Urinary Concentrations of Endocrine-Disrupting Metals and Prevalent Breast Cancer in US Women.

The toxic metals cadmium, lead, and mercury are endocrine-disrupting agents that could produce estrogenic effects involving breast carcinogenesis. In this study, we further explored the relationship between exposure to these metals and prevalent breast cancer among female participants, aged 20 years or older, in the 2007-2016 National Health and Nutrition Examination Survey (NHANES). Exposure was determined by measuring urinary concentrations of metals using inductively coupled plasma mass spectrometry. Urine creatinine-corrected concentrations of metals were calculated for each study participant. Multivariate logistic regression models were constructed to examine the association between urinary metals and prevalent breast cancer, adjusting for potential confounders. Of the 3352 study participants, 106 had been diagnosed with breast cancer (weighted prevalence, 3.13%). The results show that women with breast cancer had significantly higher urinary concentrations of lead and cadmium (both p < 0.0001) than those without breast cancer. After adjusting for all the covariates included in the study, however, only urinary lead was shown to be significantly associated with increased prevalence of breast cancer, with an odds ratio of 2.95 (95% CI: 1.13, 7.70) in the highest quartile of urinary lead concentrations (≥ 0.71 µg/g creatinine) as compared with the lowest quartile. No statistically significant associations were observed between urine cadmium or mercury levels and breast cancer. This study demonstrates a potential association between lead exposure and prevalent breast cancer among US women. Prospective and mechanistic studies are warranted to further investigate this interaction and explore the role of lead in breast carcinogenesis.

The pharmacodynamic properties of azithromycin in a kinetics-of-kill model and implications for bacterial conjunctivitis treatment.

INTRODUCTION: Antibiotics have traditionally been classified as bactericidal or bacteriostatic. Azithromycin belongs to the parent class of macrolides that are characteristically bacteriostatic. Some evidence suggests that this molecule demonstrates bactericidal kill and has concentration-dependent effects. This study tests the hypothesis that azithromycin demonstrates a bactericidal, concentration-dependent antibiotic effect at concentrations corresponding to and exceeding published tear and conjunctival levels. METHODS: The antibacterial activity of different concentrations of azithromycin 1% in DuraSite(R) (AzaSite(R); Inspire Pharmaceuticals Inc, Durham, NC, USA) was evaluated using a kinetics-of-kill model. Recent conjunctivitis isolates of Staphylococcus aureus, Streptococcus pneumoniae or Haemophilus influenzae were exposed to four concentrations of azithromycin (100, 250, 500 and 750 microg/ml). Starting concentrations were similar to the maximum concentrations (Cmax) that have been demonstrated in conjunctiva (83 microg/g) and tears (288 microg/ml) following topical ocular administration. The percentage of surviving bacteria at 30 and 60 minutes following exposure to each concentration were determined. RESULTS: Azithromycin failed to demonstrate bactericidal activity (i.e. a 3-log reduction in surviving bacteria) against S. aureus, S. pneumoniae or H. influenzae. Furthermore, the rate and extent of antibacterial activity with azithromycin did not change with higher concentrations, even at the highest tested concentration of 750 microg/ml. CONCLUSION: Similar to the parent macrolide class, azithromycin demonstrates bacteriostatic activity against common conjunctival pathogens up to the maximum tested concentration of 750 microg/ml (i.e. 2.6-times and 9-times published Cmax tear and conjunctival concentration, respectively). Azithromycin's bacteriostatic effects and prolonged elimination half-life will likely lead to a corresponding increase in the emergence of macrolide-resistant isolates.

Ocular distribution, bactericidal activity and settling characteristics of TobraDex ST ophthalmic suspension compared with TobraDex ophthalmic suspension.

INTRODUCTION: TobraDex ophthalmic suspension (tobramycin 0.3%, dexamethasone 0.1%; Alcon Laboratories Inc, Fort Worth, Tex) is frequently used for inflammatory ocular conditions where a risk of bacterial ocular infection exists. A new formulation, TobraDex ST ophthalmic suspension (tobramycin 0.3%, dexamethasone 0.05%, Alcon), utilises a novel suspension technology to reduce viscosity and help prevent settling in the container. METHODS: A rabbit model that closely mimics the human eye and a clinical study with cataract patients was used to compare the pharmacokinetics and tissue permeability of TobraDex ST and TobraDex. An in-vitro model was used to assess the bactericidal activity using the rabbit tear concentrations of tobramycin 10 minutes after a single topical dose. RESULTS: Concentrations of both tobramycin and dexamethasone were greater in the tear film and ocular tissues of rabbits treated with TobraDex ST. There was an 8.3-fold increase in tobramycin concentration in the rabbit tear film 10 minutes after dosing with TobraDex ST compared with TobraDex. Concentrations of tobramycin and dexamethasone in ocular tissues from rabbits exposed to TobraDex ST were up to 12.5-fold greater relative to TobraDex. The in-vitro bactericidal activity (>99.9% kill, 3-log reduction) of TobraDex ST toward tobramycin-resistant and methicillin-resistant Staphylococcus aureus occurred in 90 minutes. TobraDex ST killed Streptococcus pneumoniae 3-log in 5 minutes. TobraDex had no activity toward tobramycin-resistant, methicillin-resistant S. aureus and required approximately 120 minutes for 3-log reduction of S. pneumoniae. In humans, the mean ratio of dexamethasone levels in the aqueous humour at 1 hour was 1.17 in favour of TobraDex ST. CONCLUSION: TobraDex ST demonstrated improved suspension formulation characteristics, enhanced pharmacokinetic distribution and improved bactericidal characteristics, and may provide a useful alternative as compared to TobraDex.

Speed of bacterial kill with a fluoroquinolone compared with nonfluoroquinolones: clinical implications and a review of kinetics of kill studies.

It is important to rapidly eradicate bacteria in patients with bacterial conjunctivitis in order to decrease disease transmission, shorten symptom duration, and minimize the emergence of resistant bacteria. This paper presents the results of kinetics of kill studies on 3 commonly isolated pathogens in bacterial conjunctivitis. A more rapid speed of kill with moxifloxacin compared with other nonfluoroquinolone antibiotics (tobramycin, gentamicin, polymyxin B/trimethoprim, or azithromycin) was observed in Staphylococcus aureus, Streptococcus pneumoniae, and Haemophilus influenzae infections. Moxifloxacin achieved a 99.9% kill at approximately 1 h for S aureus, 2 h for S pneumoniae, and 30 min for H influenzae. In comparison, other nonfluoroquinolone therapies took longer to achieve a bactericidal (3-log) kill and some demonstrated no change or an increase in bacterial growth. Based on these findings, it is concluded that moxifloxacin kills bacteria more rapidly than nonfluoroquinolone topical ocular antibiotics.

Safety and efficacy of moxifloxacin-dexamethasone eyedrops as treatment for bacterial ocular infection associated with bacterial blepharitis.

INTRODUCTION: Treatments that offer two medications in a fixed combination have the potential to offer efficacious and safe treatment with advantages such as a regimen that is simpler than administering two separate solutions. This study evaluated the safety and efficacy of fixed-combination versus concomitant moxifloxacin 0.5% and dexamethasone 0.1% ocular solutions for the treatment of bacterial ocular inflammation and infection. METHODS: The clinical study design was a randomized, double-masked, active-controlled, parallel-group trial of 102 subjects with bacterial blepharitis in which two patients also had bacterial conjunctivitis. All subjects received two bottles of study medication: either a fixed combination of moxifloxacin 0.5%/dexamethasone 0.1% ophthalmic solution and placebo eye drops (fixed-dose group), or moxifloxacin 0.5% ophthalmic solution and dexamethasone 0.1% (concomitant group). One drop of each study medication was instilled bilaterally four times per day for 7 days. Clinical resolution, signs, symptoms, and safety were assessed. Microbiological specimens were collected from the eyelid margin and conjunctivae of each eye from each patient at the time of enrollment and at the exit visit. RESULTS: Clinical resolution occurred similarly in both groups (81.6% of eyes, fixed-dose group; 82.3% of eyes, concomitant group). Moreover, the microbiological efficacy of the treatment was also similar for both the fixed-dose group (84%) and the concomitant group (83%). Ocular symptoms and signs improved over time, with no significant differences between groups after 7 days of treatment, except the fixed-dose group had significantly more eyes with clinical resolution in eyelid erythema (100%, n = 98/98, fixed-dose group; 92.7%, n = 89/96, concomitant group; P = 0.0194) and eyelid scaling/crusting (98%, n = 96/98, fixed-dose group; 89.6%; n = 86/96 eyes, concomitant group; P = 0.0337). Both regimens were safe and well tolerated. CONCLUSION: The fixed-dose combination of moxifloxacin, 0.5% and dexamethasone, 0.1% was therapeutically equivalent and as well tolerated as the concomitant dosage.

Comparison of fluoroquinolone kinetics of kill in susceptible and resistant gram-positive conjunctival pathogens.

INTRODUCTION: The purpose of this study was to compare moxifloxacin's rate of kill of susceptible and resistant Gram-positive organisms with that of ciprofloxacin and ofloxacin, using concentrations found in human conjunctiva after instillation of one drop. METHODS: Staphylococcus aureus (S. aureus) and Streptococcus pneumoniae (S. pneumoniae) isolates were exposed to moxifloxacin, ciprofloxacin, or ofloxacin diluted to human conjunctival concentrations achieved after instillation of one drop. These treated isolates were cultured on blood agar plates at 0, 15, 30, and 60 minutes after exposure, and incubated to observe the number of surviving colony-forming units/mL. RESULTS: In susceptible S. pneumoniae, moxifloxacin showed the most rapid reduction of colonies at 15 and 30 minutes, with the fewest colonies at 60 minutes compared with ciprofloxacin and ofloxacin. In S. pneumoniae resistant to ciprofloxacin and ofloxacin, moxifloxacin had rapid reduction in colonies at each time point and near-eradication at 60 minutes, while ciprofloxacin and ofloxacin had an increase in colonies at 60 minutes. In susceptible S. aureus, moxifloxacin had a rapid decrease in colonies at 15 and 30 minutes, compared with a slight reduction in colonies at these intervals for the other antibiotics. In methicillin-resistant S. aureus with cross-resistance to fluoroquinolones and other antibiotics, moxifloxacin had a decrease in colonies at each time point compared with an increase at each time point for ciprofloxacin and ofloxacin. CONCLUSION: Moxifloxacin showed an increased speed of kill against both of the common susceptible Gram-positive conjunctival pathogens, compared with the inconsistency of killing activity of two other fluoroquinolones tested. In addition, at the concentration level achieved in the conjunctiva after the instillation of one drop, moxifloxacin effectively and rapidly killed resistant Gram-positive conjunctival pathogens, while ciprofloxacin and ofloxacin had no effect against these organisms.