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Uses

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Levofloxacin is used orally or IV for the treatment of certain respiratory tract infections, skin and skin structure infections, urinary tract infections, acute pyelonephritis, and chronic prostatitis caused by susceptible organisms. Levofloxacin also is used for postexposure prophylaxis following suspected or confirmed exposure to aerosolized anthrax spores (inhalational anthrax) or the treatment of inhalational anthrax and for the treatment or prophylaxis of plague.

Levofloxacin also is used in the treatment or prevention of travelers' diarrhea. In addition, levofloxacin is recommended as an alternative agent for the treatment of nongonococcal urethritis or urogenital chlamydial infections and for the treatment of active tuberculosis.

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 do not 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, 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

Acute Sinusitis

Levofloxacin is used for the treatment of acute bacterial sinusitis caused by susceptible Streptococcus pneumoniae, Haemophilus influenzae, or Moraxella catarrhalis.

Levofloxacin should be used for the treatment of acute bacterial sinusitis only when there are no other treatment options.Because systemic fluoroquinolones, including levofloxacin, have been associated with disabling and potentially irreversible serious adverse reactions (e.g., tendinitis and tendon rupture, peripheral neuropathy, CNS effects) that can occur together in the same patient (see Cautions)and because acute bacterial sinusitis may be self-limiting in some patients,the risks of serious adverse reactions outweigh the benefits of fluoroquinolones for patients with acute sinusitis.

Clinical Experience

In one open study in adults with acute bacterial sinusitis, therapy with oral levofloxacin (500 mg once daily) or oral amoxicillin and clavulanate potassium (500 mg of amoxicillin 3 times daily) resulted in success rates of 88 or 87%, respectively.

In a double-blind, prospective study in adults with acute bacterial sinusitis randomized to receive levofloxacin in a dosage of 500 mg once daily for 10 days or a dosage of 750 mg once daily for 5 days, safety and efficacy of both regimens were similar. The clinical success rate (defined as complete or partial resolution of pretreatment signs and symptoms of sinusitis to such an extent that no further anti-infective treatment was indicated) in the microbiologically evaluable patient population at the test-of-cure visit was 88.6% in those who received the 10-day regimen compared with 91.4% in those who received the 5-day regimen. When results were stratified according to pathogen, the clinical success rate was 96.3 or 92.6% in those with S. pneumoniae, 92.6 or 90.5% in those with H. influenzae, and 100 or 90.9% in those with M. catarrhalis.

Acute Exacerbations of Chronic Bronchitis

Levofloxacin is used for the treatment of acute bacterial exacerbations of chronic bronchitis caused by susceptible Staphylococcus aureus (oxacillin-susceptible [methicillin-susceptible] strains), S. pneumoniae,H. influenzae, H. parainfluenzae, or M. catarrhalis.

Levofloxacin should be used for the treatment of acute bacterial exacerbations of chronic bronchitis only when there are no other treatment options.Because systemic fluoroquinolones, including levofloxacin, have been associated with disabling and potentially irreversible serious adverse reactions (e.g., tendinitis and tendon rupture, peripheral neuropathy, CNS effects) that can occur together in the same patient (see Cautions)and because acute bacterial exacerbations of chronic bronchitis may be self-limiting is some patients,the risks of serious adverse reactions outweigh the benefits of fluoroquinolones for patients with these infections.

Clinical Experience

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.

Community-acquired Pneumonia

Levofloxacin is used for the treatment of community-acquired pneumonia (CAP) caused by susceptible S. aureus (oxacillin-susceptible strains), S. pneumoniae (including multidrug-resistant S. pneumoniae [MDRSP]), H. influenzae, H. parainfluenzae, Klebsiella pneumoniae, Legionella pneumophila, M. catarrhalis, Chlamydophila pneumoniae (formerly Chlamydia pneumoniae), or Mycoplasma pneumoniae.

Initial treatment of CAP generally involves use of an empiric anti-infective regimen based on the most likely pathogens and local susceptibility patterns; treatment may then be changed (if possible) to provide a more specific regimen (pathogen-directed therapy) based on results of in vitro culture and susceptibility testing. The most appropriate empiric regimen varies depending on the severity of illness at the time of presentation, whether outpatient treatment or hospitalization in or out of an intensive care unit (ICU) is indicated, and the presence or absence of cardiopulmonary disease and other modifying factors that increase the risk of certain pathogens (e.g., methicillin-resistant S. aureus [MRSA; also known as oxacillin-resistant S. aureus], penicillin-resistant S. pneumoniae, MDRSP, enteric gram-negative bacilli, Ps. aeruginosa).

For additional information on management of CAP, the current clinical practice guidelines from the Infectious Diseases Society of America (IDSA) available at http://www.idsociety.org should be consulted.

Clinical Experience

In one controlled clinical study in adults with CAP, a 7- to 14-day regimen that included IV and/or oral 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 a randomized study in CAP patients 65 years of age or older (mean age 77.9 years), the clinical cure rate at the test-of-cure visit (5-21 days after end of treatment) was 92.9% in those who received moxifloxacin and 87.9% in those who received levofloxacin; the bacteriologic success rate was 81% in those who received moxifloxacin and 75% in those who received levofloxacin.

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.

Safety and efficacy of a 5-day regimen of levofloxacin (750 mg IV or orally once daily for 5 days) was compared with that of a 10-day regimen of the drug (500 mg IV or orally once daily for 10 days) in a double-blind, randomized, prospective study in adults with clinically or radiologically confirmed mild to severe CAP. The clinical success rate (cure and improvement) was about 91% in both groups.

A clinical and bacteriologic success rate of 95% has been reported when levofloxacin was used in adults for the treatment of CAP caused by multidrug-resistant S. pneumoniae.

Nosocomial Pneumonia

Levofloxacin is used for the treatment of nosocomial pneumonia caused by susceptible S. aureus (oxacillin-susceptible strains), S. pneumoniae, H. influenzae, Escherichia coli, K. pneumoniae, Ps. aeruginosa, or Serratia marcescens. Adjunctive therapy should be used as clinically indicated. If the infection is known or suspected of being caused by Ps. aeruginosa, concomitant therapy with an antipseudomonal β-lactam anti-infective is recommended.

Local susceptibility data should be used when selecting initial empiric regimens for the treatment of nosocomial pneumonia, including hospital-acquired, ventilator-associated, and healthcare-associated pneumonia. For empiric treatment of hospital-acquired bacterial pneumonia in patients with risk factors for multidrug-resistant bacteria, the American Thoracic Society (ATS) and IDSA recommend use of anti-infectives that have a broad spectrum of activity against gram-positive, gram-negative, and anaerobic bacteria. An anti-infective active against MRSA (e.g., vancomycin, linezolid) should be included in the initial empiric regimen in hospitals where MRSA is common or if there are other factors that increase the risk for these strains.

For additional information on management of nosocomial pneumonia, the current clinical practice guidelines from IDSA available at http://www.idsociety.org should be consulted.

Clinical Experience

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 MRSA received concomitant vancomycin. The overall clinical success rate 3-15 days after completion of therapy was 58.1% for those receiving levofloxacin and 60.6% for those receiving the comparator regimen; the overall microbiologic eradication rate was 66.7 and 60.6%, respectively.

Skin and Skin Structure Infections

Levofloxacin is used for the treatment of mild to moderate uncomplicated skin and skin structure infections caused by susceptible S. aureus (oxacillin-susceptible strains) or S. pyogenes (group A β-hemolytic streptococci) and 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.

Levofloxacin has been effective for the treatment of uncomplicated abscesses, cellulitis, erysipelas, furuncles, impetigo, pyoderma, and wound or surgical infections caused by susceptible bacteria. 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 93-97.5% in patients with mild to moderate skin and skin structure infections.

In an open-label, randomized study in patients with complicated skin and skin structure infections, the overall success rate (improved or cured) in clinically evaluable patients at 2-5 days after completion of treatment was 84.1% in those randomized to receive levofloxacin (750 mg once daily for 7-14 days given IV and/or orally as indicated) and 80.3% in those randomized to the comparator regimen (fixed combination of IV ticarcillin and clavulanate followed by oral amoxicillin and clavulanate for a total duration of 7-14 days). Success rates varied depending on the diagnosis, ranging from 69% in those with infected diabetic ulcers to 90% in those with infected abscesses. In the microbiologically evaluable population, the overall rate of eradication was 83.7% in those who received levofloxacin and 71.4% in those who received the comparator regimen.

For additional information on management of skin and skin structure infections, the current clinical practice guidelines from IDSA available at http://www.idsociety.org should be consulted.

Urinary Tract Infections and Prostatitis

Uncomplicated Urinary Tract Infections

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

Levofloxacin should be used for the treatment of uncomplicated UTIs only when there are no other treatment options.Because systemic fluoroquinolones, including levofloxacin, have been associated with disabling and potentially irreversible serious adverse reactions (e.g., tendinitis and tendon rupture, peripheral neuropathy, CNS effects) that can occur together in the same patient (see Cautions)and because uncomplicated UTIs may be self-limiting in some patients,the risks of serious adverse reactions outweigh the benefits of fluoroquinolones for patients with uncomplicated UTIs.

IDSA and other experts state that fluoroquinolones (ciprofloxacin, levofloxacin, ofloxacin) should be considered alternative agents for the treatment of uncomplicated UTIs (e.g., acute cystitis) and should be used in these infections only when other urinary anti-infectives are likely to be ineffective or are contraindicated or not tolerated.

Complicated Urinary Tract Infections

Levofloxacin is used 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 acute pyelonephritis caused by susceptible E. coli, including cases with concurrent bacteremia.

In controlled clinical studies, levofloxacin therapy was as effective as ciprofloxacin 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 for the treatment of chronic prostatitis caused by susceptible E. coli, E. faecalis, or S. epidermidis (oxacillin-susceptible strains).

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 76.8% 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 81.8, 75, or 78.6%, respectively, in those who received ciprofloxacin.

Endocarditis

Levofloxacin is used as an alternative for treatment of endocarditis (native or prosthetic valve or other prosthetic material) caused by fastidious gram-negative bacilli known as the HACEK group (Haemophilus, Aggregatibacter, Cardiobacterium hominis, Eikenella corrodens, Kingella).

The American Heart Association (AHA) and IDSA recommend ceftriaxone (or other third or fourth generation cephalosporin) for the treatment of endocarditis caused by the HACEK group, but state that a fluoroquinolone (ciprofloxacin, levofloxacin, moxifloxacin) may be considered in patients who cannot tolerate cephalosporins. Because only limited data are available regarding use of fluoroquinolones for the treatment of HACEK endocarditis, an infectious disease specialist should be consulted when treating such infections in patients who cannot tolerate cephalosporins.

GI Infections

Salmonella Gastroenteritis

Levofloxacin is used as an alternative for the treatment of Salmonella gastroenteritis (with or without bacteremia).

Anti-infective therapy generally is not indicated in otherwise healthy individuals with uncomplicated (noninvasive) gastroenteritis caused by Salmonella since such therapy may prolong the duration of fecal excretion of the organism and there is no evidence that it shortens the duration of the disease; however, the US Centers for Disease Control and Prevention (CDC), American Academy of Pediatrics (AAP), IDSA, and others recommend anti-infective therapy in individuals with severe Salmonella gastroenteritis and in those who are at increased risk of invasive disease. These individuals include infants younger than 3-6 months of age; individuals older than 50 years of age; individuals with hemoglobinopathies, severe atherosclerosis or valvular heart disease, prostheses, uremia, chronic GI disease, or severe colitis; and individuals who are immunocompromised because of malignancy, immunosuppressive therapy, human immunodeficiency virus (HIV) infection, or other immunosuppressive illness.

Because HIV-infected individuals with Salmonella gastroenteritis are at high risk for bacteremia, CDC, National Institutes of Health (NIH), and IDSA recommend that such patients receive anti-infective treatment to prevent extraintestinal spread of the infection. These experts state that the initial drug of choice for the treatment of salmonella gastroenteritis (with or without bacteremia) in HIV-infected adults is ciprofloxacin; other fluoroquinolones (levofloxacin, moxifloxacin) also are likely to be effective in these patients, but clinical data are limited. Depending on results of in vitro susceptibility testing of the causative organism, alternatives for treatment of Salmonella gastroenteritis in HIV-infected adults are co-trimoxazole or third generation cephalosporins (ceftriaxone, cefotaxime).

Shigella Infections

Levofloxacin is used for the treatment of shigellosis caused by susceptible Shigella.

Infections caused by Sh. sonnei usually are self-limited (48-72 hours), and mild cases may not require treatment with anti-infectives. However, because there is some evidence that anti-infectives may shorten the duration of diarrhea and the period of fecal excretion of Shigella, anti-infective treatment generally is recommended in addition to fluid and electrolyte replacement in patients with severe shigellosis, dysentery, or underlying immunosuppression. An empiric treatment regimen can be used initially, but in vitro susceptibility testing of clinical isolates is indicated since resistance is common. A fluoroquinolone (preferably ciprofloxacin or, alternatively, levofloxacin or moxifloxacin) generally has been recommended for the treatment of shigellosis. However, fluoroquinolone-resistant Shigella have been reported in the US, especially in international travelers, the homeless, and men who have sex with men (MSM). Depending on in vitro susceptibility, alternatives to fluoroquinolones for the treatment of shigellosis include co-trimoxazole or azithromycin (not recommended in those with bacteremia); ceftriaxone or azithromycin has been recommended when the susceptibility of the isolate is unknown or when ampicillin- or co-trimoxazole-resistant strains are involved.

Travelers' Diarrhea

Oral levofloxacin is used for the short-term treatment of travelers' diarrhea and has been used for the prevention of travelers' diarrhea in adults traveling for relatively short periods of time to high-risk areas.

The most common cause of travelers' diarrhea worldwide is noninvasive enterotoxigenic strains of E. coli (ETEC), but travelers' diarrhea also can be caused by various other bacteria, including enteroadherent and other E. coli pathotypes, Campylobacter jejuni, Shigella, Salmonella, Aeromonas, Plesiomonas shigelloides, Yersinia enterocolitica, Vibrio parahaemolyticus, or non-O-group 1 V. cholerae. In some cases, travelers' diarrhea is caused by parasitic enteric pathogens (e.g., Giardia duodenalis [also known as G. lamblia or G. intestinalis], Cryptosporidium parvum, Cyclospora cayetanensis, Entamoeba histolytica, Dientamoeba fragilis) or viral enteric pathogens (e.g., norovirus, rotavirus, astrovirus).

Countries where travelers are at low risk of travelers' diarrhea include the US, Canada, Australia, New Zealand, Japan, and countries in Northern and Western Europe. Travelers are at intermediate risk for travelers' diarrhea in Eastern Europe, South Africa, and some of the Caribbean islands, but are at high risk in most of Asia, the Middle East, Africa, and Central and South America.

Treatment

Travelers' diarrhea caused by bacteria may be self-limited and often resolves within 3-7 days without anti-infective treatment. If diarrhea is moderate or severe, associated with fever or bloody stools, persisting longer than 3 days, or extremely disruptive to travel plans, short-term (1-3 days) treatment with an anti-infective usually is recommended. Since bacteria are the most common cause of travelers' diarrhea (80-90% of cases), an anti-infective directed against enteric bacterial pathogens is used for empiric treatment. CDC and other experts state that a fluoroquinolone (e.g., ciprofloxacin, levofloxacin) generally is considered the anti-infective of choice for empiric treatment, including self-treatment, of travelers' diarrhea in adults. Azithromycin can be used as a treatment alternative for individuals who should not receive fluoroquinolones (e.g., children, pregnant women) and is a drug of choice for travelers in areas with a high prevalence of fluoroquinolone-resistant Campylobacter (e.g., South and Southeast Asia) or those who have not responded after 48 hours of fluoroquinolone treatment. Rifaximin can be considered an alternative when the causative organism is enterotoxigenic E. coli, but its overall usefulness for empiric self-treatment of travelers' diarrhea remains to be determined. Antimotility agents may be used as an adjunct to anti-infective treatment to provide symptomatic relief; oral rehydration therapy should be used if indicated, especially in young children or geriatric adults.

Prophylaxis

CDC and most experts do not recommend routine prophylactic use of anti-infectives to prevent travelers' diarrhea in individuals traveling to areas of risk. Because travelers' diarrhea is a relatively nonthreatening illness that usually is mild and self-limiting and can be effectively treated and because of the risks of widespread use of prophylactic anti-infectives (i.e., potential adverse drug reactions, selection of resistant organisms, increased susceptibility to infections caused by these or other organisms), anti-infective prophylaxis for prevention of travelers' diarrhea should be considered only in select individuals. This includes short-term travelers who are high-risk individuals (e.g., HIV-infected or other immunocompromised individuals, travelers with poorly controlled diabetes mellitus or chronic renal failure) and those who are taking critical trips during which even a short period of diarrhea could adversely affect the purpose of the trip.

The use of anti-infective prophylaxis in travelers should be weighed against use of prompt, early self-treatment with anti-infectives, a strategy that can limit the duration of illness to 6-24 hours in most cases. If anti-infective prophylaxis is indicated, a fluoroquinolone (e.g., ciprofloxacin, levofloxacin) usually has been recommended for nonpregnant adults, although the increasing incidence of fluoroquinolone resistance in pathogens that cause travelers' diarrhea (e.g., Campylobacter, Shigella) should be considered and may limit their benefit in the future. Rifaximin also has been used for prevention of travelers' diarrhea. Results of controlled studies indicate that the diarrhea attack rate can be reduced by 90% or more by the use of anti-infective prophylaxis; however, efficacy depends on resistance patterns of pathogenic bacteria in each travel area and these patterns have evolved over the last several decades.

Anti-infectives recommended for prophylaxis of travelers' diarrhea may prevent bacterial illness, but are not effective in preventing diarrhea caused by parasitic or viral pathogens, 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 measures that can be used to prevent travelers' diarrhea are prudent dietary practices (e.g., avoid raw or undercooked meat and seafood, avoid raw fruits and vegetables, avoid foods or drinks purchased from street vendors or establishments where unhygienic conditions are present).

Anthrax

Levofloxacin is used for inhalational anthrax (postexposure) to reduce the incidence or progression of disease following exposure to aerosolized Bacillus anthracis in adults and children 6 months of age or older. Although efficacy of levofloxacin for postexposure prophylaxis to prevent inhalational anthrax has not been evaluated in human clinical trials, the drug is labeled by the US Food and Drug Administration (FDA) for this indication based on a surrogate end point derived from a primate model of inhalational anthrax that predicts clinical benefit based on plasma levofloxacin concentrations achievable in humans with recommended oral or IV dosages.

CDC, US Public Health Service Advisory Committee on Immunization Practices (ACIP), US Working Group on Civilian Biodefense, and US Army Medical Research Institute of Infectious Diseases (USAMRIID) recommend oral ciprofloxacin and oral doxycycline as the initial drugs of choice for postexposure prophylaxis following exposure to aerosolized anthrax spores, including exposures that occur in the context of biologic warfare or bioterrorism. Some of these experts (e.g., ACIP, US Working Group on Civilian Biodefense) state that levofloxacin or other oral fluoroquinolones (moxifloxacin, ofloxacin) are alternatives for postexposure prophylaxis when ciprofloxacin or doxycycline cannot be used.

US Working Group on Civilian Biodefense and USAMRIID also suggest that oral levofloxacin or other oral fluoroquinolones (moxifloxacin, ofloxacin) can be considered alternatives for the treatment of inhalational anthrax when a parenteral regimen is not available. Although CDC and these experts 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. In vitro data suggest that other fluoroquinolones would be as effective as and could be substituted for ciprofloxacin for treatment of inhalational anthrax. 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.

For additional information on postexposure prophylaxis and treatment of anthrax, see Uses: Anthrax in Ciprofloxacin 8:12.18.

Chlamydial Infections

Levofloxacin is considered an alternative for the treatment of urogenital infections caused by Chlamydia trachomatis. CDC states that a single oral dose of azithromycin or a 7-day regimen of oral doxycycline are the recommended regimens for the treatment of C. trachomatis urogenital infections in adults and adolescents; a 7-day regimen of oral erythromycin base or ethylsuccinate or a 7-day regimen of oral levofloxacin or ofloxacin are alternative regimens.

Individuals with HIV infection should receive the same treatment regimens recommended for other individuals with C. trachomatis urogenital infections.

Any individual who had sexual contact with a patient with C. trachomatis urogenital infection during the 60 days preceding the patient's onset of symptoms or diagnosis should be referred for evaluation, testing, and presumptive treatment with a regimen effective against Chlamydia. To minimize transmission and avoid reinfection, individuals treated for C. trachomatis urogenital infections should abstain from sexual intercourse until they and their partner(s) have been adequately treated (i.e., for 7 days after a single-dose regimen or after completion of a 7-day regimen) and symptoms have resolved.

Gonorrhea and Associated Infections

Although levofloxacin was used in the past for the treatment of uncomplicated gonorrhea caused by susceptible Neisseria gonorrhoeae, quinolone-resistant N. gonorrhoeae (QRNG) is widely disseminated throughout the world, including in the US. (See Resistance in Neisseria gonorrhoeae under Warnings/Precautions: Other Warnings/Precautions, in Cautions.) Therefore, CDC states that fluoroquinolones are no longer recommended for the treatment of gonorrhea and should not be used routinely for any associated infections that may involve N. gonorrhoeae (e.g., pelvic inflammatory disease [PID], epididymitis).

Levofloxacin is considered an alternative agent for the treatment of PID.(See Uses: Pelvic Inflammatory Disease.)

Levofloxacin is considered an alternative agent for the treatment of acute epididymitis. Although acute epididymitis in sexually active men younger than 35 years of age is most frequently caused by C. trachomatis or N. gonorrhoeae, epididymitis can also be caused by other organisms (e.g., sexually transmitted enteric bacteria, Mycoplasma, Ureaplasma, mycobacteria, fungi). Presumptive treatment is usually initiated prior to availability of all diagnostic laboratory test results, and the anti-infective regimen is selected based on the patient's risk for chlamydia, gonorrhea, and/or sexually transmitted enteric bacteria (e.g., E. coli). For treatment of acute epididymitis most likely caused by sexually transmitted chlamydia and gonorrhea, CDC recommends a single IM dose of ceftriaxone used in conjunction with a 10-day regimen of oral doxycycline. For treatment of acute epididymitis most likely caused by sexually transmitted chlamydia and gonorrhea and enteric bacteria (e.g., in men who practice insertive anal sex), CDC recommends a single IM dose of ceftriaxone given in conjunction with a 10-day regimen of oral levofloxacin or ofloxacin. If acute epididymitis is most likely caused by enteric bacteria (e.g., in men who have undergone prostate biopsy, vasectomy, or other urinary tract instrumentation procedure) and gonorrhea has been ruled out (e.g., by gram, methylene blue, or gentian violet stain), CDC states that a 10-day regimen of oral levofloxacin or ofloxacin can be used alone.

For information on current recommendations for the treatment of gonorrhea and associated infections, see Uses: Gonorrhea and Associated Infections in Ceftriaxone 8:12.06.12. For additional information on quinolone-resistantN. gonorrhoeae(QRNG), see Uses: Gonorrhea and Associated Infections in Ciprofloxacin 8:12.18.

Meningitis and CNS Infections

Levofloxacin has been used in a limited of patients for the treatment of meningitis caused by susceptible organisms (e.g., Rhodococcus equi) and has been suggested as a possible alternative for use in conjunction with other anti-infectives for the treatment of meningitis caused by susceptible bacteria.

The safety and efficacy of levofloxacin for the treatment of CNS infections have not been established. Levofloxacin is distributed into CSF to some extent, and limited data from animal studies indicate that levofloxacin used alone or in conjunction with other anti-infectives (e.g., cefotaxime, ceftriaxone, meropenem) has been effective for the treatment of experimental meningitis caused by susceptible S. pneumoniae. Some experts state that fluoroquinolones (e.g., ciprofloxacin, moxifloxacin) should be considered for the treatment of meningitis only when the infection is caused by multidrug-resistant gram-negative bacilli or when the usually recommended anti-infectives cannot be used or have been ineffective.

Mycobacterial Infections

Treatment of Active Tuberculosis

Levofloxacin is used in multiple-drug regimens for the treatment of active tuberculosis caused by Mycobacterium tuberculosis.

Although the potential role of fluoroquinolones and the optimal length of therapy have not been fully defined, ATS, CDC, IDSA, and others state that use of fluoroquinolones as alternative (second-line) agents can be considered for the treatment of active tuberculosis in patients intolerant of certain first-line agents and in those with relapse, treatment failure, or M. tuberculosis resistant to certain first-line agents. If a fluoroquinolone is used in multiple-drug regimens for the treatment of active tuberculosis, ATS, CDC, IDSA, and others recommend levofloxacin or moxifloxacin.

Although levofloxacin (or moxifloxacin) has been used instead of ethambutol during the intensive phase of treatment in adults who could not receive ethambutol and has been used instead of isoniazid throughout the course of treatment in adults who could not receive isoniazid, ATS, CDC, and IDSA state that there is no evidence that levofloxacin (or moxifloxacin) can be used to replace a rifamycin or pyrazinamide while maintaining a 6-month treatment regimen.

The fact that there are reports of fluoroquinolone-resistant M. tuberculosis and increasing reports of extensively drug-resistant tuberculosis (XDR tuberculosis) should be considered. XDR tuberculosis is caused by strains that are resistant to rifampin and isoniazid (multiple-drug resistant strains) and also are resistant to a fluoroquinolone and at least one parenteral second-line antimycobacterial (capreomycin, kanamycin, amikacin).

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

Other Mycobacterial Infections

Levofloxacin has been used in multiple-drug regimens for the treatment of disseminated M. avium complex (MAC) infections.

ATS and IDSA state that the role of fluoroquinolones in the treatment of MAC infections has not been established. If a fluoroquinolone is included in a multiple-drug treatment regimen (e.g., for macrolide-resistant MAC infections), levofloxacin or moxifloxacin may be preferred, although many strains are resistant in vitro.

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

Nongonococcal Urethritis

Levofloxacin is considered as an alternative agent for the treatment of nongonococcal urethritis (NGU). NGU can be caused by various organisms (e.g., Chlamydia, M. genitalium, Trichomonas vaginalis, Ureaplasma, enteric bacteria) and is treated presumptively at the time of diagnosis. CDC states that a single dose of oral azithromycin or a 7-day regimen of oral doxycycline are the recommended regimens for the treatment of NGU; a 7-day regimen of oral erythromycin base or ethylsuccinate or a 7-day regimen of oral levofloxacin or ofloxacin are alternative regimens.

CDC states that men with persistent or recurrent NGU who were not compliant with the treatment regimen or were reexposed to untreated sexual partner(s) can be retreated with the initial regimen. In other patients, symptoms alone (without documentation of signs or laboratory evidence of urethral inflammation) are not a sufficient basis for retreatment and an objective diagnosis of persistent or recurrent NGU should be made before considering additional treatment. Because there is some evidence that M. genitalium is the most frequent cause of persistent or recurrent NGU, CDC states that those initially treated with doxycycline should receive retreatment with a single dose of oral azithromycin and those initially treated with azithromycin should receive retreatment with a 7-day regimen of oral moxifloxacin. However, if the patient with persistent or recurrent urethritis has sex with women and is in an area where T. vaginalis is prevalent, CDC recommends presumptive retreatment with a single 2-g dose of oral metronidazole or tinidazole and referral of their partner(s) for evaluation and appropriate treatment.

NGU may facilitate transmission of HIV and men diagnosed with NGU should be tested for HIV. Individuals with HIV infection should receive the same treatment regimens recommended for other individuals with NGU.

Any individual who had sexual contact with a patient with NGU within the preceding 60 days should be referred for evaluation, testing, and presumptive treatment with a regimen effective against Chlamydia. To minimize transmission and avoid reinfection, men treated for NGU should abstain from sexual intercourse until they and their sexual partner(s) have been adequately treated.

Pelvic Inflammatory Disease

Levofloxacin is considered an alternative agent for the treatment of acute pelvic inflammatory disease (PID), but should not be used routinely for treatment of PID or any infections that may involve N. gonorrhoeae.

When a combined IM and oral regimen is used for the treatment of mild to moderately severe acute PID, CDC recommends a single IM dose of ceftriaxone, cefoxitin (with oral probenecid), or cefotaxime given in conjunction with a 14-day regimen of oral doxycycline (with or without a 14-day regimen of oral metronidazole). If parenteral cephalosporins are not feasible (e.g., because of cephalosporin allergy), CDC states that a 14-day regimen of oral levofloxacin, ofloxacin, or moxifloxacin given in conjunction with a 14-day regimen of oral metronidazole can be considered if the community prevalence and individual risk of gonorrhea are low and diagnostic testing for gonorrhea is performed. If culture results are positive for N. gonorrhoeae, the PID treatment regimen should be selected based on results of in vitro susceptibility testing. If QRNG are identified or if in vitro susceptibility cannot be determined (e.g., only nucleic acid amplification test [NAAT] for gonorrhea is available), consultation with an infectious disease specialist is recommended.

For further information on the treatment of PID, see Uses: Pelvic Inflammatory Disease in the Cephalosporins General Statement 8:12.06.

Plague

Levofloxacin is used for the treatment of plague, including pneumonic and septicemic plague, caused by Yersinia pestis and for postexposure prophylaxis of plague in adults and children 6 months of age or older. Based on results of in vitro and animal testing, fluoroquinolones (ciprofloxacin, levofloxacin, moxifloxacin, ofloxacin) are recommended as alternatives for the treatment of plague and for postexposure prophylaxis following a high-risk exposure to Y. pestis, including exposures that occur in the context of biologic warfare or bioterrorism.

Efficacy of levofloxacin for treatment or prophylaxis of plague has not been evaluated in clinical trials in humans for ethical and feasibility reasons. The drug is labeled by FDA for this indication based on an efficacy study in animals that demonstrated a survival benefit. In a placebo-controlled study, African green monkeys were exposed to an inhaled dose of Y. pestis (mean dose of 65 LD50 [ range 3-145 LD50]) and then randomized to receive a 10-day regimen of levofloxacin or placebo initiated within 6 hours after the onset of fever. In vitro testing indicated that the Y. pestis strain used in this study had a levofloxacin MIC of 0.03 mcg/mL. Pharmacokinetic data from the monkeys indicated that mean levofloxacin plasma concentrations at the end of a single 30-minute IV infusion of the drug ranged from 2.84-3.5 mcg/mL and trough concentrations 24 hours after the dose ranged from less than 0.03 to 0.06 mcg/mL. Study results indicated that mortality in the levofloxacin treatment group (1 out of 17) was significantly lower compared with mortality in the placebo group (7 out of 7). One of the levofloxacin-treated monkeys was euthanized on day 9 after exposure to Y. pestis because of a gastric complication; blood cultures in this monkey were positive for Y. pestis on day 3, but all subsequent daily blood cultures from days 4 through 7 were negative.

For the treatment of plague, IM streptomycin (or IM or IV gentamicin) historically has been considered the regimen of choice. Alternatives recommended for the treatment of plague when aminoglycosides are not used include IV doxycycline (or IV tetracycline), IV chloramphenicol (a drug of choice for plague meningitis), an IV fluoroquinolone (ciprofloxacin [a drug of choice for plague meningitis], levofloxacin, moxifloxacin), or co-trimoxazole (may be less effective than other alternatives). Anti-infective regimens recommended for treatment of naturally occurring or endemic bubonic, septicemic, or pneumonic plague also are recommended for treatment of plague that occurs following exposure to Y. pestis in the context of biologic warfare or bioterrorism. Some experts (e.g., US Working Group on Civilian Biodefense, USAMRIID) recommend that treatment of plague in the context of biologic warfare or bioterrorism be initiated with a parenteral anti-infective regimen. However, an oral regimen of doxycycline (or tetracycline) or a fluoroquinolone (ciprofloxacin, levofloxacin, moxifloxacin, 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., US Working Group on Civilian Biodefense, USAMRIID) 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 38.5°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 (ciprofloxacin, levofloxacin, moxifloxacin, 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,

Dosage and Administration

Administration

Levofloxacin is administered orally or by IV infusion. The drug should not be given IM, subcutaneously, intrathecally, or intraperitoneally.

IV administration of levofloxacin generally is reserved for patients who do not tolerate or are unable to take the drug orally and in other patients in whom the IV route offers a clinical advantage.

Patients receiving oral or IV levofloxacin should be well hydrated and instructed to drink fluids liberally to prevent highly concentrated urine and formation of crystals in urine.

Oral Administration

Levofloxacin tablets and oral solution are bioequivalent.

Levofloxacin tablets may be given without regard to meals, but levofloxacin oral solution should be given 1 hour before or 2 hours after meals.

When levofloxacin tablets are given with a standard high-fat breakfast (e.g., 2 eggs fried in butter, 2 strips of bacon, hash brown potatoes, 2 slices of toast with butter, 180 mL of milk), peak serum levofloxacin concentrations are decreased approximately 14% (not considered clinically important). When given with calcium-fortified orange juice, peak serum concentrations are decreased 18%; when given with a breakfast of calcium-fortified orange juice and whole grain, fortified, ready-to-eat cereal with skim milk, peak concentrations are decreased 24% and the time to peak concentrations is increased 46%. When levofloxacin is given as an oral solution, food reportedly decreases peak serum concentrations by approximately 25%.

Levofloxacin should be administered orally at least 2 hours before or 2 hours after antacids containing magnesium or aluminum, metal cations (e.g., iron), sucralfate, multivitamins or dietary supplements containing iron or zinc, or buffered didanosine (pediatric oral solution admixed with antacid). These drugs may interfere with oral absorption of levofloxacin, resulting in subtherapeutic systemic concentrations of the quinolone.(See Drug Interactions.)

IV Infusion

Commercially available levofloxacin premixed injection for IV infusion containing 5 mg/mL in 5% dextrose injection in single-use flexible containers is used without further dilution.

Alternatively, if commercially available levofloxacin concentrate for injection containing 25 mg/mL in single-use vials is used, the concentrate must be diluted prior to IV infusion with a compatible IV solution (e.g., 0.9% sodium chloride injection, 5% dextrose injection) to provide a solution containing 5 mg/mL.

Levofloxacin should not be admixed 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 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).

Levofloxacin solutions should be inspected visually for particulate matter prior to administration whenever solution and container permit; the solutions should be discarded if they are cloudy or contain precipitates.

Levofloxacin premixed injection for IV infusion in 5% dextrose and levofloxacin concentrate for injection for IV infusion contain no preservatives; any unused portions of the solutions should be discarded.

Rate of Administration

Levofloxacin doses of 250 or 500 mg should be administered by IV infusion over a period of 60 minutes; doses of 750 mg should be administered by IV infusion over a period of 90 minutes.

Rapid IV infusion or injection has been associated with hypotension and must be avoided.

Dosage

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Dosage of oral and IV levofloxacin is identical.

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

Safety of levofloxacin for treatment durations longer than 28 days in adults and longer than 14 days in children and adolescents has not been studied, and experience with treatment durations up to 60 days is limited; therefore, the manufacturer states that the drug should be given for prolonged periods only when potential benefits outweigh risks.

Respiratory Tract Infections

Acute Sinusitis

If levofloxacin is used for the treatment of acute bacterial sinusitis, the usual adult dosage is 500 mg once every 24 hours for 10-14 days. Alternatively, adults can receive a dosage of 750 mg once every 24 hours for 5 days.(See Acute Sinusitis under Uses: Respiratory Tract Infections.)

Acute Exacerbations of Chronic Bronchitis

If levofloxacin is used for the treatment of acute bacterial exacerbations of chronic bronchitis, the usual adult dosage of levofloxacin is 500 mg once every 24 hours for 7 days.(See Acute Exacerbations of Chronic Bronchitis under Uses: Respiratory Tract Infections.)

Community-acquired Pneumonia

For the treatment of community-acquired pneumonia (CAP), the usual adult dosage of levofloxacin is 500 mg once every 24 hours for 7-14 days. Alternatively, adults can receive a dosage of 750 mg once every 24 hours for 5 days for treatment of CAP caused by S. pneumoniae (except multidrug-resistant S. pneumonia [MDRSP]), Haemophilus influenzae, H. parainfluenzae, Chlamydophila pneumoniae, or Mycoplasma pneumoniae.

When used in empiric regimens for the treatment of CAP or for treatment of CAP caused by Pseudomonas aeruginosa, the Infectious Diseases Society of America (IDSA) and American Thoracic Society (ATS) recommend that levofloxacin be given in a dosage of 750 mg once daily.

IDSA and ATS state that CAP should be treated for a minimum of 5 days and patients should be afebrile for 48-72 hours before discontinuing anti-infective therapy.

Nosocomial Pneumonia

For the treatment of nosocomial pneumonia, the usual adult dosage of levofloxacin is 750 mg once every 24 hours for 7-14 days.

Skin and Skin Structure Infections

For the treatment of uncomplicated skin and skin structure infections, the usual adult dosage of levofloxacin is 500 mg once every 24 hours for 7-10 days.

For the treatment of complicated skin and skin structure infections, the usual adult dosage of levofloxacin is 750 mg once every 24 hours for 7-14 days.

Urinary Tract Infections and Prostatitis

If levofloxacin is used for the treatment of uncomplicated urinary tract infections (UTIs), the usual adult dosage is 250 mg once every 24 hours for 3 days.(See Uncomplicated Urinary Tract Infections under Uses: Urinary Tract Infections and Prostatitis.)

For the treatment of complicated UTIs or acute pyelonephritis, the usual adult dosage of levofloxacin is 250 mg once every 24 hours for 10 days. Alternatively, adults can receive 750 mg once every 24 hours for 5 days for the treatment of complicated UTIs caused by Escherichia coli, Klebsiella pneumoniae, or Proteus mirabilis or for the treatment of acute pyelonephritis caused by E. coli.

The usual adult dosage of levofloxacin for the treatment of chronic prostatitis is 500 mg once every 24 hours for 28 days.

GI Infections

Salmonella Gastroenteritis

For the treatment of Salmonella gastroenteritis (with or without bacteremia) in adults with human immunodeficiency virus (HIV) infection, the recommended dosage of oral or IV levofloxacin is 750 mg once daily.

The recommended duration of treatment in HIV-infected adults is 7-14 days in those with CD4 T-cell counts of 200 cells/mm or greater (14 days or longer if the patient is bacteremic or the infection is complicated) or 2-6 weeks in those with CD4 T-cell counts less than 200 cells/mm.

The role of long-term treatment (secondary prophylaxis) in those with recurrent bacteremia is not well established and the benefits must be weighed against the risks of long-term anti-infective exposure.

Shigella Infections

For the treatment of Shigella infections in HIV-infected adults, the recommended dosage of oral or IV levofloxacin is 750 mg once daily.

The recommended duration of treatment in these patients is 7-10 days for gastroenteritis or at least 14 days for bacteremic infections. Recurrent infections, especially in patients with CD4 T-cell counts less than 200 cells/mm, may require up to 6 weeks of treatment.

Travelers' Diarrhea

For the treatment of travelers' diarrhea in adults, some clinicians recommend that oral levofloxacin be given in a dosage of 500 mg once daily for 1-3 days.

Although the use of anti-infectives for prophylaxis of travelers' diarrhea generally is discouraged (see Travelers' Diarrhea under Uses: GI Infections), if oral levofloxacin is used, the recommended adult dosage is 500 mg once daily during the period of risk (not exceeding 2-3 weeks) beginning the day of travel and continuing for 1 or 2 days after leaving the area of risk.

Anthrax

Postexposure Prophylaxis of Anthrax

If levofloxacin is used for inhalational anthrax (postexposure) to reduce the incidence or progression of disease following suspected or confirmed exposure to aerosolized Bacillus anthracis spores, including exposures in the context of biologic warfare or bioterrorism, the manufacturer recommends that adults and pediatric patients 6 months of age or older weighing more than 50 kg receive a dosage of 500 mg once daily and that pediatric patients 6 months of age or older weighing less than 50 kg receive 8 mg/kg (up to 250 mg) every 12 hours.

Anti-infective prophylaxis should be initiated as soon as possible following suspected or confirmed exposure to aerosolized B. anthracis. If subsequent epidemiologic and laboratory test data indicate that individuals started on prophylaxis were not exposed, the anti-infective regimen should be discontinued.

Because of possible persistence of spores in lung tissue following an aerosol exposure, US Centers for Disease Control and Prevention (CDC), US Public Health Service Advisory Committee on Immunization Practices (ACIP), US Working Group on Civilian Biodefense, and US Army Medical Research Institute of Infectious Diseases (USAMRIID) recommend that anti-infective prophylaxis in unvaccinated individuals be continued for at least 60 days following a confirmed exposure.

If anthrax vaccine is used in conjunction with anti-infective prophylaxis for postexposure prophylaxis in exposed individuals, ACIP and USAMRIID recommend that the anti-infective prophylaxis regimen be continued until 14 days after the third dose of the vaccine series (even if this results in more than 60 days of anti-infective prophylaxis).

In fully or partially vaccinated laboratory workers or other individuals who work in occupations that result in repeated exposure to aerosolized B. anthracis spores, ACIP recommends that anti-infective postexposure prophylaxis be given for at least 30 days in conjunction with any remaining indicated doses of anthrax vaccine if there has been any type of disruption of personal protective equipment (PPE). Following an occupational exposure to B. anthracis spores in previously unvaccinated workers, ACIP recommends that anti-infective postexposure prophylaxis be given for 60 days in conjunction with postexposure vaccination; the anti-infective prophylaxis regimen should be continued until 14 days after the third vaccine dose (even if this results in more than 60 days of anti-infective prophylaxis).

Treatment of Anthrax

If oral levofloxacin is used as an alternative for the treatment of anthrax when a parenteral regimen is not available(see Uses: Anthrax), US Working Group on Civilian Biodefense suggests that adults can receive a dosage of 500 mg once daily for at least 60 days.

An initial parenteral regimen is preferred for the treatment of inhalational anthrax; an oral regimen should be used for initial treatment only when a parenteral regimen is not available (e.g., supply or logistic problems because large numbers of individuals require treatment in a mass casualty setting). Because of the possible persistence of anthrax spores in lung tissue following an aerosol exposure, the total duration of anti-infective therapy of inhalational anthrax that occurs as the result of exposure to B. anthracis in the context of biologic warfare or bioterrorism should be at least 60 days.

Chlamydial Infections

If oral levofloxacin is used as an alternative for the treatment of urogenital infections caused by Chlamydia trachomatis in adults and adolescents, CDC recommends a dosage of 500 mg once daily for 7 days.

Gonorrhea and Associated Infections

Epididymitis

For the treatment of acute epididymitis most likely caused by sexually transmitted enteric bacteria (e.g., E. coli) and when Neisseria gonorrhoeae has been ruled out, CDC recommends that oral levofloxacin be given a dosage of 500 mg once daily for 10 days.

Levofloxacin should not be used alone for treatment of epididymitis unless N. gonorrhoeae has been ruled out.(See Uses: Gonorrhea and Associated Infections.)

Mycobacterial Infections

Treatment of Active Tuberculosis

If levofloxacin is used as an alternative (second-line) agent in multiple-drug regimens for the treatment of active tuberculosis, ATS, CDC, and IDSA recommend that adults receive 0.5-1 g daily. These experts state that data are insufficient to support intermittent regimens of levofloxacin for the treatment of tuberculosis.

Other Mycobacterial Infections

If oral levofloxacin is used as an alternative in multiple-drug regimens for the treatment of disseminated infections caused by Mycobacterium avium complex (MAC) in HIV-infected adults, CDC, National Institutes of Health (NIH), and IDSA recommend a dosage of 500 mg once daily.

Nongonococcal Urethritis

If oral levofloxacin is used as an alternative for the treatment of nongonococcal urethritis (NGU), CDC recommends a dosage of 500 mg once daily for 7 days.(See Uses: Nongonococcal Urethritis.)

Pelvic Inflammatory Disease

If oral levofloxacin is used as an alternative for the treatment of mild to moderately severe acute pelvic inflammatory disease (PID), CDC recommends a dosage of 500 mg once daily for 14 days given in conjunction with oral metronidazole (500 mg twice daily for 14 days).

Levofloxacin should be used for the treatment of PID only when parenteral cephalosporins are not feasible, the community prevalence and individual risk of gonorrhea are low, and in vitro susceptibility has been confirmed.(See Uses: Pelvic Inflammatory Disease.)

Plague

If levofloxacin is used for the treatment or prophylaxis of plague caused by Yersinia pestis in adults and pediatric patients 6 months of age or older weighing more than 50 kg, the manufacturer recommends a dosage of 500 mg once daily for 10-14 days and states that these individuals can receive a higher dosage (i.e., 750 mg once daily) if clinically indicated. The manufacturer recommends a dosage of 8 mg/kg (up to 250 mg) every 12 hours for 10-14 days for the treatment or prophylaxis of plague in pediatric patients 6 months of age or older weighing less than 50 kg. The drug should be initiated as soon as possible after suspected or known exposure to Y. pestis.

Special Populations

Renal Impairment

Although levofloxacin dosage adjustment is not necessary when 250-mg doses are used for treatment of uncomplicated UTIs in adults with renal impairment, dosage of levofloxacin should be modified according to the degree of renal impairment when the drug is used for other indications in adults with creatinine clearances less than 50 mL/minute.(See Table 1.)

Although decreased dosage may be indicated in adults undergoing hemodialysis or continuous ambulatory peritoneal dialysis (CAPD), supplemental doses are not required following these procedures.

The manufacturer makes no dosage recommendations for pediatric patients with renal insufficiency.

Table 1. Levofloxacin Dosage for Adults with Renal Impairment[1 ]
Usual Daily Dosage for Normal Renal Function (Creatinine Clearance >=50 mL/minute or greater) Creatinine Clearance (mL/minute) Dosage for Renal Impairment
250 mg 20-49 Dosage adjustment not required
250 mg 10-19 Uncomplicated UTIs: Dosage adjustment not required
Other infections: 250 mg every 48 hours
250 mg Hemodialysis or CAPD patients Information not available
500 mg 20-49 Initial 500-mg dose, then 250 mg once every 24 hours
500 mg 10-19 Initial 500-mg dose, then 250 mg once every 48 hours
500 mg Hemodialysis or CAPD patients Initial 500-mg dose, then 250 mg once every 48 hours; supplemental doses not required after dialysis
750 mg 20-49 750 mg every 48 hours
750 mg 10-19 Initial 750-mg dose, then 500 mg once every 48 hours
750 mg Hemodialysis or CAPD patients Initial 750-mg dose, then 500 mg once every 48 hours; supplemental doses not required after dialysis

Hepatic Impairment

Adjustment of levofloxacin dosage in patients with hepatic insufficiency is not be expected to be necessary because most of the drug is excreted unchanged in urine.

Geriatric Patients

Adjustment of levofloxacin dosage is not necessary in geriatric patients based solely on age. However, dosage of levofloxacin should be selected carefully since geriatric patients are more likely to have decreased renal function than younger adults.(See Geriatric Use under Warnings/Precautions: Specific Populations, in Cautions.)

Cautions

Contraindications

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Levofloxacin is contraindicated in patients with known hypersensitivity to levofloxacin or other quinolones.

Warnings/Precautions

Warnings

Disabling and Potentially Irreversible Serious Adverse Reactions

Systemic fluoroquinolones, including levofloxacin, have been associated with disabling and potentially irreversible serious adverse reactions (e.g., tendinitis and tendon rupture, peripheral neuropathy, CNS effects) that can occur together in the same patient. These serious reactions may occur within hours to weeks after a systemic fluoroquinolone is initiated and have occurred in all age groups and in patients without preexisting risk factors for such adverse reactions.

Levofloxacin should be discontinued immediately at the first signs or symptoms of any serious adverse reactions.

Systemic fluoroquinolones, including levofloxacin, should be avoided in patients who have experienced any of the serious adverse reactions associated with fluoroquinolones.

Tendinitis and Tendon Rupture

Systemic fluoroquinolones, including levofloxacin, are associated with an increased risk of tendinitis and tendon rupture in all age groups.

The risk of developing fluoroquinolone-associated tendinitis and tendon rupture is increased in older adults (usually those over 60 years of age), individuals receiving concomitant corticosteroids, and kidney, heart, or lung transplant recipients.(See Geriatric Use under Warnings/Precautions: Specific Populations, in Cautions.)

Other factors that may independently increase the risk of tendon rupture include strenuous physical activity, renal failure, and previous tendon disorders such as rheumatoid arthritis. Tendinitis and tendon rupture have been reported in patients receiving fluoroquinolones who did not have any risk factors for such adverse reactions.

Fluoroquinolone-associated tendinitis and tendon rupture most frequently involve the Achilles tendon and have also been reported in the rotator cuff (shoulder), hand, biceps, thumb, and other tendon sites. Tendinitis or tendon rupture can occur within hours or days after levofloxacin is initiated or as long as several months after completion of therapy and can occur bilaterally.

Levofloxacin should be discontinued immediately if pain, swelling, inflammation, or rupture of a tendon occurs.

Systemic fluoroquinolones, including levofloxacin, should be avoided in patients who have a history of tendon disorders or have experienced tendinitis or tendon rupture.

Peripheral Neuropathy

Systemic fluoroquinolones, including levofloxacin, have been associated with an increased risk of peripheral neuropathy.

Sensory or sensorimotor axonal polyneuropathy affecting small and/or large axons resulting in paresthesias, hypoesthesias, dysesthesias, and weakness has been reported in patients receiving systemic fluoroquinolones, including levofloxacin. Symptoms may occur soon after initiation of levofloxacin and, in some patients, may be irreversible.

Levofloxacin should be discontinued immediately if symptoms of peripheral neuropathy (e.g., pain, burning, tingling, numbness, and/or weakness) occur or if there are other alterations in sensations (e.g., light touch, pain, temperature, position sense, vibratory sensation).(See Advice to Patients.)

Systemic fluoroquinolones, including levofloxacin, should be avoided in patients who have experienced peripheral neuropathy.

CNS Effects

Systemic fluoroquinolones, including levofloxacin, have been associated with an increased risk of CNS effects.

Convulsions, increased intracranial pressure (including pseudotumor cerebri), and toxic psychosis have been reported with fluoroquinolones, including levofloxacin. Fluoroquinolones may also cause CNS stimulation, which may lead to tremors, restlessness, anxiety, lightheadedness, confusion, hallucinations, paranoia, depression, nightmares, insomnia, and, rarely, suicidal thoughts or acts. These CNS effects may occur after the first dose.

If CNS effects occur, levofloxacin should be discontinued immediately and appropriate measures initiated.(See Advice to Patients.)

Levofloxacin should be used with caution in patients with known or suspected CNS disorders that predispose to seizures or lower the seizure threshold (e.g., severe cerebral arteriosclerosis, epilepsy) or with other risk factors that predispose to seizures or lower the seizure threshold (e.g., certain drugs, renal impairment).

Systemic fluoroquinolones, including levofloxacin, should be avoided in patients who have experienced CNS effects associated with fluoroquinolones.

Exacerbation of Myasthenia Gravis

Fluoroquinolones, including levofloxacin, have neuromuscular blocking activity and may exacerbate muscle weakness in individuals with myasthenia gravis. Use of fluoroquinolones in myasthenia gravis patients has resulted in requirements for ventilatory support and in death.

Levofloxacin should be avoided in patients with a known history myasthenia gravis. Patients should be advised to immediately contact a clinician if they experience any symptoms of muscle weakness, including respiratory difficulties.(See Advice to Patients.)

Sensitivity Reactions

Hypersensitivity Reactions

Serious and occasionally fatal hypersensitivity and/or anaphylactic reactions have been reported in patients receiving fluoroquinolones, including levofloxacin. These reactions often occur with the first dose.

Some hypersensitivity reactions have been accompanied by cardiovascular collapse, hypotension or shock, seizures, loss of consciousness, tingling, angioedema (e.g., edema or swelling of the tongue, larynx, throat, or face), airway obstruction (e.g., bronchospasm, shortness of breath, acute respiratory distress), dyspnea, urticaria, pruritus, and other severe skin reactions.

Other serious and sometimes fatal adverse reactions that have been reported with fluoroquinolones, including levofloxacin, and that may or may not be related to hypersensitivity reactions include one or more of the following: fever, rash or other severe dermatologic reactions (e.g., toxic epidermal necrolysis, Stevens-Johnson syndrome); vasculitis, arthralgia, myalgia, serum sickness; allergic pneumonitis; interstitial nephritis, acute renal insufficiency or failure; hepatitis, jaundice, acute hepatic necrosis or failure; anemia (including hemolytic and aplastic anemia), thrombocytopenia (including thrombotic thrombocytopenic purpura), leukopenia, agranulocytosis, pancytopenia and/or other hematologic effects.

Levofloxacin should be discontinued immediately at the first appearance of rash, jaundice, or any other sign of hypersensitivity. Appropriate therapy should be initiated as indicated (e.g., epinephrine, corticosteroids, maintenance of an adequate airway and oxygen).(See Advice to Patients.)

Photosensitivity Reactions

Moderate to severe photosensitivity/phototoxicity reactions have been reported with fluoroquinolones, including levofloxacin.

Phototoxicity may manifest as exaggerated sunburn reactions (e.g., burning, erythema, exudation, vesicles, blistering, edema) on areas exposed to sun or artificial ultraviolet (UV) light (usually the face, neck, extensor surfaces of forearms, dorsa of hands).

As with other fluoroquinolones, patients should be advised to avoid unnecessary or excessive exposure to sunlight or artificial UV light (e.g., tanning beds, UVA/UVB treatment) while receiving levofloxacin. If a patient needs to be outdoors, they should wear loose-fitting clothing that protects skin from sun exposure and use other sun protection measures (sunscreen).

Levofloxacin should be discontinued if photosensitivity or phototoxicity (sunburn-like reaction, skin eruption) occurs.

Other Warnings/Precautions

Hepatotoxicity

Severe hepatotoxicity, including acute hepatitis, has occurred in patients receiving levofloxacin and sometimes resulted in death. Most cases of severe hepatotoxicity occurred within 6-14 days of initiation of levofloxacin therapy and were not associated with hypersensitivity reactions. The majority of fatal cases of hepatotoxicity were in geriatric patients 65 years of age or older.(See Geriatric Use under Warnings/Precautions: Specific Populations, in Cautions.)

Levofloxacin should be discontinued immediately in any patient who develops signs or symptoms of hepatitis (e.g., loss of appetite, nausea, vomiting, fever, weakness, tiredness, right upper quadrant tenderness, itching, yellowing of the skin or eyes, light colored bowel movements, or dark colored urine).

Prolongation of QT Interval

Prolonged QT interval leading to ventricular arrhythmias, including torsades de pointes, has been reported with some fluoroquinolones, including levofloxacin.

Levofloxacin should be avoided in patients with a history of prolonged QT interval, in those with uncorrected electrolyte disorders (e.g., hypokalemia), and in those receiving class IA (e.g., quinidine, procainamide) or class III (e.g., amiodarone, sotalol) antiarrhythmic agents.

The risk of prolonged QT interval may be increased in geriatric patients.(See Geriatric Use under Warnings/Precautions: Specific Populations, in Cautions.)

Musculoskeletal Disorders

An increased incidence of musculoskeletal disorders (arthralgia, arthritis, tendinopathy, gait abnormality) has been reported in pediatric patients receiving levofloxacin. The manufacturer states that levofloxacin should be used in pediatric patients only for inhalational anthrax (postexposure) or treatment or prophylaxis of plague and only in those 6 months of age or older.(See Pediatric Use under Warnings/Precautions: Specific Populations, in Cautions.)

Fluoroquinolones, including levofloxacin, cause arthropathy and osteochondrosis in immature animals of various species. Persistent lesions in cartilage reported in levofloxacin studies in immature dogs; similar erosions in weight-bearing joints and other signs of arthropathy have been reported with other fluoroquinolones.

Hypoglycemia or Hyperglycemia

Alterations in blood glucose concentrations, including symptomatic hypoglycemia and hyperglycemia, have been reported with fluoroquinolones, including levofloxacin. Blood glucose disturbances usually have occurred in patients with diabetes mellitus receiving an oral hypoglycemic agent (e.g., glyburide) or insulin.

Blood glucose concentrations should be carefully monitored in diabetic patients receiving antidiabetic agents and levofloxacin concomitantly. If a hypoglycemic reaction occurs, levofloxacin should be discontinued and appropriate therapy initiated immediately.

Superinfection/Clostridium difficile-associated Diarrhea and Colitis (CDAD)

Use of levofloxacin may result in emergence and overgrowth of nonsusceptible bacteria or fungi. Appropriate therapy should be initiated if superinfection occurs.

Treatment with anti-infectives alters normal colon flora and may permit overgrowth of Clostridium difficile.C. difficile infection (CDI) and C. difficile-associated diarrhea and colitis (CDAD; also known as antibiotic-associated diarrhea and colitis or pseudomembranous colitis) have been reported with nearly all anti-infectives, including levofloxacin, and may range in severity from mild diarrhea to fatal colitis.C. difficile produces toxins A and B which contribute to development of CDAD; hypertoxin-producing strains of C. difficile are associated with increased morbidity and mortality since they may be refractory to anti-infectives and colectomy may be required.

Outbreaks of severe CDAD caused by fluoroquinolone-resistant C. difficile have been reported with increasing frequency over the last several years.

CDAD should be considered if diarrhea develops during or after therapy and managed accordingly. Careful medical history is necessary since CDAD has been reported to occur as late as 2 months or longer after anti-infective therapy is discontinued.

If CDAD is suspected or confirmed, anti-infective therapy not directed against C. difficile should be discontinued whenever possible. Patients should be managed with appropriate supportive therapy (e.g., fluid and electrolyte management, protein supplementation), anti-infective therapy directed against C. difficile (e.g., metronidazole, vancomycin), and surgical evaluation as clinically indicated.

Selection and Use of Anti-infectives

Levofloxacin should be used for the treatment of acute bacterial sinusitis, acute bacterial exacerbations of chronic bronchitis, or uncomplicated urinary tract infections (UTIs) only when no other treatment options are available. Because levofloxacin, like other systemic fluoroquinolones, has been associated with disabling and potentially irreversible serious adverse reactions (e.g., tendinitis and tendon rupture, peripheral neuropathy, CNS effects) that can occur together in the same patient, the risks of serious adverse reactions outweigh the benefits of levofloxacin for patients with these infections.

To reduce development of drug-resistant bacteria and maintain effectiveness of levofloxacin and other antibacterials, use only for treatment or prevention of infections proven or strongly suspected to be caused by susceptible bacteria.

When selecting or modifying anti-infective therapy, use results of culture and in vitro susceptibility testing. In the absence of such data, consider local epidemiology and susceptibility patterns when selecting anti-infectives for empiric therapy.

Resistance in Neisseria gonorrhoeae

N. gonorrhoeae with decreased susceptibility to fluoroquinolones (quinolone-resistant N. gonorrhoeae; QRNG) has been reported with increasing frequency within the last several years.

US data indicate that QRNG has continued to increase among men who have sex with men and among heterosexual males and is now present in all regions of the country.

CDC states that fluoroquinolones, including levofloxacin, are no longer recommended for treatment of gonorrhea and should not be used routinely for any associated infections that may involve N. gonorrhoeae (e.g., pelvic inflammatory disease [PID], epididymitis).

Specific Populations

Pregnancy

Category C.

There are no adequate and well-controlled studies of levofloxacin in pregnant women, and the drug should be used during pregnancy only if potential benefits justify potential risks to the fetus.

Reproduction studies in rats or rabbits have not revealed evidence of teratogenicity at oral doses 9.4 or 1.1 times the maximum recommended human dose, respectively, or IV doses 1.9 or 0.5 times the maximum human dose, respectively, based on relative body surface area.

Lactation

Levofloxacin is distributed into milk following oral or IV administration.

Because of the potential for serious adverse reactions in the infant, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.(See Musculoskeletal Disorders under Warnings/Precautions: Other Warnings/Precautions, in Cautions.)

Pediatric Use

Levofloxacin may be used for inhalational anthrax (postexposure) or for treatment or prophylaxis of plague in adolescents and children 6 months of age or older. Safety and efficacy of the drug have not been established for any other indication in this age group.

Safety and efficacy of levofloxacin have not been established for any indications in infants younger than 6 months of age.

Quinolones, including levofloxacin, cause arthropathy and osteochondrosis in juvenile animals of various species.(See Musculoskeletal Disorders under Warnings/Precautions: Other Warnings/Precautions, in Cautions.)

The American Academy of Pediatrics (AAP) states that use of systemic fluoroquinolones may be justified in children younger than 18 years of age in special circumstances when there are no safe and effective alternatives and after careful assessment of the risks and benefits for the individual patient.

Geriatric Use

No overall differences in safety and efficacy were observed between geriatric patients and younger adults in clinical trials, but increased sensitivity in some older individuals cannot be ruled out.

The risk of developing severe tendon disorders, including tendon rupture, is increased in older adults (usually those older than 60 years of age). This risk is further increased in those receiving concomitant corticosteroids.(See Tendinitis and Tendon Rupture under Warnings/Precautions: Warnings, in Cautions.) Caution is advised if levofloxacin is used in geriatric adults, especially those receiving concomitant corticosteroids.

Severe and sometimes fatal hepatotoxicity has been reported in patients receiving levofloxacin, and the majority of fatalities have occurred in geriatric patients 65 years of age or older.(See Hepatotoxicity under Warnings/Precautions: Other Warnings/Precautions, in Cautions.)

The risk of prolonged QT interval leading to ventricular arrhythmias may be increased in geriatric patients, especially those receiving concurrent therapy with other drugs that can prolong QT interval (e.g., class IA or III antiarrhythmic agents) or with risk factors for torsades de pointes (e.g., known QT prolongation, uncorrected hypokalemia).(See Prolongation of QT Interval under Warnings/Precautions: Other Warnings/Precautions, in Cautions.)

Because levofloxacin is substantially eliminated by the kidneys, age-related decreases in renal function should be considered when selecting dosage for geriatric patients and it may be useful to monitor renal function.(See Geriatric Patients under Dosage and Administration: Special Populations.)

Hepatic Impairment

Pharmacokinetics of levofloxacin have not been studied in patients with hepatic impairment, but pharmacokinetic alterations are unlikely.

Renal Impairment

Levofloxacin clearance is substantially reduced and plasma elimination half-life of the drug is substantially prolonged in patients with impaired renal function (creatinine clearance less than 50 mL/minute).

Levofloxacin should be used with caution in patients with renal impairment. Appropriate renal function tests should be performed prior to and during levofloxacin therapy and dosage adjusted as needed.(See Renal Impairment under Dosage and Administration: Special Populations.)

Common Adverse Effects

Adverse effected reported in 3% or more of patients receiving levofloxacin include GI effects (nausea, diarrhea, constipation), headache, insomnia, and dizziness.

Drug Interactions

Drugs That Prolong QT Interval

Potential pharmacologic interaction between levofloxacin and drugs that prolong the QT interval (additive effects on QT interval prolongation). Concomitant use of levofloxacin and class IA (e.g., quinidine, procainamide) or class III (e.g., amiodarone, sotalol) antiarrhythmic agents should be avoided.(See Prolongation of QT Interval under Warnings/Precautions: Other Warnings/Precautions, in Cautions.)

Antacids

Potential pharmacokinetic interaction between levofloxacin and antacids containing magnesium or aluminum (decreased absorption of oral levofloxacin).

Levofloxacin tablets or oral solution should be administered at least 2 hours before or 2 hours after such antacids.

Antiarrhythmic Agents

Potential pharmacologic interaction between levofloxacin and antiarrhythmic agents (additive effect on QT interval prolongation). Levofloxacin should be avoided in patients receiving class IA (e.g., quinidine, procainamide) or class III (e.g., amiodarone, sotalol) antiarrhythmic agents.(See Prolongation of QT Interval under Warnings/Precautions: Other Warnings/Precautions, in Cautions.)

Pharmacokinetic interaction between levofloxacin and procainamide (increased half-life and decreased clearance of procainamide).

Antidepressants

Potential pharmacologic interaction between levofloxacin and fluoxetine or imipramine (additive effect on QT interval prolongation).

Antidiabetic Agents

Potential pharmacodynamic interaction (altered blood glucose concentrations and symptomatic hyperglycemia or hypoglycemia) in diabetic patients receiving levofloxacin concomitantly with antidiabetic agents (e.g., insulin, glyburide). Careful monitoring of blood glucose concentrations is recommended; levofloxacin should be discontinued if a hypoglycemic reaction occurs.

Cimetidine

Pharmacokinetic interaction between levofloxacin and cimetidine (slightly increased levofloxacin area under the plasma concentration-time curve [AUC] and half-life). This interaction is not considered clinically important; levofloxacin dosage adjustments are not warranted.

Corticosteroids

Concomitant use of levofloxacin and corticosteroids increases the risk of severe tendon disorders (e.g., tendinitis, tendon rupture), especially in geriatric patients older than 60 years of age. Levofloxacin and corticosteroids should be used concomitantly with caution.(See Tendinitis and Tendon Rupture under Warnings/Precautions: Warnings, in Cautions.)

Cyclosporine and Tacrolimus

Possible pharmacokinetic interactions between levofloxacin and cyclosporine or tacrolimus (increased AUC of the immunosuppressive agent).

The manufacturer of levofloxacin states that concomitant use of cyclosporine and levofloxacin did not have a clinically important effect on the pharmacokinetics of the immunosuppressive agent and dosage adjustments are not required for either drug. Some clinicians suggest that plasma concentrations of cyclosporine or tacrolimus should be monitored if used concomitantly with levofloxacin.

Didanosine

Potential pharmacokinetic interaction between levofloxacin and buffered didanosine (decreased GI absorption of oral levofloxacin).

Levofloxacin tablets or oral solution should be administered at least 2 hours before or 2 hours after buffered didanosine (pediatric oral solution admixed with antacid).

Digoxin

Concomitant use of levofloxacin and digoxin did not result in any clinically important effects on the pharmacokinetics of either drug. Dosage adjustments are not necessary for either drug if levofloxacin and digoxin are used concomitantly.

Iron, Multivitamins, and Mineral Supplements

Potential pharmacokinetic interaction between levofloxacin and iron, multivitamins, or mineral supplements (decreased absorption of oral levofloxacin).

Levofloxacin tablets or oral solution should be administered at least 2 hours before or 2 hours after iron preparations or multivitamins or dietary supplements containing zinc, calcium, magnesium, or iron.

Nonsteroidal Anti-inflammatory Agents

Potential pharmacologic interaction between levofloxacin and nonsteroidal anti-inflammatory agents (NSAIAs) (possible increased risk of CNS stimulation and seizures). Animal studies suggest the risk may be less than that associated with some other fluoroquinolones and that risk varies depending on the specific NSAIA.

Probenecid

Pharmacokinetic interaction between levofloxacin and probenecid (slightly increased levofloxacin AUC and half-life). This interaction is not considered clinically important; levofloxacin dosage adjustments are not warranted.

Sucralfate

Potential pharmacokinetic interaction between levofloxacin and sucralfate (decreased absorption of oral levofloxacin); no pharmacokinetic interaction if given 2 hours apart. Levofloxacin tablets or oral solution should be administered at least 2 hours before or 2 hours after sucralfate.

Theophylline

Concomitant use of levofloxacin and theophylline did not have a clinically important effect on the pharmacokinetics of either drug. However, pharmacokinetic interactions (increased theophylline half-life and increased risk of theophylline-related adverse effects) have been reported with some other quinolones.

If levofloxacin and theophylline are used concomitantly, serum theophylline concentrations should be closely monitored and theophylline dosage adjusted accordingly; clinicians should consider that adverse theophylline effects (e.g., seizures) may occur with or without elevated theophylline concentrations.

Warfarin

Concomitant use of levofloxacin in patients receiving warfarin has resulted in increased prothrombin time (PT); clinical episodes of bleeding have been reported. Patients receiving the drugs concomitantly should be monitored for evidence of bleeding and PT and international normalized ratio (INR) should be monitored.

Pharmacokinetics

Absorption

Bioavailability

Levofloxacin is rapidly absorbed from the GI tract and absolute bioavailability is approximately 99%.

Peak plasma concentrations of levofloxacin usually are attained 1-2 hours after an oral dose; steady-state plasma concentrations are attained within 48 hours with once-daily regimens.

Levofloxacin tablets and oral solution are bioequivalent.

Plasma concentrations of levofloxacin and area under the plasma concentration-time curve (AUC) of the drug after oral administration are similar to those after IV administration.

Food

Tablets: Food prolongs time to peak plasma concentration and decreases peak concentrations of levofloxacin. When levofloxacin is given with a standard high-fat breakfast (e.g., 2 fried eggs in butter, 2 strips of bacon, hash brown potatoes, 2 slices of toast with butter, 180 mL of milk), peak serum concentrations of the drug are decreased approximately 14% (not considered clinically important). When levofloxacin is given with calcium-fortified orange juice, peak serum concentrations of the drug are decreased 18%; when given with a breakfast of calcium-fortified orange juice and whole grain, fortified, ready-to-eat cereal with skim milk, peak concentrations are decreased 24% and time to peak concentrations is increased 46%.

Oral solution: Food slightly prolongs time to peak plasma concentration and decreases peak concentrations of levofloxacin by approximately 25%.

Distribution

Extent

Levofloxacin is widely distributed into body tissues and fluids, including skin, blister fluid, and lungs.

Levofloxacin is distributed into CSF. Following IV administration of 400 or 500 mg of levofloxacin twice daily, CSF concentrations have been reported to be up to 47% of concurrent plasma concentrations.

The drug is distributed into milk following oral or IV administration.

Plasma Protein Binding

Levofloxacin is 24-38% bound to serum proteins, principally albumin.

Elimination

Metabolism

Levofloxacin undergoes limited metabolism to inactive metabolites. The drug is not metabolized by cytochrome P-450 (CYP) isoenzymes.

Elimination Route

Levofloxacin is eliminated principally as unchanged drug in urine by glomerular filtration and active tubular secretion. Approximately 87% of an oral dose is eliminated in urine and less than 4% is eliminated in feces.

Half-life

The terminal elimination half-life of levofloxacin is approximately 6-8 hours after oral or IV administration.

Special Populations

In pediatric patients 6 months to 16 years of age, clearance of levofloxacin is increased and plasma concentrations of the drug are decreased compared with adults.

Levofloxacin pharmacokinetics in geriatric individuals with normal renal function are similar to that reported in younger adults.

Levofloxacin pharmacokinetics have not been studied in patients with hepatic impairment, but pharmacokinetic alterations are unlikely.

In patients with impaired renal function, levofloxacin clearance is decreased and plasma half-life is prolonged. Plasma half-life may be 27 hours in those with creatinine clearances of 20-49 mL/minute and 35 hours in those with creatinine clearances less than 20 mL/minute.

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