1. Pharmacokinetic interaction between bedaquiline and clofazimine in patients with drug-resistant tuberculosis.

Int J Tuberc Lung Dis. 2017 Nov 16. doi: 10.5588/ijtld.17.0615. [Epub ahead of print]

Maartens G(1), Brill MJE(2), Pandie M(1), Svensson EM(2).

BACKGROUND: Bedaquiline (BDQ) and clofazimine (CFZ) are both recommended for treating drug-resistant tuberculosis(DR-TB). As CFZ is an inhibitor of the cytochrome P450 isoenzyme 3A4 (CYP3A4) in vitro, and BDQ a substrate of CYP3A4, there is a potential for pharmacokinetic (PK) drug-drug interaction that may result in increased BDQ exposure when co-administered with CFZ, which could increase the toxicity of BDQ.

METHODS: We assessed the effect of co-administered CFZ on BDQ bioavailability, or on clearance of BDQ and its N-monodesmethyl metabolite (M2), in patients with DR-TB using a population PK model developed from data of patients with DR-TB. This was a secondary analysis of a study designed to explore drug-drug interactions between BDQ and antiretrovirals.

RESULTS: Of 46 participants, 30 were on concomitant CFZ when intensive PK sampling of BDQ was done. CFZ did not have a statistically significant effect on BDQ bioavailability (−9.1%, 90%CI −22.8 to +7.1; P= 0.19) or on BDQ and M2 clearance (+12.2%, 90%CI −13.7 to +38; P = 0.32).

CONCLUSION: We did not find a statistically significant PK drug-drug interaction between BDQ and CFZ, but cannot exclude a potentially clinically relevant interaction due to the wide confidence intervals of the estimated interaction effects.

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2. Levofloxacin population pharmacokinetics in South African children treated for multidrug-resistant tuberculosis.

Antimicrob Agents Chemother. 2017 Nov 13. pii: AAC.01521-17. doi: 10.1128/AAC.01521-17. [Epub ahead of print]

Denti P(1), Garcia-Prats AJ(2), Draper HR(2), Wiesner L(3), Winckler J(2), Thee S(4), Dooley KE(5), Savic RM(6), McIlleron HM(3), Schaaf HS(2), Hesseling AC(2).

BACKGROUND: Levofloxacin is increasingly used in the treatment of multidrug-resistant tuberculosis (MDR-TB). There are limited paediatric pharmacokinetic data to inform dose selection for children.

METHODS: Children routinely receiving levofloxacin (250 mg adult tablets) for MDR-TB prophylaxis or disease in Cape Town, South Africa, underwent pharmacokinetic sampling following a 15 or 20 mg/kg dose, given as whole tablet(s) or crushed, orally, or by nasogastric tube. Pharmacokinetic parameters were estimated using non-linear mixed effects modelling. Model-based simulations were performed to estimate doses across weight bands that would achieve adult exposures with 750mg once-daily dosing.

RESULTS: 109 children were included, median age 2.1 years (range 0.3-8.7); median weight 12 kg (range 6-22). Levofloxacin followed 2-compartment kinetics with 1st-order elimination and absorption with a lag time. After inclusion of allometric scaling, the model characterised age-driven maturation of clearance (CL) with an effect reaching 50% around 2 months after birth and 100% by 2 years of age.. CL in a typical child (12 kg, 2-year-old) was 4.7 L/h. HIV infection reduced CL by 16%. Using the adult 250 mg formulation, Levofloxacin exposures were substantially lower than those reported in adults receiving a similar mg/kg dose. To achieve adult-equivalent exposures at a 750 mg daily dose, higher levofloxacin paediatric doses may be required -from 18 mg/kg/day for younger children with weights 3-4 kg (due to immature clearance) to 40 mg/kg/day for older children.

CONCLUSIONS: Currently recommended doses of levofloxacin for MDR-TB in children result in exposures considerably lower than in adults. The effect of different formulations and formulation manipulation require further investigation.We recommend age- and weight-banded doses of 250 mg tablets adult-formulation most likely to achieve target concentrations for prospective evaluation.

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3. What is resistance? Impact of phenotypic versus molecular drug resistance testing on multi- and extensively drug-resistant tuberculosis therapy.

Antimicrob Agents Chemother. 2017 Nov 13. pii: AAC.01550-17. doi: 10.1128/AAC.01550-17. [Epub ahead of print] 

Heyckendorf J(1)(2)(3), Andres S(4), Köser CU(5), Olaru ID(1)(2), Schön T(6)(7), Sturegård E(8), Beckert P(2)(9), Schleusener V(9), Kohl TA(2)(9), Hillemann D(4), Moradigaravand D(10), Parkhill J(10), Peacock SJ(5)(10)(11), Niemann S(12)(9), Lange C(13)(2)(3)(14)(15), Merker M(2)(9).

ABSTRACT: Rapid and accurate drug-susceptibility testing (DST) is essential for the treatment of multi- and extensively drug-resistant tuberculosis(M/XDR-TB). We compared the utility of genotypic DST assays with phenotypic DST (pDST) using BACTEC 960 MGIT or Löwenstein-Jensen to construct M/XDR-TB treatment regimens for a cohort of 25 consecutive M/XDR-TB patients and 15 possible anti-TBdrugs.Genotypic DST results from Cepheid GeneXpert MTB/RIF (Xpert) and line probe assays (LPAs: Hain GenoType MTBDRplus 2.0 and MTBDRsl 2.0)] and whole genome sequencing (WGS) were translated into individual algorithm-derived treatment regimens for each patient. We further analysed if discrepancies between the various methods were due to flaws in the genotypic or phenotypic test using MIC results.Compared with pDST, the average agreement in the number of drugs prescribed in ‘genotypic’ regimens ranged from just 49% (95% CI 39-59%) for Xpert and 63% (95% CI 56-70%) for LPAs to 93% (95% CI 88-98%) for WGS. Only the WGS regimens did not comprise any drugs to which pDST showed resistance. Importantly, MIC testing revealed that pDST likely underestimated the true rate of resistance for key drugs (rifampicin, levofloxacin, moxifloxacin, and kanamycin) because critical concentrations (CCs) were too high.WGS can be used to rule-in resistance even in M/XDR strains with complex resistance patterns, but pDST for some drugs is still needed to confirm susceptibility and construct the final regimens. Some CCs for pDST need to be re-examined to avoid systematic false-susceptible results in low-level resistant isolates.

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4. Polyclonal Pulmonary Tuberculosis Infections and Risk for Multidrug Resistance, Lima, Peru.

Emerg Infect Dis. 2017 Nov;23(11):1887-1890. doi: 10.3201/eid2311.170077.

Nathavitharana RR, Shi CX, Chindelevitch L, Calderon R, Zhang Z, Galea JT, Contreras C, Yataco R, Lecca L, Becerra MC, Murray MB, Cohen T.

ABSTRACT: Because within-host Mycobacterium tuberculosis diversity complicates diagnosis and treatment of tuberculosis (TB), we measured diversity prevalence and associated factors among 3,098 pulmonary TB patients in Lima, Peru. The 161 patients with polyclonal infection were more likely than the 115 with clonal or the 2,822 with simple infections to have multidrug-resistant TB.

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