Drug concentration in lung tissue in multidrug-resistant tuberculosis

Akkerman, Onno W.; Altena, Richard van; Klinkenberg, Theo J.; Brouwers, Adrienne H.; Bongaerts, Alphons H.H.; Werf, Tjip S. van der; Alffenaar, Jan‐Willem C.

doi:10.1183/09031936.00047413

Cited by 21 publications

(17 citation statements)

References 10 publications

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“…The only other data on the tissue penetration of fluoroquinolones among patients with TB come from a case report of a 13-year-old girl with MDR-TB who had surgical resection performed. Whole-tissue moxifloxacin concentrations were found to range from 0.73 to 0.95 g/g (9). We also determined whole-tissue drug concentrations in three patients and found concentrations to be much higher than those in this case report, with a range of 5.30 to 40.25 g/g.…”

Section: Discussionmentioning

confidence: 84%

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Cavitary Penetration of Levofloxacin among Patients with Multidrug-Resistant Tuberculosis

Kempker

Barth

Vashakidze

et al. 2015

Antimicrob Agents Chemother

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A better understanding of second-line drug (SLD) pharmacokinetics, including cavitary penetration, may help optimize SLD dosing. Patients with pulmonary multidrug-resistant tuberculosis (MDR-TB) undergoing adjunctive surgery were enrolled in Tbilisi, Georgia. Serum was obtained at 0, 1, 4, and 8 h and at the time of cavitary removal to measure levofloxacin concentrations. After surgery, microdialysis was performed using the ex vivo cavity, and levofloxacin concentrations in the collected dialysate fluid were measured. Noncompartmental analysis was performed, and a cavitary-to-serum levofloxacin concentration ratio was calculated. Twelve patients received levofloxacin for a median of 373 days before surgery (median dose, 11.8 mg/kg). The median levofloxacin concentration in serum (C max ) was 6.5 g/ml, and it was <2 g/ml in 3 (25%) patients. Among 11 patients with complete data, the median cavitary concentration of levofloxacin was 4.36 g/ml (range, 0.46 to 8.82). The median cavitary/ serum levofloxacin ratio was 1.33 (range, 0.63 to 2.36), and 7 patients (64%) had a ratio of >1. There was a significant correlation between serum and cavitary concentrations (r ‫؍‬ 0.71; P ‫؍‬ 0.01). Levofloxacin had excellent penetration into chronic cavitary TB lesions, and there was a good correlation between serum and cavitary concentrations. Optimizing serum concentrations will help ensure optimal cavitary concentrations of levofloxacin, which may enhance treatment outcomes.T he emergence of multidrug-resistant tuberculosis (MDR-TB) remains a major barrier to global TB control (1). The treatment course for MDR-TB (with resistance to isoniazid and rifampin) consists of 18 to 24 months of second-line antituberculosis drugs (SLDs), including a fluoroquinolone and an injectable agent (amikacin, kanamycin, or capreomycin). A 2009 meta-analysis of MDR-TB treatment outcomes found an overall success rate of 62% with a range of 36 to 79% (2). The most recent World Health Organization (WHO) global TB report reported an overall successful outcome rate of 48%, again with a wide range (3). These data show that we are far from the goal of a Ͼ75% successful outcome treatment rate among MDR-TB patients; however, the broad range of successful outcomes suggests that we may be able to more effectively maximize existing SLD regimens. A better knowledge of how to optimize available SLD regimens could improve outcomes and provide important principles for the efficacious use of new drugs.The clinical pharmacology of SLDs has been a neglected area of research (4). Pharmacokinetic studies among patients with drugsusceptible TB demonstrate that low concentrations of first-line drugs are associated with poor clinical outcomes, and simulation studies have found that even with perfect adherence up to 1% of patients would develop further drug resistance during treatment due to variability in drug concentrations (5-7). A recent report on 25 patients with MDR-TB found that plasma SLD concentrations were frequently low and were associated with decreased drug ...

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Section: Discussionmentioning

confidence: 84%

“…There is only one published case report evaluating SLD concentrations inside human cavitary lesions (9). Reports of worse clinical outcomes among patients with cavitary disease offer compelling but indirect evidence for low intracavitary SLD concentrations (10)(11)(12).…”

mentioning

confidence: 99%

Cavitary Penetration of Levofloxacin among Patients with Multidrug-Resistant Tuberculosis

Kempker

Barth

Vashakidze

et al. 2015

Antimicrob Agents Chemother

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“…Also in this edition of the ERJ, a letter by the same Dutch group provides an example of the clinical applications of therapeutic drug monitoring (TDM) [18]. The study provides, for the first time, evidence of anti-TB drugs' penetration into a human tissue (a TB-destroyed lung in this case) in parallel to their blood concentration.…”

mentioning

confidence: 98%

Therapeutic drug management: is it the future of multidrug-resistant tuberculosis treatment?

et al. 2013

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@ERSpublications TDM can be helpful for multidrug-resistant tuberculosis therapeutic decisions. DBS can bypass logistical issues http://ow.ly/otsFp Multidrug-and extensively drug-resistant (M/XDR) tuberculosis (TB) are emerging public health concerns [1,2]. In 2011, the World Health Organization (WHO) estimated 12 million prevalent cases of TB globally, which is equivalent to 170 cases per 100 000 population, out of these an estimated 630 000 cases were affected by MDR Mycobacterium tuberculosis strains [3]. Among the newly diagnosed patients ,3.7% were infected by MDR-TB strains, but the worrisome fact is that the prevalence of MDR-TB among new cases in some Former Soviet Union countries exceeds 30% [4,5], XDR-TB has been identified in 84 countries and the average proportion of MDR-TB cases with an XDR-TB pattern is 9.0% [3]. Further adding to the problem are the reports of ''totally drug resistant'' TB [6,7], a term currently not recognised by WHO [8,9].Treatment of drug resistant TB is more expensive and more toxic if compared with that prescribed for drugsusceptible TB, and currently takes up to 2 years of therapy [10]. The cost per patient to treat MDR-TB cases is incredibly high [11,12] and, in spite of international public health efforts, the treatment outcome is not very promising [13][14][15]. DIEL et al. [16] showed that direct treatment-related costs of MDR-TB patients can amount to J52 259 in Germany (table 1).In the largest MDR-TB cohort analysed to date [13] the proportion of cases treated successfully was 62%, with 7% failing or relapsing, 9% dying and 17% defaulting; in the XDR-TB subgroup 40% achieved treatment success, 22% failed treatment or relapsed, whereas 15% died and 16% defaulted [14,15].In this issue of the European Respiratory Journal (ERJ) a Dutch group from Groningen [17] reported on the results of a prospective pharmacokinetic (PK) study aimed at quantifying the effect of clarithromycin on the exposure to linezolid. In simple terms they observed that clarithromycin, which has some activity against TB bacilli and is well tolerated, increases linezolid exposure (i.e. increases the blood levels of linezolid, which is a very expensive and toxic drug). The authors decided to quantify this phenomenon administering a fix dose of linezolid (300 mg twice a day) plus a variable one of clarithromycin (250-500 mg once a day).Using validated PK methods they demonstrated that linezolid exposure significantly increased after the coadministration of 500 mg clarithromycin by a median (interquartile range) of 44% (23-102%), when

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“…Third, the scientific community needs to share all existing pieces of information deriving from the use of this new drug in order to have better information on its safety and efficacy. Finally, bedaquiline needs to be more widely accessible in order to evaluate best protocols for DST, MIC analyses and protocols for therapeutic drug monitoring [23][24][25]. In the original 2005 Science article, DST was performed using the radiometric BACTEC 460TB, which has since been discontinued.…”

Section: Discussionmentioning

confidence: 99%

Bedaquiline: 10 years later, the drug susceptibility testing protocol is still pending

Migliori

2015

Eur Respir J

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Drug concentration in lung tissue in multidrug-resistant tuberculosis

Cited by 21 publications

References 10 publications

Cavitary Penetration of Levofloxacin among Patients with Multidrug-Resistant Tuberculosis

Cavitary Penetration of Levofloxacin among Patients with Multidrug-Resistant Tuberculosis

Therapeutic drug management: is it the future of multidrug-resistant tuberculosis treatment?

Bedaquiline: 10 years later, the drug susceptibility testing protocol is still pending

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