Karel Allegaert, MD PhDUZ Leuven

How to improve the use of antibiotics in neonates

Clinical research supported by the Fund for Scienti fic Research, Flanders (Belgium) (FWO Vlaanderen) by a Fundamental Clinical Investig atorship (2013-2018)

less is more ?

do not simply trust ‘handbooks’ and ‘common practic es’

be aware of the PK and the PD aspects of any drug(including antibiotics)(clinical pharmacology may be helpful)

have you ever really considered the ‘magics’ of TDM ?

take home messages

Russell AB, et al. Arch Dis Child Fetal Neonatal E d 2012

Early onset sepsis

10-12 % of all babies are screened3.2 % of these had evidence for a bacterial infection

(either blood culture, clinical, laboratory)> 95 % exposed cases, in retrospect not needed

1 % of neonatal admissions11.5 % of neonatal death, primary cause

Late onset sepsis

CNS (54%) association with poor neurodevelopmental outcome

EOS

benzyl penicillin + gentamicin(alternative = amoxicillin, listeria)

cephalosporins based regimencefotaxime + ampi vs genta + ampi (OR 1.5 mortality, fungal, enterobacter)

Late

flucloxacillin + gentamicinvancomycin + gentamicinpiperacillin/tazobactam (gr-)>glazidim (klebsiella)meropenem/ciprofloxacin

Menigitiscefotaxime + amoxicillin (? Gentamicin)meropenem

Use of antibiotics in neonates

Versporten et al. Pediatr Inceft Dis J 2013; 32: e242-e253

50 European hospitals 23 non-European hospitals

Countries n = 14 n = 9

Pediatric inpatients 2760 1565

Neonatal inpatients 1153 589

(Overall antibiotic use)

(35.4%)

(21.8%)

(43.8%)

(39.4%)

Figure : Number of reported babies admitted on a neonatal ward and receiving at least 1 antimicrobial treatment, by age.

Grohskopf et al. Pediatr Infect Dis J, 2005; 24: 766-773

Multicenter US Point Prevalence survey (29 NICU’s)43.3% of neonates received antibiotics on days of surveyAminoglycosides (26.1% of patients), aminopenicillins (21.5%), vancomycin (11%)

gentamicin/ampi empiric > prophylactic > therapeuticVancomycin empiric > therapeutic > prophylacticcefazolin/amoxi prophylactic > empiric > therapeutic

Guidelines online available, provided as pdf docume nt

greater consistence, butmore investigations, and greater length of stay…

Mukherjee A. Arch Dis Child Fetal Neonatal Ed, onli ne July 2014

Ciprofloxacin (enterobacter spp), 25 % of unitsavailable data, CSF

Fluconazole (candida spp)20 fold 24h dosing range 16 % as recommended (16 mg/kg/24h)

Vandendriessche et al. Curr Ther Res Clin Exp 2014

N= 294 first vancomycin trough TDM observations included

� 78% suboptimal (<10 or >15 mg/l)

� median (range): 7.1 (1 – 37.8) mg/l

A: Neofax 2011 (N=101)

� 81/101 (=80%) suboptimal

� 77 observations <10 mg/l

� 4 observations >15 mg/l

BW and CW as covariates of suboptimal trough levels

B: Anderson 2006 (N=193)

� 148/193 (=77%) suboptimal

� 128 observations <10 mg/l

� 20 observations >15 mg/l

GA and PMA as covariates of suboptimal trough levels

Vandendriessche et al. Curr Ther Res Clin Exp 2014

Dosing guidelines amikacin in reference text books

Gestational age

(weeks)

Postnatal age

(days)

Current weight

(g)

Duration

infusion

(minutes)

Dose

(mg/kg)

Interval

(hours)

Neofax® (2009)

< 30 or **

0-7 -

30

18 48

8-28 - 15 36

> 28 - 15 24

30-34 0-7 - 18 36

> 7 - 15 24

> 34 - - 15 24

RedBook®

(2009)

- 1-30 < 1200

30

7.5 18-24

0-71200-2000 7.5 12

> 2000 7.5-10 12

>71200-2000 7.5-10 8-12

> 2000 10 8

BNFc (2009) all all - 30 15 24

De Cock et al, Clin Pharmacokinet 2012

De Cock et al, Clin Pharmacokinet 2012

drug

Dose Conc Effect

pharmacokinetics pharmacodynamics

developmental pharmacology

PK : what the body does to the drug: conc/timePD: what the drug does to the body : conc/effect

EMA decision tree

Manolis et al, Br J Clin Pharmacol 2009

PK/PD and Antimicrobial Efficacy

� 2 main patterns of bacterial killing

� Concentration dependent� Aminoglycosides, quinolones, macrolides, azalides,

clindamycin, tetracyclines, glycopeptides, oxazolidi nones� Correlated with AUC/MIC , Peak/MIC

� Time dependent with no persistent effect� Betalactams� Correlated with Time above MIC (T>MIC)

Antibiotic concentration

MIC

Time

Time

MIC

Time above MICpenicillines

Time

Area under the curve over MIC

PEAK

AUC/MIC AUC 400ratio of AUC to MIC(vanco)

Peak/MIC > 8ratio of the peakconcentration to MIC(aminoglycosides)

Ant

ibio

tic

conc

entr

atio

nMIC

Time

Area under the curve over MIC

PEAK

distribution volume and clearance are sometimes ‘c ontradicting’ in neonates

Peak/MICratio of the peakconcentration to MIC(aminoglycosides) A

ntib

iotic

co

ncen

trat

ion

MIC

Time

Area under the curve over MIC

PEAK

Ref: Kearns et al, NEJM 2003

Rakhmanina et al, 2006

body water content

Kearns et al, NEJM 2003

renal (drug) clearance: ontogeny

amikacin clearance in neonates: age/weight

De Cock et al. Clin Pharmacok 2013

drug

Dose Conc Effect

pharmacokinetics pharmacodynamics

developmental pharmacology

PK : what the body does to the drug: conc/timePD: what the drug does to the body : conc/effect

30S

50S

5’ 3’

blocked initiation

3’5’

premature termination

5’ 3’AUG

mRNA translation

+

AminoGlycoside

3’5’

incorporation of wrong amino acid

X

Mature Protein

Growing Polypeptide

Post antibiotic effectprotein synthesis inhibition >

Adaptive resistance efflux mechanism, activated in the environment with AG (median/AUC)

Biol Neonate 1998;74:351-62

AUC/MIC

ratio of AUC to MIC(vanco)

Ant

ibio

tic

conc

entr

atio

nMIC

Time

Area under the curve over MIC

PEAK

Vancomycin target concentration

5 5-10 10-15 or 15-20 mgr/l

: target range for trough concentration (intermittent dosing; 10-15 mg/L) or Css concentration (continuous dosing; 15-25 mg/L)

: concentrations above this line (40 mg/L) may lead to toxicity

: concentration is within the target range or peak concentration is not exceeding 40 mg/L

: concentration is below the target range AUC24h: AUC on the last 24 h of treatment

Proposal

intermittent

Proposal

continuous

bBW=850 g bBW=1220 gbBW=600 g bBW=2200 g bBW=2980 g

Time

MIC

Time above MICpenicillines

Frequency versus dose/24h

less is more ?

do not simply trust ‘handbooks’ and ‘common practices ’

be aware of the PK and the PD aspects of any drug(including antibiotics)(clinical pharmacology may be helpful)

have you ever really considered the ‘magics’ of TDM ?when do you measure the levelwhat technique do you use ?

take home messages