DRUG DOSING IN AKI
FEDERICO PEA
INSTITUTE OF CLINICAL PHARMACOLOGY AND TOXICOLOGY
UNIVERSITY OF UDINE
ITALY
Disclosure of interests:
Consultant: Astellas, Pfizer; Janssen-Cilag
Speaker bureau: GlaxoSmithKline, Gilead, Janssen Cilag, Merch Sharp & Dohme, Novartis, Pfizer, Sanofi Aventis, ScheringPlough, Wyeth
6° PCRRT, Rome, 08-10 April 2010
PHARMACOKINETIC CONSIDERATIONS FOR ANTIMICROBIAL THERAPY IN
PATIENTS RECEIVING RENAL REPLACEMENT THERAPY
Pea F et al. Clin Pharmacokinet 2007 (12) 997-1038
DRUG REMOVAL BY MEANS OF CRRT
DIFFUSION
CONVECTION
Institute of Clinical Pharmacology and Toxicology - UniUD
CHARACTERISTICS OF SOME RENAL REPLACEMNT THERAPIES
PROCEDURE
DIFFUSION
CONVECTION
++++
+
Fistula or Veno-Venous
IHDF
+++
++
Fistula o Veno -Venous
CAPD
++++
+
CAVH
0
++++
Arterio -Venous
CVVH
0
++++
Veno-Venous
CAVHD
++++
+
Arterio -Venous
CVVHD
++++
+
Veno-Venous
CAVHDF
+++
+++
Arteri o -Venous
CVVHDF
+++
+++
Veno-Venous
IHD
Adapted from Joy et al. Ann Pharmacother 1998; 32: 362-375
VASCULAR ACCESS
None
Institute of Clinical Pharmacology and Toxicology - UniUD
PHARMACOKINETIC CONSIDERATIONS FOR ANTIMICROBIAL THERAPY IN
PATIENTS RECEIVING RENAL REPLACEMENT THERAPY
Pea F et al. Clin Pharmacokinet 2007 (12) 997-1038
CHARACTERISTICS OF DRUG REMOVAL DURING HEMODIALYSIS
•
DRUG REMOVAL BY DIFFUSION
•
PASSIVE PROCESS
•
IN COUNTERCORRENT
•
CONDITIONED BY MW
•
LONG-TIME FOR EQUILIBRIUM
•
NO REPLACEMENT FLUID NEEDED
DIALYSATE
BFR
Institute of Clinical Pharmacology and Toxicology - UniUD
PHARMACOKINETIC CONSIDERATIONS FOR ANTIMICROBIAL THERAPY IN
PATIENTS RECEIVING RENAL REPLACEMENT THERAPY
Pea F et al. Clin Pharmacokinet 2007 (12) 997-1038
CHARACTERISTICS OF DRUG REMOVAL DURING HEMOFILTRATION

DRUG REMOVAL BY CONVECTION

ACTIVE PROCESS

PUMP DRIVEN PRESSURE GRADIENT

UNCONDITIONED BY MW

RAPID EQUILIBRIUM
REPLACEMENT FLUID
PRE
POST
BFR
UF

REPLACEMENT FLUID NEEDED
Institute of Clinical Pharmacology and Toxicology - UniUD
DRUG CLEARANCE DURING RENAL REPLACEMENT THERAPY (RRT)
HEMOFILTRATION
POST-DILUTION
Solute removed
by convection
HEMOFILTRATION
PRE-DILUTION
Solute, diluted with
substitution volume,
removed by convection
Pump
Pump
Hemofilter
Hemofilter
Saturation
e.g. 80%
Saturation 100%
Drug Clearance =
UFR
Solute removed by
diffusion, conditioned by
molecular weight
Pump
Substitution
fluid
Substitution
fluid
HEMODIALYSIS
Drug Clearance =
(UFR x BFR) / (BFR + SFR)
Substitution
fluid
Hemodialyzer
Saturation e.g.
40-90%
Drug Clearance =
conditioned by MW
Institute of Clinical Pharmacology and Toxicology - UniUD
Bohler J. Kidney Int 1999;Suppl.72:24-28
FACTORS POTENTIALLY AFFECTING DRUG CLEARANCE
DURING RENAL REPLACEMENT THERAPY
DEVICE PROPERTIES
DRUG PROPERTIES
•
MOLECULAR WEIGHT
•
COMPOSITION
•
PLASMA PROTEIN BINDING
•
SURFACE AREA
•
VOLUME OF DISTRIBUTION
•
PORE SIZE
•
PROPORTION OF RENAL CLEARANCE
•
ADSORPTION
Institute of Clinical Pharmacology and Toxicology - UniUD
Pea F and Furlanut M. Chapter 219 in Critical Care Nephrology, 2nd Ed. Ronco C, Bellum and Bellomo Editors
WHY DRUG REMOVAL BY RENAL REPLACEMENT THERAPY
IS ESPECIALLY RELEVANT FOR ANTIMICROBIAL DRUGS?
Institute of Clinical Pharmacology & Toxicology – University Hospital of Udine
SURVIVING SEPSIS CAMPAIGN: INTERNATIONAL GUIDELINES
FOR MANAGEMENT OF SEVERE SEPSIS AND SEPTIC SHOCK: 2008
Dellinger RP et al. Intensive Care Med 2008; 34: 17-60
INITIAL RESUSCITATION AND INFECTION ISSUES:
ANTIBIOTIC THERAPY
• Begin intravenous antibiotics as early as possible, and always within the first hour of recognizing severe sepsis
(1D) and septic shock (1B).
• Broad-spectrum: one or more agents active against likely bacterial/fungal pathogens and with good penetration
into presumed source (1b)
• Reassess antimicrobial regimen daily to optimise efficacy, prevent resistance, avoid toxicity & minimise costs (1c)
• Consider combination therapy in pseudomonas infections (2d)
• Consider combination empiric therapy in neutropenic patients (2d)
• Combination therapy no more than 3–5 days and deescalation following susceptibilities (2d)
• Duration of therapy typically limited to 7–10 days; longer if response slow, undrainable foci of infection, or
immunologic deficiencies (1d)
• Stop antimicrobial therapy if cause is found to be non-infectious (1d)
Institute of Clinical Pharmacology & Toxicology – University Hospital of Udine
SURVIVING SEPSIS CAMPAIGN: INTERNATIONAL GUIDELINES
FOR MANAGEMENT OF SEVERE SEPSIS AND SEPTIC SHOCK: 2008
Dellinger RP et al. Intensive Care Med 2008; 34: 17-60
INITIAL RESUSCITATION AND INFECTION ISSUES:
ANTIBIOTIC THERAPY
• Begin intravenous antibiotics as early as possible, and always within the first hour of recognizing severe sepsis
(1D) and septic shock (1B).
• Broad-spectrum: one or more agents active against likely bacterial/fungal pathogens and with good penetration
into presumed source (1b)
• Reassess antimicrobial regimen daily to optimise efficacy, prevent resistance, avoid toxicity & minimise costs (1c)
• Consider combination therapy in pseudomonas infections (2d)
• Consider combination empiric therapy in neutropenic patients (2d)
• Combination therapy no more than 3–5 days and deescalation following susceptibilities (2d)
• Duration of therapy typically limited to 7–10 days; longer if response slow, undrainable foci of infection, or
immunologic deficiencies (1d)
• Stop antimicrobial therapy if cause is found to be non-infectious (1d)
Institute of Clinical Pharmacology & Toxicology – University Hospital of Udine
ANTIMICROBIAL THERAPY IN THE CRITICALLY ILL PATIENTS:
A REVIEW OF THOSE PATHOPHYSIOLOGICAL CONDITIONS RESPONSIBLE FOR HUGE PK VARIABILITY
Pea F, Viale P, Furlanut M
Clin Pharmacokinet 2005; 44: 1009-1034
Critically ill patients
VARIATIONS IN
Vd  LD
EXTRACELLULAR
FLUID
Increased if
PLEURAL EFFUSION
FLUID
FLUID THERAPY
THERAPY
ASCITES
MEDIASTINITIS
OEDEMA
POST-SURGICAL
DRAINAGES
HYPOALBUMINAEMIA
VARIATIONS IN
RENAL
CL  MD
RENAL CLEARANCE
SEVERE SEPSIS AND CAPILLARY LEAKAGE
Increased if
DRUG ABUSE
BURNS
Decreased if
HYPERDYNAMICS
HAEMODINAMICALLY ACTIVE DRUGS
LEUKEMIA
RENAL IMPAIRMENT
DIALYSIS
HYPOALBUMINAEMIA
Antimicrobial dilution
or loss
Enhanced antimicrobial
renal excretion
Reduced antimicrobial
renal excretion
Consider
LDDOSAGE
DOSAGEINCREASE
INCREASE
Consider
DOSAGE INCREASE
Consider
DOSAGE DECREASE
Institute of Clinical Pharmacology & Toxicology – University Hospital of Udine
APPROPRIATE ANTIBIOTIC THERAPY IN SEVERE SEPSIS AND SEPTIC SHOCK:
DOES THE DOSE MATTER ?
Pea F and Viale P. Crit Care 2009; 13 (3) 214
CRITICAL ISSUES
• Appropriate antibiotic therapy in patients with severe sepsis and septic shock should
mean prompt achievement and maintenance of optimal exposure at the infection site with
broad-spectrum antimicrobial agents administered in a timely manner.
• Once that causative pathogens have been identified and tested for their in vitro
susceptibility, subsequent de-escalation of antimicrobial therapy should be applied
whenever feasible.
• The goal of appropriate antibiotic therapy must be pursued resolutely and with
continuity in the light of the ongoing explosion of antibiotic-resistant infections which
plague the ICU setting and of the continue decrease of antibiotic pipeline.
Institute of Clinical Pharmacology & Toxicology – University Hospital of Udine
APPROPRIATE ANTIBIOTIC THERAPY IN SEVERE SEPSIS AND SEPTIC SHOCK:
DOES THE DOSE MATTER ?
Pea F and Viale P. Crit Care 2009; 13 (3) 214
CRITICAL ISSUES
• Appropriate antibiotic therapy in patients with severe sepsis and septic shock should
mean prompt achievement and maintenance of optimal exposure at the infection site with
broad-spectrum antimicrobial agents administered in a timely manner.
• Once that causative pathogens have been identified and tested for their in vitro
susceptibility, subsequent de-escalation of antimicrobial therapy should be applied
whenever feasible.
• The goal of appropriate antibiotic therapy must be pursued resolutely and with
continuity in the light of the ongoing explosion of antibiotic-resistant infections which
plague the ICU setting and of the continue decrease of antibiotic pipeline.
Institute of Clinical Pharmacology & Toxicology – University Hospital of Udine
DEVELOPMENTAL CHANGES IN PHYSIOLOGIC FACTORS
THAT INFLUENCE DRUG DISPOSITION IN INFANTS, CHILDREN, AND ADOLESCENTS
Kearns GL et al. N Engl J Med 2003;349:1157-67.
FACTORS POTENTIALLY AFFECTING DRUG CLEARANCE
DURING RENAL REPLACEMENT THERAPY
DEVICE PROPERTIES
DRUG PROPERTIES
•
MOLECULAR WEIGHT
•
COMPOSITION
•
PLASMA PROTEIN BINDING
•
SURFACE AREA
•
VOLUME OF DISTRIBUTION
•
PORE SIZE
•
PROPORTION OF RENAL CLEARANCE
•
ADSORPTION
Institute of Clinical Pharmacology and Toxicology - UniUD
Pea F and Furlanut M. Chapter 219 in Critical Care Nephrology, 2nd Ed. Ronco C, Bellum and Bellomo Editors
MOLECULAR WEIGHT
Teicoplanin
Q/D
Vancomycin
Colistin
Rifampin
Ceftriaxone
Ceftazidime
Piperacillin
Cefpirome
Cefepime
Cefotaxime
M oxifloxacin
M eropenem
Aztreonam
Clindamycin
Gatifloxacin
Levofloxacin
Amoxicillin
Ampicillin
Linezolid
Ciprofloxacin
Imipenem
M etronidazole
0
500
Pea F et al. Clin Pharmacokinet 2007 (12) 997-1038
1000
1500
2000
Institute of Clinical Pharmacology and Toxicology - UniUD
FACTORS POTENTIALLY AFFECTING DRUG CLEARANCE
DURING RENAL REPLACEMENT THERAPY
DEVICE PROPERTIES
DRUG PROPERTIES
•
MOLECULAR WEIGHT
•
COMPOSITION
•
PLASMA PROTEIN BINDING
•
SURFACE AREA
•
VOLUME OF DISTRIBUTION
•
PORE SIZE
•
PROPORTION OF RENAL CLEARANCE
•
ADSORPTION
Institute of Clinical Pharmacology and Toxicology - UniUD
Pea F and Furlanut M. Chapter 219 in Critical Care Nephrology, 2nd Ed. Ronco C, Bellum and Bellomo Editors
PLASMA PROTEIN BINDING
Clindamycin
Teicoplanin
Ceftriaxone
Aztreonam
Vancomycin
M oxifloxacin
Cefotaxime
Linezolid
Levofloxacin
Ciprofloxacin
Piperacillin
Ampicillin
Gatifloxacin
Imipenem
Amoxicillin
Cefepime
Ceftazidime
M etronidazole
M eropenem
0
20
Pea F et al. Clin Pharmacokinet 2007 (12) 997-1038
40
60
80
Institute of Clinical Pharmacology and Toxicology - UniUD
100
SIEVING COEFFICIENT DURING CVVH
Sc =
CUF
CP
Cefotaxime
Amikacin
Netilmicin
Tobramycin
Imipenem
Ceftazidime
Metronidazole
Piperacillin
Gentamicin
Vancomycin
Ampicillin
Penicillin
Ciprofloxacin
Clindamycin
Ceftriaxone
Teicoplanin
Oxacillin
0
0.2
0.4
Golper TA & Marx MA. Kidney Int 1998; Suppl.66: 165-168
0.6
0.8
1
1.2
Institute of Clinical Pharmacology and Toxicology - UniUD
FACTORS POTENTIALLY AFFECTING DRUG CLEARANCE
DURING RENAL REPLACEMENT THERAPY
DEVICE PROPERTIES
DRUG PROPERTIES
•
MOLECULAR WEIGHT
•
COMPOSITION
•
PLASMA PROTEIN BINDING
•
SURFACE AREA
•
VOLUME OF DISTRIBUTION
•
PORE SIZE
•
PROPORTION OF RENAL CLEARANCE
•
ADSORPTION
Institute of Clinical Pharmacology and Toxicology - UniUD
Pea F and Furlanut M. Chapter 219 in Critical Care Nephrology, 2nd Ed. Ronco C, Bellum and Bellomo Editors
HYDROPHILIC ANTIBIOTICS
•
BETA-LACTAMS
LIPOPHILIC ANTIBIOTICS
•
MACROLIDES
•
FLUOROQUINOLONES

PENICILLINS

CEPHALOSPORINS

CARBAPENEMS
•
TETRACYCLINES

MONOBACTAMS
•
CHLORAMPHENICOL
•
GLYCOPEPTIDES
•
RIFAMPICIN
•
AMINOGLYCOSIDES
•
LINEZOLID
 LOW VOLUME OF DISTRIBUTION
 HIGH VOLUME OF DISTRIBUTION
 INABILITY OF DIFFUSING THROUGH MEMBRANES
 ABILITY OF DIFFUSING THROUGH MEMBRANES
 INACTIVITY AGAINST INTRACELLULAR PATHOGENS
 ACTIVITY AGAINST INTRACELLULAR PATHOGENS
 RENAL ELIMINATION AS UNCHANGED DRUG
 ELIMINATION AFTER LIVER METABOLIZATION
Institute of Clinical Pharmacology and Toxicology - UniUD
Pea F, Viale P, Furlanut M. Clin Pharmacokinet 2005; 44: 1009-1034
Pea F & Viale P. Clin Infect Dis 2006; 42: 1764-1771
FACTORS POTENTIALLY AFFECTING DRUG CLEARANCE
DURING RENAL REPLACEMENT THERAPY
DEVICE PROPERTIES
DRUG PROPERTIES
•
MOLECULAR WEIGHT
•
COMPOSITION
•
PLASMA PROTEIN BINDING
•
SURFACE AREA
•
VOLUME OF DISTRIBUTION
•
PORE SIZE
•
PROPORTION OF RENAL CLEARANCE
•
ADSORPTION
Institute of Clinical Pharmacology and Toxicology - UniUD
Pea F and Furlanut M. Chapter 219 in Critical Care Nephrology, 2nd Ed. Ronco C, Bellum and Bellomo Editors
HYDROPHILIC ANTIBIOTICS
•
BETA-LACTAMS
LIPOPHILIC ANTIBIOTICS
•
MACROLIDES
•
FLUOROQUINOLONES

PENICILLINS

CEPHALOSPORINS

CARBAPENEMS
•
TETRACYCLINES

MONOBACTAMS
•
CHLORAMPHENICOL
•
GLYCOPEPTIDES
•
RIFAMPICIN
•
AMINOGLYCOSIDES
•
LINEZOLID
 LOW VOLUME OF DISTRIBUTION
 HIGH VOLUME OF DISTRIBUTION
 INABILITY OF DIFFUSING THROUGH MEMBRANES
 ABILITY OF DIFFUSING THROUGH MEMBRANES
 INACTIVITY AGAINST INTRACELLULAR PATHOGENS
 ACTIVITY AGAINST INTRACELLULAR PATHOGENS
 RENAL ELIMINATION AS UNCHANGED DRUG
 ELIMINATION AFTER LIVER METABOLIZATION
Institute of Clinical Pharmacology and Toxicology - UniUD
Pea F, Viale P, Furlanut M. Clin Pharmacokinet 2005; 44: 1009-1034
Pea F & Viale P. Clin Infect Dis 2006; 42: 1764-1771
DRUG PROPERTIES CONDITIONING
THE HIGHEST POTENTIAL CLEARANCE DURING RRT
CVVH-DF
• LOW MOLECULAR WEIGHT
• LOW PLASMA PROTEIN BINDING
• LOW VOLUME OF DISTRIBUTION
• HIGH RENAL CLEARANCE
Institute of Clinical Pharmacology and Toxicology - UniUD
Pea F and Furlanut M. Chapter 219 in Critical Care Nephrology, 2nd Ed. Ronco C, Bellum and Bellomo Editors
FACTORS POTENTIALLY AFFECTING DRUG CLEARANCE
DURING RENAL REPLACEMENT THERAPY
DEVICE PROPERTIES
DRUG PROPERTIES
•
MOLECULAR WEIGHT
•
COMPOSITION
•
PLASMA PROTEIN BINDING
•
SURFACE AREA
•
VOLUME OF DISTRIBUTION
•
PORE SIZE
•
PROPORTION OF RENAL CLEARANCE
•
ADSORPTION
Institute of Clinical Pharmacology and Toxicology - UniUD
Pea F and Furlanut M. Chapter 219 in Critical Care Nephrology, 2nd Ed. Ronco C, Bellum and Bellomo Editors
In Vitro ADSORPTION OF GENTAMICIN AND NETILMICIN
BY POLYACRYLONITRILE AND POLYAMIDE HEMOFILTRATION FILTERS
Lam PKN et al. Antimicrob Agents Chemother 2010 Feb, 54: 963–965
CUMULATIVE ADSORPTION OF GENTAMICIN BY HEMOFILTERS AGAINST TIME
Institute of Clinical Pharmacology and Toxicology - UniUD
In Vitro ADSORPTION OF GENTAMICIN AND NETILMICIN
BY POLYACRYLONITRILE AND POLYAMIDE HEMOFILTRATION FILTERS
Lam PKN et al. Antimicrob Agents Chemother 2010 Feb, 54: 963–965
CUMULATIVE ADSORPTION OF NETILMICIN BY HEMOFILTERS AGAINST TIME
Institute of Clinical Pharmacology and Toxicology - UniUD
ALGORITHM FOR INDIVIDUALIZATION OF PHARMACOTHERAPY REGIMENS IN PATIENTS RECEIVING CRRT
DRUG-SPECIFIC FACTORS
1 Volume of distribution
2 Protein binding
3 Molecular weight
4 Fraction eliminated unchanged in the urine
Select CRRT
PATIENT CHARACTERISTICS
1 Residual renal frunction
2 Volume status
3 Other organ function information
CALCULATE RESIDUAL RENAL FUNCTION
1 Estimate: residual total body CL from published literature
2 Measure serum concentration-time data prior to CRRT
CAVH/CVVH/SCUF
CAVHDF/CVVHDF
1.Ultrafiltration rate
2.Hemofilter characteristics
CAVHD/CVVHD
1.Dialysate flow rate
2.Ultrafiltration rate
3. Hemofilter characteristics
1.Dialysate flow rate
2. Hemofilter characteristics
Estimate SC = literature review for published fup
Calculate SC = Cuf/Ca
CL CAVH/CVVH
CL CAVHDF/CVVHDF
CL CAVHD/CVVHD
1.Estimate:ClCVVH= Qf•SC
ClCVVH= Qf•fu
2.Measure: same as CVVHDF
1.Estimate: ClCVVHDF= fu(Qf+Qdial)
2.Measure: ClCVVHDF= (Cdf•Vdf)/AUC0-t
ClCVVHDF= (Cdf•Vdf)/Cmidpt
1.Estimate: ClCVVHD= fu•Qdial
2.Measure: ClCVVHD= (Cdial•Vdial)/AUC0-t
ClCVVHD= (Cdial•Vdial)/Cmidpt
Dosage calculation
Joy et al.
Ann Pharmacother 1998;32:362-375
Cltot= ClCRRT+Clresidual
Dose= Cp ss•Cltot•t
Institute of Clinical Pharmacology and Toxicology - UniUD
PHARMACOKINETIC CONSIDERATIONS FOR ANTIMICROBIAL THERAPY IN
PATIENTS RECEIVING RENAL REPLACEMENT THERAPY
Pea F et al. Clin Pharmacokinet 2007 (12) 997-1038
GENERAL PRINCIPLES FOR APPROPRIATELY HANDLING
RENALLY CLEARED DRUGS DURING CRRT
• Drug extraction increases linearly with QUF and/or QD applied
• CVVHDF is generally more efficient than CVVH
• Post-dilution is more efficient than pre-dilution
Institute of Clinical Pharmacology and Toxicology - UniUD
PHARMACOKINETIC CONSIDERATIONS FOR ANTIMICROBIAL THERAPY
IN PATIENTS RECEIVING RENAL REPLACEMENT THERAPY
Pea F et al. Clin Pharmacokinet 2007 (12) 997-1038
GENERAL PRINCIPLES FOR APPROPRIATELY HANDLING
RENALLY CLEARED DRUGS DURING CRRT
• Drugs normally at high CLr which exhibit high CLCRRT during CVVH or CVVHDF
may need significant dosage increase in comparison with renal failure or even
IHD  beta lactams, glycopeptides, aminoglycosides, levofloxacin, ciprofloxacin
• Conversely, drugs normally non renally cleared which exhibit very low CLCRRT
during CVVH or CVVHDF may need unmodified dosages in comparison with normal
renal function  linezolid, moxifloxacin, clindamycin, Q/D, ceftriaxone, oxacillin
Institute of Clinical Pharmacology and Toxicology - UniUD
DRUG ADMINISTRATION DURING INTERMITTENT HEMODIALYSIS
AND CONTINUOUS RENAL REPLACEMENT THERAPY:
SPECIAL CONSIDERATIONS IN PEDIATRIC PATIENTS
Veltri MA et al. Paediatr Drugs. 2004; 6: 45-65
SUGGESTED PEDIATRIC STARTING DOSAGES FOR SELECTED INTRAVENOUS (IV) MEDICATIONS
Institute of Clinical Pharmacology and Toxicology - UniUD
DRUG ADMINISTRATION DURING INTERMITTENT HEMODIALYSIS
AND CONTINUOUS RENAL REPLACEMENT THERAPY:
SPECIAL CONSIDERATIONS IN PEDIATRIC PATIENTS
Veltri MA et al. Paediatr Drugs. 2004; 6: 45-65
SUGGESTED PEDIATRIC STARTING DOSAGES FOR SELECTED INTRAVENOUS (IV) MEDICATIONS
Institute of Clinical Pharmacology and Toxicology - UniUD
DRUG ADMINISTRATION DURING INTERMITTENT HEMODIALYSIS
AND CONTINUOUS RENAL REPLACEMENT THERAPY:
SPECIAL CONSIDERATIONS IN PEDIATRIC PATIENTS
Veltri MA et al. Paediatr Drugs. 2004; 6: 45-65
SUGGESTED PEDIATRIC STARTING DOSAGES FOR SELECTED INTRAVENOUS (IV) MEDICATIONS
Institute of Clinical Pharmacology and Toxicology - UniUD
PHARMACOKINETIC CONSIDERATIONS FOR ANTIMICROBIAL THERAPY
IN PATIENTS RECEIVING RENAL REPLACEMENT THERAPY
Pea F et al. Clin Pharmacokinet 2007 (12) 997-1038
GENERAL PRINCIPLES FOR APPROPRIATELY HANDLING
RENALLY CLEARED DRUGS DURING CRRT
• Drugs normally at high CLr which exhibit high CLCRRT during CVVH or CVVHDF
may need significant dosage increase in comparison with renal failure or even
IHD  beta lactams, glycopeptides, aminoglycosides, levofloxacin, ciprofloxacin
• Conversely, drugs normally non renally cleared which exhibit very low CLCRRT
during CVVH or CVVHDF may need unmodified dosages in comparison with normal
renal function  linezolid, moxifloxacin, clindamycin, oxacillin, ceftriaxone
Institute of Clinical Pharmacology and Toxicology - UniUD
DRUG ADMINISTRATION DURING INTERMITTENT HEMODIALYSIS
AND CONTINUOUS RENAL REPLACEMENT THERAPY:
SPECIAL CONSIDERATIONS IN PEDIATRIC PATIENTS
Veltri MA et al. Paediatr Drugs. 2004; 6: 45-65
SUGGESTED PEDIATRIC STARTING DOSAGES FOR SELECTED INTRAVENOUS (IV) MEDICATIONS
Institute of Clinical Pharmacology and Toxicology - UniUD
WHICH SCHEDULE OF ADMINISTRATION FOR ANTIBIOTICS
DURING RENAL REPLACEMENT THERAPY ?
Institute of Clinical Pharmacology & Toxicology – University Hospital of Udine
PK-PD RELATIONSHIPS
BETA-LACTAMS, GLYCOPEPTIDES, OXAZOLIDINONES
• Time-dependent antibacterial activity
Antibiotic concentration
(µg/mL)
Optimal exposure:
Cmin > MIC
MIC
• TARGET  MAINTENANCE
OF CMIN > MIC
(µg/mL)
t > MIC
t > MIC
Dosing interval (h)
REFRACT DOSAGES
UNTIL TO CONTINUOUS INFUSION
Institute of Clinical Pharmacology & Toxicology – University Hospital of Udine
Viale P & Pea F in: Nosocomial pneumonia - strategies for management, Ed J. Rello, 2007
PK-PD RELATIONSHIPS
AMINOGLYCOSIDES, FLUOROQUINOLONES
• Concentration-dependent antibacterial activity
Concentration (µg/mL)
Cmax
• TARGET  ACHIEVEMENT OF THE HIGHEST CMAX AND/OR AUC
MIC
(µg/mL)
AUC
C
max/MIC
> 10
AUC/MIC > 125
Dosing interval (h)
Optimal exposure:
Cmax/MIC > 10
AUC/MIC > 40-50 vs G+
ONCE DAILY DOSING WHENEVER FEASIBLE
AUC/MIC > 125 vs GInstitute of Clinical Pharmacology & Toxicology – University Hospital of Udine
Viale P & Pea F in: Nosocomial pneumonia - strategies for management, Ed J. Rello, 2007
ANTIBIOTIC DOSING IN CRITICALLY ILL ADULT PATIENTS
RECEIVING CONTINUOUS RENAL REPLACEMENT THERAPY
Trotman LR et al. Clin Infect Dis (15 October) 2005; 41:1159–66
…..
patient, drug, and mechanical variables significantly diminish
the utility of routine pharmacokinetic calculations for
determining antimicrobial dosing during CRRT
WHENEVER FEASIBLE DRUG EXPOSURE SHOULD BE OPTIMIZED BY MEANS OF
Istituto di Farmacologia Clinica - UniUD