Professional Information
Fluoroquinolones (Systemic)
1) Ciprofloxacin
2) Enoxacin †
3) Gatifloxacin †
4) Levofloxacin
5) Lomefloxacin †
6) Moxifloxacin †
7) Norfloxacin
8) Ofloxacin
9) Sparfloxacin †
VA CLASSIFICATION
Primary: AM402
Commonly used brand name(s): Avelox6; Avelox I.V.6; Cipro1; Cipro I.V.1; Floxin8; Floxin I.V.8; Levaquin4; Maxaquin5; Noroxin7; Penetrex2; Tequin3; Zagam9.
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).
†Not commercially available in Canada.
Category:
Antibacterial (systemic)—
Indications
Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.
General considerations
Fluoroquinolones are broad-spectrum anti-infectives, active against a wide range of aerobic gram-positive and gram-negative organisms. They are active in vitro against most Enterobacteriaceae, including Citrobacter diversus , Citrobacter freundii , and Citrobacter koseri ; Enterobacter aerogenes and Enterobacter cloacae ; Escherichia coli ; Klebsiella oxytoca , Klebsiella ozaenae , and Klebsiella pneumoniae ; Morganella morganii ; Proteus mirabilis and Proteus vulgaris ; Providencia alcalifaciens , Providencia rettgeri , and Providencia stuartii ; Salmonella enteritidis and Salmonella typhi ; Shigella boydii , Shigella dysenteriae , Shigella flexneri , and Shigella sonnei ; Vibrio cholerae , Vibrio parahaemolyticus , and Vibrio vulnificus ; and Yersinia enterocolitica {11}. All of the fluoroquinolones also have good in vitro activity against penicillin-resistant strains of Neisseria gonorrhoeae , beta-lactamase–producing strains of Haemophilus influenzae and Moraxella (Branhamella) catarrhalis , and some gram-negative bacilli that are resistant to other antimicrobial agents {74}. Ciprofloxacin is the most active fluoroquinolone against Pseudomonas aeruginosa , although longitudinal studies have reported progressively decreasing susceptibility in Europe, North America, and South America {27}. It is not generally effective against most strains of Burkholderia (Pseudomonas) cepacia or some strains of Strenotrophomonas (Xanthomonas) maltophilia {04}. Ofloxacin's potency against P. aeruginosa is similar to that of norfloxacin, and greater than that of enoxacin or lomefloxacin {102} {116} {133}.
Fluoroquinolones also have good in vitro activity against Staphylococcus saprophyticus , Staphylococcus epidermidis , and Staphylococcus aureus , including some methicillin-resistant (MRSA) strains {49} {115} {116} {133}. However, most methicillin-resistant strains also are resistant to fluoroquinolones {11}. Any bacteria that are resistant to one fluoroquinolone also may be resistant to another {11} {78}. Streptococci, including Streptococcus pneumoniae , Streptococcus pyogenes , and Enterococcus faecalis , are all moderately susceptible to ofloxacin and ciprofloxacin in vitro {04} {102} {115} {116} {133}. Sparfloxacin is more active in vitro against S. pneumoniae than is ciprofloxacin, and levofloxacin appears to be equal to or slightly more active than ciprofloxacin in this regard {141} . Resistant strains of streptococci are often seen. The MIC 90 values for these species, especially E. faecalis , are often equal to or greater than the susceptible breakpoint for ciprofloxacin and ofloxacin {11}. Therapeutic failures have been reported in patients taking ciprofloxacin for the treatment of pneumococcal pneumonia {03} {55}. However, levofloxacin is highly effective against S. pneumoniae isolates, including penicillin-susceptible isolates and those with intermediate or high-level resistance to penicillin. Gatifloxacin and moxifloxacin are both effective in vitro against penicillin-resistant strains of S. pneumoniae.{155}{157}
Ciprofloxacin and ofloxacin have been found to have good in vitro activity against Chlamydia trachomatis , Mycoplasma hominis , Mycoplasma pneumoniae , and Legionella pneumophila {49} {102} {116} {133} {11}. These two fluoroquinolones have moderate activity in vitro against Mycobacterium tuberculosis , but neither antimicrobial is indicated for tuberculosis {102} {116} {11}. The susceptibility of Mycobacterium avium-intracellulare , however, is only fair to poor, and inhibition requires significantly higher drug concentrations {49} {102} {115} {116}.
Ciprofloxacin has been found to be active against Bacillus anthracisboth in vitro and by use of serum levels as a surrogate marker.
{159}{160}
The emergence of bacterial resistance to fluoroquinolones, and of cross-resistance within this class of antimicrobial agents, has become a significant clinical concern. Decreased susceptibility among Enterobacteriaceae, including E. coli , K. pneumoniae , and Salmonella , has been reported worldwide {94} {95} {96}. Strains of N. gonorrhoeae with low-level resistance to fluoroquinolones have been isolated {87} {88} {97}; strains with high-level resistance to ciprofloxacin have been documented, and treatment failures have been reported {47}. Fluoroquinolone resistance also has been documented for H. influenzae in patients with recurrent respiratory tract infections {79} {89}, and for S. epidermidis in several cases of nosocomial infections {90} {91} {117} {118}. Use of fluoroquinolones in poultry may be at least partially responsible for the emergence of fluoroquinolone resistance in Salmonella and Campylobacter {82} {83}. Mechanisms underlying fluoroquinolone resistance may include plasmid transfer, chromosomal mutations in DNA gyrase ( gyrA) or topoisomerase IV ( parC), and/or antibiotic efflux {80} {81} {94}. Extensive and continuous use of fluoroquinolones, and antimicrobials in general, encourages the multiplication and spread of resistant bacterial strains; therefore, the World Health Organization recommends that prescribing practices for antimicrobial agents should be modified to reflect this growing concern {15}.
Accepted
Anthrax, inhalational (treatment)1—Ciprofloxacin is indicated to reduce the incidence or progression of the disease following exposure to aerosolized Bacillus anthracis {159}{160}
Bone and joint infections (treatment)—Ciprofloxacin {04} {63} is indicated in the treatment of bone and joint infections caused by susceptible organisms.
Bronchitis, bacterial exacerbations (treatment)— Ciprofloxacin {04} {63}, gatifloxacin{157}, moxifloxacin, {155} levofloxacin {17}{158}, lomefloxacin1 {03}, ofloxacin {66} {98}, and sparfloxacin1 {52} are indicated in the treatment of bacterial exacerbations of chronic bronchitis caused by susceptible organisms.
Cervicitis, nongonococcal (treatment) or
Urethritis, nongonococcal (treatment)— Ofloxacin {66} {98} is indicated in the treatment of nongonococcal cervicitis or urethritis caused by C. trachomatis .
Diarrhea, infectious (treatment)—Ciprofloxacin {04} {63} is indicated in the treatment of infectious diarrhea caused by enterotoxigenic strains of Campylobacter jejuni , E. coli , S. boydii , S. dysenteriae , S. flexneri , or S. sonnei . Although ciprofloxacin is approved for the treatment of diarrhea caused by Campylobacter , use of fluoroquinolones is not generally recommended due to the high frequency with which single-step mutations occur in Campylobacter , which result in fluoroquinolone resistance {35} {139} {140} {151}.
—[Norfloxacin is indicated in the treatment of acute diarrheal disease in patients with enterotoxigenic E. coli or Shigella infection, and in patients with severe enteritis {35} {148} {149} . Norfloxacin is also effective in the treatment of symptoms due to Salmonella infection; however, treatment with norfloxacin appears to delay bacterial elimination {35} {36} {150}. (Evidence rating: I)]1
Gonorrhea, endocervical and urethral (treatment)—Ciprofloxacin {04} {63}, enoxacin1 {16}, gatifloxacin {157} , norfloxacin {09} {64}, and ofloxacin {66} {98} are indicated in the treatment of endocervical and urethral infections caused by N. gonorrhoeae . Ofloxacin {66} {98} is indicated also for mixed infections of the cervix or urethra caused by C. trachomatis and N. gonorrhoeae . Gatifloxacin is indicated for acute, uncomplicated rectal infection in women due to N. gonorrhoeae.{157}
Intra-abdominal infections (treatment)—Ciprofloxacin {04} {63}, in combination with metronidazole, is indicated in the treatment of complicated intra-abdominal infections caused by Bacteroides fragilis , E. coli , K. pneumoniae , P. mirabilis , or P. aeruginosa .
Lower respiratory tract infections (treatment)— Ciprofloxacin {04}and levofloxacin {158} is indicated in the treatment of lower respiratory tract infections caused by susceptible organisms.
Neutropenia, febrile, empiric therapy (treatment) 1—Parenteral ciprofloxacin {05}, in combination with piperacillin, is indicated for empiric therapy in patients with febrile neutropenia.
Pelvic inflammatory disease (treatment)—Ofloxacin {66} {98} is indicated in the treatment of pelvic inflammatory disease, including severe infection, caused by C. trachomatis and/or N. gonorrhoeae .
—If anaerobic microorganisms are suspected of contributing to the infection, appropriate therapy for anaerobic pathogens should also be administered {98}.
Pneumonia, community-acquired (treatment)— gatifloxacin{157}, moxifloxacin{155} levofloxacin,{17}{158} ofloxacin {66} {98}, and sparfloxacin1 {52} are indicated in the treatment of community-acquired pneumonia caused by susceptible organisms.
—Caution should be used in treating streptococcal and pneumococcal pneumonia with fluoroquinolones. Although they have been effective in limited trials, treatment failures have been reported; fluoroquinolones should not be considered the drugs of first choice in the treatment of presumed or confirmed pneumococcal pneumonia. {55}
Pneumonia, nosocomial (treatment)—Parenteral ciprofloxacin {05} {63} is indicated in the treatment of nosocomial pneumonia.
—Caution should be used in treating streptococcal and pneumococcal pneumonia with fluoroquinolones. Although they have been effective in limited trials, treatment failures have been reported; fluoroquinolones should not be considered the drugs of first choice in the treatment of presumed or confirmed pneumococcal pneumonia. {55}
Prostatitis, bacterial (treatment)—Ciprofloxacin {04} {63}, norfloxacin 1 {09}, and ofloxacin {66} {98} are indicated in the treatment of bacterial prostatitis caused by susceptible organisms.
Pyelonephritis (treatment)—Gatifloxacin{157} and levofloxacin{17}{158} are indicated in the treatment of pyelonephritis caused by susceptible E. coli .
Sinusitis, acute (treatment)—Ciprofloxacin {04}1gatifloxacin{157}, moxifloxacin{155}, and levofloxacin {17}{158} are indicated in the treatment of acute sinusitis caused by H. influenzae , M. catarrhalis , or S. pneumoniae .
Skin and soft tissue infections (treatment)—Ciprofloxacin {04}{63}, levofloxacin {17}{158}, moxifloxacin {164} and ofloxacin {66} {98} are indicated in the treatment of skin and soft tissue infections caused by susceptible organisms.
Typhoid fever (treatment)—Oral ciprofloxacin {04} {63} is indicated in the treatment of typhoid fever caused by susceptible strains of S. typhi .
Urinary tract infections, bacterial (prophylaxis) 1—Lomefloxacin {03} is indicated preoperatively for the prophylaxis of urinary tract infections in patients undergoing transurethral surgical procedures.
Urinary tract infections, bacterial (treatment)— Ciprofloxacin {04} {63}, enoxacin1 {16}, gatifloxacin{157}levofloxacin {17}{158}, lomefloxacin 1 {03}, norfloxacin {09} {64}, and ofloxacin {66} {98} are indicated in the treatment of complicated and uncomplicated urinary tract infections, including cystitis, caused by susceptible organisms.
[Chancroid (treatment)]1—Ciprofloxacin is indicated in the treatment of chancroid caused by Haemophilus ducreyi {33} {34}.
[Cystic fibrosis, pulmonary exacerbations (treatment)]1—Ciprofloxacin, alone or in combination with other antibacterial agents, is indicated in patients with cystic fibrosis for the treatment of pulmonary exacerbations caused by susceptible P. aeruginosa {23} {28} {29} {65}.
—Although studies have shown that ciprofloxacin decreases the number of viable P. aeruginosa organisms during treatment {29} {152}, the number of organisms returns to pretreatment levels within days of ciprofloxacin discontinuation {152}. Some clinical studies report that treatment with ciprofloxacin for 14 to 21 days results in low to moderate levels of resistance {29} {152}; others report no change in ciprofloxacin susceptibility over the same period of treatment {23}.
[Meningococcal carriers (treatment)]—Oral ciprofloxacin {63} is indicated in the treatment of asymptomatic carriers of Neisseria meningitidis for the elimination of meningococci from the nasopharynx.
[Septicemia, bacterial (treatment)]—Parenteral ciprofloxacin {63} is indicated in the treatment of septicemia caused by E. coli or S. typhi .
—Not all species or strains of a particular organism may be susceptible to a particular fluoroquinolone.
Unaccepted
Fluoroquinolones have not been shown to be effective in the treatment of syphilis and have poor activity against most anaerobic bacteria (including Bacteroides fragilis and Clostridium difficile ). {04} {16} {49} {98} {102} {115}
1 Not included in Canadian product labeling.
Pharmacology/Pharmacokinetics
Table 1. Pharmacology/Pharmacokinetics {03} {04} {08} {17} {27} {30} {47} {59} {60} {63} {68} {69} {70} {73} {85} {98} {99} {100} {101} {103} {104} {105} {107} {108} {109} {110} {111} {112} {130} {132} {142} {143} {144} {146}{155}{157}
| Drug | Bioavailability (%) | Half-life (hr) | Time to peak serum concentration (hr) | Peak serum concentration after dose | Peak urine concentration after dose | |||
|---|---|---|---|---|---|---|---|---|
| Normal renal function | Impaired renal function | mcg/mL | Dose (mg) | mcg/mL | Dose (mg) | |||
| Ciprofloxacin | ||||||||
| Oral | 70–80 * | 4 † | 6–8 | 1–2 | 1.2–1.4 | 250 | > 200 | 250 |
| 2.4–4.3 | 500 | |||||||
| 3.4–4.3 | 750 | |||||||
| 5.4 | 1000 | |||||||
| IV | 5–6 | End of infusion | 2.1 | 200 | > 200 | 200 | ||
| 4.6 | 400 | > 400 | 400 | |||||
| Enoxacin | ||||||||
| Oral | 90 | 3–6 | 9–10 | 1–3 | 0.9 | 200 | ||
| 2 | 400 | |||||||
| Gatifloxacin | ||||||||
| Oral | 96 | 1–2 | 2 | 200 | ||||
| 7.1 | 11.2–30.7 | 3.8 | 400 | |||||
| IV | 12.3 | End of infusion | 2.4 | 200 | ||||
| 13.9 | 4.6 | 400 | ||||||
| Levofloxacin | ||||||||
| Oral | 99 | 4–8 | 6–28 | 1–2 | 5.7 | 500 | ||
| IV | 6.4 | 500 | ||||||
| Lomefloxacin | ||||||||
| Oral | 95–98 | 21–45 | 1.5 | 0.8 | 100 | > 300 | 400 | |
| 1.4 | 200 | |||||||
| 3–5.2 | 400 | |||||||
| Moxifloxacin | ||||||||
| Oral | 90 | 12 | 1–3 | 4.5 | 400 | |||
| IV | 14.8 | End of infusion | 4.2–4.6 | 400 | ||||
| Norfloxacin | ||||||||
| Oral | 30–70 * | 3–4 | 6–9 | 1–2 | 1.4–1.6 | 400 | 98–200 | 400 |
| 2.5 | 800 | |||||||
| Ofloxacin | 4.7–7 # | 15–60 ** | ||||||
| Oral | 95–100 | 1–2 | 1.5–2.6 | 200 | ||||
| 4.6–5 | 400 | |||||||
| IV | End of infusion | 2.3–2.7 | 200 | |||||
| 5.5–7.2 | 400 | |||||||
| Sparfloxacin | ||||||||
| Oral | 92 | 16–30 | 3–6 | 1.3 | 400 | |||
| 1.1 | 200 | |||||||
† Half-life of ciprofloxacin slightly prolonged in elderly patients (approximately 6 hours).
# Half-life of ofloxacin slightly prolonged in elderly patients (approximately 6 to 8.5 hours).
** Half-life of ofloxacin also prolonged in patients who have cirrhosis with ascites (approximately 7.3 to 19.5 hours).
Table 2. Pharmacology/Pharmacokinetics * {01} {03} {04} {07} {16} {17} {47} {59} {60} {61} {62} {63} {68} {69} {70} {73} {76} {77} {92} {93} {98} {99} {100} {102} {103} {104} {105} {107} {109} {114} {120} {130} {136} {138} {142} {144} {146}{155}
| Drug | Protein binding (%) | Renal excretion (% unchanged/hrs) |
Metabolism (%) | Biliary excretion (%) | Vol D (liter/kg) | Removal by dialysis | |
|---|---|---|---|---|---|---|---|
| HD (%) | PD (%) | ||||||
| Ciprofloxacin | 20–40 | 20 | 2 | <10 | < 10 | ||
| Oral | 40–50/24 | 20–35 | |||||
| IV | 50–70/24 | 15 | |||||
| Enoxacin | 40 † | 40–60/48 | 20 | 18 | 1.6 | < 5 | |
| Gatifloxacin | 20 | 70/48 | <1 | 5 | 1.5–2 | 14 | 11‡§ |
| Levofloxacin | 24–38 | 79–87/48 | 1.09–1.26 | 12 | 12 | ||
| Lomefloxacin | 10 | 60–80/48 | 5 | 10 | 1.8–2.5 | < 3 | < 3 |
| Moxifloxacin | 50 | 20 | 55 | 25 | 1.7–2.7 | ||
| Norfloxacin | 10–15 | 26–40/24–48 | 20 | 28–30 | 3.2 | < 10 | |
| Ofloxacin | 20–25 | 70–90/36 | 3 | 4–8 | 0.9–1.8 | 10–30 | 2–10 |
| Sparfloxacin | 45 | 50/24 | 3.9 | ||||
† Approximately 14% of enoxacin is bound to plasma proteins in patients with impaired renal function.
‡ Recovered over 4 hours
§ Recovered over 8 days
Physicochemical characteristics:
Molecular weight—
Ciprofloxacin: 331.35 {18}
Ciprofloxacin hydrochloride: 385.82 {18}
Enoxacin: 320.33 {18}
Gatifloxacin: 402.42{157}
Levofloxacin: 370.38 {18}
Lomefloxacin: 351.36 {18}
Lomefloxacin hydrochloride: 387.82 {18}
Moxifloxacin: 437.9{155}
Norfloxacin: 319.34 {18}
Ofloxacin: 361.38 {18}
Sparfloxacin: 392.41 {18}
Mechanism of action/Effect:
Bactericidal; fluoroquinolones act intracellularly by inhibiting topoisomerase II (DNA gyrase) and/or topoisomerase IV. Topoisomerases are essential bacterial enzymes that are critical catalysts in the duplication, transcription, and repair of bacterial DNA. {155}{157}
Distribution:
Fluoroquinolones are widely distributed to most body fluids and tissues; high concentrations are attained in the kidneys, gallbladder, liver, lungs, gynecologic tissue, prostatic tissue, phagocytic cells, urine, sputum, and bile {03} {09} {16} {27} {101} {102} {105}{155}{157}. Ciprofloxacin is also distributed to skin, fat, muscle, bone, and cartilage {04}. The skin, fascia, and subcutaneous fat concentrations of ofloxacin are less than 50% of those found in the serum {101} {102}.
Ciprofloxacin and ofloxacin have been found to penetrate into the cerebrospinal fluid (CSF). CSF concentrations of ciprofloxacin reach 10% of the peak serum concentration with noninflamed meninges, and 30 to 50% with inflamed meninges{27}. Ofloxacin penetrates into the CSF in both the presence and the absence of meningeal inflammation (range, 14 to 60%). The CSF distribution pattern of these agents has resulted in their bactericidal CSF titers ranging from inadequate to high, depending on the microorganism and its sensitivity to these antibiotics {98} {106}.
Precautions to Consider
Cross-sensitivity and/or related problems
Patients allergic to one fluoroquinolone or other chemically related quinolone derivatives (e.g., cinoxacin, nalidixic acid) may be allergic to other fluoroquinolones also {03} {04} {09} {16} {98}{155}{157}.
Carcinogenicity/Tumorigenicity
Ciprofloxacin—Long-term carcinogenicity studies (up to 2 years) in rats and mice with oral ciprofloxacin have shown no evidence that ciprofloxacin had any carcinogenic or tumorigenic effects {04}.
Enoxacin—Long-term studies to determine the carcinogenic potential of enoxacin in animals have not been conducted {16} .
Gatifloxacin—Gatifloxacin given at doses up to 81 mg/kg/day in male and 90 mg/kg/day in female B6C3F1 mice (0.13 and 0.18 times the maximum recommended human dose (MRHD) based upon on daily systemic exposure) for 18 months showed no increases in neoplasms. In a 2–year study in Fischer 344 rats at a high dose of 100 mg/kg/day (approximately 0.74 times MRHD based upon daily systemic exposure), gatifloxacin significantly increased the incidence of large granular lymphocytes leukemia in males. {157}
Levofloxacin—In a long-term study in rats, levofloxacin did not show carcinogenic or tumorigenic potential after daily dietary administration for 2 years. The highest dose was two times the recommended human dose based on body surface area, or 10 times the recommended human dose based on body weight. {17}
Lomefloxacin—One study lasting up to 52 weeks showed that 92% of hairless (Skh-1) mice that were exposed to UVA light for 3.5 hours, five times every two weeks, and that had received lomefloxacin concurrently developed skin tumors within 16 weeks. These tumors were well-differentiated squamous cell carcinomas of the skin that were nonmetastatic and endophytic in character. Two thirds of these squamous cell carcinomas contained large keratinous inclusion masses and were thought to arise from the vestigial hair follicles in these hairless animals. In this study, mice treated with lomefloxacin alone did not develop skin or systemic tumors. The clinical significance of these findings to humans is not known. {03}
Moxifloxacin—Long-term studies to determine the carcinogenic potential of moxifloxacin in animals has not been performed.{155}
Norfloxacin—Studies lasting up to 96 weeks in rats given doses of eight to nine times the usual human dose have shown that norfloxacin causes no increase in neoplastic changes, compared with controls {09}.
Ofloxacin—Long-term studies to determine the carcinogenic potential of ofloxacin in animals have not been conducted.{98}
Sparfloxacin—Sparfloxacin was not carcinogenic in mice or rats administered 3.5 or 6.2 times, respectively, the maximum recommended human dose (MRHD) (400 mg per day), on a mg per square meter of body surface area (mg/m 2) basis, for 104 weeks. These doses correspond to plasma concentrations approximately equal to (in mice) and 2.2 times greater than (in rats) maximum human plasma concentrations. {52}
Mutagenicity
Ciprofloxacin— In vitro mutagenicity studies have shown both positive and negative results. Negative results were obtained in the Salmonella microsome test, Escherichia coli DNA repair test, Chinese hamster V79 cell HGPRT test, Syrian hamster embryo cell transformation assay, Saccharomyces cerevisiae point mutation assay, and the S. cerevisiae mitotic crossover and gene conversion assay. Positive results were obtained in the mouse lymphoma cell forward mutation assay and the rat hepatocyte DNA repair assay. Although positive results were obtained in two of eight in vitro studies, negative results were obtained in the in vivo rat hepatocyte DNA repair assay, micronucleus test in mice, and the dominant lethal test in mice. {04}
Enoxacin—Enoxacin did not induce point mutations in bacterial cells or mitotic gene conversion in yeast cells, with or without metabolic activation. Enoxacin did not induce sister chromatid exchanges or structural chromosomal aberrations in mammalian cells in vitro , with or without metabolic activation. Also, it did not induce chromosomal aberrations in mice. There was a minimal, dose-related, statistically significant increase in micronuclei at high doses of enoxacin in mice; however, the significance of these findings, in the absence of effects in other test systems, is not established. {16}
Gatifloxacin—Gatifloxacin was not mutagenic in several strains of bacteria used in the Ames test; however, it was mutagenic to Salmonella strain TA102. Gatifloxacin was negative in in vivo oral and intravenous micronucleus tests in mice, oral cytogenetics test in rats, and oral DNA repair test in rats. Gatifloxacin was positive in in vitro gene-mutation assays in Chinese hamster V-79 cells and in vivo cytogenetics assays in Chinese hamster CHL/IU cells.{157}
Levofloxacin—Levofloxacin was not mutagenic in the Ames test, CHO/HGPRT forward mutation assay, mouse micronucleus test, mouse dominant lethal assay, rat unscheduled DNA repair test, or the mouse sister chromatid exchange assay. It was positive in the in vitro chromosomal aberration (CHL cell line) and sister chromatid exchange (CHL/IU cell line) assays. {17}
Lomefloxacin—One in vitro mutagenicity test (CHO/HGPRT assay) was weakly positive at concentrations of 226 mcg per mL (mcg/mL) and higher, and negative at concentrations of less than 226 mcg/mL. Mutagenicity tests were negative in two other in vitro tests (chromosomal aberrations in Chinese hamster ovary cells and in human lymphocytes). Two in vivo mouse micronucleus mutagenicity tests were also negative. {03}
Moxifloxacin—Moxifloxacin was not mutagenic in the Ames Salmonella reversion assay and the CHO/HGPRT mammalian cell gene mutation assay. Moxifloxacin was clastogenic in the V79 chromosome aberration assay, but it did not induce unscheduled DNA synthesis in cultured rat hepatocytes. In vivo micronucleus test or dominant lethal test in mice did not show genotoxicity.{155}
Norfloxacin—Studies in mice have shown that norfloxacin causes no mutagenic effects in the dominant lethal test. Studies in hamsters and rats given doses of 30 to 60 times the usual human dose have shown that norfloxacin causes no chromosomal aberrations. The Ames test, studies in Chinese hamster fibroblasts, and the V79 mammalian cell assay have shown that norfloxacin causes no mutagenic activity in vitro . {09}
Ofloxacin—Ofloxacin was not found to be mutagenic in the Ames test, in in vitro and in vivo cytogenetic assays, in sister chromatid exchange (Chinese hamster and human cell lines) assays, in the unscheduled DNA repair test using human fibroblasts, in the mouse micronucleus assay, or in dominant lethal assays. However, ofloxacin was mutagenic in the unscheduled DNA repair test using rat hepatocytes and in the mouse lymphoma assay. {98}
Sparfloxacin—Although sparfloxacin was not mutagenic in Salmonella typhimurium TA98, TA100, TA1535, or TA1537, in E. coli strain WP2 uvrA, or in Chinese hamster lung cells, it was mutagenic in S. typhimurium TA102, and it induced DNA repair in E. coli . Sparfloxacin induced chromosomal aberrations in Chinese hamster lung cells in vitro at cytotoxic concentrations; however, no increase in chromosomal aberrations or micronuclei in bone marrow cells was observed after sparfloxacin was administered orally to mice. {52}
Pregnancy/Reproduction
Fertility—
Ciprofloxacin
Adequate and well-controlled studies in humans have not been done. Studies in rats and mice given doses of up to six times the usual daily human dose have not shown that ciprofloxacin causes adverse effects on fertility. {04}
Enoxacin
No consistent effects on fertility and reproductive parameters were noted in female rats given oral doses of up to 1000 mg per kg of body weight (mg/kg) of enoxacin. Decreased spermatogenesis and subsequent impaired fertility were noted in male rats given oral doses of 1000 mg/kg. {16}
Gatifloxacin
Gatifloxacin did not adversely affect fertility or reproduction in rats at oral doses up to 200 mg/kg/day (approximately equivalent to the maximum human recommended dose (MHRD) based on systemic exposure).{157}
Levofloxacin
Levofloxacin had no effect on the fertility or reproductive performance of male or female rats at oral doses of up to 360 mg/kg (2124 mg/m 2) per day (corresponding to 18 and 3 times the MRHD based on body weight and body surface area, respectively), or at parenteral doses of up to 100 mg/kg (590 mg/m 2) per day (corresponding to 5 and 1 times the MRHD based on body weight and body surface area, respectively). {17}
Lomefloxacin
The fertility of male and female rats was not affected when lomefloxacin was administered at oral doses of up to eight times the recommended human dose on a mg/m 2 basis, or 34 times the recommended human dose on a mg/kg basis. {03}
Moxifloxacin
Moxifloxacin had not effect on fertility in male and female rats at oral doses up to 500 mg/kg/day (approximately 12 times the MRHD based on body surface area (mg/m2). At 500 mg/kg, it had slight effects on sperm morphology (head-tail separation) in male rats and on the estrous cycle in female rats.{155}
Norfloxacin
Studies in male and female mice given oral doses of up to 30 times the usual human dose have not shown that norfloxacin causes adverse effects on fertility. {09}
Sparfloxacin
Sparfloxacin had no effect on the fertility or reproductive performance of male or female rats at oral doses of up to 15.4 times the MRHD (400 mg) on a mg/m 2 basis. {52}
Pregnancy—
For all fluoroquinolones
Adequate and well-controlled studies in humans have not been done. However, since fluoroquinolones have been shown to cause arthropathy in immature animals of a variety of species, their use is not recommended during pregnancy.
Ciprofloxacin
Ciprofloxacin crosses the placenta {119}.
Studies in rats and mice given doses of up to six times the usual daily human dose have not shown that ciprofloxacin causes adverse effects on the fetus. Studies in rabbits given oral doses of 30 and 100 mg/kg have shown that ciprofloxacin causes gastrointestinal disturbances, resulting in maternal weight loss and an increased incidence of abortion. However, these studies have not shown that ciprofloxacin is teratogenic at either dose. Studies using intravenous doses of up to 20 mg/kg have not shown that ciprofloxacin causes maternal toxicity, embryotoxicity, or teratogenic effects. {04}
FDA Pregnancy Category C {04}.
Enoxacin
Rats and mice given oral enoxacin have shown no evidence of teratogenic potential. Intravenous infusion of enoxacin into pregnant rabbits at doses of 10 to 50 mg/kg caused dose-related maternal toxicity (venous irritation, weight loss, and reduced food intake). At 50 mg/kg, there were increased incidences of postimplantation loss and stunted growth of fetuses. The incidence of fetal malformations also was significantly increased at this dose in the presence of overt maternal and fetal toxicity. {16}
FDA Pregnancy Category C {16}.
Gatifloxacin
Gatifloxacin was not teratogenic in rats or rabbits at oral doses up to 150 and 50 mg/kg, respectively (0.7 and 0.9 times the maximum human recommended dose (MHRD) based on systemic exposure). However, skeletal malformations were observed in rats at an oral dose of 200 mg/kg/day or intravenous dose of 60 mg/kg/day during organogenesis. Fetotoxicity was seen in rat fetuses at oral doses ³ 150 mg/kg or intravenous doses ³ 30 mg/kg daily during organogenesis, and in rats during late pregnancy and throughout lactation at oral doses of 200 mg/kg.{157}
FDA Pregnancy Category C
Levofloxacin
Levofloxacin was not teratogenic in rats at oral doses of up to 810 mg/kg (4779 mg/m 2) per day (corresponding to 82 and 14 times the MRHD based on body weight and body surface area, respectively), or at parenteral doses of up to 160 mg/kg (944 mg/m 2) per day (corresponding to 16 and 2.7 times the MRHD based on body weight and body surface area, respectively). Doses equivalent to 81 and 26 times the MRHD of levofloxacin (based on body weight and body surface area, respectively) caused decreased fetal body weight and increased fetal mortality in rats when administered orally at doses of 810 mg/kg (8910 mg/m 2) per day. No teratogenicity was observed when rabbits were given oral doses of up to 50 mg/kg (550 mg/m 2) per day (corresponding to 5 and 1.6 times the MRHD based on body weight and body surface area, respectively), or parenteral doses of up to 25 mg/kg (275 mg/m 2) per day (corresponding to 2.5 and 0.8 times the MRHD based on body weight and body surface area, respectively). {17}
FDA Pregnancy Category C {17}.
Lomefloxacin
Reproduction studies done in rats given oral doses of up to 34 times the recommended human dose on a mg/kg basis reported no harm to the fetus. An increased incidence of fetal loss in monkeys has been observed at approximately 6 to 12 times the recommended human dose on a mg/kg basis. No teratogenicity has been observed in rats or monkeys at doses of up to 16 times the recommended human dose. In rabbits, maternal toxicity and associated fetal toxicity, decreased placental weight, and variations of the coccygeal vertebrae occurred at doses two times the recommended human dose on a mg/m 2 basis. {03}
FDA Pregnancy Category C {03}.
Moxifloxacin
Moxifloxacin was not teratogenic in pregnant rats during organogenesis at oral doses up to 500 mg/kg/day (0.24 times the MRHD based on systemic exposure). Fetotoxicity such as decreased fetal body weights and slightly delayed fetal skeletal development were observed. There was also an increase in the incidence of rib and vertebral malformations. There was no evidence of teratogenicity when pregnant Cynomolgus monkeys were given oral doses up to 100 mg/kg/day (2.5 times the MRHD based on systemic exposure). There was an increase in incidence of smaller fetuses. At dose of 500 mg/kg/day in rats, slight increase in duration of pregnancy and prenatal loss, reduced pup birth weight, decreased neonatal survival, and treatment-related maternal mortality were observed.{155}
FDA Pregnancy Category C
Norfloxacin
The human umbilical cord serum concentration ranges from undetectable to 0.5 mg per mL (mg/mL) and the amniotic fluid concentration ranges from undetectable to 0.92 mg/mL following the administration of a single 200-mg dose of norfloxacin {64}.
Studies in monkeys given doses of 10 times the MRHD (800 mg daily) have shown that norfloxacin causes embryonic loss. Peak plasma concentrations were two to three times those seen in humans. Studies in cynomolgus monkeys given doses of 150 mg/kg per day or more have shown that norfloxacin is embryocidal and causes slight maternal toxicity (vomiting and anorexia) as well. However, studies in rats, rabbits, mice, and monkeys given doses of 6 to 50 times the usual human dose have not shown that norfloxacin is teratogenic.
FDA Pregnancy Category C {09}.
Ofloxacin
Ofloxacin crosses the placenta. In one small study, umbilical cord serum concentrations reached 80 to 90% of maternal serum concentrations after mothers received 200-mg doses. Ofloxacin was also detected in the amniotic fluid from more than 50% of the mothers {102}. Another small study found that ofloxacin concentrated in the amniotic fluid, reaching up to 35 to 257% of the simultaneous maternal serum concentration {119}.
Studies in rats and rabbits given doses of up to 810 and 160 mg/kg per day, respectively, have not shown ofloxacin to be teratogenic. Studies in rats given doses of up to 360 mg/kg per day showed no adverse effect on late fetal development, labor, delivery, lactation, neonatal viability, or growth of the newborn. Doses equivalent to 50 and 10 times the MRHD were fetotoxic in rats (decreased fetal body weight) and rabbits (increased fetal mortality), respectively. Rats given 810 mg/kg per day, greater than 10 times the MRHD, were reported to produce offspring with minor skeletal variations. {98}
FDA Pregnancy Category C {98}.
Sparfloxacin
Reproduction studies performed in rats, rabbits, and monkeys at oral doses of 6.2, 4.4, and 2.6 times the MRHD (on a mg/m 2 basis), respectively, did not show evidence of teratogenic effects. At these doses, sparfloxacin produced clear evidence of maternal toxicity in rabbits and in monkeys, and slight evidence of maternal toxicity in rats. When administered to pregnant rats at clearly defined maternally toxic doses, sparfloxacin induced a dose-dependent increase in the incidence of ventricular septal defects in fetuses. Among the three species tested, this effect was specific to the rat. {52}
FDA Pregnancy Category C {52}.
Breast-feeding
Ciprofloxacin, ofloxacin, and sparfloxacin are known to be distributed into human breast milk {04} {52} {98}. The concentration of ofloxacin in breast milk is similar to that found in plasma {98} {102}. One small study found that ofloxacin was highly concentrated in breast milk, reaching 98% of the simultaneous maternal serum level within 2 hours of administration {119}. It is not known whether enoxacin, gatifloxacin, levofloxacin, lomefloxacin, moxifloxacin, or norfloxacin is distributed into breast milk. However, based on data for ofloxacin, it is expected that levofloxacin is distributed into breast milk {17}{155}{157}. Norfloxacin was not detected in breast milk following its administration in low (200-mg) doses to nursing mothers. However, other quinolone derivatives are distributed into human breast milk {03} {09} {16}. Therefore, if an alternative antibiotic cannot be prescribed and a fluoroquinolone must be administered, breast-feeding is not recommended {98} {119}.
In immature animals, fluoroquinolones have been shown to cause permanent lesions of the cartilage of weight-bearing joints, as well as other signs of arthropathy. {98} {119} Moxifloxacin is distributed in the breast milk of lactating rats.{164}
Pediatrics
For all fluoroquinolones:
With the exception of ciprofloxacin when used post-exposure for inhalational anthrax,{159}{160} fluoroquinolones currently are not recommended for use in infants and children. Patients younger than 18 years of age usually have not been included in clinical trials because fluoroquinolones caused lameness in immature dogs due to permanent lesions of the cartilage of weight-bearing joints. Fluoroquinolones and other related quinolones have been reported to cause arthropathy in immature animals of various species; the effects vary with animal species and with quinolone dose and develop within days to weeks of the start of quinolone treatment. The mechanism by which quinolones produce this cartilage damage is unknown. {03} {04} {09} {16} {22} {98}{155}{157}
Fluoroquinolones have been used in neonates, infants, and children with serious infections that have not responded to other therapeutic regimens, or infections caused by multiple organisms resistant to other antibiotics {20} {21} {22}. More than 2500 pediatric patients to date, most of whom have cystic fibrosis, a disease that has a significant background prevalence of arthralgia and arthritis {38}, are reported to have undergone treatment with ciprofloxacin {21} {22} {54} {56} {57} {62}. The reported rate of musculoskeletal adverse events following ciprofloxacin administration in clinical trials was similar to that seen with placebo {22} {23} {28} {29} {65}, and only 1 to 2% of these events were considered to be possibly or probably due to ciprofloxacin. Arthropathy was reversible in almost all of these patients without additional treatment or fluoroquinolone discontinuation. Additional studies in pediatric patients with multidrug-resistant typhoid fever also documented no evidence of acute or subclinical joint toxicity or of diminished height velocity over a 2-year follow-up period {153}. Furthermore, postmortem examination of knee cartilage was normal in two juvenile patients who received oral ciprofloxacin for 9 to 10 months (and subsequently died secondary to complications of cystic fibrosis) {53}. There are case reports that document the reversibility of arthropathy only after discontinuation of ciprofloxacin {45} {46}. However, there has not been one report of irreversible damage to cartilage in a pediatric patient treated with fluoroquinolones {154}.
In 1993, the International Society of Chemotherapy commission developed guidelines for use of fluoroquinolones in the pediatric population based on a review of international experience. The commission does not promote the use of fluoroquinolones in children; when effective and nonrestricted alternative therapies are available for infections in pediatric patients, these therapies should be used. However, the commission also stated that critical and cautious use of fluoroquinolone antibiotics in pediatric patients suffering from specific infections complicated by pathologic or special conditions is justified by experimental and clinical data when alternative safe therapy is not available. The recommendations conclude that the risks and benefits of fluoroquinolone use should be assessed and a determination made on an individual basis for each compassionate use. {54}
Adolescents
For all fluoroquinolones
With the exception of ciprofloxacin when used post-exposure for inhalational anthrax,{159}{160} fluoroquinolones currently are not recommended for use in adolescents. Patients younger than 18 years of age usually have not been included in clinical trials because fluoroquinolones caused lameness in immature dogs due to permanent lesions of the cartilage of weight-bearing joints. One clinical report of 1219 adolescent patients (74 of whom had cystic fibrosis) who received ciprofloxacin at least once did not reveal any cases of newly diagnosed acute arthritis or joint toxicity that were likely to have been caused by the medication {61}. In general, arthralgias have been reported primarily in adolescent females who received fluoroquinolones; these arthralgias were not severe, were transient, and disappeared with either a dosage reduction or discontinuation of the medication {154}.
See also Pediatrics .
Geriatrics
For all fluoroquinolones:
Studies performed to date have not demonstrated geriatrics-specific problems that would limit the usefulness of fluoroquinolones in the elderly. However, tendinitis or tendon rupture, central nervous system (CNS) effects (e.g., hallucinations), and other side effects may occur more frequently in the elderly. Elderly patients also are more likely to have an age-related decrease in renal function, which may require an adjustment of dosage in patients receiving any of these medications. {08} {30} {61} {64} {67}{155}{157}
In geriatric intravenous moxifloxacin trials in community acquired pneumonia, the following ECG abnormalities were reported: ST-T wave changes, QT prolongation, ventricular tachycardia, atrial flutter, atrial fibrillation, supraventricular tachycardia, ventricular extrasystoles, and arrhythmia. None of these abnormalities was associated with a fatal outcome and a majority of these patients completed a full-course of therapy. {164}
Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):
Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.
Alkalizers, urinary, such as:
Carbonic anhydrase inhibitors
Citrates
Sodium bicarbonate (urinary alkalizers may reduce the solubility of ciprofloxacin or norfloxacin in the urine; patients should be observed for signs of crystalluria and nephrotoxicity, although the incidence is rare {12} {13} {14} {86})
» Aminophylline or
» Oxtriphylline or
» Theophylline (concurrent use of aminophylline, oxtriphylline, or theophylline with ciprofloxacin or enoxacin significantly reduces the hepatic metabolism and clearance of theophylline, probably by competitive inhibition at its binding sites within the cytochrome P450 enzyme system; this may result in a prolonged theophylline elimination half-life, increased serum concentration, and increased risk of theophylline-related toxicity; enoxacin has the greatest effect on theophylline clearance and it is recommended that the dose of theophylline be decreased by 50% during concurrent use; ciprofloxacin may also increase the risk of toxicity, especially in patients with theophylline concentrations at the upper end of the therapeutic range; serum theophylline concentrations should be monitored and dosage adjustments may be required; norfloxacin and ofloxacin have a minor effect on theophylline clearance; one study with ofloxacin found an increase of approximately 10% in the theophylline serum concentration; however, other studies have found that ofloxacin has a negligible effect on theophylline metabolism; theophylline dosage adjustment is usually not necessary in patients receiving norfloxacin or ofloxacin; theophylline clearance has not been found to be significantly altered by gatifloxacin, levofloxacin, lomefloxacin, or moxifloxacin {03} {04} {16} {17} {71} {98} {127} {128} {129} {135} {147}{155}{157})
» Amiodarone or
» Antidepressants, tricyclic or
» Astemizole or
» Bepredil or
» Cisapride or
» Disopyramide or
» Erythromycin or
» Pentamidine or
» Phenothiazines or
» Procainamide or
» Quinidine or
» Sotalol or
» Terfenadine or
» Other medications reported to prolong the QTc interval (concurrent use of sparfloxacin with amiodarone and disopyramide has resulted in torsades de pointes; concurrent use of sparfloxacin with any medication reported to prolong the QTc interval or to produce torsades de pointes is contraindicated {52}; concurrent use of gatifloxacin, levofloxacin {163} and moxifloxacin with class IA (e.g., quinidine, procainamide) or class III (e.g., amiodarone, sotalol) antiarrhythmic agents should be avoided.{155}{157})
» Antacids, aluminum, calcium, and/or magnesium-containing or
» Ferrous sulfate or
Laxatives, magnesium-containing or
» Sucralfate or
Zinc (antacids, ferrous sulfate, zinc, or sucralfate may reduce the absorption of fluoroquinolones by chelation, resulting in lower serum and urine concentrations; therefore, concurrent use is not recommended; because the bioavailability of enoxacin is decreased the most by concurrent administration of these medications, it is recommended that enoxacin be taken at least 2 hours before or 8 hours after taking any of these medications; ciprofloxacin should be taken at least 2 hours before or 6 hours after taking any of these medications; gatifloxacin should be taken 4 hours before taking iron, magnesium-containing antacids, and zinc; lomefloxacin should be taken at least 2 hours before or 4 hours after taking any of these medications; levofloxacin, norfloxacin, or ofloxacin should be taken at least 2 hours before or 2 hours after taking any of these medications; moxifloxacin should be taken at least 4 hours before and 8 hours after taking any of these medications; and sparfloxacin should be taken at least 4 hours before or 4 hours after taking any of these medications {03} {04} {09} {16} {17} {51} {98} {102} {147}{155}{157})
Anticonvulsants, hydantoin, especially:
» Phenytoin (concurrent administration of ciprofloxacin with phenytoin has resulted in a 34 to 80% decrease in the plasma concentration of phenytoin; caution should be used when administering quinolones, especially ciprofloxacin, to patients stabilized on phenytoin; careful monitoring of phenytoin dosage after discontinuation of quinolones is highly recommended {04} {122} {123} {124})
Antidiabetic agents, sulfonylurea, especially:
Glyburide or
Insulin (concurrent use of ciprofloxacin, or levofloxacin with glyburide or other antidiabetic agents has, on rare occasions, resulted in hypoglycemia; also, hyperglycemia and hypoglycemia have been reported in patients taking quinolone antibiotics and antidiabetic agents concurrently; since the mechanism is not understood, similar effects with other sulfonylurea antidiabetic agents may be expected when these medications are used with fluoroquinolones; careful monitoring of blood glucose concentrations is recommended when these medications are used concurrently; concurrent administration of moxifloxacin and glyburide did not result in clinically significant interaction {04} {17} {98}{155}{157})
Anti-inflammatory drugs, nonsteroidal (NSAIDs) (fluoroquinolones, particularly enoxacin and norfloxacin, are competitive inhibitors of gamma-aminobutyric acid receptor binding, and some NSAIDs have been shown to enhance this effect; seizures have been reported in patients taking enoxacin and fenbufen concurrently; concurrent administration of NSAIDs with quinolone antibiotics may increase the risks of CNS stimulation and convulsions {16} {48} {58} {147}{155})
Bismuth (the bioavailability of enoxacin is decreased by approximately 25% when bismuth subsalicylate is administered concurrently or within 60 minutes of enoxacin administration; concurrent administration of these medications is not recommended {16})
» Caffeine or
Theobromine (concurrent use of caffeine with enoxacin has been found to decrease the hepatic metabolism of caffeine, resulting in a dose-related increase in the half-life of caffeine of up to five times normal; ciprofloxacin and, to a lesser extent, norfloxacin also reduce the hepatic metabolism and clearance of caffeine, increasing its half-life and the risk of caffeine-related CNS stimulation; lomefloxacin and ofloxacin do not produce any significant change in caffeine metabolism {03} {04} {16} {29} {98})
Cyclosporine (concurrent use with ciprofloxacin or norfloxacin has been reported to elevate serum creatinine and serum cyclosporine concentrations; other studies have not found ciprofloxacin, enoxacin, or levofloxacin to alter the pharmacokinetics of cyclosporine; cyclosporine concentrations should be monitored when used concurrently with fluoroquinolones, and dosage adjustments may be required {03} {04} {09} {17} {39})
» Didanosine (concurrent use of didanosine with ciprofloxacin, norfloxacin, or ofloxacin has been shown to reduce the absorption of these fluoroquinolones due to chelation of the fluoroquinolone by the aluminum and magnesium buffers in didanosine; didanosine should not be administered concurrently with any fluoroquinolone; also, didanosine should not be taken within within 2 hours before or 2 hours after taking norfloxacin or ofloxacin; gatifloxacin should be taken 4 hours before didanosine; moxifloxacin should be taken at least 4 hours before and 8 hours after taking didanosine {09} {75} {98}{155}{157})
Digoxin (enoxacin may raise serum digoxin concentrations in some patients; digoxin serum concentrations should be monitored; gatifloxacin and moxifloxacin did not have any clinically significant interaction with digoxin {16}{155}{157})
Probenecid (concurrent use of probenecid decreases the renal tubular secretion of fluoroquinolones, resulting in decreased urinary excretion of the fluoroquinolone, prolonged elimination half-life, and increased risk of toxicity; this interaction is more significant with gatifloxacin and ofloxacin, which is excreted largely unchanged in the urine, and of less clinical significance with fluoroquinolones that have larger nonrenal elimination, such as ciprofloxacin and enoxacin; moxifloxacin did not have any clinically significant interaction with probenecid {03} {04} {147}{155}{157})
» Warfarin (concurrent use of warfarin with ciprofloxacin or norfloxacin has been reported to increase the anticoagulant effect of warfarin, increasing the chance of bleeding; other studies have not found fluoroquinolones to alter the prothrombin time [PT] significantly; enoxacin decreases the clearance of R-warfarin, the less active isomer of racemic warfarin, but not the active S-isomer; changes in clotting time have not been observed when enoxacin, gatifloxacin, levofloxacin, or moxifloxacin is administered concurrently with warfarin; however, it is recommended that the PT of patients receiving warfarin and fluoroquinolones concurrently be monitored carefully {02} {03} {04} {09} {16} {17} {126}{155})
Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):
With diagnostic test results
Mycobacterium tuberculosis culture (sparfloxacin may produce a false-negative culture result for M. tuberculosis by suppressing mycobacterial growth {52})
With physiology/laboratory test values
Alanine aminotransferase (ALT [SGPT]) and
Alkaline phosphatase and
Amylase and
Aspartate aminotransferase (AST [SGOT]) and
Lactate dehydrogenase (LDH) (serum values may be increased {03} {04} {16} {58} {98}{155})
Electrocardiogram (moxifloxacin may prolong QT interval {164})
Prothrombin time {163} (International Normalized Ratio (INR) values may be increased with levofloxacin {163})
Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).
Except under special circumstances, this medication should not be used when the following medical problems exist:
» Previous allergic reaction or hypersensitivity to fluoroquinolones or other chemically related quinolone derivatives {04} {98}
» Photosensitivity, history of (moderate to severe phototoxic reactions have occurred in patients exposed to direct or indirect sunlight or to artificial ultraviolet light during or following sparfloxacin treatment; these reactions also have occurred in patients exposed to shaded or diffuse light, including exposure through glass or during cloudy weather; sparfloxacin is contraindicated in patients with a history of photosensitivity or those whose lifestyle or employment will not permit compliance with the required safety precautions {52})
(moderate to severe phototoxic reactions also have occurred in patients exposed to direct sunlight during or following treatment with enoxacin, levofloxacin, norfloxacin, or ofloxacin; treatment with these fluoroquinolones should be discontinued if phototoxic reactions occur {09} {16} {17} {98})
(gatifloxacin and moxifloxacin does not show phototoxicity when compared to placebo, however patients should avoid exposure to excessive sunlight or artificial ultraviolet light (e.g. tanning beds){155}{157})
» QTc-interval prolongation (prolongation of the QTc interval has been observed in healthy volunteers receiving sparfloxacin or moxifloxacin; sparfloxacin is contraindicatedand moxifloxacin is not recommended in patients with known QTc-interval prolongation {52}{164})
» Tendinitis or tendon rupture, history of (fluoroquinolones have been reported to cause tendinitis or tendon rupture during or after treatment; enoxacin is contraindicated in patients with a history of tendinitis or tendon rupture; other fluoroquinolones are not recommended for patients with these problems {19}{155}{157})
Risk-benefit should be considered when the following medical problems exist
» Bradycardia, significant{163} (levofloxacin may cause cardiac arrhythmias and prolongation of the QT interval in the presence of significant bradycardia; moxifloxacin should be used with caution{164}{163})
CNS disorders, including:
» Cerebral arteriosclerosis or
» Epilepsy or
» Other factors that predispose to seizures (fluoroquinolones may cause CNS stimulation or toxicity; convulsions may occur within 3 to 4 days after the start of fluoroquinolone treatment and usually resolve with discontinuation of the fluoroquinolone; fluoroquinolones should be used with caution in patients with confirmed or suspected CNS disorders {67} {84}{155}{157})
Diabetes mellitus (levofloxacin has been reported to cause hyperglycemia and hypoglycemia, usually in diabetic patients who are taking oral hypoglycemic agents or insulin; diabetic patients should be monitored carefully {17})
Hepatic function impairment (patients with severe hepatic function impairment, such as cirrhosis with ascites, may have decreased clearance of ofloxacin, resulting in an increase in peak serum concentration and elimination half-life; patients with both hepatic and renal function impairment may require a reduction in the dosage of ciprofloxacin; cirrhosis has not been found to decrease the nonrenal clearance of lomefloxacin {03} {04} {98} {105})
» Hypokalemia, uncorrected (gatifloxacin , levofloxacin {163}and moxifloxacin may worsen QT prolongation in patients with uncorrected hypokalemia resulting in ventricular arrhythmias)
{155}
Myocardial ischemia, acute (moxifloxacin should be used with caution{164})
» Proarrhythmias (gatifloxacin, moxifloxacin, and sparfloxacin is not recommended for use in patients with ongoing proarrhythmias or cardiovascular conditions predisposing the patient to proarrhythmic conditions, including atrial fibrillation, congestive heart failure, hypokalemia, myocardial infarction, and significant bradycardia {52}{155}{157})
» Renal function impairment (in general, fluoroquinolones primarily are excreted renally; it is recommended that patients with impaired renal function be administered reduced doses of fluoroquinolones {03} {04} {16} {98}{157})
Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):
Digoxin toxicity signs and symptoms (gatifloxacin may increase digoxin serum concentrations, which should be determined in patients who showed signs of digoxin toxicity{157})
» Electrocardiogram (ECG) (patients who are being treated concurrently with sparfloxacin or moxifloxacin and medications known to produce an increase in the QTc interval and/or torsades de pointes should receive appropriate cardiac monitoring {52}{164})
Prothrombin time (PT) (the PT of patients concurrently receiving fluoroquinolones and warfarin should be monitored closely )
{155}
Side/Adverse Effects
Note: The relative insolubility of ciprofloxacin and norfloxacin at an alkaline pH has resulted in crystalluria, usually when the urinary pH exceeds 7. Because normal urinary pH is acidic, approximately 5 to 6, crystalluria is very unlikely to occur unless the patient's urine has become alkalinized. {09} {12} {27} {86}
Seizures have been reported very rarely with ciprofloxacin therapy; however, the patients who did have seizures either had a previous seizure history, were alcoholic, or were taking ciprofloxacin concurrently with theophylline. {24} {27}
Prolongation of the QTc interval was observed in healthy volunteers receiving sparfloxacin and in some moxifloxacin patients.{52}{155} The magnitude of QT prolongation may increase with increasing concentrations of moxifloxacin or increasing rates of intravenous infusion of moxifloxacin. QT prolongation may lead to an increased risk for ventricular arrhythmias including torsade de pointes.{164}
Phototoxic reactions have occurred in patients exposed to direct or indirect sunlight, or to artificial ultraviolet light, during or following sparfloxacin treatment; these reactions also have occurred in patients exposed to shaded or diffuse light, including exposure through glass or during cloudy weather. Phototoxic reactions have occurred with and without the use of sunscreens or sunblocks and have occurred after a single dose of sparfloxacin. Patients should avoid exposure to direct or indirect sunlight or artificial UV light during treatment and for 5 days following sparfloxacin treatment. Patients should discontinue sparfloxacin at the first sign or symptom of phototoxicity. Sparfloxacin is contraindicated in patients with a history of photosensitivity or those whose lifestyle or employment will not permit compliance with the required safety precautions. Patients who experience sparfloxacin-induced photosensitivity or phototoxicity should be treated within 2 weeks of the onset of symptoms to prevent development of lichenoid tissue reaction. {52} {67} {145}
Achilles tendinitis and tendon rupture have been reported in patients receiving fluoroquinolones {25}{72}. The ruptures occurred 2 to 42 days after the start of therapy. Concomitant use of corticosteroids with fluoroquinolones may increase the risk of tendon disorders or ruptures {67}. These injuries may require surgical repair or result in prolonged disability. It is recommended that fluoroquinolone treatment be discontinued at the first sign of tendon pain or inflammation, and that patients refrain from exercising until the diagnosis of tendinitis has been excluded {03} {04} {09} {16} {98} {72}.{155} {157}
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
Those indicating need for medical attention
Incidence more frequent
QTc-interval prolongation {52}{164}(irregular or slow heart rate; recurrent fainting)—for sparfloxacin and less frequent for moxifloxacin{164}
Incidence less frequent
Chest pain{164}
hypertension{164} (blurred vision; dizziness; nervousness; headache; pounding in the ears; slow or fast heartbeat )
peripheral edema{164} (bloating or swelling of face, arms, hands, lower legs, or feet; rapid weight gain; tingling of hands or feet; unusual weight gain or loss)
phototoxicity {52}(blisters; sensation of skin burning; skin itching, rash, or redness; swelling )—more frequent for lomefloxacin and sparfloxacin
Incidence rare
Note: Frequency of incidence with moxifloxacin varies between ³ 0.1% and £ 3%
Amnesia{164} (loss of memory; problems with memory)
aphasia{164} ( problems with speech or speaking)
Arthralgia {155}{164}( joint pain)
asthenia{164} (lack or loss of strength)
asthma{164} (cough; difficulty breathing; noisy breathing; shortness of breath; tightness in chest; wheezing)
atrial fibrillation{164} (fast or irregular heartbeat; dizziness; fainting)
CNS stimulation {67}{121}{155}(acute psychosis; agitation; confusion; hallucinations; tremors)
cardiovascular reactions such as palpitation {164}(fast or irregular heartbeat), vasodilation {164}(dizziness; faintness; feeling of warmth or heat; flushing or redness of skin especially on face and neck; headache; light-headedness ; sweating; weakness), or tachycardia ( fainting; fast, pounding, or irregular heartbeat or pulse ){155}{157}{164}
convulsions{164} (seizures)
depersonalization{164} (feeling of unreality; sense of detachment from self or body.)
dysphagia{164} (difficulty swallowing)
dyspnea{164} (shortness of breath; difficult or labored breathing; tightness in chest; wheezing)
electrocardiogram (ECG), abnormal{164}
eosinophilia{164}
leukopenia{164} (black, tarry stools; chest pain; chills; cough; fever; painful or difficult urination; shortness of breath; sore throat; sores, ulcers, or white spots on lips or in mouth)
face edema{164} (swelling or puffiness of face)
glossitis{164} (redness, swelling, or soreness of tongue)
hematuria {157}(blood in the urine)
hepatotoxicity {19}{67}{40}{155}(dark or amber urine; loss of appetite; pale stools; stomach pain; unusual tiredness or weakness ; yellow eyes or skin)
hyperglycemia{164} (abdominal pain; blurred vision; dry mouth; fatigue; flushed, dry skin; fruit-like breath odor; increased hunger; increased thirst; increased urination; nausea; sweating; troubled breathing; unexplained weight loss; vomiting)
hyperlipidemia{164} (large amount of fat in the blood)
hypertonia{164} (excessive muscle tone; muscle tension or tightness; muscle stiffness )
hyperuricemia{164} (joint pain, stiffness, or swelling; lower back, side, or stomach pain; swelling of feet or lower legs)
hypesthesia{164} (burning, crawling, itching, numbness, prickling, "pins and needles" , or tingling feelings)
injection site reaction{164} (bleeding; blistering; burning; coldness; discoloration of skin; feeling of pressure; hives; infection; inflammation; itching; lumps; numbness; pain; rash; redness; scarring; soreness; stinging; swelling; tenderness; tingling; ulceration; warmth)
hypersensitivity reactions {67}{125}{155}( skin rash, itching, or redness; shortness of breath; swelling of face or neck; vasculitis)
hypotension{164} (blurred vision; confusion; dizziness, faintness, or lightheadedness when getting up from a lying or sitting position suddenly; sweating; unusual tiredness or weakness)
incoordination{164}
interstitial nephritis {41}{42}{43}{44}{67}(bloody or cloudy urine; fever; skin rash; swelling of feet or lower legs)
jaundice{164} (chills; clay-colored stools; dark urine; dizziness; fever; headache; itching; loss of appetite; nausea; abdominal or stomach pain; area rash; unpleasant breath odor; unusual tiredness or weakness; vomiting of blood; yellow eyes or skin)
maculopapular rash{164} (rash with flat lesions or small raised lesions on the skin)
phlebitis {05}{132}( pain at site of injection)—for intravenous ciprofloxacin and ofloxacin; occurred in 5% of patients receiving intravenous gatifloxacin{157}
pseudomembranous colitis ( abdominal or stomach cramps and pain, severe; abdominal tenderness; diarrhea, watery and severe, which may also be bloody; fever)
Stevens-Johnson Syndrome {163}(blistering, itching, loosening, peeling, or redness of skin; diarrhea, )
stomatitis {164}(swelling or inflammation of the mouth)
superventricular tachycardia{164}
{164}
vertricular tachycardia{164} (fainting; fast, pounding, or irregular heartbeat or pulse; palpitations )
thrombocythemia{164} (pain, warmth, or burning i