Trends, seasonality and the association between outpatient antibiotic use and antimicrobial resistance among urinary bacteria in the Netherlands
Authors: Martínez Evelyn Pamela , van Rosmalen Joost , Bustillos Roberto , Natsch Stephanie , Mouton Johan W , Verbon Annelies ,   ISIS-AR study group, Cohen Stuart J W T , Weersink A J L , Notermans D W , van Dijk K , van Ogtrop M L , Werdmulle B F M , van Hees B C , Diederen B M W , Aguilar Diaz J , Alblas J , Altorf-van der Kuil W , Blijboom L , de Greeff S C , Groenendijk S , Hertroys R , Monen J C , van den Reek W , Reuland A , Schoffelen A F , Wielders C C H , Woudt S H S , van den Bijllaardt W , Kraan E M , Mattsson E E , de Jong E , Frénay H M E , Maraha B , van Griethuysen A J , van Asselt G J , Demeulemeester A , Wintermans B B , van Trijp M , Ott A , Bathoorn E , Lokate M , Sinnige J , Melles D C , de Brauwer E I G B , Stals F S , Silvis W , Bakker L J , Dorigo-Zetsma J W , Ridwan B , Waar K , Bernards A T , van Mens S P , Roescher N , Nabuurs-Franssen M H , Kolwijck E , Diederen B M W , Bode L G M , van Rijn M , Dinant S , Pontesilli O , de Man P , van Asselt G J , Leversteijn-van Hall M A , van Elzakker E P M , Muller A E , Renders N H , van Dam D W , Diederen B M W , Buiting A G M , Vlek A L M , Reuland E A , Troelstra A , Overdevest I T M A , Bosboom R W , Trienekens T A M , Ruijs G J H M , Wolfhagen M J H M 
Published: April 2020

Abstract

Objectives
To determine trends, seasonality and the association between community antibiotic use and antimicrobial resistance (AMR) in Escherichia coli and Klebsiella pneumoniae in urinary tract infections.

Methods
We analysed Dutch national databases from January 2008 to December 2016 regarding antibiotic use and AMR for nitrofurantoin, trimethoprim, fosfomycin and ciprofloxacin. Antibiotic use was expressed as DDD/1000 inhabitant-days (DID) and AMR was expressed as the percentage of resistance from total tested isolates. Temporal trends and seasonality were analysed with autoregressive integrated moving average (ARIMA) models. Each antibiotic use–resistance combination was cross-correlated with a linear regression of the ARIMA residuals.

Results
The trends of DID increased for ciprofloxacin, fosfomycin and nitrofurantoin, but decreased for trimethoprim. Similar trends were found in E. coli and K. pneumoniae resistance to the same antibiotics, except for K. pneumoniae resistance to ciprofloxacin, which decreased. Resistance levels peaked in winter/spring, whereas antibiotic use peaked in summer/autumn. In univariate analysis, the strongest and most significant cross-correlations were approximately 0.20, and had a time delay of 3–6 months between changes in antibiotic use and changes in resistance. In multivariate analysis, significant effects of nitrofurantoin use and ciprofloxacin use on resistance to these antibiotics were found in E. coli and K. pneumoniae, respectively. There was a significant association of nitrofurantoin use with trimethoprim resistance in K. pneumoniae after adjusting for trimethoprim use.

Conclusions
We found a relatively low use of antibiotics and resistance levels over a 9 year period. Although the correlations were weak, variations in antibiotic use for these four antibiotics were associated with subsequent variations in AMR in urinary pathogens.