Search Results (96)

Introduction: The combination of ceftazidime−avibactam (CAZ-AVI) with aztreonam (ATM) may be an option for the treatment of infections due to metallo-β-lactamases (MBLs) producing bacteria, as recommended by current guidelines. MBLs protect the pathogen from any available β-lactam/β-lactamase inhibitor (BL/BLI). Moreover, in vitro and clinical data suggest that double carbapenem therapy (DCT) may be an option for such infections. Materials and Methods: This retrospective study was conducted in two mixed intensive care units (ICUs) at the University Hospital of Larissa, Thessaly, Greece, and the General Hospital of Larissa, Thessaly, Greece, during a three-year period (2022−2024). Mechanically ventilated patients with bloodstream infection (BSI) caused by K. pneumoniae resistant to all BL/BLI combinations were studied. Patients were divided into three groups: in the first, patients were treated with CAZ-AVI + ATM; in the second, with DCT; and in the third, with antibiotics other than BL/BLIs that presented in vitro susceptibility. The primary outcome of the study was the change in Sequential Organ Failure Assessment (SOFA) score between the onset of infection and the fourth day of antibiotic treatment. Secondary outcomes were SOFA score evolution during the treatment period, total duration of mechanical ventilation (MV), ICU length of stay (LOS), and ICU mortality. Results: A total of 95 patients were recruited. Among them, 23 patients received CAZ-AVI + AZT, 22 received DCT, and 50 patients received another antibiotic regimen which was in vitro active against the pathogen. The baseline characteristics were similar. The mean (SE) overall age was 63.2 (1.3) years. Mean (SE) Acute Physiology and Chronic Health Evaluation II (APACHE II) and SOFA scores were 16.3 (0.6) and 7.6 (0.3), respectively. The Charlson Index was similar between groups. The control group presented a statistically lower SOFA score on day 4 compared to the other two groups [mean (SE) 8.9 (1) vs. 7.4 (0.9) vs. 6.4 (0.5) for CAZ-AVI + ATM, DCT and control group, respectively (p = 0.045)]. The duration of mechanical ventilation, ICU LOS, and mortality were similar between the groups (p > 0.05). Comparison between survivors and non-survivors revealed that survivors had a lower SOFA score on the day of BSI, higher PaO₂/FiO₂ ratio, higher platelet counts, and lower lactate levels (p < 0.05). Septic shock was more frequent among non-survivors (60.3%) in comparison to survivors (27%) (p = 0.0015). Independent factors for mortality were PaO₂/FiO₂ ratio and lactate levels (p < 0.05). None of the antibiotic regimens received by the patients was independently associated with survival. Conclusions: Treatment with CAZ-AVI + ATM or DCT may offer similar clinical outcomes for patients suffering from BSI caused by K. pneumoniae strains resistant to all available BL/BLIs. However, larger studies are required to confirm the findings. Full article

The global rise of carbapenem-resistant Acinetobacter baumannii (CRAB) strains poses a critical challenge to healthcare systems due to limited therapeutic options and high mortality rates, especially in intensive care settings. This review explores the epidemiological landscape and molecular mechanisms driving carbapenem resistance, including the production of diverse beta-lactamases (particularly OXA-type enzymes), porin loss, efflux pump overexpression, and mutations in antibiotic targets. Emerging treatment strategies are discussed, such as the use of new beta-lactam–beta-lactamase inhibitor combinations (e.g., sulbactam–durlobactam), siderophore cephalosporins, next-generation polymyxins, as well as novel agents like zosurabalpin and rifabutin (BV100). Alternative approaches—including phage therapy, antimicrobial peptides, CRISPR-based gene editing, and nanoparticle-based delivery systems—are also evaluated for their potential to bypass traditional resistance mechanisms. Furthermore, advances in artificial intelligence and multi-omics integration are highlighted as tools for identifying novel drug targets and predicting resistance profiles. Together, these innovations represent a multifaceted strategy to overcome CRAB infections, yet their successful implementation requires further clinical validation and coordinated surveillance efforts. This analysis highlights the urgent need for continued investment in innovative treatments and effective resistance monitoring to limit the spread of CRAB and protect the effectiveness of last-line antibiotics. Full article

Neonatal sepsis is a major cause of morbidity and mortality in neonates. A particular concern is the increasing prevalence of antibiotic-resistant strains among neonatal intensive care units (NICUs). Two novel beta-lactam/beta-lactamase inhibitors have recently been approved for use in neonates with multidrug-resistant infections: ceftazidime/avibactam and ceftolozane/tazobactam. These agents demonstrate efficacy against a range of multidrug-resistant gram-negative pathogens, including extended-spectrum beta-lactamases (ESBL)-producing and carbapenem-resistant Enterobacterales, as well as multidrug-resistant Pseudomonas aeruginosa. This narrative review aims to summarize the current knowledge concerning the utilization of ceftazidime/avibactam and ceftolozane/tazobactam in the NICU. According to the existing literature, both agents have been shown to be highly effective with a favorable safety profile in the neonatal population. Full article

Background: Urinary tract infections (UTIs) caused by the multidrug resistance (MDR) phenotype termed extended-spectrum beta lactamase (ESBL)-producing E. coli is a significant and growing global health concern. In response to the rising prevalence, the novel Beta Lactam-Beta Lactamase inhibitor (BL/BLI) combinations have been introduced in recent years. While these agents have shown efficacy, their clinical utility is constrained by high cost, limited availability, and emerging resistance mechanisms. The rational of this study was to test the in vitro activity of a cost-effective alternative to currently available BL–BLI combinations against ESBL-producing E. coli isolated from urinary tract infections (UTIs). Objective: This study investigates the in vitro antimicrobial activity of cefaclor (CFC), both as monotherapy and in combination with the β-lactamase inhibitors clavulanic acid (CA) and sulbactam (SUL), against 52 ESBL-producing E. coli isolates derived from urine cultures of patients diagnosed with UTIs. Methods: The susceptibility ranges were measured by disk diffusion and minimal inhibitory concentration (MIC) methods. In addition, the Time kill assay and disk approximation method were performed to measure the synergistic and bactericidal activity of the approached combination. Results: The MIC50 and MIC90 for CFC were improved from more than 128 µg/mL to 8/4 µg/mL when CFC was combined with either CA or SUL. The triple combination format of CFC/CA/SUL showed MIC50 and MIC90 values at 8/4/4 µg/mL and 64/32/32 µg/mL, respectively. The recovered susceptibility percentages were 54%, 54%, and 58% for CFC/CA, CFC/SUL, and CFC/CA/SUL combinations, respectively. Disk approximation and time–kill assay results revealed synergy and bactericidal effects when CFC combined with CA or SUL for isolates that showed susceptibility restorations of CFC when coupled with CA or SUL by the disk diffusion and MIC method. Conclusions: This study proposes a cost-effective combination that could mitigate resistance development and offer a sparing option to last resort treatment choices including carbapenems. However, testing efficacy in a clinical setting is crucial. Full article

Objective: To evaluate the antimicrobial susceptibility of Enterobacterales isolated from patients with intra-abdominal infections (IAI) in United States (US) medical centres. Methods: A total of 2036 isolates (1/patient) were consecutively collected from patients with IAI in 63 US hospitals in 2019–2023 and susceptibility tested by broth microdilution. Carbapenem-resistant Enterobacterales (CRE) were screened for carbapenemases by whole genome sequencing. Results: The most common Enterobacterales species were E. coli (47.1%), K. pneumoniae (18.7%), and E. cloacae species complex (9.8%). The most active agents were aztreonam-avibactam (MIC_50/90, ≤0.03/0.12 mg/L), ceftazidime-avibactam (MIC_50/90, 0.12/0.25 mg/L), and meropenem-vaborbactam (MIC_50/90, 0.03/0.06 mg/L) with 99.9% susceptibility. A multidrug-resistant (MDR) phenotype (nonsusceptibility to ≥3 classes) was observed in 21.4% of Enterobacterales (n = 436). Piperacillin-tazobactam was active against 87.2% of Enterobacterales overall and 50.2% of MDR isolates, and meropenem was active against 99.2% of Enterobacterales and 96.1% of MDR isolates. Only 51.6% of Enterobacterales were susceptible to ampicillin-sulbactam. An acquired broad-spectrum β-lactamase gene was identified in 207 (10.2%) isolates and included extended-spectrum β-lactamases (ESBL; n = 182), transferable AmpC (n = 24) and carbapenemases (n = 9). Eight isolates produced two β-lactamase classes. Conclusions: Aztreonam-avibactam, ceftazidime-avibactam, and meropenem-vaborbactam exhibited almost complete activity (99.9% susceptibility) against Enterobacterales causing IAI in US hospitals. In contrast, piperacillin-tazobactam exhibited limited activity against these organisms, especially those with a MDR phenotype. Full article

The introduction of new β-lactam–β-lactamase inhibitors (BLBLIs), such as ceftazidime/avibactam, meropenem/vaborbactam, and imipenem/cilastatin/relebactam, expands our therapeutic options against carbapenem-resistant Gram-negative bacteria, including those pathogens for which therapeutic options are limited. These new combinations are active against ESBL-, AmpC-, and KPC-producing Enterobacterales, with the exception of ceftazidime/avibactam, which is active in vitro against OXA-48. However, one drawback that must be taken seriously by the clinician is that they are ineffective against metallo-β-lactamases as well as Acinetobacter baumannii. The recent introduction of aztreonam/avibactam marks a significant advancement in our therapeutic armamentarium against metallo-β-lactamase-producing pathogens. The question to be answered is whether there is a preferred, newer BLBLI combination for the treatment of KPC-producing Enterobacterales infections. This review provides a thorough analysis of the similarities and differences between these new combinations to identify the most effective treatment options. The present review aims to provide clinicians with a detailed understanding of each BLBLI treatment option to guide the optimal use of these new agents for the effective treatment of difficult infections caused by carbapenemase-producing Enterobacterales infections. This review is based on literature retrieved from PubMed, Scopus, Web of Science, and the Cochrane Library. Full article

Background/Objectives: Clavulanic acid (CA) is produced by cell suspension cultures of Streptomyces clavuligerus ATCC 27064, and is widely used as a beta-lactamase inhibitor to combat antibiotic resistance. CA titers are moderate due to bioprocess complexity, prompting ongoing efforts to overcome these limitations. Methods: In this study, we aimed to evaluate the effect of live and inactivated Bacillus velezensis FZB42 cells on CA production in S. clavuligerus, and to explore the transcriptional response underlying this interaction using RNA-seq technology. Results: The addition of dead and live cells of B. velezensis improved CA production by 1.4 and 2.0-fold, respectively. Furthermore, the transcriptome of S. clavuligerus, obtained with live cells of B. velezensis FZB42 at the peak of maximum CA production, revealed that 410 genes were up-regulated and 594 were down-regulated under these conditions, with a padj < 0.05. Most of the genes from the cephamycin C and CA clusters were up-regulated, which correlates well with the increase in CA production. Likewise, S. clavuligerus ATCC 27064 enhanced the expression of genes encoding enzymes that scavenge endogenous H₂O₂, as well as other genes related to oxidative stress defense. Regarding downregulated genes, we found that S. clavuligerus decreased the expression of genes involved in the biosynthesis of terpenoids, polyketides, and lantibiotics, as well as the expression of the operon involved in the synthesis of the pyrroloquinoline quinone (PQQ) cofactor. Conclusions: These findings contribute to the understanding of S. clavuligerus metabolism and pave the way for future metabolic engineering efforts aimed at obtaining CA-overproducing strains. Full article

In this study, we evaluated in situ click chemistry as a platform for discovering boronic acid-based β-lactamase inhibitors (BLIs). Unlike conventional drug discovery approaches requiring multi-step synthesis, protection strategies, and extensive screening, the in situ method can allow for the generation and identification of potent β-lactamase inhibitors in a rapid, economic, and efficient way. Using KPC-2 (class A carbapenemase) and AmpC (class C cephalosporinase) as templates, we demonstrated their ability to catalyse azide-alkyne cycloaddition, facilitating the formation of triazole-based β-lactamase inhibitors. Initial screening of various β-lactamases and boronic warheads identified compound 3 (3-azidomethylphenyl boronic acid) as the most effective scaffold for kinetic target-guided synthesis (KTGS). KTGS experiments with AmpC and KPC-2 yielded triazole inhibitors with K_i values as low as 140 nM (compound 10a, AmpC) and 730 nM (compound 5, KPC-2). Competitive inhibition studies confirmed triazole formation within the active site, while an LC–MS analysis verified that the reversible covalent interaction of boronic acids did not affect detection of the in situ-synthesised product. While KTGS successfully identified potent inhibitors, limitations in amplification coefficients and spatial constraints highlight the need for optimised warhead designs. This study validates KTGS as a promising strategy for BLI discovery and provides insights for further refinement in fighting β-lactamase-mediated antibiotic resistance. Full article

Background: Fosfomycin, an old antibiotic attracting renewed interest, offers a broad spectrum of activity and unique synergy with other agents. While widely used in severe infections, real-world data on intravenous fosfomycin remain limited. Objectives: This study aimed to describe the clinical and microbiological characteristics of patients treated with intravenous fosfomycin and to analyze its administration modalities in a real-world setting. Methods: A multicenter retrospective cohort study was conducted across five Italian hospitals. Adult patients receiving intravenous fosfomycin between January 2020 and December 2023 were included. Results: We enrolled 393 patients. The median age was 69 years, with most patients (45%) admitted to Critical Care Units. Pneumonia (34%), bloodstream infections (22%), and urinary tract infections (21%) were the most common indications. Gram-negative bacteria, particularly E. coli and P. aeruginosa, were the predominant pathogens. Fosfomycin was used as empirical therapy in 55% of cases and was combined with other agents in almost all cases (99%). The most frequent partners were piperacillin/tazobactam (21%) and new beta-lactam/beta-lactamase inhibitor combinations (18%). The median treatment duration was seven days, with most subjects (65%) receiving a fosfomycin dosage regimen of 16 g/day. Minimum inhibitory concentrations (MICs) values for fosfomycin were available for 61 isolates (15%), with 78.7% (48/61) showing MIC ≤ 32 mg/L. C. difficile infection occurred in only 2% of patients. Mortality rates at 30, 60, and 90 days were 21.6%, 26.7%, and 29.3%, respectively. Conclusions: This study provides valuable insights into the real-world use of intravenous fosfomycin. Full article

Background: Antimicrobial consumption (AMC) patterns, besides prescribing behaviors, reflect the changing epidemiology of infectious diseases. Routine surveillance data have been used to investigate the development of AMC from 2017 to 2023 and the impact of COVID-19 within the context of the framing time periods. Methods: Data from 112 hospitals, continuously participating from 2017 to 2023 in the national surveillance system of hospital antimicrobial consumption based at the Robert Koch Institute, were analyzed according to the WHO ATC (Anatomical Therapeutic Chemical)/DDD (Defined Daily Dose) method and categorized according to the WHO AWaRe-classification. AMC was quantified by consumption density (CD) expressed in DDD/100 patient days (PD) and DDD/100 admissions (AD). The time period was subdivided into three phases: pre-pandemic phase (2017–2019), main pandemic phase (2020–2021) and transition phase (2022–2023). Linear regression models have been used to determine the presence of an overall trend, the change in intra-phasic trends and phase-specific mean consumption levels over time. Results: From 2017 to 2023 total antibiotic consumption decreased by 7% from 57.1 to 52.9 DDD/100 PD. Four main kinetic patterns emerged across different antibiotic classes: Pattern 1 displays a decreasing pre-pandemic trend, which slowed down throughout the pandemic and transition phase and was exhibited by second-generation cephalosporins and fluoroquinolones. Pattern 2 reveals a rising pre-pandemic trend, which decelerated in the pandemic phase and accelerated again in the transition phase and was expressed by aminopenicillins/beta-lactamase inhibitors, beta-lactamase sensitive pencillins, azithromycin and first-generation cephalosporins. Pattern 3 shows elevated mean consumption levels in the pandemic phase exhibited by carbapenems, glycopeptides, linezolid and third-generation cephalosporins. Pattern 4 reveals a rising trend throughout the pre-pandemic and pandemic phase, which reversed in the transition phase without achieving pre-pandemic levels and was expressed by beta-lactamase resistant penicillins, daptomycin, fosfomycin (parenteral) and ceftazidime/avibactam. Conclusions: Kinetic consumption patterns across different antibiotic classes might reflect COVID-19-related effects and associated changes in the epidemiology of co-circulating pathogens and health care supply. Broad-spectrum antibiotics with persisting elevated consumption levels throughout the transition phase require special attention and focused antimicrobial stewardship activities. Full article

Background/Objectives: Antimicrobial resistance poses a major public health challenge. The World Health Organization has identified 15 priority pathogens that require prompt development of new antibiotics. This review systematically evaluates the antibacterial resistance of the most significant bacterial pathogens, currently available treatment options, as well as complementary approaches for the management of infections caused by the most challenging multidrug-resistant (MDR) bacteria. For carbapenem-resistant Gram-negative bacteria, treatment options include combinations of beta-lactam antibiotics and beta-lactamase inhibitors, a novel siderophore cephalosporin, known as cefiderocol, as well as older antibiotics like polymixins and tigecycline. Treatment options for Gram-positive bacteria are vancomycin, daptomycin, linezolid, etc. Although the development of new antibiotics has stagnated, various agents with antibacterial properties are currently in clinical and preclinical trials. Non-antibiotic strategies encompass antibiotic potentiators, bacteriophage therapy, antivirulence therapeutics, antimicrobial peptides, antibacterial nanomaterials, host-directed therapy, vaccines, antibodies, plant-based products, repurposed drugs, as well as their combinations, including those used alongside antibiotics. Significant challenges exist in developing new antimicrobials, particularly related to scientific and technical issues, along with policy and economic factors. Currently, most of the alternative options are not part of routine treatment protocols. Conclusions and Future Directions: There is an urgent need to expedite the development of new strategies for treating infections caused by MDR bacteria. This requires a multidisciplinary approach that involves collaboration across research, healthcare, and regulatory bodies. Suggested approaches are crucial for addressing this challenge and should be backed by rational antibiotic use, enhanced infection control practices, and improved surveillance systems for emerging pathogens. Full article

Background: To aid in the development of antimicrobial stewardship programs (ASPs), we analyzed the patterns and trends in antibiotic prescriptions for patients with severe acute respiratory infection (SARI), utilizing the WHO’s AWaRe classification. Methods: We analyzed data from hospital-based influenza surveillance from January 2011 to December 2020 across nine Bangladeshi tertiary-level hospitals. Surveillance physicians collected WHO-defined SARI patient data, including demographics, clinical characteristics, and antibiotic prescriptions. Descriptive statistics and parametric and non-parametric tests were used for the analysis. Results: Of 21,566 SARI patients [median age 20 years (IQR: 1.33–45), 66% male], 91% were prescribed at least one antibiotic. A total of 25,133 antibiotics were prescribed, of which 47.0% were third-generation cephalosporins, 16.5% were macrolides, and 11.1% were beta-lactam/beta-lactamase inhibitors. According to the AWaRe classification, 28.7% were in the Access group, while 71.3% were in the Watch group, and none were from the Reserve group. A downward trend in Access group (30.4% to 25.1%; p = 0.010) and an upward trend in Watch group antibiotic prescription (69.6% to 74.9%; p = 0.010) were observed. We identified that patients aged < 5 years (aOR: 1.80; 95% CI: 1.44–2.25), who were treated in government hospitals (aOR: 1.45; 95% CI: 1.35–1.57), patients with the presence of lung diseases (aOR: 1.56; 95% CI: 1.35–1.80) had an increased likelihood of being prescribed Watch group antibiotics. Conclusions: This study reveals a concerning pattern of antibiotic overuse among SARI patients in Bangladesh, with a growing trend over the past decade towards increased Watch group antibiotic prescriptions. Only one-third of the prescribed antibiotics were from the Access group, falling short of the two-thirds threshold recommended by the WHO. Effective ASPs are crucial to optimize antibiotic prescriptions and mitigate the risk of antimicrobial resistance. Full article

Anaerobic digestion (AD) is a suitable process to use manure for biogas production. During this process, antimicrobial resistant (AMR) bacteria are reduced. In this study, we investigated the reduction of extended-spectrum beta-lactamase (ESBL)-producing, fluoroquinolone-resistant, and total Escherichia (E.) coli concentrations in chicken manure during AD. AD was performed at 30 °C and 37 °C (mesophilic temperature range), with and without sawdust addition as a lignocellulosic biomass. The initial concentrations of total E. coli were 6.43 log₁₀CFU/g to 7.84 log₁₀CFU/g. The concentration of Fluoroquinolone-resistant E. coli was approx. 6.05 log₁₀CFU/g (6.70%), and of ESBL-producing E. coli approx. 5.48 log₁₀CFU/g (0.99%). During AD, we observed that temperature had the main influence on the bacterial reduction, as E. coli abundance was below the detection limit after day 7 at 37 °C and after day 14 at 30 °C. At 37 °C we observed higher amounts of free ammonia, which is an inhibitor of the AD process. The carbon-to-nitrogen (C/N) ratio has an important impact on the AD process because a higher C/N ratio decreases the amount of generated total ammonia nitrogen. However, we did not observe a significant difference in AMR and total E. coli reduction between chicken manure with a natural C/N ratio (10:1) and an increased C/N ratio (25:1). Full article

Beta-lactam drugs hold a central place in the antibacterial arsenal, and the production of beta-lactamases by drug-resistant bacteria has severely compromised the effectiveness of nearly all available beta-lactams. Therefore, in the face of the increasing threat of drug resistance, the combined use of beta-lactamase inhibitors (BLIs) with beta-lactam antibiotics is crucial for treating infections caused by drug-resistant bacteria. Hence, the development of BLIs has always been a hot topic in the field of medicinal chemistry. In recent years, significant progress has been made in screening active drugs by enhancing the affinity of inhibitors for enzymes and the stability of their complexes, based on the design concept of competitive inhibitors. Here, we review the effects and mechanisms of newly synthesized beta-lactamase inhibitors on various BLIs in recent years, to provide ideas for the development of subsequent beta-lactamase inhibitors. Full article

Background: Meropenem–vaborbactam (MEM-VAB) is a novel carbapenem-beta-lactamase-inhibitor combination that demonstrates activity against carbapenem-resistant (CR) Gram-negative bacteria, and more specifically KPC-producers, since vaborbactam is an effective inhibitor of KPC enzymes in vitro. This study aimed to describe the initial uses and efficacy of MEM-VAB for compassionate treatment during the first 21 months following its early access in France. Method: A national multicenter retrospective study was conducted, including all patients who received at least one dose of MEM-VAB between 20 July 2020, and 5 April 2022. Clinical characteristics and outcomes were collected using a standardized questionnaire. The minimum inhibitory concentration (MIC) of antimicrobials, and complete genome sequencing of bacteria were performed when bacterial isolates were available. Results: Ultimately, 21 patients from 15 French hospitals were included in the study. The main indication for MEM-VAB treatment was respiratory tract infections (n = 9). The targeted bacteria included Pseudomonas aeruginosa (n = 12), Klebsiella pneumoniae (n = 3), Enterobacter spp (n = 3), Citrobacter freundii (n = 1), Escherichia coli (n = 1), and Burkholderia multivorans (n = 1). Overall, no significant advantage of vaborbactam over meropenem alone was observed across all strains of P. aeruginosa in terms of in vitro susceptibility. However, MEM-VAB demonstrated a notable impact, compared to carbapenem alone, on the MIC for the two KPC-3-producing K. pneumoniae and B. multivorans. Conclusions: MEM-VAB seems effective as a salvage treatment in compassionate use, but vaborbactam was shown to lack benefits compared to meropenem in treating P. aeruginosa-related infections. Therefore, it is crucial to compare meropenem to MEM-VAB MICs, particularly for P. aeruginosa, before prescribing MEM-VAB. Full article