Ofloxacin is a synthetic chemotherapeutic antibiotic of the fluoroquinolone drug class considered to be a second-generation fluoroquinolone. The original brand, Floxin, has been discontinued by the manufacturer in the United States on 18 June 2009, though generic equivalents continue to be available.Ofloxacin was first patented in 1982 (European Patent Daiichi) and received approval from the U.S. Food and Drug Administration (FDA) on December 28, 1990. Ofloxacin is sold under a wide variety of brand names as well as generic drug equivalents, for oral and intravenous administration. Ofloxacin is also available for topical use, as eye drops and ear drops (marketed as Ocuflox and Floxin Otic respectively in the United States).
Ofloxacin is a racemic mixture, which consists of 50% levofloxacin (the biologically active component) and 50% of its “mirror image” or enantiomer dextrofloxacin. When levofloxacin disks were not available in early clinical trials, a 5-pg ofloxacin disk was substituted. The U.S. Food and Drug Administration (FDA) medical reviewers considered the two drugs to be one and the same and hence interchangeable.
Like other quinolones, ofloxacin has been associated with a significant number of serious adverse drug reactions, such as tendon damage (including spontaneous tendon ruptures) and peripheral neuropathy (which may be irreversible); such reactions may manifest long after therapy had been completed, and, in severe cases, may result in life-long disabilities. Ofloxacin has also been associated with severe psychiatric adverse reactions.
Hepatotoxicity has also been reported with the use of ofloxacin. Case reports of hepatitis have been published for the older fluoroquinolones including ciprofloxacin, ofloxacin, and norfloxacin.
Oral and I.V. Floxin is not licensed by the FDA for use in children due to the risk of serious reversible and irreversible injury to the musculoskeletal system. Other fluoroquinolones do have a limited licensed uses in children but are generally not recommended due to safety concerns. Ofloxacin (and its derivatives) has also been associated with a few isolated reports of unexplained pediatric fatalities. Children (those under 18) are also at an increased risk of bone, joint, or tendon toxicities.
Prescribing ofloxacin in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of severe adverse drug reactions.
In the adult population ofloxacin is limited to the treatment of proven serious and life threatening bacterial infections such as:
- Acute bacterial exacerbations of chronic bronchitis
- Community-acquired pneumonia
- Uncomplicated skin and skin structure infections
- Nongonococcal urethritis and cervicitis
- Mixed Infections of the urethra and cervix
- Acute pelvic inflammatory disease
- Uncomplicated cystitis
- Complicated urinary tract infections
- Prostatitis
- Acute, uncomplicated urethral and cervical gonorrhea.
Ofloxacin for systemic use is available as tablets (multiple strengths), oral solution (250 mg/ml), and injectable solution (multiple strengths). It is also used as eye drops (trade name Exocin, known as Ocuflox in the United States) and ear drops (Floxin Otic).
Ofloxacin is also used in animals. Its veterinary formulation is sold as Marfloxacin (not to be confused with marbofloxacin, another veterinary-use fluoroquinolone).Action Of Ofloxacin
Ofloxacin is a broad-spectrum antibiotic that is active against both Gram-positive and Gram-negative bacteria. It functions by inhibiting DNA gyrase, a type II topoisomerase, and topoisomerase IV, which is an enzyme necessary to separate replicated DNA, thereby inhibiting cell division.
The fluoroquinolones interfere with DNA replication by inhibiting an enzyme complex called DNA gyrase. This can also affect mammalian cell replication. In particular, some congeners of this drug family 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 the quinolone is highly toxic to mammalian cells in culture, its mechanism of cytotoxic action is not known. Quinolone induced DNA damage was first reported in 1986.
Recent studies have demonstrated a correlation between mammalian cell cytotoxicity of the quinolones and the induction of micronuclei. As such some fluoroquinolones may cause injury to the chromosome of eukaryotic cells.
There is debate as to whether or not this DNA damage is to be considered one of the mechanisms of action concerning the severe and non abating adverse reactions experienced by some patients following fluoroquinolone therapy.
Adverse effects
Serious adverse events occur more commonly with fluoroquinolones than with any other antibiotic drug classes. There has been a number of regulatory actions taken as a result of such adverse reactions associated with ofloxacin therapy, which included published warnings, additional warnings and safety information added to the package inserts which includes a black box warning concerning spontaneous tendon ruptures and the resultant permanent disability. In 2008 the FDA had also requested that the manufacturers of Floxin (as well as generic ofloxacin) issue a "Dear Doctor Letter" to inform physicians of this black box warning.In 2004 the FDA requested new warning labels to be added to all of the fluoroquinolones, including ofloxacin, regarding peripheral neuropathy (irreversible nerve damage), tendon damage, heart problems (prolonged QT interval / torsades de pointes), pseudomembranous colitis, rhabdomyolysis (muscle wasting), Stevens–Johnson syndrome, as well as concurrent usage of NSAIDs contributing to the severity of these reactions. Subsequently changes were made to the package insert for Floxin to state that Floxin should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria, and additional warnings concerning irreversible peripheral neuropathy and Torsades de pointes being associated with floxin therapy were added. In 2007 warnings regarding fatal Clostridium difficile associated diarrhea (CDAD: reported to occur over two months after the administration), severe photosensitivity/phototoxicity reactions and hepatic failure (including fatal cases) and Toxic Epidermal Necrolysis (TEN) were added to the package inserts.
The psychiatric adverse events, as well as central nervous system and peripheral nervous system associated with ofloxacin has been well documented within the literature.
Adverse reactions may manifest during, as well as after fluoroquinolone therapy.
Liver damage and dysglycemia has been associated with ofloxacin. Additionally in 2005 acute rhabdomyolysis had been associated with ofloxacin/levofloxacin therapy.
Some groups refer to the presentation of these multiple adverse events as "fluoroquinolone toxicity". These groups of patients claim to have suffered serious long term harm to their health from using fluoroquinolones. This has led to a class action lawsuit being filed by these groups as well as action by the consumer advocate group Public Citizen .Partly as a result of the efforts of Public Citizen the FDA requested a Black Box Warnings on all fluoroquinolones advising consumers of the possible toxic effects of fluoroquinolones on tendons.
Severe hepatotoxicity has been reported as noted above. Reports of hepatic or hypersensitivity vasculitis occurring as a result of ofloxacin therapy have also been reported. Older patients may have an increased risk of tendinopathy (including rupture), especially with concomitant corticosteroid use and such patients may also be more susceptible to prolongation of the QT interval. Patients with known prolongation, those with hypokalemia, or being treated with other drugs that prolong the QT interval should avoid the use of ofloxacin. Hematologic reactions (including agranulocytosis, thrombocytopenia), and renal toxicities may occur after multiple doses.
Tendon damage
As with all fluoroquinolones, there is a possibility of spontaneous tendon rupture. Such ruptures may occur both during therapy and long after therapy has been discontinued; there are documented cases where rupture has occurred six months after therapy. The risk of tendon damage is greater in people taking corticosteroids and in the elderly. Since July 2008, all systemic fluoroquinolones (those taken internally, not as eye drops or ear drops) available in the United States were requested, by the FDA, to carry a black box warning of the risk of tendon damage. However, the addition of this warning was not mandatory.Overdose
There is only limited information on overdose with ofloxacin. Current advise for the management of an acute overdose of ofloxacin is emptying of the stomach, along with close observation, and making sure that the patient is appropriately hydrated. Hemodialysis or peritoneal dialysis is of only limited effectiveness. Overdose may result in central nervous system toxicity, cardiovascular toxicity, tendon/articular toxicity, and hepatic toxicity as well as renal failure and seizure. Seizures have however, been reported to occur at therapeutic dosage as well as severe psychiatric reactionsDosage
Ofloxacin should only be administered as described within the Dosage Guidelines table found within the most current package insert. 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 a fatal drug overdose. Ofloxacin is eliminated primarily by renal excretion. However, the drug is also metabolized and partially cleared through the liver. Modification of the dosage is required using the table found within the package insert for those with impaired liver or kidney function (Particularly for patients with severe renal dysfunction). 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 the usual duration is 7 to 14 days.NOTE: The patient’s serum levels should be monitored during therapy to avoid a drug overdose. See the most current Package Insert for proper dosing guidelines and relevant warnings/precautions.
