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Clostridioides difficile (C. difficile) is a predominant nosocomial infection, and guidelines for improving diagnosis and treatment were published in 2017. We conducted a single-center, retrospective 10-year cohort study of patients with primary C. difficile infectious disease (CDID) at the largest referral Lithuanian university hospital, aiming to evaluate the clinical and laboratory characteristics of CDID and their association with the outcomes, as well as implication of concordance with current Clinical Practice Guidelines. The study enrolled a total of 370 patients. Cases with non-concordant CDID treatment resulted in more CDID-related Intensive Care Unit (ICU) admissions (7.5 vs. 1.8%) and higher CDID-related mortality (13.0 vs. 1.8%) as well as 30-day all-cause mortality (61.0 vs. 36.1%) and a lower 30-day survival compared with CDID cases with concordant treatment (p < 0.05). Among cases defined by two criteria for severe CDID, only patients with non-concordant metronidazole treatment had refractory CDID (68.8 vs. 0.0%) compared with concordant vancomycin treatment. In the presence of non-concordant metronidazole treatment for severe CDID, only cases defined by two severity criteria had more CDID-related ICU admissions (18.8 vs. 0.0%) and higher CDID-related mortality (25.0 vs. 2.0%, p < 0.05) compared with cases defined by one criterion. Severe comorbidities and the continuation of concomitant antibiotics administered at CDID onset reduced (p < 0.05) the 30-day survival and increased (p = 0.053) 30-day all-cause mortality, with 57.6 vs. 10.7% and 52.0 vs. 25.0%, respectively. Conclusions: CDID treatment non-concordant with the guidelines was associated with various adverse outcomes. In CDID with leukocytes ≥ 15 × 109/L and serum creatinine level > 133 µmol/L (>1.5 mg/dL), enteral vancomycin should be used to avoid refractory response, as metronidazole use was associated with CDID-related ICU admission and CDID-related mortality. Severe comorbidities worsened the outcomes as they were associated with reduced 30-day survival. The continuation of concomitant antibiotic therapy increased 30-day all-cause mortality; thus, it needs to be reasonably justified, deescalated or stopped.

A vancomycin-sparing guideline for suspected late-onset sepsis helped reduce vancomycin usage in our level-4 neonatal intensive care unit. Significant reduction in overall vancomycin use, with its likely unit-wide beneficial downstream effects, may need to be measured against the rare case of methicillin-resistant Staphylococcus aureus infection and delayed effective therapy.

BACKGROUND: Vancomycin dosing tailored for newborns is challenging due to the significant influence of maturation and organ function on pharmacokinetics. Population pharmacokinetic (popPK) models can be used to improve target attainment in neonates.
OBJECTIVE: The primary objective was to derive and evaluate a popPK model of intravenous vancomycin for neonates. Second, the predictive performance of this popPK model was compared with published popPK models.
METHODS: This is a retrospective cohort study of neonates admitted to the neonatal intensive care unit receiving intravenous vancomycin. A popPK model was derived with 70% of the dataset using a nonlinear mixed effects modeling method. The predictive performance of the current popPK model was validated and compared with 22 published popPK models using the remaining 30% of the dataset. Monte Carlo simulations (MCS) were performed to derive optimal dosing regimens to treat neonatal sepsis caused by coagulase-negative staphylococci (CoNS).
RESULTS: Among 655 vancomycin courses from 448 neonates, 78% of vancomycin trough concentrations were outside target range (10-15 mg/L) for central nervous system infections and 43% were outside target range (5-12 mg/L) for other infections using the institution\'s vancomycin dosing. A one-compartment model best described the observed data with a mean clearance of 0.11 ± 0.03 L/kg/h and volume of distribution (V) of 1.02 ± 0.08 L/kg. Body weight (WT), postmenstrual age (PMA), and serum creatinine (SCr) were significant covariates associated with clearance (p < 0.001) and body WT was a significant covariate associated with V (p = 0.009). Our study\'s popPK model has similar or better accuracy and precision than other published models. MCS-derived vancomycin doses from the validated model achieved >90% target attainment for a steady state through target range of 10-15 mg/L in the majority of PMA and SCr categories (78%) to treat CoNS sepsis.
CONCLUSIONS: A vancomycin dosing guideline derived from a validated popPK model in neonates with CoNS sepsis is recommended to improve target attainment.

BACKGROUND: This study aimed to compare the achievement of pharmacokinetic-pharmacodynamic (PK-PD) exposure targets for vancomycin using a newly developed dosing guideline with product-information-based dosing in the treatment of adult patients with serious infections.
METHODS: In silico product-information- and guideline-based dosing simulations for vancomycin were performed across a range of doses and patient characteristics, including body weight, age, and renal function at 36-48 and 96 hours, using a pharmacokinetic model derived from a seriously ill patient population. The median simulated concentration and area under the 24-hour concentration-time curve (AUC 0-24 ) were used to measure predefined therapeutic, subtherapeutic, and toxicity PK-PD targets.
RESULTS: Ninety-six dosing simulations were performed. The pooled median trough concentration target with guideline-based dosing at 36 and 96 hours was achieved in 27.1% (13/48) and 8.3% (7/48) of simulations, respectively. The pooled median AUC 0-24 /minimum inhibitory concentration ratio with guideline-based dosing at 48 and 96 hours was attained in 39.6% (19/48) and 27.1% (13/48) of simulations, respectively. Guideline-based dosing simulations yielded improved trough target attainment compared with product-information-based dosing at 36 hours and significantly less subtherapeutic drug exposure. The toxicity threshold was exceeded in 52.1% (25/48) and 0% (0/48) for guideline- and product-information-information-based dosing, respectively ( P < 0.001).
CONCLUSIONS: A Critical care vancomycin dosing guideline appeared slightly more effective than standard dosing, as per product information, in achieving PK-PD exposure associated with an increased likelihood of effectiveness. In addition, this guideline significantly reduced the risk of subtherapeutic exposure. The risk of exceeding toxicity thresholds, however, was greater with the guideline, and further investigation is suggested to improve dosing accuracy and sensitivity.

The updated Czech guidelines differ in some aspects from the 2021 guidelines issued by the ESCMID Study Group for Clostridium difficile. The key points of these Czech recommendations may be summarized as follows: • The drug of choice for hospitalized patients is orally administered fidaxomicin or vancomycin. In outpatients with a mild first episode of C. difficile infection, metronidazole can also be used. • If the patient\'s response to treatment is good and there are no complications, the duration of antibiotic treatment can be reduced (e.g. to 5 days in case of fidaxomicin or to 6-7 days in case of vancomycin). • If oral therapy is impossible, the drug of choice is tigecycline, 100 mg i.v., b.i.d., with initial shortening of the interval between the first and second doses for faster saturation. If the severity of the disease progresses during this antibiotic treatment, it is necessary to access the ileum or cecum, i.e. to perform double ileostomy or percutaneous endoscopic cecostomy, and to instill vancomycin or fidaxomicin lavages. • Fulminant C. difficile colitis should be treated with oral fidaxomicin ± tigecycline i.v. If peristalsis ceases, fidaxomicin should be administered into the ileum or cecum as described above. If sepsis develops, a broad-spectrum beta-lactam antibiotic (piperacillin/tazobactam, carbapenem) i.v. is added to topically administered fidaxomicin instead of tigecycline i.v.; at the same time, colectomy should be considered as the last resort. • To treat first recurrence, fidaxomicin or vancomycin is administered with a subsequent fecal microbiota transplant (FMT) from a healthy donor. For second or subsequent recurrence, administration of fidaxomicin is of little benefit; the therapy of choice is oral vancomycin and subsequent FMT. Prolonged vancomycin or fidaxomicin taper and pulse treatment is appropriate only when FMT cannot be performed.

There are limited US data assessing adherence to surgical antimicrobial prophylaxis guidelines, particularly across a large, nationwide sample. Moreover, commonly prescribed inappropriate antimicrobial prophylaxis regimens remain unknown, hindering improvement initiatives.
We conducted a retrospective cohort study of adults who underwent elective craniotomy, hip replacement, knee replacement, spinal procedure, or hernia repair in 2019-2020 at hospitals in the PINC AI (Premier) Healthcare Database. We evaluated adherence of prophylaxis regimens, with respect to antimicrobial agents endorsed in the American Society of Health-System Pharmacist guidelines, accounting for patient antibiotic allergy and methicillin-resistant Staphylococcus aureus colonization status. We used multivariable logistic regression with random effects by hospital to evaluate associations between patient, procedural, and hospital characteristics and guideline adherence.
Across 825 hospitals and 521 091 inpatient elective surgeries, 308 760 (59%) were adherent to prophylaxis guidelines. In adjusted analysis, adherence varied significantly by US Census division (adjusted OR [aOR] range: .61-1.61) and was significantly lower in 2020 compared with 2019 (aOR: .92; 95% CI: .91-.94; P < .001). The most common reason for nonadherence was unnecessary vancomycin use. In a post hoc analysis, controlling for patient age, comorbidities, other nephrotoxic agent use, and patient and procedure characteristics, patients receiving cefazolin plus vancomycin had 19% higher odds of acute kidney injury (AKI) compared with patients receiving cefazolin alone (aOR: 1.19; 95% CI: 1.11-1.27; P < .001).
Adherence to antimicrobial prophylaxis guidelines remains suboptimal, largely driven by unnecessary vancomycin use, which may increase the risk of AKI. Adherence decreased in the first year of the COVID-19 pandemic.

Clostridioides difficile infection (CDI) remains a significant clinical challenge both in the management of severe and severe-complicated disease and the prevention of recurrence. Guidelines released by the Infectious Diseases Society of America and Society for Healthcare Epidemiology of America (IDSA/SHEA) and ESCMID had some consensus as well as some discrepancies in disease severity classification and treatment recommendations. We review and compare the key clinical strategies from updated IDSA/SHEA, ESCMID and current Australasian guidelines for CDI management in adults and discuss relevant issues for clinicians, particularly in the management of severe-complicated infection. Updated IDSA/SHEA and ESCMID guidelines now reflect the increased efficacy of fidaxomicin in preventing recurrence and have both promoted fidaxomicin to first-line therapy with an initial CDI episode in both non-severe and severe disease and endorsed the role of bezlotoxumab in the prevention of recurrent infection. Vancomycin remains acceptable therapy and metronidazole is not preferred. For severe-complicated infection the IDSA/SHEA recommends high-dose oral ± rectal vancomycin and IV metronidazole, whilst in an important development, ESCMID has endorsed fidaxomicin and tigecycline as part of combination anti-CDI therapy, for the first time. The role of faecal microbiota transplantation (FMT) in second CDI recurrence is now clearer, but timing and mode of FMT in severe-complicated refractory disease still requires further study.

BACKGROUND: The revised vancomycin guidelines recommend replacing trough-only with trough or peak/trough Bayesian and first-order equations monitoring, citing their better AUC predictions and poor AUC-trough R2. Yet, evidence suggesting good AUC-trough correlation has been overlooked, and the optimality of peak/trough samples has been doubted. The guidelines recommend Bayesian programs implement richly-sampled PopPK priors despite their scarcity. Therefore, whether complex Bayesian and sample-demanding first-order equations can bring significant advantages to the practice over simple trough-only monitoring is worth weighing.
OBJECTIVE: The primary aim is to compare the predictive performance of the AUC monitoring methods. Then, we investigate the impact of not adhering to trough sampling on the Bayesian-based predictions. Moreover, we report the nature of PopPK priors used in Bayesian programs to assess the applicability of the guideline recommendations.
METHODS: We calculated the predictive performance of the monitoring methods using a standard PopPK modeling and simulation approach. We thoroughly explored the prior PK models implemented in Bayesian programs.
RESULTS: Predictive performances of the monitoring methods were comparable at steady-state relative to the number of samples. Contrary to the recommendation, Bayesian trough monitoring did not result in better predictive performances compared to using random levels. Very few programs implemented richly-sampled priors.
CONCLUSIONS: All the monitoring methods can be, relatively, reliable at steady-state, if properly implemented. Although only Bayesian-based monitoring can be used pre-steady-state, its predictive performance can be modest. Trough-only monitoring is the simplest approach. Constraints regarding trough sampling times could be relaxed. The scarcity of richly-sampled Bayesian priors questions the applicability of the revised guidelines recommendation.

UNASSIGNED: The 2017 Infectious Diseases Society of America/Society for Healthcare Epidemiology of America (IDSA/SHEA) Clostridium (Clostridioides) difficile infection (CDI) guideline update recommended treatment with fidaxomicin or vancomycin for CDI. We aimed to examine outpatient CDI treatment utilization before and after the guideline update and compare clinical outcomes associated with fidaxomicin versus vancomycin use.
UNASSIGNED: A pre-post study design was employed using Medicare data. CDI treatment utilization and clinical outcomes (4- and 8-week sustained response, CDI recurrence) were compared between patients indexed from April-September 2017 (preguideline period) and those indexed from April-September 2018 (postguideline period). Clinical outcomes associated with fidaxomicin versus vancomycin were compared using propensity score-matched analyses.
UNASSIGNED: From the pre- to postguideline period, metronidazole use decreased (initial CDI: 81.2% to 53.5%; recurrent CDI: 49.7% to 27.6%) while vancomycin (initial CDI: 17.9% to 44.9%; recurrent CDI: 48.1% to 66.4%) and fidaxomicin (initial CDI: 0.87% to 1.63%; recurrent CDI: 2.2% to 6.0%) use increased significantly (P < .001 for all). However, clinical outcomes did not improve. In propensity score-matched analyses, fidaxomicin versus vancomycin users had 4-week sustained response rates that were higher by 13.5% (95% confidence interval [CI], 4.0%-22.9%; P = .0058) and 30.0% (95% CI, 16.8%-44.3%; P = .0002) in initial and recurrent CDI cohorts, respectively. Recurrence rates were numerically lower for fidaxomicin in both cohorts.
UNASSIGNED: Vancomycin use increased and metronidazole use decreased after the 2017 guideline update. Fidaxomicin use increased but remained low. Improved outcomes associated with fidaxomicin relative to vancomycin suggest benefits from its greater use in Medicare patients.