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PubMed2002

Short treatment durations for acute bacterial rhinosinusitis: Five days of gemifloxacin versus 7 days of gemifloxacin.

OBJECTIVE: The primary objective of this study was to demonstrate the clinical and radiologic efficacy of 5 days compared with 7 days of gemifloxacin therapy in the treatment of acute bacterial rhinosinusitis (ABRS). STUDY DESIGN: In this prospective, double-blind, multicenter, parallel-group study, adult patients presenting with ABRS were randomized to receive gemifloxacin 320 mg once daily for either 5 days (n = 218) or 7 days (n = 203). RESULTS: For the primary efficacy end point, clinical response to therapy at follow-up, 5 days of therapy with gemifloxacin was as effective as 7 days of therapy (per-protocol population; treatment difference 0.44%; 95% confidence interval [CI], -6.54 to 7.41). Five and 7 days of treatment with gemifloxacin were well tolerated. CONCLUSION AND SIGNIFICANCE: The clinical efficacy of gemifloxacin 320 mg daily for 5 days is at least as good as the efficacy of gemifloxacin 320 mg daily for 7 days in the treatment of ABRS.

Acute Disease↗
PubMed2000

A comparative In vitro surveillance study of gemifloxacin activities against 2,632 recent Streptococcus pneumoniae isolates from across Europe, North America, and South America. The Gemifloxacin Surveillance Study Research Group.

From 1997 to 1999, 94 study centers in 15 European, 3 North American, and 2 South American countries contributed 2,632 isolates of Streptococcus pneumoniae to an international antimicrobial susceptibility testing study. Only 62.0% of isolates were susceptible to penicillin, while 22.3% were penicillin intermediate and 15.6% were penicillin resistant. Resistance to trimethoprim-sulfamethoxazole (24.4%), azithromycin (26.0%), and clarithromycin (27.1%) was also highly prevalent. For the penicillin-resistant isolates (n = 411), the MICs at which 90% of isolates are inhibited (MIC(90)s) for gemifloxacin, levofloxacin, ofloxacin, clarithromycin, and azithromycin were 0.03, 1, 2, >16, and >64 microgram/ml, respectively. Similarly, for isolates resistant to both azithromycin and clarithromycin (n = 649), gemifloxacin, levofloxacin, ofloxacin, and penicillin MIC(90)s were 0.03, 1, 2, and 4 microgram/ml, respectively. Overall rates of resistance to trovafloxacin (0.3%), levofloxacin (0.3%), grepafloxacin (0.6%), and ofloxacin (0.7%) were low. For ofloxacin-intermediate and -resistant isolates (n = 142), gemifloxacin had the lowest MIC(90) (0.12 microgram/ml) compared to the MIC(90)s of trovafloxacin (0.5 microgram/ml), grepafloxacin (1 microgram/ml), and levofloxacin (2 microgram/ml). For all S. pneumoniae isolates tested, gemifloxacin MICs were </=0.5 microgram/ml, suggesting that gemifloxacin has the potential to be used as a treatment for pneumococcal infections, including those arising from isolates resistant to beta-lactams and macrolides.

Adolescent↗
PubMed2004

A new respiratory fluoroquinolone, oral gemifloxacin: a safety profile in context.

Gemifloxacin is a broad-spectrum quinolone antibacterial with enhanced potency against Gram-positive bacteria, including multi-drug resistant Streptococcus pneumoniae, and retained potency against Gram-negative bacilli and bacterial strains resistant to other antibiotics. It has proven particularly effective in respiratory and urinary tract infection. This review presents safety data from 6775 patients included in clinical trials, receiving either the recommended 320 mg once daily oral dose of gemifloxacin, or standard dose of other quinolones, macrolides or beta-lactams (n = 5248). Studies in healthy volunteer and special populations are also reported. Adverse experiences (AEs) were observed in 44.7% of gemifloxacin-treated patients and 47.5% of those who received comparator drugs. Mild gastro-intestinal adverse drug reactions (ADRs) (diarrhoea 5.1%, nausea 3.9%) predominated. Rash, usually maculo-papular and in no case proceeding to more severe eruptions, was observed in 3.6% of those receiving gemifloxacin. A higher incidence of rash (>20%) was observed in young women and was the subject of further study. Adverse drug reactions suspected or probably related to treatment occurred in 17.4% of patients receiving gemifloxacin and in 20% of those receiving comparator antibiotics. Diarrhoea and nausea were experienced by 3.6 and 2.7%, respectively, of gemifloxacin-treated patients (4.6 and 3.2% of comparators), rash by 2.8% (0.6% of comparators) and headache by 1.2% (1.5% of comparators). Gemifloxacin-related vomiting (0.9%), dizziness (0.8%) and taste perversion (0.3%) were uncommon. Treatment discontinuation followed one or more adverse drug reactions in 2.2% of gemifloxacin-treated patients (0.9% due to rash) and 2.1% of comparator-treated patients. A total of 63 deaths (33 receiving gemifloxacin) occurred in the trial population: none were considered related to treatment. A slight prolongation in QT interval (2.56 ms (S.D. +/-24.5)) was observed in gemifloxacin-treated patients: no cardiac arrhythmias were reported. There was a low incidence of liver function tests (LFTs) classified as of potential clinical concern: gemifloxacin (0.4-1.2%), comparators (0.2-1.3%). Serious adverse events (SAEs), occurring during but not necessarily related to therapy, occurred in 3.6% of gemifloxacin-treated patients (4.3% of comparators). SAEs related to treatment agents were rare (0.4% in each group) and included rash (0.1%) and elevated liver enzymes (<0.1%). Gemifloxacin was well tolerated by the elderly, those with renal or hepatic impairment and when co-administered with omeprazole, digoxin, theophylline, warfarin (with which there were no significant interactions) and Maalox. In conclusion, gemifloxacin 320 mg once daily demonstrated a favourable safety and tolerability profile similar to that of comparator antibiotics, including other quinolones.

Administration, Oral↗
PubMed2004

Gemifloxacin: a new fluoroquinolone.

Gemifloxacin is a dual targeted fluoroquinolone with potent in vitro activity against Gram-positive, -negative and atypical human pathogens--pathogens considered to be important causes of community-acquired respiratory tract infections. Gemifloxacin demonstrates impressive minimal inhibitory concentrations (MIC 90 ) values against clinical isolates of Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, Chlamydia pneumoniae and Legionella spp., with MIC 90 values reported to be 0.016-0.06, < 0.0008-0.06, 0.008-0.3, 0.25, 0.125 and 0.016-0.07 microg/ml, respectively. Gemifloxacin is also active in vitro against a broad range of Gram-negative bacilli with MIC 90 values against the Enterobacteriaceae in the range of 0.016 to > 16 microg/ml ( Escherichia coli and Providencia stuartii, respectively), with the majority of the genus having MIC 90 drug concentrations < 0.5 microg/ml. The in vitro activity of gemifloxacin against anaerobic organisms is variable. The MIC values for gemifloxacin are not affected by beta-lactamase production nor by penicillin or macrolide resistance in S. pneumoniae. Gemifloxacin is approved by the FDA to be clinically efficacious against multi-drug resistant S. pneumoniae. The pharmacokinetics of gemifloxacin are such that the drug can be administered orally once-daily to yield or achieve sustainable drug concentrations exceeding the MIC values of clinically important organisms. Gemifloxacin has been shown to target both DNA gyrase (preferred target) and topoisomerase IV (secondary target) - enzymes critical for DNA replication and organism survival - against clinical isolates of S. pneumoniae. This dual targeting activity is thought to be important for reducing the likelihood for selecting for quinolone resistance. Gemifloxacin has been investigated and approved for therapy in patients with community-acquired pneumonia (CAP) and acute exacerbations of chronic bronchitis. In one study, more patients receiving gemifloxacin compared to clarithromycin remained free of exacerbations for longer periods of time (p < 0.016) and gemifloxacin had a shorter time to eradication of H. influenzae than did clarithromycin (p < 0.02). From efficacy studies, gemifloxacin was found to have an adverse profile that was comparable with other compounds. The most frequent side effects were diarrhoea, abdominal pain and headache. Gemifloxacin is a welcomed addition to currently available agents for the treatment of community-acquired lower respiratory tract infections. Other potential indications appear to be within the spectrum of this compound.

Animals↗
PubMed2004

Gemifloxacin once daily for 7 days compared to amoxicillin/clavulanic acid thrice daily for 10 days for the treatment of community-acquired pneumonia of suspected pneumococcal origin.

CONTEXT: Community-acquired pneumonia (CAP) is common among adults and contributes considerably to morbidity and mortality. OBJECTIVE: To compare the safety and efficacy of gemifloxacin to high-dose amoxicillin/clavulanate for the treatment of CAP of suspected pneumococcal origin. DESIGN: Randomized, multicentre, double-blind, double-dummy, parallel group Phase III study. SETTING AND PARTICIPANTS: From September 1998 to July 1999, 324 patients with CAP were randomized at 102 centers in France, Poland and the Republic of South Africa. INTERVENTION: Patients were double-blind randomized to receive either oral gemifloxacin 320 mg once daily for 7 days or oral amoxicillin/clavulanate 1 g/125 mg three times daily for 10 days. MAIN OUTCOME MEASURES: The main outcome measures were clinical, bacteriological, and radiological responses at the end of therapy (day 12-14) and follow-up (day 24-30) visits. RESULTS: In 228 PP patients, clinical resolution at follow-up was 88.7% for 7-day gemifloxacin and 87.6% for 10-day amoxicillin/clavulanate [95% CI, -7.3, 9.5]. In 249 PP patients, clinical resolution at end of therapy was 95.3% for 7-day gemifloxacin vs. 90.1% for 10-day amoxicillin/clavulanate [95% CI, -1.2, 11.7]. Bacteriologic response rates for the PP patients at end of therapy were 96.3% for 7-day gemifloxacin and 91.8% for the amoxicillin/clavulanate group [95% CI, -4.7, 13.6]. Bacteriologic response rates at follow-up were 87.2% for 7-day gemifloxacin and 89.1% for the amoxicillin/clavulanate group [95% CI, -15.0, 11.2]. Specifically gemifloxacin eradicated 95.7% of Streptococcus pneumoniae including penicillin and macrolide resistant strains. Radiological response rates for the PP patients at end of therapy were 89.1% for 7-day gemifloxacin and 87.6% for the amoxicillin/clavulanate group. The most frequently reported drug-related events were in the gemifloxacin group, diarrhea (6.0%) and rash (3.0%) and in the amoxicillin/clavulanate group, diarrhea (11.1%) and fungal infection, vaginitis and vomiting (each 2.0%). Overall there were statistically fewer withdrawals due to lack of therapeutic effect in the gemifloxacin group compared with the amoxicillin/clavulanate cohort, (95% CI, -8.8;0.6; P = 0.03). CONCLUSION: Gemifloxacin 320 mg once daily for 7 days was found to be clinically, bacteriologically, and radiologically as effective as 10 days of amoxicillin/clavulanate 1 g/125 mg three times daily for the treatment of suspected pneumococcal CAP.

Adolescent↗
PubMed2000

Comparative efficacy of gemifloxacin in experimental models of pyelonephritis and wound infection.

Gemifloxacin (SB-265805) is a potent, novel fluoroquinolone with broad-spectrum antimicrobial activity. In this study, the efficacy of gemifloxacin was studied in experimental models of Gram-negative pyelonephritis (caused by Escherichia coli or Proteus mirabilis) and Gram-positive wound infection resulting from Streptococcus pyogenes, Staphylococcus epidermidis or Staphylococcus aureus. Gemifloxacin activity against these pathogens was compared with those of amoxycillin-clavulanate, ciprofloxacin, cefuroxime, azithromycin, trovafloxacin, grepafloxacin, levofloxacin and tosufloxacin. Oral treatment was initiated 1 h after infection and continued once or twice daily for 3 days. Around 17 h after the end of treatment, animals were killed and the infected kidneys or the skin around the wound site were excised for the enumeration of viable bacteria. In the pyelonephritis model (either microorganism), gemifloxacin reduced bacterial numbers significantly (P < 0.01) compared with no treatment. No comparator agent had a greater effect than gemifloxacin. Notably, grepafloxacin and azithromycin were significantly less effective (P < 0.01) than gemifloxacin against E. coli pyelonephritis, and amoxycillin-clavulanate, azithromycin and trovafloxacin were inferior (P < 0.01) against P. mirabilis infection. In the S. pyogenes wound infection model, gemifloxacin, amoxycillin-clavulanate, cefuroxime and azithromycin reduced bacterial numbers significantly compared with controls (P < 0.01). Results for the comparator quinolones were not significantly different from untreated controls (P > 0.05). Gemifloxacin was also effective against staphylococcal infection, as were grepafloxacin and levofloxacin, while ciprofloxacin, trovafloxacin and tosufloxacin were significantly less effective against these pathogens than gemifloxacin (P < 0.01). No comparator agent had greater activity than gemifloxacin against S. pyogenes or S. aureus infections. These data demonstrate the potential benefit of gemifloxacin in the treatment of Gram-negative urinary tract infection and Gram-positive skin and soft tissue infection.

Animals↗
PubMedDate not supplied

Lack of effect of gemifloxacin on the steady-state pharmacokinetics of theophylline in healthy volunteers.

Gemifloxacin is a novel fluoroquinolone, currently in development for the treatment of respiratory tract infections. This double-blind (with respect to gemifloxacin), randomized, crossover study investigated the possibility of pharmacokinetic interaction between gemifloxacin and theophylline. After a 4-8-day run-in phase to establish the dose of theophylline required to achieve a trough plasma concentration range of 8-15 mg/l, 15 healthy volunteers entered a randomized treatment phase. Volunteers then received oral theophylline, 300-400 mg twice daily, for 22 days. On days 5-11 and 16-22, they also received either placebo or gemifloxacin, 320 mg p.o. once daily, in a crossover fashion. Blood samples were collected up to 12 h after the morning dose of theophylline on days 11 and 22. Theophylline pharmacokinetics were not affected by the co-administration of gemifloxacin. The maximum plasma concentration (C(max)) for theophylline ranged from 8.12 to 17.71 mg/l and from 8. 79 to 16.35 mg/l during concomitant administration with gemifloxacin and placebo, respectively. The corresponding ranges of the area under the plasma concentration-time curve from time zero to the last quantifiable plasma concentration (AUC((0-12))) were 84.6-177.5 mg. h/l and 94.8-165.1 mg.h/l during gemifloxacin and placebo administration, respectively. The point estimates (90% confidence intervals) for dose-normalized AUC((0-12)) and C(max) (theophylline + gemifloxacin):(theophylline + placebo) were 0.99 (0.93, 1.05) and 1.02 (0.93, 1.11), respectively, which were entirely within the equivalence range (0.80, 1.25). The co-administration of gemifloxacin and theophylline was well tolerated, with no clinically significant changes seen in vital signs, 12-lead electrocardiogram readings or laboratory parameters. Adverse events were generally transient, mild to moderate in nature and similar during the gemifloxacin and placebo treatment periods. In conclusion, theophylline and gemifloxacin may be co-administered without any adjustment in theophylline dose.

Adolescent↗
PubMed2002

A comparison of gemifloxacin and clarithromycin in acute exacerbations of chronic bronchitis and long-term clinical outcomes.

BACKGROUND: Gemifloxacin is an enhanced-affinity quinolone with potent activity against lower respiratory tract pathogens. OBJECTIVE: The efficacy and safety of a 5-day course of gemifloxacin were compared with those of a standard 7-day regimen of clarithromycin in patients with an acute exacerbation of chronic bronchitis (AECB). The impact of treatment on the long-term (26 weeks) clinical outcome was also assessed. METHODS: The acute phase of this randomized, double-blind study was performed in 93 centers in 7 countries. Adult patients (age >40 years) with a history of chronic bronchitis and an Anthonisen type 1 acute exacerbation (increased dyspnea, cough, and sputum purulence) were eligible. Patients receiving systemic steroids at a dose of >10 mg prednisone or the equivalent were excluded. Patients were randomized to receive gemifloxacin 320 mg once daily for 5 days or clarithromycin 500 mg twice daily for 7 days. Clinical and bacteriologic response rates were assessed at the end-of-therapy visit (days 8-12), the week 2-3 follow-up visit (days 13-24), and the week 4-5 follow-up visit (days 25-38). The long-term phase (26 weeks), which included US and Canadian participants only, evaluated the proportion of patients who remained free of a recurrence of AECB requiring additional antimicrobial therapy after resolution of the initial episode. RESULTS: Seven hundred twelve patients were randomized to treatment, 351 to gemifloxacin and 361 to clarithromycin. The long-term study included 438 patients, 214 receiving gemifloxacin and 224 receiving clarithromycin. Clinical success rates at the 2-3 week follow-up visit were 85.4% for gemifloxacin and 84.6% for clarithromycin. Bacteriologic success rates were 86.7% for gemifloxacin and 73.1% for clarithromycin. Significantly more patients receiving gemifloxacin than clarithromycin remained free of AECB recurrences (71.0% vs 58.5%, respectively; P = 0.016). Both treatments were well tolerated. CONCLUSIONS: In the acute treatment of Anthonisen type 1 AECB, a 5-day course of gemifloxacin was at least as effective as a 7-day regimen of clarithromycin. In this population, significantly more patients receiving gemifloxacin remained free of AECB recurrence after 26 weeks compared with those receiving clarithromycin.

Adult↗
PubMed2002

Cost-effectiveness of gemifloxacin: results from the GLOBE study.

The cost-effectiveness of treatment with oral gemifloxacin versus oral clarithromycin for acute exacerbations of chronic bronchitis (AECB) was evaluated. Economic outcomes were assessed for the Gemifloxacin Long-term Outcomes in Bronchitis Exacerbations study. This prospective double-blind, controlled, health outcomes study compared health, economic, and clinical outcomes after randomized treatment with either oral gemifloxacin or oral clarithromycin for AECB. Base case analysis was performed from the third-party payer's perspective and considered the costs of respiratory tract infection-related medical care. Analysis from the societal perspective also included costs of lost productivity. Treatment effectiveness was measured as the proportion of patients without recurrence requiring antimicrobial treatment following resolution of the initial AECB. Data sources included the outcomes study itself and standard U.S. cost sources. Compared with clarithromycin, gemifloxacin treatment resulted in significantly more patients without AECB recurrence requiring antimicrobial treatment after 26 weeks (73.8% versus 63.8%, p = 0.024). Fewer patients receiving gemifloxacin were hospitalized (5 of 214 patients versus 14 of 224 patients, p = 0.059), and they had less time off from usual activities (8.3 days versus 10.1 days). The mean direct cost per patient receiving gemifloxacin was $127 less than with clarithromycin ($247 versus $374, respectively); mean total costs (direct plus indirect) per patient were $329 less for patients receiving gemifloxacin ($1413 versus $1742). Gemifloxacin dominated clarithromycin in cost-effectiveness analysis. Bootstrap analysis indicated that the probability of gemifloxacin being both cost saving and more effective than clarithromycin is 88% from a payer's perspective and 84% from the societal perspective. Gemifloxacin was more cost-effective, improving AECB outcomes and producing substantial cost offsets compared with clarithromycin.

Anti-Bacterial Agents↗
PubMed2000

Comparative in vivo activity of gemifloxacin in a rat model of respiratory tract infection.

The in vivo efficacy of the novel quinolone gemifloxacin (SB-265805) was examined in a rat respiratory tract infection (RTI) model against four strains of Streptococcus pneumoniae and two strains of Haemophilus influenzae with varying susceptibilities to standard antimicrobial agents. Animals were infected intrabronchially to produce pneumonia and therapy with oral gemifloxacin, amoxycillin-clavulanate, ciprofloxacin, cefuroxime, azithromycin, trovafloxacin, grepafloxacin or levofloxacin was started 24 h after infection. The doses administered were chosen to approximate in the rat the serum or tissue concentrations measured in humans following therapeutic dosing. Therapy continued once- or twice-daily for 3 days, and approximately 17 h after the end of therapy the lungs were excised for bacterial enumeration. Following infection with strains of S. pneumoniae, gemifloxacin produced a 3-5 log reduction in bacterial numbers compared with untreated animals. Gemifloxacin was as effective as amoxycillin- clavulanate, and was as potent or more potent than all other comparators. Notably, the quinolone agents trovafloxacin, ciprofloxacin, grepafloxacin and levofloxacin were significantly less effective (P < 0.01) than gemifloxacin: these agents reduced bacterial numbers by < or =3 log compared with untreated animals. Gemifloxacin produced a marked response against H. influenzae infection, reducing bacterial numbers significantly (P < 0.01) compared with untreated controls. Gemifloxacin was significantly more potent than cefuroxime and azithromycin. None of the other comparator agents was more potent than gemifloxacin. The excellent efficacy seen in these experimental models of RTI with S. pneumoniae and H. influenzae confirms the in vitro activity of gemifloxacin against these organisms. This indicates that gemifloxacin may be of significant benefit in the treatment of RTI.

Animals↗
PubMed2004

Gemifloxacin inhibits cytokine secretion by lipopolysaccharide stimulated human monocytes at the post-transcriptional level.

The fluroquinolone gemifloxacin was examined for its capacity to modulate secretion of cytokines by human monocytes stimulated with lipopolysaccharide (LPS). Monocytes from six male and two female healthy volunteers were stimulated with LPS, exposed to gemifloxacin and the amounts of secreted IL-1 alpha, IL-1 beta, IL-6, IL-10 and TNF-alpha measured at 3, 6 and 24 h. The results revealed that LPS alone increased secretion of each cytokine significantly. Treatment of the LPS-stimulated monocytes with gemifloxacin resulted in a significant inhibition (p < 0.01) of secretion of each of the cytokines from monocytes of the eight volunteers. Nuclear extracts of the human monocyte cell line, THP-1, were used in the electrophoretic mobility shift assay to determine whether gemifloxacin affects nuclear factor-kappa B (NF-kappa B) activation. In addition, RNA from THP-1 cells was used in Northern blots to determine whether inhibition of secretion of IL-1 beta and TNF-alpha by gemifloxacin occurred at the transcription or translation level. Whereas LPS induced a rapid increase in NF-kappa B activation, gemifloxacin alone did not. Gemifloxacin did not affect the kinetics or decrease the extent of activation. Northern blots indicated that the inhibitory activity of gemifloxacin occurred post-transcription. Thus, gemifloxacin may modulate the immune response by altering secretion of cytokines by human monocytes. Although the concentrations of gemifloxacin used were higher than those observed in the serum of human volunteers treated with the dose under clinical development, it should be taken into consideration that concentrations at tissue and intracellular levels may be considerably higher than serum concentrations.

Adult↗
PubMed2000

Potent antipneumococcal activity of gemifloxacin is associated with dual targeting of gyrase and topoisomerase IV, an in vivo target preference for gyrase, and enhanced stabilization of cleavable complexes in vitro.

We investigated the roles of DNA gyrase and topoisomerase IV in determining the susceptibility of Streptococcus pneumoniae to gemifloxacin, a novel fluoroquinolone which is under development as an antipneumococcal drug. Gemifloxacin displayed potent activity against S. pneumoniae 7785 (MIC, 0.06 microgram/ml) compared with ciprofloxacin (MIC, 1 to 2 microgram/ml). Complementary genetic and biochemical approaches revealed the following. (i) The gemifloxacin MICs for isogenic 7785 mutants bearing either parC or gyrA quinolone resistance mutations were marginally higher than wild type at 0.12 to 0.25 microgram/ml, whereas the presence of both mutations increased the MIC to 0.5 to 1 microgram/ml. These data suggest that both gyrase and topoisomerase IV contribute significantly as gemifloxacin targets in vivo. (ii) Gemifloxacin selected first-step gyrA mutants of S. pneumoniae 7785 (gemifloxacin MICs, 0.25 microgram/ml) encoding Ser-81 to Phe or Tyr, or Glu-85 to Lys mutations. These mutants were cross resistant to sparfloxacin (which targets gyrase) but not to ciprofloxacin (which targets topoisomerase IV). Second-step mutants (gemifloxacin MICs, 1 microgram/ml) exhibited an alteration in parC resulting in changes of ParC hot spot Ser-79 to Phe or Tyr. Thus, gyrase appears to be the preferential in vivo target. (iii) Gemifloxacin was at least 10- to 20-fold more effective than ciprofloxacin in stabilizing a cleavable complex (the cytotoxic lesion) with either S. pneumoniae gyrase or topoisomerase IV enzyme in vitro. These data suggest that gemifloxacin is an enhanced affinity fluoroquinolone that acts against gyrase and topoisomerase IV in S. pneumoniae, with gyrase the preferred in vivo target. The marked potency of gemifloxacin against wild type and quinolone-resistant mutants may accrue from greater stabilization of cleavable complexes with the target enzymes.

Anti-Infective Agents↗
PubMed2004

Gemifloxacin: a new fluoroquinolone approved for treatment of respiratory infections.

OBJECTIVE: To evaluate the microbiology, pharmacokinetic parameters, drug interactions, and results of the available clinical trials of gemifloxacin for the treatment of community-acquired pneumonia (CAP) and acute exacerbation of chronic bronchitis (AECB). DATA SOURCES: MEDLINE (1966-September 2003) was searched for primary and review articles. Data from the manufacturer were also included. Key words included adverse effects, clinical trials, drug interactions, gemifloxacin, and pharmacokinetic parameters. STUDY SELECTION AND DATA EXTRACTION: All articles and product labeling concerning gemifloxacin, a fluoroquinolone antibiotic recently approved by the Food and Drug Administration for treatment of CAP and AECB, were included for review. DATA SYNTHESIS: Compared with currently available fluoroquinolones, gemifloxacin demonstrated improved in vitro activity against Streptococcus pneumoniae (minimum inhibitory concentration for 90% eradication 0.03 microg/mL) and similar activity against gram-negative respiratory pathogens (Haemophilus influenzae, Moraxella catarrhalis) and atypical pathogens such as Chlamydia pneumoniae, Legionella pneumophila, and Mycoplasma pneumoniae. Gemifloxacin, consistent with other available fluoroquinolones, has insufficient activity against methicillin-resistant Staphylococcus aureus to allow clinical use for such infections. Gemifloxacin has adequate bioavailability and a favorable drug interaction profile. Gemifloxacin was comparable to commonly employed nonfluoroquinolone regimens for treatment of CAP and AECB, although the studies were designed to demonstrate equivalence. Gemifloxacin once daily for 5-7 days was well tolerated in controlled and uncontrolled clinical studies. Available clinical data, however, are insufficient to draw clinical or toxicologic distinctions between gemifloxacin and other fluoroquinolones. CONCLUSIONS: Gemifloxacin may be a suitable choice for empiric treatment of CAP or AECB. However, due to the significant history of fluoroquinolone-induced hepatic failure and dermatologic complications, the use of this drug should be closely monitored.

Anti-Bacterial Agents↗
PubMed2006

Activity of gemifloxacin tested against Neisseria gonorrhoeae isolates including antimicrobial-resistant phenotypes.

The antigonococcal potency of gemifloxacin and 5 reference comparator antimicrobials was determined for a selected collection of gonococcal isolates. The 250 Neisseria gonorrhoeae strains were inclusive of (1) 50 historic strains from Japan with elevated fluoroquinolone minimal inhibitory concentration values (QRNG) and (2) 200 contemporary strains from clinical specimens in 2004 (176 from 6 sentinel sites in the United States and 24 bacteremic isolates from the SENTRY Antimicrobial Surveillance Program). The rank order of potency of the tested antimicrobials for the entire collection was: ceftriaxone (MIC(90) = 0.06 microg/mL) > gemifloxacin (1 microg/mL) > tetracycline (2 microg/mL) > ciprofloxacin = levofloxacin = penicillin (4 microg/mL). The activity of gemifloxacin was not affected by penicillinase production; however, its activity was decreased for penicillin-resistant strains. Cross-resistance between gemifloxacin and the older fluoroquinolones was present, and the gemifloxacin MIC90 value was higher for the ciprofloxacin-resistant strains compared with the ciprofloxacin-susceptible strains (2 versus 0.016 mug/mL, respectively). More than 20.0% of the recent clinical strains were resistant to penicillin, tetracycline, and ciprofloxacin with >30.0% of gonococci resistant to ciprofloxacin in Washington State and Hawaii. The historic QRNG strains from the Far East were predominantly of intermediate susceptibility (88.0%) to ciprofloxacin, with a gemifloxacin MIC90 value of only 0.25 microg/mL. The bacteremic gonococcal strains were exquisitely susceptible to the 3 quinolones tested (ciprofloxacin, levofloxacin, and gemifloxacin, MIC90 at < or = 0.03 microg/mL) and ceftriaxone (MIC90 = 0.06 microg/mL). In summary, the potency of gemifloxacin was competitive and positioned between that of ceftriaxone and older quinolones or penicillin or tetracycline, irrespective of the gonococcal resistance phenotype. Gemifloxacin should be considered for further development as a therapeutic option to treat uncomplicated infections due to emerging strains resistant to penicillins, tetracycline, and some older fluoroquinolones.

Anti-Bacterial Agents↗
PubMed2000

In vitro activity of gemifloxacin against contemporary clinical bacterial isolates from eleven North American medical centers, and assessment of disk diffusion test interpretive criteria.

A total of 5499 contemporary clinical bacterial isolates were tested for susceptibility to gemifloxacin and four comparison agents by the broth microdilution method. Gemifloxacin activity against Enterobacteriaceae was generally comparable to that of ciprofloxacin and trovafloxacin, but because the gemifloxacin susceptible MIC breakpoint is lower, the percent susceptible to gemifloxacin was less than that to the other quinolones for some species. All agents were less active against Pseudomonas spp. Gemifloxacin was the most active agent tested against Gram-positive species, though Corynebacterium jeikeium and vancomycin-resistant enterococci were uniformly resistant to all agents tested. With staphylococci, a bimodal distribution of gemifloxacin MICs corresponded with susceptibility or resistance to ciprofloxacin. The significance of ciprofloxacin-resistant staphylococci that have susceptible gemifloxacin MICs is not known at this time. Disk diffusion tests were performed simultaneously with gemifloxacin and trovafloxacin as a control drug. Gemifloxacin MIC-zone diameter scattergrams indicated that interpretive discrepancy rates based on previously proposed criteria when using < or = 0.5 microg/ml as the susceptible MIC breakpoint was within acceptable limits. However, with the currently proposed MIC breakpoint of < or = 0.25 microg/ml, tentative zone diameter breakpoints of > or = 22 mm for susceptible, 19-21 mm for intermediate and < or = 18 mm for resistant are proposed.

Anti-Infective Agents↗
PubMed2000

The effect of ferrous sulphate and sucralfate on the bioavailability of oral gemifloxacin in healthy volunteers.

Sucralfate is a cytoprotectant with antacid properties and ferrous sulphate is commonly prescribed for iron-deficiency anaemia. This open, randomized, single-dose, five-way crossover study investigated the effect of sucralfate and ferrous sulphate on the bioavailability of gemifloxacin, a novel fluoroquinolone antimicrobial. Twenty-seven healthy male volunteers received gemifloxacin, 320 mg p.o., alone, 3 h after sucralfate (2 g) or ferrous sulphate (325 mg), or 2 h before sucralfate or ferrous sulphate. Each subject received all five dosing regimens in random order with at least 6 days between regimens. Plasma samples collected up to 48 h after dosing with gemifloxacin, were assayed for gemifloxacin to determine pharmacokinetic parameters. Administration of gemifloxacin 3 h after sucralfate produced a marked decrease of 53% in the area under the plasma concentration-time curve from time zero extrapolated to infinity (AUC0-infinity), and a decrease of 69% in the maximal plasma concentration (Cmax). Administration of gemifloxacin 3 h after ferrous sulphate resulted in only a modest reduction of 11% in AUC0-infinity and of 20% in Cmax, which was not considered to be clinically significant. In contrast, at the doses used neither sucralfate nor ferrous sulphate altered gemifloxacin bioavailability when it was administered 2 h before either of these agents. Gemifloxacin was well tolerated in all the regimens. The results of this study support the dosing recommendation that gemifloxacin can be safely administered at least 2 h before sucralfate or ferrous sulphate, or at least 3 h after ferrous sulphate.

Adolescent↗
PubMed2001

Urinary excretion and bactericidal activities of gemifloxacin and ofloxacin after a single oral dose in healthy volunteers.

In a randomized crossover study, 16 volunteers (8 men, 8 women) received single oral doses of 320 mg of gemifloxacin and 400 mg of ofloxacin on two separate occasions in the fasting state to assess the urinary excretion and urinary bactericidal titers (UBTs) at intervals for up to 144 h. Ofloxacin showed higher concentrations in urine compared with those of gemifloxacin. The median (range) cumulative excretion of gemifloxacin was 29.7% (8.4 to 48.7%) of the parent drug administered, and median (range) cumulative excretion of ofloxacin was 84.3% (46.5 to 95.2%) of the parent drug administered. The UBTs, i.e., the highest twofold dilutions (with antibiotic-free urine as the diluent) of urine that were still bactericidal, were determined for a reference strain and nine uropathogens for which the MICs of gemifloxacin and ofloxacin were as follows: Escherichia coli ATCC 25922, 0.016 and 0.06 microg/ml, respectively; Klebsiella pneumoniae, 0.03 and 0.06 microg/ml, respectively; Proteus mirabilis, 0.125 and 0.125 microg/ml, respectively; Escherichia coli, 0.06 and 0.5 microg/ml, respectively; Pseudomonas aeruginosa, 1 and 4 microg/ml, respectively; Staphylococcus aureus, 0.008 and 0.25 microg/ml, respectively; Enterococcus faecalis, 0.06 and 2 microg/ml, respectively; Staphylococcus aureus, 0.25 and 4 microg/ml, respectively; Enterococcus faecalis, 0.5 and 32 microg/ml, respectively; and Staphylococcus aureus, 2 and 32 microg/ml, respectively. Generally, the UBTs for gram-positive uropathogens were higher for gemifloxacin than for ofloxacin and the UBTs for gram-negative uropathogens were higher for ofloxacin than for gemifloxacin. According to the UBTs, ofloxacin-resistant uropathogens (MICs, >or=4 mg/liter) should also be considered gemifloxacin resistant. Although clinical trials have shown that gemifloxacin is effective for the treatment of uncomplicated urinary tract infections, whether an oral dosage of 320 mg of gemifloxacin once daily is also adequate for the treatment of complicated urinary tract infections has yet to be confirmed.

Adolescent↗
PubMed2001

In vitro activity of gemifloxacin (SB-265805, LB20304a) against Legionella pneumophila and its pharmacokinetics in guinea pigs with L. pneumophila pneumonia.

The activity of gemifloxacin against intracellular Legionella pneumophila and for the treatment of guinea pigs with L. pneumophila pneumonia was studied. Gemifloxacin, azithromycin, and levofloxacin (1 microg/ml) reduced bacterial counts of two L. pneumophila strains grown in guinea pig alveolar macrophages by 2 to 3 log(10) units. Gemifloxacin and levofloxacin had roughly equivalent intracellular activities. In contrast, erythromycin had static activity only. Therapy studies of gemifloxacin, azithromycin, and levofloxacin were performed in guinea pigs with L. pneumophila pneumonia. When gemifloxacin (10 mg/kg) was given by the intraperitoneal (i.p.) route to infected guinea pigs, mean peak levels in plasma were 1.3 microg/ml at 0.5 h and 1.2 microg/ml at 1 h postinjection. The terminal half-life phase of elimination from plasma was 1.3 h, and the area under the concentration-time curve from 0 to 24 h (AUC(0--24)) was 2.1 microg. h/ml. For the same drug dose, mean levels in lungs were 3.4 microg/g at both 0.5 and 1 h, with a half-life of 1.5 h and an AUC(0--24) of 6.0 microg. h/ml. All 15 L. pneumophila-infected guinea pigs treated with gemifloxacin (10 mg/kg/dose given i.p. once daily) for 2 days survived for 9 days after antimicrobial therapy, as did 13 of 14 guinea pigs treated with the same dose of gemifloxacin given for 5 days. All 12 azithromycin-treated animals (15 mg/kg/dose given i.p. once daily for 2 days) survived, as did 11 of 12 animals treated with levofloxacin (10 mg/kg/dose given i.p. once daily for 5 days). None of 12 animals treated with saline survived. Gemifloxacin is effective against L. pneumophila in infected macrophages and in a guinea pig model of Legionnaires' disease, even with an abbreviated course of therapy. These data support studies of the clinical effectiveness of gemifloxacin for the treatment of Legionnaires' disease.

Animals↗