Pharmacokinetics of piperaciillin during plasma exchange

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1 : Piperaciilin pharmacokinetics duringPlasma Exchange Jason Roberts(1,2) Jeffrey Lipman (2) (1) Pharmacy Department, Royal Brisbane and Women’s Hospital (2) Burns Trauma and Critical Care Research Centre, University of Queensland (3) Therapeutics Research Unit, University of Queensland
2 : Case Report A 17 year-old male Intubated and admitted to a tertiary intensive care unit (ICU) Diagnosed with Guillian-Barre Syndrome (GBS) Part of treatment regimen included Plasma Exchange (PE) Day 3 of the ICU admission, patient developed sepsis from aspiration pneumonia Immediate and appropriate antibiotic treatment Patient enrolled in microdialysis study
3 : Points to consider: What is GBS? What is Plasma Exchange (PE)? Why is antibiotic therapy important in ICU patients? Microdialysis? Will PE affect antibiotic therapy?
4 : GBS Guillian Barre Syndrome Acute inflammatory, peripheral neuropathy Immune system targets infectious pathogen that ‘re-directs’ host to nerve tissue causing de-myelination and axonal damage Can lead to failure of respiratory muscles leading to intubation Treatment includes Plasma Exchange
5 : Plasma Exchange A centrifugation process whereby plasma proteins including immunoglobulins are removed from the body and replaced with Albumex® Used in many disease treatments including: renal and metabolic diseases (e.g. antiglomerular basement membrane antibody disease); autoimmune and rheumatic diseases (e.g. GBS); haematologic diseases (e.g. thrombotic thrombocytopenia pupura) neurologic disorders (e.g. myasthenia gravis) Protein bound drugs also removed!!! Previously shown for vancomycin, ceftriaxone
6 : Empiric antibiotics in ICU Garnacho-Montero J, Garcia-Garmendia JL, Barrero-Almodovar A, Jimenez-Jimenez FJ, Perez-Paredes C, Ortiz-Leyba C. Impact of adequate antibiotic therapy on the outcome of patients admitted to the intensive care unit with sepsis. Crit Care Med 2003; 31:2742-2751. Kollef MH, Sherman G, Ward S, Fraser VJ. Inadequate antimicrobial treatment of infections: a risk factor for hospital mortality among critically ill patients. Chest 1999; 115:462-474. Rello J, Gallego M, Mariscal D, Sonora R, Valles J. The value of routine microbial investigation in ventilator-associated pneumonia. Am J Respir Crit Care Med 1997; 156:196-200. Iregui M, Ward S, Sherman G, Fraser VJ, Kollef MH. Clinical importance of delays in the initiation of appropriate antibiotic treatment for ventilator-associated pneumonia. Chest 2002;122:262-268. Luna CM, Vujacich P, Niederman MS, Vay C, Gherardi C, Matera J, Jolly EC. Impact of BAL data on the therapy and outcome of ventilator-associated pneumonia. Chest 1997; 111:676-685. Leibovici L, Drucker M, Konigsberger H et al. Septic shock in bacteremic patients: risk factors, features and prognosis. Scand J Infect Dis 1997; 29:71-75. Valles J, Rello J, Ochagavia A, Garnacho J, Alcala MA. Community-acquired bloodstream infection in critically ill adult patients: impact of shock and inappropriate antibiotic therapy on survival. Chest 2003; 123:1615-1624. Ibrahim EH, Sherman G, Ward S, Fraser VJ, Kollef MH. The influence of inadequate antimicrobial treatment of bloodstream infections on patient outcomes in the ICU setting. Chest 2000; 118:146-155. Alvarez-Lerma F. Modification of empiric antibiotic treatment in patients with pneumonia acquired in the intensive care unit. ICU-Acquired Pneumonia Study Group. Intensive Care Med 1996; 22:387-394. MacArthur RD, Miller M, Albertson T et al. Adequacy of early empiric antibiotic treatment and survival in severe sepsis: Experience from the MONARCS Trial. Clin Infect Dis 2003; 38:284-288. Harbarth S, Garbino J, Pugin J et al. Inappropriate initial antimicrobial therapy and its effect on survival in a clinical trial of immunomodulating therapy for severe sepsis. Am J Med 2003; 115:529-535. MacArthur RD, Miller M, Albertson T et al. Adequacy of early empiric antibiotic treatment and survival in severe sepsis: Experience from the MONARCS Trial. Clin Infect Dis 2003; 38:284-288.
7 : Microdialysis “In vivo technique for measuring molecule concentrations in tissues”
8 : Piperacillin Ureidopenicillin Broad spectrum – commonly selected as empiric therapy in sepsis Vd = 0.3L/kg Protein binding ~ 30% Excretion – mainly renal Pharmacodynamics – Time above MIC improves efficacy No publications on PE and piperacillin
9 : Intervention: Administer piperacillin-tazobactam by continuous infusion Day 1: Loading dosing 4.5gm over 20mins followed by 9gm over 24 hours; Day 2: 13.5gm over 24 hours Rationale – maximises T>MIC and may replace that which is removed by PE
10 : Blood and tissue concentrations
11 : Redistribution from tissue to serum
12 : Pharmacokinetic validation: AUC during PE = 4044mg.min/ml APE = 36.3mg (over 97 minute period) Arenal = 483.6mg (CLCR = 171ml/min) CLother = 19.0mg Amount piperacillin infused during PE = 5.55mg/min x 97min = 538.9mg 6.7% of clearance is due to PE over 97 minute period
13 : Discussion Piperacillin is eliminated by PE Amount is probably not clinically significant and effect is offset by continuous infusion Alternatively, PE before bolus dosing would minimise effect Literature shows that drugs with low Vd and high protein binding most likely to be affected by PE
14 : Conclusion Pharmacist has an essential role in optimizing pharmacotherapy in ICU Important to be aware of other interventions that may impact on pharmacotherapy Be prepared to alter traditional dosing strategies if required
15 : Acknowledgments SHPA Contemporary Therapeutics Research Grant ANZCA RBWH Foundation NHMRC


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