Levofloxacin

Levofloxacin is an Antibiotic agent belonging to Fluoroquinolones

Levofloxacin is used in the treatment of community-acquired pneumonia, including multidrug-resistant strains of Streptococcus pneumoniae (MDRSP); nosocomial pneumonia; chronic obstructive pulmonary disease, acute exacerbation; rhinosinusitis, acute bacterial (ABRS); prostatitis (chronic bacterial); urinary tract infection (uncomplicated or complicated); acute pyelonephritis; skin or skin structure infections (uncomplicated or complicated); inhalational anthrax (postexposure) to reduce incidence or disease progression; prophylaxis and treatment of plague due to Yersinia pestis. It is also used to treat Anthrax; Bite wound infection, prophylaxis or treatment (animal or human bite); Cervicitis or urethritis due to Chlamydia trachomatis infection; Diabetic foot infection; Epididymitis, acute; Helicobacter pylori eradication; Intra-abdominal infection, mild to moderate, community-acquired in patients without risk factors for resistance or treatment failure; Neutropenia (chemotherapy-induced), antibacterial prophylaxis; Odontogenic soft tissue infection, pyogenic; Osteomyelitis; Pelvic inflammatory disease; Prostatitis (acute bacterial); Prosthetic joint infection; Salmonella (nontyphoidal) infection; Shigella infection; Surgical (preoperative) prophylaxis; Surgical site incisional infection; Tuberculosis.

The Tmax of Levofloxacin was achieved within 1-2 hours .Cmax was about 2.8 and 5.2 mg/L

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

Levofloxacin is available in the form of Tablets, Oral solution and Injection Solution.

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

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

Levofloxacin is available in the form of Oral Solution, Tablets and Injection.

Oral: Tablets may be administered without regard to meals. Oral solution should be administered at least 1 hour before or 2 hours after meals. Maintain adequate hydration of patient to prevent crystalluria. Administer at least 2 hours before or 2 hours after antacids containing magnesium or aluminum, sucralfate, metal cations (eg, iron), multivitamin preparations with zinc, or didanosine chewable/buffered tablets or the pediatric powder for solution.

IV: Infuse 250 to 500 mg IV solution over 60 minutes; infuse 750 mg IV solution over 90 minutes. Too rapid of infusion can lead to hypotension. Avoid administration through an intravenous line with a solution containing multivalent cations (eg, magnesium, calcium). Maintain adequate hydration of patient to prevent crystalluria or cylindruria.

Levofloxacin is used in the treatment of community-acquired pneumonia, including multidrug-resistant strains of Streptococcus pneumoniae (MDRSP); nosocomial pneumonia; chronic obstructive pulmonary disease, acute exacerbation; rhinosinusitis, acute bacterial (ABRS); prostatitis (chronic bacterial); urinary tract infection (uncomplicated or complicated); acute pyelonephritis; skin or skin structure infections (uncomplicated or complicated); inhalational anthrax (postexposure) to reduce incidence or disease progression; prophylaxis and treatment of plague due to Yersinia pestis. It is also used to treat Anthrax; Bite wound infection, prophylaxis or treatment (animal or human bite); Cervicitis or urethritis due to Chlamydia trachomatis infection; Diabetic foot infection; Epididymitis, acute; Helicobacter pylori eradication; Intra-abdominal infection, mild to moderate, community-acquired in patients without risk factors for resistance or treatment failure; Neutropenia (chemotherapy-induced), antibacterial prophylaxis; Odontogenic soft tissue infection, pyogenic; Osteomyelitis; Pelvic inflammatory disease; Prostatitis (acute bacterial); Prosthetic joint infection; Salmonella (nontyphoidal) infection; Shigella infection; Surgical (preoperative) prophylaxis; Surgical site incisional infection; Tuberculosis.

Levofloxacin acts on DNA gyrase and toposiomerase 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.

Levofloxacin is approved for use in the following clinical indications

Treatment of community-acquired pneumonia, including multidrug-resistant strains of Streptococcus pneumoniae (MDRSP); nosocomial pneumonia; chronic obstructive pulmonary disease, acute exacerbation; rhinosinusitis, acute bacterial (ABRS); prostatitis (chronic bacterial); urinary tract infection (uncomplicated or complicated); acute pyelonephritis; skin or skin structure infections (uncomplicated or complicated); inhalational anthrax (postexposure) to reduce incidence or disease progression; prophylaxis and treatment of plague due to Yersinia pestis

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

Anthrax; Bite wound infection, prophylaxis or treatment (animal or human bite); Cervicitis or urethritis due to Chlamydia trachomatis infection; Diabetic foot infection; Epididymitis, acute; Helicobacter pylori eradication; Intra-abdominal infection, mild to moderate, community-acquired in patients without risk factors for resistance or treatment failure; Neutropenia (chemotherapy-induced), antibacterial prophylaxis; Odontogenic soft tissue infection, pyogenic; Osteomyelitis; Pelvic inflammatory disease; Prostatitis (acute bacterial); Prosthetic joint infection; Salmonella (nontyphoidal) infection; Shigella infection; Surgical (preoperative) prophylaxis; Surgical site incisional infection; Tuberculosis.

Levofloxacin is available in various strengths as 250 mg/50 mL (50 mL); 500 mg/100 mL (100 mL); 750 mg/150 mL (150 mL); 25 mg/mL (20 mL, 30 mL); 25 mg/mL (10 mL, 100 mL, 200 mL, 480 mL), 250 mg, 500 mg, 750 mg.

Levofloxacin is available in the form of Oral Solution, Injection solution and Tablets.

Dosage Adjustment in Kidney Patient

• GFR ≥30 mL/minute/1.73 m²: No adjustment necessary
• GFR 10 to 29 mL/minute/1.73 m²: 5 to 10 mg/kg/dose every 24 hours
• GFR <10 mL/minute/1.73 m²: 5 to 10 mg/kg/dose every 48 hours
• Intermittent hemodialysis: 5 to 10 mg/kg/dose every 48 hours; not removed by hemodialysis; supplemental levofloxacin doses are not required
• Peritoneal dialysis (PD): 5 to 10 mg/kg/dose every 48 hours; not removed by peritoneal dialysis; supplemental levofloxacin doses are not required
• Continuous renal replacement therapy (CRRT): 10 mg/kg/dose 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

• GFR ≥30 mL/minute/1.73 m²: No adjustment necessary
• GFR 10 to 29 mL/minute/1.73 m²: 5 to 10 mg/kg/dose every 24 hours
• GFR <10 mL/minute/1.73 m²: 5 to 10 mg/kg/dose every 48 hours
• Intermittent hemodialysis: 5 to 10 mg/kg/dose every 48 hours; not removed by hemodialysis; supplemental levofloxacin doses are not required
• Peritoneal dialysis (PD): 5 to 10 mg/kg/dose every 48 hours; not removed by peritoneal dialysis; supplemental levofloxacin doses are not required
• Continuous renal replacement therapy (CRRT): 10 mg/kg/dose every 24 hours

Anthrax: Limited data available in infants <6 months of age: Note: Levofloxacin is not preferred therapy for any prophylaxis or treatment regimens; use should be considered when patients are unable to tolerate first-line therapy (eg, cipro levofloxacin or others depending upon disease presentation). Although longer durations of therapy are recommended in guidelines in some cases based on risk: benefit assessments (eg, up to 60 days), specific safety data for levofloxacin in pediatric patients is limited to 14 days .

• Infants, Children, and Adolescents:

Cutaneous, without systemic involvement; treatment : Appropriate for all strains regardless of penicillin susceptibility or if susceptibility unknown. Treatment duration: 7 to 10 days for naturally-acquired infection, and up to 60 days for biological weapon-related event.

• <50 kg: Oral: 8 mg/kg/dose every 12 hours; maximum dose: 250 mg/dose.
• ≥50 kg: Oral: 500 mg every 24 hours.
• Inhalational (postexposure prophylaxis) : Reserve l use for penicillin-resistant strains or prior to susceptibility testing. Begin therapy as soon as possible after exposure.
• <50 kg: Oral (preferred), IV: 8 mg/kg/dose every 12 hours for 60 days; maximum dose: 250 mg/dose.
• ≥50 kg: Oral (preferred), IV: 500 mg every 24 hours for 60 days.

Systemic anthrax (excluding meningitis);

A fluoroquinolone is appropriate for all strains regardless of penicillin susceptibility or if susceptibility unknown; ciprlevofloxacin is preferred.

Initial treatment: Use in combination with a protein synthesis inhibitor (eg, clindamycin); continue therapy for at least 14 days or longer until clinical criteria for stability are met.

• <50 kg: IV: 10 mg/kg/dose every 12 hours; maximum dose: 250 mg/dose.
• ≥50 kg: IV: 500 mg every 24 hours.
• Oral step-down therapy: Use in combination with a protein synthesis inhibitor (eg, clindamycin). Duration of therapy to complete treatment course is variable; some patients may require up to 60 days additional prophylaxis from onset of illness.
• <50 kg: Oral: 8 mg/kg/dose every 12 hours; maximum dose: 250 mg/dose.
• ≥50 kg: Oral: 500 mg every 24 hours.
• Systemic anthrax; disseminated infection including meningitis (or when meningitis cannot be ruled out)
• Initial triple therapy: Use in combination with another bactericidal antimicrobial (beta-lactam or glycopeptide [depending on susceptibility]) and a protein synthesis inhibitor (eg, linezolid); continue therapy for at least 2 to 3 weeks or longer until clinical criteria for stability are met.
• <50 kg: IV: 8 mg/kg/dose every 12 hours; maximum dose: 250 mg/dose.
• ≥50 kg: IV: 500 mg every 24 hours.
• Oral step-down therapy: Use in combination with a protein synthesis inhibitor (eg, clindamycin). Duration of therapy to complete treatment course is variable; some patients may require up to 60 days additional prophylaxis from onset of illness.
• <50 kg: Oral: 8 mg/kg/dose every 12 hours; maximum dose: 250 mg/dose.
• ≥50 kg: Oral: 500 mg every 24 hour.

Bacteremia prophylaxis in patients with acute myeloid leukemia (AML) or relapsed acute lymphocytic leukemia (ALL):

• Recommended only during period when patient is severely neutropenic (ie, when absolute neutrophil count [ANC] is <500 cells/mm3)
• Infants ≥6 months and Children <5 years: Oral, IV: 10 mg/kg/dose every 12 hours.
• Children ≥5 years and Adolescents: Oral, IV: 10 mg/kg/dose every 24 hours; maximum dose: 750 mg/dose
• Catheter (peritoneal dialysis); exit-site or tunnel infection:

Infants, Children, and Adolescents: Oral: 10 mg/kg/dose every 48 hours; maximum initial dose: 500 mg; maximum subsequent doses: 250 mg

• Chlamydia trachomatis, urogenital infections:

Adolescents: Oral: 500 mg every 24 hours for 7 days

• Cystic fibrosis pulmonary exacerbation:

Infants ≥6 months, Children, and Adolescents:

6 months to <5 years: Oral, IV: 10 mg/kg/dose twice daily.

≥5 years: Oral, IV: 10 mg/kg/dose once daily; maximum dose: 750 mg/day.

Epididymitis, nongonococcal:

• Adolescents: Oral: 500 mg once daily for 10 days

Mycobacterium avium Complex , severe or disseminated disease, HIV-exposed/-infected:

• Adolescents: Oral: 500 mg once daily in combination with other antibiotics

Otitis media, acute (AOM) (alternative agent):

• Not recommended for routine empiric use; may be considered for patients with severe penicillin allergy, persistent or recurrent infection, or resistant causative bacteria.
• Infants ≥6 months and Children <5 years: Oral: 10 mg/kg/dose every 12 hours for 10 days.
• Children ≥5 years and Adolescents: Oral: 10 mg/kg/dose every 24 hours for 10 days; maximum dose: 750 mg/dose

Pelvic inflammatory disease:

• Adolescents: Oral: 500 mg once daily for 14 days with or without concomitant metronidazole; Note: Due to resistant organisms, the CDC recommends use as an alternative therapy only if standard parenteral cephalosporin therapy is not feasible and community prevalence, and individual risk of quinolone-resistant gonococcal organisms is low. Culture sensitivity must be confirmed

Plague (Yersinia pestis), prophylaxis or treatment:

• Infants ≥6 months, Children, and Adolescents: Note: Begin therapy as soon as possible after exposure:
• <50 kg: Oral, IV: 8 mg/kg/dose every 12 hours for 10 to 14 days; maximum dose: 250 mg/dose.
• ≥50 kg: Oral, IV: 500 mg every 24 hours for 10 to 14 days.

Pneumonia, community-acquired (CAP):

Note: May consider addition of vancomycin or clindamycin to empiric therapy if community-acquired MRSA suspected. Levofloxacin is not the preferred agent for CAP but may be used as an alternative agent when necessary.

• Typical pathogens (eg, H. influenzae, S. pneumoniae): Note: Oral administration is generally reserved for mild infections or step-down therapy.
• Infants ≥6 months and Children <5 years: Oral, IV: 8 to 10 mg/kg/dose every 12 hours; maximum daily dose: 750 mg/day.
• Children ≥5 years and Adolescents ≤16 years: Oral, IV: 8 to 10 mg/kg/dose once every 24 hours; maximum daily dose: 750 mg/day.
• Atypical pathogens (eg, Mycoplasma pneumonia or Chlamydia ssp):
• IV: Infants ≥6 months and Children <5 years: IV: 8 to 10 mg/kg/dose every 12 hours; maximum daily dose: 750 mg/day.
• Children ≥5 years and Adolescents ≤16 years: IV: 8 to 10 mg/kg/dose once every 24 hours; maximum daily dose: 750 mg/day.
• Oral: Mild infection/step-down therapy: Adolescents with skeletal maturity: Oral: 500 mg once daily.

Rhinosinusitis, acute bacterial:

• Recommended in the following types of patients: Type I penicillin allergy, after failure of initial therapy or in patients at risk for antibiotic resistance (eg, daycare attendance, age <2 years, recent hospitalization, antibiotic use within the past month).
• Children and Adolescents: Oral, IV: 10 to 20 mg/kg/day divided every 12 to 24 hours for 10 to 14 days; maximum daily dose: 500 mg/day.

Surgical prophylaxis:

• Children and Adolescents: IV: 10 mg/kg as a single dose 120 minutes prior to procedure; maximum dose: 500 mg/dose; Note: While fluoroquinolones have been associated with an increased risk of tendinopathy/tendon rupture in all ages, use of these agents for single-dose prophylaxis is generally safe

Tuberculosis (TB), multidrug-resistant:

• Limited data available: Note: Use in combination with at least 3 to 4 additional anti-TB agents (overall multidrug regimen dependent upon susceptibility profile/patterns) (Ref):
• Infants, Children, and Adolescents: Oral: 15 to 20 mg/kg/dose once daily; usual maximum daily dose: 1,000 mg/day; higher doses (1,250 to 1,500 mg/day) have been reported in adults

Urethritis, nongonococcal:

• Adolescents: Oral: 500 mg every 24 hours for 7 days

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

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

Concerns related to adverse effects:

• Superinfection: Prolonged use may result in fungal or bacterial superinfection.

Disease-related concerns:

• Renal impairment: Use with caution in patients with renal impairment; dosage adjustment required.

Special populations:

• Older adult: Adverse effects (eg, hepatotoxicity, tendon rupture, QT changes, aortic dissection) may be increased in the elderly.

• G6PD deficiency: Hemolytic reactions may (rarely) occur with fluoroquinolone use in patients with G6PD deficiency (Luzzatto 2020).

• Pediatric: Safety of use in pediatric patients for >14 days of therapy has not been studied; increased incidence of musculoskeletal disorders (eg, arthralgia, tendon rupture) has been observed in children.

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

Levofloxacin is present in breast milk.

Breast milk concentrations were measured in a woman receiving levofloxacin for treatment of a septic knee. Therapy was started as levofloxacin 500 mg/day IV for 9 days, followed by 14 days of oral therapy. A total of 26 breast milk samples were taken starting 10 days after the initiation of therapy and continuing after therapy was completed. During therapy, breast milk was expressed, but not fed to her preterm infant (27 weeks estimated gestation age). Steady-state peak milk concentration was 8.2 mcg/mL and occurred 5 hours after the dose. The half-life in the breast milk was approximately 7 hours, but small amounts were still detectable in the milk 65 hours after the last dose. Using a milk concentration of 8.2 mcg/mL, the estimated exposure to the breast-feeding infant would be 1.23 mg/kg/day (relative infant dose [RID] 6% based on a therapeutic infant dose of 20 mg/kg/day). In general, breastfeeding is considered acceptable when the RID is <10%

Teratogenic Effects - Pregnancy Category C

Levofloxacin 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 levofloxacin (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.

Administration with food prolonged time to peak by ~1 hour and decreased the peak concentration by ~14% and ~25% for the tablet and oral solution, respectively. Management: Tablet may be administered without regard to food; oral solution should be administered at least 1 hour before or 2 hours after food.

• Common Adverse effects

CNS effects including seizures, increased intracranial pressure, lightheadedness, dizziness, tremor; psychotic reactions (e.g. hallucinations, nervousness, delirium), sensory or sensorimotor peripheral neuropathy, prolonged QT interval, blood glucose disturbances (hypo-/hyperglycaemia), phototoxicity, superinfection (prolonged use), bronchospasm.

• Less Common Adverse effects:

CNS effects including seizures, increased intracranial pressure, lightheadedness, dizziness, tremor; psychotic reactions (e.g. hallucinations, nervousness, delirium), sensory or sensorimotor peripheral neuropathy, prolonged QT interval, blood glucose disturbances (hypo-/hyperglycaemia), phototoxicity, superinfection (prolonged use), bronchospasm

• Rare Adverse effects

Hepatitis, jaundice. Injury, poisoning and procedural complications: Infusion site reaction (e.g. pain, reddening), phlebitis. Investigations: Increased hepatic enzymes (ALT/AST, alkaline phosphatase, GGT), decreased forced expiratory volume.

Decreased absorption with Fe salts, Zn-containing multivitamins, Mg- or Al-containing antacids, didanosine. Decreased bioavailability with sucralfate. Increased risk of CNS stimulation and seizures with drugs which may affect seizure threshold (e.g. theophylline, NSAIDs). Decreased renal clearance with cimetidine and probenecid due to blockage of renal tubular secretion of levofloxacin . May increase the half-life of ciclosporin. Increased INR and/or bleeding with vitamin K antagonists (e.g. warfarin). Increased risk of severe tendon disorders with corticosteroids. Increased risk for QT interval prolongation with class IA and III antiarrhythmics, TCA, macrolides and antipsychotic agents. May result to altered blood glucose levels with antidiabetic agents (e.g. insulin, glibenclamide).

The common side effects of Levofloxacin include the following nausea,; vomiting,; diarrhea,; headache,; constipation,; difficulty sleeping (insomnia),; dizziness,. Abdominal pain.

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 protection of gastric mucosa. Elimination may be increased by forced diuresis. Monitor ECG.

Pharmacodynamic

Levofloxacin is bactericidal and exerts its antimicrobial effects via inhibition of bacterial DNA replication.⁹ It has a relatively long duration of action in comparison with other antibiotics that allows for once or twice daily dosing. Levofloxacin is associated with QTc-interval prolongation and should be used with caution in patients with other risk factors for prolongation (e.g. hypokalemia, concomitant medications).

Pharmacokinetics

• Absorption: Rapidly and completely absorbed from the gastrointestinal tract (oral). Absolute bioavailability: Approx 99% (oral).
• Distribution: Widely distributed into body tissues including bronchial mucosa and lungs, enters breastmilk. Volume of distribution: 1.27 L/kg. Plasma protein binding: Approx 24-38%, mainly to albumin.
• Metabolism: Minimally metabolised in the liver.
• Excretion: Mainly via urine (approx 87% as unchanged drug, <5% as metabolites; faeces (<4%). Elimination half-life: 6-8 hours; 0.5-1 hour (inhalation).

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