Jingwuweiqi Road, Huaiyin District, Jinan,

China 250021.

E-Mail: lihuaichen@163.com

Highlights:

The increasing prevalence of MDR TB has led to new challenges.

Studying of DR TB and MDR TB in rural areas is vital to TB

control in China.

Increasing MDR TB especially primary MDR TB characterize DR

TB cases in rural China.

Abstract

Objectives: We aim to describe the secular trends for drug-resistant

tuberculosis (DR TB) and to identify unique characteristics of

multidrug-resistant TB (MDR TB) in rural China.

Methods: A retrospective study of TB data collected from 36

tuberculosis prevention and control institutions serving rural populations

in Shandong Province, China, from 2006 to 2015 was conducted.

Results: Approximately 8.3% of patients suffered from MDR, among

which 70% were new treated patients, and this rate has increased at a

yearly rate of 1.3% during the last decade. An increase in the percentage

of overall first-line drug resistance against isoniazid (INH), rifampin

(RFP), ethambutol (EMB), and streptomycin (SM) was confirmed

(P<0.05). The percentage of MDR TB in new and previously treated

cases increased at yearly rates of 9.9% and 11.1%, respectively. MDR TB

patients were more likely to be female (OR, 1.58; 95% CI, 1.32-1.89),

smoking (OR, 1.75; 95% CI, 1.47-2.07), having recent TB contact (OR,

1.58; 95% CI, 1.04-2.42), and retreated (OR, 2.89; 95% CI, 2.46-3.41).

Conclusions: Increasing MDR TB and rates of primary MDR TB

characterize DR TB cases in rural China. Persistent efforts need to be

made among MDR TB patients in future TB control strategies.

Keywords: multidrug-resistant tuberculosis; primary transmission; rural;

epidemiology

Introduction

Microbial drug resistance has become a major public health concern

worldwide [1]. Due to persistent international efforts to combat

tuberculosis (TB), both the global mortality rate and incidence rate have

decreased over the past two decades [2]. However, the increasing

prevalence of drug-resistant tuberculosis (DR TB) has led to new

challenges [3]. As an expanding threat, it is estimated that MDR TB,

defined as resistance to isoniazid (INH) and rifampin (RFP), has grown to

480,000 new cases (2015 cohort) with 210,000 deaths/year (2013 cohort)

[2]. With catastrophic cost, poor adherence, prolonged treatment duration

and inadequate effective drugs, MDR TB has been associated with worse

treatment outcomes than drug-susceptible TB [4-7]. The serious epidemic

of MDR TB places patients just one step away from having extensively

drug-resistant (XDR) and also increases the rate of treatment failure and

causes enormous social and economic disruption [8].

China has the second highest number of TB cases and accounts for

25% of the MDR TB population in the world [9]. As China has the largest

agricultural population in the world, approximately 64.9% of TB patients

and 80% of MDR TB patients in China live in rural areas [10-11]. Due to

poor regional socioeconomic status (living conditions, health and

nutritional status, money to pay for health care and access to health

services) [12], more and more patients have delayed or received

inappropriate treatments, which have consequently increased the

prevalence and mortality rate of TB in poor rural areas compared with

economically developed urban areas [13]. With economic development

and urbanization, an increasing population, up to 211 million in 2010,

migrated from rural to urban areas in China, leading to the spreading of

TB nationwide [14]. Thus, studying of DR TB specifically MDR TB in

rural areas is of key importance for monitoring and controlling TB in

China. Previous studies on TB in rural areas were limited by the short

time span and small sample size of culture-positive TB in China [15-16].

Shandong is a province located on the east coast of China with a

population of 95 million and a rural population of 57 million according to

the Sixth National Census. An estimated 211,900 people in Shandong

were infected with TB with 66.7% of the cases being rural residents

according to the Fifth National TB Epidemiological Survey in Shandong

province [11]. The purpose of the present study was to summarize the

changes between different drug-resistant patterns over time on the basis

of drug susceptibility testing (DST) for first-line drugs among the rural

population in Shandong Province, China, in the last decade, to provide

effective intervention strategies for the prevention and control of DR TB

in similar populations.

Materials and Methods

Study population and data collection

We collected information from consecutive culture-confirmed TB cases

among the rural population in Shandong Province from the China

Information System for Disease Control and Prevention (CISDCP) from

2006 to 2015. Two province-level hospitals, Shandong Provincial

Hospital and Shandong Provincial Chest Hospital (SPCH), and 21

county-level and 13 municipal-level local health departments in

Shandong Province constituted the 36 monitoring sites in this

retrospective study. Monitoring sites were selected based on convenience

and to reflect a range of TB burdens and clinical capacity. In 2004, the

Center for TB Control and Prevention of Shandong province, including

SPCH, set up the provincial health department Katharine Hsu

International Research Center of Human Infectious Diseases (KICID),

where the patients’ information was collected and recorded by trained

researchers on standard case report forms. KICID has been responsible

for laboratory quality assurance and TB surveillance in Shandong

province since its inception.

Mycobacterium tuberculosis was identified by culturing and

susceptibility to INH, RFP, ethambutol (EMB), and streptomycin (SM)

was identified by using DST. Sociodemographic data for all of the

patients including age, sex, smoking history, excess alcohol consumption,

TB contact history and prior TB treatment history were collected and

recorded.

Laboratory Methods

All samples available were processed for smear and culture. Tissue

samples were also examined for the presence of granulomas. By using

Ziehl-Neelsen staining, the presence of acid-fast bacilli (AFB) was

confirmed. Culturing was performed on Lowenstein-Jensen (LJ) culture

medium. After thorough assessment of all the evidence derived from

growth characteristics, morphologic characteristics of the colony, and the

result for inhibition by P-nitrobenzoic acid, M. tuberculosis was selected

[9]. Furthermore, the samples containing non-tuberculosis mycobacteria

(NTM) were rejected.

Acid buffer LJ medium DST was performed using the proportion

method with the following antibiotic concentrations: (1) INH (0.2 μg/mL),

(2) RFP (40 μg/mL), (3) EMB (2.0 μg/mL), and (4) SM (4.0 μg/mL).

Resistance was defined as more than 1% growth for any anti-TB drug.

Laboratory Quality Control

External quality assessment (EQA) for smear, culture and DST in

county and district level laboratories was conducted by the prefectural

and provincial TB laboratories, accordingly, EQA in the provincial

reference laboratories and the National Tuberculosis Reference

Laboratory (NTRL) was conducted by the Supranational Tuberculosis

Reference Laboratory (STRL) based on the WHO guideline [17]. Blinded

re-testing of a random selection of approximately 10% of the isolates

from each laboratory by a superior laboratory was essential.

Data inclusion and definitions

All of the TB cases in rural areas that had a positive M. tuberculosis

culture with DST results and demographic and clinical information were

included. TB patients with non-tuberculous mycobacteria (NTM) as well

as HIV (in China HIV-positive patients are immediately transferred to an

HIV-specialized hospital) were excluded.

Drug-susceptible TB was defined as TB isolates susceptible to all the

four tested first-line drugs. MDR TB was defined as TB resistant to at

least INH and RFP. A “new case” is defined as a patient who had never

been treated for TB or had taken <1 month of anti-TB drugs in the past; A

“previously treated case” is defined as a patient who had received ≥1

month of anti-TB drugs in the past [17].

Statistical analysis

The changes in the proportions of different resistance patterns over

time were confirmed using the Chi-Square test for trends and linear

regression. Pearson’s X2 test was used to compare categorical variables

for univariable analysis. Multivariable logistic regression analysis was

used to identify unique characteristics of MDR TB. The odds ratios (OR),

95% confidence interval (CI) and P value for individual variables were

obtained using a logistic regression model, and P<0.05 was considered to

be statistically significant. We used SPSS software version 17.0 for the

statistical analysis.

Results

Case Estimates

A total of 10,977 cases were identified with M. tuberculosis in rural

Shandong during the last decade. First, we excluded 1198 (10.9%)

patients without DST result and 35 (0.3%) patients without demographic

or clinical information. Then, we excluded 171 (1.6%) patients with

NTM. Finally, sum to 9,573 (87.2%) cases were included. The average

age of these patients was 51.0 (mean±SD, 51.0±19.3) years old and

79.1% were male.

Drug Resistance Patterns

Among the 9,573 TB cases, the resistance rate for SM was 17.7%,

followed by INH (16.5%), RFP (10.0%), and EMB (4.4%). The

prevalence of MDR was 794 (8.3%), while another 951 (9.9%) patients

had resistance to either INH or RFP (but not both). A total of 2,037

(24.1%) cases were resistant to at least one first-line drug and 289 (3.0%)

cases were resistant to all the four tested first-line drugs.

MDR TB was confirmed in 6.8% of new cases and 17.1% of

previously treated cases. Another 9.2% and 14.3% of new and previously

treated TB cases, respectively, were resistant to either INH or RFP (but

not both). An estimated 21.8% and 37.1% of new and previously treated

TB cases, respectively, were resistant to at least one of the four first-line

anti-tuberculosis drugs (Table 1).

Trends Overtime

Among the included patients (9573 cases), it is noteworthy that the

percentage of drug-susceptible TB decreased from 78.6% in 2006 to

71.9% in 2015, decreasing at a yearly rate of 1.0% (R2=0.5611;

Chi-square test for trends: X2=29.242, P<0.001). In contrast, the

percentage of overall first-line drug resistance for INH, RFP, EMB and

SM, and MDR TB increased significantly (P<0.001) over the past decade

(X2=22.831 for INH resistance, increasing at a yearly rate of 4.8%

(R2=0.47) from 12.6% to 19.2%; X2=62.297 for RFP resistance,

increasing at a yearly rate of 8.2% (R2=0.69) from 6.4% to 13.1%;

X2=38.933 for EMB resistance, increasing at a yearly rate of 18.0%

(R2=0.68) from 1.5% to 6.6%; X2=36.392 for SM resistance, increasing at

a yearly rate of 5.1% (R2=0.74) from 14.7% to 22.9%; and X2=43.629 for

MDR TB, increasing at a yearly rate of 9.4% (R2=0.53) from 4.9% to

11.1%) (Figure 1 and Figure 2). Moreover, mono-resistance analysis

showed a statistically significant increase in the RFP mono-resistance

(RMR) proportion (X2=9.017, P=0.003), though INH, EMB, and SM

mono-resistance showed no statistically significant changes during the

last decade.

To better understand the epidemic trends in TB cases with different

treatment histories, a further breakdown of new and previously treated

TB cases was conducted. This breakdown estimated that there was an

increasing yearly rate of 9.9% (R2=0.53) for new treated MDR TB and

11.1% (R2=0.71) for previously treated MDR TB cases during the last

decade; these changes were statistically significant (P<0.001) using the

Chi-square test for trends (X2=51.279 and 60.481, respectively) (Figure

2).The percentage of new treated MDR TB among MDR TB patients

increased from 67.5% in 2006 to 76.0% in 2015, increasing at a yearly

rate of 1.3% (R2=0.38; Chi-square test for trends: X2=12.291, P<0.001)

(Figure 3). We also analyzed trends for other drug resistance patterns in

new and previously treated TB cases. We found that the overall drug

resistance rate was increasing significantly at a yearly rate of 4.9%

(R2=0.40), 8.8% (R2=0.56), 18.0% (R2=0.65), and 5.2% (R2=0.67) for

INH, RFP, EMB, and SM, respectively, in new TB cases during our study

period (Chi-square test for trends: X2=19.699, P<0.001; X2=53.892,

P<0.001; X2=36.196, P<0.001; and X2=35.933, P<0.001, respectively).

Coincidentally, in previously treated TB cases, the overall drug resistance

rate increased significantly at a yearly rate of 6.6% (R2=0.69), 10.0%

(R2=0.76), 19.7% (R2=0.44), and 5.4% (R2=0.53) for INH, RFP, EMB,

SM, respectively, during our study period (Chi-square test for trends:

X2=14.805, P<0.001; X2=30.753, P<0.001; X2=9.112, P=0.003; and

X2=10.369, P=0.001, respectively). The mono-resistance analysis showed

an increasing yearly rate of 9.3% (R2=0.55) for new treated RMR TB and

14.0% (R2=0.45) for previously treated RMR TB cases; these changes

were statistically significant using the Chi-square test for trends

(X2=4.506, P=0.034; and X2=8.222, P=0.004, respectively). In contrast,

INH mono-resistance in previously treated TB cases and EMB and SM

mono-resistance in both new and previously treated TB cases showed no

statistically significant changes. The percentage of INH mono-resistance

in new TB cases decreased significantly from 4.4% to 2.2%, decreasing at

a yearly rate of 7.4% (R2=0.30; Chi-square test for trends: X2=6.261,

P=0.012).

Demographic and Clinical Characteristics

Table 2 shows the characteristics of patients with or without MDR TB

in detail. Univariable comparison showed that the following

characteristics were associated with the presence of MDR TB: (1) female,

(2) smoking, (3) recent TB contact and (4) TB treatment history. Patients

aged 15-24 years were less likely to have MDR TB. On the basis of the

variables included in the univariable comparison, the final multiple

logistic regression model predicted MDR TB based on the following

characteristics: (1) female (OR, 1.58; 95% CI, 1.32-1.89), (2) smoking

(OR, 1.75; 95% CI, 1.47-2.07), (3) recent TB contact (OR, 1.58; 95% CI,

1.04-2.42) and (4) TB treatment history (OR, 2.89; 95% CI 2.46-3.41).

Discussion

This retrospective study attempted to systematically investigate the

secular trends of DR TB and to identify characteristics of MDR in M.

tuberculosis strains from TB patients in rural settings in Shandong, the

second largest province located on the eastern coast of China. To our

knowledge, this is one of the largest retrospective study from the aspect

of both time span and sample size for culture-positive TB that describes

the epidemiology of DR TB among rural populations in Shandong, China

over the past decade.

In 2009, the Chinese government established the rural New

Cooperative Medical Scheme (NCMS), a health insurance scheme for

rural patients, and devised a plan for MDR TB prevention and control

[18-19]. Although these efforts appear to be helpful, with low

reimbursement rates for in-patients and no reimbursement rates for

out-patients, this strategy may not be sufficient for TB treatment and

control in rural China and may run into bottlenecks. In this study, the

percentage of drug susceptible TB in new and previously treated cases

and INH mono-resistance TB in new cases decreased during the last

decade. In contrast, an increase in the percentage of overall first-line drug

resistance for INH, RFP, EMB and SM, RMR and MDR TB with new

and previously treated cases in rural areas during the last decade was

confirmed.

During the study periods, the percentage of new treated MDR TB

among MDR TB patients increased from 67.5% in 2006 to 76.0% in 2015,

increasing at a yearly rate of 1.3%. This indicates ongoing primary

transmission of MDR TB strains in rural China. Consistent with previous

surveys, patients who had a recent TB contact history were more likely to

have MDR TB [20-21]. To make matters worse, the percentage of recent

TB contact as a sensitive indicator for primary transmission was greatly

underestimated due to a lack of diagnosis and unawareness of the disease

for those infected as well as disguising of TB status for the susceptible

population [22]. Delays (patient, provider, diagnostic, and treatment

delays) for suspected TB patients affected the percentage of infection

among close contacts and contributed to the emergence of drug resistance,

particularly for MDR [23-24]. This phenomenon may be even more

serious in rural areas, which harbor a higher burden of TB/MDR TB and

have much poorer living conditions, poorer health and nutritional status,

less money to pay for health care, insufficient laboratory facilities, and

fewer qualified health professionals [12, 25]. Up to 70% of the patients

with MDR TB had diseases that were resistant to at least INH and RFP

before they received standard first-line short-course treatment in this

study. With poor and even no standard TB infection control (IC) measures

in some undeveloped regions in China, the primary spread of M.

tuberculosis within the general population and cross-infection between

TB patients particularly in health-care facilities are quite serious [26].

Continuous efforts are urgently needed to control the on-going primary

transmission of MDR TB in rural China.

Shandong province has implemented directly observed treatment

strategy (DOTS) therapy since 1992, the strategy has universally covered

TB patients at the county level since 1995, the cure rate of active TB

cases by DOTS reached over 90% at the county level according to

mid-evaluation on carrying out “TB control planning of China

(2001-2010)” in Shandong Province [27]. However, the prevalence and

continual rise of DR TB and MDR TB stands to derail the

implementation and completion of DOTS in rural China [28]. During the

study period, MDR TB with prior anti-TB treatment history which may

occurred by acquisition, re-infection or re-current increased from 8.4% in

2006 to 21.8% in 2015, increasing at a yearly rate of 11.1%. The

widespread and inappropriate use of anti-TB drugs might enable the

selection of drug-resistant strains, which also accelerated the occurrence

of acquired MDR [9, 29-30]. A previous study demonstrated that INH or

RMR was an independent predictor for acquired MDR TB [9]. An

increase in the overall resistance rate to INH, RFP, and RMR was

confirmed in this study. An estimated 9.2% of new and 14.3% of

previously treated TB patients had resistance to either INH or RFP (but

not both), placing them just one step away from having MDR TB. The

government provided “free” TB treatment for all TB patients covering

only some diagnostic tests and first-line anti-mycobacterial medications,

however catastrophic second-line anti-mycobacterial medications and

“out of pocket” expenditures, such as transport, additional food,

symptom-relieving medicines, or indirect expenses associated with lost

income, lead to more and more patients, especially those living in poor

rural areas, dropping out of and/or discontinuing treatment even under

DOTS [31-33]. These inadequate (poor regimens) treatment, irregular

(poor compliance) and incomplete (defaulting) treatments can exacerbate

treatment failure and increase the risk of MDR TB [5-7]. The already

serious situation of DR TB in China could easily be much worse if

increasing populations migrated from rural to urban areas [34]. Thus,

controlling MDR in rural areas may be one of the most significant factors

in future TB control strategies.

Similar to previous studies, we identified several characteristics of

MDR TB among rural TB cases. In this study, special attention should be

paid to TB patients who are female [35-36], smokers [37-38], previously

treated [20, 35] and in contact with other TB patients [20-21].

This is the first study devoted to assessing the changes in different DR

TB patterns from a retrospective perspective and identifying unique MDR

TB case characteristics in rural China. The results imply that the DR TB

situation in China could easily deteriorate if MDR TB and primary

transmission of MDR strains increase in rural areas.

This study did have some limitations. First, because only one province

on the eastern coast of China was examined, the economic and regional

disparities limited the generalizability of the results. Second, according to

the National Survey of Drug-Resistant TB in 2007, one third of patients

with MDR TB were resistant to either ofloxacin or kanamycin [9],

placing them one step away from XDR TB. However, the lack of DST for

second-line drugs impeded us from further understanding the extent of

drug-resistant, extremely DR and totally DR TB that were associated with

treatment outcomes much worse than MDR TB [39-41]. Third, because

all of the patients were culture-confirmed HIV-seronegative TB cases

with little information on their education, incomes, and living conditions

accessible from the medical records, we failed to show the relationships

between these factors and the DR TB epidemic. Finally, the lack of

genotyping, a gold standard for identifying the origin of resistant isolates,

impeded us from correlating the mutations in the prevalent strains with

observed resistance in this region of study with observations in other

parts of China and the world.

In conclusion, we demonstrated an increase in MDR TB in rural China

over the last decade. MDR TB strains are mainly transmitted by airborne

infection in rural China. Effective TB IC strategies are urgently needed to

control the on-going primary transmission of MDR TB, especially among

people grouped closely with diagnosed TB patients. DST for both first-

and second-line anti-TB drugs is essential for more individualized

anti-TB regimens. Additionally, on-going reforms for financing DOTS

(TB diagnosis and treatment) in rural areas will be essential components

of effective interventions for TB prevention and control in China.

Acknowledgements

We would like to express our deep appreciation to all the individuals

who contributed to this work. This work was supported by the Science

and technology development plan of Shandong Province (Grant Number:

2009GG10002054).

Ethical clearance

This study was approved by the Ethics Committee of Shandong

Provincial Hospital, which is affiliated to Shandong University. Patient

records were anonymized and de-identified before analysis.

Conflict of interest

None.

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Figure legends

Figure 1. Drug-resistance pattern trends among 9,573 culture-confirmed

TB cases in rural China from 2006 to 2015.

For INH resistance (X2=22.831, P<0.001; linear regression formula:

R2=0.47, x-coefficient=0.006, SE=0.130); for RFP resistance (X2=62.297,

P<0.001; linear regression formula: R2=0.69, x-coefficient=0.008,

SE=0.051); for EMB resistance (X2=38.933, P<0.001; linear regression

formula: R2=0.68, x-coefficient=0.005, SE=0.017); and for SM resistance

(X2=36.392, P<0.001; linear regression formula: R2=0.74,

x-coefficient=0.008, SE=0.131).

EMB=ethambutol, INH=isoniazid, RFP=rifampin, SE=standard error,

SM=streptomycin, and TB=tuberculosis.

Figure 2. Trends for MDR TB in rural China from 2006 to 2015.

For MDR (X2=43.629, P<0.001; linear regression formula: R2=0.53,

x-coefficient=0.006, SE=0.043); for MDR among new treated patients

(X2=51.279, P<0.001; linear regression formula: R2=0.53,

x-coefficient=0.007, SE=0.027); and for MDR among previously treated

patients (X2=60.481, P<0.001; linear regression formula: R2=0.71,

x-coefficient=0.015, SE=0.094).

MDR-TB=multidrug-resistant tuberculosis and SE=standard error.

Figure 3. Trends for the new treated MDR TB proportion among MDR

TB cases in rural China from 2006 to 2015.

(X2=12.291, P<0.001; linear regression formula: R2=0.38,

x-coefficient=0.027, SE=0.511).

MDR TB=multidrug-resistant tuberculosis and SE=standard error.

Figure 1

Figure 2

Figure 3

Table 1 Drug resistance to first-line drugs among new and previously treated patients in rural areas of Shandong, China

from 2006-2015

Drug resistance New treated patients (n=8155) Previously treated patients (n=1418) Total (n=9573)

n % n % n %

Any resistance to first-line drug 1781 (825) 21.8 (10.1) 526 (182) 37.1 (12.8) 2307 (1007) 24.1 (10.5)

INH 1196 (282) 14.7 (3.5) 386 (69) 27.2 (4.9) 1582 (351) 16.5 (3.7)

RFP 657 (64) 8.1 (0.8) 300 (31) 21.2 (2.2) 957 (95) 10.0 (1.0)

EMB 315 (24) 3.9 (0.3) 105 (5) 7.4 (0.4) 420 (29) 4.4 (0.3)

SM 1317 (455) 16.2 (5.6) 377 (77) 26.6 (5.4) 1694 (532) 17.7 (5.6)

Resistance to 2 drugs

INH+RFP 62 0.8 37 2.6 99 1.0

INH+SM 305 3.7 62 4.4 367 3.8

RFP+SM 31 0.4 23 1.6 54 0.6

Resistance to 3 drugs

INH+RFP+EMB 11 0.1 6 0.4 17 0.2

INH+RFP+SM 267 3.3 122 8.6 389 4.1

INH+EMB+SM 39 0.5 13 0.9 52 0.5

RFP+EMB+SM 7 0.1 3 0.2 10 0.1

At least INH/RFP 749 9.2 202 14.3 951 9.9

MDR, overall 552 6.8 242 17.1 794 8.3

Resistance to 4 drugs 212 2.6 77 5.4 289 3.0

EMB, ethambutol; INH, isoniazid; MDR, multidrug-resistant; RFP, rifampin; SM,streptomycin.

Numbers and rates of mono-first-line drug resistant cases are shown in parentheses.

Table 2 Univariable and multivariable logistic regression analyses of unique characteristics for MDR-TB among TB cases in

rural China from 2006 to 2015

Characteristics Non-MDR

TB

(n=8779)

MDR-

TB

(n=79

4)

Univariable

analysis

OR (95%CI)

P value

Multivariable

analysis

OR (95%CI)

P value

Age groups

0-14 63 (0.7) 3 (0.4) 0.53

(0.16-1.68)

0.27

15-24 1198

(13.6)

86

(10.8)

0.77

(0.61-0.97)

0.03

25-44 1818 174 1.08 0.42

(20.7) (21.9) (0.90-1.28)

45-64 3304

(37.6)

322

(40.6)

1.13

(0.98-1.31)

0.10

≥65 2396

(27.3)

209

(26.3)

0.95

(0.81-1.12)

0.56

Sex

Male 6982

(79.5)

592

(74.6)

Reference

Female 1797

(20.5)

202

(25.4)

1.33

(1.12-1.57)

0.00

1

1.58

(1.32-1.89

)

<0.0

01

aExcess alcohol 1243 104 0.91 0.41

consumption (14.2) (13.1) (0.74-1.13)

Smoker 1846

(21.0)

166

(20.9)

1.54

(1.31-1.81)

<0.0

01

1.75

(1.47-2.07

)

<0.0

01

bTB contact 163 (1.9) 27

(3.4)

1.86

(1.23-2.82)

0.00

3

1.58

(1.04-2.42

)

0.03

TB retreatment 1176

(13.4)

242

(30.5)

2.83

(2.41-3.34)

<0.0

01

2.89

(2.46-3.41

)

<0.0

01

a Excess alcohol consumption means ≥ 2 standard alcohol beverages per day.

b TB contact defined as contact with family members, schoolmates, or colleagues with TB.