Beta-lactam target attainment and associated outcomes in patients with bloodstream infections

Al‐Shaer, Mohammad H.; Maranchick, Nicole; Alexander, Kaitlin M.; Manigaba, Kayihura; Shoulders, Bethany; Felton, Timothy; Mathew, Sumith K; Peloquin, Charles A.

doi:10.1016/j.ijantimicag.2023.106727

Cited by 19 publications

(25 citation statements)

References 25 publications

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“…This is consistent with what was previously observed with both traditional and novel beta-lactams in critically ill adult patients. 14,15,[30][31][32][33][34] The need for a TDM-based approach is also supported by the fact that PICU patients may frequently have major pathophysiologic alterations that may affect the PK behavior of beta-lactams. 7 Occurrence of ARC or transient acute kidney injury, vasopressors requirement, use of loop diuretics and negative fluid balance may be key determinants in affecting beta-lactam exposure.…”

Section: Discussionmentioning

confidence: 99%

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Relationship Between Real-time TDM-guided Pharmacodynamic Target Attainment of Continuous Infusion Beta-lactam Monotherapy and Microbiologic Outcome in the Treatment of Critically Ill Children With Severe Documented Gram-negative Infections

Gatti,

Campoli,

Latrofa

et al. 2023

Pediatric Infectious Disease Journal

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Objectives: To explore the relationship between real-time therapeutic drug monitoring (TDM)-guided pharmacodynamic target attainment of continuous infusion (CI) beta-lactam monotherapy and microbiological outcome in the treatment of critically ill children with severe documented Gram-negative infections. Methods: Observational, monocentric, retrospective study of critically ill patients receiving CI piperacillin-tazobactam, ceftazidime, or meropenem in monotherapy for documented Gram-negative infections optimized by means of a real-time TDM-guided strategy. Average steady-state beta-lactam concentrations (Css) were calculated for each patient, and the beta-lactam Css/minimum inhibitory concentration (MIC) ratio was selected as a pharmacodynamic parameter of efficacy. The Css/MIC ratio was defined as optimal if ≥4, quasi-optimal if between 1 and 4, and suboptimal if <1. The relationship between Css/MIC and microbiological outcome was assessed. Results: Forty-six TDM assessments were carried out in 21 patients [median age 2 (interquartile range: 1–8) years]. Css/MIC ratios were optimal in 76.2% of cases. Patients with optimal Css/MIC ratios had both a significantly higher microbiological eradication rate (75.0% vs. 0.0%; P = 0.006) and lower resistance development rate (25.0% vs. 80.0%; P = 0.047) than those with quasi-optimal or suboptimal Css/MIC ratios. Quasi-optimal/suboptimal Css/MIC ratio occurred more frequently when patients had infections caused by pathogens with MIC values above the European Committee on Antimicrobial Susceptibility Testing clinical breakpoint (100.0% vs. 6.3%; P < 0.001). Conclusions: Real-time TDM-guided pharmacodynamic target attainment of CI beta-lactam monotherapy allowed to maximize treatment efficacy in most critically ill children with severe Gram-negative infections. Attaining early optimal Css/MIC ratios of CI beta-lactams could be a key determinant associated with microbiological eradication during the treatment of Gram-negative infections. Larger prospective studies are warranted for confirming our findings.

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Section: Discussionmentioning

confidence: 99%

“…This is consistent with what was previously observed with both traditional and novel beta-lactams in critically ill adult patients. 14,15,30–34…”

Section: Discussionmentioning

confidence: 99%

Relationship Between Real-time TDM-guided Pharmacodynamic Target Attainment of Continuous Infusion Beta-lactam Monotherapy and Microbiologic Outcome in the Treatment of Critically Ill Children With Severe Documented Gram-negative Infections

Gatti,

Campoli,

Latrofa

et al. 2023

Pediatric Infectious Disease Journal

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“…19 Previous non-parametric TTE analyses in retrospective studies found that patients who achieved 100% fT >MIC (patients in the ICU) or 100% fT >4×MIC (patients with bloodstream infections) had a shorter time to discharge from ICU or negative blood culture compared with those who did not. 21,22 Similarly, a recent study compared the survival outcome for different dosing groups leading to different PK/PD targets (40% fT >MIC , 100% fT >MIC , and 100%fT >4×MIC ) in a sepsis rat model. 23 Pronounced survival prolongation was observed in the treatment groups attaining 100% fT >MIC and 100% fT >4×MIC compared to the group attaining 40% fT >MIC , although the differences were not statistically significant due to the limited sample size (12 rats per group).…”

Section: How Might This Change Drug Discovery Development And/or Ther...mentioning

confidence: 99%

“…Previous non‐parametric TTE analyses in retrospective studies found that patients who achieved 100% f T >MIC (patients in the ICU) or 100% f T >4×MIC (patients with bloodstream infections) had a shorter time to discharge from ICU or negative blood culture compared with those who did not 21,22 . Similarly, a recent study compared the survival outcome for different dosing groups leading to different PK/PD targets (40% f T >MIC , 100% f T >MIC , and 100% f T >4×MIC ) in a sepsis rat model 23 .…”

Section: Introductionmentioning

confidence: 99%

Multistate modeling for survival analysis in critically ill patients treated with meropenem

Peng,

Minichmayr,

Liu

et al. 2023

CPT Pharmacom & Syst Pharma

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Appropriate antibiotic dosing to ensure early and sufficient target attainment is crucial for improving clinical outcome in critically ill patients. Parametric survival analysis is a preferred modeling method to quantify time‐varying antibiotic exposure ‐ response effects, whereas bias may be introduced in hazard functions and survival functions when competing events occur. This study investigated predictors of in‐hospital mortality in critically ill patients treated with meropenem by pharmacometric multistate modeling. A multistate model comprising five states (ongoing meropenem treatment, other antibiotic treatment, antibiotic treatment termination, discharge, and death) was developed to capture the transitions in a cohort of 577 critically ill patients treated with meropenem. Various factors were investigated as potential predictors of the transitions, including patient demographics, CLCRCG (creatinine clearance calculated by Cockcroft–Gault equation), fT>MIC (time that unbound concentrations exceed the minimum inhibitory concentration), and microbiology‐related measures. The probabilities to transit to other states from ongoing meropenem treatment increased over time. A 10 mL/min decrease in CLCRCG was found to elevate the hazard of transitioning from states of ongoing meropenem treatment and antibiotic treatment termination to the death state by 18%. The attainment of 100% fT>MIC significantly increased the transition rate from ongoing meropenem treatment to antibiotic treatment termination (by 9.7%), and was associated with improved survival outcome. The multistate model prospectively assessed predictors of death and can serve as a useful tool for survival analysis in different infection scenarios, particularly when competing risks are present.

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“…Several clinical studies showed that attaining an aggressive pharmacokinetic/ pharmacodynamic (PK/PD) target of 100%f T >4-8 × MIC with continuous infusion (CI) betalactams among critically ill patients was associated with both the maximization of clinical efficacy and the suppression of resistance development [13][14][15][16][17][18][19][20]. Failure in early attainment of this aggressive PK/PD target of piperacillin-tazobactam was shown to be as high as 80% during intermittent or extended infusion administration [21], and around 5-28% during CI administration [22][23][24][25][26].…”

Section: Introductionmentioning

confidence: 99%

Could an Optimized Joint Pharmacokinetic/Pharmacodynamic Target Attainment of Continuous Infusion Piperacillin-Tazobactam Be a Valuable Innovative Approach for Maximizing the Effectiveness of Monotherapy Even in the Treatment of Critically Ill Patients with Documented Extended-Spectrum Beta-Lactamase-Producing Enterobacterales Bloodstream Infections and/or Ventilator-Associated Pneumonia?

Gatti,

Rinaldi,

Tonetti

et al. 2023

Antibiotics

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(1) Background: Piperacillin-tazobactam represents the first-line option for treating infections caused by full- or multi-susceptible Enterobacterales and/or Pseudomonas aeruginosa in critically ill patients. Several studies reported that attaining aggressive pharmacokinetic/pharmacodynamic (PK/PD) targets with beta-lactams is associated with an improved microbiological/clinical outcome. We aimed to assess the relationship between the joint PK/PD target attainment of continuous infusion (CI) piperacillin-tazobactam and the microbiological/clinical outcome of documented Gram-negative bloodstream infections (BSI) and/or ventilator-associated pneumonia (VAP) of critically ill patients treated with CI piperacillin-tazobactam monotherapy. (2) Methods: Critically ill patients admitted to the general and post-transplant intensive care unit in the period July 2021–September 2023 treated with CI piperacillin-tazobactam monotherapy optimized by means of a real-time therapeutic drug monitoring (TDM)-guided expert clinical pharmacological advice (ECPA) program for documented Gram-negative BSIs and/or VAP were retrospectively retrieved. Steady-state plasma concentrations (Css) of piperacillin and of tazobactam were measured, and the free fractions (f) were calculated according to respective plasma protein binding. The joint PK/PD target was defined as optimal whenever both the piperacillin fCss/MIC ratio was >4 and the tazobactam fCss/target concentration (CT) ratio was > 1 (quasi-optimal or suboptimal whenever only one or none of the two weas achieved, respectively). Multivariate logistic regression analysis was performed for testing variables potentially associated with microbiological outcome. (3) Results: Overall, 43 critically ill patients (median age 69 years; male 58.1%; median SOFA score at baseline 8) treated with CI piperacillin-tazobactam monotherapy were included. Optimal joint PK/PD target was attained in 36 cases (83.7%). At multivariate analysis, optimal attaining of joint PK/PD target was protective against microbiological failure (OR 0.03; 95%CI 0.003–0.27; p = 0.002), whereas quasi-optimal/suboptimal emerged as the only independent predictor of microbiological failure (OR 37.2; 95%CI 3.66–377.86; p = 0.002). (4) Conclusion: Optimized joint PK/PD target attainment of CI piperacillin-tazobactam could represent a valuable strategy for maximizing microbiological outcome in critically ill patients with documented Gram-negative BSI and/or VAP, even when sustained by extended-spectrum beta-lactamase (ESBL)-producing Enterobacterales. In this scenario, implementing a real-time TDM-guided ECPA program may be helpful in preventing failure in attaining optimal joint PK/PD targets among critically ill patients. Larger prospective studies are warranted to confirm our findings.

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Beta-lactam target attainment and associated outcomes in patients with bloodstream infections

Cited by 19 publications

References 25 publications

Relationship Between Real-time TDM-guided Pharmacodynamic Target Attainment of Continuous Infusion Beta-lactam Monotherapy and Microbiologic Outcome in the Treatment of Critically Ill Children With Severe Documented Gram-negative Infections

Relationship Between Real-time TDM-guided Pharmacodynamic Target Attainment of Continuous Infusion Beta-lactam Monotherapy and Microbiologic Outcome in the Treatment of Critically Ill Children With Severe Documented Gram-negative Infections

Multistate modeling for survival analysis in critically ill patients treated with meropenem

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