The prevalence of resistance to extended-spectrum (ES) cephalosporins for multiple types of infections treated in US hospitals and the incidence of hospitalization with ESBL-producing Enterobacteriaceae (many of which are detected in nursing home residents) have grown markedly in recent years. Here, I review these developments, as well as evidence for their adverse consequences, including the increase in the overall burden of bacterial infections due to proliferation of ESBL-producing/ES cephalosporin-resistant bacteria, the contribution of ESBL-producing/ES cephalosporin-resistant bacteria to the increase in the burden of mortality associated with bacterial infections and the contribution of the proliferation of ESBL-producing bacteria to the prevalence of carbapenem resistance. I argue that in order to mitigate the escalation of these phenomena, a reduction in outpatient prescribing of cephalosporins, especially to older adults, mitigation of transmission of ESBL-producing organisms in nursing homes and a reduction in inpatient prescribing of ES cephalosporins (which has seen a major increase in recent years) are needed.
Pronounced growth in the prevalence of resistance to extended-spectrum (ES) cephalosporins in invasive Escherichia coli infections in hospitalized patients in the US has recently been documented,1 with prevalence of resistance increasing from 5.46% to 12.97% between 2009 and 2017. A study of device- and procedure-related E. coli infections in US hospitals between 2013 and 2017 also found a significant increase in the prevalence of resistance to ES cephalosporins.2 Many of the bacteria resistant to ES cephalosporins are ESBL-producing organisms that are challenging to treat, with ESBL-producing Enterobacteriaceae being listed among serious threats related to antimicrobial resistance by the US CDC.3 The incidence of ESBL-producing Enterobacteriaceae in hospitalized patients in the US has increased by 53.3% between 2012 and 2017, while the incidence of other important resistance phenotypes, such as VRE, MRSA and MDR Pseudomonas aeruginosa, declined during the same period.4 Another study involving 411 US hospitals found a similar increase in the rate of ESBL-producing Enterobacteriaceae detection in hospitalized patients between 2013 and 2017.5 Proliferation of ESBL-producing Enterobacteriaceae leads to several adverse effects.
(i) Increase in the burden of infections and related adverse outcomes due to recurrence of infection
Resistance to ES cephalosporins/ESBL phenotype is a risk factor for recurrent infections. For example, ES cephalosporin resistance in urinary tract infections (UTIs) with Enterobacteriaceae was found to be a hazard of a recurrent UTI6 and resistance to third-generation cephalosporins in Enterobacteriaceae-associated bacteraemia was found to carry the risk of a recurrent bacteraemia.7
(ii) Increase in the burden of severe infections due to progression to severe infections for ESBL-producing bacterial infections not cleared by antibiotic treatment
A study of 502 adult inpatients admitted to a hospital system in Utah, USA with a community-acquired UTI estimated that prior antibiotic exposure (within a 3 month period preceding the index hospitalization) is a very significant risk factor for the carriage of the ESBL phenotype.8 It is likely that in many instances of hospitalization following antibiotic treatment, ESBL infections resulting in hospitalizations were not cleared by prior antibiotic treatment of an earlier ESBL infection, rather than emerging as de novo ESBL infections following prior antibiotic treatment and leading to hospitalization, particularly for the more recent prior infections treated with antibiotics.
(iii) Contribution of ESBL phenotypes to the increase in the burden of mortality
As noted above, ESBL phenotypes/bacteria resistant to ES cephalosporins boost the volume of infections in both the inpatient and the outpatient settings, thus increasing the volume of mortality from bacterial infections. There are additional ways in which ESBL phenotypes/bacteria resistant to ES cephalosporins increase the volume of mortality from bacterial infections. Several studies found that underlying health conditions, such as cerebrovascular disease and diabetes mellitus, are risk factors for the carriage of ESBL- versus non-ESBL-producing Enterobacteriaceae in different types of infection (possibly due to differences in prior antibiotic exposure and other factors).9,10 Additionally, some studies found that resistance to ES cephalosporins is an independent risk factor for mortality for E. coli and Klebsiella pneumoniae infections,11 whereas other studies found no such additional independent risks.12,13 Altogether, mortality rates for patients with ESBL-producing E. coli and K. pneumoniae infections are higher than for patients with non-ESBL infections—even if ESBL phenotype is not an independent risk factor for mortality in bloodstream infections when adjusted for other risk factors, patients with ESBL-producing infections have a higher prevalence of underlying health conditions compared with patients with non-ESBL infections,9,10 with those underlying health conditions being risk factors for mortality in bloodstream infections.12
(iv) Contribution of ESBL phenotypes to the increase in the prevalence of carbapenem resistance
Carbapenem antibiotics are the drug of choice for treating ESBL-producing bacteria.14 Additionally, a combination of ESBL and/or AmpC production and alterations of porin synthesis is one of the mechanisms that leads to carbapenem resistance.15,16 Altogether, the rise in the prevalence of ESBL phenotypes contributes to carbapenem use and to the proliferation of carbapenem resistance.
A study of ESBL-producing E. coli and K. pneumoniae infections in hospitalized patients in the southeastern USA found that most of those infections were healthcare associated (nursing home residents, patients hospitalized within 12 months of admission and certain other categories).17 A study of ESBL-producing E. coli and K. pneumoniae infections in hospitalized patients in North Carolina found that just over half of those patients were nursing home residents.18 A study of E. coli-associated bacteriuria in Minnesota found that rates of infections resistant to ES cephalosporins are much higher in persons aged 65–79 years and over 80 years compared with persons aged 18–64 years.19 This suggests that in order to mitigate the proliferation of ESBL-producing/ES cephalosporin-resistant infections, a reduction in outpatient prescribing of cephalosporins to older adults (including unnecessary prescribing for respiratory infections) and mitigation of transmission of ESBL-producing organisms in nursing homes are needed. In particular, infection prevention (IP) training in nursing home staff contributes to better antibiotic stewardship practices in nursing homes,20 whereas antibiotic stewardship programmes in hospitals improve prescribing and microbial outcomes.21 For some studies,17,19 a sizeable proportion of ESBL-producing/ES cephalosporin-resistant infections were community-onset infections and were not healthcare associated. This, together with the prominent role of outpatient antibiotic prescribing in promoting antimicrobial resistance,22 suggests that a reduction in outpatient prescribing of cephalosporins to non-elderly individuals, both through antibiotic replacement and a reduction in unnecessary prescribing, particularly for respiratory causes, should also be beneficial for stemming the spread of ESBL-producing/ES cephalosporin-resistant infections in the USA. Additionally, there is an ongoing shift from broad-spectrum to narrow-spectrum antibiotics in the outpatient setting in the USA23 and it should also help to mitigate the proliferation of resistance to ES cephalosporins. Finally, prescribing of ES cephalosporins in US hospitals increased significantly in recent years (by 32% between 2012 and 2017).24 This, together with the relatively high frequency of prior hospitalization for ESBL-colonized residents in nursing homes reported in some studies,25 suggests the benefits of a reduction in inpatient prescribing of ES cephalosporins in the USA, particularly to older individuals.
Funding
This work was supported by the Wellcome Trust (Award # 219759/Z/19/Z) and by Award Number U54GM088558 from the National Institute of General Medical Sciences.
Transparency declarations
None to declare.
References
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