| Ciprofloxacin Granules |
| Structure |
 |
|
| Ciprofloxacin is marketed worldwide with over three hundred different brand names. In the United States, Canada, and the UK, it is marketed as Baycip,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. 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. 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. |
| 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. |
Ciprofloxacin is not recommended for the treatment of tuberculosis. As well as in combination with other specific drugs:
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. As such the pediatric use of ciprofloxacin is restricted to proven complicated urinary tract infections and pyelonephritis due to E. coli and inhalation anthrax. Although claimed to be effective, ciprofloxacin is not to be considered a first line agent for inhalation anthrax in the pediatric population. 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). 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. 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...." 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... does not appear to have changed within these current guidelines. Antibiotics may not improve the long-term clinical outcome for sinusitis. When prescribed for chronic bronchitis and acute bacterial sinusitis, the use of the fluoroquinolone class offers no compelling advantages over established treatment. Nor does antibiotic treatment help sore throats. 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. Additionally, antibiotics have no effect upon viral infections, such as the common head cold or viral respiratory infections. Note: 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 There are only four contraindications found within the 2009 package insert
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. 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. Pediatric population Fluoroquinolones are not licensed by the U.S. FDA for use in children due to the risk of fatalities 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%. Within the BPCA Pediatric Studies Summary for ciprofloxacin, 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, 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. 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. Adverse effects 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. There have been a number of regulatory actions taken as a result of such adverse reactions, which included published warnings additional warnings and safety information added to the package inserts together with the issuance of "Dear Doctor Lettersconcerning 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. 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." 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, spontaneous tendon rupture and tendonitis, acute liver failure or serious liver injury (hepatitis), QTc prolongation/torsades de pointes toxic epidermal necrolysis (TEN), and Stevens-Johnson syndrome, severe central nervous system disorders (CNS) and Clostridium difficile associated disease (CDAD:pseudomembranous colitis), as well as photosensitivity/phototoxicity reactions. Psychotic reactions and confusional states, acute pancreatitis, bone marrow depression, interstitial nephritis andhemolytic anemia may also occur during ciprofloxacin therapy. Additional serious adverse reactions include temporary, as well as permanent, loss of vision, irreversible double vision, drug induced psychosis and chorea(involuntary muscle movements), impaired color vision, exanthema, abdominal pain, malaise, drug fever, dysaesthesiaand eosinophilia. 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. Children and the elderly are at a much greater risk of experiencing such adverse reactions. Such reactions may manifest during fluoroquinolone therapy, and long after it had been discontinued. 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. As noted previously permanent double vision (diplopia) has also been reported. An unusual case of seizures has also been reported with ciprofloxacin ear drops in an elderly patient. 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. 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. 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 certainnonsteroidal anti-inflammatory drugs. 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. Ciprofloxacin can reduce phenytoin plasma levels, which may, in some cases, result in seizures. Ciprofloxacin may interfere with the levels of thyroid medications resulting in hypothyroidism. 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." 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. 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. This is the subject of Black box warnings in FDA and BNFlabeling 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. 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. 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. 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 andcaffeine). The quinolones have also been reported to enhance the effects of warfarin or its derivatives. 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 unexplainedhypothyroidism. Altered serum levels of phenytoin (increased and decreased) have been reported in patients receiving concomitant ciprofloxacin. 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. 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. 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, 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) 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. 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.). Recent studies have demonstrated a correlation between mammalian cell cytotoxicity of the quinolones and the induction ofmicronuclei. As such, some fluoroquinolones may cause injury to the chromosome of eukaryotic cells. 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. dvkdkozj d 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. 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. 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. Biotransformation is hepatic. The elimination half life is 4 hours. |
| Bioavailability | 69% |
| Metabolism | Hepatic, including CYP1A2 |
| Half-life | 4 hours |
| Excretion | Renal |