The antibiotic dose and the obese ICU patient

Transcription

1 The antibiotic dose and the obese ICU patient Philippe Montravers, M.D., Ph.D. Anaesthesia and Surgical ICU CHU Bichat Claude Bernard Assistance Publique-Hôpitaux de Paris INSERM UMR 1152 University Paris VII Denis Diderot Sorbonne Cite Paris, France

2 Disclosures Speaker for Astellas, Astra Zeneca, Basilea, Cubist, Gilead, MSD, The Medicines Company and Pfizer Advisory board membership for Astellas, Astra Zeneca, Bayer, Cubist, Menari, MSD, Parexel, Tetraphase, The Medicines Company and Pfizer

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4 Obesity in the ICU is a common situation 3 National Health Service Hospitals London ( ) Prevalence of obese patients receiving an antibiotic therapy 22% obese patients (69% normal/overweight and 9% underweight) Increased risk of complicated antibiotic therapy (Odds ratio 2.01 [ ]) (second- or third-line therapy ; (ii) IV therapy where an alternative oral therapy was appropriate; (iii) longer than the recommended duration of therapy as per local policy recommendations; (iv) repeated courses of therapy to treat the same infection; and (v) specialist advice on antimicrobial therapy) Charani E et al. J Antimicrob Chemother 2015;70: Medical centers (Canada, USA and Saudi Arabia) ( ) Impact of septic shock in obese patients 8670 patients, 33% obese patients Increased risk of SSTI and Gram-positive micro-organisms Less likely to have pneumonia No significant relationship with mortality rates Arabi YM et al. Crit Care 2013;17:R32

5 A paucity of advice and evidence Analysis (Spring 2016) of the summary of product characteristics (SPC) for 42 of the most clinically important and frequently prescribed antibacterial agents in UK. No advice provided Specific dosing strategies suggested (AMK, GEN, TOB, TEI) Caution than dose may be altered (DAP, VAN) Advice suggests that no dosing adjustment is necessary (TIGE) Boyd SE et al. J Antimicrob Chemother 2016; 71:

6 Pharmacokinetic changes Intestinal absorption of lipophilic AB Obesityassociated kidney failure Reduced hepatic metabolism due to fatty infiltration Variable effect of cytochrome P450 enzymes Delayed gastric emptying/ decreased absorption Increased glomerular filtration rate Increased volume of distribution (fat cells) Increase in serum AB concentrations Decrease in serum AB concentrations Uneasy to make any pharmacokinetic predictions linked to contradictory signals and depending of the type of drug Al-Dorzi H et al. Curr Opin Infect Dis 2014;27:

7 Pharmacokinetic changes Examples Pharmacokinetics Changes in obesity Hydrophilic drugs ß-lactamins (penicillins, cephalosporins, carbapenems) Aminoglycosides Vancomycin Colistin Most have low volume of distribution Most have a renal Clearance and low intracellular/tissue penetration Little effect on the volume of distribution Increased renal clearance (unless renal dysfunction is present) Lipophilic drugs Fluoroquinolones Macrolides Tigecycline High volume of distribution Hepatic clearance High intracellular/tissue penetration Increased volume of distribution Variables effects on hepatic clearance Al-Dorzi H et al. Curr Opin Infect Dis 2014;27:

8 49 obese patients (BMI 40 (ext 30-60) compared to 59 non-obeses (BMI 22 (15-25)) Treated for a severe infection in the ICU 12 CEF : cefepime 2 g followed by a median daily dose 6 [2-6] g 19 TZP: piperacillin/tazobactam 4g 16 [12-16] 37 MEM: meropenem 1g 3 [2-3] Obese patients Non-obese patients Target concentrations /MIC = ratio concentration / MIC between 4-8 fold MIC at 70% of the time between two doses for CEF, 50% for TZP and 40% for MEM (Breakpoints for P aeruginosa) Adequate concentrations for Overall Underdosage 32% Overdosage 25% 25% CEF 47% TZP 49% MEM Hites M et al. Antimicrob Agents Chemother 2013;57:

9 Daily dose to reach the target concentration Study population Population with/without continuous renal replacement therapy Minimal daily dose in grams median (extremes) MEM:meropenem;TZP: piperacillin-tazobactam ; CEF: cefepime Target concentration /MIC = ratio concentration / MIC between 4 and 8 times MIC at 70% of time between two doses for CEF, 50% for TZP and 40% for MEM (Breakpoints for P aeruginosa) Hites M et al. Antimicrob Agents Chemother 2013;57:

10 Pharmacokinetic changes Hydrophilic drugs Examples ß-lactamins (penicillins, cephalosporins, carbapenems) Aminoglycosides Vancomycin Colistin Pharmacokinetics Most have low volume of distribution Most have a renal Clearance and low intracellular/tissue penetration Changes in obesity Little effect on the volume de distribution Increased renal clearance rénale (unless renal dysfunction is present) Dosing in obesity Ideal or adjusted body weight is generally used for dosing Lipophilic drugs Fluoroquinolones Macrolides Tigecycline High volume of distribution Hepatic clearance High intracellular/tissue penetration Increased volume of distribution Variables effects on hepatic clearance Total body weight in generally recommended for dosing Al-Dorzi H et al. Curr Opin Infect Dis 2014;27:

11 How to assess (the weight of) our patients? Total body weight: TBW Ideal body weight: IBW Adjusted body weight: ABW Lean body mass: LBM

12 The debated definitions IBW: Ideal Body Weight Al-Dorzi H et al. Curr Opin Infect Dis 2014;27:

13 IBW in males IBW in females Devine BJ. Drug Intell Clin Pharm. 1974; 8: IBW (M) IBW (F) Ideal Body Weight = 50 kg kg/inch for height over 5 feet = 45.5 kg kg/inch for height over 5 feet = 50 kg kg/inch for height over 5 feet = 49 kg kg/inch for height over 5 feet Robinson JD et al. Am J Hosp Pharm. 1983; 40: Derived from tables used by insurance companies IBW (M) = 50 kg kg for each inch above 60 inches of height IBW (F) = 45.5 kg kg for each inch above 60 inches of height Al-Dorzi H et al. Curr Opin Infect Dis 2014;27: Other possibilities for calculating the IBW IBW = X x (height in cm ) X=50 (M) X =45 (F) Approximate IBW = Height -100 (M) or 110 (F)

14 Adjusted weight = IBW + correction factor X (TBW-IBW) Correction factor for hydrophilic drugs but a large variability Al-Dorzi H et al. Curr Opin Infect Dis 2014

15 Correction factors for aminoglycosides Bearden DT et al. Clin Pharmacokinet 2000;38:415-26

16 Lean body mass : LBM in M = 1.10 X total body weight x (TBW / height in cm) 2 in F= 1.07 X total body weight x (TBW / height in cm) 2 James WP. Research on obesity. London: Her Majesty s Stationery Office; in M = (9,270 X total body weight) / (6, X BMI) in F = (9,270 X total body weight) / (8, X BMI) Al-Dorzi H et al. Curr Opin Infect Dis 2014

17 The master word is Confusion Example : Male 180 cm / TBW = 150 kg IBW = x ( ) = 75 kg ABW = 75 + [0.5 x (150-75)] correction factor 0.5 = kg LBM = 1.10 X (150 / 180) 2 = 81.7 kg

18 In practice What could be proposed

19 Piperacillin-tazobactam Probability of target attainment in Monte-Carlo simulation Sturm AW et al. Pharmacotherapy 2014;34:28 35 Administration of high dose over 4 hours infusion (4 to 6 g every 6 hours ) Deman H et al. J Antimicrob Chemother 2012; 67: Cheatham SC et al. Int J Antimicrob Agents 2013; 41:52 56 Al-Dorzi HM et al. Curr Opin Infect Dis 2014; 27:

20 Cefepime 2 g every 6 hours Rich BS et al. Obes Surg 2012;22: By extension (but no consistent data) upper limit of normal dose for cephalosporins Al-Dorzi HM et al. Curr Opin Infect Dis 2014; 27:

21 Meropenem 9 morbidly obese patients BMI 40 kg/m 2 Probability of target attainment 54% of the time >MIC for drug with low protein binding 5 regimens administered over 30 minutes or 3 hours Infusion 30 minutes Infusion 3 hours 90% Time [free AB] >MIC 90% Time [free AB] >MIC Cheatham SC et al. J Clin Pharmacol 2013;54: Upper limit of normal dose Infusion over 3 to 4 hours for carbapenems Taccone FS et al. Antimicrob Agents Chemother 2012; 56: Roberts JA et al. Crit Care Med 2013; 41: Al-Dorzi HM et al. Curr Opin Infect Dis 2014; 27:

22 Aminoglycosides TBW over-estimates the volume of distribution = over-dosage IBW under-estimates the volume of distribution = under-dosage Taccone F. Crit Care 2010; 14:R53 Montmollin E. Intensive Care Med 2014;40: Loading dose based on LBM Loading dose based on ABW Ross AL et al. Adv Pharmacol Sci 2013;2013: Pai MP et al. Antimicrob Agents Chemother 2011; 55: Bearden DT et al.clin Pharmacokinet 2000;38: Falagas M et al. Lancet 2010;375: Velissaris D et al. J Clin Med Res 2014;6 : Therapeutic Drug Monitoring Peak concentrations for loading dose and maintenance doses Trough concentrations for maintenance doses

23 Colistin Influence of weight on the CMS volume de distribution : 15.7 X (Weight/70) 1,1 Gregoire N et al. Antimicrob Agents Chemother 2014;58: Loading dose 9 to 12 M UI (1 M UI /80 mg of colistimethate sodium) IBW is recommended for maintenance dosing Obesity (BMI > 31.5) is a risk factor of nephrotoxicity (age, diabetes, prolonged hospitalisation) Michalopoulos AS et al. Ann Intensive Care 2011; 1:30 Al-Dorzi H et al. Curr Opin Infect Dis 2014;27: Gauthier TP et al. Antimicrob Agents Chemother 2012;56: Monitoring of peak (4 mg/l) and trough (2 mg/l) concentrations for the maintenance infusions taking into consideration the kidney function

24 Fluoroquinolones Moxifloxacine No pk changes related to obesity No dose adjustment Levofloxacine No dose adjustment Kees MG et al. J Antimicrob Chemother 2011;66: Luque S et al. J Antimicrob Chemother 2011; 66: Cook AM et al. Antimicrob Agents Chemother 2011; 55: Ciprofloxacine Doses of up to 800 mg every 12h Janson B et al. Curr Opin Infect Dis 2012; 25: Al-Dorzi H et al. Curr Opin Infect Dis 2014;27: Macrolides No dose adjustment Al-Dorzi H et al. Curr Opin Infect Dis 2014;27:

25 Vancomycine ABW is not recommended for loading dose Erstad BL. Am J Health-Syst Pharm 2002; 59: TBW is recommended for loading dose to avoid any underdosage Cheymol G. Clin Pharmacokinet 2000;39: Wurtz R et al. Clin Infect Dis 1997; 25:112-8 Al-Dorzi H et al. Curr Opin Infect Dis 2014;27: Loading dose TBW mg/kg Penzack SR Ther Drug Monitor 1998;20:261-5 Bauer LA. Eur J Clin Pharmacol 1998;54: mg/kg Al-Dorzi H et al. Curr Opin Infect Dis 2014;27: Maintenance dose 30 mg/kg/j in CI Erstad BL. Intensive Care Med 2004;30:18-32 Grace E et al. J Antimicrob Chemother 2012;67: Dose (60-90 min)15-20 mg/kg/12h (TBW) Al-Dorzi H et al. Curr Opin Infect Dis 2014;27: TDM Trough concentrations > 20 mg/l

26 Daptomycine TBW is recommended Dvorchik BH et al. Journal of Clinical Pharmacology, 2005;45:48-56

27 Linezolid LNZ 60-min IV (600 mg/12h) CI group 600 mg IV over 60 min then 1200 mg/24h in continuous infusion De Pascale G et al. Intensive Care Med 2015;41:103-10

28 In summary Difficult to achieve an optimal dosing One size does not fits all Therapeutic drug monitoring is extremely helpful (aminoglycosides, glycopeptides, (ideally colistin, penicillins, cephalosporins, carbapenems) Tissue monitoring impossible in routine practice pk data are not yet available for all drugs Very few data for antifungal agents except voriconazole