gemifloxacin and Staphylococcal-Infections

Community-acquired lower respiratory tract infections (LRTIs) are more prevalent in the elderly than in children and younger adults and form a significant proportion of all consultations and hospital admissions in this older age group. Furthermore, in a world of increasing life expectancy the trend seems unlikely to be reversed. Antimicrobial treatment of community-acquired pneumonia (CAP) must cover Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis, and in many circumstances should also cover the intracellular (atypical) pathogens. In contrast, acute exacerbations of chronic bronchitis (AECB) are mainly associated with H. influenzae and S. pneumoniae and not with atypical bacteria: in severe cases, other Gram-negative bacteria may be involved. Frequently in LRTIs, the aetiology of the infection cannot be identified from the laboratory specimens and treatment has to be empirical. In such situations it is important to not only to use an antibiotic that covers all likely organisms, but also one that has good activity against these organisms given the local resistance patterns. Gemifloxacin is a new quinolone antibiotic that targets pneumococcal DNA gyrase and topoisomerase IV and is highly active against S. pneumoniae including penicillin-, macrolide- and many ciprofloxacin-resistant strains, as well as H. influenzae and the atypical pathogens. In clinical trials in CAP and AECB, gemifloxacin has been shown to be as effective a range of comparators and demonstrated an adverse event profile that was in line with the comparator agents. In one long-term study in AECB significantly more patients receiving gemifloxacin than clarithromycin remained free of recurrence after 26 weeks. The improved potency, broad spectrum of activity and proven clinical and bacteriological efficacy and safety profile should make it a useful agent in the 21st century battle against community-acquired LRTIs.

Topics: Anti-Bacterial Agents; Bronchitis; Chlamydophila Infections; Community-Acquired Infections; Fluoroquinolones; Gemifloxacin; Gram-Negative Bacterial Infections; Haemophilus Infections; Humans; Legionnaires' Disease; Moraxellaceae Infections; Naphthyridines; Pneumococcal Infections; Pneumonia, Bacterial; Pneumonia, Mycoplasma; Staphylococcal Infections

An open-label, non-comparative study assessed the clinical and bacteriological efficacy of gemifloxacin (320 mg, once-daily for 7 days) in lower respiratory tract infections (LRTI). Patients with acute exacerbation of chronic bronchitis (AECB, n=261) or community-acquired pneumonia (CAP, n=216) were enrolled into the study. Clinical success rates at follow-up (days 21-28) in the intent-to-treat (ITT) population were high, 83.1% in AECB patients (95% CI: 77.9, 87.4) and 82.9% in CAP patients (95% CI: 77.0, 87.5). High bacteriological success rates were achieved (bacteriological ITT population), 91.2% (52/57) in AECB patients (95% CI: 80.0, 96.7) and 77.9% (60/77) in CAP patients (95% CI: 66.8, 86.3). Gemifloxacin was well tolerated with a low incidence of adverse events. Gemifloxacin treatment resulted in high clinical and bacteriological success rates and is a well-tolerated therapy for the treatment of LRTIs.

Topics: Adult; Aged; Anti-Infective Agents; Bronchitis; Chronic Disease; Community-Acquired Infections; Drug Administration Schedule; Female; Fluoroquinolones; Gemifloxacin; Gram-Negative Bacterial Infections; Haemophilus Infections; Humans; Klebsiella Infections; Male; Middle Aged; Naphthyridines; Pneumococcal Infections; Pneumonia, Bacterial; Staphylococcal Infections; Treatment Failure

Herein, we report spiropyrimidinetriones (SPTs) incorporating N-linked azole substituents on a benzisoxazole scaffold with improved Gram-positive antibacterial activity relative to previously described analogues. SPTs have an unusual spirocyclic architecture and represent a new antibacterial class of bacterial DNA gyrase and topoisomerase IV inhibitors. They are not cross-resistant to fluoroquinolones and other DNA gyrase/topoisomerase IV inhibitors used clinically. The activity of the SPTs was assessed for DNA gyrase inhibition, and the antibacterial activity across Gram-positive and Gram-negative pathogens with N-linked 1,2,4-triazoles substituted on the 5-position provides the most worthwhile profile. Directed nucleophilic and electrophilic chemistry was developed to vary this 5-position with carbon, nitrogen, or oxygen substituents and explore structure-activity relationships including those around a target binding model. Compounds with favorable pharmacokinetic parameters were identified, and two compounds demonstrated cidality in a mouse model of

Topics: Animals; Anti-Bacterial Agents; Azoles; Disease Models, Animal; DNA Gyrase; Dose-Response Relationship, Drug; Isoxazoles; Mice; Microbial Sensitivity Tests; Molecular Structure; Pyrimidinones; Rats; Rats, Wistar; Spiro Compounds; Staphylococcal Infections; Staphylococcus aureus; Structure-Activity Relationship; Topoisomerase II Inhibitors

In recent years, the emergence of methicillin-resistant Staphylococcus aureus (MRSA) strains has been observed in ocular infections. Resistance of MRSA to second- and third-generation fluoroquinolones has increased interest in the fourth-generation fluoroquinolones. In this study, the antibacterial activity of gemifloxacin against MRSA ocular isolates in vitro and in a modified ex vivo rabbit keratitis model was investigated. In vitro susceptibility test results indicated that the minimum inhibitory concentrations (MICs) of gemifloxacin were lower than the MICs of other fluoroquinolones, including moxifloxacin (MIC50 range, 0.016-0.032 µg/mL; MIC90 range, 0.047-0.094 µg/mL). Results from the ex vivo keratitis model showed a statistically significant decrease in MRSA counts (0.5-2 log10 CFU/g; P <0.05) in corneas treated with 0.3% gemifloxacin every 30 min for 7 h. Moreover, the dose-response effect of different concentrations of gemifloxacin (3-3000 µg/mL) demonstrated that a dose of 30 µg/mL had the same efficacy as the highest dose of 3000 µg/mL against all S. aureus strains. Possibly, gemifloxacin reached a steady-state level in the cornea, as the fourth-generation fluoroquinolones have better anterior chamber penetration. This study demonstrated that 0.3% gemifloxacin ophthalmic solution may be an effective topical therapy for the treatment of MRSA keratitis. In addition, this reproducible, ethical and economic ex vivo infection model can be used as a mechanistically-based alternative to in vivo animal testing, bridging the gap between in vitro and in vivo results.

Topics: Animals; Anti-Bacterial Agents; Bacterial Load; Colony Count, Microbial; Fluoroquinolones; Gemifloxacin; Keratitis; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Models, Theoretical; Moxifloxacin; Naphthyridines; Rabbits; Staphylococcal Infections; Treatment Outcome

The objective of the present study was to evaluate the effectiveness of topically applied gemifloxacin for the treatment of experimental Staphylococcus aureus keratitis in a rabbit model.. Rabbit corneas were intrastromally injected with ~100 colony-forming units (CFU) of S. aureus ATCC25923. Eight hours (early treatment) or 16 h (late treatment) after the injection, 1 topical drop of balanced salt solution (BSS), gemifloxacin ophthalmic solution (0.5%), levofloxacin ophthalmic solution (0.5%), or gatifloxacin eye gel (0.3%) was applied to each eye every 15 min for 5 doses and then, every 30 min for 14 doses. The eyes were examined both before and after treatment. The corneas were harvested from treated and untreated rabbits for the quantitation of bacteria and histological observation.. In the early-treatment groups, all 3 fluoroquinolones significantly lowered the clinical severity of infection and the median erosion area of the cornea compared with the BSS control (P=0.000). In the late-treatment groups, gemifloxacin and levofloxacin did not cause a significant reduction in clinical scores compared with the BSS control (P=0.107 and 0.531, respectively), but the gatifloxacin caused a significant reduction in clinical scores compared with the BSS control (P=0.011). The median erosion area significantly decreased with treatment with gemifloxacin, gatifloxacin, and levofloxacin in both early- and late-treatment groups, when compared with the control group (P≤0.022). In the early-treatment groups, the gemifloxacin, gatifloxacin, and levofloxacin groups had significantly lower CFU recovered from the corneas compared with the control group (P<0.01), while in the late-treatment groups, levofloxacin failed to reduce the CFU recovered from the corneas compared with the control group (P=0.695). The minimal inhibitory concentrations for gemifloxacin, gatifloxacin, and levofloxacin against S. aureus ATCC25923 were 0.0625, 0.0625, and 0.125 mg/L, respectively.. Gemifloxacin, similar to gatifloxacin and levofloxacin, can significantly lower the clinical severity and CFU per cornea observed in S. aureus keratitis when early treatment is implemented. Significantly, gemifloxacin showed a significant efficacy improvement in reducing the bacterial load recovered from the corneas in the late-treatment experiment.

Topics: Animals; Anti-Infective Agents, Local; Colony Count, Microbial; Conjunctival Diseases; Cornea; Eye; Female; Fluoroquinolones; Gatifloxacin; Gemifloxacin; Keratitis; Levofloxacin; Male; Microbial Sensitivity Tests; Naphthyridines; Ofloxacin; Rabbits; Staphylococcal Infections; Staphylococcus aureus

The rapid emergence of methicillin-resistant Staphylococcus aureus from the community (CA-MRSA) presents difficulties in making treatment choices. We evaluated whether combining another orally available agent commonly used to treat CA-MRSA with gemifloxacin would enhance gemifloxacin activity against CA-MRSA.. Fifty strains of SCCmec IV, agr group 1, Panton-Valentine leucocidin-positive CA-MRSA were evaluated for susceptibilities to gemifloxacin, trimethoprim/sulfamethoxazole, doxycycline, levofloxacin, rifampicin, clindamycin and erythromycin. Twenty of these strains were evaluated for the potential for synergy between gemifloxacin and trimethoprim/sulfamethoxazole, clindamycin and rifampicin by time-kill analysis. Two strains were further evaluated in an in vitro pharmacokinetic/pharmacodynamic (PK/PD) model.. In time-kill analyses, gemifloxacin combined with trimethoprim/sulfamethoxazole produced additivity (6/20) or synergy (11/20) in 85% of the isolates tested. The addition of clindamycin to gemifloxacin showed additivity (3/20) or synergy (2/20) in 25% of the isolates. All isolates displayed indifference to the combination of gemifloxacin and rifampicin. In the PK/PD model, combining gemifloxacin and trimethoprim/sulfamethoxazole provided potent and sustained bactericidal activity to detection limits of 2 log(10) cfu/mL by 48 h; gemifloxacin combined with clindamycin or with rifampicin killed to detection limits by 56 h or later. One isolate developed efflux-mediated resistance to gemifloxacin at 96 h with gemifloxacin monotherapy. All combinations prevented the emergence of this resistance.. Synergy or additivity was demonstrated by time-kill analysis between gemifloxacin and trimethoprim/sulfamethoxazole in most isolates tested. In the PK/PD model, the addition of trimethoprim/sulfamethoxazole, clindamycin and rifampicin enhanced the activity of gemifloxacin against CA-MRSA and suppressed the emergence of resistance to gemifloxacin.

Topics: Anti-Bacterial Agents; Bacterial Proteins; Bacterial Toxins; Community-Acquired Infections; Drug Resistance, Bacterial; Drug Synergism; Exotoxins; Fluoroquinolones; Gemifloxacin; Humans; Leukocidins; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Microbial Viability; Naphthyridines; Staphylococcal Infections; Time Factors; Trans-Activators; Trimethoprim, Sulfamethoxazole Drug Combination

Staphylococcus epidermidis is a common pathogen in device-associated infections which is able to attach onto polymeric surfaces and develop multilayered biofilms. Attached S. epidermidis displays reduced susceptibility to antimicrobial agents. In this study we investigated the influence of ciprofloxacin and the group IV quinolones gatifloxacin, gemifloxacin, and moxifloxacin with the minimal attachment killing (MAK) assay. MAK concentrations were determined for three biofilm-positive wild-type strains and their isogenic biofilm-negative mutants Depending on strain and investigated quinolone, it was possible to distinguish between a heterogeneous MAK (MAKhetero), and a homogeneous resistance (MAKhomo) which corresponds to the model of a few persisting cells under antibiotic treatment. A lower MAKhomo was detected for the biofilm-negative mutants as well as for the corresponding wild-types for some of the tested quinolones, which seems to be a result of higher bacterial inocula, whereas the MAKhetero concentrations were comparable for mutants and wild-types for nearly all of the tested antibiotics and strains. These data indicate that biofilm formation is not necessary for persistence of attached S. epidermidis cells under treatment with quinolones and could explain therapeutic failure in foreign body-associated infections due to biofilm-negative S. epidermidis isolates. The individual resistance phenotypes of investigated strains indicate that the determination of MAK concentrations might help to predict the therapy outcome of foreign body-associated infections with both biofilm-positive and biofilm-negative S. epidermidis. Thus, the relatively high activity displayed by group IV quinolones against individual attached staphylococcal isolates indicates a possible treatment option with the respective quinolones for foreign body-associated infections due to these isolates.

Topics: Anti-Infective Agents; Aza Compounds; Bacterial Adhesion; Biofilms; Ciprofloxacin; Colony Count, Microbial; Dose-Response Relationship, Drug; Drug Resistance, Bacterial; Fluoroquinolones; Gatifloxacin; Gemifloxacin; Humans; Microbial Sensitivity Tests; Moxifloxacin; Mutation; Naphthyridines; Prosthesis-Related Infections; Quinolines; Quinolones; Staphylococcal Infections; Staphylococcus epidermidis

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.

Topics: Animals; Anti-Infective Agents; Bacterial Infections; Escherichia coli Infections; Fluoroquinolones; Gemifloxacin; Humans; Male; Naphthyridines; Proteus Infections; Pyelonephritis; Rats; Rats, Sprague-Dawley; Staphylococcal Infections; Streptococcal Infections; Wound Infection

To compare the antimicrobial effects (AMEs) of gemifloxacin (GEM) and ciprofloxacin (CIP) on Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa, a series of pharmacokinetic profiles of GEM (a single dose with the half-life (T(1/2)) of 7.4 h and CIP (two 12 h doses with T(1/2) of 4 h) were simulated in vitro over eight-fold ranges of the AUC/MIC ratio. Species- and strain-independent linear relationships observed between the intensity of AME (I(E)) and log AUC/MIC were not superimposed for GEM and CIP (r(2)=0.99 and 0.98, respectively). The predicted ratio for GEM that might be equivalent to a clinically established breakpoint value of AUC/MIC=125 (mg h/l)/(mg/l) for CIP was estimated at 110 (mg h/l)/(mg/l). It was calculated, that a daily dose of CIP that might provide the same AME as a clinical dose of GEM (320 mg) on a hypothetical strain of S. aureus with MICs=MIC(50)s would be as high as 2 x 3200 mg.

Topics: Anti-Infective Agents; Area Under Curve; Ciprofloxacin; Dose-Response Relationship, Drug; Escherichia coli; Escherichia coli Infections; Fluoroquinolones; Gemifloxacin; Humans; Microbial Sensitivity Tests; Models, Biological; Naphthyridines; Predictive Value of Tests; Staphylococcal Infections; Staphylococcus aureus