Fluoroquinolone restriction to control fluoroquinolone-resistant Clostridium difficile
Authors: Curtis J Donskey
Journal: The Lancet Infectious Diseases (2017)

Between 1989 and 1992, an epidemic strain of Clostridium difficile that was highly resistant to clindamycin emerged and caused outbreaks of C difficile infection in several locations in the USA.1Johnson S Samore MH Farrow KA et al.Epidemics of diarrhea caused by a clindamycin-resistant strain of Clostridium difficile in four hospitals.N Engl J Med. 1999; 341: 1645-1651Crossref PubMed Scopus (300) Google Scholar Use of clindamycin was identified as a specific risk factor for infection with the epidemic strain of C difficile and restriction of clindamycin led to rapid resolution of outbreaks. These findings provided an ominous warning that acquisition of antimicrobial resistance could play a major part in dissemination of epidemic C difficile strains and highlighted the potential to control outbreaks through restriction of specific antibiotics. In the early 2000s, a previously uncommon C difficile strain termed 027/BI/NAP1 acquired increased resistance to fluoroquinolone antibiotics and caused large outbreaks in North America and northern Europe.2He M Miyajima F Roberts P et al.Emergence and global spread of epidemic healthcare-associated Clostridium difficile.Nat Genet. 2013; 45: 109-113Crossref PubMed Scopus (525) Google Scholar Control of outbreaks often required years of effort and sequential implementation of multiple control measures, including antimicrobial stewardship.3Muto CA Blank MK Marsh JW et al.Control of an outbreak of infection with the hypervirulent Clostridium difficile BI strain in a university hospital using a comprehensive “bundle” approach.Clin Infect Dis. 2007; 45: 1266-1273Crossref PubMed Scopus (206) Google Scholar Although many countries continued to have high rates of C difficile infection, England achieved substantial reductions in C difficile infection and in the proportion of infections due to 027/BI/NAP1 after introduction of a national programme to improve infection control measures and reduce use of high-risk antibiotics, particularly cephalosporins and fluoroquinolones.4Wilcox MH Shetty N Fawley WN et al.Changing epidemiology of Clostridium difficile infection following the introduction of a national ribotyping-based surveillance scheme in England.Clin Infect Dis. 2012; 55: 1056-1063Crossref PubMed Scopus (186) Google Scholar In The Lancet Infectious Diseases, Kate Dingle and colleagues5Dingle KE Didelot X Quan T P et al.Effects of control interventions on Clostridium difficile infection in England: an observational study.Lancet Infect Dis. 2017; (published online Jan 24.)http://dx.doi.org/10.1016/S1473-3099(16)30514-XSummary Full Text Full Text PDF PubMed Scopus (216) Google Scholar report the results of an impressive investigation intended to clarify which of the control measures implemented in England was responsible for the decline in C difficile infection. The study provides compelling evidence that fluoroquinolone restriction was the most important contributor to the decrease in C difficile infections. Whole-genome sequencing analysis showed that the decline in C difficile infection was driven by reductions in fluoroquinolone-resistant isolates from four distinct genotypes, including 027/BI/NAP1, and transmissions from fluoroquinolone-resistant strains decreased markedly. By contrast, there was no reduction in the incidence of C difficile infection caused by fluoroquinolone-susceptible strains, as would have been anticipated if the decrease were due to infection control measures or cephalosporin restriction. Given the retrospective, quasi-experimental nature of the study, some caution is warranted in interpreting the results. Epidemic C difficile strains sometimes decline in the absence of antibiotic restriction. In one hospital, molecular typing showed an ever-changing dominance of specific C difficile strains over a 10-year period.6Belmares J Johnson S Parada JP et al.Molecular epidemiology of Clostridium difficile over the course of 10 years in a tertiary care hospital.Clin Infect Dis. 2009; 49: 1141-1147Crossref PubMed Scopus (39) Google Scholar In the Netherlands, the prevalence of the 027/BI/NAP1 strain decreased markedly beginning in 2007, with no change in nationwide fluoroquinolone use.7Hensgens MP Goorhuis A Notermans DW van Benthem BH Kuijper EJ Decrease of hypervirulent Clostridium difficile PCR ribotypes 027 in the Netherlands.Euro Surveill. 2009; 14: 19402PubMed Google Scholar Although fluoroquinolone restriction appeared to drive the reduction in C difficile infections in England, it is not clear that the same reduction would have been achieved in the absence of concurrent enhanced infection control measures and cephalosporin restriction. Thus, randomised trials are still needed to assess the effect of fluoroquinolone restriction on control of C difficile infection outbreaks due to fluoroquinolone-resistant epidemic strains. There are several reasons for optimism that the British approach will be widely emulated and subjected to further study. First, other approaches have been less successful. In the USA, fluoroquinolone restriction has not been a major focus of control efforts and rates of C difficile infection continue to rise, with 027/BI/NAP1 persistIing as the predominant cause.8Lessa FC Mu Y Bamberg WM et al.Burden of Clostridium difficile infection in the United States.N Engl J Med. 2015; 372: 825-834Crossref PubMed Scopus (1696) Google Scholar Second, the findings are microbiologically plausible. In a mouse model, fluoroquinolone treatment exerted selective pressure favouring growth of fluoroquinolone-resistant epidemic C difficile strains, whereas fluoroquinolone-susceptible strains were inhibited.9Adams DA Riggs MM Donskey CJ Effect of fluoroquinolone treatment on growth of and toxin production by epidemic and nonepidemic Clostridium difficile strains in the cecal contents of mice.Antimicrob Agents Chemother. 2007; 51: 2674-2678Crossref PubMed Scopus (54) Google Scholar In patients, fluoroquinolone and macrolide exposure has been associated with infection with 027/BI/NAP1 strains resistant to those drugs.10Wieczorkiewicz JT Lopansri BK Cheknis A et al.Fluoroquinolone and macrolide exposure predict Clostridium difficile infection with the highly fluoroquinolone- and macrolide-resistant epidemic C difficile strain BI/NAP1/027.Antimicrob Agents Chemother. 2015; 60: 418-423Crossref PubMed Scopus (42) Google Scholar Third, some previous interventions that included fluoroquinolone restriction were associated with reductions in C difficile infections and in the proportion of infections with fluoroquionolone-resistant 027/BI/NAP1 strains.3Muto CA Blank MK Marsh JW et al.Control of an outbreak of infection with the hypervirulent Clostridium difficile BI strain in a university hospital using a comprehensive “bundle” approach.Clin Infect Dis. 2007; 45: 1266-1273Crossref PubMed Scopus (206) Google Scholar, 11Kallen AJ Thompson A Ristaino P et al.Complete restriction of fluoroquinolone use to control an outbreak of Clostridium difficile infection.Infect Control Hosp Epidemiol. 2009; 30: 264-272Crossref PubMed Scopus (74) Google Scholar, 12Sarma JB Marshall B Cleeve V Tate D Oswald T Woolfrey S Effects of fluoroquinolone restriction (from 2007 to 2012) on Clostridium difficile infections: interrupted time-series analysis.J Hosp Infect. 2015; 91: 74-80Summary Full Text Full Text PDF PubMed Scopus (41) Google Scholar, 13Lawes T Lopez-Lozano JM Nebot CA et al.Effect of a national 4C antibiotic stewardship intervention on the clinical and molecular epidemiology of Clostridium difficile infections in a region of Scotland: a non-linear time-series analysis.Lancet Infect Dis. 2016; (published online Nov 4.)http://dx.doi.org/10.1016/S1473-3099(16)30397-8PubMed Google Scholar Fourth, with some effort, reductions in fluoroquinolone use should be very feasible because these drugs are overused. For example, my colleagues and I reported that 39% of fluoroquinolone days of therapy in a tertiary care hospital were unnecessary.14Werner NL Hecker MT Sethi AK Donskey CJ Unnecessary use of fluoroquinolone antibiotics in hospitalized patients.BMC Infect Dis. 2011; 11: 187Crossref PubMed Scopus (93) Google Scholar Finally, reducing fluoroquinolone use to control C difficile infections is likely to have collateral benefits such as reductions in resistant Gram-negative bacilli. Dingle and colleagues' study5Dingle KE Didelot X Quan T P et al.Effects of control interventions on Clostridium difficile infection in England: an observational study.Lancet Infect Dis. 2017; (published online Jan 24.)http://dx.doi.org/10.1016/S1473-3099(16)30514-XSummary Full Text Full Text PDF PubMed Scopus (216) Google Scholar might herald a new era in which antimicrobial stewardship interventions for C difficile infection outbreaks are informed by data on antimicrobial susceptibility of epidemic strains. Designing such targeted interventions requires that we know the enemy: successful efforts involving restriction of clindamycin and fluoroquinolones were only possible because epidemic strains were characterised through culture and susceptibility testing. We should anticipate that future outbreaks might involve acquisition of other resistance mechanisms or of fluoroquinolone resistance by susceptible strains. Thus, national surveillance programmes that include molecular typing and susceptibility testing are essential. CJD reports grants from Clorox, Merck, GOJO, EcoLab, and Altapure, outside the submitted work. Effects of control interventions on Clostridium difficile infection in England: an observational studyRestricting fluoroquinolone prescribing appears to explain the decline in incidence of C difficile infections, above other measures, in Oxfordshire and Leeds, England. Antimicrobial stewardship should be a central component of C difficile infection control programmes. 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