Continuing Education Activity

Ciprofloxacin is an antibiotic agent in the fluoroquinolone class used to treat bacterial infections such as urinary tract infections and pneumonia. Ciprofloxacin has FDA approval to treat urinary tract infections, sexually transmitted infections (gonorrhea and chancroid), skin, bone, joint infections, prostatitis, typhoid fever, gastrointestinal infections, lower respiratory tract infections, anthrax, plague, and salmonellosis. In addition, ciprofloxacin is an appropriate treatment option in patients with mixed infections or patients with predisposing factors for Gram-negative infections. This activity covers ciprofloxacin, a broad-spectrum quinolone antibiotic that members of the interprofessional team need to review its indications, coverage, contraindications, and adverse event profile to optimally manage patients' infectious diseases.

Objectives:

• Identify the mechanism of action of ciprofloxacin.
• Summarize the types of infections and bacterial coverage of ciprofloxacin and where it would be effective in a target population.
• Recognize the potential adverse events associated with ciprofloxacin therapy.
• Review the importance of improving care coordination amongst interprofessional team members to improve outcomes for patients with an infectious disease that would respond to ciprofloxacin therapy.

Indications

Ciprofloxacin was patented in 1983 by Bayer A.G. and approved in 1987 by the United States Food and Drug Administration (USFDA).[1] Ciprofloxacin is an antibiotic agent in the fluoroquinolone class used to treat bacterial infections such as urinary tract infections and pneumonia.[2][3][2]Ciprofloxacin is FDA approved for the treatment of urinary tract infections, sexually transmitted infections (gonorrhea and chancroid, skin and soft tissue infection, bone, joint infections, prostatitis, pneumonia, typhoid fever, gastrointestinal infections, lower respiratory tract infections, inhalation anthrax (post-exposure prophylaxis), plague, and salmonellosis, acute bacterial exacerbation of chronic bronchitis.[4][5][6] It should be recognized that  Neisseria gonorrhea has high rates of resistance to ciprofloxacin.[6] Ciprofloxacin should not be the first-line empirical treatment for respiratory tract infections if penicillin-susceptible Streptococcus pneumoniae is the primary pathogen. Ciprofloxacin is an appropriate treatment option in patients with mixed infections or patients with predisposing factors for Gram-negative infections. According to the American academy of family physicians guidelines, acute bacterial prostatitis can be treated with ciprofloxacin.[7] Ciprofloxacin is also used for chronic bacterial prostatitis(which requires 4-week therapy).[8]  Ciprofloxacin is used off-label to treat Crohn's disease associated with perianal fistula.[9]

Ciprofloxacin ophthalmic solution is FDA-approved for treating corneal ulcers and conjunctivitis caused by susceptible strains.[10][11]

Ciprofloxacin otic solution is approved for treating acute otitis externa caused by susceptible strains of Pseudomonas aeruginosa or Staphylococcus aureus.[12] Ciprofloxacin suspension gel is FDA approved for pediatric otitis media with effusion.[13]

Ciprofloxacin does not have a marketed indication for neonates worldwide; however, it is prescribed for life-threatening infections as salvage therapy for sepsis due to multi-drug resistance (mainly in Europe and developing countries). A systematic search of observational cohort studies and case reports suggests that most clinical responses were positive, and there was a lack of serious adverse events, especially joint toxicity.[14] Ciprofloxacin has also attracted interest from the scientific community due to its apoptotic and antiproliferative activities in several cancer lines.[1] Researchers observed that it could induce dose- and time-dependent growth inhibition and apoptosis of various carcinoma, osteosarcoma, and leukemia cell lines.[15] Ciprofloxacin also has potential benefits in bladder cancer management. In vitro studies on tumor cells made from transitional cell carcinoma of the bladder resulted in both a dose and time-dependent inhibition of cell growth. These results were achieved by ciprofloxacin with concentrations that are easily attainable in the urine of patients. However, these indications require additional clinical research.[16]

Mechanism of Action

Ciprofloxacin is a bactericidal antibiotic of the fluoroquinolone drug class. It inhibits DNA replication by inhibiting bacterial DNA topoisomerase and DNA-gyrase. Of the fluoroquinolone class, ciprofloxacin is the most potent against gram-negative bacilli bacteria (notably, the Enterobacteriaceae such as Escherichia coli, Salmonella spp., Shigella spp., and Neisseria).[17] Ciprofloxacin also has effectiveness against some gram-positive bacteria. Ciprofloxacin is the most active against Pseudomonas aeruginosa among the quinolones.[18] Progressively decreasing susceptibility among P. aeruginosa has been reported in Europe, North and South America, predominantly in the hospital or nursing home settings with identifiable risk factors. Ciprofloxacin is one of the few oral antibiotics to treat P. aeruginosa infections.[19]

Mechanism of Resistance:  Mutation in DNA gyrase, plasmid-mediated and efflux pump-mediated resistance confers resistance to fluoroquinolones, including ciprofloxacin. For Escherichia coli, the primary resistance mechanism is generally the GyrA subunit of gyrase.[20][21] Ciprofloxacin can be less costly and more cost-effective than traditional parenteral regimens in selected clinical settings with appropriate use. Additional well-designed studies would be helpful in further defining the most cost-efficient use of this antimicrobial agent. However, in E. coli-associated urinary tract infections, there has been an increase in ciprofloxacin resistance, more so in the hospital versus the community setting.[22] Evaluation of the use of ciprofloxacin as empiric therapy should be on a case-by-case basis.

Pharmacokinetics

Absorption: Ciprofloxacin is readily absorbed but typically does not achieve complete absorption. The bioavailability of oral ciprofloxacin is 70 to 80%. The time to peak concentrations after oral administration Tmax is 1 to 1.5 h.[18]  Avoid concurrent administration of ciprofloxacin with dairy products or calcium-fortified juices due to decreased absorption.[23]

Distribution: The volume of distribution of ciprofloxacin is high (2 to 3 L/kg). After oral administration, ciprofloxacin is extensively distributed throughout the body. Tissue concentrations usually exceed serum concentrations, and ciprofloxacin achieves therapeutic concentrations in saliva, bronchial secretions, lymph, bile, the prostate, and urine.[24][25][26] Cerebrospinal fluid concentrations are usually lower than plasma concentration, but CSF concentration increases during active meningeal inflammation.[27] Topically applied ciprofloxacin is also present in the aqueous humor of the eye.[28]

Metabolism: Ciprofloxacin is an inhibitor of human cytochrome P450 1A2 (CYP1A2). Co-administration of ciprofloxacin with other drugs metabolized by CYP1A2 results in increased plasma concentrations of these drugs and could lead to toxicity.[29]

Excretion: The elimination half-life of ciprofloxacin is 4 hours. Ciprofloxacin is excreted in the urine as an unchanged drug (40 to 50%). The renal clearance of ciprofloxacin is approximately 300 mL/minute, which is greater than the normal GFR of 120 mL/minute; thus, tubular secretion is the dominant process in the renal elimination of ciprofloxacin. Approximately 20% to 35% of an oral dose is recovered from feces. Biliary clearance and transintestinal elimination play a significant role in excretion through feces.[30]

Administration

Ciprofloxacin is available orally, intravenously, and in topical formulations (ophthalmic and otic).

Ciprofloxacin is administered orally twice daily for 7 to 14 days or at least two days after signs and symptoms of the infection are over. The recommended oral dose regimen is 250 mg twice daily to treat mild to moderate and 500 mg twice daily for severe or complicated urinary tract infections. Therapy for mild to moderate respiratory tract or skin and soft-tissue infections require 500mg twice-daily dosing. Comparatively, a dosage of 750mg twice daily is recommended for severe or complicated infections. Ciprofloxacin should be given with food to minimize gastrointestinal upset. 

An intravenous dosage of 200 to 400 mg twice daily is recommended for mild-to-moderate infections and up to 400 mg every 8 hours for severe, life-threatening infections.[31] The recommendation is a 50% reduction in daily dosage for patients with severe renal impairment (creatinine clearance = 1.2 L/hour). Ciprofloxacin is administered intravenously by slow infusion over 60 minutes. It is essential to maintain proper hydration and urine output. Usage of antacids should be avoided, or at least administer ciprofloxacin either two hours before or six hours after antacids for both the immediate or the extended-release formulations. The oral suspension should not be administered through feeding tubes as the suspension may adhere to the tube. Otic ciprofloxacin is a safe and effective antibiotic used in treating chronic otitis media compared to ciprofloxacin tablets.[32]

Specific Patient Populations

Patients with Hepatic Impairment:  In patients with liver cirrhosis, no significant changes in the pharmacokinetics of ciprofloxacin have been observed. However, ciprofloxacin's pharmacokinetics are not fully studied in patients with acute hepatic insufficiency. Additionally, ciprofloxacin has the potential to cause hepatotoxicity. Use with caution in patients with impaired hepatic function.[33] 

Patients with Renal Impairment: As discussed in pharmacokinetics, ciprofloxacin is primarily eliminated by the renal route; dosage adjustment is required, especially in severe renal impairment. 

• No dose adjustment is required for creatinine clearance > 50 mL/min/1.73m^2.
• For creatinine clearance between 30-49 mL/min/1.73m^2, 250–500 mg every 12 hours is recommended.
• For creatinine clearance between 5–29 mL/min/1.73m^2,  250–500 mg every 18 hours is recommended.
• For patients on hemodialysis or peritoneal dialysis, 250–500 mg every 24 hours (after dialysis).
• For patients on CRRT having sepsis, 200 to 400 mg every 8 to 12 hours is recommended.[34]

Pregnancy Considerations: Conventionally, ciprofloxacin and other fluoroquinolones are contraindicated during pregnancy due to bone and cartilage damage concerns. However, available clinical data haven't identified any drug-associated risk of major congenital disabilities, adverse pregnancy-associated outcomes or miscarriage, or adverse pregnancy-associated outcomes.[35][36] Hence, the recommendation is to allow fluoroquinolone(including ciprofloxacin) use in early pregnancy in antimicrobial resistance or intolerance to the first-line antibiotics. Use ciprofloxacin only for compelling indications like inhalation anthrax. Similarly, reserve ciprofloxacin for severe Crohn's disease with the perianal disease; otherwise, the use of amoxicillin-metronidazole is recommended. (American gastroenterological association guidelines).[37]

Breastfeeding Considerations: Ciprofloxacin has conventionally not been recommended in nursing mothers because of concern regarding adverse effects on the developing joints. The calcium in milk might decrease the absorption of the small amounts of fluoroquinolones in milk, but clinical data is inadequate to support this assumption. The use of ciprofloxacin is justified in nursing mothers for required indications with monitoring of the infant for adverse drug reactions such as diarrhea or candidiasis. A possible strategy to avoid an infant's exposure to ciprofloxacin in breast milk is avoiding breastfeeding for 3 to 4 hours after the last dose of ciprofloxacin.[38]

Adverse Effects

Adverse effects are mild at therapeutic doses and are mostly limited to gastrointestinal disruptions such as nausea and diarrhea. The serious adverse effects of ciprofloxacin include prolonged QT interval, hyper or hypoglycemia, and photosensitivity.[39]  Rare interactions include drug-induced bullous pemphigoid.[40]

FDA  boxed warnings include tendinitis and tendon rupture, peripheral neuropathy and neuropsychiatric adverse events, and exacerbation of myasthenia gravis. The most common type of tendon rupture involves the Achilles tendon. There have also been reports of tendinopathies in the gluteal, iliopsoas, and triceps tendons. The use of steroids and advanced age increased the risk of tendonitis. Upregulation of matrix metalloproteinases leading to collagen degradation is a possible mechanism for tendinopathy.[41][42][43] Oral fluoroquinolone therapy, including ciprofloxacin, is associated with an increased risk of peripheral neuropathy based on the cumulative dose. Evidence of small fiber damage can be detected in nerve biopsy.[44] Neuropsychiatric adverse events include agitation, tremors, hallucinations, psychosis, and seizures.[45]

Aortic aneurysm and aortic dissection have been associated with the use of fluoroquinolones. Prolonged fluoroquinolone therapy and older age are the associated risk factors. Discontinue ciprofloxacin immediately if there is a suspicion of aortic dissection.[46]

Contraindications

Contraindications to ciprofloxacin include patients with documented hypersensitivity to the drug or components of the formulation. Anaphylactoid reactions and anaphylaxis following the first dose of ciprofloxacin have been reported in the literature.[47][48] The concurrent administration of tizanidine for muscle spasms is also a contraindication. The pharmacokinetics of tizanidine are altered by CYP1A2 inhibition (ciprofloxacin), leading to increased tizanidine levels and decreased psychomotor activity, blood pressure, and heart rate.[31][49] Avoid ciprofloxacin and its fluoroquinolone class in patients with myasthenia gravis because it may exacerbate muscle weaknesses.

Monitoring

Providers should monitor patients taking ciprofloxacin for symptoms of tendinitis, altered mental status, complete blood count, and renal and hepatic function in prolonged therapy. Other significant interactions with ciprofloxacin include theophylline (particularly concurrent caffeine use), which acts on the CYP1A2 and raises theophylline levels.[31] Reports have shown that using ciprofloxacin can lead to elevated cyclosporine serum levels. Oral absorption of ciprofloxacin decreases with antacids containing agents such as aluminum and magnesium. Monitor patients for g Clostridioides difficile-associated diarrhea.[50] Monitor serum glucose levels, especially in patients with diabetes, on insulin therapy as dysglycemia is a known adverse reaction of fluoroquinolones, including ciprofloxacin.[47][51][52]

Toxicity

The elimination half-life of ciprofloxacin ranges from 3.3 to 6.8 hours in the elderly compared with three to four hours in younger persons.[53] There is limited evidence suggesting ciprofloxacin excretion in breast milk.[54]. Clinical data indicate no significant evidence of osteoarticular toxicity in newborns and children. In these studies, the drug exposure of neonates and children was at much higher doses compared to children whose exposure was via breastfeeding.[14] 

Acute kidney injury following ciprofloxacin overdose has been reported. There is no specific antidote to ciprofloxacin overdose. Consider using magnesium and calcium-containing antacids to reduce the oral absorption of ciprofloxacin. Consider intermittent hemodialysis for ciprofloxacin-induced nephrotoxicity.[55][56]

Enhancing Healthcare Team Outcomes

Ciprofloxacin can be less costly and more cost-effective than traditional parenteral regimens in selected clinical settings with appropriate use. Additional well-designed studies would be helpful in further defining the most cost-efficient use of this antimicrobial agent. However, in E. coli-associated urinary tract infections, there has been an increase in ciprofloxacin resistance, more so in the hospital versus the community setting.[22] Evaluation of the use of ciprofloxacin as empiric therapy should be on a case-by-case basis.

Ciprofloxacin is a common antibiotic prescribed and usually well-tolerated. Interprofessional health care team members must use antibiotics as targeted therapy, effectively managing infections and conferring a societal benefit in addressing drug-resistant microbes. Clinicians need to consider that the drug's pharmacokinetics can undergo alteration in patients with renal or hepatic dysfunction and order the tests to monitor patient status when used for a prolonged period. Pharmacists can review the antibiogram and verify the dosing and duration of ciprofloxacin. Nursing can counsel the patient on taking the medication, monitor patient compliance and therapeutic effectiveness, answer any questions, and report any concerns to the prescriber. Ciprofloxacin therapy requires the collaborative approach of an interprofessional healthcare team, including infectious disease specialists, clinicians (MD, DO, NP, PA), pharmacists, and specialty-trained nurses working together to achieve optimal patient outcomes. All team members must be vigilant for adverse events or therapeutic failure and immediately report any patient status changes to other team members. A study shows that hospital-based antimicrobial stewardship interventions are associated with fewer fluoroquinolone (including ciprofloxacin) prescriptions during hospitalization.[57] [Level 3]

Review Questions

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Disclosure: Tony Thai declares no relevant financial relationships with ineligible companies.

Disclosure: Blake Salisbury declares no relevant financial relationships with ineligible companies.

Disclosure: Patrick Zito declares no relevant financial relationships with ineligible companies.