Third generation cephalosporins and carbapenems are considered critically important antimicrobials in human medicine. Food animals such as swine can act as reservoirs of antimicrobial resistance (AMR) genes/bacteria resistant to these antimicrobial classes, and potential dissemination of AMR genes or resistant bacteria from pigs to humans is an ongoing public health threat. The objectives of this systematic review and meta-analysis were to: (1) estimate global proportion and animal-level prevalence of swine E. coli phenotypically resistant to third generation cephalosporins (3GCs) and carbapenems at a country level; and (2) measure abundances and global distribution of the genetic mechanisms that confer resistance to these antimicrobial classes in these E. coli isolates. Articles from four databases (CAB Abstracts, PubMed/MEDLINE, PubAg, and Web of Science) were screened to extract relevant data. Overall, proportion of E. coli resistant to 3GCs was lower in Australia, Europe, and North America compared to Asian countries. Globally, <5% of all E. coli were carbapenem-resistant. Fecal carriage rates (animal-level prevalence) were consistently manifold higher as compared to pooled proportion of resistance in E. coli isolates. bla CTX-M were the most common 3GC resistance genes globally, with the exception of North America where bla CMY were the predominant 3GC resistance genes. There was not a single dominant bla CTX-M gene subtype globally and several bla CTX-M subtypes were dominant depending on the continent. A wide variety of carbapenem-resistance genes (bla NDM-, VIM-, IMP-, OXA-48, and KPC-) were identified to be circulating in pig populations globally, albeit at very-low frequencies. However, great statistical heterogeneity and a critical lack of metadata hinders the true estimation of prevalence of phenotypic and genotypic resistance to these antimicrobials. Comparatively frequent occurrence of 3GC resistance and emergence of carbapenem resistance in certain countries underline the urgent need for improved AMR surveillance in swine production systems in these countries.

In the last decade, detection of antibiotic resistant bacteria from wildlife has received increasing interest, due to the potential risk posed by those bacteria to wild animals, livestock or humans at the interface with wildlife, and due to the ensuing contamination of the environment. According to World Health Organization, cephalosporins are critically important antibiotics to human health. However, acquired resistance to β-lactams is widely distributed and is mainly mediated by extended-spectrum beta-lactamase and AmpC beta-lactamases, such as cephalosporinases. This work thus aimed to compile and analyse the information available on the emergence and dissemination of cephalosporinases in wildlife worldwide. Results suggest a serious scenario, with reporting of cephalosporinases in 46 countries from all continents (52% in Europe), across 188 host species, mainly birds and mammals, especially gulls and ungulates. The most widely reported cephalosporinases, CTX-M-1, CTX-M-14, CTX-M-15 and CMY-2, were also the most common in wild animals, in agreement with their ubiquity in human settings, including their association to high-risk clones of Escherichia coli (E. coli), such as the worldwide distributed CTX-M-15/ST131 E. coli. Altogether, our findings show that anthropogenic activities affect the whole ecosystem and that public policies promoting animal and environmental surveillance, as well as mitigation measures to avoid antimicrobial misuse and AMR spread, are urgently needed to be out in practise.

Carbapenem-sparing regimens are needed for the treatment of infections caused by extended-spectrum-β-lactamase (ESBL)- and AmpC-producing members of the Enterobacterales We sought to compare the clinical efficacy of ceftazidime/avibactam and carbapenems against ESBL- and AmpC-producing Enterobacterales species. A systematic review and meta-analysis of randomized controlled trials comparing ceftazidime/avibactam with carbapenems for the treatment of ESBL- and AmpC-producing Enterobacterales was conducted. Five randomized controlled trials (RCTs) with ESBL- and AmpC-specific outcome data were compiled. Of the 246 patients infected with an ESBL-producing microorganism in the ceftazidime/avibactam arm, 224 (91%) had a clinical response at test of cure (TOC), versus 240 of 271 (89%) patients in the carbapenem arm (risk ratio [RR], 1.02; 95% confidence interval [CI], 0.97 to 1.08; P = 0.45; I 2 = 0%). Clinical response rates for AmpC producers in the ceftazidime/avibactam and carbapenem arms were 32/40 (80%) and 37/42 (88%), respectively (RR, 0.91; 95% CI, 0.76 to 1.10; P = 0.35; I 2 = 0%). Microbiological response and mortality rates were not reported specifically for ESBL/AmpC producers. Ceftazidime/avibactam may be a carbapenem-sparing option for the treatment of mild to moderate complicated urinary tract and intra-abdominal infections caused by ESBL-producing Enterobacterales species, and the data are too limited to provide any conclusive recommendations for the AmpC producers. Care should be taken before extrapolating this to severe infections, given that the representation of this population in the reviewed studies was negligible. Ceftazidime/avibactam is a costly drug active against carbapenem-resistant microorganisms and should be used judiciously to preserve its activity against them.

The burden of antibiotic-resistant infections among Gram-negative bacteria is increasing. Resistance to third-generation cephalosporins (3GCs) in Enterobacteriaceae is mainly conferred by the acquisition of β-lactamases or by deregulation of natural genetically-encoded β-lactamase enzymes. Enterobacteriaceae such as Enterobacter spp., Serratia marcescens, Citrobacter freundii, Providencia spp. and Morganella morganii (ESCPM group) possess chromosomally-encoded inducible AmpC β-lactamases. AmpC can be overproduced as a response to β-lactam antibiotic exposure or by constitutive dysfunction of the AmpC regulation system. This overproduction can lead to the inactivation of 3GCs. Based on small clinical studies, international guidelines and expert recommendations suggest that 3GCs should be avoided as definitive therapy for infections caused by ESCPM group organisms. In this narrative review, we discuss the published literature and evaluate the risk related to 3GC use in the case of documented ESCPM infection.