Drug Criteria & Outcomes-Gatifloxacin (Tequin): Observations on its use

By Claire Merinar, PharmD

Pharmacy Practice Resident

Medical University of South Carolina

Charleston, SC

o Indications: Gatifloxacin, manufactured by Bristol-Myers Squibb Co., is indicated for the treatment of adults (over 18 years of age) with infections caused by certain susceptible microorgan- isms in certain conditions (see table I, below).1

Table I: Indications for Gatifloxacin
Condition Bacterial Organisms
Acute bacterial exacerbation of chronic bronchitis S. pneumonia, H. influenzae, H. parainfluenzae, M. catarrhalis, S. aureus
Acute sinusitis S. pneumoniae, H. influenzae
Community-acquired pneumonia S. pneumoniae, H. influenzae, H. parainfluenzae, M. catarrhalis, S. aureus, M. pneumoniae, C. pneumoniae, L. pneumophila
Uncomplicated urinary tract infections E. coli, K. pneumoniae, P. mirabilis
Complicated urinary tract infections E. coli, K. pneumoniae, P. mirabilis
Pyleonephritis E. coli
Uncomplicated urethral and cervical gonorrhea N. gonorrhea
Acute, uncomplicated rectal gonorrhea (women only) N. gonorrhea


oPharmacology:Gatifloxacin is a synthetic 8-methoxy fluoroquinolone, which is a member of the newer fluoroquinolones. These are distinguished by their enhanced spectrum of activity, including activity against gram-positive bacteria, gram-negative bacteria, anaerobes, and atypical pathogens. All fluoroquinolones act by inhibiting the activity of DNA gyrase, which inhibits bacterial DNA replication and transcription and results in cell death. However, the newer fluoroquinolones, including gatifloxacin, also have been shown to inhibit topoisomerase IV, resulting in increased gram-positive spectrum activity.2

o Pharmacokinetics: Gatifloxacin is well-absorbed and achieves steady-state plasma levels after approximately three days of therapy. Gatifloxacin is dosed once daily. Peak and trough concentrations were consistent with both oral and intravenous routes of administration and can be considered interchangeable. Patients receiving 400 mg of oral gatifloxacin once daily achieved approximate peaks of 4.2 g/mL and troughs of 0.4 g/mL; intravenous administration of 400 mg of gatifloxacin once daily resulted in peaks of approximately 4.2 g/mL and troughs of 0.4 g/mL. The elimination half-life of gatifloxacin ranges from seven to 14 hours, and the volume of distribution for gatifloxacin is approximately 1.5-2.0 L/kg.

Gatifloxacin also exhibits 20% binding to serum proteins. Gatifloxacin undergoes limited metabolism (< 1%) in humans, and it is not metabolized by the cytochrome P450 enzyme system. It is therefore unlikely to interact with other medications that may influence the P450 system. Elimin-ation by the kidney accounts for about 70% of elimination; therefore, dosage should be adjusted in renal dysfunction (see dosage details, p. 3). About 5% is eliminated by the biliary route.1,3

o Microbiology: Gatifloxacin has shown to be active against most strains of the following organisms:1-2

Aerobic gram-positive organisms

Staphylococcus aureus (methicillin-susceptible strains only)

Streptococcus pneumoniae (penicillin-susceptible strains)

Aerobic gram-negative organisms

Escherichia coli

Haemophilus influenzae

Haemophilus parainfluenzae

Klebsiella pneumoniae

Moraxella catarrhalis

Neisseria gonorrhoeae

Proteus mirabilis

Other microorganisms

Chlamydia pneumoniae

Legionella pneumophila

Mycoplasma pneumoniae

Against Enterobacteriaceae species, gatifloxacin is approximately twofold less active than ciprofloxacin. Against gram-positive organisms, gatifloxacin exhibits two- to fourfold more activity than ciprofloxacin. Methicillin-resistant staphylococcus also is resistant to gatifloxacin. Gatifloxacin has only moderate activity against anaerobic organisms. Because of its large volume of distribution and its intracellular penetration, gatifloxacin is active against intracellular and extracellular pathogens.1-2 Gatifloxacin exhibits a post-antibiotic-effect against S. pneumoniae, S. aureus, E. faecalis, E. coli, and P. aeruginosa. Resistance to gatifloxacin is chromosomally mediated, and there may be cross-resistance with other fluoroquinolones.4

The minimum inhibitory concentration (MIC) breakpoints for gatifloxacin as established and approved by the National Committee on Clinical Laboratory Standards (NCCLS) are in table II (tables II-IV are inserted in this issue).1

o Selected clinical trials:

Acute bacterial exacerbation of chronic bronchitis: Ramirez et al. conducted a double-blind, randomized, multicenter trial comparing the safety and efficacy of oral gatifloxacin 400 mg administered once daily, oral cefuroxime axetil 250 mg twice daily, or levofloxacin 500 mg once daily in the treatment of acute bacterial exacerbation of chronic bronchitis. A total of 924 patients were enrolled and treated for seven to 10 days.

Bacterial eradication and clinical cure were the primary endpoints of this trial. Bacterial eradication was defined as absence of the original pathogen in a post-treatment sputum culture. Bacterial eradication rates were considered similar for gatifloxacin (93%), levofloxacin (94%), and cefuroxime (77%). Clinical cure rates were equivalent between gatifloxacin (91%) and comparative (88%) groups. There were no clinically significant differences in adverse side effects; diarrhea was the most common, reported in 4% of patients taking gatifloxacin vs. 7% for levofloxacin or cefuroxime. This study suggests gatifloxacin at a dose of 400 mg once daily may be safe and effective for acute exacerbation of chronic bronchitis.5

Acute sinusitis: Gatifloxacin 400 mg once daily for 10 days was compared to clarithromycin 500 mg twice daily for 14 days in a randomized, double-blind, multicenter study of 421 adult patients. The primary outcome of this trial was clinical cure, which was defined as an improvement or resolution of three signs and symptoms of acute infection (purulent discharge, sinus pain, and sinus tenderness). The treatment group results were not statistically different with 90% of patients taking gatifloxacin and 90% of patients treated with clarithromycin responding. Most adverse drug reactions were mild and did not require additional treatment. The most common side effects were nausea (gatifloxacin 13%, clarithromycin 11%) and diarrhea (gatifloxacin 5%, clarithromycin 9%). The data support the use of gatifloxacin in patients with acute sinusitis.6

Community-acquired pneumonia: Sullivan et al. conducted a randomized, double-blind, multicenter trial in 418 patients comparing gatifloxacin 400 mg once daily and levofloxacin 400 mg once daily. Clinical cure rate was the primary endpoint, and bacteriologic eradication was the secondary outcome. Clinical cure was defined as resolution or improvement of all signs and symptoms to a level that no further antimicrobial therapy was needed and an improved or stable chest X-ray. Clinical cure rates were 96% for gatifloxacin and 94% for levofloxacin.

Bacteriologic response was defined as eradication of the original pathogen from an adequate sputum sample. Bacterial cure rates were 98% for gatifloxacin and 93% for levofloxacin. The authors did not report a statistically significant difference between treatment groups. Drug-related adverse effects occurred in 28% of gatifloxacin-treated patients and 32% of levofloxacin-treated patients. The most common side effects were nausea, diarrhea, and insomnia, all of which occurred more frequently in patients treated with levofloxacin. This study demonstrates the effective use of gatifloxacin in community-acquired pneumonia.7

Uncomplicated urinary tract infections: Gatifloxacin 400 mg as a single dose was compared to gatifloxacin 200 mg twice daily for three days, or ciprofloxacin 100 mg twice daily for three days. This randomized, double-blind, multicenter trial enrolled 1,323 women. This information is available from data on file with Bristol-Myers Squibb and has not been published. The primary endpoints of this study were clinical cure and microbiologic eradication.

Clinical cure rates were 93% for gatifloxacin (400 mg once daily), 95% for gatifloxacin (200 mg twice daily), and 93% for ciprofloxacin. Bacterial eradication rates were 90% for gatifloxacin 400 mg, 88% for gatifloxacin 200 mg, and 92% for ciprofloxacin. Neither clinical cure nor microbiological cure rates were statistically significant. Adverse reactions were similar for all three treatment groups, with the most common side effects being nausea, vomiting, diarrhea, headache, and dizziness. This study suggests that gatifloxacin may be useful in the treatment of uncomplicated urinary tract infections.8

Uncomplicated urethral and cervical gonorrhea: A double-blind, randomized trial was conducted with 728 male and female patients having uncomplicated gonorrhea. Patients received either a one-time dose of gatifloxacin 400 mg, gatifloxacin 600 mg, or ofloxacin 400 mg. This information is taken from data on file at Bristol-Myers Squibb and has been presented in abstract form. Bacteriologic eradication rates and clinical cure rates were the primary efficacy endpoints for this study. There were no statistically significant differences between treatment groups for either clinical or bacteriologic cure rates. Adverse drug effects were similar in all three groups and included nausea, vomiting, headache, and diarrhea. The study supports the use of gatifloxacin in the treatment of uncomplicated gonorrhea.9

o Adverse reactions: Among patients receiving gatifloxacin, 2.9% discontinued due to adverse drug reactions. The most common adverse effects reported during clinical trials included nausea (8%), vaginitis (6%), diarrhea (4%), headache (3%), and dizziness (3%). Additional adverse events that occurred in 0.1% to 3% of study populations included allergic reaction, chills, fever, back pain, chest pain, palpitation, abdominal pain, constipation, mouth ulcer, vomiting, peripheral edema, rash, sweating, hematuria, taste alterations, abnormal vision, tinnitus, dyspnea, and pharyngitis.1,10

o Pregnancy/lactation: Gatifloxacin is classified as pregnancy category C, which means studies in animals have revealed adverse effects on the fetus but there are no controlled studies in women. Therefore, gatifloxacin should be used only if the benefits to the patient outweigh the risks to the fetus. There are currently no data available on whether gatifloxacin is excreted into human milk, but it has been shown to be excreted in the breast milk of rats. Therefore, gatifloxacin is not recommended for use in lactating women.1,2

o Contraindications: Gatifloxacin is contraindicated in patients with a history of hypersensitivity to gatifloxacin, any of the alternative fluoroquinolones products, or any other components of the product.

o Warnings: The safety and efficacy of gatifloxacin has not been established in pediatric patients less than 18 years of age or in pregnant or lactating women.1 Quinolones, including gatifloxacin, can stimulate the central nervous system and may cause side effects such as confusion, hallucinations, restlessness, insomnia, and paranoia. Gatifloxacin also should be used with caution in patients who have a seizure history.1 Phototoxicity is another common side effect of the fluoroquinolones.

Gatifloxacin has been shown to have equivalent or less phototoxic potential than ciprofloxacin.1,11 Prolongation of the QT interval also has been associated with gatifloxacin. The manufacturers recommend that gatifloxacin be avoided in patients with a known prolonged QT interval, uncorrected hypokalemia, in combination with other agents that prolong the QT interval, or with class IA or class III antiarrhythmic agents.1

Pseudomembranous colitis has been reported with gatifloxacin. Treatment with gatifloxacin may disrupt the patients natural intestinal flora, resulting in overgrowth of clostridia, which produces a diarrhea-inducing toxin. Gatifloxacin should be discontinued in patients who develop antibiotic-associated pseudomembranous colitis.1

Tendon rupture also has been associated with gatifloxacin. If this occurs, gatifloxacin should be discontinued.1,2 Stevens-Johnson syndrome and toxic epidermal necrolysis have occurred in patients treated with gatifloxacin, and it is therefore recommended to discontinue the agent if a skin rash develops.1,11

o Dosage and administration: The recommended dose of gatifloxacin is based on the type of infection (see table III, insert).1 Dosage adjustment of gatifloxacin is necessary in renal impairment to avoid accumulation (see table IV, insert).1

o Drug interaction: As with other fluoroquinolones, gatifloxacin interacts with ferrous sulfate or antacids containing aluminum or magnesium salts. Bioavailability of gatifloxacin is reduced by 54% when combined with ferrous sulfate. The manufacturers recommend separating administration of gatifloxacin from these products by four hours. Concomitant administration of probenecid results in a 42% increase in area under the curve of gatifloxacin. Concomitant administration of digoxin and gatifloxacin results in increased levels of digoxin. However, this interaction was not considered significant enough to warrant dosage adjustment. Gatifloxacin appears to have minimal effect on the levels of cimetidine, midazolam, theophylline, warfarin, or glyburide.1,10

o Drug-food interactions: No significant drug-food interactions have been reported.1

o Dosage forms available: Gatifloxacin is available in oral and intravenous forms. Tablets are available as white 200 mg and 400 mg biconvex, film-coated tablets. Gatifloxacin intravenous solution is available as single-use vials and pre-mixed bags. The single-use vials contain a pale yellow solution of gatifloxacin at a concentration of 10 mg/mL. These single-use vials are available in 20 mL and 40 mL volumes. Gatifloxacin also is available as 200 mg or 400 mg premixed bags at a concentration of 2 mg/mL. These flexible bags supply gatifloxacin mixed with 5 % dextrose solution and are available in 100 mL or 200 mL volumes.1

o Discussion: Fluoroquinolones on many hospital formularies include ciprofloxacin (Cipro) and levofloxacin (Levaquin). Ciprofloxacin, levofloxacin, and gatifloxacin are FDA-approved for the treatment of acute bacterial exacerbation of chronic bronchitis, community-acquired pneumonia, acute sinusitis, and complicated urinary tract infections. Ciprofloxacin also is approved for the treatment of skin/soft tissue and bone infections. Gatifloxacin does not offer any additional FDA-approved indications for treatment other than those offered by ciprofloxacin and levofloxacin.

Although ciprofloxacin is dosed twice daily, both levofloxacin and gatifloxacin are dosed once daily. All three quinolones are available in oral and intravenous formulations. All three are well-tolerated, and dose adjustment in renal dysfunction is required for each. Ciprofloxacin, levofloxacin, and gatifloxacin bind cation-containing antacids and ferrous sulfate, resulting in reduced absorption of the quinolones.

The order of potency of inhibitory effects on the cytochrome P450 system are as follows: ciprofloxacin > levofloxacin > gatifloxacin. Based on outpatient costs, gatifloxacin is more expensive than ciprofloxacin, but comparable to levofloxacin. For inpatient cost, gatifloxacin is less expensive than ciprofloxacin and comparable to levofloxacin.

For those reasons, gatifloxacin is now being considered for formulary approval over some of the older fluoroquinolones in many institutions.

References

1. Bristol-Myers Squibb Co. Tequin package insert. Princeton, NJ; December 1999.

2. Perry CM, Barman JA, Lamb HM. Gatifloxacin. Drugs 1999; 58:683-96.

3. Stahlberg HJ, Goehler K, Guillaume M, Mignot A. Single dose pharmacokinetics of the r- and s- enantiomers of gatifloxacin in volunteers. Drugs 1999; 58 Suppl 2:222-24.

4. Pankuch GA, Jacobs MR, Appelbaum PC. Postantibiotic effects of gatifloxacin against gram-positive and -negative organisms. Antimicrob Agents Chemother 1999; 43:2,574- 2,575.

5. Ramirez A, Molina J, Dolmann A, et al. Gatifloxacin treatment in patients with acute exacerbations of chronic bronchitis: Clinical trial results. J Resp Dis 1999; 20 Suppl: S30-39.

6. Fogarty C, McAdoo MA, Paster RZ, et al. Gatifloxacin vs. clarithromycin in the treatment of acute sinusitis. J Resp Dis 1999; 20 Suppl: S17-22.

7. Sullivan JG, McElroy AD, Honsinger RW, et al. Treating community-acquired pneumonia with once-daily gatifloxacin versus once-daily levofloxacin. J Resp Dis 1999; 20: S49-S59.

8. Richard GA, Mathew CP, Kirstein JM. Single (400 mg) and multiple (200 mg BID) dose oral gatifloxacin vs. multiple (100 mg BID) dose oral ciprofloxacin in the treatment of acute, uncomplicated urinary tract infection in women [abstract]. Bristol-Myers Squibb; Princeton, NJ. Data on file, 1999.

9. Stoner BP, Douglas JM, Martin DM. Single dose gatifloxacin (400 or 600 mg) vs. single dose ofloxacin in the treatment of uncomplicated gonococcal infections (poster). Presented at the 39th Interscience Conference on Antimicrobial Agents and Chemotherapy. San Francisco; September 1999. Abstract 1,744.

10. Lober S, Zeige S, Rau M, Schreiber G, Mignot A, Koeppe P, Lode H. Pharmacokinetics of gatifloxacin and interaction with an antacid containing aluminum and magnesium. Antimicrob Agents Chemother 1999; 43:1,067-1,071.

11. Ferguson J, McEwen J, Mignot A, Watson D. Phototoxic potential of gatifloxacin, a new fluoroquinolone antimicrobial. Drugs 1999; 58 Suppl 2: 397-399.