Mechanisms of Resistance in Gram-Negative Urinary Pathogens: From Country-Specific Molecular Insights to Global Clinical Relevance

Abstract

Urinary tract infections (UTIs) are the most frequent hospital infections and among the most commonly observed community acquired infections. Alongside their clinical importance, they are notorious because the pathogens that cause them are prone to acquiring various resistance determinants, including extended-spectrum beta-lactamases (ESBL); plasmid-encoded AmpC β-lactamases (p-AmpC); carbapenemases belonging to class A, B, and D; qnr genes encoding reduced susceptibility to fluoroquinolones; as well as genes encoding enzymes that hydrolyse aminoglycosides. In Escherichia coli and Klebsiella pneumoniae, the dominant resistance mechanisms are ESBLs belonging to the CTX-M, TEM, and SHV families; p-AmpC; and (more recently) carbapenemases belonging to classes A, B, and D. Urinary Pseudomonas aeruginosa isolates harbour metallo-beta-lactamases (MBLs) and ESBLs belonging to PER and GES families, while carbapenemases of class D are found in urinary Acinetobacter baumannii isolates. The identification of resistance mechanisms in routine diagnostic practice is primarily based on phenotypic tests for the detection of beta-lactamases, such as the double-disk synergy test or Hodge test, while polymerase chain reaction (PCR) for the detection of resistance genes is mostly pursued in reference laboratories for research purposes. As the emergence of drug-resistant bacterial strains poses serious challenges in the management of UTIs, this review aimed to appraise mechanisms of resistance in relevant Gram-negative urinary pathogens, to provide a detailed map of resistance determinants in Croatia and the world, and to discuss the implications of these resistance traits on diagnostic approaches. We summarized a sundry of different resistance mechanisms among urinary isolates and showed how their prevalence highly depends on the local epidemiological context, highlighting the need for tailored interventions in the field of antimicrobial stewardship.

Effective Antimicrobial Solutions for Eradicating Multi-Resistant and β-Lactamase-Producing Nosocomial Gram-Negative Pathogens

“…One isolate, E. coli , was found to concurrently harbour bla AmpC and bla TEM genes. These results are consistent with global reports [ 12 ] where TEM (and SHV) variants are dominant among hospital isolates. Notably, the appearance of bla CTX-M1 supports recent European studies that show there is a gradual shift from TEM and SHV mutants as the predominant ESBLs in Enterobacteriaceae to CTX-M-type [ 13 ].…”

“…Currently, the medical literature abounds with studies demonstrating the global increase in multi-drug-resistant ESBL-producing strains, where they have risen to prominence among Enterobacteriaceae isolates in both hospital and community infections [ 12 ]. In the present study, ESBL-producing isolates displayed co-resistance to multiple non-β-lactam agents, including macrolides, chloramphenicol, doxycycline and colistin ( Table 2 ).…”

Distinct Characteristics of Escherichia coli Isolated from Patients with Urinary Tract Infections in a Medical Center at a Ten-Year Interval

“…In addition, carbapenems were considered the last resort treatment for infections caused by extended-spectrum β-lactamases-producing Enterobacterales . In the last decade, the extensive use of antibiotics has resulted in the emergence of antibiotic-resistant pathogens and leads to the spread of antibiotic resistance [ 22 ]. Importantly, carbapenem-resistant UPEC in community-acquired UTIs was also reported worldwide [ 23 , 24 ].…”

Carbapenem Combinations for Infections Caused by Carbapenemase-Producing Pseudomonas aeruginosa: Experimental In Vitro and In Vivo Analysis

“…Moreover, the 3R rules [ 36 ] (Hubrecht and Carter, 2019) prevent us from increasing the numbers of animals to test the same hypothesis in male mice. As strengths of the study, the chosen isolates from the GEMARA/REIPI collection [ 23 ], both for the in vitro and in vivo studies, are representative of high-risk clones and widespread acquired carbapenemases [ 15 , 37 , 38 , 39 ].…”