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Rationale Concern for drug-drug interactions leading to treatment failure and drug resistant strains have discouraged clinicians from attempting concomitant treatment of hepatitis C (HCV) and Tuberculosis. Increased metabolism of direct-acting antivirals (DAAs) by rifamycins has hindered concurrent use. Development of an assay for ledipasvir and sofosbuvir (LDV/SOF) serum concentrations for therapeutic drug monitoring (TDM) can ensure adequate therapy. Presented are the first cases of concomitant therapy of active TB and HCV with rifamycin containing regimens and DAAs using TDM. Objectives Using TDM, we aim to determine if concomitant therapy with rifamycin containing regimens and DAAs is safe and effective for patients co-infected with TB and HCV. Methods Five individuals with TB and HCV who experienced transaminitis prior to or during TB therapy, were concomitantly treated with rifamycin containing regimens and LDV/SOF. TDM was performed for ledipasvir, sofosbuvir and rifabutin during therapy. Baseline labs and serial liver enzymes were performed. HCV viral load and mycobacterial sputum cultures were obtained upon completion of therapy to determine efficacy of therapy. Measurements and Main Results All patients were found to have nondetectable HCV viral loads and negative mycobacterial sputum cultures upon completion of therapy. No clinically significant adverse effects were reported. Conclusions These cases illustrate concomitant use of LDV/SOF and rifabutin in patients with HCV/TB coinfection. Utilizing serum drug concentration monitoring to guide dosing, correction of transaminitis were achieved which allowed the use rifamycin containing TB therapy. These findings suggest that concomitant therapy of TB/HCV is possible, safe and effective.

Enteropathy is prevalent in tuberculosis-endemic areas, and it has been shown to impair intestinal absorptive function; therefore, enteropathogen burden might negatively affect antimycobacterial pharmacokinetics, particularly among malnourished children. We sought to quantify enteropathogen burden among children initiating tuberculosis treatment in rural Tanzania and determine the effect of enteropathogen burden on serum antimycobacterial pharmacokinetics.We performed a prospective cohort study at one site in rural Tanzania as an exploratory substudy of a large multicountry cohort study. We included children younger than 15 years of age with confirmed or probable tuberculosis undergoing treatment with first-line tuberculosis therapy; children were excluded from the study if they were unable to undergo sample collection. Participants were consecutively recruited from the inpatient paediatric wards or the outpatient tuberculosis clinic at Haydom Lutheran Hospital, Tanzania. The main outcome was to quantify symptomatic enteropathogen burden and the effect on serum antimycobacterial pharmacokinetics. We quantified enteropathogen burden (defined as the sum of distinct enteropathogens detected in stool) using a multipathogen PCR capable of simultaneous detection of 37 bacterial, viral, and parasitic species or species groups from stool collected within 72 h of treatment initiation. Comprehensive clinical assessment, including presence of gastrointestinal symptoms, was performed at baseline, and serum was collected approximately 2 weeks after treatment initiation at steady state and throughout the dosing interval with concentrations of isoniazid, rifampicin, pyrazinamide, and ethambutol measured by liquid chromatography with a tandem mass spectrometry assay to quantify peak (C58 children were assessed for eligibilty and enrolled between June 25, 2016, and Feb 6, 2018; 44 had complete stool testing and serum pharmacokinetic data, and they were included in the analyses. 20 (45%) were female, and 24 (55%) were male. 37 (84%) had moderate or severe malnutrition. A mean of 2·1 (SD 1·3) enteropathogens were detected per participant. Target peak concentrations of rifampicin were reached in eight (18%) of 44 participants, isoniazid in 24 (54%) of 44 participants, pyrazinamide in 28 (74%) of 38 participants, and ethambutol in six (15%) of 39 participants. Compared with controlled comparisons, each summative additional bacterial enteropathogen detected was associated with a 40% lower rifampicin CTanzanian children undergoing tuberculosis treatment rarely attained pharmacokinetic targets; enteropathogen carriage was common and enteropathogen burden was associated with significant reductions in the concentrations of some antimycobacterial drugs. Further research should explore mechanistic relationships of individual pathogens and antimycobacterial pharmacokinetics in larger cohorts, or determine if screening for and treating enteropathogens at tuberculosis treatment initiation improves pharmacokinetic target attainment.National Institute of Allergy and Infectious Diseases, National Institutes of Health.For the Swahili translation of the abstract see Supplementary Materials section.

Few studies have evaluated clofazimine (CLOF) drug monitoring and safety in children. We treated 10 children, 8 with CF, for NTM infection with multiple antimicrobials, including CLOF. All had serial blood CLOF concentrations measured and were followed for adverse events. Despite CLOF dose escalation, most children with CF did not reach a target CLOF concentration. Our data suggest that children with CF may require earlier initiation of CLOF at higher doses than is currently recommended.

Although linezolid is effective for multidrug-resistant TB (MDR-TB) tuberculosis treatment, it is associated with cytopenias after 4 weeks of administration. Data on toxicities with long-term use of linezolid and drug pharmacodynamics in MDR-TB treatment are limited, and concerns about toxicity present barriers to wider implementation. This was a secondary analysis of a prospective cohort study of patients treated for MDR-TB in the country of Georgia from 2015 to 2017. Intensive blood sampling 4 to 6 weeks after treatment initiation with linezolid 600 mg daily was performed for pharmacokinetic (PK) analysis, including linezolid trough concentration (C(min)) and area under the curve from 0 to 24 hours (AUC(0–24)). Linezolid exposure was defined using literature-reported thresholds. Cytopenias were defined using an NIH adverse event (AE) scale. Logistic regression was used to evaluate the relationship between linezolid exposure and cytopenias. Among 76 patients receiving linezolid in their baseline treatment regimen and who had PK data available, cytopenia AEs occurred in 30 (39.5%) for an incidence rate of 46 per 100 person-years. The median duration of linezolid therapy was 526 days. No patients required dose reduction or interruption due to cytopenias. Median linezolid C(min) was 0.235 mg/L (interquartile range [IQR], 0.069 to 0.529), and median AUC(0–24) was 89.6 mg·h/L (IQR, 69.2 to 116.2). Cytopenias were associated with linezolid PK parameters (C(min) > 2 mg/L and AUC(0–24) > 160 mg·h/L). Cytopenias occurred frequently with long-term use of linezolid 600 mg/day and were associated with PK parameters but did not result in the need for treatment interruption in the management of a cohort of patients with MDR-TB.

BackgroundSuboptimal exposure to antituberculosis (anti-TB) drugs has been associated with unfavourable treatment outcomes. We aimed to investigate estimates and determinants of first-line anti-TB drug pharmacokinetics in children and adolescents at a global level.MethodsWe systematically searched MEDLINE, Embase and Web of Science (1990–2021) for pharmacokinetic studies of first-line anti-TB drugs in children and adolescents. Individual patient data were obtained from authors of eligible studies. Summary estimates of total/extrapolated area under the plasma concentration–time curve from 0 to 24 h post-dose (AUC0–24) and peak plasma concentration (Cmax) were assessed with random-effects models, normalised with current World Health Organization-recommended paediatric doses. Determinants of AUC0–24andCmaxwere assessed with linear mixed-effects models.ResultsOf 55 eligible studies, individual patient data were available for 39 (71%), including 1628 participants from 12 countries. Geometric means of steady-state AUC0–24were summarised for isoniazid (18.7 (95% CI 15.5–22.6) h·mg·L−1), rifampicin (34.4 (95% CI 29.4–40.3) h·mg·L−1), pyrazinamide (375.0 (95% CI 339.9–413.7) h·mg·L−1) and ethambutol (8.0 (95% CI 6.4–10.0) h·mg·L−1). Our multivariate models indicated that younger age (especially 0–24for all first-line anti-TB drugs, while severe malnutrition was associated with lower AUC0–24for isoniazid and pyrazinamide.N-acetyltransferase 2 rapid acetylators had lower isoniazid AUC0–24and slow acetylators had higher isoniazid AUC0–24than intermediate acetylators. Determinants ofCmaxwere generally similar to those for AUC0–24.ConclusionsThis study provides the most comprehensive estimates of plasma exposures to first-line anti-TB drugs in children and adolescents. Key determinants of drug exposures were identified. These may be relevant for population-specific dose adjustment or individualised therapeutic drug monitoring.

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Background The ability of antituberculosis drugs to cross the blood–brain barrier and reach the central nervous system is critical to their effectiveness in treating tuberculosis meningitis (TBM). We sought to fill a critical knowledge gap by providing data on the ability of new and repurposed antituberculosis drugs to penetrate into the cerebrospinal fluid (CSF). Methods We conducted a clinical pharmacology study among patients treated for TBM in Tbilisi, Georgia, from January 2019 until January 2020. Serial serum and CSF samples were collected while patients were hospitalized. CSF was collected from routine lumbar punctures with the timing of the lumbar puncture alternating between 2 and 6 hours to capture early and late CSF penetration. Results A total of 17 patients treated for TBM (8 with confirmed disease) were included; all received linezolid, with a subset receiving cycloserine (5), clofazimine (5), delamanid (4), and bedaquiline (2). All CSF measurements of bedaquiline (12), clofazimine (24), and delamanid (19) were below the limit of detection. The median CSF concentrations of cycloserine at 2 and 6 hours were 15.90 and 15.10 µg/mL with adjusted CSF/serum ratios of 0.52 and 0.66. CSF concentrations of linezolid were 0.90 and 3.14 µg/mL at 2 and 6 hours, with adjusted CSF/serum ratios of 0.25 and 0.59, respectively. CSF serum linezolid concentrations were not affected by rifampin coadministration. Conclusions Based on moderate to high CSF penetration, linezolid and cycloserine may be effective drugs for TBM treatment, whereas the utility of bedaquiline, delamanid, and clofazimine is uncertain given their low CSF penetration.

Background Tuberculosis (TB) is the leading cause of death in human immunodeficiency virus (HIV) infected people worldwide. Patients with HIV who have latent TB are 20-30 times more likely to develop active TB. Integrated antiretroviral therapy (ART) early in the treatment for tuberculosis is recommended due to improved morbidity and mortality, however, there can be serious drug interactions. Rifamycins are potent inducers of the CYP3A4 isoform, which can cause sub-therapeutic concentrations of anti-retroviral drugs, among these, rifabutin (RBN) is a less potent inducer of CYP3A4. Pharmacokinetic (PK) studies done on healthy adults showed that rifampin decreased dolutegravir (DTG) concentrations by more than 50 % whereas RBN decreased it by 30%. RBN has been preferred given that its favorable pharmacokinetic and toxicity profile. Currently there are no studies examining the use of RBN and DTG in co-infected persons. This is a case series of 4 co-infected patients receiving both agents who underwent PK analysis. Methods Retrospective analysis of patients in the respiratory care unit (RCU) at Jackson Memorial Hospital in Miami. We included adult patients, admitted to the RCU, with a concomitant diagnosis of HIV and active TB disease who received DTG and RBN, and for which DTG and RBN plasma concentrations were measured for therapeutic drug monitoring (TDM). A non-compartmental analysis was performed and the area under the concentration-time curve (AUC) was calculated for DTG and RBN. Results We report 4 patients (Figure 1) that met criteria and underwent PK analysis. All patients with TB who were treated with RBN had low concentrations of DTG, requiring higher doses of DTG (Table 1 & 2). After adjustments based on PK analysis, there was evidence of a favorable response to treatment in 2 patients, with a less than robust in the 2 others. Adequate suppression of viral load could not be determined for 3 of the patients because of the short observation time. Figure 1:Timelines of patients describing admission and HIV and tuberculosis treatment providedDTG, dolutegravir. RFB, rifabutin. VL, viral load. AFB, Acid fast bacilli. LAD, lymphadenopathy. TAF, Tenofovir alafenamide. FTC, Emtricitabine. TDF, Tenofovir Disoproxil Fumarate. INH, Isoniazid. PYZ, Pyrazinamide. BID, twice a day. QD, daily. IRIS, Immune reconstitution inflammatory syndrome. GU, genitourinary. TB, tuberculosis.Table 1:Patients’ pharmacokinetics of DTGAUCX-Y, area under the concentration-time curve from time X to Y hours; AUC0-tau, area under the concentration-time curve from time zero to the end of the dosing interval; DTG, dolutegravir; TDM, therapeutic drug monitoring. a) AUC0-6 was calculated.Table 2:Patients’ pharmacokinetics of RBNAUCX-Y, area under the concentration-time curve from time X to Y hours; AUC0-tau, area under the concentration-time curve from time zero to the end of the dosing interval; RBN, Rifabutin; TDM, therapeutic drug monitoring. a) All RBN doses given every 24 hours, b) RBN value was trace and AUC was not calculated. Conclusion All patients with HIV and TB who were treated with RBN had low concentrations of DTG. This case series demonstrates that for optimal concomitant use of rifabutin and dolutegravir it is highly recommended to use TDM. Prospective clinical studies are needed to further determine the PK interactions between RBN and DTG and virologic response to treatment. Disclosures All Authors: No reported disclosures.

Background: Latent tuberculosis infection (LTBI) treatment is an effective strategy to eliminate TB in low-incidence settings. Shorter LTBI regimens incorporating the antimicrobial class of rifamycins are designed to improve treatment completion rates. Recent evidence suggests that the rifamycins could induce irreversible gut microbiota changes that impact future anti-TB immunity. Methods: To document the immediate effect of the rifamycins on the gut microbiota, we followed six patients with LTBI initiating four months of monotherapy with rifampin (4R; n=4) or three months of rifapentine in combination with isoniazid (3HP; n=2) and tracked recovery to baseline two months posttreatment completion. We collected stool samples parallel to the LTBI group from healthy volunteers (N=6) unexposed to the rifamycins. We used a questionnaire to collect diet, antibiotics, and lifestyle changes during follow-up. We profiled the gut microbiota using 16S rRNA amplicon sequencing (V1-V2 region). Results: Rifamycin exposure resulted in a 4.24% decrease in alpha diversity, compared to a 3.27% decrease in the controls. While the change in alpha diversity was small and not statistically different from changes observed in controls, significant bacterial community dissimilarity correlated with treatment duration (R2 = 0.269, P=0.041) and dose (R2 =0.201, P = 0.001) were observed. This rifamycin-associated dysbiosis was characterized by a depletion of butyrate-producing taxa (Clostridium-XIVa and Roseburia) and expansion of potentially pathogenic taxa within the Firmicutes and Proteobacteria phyla. Recovery of the gut microbial composition was incomplete two months after treatment ended. Conclusion: TB prophylaxis with the rifamycins induced minimal changes in the overall gut microbiota diversity but a significant shift in gut microbial composition. A larger clinical study with a longer follow-up time is necessary to confirm the extent to which the gut microbiota can recover from this rifamycin-induced dysbiosis to inform strategies to mitigate potential LTBI treatment sequelae.

Objective: We present 16s rRNA gene sequencing (V1-V2 region) and sample data from a pilot observational cohort study to describe the gut microbiota dynamics in patients with latent tuberculosis infection (LTBI) treated with a three to four-month course of a rifamycin-based regimen. Our objectives were to (1) document changes to the gut microbiota following exposure to the rifamycins and (2) document recovery to baseline two months after treatment completion.Data description: Six LTBI patients were followed for 5 – 6 months. Each patient provided stool samples before, during, and two months after treatment. Six healthy controls were sampled in parallel with the LTBI patients. We report amplicon sequence variants (ASVs) and taxonomic assignments for 60 stool samples. Also provided are the raw amplicon sequences, and data on diet, medication, and lifestyle changes over the follow-up period. Additionally, phosphate buffer washes of the stool samples from the LTBI participants were analyzed by validated LC-MS-MS assay to measure concentrations of the parent and partially active metabolite rifamycins. These data could be useful for future systematic reviews and meta-analyses on the impact of LTBI therapy on the gut microbiota.

Data evaluating cefepime thresholds associated with neurotoxicity remain limited. The objectives of this study were to evaluate the incidence of cefepime-related neurotoxicity (CRN) in patients with plasma cefepime concentrations, assess the relationship between cefepime exposure and CRN, investigate clinical factors associated with CRN, and describe electroencephalogram (EEG) abnormalities in CRN.This was a retrospective study of adult inpatients admitted between 2016 and 2018 who received cefepime therapeutic drug monitoring (TDM). Potential CRN cases were identified utilizing a standard definition. The primary outcomes of the study were to determine the incidence of CRN and evaluate the relationship between cefepime trough concentrations, the average daily AUC, and neurotoxicity. Bayesian posteriors were generated for each patient using a cefepime pharmacokinetic (PK) model, and the mean daily area under the concentration-time curve (AUC) was calculated. Multiple regression was performed to assess the association between CRN, cefepime PK, and clinical predictors of neurotoxicity.Four hundred eighty-one patients with 503 hospital encounters received cefepime TDM and were included in the analysis. The incidence of CRN was 4.4% (22/503). Patients with CRN had a higher incidence of renal dysfunction, hypertension, and diabetes mellitus compared to patients without CRN (non-NT). The mean cefepime trough concentration was significantly greater in the CRN patients than in the non-NT group (61.8 ± 33.7 vs. 30 ± 27.7 mg/L, respectively, p = 0.0002). Cefepime trough concentration and renal dysfunction were independently associated with increased risk of CRN in the adjusted multiple regression model. Moderate generalized slowing of the background rhythm was the most common EEG pattern associated with CRN. Delaying cefepime TDM greater than 72 h after the initiation of cefepime was associated with a 3-fold increased risk of CRN.Cefepime should be used cautiously in hospitalized patients with renal dysfunction due to the risk of neurotoxicity. Dose optimization utilizing TDM early in cefepime treatment may minimize adverse effects and improve patient safety.

Mycobacterium tuberculosis (Mtb) exists in various metabolic states, including a nonreplicating persister (NRP) phenotype which may affect response to therapy. We have adopted a model-informed strategy to accelerate discovery of effective Mtb treatment regimens and previously found pretomanid (PMD), moxifloxacin (MXF), and bedaquiline (BDQ) to readily kill logarithmic- and acid-phase Mtb. Here, we studied multiple concentrations of each drug in flask-based, time-kill studies against NRP Mtb in single-, two- and three-drug combinations, including the active M2 metabolite of BDQ. We used nonparametric population algorithms in the Pmetrics package for R to model the data and to simulate the 95% confidence interval of bacterial population decline due to the two-drug combination regimen of PMD + MXF and compared this to observed declines with three-drug regimens. PMD + MXF at concentrations equivalent to average or peak human concentrations effectively eradicated Mtb. Unlike other states for Mtb, we observed no sustained emergence of less susceptible isolates for any regimen. The addition of BDQ as a third drug significantly (P < 0.05) shortened time to total bacterial suppression by 3 days compared to the two-drug regimen, similar to our findings for Mtb in logarithmic or acid growth phases.

Background: Tuberculosis meningitis (TBM) is the most lethal form of TB. It is difficult to treat in part due to poor or uncertain drug penetration into the central nervous system (CNS). To help fill this knowledge gap, we evaluated the cerebrospinal fluid (CSF) concentrations of fluoroquinolones and carbapenems in patients being treated for TBM.Methods: Serial serum and CSF samples were collected from hospitalized patients being treated for TBM. CSF was collected from routine lumbar punctures between alternating timepoints of 2 and 6 h after drug administration to capture early and late CSF penetration. Rich serum sampling was collected after drug administration on day 28 for non-compartmental analysis.Results: Among 22 patients treated for TBM (8 with confirmed disease), there was high use of fluoroquinolones (levofloxacin, 21; moxifloxacin, 10; ofloxacin, 6) and carbapenems (imipenem, 11; meropenem, 6). Median CSF total concentrations of levofloxacin at 2 and 6 h were 1.34 mg/L and 3.36 mg/L with adjusted CSF/serum ratios of 0.41 and 0.63, respectively. For moxifloxacin, the median CSF total concentrations at 2 and 6 h were 0.78 mg/L and 1.02 mg/L with adjusted CSF/serum ratios of 0.44 and 0.62. Serum and CSF concentrations of moxifloxacin were not affected by rifampin use. Among the 76 CSF samples measured for carbapenem concentrations, 79% were undetectable or below the limit of detection.Conclusion: Fluoroquinolones demonstrated high CSF penetration indicating their potential usefulness for the treatment of TBM. Carbapenems had lower than expected CSF concentrations.

Background: Tuberculosis (TB) is the leading cause of death in human immunodeficiency virus (HIV)-infected people worldwide. Currently there are no studies examining the use of Rifabutin (RBN) and Dolutegravir (DTG) in co-infected persons. This is a case series of 4 co-infected patients receiving both agents who underwent Pharmacokinetic (PK) analysis. Methods and Results: This is a retrospective chart review study of four patients diagnosed with both HIV and TB, receiving RBN and DTG and undergoing therapeutic drug monitoring. All 4 cases had lower than expected DTG concentrations at least once, including those on the current recommended dose of DTG with RBN, and even those receiving higher doses. Conclusions: Given the frequency of low DTG and RBN concentrations, therapeutic drug monitoring (TDM) for these drugs is advisable. Prospective clinical studies are needed to further determine the PK interactions between RBN and DTG, and virologic response to treatment.

Pretomanid is a nitroimidazole antimicrobial active against drug-resistant Mycobacterium tuberculosis and approved in combination with bedaquiline and linezolid (BPaL) to treat multidrug-resistant (MDR) pulmonary tuberculosis (TB). However, the penetration of these antibiotics into the central nervous system (CNS), and the efficacy of the BPaL regimen for TB meningitis, are not well established. Importantly, there is a lack of efficacious treatments for TB meningitis due to MDR strains, resulting in high mortality. We have developed new methods to synthesize

Hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP) are the most common intensive care unit (ICU) infections. We aimed to evaluate the association of early and cumulative beta-lactam pharmacokinetic/pharmacodynamic (PK/PD) parameters with therapy outcomes in pneumonia. Adult ICU patients who received cefepime, meropenem, or piperacillin-tazobactam for HAP or VAP and had its concentration measured were included. Beta-lactam exposure was generated for every patient for the entire duration of therapy, and the time free concentration remained above the MIC (fT(>MIC)) and the time free concentration remained above four multiples of the MIC (fT(>4×MIC)) were calculated for time frames of 0 to 24 h, 0 to 10 days, and day 0 to end of therapy. Regression analyses and machine learning were performed to evaluate the impact of PK/PD on therapy outcomes. A total of 735 patients and 840 HAP/VAP episodes (47% HAP) were included. The mean age was 56 years, and the mean weight was 80 kg. Sequential organ failure assessment (SOFA), hemodialysis, age, and weight were significantly associated with the clinical outcomes and kept in the final model. In the full cohort including all pneumonia episodes, PK/PD parameters at different time windows were associated with a favorable composite outcome, clinical cure, and mechanical ventilation (MV)-free days. In patients who had positive cultures and reported MICs, almost all PK/PD parameters were significant predictors of therapy outcomes. In the machine learning analysis, PK/PD parameters ranked high and were the primary overall predictors of clinical cure. Early target attainment and cumulative target attainment have a great impact on pneumonia outcomes. Beta-lactam exposure should be optimized early and maintained through therapy duration.

Tuberculosis (TB) remains a leading cause of infectious death worldwide, and poverty is a major driver. Clinically, TB presents as "latent" TB and active TB disease, and the treatment for each is different. TB drugs can display "early bactericidal activity (EBA)" and / or "sterilizing activity" (clearing persisters). Isoniazid is excellent at the former, and rifampin is excellent at the latter. Pyrazinamide and ethambutol complete the first-line regimen for drug-susceptible TB, each playing a specific role. Drug-resistant TB is an increasing concern, being met, in part, with repurposed drugs (including moxifloxacin, levofloxacin, linezolid, clofazimine, and beta-lactams) and new drugs (including bedaquiline, pretomanid, and delamanid). One challenge is to select drugs without overlapping adverse drug reaction profiles. QTc interval prolongation is one such concern, but to date, it has been manageable. Drug penetration into organism sanctuaries, such as the central nervous system, bone, and pulmonary TB cavities remain important challenges. The pharmacodynamics of most TB drugs can be described by the area under the curve (AUC) divided by the minimal inhibitory concentration (MIC). The hollow fiber infection model (HFIM) and various animal models (especially mouse and macaque) allow for sophisticated pharmacokinetic / pharmacodynamic experiments. These experiments may hasten the selection of the most potent, shortest possible regimens to treat even extremely drug resistant TB. These findings can be translated to humans by optimizing drug exposure in each patient, using therapeutic drug monitoring and dose individualization.

ObjectivePharmacokinetic variability drives tuberculosis (TB) treatment outcomes but measurement of serum drug concentrations for personalised dosing is inaccessible for children in TB-endemic settings. We compared rifampin urine excretion for prediction of a serum target associated with treatment outcome.DesignProspective diagnostic accuracy study.SettingInpatient wards and outpatient clinics, northern Tanzania.PatientsChildren aged 4–17 years were consecutively recruited on initiation of WHO-approved treatment regimens.InterventionsSamples were collected after directly observed therapy at least 2 weeks after initiation in the intensive phase: serum at pre-dose and 1, 2 and 6 hours post-dose, later analysed by liquid chromatography-tandem mass spectrometry for calculation of rifampin total exposure or area under the concentration time curve (AUC0-24); urine at post-dose intervals of 0–4, 4–8 and 8–24 hours, with rifampin excretion amount measured onsite by spectrophotometry.Main outcome measuresReceiver operating characteristic (ROC) curve for percentage of rifampin dose excreted in urine measured by spectrophotometry to predict serum rifampin AUC0–24target of 31.7 mg*hour/L.Results89 children, 52 (58%) female, with median age of 9.1 years, had both serum and urine collection. Only 59 (66%) reached the serum AUC0–24target, reflected by a range of urine excretion patterns. Area under the ROC curve for percentage of rifampin dose excreted in urine over 24 hours predicting serum AUC0–24target was 69.3% (95% CI 56.7% to 81.8%), p=0.007.ConclusionsUrine spectrophotometry correlated with a clinically relevant serum target for rifampin, representing a step toward personalised dosing for children in TB-endemic settings.

Nontuberculous mycobacteria can cause minimally symptomatic self-limiting infections to progressive and life-threatening disease of multiple organs. Several factors such as increased testing and prevalence have made this an emerging infectious disease. Multiple guidelines have been published to guide therapy, which remains difficult owing to the complexity of therapy, the potential for acquired resistance, the toxicity of treatment, and a high treatment failure rate. Given the long duration of therapy, complex multi-drug treatment regimens, and the risk of drug toxicity, therapeutic drug monitoring is an excellent method to optimize treatment. However, currently, there is little available guidance on therapeutic drug monitoring for this condition. The aim of this review is to provide information on the pharmacokinetic/pharmacodynamic targets for individual drugs used in the treatment of nontuberculous mycobacteria disease. Lacking data from randomized controlled trials, in vitro, in vivo, and clinical data were aggregated to facilitate recommendations for therapeutic drug monitoring to improve efficacy and reduce toxicity.

Contains fulltext : 235795.pdf (Publisher’s version ) (Open Access) Tuberculosis (TB) is still the number one cause of death due to an infectious disease. Pharmacokinetics and pharmacodynamics of anti-TB drugs are key in the optimization of TB treatment and help to prevent slow response to treatment, acquired drug resistance, and adverse drug effects. The aim of this review was to provide an update on the pharmacokinetics and pharmacodynamics of anti-TB drugs and to show how population pharmacokinetics and Bayesian dose adjustment can be used to optimize treatment. We cover aspects on preclinical, clinical, and population pharmacokinetics of different drugs used for drug-susceptible TB and multidrug-resistant TB. Moreover, we include available data to support therapeutic drug monitoring of these drugs and known pharmacokinetic and pharmacodynamic targets that can be used for optimization of therapy. We have identified a wide range of population pharmacokinetic models for first- and second-line drugs used for TB, which included models built on NONMEM, Pmetrics, ADAPT, MWPharm, Monolix, Phoenix, and NPEM2 software. The first population models were built for isoniazid and rifampicin; however, in recent years, more data have emerged for both new anti-TB drugs, but also for defining targets of older anti-TB drugs. Since the introduction of therapeutic drug monitoring for TB over 3 decades ago, further development of therapeutic drug monitoring in TB next steps will again depend on academic and clinical initiatives. We recommend close collaboration between researchers and the World Health Organization to provide important guideline updates regarding therapeutic drug monitoring and pharmacokinetics/pharmacodynamics.

Purpose To describe the implementation and operationalization of a β-lactam (BL) therapeutic drug monitoring (TDM) program at a large academic center. Summary BLs are the most used class of antibiotics. Suboptimal antibiotic exposure is a significant concern in hospitalized patients, particularly in those with altered pharmacokinetics. BL-TDM provides clinicians the opportunity to optimize drug concentrations to ensure maximal therapeutic efficacy while minimizing toxicity. However, BL-TDM has not been widely adopted due to the lack of access to assays. The University of Florida Shands Hospital developed a BL-TDM program in 2015. This is a consultative service primarily run by pharmacists and is conducted in all patient care areas. An analysis was performed on the first BL-TDM encounter for 1,438 patients. BL-TDM was most frequently performed for cefepime (61%, n = 882), piperacillin (15%, n = 218), and meropenem (11%, n = 151). BL-TDM was performed a median of 3 days (interquartile range, 1-5 days) from BL initiation. Among patients with available minimum inhibitory concentration (MIC) values and trough concentrations, the pharmacokinetic/pharmacodynamic (PK/PD) target of 100% fT>MIC was attained in 308 patients (88%). BL-TDM resulted in a dosage adjustment in 25% (n = 361) of patients. Conclusion Implementation of a BL-TDM program requires the concerted efforts of physicians, pharmacists, nursing staff, phlebotomists, and personnel in the analytical laboratory. Standard antibiotic dosing failed to achieve optimal PK/PD targets in all patients; utilizing BL-TDM, dose adjustments were made in 1 of every 4 patients.

A once-weekly oral dose of isoniazid and rifapentine for 3 months (3HP) is recommended by the CDC for treatment of latent tuberculosis infection (LTBI). The aim of this study is to assess 3HP-mediated clearance of M. tuberculosis bacteria in macaques with asymptomatic LTBI. Twelve Indian-origin rhesus macaques were infected with a low dose (~10 CFU) of M. tuberculosis CDC1551 via aerosol. Six animals were treated with 3HP and 6 were left untreated. The animals were imaged via PET/CT at frequent intervals. Upon treatment completion, all animals except 1 were coinfected with SIV to assess reactivation of LTBI to active tuberculosis (ATB). Four of 6 treated macaques showed no evidence of persistent bacilli or extrapulmonary spread until the study end point. PET/CT demonstrated the presence of significantly more granulomas in untreated animals relative to the treated group. The untreated animals harbored persistent bacilli and demonstrated tuberculosis (TB) reactivation following SIV coinfection, while none of the treated animals reactivated to ATB. 3HP treatment effectively reduced persistent infection with M. tuberculosis and prevented reactivation of TB in latently infected macaques.

Background Rifampin-resistant and/or multidrug-resistant tuberculosis (RR/MDR-TB) treatment requires multiple drugs, and outcomes remain suboptimal. Some drugs are associated with improved outcome. It is unknown whether particular pharmacokinetic-pharmacodynamic relationships predict outcome. Methods Adults with pulmonary RR/MDR-TB in Tanzania, Bangladesh, and the Russian Federation receiving local regimens were enrolled from June 2016 to July 2018. Serum was collected after 2, 4, and 8 weeks for each drug’s area under the concentration-time curve over 24 hours (AUC0–24). Quantitative susceptibility of the M. tuberculosis isolate was measured by minimum inhibitory concentrations (MICs). Individual drug AUC0–24/MIC targets were assessed by adjusted odds ratios (ORs) for favorable treatment outcome, and hazard ratios (HRs) for time to sputum culture conversion. K-means clustering algorithm separated the cohort of the most common multidrug regimen into 4 clusters by AUC0–24/MIC exposures. Results Among 290 patients, 62 (21%) experienced treatment failure, including 30 deaths. Moxifloxacin AUC0–24/MIC target of 58 was associated with favorable treatment outcome (OR, 3.75; 95% confidence interval, 1.21–11.56; P = .022); levofloxacin AUC0–24/MIC of 118.3, clofazimine AUC0–24/MIC of 50.5, and pyrazinamide AUC0–24 of 379 mg × h/L were associated with faster culture conversion (HR >1.0, P < .05). Other individual drug exposures were not predictive. Clustering by AUC0–24/MIC revealed that those with the lowest multidrug exposures had the slowest culture conversion. Conclusions Amidst multidrug regimens for RR/MDR-TB, serum pharmacokinetics and M. tuberculosis MICs were variable, yet defined parameters to certain drugs—fluoroquinolones, pyrazinamide, clofazimine—were predictive and should be optimized to improve clinical outcome. Clinical Trials Registration NCT03559582.

Introduction Therapeutic drug monitoring (TDM) has been recommended for treatment optimization in tuberculosis (TB) but is only is used in certain countries e.g. USA, Germany, the Netherlands, Sweden and Tanzania. Recently, new drugs have emerged and PK studies in TB are continuing, which contributes further evidence for TDM in TB. The aim of this review is to provide an update on drugs used in TB, treatment strategies for these drugs, and TDM to support broader implementation. Areas covered This review describes the different drug classes used for TB, multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB), along with their pharmacokinetics, dosing strategies, TDM and sampling strategies. Moreover, the review discusses TDM for patient TB and renal or liver impairment, patients co-infected with HIV or hepatitis, and special patient populations - children and pregnant women. Expert opinion TB treatment has a long history of using 'one size fits all.' This has contributed to treatment failures, treatment relapses, and the selection of drug-resistant isolates. While challenging in resource-limited circumstances, TDM offers the clinician the opportunity to individualize and optimize treatment early in treatment. This approach may help to refine treatment and thereby reduce adverse effects and poor treatment outcomes. Funding, training, and randomized controlled trials are needed to advance the use of TDM for patients with TB.

Purpose The updated World Health Organization guidelines recommend efavirenz (EFV) 400 mg as the preferred alternate first-line antiretroviral therapy to dolutegravir, with EFV 600 mg recommended only in special situations. We examined the pharmacokinetic (PK) properties of EFV 600 mg/d during pregnancy and post partum to inform EFV dosing decisions in pregnant women. Methods Ghanaian pregnant women with HIV infection initiating tenofovir disoproxil fumarate 300 mg/lamivudine 300 mg/EFV 600 mg fixed-dose combination tablet once daily were enrolled. Efavirenz concentrations were measured at 4 weeks of antiretroviral therapy initiation during pregnancy and 6 weeks post partum using validated LC-MS/MS assays. Efavirenz PK parameters were calculated using noncompartmental analysis, and within-group parameters between the 2 periods were compared. Findings Of 25 enrolled women, 19 completed PK sampling during pregnancy and post partum. The Cmax, Cmin, AUC0–24h, and CL/F for EFV during pregnancy were similar to values at 6 weeks post partum. The pregnancy/postpartum geometric mean ratios for EFV Cmax, Cmin, AUC0–24, and CL/F were 1.10 (95% CI, 0.93–1.31), 0.88 (95% CI, 0.67–1.17), 0.84 (95% CI, 0.71–0.98), and 1.20 (95% CI, 1.02–1.40), respectively. Viral load suppression (HIV RNA Implications We found that the PK parameters of EFV 600 mg once daily during pregnancy were similar to those in the postpartum period. Our findings suggest that EFV dose adjustment during pregnancy is not necessary in our study population.

Two patients with normal renal function, yet each showed unexpected, supra‐ and subtherapeutic linezolid plasma concentrations resulting in toxicity and ineffective therapy, respectively. TDM helps to early identify and correct such excursions.

Background Individual pharmacokinetic variability is a driver of poor tuberculosis (TB) treatment outcomes. We developed a method for measurement of rifampin concentrations by urine colorimetry and a mobile phone photographic application to predict clinically important serum rifampin pharmacokinetic measurements in children treated for TB. Methods Among spiked urine samples, colorimetric assay performance was tested with conventional spectrophotometric and the mobile phone/light box methods under various environmental and biologic conditions. Urine rifampin absorbance (Abs) was then determined from timed specimens from children treated for TB in Tanzania, and compared to serum pharmacokinetic measurements collected throughout the dosing interval. Results Both the mobile phone/light box and spectrophotometry demonstrated excellent correlation across a wide range of urine rifampin concentrations (7.8–1000 mg/L) in intra- and interday trials, 24-hour exposure to ambient light or darkness, and varying urinalysis profiles (all r ≥ 0.98). In 12 Tanzanian children, the urine mobile phone/light box measurement and serum peak concentration (Cmax) were significantly correlated (P = .004). Using a Cmax target of 8 mg/L, the area under the receiver operating characteristic curve was 80.1% (range, 47.2%–100%). A urine mobile phone/light box threshold of 50 Abs correctly classified all patients (n = 6) with serum measurements below target. Conclusions The urine colorimetry with mobile phone/light box assay accurately measured rifampin absorbance in varying environmental and biological conditions that may be observed clinically. Among children treated for TB, the assay was sensitive for detection of low rifampin serum concentrations. Future work will identify the optimal timing for urine collection, and operationalize use in TB-endemic settings.

Rationale: Despite therapeutic progress in treating cystic fibrosis (CF) airway disease, airway inflammation with associated mucociliary dysfunction remains largely unaddressed. Inflammation reduces the activity of apically expressed large-conductance Ca2+-activated and voltage-dependent K+ (BK) channels, critical for mucociliary function in the absence of CFTR (CF transmembrane conductance regulator).Objectives: To test losartan as an antiinflammatory therapy in CF using CF human bronchial epithelial cells and an ovine model of CF-like airway disease.Methods: Losartan's antiinflammatory effectiveness to rescue BK activity and thus mucociliary function was tested in vitro using primary, fully redifferentiated human airway epithelial cells homozygous for F508del and in vivo using a previously validated, now expanded pharmacologic sheep model of CF-like, inflammation-associated mucociliary dysfunction.Measurements and Main Results: Nasal scrapings from patients with CF showed that neutrophilic inflammation correlated with reduced expression of LRRC26 (leucine rich repeat containing 26), the γ subunit mandatory for BK function in the airways. TGF-β1 (transforming growth factor β1), downstream of neutrophil elastase, decreased mucociliary parameters in vitro. These were rescued by losartan at concentrations achieved by nebulization in the airway and oral application in the bloodstream: BK dysfunction recovered acutely and over time (the latter via an increase in LRRC26 expression), ciliary beat frequency and airway surface liquid volume improved, and mucus hyperconcentration and cellular inflammation decreased. These effects did not depend on angiotensin receptor blockade. Expanding on a validated and published nongenetic, CF-like sheep model, ewes inhaled CFTRinh172 and neutrophil elastase for 3 days, which resulted in prolonged tracheal mucus velocity reduction, mucus hyperconcentration, and increased TGF-β1. Nebulized losartan rescued both mucus transport and mucus hyperconcentration and reduced TGF-β1.Conclusions: Losartan effectively reversed CF- and inflammation-associated mucociliary dysfunction, independent of its angiotensin receptor blockade.

BACKGROUND AND OBJECTIVE: Multidrug-resistant tuberculosis has much poorer treatment outcomes compared with drug-susceptible tuberculosis because second-line drugs for treating multidrug resistant tuberculosis are less effective and are frequently associated with side effects. Optimization of drug treatment is urgently needed. Cycloserine is a second-line tuberculosis drug with variable pharmacokinetics and thus variable exposure when programmatic doses are used. The objective of this study was to develop a population pharmacokinetic model of cycloserine to assess drug exposure and to develop a limited sampling strategy for cycloserine exposure monitoring.MATERIAL AND METHODS: Patients with multidrug-/extensively drug-resistant tuberculosis who were treated for > 7 days with cycloserine were eligible for inclusion. Patients received cycloserine 500 mg (body weight ≤ 50 kg) or 750 mg (body weight > 50 kg) once daily. MW/Pharm 3.83 (Mediware, Groningen, The Netherlands) was used to parameterize the population pharmacokinetic model. The model was compared with pharmacokinetic values from the literature and evaluated with a bootstrap analysis, Monte Carlo simulation, and an external dataset. Monte Carlo simulations were used to develop a limited sampling strategy.RESULTS: Cycloserine plasma concentration vs time curves were obtained from 15 hospitalized patients (nine male, six female, median age 35 years). Mean dose/kg body weight was 11.5 mg/kg (standard deviation 2.04 mg/kg). Median area under the concentration-time curve over 24 h (AUC0-24 h) of cycloserine was 888 h mg/L (interquartile range 728-1252 h mg/L) and median maximum concentration of cycloserine was 23.31 mg/L (interquartile range 20.14-33.30 mg/L). The final population pharmacokinetic model consisted of the following pharmacokinetic parameters [mean (standard deviation)]: absorption constant Ka_po of 0.39 (0.31) h-1, distribution over the central compartment (Vd) of 0.54 (0.26) L/kg LBM, renal clearance as fraction of the estimated glomerular filtration rate of 0.092 (0.038), and metabolic clearance of 1.05 (0.75) L/h. The population pharmacokinetic model was successfully evaluated with a bootstrap analysis, Monte Carlo simulation, and an external dataset of Chinese patients (difference of 14.6% and 19.5% in measured and calculated concentrations and AUC0-24 h, respectively). Root-mean-squared-errors found in predicting the AUC0-24 h using a one- (4 h) and a two- (2 h and 7 h) limited sampling strategy were 1.60% and 0.14%, respectively.CONCLUSIONS: This developed population pharmacokinetic model can be used to calculate cycloserine concentrations and exposure in patients with multidrug-/extensively drug-resistant tuberculosis. This model was successfully validated by internal and external validation methods. This study showed that the AUC0-24 h of cycloserine can be estimated in patients with multidrug-/extensively drug-resistant tuberculosis using a 1- or 2-point limited sampling strategy in combination with the developed population pharmacokinetic model. This strategy can be used in studies to correlate drug exposure with clinical outcome. This study also showed that good target attainment rates, expressed by time above the minimal inhibitory concentration, were obtained for cycloserine with a minimal inhibitory concentration of 5 and 10 mg/L, but low rates with a minimal inhibitory concentration of 20 and 32.5 mg/L.

Cefepime is the second most common cephalosporin used in U.S. hospitals. We aim to develop and validate a cefepime population pharmacokinetic (PK) model and integrate it into a precision dosing tool for implementation. Two data sets (680 patients) were used to build the cefepime PK model in Pmetrics, and three data sets (34 patients) were used for the validation. A separate application data set (115 patients) was used for the implementation and validation of a precision dosing tool. The model support points and covariates were used to generate the optimal initial dose (OID). Cefepime PK was described by a two-compartment model including weight and creatinine clearance (CrCl) as covariates. The median rate of elimination was 0.30 h(−1) (adults) and 0.96 h(−1) (children), the central volume of distribution was 13.85 L, and the rate of transfer from the central to the peripheral compartments was 1.22 h(−1) and from the peripheral to the central compartments was 1.38 h(−1). After integration in BestDose, the observed versus predicted cefepime concentration fit using the application data set was excellent (R(2) > 0.98), and the median difference between what was observed and what BestDose predicted on a second occasion was 4%. For the OID, cefepime at a 0.5- to 1-g 4-h infusion every 8 to 24 h (q8 to 24 h) with a CrCl of

Background Nearly one in three unconscious cardiac arrest survivors experience post-anoxic status epilepticus (PASE). Historically, PASE has been deemed untreatable resulting in its exclusion from status epilepticus clinical trials. However, emerging reports of survivors achieving functional independence following early and aggressive treatment of PASE challenged this widespread therapeutic nihilism. In the absence of proven therapies specific to PASE, standard of care treatment leans on general management strategies for status epilepticus. Vigabatrin—an approved therapy for refractory focal-onset seizures in adults—inhibits the enzyme responsible for GABA catabolism, increases brain GABA levels and may act synergistically with anesthetic agents to abort seizures. Our central hypothesis is that early inhibition of GABA breakdown is possible in the post-cardiac arrest period and may be an effective adjunctive treatment in PASE. Methods This is a phase IIa, single-center, open-label, pilot clinical trial with blinded outcome assessment, of a single dose of vigabatrin in 12 consecutive PASE subjects. Subjects will receive a single loading dose of 4500 mg of vigabatrin (or dose adjusted in moderate and severe renal impairment) via enteric tube within 48 h of PASE onset. Vigabatrin levels will be monitored at 0- (baseline), 0.5-, 1-, 2-, 3-, 6-, 12-, 24-, 48-, 72- and 168-h (7 days) post-vigabatrin. Serum biomarkers of neuronal injury will be measured at 0-, 24-, 48-, 72- and 96-h post-vigabatrin. The primary feasibility endpoint is the proportion of enrolled subjects among identified eligible subjects receiving vigabatrin within 48 h of PASE onset. The primary pharmacokinetic endpoint is the measured vigabatrin level at 3 h post-administration. Descriptive statistics with rates and proportions will be obtained regarding feasibility outcomes, along with the noncompartmental method for pharmacokinetic analyses. The area under the vigabatrin concentration-time curve in plasma from zero to the time of the last quantifiable concentration (AUC0-tlqc) will be calculated to estimate dose-linear pharmacokinetics. Perspective Vigabatrin demonstrates high potential for synergism with current standard of care therapies. Demonstration of the feasibility of vigabatrin administration and preliminary safety in PASE will pave the way for future efficacy and safety trials of this pharmacotherapeutic. Trial Registration NCT04772547.

Patients admitted to the intensive care unit (ICU) may need continuous renal replacement therapy (CRRT) due to acute kidney injury or worsening of underlying chronic kidney disease. This will affect their antimicrobial exposure and may have a significant impact on the treatment. We aim to develop a cefepime pharmacokinetic (PK) model in CRRT ICU patients and generate the posterior predictions for a group and assess their therapy outcomes. Adult patients, who were admitted to the ICU, received cefepime, and had its concentration measured while on CRRT were included from three different data sets. In two data sets, samples were collected from the predialyzer, postdialyzer ports, and effluent fluid at different times within the same dosing interval. The third data set had only cefepime plasma concentration measured as part of clinical service. Patients’ demographics, cefepime regimens and concentration, CRRT parameters, and therapy outcomes were recorded. NPAG was used for population PK and posterior predictions. A total of 125 patients were included. Cefepime was described by a five-compartment model, and the CRRT flow rates described the rates of cefepime transfer between compartments. The posterior predictions were generated for the third data set and the median (range) fT(>MIC) was 100% (27%–100%) and fT(>4×MIC) was 64% (0%–100%). The mortality rate was 53%. There was no difference in target attainment in terms of clinical cure and 30-day mortality. This model can be used as a precision dosing tool in CRRT patients. Future studies may address other PK/PD targets in a larger population.

Objectives. To report a probable interaction between rifampin and carbamazepine, likely leading to a seizure, and to review conflicting reports regarding this interaction. Case Summary. A 55-year-old female was treated with carbamazepine 200 mg 3 times daily for grand mal seizures, with excellent control. A 6-hour postdose carbamazepine concentration was 10.7 µg/mL (therapeutic range = 4-10 µg/mL). After she was diagnosed with pulmonary Mycobacterium avium complex, she received rifampin 300 mg twice daily, ethambutol 800 mg daily, and clarithromycin 500 mg twice daily. At first clinic visit, rifampin was changed to 600 mg daily, and clarithromycin was replaced with azithromycin 250 mg daily. A 4-hour postdose carbamazepine concentration was 7.1 µg/mL. Two weeks later, the patient experienced a seizure (no carbamazepine concentration reported at that time), but admitted to missing doses of carbamazepine. After experiencing 2 more seizures, the patient stopped taking rifampin. Subsequently, the carbamazepine dose was increased to 400 mg twice daily and rifampin was restarted at 600 mg daily. Two follow-up peak carbamazepine concentrations were 4.7 µg/mL and 4.4 µg/mL, with no reported seizures. No additional factors were identified as potential causes of the seizures or the lower carbamazepine concentrations. A Drug Interaction Probability Scale score of 6 indicates a probable interaction. Discussion. Conflicting reports exist regarding the effect of rifampin on carbamazepine concentrations, likely reflecting rifampin’s ability to display time-dependent, mixed effects on transporters and cytochrome P450 enzymes. Conclusions. Our case report describes a patient who experienced seizures after the addition of rifampin to her regimen, followed by lower peak concentrations of carbamazepine. Therapeutic drug monitoring in patients receiving both rifampin and carbamazepine is recommended to help clinicians optimize drug therapy.

Current rifampin dosing achieves subtherapeutic concentrations within S. aureus –infected bone, which can be overcome with higher rifampin dosing.

Staphylococcus aureus is a major human pathogen causing serious implant–associated infections. Combination treatment with rifampin (10 to 15 mg/kg per day), which has dose-dependent activity, is recommended to treat S. aureus orthopedic implant–associated infections. Rifampin, however, has limited bone penetration. Here, dynamic (11)C-rifampin positron emission tomography (PET) performed in prospectively enrolled patients with confirmed S. aureus bone infection (n = 3) or without orthopedic infection (n = 12) demonstrated bone/plasma area under the concentration-time curve ratio of 0.14 (interquartile range, 0.09 to 0.19), exposures lower than previously thought. PET-based pharmacokinetic modeling predicted rifampin concentration-time profiles in bone and facilitated studies in a mouse model of S. aureus orthopedic implant infection. Administration of high-dose rifampin (human equipotent to 35 mg/kg per day) substantially increased bone concentrations (2 mg/liter versus

Tuberculous meningitis (TB meningitis) is the most severe form of tuberculosis (TB), requiring 12 months of multidrug treatment for cure, and is associated with high morbidity and mortality. High-dose rifampin (35 mg/kg/d) is safe and improves the bactericidal activity of the standard-dose (10 mg/kg/d) rifampin-containing TB regimen in pulmonary TB. However, there are conflicting clinical data regarding its benefit for TB meningitis, where outcomes may also be associated with intracerebral inflammation. We conducted cross-species studies in mice and rabbits, demonstrating that an intensified high-dose rifampin-containing regimen has significantly improved bactericidal activity for TB meningitis over the first-line, standard-dose rifampin regimen, without an increase in intracerebral inflammation. Positron emission tomography in live animals demonstrated spatially compartmentalized, lesion-specific pathology, with postmortem analyses showing discordant brain tissue and cerebrospinal fluid rifampin levels and inflammatory markers. Longitudinal multimodal imaging in the same cohort of animals during TB treatment as well as imaging studies in two cohorts of TB patients demonstrated that spatiotemporal changes in localized blood-brain barrier disruption in TB meningitis are an important driver of rifampin brain exposure. These data provide unique insights into the mechanisms underlying high-dose rifampin in TB meningitis with important implications for developing new antibiotic treatments for infections.

The US Food and Drug Administration approved a 6-month regimen of pretomanid, bedaquiline, and linezolid for extensively drug-resistant or multidrug-intolerant tuberculosis after a trial in South Africa demonstrated 90% effectiveness 6 months posttreatment. We report on a patient who completed the regimen using a lower linezolid dose.

Mycobacterium tuberculosis metabolic state affects the response to therapy. Quantifying the effect of antimicrobials in the acid and nonreplicating metabolic phases of M. tuberculosis growth will help to optimize therapy for tuberculosis. As a brute-force approach to all possible drug combinations against M. tuberculosis in all different metabolic states is impossible, we have adopted a model-informed strategy to accelerate the discovery. Using multiple concentrations of each drug in time-kill studies, we examined single drugs and two- and three-drug combinations of pretomanid, moxifloxacin, and bedaquiline plus its active metabolite against M. tuberculosis in its acid-phase metabolic state. We used a nonparametric modeling approach to generate full distributions of interaction terms between pretomanid and moxifloxacin for susceptible and less susceptible populations. From the model, we could predict the 95% confidence interval of the simulated total bacterial population decline due to the 2-drug combination regimen of pretomanid and moxifloxacin and compare this to observed declines with 3-drug regimens. We found that the combination of pretomanid and moxifloxacin at concentrations equivalent to average or peak human concentrations effectively eradicated M. tuberculosis in its acid growth phase and prevented emergence of less susceptible isolates. The addition of bedaquiline as a third drug shortened time to total and less susceptible bacterial suppression by 8 days compared to the 2-drug regimen, which was significantly faster than the 2-drug kill.

Beta-lactam antibiotics are often the backbone of treatment for Gram-negative infections in the critically ill. Beta-lactams exhibit time-dependent killing, and their efficacy depends on the percentage of dosing interval that the concentration remains above the minimum inhibitory concentration. The Gram-negative resistance rates of pathogens are increasing in the intensive care unit (ICU), and critically ill patients often possess physiology that makes dosing more challenging. The volume of distribution is usually increased, and drug clearance is variable. Augmented renal clearance and hypermetabolic states increase the clearance of beta-lactams, while acute kidney injury reduces the clearance. To overcome the factors affecting ICU patients and decreasing susceptibilities, dosing strategies involving higher doses, and extended or continuous infusions may be required. In this review, we specifically examined pharmacokinetic models in ICU patients, to determine the desired beta-lactam regimens for clinical breakpoints of Enterobacterales and Pseudomonas aeruginosa, as determined by the European Committee on Antimicrobial Susceptibility Testing. The beta-lactams evaluated included penicillins, cephalosporins, carbapenems, and monobactams. We found that when treating less-susceptible pathogens, especially P. aeruginosa, continuous infusions are frequently needed to achieve the desired pharmacokinetic/pharmacodynamic targets. More studies are needed to determine optimal dosing strategies in the novel beta-lactams.

Background: The American Thoracic Society, U.S. Centers for Disease Control and Prevention, European Respiratory Society, and Infectious Diseases Society of America jointly sponsored this new practice guideline on the treatment of drug-resistant tuberculosis (DR-TB). The document includes recommendations on the treatment of multidrug-resistant TB (MDR-TB) as well as isoniazid-resistant but rifampin-susceptible TB. Methods: Published systematic reviews, meta-analyses, and a new individual patient data meta-analysis from 12,030 patients, in 50 studies, across 25 countries with confirmed pulmonary rifampin-resistant TB were used for this guideline. Meta-analytic approaches included propensity score matching to reduce confounding. Each recommendation was discussed by an expert committee, screened for conflicts of interest, according to the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology. Results: Twenty-one Population, Intervention, Comparator, and Outcomes questions were addressed, generating 25 GRADE-based recommendations. Certainty in the evidence was judged to be very low, because the data came from observational studies with significant loss to follow-up and imbalance in background regimens between comparator groups. Good practices in the management of MDR-TB are described. On the basis of the evidence review, a clinical strategy tool for building a treatment regimen for MDR-TB is also provided. Conclusions: New recommendations are made for the choice and number of drugs in a regimen, the duration of intensive and continuation phases, and the role of injectable drugs for MDR-TB. On the basis of these recommendations, an effective all-oral regimen for MDR-TB can be assembled. Recommendations are also provided on the role of surgery in treatment of MDR-TB and for treatment of contacts exposed to MDR-TB and treatment of isoniazid-resistant TB.

Objectives The current WHO weight-based dosing recommendations for efavirenz result in a wide variability of drug exposure in children. Our objectives are to characterize the effects of rifampicin- and isoniazid-containing anti-TB therapy and CYP2B6 activity on efavirenz concentrations in children, using non-linear mixed-effects modelling. Methods This is a pharmacokinetic (PK) substudy of a prospective study that examined the interactions between anti-TB therapy and efavirenz in HIV-infected children with and without TB. PK samples were obtained 4 weeks after starting efavirenz (PK1) and repeated 4 weeks after completing TB therapy (PK2) in TB/HIV coinfected patients. Drug concentrations were measured using LC-MS/MS. Composite CYP2B6 516/983/15582 genotype was determined. Population PK modelling was performed in Monolix. Simulations were performed to obtain the predicted mid-dose concentrations (C12). Results One hundred and five HIV-infected Ghanaian children (46 with TB/HIV) were included. The median age and weight were 7 years and 19 kg. The efavirenz concentrations over time were adequately described using a one-compartment model. Weight, composite CYP2B6 genotype and PK visit had a significant influence on the PK parameters, while TB therapy had no significant effect. Simulations showed adequate C12 for intermediate composite CYP2B6 metabolizers only. Conclusions Our model showed that rifampicin- and isoniazid-containing anti-TB therapy does not influence efavirenz PK parameters. On the other hand, it describes the effect of efavirenz autoinduction after completing TB treatment. In addition, dosing efavirenz in children based only on weight results in a large variability in drug exposure. We propose dose adjustments for slow and extensive composite CYP2B6 metabolizers.

Despite updated recommendations for weight-based isoniazid dosing in children with drug-susceptible tuberculosis (TB) and higher dose isoniazid in regimens for adults with drug-resistant TB, individual pharmacokinetic variability can lead to sub-target isoniazid exposure. Host pharmacogenetics and isoniazid exposure remain understudied, especially in the East African population. We therefore employed a real-time polymerase chain reaction (qPCR) assay system to test genomic DNA extracted from saliva samples targeting the NAT2 gene responsible for isoniazid metabolism to describe the frequency of human single nucleotide polymorphisms in NAT2 within populations of children and adults in Tanzania, ascribe those polymorphisms to acetylator phenotype, and correlate to serum isoniazid exposures. In adults treated with higher dose isoniazid, genotypes with a predicted allelic phenotype of slow or intermediate acetylation were able to achieve a 0.41 μg/mL higher C(max) (p = 0.018) and a 2.9h*μg/mL higher AUC(0)–(12) (p = 0.003) per mg/kg increase in isoniazid dosage versus adults with rapid acetylation phenotype. A similar relationship was not found in the younger age population as predicted by timing of NAT2 maturation. This saliva based qPCR assay was fieldable to guide personalized isoniazid dosing in adults but not young children that may not have full NAT2 maturation and activity.

In recent years, clofazimine (CFZ) has been regaining prominence for the treatment of tuberculosis. However, it shows limited efficacy as a single drug and optimal combination partners have not been identified. Therefore, the objective of our analysis was to evaluate the efficacy of CFZ-containing two-drug regimens with pretomanid (PMD), bedaquiline (BDQ) or linezolid (LZD) by: (i) determining their pharmacodynamic (PD) mode of interaction against Mycobacterium tuberculosis (Mtb) strain H37Rv in log- phase and acid-phase metabolic states, and against Mtb strain 18b in a non-replicating persister (NRP) metabolic state; (ii) predicting bacterial cell kill of the drugs alone and in combination; and (iii) evaluating the relationship between the interaction mode and the extent of bacterial cell kill. The results of our Greco universal response surface analysis showed that CFZ was at least additive with a clear trend towards synergy when combined with PMD, BDQ and LZD against Mtb in all explored metabolic states under in vitro checkerboard assay conditions. The results further showed that all two-drug combination regimens exerted greater bacterial kill than any of the drugs alone. CFZ alone showed the least antimicrobial efficacy amongst the evaluated drugs, and there was a lack of correlation between the mode of interaction and the extent of bacterial kill. However, we may underestimate the effect of CFZ in this screening approach owing to limited in vitro study duration and neglect of target site accumulation. Clofazimine; Pretomanid; Bedaquiline; Linezolid; Combination chemotherapy; Mycobacterium tuberculosis.

Critical illness from tuberculosis (TB) bloodstream infection results in a high case fatality rate for people living with human immunodeficiency virus (HIV). Critical illness can lead to altered pharmacokinetics and suboptimal drug exposures. We enrolled adults living with HIV and hospitalized with sepsis, with and without meningitis, in Mbarara, Uganda that were starting first-line anti-TB therapy. Serum was collected two weeks after enrollment at 1-, 2-, 4-, and 6-h post-dose and drug concentrations quantified by validated LC-MS/MS methods. Non-compartmental analyses were used to determine total drug exposure, and population pharmacokinetic modeling and simulations were performed to determine optimal dosages. Eighty-one participants were enrolled. Forty-nine completed pharmacokinetic testing: 18 (22%) died prior to testing, 13 (16%) were lost to follow-up and one had incomplete testing. Isoniazid had the lowest serum attainment, with only 4.1% achieving a target exposure over 24 h (AUC0–24) of 52 mg·h/L despite appropriate weight-based dosing. Simulations to reach target AUC0–24 found necessary doses of rifampin of 1800 mg, pyrazinamide of 2500–3000 mg, and for isoniazid 900 mg or higher. Given the high case fatality ratio of TB-related critical illness in this population, an early higher dose anti-TB therapy should be trialed.

Sepsis causes half of acute kidney injuries in the intensive care unit (ICU). ICU patients may need continuous renal replacement therapy (CRRT), which will affect their antimicrobial exposure. We aimed to build a cefepime population pharmacokinetic (PK) model in CRRT ICU patients and perform simulations to assess target attainment. Patients who were ≥18 years old, were admitted to the ICU, and received cefepime 2 g every 8 h as a 4-h infusion while on CRRT were enrolled prospectively. Samples were collected from the predialyzer ports, postdialyzer ports, and effluent fluid at 1, 2, 3, 4, and 8 h after the first dose and at steady state. Age, sex, weight, urine output, and CRRT parameters were recorded. Pmetrics was used for population PK and simulations. The target exposure was 100% of the dosing interval during which the free beta-lactam concentration is above the MIC (fT(>MIC)). Ten patients were included; their mean age was 53 years, and mean weight was 119 kg. Seventy percent were males. Cefepime was described by a five-compartment model. The downtime was applied to the CRRT flow rates, which were used to describe the rates of transfer between the compartments. At MICs of ≤8 mg/liter, intermittent infusion of 2 g cefepime every 8 h achieved good target attainment both early in therapy and at steady state. Only extended- and continuous-infusion regimens achieved good target attainment at MICs of 16 mg/liter. In conclusion, 2 g cefepime infused over 30 min followed by extended infusion of 2 g every 8 h achieved good target attainment at MICs of ≤16 mg/liter with different CRRT flow rates and may be considered in resistant bacterial infections.