DRUGS INFORMATION SERV

REVIEW :

EFTRIAXONE DOSAGE REGIMENTATIO

(1 GRAM TWICE DAILY & 2 GRAMS ONCE DAILY)

MAGISTER FARMASI KLINIK

UNIVERSITAS AIRLANGGA
2012

MICROBIAL MAPPING

INTERNAL MEDICINE DEPARTMENT, RSUD DR. SOETO

MO

2011-2012

No.
1.

Gram Negative Bacterial

Pseudomonas spp

%
22%

2.

Acinetobacter spp

3.

E coli

16,9%

4.

Klebsiella pneumoniae

11,8%

5.

Enterobacter aerogenes

10,1%

No
.

Gram Positive Bacterial

22%

1.

Staphylococcus coagulase negative

82,3

2.

Staphylococcus aureus

7,2

3.

Streptococcus spp

3,9

4.

Corynebacterium spp

3,9

5.

Enterococcus

2,6

ESCHERICHIA COLI SENSITIVITY

Antibiotic

Amikacin

100

Meropenem

88,8

Ceftazidime

88,8

Gentamycine

77,7

Cefotaxime

77,7

Imipenem

77,7

Piperacilline tazobactam

77,7

Ampi sulbactam

66,6

Tobramycin

66,6

Ceftriaxone

66,6

Cefoperazone sulbactam

55,5

Amoxyclav

55,5

Ciprofloxacin

55,5

Cotrimoxazole

55,5

ACINETOBACTER SPP SENSITIVITY

Antibiotic

Meropenem

100

Amikacin

100

Cefoperazone sulbactam

83,3

Ciprofloxacine

83,3

Levofloxacin

83,3

Imipenem

66,6

Cotrimoxazole

66,6

Ampicillin Sulbactam

66,6

Gentamycine

50

Ceftazidim

50

Piperacillin tazobactam

33,3

Cefotaxime

33,3

Amoxyclav

16,7

Ceftriaxone

16,7

PSEUDOMONAS SPP. SENSITIVITY

Antibiotic

Meropenem

100

Amikacin

83,3

Cotrimoxazole

83,3

Gentamycin

50,0

Ceftazidime

50,0

Cefoperazone sulbactam

33,3

Levofloxacin

33,3

Imipenem

33,3

Ampicillin Sulbactam

16,7

Piperacillin tazobactam

16,7

Cefotaxime

16,7

Ceftriaxone

BETA LACTAM COMPOUNDS

Penicilli
ns

Cephal
osporins

Monobactam
s

Carbapenems

FOCU
S

HANISM OF ACTION OF BETA LAC

Related with PD Characteristic TIME

DEPENDENT
KILLER
Lullmann et al. 2005. Color
Atlas of
Pharmacology 3rd edition

PK/PD PARAMETERS
AFFECTING ANTIBIOTIC
EFFICACY IN VIVO
Concentration
Cmax:MIC

AUC:MIC

MIC
T>MIC
0

PAE

Time (hours)

Lodise & Drusano, Pharmacokinetics & Pharmacodynamics : Optimal Antimicrobial

Therapy in the Intensive Care Unit. Crit Care Clin 27 (2011). 1-18

THE PATTERN OF ANTIMICROBIAL ACT

IVITY
Antibiotic
PK/PD
Classification Index

Definition of PK/PD
Index

Examples of
Antibiotic

TimeT > MIC

dependen
t

Percentage time for

which the
concentration of a
drug remains more
than MIC during a
dose interval

BETALACTAM

Concentration- Cmax/ MIC

dependent

Ratio of the peak drug

concentration of the
MIC of the pathogen

Aminoglycosides

Concentration- AUC
dependent
MIC
with timedependent

Ratio of the area under

the concentration timecurve (AUC) during a
24-h period to the MIC
of the pathogen

Fluoroquinolones
Glycopeptides
Tigecycline

0-24

Carbapenems
Lincosamides

Varghese et al, Antimicrobial Pharmacokinetic and Pharmacodynamic Issues in the

Critically Ill with Severe Sepsis and Septic Shock. Crit Care Clin 27 (2011) 19-34

CONCENTRATION VS TIME DEPEND

ENT

Figure 1. Time-kill curves, ranging from one-fourth to 64 times the MIC, that
show the bactericidal pattern of activity of tobramycin, cipro floxacin, and
ticarcillin against Pseudomonas aeruginosa American Type Culture Collec
tion (ATCC) 27853.
Ambrose et al, Pharmacokinetics Pharmacodynamics of Antimicrobial Therapy:
Its Not Just for Mice Anymore. Clinical Infectious Diseases 2007; 44:7986

PHARMACOKINETIC /PHARMACODYNAM
IC BETA LACTAM
Optimization of Beta Lactam Therapy :

Maximize the f T/ MIC

Manipulati
on of
Dosing
Interval

Manipulati
on of
Infusion
Time

Crandon & Nicolau, Pharmacodynamic Approaches to Optimizing Beta-Lactam

CEPHALOSPORIN AGENTS
1st
Generation
Agents cefadroxil,
cefazolin,
cephalexin,
cephalothin,
cephapirin,
cephradine

2nd Generation

3rd
Generation

4th
Generation

cefaclor,
cefamandole,
cefonicid,
cefuroxime,
cefprozil,
cefoxitin,
cefmetazole,
cefotetan

cefoperazone cefepime
, cefotaxime,
ceftazidime,
ceftizoxime,

ceftriaxon
e, cefixime,
cefpodoxime,
cefdinir,
ceftibuten
FOCU
S

Lacy et al, 2009. Drug Information Handbook 17th Edition

Sweetman, 2009. Martindale : The Complete Drug Reference 36 th Edition

CHEMICAL STRUCTURE OF THIRD GENER

ATION CEPHALOSPORIN
CEFOTAXIME

CEFOPERAZONE

CEFTRIAXONE

CEFTAZIDIME

Sweetman, 2009. Martindale : The Complete Drug Reference 36 th

PHARMACOKINETIC CHARACTERISTICS O
F THIRD GENERATION CEPHALOSPORIN
Drugs

Volum
e
distrib
ution
(Vd)

Prote T
in
norm
bindi al
ng

T
ESR
D

Excretion

CEFTRIAX
ONE

0,080,3
L/kg

85-95
%

5-9 hr

16 hr

Urine (33-67 % as
unchanged drug); Feces
(as inactive drug)

Cefoperazone

0,17
L/kg

8293%

1.5-3
hr

2,4
hr

Urine (20-30 % as
unchanged drug); Mainly in
the bile

Cefotaxime

0,25
L/kg

30-40
%

1-1.5
hr

15 hr

Mainly in urine (40-60 % as

unchanged drug; also as
metabolites)

Ceftazidime

0,36
10 % 1-2 hr 21 hr Mainly in urine (80-90 % as
L/kg
Lacy et al, 2009. Drug
Information Handbook 17th Edition unchanged drug)
Sweetman, 2009. Martindale : The Complete Drug Reference 36 th Edition
Cunha, 2010. Antibiotic Essentials ninth edition

PHARMACOKINETIC /PHARMACODYNAM
IC

CEFTRIAXONE

The most important

aspects of its PK :
a long half-life (5-9 hr)
excellent tissue penetration
protein binding is concentrationdependent 95% at low
concentrations (<100mg l-1), 60% at
high concentrations (>400mg l-1)
Garot et al, Population pharmacokinetics of ceftriaxone in critically ill septic
patients. British Journal of Clinical Pharmacology . Vol 72, No.5, p. 758767

PHARMACOKINETIC /PHARMACODYNAM
IC

CEFTRIAXONE

Time-dependent killing maximum

efficacy at 2 - 4 times the MIC, an
exposure profile achieved when 80
-100% of the concentrations are
above the MIC.
This also coincides with an
AUC24/MIC ratio of 125. Further
increases in concentration above
these values do not kill bacteria
more rapidly

Schentag, Clinical Use of Ceftriaxone. Clin Pharmacokinet 2001; 40 (9): 685-694

DOSAGE REGIMENTATION OF

EFTRIAXONE

Dosage
No
adjustment
range:
is generally necessary; if severe impairment, particular

Lacy et al, 2009. Drug Information Handbook 17th Edition

Martin, 2011. British National Formulary 61st Edition

DOSAGE REGIMEN OF CEFTRIAXONE IN PATIENTS W

ITH RENAL AND HEPATIC IMPAIRMENT

CrCl 50-80 ml/min

No change

CrCl 10-50ml/min

No change

CrCl < 10ml/min

No change

Post HD dose

None

Post HFHD dose

No change

Post PD dose

None

CVVH dose

No change

Moderate hepatic insufficiency

No change

Severe hepatic insufficiency

No change
(max dose 2 g/day)

Cunha, 2010. Antibiotic Essentials 9th Edition. Physicians Press.

PROBLEM
Ceftriaxo
ne 2 x 1
g

Ceftriaxo
ne 1 x 2
g

CALCULATION
Ceftrixones PK characteristics :
Vd = 6-14 L
T = 5 9 hr
Do 1-2 g Cp = 0.5 300 mg/L
Formula : Css =
F x Do
Vd x 0.693 x
Do = 1 g ; = 12 hr Css = 77.30 mg/L (0.5 300
t
mg/L)
Do= 2 g; = 24 hr Css = 77.30 mg/L (0.5 300 m
g/L)

CALCULATION
% T > MIC = ln
Do
100
Vd x MIC

ln 2

%T> MIC = percentage of the dosing interval for whic

h levels exceed the MIC
= dosing interval (h)
MIC = minimum inhibitory concentration (mg/L)

Do = 1 g ; = 12 hr %T> MIC = 236.88 %

Do= 2 g; = 24 hr %T> MIC = 155.94 %

CALCULATION
Ceftrixones PK characteristics :
Vd = 6-14 L
T = 5 9 hr
Protein binding = 95 % free drug = 5 %
Do = 1000 mg; = 12 jam
Co = Do x %free
Vd
= 3.57 mg/L
After the first-twelve hours ( t = 12 hr)
Cp = Co x e kt
= 1.42 mg/L

CALCULATION
Then , the second injection is administered
Cp = Co + Cp
Cp = 3.57 + 1.42 = 4, 99 mg
Plasma concetration at 24 hr (Cp ) is assumed as MIC.
e.g Ceftriaxones MIC = 1 g/ mL
Cp = Cp x e kt
t = 20.88 hr
Cefriaxone 2 x 1 g To reach its MIC, the time needed is :
(12 + 20.88) = 32.88 hr

CALCULATION
Do = 2000 mg; = 24 jam
Co = Do x % free
Vd
= 7.14 mg/L
Plasma concetration at 24 hr (Cp ) is assumed as MIC.
e.g Ceftriaxones MIC = 1 g/ mL
Cp = Co x e kt
t = 25.53 hr
Cefriaxone 1 x 2 g To reach its MIC, the time needed is : 25.
53 hr

CLINICAL CONSIDERATION
Hypoalbuminemia

Renal CL

Pea et al, 2005. Antimicrobial Therapy in Critically Ill Patients. Clin Pharmacokinet
page 1009-1030
Varghese et al, Antimicrobial Pharmacokinetic and Pharmacodynamic Issues in the

SUMMARY
Ceftriaxone is time-dependent antibiotic which can be
adminestered 1-2 g every 12-24 hours
Do = 1 g ; = 12 hr
Css = 77.30 mg/L (0.5 300 mg/L)
%T> MIC = 236.88 %
To reach its MIC, the time needed is 32.88 hr

Do= 2 g; = 24 hr
Css = 77.30 mg/L (0.5 300 mg/L)
%T> MIC = 155.94 %
To reach its MIC, the time needed is 25.53 hr

In particular clinical condition such as hypoalbuminem

ia and fever, shortening the dosage interval ensures o
ptimal ceftriaxone concentrations over the entire dosa

REFERENCES

Ambrose et al, Pharmacokinetics Pharmacodynamics of Antimicrobial Therapy: Its No

t Just for Mice Anymore. Clinical Infectious Diseases 2007; 44:7986
Crandon & Nicolau, Pharmacodynamic Approaches to Optimizing Beta-Lactam Therap
y. Crit Care Clin 27 (2011) 77-93
Cunha, 2010. Antibiotic Essentials, 9 th edition
Garot et al, Population pharmacokinetics of ceftriaxone in critically ill septic patients.
British Journal of Clinical Pharmacology . Vol 72, No.5, p. 758767
Lacy et al, 2009. Drug Information Handbook 17 th Edition
Lodise & Drusano, Pharmacokinetics & Pharmacodynamics : Optimal Antimicrobial Th
erapy in the Intensive Care Unit. Crit Care Clin 27 (2011). 1-18
Lullmann, H, Mohr, K, Ziegler, A & Bieger, D 2005, Color Atlas of Pharmacology, 3 rd Ed.
, Thieme,New York.
Pagani et al, 2011. Year in review 2010 : Critical Care-Infection. BioMed Central Ltd pa
ge 1-7.
Pea et al, 2005. Antimicrobial Therapy in Critically Ill Patients. Clin Pharmacokinet pag
e 1009-1030
Perry & Schentag, Clinical Use of Ceftriaxone. Clin Pharmacokinet 2001; 40 (9): 685-69
4
Shargel, L, Wu-Pong, S & Yu, ABC 2007, Applied Biopharmaceutics & Pharmacokinetics,
5 th Ed.,The McGraw-Hill Companies.
th