Ceftolozane/tazobactam heteroresistance in cystic fibrosis-related Pseudomonas aeruginosa infections

Abstract Objectives Cystic fibrosis (CF) patients are often colonized with Pseudomonas aeruginosa. During treatment, P. aeruginosa can develop subpopulations exhibiting variable in vitro antimicrobial (ABX) susceptibility patterns. Heteroresistance (HR) may underlie reported discrepancies between in vitro susceptibility results and clinical responses to various ABXs. Here, we sought to examine the presence and nature of P. aeruginosa polyclonal HR (PHR) and monoclonal HR (MHR) to ceftolozane/tazobactam in isolates originating from CF pulmonary exacerbations. Methods This was a single-centre, non-controlled study. Two hundred and forty-six P. aeruginosa isolates from 26 adult CF patients were included. PHR was defined as the presence of different ceftolozane/tazobactam minimum inhibitory concentration (MIC) values among P. aeruginosa isolates originating from a single patient specimen. Population analysis profiles (PAPs) were performed to assess the presence of MHR, defined as ≥4-fold change in the ceftolozane/tazobactam MIC from a single P. aeruginosa colony. Results Sixteen of 26 patient specimens (62%) contained PHR P. aeruginosa populations. Of these 16 patients, 6 (23%) had specimens in which PHR P. aeruginosa isolates exhibited ceftolozane/tazobactam MICs with categorical differences (i.e. susceptible versus resistant) compared to results reported as part of routine care. One isolate, PSA 1311, demonstrated MHR. Canonical ceftolozane/tazobactam resistance genes were not found in the MHR isolates (MHR PSA 1311 or PHR PSA 6130). Conclusions Ceftolozane/tazobactam PHR exists among P. aeruginosa isolates in this work, and approximately a quarter of these populations contained isolates with ceftolozane/tazobactam susceptibiilty interpretations different from what was reported clinically, supporting concerns surrounding the utility of traditional susceptibility testing methodology in the setting of CF specimens. Genome sequencing of isolates with acquired MHR to ceftolozane/tazobactam revealed variants of unknown significance. Future work will be centred on determining the significance of these mutations to better understand these data in clinical context.

[1]  Xiaowei Zhan,et al.  Clinically undetected polyclonal heteroresistance among Pseudomonas aeruginosa isolated from cystic fibrosis respiratory specimens. , 2022, The Journal of antimicrobial chemotherapy.

[2]  R. Sierra,et al.  Antibiotic heteroresistance in ESKAPE pathogens, from bench to bedside. , 2022, Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases.

[3]  Yuan Tian,et al.  Combined effect of Polymyxin B and Tigecycline to overcome Heteroresistance in Carbapenem-Resistant Klebsiella pneumoniae , 2021, Microbiology spectrum.

[4]  M. Castanheira,et al.  Antimicrobial activities of ceftazidime/avibactam, ceftolozane/tazobactam, imipenem/relebactam, meropenem/vaborbactam, and Comparators against Pseudomonas aeruginosa from patients with skin and soft tissue infections. , 2021, International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases.

[5]  S. Satola,et al.  Widespread cefiderocol heteroresistance in carbapenem-resistant Gram-negative pathogens. , 2021, The Lancet. Infectious diseases.

[6]  Guangchuang Yu,et al.  Using ggtree to Visualize Data on Tree‐Like Structures , 2020, Current protocols in bioinformatics.

[7]  L. Saiman,et al.  Reconciling Antimicrobial Susceptibility Testing and Clinical Response in Antimicrobial Treatment of Chronic Cystic Fibrosis Lung Infections. , 2019, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[8]  Jan Michiels,et al.  Bacterial Heterogeneity and Antibiotic Survival: Understanding and Combatting Persistence and Heteroresistance. , 2019, Molecular cell.

[9]  A. Oliver,et al.  Epidemiology and Treatment of Multidrug-Resistant and Extensively Drug-Resistant Pseudomonas aeruginosa Infections , 2019, Clinical Microbiology Reviews.

[10]  D. Andersson,et al.  Mechanisms and clinical relevance of bacterial heteroresistance , 2019, Nature Reviews Microbiology.

[11]  E. Burd,et al.  Antibiotic combinations that exploit heteroresistance to multiple drugs effectively control infection , 2019, Nature Microbiology.

[12]  V. Waters,et al.  Antimicrobial susceptibility testing (AST) and associated clinical outcomes in individuals with cystic fibrosis: A systematic review. , 2019, Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society.

[13]  B. Levin,et al.  The high prevalence of antibiotic heteroresistance in pathogenic bacteria is mainly caused by gene amplification , 2019, Nature Microbiology.

[14]  A. Oliver,et al.  Characterization of Hypermutator Pseudomonas aeruginosa Isolates from Patients with Cystic Fibrosis in Australia , 2019, Antimicrobial Agents and Chemotherapy.

[15]  Yang Xie,et al.  VAMPr: VAriant Mapping and Prediction of antibiotic resistance via explainable features and machine learning , 2019, bioRxiv.

[16]  Emmanuel Paradis,et al.  ape 5.0: an environment for modern phylogenetics and evolutionary analyses in R , 2018, Bioinform..

[17]  D. Nicolau,et al.  Antibacterial activity of ceftolozane/tazobactam alone and in combination with other antimicrobial agents against MDR Pseudomonas aeruginosa , 2018, The Journal of antimicrobial chemotherapy.

[18]  A. Addetia,et al.  Heterogeneous Antimicrobial Susceptibility Characteristics in Pseudomonas aeruginosa Isolates from Cystic Fibrosis Patients , 2018, mSphere.

[19]  Liping Zhang,et al.  Heteroresistance to carbapenems in invasive Pseudomonas aeruginosa infections. , 2017, International journal of antimicrobial agents.

[20]  David E Greenberg,et al.  Whole-Genome Sequencing Accurately Identifies Resistance to Extended-Spectrum &bgr;-Lactams for Major Gram-Negative Bacterial Pathogens , 2017, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[21]  K. Kristóf,et al.  Colistin resistance among blood culture isolates at a tertiary care centre in Hungary. , 2017, Journal of global antimicrobial resistance.

[22]  M. Valvano,et al.  Antimicrobial Heteroresistance: an Emerging Field in Need of Clarity , 2015, Clinical Microbiology Reviews.

[23]  L. Lutz,et al.  Evaluation of heteroresistance to polymyxin B among carbapenem-susceptible and -resistant Pseudomonas aeruginosa. , 2013, Journal of medical microbiology.

[24]  Sergey I. Nikolenko,et al.  SPAdes: A New Genome Assembly Algorithm and Its Applications to Single-Cell Sequencing , 2012, J. Comput. Biol..

[25]  A. Ikonomidis,et al.  Investigation of carbapenem heteroresistance among different sequence types of Pseudomonas aeruginosa clinical isolates reveals further diversity. , 2011, Journal of medical microbiology.

[26]  G. Doern,et al.  The Clinical Predictive Value (or Lack Thereof) of the Results of In Vitro Antimicrobial Susceptibility Tests , 2011, Journal of Clinical Microbiology.

[27]  S. Salzberg,et al.  Versatile and open software for comparing large genomes , 2004, Genome Biology.

[28]  OUP accepted manuscript , 2021, Journal of Antimicrobial Chemotherapy.

[29]  Claude-Alain H. Roten,et al.  Fast and accurate short read alignment with Burrows–Wheeler transform , 2009, Bioinform..

[30]  A. Maniatis,et al.  Characterization of clinical isolates of Pseudomonas aeruginosa heterogeneously resistant to carbapenems. , 2007, Journal of medical microbiology.

[31]  M. Ferraro.  Performance standards for antimicrobial susceptibility testing , 2001 .