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July 5th, 20018th ISAP symposium 1
A critical review of PK / TD inpreventing toxicity
Paul M. Tulkens
Cellular and Molecular Pharmacology,Catholic University of Louvain, Brussels,
Belgium
8th ISAP Symposium Developments in Pharmacokinetics and
Pharmacodynamics : optimizing efficacy and prevention of resistance
Nijmegen, The Netherlands, July 4th-6th, 2001
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July 5th, 20018th ISAP symposium 2
A critical review of PK / TD inpreventing toxicity
Or, how can we reach efficacy...
without (too much) risk ...
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July 5th, 20018th ISAP symposium 3
A critical review of PK / TD inpreventing toxicity
Or, from the lab ... to the patient...
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July 5th, 20018th ISAP symposium 4
Tryingto arrivesafely
What is research all about ?
black box
basic
applied
clinical
travelling
journeying
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July 5th, 20018th ISAP symposium 5
Antibiotic treatments:What does the clinician want ?
“The”drug
Besttherapeutic
effects
Notoxiceffect
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July 5th, 20018th ISAP symposium 6
What did the textbooks say about antibioticdosages and schedules in the 70’s ?
1. Stay above the MIC...
2. Remain around for a while…
3. Hope it works...
4. Hope it is not toxic…
but how much ?
but how long ?
against everything ?
Sorry, butI can’t do much ...
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July 5th, 20018th ISAP symposium 7
What are we going to discuss ?
1. aminoglycosides … (29 slides)
2. macrolides … (5 slides)
4. β-lactams … (8 slides)
5. thanking people… (a lot of slides)
3. Fluoroquinolones (3 slides)
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July 5th, 20018th ISAP symposium 8
O
O
O
CHH2N
NH2
OH
HNH3C
CH3OH
HO
H2NO HN
R1
R2
Aminoglycosides in the 70’s ...
• Potent antimicrobials but toxic !!!! nephrotoxicity (reversible) !!!! ototoxicity (irreversible)
• All very similar biophysical, chemical,microbiological and pharmacokineticproperties, but...– variable dosage (3 to 15 mg/kg)– variable schedules (1 - 2 - 3 x/day …
or even continuous infusion, …• “necessity” to monitor, but how ??
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July 5th, 20018th ISAP symposium 9
Aminoglycosides monitoring in the 70’s ...
Very small range,isn’t it ?
toxicity !!
lack ofefficacy
avoid high peaks ... to reduce toxicity
get sufficiently high trough levels … to get efficacy
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July 5th, 20018th ISAP symposium 10
Aminoglycosides toxicity in the 70’s - 80’s ...
Patients with nephrotoxic reaction after treatment with gentamicin
0 10 20 30 40
young volunteers
random hospital populat.
critically-ill patients
Smith et al, 1982
Smith et al., 1980
Plaut et al., 1979
% All those patients were under close
monitoring ...
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July 5th, 20018th ISAP symposium 11
Aminoglycoside toxicity is not linked to peak ...
daily dose divided in :
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July 5th, 20018th ISAP symposium 12
What is the (likely) mechanism of aminoglycosidenephrotoxicity ?...
1
4
2
3and apoptosis
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July 5th, 20018th ISAP symposium 13
Aminoglycoside entry in proximal tubular cells isvia brush border binding *...
* Just et al, Naunym Schmied. Arch. Pharmacol, 1977 Silverblatt & Kuehen, Kidney Intern., 1979
binding to• megalin (Moeströp et al., 1995)
• acidic phospholipids (Humes et al, 1983)
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July 5th, 20018th ISAP symposium 14
Aminoglycoside accumulation is kidney is saturable atclinically meaningful concentrations * ...
* Giuliano et al., J. Pharm. Exp. Ther., 1986
this is where patients are in a q8h schedule !!
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July 5th, 20018th ISAP symposium 15
The once-a-day schedule gives less drug accumulation andless renal alterations in rats * ...
* Laurent et al., Amer. Soc. Microbiol., 1983 ; Laurent et al, Antimicrob. Agents Chemother., 1983
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July 5th, 20018th ISAP symposium 16
Shall you now go to humans ?
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July 5th, 20018th ISAP symposium 17
Aminoglycoside once-a-day: the philosophy of oneof the first PK / TD clinical trials (1985 ...)
• netimicin (study #1)• amikacin (study #2)• 2 x 40 young patients• women suffering from PID• conventional daily doses (N: 6mg/kg; A: 15 mg/kg)• conventional treatment duration (7 days)
• combine with ampicillin and tinidazole
• randomized• blinded to evaluators
• phospholipiduria• high tone audiometry
• choose an adapted drug (least toxic)• patients with low risk• who need treatment• do not depart from clinical standards if not part of the hypothesis to test
• test your hypothesis as correctly as possible
• use surrogate toxicity markers if avalaible and relevant
• “primum non nocere”
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July 5th, 20018th ISAP symposium 18
Phospholipiduria can be a surrogate marker ofaminoglycoside-induced renal alterations
• St Luc Clinic• gynaecology• aminoglycoside plus other drugs
• Bordet Institute• cancer• aminoglycoside only
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July 5th, 20018th ISAP symposium 19
Pharmacokinetic results (day 7)...
amikacin 1 netilmicin 2
q24h q12h q24h q8h
Vd (l/kg) 0.22 ± 0.04 0.24 ± 0.04 0.28 ± 0.04 0.34 ± 0.05 **
t ! (h) 1.52 ± 0.15 1.54 ± 0.23 1.75 ± 0.25 1.97 ± 0.25 *
AUC(mg*h/L) 119 ± 17 109 ± 18 54 ± 14 51 ± 12
peak (ml/L) 55.3 ± 8.8 25.5 ± 1.9*** 21.3 ± 3.7 6.5 ± 1.0***
* p < 0.05 ** p < 0.01 *** p < 0.0011 daily dose = 15 mg/kg ( 1 x 15 mg/kg vs 2 x 7.5 mg/kg per 24h )2 daily dose = 6.6 mg/kg ( 1 x 6.6 mg/kg vs 2 x 3.3 mg/kg per 24h )
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July 5th, 20018th ISAP symposium 20
Phospholipiduria (1)
A q24h
N q8h
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July 5th, 20018th ISAP symposium 21
Phospholipiduria (2)
A q24h
N q8h
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July 5th, 20018th ISAP symposium 22
Phospholipiduria: statistical comment ...• There is a highly significant difference between the
two medications (A < N)• For each variable, there is a highly significant time
effect• The interaction between medication and time is
highly significant. The effect of time, however, is notthe same for the two medications (N > A)
• The increase, when it occurs, is always faster forthe multiple doses schedule (q8h / q12h) than forthe once-a-day (q24h) groups
Nephrotoxicity will not be suppressed but delayed … which is what has been found in most subsequent clinical trials
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July 5th, 20018th ISAP symposium 23
Auditory alterations
no. of patients [over 20 in each group] withlesions* and total no. of frequencies affected
low tone (0.25-8 kHz) high tone (10-18 kHz)
amikacin• q24h 1 (1) 3 (4)• q12h 0 6 (6)
netilmicin• q24h 0 3 (7)• q8h 2 (3) 8 (9)
* loss of 15dB or more over baseline(max. loss recorded: 30 dB)
this is where most of thetoxicity is ...
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July 5th, 20018th ISAP symposium 24
General conclusions of the first clinical trials … * amikacin vs netilmicin
q24h vs q12h q24h vs q8h
efficacy = = =
renal alterations1 < <<* <
auditory alterations2 = = <<*
* highly significant by repeated variance analysis1 phospholipiduria2 high tone (10-18 kHz audiometry)
• Tulkens, Clerckc-Braune, et al. Safety and efficacy of aminoglycosides once-a-day: experimental data and randomized, controlled evaluation in patients suffering from pelvic inflammatory disease. J Drug Devel (1988) 1:71-82• Van der Auwera Pet al., Pharmacodynamic parameters and toxicity of netilmicin (6 mg/kg.day) given once daily or in three divided doses to cancer patients with urinary tract infection., Antimicrob Agents Chemother (1991) 35:640-647• Tulkens PM. Pharmacokinetic and toxicological evaluation of the once-daily regimen versus conventional schedules of netilmicin and amikacin. J. Antimicrob Chemother (1991) 27:49-61.
Isn’t that what you want ?
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July 5th, 20018th ISAP symposium 25
But, will once-a-day be effective ?
Aminoglycosides areconcentration-dependent
drugs... 1 x MIC
2 x MIC
4 x MIC
8 x MIC
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July 5th, 20018th ISAP symposium 26
Aminoglycosidepeak /MIC ratio is predictive ofclinical efficacy
Cmax with
q24h Cmax withq8h
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July 5th, 20018th ISAP symposium 27
How are you going to show that patients will benefitof receiving aminoglycosides once-a-day ?
success
success
moderately sick patientsProof of concept
InternalMedicine
selected severe situationsSetting
the limitsneutropenicpatients
enlarged populationHow largecan the benefit
be ?
• intensive care• neonates• nosocomial pneumonia,• ...
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July 5th, 20018th ISAP symposium 28
The worldwide progress ofthe once-a-day made by clinicians ...
• 1989 - 1993: 14 comparative studies in all major indications showing = or > efficacy and = or < toxicity
! one mini-review in AAC (Gilbert, 1991)! one ICAAC symposium
! FDA petition! one re-registration (netilmicin)
• 1993 - 1999: 245 studies (≥ eff. ; ≤ tox) in almost every indication 8 meta-analyses supporting the once-a-day ! several editorials *
! inclusion in textbooks **! isepamicin is developped and
registered once-a-day
* Gilbert, CID, 1997: “ there is no need of further studies…”** In Mandell & assoc. (aminoglycoside chapter) as from 1995
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July 5th, 20018th ISAP symposium 29
Aminoglycosides in the last 2 years
• Is the once-a-day schedule used ?• Is it good for all indications ?• Do we understand AG toxicity ?• Can we better prevent AG toxicity• Other toxicities ...• Do we still need aminoglycosides ?
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July 5th, 20018th ISAP symposium 30
Is the once-a-day schedule used ?
Clin Infect Dis 2000 Mar;30(3):433-9National survey of extended-interval aminoglycoside dosing (EIAD).Chuck SK, Raber SR, Rodvold KA, Areff D.
• 500 acute care hospitals in the United States• EIAD adopted in 3 of every 4 acute care hospitals
– 4-fold increase since 1993– written guidelines for EIAD in 64% of all hospitals
• rationale– 87.1% : equal or less toxicity (),– 76.9% : equal efficacy– 65.6% :cost-savings
• dose: > 5 mg/Kg• 47% used extended interval in case of decline in renal
function (38% with Hartford nomogram)
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July 5th, 20018th ISAP symposium 31
Is the once-a-day schedule good for all indications ?
Indications for which questions are stilloften raised:
• febrile neutropenia (what is the organism ?)• cystic fibrosis (abnormal Vd and Cl)• endocarditis (synergy)• “special situations” (like peritoneal dialysis)• ...
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July 5th, 20018th ISAP symposium 32
Once-a-day schedule in febrile neutropenia ...
J Antimicrob Chemother 2000 Mar;45(3):383-6Once-daily versus multiple-daily gentamicin in empiricalantibiotherapy of febrile neutropenia following intensivechemotherapy.Bakri FE, Pallett A, Smith AG, Duncombe AS.
• Gentamicin (7mg/kg per day qD vs multiple doses) +azlocillin
• 52 episodes of febrile neutropenia in 28 patients (80.2 % withundocumented cause...)
• response rate 3 x higher in the qD group (p = 0.012)• NS increase in toxicity
In this clinical context once-daily gentamicin is moreeffective than a multiple-daily dosing regimen but maybe more toxic...
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July 5th, 20018th ISAP symposium 33
Once-a-day schedule in cystic fibrosis ...
Cochrane Database Syst Rev 2000;(4):CD002009Once daily versus multiple daily dosing with intravenousaminoglycosides for cystic fibrosis (Cochrane Review).Tan K, Bunn H.
• Two trials (n=70 patients) qD vs tid• data on Forced Expiratory Volume at one second
(FEV1), Forced Vital Capacity (FVC), nutritionalstatus and side effects
• no significant difference in efficacy or in theincidence of ototoxicity and nephrotoxicity
There is a need for an adequately-powered,multicentre, randomised controlled trial assessing qDvs md dosing of AG in cystic fibrosis.
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July 5th, 20018th ISAP symposium 34
Once-a-day schedule in endocarditis ...
Pharmacotherapy 2000 Sep;20(9):1116-9Once-daily aminoglycoside in the treatment of Enterococcusfaecalis endocarditis: case report and review.Tam VH, Mckinnon PS, Levine DP, Brandel SM, Rybak MJ.
• To date, no case reports or clinical trials have examined itsutility in human enterococcal endocarditis.
• A patient with right-sided endocarditis caused byEnterococcus faecalis was succesfully treated by once-dailygentamicin.
• Clinical and bacteriologic cures of this patient raisequestions as to whether enterococcal endocarditis shouldstill be be regarded as contraindication to ODA.
The clinical utility of ODA in this disease deservesfurther investigation.
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July 5th, 20018th ISAP symposium 35
Once-a-day schedule in peritoneal dialysis ...
Adv Perit Dial 2000;16:280-4Use of bolus intraperitoneal aminoglycosides for treating peritonitisin end-stage renal disease patients receiving continuous ambulatoryperitoneal dialysis and continuous cycling peritoneal dialysis.Mars RL, Moles K, Pope K, Hargrove P.
• 6 patients -- 5 mg/kg tobramycin -- 6 continuousnightly cycles with daytime dwell
• t1/2 = 29.3 ±±±± 3.5 h(therapeutic blood levels persisted for 72-96 hours)
• no change in audiograms at 17 days
• no clinical oto/vestibular toxicity,• cost-effective,• convenient strategy for patients and nursing staff.
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July 5th, 20018th ISAP symposium 36
Do we understand aminoglycoside nephro-and oto-toxicity and its relation to dosage ?
• apoptosis ... ! is this the cause of the toxicity at clinical doses ?
• impairment of Mrp2 et PgP efflux systems ! does the cell get indirectly intoxicated ?
• interaction with NMDA receptor ! can we dissociate activity and toxicity ?
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July 5th, 20018th ISAP symposium 37
Mimicking human clinical dose in animals
El Mouedden et al., 2000
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July 5th, 20018th ISAP symposium 38
Evidence of apoptosis in proximal tubular cells:TUNEL staining
gentamicin 10 mg/kg, 10 days
El Mouedden et al., 2000
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July 5th, 20018th ISAP symposium 39
The severity of AG-induced regeneration (top) and apoptosis(bottom) at “clinical doses” varies among derivatives ...
TUN
EL (+
) nuc
lei
D
NA
spe
cific
(n
o./s
q m
m)
ra
dioa
ctiv
ity
0
50
100
150
a,da,db,d
a
b
020
40
60
80
a
b
cd d
ct gm nt is am
El Mouedden et al., 2000
ct = control gm = gentamicin (10mg)
nt = netilmicin (10 mg)is = isepamicin (40 mg)am = amikacin (40 mg)
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July 5th, 20018th ISAP symposium 40
Aminoglycosides inhibit Mrp2 and P-glycoprotein-mediated fluoresecin-labelled methotrexate transport in
killifish proximal tubular cells
controls
amikacin 50 µM or ∼∼∼∼ 25 mg/L
gentamicin
10 µM or ∼∼∼∼ 5 mg/L
Terlouw et al., Mol. Pharmacol. 59:1433-1440, 2001
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July 5th, 20018th ISAP symposium 41
Most frequent antibiotic-pumps in eucaryotes (1/2)
TOPOLOGY
Multiple Drug Resistance (MDR also known as PgP)
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NH 2
COOH
MECHANISM
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ATP ADP + Pi
+
+
+
+
+
ANTIBIOTICS
tetracyclinesfluoroquinoloneserythromycinlincosamidesrifampicin
chloramphenicol
aminoglycosides
+
+
Van Bambeke et al.,Biochem. Pharmacol. 2000
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July 5th, 20018th ISAP symposium 42
Most frequent antibiotic-pumps in eucaryotes (2/2)
Multidrug Resistance Proteins (Mrp1 - Mrp2)
ANTIBIOTICS
fluoroquinolonesβ-lactams
-
+ tetracyclinesmacrolides
TOPOLOGY
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NH2
COOH
MECHANISM
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ATP ADP + Pi
-
-
-
-
-
GSH
Van Bambeke et al.,Biochem. Pharmacol. 2000
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July 5th, 20018th ISAP symposium 43
Mrp2 is inactivated by nephrotoxins throuh Ca2+-inducedendothelin release and PKC activation ...
Terlouw et al., Mol. Pharmacol. 59:1433-1440, 2001
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July 5th, 20018th ISAP symposium 44
AG and NMDA receptor ...
Polyamines Activation of theNMDA receptor
cochleo-toxicity
Activation of the NMDA receptor byapramycin ( """" ) and phthalimidoapramycin (#### )Scott et al., Eur. J. Pharmacol. 387:1-7, 2000
EC50 MIC µM mg/L
N-ethyl- 3.2* 32 apramycin
apramycin 3.9 4
cyclocarbonyl- 19 8 apramycin
* ∼∼∼∼ 2 mg/L
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July 5th, 20018th ISAP symposium 45
The macrolides in 5 slides...
azithromycin (10 mg/L) causes a phospholipidosis in cultured fibroblasts within 2-3 days
… because it interacts with phospholipids
Van Bambeke et al., Eur. J. Pharmacol., 1996Montenez et al. Tox. Appl. Pharmacol. 1999
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July 5th, 20018th ISAP symposium 46
Long-term (7 days culture) exposureto low doses (0.03 to 10 mg/l) of azithromycin ...
Biochemistry:
Cathepsin B activity > 1 mg/l
Phospholipid content > 5 mg/l
Cholesterol content > 10 mg/l
Van Bambeke et al, JAC,1998
Morphology at 0.1 mg/ml:
Phospholipidosis induced by macrolides…Implication for drug early evaluation ?
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July 5th, 20018th ISAP symposium 47
Drug extracellular concentration (mg/l)
Dru
g ce
llula
r con
cent
ratio
n (m
g/l)
10 -2 10 -1 10 0 10 1 10 2100
101
102
103
104
105
Cc / Ce ≈≈≈≈ 100 Cc / Ce ≈≈≈≈ 1000
Van Bambeke et al, 1998
Phospholipidosis induced by macrolides…Implication for drug early evaluation ?
Increase in phospholipid cellular content
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July 5th, 20018th ISAP symposium 48
Long-term therapy with azithromycin ...
Toxicodynamic models for the discovery ofcellular alterations induced by macrolides
! lymphocyte of a patienttreated with azithromycin
1200 mg once-a-weekduring several weeks
Y. Van Laeyhem & F. Van Bambeke, unpublished
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July 5th, 20018th ISAP symposium 49
Unsuspected effects ....
Toxicodynamic models for the discovery ofcellular alterations induced by macrolides
Tyteca et al., Eur. J. Cell Biol., in press
Accumulation of cholesterol…(filippin staining)
… in relation with azithromycin accumulation
Impairment of endocytosis…(horseradish peroxidase uptake)
control + azithromycin
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July 5th, 20018th ISAP symposium 50
The fluoroquinolones in 3 slides …or evidencing efflux
non linear accumulationkinetics ...
diffusion
receptormediateduptake
facilitated uptake
Ce
Cc
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July 5th, 20018th ISAP symposium 51
Evidencing active efflux ...
accumulation à low concentration
Ce
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uptake is defeated by active efflux
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July 5th, 20018th ISAP symposium 52
Evidencing active efflux ...
accumulationat large concentrations ...
facilitated uptake
Ce
Cc
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saturation of efflux !
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July 5th, 20018th ISAP symposium 53
Ciprofloxacin accumulation is facilitatedupon increase of its extracellular concentration
extracellular [ciprofloxacin] - 2h incubation at 37°C
0 1 2 30
1
2
3
4
log (mg/L)
cellu
lar c
ipro
floxa
cin
log
(mg/
L)
2 4 9 17 34 68136
2.5
7.5
12.5
mg/L
Cc/C
e
5.0
10.0
0
Active efflux of ciprofloxacin
Michot et al., ICAAC 2000
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July 5th, 20018th ISAP symposium 54
Now, the β-lactams
• time-dependent antibiotics• little or no influence of the concentration
once above a treshold (4 x the MIC for most organisms)
Percent of Cmax reachable in serum in humans
ampicillinmeropenem
50 75 100
-1
0
1
25
Influence of drug concentration on listericidal activity in vitro
Cha
nge
from
orig
inal
in
ocul
um (∆ ∆∆∆
log i
n 5h
)
S. Carryn, SBIMC/BVIKM, 2000
A high peak is unnecessary ...
Why wouldn’t you try
a continuous infusion ?
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July 5th, 20018th ISAP symposium 55
Continuous infusion of ceftazidime in ICU (3 g/day)
Intermittent(n=17)
Continuous
(n=17)
C max (mg/ml)C min (mg/ml)
C mean (mg/ml)
T½½½½ (h)
AUC 0-24h
Clt (ml/min)
106.5 (34.6)10.3 (16.0)
3.2 (2.5)777.4 (474.6)142.5 (58.7)
18.2 (6.5)16.5 (5.7)17.4 (6.1)
419.7 (141.5)133.2 (37.0)
Pharmacokinetocs and Pharmacodynamics of continuous andintermittent ceftazidime during the treatment of nosocomialpneumonia. D.P. Nicolau et al. Clin Drug Invest 1999:18(2):133-139.
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July 5th, 20018th ISAP symposium 56
PK / PD in action …continuous infusion of β-lactams:
the case of ceftazidime (4g / day) in Intensive Care Units
Css = Ko / Cl
27 [µg/ml] = { 2.77 [mg/min] / 102 [ml/min] } x 103
serum concentration Clearance *
Infusion rate
Targeted level for MIC’s up to 6-8 mg/L …
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July 5th, 20018th ISAP symposium 57
PK / PD in action …continuous infusion of β-lactams:
the case of ceftazidime (4g / day) in Intensive Care Units
0
20
40
60
mean : 26.6 ±±±± 15.0 (n = 93; min = 7.6; max = 62.4)
obse
rved
ser
um c
once
ntra
tion
(mg/
L)
targetmean
Servais, Laterre & Tulkens, unpublished
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July 5th, 20018th ISAP symposium 58
But is it safe ?Ceftazidime stability studies … 25°C
Ceftazidime stability at 25°c
70
75
80
85
90
95
100
105
110
0 5 10 15 20 25 30Time (hours)
pre
sent
cef
tazi
dim
e
4%
6%
8%
10%
12%
Range oftolerance
Servais & Tulkens, AAC, in press
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July 5th, 20018th ISAP symposium 59
But is it safe ?Ceftazidime stability studies … 37°C ...
Ceftazidime stability at 37°c
50
55
60
65
70
75
80
85
90
95
100
105
110
0 5 10 15 20 25 30Time (hours)
Pre
sent
cef
tazi
dim
e
4%6%8%10%12%
Range oftolerance
Servais & Tulkens, AAC, in press
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July 5th, 20018th ISAP symposium 60
Degradation products of ceftazidime
cefazidime
[(2–amino–4-thiazolyl)(1–carboxy–1–methyletoxy) imino]acetyl–ethanal.
∆∆∆∆2-isomer
Servais & Tulkens, 11th ECCMID, 2001
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July 5th, 20018th ISAP symposium 61
Degradation pathways of ceftazidime(24h in aqueous media)
[(2–amino–4-thiazolyl)(1–carboxy–1–methyletoxy)imino] acetyl–ethanal.
∆∆∆∆2-isomercefazidime> 25 °C
Pyridine *
* < 50 mg from an amount of 4 g in 24h at temp < 25°C
Ring opening
Servais & Tulkens, AAC, in press
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July 5th, 20018th ISAP symposium 62
Pharmacodynamics ...
It ‘s a brilliantidea…. But don’t forget toxicity...
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July 5th, 20018th ISAP symposium 63
Toxicodynamics ...
There is still MUCH work...
Novel antibiotics
Intracellularinfections Efflux modulators
• in bacteria• in eucaryotes
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July 5th, 20018th ISAP symposium 64
Thanking people … *
Research is a lonely exercise but its true valueis directly related to the collaborative activitiesit leads to...
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July 5th, 20018th ISAP symposium 65
Aminoglycosides...Starting very basically in the early 80’s ...
G. LaurentM.B. CarlierR. BrasseurJ.M. Ruysschaert
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July 5th, 20018th ISAP symposium 66
Aminoglycosides...The once-a-day story...
In the late 80’s ...
S. IbrahimP. MaldagueL. GiurgeaF. RenoirdM.C. CambierG. LaurentD. Beauchamp
and
F. Clerckx-Braun * (FATC)J. Donnez (St Luc)M.P. Mingeot *P. LambrichtR. WagnerB. Rollmann (CHAM)P. Herman (SP-Belg.)M.E. De Broe (UZ-UIA)G. Verpooten (UZ-UIA)A. Giuliano (UZ-UIA)B. Kaufman (VUB)B. Derde * (VUB)
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July 5th, 20018th ISAP symposium 67
The ββββ-lactams, the macrolides, thefluoroquinolones, etc...
C. RenardM. Leto *C. BrunoF. Van Bambeke *S. BurtonC. DupriezJ.M. Michot *H. Chanteux *Y. OuadrhiriH. Servais *S. Carryn *E. Viaene….
I. Dab (UZ-VUB)B. Byl (ULB-Erasme) P.F. Laterre (St-Luc)...
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July 5th, 20018th ISAP symposium 68
intracellularpharmacodynamicsand toxicity
* AUIC
postantibioticeffect...
populationpharmacokinetics
tissueconcentrations
efficacy/toxicityratios
http://www.isap.org
But ISAP made it all possible …when we were still youngs and serious...
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July 5th, 20018th ISAP symposium 69
http://www.isap.org
And also when as young but lessserious...
toxicity isn’t that bad...
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July 5th, 20018th ISAP symposium 70
And now, en route to the future ...
To a bright future...