Fluoroquinolone Efficacy against Tuberculosis Is Driven by Penetration into Lesions and Activity against Resident Bacterial Populations

Sarathy, Jansy; Blanc, Landry; Alvarez-Cabrera, Nadine; O'Brien, Paul Edmond; Dias-Freedman, Isabela; Mina, Marizel; Zimmerman, Matthew; Kaya, Firat; Liang, Hsin-Pin Ho; Prideaux, Brendan; Dietzold, Jillian; Salgame, Padmini; Savic, Radojka M.; Linderman, Jennifer J.; Kirschner, Denise E.; Pienaar, Elsje; Dartois, Véronique

doi:10.1128/aac.02516-18

Cited by 47 publications

(39 citation statements)

References 74 publications

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“…Within FREGONESE et al [17], roughly equal numbers of studies used these two drugs, which were not directly compared. However, comparative data are available from a MDR-TB trial (no difference in treatment outcomes when comparing the two drugs; fewer adverse events for M) [23], and rabbit and mouse models (M broadly superior over Lfx) [24,25]. Lfx doses in such studies may have been too low [26,27].…”

Section: Discussionmentioning

confidence: 99%

Fluoroquinolones and isoniazid-resistant tuberculosis: implications for the 2018 WHO guidance

et al. 2019

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Introduction2018 World Health Organization (WHO) guidelines for the treatment of isoniazid (H)-resistant (Hr) tuberculosis recommend a four-drug regimen: rifampicin (R), ethambutol (E), pyrazinamide (Z) and levofloxacin (Lfx), with or without H ([H]RZE-Lfx). This is used once Hr is known, such that patients complete 6 months of Lfx (≥6[H]RZE-6Lfx). This cohort study assessed the impact of fluoroquinolones (Fq) on treatment effectiveness, accounting for Hr mutations and degree of phenotypic resistance.MethodsThis was a retrospective cohort study of 626 Hr tuberculosis patients notified in London, 2009–2013. Regimens were described and logistic regression undertaken of the association between regimen and negative regimen-specific outcomes (broadly, death due to tuberculosis, treatment failure or disease recurrence).ResultsOf 594 individuals with regimen information, 330 (55.6%) were treated with (H)RfZE (Rf=rifamycins) and 211 (35.5%) with (H)RfZE-Fq. The median overall treatment period was 11.9 months and median Z duration 2.1 months. In a univariable logistic regression model comparing (H)RfZE with and without Fqs, there was no difference in the odds of a negative regimen-specific outcome (baseline (H)RfZE, cluster-specific odds ratio 1.05 (95% CI 0.60–1.82), p=0.87; cluster NHS trust). Results varied minimally in a multivariable model. This odds ratio dropped (0.57, 95% CI 0.14–2.28) when Hr genotype was included, but this analysis lacked power (p=0.42).ConclusionsIn a high-income setting, we found a 12-month (H)RfZE regimen with a short Z duration to be similarly effective for Hr tuberculosis with or without a Fq. This regimen may result in fewer adverse events than the WHO recommendations.

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Section: Discussionmentioning

confidence: 99%

Fluoroquinolones and isoniazid-resistant tuberculosis: implications for the 2018 WHO guidance

et al. 2019

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“…Recently, several new riminophenazine derivatives that were based on CLO but possessed superior activities against M. tuberculosis in vitro and lower propensity for skin discoloration were reported (19). Of particular note is the observation that CLO is one of two drugs reported to exceed the therapeutic threshold for killing of M. tuberculosis in caseous lesions; the other drug is the fluoroquinolone moxifloxacin (20)(21)(22)(23).…”

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confidence: 99%

In Vitro Efficacies, ADME, and Pharmacokinetic Properties of Phenoxazine Derivatives Active against Mycobacterium tuberculosis

Tanner

Evans

Seldon

et al. 2019

Antimicrob Agents Chemother

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Mycobacterium tuberculosis, the causative agent of tuberculosis, remains a leading infectious killer globally, demanding the urgent development of faster-acting drugs with novel mechanisms of action. Riminophenazines such as clofazimine are clinically efficacious against both drug-susceptible and drug-resistant strains of M. tuberculosis. We determined the in vitro anti-M. tuberculosis activities, absorption, distribution, metabolism, and excretion properties, and in vivo mouse pharmacokinetics of a series of structurally related phenoxazines. One of these, PhX1, displayed promising drug-like properties and potent in vitro efficacy, supporting its further investigation in an M. tuberculosis-infected animal model.

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“…The use of CT may facilitate personalization of PTB therapy by combining CL features with pharmacokinetic data. For example, rifampin and pyrazinamide have demonstrated adequate concentrations in caseum [15], and quinolones less so, although moxifloxacin may have improved caseum penetration relative to gatifloxacin and levofloxacin [36]. In the absence of validated biomarkers, our data suggest that CT could play a larger role in the design of clinical trials testing shortened therapy for patients without identifiable CL and optimization of treatment regimens for patients with CL based on antituberculous PK properties.…”

Section: Discussionmentioning

confidence: 99%

Increasing Number and Volume of Cavitary Lesions on Chest Computed Tomography Are Associated With Prolonged Time to Culture Conversion in Pulmonary Tuberculosis

Hernández-Romieu

Little

Bernheim

et al. 2019

Open Forum Infectious Diseases

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Background Cavitary lesions (CLs) primarily identified by chest x-ray (CXR) have been associated with worse clinical outcomes among patients with pulmonary tuberculosis (PTB). Chest computed tomography (CT), which has better resolution and increased sensitivity to detect lung abnormalities, has been understudied in PTB patients. We compared detection of CLs by CT and CXR and assessed their association with time to sputum culture conversion (tSCC). Methods This was a retrospective cohort study of 141 PTB patients who underwent CT. We used multivariate Cox proportional hazards models to evaluate the association between CLs on CXR and the number and single largest volume of CLs on CT with tSCC. Results Thirty (21%) and 75 (53%) patients had CLs on CXR and CT, respectively. CT detected cavities in an additional 44 patients (31%) compared with CXR. After multivariable adjustment, we observed a negative association between CLs and tSCC, with an adjusted hazard ratio (aHR) of 0.56 (95% confidence interval [CI], 0.32 to 0.97) for single CLs and 0.31 (95% CI, 0.16 to 0.60) for multiple CLs present on CT. Patients with a CL volume ≥25 mL had a prolonged tSCC (aHR, 0.39; 95% CI, 0.21 to 0.72). CLs on CXR were not associated with increased tSCC after multivariable adjustment. Conclusions CT detected a larger number of cavities in patients with PTB relative to CXR. We observed an association between increasing number and volume of CLs on CT and delayed tSCC independent of sputum microscopy result. Our findings highlight a potential role for CT in the clinical and research setting as a tool to risk-stratify patients with PTB.

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Fluoroquinolone Efficacy against Tuberculosis Is Driven by Penetration into Lesions and Activity against Resident Bacterial Populations

Cited by 47 publications

References 74 publications

Fluoroquinolones and isoniazid-resistant tuberculosis: implications for the 2018 WHO guidance

Fluoroquinolones and isoniazid-resistant tuberculosis: implications for the 2018 WHO guidance

In Vitro Efficacies, ADME, and Pharmacokinetic Properties of Phenoxazine Derivatives Active against Mycobacterium tuberculosis

Increasing Number and Volume of Cavitary Lesions on Chest Computed Tomography Are Associated With Prolonged Time to Culture Conversion in Pulmonary Tuberculosis

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