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Background Case Presentation Conclusions Cefepime, a fourth‐generation cephalosporin, has neurotoxic side effects such as encephalopathy. Baseline conditions, including blood–brain barrier (BBB) impairment and renal dysfunction, are known to associate with elevated central nervous concentration of cefepime. Although BBB dysfunction occurs with depression or cancer, currently, neither is regarded as a risk factor for cefepime‐induced encephalopathy.A 79‐year‐old woman with a history of depression and rectal cancer was hospitalized for a bacterial liver abscess. Brain metastasis and other causes for delirium were excluded, and no renal dysfunction was observed. However, 11 days after cefepime and metronidazole administration, the patient suddenly developed confusion, disorientation, and myoclonus, with no apparent changes on brain magnetic resonance imaging. Electroencephalography revealed a consistent tri‐phasic wave pattern. Clinical symptoms were well consistent with cefepime‐induced encephalopathy; hence, cefepime and metronidazole were discontinued, followed by rapid physical and mental recovery, with no aftereffects.In terms of BBB dysfunction, depression and cancer might be possible occult risk factors for cefepime‐induced encephalopathy. Doctors need to pay attention to encephalopathy risk when administering cefepime in patients with depression or cancer because the psychiatric symptoms of encephalopathy, depression, and delirium from other causes are often confusing, leading to misdiagnosis and a poor prognosis. [ABSTRACT FROM AUTHOR]

The genomic comparison of two Klebsiella michiganensis clinical isolates recovered from the same patient, one resistant to piperacillin-tazobactam and intermediate to cefotaxime, the other resistant to ceftazidime but susceptible to piperacillin-tazobactam, revealed one mutation in the blaOXY-1-24 gene accounting for a L169M substitution in the Ω loop. Cloning experiment in Escherichia coli demonstrated the contribution of this mutation to the hydrolysis spectrum extension towards ceftazidime and cefepime, whereas the resistance to piperacillin-tazobactam was reduced. To the best of our knowledge, this study shows for the first time that ceftazidime resistance can occur in vivo from OXY-1 precursor by structural alteration. [ABSTRACT FROM AUTHOR]

Staphylococcus aureus (S. aureus) is a significant Gram-positive opportunistic pathogen behind many debilitating infections. β-lactam antibiotics are conventionally prescribed for treating S. aureus infections. However, the adaptability of S. aureus in evolving resistance to multiple β-lactams contributed to the persistence and spread of infections, exemplified in the emergence of methicillin-resistant S. aureus (MRSA). In the present study, we investigated the efficacies of the synthetic teixobactin analogue, Leu10-teixobactin, combined with the penicillinase-resistant cephalosporin cefepime against MRSA strains. The Leu10-teixobactin and cefepime combination exerted synergism against most strains tested in broth microdilution assay. Time-kill profiles showed that both Leu10-teixobactin and cefepime predominantly exhibited synergistic activity, with > 2.0-log10CFU decrease compared to monotherapy at 24 h. Moreover, biofilm assays revealed a significant inhibition of biofilm production in ATCC™43300 cells treated with sub-MICs of Leu10-teixobactin and cefepime. Subsequent electron microscopy studies showed more extensive damage with the combination therapy compared to monotherapies, including aberrant bacterial morphology, vesicle formation and substantial lysis, indicating combined damage to the cell wall. Quantitative real-time PCR revealed marked perturbation of genes mecA, sarA, atlA, and icaA, substantiating the apparent mode of combined antibacterial action of both antibiotics against peptidoglycan synthesis and initial biofilm production. Hence, the study highlights the prospective utility of the Leu10-teixobactin-cefepime combination in treating MRSA infections via β-lactam potentiation. [ABSTRACT FROM AUTHOR]

Introduction: Cefepime is a fourth-generation cephalosporin and is a workhorse for the empiric treatment of febrile neutropenia (FN). Beta-lactam therapeutic drug monitoring (TDM) has emerged as a dose optimization strategy in patient populations with altered kinetics. Prior literature has demonstrated that patients with FN exhibit augmented renal clearance which may lead to subtherapeutic drug concentrations with standard dosing regimens. The aim of this study was to evaluate pharmacokinetic/pharmacodynamic (PK/PD) target attainment and clinical outcomes in patients with hematologic malignancies and FN who were treated empirically with cefepime. Methods: This was a prospective, single-center study of adults with hematologic malignancies and FN admitted to the inpatient unit. The primary outcome was PK/PD target attainment (defined as 100% free time greater than minimum inhibitory concentration (100% f T > MIC)). Secondary clinical outcomes were time to defervescence, time to ANC recovery, in-hospital mortality, and cefepime failure. Results: There were 55 patients in our study. Forty-three (78%) patients achieved the primary outcome of PK/PD target attainment. The mean time to defervescence was similar between those that achieved PK/PD target attainment and those that did not (95% CI −0.75 to 1.25, p = 0.62). Conclusions: This study showed that standard cefepime dosing in patients with hematologic malignancies and FN does not result in achievement of 100% f T > MIC in all patients. Patients in the group that did not achieve PK/PD target attainment were younger with increased creatinine clearance, indicating that cefepime TDM may be especially beneficial in these patients. [ABSTRACT FROM AUTHOR]

Objectives We aimed to compare the stability of the newly developed β-lactams (cefiderocol) and β-lactam/β-lactamase inhibitor combinations (ceftazidime/avibactam, ceftolozane/tazobactam, aztreonam/avibactam, cefepime/taniborbactam, cefepime/zidebactam, imipenem/relebactam, meropenem/vaborbactam, meropenem/nacubactam and meropenem/xeruborbactam) against the most clinically relevant mechanisms of mutational and transferable β-lactam resistance in Pseudomonas aeruginosa. Methods We screened a collection of 61 P. aeruginosa PAO1 derivatives. Eighteen isolates displayed the most relevant mechanisms of mutational resistance to β-lactams. The other 43 constructs expressed transferable β-lactamases from genes cloned in pUCP-24. MICs were determined by reference broth microdilution. Results Cefiderocol and imipenem/relebactam exhibited excellent in vitro activity against all of the mutational resistance mechanisms studied. Aztreonam/avibactam, cefepime/taniborbactam, cefepime/zidebactam, meropenem/vaborbactam, meropenem/nacubactam and meropenem/xeruborbactam proved to be more vulnerable to mutational events, especially to overexpression of efflux operons. The agents exhibiting the widest spectrum of activity against transferable β-lactamases were aztreonam/avibactam and cefepime/zidebactam, followed by cefepime/taniborbactam, cefiderocol, meropenem/xeruborbactam and meropenem/nacubactam. However, some MBLs, particularly NDM enzymes, may affect their activity. Combined production of certain enzymes (e.g. NDM-1) with increased MexAB-OprM-mediated efflux and OprD deficiency results in resistance to almost all agents tested, including last options such as aztreonam/avibactam and cefiderocol. Conclusions Cefiderocol and new β-lactam/β-lactamase inhibitor combinations show promising and complementary in vitro activity against mutational and transferable P. aeruginosa β-lactam resistance. However, the combined effects of efflux pumps, OprD deficiency and efficient β-lactamases could still result in the loss of all therapeutic options. Resistance surveillance, judicious use of new agents and continued drug development efforts are encouraged. [ABSTRACT FROM AUTHOR]

Background Antibiotic overuse leads to the emergence of antibiotic resistance that threatens immunocompromised cancer patients. Infections caused by MDR Gram-negative pathogens are difficult to treat and associated with high mortality. Hence, empirical therapy with standard-of-care (SOC) antibiotics could be suboptimal in these vulnerable patients. New antibiotics covering potential resistant pathogens may be considered. Methods We conducted a randomized non-inferiority study comparing safety and efficacy of imipenem/cilastatin/relebactam (IPM/REL), a β-lactam/β-lactamase inhibitor combination, with SOC antibiotics (cefepime, piperacillin/tazobactam or meropenem) in cancer patients with febrile neutropenia. Patients received at least 48 h of IV antibiotics and were assessed at end-of-IV (EOIV) therapy, test of cure (TOC; Days 21–28), and late follow-up (LFU; Days 35–42). Results A total of 100 patients were enrolled (49 IPM/REL and 50 SOC). Demographics and rates of documented microbiological infections were similar in both groups. In the SOC arm, 86% of antibiotics consisted of cefepime. Patients on IPM/REL had a higher favourable clinical response at EOIV than those on SOC (90% versus 74%; P  = 0.042); however, responses were similar at TOC and LFU. Microbiological eradication was comparable at all three timepoints. Study drug-related adverse events and adverse events leading to drug discontinuation were similar in both groups, with no study drug-related mortality. Conclusions Our results suggest that compared with SOC antibiotics, predominantly cefepime, IPM/REL for empirical coverage of febrile neutropenia in cancer patients is generally safe and could be associated with a better clinical outcome at EOIV. The current SOC consisting mainly of agents that do not cover for ESBL-producing and carbapenem-resistant Enterobacterales bacteria should be reconsidered. [ABSTRACT FROM AUTHOR]

Purpose: Prior literature evaluating the importance of timely second-dose antibiotics in patients with sepsis has led to better outcomes and a possible reduction in mortality, length of mechanical ventilation, and length of time requiring vasopressors. Objective: To evaluate the impact of a newly developed pharmacist-led two-dose cefepime protocol implemented within an emergency department (ED) service. Methods: This was a retrospective, single-center, pre-post observational cohort study. Institutional review board approval was obtained. The primary endpoint was a reduction in time between the first and the second doses of antibiotics for patients with sepsis who present to the emergency department. Secondary endpoints included length of vasopressor therapy, intensive care unit (ICU) length of stay, hospital length of stay, duration of mechanical ventilation, and mortality. Results: A total of 84 patients were included in the pharmacist-led two-dose hospital protocol and 79 patients were included in the historical control. In the control cohort, the median time between the first and second dose of antibiotics was 12 hours vs 8.5 hours in the tested cohort. The average time requiring vasopressors was 1.20 days for the control cohort vs.46 days for the post-implementation group. Lastly, the median hospital length of stay in days was 8 for the control group vs 7 for the tested cohort. Conclusion: Implementation of a pharmacist-led two-dose cefepime protocol was associated with a numerically lower duration between second-dose antibiotics, days requiring vasopressors, and a slight reduction in hospital length of stay. [ABSTRACT FROM AUTHOR]

Introduction: The high-level antimicrobial resistance, particularly carbapenem resistance, in Pseudomonas aeruginosa is a global health challenge. The combination of antibiotics and synergy effects is beneficial in control of drug-resistant P. aeruginosa. The synergic interaction of antimicrobial agents is af-fected by the mechanisms of antimicrobial resistance. The aim of the current study was to evaluate the effect of efflux pump inhibition on the synergy of antibiotics against carbapenem-resistant P. aeruginosa. Methods: The antibiotics’ minimum inhibitory concentration (MIC) was determined by the microbroth dilu-tion method. The synergy effect of antibiotics was determined using the checkerboard assay with-out and with Resistance-Nodulation-Division (RND) efflux pump inhibitor phenylalanine-arginine beta-naphthylamide (PAβN). Results: The highest levels of synergistic effects were found between cefepime/tobramycin and meropenem/tobramycin combinations in 35.3% of isolates. After adding PAβN, the most frequent synergistic effects were observed between the meropenem/ciprofloxacin and cefepime/ciprofloxacin combinations, found in 64.7% of isolates. The adding PAβN led to an increase in the synergy of all combinations except tobramycin/colistin. The highest effect of PAβN on the synergy effects of antibiotics combination was observed in meropenem/ciprofloxacin, cefepime/ciprofloxacin, and ciprofloxacin/colistin (an increase of 41.2%). Conclusion: RND efflux pump inhibition has a noticeable effect on the results of synergy tests of some antimi-crobial agent combinations. Given the drug- and strain-dependent effects of PAβN on synergy results, the effects of efflux pump inhibitors should be studied on different combinations of drugs and a large population of bacterial strains. [ABSTRACT FROM AUTHOR]

Invasive sinusitis is a rare complication of sinusitis. We present the case of a woman, age 72 years, who presented with acute encephalopathy in the setting of sepsis found to have extensive invasive sinusitis with intracranial extension secondary to Streptococcus intermedius, managed with intravenous antibiotics alone. S. intermedius is a rare cause of acute bacterial sinusitis, associated with infections of relatively greater severity and risk of intracranial spread, often requiring a combination of intravenous antibiotics and surgical debridement for source control. Successful treatment of invasive sinusitis with medical management alone may be achievable if surgical intervention is contraindicated. However, the probability of meaningful recovery without surgical source control is rare and is associated with greater morbidity and mortality. Therefore, factors contributing to the success of medical management alone should be investigated. [ABSTRACT FROM AUTHOR]

The article describes cases abnormalities seen on electroencephalography (EEG) from patients experiencing neurotoxicity induced by cefepime, a cephalosporin antibiotic. A 65-year old male with a history of chronic hepatitis C and chronic right middle cerebral artery infarcts from a gliosis demonstrated right frontal sharps. A 64-year old male demonstrated myoclonic status epilepticus. An 87-year old male showed generalized sharp discharges considered as an ictal-interical continuum pattern.

The aim of this study is to evaluate the antimicrobial susceptibility of invasive isolates of Serratia marcescens , associated with blood stream infections (BSIs) in patients hospitalized in Varna University Hospital, Bulgaria, as well as to identify the genetic mechanisms responsible for 3rd generation cephalosporin and carbapenem-resistance among these isolates. A total of 45 consecutive S. marcescens isolates, obtained from blood cultures of 45 patients with BSIs, hospitalized during an 8-year period (2016–2023) were included. Species identification and antimicrobial susceptibility testing were done by Phoenix (BD, USA) and Vitek 2 (BioMerieux, France) systems and the results were interpreted according to EUCAST guidelines. The genetic mechanisms of beta-lactam resistance were studied by PCR. During the study period, a total of 45 patients were diagnosed with S. marcescens -associated BSIs. All infections were defined as nosocomial, predominantly intensive care unit-acquired (42.2%) and 28.8% were central venous catheter-associated. The following antimicrobial resistance rates were found: ceftriaxone, piperacillin/tazobactam, 57.8%; ceftazidime, 55.6%; cefepime, trimethoprime/sulfamethoxazole, 53.3%; gentamicin, 48.8%; ciprofloxacin, 44.5%; amikacin, 15.6%; carbapenems, 2.2%. The bla CTX-M was identified in 88.9% of the tested 3rd generation cephalosporin resistant isolates. Among these, 50% were also bla TEM positive. The single carbapenem-resistant isolate harboured bla KPC, bla CTX-M1/9, bla CMY-2 and bla TEM. This study demonstrates S. marcescens as a problematic nosocomial pathogen and we report a KPC-producing S. marcescens clinical isolate from a BSI in Bulgaria. [ABSTRACT FROM AUTHOR]

Chronic wounds complicated by infection pose significant clinical challenges, necessitating comprehensive treatment approaches. The widespread use of antibiotics has led to resistant microorganisms, complicating traditional therapies. This study aims to develop and evaluate modified alginate wound dressings with enhanced antimicrobial and regenerative properties. Alginate dressings were synthesized with silver nanoparticles, cefepime, and fibroblast growth factor-2 (FGF-2). The two-stage therapy involved an initial antibacterial dressing followed by a regenerative dressing. In vitro tests demonstrated high antibacterial activity, with maximum inhibition zones for P. aeruginosa (41.3 ± 0.4 mm) and S. aureus (36.6 ± 1.8 mm). In vivo studies on rats with purulent wounds showed significant healing progression in the experimental group. Histological analysis revealed complete re-epithelialization, thicker neoepithelium, dense collagen deposition, and minimal inflammation in treated wounds. These findings suggest that the modified alginate dressings significantly enhance the reparative process and are promising for treating chronic infected wounds in both veterinary and medical practices. [ABSTRACT FROM AUTHOR]

Abstract Staphylococcus aureus (S. aureus) is a significant Gram-positive opportunistic pathogen behind many debilitating infections. β-lactam antibiotics are conventionally prescribed for treating S. aureus infections. However, the adaptability of S. aureus in evolving resistance to multiple β-lactams contributed to the persistence and spread of infections, exemplified in the emergence of methicillin-resistant S. aureus (MRSA). In the present study, we investigated the efficacies of the synthetic teixobactin analogue, Leu10-teixobactin, combined with the penicillinase-resistant cephalosporin cefepime against MRSA strains. The Leu10-teixobactin and cefepime combination exerted synergism against most strains tested in broth microdilution assay. Time-kill profiles showed that both Leu10-teixobactin and cefepime predominantly exhibited synergistic activity, with > 2.0-log10CFU decrease compared to monotherapy at 24 h. Moreover, biofilm assays revealed a significant inhibition of biofilm production in ATCC™43300 cells treated with sub-MICs of Leu10-teixobactin and cefepime. Subsequent electron microscopy studies showed more extensive damage with the combination therapy compared to monotherapies, including aberrant bacterial morphology, vesicle formation and substantial lysis, indicating combined damage to the cell wall. Quantitative real-time PCR revealed marked perturbation of genes mecA, sarA, atlA, and icaA, substantiating the apparent mode of combined antibacterial action of both antibiotics against peptidoglycan synthesis and initial biofilm production. Hence, the study highlights the prospective utility of the Leu10-teixobactin-cefepime combination in treating MRSA infections via β-lactam potentiation.

Each month, subscribers to The Formulary Monograph Service receive 5 to 6 well-documented monographs on drugs that are newly released or are in late phase 3 trials. The monographs are targeted to Pharmacy & Therapeutics Committees. Subscribers also receive monthly 1-page summary monographs on agents that are useful for agendas and pharmacy/nursing in-services. A comprehensive target drug utilization evaluation/medication use evaluation (DUE/MUE) is also provided each month. With a subscription, the monographs are available online to subscribers. Monographs can be customized to meet the needs of a facility. Through the cooperation of The Formulary, Hospital Pharmacy publishes selected reviews in this column. For more information about The Formulary Monograph Service, contact Wolters Kluwer customer service at 866-397-3433. [ABSTRACT FROM AUTHOR]

Background: Reference measurement procedures are an essential element in the standardization and comparability of analytical measurement results in laboratory medicine. No LC-MS/MS-based reference measurement procedure for cefepime in serum has been published previously. Materials and methods: An isotope-dilution based two-dimensional LC-MS/MS reference measurement procedure for cefepime concentrations in human serum was developed and tested. The value assignment of unknown samples is based on a defined measurement series validation. Six unknown samples can be measured per series. Pass criteria for the run and the samples were determined empirically based on a performance evaluation. For this purpose, a between-run determination of five runs of the defined measurement series with six cefepime samples was carried out and evaluated. The goal was to define rigorous, realistic target limits and minimize measurement uncertainty. The final defined target limits are used for series-based validation and value assignment. The results for the six unknown samples are provided with the associated measurement uncertainty for this series. Results: The developed and extensively studied measurement procedure for the quantification of cefepime in serum was found to be practicable and fit for its purpose. The between-run mean imprecision of the six cefepime samples was ≤ 2.0 %, for the QCs it was ≤ 2.3 % and the between-run mean inaccuracy of the QCs was within ± 1.1 %. Conclusion: The novel isotope-dilution-LC-MS/MS measurement procedure in accordance to ISO 15193 can be recommended as candidate reference measurement procedure for the value assignment of cefepime concentrations in human serum.

Abstract Cefepime and piperacillin/tazobactam are antimicrobials recommended by IDSA/ATS guidelines for the empirical management of patients admitted to the intensive care unit (ICU) with community-acquired pneumonia (CAP). Concerns have been raised about which should be used in clinical practice. This study aims to compare the effect of cefepime and piperacillin/tazobactam in critically ill CAP patients through a targeted maximum likelihood estimation (TMLE). A total of 2026 ICU-admitted patients with CAP were included. Among them, (47%) presented respiratory failure, and (27%) developed septic shock. A total of (68%) received cefepime and (32%) piperacillin/tazobactam-based treatment. After running the TMLE, we found that cefepime and piperacillin/tazobactam-based treatments have comparable 28-day, hospital, and ICU mortality. Additionally, age, PTT, serum potassium and temperature were associated with preferring cefepime over piperacillin/tazobactam (OR 1.14 95% CI [1.01–1.27], p = 0.03), (OR 1.14 95% CI [1.03–1.26], p = 0.009), (OR 1.1 95% CI [1.01–1.22], p = 0.039) and (OR 1.13 95% CI [1.03–1.24], p = 0.014)]. Our study found a similar mortality rate among ICU-admitted CAP patients treated with cefepime and piperacillin/tazobactam. Clinicians may consider factors such as availability and safety profiles when making treatment decisions.

Introduction: Multi-drug-resistant (MDR) Pseudomonas aeruginosa is a dangerous pathogen causing nosocomial infection, particularly in low-and middle-income countries like Brazil. This retrospective study at a Brazilian university hospital examined the relationship between antimicrobial use and MDR-P. aeruginosa. Methodology: Data was collected from 358 patients with non-repetitive P. aeruginosa infections from 2009 to 2019. Antibiotic use was measured in grams and expressed as defined daily dose (DDD) per 1000 patient-days for meropenem, imipenem, polymyxin, and tigecycline. Results: Extensively drug-resistant (XDR) P. aeruginosa occurred in 36.1%, and MDR in 32.6% of cases. Risk factors for XDR infection were hospitalization prior to infection (OR = 0.9901), intensive care unit (ICU) admission (OR = 0.4766), previous antibiotic use (OR = 1.4417), and use of cefepime (OR = 0.3883). Over the ten-year period, utilization of the monitored antibiotics increased, and there was a positive correlation between the rise in MDR-P. aeruginosa and the consumption of ceftriaxone, imipenem, meropenem, and polymyxin B. The 30-day mortality rate was 40.0% for all patients and 41.0% for those infected with XDR-P. aeruginosa. Conclusions: This study highlights the negative impact of the indiscriminate use of antimicrobials, which has led to a significant increase in multidrug-resistant P. aeruginosa strains in hospitals. [ABSTRACT FROM AUTHOR]

Infections caused by multidrug-resistant (MDR) bacteria are a growing global concern. Enterobacter cloacae complex (ECC) species are particularly adept at developing antibiotic resistance. Phage therapy is proposed as an alternative treatment for pathogens that no longer respond to antibiotics. Unfortunately, ECC phages are understudied when compared to phages of many other bacterial species. In this Ghanaian-Finnish study, we isolated two ECC strains from ready-to-eat food samples and three novel phages from natural waters against these strains. We sequenced the genomic DNA of the novel Enterobacter phages, fGh-Ecl01, fGh-Ecl02, and fGh-Ecl04, and assessed their therapeutic potential. All of the phages were found to be lytic, easy to propagate, and lacking any toxic, integrase, or antibiotic resistance genes and were thus considered suitable for therapy purposes. They all were found to be related to T4-type viruses: fGh-Ecl01 and fGh-Ecl04 to karamviruses and fGh-Ecl02 to agtreviruses. Testing of Finnish clinical ECC strains showed promising susceptibility to these novel phages. As many as 61.1% of the strains were susceptible to fGh-Ecl01 and fGh-Ecl04, and 7.4% were susceptible to fGh-Ecl02. Finally, we investigated the susceptibility of the newly isolated ECC strains to three antibiotics – meropenem, ciprofloxacin, and cefepime – in combination with the novel phages. The use of phages and antibiotics together had synergistic effects. When using an antibiotic-phage combination, even low concentrations of antibiotics fully inhibited the growth of bacteria. [ABSTRACT FROM AUTHOR]

Organosulfur compounds derived from plants of the Allium genus, such as propyl‐propane‐thiosulfinate (PTS) and propyl‐propane‐thiosulfonate (PTSO), have been proposed as an alternative in antibiotic resistance. The aim of this study was to compare the activity of these substances with other antibiotics against clinical isolates of carbapenem‐resistant (CAR‐R) and carbapenem‐susceptible (CAR‐S) Gram‐negative bacteria. A total of 126 clinical isolates of CAR‐R and 155 CAR‐S bacteria were selected, including Enterobacterales, A. baumannii and P. aeruginosa. The antibiotic susceptibility of all isolates was assessed using the microdilution and Kirby–Bauer methods for PTS, PTSO, amoxicillin/clavulanate, piperacillin/tazobactam, cefotaxime, ceftazidime, cefepime, imipenem, ciprofloxacin, and amikacin. Both PTS and PTSO demonstrated in vitro bactericidal activity against CAR‐R Enterobacteriaceae and A. baumannii, with no significant difference in activity compared to their response against CAR‐S isolates. However, both compounds were less active against P. aeruginosa than against any of the other bacteria, regardless of their resistance to carbapenems. In all cases, the minimum inhibitory concentration values of PTSO were significantly lower than those of PTS. These findings offer valuable information about the potential antibacterial use of these substances, particularly against infections that currently have limited therapeutic options. [ABSTRACT FROM AUTHOR]

Purpose: Cefepime is an antibiotic associated with cefepime induced neurotoxicity (CIN), particularly in those with reduced renal function, or in cases of inappropriate medication dosing. This report describes a case of CIN associated with a change in infusion duration from 180 to30 minutes, which to the best of our knowledge has not been previously reported in the literature. Summary: A 73-year old male was treated with extended infusion cefepime over 180 minutes while hospitalized with recurrent pneumonia. On discharge, cefepime was continued as outpatient parenteral antimicrobial therapy (OPAT) administered over 30 minutes. The patient began to experience symptoms of neurotoxicity after 1 day of receiving OPAT, which subsequently led to a readmission as neurological symptoms worsened. Cefepime was discontinued and symptoms resolved within 48 hours. Renal function was stable throughout treatment and no other causes for neurotoxicity were noted. Conclusion: This is a unique case of CIN secondary to shortened infusion time, which is clinically relevant, particularly during transitions of care. Further investigation, including more widespread use of therapeutic drug monitoring will be beneficial to further elucidate the relationship between infusion time and CIN development. [ABSTRACT FROM AUTHOR]

The emergence and spread of extended-spectrum β-lactamase (ESBL)-producing Escherichia coli (E. coli) pose significant challenges to the treatment and control of urinary tract infections, particularly among vulnerable populations, such as the elderly living in nursing care homes. In this study, we investigated the occurrence of ESBL genes in commensal E. coli isolated from urine samples of 118 elderly individuals residing in Ghanaian nursing care homes. A total of 195 ESBL genes were detected among 41 E. coli isolated from the study participants. All the isolates harboured at least one ESBL gene, and the majority of them (70.1%) carried at least four ESBL genes. Among the ESBL genes detected, CTXM825 was the predominant (14.1%). In antimicrobial susceptibility testing, 65.9% of the isolates showed resistance to cefepime, a fourth-generation cephalosporin, while 56.1% showed resistance to cefotaxime, a third-generation cephalosporin. Additionally, 46.3% of the isolates were multidrug-resistant, indicating resistance to antibiotics from multiple classes. In summary, we observed relatively high rates of resistance to antibiotics as well as alarming rates of ESBL genes in the isolated pathogens. These findings emphasise the urgent need for antimicrobial stewardship and infection control programmes to mitigate the spread of multidrug-resistant pathogens in nursing care homes. [ABSTRACT FROM AUTHOR]

Cefepime is a fourth-generation cephalosporin with extended antimicrobial coverage. Concerns have been raised about the side effects of cefepime including myoclonus, encephalopathy, and seizures, especially when renal impairment is present. There have been reports of cases of adverse neurological consequences despite appropriate renal adjustment. Here, we present a case of a 69-year-old patient initially diagnosed with pneumonia and treated with cefepime. The patient later developed altered mental status, leading to differential diagnoses including stroke, drug overdose, or non-convulsive seizures. Following a comprehensive workup, it was determined that she had cefepime-induced encephalopathy, despite having normal kidney function, which resolved completely after discontinuing the medication. In addition, we include similar cases retrieved from PubMed up to the present date, to the best of our knowledge. [ABSTRACT FROM AUTHOR]

In a retrospective multicenter study of 575 patients with bloodstream infections or pneumonia due to wild-type AmpC β-lactamase–producing Enterobacterales, species with low in vitro mutation rates for AmpC derepression were associated with fewer treatment failures due to AmpC overproduction (adjusted hazard ratio, 0.5 [95% CI,.2–.9]). However, compared to cefepime/carbapenems, using third-generation cephalosporins as definitive therapy remained associated with this adverse outcome (15% vs 1%). [ABSTRACT FROM AUTHOR]

Background The bla B, bla GOB and bla CME genes are thought to confer β-lactam resistance to Elizabethkingia anophelis , based on experiments conducted primarily on Escherichia coli. Objectives To determine the individual contributions of β-lactamase genes to increased MICs in E. anophelis and to assess their impact on the in vivo efficacy of carbapenem therapy. Methods Scarless gene deletion of one or more β-lactamase gene(s) was performed in three clinical E. anophelis isolates. MICs were determined by broth microdilution. Hydrolytic activity and expressions of β-lactamase genes were measured by an enzymatic assay and quantitative RT–PCR, respectively. In vivo efficacy was determined using Galleria mellonella and murine thigh infection models. Results The presence of bla B resulted in >16-fold increases, while bla GOB caused 4–16-fold increases of carbapenem MICs. Hydrolysis of carbapenems was highest in lysates of bla B-positive strains, possibly due to the constitutionally higher expression of bla B. Imipenem was ineffective against bla B-positive isolates in vivo in terms of improvement of the survival of wax moth larvae and reduction of murine bacterial load. The deletion of bla B restored the efficacy of imipenem. The bla B gene was also responsible for a >4-fold increase of ampicillin/sulbactam and piperacillin/tazobactam MICs. The presence of bla CME, but not bla B or bla GOB, increased the MICs of ceftazidime and cefepime by 8–16- and 4–8-fold, respectively. Conclusions The constitutionally and highly expressed bla B gene in E. anophelis was responsible for increased MICs of carbapenems and led to their poor in vivo efficacy. bla CME increased the MICs of ceftazidime and cefepime. [ABSTRACT FROM AUTHOR]

Objectives: The emergence of multidrug-resistant (MDR) Salmonella strains, especially resistant ones toward critically important antimicrobial classes such as fluoroquinolones and third- and fourth-generation cephalosporins, is a growing public health concern. The current study, therefore, aimed to determine the prevalence, and existence of virulence genes (invA, stn, and spvC genes), antimicrobial resistance profiles, and the presence of β-lactamase resistance genes (blaOXA, blaCTX-M1, blaSHV, and blaTEM) in Salmonella strains isolated from native chicken carcasses in Egypt marketed in Mansoura, Egypt, as well as spotlight the risk of isolated MDR, colistin-, cefepime-, and levofloxacin-resistant Salmonella enterica serovars to public health. Methods: One hundred fifty freshly dressed native chicken carcasses were collected from different poultry shops in Mansoura City, Egypt between July 2022 and November 2022. Salmonella isolation was performed using standard bacteriological techniques, including pre-enrichment in buffered peptone water (BPW), selective enrichment in Rappaport Vassiliadis broth (RVS), and cultivating on the surface of xylose-lysine-desoxycholate (XLD) agar. All suspected Salmonella colonies were subjected to biochemical tests, serological identification using slide agglutination test, and Polymerase Chain Reaction (PCR) targeting the invasion A gene (invA; Salmonella marker gene). Afterward, all molecularly verified isolates were screened for the presence of virulence genes (stn and spvC). The antimicrobial susceptibility testing for isolated Salmonella strains towards the 16 antimicrobial agents tested was analyzed by Kirby–Bauer disc diffusion method, except for colistin, in which the minimum inhibition concentration (MIC) was determined by broth microdilution technique. Furthermore, 82 cefotaxime-resistant Salmonella isolates were tested using multiplex PCR targeting the β-lactamase resistance genes, including blaOXA, blaCTX-M1, blaSHV, and blaTEM genes. Results: Salmonella enterica species were molecularly confirmed via the invA Salmonella marker gene in 18% (27/150) of the freshly dressed native chicken carcasses. Twelve Salmonella serotypes were identified among 129 confirmed Salmonella isolates with the most predominant serotypes were S. Kentucky, S. Enteritidis, S. Typhimurium, and S. Molade with an incidence of 19.4% (25/129), 17.1% (22/129), 17.1% (22/129), and 10.9% (14/129), respectively. All the identified Salmonella isolates (n = 129) were positive for both invA and stn genes, while only 31.8% (41/129) of isolates were positive for the spvC gene. One hundred twenty-one (93.8%) of the 129 Salmonella-verified isolates were resistant to at least three antibiotics. Interestingly, 3.9%, 14.7%, and 75.2% of isolates were categorized into pan-drug-resistant, extensively drug-resistant, and multidrug-resistant, respectively. The average MAR index for the 129 isolates tested was 0.505. Exactly, 82.2%, 82.2%, 63.6%, 51.9%, 50.4%, 48.8%, 11.6%, and 10.1% of isolated Salmonella strains were resistant to cefepime, colistin, cefotaxime, ceftazidime/clavulanic acid, levofloxacin, ciprofloxacin, azithromycin, and meropenem, respectively. Thirty-one out (37.8%) of the 82 cefotaxime-resistant Salmonella isolates were β-lactamase producers with the blaTEM as the most predominant β-lactamase resistance gene, followed by blaCTX-M1 and blaOXA genes, which were detected in 21, 16, and 14 isolates respectively). Conclusion: The high prevalence of MDR-, colistin-, cefepime-, and levofloxacin-resistant Salmonella serovars among Salmonella isolates from native chicken is alarming as these antimicrobials are critically important in treating severe salmonellosis cases and boost the urgent need for controlling antibiotic usage in veterinary and human medicine to protect public health. [ABSTRACT FROM AUTHOR]

Infections due to drug-resistant Acinetobacter baumannii strains are increasing and cause significant morbidity and mortality, especially in hospitalized and critically ill patients. A. baumannii rapidly develops resistance to numerous antibiotics, and antibiotics traditionally used against this deadly pathogen have been failing in recent years, highlighting the need to identify new treatment strategies. Treatment options that have shown promise include revisiting common antibiotics not typically used against A. baumannii, evaluating new antibiotics recently introduced to market, and identifying combinations of antibiotics that display synergistic interactions. In this study, we characterized the antibiotic susceptibility profiles of extensively (XDR) and pandrug-resistant (PDR) A. baumannii patient isolates. We examined the potency of 22 standard-of-care antibiotics and the newer antibiotics eravacycline, omadacycline, and plazomicin against these strains. Furthermore, we examined combinations of these antibiotics against our collection to identify synergistic effects. We found that this collection is highly resistant to most or all standard-of-care antibiotics, except for minocycline and rifampin. We show that eravacycline and omadacycline are effective against these strains based on minimum inhibitory concentrations. We also identified two highly effective combinations, cefepime and amikacin and cefepime and ampicillin–sulbactam, which exhibited high rates of synergy against this collection. This information is valuable in our battle against highly drug resistant and virtually untreatable A. baumannii infections. [ABSTRACT FROM AUTHOR]

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Purpose Intravenous push antibiotics can serve as an alternative to intravenous piggyback antibiotics while providing the same pharmacodynamics and adverse effect profile, easing shortage pressures and decreasing order to administration time, as well as representing a potential cost savings. The purpose of this study was to determine whether intravenous push antibiotics could decrease the time from an order to the start of administration compared to piggyback antibiotics in emergency departments. This study also measured the cost savings of antibiotic preparation and administration and assessed nursing satisfaction when using intravenous push antibiotics. Methods Sample instances of use of intravenous push and piggyback antibiotics were identified. Patients were included if they were 18 years of age or older and received at least a single dose of intravenous push or piggyback ceftriaxone, cefepime, cefazolin, or meropenem in one of the institution's emergency departments. The primary outcome of the study was to compare the time from the order to the start of administration of intravenous push vs piggyback antibiotics. The secondary outcome was to compare the cost of antibiotic preparation for the 2 methods. Results The intravenous push and piggyback groups each had 43 patients. The time from the order to the start of administration decreased from 74 (interquartile range, 29-114) minutes in the piggyback group to 31 (interquartile range, 21-52) minutes in the push group (P = 0.003). When the estimated monthly cost savings for ceftriaxone, cefepime, and meropenem were added together, across the emergency departments, an estimated $227,930.88 is saved per year when using intravenous push antibiotics. Conclusion Intravenous push antibiotics decrease the time from ordering to the start of administration and result in significant cost savings. [ABSTRACT FROM AUTHOR]

Purpose Multidrug-resistant (MDR) infections are challenging to treat due to underlying patient conditions, pathogen characteristics, and high antibiotic resistance rates. As newer antibiotic therapies come to market, limited data exist about their real-world utilization. Methods This was a national retrospective cohort study of ceftazidime/avibactam (approved in 2015) utilization among inpatients from the Veterans Affairs (VA) Healthcare System, from 2015 through 2021. Joinpoint regression was used to estimate time trends in utilization. Results Ceftazidime/avibactam use increased by 52.3% each year (days of therapy per 1,000 bed days; 95% confidence interval, 12.4%-106.4%). We identified 1,048 unique predominantly male (98.3%) and white (66.2%; Black, 27.7%) patients treated with ceftazidime/avibactam, with a mean (SD) age of 71.5 (11.9) years. The most commonly isolated organisms were Pseudomonas aeruginosa (36.3%; carbapenem resistant, 80.6%; MDR, 65.0%) and Klebsiella species (34.1%; carbapenem resistant, 78.4%; extended-spectrum cephalosporin resistant, 90.7%). Common comorbid conditions included hypertension (74.8%), nervous system disorders (60.2%), diabetes mellitus (48.7%), and cancer (45.1%). Median time to ceftazidime/avibactam initiation from admission was 6 days, with a median of 3 changes in therapy before ceftazidime/avibactam initiation and a subsequent median length of inpatient stay of 14 days (median of 8 days of ceftazidime/avibactam therapy). Treatment heterogeneity was high, both before ceftazidime/avibactam initiation (89.6%) and during ceftazidime/avibactam treatment (85.6%), and common concomitant antibiotics included vancomycin (41.4%), meropenem (24.1%), cefepime (15.2%), and piperacillin/tazobactam (15.2%). The inpatient mortality rate was 23.6%, and 20.8% of patients had a subsequent admission with ceftazidime/avibactam treatment. Conclusion Utilization of ceftazidime/avibactam increased from 2015 to 2021 in the national VA Healthcare System. Ceftazidime/avibactam was utilized in complex, difficult-to-treat patients, with substantial treatment heterogeneity and variation in the causative organism and culture sites. [ABSTRACT FROM AUTHOR]

Cefepime and piperacillin/tazobactam are antimicrobials recommended by IDSA/ATS guidelines for the empirical management of patients admitted to the intensive care unit (ICU) with community-acquired pneumonia (CAP). Concerns have been raised about which should be used in clinical practice. This study aims to compare the effect of cefepime and piperacillin/tazobactam in critically ill CAP patients through a targeted maximum likelihood estimation (TMLE). A total of 2026 ICU-admitted patients with CAP were included. Among them, (47%) presented respiratory failure, and (27%) developed septic shock. A total of (68%) received cefepime and (32%) piperacillin/tazobactam-based treatment. After running the TMLE, we found that cefepime and piperacillin/tazobactam-based treatments have comparable 28-day, hospital, and ICU mortality. Additionally, age, PTT, serum potassium and temperature were associated with preferring cefepime over piperacillin/tazobactam (OR 1.14 95% CI [1.01–1.27], p = 0.03), (OR 1.14 95% CI [1.03–1.26], p = 0.009), (OR 1.1 95% CI [1.01–1.22], p = 0.039) and (OR 1.13 95% CI [1.03–1.24], p = 0.014)]. Our study found a similar mortality rate among ICU-admitted CAP patients treated with cefepime and piperacillin/tazobactam. Clinicians may consider factors such as availability and safety profiles when making treatment decisions. [ABSTRACT FROM AUTHOR]

Introduction Antimicrobial resistance (AMR) is among the greatest threats to global healthcare. The World Health Organization (WHO) estimates that by 2050 ten million deaths will be attributed to AMR annually. In response, the WHO has implemented antibiotic stewardship programs which focus on optimizing antibiotic use and raise, amongst others, the issue of the preferred method of intravenous antibiotic administration. Various studies have attempted to answer this question with conflicting results. Review This review examined several studies assessing extended/continuous infusion compared to intermittent infusion of three beta-lactams: piperacillin-tazobactam, cefepime, and meropenem. The findings and conclusions of each study were summarized and compared to one another to provide a general overview of the current evidence. Conclusions We conclude that continuous/extended infusion showed a greater clinical benefit in highly critical cases, namely sepsis and febrile neutropenia, compared to intermittent infusion. Additionally, in cases where a pathogen was identified, continuous/extended infusion showed superiority. Nonetheless, high-quality studies with larger samples are needed to demonstrate the difference between these two modes of infusion in a way that would better inform guidelines and policies, aiding in the fight against AMR. [ABSTRACT FROM AUTHOR]

Cefepime/enmetazobactam (EXBLIFEP®), an intravenous (IV) antibacterial fixed-dose combination of a 4th generation cephalosporin and an extended-spectrum β-lactamase (ESBL) inhibitor, is being developed by Allecra Therapeutics and ADVANZ PHARMA for the treatment of infections caused by multi-drug-resistant (MDR) Gram-negative bacteria. In February 2024, cefepime/enmetazobactam was approved in the USA for use in adults with complicated urinary tract infections (cUTI) including pyelonephritis, caused by susceptible strains of Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Proteus mirabilis, and Enterobacter cloacae complex. In March 2024, cefepime/enmetazobactam was approved in the EU for use in adults for the treatment of cUTI, including pyelonephritis, and hospital-acquired pneumonia, including ventilator associated pneumonia, and the treatment of patients with bacteraemia occurring in association with or suspected to be associated with any of these infections. This article summarizes the milestones in the development of cefepime/enmetazobactam leading to this first approval for the treatment of adults with infections caused by MDR Gram-negative bacteria. [ABSTRACT FROM AUTHOR]

Studies had reported the association between cefepime and neurotoxicity. The neurotoxicity incidence was well documented regarding the intensive care unit (ICU). This study was aimed to evaluate the incidence and characteristics of neurotoxicity caused by cefepime in the medical patients. A retrospective study was conducted on the medical patients treated with cefepime. Patients having received cefepime were eligible for the screening. Exclusion criteria were as follows: admitted in ICU, Alzheimer’s disease, admitted with the altered mental status because of any cause or epilepsy history. Naranjo adverse event scale described the probability of adverse events in suspected cases and categorized as definite, probable, possible and doubtful. A total of 601 patients were screened wherein 93 met the inclusion criteria. The mean age (±standard deviation (SD)) was 56 years (±17). The patients’ majority was male (66%) with the normal kidney function (73%). Common comorbidities included hypertension (60%) and diabetes (40%). Only 2 patients (2%) had developed neurological symptoms. The cases were carefully evaluated where one was doubtful and the other possibly had cefepime-induced neurotoxicity. The neurotoxicity incidence among medical patients was low, and might relate to the disease states affecting central nervous system. Hence, a careful evaluation of other possible causes for neurological symptoms deemed necessary while being on cefepime therapy. [ABSTRACT FROM AUTHOR]

Background: Carbapenem-resistant (Car-R) Pseudomonas aeruginosa is an urgent threat. These isolates may remain susceptible to traditional noncarbapenem antipseudomonal β-lactams, but it is unclear if carbapenem resistance impacts the effectiveness of these agents. Objective: The purpose of this study was to compare clinical outcomes in Car-R and cephalosporin-susceptible (Ceph-S) P. aeruginosa pneumonia treated with cefepime versus other susceptible agents. Methods: This retrospective cohort study evaluated patients diagnosed with hospital-acquired or ventilator-associated pneumonia who had a respiratory isolate of Car-R Ceph-S P. aeruginosa. Patients were excluded if they had polymicrobial respiratory cultures, other concomitant infections, empyema, death within 3 days of index culture, or received less than 3 days of susceptible therapy. Patients treated with cefepime were compared to other susceptible therapies. The primary endpoint was 30-day in-hospital mortality. Results: Eighty-seven patients were included: cefepime, n = 61; other susceptible therapies, n = 26. There were no differences in 30-day in-hospital mortality between cefepime and other susceptible therapies (19.6% vs. 19.2%, p value = 0.719). In addition, there were no differences between clinical cure rates (cefepime 65.6% vs. other therapies 72 %, p value = 0.47). In multivariate logistic regression, treatment with cefepime (odds ratio [OR], 0.57; 95% confidence interval [CI], 0.11-2.52) was not independently associated with 30-day in-hospital mortality. Conclusion and Relevance: For the treatment of Car-R Ceph-S P. aeruginosa pneumonia, cefepime showed similar rates of 30-day in-hospital mortality and clinical outcomes when compared to other susceptible therapies. Cefepime may be utilized to conserve novel β-lactam and β-lactamase inhibitors. [ABSTRACT FROM AUTHOR]

In order to combat resistance, it is necessary to develop antimicrobial agents that act differently from conventional antibiotics. Fluorothiazinone, 300 mg tablet (The Gamaleya National Research Center), is an original antibacterial drug based on a new small molecule T3SS and flagellum inhibitor. A total of 357 patients with complicated urinary tract infections (UTIs) were divided into two groups and given Fluorothiazinone 1200 mg/day or a placebo for 7 days to evaluate the efficacy and safety of the drug. Additionally, all patients were given Cefepime 2000 mg/day. Fluorothiazinone with Cefepime showed superiority over placebo/Cefepime based on the assessment of the proportion of patients with an overall outcome in the form of a cure after 21 days post-therapy (primary outcome), overall outcome in cure rates, clinical cure rates, and microbiological efficacy at the end of therapy and after 21 days post-therapy (secondary outcomes). In patients who received Fluorothiazinone, the rate of infection recurrences 53 and 83 days after the end of the therapy was lower by 18.9%, compared with patients who received placebo. Fluorothiazinone demonstrated a favorable safety profile with no serious unexpected adverse events reported. The results showed superiority of the therapy with Fluorothiazinone in combination with Cefepime compared with placebo/Cefepime in patients with cUTIs. [ABSTRACT FROM AUTHOR]

This research aimed to overcome challenges posed by cefepime excessive elimination rate and poor patient compliance by developing transdermal delivery system using nano-transfersomes based chitosan gel. Rotary evaporation-sonication method and the Box-Behnken model were used to prepare cefepime loaded nano-transfersomes (CPE-NTFs). The physiochemical characterization of CPE-NTFs were analyzed including DLS, deformability index, DSC and antimicrobial study. Optimized CPE-NTFs loaded into chitosan gel and appropriately characterized. In vitro release, ex vivo and in vivo studies were performed. The CPE-NTFs were physically stable with particle size 222.6 ± 1.8 nm, polydispersity index 0.163 ± 0.02, zeta potential −20.8 ± 0.1 mv, entrapment efficiency 81.4 ± 1.1% and deformability index 71 ± 0.2. DSC analysis confirmed successful drug loading and thermal stability. FTIR analysis showed no chemical interaction among the excipients of CPE-NTFs gel. The antibacterial activity demonstrated a remarkable reduction in the minimum inhibitory concentration of cefepime when incorporated into nano-transfersomes. CPE-NTFs based chitosan gel (CPE-NTFs gel) showed significant physicochemical properties. In vitro release studies exhibited sustained release behavior over 24 h, and ex vivo studies indicated enhanced permeation and retention compared to conventional cefepime gel. In vivo skin irritation studies confirmed CPE-NTFs gel was nonirritating and biocompatible for transdermal delivery. This research showed nano-transfersomes based chitosan gel is a promising approach for cefepime transdermal delivery and provides sustained release of cefepime. [ABSTRACT FROM AUTHOR]