Dose-dependent Synergistic Interactions of #Colistin with #Rifampicin, #Meropenem and #Tigecycline against #Carbapenem-resistant #Klebsiella pneumoniae #Biofilms (Antimicrob Agents Chemother., abstract)

[Source: Antimicrobial Agents and Chemotherapy, full page: (LINK). Abstract, edited.]

Dose-dependent Synergistic Interactions of Colistin with Rifampicin, Meropenem and Tigecycline against Carbapenem-resistant Klebsiella pneumoniae Biofilms

Anastasia Geladari, Maria Simitsopoulou, Charalampos Antachopoulos, Emmanuel Roilides

DOI: 10.1128/AAC.02357-18

 

ABSTRACT

Carbapenem-resistant Klebsiella pneumoniae (CR-Kp) can cause biofilm-related bloodstream infections associated with significant morbidity and mortality worldwide. We investigated the bactericidal activities of colistin (CST), rifampicin (RIF), meropenem (MEM), gentamicin (GEN) and tigecycline (TGC) alone and that of CST in combination with RIF, MEM, GEN or TGC against CR-Kp mature biofilms. Twenty CR-Kp blood isolates were derived from equal number of bloodstream infections in adult patients. Biofilm formation was assessed by staining with 0.4% crystal violet and measuring optical density spectrophotometrically at 545 nm. Biofilm damage was measured as % reduction of metabolic activity by XTT assay. MIC50 for biofilms was determined as the minimum concentration that caused ≥50% bacterial damage compared to that for untreated controls. Antibacterial drug interactions were analyzed by the Bliss independence model. Four of the twenty CR-Kp isolates were biofilm producers. Biofilm MIC50’s of CST, RIF, MEM, GEN and TGC for these isolates were 64, 8, >256, 128 and 8 mg/L, respectively. Synergistic interactions were observed at 32-64 mg/L of CST combined with 0.25-4 mg/L of RIF, at 32 mg/L of CST combined with 0.007-0.25 mg/L of MEM, and at 16-32 mg/L of CST combined with 16-64 mg/L of TGC. The synergy was highest for CST+RIF, with %ΔE±SE 49.87±9.22 compared to 29.52±4.97 for CST+MEM (p<0.001) and 32.44±6.49 for CST+TGC (p<0.001). Indifferent results were exhibited by CST+GEN. None of the combinations exhibited antagonism. These drug interactive findings, especially that of CST with RIF, may be of importance in the treatment of biofilm-related CR-Kp infections.

Copyright © 2019 American Society for Microbiology. All Rights Reserved.

Keywords: Antibiotics; Drugs Resistance; Carbapene; Klebsiella pneumoniae; Colistin; Gentamicin; Tigecycline; Meropenem; Rifampicin.

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Novel partners with #colistin to increase its in vivo therapeutic effectiveness and prevent the occurrence of colistin #resistance in #NDM- and #MCR-co-producing #Ecoli in a murine infection model (J Antimicrob Chemother., abstract)

[Source: Journal of Antimicrobial Chemotherapy, full page: (LINK). Abstract, edited.]

Novel partners with colistin to increase its in vivotherapeutic effectiveness and prevent the occurrence of colistin resistance in NDM- and MCR-co-producing Escherichia coli in a murine infection model

Yang Yu, Timothy R Walsh, Run-Shi Yang, Mei Zheng, Meng-Chao Wei, Jonathan M Tyrrell, Yang Wang, Xiao-Ping Liao, Jian Sun, Ya-Hong Liu

Journal of Antimicrobial Chemotherapy, dky413, https://doi.org/10.1093/jac/dky413

Published: 20 October 2018

 

Abstract

Objectives

The emergence of NDM- and MCR-1-co-producing Escherichia coli has compromised the use of carbapenems and colistin, which are critically important in clinical therapy, and represents a severe threat to public health worldwide. Here, we demonstrate synergism of colistin combined with existing antibiotics as a potential strategy to overcome XDR E. coli co-harbouring NDM and MCR-1 genes.

Methods

To comprehensively evaluate their combined activity, antibiotic combinations were tested against 34 different E. coli strains carrying both NDM and MCR-1 genes. Antibiotic resistance profiles and molecular characteristics were investigated by susceptibility testing, PCR, MLST, S1-PFGE and WGS. Antibiotic synergistic efficacy was evaluated through in vitro chequerboard experiments and dose–response assays. A mouse model was used to confirm active combination therapies. Additionally, combinations were tested for their ability to prevent high-level colistin-resistant mutants (HLCRMs).

Results

Combinations of colistin with rifampicin, rifabutin and minocycline showed synergistic activity against 34 XDR NDM- and MCR-1-co-producing E. coli strains, restoring, in part, susceptibility to both colistin and the partnering antibiotics. The therapeutic effectiveness of colistin combined with rifampicin or minocycline was demonstrated in a mouse model. Furthermore, colistin plus rifampicin showed significant activity in preventing the occurrence of HLCRMs.

Conclusions

The synergism of colistin in combinations with rifampicin, rifabutin or minocycline offers viable therapeutic alternatives against XDR NDM- and MCR-positive E. coli.

Issue Section: ORIGINAL RESEARCH

© The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.

This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)

Keywords: Research; Abstracts; Antibiotics; Drugs Resistance; Colistin; E. Coli; Rifampicin; Rifabutin; Minocycline; MCR; NDM.

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#Antibiotic susceptibility of #Legionella pneumophila strains isolated in #England and #Wales 2007–17 (J Antimicrob Chemother., abstract)

[Source: Journal of Antimicrobial Chemotherapy, full page: (LINK). Abstract, edited.]

Antibiotic susceptibility of Legionella pneumophilastrains isolated in England and Wales 2007–17

R E Wilson, R L R Hill, V J Chalker, M Mentasti, D Ready

Journal of Antimicrobial Chemotherapy, dky253, https://doi.org/10.1093/jac/dky253

Published: 24 July 2018

 

Abstract

Objectives

Antibiotic susceptibility of Legionella pneumophila is poorly understood, with treatment of Legionnaires’ disease often based on empirical choice. The aim of this study was to determine the antibiotic susceptibility of L. pneumophilastrains.

Methods

Antibiotic susceptibility of 92 L. pneumophila strains isolated in England and Wales between 2007 and 2017 was determined using a microbroth dilution methodology for each agent tested. MICs and MBCs were determined and compared with published intracellular concentrations of each agent tested.

Results

The MIC range of erythromycin was 0.06–1 mg/L, the MIC range of rifampicin was 0.0001 mg/L, the MIC range of ciprofloxacin was 0.004–0.25 mg/L and the MIC range of levofloxacin and moxifloxacin was 0.03–0.25 mg/L. The MBC range of erythromycin was 1–32 mg/L, but the MBC range of ciprofloxacin was the same as the MIC range. For levofloxacin and moxifloxacin the MBC range was elevated by one dilution and two dilutions, respectively. Typically, intracellular bronchial secretion concentrations of erythromycin might be expected to reach a suitable level to exceed the MIC range; however, 91 of 92 (98.9%) isolates had an MBC below the expected intracellular concentrations, which indicated erythromycin may have variable efficacy. MIC and MBC values of ciprofloxacin, levofloxacin and moxifloxacin were below achievable intracellular levels within bronchial secretions. Comparison of the MIC/MBC correlation showed very little clustering for erythromycin, but strong clustering for levofloxacin and to a lesser extent ciprofloxacin.

Conclusions

Use of the MIC/MBC linkage analysis seems an appropriate way forward for antimicrobial susceptibility testing and supports current guidance recommending levofloxacin for the treatment of Legionnaires’ disease.

Topic: antibiotics – rifampin – erythromycin – genetic linkage analysis – ciprofloxacin – bodily secretions – legionella pneumophila – legionnaires’ disease – country of wales – levofloxacin – moxifloxacin – antimicrobial susceptibility – antimicrobial susceptibility test – dilution technique – dilute (action) – malnutrition-inflammation-cachexia syndrome

Issue Section: ORIGINAL RESEARCH

© The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.

This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)

Keywords: Antibiotics; Drugs Resistance; Legionalla pneumophila; England; Wales; rifampin; erythromycin; ciprofloxacin; levofloxacin; moxifloxacin.

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#Prevalence of drug- #resistant #tuberculosis and imputed burden in #SouthAfrica: a national and sub-national cross-sectional survey (Lancet Infect Dis., abstract)

[Source: The Lancet Infectious Diseases, full page: (LINK). Abstract, edited.]

Prevalence of drug-resistant tuberculosis and imputed burden in South Africa: a national and sub-national cross-sectional survey

Nazir Ahmed Ismail, FCPath, Lindiwe Mvusi, MBChB, Ananta Nanoo, MSc, Andries Dreyer, FCPath, Shaheed V Omar, PhD, Sanni Babatunde, PhD, Thabo Molebatsi, MPH, Martie van der Walt, PhD, Adeboye Adelekan, PhD, Varough Deyde, PhD, Chikwe Ihekweazu, FFPH†, Prof Shabir A Madhi, PhD†

† Contributed equally

Published: 20 April 2018 / DOI: https://doi.org/10.1016/S1473-3099(18)30222-6

© 2018 Elsevier Ltd. All rights reserved.

 

Summary

Background

Globally, per-capita, South Africa reports a disproportionately high number of cases of multidrug-resistant (MDR) tuberculosis and extensively drug-resistant (XDR) tuberculosis. We sought to estimate the prevalence of resistance to tuberculosis drugs in newly diagnosed and retreated patients with tuberculosis provincially and nationally, and compared these with the 2001–02 estimates.

Methods

A cross-sectional survey was done between June 15, 2012–June 14, 2014, using population proportionate randomised cluster sampling in the nine provinces in South Africa. 343 clusters were included, ranging between 31 and 48 per province. A patient was eligible for inclusion in the survey if he or she presented as a presumptive case during the intake period at a drug resistance survey enrolling facility. Consenting participants (≥18 years old) completed a questionnaire and had a sputum sample tested for resistance to first-line and second-line drugs. Analysis was by logistic regression with robust SEs, inverse probability weighted against routine data, and estimates were derived using a random effects model.

Findings

101 422 participants were tested in 2012–14. Nationally, the prevalence of MDR tuberculosis was 2·1% (95% CI 1·5–2·7) among new tuberculosis cases and 4·6% (3·2–6·0) among retreatment cases. The provincial point prevalence of MDR tuberculosis ranged between 1·6% (95% CI 0·9–2·9) and 5·1% (3·7–7·0). Overall, the prevalence of rifampicin-resistant tuberculosis (4·6%, 95% CI 3·5–5·7) was higher than the prevalence of MDR tuberculosis (2·8%, 2·0–3·6; p=0·01). Comparing the current survey with the previous (2001–02) survey, the overall MDR tuberculosis prevalence was 2·8% versus 2·9% and prevalance of rifampicin-resistant tuberculosis was 3·4% versus 1·8%, respectively. The prevalence of isoniazid mono-resistant tuberculosis was above 5% in all provinces. The prevalence of ethionamide and pyrazinamide resistance among MDR tuberculosis cases was 44·7% (95% CI 25·9–63·6) and 59·1% (49·0–69·1), respectively. The prevalence of XDR tuberculosis was 4·9% (95% CI 1·0–8·8). Nationally, the estimated numbers of cases of rifampicin-resistant tuberculosis, MDR tuberculosis, and isoniazid mono-resistant tuberculosis for 2014 were 13 551, 8249, and 17 970, respectively.

Interpretation

The overall prevalence of MDR tuberculosis in South Africa in 2012–14 was similar to that in 2001–02; however, prevalence of rifampicin-resistant tuberculosis almost doubled among new cases. Furthermore, the high prevalence of isoniazid mono-resistant tuberculosis, not routinely screened for, and resistance to second-line drugs has implications for empirical management.

Funding

President’s Emergency Plan for AIDS Relief through the Centers for Disease Control and Prevention under the terms of 1U19GH000571.

Keywords: South Africa; Tuberculosis; Antibiotics; Drugs Resistance; MDR-TB; Rifampicin; Isoniazid.

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Increasing Prevalence of #Rifampicin-Resistant Mycobacterium #tuberculosis is Associated with the Transmission of Strains Harboring Compensatory Mutations in #China: A 10-year Comparative Analysis (AAC, abstract)

[Source: Antimicrobial Agents and Chemotherapy, full page: (LINK). Abstract, edited.]

Increasing Prevalence of Rifampicin-Resistant Mycobacterium tuberculosis is Associated with the Transmission of Strains Harboring Compensatory Mutations in China: A 10-year Comparative Analysis

Fengmin Huo1,  Jingjing Luo1,  Jin Shi2,  Zhaojing Zong1,  Wei Jing1, Wenzhu Dong1,  Lingling Dong1,  Yifeng Ma1,  Qian Liang1,  Yuanyuan Shang1, Hairong Huang1* and Yu Pang1*

Author Affiliations: 1 National Clinical Laboratory on Tuberculosis, Beijing Key laboratory on Drug-resistant Tuberculosis Research, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Institute, Beijing, China; 2 Beijing Key Laboratory for Pediatric Diseases of Otolaryngology, Head and Neck Surgery, Beijing Pediatric Research Institute, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing 100045, China

 

ABSTRACT

In this report, we conducted bacterial population profile studies to assess trends of rifampicin (RIF) resistance from 2005 to 2015 of Mycobacterium tuberculosis (MTB) isolates collected across China. A total of randomly selected 273 and 269 MTB isolates from 2005 and 2015, respectively, were analyzed. The rates of RIF resistance (36.4%), isoniazid resistance (39.0%), and levofloxacin resistance (25.7%) in 2015 were significantly higher than in 2005 (28.2%, 30.0%, and 15.4%, respectively; P < 0.05). Genotypic data revealed 256 (95.2%) Beijing-type isolates in 2015, a rate significantly higher than that of 2005 (86.4%) (P < 0.01). A higher proportion of mutations were identified within the rifampin resistance determining region (RRDR) of rpoB in isolates from 2015 (99.0%) than in 2005 isolates (85.7%, P< 0.01). In addition, a significantly higher proportion of RIF-resistant isolates carrying compensatory mutations were observed in 2015 (31.6%) than in 2005 (7.8%). Notably, the great majority of these compensatory mutations (91.9%) were observed in isolates that harbored a mutation of codon 531 of the rpoB gene. In conclusion, our data demonstrate that resistance to RIF, isoniazid, and levofloxacin has become significantly more prevalent during the past decade. In addition, the prevalence of the Beijing genotype significantly increased from 2005 to 2015. Notably, a significantly increased frequency of strains with mutations in rpoC or rpoA is observed in those that have codon 531 mutations suggests that they may be compensatory, and may play a role in facilitating transmission.

 

FOOTNOTES

*Corresponding author. Mailing address for Yu Pang: Beijing Chest Hospital, Capital Medical University, No. 97, Machang, Tongzhou District, Beijing, 101149, China. Phone: 86 10 8950 9359. Fax: 86 10 8950 9359. E-mail: pangyupound@163.com.

*Mailing address for Hairong Huang: Beijing Chest Hospital, Capital Medical University, No. 97, Machang, Tongzhou District, Beijing, 101149, China. Phone: 86 10 8950 9359. Fax: 86 10 8950 9359. E-mail: huanghairong@tb123.org.

Copyright © 2018 American Society for Microbiology. All Rights Reserved.

Keywords: Antibiotics; Drugs Resistance; Tuberculosis; China; Rifampicin.

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#Vitamin C potentiates the killing of #Mycobacterium tuberculosis by the first-line #tuberculosis drugs #isoniazid and #rifampicin in mice (J Antimicrob Chemother., abstract)

[Source: Antimicrobial Agents and Chemotherapy, full page: (LINK). Abstract, edited.]

Vitamin C potentiates the killing of Mycobacterium tuberculosis by the first-line tuberculosis drugs isoniazid and rifampicin in mice

Catherine Vilchèze,  John Kim and  William R. Jacobs Jr*

Author Affiliations: Howard Hughes Medical Institute, Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA

 

ABSTRACT

The treatment of drug-susceptible tuberculosis (TB) is long and cumbersome. Mismanagement of TB treatment can lead to the emergence of drug resistance in patients, so shortening the treatment duration could significantly improve TB chemotherapy and prevent the development of drug resistance. We had previously discovered that high concentrations of vitamin C sterilize cultures of drug-susceptible and drug-resistant Mycobacterium tuberculosis. Here, we tested sub-inhibitory concentration of vitamin C in combination with TB drugs against M. tuberculosis in vitro and in a mouse model of M. tuberculosis infection. In vivo, we showed that vitamin C level in mouse serum can be increased by intraperitoneal injection of vitamin C to reach vitamin C levels close to the concentrations required for activity in vitro. Although vitamin C had no activity by itself in M. tuberculosis-infected mice, the combination of vitamin C with the first-line TB drugs isoniazid and rifampicin reduced the bacterial burden in the lungs of M. tuberculosis-infected mice faster than isoniazid and rifampicin combined in two independent experiments. These experiments suggest that the addition of vitamin C to first-line TB drugs could shorten TB treatment. Vitamin C, an inexpensive and non-toxic compound, could be easily added to the TB pharmacopeia to substantially improve chemotherapy outcome, which would have a significant impact on the worldwide TB community.

 

FOOTNOTES

*Corresponding author. Tel: (718) 678-1075; Fax: (718) 678-1085; E-mail: jacobsw@hhmi.org

Copyright © 2018 American Society for Microbiology. All Rights Reserved.

Keywords: Tuberculosis; Antibiotics; Vitamic C; Isoniazid; Rifampicin.

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Adjunctive #rifampicin for #Staphylococcus aureus #bacteraemia (ARREST): a multicentre, randomised, double-blind, placebo-controlled trial (Lancet, abstract)

[Source: The Lancet, full page: (LINK). Abstract, edited.]

Adjunctive rifampicin for Staphylococcus aureus bacteraemia (ARREST): a multicentre, randomised, double-blind, placebo-controlled trial

Prof Guy E Thwaites, FRCP, Matthew Scarborough, PhD, Alexander Szubert, MSc, Emmanuel Nsutebu, FRCP, Robert Tilley, MBChB, Julia Greig, FRCP, Sarah A Wyllie, FRCPath, Prof Peter Wilson, MD, Cressida Auckland, FRCPath, Janet Cairns, MSc, Denise Ward, BSc, Pankaj Lal, MD, Achyut Guleri, MD, Neil Jenkins, PhD, Julian Sutton, MD, Prof Martin Wiselka, FRCP, Gonzalez-Ruiz Armando, MD, Clive Graham, MD, Paul R Chadwick, FRCPath, Gavin Barlow, FRCP, N Claire Gordon, FRCPath, Bernadette Young, MBBS, Sarah Meisner, FRCPath, Paul McWhinney, MD, David A Price, MD, David Harvey, MD, Deepa Nayar, MD, Dakshika Jeyaratnam, MD, Tim Planche, FRCP, Jane Minton, MD, Fleur Hudson, MSc, Susan Hopkins, MD, John Williams, MD, M Estee Török, MD, Prof Martin J Llewelyn, PhD, Prof Jonathan D Edgeworth, FRCPath, Prof A Sarah Walker, PhD on behalf of the United Kingdom Clinical Infection Research Group (UKCIRG)†

†See appendix for full list of investigators

Open Access  / DOI: http://dx.doi.org/10.1016/S0140-6736(17)32456-X

© 2017 The Author(s). Published by Elsevier Ltd.

 

Summary

Background

Staphylococcus aureus bacteraemia is a common cause of severe community-acquired and hospital-acquired infection worldwide. We tested the hypothesis that adjunctive rifampicin would reduce bacteriologically confirmed treatment failure or disease recurrence, or death, by enhancing early S aureus killing, sterilising infected foci and blood faster, and reducing risks of dissemination and metastatic infection.

Methods

In this multicentre, randomised, double-blind, placebo-controlled trial, adults (≥18 years) with S aureus bacteraemia who had received ≤96 h of active antibiotic therapy were recruited from 29 UK hospitals. Patients were randomly assigned (1:1) via a computer-generated sequential randomisation list to receive 2 weeks of adjunctive rifampicin (600 mg or 900 mg per day according to weight, oral or intravenous) versus identical placebo, together with standard antibiotic therapy. Randomisation was stratified by centre. Patients, investigators, and those caring for the patients were masked to group allocation. The primary outcome was time to bacteriologically confirmed treatment failure or disease recurrence, or death (all-cause), from randomisation to 12 weeks, adjudicated by an independent review committee masked to the treatment. Analysis was intention to treat. This trial was registered, number ISRCTN37666216, and is closed to new participants.

Findings

Between Dec 10, 2012, and Oct 25, 2016, 758 eligible participants were randomly assigned: 370 to rifampicin and 388 to placebo. 485 (64%) participants had community-acquired S aureus infections, and 132 (17%) had nosocomial S aureus infections. 47 (6%) had meticillin-resistant infections. 301 (40%) participants had an initial deep infection focus. Standard antibiotics were given for 29 (IQR 18–45) days; 619 (82%) participants received flucloxacillin. By week 12, 62 (17%) of participants who received rifampicin versus 71 (18%) who received placebo experienced treatment failure or disease recurrence, or died (absolute risk difference −1·4%, 95% CI −7·0 to 4·3; hazard ratio 0·96, 0·68–1·35, p=0·81). From randomisation to 12 weeks, no evidence of differences in serious (p=0·17) or grade 3–4 (p=0·36) adverse events were observed; however, 63 (17%) participants in the rifampicin group versus 39 (10%) in the placebo group had antibiotic or trial drug-modifying adverse events (p=0·004), and 24 (6%) versus six (2%) had drug interactions (p=0·0005).

Interpretation

Adjunctive rifampicin provided no overall benefit over standard antibiotic therapy in adults with S aureus bacteraemia.

Funding

UK National Institute for Health Research Health Technology Assessment.

Keywords: Rifampicin; Antibiotics; Staphylococcus Aureus; Bacteremia.

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