Search Results (13)

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: Carbapenem-resistant Enterobacterales (CRE) and carbapenem-resistant Pseudomonas aeruginosa (CRPA) are challenging multidrug-resistant pathogens. This study evaluated the in vitro susceptibility of CRE and CRPA blood isolates from Korea to novel β-lactam/β-lactamase inhibitor combinations: ceftolozane/tazobactam (C/T), ceftazidime/avibactam (CZA), imipenem/cilastatin/relebactam (IMR), and meropenem/vaborbactam (MEV). Methods: Blood isolates of CRE (n = 55) and CRPA (n = 65) collected between September 2017 and September 2022 in a Korean tertiary hospital were included. Carbapenemase production was determined using phenotypic and molecular methods. In vitro susceptibility to C/T, CZA, IMR, and MEV was determined primarily by broth microdilution using current CLSI/EUCAST breakpoints. Clinical characteristics and in-hospital mortality were retrospectively reviewed. Results: Among non-carbapenemase-producing (non-CP) CRPA isolates (n = 47), susceptibility rates were 83.0% to C/T and 70.2% to CZA. For KPC-producing CRE isolates (n = 28), susceptibility rates were high to CZA (92.9%), IMR (82.1%), and MEV (96.4%). However, non-CP CRE isolates (n = 22) showed low susceptibility to C/T (18.2%) but high susceptibility to CZA (100%), IMR (81.8%), and MEV (95.5%). CRE infections were associated with higher rates of hematologic malignancy, immunosuppression, and in-hospital mortality (63.6% vs. 18.5% for CRPA, p < 0.001). Conclusions: The susceptibility of CRE and CRPA to novel β-lactam/β-lactamase inhibitors varies significantly by species and carbapenemase production. CZA, IMR, and MEV showed promising activity against KPC-producing CRE. These findings can inform empirical therapy and stewardship efforts in Korea. 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

Antimicrobial resistance remains a public health problem of global concern with a great health and financial burden. Its recognition as a threat by political leadership has boosted the research and development of new antibiotics and particularly novel combinations of β-lactams/β-lactamase inhibitors against multidrug-resistant (MDR) Gram-negative pathogens, which remain the major concern in clinical practice. The incorporation of ceftolozane/tazobactam, ceftazidime/avibactam, meropenem/vaborbactam, and imipenem/cilastatin/relebactam has provided new therapeutic options in the treatment of patients with infections due to MDR pathogens. Cefiderocol along with cefepime/enmetazobactam, avibactam/aztreonam, and sulbactam/durlobactam have been recently added to these agents as therapeutic choices, particularly for metallo-β-lactamase producing Gram-negative bacteria. Currently, many combinations are being studied for their in vitro activity against both serine- and metallo-β-lactamases. However, only a few have advanced through phase 1, 2, and 3 clinical trials. Among them, in this article, we focus on the most promising combinations of cefepime/zidebactam, cefepime/taniborbactam, and imipenem/cilastatin/funobactam, which are currently under investigation in phase 3 trials. Full article

(1) Background: Infections caused by multidrug-resistant (MDR) bacteria represent one of the major global public health problems of the 21st century. Beta-lactam antibacterial agents are commonly used to treat infections due to Gram-negative pathogens. New β-lactam/β-lactamase inhibitor combinations are urgently needed. Combining relebactam (REL) with imipenem (IMI) and cilastatin (CS) can restore its activity against many imipenem-nonsusceptible Gram-negative pathogens. (2) Methods: we performed a systematic review of the studies reporting on the use of in vivo REAL/IPM/CS. (3) Results: A total of eight studies were included in this review. The primary diagnosis was as follows: complicated urinary tract infection (n = 234), complicated intra-abdominal infections (n = 220), hospital-acquired pneumonia (n = 276), and ventilator-associated pneumonia (n = 157). Patients with normal renal function received REL/IPM/CS (250 mg/500 mg/500 mg). The most frequently reported AEs occurring in patients treated with imipenem/cilastatin plus REL/IPM/CS were nausea (11.5%), diarrhea (9.8%), vomiting (9.8%), and infusion site disorders (4.0%). Treatment outcomes in these high-risk patients receiving REL/IPM/CS were generally favorable. A total of 70.6% of patients treated with REL/IPM/CS reported a favorable clinical response at follow-up. (4) Conclusions: this review indicates that REL/IPM/CS is active against important MDR Gram-negative organisms. Full article

Infections due to carbapenem-resistant Enterobacterales (CRE) are increasingly prevalent in children and are associated with poor clinical outcomes, especially in critically ill patients. Novel beta lactam antibiotics, including ceftolozane-tazobactam, ceftazidime-avibactam, meropenem-vaborbactam, imipenem-cilastatin-relebactam, and cefiderocol, have been released in recent years to face the emerging challenge of multidrug-resistant (MDR) Gram-negative bacteria. Nonetheless, several novel agents lack pediatric indications approved by the Food and Drug Administration (FDA) and the European Medicine Agency (EMA), leading to uncertain pediatric-specific treatment strategies and uncertain dosing regimens in the pediatric population. In this narrative review we have summarized the available clinical and pharmacological data, current limitations and future prospects of novel beta lactam antibiotics in the pediatric population. Full article

Antimicrobial resistance has become a significant public health problem globally with multidrug resistant Gram negative (MDR-GN) bacteria being the main representatives. The emergence of these pathogens in neonatal settings threatens the well-being of the vulnerable neonatal population given the dearth of safe and effective therapeutic options. Evidence from studies mainly in adults is now available for several novel antimicrobial compounds, such as new β-lactam/β-lactamase inhibitors (e.g., ceftazidime–avibactam, meropenem–vaborbactam, imipenem/cilastatin–relebactam), although old antibiotics such as colistin, tigecycline, and fosfomycin are also encompassed in the fight against MDR-GN infections that remain challenging. Data in the neonatal population are scarce, with few clinical trials enrolling neonates for the evaluation of the efficacy, safety, and dosing of new antibiotics, while the majority of old antibiotics are used off-label. In this article we review data about some novel and old antibiotics that are active against MDR-GN bacteria causing sepsis and are of interest to be used in the neonatal population. Full article

Resistance to carbapenems in Enterobacterales has become a matter of the highest concern in the last decade. Recently, Enterobacterales harboring multiple carbapenemases were detected in three hospital centers in Croatia and in the outpatient setting, posing a serious therapeutic challenge for clinicians. In this study, we analyzed eight Klebsiella pneumoniae and two Enterobacter cloacae complex isolates with multiple carbapenemases, with regard to antibiotic susceptibility, β-lactamase production and plasmid content. The isolates demonstrated uniform resistance to amoxicillin/clavulanate, piperacillin/tazobactam, cefuroxime, ceftazidime, cefotaxime, ceftriaxone and ertapenem. Among novel β-lactam/inhibitor combinations, ceftazidime/avibactam exhibited moderate activity, with 50% of isolates susceptible. All isolates demonstrated resistance to imipenem/cilastatin/relebactam, and all but one to ceftolozane/tazobactam. Four isolates exhibited a multidrug-resistant phenotype (MDR), whereas six were allocated to an extensively drug-resistant phenotype (XDR). OKNV detected three combinations of carbapenemases: OXA-48+NDM (five isolates), OXA-48+VIM (three isolates) and OXA-48+KPC (two isolates). Inter-array testing identified a wide variety of resistance genes for β-lactam antibiotics: bla_CTX-M-15, bla_TEM, bla_SHV, bla_OXA-1, bla_OXA-2, bla_OXA-9, aminoglycosides: aac6, aad, rmt, arm and aph, fluoroquinolones: qnrA, qnrB and qnrS, sulphonamides: sul1 and sul2 and trimethoprim: dfrA5, dfrA7, dfrA14, dfrA17 and dfrA19. mcr genes were reported for the first time in Croatia. This study demonstrated the ability of K. pneumoniae and E. cloacae to acquire various resistance determinants under the selection pressure of antibiotics widely used during the COVID-19 pandemic. The novel inter-array method showed good correlation with OKNV and PCR, although some discrepancies were found. Full article

Gram-negative bacterial resistance to antimicrobials has had an exponential increase at a global level during the last decades and represent an everyday challenge, especially for the hospital practice of our era. Concerted efforts from the researchers and the industry have recently provided several novel promising antimicrobials, resilient to various bacterial resistance mechanisms. There are new antimicrobials that became commercially available during the last five years, namely, cefiderocol, imipenem-cilastatin-relebactam, eravacycline, omadacycline, and plazomicin. Furthermore, other agents are in advanced development, having reached phase 3 clinical trials, namely, aztreonam-avibactam, cefepime-enmetazobactam, cefepime-taniborbactam, cefepime-zidebactam, sulopenem, tebipenem, and benapenem. In this present review, we critically discuss the characteristics of the above-mentioned antimicrobials, their pharmacokinetic/pharmacodynamic properties and the current clinical data. Full article

Multidrug-resistant (MDR)/extensively drug-resistant (XDR) Pseudomonas aeruginosa is emerging as a major threat related to adverse patient outcomes. The goal of this review is to describe evidence-based empiric and targeted treatment regimens that can be exploited when dealing with suspected or confirmed infections due to MDR/XDR P. aeruginosa. P. aeruginosa has inherent resistance to many drug classes, the capacity to form biofilms, and most importantly, the ability to quickly acquire resistance to ongoing treatments. Based on the presence of risk factors for MDR/XDR infections and local epidemiology, where large proportions of strains are resistant to classic beta-lactams, the recommended empirical treatment for suspected P. aeruginosa infections is based on ceftolozane-tazobactam or ceftazidime-avibactam. Where local epidemiology indicates low rates of MDR/XDR and there are no risk factors, a third or fourth generation cephalosporin can be used in the context of a “carbapenem-sparing” strategy. Whenever feasible, antibiotic de-escalation is recommended after antimicrobial susceptibility tests suggest that it is appropriate, and de-escalation is based on different resistance mechanisms. Cefiderocol and imipenem-cilastatin-relebactam withstand most resistance mechanisms and may remain active in cases with resistance to other new antibiotics. Confronting the growing threat of MDR/XDR P. aeruginosa, treatment choices should be wise, sparing newer antibiotics when dealing with a suspected/confirmed susceptible P. aeruginosa strain and choosing the right option for MDR/XDR P. aeruginosa based on specific types and resistance mechanisms. Full article

Klebsiella pneumoniae is a Gram-negative opportunistic pathogen responsible for a variety of community and hospital infections. Infections caused by carbapenem-resistant K. pneumoniae (CRKP) constitute a major threat for public health and are strongly associated with high rates of mortality, especially in immunocompromised and critically ill patients. Adhesive fimbriae, capsule, lipopolysaccharide (LPS), and siderophores or iron carriers constitute the main virulence factors which contribute to the pathogenicity of K. pneumoniae. Colistin and tigecycline constitute some of the last resorts for the treatment of CRKP infections. Carbapenemase production, especially K. pneumoniae carbapenemase (KPC) and metallo-β-lactamase (MBL), constitutes the basic molecular mechanism of CRKP emergence. Knowledge of the mechanism of CRKP appearance is crucial, as it can determine the selection of the most suitable antimicrobial agent among those most recently launched. Plazomicin, eravacycline, cefiderocol, temocillin, ceftolozane–tazobactam, imipenem–cilastatin/relebactam, meropenem–vaborbactam, ceftazidime–avibactam and aztreonam–avibactam constitute potent alternatives for treating CRKP infections. The aim of the current review is to highlight the virulence factors and molecular pathogenesis of CRKP and provide recent updates on the molecular epidemiology and antimicrobial treatment options. Full article

Multidrug-resistant Gram-negative bacteria (MDR-GNB) cause serious infections and aggravate disease progression. Last resort antibiotics are effective against MDR-GNB and are reimbursed by flat rates based on German diagnosis-related groups (G-DRG). From a hospital management perspective, this analysis compared hospital reimbursement for last resort antibiotics with their acquisition costs to outline potential funding gaps. Retrospective analyses based on medical charts and real-life reimbursement data included patients with pneumonia due to MDR-GNB treated in intensive care units (ICU) of a German tertiary care hospital (University Hospital Cologne) between January 2017 and December 2020. Drug-associated hospital reimbursement of G-DRG was compared with drug acquisition costs based on preliminarily approved last resort antibiotics (cefiderocol, ceftazidime-avibactam, ceftolozane-tazobactam, and imipenem-cilastatin-relebactam) according to label. Funding gaps were determined for the treatment of Enterobacterales, Pseudomonas aeruginosa, Acinetobacter baumannii, and mixed infections, respectively. Most of the 31 patients were infected with Enterobacterales (n = 15; 48.4%) and P. aeruginosa (n = 13; 41.9%). Drug-associated G-DRG reimbursement varied from 44.50 EUR (mixed infection of P. aeruginosa and Enterobacterales) to 2265.27 EUR (P. aeruginosa; mixed infection of P. aeruginosa and Enterobacterales). Drug acquisition costs ranged from 3284.40 EUR in ceftazidime-avibactam (minimum duration) to 15,827.01 EUR for imipenem-cilastatin-relebactam (maximum duration). Underfunding was found for all MDR-GNB, reaching from 1019.13 EUR (P. aeruginosa; mixed infection of P. aeruginosa and Enterobacterales) to 14,591.24 EUR (Enterobacterales). This analysis revealed the underfunding of last resort antibiotics in German hospital treatment. Insufficient reimbursement implies less research in this field, leading to a more frequent use of inappropriate antibiotics. The cycle closes as this contributes to the development of multi-drug resistant bacteria. Full article

P. aeruginosa is still one of the most threatening pathogens responsible for serious hospital-acquired infections. It is intrinsically resistant to many antimicrobial agents and additional acquired resistance further complicates the management of such infections. High rates of combined antimicrobial resistance persist in many countries, especially in the eastern and south-eastern parts of Europe. The aim of this narrative review is to provide a comprehensive assessment of the epidemiology, latest data, and clinical evidence on the current and new available drugs active against P. aeruginosa isolates with limited treatment options. The latest evidence and recommendations supporting the use of ceftolozane-tazobactam and ceftazidime-avibactam, characterized by targeted clinical activity against a significant proportion of P. aeruginosa strains with limited treatment options, are described based on a review of the latest microbiological and clinical studies. Cefiderocol, with excellent in vitro activity against P. aeruginosa isolates, good stability to all β-lactamases and against porin and efflux pumps mutations, is also examined. New carbapenem combinations are explored, reviewing the latest experimental and initial clinical evidence. One section is devoted to a review of new anti-pseudomonal antibiotics in the pipeline, such as cefepime-taniborbactam and cefepime-zidebactam. Finally, other “old” antimicrobials, mainly fosfomycin, that can be used as combination strategies, are described. Full article