Combination of #Azithromycin and #Gentamicin for Efficient #Treatment of #Pseudomonas aeruginosa Infections (J Infect Dis., abstract)

[Source: Journal of Infectious Diseases, full page. (LINK). Abstract, edited.]

Combination of Azithromycin and Gentamicin for Efficient Treatment of Pseudomonas aeruginosa Infections

Huan Ren, Yiwei Liu, Jingyi Zhou, Yuqing Long, Chang Liu, Bin Xia, Jing Shi, Zheng Fan,Yuying Liang, Shuiping Chen, Jun Xu, Penghua Wang, Yanhong Zhang, Guangbo Zhu,Huimin Liu, Yongxin Jin, Fang Bai, Zhihui Cheng, Shouguang Jin, Weihui Wu

The Journal of Infectious Diseases, jiz341, https://doi.org/10.1093/infdis/jiz341

Published: 16 August 2019

 

Abstract

Background

Trans-translation is a ribosome rescue system that plays an important role in bacterial tolerance to environmental stresses. It is absent in animals, making it a potential treatment target. However, its role in antibiotic tolerance in Pseudomonas aeruginosa remains unknown.

Methods

The role and activity of trans-translation during antibiotic treatment were examined with a trans-translation–deficient strain and a genetically modified trans-translation component gene, respectively. In vitro assays and murine infection models were used to examine the effects of suppression of trans-translation.

Results

We found that the trans-translation system plays an essential role in P. aeruginosa tolerance to azithromycin and multiple aminoglycoside antibiotics. We further demonstrated that gentamicin could suppress the azithromycin-induced activation of trans-translation. Compared with each antibiotic individually, gentamicin and azithromycin combined increased the killing efficacy against planktonic and biofilm-associated P. aeruginosa cells, including a reference strain PA14 and its isogenic carbapenem-resistance oprD mutant, the mucoid strain FRD1, and multiple clinical isolates. Furthermore, the gentamicin-azithromycin resulted in improved bacterial clearance in murine acute pneumonia, biofilm implant, and cutaneous abscess infection models.

Conclusions

Combination treatment with gentamicin and azithromycin is a promising strategy in combating P. aeruginosa infections.

Pseudomonas aeruginosa, trans-translation, azithromycin, antibiotic combination

Topic: antibiotics – pseudomonas aeruginosa – gentamicin sulfate (usp) – azithromycin – biofilms – gentamicins – infection – killing

Issue Section: Major Article

© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: 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: Antibiotics; Drugs Resistance; Aminoglycosides; Gentamicin; Azithromycin; Pseudomonas aeruginosa; Biofilm.

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A selective #membrane-targeting #repurposed #antibiotic with activity against persistent #MRSA (Proc Natl Acad Sci USA, abstract)

[Source: Proceedings of the National Academy of Sciences of the United States of America, full page: (LINK). Abstract, edited.]

A selective membrane-targeting repurposed antibiotic with activity against persistent methicillin-resistant Staphylococcus aureus

Wooseong Kim, Guijin Zou, Taylor P. A. Hari, Ingrid K. Wilt, Wenpeng Zhu, Nicolas Galle, Hammad A. Faizi, Gabriel L. Hendricks, Katerina Tori, Wen Pan, Xiaowen Huang, Andrew D. Steele, Erika E. Csatary, Madeline M. Dekarske, Jake L. Rosen, Noelly de Queiroz Ribeiro, Kiho Lee, Jenna Port, Beth Burgwyn Fuchs, Petia M. Vlahovska, William M. Wuest, Huajian Gao, Frederick M. Ausubel, and Eleftherios Mylonakis

PNAS first published July 29, 2019 / DOI: https://doi.org/10.1073/pnas.1904700116

Contributed by Frederick M. Ausubel, June 17, 2019 (sent for review March 22, 2019; reviewed by Dale L. Boger and Ruhong Zhou)

 

Significance

There is a critical lack of therapeutic agents to treat infections caused by nongrowing persister forms of methicillin-resistant Staphylococcus aureus (MRSA). Although membrane-disrupting agents can kill persister cells, their therapeutic potential has been mostly overlooked because of low selectivity for bacterial versus mammalian membranes. We report that the clinically approved anthelmintic drug bithionol kills MRSA persisters by disrupting membrane lipid bilayers at concentrations that exhibit low levels of toxicity to mammalian cells. The selectivity of bithionol results from the presence of cholesterol in mammalian but not in bacterial membranes. We also show that the antipersister potency of membrane-active antimicrobial agents correlates with their ability to increase membrane fluidity. Our results significantly enhance our understanding of bacterial membrane disruption and membrane selectivity.

 

Abstract

Treatment of Staphylococcus aureus infections is complicated by the development of antibiotic tolerance, a consequence of the ability of S. aureus to enter into a nongrowing, dormant state in which the organisms are referred to as persisters. We report that the clinically approved anthelmintic agent bithionol kills methicillin-resistant S. aureus (MRSA) persister cells, which correlates with its ability to disrupt the integrity of Gram-positive bacterial membranes. Critically, bithionol exhibits significant selectivity for bacterial compared with mammalian cell membranes. All-atom molecular dynamics (MD) simulations demonstrate that the selectivity of bithionol for bacterial membranes correlates with its ability to penetrate and embed in bacterial-mimic lipid bilayers, but not in cholesterol-rich mammalian-mimic lipid bilayers. In addition to causing rapid membrane permeabilization, the insertion of bithionol increases membrane fluidity. By using bithionol and nTZDpa (another membrane-active antimicrobial agent), as well as analogs of these compounds, we show that the activity of membrane-active compounds against MRSA persisters positively correlates with their ability to increase membrane fluidity, thereby establishing an accurate biophysical indicator for estimating antipersister potency. Finally, we demonstrate that, in combination with gentamicin, bithionol effectively reduces bacterial burdens in a mouse model of chronic deep-seated MRSA infection. This work highlights the potential repurposing of bithionol as an antipersister therapeutic agent.

MRSA – bacterial persister – drug repurposing – membrane-active antimicrobials – membrane selectivity

 

Footnotes

1 To whom correspondence may be addressed. Email: ausubel@molbio.mgh.harvard.edu or emylonakis@lifespan.org.

Author contributions: W.K., G.Z., T.P.A.H., I.K.W., W.Z., N.G., H.A.F., G.L.H., W.M.W., H.G., F.M.A., and E.M. designed research; W.K., G.Z., T.P.A.H., I.K.W., W.Z., N.G., H.A.F., G.L.H., K.T., W.P., X.H., N.d.Q.R., K.L., J.P., and B.B.F. performed research; T.P.A.H., I.K.W., A.D.S., E.E.C., M.M.D., J.L.R., B.B.F., P.M.V., W.M.W., H.G., F.M.A., and E.M. contributed new reagents/analytic tools; W.K., G.Z., T.P.A.H., I.K.W., W.Z., N.G., H.A.F., G.L.H., P.M.V., W.M.W., H.G., F.M.A., and E.M. analyzed data; and W.K., G.Z., W.M.W., H.G., F.M.A., and E.M. wrote the paper.

Reviewers: D.L.B., The Scripps Research Institute; and R.Z., Columbia University.

Conflict of interest statement: F.M.A. and E.M. have financial interests in Genma Biosciences and Octagon Therapeutics, companies that are engaged in developing antimicrobial compounds. E.M.’s and F.M.A.’s interests were reviewed and are managed by Rhode Island Hospital (E.M.) and Massachusetts General Hospital and Partners HealthCare (F.M.A.) in accordance with their conflict of interest policies. The remaining authors declare no competing financial interests.

This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1904700116/-/DCSupplemental.

Published under the PNAS license.

Keywords: Antibiotics; Drugs Resistance; Staphylococcus aureus; MRSA; Bithionol; Gentamicin.

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#Gentamicin compared with #ceftriaxone for the #treatment of #gonorrhoea (G-ToG): a randomised non-inferiority trial (Lancet, abstract)

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

Gentamicin compared with ceftriaxone for the treatment of gonorrhoea (G-ToG): a randomised non-inferiority trial

Prof Jonathan D C Ross, MD, Clare Brittain, BMedSc, Michelle Cole, DBMS, Claire Dewsnap, MD, Jan Harding, PhD, Trish Hepburn, BSc, Louise Jackson, PhD, Matthew Keogh, Tessa Lawrence, PhD, Prof Alan A Montgomery, PhD, Prof Tracy E Roberts, PhD, Kirsty Sprange, MSc, Wei Tan, MSc, Sukhwinder Thandi, PhD, John White, FRCP, Janet Wilson, FRCP, Prof Lelia Duley, MD, on behalf of theG-ToG trial team

Published: May 02, 2019 / DOI: https://doi.org/10.1016/S0140-6736(18)32817-4

 

Summary

Background

Gonorrhoea is a common sexually transmitted infection for which ceftriaxone is the current first-line treatment, but antimicrobial resistance is emerging. The objective of this study was to assess the effectiveness of gentamicin as an alternative to ceftriaxone (both combined with azithromycin) for treatment of gonorrhoea.

Methods

G-ToG was a multicentre, parallel-group, pragmatic, randomised, non-inferiority trial comparing treatment with gentamicin to treatment with ceftriaxone for patients with gonorrhoea. The patients, treating physician, and assessing physician were masked to treatment but the treating nurse was not. The trial took place at 14 sexual health clinics in England. Adults aged 16–70 years were eligible for participation if they had a diagnosis of uncomplicated genital, pharyngeal, or rectal gonorrhoea. Participants were randomly assigned to receive a single intramuscular dose of either gentamicin 240 mg (gentamicin group) or ceftriaxone 500 mg (ceftriaxone group). All participants also received a single 1 g dose of oral azithromycin. Randomisation (1:1) was stratified by clinic and performed using a secure web-based system. The primary outcome was clearance of Neisseria gonorrhoeae at all initially infected sites, defined as a negative nucleic acid amplification test 2 weeks post treatment. Primary outcome analyses included only participants who had follow-up data, irrespective of the baseline visit N gonorrhoeae test result. The margin used to establish non-inferiority was a lower confidence limit of 5% for the risk difference. This trial is registered with ISRCTN, number ISRCTN51783227.

Findings

Of 1762 patients assessed, we enrolled 720 participants between Oct 7, 2014, and Nov 14, 2016, and randomly assigned 358 to gentamicin and 362 to ceftriaxone. Primary outcome data were available for 306 (85%) of 362 participants allocated to ceftriaxone and 292 (82%) of 358 participants allocated to gentamicin. At 2 weeks after treatment, infection had cleared for 299 (98%) of 306 participants in the ceftriaxone group compared with 267 (91%) of 292 participants in the gentamicin group (adjusted risk difference −6·4%, 95% CI −10·4% to −2·4%). Of the 328 participants who had a genital infection, 151 (98%) of 154 in the ceftriaxone group and 163 (94%) of 174 in the gentamicin group had clearance at follow-up (adjusted risk difference −4·4%, −8·7 to 0). For participants with a pharyngeal infection, a greater proportion receiving ceftriaxone had clearance at follow-up (108 [96%] in the ceftriaxone group compared with 82 [80%] in the gentamicin group; adjusted risk difference −15·3%, −24·0 to −6·5). Similarly, a greater proportion of participants with rectal infection in the ceftriaxone group had clearance (134 [98%] in the ceftriaxone group compared with 107 [90%] in the gentamicin group; adjusted risk difference −7·8%, −13·6 to −2·0). Thus, we did not find that a single dose of gentamicin 240 mg was non-inferior to a single dose of ceftriaxone 500 mg for the treatment of gonorrhoea, when both drugs were combined with a 1 g dose of oral azithromycin. The side-effect profiles were similar between groups, although severity of pain at the injection site was higher for gentamicin (mean visual analogue pain score 36 of 100 in the gentamicin group vs 21 of 100 in the ceftriaxone group).

Interpretation

Gentamicin is not appropriate as first-line treatment for gonorrhoea but remains potentially useful for patients with isolated genital infection, or for patients who are allergic or intolerant to ceftriaxone, or harbour a ceftriaxone-resistant isolate. Further research is required to identify and test new alternatives to ceftriaxone for the treatment of gonorrhoea.

Funding

UK National Institute for Health Research.

Keywords: Antibiotics; Drugs Resistance; Neisseria gonorrhoeae; Ceftriaxone; Azithromycin; Gentamicin.

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#Gentamicin susceptibility among a sample of #MDR #Neisseria #gonorrhoeae isolates in #India (Antimicrob Agents Chemother., abstract)

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

Gentamicin susceptibility among a sample of multi-drug resistant Neisseria gonorrhoeae isolates in India

Manju Bala a⇑, Vikram Singh a,b, Aradhana Bhargava a, Monika Kakran a, Naveen Chandra Joshi a and Ravi Bhatnagar b

Author Affiliations: Apex Regional STD Teaching, Training & Research Centre, Vardhman Mahavir Medical College & Safdarjung Hospital, New Delhi, India[a]; Department of Life Sciences, SunRise University, Alwar, Rajasthan, India[b]

 

ABSTRACT

Antimicrobial susceptibility testing of 258 N. gonorrhoeae isolates by Etest determined that 60.1% were MDR while 5% strains had decreased susceptibility to currently recommended extended-spectrum cephalosporins (ESCs). Among these, 84.5% MDR and 76.9% strains having decreased susceptibility to ESCs were susceptible to gentamicin. No MDR isolate was resistant to gentamicin. These in vitro results suggest that gentamicin might be an effective treatment option for the MDR strains and in dual therapy for gonorrhea. However, further research regarding the clinical treatment outcomes is essential.

 

FOOTNOTES

Correspondence: Dr. Manju Bala, Consultant and Professor (Microbiology), Apex Regional STD Teaching, Training & Research Centre, Vardhman Mahavir Medical College & Safdarjung Hospital, New Delhi, India. Telephone number: 91-11-26196740, Fax number: 91-11-26163072, Email:manjubala_2@hotmail.com

Copyright © 2016, American Society for Microbiology. All Rights Reserved.

Keywords: Neisseria Gonorrhoeae; Antibiotics; Drugs Resistance; Gentamicin.

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