Continuing Education Activity

Levofloxacin is FDA-approved for the treatment of nosocomial pneumonia, community-acquired pneumonia, acute bacterial rhinosinusitis, acute bacterial exacerbation of chronic bronchitis, acute bacterial prostatitis, acute pyelonephritis, urinary tract infection, skin or skin structure infections, prophylaxis, and treatment of plaque due to Yersinia pestis, and to reduce the incidence of disease progression of inhalational anthrax. The drug is in the fluoroquinolone class of medications, and adverse effects include pseudomembranous colitis, hepatotoxicity, and QT prolongation, necessitating patient education on discontinuation if such symptoms arise. This activity reviews monitoring strategies, FDA-issued box warnings, clinical toxicology, and relevant interactions pertinent to healthcare team members in treating patients with bacterial infections.

Given this fluoroquinolone's relevance in primary and specialized care, contextualizing the indications of levofloxacin leads to improved clinical practice. Participating clinicians are equipped with the knowledge to seamlessly integrate levofloxacin into the patient-centric framework of clinical practice, ensuring the optimal treatment of bacterial infections.

Objectives:

• Identify the mechanism of action of levofloxacin compared to antibiotics of its class.

• Differentiate between the FDA-approved and off-label indications of levofloxacin, selecting alternatives when needed.

• Evaluate the adverse effects, contraindications, and risk factors before prescribing levofloxacin.

• Implement effective communication among interprofessional team members to improve treatment efficacy for patients who might benefit from levofloxacin.

Indications

Levofloxacin is a broad-spectrum, third-generation fluoroquinolone antibiotic used to treat bacterial infections. Levofloxacin is a safe and effective medicine on the World Health Organization's essential medicines list. The antibiotic was patented in 1987 and subsequently received FDA approval in 1996 for medical use in the United States.[1]

FDA-Approved Indications

• Nosocomial pneumonia

• Community-acquired pneumonia

• Skin and skin structure infections (SSTI) complicated and uncomplicated 

• Chronic bacterial prostatitis 

• Acute bacterial exacerbation of chronic bronchitis 

• Acute bacterial sinusitis

• Inhalational anthrax, post-exposure in adult and pediatric patients

• Plague in adult and pediatric patients 

• Urinary tract infections (UTI)

• Acute pyelonephritis

• Bacterial conjunctivitis (ophthalmic formulation)[2]

Off-Label Uses

• Diabetic foot infection

• Osteomyelitis[3]

Due to an increased risk of severe adverse effects (eg, tendinitis and tendon rupture, peripheral neuropathy, and CNS effects), levofloxacin is used in patients with acute exacerbation of chronic bronchitis, acute bacterial sinusitis, and uncomplicated urinary tract infections that do not have alternative treatment options.[4]

To decrease the development of drug-resistant bacteria, the FDA has recommended using levofloxacin only for strongly suspected bacterial infections. Also, levofloxacin should not be used empirically in patients at risk of multidrug-resistant Escherichia coli.[5] According to Infectious Diseases Society of America (IDSA) 2022 guidelines, levofloxacin is suggested for infections caused by ESBL-E (extended-spectrum β-lactamase-producing enterobacterales), AmpC-E (AmpC β-lactamase-producing enterobacterales), or Stenotrophomonas maltophilia (mild infection).[6]

Mechanism of Action

Levofloxacin is a bactericidal antibiotic of the fluoroquinolone drug class that directly inhibits bacterial DNA synthesis. Levofloxacin promotes the breakage of DNA strands by inhibiting DNA-gyrase in susceptible organisms, which inhibits the relaxation of supercoiled DNA. Of the fluoroquinolone class, levofloxacin has the most enhanced activity against gram-positive penicillin-sensitive and resistant organisms, notably Streptococcus pneumoniae and reduced action against gram-negative bacilli, notably Pseudomonas aeruginosa, compared to ciprofloxacin. Levofloxacin has effectiveness against other common respiratory organisms, notably Haemophilus influenzae, Moraxella catarrhalis, Legionella spp, Mycoplasma spp, and Chlamydia pneumoniae.[5] Levofloxacin also has a higher in-vitro activity against Mycobacterium tuberculosis and is preferred over the other fluoroquinolones as second-line antitubercular therapy.[7] A growing concern about drug resistance to fluoroquinolones exists worldwide, which can occur through chromosome-encoded or plasmid-mediated mechanisms.

Pharmacokinetics

Absorption: Levofloxacin is rapidly absorbed and widely distributed in the body. The bioavailability of levofloxacin is 99%; therefore, levofloxacin's intravenous (IV) and oral preparations are used interchangeably. The time to peak plasma concentration (Tmax) is approximately 1.5 hours.

Distribution: The volume of distribution of levofloxacin generally varies from 74 to 112 L (single and multiple 500 or 750 mg doses), demonstrating extensive distribution in body tissues. Outcomes of the study suggest that levofloxacin is widely distributed in the skin, muscles, liver, kidney, and spleen. Drug concentrations in tissues and fluids are typically higher than in plasma. Levofloxacin has plasma protein binding of  24% to 38% and binds primarily to albumin.

Metabolism: Levofloxacin undergoes little hepatic metabolism in humans and is eliminated unchanged in the urine.[8]

Excretion: Levofloxacin clearance is primarily via the renal route (87%). The mean plasma elimination half-life of levofloxacin is approximately 6 to 8 hours following single or multiple doses of levofloxacin.[9]

Administration

Available Dosage Forms and Strengths

Levofloxacin is available in oral tablets, oral solutions, and intravenous (IV) formulations. Levofloxacin is unavailable for administration through intramuscular (IM), intrathecal, or subcutaneous (SQ) routes. The marketed oral dosage strengths for levofloxacin are 250, 500, and 750 mg. Oral dosing with tablets can be without regard to meals. However, the oral solution should be taken 1 hour before or 2 hours after meals. Patients should avoid using antacids, or levofloxacin should be administered 2 hours before or 2 hours after taking antacids containing magnesium or aluminum. Adequate hydration is essential to prevent crystalluria. 

Levofloxacin injection should be administered for adult and pediatric patients by slow IV infusion over 60 minutes (250 to 500 mg) and over 90 minutes (for 750 mg). Due to an increased risk of hypotension, bolus or rapid IV administration should be avoided. In addition, the infusion should not use a solution containing multivalent cations. The ophthalmic levofloxacin solution is a safe and effective antibiotic used for 7 days to treat bacterial conjunctivitis.

Adult Dosage

• The recommended oral dose regimen is 750 mg daily to treat nosocomial pneumonia, complicated skin and skin structure infections (7 to 14 days), community-acquired pneumonia, acute bacterial sinusitis, complicated urinary tract infection (UTI), or acute pyelonephritis (5 days).

• The daily dosing of 500 mg daily is recommended to treat nosocomial pneumonia (7 to 14 days), acute bacterial sinusitis (5 to 14 days), acute bacterial exacerbation of chronic bronchitis (7 days), uncomplicated skin and skin structure infections (7 to 10 days), chronic bacterial prostatitis (28 days), and post-exposure inhalational anthrax (60 days).[2]

• The daily dosing of 250 mg is recommended for patients with complicated urinary tract infections, acute pyelonephritis (10 days), or uncomplicated urinary tract infections (3 days).[1] 

• The daily dosing of 750 mg IV or orally daily (5-day regimen) is recommended for complicated UTIs or acute pyelonephritis.[10]

Specific Patient Populations

Hepatic impairment: No dose adjustment is provided in the manufacturer's labeling. As levofloxacin is eliminated primarily by the kidney and undergoes minimal hepatic metabolism, dose adjustment may not be required. In addition, levofloxacin is used in patients with cirrhosis to prevent spontaneous bacterial peritonitis (SBP). The preferred drug for SBP prophylaxis is 3rd generation cephalosporin. Levofloxacin can be used in patients allergic to cephalosporins.[11]

Renal impairment: A 50% reduction in the total daily dosage is recommended in patients with renal impairment (glomerular filtration rate between 10 and 50 mL/min) and extended to every 48 hours if the glomerular filtration rate falls less than 10 mL/min).[1]

Pregnancy considerations: Guidelines for acute and recurrent urinary tract infections in pregnant women recommend using agents other than levofloxacin, such as amoxicillin/clavulanic acid and cefuroxime. According to joint guidelines published by the American Thoracic Society, CDC, European Respiratory Society, and IDSA, in patients with multi-drug resistant tuberculosis, levofloxacin can be considered in pregnancy if the benefits of treatment to the mother outweigh the harms.[12] However, the risk-benefit analysis should always be considered, and levofloxacin should be prescribed if essential. Levofloxacin should generally be avoided during pregnancy.

Breastfeeding considerations: Levofloxacin has not been used in infants because of consideration of adverse consequences on the infants' developing joints. Clinical data indicate that breast milk has a low concentration of levofloxacin, which is unlikely to cause damaging effects in breastfed babies. Using levofloxacin with breastfeeding mothers is acceptable with monitoring the infant for possible GI adverse effects (diarrhea or candidiasis). Additionally, pregnant women should be counseled not to breastfeed during treatment with levofloxacin and for 2 days after the last dose of levofloxacin.[13]

Pediatric patients: The AAP states that levofloxacin should be reserved only for managing infections with no effective alternative due to the risk of tendinopathy and musculoskeletal toxicity.[14] The safety of extended levofloxacin tablet therapy in pediatric patients beyond 14 days has not been extensively studied. Prolonged use should only be considered when the potential benefits outweigh the associated risks. Initiate drug administration promptly following suspected or confirmed exposure to aerosolized Bacillus anthracis or Yersinia pestis.[15]

Pediatric dosage (≥ 6 Months of age)

Inhalational Anthrax (Post-exposure)

• Pediatric patients >50 kg: Administer 500 mg every 24 hours as soon as possible after exposure.

• Pediatric patients <50 kg and ≥ 6 months of age: Administer 8 mg/kg (not exceeding 250 mg per dose) every 12 hours for 60 days.

Plague

• Pediatric patients >50 kg: Administer 500 mg every 24 hours for 10 to 14 days.
• Pediatric patients <50 kg and ≥ 6 months of age: Administer 8 mg/kg (not exceeding 250 mg per dose) every 12 hours for 10 to 14 days.

Older patients: Older patients on corticosteroid therapy have an increased risk of severe tendon disorders, including rupture, months after fluoroquinolone treatment, requiring prompt discontinuation if symptoms occur. Caution is advised in older patients due to potential QT interval effects, especially when co-administering drugs causing QT prolongation or in those with torsade de pointes risk factors. Hepatotoxicity has been reported in older patients. Immediate discontinuation is crucial if signs of hepatitis appear.[16]

Adverse Effects

The primary adverse effects of levofloxacin include nausea, photosensitivity, diarrhea, headache, tendinitis, tendon rupture, hyper-hypoglycemia, seizures, prolonged QT interval, and peripheral neuropathy. Clinicians should carefully prescribe levofloxacin to patients with a history of prolonged QT intervals.[17] Avoid or minimize exposure to natural or artificial sunlight while taking levofloxacin to reduce the occurrence of phototoxicity. Research has determined prolonged levofloxacin is linked with a higher risk of fungal and bacterial superinfection (eg, pseudomembranous colitis).[18]

Levofloxacin can cause hepatotoxicity. The pattern of enzyme elevation is hepatocellular, cholestatic, or mixed. The cases of jaundice and vanishing bile duct syndrome have been described. Hepatotoxicity can be associated with immunoallergic presentations such as fever, rash, and eosinophilia. The latency to onset is usually short (1 to 3 weeks), and the onset is abrupt with enzyme elevation, jaundice, and sometimes hepatic failure. Hence, the likelihood score for hepatotoxicity is A (well-established cause of clinically apparent liver injury).[19] The FDA has warned that fluoroquinolones, including levofloxacin, elevate the risk of aortic aneurysm and aortic dissection. Avoid prescribing levofloxacin to older patients and patients with a history of Marfan or Ehlers-Danlos syndrome.[20]

Drug-Drug Interactions

Concomitant administration of oral hypoglycemic agents such as glimepiride increases the risk of hypoglycemia. Careful monitoring of blood glucose is advised for patients taking concurrent antidiabetic medications due to the risk of glucose dysregulation.[21] Unlike ciprofloxacin, levofloxacin does not inhibit the drug-metabolizing enzyme CYP1A2; however, its weak inhibiting potential on the CYP2C9 enzyme, bleeding can occur with concurrent administration of warfarin.[22] A study indicates that simultaneous administration of levofloxacin with NSAIDs such as diclofenac can cause seizures. A risk of QTc prolongation exists when levofloxacin and thioridazine are administered together.[23] Cations in aluminum hydroxide, magnesium oxide, ferrous sulfate, and calcium carbonate can chelate and reduce the absorption of levofloxacin. Consequently, these drugs should be administered at least 2 hours before or after levofloxacin.[24] A study revealed that levofloxacin cross-reacts with immunoassays for 2 related opioids (buprenorphine and morphine). Urine concentrations of levofloxacin consistent with therapeutic use produced results above commonly used cutoffs for positivity, highlighting the necessity of confirmatory testing.[25]

Contraindications

Warnings and Precautions

The concurrent administration of levofloxacin with drugs that prolong the QT interval is contraindicated.[26] Levofloxacin should not be administered to patients with a confirmed hypersensitivity to the drug or its components, as anaphylaxis has been reported.[27] Fluoroquinolones, including levofloxacin, are contraindicated in pregnancy. Research has indicated that risk is highest during the first trimester; levofloxacin administration should generally be avoided during pregnancy and lactation unless a safer alternative is unavailable. More research is needed to establish the role of fluoroquinolone during pregnancy.[28]

Box Warning

The FDA has issued a warning for using levofloxacin and other fluoroquinolones due to the increased risk of disabling and irreversible adverse effects, including tendinitis and tendon rupture, and central nervous system (CNS) effects (eg, seizures, increased intracranial pressure), peripheral neuropathy in all ages. Older patients > 60 years, those taking corticosteroids and with kidney, heart, or lung transplants, are at increased risk of severe tendon disorders.[29] Avoiding levofloxacin and other fluoroquinolone antibiotics is recommended in patients with myasthenia gravis due to an increased risk of exacerbating preexisting muscle weakness.[30]

Monitoring

Clinicians should monitor patients prescribed levofloxacin for crystalluria, dysglycemia, altered mental status, CBC (especially white blood cell counts), and signs and symptoms of tendonitis and infection. During treatment, periodic evaluation of organ system functions is necessary. Monitoring for signs of bleeding is imperative due to the drug interaction between levofloxacin and warfarin. Levofloxacin affects the CYP2C9 enzyme, leading to elevated warfarin levels.[31] Unlike ciprofloxacin, monitoring patients concurrently prescribed theophylline is unnecessary as levofloxacin does not inhibit the enzyme CYP1A2.[22]

Toxicity

The elimination half-life of levofloxacin ranges from 27 to 35 hours in adults with renal impairment, depending on severity, compared with 6 to 8 hours in healthy adults. This prolonged half-life indicates that dosing adjustment is necessary for these patients. Neurotoxicity, including non-convulsive status epilepticus, has been reported with levofloxacin.[32] Levofloxacin has a low potential for acute toxicity; however, the stomach needs to be emptied during an acute overdose. The patient should be under observation with adequate maintenance of hydration. Hemodialysis or peritoneal dialysis can not adequately remove levofloxacin. The role of enhancing drug elimination with forced dilution is not clear. Activated oral charcoal administration is also a recommended approach with appropriate conditions.[13]

Enhancing Healthcare Team Outcomes

Levofloxacin is a widely prescribed respiratory fluoroquinolone by many clinicians for a broad spectrum of bacterial infections. Levofloxacin is well-known to increase the risk of tendinitis and tendon rupture in all ages, especially in patients aged over 60, taking corticosteroids, and with a history of kidney, heart, or lung transplants. All prescribers should stratify patients earlier for risk of complications and sparingly use the drug for patients with acute sinusitis, acute bronchitis, and uncomplicated urinary tract infections. Healthcare staff should counsel patients to maintain adequate hydration to prevent crystalluria and avoid antacids to enhance bioavailability. As levofloxacin excretion is primarily via the kidney, clinicians should carefully adjust the dose in the presence of renal insufficiency to prevent levofloxacin accumulation. Consultation with an infectious diseases specialist is required to treat resistant infections.

Clinicians should monitor patients for changes in bowel frequency, fever, abdominal cramps, loss of appetite, nausea, vomiting, right upper quadrant tenderness, jaundice, dark-colored urine, or palpitations. Levofloxacin is well-known to cause pseudomembranous colitis, hepatotoxicity, and QT prolongation; patients should receive education to discontinue treatment when the clinical features develop. If diarrhea develops, it is essential to manage fluid and electrolyte replacement in this patient population adequately. Due to the global concern regarding drug resistance of levofloxacin and other fluoroquinolones, limiting the duration of levofloxacin therapy and avoiding its empirical prescribing is important.

A cross-sectional study examined changes in fluoroquinolone prescribing patterns following FDA warnings in 2013 and 2016. The research used Medicare data and clinician information from 2011 to 2017, focusing on outpatient visits for specific conditions. The study revealed a general decrease in fluoroquinolone prescriptions, with prescribing behavior influenced by physician and organizational attributes such as hospital affiliation and specialization. This research provides key insights for improving fluoroquinolone de-adoption strategies in response to FDA warnings, which can improve patient safety.[33]

Clear communication between clinicians (MD, DO, NP,  PA) and nurses is necessary to administer levofloxacin by slow infusion to avoid the risk of hypotension. Pharmacists need to verify dosing and treatment duration and check for drug-drug interactions. Nursing is on the front lines of observing adverse effects and promptly reporting these to the rest of the team. A concerted and collaborative interprofessional team effort between patients, clinicians, nurses, and pharmacists is necessary to achieve improved patient outcomes with reduced risk of adverse drug reactions and increased patient satisfaction related to levofloxacin therapy.