Abstract
Cefiderocol is a novel siderophore cephalosporin that forms a complex with extracellular free ferric iron, which leads to transportation across the outer cell membrane to exert its ...bactericidal activity through cell wall synthesis inhibition. This pharmacological property has rendered cefiderocol active against several clinically relevant MDR Gram-negative bacteria as evidenced by several in vitro and in vivo studies. Cefiderocol was first approved by the US FDA on 14 November 2019 for the treatment of complicated urinary tract infections. On 28 September 2020, cefiderocol was approved for the treatment of hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia. The FDA-approved indications are based on clinical data from the APEKS-cUTI, APEKS-NP and CREDIBLE-CR trials. In APEKS-cUTI, cefiderocol demonstrated non-inferiority to imipenem/cilastatin for the treatment of complicated urinary tract infection caused by MDR Gram-negative bacteria. In APEKS-NP, cefiderocol demonstrated non-inferiority to meropenem for treatment of nosocomial pneumonia. However, in CREDIBLE-CR, higher all-cause mortality was observed with cefiderocol compared with best available therapy for the treatment of severe infections caused by Gram-negative bacteria, primarily in the subset of patients with Acinetobacter spp. infections. Several case reports/series have demonstrated clinical success with cefiderocol for a variety of severe infections. The purpose of this article is to review available data on the mechanism of action, in vitro and in vivo data, pharmacokinetics, pharmacodynamics, susceptibility testing, efficacy and safety of cefiderocol to address its role in therapy.
Abstract
Purpose
The purpose of this study was to (1) determine whether academic medical centers implemented area under the concentration–time curve (AUC)–based monitoring for vancomycin and (2) ...characterize perceived barriers to implementation and challenges experienced during the implementation process.
Methods
A multicenter, cross-sectional electronic survey was distributed to pharmacy representatives from 124 academic medical centers within the Vizient University Health System Consortium Pharmacy Network.
Results
Seventy-eight institutions completed the survey, representing a 62.9% response rate. Most institutions were approximately 500–1,000 beds (68/78, 87.2%), and pharmacists were primarily responsible for vancomycin therapeutic drug monitoring (66/78, 84.6%) using pharmacist-driven protocols (57/78, 73.1%). Less than one fourth (18/78, 23.1%) of responding academic medical centers performed AUC-based vancomycin monitoring, and the majority (12/18, 66.7%) used 2-point pharmacokinetics, with a smaller fraction using either Bayesian software or population-based pharmacokinetics. Of the responding institutions that only perform trough-based therapeutic drug monitoring (60/78, 76.9%), most (53/60, 88.3%) did not plan to or were unsure about transitioning to AUC-based monitoring within the next year. Both the most common challenge encountered (13/18, 72.2%) for institutions performing AUC-based monitoring and the most common barrier (44/60, 73.3%) to implementation of this monitoring strategy were pharmacist and/or provider unfamiliarity.
Conclusion
The majority of surveyed academic medical centers have not yet implemented AUC-based vancomycin monitoring, and most institutions did not plan to adopt or were unsure about adopting this monitoring strategy within the next year.
Abstract
Background
To date, no real-world data are available to describe cefiderocol use in carbapenem-resistant Acinetobacter baumannii (CRAB) meningitis. Furthermore, cefiderocol pharmacokinetic ...(PK) data to support CNS penetration in human subjects are limited. These gaps pose a significant concern for clinicians who are faced with treating such infections when considering cefiderocol use.
Objectives
To describe cefiderocol CSF and plasma PK and pharmacodynamic (PD) data from two different dosing regimens 2 g IV q6h (regimen 1) and 2 g IV q8h (regimen 2) during treatment of CRAB meningitis.
Patients and methods
A 61-year-old woman with CRAB meningitis was treated with cefiderocol and intraventricular gentamicin. Steady-state plasma and CSF cefiderocol concentrations were evaluated on Day 19 (regimen 1) and Day 24 (regimen 2) during the cefiderocol treatment course.
Results
CSF AUC was 146.49 and 118.28 mg·h/L, as determined by the linear-log trapezoidal method for regimens 1 and 2, respectively. Penetration into CSF estimated as the AUCCSF/AUCfree plasma ratio was 68% and 60% for regimens 1 and 2, respectively. Estimated free plasma and CSF concentrations exceeded the MIC of the isolate for 100% of the dosing interval. Microbiological and clinical cure were achieved, and no cefiderocol-associated adverse effects were observed.
Conclusions
Cefiderocol, when given as 2 g q8h and 2 g q6h, attained CSF concentrations that exceeded the organism-specific MIC and the CLSI susceptible breakpoint (≤4 mg/L) for 100% of the dosing interval.
•Vancomycin AUC thresholds were assessed using two-point pharmacokinetic monitoring.•AUC thresholds for success and nephrotoxicity were ≥297 mg·h/L and ≥710 mg·h/L.•Rates of clinical failure (18.2%) ...and nephrotoxicity (13.0%) were low.•These data support evidence to target a vancomycin AUC range of 400–600 mg·h/L.•Adoption of AUC-based vancomycin monitoring may improve safety and efficacy.
Limited evidence exists evaluating pharmacokinetic thresholds for vancomycin efficacy and nephrotoxicity using non-Bayesian methods. The objective of this study was to evaluate the 24-h steady-state vancomycin area under the concentration–time curve (AUC24) thresholds for efficacy and nephrotoxicity in patients with methicillin-resistant Staphylococcus aureus bacteraemia (MRSA-B) after implementing two-point pharmacokinetic therapeutic drug monitoring. A single-centre, retrospective cohort study was performed including adult patients admitted between 1 June 2016 and 1 January 2018 with MRSA-B treated with vancomycin for ≥72 h. The AUC24 was calculated using peak and trough vancomycin serum concentrations. Clinical success was defined as defervescence and blood culture sterilisation by Day 7. Nephrotoxicity was defined as an increase in serum creatinine of >0.5 mg/dL (or ≥50%) from baseline. Classification and regression tree (CART) analyses were performed to identify AUC24 thresholds for efficacy and nephrotoxicity. Forty-six patients were included in the study. Clinical success and nephrotoxicity were observed in 81.8% and 13.0%, respectively. The CART-derived vancomycin AUC24 thresholds for clinical success and nephrotoxicity were ≥297 mg·h/L and ≥710 mg·h/L, respectively. Patients with an AUC24 ≥297 mg·h/L had a >2.7-fold increase in clinical success compared with those who did not (89.5% vs. 33.3%, respectively; P = 0.01), and patients with an AUC24 ≥710 mg·h/L had a >7-fold increase in nephrotoxicity compared with those with an AUC24 <710 mg·h/L (66.7% vs. 9.3%, respectively; P = 0.04). This study supports current recommendations to target vancomycin AUC24 values of 400–600 mg·h/L when calculated using two-point pharmacokinetics, although a wider range may exist.
Abstract
Delafloxacin is a novel anionic fluoroquinolone (FQ) approved for treatment of acute bacterial skin and skin structure infections (ABSSSIs) caused by a number of Gram-positive and ...Gram-negative organisms including MRSA and Pseudomonas aeruginosa. The unique chemical structure of delafloxacin renders it a weak acid and results in increased potency in acidic environments. In Phase III studies, delafloxacin had similar outcomes to comparator regimens for treatment of ABSSSIs, and was well tolerated overall. Similar to other FQs, delafloxacin is available in both intravenous and oral formulations, but differs in that delafloxacin exerts a minimal effect on cytochrome P450 enzymes and on the corrected QT interval. This novel FQ has the potential to be utilized across a wide variety of clinical settings; however, post-marketing surveillance and long-term safety and resistance data will be essential to identify optimal use scenarios.
•The risk of linezolid-associated serotonin toxicity remains unclear.•Management of clinical scenarios with linezolid and serotonergic agents is challenging.•In total, 1743 patients received ...linezolid with or without concurrent serotonergic agents.•Several patients received multiple serotonergic agents, including moderate and/or high doses.•No cases of serotonin toxicity were identified based on the Hunter criteria.
The risk of linezolid-associated serotonin toxicity remains unclear. This study sought to evaluate the incidence of serotonin toxicity among hospitalized patients who received linezolid with or without concurrent serotonergic agents (SAs). Secondary outcomes were to assess the dose, agent selection and number of SAs.
A single-centre, retrospective cohort study of hospitalized patients aged ≥18 years who received at least one dose of linezolid with or without SAs between 1 January 2014 and 30 June 2021 was performed. Patients were excluded if they were aged <18 years, had linezolid ordered but not administered, were pregnant or were incarcerated. Up to five concurrent SAs were assessed, and dose category was classed as low, moderate or high (dose <33%, 33–66% or >66% of maximum daily dose, respectively). Serotonin toxicity was identified by searching patients’ electronic medical records. If identified, the Sternbach criteria and Hunter criteria were applied.
Of 2022 patients screened, 1743 were included in this study. Mean age, weight and linezolid duration were 58.5 years, 90.7 kg and 3.8 days, respectively. Approximately 67% (1168/1743) of patients received linezolid with at least one SA, and several patients received multiple SAs. Most patients (53.8%; 616/1144) received moderate- and/or high-dose SAs. Only two patients (0.11%) were identified as possible cases of serotonin toxicity based on the electronic medical record search. However, the incidence of serotonin toxicity was 0.06% (1/1743) based on the Sternbach criteria and 0% (0/1743) based on the Hunter criteria.
Serotonin toxicity among hospitalized patients who received linezolid with or without SAs was exceedingly rare, even among those who received multiple and high-dose SAs.
Background:
The preferred antibiotic salvage regimen for persistent methicillin-susceptible Staphylococcus aureus bacteremia (MSSAB) is unclear. Ertapenem with cefazolin or an antistaphylococcal ...penicillin has been primarily described, but identifying alternative carbapenem-sparing options may support antibiotic stewardship efforts and decrease the risk of antibiotic-associated Clostridioides difficile infection.
Objective:
We sought to evaluate the effectiveness and safety of daptomycin plus oxacillin (D/O) for persistent MSSAB.
Methods:
This was a single-center, retrospective cohort of patients with persistent MSSAB who received D/O between January 1, 2014, and January 1, 2023. Adult patients were included if they had blood cultures positive for MSSA ≥72 hours and received D/O combination for ≥48 hours. Patients were excluded if they were pregnant, incarcerated, or received another antibiotic considered to have excellent activity against MSSA. The primary outcome was time to MSSA bacteremia clearance post-daptomycin initiation. Secondary outcomes included microbiological cure, hospital length of stay, 90-day all-cause mortality, MSSA bacteremia-related mortality, 90-day readmission for MSSAB, and incidence of antibiotic-associated adverse effects. Time to MSSAB clearance post-D/O initiation was plotted using Kaplan-Meier estimation.
Results:
Seven unique patient encounters were identified including 4 with endocarditis. Despite a median MSSA bacteremia duration of 7.8 days, median clearance was 2 days post-daptomycin initiation. All achieved microbiological cure, and no adverse effects were reported. Ninety-day all-cause mortality, MSSAB-related mortality, and 90-day readmission for MSSAB occurred in 28.6%, 14.3%, and 14.3% of patients, respectively.
Conclusions and Relevance:
D/O was an effective, well-tolerated salvage regimen in this cohort and may represent a carbapenem-sparing option for persistent MSSAB.
Background:
Approximately 30% of antimicrobials prescribed in the outpatient setting are unnecessary and up to 50% are inappropriate. Despite this, antimicrobial stewardship (AS) efforts mostly focus ...on the inpatient setting, and limited data describe AS interventions at hospital discharge. Acknowledging the potential value of discharge AS, we used our existing resources to review discharge oral antimicrobial prescriptions.
Objective:
The primary objective of this retrospective, single-center study was to evaluate the impact of an AS program on discharge oral antimicrobial prescriptions.
Methods
Discharge oral antimicrobial prescriptions sent to our hospital-operated outpatient pharmacy, reviewed by an infectious diseases (ID) pharmacist, and recorded into our data collection tool from September 1, 2020, to February 28, 2021, were evaluated retrospectively. The primary outcome was to identify the frequency a drug-related problem (DRP) was identified by an ID pharmacist. Secondary outcomes included DRP characterization, percentage of prescriptions with interventions, intervention acceptance rate, and reduction in antimicrobial days dispensed at discharge when interventions to limit treatment duration were accepted.
Results:
Of the 803 discharge oral antimicrobial prescriptions reviewed, at least 1 DRP was identified in 43.1% (346/803). The most frequently identified DRPs pertained to treatment duration, drug selection, and dose selection. At least 1 intervention was recommended in 42.8% (344/803) of prescriptions. In total, 438 interventions were made and the acceptance rate was 75.6% (331/438). The most common types of interventions included recommendations for a different duration, a different dose or frequency, and antimicrobial discontinuation. When interventions to reduce treatment duration were accepted, the median (interquartile range) number of antimicrobial days decreased from 8 (5-10) days to 4 (0-5.5) days (P < 0.001).
Conclusion and Relevance:
An ID pharmacist’s review of discharge oral antimicrobial prescriptions sent to our hospital-operated outpatient pharmacy resulted in identification of DRPs and subsequent interventions in a substantial number of prescriptions.
Background:
Skin and soft tissue infections (SSTIs) are often caused by gram-positive bacteria that colonize the skin. Given the overuse of antibiotics, SSTIs are increasingly caused by resistant ...bacteria, including methicillin-resistant Staphylococcus aureus (MRSA). Guidance on the utility of MRSA nasal screening for MRSA SSTI is limited.
Objective:
To determine whether MRSA nasal screening predicts the risk of MRSA SSTIs.
Methods:
This was a single-center, retrospective cohort study of adult patients with an SSTI diagnosis that had MRSA nasal screening and wound cultures obtained within 48 hours of starting antibiotics. Sensitivity, specificity, positive and negative predictive value, and positive and negative likelihood ratios were calculated using VassarStats. Pretest and posttest probabilities were estimated with Microsoft Excel.
Results:
A total of 884 patient encounters were reviewed between December 1, 2018, and October 31, 2021, and 300 patient encounters were included. The prevalence of MRSA SSTI was 18.3%. The MRSA nasal colonization had a sensitivity of 63.6%, specificity of 93.9%, positive predictive value of 70.0% (95% CI = 55.2%-81.7%), negative predictive value of 92.0% (95% CI = 87.7%-94.9%), positive likelihood ratio of 10.39 (95% CI = 6.12-17.65), negative likelihood ratio of 0.39 (95% CI = 0.27-0.55), positive posttest probability of 70.0%, and negative posttest probability of 8.0%.
Conclusions:
Given the high positive likelihood ratio, a positive MRSA nasal screen was associated with a large increase in the probability of MRSA SSTI at our institution, and a negative MRSA nasal screen was associated with a small but potentially significant decrease in the probability of MRSA SSTI.
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