Universal #antibiotic #tolerance arising from antibiotic-triggered accumulation of #pyocyanin in #Pseudomonas aeruginosa (PLOS Biol., abstract)

[Source: PLOS Biology, full page: (LINK). Abstract, edited.]


Universal antibiotic tolerance arising from antibiotic-triggered accumulation of pyocyanin in Pseudomonas aeruginosa

Kui Zhu, Shang Chen, Tatyana A. Sysoeva, Lingchong You


Published: December 16, 2019 / DOI: https://doi.org/10.1371/journal.pbio.3000573 / This is an uncorrected proof.



Pseudomonas aeruginosa is an opportunistic pathogen that often infects open wounds or patients with cystic fibrosis. Once established, P. aeruginosa infections are notoriously difficult to eradicate. This difficulty is in part due to the ability of P. aeruginosa to tolerate antibiotic treatment at the individual-cell level or through collective behaviors. Here, we describe a new phenomenon by which P. aeruginosa tolerates antibiotic treatment. In particular, treatment of P. aeruginosa with sublethal concentrations of antibiotics covering all major classes promoted accumulation of the redox-sensitive phenazine pyocyanin (PYO). PYO in turn conferred general tolerance against diverse antibiotics for both P. aeruginosa and other gram-negative and gram-positive bacteria. This property is shared by other redox-active phenazines produced by P. aeruginosa. Our discovery sheds new insights into the physiological functions of phenazines and has implications for designing effective antibiotic treatment protocols.


Citation: Zhu K, Chen S, Sysoeva TA, You L (2019) Universal antibiotic tolerance arising from antibiotic-triggered accumulation of pyocyanin in Pseudomonas aeruginosa. PLoS Biol 17(12): e3000573. https://doi.org/10.1371/journal.pbio.3000573

Academic Editor: Nathalie Balaban, Hebrew University, ISRAEL

Received: November 1, 2018; Accepted: December 2, 2019; Published: December 16, 2019

Copyright: © 2019 Zhu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: All relevant data are within the paper and its Supporting Information files.

Funding: The work was partially supported by the National Key Research and Development Program of China (KZ, 2017YFC1600305), National Natural Science Foundation of China (21861142006, KZ), NIH (LY, R01GM098642) and a David and Lucile Packard Fellowship (LY). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.

Abbreviations: A600 nm, absorbance 600 nm; ATCC, American Type Culture Collection; BHI, brain-heart infusion; CLSI, Clinical and Laboratory Standards Institute; ESBL, extended-spectrum beta-lactamase; Kan, kanamycin; LB, Luria-Bertani; MIC, minimum inhibitory concentration; PYO, pyocyanin; QS, quorum sensing; ROS, reactive oxygen species

Keywords: Antibiotics; Drugs Resistance; Pseudomon

#Predictors of #Mortality in #Bloodstream #Infections Caused by #Pseudomonas aeruginosa: Impact of #Antimicrobial #Resistance and Bacterial Virulence (Antimicrob Agents Chemother., abstract)

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

Predictors of Mortality in Bloodstream Infections Caused by Pseudomonas aeruginosa: Impact of Antimicrobial Resistance and Bacterial Virulence

Raúl Recio, Mikel Mancheño, Esther Viedma, Jennifer Villa, María Ángeles Orellana, Jaime Lora-Tamayo, Fernando Chaves

DOI: 10.1128/AAC.01759-19



Whether multidrug-resistance (MDR) is associated with mortality in patients with Pseudomonas aeruginosa (PA) bloodstream infection (BSI) remains controversial. Here, we explored the prognostic factors of PA BSI with emphasis on antimicrobial resistance and virulence. All PA BSI episodes in a 5-year period were retrospectively analyzed. The impact in early (5-day) and late (30-day) crude mortality of host, antibiotic treatment and pathogen factors was assessed by multivariate logistic regression analysis. Of 243 episodes, 93 (38.3%) were caused by MDR-PA. Crude 5-day (20%) and 30-day (33%) mortality was more frequent in patients with MDR-PA (34.4% vs. 11.3%, p<0.001 and 52.7% vs. 21.3%, p<0.001, respectively). Early mortality was associated with neutropenia (adjusted odds ratio [aOR], 9.21; 95% confidence interval [95% CI], 3.40-24.9; p<0.001), increased Pitt score (aOR, 2.42; 95% CI, 1.34-4.36; p=0.003), respiratory source (aOR, 3.23; 95% CI, 2.01-5.16; p<0.001), inadequate empirical therapy (aOR, 4.57; 95% CI, 1.59-13.1; p=0.005), shorter time to positivity of blood culture (aOR, 0.88; 95% CI, 0.80-0.97; p=0.010), exoU-positive genotype (aOR, 3.58; 95% CI, 1.31-9.79; p=0.013), and O11 serotype (aOR, 3.64; 95% CI, 1.20-11.1; p=0.022). These risk factors were also identified for late mortality, as well as MDR phenotype (aOR, 2.18; 95% CI, 1.04-4.58; p=0.040). Moreover, O11 serotype (15.2%, 37/243) was common among MDR (78.4%, 29/37) and exoU-positive (89.2%, 33/37) strains. Besides relevant clinical variables and inadequate empirical therapy, pathogen factors such as MDR phenotype, exoU-positive genotype, and O11 serotype adversely affect the outcome of PA BSI.

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

Keywords: Antibiotics; Drugs Resistance; Pseudomonas aeruginosa; Bacteremia.


Activity of #imipenem / #relebactam against a large collection of #Pseudomonas aeruginosa #clinical isolates and isogenic β-lactam resistant mutants (Antimicrob Agents Chemother., abstract)

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

Activity of imipenem/relebactam against a large collection of Pseudomonas aeruginosa clinical isolates and isogenic β-lactam resistant mutants

Pablo Fraile-Ribot, Laura Zamorano, Rocío Orellana, Ester del Barrio-Tofiño, Irina Sánchez-Diener, Sara Cortes-Lara, Carla López-Causapé, Gabriel Cabot, Germán Bou, Luis Martínez-Martínez, Antonio Oliver,  and on behalf of GEMARA-SEIMC/REIPI Pseudomonas study Group

DOI: 10.1128/AAC.02165-19



Imipenem and Imipenem/relebactam MICs were determined for 1,445 P. aeruginosa clinical isolates and a large panel of isogenic mutants showing the most relevant mutation-driven β-lactam resistance mechanisms. Imipenem/relebactam showed highest susceptibility rates (97.3%), followed by colistin and ceftolozane/tazobactam (both 94.6%). Imipenem/relebactam MICs remained ≤2 μg/mL in all 16 isogenic PAO1 mutants and in 8 pairs of XDR clinical strains that had developed resistance to ceftolozane/tazobactam and ceftazidime/avibactam due to mutations in OXA-10 or AmpC.

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

Keywords: Antibiotics; Drugs Resistance; Pseudomonas aeruginosa; Imipenem; Relebactam.


High- #Risk #International #Clones of #Carbapenem-Nonsusceptible #Pseudomonas aeruginosa Endemic to #Indonesian #ICUs: Impact of a Multifaceted Infection Control Intervention Analyzed at the Genomic Level (MBio, abstract)

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

High-Risk International Clones of Carbapenem-Nonsusceptible Pseudomonas aeruginosa Endemic to Indonesian Intensive Care Units: Impact of a Multifaceted Infection Control Intervention Analyzed at the Genomic Level

Andreu Coello Pelegrin, Yulia Rosa Saharman, Aurélien Griffon, Mattia Palmieri, Caroline Mirande, Anis Karuniawati, Rudyanto Sedono, Dita Aditianingsih, Wil H. F. Goessens, Alex van Belkum, Henri A. Verbrugh, Corné H. W. Klaassen, Juliëtte A. Severin

Peter Gilligan, Editor

DOI: 10.1128/mBio.02384-19



Infection control effectiveness evaluations require detailed epidemiological and microbiological data. We analyzed the genomic profiles of carbapenem-nonsusceptible Pseudomonas aeruginosa (CNPA) strains collected from two intensive care units (ICUs) in the national referral hospital in Jakarta, Indonesia, where a multifaceted infection control intervention was applied. We used clinical data combined with whole-genome sequencing (WGS) of systematically collected CNPA to infer the transmission dynamics of CNPA strains and to characterize their resistome. We found that the number of CNPA transmissions and acquisitions by patients was highly variable over time but that, overall, the rates were not significantly reduced by the intervention. Environmental sources were involved in these transmissions and acquisitions. Four high-risk international CNPA clones (ST235, ST823, ST375, and ST446) dominated, but the distribution of these clones changed significantly after the intervention was implemented. Using resistome analysis, carbapenem resistance was explained by the presence of various carbapenemase-encoding genes (blaGES-5, blaVIM-2-8, and blaIMP-1-7-43) and by mutations within the porin OprD. Our results reveal for the first time the dynamics of P. aeruginosa antimicrobial resistance (AMR) profiles in Indonesia and additionally show the utility of WGS in combination with clinical data to evaluate the impact of an infection control intervention. (This study has been registered at www.trialregister.nl under registration no. NTR5541).



In low-to-middle-income countries such as Indonesia, work in intensive care units (ICUs) can be hampered by lack of resources. Conducting large epidemiological studies in such settings using genomic tools is rather challenging. Still, we were able to systematically study the transmissions of carbapenem-nonsusceptible strains of P. aeruginosa (CNPA) within and between ICUs, before and after an infection control intervention. Our data show the importance of the broad dissemination of the internationally recognized CNPA clones, the relevance of environmental reservoirs, and the mixed effects of the implemented intervention; it led to a profound change in the clonal make-up of CNPA, but it did not reduce the patients’ risk of CNPA acquisitions. Thus, CNPA epidemiology in Indonesian ICUs is part of a global expansion of multiple CNPA clones that remains difficult to control by infection prevention measures.

Keywords: Antibiotics; Drugs Resistance; Carbapenem; Pseudomonas aeruginosa; ICU; Nosocomial outbreaks; Indonesia.


Simultaneous #Infection with #Enterobacteriaceae and #Pseudomonas aeruginosa harboring Multiple #Carbapenemases in a Returning #Traveler colonized with #Candida auris (AAC, abstract)

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

Simultaneous Infection with Enterobacteriaceae and Pseudomonas aeruginosa harboring Multiple Carbapenemases in a Returning Traveler colonized with Candida auris

Ayesha Khan, William C. Shropshire, Blake Hanson, An Q. Dinh, Audrey Wanger, Luis Ostrosky-Zeichner, Cesar A. Arias, William R. Miller

DOI: 10.1128/AAC.01466-19



We report our clinical experience treating a critically ill patient with polymicrobial infections due to multi-drug resistant Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa in a 56 year-old woman who received healthcare in India and was also colonized by Candida auris. A precision medicine approach using whole genome sequencing revealed a multiplicity of mobile elements associated with NDM-1, NDM-5, and OXA-181 and, supplemented by susceptibility testing, guided the selection of rational antimicrobial therapy.

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

Keywords: Antibiotics; Drugs Resistance; NDM1; E. Coli; Klebsiella pneumoniae; Pseudomonas aeruginosa; Candida auris.


Changes in the #resistance and #epidemiological characteristics of #Pseudomonas aeruginosa during a ten-year period (J Microbiol Immunol Infect., abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

J Microbiol Immunol Infect. 2019 Sep 30. pii: S1684-1182(19)30153-7. doi: 10.1016/j.jmii.2019.08.017. [Epub ahead of print]

Changes in the resistance and epidemiological characteristics of Pseudomonas aeruginosa during a ten-year period.

Feng W1, Huang Q2, Wang Y1, Yuan Q1, Li X3, Xia P4, Sun F5.

Author information: 1 Department of Pharmacy, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China. 2 Department of Laboratory Medicine, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China. 3 Department of Pharmacy, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China; Department of Pharmacy, Handan Branch of Chinese PLA 980 Hospital, Handan, Hebei province, China. 4 Department of Pharmacy, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China. Electronic address: peiyuan_xia2013@163.com. 5 Department of Pharmacy, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China. Electronic address: fengj_sun@163.com.




The aim of this study was to investigate the changes over a ten-year period in the resistance and epidemiological characteristics of Pseudomonas aeruginosa strains isolated from the Department of Respiratory in Southwest Hospital.


Antimicrobial resistance was detected using the plate double dilution method. PCR amplification and sequencing were performed to evaluate the carbapenemase genes and the oprD gene. Bacterial genotypes were analyzed by multilocus sequence typing (MLST). Quantitative real-time PCR experiments were performed to assess the expression of efflux pump (mexA and mexX) and ampC gene.


We collected 233 P. aeruginosa isolates in 2006-2007 and 128 isolates in 2016-2017. The resistance rate of P. aeruginosa strains to the tested antibiotics was significantly lower in 2016-2017 than in 2006-2007. The MLST results showed 27 genotypes in 2006-2007 and 18 genotypes in 2016-2017. ST235 was the most prevalent sequence type, and there was no significant change in the genotypes over the ten-year period. Both VIM-2 and IMP-4 genes were found in 2006-2007, whereas only IMP-4 was found in 2016-2017. The oprD mutational inactivation was the main factor responsible for carbapenem resistance, and the overexpression of mexX had a good correlation with aminoglycoside resistance.


These results indicated that the antibiotic resistance of P. aeruginosa in our respiratory department decreased. The loss of oprD gene was the main mechanism of carbapenem resistance, and mexX overexpression was the major contributing factor to aminoglycoside resistance.

Copyright © 2019. Published by Elsevier B.V.

KEYWORDS: Efflux pump; Epidemiology; OprD; Pseudomonas aeruginosa; Resistance

PMID: 31628088 DOI: 10.1016/j.jmii.2019.08.017

Keywords: Antibiotics; Drugs Resistance; Carbapenem; Aminoglycosides; Pseudomonas aeruginosa; China.


Transposable temperate #phages promote the #evolution of divergent social strategies in #Pseudomonas aeruginosa populations (Proc Roy Soc B., abstract)

[Source: Proceedings of the Royal Society, Biological Sciences, full page: (LINK). Abstract, edited.]

Transposable temperate phages promote the evolution of divergent social strategies in Pseudomonas aeruginosa populations

Siobhán O’Brien, Rolf Kümmerli, Steve Paterson, Craig Winstanley and Michael A. Brockhurst

Published: 09 October 2019 / DOI: https://doi.org/10.1098/rspb.2019.1794



Transposable temperate phages randomly insert into bacterial genomes, providing increased supply and altered spectra of mutations available to selection, thus opening alternative evolutionary trajectories. Transposable phages accelerate bacterial adaptation to new environments, but their effect on adaptation to the social environment is unclear. Using experimental evolution of Pseudomonas aeruginosa in iron-limited and iron-rich environments, where the cost of producing cooperative iron-chelating siderophores is high and low, respectively, we show that transposable phages promote divergence into extreme siderophore production phenotypes. Iron-limited populations with transposable phages evolved siderophore overproducing clones alongside siderophore non-producing cheats. Low siderophore production was associated with parallel mutations in pvd genes, encoding pyoverdine biosynthesis, and pqs genes, encoding quinolone signalling, while high siderophore production was associated with parallel mutations in phenazine-associated gene clusters. Notably, some of these parallel mutations were caused by phage insertional inactivation. These data suggest that transposable phages, which are widespread in microbial communities, can mediate the evolutionary divergence of social strategies.



Electronic supplementary material is available online at https://doi.org/10.6084/m9.figshare.c.4674518

Keywords: Bacteriophages; Evolution; Pseudomonas aeruginosa.


#Risk #Factors for #Carbapenem-Resistant #Pseudomonas aeruginosa, #Zhejiang Province, #China (Emerg Infect Dis., abstract)

[Source: US Centers for Disease Control and Prevention (CDC), Emerging Infectious Diseases Journal, full page: (LINK). Abstract, edited.]

Volume 25, Number 10—October 2019 / Research

Risk Factors for Carbapenem-Resistant Pseudomonas aeruginosa, Zhejiang Province, China

Yan-Yan Hu, Jun-Min Cao, Qing Yang, Shi Chen, Huo-Yang Lv, Hong-Wei Zhou, Zuowei Wu, and Rong Zhang

Author affiliations: Zhejiang University, Hangzhou, China (Y.-Y. Hu, Q. Yang, H.-W. Zhou, R. Zhang); Zhejiang Provincial Hospital of Traditional Chinese Medicine, Hangzhou (J.-M. Cao, H.-Y. Lv); Hangzhou Third People’s Hospital, Hangzhou (S. Chen); Iowa State University, Ames, Iowa, USA (Z. Wu)



Carbapenem-resistant Pseudomonas aeruginosa (CRPA) is a public health concern worldwide, but comprehensive analysis of risk factors for CRPA remains limited in China. We conducted a retrospective observational study of carbapenem resistance in 71,880 P. aeruginosa isolates collected in Zhejiang Province during 2015–2017. We analyzed risk factors for CRPA, including the type of clinical specimen; the year, season, and region, in which it was collected; patient information, including age, whether they were an outpatient or inpatient, and whether inpatients were in the intensive care unit or general ward; and the level of hospital submitting isolates. We found CRPA was more prevalent among isolates from patients >60 years of age and in inpatients, especially in intensive care units. In addition, specimen types and seasons in which they were collected were associated with higher rates of CRPA. Our findings can help hospitals reduce the spread of P. aeruginosa and optimize antimicrobial drug use.

Keywords: Antibiotics; Drugs Resistance; Carbapenem; Pseudomonas aeruginosa; Zhejiang; China.


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




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.


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.


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.


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.


#Resistance and hetero-resistance to #colistin in #Pseudomonas aeruginosa isolates from Wenzhou, #China (Antimicrob Agents Chemother., abstract)

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

Resistance and hetero-resistance to colistin in Pseudomonas aeruginosa isolates from Wenzhou, China

Jie Lin, Chunquan Xu, Renchi Fang, Jianming Cao, Xiucai Zhang, Yajie Zhao, Guofeng Dong, Yao Sun, Tieli Zhou

DOI: 10.1128/AAC.00556-19




To investigate the mechanisms of colistin resistance and hetero-resistance in Pseudomonas aeruginosa clinical isolates.


Colistin resistance was determined by broth microdilution method. Colistin hetero-resistance was evaluated by population analysis profiles (PAPs). Time-kill assays were also conducted. Polymerase chain reaction (PCR) sequencing was performed to detect the resistance genes among (hetero-)resistant isolates, and quantitative real-time PCR (qRT-PCR) was performed to determine their expression levels. Pulsed field gel electrophoresis (PFGE) and multilocus sequence typing (MLST) were analyzed. Lipid A characteristic were determined via MALDI-TOF MS.


Two resistant isolates and nine hetero-resistant isolates were selected respectively in this study. Mutations in PmrB were detected in two resistant isolates. In hetero-resistant isolates, eight of nine hetero-resistant isolates had non-synonymous PmrB mutations, and two isolates, including one with PmrB mutation, had PhoQ alterations. Correspondingly, the expression levels of pmrA or phoP were up-regulated in PmrB- or PhoQ-mutated isolates. One isolate also found alterations in ParRS and CprRS. The transcript levels of pmrH gene were observed to increase across all investigated isolates. MALDI-TOF MS showed additional 4-amino-4-deoxy-L-arabinose (L-Ara4N) moieties in lipid A profiles in (hetero-)resistant isolates.


In conclusion, both colistin resistance and hetero-resistance in P. aeruginosa in this study were mainly involved by alterations of the PmrAB regulatory system. There was strong association between mutations in specific genetic loci lipid A synthesis and regulating modifications to lipid A. The transition of colistin hetero-resistance to resistance should be concerned in future clinical surveillance.

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

Keywords: Antibiotics; Drugs Resistance; Colistin; Pseudomonas aeruginosa; China.