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Original Research |

Subtherapeutic Initial β-Lactam Concentrations in Select Critically Ill PatientsCreatinine Clearance and 03B2-Lactams: Association Between Augmented Renal Clearance and Low Trough Drug Concentrations

Andrew A. Udy, MBChB; Julie M. Varghese, BPharm (Hons); Mahdi Altukroni, MD; Scott Briscoe, MSc; Brett C. McWhinney, MPhil; Jacobus P. Ungerer, MBChB; Jeffrey Lipman, MD; Jason A. Roberts, PhD; Beginning and Ending Supportive Therapy for the Kidney (BEST Kidney) Investigators
Author and Funding Information

From the Department of Intensive Care Medicine (Drs Udy, Altukroni, Lipman, and Roberts and Ms Varghese), the Pharmacy Department (Ms Varghese and Dr Roberts), and the Department of Chemical Pathology, Pathology Queensland (Messrs Briscoe and McWhinney and Dr Ungerer), Royal Brisbane and Women’s Hospital; and the Burns, Trauma, and Critical Care Research Center (Drs Udy, Lipman, and Roberts and Ms Varghese), University of Queensland, Herston, Brisbane, QLD, Australia.

Correspondence to: Jason A. Roberts, PhD, Burns, Trauma, Critical Care Research Center, University of Queensland, Level 3 Ned Hanlon Building, Royal Brisbane and Women’s Hospital, Brisbane, QLD, 4029, Australia; e-mail: j.roberts2@uq.edu.au

Financial/nonfinancial disclosures: The authors have reported to CHEST the following conflicts of interest: Dr Lipman is a consultant to AstraZeneca and Janssen-Cilag and has received honoraria from AstraZeneca, Janssen-Cilag, and Wyeth Australia. AstraZeneca provides an annual donation to the Burns, Trauma, and Critical Care Research Center. Drs Udy, Altukroni, Ungerer, and Roberts, Ms Varghese, and Messrs Briscoe and McWhinney have reported that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Role of sponsors: The sponsor had no role in the design of the study, the collection and analysis of the data, or in the preparation of the manuscript.

Funding/Support: Dr Roberts is supported in part by the Australian National Health and Medical Research Council [Australian Based Health Professional Research Fellowship 569917].


For editorial comment see page 8

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.

Funding/Support: Dr Roberts is supported in part by the Australian National Health and Medical Research Council [Australian Based Health Professional Research Fellowship 569917].


Chest. 2012;142(1):30-39. doi:10.1378/chest.11-1671
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Background:  β-Lactams are routinely used as empirical therapy in critical illness, with extended concentrations above the minimum inhibitory concentration (MIC) of the infecting organism required for effective treatment. Changes in renal function in this setting can significantly impact the probability of achieving such targets.

Methods:  Analysis was made of trough plasma drug concentrations obtained via therapeutic drug monitoring, compared with renal function, in critically ill patients receiving empirical β-lactam therapy. Drug concentrations were measured by means of high-performance liquid chromatography and corrected for protein binding. Therapeutic levels were defined as greater than or equal to MIC and greater than or equal to four times MIC (maximum bacterial eradication), respectively. Renal function was assessed by means of an 8-h creatinine clearance (CLCR).

Results:  Fifty-two concurrent trough concentrations and CLCR measures were used in analysis. Piperacillin was the most frequent β-lactam prescribed (48%), whereas empirical cover and Staphylococcus species were the most common indications for therapy (62%). Most patients were mechanically ventilated on the day of study (85%), although only 25% were receiving vasopressors. In only 58% (n = 30) was the trough drug concentration greater than or equal to MIC, falling to 31% (n = 16) when using four times MIC as the target. CLCR values ≥ 130 mL/min/1.73 m2 were associated with trough concentrations less than MIC in 82% (P < .001) and less than four times MIC in 72% (P < .001). CLCR remained a significant predictor of subtherapeutic concentrations in multivariate analysis.

Conclusion:  Elevated CLCR appears to be an important predictor of subtherapeutic β-lactam concentrations and suggests an important role in identifying such patients in the ICU.

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