scholarly journals Peak Plasma Concentration of Azithromycin and Treatment Responses in Mycobacterium avium Complex Lung Disease

2016 ◽  
Vol 60 (10) ◽  
pp. 6076-6083 ◽  
Author(s):  
Byeong-Ho Jeong ◽  
Kyeongman Jeon ◽  
Hye Yun Park ◽  
Seong Mi Moon ◽  
Su-Young Kim ◽  
...  
Keyword(s):  
Lung Disease ◽  
Mycobacterium Avium ◽  
Peak Plasma ◽  
Peak Plasma Concentration ◽  
Plasma Concentrations ◽  
Mycobacterium Abscessus ◽  
Intermittent Therapy ◽  
Daily Regimen ◽  
Content Type ◽  
Intermittent Regimen

ABSTRACTMacrolides, such as azithromycin (AZM) and clarithromycin, are the cornerstones of treatment forMycobacterium aviumcomplex lung disease (MAC-LD). Current guidelines recommend daily therapy with AZM for cavitary MAC-LD and intermittent therapy for noncavitary MAC-LD, but the effectiveness of these regimens has not been thoroughly investigated. This study evaluated associations between microbiological response and estimated peak plasma concentrations (Cmax) of AZM. The AZMCmaxwas measured in patients receiving daily therapy (250 mg of AZM daily,n= 77) or intermittent therapy (500 mg of AZM three times weekly,n= 89) for MAC-LD and daily therapy forMycobacterium abscessuscomplex LD (MABC-LD) (250 mg of AZM daily,n= 55). The AZMCmaxwas lower with the daily regimen for MAC-LD (median, 0.24 μg/ml) than with the intermittent regimen for MAC-LD (median, 0.65 μg/ml;P< 0.001) or daily therapy for MABC-LD (median, 0.53 μg/ml;P< 0.001). After adjusting for confounding factors, AZMCmaxwas independently associated with favorable microbiological responses in MAC-LD patients receiving a daily regimen (adjusted odds ratio [aOR], 1.58; 95% confidence interval [CI], 1.01 to 2.48;P= 0.044) but not an intermittent regimen (aOR, 0.85; 95% CI, 0.58 to 1.23,P= 0.379). With the daily AZM-based multidrug regimen for MAC-LD, a low AZMCmaxwas common, whereas a higher AZMCmaxwas associated with favorable microbiologic responses. The results also suggested that the addition of rifampin may lower AZMCmax. When a daily AZM-based multidrug regimen is used for treating severe MAC-LD, such as cavitary disease, the currently recommended AZM dose might be suboptimal. (This study has been registered at ClinicalTrials.gov under identifier NCT00970801.)

scholarly journals Intermittent Antibiotic Therapy for Recurrent Nodular Bronchiectatic Mycobacterium avium Complex Lung Disease

2017 ◽  
Vol 62 (2) ◽  
Author(s):  
Byung Woo Jhun ◽  
Seong Mi Moon ◽  
Su-Young Kim ◽  
Hye Yun Park ◽  
Kyeongman Jeon ◽  
...  
Keyword(s):  
Antibiotic Therapy ◽  
Lung Disease ◽  
Mycobacterium Avium ◽  
Previous Treatment ◽  
Intermittent Therapy ◽  
Oral Antibiotic ◽  
Content Type ◽  
Oral Antibiotic Therapy ◽  
Conversion Rates ◽  
Previously Treated

ABSTRACT Intermittent, three-times-weekly oral antibiotic therapy is recommended for the initial treatment of noncavitary nodular bronchiectatic (NB) Mycobacterium avium complex (MAC) lung disease. However, intermittent therapy is not recommended for patients who have been previously treated. We evaluated 53 patients with recurrent noncavitary NB MAC lung disease who underwent antibiotic treatment for ≥12 months with daily therapy (n = 26) or intermittent therapy (n = 27) between January 2008 and December 2015. Baseline characteristics were comparable between daily therapy and intermittent therapy groups. Sputum culture conversion rates did not differ between daily therapy (21/26, 81%) and intermittent therapy (22/27, 82%) groups. Compared to the etiologic organism at the time of previous treatment, recurrent MAC lung disease was caused by the same MAC species in 38 patients (72%) and by a different MAC species in 15 patients (28%). Genotype analysis in patients with sequenced paired isolates revealed that 86% (12/14) of cases with same species recurrence were due to reinfection with a new MAC genotype. In conclusion, most recurrent noncavitary NB MAC lung disease cases were caused by reinfection rather than relapse. Intermittent antibiotic therapy is a reasonable treatment strategy for recurrent noncavitary NB MAC lung disease.

scholarly journals Nontuberculous Mycobacterial Lung Diseases Caused by Mixed Infection with Mycobacterium avium Complex and Mycobacterium abscessus Complex

2018 ◽  
Vol 62 (10) ◽  
Author(s):  
Sun Hye Shin ◽  
Byung Woo Jhun ◽  
Su-Young Kim ◽  
Junsu Choe ◽  
Kyeongman Jeon ◽  
...  
Keyword(s):  
Lung Disease ◽  
Treatment Outcomes ◽  
Mycobacterium Avium ◽  
Mixed Infection ◽  
Mycobacterium Abscessus ◽  
Limited Data ◽  
Content Type ◽  
Nontuberculous Mycobacterial Lung Disease ◽  
Conversion Rates ◽  
Ntm Lung Disease

ABSTRACT Mycobacterium avium complex (MAC) and M. abscessus complex (MABC) comprise the two most important human pathogen groups causing nontuberculous mycobacterial lung disease (NTM-LD). However, there are limited data regarding NTM-LD caused by mixed NTM infections. This study aimed to evaluate the clinical characteristics and treatment outcomes in patients with NTM-LD caused by mixed infection with these two major NTM pathogen groups. Seventy-one consecutive patients who had been diagnosed with NTM-LD caused by mixed infection with MAC (M. avium or M. intracellulare) and MABC (M. abscessus or M. massiliense) between January 2010 and December 2015 were identified. Nearly all patients (96%) had the nodular bronchiectatic form of NTM-LD. Mixed infection with MAC and M. massiliense (n = 47, 66%) was more common than mixed infection with MAC and M. abscessus (n = 24, 34%), and among the 43 (61%) patients who were treated for NTM-LD for more than 12 months, sputum culture conversion rates were significantly lower in patients infected with MAC and M. abscessus (25% [3/12]) than in patients infected with MAC and M. massiliense (61% [19/31, P = 0.033]). Additionally, M. massiliense and M. abscessus showed marked differences in clarithromycin susceptibility (90% versus 6%, P < 0.001). Of the 23 patients who successfully completed treatment, 11 (48%) redeveloped NTM lung disease, with mycobacterial genotyping results indicating that the majority of cases were due to reinfection. Precise identification of etiologic NTM organisms could help predict treatment outcomes in patients with NTM-LD due to mixed infections.

scholarly journals Response to Switch from Intermittent Therapy to Daily Therapy for Refractory Nodular Bronchiectatic Mycobacterium avium Complex Lung Disease

2015 ◽  
Vol 59 (8) ◽  
pp. 4994-4996 ◽  
Author(s):  
Won-Jung Koh ◽  
Byeong-Ho Jeong ◽  
Kyeongman Jeon ◽  
Hye Yun Park ◽  
Su-Young Kim ◽  
...  
Keyword(s):  
Antibiotic Therapy ◽  
Lung Disease ◽  
Clinical Efficacy ◽  
Mycobacterium Avium ◽  
Initial Treatment ◽  
Mycobacterium Avium Complex ◽  
Intermittent Therapy ◽  
Content Type ◽  
Negative Culture

ABSTRACTIntermittent three-times-weekly antibiotic therapy is recommended for the initial treatment of patients with noncavitary nodular bronchiectaticMycobacterium aviumcomplex lung disease. Although some experts recommend switching from intermittent to daily therapy for patients whose sputum has persistent positive cultures after intermittent therapy, the clinical efficacy of these modifications is unknown. Of 20 patients whose sputum had persistent positive cultures after 12 months of intermittent antibiotic therapy, specimens from 6 patients (30%) achieved a negative culture after a change to daily therapy.

scholarly journals Effective Treatment of Mycobacterium avium subsp. hominissuis and Mycobacterium abscessus Species Infections in Macrophages, Biofilm, and Mice by Using Liposomal Ciprofloxacin

2018 ◽  
Vol 62 (10) ◽  
Author(s):  
James D. Blanchard ◽  
Valerie Elias ◽  
David Cipolla ◽  
Igor Gonda ◽  
Luiz E. Bermudez
Keyword(s):  
Effective Treatment ◽  
Mouse Models ◽  
Mycobacterium Avium ◽  
Nontuberculous Mycobacteria ◽  
Mycobacterium Abscessus ◽  
Content Type ◽  
Number Of Individuals ◽  
Intranasal Instillation

ABSTRACT Nontuberculous mycobacteria (NTM) affect an increasing number of individuals worldwide. Infection with these organisms is more common in patients with chronic lung conditions, and treatment is challenging. Quinolones, such as ciprofloxacin, have been used to treat patients, but the results have not been encouraging. In this report, we evaluate novel formulations of liposome-encapsulated ciprofloxacin (liposomal ciprofloxacin) in vitro and in vivo. Its efficacy against Mycobacterium avium and Mycobacterium abscessus was examined in macrophages, in biofilms, and in vivo using intranasal instillation mouse models. Liposomal ciprofloxacin was significantly more active than free ciprofloxacin against both pathogens in macrophages and biofilms. When evaluated in vivo, treatment with the liposomal ciprofloxacin formulations was associated with significant decreases in the bacterial loads in the lungs of animals infected with M. avium and M. abscessus. In summary, topical delivery of liposomal ciprofloxacin in the lung at concentrations greater than those achieved in the serum can be effective in the treatment of NTM, and further evaluation is warranted.

scholarly journals Rifabutin Is Active against Mycobacterium abscessus in Mice

2019 ◽  
Vol 64 (2) ◽  
Author(s):  
Thomas Dick ◽  
Sung Jae Shin ◽  
Won-Jung Koh ◽  
Véronique Dartois ◽  
Martin Gengenbacher
Keyword(s):  
Lung Disease ◽  
Mycobacterium Abscessus ◽  
Content Type

ABSTRACT There is no reliable cure for Mycobacterium abscessus lung disease. Rifampin is not used clinically due to poor in vitro potency. In contrast, we have shown that rifabutin, another approved rifamycin used to treat tuberculosis, is potent in vitro against M. abscessus. Here, we report that rifabutin is as active as clarithromycin against M. abscessus K21 in NOD.CB17-Prkdcscid/NCrCrl mice. This suggests that rifabutin should be considered a repurposing candidate for patients with M. abscessus disease.

scholarly journals GenoType NTM-DR Performance Evaluation for Identification of Mycobacterium avium Complex and Mycobacterium abscessus and Determination of Clarithromycin and Amikacin Resistance

2019 ◽  
Vol 57 (8) ◽  
Author(s):  
Hee Jae Huh ◽  
Su-Young Kim ◽  
Hyang Jin Shim ◽  
Dae Hun Kim ◽  
In Young Yoo ◽  
...  
Keyword(s):  
Mycobacterium Avium ◽  
Drug Susceptibility ◽  
Rapid Identification ◽  
Drug Susceptibility Testing ◽  
Mycobacterium Abscessus ◽  
Clinical Isolates ◽  
Resistance Mutations ◽  
Content Type ◽  
Clarithromycin Resistance ◽  
Reference Strains

ABSTRACT We evaluated the GenoType NTM-DR (NTM-DR) line probe assay for identifying Mycobacterium avium complex (MAC) species and Mycobacterium abscessus subspecies and for determining clarithromycin and amikacin resistance. Thirty-eight reference strains and 145 clinical isolates (58 MAC and 87 M. abscessus isolates), including 54 clarithromycin- and/or amikacin-resistant strains, were involved. The performance of the NTM-DR assay in rapid identification was evaluated by comparison with results of multigene sequence-based typing, whereas performance in rapid detection of clarithromycin and amikacin resistance was evaluated by comparison with sequencing of the erm(41), rrl, and rrs genes and drug susceptibility testing (DST). The accuracies of MAC and M. abscessus (sub)species identification were 92.1% (35/38) and 100% (145/145) for the 38 reference strains and 145 clinical isolates, respectively. Three MAC strains other than M. intracellulare were found to cross-react with the M. intracellulare probe in the assay. Regarding clarithromycin resistance, NTM-DR detected rrl mutations in 52 isolates and yielded 99.3% (144/145) and 98.6% (143/145) concordant results with sequencing and DST, respectively. NTM-DR sensitivity and specificity in the detection of clarithromycin resistance were 96.3% (52/54) and 100% (91/91), respectively. The NTM-DR yielded accurate erm(41) genotype results for all 87 M. abscessus isolates. Regarding amikacin resistance, NTM-DR detected rrs mutations in five isolates and yielded 99.3% (144/145) and 97.9% (142/145) concordant results with sequencing and DST, respectively. Our results indicate that the NTM-DR assay is a straightforward and accurate approach for discriminating MAC and M. abscessus (sub)species and for detecting clarithromycin and amikacin resistance mutations and that it is a useful tool in the clinical setting.

scholarly journals Thioridazine Is an Efflux Pump Inhibitor in Mycobacterium avium Complex but of Limited Clinical Relevance

2020 ◽  
Vol 64 (7) ◽  
Author(s):  
Mike Marvin Ruth ◽  
Lian J. Pennings ◽  
Valerie A. C. M. Koeken ◽  
Jodie A. Schildkraut ◽  
Aria Hashemi ◽  
...  
Keyword(s):  
Mycobacterium Avium ◽  
Mycobacterium Avium Complex ◽  
Efflux Pump ◽  
Ex Vivo ◽  
Plasma Concentrations ◽  
Intracellular Growth ◽  
Macrophage Infection ◽  
Efflux Pump Inhibitor ◽  
Content Type ◽  
Time Kill

ABSTRACT Treatment of Mycobacterium avium complex pulmonary disease (MAC-PD) is challenging partly due to high efflux pump expression. Thioridazine might block these efflux pumps. We explore the efficacy of thioridazine against M. avium isolates using MICs, time-kill combination assays, ex vivo macrophage infection assays, and efflux assays. Thioridazine is bactericidal against M. avium, inhibits intracellular growth at 2× MIC, and blocks ethidium bromide efflux. However, its toxicity and low plasma concentrations make it unlikely to add efficacy to MAC-PD therapy.

scholarly journals Levodopa and executive performance in Parkinson's disease: A randomized study

2008 ◽  
Vol 14 (5) ◽  
pp. 832-841 ◽  
Author(s):  
BERTA PASCUAL-SEDANO ◽  
JAIME KULISEVSKY ◽  
MANEL BARBANOJ ◽  
CARMEN GARCÍA-SÁNCHEZ ◽  
ANTONIA CAMPOLONGO ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Peak Plasma ◽  
Peak Plasma Concentration ◽  
Randomized Study ◽  
Plasma Concentrations ◽  
Wisconsin Card Sorting Test ◽  
Cognitive Changes ◽  
Executive Performance ◽  
Tower Of Hanoi

Parkinson's disease (PD) patients may experience fluctuations in executive performance after oral levodopa (LD). Their relationship with the pharmacokinetic profile of LD and with distinct cognitive processes associated with frontal-basal ganglia circuits is not well understood. In this randomized, double-blind, crossover study we plotted acute cognitive changes in 14 PD patients challenged with faster (immediate-release, IR) versus slower (controlled-release, CR) increases in LD plasma concentrations. We monitored motor status, LD plasma levels, and performance on four tasks of executive function (Wisconsin Card Sorting Test—WCST, Sternberg test, Stroop and Tower of Hanoi), 1 hr before and over +6 hr after IR and CR-LD dose. Analysis of variance demonstrated significant but divergent changes in the Sternberg (6-digit but not 2- and 4-digit) test: improvement after CR-LD and worsening after IR-LD. Marginal improvement (p = .085) was observed with CR-LD in the WCST, while no significant differences were seen for the Stroop or Tower of Hanoi tests. Executive-related performance after LD challenge may differ depending on the LD time-to-peak plasma concentration and specific task demands. A slower rise in LD levels appears to have a more favorable impact on more difficult working memory tests. These results require replication to determine their generalization. (JINS, 2008, 14, 832–841.)

scholarly journals Coadministration of Allopurinol To Increase Antimycobacterial Efficacy of Pyrazinamide as Evaluated in a Whole-Blood Bactericidal Activity Model

2017 ◽  
Vol 61 (10) ◽  
Author(s):  
Claire M. Naftalin ◽  
Rupangi Verma ◽  
Meera Gurumurthy ◽  
Qingshu Lu ◽  
Matthew Zimmerman ◽  
...  
Keyword(s):  
Bactericidal Activity ◽  
Whole Blood ◽  
Peak Plasma ◽  
Peak Plasma Concentration ◽  
Oxidase Inhibitor ◽  
Time Curve ◽  
Xanthine Oxidase Inhibitor ◽  
Content Type ◽  
Liquid Chromatography Tandem Mass ◽  
The Relationship

ABSTRACT Coadministering pyrazinamide (PZA) with the xanthine oxidase inhibitor allopurinol increases systemic levels of the active metabolite, pyrazinoic acid (POA), but the effects on bactericidal activity against tuberculosis are unknown. We randomized healthy volunteers to take a single dose of PZA (either 10 or 25 mg/kg of body weight) at the first visit and the same dose 7 days later, coadministered with allopurinol (100 mg daily; 2 days before to 1 day after the PZA dose). Blood was drawn at intervals until 48 h after each PZA dose, and drug levels were measured using liquid chromatography-tandem mass spectrometry. Whole-blood bactericidal activity (WBA) was measured by inoculating blood samples with Mycobacterium tuberculosis and estimating the change in bacterial CFU after 72 h of incubation. Allopurinol increased the POA area under the concentration-time curve from 0 to 8 h (AUC0–8) (18.32 h · μg/ml versus 24.63 h · μg/ml for PZA alone versus PZA plus allopurinol) (P < 0.001) and its peak plasma concentration (C max) (2.81 μg/ml versus 4.00 μg/ml) (P < 0.001). There was no effect of allopurinol on mean cumulative WBA (0.01 ± 0.02 ΔlogCFU versus 0.00 ± 0.02 ΔlogCFU for PZA alone versus PZA plus allopurinol) (P = 0.49). Higher systemic POA levels were associated with greater WBA levels (P < 0.001), but the relationship was evident only at low POA concentrations. The lack of an effect of allopurinol on WBA despite a significant increase in blood POA levels suggests that host-generated POA may be less effective than POA generated inside bacteria. Coadministration of allopurinol does not appear to be a useful strategy for increasing the efficacy of PZA in clinical practice. (This study has been registered at ClinicalTrials.gov under registration no. NCT02700347.)

The disposition of TCNU (tauromustine) in human malignant glioma: pharmacokinetic studies and clinical implications

1990 ◽  
Vol 72 (5) ◽  
pp. 721-725 ◽  
Author(s):  
Ian R. Whittle ◽  
Janet S. MacPherson ◽  
J. Douglas Miller ◽  
John F. Smyth
Keyword(s):  
Malignant Glioma ◽  
High Performance ◽  
Peak Plasma ◽  
Linear Regression Analysis ◽  
Plasma Concentrations ◽  
Tissue Level ◽  
Pharmacokinetic Studies ◽  
Tissue Concentrations ◽  
Content Type ◽  
Chromatography Analysis

✓ Tauromustine (TCNU), 130 mg/sq m, was administered intraoperatively by nasogastric tube to 10 patients with malignant glioma (seven glioblastomas and three anaplastic astrocytomas). High-performance liquid chromatography analysis of 32 tumor specimens for TCNU revealed that tissue concentrations ranged from 0 to 554 ng/gm; TCNU was not detected in necrotic regions of the tumor. Levels of TCNU in brain adjacent to tumor were similar to those recorded within the gliomas (range 0 to 635 ng/gm). The variability in the tissue level of TCNU was partly attributable to variable absorption of the drug, since peak plasma TCNU levels ranged from 164 to 3333 ng/ml. There were close quantitative and temporal relationships between the times of peak plasma levels (median 456 ng/ml at 45 minutes after administration), peak tumor levels (median 250 ng/gm tissue at 55 minutes), and brain adjacent to tumor levels (median 256 ng/gm tissue at 50 minutes). Linear regression analysis of the ratio between tissue and plasma TCNU levels at particular times after drug administration suggest that plasma concentrations can be used to estimate tissue concentrations. This study demonstrates that TCNU enters malignant glioma. In view of the activity of TCNU against a range of tumors, a full clinical evaluation of this new nitrosourea in malignant glioma seems justified.

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