Ofloxacin

Mechanism of Action

As with other second-generation fluoroquinolone drugs, ofloxacin is a broad-spectrum antimicrobial that exhibits a bactericidal effect. It works by binding to and inhibiting bacterial topoisomerase II (DNA gyrase), an enzyme that relaxes supercoiled DNA, and topoisomerase IV, an enzyme that separates linked daughter chromosomes following replication. These inhibitory effects interrupt DNA replication, transcription, and repair, thereby preventing cell division in bacterial cells.[6] In addition, fluoroquinolones are bactericidal and are concentrated intracellularly, resulting in rapid intracellular killing. 

Mechanism of Resistance

• Chromosome-encoded mutation in DNA gyrase
• Plasmid-mediated resistance, efflux pumps[7]

Pharmacokinetics

Absorption: After oral administration, the bioavailability of the ofloxacin tablet is approximately 98%. Maximum serum concentrations (Cmax) are achieved one to two hours after an oral dose.[8]

Distribution: In vitro, approximately 32% of the drug in plasma is protein bound. After oral administration of recommended therapeutic doses, ofloxacin has been detected in lung tissue, blister fluid, cervix, ovary, prostatic fluid, prostatic tissue, sputum, and skin.

Metabolism: Ofloxacin has a pyridobenzoxazine ring that appears to decrease the extent of parent compound metabolism.

Excretion: Ofloxacin has biphasic elimination. Between 65% to 80% of an administered oral dose of ofloxacin is excreted unchanged via the kidneys within 48 hours of dosing. In addition, studies indicate that 4% to 8% percent of an ofloxacin dose is excreted in the feces indicating a small degree of biliary excretion of ofloxacin.

Administration

Dosage Formulations

• Oral:Ofloxacin tablets 200 mg, 300 mg,400 mg
• Topical: Ofloxacin Ophthalmic Solution USP 0.3% is used
• Topical: Ofloxacin Otic Solution USP, 0.3%

General infections receive oral or intravenous ofloxacin. In severe infection, intravenous administration is preferable as it allows higher dosing, leading to higher drug concentrations, ultimately increasing clinical cure rates.[9] Topical preparations exist for specific cases. For otitis externa and otitis media, patients have treatment with an ofloxacin otic drop solution. Topical ofloxacin penetrates the tympanic membrane, achieving similar middle ear concentrations through topical or systemic administration.[10] Patients can receive an ofloxacin ophthalmic drop solution for bacterial conjunctivitis and corneal ulcers. An animal study demonstrated that topical ofloxacin permeates the cornea, achieving therapeutic concentrations in the anterior and posterior chambers of the eye while sparing the retina from any toxic effects.[11]

Use in Specific Patient Population

Renal Impairment: Clearance of ofloxacin is reduced in patients with impaired renal function (creatinine clearance rate ≤50 mL/min), and dosage adjustment is required.

Hepatic Impairment: No dosage adjustments are provided in the manufacturer's labeling; use caution. Administer ofloxacin with caution in patients with hepatic insufficiency and /or impairment.

Pregnancy Considerations: Contraindicated during pregnancy or breastfeeding and in children < 18 years old due to possible damage to the cartilage. Based on available data, an increased risk of teratogenic effects has not been observed following ofloxacin use during pregnancy, and literature is conflicting regarding their safety in humans. Ofloxacin should be used for pregnant women only if the potential benefit outweighs the potential risk to the fetus. Alternative antibiotics should be preferred till more safety data is available. (FDA Pregnancy Category C).[12]

Breastfeeding Considerations: Ofloxacin is distributed in breastmilk at low levels. Fluoroquinolones have traditionally not been used in infants because of concern about adverse effects on the infants' developing joints. However, recent studies indicate little risk. The calcium in milk might prevent the absorption of small amounts of fluoroquinolones. Insufficient data exist to prove or disprove this assertion. Developmental problems have been reported in two infants exposed to ofloxacin in breastmilk, but their mothers were also exposed to several drugs during the peripartum period; hence the adverse drug reaction cannot necessarily be attributed to ofloxacin. The use of ofloxacin is permitted in nursing mothers with monitoring of the infant for potential effects on the gut flora, such as diarrhea or candidiasis (thrush, diaper rash).

Avoiding breastfeeding for 4 to 6 hours after a dose should decrease the infant's exposure to ofloxacin in breastmilk. Maternal use of an ear drop or eye drop that contains ofloxacin presents a negligible risk for the nursing infant. To substantially decrease the amount of drug that reaches the breastmilk after eye drops, apply pressure over the tear duct by the corner of the eye for one minute and remove the leftover solution with an absorbent tissue. A literature search reveals that ofloxacin was used to treat two pregnant women with MDR tuberculosis. Subsequently, the children had normal development except for a mild speech delay and hyperactivity in the other.[13]

Adverse Effects

Tendinopathy: The most characteristic adverse effect of ofloxacin treatment and other fluoroquinolone treatments is tendinopathy, typically presenting as pain or swelling along a tendon’s path. Such injury has been observed both during drug administration and several months after. In addition, there is a particularly high risk of tendon rupture in patients receiving corticosteroid therapy or engaging in strenuous physical activity with concurrent ofloxacin administration. This injury primarily affects the Achilles tendon and necessitates surgical repair.  

Central Nervous System ADRs: It is also possible for ofloxacin treatment to cause increased intracranial pressure and psychosis.[14] As ofloxacin may stimulate the central nervous system, neurological effects such as seizures, lightheadedness, hallucinations, restlessness, tremors, anxiety, depression, confusion, difficulty sleeping, nightmares, paranoia, or suicidal thoughts or acts occur. These effects may develop after as little as one dose and call for immediate termination of treatment. Caution is necessary when considering therapy for patients with preexisting conditions or risk factors predisposing to seizures or other CNS effects. 

Hypersensitivity reactions: Hypersensitivity reactions are another adverse effect occasionally observed with ofloxacin treatment, most frequently following the initial dose. This Type I hypersensitivity reaction results from some patients performing serum IgE against ofloxacin. Reported signs of a hypersensitivity reaction include seizure, cardiovascular collapse, shock, loss of consciousness, airway obstruction, dyspnea, tingling, angioedema, urticaria, itching, and other allergic skin manifestations. 

On a rare occasion and following multiple doses, other serious and sometimes fatal hypersensitivity-associated events have been observed, involving fever, rash, severe dermatologic reactions, vasculitis, serum sickness, arthralgia, myalgia, allergic pneumonitis, interstitial nephritis, acute renal insufficiency or failure, acute hepatic necrosis or failure, hepatitis, jaundice, hemolytic or aplastic anemia, thrombocytopenia, leukopenia, agranulocytosis, pancytopenia, and other hematologic disorders. As with other hypersensitivity reactions, the earliest indication of these clinical manifestations calls for immediate treatment discontinuation.[15]

Peripheral Neuropathy: Though uncommon, ofloxacin treatment has also led to reports of peripheral neuropathy, as manifested by pain, burning, tingling, numbness, weakness, and altered sensation. Exacerbation of muscle weakness in a patient with myasthenia gravis is a dangerous possibility. The earliest indication of these clinical manifestations calls for immediate discontinuation of treatment. 

Hepatotoxicity: The severity of the ofloxacin-induced liver injury ranges from mild and transient serum enzyme elevations to self-limited jaundice to acute liver failure. Recovery is usually rapid (2 to 8 weeks) after stopping the medication. Cross-reactivity between different fluoroquinolones has not been well defined but is presumed based on the similarity of injury and clinical patterns. Thus, patients should avoid further exposure to fluoroquinolones, particularly levofloxacin, the isomer of ofloxacin.[16]

Dysglycemia: Fluoroquinolones have been associated with symptomatic hyperglycemia and hypoglycemia, usually in diabetic patients getting concomitant treatment with an oral hypoglycemic agent or with insulin. In these patients, meticulous monitoring of blood glucose is recommended.[17]

Aortic Aneurysm: Other rare and serious adverse effects include prolonging the QTc interval and aortic aneurysms.[18]

Contraindications

Ofloxacin use is contraindicated in patients with a history of quinolone-associated hypersensitivity reactions, myasthenia gravis, and prolonged QTc interval. Unless there is no other option, it is also contraindicated in patients with a history of or at increased risk for aortic aneurysm, Marfan syndrome, or Ehlers-Danlos syndrome.

US Boxed Warning

Fluoroquinolones, including ofloxacin, have been associated with potentially irreversible serious adverse reactions that have occurred together, including:

• Tendinitis and tendon rupture
• Peripheral neuropathy
• Central nervous system effects 
• Exacerbation of Myasthenia Gravis[19]

Monitoring

Ofloxacin is regarded as a safe drug with a considerable safety margin.[20][21] Tests are recommended for patients with an increased risk of adverse effects or in cases with a long treatment course.

Monitoring parameters include:

• Serum plasma creatinine concentrations
• Liver function tests
• Serum glucose levels in diabetic patients[17]
• EKG monitoring for ofloxacin-induced QTc prolongation, although the risk is low for ofloxacin compared to other fluoroquinolones.[22]

Toxicity

Information on toxicity with ofloxacin is limited. One case report of accidental overdosage has been described in which an adult female received 3 grams of ofloxacin intravenously over 45 minutes. The patient developed dizziness, hot and cold flushes, drowsiness, nausea, slurring of speech, and mild to moderate disorientation during the infusion. Laboratory testing detected no clinically significant changes in routine parameters in this patient. 

In overdose cases, gastric lavage and sufficient hydration are the recommended interventions. Unfortunately, no antidotes exist, and dialysis treatments are ineffective in reversing toxicity.[21] Activated charcoal may decrease ofloxacin absorption and reduce the likelihood of systemic toxicity if orally ingested.[23]

Enhancing Healthcare Team Outcomes

Many severe adverse effects of ofloxacin treatment are avoidable by supporting patients with diverse interprofessional teams of healthcare providers. A nurse or clinician (MD, DO, NP, or PA) taking the patient's history may identify patients at high risk due to previous hypersensitivity reactions, tendon disorders, cardiovascular disorders, Marfan syndrome, Ehlers-Danlos syndrome, or risk factors that lower the seizure threshold. Pharmacists may notice red flags for patients already taking corticosteroids, antiarrhythmics, or CNS medications whose adverse effects would be compounded by ofloxacin treatment.

In these cases, the patients benefit from proactive interprofessional teams capable of working together to devise alternative drug treatment plans or ensure proper monitoring to ensure successful treatment and avoid adverse effects. The pharmacist should assist the team by verifying dosing, and in severe cases, an infectious disease board-certified pharmacist can provide antibiogram data to direct agent selection. Nursing can monitor for adverse events and treatment effectiveness. All interprofessional team members must document any changes in the patient's status immediately in the permanent health record, so all team members have access to the same patient data and reach out to other team members as appropriate so therapeutic changes can occur, if necessary. This type of interprofessional team paradigm enhances positive results while minimizing adverse effects. [Level 5]