Participating laboratories reported a total of 123,724 test results on 116 isolates. For first-line drugs, 65,542 results were reported that included tests for duplicate and repeated strains. For the purpose of these analyses, shows that a total of 57,733 test results were performed for first-line drugs on 94 unique MTBC strains from 216 laboratories. Out of 94 unique strains, 68 strains were resistant; this included 15 low-level INH-resistant strains. Results were not included when not performed according to CLSI-recommended combinations of methods and drug concentrations for the first-line drugs, second-line drugs, or nonstandard drugs. demonstrates that most results were reported as susceptible, because four drugs are tested for each strain and most strains were resistant to only one drug (or susceptible to the four first-line drugs). There were fewer PZA results, because this drug is not recommended for testing with the AP method. The agreement rates for resistance to the four first-line drugs varied: INH, 92.2%; RMP, 91.5%; EMB, 79.0%; and PZA, 97.5%.
shows the distribution of the results by test method and reflects that most participants used the recommended rapid method, which was Bactec for most of the period of this analysis. The agreement rates by methods for resistant strains were 91.3% for AP, 93.0% for Bactec, and 82.6% for MGIT.
Numbers of drug susceptibility tests by laboratory method and resulta
shows the trends in laboratories reporting results by testing method and represents the number of laboratories reporting results for the AP, Bactec, and MGIT methods over the course of the study period. These results demonstrate the gradual adoption of MGIT by the laboratories after FDA clearance of this assay in 2003. Some laboratories reported results for more than one method. Most laboratories reporting results for AP also reported results by Bactec or MGIT. Many referral laboratories, including state public health laboratories, maintain both the reference AP method in addition to a recommended rapid liquid culture and would use the MPEP to assess both test methods side by side for each strain and therefore provided more than one set of results for each strain.
Fig 1 Trends in laboratories reporting results by testing method. Method use during the study, showing the adoption of MGIT since its inception in 2003 by the majority of laboratories. Some labs reported results for more than one method. (The majority of laboratories (more ...)
provides the success rate of detecting drug resistance or susceptibility as determined by the majority result for each drug. This table breaks down all of the results by aggregated participant results and whether each achieved the expected result for susceptibility or resistance for every combination of method and drug. Overall agreement with the expected result was 97.0% for INH, RIF, EMB, and PZA by AP, Bactec, and MGIT methods. The ability to detect susceptibility is generally high (≥95%) for all drug-method combinations, and the combined success rate among susceptible strains was 98.4%. In our analysis, failure to detect resistance was more common than finding false resistance, and the combined success rate for detecting resistance among all methods was 91.0%. divides the results for the combined detection of all INH resistance and the results in specifically detecting INH resistance with the 15 strains exhibiting low-level INH resistance. The overall detection of INH resistance, which was 92.9% by AP, 91.6% by Bactec, and 92.6% by MGIT, is skewed by the relatively easier detection of the 18 strains with high-level INH resistance that were detected with agreement rates of 99% by AP and 98% by Bactec and MGIT (data not shown). For low-level INH-resistant strains, the agreement rate dropped to 82.8% by AP, 82.3% by Bactec, and 79.6% by MGIT. The combined data indicate equivalent performance for INH by all three methods with both high-level and low-level resistant strains. However, when examining low-level INH-resistant strains, there is notable variation by each method. illustrates the proportion of participants detecting low-level INH resistance for each of the six low-level INH resistance strains for which results were available using each of the three methods during the study period. Although aggregate results indicate equivalency among the methods for these strains, there is significant variation in detection of individual strains by method.
Success rate of detecting drug resistance or susceptibility as determined by the majority result for each druga
Fig 2 Success rate for 6 strains with low-level INH resistance for which test results were available for all three methods. These selected strains demonstrate the variability in detecting low-level INH resistance among the methods. No one method was uniformly (more ...)
indicates some specific problems with detection of EMB resistance with the 7H11 and MGIT methods. Although there were fewer laboratories using 7H11, the results for EMB were distributed throughout the study period. In the case of MGIT, this decreased detection represents only a few strains in the last 5 years of the analysis; however, for these strains, the differences in performance between 7H10, Bactec, and MGIT are substantial. There was reduced detection of RMP resistance with the MGIT method, with a 66.7% agreement rate compared to 94.4% for AP and 95.0% for Bactec. These results were largely due to two RMP-resistant strains sent in June 2006 and June 2008 that resulted in substantial discordance between the methods, with detection of RMP resistance at 69.7% for AP, 58.6% for Bactec, and 28.3% for the MGIT method for the June 2006 strain and 70.4% for AP, 41.7% for Bactec, and 18.8% for the MGIT method for the June 2008 strain. These two strains were later characterized as having rpoB
mutations (His526Leu) that were documented by Van Deun et al. (26
) and characterized by that group as having what was termed “borderline RMP resistance.” There was no prior knowledge of this particular level of resistance, however, and both strains were selected based on the pattern of resistance to RMP and susceptibility to INH among drugs tested.
shows the percentage of laboratories achieving a given success rate for detection of resistance for each of the first-line drugs. Results are shown only for either of the recommended rapid liquid-culture methods because, unlike AP, the rapid methods would be the methods used to routinely test patient isolates for drug resistance. Although there are a few laboratories with lower performance for each drug, agreement in detecting resistance is distributed widely. There are lower agreement rates for detection of EMB resistance across a large proportion of the laboratories. There were fewer PZA-resistant strains included in the panels, and these presented less of a performance challenge in this program.
Fig 3 Percent of laboratories achieving success rate in detecting resistance among the resistant strains, susceptibility among susceptible strains, and resistance and susceptibility for all strains by all laboratories using rapid methods for the first-line (more ...)
No significant difference in performance of testing was observed either by laboratory type (health department, hospital, independent) or by test volume (range of 1 to 17,000 tests per year). Independent laboratories, health departments, and hospitals achieved 96.6%, 96.2%, and 95.8% success, respectively (analysis of variance [ANOVA], F-test, P = 0.579); for susceptible specimens only, concordance rates were 97.8%, 97.8%, and 97.3%, respectively (P = 0.596); for resistant specimens, concordance rates were 90.9%, 87.8%, and 88.2%, respectively (P = 0.514). Annual test volume was divided into four groups: group 1 (<14 tests), group 2 (14 to 120 tests), group 3 (120 to 1,145 tests), and group 4 (>1,145 tests). Overall concordance was 95.2%, 96.2%, 96.4%, and 94.5% for the four groups, respectively (ANOVA, F-test, P = 0.175). For susceptible specimens, concordance rates were 96.6%, 97.6%, 98.1%, and 96.1%, respectively (P = 0.088). For resistant specimens, concordance rates were 89.3%, 89.3%, 87.7%, and 85.0%, respectively (P = 0.458).