Use of Drug-Susceptibility Testing
for Management of Drug-Resistant
Tuberculosis, Thailand, 2004–2008
Eugene Lam, Sriprapa Nateniyom, Sara Whitehead, Amornrat Anuwatnonthakate,
Patama Monkongdee, Apiratee Kanphukiew, Jiraphan Inyaphong, Wanlaya Sitti, Navarat Chiengsorn,
Saiyud Moolphate, Suporn Kavinum, Narin Suriyon, Pranom Limsomboon, Junya Danyutapolchai,
Chalinthorn Sinthuwattanawibool, and Laura Jean Podewils
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Release date: February 19, 2014; Expiration date: February 19, 2015
• Distinguish the clinical turnaround time for drug-susceptibility?testing?(DST)?in?the?current?study
• Evaluate physician actions based on the results of DST in the current study
• Analyze risk factors for worse clinical outcomes of TB treatment in the current study.
Claudia Chesley, Technical?Writer/Editor,?Emerging Infectious Diseases. Disclosure: Claudia Chesley has disclosed no relevant
Charles P. Vega, MD, Health?Sciences?Clinical?Professor;?Residency?Director,?Department?of?Family?Medicine,?University?of?
California,?Irvine.?Disclosure: Charles P. Vega, MD, has disclosed no relevant financial relationships.
Disclosure: Eugene Lam, MD, MSPH, MSc; Sriprapa Nateniyom, MD; Sara Whitehead, MD, MPH; Amornrat
Anuwatnonthakate, MSc, PhD; Patama Monkongdee, MSc; Apiratee Kanphukiew, MSc; Jiraphun Inyapong, BNs; Wanlaya
Sitti, MSc; Navarat Chiengsorn, BN; Saiyud Moolphate, MPH; Suporn Kavinum, MPH; Narin Suriyon, MPH; Pranom
Limsomboon, BN; Junya Danyutapolchai, MA; Chalinthorn Sinthuwattanawibool, MSc; and Laura Jean Podewils, PhD, MS,
have disclosed no relevant financial relationships..
(US? CDC),? Atlanta,? Georgia,? USA? (E.? Lam,? S.? Whitehead,?
L.J.? Podewils);? Thailand? Ministry? of? Public? Health? (MOPH),?
Nonthaburi? (S.? Whitehead,?A.?Anuwatnonthakate,? P.? Monkong-
Office? of? Disease? Prevention? and? Control? 7,? Ubon-ratchathani,?
mine if DST results were being used to guide treatment,
we conducted a retrospective chart review for patients with
time from clinical sample collection to physician review of
TB were empirically prescribed an appropriate regimen; an
had received category II treatment before DST results were
reviewed had less successful outcomes. Overall, review of
available DST results was delayed, and results were rarely
used to improve treatment.
million incident cases and 1.3 million deaths were attrib-
uted to TB in 2012 (1). A severe threat to TB control is the
emergence of multidrug-resistant (MDR) TB: worldwide,
there are an estimated 650,000 MDR TB cases (1). To
manage MDR TB, the World Health Organization (WHO)
recommends empirically basing treatment on the general
drug-susceptibility testing (DST) pattern of the population
for patients in settings with limited laboratory capacity or
for patients with pending DST results. Once laboratory
results become available, WHO recommends treatment
modification, as needed, according to the DST results (2).
Algorithms have been proposed to assist with clinical
decision-making, but a proper laboratory diagnosis remains
the benchmark for informing an effective and suitable treat-
ment regimen (3). New technologies to more quickly detect
TB, including drug-resistant TB, have become increas-
ingly available (4–8). These tests are in use throughout the
world, potentially improving the clinical management of
TB by informing clinicians of which drugs may be most
effective for individual patients. However, because of de-
lays in receiving laboratory results (3), clinicians may have
adopted a convention of patient clinical management that
relies on epidemiologic data, medical history, and clinical
signs and symptoms. Continuation of ineffective treatment
causes excess patient illness and increases the potential for
drug resistance, relapse, death, and transmission of drug-
resistant M. tuberculosis strains. Earlier initiation of proper
therapy may therefore result in substantial cost savings (9).
Thus, with these new diagnostic technologies has come the
critical need to examine how test results are being used in
the clinical management of TB patients.
In 2004, the Thailand Ministry of Public Health–US
Centers for Disease Control and Prevention Collaboration
uberculosis (TB), caused by the bacterium Mycobac-
terium tuberculosis, is a global public health issue; 8.6
implemented routine liquid culture and DST of clinical
samples for all persons with a diagnosis of TB disease in 5
provinces participating in the Active TB Surveillance Net-
work (10). Clinicians were provided orientation to the new
diagnostic tests and their interpretation and limitations. Al-
though these procedures had been implemented, the extent
to which clinicians were using DST results to inform treat-
ment decision making was not known. During 2004–2008,
we conducted a retrospective chart review to 1) determine
sociodemographic, clinical, and laboratory characteristics
of persons with a diagnosis of rifampin (RIF)-resistant TB
or MDR TB (i.e., resistance to RIF and isoniazid [INH]); 2)
determine the timing and use of DST results; 3) determine
the effect of DST results on treatment regimens used for
RIF-resistant and MDR TB; and 4) determine the associa-
tion between treatment regimen characteristics and treat-
Materials and Methods
For the evaluation, we selected patients with DST re-
sults demonstrating infection with RIF-resistant or MDR
TB who were registered for TB treatment during October
2004–September 2008 at health facilities within the Thai-
land TB Active Surveillance Network (10). The surveil-
lance network included 7 health centers in the Bangkok
Metropolitan Area and government hospitals in Chiang
Rai, Phuket, Ubon Rachathani, and Tak Provinces. Patients
from health facilities operated by private practitioners, non-
governmental organizations, or facilities serving solely as
referral centers that do not manage ongoing treatment and
outpatient care were excluded. Patients with incomplete
laboratory data (e.g., missing date of specimen collection
or missing DST results) and those with non-TB mycobacte-
rium infection or a change in diagnosis were also excluded.
Data Collection and Laboratory Testing
Trained clinic staff retrospectively collected patient in-
formation from routine medical and laboratory records onto
standardized forms. For each patient, we recorded dates for
the following: specimen collection for DST, receipt of DST
results at the clinic, and first clinic visit for patients after
DST results became available. We also recorded the date
of each clinic visit, all drugs and dosages included in treat-
ment regimens, and all treatment changes throughout the
course of treatment.
Sputum specimens from patients were cultured at a
provincial government laboratory by using Lowenstein-
Jensen solid culture and Mycobacterial Growth Indica-
tor Tube (MGIT) liquid culture (BACTEC 960, Becton-
Dickinson, Franklin Lakes, NJ, USA) according to stan-
dard procedures (11). Isolates were sent to the Bangkok
or Thailand Ministry of Public Health National Reference
Laboratory for identification and DST for first-line anti-TB
drugs (i.e., streptomycin [STR], INH, RIF, and ethambu-
tol [EMB]); Lowenstein-Jensen–based and MGIT-based
methods were used for DST.
Definitions and Treatment Regimens
Standard WHO definitions were used to categorize
patients according to TB treatment history, site of TB in-
fection, and treatment outcomes (2,12). Patients who com-
pleted treatment and those who were cured of TB were
considered to have successful outcomes; patients for whom
treatment failed and those who defaulted or died were con-
sidered to have poor treatment outcomes.
At the time this cohort of patients received a diagnosis
and was clinically managed, national guidelines in Thailand
recommended the use of standardized TB treatment regi-
mens for MDR TB (13). These guidelines were not consis-
tent with WHO guidelines (2); instead, they included only
3 months of a standard intensive-phase, injectable-based
regimen and provided the option of using STR, rather than
an aminoglycoside, as the injectable drug if the organism
did not have documented STR resistance (2,13). Second-
line drugs for MDR TB treatment were available to clini-
cians on request from a single source supported by the De-
partment of Disease Control, Thailand Ministry of Public
Health; the request process was not well standardized. For
the purposes of this analysis, anti-TB treatment for MDR
TB was considered appropriate if it was consistent with the
Thailand national guidelines or if it was based on at least
3 drugs presumed to be effective according to the patient’s
first-line DST results (13). At the time, there were no spe-
cific recommendations for treatment of RIF-resistant TB
in Thailand, and treating physicians were not required to
follow a specific standard for drug-resistant TB treatment.
We used frequencies and summary statistics to de-
scribe patient characteristics, DST patterns, DST turn-
around times, and treatment regimens prescribed for pa-
tients. Characteristics were assessed by each category of
drug-resistance (RIF-resistant or MDR TB) and for the to-
tal sample population. Baseline characteristics of patients
included in the analysis and of those excluded from analy-
sis were compared by using the Wilcoxon-Mann-Whitney
test for continuous variables and the χ2 test for categorical
variables; these tests were also used to compare RIF-resis-
tant and MDR TB patient groups in the analytic sample.
We used log-binomial analysis to calculate the odds ra-
tios (ORs) and 95% CIs to evaluate the association between
baseline demographic and clinical factors and prescription
of an inappropriate treatment among patients with MDR
TB. The analytic sample for evaluating the association
between treatment characteristics and treatment outcomes
was restricted to patients with final treatment outcomes
available (excluding patients who transferred out or who
were still receiving treatment) at the time of analysis. We
also used log-binomial regression analysis to calculate the
OR and 95% CI for the association between characteristics
of the treatment regimen and final treatment outcomes for
patients with RIF-resistant or MDR TB. All models were
initially age-adjusted, and other factors were chosen for in-
clusion in multivariate analyses if the p value was <0.20 in
bivariate analysis or if there was epidemiologic plausibility
or previously published evidence suggesting an association
with treatment outcomes. Collinearity and effect modifi-
cation were assessed for all variables in the multivariate
models. Significance was considered at p<0.05. We used
STATA version 10 (StataCorp, College Station, TX, USA)
for all analyses.
Patient and Clinical Characteristics
We identified a total of 490 patients as having TB that
was RIF-resistant (n = 121) or MDR (n = 369) (Figure
1). Of these 490 patients, 208 (36 with RIF-resistant TB
and 172 with MDR TB) were included in the evaluation.
Patients with RIF-resistant TB who were excluded from
analysis were substantially younger than those who were
included in the analysis, and a substantially larger propor-
tion of patients with HIV infection plus extrapulmonary
or pulmonary and extrapulmonary disease were excluded
from the RIF-resistant and MDR TB patient groups (Tables
1 and 2).
Among the 172 patients with MDR TB included in the
analysis, 89 (51.7%) were new TB patients, 60 (34.9%)
were retreatment patients, and 10 (5.8%) transferred in
from another facility (Table 2). Among the 36 patients with
RIF-resistant TB, 26 (72.2%) had newly diagnosed infec-
tion and 9 (25.0%) were retreatment patients (Table 2).
The median age of patients with RIF-resistant and MDR
TB was 42 years (interquartile range [IQR] 34–58) and 39
years (IQR 29–50), respectively (Table 1). Overall, base-
line characteristics were comparable for patients with RIF-
resistant and MDR TB. Most patients in both groups were
male, married, and HIVseronegative.
Of the 36 patients with RIF-resistant TB, 28 (77.8%)
had resistance to RIF alone. Another 4 (11.1%) also had
resistance to RIF and STR; 2 (5.6%) had resistance to
RIF and EMB; and 2 (5.6%) had resistance to RIF, EMB,
Among the 172 patients with MDR TB, 69 (40.1%)
had resistance to only INH and RIF. Another 13 (7.6%) had
resistance to INH, RIF, and EMB; 55 (32.0%) had resis-
tance to INH, RIF, and STR; and 35 (20.3%) had resistance
to STR and EMB.
Turnaround for Drug-Susceptibility Testing Results
The median time from collection of patient sputum
samples to clinic receipt of DST results was 97.5 days (IQR
66–133.3) (Table 3). The median time from clinic receipt
of DST results to physician review of results at the first
post-DST visit was 7 days (IQR 1–21). Overall, the median
time from sputum collection to the first physician review
of the DST result was 109.5 days (IQR 73–150). Patients
with MDR TB had longer diagnostic turnaround times than
patients with RIF-resistant TB.
Of the 172 patients with MDR TB included in the
analysis, 10 (5.8%) were initially prescribed an appropriate
treatment regimen, and 51 (29.7%) were prescribed appro-
priate treatment at some point during the treatment course.
Forty-one patients with MDR TB and 13 with RIF-resistant
TB were not eligible for treatment changes after clinic re-
sults became available: 31 of these MDR TB and all 13 pa-
tients with RIF-resistant TB had treatment outcomes before
the return of DST results, and the other 10 patients with
MDR TB were empirically treated with appropriate drugs.
Of the remaining 131 patients with MDR TB, 37
(28.2%) never had a treatment change, 53 (40.5%) had a
treatment change at the first clinic visit following availabil-
ity of DST results, and 41 (31.3%) had changes made later
in the treatment course. Of the 53 patients with a change
made at the first post-DST visit, 24 (45.3%; 18.3% of those
eligible for change) were prescribed on appropriate regi-
mens; 9 of the 24 changes were in accord with the national
treatment guidelines, and the 15 other changes were to >3
drugs presumed to be effective (Figure 2). Of the remain-
ing 29 MDR TB patients who had a regimen change at the
first post-DST visit, 3 were changed to a category I regimen
and 26 were placed on a nonstandard second-line treatment
combination. By 3 months after the first physician review
of the DST results, 51.7% of these 131 patients with MDR
TB received changes to their treatment plan, of which
≈20% were appropriate changes. At 12 months and onward
after the first physician review of DST results, ≈85% of
patients with MDR TB had changes to their treatment, of
which ≈30% were classified as appropriate adjustments.
Of the 23 patients with RIF-resistant TB who were
eligible for treatment changes, 4 (17.4%) had a treatment
Figure? 1.? Selection? of? patients? for? an?
analysis of drug-susceptibility testing
tuberculosis,? Thailand,? October? 2004–
and? were? from? 5? Thailand? provinces?
participating in the Thailand Active TB
Surveillance? Network.? TB,? tuberculosis;?
DST,? drug-susceptibility? testing;? MDR,?
patient? from? private? hospital;? NGO,?
patient from nongovernmental hospital;
change at the first post-DST visit, and the remaining 19
(82.6%) patients had changes made during subsequent
post-DST clinic visits. Of the 4 patients with RIF-resistant
TB who received regimen changes at the first post-DST
visit, 2 were changed to a nonstandard first-line treatment
combination (INH + pyrazinamide + EMB + STR or INH
+ EMB), 1 was changed to a nonstandard second-line
treatment combination (INH + EMB + ofloxacin), and 1
discontinued treatment due to hepatic cirrhosis. Figure 2
is restricted to MDR TB patients because there was no
written guideline on appropriate treatment of patients
with RIF-resistant TB in Thailand during the study pe-
riod; therefore, we were unable to differentiate between
appropriate and inappropriate changes for the patients
with RIF-resistant TB.
Baseline Factors and Appropriateness of Treatment
Examination of baseline factors associated with
prescription of an inappropriate treatment for MDR TB
case-patients indicated that retreatment patients were sig-
nificantly more likely than new patients to be prescribed
an inappropriate regimen (age-adjusted OR 2.6, 95% CI
1.0–6.3; p = 0.04) (Table 4). A significant association was
not identified between the time delay between sputum col-
lection and the first clinic visit following availability of
DST results and whether patients were prescribed appro-
Patient Group and Treatment Outcome
Twelve patients (2 with RIF-resistant TB, 10 with
MDR TB) with treatment outcomes that indicated they had
transferred out and 2 patients with MDR TB who were still
receiving treatment at the time of the evaluation were ex-
cluded from the final analytic sample (final n = 194; 34 RIF-
resistant TB and 160 MDR TB cases). Treatment success
was slightly greater among the RIF-resistant TB group than
the MDR TB group (76.5% vs. 60.6%, p = 0.08). Patients
who were not married (adjusted OR 2.3, 95% CI 1.2–4.6; p
= 0.01), who were HIV positive (adjusted OR 2.2, 95% CI
1.1–4.4; p = 0.04), and who received category II treatment
before receiving DST results (adjusted OR 2.6, 95% CI
1.1–6.4; p = 0.05) had poorer treatment outcomes (Table 5,
htm). In the analysis restricted to patients with MDR TB,
receiving inappropriate treatment was not significantly as-
sociated with poor treatment outcomes (OR = 0.77, 95% CI
0.3–1.8; p = 0.55).
This evaluation revealed that most treatment regimens
assigned to patients with RIF-resistant or MDR TB in se-
lected areas of Thailand were not based on DST results.
Less than one third of patients with MDR TB received ap-
propriate treatment, and patients who had previously re-
ceived treatment for TB were >2 times more likely to be
prescribed an inappropriate treatment regimen. When DST
results were available, treatment changes did not neces-
sarily reflect nationally recommended standard regimens
for drug-resistant TB or the resistance profile of the in-
fecting TB strain. In some cases, physicians probably did
not change to second-line treatment because of the clini-
cal condition of the patient; only 16% of patients overall
had smear-positive test results at month 5 (data not shown).
Persistence of smear-negative test results among identified
MDR TB cases has been cited as a reason for not changing
to a standardized MDR TB treatment regimen; other reasons
have included patient loss to follow-up, patient death, and
patient refusal to change treatment (14). A study evaluating
the influence of the microscopic observation drug suscep-
tibility (MODS) assay, which allows for determination of
drug susceptibility directly from sputum in just 7–10 days,
on the clinical management of TB patients also reported
that even when indicated, appropriate treatment regimen
changes were not always made (15). MDR TB treatment is
†p values reflect comparison between included and excluded patients in each TB drug resistance group.
‡p values reflect comparison between included RIF-resistant?patients?and?MDR?TB?patients.
TB, p value‡
highly decentralized in Thailand, and some clinicians may
not have been familiar with treatment guidelines.
The median delay from the time of sputum collec-
tion to the time DST results were available at the clinic
exceeded 14 weeks, and further delays were noted between
availability of results and a clinical encounter. During the
evaluation period, MGIT liquid culture was used for diag-
nosis of TB and of drug resistance; the turnaround time for
culture results is generally 4–6 weeks (4). Other studies
have also demonstrated the effect of clinic delays on TB
management, even when laboratory results are available in
a timely manner (9,14,16). The time interval for diagnosing
RIF-resistant and MDR TB in this evaluation was longer
than expected, probably due to constraints with specimen
transport, laboratory capacity, and administrative delays
in providing results to clinics. In addition, MDR TB result
reporting was further delayed because the implications for
regimen change were considered more serious for MDR TB
than for RIF-resistant TB; the reference laboratories tended
to hold MGIT-based DST results until they were confirmed
by solid culture. Our findings highlight these other sources
of delay beyond those intrinsic to a given assay as pivotal
for ensuring the benefits of rapid diagnostic technologies.
In this evaluation, patients with MDR TB were more
likely to receive an inappropriate initial treatment regimen
if they were a retreatment patient rather than a new pa-
tient. This finding suggests that retreatment cases should
be prioritized when considering the application of rapid
diagnostic technologies, and actions should be taken to ex-
pedite the transport and testing of specimens and reporting
results to the clinician. In addition, patients who initially
received category II treatment were significantly more
Site of TB
Abnormal, no cavity
Abnormal, with cavity
†p values reflect comparison between included and excluded patients in each TB drug resistance group.
likely to default, fail treatment, or die. This finding is con-
sistent with those of previous studies demonstrating the as-
sociation between category II treatment and poor outcomes
and the growing body of evidence advocating for the elimi-
nation of the category II retreatment regimen (17–21).
Multiple studies have reported high rates of treatment
success among patients prescribed individualized regimens
tailored to DST results (22–27). In a recent meta-analysis
of 33 studies in 20 countries evaluating MDR TB treatment
outcomes, individualized treatment had higher treatment
success compared with standardized regimens based on
local drug-susceptibility patterns (64 vs. 54%), although
the difference was not statistically significant (28). In our
study, the lack of direct association between the appropri-
ateness of the treatment regimen and treatment outcomes
among patients with MDR TB may have been due to the
small number of patients prescribed appropriate regimens
during the treatment course, or it may be that treatment de-
cisions based on other clinical factors were more pertinent
to determining outcomes.
Our analysis has limitations. First, patients were ex-
cluded if they had incomplete laboratory or clinic data, in-
cluding patients for whom the date of specimen collection
or receiving or reviewing the DST results at the clinic were
not recorded. However, we do not have any indication that
the omission of this information was systematic. Second,
it is possible that our conclusions are not representative of
all patients in Thailand with RIF-resistant or MDR TB. We
noted that a higher proportion of patients in the excluded
group than in the analytic sample were HIV positive and had
extrapulmonary TB; this disproportion possibly occurred
because of our inclusion requirement of complete labora-
tory data, and the microbiological yield from these 2 clinical
groups is often low. In addition, one referral facility with a
high proportion of HIV-associated TB cases was excluded
because as a facility providing episodic tertiary consultation,
they rarely have complete diagnostic and treatment data for
patients. Last, the data for our study were abstracted from
medical charts and routine surveillance not intended for spe-
cific research purposes; it is possible that some drug adjust-
ments were not identified. Because of the retrospective study
design, detailed information on factors considered in clini-
cal decision-making and treatment prescriptions for patients
was not available if it was not explicitly documented in the
medical records. DST is only one component considered in
prescribing treatment; the patient’s clinical status and risks
involved with alternate drugs are also key factors. The long
delays in obtaining DST findings may result in a heavier reli-
ance on clinical factors for prescribing decisions.
Future research that identifies reasons for the low
utilization of laboratory results when prescribing anti-TB
therapy will help to develop interventions that can facili-
tate optimal treatment for drug-resistant TB. Furthermore,
evaluation is needed to determine where and why delays
Table 3. Diagnostic turnaround for DST results for 130?RIF-resistant and?MDR?TB patients, Thailand?2004–2008*
Time from sputum collection to clinic receipt of results
Time from clinic receipt of results to review by physician†
Time from sputum collection to result review by physician†
*The?130?TB patients represented here were among?208?patients?from?5?Thailand provinces?participating?in?the?Thailand?Active?TB?Surveillance?Network.
Calculations?were?restricted?to?patients?who?had?complete?information?for?sputum?collection?date,?date?of?receipt?of?DST?at?the clinic, and date of the first
physician visit after availability of DST results. Three?MDR?TB?patients?were?missing?initial?sputum?collection?date,?14?RIF-resistant?and?41?MDR?TB?
patients?were?missing?date?of?receipt?of?DST?results?at?the?clinic,?and?16?RIF-resistant?and?47?MDR?TB?patients?were?missing?date?of first clinic visit
following receipt of DST results. DST, drug susceptibility test; RIF, rifampin;?MDR, multidrug-resistant; TB, tuberculosis;?IQR, interquartile range.
†Represents first post-DST clinic visit.
RIF-resistant TB (n?=?18)
Figure? 2.? Percentage? of? MDR-
TB patients who were eligible for
a? treatment? regimen? change? (n?
according? to? time? from? the? first?
review of DST result by the
physician, TB Active Surveillance
Network,? Thailand? 2004–2008.?
unrelated to assay result turnaround times occurred; such
delays may occur during specimen transport or processing,
or they may be related to the timing of clinic notifications
or the review of results by clinic physicians. Physicians’
knowledge of the national guidelines and treatment al-
gorithms as well as their ability to interpret and use DST
results to improve treatment regimens should be assessed.
Assessment of DST result uptake in other health sectors
(e.g., private practice, nongovernmental organizations, and
referral centers) would be informative because several par-
ticipants who were at high risk for treatment failure (i.e.,
patients with HIV infection or extrapulmonary disease)
were excluded from the current study.
In conclusion, utilization of DST results in the clini-
cal management of patients with RIF-resistant or MDR TB
was poor in Thailand during 2004–2008. Since the time of
this evaluation, access to second-line drugs has improved in
Thailand: the request process has been streamlined and stan-
dardized, and the national treatment guidelines have been
clarified and strengthened and disseminated to clinicians.
Attention to the DST reporting system has also reduced de-
lays somewhat. These factors will need to be considered in
assessing the effect of more rapid molecular testing methods.
This project was supported by the US Centers for
Disease Control and Prevention and US Agency for Interna-
Dr Lam is an Epidemic Intelligence Service Officer in the
Office of Surveillance, Epidemiology, and Laboratory Services,
Centers for Disease Control and Prevention, Atlanta, GA, USA.
His research interests include vaccine preventable diseases, TB
control, and DST.
Site of TB
Delay from sputum collection to firs post-DST visit, d
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