Ciprofloxacin (Page 2 of 13)

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 Ciprofloxacin Hydrochloride Tablets USP, 250mg, 500mg and 750mg.

Aerobic gram-positive microorganisms


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

Aerobic gram-negative microorganisms


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 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
Streptococcus pneumoniae (penicillin-resistant strains only)

Aerobic gram-negative microorganisms


Acinetobacter Iwoffii 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 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)
0.12 – 0.5 Intermediate (I)
≥ 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
E. coli ATCC 25922 0.004 – 0.015
H. influenzae a ATCC 49247 0.004 – 0.03
P. aeruginosa ATCC 27853 0.25 – 1.0
S. aureus ATCC 29213 0.12 – 0.5
C. jejuni b ATCC 33560 0.06 – 0.25 and 0.03 – 0.12
N. gonorrhoeae c ATCC 49226 0.001– 0.008


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 C. jejuni ATCC 33560 tested by broth microdilution procedure using cation adjusted Mueller Hinton broth with 2.5-5% lysed horse blood in a microaerophilic environment at 36-37°C for 48 hours and for 42°C at 24 hours2 , respectively.
c N. gonorrhoeae ATCC 49226 tested by agar dilution procedure using GC agar and 1% defined growth supplement in a 5% CO2 environment at 35-37°C for 20-24 hours3.

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