title: Ciprofloxacin treatment failure in a murine model of pyelonephritis due to an AAC(6')-Ib-cr-producing Escherichia coli strain susceptible to ciprofloxacin in vitro.
abstract: AAC(6')-Ib-cr is a plasmid-mediated quinolone resistance mechanism described worldwide for Escherichia coli. Since it confers in vitro only a low level of resistance to ciprofloxacin, we evaluated its impact on the in vivo activity of ciprofloxacin. Isogenic strains were obtained by transferring plasmid p449, harboring aac(6')-Ib-cr, into the quinolone-susceptible strain E. coli CFT073-RR and its D87G gyrA mutant. MICs were 0.015, 0.06, 0.25, and 0.5 μg/ml against E. coli strains CFT073-RR, CFT073-RR/p449, CFT073-RR GyrA(r), and CFT073-RR GyrA(r)/p449, respectively. Bactericidal activity was reduced at 1× the MIC for the three resistant derivatives, while at a fixed concentration of 0.5 μg/ml, 99.9% killing was observed for all strains except E. coli CFT073-RR GyrA(r)/p449. In the murine model of pyelonephritis, an optimal regimen of ciprofloxacin (10 mg/kg of body weight twice a day [b.i.d.]) significantly decreased the bacterial count in the kidneys of mice infected with E. coli CFT073 (1.6 versus 4.3 log10 CFU/g of kidney compared to untreated controls; P = 0.0001), while no significant decrease was observed for E. coli CFT073-RR/p449 (2.7 versus 3.1 log10 CFU/g; P = 0.84), E. coli CFT073-RR GyrA(r) (4.2 versus 4.1 log10 CFU/g; P = 0.35), or E. coli CFT073-RR GyrA(r)/p449 (2.9 versus 3.6 log10 CFU/g; P = 0.47). While pharmacokinetic and pharmacodynamic (PK/PD) parameters accounted for ciprofloxacin failure against gyrA-containing mutants, this was not the case for the aac(6')-Ib-cr-containing strains, suggesting an in situ hydrolysis of ciprofloxacin in the latter case.
authors.affiliation: Université de Reims Champagne-Ardenne, EA4687 SFR CAP-Santé, Reims, France.
authors.forename: T
authors.initials: T
authors.lastname: Guillard
authors.forename: E
authors.initials: E
authors.lastname: Cambau
authors.forename: F
authors.initials: F
authors.lastname: Chau
authors.forename: L
authors.initials: L
authors.lastname: Massias
authors.forename: C
authors.initials: C
authors.lastname: de Champs
authors.forename: B
authors.initials: B
authors.lastname: Fantin
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D002939:Ciprofloxacin / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D027081:DNA Gyrase / Q000235:genetics; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D024881:Drug Resistance, Bacterial / Q000235:genetics; D004926:Escherichia coli / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D004927:Escherichia coli Infections / Q000188:drug therapy* / Q000382:microbiology; D005260:Female; D006868:Hydrolysis; D051379:Mice; D008808:Mice, Inbred CBA; D008826:Microbial Sensitivity Tests; D009154:Mutation; D010957:Plasmids; D011704:Pyelonephritis / Q000188:drug therapy* / Q000382:microbiology; D014169:Transformation, Bacterial; D017211:Treatment Failure
chemical_list: D000900:Anti-Bacterial Agents; D002939:Ciprofloxacin; D027081:DNA Gyrase
references.citation: Antimicrob Agents Chemother. 2009 Feb;53(2):519-24
references.pmid: 18936192
references.citation: FEMS Immunol Med Microbiol. 2005 Jun 1;44(3):317-21
references.pmid: 15907455
references.citation: J Infect Dis. 2001 Mar 1;183 Suppl 1:S1-4
references.pmid: 11171002
references.citation: Clin Infect Dis. 2000 Aug;31 Suppl 2:S40-4
references.pmid: 10984327
references.citation: Lancet. 1998 Mar 14;351(9105):797-9
references.pmid: 9519952
references.citation: Clin Microbiol Infect. 2000 Sep;6(9):509-15
references.pmid: 11168187
references.citation: Antimicrob Agents Chemother. 2008 Feb;52(2):385-92
references.pmid: 17724149
references.citation: J Clin Microbiol. 2010 Jan;48(1):286-9
references.pmid: 19923484
references.citation: Clin Microbiol Rev. 2009 Oct;22(4):664-89
references.pmid: 19822894
references.citation: Diagn Microbiol Infect Dis. 2011 Jun;70(2):253-9
references.pmid: 21596225
references.citation: J Infect Dis. 2009 Aug 1;200(3):390-8
references.pmid: 19563257
references.citation: Clin Infect Dis. 1997 Apr;24(4):707-9
references.pmid: 9145746
references.citation: J Antimicrob Chemother. 2012 Oct;67(10):2438-44
references.pmid: 22685162
references.citation: Clin Infect Dis. 2000 Aug;31 Suppl 2:S24-8
references.pmid: 10984324
references.citation: Antimicrob Agents Chemother. 2009 Oct;53(10):4292-7
references.pmid: 19635960
references.citation: Antimicrob Agents Chemother. 2007 Jul;51(7):2464-9
references.pmid: 17470656
references.citation: Antimicrob Agents Chemother. 1999 Nov;43(11):2736-41
references.pmid: 10543756
references.citation: Clin Infect Dis. 1998 Feb;26(2):535-6
references.pmid: 9502506
references.citation: Antimicrob Agents Chemother. 1996 Dec;40(12):2848-53
references.pmid: 9124853
references.citation: Nat Med. 2006 Jan;12(1):83-8
references.pmid: 16369542
references.citation: Clin Infect Dis. 2004 Jan 15;38(2):243-51
references.pmid: 14699457
references.citation: Antimicrob Agents Chemother. 2003 Feb;47(2):798-9
references.pmid: 12543696
references.citation: Antimicrob Agents Chemother. 2006 Nov;50(11):3953-5
references.pmid: 16954321
references.citation: J Infect Dis. 2006 Oct 15;194(8):1141-50
references.pmid: 16991090
references.citation: J Infect Dis. 1994 Jan;169(1):218-21
references.pmid: 8277187
references.citation: Diagn Microbiol Infect Dis. 1990 Mar-Apr;13(2):103-14
references.pmid: 2196148
references.citation: J Antimicrob Chemother. 2002 Sep;50(3):421-4
references.pmid: 12205069
references.citation: Antimicrob Agents Chemother. 2008 Dec;52(12):4268-73
references.pmid: 18809939
references.citation: J Appl Microbiol. 2009 Feb;106(2):564-71
references.pmid: 19200322
references.citation: J Antimicrob Chemother. 2008 Dec;62(6):1245-51
references.pmid: 18827034
references.citation: Diagn Microbiol Infect Dis. 2010 Apr;66(4):425-31
references.pmid: 20226333
references.citation: Clin Microbiol Infect. 2008 Jul;14(7):691-7
references.pmid: 18558942
references.citation: Clin Microbiol Infect. 2009 Apr;15 Suppl 3:12-5
references.pmid: 19366364
references.citation: J Clin Microbiol. 2011 Jun;49(6):2378-9
references.pmid: 21471342
references.citation: Int J Antimicrob Agents. 2001 Apr;17(4):343-8
references.pmid: 11295419