IL TDM DEGLI ANTI-INFETTIVI: TEORIA E PRATICAto clinicians within timeframes useful for the personalization of antimicrobial dosing regimens in different patients’populations according

IL TDM DEGLI ANTI-INFETTIVI:

TEORIA E PRATICA

FEDERICO PEA

ISTITUTO DI FARMACOLOGIA CLINICA

DIPARTIMENTO AREA MEDICA

UNIVERSITA’ DEGLI STUDI DI UDINE

PRESIDIO OSPEDALIERO UNIVERSITARIO SM MISERICORDIA UDINE

Torino, 27-28 Settembre 2018

9° CONGRESSO NAZIONALE SITA

Istituto di Farmacologia Clinica - 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

Institute of Clinical Pharmacology - UniUD


TDM OF ANTI-INFECTIVE AGENTS IN CRITICALLY ILL PATIENTS

Jager NG et al. Expert Rev Clin Pharmacol 2016 Jul; 9(7): 961-79

PHARMACOKINETIC/PHARMACODYNAMICS INDICES OF ANTI-INFECTIVE AGENTS.


REVOLUTION

THE

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


STUDY DESIGN

DETERMINING B-LACTAM EXPOSURE THRESHOLD TO SUPPRESS RESISTANCE DEVELOPMENT IN GRAM-NEGATIVE BACTERIA

Tam V et al. J Antimicrob Chemother 2017; 72: 1421–1428

• Two strains of Klebsiella pneumoniae and two strains of Pseudomonas aeruginosa were

examined

• Various dosing exposures of cefepime, ceftazidime and meropenem were simulated in

the hollow-fibre infection model

• Serial samples were obtained to ascertain the pharmacokinetic simulations and viable

bacterial burden for up to 120 h

• Resistance development was detected by quantitative culture on drug-supplemented

media plates

• The Cmin/MIC breakpoint threshold to prevent bacterial regrowth was identified by

classification and regression tree (CART) analysis


SUSCEPTIBILITY AND RESISTANCE MECHANISMS OF THE CLINICAL STRAINS USED

TYPICAL SIMULATED PHARMACOKINETIC PROFILE OF 2 G MEROPENEM Q8H OVER 30 MIN

CMIN 0.4-0.5 MG/L




DRUG EXPOSURES (CMIN/MIC) STRATIFIED BY OUTCOMES

3.8 CMIN/MIC




PERSPECTIVES

• Dosing based on factors, such as weight, body surface area, or organ

impairment, may not always be sufficient to overcome the variability

• TDM based on a drug exposure or a pharmacodynamics measure could be

useful to further individualize the doses given in critically ill patients

• TDM could also be important to assess intrapatient changes in drug exposure

over time

• After initiation of drug therapy, pathophysiological changes may occur with

disease progression, which could result in altered drug exposure that may

alter a patient’s response to the drug

THERAPEUTIC DRUG MONITORING:A PATIENT MANAGEMENT TOOL FOR PRECISION MEDICINE

Jang SH et al. Clin Pharmacol Ther 2016; 99: 148-150


THERAPEUTIC DRUG MONITORING OF ANTIMICROBIALSRoberts J et al. Br J Clin Pharmacol 2011; 73: 27-36

KEY POINTS

• Therapeutic drug monitoring or target concentration intervention?

• TDM: the importance of the MIC

• TDM: the importance of PK

• TDM: the relevance of antimicrobial toxicity


PHARMACOKINETIC AND PHARMACODYNAMIC PROPERTIES

OF ANTIMICROBIAL AGENTS

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

ODD MDD EI - CI




CLINICAL STUDIES PROVIDING RELEVANT DATA ON INDIVIDUALIZATION OF DOSING ANTI-

INFECTIVE AGENTS BASED ON DRUG LEVEL MONITORING IN CRITICALLY ILL ADULT PATIENTS


KEY ISSUES

• Pathophysiological changes in critically ill patients result in altered pharmacokinetics of anti-

infectives, especially for hydrophilic agents.

• Therapeutic drug monitoring (TDM) is recommended for all critically ill patients treated with

aminoglycosides, glycopeptides, β-lactams, fluoroquinolones, flucytosine, itraconazole,

voriconazole, and posaconazole.

• For renally cleared anti-infectives, dosing should be adjusted to renal function and monitoring

of plasma concentrations performed in patients with a high risk of deviating pharmacokinetics,

such as critically ill patients with sepsis, burns, organ failure or in patients using concomitant

medication known to influence concentrations of the antiinfective agent.



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

ANTIMICROBIAL DOSING PERSONALITAZION

AT UDINE UNIVERSITY HOSPITAL

CLINICAL PHARMACOLOGICAL ADVICE

IN INTRANET WITHIN 18.00 PM

OF THE SAME DAY

SAMPLE DELIVERYWITHIN 11.00 AM

TURN AROUND TIME (TAT)

MUST BE ADAPTED TO CRITICAL ILLNESS


PERSONALIZATION OF ANTIMICROBIAL DOSING REGIMENS:

INDICATORS OF PERFORMANCEPea F et al. Ital J Pub Health 2012; 9: e8668; 1-7

STUDY DESIGN

• To assess the efficiency and effectiveness of the organizational system of a Clinical

Pharmacological Service of an Italian tertiary care teaching hospital in providing advices (CPAs)

to clinicians within timeframes useful for the personalization of antimicrobial dosing regimens in

different patients’ populations according to the clinical benefit for patient care.

• Frequency per week of the various typologies of CPA was defined on the basis of prior

evaluations aimed at estimating the clinical benefit for patient care

• high priority level, for antimicrobials used to treat acute infections in the critically ill

patients;

• moderate priority level, for those used to treat cytomegalovirus infections in solid organ

transplant recipients;

• mild priority level, for those used to treat chronic infections.

• The CPAs provided between December 2011 and June 2012 represented the starting

database.













MEAN ± SD OF TURNAROUND TIME (TAT) OF CLINICAL PHARMACOLOGICAL ADVICES (CPA) FOR DOSING REGIMEN INDIVIDUALIZATION OF ANTIMICROBIALS CLASSIFIED

AT HIGH OR MODERATE PRIORITY LEVEL AND SCHEDULED 5 TIMES WEEKLY


0 12 24 36 48 60 72 84 96

TAT (h)

Ceftazidime (n = 32)

Daptomycin (n = 797)

Fluconazole (n = 452)

Linezolid (n = 827)

Meropenem (n = 722)

Piperacillin (n = 74)

Ganciclovir (n = 275)



MEAN ± SD OF TURNAROUND TIME (TAT) OF CLINICAL PHARMACOLOGICAL ADVICES (CPA) FOR DOSING REGIMEN INDIVIDUALIZATION OF ANTIMICROBIALS CLASSIFIED

AT HIGH OR MODERATE PRIORITY LEVEL AND SCHEDULED 3 OR 2 TIMES WEEKLY


TDM-GUIDED THERAPY:

CLINICAL CASES


WHICH DOSAGES OF MEROPENEM AND DAPTOMYCIN ???

Male, 250 KG, BMI 81.6 !!!Severe SSTIsSCr 4,6 mg/dL

Institute of Clinical Pharmacology - UniUD0 48 96 144 192 240 288 336 384 432 480 528 576 624 672 720

0 48 96 144 192 240 288 336 384 432 480 528 576 624 672 720

SCr

(mg/

dL)

0

1

2

3

4

5

Dapt

omycin

conc

ent

ration

(mg/

L)

0

20

40

60

80

100

SCK (UI/L

)

0

500

1000

1500

2000

2500

Mero

pene

m c

once

ntra

tion

(mg/

L)

0

10

20

30

40

Daptomycin Cmin

Daptomycin Cmax

Daptomycin Crandom

SCK

Meropenem Css

SCr

2gLD

0.75gdie

1gdie

2gdie

3gdie

Meropenem dosage

Daptomycin dosage

1200 mg every

TDM-GUIDED THERAPY WITH HIGH DOSAGE DAPTOMYCIN AND CONTINUOUS INFUSION MEROPENEM IN A MORBIDLY OBESE CRITICALLY ILL PATIENT WITH SEVERE CELLULITIS AND IMPAIRED RENAL FUNCTION

Pea F et al. Ann Pharmacother 2011 July; 45: e37-42

Pea F et al. Int J Antimicrob Agents. 2014; 44: 567–571

VRE (MIC for LINEZOLID = 1 mg/L)

600 mg q12h (AMIODARONE)

MDR P. aeruginosa

450 mg q 48h

600 mg q24h

MICs

2 mg/L colistin

8 mg/L meropenem

16 mg/L ceftazidime

>128 mg/L piperacillin/tazobactam

>16 mg/L amikacin

>2 mg/L ciprofloxacin

colistin 4.5 MIU q12h after 9 MIU loading +

meropenem 0.5 g q6h CI after 2g loading

estimated CLCr 47.5 mL/min

ceftazidime 2g q24h CI after 3g loading +

ciprofloxacin 400 mg q12h iv

estimated CLCr29 mL/min)

Linezolid

Meropenem +

ColistinCeftazidime +

Ciprofloxacin

Days of therapy

0 10 20 30

Lin

ezo

lid C

min (

mg

/L)

0

5

10

15

20

25

30

35

40

Lin

ezo

lid P

K/P

D in

de

x in

ple

ura

l flu

id (

AU

C0

-24

h/M

IC r

atio

)

0

100

200

300

400

500

Be

ta-la

cta

m C

ss (

mg

/L)

0

20

40

60

80

100

Be

ta-la

cta

m P

K/P

D in

de

x in

ple

ura

l flu

id (

Cs

s/M

IC r

atio

)

0

1

2

3

4

5

Linezolid

Meropenem

Ceftazidime

Concentrations in

plasma

pleural

fluid

PK/PD

index in

pleural fluid

TREATMENT OF CONSECUTIVE EPISODES OF MDR BACTERIAL PLEURISY WITH

DIFFERENT ETIOLOGY IN A HEART TRANSPLANT CANDIDATE: PROOF OF CONCEPT

OF PK/PD OPTIMIZATION OF ANTIMICROBIAL THERAPY AT THE INFECTION SITE

HIGHER THAN STANDARD MEROPENEM AND LINEZOLID DOSAGES NEEDED FOR APPROPRIATE TREATMENT OF AN INTRACEREBRAL HEMORRHAGE PATIENT

WITH AUGMENTED RENAL CLEARANCECojutti PG, Barbarino C, De Monte A, Hope W, Pea F. Eur J Clin Pharmacol 2018 Aug; 74: 1091-1092

CASE REPORT

• A 57-year-old, 49 kg female was admitted at the Emergency Department after

severe intracerebral hemorrhage.

• Head CT scan revealed rupture of a saccular aneurysm of the right middle cerebral

artery.

• External ventricular drain (EVD) was placed in the right lateral ventricle to treat

hydrocephalus, and endovascular coiling of the cerebral aneurysm was performed.

• On day 3, an EVD-related infection was suspected [C-reactive protein (C-RP) of

82.56 mg/L, normal range 0–5 mg/L; and pro-calcitonin (PCT) of 0.87 ng/mL, normal

range < 0.10 ng/mL], and empirical antimicrobial therapy was started intravenously

with cefotaxime 2 g q8h.

• On day 8, C-RP was 110.03 mg/L, and antimicrobial therapy was escalated to

meropenem [500 mg q6h over 6 h (i.e., by continuous infusion, CI) after 2 g loading]

plus linezolid (600 mg q12h intravenously).

• Despite escalated therapy, C-RP increased furtherly and peaked on day 13 (241.47

mg/L). Therapeutic drug monitoring (TDM) was performed for assessing drug

exposure [desired trough linezolid concentrations (Cmin) of 2–8 mg/L and steady-

state meropenem concentrations (Css) of 8–16 mg/ L].

• TDM revealed suboptimal exposure for both antibiotics (linezolid Cmin of 0.3 mg/L;

meropenem Css of 3.82 mg/L).

• Suspecting augmented renal clearance (ARC), creatinine clearance (CLCR) was

measured on day 16 and 18.

• Supraphysiological CLCR values confirmed ARC in both occasions (131.0 and 160.2

mL/min, respectively).

• Attainment of the desired antibiotic targets was achieved only after three

subsequent dosage increases, up to 600 mg q8h for linezolid and to 1500 mg q6h by

CI for meropenem.



CASE REPORT

MEAN LINEZOLID AND MEROPENEM CLEARANCE IN THE DESCRIBED

PATIENT COMPARED TO PREVIOUSLY REPORTED DATA

• Afterwards, significant clinical improvement was observed with a consistent drop of

both C-RP (24.27 mg/L) and PCT (0.13 ng/mL). Antimicrobial therapy was finally

stopped on day 21

• Our findings showed that intracerebral hemorrhage patients with ARC might be at

risk of suboptimal exposure during treatment with meropenem and linezolid at

standard dosages

• Real-time TDM might represent a helpful tool for optimizing antibiotic therapy in

these cases

CONCLUSION



CASE REPORT


TDM FOR OPTIMAL TREATMENT

OF GRAM-POSITIVE INFECTIONS




CLINICAL STUDIES PROVIDING RELEVANT DATA ON INDIVIDUALIZATION OF DOSING ANTI-INFECTIVE AGENTS

BASED ON DRUG LEVEL MONITORING IN CRITICALLY ILL ADULT PATIENTS


A 10-YEAR EXPERIENCE OF TDM OF LINEZOLID IN A HOSPITAL-WIDE POPULATION OF PATIENTS RECEIVING CONVENTIONAL DOSING:

IS THERE ENOUGH EVIDENCE FOR SUGGESTING TDM IN THE MAJORITY OF PATIENTS?Pea F et al. Basic Clin Pharmacol Toxicol 2017 Oct; 121 (4): 303-308

PATIENTS’ CHARACTERISTICS


BEESWARM PLOT OF THE DISTRIBUTIONS OF EACH LINEZOLID TROUGH CONCENTRATIONS IN PATIENTS

ACCORDING TO THE TYPE OF WARD OF ADMISSION

2 LOG ∆




UNIVARIATE AND MULTIVARIATE ANALYSES OF VARIABLES TESTED FOR POTENTIAL ASSOCIATION WITH

LINEZOLID OVEREXPOSURE (CMIN > 7 MG/L)

UNIVARIATE AND MULTIVARIATE ANALYSES OF VARIABLES TESTED FOR POTENTIAL ASSOCIATION WITH

LINEZOLID UNDEREXPOSURE (CMIN < 2 MG/L)




RELATIONSHIP BETWEEN LINEZOLID CMIN AND COCKCROFT AND GAULT-BASED CREATININE CLEARANCE ESTIMATES




CONCLUSIONS

• Only 32% of the patients with linezolid overexposure had also CLCrC-G estimates ≤40

mL/min

• This is in agreement with the finding that renal clearance should account for around

30–40% of the total linezolid clearance

• Consistently, the wide interindividual variability of linezolid Cmin is partially dependent

on variability in renal function, but it is probably related also to drug–drug

interactions and/or other pathophysiological conditions.

• This suggests that TDM could represent an opportunity to optimize therapy with

linezolid in several patients, especially when dealing with long-term treatment.




TDM FOR OPTIMAL TREATMENT

OF MDR-GRAM NEGATIVE INFECTIONS

CONFRONTING THE THREAT OF MULTIDRUG-RESISTANT

GRAM-NEGATIVE BACTERIA IN CRITICALLY ILL PATIENTSCohen J. J Antimicrob Chemother 2013, 68(3): 490-491.

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


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)




SUMMARY OF RECOMMENDATIONS FOR SPECIFIC ANTIBIOTICS

TREATMENT OF INFECTIONS CAUSED BY MDR GRAM-NEGATIVE BACTERIA:

REPORT OF THE BSAC/HIS/BIA JOINT WORKING PARTY

Hawkey PM et al. J Antimicrob Chemother 2018 Mar: 73 Suppl 3: iii2–iii78


7.18 INTRAVENOUS COMBINATION THERAPY FOR INFECTIONS DUE TO CARBAPENEMASE PRODUCERS

• Much higher doses of meropenem by continuous infusion can also be used (see Section

7.1). This extends the MIC range of strains that can be treated

• Continuous infusion therapy of meropenem with doses up to 13.2 g daily with levels

optimized by therapeutic drug monitoring when used in combinations (mainly with

colistin and tigecycline) were associated with 73% clinical cures in patients with KPC-

producing K. pneumoniae with MIC 16 to 64 mg/L.

• These are better outcomes in treatment of more-resistant KPCproducing Klebsiella

than apparent in earlier studies of these more-resistant KPC-producing Klebsiella.

TREATMENT OF INFECTIONS CAUSED BY MDR GRAM-NEGATIVE BACTERIA:

REPORT OF THE BSAC/HIS/BIA JOINT WORKING PARTY

Hawkey PM et al. J Antimicrob Chemother 2018 Mar: 73 Suppl 3: iii2–iii78


• 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.

Documents

IL TDM DEGLI ANTI-INFETTIVI: TEORIA E PRATICAto clinicians within timeframes useful for the personalization of antimicrobial dosing regimens in different patients’populations according