Antibiotic resistance and its cost: is it possible to reverse resistance?

Most antibiotic resistance mechanisms are associated with a fitness cost that is typically observed as a reduced bacterial growth rate. The magnitude of this cost is the main biological parameter that influences the rate of development of resistance, the stability of the resistance and the rate at which the resistance might decrease if antibiotic use were reduced. These findings suggest that the fitness costs of resistance will allow susceptible bacteria to outcompete resistant bacteria if the selective pressure from antibiotics is reduced. Unfortunately, the available data suggest that the rate of reversibility will be slow at the community level. Here, we review the factors that influence the fitness costs of antibiotic resistance, the ways by which bacteria can reduce these costs and the possibility of exploiting them.

[1]  G. Eliopoulos,et al.  Linezolid resistance in sequential Staphylococcus aureus isolates associated with a T2500A mutation in the 23S rRNA gene and loss of a single copy of rRNA. , 2004, The Journal of infectious diseases.

[2]  D. Sandvang,et al.  Biological Cost of Single and Multiple Norfloxacin Resistance Mutations in Escherichia coli Implicated in Urinary Tract Infections , 2005, Antimicrobial Agents and Chemotherapy.

[3]  H. Juan Small Colony Variants: a Pathogenic Form of Bacteria that Facilitates Persistent and Recurrent Infections , 2009 .

[4]  Cecilia Dahlberg,et al.  Amelioration of the cost of conjugative plasmid carriage in Eschericha coli K12. , 2003, Genetics.

[5]  O. Berg,et al.  Mutation frequency and biological cost of antibiotic resistance in Helicobacter pylori , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[6]  D. Guay Contemporary Management of Uncomplicated Urinary Tract Infections , 2012, Drugs.

[7]  O. Sahin,et al.  Enhanced in vivo fitness of fluoroquinolone-resistant Campylobacter jejuni in the absence of antibiotic selection pressure. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[8]  P. Bennett,et al.  Rifampicin resistance and its fitness cost in Enterococcus faecium. , 2004, The Journal of antimicrobial chemotherapy.

[9]  M. Lipsitch,et al.  Understanding the spread of antibiotic resistant pathogens in hospitals: mathematical models as tools for control. , 2001, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[10]  S. Schrag,et al.  Reducing antibiotic resistance , 1996, Nature.

[11]  D. Andersson,et al.  The Fitness Cost of Streptomycin Resistance Depends on rpsL Mutation, Carbon Source and RpoS (σS) , 2009, Genetics.

[12]  F. Claverie-Martin,et al.  Glycopeptide resistance in enterococci. , 2000, International microbiology : the official journal of the Spanish Society for Microbiology.

[13]  J. Mcgowan Minimizing Antimicrobial Resistance in Hospital Bacteria: Can Switching or Cycling Drugs Help? , 1986, Infection Control.

[14]  F. M. Stewart,et al.  The population genetics of antibiotic resistance. , 1997, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[15]  Andreas Handel,et al.  The Role of Compensatory Mutations in the Emergence of Drug Resistance , 2006, PLoS Comput. Biol..

[16]  D. Andersson,et al.  Reduction of the fitness burden of quinolone resistance in Pseudomonas aeruginosa. , 2005, The Journal of antimicrobial chemotherapy.

[17]  A. Robicsek,et al.  The worldwide emergence of plasmid-mediated quinolone resistance. , 2006, The Lancet. Infectious diseases.

[18]  I. Chopra,et al.  Genetic Basis of Resistance to Fusidic Acid in Staphylococci , 2007, Antimicrobial Agents and Chemotherapy.

[19]  M G Reynolds,et al.  Compensatory evolution in rifampin-resistant Escherichia coli. , 2000, Genetics.

[20]  B. Spratt,et al.  Antibiotic resistance: Counting the cost , 1996, Current Biology.

[21]  M. Bidochka,et al.  Bacterial fitness and plasmid loss: the importance of culture conditions and plasmid size. , 1998, Canadian journal of microbiology.

[22]  Jonathan D. Cryer,et al.  Time Series Analysis , 1986 .

[23]  S. Gillespie,et al.  Analysis of rpoB and pncA mutations in the published literature: an insight into the role of oxidative stress in Mycobacterium tuberculosis evolution? , 2005, The Journal of antimicrobial chemotherapy.

[24]  M. Skurnik,et al.  Erythromycin Resistance Genes in Group A Streptococci in Finland , 1999, Antimicrobial Agents and Chemotherapy.

[25]  D. Hughes,et al.  Genetic Determinants of Resistance to Fusidic Acid among Clinical Bacteremia Isolates of Staphylococcus aureus , 2009, Antimicrobial Agents and Chemotherapy.

[26]  Lotte Lambertsen,et al.  Mini-Tn7 transposons for site-specific tagging of bacteria with fluorescent proteins. , 2004, Environmental microbiology.

[27]  R. Wise Antimicrobial resistance: priorities for action. , 2002, The Journal of antimicrobial chemotherapy.

[28]  D. Andersson,et al.  Novel ribosomal mutations affecting translational accuracy, antibiotic resistance and virulence of Salmonella typhimurium , 1999, Molecular microbiology.

[29]  C. Fishwick,et al.  Analysis of Mupirocin Resistance and Fitness in Staphylococcus aureus by Molecular Genetic and Structural Modeling Techniques , 2004, Antimicrobial Agents and Chemotherapy.

[30]  C. Fishwick,et al.  Molecular Genetic and Structural Modeling Studies of Staphylococcus aureus RNA Polymerase and the Fitness of Rifampin Resistance Genotypes in Relation to Clinical Prevalence , 2006, Antimicrobial Agents and Chemotherapy.

[31]  T. Wichelhaus,et al.  Compensatory Adaptation to the Loss of Biological Fitness Associated with Acquisition of Fusidic Acid Resistance in Staphylococcus aureus , 2005, Antimicrobial Agents and Chemotherapy.

[32]  D. Andersson,et al.  Effect of rpoB Mutations Conferring Rifampin Resistance on Fitness of Mycobacterium tuberculosis , 2004, Antimicrobial Agents and Chemotherapy.

[33]  O. Berg,et al.  Biological Costs and Mechanisms of Fosfomycin Resistance in Escherichia coli , 2003, Antimicrobial Agents and Chemotherapy.

[34]  J. Frère,et al.  Cytosolic Intermediates for Cell Wall Biosynthesis and Degradation Control Inducible β-Lactam Resistance in Gram-Negative Bacteria , 1997, Cell.

[35]  J. Daurès,et al.  Impact of infection control interventions and antibiotic use on hospital MRSA: a multivariate interrupted time-series analysis. , 2007, International journal of antimicrobial agents.

[36]  D. Rouse,et al.  Expression of katG in Mycobacterium tuberculosis is associated with its growth and persistence in mice and guinea pigs. , 1998, The Journal of infectious diseases.

[37]  G Kahlmeter,et al.  Little evidence for reversibility of trimethoprim resistance after a drastic reduction in trimethoprim use. , 2010, The Journal of antimicrobial chemotherapy.

[38]  M. Blaser,et al.  Persistence of Resistant Staphylococcus epidermidis after Single Course of Clarithromycin , 2005, Emerging infectious diseases.

[39]  Ted Cohen,et al.  The effect of drug resistance on the fitness of Mycobacterium tuberculosis. , 2003, The Lancet. Infectious diseases.

[40]  M. Blaser,et al.  Long-Term Persistence of Resistant Enterococcus Species after Antibiotics To Eradicate Helicobacter pylori , 2003, Annals of Internal Medicine.

[41]  N. Woodford,et al.  Infections caused by Gram-positive bacteria: a review of the global challenge. , 2009, The Journal of infection.

[42]  S. Eriksson,et al.  Fusidic Acid-Resistant Mutants of Salmonella enterica Serovar Typhimurium with Low Fitness In Vivo Are Defective in RpoS Induction , 2003, Antimicrobial Agents and Chemotherapy.

[43]  S. Cole,et al.  Effects of overexpression of the alkyl hydroperoxide reductase AhpC on the virulence and isoniazid resistance of Mycobacterium tuberculosis , 1997, Infection and immunity.

[44]  D. Livermore,et al.  Enhancement of host fitness by the sul2-coding plasmid p9123 in the absence of selective pressure. , 2004, The Journal of antimicrobial chemotherapy.

[45]  Y. Arakawa,et al.  Growth Competition of Macrolide‐Resistant and ‐Susceptible Helicobacter pylori Strains , 2004, Microbiology and immunology.

[46]  T. Wilson,et al.  Effect of inhA and katG on isoniazid resistance and virulence of Mycobacterium bovis , 1995, Molecular microbiology.

[47]  H. Nikaido Multidrug resistance in bacteria. , 2009, Annual review of biochemistry.

[48]  G. Swedberg,et al.  Adaptation to sulfonamide resistance in Neisseria meningitidis may have required compensatory changes to retain enzyme function: kinetic analysis of dihydropteroate synthases from N. meningitidis expressed in a knockout mutant of Escherichia coli , 1997, Journal of bacteriology.

[49]  I. Chopra,et al.  Characterization of the Epidemic European Fusidic Acid-Resistant Impetigo Clone of Staphylococcus aureus , 2007, Journal of Clinical Microbiology.

[50]  C. D. Long,et al.  The Competitive Cost of Antibiotic Resistance in Mycobacterium tuberculosis , 2006, Science.

[51]  D. Hughes,et al.  Genetic and Phenotypic Identification of Fusidic Acid-Resistant Mutants with the Small-Colony-Variant Phenotype in Staphylococcus aureus , 2007, Antimicrobial Agents and Chemotherapy.

[52]  D. Farrell,et al.  Heterogeneous Macrolide Resistance and Gene Conversion in the Pneumococcus , 2006, Antimicrobial Agents and Chemotherapy.

[53]  O. Berg,et al.  Reducing the fitness cost of antibiotic resistance by amplification of initiator tRNA genes. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[54]  R. Cantón Antibiotic resistance genes from the environment: a perspective through newly identified antibiotic resistance mechanisms in the clinical setting. , 2009, Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases.

[55]  C. Walsh,et al.  Molecular basis for vancomycin resistance in Enterococcus faecium BM4147: biosynthesis of a depsipeptide peptidoglycan precursor by vancomycin resistance proteins VanH and VanA. , 1991, Biochemistry.

[56]  D. Hughes,et al.  Hyper-susceptibility of a fusidic acid-resistant mutant of Salmonella to different classes of antibiotics. , 2005, FEMS microbiology letters.

[57]  R. Anderson,et al.  Vancomycin-resistant enterococci in intensive-care hospital settings: transmission dynamics, persistence, and the impact of infection control programs. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[58]  Ted Cohen,et al.  Isoniazid resistance and the future of drug-resistant tuberculosis. , 2004, Microbial drug resistance.

[59]  Lars Liljas,et al.  Compensatory adaptation to the deleterious effect of antibiotic resistance in Salmonella typhimurium , 2002, Molecular microbiology.

[60]  Valeria Souza,et al.  Stress-Induced Mutagenesis in Bacteria , 2003, Science.

[61]  S. Gudmundsson,et al.  Clonal spread of resistant pneumococci despite diminished antimicrobial use. , 2002, Microbial drug resistance.

[62]  B. Levin,et al.  Fitness Costs of Fluoroquinolone Resistance in Streptococcus pneumoniae , 2006, Antimicrobial Agents and Chemotherapy.

[63]  Carl T. Bergstrom,et al.  The epidemiology of antibiotic resistance in hospitals: paradoxes and prescriptions. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[64]  A. Sundsfjord,et al.  Stability, persistence, and evolution of plasmid-encoded VanA glycopeptide resistance in enterococci in the absence of antibiotic selection in vitro and in gnotobiotic mice. , 2002, Microbial drug resistance.

[65]  S. Nyberg,et al.  Association between Antimicrobial Consumption and Resistance in Escherichia coli , 2008, Antimicrobial Agents and Chemotherapy.

[66]  P. E. Kopp,et al.  Superspreading and the effect of individual variation on disease emergence , 2005, Nature.

[67]  E. Böttger,et al.  Fitness of antibiotic-resistant microorganisms and compensatory mutations , 1998, Nature Medicine.

[68]  K. Francis,et al.  Real-Time In Vivo Bioluminescent Imaging for Evaluating the Efficacy of Antibiotics in a Rat Staphylococcus aureus Endocarditis Model , 2005, Antimicrobial Agents and Chemotherapy.

[69]  D. Ince,et al.  Quinolone Resistance Due to Reduced Target Enzyme Expression , 2003, Journal of bacteriology.

[70]  M. Arthur,et al.  The VanS-VanR two-component regulatory system controls synthesis of depsipeptide peptidoglycan precursors in Enterococcus faecium BM4147 , 1992, Journal of bacteriology.

[71]  P. Laippala,et al.  Effect of macrolide consumption on erythromycin resistance in Streptococcus pyogenes in Finland in 1997-2001. , 2004, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[72]  G. Jacoby,et al.  Quinolone resistance from a transferable plasmid , 1998, The Lancet.

[73]  P Huovinen,et al.  The effect of changes in the consumption of macrolide antibiotics on erythromycin resistance in group A streptococci in Finland. Finnish Study Group for Antimicrobial Resistance. , 1997, The New England journal of medicine.

[74]  D. Hughes,et al.  Interplay in the Selection of Fluoroquinolone Resistance and Bacterial Fitness , 2009, PLoS pathogens.

[75]  Zaid Abdo,et al.  Combining Mathematical Models and Statistical Methods to Understand and Predict the Dynamics of Antibiotic-Sensitive Mutants in a Population of Resistant Bacteria During Experimental Evolution , 2004, Genetics.

[76]  K. Johnson An Update. , 1984, Journal of food protection.

[77]  B. Levin,et al.  Compensatory mutations, antibiotic resistance and the population genetics of adaptive evolution in bacteria. , 2000, Genetics.

[78]  J. E. Bouma,et al.  Effects of segregation and selection on instability of plasmid pACYC184 in Escherichia coli B , 1987, Journal of bacteriology.

[79]  P M Bennett,et al.  Assessment of the fitness impacts on Escherichia coli of acquisition of antibiotic resistance genes encoded by different types of genetic element. , 2005, The Journal of antimicrobial chemotherapy.

[80]  Dykes,et al.  Fitness costs associated with class IIa bacteriocin resistance in Listeria monocytogenes B73 , 1998, Letters in applied microbiology.

[81]  R. Anderson,et al.  Studies of antibiotic resistance within the patient, hospitals and the community using simple mathematical models. , 1999, Philosophical transactions of the Royal Society of London. Series B, Biological sciences.

[82]  Diarmaid Hughes,et al.  Gene amplification and adaptive evolution in bacteria. , 2009, Annual review of genetics.

[83]  D. Briles,et al.  Relative Fitness of Fluoroquinolone-resistant Streptococcus pneumoniae , 2005, Emerging infectious diseases.

[84]  F. Ausubel,et al.  Caenorhabditis elegans: a model genetic host to study Pseudomonas aeruginosa pathogenesis. , 2000, Current opinion in microbiology.

[85]  D. Livermore,et al.  Resistance among Escherichia coli to sulphonamides and other antimicrobials now little used in man. , 2005, The Journal of antimicrobial chemotherapy.

[86]  Kshitij D Modi,et al.  Noninvasive Monitoring of Pneumococcal Meningitis and Evaluation of Treatment Efficacy in an Experimental Mouse Model* , 2005, Molecular imaging.

[87]  M. Pai,et al.  Initial Drug Resistance and Tuberculosis Treatment Outcomes: Systematic Review and Meta-analysis , 2008, Annals of Internal Medicine.

[88]  T. Wichelhaus,et al.  Biological Cost of Rifampin Resistance from the Perspective of Staphylococcus aureus , 2002, Antimicrobial Agents and Chemotherapy.

[89]  P. Small,et al.  Effect of drug resistance on the generation of secondary cases of tuberculosis. , 2003, The Journal of infectious diseases.

[90]  T. Wichelhaus,et al.  Molecular analysis of fusidic acid resistance in Staphylococcus aureus , 2003, Molecular microbiology.

[91]  G. Eliopoulos,et al.  Reversion to susceptibility in a linezolid-resistant clinical isolate of Staphylococcus aureus. , 2004, The Journal of antimicrobial chemotherapy.

[92]  B. Levin,et al.  The biological cost of antibiotic resistance. , 1999, Current opinion in microbiology.

[93]  P. Courvalin,et al.  Fitness Cost of VanA-Type Vancomycin Resistance in Methicillin-Resistant Staphylococcus aureus , 2009, Antimicrobial Agents and Chemotherapy.

[94]  N. McCallum,et al.  Fitness Cost of SCCmec and Methicillin Resistance Levels in Staphylococcus aureus , 2004, Antimicrobial Agents and Chemotherapy.

[95]  D. Hughes,et al.  Fusidic Acid-Resistant Mutants of Salmonella enterica Serovar Typhimurium Have Low Levels of Heme and a Reduced Rate of Respiration and Are Sensitive to Oxidative Stress , 2004, Antimicrobial Agents and Chemotherapy.

[96]  C E Nord,et al.  Effect of antimicrobial agents on the ecological balance of human microflora. , 2001, The Lancet. Infectious diseases.

[97]  S. Normark beta-Lactamase induction in gram-negative bacteria is intimately linked to peptidoglycan recycling. , 1995, Microbial drug resistance.

[98]  N. Ward,et al.  Priorities for action , 2019, Ready for the Dry Years: Building Resilience to Drought in South-East Asia.

[99]  A. Maurelli,et al.  Fitness Cost Due to Mutations in the 16S rRNA Associated with Spectinomycin Resistance in Chlamydia psittaci 6BC , 2005, Antimicrobial Agents and Chemotherapy.

[100]  D. Andersson,et al.  Biological cost and compensatory evolution in fusidic acid‐resistant Staphylococcus aureus , 2001, Molecular microbiology.

[101]  Levin Br Models for the spread of resistant pathogens. , 2002 .

[102]  Clifton E. Barry,et al.  Compensatory ahpC Gene Expression in Isoniazid-Resistant Mycobacterium tuberculosis , 1996, Science.

[103]  O. Berg,et al.  Effects of environment on compensatory mutations to ameliorate costs of antibiotic resistance. , 2000, Science.

[104]  D. Livermore,et al.  Persistence of sulphonamide resistance in Escherichia coli in the UK despite national prescribing restriction , 2001, The Lancet.

[105]  J. Roth,et al.  Accumulation of mutants in “aging” bacterial colonies is due to growth under selection, not stress-induced mutagenesis , 2008, Proceedings of the National Academy of Sciences.

[106]  S. Normark,et al.  Bacterial cell wall recycling provides cytosolic muropeptides as effectors for beta‐lactamase induction. , 1994, The EMBO journal.

[107]  Hiroshi Nikaido,et al.  Efflux-Mediated Drug Resistance in Bacteria , 2012, Drugs.

[108]  F. Baquero,et al.  Fitness of in vitro selected Pseudomonas aeruginosa nalB and nfxB multidrug resistant mutants. , 2002, The Journal of antimicrobial chemotherapy.

[109]  D. Andersson,et al.  Drug resistance and fitness in Mycobacterium tuberculosis infection. , 2005, The Journal of infectious diseases.

[110]  Kshitij D Modi,et al.  Noninvasive Biophotonic Imaging for Monitoring of Catheter-Associated Urinary Tract Infections and Therapy in Mice , 2005, Infection and Immunity.

[111]  S. Gillespie,et al.  Multiple drug-resistant Mycobacterium tuberculosis: evidence for changing fitness following passage through human hosts. , 2002, Microbial drug resistance.

[112]  Linus Sandegren,et al.  Bacterial gene amplification: implications for the evolution of antibiotic resistance , 2009, Nature Reviews Microbiology.

[113]  O. Cars,et al.  Fitness of antibiotic resistant Staphylococcus epidermidis assessed by competition on the skin of human volunteers. , 2003, The Journal of antimicrobial chemotherapy.

[114]  B. Levin,et al.  Minimizing potential resistance: a population dynamics view. , 2001, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[115]  D. Andersson,et al.  Multiple mechanisms to ameliorate the fitness burden of mupirocin resistance in Salmonella typhimurium , 2007, Molecular microbiology.

[116]  F. Baquero,et al.  Biological Cost of AmpC Production forSalmonella enterica Serotype Typhimurium , 2000, Antimicrobial Agents and Chemotherapy.

[117]  E. Giraud,et al.  Fitness cost of fluoroquinolone resistance in Salmonella enterica serovar Typhimurium. , 2003, Journal of medical microbiology.

[118]  B. Levin,et al.  Adaptation to the fitness costs of antibiotic resistance in Escherichia coli , 1997, Proceedings of the Royal Society of London. Series B: Biological Sciences.

[119]  D. Hughes,et al.  Mutation Rate and Evolution of Fluoroquinolone Resistance in Escherichia coli Isolates from Patients with Urinary Tract Infections , 2003, Antimicrobial Agents and Chemotherapy.

[120]  G. Church,et al.  Functional Characterization of the Antibiotic Resistance Reservoir in the Human Microflora , 2009, Science.

[121]  M. Ehrenberg,et al.  Fusidic acid‐resistant EF‐G perturbs the accumulation of ppGpp , 2000, Molecular microbiology.

[122]  S. Gillespie,et al.  Physiological Cost of Rifampin Resistance Induced In Vitro in Mycobacterium tuberculosis , 1999, Antimicrobial Agents and Chemotherapy.

[123]  S. Levy,et al.  Survival of rifampin-resistant mutants of Pseudomonas fluorescens and Pseudomonas putida in soil systems. , 1988, Applied and environmental microbiology.

[124]  Georg Peters,et al.  Identification of the Genetic Basis for Clinical Menadione-Auxotrophic Small-Colony Variant Isolates of Staphylococcus aureus , 2008, Antimicrobial Agents and Chemotherapy.

[125]  S. Gillespie,et al.  Comparison of fitness of two isolates of Mycobacterium tuberculosis, one of which had developed multi-drug resistance during the course of treatment. , 2000, The Journal of infection.

[126]  J. E. Bouma,et al.  Evolution of a bacteria/plasmid association , 1988, Nature.

[127]  B. Levin Models for the spread of resistant pathogens. , 2002, The Netherlands journal of medicine.

[128]  A. Robicsek,et al.  Fluoroquinolone-modifying enzyme: a new adaptation of a common aminoglycoside acetyltransferase , 2006, Nature Medicine.

[129]  A. Liljas,et al.  The dynamic structure of EF-G studied by fusidic acid resistance and internal revertants. , 1996, Journal of molecular biology.

[130]  K. Kristinsson,et al.  Effect of antimicrobial use and other risk factors on antimicrobial resistance in pneumococci. , 1997, Microbial drug resistance.

[131]  R. May,et al.  Infectious disease dynamics: What characterizes a successful invader? , 2001, Philosophical transactions of the Royal Society of London. Series B, Biological sciences.

[132]  I. Chopra,et al.  The isoleucyl-tRNA synthetase mutation V588F conferring mupirocin resistance in glycopeptide-intermediate Staphylococcus aureus is not associated with a significant fitness burden. , 2003, The Journal of antimicrobial chemotherapy.

[133]  S. Lindquist,et al.  Coordinate regulation of beta-lactamase induction and peptidoglycan composition by the amp operon. , 1991, Science.

[134]  D. Andersson,et al.  Virulence of antibiotic-resistant Salmonella typhimurium. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[135]  S. Normark,et al.  Components of the peptidoglycan‐recycling pathway modulate invasion and intracellular survival of Salmonella enterica serovar Typhimurium , 2004, Cellular microbiology.

[136]  Fernando Baquero,et al.  Predicting antibiotic resistance , 2007, Nature Reviews Microbiology.

[137]  Andrew R. Francis,et al.  The epidemiological fitness cost of drug resistance in Mycobacterium tuberculosis , 2009, Proceedings of the National Academy of Sciences.

[138]  R. Lenski Quantifying fitness and gene stability in microorganisms. , 1991, Biotechnology.

[139]  I. Tubulekas,et al.  Suppression of rpsL phenotypes by tuf mutations reveals a unique relationship between translation elongation and growth rate , 1993, Molecular microbiology.

[140]  J. McElnay,et al.  Modelling the impact of antibiotic use and infection control practices on the incidence of hospital-acquired methicillin-resistant Staphylococcus aureus: a time-series analysis. , 2008, The Journal of antimicrobial chemotherapy.

[141]  I. Chopra,et al.  Molecular basis of fusB‐mediated resistance to fusidic acid in Staphylococcus aureus , 2006, Molecular microbiology.

[142]  E. Böttger,et al.  Fitness Cost of Chromosomal Drug Resistance-Conferring Mutations , 2002, Antimicrobial Agents and Chemotherapy.

[143]  S. Cole,et al.  Effect of katG Mutations on the Virulence of Mycobacterium tuberculosis and the Implication for Transmission in Humans , 2002, Infection and Immunity.

[144]  K. Francis,et al.  Monitoring in vivo fitness of rifampicin-resistant Staphylococcus aureus mutants in a mouse biofilm infection model. , 2005, The Journal of antimicrobial chemotherapy.