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MAJOR ARTICLE
Background. Individualized treatment for multidrug-resistant (MDR) tuberculosis and extensively drug-
resistant (XDR) tuberculosis depends upon reliable and valid drug susceptibility testing (DST) for pyrazinamide,
ethambutol, and second-line tuberculosis drugs. However, the reliability of these tests is uncertain, due to unresolved
methodological issues. We estimated the association of DST results for pyrazinamide, ethambutol, and second-line
drugs with treatment outcomes in patients with MDR tuberculosis and XDR tuberculosis.
Methods. We conducted an analysis of individual patient data assembled from 31 previously published cohort
studies of patients with MDR and XDR tuberculosis. We used data on patients’ clinical characteristics including DST
results, treatment received, outcomes, and laboratory methods in each center.
Results. DST methods and treatment regimens used in different centers varied considerably. Among 8955
analyzed patients, in vitro susceptibility to individual drugs was consistently and significantly associated with higher
odds of treatment success (compared with resistance to the drug), if that drug was used in the treatment regimen.
Various adjusted and sensitivity analyses suggest that this was not explained by confounding. The adjusted odds of
treatment success for ethambutol, pyrazinamide, and the group 4 drugs ranged from 1.7 to 2.3, whereas for second-
line injectables and fluoroquinolones, odds ranged from 2.4 to 4.6.
Conclusions. DST for ethambutol, pyrazinamide, and second-line tuberculosis drugs appears to provide
clinically useful information to guide selection of treatment regimens for MDR and XDR tuberculosis.
Keywords. tuberculosis; drug susceptibility test; treatment outcomes; multidrug resistant; meta-analysis.
2 • CID • Bastos et al
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Figure 1. Flowchart of study selection. Abbreviations: MDR-TB, multidrug-resistant tuberculosis; XDR-TB, extensively drug-resistant tuberculosis.
clarithromycin, azithromycin, linezolid, thioacetazone) were outcome was defined in 2 ways: (1) as failure or relapse, or (2) as
not analyzed because very few centers performed DST for failure or relapse or death [13].
these drugs. Patients who received >1 quinolone or injectable The primary analyses estimated odds of treatment success (vs
drug were excluded from this analysis. fail/relapse or fail/relapse/death) associated with use of each
drug when their Mycobacterium tuberculosis isolate was suscep-
Data Analysis tible vs resistant to that drug. In secondary analysis; treatment
We defined treatment outcomes as successful if cure was outcomes were assessed in 2 strata: when critical concentrations
achieved or treatment was completed, whereas an unsuccessful used to define drug resistance were as recommended, or higher
and 68% were male; 60% had had previous treatment with Abbreviations: DST, drug susceptibility testing; FLD, first-line drug; HIV, human
immunodeficiency virus; PAS, para-aminosalicylic acid; SLD, second-line drug.
first-line tuberculosis drugs, and 11% with second-line drugs. a
Patients with at least 1 result of DST to any second-line tuberculosis drug
Extensive disease, defined as cavities on chest radiography (other than streptomycin).
and/or acid-fast bacilli smear positive, was present in 72%. b
Patients without any results of DST for second-line tuberculosis drugs.
c
HIV serology was positive in 12% of patients, but only 1.3% Only 15 patients on antiretrovirals, 14 who had second-line DST.
d
of these patients were placed on antiretroviral therapy during Extensive disease defined as acid-fast bacilli smear positive and/or cavities on
chest radiography.
tuberculosis treatment (Table 1).
Among the 31 included studies, 27 reported results of DST
to PZA and EMB, and 26 studies reported methods and results
of DST to second-line drugs. Solid media were more common- drugs (Supplementary Table 2) used in the laboratories of
ly used. Methods of DST and critical concentrations for first- the participating centers are detailed in the Supplementary
line (Supplementary Table 1) and second-line tuberculosis Data.
4 • CID • Bastos et al
Table 2. Treatment Outcomes (Cure/Complete Versus Failure/Relapse) According to Drug-Specific Susceptibility Testing Result Among
Patients With Multidrug-Resistant and Extensively Drug-Resistant Tuberculosis Who Took That Drug
Association of DST Results and Treatment Outcomes compared with resistant to that specific drug (Table 2). Similar
Compared with failure/relapse, use of each of the drugs ana- results were found when death was included as part of the un-
lyzed was associated with significantly higher odds of treat- successful outcomes (ie, success vs failure/relapse/death)
ment success when the M. tuberculosis isolate was susceptible (Table 3).
Table 3. Treatment Outcomes (Cure/Complete Versus Failure/Relapse/Death) According to Drug-Specific Susceptibility Testing Result
Among Patients With Multidrug-Resistant and Extensively Drug-Resistant Tuberculosis Who Took That Drug
The estimated association of resistance and drug effect did Next, use of each drug when the isolate was resistant or
not vary importantly across studies in most cases. The estimated sensitive to that drug was assessed according to whether the iso-
heterogeneity of parameter estimates was nonzero and statisti- late was also resistant to another second-line drug. As seen in
cally significant only for ethambutol when the unsuccessful out- Table 6, the use of any of the drugs when resistant to those
come was failure/relapse/death. The estimate was nonzero and drugs was not associated with resistance to most of the other
statistically significant for kanamycin and ofloxacin for failure/ drugs, with a few exceptions. The most consistent finding was
relapse (data not shown in tabular form). that when there was resistance to fluoroquinolones, then PZA,
amikacin/kanamycin, ethionamide/prothionamide, and cyclo-
Assessment of Potential Confounding serine were all more likely to have been used despite in vitro re-
Use of a certain drug despite in vitro resistance to that drug may sistance to these agents. The other consistent finding was use of
be associated with worse outcomes simply because fewer treat- capreomycin, despite resistance, if the isolate was resistant to
ment options were available—because of associated resistance to pyrazinamide, streptomycin, or amikacin/kanamycin.
other drugs, or fewer second-line drugs available at a given cen- The use of PZA, EMB, fluoroquinolones, or second-line inject-
ter. To assess this, we performed several analyses. ables despite in vitro resistance to the same drugs was seen in vir-
First, estimates were adjusted for the same clinical character- tually all centers. There was no discernible association with use of
istics as in Tables 2 and 3, plus PZA resistance, or also PZA and/ other second-line drugs, or patterns of resistance to other second-
or fluoroquinolone resistance, or also PZA, fluoroquinolone, line drugs (Supplementary Tables 4A–E). This suggests that lim-
and/or second-line injectable resistance. As seen in Tables 4 ited availability of alternative drugs at the participating centers was
and 5, even after these additional adjustments, odds of treat- not an explanation for the use of drugs despite in vitro resistance.
ment success remained significantly greater if the isolate was Finally, the effect of PZA, EMB, streptomycin, cycloserine,
sensitive to the drug in question with a few exceptions. PAS, and capreomycin resistance was stratified by the critical
6 • CID • Bastos et al
Table 5. Treatment Outcomes (Cure/Complete Versus Failure/Relapse/Death) According to Drug-Specific Susceptibility Testing Result
Among Patients With Multidrug-Resistant and Extensively Drug-Resistant Tuberculosis Who Took That Drug: Additional Adjustments
concentrations used. If M. tuberculosis isolates were considered isolate was known to be resistant to that drug was because of
to be susceptible to PZA or EMB, the odds of success compared additional resistance or lack of access to certain drugs at some
to failure/relapse were somewhat higher when the critical con- centers. These findings suggest that DST results, using current
centration values to distinguish susceptible from resistant were methods, can be useful for selection of tuberculosis drugs in in-
higher than recommended (Table 7). There was no difference in dividualized treatment of patients with MDR tuberculosis.
outcomes for the other drugs analyzed. Results were similar This study had a number of strengths. The most important
when success was compared with failure/relapse/death (Supple- was the size of the study population—8955 patients with
mentary Table 3). Additional analyses stratified by performance MDR tuberculosis were included, making this the largest anal-
of DST on solid or liquid media found no substantial or consis- ysis of the clinical significance of DST for second-line drugs. To
tent difference in findings (results not shown in tabular form). our knowledge, this is the first evidence of the association of
DST results for second-line drugs and treatment outcomes.
DISCUSSION These analyses also represent an important extension of find-
ings from the original 31 cohorts. No single cohort had ade-
In this study, the impact of in vitro resistance to various second- quate power to assess the utility of DST to individual drugs;
line drugs on individual treatment outcomes was analyzed compiling all patients into 1 large dataset provided much great-
among 8955 patients from 31 centers located in countries in er power for this analysis. In this regard, the results for group
all WHO health regions. For all drugs tested, use of that drug drugs 4 should be particularly useful, as there is very little evi-
was associated with higher odds of treatment success compared dence regarding clinical utility and validity of DST for this class
with failure and relapse, or compared with failure, relapse, and of drugs [4].
death if the isolate was susceptible rather than resistant to that These findings should be generalizable, as the patients were
drug. We did not find evidence that use of a drug when the treated at 31 different centers, which were located in all WHO
Capreomycin-
PZA-Resistant Ethambutol- Streptomycin- Amikacin/Kanamycin- Resistant
Strains Resistant Strains Resistant Strains Resistant Strains Strains
Drug DST Result No. PZA Used No. EMB Used No. SM Used No. AMK Used No. CAP Used
Use of drug when MDR tuberculosis strain also resistant to:
PZA Sensitive ... ... 1196 22% 1156 10% 357 17% 107 32%
Resistant ... ... 1865 26% 1733 7% 884 21% 380 47%
EMB Sensitive 607 24% ... ... 1239 11% 311 17% 134 43%
Resistant 1863 35% ... ... 2656 9% 1351 19% 471 48%
SM Sensitive 815 36% 1136 24% ... ... 236 20% 66 12%
Resistant 1733 31% 2656 25% ... ... 1441 18% 539 51%
AMK/KAN Sensitive 1612 33% 1351 24% 2195 7% ... ... 133 15%
Resistant 884 34% 2264 26% 1441 9% ... ... 467 55%
CAP Sensitive 1377 35% 2056 28% 2434 5% 892 17% ... ...
Resistant 380 31% 471 28% 539 9% 467 18% ... ...
FQN Sensitive 1620 26% 2461 17% 2528 6% 1042 17% 399 47%
Resistant 466 38% 609 21% 532 10% 383 30% 104 47%
Drug DST Result No. FQN Used No. ETH Used No. Cs Used No. PAS Used
8 • CID • Bastos et al
Table 7. Treatment Outcomes (Cure/Complete Versus Failure/Relapse) According to Drug Susceptibility Testing Using Recommended or
Higher Than Recommended Critical Concentrations Among Patients Who Took That Druga
OR of Treatment Success if Susceptible to the Drug OR of Treatment Success if Susceptible to the Drug
Used (Cure/Complete vs Failure/Relapse); Used (Cure/Complete vs Failure/Relapse);
Reference = Resistant to Drug Used Reference = Resistant to Drug Used
No. Given the Drug, No. Given the Drug, No. Given the Drug, No. Given the Drug,
Unadjusted OR Adjusted ORb Unadjusted OR Adjusted ORb
DST for Drug (95% CI) (95% CI) (95% CI) (95% CI)
Pyrazinamide: 1275 1275 68 68
21 studies at recommended and 2 2.0 (1.4–3.0) 2.0 (1.3–3.0) 3.9 (1.0–16.2) No convergencec
studies at higher
Ethambutol: 1148 1148 185 185
17 studies at recommended and 3 1.6 (1.1–2.3) 1.5 (1.1–2.4) 2.0 (.9–4.7) 2.2 (1.0–5.3)
studies at higher
Streptomycin: 197 197 434 434
7 studies at recommended and 12 1.1 (.2–5.0) No convergencec 1.8 (.9–3.4) 1.8 (.9–3.5)
at studies higher
Capreomycin: 240 240 235 235
world regions, including some very resource-limited settings. and therapy was individualized in most patients. Therefore,
Hence, local treatment practice, study populations, and strains the use of certain drugs was likely to have been influenced by
of M. tuberculosis were highly variable. Treatment regimens also clinical characteristics such as disease severity, prior treatment,
varied considerably at different centers, more than would be ex- resistance patterns, and concomitant use of other drugs. To ac-
plained on the basis of different patient characteristics, includ- count for this, we adjusted in multivariate analysis for several
ing DST results. Instead, these differences may have reflected factors, including HIV coinfection and severity of disease. How-
local medical opinions and beliefs. We did not find evidence ever, we did not have data on the duration of treatment with
that this was due to lack of availability of certain drugs, but some each individual drug; therefore, we could not analyze the impact
physicians may have considered the DST unreliable for second- of length of treatment with each drug on odds of treatment suc-
line drugs or for PZA and EMB and thus not used these results cess when the tuberculosis was susceptible or resistant to that
to guide therapy. This quasi-experimental evidence from vary- drug.
ing treatment approaches in many different centers, indepen- Even after adjusting for patient characteristics and extent of
dent of patient characteristics and DST results, strengthens drug resistance, residual confounding could remain, due to un-
the value of these findings related to use or nonuse of certain measured differences between patients who received different
drugs despite DST results. therapy. This residual confounding would best be controlled
However, this study also had important limitations. All the by conducting multiple randomized clinical trials comparing
data available were derived from observational cohort studies, the use or nonuse of each individual drug with randomization
10 • CID • Bastos et al
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