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
Cipro Pharmacology, Pharmacokinetics, Studies, Metabolism - Ciprofloxacin
Cipro Pharmacology, Pharmacokinetics, Studies, Metabolism - Ciprofloxacin
CLINICAL PHARMACOLOGY
Absorption: Ciprofloxacin given as an oral tablet is
rapidly and well absorbed from the gastrointestinal tract after oral administration.
The absolute bioavailability is approximately 70% with no substantial loss by
first pass metabolism. Ciprofloxacin maximum serum concentrations and area under
the curve are shown in the chart for the 250 mg to 1000 mg dose range.
|
Dose (mg)
|
Maximum Serum Concentration (mg/mL)
|
Area Under Curve (AUC) (mg•hr/mL)
|
|
250
|
1.2
|
4.8
|
|
500
|
2.4
|
11.6
|
|
750
|
4.3
|
20.2
|
|
1000
|
5.4
|
30.8
|
Maximum serum concentrations are attained 1 to 2 hours after
oral dosing. Mean concentrations 12 hours after dosing with 250, 500, or 750
mg are 0.1, 0.2, and 0.4 mg/mL, respectively. The
serum elimination half-life in subjects with normal renal function is approximately
4 hours. Serum concentrations increase proportionately with doses up to 1000
mg.
A 500 mg oral dose given every 12 hours has been shown to produce
an area under the serum concentration time curve (AUC) equivalent to that produced
by an intravenous infusion of 400 mg ciprofloxacin given over 60 minutes every
12 hours. A 750 mg oral dose given every 12 hours has been shown to produce
an AUC at steady-state equivalent to that produced by an intravenous infusion
of 400 mg given over 60 minutes every 8 hours. A 750 mg oral dose results in
a Cmax similar to that observed with a 400 mg I.V. dose. A 250 mg
oral dose given every 12 hours produces an AUC equivalent to that produced by
an infusion of 200 mg ciprofloxacin given every 12 hours.
|
Steady-state Pharmacokinetic Parameters Following Multiple
Oral and I.V. Doses
|
|
Parameters
|
500 mg q12h, P.O.
|
400 mg q12h, I.V.
|
750 mg q12h, P.O.
|
400 mg q8h, I.V.
|
|
AUC (mg•hr/mL)
|
13.7a
|
12.7a
|
31.6b
|
32.9c
|
|
Cmax (mg/mL)
|
2.97
|
4.56
|
3.59
|
4.07
|
|
aAUC 0-12h
|
|
bAUC 24h=AUC0-12h x 2
|
|
cAUC 24h=AUC0-8h x 3
|
Distribution: The binding of ciprofloxacin to serum
proteins is 20 to 40% which is not likely to be high enough to cause significant
protein binding interactions with other drugs.
After oral administration, ciprofloxacin is widely distributed
throughout the body. Tissue concentrations often exceed serum concentrations
in both men and women, particularly in genital tissue including the prostate.
Ciprofloxacin is present in active form in the saliva, nasal and bronchial secretions,
mucosa of the sinuses, sputum, skin blister fluid, lymph, peritoneal fluid,
bile, and prostatic secretions. Ciprofloxacin has also been detected in lung,
skin, fat, muscle, cartilage, and bone. The drug diffuses into the cerebrospinal
fluid (CSF); however, CSF concentrations are generally less than 10% of peak
serum concentrations. Low levels of the drug have been detected in the aqueous
and vitreous humors of the eye.
Metabolism: Four metabolites have been identified in
human urine which together account for approximately 15% of an oral dose. The
metabolites have antimicrobial activity, but are less active than unchanged
ciprofloxacin.
Excretion: The serum elimination half-life in subjects
with normal renal function is approximately 4 hours. Approximately 40 to 50%
of an orally administered dose is excreted in the urine as unchanged drug. After
a 250 mg oral dose, urine concentrations of ciprofloxacin usually exceed 200
mg/mL during the first two hours and are approximately
30 mg/mL at 8 to 12 hours after dosing. The urinary
excretion of ciprofloxacin is virtually complete within 24 hours after dosing.
The renal clearance of ciprofloxacin, which is approximately 300 mL/minute,
exceeds the normal glomerular filtration rate of 120 mL/minute. Thus, active
tubular secretion would seem to play a significant role in its elimination.
Co-administration of probenecid with ciprofloxacin results in about a 50% reduction
in the ciprofloxacin renal clearance and a 50% increase in its concentration
in the systemic circulation. Although bile concentrations of ciprofloxacin are
several fold higher than serum concentrations after oral dosing, only a small
amount of the dose administered is recovered from the bile as unchanged drug.
An additional 1 to 2% of the dose is recovered from the bile in the form of
metabolites. Approximately 20 to 35% of an oral dose is recovered from the feces
within 5 days after dosing. This may arise from either biliary clearance or
transintestinal elimination.
With oral administration, a 500 mg dose, given as 10 mL of
the 5% CIPRO Suspension (containing 250 mg ciprofloxacin/5mL) is bioequivalent
to the 500 mg tablet. A 10 mL volume of the 5% CIPRO Suspension (containing
250 mg ciprofloxacin/5mL) is bioequivalent to a 5 mL volume of the 10% CIPRO
Suspension (containing 500 mg ciprofloxacin/5mL).
Drug-drug Interactions: When CIPRO Tablet is given concomitantly
with food, there is a delay in the absorption of the drug, resulting in peak
concentrations that occur closer to 2 hours after dosing rather than 1 hour
whereas there is no delay observed when CIPRO Suspension is given with food.
The overall absorption of CIPRO Tablet or CIPRO Suspension, however, is not
substantially affected. The pharmacokinetics of ciprofloxacin given as the suspension
are also not affected by food. Concurrent administration of antacids containing
magnesium hydroxide or aluminum hydroxide may reduce the bioavailability of
ciprofloxacin by as much as 90%. (See PRECAUTIONS.)
The serum concentrations of ciprofloxacin and metronidazole
were not altered when these two drugs were given concomitantly.
Concomitant administration of ciprofloxacin with theophylline
decreases the clearance of theophylline resulting in elevated serum theophylline
levels and increased risk of a patient developing CNS or other adverse reactions.
Ciprofloxacin also decreases caffeine clearance and inhibits the formation of
paraxanthine after caffeine administration. (See PRECAUTIONS.)
Special Populations: Pharmacokinetic studies of the
oral (single dose) and intravenous (single and multiple dose) forms of ciprofloxacin
indicate that plasma concentrations of ciprofloxacin are higher in elderly subjects
(> 65 years) as compared to young adults. Although the Cmax is
increased 16-40%, the increase in mean AUC is approximately 30%, and can be
at least partially attributed to decreased renal clearance in the elderly. Elimination
half-life is only slightly (~20%) prolonged in the elderly. These differences
are not considered clinically significant. (See PRECAUTIONS:
Geriatric Use.)
In patients with reduced renal function, the half-life of ciprofloxacin
is slightly prolonged. Dosage adjustments may be required. (See DOSAGE
AND ADMINISTRATION.) In preliminary studies in patients with stable
chronic liver cirrhosis, no significant changes in ciprofloxacin pharmacokinetics
have been observed. The kinetics of ciprofloxacin in patients with acute hepatic
insufficiency, however, have not been fully elucidated.
Microbiology: Ciprofloxacin has in vitro activity
against a wide range of gram-negative and gram-positive microorganisms. The
bactericidal action of ciprofloxacin results from inhibition of the enzymes
topoisomerase II (DNA gyrase) and topoisomerase IV, which are required for bacterial
DNA replication, transcription, repair, and recombination. The mechanism of
action of fluoroquinolones, including ciprofloxacin, is different from that
of penicillins, cephalosporins, aminoglycosides, macrolides, and tetracyclines;
therefore, microorganisms resistant to these classes of drugs may be susceptible
to ciprofloxacin and other quinolones. There is no known cross-resistance between
ciprofloxacin and other classes of antimicrobials. In vitro resistance
to ciprofloxacin develops slowly by multiple step mutations.
Ciprofloxacin is slightly less active when tested at acidic
pH. The inoculum size has little effect when tested in vitro. The minimal
bactericidal concentration (MBC) generally does not exceed the minimal inhibitory
concentration (MIC) by more than a factor of 2.
Ciprofloxacin has been shown to be active against most strains
of the following microorganisms, both in vitro and in clinical infections
as described in the INDICATIONS AND USAGE section of the package insert
for CIPRO (ciprofloxacin hydrochloride) Tablets and CIPRO (ciprofloxacin*) 5%
and 10% Oral Suspension.
Enterococcus faecalis (Many strains are only moderately
susceptible.)
Staphylococcus aureus (methicillin-susceptible strains
only)
Staphylococcus epidermidis (methicillin-susceptible
strains only)
|
Staphylococcus saprophyticus
|
|
Streptococcus pneumoniae (penicillin-susceptible
strains only)
|
|
Streptococcus pyogenes
|
| |
|
|
Campylobacter jejuni
|
Proteus mirabilis
|
|
Citrobacter diversus
|
Proteus vulgaris
|
|
Citrobacter freundii
|
Providencia rettgeri
|
|
Enterobacter cloacae
|
Providencia stuartii
|
|
Escherichia coli
|
Pseudomonas aeruginosa
|
|
Haemophilus influenzae
|
Salmonella typhi
|
|
Haemophilus parainfluenzae
|
Serratia marcescens
|
|
Klebsiella pneumoniae
|
Shigella boydii
|
|
Moraxella catarrhalis
|
Shigella dysenteriae
|
|
Morganella morganii
|
Shigella flexneri
|
|
Neisseria gonorrhoeae
|
Shigella sonnei
|
Ciprofloxacin has been shown to be active against Bacillus
anthracis both in vitro and by use of serum levels as a surrogate
marker (see INDICATIONS AND USAGE and INHALATIONAL
ANTHRAX – ADDITIONAL INFORMATION).
The following in vitro data are available, but their
clinical significance is unknown. Ciprofloxacin exhibits in vitro
minimum inhibitory concentrations (MICs) of 1 mg/mL
or less against most (³ 90%) strains of the following
microorganisms; however, the safety and effectiveness of ciprofloxacin in treating
clinical infections due to these microorganisms have not been established in
adequate and well-controlled clinical trials.
|
Staphylococcus haemolyticus
|
|
Staphylococcus hominis
|
|
Streptococcus pneumoniae (penicillin-resistant
strains only)
|
| |
|
|
Acinetobacter Iwoffi
|
Pasteurella multocida
|
|
Aeromonas hydrophila
|
Salmonella enteritidis
|
|
Edwardsiella tarda
|
Vibrio cholerae
|
|
Enterobacter aerogenes
|
Vibrio parahaemolyticus
|
|
Klebsiella oxytoca
|
Vibrio vulnificus
|
|
Legionella pneumophila
|
Yersinia enterocolitica
|
Most strains of Burkholderia cepacia and some strains
of Stenotrophomonas maltophilia are resistant to ciprofloxacin as are
most anaerobic bacteria, including Bacteroides fragilis and Clostridium
difficile.
Susceptibility Tests
Dilution Techniques: Quantitative methods are used to
determine antimicrobial minimum inhibitory concentrations (MICs). These MICs
provide estimates of the susceptibility of bacteria to antimicrobial compounds.
The MICs should be determined using a standardized procedure. Standardized procedures
are based on a dilution method1 (broth or agar) or equivalent with
standardized inoculum concentrations and standardized concentrations of ciprofloxacin
powder. The MIC values should be interpreted according to the following criteria:
For testing aerobic microorganisms other than Haemophilus influenzae,
Haemophilus parainfluenzae, and Neisseria gonorrhoeaea:
|
MIC (µg/mL)
|
Interpretation
|
|
£ 1
|
Susceptible (S)
|
|
2
|
Intermediate (I)
|
|
³ 4
|
Resistant (R)
|
aThese interpretive standards are applicable only
to broth microdilution susceptibility tests with streptococci using cation-adjusted
Mueller-Hinton broth with 2-5% lysed horse blood.
For testing Haemophilus influenzae and Haemophilus
parainfluenzaeb:
|
MIC (mg/mL)
|
Interpretation
|
|
£ 1
|
Susceptible (S)
|
b This interpretive standard is applicable only
to broth microdilution susceptibility tests with Haemophilus influenzae
and Haemophilus parainfluenzae using Haemophilus Test Medium1.
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 testing Neisseria gonorrhoeaec:
|
MIC (mg/mL)
|
Interpretation
|
|
£ 0.06
|
Susceptible (S)
|
|
0.12 – 0.5
|
Intermediate (I)
|
|
³ 1
|
Resistant (R)
|
c This interpretive standard is applicable only
to agar dilution test with GC agar base and 1% defined growth supplement.
A report of "Susceptible" indicates that the pathogen
is likely to be inhibited if the antimicrobial compound in the blood reaches
the concentrations 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 the
laboratory procedures. Standard ciprofloxacin powder should provide the following
MIC values:
|
Organism
|
|
MIC (µg/mL)
|
|
E. faecalis
|
ATCC 29212
|
0.25 – 2.0
|
|
E. coli
|
ATCC 25922
|
0.004– 0.015
|
|
H. influenzaea
|
ATCC 49247
|
0.004– 0.03
|
|
N. gonorrhoeaeb
|
ATCC 49226
|
0.001– 0.008
|
|
P. aeruginosa
|
ATCC 27853
|
0.25 – 1.0
|
|
S. aureus
|
ATCC 29213
|
0.12 – 0.5
|
aThis quality control range is applicable to only
H. influenzae ATCC 49247 tested by a broth microdilution procedure using
Haemophilus Test Medium (HTM)1.
bThis quality control range is applicable to only
N. gonorrhoeae ATCC 49226 tested by an agar dilution procedure using
GC agar base and 1% defined growth supplement.
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-mg ciprofloxacin to
test the susceptibility of microorganisms to ciprofloxacin.
Reports from the laboratory providing results of the standard
single-disk susceptibility test with a 5- mg ciprofloxacin
disk should be interpreted according to the following criteria:
For testing aerobic microorganisms other than Haemophilus
influenzae, Haemophilus parainfluenzae, and Neisseria gonorrhoeaea:
|
Zone Diameter (mm)
|
Interpretation
|
|
³ 21
|
Susceptible (S)
|
|
16 – 20
|
Intermediate (I)
|
|
£ 15
|
Resistant (R)
|
aThese zone diameter standards are applicable only
to tests performed for streptococci using Mueller-Hinton agar supplemented with
5% sheep blood incubated in 5% CO2.
For testing Haemophilus influenzae and Haemophilus
parainfluenzaeb:
|
Zone Diameter (mm)
|
Interpretation
|
|
³ 21
|
Susceptible (S)
|
bThis zone diameter standard is applicable only
to tests with Haemophilus influenzae and
Haemophilus parainfluenzae using Haemophilus
Test Medium (HTM)2.
The current absence of data on resistant strains precludes
defining any results other than "Susceptible". Strains yielding zone
diameter results suggestive of a "nonsusceptible" category should
be submitted to a reference laboratory for further testing.
For testing Neisseria gonorrhoeaec:
|
Zone Diameter (mm)
|
Interpretation
|
|
³ 41
|
Susceptible (S)
|
|
28 – 40
|
Intermediate (I)
|
|
£ 27
|
Resistant (R)
|
cThis zone diameter standard is applicable only
to disk diffusion tests with GC agar base and 1% defined growth supplement.
Interpretation should be as stated above for results using
dilution techniques. Interpretation involves correlation of the diameter obtained
in the disk test with the MIC for ciprofloxacin. As with standardized dilution
techniques, diffusion methods require the use of laboratory control microorganisms
that are used to control the technical aspects of the laboratory procedures.
For the diffusion technique, the 5-mg ciprofloxacin
disk should provide the following zone diameters in these laboratory test quality
control strains:
|
Organism
|
|
Zone Diameter (mm)
|
|
E. coli
|
ATCC 25922
|
30 – 40
|
|
H. influenzaea
|
ATCC 49247
|
34 – 42
|
|
N. gonorrhoeaeb
|
ATCC 49226
|
48 – 58
|
|
P. aeruginosa
|
ATCC 27853
|
25 – 33
|
|
S. aureus
|
ATCC 25923
|
22 – 30
|
a These quality control limits are applicable to
only H. influenzae ATCC 49247 testing using Haemophilus Test Medium
(HTM)2.
b These quality control limits are applicable only
to tests conducted with N. gonorrhoeae ATCC 49226 performed by disk diffusion
using GC agar base and 1% defined growth supplement.
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