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504600.9970Molecular mechanisms of colistin- and multidrug-resistance in bacteria among patients with hospital-acquired infections. AIM: The increasing burden of resistance in Gram-negative bacteria (GNB) is becoming a major issue for hospital-acquired infections. Therefore, understanding the molecular mechanisms is important. METHODOLOGY: Resistance genes of phenotypically colistin-resistant GNB (n = 60) were determined using whole genome sequencing. Antimicrobial susceptibility patterns were detected by Vitek®2 & broth microdilution. RESULTS: Of these phenotypically colistin-resistant isolates, 78% were also genetically resistant to colistin. Activation of efflux pumps, and point-mutations in pmrB, and MgrB genes conferred colistin resistance among GNB. Eight different strains of K. pneumoniae were identified and ST43 was the most prominent strain with capsular type-specific (cps) gene KL30. DISCUSSION: These results, in combination with rapid diagnostic methods, will help us better advice appropriate antimicrobial regimens.202337753358
504510.9970Emergence of colistin-resistance in extremely drug-resistant Acinetobacter baumannii containing a novel pmrCAB operon during colistin therapy of wound infections. BACKGROUND: Colistin resistance is of concern since it is increasingly needed to treat infections caused by bacteria resistant to all other antibiotics and has been associated with poorer outcomes. Longitudinal data from in vivo series are sparse. METHODS: Under a quality-improvement directive to intensify infection-control measures, extremely drug-resistant (XDR) bacteria undergo phenotypic and molecular analysis. RESULTS: Twenty-eight XDR Acinetobacter baumannii isolates were longitudinally recovered during colistin therapy. Fourteen were susceptible to colistin, and 14 were resistant to colistin. Acquisition of colistin resistance did not alter resistance to other antibiotics. Isolates had low minimum inhibitory concentrations of an investigational aminoglycoside, belonged to multi-locus sequence type 94, were indistinguishable by pulsed-field gel electrophoresis and optical mapping, and harbored a novel pmrC1A1B allele. Colistin resistance was associated with point mutations in the pmrA1 and/or pmrB genes. Additional pmrC homologs, designated eptA-1 and eptA-2, were at distant locations from the operon. Compared with colistin-susceptible isolates, colistin-resistant isolates displayed significantly enhanced expression of pmrC1A1B, eptA-1, and eptA-2; lower growth rates; and lowered fitness. Phylogenetic analysis suggested that colistin resistance emerged from a single progenitor colistin-susceptible isolate. CONCLUSIONS: We provide insights into the in vivo evolution of colistin resistance in a series of XDR A. baumannii isolates recovered during therapy of infections and emphasize the importance of antibiotic stewardship and surveillance.201323812239
226420.9969Assessment of three antibiotic combination regimens against Gram-negative bacteria causing neonatal sepsis in low- and middle-income countries. Gram-negative bacteria (GNB) are a major cause of neonatal sepsis in low- and middle-income countries (LMICs). Although the World Health Organization (WHO) reports that over 80% of these sepsis deaths could be prevented through improved treatment, the efficacy of the currently recommended first- and second-line treatment regimens for this condition is increasingly affected by high rates of drug resistance. Here we assess three well known antibiotics, fosfomycin, flomoxef and amikacin, in combination as potential antibiotic treatment regimens by investigating the drug resistance and genetic profiles of commonly isolated GNB causing neonatal sepsis in LMICs. The five most prevalent bacterial isolates in the NeoOBS study (NCT03721302) are Klebsiella pneumoniae, Acinetobacter baumannii, E. coli, Serratia marcescens and Enterobacter cloacae complex. Among these isolates, high levels of ESBL and carbapenemase encoding genes are detected along with resistance to ampicillin, gentamicin and cefotaxime, the current WHO recommended empiric regimens. The three new combinations show excellent in vitro activity against ESBL-producing K. pneumoniae and E. coli isolates. Our data should further inform and support the clinical evaluation of these three antibiotic combinations for the treatment of neonatal sepsis in areas with high rates of multidrug-resistant Gram-negative bacteria.202438729951
250830.9968Genetics of Acquired Antibiotic Resistance Genes in Proteus spp. Proteus spp. are commensal Enterobacterales of the human digestive tract. At the same time, P. mirabilis is commonly involved in urinary tract infections (UTI). P. mirabilis is naturally resistant to several antibiotics including colistin and shows reduced susceptibility to imipenem. However higher levels of resistance to imipenem commonly occur in P. mirabilis isolates consecutively to the loss of porins, reduced expression of penicillin binding proteins (PBPs) PBP1a, PBP2, or acquisition of several antibiotic resistance genes, including carbapenemase genes. In addition, resistance to non-β-lactams is also frequently reported including molecules used for treating UTI infections (e.g., fluoroquinolones, nitrofurans). Emergence and spread of multidrug resistant P. mirabilis isolates, including those producing ESBLs, AmpC cephalosporinases and carbapenemases, are being more and more frequently reported. This review covers Proteus spp. with a focus on the different genetic mechanisms involved in the acquisition of resistance genes to multiple antibiotic classes turning P. mirabilis into a dreadful pandrug resistant bacteria and resulting in difficult to treat infections.202032153540
569840.9968Evolutionary Trajectories toward High-Level β-Lactam/β-Lactamase Inhibitor Resistance in the Presence of Multiple β-Lactamases. β-Lactam antibiotics are the first choice for the treatment of most bacterial infections. However, the increased prevalence of β-lactamases, in particular extended-spectrum β-lactamases, in pathogenic bacteria has severely limited the possibility of using β-lactam treatments. Combining β-lactam antibiotics with β-lactamase inhibitors can restore treatment efficacy by negating the effect of the β-lactamase and has become increasingly important against infections caused by β-lactamase-producing strains. Not surprisingly, bacteria with resistance to even these combinations have been found in patients. Studies on the development of bacterial resistance to β-lactam/β-lactamase inhibitor combinations have focused mainly on the effects of single, chromosomal or plasmid-borne, β-lactamases. However, clinical isolates often carry more than one β-lactamase in addition to multiple other resistance genes. Here, we investigate how the evolutionary trajectories of the development of resistance to three commonly used β-lactam/β-lactamase inhibitor combinations, ampicillin-sulbactam, piperacillin-tazobactam, and ceftazidime-avibactam, were affected by the presence of three common β-lactamases, TEM-1, CTX-M-15, and OXA-1. First-step resistance was due mainly to extensive gene amplifications of one or several of the β-lactamase genes where the amplification pattern directly depended on the respective drug combination. Amplifications also served as a stepping-stone for high-level resistance in combination with additional mutations that reduced drug influx or mutations in the β-lactamase gene bla(CTX-M-15). This illustrates that the evolutionary trajectories of resistance to β-lactam/β-lactamase inhibitor combinations are strongly influenced by the frequent and transient nature of gene amplifications and how the presence of multiple β-lactamases shapes the evolution to higher-level resistance.202235652643
155650.9968Resistance to Colistin in Klebsiella Pneumoniae: A 4.0 Strain? The global rise of multidrug-resistant gram-negative bacteria represents an increasing threat to patient safety. From the first observation of a carbapenem-resistant gram-negative bacteria a global spread of extended-spectrum beta-lactamases and carbapenemases producing Klebsiella pneumoniae has been observed. Treatment options for multidrug-resistant K. pneumoniae are actually limited to combination therapy with some aminoglycosides, tigecycline and to older antimicrobial agents. Unfortunately, the prevalence of colistin-resistant and tigecycline-resistant K. pneumoniae is increasing globally. Infection due to colistin-resistant K. pneumoniae represents an independent risk factor for mortality. Resistance to colistin in K. pneumoniae may be multifactorial, as it is mediated by chromosomal genes or plasmids. The emergence of transmissible, plasmid-mediated colistin resistance is an alarming finding. The absence of new agents effective against resistant Gram-negative pathogens means that enhanced surveillance, compliance with infection prevention procedures, and antimicrobial stewardship programs will be required to limit the spread of colistin-resistant K. pneumoniae.201728626539
246060.9967Emergence of cefiderocol resistance during therapy in NDM-5-producing Klebsiella pneumoniae isolates harboring siderophore receptors mutations. Cefiderocol, a siderophore-conjugated cephalosporine, is a promising drug used to treat infection with carbapenem-resistant gram-negative bacteria. Here, we report a case of pneumonia induced by multiple gram-negative pathogens, including a carbapenem-resistant Klebsiella pneumoniae developing cefiderocol resistance within 32 days of cefiderocol therapy. Whole genome sequencing of three consecutive K. pneumoniae isolates revealed that the bacteria were isogenic and were carrying several broad-spectrum β-lactamases (bla(NDM5) and bla(CTX-M-15)). Two isolates with elevated minimum inhibitory concentration against cefiderocol harbored mutations in genes encoding siderophore: one in the cirA gene and one in both the cirA and the fiu genes. The combination of a metallo-β-lactamase background and mutations in siderophore receptors was associated with phenotypic resistance to cefiderocol.202539617206
166070.9967Emergence of Plasmid-Mediated Fosfomycin-Resistance Genes among Escherichia coli Isolates, France. FosA, a glutathione S-transferase that inactivates fosfomycin, has been reported as the cause of enzymatic resistance to fosfomycin. We show that multiple lineages of FosA-producing extended spectrum β-lactamase Escherichia coli have circulated in France since 2012, potentially reducing the efficacy of fosfomycin in treating infections with antimicrobial drug-resistant gram-negative bacilli.201728820368
245580.9967Molecular Mechanisms of Colistin Resistance Among Klebsiella Pneumoniae Strains. BACKGROUND: The increasing rate of infections caused by multiple drug resistant gram-negative bacteria has led to resuscitation of colistin. As a result, colistin resistance, mainly among Klebsiella pneumoniae strains has also been increased. The aim of this study was to investigate molecular mechanisms behind colistin resistance. METHODS: Twenty colistin-resistant K. pneumoniae strains isolated from clinical samples of different patients were involved in this study. VITEK2 automated ID/AST system (Biomeriux, France) was used for the identification and also the susceptibility testing for antibiotics other than colistin. Colistin susceptibility was determined by broth microdilution method. To identify the mechanisms of resistance, mutations on mgrB genes, expression levels of pmrA, pmrB, pmrC, pmrD, pmrE, pmrK, phoQ, and phoP genes, and the presence of plasmid mediated colistin resistance genes, mcr-1 and mcr-2 were investigated. RESULTS: As a result of the study, increased expression levels of the pmrA, pmrB, pmrD, pmrK, phoP, and phoQ genes were observed. All colistin resistant strains were found wild type for the mgrB gene which is thought to be esponsible for colistin resistance. Also, no mcr-1 or mcr-2 genes which are the causes of plasmid mediated colistin resistance have been detected in any of the strains. CONCLUSIONS: Among the colistin resistant K. pneumoniae strains included in our study, increased expression Levels of the genes responsible for cell membrane modifications related with colistin resistance were the most common mechanisms.201931307167
155590.9967Carbapenemase-producing Gram-negative bacteria: current epidemics, antimicrobial susceptibility and treatment options. Carbapenemases, with versatile hydrolytic capacity against β-lactams, are now an important cause of resistance of Gram-negative bacteria. The genes encoding for the acquired carbapenemases are associated with a high potential for dissemination. In addition, infections due to Gram-negative bacteria with acquired carbapenemase production would lead to high clinical mortality rates. Of the acquired carbapenemases, Klebsiella pneumoniae carbapenemase (Ambler class A), Verona integron-encoded metallo-β-lactamase (Ambler class B), New Delhi metallo-β-lactamase (Ambler class B) and many OXA enzymes (OXA-23-like, OXA-24-like, OXA-48-like, OXA-58-like, class D) are considered to be responsible for the worldwide resistance epidemics. As compared with monotherapy with colistin or tigecycline, combination therapy has been shown to effectively lower case-fatality rates. However, development of new antibiotics is crucial in the present pandrug-resistant era.201525812463
2265100.9967Genotypic Patterns of Multidrug-Resistant Acinetobacter baumannii: A Systematic Review. Acinetobacter baumannii (A. baumannii) is one of the most common bacteria in nosocomial infections. Inappropriate usage of antibiotics has led to expanding emergence resistance to A. baumannii as a multidrug-resistant (MDR) strain. Empirical antibiotic therapy is necessary to evaluate the resistant gene pattern of MDR A. baumannii. For this purpose, the present study evaluated the resistance genes pattern of MDR A. baumannii collected from hospitalized patients using a genotypic diagnostic technique. To find evidence related to the study objectives, databases were searched such as Google Scholar, Web of Science, Science Direct, PubMed, and Scopus from 2000 to 2022, with specified keywords in the title and text of the articles. Articles were included based on inclusion and exclusion criteria. The mentioned database displayed 284 articles. After screening, 65 eligible articles were included. The results showed that various b-lactamases genes, aminoglycoside-modifying enzymes (AMEs) genes, and pump-expressing genes are resistance gene patterns in MDR A. baumannii isolates. MDR A. baumannii has significantly become resistant to b-lactams, carbapenems, and aminoglycosides.202337200758
5047110.9967Phenotypic and Genotypic Characterization of Pan-Drug-Resistant Klebsiella pneumoniae Isolated in Qatar. In secondary healthcare, carbapenem-resistant Enterobacterales (CREs), such as those observed in Klebsiella pneumoniae, are a global public health priority with significant clinical outcomes. In this study, we described the clinical, phenotypic, and genotypic characteristics of three pan-drug-resistant (PDR) isolates that demonstrated extended resistance to conventional and novel antimicrobials. All patients had risk factors for the acquisition of multidrug-resistant organisms, while microbiological susceptibility testing showed resistance to all conventional antimicrobials. Advanced susceptibility testing demonstrated resistance to broad agents, such as ceftazidime-avibactam, ceftolozane-tazobactam, and meropenem-vaborbactam. Nevertheless, all isolates were susceptible to cefiderocol, suggested as one of the novel antimicrobials that demonstrated potent in vitro activity against resistant Gram-negative bacteria, including CREs, pointing toward its potential therapeutic role for PDR pathogens. Expanded genomic studies revealed multiple antimicrobial-resistant genes (ARGs), including bla(NMD-5) and bla(OXA) derivative types, as well as a mutated outer membrane porin protein (OmpK37).202438534710
5048120.9966Alliance of Efflux Pumps with β-Lactamases in Multidrug-Resistant Klebsiella pneumoniae Isolates. Nosocomial infections caused by Klebsiella pneumoniae are primarily characterized by a high prevalence of extended-spectrum β-lactamases (ESBL's) and a soaring pace of carbapenemase dissemination. Availability of limited antimicrobial agents as a therapeutic option for multidrug-resistant bacteria raises an alarming concern. This study aimed at the molecular characterization of multidrug-resistant K. pneumoniae clinical isolates and studied the role of efflux pumps in β-lactam resistance. Thirty-three isolates confirmed as ESBL-positive K. pneumoniae that harbored resistance genes to major classes of antibiotics. The results showed that CTX-M15 was the preeminent β-lactamase along with carbapenemases in ESBL-positive isolates. However, the efficacy of different antibiotics varied in the presence of lactamase inhibitors and efflux pump inhibitors (EPIs). Those showing increased efficacy of antibiotics with EPI were further explored for the expression of efflux pump genes and expressed a significantly different level of efflux pumps. We found that an isolate had higher expression of kpnF (SMR family) and kdeA (MATE family) pump genes relative to RND family pump genes. No mutations were observed in the genes for porins. Together, the findings suggest that β-lactamases are not the only single factor responsible for providing resistance against the existing β-lactam drugs. Resistance may increase many folds by simultaneous expression of RND family (the most prominent family in Gram-negative bacteria) and other efflux pump family.201931613200
2305130.9966In-vitro activity of tigecycline against multidrug-resistant Gram negative bacteria: The experience of a university hospital. The emergence of multidrug-resistant Gram negative bacteria has given rise to significant therapeutic challenges. These pathogens may have developed resistance to tigecycline, which is an alternative antibiotic used empirically in the treatment of serious infections. The objectives of this study were to identify the in-vitro activity of tigecycline against multidrug-resistant Gram negative strains isolated from clinical specimens and their related genes, at a university hospital. For this, 150 clinical isolates of multidrug-resistant Gram negative cultures from various clinical specimens were collected. Bacterial isolates were cultured, identified and their antibiotic susceptibilities were determined. Polymerase chain reaction was performed to amplify AcrB, AmpC, RamR, MexR, AdeB, TetA genes. Results revealed that all isolates were multidrug-resistant. The resistance of isolates was 91.4% to aztreonam, 94.6% to piperacillin, 34% to imipenem, 38.7% to meropenem, 71.3% to levofloxacin, 97.3% to ceftriaxone, 94.7% to cefepime, 9.3% to colistin, 78% to tetracycline, 21.4% to tigecycline and 68% to trimethoprim. AcrB, AmpC, RamR, MexR, AdeB, TetA genes were present in multidrug-resistant Gram negative bacteria. AcrB, RamR, TetA genes were related to tigecycline resistance. It is concluded that infections caused by multidrug-resistant Gram negative bacteria occur at a high rate. Most isolates were multi drug resistant, with 21.4% being resistant to tigecycline.202133743369
2505140.9966Resistance in nonfermenting gram-negative bacteria: multidrug resistance to the maximum. Nonfermenting gram-negative bacteria pose a particular difficulty for the healthcare community because they represent the problem of multidrug resistance to the maximum. Important members of the group in the United States include Pseudomonas aeruginosa, Acinetobacter baumannii, Stenotrophomonas maltophilia, and Burkholderia cepacia. These organisms are niche pathogens that primarily cause opportunistic healthcare-associated infections in patients who are critically ill or immunocompromised. Multidrug resistance is common and increasing among gram-negative nonfermenters, and a number of strains have now been identified that exhibit resistance to essentially all commonly used antibiotics, including antipseudomonal penicillins and cephalosporins, aminoglycosides, tetracyclines, fluoroquinolones, trimethoprim-sulfamethoxazole, and carbapenems. Polymyxins are the remaining antibiotic drug class with fairly consistent activity against multidrug-resistant strains of P aeruginosa, Acinetobacter spp, and S maltophilia. However, most multidrug-resistant B cepacia are not susceptible to polymyxins, and systemic polymyxins carry the risk of nephrotoxicity for all patients treated with these agents, the elderly in particular. A variety of resistance mechanisms have been identified in P aeruginosa and other gram-negative nonfermenters, including enzyme production, overexpression of efflux pumps, porin deficiencies, and target-site alterations. Multiple resistance genes frequently coexist in the same organism. Multidrug resistance in gram-negative nonfermenters makes treatment of infections caused by these pathogens both difficult and expensive. Improved methods for susceptibility testing are needed when dealing with these organisms, including emerging strains expressing metallo-beta-lactamases. Improved antibiotic stewardship and infection-control measures will be needed to prevent or slow the emergence and spread of multidrug-resistant, nonfermenting gram-negative bacilli in the healthcare setting.200616813979
2504150.9966Resistance in nonfermenting gram-negative bacteria: multidrug resistance to the maximum. Nonfermenting gram-negative bacteria pose a particular difficulty for the healthcare community because they represent the problem of multidrug resistance to the maximum. Important members of the group in the United States include Pseudomonas aeruginosa, Acinetobacter baumannii, Stenotrophomonas maltophilia, and Burkholderia cepacia. These organisms are niche pathogens that primarily cause opportunistic healthcare-associated infections in patients who are critically ill or immunocompromised. Multidrug resistance is common and increasing among gram-negative nonfermenters, and a number of strains have now been identified that exhibit resistance to essentially all commonly used antibiotics, including antipseudomonal penicillins and cephalosporins, aminoglycosides, tetracyclines, fluoroquinolones, trimethoprim-sulfamethoxazole, and carbapenems. Polymyxins are the remaining antibiotic drug class with fairly consistent activity against multidrug-resistant strains of P aeruginosa, Acinetobacter spp, and S maltophilia. However, most multidrug-resistant B cepacia are not susceptible to polymyxins, and systemic polymyxins carry the risk of nephrotoxicity for all patients treated with these agents, the elderly in particular. A variety of resistance mechanisms have been identified in P aeruginosa and other gram-negative nonfermenters, including enzyme production, overexpression of efflux pumps, porin deficiencies, and target-site alterations. Multiple resistance genes frequently coexist in the same organism. Multidrug resistance in gram-negative nonfermenters makes treatment of infections caused by these pathogens both difficult and expensive. Improved methods for susceptibility testing are needed when dealing with these organisms, including emerging strains expressing metallo-beta-lactamases. Improved antibiotic stewardship and infection-control measures will be needed to prevent or slow the emergence and spread of multidrug-resistant, nonfermenting gram-negative bacilli in the healthcare setting.200616735148
2306160.9966Resistance to nitrofurantoin is an indicator of extensive drug-resistant (XDR) Enterobacteriaceae. Introduction. Nitrofurantoin is one of the preferred antibiotics in the treatment of uropathogenic multidrug-resistant (MDR) infections. However, resistance to nitrofurantoin in extensively drug-resistant (XDR) bacteria has severely limited the treatment options.Gap statement. Information related to co-resistance or collateral sensitivity (CS) with reference to nitrofurantoin resistant bacteria is limited.Aim. To study the potential of nitrofurantoin resistance as an indicator of the XDR phenotype in Enterobacteriaceae.Methods. One hundred (45 nitrofurantoin-resistant, 21 intermediately resistant and 34 nitrofurantoin-susceptible) Enterobacteriaceae were analysed in this study. Antibiotic susceptibility testing (AST) against nitrofurantoin and 17 other antimicrobial agents across eight different classes was performed by using the Vitek 2.0 system. The isolates were screened for the prevalence of acquired antimicrobial resistance (AMR) and efflux pump genes by PCR.Results. In total, 51 % of nitrofurantoin-resistant and 28 % of intermediately nitrofurantoin resistant isolates exhibited XDR characteristics, while only 3 % of nitrofurantoin-sensitive isolates were XDR (P=0.0001). Significant co-resistance was observed between nitrofurantoin and other tested antibiotics (β-lactam, cephalosporin, carbapenem, aminoglycoside and tetracycline). Further, the prevalence of AMR and efflux pump genes was higher in the nitrofurantoin-resistant strains compared to the susceptible isolates. A strong association was observed between nitrofurantoin resistance and the presence of bla (PER-1), bla (NDM-1), bla (OXA-48), ant(2) and oqxA-oqxB genes. Tigecycline (84 %) and colistin (95 %) were the only antibiotics to which the majority of the isolates were susceptible.Conclusion. Nitrofurantoin resistance could be an indicator of the XDR phenotype among Enterobacteriaceae, harbouring multiple AMR and efflux pump genes. Tigecycline and colistin are the only antibiotics that could be used in the treatment of such XDR infections. A deeper understanding of the co-resistance mechanisms in XDR pathogens and prescription of AST-based appropriate combination therapy may help mitigate this problem.202133830906
2515170.9966High-risk Pseudomonas aeruginosa clones harboring β-lactamases: 2024 update. Carbapenem-resistant Pseudomonas aeruginosa is defined by the World Health Organization as a "high priority" in developing new antimicrobials. Indeed, the emergence and spread of multidrug-resistant (MDR) or extensively drug-resistant (XDR) bacteria increase the morbidity and mortality risk of infected patients. Genomic variants of P. aeruginosa that display phenotypes of MDR/XDR have been defined as high-risk global clones. In this mini-review, we describe some international high-risk clones that carry β-lactamase genes that can produce chronic colonization and increase infected patients' morbidity and mortality rates.202539850428
2275180.9966Contribution of β-lactamase and efflux pump overproduction to tazobactam-piperacillin resistance in clinical isolates of Escherichia coli. INTRODUCTION: Tazobactam-piperacillin (TZP) is a mixture of a broad-spectrum penicillin and an irreversible β-lactamase inhibitor. TZP is effective against Gram-negative bacteria that produce extended-spectrum β-lactamases, and it is used as a first-line or second-line drug to treat serious infections. METHODS: This study identified three TZP-resistant and two TZP-intermediate strains among 514 clinical isolates of Escherichia coli. RESULTS: These five isolates possessed one or more β-lactamase genes, bla(TEM-1), bla(CTX-M-2), bla(CTX-M-14), and/or bla(CMY-8). The expression levels of β-lactamase genes and acrAB genes in the strains were examined by using real-time reverse transcription PCR. The total enzymatic piperacillin-degrading activity in cells was determined. Two TZP-resistance mechanisms were identified: hyperproduction of TEM-1 in the two resistant strains; and simultaneous high production of β-lactamase and efflux pump AcrAB in the two TZP-intermediate isolates. The latter are an international high-risk clone O25b:H4-ST131-H30R. CONCLUSION: TZP resistance is still rare in clinical isolates of E. coli. However, resistance can develop on high production and/or combinations of known antimicrobial resistance mechanisms in different ways.202032062000
1551190.9966Mechanisms of Resistance in Gram-Negative Urinary Pathogens: From Country-Specific Molecular Insights to Global Clinical Relevance. 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.202133925181