besifloxacin and Staphylococcal-Infections

Penetration of antibiotics into and through the cornea is a major limiting factor in the treatment of ocular infections. Several strategies are in vogue to overcome this limitation such as use of fortified drops, gels, and subconjunctival injections. Here, we present the fabrication of rapidly dissolving polymeric microneedle array to effectively deliver besifloxacin through the cornea. Microneedles were prepared using polyvinyl alcohol and polyvinyl pyrrolidone by the micromolding technique. The model fluoroquinolone antibiotic, besifloxacin, was loaded in 36 microneedles arranged in a 6 × 6 array format within a 1 cm

Topics: Administration, Ophthalmic; Anti-Bacterial Agents; Azepines; Biocompatible Materials; Cornea; Drug Delivery Systems; Drug Liberation; Fluoroquinolones; Humans; Microinjections; Needles; Polyvinyl Alcohol; Povidone; Solubility; Staphylococcal Infections; Staphylococcus aureus

Besifloxacin is a novel fluoroquinolone antibiotic developed to provide alternative coverage for ocular pathogens with current and emerging in vitro and in vivo resistance to present fluoroquinolones and other commonly dispensed ocular antibiotics. The purpose of this study was to investigate the in vitro efficacy of besifloxacin and 7 comparators against ciprofloxacin- and methicillin-susceptible and nonsusceptible staphylococcal isolates from conjunctivitis, blepharitiis, keratitis, endophthalmitis, and other ocular surface disorders.. Nonconsecutive ocular Staphylococcus aureus (N=154) and Coagulase-negative Staphylococcus (N=89, including 84 Staphylococcus epidermidis) isolates collected from patients presenting during the 6 years (2003-2008) were evaluated using frozen minimal inhibitory concentration (MIC) panels containing serial dilutions (μg/mL) of besifloxacin (0.004-32), moxifloxacin (0.004-128), ciprofloxacin (0.03-256), azithromycin (0.12-128), oxacillin (0.03-32), gentamicin (0.03-128), trimethoprim (0.5-16), and vancomycin (0.12-32).. Among the fluoroquinolones group, besifloxacin had the lowest MIC90s. MIC90 values (μg/mL) for besifloxacin (4) was 8-fold lower than for moxifloxacin (32) and 32-fold lower than ciprofloxacin (128). Among the nonfluoroquinolone comparators, vancomycin (2) had the lowest MICs followed by gentamicin (16) and trimethoprim (16). Besifloxacin MIC90s (μg/mL) were lowest for isolates recovered from the lacrimal sac (0.25), followed by lids (1), conjunctiva (2), keratitis (4), and intraocular fluids (4).. Due to its improved coverage for ciprofloxacin- and methicillin-resistant staphylococci, besifloxacin may offer extended coverage for some ocular pathogens resistant to current fluoroquinolones recovered from a diverse group of ocular sources. Ninety-five percent of all isolates were covered by a besifloxacin MIC90 of 4 μg/mL.

Topics: Anti-Bacterial Agents; Azepines; Ciprofloxacin; Drug Resistance, Multiple, Bacterial; Eye Infections, Bacterial; Fluoroquinolones; Humans; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Staphylococcal Infections; Staphylococcus aureus; Staphylococcus epidermidis

Besifloxacin is a novel fluoroquinolone that, like other fluoroquinolones, acts by inhibiting the essential bacterial enzymes DNA gyrase and topoisomerase IV. Topical besifloxacin ophthalmic suspension 0.6% is indicated for use in patients with bacterial conjunctivitis caused by susceptible bacteria. Besifloxacin had in vitro activity against a broad spectrum of Gram-positive and -negative bacteria that commonly cause ocular infections (e.g. Haemophilus influenzae, Staphylococcus aureus, S. epidermidis and Streptococcus pneumoniae), including drug-resistant strains. In two randomized, double-blind, multicentre trials, besifloxacin ophthalmic suspension 0.6% administered at the recommended dose for 5 days in patients aged > or =1 year with bacterial conjunctivitis was significantly (p < 0.01) more effective than vehicle in terms of clinical resolution and microbial eradication rates (coprimary endpoints) at study visit two (day 5+/-1) or three (day 8 or 9) [primary timepoints]. Besifloxacin ophthalmic suspension 0.6% was noninferior to moxifloxacin ophthalmic solution 0.5% in patients aged > or =1 year with bacterial conjunctivitis with regard to clinical resolution (58.3% vs 59.4%) and microbial eradication (93.3% vs 91.1%) rates on day 5 +/- 1 of treatment (coprimary endpoints) in a randomized, double-blind, multicentre trial; both drugs were administered at a dosage of one drop in the affected eye(s) three times daily for 5 days. Besifloxacin ophthalmic suspension 0.6% was generally well tolerated in clinical trials, with most adverse events being mild in severity. The tolerability profile of besifloxacin ophthalmic suspension 0.6% was similar to that of moxifloxacin ophthalmic solution 0.5%.

Topics: Administration, Topical; Anti-Bacterial Agents; Antifungal Agents; Aza Compounds; Azepines; Colony Count, Microbial; Conjunctivitis, Bacterial; DNA Gyrase; DNA Topoisomerase IV; Double-Blind Method; Drug Administration Schedule; Eye; Fluoroquinolones; Humans; Methicillin Resistance; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Moxifloxacin; Ophthalmic Solutions; Quinolines; Staphylococcal Infections; Staphylococcus aureus; Streptococcus pneumoniae; Suspensions

To determine the effectiveness of topically applied besifloxacin, gatifloxacin, and moxifloxacin for the early treatment of experimental methicillin-resistant Staphylococcus aureus (MRSA) keratitis.. Ten hours post-MRSA infection, rabbit eyes were treated topically with 19 doses of phosphate-buffered saline (PBS), besifloxacin, gatifloxacin, or moxifloxacin. Slit-lamp examinations were performed before and after the inoculation. Corneas were harvested for bacterial quantitation and minimal inhibitory concentrations (MICs) were determined.. All 3 fluoroquinolones significantly lowered the clinical severity of the infection as compared to treatment with PBS (P < 0.05). However, the mean log(10) colony-forming unit (CFU) recovered from besifloxacin-treated corneas was significantly lower than all other treatment groups (P < 0.01). CFU recovered from corneas treated with moxifloxacin and PBS showed no significant difference (P = 0.12). Corneas treated with gatifloxacin had a significantly lower log(10) CFU recovered as compared to PBS-treated corneas (P < 0.01). The MICs for gatifloxacin and moxifloxacin were 8 microg/mL, whereas the MIC for besifloxacin was 1 microg/mL.. All 3 fluoroquinolones significantly lowered the clinical severity of the infection. Besifloxacin had an 8-fold lower MIC for MRSA than gatifloxacin and moxifloxacin, and was significantly more effective than gatifloxacin and moxifloxacin in reducing the number of MRSA in the rabbit cornea.

Topics: Administration, Topical; Animals; Anti-Bacterial Agents; Aza Compounds; Azepines; Colony Count, Microbial; Cornea; Corneal Ulcer; Disease Models, Animal; Eye Infections, Bacterial; Female; Fluoroquinolones; Gatifloxacin; Male; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Moxifloxacin; Quinolines; Rabbits; Specific Pathogen-Free Organisms; Staphylococcal Infections; Treatment Outcome

The purpose of this investigation was to evaluate the ocular pharmacokinetic/pharmacodynamic (PK/PD) relationship for besifloxacin, moxifloxacin, and gatifloxacin using rabbit ocular PK data, along with in vitro minimum inhibitory concentration (MIC90) values against methicillin- and ciprofloxacin-resistant Staphylococcus aureus (MRSA-CR) and Staphylococcus epidermidis (MRSE-CR).. Rabbits received a topical instillation of Besivance™ (besifloxacin ophthalmic suspension, 0.6%), Vigamox (moxifloxacin hydrochloride ophthalmic solution, 0.5% as base), or Zymar (gatifloxacin ophthalmic solution, 0.3%), and ocular tissues and plasma were collected from 4 animals/treatment/collection time at 8 predetermined time intervals during the 24h after dosing. Ocular levels of each agent were measured by LC/MS/MS, and PK parameters (Cmax, Tmax, and AUC₀₋₂₄) were determined. AUC₀₋₂₄/MIC₉₀ ratios were calculated for tears, conjunctiva, cornea, and aqueous humor using previously reported MIC₉₀values for MRSA-CR and MRSE-CR.. All of the fluoroquinolones tested demonstrated rapid penetration into ocular tissues after a single instillation. Besifloxacin demonstrated the highest exposure in tear fluid, while exposure in conjunctiva was comparable for all 3 compounds. Peak concentrations of all fluoroquinolones in aqueous humor were at or below ~1g/mL. In comparison with their MIC₉₀values against MRSE-CR and MRSA-CR, besifloxacin achieved an AUC₀₋₂₄/MIC₉₀ ratio of ~800 in tears, compared with values of ≤10 for moxifloxacin and gatifloxacin. In cornea, conjunctiva, and aqueous humor, the AUC₀₋₂₄/MIC₉₀ ratios were <10 for all compounds. However, in these tissues AUC₀₋₂₄/MIC₉₀ ratios for besifloxacin were 1.5- to 38-fold higher than moxifloxacin and gatifloxacin.. In rabbits, besifloxacin demonstrates a nonclinical ocular PK profile characterized by high and sustained concentrations in tear fluid, resulting in AUC₀₋₂₄/MIC₉₀ ratios of ~800 for ciprofloxacin-resistant MRSE and MRSA after a single administration. Although besifloxacin had the highest AUC₀₋₂₄/MIC₉₀ratios for intraocular tissues, the ratios for all of the drugs were below the target values needed for effective bacterial killing of ciprofloxacin-resistant MRSE and MRSA. Taken together, these nonclinical data indicate that besifloxacin has a favorable ocular PK/PD profile, consistent with the reported clinical efficacy of besifloxacin in the treatment of bacterial conjunctivitis, and consistent with the profile needed for ocular surface sterilization.

Topics: Administration, Topical; Animals; Aqueous Humor; Area Under Curve; Aza Compounds; Azepines; Conjunctivitis, Bacterial; Eye; Fluoroquinolones; Gatifloxacin; Haemophilus Infections; Male; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Moxifloxacin; Quinolines; Rabbits; Staphylococcal Infections; Streptococcal Infections

To determine the effectiveness of moxifloxacin and besifloxacin prophylactic therapy for experimental Staphylococcus aureus infections originating in the rabbit anterior chamber.. Microbiology Department, University of Mississippi Medical Center, Jackson, Mississippi, USA.. Experimental study.. Minimum inhibitory concentrations (MICs) of moxifloxacin 0.5% and besifloxacin 0.6% for methicillin-sensitive Staphylococcus aureus (MSSA) and methicillin-resistant Staphylococcus aureus (MRSA) strains were determined. Eyes were treated with moxifloxacin, a moxifloxacin alternative formulation 0.5%, or besifloxacin (45 μL) 30 minutes or 60 minutes before anterior chamber infection (10(6) colony-forming units [CFUs]). Aqueous humor was removed 30 minutes after infection for quantification of antibiotic and bacteria.. The MIC for both organisms was 0.06 μg/mL for moxifloxacin and 0.03 μg/mL for besifloxacin. In MSSA infections, the untreated eyes contained 5.18 log CFU/mL, which was similar to besifloxacin-treated eyes with either treatment (P≥.1091). Eyes treated with moxifloxacin or moxifloxacin alternative formulation contained significantly fewer CFUs than untreated controls or besifloxacin-treated eyes with either treatment (P≤.0020). The aqueous humor in eyes treated with moxifloxacin or moxifloxacin alternative formulation contained significantly more drug than besifloxacin-treated eyes at both prophylactic time points (P≤.0012). In MRSA infections, the untreated eyes contained 4.91 log CFU/mL, which was similar to besifloxacin-treated eyes with either treatment (P≥.5830). Eyes treated with moxifloxacin or moxifloxacin alternative formulation contained significantly fewer CFUs than untreated controls or besifloxacin-treated eyes at both prophylactic time points (P≤.0008).. Moxifloxacin had greater in vivo effectiveness against MSSA and MRSA than besifloxacin. The aqueous antibiotic concentrations suggest limited penetration by besifloxacin, accounting for its lack of effectiveness.

Topics: Animals; Anti-Infective Agents; Aqueous Humor; Aza Compounds; Azepines; Biological Availability; Colony-Forming Units Assay; Disease Models, Animal; Eye Infections, Bacterial; Fluoroquinolones; Methicillin Resistance; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Moxifloxacin; Quinolines; Rabbits; Staphylococcal Infections; Treatment Outcome

The purpose of this study was to determine the effectiveness of topically applied besifloxacin (0.6%), gatifloxacin (0.3%), and moxifloxacin (0.5%) for the late treatment of experimental methicillin-resistant Staphylococcus aureus (MRSA) keratitis.. One hundred colony-forming units (CFUs) of bacteria were injected intrastromally into rabbit corneas. Sixteen hours after infection, one topical drop of phosphate-buffered saline, besifloxacin, gatifloxacin, or moxifloxacin was applied to each eye every 15 minutes for 5 doses and then every 30 minutes for 14 doses. Eyes were examined before and after treatment by slit lamp biomicroscopy. Corneas were harvested from treated and untreated rabbits for the quantitation of bacteria. Minimal inhibitory concentrations (MICs) were determined in vitro for each fluoroquinolone.. None of the treatments had an effect on clinical severity (P > 0.05). Although there were no differences in clinical severity between any groups after treatment, the mean log10 CFU of MRSA recovered from besifloxacin-treated corneas (5.111 +/- 0.251) was significantly lower than the CFU recovered from corneas treated with phosphate-buffered saline (7.006 +/- 0.144), gatifloxacin (7.108 +/- 0.346), and moxifloxacin (7.473 +/- 0.144; P < 0.001). CFU recovered from gatifloxacin- and moxifloxacin-treated corneas were not significantly different from phosphate-buffered saline-treated corneas (P = 1.000). The MICs against the MRSA strain were 8 microg/mL for both gatifloxacin and moxifloxacin, whereas the MIC for besifloxacin was 1 microg/mL.. Besifloxacin had an 8-fold lower MIC for MRSA than gatifloxacin and moxifloxacin and was significantly more effective than gatifloxacin and moxifloxacin in reducing the number of MRSA in the rabbit cornea 16 hours after infection.

Topics: Administration, Topical; Animals; Anti-Bacterial Agents; Aza Compounds; Azepines; Colony Count, Microbial; Corneal Ulcer; Disease Models, Animal; Eye Infections, Bacterial; Female; Fluoroquinolones; Gatifloxacin; Male; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Moxifloxacin; Ophthalmic Solutions; Quinolines; Rabbits; Staphylococcal Infections; Treatment Outcome