Time Above all Else: Pharmacodynamic Analysis of β‐Lactams in Critically Ill Patients

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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Time Above All Else: Pharmacodynamic Analysis of Β-Lactams in Critically Ill Patients

Antimicrobial Stewardship & Healthcare Epidemiology ◽

10.1017/ash.2021.135 ◽

2021 ◽

Vol 1 (S1) ◽

pp. s70-s70

Author(s):

Katherine Landmesser ◽

David Burgess ◽

Justin Clark

Keyword(s):

Critically Ill ◽

Critically Ill Patients ◽

Intermittent Infusion ◽

Healthcare Setting ◽

Negative Resistance ◽

Distribution Data ◽

Parameter Estimates ◽

Gram Negative ◽

Development Of Resistance ◽

Pharmacodynamic Analysis

Background: Despite the development of new β-lactam agents, gram-negative resistance continues to be an increasing concern in the healthcare setting. The understanding and optimizing antimicrobial pharmacokinetics and pharmacodynamics are essential to enhance activity of appropriate therapy, improve clinical outcomes, and reduce the development of resistance. Methods: A pharmacodynamic analysis was performed for 4 β-lactams (aztreonam, cefepime, piperacillin/tazobactam, and meropenem) and 14 dosage regimens as either intermittent bolus (IB) or prolonged infusion (PI) against 7 gram-negative pathogens: Klebsiella pneumoniae, K. oxytoca, Escherichia coli, Enterobacter cloacae, E. aerogenes, Acinetobacter baumannii, and Pseudomonas aeruginosa. Unit-specific minimum inhibitory concentration (MIC) distribution data were generated using antibiogram data over a decade for 4 intensive care units within our institution: medical ICU, cardiovascular ICU, surgical ICU, and neurosurgical ICU. Published pharmacokinetic parameter estimates in critically ill patients, combined with this MIC distribution data, were utilized to perform Monte Carlo simulations for each antimicrobial regimen. The percentage of time for which the unbound concentration of antibiotic remained above the MIC (ƒT>MIC) was utilized as the pharmacodynamic target for each agent: 40% ƒT>MIC for meropenem, 50% ƒT>MIC for piperacillin/tazobactam, 60% ƒT>MIC for aztreonam, and 70% ƒT>MIC for cefepime. Regimens were modeled using Oracle Crystal Ball software to determine the likelihood of achieving >90% probability of target attainment (PTA). Because resistance rates were significantly higher for P. aeruginosa and A. baumannii, cumulative PTAs for K. pneumoniae, K. oxytoca, E. coli, E. cloacae, and E. aerogenes were analyzed separately to determine the relative PTA for Enterobacterales in each ICU. Results: No intermittent infusion regimens of piperacillin/tazobactam, aztreonam, or cefepime achieved >90% PTA for any organism. Piperacillin/tazobactam 4.5 g infused over 4 hours (PI q6h) and aztreonam 2 g PI q6h failed to achieve adequate PTA for Enterobacterales with only 84% and 85% PTA, respectively. For Enterobacterales, the only regimens to achieve >90% PTA included cefepime 2 g infused over 3 hours (PI q8h) and meropenem 1g IB q8h with 95% and 99% PTA, respectively. Meropenem 2 g PI q8h was the only regimen capable of achieving >90% PTA for both A. baumannii and P. aeruginosa with 97% and 92% PTA, respectively. Conclusions: Although utilization of high doses and prolonged infusions dramatically improve the pharmacodynamics of β-lactam therapy, the only regimen capable of achieving adequate PTA for all organisms analyzed was meropenem 2g PI q8h. To reduce carbapenem use, combination therapy may be considered for critically ill patients receiving aztreonam, cefepime, or piperacillin/tazobactam for empiric treatment of gram-negative infections.Funding: NoDisclosures: None

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