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
Omnicef Pharmacology, Pharmacokinetics, Studies, Metabolism - Cefdinir
Omnicef Pharmacology, Pharmacokinetics, Studies, Metabolism - Cefdinir
CLINICAL PHARMACOLOGY
Pharmacokinetics and Drug Metabolism
Absorption
Oral Bioavailability:
Maximal plasma cefdinir concentrations
occur 2 to 4 hours postdose following capsule or suspension
administration. Plasma cefdinir concentrations increase with dose,
but the increases are less than dose-proportional from 300 mg
(7 mg/kg) to 600 mg (14 mg/kg).
Following administration
of suspension to
healthy adults, cefdinir bioavailability
is 120% relative to capsules. Estimated bioavailability
of cefdinir capsules is 21% following administration of a 300 mg
capsule dose, and 16%
following administration
of a 600 mg capsule dose. Estimated absolute
bioavailability
of cefdinir suspension is 25%.
Effect of Food: Although
the rate (Cmax)
and extent (AUC) of cefdinir absorption
from the capsules are reduced by 16% and 10%, respectively, when
given with a high-fat meal, the magnitude
of these reductions is not likely to be clinically significant.
Therefore, cefdinir may be taken without regard to food.
Cefdinir Capsules:
Cefdinir plasma concentrations
and pharmacokinetic parameter
values following administration of single 300- and 600-mg oral
doses of cefdinir to adult
subjects are presented in the following table:
|
Mean (±SD) Plasma Cefdinir Pharmacokinetic
Parameter Values Following Administration of Capsules
to Adult Subjects
|
|
Dose
|
Cmax
(µg/mL)
|
tmax
(hr)
|
AUC
|
|
300 mg
|
1.60
(0.55)
|
2.9
(0.89)
|
7.05
(2.17)
|
|
600 mg
|
2.87
(1.01)
|
3.0
(0.66)
|
11.1
(3.87)
|
Cefdinir Suspension: Cefdinir
plasma concentrations and pharmacokinetic parameter
values following administration of single 7- and 14-mg/kg oral
doses of cefdinir to pediatric
subjects (age 6 months-12 years) are presented in the following
table:
|
Mean (± SD) Plasma Cefdinir Pharmacokinetic
Parameter Values Following Administration of Suspension
to Pediatric Subjects
|
|
Dose
|
Cmax
(µg/mL)
|
tmax
(hr)
|
AUC
(µg·hr/mL)
|
|
7 mg/ kg
|
2.30
(0.65)
|
2.2
(0.6)
|
8.31
(2.50)
|
|
14 mg/ kg
|
3.86
(0.62)
|
1.8
(0.4)
|
13.4
(2.64)
|
Multiple Dosing:
Cefdinir does not accumulate in plasma
following once- or twice-daily administration to subjects with normal
renal function.
Distribution
The mean
volume of distribution
(Vdarea) of cefdinir in adult
subjects is 0.35 L/kg (±0.29);
in pediatric subjects
(age 6 months-12 years), cefdinir Vdarea
is 0.67 L/kg (±0.38).
Cefdinir is 60% to 70% bound
to plasma proteins in
both adult and pediatric
subjects; binding is independent of concentration.
Skin Blister: In
adult subjects, median
(range) maximal blister
fluid cefdinir concentrations
of 0.65 (0.33-1.1) and 1.1 (0.49-1.9) µg/mL were observed
4 to 5 hours following administration
of 300- and 600-mg doses, respectively. Mean (±SD)
blister Cmax
and AUC(0-¥)
values were 48% (±13)
and 91% (±18)
of corresponding
plasma values.
Tonsil Tissue: In
adult patients undergoing elective tonsillectomy, respective median
tonsil tissue cefdinir concentrations 4 hours after administration
of single 300- and 600-mg doses were 0.25 (0.22-0.46) and 0.36 (0.22-0.80)
µg/g. Mean tonsil
tissue concentrations
were 24% (±8) of corresponding plasma concentrations.
Sinus Tissue: In
adult patients undergoing elective maxillary
and ethmoid sinus
surgery, respective median
sinus tissue
cefdinir concentrations 4 hours after administration of single 300-
and 600-mg doses were <0.12 (<0.12-0.46) and 0.21 (<0.12-2.0)
µg/g. Mean sinus
tissue concentrations
were 16% (±20) of corresponding
plasma concentrations.
Lung Tissue: In
adult patients undergoing diagnostic
bronchoscopy, respective median
bronchial mucosa cefdinir concentrations 4 hours after administration
of single 300- and 600-mg doses were 0.78 (<0.06-1.33) and 1.14
(<0.06-1.92) µg/mL, and were 31% (±18) of corresponding
plasma concentrations.
Respective median epithelial lining fluid
concentrations were 0.29 (<0.3-4.73) and 0.49 (<0.3-0.59)
µg/mL, and were 35% (±83)of corresponding plasma concentrations.
Middle Ear Fluid: In
14 pediatric patients
with acute bacterial otitis
media, respective median middle ear
fluid cefdinir concentrations
3 hours after administration
of single 7- and 14-mg/kg doses were 0.21 (<0.09-0.94) and 0.72
(0.14-1.42) µg/mL. Mean middle ear
fluid concentrations were
15% (±15) of corresponding
plasma concentrations.
CSF: Data
on cefdinir penetration
into human cerebrospinal
fluid are not available.
Metabolism and Excretion
Cefdinir is not appreciably metabolized.
Activity is primarily due to parent
drug. Cefdinir is eliminated principally via renal
excretion with a mean
plasma elimination
half-life (t½)
of 1.7 (±0.6) hours. In
healthy subjects with
normal renal
function, renal clearance
is 2.0 (±1.0) mL/min/kg, and apparent
oral clearance is 11.6
(±6.0) and 15.5 (±5.4) mL/min/kg following doses of
300 and 600 mg, respectively. Mean percent
of dose recovered unchanged
in the urine following
300- and 600-mg doses is 18.4% (±6.4) and 11.6% (±4.6),
respectively. Cefdinir clearance
is reduced in patients with renal
dysfunction (see
Special Populations: Patients
with Renal Insufficiency
below).
Because renal
excretion is the predominant
pathway of elimination, dosage
should be adjusted in patients with markedly compromised renal
function or who are
undergoing hemodialysis
(see DOSAGE
AND ADMINISTRATION).
Special Populations
Patients with Renal Insufficiency:
Cefdinir pharmacokinetics
were investigated in 21 adult
subjects with varying degrees of renal
function. Decreases in cefdinir elimination
rate, apparent oral
clearance (CL/F),
and renal clearance were approximately proportional to the reduction
in creatinine clearance (CLcr). As
a result, plasma cefdinir
concentrations were higher and persisted longer in subjects with
renal impairment
than in those without renal
impairment. In subjects with
CLcr between 30 and 60 mL/min, Cmax
and t½ increased by approximately
2-fold and AUC by approximately 3-fold. In
subjects with CLcr <30 mL/min,
Cmax increased by approximately
2-fold, t½ by approximately
5-fold, and AUC by approximately
6-fold. Dosage adjustment is recommended in patients with markedly
compromised renal function
(creatinine clearance <30 mL/min; see DOSAGE
AND ADMINISTRATION).
Hemodialysis: Cefdinir
pharmacokinetics were studied in 8 adult
subjects undergoing hemodialysis. Dialysis (4 hours duration) removed
63% of cefdinir from the body
and reduced apparent elimination
t½ from 16 (±3.5) to 3.2 (±1.2)
hours. Dosage adjustment
is recommended in this patient population (see DOSAGE
AND ADMINISTRATION).
Hepatic Disease: Because
cefdinir is predominantly renally eliminated and not appreciably
metabolized, studies in patients with hepatic
impairment were not
conducted. It is not expected that dosage
adjustment will
be required in this population.
Geriatric Patients:
The effect of age
on cefdinir pharmacokinetics
after a single 300-mg dose
was evaluated in 32 subjects 19 to 91 years of age. Systemic exposure
to cefdinir was substantially increased in older subjects (N = 16),
Cmax by 44% and AUC
by 86%. This increase was due to a reduction
in cefdinir clearance. The apparent
volume of distribution
was also reduced, thus no appreciable alterations in apparent
elimination half-life
were observed (elderly: 2.2 ± 0.6 hours vs young: 1.8 ±
0.4 hours). Since cefdinir clearance
has been shown to be primarily related to changes in renal function
rather than age, elderly patients do not require dosage adjustment
unless they have markedly compromised renal
function (creatinine
clearance <30 mL/min, see Patients
with Renal Insufficiency,
above).
Gender and Race: The
results of a meta-analysis
of clinical pharmacokinetics
(N = 217) indicated no significant
impact of either gender
or race on cefdinir pharmacokinetics.
Microbiology
As with other cephalosporins, bactericidal
activity of cefdinir results from inhibition
of cell wall
synthesis. Cefdinir is stable
in the presence of some, but not all, b-lactamase
enzymes. As a result, many
organisms resistant to penicillins and some cephalosporins are susceptible
to cefdinir.
Cefdinir has been shown to be active
against most strains of the following microorganisms, both in
vitro and in clinical
infections as described in INDICATIONS.
Aerobic Gram-Positive Microorganisms:
- Staphylococcus aureus
(including b-lactamase
producing strains)
- NOTE: Cefdinir is inactive against
methicillin-resistant staphylococci.
- Streptococcus pneumoniae
(penicillin-susceptible
strains only)
- Streptococcus pyogenes
Aerobic Gram-Negative Microorganisms:
- Haemophilus influenzae
(including b-lactamase
producing strains)
- Haemophilus parainfluenzae
(including b
-lactamase producing
strains)
- Moraxella catarrhalis
(including b-lactamase
producing strains).
The following in
vitro data are available,
but their clinical
significance is unknown.
Cefdinir exhibits in
vitro minimum inhibitory
concentrations (MICs) of 1 µg/mL or less against (³90%)
strains of the following microorganisms; however, the safety and
effectiveness of cefdinir in treating clinical
infections due to these microorganisms have not been established
in adequate and well-controlled clinical
trials.
Aerobic Gram-Positive Microorganisms:
- Staphylococcus epidermidis
(methicillin-susceptible
strains only)
- Streptococcus agalactiae
- Viridans group
streptococci
NOTE: Cefdinir is inactive against Enterococcus
and methicillin-resistant
Staphylococcus species.
Aerobic Gram-Negative Microorganisms:
- Citrobacter diversus
- Escherichia coli
- Klebsiella pneumoniae
- Proteus mirabilis
NOTE: Cefdinir is inactive against Pseudomonas
and Enterobacter
species.
Susceptibility Tests
Dilution Techniques:
Quantitative methods are used to determine antimicrobial
minimum inhibitory concentrations
(MICs). These M.C. provide
estimates of the susceptibility of bacteria
to antimicrobial
compounds. The M.C. should
be determined using a standardized procedure. Standardized procedures
are based on a dilution method (broth or agar) or equivalent
with standardized inoculum
concentrations and standardized concentrations of cefdinir powder.
The MIC values should be
interpreted according to the following criteria:
For organisms other than Haemophilus
spp. and Streptococcus
spp:
|
MIC (µg/mL)
|
Interpretation
|
|
£1 1
|
Susceptible (S)
|
|
2
|
Intermediate (I)
|
|
³4
|
Resistant (R)
|
For Haemophilus
spp:a
|
MIC (µg/mL)
|
Interpretation b
|
|
£1
|
Susceptible (S)
|
- aThese interpretive
standards are applicable only
- to broth
microdilution susceptibility tests with
- Haemophilus
spp. using Haemophilus
Test
- Medium (HTM).1
- b The current
absence of data on resistant strains
- precludes defining
any results other than
- "Susceptible".
Strains yielding MIC results
- suggestive of a "nonsusceptible"
category
- should be submitted
to a reference laboratory
- for further testing.
For Streptococcus
spp:
Streptococcus pneumoniae that
are susceptible
to penicillin (MIC
£0.06
µg/mL), or streptococci
other than S. pneumoniae
that are susceptible
to penicillin (MIC £0.12
µg/mL), can be considered susceptible
to cefdinir. Testing of cefdinir against penicillin-intermediate
or penicillin-resistant isolates is not recommended. Reliable interpretive
criteria for cefdinir are not available.
A report
of "Susceptible" indicates that the pathogen
is likely to be inhibited if the antimicrobial
compound in the blood
reaches the concentration
usually achievable. A report
of "Intermediate" indicates that the result should be
considered equivocal, and
if the microorganism
is not fully susceptible
to alternative, clinically feasible drugs, the test
should be repeated. This category implies possible clinical
applicability in body sites
where the drug is physiologically
concentrated or in situations where high dosage
of drug can be used. This
category also provides a buffer
zone which prevents small
uncontrolled technical factors from causing major discrepancies
in interpretation. A report of "Resistant" indicates that
the pathogen is not
likely to be inhibited if the antimicrobial
compound in the blood
reaches the concentrations usually achievable; other therapy
should be selected.
Standardized susceptibility
test procedures require
the use of laboratory
control microorganisms
to control the technical
aspects of laboratory
procedures. Standard cefdinir powder
should provide the following MIC
values:
|
Microorganism
|
MIC Range (µg/mL)
|
|
Escherichia coli A.C.
25922
|
0.12- 0.5
|
|
Haemophilus influenzae A.C.
49766 c
|
0.12- 0.5
|
|
Staphylococcus aureus A.C.
29213
|
0.12- 0.5
|
- c This quality
control range is applicable
only to H. influenzae
- ATCC 49766 tested by
a broth microdilution procedure
using HTM.
Diffusion Techniques:
Quantitative methods that require measurement of zone
diameters also provide reproducible estimates of the susceptibility
of bacteria to antimicrobial
compounds. One such standardized
procedure2 requires the use of standardized
inoculum concentrations.
This procedure uses
paper disks impregnated with 5-µg cefdinir to test
the susceptibility
of microorganisms to cefdinir.
Reports from the laboratory
providing results of the standard
single-disk susceptibility
test with a 5-µg
cefdinir disk should be interpreted according to the following criteria:
For organisms other than Haemophilus
spp. and Streptococcus
spp:d
|
Zone Diameter (mm)
|
Interpretation
|
|
³20
|
Susceptible (S)
|
|
17-19
|
Intermediate (I)
|
|
£16
|
Resistant (R)
|
- d Because
certain strains of Citrobacter,
Providencia,
and Enterobacter
- spp. have been reported
to give false susceptible
results with the cefdinir
- disk, strains of these
genera should not be tested and reported with this
- disk.
For Haemophilus
spp:e
|
Zone Diameter (mm)
|
Interpretationf
|
|
³20
|
Susceptible (S)
|
- e These
zone diameter standards
are applicable only to tests with
- Haemophilus
spp. using HTM.2
- f The current
absence of data on resistant strains precludes defining any
- results other than
"Susceptible." Strains yielding results suggestive
of a
- "nonsusceptible"
category should be submitted to a
- reference laboratory
for further testing.
For Streptococcus
spp:
Isolates of Streptococcus
pneumoniae should be tested
against a 1-µg oxacillin
disk. Isolates with oxacillin
zone sizes ³20
mm are susceptible
to penicillin and
can be considered susceptible
to cefdinir. Streptococci other than S.
pneumoniae should be tested
with a 10-unit penicillin
disk. Isolates with penicillin
zone sizes ³28
mm are susceptible
to penicillin and
can be considered susceptible
to cefdinir.
As with standardized dilution
techniques, diffusion methods require the use of laboratory
control microorganisms
to control the technical
aspects of laboratory
procedures. For the diffusion technique the 5-µg cefdinir
disk should provide the
following zone diameters in these laboratory
quality control
strains:
|
Organism
|
Zone Diameter (mm)
|
|
Escherichia coli A.C.
25922
|
24- 28
|
|
Haemophilus influenzae A.C.
49766 g
|
24- 31
|
|
Staphylococcus aureus A.C.
25923
|
25- 32
|
CLINICAL
STUDIES
Community-Acquired Bacterial
Pneumonia
In a controlled, double-blind study
in adults and adolescents conducted in the US, cefdinir BID was
compared with cefaclor 500 mg
TID. Using strict evaluability and microbiologic/clinical response
criteria 6 to 14 days posttherapy, the following clinical
cure rates, presumptive
microbiologic eradication
rates, and statistical
outcomes were obtained:
|
US Community- Acquired Pneumonia Study
Cefdinir vs Cefaclor
|
|
|
Cefdinir BID
|
Cefaclor TID
|
Outcome
|
|
Clinical Cure Rates
|
150/ 187
|
(80%)
|
147/186
|
(79%)
|
Cefdinir equivalent
to control
|
|
Eradication Rates
|
|
Overall
|
177/ 195
|
(91%)
|
184/200
|
(92%)
|
Cefdinir equivalent
to control
|
|
S. pneumoniae
|
31/ 31
|
(100%)
|
35/35
|
(100%)
|
|
|
H. influenzae
|
55/ 65
|
(85%)
|
60/72
|
(83%)
|
|
|
M. catarrhalis
|
10/ 10
|
(100%)
|
11/11
|
(100%)
|
|
|
H. parainfluenzae
|
81/ 89
|
(91%)
|
78/82
|
(95%)
|
|
In a second controlled, investigator-blind
study in adults and adolescents conducted primarily in Europe, cefdinir
BID was compared with amoxicillin/clavulanate 500/125 mg
TID. Using strict evaluability and clinical
response criteria 6
to 14 days posttherapy, the following clinical
cure rates, presumptive
microbiologic eradication
rates, and statistical
outcomes were obtained:
|
European Community- Acquired Pneumonia
Study
Cefdinir vs Amoxicillin/Clavulanate
|
|
|
Cefdinir BID
|
Amoxicillin/Clavulanate TID
|
Outcome
|
|
Clinical Cure Rates
|
83/104
|
(80%)
|
86/97
|
(89%)
|
Cefdinir not equivalent
to control
|
|
Eradication Rates
|
|
Overall
|
85/96
|
(89%)
|
84/90
|
(93%)
|
Cefdinir equivalent
to control
|
|
S. pneumoniae
|
42/44
|
(95%)
|
43/44
|
(98%)
|
|
|
H. influenzae
|
26/35
|
(74%)
|
21/26
|
(81%)
|
|
M. catarrhalis
|
6/6
|
(100%)
|
8/8
|
(100%)
|
|
H. parainfluenzae
|
11/11
|
(100%)
|
12/12
|
(100%)
|
Streptococcal Pharyngitis/Tonsillitis
In four controlled studies conducted
in the United States, cefdinir was compared with 10 days of penicillin
in adults, adolescents, and pediatric
patients. Two studies (one in adults and adolescents, the other
in pediatric patients)
compared 10 days of cefdinir QD or BID to penicillin
250 mg or 10 mg/kg QID. Using
strict evaluability and microbiologic/ clinical response
criteria 5 to 10 days posttherapy, the following clinical cure rates,
microbiologic eradication
rates, and statistical
outcomes were obtained:
- Pharyngitis/ Tonsillitis Studies Cefdinir
(10 days) vs Penicillin (10 days)
|
- Study
|
- Efficacy Parameter
|
- Cefdinir QD
|
- Cefdinir BID
|
- Penicillin QID
|
- Outcome
|
- Adults/ Adolescents
|
- Eradication of S. pyogenes
|
- 192/210
|
- (91%)
|
- 199/217
|
- (92%)
|
- 181/217
|
- (83%)
|
- Cefdinir superior
to control
|
- Clinical Cure Rates
|
- 199/210
|
- (95%)
|
- 209/217
|
- (96%)
|
- 193/217
|
- (89%)
|
- Cefdinir superior
to control
|
- Pediatric Patients
|
- Eradication of S. pyogenes
|
- 215/228
|
- (94%)
|
- 214/227
|
- (94%)
|
- 159/227
|
- (70%)
|
- Cefdinir superior
to control
|
- Clinical Cure Rates
|
- 222/228
|
- (97%)
|
- 218/227
|
- (96%)
|
- 196/227
|
- (86%)
|
- Cefdinir superior
to control
|
Two studies (one in adults and adolescents,
the other in pediatric
patients) compared 5 days of cefdinir BID to 10 days of penicillin
250 mg or 10 mg/kg QID. Using
strict evaluability and microbiologic/clinical response
criteria 4 to 10 days posttherapy, the following clinical
cure rates, microbiologic
eradication rates,
and statistical outcomes were obtained:
|
Pharyngitis/Tonsillitis Studies
Cefdinir (5 days) vs Penicillin (10 days)
|
|
Study
|
Efficacy Parameter
|
Cefdinir BID
|
Penicillin QID
|
Outcome
|
|
Adults/
Adolescents
|
Eradication of S. pyogenes
|
193/218
|
(89%)
|
176/214
|
(82%)
|
Cefdinir equivalent
to control
|
|
Clinical Cure Rates
|
194/218
|
(89%)
|
181/214
|
(85%)
|
Cefdinir equivalent
to control
|
|
Pediatric Patients
|
Eradication of S. pyogenes
|
176/196
|
(90%)
|
135/193
|
(70%)
|
Cefdinir superior
to control
|
|
Clinical Cure Rates
|
179/196
|
(91%)
|
173/193
|
(90%)
|
Cefdinir equivalent
to control
|
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