Ciprofloxacin

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Not to be confused with Cipralex, a brand name of the antidepressant escitalopram.
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%[1]
Metabolism Hepatic, including CYP1A2
Half-life 4 hours
Excretion Renal
Identifiers
CAS number 85721-33-1 YesY
ATC code J01MA02 S01AE03 S02AA15 S03AA07
PubChem CID 2764
DrugBank DB00537
ChemSpider 2662 YesY
UNII 5E8K9I0O4U YesY
KEGG D00186 YesY
ChEBI CHEBI:100241 YesY
ChEMBL CHEMBL8 YesY
NIAID ChemDB 001992
Chemical data
Formula C17H18FN3O3 
Mol. mass 331.346
 YesY (what is this?)  (verify)

Ciprofloxacin (INN) is a second-generation fluoroquinolone antibiotic.[2][3] Its spectrum of activity includes most strains of bacterial pathogens responsible for respiratory, urinary tract, gastrointestinal, and abdominal infections, including Gram-(-) (Escherichia coli, Haemophilus influenzae, Klebsiella pneumoniae, Legionella pneumophila, Moraxella catarrhalis, Proteus mirabilis, and Pseudomonas aeruginosa), and Gram-(+) (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.[4] (Many antibacterials used in serious infections must be dosed intravenously.)

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[5][6] and abdominal infections[7] among others. It is also used for the treatment of infections caused by specific pathogens known to be sensitive. 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.[8]

It is a second-generation fluoroquinolone antibacterial. It kills bacteria by interfering with the enzymes that cause DNA to rewind after being copied, which stops synthesis of DNA and of protein.

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).

Contents

Medical uses [edit]

Ciprofloxacin is used to treat a number of infections, including infections of bones and joints, endocarditis, gastroenteritis, malignant otitis externa, respiratory tract infections, cellulitis, urinary tract infections, prostatitis, anthrax, and chancroid, as well as:[9]

  • Urinary tract infections (recommended as a first-line antibiotic)[10]
  • Acute uncomplicated cystitis in females
  • Chronic bacterial prostatitis (recommended as a first-line antibiotic choice)[11][12]
  • Lower respiratory tract infections (not recommended as a first-line antibiotic choice)[13][14][15]
  • Acute sinusitis (not recommended as a first-line antibiotic choice)[16][17]
  • Skin and skin structure infections
  • Bone and joint infections
  • Infectious diarrhea
  • Typhoid fever (enteric fever) caused by Salmonella typhi
  • Uncomplicated cervical and urethral gonorrhea (due to N. gonorrhoeae) – however, this indication is no longer effective in some areas (for example, Asian countries,[18] United States (including Hawaii), Canada,[19] and Scotland)[20] due to bacterial resistance. Fluoroquinolones are no longer recommended in the USA for this indication.[21]

Ciprofloxacin is not recommended for the treatment of tuberculosis.[22]

It is also used in combination with other specific drugs:

  • Complicated intra-abdominal infections (in combination with metronidazole);
  • Empirical therapy for febrile neutropenic patients (in combination with piperacillin)

Oral and intravenous fluoroquinolones are not licensed by the FDA for use in children due to the risk of permanent injury to the musculoskeletal system, with two exceptions as outlined below.

Indications include:

Ciprofloxacin is not recommended to treat community-acquired pneumonia (CAP) as a stand-alone first-line agent due to its modest activity against Streptococcus pneumoniae, a common causative pathogen. "Respiratory quiniolones" such as levofloxacin, having greater activity against this pathogen, are recommended as first line agents for the treatment of CAP in patients with important co-morbidities and in patients requiring hospitalization (Infectious Diseases Society of America 2007). The guidelines include a warning that "Data exist suggesting that resistance to macrolides and older fluoroquinolones (ciprofloxacin and levofloxacin) results in clinical failure. Other studies have shown that repeated use of fluoroquinolones predicts an increased risk of infection with fluoroquinolone-resistant pneumococci...."[25]

Ciprofloxacin may be licensed for other uses, or restricted, by the various regulatory agencies worldwide.

Availability [edit]

Ciprofloxacin is available as tablets, syrups, intravenous solutions, and eye and ear drops.

Contraindications [edit]

Only four contraindications are found within the 2009 package insert:[26]

  • "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."
  • "Local IV site reactions are more frequent if the infusion time is 30 minutes or less. These may appear as local skin reactions that resolve rapidly upon completion of the infusion. Subsequent intravenous administration is not contraindicated unless the reactions recur or worsen."

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

Pregnancy [edit]

According to the FDA-approved drug label, ciprofloxacin is Pregnancy Category C. This category includes drugs for which there are no adequate and well-controlled studies in human pregnancy, but for which animal studies have suggested the potential for harm to the fetus. The label further states, "Ciprofloxacin should not be used during pregnancy unless the potential benefit justifies the potential risk to both fetus and mother."

A controlled prospective observational study followed 200 women exposed to fluoroquinolones (52.5% exposed to ciprofloxacin and 68% first-trimester exposures) during gestation.[27] 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.[28] 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."

The fluoroquinolones rapidly cross the blood-placenta and blood-milk barriers, and are extensively distributed into the fetal tissues. The fluoroquinolones have also been reported as being present in the mother's milk and are passed on to the nursing child.[29][30]

Pediatric population [edit]

Fluoroquinolones are not licensed by the FDA for use in children due to the risk of permanent injury to the musculoskeletal system, with two exceptions. Ciprofloxacin is being licensed for the treatment of complicated urinary tract infections and pyelonephritis due to Escherichia coli, and inhalational anthrax (postexposure), and levofloxacin was recently licensed for the treatment of inhalational anthrax (postexposure). However, the fluoroquinolones are licensed to treat lower respiratory infections in children with cystic fibrosis in the UK.

The risks associated with the use of ciprofloxacin in pediatric patients were recently evaluated in a systematic review of 105 research publications describing the use of ciprofloxacin in 16,184 patients 17 years and younger. The most frequently reported adverse events (AEs) were musculoskeletal AEs, abnormal liver tests, nausea, changes in white blood cell counts, and vomiting. Twenty-three patients discontinued treatment due to AEs (0.1%). A single death occurred in a neonate who experienced an anaphylactic reaction. Forty-eight patients (0.3%) experienced a joint or tendon disorder.[31]

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.[32]

Ciprofloxacin should not be used in infants as they have not developed sufficient enzymes to metabolize the drug.[citation needed] Severe adverse reaction may occur in this patient group.

Special precautions [edit]

The status of the patient's renal and hepatic functions must also be taken into consideration to avoid an accumulation that may lead to an overdose and the development of toxicity. Ciprofloxacin is eliminated primarily by renal excretion. However, the drug is also metabolized and partially cleared through the liver and the intestines. Modification of the dosage is 'recommended' using the table found within the package insert for those with impaired liver or kidney function. However, since the drug is known to be substantially excreted by the kidneys, the risk of toxic reactions to this drug may be greater in patients with impaired renal function. The duration of treatment depends upon the severity of infection, and is usually seven to 14 days.[33]

Adverse effects [edit]

See also: Adverse effects of fluoroquinolones

The safety of fluoroquinolones is similar to that of other antibiotics.[34] In most, adverse reactions are mild to moderate; but serious adverse effects occur on occasion.[34][35]

According to the FDA-approved package insert, 49,038 patients received courses of ciprofloxacin in pre-approval clinical trials. 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%.

A number of regulatory actions have been taken as a result of such adverse reactions, which included published warnings,[36][37] additional warnings and safety information added to the package inserts[38] together with the issuance of "Dear Doctor Letters"[39] concerning the recent addition of black box warnings.

Black box warnings [edit]

See the Quinolones article for a discussion of the history of these warnings and the role of public advocacy groups in their inclusion in the product label.

As of 2011, the FDA has added two black box warnings for this drug in reference to spontaneous tendon ruptures and because ciprofloxacin may cause worsening of myasthenia gravis symptoms, including muscle weakness and potentially life-threatening breathing problems.[40] A case control study[41] 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.[42]

Tendonitis and other forms of tendon damage may manifest during fluoroquinolone therapy, and long after it had been discontinued.[43]

Genotoxicity and carcinogenicity studies [edit]

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 including the rat hepatocyte DNA repair assay, micronucleus test (mice) or the dominant lethal test (mice).[44] 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. 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 mg/m2), as opposed to 34 weeks when animals were treated with both UVA and vehicle.

Other adverse effects [edit]

The administration of Ciprofloxacin has been associated with a number of rare but serious side effects, including SIADH[45]peripheral neuropathy[46] acute liver failure or serious liver injury (hepatitis),[47][48] QTc prolongation/torsades de pointes,[33] toxic epidermal necrolysis (TEN),[49][50][50] and Stevens–Johnson syndrome, severe central nervous system disorders (CNS)[23] and Clostridium difficile associated disease (CDAD: pseudomembranous colitis),[51][52] as well as photosensitivity/phototoxicity reactions.

Psychotic reactions and confusional states, acute pancreatitis,[53] interstitial nephritis, and hemolytic anemia may also occur during ciprofloxacin therapy.[54][55] Additional serious adverse reactions include temporary loss of vision,[56][57] double vision,[58] drug induced psychosis,[59][60] impaired color vision, exanthema, abdominal pain, malaise, drug fever, dysaesthesia, and eosinophilia.[61][62]

Children and the elderly are at a much greater risk of experiencing such adverse reactions.[63][64]

Interactions [edit]

Ciprofloxacin interacts with other drugs and herbal and natural supplements, a characteristic it shares with other widely used antibacterial drugs, such as amoxicillin, trimethoprim, azithromycin, cephalexin, and doxycycline.[65]

Concurrent administration of ciprofloxacin with magnesium or aluminium antacids, sucralfate, or products containing calcium, iron, or zinc (including multivitamins or other dietary supplements) may substantially decrease the absorption of ciprofloxacin, resulting in serum and urine levels considerably lower than desired.[66]

Serum levels of certain drugs metabolised by the cytochrome P450 system is enhanced by concomitant use of some quinolones. Coadministration may dangerously increase coumadin (warfarin) activity; INR should be monitored closely. Levels of tizanidine and methylxanthines (for example, theophylline and caffeine) may be increased due to ciprofloxacin's interaction with the cytochrome P-450 enzyme CYP1A2.[67][68]

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.[33][69] The interaction between quinolones and NSAIDs is important, because it has the potential for considerable CNS toxicity. The mechanism for this interaction is believed to be due to a synergistic increased antagonism of GABA neurotransmission.[35][70]

Ciprofloxacin's renal clearance may affect other drugs subject to renal clearance or otherwise affecting the kidney. The use of ciprofloxacin concomitantly with cyclosporine has also been associated with transient elevations in serum creatinine. Renal tubular transport of methotrexate may be inhibited by concomitant administration of ciprofloxacin, potentially leading to increased plasma levels of methotrexate and risk of methotrexate toxicity. Probenecid interferes with renal tubular secretion of ciprofloxacin and produces an increase in the level of ciprofloxacin in serum.[33]

Altered serum levels of the anti-epileptic drugs phenytoin and carbamazepine (increased and decreased) have been reported in patients receiving concomitant ciprofloxacin.[33][71][72]

Current or past treatment with oral corticosteroids is associated with an increased risk of Achilles tendon rupture, especially in elderly patients who are also taking the fluoroquinolones.[73] This is the subject of Black box warnings in FDA and BNF labeling for quinolones.

Overdose [edit]

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.[66] 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.[74]

Mechanism of action [edit]

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,[75] enzymes necessary to separate bacterial DNA, thereby inhibiting cell division.

Chemistry [edit]

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.[66]

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.[66]

Pharmacokinetics [edit]

The effects of 200–400 mg of ciprofloxacin given intravenously are linear; drug accumulation does not occur when administered at 12-hour intervals. Bioavailability is approximately 70-80%, with no significant first pass effect. IV administration produces a similar serum levels as those achieved with administration of 500 mg administered orally. IV administration over 60 min given every 8 h produces similar serum levels of the drug as 750 mg administered orally every 12 h.[66] Biotransformation is hepatic. The elimination half life is 4 h.[33]

History [edit]

Ciprofloxacin 250-mg tablets from Ukraine

The patent history for ciprofloxacin makes reference to a 1982 European patent (patent number 0049355), as well a German patent dated 21 January 1986. Bayer introduced ciprofloxacin in 1987 and it was later approved by the US FDA on 22 October 1987 for use in the United States to treat specific bacterial infections. In 1991, the intravenous formulation was introduced. The current US patent appears to be held by Bayer, being the assignee.[76] The United States patent was applied for in January 1987, but was not approved until 1996 according to the patent history.

In 2004, ciprofloxacin and levofloxacin together commanded 65% ($3.3 billion) of the global sales of the fluoroquinolone class.[77] The first 9 months of 2008 sales for ciprofloxacin were $242 million, as compared to $324 million for Bayer aspirin.[78] Ciprofloxacin has been a highly successful drug for Bayer A. G., generating billions of dollars in revenue. "In 1999, Cipro was the eleventh most prescribed drug in the United States based on new prescriptions, and ranked twentieth in total United States sales. In 1999, Bayer's gross sales of Cipro in the United States were approximately $1.04 billion."[79] 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.

Generic equivalents [edit]

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,[80] in effect upholding Bayer's agreement with its competitors.

Bacterial resistance [edit]

See also: Antibiotic abuse and Antibiotic resistance

Ciprofloxacin is commonly used for urinary tract and intestinal infections (traveler's diarrhea), and was once considered a powerful antibiotic of last resort,[81][82][83] 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.[84][85]

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.[86] Widespread veterinary usage of the fluoroquinolones, particularly in Europe, has been implicated.[87] Meanwhile, some Burkholderia cepacia, Clostridium innocuum and Enterococcus faecium strains have developed resistance to ciprofloxacin to varying degrees.[88]

Fluoroquinolones had become the most commonly prescribed class of antibiotics to adults in 2002.[89] 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.[89][90] 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 [edit]

Bayer AG 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.[91] 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.[92][93][94]

Brand names [edit]

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, Ciproxin, Prociflor, and most recently, Proquin. It is also marketed as Neofloxin and Cipro-A in Bangladesh; in India it is marketed as Alcipro, in Russia as Ciprex, and as Cetraxal in Spain. In Pakistan, it is marketed as Ciproheim. 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.

See also [edit]

References [edit]

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Antifolates
(inhibits
purine metabolism,
thereby inhibiting
DNA and RNA synthesis)
DHFR inhibitor
Sulfonamides
(DHPS inhibitor)
Short-
acting
Intermediate-
acting
Long-
acting
Other/ungrouped
Combinations
Topoisomerase
inhibitors/
quinolones/
(inhibits
DNA replication)
1st g.
Fluoro-
quinolones
2nd g.
3rd g.
4th g.
Vet.
Related (DG)
Anaerobic DNA
inhibitors
Nitro- imidazole derivatives
Nitrofuran derivatives
RNA synthesis
Rifamycins/
RNA polymerase

M: BAC

drug (J1p, w, n, m, vacc)
Anti-infectives
Corticosteroids
Analgesics and anesthetics

M: EAR

anat (e/p)/phys/devp

proc, drug (S2)
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