Drug-Penetration Gradients Associated with Acquired Drug Resistance in Patients with Tuberculosis

Dheda, Keertan; Lenders, Laura; Magombedze, Gesham; Srivastava, Shashikant; Raj, Prithvi; Arning, Erland; Ashcraft, Paula; Bottiglieri, Teodoro; Wainwright, Helen; Pennel, Timothy; Linegar, Anthony; Moodley, Loven; Pooran, Anil; Pasipanodya, Jotam G.; Sirgel, Frederick A.; Helden, Paul D. van; Wakeland, Edward K.; Warren, Robin M.; Gumbo, Tawanda

doi:10.1164/rccm.201711-2333oc

Cited by 123 publications

(135 citation statements)

References 45 publications

(80 reference statements)

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“…Rv0678 bedaquiline/clofazimine RAVs often persisted as heterozygous variants often throughout treatment, suggesting there is an as yet undetermined underlying biological explanation why they fail to reach fixation. A driving factor behind heteroresistance to other antimycobacterial drugs may be the existence of Mtb subpopulations in lung cavities, where some drugs may penetrate at subtherapeutic concentrations or not at all (20,62). While this has not yet been conclusively demonstrated for bedaquiline, along with clofazimine it is predicted to exhibit poor penetration into cavities (63).…”

Section: Discussionmentioning

confidence: 99%

Dynamics of within-hostMycobacterium tuberculosisdiversity and heteroresistance during treatment

Nimmo

Brien

Millard

et al. 2020

Preprint

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Section: Discussionmentioning

confidence: 99%

Dynamics of within-hostMycobacterium tuberculosisdiversity and heteroresistance during treatment

Nimmo

Brien

Millard

et al. 2020

Preprint

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“…For d-cycloserine population pharmacokinetics, we used the results of Alsultan et al (contributed to us by Dr Charles Peloquin) based on 130 patients who had MDR-TB, as well by Chang et al, shown in Table 1 [38,39]. For lung cavity penetration ratios of d-cycloserine, we used the mean ± standard deviation lung cavity-to-serum penetration ratios of 0.063 ± 0.026 among those who had detectable cycloserine cavitary concentrations [40]. The penetration of d-cycloserine into cerebrospinal fluid (CSF) is about 80%-100% of concurrent serum concentrations in inflamed meninges; case reports suggest that the clearance from subarachnoid space may be slower than in serum [41,42].…”

Section: Monte Carlo Experiments For Dose Selectionmentioning

confidence: 99%

d-Cycloserine Pharmacokinetics/Pharmacodynamics, Susceptibility, and Dosing Implications in Multidrug-resistant Tuberculosis: A Faustian Deal

Deshpande

Alffenaar

Köser

et al. 2018

Clinical Infectious Diseases

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Background. d-cycloserine is used to treat multidrug-resistant tuberculosis. Its efficacy, contribution in combination therapy, and best clinical dose are unclear, also data on the d-cycloserine minimum inhibitory concentration (MIC) distributions is scant. Methods. We performed a systematic search to identify pharmacokinetic and pharmacodynamic studies performed with d-cycloserine. We then performed a combined exposure-effect and dose fractionation study of d-cycloserine in the hollow fiber system model of tuberculosis (HFS-TB). In parallel, we identified d-cycloserine MICs in 415 clinical Mycobacterium tuberculosis (Mtb) isolates from patients. We utilized these results, including intracavitary concentrations, to identify the clinical dose that would be able to achieve or exceed target exposures in 10 000 patients using Monte Carlo experiments (MCEs). Results. There were no published d-cycloserine pharmacokinetics/pharmacodynamics studies identified. Therefore, we performed new HFS-TB experiments. Cyloserine killed 6.3 log 10 colony-forming units (CFU)/mL extracellular bacilli over 28 days. Efficacy was driven by the percentage of time concentration persisted above MIC (%T MIC), with 1.0 log 10 CFU/mL kill achieved by %T MIC = 30% (target exposure). The tentative epidemiological cutoff value with the Sensititre MYCOTB assay was 64 mg/L. In MCEs, 750 mg twice daily achieved target exposure in lung cavities of 92% of patients whereas 500 mg twice daily achieved target exposure in 85% of patients with meningitis. The proposed MCE-derived clinical susceptibility breakpoint at the proposed doses was 64 mg/L. Conclusions. Cycloserine is cidal against Mtb. The susceptibility breakpoint is 64 mg/L. However, the doses likely to achieve the cidality in patients are high, and could be neurotoxic.

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“…MCEs allow the generation of a distribution of PK parameters and exposures such as AUC 0-24 , peak, and concentration-time profiles in up to 10 000 random patients. Because serum or plasma concentrations are the most accessible data, the penetration into tuberculosis lung cavities and subarachnoid space is also taken into consideration in calculating the final concentrations in different tuberculosis anatomic sites [34][35][36]. Different doses are examined to generate AUC 0-24 , peak concentrations, and T MIC .…”

Section: Mces Integrate Invariant Relationships Pk and Mic Variabilitymentioning

confidence: 99%

Pharmacokinetic/Pharmacodynamic Background and Methods and Scientific Evidence Base for Dosing of Second-line Tuberculosis Drugs

Gumbo

Alffenaar

2018

Clinical Infectious Diseases

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A World Health Organization workshop systematically examined the evidence base for dosing second-line tuberculosis drugs, identifying knowledge gaps. To fill these in, pharmacokinetics/pharmacodynamics, Monte Carlo experiments, and artificial intelligence algorithms were used in hollow-fiber model studies and clinical data analyses. Keywords. WHO second-line drugs; pharmacokinetics/pharmacodynamics; systematic analyses; hollow-fiber system model of tuberculosis; optimal dosing. What has been will be again, what has been done will be done again; there is nothing new under the sun. Is there anything of which one can say, "Look! This is something new"? It was here already, long ago; it was here before our time.

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Drug-Penetration Gradients Associated with Acquired Drug Resistance in Patients with Tuberculosis

Abstract: These data inform interventional strategies relevant to drug delivery, dosing, and diagnostics to prevent the development of acquired resistance. The role of high intracavitary penetration as a biomarker of antibiotic efficacy, when assessing new regimens, requires clarification.

Cited by 123 publications

References 45 publications

Dynamics of within-hostMycobacterium tuberculosisdiversity and heteroresistance during treatment

Dynamics of within-hostMycobacterium tuberculosisdiversity and heteroresistance during treatment

d-Cycloserine Pharmacokinetics/Pharmacodynamics, Susceptibility, and Dosing Implications in Multidrug-resistant Tuberculosis: A Faustian Deal

Pharmacokinetic/Pharmacodynamic Background and Methods and Scientific Evidence Base for Dosing of Second-line Tuberculosis Drugs

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