Monitoring for Slow Response to TB Treatment | CDC EID

EID Journal Home > Volume 16, Number 10–October 2010
Volume 16, Number 10–October 2010
Research
Therapeutic Drug Monitoring for Slow Response to Tuberculosis Treatment in a State Control Program, Virginia, USA

Scott K. Heysell Comments to Author, Jane L. Moore, Suzanne J. Keller, and Eric R. Houpt
Author affiliations: University of Virginia, Charlottesville, Virginia, USA (S.K. Heysell, E.R. Houpt); and Virginia Department of Health, Richmond, Virginia, USA (J.L. Moore, S.J. Keller)

Suggested citation for this article

Abstract
Therapeutic drug monitoring may be useful in tuberculosis management, but programmatic implementation is understudied. We performed a retrospective cohort study to determine prevalence of lower than expected levels of isoniazid, rifampin, ethambutol, and pyrazinamide measured at time of estimated peak serum concentration. Patients were tested for serum concentration at 2 hours after medication administration. When patients were tested, 22 had concentrations lower than expected range for rifampin, 23 of 39 patients had low levels of isoniazid, and 8 of 26 patients had low levels of ethambutol; all 20 patients tested for pyrazinamide were within expected range. Over 26 months, 42 patients met criteria for slow response. Diabetes was associated with slow response (p<0.001), and persons with diabetes were more likely than persons without diabetes to have low rifampin levels (p = 0.03). Dosage adjustment of rifampin was more likely to elevate serum concentration to the target range than adjustment of isoniazid given in daily doses (p = 0.01).

Worldwide, tuberculosis (TB) remains the leading cause of death from a curable infectious disease; »1.4 million deaths occurred in 2008 alone (1). Death is a consequence of delayed diagnosis and ineffective or incomplete treatment because cure rates exceed 95% with appropriate therapy (2). Slow response to therapy can lead to prolonged infectiousness, extended treatment duration, acquired drug resistance, or recurrence of TB after treatment. The reasons for slow response are diverse, but measurement of serum anti-TB drug levels, or therapeutic drug monitoring (TDM), is a potentially useful tool for uncovering the causes of slow response (3,4). Low serum levels can be a consequence of malabsorption, inaccurate dosing, altered metabolism, or drug–drug interactions (4), but in most instances low serum levels can be readily corrected with dose adjustment.

TDM is currently recommended in TB treatment guidelines as optional (5), and few large TB control programs have access to routine TDM. Although published reports describe patients for whom slow response was attributable to low drug levels, questions remain about how best to implement TDM on a programmatic scale (6,7). Definitions of slow response vary, and recommendations for which medications to prioritize for TDM are lacking. Furthermore, for general populations receiving TB therapy, TDM is unlikely to be of benefit, given the infrequency of treatment failure or TB recurrence (8). Although it is well known that certain patients, such as those infected with HIV and thus prone to malabsorption, are at higher risk for low drug levels (9–12), studies of TDM that included patients responding well to anti-TB medications found lower than expected drug levels of isoniazid and rifampin in many patients with adequate clinical response (13,14). Therefore, identification of patients at risk for slow response is critical within a TB control program. In addition, TDM performed earlier in the time course of slow response may also affect other major programmatic outcomes, such as treatment duration.

In the state of Virginia it is mandatory for providers to report all cases of TB to the Virginia Department of Health. Each case is assigned to a nurse case manager, who oversees and monitors the progress of each patient until treatment is completed. Directly observed therapy is administered by the nurse case manager or a trained outreach worker. After 4 weeks of therapy, patients are screened by the nurse case manager. Medical consultation for patients with ongoing symptoms is provided by the state TB clinicians in an effort to identify slow response earlier and to prevent acquired drug resistance. Clinicians define slow response in a patient as after ≥30 days from the start of treatment the patient has ≥2 of the following findings: sputum smear positive for acid-fast bacilli; no improvement in TB-specific symptoms, including fever, cough, weight loss, and/or night sweats; and no improvement in chest radiograph lesions previously identified as consistent with TB. Routine TDM among patients who met criteria for slow response was instituted by March 2007.

We performed a retrospective cohort study among patients slow to respond to pulmonary TB treatment in the state of Virginia to determine the prevalence of lower than expected levels of isoniazid, rifampin, ethambutol, and pyrazinamide measured at the time of estimated peak serum concentration (Cmax). Secondary aims included investigation of risk factors for levels below the expected range, evaluation of the mean change and likelihood of achieving a level within the expected range after dose adjustment, and comparison of outcomes between persons with slow responses with those with low and expected levels. The study was approved by the institutional review boards for human subjects research at the University of Virginia and the Virginia Department of Health.

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Suggested Citation for this Article

Heysell SK, Moore JL, Keller SH, Houpt ER. Therapeutic drug monitoring for slow response to tuberculosis treatment in a state control program, Virginia, USA. Emerg Infect Dis [serial on the Internet]. 2010 Oct [date cited].
http://www.cdc.gov/EID/content/16/10/1546.htm

DOI: 10.3201/eid1610.100374