During the study, 350 patients were treated with an initial regimen of isoniazid, rifampin, ethambutol, and pyrazinamide for pulmonary TB; of these patients, 45 (13%) met criteria for slow response. Thirty-seven patients were excluded from the study (34 with normal response and 3 with slow response) after drug-susceptibility testing showed resistance to >1 medication of the treatment regimen. An additional 2 patients were excluded because TDM was performed for reasons other than slow response. Thus, 311 patients were included in the study, of whom 42 (14%) met criteria for slow response (Table 1). At the time of TDM among patients meeting criteria for slow response, all had persistent TB-related symptoms. Of the 23 patients with initial smear-positive sputum specimens, 17 (74%) had specimens that remained smear positive.

The mean (SD) age for patients in the study was 46 years (20 years), and 204 (65%) were men (Table 1). The most common ethnicity was Asian (102 [33%]) and 228 (73%) were foreign born. Among all patients, 291 (93%) had no history of TB. Most patients tested had a positive tuberculin skin test (TST) result, although 85 (27%) did not have a TST reading recorded. There were 287 patients with a sputum smear recorded at the time of diagnosis; of these smears, 193 (62%) were positive for acid-fast bacilli. Ninety-five percent (295) of patients had a chest radiograph with findings suggestive of TB, of which 122 (39%) were cavitary. There was no significant difference in the proportion of patients with a positive TST result, a positive sputum smear, or a chest radiograph showing cavitation among the 42 with a slow response and the remaining patients with adequate response. Among patients meeting criteria for slow response, none were HIV infected and none reported using illicit drugs (either intravenous or nonintravenous). The only significant predictor of slow response was diabetes (unadjusted odds ratio [OR] 6.5, 95% confidence interval [CI] 3.2–13.5, p<0.001; adjusted OR [aOR] 6.3, 95% CI 2.8–14.0, p<0.001).

The major finding of this study is that among patients being treated for pulmonary TB in Virginia, most patients that met criteria for slow response to therapy were found to have C_2hr levels of rifampin and isoniazid below the expected range; many patients also had low levels of ethambutol. Given the high frequency of patients who were slow to respond to both key first-line medications, isoniazid and rifampin, and the well-tolerated subsequent increase in levels documented after dose adjustment, TDM appears to be a useful strategy for identifying a remediable cause of slow response at a programmatic level. Furthermore, the median duration of therapy for patients with rifampin levels below the expected range was nearly 2 months shorter than that for patients with normal rifampin levels. Although it is not specifically known if identification and correction of lower than expected levels brought about a rapid improvement in TB clinical signs and symptoms, the comparatively shorter course represents a substantial cost savings when considering personnel involved in monitoring and medication administration, as well as diagnostic tests averted in the work-up of otherwise unexplained slow response.

We found that ≈90% of patients with lower than expected rifampin levels who were subsequently tested after the first dose adjustment achieved target levels. Dose-titration studies of rifampin confirm a continuously increasing response of early bactericidal activity by measurement of sputum colony counts with corresponding increase in rifampin dose (16,17). Rifampin has been tolerated at doses as high as 1,200 mg in small studies, and larger trials are ongoing to study high-dose rifampin in an effort to shorten therapeutic duration (18,19). Given increasing evidence that rifampin may be underdosed for many patients regardless of TB outcome (20), the findings of this study suggest that rifampin is a prime medication to prioritize for early TDM for patients for whom TB therapy is failing.

Diabetes was significantly associated with slow response in our study population, and, among persons with a slow response with diabetes, C_2hr levels of rifampin were significantly more likely to be below the expected range. Patients with diabetes are at greater risk for incident TB (21,22) and are more likely to have poor TB treatment outcomes (23,24), which may partially be explained by inadequate pharmacotherapy. A growing body of evidence has demonstrated reduced rifampin exposure in patients with TB and diabetes, which may be in part related to impaired absorption (25,26). Although rifampin absorption may not be blunted by delayed gastric emptying (27), hyperglycemia can decrease gastric hydrochloric acid secretion, which results in a higher gastric pH and reduced rifampin absorption (25). Markers of glycemic control were not available for analysis in this study, but it may be of further use to risk stratify patients with diabetes based on disease severity. It is suspected, though not tested, that drug–drug interactions were also playing a role in the observed lower levels of rifampin in patients with diabetes from our study population. Given preexisting knowledge of the association between diabetes and poor treatment outcome, there may have been a bias on behalf of the TB control staff to characterize a patient with diabetes as a person with a slow response based on symptom persistence. Nevertheless, our findings raise the possibility of TB programs studying the benefit of routine TDM for rifampin among all patients with diabetes at the start of TB therapy.

Routine TDM among persons with slow responses at a relatively early point in the treatment course reflects policy change within Virginia’s TB control program. Given the high prevalence of low levels of key medications and the observed ease of correction after dose adjustment, we recommend that similar TB programs investigate the applicability of TDM within their own settings. Further generalization must be cautiously considered, however, because relevant factors that may adversely affect pharmacokinetics, such as the patient’s weight at the time of TDM, concurrent medication use, chronic kidney disease, or cirrhosis, were not available in these surveillance data for comparison (28–30). Other limitations to the study must be taken into account. Blood was collected at 2 hours after medication administration to estimate C_max. A second blood collection at 6 hours can additionally distinguish patients whose absorption may be delayed secondary to poor gastric emptying (4); however, the frequency of delayed absorption has been rare in other cohorts for which 2 and 6 hour measurements were performed (10).

Additionally, given that the prevalence of lower than expected drug levels was not known for patients with adequate response to anti-TB therapy, the overall contribution of pharmacotherapy to the cause of slow response in this cohort cannot be fully assessed. Surveillance data did not permit comparison of culture positivity in patients who met criteria for slow response at the time of TDM matched to patients with adequate response for whom TDM was not performed. Use of TDM as early as 4 weeks, as was performed in this study, may have selected for patients that might otherwise have improved after 8 weeks of therapy regardless of other interventions. Lastly, further study may find, given that the cost of TDM (≈$80 US per individual drug) may be substantial for some TB control programs, that it is more economical to start therapy with increased drug dosages for patients at higher risk for slow response.

In summary, routine TDM among patients meeting criteria for slow response to TB therapy in Virginia identified most of those tested to have C_2hr levels of rifampin and isoniazid below the expected range; many patients also had low levels of ethambutol. Most patients with repeat TDM following dose adjustment to rifampin and isoniazid had levels within the expected range, suggesting a clinically actionable result. Given the comparative ease of correcting low rifampin levels and the shorter duration of therapy in those with a correctable rifampin level, this medication is particularly appealing to target for programmatic intervention. Further prospective studies should evaluate the benefit of routine TDM for rifampin early in the treatment course among patients with diabetes or of higher initial doses of rifampin among all groups at risk for slow response.