Pharmacokinetics/Pharmacodynamics of β-Lactams and Therapeutic Drug Monitoring: From Theory to Practical Issues in the Intensive Care Unit

Paul Williams; Menino Osbert Cotta; Jason A. Roberts

doi:10.1055/s-0039-1693498

Seminars in Respiratory and Critical Care Medicine, Inhaltsverzeichnis

Semin Respir Crit Care Med 2019; 40(04): 476-487
DOI: 10.1055/s-0039-1693498

Review Article

Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Pharmacokinetics/Pharmacodynamics of β-Lactams and Therapeutic Drug Monitoring: From Theory to Practical Issues in the Intensive Care Unit

Autor*innen

Paul Williams

¹University of Queensland Centre for Clinical Research, Faculty of Medicine, Royal Brisbane and Women's Hospital, The University of Queensland, Brisbane, Queensland, Australia

²Pharmacy Department, Sunshine Coast University Hospital, Birtinya, Queensland, Australia
Menino Osbert Cotta

¹University of Queensland Centre for Clinical Research, Faculty of Medicine, Royal Brisbane and Women's Hospital, The University of Queensland, Brisbane, Queensland, Australia

³School of Pharmacy, Centre for Translational Anti-Infective Pharmacodynamics, The University of Queensland, Brisbane, Queensland, Australia
Jason A. Roberts

¹University of Queensland Centre for Clinical Research, Faculty of Medicine, Royal Brisbane and Women's Hospital, The University of Queensland, Brisbane, Queensland, Australia

³School of Pharmacy, Centre for Translational Anti-Infective Pharmacodynamics, The University of Queensland, Brisbane, Queensland, Australia

⁴Department of Intensive Care Medicine, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia

⁵Pharmacy Department, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia

⁶Division of Anaesthesiology Critical Care Emergency and Pain Medicine, Nîmes University Hospital, University of Montpellier, Nîmes, France

Abstract

Despite therapeutic advances over recent decades, the mortality rate for sepsis and septic shock is still approximately 25% worldwide. Early administration of appropriate intravenous antibiotics in the right dose is one of the cornerstones of treatment of sepsis. β-Lactam antibiotics are the most commonly prescribed in critically ill patients, and dosages that do not achieve specific pharmacokinetic/pharmacodynamic targets may increase the likelihood of treatment failure and even emergence of antibiotic resistance. Fluctuations in physiological parameters are often observed in critically ill patients, leading to altered pharmacokinetics and increased risk of suboptimal exposures, especially if standard dosing according to the product information is prescribed. Contemporary evidence illustrates that therapeutic β-lactam concentrations are inconsistently achieved at steady state. This review will investigate alternative β-lactam dose optimization strategies including prolonged infusions, guideline-based dosing, therapeutic drug monitoring (TDM), and the use of dose optimization software, all of which aim to increase the likelihood of achieving therapeutic drug concentrations and improve clinical outcomes as compared with the standard dosing approach. These dose optimization strategies have been the subject of a growing body of evidence; however, further investigation into the outcome benefits and validity of both non-TDM and TDM dosing strategies is required. For the clinician, it is important to select a feasible dosing strategy tailored for the individual patient, which will maximize the likelihood of achieving therapeutic concentrations at steady state and maintain these exposures throughout the course of therapy.

Keywords

β-lactam - pharmacokinetics - pharmacodynamics - critically ill - guideline - therapeutic drug monitoring - dose optimization software

Volltext

Referenzen

References
1 Dellinger RP, Levy MM, Rhodes A. , et al; Surviving Sepsis Campaign Guidelines Committee including the Pediatric Subgroup. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med 2013; 41 (02) 580-637
2 Levy MM, Evans LE, Rhodes A. The Surviving Sepsis Campaign Bundle: 2018 update. Intensive Care Med 2018; 44 (06) 925-928
3 Roberts JA, Abdul-Aziz MH, Davis JS. , et al. Continuous versus intermittent β-lactam infusion in severe sepsis: A meta-analysis of individual patient data from randomized trials. Am J Respir Crit Care Med 2016; 194 (06) 681-691
4 Tsai D, Lipman J, Roberts JA. Pharmacokinetic/pharmacodynamic considerations for the optimization of antimicrobial delivery in the critically ill. Curr Opin Crit Care 2015; 21 (05) 412-420
5 Roberts JA. Using PK/PD to optimize antibiotic dosing for critically ill patients. Curr Pharm Biotechnol 2011; 12 (12) 2070-2079
6 Dulhunty JM, Roberts JA, Davis JS. , et al; BLING II Investigators for the ANZICS Clinical Trials Group*. A multicenter randomized trial of continuous versus intermittent β-lactam infusion in severe sepsis. Am J Respir Crit Care Med 2015; 192 (11) 1298-1305
7 World Health Organization. Global Action Plan on Antimicrobial Resistance. https://www.who.int/antimicrobial-resistance/global-action-plan/en/ . Accessed 8th April 2019
8 Tam VH, Schilling AN, Neshat S, Poole K, Melnick DA, Coyle EA. Optimization of meropenem minimum concentration/MIC ratio to suppress in vitro resistance of Pseudomonas aeruginosa . Antimicrob Agents Chemother 2005; 49 (12) 4920-4927
9 Roberts JA, Kruger P, Paterson DL, Lipman J. Antibiotic resistance--what's dosing got to do with it?. Crit Care Med 2008; 36 (08) 2433-2440
10 Roberts JA, Lipman J. Optimizing use of beta-lactam antibiotics in the critically ill. Semin Respir Crit Care Med 2007; 28 (06) 579-585
11 Worthington RJ, Melander C. Overcoming resistance to β-lactam antibiotics. J Org Chem 2013; 78 (09) 4207-4213
12 Fernandes R, Amador P, Prudêncio C. β-Lactams: chemical structure, mode of action and mechanisms of resistance. Rev Med Microbiol 2013; 24: 7-17
13 Wanger A, Chavez V, Huang RSP, Wahed A, Actor JK, Dasgupta A. Antibiotics, antimicrobial resistance, antibiotic susceptibility testing, and therapeutic drug monitoring for selected drugs. In: Wanger A, Chavez V, Huang RSP, Wahed A, Actor JK, Dasgupta A. , eds. Microbiology and Molecular Diagnosis in Pathology. Oxford: Elsevier; 2017: 119-153
14 Ulldemolins M, Roberts JA, Lipman J, Rello J. Antibiotic dosing in multiple organ dysfunction syndrome. Chest 2011; 139 (05) 1210-1220
15 Blot SI, Pea F, Lipman J. The effect of pathophysiology on pharmacokinetics in the critically ill patient--concepts appraised by the example of antimicrobial agents. Adv Drug Deliv Rev 2014; 77: 3-11
16 Duszyńska W. Pharmacokinetic-pharmacodynamic modelling of antibiotic therapy in severe sepsis. Anaesthesiol Intensive Ther 2012; 44 (03) 158-164
17 Pea F, Viale P, Furlanut M. Antimicrobial therapy in critically ill patients: a review of pathophysiological conditions responsible for altered disposition and pharmacokinetic variability. Clin Pharmacokinet 2005; 44 (10) 1009-1034
18 Dzierba AL, Abrams D, Brodie D. Medicating patients during extracorporeal membrane oxygenation: the evidence is building. Crit Care 2017; 21 (01) 66
19 Rodvold KA, Hope WW, Boyd SE. Considerations for effect site pharmacokinetics to estimate drug exposure: concentrations of antibiotics in the lung. Curr Opin Pharmacol 2017; 36: 114-123
20 Ciofu O, Rojo-Molinero E, Macià MD, Oliver A. Antibiotic treatment of biofilm infections. APMIS 2017; 125 (04) 304-319
21 Felton TW, McCalman K, Malagon I. , et al. Pulmonary penetration of piperacillin and tazobactam in critically ill patients. Clin Pharmacol Ther 2014; 96 (04) 438-448
22 Mahmoud SH, Shen C. Augmented renal clearance in critical illness: an important consideration in drug dosing. Pharmaceutics 2017; 9 (03) 9
23 Sime FB, Udy AA, Roberts JA. Augmented renal clearance in critically ill patients: etiology, definition and implications for beta-lactam dose optimization. Curr Opin Pharmacol 2015; 24: 1-6
24 Bragadottir G, Redfors B, Ricksten S-E. Assessing glomerular filtration rate (GFR) in critically ill patients with acute kidney injury--true GFR versus urinary creatinine clearance and estimating equations. Crit Care 2013; 17 (03) R108
25 Roberts JA, Hope WW, Lipman J. Therapeutic drug monitoring of β-lactams for critically ill patients: unwarranted or essential?. Int J Antimicrob Agents 2010; 35 (05) 419-420
26 Udy AA, Dulhunty JM, Roberts JA. , et al; BLING-II Investigators; ANZICS Clinical Trials Group. Association between augmented renal clearance and clinical outcomes in patients receiving β-lactam antibiotic therapy by continuous or intermittent infusion: a nested cohort study of the BLING-II randomised, placebo-controlled, clinical trial. Int J Antimicrob Agents 2017; 49 (05) 624-630
27 Udy AA, Lipman J, Jarrett P. , et al. Are standard doses of piperacillin sufficient for critically ill patients with augmented creatinine clearance?. Crit Care 2015; 19: 28
28 Udy AA, Roberts JA, Shorr AF, Boots RJ, Lipman J. Augmented renal clearance in septic and traumatized patients with normal plasma creatinine concentrations: identifying at-risk patients. Crit Care 2013; 17 (01) R35
29 Akers KS, Niece KL, Chung KK, Cannon JW, Cota JM, Murray CK. Modified Augmented Renal Clearance score predicts rapid piperacillin and tazobactam clearance in critically ill surgery and trauma patients. J Trauma Acute Care Surg 2014; 77 (03) (Suppl. 02) S163-S170
30 Nicolau DP. Optimizing outcomes with antimicrobial therapy through pharmacodynamic profiling. J Infect Chemother 2003; 9 (04) 292-296
31 Roberts JA, Pea F, Lipman J. The clinical relevance of plasma protein binding changes. Clin Pharmacokinet 2013; 52 (01) 1-8
32 Finfer S, Bellomo R, McEvoy S. , et al; SAFE Study Investigators. Effect of baseline serum albumin concentration on outcome of resuscitation with albumin or saline in patients in intensive care units: analysis of data from the saline versus albumin fluid evaluation (SAFE) study. BMJ 2006; 333 (7577): 1044
33 Jager NGL, van Hest RM, Lipman J, Taccone FS, Roberts JA. Therapeutic drug monitoring of anti-infective agents in critically ill patients. Expert Rev Clin Pharmacol 2016; 9 (07) 961-979
34 Mouton JW, Brown DFJ, Apfalter P. , et al. The role of pharmacokinetics/pharmacodynamics in setting clinical MIC breakpoints: the EUCAST approach. Clin Microbiol Infect 2012; 18 (03) E37-E45
35 Clinical Laboratory Standards Institute. Performance Standards for Antimicrobial Susceptibility Testing. 29th ed. CLSI supplement M100. Wayne, PA: Clinical and Laboratory Standards Institute; 2019
36 Roberts JA, Abdul-Aziz MH, Lipman J. , et al; International Society of Anti-Infective Pharmacology and the Pharmacokinetics and Pharmacodynamics Study Group of the European Society of Clinical Microbiology and Infectious Diseases. Individualised antibiotic dosing for patients who are critically ill: challenges and potential solutions. Lancet Infect Dis 2014; 14 (06) 498-509
37 Mouton JW, Muller AE, Canton R, Giske CG, Kahlmeter G, Turnidge J. MIC-based dose adjustment: facts and fables. J Antimicrob Chemother 2018; 73 (03) 564-568
38 European Committee on Antimicrobial Susceptibility Testing. Piperacillin-tazobactam: Rationale for the Clinical Breakpoints, version 1.0. 2010. Available at http://www.eucast.org . Accessed December 1, 2017
39 McKinnon PS, Paladino JA, Schentag JJ. Evaluation of area under the inhibitory curve (AUIC) and time above the minimum inhibitory concentration (T>MIC) as predictors of outcome for cefepime and ceftazidime in serious bacterial infections. Int J Antimicrob Agents 2008; 31 (04) 345-351
40 Roberts JA, Paul SK, Akova M. , et al; DALI Study. DALI: defining antibiotic levels in intensive care unit patients: are current β-lactam antibiotic doses sufficient for critically ill patients?. Clin Infect Dis 2014; 58 (08) 1072-1083
41 Roberts JA, Ulldemolins M, Roberts MS. , et al. Therapeutic drug monitoring of beta-lactams in critically ill patients: proof of concept. Int J Antimicrob Agents 2010; 36 (04) 332-339
42 Roberts JA, De Waele JJ, Dimopoulos G. , et al. DALI: Defining Antibiotic Levels in Intensive care unit patients: a multi-centre point of prevalence study to determine whether contemporary antibiotic dosing for critically ill patients is therapeutic. BMC Infect Dis 2012; 12: 152
43 Blondiaux N, Wallet F, Favory R. , et al. Daily serum piperacillin monitoring is advisable in critically ill patients. Int J Antimicrob Agents 2010; 35 (05) 500-503
44 Taccone FS, Laterre PF, Dugernier T. , et al. Insufficient β-lactam concentrations in the early phase of severe sepsis and septic shock. Crit Care 2010; 14 (04) R126
45 Aubert G, Carricajo A, Coudrot M, Guyomarc'h S, Auboyer C, Zeni F. Prospective determination of serum ceftazidime concentrations in intensive care units. Ther Drug Monit 2010; 32 (04) 517-519
46 De Waele JJ, Carrette S, Carlier M. , et al. Therapeutic drug monitoring-based dose optimisation of piperacillin and meropenem: a randomised controlled trial. Intensive Care Med 2014; 40 (03) 380-387
47 Abdul-Aziz MH, Lipman J, Akova M. , et al; DALI Study Group. Is prolonged infusion of piperacillin/tazobactam and meropenem in critically ill patients associated with improved pharmacokinetic/pharmacodynamic and patient outcomes? An observation from the Defining Antibiotic Levels in Intensive care unit patients (DALI) cohort. J Antimicrob Chemother 2016; 71 (01) 196-207
48 Nicasio AM, Eagye KJ, Nicolau DP. , et al. Pharmacodynamic-based clinical pathway for empiric antibiotic choice in patients with ventilator-associated pneumonia. J Crit Care 2010; 25 (01) 69-77
49 Pea F, Furlanut M, Negri C. , et al. Prospectively validated dosing nomograms for maximizing the pharmacodynamics of vancomycin administered by continuous infusion in critically ill patients. Antimicrob Agents Chemother 2009; 53 (05) 1863-1867
50 Pea F, Viale P, Cojutti P, Furlanut M. Dosing nomograms for attaining optimum concentrations of meropenem by continuous infusion in critically ill patients with severe gram-negative infections: a pharmacokinetics/pharmacodynamics-based approach. Antimicrob Agents Chemother 2012; 56 (12) 6343-6348
51 Golenia BS, Levine AR, Moawad IM, Yeh DD, Arpino PA. Evaluation of a vancomycin dosing nomogram based on the Modification of Diet in Renal Disease equation in intensive care unit patients. J Crit Care 2013; 28 (05) 710-716
52 Bodí M, Rodríguez A, Solé-Violán J. , et al; Community-Acquired Pneumonia Intensive Care Units (CAPUCI) Study Investigators. Antibiotic prescription for community-acquired pneumonia in the intensive care unit: impact of adherence to Infectious Diseases Society of America guidelines on survival. Clin Infect Dis 2005; 41 (12) 1709-1716
53 Baudel JL, Tankovic J, Carrat F. , et al. Does nonadherence to local recommendations for empirical antibiotic therapy on admission to the intensive care unit have an impact on in-hospital mortality?. Ther Clin Risk Manag 2009; 5 (03) 491-498
54 Worrall CL, Anger BP, Simpson KN, Leon SM. Impact of a hospital-acquired/ventilator-associated/healthcare-associated pneumonia practice guideline on outcomes in surgical trauma patients. J Trauma 2010; 68 (02) 382-386
55 Lancaster JW, Lawrence KR, Fong JJ. , et al. Impact of an institution-specific hospital-acquired pneumonia protocol on the appropriateness of antibiotic therapy and patient outcomes. Pharmacotherapy 2008; 28 (07) 852-862
56 Charani E, Castro-Sanchez E, Sevdalis N. , et al. Understanding the determinants of antimicrobial prescribing within hospitals: the role of “prescribing etiquette”. Clin Infect Dis 2013; 57 (02) 188-196
57 De Souza V, MacFarlane A, Murphy AW, Hanahoe B, Barber A, Cormican M. A qualitative study of factors influencing antimicrobial prescribing by non-consultant hospital doctors. J Antimicrob Chemother 2006; 58 (04) 840-843
58 Charmillon A, Novy E, Agrinier N. , et al. The ANTIBIOPERF study: a nationwide cross-sectional survey about practices for β-lactam administration and therapeutic drug monitoring among critically ill patients in France. Clin Microbiol Infect 2016; 22 (07) 625-631
59 Mouton JW, den Hollander JG. Killing of Pseudomonas aeruginosa during continuous and intermittent infusion of ceftazidime in an in vitro pharmacokinetic model. Antimicrob Agents Chemother 1994; 38 (05) 931-936
60 Lorente L, Jiménez A, Martín MM, Iribarren JL, Jiménez JJ, Mora ML. Clinical cure of ventilator-associated pneumonia treated with piperacillin/tazobactam administered by continuous or intermittent infusion. Int J Antimicrob Agents 2009; 33 (05) 464-468
61 Lodise Jr TP, Lomaestro B, Drusano GL. Piperacillin-tazobactam for Pseudomonas aeruginosa infection: clinical implications of an extended-infusion dosing strategy. Clin Infect Dis 2007; 44 (03) 357-363
62 Abdul-Aziz MH, Sulaiman H, Mat-Nor MB. , et al. Beta-Lactam Infusion in Severe Sepsis (BLISS): a prospective, two-centre, open-labelled randomised controlled trial of continuous versus intermittent beta-lactam infusion in critically ill patients with severe sepsis. Intensive Care Med 2016; 42 (10) 1535-1545
63 Dulhunty JM, Roberts JA, Davis JS. , et al. Continuous infusion of beta-lactam antibiotics in severe sepsis: a multicenter double-blind, randomized controlled trial. Clin Infect Dis 2013; 56 (02) 236-244
64 Lipman J, Brett SJ, De Waele JJ. , et al. A protocol for a phase 3 multicentre randomised controlled trial of continuous versus intermittent β-lactam antibiotic infusion in critically ill patients with sepsis: BLING III. Crit Care Resusc 2019; 21 (01) 63-68
65 Wong G, Briscoe S, McWhinney B. , et al. Therapeutic drug monitoring of β-lactam antibiotics in the critically ill: direct measurement of unbound drug concentrations to achieve appropriate drug exposures. J Antimicrob Chemother 2018; 73 (11) 3087-3094
66 Felton TW, Roberts JA, Lodise TP. , et al. Individualization of piperacillin dosing for critically ill patients: dosing software to optimize antimicrobial therapy. Antimicrob Agents Chemother 2014; 58 (07) 4094-4102
67 Heil EL, Nicolau DP, Farkas A, Roberts JA, Thom KA. Pharmacodynamic target attainment for cefepime, meropenem and piperacillin/tazobactam using a pharmacokinetic/pharmacodynamic-based dosing calculator in critically ill patients. Antimicrob Agents Chemother 2018; 62 (09) e01008-18
68 Neely MN, Kato L, Youn G. , et al. Prospective trial on the use of trough concentration versus area under the curve to determine therapeutic vancomycin dosing. Antimicrob Agents Chemother 2018; 62 (02) 62
69 van Lent-Evers NA, Mathôt RA, Geus WP, van Hout BA, Vinks AA. Impact of goal-oriented and model-based clinical pharmacokinetic dosing of aminoglycosides on clinical outcome: a cost-effectiveness analysis. Ther Drug Monit 1999; 21 (01) 63-73
70 Wong G, Farkas A, Sussman R. , et al. Comparison of the accuracy and precision of pharmacokinetic equations to predict free meropenem concentrations in critically ill patients. Antimicrob Agents Chemother 2015; 59 (03) 1411-1417
71 Nunn MO, Corallo CE, Aubron C, Poole S, Dooley MJ, Cheng AC. Vancomycin dosing: assessment of time to therapeutic concentration and predictive accuracy of pharmacokinetic modeling software. Ann Pharmacother 2011; 45 (06) 757-763