Microbial drug resistance最新文献

Carbapenem-resistant gram-negative organisms are a rising global concern, and novel therapeutic options are urgently needed. Cefepime/enmetazobactam (FEP/META), approved for the treatment of complicated urinary tract infections, could be an important asset in clinical care. This study aimed to determine the activity of FEP/META in a collection of genetically characterized carbapenem-resistant Enterobacterales and Pseudomonas aeruginosa. FEP/META susceptibility was tested in 104 carbapenem-resistant clinical isolates (Escherichia coli, 14; Klebsiella pneumoniae, 30; other Enterobacterales [oEs]), 29; P. aeruginosa, 31) as tested by agar disk diffusion according to the European Committee on Antimicrobial Susceptibility Testing protocols. A carbapenemase gene was identified in 75% (78/104) of all isolates. A cefepime-resistant phenotype was detected in 89% (93/104) of all isolates. FEP/META was active against 29% (30/104) of all isolates tested, including 2 E. coli, 5 K. pneumoniae, 11 oEs, and 12 P. aeruginosa isolates. Twenty-two out of 78 (28%) of all carbapenemase-positive and 8 out of 26 (31%) of all carbapenemase-negative isolates were tested susceptible to FEP/META, respectively. META restored FEP susceptibility in 22/93 (24%) of cefepime-resistant isolates (16 carbapenemase-positive, 6 carbapenemase-negative), indicating a direct META effect to restore cefepime susceptibility. In conclusion, this study provides evidence for activity of FEP/META in selected carbapenem-resistant Enterobacterales and P. aeruginosa. Susceptibility varied across resistance genotypes and included isolates carrying resistance determinants formally not targeted by META. FEP/META could be an option for carbapenem-resistant organisms if other recommended therapies fail.

Pseudomonas aeruginosa is a major Gram-negative pathogen causing diverse infections, including complicated urinary tract infections (cUTIs). Although such cUTIs are usually treatable with standard antipseudomonal β-lactams, the rise of carbapenem-resistant P. aeruginosa, particularly those producing New Delhi metallo-β-lactamase (NDM), has made therapeutic options extremely limited. We report a 58-year-old man with diabetes, hypertension, and ischemic heart disease who presented with pyelonephritis in the setting of a long-retained ureteric stent. Urine culture grew P. aeruginosa resistant to meropenem, and molecular testing confirmed the presence of NDM. The whole-genome sequencing revealed that the isolate belonged to high-risk sequence type 308 clone carrying NDM-1 and multiple additional resistance determinants. Given the lack of effective alternative antibiotics and the patient's deteriorating clinical course with underlying renal impairment precluding the use of colistin, investigational drug cefepime/zidebactam (WCK 5222) was initiated under compassionate ground. The patient underwent source control with percutaneous nephrostomy and stone clearance. He received 37 days of cefepime/zidebactam, during which he showed rapid clinical improvement, resolution of pyelonephritis, and sterile urine cultures. This case underscores how infections such as cUTI or pyelonephritis, usually considered manageable, can become untreatable in NDM-endemic settings and highlights cefepime/zidebactam as a promising therapeutic option for highly resistant P. aeruginosa.

Biliary tract infections (BTI) are common intra-abdominal infections associated with significant morbidity and mortality. We aimed to evaluate the causative agents of BTIs, their resistance profiles, and factors associated with resistant infections and mortality. This retrospective study included patients aged ≥18 years who had bile cultures obtained for BTI between January 2022 and January 2024 in a tertiary health-care center. A total of 148 bile cultures from 101 patients were analyzed. Pathogens were identified in 73% of the cultures; Escherichia coli and Enterococcus spp. were the most common pathogens. Extended-spectrum β-lactamase (ESBL) production was detected in 37.3% of Enterobacterales isolates, and ampicillin resistance was observed in 50% of enterococci. Among all identified pathogens, 31 (28.7%) were resistant microorganisms. The 30-day mortality rate was 13% and was significantly higher in patients with resistant infection, health care-associated infection, or malignancy. In multivariate analysis, resistant infections were associated with an eightfold increase in mortality. Currently antimicrobial resistance is becoming one of the leading causes of death. Resistant pathogens were frequently identified, even in community-acquired infections, and were associated with a significant increase in mortality. It is crucial to identify factors influencing resistant infections and mortality for optimizing empirical treatment strategies.

Staphylococcus aureusis a critical global health threat due to its multidrug resistance (MDR) and virulence. We examined the relationship between MDR and virulence in 250 clinical S. aureus isolates using the Galleria mellonella infection model. Alpha-hemolysin was the most prevalent toxin, with its gene, hla, present in the majority of hemolytic strains. Other virulence genes, including sigB, codY, fnbA, fnbB, clfA, saeS, sarA, arlS, yycG, spoVG, rot, and PVL, were widely distributed across methicillin-resistant S. aureus (MRSA) and methicillin-sensitive S. aureus (MSSA) isolates. The ica gene showed a notable increase in expression in hospital-acquired (HA-MRSA) and community-acquired (CA-MRSA) strains. In vivo infections revealed that HA-MRSA strains were more virulent than vancomycin intermediate S. aureus VISA, CA-MRSA, MSSA, and an agr mutant strain, while locally sourced CA-MRSA exhibited the highest virulence among tested strains. Despite differences in antibiotic resistance, MRSA and MSSA shared largely similar virulence gene profiles. These findings highlight the complex interplay between MDR and virulence in S. aureus and emphasize the need for further mechanistic studies.Importance: S. aureus remains a major clinical concern due to its increasing multidrug resistance (MDR) and virulence. Understanding the relationship between resistance mechanisms and virulence is essential for guiding effective treatment and infection control. This study assessed the virulence potential of 250 MDR S. aureus isolates using a clinically relevant invertebrate model (G. mellonella), revealing key virulence gene profiles. Notably, CA-MRSA strains exhibited hypervirulence, with alpha-hemolysin as the most prevalent toxin and significant upregulation of the ica gene in both CA- and HA-MRSA isolates. These findings emphasize the growing threat of CA-MRSA and the importance of integrated surveillance of both resistance and virulence in S. aureus populations.

Within-host pneumococcal evolution during asymptomatic carriage remains poorly characterized in high-transmission settings. We performed whole-genome sequencing of 259 isolates sampled monthly for 1 year from 47 children attending a single day-care to assess clonal dynamics, mutation accumulation, and the role of recombination. Isolates were resolved into 22 lineages based on serotype and multilocus sequence type. Most genomic changes were nonsynonymous single-nucleotide polymorphism, with only 30% of 357 mutations observed in more than 1 isolate. The mean mutation rate was 4.85 × 10^-6 substitutions/site/year, with elevated rates in specific clones (notably 6B-176, 23F-81, and 19F-177). Outlier strains revealed co-circulating sublineages and room-structured divergence in a nontypeable lineage. Putative recombination accounted for ≈4% of mutations, indicating a limited detectable role during the study period. Parallel mutations occurred in genes linked to metabolism, regulation, and immune evasion (e.g., piaA, prtA, pspA, and ciaH). Antimicrobial exposure was not associated with increased mutational burden, and only a handful of mutations persisted when compared with a 2018-2019 regional collection. Overall, pneumococcal microevolution in this high-transmission setting was rapid but largely transient, with little contribution from recombination. These findings indicate that the dynamics captured over this 1-year period reflect rapid, short-term adaptive responses to host or niche pressures, with limited opportunity for longer-term evolutionary change.

Background: There are limited oral treatment options available for resistant Gram-negative bacterial (GNB) infections. Minocycline, a second-generation tetracycline antibiotic, offers good bioavailability and broad-spectrum coverage that may be an option for GNB infections.

Methods: We conducted a retrospective review of minocycline susceptibility testing performed on GNB isolates at the Mayo Clinic reference lab between 2013 and 2022. Minocycline susceptibility was evaluated with a focus on difficult-to-treat organisms and relevant anatomic source. Organisms included resistant isolates of Escherichia coli and Klebsiella pneumoniae; high-risk ampC-derepressors, including Citrobacter freundii, Enterobacter cloacae, and K. aerogenes; and clinically challenging non-Enterobacterales, Acinetobacter species, Achromobacter species, and Stenotrophomonas maltophilia.

Results: Of 217,206 GNB isolates, 18,148 Enterobacterales (EB) and 8,190 non-Enterobacter isolates were tested for minocycline susceptibility. Of these, 80% of all EB and 92% of non-EB isolates were susceptible. Among E. coli isolates with ceftriaxone, ciprofloxacin, meropenem, or multidrug resistance, minocycline susceptibility was 78%, 76%, 70%, and 70.9%, respectively. Among the K. pneumoniae isolates with ceftriaxone, ciprofloxacin, meropenem, or multidrug resistance, minocycline susceptibility was 46%, 38%, 37%, and 39.3%, respectively. 85% of C. freundii, 81% of E. cloacae, and 85% of K. aerogenes isolates were susceptible to Minocycline. 83.5% of Achromobacter species isolates, 66% of Acinetobacter species isolates, and 99.1% of S. maltophilia isolates were susceptible.

Conclusions: Our study reports the largest collection of minocycline susceptibility findings in GNB. Minocycline showed in vitro activity against many difficult-to-treat GNB isolates, including ceftriaxone- and multidrug-resistant E. coli and some K. pneumoniae isolates, common Amp-C-producing species, and non-fermenting GNB, including Stenotrophomonas, Acinetobacter, and Achromobacter.

Cefiderocol (FDC) shows promise against carbapenem resistance, with differing carbapenemase epidemiology across Southeast and East Asia, including India. This study evaluated the susceptibility of carbapenem-resistant Klebsiella pneumoniae (CRKP) and carbapenem-resistant Acinetobacter baumannii (CRAB) against FDC and assessed carbapenemase genetic influences on susceptibility. A total of 100 clinical isolates of CRAB and 100 clinical isolates of CRKP were studied. The minimum inhibitory concentration for FDC, ceftazidime-avibactam (CZA), aztreonam, polymyxins in CRKP, and polymyxins and minocycline in CRAB was determined by the broth microdilution method. Carbapenemases were detected using the ethylenediaminetetraacetic acid-modified carbapenem inactivation method in CRKP and the modified Hodge test for CRAB. The confirmation of carbapenemases (bla_SME, bla_NMC, bla_GES, bla_KPC, bla_IMP, bla_VIM, and bla_NDM for all; bla_OXA-48 in CRKP; and bla_{OXA-23 like} bla_OXA-24/40 and bla_OXA-58 in CRAB) was performed by multiplex PCR. FDC resistance in CRKP and CRAB was 1% and 6%, respectively. CRKP isolates showed significant resistance to polymyxin B (31%), colistin (21%), aztreonam (34%), and CZA (41%; p < 0.05) as compared to FDC, while CRAB isolates exhibited higher FDC resistance (p < 0.05). Moreover, 96% of CRKP and 100% of CRAB were carbapenemase producers. For CRKP, bla_OXA-48 + bla_NDM combination and for CRAB, bla_NDM was significantly associated with FDC resistance. The study revealed the presence of bla_NDM as one of the causes for reduced susceptibility to FDC in these isolates.

Stenotrophomonas maltophilia is a Gram-negative opportunistic pathogen associated with severe hospital-acquired infections. The multiple drug-resistant nature of S. maltophilia poses significant challenges in treating infections caused by it. In this study, genomic, antimicrobial susceptibility, and virulence phenotypic analyses of four S. maltophilia clinical isolates-strains SMC1291, SMC3920, SMC5345, and SMC5580-were conducted. Comparative genome analysis of these strains against publicly available clinical and environmental isolates revealed its relativeness and key antimicrobial resistance mechanisms. A phylogenetic tree revealed that S. maltophilia SMC5345 is closely related to SMC3920, whereas SMC5580 is closely related to Stenotrophomonas sepilia-the S. maltophilia complex. SMC1291 exhibited resistance to trimethoprim-sulfamethoxazole and gentamicin due to the acquisition of the antibiotic resistance genes sul1 and aac(6')-Ib, resulting in an extensively drug-resistant strain. SMC3920 showed resistance to trimethoprim-sulfamethoxazole and quaternary ammonium compounds, arising from the acquisition of antimicrobial resistance genes sul1 and qacF. SMC3920 also demonstrated resistance to levofloxacin and minocycline, which was attributed to the L116Q amino acid substitution in SmeT. The combined acquisition of antimicrobial resistance genes and a chromosomal mutation rendered strain SMC3920 resistant to all clinically relevant antibiotics, classifying it as a pandrug-resistant (PDR) strain. Notably, sul1, aac(6')-Ib, and qacF were encoded within the mobile genetic element class 1 integron. The effects of sul1 and qacF upon gene transfer were studied, corroborating their contribution to the antimicrobial resistance phenotype. Even though the PDR strain SMC3920 remained susceptible to aztreonam and ceftazidime/avibactam combination, exploration of novel therapeutic strategies is urgently needed to combat these difficult-to-treat S. maltophilia infections.

Background: Carbapenem-resistant Klebsiella pneumoniae (CRKP) is a critical global health threat, particularly for older adults. Understanding its precise burden and the associated health inequalities in the elderly population is crucial for informed policy-making.

Methods: Using data from the Global Burden of Disease 2021 study, we analyzed deaths and disability-adjusted life years attributable to and associated with CRKP in individuals aged ≥ 65 years from 1990 to 2021. We calculated age-standardized rates, assessed temporal trends via average annual percentage change (AAPC), and quantified health inequalities using the Slope Index of Inequality (SII) and Relative Concentration Index. Frontier analysis identified countries with the greatest potential for burden reduction.

Results: The CRKP burden in the elderly increased substantially over the past three decades, as the age-standardized mortality rate associated with CRKP more than doubled from 7.44 (95% CI: 5.65 to 9.23) to 16.17 (95% CI: 13.1 to 19.25) per 100,000 (AAPC = 2.54, p < 0.001), with the most rapid increases occurring in South Asia, Eastern Europe, and Latin America. Conversely, high-income regions such as Western Europe witnessed substantial declines. Health inequalities widened markedly, as the absolute mortality gap (SII) associated with CRKP expanded from -8.69 (95% CI: -11.25,-6.14) to -41.96 (95% CI: -46.97,-36.95), an approximate fivefold increase. Frontier analysis further revealed significant potentially avoidable burden in low- and middle-income countries, independent of socioeconomic development.

Conclusion: Formal assessment of socioeconomic trends and health inequalities demonstrates an increasing concentration of the CRKP burden in low- and middle-income regions, exacerbating global health inequities. Combating this requires integrated strategies that combine antimicrobial stewardship and infection control with broader improvements in health care infrastructure and social determinants.

The molecules that make up the bacterial cell wall should be viewed not only as passive structural components of the murein sacculus, which protect and enclose the inner membrane containing the bacterial cytoplasm. They are also bioactive molecules released during bacterial replication, especially after cell lysis, involving the disintegration of the cell wall. These molecules range in structure from simple acetylated monosaccharides or amino acids, such as d-amino acids, to more complex muropeptides and cross-linked peptides. They can be classified as cell wall bioactive molecules (CWBAMs), which have signaling and effector roles that influence bacterial physiology, including biofilm formation, sporulation, and antibiotic resistance. CWBAMs also participate in interactions with other bacteria, the microbiota, and immune cells from human and animal organs, including the central nervous system. The effects of CWBAMs released during cell wall breakdown remain largely unknown, especially since they can translocate from mucosal surfaces colonized by microbiota into the bloodstream. CWBAMs are not necessarily toxins and should be distinguished from endotoxins. Their role in bacterial-host interactions is a promising area for future research.