β-Lactam pharmacodynamics in Gram-negative bloodstream infections in the critically ill

Abstract Objectives To determine the β-lactam exposure associated with positive clinical outcomes for Gram-negative blood stream infection (BSI) in critically ill patients. Patients and methods Pooled data of critically ill patients with mono-microbial Gram-negative BSI treated with β-lactams were collected from two databases. Free minimum concentrations (fCmin) of aztreonam, cefepime, ceftazidime, ceftriaxone, piperacillin (co-administered with tazobactam) and meropenem were interpreted in relation to the measured MIC for targeted bacteria (fCmin/MIC). A positive clinical outcome was defined as completion of the treatment course or de-escalation, without other change of antibiotic therapy, and with no additional antibiotics commenced within 48 h of cessation. Drug exposure breakpoints associated with positive clinical outcome were determined by classification and regression tree (CART) analysis. Results Data from 98 patients were included. Meropenem (46.9%) and piperacillin/tazobactam (36.7%) were the most commonly prescribed antibiotics. The most common pathogens were Escherichia coli (28.6%), Pseudomonas aeruginosa (19.4%) and Klebsiella pneumoniae (13.3%). In all patients, 87.8% and 71.4% achieved fCmin/MIC ≥1 and fCmin/MIC >5, respectively. Seventy-eight patients (79.6%) achieved positive clinical outcome. Two drug exposure breakpoints were identified: fCmin/MIC >1.3 for all β-lactams (predicted difference in positive outcome 84.5% versus 15.5%, P < 0.05) and fCmin/MIC >4.95 for meropenem, aztreonam or ceftriaxone (predicted difference in positive outcome 97.7% versus 2.3%, P < 0.05). Conclusions A β-lactam fCmin/MIC >1.3 was a significant predictor of a positive clinical outcome in critically ill patients with Gram-negative BSI and could be considered an antibiotic dosing target.

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Nosocomial Bacteremia Caused by Antibiotic‐Resistant Gram‐Negative Bacteria in Critically Ill Patients: Clinical Outcome and Length of Hospitalization

Clinical Infectious Diseases ◽

10.1086/340616 ◽

2002 ◽

Vol 34 (12) ◽

pp. 1600-1606 ◽

Cited By ~ 132

Author(s):

Stijn Blot ◽

Koenraad Vandewoude ◽

Dirk De Bacquer ◽

Francis Colardyn

Keyword(s):

Clinical Outcome ◽

Critically Ill ◽

Critically Ill Patients ◽

Gram Negative Bacteria ◽

Antibiotic Resistant ◽

Gram Negative ◽

Nosocomial Bacteremia ◽

Length Of Hospitalization

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Defining Clinical Exposures of Cefepime for Gram-Negative Bloodstream Infections That Are Associated with Improved Survival

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01956-15 ◽

2015 ◽

Vol 60 (3) ◽

pp. 1401-1410 ◽

Cited By ~ 27

Author(s):

Nathaniel J. Rhodes ◽

Joseph L. Kuti ◽

David P. Nicolau ◽

Scott Van Wart ◽

Anthony M. Nicasio ◽

...

Keyword(s):

Regression Tree ◽

Bloodstream Infections ◽

Classification And Regression Tree ◽

Apache Ii Score ◽

Population Pharmacokinetic ◽

Model Parameters ◽

Gram Negative ◽

Cart Analysis ◽

Categorical Representation ◽

Drug Concentrations

The percentage of time that free drug concentrations remain above the MIC (fT>MIC) that is necessary to prevent mortality among cefepime-treated patients with Gram-negative bloodstream infections (GNBSI) is poorly defined. We conducted a retrospective study of adult patients with GNBSI. Eligible cases were frequency matched to ensure categorical representation from all MICs. Organism, MIC, infection source, gender, age, serum creatinine, weight, antibiotic history, and modified APACHE II score were collected from hospital records. Two population pharmacokinetic models (models 1 and 2) were used to impute exposures over the first 24 h in each patient from mean model parameters, covariates, and dosing history. From the imputed exposures, survival thresholds forfT>MICwere identified using classification and regression tree (CART) analysis and analyzed as nominal variables for univariate and multivariate regressions. A total of 180 patients were included in the analysis, of whom 13.9% died and 86.1% survived. Many patients (46.7% [n= 84/180]) received combination therapy with cefepime. Survivors had higher mean (standard deviation [SD])fT>MICthan those who died (model 1, 74.2% [29.6%] versus 52.1% [33.8%],P< 0.001; model 2, 85.9% [24.0%] versus 64.4% [31.4%],P< 0.001). CART identifiedfT>MICthreshold values for greater survival according to models 1 and 2 at >68% and >74%, respectively. Survival was improved for those withfT>MICof >68% (model 1 adjusted odds ratio [aOR], 7.12; 95% confidence interval [CI], 1.90 to 26.7;P= 0.004) and >74% (model 2 aOR, 6.48; 95% CI, 1.90 to 22.1) after controlling for clinical covariates. Similarly, each 1% increase in cefepimefT>MICresulted in a 2% improvement in multivariate survival probability (P= 0.015). Achieving a cefepimefT>MICof 68 to 74% was associated with a higher odds of survival for patients with GNBSI. Regimens targeting this exposure should be aggressively pursued.

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Development of Institutional Guidelines for Management of Gram-Negative Bloodstream Infections: Incorporating Local Evidence

Hospital Pharmacy ◽

10.1177/0018578717720506 ◽

2017 ◽

Vol 52 (10) ◽

pp. 691-697 ◽

Cited By ~ 9

Author(s):

Elizabeth B. Nimmich ◽

P. Brandon Bookstaver ◽

Joseph Kohn ◽

Julie Ann Justo ◽

Katie L. Hammer ◽

...

Keyword(s):

Health Care ◽

Critically Ill ◽

Antimicrobial Therapy ◽

Critically Ill Patients ◽

Severity Of Illness ◽

Bloodstream Infections ◽

Evidence Based ◽

Gram Negative ◽

Empirical Antimicrobial Therapy ◽

Hospital Acquired

Background: Appropriate empirical antimicrobial therapy is associated with improved outcomes of patients with Gram-negative bloodstream infections (BSI). Objective: Development of evidence-based institutional management guidelines for empirical antimicrobial therapy of Gram-negative BSI. Methods: Hospitalized adults with Gram-negative BSI in 2011-2012 at Palmetto Health hospitals in Columbia, SC, USA, were identified. Logistic regression was used to examine the association between site of infection acquisition and BSI due to Pseudomonas aeruginosa or chromosomally mediated AmpC-producing Enterobacteriaceae (CAE). Antimicrobial susceptibility rates of bloodstream isolates were stratified by site of acquisition and acute severity of illness. Retained antimicrobial regimens had predefined susceptibility rates ≥90% for noncritically ill and ≥95% for critically ill patients. Results: Among 390 patients, health care–associated (odds ratio [OR]: 3.0, 95% confidence interval [CI]: 1.5-6.3] and hospital-acquired sites of acquisition (OR: 3.7, 95% CI: 1.6-8.4) were identified as risk factors for BSI due to P aeruginosa or CAE, compared with community-acquired BSI (referent). Based on stratified bloodstream antibiogram, ceftriaxone met predefined susceptibility criteria for community-acquired BSI in noncritically ill patients (95%). Cefepime and piperacillin-tazobactam monotherapy achieved predefined susceptibility criteria in noncritically ill (95% both) and critically ill patients with health care–associated and hospital-acquired BSI (96% and 97%, respectively) and critically ill patients with community-acquired BSI (100% both). Conclusions: Incorporation of site of acquisition, local antimicrobial susceptibility rates, and acute severity of illness into institutional guidelines provides objective evidence-based approach for optimizing empirical antimicrobial therapy for Gram-negative BSI. The suggested methodology provides a framework for guideline development in other institutions.

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Impact of Maximizing Css/MIC Ratio on Efficacy of Continuous Infusion Meropenem Against Documented Gram-Negative Infections in Critically Ill Patients and Population Pharmacokinetic/Pharmacodynamic Analysis to Support Treatment Optimization

Frontiers in Pharmacology ◽

10.3389/fphar.2021.781892 ◽

2021 ◽

Vol 12 ◽

Author(s):

Pier Giorgio Cojutti ◽

Milo Gatti ◽

Matteo Rinaldi ◽

Tommaso Tonetti ◽

Cristiana Laici ◽

...

Keyword(s):

Renal Function ◽

Critically Ill ◽

Critically Ill Patients ◽

Population Pharmacokinetic ◽

Treatment Optimization ◽

Gram Negative ◽

Cart Analysis ◽

Pharmacodynamic Analysis ◽

Favorable Clinical Outcome ◽

Support Treatment

Introduction: optimal treatment of Gram-negative infections in critically ill patients is challenged by changing pathophysiological conditions, reduced antimicrobial susceptibility and limited therapeutic options. The aim of this study was to assess the impact of maximizing Css/MIC ratio on efficacy of continuous infusion (CI) meropenem in treating documented Gram-negative infections in critically ill patients and to perform a population pharmacokinetic/pharmacodynamic analysis to support treatment optimization.Materials and Methods: Classification and regression tree (CART) analysis was used to identify whether a cutoff of steady-state meropenem concentration (Css)-to-minimum inhibitory concentration (MIC) (Css/MIC) ratio correlated with favorable clinical outcome. A non-parametric approach with Pmetrics was used for pharmacokinetic analysis and covariate evaluation. The probability of target attainment (PTA) of the identified Css/MIC ratio was calculated by means of Monte Carlo simulations. Cumulative fraction of response (CFRs) were calculated against common Enterobacterales, P. aeruginosa and A. baumannii as well.Results: a total of 74 patients with 183 meropenem Css were included. CART analysis identified a Css/MIC ratio ≥4.63 as cutoff value significantly associated with favorable clinical outcomes. Multivariate regression analysis confirmed the association [OR (95%CI): 20.440 (2.063–202.522); p < 0.01]. Creatinine clearance (CLCR) was the only covariate associated with meropenem clearance. Monte Carlo simulations showed that, across different classes of renal function, dosages of meropenem ranging between 0.5 and 2 g q6h over 6 h (namely by CI) may grant PTAs of Css/MIC ratios ≥4.63 against susceptible pathogens with an MIC up to the EUCAST clinical breakpoint of 2 mg/L. The CFRs achievable with these dosages were very high (>90%) against Enterobacterales across all the classes of renal function and against P. aeruginosa among patients with CLCR < 30 ml/min/1.73 m2, and quite lower against A. baumannii.Discussion: our findings suggest that Css/MIC ratio ≥4.63 may be considered the pharmacodynamic target useful at maximizing the efficacy of CI meropenem in the treatment of Gram-negative infections in critically ill patients. Dosages ranging between 0.5 g q6h and 2 g q6h by CI may maximize the probability of favorable clinical outcome against meropenem-susceptible Gram-negative pathogens among critically ill patients having different degrees of renal function.

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Are Follow-Up Blood Cultures Useful in the Antimicrobial Management of Gram Negative Bacteremia? A Reappraisal of Their Role Based on Current Knowledge

Antibiotics ◽

10.3390/antibiotics9120895 ◽

2020 ◽

Vol 9 (12) ◽

pp. 895

Author(s):

Francesco Cogliati Dezza ◽

Ambrogio Curtolo ◽

Lorenzo Volpicelli ◽

Giancarlo Ceccarelli ◽

Alessandra Oliva ◽

...

Keyword(s):

Critically Ill ◽

Critically Ill Patients ◽

Current Knowledge ◽

Bloodstream Infections ◽

Blood Cultures ◽

Source Control ◽

Candida Spp ◽

Gram Negative ◽

Gram Negative Bacteremia

Bloodstream infections still constitute an outstanding cause of in-hospital morbidity and mortality, especially among critically ill patients. Follow up blood cultures (FUBCs) are widely recommended for proper management of Staphylococcus aureus and Candida spp. infections. On the other hand, their role is still a matter of controversy as far as Gram negative bacteremias are concerned. We revised, analyzed, and commented on the literature addressing this issue, to define the clinical settings in which the application of FUBCs could better reveal its value. The results of this review show that critically ill patients, endovascular and/or non-eradicable source of infection, isolation of a multi-drug resistant pathogen, end-stage renal disease, and immunodeficiencies are some factors that may predispose patients to persistent Gram negative bacteremia. An analysis of the different burdens that each of these factors have in this clinical setting allowed us to suggest which patients’ FUBCs have the potential to modify treatment choices, prompt an early source control, and finally, improve clinical outcome.

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Evaluation of Clinical Outcomes in Patients with Bloodstream Infections Due to Gram-Negative Bacteria According to Carbapenem MIC Stratification

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.06365-11 ◽

2012 ◽

Vol 56 (9) ◽

pp. 4885-4890 ◽

Cited By ~ 55

Author(s):

John S. Esterly ◽

Jamie Wagner ◽

Milena M. McLaughlin ◽

Michael J. Postelnick ◽

Chao Qi ◽

...

Keyword(s):

Clinical Success ◽

Bloodstream Infections ◽

Primary Objective ◽

Classification And Regression Tree ◽

Gram Negative Bacteria ◽

Gram Negative ◽

Content Type ◽

Extended Spectrum Beta Lactamase ◽

Clinical Patient ◽

Cart Analysis

ABSTRACTPredictive modeling suggests that actual carbapenem MIC results are more predictive of clinical patient outcomes than categorical classification of the MIC as susceptible, intermediate, or resistant. Some have speculated that current CLSI guidelines' suggested thresholds are too high and that clinical success is more likely if the MIC value is ≤1 mg/liter for certain organisms. Patients treated with carbapenems and with positive blood cultures forPseudomonas aeruginosa,Acinetobacter baumannii, or extended-spectrum beta-lactamase (ESBL)-producing Gram-negative bacteria were considered for evaluation in this clinical retrospective cohort study. Relevant patient demographics and microbiologic variables were collected, including carbapenem MIC. The primary objective was to define a risk-adjusted all-cause hospital mortality breakpoint for carbapenem MICs. Secondarily, we sought to determine if a similar breakpoint existed for indirect outcomes (e.g., time to mortality and length of stay [LOS] postinfection for survivors). Seventy-one patients met the criteria for study inclusion. Overall, 52 patients survived, and 19 died. Classification and regression tree (CART) analysis determined a split of organism MIC between 2 and 4 mg/liter and predicted differences in mortality (16.1% versus 76.9%;P< 0.01). Logistic regression controlling for confounders identified each imipenem MIC doubling dilution as increasing the probability of death 2-fold (adjusted odds ratio [aOR] 2.0; 95% confidence interval [CI], 1.3 to 3.2). Secondary outcomes were similar between groups. This study revealed that patients with organisms that had a MIC of ≥4 mg/liter had worse outcomes than patients whose isolates had a MIC of ≤2 mg/liter, even after adjustment for confounding variables. We recommend additional clinical studies to better understand the susceptibility breakpoint for carbapenems.

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The diagnostic ability of procalcitonin to differentiate Gram-negative bacteria from Gram-positive bacteria and fungal bloodstream infections in critically ill patients

European Journal of Inflammation ◽

10.1177/2058739219841469 ◽

2019 ◽

Vol 17 ◽

pp. 205873921984146

Author(s):

Di Wang ◽

Xiaogen Tao ◽

Wei Guo ◽

Haihua Liu ◽

Shaohui Cheng ◽

...

Keyword(s):

Critically Ill ◽

Critically Ill Patients ◽

Operating Characteristic ◽

Bloodstream Infections ◽

Gram Negative Bacteria ◽

Diagnostic Ability ◽

Gram Positive ◽

Gram Negative ◽

Receiver Operating Characteristic Curves ◽

Gram Positive Bacteria

Bloodstream infection (BSI) is a severe infectious complication in critically ill patients. This study was aimed to investigate the diagnostic accuracy of procalcitonin (PCT) to differentiate Gram-negative bacteria (Gram-neg) from Gram-positive bacteria (Gram-pos) and fungal BSI. PCT and other inflammation markers of monomicrobial BSI patients were retrospectively collected and compared between patients with Gram-neg, Gram-pos, or fungal BSI. The differential diagnosis performance of PCT was evaluated by receiver operating characteristic curves (ROC). The area under curve (AUC) of PCT for differentiating Gram-neg BSI from Gram-pos BSI was 0.95 with an optimal cut-off value of 4.15 ng/mL, a sensitivity of 82.05%, and a specificity of 96.15%. AUC of PCT for differentiating Gram-neg BSI from fungal BSI was 0.92 with an optimal cut-off value of 3.13 ng/mL, a sensitivity of 84.62%, and a specificity of 88.89%. Serum PCT concentration can be used to differentiate Gram-neg from Gram-pos and fungal BSI.

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1316. Pharmacokinetic/Pharmacodynamic Analyses of Cefiderocol in Critically Ill Patients

Open Forum Infectious Diseases ◽

10.1093/ofid/ofaa439.1498 ◽

2020 ◽

Vol 7 (Supplement_1) ◽

pp. S669-S670

Author(s):

Takayuki Katsube ◽

Nao Kawaguchi ◽

Yuko Matsunaga ◽

Mari Ariyasu ◽

Tsutae Den Nagata ◽

...

Keyword(s):

Critically Ill ◽

Critically Ill Patients ◽

Clinical Cure ◽

Drug Exposure ◽

Survival Rates ◽

Panel Member ◽

Research Support ◽

Review Panel ◽

Gram Negative ◽

Wide Range

Abstract Background Cefiderocol (CFDC), a novel siderophore cephalosporin, has demonstrated potent antibacterial activity against a wide range of Gram-negative bacteria including carbapenem-resistant strains. We aimed to evaluate relationships between drug exposure and outcomes in critically ill patients. Methods Sparse pharmacokinetic (PK) samples at steady state from critically ill patients with pneumonia, bloodstream infection/sepsis, or complicated urinary tract infection receiving CFDC in two Phase 3 studies were analyzed. Percent time of dosing interval of free drug concentration exceeding the minimum inhibitory concentration (MIC) in plasma and epithelial lining fluid (ELF) (%fT>MIC and %fT>MIC,ELF, respectively) were determined for 60 (CREDIBLE-CR; NCT02714595) and 97 patients (APEKS-NP; NCT03032380), using a 3-compartment population PK model. The %fT>MIC,ELF was calculated for 125 pneumonia patients based on an intrapulmonary PK model. Relationships between %fT>MIC, %fT>MIC,ELF and clinical and microbiological outcomes at test of cure (TOC), or mortality at Day 28 were assessed. Results The median (90th percentile) MICs of Gram-negative pathogens in the PK/pharmacodynamic (PD) analyses were 0.25 (4) µg/mL (CREDIBLE-CR) and 0.25 (2) µg/mL (APEKS-NP), respectively. Individual plasma %fT>MIC was 100% in ≥95% of patients in each study, and estimated %fT>MIC,ELF was 100% in 89.3% (25/28 pneumonia patients; CREDIBLE-CR) and 97.9% (95/97 pneumonia patients; APEKS-NP). Clinical cure rates and survival rates in patients with 100% fT>MIC or %fT>MIC,ELF were similar between the two studies (Table). No PK/PD relationships between %fT>MIC, %fT>MIC,ELF and clinical cure, microbiological eradication, or survival were identified in either study because high %fT>MIC or %fT>MIC,ELF was achieved in all patients. Table. Clinical cure and survival rates in patients with 100% fT>MIC or %fT>MIC,ELF in CREDIBLE-CR and APEKS-NP studies Conclusion PK/PD relationship was not identified between CFDC plasma or ELF exposure and clinical or microbiological outcomes, or mortality as high %fT>MIC and %fT>MIC,ELF were achieved, suggesting the recommended dosing regimen of 2 g q8h or renally adjusted dosage (including augmented renal clearance), infused over 3 hours, provides sufficient exposure to CFDC in critically ill patients. Disclosures Takayuki Katsube, PhD, Shionogi & Co., Ltd. (Employee) Nao Kawaguchi, BPharm, Shionogi & Co., Ltd. (Employee) Yuko Matsunaga, MD, Shionogi Inc. (Employee) Mari Ariyasu, BPharm, Shionogi & Co., Ltd. (Employee) Tsutae Den Nagata, MD, Shionogi & Co., Ltd. (Employee) Simon Portsmouth, MD, Shionogi Inc. (Employee) David Paterson, Accelerate (Speaker’s Bureau)BioMerieux (Speaker’s Bureau)BioMerieux (Advisor or Review Panel member)Entasis (Advisor or Review Panel member)Merck (Advisor or Review Panel member)Merck (Grant/Research Support)Merck (Speaker’s Bureau)Pfizer (Speaker’s Bureau)Shionogi & Co., Ltd. (Grant/Research Support)VenatoRx (Advisor or Review Panel member) Michael J. Satlin, MD, MS, Achaogen (Consultant)Allergan (Grant/Research Support)Merck (Grant/Research Support)Shionogi Inc. (Consultant) Roger Echols, MD, Shionogi Inc. (Consultant) Toshihiro Wajima, PhD, Shionogi & Co., Ltd. (Employee)

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