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ABSTRACT: A key issue in the treatment of disease caused by slow-growing nontuberculous mycobacteria is the limited association between in vitro minimum inhibitory concentrations (MICs) of rifampicin and ethambutol alone and the in vivo outcome of treatment with these drugs. Combined susceptibility testing to rifampicin and ethambutol could provide a more realistic view of the efficacy of these drugs. In this study, Mycobacterium avium (n=5), Mycobacterium chimaera (n=6), Mycobacterium intracellulare (n=4), Mycobacterium xenopi (n=4), Mycobacterium malmoense (n=3) and Mycobacterium simiae (n=2) clinical isolates were selected and the MICs of rifampicin and ethambutol alone and in combination were measured using the Middlebrook 7H10 agar dilution method. Synergy was defined as a fractional inhibitory concentration index ≤0.5. Rifampicin and ethambutol showed synergistic activity against the majority of M. avium (4/5), M. chimaera (5/6) and M. intracellulare (3/4) isolates and 1 of 2 eligible M. malmoense isolates. No synergistic activity was measured against M. xenopi and M. simiae. Synergy was neither universal for all species nor for all isolates of one species; it thus needs to be tested for rather than assumed. Even if this synergy exists in vivo, it is questionable whether the MICs to the combined drugs can be overcome by the drug exposure attained by current regimens at the recommended dosages. New dosing strategies for rifampicin and ethambutol should be studied to increase the exposure to these drugs and thus maximise their impact.
International journal of antimicrobial agents 05/2013; · 3.03 Impact Factor
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ABSTRACT: Introduction: East Africa has a high tuberculosis (TB) incidence and mortality, yet there is very limited data on exposure to TB drug in patients from this region. We therefore determined the pharmacokinetic characteristics of firstline TB drugs in Tanzanian patients using intensive pharmacokinetic sampling.Methods: In twenty adult TB patients, plasma concentrations were determined just before and at 1, 2, 3, 4, 6, 8, 10 and 24 hours after observed drug intake with food to estimate the area under the curve (AUC0-24h) and peak plasma concentrations (Cmax) of isoniazid, rifampicin, pyrazinamide and ethambutol. Acetylator status for isoniazid was assessed phenotypically using the isoniazid elimination half-life and the acetylisoniazid/isoniazid metabolic ratio at 3 hours post dose.Results: The geometric mean AUC0-24h of isoniazid was 11.0 h*mg/L, rifampicin 39.9 h*mg/L, pyrazinamide 344 h*mg/L and ethambutol 20.2 h*mg/L. Cmax was below the reference range for isoniazid in 10/19 patients and for rifampicin in 7/20 patients. In none of the patients, the Cmax values for pyrazinamide and ethambutol were below the reference range. Elimination half-life and metabolic ratio of isoniazid gave discordant phenotyping results in only 2/19 patients.Discussion: A substantial proportion of patients had an isoniazid and/or rifampicin Cmax below the reference range. Intake of TB drugs with food may partly explain these low drug levels, but such drug intake reflects common practice. The finding of low TB drug concentrations is concerning because low concentrations have been associated with worse treatment outcome in several other studies.
Antimicrobial Agents and Chemotherapy 04/2013; · 4.84 Impact Factor
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ABSTRACT: RATIONALE: The dosage of 10 mg/kg/day rifampin, as currently used in the treatment of tuberculosis (TB), is not an optimal dose. Shortening of treatment duration might be achievable using an increased rifampin dose. OBJECTIVES: Determination of optimal rifampin dosage in mice, resulting in maximum therapeutic effect and without adverse effects. Assessment of associated pharmacokinetic (PK) parameters and pharmacokinetic/pharmacodynamic (PK/PD) indices. METHODS: A murine TB infection using a Beijing genotype Mycobacterium tuberculosis strain was established by intratracheal bacterial instillation followed by proper inhalation, while keeping mice in a vertical position. We assessed dose-dependent activity of rifampin in single-drug treatment during 3 weeks. Also the maximum tolerated dosage (MTD), PK parameters and PK/PD index were determined. Secondly, therapeutic efficacy of a range of rifampin (R) dosages added to a regimen of isoniazid (H) and pyrazinamide (Z) was assessed. MEASUREMENTS AND MAIN RESULTS: MTD of rifampin in the murine TB was 160 mg/kg/day. PK measurement in HR(10)Z and HR(160)Z therapy regimens showed for rifampin a Cmax of 16.2 and 157.3 mg/L, an AUC0-24h of 132 and 1782 h*mg/L and AUC0-24h /MIC ratios of 528 and 7129, respectively. A clear dose-effect correlation was observed for rifampin after 3-weeks single-drug treatment. Administration of HR(80)Z allowed 9-week treatment duration to be effective without relapse of infection. CONCLUSION: Our findings indicate that the currently used rifampin dosage in the therapy of TB is too low. In our murine TB model a rifampin dosage of 80 mg/kg/day enabled a significant reduction in therapy duration without adverse effects.
American Journal of Respiratory and Critical Care Medicine 03/2013; · 11.08 Impact Factor
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Sami O. Simons,
Jette E. Kristiansen,
Gyorgy Hajos,
Tridia van der Laan,
József Molnár, Martin J. Boeree,
Jakko van Ingen,
Jørn B. Christensen,
Miguel Viveiros,
Zsuzsanna Riedl,
Leonard Amaral,
Dick van Soolingen
Iinternational Journal Antmicrobial Agents. 02/2013; 41(In Press).
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Sami O Simons,
Jette E Kristiansen,
Gyorgy Hajos,
Tridia van der Laan,
József Molnár, Martin J Boeree,
Jakko van Ingen,
Jørn B Christensen,
Miguel Viveiros,
Zsuzsanna Riedl,
Leonard Amaral,
Dick van Soolingen
International journal of antimicrobial agents 02/2013; · 3.03 Impact Factor
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The Journal of infection 01/2013; · 4.13 Impact Factor
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Journal of clinical microbiology 01/2013; 51(1):382. · 4.16 Impact Factor
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European Respiratory Journal 12/2012; 40(6):1576-8. · 5.89 Impact Factor
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Hadija H Semvua,
Charles M Mtabho,
Quirine Fillekes,
Jossy van den Boogaard,
Riziki M Kisonga,
Liberate Mleoh,
Arnold Ndaro,
Elton R Kisanga,
Andre van der Ven,
Rob E Aarnoutse,
Gibson S Kibiki, Martin J Boeree,
David M Burger
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ABSTRACT: OBJECTIVES: To evaluate the effect of rifampicin based tuberculosis (TB) treatment on the pharmacokinetics of efavirenz/tenofovir/emtricitabine in a fixed-dose combination tablet, and vice versa, in Tanzanian TB/HIV co-infected patients. DESIGN: Phase II, open label, multiple doses, pharmacokinetic and safety study. METHODS: This study was conducted in TB/HIV co-infected Tanzanian patients who started TB treatment (rifampicin/isoniazid/pyrazinamide/ethambutol) at week 1 to week 8 and continued with rifampicin and isoniazid for another 16 weeks. Antiretroviral treatment (ART) of efavirenz/tenofovir/emtricitabine in a fixed dose combination tablet was started at week 4 after initiation of TB treatment. A 24-hour pharmacokinetic sampling curve was recorded at week 8 (with TB treatment) and week 28 (ART alone). For TB drugs, blood samples at two and six hours post-dose were taken at week 3 (TB treatment alone) and week 8 (with ART). RESULTS: Twenty-five patients (56% male) completed the study, twenty-one had evaluable pharmacokinetic profiles. The area under the curve AUC(0-24h) of efavirenz, tenofovir and emtricitabine were slightly higher when these drugs were co-administered with TB drugs: geometric mean ratios (90%CI) were 1.08 (0.90-1.30), 1.13 (0.93-1.38) and 1.05 (0.85-1.29) respectively. For TB drugs, equivalence was suggested for peak plasma concentrations when administered with and without efavirenz/tenofovir/emtricitabine. Adverse events were mostly mild and no SAEs or drug discontinuations were reported. CONCLUSION: Co-administration of efavirenz, tenofovir and emtricitabine with a standard first line TB treatment regimen did not significantly alter the pharmacokinetic parameters of these drugs and was tolerated well by Tanzanian TB patients who are co-infected with HIV.
Antiviral therapy 10/2012; · 3.16 Impact Factor
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ABSTRACT: Disease caused by nontuberculous mycobacteria (NTM) is increasing in frequency. The outcome of treatment for NTM lung disease is poor, particularly lung disease caused by Mycobacterium simiae and M. abscessus. Exploring synergy between active available drugs is a sensible way forward given the lack of new active drugs.We tested for synergy between amikacin and clofazimine in 564 consecutive clinical isolates identified as 21 species of rapidly growing mycobacteria, 16 clinical M. avium complex isolates and 10 M. simiae isolates, using standardized methods.Clofazimine and amikacin are active in vitro against NTM alone; 97% (n=548) of the rapid growers revealed MICs of clofazimine ≤1 μg/ml, 93% (n=524) proved susceptible to amikacin. The combination showed significant synergistic activity in 56 of 68 (82%) eligible M. abscessus isolates, 4 of 5 M. chelonae isolates and 1 M. fortuitum and 1 M. cosmeticum isolate, with 4-8 fold decreases in MICs to both drugs. Significant synergy could also be demonstrated against all M. avium complex and M. simiae isolates, with FICs <0.5.Clofazimine and amikacin show significant synergistic activity against both rapid and slow growing nontuberculous mycobacteria. The safety and tolerability of adding clofazimine to amikacin-containing regimens should be tested in clinical trials and the results of susceptibility tests to these two compounds and their combination merit clinical validation. Synergy between clofazimine and other antibiotics with intracellular targets should be explored.
Antimicrobial Agents and Chemotherapy 10/2012; · 4.84 Impact Factor
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ABSTRACT: Despite great effort by health organizations worldwide in fighting tuberculosis (TB), morbidity and mortality are not declining as expected. One of the reasons is related to the evolutionary development of Mycobacterium tuberculosis, in particular the Beijing genotype strains. In a previous study, we showed the association between the Beijing genotype and an increased mutation frequency for rifampin resistance. In this study, we use a Beijing genotype strain and an East-African/Indian genotype strain to investigate with our mouse TB model whether the higher mutation frequency observed in a Beijing genotype strain is associated with treatment failure particularly during noncompliance therapy. Both genotype strains showed high virulence in comparison to that of M. tuberculosis strain H37Rv, resulting in a highly progressive infection with a rapid lethal outcome in untreated mice. Compliance treatment was effective without relapse of TB irrespective of the infecting strain, showing similar decreases in the mycobacterial load in infected organs and similar histopathological changes. Noncompliance treatment, simulated by a reduced duration and dosing frequency, resulted in a relapse of infection. Relapse rates were correlated with the level of noncompliance and were identical for Beijing infection and East African/Indian infection. However, only in Beijing-infected mice, isoniazid-resistant mutants were selected at the highest level of noncompliance. This is in line with the substantial selection of isoniazid-resistant mutants in vitro in a wide isoniazid concentration window observed for the Beijing strain and not for the EAI strain. These results suggest that genotype diversity of M. tuberculosis may be involved in emergence of resistance and indicates that genotype-tailor-made treatment should be investigated.
Antimicrobial Agents and Chemotherapy 07/2012; 56(9):4937-44. · 4.84 Impact Factor
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ABSTRACT: Rationale: Currently recommended multidrug treatment regimens for Mycobacterium avium complex (MAC) lung disease yield limited cure rates. This results, in part, from incomplete understanding of the pharmacokinetics and pharmacodynamics of the drugs. Objectives: To study pharmacokinetics, pharmacodynamics, and drug interactions of multidrug treatment regimens in a large cohort of patients with MAC lung disease. Methods: We retrospectively collected pharmacokinetic data of all patients treated for MAC lung disease in the Adult Care Unit at National Jewish Health, Denver, Colorado, in the January 2006 to January 2010 period; we retrospectively calculated areas under the time-concentration curve (AUC). Minimum inhibitory concentrations (MIC) of their MAC isolates were retrieved for pharmacodynamic calculations. Measurements and Main Results: We included 531 pharmacokinetic analyses, performed for 481 patients (84% females; mean age, 63 yr; mean body mass index, 21.6). Peak serum concentrations (C(max)) below target range were frequent for ethambutol (48% of patients); clarithromycin (56%); and azithromycin (35%). Concurrent administration of rifampicin led to 68%, 23%, and 10% decreases in C(max) of clarithromycin, azithromycin, and moxifloxacin. C(max)/MIC or AUC/MIC ratios associated with bactericidal activity were seldom met; 57% of patients achieved target ratios for ethambutol, versus 42% for clarithromycin, 19% for amikacin, 18% for rifampicin, and 11% for moxifloxacin. Conclusions: Currently recommended regimens for MAC lung disease yield important pharmacologic interactions and low concentrations of key drugs including macrolides. Pharmacodynamic indices for rifampicin, clarithromycin, amikacin, and moxifloxacin are seldom met. This may partly explain the poor outcomes of currently recommended treatment regimens. Trials of new drugs and new dosing strategies are needed.
American Journal of Respiratory and Critical Care Medicine 06/2012; 186(6):559-65. · 11.08 Impact Factor
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ABSTRACT: In this study, nonchromogenic mycobacteria were isolated from pulmonary samples of three patients in the Netherlands. All isolates had identical, unique 16S rRNA gene and 16S-23S ITS sequences, which were closely related to those of Mycobacterium chimaera and Mycobacterium marseillense. The biochemical features of the isolates differed slightly from those of M. chimaera, suggesting that the isolates may represent a possible separate species within the Mycobacterium avium complex (MAC). However, the cell-wall mycolic acid pattern, analysed by HPLC, and the partial sequences of the hsp65 and rpoB genes were identical to those of M. chimaera. We concluded that the isolates represent a novel variant of M. chimaera. The results of this analysis have led us to question the currently used methods of species definition for members of the genus Mycobacterium, which are based largely on 16S rRNA or rpoB gene sequencing. Definitions based on a single genetic target are likely to be insufficient. Genetic divergence, especially in the MAC, yields strains that cannot be confidently assigned to a specific species based on the analysis of a single genetic target.
Journal of Medical Microbiology 06/2012; 61(Pt 9):1234-9. · 2.50 Impact Factor
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ABSTRACT: Nontuberculous mycobacteria (NTM) are increasingly recognized as causative agents of opportunistic infections in humans. For most NTM infections the therapy of choice is drug treatment, but treatment regimens differ by species, in particular between slow (e.g. Mycobacterium avium complex, Mycobacterium kansasii) and rapid growers (e.g. Mycobacterium abscessus, Mycobacterium fortuitum). In general, drug treatment is long, costly, and often associated with drug-related toxicities; outcome of drug treatment is poor and is likely related to the high levels of natural antibiotic resistance in NTM. The role of drug susceptibility testing (DST) in the choice of agents for antimicrobial treatment of NTM disease, mainly that by slow growers, remains subject of debate. There are important discrepancies between drug susceptibility measured in vitro and the activity of the drug observed in vivo. In part, these discrepancies derive from laboratory technical issues. There is still no consensus on a standardized method. With the increasing clinical importance of NTM disease, DST of NTM is again in the spotlight. This review provides a comprehensive overview of the mechanisms of drug resistance in NTM, phenotypic methods for testing susceptibility in past and current use for DST of NTM, as well as molecular approaches to assess drug resistance.
Drug resistance updates: reviews and commentaries in antimicrobial and anticancer chemotherapy 04/2012; 15(3):149-61. · 12.58 Impact Factor
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ABSTRACT: The oryx bacilli are Mycobacterium tuberculosis complex organisms for which phylogenetic position and host range are unsettled. We characterized 22 isolates by molecular methods and propose elevation to subspecies status as M. orygis. M. orygis is a causative agent of tuberculosis in animals and humans from Africa and South Asia.
Emerging Infectious Diseases 04/2012; 18(4):653-5. · 6.79 Impact Factor
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ABSTRACT: To determine differences in the ability of Mycobacterium tuberculosis strains to withstand antituberculosis drug treatment, we compared the activity of antituberculosis drugs against susceptible Beijing and East-African/Indian genotype M. tuberculosis strains. Beijing genotype strains showed high rates of mutation within a wide range of drug concentrations, possibly explaining this genotype's association with multidrug-resistant tuberculosis.
Emerging Infectious Diseases 04/2012; 18(4):660-3. · 6.79 Impact Factor
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ABSTRACT: Pyrazinamide is important in the treatment of tuberculosis. Unfortunately, the diagnosis of pyrazinamide resistance is hampered by technical difficulties. We hypothesized that mutation analysis combined with the mycobacterial growth indicator tube (MGIT) phenotypic method would be a good predictor of pyrazinamide resistance. We prospectively analyzed 1,650 M. tuberculosis isolates referred to our tuberculosis reference laboratory in 2008 and 2009. In our laboratory, the MGIT 960 system was used for pyrazinamide resistance screening. If a pyrazinamide-resistant strain was detected, we performed a pncA gene mutation analysis. A second MGIT 960 susceptibility assay was performed afterwards to evaluate the accuracy of the pncA mutation analysis to detect true- or false-positive MGIT results. We observed pyrazinamide resistance in 69 samples using the first MGIT 960 analysis. In a second MGIT 960 analysis, 47 of the 69 samples proved susceptible (68% false positivity). Sensitivity of nonsynonymous pncA mutations for detecting resistant isolates was 73% (95% confidence interval [CI], 61% to 73%), and specificity was 100% (95% CI, 95% to 100%). A diagnostic algorithm incorporating phenotypic and molecular methods would have a 100% positive predictive value for detecting pyrazinamide-resistant isolates, indicating that such an algorithm, based on both methods, is a good predictor for pyrazinamide resistance in routine diagnostics.
Journal of clinical microbiology 11/2011; 50(2):428-34. · 4.16 Impact Factor
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ABSTRACT: The Mycobacterium simiae complex bacteria can cause opportunistic infections in humans. In the case of definite disease, there are no evidence-based treatment regimens and outcomes are very disappointing. To increase the evidence base underpinning treatment regimens for M. simiae complex disease, drug susceptibility patterns and rifampicin/ethambutol synergy were assessed retrospectively in 69 clinical M. simiae complex isolates from 60 patients (22 patients with M. simiae, 24 with Mycobacterium lentiflavum, 8 with Mycobacterium triplex, 5 with Mycobacterium parascrofulaceum and 1 with Mycobacterium stomatepiae) submitted to the mycobacteriology laboratory at National Jewish Health (Denver, CO). Quantitative drug susceptibility testing (DST) was performed using the radiometric BacTec 460 macrodilution method. Results were related to pharmacokinetic (PK) measurements, where available. All M. simiae complex species proved susceptible to clarithromycin and, to a lesser extent, rifabutin, clofazimine, streptomycin and moxifloxacin. Synergy or additive action between rifampicin and ethambutol was observed for all species except M. simiae. Mycobacterium simiae is poorly susceptible in vitro to rifampicin and ethambutol alone as well as in combination; PK measurements support the limited efficacy of these drugs against M. simiae. The triple-drug regimen of a rifamycin, ethambutol and a macrolide may be advised to treat disease caused by M. lentiflavum, M. triplex, M. parascrofulaceum and M. stomatepiae; for M. simiae, this regimen appears less active. These findings may partly explain the limited treatment results in M. simiae disease. A treatment regimen including a macrolide, moxifloxacin and one or two additional drugs based on DST results may be advisable; clofazimine and amikacin or streptomycin are potential candidates.
International journal of antimicrobial agents 11/2011; 39(2):173-6. · 3.03 Impact Factor
