Amikacin Concentrations Predictive of Ototoxicity in Multidrug-Resistant Tuberculosis Patients

Aminoglycosides, such as amikacin, are used to treat multidrug-resistant tuberculosis. However, ototoxicity is a common problem and is monitored using peak and trough amikacin concentrations based on World Health Organization recommendations. Our objective was to identify clinical factors predictive of ototoxicity using an agnostic machine learning method. We used classification and regression tree (CART) analyses to identify clinical factors, including amikacin concentration t hresholds that pre- dicted audiometry-confirmed ototoxicity among 28 multidrug-resistant pulmonary tuberculosis patients in Botswana. Amika- cin concentrations were measured for all patients. The quantitative relationship between predictive factors and the probability of ototoxicity were then identified using probit analyses. The primary predictors of ototoxicity on CART analyses were cumula- tive days of therapy, followed by cumulative area under the concentration-time curve (AUC), which improved on the primary predictor by 87%. The area under the receiver operating curve was 0.97 on the test set. Peak and trough were not predictors in any tree. When algorithms were forced to pick peak and trough as primary predictors, the area under the receiver operating curve fell to 0.46. Probit analysis revealed that the probability of ototoxicity increased sharply starting after 6 months of therapy to near maximum at 9 months. A 10% probability of ototoxicity occurred with a threshold cumulative AUC of 87,232 days · mg · h/liter, while that of 20% occurred at 120,000 days · mg · h/liter. Thus, cumulative amikacin AUC and duration of therapy, and not peak and trough concentrations, should be used as the primary decision-making parameters to minimize the likelihood of ototoxicity in multidrug-resistant tuberculosis

Personal and Societal Health Quality Lost to Tuberculosis

Background: In developed countries, tuberculosis is considered a disease with little loss of Quality-Adjusted Life Years (QALYs). Tuberculosis treatment is predominantly ambulatory and death from tuberculosis is rare. Research has shown that there are chronic pulmonary sequelae in a majority of patients who have completed treatment for pulmonary tuberculosis (PTB). This and other health effects of tuberculosis have not been considered in QALY calculations. Consequently both the burden of tuberculosis on the individual and the value of tuberculosis prevention to society are underestimated. We estimated QALYs lost to pulmonary TB patients from all known sources, and estimated health loss to prevalent TB disease. Methodology/Principal Findings: We calculated values for health during illness and treatment, pulmonary impairment after tuberculosis (PIAT), death rates, years-of-life-lost to death, and normal population health. We then compared the lifetime expected QALYs for a cohort of tuberculosis patients with that expected for comparison populations with latent tuberculosis infection and without tuberculosis infection. Persons with culture-confirmed tuberculosis accrued fewer lifetime QALYs than those without tuberculosis. Acute tuberculosis morbidity cost 0.046 QALYs (4% of total) per individual. Chronic morbidity accounted for an average of 0.96 QALYs (78% of total). Mortality accounted for 0.22 QALYs lost (18% of total). The net benefit to society of averting one case of PTB was about 1.4 QALYs. Conclusions/Significance: Tuberculosis, a preventable disease, results in QALYs lost owing to illness, impairment, and death. The majority of QALYs lost from tuberculosis resulted from impairment after microbiologic cure. Successful TB prevention efforts yield more health quality than previously thought and should be given high priority by health policy makers. (Refer to Abstracto S1 for Spanish language abstract

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 ?-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

Tuberculous Pericarditis is Multibacillary and Bacterial Burden Drives High Mortality

AbstractBackgroundTuberculous pericarditis is considered to be a paucibacillary process; the large pericardial fluid accumulation is attributed to an inflammatory response to tuberculoproteins. Mortality rates are high. We investigated the role of clinical and microbial factors predictive of tuberculous pericarditis mortality using the artificial intelligence algorithm termed classification and regression tree (CART) analysis.MethodsPatients were prospectively enrolled and followed in the Investigation of the Management of Pericarditis (IMPI) registry. Clinical and laboratory data of 70 patients with confirmed tuberculous pericarditis, including time-to-positive (TTP) cultures from pericardial fluid, were extracted and analyzed for mortality outcomes using CART. TTP was translated to log10 colony forming units (CFUs) per mL, and compared to that obtained from sputum in some of our patients.FindingsSeventy patients with proven tuberculous pericarditis were enrolled. The median patient age was 35 (range: 20–71) years. The median, follow up was for 11.97 (range: 0·03–74.73) months. The median TTP for pericardial fluid cultures was 22 (range: 4–58) days or 3.91(range: 0·5–8·96) log10CFU/mL, which overlapped with the range of 3.24–7.42 log10CFU/mL encountered in sputum, a multi-bacillary disease. The overall mortality rate was 1.43 per 100 person-months. CART identified follow-up duration of 5·23months on directly observed therapy, a CD4+ count of ≤199.5/mL, and TTP≤14days (bacillary load≥5.53 log10 CFU/mL) as predictive of mortality. TTP interacted with follow-up duration in a non-linear fashion.InterpretationPatients with culture confirmed tuberculous pericarditis have a high bacillary burden, and this bacterial burden drives mortality. Thus proven tuberculosis pericarditis is not a paucibacillary disease. Moreover, the severe immunosuppression suggests limited inflammation. There is a need for the design of a highly bactericidal regimen for this condition

Artificial Intelligence and Amikacin Exposures Predictive of Outcomes in Multidrug-Resistant Tuberculosis Patients

Aminoglycosides such as amikacin continue to be part of the backbone of treatment of multidrug-resistant tuberculosis (MDR- TB). We measured amikacin concentrations in 28 MDR-TB patients in Botswana receiving amikacin therapy together with oral levofloxacin, ethionamide, cycloserine, and pyrazinamide and calculated areas under the concentration-time curves from 0 to 24 h (AUC0 –24). The patients were followed monthly for sputum culture conversion based on liquid cultures. The median duration of amikacin therapy was 184 (range, 28 to 866) days, at a median dose of 17.30 (range 11.11 to 19.23) mg/kg. Only 11 (39%) pa- tients had sputum culture conversion during treatment; the rest failed. We utilized classification and regression tree analyses (CART) to examine all potential predictors of failure, including clinical and demographic features, comorbidities, and amikacin peak concentrations (Cmax), AUC0 –24, and trough concentrations. The primary node for failure had two competing variables, Cmax of \u3c67 mg/liter and AUC0 –24 of \u3c568.30 mg · h/L; weight of \u3e41 kg was a secondary node with a score of 35% relative to the primary node. The area under the receiver operating characteristic curve for the CART model was an R2 �� 0.90 on posttest. In patients weighing \u3e41 kg, sputum conversion was 3/3 (100%) in those with an amikacin Cmax of \u3e67 mg/liter versus 3/15 (20%) in those with a Cmax of \u3c67 mg/liter (relative risk [RR] �� 5.00; 95% confidence interval [CI], 1.82 to 13.76). In all patients who had both amikacin Cmax and AUC0 –24 below the threshold, 7/7 (100%) failed, compared to 7/15 (47%) of those who had these parameters above threshold (RR �� 2.14; 95% CI, 1.25 to 43.68). These amikacin dose-schedule patterns and exposures are virtually the same as those identified in the hollow-fiber system model

Pulmonary impairment after tuberculosis and its contribution to TB burden

<p>Abstract</p> <p>Background</p> <p>The health impacts of pulmonary impairment after tuberculosis (TB) treatment have not been included in assessments of TB burden. Therefore, previous global and national TB burden estimates do not reflect the full consequences of surviving TB. We assessed the burden of TB including pulmonary impairment after tuberculosis in Tarrant County, Texas using Disability-adjusted Life Years (DALYs).</p> <p>Methods</p> <p>TB burden was calculated for all culture-confirmed TB patients treated at Tarrant County Public Health between January 2005 and December 2006 using identical methods and life tables as the Global Burden of Disease Study. Years of life-lost were calculated as the difference between life expectancy using standardized life tables and age-at-death from TB. Years lived-with-disability were calculated from age and gender-specific TB disease incidence using published disability weights. Non-fatal health impacts of TB were divided into years lived-with-disability-acute and years lived-with-disability-chronic. Years lived-with-disability-acute was defined as TB burden resulting from illness prior to completion of treatment including the burden from treatment-related side effects. Years lived-with-disability-chronic was defined as TB burden from disability resulting from pulmonary impairment after tuberculosis.</p> <p>Results</p> <p>There were 224 TB cases in the time period, of these 177 were culture confirmed. These 177 subjects lost a total of 1189 DALYs. Of these 1189 DALYs 23% were from years of life-lost, 2% were from years lived-with-disability-acute and 75% were from years lived-with-disability-chronic.</p> <p>Conclusions</p> <p>Our findings demonstrate that the disease burden from TB is greater than previously estimated. Pulmonary impairment after tuberculosis was responsible for the majority of the burden. These data demonstrate that successful TB control efforts may reduce the health burden more than previously recognized.</p

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

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

Machine learning reveals that Mycobacterium tuberculosis genotypes and anatomic disease site impacts drug resistance and disease transmission among patients with proven extra-pulmonary tuberculosis

BACKGROUND: There is a general dearth of information on extrapulmonary tuberculosis (EPTB). Here, we investigated Mycobacterium tuberculosis (Mtb) drug resistance and transmission patterns in EPTB patients treated in the Tshwane metropolitan area, in South Africa. METHODS: Consecutive Mtb culture-positive non-pulmonary samples from unique EPTB patients underwent mycobacterial genotyping and were assigned to phylogenetic lineages and transmission clusters based on spoligotypes. MTBDRplus assay was used to search mutations for isoniazid and rifampin resistance. Machine learning algorithms were used to identify clinically meaningful patterns in data. We computed odds ratio (OR), attributable risk (AR) and corresponding 95% confidence intervals (CI). RESULTS: Of the 70 isolates examined, the largest cluster comprised 25 (36%) Mtb strains that belonged to the East Asian lineage. East Asian lineage was significantly more likely to occur within chains of transmission when compared to the Euro-American and East-African Indian lineages: OR = 10.11 (95% CI: 1.56–116). Lymphadenitis, meningitis and cutaneous TB, were significantly more likely to be associated with drug resistance: OR = 12.69 (95% CI: 1.82–141.60) and AR = 0.25 (95% CI: 0.06–0.43) when compared with other EPTB sites, which suggests that poor rifampin penetration might be a contributing factor. CONCLUSIONS: The majority of Mtb strains circulating in the Tshwane metropolis belongs to East Asian, EuroAmerican and East-African Indian lineages. Each of these are likely to be clustered, suggesting on-going EPTB transmission. Since 25% of the drug resistance was attributable to sanctuary EPTB sites notorious for poor rifampin penetration, we hypothesize that poor anti-tuberculosis drug dosing might have a role in the development of resistance.http://www.biomedcentral.com/bmcinfectdispm2020Medical Microbiolog

A Long-term Co-perfused Disseminated Tuberculosis-3D Liver Hollow Fiber Model for Both Drug Efficacy and Hepatotoxicity in Babies

AbstractTreatment of disseminated tuberculosis in children≤6years has not been optimized. The pyrazinamide-containing combination regimen used to treat disseminated tuberculosis in babies and toddlers was extrapolated from adult pulmonary tuberculosis. Due to hepatotoxicity worries, there are no dose–response studies in children. We designed a hollow fiber system model of disseminated intracellular tuberculosis with co-perfused three-dimensional organotypic liver modules to simultaneously test for efficacy and toxicity. We utilized pediatric pharmacokinetics of pyrazinamide and acetaminophen to determine dose-dependent pyrazinamide efficacy and hepatotoxicity. Acetaminophen concentrations that cause hepatotoxicity in children led to elevated liver function tests, while 100mg/kg pyrazinamide did not. Surprisingly, pyrazinamide did not kill intracellular Mycobacterium tuberculosis up to fourfold the standard dose as monotherapy or as combination therapy, despite achieving high intracellular concentrations. Host-pathogen RNA-sequencing revealed lack of a pyrazinamide exposure transcript signature in intracellular bacteria or of phagolysosome acidification on pH imaging. Artificial intelligence algorithms confirmed that pyrazinamide was not predictive of good clinical outcomes in children≤6years who had extrapulmonary tuberculosis. Thus, adding a drug that works inside macrophages could benefit children with disseminated tuberculosis. Our in vitro model can be used to identify such new regimens that could accelerate cure while minimizing toxicity