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
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 µg/mL, respectively; the concentrations at 12 hours were 0.1 and 0.2
µg/mL, respectively.
Steady-state Ciprofloxacin Serum Concentrations (µg/mL)
After 60-minute I.V. Infusions q 12 h.
| |
Time after starting the infusion |
| Dose |
30 min |
1 hr |
3 hr |
6 hr |
8 hr |
12 hr |
| 200 mg |
1.7 |
2.1 |
0.6 |
0.3 |
0.2 |
0.1 |
| 400 mg |
3.7 |
4.6 |
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 C max 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.
Steady-state Pharmacokinetic Parameter
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 (µg·hr/mL)
|
13.7 a |
12.7 a |
31.6 b |
32.9 c |
|
C max (µg/mL)
|
2.97 |
4.56 |
3.59 |
4.07 |
|
a AUC 0-12h
|
|
b AUC 24h=AUC 0-12h × 2
|
|
c AUC 24h=AUC 0-8h × 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 exceed 200 µg/mL 0-2 hours after dosing and are generally greater
than 15 µg/mL 8-12 hours after dosing. Following a 400-mg I.V. dose, urine concentrations
generally exceed 400 µg/mL 0-2 hours after dosing and are usually greater than
30 µg/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 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.
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 C max 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 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 µg/mL ½ hour and 1.18 µg/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
(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.
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 the INDICATIONS AND USAGE section of the package insert for CIPRO®
I.V. (ciprofloxacin for intravenous infusion).
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
Citrobacter diversus
Citrobacter freundii
Enterobacter cloacae
Escherichia coli
Haemophilus influenzae
Haemophilus parainfluenzae
Klebsiella pneumoniae
Moraxella catarrhalis
Morganella morganii
Proteus mirabilis
Proteus vulgaris
Providencia rettgeri
Providencia stuartii
Pseudomonas aeruginosa
Serratia marcescens
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.
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
Citrobacter diversus
Citrobacter freundii
Enterobacter cloacae
Escherichia coli
Haemophilus influenzae
Haemophilus parainfluenzae
Klebsiella pneumoniae
Moraxella catarrhalis
Morganella morganii
Neisseria gonorrhoeae
Proteus mirabilis
Proteus vulgaris
Providencia rettgeri
Providencia stuartii
Pseudomonas aeruginosa
Salmonella typhi
Serratia marcescens
Shigella boydii
Shigella dysenteriae
Shigella flexneri
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 µg/mL or less against most ( ≥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.
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 minimum inhibitory concentration
(MIC) by more than a factor of 2. Resistance to ciprofloxacin in vitro usually
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 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 method 1 (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 gonorrhoeae a :
| MIC (µg/mL) |
Interpretation
|
| ≤ 1 |
Susceptible (S)
|
| 2 |
Intermediate
(I)
|
| ≥ 4 |
Resistant (R)
|
a 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
b :
| MIC (µg/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 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 c :
| MIC (µg/mL) |
Interpretation |
| ≤0.06 |
Susceptible (S) |
c 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 microoganism 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. influenzae a
|
ATCC 49247
|
0.004-0.03
|
|
N. gonorrhoeae b
|
ATCC 49226
|
0.001-0.008
|
|
P. aeruginosa
|
ATCC 27853
|
0.25 -1.0
|
|
S. aureus
|
ATCC 29213
|
0.12 -0.5
|
|
a This quality control range is applicable
to only H. influenzae ATCC 49247 tested by a broth microdilution
procedure using Haemophilus Test Medium (HTM) 1 .
|
|
b 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 procedure 2
requires the use of standardized inoculum concentrations. This procedure
uses paper disks impregnated with 5-µg 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-µg ciprofloxacin disk should be interpreted according to the following
criteria:
For testing aerobic microorganisms other than Haemophilus influenzae, Haemophilus
parainfluenzae, and Neisseria gonorrhoeae a :
| Zone Diameter (mm) |
Interpretation |
| ≥ 21 |
Susceptible (S) |
| 16-20 |
Intermediate (I) |
| ≤ 15 |
Resistant (R) |
a These zone diameter standards are applicable only to tests performed
for streptococci using Mueller-Hinton agar supplemented with 5% sheep blood incubated
in 5% CO
2 .
For testing Haemophilus influenzae and Haemophilus parainfluenzae
b :
| Zone Diameter (mm) |
Interpretation |
| ≥ 21 |
Susceptible (S) |
b 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 c :
| Zone Diameter (mm) |
Interpretation |
| ≥36 |
Susceptible (S) |
c 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 microorganisms that are used to control the technical
aspects of the laboratory procedures. For the diffusion technique, the 5-µg
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. influenzae a
|
ATCC 49247
|
34-42
|
|
N. gonorrhoeae b
|
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.
|
CLINICAL STUDIES
EMPIRICAL THERAPY IN FEBRILE NEUTROPENIC PATIENTS
The safety and efficacy of ciprofloxacin, 400 mg I.V. q 8h, in combination
with piperacillin sodium 50 mg/kg I.V. q 4h, for the empirical therapy of febrile
neutropenic patients were studied in one large pivotal multicenter, randomized
trial and were compared to those of tobramycin, 2 mg/kg I.V. q 8h, in combination
with piperacillin sodium, 50 mg/kg I.V. q 4h.
The demographics of the evaluable patients were as follows:
|
Total
|
Ciprofloxacin/Piperacillin
N = 233
|
Tobramycin/Piperacillin
N = 237
|
|
Median Age (years)
|
47.0 (range 19-84)
|
50.0 (range 18-81)
|
|
Male
|
114 (48.9%)
|
117 (49.4%)
|
|
Female
|
119 (51.1%)
|
120 (50.6%)
|
|
Leukemia/Bone
Marrow Transplant
|
165 (70.8%)
|
158 (66.7%)
|
|
Solid Tumor/Lymphoma
|
68 (29.2%)
|
79 (33.3%)
|
|
Medial Duration of
Neutropenia (days)
|
15.0 (range 1-61)
|
14.0 (range 1-89)
|
Clinical response rates observed in this study were as follows:
|
Outcomes
|
Ciprofloxacin/Piperacillin
N = 233
Success (%) |
Tobramycin/Piperacillin
N = 237
Success (%) |
|
Clinical Resolution of
Initial Febrile Episode
with No Modifications of
Empirical Regimen *
|
63 (27.0%) |
52 (21.9%) |
|
Clinical Resolution of
Initial Febrile Episode
Including Patients with
Modifications of
Empirical Regimen
|
187 (80.3%) |
185 (78.1%) |
|
Overall Survival
|
224 (96.1%) |
223 (94.1%) |
|
* To be evaluated as a clinical resolution, patients had
to have: (1) resolution of fever; (2) microbiological eradication of
infection (if an infection was microbiologically documented); (3) resolution
of signs/symptoms of infection; and (4) no modification of empirical
antibiotic regimen.
|
ANIMAL PHARMACOLOGY
Ciprofloxacin and other quinolones have been shown to cause arthropathy in
immature animals of most species tested. (See WARNINGS.) Damage of weight-bearing
joints was observed in juvenile dogs and rats. In young beagles, 100 mg/kg ciprofloxacin
given daily for 4 weeks caused degenerative articular changes of the knee joint.
At 30 mg/kg, the effect on the joint was minimal. In a subsequent study in beagles,
removal of weight-bearing from the joint reduced the lesions but did not totally
prevent them.
Crystalluria, sometimes associated with secondary nephropathy, occurs in laboratory
animals dosed with ciprofloxacin. This is primarily related to the reduced solubility
of ciprofloxacin under alkaline conditions, which predominate in the urine of
test animals; in man, crystalluria is rare since human urine is typically acidic.
In rhesus monkeys, crystalluria without nephropathy has been noted after intravenous
doses as low as 5 mg/kg. After 6 months of intravenous dosing at 10 mg/kg/day,
no nephropathological changes were noted; however, nephropathy was observed
after dosing at 20 mg/kg/day for the same duration.
In dogs, ciprofloxacin administered at 3 and 10 mg/kg by rapid intravenous
injection (15 sec.) produces pronounced hypotensive effects. These effects are
considered to be related to histamine release because they are partially antagonized
by pyrilamine, an antihistamine. In rhesus monkeys, rapid intravenous injection
also produces hypotension, but the effect in this species is inconsistent and
less pronounced.
In mice, concomitant administration of nonsteroidal anti-inflammatory drugs,
such as phenylbutazone and indomethacin, with quinolones has been reported to
enhance the CNS stimulatory effect of quinolones.
Ocular toxicity, seen with some related drugs, has not been observed in ciprofloxacin-treated
animals.
INHALATIONAL ANTHRAX ADDITIONAL INFORMATION
The mean serum concentrations of ciprofloxacin associated with a statistically
significant improvement in survival in the rhesus monkey model of inhalational
anthrax are reached or exceeded in adult and pediatric patients receiving oral
and intravenous regimens. (See DOSAGE AND ADMINISTRATION .) Ciprofloxacin
pharmacokinetics have been evaluated in various human populations. The mean
peak serum concentration achieved at steady-state in human adults receiving
500 mg orally every 12 hours is 2.97 µg/mL, and 4.56 µg/mL following 400 mg
intravenously every 12 hours. The mean trough serum concentration at steady-state
for both of these regimens is 0.2 µg/mL. In a study of 10 pediatric patients
between 6 and 16 years of age, the mean peak plasma concentration achieved is
8.3 µg/mL and trough concentrations range from 0.09 to 0.26 µg/mL, following
two 30-minute intravenous infusions of 10 mg/kg administered 12 hours apart.
After the second intravenous infusion patients switched to 15 mg/kg orally every
12 hours achieve a mean peak concentration of 3.6 µg/mL after the initial oral
dose. Long-term safety data, including effects on cartilage, following the administration
of ciprofloxacin to pediatric patients are limited. (For additional information,
see PRECAUTIONS , Pediatric Use .) Ciprofloxacin serum concentrations
achieved in humans serve as a surrogate endpoint reasonably likely to predict
clinical benefit and provide the basis for this indication. 4
A placebo-controlled animal study in rhesus monkeys exposed to an inhaled mean
dose of 11 LD 50 (~5.5 × 10 5 ) spores (range 5-30 LD
50 ) of B. anthracis was conducted. The minimal inhibitory
concentration (MIC) of ciprofloxacin for the anthrax strain used in this study
was 0.08 µg/mL. In the animals studied, mean serum concentrations of ciprofloxacin
achieved at expected T max (1 hour post-dose) following oral dosing
to steady-state ranged form 0.98 to 1.69 µg/mL. 5 Mean steady-state
trough concentrations at 12 hours post-dose ranged from 0.12 to 0.19 µg/mL.
5 Mortality due to anthrax for animals that received a 30-day regimen
of oral ciprofloxacin beginning 24 hours post-exposure was significantly lower
(1/9), compared to the placebo group (9/10) [p=0.001]. The one ciprofloxacin-treated
animal that died of anthrax did so following the 30-day administration period.
6
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