Dingle Kate E, Didelot Xavier, Quan T Phuong, Eyre David W, Stoesser Nicole, Golubchik Tanya, Harding Rosalind M, Wilson Daniel J, Griffiths David, Vaughan Alison, Finney John M, Wyllie David H, Oakley Sarah J, Fawley Warren N, Freeman Jane, Morris Kirsti, Martin Jessica, Howard Philip, Gorbach Sherwood, Goldstein Ellie J C, Citron Diane M, Hopkins Susan, Hope Russell, Johnson Alan P, Wilcox Mark H, Peto Timothy E A, Walker A Sarah, Crook Derrick W
Nuffield Department of Clinical Medicine, Oxford University, Oxford, UK; National Institute for Health Research (NIHR) Oxford Biomedical Research Centre, John Radcliffe Hospital, Oxford, UK; NIHR Health Protection Research Unit in Healthcare Associated Infection and Antimicrobial Resistance at University of Oxford in partnership with Public Health England, Oxford, UK.
Department of Infectious Disease Epidemiology, and NIHR Health Protection Research Unit in Healthcare Associated Infection and Antimicrobial Resistance at Imperial College London in partnership with Public Health England, Imperial College, London, London, UK.
Lancet Infect Dis. 2017 Apr;17(4):411-421. doi: 10.1016/S1473-3099(16)30514-X. Epub 2017 Jan 25.
The control of Clostridium difficile infections is an international clinical challenge. The incidence of C difficile in England declined by roughly 80% after 2006, following the implementation of national control policies; we tested two hypotheses to investigate their role in this decline. First, if C difficile infection declines in England were driven by reductions in use of particular antibiotics, then incidence of C difficile infections caused by resistant isolates should decline faster than that caused by susceptible isolates across multiple genotypes. Second, if C difficile infection declines were driven by improvements in hospital infection control, then transmitted (secondary) cases should decline regardless of susceptibility.
Regional (Oxfordshire and Leeds, UK) and national data for the incidence of C difficile infections and antimicrobial prescribing data (1998-2014) were combined with whole genome sequences from 4045 national and international C difficile isolates. Genotype (multilocus sequence type) and fluoroquinolone susceptibility were determined from whole genome sequences. The incidence of C difficile infections caused by fluoroquinolone-resistant and fluoroquinolone-susceptible isolates was estimated with negative-binomial regression, overall and per genotype. Selection and transmission were investigated with phylogenetic analyses.
National fluoroquinolone and cephalosporin prescribing correlated highly with incidence of C difficile infections (cross-correlations >0·88), by contrast with total antibiotic prescribing (cross-correlations <0·59). Regionally, C difficile decline was driven by elimination of fluoroquinolone-resistant isolates (approximately 67% of Oxfordshire infections in September, 2006, falling to approximately 3% in February, 2013; annual incidence rate ratio 0·52, 95% CI 0·48-0·56 vs fluoroquinolone-susceptible isolates: 1·02, 0·97-1·08). C difficile infections caused by fluoroquinolone-resistant isolates declined in four distinct genotypes (p<0·01). The regions of phylogenies containing fluoroquinolone-resistant isolates were short-branched and geographically structured, consistent with selection and rapid transmission. The importance of fluoroquinolone restriction over infection control was shown by significant declines in inferred secondary (transmitted) cases caused by fluoroquinolone-resistant isolates with or without hospital contact (p<0·0001) versus no change in either group of cases caused by fluoroquinolone-susceptible isolates (p>0·2).
Restricting 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.
UK Clinical Research Collaboration (Medical Research Council, Wellcome Trust, National Institute for Health Research); NIHR Oxford Biomedical Research Centre; NIHR Health Protection Research Unit on Healthcare Associated Infection and Antimicrobial Resistance (Oxford University in partnership with Public Health England [PHE]), and on Modelling Methodology (Imperial College, London in partnership with PHE); and the Health Innovation Challenge Fund.
艰难梭菌感染的控制是一项国际临床挑战。2006年后，随着国家控制政策的实施，英国艰难梭菌的发病率下降了约80%；我们检验了两种假设以探究它们在这一下降过程中的作用。其一，如果英国艰难梭菌感染率的下降是由于特定抗生素使用量的减少，那么在多种基因型中，由耐药菌株引起的艰难梭菌感染发病率的下降速度应快于由敏感菌株引起的感染发病率。其二，如果艰难梭菌感染率的下降是由于医院感染控制的改善，那么无论易感性如何，传播性（继发性）病例都应减少。
将英国牛津郡和利兹地区以及全国的艰难梭菌感染发病率数据和抗菌药物处方数据（1998 - 2014年）与来自4045株国内外艰难梭菌分离株的全基因组序列相结合。从全基因组序列中确定基因型（多位点序列类型）和氟喹诺酮敏感性。采用负二项回归总体及按基因型估计由氟喹诺酮耐药和氟喹诺酮敏感菌株引起的艰难梭菌感染发病率。通过系统发育分析研究选择和传播情况。
全国氟喹诺酮和头孢菌素的处方量与艰难梭菌感染发病率高度相关（交叉相关性>0.88），而与总抗生素处方量相反（交叉相关性<0.59）。在地区层面，艰难梭菌感染率的下降是由于氟喹诺酮耐药菌株的消除（2006年9月牛津郡约67%的感染病例，降至2013年2月的约3%；年发病率比为0.52，95%可信区间为0.48 - 0.56，而氟喹诺酮敏感菌株为1.02，0.97 - 1.08）。由氟喹诺酮耐药菌株引起的艰难梭菌感染在四种不同基因型中均下降（p<0.01）。含有氟喹诺酮耐药菌株的系统发育区域分支较短且具有地理结构，这与选择和快速传播一致。氟喹诺酮限制相对于感染控制的重要性体现在，无论是否有医院接触，由氟喹诺酮耐药菌株引起的推断继发性（传播性）病例均显著下降（p<0.0001），而由氟喹诺酮敏感菌株引起的两组病例均无变化（p>0.2）。
在英国牛津郡和利兹，限制氟喹诺酮处方似乎比其他措施更能解释艰难梭菌感染发病率的下降。抗菌药物管理应成为艰难梭菌感染控制计划的核心组成部分。
英国临床研究合作组织（医学研究理事会、惠康信托基金会、国家卫生研究院）；国家卫生研究院牛津生物医学研究中心；国家卫生研究院医疗相关感染和抗菌药物耐药性健康保护研究组（牛津大学与英国公共卫生署合作）以及建模方法研究组（伦敦帝国理工学院与英国公共卫生署合作）；以及健康创新挑战基金。
