Treatment of Mycobacterium avium-intracellulare complex: a great leap forward

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Sterilizing Effect of Ertapenem-Clavulanate in a Hollow-Fiber Model of Tuberculosis and Implications on Clinical Dosing

Carbapenems are now being explored for treatment of multidrug-resistant tuberculosis (MDR-TB), especially in conjunction with clavulanate. Clinical use is constrained by the need for multiple parenteral doses per day and the lack of knowledge of the optimal dose for sterilizing effect. Our objective was to identify the ertapenem exposure associated with optimal sterilizing effect and then design a once-a-day dose for clinical use. We utilized the hollow-fiber system model of tuberculosis in a 28-day exposure-response study of 8 different ertapenem doses in combination with clavulanate. The systems were sampled at predetermined time points to verify the concentration-time profile and identify the total bacterial burden. Inhibitory sigmoid maximum-effect (Emax) modeling was used to identify the relationship between total bacterial burden and the drug exposure and to identify optimal exposures. Contrary to the literature, ertapenem-clavulanate combination demonstrated good microbial kill and sterilizing effect. In a dose fractionation hollow-fiber study, efficacy was linked to percentage of the 24-h dosing interval of ertapenem concentration persisting above MIC (%TMIC). We performed 10,000 MDR-TB patient computer-aided clinical trial simulations, based on Monte Carlo methods, to identify the doses and schedule that would achieve or exceed a %TMIC of >/=40%. We identified an intravenous dosage of 2 g once per day as achieving the target in 96% of patients. An ertapenem susceptibility breakpoint MIC of 2 mg/liter was identified for that dose. An ertapenem dosage of 2 g once daily is the most suitable to be tested in a phase II study of sterilizing effect in MDR-TB patients

A Model-Informed Method for the Purpose of Precision Dosing of Isoniazid in Pulmonary Tuberculosis

BACKGROUND AND OBJECTIVE: This study aimed to develop and evaluate a population pharmacokinetic model and limited sampling strategy for isoniazid to be used in model-based therapeutic drug monitoring. METHODS: A population pharmacokinetic model was developed based on isoniazid and acetyl-isoniazid pharmacokinetic data from seven studies with in total 466 patients from three continents. Three limited sampling strategies were tested based on the available sampling times in the dataset and practical considerations. The tested limited sampling strategies sampled at 2, 4, and 6 h, 2 and 4 h, and 2 h after dosing. The model-predicted area under the concentration-time curve from 0 to 24 h (AUC(24)) and the peak concentration from the limited sampling strategies were compared to predictions using the full pharmacokinetic curve. Bias and precision were assessed using the mean error (ME) and the root mean square error (RMSE), both expressed as a percentage of the mean model-predicted AUC(24) or peak concentration on the full pharmacokinetic curve. RESULTS: Performance of the developed model was acceptable and the uncertainty in parameter estimations was generally low (the highest relative standard error was 39% coefficient of variation). The limited sampling strategy with sampling at 2 and 4 h was determined as most suitable with an ME of 1.1% and RMSE of 23.4% for AUC(24) prediction, and ME of 2.7% and RMSE of 23.8% for peak concentration prediction. For the performance of this strategy, it is important that data on both isoniazid and acetyl-isoniazid are used. If only data on isoniazid are available, a limited sampling strategy using 2, 4, and 6 h can be employed with an ME of 1.7% and RMSE of 20.9% for AUC(24) prediction, and ME of 1.2% and RMSE of 23.8% for peak concentration prediction. CONCLUSIONS: A model-based therapeutic drug monitoring strategy for personalized dosing of isoniazid using sampling at 2 and 4 h after dosing was successfully developed. Prospective evaluation of this strategy will show how it performs in a clinical therapeutic drug monitoring setting

Broad Decline in Viral Infections During COVID-19 Lockdown: Association with Lung Function in Lung Transplant Recipients

Purpose In April 2020 COVID-19 lockdown measures were instigated leading to a dramatic drop in non-COVID respiratory virus infections (RVI). This provided a unique situation to assess the impact of RVI on annual FEV1 decline, episodes of temporary drop in lung function suggestive of infection (TDLF) and CLAD in lung transplant recipients (LTR). Methods All lung function tests (LFT) of LTR transplanted between 2009-April 2020 were used from post-transplant baseline onward. LFT were censored after COVID-19 infection. Weekly RVI counts from the virology department defined RVI pressure over time. TDLF was defined as sudden, reversible FEV1 drop compared to previous 4 values (any TDLF ≥10% and ≥200ml, severe TDLF ≥20% and ≥500ml). Annual FEV1 decline was estimated using linear mixed effects models with separate estimates for 2009/20 and 2020/21. Effect modification by TDLF frequency of individual LTR (two subgroups, split at median) and RVI pressure was tested. Rates of CLAD and TDLF were analyzed over time. Results 479 LTR (12,775 LFT) were included. Annual FEV1 change in 2009/20 was -114ml [95%CI -133; -94], while in 2020/21 this was significantly less: 5ml [-38; 48] (p<0.001). RVI pressure significantly affected FEV1 level (an increase in weekly RVI-count of 10 leading to a 7ml [-10; -5] lower FEV1 (p<0.001). FEV1 decline in 2009/20 was faster in frequent TDLF LTR vs. infrequent (-150ml [-181; -120] vs. -90ml [-115; -65] p=0.003 Fig A). 2020/21 showed significant decreases in number of any TDLF (OR 0.53 [0.33; 0.85], p=0.008) and severe TDLF (OR 0.34 [0.16; 0.71] p=0.005) and numerically lower CLAD (OR 0.53 [0.27; 1.02] p=0.060). Effect modification by RVI pressure (Figures B-D) indicated an association between the events and RVI. Conclusion During the lockdown year 2020/21 the broad decline in RVI coincided with substantially less FEV1 decline, TDLFs and possibly CLAD. All these outcomes were moderated by RVI pressure suggesting an important role for RVI in lung function decline in LTR

Global estimates and determinants of antituberculosis drug pharmacokinetics in children and adolescents: a systematic review and individual patient data meta-analysis.

BACKGROUND: Suboptimal 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. METHODS: We 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 (AUC(0-24)) and peak plasma concentration (C (max)) were assessed with random-effects models, normalised with current World Health Organization-recommended paediatric doses. Determinants of AUC(0-24) and C (max) were assessed with linear mixed-effects models. RESULTS: Of 55 eligible studies, individual patient data were available for 39 (71%), including 1628 participants from 12 countries. Geometric means of steady-state AUC(0-24) were 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 <2 years) and HIV-positive status were associated with lower AUC(0-24) for all first-line anti-TB drugs, while severe malnutrition was associated with lower AUC(0-24) for isoniazid and pyrazinamide. N-acetyltransferase 2 rapid acetylators had lower isoniazid AUC(0-24) and slow acetylators had higher isoniazid AUC(0-24) than intermediate acetylators. Determinants of C (max) were generally similar to those for AUC(0-24). CONCLUSIONS: This 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

Treatment correlates of successful outcomes in pulmonary multidrug-resistant tuberculosis: an individual patient data meta-analysis

Item does not contain fulltextBACKGROUND: Treatment outcomes for multidrug-resistant tuberculosis remain poor. We aimed to estimate the association of treatment success and death with the use of individual drugs, and the optimal number and duration of treatment with those drugs in patients with multidrug-resistant tuberculosis. METHODS: In this individual patient data meta-analysis, we searched MEDLINE, Embase, and the Cochrane Library to identify potentially eligible observational and experimental studies published between Jan 1, 2009, and April 30, 2016. We also searched reference lists from all systematic reviews of treatment of multidrug-resistant tuberculosis published since 2009. To be eligible, studies had to report original results, with end of treatment outcomes (treatment completion [success], failure, or relapse) in cohorts of at least 25 adults (aged >18 years). We used anonymised individual patient data from eligible studies, provided by study investigators, regarding clinical characteristics, treatment, and outcomes. Using propensity score-matched generalised mixed effects logistic, or linear regression, we calculated adjusted odds ratios and adjusted risk differences for success or death during treatment, for specific drugs currently used to treat multidrug-resistant tuberculosis, as well as the number of drugs used and treatment duration. FINDINGS: Of 12 030 patients from 25 countries in 50 studies, 7346 (61%) had treatment success, 1017 (8%) had failure or relapse, and 1729 (14%) died. Compared with failure or relapse, treatment success was positively associated with the use of linezolid (adjusted risk difference 0.15, 95% CI 0.11 to 0.18), levofloxacin (0.15, 0.13 to 0.18), carbapenems (0.14, 0.06 to 0.21), moxifloxacin (0.11, 0.08 to 0.14), bedaquiline (0.10, 0.05 to 0.14), and clofazimine (0.06, 0.01 to 0.10). There was a significant association between reduced mortality and use of linezolid (-0.20, -0.23 to -0.16), levofloxacin (-0.06, -0.09 to -0.04), moxifloxacin (-0.07, -0.10 to -0.04), or bedaquiline (-0.14, -0.19 to -0.10). Compared with regimens without any injectable drug, amikacin provided modest benefits, but kanamycin and capreomycin were associated with worse outcomes. The remaining drugs were associated with slight or no improvements in outcomes. Treatment outcomes were significantly worse for most drugs if they were used despite in-vitro resistance. The optimal number of effective drugs seemed to be five in the initial phase, and four in the continuation phase. In these adjusted analyses, heterogeneity, based on a simulated I(2) method, was high for approximately half the estimates for specific drugs, although relatively low for number of drugs and durations analyses. INTERPRETATION: Although inferences are limited by the observational nature of these data, treatment outcomes were significantly better with use of linezolid, later generation fluoroquinolones, bedaquiline, clofazimine, and carbapenems for treatment of multidrug-resistant tuberculosis. These findings emphasise the need for trials to ascertain the optimal combination and duration of these drugs for treatment of this condition. FUNDING: American Thoracic Society, Canadian Institutes of Health Research, US Centers for Disease Control and Prevention, European Respiratory Society, Infectious Diseases Society of America