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Farmacocintica (PK) e Farmacodinmica (PD)

dos Antibiticos na Prtica Clnica
Joana Estilita
UCI CHBA
Maio 2011
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Farmacocintica Farmacodinmica
Tempo e concentrao
do frmaco no
hospedeiro
Concentrao do
frmaco no agente
patognico
Absoro
Distribuio
Metabolismo
Eliminao
Efeito ps-AB
MIC
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Farmacocintica Farmacodinmica
Dose
Concentrao
Srica
Concentrao
Alvo
Efeito
Resultado
Clnico
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Farmacocintica
O que o corpo faz ao frmaco
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Farmacocintica
Volume de
Distribuio (Vd)
Clearance (Cl)
Tempo de Semi-
Vida (t!)
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Farmacocintica
C
o
n
c
e
n
t
r
a

o

S

r
i
c
a

Tempo (t)
Cmx (pico)
AUC
rea Sob a Curva
(quantidade de frmaco)
Cmin (vale)
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Farmacocintica
AB
Hidroflicos
V
d
baixo
Cl renal
Fraca penetrao intracelular
Beta-lactmicos
Carbapenems
Aminoglicosidos
Glicopptidos
Linezolide
AB
Lipoflicos
V
d
elevado
Cl heptica
Boa penetrao intracelular
Fluoroquinolonas
Macrlidos
Tigeciclina
Lincosamidas
Concentrao Extravascular
Barreiras restritivas:
! Sistema Nervoso Central
! Fluido Ocular
! Epitlio Pulmonar
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Farmacocintica
" Absoro (biodisponibilidade)
" Interaces
" Distribuio
" Capacidade de penetrao
" Vascularizao
" Metabolismo/excreo
" Ligao s protenas plasmticas
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Farmacocintica
Shift de fluidos (perdas, 3 espao)
Alteraes no metabolismo rim/fgado
Penetrao tecidular (edema, inflamao)
Ligao s protenas* (hipoproteinmia)
*Ceftriaxone, Ertapenem, Teicoplanina, Flucloxacilina
Tam VH, Louie A, Fritsche TR, et al. Impact of drug-exposure intensity and duration of therapy on the emergence of Staphylococcus aureus resistance to a quinolone antimicrobial. J Infect Dis
2007;195:181827.
Drusano GL, LiuW, Fregeau C, et al. Differing effects of combination chemotherapy with meropenem and tobramycin on cell kill and suppression of resistance of wildtype Pseudomonas
aeruginosa PAO1 and its isogenic MexAB efflux pump-overexpressed mutant. Antimicrob Agents Chemother 2009;53:226673.
Louie A, Grasso C, Bahniuk N, et al. The combination of meropenem and levofloxacin is synergistic with respect to both Pseudomonas aeruginosa kill rate and resistance suppression.
Antimicrob Agents Chemother 2010;54:264654.
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Farmacodinmica
O que o frmaco faz ao corpo
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Farmacodinmica
Minimum Inhibitory Concentration (MIC)
Concentrao mais baixa de AB com a qual no se
observa crescimento bacteriano (in vitro)
determinada para par patognio AB (breakpoint)
Susceptibilidade vs Resistncia (Potncia)
Susceptvel se MIC < Breakpoint
Resistente se MIC > Breakpoint

pouco importante no processo de escolha do AB
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Farmacodinmica
MIC
50
MIC necessria para inibir crescimento de
50% dos isolados
MIC
90
MIC necessria para inibir 90% dos
isolados
Se MIC
90
da Ciprofloxacina contra 100 estirpes de P. aeruginosa for 4mcg/ml,
O breakpoint de susceptibilidade 1mcg/ml
Logo, menos de 90% dos isolados de P. aeruginosa sero susceptveis Ciprofloxacina
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Farmacodinmica
No mimetiza condies fisiolgicas
No contempla flutuaes de frmaco
No reflecte a dinmica de irradicao bacteriana
No toma em conta os efeitos ps-antibiticos
MIC
Lodise TP, Lomaestro BM, Drusano GL. Application of antimicrobial pharmacodynamic concepts into clinical practice: focus on beta-lactam
antibiotics: insights from the Society of Infectious Diseases Pharmacists. Pharmacotherapy 2006; 26:132032.
Medida Esttica
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Avaliao da Concentrao de AB ao longo do tempo
Actividade intrnseca contra uma dada bactria
Farmacodinmica
Farmacocintica
ndice PK/PD
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Farmacodinmica
C
o
n
c
e
n
t
r
a

o

S

r
i
c
a

Tempo (t)
C
mx
AUC
MIC
" T > MIC
" Pico/MIC
" AUC/MIC
C
min
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" T > MIC
" Pico/MIC
" AUC/MIC
Tempo - Dependente
Concentrao - Dependente
Efeito Ps-Antibitico
E
f
e
i
t
o
P

s
-
A
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o

T
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s
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r
io
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to
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n
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e
in
ic
ie

c
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e
s
c
im
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n
to
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o
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m
a
l a
p

s

e
x
p
o
s
i

o
a
o
a
g
e
n
te

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Farmacodinmica
Relao linear Concentrao/taxa bactericida
Efeitos persistentes dose-dependentes
Taxa bactericida saturvel,
independente da concentrao
Sem efeitos persistentes
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Farmacodinmica
Padro de Actividade AB Objectivo
Parmetro
PK/PD
Tempo Dependente
(# EPA)
Carbapenemes
Cefalosporinas
Penicilinas
Vancomicina
Maximizar a durao
da exposio
Tempo>MIC
Concentrao
Dependente + EPA
Aminoglicosidos
Daptomicina
Fluoroquinolonas
Quetlidos
Maximizar a
concentrao
Pico/MIC
(AUC/MIC)
Tempo Dependente
+ EPA
Clindamicina
Claritromicina
Tetraciclinas
Linezolide
Eritromicina
Tigeciclina
Estreptograminas
Maximizar a
quantidade de
frmaco
AUC/MIC
(Tempo>MIC)
Levison ME. Pharmacodynamics of antimicrobial drugs. Infect Dis Clin North Am. 2004 Sep;18:451-465
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Crit Care Clin 27 (2011)
$ Crit
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Beta-lactmicos
PK PD
Hidroflicos
Excreo renal*
Ligao varivel s protenas

SEPSIS:
Concentraes variveis
Clearance Creatinina
Melhor ndice: T>MIC

Melhor perfil farmacodinmico
1
:
Dosagem mais frequente
Infuso contnua

Penicilinas/Cefalosporinas
*Ceftriaxone e oxacilina exc. Biliar
Lipman J, Wallis SC, Rickard C. Low plasma cefepime levels in critically ill septic patients: pharmacokinetic modeling indicates improved troughs with revised dosing. Antimicrob Agents
Chemother 1999;43(10):255961.
Boselli E, Breilh D, Duflo F, et al. Steady-state plasma and intrapulmonary concentrations of cefepime administered in continuous infusion in critically ill patients with severe nosocomial
pneumonia. Crit Care Med 2003;31(8):21026.
Burgess DS, Hastings RW, Hardin TC. Pharmacokinetics and pharmacodynamics of cefepime administered by intermittent and continuous infusion. Clin Ther 2000;22(1):6675.
Georges B, Conil JM, Cougot P, et al. Cefepime in critically ill patients: continuous infusion versus an intermittent dosing regimen. Int J Clin Pharmacol Ther 2005; 43(8):3609.
Roos JF, Bulitta J, Lipman J, et al. Pharmacokinetic-pharmacodynamic rationale for cefepime dosing regimens in intensive care units. J Antimicrob Chemother 2006;58(5):98793.
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Beta-lactmicos
PK PD
Hidroflicos
Excreo renal*
Ligao varivel s protenas

SEPSIS:
Concentraes variveis
Aumento V
d
e Clearance
Melhor ndice: T>MIC
Efeitos Ps Antibiticos

Melhor perfil farmacodinmico
1
:
Infuso contnua/prolongada

Carbapenemes
Jaruratanasirikul S, Sriwiriyajan S, Punyo J. Comparison of the pharmacodynamics of meropenem in patients with ventilator-associated pneumonia following administration by 3-hour
infusion or bolus injection. Antimicrob Agents Chemother 2005;49(4):13379.
Li C, Kuti JL, Nightingale CH, et al. Population pharmacokinetic analysis and dosing regimen optimization of meropenem in adult patients. J Clin Pharmacol 2006;46(10):11718.
Lomaestro BM, Drusano GL. Pharmacodynamic evaluation of extending the administration time of meropenem using a Monte Carlo simulation. Antimicrob Agents Chemother 2005;49(1):
4613.
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Quinolonas
PK PD
Lipoflicos
Efeito mnimo no V
d

SEPSIS:
Exposio mxima do AB
Melhor ndice: Pico/MIC
(AUC/MIC para Gram-)

Melhor perfil farmacodinmico
1
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Cipro Dose total diria 1200mg
(600bid ou 400tid)
Levo 750mg
Cipro/ Levofloxacina
Lipman J, Scribante J, Gous AG, et al. Pharmacokinetic profiles of high-dose intravenous ciprofloxacin in severe sepsis. The Baragwanath Ciprofloxacin Study Group. Antimicrob Agents
Chemother 1998;42(9):22359.
Conil JM, Georges B, de Lussy A, et al. Ciprofloxacin use in critically ill patients: pharmacokinetic and pharmacodynamic approaches. Int J Antimicrob Agents 2008;32(6):50510.
Van Zanten AR, Polderman KH, van Geijlswijk IM, et al. Ciprofloxacin pharmacokinetics in critically ill patients: a prospective cohort study. J Crit Care 2008;23(3): 42230.
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Aminoglicosidos
PK PD
Hidroflicos
Excreo renal
Alteraes com o V
d

SEPSIS:
Concentraes variveis
Vigilncia da Toxicidade
Melhor ndice: Pico/MIC
AUC/MIC
Efeito Ps Antibitico

Melhor perfil farmacodinmico
1
:
Dosagem mais intervalada
MIC vs Toxicidade

Genta/Amika/Tobramicina
Vogelman BS, Craig WA. Postantimicrobial effects. J Antimicrob Chemother 1985;15(Suppl A):3746.
Beckhouse MJ, Whyte IM, Byth PL, et al. Altered aminoglycoside pharmacokinetics in the critically ill. Anaesth Intensive Care 1988;16(4):41822.
Buijk SE, Mouton JW, Gyssens IC, et al. Experience with a once-daily dosing program of aminoglycosides in critically ill patients. Intensive Care Med 2002; 28(7):93642.
Triginer C, Izquierdo I, Fernandez R, et al. Gentamicin volume of distribution in critically ill septic patients. Intensive Care Med 1990;16(5):3036.
Marik PE. Aminoglycoside volume of distribution and illness severity in critically ill septic patients. Anaesth Intensive Care 1993;21(2):1723.Georges B, Conil JM, Cougot P, et al. Cefepime in
critically ill patients: continuous infusion versus an intermittent dosing regimen. Int J Clin Pharmacol Ther 2005; 43(8):3609.
Roos JF, Bulitta J, Lipman J, et al. Pharmacokinetic-pharmacodynamic rationale for cefepime dosing regimens in intensive care units. J Antimicrob Chemother 2006;58(5):98793.
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Glicopptidos
PK PD
Hidroflicos
V
d
aumentado
Maior ligao s protenas


SEPSIS:
Concentraes variveis
Vigilncia da Toxicidade
Melhor ndice: No conhecido
In vitro T>MIC
Modelos animais AUC>MIC (400)

Melhor perfil farmacodinmico
1
:
Infuso contnua de doses
moderadas (30-40mg/kg/dia)

Vancomicina/ Teicoplanina
MacGowan AP. Pharmacodynamics, pharmacokinetics, and therapeutic drug monitoring of glycopeptides. Ther Drug Monit 1998;20(5):4737.
Rybak MJ. The pharmacokinetic and pharmacodynamic properties of vancomycin. Clin Infect Dis 2006;42(S1):S359.
Rybak MJ, Lomaestro BM, Rotschafer JC, et al. Vancomycin Therapeutic Guidelines: A summary of consensus recommendations from the infectious diseases Society of America, the American
Society of Health System Pharmacists, and the Society of Infectious Diseases Pharmacists. Clin Infect Dis 2009;49(3):3257.
Pea F, Furlanut M, Negri C, et al. Prospectively validated dosing nomograms for maximizing the pharmacodynamics of vancomycin administered by continuous infusion in critically ill patients.
Antimicrob Agents Chemother 2009;53(5):18637.
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Outros
Lincosaminas Lipoflicas
ndice: T>MIC
Diminuio do clearance heptico
Linezolide Hidroflico
Excreo heptica e renal
Boa penetrao tecidular
ndice: AUC>MIC
Tigeciclina Lipoflico
Vd Elevado
ndice: AUC>MIC
Efeito Ps-Antibitico
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Fluxograma Decisional
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Fluxograma Decisional
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Como monitorizar?
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Como monitorizar?
" T > MIC
" Pico/MIC
" AUC/MIC
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Concluses
$ ndices PK/PD
$ So os melhores preditores de eficcia AB
$ Os mais usados para comparao de actividade
AB in vivo
$ Esto relacionados com aumento da hiptese de
irradicao e diminuio do padro de
resistncia
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Concluses
$ ndices PK/PD
$ No est esclarecido do seu papel na preveno
de mutaes

$ Do ponto de vista concreto de aplicao difcil
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Concluses