Therapeutic Drug Monitoring of Antimycobacterial Drugs in Patients with Both Tuberculosis and Advanced Human Immunodeficiency Virus Infection

Therapeutic drug monitoring in tuberculosis remains controversial. We evaluated the relationship between antituberculosis drug levels in blood and clinical outcome. Serum concentrations of first-line antituberculosis drugs were measured in tuberculosis patients between March 2006 and April 2013. Venous blood was drawn 2 h after drug ingestion and was analyzed using highperformance liquid chromatography-tandem mass spectrometry. We retrospectively reviewed the data and determined the association of serum drug levels with clinical outcome. Among 413 patients, the prevalences of low serum concentrations of isoniazid (INH), rifampin (RMP), ethambutol (EMB), and pyrazinamide (PZA) were 59.9%, 27.8%, 12.8%, and 8.7%, respectively. The low INH group had a greater percentage of patients with a history of tuberculosis treatment (19.2% versus 11.0%; P ‫؍‬ 0.026) and was more likely to present with drug-resistant strains (17.6% versus 8.8%; P ‫؍‬ 0.049) than the normal INH group; however, low levels of INH, RMP, EMB, and PZA were not related to treatment outcome. Low INH level had a tendency to be associated with 2-month culture positivity, but it was not statistically significant (P ‫؍‬ 0.072) in multivariate analysis. Seventeen (4.1%) patients experienced a recurrence. However, the recurrence rate was not statistically different between the low and normal INH groups. Low serum INH may play a role in recurrence and in acquired drug resistance. However, the serum level of INH was not directly related to either treatment response or recurrence rate. The role and usefulness of therapeutic drug monitoring should be evaluated in further prospective studies.

Section: Discussionmentioning

confidence: 99%

Serum Levels of Antituberculosis Drugs and Their Effect on Tuberculosis Treatment Outcome

Park

Lee

et al. 2016

“…In addition, 6 weeks after inclusion in the study, full pharmacokinetic curves were obtained in nine subjects. Serial venous blood samples were collected just before, and at 0.5, 1, 1.5, 2, 2.5, 3,4,6,8,12, and 24 h after observed TB drug intake. Plasma was separated and stored at Ϫ80°C immediately until transport on dry ice to the Netherlands for bioanalysis.…”

Section: Methodsmentioning

confidence: 99%

“…Inadequate exposure to anti-TB drugs may constitute one of the factors underlying suboptimal treatment response (1,2). Among adults, low plasma concentrations of anti-TB drugs have been found in patients with HIV infection, gastrointestinal tract disorders, high body weight, male gender, or diabetes mellitus (DM) (3)(4)(5)(6)(7)(8)(9)(10)(11) and in fast acetylators for isoniazid (12). Low plasma concentrations can also result from interindividual variability in drug absorption, metabolism, or excretion (3,13).…”

mentioning

confidence: 99%

Isoniazid, Rifampin, and Pyrazinamide Plasma Concentrations in Relation to Treatment Response in Indonesian Pulmonary Tuberculosis Patients

Burhan

Ruesen

Ruslami

et al. 2013

f Numerous studies have reported low concentrations of antituberculosis drugs in tuberculosis (TB) patients, but few studies have examined whether low drug concentrations affect TB treatment response. We examined steady-state plasma concentrations of isoniazid, rifampin, and pyrazinamide at 2 h after the administration of drugs (C 2 h ) among 181 patients with pulmonary tuberculosis in Indonesia and related these to bacteriological response during treatment. C 2 h values below reference values for either isoniazid, rifampin, or pyrazinamide were found in 91% of patients; 60% had at least two low C 2 h concentrations. The isoniazid C 2 h was noticeably lower in fast versus slow acetylators (0.9 mg/liter versus 2.2 mg/liter, P < 0.001). At the end of treatment, 82% of the patients were cured, whereas 30 patients (17%) had dropped out during the study, and 2 patients (1%) failed treatment. No association was found between C 2 h concentrations and sputum culture results at 8 weeks of treatment. Post hoc analysis showed that patients with low pyrazinamide C 2 h (P ‫؍‬ 0.01) and patients with large extensive lung lesions (P ‫؍‬ 0.01) were at risk of at least one positive culture at week 4, 8, or 24/32. Antituberculosis drug concentrations were often low, but treatment response was nevertheless good. No association was found between drug concentrations and 8 weeks culture conversion, but low pyrazinamide drug concentrations may be associated with a less favorable bacteriological response. The use of higher doses of pyrazinamide may warrant further investigation. G enerally, first-line treatment of drug-susceptible tuberculosis (TB) is highly effective. However, a number of patients do not respond adequately to treatment, develop drug resistance or experience a relapse of TB after completion of treatment. Inadequate exposure to anti-TB drugs may constitute one of the factors underlying suboptimal treatment response (1, 2). Among adults, low plasma concentrations of anti-TB drugs have been found in patients with HIV infection, gastrointestinal tract disorders, high body weight, male gender, or diabetes mellitus (DM) (3-11) and in fast acetylators for isoniazid (12). Low plasma concentrations can also result from interindividual variability in drug absorption, metabolism, or excretion (3, 13). Some studies have reported associations between low concentrations of anti-TB drugs and poor treatment response (1-3, 14), although this was not found in other studies (7,15). In a recent study performed in a preclinical model, pharmacokinetic variability appeared to be more important in the emergence of multidrug-resistant tuberculosis (MDR-TB) than nonadherence (16). Furthermore, a systematic review showed that pharmacokinetic variability to isoniazid in multi-drug TB regimens is significantly associated with therapy failure and acquired drug resistance (17).Nevertheless, the number of studies examining the relation between plasma concentrations of anti-TB drugs and treatment response remains limited and the majority of them inves...

“…Thus, for a drug such as the fluoroquinolone, a low C 2 level may underestimate the overall regimen efficacy when the best pharmacokinetic/pharmacodynamic parameter is the AUC/MIC (18). Therefore, while measurement of the drug concentration at the C 2 time point has been operationalized for the management of drugsusceptible TB (27,28), comparison of plasma drug concentrations and TDA at multiple time points in the dosing interval and at a later date in the treatment schedule may be informative for cases of MDR-TB. Furthermore, no subject's M. tuberculosis isolate had MICs indicative of XDR-TB.…”

Section: Figmentioning

confidence: 99%

Plasma Drug Activity in Patients on Treatment for Multidrug-Resistant Tuberculosis

Mpagama

Ndusilo

Stroup

et al. 2014

Little is known about plasma drug concentrations relative to quantitative susceptibility in patients with multidrug-resistant tuberculosis (MDR-TB). We previously described a TB drug activity (TDA) assay that determines the ratio of the time to detection of plasma-cocultured Mycobacterium tuberculosis versus control growth in a Bactec MGIT system. Here, we assess the activity of individual drugs in a typical MDR-TB regimen using the TDA assay. We also examined the relationship of the TDA to the drug concentration at 2 h (C 2 ) and the MICs among adults on a MDR-TB regimen in Tanzania. These parameters were also compared to the treatment outcome of sputum culture conversion. Individually, moxifloxacin yielded superior TDA results versus ofloxacin, and only moxifloxacin and amikacin yielded TDAs equivalent to a ؊2-log killing. In the 25 patients enrolled on a regimen of kanamycin, levofloxacin, ethionamide, pyrazinamide, and cycloserine, the C 2 values were found to be below the expected range for levofloxacin in 13 (52%) and kanamycin in 10 (40%). Three subjects with the lowest TDA result (<1.5, a finding indicative of poor killing) had significantly lower kanamycin C 2 /MIC ratios than subjects with a TDA of >1.5 (9.8 ؎ 8.7 versus 27.0 ؎ 19.1; P ‫؍‬ 0.04). The mean TDAs were 2.52 ؎ 0.76 in subjects converting to negative in <2 months and 1.88 ؎ 0.57 in subjects converting to negative in >2 months (P ‫؍‬ 0.08). In Tanzania, MDR-TB drug concentrations were frequently low, and a wide concentration/MIC range was observed that affected plasma drug activity ex vivo. An opportunity exists for pharmacokinetic optimization in current MDR-TB regimens, which may improve treatment response.T reatment outcomes for multidrug-resistant tuberculosis (MDR-TB), defined as resistance to isoniazid and rifampin, remain inferior to drug-susceptible TB largely because secondline medications used in the treatment of MDR-TB are less potent, may require an extended treatment duration, and are associated with a greater number of side effects (1). Therefore, understanding the relative activity of an individual patient's MDR-TB regimen may inform treatment decisions, particularly in the presence of a poor response to therapy. Both murine models and human experience have demonstrated the importance of optimized drug exposure, leading to greater bacterial killing and better treatment outcomes (2-4). However, pharmacokinetic tools, such as plasma drug concentration monitoring and MIC testing, are not readily available in most areas where TB is endemic, and it remains unclear how such measurements are best utilized.We have previously described the role of a plasma TB drug activity (TDA) assay in patients treated for drug-susceptible TB in Tanzania, which has been designated a high-burden TB country by the World Health Organization (5). Based on the original Schlichter test for bactericidal endocarditis (6, 7) and prior work in whole-blood culture of Mycobacterium tuberculosis (8), the TDA assay uses a patient's plasma collected during TB treatm...