Search Results (154)

Introduction: Carbapenem-resistant Klebsiella pneumoniae (CRKP) represents a critical public health threat due to its rapid nosocomial dissemination, limited therapeutic options, and elevated mortality rates. This study aimed to characterize the epidemiology, carbapenemase profiles, and antimicrobial susceptibility patterns of CRKP isolates, as well as the clinical features and outcomes observed in infected or colonized patients. Materials and Methods: We conducted a retrospective analysis of clinical and microbiological data from patients with CRKP infections or colonization admitted between January 2023 and January 2024. Descriptive statistics were used to assess prevalence, resistance patterns, and patient outcomes. Two binary logistic regression models were applied to identify independent predictors of sepsis and in-hospital mortality. Results: Among 89 CRKP isolates, 45 underwent carbapenemase typing. More than half were metallo-β-lactamase (MBL) producers, with 44.4% co-harbouring NDM and OXA-48-like enzymes. Surgical intervention was associated with a significantly lower risk of sepsis (p < 0.01) and in-hospital mortality (p = 0.045), whereas intensive care unit (ICU) stay was a strong predictor of both outcomes. ICU admission conferred a 10-fold higher risk of sepsis (95%Cl 2.4–41.0) and a 40.8-fold higher risk of in-hospital death (95% Cl 3.5–473.3). Limitations: This single-center retrospective study included a limited number of isolates in certain groups. Additionally, cefiderocol (FDC) susceptibility was assessed by disk diffusion rather than by the broth microdilution method. Conclusions: Our study underscores the increasing prevalence of metallo-beta-lactamase-producing CRKP, particularly strains harbouring dual carbapenemases. Timely recognition of high-risk patients, combined with the implementation of targeted infection control measures and the integration of novel therapeutic options, is crucial to optimize clinical management and reduce mortality associated with CRKP. Full article

Background/Objectives: Non-fermenting Gram-negative bacilli (NFGNB) represent a significant clinical challenge due to their intrinsic and acquired resistance, particularly in immunocompromised patients. Infections cause by NFGNB are associated with high morbidity and mortality, especially among patients with cystic fibrosis and hematologic malignancies. This study aimed to assess the in vitro susceptibility of clinically relevant NFGNB isolates to two newer antibiotics, cefiderocol and aztreonam/avibactam, and an established antibiotic, trimethoprim/sulfamethoxazole. Methods: This retrospective, monocentric study analysed 94 NFGNB isolates (30 Pseudomonas aeruginosa, 30 Acinetobacter sp., 24 Stenotrophomonas maltophilia, and 10 Burkholderia cepacia complex). Susceptibility testing for cefiderocol, aztreonam/avibactam, and trimethoprim/sulfamethoxazole was conducted using gradient strip method. MIC values were interpreted using EUCAST breakpoints, ECOFFs, or alternative criteria when necessary. Results: All S. maltophilia isolates were susceptible to cefiderocol (FCR) and aztreonam/avibactam (A/A) based on ECOFFs, with one strain resistant to trimethoprim–sulfamethoxazole (COT). Burkholderia cepacia complex strains also showed high susceptibility to FCR, with only one isolate exceeding the ECOFF for A/A, and 20% resistant to COT. All Acinetobacter sp. isolates were susceptible to FCR; however, most MIC values clustered at or just below the ECOFF value. In P. aeruginosa, one isolate was resistant to FCR, and three isolates (10%) were resistant to A/A. Interestingly, confirmed carbapenemase producers remained susceptible to both FCR and A/A. Most A/A MIC values for P. aeruginosa were just below the ECOFF. Conclusions: Cefiderocol and aztreonam/avibactam demonstrated promising in vitro activity against clinically relevant NFGNB, including carbapenem-resistant strains. These findings support their potential role as therapeutic options for difficult-to-treat infections, particularly in immunocompromised patients. Full article

Background: Cefiderocol (FDC) presents challenges in antimicrobial susceptibility testing (AST). The reference standard is the broth microdilution (BMD) method with iron-depleted cation-adjusted Mueller-Hinton broth (ID-CAMHB). Still, it is cumbersome for routine clinical laboratory use, while variable accuracy has been reported with available commercial systems. Variability in interpretive criteria and areas of technical uncertainty (ATUs) further complicate assessments. Methods: This review and expert opinion presents: (1) an overview of non-susceptibility to FDC and then delves into the performance of current FDC AST methods for Enterobacterales, Pseudomonas aeruginosa, and Acinetobacter baumannii complex; (2) a practical decision framework to guide clinical microbiologists in making informed choices. Results and Conclusions: For Enterobacterales, including carbapenem-resistant Enterobacterales (CRE), and Pseudomonas aeruginosa, we propose disk diffusion (DD) as a preliminary screening tool to classify isolates as susceptible (S) or resistant (R). Confirmatory testing using the UMIC^® FDC system or the ID-CAMHB BMD method is recommended for R isolates. In cases of discrepancy, repeating the test with ID-CAMHB BMD is advised. Additionally, isolates falling within the ATU during DD testing should be retested using the UMIC^® system or ID-CAMHB BMD. For A. baumannii complex, since EUCAST breakpoints have not been defined yet, we propose a stepwise framework based on the first DD result: isolates with inhibition zones < 17 mm are considered non-susceptible and should be confirmed with standard BMD. Those between 17 and 22 mm require retesting with a commercial BMD method, with further confirmation recommended if S isolates with zones ≥ 23 mm may be considered S without additional testing. Full article

Background/objectives: Proteus mirabilis is a frequent causative agent of urinary and wound infections in both community and hospital settings. It develops resistance to expanded-spectrum cephalosporins (ESCs) due to the production of extended-spectrum β-lactamases (ESBLs) or plasmid-mediated AmpC β-lactamases (p-AmpCs). Recently, carbapenem-resistant isolates of P. mirabilis emerged due to the production of carbapenemases, mostly belonging to Ambler classes B and D. Here, we report an outbreak of infections due to carbapenem-resistant P. mirabilis that were observed in a psychiatric hospital in Zagreb, Croatia. The characteristics of ESBL and carbapenemase-producing P. mirabilis isolates, associated with an outbreak, were analyzed. Materials and methods: The antibiotic susceptibility testing was performed by the disk-diffusion and broth dilution methods. The double-disk synergy test (DDST) and inhibitor-based test with clavulanic and phenylboronic acid were applied to screen for ESBLs and p-AmpCs, respectively. Carbapenemases were screened by the modified Hodge test (MHT), while carbapenem hydrolysis was investigated by the carbapenem inactivation method (CIM) and EDTA-carbapenem-inactivation method (eCIM). The nature of the ESBLs, carbapenemases, and fluoroquinolone-resistance determinants was investigated by PCR. Plasmids were characterized by PCR-based replicon typing (PBRT). Selected isolates were subjected to molecular characterization of the resistome by an Inter-Array Genotyping Kit CarbaResisit and whole-genome sequencing (WGS). Results: In total, 20 isolates were collected and analyzed. All isolates exhibited resistance to amoxicillin alone and when combined with clavulanic acid, cefuroxime, cefotaxime, ceftriaxone, cefepime, imipenem, ceftazidime–avibactam, ceftolozane–tazobactam, gentamicin, amikacin, and ciprofloxacin. There was uniform susceptibility to ertapenem, meropenem, and cefiderocol. The DDST and combined disk test with clavulanic acid were positive, indicating the production of an ESBL. The MHT was negative in all except one isolate, while the CIM showed moderate sensitivity, but only with imipenem as the indicator disk. Furthermore, eCIM tested positive in all of the CIM-positive isolates, consistent with a metallo-β-lactamase (MBL). PCR and sequencing of the selected amplicons identified VIM-1 and VIM-4. The Inter-Array Genotyping Kit CarbaResist and WGS identified β-lactam resistance genes bla_VIM, bla_CTX-M-15, and bla_TEM genes; aminoglycoside resistance genes aac(3)-IId, aph(6)-Id, aph(3″)-Ib, aadA1, armA, and aac(6′)-IIc; as well as resistance genes for sulphonamides sul1 and sul2, trimethoprim dfr1, chloramphenicol cat, and tetracycline tet(J). Conclusions: This study revealed an epidemic spread of carbapenemase-producing P. mirabilis in two wards in a psychiatric hospital. Due to the extensively resistant phenotype (XDR), therapeutic options were limited. This is the first report of carbapenemase-producing P. mirabilis in Croatia. Full article

Objectives: Cefideroccol (FDC) is a siderophore cephalosporin with potent antibacterial activity against a wide range of Gram-negative multidrug-resistant (MDR) microorganisms. We investigated the anti-biofilm capacity of FDC against clinical strains. Methods: This multicenter study was conducted on 28 selected strains of MDR Gram-negative bacilli isolated from clinical samples of Pseudomonas aeruginosa (n = 5), Acinetobacter baumannii (n = 11), and Klebsiella pneumoniae (n = 12). We first determined the minimum inhibitory concentration (MIC) of each strain using the microdilution method. We also defined the minimum biofilm inhibitory concentration (MBIC) as a ≥50% reduction in tetrazolium salt (XTT) (as recommended in the 2017 Spanish Microbiology Protocols [SEIMC] for the microbiological diagnosis of infections related to the formation of biofilms). We also analyzed the reduction in the following biofilm variables after an 8 mg/mL FDC treatment: the CFU count, the cell viability, the biomass, the metabolic activity, and extracellular α or β polysaccharides. Results: The MIC₅₀ and MBIC₅₀ of FDC were 0.5 mg/L and 64 mg/L, respectively. We observed a mean (SD) fold increase in the susceptibility to FDC between planktonic and sessile cells for P. aeruginosa, A. baumannii, and K. pneumoniae of 9.60 (0.55), 6.27 (2.28), and 6.25 (2.80), respectively. When 8 mg/mL of FDC was tested, we observed that the best median (IQR) percentage reductions were obtained for cell viability and the extracellular matrix (73.1 [12.4–86.5] and 79.5 [37.3–95.5], respectively), particularly for P. aeruginosa. The lowest percentage reduction rates were those obtained for biomass. Conclusions: We demonstrated that the susceptibility to FDC was significantly reduced when strains were in a biofilm state. The best percentage reduction rates for all biofilm-defining variables were observed for P. aeruginosa. Our results need to be validated using a larger collection of clinical samples. Full article

This study evaluated the antimicrobial efficacy of cefiderocol and various forms of silver (ionic and nanoparticulate) as potential components of wound-dressing reagents against both reference and multidrug-resistant (MDR) Gram-negative bacteria. The anticipated synergistic effect between cefiderocol and nanosilver was not consistently observed; in fact, for reference strains, the combination was less effective than cefiderocol alone. However, in MDR and cefiderocol-resistant A. baumannii strains, combining both agents enhanced antibacterial efficacy. Notably, the effectiveness of silver did not increase with concentration, and low or medium nanosilver concentrations were often more effective. Mechanistically, high concentrations of silver may antagonize cefiderocol’s action by inhibiting bacterial surface proteins involved in siderophore-mediated uptake. Generalized linear modeling confirmed that the strain type, silver form, concentration, and their interactions significantly influenced inhibition zones. These findings highlight the importance of agent selection, concentration, and formulation in designing effective antimicrobial wound dressings. They also suggest that further research is needed to optimize such combination therapies for clinical use. Full article

Drug-induced nephrotoxicity is a common and serious problem in clinical practice. We conducted a systematic review of studies reporting nephrotoxicity events associated with antibiotics approved since 2018. The agents assessed included aztreonam/avibactam, cefepime/enmetazobactam, cefiderocol, ceftobiprole, contezolid, gepotidacin, imipenem/cilastatin/relebactam, lascufloxacin, lefamulin, levonadifloxacin, plazomicin, and sulbactam/durlobactam. Literature searches were conducted in PubMed, Scopus, Web of Science, and major pharmacovigilance databases (Vigibase, FAERS, EudraVigilance, EMA, FDA, NMPA, PMDA, and CDSCO) in May 2025, along with reference citation tracking. Studies were included if they reported safety or adverse event data. The risk of bias was assessed using validated tools in accordance with the study design. Out of 2105 potentially relevant records, 74 studies met inclusion criteria, comprising 52 clinical trials, 17 observational studies, 1 registry-based study, 3 case series, and 1 case report. Nephrotoxicity was rarely reported for any of the newly approved antibiotics. No renal adverse events were found in the available studies for aztreonam/avibactam, levonadifloxacin, and contezolid. Most studies were of moderate to high quality; two were classified as low quality. However, nephrotoxicity was inconsistently assessed, with variable definitions and methodologies used. Although current data suggest a low frequency of nephrotoxicity, limitations in study design and reporting preclude firm conclusions. There is a need for post-marketing studies to better characterize renal safety. Clinicians should remain vigilant and continue to monitor for and report renal-related adverse events. Full article

Background/Objectives: Cefiderocol is a novel siderophore cephalosporin with potent in vitro activity against a broad spectrum of Gram-negative bacteria, including carbapenemase-producing Enterobacterales (CPE). However, the recent emergence of resistance in clinical settings raises important concerns regarding its long-term effectiveness. This study aims to investigate the genomic determinants associated with cefiderocol resistance in CPE isolates of human origin. Methods: Comparative genomic analyses were conducted between cefiderocol-susceptible and -resistant CPE isolates recovered from human clinical and epidemiological samples at a tertiary care hospital. Whole-genome sequencing, variant annotation, structural modelling, and pangenome analysis were performed to characterize resistance mechanisms. Results: A total of 59 isolates (29 resistant and 30 susceptible) were analyzed, predominantly comprising Klebsiella pneumoniae, Escherichia coli, and Enterobacter cloacae. The most frequent carbapenemase gene among the resistant isolates was bla_NDM, which was also present in a subset of susceptible strains. The resistant isolates exhibited a significantly higher burden of non-synonymous mutations in their siderophore receptor genes, notably within fecR, fecA, fiu, and cirA. Structural modelling predicted deleterious effects for mutations such as fecR:G104S and fecA:A190T. Additionally, porin loss and loop 3 insertions (e.g., GD/TD) in OmpK36, as well as OmpK35 truncations, were more frequent in the resistant isolates, particularly in high-risk clones such as ST395 and ST512. Genes associated with toxin–antitoxin systems (chpB2, pemI) and a hypothetical metalloprotease (group_2577) were uniquely found in the resistant group. Conclusions: Cefiderocol resistance in CPE appears to be multifactorial. NDM-type metallo-β-lactamases and missense mutations in siderophore uptake systems—especially in those encoded by fec, fhu, and cir operons—play a central role. These may be further potentiated by alterations in membrane permeability, such as porin disruption and efflux deregulation. The integration of genomic and structural approaches provides valuable insights into emerging resistance mechanisms and may support the development of diagnostic tools and therapeutic strategies. Full article

Respiratory tract infections are frequently encountered in clinical practice. The growing incidence of antimicrobial resistance among the causative pathogens exerts sustained pressure on the existing therapeutic options. The emergence of antimicrobial resistance limits the treatment options and often leads to unfavorable patient outcomes. However, in the past few years, newly developed antibiotics have become available, providing viable choices for antibiotic-resistant infections. New β-lactam/β-lactamase combinations, such as ceftazidime/avibactam, meropenem/vaborbactam, and imipenem/relebactam, are effective against carbapenem-resistant Enterobacterales. Several new drugs including ceftolozane/tazobactam are active against multi-drug-resistant Pseudomonas aeruginosa, while sulbactam/durlobactam and cefiderocol have potent activity against Acinetobacter baumannii. A number of new options, such as lefamulin, omadacycline, and delafloxacin, have also emerged for pathogens commonly associated with community acquired pneumonia. This article aims to review the characteristics of newly approved antibiotics for the treatment of respiratory tract infections, as well as to discuss some investigational agents that are currently under development. Full article

Accurate antimicrobial susceptibility testing (AST) of cefiderocol remains a diagnostic challenge, especially in infections caused by metallo-β-lactamase (MBL)-producing Klebsiella pneumoniae. While disk diffusion offers a cost-effective alternative to broth microdilution, it is highly sensitive to factors such as media composition and the presence of atypical colony morphology. The objective of this study was to evaluate how different agar media and interpretations of isolated colonies affect the performance and reliability of cefiderocol AST by disk diffusion. A total of 50 clinical K. pneumoniae MBL isolates were tested using disk diffusion on Columbia with blood, MacConkey, and chromogenic agars from three manufacturers. Inhibition zones were compared with MICs from broth microdilution. Statistical analyses included paired t-tests and Spearman correlation to assess media effects and zone morphology impact. Variability in inhibition zone diameters was observed between media, notably with chromogenic agar. The most consistent results were obtained using Graso Biotech and Thermo Fisher Columbia with blood agar. Isolated colonies were observed in over half the samples and, depending on how they were interpreted, led to major changes in classification accuracy. Up to 64% of results fell into the EUCAST area of technical uncertainty (ATU), and categorical agreement varied across media and interpretive criteria. Disk diffusion for cefiderocol may be used in resource-limited settings but only if rigorously standardized using validated media, consistent zone reading, and ATU-aware interpretive strategies. In borderline cases or when morphological anomalies are present, broth microdilution should be considered the sole reliable method. Clinical microbiologists are advised to exercise caution with ambiguous results and seek expert or confirmatory testing when needed. Full article

The global emergence of carbapenem-resistant Acinetobacter baumanii (CRAB) represents a significant public health threat. In the summer of 2022, a polyclonal CRAB outbreak occurred in our hospital, marking the first detection of an NDM-1 plus OXA-23 co-producing A. baumannii strain in Spain. The aim of this study was to phenotypically and genotypically characterize the clonal spread of NDM-1 and OXA-23 co-producing A. baumannii isolates and to describe the infection control measures implemented to contain the outbreak. Patients with multidrug-resistant A. baumannii isolates (July 2022–May 2023) were included in the study. Isolates were identified via MALDI-TOF, and antimicrobial susceptibility was tested using a broth microdilution method (DKMGN SensititreTM panels). Whole-genome sequencing was performed on 24 representative isolates. Phylogenetic analysis was performed using Ridom SeqSphere+ (cgMLST), while sequence typing was performed using ARIBA (Pasteur and Oxford schemes). A. baumannii isolates from the affected patients belonged to five different sequence types. The two main STs were ST1Pas/ST231Oxf (NDM-1- and OXA-23-co-producing), which accounted for 58%, and ST136Pas/ST406Oxf (OXA-23-producing), which accounted for 21%. All isolates were resistant to fluoroquinolones, trimethoprim/sulfamethoxazole, aminoglycosides, and carbapenems. In addition, 8% were resistant to colistin and 17% to cefiderocol. Finally, the affected patients were cohorted, and a thorough cleaning of the affected units was carried out. This study documents the clonal spread of an NDM-1- and OXA-23-co-producing A. baumannii strain in Spain, linked to a Libyan patient, highlighting the risk of cross-border spread. Although infection control measures successfully contained the outbreak, surveillance is essential as the incidence of CRAB infections is expected to increase. Full article

Background/Objectives: The global spread of carbapenemase-producing K. pneumoniae (CPKP) strains represent a severe public health threat due to very limited choice of antibacterial therapy. Cefiderocol, a novel siderophore-cephalosporin, may represent a new therapeutic option but resistance is increasingly being described. Our aim was to investigate in vitro cefiderocol susceptibility among CPKP strains in Hungary and assess correlations between resistance, carbapenemase types, and clonal lineages. Methods: The study was performed on 420 CPKP strains from 34 Hungarian healthcare institutes (HCIs) submitted to the National Reference Laboratory of Antimicrobial Resistance (March 2021 to April 2023). The disk diffusion method (Liofilchem, Via Scozia, Italy) was used for in vitro cefiderocol susceptibility testing (according to EUCAST guidelines). For molecular epidemiologic investigation, we used whole genome sequencing (Illumina MiSeq, 150 bp paired-end) and pulsed-field gel electrophoresis (PFGE). Carbapenemase gene type was determined by multiplex PCR. Statistical analysis was performed in R (v.4.2.0). Results: Dominant high-risk clones (ST147, ST395, ST258) exhibited regional distribution, with ST147/NDM-1 strains showing the highest cefiderocol resistance (75%). Overall resistance was 65%. Carbapenemase gene types occurred as follows: 35 bla_VIM, 53 bla_KPC, 57 bla_OXA-48-like, 153 bla_NDM, and 122 bla_OXA-48-like+bla_NDM. Cefiderocol resistance rates by carbapenemase type were 20%, 44%, 70%, and 75% in the case of bla_VIM, bla_OXA-48-like, bla_KPC, bla_NDM, and bla_OXA-48-like+bla_NDM. Conclusions: The results show a high prevalence of cefiderocol resistance in CPKP in Hungary, with different rates of resistance in different carbapenemase gene-carrying high-risk clones, highlighting the growing challenge in treating these infections. Full article

Background: The use of an elastomeric diffuser is favored to administer outpatient antibiotic therapy. A study published in 2022 highlighted the instability of several antibiotics in elastomeric devices at 37 °C. The objective was to evaluate the stability of nine time-dependent antibiotics that are unstable at 37 °C at lower concentrations and a reduced storage temperature of 32 °C. Methods: Chemical stability was assessed by pH measurement and high-performance liquid chromatography. Physical stability was evaluated by visual and subvisual inspection. The solutions were considered stable if the remaining drug percentage was ≥90%, the maximum variation in pH was less than 1, the particle count was within acceptable limits and the visual aspect remained unchanged after storage. Results: Solutions showing stability for 24 h are composed of 12.5 mg/mL cefiderocol in NS (normal saline) and 50–133 mg/mL piperacillin in NS-D5W (5% dextrose). Additionally, 12.5 mg/mL amoxicillin in NS; 12.5 mg/mL cefepime in NS-D5W; 12.5 mg/mL cefiderocol in D5W; 25 mg/mL cefiderocol in NS-D5W; 12.5 mg/mL cefotaxime in NS-D5W; 12.5 mg/mL cefoxitin in NS-D5W; 12.5 mg/mL ceftazidime in NS-D5W; 25 mg/mL ceftazidime in NS; 25 mg/mL cloxacillin in NS-D5W; and 25–50 mg/mL oxacillin in NS were shown to be stable for 12 h. Notably, 25 mg/mL amoxicillin in NS, 50 mg/mL cloxacillin in NS and 25 mg/mL oxacillin in D5W were shown to be stable for 8 h. Conclusions: These 12–24 h stability data indicate that these antibiotics can be administered by continuous infusion using only one–two elastomeric devices per day, facilitating outpatient parenteral antimicrobial therapy (OPAT). Full article

Background: Cefiderocol (CFD) is a novel siderophore cephalosporin developed for the treatment of infections involving multidrug-resistant (MDR) Gram-negative bacilli (GNB) infections (1–3). For bone and joint infections (BJIs), the use of CFD is currently neither part of its market authorization nor recommended, and has not yet been assessed by large-scale studies. Objectives: To fill the scarcity of data regarding the use of CFD in BJIs, we aimed to describe patients’ and infection characteristics along with the outcomes of the infection. Methods: We conducted a retrospective observational multicenter study in 22 French centers from January 2019 to December 2023. Results: From January 2019 to December 2023, 45 patients were included. Patients were mainly males (73%) with a median age of 62 years (interquartile range [IQR] 29), and a median Charlson comorbidity index of 3. Implant-related infections (20) were the most prominent, accounting for 44% of the cases. Carbapenemase-producing GNB were involved in 74% of the cases (n = 17/23), among which Pseudomonas aeruginosa accounted for 38% of these cases. Most patients received 6 g of CFD per day. CFD was used in combination with an antibiotic in 40 out of 45 cases (89%). The median duration of CFD treatment was 34 days. Seven patients (16%) experienced side effects, mainly gastro-intestinal disorders, including three (7%) who induced treatment cessation. Infection control included surgery in 37 (82%) patients. Failures and deaths occurred, respectively, in 22 (49%) and 10 (22%) cases. Conclusions: Our results suggest that CFD may be an alternative in MDR-GNB infections with limited therapeutic options. Full article

Carbapenem-resistant Acinetobacter baumannii (CRAB) is an emerging and important major cause of nosocomial infections, posing a significant challenge to clinicians worldwide. The intrinsic and acquired resistance mechanisms exhibited by CRAB, associated with its ability to persist in healthcare environments, have transformed it into a critical public health concern. The clinical implications of CRAB infections include severe manifestations, like ventilator-associated pneumonia and bloodstream infections. These infections are often associated with increased morbidity and mortality, particularly in critically ill patients, such as those in intensive care units, immunocompromised, and those undergoing invasive procedures. Considering these characteristics, the therapeutic armamentarium for the treatment of CRAB infections is increasingly limited, as these strains exhibit resistance to a broad range of antibiotics, including carbapenems and the new β-lactam inhibitors, which are considered last-line agents for many bacterial infections. An important role is represented by cefiderocol and data from real-world evidence. The aim of this narrative review is to discuss the main topics of CRAB infection and strategies for prevention, management, and therapy. Full article