Gemifloxacin (Factive) Drug Evaluation
By Tonya Blackwood, PharmD candidate Written while a student at McWhorter School of Pharmacy Samford University, Birmingham, AL
Fluoroquinolones
Gemifloxacin mesylate (Factive) — Genesoft Pharmaceuticals
Levofloxacin (Levaquin) — Ortho-McNeil Pharmaceutical
Gatifloxacin (Tequin) — Bristol-Myers Squibb Co.
Mechanism of action
Gemifloxacin, levofloxacin, and gatifloxacin all exert their bactericidal effects by inhibiting DNA synthesis through the inhibition of both DNA gyrase and topoisomerase IV, which are essential for bacterial growth.1-3
Indications
All three drugs are used for the treatment of various infections due to susceptible bacterial strains causing the following infections (see Table 1). 1-3
Organisms generally susceptible in vitro
Each drug has been tested in vitro and has shown inhibitory effects against the strains listed in Table 2; however, for certain organisms the safety and efficacy have not been established in clinical trials.
Pharmacokinetics
The pharmacokinetic parameters are fairly similar among the three drugs (see Table 3), but there are a few minor variations.1-4 Gemifloxa-cin is more protein-bound than the other two fluoroquinolones, which has the potential for more drug interactions. However, it is probably not likely at these percentages.
Gemifloxacin also is excreted to a greater degree in the feces than in the urine, unlike the other two quinolones. The peak effect of all three is similar. Gemifloxacin also has decreased bioavailability compared to the other two quinolones.
Dosing
In patients with normal renal function, the dose is comparable for each indication, and the durations are fairly similar (see Table 4).1-3
In patients with impaired renal function, each drug must be adjusted based on the creatinine clearance of each patient (see Tables 5-7).1-3 The dose of levofloxacin must be reduced at a lower creatinine clearance level than the other two quinolones.
Contraindications
Each drug is contraindicated for hypersensitivity to the active ingredient, quinolone antibiotics, or any other component of the product. 1-3
Warnings/precautions
All three drugs have similar warnings and precautions; however, disturbance of glucose levels and safety in lactating women have not been established with gemifloxacin (see Table 8).1-3,5 This is possibly because of the little experience with gemifloxacin in certain patient populations.
Drug interactions
All three drugs have similar drug interaction profiles; however, gemifloxacin does not seem to interact with nonsteroidal anti-inflammatory drugs like levofloxacin and gatifloxacin do (see Table 9). This, too, could be due to the lack of experience with gemifloxacin.
Adverse effects
The adverse effect profiles of the fluoroquinolone agents are similar in nature (see Table 10).1-3,5 Nausea has the highest incidence rate with all three drugs. The most common adverse reactions with gemifloxacin appear to be nausea, diarrhea, and rash. Other adverse drug reactions occurred with each drug, but at a very small percentage.
Monitoring parameters
Patients treated with gemifloxacin, levofloxacin, or gatifloxacin should be evaluated for renal function, pregnancy status, and predisposition to seizures before receiving the medication.1-3 Patients with diabetes should monitor their blood glucose levels while taking the medication. White blood cell counts also should be taken to monitor for resolution or improvement of infection.
Cost comparison
At the time of this writing, gemifloxacin had not been released for use and cost information was not available; however, it will only be available in a tablet form, not in intravenous form.6
Potential for medication error
There may be possible confusion with gatifloxacin in written and verbal orders.
Clinical Trials
Gemifloxacin Compared with Other Antibiotic Classes7
Wilson R, Schentag JJ, Ball P, et al. A comparison of gemifloxacin and clarithromycin in acute exacerbations of chronic bronchitis and long-term clinical outcomes. Clin Ther 2002;24:639-652.
Objective: (two-part study)
Part 1:To compare the efficacy and safety of a five-day course of gemifloxacin with the standard-dose, seven-day regimen of clarithromycin in patients with acute exacerbations of chronic bronchitis (AECB). Part 2: GLOBE (Gemifloxacin Long-term Outcomes in Bronchitis Exacerbation); the impact of the treatment on the long-term clinical outcome was also assessed.
Study design: A randomized, double-blind, double-dummy, parallel-group design including 709 patients.
Intervention: Patients were randomized to receive either gemifloxacin 320 mg once daily for five days plus clarithromycin placebo twice daily for seven days, or clarithromycin 500 mg twice daily for seven days plus gemifloxacin placebo once daily for five days.
Patient population
• Inclusion criteria:
— Adult patients (older than 40 years) with a history of chronic bronchitis and an Anthonisen type I acute exacerbation (characterized by increases in dyspnea, cough, and sputum purulence).
— Patients had to be able to take oral therapy.
• Exclusion criteria:
— Diagnosis of pneumonia.
— Another antibacterial agent taken within seven days of study entry.
— Hypersensitivity to quinolone or macrolide antimicrobial agents.
— Taking a medication that interacts with these agents.
— Received systemic steroids at a dose of greater than 10 mg prednisone or the equivalent.
Outcomes measured
• Primary efficacy measure:
— Clinical response at the week 2-3 follow-up. (Investigators determined clinical outcomes based on the signs and symptoms of AECB.)
— In the GLOBE, the proportion of the patients with resolution of the initial episode of AECB who remained free from recurrences of AECB requiring additional antimicrobial treatment.
• Secondary efficacy measure:
— Bacteriologic outcomes at the end-of-therapy visit and both follow-up visits. (Bacteriologic outcome was assessed based on the results of sputum culture and Gram’s staining at the end-of-therapy visit and both follow-up visits.)
— Time to bacterial eradication in patients with H. influenzae. (Time to bacterial eradication was defined as the time in days to the first day on which there was an outcome of eradication.)
Results: Clinical success rate was the primary endpoint measured, and it was reported as per protocol (PP) and intention to treat (ITT) (see Table 11). Bacteriology was one of the secondary endpoints measured. The sample size was considerably smaller than the actual number of patients who were taking each medication because at least one pathogen had to be identified at the beginning of the study to be included in the measurement. The percentage of patients without a recurrence of AECB requiring further antimicrobial treatment was the primary endpoint of the GLOBE portion of the study. This sample size was 438 patients.
Strengths
- Randomized, double-blind, double-dummy trial.
- ITT and PP analysis utilized.
- Written, informed consent obtained.
- Patient demographics and baseline clinical characteristics well matched.
- Inclusion and exclusion criteria appropriate and clearly stated.
Limitations
- No P values given — only confidence intervals.
- No power given to know if appropriate sample size was included.
- Some endpoints only reported as percentages, not actual numbers.
Author’s conclusions: Oral gemifloxacin given once daily for five days was well tolerated in the treatment of Anthonisen type I AECB, and was at least as effective as oral clarithromycin given twice daily for seven days. Treatment with gemifloxacin resulted in significantly more patients remaining recurrence-free and fewer hospitalizations due to respiratory tract infection-related episodes compared to clarithromycin after 26 weeks.
Other clinical trials comparing gemifloxacin to antibiotics in other classes have been conducted. One trial compared gemifloxacin once daily for five days with IV ceftriaxone/oral cefuroxime for the treatment of ABECB. This open-label, controlled, multicenter study included 272 patients and compared safety, tolerability, and bacteriological efficacy. Gemifloxacin was shown to be as effective as the sequential IV ceftiaxone/oral cefuroxime.8 The other clinical trial compared gemifloxacin with amoxicillin/ clavulanate potassium. This randomized, double-blind, double-dummy, multicenter parallel group study involving 600 patients compared the efficacy and safety of gemifloxacin for the treatment of ABECB. Both drugs were well-tolerated and equally effective.9
Gemifloxacin compared with another fluoroquinolone10
File TM, Schlemmer B, Garau J, et al. Efficacy and safety of gemifloxacin in the treatment of community-acquired pneumonia: A randomized, double-blind comparison with trovafloxacin. J Antimicrbo Chemother 2001;48:67-74.
Objective: To compare the clinical and antibacterial efficacy of oral gemifloxacin with that of oral trovafloxacin in the treatment of community-acquired pneumonia (CAP).
Study Design: A randomized, multicenter, double-blind, parallel group study carried out in the United States, Mexico, and Spain involving 571 patients.
Intervention: Patients were randomized to receive either oral gemifloxacin 320 mg once daily or oral trovafloxacin 200 mg once daily for seven days. The treatment duration could be extended to 14 days if a patient had a severe infection, a confirmed or probable diagnosis of infection with an atypical pathogen, or at the investigator’s discretion.
Patient population
• Inclusion criteria:
— Adult patients with a radiological and clinical diagnosis of CAP.
— Patients were required to have one of the following: fever (> 38° C, oral), or elevated white blood count > 10,000 cells/mm3, >15% immature neutrophils, or leukopenia with a total white blood cell count of < 4,500 cells/mm3.
• Exclusion criteria:
— Hypersensitivity to quinolones or a history of tendonitis while taking fluoroquinolones.
— Bronchial obstruction or a history of post-obstructive pneumonia, aspiration pneumonia, cystic fibrosis, active tuberculosis, bronchiectasis, active lung malignancies, hospital-acquired pneumonia, or hospitalization within two weeks of entry into the study.
— Patients requiring parenteral antibiotic therapy and those who had received more than 24 hours of treatment with any other antibacterial agent for the current episode of CAP.
— Women who were pregnant or lactating.
— Women of childbearing age had to be using an accepted method of birth control.
Outcomes measured
• Primary efficacy variable:
— Clinical response at follow-up.
• Secondary efficacy variables:
— Clinical response at the end of therapy.
— Bacteriological response at the end of therapy and at follow-up.
— Radiological response at the end of therapy and at follow-up.
— Therapeutic response.
Results: Clinical response was the primary efficacy variable, and it was reported as per protocol (PP) and intention to treat (ITT) (see Table 12). Bacteriological response was one of the secondary endpoints measured. The sample size was considerably smaller than the actual number of patients who were taking each medication because at least one pathogen had to be identified at the beginning of the study to be included in the measurement. It was also reported as PP and ITT.
Strengths
- Randomized, multicenter, double-blind, parallel-group study.
- Informed consent obtained.
- Inclusion and exclusion criteria clearly stated.
- Patient demographics were similar at baseline.
- ITT and PP analysis utilized.
- Susceptibility testing was conducted in accordance with National Committee for Clinical Laboratory Standards.
Limitations
- No P values given — only confidence intervals.
- No power given to know if appropriate sample size was included.
- Some endpoints were reported only as percentages, not actual numbers.
- No explanations were given for patient withdrawals.
Author’s conclusions: This study demonstrated that gemifloxacin 320 mg once daily was as effective as trovafloxacin 200 mg once daily for 7-14 days in the treatment of CAP. With regard to bacteriological response, gemifloxacin was shown to be at least as effective as trovafloxacin. For clinical response, gemifloxacin was significantly superior to trovafloxacin in the ITT population.
Another trial comparing gemifloxacin with trovafloxacin was conducted in 1998-99; however, it examined efficacy and safety in the treatment of ABECB. This trial was a randomized, double-blind comparison including 617 patients in which gemifloxacin was found to be at least as effective as trovafloxacin.11
Summary and recommendations
Gemifloxacin is effective as standard treatment for the treatment of ABECB and CAP; however, in limited trials it does not seem to be more efficacious or safe than other standard drug therapy for these indications. Clinical trials have shown gemifloxacin to be as effective as other classes of drugs and a fluoroquinolone for the treatment of ABECB and CAP. Most of the drug properties (such as pharmacokinetics, drug interactions, and adverse drug reactions) are similar to levofloxacin and gatifloxacin. One advantage of gemifloxacin is that it is excreted in both the urine and feces. Disadvantages of gemifloxacin include: it is only available as a tablet and it has decreased bioavailability when compared to the other fluoroquinolones.
It is recommended that gemifloxacin be classified as a nonformulary drug, and be placed in the quinolone automatic interchange program. Orders written for gemifloxacin 320 mg should be interchanged with gatifloxacin 400 mg; dosage should be adjusted for appropriate level of renal function.
References
1. Genesoft Pharmaceuticals. Gemifloxacin Prescribing Information. San Francisco; 2003.
2. Ortho-McNeil Pharmaceuticals. Levaquin Package Insert. Raritan, NJ; 2002.
3. Bristol-Myers Squibb. Tequin Package Insert. Princeton, NJ; 2002.
4. Lomaestro BM. Gemifloxacin: A broad-spectrum oral quinolone for treatment of respiratory and urinary tract infections. Formulary 2000;35:961-968.
5. Fluoroquinolones. Drug Facts and Comparisons. St. Louis: Facts and Comparisons; 2001:1286a-1289a.
6. E-mail communication. Christine Nash, employee. Genesoft Pharmaceuticals. July 2003.
7. Wilson R, Schentag JJ, Ball P, et al. A comparison of gemifloxain and clarithromycin in acute exacerbations of chronic bronchitis and long-term clinical outcomes. Clin Ther 2002;24:639-652.
8. Wilson R, Langan C, Ball P, et al. Oral gemifloxacin once daily for five days compared with sequential therapy of IV ceftriaxone/oral cefuroxime (maximum of 10 days) in the treatment of hospitalized patients with acute exacerbations of chronic bronchitis. Respir Med 2003;97:242-249.
9. File T, Schlemmer B, Garau J, et al. Gemifloxa-cin versus amoxicillin/clavulanate in the treatment of acute exacerbations of chronic bronchitis. J Chemother 2000;12:314-25.
10. File TM, Schlemmer B, Garau J, et al. Efficacy and safety of gemifloxacin in the treatment of community-acquired pneumonia: A randomized, double-blind comparison with trovafloxacin. J Antimicrbo Chemother 2001;48:67-74.
11. Ball P, Wilson R, Mandell L, et al. Efficacy of gemifloxacin in acute exacerbations of chronic bronchitis; randomised, double-blind comparison with trovafloxacin. J Chemother 2001;13:288-298.
Gemifloxacin is effective as standard treatment for the treatment of ABECB and CAP; however, in limited trials it does not seem to be more efficacious or safe than other standard drug therapy for these indications.You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
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