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Andrea Novelli
Dipartimento di Scienze della Salute Sezione di Farmacologia Clinica & Oncologia
Farmacologia dell’ospite critico: Terapia anti-infettiva nell’insufficienza d’organo e
cirtcolazione extra-corporea
• Angelini • Menarini Group • MSD
• Named • Valeas • Zambon Group
Transparency Declaration Honoraria or grant support received from:
Approach to the infected patient for the provision of optimal antibiotic therapy
Infected patient
Pharmacodynamic considerations
Time course of bacterial killing
Post-antibiotic effect Preclinical infection models
Pharmacokinetic considerations
Relative solubility
Protein binding Clearance mechanism
Clinical considerations
Site of infection Severity of illness Body composition Likely pathogens
Local resistance patterns
Clinical trial data
Modelling and simulation
Optimal antibiotic
dosing regimen
Onufrak NJ et al., Clin Ther, 2016
Causes of poor clinical evolution or therapeutic failure
• Lack of activity in empirical use (inappropriate treatment)
• Severe immunosuppression in the host • Concomitant diseases in advanced stage • Related adverse effects • Underdosing • Poor penetration in the infected tissue
Alvarez-Lerma F & Grau S, Drugs, 2012
PK-PD of antibacterials Antibacterial class Optimal PD
parameter PK-PD magnitude required for
efficacy
Theoretical Clinically needful Aminoglycosides Cmax/MIC 8 10 – 12 β-lactams (penicillins) T > MIC 50 > 70
Carbapenems T > MIC 30 > 45
Vancomycin AUC/MIC 400 > 400 Linezolid AUC/MIC 80 > 100 Daptomycin AUC/MIC 400-600 > 600
Tigecycline AUC/MIC ≥ 7 > 18
Adembri C & Novelli A, Clin Pharmacokinet 2009 ; Scaglione F & Paraboni L, Int J Antimicrob Agents, 2008; Alvarez-Lerma F & Grau S, Drugs, 2012; Canut A et al., Eur J Clin Microbiol Infect Dis, 2012.
• Low Vd • Predominant renal Cl • Low intracellular penetration
• High Vd • Predominant hepatic Cl • Good intracellular penetration
• ↑ Vd • Cl ↑ or ↓ dependent on renal
function
• Vd largely unchanged • Cl ↑ or ↓ dependent on
hepatic function
• β-lactams • Aminoglycosides • Glycopeptides • Daptomycin • Colistin
• Fluoroquinolones • Macrolides • Lincosamides • Linezolid •Tigecycline
General PK
Altered ICU PK
Examples
Hydrophilic antibiotics Lipophilic antibiotics
Roberts JA et al., Crit Care Med, 2009, mod
Severe sepsis/septic shock and impact on antibiotic pharmacokinetics
Cotta MO et al., Med Intensiva, 2015
Gentamicin
Relationship between albumin levels and volume of distribution or peak concentration
Bukkems LH et al., Int J Antomicrob Agents, 2018
Vd Cmax
Aminoglycoside use
Univariate analysis of risk associated with renal impairment
No renal impairment
n (%)
Renal impairment
n (%)
OR (95% CI)
P value
Sex Male
71 (57.3)
22 (73.3)
2.1 (0.85-4.97)
0.11
Nephrotoxic drug Yes
83 (66.9)
27 (90.0)
4.5 (1.27-15.52)
0.02
Prescription duration ≥ 3 days
26 (21.0)
16 (53.3)
4.3 (1.86-9.95)
< 0.001
N. administration per day > 1
9 (7.3)
6 (20.0)
3.2 (1.04-9.82)
0.04
Monitoring residual level Yes
45 (36.3)
17 (56.7)
2.3 (1.02-5.16)
0.04
Fraisse T et al., Age and Ageing 2014
• When prescribing aminoglycosides, it is important:
• to use the highest dose and the shortest as possible (<3 days) • limiting other nephrotoxic drugs • PK monitoring is to adapt aminoglycoside dose
β-lactam antibiotics
SHORT DOSING INTERVALS OR
CONTINUOUS INFUSION ?
PROLONGED INFUSION (3-4 h)
Betalactams
Study endpoints by treatment group
Endpoint Continuous infusion
Intermittent bolus
P
Plasma antibiotic concentration > MIC
18/22 (81.8%) 6/21 (28.6%) 0.001
Piperacillin/tazobactam 9/12 (75%) 4/11 (36%) Meropenem 8/8 (100%) 2/9 (22%) Clinical cure (test of cure date)
23/30 (76.7%)
13/30 (43.3%)
0.032
Dulhunty JM et al., Clin Infect Dis, 2013
Clinical cure rate for patients treated by prolonged-infusion or IV bolus dosing
* P < 0.05 prolonged-infusion vs IB dosing; n = number of patients in the subgroup
Abdul-Aziz MH et al., J Antimicrob Chemother, 2016
* P < 0.05 prolonged-infusion vs IB dosing; n = number of patients in the subgroup
Abdul-Aziz MH et al., J Antimicrob Chemother, 2016
30 day survival in patients treated by prolonged-infusion or IV bolus dosing
Piperacillin/tazobactam in severly ill patients
Meta-analysis of clinical cure according to infusion scheme
Rhodes NJ et al., Crit Care Med, 2018
>20%
<20%
Daptomycin
Mean pharmacokinetic parameters in healthy volunteers and severely ill patients
Parameter
6 mg/kg 8 mg/kg
Volunt.a
(6) Pts.c
(13) P* Volunt.b
(6) Pts.c
(7) P*
Cmax (mg/l) 86.4 55.7 < 0.01 106.2 85.1 = 0.05
t½ (h) 7.8 8.8 NS 7.3 8.6 NS
AUC (mg·h/l) 705 406.1 < 0.01 773.3 584.3 < 0.05
Cl (ml/h/kg) 8.6 18.0 < 0.05 10.1 20.4 < 0.05
Vd (l/kg) 0.096 0.22 < 0.01 0.102 0.25 < 0.01
( ) no. Cases * ANOVA test a Dvorchik BH et al., Antimicrob Agents Chemother, 2009 b Benvenuto M et al., Antimicrob Agents Chemother, 2006 c Falcone M, Venditti M, Novelli A, 21st ECCMID-27th ISC Milan, Italy, 2011
Cmax (mg/l) 86.4 55.7 < 0.01 106.2 85.1 = 0.05
AUC (mg·h/l) 705 406.1 < 0.01 773.3 584.3 < 0.05
Cl (ml/h/kg) 8.6 18.0 < 0.05 10.1 20.4 < 0.05 Vd (l/kg) 0.096 0.22 < 0.01 0.102 0.25 < 0.01
Considerations for Higher Doses of Daptomycin in Critically Ill Patients With Methicillin-Resistant S. aureus Bacteremia Falcone M, Russo A, Venditti M, Novelli A, Pai MP
• Methods. We evaluated the plasma pharmacokinetics (PK) and clinical outcomes of a cohort of critically ill patients treated with daptomycin 6–8 mg/kg/day for primarily Staphylococcus species–related infections. Data were modeled by population PK analyses, with Monte Carlo simulation to estimate the probabilities of effect and toxicity with standard and alternate dosing regimens.
• Results. Significantly lower daptomycin exposures were observed despite comparable
doses in a subset of patients (n = 13) with augmented clearance (CL). • This subset was significantly more likely to:
– be in severe sepsis or septic shock – have higher Sequential Organ Failure Assessment scores – have MRSA bacteremia.
In-hospital mortality was significantly higher (30.7% vs 10.8%) in patients with augmented daptomycin CL.
Use of an empiric fixed dose of 750 mg of daptomycin is predicted to achieve a comparable PTA with a lower probability of toxicity as compared to the use of 10 mg/kg in critically ill patients.
Clin Infect Dis, 57(11): 1568-1576, 2013
Tissue penetration of antimicrobial drugs and severity of organ failure
(AU
C tis
sue :
AU
C pl
asm
a,fre
e ra
tio)
1.4 1.2 1.0 0.8 06 0.4 0.2 0.0
SOFA Score 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14
Levofloxacin
Piperacillin
Zeitlinger Clin Pharmacokin 2007
Meropenem*
Concentration-time profile in plasma and ELF in 39 VAP patients
Parameter AUCplasma (mg·h/l)
AUCELF (mg·h/l)
Penetration ratio (%)
Mean 150.8 82.3 81.6
Median 130.9 35.0 25.42
SD 87.4 140.1 223.0
Percentile
10th 63.9 4.76 3.67
25th 90.14 12.52 9.0
50th 130.9 35.0 25.42
75th 189.3 92.1 70.14
90th 262.1 204.7 177.9
* 2g prolonged infusion Lodise TP et al., Antimicrob Agents Chemother, 2011
PK/PD of linezolid after intermittent or continuous infusion
0 6 12 18 24 30 36 42 48 54 60 66 72 780
5
10
15
20Intermittent Continuous
** **
*** ** **
*p< 0.05 **p< 0.01
* *
Time (h)
Con
cent
ratio
n (m
g/L)
4 mg/l = Susceptibility breakpoint
2 mg/l = for Staphylococcus spp. and Enterococcus spp.
Parameter Group I Group C
AUC/MIC 92.2 ± 45.2a 103.03 ± 39.8a
AUC/MIC (2mg/l) ≥ 85
5/8 (62.5%) 7/8 (87.5%)
Tfree > 2 mg/L MIC (%) > 80%
3/8 (40%)* 8/8 (100%)*
Adembri C et al., Int J Antimicrob Agents, 2007
a mean ± SD * P < 0.05 Group I vs Group C
Optimization of linezolid therapy in the critically ill: the effect of adjusted infusion regimens Taubert M, Zander J, Frechen S, Scharf C, Frey L, Vogeser M, Fuhr U, Zoller M
• RESULTS: Best target attainment according to T>MIC was observed for continuous infusions, followed by q6h, q8h and q12h.
• A substantially reduced target attainment was observed in patients with acute respiratory distress syndrome (ARDS)
• In patients without ARDS a dose of 1400 mg/day administered q6h or by continuous infusions provided an acceptable target attainment (e.g. cumulative fraction of response with regards to T>MIC≥93%)
• CONCLUSIONS: Irrespective of the regimen, 1200 mg/day linezolid might be insufficient for the treatment of ICU patients. Patients without ARDS might particularly benefit from q6h infusions with increased daily doses (e.g. 1400mg/day)
J Antimicrob Chemother, 72: 2304–2310, 2017
Antimicrobial drugs
PK considerations and adaptation of dosing regimen
Infection site PK alteration Potential change to dosing regimen
Blood Expanded Vd, enhanced Cl Provision of LD, increase frequency
Lung Impaired permeability Increase dose Soft tissue Contingent on body composition Increase dose in obesity Bone Impaired permeability Increase dose, duration of
therapy
CNS Impaired permeability Maximal dose
Onufrak NJ et al., Clin Ther, 2016
Cefepime-induced neurotoxicity
A clinical picture
• Renal dysfunction • Critical illness • Altered BBB • Older age • Drug overdose
• Altered mental status • Reduced consciousness • Confusion • Myoclonus • Aphasia • Agitation • Seizures
Risk factors Signs and symptoms
Payne LE et al., Crical Care, 2017
Vancomycin in ICU patients
Distribution of trough concentration versus age
Scaling: the marker size represents the number of patients in the vicinity of the spot Qian X et al., Int J Infect Dis, 2017
Scaling: the marker size represents the number of patients in the vicinity of the spot Qian X et al., Int J Infect Dis, 2017
Vancomycin in ICU patients
Distribution of trough concentration versus estimated glomerular filtration rate (eGFR)
Altered PK in Critically ill Patients
Increased Vd Decreased Cl Increased Cl Variable changes in Vd and/or Cl
Hypoalbuminaemia, leading to increased unbound drug
Renal hypoperfusion Augmented renal clearance
Extracorporeal interventions (eg RRT, ECMO)
Capillary leakage Acute kidney injury
Fluid resuscitation Renal/hepatic dysfunction
Third space loss
Wong G et al., BMC Infect Dis, 2014
Antibiotic Dosing in Critically Ill Patients Receiving CRRT: Underdosing is Overprevalent Lewis SJ and Mueller BA
• In CRRT patients our too-careful practice of “starting low and going slow” with antibiotic dosing to avoid the risk of toxicity may lead to an “overprevalence” of antibiotic underdosing and call for clinicians to strike a more aggressive antibiotic prescription in the intensive care unit
Semin Dial, 27(5):441-5, 2014
Amikacin in critical ill patients on CRRT
PTA of efficacy (Cmax/MIC ratio ≥8) and toxicity (Cmin2.5 mg/l)
Weight = 80kg and pathogens with 4 mg/l MIC Roger C et al., Antimicrob Agents Chemother, 2016
CVVH
Roger C et al., Antimicrob Agents Chemother, 2016
Amikacin in critical ill patients on CRRT
PTA of efficacy (Cmax/MIC ratio ≥8) and toxicity (Cmin2.5 mg/l) CVVHDF
Weight = 80kg and pathogens with 4 mg/l MIC
Population pharmacokinetics of daptomycin in adult patients undergoing continuous renal replacement therapy Xu X, Khadzhynov D, Peters H, Chaves RL, Hamed K, Levi M, Corti N
• AIM: the objective of this population pharmacokinetic (PK) analysis was to provide guidance for the dosing interval of daptomycin in patients undergoing continuous renal replacement therapy (CRRT)
• CONCLUSIONS: Q24 h dosing of daptomycin up to 12 mg/kg provides comparable drug exposure in patients on CVVHD and in those with CrCl ≥ 30 ml/min. Daily daptomycin use up to 8 mg/kg doses are appropriate for patients on CVVHDF, but higher doses may increase the risk of toxicity
Br J Clin Pharmacol, 83: 498–509, 2017
Cefepime in CVVHDF* simulated patients
Shaw AR et al., Seminars in Dialysis, 2016
* 25 ml/kg/hour effluent flow rate for the first 48 hours
Effects of continuous renal replacement therapy on linezolid pharmacokinetic/ pharmacodynamics: a systematic review Villa G, Di Maggio P, De Gaudio AR, Novelli A, Antoniotti R, Fiaccadori E and Adembri C
• Major alterations in linezolid PK/PD parameters might be expected in critically ill septic patients CRRT
• The optimal AUC/MIC ratio was reached for pathogens with an MIC of 4 mg/L in one study only
• Wide variability in linezolid PK/PD parameters has been observed across critically ill septic patients treated with CRRT. Particular attention should be paid to linezolid therapy in order to avoid antibiotic failure in these patients. Strategies to improve the effectiveness of this antimicrobial therapy (such as routine use of target drug monitoring, increased posology or extended infusion) should be carefully evaluated, both in clinical and research settings
Villa G et al., Critical Care (2016)
Population Pharmacokinetics and Dose Optimization of Teicoplanin during Venoarterial Extracorporeal Membrane Oxygenation Wi J, Noh H, Min KL, Yang S, Jin BH, Hahn J, Bae SK, Kim J, Park MS, Choi D, Chang MJ
• The presence of ECMO was associated with a lower central volume of distribution, and continuous renal replacement therapy (CRRT) was associated with a higher peripheral volume of distribution
• For severe infections, an optimal dose was an LD of 1,000 mg and an MD of 800 mg for ECMO patients not receiving CRRT and an LD of 1,200 mg and an MD of 1,000 mg for those receiving CRRT
• In conclusion, doses higher than the standard doses are needed to achieve fast and appropriate teicoplanin exposure during ECMO
Antimicrobial Agents and Chemotherapy, 61 (9): e01015-17, 2017
Dzierba AL et al., Critical Care, 2017 1 increased α1‐acid glycoprotein and decreased albumin concentrations 2 mostly affecting hydrophilic drugs
Critically ill patients and ECMO
Hydrophilic drugs Lipophilic drugs Volume of distribution (Vd) Low High Primary mode of clearance Renal Hepatic Log P Low High Potential effect of critical illness on PK
Increased Vd No change in Vd
Effect of ECMO on PK Increased Vd No change in clearance
Increased Vd Increased clearance
Dzierba AL et al., Critical Care, 2017
Factors affecting drug pharmacokinetic in patients receiving ECMO
Ha MA & Sieg AC, Pharmacotherapy, 2017
Age-dependent impact of extracorporeal membrane oxygenation (ECMO) prime volume on native blood volume
Sherwin J et al., Clin Ther, 2016
ECMO
Drug sequestration based on octanol/water partition coefficient and protein binding
Octanol/water partition coefficient
Protein binding
< 30% 30 – 70% > 70%
< 1 Minimal Minimal to moderate Moderate
1 – 2 Minimal to moderate Moderate Moderate to high
> 2 Moderate Moderate to high High
Ha MA & Sieg AC, Pharmacotherapy, 2017
Drug sequestration Dose adjustment
Minimal Dose adjustment likely not required
Moderate Increased dose, frequency or infusion rate may be required
High Increased dose, frequency or infusion rate likely required
ECMO
Manteinance dose adjustment based on drug sequestration
Ha MA & Sieg AC, Pharmacotherapy, 2017
What can be done in the clinical setting Pharmacological tricks for resistant strains
• Know the target pharmacokinetic/pharmacodynamic parameter for the specific drug in use
• Select the most appropriate administration modality according to pharmacokinetic/pharmacodynamic parameters
• Remember that standard susceptibility breakpoints may be inaccurate for the clinical scenario
• Maximize dosing, especially in severely ill patients, according to renal function, but limit the duration of therapy when possible
• Assess serum antimicrobial concentrations whenever possible Adembri C and Novelli A, PK-PD and potential for providing dosing regimens that are less vulnerable to resistance Clin Pharmacokinet, 2009