Research Spotlight

Posted November 15th 2016

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

Tawanda Gumbo M.D.

Tawanda Gumbo M.D.

Srivastava, S., D. Deshpande, J. Pasipanodya, E. Nuermberger, S. Swaminathan and T. Gumbo (2016). “Optimal clinical doses of faropenem, linezolid, and moxifloxacin in children with disseminated tuberculosis: Goldilocks.” Clin Infect Dis 63(suppl 3): S102-s109.

Full text of this article.

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 x 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.


Posted November 15th 2016

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

Tawanda Gumbo M.D.

Tawanda Gumbo M.D.

Srivastava, S., D. Deshpande, J. G. Pasipanodya, T. Thomas, S. Swaminathan, E. Nuermberger and T. Gumbo (2016). “A combination regimen design program based on pharmacodynamic target setting for childhood tuberculosis: Design rules for the playground.” Clin Infect Dis 63(suppl 3): S75-s79.

Full text of this article.

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.


Posted November 15th 2016

Drug Concentration Thresholds Predictive of Therapy Failure and Death in Children With Tuberculosis: Bread Crumb Trails in Random Forests.

Tawanda Gumbo M.D.

Tawanda Gumbo M.D.

Swaminathan, S., J. G. Pasipanodya, G. Ramachandran, A. K. Hemanth Kumar, S. Srivastava, D. Deshpande, E. Nuermberger and T. Gumbo (2016). “Drug concentration thresholds predictive of therapy failure and death in children with tuberculosis: Bread crumb trails in random forests.” Clin Infect Dis 63(suppl 3): S63-s74.

Full text of this article.

BACKGROUND: The role of drug concentrations in clinical outcomes in children with tuberculosis is unclear. Target concentrations for dose optimization are unknown. METHODS: Plasma drug concentrations measured in Indian children with tuberculosis were modeled using compartmental pharmacokinetic analyses. The children were followed until end of therapy to ascertain therapy failure or death. An ensemble of artificial intelligence algorithms, including random forests, was used to identify predictors of clinical outcome from among 30 clinical, laboratory, and pharmacokinetic variables. RESULTS: Among the 143 children with known outcomes, there was high between-child variability of isoniazid, rifampin, and pyrazinamide concentrations: 110 (77%) completed therapy, 24 (17%) failed therapy, and 9 (6%) died. The main predictors of therapy failure or death were a pyrazinamide peak concentration <38.10 mg/L and rifampin peak concentration <3.01 mg/L. The relative risk of these poor outcomes below these peak concentration thresholds was 3.64 (95% confidence interval [CI], 2.28-5.83). Isoniazid had concentration-dependent antagonism with rifampin and pyrazinamide, with an adjusted odds ratio for therapy failure of 3.00 (95% CI, 2.08-4.33) in antagonism concentration range. In regard to death alone as an outcome, the same drug concentrations, plus z scores (indicators of malnutrition), and age <3 years, were highly ranked predictors. In children <3 years old, isoniazid 0- to 24-hour area under the concentration-time curve <11.95 mg/L x hour and/or rifampin peak <3.10 mg/L were the best predictors of therapy failure, with relative risk of 3.43 (95% CI, .99-11.82). CONCLUSIONS: We have identified new antibiotic target concentrations, which are potential biomarkers associated with treatment failure and death in children with tuberculosis.


Posted November 15th 2016

Isoniazid clearance is impaired among HIV/tuberculosis patients with high levels of immune activation.

Tawanda Gumbo M.D.

Tawanda Gumbo M.D.

Vinnard, C., S. Ravimohan, N. Tamuhla, V. Ivaturi, J. Pasipanodya, S. Srivastava, C. Modongo, N. M. Zetola, D. Weissman, T. Gumbo and G. P. Bisson (2016). “Isoniazid clearance is impaired among hiv/tuberculosis patients with high levels of immune activation.” Br J Clin Pharmacol: 2016 Oct [Epub ahead of print].

Full text of this article.

AIMS: Immune activation, which is characteristic of both tuberculosis (TB) and human immunodeficiency virus (HIV) infection, is associated with impaired drug metabolism. We tested the hypothesis that elevated levels of systemic immune activation among adults with HIV/TB initiating ART would be associated with impaired clearance of isoniazid. METHODS: We conducted a prospective observational study of isoniazid pharmacokinetics and systemic immune activation prior to and one month after antiretroviral therapy (ART) initiation. Non-linear mixed effects analysis was performed to measure the covariate effect of immune activation on isoniazid clearance in a model that also included N-acetyltransferase-2 (NAT-2) genotype and inter-occasional variability on clearance (thereby analyzing the pharmacokinetic data before and after ART initiation in a single model). RESULTS: We enrolled 40 patients in the pharmacokinetic visit prior to ART, and 24 patients returned for the second visit a median of 33 days after initiating antiretroviral therapy. The isoniazid concentration data were best described by a 2-compartment model with first-order elimination. After accounting for NAT-2 genotype, increasing levels of CD38 and HLA-DR expression on CD8+ T cells (CD38+ DR+ CD8+ ) were associated with decreasing isoniazid clearance. CONCLUSION: HIV/TB patients with high levels of immune activation demonstrated impaired isoniazid clearance. Future efforts should determine the role of this relationship in clinical hepatotoxicity events.


Posted November 15th 2016

Intensive Hemodialysis, Blood Pressure, and Antihypertensive Medication Use.

Peter McCullough M.D.

Peter McCullough M.D.

Bakris, G. L., J. M. Burkart, E. D. Weinhandl, P. A. McCullough and M. A. Kraus (2016). “Intensive hemodialysis, blood pressure, and antihypertensive medication use.” Am J Kidney Dis 68(5s1): S15-s23.

Full text of this article.

Hypertension is a cardinal feature of end-stage renal disease (ESRD). Hypertensive nephropathy is the primary cause of ESRD for nearly 30% of patients, and the prevalence of hypertension is >85% in new patients with ESRD. In contemporary hemodialysis (HD) patients, mean predialysis systolic blood pressure (SBP) is nearly 150mmHg, and about 70%, 50%, and 40% use beta-blockers, calcium channel blockers, and renin-angiotensin system inhibitors, respectively. Predialysis SBP generally exhibits a U-shaped association with mortality risk. Interdialytic ambulatory SBP is more strongly associated with risk. Hypertension is multifactorial; key causes include persistent hypervolemia and elevated peripheral resistance. With 3 HD sessions per week, blood pressure (BP) climbs during the interdialytic interval, in step with interdialytic weight gain, particularly among elderly patients and those with higher dry weight. Elevated peripheral resistance can be attributed to inappropriate activation of the sympathetic nervous system due to higher plasma norepinephrine concentrations. Multiple randomized clinical trials show that intensive HD reduces BP and the need for oral medications indicated for hypertension. In the first 2 months of the Frequent Hemodialysis Network trial, the short daily schedule reduced predialysis SBP by 7.7mmHg, whereas the nocturnal schedule reduced predialysis SBP by 7.3mmHg, both relative to 3 sessions per week. Improvements were sustained after 12 months. Both schedules reduced antihypertensive medication use relative to 3 sessions per week. In FREEDOM (Following Rehabilitation, Economics, and Everyday-Dialysis Outcome Measurements), a prospective cohort study of short daily HD, the mean number of prescribed antihypertensive agents decreased from 1.7 to 1.0 in 1 year, whereas the percentage of patients not prescribed antihypertensive agents increased from 21% to 47%. Nocturnal HD appears to markedly reduce total peripheral resistance and plasma norepinephrine and restore endothelium-dependent vasodilation. In conclusion, intensive HD reduces BP and the need for antihypertensive medications.