Mechanisms of ciprofloxacin resistance in Pseudomonas aeruginosa: new approaches to an old problem.

The antibiotic ciprofloxacin is used extensively to treat a wide range of infections caused by the opportunistic pathogen Pseudomonas aeruginosa. Due to its extensive use, the proportion of ciprofloxacin-resistant P. aeruginosa isolates is rapidly increasing. Ciprofloxacin resistance can arise through the acquisition of mutations in genes encoding the target proteins of ciprofloxacin and regulators of efflux pumps, which leads to overexpression of these pumps. However, understanding of the basis of ciprofloxacin resistance is not yet complete. Recent advances using high-throughput screens and experimental evolution combined with whole-genome sequencing and protein analysis are enhancing our understanding of the genetic and biochemical mechanisms involved in ciprofloxacin resistance. Better insights into the mechanisms of ciprofloxacin resistance may facilitate the development of new or improved therapeutic regimes effective against P. aeruginosa. In this review we discuss the current understanding of the mechanisms of ciprofloxacin resistance and summarize the genetic basis of ciprofloxacin resistance in P. aeruginosa, in the context of current and future use of this antibiotic.

[1]  N. Høiby,et al.  Modelling of ciprofloxacin killing enhanced by hyperbaric oxygen treatment in Pseudomonas aeruginosa PAO1 biofilms , 2018, PloS one.

[2]  M. Sommer,et al.  Evolution of Antibiotic Resistance in Biofilm and Planktonic Pseudomonas aeruginosa Populations Exposed to Subinhibitory Levels of Ciprofloxacin , 2018, Antimicrobial Agents and Chemotherapy.

[3]  J. Campos-García,et al.  CrpP Is a Novel Ciprofloxacin-Modifying Enzyme Encoded by the Pseudomonas aeruginosa pUM505 Plasmid , 2018, Antimicrobial Agents and Chemotherapy.

[4]  J. Capelo,et al.  Mechanisms of quinolone action and resistance: where do we stand? , 2017, Journal of medical microbiology.

[5]  B. Rehm,et al.  Pseudomonas aeruginosa Lifestyle: A Paradigm for Adaptation, Survival, and Persistence , 2017, Front. Cell. Infect. Microbiol..

[6]  Jeffrey Hill,et al.  Pseudomonas aeruginosa develops Ciprofloxacin resistance from low to high level with distinctive proteome changes. , 2017, Journal of proteomics.

[7]  F. Månsson,et al.  Antimicrobial combination treatment including ciprofloxacin decreased the mortality rate of Pseudomonas aeruginosa bacteraemia: a retrospective cohort study , 2017, European Journal of Clinical Microbiology & Infectious Diseases.

[8]  H. Samadi kafil,et al.  Contribution of mexAB-oprM and mexXY (-oprA) efflux operons in antibiotic resistance of clinical Pseudomonas aeruginosa isolates in Tabriz, Iran. , 2016, Infection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases.

[9]  T. Rades,et al.  Inhalable Antimicrobials for Treatment of Bacterial Biofilm-Associated Sinusitis in Cystic Fibrosis Patients: Challenges and Drug Delivery Approaches , 2016, International journal of molecular sciences.

[10]  M. Ahangarzadeh Rezaee,et al.  The role of gyrA and parC mutations in fluoroquinolones-resistant Pseudomonas aeruginosa isolates from Iran , 2016, Brazilian journal of microbiology : [publication of the Brazilian Society for Microbiology].

[11]  T. Remmington,et al.  Oral anti-pseudomonal antibiotics for cystic fibrosis. , 2016, The Cochrane database of systematic reviews.

[12]  M. Jonker,et al.  Dynamics of Mutations during Development of Resistance by Pseudomonas aeruginosa against Five Antibiotics , 2016, Antimicrobial Agents and Chemotherapy.

[13]  M. Behr,et al.  The implications of whole-genome sequencing in the control of tuberculosis , 2016, Therapeutic advances in infectious disease.

[14]  I. Gonda,et al.  Development of Liposomal Ciprofloxacin to Treat Lung Infections , 2016, Pharmaceutics.

[15]  I. Patry,et al.  Amino Acid Substitutions Account for Most MexS Alterations in Clinical nfxC Mutants of Pseudomonas aeruginosa , 2016, Antimicrobial Agents and Chemotherapy.

[16]  J. Berger,et al.  Crystal structure and stability of gyrase–fluoroquinolone cleaved complexes from Mycobacterium tuberculosis , 2016, Proceedings of the National Academy of Sciences.

[17]  S. Bell,et al.  Genotypic Diversity within a Single Pseudomonas aeruginosa Strain Commonly Shared by Australian Patients with Cystic Fibrosis , 2015, PloS one.

[18]  E. Marcotte,et al.  Intrinsic Antimicrobial Resistance Determinants in the Superbug Pseudomonas aeruginosa , 2015, mBio.

[19]  Chao Wang,et al.  Insights into the evolutionary trajectories of fluoroquinolone resistance in Streptococcus pneumoniae. , 2015, The Journal of antimicrobial chemotherapy.

[20]  Balázs Papp,et al.  Collateral sensitivity of antibiotic-resistant microbes. , 2015, Trends in microbiology.

[21]  Michael J E Sternberg,et al.  The Phyre2 web portal for protein modeling, prediction and analysis , 2015, Nature Protocols.

[22]  N. McCallum,et al.  Whole genome sequencing in clinical and public health microbiology , 2015, Pathology.

[23]  Zhuo-peng Ye,et al.  Prevalence and fluoroquinolone resistance of pseudomonas aeruginosa in a hospital of South China. , 2015, International journal of clinical and experimental medicine.

[24]  A. Oliver,et al.  Evolution of Pseudomonas aeruginosa Antimicrobial Resistance and Fitness under Low and High Mutation Rates , 2015, Antimicrobial Agents and Chemotherapy.

[25]  Y. Kawamura,et al.  Efflux-mediated fluoroquinolone resistance in the multidrug-resistant Pseudomonas aeruginosa clinical isolate PA7: identification of a novel MexS variant involved in upregulation of the mexEF-oprN multidrug efflux operon , 2014, Front. Microbiol..

[26]  S. Molin,et al.  Convergent evolution and adaptation of Pseudomonas aeruginosa within patients with cystic fibrosis , 2014, Nature Genetics.

[27]  A. Yan,et al.  Bacterial multidrug efflux pumps: mechanisms, physiology and pharmacological exploitations. , 2014, Biochemical and biophysical research communications.

[28]  Sharon J. Peacock,et al.  Whole-genome sequencing to control antimicrobial resistance , 2014, Trends in genetics : TIG.

[29]  S. Koo,et al.  Correlation Between Virulence Genotype and Fluoroquinolone Resistance in Carbapenem-Resistant Pseudomonas aeruginosa , 2014, Annals of laboratory medicine.

[30]  Mei-Feng Lee,et al.  Mutations in the quinolone resistance-determining regions associated with ciprofloxacin resistance in Pseudomonas aeruginosa isolates from Southern Taiwan , 2014 .

[31]  Gaël Chambonnier,et al.  Pseudomonas aeruginosa Genome Evolution in Patients and under the Hospital Environment , 2014, Pathogens.

[32]  N. Høiby,et al.  Formation of hydroxyl radicals contributes to the bactericidal activity of ciprofloxacin against Pseudomonas aeruginosa biofilms. , 2014, Pathogens and disease.

[33]  N. Osheroff,et al.  Mechanism of Quinolone Action and Resistance , 2014, Biochemistry.

[34]  Robert E W Hancock,et al.  Bacterial biofilm development as a multicellular adaptation: antibiotic resistance and new therapeutic strategies. , 2013, Current opinion in microbiology.

[35]  K. Poole,et al.  Functional characterization of the NfxB repressor of the mexCD-oprJ multidrug efflux operon of Pseudomonas aeruginosa. , 2013, Microbiology.

[36]  M. Sommer,et al.  Use of Collateral Sensitivity Networks to Design Drug Cycling Protocols That Avoid Resistance Development , 2013, Science Translational Medicine.

[37]  S. Molin,et al.  Sublethal Ciprofloxacin Treatment Leads to Rapid Development of High-Level Ciprofloxacin Resistance during Long-Term Experimental Evolution of Pseudomonas aeruginosa , 2013, Antimicrobial Agents and Chemotherapy.

[38]  N. R. Morero,et al.  nfxB as a Novel Target for Analysis of Mutation Spectra in Pseudomonas aeruginosa , 2013, PloS one.

[39]  N. Osheroff,et al.  Topoisomerase IV-quinolone interactions are mediated through a water-metal ion bridge: mechanistic basis of quinolone resistance , 2013, Nucleic acids research.

[40]  Andreas Dötsch,et al.  Quantitative Contributions of Target Alteration and Decreased Drug Accumulation to Pseudomonas aeruginosa Fluoroquinolone Resistance , 2012, Antimicrobial Agents and Chemotherapy.

[41]  Yongyu Rui,et al.  Novel ISCR1-linked resistance genes found in multidrug-resistant Gram-negative bacteria in southern China. , 2012, International journal of antimicrobial agents.

[42]  L. Fernández,et al.  Adaptive and Mutational Resistance: Role of Porins and Efflux Pumps in Drug Resistance , 2012, Clinical Microbiology Reviews.

[43]  A. Wong,et al.  Genomics of Adaptation during Experimental Evolution of the Opportunistic Pathogen Pseudomonas aeruginosa , 2012, PLoS genetics.

[44]  R. Hancock,et al.  Involvement of the Lon Protease in the SOS Response Triggered by Ciprofloxacin in Pseudomonas aeruginosa PAO1 , 2012, Antimicrobial Agents and Chemotherapy.

[45]  R. Fani,et al.  Evaluation of fluoroquinolone resistance mechanisms in Pseudomonas aeruginosa multidrug resistance clinical isolates. , 2012, Microbial drug resistance.

[46]  N. Osheroff,et al.  Drug interactions with Bacillus anthracis topoisomerase IV: biochemical basis for quinolone action and resistance. , 2012, Biochemistry.

[47]  J. Michiels,et al.  Phenotypic and Genome-Wide Analysis of an Antibiotic-Resistant Small Colony Variant (SCV) of Pseudomonas aeruginosa , 2011, PloS one.

[48]  C. van Delden,et al.  Role of the MexEF-OprN Efflux System in Low-Level Resistance of Pseudomonas aeruginosa to Ciprofloxacin , 2011, Antimicrobial Agents and Chemotherapy.

[49]  R. Mösges,et al.  Treatment of acute otitis externa with ciprofloxacin otic 0.2% antibiotic ear solution , 2011, Therapeutics and clinical risk management.

[50]  A. Wong,et al.  Parallel evolution and local differentiation in quinolone resistance in Pseudomonas aeruginosa. , 2011, Microbiology.

[51]  K. Poole.  Pseudomonas Aeruginosa: Resistance to the Max , 2011, Front. Microbio..

[52]  A. Fosberry,et al.  Structural basis of quinolone inhibition of type IIA topoisomerases and target-mediated resistance , 2010, Nature Structural &Molecular Biology.

[53]  Morgan C. Giddings,et al.  The Development of Ciprofloxacin Resistance in Pseudomonas aeruginosa Involves Multiple Response Stages and Multiple Proteins , 2010, Antimicrobial Agents and Chemotherapy.

[54]  T. Kiser,et al.  Efflux Pump Contribution to Multidrug Resistance in Clinical Isolates of Pseudomonas aeruginosa , 2010, Pharmacotherapy.

[55]  Z. Zoumot,et al.  Respiratory infection in noncystic fibrosis bronchiectasis , 2010, Current opinion in infectious diseases.

[56]  Diarmaid Hughes,et al.  Antibiotic resistance and its cost: is it possible to reverse resistance? , 2010, Nature Reviews Microbiology.

[57]  C. McPherson,et al.  The relative contribution of efflux and target gene mutations to fluoroquinolone resistance in recent clinical isolates of Pseudomonas aeruginosa , 2010, European Journal of Clinical Microbiology & Infectious Diseases.

[58]  Jordi Rello,et al.  International study of the prevalence and outcomes of infection in intensive care units. , 2009, JAMA.

[59]  Nancy D. Hanson,et al.  Antibacterial-Resistant Pseudomonas aeruginosa: Clinical Impact and Complex Regulation of Chromosomally Encoded Resistance Mechanisms , 2009, Clinical Microbiology Reviews.

[60]  Y. Carmeli,et al.  Impact of quinolone restriction on resistance patterns of Escherichia coli isolated from urine by culture in a community setting. , 2009, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[61]  H. Zgurskaya.  Multicomponent drug efflux complexes: architecture and mechanism of assembly. , 2009, Future microbiology.

[62]  Xilin Zhao,et al.  Quinolones: Action and Resistance Updated , 2009, Current Topics in Medicinal Chemistry.

[63]  J. Townsend,et al.  Factors affecting the reversal of antimicrobial-drug resistance. , 2009, The Lancet. Infectious diseases.

[64]  G. Phan,et al.  Efflux Unbalance in Pseudomonas aeruginosa Isolates from Cystic Fibrosis Patients , 2009, Antimicrobial Agents and Chemotherapy.

[65]  V. Jarlier,et al.  Contribution of ParE Mutation and Efflux to Ciprofloxacin Resistance in Pseudomonas aeruginosa Clinical Isolates , 2008, Journal of chemotherapy.

[66]  Robert E. W. Hancock,et al.  Complex Ciprofloxacin Resistome Revealed by Screening a Pseudomonas aeruginosa Mutant Library for Altered Susceptibility , 2008, Antimicrobial Agents and Chemotherapy.

[67]  K. Tanimoto,et al.  Fluoroquinolone Enhances the Mutation Frequency for Meropenem-Selected Carbapenem Resistance in Pseudomonas aeruginosa, but Use of the High-Potency Drug Doripenem Inhibits Mutant Formation , 2008, Antimicrobial Agents and Chemotherapy.

[68]  D. Monnet,et al.  Relationship between Antibiotic Use and Incidence of MexXY-OprM Overproducers among Clinical Isolates of Pseudomonas aeruginosa , 2008, Antimicrobial Agents and Chemotherapy.

[69]  H. Seifert,et al.  Activity of Meropenem with and without Ciprofloxacin and Colistin against Pseudomonas aeruginosa and Acinetobacter baumannii , 2007, Antimicrobial Agents and Chemotherapy.

[70]  I. Wiegand,et al.  Resistance Mechanisms of Multiresistant Pseudomonas aeruginosa Strains from Germany and Correlation with Hypermutation , 2007, Antimicrobial Agents and Chemotherapy.

[71]  D. Landman,et al.  Evolution of antimicrobial resistance among Pseudomonas aeruginosa, Acinetobacter baumannii and Klebsiella pneumoniae in Brooklyn, NY. , 2007, The Journal of antimicrobial chemotherapy.

[72]  N. Hanson,et al.  Increased Expression of ampC in Pseudomonas aeruginosa Mutants Selected with Ciprofloxacin , 2007, Antimicrobial Agents and Chemotherapy.

[73]  I. Matic,et al.  Antibiotic‐mediated recombination: ciprofloxacin stimulates SOS‐independent recombination of divergent sequences in Escherichia coli , 2007, Molecular microbiology.

[74]  S. Levy,et al.  Molecular Mechanisms of Antibacterial Multidrug Resistance , 2007, Cell.

[75]  F. Baquero,et al.  Antibiotics as intermicrobial signaling agents instead of weapons , 2006, Proceedings of the National Academy of Sciences.

[76]  Steven R. Head,et al.  Defining the Pseudomonas aeruginosa SOS Response and Its Role in the Global Response to the Antibiotic Ciprofloxacin , 2006, Journal of bacteriology.

[77]  David A. D'Argenio,et al.  Genetic adaptation by Pseudomonas aeruginosa to the airways of cystic fibrosis patients. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[78]  D. Livermore,et al.  Effect of subinhibitory concentrations of antibiotics on mutation frequency in Streptococcus pneumoniae. , 2006, The Journal of antimicrobial chemotherapy.

[79]  D. Wolter,et al.  Levofloxacin/imipenem prevents the emergence of high-level resistance among Pseudomonas aeruginosa strains already lacking susceptibility to one or both drugs. , 2006, The Journal of antimicrobial chemotherapy.

[80]  Jonathan R Edwards,et al.  Overview of nosocomial infections caused by gram-negative bacilli. , 2005, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[81]  Michelle D. Brazas,et al.  Ciprofloxacin Induction of a Susceptibility Determinant in Pseudomonas aeruginosa , 2005, Antimicrobial Agents and Chemotherapy.

[82]  V. Andriole.  The quinolones: past, present, and future. , 2005, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[83]  G. Jacoby.  Mechanisms of resistance to quinolones. , 2005, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[84]  K. Poole.  Efflux-mediated antimicrobial resistance. , 2005, The Journal of antimicrobial chemotherapy.

[85]  Floyd E Romesberg,et al.  Inhibition of Mutation and Combating the Evolution of Antibiotic Resistance , 2005, PLoS biology.

[86]  Bong Su Kim,et al.  Alterations in the GyrA and GyrB subunits of topoisomerase II and the ParC and ParE subunits of topoisomerase IV in ciprofloxacin-resistant clinical isolates of Pseudomonas aeruginosa. , 2005, International journal of antimicrobial agents.

[87]  L. Mitscher.  Bacterial topoisomerase inhibitors: quinolone and pyridone antibacterial agents. , 2005, Chemical reviews.

[88]  E. Romanowski,et al.  A laboratory evaluation of antibiotic therapy for ciprofloxacin-resistant Pseudomonas aeruginosa. , 2004, American journal of ophthalmology.

[89]  M. Kilian,et al.  Ciprofloxacin susceptibility of Pseudomonas aeruginosa isolates from keratitis , 2003, The British journal of ophthalmology.

[90]  M. Stefanidou,et al.  Survey of resistance of Pseudomonas aeruginosa from UK patients with cystic fibrosis to six commonly prescribed antimicrobial agents , 2003, Thorax.

[91]  J. Verhoef,et al.  Mutations in GyrA, ParC, MexR and NfxB in clinical isolates of Pseudomonas aeruginosa. , 2003, International journal of antimicrobial agents.

[92]  Philip S. Stewart,et al.  Contributions of Antibiotic Penetration, Oxygen Limitation, and Low Metabolic Activity to Tolerance of Pseudomonas aeruginosa Biofilms to Ciprofloxacin and Tobramycin , 2003, Antimicrobial Agents and Chemotherapy.

[93]  JAMES C. Wang,et al.  Cellular roles of DNA topoisomerases: a molecular perspective , 2002, Nature Reviews Molecular Cell Biology.

[94]  D. Livermore,et al.  Multiple mechanisms of antimicrobial resistance in Pseudomonas aeruginosa: our worst nightmare? , 2002, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[95]  O. Clermont,et al.  In vivo selection of a target/efflux double mutant of Pseudomonas aeruginosa by ciprofloxacin therapy. , 2001, The Journal of antimicrobial chemotherapy.

[96]  A. Yamaguchi,et al.  Type II Topoisomerase Mutations in Fluoroquinolone-Resistant Clinical Strains of Pseudomonas aeruginosa Isolated in 1998 and 1999: Role of Target Enzyme in Mechanism of Fluoroquinolone Resistance , 2001, Antimicrobial Agents and Chemotherapy.

[97]  Anthony Maxwell,et al.  Interaction between DNA Gyrase and Quinolones: Effects of Alanine Mutations at GyrA Subunit Residues Ser83and Asp87 , 2001, Antimicrobial Agents and Chemotherapy.

[98]  J. Courcelle,et al.  Comparative gene expression profiles following UV exposure in wild-type and SOS-deficient Escherichia coli. , 2001, Genetics.

[99]  N. Masuda,et al.  Hypersusceptibility of the Pseudomonas aeruginosa nfxB Mutant to β-Lactams Due to Reduced Expression of the AmpC β-Lactamase , 2001, Antimicrobial Agents and Chemotherapy.

[100]  J. Emerson,et al.  Longitudinal assessment of Pseudomonas aeruginosa in young children with cystic fibrosis. , 2001, The Journal of infectious diseases.

[101]  J. Lyczak,et al.  Establishment of Pseudomonas aeruginosa infection: lessons from a versatile opportunist. , 2000, Microbes and infection.

[102]  N. Høiby,et al.  Molecular Mechanisms of Fluoroquinolone Resistance in Pseudomonas aeruginosa Isolates from Cystic Fibrosis Patients , 2000, Antimicrobial Agents and Chemotherapy.

[103]  D. Hooper.  New uses for new and old quinolones and the challenge of resistance. , 2000, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[104]  H. Nikaido,et al.  Involvement of an Active Efflux System in the Natural Resistance of Pseudomonas aeruginosa to Aminoglycosides , 1999 .

[105]  Y. Onodera,et al.  Cloning, Expression, and Enzymatic Characterization of Pseudomonas aeruginosaTopoisomerase IV , 1999, Antimicrobial Agents and Chemotherapy.

[106]  V. Jarlier,et al.  Type II Topoisomerase Mutations in Ciprofloxacin-Resistant Strains of Pseudomonas aeruginosa , 1999, Antimicrobial Agents and Chemotherapy.

[107]  H. Nikaido,et al.  Multiple antibiotic resistance and efflux. , 1998, Current opinion in microbiology.

[108]  H. Hiasa,et al.  DNA gyrase and topoisomerase IV: biochemical activities, physiological roles during chromosome replication, and drug sensitivities. , 1998, Biochimica et biophysica acta.

[109]  K. Drlica,et al.  DNA gyrase, topoisomerase IV, and the 4-quinolones , 1997, Microbiology and molecular biology reviews : MMBR.

[110]  P. Stewart,et al.  Comparison of recalcitrance to ciprofloxacin and levofloxacin exhibited by Pseudomonas aeruginosa bofilms displaying rapid-transport characteristics , 1997, Antimicrobial agents and chemotherapy.

[111]  N. Gotoh,et al.  Characterization of MexE–MexF–OprN, a positively regulated multidrug efflux system of Pseudomonas aeruginosa , 1997, Molecular microbiology.

[112]  K. Poole,et al.  Overexpression of the mexC–mexD–oprJ efflux operon in nfxB‐type multidrug‐resistant strains of Pseudomonas aeruginosa , 1996, Molecular microbiology.

[113]  R. Raz,et al.  Oral ciprofloxacin for treatment of infection following nail puncture wounds of the foot. , 1995, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[114]  A. Maxwell,et al.  A single point mutation in the DNA gyrase A protein greatly reduces binding of fluoroquinolones to the gyrase-DNA complex , 1993, Antimicrobial Agents and Chemotherapy.

[115]  H. Niki,et al.  New topoisomerase essential for chromosome segregation in E. coli , 1990, Cell.

[116]  C. Bailey,et al.  Relapsing malignant otitis externa successfully treated with ciprofloxacin , 1988, The Journal of Laryngology & Otology.

[117]  A. Scarpa,et al.  Genetic and physiological characterization of ciprofloxacin resistance in Pseudomonas aeruginosa PAO , 1988, Antimicrobial Agents and Chemotherapy.

[118]  R. Auckenthaler,et al.  Combination therapy: a way to limit emergence of resistance? , 1986, The American journal of medicine.

[119]  Bing Li,et al.  Complete sequence of pBM413, a novel multidrug resistance megaplasmid carrying qnrVC6 and blaIMP-45 from pseudomonas aeruginosa. , 2018, International journal of antimicrobial agents.

[120]  B. Kégl,et al.  Bacterial evolution of antibiotic hypersensitivity , 2013, Molecular systems biology.

[121]  M. Kollef,et al.  The Epidemiology, Pathogenesis and Treatment of Pseudomonas aeruginosa Infections , 2012, Drugs.

[122]  D. Hooper.  Mode of Action of Fluoroquinolones , 2012, Drugs.

[123]  M. Webber,et al.  High levels of multidrug resistance in clinical isolates of Gram-negative pathogens from Nigeria. , 2011, International journal of antimicrobial agents.

[124]  E. Friedberg,et al.  DNA Repair and Mutagenesis , 2006 .

[125]  U. Mazurek,et al.  GyrA mutations in ciprofloxacin-resistant clinical isolates of Pseudomonas aeruginosa in a Silesian Hospital in Poland. , 2005, Polish journal of microbiology.

[126]  H. Oh,et al.  Role of efflux pumps and mutations in genes for topoisomerases II and IV in fluoroquinolone-resistant Pseudomonas aeruginosa strains. , 2003, Microbial drug resistance.

[127]  N. Masuda,et al.  Hypersusceptibility of the Pseudomonas aeruginosa nfxB mutant to beta-lactams due to reduced expression of the ampC beta-lactamase. , 2001, Antimicrobial agents and chemotherapy.

[128]  M. Hoşgör,et al.  Investigation of synergism of meropenem and ciprofloxacin against Pseudomonas aeruginosa and Acinetobacter strains isolated from intensive care unit infections. , 2001, Scandinavian journal of infectious diseases.

[129]  B. Wretlind,et al.  Mechanisms of quinolone resistance in clinical strains of Pseudomonas aeruginosa. , 1998, Microbial drug resistance.