Mechanism of Action
The bactericidal action of ciprofloxacin results from inhibition of the enzymes topoisomerase II (DNA gyrase) and topoisomerase IV (both Type II topoisomerases), which are required for bacterial DNA replication, transcription, repair, and recombination.
Mechanism of Resistance
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. Resistance to fluoroquinolones occurs primarily by either mutations in the DNA gyrases, decreased outer membrane permeability, or drug efflux. In vitro resistance to ciprofloxacin develops slowly by multiple step mutations. Resistance to ciprofloxacin due to spontaneous mutations occurs at a general frequency of between < 10-9 to 1×10-6 .
There is no known cross-resistance between ciprofloxacin and other classes of antimicrobials.
Ciprofloxacin has been shown to be active against most isolates of the following bacteria, both in vitro and in clinical infections [see Indications and Usage (1)].
Staphylococcus aureus (methicillin-susceptible isolates only)
Staphylococcus epidermidis (methicillin-susceptible isolates only)
The following in vitro data are available, but their clinical significance is unknown. At least 90 percent of the following bacteria exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for ciprofloxacin against isolates of similar genus or organism group. However, the efficacy of ciprofloxacin in treating clinical infections caused by these bacteria has not been established in adequate and well-controlled clinical trials.
Staphylococcus haemolyticus (methicillin-susceptible isolates only)
Staphylococcus hominis (methicillin-susceptible isolates only)
For specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by FDA for this drug, please see: https://www.fda.gov/STIC.
Eight in vitro mutagenicity tests have been conducted with ciprofloxacin, and the test results are listed below:
- Salmonella/Microsome Test (Negative)
- E. coli DNA Repair Assay (Negative)
- Mouse Lymphoma Cell Forward Mutation Assay (Positive)
- Chinese Hamster V79 Cell HGPRT Test (Negative)
- Syrian Hamster Embryo Cell Transformation Assay (Negative)
- Saccharomyces cerevisiae Point Mutation Assay (Negative)
- Saccharomyces cerevisiae Mitotic Crossover and Gene Conversion Assay (Negative)
- Rat Hepatocyte DNA Repair Assay (Positive)
Thus, 2 of the 8 tests were positive, but results of the following 3 in vivo test systems gave negative results:
- Rat Hepatocyte DNA Repair Assay
- Micronucleus Test (Mice)
- Dominant Lethal Test (Mice)
Long-term carcinogenicity studies in rats and mice resulted in no carcinogenic or tumorigenic effects due to ciprofloxacin at daily oral dose levels up to 250 mg/kg and 750 mg/kg to rats and mice, respectively (approximately 1.7- and 2.5- times the highest recommended therapeutic dose based upon body surface area, respectively).
Results from photo co-carcinogenicity testing indicate that ciprofloxacin does not reduce the time to appearance of UV-induced skin tumors as compared to vehicle control. Hairless (Skh-1) mice were exposed to UVA light for 3.5 hours five times every two weeks for up to 78 weeks while concurrently being administered ciprofloxacin. The time to development of the first skin tumors was 50 weeks in mice treated concomitantly with UVA and ciprofloxacin (mouse dose approximately equal to maximum recommended human dose based upon body surface area), as opposed to 34 weeks when animals were treated with both UVA and vehicle. The times to development of skin tumors ranged from 16 weeks to 32 weeks in mice treated concomitantly with UVA and other quinolones.5
In this model, mice treated with ciprofloxacin alone did not develop skin or systemic tumors. There are no data from similar models using pigmented mice and/or fully haired mice. The clinical significance of these findings to humans is unknown.
Fertility studies performed in male and female rats at oral doses of ciprofloxacin up to 100 mg/kg (approximately 0.6 times the highest recommended therapeutic oral dose based upon body surface area) revealed no evidence of impairment. Male rats received oral ciprofloxacin for 10 weeks prior to mating and females were dosed for 3 weeks prior to mating through Gestation Day 7.
Ciprofloxacin and other quinolones have been shown to cause arthropathy in immature animals of most species tested [see Warnings and Precautions (5.13)]. 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 young beagle dogs, oral ciprofloxacin doses of 30 mg/kg and 90 mg/kg ciprofloxacin (approximately 1.3-times and 3.5-times the pediatric dose based upon comparative plasma AUCs) given daily for 2 weeks caused articular changes which were still observed by histopathology after a treatment-free period of 5 months. At 10 mg/kg (approximately 0.6-times the pediatric dose based upon comparative plasma AUCs), no effects on joints were observed. This dose was also not associated with arthrotoxicity after an additional treatment-free period of 5 months. In another study, 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 was noted after single oral doses as low as 5 mg/kg. (approximately 0.07-times the highest recommended therapeutic dose based upon body surface area). 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 (approximately 0.2-times the highest recommended therapeutic dose based upon body surface area).
In dogs, ciprofloxacin at 3 mg/kg and 10 mg/kg by rapid intravenous injection (15 sec.) produces pronounced hypotensive effects. These effects are considered to be related to histamine release, since 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.
Ciprofloxacin administered intravenously and/or orally was compared to a cephalosporin for treatment of cUTI and pyelonephritis in pediatric patients 1 to 17 years of age (mean age of 6 ± 4 years). The trial was conducted in the U.S., Canada, Argentina, Peru, Costa Rica, Mexico, South Africa, and Germany. The duration of therapy was 10 to 21 days (mean duration of treatment was 11 days with a range of 1 to 88 days). The primary objective of the study was to assess musculoskeletal and neurological safety.
Patients were evaluated for clinical success and bacteriological eradication of the baseline organism(s) with no new infection or superinfection at 5 to 9 days post-therapy (Test of Cure or TOC). The Per Protocol population had a causative organism(s) with protocol specified colony count(s) at baseline, no protocol violation, and no premature discontinuation or loss to follow-up (among other criteria).
The clinical success and bacteriologic eradication rates in the Per Protocol population were similar between ciprofloxacin and the comparator group as shown below.
|1. Patients with baseline pathogen(s) eradicated and no new infections or superinfections/total number of patients. There were 5.5% (6/211) ciprofloxacin and 9.5% (22/231) comparator patients with superinfections or new infections.|
|Per Protocol Patients||211||231|
|Clinical Response at 5 to 9 Days Post-Treatment||95.7% (202/211)||92.6% (214/231)|
|95% CI [-1.3%, 7.3%]|
|Bacteriologic Eradication by Patient at 5 to 9 Days Post-Treatment 1||84.4% (178/211)||78.3% (181/231)|
|95% CI [-1.3%, 13.1%]|
|Bacteriologic Eradication of the Baseline Pathogen at 5 to 9 Days Post-Treatment|
|Escherichia coli||156/178 (88%)||161/179 (90%)|
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