Temporal association of antimicrobial use in livestock with antimicrobial resistance in non-typhoid Salmonella human infections in the Netherlands, 2008-2019.

Background: Antimicrobial use (AMU) in livestock contributes to antimicrobial resistance (AMR) among zoonotic pathogens, such as non-typhoid Salmonella (NTS). Since 2009, the Netherlands has made substantial efforts to reduce AMU in livestock. Objectives: To assess the association between AMU in livestock and AMR in NTS human isolates. Additionally, associations between AMU in broilers/pigs and AMR in NTS broiler/pig isolates, and between AMR in broilers/pigs and in human NTS isolates were assessed. The focus was on Salmonella Enteritidis (SE) and Salmonella Typhimurium including its monophasic variant (ST/STM). Methods: A national population registry-based study was conducted in the Netherlands from 2008 to 2019. Multivariable logistic regression models were used to assess the associations between livestock AMU and NTS resistance proportion in humans and broilers/pigs, overall as well as per class-specific antimicrobials. Correlation analysis was performed to relate AMR proportions between human and broiler/pig NTS isolates. Results: For SE, only a positive association between penicillins use in broilers and resistance to ampicillin among human isolates was significant. For ST/STM, most associations between AMU in livestock and AMR among human isolates were significantly positive, overall and per class-specific antimicrobials, namely for penicillins-ampicillin, tetracyclines-tetracycline and sulfonamides/trimethoprim-sulfamethoxazole/trimethoprim. Significantly positive associations between AMU in broilers/pigs and AMR in broiler/pig ST/STM isolates were also observed, but not between broiler/pig and human AMR levels. Conclusions: Significant associations were generally found between livestock AMU and AMR in human and broiler/pig ST/STM isolates. However, confounding factors, such as imported meat and travel are of concern. To fully comprehend the impact of livestock AMU on resistance in human NTS isolates, it is imperative to enhance AMR surveillance of NTS.

Fluoroquinolone resistance in Escherichia coli isolates after exposure to non-fluoroquinolone antibiotics: a retrospective case-control study.

OBJECTIVES: To investigate whether prior exposure to non-fluoroquinolone antibiotics increases the risk of fluoroquinolone resistance in Escherichia coli. METHODS: This was a secondary analysis of data collected retrospectively in a case-control study linking microbiological test results (isolated bacteria and their susceptibility) of urine samples routinely collected from primary, secondary and tertiary care patients in Belgium with information on prior antibiotic use at the patient level up to 1 year previously. RESULTS: In urine samples from 6125 patients, 7204 E. coli isolates were retrieved [1949 fluoroquinolone-resistant isolates (cases) and 5255 fluoroquinolone-susceptible isolates (controls)]. After adjusting for potential confounders (including fluoroquinolone use) and correcting for multiple testing there were lower odds of fluoroquinolone resistance in E. coli isolates after exposure to cefazolin (OR = 0.65; 95% CI = 0.52-0.81; P = 0.00014) and higher odds after exposure to trimethoprim/sulfamethoxazole (OR = 1.56; 95% CI = 1.23-1.97; P =0.00020) or nitrofurantoin (OR = 1.50; 95% CI = 1.23-1.84; P =0.000083). A sensitivity analysis excluding samples with antibiotic use during the 6 months prior to the sampling date confirmed the higher odds of fluoroquinolone resistance after exposure to trimethoprim/sulfamethoxazole and nitrofurantoin. CONCLUSIONS: Assuming no residual confounding or other biases, this study suggests that exposure to non-fluoroquinolone antibiotics, i.e. trimethoprim/sulfamethoxazole and nitrofurantoin, might be causally related to fluoroquinolone resistance in E. coli isolates from urinary samples. Future prospective research is needed to confirm non-fluoroquinolone antibiotics as potential drivers of fluoroquinolone resistance.

Determination of the time-dependent association between ciprofloxacin consumption and ciprofloxacin resistance using a weighted cumulative exposure model compared with standard models.

OBJECTIVES: To obtain comprehensive insight into the association of ciprofloxacin use at different times in the past with the current risk of detecting resistance. METHODS: This retrospective nested case-control study of ciprofloxacin users used Dutch data from the PHARMO Database Network and one laboratory for the period 2003-14. Cases and controls were selected as patients with an antibiotic susceptibility test (AST) indicating ciprofloxacin resistance or susceptibility, respectively. We performed univariable and multivariable conditional logistic regression analyses, defining time-dependent exposure using standard definitions (current ciprofloxacin use, used 0-30, 31-90, 91-180 and 181-360 days ago) and a flexible weighted cumulative effect (WCE) model with four alternative time windows of past doses (0-30, 0-90, 0-180 and 0-360 days). RESULTS: The study population consisted of 230 cases and 909 controls. Under the standard exposure definitions, the association of ciprofloxacin use with resistance decreased with time [current use: adjusted OR 6.8 (95% CI 3.6-12.4); used 181-360 days ago: 1.3 (0.8-1.9)]. Under the 90 day WCE model (best-fitting model), more recent doses were more strongly associated with resistance than past doses, as was longer or repeated treatment. The 180 day WCE model, which fitted the data equally well, suggested that doses taken 91-180 days ago were also significantly associated with resistance. CONCLUSIONS: The estimates for the association between ciprofloxacin use at different times and resistance show that ciprofloxacin prescribers should consider ciprofloxacin use 0-180 days ago to ensure that patients receive suitable treatment. The OR of ciprofloxacin resistance could be reduced by eliminating repeated ciprofloxacin prescription within 180 days and by treating for no longer than necessary.