Omadacycline pharmacokinetics/pharmacodynamics and efficacy against multidrug-resistant Mycobacterium tuberculosis in the hollow fiber system model.

Seventy-five years ago, first-generation tetracyclines demonstrated limited efficacy in the treatment of tuberculosis but were more toxic than efficacious. We performed a series of pharmacokinetic/pharmacodynamic (PK/PD) experiments with a potentially safer third-generation tetracycline, omadacycline, for the treatment of multidrug-resistant tuberculosis (MDR-TB). Mycobacterium tuberculosis (Mtb) H37Rv and an MDR-TB clinical strain (16D) were used in the minimum inhibitory concentration (MIC) and static concentration-response studies in test tubes, followed by a PK/PD study using the hollow fiber system model of TB (HFS-TB) that examined six human-like omadacycline doses. The inhibitory sigmoid maximal effect (Emax) model and Monte Carlo experiments (MCEs) were used for data analysis and clinical dose-finding, respectively. The omadacycline MIC for both Mtb H37Rv and MDR-TB clinical strain was 16 mg/L but dropped to 4 mg/L with daily drug supplementation to account for omadacycline degradation. The Mycobacteria Growth Indicator Tube MIC was 2 mg/L. In the test tubes, omadacycline killed 4.39 log10 CFU/mL in 7 days. On Day 28 of the HFS-TB study, the Emax was 4.64 log10 CFU/mL, while exposure mediating 50% of Emax (EC50) was an area under the concentration-time curve to MIC (AUC0-24/MIC) ratio of 22.86. This translates to PK/PD optimal exposure or EC80 as AUC0-24/MIC of 26.93. The target attainment probability of the 300-mg daily oral dose was 90% but fell at MIC ≧4 mg/L. Omadacycline demonstrated efficacy and potency against both drug-susceptible and MDR-TB. Further studies are needed to identify the omadacycline effect in combination therapy for the treatment of both drug-susceptible and MDR-TB.

Sarecycline pharmacokinetics/pharmacodynamics in the hollow-fibre model of Mycobacterium avium complex: so near and yet so far.

BACKGROUND: Poor sustained sputum culture conversion rates with the standard-of-care therapy highlight the need for better drugs to treat Mycobacterium avium complex pulmonary disease (MAC-PD). OBJECTIVE: To determine the pharmacokinetics/pharmacodynamics (PK/PD)-optimized exposure of sarecycline and its potential role in treating MAC-PD. METHODS: We performed MIC studies with MAC ATCC 700898 and 19 clinical isolates and test-tube static concentration-response studies. A dynamic hollow-fibre system model of intracellular MAC (HFS-MAC) study was performed mimicking six human-equivalent sarecycline dose concentration-time profiles to identify the PK/PD optimal exposure of sarecycline for MAC kill. The inhibitory sigmoid maximal effect (Emax) model was used for PK/PD analysis. RESULTS: The sarecycline MIC of MAC ATCC 700898 was 1 mg/L, while the MIC for the 19 clinical strains ranged between 32 and >256 mg/L. The concentration mediating 50% of Emax (EC50) was similar between intracellular and extracellular MAC. In the HFS-MAC, all six sarecycline doses killed intracellular MAC, with an Emax of 1.0 log10 cfu/mL below Day 0 burden (stasis). The sarecycline EC80 (optimal) exposure was identified as AUC0-24/MIC = 139.46. CONCLUSIONS: Sarecycline demonstrated anti-MAC Emax in the HFS-MAC model better than ethambutol but worse than omadacycline (>5 log10 cfu/mL below stasis) in HFS-MAC. However, since currently approved highest oral sarecycline dose achieves an AUC0-24 of 48.2 mg·h/L and MAC MICs are >32 mg/L, the target AUC0-24/MIC of 139.46 is unlikely to be achieved in patients.

Ceftriaxone efficacy for Mycobacterium avium complex lung disease in the hollow fiber and translation to sustained sputum culture conversion in patients.

BACKGROUND: Only 35.6%-50.8% of patients with Mycobacterium avium complex (MAC) pulmonary disease achieve sustained sputum culture conversion (SSCC) on treatment with the azithromycin-ethambutol-rifabutin standard of care (SOC). We tested the efficacy of ceftriaxone, a ß-lactam with a lung penetration ratio of 12.18-fold. METHODS: We mimicked lung concentration-time profiles of seven ceftriaxone once-daily doses for 28 days in the hollow fiber system model of intracellular MAC (HFS- MAC). Monte Carlo experiments were used for dose selection.We also compared the once-daily ceftriaxone monotherapy to three-drug SOC against five MAC clinical isolates in HFS-MAC using γ (kill)-slopes. Results were translated to SSCC rates. RESULTS: Ceftriaxone killed 1.02-3.82 log10 cfu/mL in dose-response studies. Ceftriaxone 2G once-daily was identified as the optimal dose. Ceftriaxone killed all five strains below day 0 versus 2/5 for SOC. The median γ (95% confidence interval) was 0.49(0.47-0.52) log10 cfu/mL/day for ceftriaxone and 0.38(0.34-0.43) log10 cfu/mL/day for SOC. In patients, the SOC was predicted to achieve SSCC rates of 39.3%(36%-42%) at 6 months (similar to meta-analyses results). The SOC SSCC was 50% at 8.18(3.64-27.66) months versus 3.58(2.20-7.23) months for ceftriaxone. Thus, ceftriaxone shortened time-to-SSCC 2.35-fold compared to SOC. CONCLUSION: Ceftriaxone is a promising agent for creation of short-course chemotherapy.

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.

Optimizing anidulafungin exposure across a wide adult body size range.

Echinocandins like anidulafungin are first-line therapies for candidemia and invasive candidiasis, but their dosing may be suboptimal in obese patients. Our objective was to quantify anidulafungin exposure in a cohort of adults across a wide body size range to test if body size affects anidulafungin pharmacokinetics (PK). We enrolled 20 adults between the ages of 18 and 80 years, with an equal distribution of patients above and below a body mass index of 30 kg/m2. A single 100-mg dose of anidulafungin was administered, followed by intensive sampling over 72 h. Population PK analysis was used to identify and compare covariates of anidulafungin PK parameters. Monte Carlo simulations were performed to compute the probability of target attainment (PTA) based on alternative dosing regimens. Participants (45% males) had a median (range) age of 45 (21-78) years and a median (range) weight of 82.7 (42.4-208.3) kg. The observed median (range) of AUC0-∞ was 106.4 (51.9, 138.4) mg∙h/L. Lean body weight (LBW) and adjusted body weight (AdjBW) were more influential than weight as covariates of anidulafungin PK parameters. The conventional 100 mg daily maintenance is predicted to have a PTA below 90% in adults with an LBW > 55 kg or an AdjBW > 75 kg. A daily maintenance dose of 150-200 mg is predicted in these heavier adults. Anidulafungin AUC0-∞ declines with increasing body size. A higher maintenance dose will increase the PTA compared to the current approach in obese patients.

Nouveau short-course therapy and morphism mapping for clinical pulmonary Mycobacterium kansasii.

Standard therapy [isoniazid, rifampin, ethambutol], with or without a macrolide, for pulmonary Mycobacterium kansasii lasts more than a year. Therefore, shorter treatment duration regimens are required. We used data from 32 Taiwanese patients treated with standard therapy who were followed using repetitive sampling-based sputum Mkn time-to-positivity in liquid cultures to calculate kill slopes [γ] based on ordinary differential equations and time-to-extinction of each patient's bacterial burden. The γ was 0.18 [95% Confidence Interval (CI): 0.16-0.20] log10 CFU/mL/day on standard therapy. Next, we identified Mkn time-to-extinction in the hollow fiber system model of pulmonary M. kansasii disease [HFS-Mkn] treated with standard therapy, which was a γ of 0.60 [95% CI: 0.45-0.69) log10 CFU/mL/day. The γs and time-to-extinctions between the two datasets formed structure-preserving maps based on category theory: thus, we could map them from one to the other using morphisms. This mapping identified a multistep non-linear transformation-factor for time-to-extinction from HFS-Mkn to patients. Next, a head-to-head study in the HFS-Mkn identified median time-to-extinction for standard therapy of 38.7 [95% CI: 29.1-53.2) days, isoniazid-rifampin-ethambutol-moxifloxacin of 21.7 [95% CI: 19.1-25) days, isoniazid-rifampin-moxifloxacin of 22 [96% CI: 20.1-24.5) days, and rifampin-moxifloxacin-tedizolid of 20.7 [95% CI:18.5-29) days. Our transformation-factor based translation predicted the proportion of patients of 90.7 [88.74-92.35)% achieving cure with standard therapy at 12 months, and 6-months cure rates of 99.8 [95% CI: 99.27-99.95)% for isoniazid-rifampin-ethambutol-moxifloxacin, 92.2 [90.37-93.71)% for isoniazid-rifampin-moxifloxacin, and 99.9 [99.44-99.99)% for rifampin-moxifloxacin-tedizolid. Thus, rifampin-moxifloxacin-tedizolid and isoniazid-rifampin-ethambutol-moxifloxacin are predicted to be short-course chemotherapy regimens for pulmonary M. kansasii disease.

Hollow-fibre system model of tuberculosis reproducibility and performance specifications for best practice in drug and combination therapy development.

BACKGROUND: The hollow-fibre system model of tuberculosis (HFS-TB) has been endorsed by regulators; however, application of HFS-TB requires a thorough understanding of intra- and inter-team variability, statistical power and quality controls. METHODS: Three teams evaluated regimens matching those in the Rapid Evaluation of Moxifloxacin in Tuberculosis (REMoxTB) study, plus two high-dose rifampicin/pyrazinamide/moxifloxacin regimens, administered daily for up to 28 or 56 days against Mycobacterium tuberculosis (Mtb) under log-phase growth, intracellular growth or semidormant growth under acidic conditions. Target inoculum and pharmacokinetic parameters were pre-specified, and the accuracy and bias at achieving these calculated using percent coefficient of variation (%CV) at each sampling point and two-way analysis of variance (ANOVA). RESULTS: A total of 10 530 individual drug concentrations, and 1026 individual cfu counts were measured. The accuracy in achieving intended inoculum was >98%, and >88% for pharmacokinetic exposures. The 95% CI for the bias crossed zero in all cases. ANOVA revealed that the team effect accounted for <1% of variation in log10 cfu/mL at each timepoint. The %CV in kill slopes for each regimen and different Mtb metabolic populations was 5.10% (95% CI: 3.36%-6.85%). All REMoxTB arms exhibited nearly identical kill slopes whereas high dose regimens were 33% faster. Sample size analysis revealed that at least three replicate HFS-TB units are needed to identify >20% difference in slope, with a power of >99%. CONCLUSIONS: HFS-TB is a highly tractable tool for choosing combination regimens with little variability between teams, and between replicates.

Omadacycline Pharmacokinetics/Pharmacodynamics in the Hollow Fiber System Model and Potential Combination Regimen for Short Course Treatment of Mycobacterium kansasii Pulmonary Disease.

The 12-month therapy duration for the treatment of Mycobacterium kansasii pulmonary disease calls for more efficacious drugs for better treatment outcomes and to shorten the therapy duration. We performed (i) omadacycline MIC with M. kansasii ATCC 12478 strain and 21 clinical isolates, (ii) dose-response study in the hollow fiber system model of M. kansasii (HFS-Mkn) with six human equivalent omadacycline daily doses to determine the optimal drug exposure for the maximal kill, and (iii) a second HFS-Mkn study to determine the efficacy of omadacycline (300 mg/day) plus moxifloxacin (600 mg/day) plus tedizolid (200 mg/day) combination regimen with standard regimen as comparator. GraphPad Prism was used for data analysis and graphing. MIC of the reference strain was 4 mg/L but ranged from 8 to 32 mg/L among the 21 clinical isolates. In the HFS-Mkn, the exposure required for 50% of the maximal effect (EC50) was an omadacycline area under the concentration-time curve to MIC (AUC0-24/MIC) ratio of 1.95. The optimal exposure was an AUC0-24/MIC of 3.05, which could be achieved with 300 mg/day clinical dose. The omadacycline-moxifloxacin-tedizolid combination sterilized the HFS-Mkn in 14 days with a linear-regression based kill rate of -0.309 ± 0.044 log10 CFU/mL/day compared to the kill rate of -0.084 ± 0.036log10 CFU/mL/day with the standard regimen or 3.7-times faster. Omadacycline has efficacy against M. kansasii and could be used at 300 mg/day in combination with moxifloxacin and tedizolid for the treatment of M. kansasii pulmonary diseases with the potential to shorten the currently recommended 12-month therapy duration.

Rifampin Pharmacokinetics/Pharmacodynamics in the Hollow-Fiber Model of Mycobacterium kansasii Infection.

There is limited high-quality evidence to guide the optimal treatment of Mycobacterium kansasii pulmonary disease. We retrospectively collected clinical data from 33 patients with M. kansasii pulmonary disease to determine the time-to-sputum culture conversion (SCC) upon treatment with a standard combination regimen consist of isoniazid-rifampin-ethambutol. Next, MIC experiments with 20 clinical isolates were performed, followed by a dose-response study with the standard laboratory strain using the hollow-fiber system model of M. kansasii infection (HFS-Mkn). The inhibitory sigmoid maximum effect (Emax) model was used to describe the relationship between the bacterial burden and rifampin concentrations. Finally, in silico clinical trial simulations were performed to determine the clinical dose to achieve the optimal rifampin exposure in patients. The SCC rate in patients treated with combination regimen containing rifampin at 10 mg/kg of body weight/day was 73%, the mean time to SSC was 108 days, and the mean duration of therapy was 382 days. The MIC of the M. kansasii laboratory strain was 0.125 mg/L, whereas the MICs of the clinical isolates ranged between 0.5 and 4 mg/L. In the HFS-Mkn model, a maximum kill (Emax) of 7.82 log10 CFU/mL was recorded on study day 21. The effective concentration mediating 80% of the Emax (EC80) was calculated as the ratio of the maximum concentration of drug in serum for the free, unbound fraction (fCmax) to MIC of 34.22. The target attainment probability of the standard 10-mg/kg/day dose fell below 90% even at the MIC of 0.0625 mg/L. Despite the initial kill, there was M. kansasii regrowth with the standard rifampin dose in the HFS-Mkn model. Doses higher than 10 mg/kg/day, in combination with other drugs, need to be evaluated for better treatment outcome.

Omadacycline efficacy in the hollow fibre system model of pulmonary Mycobacterium avium complex and potency at clinically attainable doses.

OBJECTIVES: The standard of care (SOC) for the treatment of pulmonary Mycobacterium avium complex (MAC) disease (clarithromycin, rifabutin, and ethambutol) achieves sustained sputum conversion rates of only 54%. Thus, new treatments should be prioritized. METHODS: We identified the omadacycline MIC against one laboratory MAC strain and calculated drug half life in solution, which we compared with measured MAC doubling times. Next, we performed an omadacycline hollow fibre system model of intracellular MAC (HFS-MAC) exposure-effect study, as well as the three-drug SOC, using pharmacokinetics achieved in patient lung lesions. Data was analysed using bacterial kill slopes (γ-slopes) and inhibitory sigmoid Emax bacterial burden versus exposure analyses. Monte Carlo experiments (MCE) were used to identify the optimal omadacycline clinical dose. RESULTS: Omadacycline concentration declined in solution with a half-life of 27.7 h versus a MAC doubling time of 16.3 h, leading to artefactually high MICs. Exposures mediating 80% of maximal effect changed up to 8-fold depending on sampling day with bacterial burden versus exposure analyses, while γ-slope-based analyses gave a single robust estimate. The highest omadacycline monotherapy γ-slope was -0.114 (95% CI: -0.141 to -0.087) (r2 = 0.98) versus -0.114 (95% CI: -0.133 to -0.094) (r2 = 0.99) with the SOC. MCEs demonstrated that 450 mg of omadacycline given orally on the first 2 days followed by 300 mg daily would achieve the AUC0-24 target of 39.67 mg·h/L. CONCLUSIONS: Omadacycline may be a potential treatment option for pulmonary MAC, possibly as a back-bone treatment for a new MAC regimen and warrants future study in treatment of this disease.