Ciprofloxacin

Ciprofloxacin
Not to be confused with Cipralex, a brand name of the antidepressant escitalopram.
"Cipro" redirects here. For the Rome Metro station, see Cipro (Rome Metro).
Ciprofloxacin
Systematic (IUPAC) name
1-cyclopropyl-6-fluoro-4-oxo-7-(piperazin-1-yl)-quinoline-3-carboxylic acid
Clinical data
Trade names Ciloxan, Cipro
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 S01AX13 S02AA15 S03AA07
PubChem CID 2764
DrugBank DB00537
ChemSpider 2662 YesY
UNII 5E8K9I0O4U YesY
KEGG D00186 YesY
ChEBI CHEBI:100241 YesY
ChEMBL CHEMBL8 YesY
Chemical data
Formula C17H18FN3O3 
Mol. mass 331.346
SMILES eMolecules & PubChem
 YesY(what is this?)  (verify)

Ciprofloxacin (INN) is a synthetic chemotherapeutic antibiotic of the fluoroquinolone drug class.[2][3] 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 U.S. 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). Ciprofloxacin interacts with other drugs, herbal and natural supplements, and thyroid medications.[4]

As of 2011 the FDA has added two black box warnings for this drug in reference to spontaneous tendon ruptures and the fact that ciprofloxacin may cause worsening of myasthenia gravis symptoms, including muscle weakness and breathing problems. Such an adverse reaction is a potentially life-threatening event and may require ventilatory support.[5]

Contents

Medical uses

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, chancroid, among others.[6]

  • Urinary tract infections (not recommended as a first-line antibiotic)[7]
  • Acute uncomplicated cystitis in females
  • Chronic bacterial prostatitis (not recommended as a first-line antibiotic choice)[8][9]
  • Lower respiratory tract infections (not recommended as a first-line antibiotic choice)[10][11][12]
  • Acute sinusitis (not recommended as a first-line antibiotic choice)[13]
  • Skin and skin structure infections
  • Bone and joint infections
  • Infectious diarrhea
  • Typhoid fever (enteric fever) caused by Salmonella typhi
  • Uncomplicated cervical and urethra gonorrhea (due to N. gonorrhoeae) – however, this indication is no longer effective in some areas (for example, Asian countries,[14] United States (including Hawaii), Canada,[15] and Scotland)[16] due to bacterial resistance. Fluoroquinolones are no longer recommended in the USA for this indication.[17]

Ciprofloxacin is not recommended for the treatment of tuberculosis.[18]

As well as 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 U.S. FDA for use in children due to the risk of permanent injury to the musculoskeletal system, with two exceptions as outlined below. Within the studies submitted in response to a Pediatric Written Request (ciprofloxacin, circa 2004) the rate of arthropathy was reported to be 9.3% at one month and 13.6% at one year.[19] As such the pediatric use of ciprofloxacin is restricted to proven complicated urinary tract infections and pyelonephritis due to E. coli and inhalation anthrax.[20] Although claimed to be effective, ciprofloxacin is not to be considered a first line agent for inhalation anthrax in the pediatric population.[19][21][22][23] The CDC revoked its recommendation regarding the use of ciprofloxacin as a first line agent in treating anthrax due to the unacceptable risk documented within the Antimicrobial Postexposure Prophylaxis for Anthrax study (aka Cipro 60 day study).[24] However, the fluoroquinolones are licensed to treat lower respiratory infections in children with cystic fibrosis in the UK.

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.[25]

Indications include:

Ciprofloxacin is not recommended to treat community acquired pneumonia (CAP) as a stand-alone first-line agent. The current guidelines (Infectious Diseases Society of America 2007) state, in very limited circumstances, ciprofloxacin or levofloxacin should be combined with other drugs such as a beta-lactam drug to treat specific CAP infections, but neither drug is recommended to be used separately as a stand-alone first-line agent. In addition, the current guidelines state: "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...."[28]

As such, the general opinion stated in 1994 that ciprofloxacin "is not to be considered a suitable agent for use in general practice for the blind initial treatment of chest infections...."[12][29] does not appear to have changed within these current guidelines.

Antibiotics may not improve the long-term clinical outcome for sinusitis.[30] When prescribed for chronic bronchitis and acute bacterial sinusitis, the use of the fluoroquinolone class offers no compelling advantages over established treatment.[31] Nor does antibiotic treatment help sore throats.[32] The use of antibiotics such as ciprofloxacin to treat bronchitis is to be considered unnecessary and as such exposes the patient to an unacceptable risk of suffering a severe adverse reaction.[33] Additionally, antibiotics have no effect upon viral infections, such as the common head cold or viral respiratory infections.

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.

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

Availability

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

Contraindications

As noted above, under licensed use, ciprofloxacin is also now considered to be contraindicated for the treatment of certain sexually transmitted diseases by some experts due to bacterial resistance.[34]

There are only four contraindications found within the 2009 package insert:[35]

  • "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 I.V. 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."

Due to growing prevalence of antibiotic resistance to the fluoroquinolones in southeast Asia, the use of ciprofloxacin in patients having been to southeast Asia is increasingly being discouraged.[36]

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

The fluoroquinolones rapidly cross the blood-placenta and blood-milk barriers, and are extensively distributed into the fetal tissues. For this reason, the fluoroquinolones are contraindicated during pregnancy due to the risk of spontaneous abortions and birth defects. The fluoroquinolones have also been reported as being present in the mother's milk and are passed on to the nursing child, which may increases the risk of the child suffering from this syndrome as well, even though the child had never been prescribed or taken any of the drugs found within this class.[37][38]

  • Pediatric population

Fluoroquinolones are not licensed by the U.S. FDA for use in children due to the risk of fatalities[39] as well as 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.

Within the studies submitted in response to a Pediatric Written Request (ciprofloxacin, circa 2004), the rate of atrophy was reported to be 9.3%.[40] Within the BPCA Pediatric Studies Summary for ciprofloxacin,[40] it was stated that the overall incidence of adverse events at six weeks was 41%. This would be consistent with the safety profile found with the other fluoroquinolones studied in the pediatric population. As such, the current ban on the use of the fluoroquinolones in the pediatric population is both reasonable and supported by various clinical studies. The most recent long term study, BAY 0 9867 Cipro Pediatric Use Study (QUIP), which followed pediatric patients from 1999–2008,[41] supports the current expert opinion that the risk of permanent injury continues to outweigh the potential benefits of ciprofloxacin therapy in the pediatric population.

Within the United States, the FDA has stated it is their intention to pursue the licensing of the fluoroquinolones for pediatric use in spite of the evidence presented at that 62 Meeting of the Anti-Infective Drugs Advisory Committee that the fluoroquinolones cause irreversible joint damage in the pediatric population.[42]

Special precautions

The status of the patient's renal function and hepatic function 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 7 to 14 days.[20]

Adverse effects

See also: Adverse effects of fluoroquinolones

Serious adverse events occur more commonly with fluoroquinolones than with any other antibiotic drug classes. In most, adverse reactions are mild to moderate; however, occasionally serious adverse effects occur.[43][44] There have been a number of regulatory actions taken as a result of such adverse reactions, which included published warnings,[45][46] additional warnings and safety information added to the package inserts[47] together with the issuance of "Dear Doctor Letters"[48] concerning the recent addition of Black Box Warnings. In 2004, the U.S. FDA requested new warning labels to be added to all of the fluoroquinolones, including ciprofloxacin, regarding peripheral neuropathy (irreversible nerve damage), tendon damage, heart problems (prolonged QT Interval / torsades de pointes), pseudomembranous colitis, rhabdomyolysis (muscle breakdown), Stevens-Johnson syndrome, as well as concurrent usage of NSAIDs contributing to the severity of these reactions.[citation needed]

Subsequent to this, on 25 June 2007, the U.S. FDA required manufacturers to add an additional warning to the package inserts that stated "Other serious and sometimes fatal events, some due to hypersensitivity, and some due to uncertain etiology, have been reported in patients receiving therapy with quinolones, including ciprofloxacin."[49] It was not until 2008, (four years later) that the label revisions for ciprofloxacin included any warnings concerning heart problems (prolonged QT interval / torsade de pointes). Warnings concerning rhabdomyolysis and Stevens-Johnson syndrome were still absent from the package inserts as of September 2009.

The serious adverse effects that may occur as a result of ciprofloxacin therapy include irreversible peripheral neuropathy,[50][51] spontaneous tendon rupture and tendonitis,[52][53][54][55] acute liver failure or serious liver injury (hepatitis),[56][57] QTc prolongation/torsades de pointes,[20] toxic epidermal necrolysis (TEN),[58][59][59] and Stevens-Johnson syndrome, severe central nervous system disorders (CNS)[26] and Clostridium difficile associated disease (CDAD: pseudomembranous colitis),[60][61] as well as photosensitivity/phototoxicity reactions.

Psychotic reactions and confusional states, acute pancreatitis,[62] bone marrow depression, interstitial nephritis and hemolytic anemia may also occur during ciprofloxacin therapy.[63][64] Additional serious adverse reactions include temporary, as well as permanent, loss of vision,[65][66] irreversible double vision,[67] drug induced psychosis[68][69] and chorea (involuntary muscle movements),[70] impaired color vision, exanthema, abdominal pain, malaise, drug fever, dysaesthesia and eosinophilia.[71][72] Pseudotumor cerebri, commonly known as idiopathic intracranial hypertension (IIH), (also referred to as increased intracranial pressure), has been reported to occur as a serious adverse reaction to ciprofloxacin.[73]

Children and the elderly are at a much greater risk of experiencing such adverse reactions.[74][75] Such reactions may manifest during fluoroquinolone therapy, and long after it had been discontinued.[76]

Serious visual complications have also been reported to occur with ophthalmic fluoroquinolone therapy, which may also occur with ciprofloxacin eye drops, especially corneal perforation, but also evisceration and enucleation. This increased incidents of corneal perforation may be due to fluoroquinolones causing alterations in stromal collagen, leading to a reduction in tectonic strength.[77][78] As noted previously permanent double vision (diplopia) has also been reported.[67] An unusual case of seizures has also been reported with ciprofloxacin ear drops in an elderly patient.[79]

Some groups refer to these adverse events as "fluoroquinolone toxicity". These groups of people claim to have suffered serious long term harm to their health from using fluoroquinolones. This has led to a class action lawsuit by people harmed by the use of fluoroquinolones, as well as legal action by the consumer advocate group Public Citizen.[80] Partly as a result of the efforts of the State of Illinois and Public Citizen, the FDA ordered black box warnings on all fluoroquinolones advising consumers of the possible toxic effects of fluoroquinolones on tendons.[81]

Interactions

The toxicity of drugs that are metabolised by the cytochrome P450 system is enhanced by concomitant use of some quinolones. Coadministration may dangerously increase coumarin (warfarin) activity; INR should be monitored closely. They may also interact with the GABA A receptor and cause neurological symptoms; this effect is augmented by certain nonsteroidal anti-inflammatory drugs.[82] Quercetin, a flavonol, occasionally used as a dietary supplement, may interact with fluoroquinolones, as quercetin competitively binds to bacterial DNA gyrase. Some foods, such as garlic and apples, contain high levels of quercetin; whether this inhibits or enhances the effect of fluoroquinolones is not entirely clear.[83] Ciprofloxacin can reduce phenytoin plasma levels, which may, in some cases, result in seizures.[84] Ciprofloxacin may interfere with the levels of thyroid medications resulting in hypothyroidism.[85]

On 9 November 2005, the U.S. FDA required manufacturers to provide additional warnings within the package inserts concerning ciprofloxacin being an inhibitor of human cytochrome P450 1A2 (CYP1A2) mediated metabolism. The new warning stated:

"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."[86]

Concurrent administration of ciprofloxacin with magnesium or aluminum 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.[87]

Significant drug interactions

Ciprofloxacin can alter and be altered by the metabolism and effects of other drugs, resulting in some significant drug-drug interactions that may affect the musculoskeletal, central nervous, renal, and other systems.

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.[88] This is the subject of Black box warnings in FDA and BNF labeling for quinolones.

The Committee on the Safety of Medicines and the FDA warn that central nervous system adverse effects, including seizure risk, may be increased when NSAIDs are combined with quinolones.[20][89] 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.[44]

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.[20]

Some quinolones, including ciprofloxacin, exert an inhibitory effect on the cytochrome P-450 enzyme CYP1A2, thereby reducing clearance, and thus increasing blood levels of tizanidine and methylxanthines (for example,, theophylline and caffeine).[90][91] The quinolones have also been reported to enhance the effects of warfarin or its derivatives.[20] Such interactions can augment the effects of the co-administered drug, including adverse effects. Ciprofloxacin can reduce effects of other drugs; for example, it has been shown to interact with thyroid medications (levothyroxine), resulting in unexplained hypothyroidism.[92] Altered serum levels of phenytoin (increased and decreased) have been reported in patients receiving concomitant ciprofloxacin.[20]

Overdose

Overdose of ciprofloxacin may result in reversible renal toxicity. Treatment of overdose includes emptying of the stomach via induced vomiting or by gastric lavage. Careful monitoring and supportive treatment, monitoring of renal function and maintaining adequate hydration is recommended by the manufacturer. Administration of magnesium, aluminum, or calcium containing antacids can reduce the absorption of ciprofloxacin. Hemodialysis or peritoneal dialysis removes only less than 10 percent of ciprofloxacin.[87] Ciprofloxacin may be quantitated 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.[93]

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

This mechanism can also affect mammalian cell replication. In particular, some congeners of this drug family (for example those that contain the C-8 fluorine)[95] display high activity not only against bacterial topoisomerases but also against eukaryotic topoisomerases and are toxic to cultured mammalian cells and in vivo tumor models.[96] Although quinolones are highly toxic to mammalian cells in culture, its mechanism of cytotoxic action is not known. Quinolone-induced DNA damage was first reported in 1986 (Hussy and others.).[97]

Recent studies have demonstrated a correlation between mammalian cell cytotoxicity of the quinolones and the induction of micronuclei.[98][99][100][101] As such, some fluoroquinolones may cause injury to the chromosome of eukaryotic cells.[102][103][104][105][106][107]

There continues to be debate as to whether or not this DNA damage is to be considered one of the mechanisms of action concerning the severe adverse reactions experienced by some patients following fluoroquinolone therapy.[96][108][109]

Chemistry

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.[87]

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.[87]

Pharmacokinetics

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 minutes given every 8 hours produces similar serum levels of the drug as 750 mg administered orally every 12 hours.[87] Biotransformation is hepatic. The elimination half life is 4 hours.[20]

History

Ciprofloxacin 250mg 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 U.S. 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 United States patent appears to be held by Bayer, being the assignee.[110] 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.[111] The first nine months of 2008 sales for ciprofloxacin were $242 million, as compared to $324 million for Bayer aspirin.[112] 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."[113] 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. A full course of ciprofloxacin for postexposure prophylaxis (60 days) resulting from this arrangement costs the government $204 per person treated, compared with $12 per person treated with doxycycline, the drug normally used to treat anthrax, a difference of $192.[114]

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 it 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 the price and supply of ciprofloxacin. 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,[115] in effect upholding Bayer's agreement with its competitors.

Black box warnings

See also: Quinolone#Black box warnings

Musculoskeletal disorders attributed to use of quinolone antibiotics were first reported in the medical literature in 1972, as an adverse reaction to nalidixic acid.[116] Rheumatic disease after use of a fluoroquinolone (norfloxacin) was first reported 11 years later.[117] In response to a 1995 letter published in the New England Journal of Medicine, representatives of the U.S. Food and Drug Administration (FDA) stated that the agency would "update the labeling [package insert] for all marketed fluoroquinolones to include a warning about the possibility of tendon rupture."[118]

By August 1996, the FDA had not taken action, and the consumer advocacy group Public Citizen filed a petition with the FDA prompting the agency to act.[119] Two months later, the FDA published an alert in the FDA Medical Bulletin and requested that fluoroquinolone package inserts be amended to include information on this risk.[52]

Nine years later, in 2005, the Illinois Attorney General filed a second petition with the FDA again seeking Black Box Warnings and "Dear Doctor" letters emphasizing the risk of tendon rupture; the FDA responded that it had not yet been able to reach a decision on the matter.[120] In 2006, Public Citizen, supported by the Illinois Attorney General, renewed its demand of ten years prior for Black Box Warnings by filing a third petition requesting such changes be made.[120][121] When the FDA failed to respond to these two petitions as required by law Public Citizen, in January 2008, filed suit to compel the FDA to respond to their 2006 petition.[122][123] On July 7, 2008 the FDA requested that the makers of systemic-use fluoroquinolones add a boxed warning regarding spontaneous tendon ruptures, and to develop a Medication Guide for patients.[124] The package inserts for Ciprofloxacin, Avelox (moxifloxacin), Proquin XR, Factive (gemifloxacin), Floxin (ofloxacin), Noroxin (norfloxacin) and Levaquin (levofloxacin) were amended on September 8, 2008 to include these new warnings.[125] Bayer, which manufactures Cipro, Avelox and Proquin XR, issued a Dear Healthcare Professional letter on October 22 concerning these changes.[126] Ortho-McNeil, the manufacturers of Levaquin, issued a similar letter in November.[127] through the Health Care Notification Network, a registration-only website that distributes drug alerts to licensed healthcare professionals.

On February 25, 2011[128] an additional Black Box warning was added to all the drugs within this class, including ciprofloxacin, stating that the fluoroquinolone class may cause worsening of myasthenia gravis symptoms, including muscle weakness and breathing problems. Such an adverse reaction is a potentially life-threatening event and may require ventilatory support.

Review of the FDA website indicates that the majority of the generic versions of the fluoroquinolones have not been updated to include this Black Box Warning as of September 2009. Additionally there are numerous reports that this information has not been dessiminated to the pharmacist, the name brand products continue to contain the previous labels that are absent of this warning, and the Medication Guide has not been made available to the pharmicist or physician for distribution.

FDA warning letters

Additionally the manufacturers of ciprofloxacin (Bayer A.G.) received numerous warning letters from the United States Food and Drug Administration regarding false advertising and failure to provide adequate warnings within their promotional materials.[129][130]

Bacterial resistance

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,[131][132][133] 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 non-approved uses. As a result in recent years many bacteria have developed resistance to this drug, leaving it significantly less effective than it would have been otherwise.[134][135]

Resistance to ciprofloxacin and other fluoroquinolones may evolve rapidly, even during a course of treatment. Numerous pathogens, including Staphylococcus aureus, enterococci, and Streptococcus pyogenes now exhibit resistance worldwide.[136] Widespread veterinary usage of the fluoroquinolones, particularly in Europe, has been implicated.[137]

Fluoroquinolones had become the most commonly prescribed class of antibiotics to adults in 2002.[138] 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 that was supported in part by the Agency for Healthcare Research and Quality.[138][139] 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

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 U.S. Capitol, along with employees of American Media, Inc. in Florida and postal workers in general who alleged that they suffered serious adverse effects from taking the antibiotic ciprofloxacin (Cipro) in the aftermath of the anthrax attacks in 2001. The adverse effects included; tendon rupture, seizures, intestinal problems, tendonitis, anxiety, insomnia, muscle aches, depression and meniscus tears. The action alleged that 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 complaint further alleged that, as a result of taking Cipro, many individuals suffered severe and debilitating injuries. The action sought funding for a medical monitoring program and compensatory damages for those workers who have suffered side effects. In 2004, the law firm of Goodell, DeVries, Leech & Dann, LLP were retained as national counsel in this litigation. The class action was defeated and the litigation abandoned by the plaintiffs.[140][141][142] A similar action had been filed in New Jersey that covers New Jersey postal workers. Final disposition of that lawsuit is unknown. Following the addition of the Black Box Warning in 2008, regarding tendon damage, a significant number of product liability law firms began soliciting clients who have suffered a spontaneous tendon rupture following fluoroquinolone therapy.[143][144][145]


Brand names

Ciprofloxacin is marketed worldwide with over three hundred different brand names. In the United States, Canada, and the UK, it is marketed asBaycip, Ciloxan, Ciflox, Cipro, Cipro XR, Cipro XL, Ciproxin, Prociflor, and most recently,Proquin. It is also marketed as Ciprex in India and Russia and "Cetraxal" in Spain. 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

  • Adverse effects of fluoroquinolones
  • Fluoroquinolone toxicity
  • Quinolone

References

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  2. ^ Nelson, JM.; Chiller, TM.; Powers, JH.; Angulo, FJ. (Apr 2007). "Fluoroquinolone-resistant Campylobacter species and the withdrawal of fluoroquinolones from use in poultry: a public health success story.". Clin Infect Dis 44 (7): 977–80. doi:10.1086/512369. PMID 17342653. 
  3. ^ Kawahara, S. (Dec 1998). "[Chemotherapeutic agents under study]". Nippon Rinsho 56 (12): 3096–9. PMID 9883617. 
  4. ^ Cooper JG, Harboe K, Frost SK, Skadberg Ø, JG (April 2005). "Ciprofloxacin interacts with thyroid replacement therapy". BMJ 330 (7498): 1002. doi:10.1136/bmj.330.7498.1002. ISSN 0959-8138. PMC 557149. PMID 15860826. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=557149. 
  5. ^ http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/019537s075,020780s033lbl.pdf
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External links


v · d · eAntibacterials: nucleic acid inhibitors (J01E, J01M)
Antifolates
(inhibits
purine metabolism,
thereby inhibiting
DNA and RNA synthesis)
2,4-Diaminopyrimidine (Trimethoprim#, Brodimoprim, Tetroxoprim, Iclaprim†)
Sulfonamides
(DHPS inhibitor)
Other/ungrouped
Combinations
Topoisomerase
inhibitors/
quinolones/
(inhibits
DNA replication)
1st g.
2nd g.
Ciprofloxacin#  • Enoxacin‡ • Fleroxacin‡ • Lomefloxacin • Nadifloxacin • Ofloxacin • Norfloxacin • Pefloxacin • Rufloxacin
3rd g.
4th g.
Vet.
Related (DG)
Anaerobic DNA
inhibitors
Nitro- imidazole derivatives
Nitrofuran derivatives
RNA synthesis

M: BAC

bact (clas)

gr+f/gr+a(t)/gr-p(c)/gr-o

drug(J1p, w, n, m, vacc)
v · d · eOtologicals (S02)
Anti-infectives
Acetic acid • Aluminium acetotartrate • Boric acid • Chloramphenicol • Chlorhexidine • Ciprofloxacin • Clioquinol • Gentamicin • Hydrogen peroxide • Miconazole • Neomycin • Nitrofurazone • Ofloxacin • Polymyxin B • Rifamycin • Tetracycline
Corticosteroids
Analgesics and anesthetics

M: EAR

anat(e/p)/phys/devp

noco/cong, epon

proc, drug(S2)

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