Ofloxacin

Ofloxacin is an Antibiotic agent belonging to Fluoroquinolones

Ofloxacin is used in the treatment of community-acquired pneumonia, skin and soft tissue infections (uncomplicated), urethritis and cervicitis (nongonococcal) due to Chlamydia trachomatis infection, pelvic inflammatory disease (acute), cystitis (uncomplicated), urinary tract infections (complicated), prostatitis. It is also used to treat Epididymitis, acute; Plague (Yersinia pestis); Traveler's diarrhea.

Ofloxacin is Rapidly and well absorbed from the gastrointestinal tract. Well maintained in the tear-film after ophthalmic instillation. Bioavailability: Approx 98% (oral). It is Widely distributed into body fluids, including CSF; good penetration into tissues. Crosses the placenta and enters breast milk. Volume of distribution: 120 L. Plasma protein binding: Approx. 20-32% with limited metabolism to desmethyl and N-oxide metabolites and excreted Via urine (65-80% as unchanged drug; <5% as metabolites); faeces (4-8%). Elimination half-life was Approx. 9 hours; Biphasic: Approx. 4-5 hours and 20-25 hours.

The Tmax of Ofloxacin was achieved within 1-2 hours .Cmax was about 4.71± 2.27 μg/ml.

Ofloxacin shows common side effects like Headache, dizziness, Diarrhea, sore throat, runny nose, sneezing, joint pain, etc.

Ofloxacin is available in the form of Tablets

Ofloxacin is available in India, Germany, Canada, Italy, USA

Ofloxacin is a fluoroquinolone antibacterial which inhibits bacterial topoisomerase IV and DNA gyrase enzymes required for DNA replication, transcription, repair, transposition and recombination.

Ofloxacin is available in the form of Tablets

Administer with or without food. Do not take within 2 hours of sucralfate, didanosine, iron, zinc, or antacids containing magnesium, calcium, or aluminum.

Ofloxacin is used in the treatment of community-acquired pneumonia, skin and soft tissue infections (uncomplicated), urethritis and cervicitis (nongonococcal) due to Chlamydia trachomatis infection, pelvic inflammatory disease (acute), cystitis (uncomplicated), urinary tract infections (complicated), prostatitis. It is also used to treat Epididymitis, acute; Plague (Yersinia pestis); Traveler’s diarrhea.

Ofloxacin acts on DNA gyrase and topoisomerase IV, enzymes which, like human topoisomerase, prevents the excessive supercoiling of DNA during replication or transcription. By inhibiting their function, the drug thereby inhibits normal cell division.

Ofloxacin is approved for use in the following clinical indications

Treatment of community-acquired pneumonia, skin and soft tissue infections (uncomplicated), urethritis and cervicitis (nongonococcal) due to Chlamydia trachomatis infection, pelvic inflammatory disease (acute), cystitis (uncomplicated), urinary tract infections (complicated), prostatitis.

• Although not approved there have been certain off label use documented for Ofloxacin which includes:

Epididymitis, acute; Plague (Yersinia pestis); Traveler’s diarrhea

Ofloxacin is available in various strengths as 200 mg, 300 mg, 400 mg

Ofloxacin is available in the form of Tablets.

• Dosage Adjustment in Kidney Patient

CrCl >50 mL/minute: No dosage adjustment necessary.

CrCl 20 to 50 mL/minute: Administer usual recommended dose every 24 hours.

CrCl <20 mL/minute: Administer half the usual recommended dose every 24 hours.

Intermittent hemodialysis (IHD): 100 to 200 mg after dialysis

Peritoneal dialysis: 200 mg every 24 hours

Continuous renal replacement therapy (CRRT): 300 mg every 24 hours

• Dosage Adjustment in Hepatic impairment Patient

Mild to moderate impairment: There are no dosage adjustments provided in the manufacturer’s labeling; use with caution.

Severe impairment (eg, cirrhosis with or without ascites): Maximum dose: 400 mg/day

● Dosage Adjustment for Pediatric Patients:-

• Chlamydia trachomatis anogenital tract infection: Limited data available: Children weighing ≥45 kg and Adolescents: Oral: 300 mg twice daily for 7 days
• Epididymitis: Likely caused by enteric organisms (eg, Escherichia coli) in males who practice insertive anal sex: Children weighing ≥45 kg and Adolescents: Limited data available: Oral: 300 mg every 12 hours for 10 days in combination with ceftriaxone
• Pelvic inflammatory disease (alternative therapy): Children weighing ≥45 kg and Adolescents: Limited data available: Oral: 400 mg every 12 hours for 10 to 14 days in combination with metronidazole (CDC [Workowski 2015]; Red Book [AAP 2018]). Note: The CDC recommends use only if standard cephalosporin therapy is not feasible (patients with severe cephalosporin allergy) and community prevalence of quinolone-resistant gonococcal organisms is low. Culture and susceptibility must be confirmed, and patient follow-up should be ensured

Do not take with food; avoid tyramine- and/or histamine-containing foods. Increase dietary intake of folate, niacin, magnesium

Hypersensitivity to ofloxacin or to other quinolone antibacterial. History of tendon disorders associated with quinolone use, epilepsy or lowered seizure threshold.

Concerns related to adverse effects:

• Altered cardiac conduction: Fluoroquinolones may prolong QTc interval; avoid use in patients with a history of QTc prolongation, uncorrected hypokalemia, hypomagnesemia, or concurrent administration of other medications known to prolong the QT interval (including Class Ia and Class III antiarrhythmics, cisapride, erythromycin, antipsychotics, and tricyclic antidepressants).

• Aortic aneurysm and dissection: Fluoroquinolones have been associated with aortic aneurysm ruptures or dissection within 2 months following use, particularly in elderly patients. Fluoroquinolones should not be used in patients with a known history of aortic aneurysm or those at increased risk, including patients with peripheral atherosclerotic vascular diseases, hypertension, genetic disorders involving blood vessel changes (eg, Marfan syndrome, Ehlers-Danlos syndrome), and elderly patients, unless no other treatment options are available. Longer treatment duration (eg, >14 days) may increase risk (Lee 2018).

• CNS effects: Fluoroquinolones have been associated with an increased risk of CNS effects including seizures, increased intracranial pressure (including pseudotumor cerebri), dizziness, lightheadedness, and tremors. Use with caution in patients with known or suspected CNS disorders (eg, severe cerebral arteriosclerosis, epilepsy) or other risk factors that may predispose to seizures or lower the seizure threshold.

• Glucose regulation: Fluoroquinolones have been associated with disturbances in glucose regulation, including hyperglycemia and hypoglycemia. These events have occurred most often in patients receiving concomitant oral hypoglycemic agents or insulin. Severe cases of hypoglycemia, including coma and death, have been reported. Diabetic patients should be monitored closely for signs/symptoms of disordered glucose regulation. Discontinue if a hypoglycemic reaction occurs and immediately initiate appropriate therapy.

• Hypersensitivity reactions: Severe, sometimes fatal, hypersensitivity reactions, including anaphylaxis, have occurred with quinolone therapy. The spectrum of these reactions can vary widely; reactions may present as typical allergic symptoms (eg, itching, urticaria, rash, edema) after a single dose, or may manifest as severe idiosyncratic dermatologic (eg, Stevens-Johnson, toxic epidermal necrolysis), vascular (eg, vasculitis), pulmonary (eg, pneumonitis), renal (eg, nephritis), hepatic (eg, hepatic failure or necrosis), and/or hematologic (eg, anemia, cytopenias) events, usually after multiple doses. Prompt discontinuation of drug should occur if skin rash or other symptoms arise.

• Peripheral neuropathy: Peripheral neuropathy has been reported (rare); may occur soon after initiation of therapy and may be irreversible; discontinue if symptoms of sensory or sensorimotor neuropathy occur.

• Phototoxicity: Avoid excessive sunlight and take precautions to limit exposure (eg, loose fitting clothing, sunscreen); may cause moderate to severe phototoxicity reactions. Discontinue use if photosensitivity occurs.

• Psychiatric reactions: Fluoroquinolones have been associated with an increased risk of psychiatric reactions, including toxic psychosis or hallucinations; may also cause nervousness, agitation, confusion, disorientation, delirium, attention disturbances, and memory impairment. Use with caution in patients with a history of or risk factor for depression; discontinue if reaction occurs and institute appropriate therapy

• Superinfection: Prolonged use may result in fungal or bacterial superinfection, including C. difficile-associated diarrhea (CDAD) and pseudomembranous colitis; CDAD has been observed >2 months postantibiotic treatment.

Ofloxacin may cause liver problems, and using it with substantial quantities of ethanol may increase that risk.

Ofloxacin is present in breast milk.

● Following administration of ofloxacin as a single oral dose, breast milk concentrations were similar to those in the maternal plasma.

● Due to the potential for serious adverse reactions in the nursing infant, the manufacturer recommends a decision be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of treatment to the mother.

● Ofloxacin is used in the management of plague (Y. pestis). The risk for transmission of Y. pestis via breast milk is considered low. Patients with pneumonic plague can breastfeed if both the mother and infant are receiving antibiotic treatment or the infant is receiving postexposure prophylaxis, considering the risk of exposure to the drug via breast milk. If the infant is not being treated, breast milk should be expressed for at least 48 hours of maternal antibiotic therapy to limit person-to-person contact with the infant. The expressed breast milk may be given to the infant. Once maternal clinical improvement is observed, direct breastfeeding may resume. Patients taking ofloxacin for the treatment of plague can decrease infant exposure via breast milk by feeding 4 to 6 hours after the dose

Teratogenic Effects - Pregnancy Category C

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.

Food decreases rate, but not the extent, of absorption. Ofloxacin may increase serum caffeine levels if taken concurrently. Rarely, crystalluria may occur. Enteral feedings may decrease plasma concentrations of Ofloxacin probably by >30% inhibition of absorption. Management: May administer with most foods to minimize GI upset. If unable to avoid the following foods, administer Ofloxacin at least 2 hours before or 6 hours after dairy products or calcium-fortified juices alone or in a meal containing >800 mg calcium. Restrict caffeine intake if excessive cardiac or CNS stimulation occurs. Ensure adequate hydration during therapy. Ofloxacin should not be administered with enteral feedings. The feeding would need to be discontinued for 1 to 2 hours prior to and after Ofloxacin administration. Nasogastric administration produces a greater loss of Ofloxacin bioavailability than does nasoduodenal administration

• Common Adverse effects

Tendon rupture or tendinitis, aortic aneurysm ruptures or dissection, CNS effects (e.g. seizures, tremors, dizziness, lightheadedness, increased intracranial pressure), hyperglycemia, psychiatric reactions (e.g. hallucinations, toxic psychosis), phototoxicity.

• Less Common Adverse effects

Nasopharyngitis, cough. Skin and subcutaneous tissue disorders: Pruritus, rash. Vascular disorders: Phlebitis (IV).

• Rare Adverse effects

Peripheral neuropathy, QT interval prolongation, torsades de pointes, haemolytic reactions (G6PD deficient patients).

Increased risk of tendon rupture or inflammation with concomitant use of corticosteroids. Increased risk of QT interval prolongation with Class IA and III antiarrhythmics, TCAs, macrolides, antipsychotics. It may increase the risk of bleeding when given with vitamin K antagonists (e.g., warfarin). Reduced absorption with Mg-, Ca- or Al-containing antacids, Zn or Fe preparations, sucralfate and didanosine chewable or buffered tab. Decreased clearance with drugs that affect the renal tubular secretion (e.g., probenecid, furosemide, cimetidine, methotrexate). May slightly increase plasma levels of glibenclamide. Theophylline and NSAIDs may cause pronounced lowering of cerebral seizure threshold.

The common side effects of Ofloxacin include the following low blood sugar, headache, hunger, sweating, irritability, dizziness, nausea.

Symptoms: Dizziness, confusion, impaired consciousness, increased QT interval, convulsive seizures, nausea, mucosal erosions.

Management: Symptomatic treatment. May employ gastric lavage or administer adsorbents and Na sulfate during the 1st 30 minutes to remove any unabsorbed drug. Antacids may be given for the protection of gastric mucosa. Elimination may be increased by forced diuresis. Monitor ECG.

Pharmacodynamic

Ofloxacin is a quinolone/fluoroquinolone antibiotic. Ofloxacin is bactericidal and its mode of action depends on blocking of bacterial DNA replication by binding itself to an enzyme called DNA gyrase, which allows the untwisting required to replicate one DNA double helix into two. Notably the drug has 100 times higher affinity for bacterial DNA gyrase than for mammalian. Ofloxacin is a broad-spectrum antibiotic that is active against both Gram-positive and Gram-negative bacteria.

Pharmacokinetics

• Absorption: Rapidly and well absorbed from the gastrointestinal tract. Well maintained in the tear-film after ophthalmic instillation. Bioavailability: Approx 98% (oral). Time to peak plasma concentration: 1-2 hours.
• Distribution: Widely distributed into body fluids, including CSF; good penetration into tissues. Crosses the placenta and enters breast milk. Volume of distribution: 120 L. Plasma protein binding: Approx 20-32%.
• Metabolism: Limited metabolism to desmethyl and N-oxide metabolites.
• Excretion: Via urine (65-80% as unchanged drug; <5% as metabolites); faeces (4-8%). Elimination half-life: Approx 9 hours; Biphasic: Approx 4-5 hours and 20-25 hours.

• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1364710/
• https://reference.medscape.com/drug/colestid-Ofloxacin -342452
• https://go.drugbank.com/drugs/DB00375
• https://www.sciencedirect.com/topics/medicine-and-dentistry/Ofloxacin
• https://europepmc.org/article/med/6988203