Ofloxacin

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Ofloxacin
Ofloxacin.svg
Ofloxacin ball-and-stick.png
Systematic (IUPAC) name
(RS)-7-fluoro-2-methyl-6-(4-methylpiperazin-1-yl)-10-oxo-4-oxa-1-azatricyclo[7.3.1.05,13]trideca-5(13),6,8,11-tetraene-11-carboxylic acid
Clinical data
Trade namesFloxin, Ocuflox
AHFS/Drugs.commonograph
MedlinePlusa691005
Pregnancy cat.C (US)
Legal status-only (US)
RoutesOral, IV, topical (eye drops and ear drops)
Pharmacokinetic data
Bioavailability85% - 95%
Protein binding32%
Half-life8–9 hours
Identifiers
CAS number82419-36-1 YesY
ATC codeJ01MA01 ,S01AE01, S02AA16
PubChemCID 4583
DrugBankDB01165
ChemSpider4422 YesY
UNIIA4P49JAZ9H YesY
KEGGD00453 YesY
ChEBICHEBI:7731 YesY
ChEMBLCHEMBL4 YesY
Synonyms(±)-9-fluoro-2,3-dihydro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid
Chemical data
FormulaC18H20FN3O4 
Mol. mass361.368 g/mol
 YesY (what is this?)  (verify)
 
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Ofloxacin
Ofloxacin.svg
Ofloxacin ball-and-stick.png
Systematic (IUPAC) name
(RS)-7-fluoro-2-methyl-6-(4-methylpiperazin-1-yl)-10-oxo-4-oxa-1-azatricyclo[7.3.1.05,13]trideca-5(13),6,8,11-tetraene-11-carboxylic acid
Clinical data
Trade namesFloxin, Ocuflox
AHFS/Drugs.commonograph
MedlinePlusa691005
Pregnancy cat.C (US)
Legal status-only (US)
RoutesOral, IV, topical (eye drops and ear drops)
Pharmacokinetic data
Bioavailability85% - 95%
Protein binding32%
Half-life8–9 hours
Identifiers
CAS number82419-36-1 YesY
ATC codeJ01MA01 ,S01AE01, S02AA16
PubChemCID 4583
DrugBankDB01165
ChemSpider4422 YesY
UNIIA4P49JAZ9H YesY
KEGGD00453 YesY
ChEBICHEBI:7731 YesY
ChEMBLCHEMBL4 YesY
Synonyms(±)-9-fluoro-2,3-dihydro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid
Chemical data
FormulaC18H20FN3O4 
Mol. mass361.368 g/mol
 YesY (what is this?)  (verify)

Ofloxacin is a synthetic antibiotic of the fluoroquinolone drug class considered to be a second-generation fluoroquinolone.[1][2] 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 and marketed as Optiflox, eylox respectively in Jordan and Saudi Arabia[3]).

Ofloxacin is a racemic mixture, which consists of 50% levofloxacin (the biologically active component) and 50% of its “mirror image” or enantiomer dextrofloxacin.[4]

Ofloxacin has been associated with adverse drug reactions, such as tendon damage (including spontaneous tendon ruptures) and peripheral neuropathy (which may be irreversible); tendon damange may manifest long after therapy had been completed, and, in severe cases, may result in lifelong disabilities.[5]

History[edit]

Ofloxacin was developed as a broader-spectrum analog of norfloxacin, the first fluoroquinolone antibiotic,[6] Ofloxacin was first patented in 1982 (European Patent Daiichi) and received U.S. Food and Drug Administration (FDA) approval December 28, 1990.

In the United States name branded ofloxacin is rarely used anymore, having been discontinued by the manufacturer, Ortho-McNeil-Janssen, a subsidiary of Johnson & Johnson.[7] Johnson and Johnson's annual sales of Floxin in 2003 was approximately $30 million, whereas their combined sales of Levaquin/Floxin exceeded $ 1.15 billion in the same year.[8][9] However generic use continues. The FDA website lists Floxin (Ortho McNeil Jannsen) as being discontinued, with just a few generic equivalents still in use. The otic solution continues to be listed as being available both as an original drug as well as a generic equivalent.

Medical uses[edit]

In the in the U.S. ofloxacin is approved for the treatment of bacterial infections such as:

Ofloxacin has not been shown to be effective in the treatment of syphilis.[10] Floxin is no longer considered a first line treatment for gonnorrhea due to bacterial resistance.[11]

Available forms[edit]

Ofloxacin for systemic use is available as tablet (multiple strengths), oral solution (250 mg/mL), and injectable solution (multiple strengths). It is also used as eye drops and ear drops. It is also available in combination with ornidazole.

Mode of action[edit]

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,[12] which is an enzyme necessary to separate (mostly in prokaryotes, in bacteria in particular) replicated DNA, thereby inhibiting bacterial cell division.

Contraindications[edit]

As noted above, under licensed use, ofloxacin is now considered to be contraindicated for the treatment of certain sexually transmitted diseases by some experts due to bacterial resistance.[11]

Due to growing prevalence of antibiotic resistance to the fluoroquinolones in southeast Asia, the use of ofloxacin in patients who have been to southeast Asia is increasingly being contraindicated.[13]

Caution in patients with liver disease.[14] The excretion of ofloxacin may be reduced in patients with severe liver function disorders (e.g., cirrhosis with or without ascites).

Ofloxacin is also considered to be contraindicated within the pediatric population, pregnancy, nursing mothers, patients with psychiatric illnesses and in patients with epilepsy or other seizure disorders.

Pregnancy[edit]

[15][16]

Ofloxacin has not been shown to have any teratogenic effects at oral doses as high as 810 mg/kg/day (11 times the recommended maximum human dose based on mg/m2 or 50 times based on mg/kg) and 160 mg/kg/day (4 times the recommended maximum human dose based on mg/m2 or 10 times based on mg/kg) when administered to pregnant rats and rabbits, respectively. Additional studies in rats with oral doses up to 360 mg/kg/day (5 times the recommended maximum human dose based on mg/m2 or 23 times based on mg/kg) demonstrated no adverse effect on late fetal development, labor, delivery, lactation, neonatal viability, or growth of the newborn. Doses equivalent to 50 and 10 times the recommended maximum human dose of ofloxacin (based on mg/kg) were fetotoxic (i.e., decreased fetal body weight and increased fetal mortality) in rats and rabbits, respectively. Minor skeletal variations were reported in rats receiving doses of 810 mg/kg/day, which is more than 10 times higher than the recommended maximum human dose based on mg/m2. There are, however, no adequate and well-controlled studies in pregnant women. Ofloxacin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.[17]

Pediatric use[edit]

Oral and intravenous ofloxacin are not licensed for use in children, except as noted above, due to the risk of musculoskeletal injury. In one study,[18][19] 1534 juvenile patients (age 6 months to 16 years) treated with levofloxacin as part of three efficacy trials were followed up to assess all musculoskeletal events occurring up to 12 months post-treatment. At 12 months follow-up the cumulative incidence of musculoskeletal adverse events was 3.4%, compared to 1.8% among 893 patients treated with other antibiotics. In the levafloxacin-treated group, approximately two-thirds of these musculoskeletal adverse events occurred in the first 60 days, 86% were mild, 17% were moderate, and all resolved without long-term sequelae.

In a study comparing the safety and efficacy of levofloxacin to that of azithromycin or the ceftriaxone in 712 children with community-acquired pneumonia, adverse events were experienced by 6% of those treated with levofloxacin and 4% of those treated with comparator antibiotics. Most of these adverse events were thought to be unrelated or doubtfully related to the levofloxacin. Two deaths were observed in the levofloxacin group, neither of which was thought to be treatment-related. Spontaneous reports to the FDA Adverse Effects Reporting System at the time of the 20 September 2011 FDA Pediatric Drugs Advisory Committee include musculoskeletal events (39, including 5 cases of tendon rupture) and central nervous system events (19, including 5 cases of seizures) as the most common spontaneous reports between April 2005 and March 2008. An estimated 130,000 pediatric prescriptions for levofloxacin were filled on behalf of 112,000 pediatric patients during that period.[20]

Adverse effects[edit]

In general, fluoroquinolones are well tolerated, with most side-effects being mild to moderate.[21] On occasion, serious adverse effects occur.[22] Common side-effects include gastrointestinal effects such as nausea, vomiting, and diarrhea, as well as headache and insomnia.

The overall rate of adverse events in patients treated with fluoroquinolones is roughly similar to that seen in patients treated with other antibiotic classes.[23][24][25][26] A U.S. Centers for Disease Control study found patients treated with fluoroquinolones experienced adverse events severe enough to lead to an emergency department visit more frequently than those treated with cephalosporins or macrolides, but less frequently than those treated with penicillins, clindamycin, sulfonamides, or vancomycin.[27]

Post-marketing surveillance has revealed a variety of relatively rare but serious adverse effects that are associated with all members of the fluoroquinolone antibacterial class. Among these, tendon problems and exacerbation of the symptoms of the neurological disorder myasthenia gravis are the subject of "black box" warnings in the United States. The most severe form of tendonopathy associated with fluoroquinolone administration is tendon rupture, which in the great majority of cases involves the Achilles tendon. Younger people typically experience good recovery, but permanent disability is possible, and is more likely in older patients.[28] The overall frequency of fluoroquinolone-associated Achilles tendon rupture in patients treated with ciprofloxacin or levofloxacin is has been estimated at 17 per 100,000 treatments.[29][30] Risk is substantially elevated in the elderly and in those with recent exposure to topical or systemic corticosteroid therapy. Simultaneous use of corticosteroids is present in almost one-third of quinolone-associated tendon rupture.[31] Tendon damage may manifest during, as well as up to a year after fluoroquinolone therapy has been completed.[32]

FQs prolong the QT interval by blocking voltage-gated potassium channels.[33] Prolongation of the QT interval can lead to torsades de pointes, a life-threatening arrhythmia, but in practice this appears relatively uncommon in part because the most widely prescribed fluoroquinolones (ciprofloxacin and levofloxacin) only minimally prolong the QT interval.[34]

Clostridium difficile-associated diarrhea may occur in connection with the use of any antibacterial drug, especially those with a broad spectrum of activity such as clindamycin, cephalosporins, and fluoroquinolones. Fluoroquinoline treatment is associated with risk that is simlar to[35] or less [36][37] than that associated with broad spectrum cephalosporins. Fluoroquinoline administration may be associated with the acquisition and outgrowth of a particularly virulent Clostridium strain.[38]

The U.S. prescribing information contains a warning regarding uncommon cases of peripheral neuropathy, which can be permanent.[39] Other nervous system effects include insomnia, restlessness, and rarely, seizure, convulsions, and psychosis[40] Other rare and serious adverse events have been observed with varying degrees of evidence for causation.[41][42][43][44]

Events that may occur in acute overdose are rare, and include renal failure and seizure.[45] Susceptible groups of patients, such as children and the elderly, are at greater risk of adverse reactions during therapeutic use.[21][46][47]

Ofloxacin, like some other fluoroquinolones, may inhibit drug metabolizing enzymes and thereby increase blood levels of other drugs such as cyclosporine, theophyline, and warfarin, among others. These increased blood levels may result in a greater risk of side effects.

Careful monitoring of serum glucose is advised when ofloxacin or other fluorquinolones are used by people who are taking sulfonylurea anti-diabetes drugs.

The concomitant administration of a non-steroidal anti-inflammatory drug with a quinolone, including ofloxacin, may increase the risk of CNS stimulation and convulsive seizures.

The fluoroquinolones have been shown to increase the anticoagulant effect of Acenocoumarol, Anisindione, and Dicumarol. Additionally there is an increase the risk of cardiotoxicity and arrhythmias when co administered with drugs such as Dihydroquinidine barbiturate, Quinidine, and Quinidine barbiturate.[48]

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.[49]

Overdose[edit]

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.[10] Overdose may result in central nervous system toxicity, cardiovascular toxicity, tendon/articular toxicity, and hepatic toxicity[45] as well as renal failure and seizure.[45] Seizures have however, been reported to occur at therapeutic dosage as well as severe psychiatric reactions.[50][51][52]

Pharmacology[edit]

The bioavailability of ofloxacin in the tablet form is approximately 98% following oral administration reaching maximum serum concentrations within one to two hours. Between 65% and 80% of an administered oral dose of ofloxacin is excreted unchanged via the kidneys within 48 hours of dosing. Therefore elimination is mainly by renal excretion. However, four to eight percent of an ofloxacin dose is excreted in the feces. This would indicate a small degree of biliary excretion as well. Plasma elimination half-life is approximately 4 to 5 hours in patients and approximately 6.4 to 7.4 hours in elderly patients.[10]

Pharmacokinetics[edit]

"After multiple-dose administration of 200 mg and 300 mg doses, peak serum levels of 2.2 μg/mL and 3.6 μg/mL, respectively, are predicted at steady-state. In vitro, approximately 32% of the drug in plasma is protein bound. Floxin is widely distributed to body tissues. Ofloxacin has been detected in blister fluid, cervix, lung tissue, ovary, prostatic fluid, prostatic tissue, skin, and sputum. Pyridobenzoxazine ring appears to decrease the extent of parent compound metabolism. Less than 5% is eliminated by the kidneys as desmethyl or N-oxide metabolites; 4% to 8% by feces."[10][53]

There are a number of the endogenous compounds that have been reported to be affected by ofloxacin as inhibitors, alteraters and depletors. See the latest package insert for Ofloxacin for additional details.[10]

Dosage[edit]

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.[10]

Susceptible bacteria[edit]

According to the product packing insert, ofloxacin is effective against the following microorganisms. Aerobic Gram-positive microorganisms:

Aerobic Gram-negative microorganisms

Other microorganisms:

History of the black box warnings[edit]

Musculoskeletal disorders attributed to use of quinolone antibiotics were first reported in the medical literature in 1972, as an adverse reaction to nalidixic acid.[54] Rheumatic disease after use of a fluoroquinolone (norfloxacin) was first reported eleven years later.[55] In 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."[56]

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.[57] 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.[58]

In 2005, the Illinois Attorney General filed a petition with the FDA 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, though they had been reviewing this issue since 1995.[59] In 2006, Public Citizen, supported by the Illinois Attorney General, renewed its demand of ten years prior for a Black Box Warning.[59][60] In January 2008, Public Citizen filed suit in Federal Court to compel the FDA to respond to their 2006 petition.[61][62] On July 7, 2008 the FDA requested that the makers of systemic-use fluoroquinolones add a boxed warning regarding tendon rupture, and to develop a Medication Guide for patients.[63] 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.[64][65] Bayer, which manufactures Cipro, Avelox and Proquin XR, issued a Dear Healthcare Professional letter on October 22, 2008 concerning these changes.[66]

Antibiotic abuse and bacterial resistance[edit]

Resistance to ofloxacin 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.[67]

floxacin and other fluoroquinolones had become the most commonly prescribed class of antibiotics to adults in 2002. Nearly half (42%) of these 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.[68][69] Additionally they are commonly prescribed for medical conditions that are not even bacterial to begin with, such as viral infections, or those to which no proven benefit exists.

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