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

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 noninfected 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 0.66e3.09) and 1.32 (1.06e1.65), respectively). By dividing these, the RR reflecting attributable mortality of resistance was calculated as 1.08 (0.48e2.41). Conclusions: In the Netherlands, antibiotic resistance did not increase 30-day mortality in Gram-negative infections.

Phenotypic and genotypic detection methods for antimicrobial resistance in ESKAPE pathogens (Review)

“…Both Klebsiella pneumoniae and Enterobacter spp. are members of the Enterobacterales family and are gram-negative bacilli capable of inducing great levels of morbidity and mortality ( 22 , 23 ). Due to their high efficacy and safety profile, β-lactams are the primary antibiotics used to treat infections caused by enterobacteria.…”

Threats of antibiotic resistance: an obliged reappraisal

“…The way to obtain reliable figures requires precise case-control studies, comparison of the mortality of patients of the same age, same underlying conditions, in the same setting, with the same infection caused be the same pathogen (either antibiotic-resistant or not), and treated in an identical way. Useful approximations to this ideal approach have been attempted in the Netherlands, for instance, matching (1:1) cohorts of patients with the same age, length of stay in the hospital at infection onset with gram-negative infections attributed or not to multi-drug antibiotic-resistant organisms; 30-day mortality after the infection onset was almost identical (Rottier et al 2020). A few years ago, the European Antimicrobial Resistance Surveillance Network (in the European Center for Disease Control) reported an extremely high frequency of bacteremic Klebsiella pneumoniae multi-resistant strains, including carbapenems, in Greece.…”

“…The key-difficulty is to discern between “deaths in infected patients with antibiotic-resistant bacteria” and “deaths in patients where the infection is caused by antibiotic-resistant bacteria and death results from resistance to standard therapy.” Of course, mortality is highly dependent on the age and the underlying diseases, so that critical patients dying from any cause, but carrying multi-drug resistant bacteria, and being under preventive or therapeutic antibiotic exposure might be falsely categorized as “deaths because of resistance.” The way to obtain reliable figures requires precise case–control studies, comparison of the mortality of patients of the same age, same underlying conditions, in the same setting, with the same infection caused be the same pathogen (either antibiotic-resistant or not), and treated in an identical way. Useful approximations to this ideal approach have been attempted in the Netherlands, for instance, matching (1:1) cohorts of patients with the same age, length of stay in the hospital at infection onset with gram-negative infections attributed or not to multi-drug antibiotic-resistant organisms; 30-day mortality after the infection onset was almost identical (Rottier et al 2020 ). A few years ago, the European Antimicrobial Resistance Surveillance Network (in the European Center for Disease Control) reported an extremely high frequency of bacteremic Klebsiella pneumoniae multi-resistant strains, including carbapenems, in Greece.…”

The burden of bacteremic and non-bacteremic Gram-negative infections: A prospective multicenter cohort study in a low-resistance country

“…We previously estimated that the attributable mortality due to antibiotic resistance in GNI in the Netherlands, which predominantly reflects resistance to third-generation cephalosporins among Enterobacterales, is close to zero. 15 Thus, interventions to solely reduce antibiotic resistant infections and transmission (like isolation strategies) are unlikely to have a major impact on the total burden of disease caused by Gram-negative bacteria. Second, our study underlines the heterogeneity of clinical presentations of GNI, which are usually described as more specific infections, such as BSI or UTI.…”