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
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