Patients with severe carbapenem-resistant Acinetobacter baumannii (CRAB) infections currently face significant treatment challenges. When patients display signs of infection and the clinical suspicion of CRAB infections is high, appropriate treatment should be immediately provided. However, current treatment plans and clinical data for CRAB are limited. Inherent and acquired resistance mechanisms, as well as host factors, significantly restrict options for empirical medication. Moreover, inappropriate drug coverage can have detrimental effects on patients. Most existing studies have limitations, such as a restricted sample size, and are predominantly observational or non-randomized, which report significant variability in patient infection severity and comorbidities. Therefore, a gold-standard therapy remains lacking. Current and future treatment options of infections due to CRAB were described in this review. The dose and considerable side effects restrict treatment options for polymyxins, and high doses of ampicillin-sulbactam or tigecycline appear to be the best option at the time of initial treatment. Moreover, new drugs such as durlobactam and cefiderocol have substantial therapeutic capabilities and may be effective salvage treatments. Bacteriophages and antimicrobial peptides may serve as alternative treatment options in the near future. The advantages of a combination antimicrobial regimen appear to predominate those of a single regimen. Despite its significant nephrotoxicity, colistin is considered a primary treatment and is often used in combination with antimicrobials, such as tigecycline, ampicillin-sulbactam, meropenem, or fosfomycin. The Infectious Diseases Society of America (IDSA) has deemed high-dose ampicillin-sulbactam, which is typically combined with high-dose tigecycline, polymyxin, and other antibacterial agents, the best option for treating serious CRAB infections. A rational combination of drug use and the exploration of new therapeutic drugs can alleviate or prevent the effects of CRAB infections, shorten hospital stays, and reduce patient mortality.

BACKGROUND: H. influenzae carriage may evolve into respiratory or systemic infections. However, no surveillancesystem is in place in Belgium to monitor carriage strains.
METHODS: This study provides a detailed description of H. influenzae strains isolated from both carriage and lower respiratory infections, collected during a six-month national surveillance. Subsequently, a comparison is conducted with invasive isolates collected during the same period at the National Reference Centre (NRC).
CONCLUSIONS: From November 2021 to April 2022, 39 clinical laboratories collected 142 and 210 strains of H. influenzae from carriage and infection, respectively, and 56 strains of blood were submitted to the NRC. In each group, the biotype II comprised more than 40%, followed by biotypes III and I. The majority of strains were non-typeable H. influenzae, with a notable increase in the number of encapsulated strains in the invasive group (14.3% vs. 1-2%). A beta-lactamase was identified in 18.5% and 12.5% of surveillance and invasive strains, respectively. Resistance to the amoxicillin-clavulanic acid combination accounted for 7% in the surveillance strains and 10.7% in invasive strains. The overall resistance to third-generation cephalosporins at 1.2% is consistent with rates observed in other European countries. Of particular significance is the identification of mutations in the ftsI gene in both carriage and infected strains, which are associated with high-level beta-lactam resistance.
CONCLUSIONS: NRC must engage in regular and systematic monitoring of beta-lactam susceptibility of H. influenzae to guarantee safe empiric therapy in severe cases and identify potential transitions from low-level to high-level resistance in the future.

The high-level resistance to next-generation β-lactams frequently found in Staphylococcus aureus isolates lacking mec, which encodes the transpeptidase PBP2a traditionally associated with methicillin-resistant Staphylococcus aureus (MRSA), has remained incompletely understood for decades. A new study by Lai et al. found that the co-occurrence of mutations in pbp4 and gdpP, which respectively cause increased PBP4-mediated cell wall crosslinking and elevated cyclic-di-AMP levels, produces synergistic β-lactam resistance rivaling that of PBP2a-producing MRSA (L.-Y. Lai, N. Satishkumar, S. Cardozo, V. Hemmadi, et al., mBio 15:e02889-23. 2024, https://doi.org/10.1128/mbio.02889-23). The combined mutations are sufficient to explain the high-level β-lactam resistance of some mec-lacking strains, but the mechanism of synergy remains elusive and an avenue for further research. Importantly, the authors establish that co-occurrence of these mutations leads to antibiotic therapy failure in a Caenorhabditis elegans infection model. These results underscore the need to consider this unique and novel β-lactam resistance mechanism during the clinical diagnosis of MRSA, rather than relying on mec as a diagnostic.

The VITEK®2 AES β-lactam phenotypes of 488 Enterobacterales from North and Latin America generated by the VITEK®2 were compared to the resistance genotypes provided by whole genome sequencing (WGS). The AES provided phenotypic reports for 447 (91.6 %) isolates, including isolates harbouring carbapenemases (195; 43.6 %), ESBLs (103; 23.0 %) and transferable AmpCs (tAmpC; 28; 6.3 %) genes, as well as wildtype isolates (WT; 121; 27.1 %). Overall, the AES report was accurate for 433/447 (96.9 %) isolates. The AES accurately reported carbapenemase, ESBL, and tAmpC phenotypes for 93.7 %, 93.7 %, and 98.4 % of isolates, respectively, and sensitivity/specificity rates were 96.4 %/91.7 %, 98.1 %/92.4 %, 82.1 %/99.5 %, and 100 %/98.8 %. 14 isolates carrying carbapenemase (7 total; 3 KPC, 2 MBL, 2 OXA-48-like), ESBL (2), and tAmpC-encoding genes (5) were not correctly identified by AES. The AES phenotypic report detected resistance mechanisms among Enterobacterales rapidly and could significantly aid future antimicrobial stewardship initiatives and patient care.

BACKGROUND: Viridans group streptococci (VGS) bloodstream infection (BSI) frequently occurs in cancer patients receiving chemotherapy, and is associated with infective endocarditis (IE) in up to 20% of cases in the general population.
OBJECTIVE: In cancer patients receiving chemotherapy with VGS BSI, we aimed to: (i) determine the incidence of infective complications including IE, (ii) assess the utility of echocardiography in this patient population, (iii) determine the duration and type of antimicrobial therapy received for monomicrobial infections, and (iv) determine the evolution of antimicrobial resistance.
METHODS: VGS BSIs (excluding Streptococcus pneumoniae and Streptococcus pseudopneumoniae) in cancer patients receiving chemotherapy were identified from a statewide public pathology database between 2013 and 2022 at our tertiary centre. Medical records were accessed for clinical, microbiological and radiological data.
RESULTS: Of 581 patient episodes screened, 183 episodes involving 171 patients met inclusion criteria. Of these, 51% were bone marrow transplantation (BMT) patients, 40% were non-BMT haematology patients, and 8% were solid organ malignancy patients. The median age was 55 years, and 96% were neutropenic at the time of blood culture collection. A transthoracic echocardiogram was performed for 71% of episodes, and one patient met modified Duke\'s criteria for definite IE, although this diagnosis was not suspected on clinical grounds. Other complications were uncommon. Benzylpenicillin resistance was rare (2.9%) and did not change over time. Most episodes (75%) were treated with piperacillin/tazobactam. For monomicrobial BSIs, the median antibiotic duration was 5 days (IQR 2-7) post-neutropenia resolution.
CONCLUSIONS: Infective complications and antimicrobial resistance are rare in cancer patients with VGS BSI. This may provide a safe opportunity to limit both investigations (e.g. echocardiogram) and prolonged exposure to broad-spectrum antimicrobials.

BACKGROUND: According to international pediatric urinary tract infection (UTI) guidelines, selecting ampicillin/sulbactam or amoxicillin/clavulanate is recommended as the first-line treatment for pediatric UTI. In Korea, elevated resistance to ampicillin and ampicillin/sulbactam has resulted in the widespread use of third-generation cephalosporins for treating pediatric UTIs. This study aims to compare the efficacy of piperacillin-tazobactam (TZP) and cefotaxime (CTX) as first-line treatments in hospitalized children with UTIs.
METHODS: The study, conducted at Jeju National University Hospital, retrospectively analyzed medical records of children hospitalized for febrile UTIs between 2014 and 2017. UTI diagnosis included unexplained fever, abnormal urinalysis, and the presence of significant uropathogens. Treatment responses, recurrence, and antimicrobial susceptibility were assessed.
RESULTS: Out of 323 patients, 220 met the inclusion criteria. Demographics and clinical characteristics were similar between TZP and CTX groups. For children aged ≥3 months, no significant differences were found in treatment responses and recurrence. Extended-spectrum beta-lactamase (ESBL)-positive strains were associated with recurrence in those <3 months.
CONCLUSIONS: In Korea, escalating resistance to empirical antibiotics has led to the adoption of broad-spectrum empirical treatment. TZP emerged as a viable alternative to CTX for hospitalized children aged ≥3 months with UTIs. Consideration of ESBL-positive strains and individualized approaches for those <3 months are crucial.

Antibiotic resistance has become a global threat as it is continuously growing due to the evolution of β-lactamases diminishing the activity of classic β-lactam (BL) antibiotics. Recent antibiotic discovery and development efforts have led to the availability of β-lactamase inhibitors (BLIs) with activity against extended-spectrum β-lactamases as well as Klebsiella pneumoniae carbapenemase (KPC)-producing carbapenem-resistant organisms (CRO). Nevertheless, there is still a lack of drugs that target metallo-β-lactamases (MBL), which hydrolyze carbapenems efficiently, and oxacillinases (OXA) often present in carbapenem-resistant Acinetobacter baumannii. This review aims to provide a snapshot of microbiology, pharmacology, and clinical data for currently available BL/BLI treatment options as well as agents in late stage development for CRO harboring various β-lactamases including MBL and OXA-enzymes.

Pseudomonas aeruginosa encodes the beta-lactamase AmpC, which promotes resistance to beta-lactam antibiotics. Expression of ampC is induced by anhydro-muropeptides (AMPs) released from the peptidoglycan (PG) cell wall upon beta-lactam treatment. AmpC can also be induced via genetic inactivation of PG biogenesis factors such as the endopeptidase DacB that cleaves PG crosslinks. Mutants in dacB occur in beta-lactam-resistant clinical isolates of P. aeruginosa, but it has remained unclear why DacB inactivation promotes ampC induction. Similarly, the inactivation of lytic transglycosylase (LT) enzymes such as SltB1 that cut PG glycans has also been associated with ampC induction and beta-lactam resistance. Given that LT enzymes are capable of producing AMP products that serve as ampC inducers, this latter observation has been especially difficult to explain. Here, we show that ampC induction in sltB1 or dacB mutants requires another LT enzyme called MltG. In Escherichia coli, MltG has been implicated in the degradation of nascent PG strands produced upon beta-lactam treatment. Accordingly, in P. aeruginosa sltB1 and dacB mutants, we detected the MltG-dependent production of pentapeptide-containing AMP products that are signatures of nascent PG degradation. Our results therefore support a model in which SltB1 and DacB use their PG-cleaving activity to open space in the PG matrix for the insertion of new material. Thus, their inactivation mimics low-level beta-lactam treatment by reducing the efficiency of new PG insertion into the wall, causing the degradation of some nascent PG material by MltG to produce the ampC-inducing signal.
OBJECTIVE: Inducible beta-lactamases like the ampC system of Pseudomonas aeruginosa are a common determinant of beta-lactam resistance among gram-negative bacteria. The regulation of ampC is elegantly tuned to detect defects in cell wall synthesis caused by beta-lactam drugs. Studies of mutations causing ampC induction in the absence of drug therefore promise to reveal new insights into the process of cell wall biogenesis in addition to aiding our understanding of how resistance to beta-lactam antibiotics arises in the clinic. In this study, the ampC induction phenotype for mutants lacking a glycan-cleaving enzyme or an enzyme that cuts cell wall crosslinks was used to uncover a potential role for these enzymes in making space in the wall matrix for the insertion of new material during cell growth.

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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.