Pharmacokinetics and Pharmacodynamics of Antimicrobials in the Critically Ill Patient Rania El-Lababidi, Pharm.D., BCPS (AQ-ID), AAHIVP Manager, Pharmacy Education and Training Cleveland Clinic Abu Dhabi
Objectives Basic Pharmacokinetics and Pharmacodynamics (PK/PD) principles of antimicrobials Importance of PK/PD of antimicrobials in critically ill patients PK/PD parameters of common antimicrobials Recent literature and clinical applications of PK/PD of antimicrobials i in the critically ill
Drusano s Patient A patient was admitted to the intensive care unit with Klebsiella pneumoniae pneumonia. As with any great case, I and the other residents would seek the wise counsel of Dr. Woodward. I ran up to him in the hallway, presented the case quickly, and said Dr. Woodward, we re treating the patient with cefazolin plus gentamicin. How much should we give him and for how long? After about 5 seconds of consideration, Dr. Woodward said George, you treat him with enough and you treat him for long enough! Dr. G. L. Drusano
Antimicrobial Therapy in the ICU Initial inappropriate antimicrobial therapy associated with increased mortality Surviving Sepsis Guidelines Administer antibiotics within an hour Broad-spectrum antibiotics with good tissue penetration Reassess antimicrobials daily What about appropriate initial dosing of antimicrobials? Suboptimal outcomes even if initial antimicrobial choice is appropriate Dellinger RP. CCM 2013; 41:580-637. Zilberberg MD et al.chest 2008;134:963-8. Pea F, Viale P. CID 2006; 42:1764-71.
Antimicrobial Therapy Puzzle Source: Adapted from Pea et al. CID 2006;42:1764-71
Basic Principles MIC Minimum m concentration of antibiotic necessary to inhibit growth of bacteria MBC Minimum concentration necessary to kill bacteria
Basic Principles Bacteriostatic agents Agents that inhibit antimicrobial growth: e.g. clindamycin, cin azithromycin, tetracyclines, linezolid, chloramphenicol MIC < MBC Bactericidal agents Agents that rapidly kill bacteria e.g. beta-lactams, daptomycin, vancomycin, metronidazole, FQs MIC = MBC
From Bedside to Bench Pharmacokinetics The interrelationship between een drug dose and variations in concentrations in plasma and tissue over time Cmax: Peak concentration after a single dose Vd: Volume of distribution of drug administered Clearance (CL): loss of drug through metabolism or excretion e Elimination half-life (t ½ ): time required for the drug plasma concentration to fall by one-half AUC 24 : total area under the concentration curve over 0 to 24 h
Pharmacokinetics of Antimicrobials Oral administration Drug s bioavailability ailabilit e.g. FQs vs macrolides Esterified cephalosporins e.g. cefuroxime axetil Disease states that lower bioavailability e.g. sepsis IV Administration Bolus administration Extended infusion Continuous infusion
Pharmacokinetics of Antimicrobials Distribution Process by which drug diffuses from the intravascular asc fluid space to extravascular fluid spaces Plasma protein binding, disease states, lipid solubility, molecular size, tissue perfusion, diffusion (prostate, eye, brain) Issues that influence Vd in the critically ill patients Large volume and blood product infusions Positive pressure ventilation Capillary leak and reduction in albumin serum concentrations
Pharmacokinetics of Antimicrobials Activity of antimicrobials is influenced by: Protein binding ph of surrounding tissue e.g. aminoglycosides and abscess Slow growing bacteria Presence of a biofilm I t ll l th Chl di Li t i Intracellular pathogens e.g. Chlamydia spp., Listeria spp., Salmonella
Solubility Profiles of Antimicrobials β-lactam Penicillins Cephalosporins Carbapenems Glycopeptides Aminoglycosides Macrolides Fluoroquinolones Tetracycline Rifampin Linezolid Limited Vd Renally as unchanged drug Limited diffusion ability Large Vd Intracellular pathogens activity Hepatic metabolism Diffuses freely to plasma membrane Source: Pea et al. CID 2006;42:1764-71
Question 1 Which of the following antimicrobials would be most effective against Rickettsia spp? a. Penicillin b. Vancomycin c. Doxycycline d. Gentamicin 13
Pharmacokinetics of Antimicrobials Elimination Liver: erythromycin, azithromycin, nafcillin, rifampin Renal: β-lactam antibiotics Bile: ceftriaxone Gut: doxycycline
Impact of MODS on Antibiotic PK Implication of MODS on Antibiotic Pharmacokinetics GI Dysfunction Tissue Hypoperfusion Hepatic Dysfunction Renal Dysfunction Decreased Decreased Decreased Decreased Decreased absorption of antibiotic tissue protein elimination elimination of enterally concentration binding of of lipophilic hydrophilic administered antibiotics highly bound antibiotics antibiotics antibiotics UNDERDOSING OVERDOSING Source: Ulldemolins M. Chest 2011;139:1210-20. PK: Pharmacokinetics; MODS: Multiple Organ Dysfunction Syndrome
Pharmacokinetic Changes in Critically Ill Patients Healthy Patient Septic Patient Renal Dysfunction Source: Gonçalves-Pereira, Póvoa. Critical Care 2011;15:R206.
Optimizing Dosing in Critically Ill Patients Increased Vd and increased clearance of antimicrobials Literature demonstrates suboptimal initial antimicrobial levels Roberts et al., 70% of patients did NOT achieve adequate β-lactam levels Taccone et al., less than 50% of patients achieved adequate PK/PD targets for β-lactam administered Loading Dose Vd x Cp Dose Roberts JA et al. Int J Antimicrob Agents. 2010 ;36 : 332-339. Taccone et al. Crit Care. 2010 ;14: R126.
Guidelines for Optimizing Dosing in the Critically Ill Antibiotic Solubility Organ System LD in Patients with increased Vd MD in Kidney Failure MD in Hepatic Failure β-lactam Hydrophilic Renal Administer a high LD initially Decrease dose Normal Dosing Aminoglycosides Hydrophilic Renal Administer a high LD initially Decrease dose; Dose titrated based on levels Normal Dosing Vancomycin Hydrophilic Renal Administer a high LD initially Decrease dose; Dose titrated based on levels Normal Dosing Fluoroquinolones Lipophilic Renal and hepatic Administer normal dose initially Decrease dose based on principal organ responsible for clearance Decrease dose based on principal organ responsible for clearance Glycylcyclines Lipophilic Hepatic Administer a high LD initially Normal dosing Decrease dosing LD: loading dose; MD: Maintenance dose Ulldemolins M et al. Chest 2011;139;1210-1220.
Pharmacodynamics of Antimicrobials Antimicrobial pharmacodynamics Links measures of drug exposure to microbiological or clinical effects Affected by: Biochemical and physiological effects of the drug
Pharmacodynamic Parameters Time-dependent PK/PD index: ƒt > MIC Cell-wall active agents: Beta-lactams Decrease the interval for re-dosing Concentration-dependent PK/PD index: Cmax/MIC or ƒauc 0-24 /MIC Fluoroquinolones, tetracycline, metronidazole, clindamycin, glycyclines Increase the dose
Common Pharmacodynamic Principles Source: Craig WA. CID 1998;26:1-10.
Pharmacodynamic (PD) parameters correlating with efficacy Antibacterial Class Optimal PK/PD PK/PD magnitude Parameter required for efficacy Aminoglycosides C max /MIC 10-12 Fluoroquinolones AUC/MIC > 25, >100 Beta-lactams T>MIC 50%; 70% Linezolid AUC/MIC >80 Daptomycin AUC/MIC 189 Tigecycline AUC/MIC 15-20 Scaglione F et al. AAC 2008; 32; 4: 294-301. Rubino CM et al. AAC 2012; 56: 130-6.
Pharmacokinetics Meets Pharmacodynamics Elimination Drug Administration Plasma Concentration Target Site Concentration Pharmacological Effect Pharmacokinetics Pharmacokinetics Pharmacodynamics Pharmacokinetics/Pharmacodynamics Source: Ulldemolins M. Chest 2011;139:1210-20.
Penicillins and Cephalosporins Time-dependent Dosage strategies to maintain T> MIC 60-70% of the time Strategies: extended infusion, continuous infusion
Carbapenems Time-dependent T > MIC 30 40 % of the time Prolonged or extended infusion
Quinolones Concentration-dependent AUC/MIC and C max /MIC Gram-negative bacteria: AUC/MIC > 125 Gram-positive bacteria AUC/MIC > 250 500
Quinolone Pharmacodynamics Lomefloxacin 40 mg/kg q12h Lomefloxacin 80 mg/kg q24h 40% survival 75% survival Adapted from Drusano GL et al. AAC 1993; 37:483 90.
Quinolones Pharmacokinetic study in patients with nosocomial pneumonia Levofloxacin 750 mg IV q24h AUC/MIC cut-off of 87 Failure to attain this AUC/MIC ratio resulted in failure to eradicate pathogens Drusano GL et al. J Infect Dis 2004;189;1590-97.
Aminoglycosides Concentration-dependent C max /MIC: 8 12 Clinical outcomes well correlated with AUC/MIC Kashuba AD. AAC 1999; 43:623-29.
Once Daily Dosing of Aminoglycosides Once daily dosing and probability of nephrotoxicity Twice Daily Dosing Once Daily Dosing Source: Rybak MJ et al. AAC 1999;43:1549 55.
Question 2 What percentage of time above the MIC is most ideal for meropenem? A. 80% B. 60% C. 40% D. 20% 31
Vancomycin Time dependent AUC/MIC 400 Loading dose 20-25 mg/kg/dose Nephrotoxicity 5-43% in literature Higher in critically ill patients Trough levels > 20 mg/l Patel N et al. Clin Infect Dis. 2011;52:969-974. Van Hal SJ. Antimicrob. Agents Chemother 2013;57:734-44.
Tigecycline Glycylcycline antibiotic FDA approved for cssti, CAP, ciai Did not meet primary endpoints for HAP or diabetic foot infections Time dependent AUC/MIC Increase in all-cause mortality in tigecycline-treated treated patients in clinical trials Overall mortality rate was higher, compared with comparator antibiotics (RD, 0.7%; 95% [CI],.1 1.2; P =.01) Prasad P. Clin Infect Dis 2012; 54: 1699-1709.
Tigecycline and Increased Mortality Inadequate antimicrobial activity Tigecyclinecline is a static antimicrobial Non-linear high protein binding Very large Vd (5-10 L/kg) Standard dosing of 100 mg IV, 50 mg q12h Css= 0.6 mcg/ml too low compared to breakpoints Severe infections with bacteremia compound inadequate microbiological response US FDA issued Boxed Warning Prasad P. Clin Infect Dis 2012; 54: 1699-1709.
Monte-Carlo Simulations Mathematical modeling used to design antimicrobial dosing regimens with optimal PD profiles Integrates t PK/PD profiles and MIC data simulates the dispersion of concentration-time profiles seen in a large population Calculates the probability of target attainment (PTA) at p y g ( ) each MIC value
Monte-Carlo Simulations Source: De Ryke A et al. Diag Mic Inf Dis 2007;58:337-44.
Extended Infusion β-lactams Extending the infusion Sustained concentrations above the MIC for longer periods Achieve more favorable PK/PD profile even against organisms with higher MICs Prolonged (3 or 4 hours) vs. continuous infusion yield similar PK/PD profiles Source: Kim A. Pharmacotherapy 2007;27:1490 7.
Extended Infusion β-lactams Where is the Evidence? Retrospective, comparative study Two dosing regimens compared in critcially ill patients Piperacillin-tazobactam 3.375 gm IV q6 4h over 30 min vs Piperacillin-tazobactam 3.375 gm IV q8h over 4 hours Outcomes of patients with P. aeruginosa retrospectively evaluated ed Lodise TP. Clin Infect Dis 2007;44:357 63.
Extended Infusion β-lactams Where is the Evidence? Lodise TP. Clin Infect Dis 2007;44:357 63.
Question 3 A 60 yo male is admitted with MDR P. aeruginosa bacteremia. The MIC to piperacillin-tazobactam is 16 mcg/ml. Which of the regimens would you use in this patient? A. 30 min infusion of piperacillin-tazobactam 3.375 gm IV q6hr B. 4 hour infusion of piperacillin-tazobactam 3.375 gm IV q8hr C. Continuous infusion of 18 gm of piperacillintazobactam D. A much stronger antibiotic than piperacillin- tazobactam 40
What about prospective data? Dulhunty et al recently conducted a prospective, randomized, double-blind, controlled trial Compared continuous infusion to bolus administration of β-lactams in septic patients 60 patients enrolled into study Study endpoints Primary endpoint: plasma concentrations above the MIC Secondary endpoint: clinical cure Dulhunty et al. Clinical Infectious Diseases 2013;56:236 44.
Continuous vs. Bolus Administration of β-lactams Percentage of plasma concentration above the MIC Meropenem: 100% in the intervention ention vs 22% inthe control group Piperacillin-tazobactam: 75% in the intervention vs. 36% in the control group Ticarcillin-clavulanate: 50% in the intervention vs. 0% in the control group Dulhunty et al. Clinical Infectious Diseases 2013;56:236 44.
Continuous vs. Bolus Administration of β-lactams Dulhunty et al. Clinical Infectious Diseases 2013;56:236 44.
Findings from a Meta-analysis Falagas et al. conducted a meta-analysis of non- randomized studies Compared clinical outcomes of extended or continuous infusion of β-lactams to short infusion Included 14 studies in the meta-analysis Outcomes: Primary outcomes: All-cause mortality and clinical cure Secondary outcomes: emergence of resistance and adverse events Falagas ME. CID 2013;56:272 82.
Meta-analysis Results Mortality was lower among patients who received extended or continuous infusions β-lactams compared to short infusion RR = 0.59 (95% CI, 0.41, 0.83) Falagas ME. CID 2013;56:272 82.
Conclusion and Future Directions Careful consideration of antimicrobial dosing in critically ill patients based on PK/PD parameters Extended or continuous infusion β-lactams optimizes outcomes in critically ill patients Additional multicenter trials with sufficient power to delineate differences in outcomes With new antimicrobials developed, pre-clinical PK/PD data is necessary to identify optimal dosing regimens
QUESTIONS?