Clinical Validation of the Analysis of Linezolid and Clarithromycin in Oral Fluid of Patients with Multidrug-Resistant Tuberculosis

Abstract

dLinezolid plays an increasingly important role in the treatment of multidrug-resistant tuberculosis (MDR-TB). However, patients should be carefully monitored due to time-and dose-dependent toxicity. Clarithromycin plays a more modest role. Therapeutic drug monitoring may contribute to assessment of treatment regimens, helping to reduce toxicity while maintaining adequate drug exposure. Oral fluid sampling could provide a welcome alternative in cases where conventional plasma sampling is not possible or desirable. The aim of this study was to clinically validate the analysis of linezolid and clarithromycin and its metabolite hydroxyclarithromycin in oral fluid of patients with multidrug-resistant tuberculosis. Serum and oral fluid samples were simultaneously obtained and analyzed by using validated methods, after extensive cross-validation between the two matrices. Passing-Bablok regressions and Bland-Altman analysis showed that oral fluid analysis of linezolid and clarithromycin appeared to be suitable for therapeutic drug monitoring in MDR-TB patients. No correction factor is needed for the interpretation of linezolid oral fluid concentrations with a ratio of the linezolid concentration in serum to that in oral fluid of 0.97 (95% confidence interval [CI], 0.92 to 1.02). However, the clarithromycin concentration serum/clarithromycin concentration in oral fluid ratio is 3.07 (95% CI, 2.45 to 3.69). Analysis of hydroxyclarithromycin in oral fluid was not possible in this study due to a nonlinear relationship between the concentration in serum and that in oral fluid. In conclusion, the analysis of linezolid (no correction factor) and clarithromycin (correction factor of 3) in oral fluid is applicable for therapeutic drug monitoring in cases of multidrug-resistant tuberculosis as an alternative to conventional serum sampling. Easy sampling using a noninvasive technique may facilitate therapeutic drug monitoring for specific patient categories. T uberculosis (TB) is a mostly curable and preventable infectious disease caused by Mycobacterium tuberculosis. Approximately 3.7% of new tuberculosis patients and 20% of previously treated patients are infected with multidrug-resistant strains that are resistant to at least rifampin and isoniazid (1). Treatment regimens of multidrug-resistant tuberculosis (MDR-TB) should consist of at least four anti-TB drugs to which the bacterium is susceptible (2).The oxazolidinone linezolid is effective against M. tuberculosis and is increasingly used as a part of treatment regimens in patients with multidrug-resistant or extensively drug-resistant tuberculosis (3). However, patients should be carefully monitored due to the time-and dose-dependent serious toxicity of linezolid, such as myelosuppression and polyneuropathy (4).Clarithromycin has a less pronounced place in MDR-TB treatment regimens due to serum concentrations that usually do not reach MICs (5). Nevertheless, sufficiently high local clarithromycin concentrations are reached in epithelial lining fluid and alveolar cells (6, 7...

How do we use therapeutic drug monitoring to improve outcomes from severe infections in critically ill patients?

“…HPLC methods have been published for linezolid TDM in plasma [ 128 , 130 ], dried plasma spots [ 131 , 132 ] and oral fluid [ 133 ] with good correlations between methods.…”

A simple high‐performance liquid chromatography for the determination of linezolid in human plasma and saliva

“…Table shows the changes in the plasma and saliva levels of LZD at 3, 7 and 12 h after intake. These results were quite similar to the results of Bolhuis et al (). However, the difference between each plasma and saliva level at 3 h was slightly larger than that at 12 h. This result suggests that the trough level of saliva is useful for LZD monitoring.…”

“…Recently, Bolhuis et al . () reported that the LZD concentration in serum correlated well with that in saliva at steady state. Hence, we developed a practical analytical HPLC method for the determination of LZD in plasma and saliva.…”

LC-MS/MS for Therapeutic Drug Monitoring of anti-infective drugs

“…As there are many other determinants of the salivary drug concentration, such as salivary flow rate, stability of the drug and its metabolites, time of sample collection and ingestion of food or beverages [52], target concentrations in saliva should be established on a drug-to-drug basis [43]. Saliva methods using LC-MS/MS have been published for a few anti-infective drugs (doxycycline, fluconazole, linezolid, lopinavir and oseltamivir) [52][53][54].…”