Ciprofloxacin

Ciprofloxacin

Systematic (IUPAC) name
1-cyclopropyl-6-fluoro-4-oxo-7-(piperazin-1-yl)-quinoline-3-carboxylic acid
Clinical data
Trade names	Ciloxan, Cipro, Neofloxin
AHFS/Drugs.com	monograph
MedlinePlus	a688016
Licence data	US FDA:link
Pregnancy cat.	B3 (AU) C (US)
Legal status	Prescription Only (S4) (AU) POM (UK) ℞-only (US)
Routes	Oral, intravenous, topical (ear drops, eye drops)
Pharmacokinetic data
Bioavailability	69%[2]
Metabolism	Hepatic, including CYP1A2
Half-life	4 hours
Excretion	Renal
Identifiers
CAS number	85721-33-1 Y
ATC code	J01MA02 S01AE03 S02AA15 S03AA07
PubChem	CID 2764
DrugBank	DB00537
ChemSpider	2662 Y
UNII	5E8K9I0O4U Y
KEGG	D00186 Y
ChEBI	CHEBI:100241 Y
ChEMBL	CHEMBL8 Y
NIAID ChemDB	001992
Chemical data
Formula	C17H18FN3O3
Mol. mass	331.346 g/mol
SMILES c1c2c(cc(c1F)N3CCNCC3)n(cc(c2=O)C(=O)O)C4CC4
InChI InChI=1S/C17H18FN3O3/c18-13-7-11-14(8-15(13)20-5-3-19-4-6-20)21(10-1-2-10)9-12(16(11)22)17(23)24/h7-10,19H,1-6H2,(H,23,24) Y Key:MYSWGUAQZAJSOK-UHFFFAOYSA-N Y
Y (what is this?)  (verify)

Ciprofloxacin (INN) is a second-generation fluoroquinolone antibiotic.^[3][4] Its spectrum of activity includes most strains of bacterial pathogens responsible for respiratory, urinary tract, gastrointestinal, and abdominal infections, including Gram-negative (Escherichia coli, Haemophilus influenzae, Klebsiella pneumoniae, Legionella pneumophila, Moraxella catarrhalis, Proteus mirabilis, and Pseudomonas aeruginosa), and Gram-positive (methicillin-sensitive but not methicillin-resistant Staphylococcus aureus, Streptococcus pneumoniae, Staphylococcus epidermidis, Enterococcus faecalis, and Streptococcus pyogenes) bacterial pathogens. Ciprofloxacin and other fluoroquinolones are valued for this broad spectrum of activity, excellent tissue penetration, and for their availability in both oral and intravenous formulations.^[5]

Ciprofloxacin is used alone or in combination with other antibacterial drugs in the empiric treatment of infections for which the bacterial pathogen has not been identified, including urinary tract infections^[6][7] and abdominal infections^[8] among others. It is also used for the treatment of infections caused by specific pathogens known to be sensitive.

Ciprofloxacin is the most widely used of the second generation quinolone antibiotics that came into clinical use in the late 1980s and early 1990s.^[9][10] In 2010 over 20 million outpatient prescriptions were written for ciprofloxacin, making it the 35th most commonly prescribed drug, and the 5th most commonly prescribed antibacterial, in the US.^[11] Ciprofloxacin was first patented in 1983 by Bayer A.G. and subsequently approved by the US Food and Drug Administration (FDA) in 1987. Ciprofloxacin has 12 FDA-approved human uses and other veterinary uses, but it is often used for unapproved uses (off-label).

Overall, the safety of ciprofloxacin and other fluoroquinolones appears to be similar to that of other antibiotics, but serious side effects occur on occasion. There is some disagreement in the literature regarding whether fluoroquinolones produce serious adverse events at a higher rate than other broad-spectrum antibiotics.^{[12][13][14][15][16]} The U.S. FDA-approved label for ciprofloxacin includes a "black box" warning of increased risk of tendon damage and/or rupture and for exacerbation of muscle weakness in patients with the neurological disorder myasthenia gravis.^[17]

Medical uses

Ciprofloxacin is used to treat a wide variety of infections, including infections of bones and joints, endocarditis, gastroenteritis, malignant otitis externa, respiratory tract infections, cellulitis, urinary tract infections, prostatitis, anthrax, and chancroid.^[18]

Ciprofloxacin occupies an important role in treatment guidelines issued by major medical societies for the treatment of serious infections, especially those likely to be cause by Gram-(-) bacteria, including Pseudomonas aeruginosa. For example, ciprofloxacin in combination with metronidazole is one of several first line antibiotic regimens recommended by the Infectious Disease Society of America for the treatment of community-acquired abdominal infections in adults.^[19] Ciprofloxacin also features prominently in treatment guidelines for acute pyelonephritis, complicated or hospital-acquired urinary tract infection, acute or chronic prostatitis,^[20] certain types of endocarditis,^[21] certain skin infections,^[22] and prosthetic joint infections.^[23]

In other cases treatment guidelines are more restrictive, recommending in most cases that older, narrower spectrum drugs be used as first line therapy for less severe infections in order to minimize fluoroquinlone resistance development. For example, the Infectious Disease Society of America recommends that the use of ciprofloxacin and other fluoroquinolones in acute cystisis be reserved to cases of proven or expected resistance to narrower spectrum drugs such as nitrorfurantoin or trimethoprim-sulfamethoxazole.^[24] The European Association for Urology recommends ciprofloxacin as an alternative regimen for the treatment of uncomplicated urinary tract infections, but cautions that the potential for “adverse events have to be considered”.^[20]

Although approved by regulatory authorities for the treatment of respiratory infections, most treatment guidelines recommend against the use of ciprofloxacin in these indications, in part due to its modest activity against the common respiratory pathogen Streptococcus pneumoniae.^{[25][26][27][28]} "Respiratory quiniolones" such as levofloxacin, having greater activity against this pathogen, are recommended as first line agents for the treatment of community acquired pneumonia in patients with important co-morbidities and in patients requiring hospitalization (Infectious Diseases Society of America 2007). Similarly, ciprofloxacin is not recommended as a first-line treatment for acute sinusitis^[29][30]

Ciprofloxacin is approved for the treatment of gonorrhea in many countries, but this recommendation is widely regarded as obsolete due to resistance development.^{[31][32][33][34]}

Available forms

Ciprofloxacin for systemic administration is available as immediate release tablets, as extended release tablets, as an oral suspension, and as a solution for intravenous infusion. It is also available for local administration as eye drops and ear drops.

Specific populations

Pregnancy

The U.S. FDA categorizes ciprofloxacin in Pregnancy Category C.^[35] This category includes drugs for which there are no adequate and well-controlled studies in human pregnancy, and for which animal studies have suggested the potential for harm to the fetus, but potential benefits may warrant use of the drug in pregnant women despite potential risks. An expert review of published data on experiences with ciprofloxacin use during pregnancy by TERIS – the Teratogen Information System – concluded that therapeutic doses during pregnancy are unlikely to pose a substantial teratogenic risk (quantity and quality of data=fair), but the data are insufficient to state that there is no risk.^[36]

A controlled prospective observational study followed 200 women exposed to fluoroquinolones (52.5% exposed to ciprofloxacin and 68% first-trimester exposures) during gestation.^[37] In utero exposure to fluoroquinolones during embryogenesis was not associated with increased risk of major malformations. Rates of spontaneous abortions, prematurity and low birth weight did not differ between the groups, and there were no clinically significant musculoskeletal dysfunctions up to one year of age in the ciprofloxacin-exposed children. Similar results were obtained in a second study of 549 pregnancies with fluoroquinoline exposure, of which 70 involved ciprofloxacin.^[38] The label notes, however, "these small post-marketing epidemiology studies, of which most experience is from short term, first trimester exposure, are insufficient to evaluate the risk for less common defects or to permit reliable and definitive conclusions regarding the safety of ciprofloxacin in pregnant women and their developing fetuses."

Lactation

The fluoroquinolones have also been reported as being present in the mother's milk and are passed on to the nursing child.^[39][40] The United States FDA recommends that because of the risk of serious adverse reactions (including articular damage) in infants nursing from mothers taking ciprofloxacin, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Children

Oral and intravenous ciprofloxacin are approved by the FDA for use in children for only two indications due to the risk of permanent injury to the musculoskeletal system. These include complicated urinary tract infections and pyelonephritis due to Escherichia coli^[41] and inhalational anthrax (postexposure)^[42] Current recommendations by the American Academy of Pediatrics note the systemic use of ciprofloxacin in children should be restricted to infections caused by multidrug-resistant pathogens or when no safe or effective alternatives are available.^[43]

Adverse effects

Overall, the safety of ciprofloxacin and other fluoroquinolones appears to be similar to that of other antibiotics, but serious side effects occur on occasion. There is some disagreement in the literature regarding whether fluoroquinolones produce serious adverse events at a higher rate than other broad-spectrum antibiotics.^{[12][13][14][15][16]}

49,038 patients received courses of ciprofloxacin in pre-approval clinical trials.^[44] Most of the adverse events reported were described as only mild or moderate in severity, abated soon after the drug was discontinued, and required no treatment. Ciprofloxacin was discontinued because of an adverse event in 1% of orally treated patients. The most frequently reported drug-related events, from clinical trials of all formulations, all dosages, all drug-therapy durations, and for all indications of ciprofloxacin therapy, were nausea (2.5%), diarrhea (1.6%), abnormal liver function tests (1.3%), vomiting (1%), and rash (1%). Other adverse events occurred at rates of <1%.

Post-marketing surveillance has revealed tendonopathy, tendon rupture, and exacerbation of the symptoms of the neurological disorder myasthenia gravis as important serious adverse effects. The U.S. FDA-approved label for ciprofloxacin includes a "black box" warning of increased risk of tendon damage and/or rupture and for exacerbation of muscle weakness in patients with the neurological disorder myasthenia gravis.<ref name="www.accessdata.fda.gov"/^[45] A case control study^[46] performed using a UK medical care database found that fluoroquinolone use was associated with a 1.9-fold increase in tendon problems. The relative risk increased to 3.2 in those over 60 years of age and to 6.2 in those over the age of 60 who were also taking corticosteroids. Among the 46,766 quinolone users in the study, 38 (0.1%) cases of Achilles tendon rupture were identified. A study performed using an Italian healthcare database reached qualitatively similar conclusions.^[47] Tendonitis and other forms of tendon damage may manifest during fluoroquinolone therapy, and long after it had been discontinued.^[48]

Clostridium difficile associated diarrhea is a serious adverse effect of ciprofloxacin and other fluoroquinolones; it is unclear whether the risk is higher than with other broad spectrum antibiotics.^[49]

In 2013 the U.S. FDA issued a Safety Communication stating that its examination of spontaneous adverse event reports indicated an association of fluoroquinolone use with peripheral neuropathy, symptoms of which in some cases may be permanent.^[50] Headache, dizziness, and insomnia have been reported as occurring fairly commonly in post-approval review articles, along with a much lower incidence of serious CNS side effects not limited to but including tremors, psychosis, anxiety, hallucinations, paranoia, and suicide attempts, especially at higher doses.^[12] Rare cases of liver failure have been reported.^[51] A wide range of other apparently rare side effects including but not limited to Stevens-Johnson syndrome, heart arrhythmias (torsades des pointes), toxic epidermal necrolysis, vision problems, and bone marrow suppression have been spontaneously reported to the U.S FDA or have been the subject of case reports published in medical journals.^[52]

Children and the elderly are at a much greater risk of experiencing adverse reactions.^[53][54]

Contraindications

Three contraindications are found within the 2009 package insert:^[55]

• "Coadministration of ciprofloxacin with other drugs primarily metabolized by CYP1A2 results in increased plasma concentrations of these drugs and could lead to clinically significant adverse events of the coadministered drug."

• "Concomitant administration with tizanidine is contraindicated."

• "Ciprofloxacin is contraindicated in persons with a history of hypersensitivity to ciprofloxacin, any member of the quinolone class of antimicrobial agents, or any of the product components."

Ciprofloxacin is also considered to be contraindicated within the pediatric population (except for the indications outlined above), pregnancy, nursing mothers, and in patients with epilepsy or other seizure disorders.

Genotoxicity and carcinogenicity studies

Ciprofloxacin is active in six of eight in vitro assays used as rapid screens for the detection of genotoxic effects, but is not active in in vivo assays of genotoxicity.^[56] 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 and 750 mg/kg to rats and mice, respectively (about 1.7 and 2.5 times the highest recommended therapeutic dose based upon mg/m2). Results from photo co-carcinogenicity testing indicate ciprofloxacin does not reduce the time to appearance of UV-induced skin tumors as compared to vehicle control.

Interactions

Ciprofloxacin interacts with certain foods and several other drugs leading to undesirable increases or decreases in the serum levels or distribution of one or both drugs.

Co-administration of ciprofloxacin with anti-acids containing magnesium hydroxide or aluminum hydroxide leads to the formation of insoluble salts that are not readily absorbed from the intestinal tract. Peak serum concentrations of ciprofloxacin may be reduced by 90% or more, leading to therapeutic failure. Similar results have been reported when ciprofloxacin is co-administered with iron supplements and multi-vitamins containing zinc.^[57][58]

Coadministration of ciprofloxacin with orange juice or dairy products has been reported to reduce both the peak serum concentration and the area under the serum concentration-time curve (AUC). In the case of calcium-fortified orange juice, reductions of up to 40% have been reported.^[59]

Ciprofloxacin inhibits the drug-metabolizing enzyme CYP1A2 and thereby can reduce the clearance of drugs metabolized by that enzyme. Co-administration of ciprofloxacin with the CYP1A2 substrate tizanidine (Zanaflex) is contradicted due to a 583% increase in the peak serum concentrations of tizanidine when administered with ciprofloxacin as compared to administration of tizanidine alone. Other CYP1A2 substrates that exhibit increased serum levels in ciprofloxacin-treated patients include theophylline, caffeine, and clozapine, though in these cases the observed increase in peak serum levels is less profound that in the case of tizanidine. The authors of one review recommended that patients being treated with ciprofloxacin reduce their caffeine intake. Evidence for significant interactions with several other CYP1A2 substrates such as cyclosporine is equivocal or conflicting.^[59][60][61]

The Committee on the Safety of Medicines and the FDA warn that central nervous system (CNS) adverse effects, including seizure risk, may be increased when NSAIDs are combined with quinolones.^[60][62] The mechanism for this interaction may involve a synergistic increased antagonism of GABA neurotransmission.^[16][63]

Altered serum levels of the anti-epileptic drugs phenytoin and carbamazepine (increased and decreased) have been reported in patients receiving concomitant ciprofloxacin.^[60][64][65]

Overdose

Overdose of ciprofloxacin may result in reversible renal toxicity. Treatment of overdose includes emptying of the stomach by induced vomiting or gastric lavage. Careful monitoring and supportive treatment, monitoring of renal function, and maintaining adequate hydration is recommended by the manufacturer. Administration of magnesium-, aluminium-, or calcium-containing antacids can reduce the absorption of ciprofloxacin. Hemodialysis or peritoneal dialysis removes only less than 10% of ciprofloxacin.^[58] Ciprofloxacin may be quantified in plasma or serum to monitor for drug accumulation in patients with hepatic dysfunction or to confirm a diagnosis of poisoning in acute overdose victims.^[66]

Chemical Properties

Ciprofloxacin is 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid. Its empirical formula is C₁₇H₁₈FN₃O₃ and its molecular weight is 331.4 g/mol. It is a faintly yellowish to light yellow crystalline substance.^[58]

Ciprofloxacin hydrochloride (USP) is the monohydrochloride monohydrate salt of ciprofloxacin. It is a faintly yellowish to light yellow crystalline substance with a molecular weight of 385.8 g/mol. Its empirical formula is C₁₇H₁₈FN₃O₃HCl•H₂O.^[58]

Mechanism of action

Ciprofloxacin is a broad-spectrum antibiotic active against both Gram-positive and Gram-negative bacteria. It functions by inhibiting DNA gyrase, a type II topoisomerase, and topoisomerase IV,^[67] enzymes ^[68] necessary to separate bacterial DNA, thereby inhibiting cell division.

Pharmacokinetics

Ciprofloxacin for systemic administration is available as immediate release tablets, extended release tablets, an oral suspension, and as a solution for intravenous administration. When administered over one hour as an intravenous infusion,^[69] ciprofloxacin rapidly distributes into the tissues, with levels in some tissues exceeding those in the serum. Penetration into the central nervous system is relatively modest, with cerebrospinal fluid levels normally less than 10% of peak serum concentrations. The serum half-life of ciprofloxacin is about 4–6 hours, with 50-70% of an administered dose being excreted in the urine as unmetabolized drug. An additional 10% is excreted in urine as metabolites. Urinary excretion is virtually complete by 24 hours after administration. Dose adjustment is required in the elderly and in those with renal impairment.

Ciprofloxacin is weakly bound to serum proteins (20-40%) but is an inhibitor of the drug-metabolizing enzyme cytochrome P450 1A2, which leads to the potential for clinically important drug interactions with drugs metabolized by that enzyme.

Ciprofloxacin is about 70% orally available when administered orally, so a slightly higher dose is needed to achieve the same exposure when switching from I.V. to oral administration. A 750 mg immediate release oral tablet given every 12 hours produces about the same area under the serum concentration curve (AUC) and peak serum concentration (Cmax) as a 400 mg dose given every 8 hours I.V.^[52] The extended release oral tablets^[70] allow once daily administration by releasing the drug more slowly in the gastrointestinal tract. These tablets contain 35% of the administered dose in an immediate release form and 65% in a slow release matrix. Maximum serum concentrations are achieved between 1 and 4 hours post-administration. Compared to the 250 and 500 mg immediate release tablets, the 500 mg and 1000 mg XR tablets provide higher Cmax but the 24 hour AUCs are equivalent.

Ciprofloxacin immediate release tablets contain ciprofloxacin as the hydrochloride salt, and the XR tablets contain a mixture of the hydrochloride salt as the free base.

History

The first members of the quinolone antibacterial class were relatively low potency drugs such as nalidixic acid, used mainly in the treatment of urinary tract infections owing to their renal excretion and propensity to be concentrated in urine.^[71] In 1979 the publication of a patent^[72] filed by the pharmaceutical arm of Kyorin Seiyaku Kabushiki Kaisha disclosed the discovery of norfloxacin, and the demonstration that certain structural modifications including the attachment of a fluorine atom to the quinolone ring leads to dramatically enhanced antibacterial potency.^[73] In the aftermath of this disclosure, several other pharmaceutical companies initiated research and development programs with the goal of discovering additional antibacterial agents of the fluoroquinolone class. The fluoroquinolone program at Bayer focused on examining the effects of very minor changes to the norfloxacin structure.^[74][75] In 1983, the company published in vitro potency data for ciprofloxacin, a fluoroquinolone antibacterial having a chemical structure that differs from that of norfloxacin by the presence of a single carbon atom.^[76] This small change led to a 2 to 10-fold increase in potency against most strains of Gram-(-) bacteria. Importantly, this structural change led to a four-fold improvement in activity against the important Gram-(-) pathogen Pseudomonas aeruginosa, making ciprofloxacin one of the most potent known drugs for the treatment of this intrinsically antibiotic-resistant pathogen.

The oral tablet form of ciprofloxacin was approved in October 1987,^[77] just one year after the approval of norfloxacin^[78] In 1991, the intravenous formulation was introduced. Ciprofloxacin sales reached 1.52 million Euros in 1999, representing 30% of Bayer’s total pharmaceutical revenues.^{[79] [80]} The sale of ciprofloxacin increased dramatically following the anthrax scare of 2001. On 24 October 2002, the Bush administration (2001–2009) announced a deal between the government and Bayer Pharmaceuticals to purchase 100 million tablets of ciprofloxacin at a reduced price of $0.95 per pill.

Society and Culture

Generic equivalents

On 24 October 2001, The Prescription Access Litigation (PAL) filed suit to dissolve an agreement between Bayer and three of its competitors which produced generic versions of drugs (Barr Laboratories, Rugby Laboratories, and Hoechst-Marion-Roussel) that PAL claimed was blocking access to adequate supplies and cheaper, generic versions of ciprofloxacin. The plaintiffs charged that Bayer Corporation, a unit of Bayer AG, had unlawfully paid the three competing companies a total of $200 million to prevent cheaper, generic versions of ciprofloxacin from being brought to the market, as well as manipulating its price and supply. Numerous other consumer advocacy groups joined the lawsuit. On 15 October 2008, five years after Bayer's patent had expired, the United States District Court for the Eastern District of New York granted Bayer's and the other defendants' motion for summary judgment, holding that any anticompetitive effects caused by the settlement agreements between Bayer and its codefendants were within the exclusionary zone of the patent and thus could not be redressed by federal antitrust law,^[81] in effect upholding Bayer's agreement with its competitors.

Bacterial resistance

Ciprofloxacin is commonly used for urinary tract and intestinal infections (traveler's diarrhea), and was once considered a powerful antibiotic of last resort,^[82][83][84] used to treat especially tenacious infections. Not all physicians agreed with this assessment, as evidenced by its widespread use to treat minor infections, as well as unapproved uses. As a result, many bacteria have developed resistance to this drug in recent years, leaving it significantly less effective than it would have been otherwise.^[85][86]

Resistance to ciprofloxacin and other fluoroquinolones may evolve rapidly, even during a course of treatment. Numerous pathogens, including Staphylococcus aureus, enterococci, Streptococcus pyogenes and Klebsiella pneumoniae (quinolone-resistant) now exhibit resistance worldwide.^[87] Widespread veterinary usage of the fluoroquinolones, particularly in Europe, has been implicated.^[88] Meanwhile, some Burkholderia cepacia, Clostridium innocuum and Enterococcus faecium strains have developed resistance to ciprofloxacin to varying degrees.^[89]

Fluoroquinolones had become the most commonly prescribed class of antibiotics to adults in 2002.^[90] Nearly half (42%) of those prescriptions were for conditions not approved by the FDA, such as acute bronchitis, otitis media, and acute upper respiratory tract infection, according to a study supported in part by the Agency for Healthcare Research and Quality.^[90][91] Additionally, they were commonly prescribed for medical conditions that were not even bacterial to begin with, such as viral infections, or those to which no proven benefit existed.

Litigation

A class action was filed against Bayer AG on behalf of employees of the Brentwood Post Office in Washington, D.C., and workers at the US Capitol, along with employees of American Media, Inc. in Florida and postal workers in general who alleged they suffered serious adverse effects from taking ciprofloxacin (Cipro) in the aftermath of the anthrax attacks in 2001. The action alleged Bayer failed to warn class members of the potential side effects of the drug, thereby violating the Pennsylvania Unfair Trade Practices and Consumer Protection Laws. According to the allegations within the complaint, exposed individuals were not informed of the true safety profile of ciprofloxacin, the high rate of adverse events associated with its use, or the availability of safer and equally effective alternative drugs. The class action was defeated and the litigation abandoned by the plaintiffs.^[92] A similar action had been filed in New Jersey to cover New Jersey postal workers. Final disposition of that lawsuit is unknown. Following the addition of the black box warning in 2008, regarding tendon damage, product liability law firms began soliciting clients who have suffered a spontaneous tendon rupture following fluoroquinolone therapy.^[93][94][95]

Brand names

Ciprofloxacin is marketed worldwide with over 300 different brand names. In the United States, Canada, and the UK, it is marketed as Baycip, Ciloxan, Ciflox, Ciplox, Cipro, Cipro XR, Cipro XL, Cifran, Ciproxin, Prociflor, and Proquin. It is also marketed as Hiflox, Neofloxin and Cipro-A in Bangladesh; in India it is marketed as Alcipro, in Russia as Ciprex,in Jordan as Ciprocin eye/ear drops,^[96] and as Cetraxal in Spain. In Pakistan, it is marketed as Ciproheim, Cipesta, and Novidat. In addition, ciprofloxacin is available as a generic drug under a variety of different brand names and is also available for limited use in veterinary medicine.

References

External links

Wikimedia Commons has media related to Ciprofloxacin.

• Ciprofloxacin on the Open Directory Project
• How Stuff Works - Cipro
• U.S. National Library of Medicine: Drug Information Portal - Ciprofloxacin
• Cipro Package Insert
• Proquin XR Package Insert
• Ciloxan Package Insert
• Ciprofloxacin Ophthalmic

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