Attributable mortality of antibiotic resistance in gram-negative infections in the Netherlands: a parallel matched cohort study

Wouter C Rottier; J W Timotëus Deelen; Giorgia Caruana; Anton G M Buiting; J Wendelien Dorigo-Zetsma; Jan A J W Kluytmans; Paul D van der Linden; Steven F T Thijsen; Bart J M Vlaminckx; Annemarie J L Weersink; Heidi S M Ammerlaan; Marc J M Bonten

doi:10.1016/j.cmi.2020.07.014

Attributable mortality of antibiotic resistance in gram-negative infections in the Netherlands: a parallel matched cohort study

Clin Microbiol Infect. 2020 Jul 19:S1198-743X(20)30420-1. doi: 10.1016/j.cmi.2020.07.014. Online ahead of print.

Affiliations

¹ Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands. Electronic address: w.c.rottier-2@umcutrecht.nl.
² Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands.
³ Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands; Unit of Infectious Diseases, Department of Medical, Surgical and Experimental Sciences, University of Sassari, Sassari, Italy.
⁴ Laboratory for Medical Microbiology and Immunology, Elisabeth-TweeSteden Hospital, Tilburg/Waalwijk, the Netherlands.
⁵ Central Laboratory for Bacteriology and Serology, Tergooi Hospitals, Hilversum, the Netherlands.
⁶ Laboratory for Microbiology and Infection Control, Amphia Hospital, Breda, the Netherlands.
⁷ Department of Clinical Pharmacy, Tergooi Hospitals, Hilversum, the Netherlands.
⁸ Department of Medical Microbiology and Immunology, Diakonessenhuis, Utrecht, the Netherlands.
⁹ Department of Medical Microbiology and Immunology, St. Antonius Hospital, Utrecht/Nieuwegein, the Netherlands.
¹⁰ Laboratory for Medical Microbiology and Immunology, Meander Medical Center, Amersfoort, the Netherlands.
¹¹ Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands; Department of Internal Medicine, Catharina Hospital, Eindhoven, the Netherlands.
¹² Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands; Department of Medical Microbiology, University Medical Center Utrecht, Utrecht, the Netherlands.

PMID: 32698043
DOI: 10.1016/j.cmi.2020.07.014

Abstract

Objectives: Antibiotic resistance in Gram-negative bacteria has been associated with increased mortality. This was demonstrated mostly for third-generation cephalosporin-resistant (3GC-R) Enterobacterales bacteraemia in international studies. Yet, the burden of resistance specifically in the Netherlands and created by all types of Gram-negative infection has not been quantified. We therefore investigated the attributable mortality of antibiotic resistance in Gram-negative infections in the Netherlands.

Methods: In eight hospitals, a sample of Gram-negative infections was identified between 2013 and 2016, and separated into resistant and susceptible infection cohorts. Both cohorts were matched 1:1 to non-infected control patients on hospital, length of stay at infection onset, and age. In this parallel matched cohort set-up, 30-day mortality was compared between infected and non-infected patients. The impact of resistance was then assessed by dividing the two separate risk ratios (RRs) for mortality attributable to Gram-negative infection.

Results: We identified 1954 Gram-negative infections, of which 1190 (61%) involved Escherichia coli, 210 (11%) Pseudomonas aeruginosa, and 758 (39%) bacteraemia. Resistant Gram-negatives caused 243 infections (12%; 189 (78%) 3GC-R Enterobacterales, nine (4%) multidrug-resistant P. aeruginosa, no carbapenemase-producing Enterobacterales). Subsequently, we matched 1941 non-infected controls. After adjustment, point estimates for RRs comparing mortality between infections and controls were similarly higher than 1 in case of resistant infections and susceptible infections (1.42 (95% confidence interval 0.66-3.09) and 1.32 (1.06-1.65), respectively). By dividing these, the RR reflecting attributable mortality of resistance was calculated as 1.08 (0.48-2.41).

Conclusions: In the Netherlands, antibiotic resistance did not increase 30-day mortality in Gram-negative infections.

Keywords: Bacteraemia; Burden of antimicrobial resistance; Enterobacterales; Extended-spectrum beta-lactamase; Nonbacteraemic infection.