Characterization of baseline polybacterial versus monobacterial infections in three randomized controlled bacterial conjunctivitis trials and microbial outcomes with besifloxacin ophthalmic suspension 0.6.

BACKGROUND/PURPOSE: To date, studies examining polymicrobial infections in ocular disease have mostly been limited to keratitis or endophthalmitis. We characterized polybacterial infections compared to monobacterial infections in prior clinical studies evaluating besifloxacin ophthalmic suspension 0.6% for the treatment of bacterial conjunctivitis and report on associated microbiological outcomes. METHODS: In this post-hoc analysis, microbiological data for subjects with conjunctivitis due to one or more than one bacterial species in three previous studies (two vehicle-, one active-controlled) of besifloxacin were extracted. Bacterial species identified at baseline were deemed causative if their colony count equaled or exceeded species-specific prespecified threshold criteria. In subjects with polybacterial infections, the fold-increase over threshold was used to rank order the contribution of individual species. Baseline pathogens and their minimum inhibitory concentrations (MICs) for common ophthalmic antibiotics were compared by infection type, as were microbial eradication rates following treatment with besifloxacin. RESULTS: Of 1041 subjects with culture-confirmed conjunctivitis, 17% had polybacterial and 83% had monobacterial conjunctivitis at baseline. In polybacterial compared to monobacterial infections, Haemophilus influenzae and Streptococcus pneumoniae were identified less frequently as the dominant infecting species (P = 0.042 and P<0.001, respectively), whereas Streptococcus mitis/S. mitis group was identified more frequently as dominant (P<0.001). Viral coinfection was also identified more frequently in polybacterial infections (P<0.001). Staphylococcus aureus was the most common coinfecting species in polybacterial infections and the second most common dominant species in such infections. With few exceptions, MICs for individual species were comparable regardless of infection type. Clinical microbial eradication rates with besifloxacin were high regardless of infection type (P≤0.016 vs vehicle at follow-up visits). CONCLUSIONS: Approximately one in five subjects with bacterial conjunctivitis are infected with more than one bacterial species underscoring the need for a broad-spectrum antibiotic for such infections. Besifloxacin treatment resulted in robust eradication rates of these infections comparable to monobacterial infections. TRIAL REGISTRATION: NCT000622908, NCT00347932, NCT00348348.

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.

Current issues in the management of urinary tract infections: extended-release ciprofloxacin as a novel treatment option.

Symptomatic urinary tract infections (UTIs) are a major public health concern in the developed world, accounting for almost 8 million annual outpatient and emergency department visits in the US alone, while also representing one of the most common hospital-acquired infections. The vast majority of uncomplicated UTIs are caused by the Gram-negative bacillus Escherichia coli, with other pathogens including enterococci, Staphylococcus saprophyticus, Klebsiella spp. and Proteus mirabilis. Effective management of UTIs in both the inpatient and outpatient settings has been complicated by the fact that many uropathogenic strains have developed resistance to antimicrobials, including cotrimoxazole (trimethoprim/sulfamethoxazole), the current first-line treatment for uncomplicated UTIs in the US and many other countries. In some countries, other antimicrobial therapies, such as trimethoprim and nitrofurantoin, are also used for treatment of uncomplicated UTIs. Antimicrobial resistance has been associated with an increased rate of clinical failure, and reports from Canada and the US indicate that the prevalence of cotrimoxazole resistance exceeds 15% and can be as high as 25%.The emergence and dissemination of antimicrobial resistance can be reduced with the use of agents that have favourable pharmacokinetic/pharmacodynamic profiles and convenient dose administration regimens that facilitate patient adherence and, therefore, pathogen eradication. Fluoroquinolones have been used successfully to treat a wide range of community- and hospital-acquired infections, and the rates of fluoroquinolone resistance have remained low. Use of fluoroquinolones is recommended for uncomplicated UTIs in areas where the incidence of cotrimoxazole resistance exceeds 10%, as well as for the treatment of complicated UTIs and acute pyelonephritis. Ciprofloxacin is a widely used fluoroquinolone with high bactericidal activity against uropathogens and well established clinical efficacy in the treatment of UTIs. A new, extended-release formulation of ciprofloxacin (Cipro XR) provides systemic drug exposure comparable with that achieved with twice-daily administration of conventional, immediate-release ciprofloxacin, while also attaining higher maximum plasma concentrations with less interpatient variability. Therapeutic drug concentrations with extended-release ciprofloxacin are established immediately after dose administration and maintained throughout the 24-hour dosage interval, permitting convenient, once-daily treatment. Clinical trial results confirm that extended-release ciprofloxacin is as safely used and effective as the conventional, immediate-release formulation of ciprofloxacin in patients with uncomplicated UTIs, complicated UTIs or acute uncomplicated pyelonephritis. These findings support the use of extended-release ciprofloxacin as a well tolerated, effective and convenient therapy for UTIs, which may improve patients' adherence to therapy and, thereby, reduce the risk of infection recurrence and emergence of antimicrobial resistance.

The role of fluoroquinolones in skin and skin structure infections.

Skin and skin structure infections encompass a broad range of clinical presentations and disease severity. Antimicrobial therapy is clearly beneficial for both recovery from these infections as well as preventing disease progression. Fluoroquinolones are potent broad spectrum antimicrobial agents with the older agents characterized as having broad spectrum anti-Gram-negative activity, borderline activity against clinically important Gram-positive pathogens and little or no anti-anaerobic bacteria activity. In contrast, the new quinolones are characterized by having enhanced activity against Gram-positive pathogens, anti-anaerobic activity and they remain highly active against aerobic-Gram-negative bacilli. Several fluoroquinolones have been evaluated for the treatment of uncomplicated skin and soft tissue infection, difficult skin and soft tissue infection and serious skin and skin structure infections. Clinical cure rates were found to be equivalent to comparators suggesting a role for the fluoroquinolone in treating these infections. It may be necessary to use some fluoroquinolones in combination with anti-anaerobic agents for those infections with mixed aerobic and anaerobic pathogens. Some additional clinical trials are necessary to identify the full potential of newer fluoroquinolones for skin and skin structure infections. At present, quinolones are, in general, equivalent to beta-lactam agents in the treatment of skin and soft tissue infection.