Additional Drug Resistance in Mycobacterium tuberculosis Isolates From Resected Cavities Among Patients With Multidrug-Resistant or Extensively Drug-Resistant Pulmonary Tuberculosis

Kempker, Russell R.; Rabin, Alon; Nikolaishvili, Ketino; Kalandadze, Iagor; Gogishvili, Shota; Blumberg, Henry M.; Vashakidze, Sergo

doi:10.1093/cid/cir904

Cited by 58 publications

(52 citation statements)

References 7 publications

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“…Cavitary lesions are heterogeneous and characterized by various levels of fibrosis, necrosis, and vascularization, as demonstrated by the histopathology from our study, and they contain high numbers of M. tuberculosis organisms, many of which reside extracellularly in the caseous center. Clinically, studies have shown the presence of cavitary lesions to be associated with longer time to sputum culture conversion (26), high rates of relapse (27), the development of acquired dug resistance (12,28), and worse treatment outcomes among patients with MDR-TB (29,30). These clinical studies suggest that drug penetration into cavitary lesions may be hindered, possibly due to the physical and functional barriers of cavitary lesions.…”

Section: Discussionmentioning

confidence: 99%

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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: 99%

“…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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“…Adjunctive pulmonary resection has been advocated in selected patients with localized MDR-TB and cavitary lesions or a single destroyed lobe [3,22,23,24,25,26,27,28,29,30,31,33]. However, not all patients are suitable candidates, and surgery frequently involves postoperative complications.…”

Section: Discussionmentioning

confidence: 99%

“…The surgical removal of cavities could enhance the sterilizing properties of postsurgical chemotherapy and increase the likelihood of treatment success in these selected patients [24,31,32]. Kempker et al [33] demonstrated that the tuberculous cavity promotes the emergence of increasingly drug-resistant bacilli populations during treatment in M. tuberculosis isolates from resected cavities among patients with MDR and XDR-TB.…”

Section: Introductionmentioning

confidence: 99%

Lobar Collapse Therapy Using Endobronchial Valves as a New Complementary Approach to Treat Cavities in Multidrug-Resistant Tuberculosis and Difficult-to-Treat Tuberculosis: A Case Series

et al. 2016

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Background: The poor treatment outcomes of multidrug-resistant tuberculosis (TB) and the emergence of extensively drug-resistant TB and extremely and totally drug-resistant TB highlight the urgent need for new antituberculous drugs and other adjuvant treatment approaches. Objectives: We have treated cavitary tuberculosis by the application of endobronchial one-way valves (Zephyr®; Pulmonx Inc., Redwood City, Calif., USA) to induce lobar volume reduction as an adjunct to drug treatment. This report describes the feasibility, effectiveness and safety of the procedure. Methods: Patients with severe lung destruction, one or more cavities or those who were ineligible for surgical resection and showed an unsatisfactory response to standard drug treatments were enrolled. During bronchoscopy, endobronchial valves were implanted in the lobar or segmental bronchi in order to induce atelectasis and reduce the cavity size. Results: Four TB patients and 1 patient with atypical mycobacteriosis were treated. The mean patient age was 52.6 years. Complete cavity collapses were observed on CT scans in 4 of the 5 cases. All patients showed improvements in their clinical status, and sputum smears became negative within 3-5 months. There were no severe short- or long-term complications. The valves were removed in 3 of the 5 patients after 8 months on average; there was no relapse after 15 months of follow-up. Conclusion: These data suggest that endobronchial valves are likely to be useful adjuncts to the treatment of therapeutically difficult patients. More data are required to confirm our findings.

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“…To develop new therapeutic approaches, it is critical to understand underlying mechanisms of disease. In pulmonary TB, extracellular matrix (ECM) breakdown causes cavitation and facilitates Mtb transmission (2) and drug resistance (3), and also increases morbidity and mortality (4). Matrix metalloproteinases (MMPs) are zincdependent proteolytic enzymes, which are involved in pulmonary ECM turnover and have diverse immunological roles, such as chemokine processing (5).…”

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confidence: 99%

Early Secretory Antigenic Target-6 Drives Matrix Metalloproteinase-10 Gene Expression and Secretion in Tuberculosis

Brilha

Sathyamoorthy

Stuttaford

et al. 2017

Am J Respir Cell Mol Biol

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Tuberculosis (TB) causes disease worldwide, and multidrug resistance is an increasing problem. Matrix metalloproteinases (MMPs), particularly the collagenase MMP-1, cause lung extracellular matrix destruction, which drives disease transmission and morbidity. The role in such tissue damage of the stromelysin MMP-10, a key activator of the collagenase MMP-1, was investigated in direct Mycobacterium tuberculosis (Mtb)-infected macrophages and in conditioned medium from Mtb-infected monocyte-stimulated cells. Mtb infection increased MMP-10 secretion from primary human macrophages 29-fold, whereas Mtb-infected monocytes increased secretion by 4.5-fold from pulmonary epithelial cells and 10.5-fold from fibroblasts. Inhibition of MMP-10 activity decreased collagen breakdown. In two independent cohorts of patients with TB from different continents, MMP-10 was increased in both induced sputum and bronchoalveolar lavage fluid compared with control subjects and patients with other respiratory diseases (both P , 0.05). Mtb drove 3.5-fold greater MMP-10 secretion from human macrophages than the vaccine strain bacillus Calmette-Guerin (P , 0.001), whereas both mycobacteria up-regulated TNF-a secretion equally. Using overlapping, short, linear peptides covering the sequence of early secretory antigenic target-6, a virulence factor secreted by Mtb, but not bacillus Calmette-Guerin, we found that stimulation of human macrophages with a single specific 15-amino acid peptide sequence drove threefold greater MMP-10 secretion than any other peptide (P , 0.001). Mtb-driven MMP-10 secretion was inhibited in a dose-dependent manner by p38 and extracellular signal-related kinase mitogen-activated protein kinase blockade (P , 0.001 and P , 0.01 respectively), but it was not affected by inhibition of NF-kB. In summary, Mtb activates inflammatory and stromal cells to secrete MMP-10, and this is partly driven by the virulence factor early secretory antigenic target-6, implicating it in TB-associated tissue destruction.

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Additional Drug Resistance in Mycobacterium tuberculosis Isolates From Resected Cavities Among Patients With Multidrug-Resistant or Extensively Drug-Resistant Pulmonary Tuberculosis

Cited by 58 publications

References 7 publications

Cavitary Penetration of Levofloxacin among Patients with Multidrug-Resistant Tuberculosis

Cavitary Penetration of Levofloxacin among Patients with Multidrug-Resistant Tuberculosis

Lobar Collapse Therapy Using Endobronchial Valves as a New Complementary Approach to Treat Cavities in Multidrug-Resistant Tuberculosis and Difficult-to-Treat Tuberculosis: A Case Series

Early Secretory Antigenic Target-6 Drives Matrix Metalloproteinase-10 Gene Expression and Secretion in Tuberculosis

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