Therapeutic drug monitoring in the treatment of tuberculosis: a retrospective analysis

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%

“…Recently, several studies tried to evaluate the effect of anti-TB drug concentrations on treatment outcomes (3,(12)(13)(14). One study performed in the United States included 42 patients with slow responses to treatment.…”

Section: Discussionmentioning

confidence: 99%

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

Park

Lee

et al. 2016

“…TDM has been shown to be beneficial in the treatment of TB (14)(15)(16)(17)(18)(19). Additionally, several studies have shown that TB drug concentrations lower than the expected range are a risk factor for treatment failure (20)(21)(22)(23).…”

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confidence: 99%

Limited Sampling Strategy and Target Attainment Analysis for Levofloxacin in Patients with Tuberculosis

Alsultan

Peloquin

2015

There is an urgent need to improve and shorten the treatment of tuberculosis (TB) and multidrug resistant tuberculosis (MDR-TB). Levofloxacin, a newer fluoroquinolone, has potent activity against TB both in vitro and in vivo. Levofloxacin dosing can be optimized to improve the treatment of both TB and MDR-TB. Levofloxacin efficacy is linked primarily to the ratio of the area under the concentration-time curve for the free fraction of drug (fAUC) to the MIC. Since obtaining a full-time concentration profile is not feasible in the clinic, we developed a limited sampling strategy (LSS) to estimate the AUC. We also utilized Monte Carlo simulations to evaluate the dosing of levofloxacin. Pharmacokinetic data were obtained from 10 Brazilian TB patients. The pharmacokinetic data were fitted with a one-compartment model. LSSs were developed using two methods: linear regression and Bayesian approaches. Several LSSs predicted levofloxacin AUC with good accuracy and precision. The most accurate were the method using two samples collected at 4 and 6 h (R 2 ‫؍‬ 0.91 using linear regression and 0.97 using Bayesian approaches) and that using samples collected at 2 and 6 h (R 2 ‫؍‬ 0.90 using linear regression and 0.96 using Bayesian approaches). The 2-and-6-h approach also provides a good estimate of the maximum concentration of the drug in serum (C max ). Our target attainment analysis showed that higher doses (17 to 20 mg/kg of body weight) of levofloxacin might be needed to improve its activity. Doses in the range of 17 to 20 mg/kg showed good target attainment for MICs from 0.25 to 0.50. At an MIC of 2, poor target attainment was observed across all doses. This LSS for levofloxacin can be used for therapeutic drug monitoring and for future pharmacokinetic/ pharmacodynamic studies.T uberculosis (TB) is the second leading cause of death from an infectious disease, behind HIV. In 2012, 8.6 million people developed TB, and 1.3 million died from it. Also, multidrug-resistant (MDR) and extensively drug-resistant (XDR) TB are on the rise. The WHO estimates that about 5% of the new TB cases globally are caused by MDR-TB, and of those, 9% are XDR-TB (1). This indicates that the current treatment is not adequate. The standard treatment of TB consists of rifampin, isoniazid, pyrazinamide, and ethambutol for 2 months, followed by rifampin and isoniazid for 4 to 7 months. The success rate for this regimen is relatively high (greater than 95%) based on per-protocol analyses of the initial clinical trials (2, 3). However, TB is still a worldwide pandemic, and even in the United States, with its excellent TB control efforts, only about 89% of patients complete treatment within 12 months, not 6 (4). Lack of adherence may lead to treatment failure and development of MDR TB.The treatment of MDR-TB currently requires treatment for a minimum of 18 months with at least 4 drugs, including an injectable (aminoglycoside or polypeptide). Examples of second-line drugs used for MDR-TB include ethionamide, cycloserine, and p-aminosalicylic acid. Drugs...

“…However, ineffective drug therapy due to suboptimal drug dosages likely contributes to the high risk of death (6,7,10) or relapse after treatment (5,11). Clinical studies in adults with TB have shown that low plasma antituberculosis (anti-TB) drug concentrations are associated with a delayed treatment response (12,13) or risk of treatment failure (14)(15)(16). In particular, low plasma exposure to the rifamycins in the setting of intermittent therapy in HIV-infected patients with TB has been associated with treatment failure and emergence of rifampin resistance (16)(17)(18).…”

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confidence: 99%

Pharmacokinetics of the First-Line Antituberculosis Drugs in Ghanaian Children with Tuberculosis with or without HIV Coinfection

Antwi

Yang

Enimil

et al. 2017

Although human immunodeficiency virus (HIV) coinfection is the most important risk factor for a poor antituberculosis (anti-TB) treatment response, its effect on the pharmacokinetics of the first-line drugs in children is understudied. This study examined the pharmacokinetics of the four first-line anti-TB drugs in children with TB with and without HIV coinfection. Ghanaian children with TB on isoniazid, rifampin, pyrazinamide, and ethambutol for at least 4 weeks had blood samples collected predose and at 1, 2, 4, and 8 hours postdose. Drug concentrations were determined by validated liquid chromatography-mass spectrometry methods and pharmacokinetic parameters calculated using noncompartmental analysis. The area under the concentration-time curve from 0 to 8 h (AUC 0 -8 ), maximum concentration (C max ), and apparent oral clearance divided by bioavailability (CL/F) for each drug were compared between children with and without HIV coinfection. Of 113 participants, 59 (52.2%) had HIV coinfection. The baseline characteristics were similar except that the coinfected patients were more likely to have lower weight-for-age and height-for-age Z scores (P Ͻ 0.05). Rifampin, pyrazinamide, and ethambutol median body weight-normalized CL/F values were significantly higher, whereas the plasma AUC 0 -8 values were lower, in the coinfected children than in those with TB alone. In the multivariate analysis, drug dose and HIV coinfection jointly influenced the apparent oral clearance and AUC 0 -8 for rifampin, pyrazinamide, and ethambutol. Isoniazid pharmacokinetics were not different by HIV coinfection status. HIV coinfection was associated with lower plasma exposure of three of the four first-line anti-TB drugs in children. Whether TB/HIV-coinfected children need higher dosages of rifampin, pyrazinamide, and ethambutol requires further investigation. (This study has been registered at ClinicalTrials.gov under identifier NCT01687504.)