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ciprofloxacin hcl 250 mg tab

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Uses

Ciprofloxacin is used orally or IV for the treatment of urinary tract infections (UTIs), chronic bacterial prostatitis, acute sinusitis, lower respiratory tract infections (including nosocomial pneumonia and acute exacerbations of chronic bronchitis), GI infections, skin and skin structure infections, or bone and joint infections caused by susceptible gram-negative and gram-positive aerobic bacteria. Ciprofloxacin is used orally or IV for inhalational anthrax (postexposure) following suspected or confirmed exposure to aerosolized Bacillus anthracis spores and also is used for prophylaxis following ingestion of B. anthracis spores and for the treatment of inhalational anthrax, cutaneous anthrax, or GI and oropharyngeal anthrax. Ciprofloxacin is used orally or IV for the treatment or prophylaxis of plague. In addition, ciprofloxacin is used orally or IV in conjunction with metronidazole for the treatment of complicated intra-abdominal infections caused by Escherichia coli, Pseudomonas aeruginosa, Proteus mirabilis, Klebsiella pneumoniae, or Bacteroides fragilis. Because ciprofloxacin is inactive against most anaerobic bacteria, the drug is ineffective in and should not be used alone if a mixed aerobic-anaerobic bacterial infection is suspected. Ciprofloxacin has been used in conjunction with other anti-infectives for empiric anti-infective therapy in febrile neutropenic patients.

Ciprofloxacin extended-release tablets containing both the hydrochloride and the base are used in adults for the treatment of uncomplicated UTIs (acute cystitis), complicated UTIs, or acute uncomplicated pyelonephritis. Safety and efficacy of ciprofloxacin extended-release tablets have been established only for infections involving the urinary tract; the extended-release tablets should not be used for the treatment of infections at other sites (e.g., respiratory tract, skin and skin structure, bone and joint, GI tract, intra-abdominal) that are treated with ciprofloxacin conventional tablets or oral suspension or with IV ciprofloxacin.

Prior to initiation of ciprofloxacin therapy, appropriate specimens should be obtained for identification of the causative organism(s) and in vitro susceptibility tests. Ciprofloxacin 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 ciprofloxacin. Because resistant strains of Pseudomonas aeruginosa have developed during ciprofloxacin therapy, in vitro susceptibility tests should be performed periodically when the drug is used in the treatment of infections caused by this organism. Because staphylococci may develop resistance to ciprofloxacin during prolonged therapy with the drug, in vitro susceptibility tests should be repeated during therapy, especially when infections are caused by oxacillin-resistant strains of Staphylococcus aureus (previously known as methicillin-resistant S. aureus or MRSA).

Bone and Joint Infections

Ciprofloxacin (IV, conventional tablets, oral suspension) is used in adults for the treatment of bone and joint infections, including osteomyelitis, caused by susceptible E. aerogenes,E. cloacae,E. coli,K. pneumoniae,M. morganii,P. mirabilis,Ps. aeruginosa, or S. marcescens. The drug also has been used in adults for the treatment of bone and joint infections caused by susceptible S. aureus,S. epidermidis, other coagulase-negative staphylococci, or Enterococcus faecalis (formerly S. faecalis), but other anti-infectives generally are preferred for these infections. Although resistance to ciprofloxacin has been reported in some strains of oxacillin-resistant S. aureus, oral ciprofloxacin may be a useful alternative to parenteral anti-infectives for the treatment of infections caused by susceptible oxacillin-resistant staphylococci.

Clinical response has been reported in 61-86% and bacteriologic cure has been reported in 75-81% of patients with bone and joint infections (caused principally by gram-negative aerobes) who received oral ciprofloxacin. Treatment failures have been reported most frequently in patients with an underlying metal appliance at the site of infection and in patients with ciprofloxacin-resistant Ps. aeruginosa or S. aureus. However, there is evidence from a randomized, controlled study in patients with culture-proven staphylococcal infections associated with stable orthopedic implants that a long-term regimen (3-6 weeks) of ciprofloxacin and rifampin given after initial debridement and a 2-week IV regimen of flucloxacillin (not commercially available in the US) or vancomycin with rifampin or placebo can result in cure of the infection without removal of the implant.

Endocarditis

Endocarditis Caused by the HACEK Group

Ciprofloxacin is used as an alternative for the 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 HACEK group accounts for up to 10% of cases of community-acquired native valve endocarditis in patients who are not IV drug abusers. These organisms should be considered ampicillin-resistant, but may be susceptible to third or fourth generation cephalosporins or fluoroquinolones.

The American Heart Association (AHA) and Infectious Diseases Society of America (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

Infectious Diarrhea

Ciprofloxacin (conventional tablets, oral suspension) is used in adults for the treatment of infectious diarrhea caused by susceptible strains of enterotoxigenic E. coli,Campylobacter fetus subsp. jejuni,Salmonella(see Uses: Typhoid Fever and other Salmonella Infections),Shigella (S. flexneri,S. boydii, S. sonnei,S. dysenteriae), or Vibrio(see Uses: Vibrio Infections). Because ciprofloxacin is active in vitro against many pathogens associated with infectious diarrhea, including E. coli, Shigella, Salmonella, Aeromonas, Vibrio, Yersinia enterocolitica, and some strains of Campylobacter, some clinicians suggest that it may be a drug of choice for empiric treatment of the disease. However, because of concerns about increasing emergence of fluoroquinolone-resistant strains of Campylobacter secondary to widespread use of the drugs, judicious use of fluoroquinolones for the treatment and prevention of enteropathogenic diarrhea is warranted.

Cyclospora and Cystoisospora Infections

Although co-trimoxazole is the drug of choice for GI infections caused by Cyclospora cayetanensis or Cystoisospora belli (formerly Isospora belli), ciprofloxacin is recommended as an alternative for the treatment of cyclosporiasis and has been used for the treatment of cystoisosporiasis (formerly isosporiasis). Ciprofloxacin may not be as effective as co-trimoxazole, but may be useful for the treatment of these infections in patients who cannot tolerate co-trimoxazole.

In HIV-infected patients, ciprofloxacin is recommended as an alternative to co-trimoxazole for treatment and chronic maintenance therapy (secondary prophylaxis) of cystoisosporiasis.

Shigella Infections

Ciprofloxacin (conventional tablets, oral suspension) 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 are considered drugs of choice for the treatment of shigellosis when the susceptibility of the isolate is unknown or when ampicillin- or co-trimoxazole-resistant strains are involved.

Yersinia Infections

Although GI infections caused by Yersinia enterocolitica or Y. pseudotuberculosis usually are self-limited and anti-infective therapy unnecessary, the American Academy of Pediatrics (AAP), US Centers for Disease Control and Prevention (CDC), IDSA, and others recommend use of anti-infectives in immunocompromised individuals or for the treatment of severe infections or when septicemia or other invasive disease occurs. GI infections caused by Y. enterocolitica or Y. pseudotuberculosis can occur as the result of ingesting undercooked pork, unpasteurized milk, or contaminated water; infection has occurred in infants whose caregivers handled contaminated chitterlings (raw pork intestines) or tofu. The incubation period usually is 24-48 hours. Use of co-trimoxazole, an aminoglycoside (e.g., amikacin, gentamicin, tobramycin), a fluoroquinolone (e.g., ciprofloxacin), doxycycline, or cefotaxime has been recommended when treatment is considered necessary; combination therapy may be necessary. Some clinicians suggest that the role of anti-infectives in the management of enterocolitis, pseudoappendicitis syndrome, or mesenteric adenitis caused by Yersinia needs further evaluation.

Travelers' Diarrhea

Ciprofloxacin (conventional tablets, oral suspension) 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, A. hydrophila, Plesiomonas shigelloides, Yersinia enterocolitica, or V. 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., rotavirus, norovirus, 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 high 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 is another alternative for the treatment of travelers' diarrhea caused by noninvasive E. coli. 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 is recommended for nonpregnant adults, although the increasing incidence of quinolone resistance in pathogens that cause travelers' diarrhea (e.g., Campylobacter) should be considered and may limit their benefit in the future. Azithromycin and rifaximin also have 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 vegetable, avoid foods or drinks purchased from street vendors or establishments where unhygienic conditions are present).

HIV-Infected Individuals

CDC, National Institutes of Health (NIH), and IDSA state that decisions regarding treatment of travelers' diarrhea in HIV-infected individuals are similar to those in immunocompetent individuals and should be based on diarrhea severity and hydration status. If possible, treatment decisions should be based on results of stool samples and in vitro susceptibility testing. Oral hydration without anti-infective treatment may be sufficient for management of HIV-infected patients with CD4 T-cell counts exceeding 500 cells/mm who have had only 1-2 days of loose stools without blood or fever. Anti-infective treatment may be indicated in those with CD4 T-cell counts of 200-500 cells/mm who have severe diarrhea affecting quality of life or ability to work. Diagnostic evaluation and anti-infective treatment is indicated in those with advanced HIV disease (CD4 T-cell counts less than 200 cells/mm or concomitant AIDS-defining illness) who have clinically severe diarrhea (i.e., 6 or more stools per day or bloody stools and/or accompanied by fever or chills). These experts state that empiric treatment with a fluoroquinolone is reasonable in HIV-infected individuals, and IV ceftriaxone and IV cefotaxime are reasonable alternatives.

CDC, NIH, and IDSA state that, while prophylaxis against travelers' diarrhea is not generally recommended for HIV-infected travelers, such prophylaxis may be considered for some of these individuals, depending on their level of immunosuppression and the region and duration of travel. These clinicians suggest that oral fluoroquinolones (e.g., ciprofloxacin) can be used in HIV-infected adults when prophylaxis of travelers' diarrhea is considered necessary. Rifaximin also can be considered for such prophylaxis. For HIV-infected patients who are pregnant or are already receiving co-trimoxazole for prophylaxis of Pneumocystis jirovecii (formerly Pneumocystis carinii) pneumonia (PCP), co-trimoxazole may provide some degree of protection from travelers' diarrhea; however, co-trimoxazole probably should not be administered solely for prophylaxis of travelers' diarrhea in HIV-infected patients because of the risk of adverse effects.

Intra-abdominal Infections

Ciprofloxacin (IV, conventional tablets, oral suspension) is used in conjunction with metronidazole for the treatment of complicated intra-abdominal infections caused by E. coli, Ps. aeruginosa, P. mirabilis, K. pneumoniae, or Bacteroides fragilis.

For initial empiric treatment of mild to moderately severe community-acquired, extrabiliary, complicated intra-abdominal infections in adults (e.g., perforated or abscessed appendicitis), IDSA recommends either monotherapy with cefoxitin, ertapenem, moxifloxacin, tigecycline, or the fixed combination of ticarcillin and clavulanic acid, or a combination regimen that includes either a cephalosporin (cefazolin, ceftriaxone, cefotaxime, cefuroxime) or fluoroquinolone (ciprofloxacin, levofloxacin) in conjunction with metronidazole.

For initial empiric treatment of high-risk or severe community-acquired, extrabiliary, complicated intra-abdominal infections in adults (e.g., those with advanced age, immunocompromise, severe physiologic disturbance), IDSA recommends either monotherapy with a carbapenem (doripenem, imipenem, meropenem) or the fixed combination of piperacillin and tazobactam, or a combination regimen that includes either a cephalosporin (cefepime, ceftazidime) or fluoroquinolone (ciprofloxacin, levofloxacin) in conjunction with metronidazole.

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

Meningitis and Other CNS Infections

IV ciprofloxacin has been used with some success for the treatment of meningitis caused by gram-negative bacteria. However, only low concentrations of ciprofloxacin are distributed into CSF, and further study is needed to more fully evaluate efficacy and safety of the drug in the treatment of CNS infections. Some clinicians suggest that fluoroquinolones (including ciprofloxacin) 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.

Ciprofloxacin has been effective when used alone or in conjunction with other drugs (e.g., antipseudomonal aminoglycosides) to treat meningitis and other CNS infections caused by susceptible Ps. aeruginosa. Some clinicians suggest that a regimen of ciprofloxacin with or without an aminoglycoside can be used as an alternative for the treatment of Ps. aeruginosa meningitis when cefepime or ceftazidime cannot be used.

Ciprofloxacin also has been used for the treatment of meningitis and other CNS infections caused by susceptible Salmonella. Some clinicians suggest that ciprofloxacin alone or in conjunction with a third generation cephalosporin (cefotaxime, ceftriaxone) may be a drug of choice for the treatment of Salmonella meningitis in pediatric patients, especially when the causative organism is resistant to other drugs.

Ophthalmic and Otic Infections

Oral or IV ciprofloxacin is used in the treatment of malignant otitis externa caused by Ps. aeruginosa. Bacterial otitis externa usually is caused by Ps. aeruginosa or S. aureus. Although acute bacterial otitis externa localized in the external auditory canal may be effectively treated using topical anti-infectives (e.g., ciprofloxacin otic suspension, ofloxacin otic solution), malignant otitis externa is an invasive, potentially life-threatening infection, especially in immunocompromised patients such as those with diabetes mellitus or HIV infection, and requires prompt diagnosis and long-term treatment with systemic anti-infectives. The treatment of choice for malignant otitis externa usually is ciprofloxacin or an antipseudomonal β-lactam (e.g., ceftazidime, imipenem). Because ciprofloxacin-resistant Ps. aeruginosa have been reported with increasing frequency in patients with malignant otitis externa and has been associated with treatment failure, clinical isolates should be tested for in vitro susceptibility, especially if there is an inadequate response to treatment.

For use of ciprofloxacin hydrochloride in the topical treatment of ophthalmic and otic infections caused by susceptible bacteria,

Respiratory Tract Infections

Ciprofloxacin (IV, conventional tablets, oral suspension) is used in adults for the treatment of respiratory tract infections, including acute sinusitis, acute exacerbations of chronic bronchitis), bronchiectasis, lung abscess, and pneumonia, caused by susceptible E. aerogenes,E. cloacae,E. coli,Haemophilus influenzae,H. parainfluenzae,K. oxytoca,K. pneumoniae,P. mirabilis,Ps. aeruginosa,S. aureus, or S. pneumoniae (penicillin-susceptible strains). The drug also is used for the treatment of respiratory tract infections caused by susceptible Moraxella catarrhalis.

IV ciprofloxacin is used for the treatment of nosocomial pneumonia caused by susceptible H. influenzae or K. pneumoniae and for the treatment of acute bacterial sinusitis caused by H. influenzae, S. pneumoniae (penicillin-susceptible strains), or M. catarrhalis.

Ciprofloxacin should be used for the treatment of acute bacterial sinusitis or acute bacterial exacerbations of chronic bronchitis only when there are no other treatment options.Because systemic fluoroquinolones, including ciprofloxacin, 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 and acute bacterial exacerbations of chronic bronchitis may be self-limiting in some patients,the risks of serious adverse reactions outweigh the benefits of fluoroquinolones for patients with these infections.

In controlled studies in adults with respiratory tract infections, oral ciprofloxacin therapy was as effective as therapy with oral amoxicillin, oral ampicillin, IV cefamandole, oral doxycycline, or IV imipenem and cilastatin sodium. Oral ciprofloxacin therapy generally resulted in a bacteriologic cure rate of 80-98% in adults with respiratory tract infections. Oral ciprofloxacin has been most effective in the treatment of respiratory tract infections caused by H. influenzae or M. catarrhalis; treatment failures have occurred when the drug was used in the treatment of infections caused by S. pneumoniae or Ps. aeruginosa. Treatment failure of S. pneumoniae respiratory tract infections may be related to the moderate in vitro susceptibility of this organism to ciprofloxacin. Although ciprofloxacin may be effective, it is not a drug of first choice for the treatment of presumed or confirmed pneumonia secondary to S. pneumoniae, and some clinicians suggest that ciprofloxacin generally not be used for empiric treatment of community-acquired pneumonia when S. pneumoniae is likely or suspected as the causative organism. A β-lactam antibiotic generally is preferred for empiric treatment of these infections and also is preferred in other respiratory tract infections known or suspected to be caused by pneumococci or streptococci. Ciprofloxacin probably should not be used in the treatment of aspiration pneumonia because these infections generally involve anaerobic bacteria.

Acute Exacerbations of Chronic Bronchitis

Clinical improvement has occurred when oral ciprofloxacin was used alone for the treatment of acute exacerbations of bronchopulmonary Ps. aeruginosa infections in adults with cystic fibrosis. As with other anti-infectives, Ps. aeruginosa may be cleared temporarily from the sputum, but a bacteriologic cure rarely is obtained and should not be expected in these patients.

Resistant strains of Ps. aeruginosa have developed during ciprofloxacin therapy; in one study, up to 45% of cystic fibrosis patients developed resistance after 2 weeks of therapy with the drug. Clinical improvement occurred in some patients despite the emergence of resistant Ps. aeruginosa; in some cases, the resistant organisms reverted to being susceptible after ciprofloxacin therapy was discontinued. Further study is necessary to determine if emergence of resistance will limit use of ciprofloxacin in the treatment of Ps. aeruginosa infections in cystic fibrosis patients. Some clinicians caution against long-term use of ciprofloxacin in these patients and recommend that the drug be used in short courses (e.g., 14 days), alternated with other anti-infectives active against Ps. aeruginosa (e.g., aztreonam, extended-spectrum penicillins, third generation cephalosporins) and/or used in conjunction with one of these agents. If ciprofloxacin is used, it is important that susceptibility of isolates be tested carefully in subsequent exacerbations.

Although many cystic fibrosis patients are children, ciprofloxacin, like other quinolones, generally should not be used in children younger than 18 years of age. Some clinicians suggest that the possible benefits of ciprofloxacin therapy may outweigh the possible risks in certain cystic fibrosis patients 9-18 years of age with infections that were known to be resistant to or failed to respond to other available anti-infectives.(See Cautions: Pediatric Precautions.)

Nosocomial Pneumonia

Ciprofloxacin is used IV for the treatment of nosocomial pneumonia, including hospital-acquired, ventilator-associated, and healthcare-associated pneumonia.

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 methicillin-resistant S. aureus (MRSA; also known as oxacillin-resistant S. aureus) (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.

Skin and Skin Structure Infections

Ciprofloxacin (IV, conventional tablets, oral suspension) is used in adults for the treatment of skin and skin structure infections caused by susceptible C. freundii,E. cloacae,E. coli, K. oxytoca,K. pneumoniae,M. morganii,P. mirabilis,P. vulgaris,P. stuartii,Ps. aeruginosa,Serratia marcescens,S. aureus (oxacillin-susceptible strains),S. epidermidis (oxacillin-susceptible strains), or S. pyogenes (group A β-hemolytic streptococci). The drug has been effective in the treatment of cellulitis, abscesses, folliculitis, furunculosis, pyoderma, postoperative wound infections, and infected ulcers, burns, or wounds.

Ciprofloxacin may be particularly useful as an oral agent for the treatment of skin and skin structure infections caused by susceptible gram-negative bacteria. Because staphylococci, streptococci, and anaerobes are only moderately susceptible to ciprofloxacin, ciprofloxacin generally should not be used alone and other anti-infectives remain the drugs of choice for skin and skin structure infections caused by these bacteria. Treatment failures have been reported in patients with skin or skin structure infections caused by S. aureus and the increasing emergence of strains of staphylococci resistant to quinolones limits the usefulness of the drugs in the treatment of these infections. Some clinicians suggest that ciprofloxacin therapy may be particularly useful for the treatment of hospital-acquired decubitus ulcers when anti-infective therapy is indicated.

In several controlled studies, oral ciprofloxacin was at least as effective as IV cefotaxime in the treatment of skin and skin structure infections caused by susceptible organisms. Oral ciprofloxacin resulted in a bacteriologic cure rate of 80-92% in patients with skin and skin structure infections.

Although ciprofloxacin is active in vitro against most common aerobic pathogens isolated from animal and human bite wounds, including Flavobacterium and Eikenella corrodens, the in vitro activity of the drug against streptococci, which frequently are isolated from such wounds (usually in mixed cultures), and against anaerobes generally is poor. Therefore, use of the drug as monotherapy in these infections is not recommended pending accumulation of additional efficacy data.

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 and Complicated Urinary Tract Infections

Ciprofloxacin extended-release tablets containing both the hydrochloride and the base are used only for the treatment of uncomplicated UTIs (acute cystitis) caused by susceptible E. faecalis, E. coli, P. mirabilis, or S. saprophyticus, complicated UTIs caused by susceptible E. coli, K. pneumoniae, P. mirabilis, Ps. aeruginosa, or E. faecalis, or acute uncomplicated pyelonephritis caused by E. coli in adults.

Ciprofloxacin (IV, conventional tablets, oral suspension) is used in adults for the treatment of complicated or uncomplicated UTIs caused by susceptible Citrobacter koseri (formerly C. diversus),C. freundii,Enterobacter cloacae,E. aerogenes,E. coli,Klebsiella oxytoca,K. pneumoniae,Morganella morganii,Proteus mirabilis,Providenciarettgeri,P. stuartii,Pseudomonas aeruginosa, or Serratia marcescens. The drug also is used in adults for the treatment of UTIs caused by susceptible gram-positive bacteria, including Staphylococcus aureus,S. epidermidis (oxacillin-susceptible strains),S. saprophyticus, or E. faecalis.

Ciprofloxacin (IV, conventional tablets, oral suspension) is used in pediatric patients 1 year of age or older for the treatment of complicated UTIs and pyelonephritis caused by susceptible E. coli. Although effective in UTIs, ciprofloxacin is not a drug of first choice for these infections in pediatric patients because of the risk of adverse effects (e.g., musculoskeletal effects) reported in this patient population.(See Cautions: Pediatric Precautions.)

Ciprofloxacin should be used for the treatment of uncomplicated UTIs only when there are no other treatment options.Because systemic fluoroquinolones, including ciprofloxacin, 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 risk of serious adverse reactions outweigh the benefits of fluoroquinolones for patients with uncomplicated UTIs.

Some clinicians suggest that ciprofloxacin be reserved for the treatment of complicated UTIs, especially those caused by multidrug-resistant bacteria. IDSA and other experts state that fluoroquinolones (ciprofloxacin, levofloxacin, ofloxacin) generally should be considered alternatives 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.

Clinical Experience

In controlled studies in men and women, oral ciprofloxacin therapy was as effective as therapy with oral co-trimoxazole in the treatment of uncomplicated UTIs; bacteriologic cure rates and rate of relapse and/or reinfection were similar with both drugs. Oral ciprofloxacin therapy generally results in a bacteriologic cure in 80-100% of patients with UTIs. Oral ciprofloxacin is more effective in the treatment of uncomplicated UTIs than in complicated infections, and most treatment failures occur in patients with underlying structural abnormalities of the urinary tract (e.g., obstructions, neurogenic bladder) or indwelling catheters.

Oral ciprofloxacin has been as effective as oral co-trimoxazole in the treatment of complicated UTIs, and has been effective in the treatment of UTIs caused by organisms resistant to co-trimoxazole. Prolonged, high-dose oral ciprofloxacin therapy (500-750 mg every 12 hours) has been effective in the treatment of complicated UTIs caused by multidrug-resistant Ps. aeruginosa.

A 3-day regimen of oral ciprofloxacin (conventional tablets) generally is effective for the treatment of acute, uncomplicated cystitis caused by susceptible strains of E. coli, E. faecalis, P. mirabilis, or S. saprophyticus (bacteriologic eradication rate 81-100%). Oral ciprofloxacin (conventional tablets) has been effective in women for the treatment of uncomplicated UTIs when given as a single 100- or 250-mg dose. However, efficacy of a single dose of the drug for the treatment of these infections has not been clearly established; single-dose therapy was less effective in the treatment of UTIs caused by gram-positive bacteria than in those caused by gram-negative bacteria.

Safety and efficacy of ciprofloxacin extended-release tablets for the treatment of uncomplicated UTIs (acute cystitis) have been evaluated in a randomized, double-blind, controlled study in adults. In this study, adults were randomized to receive ciprofloxacin extended-release tablets (500 mg once daily for 3 days) or conventional ciprofloxacin tablets (250 mg twice daily for 3 days). The bacteriologic eradication rate with no new infections or superinfections at the time of test of cure (post-therapy day 4-11) was 94.5% in those who received the extended-release tablets and 93.7% in those who received conventional tablets. Safety and efficacy of ciprofloxacin extended-release tablets for the treatment of complicated UTIs or acute uncomplicated pyelonephritis also have been evaluated in a randomized, double-blind study. In this study, adults were randomized to receive ciprofloxacin extended-release tablets (1 g once daily for 7-14 days) or conventional ciprofloxacin tablets (500 mg twice daily for 7-14 days). In the per-protocol population, the bacteriologic eradication rate with no new infections or superinfections at the time of test of cure (post-therapy day 5-11) in those who received the extended-release tablets was 89.2 or 87.5% in those with complicated UTIs or uncomplicated pyelonephritis, respectively; in those who received the conventional tablets, the rates were 81.4 or 98.1%, respectively.

In clinical studies evaluating IV or oral ciprofloxacin for the treatment of complicated UTIs and pyelonephritis in pediatric patients 1-17 years of age, the bacteriologic eradication rate was about 84% in those receiving ciprofloxacin compared with about 78% in those receiving a cephalosporin.

Prostatitis

Ciprofloxacin (IV, conventional tablets, oral suspension) is used in men for the treatment of recurrent UTIs and chronic prostatitis caused by E. coli or P. mirabilis. Ciprofloxacin has been most effective in the treatment of prostatitis caused by E. coli or other Enterobacteriaceae, and has been effective in infections that did not respond to co-trimoxazole therapy. Prostatitis caused by Ps. aeruginosa, enterococci, or staphylococci may respond poorly to the drug. Because high concentrations of ciprofloxacin are attained in prostatic tissues, the drug may become a drug of choice for the treatment of recurrent UTIs associated with prostatitis; however, further study is needed to compare efficacy of ciprofloxacin with that of other anti-infectives used in the treatment of these infections.

Anthrax

Ciprofloxacin (conventional tablets, oral suspension) is used for inhalational anthrax (postexposure) to reduce the incidence or progression of disease following suspected or confirmed exposure to aerosolized Bacillus anthracis spores in adults and children. Ciprofloxacin (IV, conventional tablets, oral suspension) is used for the treatment of clinically apparent inhalational anthrax, cutaneous anthrax, or GI and oropharyngeal anthrax, and for prophylaxis following ingestion of B. anthracis spores in contaminated meat.

Naturally occurring or endemic cutaneous anthrax in humans can occur after exposure to B. anthracis spores following contact with contaminated soil or infected animals (e.g., goats, sheep, cattle, swine, horses, buffalo, deer) or animal by-products (e.g., hides, hair, wool, carcasses, bone meal); GI or oropharyngeal anthrax can occur after ingestion of anthrax spores (e.g., in contaminated, raw or undercooked meat); and inhalational anthrax can occur after exposure to B. anthracis spores aerosolized during industrial processing of contaminated animal by-products or in the laboratory. Inhalational or cutaneous anthrax also may occur as the result of exposure to aerosolized B. anthracis spores in the context of biologic warfare or bioterrorism, including exposure to mail or other fomites contaminated with anthrax spores.

Following exposure to aerosolized B. anthracis spores, inhalational anthrax may develop if spore-containing particles are deposited into alveolar spaces. Macrophages ingest the spores and some undergo lysis and destruction. Surviving spores are transported via the lymph system to mediastinal lymph nodes where germination and vegetative growth may occur after a period of spore dormancy. Monkey studies have demonstrated that viable spores can persist in a dormant state in alveolar surface epithelium and mediastinal lymph nodes for up to 100 days after inhalation. The process responsible for the delayed transformation of spores to vegetative cells remains to be elucidated. Once germination occurs, disease follows rapidly. Replicating B. anthracis release toxins that can result in hemorrhage, edema, and necrosis. Cutaneous anthrax may occur if B. anthracis spores are introduced into a cut or abrasion (e.g., on the face, neck, or arms). Septicemia and meningeal anthrax result from hematogenous spread of the organism from the primary cutaneous, GI, or inhalation site. Although discharge from cutaneous lesions might be infectious, the risk for person-to-person transmission of cutaneous anthrax is low. Person-to-person transmission and secondary cases of anthrax (e.g., in medical personnel) have not been documented to date.

For the treatment of clinically apparent inhalational, GI, or meningeal anthrax and anthrax septicemia that occurs as the result of natural or endemic exposures to B. anthracis, parenteral penicillin historically has been considered the drug of choice and IV ciprofloxacin or IV doxycycline have been suggested as alternatives. However, it has been postulated that exposures to B. anthracis that occur in the context of biologic warfare or bioterrorism may involve bioengineered resistant strains and this concern should be considered when selecting initial anti-infective regimens for treatment of anthrax that occurs as the result of bioterrorism-related exposures or when selecting anti-infectives for postexposure prophylaxis following such exposures.B. anthracis with natural resistance to penicillins have been reported and there are published reports of B. anthracis strains that have been engineered to have tetracycline and penicillin resistance as well as resistance to other anti-infectives (e.g., macrolides, chloramphenicol, rifampin). In addition, reduced susceptibility to ofloxacin (4-fold increase in MICs from baseline) has been produced in vitro following sequential subculture of the Sterne strain of B. anthracis in subinhibitory concentrations of the fluoroquinolone.

Recommendations for the treatment and prophylaxis of anthrax have evolved based on experience gained in treating US patients who developed inhalational or cutaneous anthrax during September and October 2001 following bioterrorism-related exposures to B. anthracis spores as well results of animal studies and concerns related to treating large numbers of individuals in a mass casualty setting.

In addition to the information contained in the following sections, infectious disease and public health experts should be consulted for the most recent information on public health ramifications of bioterrorism-related exposures to anthrax spores and possible changes in recommendations for the treatment or prophylaxis of anthrax following such exposures. Information on ongoing developments also can be obtained at http://www.bt.cdc.gov.

Postexposure Prophylaxis of Anthrax

Ciprofloxacin is used for inhalational anthrax (postexposure) to reduce the incidence or progression of disease following suspected or confirmed exposure to aerosolized B. anthracis spores in adults or children. 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.

Ciprofloxacin and doxycycline are considered equally effective for postexposure prophylaxis following exposure to aerosolized B. anthracis spores. During the bioterrorism-related exposures to B. anthracis spores in September and October 2001, CDC initially recommended postexposure prophylaxis with either ciprofloxacin or doxycycline; however, CDC subsequently revised these recommendations because of the large number of individuals exposed to B. anthracis who required postexposure prophylaxis. Widespread use of any anti-infective agent can promote resistance to that drug and because many common pathogens already are resistant to tetracycline but fluoroquinolone resistance is not yet common among these same organisms, CDC suggested that use of doxycycline for postexposure prophylaxis was preferable for this event since it would preserve effectiveness of ciprofloxacin against other organisms. Ultimately, however, selection of an anti-infective agent for postexposure prophylaxis should be based on the clinical setting, susceptibility, and reported adverse effects associated with the drugs and either doxycycline or ciprofloxacin (or another fluoroquinolone) may be preferable for an individual patient.

Following natural, occupational, or bioterrorism-related exposures to aerosolized B. anthracis spores, anti-infective postexposure prophylaxis should be initiated immediately or as soon as possible. Postexposure vaccination with anthrax vaccine (if available) may be indicated in conjunction with anti-infective postexposure prophylaxis in some individuals. Vaccine-induced immunity provides protection if there are issues related to the anti-infective postexposure prophylaxis regimen (e.g., poor adherence, early discontinuance because of adverse effects) or if there are residual spores that germinate after the anti-infective regimen has been completed. When indicated and available, vaccination with anthrax vaccine should be initiated as soon as possible, preferably within 10 days of the exposure.

The optimum duration of postexposure prophylaxis after an inhalation exposure to B. anthracis spores is unclear. Because of the possible persistence of anthrax spores in lung tissue following an aerosol exposure, prolonged postexposure prophylaxis usually is required. Based on a competing-risks model, some clinicians suggest that the optimum duration of prophylaxis depends on the dose of inhaled spores. These clinicians state that a duration of 60 days may be adequate for a low-dose exposure, but that a duration exceeding 4 months may be necessary to reduce the risk following a high-dose exposure. ACIP, CDC, US Working Group on Civilian Biodefense, and USAMRIID recommend that postexposure prophylaxis following a confirmed exposure (including in laboratory workers with confirmed exposures to B. anthracis cultures) should be continued for at least 60 days in previously unvaccinated individuals. If anthrax vaccine is used in conjunction with anti-infective prophylaxis for postexposure prophylaxis in exposed individuals, ACIP and USAMRIID recommend continuing anti-infective prophylaxis until 14 days after the third dose of the vaccine series (even if this results in more than 60 days of anti-infective prophylaxis).

Postexposure anti-infective prophylaxis may be indicated in laboratory workers and other individuals who work in occupations that result in exposure to B. anthracis and may also be considered following a naturally occurring GI exposure to B. anthracis (e.g., ingestion of meat from an undercooked carcass of an anthrax-infected animal).

Infants and Children

Although ciprofloxacin generally is not recommended for use in infants and children (see Cautions: Pediatric Precautions), the benefits of ciprofloxacin prophylaxis outweigh the risks for inhalational anthrax (postexposure) and the drug may be used in children to reduce the incidence or progression of disease following exposure to aerosolized B. anthracis spores. ACIP, CDC, and other experts recommend that infants and children receive ciprofloxacin or doxycycline for initial anti-infective prophylaxis following suspected bioterrorism-related exposures to B. anthracis spores; however, if exposure has been confirmed and in vitro tests indicate that the organism is susceptible to penicillin, the postexposure prophylaxis regimen in children may be switched to oral amoxicillin . Although monotherapy with a penicillin is not recommended for treatment of inhalational anthrax when high concentrations of the organism are likely to be present, penicillins (e.g., amoxicillin, amoxicillin and clavulanate potassium, penicillin G procaine) may be considered an option for anti-infective prophylaxis, including when ciprofloxacin or doxycycline are contraindicated. The likelihood of β-lactamase induction resulting in an increase in penicillin MICs is lower when only a small number of vegetative cells are present and, therefore, penicillin monotherapy can be considered for postexposure prophylaxis.

Pregnant and Breast-feeding Women

The possible benefits of postexposure prophylaxis against anthrax should be weighed against the possible risks to the fetus when choosing an anti-infective for postexposure prophylaxis in pregnant women. ACIP, CDC, and other experts state that ciprofloxacin should be considered the drug of choice for initial postexposure prophylaxis in pregnant women exposed to B. anthracis spores and that, if in vitro studies indicate that the organism is susceptible to penicillin, then consideration can be given to changing the postexposure regimen to amoxicillin. Women who become pregnant while receiving anti-infective prophylaxis should continue the existing regimen and consult with a healthcare provider or public health official to discuss whether an alternative regimen might be more appropriate.

AAP considers ciprofloxacin to be usually compatible with breast-feeding since the amount of the quinolone potentially absorbed by nursing infants would be small and no observable change in infants associated with such exposure has been reported to date. Because the long-term safety of prolonged exposure of nursing infants (e.g., during a 60-day regimen for anthrax) to breast milk from ciprofloxacin-treated women currently is not known, CDC recommends that lactating women who are concerned about the use of ciprofloxacin during anthrax prophylaxis consider expressing and then discarding their breast milk so that breast-feeding can be resumed once anti-infective prophylaxis is complete.(See Cautions: Pregnancy, Fertility, and Lactation.) ACIP states that amoxicillin is an option for postexposure prophylaxis in nursing women if in vitro studies indicate that the organism is susceptible to penicillin. If the infant has been exposed to B. anthracis and is receiving postexposure prophylaxis, the anti-infective used in the woman should be the same as that used in the nursing infant, whenever possible.

Individuals at Contaminated Sites

For the bioterrorism-related exposures to B. anthracis spores that occurred in the US during the fall of 2001, CDC recommended that anti-infective prophylaxis be initiated (pending additional information) in individuals exposed to an air space where a suspicious material may have been aerosolized (e.g., near a suspicious powder-containing letter during opening) and in individuals who shared the air spaces likely to be the source of an inhalational anthrax case. While culture of nasal swabs can occasionally document exposure and provide clues to help assess the exposure circumstances, these nasal swabs are investigative tools only and results cannot be used to rule out exposure to B. anthracis. Following confirmation of the presence of B. anthracis spores, CDC recommended that a full 60-day postexposure regimen be completed in individuals exposed to an air space known to be contaminated with aerosolized B. anthracis, in individuals exposed to an air space known to be the source of an inhalational anthrax case, and in individuals along the transit path of an envelope or other vehicle containing B. anthracis that may have been aerosolized (e.g., a postal sorting facility in which an envelope containing B. anthracis was processed).

Remediation workers with repeated entries into contaminated sites over a prolonged period of time may require anti-infective prophylaxis for considerably longer than the 60 days recommended for individuals with a single exposure. Some remediation workers exposed during the bioterrorism-related events that occurred in the US during the fall of 2001 received anti-infective prophylaxis for more than 6 months. At that time, CDC recommended that anti-infective prophylaxis be continued throughout the period of risk and for 60 days after the risk of exposure ended, unless a 6-dose series of anthrax vaccine had been completed and annual boosters were up to date.

Laboratory Workers and Other Individuals

Laboratory workers and other individuals who work in occupations that might result in repeated exposure to aerosolized B. anthracis spores should receive preexposure vaccination with anthrax vaccine adsorbed. ACIP states that anti-infective postexposure prophylaxis is not necessary in fully vaccinated workers who wear appropriate personal protective equipment (PPE) while working in environments contaminated with B. anthracis spores, unless PPE is disrupted. If there is any type of disruption of PPE in a worker who is fully or partially vaccinated against anthrax, ACIP recommends that anti-infective postexposure prophylaxis be given for at least 30 days in conjunction with any remaining indicated doses of anthrax vaccine. 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 and states that the anti-infective prophylaxis regimen should be continued for 14 days after the third vaccine dose (even if this results in more than 60 days of anti-infective prophylaxis).

Following a bioterrorism-related event, use of anti-infective prophylaxis in asymptomatic individuals in the general population is not indicated unless appropriate public health or law-enforcement agencies have ascertained that a risk of exposure to B. anthracis spores exists. In addition, CDC states that postexposure prophylaxis is not indicated for the prevention of cutaneous anthrax, for autopsy personnel examining bodies infected with anthrax when appropriate isolation precautions and procedures are followed, for hospital personnel caring for patients with anthrax, or for individuals who routinely open or handle mail in the absence of a suspicious letter or credible threat.

Clinical Experience

Although controlled studies evaluating ciprofloxacin for aerosolized anthrax exposure in humans have not been conducted for ethical reasons, the indication for use of ciprofloxacin is based on serum concentrations of the drug achieved in humans, a surrogate end point reasonably likely to predict clinical benefit. Efficacy of ciprofloxacin has been evaluated in a rhesus monkey model of inhalational anthrax. In this study, rhesus monkeys were exposed to an inhaled mean dose of 11 LD50 (approximately 5.5 x 10) spores (range: 5-30 LD50) of B. anthracis and then received a 30-day regimen of placebo or oral ciprofloxacin beginning 24 hours after exposure. Mortality due to anthrax was significantly lower in monkeys that received ciprofloxacin (1/9) compared with those that received placebo (9/10); the one ciprofloxacin-treated monkey that died of anthrax did so following the 30-day drug administration period. In the monkeys studied, mean serum concentrations of ciprofloxacin 1 hour after dosing (at the expected time of peak serum concentrations) following oral dosing to steady state ranged from 0.98-1.69 mcg/mL; mean steady-state trough concentrations at 12 hours after dosing ranged from 0.12-0.19 mcg/mL. The mean serum concentrations of ciprofloxacin associated with a statistically significant improvement in survival in this rhesus monkey model of inhalational anthrax are reached or exceeded in adult and pediatric patients receiving oral or IV ciprofloxacin.

Some data regarding efficacy of ciprofloxacin for postexposure prophylaxis in humans following exposure to aerosolized B. anthracis spores is available since the drug was used for postexposure prophylaxis in individuals in the US who were exposed to B. anthracis spores in bioterrorism-related incidences that occurred during September and October 2001. Approximately 300 postal or other facilities were tested for B. anthracis spores and anti-infective prophylaxis with ciprofloxacin or other anti-infectives was initiated in approximately 32,000 individuals in Florida, New Jersey, New York, and the District of Columbia who had potential exposures. A full 60-day postexposure prophylaxis regimen was recommended for approximately 8424 of these individuals. To date, no individual who received anti-infective prophylaxis following these bioterrorism-related exposures developed microbiologically confirmed anthrax. Although ciprofloxacin postexposure prophylaxis generally was well tolerated, the incidence of adverse effects was higher than that reported previously in controlled clinical trials evaluating the drug for other indications.(See Cautions.)

Treatment of Inhalational Anthrax

The rapid course of symptomatic inhalational anthrax and high mortality rate make early initiation of anti-infective therapy essential. Because of the difficulty in making a rapid microbiologic diagnosis of anthrax, high-risk individuals who develop fever or other evidence of systemic infection should promptly receive therapy for possible anthrax infection while waiting for results of laboratory studies.

Based on clinical experience from the bioterrorism-related anthrax exposures of 2001 and the possibility that a B. anthracis strain resistant to one or more anti-infectives might be used in a future bioterrorism event, CDC and other experts (e.g., US Working Group on Civilian Biodefense, USAMRIID) recommend that treatment of clinically apparent inhalational anthrax in adults, adolescents, or children that occurs as the result of exposure to anthrax spores in the context of biologic warfare or bioterrorism be initiated with a multiple-drug parenteral regimen that includes ciprofloxacin or doxycycline and 1 or 2 additional anti-infectives predicted to be effective. Other drugs to be included in the initial treatment regimen with ciprofloxacin or doxycycline should be selected based on in vitro susceptibility, possibility of efficacy, adverse effects, and cost. Based on in vitro data, other drugs that have been suggested as possibilities to augment ciprofloxacin or doxycycline in such multiple-drug regimens include chloramphenicol, clindamycin, rifampin, vancomycin, macrolides (azithromycin, clarithromycin, erythromycin), imipenem, meropenem, penicillin, ampicillin, daptomycin, quinupristin and dalfopristin, linezolid, and aminoglycosides (gentamicin).

Optimum regimens for treatment of anthrax meningitis are unknown. However, if meningitis is established or suspected, early and aggressive anti-infective treatment is critical. Some clinicians suggest a multiple-drug regimen that includes a fluoroquinolone (e.g., ciprofloxacin) and 1 or 2 additional agents with good CSF penetration (e.g., ampicillin or penicillin, meropenem, rifampin, vancomycin, chloramphenicol).

Results of in vitro susceptibility testing of strains of B. anthracis that were associated with cases of inhalational or cutaneous anthrax that occurred in the US (Florida, New York, District of Columbia) during September and October 2001 in the context of bioterrorism-related exposures to anthrax spores indicate that these strains were susceptible to ciprofloxacin, doxycycline, tetracycline, rifampin, clindamycin, vancomycin, and chloramphenicol. However, only limited or no clinical data are available regarding use of these drugs in the treatment of anthrax. A multiple-drug parenteral regimen that was used in 2 patients who survived inhalational anthrax following the bioterrorism-related exposures in 2001 was a 3-drug regimen of ciprofloxacin (400 mg every 8 hours), rifampin (300 mg every 12 hours), and clindamycin (900 mg every 8 hours). Other multiple-drug regimens that were used for the initial treatment of patients who survived inhalational anthrax following these bioterrorism-related anthrax exposures were ciprofloxacin/cefotaxime/azithromycin (1 patient); levofloxacin/rifampin initially then ciprofloxacin rifampin/vancomycin (1 patient); and oral levofloxacin (prior to diagnosis), then ciprofloxacin/azithromycin, then clindamycin/ceftriaxone/azithromycin, then doxycycline (1 patient). Although it is unclear whether the deaths were related to ineffective regimens and/or delays in initiation of therapy, the regimens used in patients who died of inhalational anthrax following these exposures were levofloxacin/clindamycin/penicillin G (1 patient, initiated on the second day of hospitalization after various anti-infectives, died 3 days after admission); levofloxacin monotherapy (1 patient, died day of admission); levofloxacin/rifampin/penicillin G/ceftriaxone (1 patient, died day of admission); levofloxacin monotherapy, then levofloxacin/rifampin/gentamicin/nafcillin, then ciprofloxacin/rifampin/clindamycin/ceftazidime (1 patient, died 3 days after admission); ampicillin-sulbactam/ciprofloxacin/clindamycin (1 patient, initiated on the third day of hospita

Dosage and Administration

Administration

Ciprofloxacin is administered orally as conventional tablets containing the hydrochloride, as a conventional oral suspension containing the base, and as extended-release tablets containing both the hydrochloride and the base. Ciprofloxacin is given by IV infusion as the base.

Patients receiving initial therapy with IV ciprofloxacin may be switched to oral ciprofloxacin (conventional tablets, oral suspension) when clinically appropriate.

Ciprofloxacin extended-release tablets are used only for the treatment of certain urinary tract infections (UTIs). The extended-release tablets are not interchangeable with other oral ciprofloxacin preparations (conventional tablets, oral suspension).

Because of the risk of crystalluria, patients receiving oral or IV ciprofloxacin should be adequately hydrated and should be instructed to drink fluids liberally to prevent formation of highly concentrated urine.(See Cautions: Genitourinary Effects.)

Oral Administration

The manufacturers state that ciprofloxacin conventional tablets, extended-release tablets, or oral suspension may be given without regard to meals.(See Pharmacokinetics.)

Ciprofloxacin conventional tablets, extended-release tablets, or oral suspension should not be administered concurrently with dairy products (e.g., milk, yogurt) or calcium-fortified products (e.g., juices) alone (without a meal) since absorption of the drug may be substantially reduced. Doses should preferably be taken 2 hours before or after these calcium-fortified products or substantial calcium intake (greater than 800 mg).

Conventional tablets and extended-release tablets should be swallowed whole and should not be split, crushed, or chewed.

The microcapsules contained in the reconstituted oral suspensions should be swallowed and should not be chewed.

Reconstitution

Ciprofloxacin microcapsules for oral suspension are provided in a kit that contains a bottle of microcapsules, a bottle of oral suspension diluent, and a graduated dosing spoon. At the time of dispensing, the bottle containing the microcapsules (either 5 or 10 g of ciprofloxacin) should be added to the bottle of diluent according to the manufacturer's directions and shaken vigorously for about 15 seconds to provide a suspension containing 250 or 500 mg of ciprofloxacin per 5 mL, respectively. Only the diluent supplied in the kit should be used; water should not be added to the oral suspension.

Prior to administration of each dose, the reconstituted oral suspension should be shaken vigorously for about 15 seconds.

IV Infusion

Prior to IV infusion, commercially available ciprofloxacin concentrate for injection containing 10 mg/mL must be diluted with a compatible IV solution (e.g., 0.9% sodium chloride injection, 5% dextrose injection) to provide a solution containing 1-2 mg/mL. Alternatively, commercially available ciprofloxacin injection for IV infusion containing 2 mg/mL in 5% dextrose injection may be used without further dilution.

IV infusions should be given into a large vein to minimize discomfort and reduce the risk of venous irritation. If a Y-type administration set is used, the other IV solution flowing through the tubing should be discontinued while ciprofloxacin is being infused. If concomitant use of IV ciprofloxacin and another parenteral drug is necessary, each drug should be given separately.

Rate of Administration

IV infusions of ciprofloxacin should be infused over 1 hour.

Because local reactions (e.g., thrombophlebitis, burning, pain, pruritus, paresthesia, erythema, swelling) at the site of IV infusion are more frequent when the drug is administered rapidly (e.g., over 30 minutes or less) or via a small vein, ciprofloxacin should be infused IV slowly over a period of 1 hour as a dilute solution (1-2 mg of ciprofloxacin per mL) via a large vein. If such reactions occur despite these precautions, they generally resolve rapidly following completion of the infusion; the manufacturers state that subsequent IV administration of ciprofloxacin is not contraindicated unless the reaction recurs or worsens.

Dosage

Dosage of ciprofloxacin hydrochloride and ciprofloxacin is expressed in terms of ciprofloxacin.

The extended-release tablets are not interchangeable with the conventional tablets or oral suspension.

Based on pharmacokinetic parameters (i.e., area under the plasma concentration-time curve [AUC]), the following oral and IV ciprofloxacin regimens are considered equivalent: 250 mg orally every 12 hours (conventional tablets) is equivalent to 200 mg IV every 12 hours; 500 mg orally every 12 hours (conventional tablets) is equivalent to 400 mg IV every 12 hours; and 750 mg orally every 12 hours (conventional tablets) is equivalent to 400 mg IV every 8 hours.

The duration of ciprofloxacin therapy depends on the type and severity of infection, and should be determined by the clinical and bacteriologic response of the patient.

Bone and Joint Infections

For the treatment of bone and joint infections, the usual dosage of oral ciprofloxacin (conventional tablets or oral suspension) for adults is 500-750 mg every 12 hours for 4-8 weeks.

The usual IV dosage of ciprofloxacin for the treatment of bone and joint infections in adults is 400 mg every 8 to 12 hours; severe or complicated infections should be treated with 400 mg IV every 8 hours. The usual duration of treatment is at least 4-8 weeks.

Endocarditis

Endocarditis Caused by the HACEK Group

For the treatment of endocarditis (native or prosthetic valve or other prosthetic material) caused by fastidious gram-negative bacilli of the HACEK group when ceftriaxone (or other third or fourth generation cephalosporin) cannot be used (see Endocarditis Caused by the HACEK Group under Uses: Endocarditis), the American Heart Association (AHA) and Infectious Diseases Society of America (IDSA) suggest that adults receive IV ciprofloxacin in a dosage of 800 mg daily given in 2 equally divided doses or oral ciprofloxacin (conventional tablets or oral suspension) in a dosage of 1 g daily given in 2 equally divided doses. Treatment should be continued for 4 weeks in those with native valve endocarditis or for 6 weeks in those with endocarditis involving prosthetic cardiac valves or other prosthetic cardiac material. Because only limited data are available regarding use of ciprofloxacin for the treatment of these infections, AHA and IDSA recommend that patients with HACEK endocarditis who cannot receive ceftriaxone be treated in consultation with an infectious disease specialist.

GI Infections

Infectious Diarrhea

The usual oral dosage of ciprofloxacin (conventional tablets or oral suspension) for the treatment of infectious diarrhea in adults is 500 mg every 12 hours for 5-7 days. A single 1-g dose or two 1-g doses of ciprofloxacin (conventional tablets or oral suspension) administered 24 hours apart have been effective for the treatment of infectious diarrhea secondary to Shigella strains other than S. dysenteriae type 1; more prolonged therapy (e.g., 500 mg every 12 hours for 5 days) generally appears necessary for diarrhea secondary to this latter strain.

Cyclospora or Cystoisospora Infections

For the treatment of GI infections caused by Cyclospora cayetanensis, the recommended dosage of oral ciprofloxacin (conventional tablets or oral suspension) for adults is 500 mg twice daily for 7 days.

For the treatment of GI infections caused by Cystoisospora belli (formerly Isospora belli) in adults with human immunodeficiency virus (HIV) infection, the recommended dosage of oral ciprofloxacin (conventional tablets or oral suspension) is 500 mg twice daily for 7 days. If oral ciprofloxacin is used for chronic maintenance therapy (secondary prophylaxis) in HIV-infected adults with CD4 T-cell counts less than 200 cells/mm, a dosage of 500 mg 3 times weekly is recommended based on limited data. Consideration can be given to discontinuing such prophylaxis if CD4 T-cell counts exceed 200 cells/mm for more than 6 months in response to antiretroviral therapy.

Shigella Infections

For the treatment of shigellosis in HIV-infected adults, the recommended dosage of oral ciprofloxacin (conventional tablets or oral suspension) is 500-750 mg every 12 hours. Alternatively, 400 mg can be given IV every 12 hours.

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 ciprofloxacin (conventional tablets or oral suspension) be given in a dosage of 500 or 750 mg once daily for 1-3 days or 500 mg twice daily for 1-3 days. Alternatively, if ciprofloxacin extended-release tablets are used, some clinicians recommend a dosage of 500 mg or 1 g once daily for 1-3 days.

If ciprofloxacin is used for empiric treatment of travelers' diarrhea in HIV-infected adults, an oral dosage of 500-750 mg every 12 hours or IV dosage of 400 mg every 12 hours is recommended. If there is no clinical response after 5-7 days of treatment, stool culture and in vitro susceptibility testing should be considered.

Although the use of anti-infectives for prophylaxis of travelers' diarrhea generally is discouraged, if oral ciprofloxacin (conventional tablets or oral suspension) 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.

Intra-abdominal Infections

When ciprofloxacin is used for the treatment of complicated intra-abdominal infections, the recommended dosage for adults is 400 mg IV every 12 hours given in conjunction with metronidazole. If oral ciprofloxacin (conventional tablets or oral suspension) is used for the treatment of complicated intra-abdominal infections, the recommended dosage for adults is 500 mg every 12 hours in conjunction with metronidazole.

The manufacturers recommend a total treatment duration of 7-14 days. IDSA states that the usual duration of treatment for intra-abdominal infections is 4-7 days. A longer duration of treatment has not been associated with improved outcome and is not recommended unless adequate source control is difficult to achieve.

Malignant Otitis Externa

If oral ciprofloxacin (conventional tablets or oral suspension) is used for the treatment of malignant otitis externa, some clinicians recommend a dosage of 750 mg twice daily. Although there may be rapid relief of symptoms (pain, otorrhea), treatment should be continued for 6-8 weeks.

Because ciprofloxacin-resistant Pseudomonas aeruginosa have been isolated from patients with malignant otitis externa with increasing frequency, in vitro susceptibility testing is indicated, especially if there is an inadequate response to treatment.

Meningitis and Other CNS Infections

Although efficacy and safety have not been established, some clinicians suggest that adults can receive ciprofloxacin in a dosage of 400 mg IV every 8 hours for the treatment of meningitis caused by susceptible gram-negative bacteria. Other clinicians recommend an adult dosage of 800-1200 mg daily for the treatment of meningitis in adults.

For the treatment of meningitis caused by susceptible Salmonella, several pediatric patients have received IV ciprofloxacin in a dosage of 10-30 mg/kg daily alone or in conjunction with cefotaxime.

Respiratory Tract Infections

Acute Sinusitis

If ciprofloxacin (conventional tablets or oral suspension) is used for the treatment of acute sinusitis (see Uses: Respiratory Tract Infections), dosage in adults is 500 mg every 12 hours for 10 days.

The usual IV dosage of ciprofloxacin for the treatment of acute sinusitis in adults is 400 mg every 12 hours for 10 days.

Lower Respiratory Tract Infections

If oral ciprofloxacin (conventional tablets or oral suspension) is used for the treatment of acute bacterial exacerbations of chronic bronchitis (see Uses: Respiratory Tract Infections), dosage in adults is 500-750 mg every 12 hours for 7-14 days.

The usual dosage of oral ciprofloxacin (conventional tablets or oral suspension) for the treatment of lower respiratory tract infections in adults is 500-750 mg every 12 hours for 7-14 days.

The usual IV dosage of ciprofloxacin for the treatment of lower respiratory tract infections in adults is 400 mg every 8 to 12 hours; severe or complicated lower respiratory tract infections should be treated with 400 mg IV every 8 hours. The usual duration of treatment is 7-14 days.

Nosocomial Pneumonia

The usual IV dosage of ciprofloxacin for the treatment of nosocomial pneumonia in adults is 400 mg every 8 hours for 10-14 days.

Skin and Skin Structure Infections

For the treatment of skin and skin structure infections, the usual dosage of oral ciprofloxacin (conventional tablets or oral suspension) for adults is 500-750 mg every 12 hours for 7-14 days.

The usual IV dosage of ciprofloxacin for the treatment of skin and skin structure infections in adults is 400 mg every 8 to 12 hours; severe or complicated infections should be treated with 400 mg IV every 8 hours. The usual duration of treatment is 7-14 days.

Urinary Tract Infections and Prostatitis

Acute, Uncomplicated Cystitis

If ciprofloxacin (conventional tablets or oral suspension) is used for the treatment of acute, uncomplicated cystitis (see Uncomplicated and Complicated Urinary Tract Infections under Uses: Urinary Tract Infections and Prostatitis), dosage in adults is 250 mg every 12 hours for 3 days.

If ciprofloxacin extended-release tablets are used for the treatment of uncomplicated UTIs (acute cystitis) caused by susceptible Enterobacter faecalis, Escherichia coli, Proteus mirabilis, or Staphylococcus saprophyticus(see Uncomplicated and Complicated Urinary Tract Infections under Uses: Urinary Tract Infections and Prostatitis), dosage in adults is 500 mg once every 24 hours for 3 days.

Complicated Urinary Tract Infections and Pyelonephritis

The usual oral dosage of ciprofloxacin (conventional tablets or oral suspension) for the treatment of UTIs in adults is 250-500 mg every 12 hours for 7-14 days.

If ciprofloxacin extended-release tablets are used for the treatment of complicated UTIs or acute, uncomplicated pyelonephritis caused by susceptible bacteria, the usual adult dosage is 1 g once every 24 hours for 7-14 days.

The usual IV dosage of ciprofloxacin for the treatment of UTIs in adults is 200-400 mg every 8 to 12 hours; severe or complicated infections should be treated with 400 mg IV every 8 or 12 hours. The usual duration of treatment is 7-14 days.

If ciprofloxacin is used for the treatment of complicated UTIs or pyelonephritis in children 1-17 years of age, dosage and route of administration should be based on infection severity. Based on clinical studies, treatment may be initiated with a ciprofloxacin dosage of 6-10 mg/kg (up to 400 mg) given IV every 8 hours and then, when clinically indicated, switched to oral ciprofloxacin (conventional tablets or oral suspension) in a dosage of 10-20 mg/kg (up to 750 mg) every 12 hours. In clinical studies, the mean total duration of treatment was 11 days (range 10-21 days).

Prostatitis

For the treatment of chronic bacterial prostatitis in men, the usual oral dosage of ciprofloxacin (conventional tablets or oral suspension) is 500 mg every 12 hours for 28 days.

The usual IV dosage of ciprofloxacin for the treatment of chronic bacterial prostatitis is 400 mg every 12 hours for 28 days.

Anthrax

Postexposure Prophylaxis of Anthrax

When oral ciprofloxacin (conventional tablets or oral suspension) is used for inhalational anthrax (postexposure) to reduce the incidence or progression of disease following exposure to aerosolized Bacillus anthracis spores, including exposures in the context of biologic warfare or bioterrorism, adults should receive 500 mg every 12 hours and children 17 years of age or younger should receive 15 mg/kg (maximum 500 mg) every 12 hours. If IV ciprofloxacin is used for inhalational anthrax (postexposure), adults should receive 400 mg IV every 12 hours and children 17 years of age or younger should receive 10 mg/kg (maximum 400 mg) every 12 hours.

Anti-infective prophylaxis should be initiated as soon as possible following suspected or confirmed anthrax exposure. 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 Public Health Service Advisory Committee on Immunization Practices (ACIP), US Centers for Disease Control and Prevention (CDC), US Working Group on Civilian Biodefense, and US Army Medical Research Institute of Infectious Diseases (USAMRIID) recommend that anti-infective prophylaxis be continued for at least 60 days (see Postexposure Prophylaxis of Anthrax under Uses: Anthrax). However, because of potential adverse effects from prolonged use of ciprofloxacin in infants and children, amoxicillin is an alternative to ciprofloxacin or doxycycline prophylaxis when susceptibility to penicillin is known.

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).

For prophylaxis following ingestion of B. anthracis spores in contaminated meat, a ciprofloxacin dosage of 500 mg orally twice daily has been recommended for adults. If anti-infective prophylaxis is used following a naturally occurring GI exposure to B. anthracis (e.g., ingestion of meat from an undercooked carcass of an anthrax-infected animal), ACIP states that a duration of 7-14 days can be considered.

Treatment of Inhalational Anthrax

When ciprofloxacin is used for the treatment of inhalational anthrax following exposure to B. anthracis spores in the context of biologic warfare or bioterrorism, adults should receive an initial regimen of 400 mg IV every 12 hours and infants and children should receive 10-15 mg/kg IV every 12 hours (maximum 1 g daily). When clinically appropriate, therapy can be changed to oral ciprofloxacin (conventional tablets or oral suspension) and adults should receive 500 mg orally twice daily and children should receive 10-15 mg/kg every 12 hours (maximum 1 g daily). CDC and other experts (US Working Group on Civilian Biodefense, USAMRIID) 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. A parenteral regimen of ciprofloxacin (400 mg every 8 hours), rifampin (300 mg every 12 hours), and clindamycin (900 mg every 8 hours) has been used for initial treatment of inhalational anthrax in at least 2 adults.

If oral ciprofloxacin (conventional tablets or oral suspension) is used 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), some experts (US Working Group on Civilian Biodefense, USAMRIID) recommend that adults receive an oral dosage of 500 mg every 12 hours and that children receive a dosage of 10-15 mg/kg every 12 hours (maximum 500 mg per dose).

Because of the possible persistence of anthrax spores in lung tissue following an aerosol exposure, CDC and other experts recommend that 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 continued for at least 60 days. Because of potential adverse effects from prolonged use of ciprofloxacin in infants and children, amoxicillin is an option for completion of the remaining 60 days of therapy (i.e., after an initial 14-21 days of multiple-drug therapy for inhalational anthrax that included ciprofloxacin or doxycycline) when susceptibility to penicillin is known; amoxicillin is not recommended for initial treatment.

Treatment of Cutaneous Anthrax

For the treatment of uncomplicated, localized cutaneous anthrax that occurs following exposure to B. anthracis spores in the context of biologic warfare or bioterrorism, CDC and other experts (US Working Group on Civilian Biodefense) recommend that adults receive 500 mg of oral ciprofloxacin (conventional tablets or oral suspension) twice daily and that children receive 10-15 mg/kg orally every 12 hours (maximum 1 g daily). However, if there are signs of systemic involvement, extensive edema, or head and neck lesions, therapy should be initiated with the same parenteral multiple-drug regimen recommended for treatment of inhalational anthrax.(See Treatment of Inhalational Anthrax under Dosage: Anthrax.)

Although 5-10 days of treatment may be adequate for mild, uncomplicated cutaneous anthrax that occurs as the result of naturally occurring or endemic anthrax exposures, CDC and other experts recommend that anti-infective therapy be continued for at least 60 days for treatment of cutaneous anthrax that occurs as the result of exposure to aerosolized anthrax spores in the context of biologic warfare or bioterrorism since the possibility of inhalational anthrax would also exist.

Because of potential adverse effects from prolonged use of ciprofloxacin in infants and children, amoxicillin is an option for completion of the remaining 60 days of therapy (i.e., after an initial 14-21 or 7-10 days of multiple-drug therapy for complicated or uncomplicated cutaneous anthrax, respectively, that included ciprofloxacin or doxycycline) when susceptibility to penicillin is known; amoxicillin is not recommended for initial treatment.

Treatment of GI or Oropharyngeal Anthrax

For treatment of GI and oropharyngeal anthrax that occurs in the context of biologic warfare or bioterrorism, CDC and other experts (US Working Group on Civilian Biodefense, USAMRIID) recommend that therapy be initiated with the same parenteral multiple-drug regimen recommended for treatment of inhalational anthrax.(See Treatment of Inhalational Anthrax under Dosage: Anthrax.).

Bartonella Infections

For the treatment of cat scratch disease caused by Bartonella henselae, oral ciprofloxacin has been given in a dosage of 500 mg twice daily for 10-16 days.

Brucellosis

For the treatment of brucellosis caused by Brucella melitensis, some clinicians recommend that oral ciprofloxacin be given in a dosage of 500 mg twice daily in conjunction with oral rifampin (600 mg once daily). Oral ciprofloxacin also has been given in a dosage of 500 mg 2 or 3 times daily for 6-12 weeks or 750 mg 3 times daily for 6-8 weeks for the treatment of brucellosis or acute brucella arthritis-diskitis. Monotherapy or treatment regimens shorter than 4-6 weeks are not recommended.

Chancroid

When oral ciprofloxacin (conventional tablets or oral suspension) is used in the treatment of chancroid, CDC recommends that adults receive 500 mg twice daily for 3 days.

Crohn's Disease

Oral ciprofloxacin has been given in a dosage of 500 mg twice daily (with or without metronidazole) for induction of remission of mildly to moderately active Crohn's disease.

Gonorrhea and Associated Infections

Although ciprofloxacin is no longer recommended for the treatment of gonorrhea (see Uses: Gonorrhea and Associated Infections), the manufacturer recommends a single 250-mg dose of oral ciprofloxacin (conventional tablets or oral suspension) for the treatment of uncomplicated urethral or endocervical gonorrhea caused by susceptible Neisseria gonorrhoeae.

Granuloma Inguinale (Donovanosis)

For the treatment of granuloma inguinale (donovanosis) caused by Klebsiella granulomatis (formerly Calymmatobacterium granulomatis), 750 mg of oral ciprofloxacin (conventional tablets or oral suspension) should be given twice daily for at least 3 weeks and until all lesions have completely healed. Consideration can be given to adding a parenteral aminoglycoside (e.g., gentamicin 1 mg/kg IV every 8 hours) if improvement is not evident within the first few days of treatment.

Legionnaires' Disease

For the treatment of Legionnaires' disease, some clinicians recommend that 500 mg of ciprofloxacin be given orally every 12 hours or 400 mg be given IV every 12 hours for 2-3 weeks.

Mycobacterial Infections

When used in multiple-drug regimens for the treatment of Mycobacterium avium complex (MAC) infections, oral ciprofloxacin has been given to adults in a dosage of 750 mg twice daily.

Neisseria meningitidis Infections

When ciprofloxacin (conventional tablets or oral suspension) is used to eliminate nasopharyngeal carriage of Neisseria meningitidis or for chemoprophylaxis in close contacts of individuals with invasive meningococcal disease, adults should receive a single 500-mg oral dose.

If use of ciprofloxacin is considered necessary in children and infants 1 month of age or older to eliminate nasopharyngeal carriage of Neisseria meningitidis or for chemoprophylaxis in close contacts of individuals with invasive meningococcal disease when other anti-infectives (e.g., rifampin) cannot be used (see Cautions: Pediatric Precautions), the American Academy of Pediatrics (AAP) recommends a single oral dose of 20 mg/kg (maximum 500 mg).

Plague

Treatment of Plague

When IV ciprofloxacin is used for the treatment of plague caused by Yersinia pestis, the manufacturer recommends that adults receive a dosage of 400 mg IV every 8 to 12 hours for 14 days and that infants and children 17 years of age or younger receive a dosage of 10 mg/kg (maximum 400 mg) IV every 8 to 12 hours for 10-21 days. If oral ciprofloxacin (conventional tablets or oral suspension) is used for the treatment of plague, the manufacturer recommends that adults receive a dosage of 500-750 mg orally every 12 hours for 14 days and that infants and children 17 years of age or younger receive a dosage of 15 mg/kg (maximum 500 mg) orally every 8 or 12 hours for 10-21 days.

If IV ciprofloxacin is used for as an alternative for the treatment of pneumonic plague that occurs as the result of 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 adults receive a dosage of 400 mg IV every 12 hours and that children receive 15 mg/kg IV every 12 hours (maximum 1 g daily). Oral therapy may be substituted when the patient's condition improves. If oral ciprofloxacin (conventional tablets or oral suspension) is used for the treatment of plague when the patient's clinical condition improves or when a parenteral regimen is not available (e.g., in mass casualty settings), these experts recommend that adults receive 500-750 mg orally twice daily and that children receive 20 mg/kg orally twice daily (maximum 1 g daily). These experts recommend a treatment duration of at least 10-14 days.

Postexposure Prophylaxis of Plague

When oral ciprofloxacin (conventional tablets or oral suspension) is used for prophylaxis of plague, the manufacturer recommends that adults receive a dosage of 500-750 mg orally every 12 hours for 14 days and that infants and children 17 years of age or younger receive a dosage of 15 mg/kg (maximum 500 mg) orally every 8 or 12 hours for 10-21 days. If IV ciprofloxacin is used for prophylaxis of plague, the manufacturer recommends that adults receive a dosage of 400 mg IV every 8 to 12 hours for 14 days and that infants and children 17 years of age or younger receive a dosage of 10 mg/kg (maximum 400 mg) IV every 8 to 12 hours for 10-21 days.

If oral ciprofloxacin (conventional tablets or oral suspension) is used for postexposure prophylaxis 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 adults receive 500 mg orally twice daily and that children receive 20 mg/kg twice daily (maximum 1 g daily).

Ciprofloxacin should be initiated as soon as possible after suspected or confirmed exposure to Y. pestis. In close contacts of patients with pneumonic plague or individuals exposed to plague aerosol (e.g., in the context of biologic warfare or bioterrorism), prophylaxis should be continued for 7 days or for the duration of the risk of exposure plus 7 days. If fever or cough develops during prophylaxis, the regimen should be switch to that used for treatment of plague.

Tularemia

Treatment of Tularemia

If ciprofloxacin is used for the treatment of tularemia that occurs as the result of exposure to Francisella tularensis in the context of biologic warfare or bioterrorism, some experts (e.g., US Working Group on Civilian Biodefense, USAMRIID) recommend that adults receive a dosage of 400 mg IV every 12 hours and that children receive 15 mg/kg IV ever 12 hours (maximum 1 g daily) for at least 10-14 days. Oral therapy may be substituted when the patient's condition improves. If oral ciprofloxacin (conventional tablets or oral suspension) is used for the treatment of tularemia when the patient's clinical condition improves or if a parenteral regimen is not available, adults should receive 500 mg orally twice daily and children should receive 15 mg/kg twice daily (maximum 1 g daily) for a total treatment duration of at least 10-14 days.

Postexposure Prophylaxis of Tularemia

If oral ciprofloxacin (conventional tablets or oral suspension) is used for postexposure prophylaxis of tularemia following exposure to F. tularensis that occurs in the context of biologic warfare or bioterrorism, some experts (e.g., US Working Group on Civilian Biodefense, USAMRIID) recommend that adults receive 500 mg orally every 12 hours and that children receive 15 mg/kg orally twice daily (maximum 1 g daily). Postexposure prophylaxis ideally should be initiated within 24 hours of exposure and continued for at least 14 days.

Typhoid Fever and Other Salmonella Infections

The usual adult oral dosage of ciprofloxacin (conventional tablets or oral suspension) for the treatment of mild to moderate typhoid fever is 500 mg every 12 hours for 10 days.

Although the optimum dosage and duration of therapy have not been established, oral ciprofloxacin dosages of 750 mg twice daily for 28 days have been used in adults for the treatment of chronic typhoid carriers.

For the treatment of Salmonella gastroenteritis (with or without bacteremia) in HIV-infected adults, the recommended dosage of oral ciprofloxacin is 500-750 mg every 12 hours. Alternatively, 400 mg can be given IV every 12 hours. The recommended duration of treatment in these patients 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 benefits must be weighed against the risks of long-term anti-infective exposure.(See HIV-infected Individuals under Uses: Typhoid Fever and Other Salmonella Infections.)

Vibrio Infections

Cholera

For the treatment of cholera caused by Vibrio cholerae 01 or 0139, adults have received oral ciprofloxacin in a dosage of 1 g given either as a single dose or in 2 divided doses 12 hours apart.

Children 2-12 years of age have received a single oral ciprofloxacin dose of 20 mg/kg (up to 750 mg) for the treatment of cholera caused by V. cholerae 01 or 0139.

Perioperative Prophylaxis

If ciprofloxacin is used for perioperative prophylaxis in high risk patients undergoing genitourinary procedures (see Uses: Perioperative Prophylaxis), some clinicians recommend that a single 500-mg oral dose or a single 400-mg IV dose of ciprofloxacin be given prior to the procedure. If IV ciprofloxacin is used, the dose should be given within 1-2 hours prior to the procedure or initial incision. Postoperative doses generally are unnecessary and should not be used.

Empiric Therapy in Febrile Neutropenic Patients

For empiric anti-infective therapy in febrile neutropenic patients, the manufacturers recommend that adults receive ciprofloxacin in a dosage of 400 mg IV every 8 hours given in conjunction with piperacillin sodium (50 mg/kg IV every 4 hours, not to exceed 24 g/daily or 300 mg/kg daily; no longer commercially available in the US as a single-entity preparation). The usual duration of therapy for this indication is 7-14 days.

Dosage in Renal and Hepatic Impairment

Renal Impairment

Dosage adjustments may be necessary when ciprofloxacin is used in adults with renal impairment, especially those with severe impairment. Dosage recommendations are not available for use of ciprofloxacin in pediatric patients with impaired renal function (creatinine clearances less than 50 mL/minute).

When ciprofloxacin conventional tablets or oral suspension is used in adults, modification of the usual dosage is unnecessary in patients with creatinine clearances exceeding 50 mL/minute. However, dosage should be decreased in adults with creatinine clearances of 50 mL/minute or less.(See Table 1.) The manufacturer states that a dosage of 750 mg administered at the intervals noted in Table 1 may be used with close monitoring in adults with severe infections and severe renal impairment.

Table 1. Dosage of Ciprofloxacin Conventional Tablets or Oral Suspension in Adults with Renal Impairment[1 ]
Creatinine Clearance (mL/minute) Dosage
>50 No dosage adjustment
30-50 250-500 mg every 12 hours
5-29 250-500 mg every 18 hours
Hemodialysis or peritoneal dialysis patients 250-500 mg once every 24 hours; give dose after dialysis

Dosage adjustments are not needed when ciprofloxacin 500-mg extended-release tablets are used for the treatment of uncomplicated UTIs (acute cystitis) in adults with renal impairment. However, a decreased dosage of 500 mg once daily is recommended when extended-release tablets are used for the treatment of complicated UTIs or acute uncomplicated pyelonephritis in adults with creatinine clearances of 30 mL/minute or less.(See Table 2.) The maximum dosage of ciprofloxacin extended-release tablets in adults undergoing hemodialysis or peritoneal dialysis (including continuous ambulatory peritoneal dialysis) is 500 mg once daily. The manufacturers state that the 1-g extended-release tablets are not recommended in adults who have creatinine clearances of 30 mL/minute or less or are undergoing hemodialysis or peritoneal dialysis.

Table 2. Dosage of Ciprofloxacin Extended-release Tablets in Adults with Renal Impairment[856 ]
Creatinine Clearance (mL/minute) Dosage
<=30 (complicated UTIs or acute uncomplicated pyelonephritis) 500 mg once daily
Hemodialysis or peritoneal dialysis patients Give dose after dialysis period (maximum 500 mg once daily)
Continuous ambulatory peritoneal dialysis Maximum 500 mg once daily

Dosage adjustments are not needed when IV ciprofloxacin is used in adults with creatinine clearances exceeding 30 mL/minute. However, dosage should be decreased in those with creatinine clearances less than 30 mL/minute.(See Table 3.)

Table 3. Dosage of IV Ciprofloxacin in Adults with Renal Impairment[579 ][778 ]
Creatinine Clearance (mL/minute) Dosage
>30 No dosage adjustment
5-29 200-400 mg every 18-24 hours

Hepatic Impairment

The manufacturers make no specific dosage recommendations for patients with impaired hepatic function. Patients with both hepatic and renal impairment should be carefully monitored.(See Renal Impairment under Dosage and Administration: Dosage in Renal and Hepatic Impairment.)

In preliminary studies in patients with stable chronic liver cirrhosis, no clinically important changes in ciprofloxacin pharmacokinetics were observed; however, the pharmacokinetics of the drug in patients with acute hepatic insufficiency have not been fully studied.

Cautions

Adverse effects reported with ciprofloxacin are similar to those reported with other fluoroquinolone anti-infectives (e.g., gemifloxacin, levofloxacin, moxifloxacin, ofloxacin). Adverse effects have been reported in 5-14% of patients receiving ciprofloxacin, and have been severe enough to require discontinuance in up to 3.5% of patients. The most frequent adverse effects of the drug include nausea, diarrhea, vomiting, abnormal liver function test results and rash.

Systemic fluoroquinolones, including ciprofloxacin, 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.(See Cautions: Precautions and Contraindications.)

Tendinitis and Tendon Rupture

Systemic fluoroquinolones, including ciprofloxacin, 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 older than 60 years of age), individuals receiving concomitant corticosteroids, and kidney, heart, or lung transplant recipients. 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. However, tendinitis and tendon rupture have been reported in patients receiving fluoroquinolones who did not have any risk factors for such adverse effects.

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 ciprofloxacin is initiated or as long as several months after completion of therapy and can occur bilaterally.

Ciprofloxacin should be discontinued immediately if pain, swelling, inflammation, or rupture of a tendon occurs.(See Cautions: Precautions and Contraindications.)

Peripheral Neuropathy

Systemic fluoroquinolones, including ciprofloxacin, 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 ciprofloxacin. Symptoms may occur soon after initiation of ciprofloxacin and, in some patients, may be irreversible.

Ciprofloxacin 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 Cautions: Precautions and Contraindications.)

CNS Effects

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

Convulsions, increased intracranial pressure (including pseudotumor cerebri), and toxic psychosis have been reported. Fluoroquinolones may also cause nervousness, agitation, insomnia, anxiety, nightmares, paranoia, dizziness, confusion, tremors, hallucinations, and depression. Psychotic reactions have progressed to suicidal ideation/thoughts and self-injurious behavior such as attempted or completed suicide. These CNS effects may occur after the first dose.

Ciprofloxacin, like other fluoroquinolones, is known to trigger seizures or lower the seizure threshold. Status epilepticus has been reported.

Headache, dizziness, and restlessness have been reported in 1-3% or more of patients receiving ciprofloxacin. Lightheadedness, insomnia, nightmares, hallucinations, paranoia, manic reaction, toxic psychosis, irritability, tremor, ataxia, seizures, lethargy, drowsiness, vertigo, anxiety, nervousness, agitation, confusion, weakness, malaise, phobia, depersonalization, depression, psychotic reactions, suicidal thoughts or acts, paresthesia, and increased intracranial pressure (including pseudotumor cerebri) have also been reported.

Some adverse nervous system effects of ciprofloxacin may be related to the fact that the drug, like other fluoroquinolones, is a γ-aminobutyric acid (GABA) inhibitor. In addition, it has been suggested that some CNS stimulant effects reported in patients receiving the drug may have resulted from ciprofloxacin-induced alterations in caffeine pharmacokinetics.(See Drug Interactions: Xanthine Derivatives.)

If seizures or other CNS effects occur during ciprofloxacin therapy, the drug should be discontinued immediately and appropriate measures instituted.(See Cautions: Precautions and Contraindications.)

Exacerbation of Myasthenia Gravis

Fluoroquinolones, including ciprofloxacin, 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.(See Cautions: Precautions and Contraindications.)

Dermatologic and Sensitivity Reactions

Mild, transient rash has been reported in 1-4% and eosinophilia, pruritus, urticaria, cutaneous candidiasis, hyperpigmentation, erythema nodosum, angioedema, and edema of the face, neck, lips, conjunctivae, or hands have been reported in less than 1% of patients. Flushing, fever, and chills also have been reported in less than 1% of patients receiving the drug.

Hypersensitivity Reactions

Severe hypersensitivity reactions characterized by rash, fever, eosinophilia, jaundice, and hepatic necrosis and that were fatal have been reported rarely in patients receiving ciprofloxacin and other drugs concomitantly. Toxic epidermal necrolysis (Lyell's syndrome) also has been reported rarely in patients receiving ciprofloxacin. The possibility that these reactions were related to ciprofloxacin therapy could not be excluded. Other serious and occasionally fatal hypersensitivity (anaphylactic and anaphylactoid) reactions have occurred, some with the initial dose, in patients receiving quinolone therapy, including ciprofloxacin.

Some hypersensitivity reactions reported in patients receiving fluoroquinolones, including ciprofloxacin, have been accompanied by cardiovascular collapse, loss of consciousness, paresthesia, pharyngeal or facial edema, dyspnea, urticaria, and/or pruritus.

Other serious and sometimes fatal adverse reactions that have been reported with fluoroquinolones, including ciprofloxacin, and that may or may not be related to hypersensitivity reactions include one of more of the following: fever, rash or severe dermatologic reaction (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 abnormalities.

Ciprofloxacin should be discontinued immediately at the first appearance of rash, jaundice, or any other sign of hypersensitivity. Appropriate therapy (e.g., epinephrine, corticosteroids, maintenance of an adequate airway, oxygen, maintenance of blood pressure) should be initiated as indicated.

Photosensitivity Reactions

Moderate to severe photosensitivity/phototoxicity reactions have been reported in patients receiving fluoroquinolones, including ciprofloxacin.

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).

Ciprofloxacin should be discontinued if photosensitivity or phototoxicity (sunburn-like reaction, skin eruption) occurs.(See Cautions: Precautions and Contraindications.)

Hepatotoxicity

Severe hepatotoxicity, including hepatic necrosis, life-threatening hepatic failure, and fatal events, has been reported in patients receiving ciprofloxacin. Most fatalities have occurred in adults older than 55 years of age.

Acute liver injury has a rapid onset (range 1-39 days) and is often associated with hypersensitivity. The pattern of injury can be hepatocellular, cholestatic, or mixed. Temporary increase in aminotransferase or alkaline phosphatase concentrations or cholestatic jaundice may occur, especially in patients with previous liver damage.

Increased serum concentrations of AST (SGOT) and ALT (SGPT) have been reported in about 2% and increased serum concentrations of alkaline phosphatase, LDH, bilirubin, and γ-glutamyltransferase (GGT, γ-glutamyl transpeptidase, GGTP) have been reported in less than 1% of patients receiving the drug. In addition, fulminant and occasionally fatal hepatic failure has occurred rarely in patients receiving ciprofloxacin.

Ciprofloxacin should be discontinued immediately if any signs or symptoms of hepatitis (e.g., anorexia, jaundice, dark urine, pruritus, tender abdomen) occur.(See Cautions: Precautions and Contraindications.)

Cardiovascular Effects

Prolonged QT interval leading to ventricular arrhythmias, including torsades de pointes, has been reported with some fluoroquinolones, including ciprofloxacin. Patients with known prolongation of the QT interval or with risk factors for QT interval prolongation or torsades de pointes, patients receiving drugs known to prolong the QT interval (e.g., class IA or III antiarrhythmic agents, tricyclic antidepressants, macrolides, antipsychotics), and geriatric patients may be more susceptible to drug-associated effects on the QT interval.(See Cautions: Precautions and Contraindications.)

Palpitation, atrial flutter, ventricular ectopy, syncope, hypertension, angina pectoris, chest pain, myocardial infarction, cardiopulmonary arrest, and cerebral thrombosis have been reported in less than 1% of patients receiving ciprofloxacin.

GI Effects

Nausea, diarrhea, vomiting, and abdominal pain/discomfort have been reported in 1-10% of patients receiving ciprofloxacin. These effects generally are mild and transient and occur most frequently in geriatric patients and/or when high dosage is used. Anorexia, dyspepsia, flatulence, GI erosion and bleeding, dysphagia, bad taste, intestinal perforation, painful oral mucosa, and oral candidiasis have been reported in less than 1% of patients receiving the drug.

Effects on Fecal Flora

Ciprofloxacin exerts a selective effect on normal bowel flora.

Total bacterial counts of normal anaerobic fecal flora generally are unaffected during or following ciprofloxacin therapy. However, total bacterial counts of normal aerobic fecal flora are decreased within 2-5 days following initiation of therapy with the drug and generally return to pretreatment levels within 1-4 weeks after the drug is discontinued. Ciprofloxacin therapy generally markedly reduces or completely eradicates normal fecal Enterobacteriaceae; the drug reduces fecal aerobic gram-positive bacteria to a lesser extent. Ciprofloxacin therapy does not appear to affect total bacterial counts of normal salivary flora, including streptococci, staphylococci, and anaerobic bacteria.

Clostridium difficile-associated Diarrhea and Colitis

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 ciprofloxacin, and may range in severity from mild diarrhea to fatal colitis.C. difficile produces toxins A and B, which contribute to the 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.(See Superinfection/Clostridium difficile-associated Diarrhea and Colitis under Cautions: Precautions and Contraindications.)

C. difficile generally is resistant to ciprofloxacin. When fluoroquinolones were first marketed, there appeared to be a relative lack of association between use of the drugs and CDAD and the risk of CDAD appeared to be lower than that reported with some other anti-infectives. However, there now is some evidence that increasing use of the drugs may have resulted in emergence of C. difficile that are more resistant and/or more virulent than previous strains. Outbreaks of severe CDAD caused by fluoroquinolone-resistant C. difficile have been reported in US health-care facilities with increasing frequency over the last several years. Many of these CDAD cases occurred in patients who had received a fluoroquinolone (ciprofloxacin, gatifloxacin [no longer commercially available in the US], levofloxacin, moxifloxacin) or cephalosporin within the prior 4-6 weeks.

Genitourinary Effects

Increased serum creatinine and BUN concentrations have occurred in about 1% of patients receiving ciprofloxacin. Interstitial nephritis, nephritis, renal failure, dysuria, polyuria, urinary retention, albuminuria, urethral bleeding, vaginitis, and acidosis have been reported in less than 1% of patients receiving the drug. In at least one patient, acute renal failure associated with interstitial nephritis occurred within about 2 weeks after initiating ciprofloxacin and appeared to be a hypersensitivity reaction to ciprofloxacin; renal biopsy showed marked interstitial edema, with extensive lymphocytic infiltrations and occasional eosinophils.

Crystalluria, cylindruria, and hematuria have been reported rarely in patients receiving ciprofloxacin. Crystalluria generally occurs in patients with alkaline urine who receive high dosage of the drug, and has not been associated with changes in renal function. The risk of crystal formation and crystalluria in patients receiving usual recommended dosages of the drug (250-750 mg) is low if urine pH is within the usual range (i.e., less than 6.8). Patients receiving the drug, particularly at relatively high dosages, should maintain adequate fluid intake; in addition, alkaline urine should be avoided.(See Other Precautions and Contraindications under Cautions: Precautions and Contraindications.) Crystalluria, sometimes associated with nephropathy, occurs in animals receiving ciprofloxacin. This may be related to the fact that ciprofloxacin has reduced solubility under alkaline conditions and the urine of test animals (e.g., rats, monkeys) is predominantly alkaline. In studies in rhesus monkeys, crystalluria (without evidence of nephropathy) has occurred after a single oral ciprofloxacin dose as low as 5 mg/kg (approximately 0.07 times the highest recommended therapeutic dosage based on body surface area [BSA]). Nephropathy did not occur when these monkeys received 6 months of IV ciprofloxacin at a dosage of 10 mg/kg daily; however, nephropathy occurred after 6 months of therapy at a dosage of 20 mg/kg daily (approximately 0.2 times the highest recommended therapeutic dosage based on BSA).

Musculoskeletal Effects

Arthralgia, joint or back pain, joint inflammation, joint stiffness, achiness, vasculitis, neck or chest pain, and flare-up of gout have been reported in less than 1% of patients receiving ciprofloxacin.

An increased incidence of musculoskeletal disorders related to joints and/or surrounding tissues (e.g., arthralgia, abnormal gait, abnormal joint exam, joint sprains, leg pain, back pain, arthrosis, bone pain, myalgia, arm pain, decreased range of motion in a joint) has been reported in pediatric patients receiving ciprofloxacin. These events usually were mild to moderate in intensity and those that occurred by week 6 usually resolved (clinical resolution of signs and symptoms) within 30 days after treatment ended.

Fluoroquinolones, including ciprofloxacin, cause arthropathies (arthrosis) in immature animals of various species.(See Cautions: Pediatric Precautions.) In young beagles, ciprofloxacin given in a dosage of 100 mg/kg daily for 4 weeks caused degenerative articular changes of the knee joint; in a daily dosage of 30 mg/kg, effects on the joint were minimal, although some damage to weight-bearing joints was observed even at the lower dosage. In another study, removal of weight bearing from the joint reduced the lesions, but did not totally prevent them. In a subsequent study in young beagle dogs, oral ciprofloxacin in a dosage of 30 mg/kg or 90 mg/kg daily for 2 weeks (approximately 1.3 or 3.5 times the pediatric dosage based on comparative plasma AUCs) caused articular changes that were still evident on histologic evaluation after a treatment-free period of 5 months. However, a dosage of 10 mg/kg (approximately 0.6 times the pediatric dosage based on comparative plasma AUCs) had no effects on joints and was not associated with arthrotoxicity after an additional treatment-free period of 5 months.

Morphologic changes observed in animals with quinolone-induced arthropathies include erosions in joint cartilage accompanied by noninflammatory, cell-free effusion of the joint space; the cartilage is incapable of regeneration and may serve as a site for the development of arthropathy deformans. In addition, breakdown products of the cartilage may irritate the synovia. The relationship of these effects in animals and the rheumatologic symptoms associated with use of ciprofloxacin in humans is unknown.

Hematologic Effects

Eosinophilia, leukopenia, neutropenia, increased or decreased platelet count, and pancytopenia have been reported in less than 1% of patients receiving ciprofloxacin.Anemia, decreased hemoglobin, increased monocytes, leukocytosis, and bleeding diathesis have been reported in less than 1% of patients receiving the drug. In at least one patient, decreased hemoglobin was associated with GI bleeding, although there was no evidence of such bleeding in some other patients with hemoglobin reductions. In addition, transient acquired von Willebrand's disease has been reported rarely in patients receiving ciprofloxacin; factor VIII concentration returned to normal values several months (i.e., 5-6 months) following discontinuance of the drug in these patients.

Local Effects

Local adverse effects have been reported at the site of infusion following IV administration of ciprofloxacin. These reactions generally resolve rapidly after completion of the infusion and have been reported most frequently when IV infusions of the drug were given over 30 minutes or less. The manufacturers state that adverse local reactions to IV ciprofloxacin do not contraindicate subsequent IV administration of the drug, unless the reactions recur or worsen.

Other Adverse Effects

Epistaxis, laryngeal or pulmonary edema, hiccups, hemoptysis, dyspnea, bronchospasm, and pulmonary embolism have been reported in less than 1% of patients receiving ciprofloxacin.

Blurred vision, disturbed vision (e.g., change in color perception, overbrightness of lights), decreased visual acuity, diplopia, and eye pain have been reported in less than 1% of patients receiving ciprofloxacin. Although reported with some other quinolones, there has been no evidence of ocular toxicity in animal studies using ciprofloxacin. Tinnitus, increased serum amylase, decreased blood glucose, and increased serum uric acid concentrations have been reported rarely (i.e., in less than 0.1% of patients).

Adverse Effects Reported when Used for Inhalational Anthrax (Postexposure)

Some information regarding the safety of ciprofloxacin for long-term postexposure prophylaxis of anthrax are available based on use of the drug in the fall of 2001 following bioterrorism-related exposures to Bacillus anthracis spores. Among individuals surveyed by the US Centers for Disease Control and Prevention (CDC), adverse GI effects (nausea, vomiting, diarrhea, stomach pain), neurologic effects (problems sleeping, nightmares, headache, dizziness, lightheadedness), and musculoskeletal effects (muscle or tendon pain and joint swelling or pain) were reported more frequently than in controlled clinical studies evaluating the drug for other indications. This higher incidence in the absence of a control group could be the result of report bias, concurrent medical conditions, other concomitant drug therapy, emotional stress or other confounding factors, and/or the long duration of ciprofloxacin treatment required for prophylaxis. In response to a questionnaire given to 490 such individuals in Florida on approximately day 7 or 14 of anti-infective prophylaxis, 19% sought medical attention for any anti-infective related adverse effect or reported one or more of the following: pruritus, breathing problems, or swelling of the face, neck, or throat. Although the percentage of patients in this subgroup who received ciprofloxacin versus other anti-infectives was not reported, 86% of all patients (i.e., those who did or did not answer the questionnaire) received ciprofloxacin and 80% continued to receive prophylaxis beyond 14 days.

In an epidemiologic evaluation in 8424 postal workers who were offered 60 days of prophylaxis for anthrax and given a questionnaire in New Jersey, New York City, and the District of Columbia on days 7-10 of anti-infective prophylaxis, 5819 completed or were administered the questionnaire, of whom 3863 had initiated prophylaxis (3428 with ciprofloxacin). Of the ciprofloxacin-treated individuals, 19% reported severe nausea, vomiting, diarrhea, and/or abdominal pain; 14% reported fainting, lightheadedness, and/or dizziness; 7% reported heartburn or acid reflux; 6% reported rash, urticaria, and/or pruritus; and 8% discontinued therapy with the drug (3% for adverse effects, 1% for fear of developing an adverse effect, and 1% because they were confused about the need). Only 2% of those on any anti-infective sought medical attention for possible manifestations of anaphylaxis, none of whom required hospitalization.

Precautions and Contraindications

Ciprofloxacin is contraindicated in patients with a history of hypersensitivity to the drug, other quinolones, or any ingredient in the formulation.

Systemic fluoroquinolones, including ciprofloxacin, 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. Patients receiving ciprofloxacin should be informed about these serious adverse reactions and advised to immediately discontinue ciprofloxacin and contact a clinician if they experience any signs or symptoms of serious adverse effects (e.g., unusual joint or tendon pain, muscle weakness, a ''pins and needles'' tingling or pricking sensation, numbness of the arms or legs, confusion, hallucinations) while taking the drug. Systemic fluoroquinolones, including ciprofloxacin, should be avoided in patients who have experienced any of the serious adverse reactions associated with fluoroquinolones.

Because fluoroquinolones, including ciprofloxacin, are associated with an increased risk of tendinitis and tendon rupture in all age groups (see Cautions: Tendinitis and Tendon Rupture), patients receiving ciprofloxacin should be informed of this potentially irreversible adverse effect and the drug should be discontinued immediately if pain, swelling, inflammation, or rupture of a tendon occurs. The risk of developing fluoroquinolone-associated tendinitis and tendon rupture is increased in adults older than 60 years of age, individuals receiving concomitant corticosteroids, and kidney, heart, or lung transplant recipients. (See Cautions: Geriatric Precautions and see Drug Interactions: Corticosteroids.) Patients should be advised to rest and refrain from exercise at the first sign of tendinitis or tendon rupture (e.g., pain, swelling, or inflammation of a tendon or weakness or inability to use a joint) and advised to immediately discontinue the drug and contact a clinician. Systemic fluoroquinolones, including ciprofloxacin, should be avoided in patients who have a history of tendon disorders or have experienced tendinitis or tendon rupture.

Because fluoroquinolones, including ciprofloxacin, are associated with an increased risk of peripheral neuropathy (see Cautions: Peripheral Neuropathy), ciprofloxacin 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) and/or motor strength since this may minimize development of an irreversible condition. Patients receiving ciprofloxacin should be advised that peripheral neuropathies have been reported in patients receiving systemic fluoroquinolones, including ciprofloxacin, and that symptoms may occur soon after initiation of therapy and, in some patients, may be irreversible. Patients should be advised of the importance of immediately discontinuing the drug and contacting a clinician if such symptoms occur. Systemic fluoroquinolones, including ciprofloxacin, should be avoided in patients who have experienced peripheral neuropathy.

Fluoroquinolones, including ciprofloxacin, have been associated with an increased risk of adverse CNS effects (e.g., convulsions, dizziness, lightheadedness, increased intracranial pressure, toxic psychosis) that can occur following the first dose. Because fluoroquinolones are known to trigger seizures or lower the seizure threshold, ciprofloxacin should be used with caution, and only if potential benefits outweigh risks, in epileptic patients, in patients with known or suspected CNS disorders that predispose to seizures or lower the seizure threshold (e.g., severe cerebral arteriosclerosis, history of convulsions, reduced cerebral blood flow, altered brain structure, stroke), and in the presence of other factors that predispose to seizures or lower the seizure threshold (e.g., certain drug therapies, renal dysfunction). Patients should be informed that seizures have been reported in patients receiving ciprofloxacin and advised to inform their clinician of any history of seizures before initiating therapy with the drug. Because increased intracranial pressure has been reported, patients receiving ciprofloxacin should be advised to notify their clinician if persistent headache (with or without blurred vision) occurs. Patients receiving ciprofloxacin also should be advised that ciprofloxacin may cause dizziness or lightheadedness and cautioned not to engage in activities requiring mental alertness and motor coordination (e.g., driving or operating machinery) until they experience how the drug affects them. If seizures or other CNS effects occur, ciprofloxacin should be discontinued immediately and appropriate measures instituted. Systemic fluoroquinolones, including ciprofloxacin, should be avoided in patients who have experienced CNS effects associated with fluoroquinolones.

Ciprofloxacin should be avoided in patients with a known history of myasthenia gravis since fluoroquinolones may exacerbate myasthenia gravis symptoms. Patients should be advised of the importance of informing their clinician of any history of myasthenia gravis. Patients also should be advised to immediately contact a clinician if any symptoms of muscle weakness, including respiratory difficulties, occur.

Because severe hepatotoxicity, including acute hepatitis and fatalities, has been reported in patients receiving ciprofloxacin, the drug should be discontinued immediately if any sign or symptom of hepatitis (e.g., anorexia, jaundice, dark urine, pruritus, tender abdomen) occurs. Patients should be advised to contact their clinician if any sign or symptom of hepatotoxicity (e.g., loss of appetite, nausea, vomiting, fever, weakness, tiredness, right upper quadrant tenderness, itching, yellowing of skin or eyes, light colored bowel movements, dark colored urine) occurs.

Because prolongation of the QT interval has been reported in patients receiving ciprofloxacin, the drug should be avoided in patients with known prolongation of the QT interval or with risk factors for QT interval prolongation or torsades de pointes (e.g., congenital long QT syndrome, uncorrected electrolyte imbalance such as hypokalemia or hypomagnesemia, cardiac disease such as heart failure, myocardial infarction, or bradycardia). Ciprofloxacin also should be avoided in patients receiving drugs known to prolong the QT interval, including class IA antiarrhythmic agents (quinidine, procainamide), class III antiarrhythmic agents (amiodarone, sotalol), tricyclic antidepressants, macrolides, and antipsychotics.(See Drug Interactions: Drugs that Prolong the QT Interval.) Patients should be advised of the importance of informing their clinician of a personal or family history of QT interval prolongation or proarrhythmic conditions (e.g., hypokalemia, bradycardia, recent myocardial ischemia) or current therapy with any class IA (e.g., quinidine, procainamide) or class III (amiodarone, sotalol) antiarrhythmic agents; patients should be advised to contact their clinician if any symptoms of prolongation of QT interval, including prolonged heart palpitations or loss of consciousness, occur.

Ciprofloxacin inhibits cytochrome P-450 (CYP) isoenzyme 1A2, and concomitant use with drugs metabolized by this enzyme (e.g., clozapine, methylxanthines [e.g., caffeine, theophylline], olanzapine, ropinirole, tizanidine) may result in increased plasma concentrations of the concomitant drug and could lead to clinically important adverse effects. Because of an increased risk of adverse effects, ciprofloxacin is contraindicated in patients receiving tizanidine. Concomitant use with theophylline should be avoided since serious and sometimes fatal reactions (e.g., cardiac arrest, seizures, status epilepticus, respiratory failure) have occurred in patients receiving the drugs concomitantly. In addition, concomitant use of ciprofloxacin and other drugs metabolized by CYP1A2 should be avoided or requires particular caution. (See Drug Interactions.)

Because concomitant use of ciprofloxacin and oral antidiabetic agents (e.g., sulfonylurea agents such as glimepiride or glyburide) has resulted in hypoglycemia (see Drug Interactions: Antidiabetic Agents), patients receiving such drugs should be advised to contact their clinician if low blood glucose occurs during ciprofloxacin therapy so that the clinician can determine whether the anti-infective should be changed.

Sensitivity Reactions

Ciprofloxacin, like other quinolones, can cause serious, potentially fatal hypersensitivity reactions, occasionally following the initial dose.(See Cautions: Dermatologic and Sensitivity Reactions.) Patients receiving ciprofloxacin should be advised of this possibility and instructed to immediately discontinue the drug and contact a clinician at the first sign of rash, hives, other skin reaction, jaundice, rapid heartbeat, difficulty swallowing or breathing, any swelling suggesting angioedema (e.g., swelling of lips, tongue, or face; tightness of throat; hoarseness), or any other sign of hypersensitivity. Serious anaphylactic reactions require immediate emergency treatment with epinephrine and other resuscitation measures (e.g., oxygen, IV fluids, IV antihistamines, corticosteroids, pressor amines, airway management such as intubation) as indicated.

Because photosensitivity/phototoxicity reactions have been reported with fluoroquinolones, unnecessary or excessive exposure to sunlight or artificial UV light (sunlamps, tanning beds, UVA/UVB treatment) should be avoided during ciprofloxacin therapy. If the patient needs to be outdoors, they should use sunscreen and wear a hat and clothing that protects skin from sun exposure. Patients should be advised to discontinue ciprofloxacin and contact a clinician if photosensitivity or phototoxicity (sunburn-like reaction, skin eruption) occurs.

Selection and Use of Anti-infectives

Ciprofloxacin 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 ciprofloxacin, 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 ciprofloxacin for patients with these infections.

To reduce development of drug-resistant bacteria and maintain effectiveness of ciprofloxacin and other antibacterials, the drug should be used only for the 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. Culture and susceptibility testing performed periodically during therapy provides information on the therapeutic effect of the anti-infective agent and the possible emergence of bacterial resistance.

Patients should be advised that antibacterials (including ciprofloxacin) should only be used to treat bacterial infections and not used to treat viral infections (e.g., the common cold). Patients also should be advised about the importance of completing the full course of therapy, even if feeling better after a few days, and that skipping doses or not completing therapy may decrease effectiveness and increase the likelihood that bacteria will develop resistance and will not be treatable with ciprofloxacin or other antibacterials in the future.

Superinfection/Clostridium difficile-associated Diarrhea and Colitis

As with other anti-infectives, use of ciprofloxacin may result in overgrowth of nonsusceptible organisms, especially enterococci or Candida. Resistant strains of some organisms (e.g., Pseudomonas aeruginosa, staphylococci) have developed during ciprofloxacin therapy. Careful monitoring of the patient and periodic in vitro susceptibility tests are essential. If superinfection occurs, appropriate therapy should be instituted.

Because CDAD has been reported with the use of nearly all anti-infectives, including ciprofloxacin, it should be considered in the differential diagnosis in patients who develop diarrhea during or after ciprofloxacin therapy. 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. Other causes of colitis also should be considered.

Patients should be advised that diarrhea is a common problem caused by anti-infectives and usually ends when the drug is discontinued; however, it is important to contact a clinician if watery and bloody stools (with or without stomach cramps and fever) occur during or as late as 2 months or longer after the last dose.

Other Precautions and Contraindications

Crystalluria has been reported rarely in patients receiving ciprofloxacin. Although crystalluria is not expected to occur under usual conditions with the usual recommended dosages of the drug, patients should be instructed to drink sufficient quantities of fluids to ensure proper hydration and adequate urinary output during ciprofloxacin therapy. Measures also should be taken to avoid alkaline urine.

Ciprofloxacin has not been shown to be effective in the treatment of syphilis. Because use of anti-infectives given in high dosage for short periods of time to treat gonorrhea may mask or delay symptoms of incubating syphilis, serologic tests for syphilis should be performed at the time of diagnosis of gonorrhea. If ciprofloxacin is used for the treatment of gonorrhea (see Uses: Gonorrhea and Associated Infections), follow-up serologic tests for syphilis should be performed 3 months after gonorrhea treatment is completed.

Doses and/or frequency of administration of ciprofloxacin should be decreased in patients with severe renal impairment since serum concentrations of the drug are higher and prolonged in these patients compared with patients with normal renal function. (See Dosage and Administration: Dosage in Renal and Hepatic Impairment.)

Pediatric Precautions

Ciprofloxacin, like other fluoroquinolones, is associated with arthropathy and histopathologic changes in weight-bearing joints of juvenile animals. Oral ciprofloxacin caused lameness in immature dogs; histologic evaluation of the weight-bearing joints of these dogs revealed permanent lesions of the cartilage. When used in pediatric patients younger than 18 years of age, ciprofloxacin has been associated with an increased rate of adverse effects involving joints and/or surrounding tissue (e.g., tendons) compared with comparator anti-infectives.(See Cautions: Musculoskeletal Effects.)

The manufacturers state that ciprofloxacin (IV, conventional tablets, oral suspension) should be used in pediatric patients younger than 18 years of age only for the treatment of complicated UTIs and pyelonephritis caused by susceptible Escherichia coli, inhalational anthrax (postexposure), and treatment and prophylaxis of plague. However, the American Academy of Pediatrics (AAP) and other experts (e.g., the American Heart Association [AHA], Infectious Diseases Society of America [IDSA]) state that use of fluoroquinolones in pediatric patients younger than 18 years of age also may be justified in certain other infections (e.g., endocarditis, multidrug-resistant gram-negative infections).(See Other Infections under Cautions: Pediatric Precautions.) Parents should be advised to inform their child's clinician if the child has a history of joint-related problems present before ciprofloxacin is initiated or if such problems occur during or after therapy with the drug.

Ciprofloxacin extended-release tablets should not be used in children and adolescents younger than 18 years of age since safety and efficacy of the extended-release preparation have not been established for any indication in pediatric patients.

Urinary Tract Infections

Ciprofloxacin (IV, conventional tablets, oral suspension) is labeled by FDA for the treatment of complicated UTIs and pyelonephritis caused by susceptible E. coli in pediatric patients 1-17 years of age. However, ciprofloxacin is not considered a drug of first choice for these infections in pediatric patients because an increased incidence of adverse effects has been reported in such patients. In clinical studies evaluating IV or oral ciprofloxacin for the treatment of complicated UTIs and pyelonephritis in pediatric patients 1-17 years of age, the rate of adverse effects (including events related to joints and/or surrounding tissues) occurring during 6 weeks of follow-up was 9.3% in those receiving ciprofloxacin compared with 6% in those receiving a cephalosporin. The rate of adverse effects occurring at any time up to 1 year was 13.7% or 9.5%, respectively and the rate of all adverse effects (regardless of drug relationship) at 6 weeks was 41 or 31%, respectively.

Anthrax

Ciprofloxacin (IV, conventional tablets, oral suspension) is labeled by FDA for inhalational anthrax (postexposure) to reduce the incidence or progression of disease following exposure to aerosolized Bacillus anthracis spores in pediatric patients from birth to 17 years of age. The manufacturers state that risk-benefit assessment indicates that use of ciprofloxacin is appropriate for this indication in pediatric patients. CDC and other experts (US Working Group on Civilian Biodefense, USAMRIID) currently recommend that initial treatment of inhalational or systemic (including GI and oropharyngeal) should consist of either IV ciprofloxacin or doxycycline plus 1 or 2 additional anti-infectives. Because of potential adverse effects from prolonged use of ciprofloxacin in infants and children, amoxicillin is an option for completion of the remaining 60 days of therapy (i.e., after an initial 14-21 or 7-10 days of multiple-drug therapy for inhalational or uncomplicated cutaneous anthrax, respectively, that included ciprofloxacin or doxycycline) when susceptibility to penicillin is known; amoxicillin is not recommended for initial treatment. Amoxicillin also can be considered as an alternative to ciprofloxacin for postexposure prophylaxis when there are concerns about the potential adverse effects of prolonged quinolone therapy in children.

Plague

Ciprofloxacin (IV, conventional tablets, oral suspension) is labeled by FDA for treatment of plague, including pneumonic and septicemic plague, and for prophylaxis of plague in pediatric patients from birth to 17 years of age. The manufacturers state that risk-benefit assessment indicates that use of ciprofloxacin is appropriate for this indication in pediatric patients.

Other Infections

Some clinicians suggest that quinolones may be used cautiously in adolescents if skeletal growth is complete and that the potential benefits of ciprofloxacin therapy may outweigh the possible risks in certain children 9-18 years of age with serious infections (e.g., cystic fibrosis, typhoid fever) when the causative organism is resistant to other available anti-infectives.

AAP states that use of systemic fluoroquinolones (e.g., ciprofloxacin, levofloxacin, moxifloxacin, ofloxacin) may be justified in children younger than 18 years of age in special circumstances when there are no safe and effective alternatives; however, the drugs should be used only after careful assessment of the risks and benefits for the individual patient and after these benefits and risks have been explained to the parents or caregivers. AAP states that use of fluoroquinolones may be justified in pediatric patients when parenteral therapy is not practical and no other safe and effective oral agent is available or when the pediatric patient has an infection caused by a multidrug-resistant organism (e.g., Pseudomonas, Mycobacterium) for which there is no safe and effective alternative. Therefore, in addition to use after exposure to aerosolized B. anthracis (to decrease the incidence or progression of the disease), other possible uses of fluoroquinolones in pediatric patients include the treatment of urinary tract infections caused by Ps. aeruginosa or other multidrug-resistant gram-negative bacteria, infections caused by multidrug-resistant Streptococcus pneumoniae (e.g., serotype 19a), chronic suppurative otitis media or malignant otitis externa caused by Ps. aeruginosa, chronic or acute osteomyelitis or osteochondritis caused by Ps. aeruginosa or other multidrug-resistant gram-negative bacteria known to be susceptible to fluoroquinolones and resistant to other alternatives, mycobacterial infections caused by isolates known to be susceptible to fluoroquinolones, gram-negative bacterial infections in immunocompromised patients when oral therapy is desired or when the causative agent is resistant to other alternatives, GI infections known or suspected to be caused by multidrug-resistant Shigella, Salmonella, Vibrio cholerae, or Campylobacter, or serious infections caused by fluoroquinolone-susceptible pathogens in pediatric patients with severe allergy to alternative anti-infectives.

Ciprofloxacin has been used in children with cystic fibrosis (see Uses: Lower Respiratory Tract Infections), but transient arthropathy has occurred occasionally in such children. In at least one 16-year-old child, arthropathy was associated with administration of relatively high dosages of the drug (750 mg twice daily) for several weeks.

Short-term safety data regarding use of ciprofloxacin in children and adolescents are available from a randomized, double-blind study that evaluated IV ciprofloxacin for the treatment of acute pulmonary exacerbations in cystic fibrosis patients 5-7 years of age. These pediatric patients were randomized to receive IV ciprofloxacin (10 mg/kg every 8 hours) for 1 week followed by oral ciprofloxacin (20 mg/kg every 12 hours) to complete 10-21 days of therapy or a regimen of IV ceftazidime (50 mg/kg every 8 hours) and IV tobramycin (3 mg/kg every 8 hours) given for 10-21 days. Safety was monitored by periodic range of motion examinations and gait assessments; patients were followed for an average of 23 days after completion of therapy (range: 0-93 days). The study was not designed to determine long-term effects or the safety of repeated exposure to ciprofloxacin. In the ciprofloxacin treatment group, adverse musculoskeletal effects, decreased range of motion, and arthralgia were reported in 22, 12, and 10%, respectively; in the combination treatment group, these effects were reported in 21, 16, and 11%, respectively.

Oral or IV ciprofloxacin has been used in a limited number of children with typhoid fever resistant to other anti-infectives (e.g., ampicillin, amoxicillin, chloramphenicol, co-trimoxazole).

AHA and IDSA indicate that IV or oral ciprofloxacin also may be considered in pediatric patients for the treatment of certain forms of endocarditis when the drugs of choice cannot be used.(See Uses: Endocarditis.)

Geriatric Precautions

Retrospective analysis of 23 multiple-dose controlled clinical studies evaluating ciprofloxacin in over 3500 patients revealed that 25% of patients included in these studies were 65 years of age or older and 10% were 75 years of age or older. In a large, prospective, randomized study evaluating use of ciprofloxacin extended-release tablets for treatment of complicated UTIs, 49% of patients were 65 years of age or older and 30% were 75 years of age or older. Although no overall differences in safety or efficacy were observed between geriatric individuals and younger adults in these studies and other clinical experience revealed no evidence of age-related differences, the possibility that some older patients may exhibit increased sensitivity to the drug cannot be ruled out.

The risk of severe tendon disorders, including tendon rupture, is increased in geriatric adults older than 60 years of age. This risk is further increased in those receiving concomitant corticosteroids.(See Cautions: Precautions and Contraindications.) Ciprofloxacin should be used with caution in geriatric adults, especially those receiving concomitant corticosteroids.

The risk of prolonged QT interval leading to ventricular arrhythmias may be increased in geriatric patients. Ciprofloxacin should be used with caution in those receiving concurrent therapy with drugs that can prolong the QT interval (e.g., class IA or III antiarrhythmic agents) or those with risk factors for torsades de pointes (e.g., known QT prolongation, uncorrected hypokalemia).

Ciprofloxacin is substantially eliminated by the kidney, and the risk of adverse reactions may be greater in patients with impaired renal function. Although dosage of ciprofloxacin does not need to be modified in individuals older than 65 years of age with normal renal function, the greater frequency of decreased renal function observed in the elderly should be considered and dosage carefully selected in geriatric patients; monitoring renal function may be useful in these patients.

Mutagenicity and Carcinogenicity

Ciprofloxacin was not mutagenic in vivo in the rat hepatocyte DNA repair assay or dominant lethal or micronucleus tests in mice. Although ciprofloxacin was positive for mutagenicity in vitro in the mouse lymphoma cell forward mutation assay and rat hepatocyte DNA repair assay, the drug was not mutagenic in other in vitro studies, including the Salmonella microsome test, mouse lymphoma cell forward mutation assay, Escherichia coli DNA repair assay, Chinese hamster V-79 cell HGPRT test, Syrian hamster embryo cell transformation assay, Saccharomyces cerevisiae point mutation assay, and S. cerevisiae mitotic crossover and gene conversion assay.

In 2-year carcinogenicity studies in rats or mice, there was no evidence of carcinogenic or tumorigenic potential with oral ciprofloxacin in a dosage of 250 or 750 mg/kg daily (equivalent to approximately 2 or 3 times, respectively, a human dosage of 1 g daily based on BSA).

Pregnancy, Fertility, and Lactation

Pregnancy

There are no adequate and controlled studies to date using ciprofloxacin in pregnant women. Because ciprofloxacin, like most other fluoroquinolones, causes arthropathy in immature animals, the drug should not be used in pregnant women unless potential benefits justify potential risks to the fetus and mother. CDC and other experts state that ciprofloxacin can be considered for initial postexposure prophylaxis in pregnant women exposed to B. anthracis spores.(See Pregnant and Breast-feeding Women under Inhalational Anthrax: Postexposure Prophylaxis, in Uses.)

An expert review of published data regarding clinical experience with use of ciprofloxacin during pregnancy concluded that therapeutic doses of the drug during pregnancy are unlikely to pose a substantial teratogenic risk, but that data are insufficient to state that there is no risk. Although some safety data are available from several postmarketing epidemiology studies involving short-term, first-trimester exposures to ciprofloxacin, these studies are insufficient to evaluate the risk for less common defects or to permit reliable and definitive conclusions regarding the safety of ciprofloxacin in pregnant women and their developing fetuses. In one controlled prospective observational study of 200 women exposed to fluoroquinolones during pregnancy (68% were first-trimester exposures, 52.5% of exposures involved ciprofloxacin), in utero exposure to fluoroquinolones during embryogenesis did not appear to be associated with an increased risk of major congenital malformations (incidence was 2.2% in the fluoroquinolone group and 2.6% in the control group; background incidence is 1-5%). There also was no evidence of increases in the rates of spontaneous abortion, prematurity, or low birthweight and no clinically important increase in musculoskeletal dysfunction in the ciprofloxacin-exposed children followed to 1 year of age. In another prospective follow-up study that included 549 pregnancies with fluoroquinolone exposure (93% were first-trimester exposures, 70 first-trimester exposures involved ciprofloxacin), there was no increase in the rates of spontaneous abortion, prematurity, or low birthweight, and the malformation rate was similar to the background incidence rate with no evidence of any specific patterns of congenital abnormalities.

Reproduction studies in rats and mice using oral ciprofloxacin dosages up to 100 mg/kg (0.6 and 0.3 times, respectively, the maximum daily human dosage of 1 g based on BSA) have not revealed evidence of harm to the fetus. In rabbits, oral ciprofloxacin dosages of 30 and 100 mg/kg (approximately 0.4 and 1.3 times, respectively, the highest recommended therapeutic dosage based on BSA) caused GI toxicity resulting in maternal weight loss and an increased incidence of abortion, but there was no evidence of teratogenicity. IV ciprofloxacin given to rabbits at dosages up to 20 mg/kg (approximately 0.3 times the highest recommended therapeutic dosage based on BSA) has not resulted in maternal toxicity, embryotoxicity, or teratogenicity.

Fertility

Fertility studies in rats using oral ciprofloxacin dosages up to 100 mg/kg (equivalent to the highest recommended daily human dose of 1 g based on BSA) did not reveal evidence of impaired fertility.

Administration of high dosages (100 mg/kg daily) of some quinolones (e.g., norfloxacin [no longer commercially available in the US], pefloxacin [not commercially available in the US] and pipemidic acid [not commercially available in the US]) has been associated with impaired spermatogenesis and/or testicular damage (atrophy in rats and dogs) in chronic (for 3 months or longer) toxicity studies.

Lactation

Ciprofloxacin is distributed into milk, but the amount of the drug absorbed by a nursing infant is unknown. Because of the potential for serious adverse effects of ciprofloxacin (including articular damage) in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman. However, AAP considers ciprofloxacin to be usually compatible with breast-feeding since the amount of the fluoroquinolone potentially absorbed by nursing infants would be small and no observable change in infants associated with such exposure has been reported to date.

Because the long-term safety of prolonged exposure of nursing infants (e.g., during a 60-day regimen for anthrax) to breast milk from ciprofloxacin-treated women currently is not known, CDC recommends that lactating women who are concerned about the use of ciprofloxacin during anthrax prophylaxis consider expressing and then discarding their breast milk so that breast-feeding can be resumed once anti-infective prophylaxis is complete. Decisions about anti-infective choice and continuation of breast-feeding should be made by the woman and the infant's clinicians, taking into consideration the efficacy of the anti-infective, safety for the infant, and benefits of breast-feeding.

Drug Interactions

Drugs Metabolized by Hepatic Microsomal Enzymes

Ciprofloxacin inhibits cytochrome P-450 (CYP) isoenzyme 1A2. Concomitant use with CYP1A2 substrates (e.g., clozapine, methylxanthines [e.g., caffeine, theophylline], olanzapine, ropinirole, tizanidine) may result in increased plasma concentrations and increased pharmacologic or adverse effects of the concomitant drug.

Drugs that Prolong the QT Interval

Concomitant use of ciprofloxacin and drugs known to prolong the QT interval, including class IA antiarrhythmics (e.g., quinidine, procainamide), class III antiarrhythmics (e.g., amiodarone, sotalol), tricyclic antidepressants, macrolides, and antipsychotics, may result in additive effects on QT interval prolongation. Concomitant use with these drugs should be avoided; if concomitant use is necessary, caution is advised.

Antacids

Antacids containing magnesium, aluminum, or calcium decrease absorption of oral ciprofloxacin, resulting in decreased serum and urine concentrations of the anti-infective agent. Ciprofloxacin bioavailability may be decreased by as much as 90% and serum ciprofloxacin concentrations generally are decreased by 14-50% in patients receiving an antacid concomitantly; anti-infective treatment failure may occur as a result of reduced quinolone absorption in these patients. The mechanism of this interaction has not been fully elucidated to date, but magnesium, aluminum, and other divalent ions may bind to, and form insoluble complexes with, quinolones in the GI tract.

The manufacturers state that ciprofloxacin conventional tablets, extended-release tablets, or oral suspension should be administered at least 2 hours before or 6 hours after antacids containing magnesium or aluminum. Some clinicians suggest that patients be instructed not to ingest antacids containing magnesium, aluminum, or calcium concomitantly with or within 2-4 hours of a ciprofloxacin dose; however, other clinicians state that these antacids should not be used in patients receiving ciprofloxacin and that ciprofloxacin probably should not be used in patients with renal failure who require aluminum hydroxide or aluminum carbonate for intestinal binding of phosphate.

Aminoglycosides

The antibacterial activities of ciprofloxacin and aminoglycosides have been additive or synergistic in vitro against some strains of Enterobacteriaceae and Pseudomonas aeruginosa. However, synergism between the drugs is unpredictable, and indifference generally occurs when ciprofloxacin is used in conjunction with amikacin, gentamicin, or tobramycin against Ps. aeruginosa or Enterobacteriaceae. Indifference also generally occurs when the drug is used in conjunction with tobramycin against Acinetobacter.

Antiarrhythmic Agents

Use ciprofloxacin with caution in those receiving concurrent therapy with drugs that can prolong the QT interval (e.g., class IA or III antiarrhythmic agents).(See Cautions: Geriatric Precautions.)

Anticoagulants

Initiation of oral ciprofloxacin therapy in patients stabilized on warfarin has resulted in prolongation of the prothrombin time; hematemesis occurred in at least 1 patient. The mechanism of this interaction has not been determined to date, but ciprofloxacin may displace the anticoagulant from serum albumin binding sites. The risk may vary with the underlying infection, age, and general status of the patient so that the contribution of ciprofloxacin to the increase in international normalized ratio (INR) is difficult to assess.

Ciprofloxacin should be used with caution in patients receiving warfarin, and prothrombin time and international normalized ratio (INR) should be monitored frequently during and shortly after concomitant therapy.

Antidiabetic Agents

Concomitant use of ciprofloxacin and oral antidiabetic agents (e.g., sulfonylurea agents such as glimepiride or glyburide) has resulted in hypoglycemia, presumably by potentiating the glucose-lowering effect of the antidiabetic agent. Severe hypoglycemia and some fatalities have been reported.

Ciprofloxacin should be used with caution in patients receiving oral antidiabetic agents, and blood glucose concentrations should be monitored. Patients receiving an oral antidiabetic agent and ciprofloxacin concomitantly should be advised to contact their clinician if low blood glucose occurs during ciprofloxacin therapy so that the clinician can determine whether the anti-infective should be changed.

Antimuscarinics

Although the clinical importance has not been determined and further study is needed to evaluate the interactions, concomitant administration of antimuscarinics (e.g., pirenzepine, scopolamine) delays GI absorption of the anti-infective.

Bismuth Subsalicylate

Concomitant administration of a single dose of oral bismuth subsalicylate (428 mg) and a single dose of oral ciprofloxacin (750 mg) results in a slight decrease in peak plasma concentrations and area under the concentration-time curve (AUC) of ciprofloxacin, but this is not considered clinically important.

Clindamycin

The combination of ciprofloxacin and clindamycin has been synergistic in vitro against many strains of Peptostreptococcus,Lactobacillus, and B. fragilis tested.

Corticosteroids

Concomitant use of corticosteroids increases the risk of severe tendon disorders (e.g., tendinitis, tendon rupture), especially in geriatric patients older than 60 years of age.(See Cautions: Tendinitis and Tendon Rupture.)

Clozapine

Concomitant use of ciprofloxacin (250 mg) and clozapine (304 mg) for 7 days increased serum concentrations of clozapine and N-desmethylclozapine by 29 and 31%, respectively, potentially resulting in adverse effects.

Clozapine and ciprofloxacin should be used concomitantly with caution; patients should be carefully monitored for clozapine adverse effects during and shortly after concomitant therapy and appropriate clozapine dosage adjustments made.

Cyclosporine

Concomitant use of cyclosporine and ciprofloxacin may result in transient increases in serum creatinine. Acute renal failure occurred within 4 days after initiation of ciprofloxacin in a patient receiving cyclosporine maintenance therapy. The mechanism of this potential interaction has not been elucidated, but could involve synergistic nephrotoxic effects of the drugs and/or interference of cyclosporine metabolism by ciprofloxacin.

Cyclosporine and ciprofloxacin should be used concomitantly with caution and renal function (especially serum creatinine concentrations) should be monitored.

Didanosine

Concomitant use of oral ciprofloxacin and buffered didanosine preparations (pediatric oral solution admixed with antacid) may decrease absorption of ciprofloxacin resulting in decreased serum and urine concentrations of the quinolone.

The manufacturers state that ciprofloxacin conventional tablets, extended-release tablets, or oral suspension should be administered at least 2 hours before or 6 hours after buffered didanosine preparations.

Duloxetine

Concomitant use of duloxetine and potent CYP1A2 inhibitors may result in increased mean peak concentrations and AUC of duloxetine. Although clinical data are not available regarding a possible interaction between duloxetine and ciprofloxacin, similar effects on duloxetine exposure can be expected if duloxetine and ciprofloxacin are administered concomitantly.

Concomitant use of duloxetine and ciprofloxacin should be avoided. If concomitant use cannot be avoided, patients should be monitored for duloxetine toxicity.

Histamine H2-receptor Antagonists

Histamine H2-receptor antagonists do not appear to have a clinically important effect on bioavailability of ciprofloxacin. Concomitant cimetidine or ranitidine does not appear to alter GI absorption of ciprofloxacin.

Iron, Multivitamins, and Mineral Supplements

Oral multivitamin and mineral supplements containing divalent or trivalent cations such as calcium, iron, or zinc may interfere with oral absorption of ciprofloxacin resulting in decreased serum and urine concentrations of the quinolone. Therefore, these multivitamins and/or mineral supplements should not be ingested concomitantly with ciprofloxacin.

The manufacturers state that ciprofloxacin conventional tablets, extended-release tablets, or oral suspension should be administered at least 2 hours before or 6 hours after preparations containing calcium, iron, or zinc.

β-Lactam Antibiotics

An additive or synergistic effect has occurred occasionally in vitro against some strains of Ps. aeruginosa and Ps. maltophilia when ciprofloxacin was used concomitantly with an extended-spectrum penicillin (e.g., mezlocillin, piperacillin). Indifference generally occurs when ciprofloxacin is used in conjunction with an extended-spectrum penicillin against Enterobacteriaceae.

Ciprofloxacin used in conjunction with imipenem, cefoxitin, or a cephalosporin (e.g., cefotaxime, ceftazidime) has been reported to be additive or synergistic against some strains of Ps. aeruginosa or Enterobacteriaceae; however, these combinations generally are indifferent rather than additive or synergistic against these bacteria. Although the clinical importance has not been determined, ciprofloxacin used in conjunction with cefotaxime in vitro resulted in a synergistic effect against many strains of Bacteroides fragilis tested; antagonism did not occur.

Lanthanum Carbonate

Concomitant administration of lanthanum carbonate may decrease GI absorption of ciprofloxacin and result in a substantial decrease in serum and urine concentrations of the anti-infective agent.

The manufacturers state that ciprofloxacin conventional tablets, extended-release tablets, or oral suspension should be administered at least 2 hours before or 6 hours after lanthanum carbonate.

Lidocaine

Concomitant use of IV lidocaine hydrochloride (1.5 mg/kg) and ciprofloxacin (500 mg twice daily) increased the peak concentrations and AUC of lidocaine by 12 and 26%, respectively. Although lidocaine treatment was well tolerated at this elevated exposure, a possible interaction with ciprofloxacin and increase in lidocaine-associated adverse effects should be considered if the drugs are used concomitantly.

Methotrexate

Concomitant use of ciprofloxacin and methotrexate may result in increased plasma concentrations of methotrexate (as the result of renal tubular transport inhibition) and may increase the risk of methotrexate-associated toxic reactions.

Methotrexate and ciprofloxacin should be used concomitantly with caution; patients should be carefully monitored.

Metoclopramide

Although bioavailability of ciprofloxacin does not appear to be affected, concomitant use of metoclopramide reportedly accelerates the rate of GI absorption of ciprofloxacin resulting in a shorter time to peak plasma concentrations of the drug.

Metronidazole

Concomitant use of metronidazole and ciprofloxacin does not affect serum concentrations of either drug.

Nonsteroidal Anti-inflammatory Agents

Concomitant use of ciprofloxacin and a nonsteroidal anti-inflammatory agent (NSAIA) could increase the risk of CNS stimulation (e.g., seizures). In preclinical studies and during postmarketing experience, concomitant use of ciprofloxacin and very high doses of an NSAIA (except aspirin) provoked seizures. Animal studies suggest that the risk may vary depending on the specific NSAIA.

NSAIAs and ciprofloxacin should be used concomitantly with caution.

Omeprazole

Concomitant administration of a single 500-mg conventional tablet of ciprofloxacin and omeprazole (20 mg once daily for 4 days) resulted in a 16% decrease in mean peak concentration and AUC of ciprofloxacin. Concomitant administration of ciprofloxacin extended-release tablets (single 1-g dose) and omeprazole (40 mg once daily for 3 days) in healthy individuals reduced peak plasma concentrations and AUC of ciprofloxacin by 23 and 20%, respectively. The clinical importance of this interaction has not been determined.

Phenytoin

Concomitant use of ciprofloxacin and phenytoin has resulted in altered serum concentrations of phenytoin (increased or decreased).

Phenytoin and ciprofloxacin should be used concomitantly with caution. To avoid loss of seizure control and prevent adverse effects associated with phenytoin overdosage, phenytoin serum concentrations should be monitored during and shortly after concomitant therapy with ciprofloxacin.

Phosphodiesterase Type 5 Inhibitors

Concomitant use of a single oral dose of sildenafil (50 mg) with ciprofloxacin (500 mg) in healthy individuals increased the mean peak concentration and AUC of sildenafil approximately twofold.

Sildenafil and ciprofloxacin should be used concomitantly with caution; patients should be monitored for sildenafil toxicity.

Probenecid

Concomitant administration of probenecid interferes with renal tubular secretion of ciprofloxacin, resulting in a 50% decrease in renal clearance of ciprofloxacin, a 50% increase in systemic ciprofloxacin concentrations, and a prolonged serum half-life of the drug. This effect may potentiate ciprofloxacin toxicity.

Probenecid and ciprofloxacin should be used concomitantly with caution.

Rifampin

Concomitant use of oral ciprofloxacin (750 mg twice daily) and oral rifampin (300 mg twice daily) does not appear to affect the pharmacokinetics of either drug.

In vitro, the combination of ciprofloxacin and rifampin generally is indifferent against S. aureus; however, antagonism also has been reported rarely.

Ropinirole

Concomitant use of oral ciprofloxacin (500 mg twice daily) and oral ropinirole (6 mg daily) has resulted in 60 and 84% increases in peak concentrations and AUC of ropinirole, respectively.

Ropinirole and ciprofloxacin should be used concomitantly with caution; patients should be monitored for ropinirole-associated adverse effects during and shortly after concomitant therapy and ropinirole dosage adjustments should be made as necessary.

Sevelamer

Concomitant administration of sevelamer may decrease GI absorption of ciprofloxacin and result in a substantial decrease in serum and urine concentrations of the anti-infective agent.

The manufacturers state that ciprofloxacin conventional tablets, extended-release tablets, or oral suspension should be administered at least 2 hours before or 6 hours after sevelamer.

Sucralfate

Concomitant sucralfate, presumably because of its aluminum content, decreases GI absorption of ciprofloxacin and may result in a substantial (50-90%) decrease in serum concentrations of the anti-infective agent.

The manufacturers state that ciprofloxacin extended-release tablets, conventional tablets, or oral suspension should be administered at least 2 hours before or 6 hours after sucralfate.

Tizanidine

Concomitant use of tizanidine (single dose of 4 mg) and ciprofloxacin (500 mg twice daily for 3 days) increased peak serum concentrations and AUC of tizanidine by sevenfold and tenfold, respectively.

Concomitant use of ciprofloxacin and tizanidine is contraindicated because the hypotensive and sedative effects of tizanidine are potentiated.

Vancomycin

Synergism does not occur in vitro when ciprofloxacin is used in conjunction with vancomycin against Staphylococcus epidermidis,S. aureus (including oxacillin-resistant S. aureus),Corynebacterium, or Listeria monocytogenes.

Xanthine Derivatives

Theophyllines

Concomitant administration of ciprofloxacin in patients receiving a theophylline derivative may result in higher and prolonged serum theophylline concentrations and may increase the risk of theophylline-related adverse effects. Alterations in theophylline pharmacokinetics have shown considerable interindividual variation, with serum theophylline concentrations reportedly increasing by 17-254% and theophylline clearance decreasing by 18-112% following initiation of ciprofloxacin. Generally, however, reductions in theophylline clearance induced by ciprofloxacin have averaged 20-35%. Alterations in theophylline pharmacokinetics may be related to inhibition of metabolism in the liver by the 4-oxo metabolites of these quinolones. However, the potential contribution of the 4-oxo metabolites to this interaction has not been fully elucidated, and there is some evidence that, while formation of these metabolites may correlate with inhibition of theophylline metabolism, the 4-oxo metabolites themselves may not be responsible for the observed inhibition. Theophyllines do not appear to affect the pharmacokinetics of quinolones. However, there is limited in vitro evidence that theophyllines may potentiate quinolone-induced inhibition of γ-aminobutyric acid (GABA), thus possibly potentiating CNS stimulation.

Serious and sometimes fatal reactions (e.g., cardiac arrest, seizures, status epilepticus, respiratory failure) have occurred in patients receiving ciprofloxacin and theophylline concomitantly. Death in at least one patient was associated with seizures and atrial fibrillation during concomitant therapy with the drugs. Other adverse reactions reported during concomitant therapy with the drugs include nausea, vomiting, dizziness, headache, tremor, restlessness, agitation, irritability, confusion, hallucinations, tachycardia, and palpitations. These adverse effects apparently occurred as the result of increased serum theophylline concentrations. While similar effects also have been reported in theophylline-treated patients who were not receiving ciprofloxacin concomitantly, the possibility that such toxicity may have been potentiated by ciprofloxacin cannot be excluded.

Concomitant use of ciprofloxacin and a theophylline derivative should be avoided, if possible, because of the risk of toxicity (e.g., CNS or other adverse effects) associated with increased plasma concentrations of theophylline. If concomitant use of theophylline and ciprofloxacin cannot be avoided, plasma theophylline concentrations should be monitored, the patient observed for manifestations of theophylline toxicity, and appropriate theophylline dosage adjustments made as needed, especially in geriatric patients. The need for theophylline dosage adjustment also should be considered when ciprofloxacin is discontinued since subtherapeutic concentrations may occur.

Caffeine

Ciprofloxacin inhibits formation of paraxanthine after caffeine administration, resulting in increased serum concentrations, reduced clearance, and prolonged elimination half-life of caffeine.

Caffeine and ciprofloxacin should be used concomitantly with caution. Patients receiving ciprofloxacin should be advised that regular consumption of large quantities of coffee, tea, or caffeine-containing soft drinks or drugs during therapy with the anti-infective may result in exaggerated or prolonged effects of caffeine. If excessive cardiac or CNS stimulation (e.g., nervousness, insomnia, anxiety, tachycardia) occurs, caffeine intake should be restricted. In addition, caffeine intake should be restricted during ciprofloxacin therapy in patients at risk of adverse effects from CNS or cardiac stimulation.

Pentoxifylline

Concomitant use of pentoxifylline and ciprofloxacin results in increased serum concentrations, reduced clearance, and prolonged elimination half-life of pentoxifylline. Ciprofloxacin and pentoxifylline should be used concomitantly with caution; patients should be monitored for xanthine toxicity and dosage adjusted as necessary.

Pharmacokinetics

In studies in the Pharmacokinetics section, ciprofloxacin was administered orally as conventional tablets containing the monohydrochloride monohydrate salt (i.e., ciprofloxacin hydrochloride), as extended-release tablets containing both ciprofloxacin hydrochloride and ciprofloxacin (base), or as an oral suspension containing the base; ciprofloxacin also was administered parenterally. Dosages and concentrations of the drug are expressed in terms of ciprofloxacin.

Body fluid and tissue concentrations of ciprofloxacin were measured with either a high-pressure liquid chromatographic (HPLC) assay or a microbiologic assay. HPLC assays are more specific for ciprofloxacin than microbiologic assays since the latter method measures the antibacterial activity of the parent drug as well as its microbiologically active metabolites. Controlled studies using HPLC and microbiologic assays indicate that there is good correlation between both methods for serum ciprofloxacin concentrations and pharmacokinetic parameters determined using these serum concentrations. However, mean ciprofloxacin concentrations in urine or bile generally are 30-40% higher when a microbiologic assay is used than when an HPLC assay is used.

The pharmacokinetics of ciprofloxacin after oral administration (as the hydrochloride) are best described by a 2-compartment model assuming zero-order absorption, and pharmacokinetics after IV administration are best described by an open, 3-compartment model.

The manufacturer states that a 500-mg dose of ciprofloxacin administered as ciprofloxacin oral suspension containing 250 mg/5 mL is bioequivalent to a 500-mg conventional tablet and that 10 mL of the ciprofloxacin oral suspension containing 250 mg/5 mL is bioequivalent to 5 mL of the oral suspension containing 500 mg/5 mL.

Ciprofloxacin conventional tablets are not bioequivalent to ciprofloxacin extended-release tablets.

Absorption

Oral Administration

Ciprofloxacin hydrochloride is rapidly and well absorbed from the GI tract following oral administration, and undergoes minimal first-pass metabolism.

The oral bioavailability of ciprofloxacin administered as conventional tablets is 50-85% in healthy, fasting adults, and peak serum concentrations of the drug generally are attained within 0.5-2.3 hours. Peak serum concentrations and area under the serum concentration-time curve (AUC) increase in proportion to the dose over the oral dosage range of 250-1000 mg and are unaffected by gender. Following oral administration of a single 250-, 500-, 750-, or 1000-mg dose of ciprofloxacin as conventional tablets or oral suspension in healthy, fasting adults, peak serum concentrations average 0.76-1.5, 1.6-2.9, 2.5-4.3, or 3.4-5.4 mcg/mL, respectively; serum concentrations 12 hours after the dose average 0.1, 0.2, 0.4, or 0.6 mcg/mL, respectively. In adults, oral administration of 500 mg of ciprofloxacin as conventional tablets every 12 hours results in mean peak or trough serum concentrations at steady-state of 2.97 or 0.2 mcg/mL, respectively.

Following oral administration of extended-release tablets containing ciprofloxacin hydrochloride and base, peak plasma concentrations of ciprofloxacin are attained within 1-4 hours. Ciprofloxacin extended-release tablets contain approximately 35% of the dose within an immediate-release component; the remaining 65% of the dose is contained in a slow-release matrix. Oral administration of ciprofloxacin 500 mg once daily as ciprofloxacin extended-release tablets or 250 mg twice daily as conventional tablets results in steady-state mean peak plasma concentrations of 1.59 or 1.14 mcg/mL, respectively; however, the area under the concentration-time curve (AUC) is similar with both regimens. Oral administration of 1 g once daily as ciprofloxacin extended-release tablets or 500 mg twice daily as conventional tablets results in steady-state mean peak plasma concentrations of 3.11 or 2.06 mcg/mL, respectively; the AUC is similar with both regimens.

Data indicate that peak serum concentrations and AUCs of ciprofloxacin are slightly higher in geriatric patients than in younger adults; this may occur because of increased bioavailability, reduced volume of distribution, and/or reduced renal clearance in these patients. Single-dose oral studies using ciprofloxacin conventional tablets and single- and multiple-dose IV studies indicate that, compared with younger adults, peak plasma concentrations are 16-40% higher, mean AUC is approximately 30% higher, and elimination half-life is prolonged approximately 20% in individuals older than 65 years of age. These differences can be at least partially attributed to decreased renal clearance in this age group and are not clinically important.

Based on population pharmacokinetics, bioavailability of ciprofloxacin oral suspension in children is approximately 60%. Following a single oral dose of 10 mg/kg of ciprofloxacin given as the oral suspension to children 4 months to 7 years of age, the mean peak plasma concentration was 2.4 mcg/mL. There was no apparent age dependence and no increase in peak plasma concentrations following multiple doses.

In one study, GI absorption of ciprofloxacin was slower and the elimination half-life of the drug was shorter in cystic fibrosis patients 18 years of age or older than in healthy adults. Several other studies, however, indicate that the pharmacokinetics of ciprofloxacin are not appreciably altered in cystic fibrosis patients 18 years of age or older compared with healthy adults.

Although peak serum concentrations of ciprofloxacin and the AUC increased slightly after repeated oral doses in a few studies in fasting, healthy adults, most multiple-dose studies in fasting, healthy adults with normal renal function indicate that neither peak nor trough serum concentrations of ciprofloxacin increase after repeated oral doses and that the drug does not accumulate.

Magnesium-, aluminum-, and/or calcium-containing antacids or products containing calcium, iron, or zinc decrease the oral bioavailability of ciprofloxacin hydrochloride.(See Drug Interactions: Antacids.)

Food or Milk

The effect of food and/or milk on GI absorption of ciprofloxacin varies depending on the specific ciprofloxacin preparation (conventional tablets, extended-release tablets, oral solution) and situation.

When ciprofloxacin conventional tablets are administered concomitantly with food, there is a delay in absorption of the drug, but overall absorption is not substantially affected.

The manufacturer states that food does not affect the rate or extent of absorption of ciprofloxacin administered as the oral suspension.

The manufacturers state that, based on pharmacokinetic studies, ciprofloxacin extended-release tablets can be administered with or without food (e.g., with a high- or low-fat meal or under fasting conditions).

Concomitant administration of oral ciprofloxacin with dairy products (e.g., milk, yogurt) or calcium-fortified juices alone (i.e., without a meal) or with substantial calcium intake (greater than 800 mg) can reduce GI absorption of ciprofloxacin. In one study, administration of a 500-mg dose of ciprofloxacin (conventional tablet) with 300 mL of whole milk (360 mg calcium, 33 mg magnesium) or unflavored yogurt (450 mg calcium, 40 mg magnesium) decreased the AUC by 33 or 36%, respectively, and decreased peak plasma concentrations by 36 or 47%, respectively, compared with administration with water. The manufacturers state that oral ciprofloxacin can be taken with dairy products or calcium-fortified juices that are part of a meal.

Concomitant administration with nutritional supplements or enteral feedings may affect GI absorption of ciprofloxacin. When a 750-mg conventional ciprofloxacin tablet was crushed, mixed with 120 mL of enteral premixed liquid (Ensure), and swallowed, the AUC was 28% lower and peak plasma concentrations were 47% lower compared with results attained when the tablet was crushed and mixed with water before swallowing. In another crossover study in healthy adults, the AUC of the drug was 25% lower when a 750-mg conventional ciprofloxacin tablet was administered with 240 mL of a nutritional supplement containing calcium, magnesium, iron, and zinc (Resource) compared with administration with water.

IV Administration

Following IV infusion over 60 minutes of a single 200- or 400-mg dose of ciprofloxacin in healthy adults, peak serum concentrations average 2.1 and 4.6 mcg/mL, respectively, immediately following the infusion; serum concentrations 6 hours after the start of infusion (i.e., 5 hours after completion) average 0.3 and 0.7 mcg/mL and those 12 hours after the start of infusion average 0.1 and 0.2 mcg/mL, respectively. In adults receiving 400 mg of ciprofloxacin IV every 12 hours, mean peak or trough serum concentrations at steady-state are 4.56 or 0.2 mcg/mL, respectively.

Following IV injection over 15 minutes of a single 100-mg dose of ciprofloxacin in healthy adults, serum concentrations of the drug average 2.8 mcg/mL immediately following the injection and 0.32, 0.14, and 0.07 mcg/mL at 1, 6, and 12 hours, respectively, after the dose. In healthy adults who receive a single 200-mg dose of ciprofloxacin by IV injection over 10 minutes, serum concentrations of the drug immediately following the injection average 6.3-6.5 mcg/mL and serum concentrations 1 and 12 hours later average 0.87 and 0.1 mcg/mL, respectively.

In a limited number of pediatric patients with severe sepsis who received ciprofloxacin 10 mg/kg given by IV infusion over 1 hour, mean peak plasma concentrations were 6.1 mcg/mL in those younger than 1 year of age and 7.2 mcg/mL in those 1-5 years of age.

Distribution

Ciprofloxacin is widely distributed into body tissues and fluids following oral or IV administration. Highest concentrations of the drug generally are attained in bile, lungs, kidney, liver, gallbladder, uterus, seminal fluid, prostatic tissue and fluid, tonsils, endometrium, fallopian tubes, and ovaries. Concentrations of the drug achieved in most of these tissues and fluids substantially exceed those in serum. The drug also is distributed into adipose tissue, aqueous humor, bone, cartilage, heart tissue (heart valves, myocardia), muscle, nasal secretions, saliva, skin, sputum, and pleural, peritoneal, ascitic, blister, lymphatic, and renal cyst fluid. Ciprofloxacin is concentrated within neutrophils, achieving concentrations in these cells that may be 2-7 times greater than extracellular concentrations.

In healthy adults, the apparent volume of distribution of ciprofloxacin is 2-3.5 L/kg and the apparent volume of distribution at steady state is 1.7-2.7 L/kg. The apparent volume of distribution of ciprofloxacin in geriatric patients 64-91 years of age averages 3.5-3.6 L/kg.

Only low concentrations of ciprofloxacin are distributed into CSF; peak CSF concentrations may be 6-10% of peak serum concentrations. In adults with meningitis who received 200-mg doses of ciprofloxacin every 12 hours by IV infusion over 30 minutes, the ratio of CSF/serum concentrations in samples obtained 1-2 hours after a dose was 0.11-0.46 during the first 2-4 days of therapy when meninges were inflamed and 0.04-0.3 during days 10-14 when meninges were uninflamed. In one patient with meningitis caused by Ps. aeruginosa who received IV ciprofloxacin in a dosage of 400 mg every 8 hours, CSF concentrations of the drug were about 1 mg/mL and drug accumulation in CSF did not occur.

Following oral or IV administration of the drug, biliary ciprofloxacin concentrations are several fold higher than simultaneous serum concentrations of the drug. In adults undergoing cholecystectomy who received a single 750-mg oral dose of ciprofloxacin, peak concentrations of the drug and active metabolites ranged from 68-225 mcg/mL in gallbladder bile, 16-17 mcg/mL in common duct bile, 3.6-32.4 mcg/g in liver, 0.8-14.1 mcg/g in gallbladder, and 1.5-7.8 mcg/mL in serum.

Following oral administration, ciprofloxacin concentrations in prostatic tissue and fluid generally exceed concurrent serum concentrations of the drug. In a study in men undergoing transurethral resection for prostatic hyperplasia or cancer who received 500 mg of the drug orally every 12 hours, ciprofloxacin concentrations in prostatic tissue obtained 75-120 minutes after a dose averaged 3 mg/kg and the ratio of prostate/serum concentrations ranged from 1-7.

Ciprofloxacin is 16-43% bound to serum proteins in vitro.

Ciprofloxacin crosses the placenta and is distributed into amniotic fluid in humans.

Ciprofloxacin is distributed into milk. In lactating women who received 750 mg of ciprofloxacin every 12 hours for 3 doses, concentrations of the drug in milk obtained 2-4 hours after a dose averaged 2.26-3.79 mcg/mL; milk concentrations were higher than concomitant serum concentrations for up to 12 hours after a dose.

Elimination

The serum elimination half-life of ciprofloxacin in adults with normal renal function is 3-7 hours. Following IV administration in healthy adults, the distribution half-life of ciprofloxacin averages 0.18-0.37 hours and the elimination half-life averages 3-4.8 hours.

The elimination half-life of the drug is slightly longer in geriatric adults than in younger adults, and ranges from 3.3-6.8 hours in adults 60-91 years of age with renal function normal for their age.

Based on population pharmacokinetic analysis of pediatric patients with various infections, the predicted mean half-life of ciprofloxacin in children is approximately 4-5 hours.

In patients with impaired renal function, serum concentrations of ciprofloxacin are higher and the half-life prolonged. In adults with creatinine clearances of 30 mL/minute or less, half-life of the drug ranges from 4.4-12.6 hours.

Further study is needed to evaluate that pharmacokinetics in patients with hepatic impairment. In one study in patients with stable chronic liver cirrhosis, there was no clinically important change in ciprofloxacin pharmacokinetics; however, slightly prolonged half-life has been reported in some other patients with hepatic impairment.

Ciprofloxacin is eliminated by renal and nonrenal mechanisms. The drug is partially metabolized in the liver by modification of the piperazinyl group to at least 4 metabolites. These metabolites, which have been identified as desethyleneciprofloxacin (M1), sulfociprofloxacin (M2), oxociprofloxacin (M3), and N-formylciprofloxacin (M4), have microbiologic activity that is less than that of the parent drug.

Ciprofloxacin and its metabolites are excreted in urine and feces. Unchanged ciprofloxacin is excreted in urine by both glomerular filtration and tubular secretion. Following oral administration of a single 250-, 500-, or 750-mg dose in adults with normal renal function, 15-50% of the dose is excreted in urine as unchanged drug and 10-15% as metabolites within 24 hours; 20-40% of the dose is excreted in feces as unchanged drug and metabolites within 5 days. Most, but not all, of unchanged ciprofloxacin in feces appears to result from biliary excretion.

Renal clearance of ciprofloxacin averages 300-479 mL/minute in adults with normal renal function. Urinary concentrations of ciprofloxacin generally exceed 200 mcg/mL during the first 2 hours and average about 30 mcg/mL 8-12 hours after a single 250-mg oral dose of the drug. Following oral administration of a single 500-mg dose in adults with normal renal function, urinary concentrations of ciprofloxacin and active metabolites average 350, 162, and 105 mcg/mL in urine collected over 1-3, 3-6, and 6-12 hours, respectively, after the dose.Concentrations of unchanged drug and active metabolites in feces range from 185-2220 mcg/g after 7 days of therapy with the drug in a dosage of 500 mg every 12 hours.

Small amounts of ciprofloxacin are removed by hemodialysis. The amount of the drug removed during hemodialysis depends on several factors (e.g., type of coil used, dialysis flow rate). In patients with end-stage renal disease undergoing hemodialysis, the serum half-life of ciprofloxacin averaged 3.2 hours during hemodialysis and 5.8 hours between dialysis sessions. A 4-hour period of hemodialysis generally removes into the dialysate 2-30% of a single 250- or 500-mg oral dose of the drug. Only small amounts of ciprofloxacin appear to be removed by peritoneal dialysis.

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