Continuous Infusion of Antibiotics In The ICU: What Is Proven? Professor of Medicine Vice-Chairman, Department of Medicine SUNY at Stony Brook

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1 Continuous Infusion of Antibiotics In The ICU: What Is Proven? Michael S. Niederman, M.D. Chairman, Department of Medicine Winthrop-University Hospital Mineola, NY Professor of Medicine Vice-Chairman, Department of Medicine SUNY at Stony Brook

2 Factors Affecting Clinical Success In Pneumonia Therapy Lippman et al. Curr Opin Infect Dis 2013, in press

3 FACTORS AFFECTING ANTIBIOTIC CONCENTRATIONS IN THE LUNG Penetration, Protein Binding, Volume of Distribution (Vd), Clearance Often enhanced renal clearance (beta-lactams) in hyperdynamic septic patients (ARC, augmented renal clearance) Volume of distribution > 3L means concentration outside of plasma Lipophilic drugs have a high Vd Hydrophilic drugs expand their Vd with sepsis and leaky capillaries (can underdose) Obesity: If use IBW can underdose (esp lipophilic drugs). Generally use TBW, BUT if calculate dose on TBW can overdose hydrophilic drugs (extracellular water does not expand as much). Free drug is active and thus with low serum proteins, may increase BOTH Vd and Clearance

4 PHARMACODYNAMIC CONSIDERATIONS Bactericidal in a concentration-dependent fashion: aminoglycosides, quinolones, ketolides, daptomycin Bactericidal in a time-dependent fashion (if > MIC for at least 40-70% of the dosing interval) : beta-lactams, carbapenems, aztreonam, macrolides, linezolid Time-dependent with prolonged and persistent killing: clindamycin, vancomycin, azithromycin, tetracyclines. (AUIC and trough may matter in addition to time > MIC) Prolonged PAE against gram-negatives: aminoglycosides, quinolones, tetracyclines, rifampin Little or no PAE for gram-negatives: beta-lactams (except penems)

5 Can We Use Pharmacokinetic/ Pharmacodynamic Principles To Improve Adequacy of Therapy? T> MIC to be bactericidal: 60-70% cephalosporins; 50% PCNs; 40% carbapenems Target a steady state concentration of 4X MIC during continuous infusion

6 Doripenem Concentration (mg/l) Effect of Doripenem By Extended Infusion on %T > MIC % 49% 4 MIC = Time Since Start of Infusion (h) Dose 500 mg 1 h 500 mg 4 h Can Use Higher Doses 1500 mg 24 h

7 Prolonged Infusion of High Dose Carbapenems To Optimize Therapy of MDR Pathogens COMPACT II study of ICU and non- ICU isolates in Asia. Imipenem, meropenem, doripenem cumulative fraction of response (CFR) in Monte Carlo analysis, varing dosing and infusion time Best CFR effect against P. aeruginosa of doripenem 1 and 2 gm q8 h (4 hours) (91.5%, 95.3%) and meropenem 2 gm q8h (3 hours) (91.3%), but less with imipenem 1 gm q8h (3 hours) (77.9%) (vs 65.2% with imipenem 1 gm, 30 min) None ideal against Acinetobacter, but best with high dose, prolonged infusion Kiratisin P, et al. Int J Antimicrob Agents 2013; 41: Similar data in US, except better vs. Acinetobacter.Koomanachai P, et al. Clin Ther 2010; 32: 776=779

8 Nomogram for Meropenem Dosing Based On Renal Function in Critically Ill Meropenem 1-2 gm loading dose, then continuous infusion to achieve target MIC values. Up to 8 gm per day, if needed Pea F, et al. Antimicrob Agents Chemother 2012; 56:

9 Optimizing Dosing of Carbapenems in the ICU In clinical trials, patients getting doripenem and with Cr Cl > 150ml/min, have a reduced clinical efficacy (underdosing) Studied impact of Cr Cl, weight and infusion method on % target attainment by MIC, using doripenem clinical trial data in 31 NP patients 1 Hour Infusion Drug clearance influenced by Cr Cl Volume distribution relates to weight Prolonged (4 hour) infusion eliminated most of the variability induced by weight and Cr Cl on % target attainment of MIC 4 Hour Infusion Roberts JA, Lipman J. Crit Care Med 2013; 41

10 CI of Beta Lactams in Severe Sepsis: Multicenter Double Blind Randomized Trial 30 pts with Continous Infusion (ticar/clav, pip/taz or meropen) vs. 30 bolus Same total dose 5 ICUs, all patients with severe sepsis CI: More target attainment of MIC, higher clinical cure, same survival Dulhunty JM, et al. Clin Infect Dis 2013; 56:236-44

11 Meropenem: Intermittent vs. Continuous Infusion in Severe ICU Infection 120 pts. Continuous: 2 gm load, 4 gm over 24 h (4 infusions of 1 gm over 6 h) 120 intermittent: 2gm q8h 96 and 102 micro eval Comparable clinical cure, higher micro success with continuous infusion (90% vs 78%,p=0.02), shorter ICU stay, duration therapy, lower total meropenem dose Chytra I,et al. Crit Care 2012; 16:R113

12 Prolonged Carbapenem Infusion in VAP: Making Appropriate Therapy More Adequate Prospective, randomized, openlabel comparison of 4 hour infusion of doripenem (500 mg) q 8 h vs. imipenem ( 500 mg q6h or 1 gm q 8h) 531 randomized, 525 in ITT, 226 microbiologically eval. Gram negatives most common. 56 with P. aeruginosa, 31 Acinetobacter With P. aeruginosa higher clinical (80% vs. 43%) and microbiologic cure (65% vs. 36%) with doripenem. Both therapies equivalent in overall effect in ITT populations Chastre et al. Crit Care Med 2008; 36:

13 Using Pk/PD Principles DID NOT Reduce VAP Therapy Duration 227 patients in prospective, randomized, double blind study of 7 days of 1 gram doripenem over 4 hours q 8h vs. 10 days of 1 gram imipenem over 1 hour q 8h 7 day therapy with sig less clinical cure and higher 28 day mortality, esp with P. aeruginosa Kollef et al. Crit Care 2012; 16:R 218

14 Using PK/PD Principles to Optimize VAP Therapy Prospective observational study of optimized therapy of VAP, based on local antibiogram 94 with pathway, 74 historical controls Optimal rx with 3 hour infusions of cefepime 2g q8h OR meropenem 2 g q8h PLUS tobramycin and vancomycin Pathway reduced infection related (not all cause 28 day) mortality (8.5% vs 21.6%) and LOS. More appropriate rx (71% vs. 48%).Able to treat non-susceptible P. aeruginosa Nicasio AN, et al. J crit Care 2010; 25: 69-77

15 No Benefit From Prolonged Infusion When Dose NOT Optimized and Little Resistance Before and after comparison of two time periods with 30 minute infusion vs. 3 hour infusion of pip/taz, cefepime, carbapenem Same dosing with prolonged inf. Few highly resistant organisms 242 intermittent, 261 prolonged infusion Treatment success the same in both groups (56% vs 51%). Same mortality Arnold HM et al. Ann Pharmacother 2013.

16 Meta-Analysis of CI or Extended Infusion 14 studies of Pip/tazobactam or carbapenems Mostly non-randomized, but a mortality benefit overall and for pneumonia Greater benefit for pip/taz than carbapenems by CI or EI vs. Intermittent Infusion Falagas ME, et al. CID 2013; 56:

17 Does Continuous Infusion of Beta- Lactams Improve Outcomes? In vitro advantage for CI or prolonged infusion, but no sig clinical difference to date Design issues: severity of illness, degree of resistance, dosing used Ideally of benefit in : severely ill, high MIC organisms, same daily doses as intermittent infusion, gram-negative infection, loading dose with CI Abdul-Aziz MH, et al. Ann Intensive Care 2012; 2:37

18 MRSA nosocomial pneumonia: Improved Outcome With Continuous Infusion of Vancomycin Case-control study of MRSA VAP 75 cases with VAP; 75 controls (23 with VAP) All MRSA treated with vancomycin (n=69) or teicoplanin (n=6) (Appropriate therapy) Mortality of MRSA VAP 48% vs 25.3% in controls (p=0.01) Mortality lower with continuousinfusion vancomycin (n=16) vs intermittent: 25% vs 54.7% (p=0.03) Rello et al. Crit Care Med 2005;33:

19 How To Dose Continuous Vancomycin Infusions in ICU Loading dose of 20 mg/kg over 3 hours (max 2 gm) 30 mg/kg (max 3 gm) per 24 h if normal renal fxn, 20 mg/kg (max 2 gm) if renal impairment Daily adjust to serum concentration of mg/l Studied in 34 patients. Serum levels often too high Saugel B, et al. J Crit Care 2014

20 Is There A Proven Benefit From Continuous Vancomycin Infusion? Time dependent killing, but 6x more clinical success if AUC/MIC is > clinical trials: 2 prospective, 1 meta-anlaysis, 11 retrospective No efficacy benefit for invasive MRSA Uncertain if any impact on nephrotoxicity risk DiMondi VP, Rafferty K. Ann Pharmacother 2013; 47:

21 Key Points on Continous Infusion of Antibiotics (1) Continuous or Prolonged infusions (3-4 hours) of betalactams with high doses allow targeting of organisms with high MIC values Need an initial loading dose, then prolonged infusion Doripenem most stable in solution at room temperature Meropenem more stable at room temperature than imipenem High doses of imipenem present a seizure risk > for meropenem Better mortality effect for pip/taz than carbapenem CI done with vancomycin with no proven benefit

22 Key Points on Continous Infusion of Antibiotics (2) When resistance is present (ESBLs and P. aeruginosa a concern) Use high dose and prolonged infusion of most active agents Imipenem can be used up to 1 gm load and 1 gm over 2-3 hours to target up to MIC of 4 mg/l Meropenem can be used up to 2 gm q 6h (over 3 hours) 1 gm over 3 h can cover up to MIC of 8; higher MICs if use higher doses Doripenem can be used up to 2 gm every 8 hours, given over 4 hours, and this regimen is the most active of all carbapenems and dosing regimens against P. aeruginosa. Prolonged infusion of doripenem optimizes therapy in obesity Prolonged infusions cannot improve outcomes unless dosing is optimized and there is a high prevalence of MDR pathogens.

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24 Challenges in VAP and ICU Infection Management: 2014 Increasingly resistant gram-negative pathogens Pseudomonas aeruginosa Acinetobacter spp. MDR Enterobacteriacea Few new systemic antibiotics on the horizon No development of drugs for resistant gram-negatives Need to avoid the overuse of systemic antibiotics Avoid toxicity and selection of resistance Try to use shorter durations of systemic therapy How can we do more with what we have? Optimizing dosing and delivery of the drugs we have

25 Doripenem Doripenem Meropenem Imipenem Jones et al. J Antimicrob Chemother 2004;54: Jones et al. Antimicrob Agents Chemother 2004;48: Parenteral 1-β-methyl carbapenem Stable to human renal dehydropeptidases Stable in presence of ESBLs No seizure risk Stable in solution for up to 8 hours in saline at room temperature. Prolonged infusion in critically ill. Pharmacokinetic and pharmacodynamic qualities similar to meropenem Activity vs. gram-negatives higher than meropenem

26 Continuous Infusion Imipenem Only achieves MIC Target Attainment for MIC critically ill patients with ICUacquired HAP 14 with brain injury or stroke (no seizures with therapy) Randomized, prospective, controlled study (10 each arm) of 1 g imipenem infusion and then 2 g continuous over 24 h vs. 1 g q 8H Measure plasma levels and Monte Carlo simulation Time > 40% above MIC : 1-2 mg/l for intermittent infusion vs. MIC of 2-4 mg/l for continuous infusion Sakka SG, et al. AAC 2007; 51:

27 Prolonged Infusion of Imipenem 9 patients with VAP rx with 0.5 gm imipenem q6h in 30 min vs. 0.5 gm q 6h over 2 hours vs. 1 gm q 6h over 2 hours. Best target attainment with 1 gm q 6h over 2 hours, with plasma conc > MIC of 4 mg/l for 60% of the dosing interval. No higher Cmax with 2 h infusion of 1 g vs 0.5 gm rapid infusion Jaruratanasirikul S et al. JAC 2009; 63: