Population Pharmacokinetic Model and Optimal Sampling Strategies for Micafungin in Critically Ill Patients Diagnosed with Invasive Candidiasis.

Candida bloodstream infections are associated with high attributable mortality, where early initiation of adequate antifungal therapy is important to increase survival in critically ill patients. The exposure variability of micafungin, a first-line agent used for the treatment of invasive candidiasis, in critically ill patients is significant, potentially resulting in underexposure in a substantial portion of these patients. The objective of this study was to develop a population pharmacokinetic model including appropriate sampling strategies for assessing micafungin drug exposure in critically ill patients to support adequate area under the concentration-time curve (AUC) determination. A two-compartment pharmacokinetic model was developed using data from intensive care unit (ICU) patients (n = 19), with the following parameters: total body clearance (CL), volume of distribution of the central compartment (V1), inter-compartmental clearance (CL12), and volume of distribution of the peripheral compartment (V2). The final model was evaluated with bootstrap analysis and the goodness-of-fit plots for the population and individual predicted micafungin plasma concentrations. Optimal sampling strategies (with sampling every hour, 24 h per day) were developed with 1- and 2-point sampling schemes. Final model parameters (±SD) were: CL = 1.03 (0.37) (L/h/1.85 m2), V1 = 0.17 (0.07) (L/kg LBMc), CL12 = 1.80 (4.07) (L/h/1.85 m2), and V2 = 0.12 (0.06) (L/kg LBMc). Sampling strategies with acceptable accuracy and precision were developed to determine the micafungin AUC. The developed model with optimal sampling procedures provides the opportunity to achieve quick optimization of the micafungin exposure from a single blood sample using Bayesian software and may be helpful in guiding early dose decision-making.

Optimization of Fluconazole Dosing for the Prevention and Treatment of Invasive Candidiasis Based on the Pharmacokinetics of Fluconazole in Critically Ill Patients.

The efficacy of fluconazole is related to the area under the plasma concentration-time curve (AUC) over the MIC of the microorganism. Physiological changes in critically ill patients may affect the exposure of fluconazole, and therefore dosing adjustments might be needed. The aim of this study was to evaluate variability in fluconazole drug concentration in intensive care unit (ICU) patients and to develop a pharmacokinetic model to support personalized fluconazole dosing. A prospective observational pharmacokinetic study was performed in critically ill patients receiving fluconazole either as prophylaxis or as treatment. The association between fluconazole exposure and patient variables was studied. Pharmacokinetic modeling was performed with a nonparametric adaptive grid (NPAG) algorithm using R package Pmetrics. Data from 33 patients were available for pharmacokinetic analysis. Patients on dialysis and solid organ transplant patients had a significantly lower exposure to fluconazole. The population was best described with a one-compartment model, where the mean volume of distribution was 51.52 liters (standard deviation [SD], 19.81) and the mean clearance was 0.767 liters/h (SD, 0.46). Creatinine clearance was tested as a potential covariate in the model, but was not included in the final population model. A significant positive correlation was found between the fluconazole exposure (AUC) and the trough concentration (Cmin). Substantial variability in fluconazole plasma concentrations in critically ill adults was observed, where the majority of patients were underexposed. Fluconazole Cmin therapeutic drug monitoring (TDM)-guided dosing can be used to optimize therapy in critically ill patients. (This study has been registered at ClinicalTrials.gov under identifier NCT02491151.).

In Vitro Susceptibility of Mycobacterium tuberculosis to Amikacin, Kanamycin, and Capreomycin.

Amikacin, kanamycin, and capreomycin are among the most important second-line drugs for multidrug-resistant tuberculosis. Although amikacin and kanamycin are administered at the same dose and show the same pharmacokinetics, they have different WHO breakpoints, suggesting that the two drugs have different MICs. The aim of this study was to investigate possible differences in MICs between the aminoglycosides and capreomycin. Using the direct concentration method, a range of concentrations of amikacin, kanamycin, and capreomycin (0.25, 0.50, 1.0, 2.0, 4.0, 8.0, 16.0, 32.0, and 64.0 mg/liter) were tested against 57 clinical Mycobacterium tuberculosis strains. The 7H10 agar plates were examined for mycobacterial growth after 14 days. At 2 mg/liter, 48 strains (84%) were inhibited by amikacin and only 5 strains (9%) were inhibited by kanamycin (P < 0.05, Wilcoxon signed-rank test). The median MICs of amikacin, kanamycin, and capreomycin were 2, 4, and 8 mg/liter, respectively. No difference in amikacin, kanamycin, and capreomycin MIC distributions was observed between multidrug-resistant strains and fully susceptible strains. The results indicate that amikacin is more active than kanamycin and capreomycin against M. tuberculosis with the absolute concentration method. Determination of the impact of this difference on clinical outcomes in daily practice requires a prospective study, including pharmacokinetic and pharmacodynamic evaluations.

Pharmacokinetics of 2,000 Milligram Ertapenem in Tuberculosis Patients.

Ertapenem is a carbapenem antibiotic with activity against Mycobacterium tuberculosis Dose simulations in a hollow-fiber infection model showed that 2,000 mg once daily is an appropriate dose to be tested in clinical studies. Before using this dose in a phase II study, the aim of this prospective pharmacokinetic study was to confirm the pharmacokinetics of 2,000 mg once daily in tuberculosis (TB) patients. Twelve TB patients received a single intravenous dose of 2,000 mg ertapenem as a 30-min infusion. Blood samples were collected at 0, 0.5, 1, 2, 3, 4, 8, 12, and 24 h postadministration. Drug concentrations were measured using a validated liquid chromatography-tandem mass spectrometry assay. A large interindividual variation in the pharmacokinetics of ertapenem was observed. The median (interquartile range) area under the plasma concentration-time curve to infinity (AUC0-∞) was 2,032 (1,751 to 2,346) mg · h/liter, the intercompartmental clearance (CL12) was 1.941 (0.979 to 2.817) liters/h, and the volume of distribution in the central compartment (V1) was 1.514 (1.064 to 2.210) liters. A more than dose-proportional increase in AUC was observed compared to results reported for 1,000 mg ertapenem in multidrug-resistant TB patients. Based on a MIC of 1.0 mg/liter, 11 out of 12 patients would have reached the target value of unbound drug exceeding the MIC over 40% of the time (f40% T>MIC). In conclusion, this study shows that 2,000 mg ertapenem once daily in TB patients reached the expected f40% T>MIC for most of the patients, and exploration in a phase 2 study can be advocated.

Pharmacokinetics of rifampicin in adult TB patients and healthy volunteers: a systematic review and meta-analysis.

Objectives: The objectives of this study were to explore inter-study heterogeneity in the pharmacokinetics (PK) of orally administered rifampicin, to derive summary estimates of rifampicin PK parameters at standard dosages and to compare these with summary estimates for higher dosages. Methods: A systematic search was performed for studies of rifampicin PK published in the English language up to May 2017. Data describing the Cmax and AUC were extracted. Meta-analysis provided summary estimates for PK parameter estimates at standard rifampicin dosages. Heterogeneity was assessed by estimation of the I2 statistic and visual inspection of forest plots. Summary AUC estimates at standard and higher dosages were compared graphically and contextualized using preclinical pharmacodynamic (PD) data. Results: Substantial heterogeneity in PK parameters was evident and upheld in meta-regression. Treatment duration had a significant impact on the summary estimates for rifampicin PK parameters, with Cmax 8.98 mg/L (SEM 2.19) after a single dose and 5.79 mg/L (SEM 2.14) at steady-state dosing, and AUC 72.56 mg·h/L (SEM 2.60) and 38.73 mg·h/L (SEM 4.33) after single and steady-state dosing, respectively. Rifampicin dosages of at least 25 mg/kg are required to achieve plasma PK/PD targets defined in preclinical studies. Conclusions: Vast inter-study heterogeneity exists in rifampicin PK parameter estimates. This is not explained by the available modifying variables. The recommended dosage of rifampicin should be increased to improve efficacy. This study provides an important point of reference for understanding rifampicin PK at standard dosages as efforts to explore higher dosing strategies continue in this field.

Pharmacokinetic Modeling and Limited Sampling Strategies Based on Healthy Volunteers for Monitoring of Ertapenem in Patients with Multidrug-Resistant Tuberculosis.

Ertapenem is a broad-spectrum carbapenem antibiotic whose activity against Mycobacterium tuberculosis is being explored. Carbapenems have antibacterial activity when the plasma concentration exceeds the MIC at least 40% of the time (40% TMIC). To assess the 40% TMIC in multidrug-resistant tuberculosis (MDR-TB) patients, a limited sampling strategy was developed using a population pharmacokinetic model based on data for healthy volunteers. A two-compartment population pharmacokinetic model was developed with data for 42 healthy volunteers using an iterative two-stage Bayesian method. External validation was performed by Bayesian fitting of the model developed with data for volunteers to the data for individual MDR-TB patients (in which the fitted values of the area under the concentration-time curve from 0 to 24 h [AUC0-24, fit values] were used) using the population model developed for volunteers as a prior. A Monte Carlo simulation (n = 1,000) was used to evaluate limited sampling strategies. Additionally, the 40% TMIC with the free fraction (f 40% TMIC) of ertapenem in MDR-TB patients was estimated with the population pharmacokinetic model. The population pharmacokinetic model that was developed was shown to overestimate the area under the concentration-time curve from 0 to 24 h (AUC0-24) in MDR-TB patients by 6.8% (range, -17.2 to 30.7%). The best-performing limited sampling strategy, which had a time restriction of 0 to 6 h, was found to be sampling at 1 and 5 h (r2 = 0.78, mean prediction error = -0.33%, root mean square error = 5.5%). Drug exposure was overestimated by a mean percentage of 4.2% (range, -15.2 to 23.6%). When a free fraction of 5% was considered and the MIC was set at 0.5 mg/liter, the minimum f 40% TMIC would have been exceeded in 9 out of 12 patients. A population pharmacokinetic model and limited sampling strategy, developed using data from healthy volunteers, were shown to be adequate to predict ertapenem exposure in MDR-TB patients.

Reduced Chance of Hearing Loss Associated with Therapeutic Drug Monitoring of Aminoglycosides in the Treatment of Multidrug-Resistant Tuberculosis.

Hearing loss and nephrotoxicity are associated with prolonged treatment duration and higher dosage of amikacin and kanamycin. In our tuberculosis center, we used therapeutic drug monitoring (TDM) targeting preset pharmacokinetic/pharmacodynamic (PK/PD) surrogate endpoints in an attempt to maintain efficacy while preventing (oto)toxicity. To evaluate this strategy, we retrospectively evaluated medical charts of tuberculosis (TB) patients treated with amikacin or kanamycin in the period from 2000 to 2012. Patients with culture-confirmed multiresistant or extensively drug-resistant tuberculosis (MDR/XDR-TB) receiving amikacin or kanamycin as part of their TB treatment for at least 3 days were eligible for inclusion in this retrospective study. Clinical data, including maximum concentration (Cmax), Cmin, and audiometry data, were extracted from the patients' medical charts. A total of 80 patients met the inclusion criteria. The mean weighted Cmax/MIC ratios obtained from 57 patients were 31.2 for amikacin and 12.3 for kanamycin. The extent of hearing loss was limited and correlated with the cumulative drug dose per kg of body weight during daily administration. At follow-up, 35 (67.3%) of all patients had successful outcome; there were no relapses. At a median dose of 6.5 mg/kg, a correlation was found between the dose per kg of body weight during daily dosing and the extent of hearing loss in dB at 8,000 Hz. These findings suggest that the efficacy at this lower dosage is maintained with limited toxicity. A randomized controlled trial should provide final proof of the safety and efficacy of TDM-guided use of aminoglycosides in MDR-TB treatment.

Pharmacokinetic Properties of Micafungin in Critically Ill Patients Diagnosed with Invasive Candidiasis.

The estimated attributable mortality rate for invasive candidiasis (IC) in the intensive care unit (ICU) setting varies from 30 to 40%. Physiological changes in critically ill patients may affect the distribution and elimination of micafungin, and therefore, dosing adjustments might be mandatory. The objective of this study was to determine the pharmacokinetic parameters of micafungin in critically ill patients and assess the probability of target attainment. Micafungin plasma concentrations were measured to estimate the pharmacokinetic properties of micafungin. MIC values for Candida isolates were determined to assess the probability of target attainment for patients. Data from 19 patients with suspected or proven invasive candidiasis were available for analysis. The median area under the concentration-time curve from 0 to 24 h at steady state (AUC0-24) was 89.6 mg · h/liter (interquartile range [IQR], 75.4 to 113.6 mg · h/liter); this was significantly lower than the median micafungin AUC0-24 values of 152.0 mg · h/liter (IQR, 136.0 to 162.0 mg · h/liter) and 134.0 mg · h/liter (IQR, 118.0 to 148.6 mg · h/liter) in healthy volunteers (P = <0.0001 and P = <0.001, respectively). All Candida isolates were susceptible to micafungin, with a median MIC of 0.016 mg/liter (IQR, 0.012 to 0.023 mg/liter). The median AUC0-24/MIC ratio was 5,684 (IQR, 4,325 to 7,578), and 3 of the 17 evaluable patients (17.6%) diagnosed with proven invasive candidiasis did not meet the AUC/MIC ratio target of 5,000. Micafungin exposure was lower in critically ill patients than in healthy volunteers. The variability in micafungin exposure in this ICU population could be explained by the patients' body weight. Our findings suggest that healthier patients (sequential organ failure assessment [SOFA] score of <10) weighing more than 100 kg and receiving 100 mg micafungin daily are at risk for inappropriate micafungin exposure and potentially inadequate antifungal treatment. (This study has been registered at ClinicalTrials.gov under identifier NCT01716988.).

Immunoassay Analysis of Kanamycin in Serum Using the Tobramycin Kit.

Kanamycin is one of the aminoglycosides used in the treatment of multidrug-resistant tuberculosis. Blood concentrations of kanamycin are predictive for the treatment efficacy and the occurrence of side effects, and dose adjustments can be needed to optimize therapy. However, an immunoassay method for the quantification of kanamycin is not commercially available. We modified the existing tobramycin immunoassay to analyze kanamycin. This modified method was tested in a concentration range of 0.3 to 80.0 mg/liter for inaccuracy and imprecision. In addition, the analytical results of the immunoassay method were compared to those obtained by a liquid chromatography-tandem mass spectrometry (LC-MS/MS) analytical method using Passing and Bablok regression. Within-day imprecision varied from 2.3 to 13.3%, and between-day imprecision ranged from 0.0 to 11.3%. The inaccuracy ranged from -5.2 to 7.6%. No significant cross-reactivity with other antimicrobials and antiviral agents was observed. The results of the modified immunoassay method were comparable with the LC-MS/MS analytical outcome. This new immunoassay method enables laboratories to perform therapeutic drug monitoring of kanamycin without the need for complex and expensive LC-MS/MS equipment.

Longitudinal Analysis of the Effect of Inflammation on Voriconazole Trough Concentrations.

Voriconazole (VCZ) exhibits great inter- and intrapatient variability. The latter variation cannot exclusively be explained by concomitant medications, liver disease or dysfunction, and genetic polymorphisms in cytochrome P450 2C19 (CYP2C19). We hypothesized that inflammatory response in patients under VCZ medication might also influence this fluctuation in concentrations. In this study, we explored the association between inflammation, reflected by the C-reactive protein (CRP) concentration, and VCZ trough concentrations over time. A retrospective analysis of data was performed for patients with more than one steady-state VCZ trough concentration and a CRP concentration measured on the same day. A longitudinal analysis was used for series of observations obtained from many study participants over time. The approach involved inclusion of random effects and autocorrelation in linear models to reflect within-person cross-time correlation. A total of 50 patients were eligible for the study, resulting in 139 observations (paired VCZ and CRP concentrations) for the analysis, ranging from 2 to 6 observations per study participant. Inflammation, marked by the CRP concentration, had a significant association with VCZ trough concentrations (P < 0.001). Covariates such as age and interacting comedication ([es]omeprazole), also showed a significant correlation between VCZ and CRP concentrations (P < 0.05). The intrapatient variation of trough concentrations of VCZ was 1.401 (confidence interval [CI], 0.881 to 2.567), and the interpatient variation was 1.756 (CI, 0.934 to 4.440). The autocorrelation between VCZ trough concentrations at two sequential time points was calculated at 0.71 (CI, 0.51 to 0.92). The inflammatory response appears to play a significant role in the largely unpredictable pharmacokinetics of VCZ, especially in patients with high inflammatory response, as reflected by high CRP concentrations.

Pharmacokinetic Evaluation of Sulfamethoxazole at 800 Milligrams Once Daily in the Treatment of Tuberculosis.

For treatment of multidrug-resistant tuberculosis (MDR-TB), there is a scarcity of antituberculosis drugs. Co-trimoxazole is one of the available drug candidates, and it is already frequently coprescribed for TB-HIV-coinfected patients. However, only limited data are available on the pharmacokinetic (PK) and pharmacodynamic (PD) parameters of co-trimoxazole in TB patients. The objective of this study was to evaluate the PK parameters and in vitro PD data on the effective part of co-trimoxazole: sulfamethoxazole. In a prospective PK study in patients infected with drug-susceptible Mycobacterium tuberculosis (drug-susceptible TB patients) (age, >18), sulfamethoxazole-trimethoprim (SXT) was administered orally at a dose of 960 mg once daily. One-compartment population pharmacokinetic modeling was performed using MW\Pharm 3.81 (Mediware, Groningen, The Netherlands). The area under the concentration-time curve for the free, unbound fraction of a drug (ƒAUC)/MIC ratio and the period in which the free concentration exceeded the MIC (fT > MIC) were calculated. Twelve patients received 960 mg co-trimoxazole in addition to first-line drugs. The pharmacokinetic parameters of the population model were as follows (geometric mean ± standard deviation [SD]): metabolic clearance (CLm), 1.57 ± 3.71 liters/h; volume of distribution (V), 0.30 ± 0.05 liters · kg lean body mass(-1); drug clearance/creatinine clearance ratio (fr), 0.02 ± 0.13; gamma distribution rate constant (ktr_po), 2.18 ± 1.14; gamma distribution shape factor (n_po), 2.15 ± 0.39. The free fraction of sulfamethoxazole was 0.3, but ranged between 0.2 and 0.4. The median value of the MICs was 9.5 mg/liter (interquartile range [IQR], 4.75 to 9.5), and that of theƒAUC/MIC ratio was 14.3 (IQR, 13.0 to 17.5). The percentage of ƒT > MIC ranged between 43 and 100% of the dosing interval. The PK and PD data from this study are useful to explore a future dosing regimen of co-trimoxazole for MDR-TB treatment. (This study has been registered at ClinicalTrials.gov under registration no. NCT01832987.).

Emerging drugs and alternative possibilities in the treatment of tuberculosis.

INTRODUCTION: Tuberculosis (TB) remains a global health problem. Drug resistance, treatment duration, complexity, and adverse drug reactions associated with anti-TB regimens are associated with treatment failure, prolonged infectiousness and relapse. With the current set of anti-TB drugs the goal to end TB has not been met. New drugs and new treatment regimens are needed to eradicate TB. AREAS COVERED: Literature was explored to select publications on drugs currently in phase II and phase III trials. These include new chemical entities, immunotherapy, established drugs in new treatment regimens and vaccines for the prophylaxis of TB. EXPERT OPINION: Well designed trials, with detailed pharmacokinetic/pharmacodynamic analysis, in which information on drug exposure and drug susceptibility of the entire anti-TB regimen is included, in combination with long-term follow-up will provide relevant data to optimize TB treatment. The new multi arm multistage trial design could be used to test new combinations of compounds, immunotherapy and therapeutic vaccines. This new approach will both reduce the number of patients exposed to inferior treatment and the financial burden. Moreover, it will speed up drug evaluation. Considering the investments involved in development of new drugs it is worthwhile to thoroughly investigate existing, non-TB drugs in new regimens.

Influence of inflammation on voriconazole metabolism.

Voriconazole pharmacokinetics shows a large inter- and intrapatient variability. Inflammation is associated with changes in the expression of CYP isoenzymes. Here, we evaluated the influence of inflammation, marked by C-reactive protein (CRP) levels in blood, on the metabolism of voriconazole. Observational data showed an association between CRP level and the ratio of voriconazole N-oxide to voriconazole.

Quantification and validation of ertapenem using a liquid chromatography-tandem mass spectrometry method.

Ertapenem, a carbapenem, relies on time-dependent killing. Therapeutic drug monitoring (TDM) should be considered, when ertapenem is used in specific populations, to achieve optimal bactericidal activity and optimize drug-dosing regimens. No validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method has been reported using deuterated ertapenem as the internal standard. A new simple and robust LC-MS/MS method using a quadrupole mass spectrometer was developed for analysis of ertapenem in human plasma, using deuterated ertapenem as the internal standard. The calibration curve was linear over a range of 0.1 (lower limit of quantification [LLOQ]) to 125 mg/liter. The calculated accuracy ranged from -2.4% to 10.3%. Within-run coefficients of variation (CV) ranged from 2.7% to 11.8%, and between-run CV ranged from 0% to 8.4%. Freeze-thaw stability had a bias of -3.3% and 0.1%. Storage of QC samples for 96 h at 4°C had a bias of -4.3 to 5.6%, storage at room temperature for 24 h had a bias of -10.7% to -14.8%, and storage in the autosampler had a bias between -2.9% and -10.0%. A simple LC-MS/MS method to quantify ertapenem in human plasma using deuterated ertapenem as the internal standard has been validated. This method can be used in pharmacokinetic studies and in clinical studies by performing TDM.

Five year results of an international proficiency testing programme for measurement of antifungal drug concentrations.

OBJECTIVES: Since 2007 the Dutch Association for Quality Assessment in Therapeutic Drug Monitoring (KKGT) has organized an international interlaboratory proficiency testing (PT) programme for measurement of antifungal drugs in plasma. We describe the 5 year results of the laboratories' performance. METHODS: Twice a year, laboratories received a set of blind plasma samples containing low or high concentrations of fluconazole, itraconazole, hydroxyitraconazole, posaconazole, voriconazole and flucytosine. Participating laboratories were asked to report their results within 6 weeks after dispatch and provide details of their analytical methods. Results deviating >20% from the weighed-in concentration were considered inaccurate. Four-way ANOVA was performed to assess the effect of antifungal drug measured, concentration, analytical method and performing laboratory on the absolute inaccuracy. In 2012, a questionnaire based on the CLSI guidelines was dispatched with the request to provide input on sources of error. RESULTS: Fifty-seven laboratories (13 countries) reported 2251 results (287 fluconazole, 451 itraconazole, 348 hydroxyitraconazole, 402 posaconazole, 652 voriconazole and 111 flucytosine) in 5 years. Analyses were performed using HPLC (55.0%), LC-MS(/MS) (43.4%), UPLC (1.4%) or GC-MS (0.2%). Overall, 432 (19.2%) analyses were inaccurate. The performing laboratory was the only factor clearly associated with inaccuracies. The questionnaire results indicated that laboratories encounter significant problems analysing low concentrations (15.4% of all inaccuracies). CONCLUSIONS: Results of the PT programme suggest that one out of five measurements is inaccurate. The performing laboratory is the main determinant of inaccuracy, suggesting that internal quality assurance is pivotal in preventing inaccuracies, irrespective of the antifungal drug measured, concentration and analytical equipment.

A systematic review on the effect of diabetes mellitus on the pharmacokinetics of TB drugs.

The coexistence of TB and diabetes mellitus (DM) (TB-DM) is associated with an increased risk of treatment failure, death, delayed culture conversion, and drug resistance. Because plasma concentrations may influence clinical outcomes, we evaluated the evidence on the pharmacokinetic (PK) of TB drugs in individuals with DM to guide management.We performed a systematic review and meta-analysis through searches of major databases from 1946 to 6 July 2023. PROSPERO (CRD42022323566).Of 4,173 potentially relevant articles, we identified 16 studies assessing rifampicin (RIF) PK, 9 on isoniazid (INH), 8 on pyrazinamide (PZA), and 3 on ethambutol (EMB). Two studies reported on second-line anti-TB drugs. According to our meta-analysis, RIF time to maximum concentration (Tmax) was significantly prolonged in patients with DM compared with non-DM patients. We found no significant differences for RIF Cmax, area under the curve (AUC) 0-24 or drug concentration at 2 h (C2h), INH C2h, PZA C2h, PZA Tmax, and EMB Tmax. Although RIF C2h was slightly reduced in patients with TB-DM, this finding was not statistically significant.This review comprehensively examines the impact of DM on the PK of TB drugs. We observed significant heterogeneity among the studies. Given the association between lower plasma concentrations and poor clinical outcomes among patients with DM, we recommend a higher dose limit to compensate for the larger body weight of patients with DM..

Clinical validation of the analysis of linezolid and clarithromycin in oral fluid of patients with multidrug-resistant tuberculosis.

Linezolid 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.