Determining the Delamanid Pharmacokinetics/Pharmacodynamics Susceptibility Breakpoint Using Monte Carlo Experiments.

Antimicrobial susceptibility testing, based on clinical breakpoints that incorporate pharmacokinetics/pharmacodynamics (PK/PD) and clinical outcomes, is becoming a new standard in guiding individual patient therapy as well as for drug resistance surveillance. However, for most antituberculosis drugs, breakpoints are instead defined by the epidemiological cutoff values of the MIC of phenotypically wild-type strains irrespective of PK/PD or dose. In this study, we determined the PK/PD breakpoint for delamanid by estimating the probability of target attainment for the approved dose administered at 100 mg twice daily using Monte Carlo experiments. We used the PK/PD targets (0- to 24-h area under the concentration-time curve to MIC) identified in a murine chronic tuberculosis model, hollow fiber system model of tuberculosis, early bactericidal activity studies of patients with drug-susceptible tuberculosis, and population pharmacokinetics in patients with tuberculosis. At the MIC of 0.016 mg/L, determined using Middlebrook 7H11 agar, the probability of target attainment was 100% in the 10,000 simulated subjects. The probability of target attainment fell to 25%, 40%, and 68% for PK/PD targets derived from the mouse model, the hollow fiber system model of tuberculosis, and patients, respectively, at the MIC of 0.031 mg/L. This indicates that an MIC of 0.016 mg/L is the delamanid PK/PD breakpoint for delamanid at 100 mg twice daily. Our study demonstrated that it is feasible to use PK/PD approaches to define a breakpoint for an antituberculosis drug.

Bacterial load slopes represent biomarkers of tuberculosis therapy success, failure, and relapse.

There is an urgent need to discover biomarkers that are predictive of long-term TB treatment outcomes, since treatment is expense and prolonged to document relapse. We used mathematical modeling and machine learning to characterize a predictive biomarker for TB treatment outcomes. We computed bacterial kill rates, γf for fast- and γs for slow/non-replicating bacteria, using patient sputum data to determine treatment duration by computing time-to-extinction of all bacterial subpopulations. We then derived a γs-slope-based rule using first 8 weeks sputum data, that demonstrated a sensitivity of 92% and a specificity of 89% at predicting relapse-free cure for 2, 3, 4, and 6 months TB regimens. In comparison, current methods (two-month sputum culture conversion and the Extended-EBA) methods performed poorly, with sensitivities less than 34%. These biomarkers will accelerate evaluation of novel TB regimens, aid better clinical trial designs and will allow personalization of therapy duration in routine treatment programs.

Ethionamide Pharmacokinetics/Pharmacodynamics-derived Dose, the Role of MICs in Clinical Outcome, and the Resistance Arrow of Time in Multidrug-resistant Tuberculosis.

Background: Ethionamide is used to treat multidrug-resistant tuberculosis (MDR-TB). The antimicrobial pharmacokinetics/pharmacodynamics, the contribution of ethionamide to the multidrug regimen, and events that lead to acquired drug resistance (ADR) are unclear. Methods: We performed a multidose hollow fiber system model of tuberculosis (HFS-TB) study to identify the 0-24 hour area under the concentration-time curve (AUC0-24) to minimum inhibitory concentration (MIC) ratios that achieved maximal kill and ADR suppression, defined as target exposures. Ethionamide-resistant isolates underwent whole-genome and targeted Sanger sequencing. We utilized Monte Carlo experiments (MCEs) to identify ethionamide doses that would achieve the target exposures in 10000 patients with pulmonary tuberculosis. We also identified predictors of time-to-sputum conversion in Tanzanian patients on ethionamide- and levofloxacin-based regimens using multivariate adaptive regression splines (MARS). Results: An AUC0-24/MIC >56.2 was identified as the target exposure in the HFS-TB. Early efflux pump induction to ethionamide monotherapy led to simultaneous ethambutol and isoniazid ADR, which abrogated microbial kill of an isoniazid-ethambutol-ethionamide regimen. Genome sequencing of isolates that arose during ethionamide monotherapy revealed mutations in both ethA and embA. In MCEs, 20 mg/kg/day achieved the AUC0-24/MIC >56.2 in >95% of patients, provided the Sensititre assay MIC was <2.5 mg/L. In the clinic, MARS revealed that ethionamide Sensititre MIC had linear negative relationships with time-to-sputum conversion until an MIC of 2.5 mg/L, above which patients with MDR-TB failed combination therapy. Conclusions: Ethionamide is an important contributor to MDR-TB treatment regimens, at Sensititre MIC <2.5 mg/L. Suboptimal ethionamide exposures led to efflux pump-mediated ADR.

Gatifloxacin Pharmacokinetics/Pharmacodynamics-based Optimal Dosing for Pulmonary and Meningeal Multidrug-resistant Tuberculosis.

Background: Gatifloxacin is used for the treatment of multidrug-resistant tuberculosis (MDR-TB). The optimal dose is unknown. Methods: We performed a 28-day gatifloxacin hollow-fiber system model of tuberculosis (HFS-TB) study in order to identify the target exposures associated with optimal kill rates and resistance suppression. Monte Carlo experiments (MCE) were used to identify the dose that would achieve the target exposure in 10000 adult patients with meningeal or pulmonary MDR-TB. The optimal doses identified were validated using probit analyses of clinical data from 2 prospective clinical trials of patients with pulmonary and meningeal tuberculosis. Classification and regression-tree (CART) analyses were used to identify the gatifloxacin minimum inhibitory concentration (MIC) below which patients failed or relapsed on combination therapy. Results: The target exposure associated with optimal microbial kill rates and resistance suppression in the HFS-TB was a 0-24 hour area under the concentration-time curve-to-MIC of 184. MCE identified an optimal gatifloxacin dose of 800 mg/day for pulmonary and 1200 mg/day for meningeal MDR-TB, and a clinical susceptibility breakpoint of MIC ≤ 0.5 mg/L. In clinical trials, CART identified that 79% patients failed therapy if MIC was >2 mg/L, but 98% were cured if MIC was ≤0.5 mg/L. Probit analysis of clinical data demonstrated a >90% probability of a cure in patients if treated with 800 mg/day for pulmonary tuberculosis and 1200 mg/day for meningeal tuberculosis. Doses ≤400 mg/day were suboptimal. Conclusions: Gatifloxacin doses of 800 mg/day and 1200 mg/day are recommended for pulmonary and meningeal MDR-TB treatment, respectively. Gatifloxacin has a susceptible dose-dependent zone at MICs 0.5-2 mg/L.

Levofloxacin Pharmacokinetics/Pharmacodynamics, Dosing, Susceptibility Breakpoints, and Artificial Intelligence in the Treatment of Multidrug-resistant Tuberculosis.

Background: Levofloxacin is used for the treatment of multidrug-resistant tuberculosis; however the optimal dose is unknown. Methods: We used the hollow fiber system model of tuberculosis (HFS-TB) to identify 0-24 hour area under the concentration-time curve (AUC0-24) to minimum inhibitory concentration (MIC) ratios associated with maximal microbial kill and suppression of acquired drug resistance (ADR) of Mycobacterium tuberculosis (Mtb). Levofloxacin-resistant isolates underwent whole-genome sequencing. Ten thousands patient Monte Carlo experiments (MCEs) were used to identify doses best able to achieve the HFS-TB-derived target exposures in cavitary tuberculosis and tuberculous meningitis. Next, we used an ensemble of artificial intelligence (AI) algorithms to identify the most important predictors of sputum conversion, ADR, and death in Tanzanian patients with pulmonary multidrug-resistant tuberculosis treated with a levofloxacin-containing regimen. We also performed probit regression to identify optimal levofloxacin doses in Vietnamese tuberculous meningitis patients. Results: In the HFS-TB, the AUC0-24/MIC associated with maximal Mtb kill was 146, while that associated with suppression of resistance was 360. The most common gyrA mutations in resistant Mtb were Asp94Gly, Asp94Asn, and Asp94Tyr. The minimum dose to achieve target exposures in MCEs was 1500 mg/day. AI algorithms identified an AUC0-24/MIC of 160 as predictive of microbiologic cure, followed by levofloxacin 2-hour peak concentration and body weight. Probit regression identified an optimal dose of 25 mg/kg as associated with >90% favorable response in adults with pulmonary tuberculosis. Conclusions: The levofloxacin dose of 25 mg/kg or 1500 mg/day was adequate for replacement of high-dose moxifloxacin in treatment of multidrug-resistant tuberculosis.

Intermediate Susceptibility Dose-Dependent Breakpoints For High-Dose Rifampin, Isoniazid, and Pyrazinamide Treatment in Multidrug-Resistant Tuberculosis Programs.

Background: Bacterial susceptibility is categorized as susceptible, intermediate-susceptible dose-dependent (ISDD), and resistant. The strategy is to use higher doses of first-line agents in the ISDD category, thereby preserving the use of these drugs. This system has not been applied to antituberculosis drugs. Pharmacokinetic/pharmacodynamic (PK/PD) target exposures, in tandem with Monte Carlo experiments, recently identified susceptibility breakpoints of 0.0312 mg/L for isoniazid, 0.0625 mg/L for rifampin, and 50 mg/L for pyrazinamide. These have been confirmed in clinical studies. Methods: Target attainment studies were carried out using Monte Carlo experiments to investigate whether rifampin, isoniazid, and pyrazinamide dose increases would achieve the PK/PD target in >90% of 10000 patients with tuberculosis caused by bacteria, revealing minimum inhibitory concentrations (MICs) between the proposed and the traditional breakpoints. Results: We found that an isoniazid dose of 900 mg/day identified a new ISDD MIC range of 0.0312-0.25 mg/L and resistance at MIC ≥0.5 mg/L. Rifampin 1800 mg/day would result in an ISDD of 0.0625-0.25 mg/L and resistance at MIC ≥0.5 mg/L. At a dose of pyrazinamide 4 g/day, the ISDD MIC range was 37.5-50 mg/L and resistance at MIC ≥100 mg/L. Based on MIC distributions, 93% (isoniazid), 78% (rifampin), and 27% (pyrazinamide) of isolates would be within the ISDD range. Conclusions: Drug susceptibility testing at 2 concentrations delineating the ISDD range, and subsequently using higher doses, could prevent switching to a more toxic second-line treatment. Confirmatory clinical studies would provide evidence to change treatment guidelines.

Antibacterial and Sterilizing Effect of Benzylpenicillin in Tuberculosis.

The modern chemotherapy era started with Fleming's discovery of benzylpenicillin. He demonstrated that benzylpenicillin did not kill Mycobacterium tuberculosis In this study, we found that >64 mg/liter of static benzylpenicillin concentrations killed 1.16 to 1.43 log10 CFU/ml below starting inoculum of extracellular and intracellular M. tuberculosis over 7 days. When we added the ß-lactamase inhibitor avibactam, benzylpenicillin maximal kill (Emax) of extracellular log-phase-growth M. tuberculosis was 6.80 ± 0.45 log10 CFU/ml at a 50% effective concentration (EC50) of 15.11 ± 2.31 mg/liter, while for intracellular M. tuberculosis it was 2.42 ± 0.14 log10 CFU/ml at an EC50 of 6.70 ± 0.56 mg/liter. The median penicillin (plus avibactam) MIC against South African clinical M. tuberculosis strains (80% either multidrug or extensively drug resistant) was 2 mg/liter. We mimicked human-like benzylpenicillin and avibactam concentration-time profiles in the hollow-fiber model of tuberculosis (HFS-TB). The percent time above the MIC was linked to effect, with an optimal exposure of ≥65%. At optimal exposure in the HFS-TB, the bactericidal activity in log-phase-growth M. tuberculosis was 1.44 log10 CFU/ml/day, while 3.28 log10 CFU/ml of intracellular M. tuberculosis was killed over 3 weeks. In an 8-week HFS-TB study of nonreplicating persistent M. tuberculosis, penicillin-avibactam alone and the drug combination of isoniazid, rifampin, and pyrazinamide both killed >7.0 log10 CFU/ml. Monte Carlo simulations of 10,000 preterm infants with disseminated disease identified an optimal dose of 10,000 U/kg (of body weight)/h, while for pregnant women or nonpregnant adults with pulmonary tuberculosis the optimal dose was 25,000 U/kg/h, by continuous intravenous infusion. Penicillin-avibactam should be examined for effect in pregnant women and infants with drug-resistant tuberculosis, to replace injectable ototoxic and teratogenic second-line drugs.

Tedizolid is highly bactericidal in the treatment of pulmonary Mycobacterium avium complex disease.

OBJECTIVES: To determine if tedizolid is effective for pulmonary Mycobacterium avium complex (MAC) disease, and to use pharmacokinetics/pharmacodynamics to design optimal doses. METHODS: We performed an exposure-response experiment in the hollow-fibre system model of intracellular MAC (HFS-MAC). We mimicked the tedizolid concentration-time profiles achieved in the lungs of patients treated once daily for 28 days. The HFS-MAC was sampled at intervals to determine the tedizolid pharmacokinetics and MAC intracellular burden. We identified the 0-24 h area under the concentration-time curves to MIC (AUC0-24/MIC) ratios associated with the following targets: 80% of maximal kill (EC80), bacteriostasis, and 1.0 and 2.0 log10 cfu/mL kill. We then performed 10 000 patient Monte Carlo simulations to identify the optimal dose for each of the exposure targets. RESULTS: Tedizolid achieved the feat of 2.0 log10 cfu/mL kill below initial bacterial burden, an effect not seen before in this model with other antibiotics. The tedizolid exposure associated with 1.0 log10 cfu/mL kill was a non-protein bound AUC0-24/MIC ratio of 23.46, while that associated with 2.0 log10 cfu/mL kill was 37.50, and the EC80 was 21.71. The clinical dose of 200 mg achieved each of these targets in ∼100% of the 10 000 patients, except the 2.0 log10 cfu/mL kill which required 300 mg/day. A tedizolid susceptibility MIC breakpoint of 1 mg/L is proposed. CONCLUSIONS: Tedizolid, at standard clinical doses, is expected to be bactericidal, and even achieved an unprecedented 2.0 log10 cfu/mL kill of MAC as monotherapy. We propose it as the backbone of short-course anti-MAC chemotherapy.

Linezolid as treatment for pulmonary Mycobacterium avium disease.

OBJECTIVES: To identify the pharmacokinetic/pharmacodynamic parameters and exposures of linezolid in the treatment of pulmonary Mycobacterium avium complex (MAC) disease. METHODS: Human-derived monocytes infected with MAC were inoculated into hollow-fibre systems for dose-effect and dose-scheduling studies. We mimicked linezolid concentration-time profiles achieved in adult human lungs treated for 28 days. Sampling to confirm that the intended linezolid pharmacokinetics had been achieved, and for enumeration of MAC colony-forming units, was performed based on repetitive sampling from each system over the 28 days. We then performed 10 000 patient Monte Carlo simulations to identify doses associated with optimal effect in the clinic. RESULTS: Linezolid achieved a hitherto unprecedented feat of at least 1.0 log10 cfu/mL reduction. Efficacy was most closely linked to the AUC0-24/MIC ratio. The AUC0-24/MIC ratio associated with no change in bacterial burden or bacteriostasis was 7.82, while that associated with 1.0 log10 cfu/mL kill was 42.06. The clinical dose of 600 mg/day achieved or exceeded the bacteriostasis exposure in 98.73% of patients. The proportion of 10 000 patients treated with the standard 1200 mg/day who achieved the exposure for 1.0 log10 cfu/mL kill was 70.64%, but was 90% for 1800 mg/day. The proposed MIC breakpoint for linezolid is 16 mg/L, with which 49%-80% of clinical isolates would be considered resistant. CONCLUSIONS: Linezolid is associated with a bactericidal effect in pulmonary MAC that is greater than that seen with other recommended drugs. However, because of the MIC distribution, doses that would optimize the bactericidal effect would be associated with a high adverse event rate.

The epidemiology, pathogenesis, transmission, diagnosis, and management of multidrug-resistant, extensively drug-resistant, and incurable tuberculosis.

Global tuberculosis incidence has declined marginally over the past decade, and tuberculosis remains out of control in several parts of the world including Africa and Asia. Although tuberculosis control has been effective in some regions of the world, these gains are threatened by the increasing burden of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis. XDR tuberculosis has evolved in several tuberculosis-endemic countries to drug-incurable or programmatically incurable tuberculosis (totally drug-resistant tuberculosis). This poses several challenges similar to those encountered in the pre-chemotherapy era, including the inability to cure tuberculosis, high mortality, and the need for alternative methods to prevent disease transmission. This phenomenon mirrors the worldwide increase in antimicrobial resistance and the emergence of other MDR pathogens, such as malaria, HIV, and Gram-negative bacteria. MDR and XDR tuberculosis are associated with high morbidity and substantial mortality, are a threat to health-care workers, prohibitively expensive to treat, and are therefore a serious public health problem. In this Commission, we examine several aspects of drug-resistant tuberculosis. The traditional view that acquired resistance to antituberculous drugs is driven by poor compliance and programmatic failure is now being questioned, and several lines of evidence suggest that alternative mechanisms-including pharmacokinetic variability, induction of efflux pumps that transport the drug out of cells, and suboptimal drug penetration into tuberculosis lesions-are likely crucial to the pathogenesis of drug-resistant tuberculosis. These factors have implications for the design of new interventions, drug delivery and dosing mechanisms, and public health policy. We discuss epidemiology and transmission dynamics, including new insights into the fundamental biology of transmission, and we review the utility of newer diagnostic tools, including molecular tests and next-generation whole-genome sequencing, and their potential for clinical effectiveness. Relevant research priorities are highlighted, including optimal medical and surgical management, the role of newer and repurposed drugs (including bedaquiline, delamanid, and linezolid), pharmacokinetic and pharmacodynamic considerations, preventive strategies (such as prophylaxis in MDR and XDR contacts), palliative and patient-orientated care aspects, and medicolegal and ethical issues.

A Combination Regimen Design Program Based on Pharmacodynamic Target Setting for Childhood Tuberculosis: Design Rules for the Playground.

Children with tuberculosis are treated with drug regimens copied from adults despite significant differences in antibiotic pharmacokinetics, pathology, and the microbial burden between childhood and adult tuberculosis. We sought to develop a new and effective oral treatment regimen specific to children of different ages. We investigated and validated the concept that target drug concentrations associated with therapy failure and death in children are different from those of adults. On that basis, we proposed a 4-step program to rapidly develop treatment regimens for children. First, target drug concentrations for optimal efficacy are derived from preclinical models of disseminated tuberculosis that recapitulate pediatric pharmacokinetics, starting with monotherapy. Second, 2-drug combinations were examined for zones of synergy, antagonism, and additivity based on a whole exposure-response surface. Exposures associated with additivity or synergy were then combined and the regimen was compared to standard therapy. Third, several exposures of the third drug were added, and a 3-drug regimen was identified based on kill slopes in comparison to standard therapy. Fourth, computer-aided clinical trial simulations are used to identify clinical doses that achieve these kill rates in children in different age groups. The proposed program led to the development of a 3-drug combination regimen for children from scratch, independent of adult regimens, in <2 years. The regimens and doses can be tested in animal models and in clinical trials.

Optimal Clinical Doses of Faropenem, Linezolid, and Moxifloxacin in Children With Disseminated Tuberculosis: Goldilocks.

BACKGROUND: When treated with the same antibiotic dose, children achieve different 0- to 24-hour area under the concentration-time curves (AUC0-24) because of maturation and between-child physiological variability on drug clearance. Children are also infected by Mycobacterium tuberculosis isolates with different antibiotic minimum inhibitory concentrations (MICs). Thus, each child will achieve different AUC0-24/MIC ratios when treated with the same dose. METHODS: We used 10 000-subject Monte Carlo experiments to identify the oral doses of linezolid, moxifloxacin, and faropenem that would achieve optimal target exposures associated with optimal efficacy in children with disseminated tuberculosis. The linezolid and moxifloxacin exposure targets were AUC0-24/MIC ratios of 62 and 122, and a faropenem percentage of time above MIC >60%, in combination therapy. A linezolid AUC0-24 of 93.4 mg × hour/L was target for toxicity. Population pharmacokinetic parameters of each drug and between-child variability, as well as MIC distribution, were used, and the cumulative fraction of response (CFR) was calculated. We also considered drug penetration indices into meninges, bone, and peritoneum. RESULTS: The linezolid dose of 15 mg/kg in full-term neonates and infants aged up to 3 months and 10 mg/kg in toddlers, administered once daily, achieved CFR ≥ 90%, with <10% achieving linezolid AUC0-24 associated with toxicity. The moxifloxacin dose of 25 mg/kg/day achieved a CFR > 90% in infants, but the optimal dose was 20 mg/kg/day in older children. The faropenem medoxomil optimal dosage was 30 mg/kg 3-4 times daily. CONCLUSIONS: The regimen and doses of linezolid, moxifloxacin, and faropenem identified are proposed to be adequate for all disseminated tuberculosis syndromes, whether drug-resistant or -susceptible.

Moxifloxacin's Limited Efficacy in the Hollow-Fiber Model of Mycobacterium abscessus Disease.

Current regimens used to treat pulmonary Mycobacterium abscessus disease have limited efficacy. There is an urgent need for new drugs and optimized combinations and doses. We performed hollow-fiber-system studies in which M. abscessus was exposed to moxifloxacin lung concentration-time profiles similar to human doses of between 0 and 800 mg/day. The minimum bactericidal concentration and MIC were 8 and 2 mg/liter, respectively, in our M. abscessus strain, suggesting bactericidal activity. Measurement of the moxifloxacin concentrations in each hollow-fiber system revealed an elimination rate constant (kel) of 0.11 ± 0.05 h(-1) (mean ± standard deviation) (half-life of 9.8 h). Inhibitory sigmoid maximal effect (Emax) modeling revealed that the highest Emax was 3.15 ± 1.84 log10 CFU/ml on day 3, and the exposure mediating 50% of Emax (EC50) was a 0- to 24-h area under the concentration time curve (AUC0-24)-to-MIC ratio of 41.99 ± 31.78 (r(2) = 0.99). The EC80 was an AUC0-24/MIC ratio of 102.11. However, no moxifloxacin concentration killed the bacteria to burdens below the starting inoculum. There was regrowth beyond day 3 in all doses, with replacement by a resistant subpopulation that had an MIC of >32 mg/liter by the end of the experiment. A quadratic function best described the relationship between the AUC0-24/MIC ratio and the moxifloxacin-resistant subpopulation. Monte Carlo simulations of 10,000 patients revealed that the 400- to 800-mg/day doses would achieve or exceed the EC80 in ≤12.5% of patients. The moxifloxacin susceptibility breakpoint was 0.25 mg/liter, which means that almost all M. abscessus clinical strains are moxifloxacin resistant by these criteria. While moxifloxacin's efficacy against M. abscessus was poor, formal combination therapy studies with moxifloxacin are still recommended.

Tigecycline Is Highly Efficacious against Mycobacterium abscessus Pulmonary Disease.

Mycobacterium abscessus causes chronic pulmonary infections that are extremely difficult to cure. The currently recommended combination therapy is associated with high failure rates and relapse. Tigecycline has been explored in salvage regimens, with a response rate of 43% in those who received at least a month of therapy. We performed a dose-response study in a hollow-fiber system model of pulmonary M. abscessus infection in which we recapitulated tigecycline human pulmonary concentration-time profiles of 8 different doses for 21 days. We identified the maximal kill or efficacy in CFU per milliliter and the ratio of the 0- to 24-h area under the concentration-time curve to MIC (AUC/MIC) associated with 80% efficacy (EC80). The tigecycline efficacy was 5.38 ± 2.35 log10 CFU/ml, and the drug achieved the unprecedented feat of a bacterial level of 1.0 log10 CFU/ml below the pretreatment inoculum (1-log kill) of M. abscessus in the hollow-fiber system. The EC80 AUC/MIC ratio was 36.65, while that for a 1-log kill was 44.6. Monte Carlo experiments with 10,000 patients were used to identify the clinical dose best able to achieve the EC80 or 1-log kill. The standard dose of 100 mg/day had a cumulative fraction of response of 51% for the EC80 and 46% for 1-log kill. For both the EC80 target and 1-log kill, the optimal tigecycline clinical dose was identified as 200 mg/day. The susceptibility breakpoint was ≤0.5 mg/liter. Tigecycline is the most active single agent evaluated to date, and we propose that 200 mg/day be examined as the backbone of new combination therapy regimens to replace current treatment.

Azithromycin Dose To Maximize Efficacy and Suppress Acquired Drug Resistance in Pulmonary Mycobacterium avium Disease.

Mycobacterium aviumcomplex is now the leading mycobacterial cause of chronic pneumonia in the United States. Macrolides and ethambutol form the backbone of the regimen used in the treatment of pulmonary disease. However, therapy outcomes remain poor, with microbial cure rates of 4% in cavitary disease. The treatment dose of azithromycin has mostly been borrowed from that used to treat other bacterial pneumonias; there are no formal dose-response studies in pulmonaryM. aviumdisease and the optimal dose is unclear. We utilized population pharmacokinetics and pharmacokinetics/pharmacodynamics-derived azithromycin exposures associated with optimal microbial kill or resistance suppression to perform 10,000 patient Monte Carlo simulations of dose effect studies for daily azithromycin doses of 0.5 to 10 g. The currently recommended dose of 500 mg per day achieved the target exposures in 0% of patients. Exposures associated with optimal kill and resistance suppression were achieved in 87 and 54% of patients, respectively, only by the very high dose of 8 g per day. The azithromycin susceptibility breakpoint above which patients failed therapy on the very high doses of 8 g per day was an MIC of 16 mg/liter, suggesting a critical concentration of 32 mg/liter, which is 8-fold lower than the currently used susceptibility breakpoint of 256 mg/liter. If the standard dose of 500 mg a day were used, then the critical concentration would fall to 2 mg/liter, 128-fold lower than 256 mg/liter. The misclassification of resistant isolates as susceptible could explain the high failure rates of current doses.

Amikacin Pharmacokinetics/Pharmacodynamics in a Novel Hollow-Fiber Mycobacterium abscessus Disease Model.

The treatment of pulmonary Mycobacterium abscessus disease is associated with very high failure rates and easily acquired drug resistance. Amikacin is the key drug in treatment regimens, but the optimal doses are unknown. No good preclinical model exists to perform formal pharmacokinetics/pharmacodynamics experiments to determine these optimal doses. We developed a hollow-fiber system model of M. abscessus disease and studied amikacin exposure effects and dose scheduling. We mimicked amikacin human pulmonary pharmacokinetics. Both amikacin microbial kill and acquired drug resistance were linked to the peak concentration-to-MIC ratios; the peak/MIC ratio associated with 80% of maximal kill (EC80) was 3.20. However, on the day of the most extensive microbial kill, the bacillary burden did not fall below the starting inoculum. We performed Monte Carlo simulations of 10,000 patients with pulmonary M. abscessus infection and examined the probability that patients treated with one of 6 doses from 750 mg to 4,000 mg would achieve or exceed the EC80. We also examined these doses for the ability to achieve a cumulative area under the concentration-time curve of 82,232 mg · h/liter × days, which is associated with ototoxicity. The standard amikacin doses of 750 to 1,500 mg a day achieved the EC80 in ≤ 21% of the patients, while a dose of 4 g/day achieved this in 70% of the patients but at the cost of high rates of ototoxicity within a month or two. The susceptibility breakpoint was an MIC of 8 to 16 mg/liter. Thus, amikacin, as currently dosed, has limited efficacy against M. abscessus. It is urgent that different antibiotics be tested using our preclinical model and new regimens developed.

Systematic Analysis of Hollow Fiber Model of Tuberculosis Experiments.

BACKGROUND: The in vitro hollow fiber system model of tuberculosis (HFS-TB), in tandem with Monte Carlo experiments, was introduced more than a decade ago. Since then, it has been used to perform a large number of tuberculosis pharmacokinetics/pharmacodynamics (PK/PD) studies that have not been subjected to systematic analysis. METHODS: We performed a literature search to identify all HFS-TB experiments published between 1 January 2000 and 31 December 2012. There was no exclusion of articles by language. Bias minimization was according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Steps for reporting systematic reviews were followed. RESULTS: There were 22 HFS-TB studies published, of which 12 were combination therapy studies and 10 were monotherapy studies. There were 4 stand-alone Monte Carlo experiments that utilized quantitative output from the HFS-TB. All experiments reported drug pharmacokinetics, which recapitulated those encountered in humans. HFS-TB studies included log-phase growth studies under ambient air, semidormant bacteria at pH 5.8, and nonreplicating persisters at low oxygen tension of ≤ 10 parts per billion. The studies identified antibiotic exposures associated with optimal kill of Mycobacterium tuberculosis and suppression of acquired drug resistance (ADR) and informed predictions about optimal clinical doses, expected performance of standard doses and regimens in patients, and expected rates of ADR, as well as a proposal of new susceptibility breakpoints. CONCLUSIONS: The HFS-TB model offers the ability to perform PK/PD studies including humanlike drug exposures, to identify bactericidal and sterilizing effect rates, and to identify exposures associated with suppression of drug resistance. Because of the ability to perform repetitive sampling from the same unit over time, the HFS-TB vastly improves statistical power and facilitates the execution of time-to-event analyses and repeated event analyses, as well as dynamic system pharmacology mathematical models.

Forecasting Accuracy of the Hollow Fiber Model of Tuberculosis for Clinical Therapeutic Outcomes.

BACKGROUND: The hollow fiber system model of tuberculosis (HFS-TB), in tandem with Monte Carlo experiments, represents a drug development tool (DDT) with the potential for use to develop tuberculosis treatment regimens. However, the predictive accuracy of the HFS-TB, or any other nonclinical DDT such as an animal model, has yet to be robustly evaluated. METHODS: To avoid hindsight bias, a literature search was performed to identify clinical studies published at least 6 months after HFS-TB experiments' quantitative predictions. Steps to minimize bias and for reporting systematic reviews were applied as outlined in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. Publications were scored for quality of evidence. Accuracy was calculated using the mean absolute percentage error, then summated with weighting assigned by sample size and quality-of-evidence score. Given the lack of a gold-standard tuberculosis DDT, the forecasting accuracy of a completely unreliable tool was also calculated from 1000 simulated experiments for a random or "total guesswork" model. RESULTS: The quantitative forecasting accuracy (95% confidence interval [CI]) for the "total guesswork" model was 15.6% (95% CI, 8.7%-22.5%); bias was -0.1% (95% CI, -2.5% to 2.2%). Twenty clinical studies were published after HFS-TB experiments predicted optimal drug exposures and doses, susceptibility breakpoints, and optimal combination regimens. Based on these clinical studies, the predictive accuracy of the HFS-TB was 94.4% (95% CI, 84.3%-99.9%), and bias was 1.8% (95% CI, -13.7% to 6.2%). CONCLUSIONS: The HFS-TB model is highly accurate at forecasting optimal drug exposures, doses, and dosing schedules for use in the clinic.

Therapy duration and long-term outcomes in extra-pulmonary tuberculosis.

BACKGROUND: Tuberculosis is classified as either pulmonary or extra-pulmonary (EPTB). While much focus has been paid to pulmonary tuberculosis, EPTB has received scant attention. Moreover, EPTB is viewed as one wastebasket diagnosis, as "the other" which is not pulmonary. METHODS: This is a retrospective cohort study of all patients treated for EPTB in the state of Texas between January 2000 and December 2005, who had no pulmonary disease. Clinical and epidemiological factors were abstracted from electronic records of the Report of Verified Case of Tuberculosis. The long-term outcome, which is death by December 2011, was established using the Social Security Administration Death Master File database. Survival in EPTB patients was compared to those with latent tuberculosis, as well as between different types of EPTB, using Cox proportional hazard models. A hybrid of the machine learning method of classification and regression tree analyses and standard regression models was used to identify high-order interactions and clinical factors predictive of long-term all-cause mortality. RESULTS: Four hundred and thirty eight patients met study criteria; the median study follow-up period for the cohort was 7.8 (inter-quartile range 6.0-10.1) years. The overall all-cause mortality rate was 0.025 (95% confidence interval [CI]: 0.021-0.030) per 100 person-year of follow-up. The significant predictors of poor long-term outcome were age (hazard ratio [HR] for each year of age-at-diagnosis was 1.05 [CI: 1.04-1.06], treatment duration, type of EPTB and HIV-infection (HR = 2.16; CI: 1.22, 3.83). Mortality in genitourinary tuberculosis was no different from latent tuberculosis, while meningitis had the poorest long-term outcome of 46.2%. Compared to meningitis the HR for death was 0.50 (CI: 0.27-0.91) for lymphatic disease, 0.42 (CI: 0.21-0.81) for bone/joint disease, and 0.59 (CI: 0.27-1.31) for peritonitis. The relationship between mortality and therapy duration for each type of EPTB was a unique "V" shaped curve, with the lowest mortality observed at different therapy durations for each, beyond which mortality increased. CONCLUSIONS: EPTB is comprised of several different diseases with different outcomes and durations of therapy. The "V" shaped relationship between therapy duration and outcome leads to the hypothesis that longer duration of therapy may lead to higher patient mortality.

Non-hispanic whites have higher risk for pulmonary impairment from pulmonary tuberculosis.

BACKGROUND: Disparities in outcomes associated with race and ethnicity are well documented for many diseases and patient populations. Tuberculosis (TB) disproportionately affects economically disadvantaged, racial and ethnic minority populations. Pulmonary impairment after tuberculosis (PIAT) contributes heavily to the societal burden of TB. Individual impacts associated with PIAT may vary by race/ethnicity or socioeconomic status. METHODS: We analyzed the pulmonary function of 320 prospectively identified patients with pulmonary tuberculosis who had completed at least 20 weeks standard anti-TB regimes by directly observed therapy. We compared frequency and severity of spirometry-defined PIAT in groups stratified by demographics, pulmonary risk factors, and race/ethnicity, and examined clinical correlates to pulmonary function deficits. RESULTS: Pulmonary impairment after tuberculosis was identified in 71% of non-Hispanic Whites, 58% of non-Hispanic Blacks, 49% of Asians and 32% of Hispanics (p < 0.001). Predictors for PIAT varied between race/ethnicity. PIAT was evenly distributed across all levels of socioeconomic status suggesting that PIAT and socioeconomic status are not related. PIAT and its severity were significantly associated with abnormal chest x-ray, p < 0.0001. There was no association between race/ethnicity and time to beginning TB treatment, p = 0.978. CONCLUSIONS: Despite controlling for cigarette smoking, socioeconomic status and time to beginning TB treatment, non-Hispanic White race/ethnicity remained an independent predictor for disproportionately frequent and severe pulmonary impairment after tuberculosis relative to other race/ethnic groups. Since race/ethnicity was self reported and that race is not a biological construct: these findings must be interpreted with caution. However, because race/ethnicity is a proxy for several other unmeasured host, pathogen or environment factors that may contribute to disparate health outcomes, these results are meant to suggest hypotheses for further research.