Integrating Pharmacokinetics and Pharmacodynamics in Operational Research to End Tuberculosis

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Abstract

Tuberculosis (TB) elimination requires innovative approaches. The new Global Tuberculosis Network (GTN) aims to conduct research on key unmet therapeutic and diagnostic needs in the field of TB elimination using multidisciplinary, multisectorial approaches. The TB Pharmacology section within the new GTN aims to detect and study the current knowledge gaps, test potential solutions using human pharmacokinetics informed through preclinical infection systems, and return those findings to the bedside. Moreover, this approach would allow prospective identification and validation of optimal shorter therapeutic durations with new regimens. Optimized treatment using available and repurposed drugs may have an increased impact when prioritizing a person-centered approach and acknowledge the importance of age, gender, comorbidities, and both social and programmatic environments. In this viewpoint article, we present an in-depth discussion on how TB pharmacology and the related strategies will contribute to TB elimination.

Abstract

An enhanced understanding of tuberculosis (TB) pharmacology aims to use pharmacokinetics and pharmacodynamics, operational research, and therapeutic drug monitoring to support TB elimination.

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Most cited references 40

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Bacterial Factors That Predict Relapse after Tuberculosis Therapy

David Alland, W. Boom, Reynaldo Dietze … (2018)

BACKGROUND Approximately 5% of patients with drug-susceptible tuberculosis have a relapse after 6 months of first-line therapy, as do approximately 20% of patients after 4 months of short-course therapy. We postulated that by analyzing pretreatment isolates of Mycobacterium tuberculosis obtained from patients who subsequently had a relapse or were cured, we could determine any correlations between the minimum inhibitory concentration (MIC) of a drug below the standard resistance breakpoint and the relapse risk after treatment. METHODS Using data from the Tuberculosis Trials Consortium Study 22 (development cohort), we assessed relapse and cure isolates to determine the MIC values of isoniazid and rifampin that were below the standard resistance breakpoint (0.1 μ g per milliliter for isoniazid and 1.0 μ g per milliliter for rifampin). We combined this analysis with clinical, radiologic, and laboratory data to generate predictive relapse models, which we validated by analyzing data from the DMID 01–009 study (validation cohort). RESULTS In the development cohort, the mean (±SD) MIC of isoniazid below the breakpoint was 0.0334±0.0085 μ g per milliliter in the relapse group and 0.0286±0.0092 μ g per milliliter in the cure group, which represented a higher value in the relapse group by a factor of 1.17 (P=0.02). The corresponding MIC values of rifampin were 0.0695±0.0276 and 0.0453±0.0223 μ g per milliliter, respectively, which represented a higher value in the relapse group by a factor of 1.53 (P<0.001). Higher MIC values remained associated with relapse in a multivariable analysis that included other significant between-group differences. In an analysis of receiver-operating-characteristic curves of relapse based on these MIC values, the area under the curve (AUC) was 0.779. In the development cohort, the AUC in a multivariable model that included MIC values was 0.875. In the validation cohort, the MIC values either alone or combined with other patient characteristics were also predictive of relapse, with AUC values of 0.964 and 0.929, respectively. The use of a model score for the MIC values of isoniazid and rifampin to achieve 75.0% sensitivity in cross-validation analysis predicted relapse with a specificity of 76.5% in the development cohort and a sensitivity of 70.0% and a specificity of 100% in the validation cohort. CONCLUSIONS In pretreatment isolates of M. tuberculosis with decrements of MIC values of isoniazid or rifampin below standard resistance breakpoints, higher MIC values were associated with a greater risk of relapse than lower MIC values. (Funded by the National Institute of Allergy and Infectious Diseases.)

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Role of Disputed Mutations in the rpoB Gene in Interpretation of Automated Liquid MGIT Culture Results for Rifampin Susceptibility Testing of Mycobacterium tuberculosis

Paolo Miotto, Andrea Cabibbe, Emanuele Borroni … (2018)

Low-level rifampin resistance associated with specific rpoB mutations (referred as “disputed”) in Mycobacterium tuberculosis is easily missed by some phenotypic methods. To understand the mechanism by which some mutations are systematically missed by MGIT phenotypic testing, we performed an in silico analysis of their effect on the structural interaction between the RpoB protein and rifampin. We also characterized 24 representative clinical isolates by determining MICs on 7H10 agar and testing them by an extended MGIT protocol. We analyzed 2,097 line probe assays, and 156 (7.4%) cases showed a hybridization pattern referred to here as “no wild type + no mutation.” Isolates harboring “disputed” mutations (L430P, D435Y, H445C/L/N/S, and L452P) tested susceptible in MGIT, with prevalence ranging from 15 to 57% (overall, 16 out of 55 isolates [29%]). Our in silico analysis did not highlight any difference between “disputed” and “undisputed” substitutions, indicating that all rpoB missense mutations affect the rifampin binding site. MIC testing showed that “undisputed” mutations are associated with higher MIC values (≥20 mg/liter) compared to “disputed” mutations (4 to >20 mg/liter). Whereas “undisputed” mutations didn't show any delay (Δ) in time to positivity of the test tube compared to the control tube on extended MGIT protocol, “disputed” mutations showed a mean Δ of 7.2 days (95% confidence interval [CI], 4.2 to 10.2 days; P < 0.05), providing evidence that mutations conferring low-level resistance are associated with a delay in growth on MGIT. Considering the proved relevance of L430P, D435Y, H445C/L/N, and L452P mutations in determining clinical resistance, genotypic drug susceptibility testing (DST) should be used to replace phenotypic results (MGIT) when such mutations are found.

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Impact of nonlinear interactions of pharmacokinetics and MICs on sputum bacillary kill rates as a marker of sterilizing effect in tuberculosis.

Emmanuel Chigutsa, Jotam Pasipanodya, Marianne E. Visser … (2015)

The relationships between antituberculosis drug exposure and treatment effects on humans receiving multidrug therapy are complex and nonlinear. In patients on treatment, an analysis of the rate of decline in the sputum bacillary burden reveals two slopes. The first is the α-slope, which is thought to reflect bactericidal effect, followed by a β-slope, which is thought to reflect sterilizing activity. We sought to characterize the effects of standard first-line treatment on sterilizing activity. Fifty-four patients receiving combination therapy for pulmonary tuberculosis in a clinical trial had drug concentrations measured and Mycobacterium tuberculosis isolates available for MIC identification. Sputum sample cultures were performed at baseline and weekly for 8 weeks. A time-to-event model based on the days to positivity in the liquid cultures was used to estimate the β-slope. The pharmacokinetic parameters of rifampin, isoniazid, ethambutol, and pyrazinamide were determined for each patient. Multivariate adaptive regression splines analyses, which simultaneously perform linear and nonlinear analyses, were used to identify the relationships between the predictors and the β-slope. The potential predictors examined included HIV status, lung cavitation, 24-h area under the concentration-time curve (AUC), peak drug concentration (Cmax), AUC/MIC ratio, Cmax/MIC ratio, and the time that that concentration persisted above MIC. A rifampin Cmax of >8.2 mg/liter and a pyrazinamide AUC/MIC of >11.3 were key predictors of the β-slope and interacted positively to increase the β-slope. In patients with a rifampin AUC of <35.4 mg · h/liter, an increase in the pyrazinamide AUC/MIC and/or ethambutol Cmax/MIC increased the β-slope, while increasing isoniazid Cmax decreased it, suggesting isoniazid antagonism. Antibiotic concentrations and MICs interact in a nonlinear fashion as the main drivers of a sterilizing effect. The results suggest that faster speeds of sterilizing effect might be achieved by omitting isoniazid and by increasing rifampin, pyrazinamide, and ethambutol exposures. However, isoniazid and ethambutol exposures may only be of importance when rifampin exposure is low. These findings need confirmation in larger studies. (This study has been registered at controlled-trials.com under registration no. ISRCTN80852505.).

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Author and article information

Journal

Journal ID (nlm-ta): Clin Infect Dis

Journal ID (iso-abbrev): Clin. Infect. Dis

Journal ID (publisher-id): cid

Title: Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America

Publisher: Oxford University Press (US )

ISSN (Print): 1058-4838

ISSN (Electronic): 1537-6591

Publication date (Print): 15 April 2020

Publication date (Electronic): 27 September 2019

Publication date PMC-release: 27 September 2019

Volume: 70

Issue: 8

Pages: 1774-1780

Affiliations

[1 ] University of Sydney, Faculty of Medicine and Health , School of Pharmacy, Sydney, Australia

[2 ] Westmead Hospital , Sydney, Australia

[3 ] Center for Infectious Diseases Research and Experimental Therapeutics, Baylor Research Institute, Baylor University Medical Center , Dallas, Texas, USA

[4 ] Division of Clinical Pharmacology, Division of Infectious Diseases, Department of Medicine, Johns Hopkins University School of Medicine , Baltimore, Maryland, USA

[5 ] Infectious Disease Pharmacokinetics Laboratory, University of Florida College of Pharmacy , Gainesville, Florida, USA

[6 ] Division of Clinical Pharmacology, Department of Medicine , University of Cape Town, Cape Town, South Africa

[7 ] Management Sciences for Health , Arlington, Virginia, USA

[8 ] Emerging Bacterial Pathogens Unit, Division of Immunology, Transplantation and Infectious Diseases, Istituto Di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele Scientific Institute , Milan, Italy

[9 ] University of Virginia, Division of Infectious Diseases and International Health , Charlottesville, Virginia, USA

[10 ] Faculdade de Medicina, Universidade Federal do Rio Grande do Sul , Porto Alegre, Brazil

[11 ] Servizio di Epidemiologia Clinica delle Malattie Respiratorie, Istituti Clinici Scientifici Maugeri IRCCS , Tradate, Italy

Author notes

Correspondence: J.W.C. Alffenaar, University of Sydney, Faculty of Medicine and Health, School of Pharmacy and Westmead Hospital, Sydney, NSW, Australia ( johannes.alffenaar@ 123456sydney.edu.au ).

Article

Publisher ID: ciz942

DOI: 10.1093/cid/ciz942

PMC ID: 7146003

PubMed ID: 31560376

SO-VID: 2b24274f-d1f4-45cf-9b1a-2307e33f0fb7

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This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com.

History

Date received : 10 June 2019

Date accepted : 20 September 2019

Date: 17 September 2019

Date: 01 November 2019

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Integrating Pharmacokinetics and Pharmacodynamics in Operational Research to End Tuberculosis

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Point-Of-Care Testing for Tuberculosis

Most cited references 40

Bacterial Factors That Predict Relapse after Tuberculosis Therapy

Role of Disputed Mutations in the rpoB Gene in Interpretation of Automated Liquid MGIT Culture Results for Rifampin Susceptibility Testing of Mycobacterium tuberculosis

Impact of nonlinear interactions of pharmacokinetics and MICs on sputum bacillary kill rates as a marker of sterilizing effect in tuberculosis.

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