Levaquin (Levofloxacin)

Levofloxacin (Johnson & Johnson’s Levaquin, Sanofi-Aventis’ Tavanic, Daiichi’s Cravit) (Figure 12) is a widely successful fluoroquinolone approved for the treatment of community-acquired pneumonia and several other bacterial infections (e.g., bronchitis, urinary tract infection, skin infections). In the United States, the agent is a leading antibiotic for community-acquired pneumonia, owing to its high bioavailability, broad-spectrum activity, tolerability, and once-daily dosing.

Levofloxacin was first launched in Japan in 1993 and has been widely available since 1998. Most recently, a new, high-dose formulation (750 mg) has been approved that provides patients an abbreviated five-day treatment course for community-acquired pneumonia. The agent lost patent protection in the United States and Japan in 2010 (the Patent Cliff) and in Europe in 2011. The drug is available in oral and IV formulations.

Levofloxacin Overview: Efficacy, Studies

Levofloxacin is the levo enantiomer of ofloxacin. The agent’s mechanism of action involves inhibition of bacterial topoisomerase IV and DNA gyrase, which are enzymes required for DNA replication, transcription, repair, and recombination. Levofloxacin has in vitro activity against a wide range of gram-negative and gram-positive microorganisms.

Observational Studies

In 10 patients who took levofloxacin 500 mg/day and rifampicin 600 mg/day for 2-6 months, there were no adverse reactions in 46% of patients, occasional digestive symptoms in 40%, and mild diarrhea in 13%; these patients also took unspecified anti-inflammatory drugs. There was sleeplessness in 6%, but neither tendinitis nor changes in liver function.

In a prospective, multicenter, open trial, 313 patients with clinical signs and symptoms of bacterial infections of the respiratory tract, skin, or urinary tract were treated with levofloxacin. Of these, 134 patients had a pathogen recovered from the primary infection site and had a MIC of the pathogen to levofloxacin determined.

Levofloxacin generated clinical and microbiological response rates of about 95%. These response rates included pathogens such as Streptococcus pneumoniae and Staphylococcus aureus. In a logistic regression analysis, the clinical outcome was predicted by the ratio of peak plasma concentration to MIC and site of infection. Microbiological eradication was predicted by the peak concentration/MIC ratio. Both clinical and microbiological outcomes were most likely to be favorable if the peak concentration/MIC ratio was at least 12.

Of 17 individuals with suspected latent multidrug-resistant tuberculosis treated with pyrazinamide and levofloxacin, 11 developed musculoskeletal adverse effects related to therapy, 5 had nervous system effects, and 15 had raised liver enzymes, uric acid, or creatinine kinase.

Comparative Studies

Levofloxacin’s efficacy in adult inpatients and outpatients with community-acquired pneumonia was evaluated in two pivotal Phase III clinical studies. In the first study, 590 patients were treated with levofloxacin (500 mg) once daily orally or intravenously for 7 to 14 days or with the cephalosporin ceftriaxone (1-2 grams), administered intravenously once or twice daily, followed by the cephalosporin cefuroxime axetil (500 mg) administered orally twice daily for a total of 7 to 14 days (Ortho-McNeil, 2004).

Patients assigned to treatment with the cephalosporins were allowed to receive erythromycin (or doxycycline if intolerant of erythromycin) if an infection due to atypical pathogens was suspected or proven. Clinical success (defined as the percentage of patients cured or improved at 5 to 7 days post-therapy) with levofloxacin was superior (95%) to success in the control group (83%). In a second, noncomparative study, 264 patients were treated with 500 mg levofloxacin orally or intravenously once daily for 7 to 14 days; the clinical success rate of evaluable patients in this study was 93%.

In comparative trials involving commonly used regimens, levofloxacin had equivalent if not greater activity in the treatment of community-acquired pneumonia, acute bacterial exacerbations of chronic bronchitis, acute bacterial sinusitis, acute pyelonephritis, and complicated urinary tract infection.

Drug Nomenclature: British Approved Name, US Adopted Name, rINN

International Nonproprietary Names (INNs) in main languages (French, Latin, Russian, and Spanish):

• Synonyms: S-(-)-Ofloxacin; DR-3355; HR-355; Levofloksasiini; Levofloxacin; Levofloxacino; Levofloxacinum; RWJ-25213;
• BAN: Levofloxacin;
• USAN: Levofloxacin;
• INN: Levofloxacin [rINN (en)];
• INN: Levofloxacino [rINN (es)];
• INN: Lévofloxacine [rINN (fr)];
• INN: Levofloxacinum [rINN (la)];
• INN: Левофлоксацин [rINN (ru)];

Chemical name: (-)-(S)-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.

Molecular formula: C18H20FN3O4 =361.4.

CAS: 100986-85-4 (levofloxacin); 138199-71-0 (levofloxacin hemihydrate).

ATC code: J01MA12; S01AX19.

Read code: y0C5m.

Generic Name: Levofloxacin

In pharmacies of the United States, Great Britain, and Canada, the pharmacists offer you to buy Levofloxacin according to your prescription or without a prescription under such brand names and in such strengths and dosage forms:

UK	US	Canada
Evoxil 250mg film-coated tablets Evoxil 500mg film-coated tablets Evoxil 5mg/ml solution for infusion Levofloxacin 250mg Tablets Levofloxacin 500mg Tablets Levofloxacin 5mg/ml Solution for Infusion Tavanic I.V. 5 mg/ml Tavanic 250 mg Tablets Tavanic 500 mg Tablets	Levaquin 250 mg Tablets Levaquin 500 mg Tablets Levaquin 750 mg Tablets Levaquin Solution 250mg/10ml Levaquin Injectable 500mg/20ml Levaquin Injectable 750mg/30ml Levofloxacin 250 mg Tablets Levofloxacin 500 mg Tablets Levofloxacin 750 mg Tablets	Levaquin 250 mg Tablets Levaquin 500 mg Tablets Levaquin 750 mg Tablets Novo-Levofloxacin 250 mg Tablets Mylan-Levofloxacin 500 mg Tablets Apo-Levofloxacin 750 mg Tablets Levofloxacin Solution 250mg/10ml Levofloxacin Injectable 500mg/20ml Levofloxacin Injectable 750mg/30ml

Interactions

As for Ciprofloxacin. The use of levofloxacin with drugs that alter blood-glucose concentrations increases the risk of blood-glucose disturbances.

Chinese Medicines

Chinese medicines did not influence the systemic availability or renal excretion of levofloxacin.

Efavirenz

Levofloxacin pharmacokinetics in HIV-positive patients were not altered by steady-state treatment with efavirenz.

HIV protease inhibitors

Levofloxacin pharmacokinetics in HIV-positive patients were not altered by steady-state treatment with nelfinavir.

Lithium

Co-administration with levofloxacin can cause severe lithium toxicity; the authors did not discuss the mechanism.

Theophylline

Theophylline clearance was reduced by levofloxacin plus clarithromycin in a 59-year-old Japanese man, who had stimulation, insomnia, and tachycardia due to theophylline toxicity.

The mechanism was probably inhibition of theophylline metabolism by CYP1A2 and CYP3A4.

Warfarin

Enhanced hypoprothrombinemia has been reported when levofloxacin was given with warfarin.

Medicines to Notify the Doctor About

Notify your doctor if you’re taking any of the following:

• Iron salts (used to treat anemia), magnesium- or aluminum-containing antacids (medicines against heartburn and stomach pain), or medicines containing these salts. These drugs can reduce the absorption and efficacy of levofloxacin, and as such, they should be taken at least 2 hours before or after Evoxil tablets (US: Levaquin Tablets);
• Sucralfate (used to protect the stomach wall). It may affect the absorption and reduce the efficacy of levofloxacin. It is best to take sucralfate 2 hours after Evoxil tablets (or other levofloxacin-containing medicine);
• Probenecid (used to prevent gout) or cimetidine (used to treat ulcers) as they reduce your kidneys’ ability to excrete levofloxacin;
• Ciclosporin (e.g., used to treat psoriasis, dermatitis, rheumatism). The effect of this medicine may be prolonged if used in combination with levofloxacin;
• Corticosteroids, sometimes called steroids ― used for inflammation. You may be more likely to have inflammation and/or breakage of your tendons;
• Non-steroidal anti-inflammatory drugs ― used for pain and inflammation such as aspirin, ibuprofen, fenbufen, ketoprofen, and indomethacin. You are more likely to have a fit (seizure) if taken with Evoxil tablets;
• Medicines that can alter your heart rhythm: medicines that belong to the group of antiarrhythmics (e.g., quinidine, hydroquinone, disopyramide, amiodarone, sotalol, dofetilide, ibutilide), tricyclic antidepressants, some antimicrobials (that belong to the group of macrolides), and some antipsychotics.

Taking Levofloxacin with Food and Drink

Evoxil tablets may be taken during meals or at any time between meals. Swallow the tablets with a glass of water.

Antimicrobial Action

As for Ciprofloxacin. Levofloxacin is generally considered to be about twice as active as ofloxacin, the racemic substance. Levofloxacin has a broad spectrum of activity, which includes Gram-positive bacteria.

Pharmacokinetics

Levofloxacin is rapidly and almost completely absorbed after oral doses with peak plasma concentrations occurring within 1 to 2 hours. It is widely distributed into body tissues, including the bronchial mucosa and lungs, but penetration into CSF is relatively poor. Levofloxacin is about 30 to 40% bound to plasma proteins. Only small amounts are metabolized to inactive metabolites. The elimination half-life of levofloxacin is 6 to 8 hours, although this may be prolonged in patients with renal impairment. Levofloxacin is excreted largely unchanged, primarily in the urine, with less than 5% as metabolites. It is not removed by hemodialysis or peritoneal dialysis.

Uses and Administration

Levofloxacin is the S-(-)-isomer of the fluoroquinolone antibacterial ofloxacin. It is given orally or by intravenous infusion as a 5 mg/mL solution over 30 to 90 minutes to treat susceptible infections, including tuberculosis.

Uses

Evoxil and other Levofloxacin tablets are used to treat infections caused by bacteria that are sensitive to levofloxacin. Your doctor will have decided if your infection can be treated with this medicine. Levofloxacin can be used to treat infections of the:

• Sinuses;
• Lungs, in people with long-term breathing problems or pneumonia;
• Urinary tract, including your kidneys or bladder;
• The prostate gland, where you have a long-lasting infection;
• Skin and underneath the skin, including muscles. This is sometimes called ‘soft tissue.’

Oral Administration

Oral levofloxacin may be given without regard to meals. Food does not appreciably affect the rate or extent of absorption of the drug.

Antacids containing magnesium or aluminum, sucralfate, metal cations such as iron or zinc, and didanosine (Videx®) chewable/dispersible tablets or unbuffered pediatric powder for an oral solution prepared for administration as an admixture with antacids may interfere with oral absorption of levofloxacin, resulting in subtherapeutic systemic concentrations of the quinolone. To minimize the possibility of an interaction, patients should be instructed not to ingest antacids containing magnesium or aluminum, sucralfate, metal cations such as iron or zinc (including multivitamin preparations containing zinc), or didanosine (Videx®) chewable/dispersible tablets or unbuffered pediatric powder for an oral solution prepared for administration as an admixture with antacids concomitantly with or within 2 hours of a levofloxacin oral dose.

IV Infusion

Prior to IV infusion, commercially available levofloxacin concentrate for injection in single-use vials containing 25 mg/mL must be diluted with a compatible IV solution to provide a solution containing 5 mg/mL. Alternatively, commercially available levofloxacin injection for IV infusion containing 5 mg/mL in 5% dextrose injection may be used without further dilution. Because commercially available levofloxacin concentrate for injection and levofloxacin injection for IV infusion contains no preservative, any unused portions of the solutions should be discarded.

Solutions compatible with levofloxacin IV include:

• 9% Sodium Chloride Injection;
• 5% Dextrose Injection;
• 5% Dextrose/0.9% Sodium Chloride Injection;
• 5% Dextrose in Lactated Ringers;
• Plasma-Lyte 56/5% Dextrose Injection;
• 5% Dextrose/0.45% Sodium Chloride;
• 15% Potassium Chloride Injection;
• Sodium Lactate Injection (M/6).

IV infusions of levofloxacin should be infused slowly. Levofloxacin doses of 250 or 500 mg should be administered over a period of 60 minutes. Levofloxacin doses of 750 mg should be administered over a period of 90 minutes. Because of the risk of hypotension, more rapid or bolus IV infusion should be avoided. Levofloxacin solutions should be inspected visually for particulate matter prior to administration whenever solution and container permit.

Because only limited information is available on the physical and/or chemical compatibility of levofloxacin and other drugs, levofloxacin should not be mixed with other drugs or infused simultaneously through the same tubing with other drugs. Fluoroquinolones, including levofloxacin, should not be infused through the same tubing with any solution containing multivalent cations (e.g., magnesium). If a Y-type administration set is used, the other IV solution flowing through the tubing should be discontinued while levofloxacin is being infused. If the same administration set is used for sequential infusion of several different drugs, the tubing should be flushed before and after administration of levofloxacin with an IV solution that is compatible with both levofloxacin and the other drug(s).

Dosage

The dosage of oral and IV levofloxacin is identical.

When levofloxacin therapy is initiated using IV levofloxacin, therapy may be changed when appropriate to oral levofloxacin given in the same dosage to complete the course of therapy. The timing of the change from IV to oral therapy should be individualized, taking into account the clinical status of the patient.

The dosage of levofloxacin does not need to be modified in geriatric patients based on age alone.

Respiratory Tract Infections

For the treatment of acute maxillary sinusitis, acute bacterial exacerbations of chronic bronchitis, or community-acquired pneumonia in adults, the usual dosage of levofloxacin is 500 mg once every 24 hours. The usual duration of therapy is 10-14 days for the treatment of acute maxillary sinusitis, 7 days for acute bacterial exacerbations of chronic bronchitis, and 7-14 days for community-acquired pneumonia.

For the treatment of nosocomial pneumonia in adults, the usual dosage of levofloxacin is 750 mg once daily for 7-14 days.

Skin and Skin Structure Infections

For the treatment of uncomplicated skin and skin structure infections in adults, the usual dosage of levofloxacin is 500 mg once every 24 hours for 7-10 days. The usual dosage for the treatment of complicated skin and skin structure infections in adults is 750 mg once every 24 hours for 7-14 days.

Urinary Tract Infections and Prostatitis

The usual dosage of levofloxacin for the treatment of uncomplicated urinary tract infections, complicated urinary tract infections, or acute pyelonephritis in adults is 250 mg once every 24 hours. The usual duration of therapy is 3 days for the treatment of uncomplicated urinary tract infections and 10 days for complicated urinary tract infections and acute pyelonephritis.

The usual dosage of levofloxacin for the treatment of chronic prostatitis in adults is 500 mg once daily for 28 days.

GI Infections

For the treatment of travelers’ diarrhea that is severe or associated with fever or bloody stools, some clinicians recommend that 500 mg of levofloxacin be given once daily for up to 3 days. Although the use of anti-infectives for prophylaxis of travelers’ diarrhea is generally discouraged, if levofloxacin is used, the recommended oral dosage of the drug is 500 mg once daily during the period of risk (for up to 3 weeks).

Treatment of Active Tuberculosis

If oral levofloxacin is used as an alternative agent in multiple-drug regimens for the treatment of active tuberculosis, the US Centers for Disease Control and Prevention (CDC), American Thoracic Society (ATS), and Infectious Diseases Society of America (IDSA) recommend that adults and children 15 years of age or older receive 0.5-1 g daily. These experts state that data are not available to support intermittent regimens of levofloxacin for the treatment of tuberculosis.

Anthrax

If oral levofloxacin is used as an alternative agent for postexposure prophylaxis following suspected or confirmed exposure to aerosolized anthrax spores (inhalational anthrax) or if oral levofloxacin is used for the treatment of anthrax when a parenteral regimen is not available (e.g., when there are supply or logistic problems because large numbers of individuals require treatment in a mass casualty setting), the US Working Group on Civilian Biodefense suggests that adults can receive a dosage of 500 mg once daily.

Because of the possible persistence of anthrax spores in lung tissue following an aerosol exposure, the US Centers for Disease Control and Prevention (CDC) and the Working Group on Civilian Biodefense state that anti-infective therapy for treatment of inhalation anthrax or for postexposure prophylaxis should be continued for 60 days.

Gonorrhea and Associated Infections

If oral levofloxacin is used for the treatment of uncomplicated cervical, urethral, or rectal gonorrhea in adults and adolescents, the CDC recommends a single 250-mg dose. If levofloxacin is used for the treatment of disseminated gonococcal infection in adults and adolescents, the CDC recommends an initial IV dosage 250 mg once daily, continued for 24-48 hours after improvement begins; therapy may be switched to an oral levofloxacin regimen of 500 mg once daily to complete at least 1 week of therapy.

Unless the presence of coexisting chlamydial infection has been excluded by appropriate testing, patients receiving levofloxacin therapy for uncomplicated or disseminated gonococcal infections also should receive an anti-infective regimen effective for presumptive treatment of chlamydia (e.g., a single dose of oral azithromycin or a 7-day regimen of oral doxycycline).

Nongonococcal Urethritis

If oral levofloxacin is used for the treatment of nongonococcal urethritis, the CDC recommends 500 mg once daily for 7 days.

Chlamydial Infections

For the treatment of urogenital chlamydial infections in adults and adolescents, the CDC recommends oral levofloxacin in a dosage 500 mg once daily for 7 days.

Pelvic Inflammatory Disease

For the treatment of acute pelvic inflammatory disease (PID) in adults and adolescents, when a parenteral regimen is indicated, IV levofloxacin may be given in a dosage of 500 mg once daily with or without IV metronidazole (500 mg every 8 hours). The parenteral regimen may be discontinued 24 hours after clinical improvement; however, oral doxycycline (100 mg twice daily) should be continued to complete 14 days of therapy. If an oral levofloxacin regimen is used for the treatment of PID, the drug should be given in a dosage of 500 mg once daily for 14 days with or without oral metronidazole (500 mg twice daily for 14 days).

Levofloxacin is also used topically as the hemihydrate in eye drops. A solution containing the equivalent of 0.5% of levofloxacin is used for the treatment of bacterial conjunctivitis and 1.5% for corneal ulcers caused by susceptible strains of bacteria.

Overdose

If you accidentally take an extra tablet, there should be no serious long-term consequences. Contact your doctor as soon as possible for precise instructions. If possible, take your tablets or the box with you to show the doctor. The signs of an overdose include:

• Confusion;
• Dizziness;
• Impairment of consciousness;
• Convulsive fits and heart disorder;
• Abnormal heart rhythm.

Missing a Dose

If you forget to take a dose, take it as soon as you remember unless it is nearly time for you to take your next dose. Then go on as prescribed. Do not take a double dose to make up for a missed dose.

Stopping the Course Prematurely

It is important to finish your course of tablets as prescribed by your doctor. Do not stop, even if you begin to feel better before having finished them all. Stopping taking the medicine prematurely may lead to condition deterioration.

If there are signs of a side effect, tell a doctor immediately to get advice before taking the next dose. If you have any further questions on the use of this product, ask your doctor or your pharmacist.

Administration in Children

Since fluoroquinolones can cause degenerative changes in weight-bearing joints of young animals, they should only be used in children and adolescents where their use may be justified if the benefits outweigh the risks. Although levofloxacin is not licensed for use in this age group in either the UK or United States of America (USA), a pharmacokinetic study has suggested that the following doses would be needed:

• Children 5 years of age and older: 10 mg/kg daily;
• Infants and children from 6 months to less than 5 years of age: 10 mg/kg every 12 hours.

Administration in Renal Impairment Patients

Although initial doses (see above) remain unchanged in patients with renal impairment, subsequent doses of levofloxacin should be adjusted according to creatinine clearance (CC). In the UK, the following doses are recommended:

• CC 20 to 50 mL/minute: subsequent doses are halved;
• CC 10 to 19 mL/minute: subsequent doses are reduced to one-quarter of the usual dose; a regimen of 250 mg daily should be reduced to 125 mg every 48 hours;
• CC less than 10 mL/minute (including hemodialysis and continuous peritoneal dialysis patients): usual doses of 250 mg or 500 mg daily are reduced to 125 mg every 48 or 24 hours, respectively; a regimen of 500 mg twice daily is reduced to 125 mg every 24 hours In the United States of America (USA), the following dose modifications are recommended:

After an initial dose of 750 mg daily:

• CC 20 to 49 mL/minute: subsequent doses are 750 mg every 48 hours;
• CC up to 19 mL/minute (including hemodialysis and continuous peritoneal dialysis patients): subsequent doses are 500 mg every 48 hours.

After an initial dose of 500 mg daily:

• CC 20 to 49 mL/minute: subsequent doses are 250 mg every 24 hours;
• CC up to 19 mL/minute (including hemodialysis and continuous peritoneal dialysis patients): subsequent doses are 250 mg every 48 hours.

After an initial dose of 250 mg daily:

• CC 10 to 19 mL/minute: subsequent doses are 250 mg every 48 hours.

A pharmacokinetic study in 10 critically ill patients undergoing continuous renal replacement therapy with either venovenous haemofiltration or haemodiafiltration suggested that a dose of either levofloxacin 250 mg every 24 hours or 500 mg every 48 hours would be suitable in such situations.

Peptic Ulcer Disease

Proceed here to find out the effects of levofloxacin in eradication regimens for Helicobacter pylori.

Levofloxacin Effect on Different Systems

Cardiovascular

Preclinical and clinical trial data and data from phase IV studies have suggested that levofloxacin causes prolongation of the QT interval. There were cardiovascular problems in 1 in 15 million prescriptions compared with 1-3% of patients taking sparfloxacin, who had QTC prolongation to over 500 ms. Polymorphic ventricular tachycardia with a normal QT interval has been associated with oral levofloxacin in the absence of other causes.

Among 23 patients who took levofloxacin 500 mg/day, there was a prolongation of the QTC interval by more than 30 ms in four patients and 60 ms in two patients.

There was absolute QT interval prolongation to over 500 ms in four patients, one of whom developed torsade de pointes.

Phlebitis can occur during parenteral administration of levofloxacin. High concentrations of levofloxacin (5 mg/ml) significantly reduced intracellular Adenosine and adenosine triphosphate content in cultured endothelial cells and reduced ADP, GTP, and GDP concentrations. These in vitro data suggest that high doses of levofloxacin are not compatible with the maintenance of endothelial cell function and may explain the occurrence of phlebitis. Commercial formulations should be diluted and given into large veins.

Respiratory

Eosinophilic pneumonia complicated by bronchial asthma has been attributed to levofloxacin.

A 76-year-old woman took levofloxacin for a productive cough with non-segmental infiltration in both lung fields. She developed eosinophilia in both the peripheral blood (24%) and the sputum (10%), airflow limitation, hypoxemia, and increased airway responsiveness to methacholine.

Bronchoalveolar lavage fluid showed increased total cells and a 55% increase in eosinophils, and the CD4/CD8 ratio was reduced to 0.8. Histological features included increased infiltration of eosinophils in the alveolar and interstitial compartments and goblet cell metaplasia. Levofloxacin was withdrawn, and her symptoms improved without steroid therapy. A leukocyte migration test for levofloxacin was weakly positive.

Nervous System

Levofloxacin can cause seizures. In one study, convulsions occurred in two per million prescriptions.

• A 75-year-old white woman was given oral levofloxacin (500 mg on day 1 followed by 250 mg/day) for ischemic toes. After three doses, she had a seizure. One month later, she was challenged with ciprofloxacin 400 mg intravenously every 12 hours and again had a seizure;
• A 74-year-old white woman was given oral levofloxacin 500 mg/day for bacterial pneumonia and had a seizure after five doses.

Sensory Systems

Taste disturbance occurred in less than three per million prescriptions of levofloxacin.

Gastrointestinal

Of 48 patients taking pyrazinamide 30 mg/kg/day plus levofloxacin 500 mg/day for 1 year, 27 discontinued therapy within 4 months owing to adverse events. Gastrointestinal intolerance was the major adverse event that resulted in early withdrawal.

Levofloxacin can cause pseudomembranous colitis due to Clostridium difficile.

Liver

In a study based on European and international data from about 130 million prescriptions, the adverse effects profile of levofloxacin was compared with that of other fluoro-quinolones; there was a low rate of hepatic abnormalities (1/1). However, two cases of severe acute liver toxicity were reported in patients who had received intravenous levofloxacin.

Pancreas

Two case reports have suggested that levofloxacin can cause pancreatitis.

Urinary Tract

Two reports have suggested that levofloxacin can cause tubulointerstitial nephritis. A case of nephrotoxicity and purpura associated with levofloxacin has also been reported; allergic interstitial nephritis or vasculitis was believed to be the underlying pathologic process.

A 73-year-old white man took levofloxacin for a lower urinary tract infection for 3 days and developed palpable purpura and erythematous skin lesions over the lower limbs and trunk, with a markedly reduced urine output. Serum creatinine was 560 µmol/l (6.4 mg/dl). Levofloxacin was withdrawn, and prednisone, furosemide, and intravenous fluids were given. The patient recovered fully over the next 4 weeks.

Skin

In a double-blind, randomized study in 30 healthy adults, oral levofloxacin (500 mg/day for 5 days) had a low photosensitizing potential, as it did in preclinical animal studies and postmarketing surveillance. In preclinical studies, levofloxacin was 20 times less phototoxic than sparfloxacin. Phototoxicity occurs in only 1 in 1.8 million cases.

Levofloxacin can cause a rash similar to the ampicillin rash in patients with infectious mononucleosis.

A 78-year-old woman developed a rash with blistering 2 days after completing a course of levofloxacin. The rash progressed to toxic epidermal necrolysis in 7 days. She was treated with intravenous fluids and wound dressings. Her condition improved, and she was discharged after 22 days.

Musculoskeletal

Tendinopathy has been reported with levofloxacin. Four cases of Achilles tendinitis have been reported in patients taking levofloxacin. Two were on chronic dialysis, one was a kidney transplant recipient, and one had chronic vasculitis. In all four cases, tendinitis had an acute onset with bilateral involvement and was incapacitating. In three cases, the onset was early during levofloxacin treatment, and in one case, it began 10 days after the end of treatment. All the patients recovered completely after 3-8 weeks.

Old age, renal dysfunction, and concomitant corticosteroid therapy are predisposing risk factors. Tendon rupture occurred in less than four per million prescriptions.

Immunologic

Anaphylactic and anaphylactoid reactions are rare adverse events after the administration of fluoroquinolones (about 0.46-1.2 per 100 000 patients).

On two occasions, a 49-year-old asthmatic woman who took levofloxacin for a chest infection developed worse respiratory distress, requiring intubation. The second reaction was accompanied by a marked skin reaction.

An in vitro study in rat peritoneal mast cells showed that levofloxacin-mediated release of histamine might be closely linked to the activation of pertussis toxin-sensitive G proteins.

Susceptibility Factors

The pharmacokinetics of intravenous levofloxacin have been studied in intensive care unit patients during continuous venous hemofiltration or hemodiafiltration. Levofloxacin clearance was substantially increased during both types of continuous renal replacement therapy. Levofloxacin 250 mg/day maintained effective plasma drug concentrations in these patients.

Warnings and Precautions

Do not use Evoxil tablets (US: Levaquin):

• If you are allergic (hypersensitive) to Levofloxacin or to other active substances that belong to the same group of antibiotics (i.e., quinolones) or to any of the other ingredients of the medicine;
• If you suffer from epilepsy. Otherwise, your risk of getting “fits” (convulsions) is increased;
• If you had ever had tendon problems (e.g., tendonitis) relating to treatment with an active substance that belongs to the same class of antibiotics (i.e., fluoroquinolones);
• If you are or planning to become pregnant or if you are breastfeeding;
• If the tablets have been prescribed to children or growing teenagers. They could harm the cartilage of their growing bones.

Notify your doctor before taking the medicine:

• If you have experienced “fits” or brain damage in the past (such as stroke or severe brain injury). Make sure your doctor knows about your medical history, so he can give you appropriate advice;
• If you are exposed to sunlight or UV light. Do not stay out in strong sunlight for unnecessarily long periods and do not use a sun-lamp or solarium. Your skin may become more sensitive to light whilst using this medicine (may cause sunburn-like reactions);
• If you get pain or inflammation in your tendons, particularly if you are elderly or taking any medicines known as the corticosteroids (cortisone or similar medicines used as anti-inflammatories in many disorders such as asthma, allergic conditions/reactions, and arthritis). If you experience any tendon complaints whilst or shortly after taking the tablets, you should seek medical advice immediately and rest the affected limb to avoid tendon damage. Do not take the next dose of levofloxacin unless your doctor tells you to;
• If you have severe, persisten, and/or bloody diarrhea during or after treatment with the tablets. This may be a sign of serious bowel inflammation (pseudomembranous colitis), which can occur following treatment with antibiotics. Tell your doctor immediately. It may be necessary to stop treatment and start specific therapy;
• If you have a family history of or have an actual defect in the liver enzyme called glucose-6-phosphate dehydrogenase (G6PD) (a rare hereditary disease). Patients with G6PD deficiency may be prone to the destruction of red blood cells (hemolysis) when treated with quinolone antibacterial agents;
• If you suffer from a kidney condition. Patients with reduced kidney activity (renal insufficiency);
• If you are taking anticoagulants;
• If you have ever had mental health problems. Tell your doctor immediately if you suspect a psychotic reaction;
• If you have ever had symptoms due to nerve damage such as kinetic or sensory problems in hand and feet;
• If you are diabetic and taking oral medicines that lower blood glucose levels;
• If you have ever had liver problems. You should stop treatment and contact your doctor immediately if symptoms of liver disease develop, such as reduced appetite, yellowing of the skin or whites of the eyes (jaundice), dark urine, itching, or gastrointestinal disturbances;
• If you were born with or have a family history of the prolonged QT interval (seen on ECG), have a salt imbalance in the blood (especially low level of potassium or magnesium in the blood), have a very slow heart rhythm (called ‘bradycardia’), have a weak heart, have ever had a heart attack (myocardial infarction).

Preparations

Proprietary Preparations

Argentina: Floxlevo; Grepiflox; Leflumax; Levaquin; Septibiotic; Tavanic; Teraquin; Ultraquin; Uniflox; Valiflox; Austria: Tavanic; Belgium: Tavanic; Brazil: Levaquin; Levotac; Levoxin; Tamiram; Tavanic; Canada: Levaquin; Chile: Auxxil; Medibiox; Novacilina; Quinobiot; Recamicina; Tavanic; Czech Republic: Oftaquix; Tavanic; Denmark: Oftaquix; Finland: Oftaquix; Tavanic; France: Tavanic; Germany: Oftaquix; Tavanic; Greece: Tavanic; Hong Kong: Cravit; Hungary: Leflokin; Oftaquix; Tavanic; India: Glevo; Leeflox; Levocide; Levof; Levoflox; Lufi; Tavanic; Indonesia: Armolev; Cravit; Cravox; Difloxin; Farlev; Lefos; Levocin; Levores; Levovid; Levoxal; Lexa; Lovequin; Mosardal; Nislev; Nufalev; Prolecin; Prolevox; Reskuin; Rinvox; Tevox; Volequin; Voxin; Ireland: Tavanic; Israel: Levo; Tavanic; Italy: Levoxacin; Oftaquix; Prixar; Tavanic; Japan: Cravit; Malaysia: Cravit; Glevo; Loxo; Mexico: Elequine; Ran-Levo; Tavanic; The Netherlands: Oftaquix; Prixar; Tavanic; Philippines: Floxel; Levox; Oftaquix; Poland: Oftaquix; Portugal: Oftaquix; Tavanic; Russia: Lefoxin; Tavanic; South Africa: Tavanic; Singapore: Cravit; Spain: Tavanic; Sweden: Oftaquix; Tavanic; Switzerland: Tavanic; Thailand: Cravit; Lefloxin; Turkey: Cravit; Tavanic; UAE: Jenoquine; United Kingdom (UK): Oftaquix; Tavanic; United States of America (US and USA): Iquix; Levaquin; Quixin; Venezuela: Levaquin; Proxime; Tavanic.

Multi-Ingredient

India: Levoflox Oz Kit

Levofloxacin: Uses

Levofloxacin is used orally or IV for the treatment of respiratory tract infections (acute bacterial exacerbations of chronic bronchitis, acute maxillary sinusitis, community-acquired pneumonia, nosocomial pneumonia), uncomplicated or complicated skin and skin structure infections, uncomplicated or complicated urinary tract infections, acute pyelonephritis, and chronic prostatitis caused by susceptible organisms.

Levofloxacin also is used in the treatment of travelers’ diarrhea and pelvic inflammatory disease. In addition, levofloxacin is recommended as an alternative agent for the treatment of gonorrhea, nongonococcal urethritis, or urogenital chlamydial infections; for the treatment of active tuberculosis; for postexposure prophylaxis following suspected or confirmed exposure to aerosolized anthrax spores (inhalational anthrax) or for treatment of inhalational anthrax; and for the treatment or prophylaxis of plague. In the absence of factors that may interfere with absorption of an orally administered drug (e.g., vomiting), IV levofloxacin does not provide a higher degree of efficacy nor more potent antimicrobial activity than an equivalent dosage of oral levofloxacin.

Therefore, IV levofloxacin generally is reserved for patients who cannot tolerate or are unable to take an oral dosage form or in whom the IV route offers a clinical advantage. Prior to initiation of levofloxacin therapy, appropriate specimens should be obtained for identification of the causative organism(s) and in vitro susceptibility tests.

Levofloxacin therapy may be started pending results of susceptibility tests, but should be discontinued and other appropriate anti-infective therapy substituted if the organism is found to be resistant to levofloxacin. In vitro susceptibility tests should be repeated periodically during levofloxacin therapy to assess effectiveness of the drug and to detect emergence of levofloxacin-resistant strains, which may develop during therapy with the drug.

Because resistant strains of Pseudomonas aeruginosa have developed during fluoroquinolone therapy, in vitro susceptibility tests are particularly important when levofloxacin is used in the treatment of infections caused by this organism.

Respiratory Tract Infections

Levofloxacin is used in adults for the treatment of acute bacterial exacerbations of chronic bronchitis, acute maxillary sinusitis, community-acquired pneumonia (CAP), and nosocomial pneumonia caused by susceptible organisms.

Acute Exacerbations of Chronic Bronchitis

Levofloxacin is used in adults for the treatment of acute bacterial exacerbations of chronic bronchitis caused by susceptible Haemophilus influenzae, H. parainfluenzae, Moraxella catarrhalis, Staphylococcus aureus, or Streptococcus pneumoniae. In controlled clinical studies in adults with acute bacterial exacerbations of chronic bronchitis, levofloxacin was as effective as therapy with cefaclor or cefuroxime. Levofloxacin therapy generally resulted in bacterial cure rates of 95-97% in patients with acute bacterial exacerbations of chronic bronchitis. The most prevalent pathogens in these studies were H. influenzae, H. parainfluenzae, M. catarrhalis, and S. pneumoniae.

Acute Sinusitis

Levofloxacin is used in adults for the treatment of acute maxillary sinusitis caused by susceptible H. influenzae, M. catarrhalis, or S. pneumoniae. In one open study in adults with acute maxillary sinusitis, therapy with levofloxacin or amoxicillin and clavulanate potassium resulted in clinical success rates of 87-88%.

Community-acquired Pneumonia

Levofloxacin is used in adults for the treatment of CAP1, 21 caused by susceptible Chlamydia pneumoniae, H. influenzae, H. parainfluenzae, Klebsiella pneumoniae, Legionella pneumophila, M. catarrhalis, Mycoplasma pneumoniae, S. aureus, or S. pneumoniae (including penicillin-resistant strains [penicillin MIC =2mcg/mL).

In one controlled clinical study in adults with CAP, a regimen that included IV and/or oral administration of levofloxacin was as effective as a regimen that included IV ceftriaxone and/or oral cefuroxime. Levofloxacin generally resulted in clinical success (cure or improvement) 5-7 days following completion of therapy in 93-95% of adults with CAP. In controlled clinical studies, presumptive bacteriologic eradication 5-7 days following completion of therapy was evident in 98% of patients with H. influenzae infection, 95% of those with H. parainfluenzae infection, 100% of those with K. pneumoniae infection, 94% of those with M. catarrhalis infection, 88% of those with S. aureus infection, and 95% of those with S. pneumoniae infection.

Clinical success rate 5-7 days following completion of therapy in patients with atypical pneumonia caused by C. pneumoniae, M. pneumoniae, or L. pneumoniae was 96, 96, or 70%, respectively. Data on the efficacy of levofloxacin in adults with CAP due to S. pneumoniae has been obtained from 8 clinical studies. In these studies, levofloxacin therapy resulted in clinical success (cure or improvement) in 98% of the 250 levofloxacin-treated patients with CAP due to S. pneumoniae. Infection due to penicillin-resistant S. pneumoniae was documented in 18 levofloxacin-treated patients in these studies; evaluation of 15 of these patients who completed therapy indicates that levofloxacin is effective in patients with infection due to penicillin-resistant S. pneumoniae (clinical success rate 100%). Some clinicians, including the American Thoracic Society (ATS) and Infectious Diseases Society of America (IDSA), suggest that fluoroquinolones with enhanced activity against S. pneumoniae (e.g., gatifloxacin, levofloxacin, moxifloxacin) are drugs of choice for the treatment of CAP in adults.

However, there is disagreement over the role of these drugs in the outpatient treatment of CAP. The IDSA recommends monotherapy with these oral fluoroquinolones as one of several possible regimens for empiric outpatient treatment of acute CAP in immunocompetent adults, but the ATS suggests that these agents not be used for outpatient treatment of CAP in immunocompetent adults without cardiopulmonary disease or other modifying factors that would increase the risk of multidrug-resistant S. pneumonia. To limit emergence of fluoroquinolone-resistant strains, the US Centers for Disease Control and Prevention (CDC) suggest that use of these oral fluoroquinolones in the outpatient treatment of CAP be reserved for when other anti-infectives are ineffective or cannot be used or when highly penicillin-resistant S. pneumoniae (penicillin MIC greater than or equal to 2 mcg/mL) are identified as the cause of infection.

Nosocomial Pneumonia

Levofloxacin is used in adults for the treatment of nosocomial pneumonia caused by susceptible H. influenzae, Escherichia coli, K. pneumoniae, Serratia marcescens, Ps. aeruginosa, S. aureus (oxacillin-susceptible strains only), or S. pneumoniae. If the infection is known or suspected of being caused by Ps. aeruginosa, concomitant therapy with an antipseudomonal b-lactam anti-infective is recommended. In a multicenter, randomized, open-label study in adults with clinical and radiologically documented nosocomial pneumonia, patients were randomized to receive a 7- to 15-day regimen of IV levofloxacin (750 mg once daily) following by oral levofloxacin (750 mg once daily) or IV imipenem and cilastatin sodium (500-1000 mg every 6-8 hours) followed by oral ciprofloxacin (750 mg every 12 hours).

Patients with documented Ps. aeruginosa infections received adjunctive therapy with ceftazidime or piperacillin and tazobactam sodium (for those receiving levofloxacin) or an aminoglycoside (for those receiving the comparator regimen); those with suspected oxacillin-resistant S. aureus (ORSA; previously known as methicillin-resistant S. aureus or MRSA) received concomitant vancomycin. The overall clinical success rate 3-15 days after completion of therapy was 58.% for those receiving levofloxacin and 60.% for those receiving the comparator regimen; the overall microbiologic eradication rate was 66. and 60.%, respectively.

Skin and Skin Structure Infections

Levofloxacin is used in adults for the treatment of mild to moderate uncomplicated skin and skin structure infections caused by susceptible S. aureus or S. pyogenes (group A b-hemolytic streptococci). The drug has been effective in the treatment of abscesses, cellulitis, furuncles, impetigo, pyoderma, and wound infections. In 2 controlled studies, oral levofloxacin was as effective as oral ciprofloxacin in the treatment of mild to moderate skin infections caused by susceptible bacteria, mainly S. aureus and S. pyogenes. Levofloxacin resulted in a bacteriologic cure rate of 93.2-97.5% in patients with mild to moderate skin and skin structure infections. Levofloxacin also is used in adults for the treatment of complicated skin and skin structure infections caused by susceptible S. aureus (oxacillin-susceptible strains), Enterococcus faecalis, S. pyogenes, or Proteus mirabilis.

Urinary Tract Infections and Prostatitis

Uncomplicated Urinary Tract Infections

Levofloxacin is used in adults for the treatment of mild to moderate uncomplicated urinary tract infections (UTIs) caused by susceptible E. coli, K. pneumoniae, or S. saprophyticus.

Complicated Urinary Tract Infections

Levofloxacin is used in adults for the treatment of mild to moderate complicated UTIs caused by susceptible E. faecalis, Enterobacter cloacae, E. coli, K. pneumoniae, P. mirabilis, or Ps. aeruginosa and mild to moderate acute pyelonephritis caused by susceptible E. coli. In controlled clinical studies, levofloxacin therapy was as effective as ciprofloxacin or lomefloxacin in the treatment of complicated UTIs or pyelonephritis. In one study in adults with complicated UTIs, bacterial eradication 5-9 days following completion of therapy was evident in 93% of patients with E. coli infection, 97% of those with K. pneumoniae infection, and 90% of those with P. mirabilis infection.

Prostatitis

Levofloxacin is used in adults for the treatment of chronic prostatitis caused by susceptible E. coli, E. faecalis, or S. epidermidis. In one double-blind controlled study, adults with prostatitis were randomized to receive a 28-day regimen of oral levofloxacin (500 mg once daily) or ciprofloxacin (500 mg twice daily). The overall microbiologic eradication rate 5-18 days after completion of treatment was 75% in those who received levofloxacin and 76.% in those who received ciprofloxacin. In those with infections caused by E. coli, E. faecalis, or S. epidermidis, the eradication rate was 93.3,72.2 or 81.8%, respectively, in those who received levofloxacin and 81., or 78.%, respectively, in those who received ciprofloxacin.

GI Infections

Travelers’ Diarrhea

Oral levofloxacin is used in the treatment of travelers’ diarrhea. The principal cause of travelers’ diarrhea is infection with enterotoxigenic E. coli, but other infectious agents (e.g., Shigella, Salmonella, Campylobacter spp, Vibrio parahaemolyticus) also have been associated with the disease.

Treatment of travelers’ diarrhea depends on the severity of the illness. In individuals with mild to moderate disease, replacement therapy with oral fluids and electrolytes may be sufficient, although therapy with nonspecific or antimotility agents (e.g., bismuth subsalicylate, loperamide) may be useful for temporary relief of associated symptoms (e.g., abdominal cramps, diarrhea). Travelers who develop diarrhea with at least 3 loose stools in an 8-hour period, especially if associated with nausea, vomiting, abdominal cramps, fever, or bloody stools, may benefit from short-term treatment with an anti-infective agent. An effective anti-infective agent can shorten a typical 3- to 5-day illness to 1-1. days. When use of an anti-infective agent is indicated for treatment of travelers’ diarrhea, ciprofloxacin, levofloxacin, norfloxacin, or ofloxacin generally is recommended. Some clinicians suggest that azithromycin can be used as an alternative agent in children and pregnant women and may be a drug of choice for travelers in areas with a high prevalence of Campylobacter resistant to fluoroquinolones (e.g., Thailand).

Co-trimoxazole also can be used for the treatment of travelers’ diarrhea in children and pregnant women who cannot receive fluoroquinolones; however, resistance to co-trimoxazole has been reported in many areas. Efficacy of anti-infective therapy may depend on the etiologic agent and its susceptibility to anti-infectives. Nausea and vomiting without diarrhea should not be treated with anti-infectives. Travelers should consult a physician, rather than attempt self-medication, if the diarrhea is severe or fails to respond to several days of therapy, the stools contain blood and/or mucus, fever with shaking chills occurs, or dehydration and persistent diarrhea develop.

Because travelers’ diarrhea is a relatively nonthreatening illness that is usually mild and self-limiting and can be effectively treated and because of the risks of widespread use of prophylactic anti-infectives (e.g., potential adverse drug reactions, selection of resistant organisms, increased susceptibility to infections caused by these or other organisms), the US Centers for Disease Control (CDC) and most experts recommend that anti-infectives not be used prophylactically by most individuals traveling to areas of risk. In addition, although controlled studies have indicated that various anti-infectives when taken prophylactically have been 52-95% effective in preventing travelers’ diarrhea in several developing areas of the world, efficacy depends on resistance patterns of pathogenic bacteria in each travel area, and such information seldom is available.

While fluoroquinolone resistance for bacteria causing travelers’ diarrhea currently is least common, this could change as use of these drugs increases worldwide. The CDC states that although use of anti-infectives for prophylaxis of travelers’ diarrhea in certain high-risk groups (e.g., travelers with immunosuppression or immunodeficiency) may seem reasonable, currently there are no specific data to support such prevention in these populations. (For information on prophylaxis of travelers’ diarrhea in HIV-infected individuals, see Travelers’ Diarrhea under Uses: GI Infections, in Ciprofloxacin 8:12.18.)

Anti-infectives that have been used for prophylaxis of travelers’ diarrhea are not effective in preventing diarrhea caused by viral or parasitic infections, and use of such prophylaxis may give a false sense of security to the traveler about the risk associated with consuming certain local foods and beverages. The principal preventive measure is prudent dietary practices. If prophylaxis is used, ciprofloxacin, levofloxacin, norfloxacin, or ofloxacin can be given for a maximum of 3 weeks.

Gonorrhea and Associated Infections

Levofloxacin is one of several drugs of choice recommended for the treatment of uncomplicated gonorrhea and is one of several alternatives recommended for the treatment of disseminated gonococcal infection in adults and adolescents. The CDC states that uncomplicated cervical, urethral, or rectal gonorrhea in adults and adolescents may be treated with a single IM dose of ceftriaxone, a single oral dose of cefixime, or a single oral dose of certain fluoroquinolones (ciprofloxacin, ofloxacin, levofloxacin) given in conjunction with an anti-infective regimen effective for presumptive treatment of chlamydia (e.g., a single dose of oral azithromycin or a 7-day regimen of oral doxycycline).

For the treatment of disseminated gonococcal infections in adults and adolescents, the CDC recommends a multiple-dose regimen of IM or IV ceftriaxone or, alternatively, a multiple-dose parenteral regimen of certain IV cephalosporins (cefotaxime, ceftizoxime), certain IV fluoroquinolones (ciprofloxacin, levofloxacin), or IM spectinomycin. However, fluoroquinolones should not be used for the treatment of gonococcal infections acquired in Asia or the Pacific islands (including Hawaii) and may be inadvisable for infections acquired in other areas where Neisseria gonorrhoeae with quinolone resistance have been reported (including California). For additional information on current recommendations for the treatment of gonorrhea and associated infections.

Nongonococcal Urethritis

The CDC recommends oral levofloxacin as an alternative agent for the treatment of nongonococcal urethritis. The CDC currently considers a single oral dose of azithromycin or a 7-day regimen of oral doxycycline the regimens of choice for the treatment of nongonococcal urethritis. Alternative regimens recommended by the CDC are a 7-day regimen of oral erythromycin base or ethylsuccinate or a 7-day regimen of oral ofloxacin or oral levofloxacin.

Patients treated for nongonococcal urethritis should be instructed to abstain from sexual intercourse until 7 days after initiation of treatment and to return for evaluation if symptoms persist or recur after completion of therapy; symptoms alone (without documentation of signs or laboratory evidence of urethral inflammation) are not sufficient basis for retreatment. Patients with persistent or recurrent urethritis who were not compliant with the treatment regimen or were reexposed to untreated sexual partner(s) should be retreated with the initial regimen. If the patient has recurrent and persistent urethritis, was compliant with the regimen, and reexposure can be excluded, the CDC recommends a 7-day regimen of oral erythromycin base or ethylsuccinate given in conjunction with a single 2-g dose of oral metronidazole.

Chlamydial Infections

Although levofloxacin has not been evaluated in clinical trials for the treatment of chlamydial infections, the CDC states that the drug can be considered an alternative agent for the treatment of urogenital chlamydial infections. The CDC currently considers a single oral dose of azithromycin or a 7-day regimen of oral doxycycline the regimens of choice for the treatment of urogenital chlamydial infections in adults and adolescents and recommends a 7-day regimen of oral erythromycin base or ethylsuccinate or a 7-day regimen of oral ofloxacin or oral levofloxacin as alternative regimens.

Pelvic Inflammatory Disease

Oral or IV levofloxacin is recommended for use in the treatment of acute pelvic inflammatory disease (PID). When a parenteral regimen is indicated for the treatment of PID, the CDC generally recommends a regimen of IV cefotetan or IV cefoxitin given in conjunction with IV or oral doxycycline or a regimen of IV clindamycin given in conjunction with IV or IM gentamicin; however, a regimen of IV levofloxacin given with or without IV metronidazole is one of several alternative parenteral regimens. When an oral regimen is indicated for the treatment of PID, oral levofloxacin with or without oral metronidazole is one of several regimens recommended by the CDC. Although fluoroquinolones are effective against both N. gonorrhoeae and C. trachomatis, metronidazole usually is included in fluoroquinolone regimens to provide coverage for anaerobes. For further information on treatment of PID.

Mycobacterial Infections

Treatment of Active Tuberculosis

Fluoroquinolones, including levofloxacin, have been used in multiple-drug regimens for the treatment of active tuberculosis in patients with infections caused by Mycobacterium tuberculosis resistant to first-line agents and in patients intolerant of some first-line agents.

Although the potential role of fluoroquinolones and the optimal length of therapy have not been fully defined, the CDC, ATS, and IDSA state that use of fluoroquinolones as alternative agents for the treatment of active tuberculosis can be considered in patients with relapse, treatment failure, or M. tuberculosis resistant to isoniazid and/or rifampin or when first-line drugs cannot be tolerated. It has been theorized that adding a fluoroquinolone to a first-line multiple-drug regimen possibly may enhance the bactericidal efficacy of the regimen, prevent development of resistance, or shorten the duration of treatment needed; however, the CDC, ATS, and IDSA state that fluoroquinolones should not be considered first-line agents for the treatment of tuberculosis caused by M. tuberculosis susceptible to first-line agents.

Although there is clinical experience with several fluoroquinolones in the treatment of tuberculosis, the ATS, CDC, and IDSA recommend use of gatifloxacin, levofloxacin, or moxifloxacin as second-line agents and, on the basis of cumulative experience, these experts suggest that levofloxacin may be the preferred oral fluoroquinolone when use of one of these drugs is considered necessary in the treatment of the disease.

When an alternative regimen is indicated for the treatment of active tuberculosis because of drug resistance or intolerance and when rifampin cannot be used (e.g., because of rifampin-resistant strains), the CDC, ATS, and IDSA suggest that a regimen of isoniazid, ethambutol, and a fluoroquinolone given for 12-18 months (with pyrazinamide given during at least the first 2 months) can be considered. For the treatment of pulmonary tuberculosis caused by isoniazid-resistant M. tuberculosis (with or without resistance to streptomycin), these experts suggest that adding a fluoroquinolone to a 6-month regimen of rifampin, ethambutol, and pyrazinamide can be considered for patients who have extensive disease.

For the treatment of pulmonary tuberculosis caused by isoniazid- and rifampin-resistant strains (with or without resistance to streptomycin), an 18- to 24-month regimen of a fluoroquinolone, ethambutol, pyrazinamide, a parenteral agent (e.g., streptomycin, amikacin, kanamycin, capreomycin) with or without another alternative agent can be considered. When the infection is caused by strains resistant to isoniazid, rifampin, ethambutol, and/or pyrazinamide (with or without streptomycin resistance), a 24-month regimen of a fluoroquinolone, ethambutol or pyrazinamide (if active), a parenteral agent (e.g., streptomycin, amikacin, kanamycin, capreomycin), and 2 other alternative agents can be considered.

The most recent CDC, ATS, and IDSA recommendations for the treatment of tuberculosis should be consulted for more specific information.

Anthrax

The US Working Group on Civilian Biodefense suggests that, based on in vitro data, oral levofloxacin can be considered an alternative agent for postexposure prophylaxis following suspected or confirmed exposure to aerosolized anthrax spores (inhalational anthrax) when oral ciprofloxacin and oral doxycycline are unavailable. These experts also suggest that oral levofloxacin can be considered an alternative for the treatment of inhalational anthrax when a parenteral regimen is not available (e.g., when there are supply or logistic problems because large numbers of individuals require treatment in a mass casualty setting).

Although the CDC and other experts (e.g., US Working Group on Civilian Biodefense) recommend that treatment of inhalational anthrax be initiated with a multiple-drug parenteral regimen that includes ciprofloxacin or doxycycline and 1 or 2 other anti-infectives predicted to be effective, use of these parenteral regimens may not be possible if large numbers of individuals require treatment in a mass casualty setting and it may be necessary to use an oral regimen. IV levofloxacin was included in some multiple-drug parenteral regimens that were used for the initial treatment of several patients who developed inhalational anthrax following bioterrorism-related exposures to Bacillus anthracis spores that occurred in the US during September and October 2001.

Although there are no animal or human studies to date evaluating use of levofloxacin for treatment or prophylaxis of anthrax and fluoroquinolones other than ciprofloxacin currently are not included in CDC’s recommended regimens, in vitro evidence suggests that other fluoroquinolones would be as effective as ciprofloxacin in treating anthrax. For additional information on treatment of anthrax and recommendations for prophylaxis following exposure to anthrax spores.

Plague

Fluoroquinolones (e.g., ciprofloxacin, levofloxacin, ofloxacin) have been suggested as alternative agents for the treatment of plague caused by Yersinia pestis and also have been recommended for postexposure prophylaxis following a high risk exposure to Y. pestis, including exposure in the context of biologic warfare or bioterrorism. The recommendation for use of fluoroquinolones for treatment or prophylaxis of plague is based on results of in vitro and animal testing.

Although human studies are not available, results of in vitro studies indicate that levofloxacin is active against Y. pestis. For the treatment of plague, IM streptomycin (or IM or IV gentamicin) generally is considered the regimen of choice. Alternative drugs recommended for the treatment of plague when aminoglycosides are not used include IV doxycycline, IV chloramphenicol (drug of choice for plague meningitis), an IV fluoroquinolone (e.g., ciprofloxacin, levofloxacin), or co-trimoxazole (may be less effective than other alternatives).

However, an oral regimen of doxycycline (or tetracycline) or a fluoroquinolone (e.g., ciprofloxacin, levofloxacin, ofloxacin) may be substituted when the patient’s condition improves or when a parenteral regimen is unavailable (e.g., when there are supply or logistic problems because large numbers of individuals require treatment in a mass casualty setting); oral chloramphenicol is considered an alternative in these situations.

In the context of biologic warfare or bioterrorism, some experts (e.g., the US Working Group on Civilian Biodefense, US Army Medical Research Institute of Infectious Diseases) recommend that asymptomatic individuals with exposure to plague aerosol or asymptomatic individuals with household, hospital, or other close contact (within about 2 m) with an individual who has pneumonic plague receive an oral anti-infective regimen for postexposure prophylaxis; however, any exposed individual who develops a temperature of 38.°C or higher or new cough should promptly receive a parenteral anti-infective for treatment of the disease.

If postexposure prophylaxis is indicated, these experts recommend a regimen of oral doxycycline (or tetracycline) or an oral fluoroquinolone (e.g., ciprofloxacin, levofloxacin, ofloxacin); oral chloramphenicol is considered an alternative. For additional information on use of fluoroquinolones for treatment or prophylaxis of plague.

Ophthalmic Infections

For use of levofloxacin in the topical treatment of ophthalmic infections caused by susceptible organisms.

Levofloxacin: Side Effects

Levofloxacin, the levorotatory (S)-enantiomer of the racemate ofloxacin, is an oral and parenteral fluoroquinolone that has bactericidal activity against a wide spectrum of Gram-negative and Gram-positive bacteria (including Streptococcus pneumoniae), as well as atypical respiratory pathogens.

In patients with meningitis, levofloxacin penetration in cerebrospinal fluid and the liquor-to-plasma ratio was assessed at 2 hours after dosing in five patients with spontaneous acute bacterial meningitis. Cerebrospinal fluid levofloxacin concentration at 2 hours after dosing was 2.0 µg/ml, and the liquor-to-plasma ratio at 2 hours after dosing was 0.35.

As for Ciprofloxacin, symptomatic hyperglycemia and/or hypoglycemia have been reported, usually in diabetics who are also taking hypoglycemics or insulin. Such patients should have their blood-glucose concentrations closely monitored, and if signs or symptoms of glucose disturbances develop, levofloxacin should be stopped.

General Adverse Effects

The adverse effects rates of levofloxacin are:

• 3% for nausea;
• 1% for anxiety;
• 3% for insomnia;
• 1% for headache.

No levofloxacin-related adverse events were reported at a rate higher than 1.3%, and most were less common.

High-dose levofloxacin (750 mg) was also well tolerated. Surveillance data reported low adverse event rates:

• Nausea 0.8%;
• Rash 0.5%;
• Abdominal pain 0.4%;
• Diarrhea, dizziness, and vomiting 0.3%.

The adverse drug reaction rate for levofloxacin is still one of the lowest of any fluoroquinolone, at 2% compared with 2-10% for other fluoroquinolones.

Other Rare Side Effects

• Fast heart rate, low blood pressure, fever, breathing problems, shock;
• Swelling of the face, tongue, and throat; skin reactions such as swelling and redness;
• Blood problems, ulcers in the mouth, eyes, gut, and genital organs;
• Unaccountable muscle pain, muscle weakness, muscle cramps;
• Tendon rupture, which may occur within 48 hours after starting treatment and may be bilateral, muscular weakness, which may be of special importance in patients with myasthenia gravis (a rare disease of the nervous system).

Levofloxacin may cause a reduction in the number of white blood cells, and your resistance to infection may be decreased. If you experience an infection with symptoms such as fever and serious deterioration of your general condition, or fever with local infection symptoms such as sore throat/pharynx/mouth or urinary problems, you should see your doctor immediately. A blood test will be taken to check possible reduction of white blood cells (agranulocytosis).

Driving and Using Machinery

Some side-effects like dizziness, drowsiness, and visual disturbances are rare but may impair your ability to concentrate and react. Do not drive, operate dangerous machinery, or have similar activities if you feel that your ability to concentrate and react is impaired.

Storage

Here are some recommendations:

• Keep out of the reach and sight of children;
• Do not use this medicine after the expiry date, which is shown on the packaging. The expiry date refers to the last day of the month;
• Keep the blister in the outer carton in order to protect from light;

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help protect the environment.