CLINICAL PHARMACOLOGY
Oral
TABLE 1
|
| Dose (mg) |
Maximum Serum Concentration
(mcg/ml) |
Area Under Curve (AUC)
(mcg·hr/ml) |
| 250 |
1.2 |
4.8 |
| 500 |
2.4 |
11.6 |
| 750 |
4.3 |
20.2 |
| 1000 |
5.4 |
30.8 |
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 TABLE 1 for the 250-mg to 1000-mg
dose range.
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
mcg/ml, respectively. The serum elimination half-file
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
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. See TABLE 3.
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 probenacid 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. 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.
With oral administration, a 500-mg dose, given as 10
ml of the 5% ciprofloxacin suspension (containing 250-mg
ciprofloxacin/5ml) is bioequivalent to the 500-mg tablet.
A 10 ml volume of the 5% ciprofloxacin suspension (containing
250-mg ciprofloxacin/5ml) is bioequivalent to a 5 ml volume
of the 10% ciprofloxacin suspension (containing 500-mg
ciprofloxacin/5ml).
When ciprofloxacin HCl 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 ciprofloxacin suspension is
given with food. The overall absorption of ciprofloxacin
HCl tablet or ciprofloxacin 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.)
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.
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.
I.V.
Following 60-minute intravenous infusions of 200 mg and
400 mg ciprofloxacin to normal volunteers, the mean maximum
serum concentrations achieved were 2.1 and 4.6 mcg/ml,
respectively; the concentrations at 12 hours were 0.1
and 0.2 mcg/ml, respectively. (See TABLE 2.)
TABLE 2 Steady-state Ciprofloxacin Serum Concentrations
(mcg/ml) After 60-minute I.V. Infusions q12h
|
| |
Time after
starting the infusion |
|
|
30 min |
1 hr |
3 hr |
5 hr |
8 hr |
12 hr |
|
|
1.7 |
2.1 |
0.8 |
0.3 |
0.2 |
0.1 |
|
|
3.7 |
4.8 |
1.3 |
0.7 |
0.5 |
0.2 |
The pharmacokinetics of ciprofloxacin are linear over
the dose range of 200 to 400 mg administered intravenously.
The serum elimination half-life is approximately 5-6 hours
and the total clearance is around 35 L/hr. Comparison
of the pharmacokinetic parameters following the 1st and
5th I.V. dose on a q 12 h regimen indicates no evidence
of drug accumulation.
The absolute bioavailability of oral ciprofloxacin is
within a range of 70-80% with no substantial loss by first
pass metabolism. An intravenous infusion of 400 mg ciprofloxacin
given over 60 minutes every 12 hours has been shown to
produce an area under the serum concentration time curve
(AUC) equivalent to that produced by a 500-mg oral dose
given every 12 hours. An intravenous infusion of 400 mg
ciprofloxacin given over 60 minutes every 8 hours has
been shown to produce an AUC at steady-state equivalent
to that produced by a 750-mg oral dose given every 12
hours. A 400-mg I.V. dose results in a Cmax similar to
that observed with a 750-mg oral dose. An infusion of
200 mg ciprofloxacin given every 12 hours produces an
AUC equivalent to that produced by a 250-mg oral dose
given every 12 hours.
TABLE 3 Steady-state Pharmacokinetic Parameter Following
Multiple Oral and I.V. Doses
|
Parameters
|
500-mg
|
400-mg
|
750-mg
|
400-mg
|
|
q12h, PO
|
q12h, IV
|
q12h, PO
|
q8h, IV
|
|
|
13.7*
|
12.7*
|
31.6†
|
32.8‡
|
|
|
2.97
|
4.56
|
3.59
|
4.07
|
| * AUC0-12h |
| † AUC
24h-AUC0-12h ´
2 |
| ‡ AUC
24h-AUC0-8h ´
3 |
After intravenous administration, approximately 50% to 70%
of the dose is excreted in the urine as unchanged drug.
Following a 200-mg I.V. dose, concentrations in the urine
usually exceed 200 mcg/ml 0-2 hours after dosing and are
generally greater than 16 mcg/ml 8-12 hours after dosing.
Following a 400-mg I.V. dose, urine concentrations generally
exceed 400 mcg/ml 0-2 hours after dosing and are usually
greater than 30 mcg/ml 8-12 hours after dosing. The renal
clearance is approximately 22 L/hr. The urinary excretion
of ciprofloxacin is virtually complete by 24 hours after
dosing.
The serum concentrations of ciprofloxacin and metronidazole
were not altered when these two drugs were given concomitantly.
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 severalfold higher than serum concentrations after
intravenous dosing, only a small amount of the administered
dose (<1%) is recovered from the bile as unchanged
drug. Approximately 15% of an I.V. dose is recovered from
the feces within 5 days after dosing.
After I.V. administration, three metabolites of ciprofloxacin
have been identified in human urine which together account
for approximately 10% of the intravenous dose.
In patients with reduced renal function, the half-life
of ciprofloxacin is slightly prolonged and 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. However, the kinetics
of ciprofloxacin in patients with acute hepatic insufficiency
have not been fully elucidated.
Following infusion of 400 mg I.V. ciprofloxacin every
eight hours in combination with 50 mg/kg I.V. piperacillin
sodium every 4 hours, mean serum ciprofloxacin concentrations
were 3.02 mcg/ml ½ hour and 1 18 mcg/ml between
6-8 hours after the end of infusion.
The binding of ciprofloxacin to serum proteins is 20
to 40%.
After intravenous administration, ciprofloxacin is present
in saliva, nasal and bronchial secretions, sputum, skin
blister fluid, lymph, peritoneal fluid, bile, and prostatic
secretions. It has also been detected in the lung, skin,
fat, muscle, cartilage, and bone. Although the drug diffuses
into cerebrospinal fluid (CSF), CSF concentrations are
generally less than 10% of peak serum concentrations.
Levels of the drug in the aqueous and vitreous chambers
of the eye are lower than in serum.
Oral and I.V.
Microbiology
Ciprofloxacin has in vitro activity against a wide range
of gram-negative and gram-positive microorganisms. The
bactericidal action of ciprofloxacin results from interference
with the enzyme DNA gyrase which is needed for the synthesis
of bacterial DNA.
Ciprofloxacin has been shown to be active against most
strains of the following microorganisms, both in vitro
and in clinical infections as described in INDICATIONS
AND USAGE.
Aerobic Gram-positive Microorganisms
Enterococcus faecalis (Many strains are only moderately
susceptible).
Staphylococcus aureus (methicillin susceptible).
Staphylococcus epidermidis.
Staphylococcus saprophyticus.
Streptococcus pneumoniae.
Streptococcus pyogenes.
Aerobic Gram-negative Microorganisms
Campylobacter jejuni. (Oral only.)
Citrobacter diversus.
Citrobacter freundii.
Enterobacter cloacae.
Escherichia coli.
Haemophilus influenzae.
Haemophilus parainfluenzae.
Klebsiella pneumoniae.
Moraxella catarrhalis. (Oral only.)
Morganella morganii.
Neisseria gonorrhoeae. (Oral only.)
Proteus mirabilis.
Proteus vulgaris.
Providencia rettgeri.
Providencia stuartii.
Pseudomonas aeruginosa.
Salmonella typhi. (Oral only.)
Serratia marcescens.
Shigella boydii. (Oral only.)
Shigella dysenteriae. (Oral only.)
Shigella flexneri. (Oral only.)
Shigella sonnei. (Oral only.)
Ciprofloxacin has been shown to be active against most
strains of the following microorganisms, both in vitro
and in clinical infections as described in INDICATIONS
AND USAGE.
Aerobic Gram-positive Microorganisms
Enterococcus faecalis (Many strains are only moderately
susceptible).
Staphylococcus aureus (methicillin susceptible).
Staphylococcus epidermidis.
Staphylococcus saprophyticus.
Streptococcus pneumoniae.
Streptococcus pyogenes.
Aerobic Gram-negative Microorganisms
Campylobacter jejuni (I.V. only.)
Citrobacter diversus.
Citrobacter freundii.
Enterobacter cloacae.
Escherichia coli.
Haemophilus influenzae.
Haemophilus parainfluenzae.
Klebsiella pneumoniae.
Moraxella catarrhalis (I.V. only.)
Morganella morganii.
Neisseria gonorrhoeae (I.V. only.)
Proteus mirabilis.
Proteus vulgaris.
Providencia rettgeri.
Providencia stuartii.
Pseudomonas aeruginosa.
Salmonella typhi (I.V. only.)
Serratia marcescens.
Shigella boydii (I.V. only.)
Shigella dysenteriae (I.V. only.)
Shigella flexneri (I.V. only.)
Shigella sonnei (I.V. only.)
The following in vitro data are available, but their clinical
significance is unknown.
Ciprofloxacin exhibits in vitro minimum inhibitory concentrations
(MICs) of 1 mcg/ml or less against most (³90%) 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.
Aerobic Gram-positive Microorganisms
Staphylococcus haemolyticus.
Staphylococcus hominis.
Aerobic Gram-negative Microorganisms
Acinetobacter Iwoffi.
Aeromonas hydrophila.
Edwardsiella tarda.
Enterobacter aerogenes.
Klebsiella oxytoca.
Legionella pneumophila.
Pasteurella multocida.
Salmonella enteritidis.
Vibrio cholerae.
Vibrio parahaemolyticus.
Vibrio vulnificus.
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.
Ciprofloxacin is slightly less active when tested at
acidic pH. The inoculum size has little effect when tested
in vitro. The minimum bactericidal concentration (MBC)
generally does not exceed the minimal inhibitory concentration
(MIC) by more than a factor of 2. Resistance to ciprofloxacin
in vitro develops slowly (multiple-step mutation).
Ciprofloxacin does not cross-react with other antimicrobial
agents such as beta-lactams or aminoglycosides; therefore,
organisms resistant to these drugs may be susceptible
to ciprofloxacin.
In vitro studies have shown that additive activity often
results when ciprofloxacin is combined with other antimicrobial
agents such as beta-lactams, aminoglycosides, clindamycin,
or metronidazole. Synergy has been reported particularly
with the combination of ciprofloxacin and a beta-lactam;
antagonism is observed only rarely.
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 criteria found in TABLE 4.
For testing aerobic microorganisms other than Haemophilus
influenzae, Haemophilus parainfluenzae, and Neisseria
gonorrhoeae.*
TABLE 4
|
| MIC (mcg/ml) |
Interpretation |
| £1 |
Susceptible (S) |
| 2 |
Intermediate (I) |
| ³4 |
Resistant (R) |
| * These
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 parainfluenzae,*
see TABLE 5.
TABLE 5
|
| MIC (mcg/ml) |
Interpretation |
| £1 |
Susceptible (S) |
| * This
interpretive standard is applicable only to broth
microdilution susceptibility tests with Haemophilus
influenzae and Haemophilus parainfluenzae using
Haemophilus Test Medium.1 |
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 gonorrhoeae.* (See TABLE 6.)
TABLE 6
|
| MIC (mcg/ml) |
Interpretation |
| £0.06 |
Susceptible (S) |
| * This
interpretive standard is applicable only to agar
dilution test with GC agar base and 1% defined growth
supplement. |
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.
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 MIC values found
in TABLE 7.
TABLE 7
|
Organism
|
|
MIC (mcg/ml)
|
|
|
ATCC 29212
|
0.25 - 2.0
|
|
|
ATCC 25922
|
0.004 - 0.015
|
|
|
ATCC 49247
|
0.004 - 0.03
|
|
|
ATCC 49226
|
0.001 - 0.008
|
|
|
ATCC 27853
|
0.25 - 1.0
|
|
|
ATCC 29213
|
0.12 - 0.5
|
| * This
quality control range is applicable to only H. influenzae
ATCC 49247 tested by a broth microdilution procedure
using Haemophilus Test Medium (HTM)1. |
| † This
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-mcg
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 mcg
ciprofloxacin disk should be interpreted according to
the criteria found in TABLE 8.
For testing aerobic microorganisms other than Haemophilus
influenzae, Haemophilus parainfluenzae, and Neisseria
gonorrhoeae.*
TABLE 8
|
| Zone Diameter (mm) |
Interpretation |
| ³21 |
Susceptible (S) |
| 16-20 |
Intermediate (I) |
| £15 |
Resistant (R) |
| * These
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 parainfluenzae.*
See TABLE 9.
TABLE 9
|
| Zone Diameter (mm) |
Interpretation |
| ³21 |
Susceptible (S) |
| * This
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 gonorrhoeae,* see TABLE 10.
TABLE 10
|
| Zone Diameter (mm) |
Interpretation |
| ³36 |
Susceptible (S) |
| * This
zone diameter standard is applicable only to disk
diffusion tests with GC agar base and 1% defined
growth supplement. |
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.
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 microorganis
| |
