Carbapenemases, a class of enzymes specialized in the hydrolysis of carbapenems, represent a significant threat to global public health. These enzymes are classified into different Ambler\'s classes based on their active sites, categorized into classes A, D, and B. Among the most prevalent types are IMI/NMC-A, KPC, VIM, IMP, and OXA-48, commonly associated with pathogenic species such as Acinetobacter baumannii, Klebsiella pneumoniae, and Pseudomonas aeruginosa. The emergence and dissemination of carbapenemase-producing bacteria have raised substantial concerns due to their ability to infect humans and animals (both companion and food-producing) and their presence in environmental reservoirs. Adopting a holistic One Health approach, concerted efforts have been directed toward devising comprehensive strategies to mitigate the impact of antimicrobial resistance dissemination. This entails collaborative interventions, highlighting proactive measures by global organizations like the World Health Organization, the Center for Disease Control and Prevention, and the Food and Agriculture Organization. By synthesizing the evolving landscape of carbapenemase epidemiology in Portugal and tracing the trajectory from initial isolated cases to contemporary reports, this review highlights key factors driving antibiotic resistance, such as antimicrobial use and healthcare practices, and underscores the imperative for sustained vigilance, interdisciplinary collaboration, and innovative interventions to curb the escalating threat posed by antibiotic-resistant pathogens. Finally, it discusses potential alternatives and innovations aimed at tackling carbapenemase-mediated antibiotic resistance, including new therapies, enhanced surveillance, and public awareness campaigns.

UNASSIGNED: Multi-drug-resistant pathogens pose a significant threat as they can rapidly spread, leading to severe healthcare-associated invasive infections. In developing countries, diarrheagenic Escherichia coli (DEC) is a major bacterial pathogen responsible for causing diarrhea. However, the outbreak of resistant strains has made the treatment of DEC infections much more challenging. This study aimed to investigate the relationship between antibiotic resistance genes and other virulence categories in E. coli strains that cause diarrhea, particularly DEC.
UNASSIGNED: The phylogenetic grouping was defined using PCR and multi-locus sequence type (MLST) methods.
UNASSIGNED: Among the isolates analyzed, 14 were identified as resistant and were classified into eight distinct sequence types: ST3, ST53, ST77, ST483, ST512, ST636, ST833, and ST774, indicating genetic diversity among the resistant strains. Certain sequence types, notably ST512 and ST636, were found to be associated with multiple antibiotic resistance in DEC. Regarding antibiotic susceptibility, strains showed the highest resistance to amoxicillin, suggesting that this antibiotic may not be effective in treating DEC infections. On the other hand, the isolates demonstrated susceptibility to amikacin and chloramphenicol, implying that these antibiotics could be more suitable treatment options for DEC infections.
UNASSIGNED: The findings underscore the importance of promptly identifying antibiotic resistance patterns and their correlation with specific pathogenic virulence categories, as this knowledge can aid in selecting the most appropriate antibiotics for treating DEC infections. Considering the antibiotic resistance profiles and associated resistance genes is crucial in managing and containing diarrheal outbreaks and in selecting effective antibiotic therapies for DEC infections.

Inappropriate antibiotic use not only amplifies the threat of antimicrobial resistance (AMR), moreover exacerbates the spread of resistant bacterial strains and genes in the environment, underscoring the critical need for effective research and interventions. Our aim is to assess the prevalence and resistance characteristics of β-lactam resistant bacteria (BLRB) and β-lactamase resistant bacterial genes (BLRBGs) under various environmental conditions within Delhi NCR, India. Using a culture-dependent method, we isolated 130 BLRB from 75 different environmental samples, including lakes, ponds, the Yamuna River, agricultural soil, aquatic weeds, drains, dumping yards, STPs, and gaushalas. Tests for antibiotic susceptibility were conducted in addition to phenotypic and genotypic identification of BLs and integron genes. The water and sediment samples recorded an average bacterial abundance of 3.6 × 106 CFU/mL and an average ampicillin-resistant bacterial count of 2.2 × 106 CFU/mL, which can be considered a potent reservoir of BLRB and BLRBGs. The majority of the BLRB discovered are opportunistic pathogens from the Bacillus, Aeromonas, Pseudomonas, Enterobacter, Escherichia, and Klebsiella genera, with Multiple Antibiotic Resistance (MAR) index ≥0.2 against a wide variety of β-lactams and β-lactamase (BLs) inhibitor combinations. The antibiotic resistance pattern was similar in the case of bacteria isolated from STPs. Meanwhile, bacteria isolated from other sources were diverse in their antibiotic resistance profile. Interestingly, we discovered that 10 isolates of various origins produce both Extended Spectrum BLs and Metallo BLs, as well as found harboring blaTEM, blaCTX, blaOXA, blaSHV, int-1, and int-3 genes. Enterobacter cloacae (S50/A), a common nosocomial pathogen isolated from Yamuna River sediment samples at Nizamuddin point, possesses three BLRBGs (blaTEM, blaCTX, and blaOXA) and a MAR index of 1.0, which is a major cause for concern. Therefore, identifying the source, origin and dissemination of BLRB and BLRGs in the environment is of the utmost importance for designing effective mitigation approaches to reduce a load of antimicrobial resistance factors in the environmental settings.

NaHCO3 responsiveness is a novel phenotype where some methicillin-resistant Staphylococcus aureus (MRSA) isolates exhibit significantly lower minimal inhibitory concentrations (MIC) to oxacillin and/or cefazolin in the presence of NaHCO3. NaHCO3 responsiveness correlated with treatment response to β-lactams in an endocarditis animal model. We investigated whether treatment of NaHCO3-responsive strains with β-lactams was associated with faster clearance of bacteremia. The CAMERA2 trial (Combination Antibiotics for Methicillin-Resistant Staphylococcus aureus) randomly assigned participants with MRSA bloodstream infections to standard therapy, or to standard therapy plus an anti-staphylococcal β-lactam (combination therapy). For 117 CAMERA2 MRSA isolates, we determined by broth microdilution the MIC of cefazolin and oxacillin, with and without 44 mM of NaHCO3. Isolates exhibiting ≥4-fold decrease in the MIC to cefazolin or oxacillin in the presence of NaHCO3 were considered \"NaHCO3-responsive\" to that agent. We compared the rate of persistent bacteremia among participants who had infections caused by NaHCO3-responsive and non-responsive strains, and that were assigned to combination treatment with a β-lactam. Thirty-one percent (36/117) and 25% (21/85) of MRSA isolates were NaHCO3-responsive to cefazolin and oxacillin, respectively. The NaHCO3-responsive phenotype was significantly associated with sequence type 93, SCCmec type IVa, and mecA alleles with substitutions in positions -7 and -38 in the regulatory region. Among participants treated with a β-lactam, there was no association between the NaHCO3-responsive phenotype and persistent bacteremia (cefazolin, P = 0.82; oxacillin, P = 0.81). In patients from a randomized clinical trial with MRSA bloodstream infection, isolates with an in vitro β-lactam-NaHCO3-responsive phenotype were associated with distinctive genetic signatures, but not with a shorter duration of bacteremia among those treated with a β-lactam.

BACKGROUND: Approximately 10% of European children are classified as allergic to drugs. In the majority of these children, no allergy to β-lactam antibiotics (BLA) can be found. In most cases, the exanthema is caused by the infection.
METHODS: The objective of this paper is to describe the causes and consequences of a misdiagnosis of drug allergy. We propose a method for establishing a correct diagnosis in the case of a history of a delayed reaction during treatment with a BLA. For this purpose, a proposal was discussed via e-mail communication, and consensus was reached among the members of the drug allergy working groups of the participating medical societies.
RESULTS: The suspicion of a BLA allergy based on the medical history alone can have a negative impact on future antibiotic treatment. Exanthema associated with febrile infections not related to drug administration is a frequent finding in children. This makes it all the more important to be able to recommend a standardized procedure for clarification in children and adolescents with suspected hypersensitivity reactions. The medical history should be the basis on which to diagnose either a drug allergy or another possible differential diagnosis. A mild maculopapular exanthema (MPE) can be an expression of a drug allergy or a nonspecific viral exanthema. Uncomplicated MPE is not associated with significant systemic involvement, and there is no involvement of the mucous membranes or cutaneous blistering. Only a small number of children with uncomplicated MPE show positive skin tests and only ~ 7 - 16% of suspected BLA diagnoses can be confirmed by provocation tests. Thus, in children with uncomplicated MPE, drug provocation can be performed in an outpatient setting even without prior skin testing. This paper presents a 3-day outpatient direct provocation scheme for BLA delabeling in children with uncomplicated MPE.
CONCLUSIONS: Many children and adolescents are unnecessarily denied treatment with BLA after an uncomplicated MPE while being treated with a BLA.

Ertapenem-induced neurotoxicity has not been well characterized and is potentially underreported. We conducted a systematic review of the literature and included 11 additional cases from the University of Washington Medicine health system. A total of 125 individual patient cases were included in the data analysis. The mean age was 72 years, and 62% and 42% of patients had renal dysfunction and preexisting central nervous system (CNS) conditions, respectively. Only 15% of patients received inappropriately high ertapenem dosing based on kidney function. Patients developed neurological signs and symptoms after a median of 4 days (interquartile range, 3-9 days). The most common clinical features were seizures (70%), altered level of consciousness or delirium (27%), and hallucinations (17%). An estimated incidence in our health system was 1 in 102 courses of ertapenem. Ertapenem neurotoxicity should be suspected when a patient with renal dysfunction or predisposing CNS conditions develops neurological signs and symptoms, especially within several days after initiating the antibiotic. This study underscores the need for a large prospective study to assess the true incidence and outcomes of ertapenem neurotoxicity.

UNASSIGNED: Robust data are lacking regarding the optimal route, duration, and antibiotic choice for gram-negative bloodstream infection from a complicated urinary tract infection source (GN-BSI/cUTI).
UNASSIGNED: In this multicenter observational cohort study, we simulated a 4-arm registry trial using a causal inference method to compare effectiveness of the following regimens for GN-BSI/cUTI: complete course of an intravenous β-lactam (IVBL) or oral stepdown therapy within 7 days using fluoroquinolones (FQs), trimethoprim-sulfamethoxazole (TMP-SMX), or high-bioavailability β-lactams (HBBLs). Adults treated between January 2016 and December 2022 for Escherichia coli or Klebsiella species GN-BSI/cUTI were included. Propensity weighting was used to balance characteristics between groups. The 60-day recurrence was compared using a multinomial Cox proportional hazards model with probability of treatment weighting.
UNASSIGNED: Of 2571 patients screened, 759 (30%) were included. Characteristics were similar between groups. Compared with IVBLs, we did not observe a difference in effectiveness for FQs (adjusted hazard ratio, 1.09 [95% confidence interval, .49-2.43]) or TMP-SMX (1.44 [.54-3.87]), and the effectiveness of TMP-SMX/FQ appeared to be optimal at durations of >10 days. HBBLs were associated with nearly 4-fold higher risk of recurrence (adjusted hazard ratio, 3.83 [95% confidence interval, 1.76-8.33]), which was not mitigated by longer treatment durations. Most HBBLs (67%) were not optimally dosed for bacteremia. Results were robust to multiple sensitivity analyses.
UNASSIGNED: These real-world data suggest that oral stepdown therapy with FQs or TMP-SMX have similar effectiveness as IVBLs. HBBLs were associated with higher recurrence rates, but dosing was suboptimal. Further data are needed to define optimal dosing and duration to mitigate treatment failures.

Background: Prophylactic antibacterial drugs are used for patients with liver cirrhosis and upper gastrointestinal bleeding, and independent studies have concluded that they can decrease the rate of infection, mortality, and rebleeding in these diseases. However, no comprehensive assessment of this effect has been reported in recent years and available data pertaining to the prognostic implications of diverse categories of antibiotic prophylaxis in individuals afflicted with cirrhosis are notably limited. The objective of this article is to assess the clinical effectiveness of prophylactic antibacterial drugs for patients with liver cirrhosis and upper gastrointestinal bleeding. Methods: Relevant randomized controlled studies and cohort studies which examined the value of prophylactic antibacterial drugs for patients with liver cirrhosis and upper gastrointestinal bleeding were retrieved via Cochrane Library, EMBASE, MedLine, and Web of Science. The search period was from database inception until 30 April 2023. Summing up the relevant data, the dichotomous variable was statistically analysed using the relative risk (RR) value and its 95% confidence interval (CI) and the continuous variable using the mean difference (MD) value and its 95% CI. All analyses were performed using Revman 5.4 software. The study has been registered on the PROSPERO website under registration number CRD42022343352. Results: Twenty-six studies (18 RCTs and 8 cohort studies, including 13,670 participants) were included to evaluate the effect of antibacterial prophylaxis versus no antibacterial prophylaxis or placebo. Prophylactic antibiotics reduced mortality rates (RR 0.66, 95% CI 0.51-0.83), infection rates (RR 0.41, 95% CI 0.35-0.49), rebleeding rates (RR 0.42, 95% CI 0.31-0.56), and length of hospital stay (MD -5.29, 95% CI -7.53, -3.04). Subgroup analysis revealed that the prophylactic administration of quinolone antimicrobials demonstrated the most favorable efficacy, followed by cephalosporins. Both interventions were effective in averting infections frequently observed in patients with liver cirrhosis and upper gastrointestinal bleeding. Conclusion: Based on our investigation, the prophylactic antibacterial drugs confers noteworthy advantages in patients afflicted by liver cirrhosis with upper gastrointestinal bleeding. It has been associated with reductions in mortality, infection incidence, rebleeding occurrences, and the duration of hospitalization. Among prophylactic antibacterial options, quinolones emerged as the foremost choice, with cephalosporins ranking closely thereafter. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022343352, identifier CRD42022343352.

The consumption of seafood is crucial for food security, but poor hygiene along the food production chain can result in low microbiological quality, posing significant risks for public health and seafood quality. Thus, this study aimed to assess the microbiological quality and antimicrobial sensitivity of E. coli from 69 samples of illegally marketed shrimp and mussels in the Vitória Region, Brazil. These foods exhibited poor microbiological quality due to high counts of mesophilic, psychrotrophic, and enterobacteria microorganisms. While this issue is widespread in this area, shrimp samples displayed higher microbial counts compared to mussels, and fresh mussels had elevated counts of enterobacteria compared to frozen ones. Among the 10 E. coli isolates, none carried the genes blaCTX-M-1, blaCTX-M-2, blaCTX-M-3, blaCTX-M-15, mcr-1, mcr-2, mcr-3, mcr-4, and tet, associated with antibiotic resistance. Phenotypical resistance to tetracycline and fosfomycin was not observed in any isolate, while only 20% demonstrated resistance to ciprofloxacin. Regarding ampicillin and amoxicillin with clavulanic acid, 60% of isolates were resistant, 10% showed intermediate susceptibility, and 30% were sensitive. One isolate was considered simultaneously resistant to β-lactams and quinolones, and none were conserved as ESBL producers. These findings highlight the inherent risks to local public health that arise from consuming improperly prepared seafood in this area.

We subjected seven P. aeruginosa isolates to a 10-day serial passaging against five antipseudomonal agents to evaluate resistance levels post-exposure and putative resistance mechanisms in terminal mutants were analyzed by whole-genome sequencing analysis. Meropenem (mean, 38-fold increase), cefepime (14.4-fold), and piperacillin-tazobactam (52.9-fold) terminal mutants displayed high minimum inhibitory concentration (MIC) values compared to those obtained after exposure to ceftolozane-tazobactam (11.4-fold) and ceftazidime-avibactam (5.7-fold). Fewer isolates developed elevated MIC values for other β-lactams and agents belonging to other classes when exposed to meropenem in comparison to other agents. Alterations in nalC and nalD, involved in the upregulation of the efflux pump system MexAB-OprM, were common and observed more frequently in isolates exposed to ceftazidime-avibactam and meropenem. These alterations, along with ones in mexR and amrR, provided resistance to most β-lactams and levofloxacin but not imipenem. The second most common gene altered was mpl, which is involved in the recycling of the cell wall peptidoglycan. These alterations were mainly noted in isolates exposed to ceftolozane-tazobactam and piperacillin-tazobactam but also in one cefepime-exposed isolate. Alterations in other genes known to be involved in β-lactam resistance (ftsI, oprD, phoP, pepA, and cplA) and multiple genes involved in lipopolysaccharide biosynthesis were also present. The data generated here suggest that there is a difference in the mechanisms selected for high-level resistance between newer β-lactam/β-lactamase inhibitor combinations and older agents. Nevertheless, the isolates exposed to all agents displayed elevated MIC values for other β-lactams (except imipenem) and quinolones tested mainly due to alterations in the MexAB-OprM regulators that extrude these agents.