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OPTIMISING PK/PD FOR TREATMENT OF GNB

FEDERICO PEA INSTITUTE OF CLINICAL PHARMACOLOGY

SM MISERICORDIA UNIVERSITY HOSPITAL UDINE

ITALY

London, 14 March 2017

Istituto di Farmacologia Clinica - UniUD

USE OF BROAD-SPECTRUM ANTIMICROBIALS FOR THE TREATMENT OF

PNEUMONIA IN SERIOUSLY ILL PATIENTS: MAXIMIZING CLINICAL OUTCOMES

AND MINIMIZING SELECTION OF RESISTANT ORGANISMS Niedermann MS, Clin Infect Dis 2006; 42:S72–81

ALAVREZ LERMA 1996

RELLO 1997

LUNA 1997

KOLLEF 1998

KOLLEF 1999

IBRAHIM 2000

STUDY

MORT

ALI

TY R

ATE

(%)

100

80

60

40

20

0

INITIAL ADEQUATE THERAPY

INITIAL INADEQUATE THERAPY

Institute of Clinical Pharmacology - UniUD

DEFINING ADEQUATE ANTIMICROBIAL THERAPY IN SEVERE INFECTIONS

•  For antimicrobial therapy to be adequate, three requirements need to be fulfilled.

•  First, the antimicrobial agent(s) should be initiated as soon as possible after the onset

of sepsis.

•  Second, as therapy is to be initiated empirically, the antimicrobial spectrum of the

agent should be broad enough to cover the potential causative microorganisms.

•  Finally, appropriate antimicrobial dosing is required to:

•  maximize microbial killing,

•  minimize the development of multidrug antimicrobial resistance,

•  and avoid concentration-related adverse drug reactions.

Blot S, Pea F, Lipman J. Adv Drug Deliv Rev 2014; 77: 3-11


PHARMACOKINETIC AND PHARMACODYNAMIC PROPERTIES OF ANTIMICROBIAL AGENTS

Blot S, Pea F, Lipman J. Adv Drug Deliv Rev 2014; 77: 3-11

ODD MDD à EI - CI


REVOLUTION

THE


SUMMARY OF THE PROCESS OF SETTING PK / PD BREAKPOINTS BY EUCAST

THE ROLE OF PK / PD IN SETTING CLINICAL MIC BREAKPOINTS:

THE EUCAST APPROACH Mouton JW et al. Clin Microbiol Infect 2012; 18: E37–E45

Institute of Clinical Pharmacology & Toxicology – University Hospital of Udine

MONTE CARLO SIMULATIONS AND PK/PD BREAKPOINTS OF MEROPENEM

www.eucast.org – Rationale documents

CLINICAL BREAKPOINT = 2 MG/L


PK/PD PERSPECTIVE

FOR OPTIMAL TREATMENT OF MDR-GRAM NEGATIVE INFECTIONS


CONFRONTING THE THREAT OF MULTIDRUG-RESISTANT GRAM-NEGATIVE BACTERIA IN CRITICALLY ILL PATIENTS

Cohen J. J Antimicrob Chemother 2013, 68(3): 490-491.

POSSIBLE STRATEGIES TO DEAL WITH THE PROBLEM OF MDR GRAM-NEGATIVE INFECTIONS IN CRITICALLY ILL PATIENTS


•  HYDROPHYLIC ANTIBIOTICS

•  T I M E - D E P E N D E N T

BACTERICIDAL ACTIVITY

•  PD DETERMINANT à CMIN > MIC

EXTENDED OR CONTINUOUS INFUSION

•  IS THE BEST WAY TO MAXIMIZE THE

BACTERICIDAL EFFECT OF BETA-LACTAMS

UNDER THE SAME DAILY DOSE

BETA-LACTAMS IN SEPTIC PATIENTS

Pea F. Curr Clin Pharmacol 2013; 8: 5-12


HOW SEVERE IS ANTIBIOTIC PK VARIABILITY IN CRITICALLY ILL PATIENTS AND WHAT CAN BE DONE ABOUT IT ?

Felton TW et al. Diagn Microbiol Infect Dis 2014 Aug; 79 (4): 441-7

PROPOSED OPTIMAL PK-PD INDICES AND ASSOCIATED PK-PD TARGETS FOR PIPERACILLIN



TREATMENT OF MDR GRAM-NEGATIVE INFECTIONS IN CHILDREN Hsu AJ and Tamma PD Clin Infect Dis 2014 May; 58: 1439-1448

SUGGESTED ANTIMICROBIAL AGENTS FOR THE TREATMENT OF MDR GRAM-NEGATIVE INFECTIONS IN CHILDREN


TREATMENT OF MDR GRAM-NEGATIVE INFECTIONS IN CHILDREN Hsu AJ and Tamma PD Clin Infect Dis 2014 May; 58: 1439-1448

PROPOSED TREATMENT ALGORITHM FOR CARBAPENEM-RESISTANT GRAM-NEGATIVE ORGANISMS


NOMOGRAMS FOR THE CALCULATION OF THE MEROPENEM DAILY DOSAGE ADMINISTERED BY CONTINUOUS INFUSION WHICH IS NECESSARY FOR

THE ACHIEVEMENT OF TARGET CSS IN CRITICALLY ILL PATIENTS

DOSING NOMOGRAMS FOR ATTAINING OPTIMUM CONCENTRATIONS OF MEROPENEM BY CONTINUOUS INFUSION IN CRITICALLY ILL PATIENTS FOR SEVERE GRAM-NEGATIVE INFECTIONS: A PK/PD BASED APPROACH

Pea F et al. Antimicrob Agents Chemother 2012 Dec; 56: 6343-6348


DOSING AND MONITORING

AMINOGLYCOSIDES: HOW SHOULD WE USE THEM IN THE 21ST CENTURY ?

Jackson J et al. Curr Opin Infect Dis 2013 Dec; 26(6): 516-25

•  Cmax/MIC and AUC/MIC ratios are the best PK/PD predictors associated with

aminoglycoside efficacy

•  Increasing evidence suggests that AGAs should be administered as a once daily dose

(ODD), taking advantage of their concentration-dependent bactericidal effect as well as

their postantibiotic effect

•  Some evidence suggests clinical outcomes may be improved and nephrotoxicity reduced

with ODD

•  ODD in antibiotic courses <10 days may be particularly beneficial in delaying or

preventing renal impairment


POP PK ANALYSIS OF COLISTIN METHANESULFONATE AND COLISTIN AFTER IV ADMINISTRATION IN CRITICALLY ILL PATIENTS

WITH INFECTIONS CAUSED BY GRAM-NEGATIVE BACTERIA Plachouras D et al. Antimicrob Agents Chemother 2009; 53: 3430–3436

PREDICTED COLISTIN PLASMA LEVELS


KEYPOINTS FOR OPTIMAL DOSAGE OF FOSFOMYCIN IN THE CRITICALLY ILL

WHAT IS THE RELEVANCE OF FOSFOMYCIN PK IN THE TREATMENT OF SERIOUS INFECTIONS IN CRITICALLY ILL PATIENTS?

Parker S et al. Int J Antimicrob Agents 2013; 42: 289-293

•  Fosfomycin is hydrophilic à ↑ Vd plus ↑ CLR are expected in septic patients

•  PD à time-dependent activity

•  T1/2 à ∼ 2h in presence of normal renal clearance (NRC) or < 2h in ARC

•  Dosage of fosfomycin disodium à up to 16-18 g/day

•  in 4 refracted doses (NRC) à up to 3-4g q6h

•  in 6 refracted doses (ARC) à up to 2-3 g q 4h ?

•  ↓ dose amount but maintain dosing interval in IRC

•  WARNING à 330 mg Na+ per gram of fosfomycin disodium

à avoid use in patients with heart failure (Reffert J et al. Pharmacotherapy. 2014; 34: 845-57)

Institute of Clinical Pharmacology & Toxicology – University Hospital of Udine


GLOBAL DISSEMINATION OF CARBAPENEMASE-PRODUCING K. pneumoniae Lee CM et al. Front Microbiol 2016 Jun 13; 7: 895


STUDY DESIGN

•  Restrospective analysis (Jun 2012-Jan 2016) for all of the patients who had a

documented KPC-Kp infection at our tertiary hospital, and who were treated

with an antimicrobial combination therapy containing high dose continuous infusion

meropenem optimized by means of real-time therapeutic drug monitoring (TDM)

•  The strategy adopted for PK/PD optimization of meropenem is based on two

rationales.

•  Firstly, the in vitro susceptibility of the yielded strain to meropenem, (broth

microdilution range 0.125 to 64 mg/L; EUCAST susceptible, MIC ≤ 2 mg/L)

•  Secondly, the necessity of defining a maximum permissible steady-state

concentration (Css) of meropenem due to safety concerns, which was arbitrarily

set at 100-120 mg/L.

MIGHT REAL-TIME PK/PD OPTIMIZATION OF HIGH DOSE CONTINUOUS INFUSION MEROPENEM IMPROVE CLINICAL CURE IN THE TREATMENT OF

INFECTIONS CAUSED BY KPC-PRODUCING Klebsiella pneumoniae? Pea F et al. Int J Antimicrob Agents 2017 Feb; 49(2): 255-258


TARGET Css/MIC RATIOS

•  Css/MIC ratio > 4 if MIC ≤ 16 mg/L

•  Css/MIC ratio 1 – 3 if MIC 32 or 64 mg/L

•  Css/MIC ratio < 1 if MIC > 64 mg/L




PK/PD ANALYSIS OF CONTINUOUS-INFUSION MEROPENEM THERAPY OPTIMIZED BY MEANS OF CPA IN PTS WITH KP-PKC INFECTIONS (N = 30)



73.3 %


UNIVARIATE LOGISTIC REGRESSION ANALYSIS OF VARIABLES ASSOCIATED WITH CLINICAL CURE FROM KP-KPC-RELATED INFECTIONS (N = 30)




•  Our study seem to suggest that high dose continuous infusion meropenem optimized by

means of rapid regimen adjustment based on real-time TDM may be helpful in

improving clinical outcome when dealing with the treatment of infections caused by

KPC-Kp with an MIC for meropenem of ≤ 64 mg/L

•  Consistently, knowledge of local prevalence data of KPC-Kp epidemiology should be

considered mandatory nowadays, since the proportion of strains with an MIC > 64 mg/

L for meropenem may vary greatly from hospital to hospital. It’s worth noting that it

was only of 10% in our case-series

•  In settings endemic for KPC-Kp, we believe that the meropenem-based screening

approaches for in vitro susceptibility testing of the clinical isolates should include

broth microdilution methods with a cut-off MIC value for meropenem of 64 mg/L

•  This may helpfully steer clinicians toward including or not high dose continuous infusion

meropenem in the combination regimen for the treatment of KPC-Kp infections

KEY POINTS



Institute of Clinical Pharmacology - UniUD Adapted from Pai MP et al. Adv Drug Deliv Rev 2014; 77: 50–57

REAL-TIME ANTIMICROBIAL DOSING PERSONALITAZION

AT UDINE UNIVERSITY HOSPITAL

CLINICAL PHARMACOLOGICAL ADVICE IN INTRANET WITHIN 6.00 PM

OF THE SAME DAY

SAMPLE DELIVERY WITHIN 11.00 AM


CAUSES AND CONSEQUENCES OF AUGMENTED RENAL CLEARANCE IN THE CRITICALLY ILL

AUGMENTED RENAL CLEARANCE IN CRITICALLY ILL PATIENTS: ETIOLOGY, DEFINITION AND IMPLICATIONS FOR BETA-LACTAM DOSE OPTIMIZATION

Sime FB et al. Curr Opin Pharmacol 2015; 24: 1-6


●  TRAUMA BRAIN INJURY

●  ACUTE MYELOID LEUKEMIA

●  EXTENSIVE BURNS (> 30% BSA)

●  OBESITY WITH TYPE 2 DIABETES

SEPTIC PATIENTS AT HIGH RISK OF ARC

Adapted from Udy AA et al. Clin Pharmacokinet 2010;49(1):1-16


PHARMACOKINETIC/PHARMACODYNAMIC OPTIMIZATION OF ANTIBIOTIC THERAPY

EXECUTIVE SUMMARY: MANAGEMENT OF ADULTS WITH HAP AND VAP: 2016 CLINICAL PRACTICE GUIDELINES BY IDSA AND ATS

Kalil AC et al. Clin Infect Dis 2016 Sep 1; 63(5): 575-82

•  For patients with HAP/VAP, we suggest that antibiotic dosing be determined using PK/

PD data, rather than the manufacturer’s prescribing information (weak recommendation,

very low-quality evidence)

•  Values and Preferences: This recommendation places a high value on improving clinical

outcome by optimization of therapy

•  Remarks: PK/PD-optimized dosing refers to the use of antibiotic blood concentrations,

extended and continuous infusions, and weight-based dosing for certain antibiotics

XIII. SHOULD ANTIBIOTIC DOSING BE DETERMINED BY PK/PD DATA OR THE MANUFACTURER’S PRESCRIBING INFORMATION IN PATIENTS WITH HAP/VAP?


FLOWCHART FOR IDENTIFICATION OF INCLUDED STUDIES

CONTINUOUS vs. INTERMITTENT B-LACTAM INFUSION IN SEVERE SEPSIS A META-ANALYSIS OF INDIVIDUAL PATIENT DATA FROM RANDOMIZED TRIALS

Roberts JA et al. Am J Respir Crit Care Med. 2016 Sep 15;194(6):681-91.


BASELINE DEMOGRAPHIC AND CLINICAL CHARACTERISTICS OF THE COMBINED STUDY POPULATION






HOSPITAL MORTALITY CENSORED AT DAY 30

INTENSIVE CARE UNIT MORTALITY

DIFFERENCES IN MORTALITY FOR CONTINUOUS INFUSION (CI) VERSUS INTERMITTENT INFUSION


•  Individual patients might benefit from dose adjustments based on rapidly

determined drug levels that are compared with the scarce pharmacokinetic

data available.

•  In a sense, laboratories would, therefore, simultaneously generate both drug

development and TDM data.

•  This exciting and novel application of TDM requires .....rapid turnaround

times so that assays can be used for drug development and individual patient

care.

•  This new and exciting era of precision medicine has created never-before-

seen opportunities for TDM in support of drug development and patient care.

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