A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Rocephin Pharmacology, Pharmacokinetics, Studies, Metabolism - Ceftriaxone
Rocephin Pharmacology, Pharmacokinetics, Studies, Metabolism - Ceftriaxone
CLINICAL PHARMACOLOGY
Average plasma concentrations
of ceftriaxone following
a single 30-minute intravenous (IV) infusion
of a 0.5, 1 or 2 g dose
and intramuscular
(IM) administration of a single 0.5 (250 mg/mL or 350 mg/mL concentrations)
or 1 g dose in healthy
subjects are presented in Table 1.
TABLE 1: Ceftriaxone Plasma Concentrations After Single Dose
Administration
| Dose/Route
|
Average Plasma Concentrations (µg/mL)
|
|
0.5 hr
|
1 hr
|
2 hr
|
4 hr
|
6 hr
|
8 hr
|
12 hr
|
16 hr
|
24 hr
|
| 0.5 gm IV* |
82
|
59
|
48
|
37
|
29
|
23
|
15
|
10
|
5
|
| 0.5 gm
IM 250 mg/mL |
22
|
33
|
38
|
35
|
30
|
26
|
16
|
ND
|
5
|
| 0.5 gm
IM 350 mg/mL |
20
|
32
|
38
|
34
|
31
|
24
|
16
|
ND
|
5
|
| 1 gm IV* |
151
|
111
|
88
|
67
|
53
|
43
|
28
|
18
|
9
|
| 1 gm IM |
40
|
68
|
76
|
68
|
56
|
44
|
29
|
ND
|
ND
|
| 2 gm
IV* |
257
|
192
|
154
|
117
|
89
|
74
|
46
|
31
|
15
|
- * IV doses
were infused at a constant
rate over 30 minutes.
- ND = Not determined.
Ceftriaxone was completely absorbed following IM administration
with mean maximum plasma
concentrations occurring between 2 and 3 hours postdosing. Multiple
IV or IM doses ranging from
0.5 to 2 gms at 12- to 24-hour intervals resulted in 15% to 36%
accumulation of ceftriaxone
above single dose values.
Ceftriaxone concentrations in urine
are high, as shown in Table 2.
TABLE 2: Urinary Concentrations of Ceftriaxone After Single
Dose Administration
|
Dose/Route
|
Average Urinary Concentrations (µg/mL)
|
|
0-2 hr
|
2-4 hr
|
4-8 hr
|
8-12 hr
|
12-24 hr
|
24-48 hr
|
| 0.5 gm IV
|
526
|
366
|
142
|
87
|
70
|
15
|
| 0.5 gm IM |
115
|
425
|
308
|
127
|
96
|
28
|
| 1 gm IV
|
995
|
855
|
293
|
147
|
132
|
32
|
| 1 gm IM |
504
|
628
|
418
|
237
|
ND
|
ND
|
| 2 gm IV
|
2692
|
1976
|
757
|
274
|
198
|
40
|
Thirty-three percent
to 67% of a ceftriaxone
dose was excreted in the
urine as unchanged drug
and the remainder was secreted in the bile
and ultimately found in the feces
as microbiologically inactive compounds. After a 1 gm IV
dose, average concentrations
of ceftriaxone determined
from 1 to 3 hours after dosing, were 581 µg/mL in the gallbladder
bile, 788 µg/mL in the common duct
bile, 898 µg/mL in the cystic duct bile, 78.2 µg/gm
in the gallbladder
wall and 62.1 µg/mL
in the concurrent plasma.
Over a 0.15 to 3 gm dose
range in healthy
adult subjects, the values
of elimination half-life
ranged from 5.8 to 8.7 hours; apparent
volume of distribution
from 5.78 to 13.5 L; plasma
clearance from 0.58
to 1.45 L/hour; and renal
clearance from 0.32
to 0.73 L/hour. Ceftriaxone is reversibly bound to human
plasma proteins, and
the binding decrease from a value
of 95% bound at plasma
concentrations of <25 µg/mL to a value
of 85% bound at 300 µg/mL.
The average values of
maximum plasma
concentration, elimination half-life, plasma
clearance and volume
of distribution
after a 50 mg/kg IV dose
and after a 75 mg/kg IV dose
in pediatric patients
suffering from bacterial meningitis
are shown in table 3.
Ceftriaxone penetrated the inflamed meninges
of infants and children; CSF
concentrations after a 50 mg/kg IV
dose and after a 75 mg/kg
IV dose
are also shown in Table 3.
TABLE 3: Average Pharmacokinetic Parameters of Ceftriaxone
in Pediatric Patients With Meningitis
| |
50 mg/kg IV
|
75 mg/ kg
IV
|
| Maximum Plasma Concentrations
(µg/mL) |
216
|
275
|
| Elimination Half-life
(hr) |
4.6
|
4. 3
|
| Plasma Clearance
(mL/kg) |
49
|
60
|
| Volume of Distribution
(mL/kg) |
338
|
373
|
| CSF Concentration
- inflamed meninges (µg/mL) |
5.6
|
6.4
|
| Range (µg/mL)
|
1.3-18.5
|
1.3-44
|
| Time after dose
(hr) |
3.7 (± 1.6)
|
3.3 (± 1.4)
|
Compared to that in healthy
adult subjects, the pharmacokinetics
of ceftriaxone were only minimally altered in elderly subjects and
in patients with renal
impairment or hepatic
dysfunction (Table
4); therefore dosage adjustments are not necessary for these patients
with ceftriaxone
dosages up to 2 gm per day.
Ceftriaxone was not removed to any significant
extent from the plasma
by hemodialysis. In 6 of
26 dialysis patients,
the elimination rate of ceftriaxone
was markedly reduced, suggesting that plasma
concentrations of ceftriaxone
should be monitored in these patients to determine if dosage adjustments
are necessary.
TABLE 4: Average Pharmacokinetic Parameters of Ceftriaxone
in Humans
|
Subject
Group
|
Elimination
Half-Life (hr)
|
Plasma
Clearance (L/hr)
|
Volume of
Distribution (L)
|
| Healthy Subjects
|
58-8.7
|
0.58-1.45
|
58-13.5
|
| Elderly Subjects
(mean age, 70.5 years
|
8.9
|
0.83
|
10.7
|
| Patients with renal
impairment |
| Hemodialysis patients
(0-5 mL/min)* |
14.7
|
0.65
|
13.7
|
| Severe (5-15 mL/min)
|
15.7
|
0.56
|
12.5
|
| Moderate (16-30 mL/min)
|
11.4
|
0.72
|
11.8
|
| Mild (31-60 mL/min)
|
12.4
|
0.70
|
13.3
|
| Patients with
liver disease |
8.8
|
1.1
|
13.6
|
Pharmacokinetics in the Middle Ear Fluid
In one study, total ceftriaxone
concentrations (bound and unbound) were measured in middle ear
fluid obtained during
the insertion of tympanostomy
tubes in 42 pediatric
patients with otitis
media. Sampling times were from 1 to 50 hours after a single intramuscular
injection of 50 mg/kg
of ceftriaxone. Mean (±SD) ceftriaxone
levels in the middle ear
reached a peak of 35 (±12) µg/mL at 24 hours, and remained
at 19 (±7) µg/mL at 48 hours. Based on middle ear
fluid ceftriaxone
concentrations in the 23 to 25 hour and the 46 to 50 hour sampling
time intervals, a half-life
of 25 hours was calculated. Ceftriaxone is highly bound
to plasma proteins. The
extent of binding to proteins in the middle ear
fluid is unknown.
Microbiology
The bactericidal
activity of ceftriaxone
results from inhibition
of cell wall synthesis.
Ceftriaxone has a high degree
of stability in the
presence of beta-lactamases, both penicillinases and cephalosporinases
of gram-negative
and positive bacteria.
Gram-Negative Aerobes:
Acinetobacter calcoaceticus
Enterobacter aerogenes
Enterobacter cloacae
Escherichia coli
Haemophilus influenzae (including ampicillin-resistant
and beta-lactamase producing strains)
Haemophilus parainfluenzae
Klebsiella oxytoca
Klebsiella pneumoniae
Moraxella catarrhalis (including beta-lactamase producing
strains)
Morganella morganii
Neisseria gonorrhoeae (including penicillinase
- and nonpenicillinase-producing strains)
Neisseria meningitidis
Proteus mirabilis
Proteus vulgaris
Serratia marcescens
Ceftriaxone is also active against many strains of Pseudomonas
aeruginosa.
NOTE: Many strains of the above organisms that are multiply
resistant to other antibiotics, eg, penicillins, cephalosporins
and aminoglycosides, are susceptible
to ceftriaxone.
Gram-Positive Aerobes:
Staphylococcus aureus (including penicillinase-producing
strains)
Staphylococcus epidermidis
Streptococcus pneumoniae
Streptococcus pyogenes
Viridans group streptococci
NOTE: Methicillin-resistant staphylococci
are resistant to cephalosporins, including ceftriaxone. Most strains
of Group D streptococci
and enterococci, e.g., Enterococcus (Streptococcus) faecalis,
are resistant.
Anaerobes:
Bacteroides fragilis
Clostridium species
Peptostreptococcus species
NOTE: Most strains of C. difficile are resistant.
Ceftriaxone also demonstrates in vitro activity
against most strains of the following microorganisms, although the
clinical significance
is unknown:
Gram-Negative Aerobes:
Citrobacter diversus
Citrobacter freundii
Providencia species
(including Providencia rettgeri)
Salmonella species
(including S. typhi)
Shigella species
Gram-Positive Aerobes:
Streptococcus agalactiae
ANAEROBES:
Bacteroides bivius
Bacteroides melaninogenicus
Susceptibility Tests
Diffusion Techniques: Quantitative methods that require
the measurement of zone
diameters give the most precise estimate of the susceptibility of
bacteria to antimicrobial
agents. One such standard
procedure¹ which has been recommended for use with disks to
test susceptibility
of organisms to ceftriaxone
uses a 30-µg ceftriaxone
disk. Interpretation involves the correlation
of the diameters obtained in the disk
test with the minimum
inhibitory concentration
(MIC) for ceftriaxone.
Reports from the laboratory
giving results of the standardized single disk susceptibility
test using a 30-mcg ceftriaxone
disk should be interpreted
for ceftriaxone
according to the following criteria:
|
Zone Diameter (mm)
|
Interpretation
|
|
³18
|
(S) Susceptible
|
|
14 - 17
|
(MS) Moderately Susceptible
|
|
£13
|
(R) Resistant
|
A report of ''Susceptible''
indicates that the pathogen
is likely to be inhibited by generally achievable levels. A report
of ''Moderately Susceptible" suggests that the organism
would be susceptible
if high dose (not to exceed
4 gm/day) is used or if the infection
is confined to tissues and fluids in which high antimicrobial
levels are attained. A report
of "Resistant'' indicates that achievable concentrations are
unlikely to be inhibitory, and other therapy
should be selected. Standardized procedures require the use of laboratory
control organisms. The
30-µg ceftriaxone
disk should give the following
zone diameters:
|
Organism
|
Zone Diameter (mm)
|
|
Staphylococcus aureus
ATCC 25923
|
22-28
|
|
Escherichia coli
ATCC 25922
|
29-35
|
|
Pseudomonas aeruginosa
ATCC 27853
|
17-23
|
Dilution Techniques: Use a standardized dilution
method² (broth, agar, microdilution) or equivalent
with ceftriaxone
powder. The MIC values obtained should be interpreted according
to the following criteria:
|
MIC (mcg/mL)
|
Interpretation
|
|
£ 16
|
Susceptible
|
|
>16 - <64
|
Moderately Susceptible
|
|
³ 64
|
Resistant
|
As with standard diffusion
techniques, dilution
methods require the use of laboratory
control organisms. Standard
ceftriaxone powder
should provide the following MIC
values:
|
Organism
|
MIC (mcg/mL)
|
|
Staphylococcus aureus
ATCC 29213
|
1 - 8
|
|
Escherichia coli
ATCC 25922
|
0.03 - 0.12
|
|
Pseudomonas aeruginosa
ATCC 27853
|
8 - 32
|
ANIMAL PHARMACOLOGY
Concretions consisting of the precipitated calcium
salt of ceftriaxone have
been found in the gallbladder
bile of dogs and baboons
treated with ceftriaxone. These appeared as a gritty sediment
in dogs that received 100 mg/kg/day for 4 weeks. A similar phenomenon
has been observed in baboons but only after a protracted dosing
period (6 months) at
higher dose levels (335/mg/kg/day
or more). The likelihood of this occurrence in humans is considered
to be low, since ceftriaxone
has a greater plasma
half-life in humans, the calcium
salt of ceftriaxone
is more soluble in human
gallbladder bile and the calcium
content of human gallbladder
bile is relatively low.
CLINICAL STUDIES
Clinical Trials in Pediatric Patients With Acute Bacterial
Otitis Media: In
two adequate and well-controlled US clinical
trials a single IM dose
of ceftriaxone was
compared with a 10 day course of oral antibiotic in pediatric
patients between the ages of 3 months and 6 years. The clinical
cure rates and statistical
outcome appear in the
table below:
|
Study Day
|
Ceftriaxone
Single Dose
|
Comparator - 10 days
of Oral Therapy
|
95% Confidence
Interval
|
Statistical
Outcome
|
|
Study 1 — US
|
74% (220/296)
|
amoxicillin/clavulanate
82% (247/302)
|
(-14.4%,-0.5%)
|
Ceftriaxone is lower than control
at study day 14 and 28.
|
|
14
|
|
28
|
58% (167/288)
|
67% (200/297)
|
(-17.5%,-1.2%)
|
|
Study 2 — US3
|
54% (113/210)
|
TMP- SMZ
60% (124/206)
|
(- 16.4%, 3.6%)
|
Ceftriaxone is equivalent
to control
at study day 14 and 28.
|
|
14
|
|
28
|
35% (73/206)
|
45% (93/205)
|
(- 19.9%, 0.0%)
|
An open-label bacteriologic
study ceftriaxone
without a comparator enrolled 108 pediatric
patients, 79 of whom had positive
base-line cultures for one or more of the common pathogens. The
results of this study are tabulated as follows:
Week 2 and 4 Bacteriologic Eradication Rates in the Per Protocol
Analysis in the Roche Bacteriologic Study by pathogen:
| |
Study Day
13- 15
|
Study Day
30 + 2
|
| Organism |
No. Analyzed
|
No. Erad. (%)
|
No. Analyzed
|
No. Erad. (%)
|
| S. pneumoniae
|
38
|
32 (84)
|
35
|
25 (71)
|
| H. influenzae
|
33
|
28 (85)
|
31
|
22 (71)
|
| M. catarrhalis
|
15
|
12 (80)
|
15
|
9 (60)
|
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