Article

Multidrug-Resistant Tuberculosis Not Due to Noncompliance but to Between-Patient Pharmacokinetic Variability

Department of Medicine, University of Texas Southwestern Medical Center at Dallas, TX, USA.
The Journal of Infectious Diseases (Impact Factor: 6). 12/2011; 204(12):1951-9. DOI: 10.1093/infdis/jir658
Source: PubMed

ABSTRACT

It is believed that nonadherence is the proximate cause of multidrug-resistant tuberculosis (MDR-tuberculosis) emergence. The level of nonadherence associated with emergence of MDR-tuberculosis is unknown. Performance of a randomized controlled trial in which some patients are randomized to nonadherence would be unethical; therefore, other study designs should be utilized.
We performed hollow fiber studies for both bactericidal and sterilizing effect, with inoculum spiked with 0.5% rifampin- and isoniazid-resistant isogenic strains in some experiments. Standard therapy was administered daily for 28-56 days, with extents of nonadherence varying between 0% and 100%. Sizes of drug-resistant populations were compared using analysis of variance. We also explored the effect of pharmacokinetic variability on MDR-tuberculosis emergence using computer-aided clinical trial simulations of 10 000 Cape Town, South Africa, tuberculosis patients.
Therapy failure was only encountered at extents of nonadherence ≥60%. Surprisingly, isoniazid- and rifampin-resistant populations did not achieve ≥1% proportion in any experiment and did not achieve a higher proportion with nonadherence. However, clinical trial simulations demonstrated that approximately 1% of tuberculosis patients with perfect adherence would still develop MDR-tuberculosis due to pharmacokinetic variability alone.
These data, based on a preclinical model, demonstrate that nonadherence alone is not a sufficient condition for MDR-tuberculosis emergence.

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    • "Prior to this study, research had not been done using Parsonian sickrole behaviour concept to determine the pattern of deviance especially the sickrole behavioural responses on the part of people who are on TB treatment. Research elsewhere has shown that noncompliance to the DOTS regimen, which is an abrogation of the sickrole behaviour, leads to treatment failure, relapse, and extensively drug resistant tuberculosis (Khan et al., 2001; Sharma & Mohan, 2004; Zai et al., 2010; Srivastava et al., 2011; WHO, 2014b). Hence, the aim of the present study was to profile the level and pattern of patient behaviour in terms of compliance as well as non-compliance with the doctor's orders of adherence to the sickrole behaviour (fulfilling customary obligations that surround TB as a disease) inter alias taking prescribed medication doses at prescribed intervals, keeping medical appointments and following advice related to behaviours other than medication taking, such as diet restrictions and exercise (Cramer, 1991; O'Brien et al., 1992; Besch, 1995; Volmink et al., 2000). "

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    • "First, it is most likely that there are inadequate antibiotic concentrations in TB pericardial fluid, especially of the primary sterilizing effect drugs rifampin and pyrazinamide, due to poor penetration, as we have shown elsewhere (Shenje et al., 2015). There is now sufficient hollow fiber and prospective clinical studies evidence to show that both the bactericidal activities and the sterilizing effect of antibiotics in TB is driven by high peak concentration and the area under the concentration-time curve of each drug, and that evolution-mandated pharmacokinetic variability drives many patients on recommended doses to not achieve optimal peak and area under the concentration–time curve concentrations (Shenje et al., 2015; Pasipanodya and Gumbo, 2011; Gumbo et al., 2015; Pasipanodya et al., 2013; Srivastava et al., 2011). Secondly, CART identified a CD4+ T cell count ≤199.5 as a major predictor. "
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    ABSTRACT: Background: Tuberculous 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. Methods: Patients 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. Findings: Seventy 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. Interpretation: Patients 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.
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    • "However, administration of the studied rifampicin and moxifloxacin doses resulted in large interindividual variability in exposures both in plasma and CSF [6]. Accumulating data suggest that exposure to TB drugs is relevant for outcome in pulmonary TB [7] [8] [9] [10] [11] [12]. "
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    ABSTRACT: Recent data suggest that intensified antimicrobial treatment may improve the outcome of tuberculous meningitis (TBM). Considering that drug exposure is the intermediate link between dose and effect, we examined the concentration-response relationship for rifampicin and moxifloxacin in TBM patients. In an open-label, phase 2 clinical trial performed in Indonesia (ClinicalTrials.gov NCT01158755), 60 TBM patients were randomised to receive standard-dose (450mg oral) or high-dose rifampicin (600mg intravenous) plus either oral moxifloxacin (400mg or 800mg) or ethambutol (750mg). After 14 days, all patients continued with standard tuberculosis treatment. Pharmacokinetic sampling was performed once in every patient during the first three critical days. Differences in exposure between patients who died or survived were tested with independent samples t-tests. The relationship between drug exposure and mortality was examined using Cox regression. Compared with patients who died during the 2 weeks of intensified treatment, surviving patients had significantly higher rifampicin plasma AUC0-6h, plasma Cmax and CSF Chighest. Additionally, patients had a 32-43% lower relative likelihood of dying with an interquartile range increase in rifampicin exposure. Moxifloxacin exposure did not show a clear relationship with survival. From exposure-response curves, a rifampicin plasma AUC0-6h of ∼70mg·h/L (AUC0-24h of ∼116mgh/L) and a Cmax of ∼22mg/L were deduced as minimum target values for treatment. A strong concentration-effect relationship was found, with higher rifampicin exposure leading to better TBM survival. The current treatment dose of rifampicin is suboptimal; higher doses of rifampicin should be evaluated. Copyright © 2015 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.
    Full-text · Article · Feb 2015 · International Journal of Antimicrobial Agents
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