Fluoroquinolone resistance: Mechanisms, restrictive dosing, and anti-mutant screening strategies for new compounds

Antibiotic Discovery and Development

Volumn 9781461414001, Issue , 2012, Pages 485-514

  Drlica, Karl ^a   Zhao, Xilin ^a   Malik, Muhammad ^a   Salz, Tal ^a   Kerns, Robert ^b  

^a PUBLIC HEALTH RESEARCH INSTITUTE   (United States)

^b UNIVERSITY OF IOWA   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

EID: 84900019667     PISSN: None     EISSN: None     Source Type: Book    
DOI: 10.1007/978-1-4614-1400-1_14     Document Type: Chapter

References (206)

1. Lu T, Malik M, Drlica-Wagner A (2001) C-8-methoxy fluoroquinolones. Res Adv Antimicrob Agents Chemother 2:29-41
2. Kim O, Ohemeng K, Barrett J (2001) Advances in DNA gyrase inhibitors. Exp Opin Invest Drugs 10:199-212
3. Gellert M, Mizuuchi K, O'Dea MH et al (1977) Nalidixic acid resistance: a second genetic character involved in DNA gyrase activity. Proc Natl Acad Sci USA 74:4772-4776
4. Kato JI, Nishimura Y, Imamura R et al (1990) New topoisomerase essential for chromosome segregation in E. coli. Cell 63:393-404s
5. Kreuzer KN, Cozzarelli NR (1980) Formation and resolution of DNA catenanes by DNA gyrase. Cell 20:245-254
6. Mizuuchi K, Fisher LM, O'Dea M, Gellert M (1980) DNA gyrase action involves the introduction of transient double-strand breaks into DNA. Proc Natl Acad Sci USA 77:1847-1851
7. Zhao X, Malik M, Chan N, Drlica-Wagner A, Drlica K et al (2006) Lethal action of quinolones with a temperature-sensitive dnaB replication mutant of Escherichia coli. Antimicrob Agents Chemother 50:362-364
8. Drlica K, Hiasa H, Kerns R, Malik M et al (2009) Quinolones: action and resistance updated. CurrTopics in Med Chem 9:981-998
9. Drlica K, Malik M, Kerns RJ, Zhao X (2008) Quinolone-mediated bacterial death. Antimicrob Agents Chemother 52:385-392
10. Malik M, Hussain S, Drlica K (2007) Effect of anaerobic growth on quinolone lethality with Escherichia coli. Antimicrob Agents Chemother 51:28-34
11. Wang X, Zhao X, Malik M, Drlica K (2010) Contribution of reactive oxygen species to pathways of quinolone-mediated bacterial cell death. J Antimicrob Chemother 65(3):520-524
12. Dwyer D, Kohanski M, Hayete B, Collins J (2007) Gyrase inhibitors induce an oxidative damage cellular death pathway in Escherichia coli. Mol Syst Biol 3:91
13. Kohanski M, Dwyer D, Hayete B, Lawrence C, Collins J (2007) A common mechanism of cellular death induced by bactericidal antibiotics. Cell 130:797-810
14. Wang X, Zhao X (2009) Contribution of oxidative damage to antimicrobial lethality. Antimicrob Agents Chemother 53:1395-1402
15. Khodursky A, Cozzarelli N (1998) The mechanism of inhibition of topoisomerase IV by quinolone antibacterials. J Biol Chem 273:27668-27677
16. Madabhushi R, Marians K (2009) Actin homolog MreB affects chromosome segregation by regulating topoisomerase IV in Escherichia coli. Mol Cell 33:171-180
17. Li X, Zhao X, Drlica K (2002) Selection of Streptococcus pneumoniae mutants having reduced susceptibility to levofloxacin and moxifloxacin. Antimicrob Agents Chemother 46: 522-524
18. Pan XS, Ambler J, Mehtar S, Fisher LM (1996) Involvement of topoisomerase IV and DNA gyrase as ciprofloxacin targets in Streptococcus pneumoniae. Antimicrob Agents Chemother 40:2321-2326
19. Zhou J, Dong Y, Zhao X, Lee S et al (2000) Selection of antibiotic resistant bacterial mutants: allelic diversity among fluoroquinolone-resistant mutations. J Inf Dis 182:517-525
20. Ferrero L, Cameron B, Manse B, Lagneaux D, Blanche F et al (1994) Cloning and primary structure of Staphylococcus aureus DNA topoisomerase IV: a primary target of fluoroquinolones. Mol Microbiol 13:641-653
21. Kern W, Oethinger M, Jellen-Ritter A, Levy S (2004) Non-target gene mutations in the development of fluoroquinolone resistance in Escherichia coli. Antimicrob Agents Chemother 44:814-820
22. Ferrero L, Cameron B, Crouzet J (1995) Analysis of gyrA and grlA mutations in stepwiseselected ciprofloxacin-resistant mutants of Staphylococcus aureus. Antimicrob Agents Chemother 39:1554-1558
23. Acar J, Goldstein F (1997) Trends in bacterial resistance to fluoroquinolones. Clin Infect Dis 24:S67-S73
24. Johnson AP (1998) Antibiotic resistance among clinically important gram-positive bacteria in the UK. J Hosp Infect 40:17-26
25. Garcia-Rey C, Aguilar L, Baquero F (2000) Influences of different factors on prevalence of ciprofloxacin resistance in Streptococcus pneumoniae in Spain. Antimicrob Agents Chemother 44:3481-3482
26. Baquero F, Martinez-Beltran J, Loza E (1991) A review of antibiotic resistance patterns of Streptococcus pneumoniae in Europe. J Antimicrob Chemother 28(Suppl C):31-38
27. Bronzwaer SL, Cars O, Buchholz U, Mölstad S et al (2002) European-antimicrobialresistance- surveillance-system. A European study on the relationship between antimicrobial use and antimicrobial resistance. Emerg Infect Dis 8:278-282
28. Sahm D, Peterson D, Critchley I, Thronsberry C (2000) Analysis of ciprofloxacin activity against Streptococcus pneumoniae after 10 years of use in the United States. Antimicrob Agents Chemother 44:2521-2524
29. Hooper D (2000) New uses for new and old quinolones and the challenge of resistance. Clin Infect Dis 30:243-254
30. Aarestrup F, Jensen N, Jorsal S, Nielsen T (2000) Emergence of resistance to fluoroquinolones among bacteria causing infections in food animals in Denmark. Vet Record 146:76-78
31. Aarestrup F, Agerso Y, Ahrens P et al (2000) Antimicrobial susceptibility and presence of resistance genes in staphylococci from poultry. Vet Microbiol 74:353-364
32. Angulo F, Johnson K, Tauxe R, Cohen M (2000) Origins and consequences of antimicrobialresistant nontyphoidal Salmonella: implications for the use of fluoroquinolones in food animals. Microb Drug Resist 6:77-83
33. Engberg J, Aarestrup F, Taylor D et al (2001) Quinolone and macrolide resistance in Campylobacter jejuni and C. coli: resistance mechanisms and trends in human isolates. Emerg Infect Dis 7:24-34
34. Nelson J, Chiller T, Powers J, Angulo F (2007) Fluoroquinolone-resistant Campylobacter species and the withdrawal of fluoroquinolones from use in poultry: a public health success story. Clin Inf Dis 44:977-980
35. Duong HA, Nguyen HT, Hoang TT et al (2008) Occurrence, fate and antibiotic resistance of fluoroquinolone antibacterials in hospital wastewaters in Hanoi, Vietnam. Chemosphere 72:968-973
36. Davidson R, Davis I, Willey B et al (2008) Antimalarial therapy selection for quinolone resistance among Escherichia coli in the absence of quinolone exposure, in tropical South America. PLoS ONE 3:e2727
37. Gross MD, Siegel EC (1981) Incidence of mutator strains in Escherichia coli and coliforms in nature. Mutat Res 91:107-110
38. Jyssum K (1960) Observation of two types of genetic instability in Escherichia coli. Acta Pathol Microbiol Immunol Scand 48:113-120
39. LeClerc JE, Li B, Payne W, Cebula T (1996) High mutation frequencies among Escherichia coli and Salmonella pathogens. Science 274:1208
40. Negri M, Morosini M, Baquero M et al (2002) Very low cefotaxime concentrations select for hypermutable Streptococcus pneumoniae populations. Antimicrob Agents Chemother 46:528-530
41. Sniegowski PD, Gerrish PJ, Lenski RE (1997) Evolution of high mutation rates in experimental populations of E. coli. Nature 387:703-705
42. Arriaga-Alba M, Rivera-Sanchez R, Parra-Cervantes G et al (2000) Antimutagenesis of betacarotene to mutations induced by quinolone on Salmonella typhimurium. Arch Med Res 31:156-161
43. Arriaga-Alba M, Barron-Moreno F, Flores-Paz R et al (1998) Genotoxic evaluation of norfloxacin and pipemidic acid with the Escherichia coli PolA-/PolA + and the Ames test. Arch Med Res 29:235-240
44. Clerch B, Barbe J, Llagostera M (1992) The role of excision and error-prone repair systems in mutagenesis by fluorinated quinolones in Salmonella typhimurium. Mut Res 281: 207-213
45. Mamber S, Kolek B, Brookshire K et al (1993) Activity of quinolones in the Ames Salmonella TA102 mutagenicity test and other bacterial genotoxicity assays. Antimicrob Agents Chemother 37:213-217
46. Phillips I (1987) Bacterial mutagenicity and the 4-quinolones. J Antimicrob Chemother 20: 771-773
47. Cirz R, Romesberg F (2006) Induction and inhibition of ciprofloxacin resistance-conferring mutations in hypermutator bacteria. Antimicrob Agents Chemother 50:220-225
48. Cirz R, Chin J, Andes D et al (2005) Inhibition of mutation and combating the evolution of antibiotic resistance. Plos Biology 3:1024-1033
49. Malik M, Hoatam G, Chavda K et al (2010) Novel approach for comparing quinolones for emergence of resistant mutants during quinolone exposure. Antimicrob Agents Chemother 54(1):149-156
50. Jones R, Pfaller M (2001) Can antimicrobial susceptibility testing results for ciprofloxacin or levofloxacin predict susceptibility to a newer fluoroquinolone, gatifloxacin? report from the SENTRY antimicrobial surveillance program (1997-99). Diagnos Microb Infect Dis 39: 237-243
51. Fukuda H, Kishii R, Takei M, Hosaka M (2001) Contributions of the 8-methoxy group of gatifloxacin to resistance selectivity, target preference, and antibacterial activity against Streptococcus pneumoniae. Antimicrob Agents Chemother 45:1649-1653
52. Cambau E, Borden F, Collatz E, Gutmann L (1993) Novel gyrA point mutation in a strain of Escherichia coli resistant to fluoroquinolones but not to nalidixic acid. Antimicrob Agents Chemother 37:1247-1252
53. Hancock R (1997) The bacterial outer membrane as a drug barrier. Trends Microbiol 5:37-42
54. Michea-Hamzehpour M, Furet Y, Pechere JC (1991) Role of protein D2 and lipopolysaccharide in diffusion of quinolones through the outer membrane of Pseudomonas aeruginosa. Antimicrob Agents Chemother 35:2091-2097
55. Mitsuyama JI, Itoh Y, Takahata M et al (1992) In vitro antibacterial activities of tosufloxacin against and uptake of tosufloxacin by outer membrane mutants of Escherichia coli, Proteus mirabilis, and Salmonella typhimurium. Antimicrob Agents Chemother 36:2030-2036
56. Giraud E, Cloeckaert A, Kerboeuf D, Chaslus-Dancla E (2000) Evidence for active efflux as the primary mechanism of resistance to ciprofloxacin in Salmonella enterica serovar typhimurium. Antimicrob Agents Chemother 44:1223-1228
57. Cohen S, McMurry L, Levy S (1988) marA locus causes decreased expression of OmpF porin in multiple-antibiotic-resistant (Mar) mutants of Escherichia coli. J Bacteriol 170:5416-5422
58. Cohen SP, McMurry LM, Hooper DC et al (1989) Cross-resistance to fluoroquinolones in multiple-antibiotic-resistant (Mar) Escherichia coli selected by tetracycline or chloramphenicol: decreased drug accumulation associated with membrane changes in addition to OmpF reduction. Antimicrob Agents Chemother 33:1318-1325
59. Piddock L (2006) Multidrug-resistance efflux pumps - not just for resistance. Nat Rev Microbiol 4:629-636
60. Poole K (2008) Bacterial multidrug efflux pumps serve other functions. Microbe 3:179-185
61. Piddock L (2006) Clinically relevant chromosomally encoded multidrug resistance efflux pumps in bacteria. Clin Rev Microbiol 19:382-402
62. Nishino K, Yamaguchi A (2001) Analysis of a complete library of putative drug transporter genes in Escherichia coli. J Bacteriol 183:5803-5812
63. Lomovskaya O, Lewis K (1992) Emr, an Escherichia coli locus for multidrug resistance. Proc Natl Acad Sci USA 89:8938-8942
64. Yang S, Clayton S, Zechiedrich EL (2003) Relative contributions of the AcrAB, MdfA and NorE efflux pumps to quinolone resistance in Escherichia coli. J Antimicrob Chemother 51:545-556
65. Pankey G, Ashcraft D (2005) In vitro synergy of ciprofloxacin and gatifloxacin against ciprofloxacin-resistant Pseudomonas aeruginosa. Antimicrob Agents Chemother 49:2959-2964
66. Cloeckaert A, Chaslus-Dancla E (2001) Mechanisms of quinolone resistance in Salmonella. Vet Res 32:291-300
67. Oethinger M, Podglajen I, Kern W, Levy S (1998) Overexpression of the marA and soxS regulatory gene in clinical topoisomerase mutants of Escherichia coli. Antimicrob Agents Chemother 42:2089-2094
68. Mazzariol A, Tokue Y, Kanegawa T et al (2000) High-level fluoroquinolone-resistant clinical isolates of Escherichia coli overproduce multidrug efflux protein AcrA. Antimicrob Agents Chemother 44:3441-3443
69. Hirakawa H, Takumi-Kobayashi A, Theisen U et al (2008) AcrS/EnvR represses expression of the acrAB multidrug efflux genes in Escherichia coli. J Bacteriol 190:6276-6279
70. Wang H, Dzink-Fox J, Chen M, Levy SB (2001) Genetic characterization of highly fluoroquinolone- resistant clinical Escherichia coli strains from China: role of acrR mutations. Antimicrob Agents Chemother 45:1515-1521
71. Dupont P, Hocquet D, Jeannot K, Chavanet P et al (2005) Bacteriostatic and bactericidal activities of eight fluoroquinolones against MexAB-OprM-overproducing clinical strains of Pseudomonas aeruginosa. J Antimicrob Chemother 55:518-522
72. Masuda N, Sakagawa E, Ohya S et al (2000) Substrate specificities of MexAB-OprM, MexCD-OprJ, and MexXY-oprM efflux pumps in Pseudomonas aeruginosa. Antimicrob Agents Chemother 44:3322-3327
73. Poole K (2000) Efflux-mediated resistance to fluoroquinolones in gram-negative bacteria. Antimicrob Agents Chemother 44:2233-2241
74. Nakajima A, Sugimoto Y, Yoneyama H, Nakae T (2002) High-level fluoroquinolone resistance in Pseudomonas aeruginosa due to interplay of the MexAB-OprM efflux pump and the DNA gyrase mutation. Microbiol Immunol 46:391-395
75. Niga T, Ito H, Oyamada Y et al (2005) Cooperation between alteration of DNA gyrase genes and over-expression of MexB and MexX confers high-level fluoroquinolone resistance in Pseudomonas aeruginosa strains isolated from a patient who received a liver transplant followed by treatment with fluoroquinolones. Microbiol Immunol 49:443-446
76. Lee J, Lee Y, Park Y, Kim B (2005) 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. Int J Antimicrob Agents 25:290-295
77. Hansen G, Zhao X, Drlica K, Blondeau J (2006) Mutant prevention concentration for ciprofloxacin and levofloxacin with Pseudomonas aeruginosa. Int J Antimicrob Agents 27:120-124
78. Kriengkauykiat J, Porter E, Lomovskaya O, Wong-Beringer A (2005) Use of an efflux pump inhibitor to determine the prevalence of efflux pump-mediated fluoroquinolone resistance and multidrug resistance in Pseudomonas aeruginosa. Antimicrob Agents Chemother 49:565-570
79. Fukuda H, Hori S, Hiramatsu K (1998) Antibacterial activity of gatifloxacin (AM-1155, CG5501, BMS-206584), a newly developed fluoroquinolone, against sequentially acquired quinolone-resistant mutants and the norA transformant of Staphylococcus aureus. Antimicrob Agents Chemother 42:1917-1922
80. Kaatz GW, Seo SM (1995) Inducible norA -mediated multidrug resistance in Staphylococcus aureus. Antimicrob Agents Chemother 39:2650-2655
81. Neyfakh A, Borsch C, Kaatz G (1993) Fluoroquinolone resistance protein NorA of Staphylococcus aureus is a multidrug efflux transporter. Antimicrob Agents Chemother 37:128-129
82. Ng EY, Trucksis M, Hooper DC (1994) Quinolone resistance mediated by norA: physiologic characterization and relationship to flqB, a quinolone resistance locus on the Staphylococcus aureus chromosome. Antimicrobial Agents Chemother 38:1345-1355
83. Sun L, Sreedharan S, Plummer K, Fisher LM (1996) NorA plasmid resistance to fluoroquinolones: role of copy number and norA frameshift mutations. Antimicrob Agents Chemother 40:1665-1669
84. Ubukata K, Itoh NY, Konno M (1989) Cloning and expression of the norA gene for fluoroquinolone resistance in Staphylococcus aureus. AntimicrobAgents Chemother 33:1535-1539
85. Yoshida H, Bogaki M, Nakamura S et al (1990) Nucleotide sequence and characterization of the Staphylococcus aureus norA gene, which confers resistance to quinolones. J Bacteriol 172:6942-6949
86. Huet A, Raygada JL, Mendiratta K et al (2008) Multidrug efflux pump overexpression in Staphylococcus aureus after single and multiple in vitro exposures to biocides and dyes. Microbiology 154:3144-3153
87. Truong-Bolduc Q, Strahilevitz J, Hooper DC (2006) NorC, a new efflux pump regulated by MgrA of Staphylococcus aureus. Antimicrob Agents Chemother 50:1104-1107
88. Kaatz GW, McAleese F, Seo SM (2005) Multidrug resistance in Staphylococcus aureus due to overexpression of a novel multidrug and toxin extrusion (MATE) transport protein. Antimicrob Agents Chemother 49:1857-1864
89. Kumaraswami M, Schuman JT, Seo SM, Kaatz GW, Brennan RG (2009) Structural and biochemical characterization of MepR, a multidrug binding transcription regulator of the Staphylococcus aureus multidrug efflux pump MepA. Nucleic Acids Res 37(4):1211-1224
90. Gill MJ, Brenwald NP, Wise R (1999) Identification of an efflux pump gene, pmrA, associated with fluoroquinolone resistance in S. pneumoniae. Antimicrob Agents Chemother 43:187-189
91. Beyer R, Pestova E, Millichap JJ et al (2000) A convenient assay for estimating the possible involvement of efflux of fluoroquinolones by Streptococcus pneumoniae and Staphylococcus aureus: evidence for diminished moxifloxacin, sparfloxacin, and trovafloxacin efflux. Antimicrob Agents Chemother 44:798-801
92. Daporta M, Muñoz-Bellido JL, Guirao GY et al (2004) In vitro activity of older and newer fluoroquinolones against efflux-mediated high-level ciprofloxacin-resistant Streptococcus pneumoniae. Int J Antimicrob Agents 24:185-187
93. Jumbe N, Louie A, Miller MH et al (2006) Quinolone efflux pumps play a central role in emergence of fluoroquinolone resistance in Streptococcus pneumoniae. Antimicrob Agents Chemother 50:310-317
94. Louie A, Brown DL, Liu W et al (2007) In vitro infection model characterizing the effect of efflux pump inhibition on prevention of resistance to levofloxacin and ciprofloxacin in Streptococcus pneumoniae. Antimicrob Agents Chemother 51:3988-4000
95. Zhanel G, Hoban DJ, Schurek K, Karlowsky JA (2004) Role of efflux mechanisms on fluoroquinolone resistance in Streptococcus pneumoniae and Pseudomonas aeruginosa. Int J Antimicrob Agents 24:529-535
96. Avrain L, Garvey M, Mesaros N et al (2007) Selection of quinolone resistance in Streptococcus pneumoniae exposed in vitro to subinhibitory drug concentrations. J Antimicrob Chemother 60:965-972
97. Marrer E, Schad K, Satoh AT et al (2006) Involvement of the putative ATP-dependent efflux proteins PatA and PatB in fluoroquinolone resistance of a multidrug-resistant mutant of Streptococcus pneumoniae. Antimicrob Agents Chemother 50:685-693
98. Lomovskaya O, Lee A, Hoshino K et al (1999) Use of genetic approach to evaluate the consequences of inhibition of efflux pumps in Pseudomonal aeruginosa. Antimicrob Agents Chemother 43:1340-1346
99. Takiff HE, Cimino M, Musso MC et al (1996) Efflux pump of the proton antiporter family confers low-level fluoroquinolone resistance in Mycobacterium smegmatis. Proc Natl Acad Sci USA 93:362-366
100. Lomovskaya O, Warren M, Lee A et al (2001) Identification and characterization of inhibitors of multidrug resistance efflux pumps in Pseudomonas aeruginosa: novel agents for combination therapy. Antimicrob Agents Chemother 45:105-116
101. Markham P (1999) Inhibition of the emergence of ciprofloxacin resistance in Streptococcus pneumoniae by the multidrug efflux inhibitor reserpine. Antimicrob Agents Chemother 43:988-989
102. Markham P, Neyfakh A (1996) Inhibition of the multidrug transporter NorA prevents emergence of norfloxacin resistance in Staphylococcus aureus. Antimicrob Agents Chemother 40:2673-2675
103. Markham PN, Wasthaus E, Klyachko K et al (1999) Multiple novel inhibitors of NorA multidrug transporter of Staphylococcus aureus. Antimicrob Agents Chemother 43: 2404-2408
104. Dong Y, Zhao X, Domagala J et al (1999) Effect of fluoroquinolone concentration on selection of resistant mutants of Mycobacterium bovis BCG and Staphylococcus aureus. Antimicrob Agents Chemother 43:1756-1758
105. Pestova E, Millichap J, Noskin G, Peterson L (2000) Intracellular targets of moxifloxacin: a comparison with other fluoroquinolones. J Antimicrob Chemother 45:583-590
106. Takenouchi T, Tabata F, Iwata Y et al (1996) Hydrophilicity of quinolones is not an exclusive factor for decreased activity in efflux-mediated resistant mutants of Staphylococcus aureus. Antimicrob Agents Chemother 40:1835-1842
107. Lomovskaya O, Bostian KA (2006) Practical applications and feasibility of efflux pump inhibitors in the clinic-a vision for applied use. Biochem Pharmcol 71:910-918
108. Lynch AS (2006) Efflux systems in bacterial pathogens: an opportunity for therapeutic intervention? An industry view. Biochem Pharmacol 71:949-956
109. Poole K, Lomovskaya O (2006) Can efflux inhibitors really counter resistance? Drug Discov Today 3:145-152
110. Martinez-Martinez L, Pascual A, Jacoby G (1998) Quinolone resistance from a transferrable plasmid. Lancet 351:797-799
111. Jacoby G, Walsh K, Mills D, Moreno F (2004) A new plasmid-mediated gene for quinolone resistance. In: Forty-fourth interscience conference on antimicrobial agents and chemotherapy. American Society for Microbiology, Washington, DC
112. Hata M, Suzuki M, Matsumoto M et al (2005) Cloning of a novel gene for quinolone resistance from a transferable plasmid in Shigella flexneri 2b. Antimicrob Agents Chemother 49:801-803
113. Tran J, Jacoby G (2002) The mechanism of plasmid-mediated quinolone resistance. Proc Natl Acad Sci USA 99:5638-5642
114. Bateman A, Murzin A, Teichmann S (1998) Structure and distribution of pentapeptide repeats in bacteria. Protein Sci 7:1477-1480
115. Vetting M, Hegde S, Fajardo J, Blanchard J et al (2006) Pentapeptide repeat proteins. Biochemistry 45:1-10
116. Hegde S, Vetting M, Roderick S et al (2005) A fluoroquinolone resistance protein from Mycobacterium tuberculosis that mimics DNA. Science 308:1480-1483
117. Montero C, Mateu G, Rodriguez R et al (2001) Intrinsic resistance of Mycobacterium smegmatis to fluoroquinolones may be influenced by new pentapeptide protein MfpA. Antimicrob Agents Chemother 45:3387-3392
118. Tran J, Jacoby G, Hooper D (2005) Interaction of the plasmid-encoded quinolone resistance protein Qnr with Escherichia coli DNA gyrase. Antimicrob Agents Chemother 49:118-125
119. Tran J, Jacoby G, Hooper D (2005) Interaction of the plasmid-encoded quinlone resistance protein QnrA with Escherichia coli topoisomerase IV. Antimicrob Agents Chemother 49:3050-3052
120. Mammeri H, VanDeLoo M, Poirel L et al (2005) Emergence of plasmid-mediated quinolone resistance in Escherichia coli in Europe. Antimicrob Agents Chemother 49:71-76
121. Wang M, Sahm D, Jacoby G et al (2004) Activities of newer quinolones against Escherichia coli and Klebsiella pneumoniae containing the plasmid-mediated quinolone resistance determinant qnr. Antimicrob Agents Chemother 48:1400-1401
122. Jacoby G (2005) Mechanisms of resistance to quinolones. Clin Inf Dis 41:S120-S126
123. Robicsek A, Strahilevitz J, Jacoby G et al (2006) Fluoroquinolone-modifying enzyme: a new adaptation of a common aminoglycoside acetyltransferase. Nat Med 12:83-88
124. Tolmasky M, Roberts M, Woloj M et al (1986) Molecular cloning of amikacin resistance determinants from a Klebsiella pneumoniae plasmid. Antimicrob Agents Chemother 30:315-320
125. Robicsek A, Jacoby G, Hooper D (2006) The worldwide emergence of plasmid-mediated quinolone resistance. Lancet Infect Dis 6:629-640
126. Cullen M, Wyke A, Kuroda R, Fisher L (1989) Cloning and characterization of a DNA gyrase A gene from Escherichia coli that confers clinical resistance to 4-quinolones. Antimicrobial Agents Chemother 33:886-894
127. Friedman SM, Lu T, Drlica K (2001) A mutation in the DNA gyrase A gene of Escherichia coli that expands the quinolone-resistance-determining region. Antimicrob Agents Chemother 45:2378-2380
128. Oram M, Fisher M (1991) 4-quinolone resistance mutations in the DNA gyrase of Escherichia coli clinical isolates identified by using the polymerase chain reaction. Antimicrob Agents Chemother 35:387-389
129. Yoshida H, Bogaki M, Nakamura M, Nakamura S (1990) Quinolone resistance-determining region in the DNA gyrase gyrA gene of Escherichia coli. Antimicrob Agents Chemother 34:1271-1272
130. Kampranis S, Maxwell A (1998) Conformational changes in DNA gyrase revealed by limited proteolysis. J Biol Chem 273:22606-22614
131. Fass D, Bogden CE, Berger JM (1999) Quaternary changes in topoisomerase II may direct orthogonal movement of two DNA strands. Nat Struct Biol 6:322-326
132. Dong KC, Berger JM (2007) Structural basis for gate-DNA recognition and bending by type IIA topoisomerases. Nature 450:1201-1205
133. Sindelar G, Zhao X, Liew A, Dong Y et al (2000) Mutant prevention concentration as a measure of fluoroquinolone potency against mycobacteria. Antimicrob Agents Chemother 44:3337-3343
134. Fournier B, Hooper D (1998) Effects of mutations in grlA of topoisomerase IV from Staphylococcus aureus on quinolone and coumarin activity. Antimicrob Agents Chemother 42:2109-2112
135. Fukuda H, Hiramatsu K (1999) Primary targets of fluoroquinolones in Streptococcus pneumoniae. Antimicrob Agents Chemother 43:410-412
136. Pan X, Fisher LM (1997) Targeting of DNA gyrase in Streptococcus pneumoniae by sparfloxacin: selective targeting of gyrase or topoisomerase IV by quinolones. Antimicrob Agents Chemother 41:471-474
137. Yague G, Morris J, Pan XS et al (2002) Cleavable-complex formation by wild-type and quinolone- resistant Streptococcus pneumoniae type II topoisomerases mediated by gemifloxacin and other fluoroquinolones. Antimicrob Agents Chemother 46:413-419
138. Baquero F (1990) Resistance to quinolones in gram-negative microorganisms: mechanisms and prevention. Eur Urol 17(Suppl 1):3-12
139. Baquero F, Negri M (1997) Strategies to minimize the development of antibiotic resistance. J Chemother 9(Suppl):29-37
140. Zhao X, Drlica K (2002) Restricting the selection of antibiotic-resistant mutants: measurement and potential uses of the mutant selection window. J Inf Dis 185:561-565
141. Drlica K (2003) The mutant selection window and antimicrobial resistance. J Antimicrob Chemother 52:11-17
142. Quinn B, Hussain S, Malik M et al (2007) Daptomycin inoculum effects and mutant prevention concentration with Staphylococcus aureus. J Antimicrob Chemother 60:1380-1383
143. Campion J, McNamara P, Evans ME (2004) Evolution of ciprofloxacin-resistant Staphylococcus aureus in in vitro pharmacokinetic environments. Antimicrob Agents Chemother 48:4733-4744
144. Campion J, Chung P, McNamara P et al (2005) Pharmacodynamic modeling of the evolution of levofloxacin resistance in Staphylococcus aureus. Antimicrob Agents Chemother 49: 2189-2199
145. Campion J, McNamara P, Evans M (2005) Pharmacodynamic modeling of ciprofloxacin resistance in Staphylococcus aureus. Antimicrob Agents Chemother 49:209-219
146. Firsov A, Vostrov S, Lubenko I et al (2003) In vitro pharmacodynamic evaluation of the mutant selection window hypothesis: four fluoroquinolones against Staphylococcus aureus. Antimicrob Agents Chemother 47:1604-1613
147. Firsov A, Vostrov S, Lubenko I et al (2004) ABT492 and levofloxacin: comparison of their pharmacodynamics and their abilities to prevent the selection of resistant Staphylococcus aureus in an in vitro dynamic model. J Antimicrob Chemother 54:178-186
148. Firsov A, Vostrov S, Lubenko I et al (2004) Prevention of the selection of resistant Staphylococcus aureus by moxifloxacin plus doxycycline in an in vitro dynamic model: an additive effect of the combination. Int J Antimicrob Agents 23:451-456
149. Firsov A, Vostrov S, Lubenko I et al (2004) Concentration-dependent changes in the susceptibility and killing of Staphylococcus aureus in an in vitro dynamic model that simulates normal and impaired gatifloxacin elimination. Int J Antimicrob Agents 23:60-66
150. Firsov A, Smirnova M, Lubenko I et al (2006) Testing the mutant selection window hypothesis with Staphylococcus aureus exposed to daptomycin and vancomycin in an in vitro dynamic model. J Antimicrob Chemother 58:1185-1192
151. Olofsson S, Marcusson L, Komp-Lindgren P et al (2006) Selection of ciprofloxacin resistance in Escherichia coli in an in vitro kinetic model: relation between drug exposure and mutant prevention concentration. J Antimicrob Chemother 57:1116-1121
152. Olofsson S, Marcusson L, Stomback A et al (2007) Dose-related selection of fluoroquinoloneresistant Escherichia coli. J Antimicrob Chemother 60:795-801
153. Cui J, Liu Y, Wang R et al (2006) The mutant selection window demonstrated in rabbits infected with Staphylococcus aureus. J Inf Dis 194:1601-1608
154. Ambrose P, Zoe-Powers A, Russo R et al (2002) Utilizing pharmacodynamics and pharmacoeconomics in clinical and formulary decision making, in antimicrobial pharmacodynamics in theory and clinical practice. In: Nightingale C, Murakawa T, Ambrose P (eds) Antimicrobial pharmacodynamics in theory and clinical practice. Marcel Dekker, New York, pp 385-409
155. Stratton C (2003) Dead bugs don't mutate: susceptibility issues in the emergence of bacterial resistance. Emerg Infect Dis 9:10-16
156. Liu Y, Cui J, Wang R et al (2005) Selection of rifampicin-resistant Staphylococcus aureus during tuberculosis therapy: concurrent bacterial eradication and acquisition of resistance. J Antimicrob Chemother 56:1172-1175
157. Dong Y, Xu C, Zhao X et al (1998) Fluoroquinolone action against mycobacteria: effects of C8 substituents on bacterial growth, survival, and resistance. Antimicrob Agents Chemother 42:2978-2984
158. Lu T, Zhao X, Drlica K (1999) Gatifloxacin activity against quinolone-resistant gyrase: allele-specific enhancement of bacteriostatic and bactericidal activity by the C-8-methoxy group. Antimicrob Agents Chemother 43:2969-2974
159. Lu T, Zhao X, Li X et al (2001) Enhancement of fluoroquinolone activity by C-8 halogen and methoxy moieties: action against a gyrase resistance mutant of Mycobacterium smegmatis and a gyrase-topoisomerase IV double mutant of Staphylococcus aureus. Antimicrob Agents Chemother 45:2703-2709
160. Zhao X, Xu C, Domagala J, Drlica K (1997) DNA topoisomerase targets of the fluoroquinolones: a strategy for avoiding bacterial resistance. Proc Natl Acad Sci USA 94:13991-13996
161. Zhao BY, Pine R, Domagala J et al (1999) Fluoroquinolone action against clinical isolates of Mycobacterium tuberculosis: effects of a C8-methoxyl group on survival in liquid media and in human macrophages. Antimicrob Agents Chemother 43:661-666
162. Pan X, Fisher LM (1998) DNA gyrase and topoisomerase IV are dual targets of clinafloxacin action in Streptococcus pneumoniae. Antimicrob Agents Chemother 42:2810-2816
163. Craig W (1998) Pharmacokinetic/pharmacodynamic parameters: rationale for antibacterial dosing of mice and men. Clin Infect Dis 26:1-12
164. Schentag J (1999) Antimicrobial action and pharmacokinetics/pharmacodynamics: the use of AUIC to improve efficacy and avoid resistance. J Chemother 11:426-439
165. Drlica K, Zhao X (2007) Mutant selection window hypothesis updated. Clin Inf Dis 44:681-688
166. Zhao X, Drlica K (2002) A unified anti-mutant dosing strategy. J Antimicrob Chemother 62:434-436
167. Ambrose P, Grasela D (2000) The use of Monte Carlo simulation to examine pharmacodynamic variance of drugs: fluoroquinolone pharmcodynamics against Streptococcus pneumoniae. Diagn Microbiol Infect Dis 38:151-157
168. Preston S, Drusano G, Berman A et al (1998) Pharmacodyamics of levofloxacin: a new paradigm for early clinical trials. J Am Med Assoc 279:125-129
169. Blondeau J, Zhao X, Hansen G, Drlica K (2001) Mutant prevention concentrations (MPC) for fluoroquinolones with clinical isolates of Streptococcus pneumoniae. Antimicrob Agents Chemother 45:433-438
170. Metzler K, Hansen G, Hedlin P et al (2004) Comparison of minimal inhibitory and mutant prevention concentrations of 4 fluoroquinolones: methicillin-susceptible and -resistant Staphylococcus aureus. Int J Antimicrob Agents 24:161-167
171. Drlica K (2001) A strategy for fighting antibiotic resistance. ASM News 67:27-33
172. Zhao X, Drlica K (2001) Restricting the selection of antibiotic-resistant mutants: a general strategy derived from fluoroquinolone studies. Clin Inf Dis 33(Suppl 3):S147-S156
173. Vernon A, Burman W, Benator D et al (1999) Acquired rifamycin monoresistance in patients with HIV-related tuberculosis treated with once-weekly rifapentine and isoniazid. The Lancet 353:1843-1847
174. German N, Malik M, Rosen J et al (2008) Use of gyrase resistance mutants to guide selection of 8-methoxy-quinazoline-2,4-diones. Antimicrob Agents Chemother 52:3915-3921
175. Ince D, Zhang X, Silver LC, Hooper DC (2002) Dual targeting of DNA gyrase and topoisomerase IV: target interactions of garenoxacin (BMS-284756, T-3811ME), a new desfluoroquinolone. Antimicrob Agents Chemother 46:3370-3380
176. Ng EY, Trucksis M, Hooper DC (1996) Quinolone resistance mutations in topoisomerase IV: relationship to the flqA locus and genetic evidence that topoisomerase IV is the primary target and DNA gyrase is the secondary target of fluoroquinolones in Staphylococcus aureus. Antimicrob Agents Chemother 40:1881-1888
177. Pan XS, Fisher LM (1999) Streptococcus pneumoniae DNA gyrase and topoisomerase IV: overexpression, purification, and differential inhibition by fluoroquinolones. Antimicrob Agents Chemother 43:1129-1136
178. Strahilevitz J, Hooper DC (2005) Dual targeting of topoisomerase IV and gyrase to reduce mutant selection: direct testing of the paradigm by using WCK-1734, a new fluoroquinolone, and ciprofloxacin. Antimicrob Agents Chemother 49:1949-1956
179. Alonso G, Baptista K, Ngo T, Taylor D (2005) Transcriptional organization of the temperaturesensitive transfer system from the IncHI1 plasmid R27. Microbiology 35:3563-3573
180. Luo H, Wan K, Wang H (2005) High-frequency conjugation system facilitates biofilm formation and pAMb1 transmission by Lactococcus lactis. Appl Environ Microbiol 71: 2970-2978
181. Oppegaard H, Steinum T, Wasteson Y (2001) Horizontal transfer of a multi-drug resistance plasmid between coliform bacteria of human and bovine origin in a farm environment. App Environ Microbiol 67:3732-3734
182. Yamane K, Wachino J, Suzuki S, Arakawa Y (2008) Plasmid-mediated qepA gene among Escherichia coli clinical isolates from Japan. Antimicrob Agents Chemother 52:1564-1566
183. Périchon B, Courvalin P, Galimand M (2007) Transferable resistance to aminoglycosides by methylation of G1405 in 16 S rRNA and to hydrophilic fluoroquinolones by QepA-mediated efflux in Escherichia coli. Antimicrob Agents Chemother 51:2464-2469
184. Nordmann P, Poirel L (2005) Emergence of plasmid-mediated resistance to quinolones in Enterobacteriaceae. J Antimicrob Chemother 56:463-469
185. Casin I, Bordon F, Bertin P et al (1998) Aminoglycoside 6'-N-acetyltransferase variants of the Ib type with altered substrate profile in clinical isolates of Enterobacter cloacae and Citrobacter freundii. Antimicrob Agents Chemother 42:209-215
186. Munshi MH, Davida S, Haider K, Ahmed ZU et al (1987) Plasmid-mediated resistance to nalidixic acid in Shigella dysenteriae type 1. Lancet 2(8556):419-4221
187. Wang M, Tran J, Jacoby G et al (2003) Plasmid-mediated quinolone resistance in clinical isolates of Escherichia coli from Shanghai, China. Antimicrob Agents Chemother 47:2242-2248
188. Wang A, Yang Y, Lu Q et al (2008) Presence of qnr gene in Escherichia coli and Klebsiella pneumoniae resistant to ciprofloxacin isolated from pediatric patients in China. BMC Microbiol 8:68
189. Yang H, Chen H, Yang Q et al (2008) High prevalence of plasmid-mediated quinolone resistance genes qnr and aac(6')-Ib-cr in clinical isolates of Enterobacteriaceae from nine teaching hospitals in China. Antimicrob Agents Chemother 52:4268-4273
190. Poirel L, Leviandier C, Nordmann P (2006) Prevalence and genetic analysis of plasmidmediated quinolone resistance determinants QnrA and QnrS in Enterobacteriaceae isolates from a French university hospital. Antimicrob Agents Chemother 50:3992-3997
191. Jonas D, Biehler K, Hartung D et al (2005) Plasmid-mediated quinolone resistance in isolates obtained in German intensive care units. Antimicrob Agents Chemother 49:773-775
192. Park Y, Yu J, Lee S et al (2007) Prevalence and diversity of qnr alleles in AmpC-producing Enterobacter cloacae, Enterobacter aerogenes, Citrobacter freundii and Serratia marcescens: a multicentre study from Korea. J Antimicrob Chemother 60:868-871
193. Wu J, Ko W, Tsai S et al (2007) Prevalence of plasmid-mediated quinolone resistance determinants QnrA, QnrB, and QnrS among clinical isolates of Enterobacter cloacae in a Taiwanese hospital. Antimicrob Agents Chemother 51:1223-1227
194. Poirel L, VanDeLoo M, Mammeri H, Nordmann P (2005) Association of plasmid-mediated quinolone resistance with extended-spectrum beta-lactamase VEB-1. Antimicrob Agents Chemother 49:3091-3094
195. Nazic H, Poirel L, Nordmann P (2005) Further identification of plasmid-mediated quinolone resistance determinant in Enterobacteriaceae in Turkey. Antimicrob Agents Chemother 49:2146-2147
196. Corkill J, Anson J, Hart C (2005) High prevalence of the plasmid-mediated quinolone resistance determinant qnrA in multidrug-resistant Enterobacteriaceae from blood cultures in Liverpool, UK. J Antimicrob Chemother 56:1115-1117
197. Robicsek A, Strahilevitz J, Sahm D et al (2006) qnr prevalence in ceftazidime-resistant Enterobacteriaceae isolates from the United States. Antimicrob Agents Chemother 50:2872-2874
198. Wang M, Sahm D, Jacoby G, Hooper D (2004) Emerging plasmid-mediated quinolone resistance associated with the qnr gene in Klebsiella pneumoniae clinical isolates in the United States. Antimicrob Agents Chemother 48:1295-1299
199. Gay K, Robicsek A, Strahilevitz J et al (2006) Plasmid-mediated quinolone resistance in non- Typhi serotypes of Salmonella enterica. Clin Inf Dis 43:297-304
200. Li X (2005) Quinolone resistance in bacteria: emphasis on plasmid-mediated mechanisms. Int J Antimicrob Agents 25:453-463
201. Fihman V, Lartigue M, Jacquier H et al (2008) Appearance of aac(6')-Ib-cr gene among extended-spectrum beta-lactamase-producing Enterobacteriaceae in a French hospital. J Infect 56:454-459
202. Park C, Robicsek A, Jacoby G et al (2006) Prevalence in the United States of aac (6')-Ib-cr encoding a ciprofloxacin-modifying enzyme. Antimicrob Agents Chemother 50:3953-3955
203. Cordeiro N, Robino L, Medina J et al (2008) Ciprofloxacin-resistant enterobacteria harboring the aac(6')-Ib-cr variant isolated from feces of inpatients in an intensive care unit in Uruguay. Antimicrob Agents Chemother 52:806-807
204. Cattoir V, Poirel L, Nordmann P (2008) Plasmid-mediated quinolone resistance pump QepA2 in an Escherichia coli isolate from France. Antimicrob Agents Chemother 52:3801-3804
205. Liu J, Deng Y, Zeng Z et al (2008) Coprevalence of plasmid-mediated quinolone resistance determinants QepA, Qnr, and AAC(6')-Ib-cr among 16 S rRNA methylase RmtB-producing Escherichia coli isolates from pigs. Antimicrob Agents Chemother 52:2992-2993
206. Lujan S, Guogas L, Ragonese H, Matson S, Redinbo M (2007) Disrupting antibiotic resistance propagation by inhibiting the conjugative DNA relaxase. Proc Natl Acad Sci USA 104:12282-12287