Ciprofloxacin

Tony Thai; Blake Salisbury; Patrick Zito

Ciprofloxacin

Earn CME/CE in your profession:

Free Review Questions

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]

Details

References

[1]

Sharma PC,Jain A,Jain S,Pahwa R,Yar MS, Ciprofloxacin: review on developments in synthetic, analytical, and medicinal aspects. Journal of enzyme inhibition and medicinal chemistry. 2010 Aug [PubMed PMID: 20235755]

[2]

Zhang HL, Tan M, Qiu AM, Tao Z, Wang CH. Antibiotics for treatment of acute exacerbation of chronic obstructive pulmonary disease: a network meta-analysis. BMC pulmonary medicine. 2017 Dec 12:17(1):196. doi: 10.1186/s12890-017-0541-0. Epub 2017 Dec 12 [PubMed PMID: 29233130]

Level 2 (mid-level) evidence

[3]

Bartolomé-Álvarez J, Solves-Ferriz V. [Increase in methicillin-resistant and ciprofloxacin-susceptible Staphylococcus aureus in osteoarticular, skin and soft tissue infections]. Revista espanola de quimioterapia : publicacion oficial de la Sociedad Espanola de Quimioterapia. 2020 Apr:33(2):143-144. doi: 10.37201/req/082.2019. Epub 2020 Mar 11 [PubMed PMID: 32157857]

[4]

Meyerhoff A, Albrecht R, Meyer JM, Dionne P, Higgins K, Murphy D. US Food and Drug Administration approval of ciprofloxacin hydrochloride for management of postexposure inhalational anthrax. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2004 Aug 1:39(3):303-8 [PubMed PMID: 15306995]

[5]

Apangu T, Griffith K, Abaru J, Candini G, Apio H, Okoth F, Okello R, Kaggwa J, Acayo S, Ezama G, Yockey B, Sexton C, Schriefer M, Mbidde EK, Mead P. Successful Treatment of Human Plague with Oral Ciprofloxacin. Emerging infectious diseases. 2017 Mar:23(3):553-5. doi: 10.3201/eid2303.161212. Epub [PubMed PMID: 28125398]

[6]

Unemo M, Lahra MM, Cole M, Galarza P, Ndowa F, Martin I, Dillon JR, Ramon-Pardo P, Bolan G, Wi T. World Health Organization Global Gonococcal Antimicrobial Surveillance Program (WHO GASP): review of new data and evidence to inform international collaborative actions and research efforts. Sexual health. 2019 Sep:16(5):412-425. doi: 10.1071/SH19023. Epub [PubMed PMID: 31437420]

[7]

Coker TJ, Dierfeldt DM. Acute Bacterial Prostatitis: Diagnosis and Management. American family physician. 2016 Jan 15:93(2):114-20 [PubMed PMID: 26926407]

[8]

Heras-Cañas V, Gutiérrez-Soto B, Almonte-Fernández H, Lara-Oya A, Navarro-Marí JM, Garrido-Frenich A, Vázquez-Alonso F, Gutiérrez-Fernández J. Antibiotic activity and concentrations in clinical samples from patients with chronic bacterial prostatitis. Actas urologicas espanolas. 2017 Dec:41(10):631-638. doi: 10.1016/j.acuro.2017.03.008. Epub 2017 Jun 19 [PubMed PMID: 28641870]

[9]

Wu XW, Ji HZ, Wang FY. Meta-analysis of ciprofloxacin in treatment of Crohn's disease. Biomedical reports. 2015 Jan:3(1):70-74 [PubMed PMID: 25469250]

Level 1 (high-level) evidence

[10]

McDonald EM, Ram FS, Patel DV, McGhee CN. Topical antibiotics for the management of bacterial keratitis: an evidence-based review of high quality randomised controlled trials. The British journal of ophthalmology. 2014 Nov:98(11):1470-7. doi: 10.1136/bjophthalmol-2013-304660. Epub 2014 Apr 12 [PubMed PMID: 24729078]

Level 2 (mid-level) evidence

[11]

Mohamed S, Elmohamady MN, Abdelrahman S, Amer MM, Abdelhamid AG. Antibacterial effects of antibiotics and cell-free preparations of probiotics against Staphylococcus aureus and Staphylococcus epidermidis associated with conjunctivitis. Saudi pharmaceutical journal : SPJ : the official publication of the Saudi Pharmaceutical Society. 2020 Dec:28(12):1558-1565. doi: 10.1016/j.jsps.2020.10.002. Epub 2020 Oct 22 [PubMed PMID: 33424249]

[12]

Wiegand S, Berner R, Schneider A, Lundershausen E, Dietz A. Otitis Externa. Deutsches Arzteblatt international. 2019 Mar 29:116(13):224-234. doi: 10.3238/arztebl.2019.0224. Epub [PubMed PMID: 31064650]

[13]

Edmunds AL. Otiprio: An FDA-Approved Ciprofloxacin Suspension Gel for Pediatric Otitis Media With Effusion. P & T : a peer-reviewed journal for formulary management. 2017 May:42(5):307-311 [PubMed PMID: 28479839]

[14]

Kaguelidou F, Turner MA, Choonara I, Jacqz-Aigrain E. Ciprofloxacin use in neonates: a systematic review of the literature. The Pediatric infectious disease journal. 2011 Feb:30(2):e29-37. doi: 10.1097/INF.0b013e3181fe353d. Epub [PubMed PMID: 21048525]

Level 1 (high-level) evidence

[15]

Herold C, Ocker M, Ganslmayer M, Gerauer H, Hahn EG, Schuppan D. Ciprofloxacin induces apoptosis and inhibits proliferation of human colorectal carcinoma cells. British journal of cancer. 2002 Feb 1:86(3):443-8 [PubMed PMID: 11875713]

[16]

Aranha O, Wood DP Jr, Sarkar FH. Ciprofloxacin mediated cell growth inhibition, S/G2-M cell cycle arrest, and apoptosis in a human transitional cell carcinoma of the bladder cell line. Clinical cancer research : an official journal of the American Association for Cancer Research. 2000 Mar:6(3):891-900 [PubMed PMID: 10741713]

[17]

Campoli-Richards DM, Monk JP, Price A, Benfield P, Todd PA, Ward A. Ciprofloxacin. A review of its antibacterial activity, pharmacokinetic properties and therapeutic use. Drugs. 1988 Apr:35(4):373-447 [PubMed PMID: 3292209]

[18]

LeBel M. Ciprofloxacin: chemistry, mechanism of action, resistance, antimicrobial spectrum, pharmacokinetics, clinical trials, and adverse reactions. Pharmacotherapy. 1988:8(1):3-33 [PubMed PMID: 2836821]

[19]

Rehman A, Patrick WM, Lamont IL. Mechanisms of ciprofloxacin resistance in Pseudomonas aeruginosa: new approaches to an old problem. Journal of medical microbiology. 2019 Jan:68(1):1-10. doi: 10.1099/jmm.0.000873. Epub [PubMed PMID: 30605076]

[20]

Güler G, Eraç B. [Investigation of fluoroquinolone resistance mechanisms in clinical Acinetobacter baumannii isolates]. Mikrobiyoloji bulteni. 2016 Apr:50(2):278-86 [PubMed PMID: 27175500]

[21]

Chang MX, Zhang JF, Sun YH, Li RS, Lin XL, Yang L, Webber MA, Jiang HX. Contribution of Different Mechanisms to Ciprofloxacin Resistance in Salmonella spp. Frontiers in microbiology. 2021:12():663731. doi: 10.3389/fmicb.2021.663731. Epub 2021 May 6 [PubMed PMID: 34025618]

[22]

Fasugba O, Gardner A, Mitchell BG, Mnatzaganian G. Ciprofloxacin resistance in community- and hospital-acquired Escherichia coli urinary tract infections: a systematic review and meta-analysis of observational studies. BMC infectious diseases. 2015 Nov 25:15():545. doi: 10.1186/s12879-015-1282-4. Epub 2015 Nov 25 [PubMed PMID: 26607324]

Level 1 (high-level) evidence

[23]

El-Sabawi D, Abu-Dahab R, Zalloum WA, Ijbara F, Hamdan II. The effect of ferrous ions, calcium ions and citric acid on absorption of ciprofloxacin across caco-2 cells: practical and structural approach. Drug development and industrial pharmacy. 2019 Feb:45(2):292-303. doi: 10.1080/03639045.2018.1539495. Epub 2018 Dec 2 [PubMed PMID: 30348012]

[24]

Radovanovic M, Dushenkovska T, Cvorovic I, Radovanovic N, Ramasamy V, Milosavljevic K, Surla J, Jecmenica M, Radulovic M, Milovanovic T, Dumic I. Idiosyncratic Drug-Induced Liver Injury Due to Ciprofloxacin: A Report of Two Cases and Review of the Literature. The American journal of case reports. 2018 Sep 29:19():1152-1161. doi: 10.12659/AJCR.911393. Epub 2018 Sep 29 [PubMed PMID: 30266895]

Level 3 (low-level) evidence

[25]

Schlender JF, Teutonico D, Coboeken K, Schnizler K, Eissing T, Willmann S, Jaehde U, Stass H. A Physiologically-Based Pharmacokinetic Model to Describe Ciprofloxacin Pharmacokinetics Over the Entire Span of Life. Clinical pharmacokinetics. 2018 Dec:57(12):1613-1634. doi: 10.1007/s40262-018-0661-6. Epub [PubMed PMID: 29737457]

[26]

Eyler RF, Shvets K. Clinical Pharmacology of Antibiotics. Clinical journal of the American Society of Nephrology : CJASN. 2019 Jul 5:14(7):1080-1090. doi: 10.2215/CJN.08140718. Epub 2019 Mar 12 [PubMed PMID: 30862698]

[27]

Nau R, Sörgel F, Eiffert H. Penetration of drugs through the blood-cerebrospinal fluid/blood-brain barrier for treatment of central nervous system infections. Clinical microbiology reviews. 2010 Oct:23(4):858-83. doi: 10.1128/CMR.00007-10. Epub [PubMed PMID: 20930076]

[28]

Silva GCM, Jabor VAP, Bonato PS, Martinez EZ, Faria-E-Sousa SJ. Penetration of 0.3% ciprofloxacin, 0.3% ofloxacin, and 0.5% moxifloxacin into the cornea and aqueous humor of enucleated human eyes. Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas. 2017 Jul 3:50(7):e5901. doi: 10.1590/1414-431X20175901. Epub 2017 Jul 3 [PubMed PMID: 28678917]

[29]

Rudolph A, Dahmke H, Kupferschmidt H, Burden A, Weiler S. Coadministration of tizanidine and ciprofloxacin: a retrospective analysis of the WHO pharmacovigilance database. European journal of clinical pharmacology. 2021 Jun:77(6):895-902. doi: 10.1007/s00228-020-02981-2. Epub 2021 Jan 6 [PubMed PMID: 33404754]

Level 2 (mid-level) evidence

[30]

Begg EJ, Robson RA, Saunders DA, Graham GG, Buttimore RC, Neill AM, Town GI. The pharmacokinetics of oral fleroxacin and ciprofloxacin in plasma and sputum during acute and chronic dosing. British journal of clinical pharmacology. 2000 Jan:49(1):32-8 [PubMed PMID: 10606835]

[31]

Davis R, Markham A, Balfour JA. Ciprofloxacin. An updated review of its pharmacology, therapeutic efficacy and tolerability. Drugs. 1996 Jun:51(6):1019-74 [PubMed PMID: 8736621]

[32]

Samarei R. Comparison of local and systemic ciprofloxacin ototoxicity in the treatment of chronic media otitis. Global journal of health science. 2014 Sep 18:6(7 Spec No):144-9. doi: 10.5539/gjhs.v6n7p144. Epub 2014 Sep 18 [PubMed PMID: 25363170]

[33]

. Ciprofloxacin. LiverTox: Clinical and Research Information on Drug-Induced Liver Injury. 2012:(): [PubMed PMID: 31643397]

[34]

Roger C, Wallis SC, Louart B, Lefrant JY, Lipman J, Muller L, Roberts JA. Comparison of equal doses of continuous venovenous haemofiltration and haemodiafiltration on ciprofloxacin population pharmacokinetics in critically ill patients. The Journal of antimicrobial chemotherapy. 2016 Jun:71(6):1643-50. doi: 10.1093/jac/dkw043. Epub 2016 Mar 7 [PubMed PMID: 26957490]

[35]

Padberg S, Wacker E, Meister R, Panse M, Weber-Schoendorfer C, Oppermann M, Schaefer C. Observational cohort study of pregnancy outcome after first-trimester exposure to fluoroquinolones. Antimicrobial agents and chemotherapy. 2014 Aug:58(8):4392-8. doi: 10.1128/AAC.02413-14. Epub 2014 May 19 [PubMed PMID: 24841264]

[36]

Yefet E, Schwartz N, Chazan B, Salim R, Romano S, Nachum Z. The safety of quinolones and fluoroquinolones in pregnancy: a meta-analysis. BJOG : an international journal of obstetrics and gynaecology. 2018 Aug:125(9):1069-1076. doi: 10.1111/1471-0528.15119. Epub 2018 Feb 22 [PubMed PMID: 29319210]

Level 1 (high-level) evidence

[37]

Mahadevan U, Robinson C, Bernasko N, Boland B, Chambers C, Dubinsky M, Friedman S, Kane S, Manthey J, Sauberan J, Stone J, Jain R. Inflammatory Bowel Disease in Pregnancy Clinical Care Pathway: A Report From the American Gastroenterological Association IBD Parenthood Project Working Group. Gastroenterology. 2019 Apr:156(5):1508-1524. doi: 10.1053/j.gastro.2018.12.022. Epub 2019 Jan 16 [PubMed PMID: 30658060]

[38]

. Ciprofloxacin. Drugs and Lactation Database (LactMed®). 2006:(): [PubMed PMID: 30000643]

[39]

Blondeau JM. Expanded activity and utility of the new fluoroquinolones: a review. Clinical therapeutics. 1999 Jan:21(1):3-40; discussion 1-2 [PubMed PMID: 10090423]

[40]

Cozzani E, Chinazzo C, Burlando M, Romagnoli M, Parodi A. Ciprofloxacin as a Trigger for Bullous Pemphigoid: The Second Case in the Literature. American journal of therapeutics. 2016 Sep-Oct:23(5):e1202-4. doi: 10.1097/MJT.0000000000000283. Epub [PubMed PMID: 26164023]

Level 3 (low-level) evidence

[41]

Shimatsu K, Subramaniam S, Sim H, Aronowitz P. Ciprofloxacin-induced tendinopathy of the gluteal tendons. Journal of general internal medicine. 2014 Nov:29(11):1559-62. doi: 10.1007/s11606-014-2960-4. Epub [PubMed PMID: 25047394]

[42]

Smith N, Fackrell R, Henderson E. Ciprofloxacin-associated bilateral iliopsoas tendon rupture: a case report. Age and ageing. 2016 Sep:45(5):737-8. doi: 10.1093/ageing/afw092. Epub 2016 May 23 [PubMed PMID: 27220702]

Level 3 (low-level) evidence

[43]

Shybut TB, Puckett ER. Triceps Ruptures After Fluoroquinolone Antibiotics: A Report of 2 Cases. Sports health. 2017 Sep/Oct:9(5):474-476. doi: 10.1177/1941738117713686. Epub 2017 Jun 13 [PubMed PMID: 28610536]

Level 3 (low-level) evidence

[44]

Morales D, Pacurariu A, Slattery J, Pinheiro L, McGettigan P, Kurz X. Association Between Peripheral Neuropathy and Exposure to Oral Fluoroquinolone or Amoxicillin-Clavulanate Therapy. JAMA neurology. 2019 Jul 1:76(7):827-833. doi: 10.1001/jamaneurol.2019.0887. Epub [PubMed PMID: 31034074]

[45]

Baggio D, Ananda-Rajah MR. Fluoroquinolone antibiotics and adverse events. Australian prescriber. 2021 Oct:44(5):161-164. doi: 10.18773/austprescr.2021.035. Epub 2021 Oct 1 [PubMed PMID: 34728881]

[46]

Dai XC, Yang XX, Ma L, Tang GM, Pan YY, Hu HL. Relationship between fluoroquinolones and the risk of aortic diseases: a meta-analysis of observational studies. BMC cardiovascular disorders. 2020 Feb 3:20(1):49. doi: 10.1186/s12872-020-01354-y. Epub 2020 Feb 3 [PubMed PMID: 32013928]

Level 1 (high-level) evidence

[47]

Tang W, Rao E. Anaphylaxis to Ciprofloxacin Requiring Emergent Surgical Cricothyrotomy. European journal of case reports in internal medicine. 2022:9(2):003180. doi: 10.12890/2022_003180. Epub 2022 Feb 24 [PubMed PMID: 35265553]

Level 3 (low-level) evidence

[48]

Kelesidis T, Fleisher J, Tsiodras S. Anaphylactoid reaction considered ciprofloxacin related: a case report and literature review. Clinical therapeutics. 2010 Mar:32(3):515-26. doi: 10.1016/j.clinthera.2010.03.002. Epub [PubMed PMID: 20399988]

Level 3 (low-level) evidence

[49]

Abd-Elsayed A, Elsharkawy H, Sakr W. A severe interaction between Tizanidine and Ciprofloxacin. Journal of clinical anesthesia. 2015 Dec:27(8):698. doi: 10.1016/j.jclinane.2015.05.016. Epub 2015 Jun 29 [PubMed PMID: 26138629]

[50]

Brown KA, Langford B, Schwartz KL, Diong C, Garber G, Daneman N. Antibiotic Prescribing Choices and Their Comparative C. Difficile Infection Risks: A Longitudinal Case-Cohort Study. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2021 Mar 1:72(5):836-844. doi: 10.1093/cid/ciaa124. Epub [PubMed PMID: 32069358]

Level 2 (mid-level) evidence

[51]

Berhe A, Russom M, Bahran F, Hagos G. Ciprofloxacin and risk of hypolycemia in non-diabetic patients. Journal of medical case reports. 2019 May 12:13(1):142. doi: 10.1186/s13256-019-2083-y. Epub 2019 May 12 [PubMed PMID: 31078137]

Level 3 (low-level) evidence

[52]

Chou HW, Wang JL, Chang CH, Lee JJ, Shau WY, Lai MS. Risk of severe dysglycemia among diabetic patients receiving levofloxacin, ciprofloxacin, or moxifloxacin in Taiwan. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2013 Oct:57(7):971-80. doi: 10.1093/cid/cit439. Epub 2013 Aug 14 [PubMed PMID: 23948133]

[53]

Wiseman LR, Balfour JA. Ciprofloxacin. A review of its pharmacological profile and therapeutic use in the elderly. Drugs & aging. 1994 Feb:4(2):145-73 [PubMed PMID: 8186542]

[54]

Kaplan YC, Koren G. Use of ciprofloxacin during breastfeeding. Canadian family physician Medecin de famille canadien. 2015 Apr:61(4):343-4 [PubMed PMID: 26052598]

[55]

Walden DM, Khotimchenko M, Hou H, Chakravarty K, Varshney J. Effects of Magnesium, Calcium, and Aluminum Chelation on Fluoroquinolone Absorption Rate and Bioavailability: A Computational Study. Pharmaceutics. 2021 Apr 21:13(5):. doi: 10.3390/pharmaceutics13050594. Epub 2021 Apr 21 [PubMed PMID: 33919271]

[56]

Hajji M, Jebali H, Mrad A, Blel Y, Brahmi N, Kheder R, Beji S, Fatma LB, Smaoui W, Krid M, Hmida FB, Rais L, Zouaghi MK. Nephrotoxicity of Ciprofloxacin: Five Cases and a Review of the Literature. Drug safety - case reports. 2018 Apr 18:5(1):17. doi: 10.1007/s40800-018-0073-4. Epub 2018 Apr 18 [PubMed PMID: 29671145]

Level 3 (low-level) evidence

[57]

Vaughn VM, Gandhi T, Conlon A, Chopra V, Malani AN, Flanders SA. The Association of Antibiotic Stewardship With Fluoroquinolone Prescribing in Michigan Hospitals: A Multi-hospital Cohort Study. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2019 Sep 27:69(8):1269-1277. doi: 10.1093/cid/ciy1102. Epub [PubMed PMID: 30759198]