Adriana Papiež
Clatworthy AE, Pierson E, Hung DT.Targeting virulence: a new paradigm for antimicrobial therapy. Nat Chem Biol. 2007 Sep;3(9):541–8
 Lack of awareness & evidence based practice
 Fear of secondary infection
 False sense of security
 Fear of losing patient
 Parental/patient anxiety & pressure
Daughter DES. Get well soon without antibiotics [Internet]. 2014 [cited 2018 Apr 15]. Available from:
https://www.flickr.com/photos/diethylstilbestrol/15312609008/
~ 30 % of all hospitalised inpatients at any given time receive
antibiotics
over 30 % of antibiotics are prescribed inappropriately in the
community
up to 30 % of all surgical prophylaxis is inappropriate
10 – 30 % of hospital pharmacy costs can be saved by
antimicrobial stewardship programs
Hoffman et al., 2007,Wise et al., 1999, John et al., 1997
Natural Alternatives for Antibiotic Resistance and Antibiotic Treatment [Internet]. [cited 2018 Apr 15]. Available from:
https://www.livehealthynaturally.info/antibiotic.htm
Department
2017
Σ Number of hospitalizations % hosp.
I. IKAK 160 5260,00 3,04%
II. IK 169 3048,00 5,54%
DRO 69 711,00 9,70%
I. DVK 17 1258,00 1,35%
I. CHK 79 3310,00 2,39%
II. CHK 22 1867,00 1,18%
I. ORTK 14 2313,00 0,61%
NCHK 17 940,00 1,81%
KPECH 1 2538,00 0,04%
KOCHHK
8
1680,00
0,48%
I. NK 55 2126,00 2,59%
ARK 95 696,00 13,65%
URO 54 1990,00 2,71%
KTLR 7 693,00 1,01%
OCHO 5 835,00 0,60%
Summary
772
29265,00
2,64%
 Incidence of inadequate ATB therapy is 25.8 – 45.4 % in ICUs
 Independent predictive mortality factor
 Adequate ATB therapy reduces
the mortality of patients in
 Sepsis (19.8 %)
 Severe sepsis (23.1 %)
 Septic shock (49 %)
Kula R. et al.: Současné trendy antibiotické terapie v léčbě těžké sepse.
 Infectious agent is insensitive to treatment
 Infectious agent is sensitive to treatment,
but the administration of the ATB was delayed
 Infectious agent is sensitive to the ATB,
but the dose is inappropriate
 Administration of ATB therapy in the absence of signs of
infection
 „hit early and hard“
 high dose, broad spectrum, ASAP
 „get to the point“
 take into account PK and PD changes
 „focus, focus, focus“
 changes in ATB therapy according to microbiological results
 „listen to your hospital“
 monitoring of the microbiological situation in the hospital
 „look at your patient“
 comorbidities, previous ATB therapy, current patient status
Engelmann L, Schmitt DV. [Tarragona strategy--appropriate antibiotic therapy in the ICU]. Med Klin Intensivmed Notfallmedizin. 2014 Apr;109(3):156–61.
Focus | [Internet]. [cited 2018 Apr 15]. Available from: http://www.sueurda.com/tag/focus/
Antibiotic Stewardship
Rapid identification of patients with bacterial sepsis
Better empirical treatment selection
Optimized antibiotic dosing with PK-PD models
De-escalation when culture results are available
Shortening therapy duration
Early initiating of
ATB therapy is
closely related to
improved survival
Kumar A, Roberts D,Wood KE, Light B, Parrillo JE, Sharma S, et al. Duration of hypotension before initiation of effective antimicrobial therapy is the
critical determinant of survival in human septic shock. Crit Care Med. 2006 Jun;34(6):1589–96.
Ideal situation
 identified pathogen – ATB according to the sensitivity
Real situation
 need to „hit early“ – pathogen unknown
empiric use of broad spectrum ATBs
 In 30-40 % of patients – unable to prove
the infectous agent during whole hospitalization
predicted pathogen
According to the:
site of infection
time association
with the onset of
infection
epidemiologic situation in the
locality of the hospital
nosocomial /
community aquired
Pathogen.jpg (250×199) [Internet]. [cited 2018 Apr 15]. Available from:http://phoenixrising.me/wp-content/uploads/Pathogen.jpg
Human Body Infographic Pictures to Pin on Pinterest - PinsDaddy [Internet]. [cited 2018 Apr 15]. Available from: http://www.pinsdaddy.com/human-
body-infographic
You know the basic ATB characteristics
 lipophilic ATB
 hydrophilic ATB
 tissue penetration
You track the changes in patients´characteristics
 volume status
 organ dysfunction
You track the pathophysiologic characteristics
 systemic inflammation
 hemodynamics
 site of infection
Type of ATB
Pharmacokinetics
In healthy individuals In critically ill
Hydrophilic ATBs
beta-lactams, carbapenems,
aminoglycosides,
glycopeptides, colistin
Limited intracellular
penetration
Low Vd
Predominantly renal
elimination
Increased Vd resulting in
decreased plasma
concentration
Clearance increased if
augmented renal clearance or
decreased if renal impairment
Lipophilic ATBs
macrolides,
linezolid, tigecyclinem
fluoroquinolones,
clindamycin
High intracellular penetration
Large Vd
Elimination predominantly by
hepatic metabolism
Minimal change in Vd
Clearance dependent mostly
on hepatic function
 73 years old woman admitted to ICU with febrilia, oligoanuria and respiratory
distress (need of intubation), need of catecholamines
 CRP 248mg/l, leucocytes 12, Urea 16 mmol/l, Kreat 140 µmol/l
 X-ray – fluidothorax on the left
 Suspected pneumonia (PN) with urinary tract infection (UTI)
 Empirically started on piperacillin/tazobactam and clarithromycin
 After 3 days in microbiological results:
 Enterococcus faecalis resistant to penicillins from the urinary tract
 E. faecalis and H.influenzae from the tracheal aspirate
 CRP slightly decreased (210), leucocytes 11, patient still febrile
 Is the antibiotic treatment sufficient? Would you make any changes?
 vancomycin added to piperacillin/tazobactam, clarithromycin after 5 days
ex
 After another 4 days – results from the lab showed the presence of VRE
(vancomycin resistant enterococcus)
 What is the next option for the treatment of PN and UTI caused by VRE?
nitrofurantoin, linezolid, daptomycin, tigecycline
Per oral form,
for non-complicated
UTI, not for PN
Unavailable in
Czechia
Low excretion in the
urine (10-15%), risk
of underdosing in
UTI, need of higher
doses for
pneumonia too
30% excreted into
urine,
recommended as
an option for UTI,
excellent lung
penetration
Generally, in AKI dose reduction of ATB during the first
24 to 48 (72) hours is not necessary.
In case of toxic antibiotics (vancomycin, aminoglycosides) the
loading dose should be the same as for normal renal function,
followed by adjusted maintenance doses according to serum
drug levels.
Suggested dose reductions for ATBs in patients with impaired
renal function are mostly derived from studies in chronic
(stable) renal failure - these doses may be insufficient for
critically ill patients!
Blot S, Lipman J, Roberts DM, Roberts JA (2014) The influence of acute kidney injury on antimicrobial dosing in
critically ill patients: are dose reductions always necessary? Diagn Microbiol Infect Dis 79:77–84
clearance of ATB by RRT defined by
 molecule size, solubility, plasma protein binding
 filter permeability and porosity, blood and dialysis solution flow rate, dialysis
regimen...)
 amount of the drug in plasma (timing of dialysis)
 intermittent (IHD, SLED) vs continuous
elimination methods
(CVVD, CVVHD, CVVHDF)
 high-flux vs low-flux dialysis membranes
 supplemental doses after dialysis cycle
in highly dialyzed ATB
Kidney Dialysis – Scott D. McDowall [Internet]. [cited 2018 Apr 15]. Available from:
http://scottdmcdowallmd.com/kidney-dialysis/
Silanas D oleh I, Apt., M.Kes. ANTIBIOTIK MANA YANG TERMASUK DALAM KATEGORI TIME DEPENDENT (TD) DAN CONCENTRATION DEPENDENT
(CD)? [Internet]. [cited 2018 Apr 15]. Available from: https://ilmanapt.blogspot.com/2016/07/antibiotik-mana-yang-termasuk-dalam.html
Antibiotic Optimal PK/PD
parameter
Time-dependent ATB Β-lactams, carbapenems,
clarithromycin,
lincosamides
T > MIC
Concentration-dependent
ATB
aminoglycosides,
daptomycin,
quinupristin/dalfopristin,
ketolides
Cmax / MIC
Concentration-dependent
ATB with time-
dependence
fluoroquinolones,
glycopeptides,
tetracyclines, tigecykline,
linezolid
24h-AUC / MIC
For ATB, PD parameters are closely related to PK properties
Each ATB has its own pharmacokinetic profile
Different antibiotic classes have been shown to have different
kill characteristics on bacteria
Dosing regimens that maximize the rate of response in ICU
patients improve patient outcomes and minimize antibiotic
resistance
Clinical status of the critically ill changes from day to day –
CONSIDER DOSE READJUSTMENT REPEATEDLY
Beta-lactams
Carbapenems
Clarithromycin
Clindamycin
Kill characteristics of antibiotic agents - Deranged Physiology [Internet]. [cited 2018 Apr 15]. Available from:
http://www.derangedphysiology.com/main/required-reading/infectious-diseases-antibiotics-and-sepsis
Maximum bactericidal/bacteriostatic effect achieved
at concentrations 4-5 times above the MIC
 Further increase in concentration doesn´t improve ATB killing, but
increases the toxicity of the drug
Maintain blood concentrations above the MIC for prolonged
time periods
Ideally in critically ill > 80 - 90% of between-dose interval
above MIC
More frequent dosing OR
Prolonged / continuous infusions
Roberts JA et al (2014)
DALI: defining antibiotic
levels in intensive care
unit patients: are current
β-lactam antibiotic doses
sufficient for critically ill
patients? Clin Infect Dis
Off Publ Infect Dis Soc
Am 58:1072–1083
Dosing in SPC
 Mainly based on clinical trials with
 healthy volunteers
 non-critically ill patients
Uptodate, Sanford Guide, Micromedex
 more information, but still a gap in the dosing for ICU patients
Pathophysiological changes in critically ill
Important to look for data in studies
conducted on critically ill
Grupper M, Kuti JL, Nicolau
DP (2016) Continuous and
Prolonged Intravenous βLactam
Dosing:
Implications for the Clinical
Laboratory. Clin Microbiol
Rev 29:759–772
 To overcome the slow onset of action of the ATB – LOADING DOSE before
starting the extended/continuous infusion is advised
Continuous intravenous infusion (one-compartment
model) - ppt video online download [Internet]. [cited
2018 Apr 15]. Available from:
http://slideplayer.com/slide/9175396/
piperacillin 4.5 g
q 6 hours
administered as
a 30min infusion
piperacillin 4.5 g
LD followed by
4.5 g every 6 h
administered as a
4h prolonged
infusion
the rate of bacterial eradication rises with increasing
concentration up to a specific level (Cmax/MIC)
the best responses occur when the concentrations are at least
8-10 times above the MIC for their target organism(s) at the site
of infection
ideal dosing strategy is to administer high
doses separated with longer time intervals
aminoglycosides
Kill characteristics of antibiotic agents - Deranged Physiology [Internet]. [cited 2018 Apr 15]. Available from:
http://www.derangedphysiology.com/main/required-reading/infectious-diseases-antibiotics-and-sepsis
 amikacin, gentamicin, (tobramycin)
 primarily used to treat aerobic G – infections (PSAE, Enterobacter)
 long post-antibiotic effect
 elimination via kidneys (85-95 % by glomerular filtration)
 nephrotoxicity
 retention of the drug in the proximal tubular cells
 usually reversible
 ototoxicity
 2-10 %
 ireversible cochlear or vestibular damage
 Preferred once daily dosing
Themes (2016)
Aminoglycosides. In:
Basicmedical Key.
https://basicmedicalkey.co
m/aminoglycosides-4/.
Accessed 24 Feb 2018
ONCE DAILY dosing:
- higher efficacy
- lower toxicity
- lower risk for
resistance
development
- less work for
nurses 
Gentamicin, tobramycin 5-7 mg/kg q 24 h
Amikacin 15 mg/kg q 24 h
Patients with changes in distribution volume (burns, ascites) –
lack of data
 risk of under/overdosing
 need of therapeutic drug monitoring (TDM)
Dose reduction needed in renal impairment
 prolonged elimination half-life
 lack of data
 Conventional dosing (3 x daily)
 Once daily dosing
Trough concentration Peak concentration
Amikacin 4 – 8 mg/l 20 – 30 mg/l
25 – 35 mg/l life threatening infections
Gentamicin
Tobramycin
1 – 2 mg/l 5 – 8 mg/l
8 – 10 mg/l life threatening infections
Trough concentration Peak concentration
Amikacin < 1 mg/l 40 – 60 mg/l
60 – 80 mg/l life threatening infections
Gentamicin
Tobramycin
< 1 mg/l > 10 mg/l
15 – 20 mg/l life threatening infections
Nicolau DP, Freeman CD,
Belliveau PP, et al (1995)
Experience with a oncedaily
aminoglycoside
program administered to
2,184 adult patients.
Antimicrob Agents
Chemother 39:650–655
Applies for dosing
5-7 mg/kg q 24h
 Septic patient in ICU with kidney impairment with the need for regular
daily dialysis
 The antibiotic center recommended adding of gentamicin
What dosing regimen would you suggest?
 Facts:
 Concentration dependent antibiotic
 Elimination via kidneys (85-95 % by glomerular filtration)
 Dialysable (cca 60 % of the administered dose)
Quality Patients: Are Yours ‘Low-Quality’? - MGE: Management Experts [Internet]. MGE: Management
Experts Inc. 2016 [cited 2018 Apr 15]. Available from: http://www.mgeonline.com/2016/getting-too-many-
low-quality-new-patients/
 Dosing according to SPC
 Gentamicin 1-1,7 mg/kg after HD, amikacin 5-7,5 mg/kg after HD
 Low Cmax and high concentrations in time between dialysis sessions
 Risk of toxicity and insufficient concentrations for bacteria killing
 Administration of high doses before HD
 gentamicin 4-5 mg/kg administered
1 hour before HD
 sufficient Cmax
 dialysis ensures rapid drop
in gentamicin concentration
Veinstein A et al (2013) Gentamicin in Hemodialyzed Critical Care Patients: Early
Dialysis after Administration of a High Dose Should Be Considered. Antimicrob Agents
Chemother 57:977–982
Matsuo H et al (1997) Administration of aminoglycosides to hemodialysis patients
immediately before dialysis: a new dosing modality. Antimicrob Agents Chemother
41:2597–2601
optimal PK/PD parameter is the AUC-24h/MIC
difficult to generally determine which dosing scheme is the
most suitable
 best option would be using TDM
Glycopeptides (vancomycin, teicoplanine)
Fluoroquinolones
Tigecycline
Linezolid
Colistin
Cole TS, Riordan A (2013) Vancomycin dosing in children: what
is the question? Arch Dis Child archdischild-2013-304169
Intermittent (traditional) dosing
Loading dose 25-30mg/kg (severe infections)
CAVE!
„red man syndrome“
-slow infusions!
Dilution:
-central line – 10mg/ml
-peripheral line – 5mg/ml
Intermittent (traditional) dosing
Maintenance dose
Creatinine clearance (ml/min) Dose & Frequency (TBW)
> 50 15 – 20 mg/kg q 8 – 12 h
30 – 49 15 – 20 mg/kg q 12 – 24 h
15 – 29 10 – 15 mg/kg q 24 h
< 15 10 – 15 mg/kg q 24 – 48 h
 goal trough concentrations in SPC are OUTDATED
 for resistance prevention higher trough level are needed
 In critically ill patients with sepsis – measure concentration of vancomycin
after 24 h from therapy initiation (before 3.rd dose)
 optimum efficacy at AUC/MIC > 400
 no longer nicknamed as
„Mississippi mud“
 newer formulations lack high
risk of ototoxicity and
nephrotoxicity, so aggressive
dosing is possible
 in severe infections trough
levels 15-20 mg/l are needed
instead of previously
recommended 5-10 mg/l
Nolin TD (2016) Vancomycin and the Risk of AKI: Now Clearer than Mississippi Mud. Clin J Am Soc Nephrol CJASN 11:2101–2103
D L.Vancomycin: A History. Clin Infect Dis. 2006;42(Supplement 1):0
lower daily doses needed to achieve therapeutic range
slower onset of nephrotoxicity
goal serum concentrations 20 – 25 mg/l
sampling for TDM anytime during the day (lower risk of error in
serum concentraction interpretation)
possibility of prompt dose adjustment
in patients on CVVHD the target level achieved faster
watch out for incompatibilities!
Patient 56 years old, male, 72kg, admitted to ICU in septic
shock, combination of vancomycin + meropenem was started
Signs of multiorgan failure
 Urea 14, Kreat 192
 Elevated liver enzymes
 Need for catecholamines and volume substitution
Vancomycin – LD of 1500 mg, followed by 1g q 12 hours,
vancomycin level measured after 48 hours
Do you agree with the dosing, plan for TDM?
- In ICU patients –
measure the level after
24h – before 3rd dose!
- Don´t wait for steady-
state
- Actually, there is no
steady state in critically
ill
available from 1959, polypeptide ATB effective against
G- bacilli
CMS is an inactive prodrug, converted in the body to colistin
(CBA)
displaced with aminoglycosides in 70´s – 80´s for lower toxicity
2003 – 2009 – first PK/PD data
reassessment of the dosage
Li J. et al.: J chromatogr B Biomed Sci Appl, 2001 ; Li J. et al.: Antimicrom. Agents Chemother, 2002 ;
Jansson B. et al.: J Pharm Biomed Anal, 2009
Europe
USA
3-6MIU/day
6-12 MIU/day
9-12 MIU loading+ 4.5 MIU q 12 h
10 MIU loading+ 12 MIU/24h (in 3 doses q 8 h)
1 MIU CMS = 80 mg CMS = 30 mg CBA
Ortwine JK et al.: Pharmacotherapy, 2015; Plachouras D et al.: Antimicrob Agents Chemother, 2008
Garonzik SM et al.: Antimicrob Agents Chemother, 2011
48-72htoachieveCss
Css > 2mg/l
Conclusion:
need of a LD 9 – 12 MIU,
maintenance dose 4,5
MIU every 12 hours
Plachouras et al.:Antimicrob Agents
Chemother,2008
Clcr Daily dose of CMS
30 – 50 ml/min 5,5 – 7,5 MIU
10 – 30 ml/min 4 – 5,5 MIU
< 10 ml/min 2 - 3,5 MIU
No reduction in CRRT (Karvenen 2013), or even higher dosing: LD 9 – 12 MIU,
maintenance dose 4,5 MIU q 8h OR 6,5 MIU q 12 hours (Karaiskos 2016).
- elimination in CRRT greater than in patients with normal renal function
Michalopoulos et al.: Annals of intensive Care, 2011
Garonzik et al.: Antimicrob Agents Chemother,2011
Gauthier et al.:Antimicrob Agents Chemother, 2012; Dalfino et.al.:Clin Infect Dis. 2012;
Karvenen M et al.:Antimicrob Agents Chemother,2013; Visser Kift et al.:SAMJ March 2014; EMA 2014
Serious infection clinically suspected
Obtain appropriate cultures, then start empiric
antibiotics
Pursue
aggressive
source control
„48-72 hr antibiotic Time-out“
Reassess clinical status and culture results
Clinical improvement at 48 – 72 hours?
YES NO
Cultures –
Search for other
pathogenes,
complications,
diagnoses
Cultures +
Adjust ATB therapy
Cultures –
Consider stopping
antibiotics
Cultures +
De-escalate ATB, treat
for shortest duration
appropriate for site of
infection
Application of this strategy is problematic
 Absence of microbiological results
 Isolation of multi-resistant pathogens preventing de-escalation
 Reluctance of some clinicians to change antibacterials in patients with a favorable
clinical course
 A systematic review of 493 studies concluded that there was not sufficient
evidence to determine whether de-escalation of antibiotic agents was
effective and safe for adults with sepsis
Despite limitations, antimicrobial de-escalation therapy has
been recommended
 ATS guideline for the management of adults with hospital acquired, ventilator
associated, and healthcare associated pneumonia, AJRCCM 2005;171:388-416
the optimal duration of ATB therapy for bacteremia is unknown
 long antibiotic courses are associated with
 MDR pathogen selection and spread
 increased risks of toxicity
 higher costs
 too short courses may lead to inadequate bacterial eradication and relapse
 current guidelines advise a 7–10 day course, unless poor prognosis
predictors are present (e.g., initial clinical failure, undrainable foci of
infection)
Vincent J-L, Bassetti M, François B, et al (2016) Advances in antibiotic therapy in the critically ill. Crit Care 20:133
 A systematic review of 24 studies that compared a shorter (5–7 day)
regimen versus a longer (7–21 day) antibiotic course for critically ill
patients with various infections identified no differences in terms of
clinical cure, microbiological eradication, or survival.
Havey TC, Fowler RA, Daneman N (2011) Duration of antibiotic therapy for bacteremia: a systematic review and meta-analysis.
Crit Care Lond Engl 15:R267
PRORATA trial – PCT guided duration of ATB therapy
- significantly fewer patients
assigned to the PCT group
received ATB than did those
assigned to the control
group
- no significant difference in
survival between the two
groups
Bouadma L et al (2010) Use of procalcitonin to reduce patients’
exposure to antibiotics in intensive care units (PRORATA trial): a
multicentre randomised controlled trial.The Lancet 375:463–474
PCT guided duration of ATB therapy
Bouadma L, Luyt C-E,Tubach F,et al (2010) Use of procalcitonin to reduce patients’ exposure to antibiotics in
intensive care units (PRORATA trial): a multicentre randomised controlled trial.The Lancet 375:463–474
 irrational use can worsen the already alarming scenario of antibiotic
resistance
 appropriate in empirical regimens (organism unknown) to cover all
possibble pathogens
 used in critically ill patients due to widespread emergence of multidrug
resistant organisms (MDRO)
 MDRO = resistant to at least 1 agent in 3 or more ATB categories
 fixed dose ATB combination?
trimetoprim/sulfamethoxazole = Cotrimoxazole
 sulfamethoxazole -> inhibits bacterial synthesis of dihydrofolic acid
 trimethoprim -> blocks production of tetrahydrofolic acid
 blocks two consecutive steps in the biosynthesis of nucleic acids and proteins
essential to bacteria
 synergy or additivity
 decrease resistance
 broaden spectrum
 Synergy:
 Penicillin + Gentamicin
 penicillin is bacteriostatic against enterococci
 aminoglycosides are inactive against enterococci
 combination is bactericidal
 issues with administration (incompatibility)
- no indication for monotherapy
Adding rifampicin to combinations
PROs
 highly active against S.aureus
 excellent tissue penetration
CONs
 Significant adverse effects
(increased transaminases &
drug interactions)
 Rapid resistance development
(21% of patients with S. aureus
native-valve endocarditis)
Levine DP, Intern Med 1991;115:674-80.
Cosgrove S, Clin Infect Dis. (2008) 46 S386-S393.
Patient 86 years, male, admitted to the ICU for respiratory
failure
Suspected pneumonia and flu – empiric ATB treatment started:
amoxicillin/clavulanate + clarithromycin + oseltamivir
3rd day – Staph. aureus (MSSA) in hemocultures
- PCR positive for FLU
ATB center recommended oxacillin + linezolid, continue with
oseltamivir
Do you agree with the combination of ATB?
Do you have different suggestion?
Wellington ICU Antibiotic Summary. In: Scribd. https://www.scribd.com/document/360193700/Wellington-ICU-Antibiotic-Summary. Accessed 17 Mar 2018
 linezolid x serotonergic drugs
 linezolid is an IMAO
 increased risk of serotonin syndrome
 clarithromycin x CYP3A4 and P-gp substrates
 increase in drug levels (statins, warfarin, ticagrelor...)
 decrease the formation of active substance in case of clopidogrel (prodrug)
 Rifampicin x CYP3A4 and P-gp substrates
 decrease in drug levels (statins, warfarin, ticagrelor, clarithromycin,
valproate...)
Drug interactions – What you should know. [cited 2018 Apr 15]. Available from: https://thedrugcode.wordpress.com/2016/07/12/drug-
interactions-what-you-should-know-%F0%9F%92%8A/
 63 years old man with a history of stroke and COPD admitted to the
hospital for pneumonia empirically treated with
 ampicillin/sulbactam + clarithromycin
 theophylline, salbutamol + ipratropium for spasticity
 transferred to ICU for status epilepticus
What might be the cause of the seizures?
 63 years old man with a history of stroke, admitted to the hospital for
pneumonia empirically treated with ampicillin/sulbactam +
clarithromycin, theophylline, salbutamol + ipratropium
 transferred to ICU for status epilepticus
 level of theophylline in therapeutic range
 antibiotic doses suitable for the patient
 valproate was initiated with good response
 after 2 days ATBs switched to meropenem (KLPN ESBL in cultures)
 2 days later there was a rapid drop in valproate serum concentrations,
subtherapeutic levels even after doses of 5g/day of valproate
What was the cause and how to deal with it?
 significant reduction in valproate serum concentration
 Possible mechanisms of the interaction
 induction of the formation of valproate-glucuronide in the liver and inhibition
of its hydrolysis to active valproate?
 increasing the renal elimination of VPA-glucuronide?
 Management of the interaction
 stopping the carbapenem is not enough
 it may take 5 to 14 days to achieve therapeutic drug concentrations of
valproate after carbapenem discontinuation
 switch to another antiepileptic drug (levetiracetam)
Taha FA, Hammond DN,
Sheth RD (2013) Seizures
From Valproate–
Carbapenem Interaction.
Pediatr Neurol 49:279–281
 Early administration of adequate ATB at sufficient dose is crucial for the
treatment of sepsis and positively influences the outcome of the patient
 Given that most antibiotic regimens have been derived from trials with patients
who are not critically ill, there are often required higher doses of ATBs in the
critically ill
 To optimize dosing, the antibiotic’s pharmacodynamic properties, as well as the
potential altered antibiotic pharmacokinetics, need to be considered by the
clinician
 Do not reduce the antibiotic dose within the first 24 – 48 hours in case of acute
renal or hepatic failure
 Therapeutic drug monitoring based on the serum levels, if possible, should be
attempted.
 Gilbert DN MD, Eliopoulos GM MD, Chambers HF MD, et al (2017) The Sanford Guide to
Antimicrobial Therapy 2017, 47 edition. Antimicrobial Therapy
 Blot SI, Pea F, Lipman J (2014) The effect of pathophysiology on pharmacokinetics in the
critically ill patient — Concepts appraised by the example of antimicrobial agents. Adv
Drug Deliv Rev 77:3–11
 Roberts JA, Lipman J (2009) Pharmacokinetic issues for antibiotics in the critically ill
patient. Crit Care Med 37:840–851; quiz 859.
 Blot S, Lipman J, Roberts DM, Roberts JA (2014) The influence of acute kidney injury on
antimicrobial dosing in critically ill patients: are dose reductions always necessary?
Diagn Microbiol Infect Dis 79:77–84.
 Lewis SJ, Mueller BA (2014) Antibiotic dosing in critically ill patients receiving CRRT:
underdosing is overprevalent. Semin Dial 27:441–445.
adriana.papiez@fnusa.cz