Fluoroquinolones compared with β-lactam antibiotics for the treatment of acute bacterial sinusitis: a meta-analysis of randomized controlled trials

Background

The presumed superiority of newer fluoroquinolones for the treatment of acute bacterial sinusitis is based on laboratory data but has not yet been established on clinical grounds.

Methods

We performed a meta-analysis of randomized controlled trials comparing the effectiveness and safety of fluoroquinolones and β-lactams in acute bacterial sinusitis.

Results

We identified 8 randomized controlled trials investigating the newer “respiratory” fluoroquinolones moxifloxacin, levofloxacin and gatifloxacin. In the primary effectiveness analysis involving 2133 intention-to-treat patients from 5 randomized controlled trials, the extent of clinical cure and improvement did not differ between fluoroquinolones and β-lactams (odds ratio [OR] 1.09, 95% confidence interval [CI] 0.85–1.39) at the test-of-cure assessment, which varied from 10 to 31 days after the start of treatment. Fluoroquinolones were associated with an increased chance of clinical success among the clinically evaluable patients in all of the randomized controlled trials (OR 1.29, 95% CI 1.03–1.63) and in 4 blinded randomized controlled trials (OR 1.45, 95% CI 1.05–2.00). There was no statistically significant difference between fluoroquinolones and amoxicillin–clavulanate (OR 1.24, 95% CI 0.93–1.65). Eradication or presumed eradication of the pathogens isolated before treatment was more likely with fluoroquinolone treatment than with β-lactam treatment (OR 2.11, 95% CI 1.09–4.08). In the primary safety analysis, adverse events did not differ between treatments (OR 1.17, 95% CI 0.86–1.59). However, more adverse events occurred with fluoroquinolone use than with β-lactam use in 2 blinded randomized controlled trials. The associations described here were generally consistent when we included 3 additional studies involving other fluoroquinolones (ciprofloxacin and sparfloxacin) in the analysis.

Interpretation

In the treatment of acute bacterial sinusitis, newer fluoroquinolones conferred no benefit over β-lactam antibiotics. The use of fluoroquinolones as first-line therapy cannot be endorsed.Acute bacterial sinusitis (more accurately known as rhinosinusitis, given that the nasal mucosa is commonly involved¹) is one of the most frequent health disorders;² it has an adverse impact on patients'' quality of life³ and accounts for nearly 3 million ambulatory care visits in the United States annually⁴ and substantial health care costs.⁵Acute bacterial sinusitis typically follows an episode of viral upper respiratory tract illness.² The diagnosis of bacterial disease in routine clinical practice is usually based on the presence of a constellation of clinical manifestations.¹ The bacterial pathogens most commonly involved are Streptococcus pneumoniae, Haemophilus influenzae and, to a lesser degree, Moraxella catarrhalis.^6,7 Over the years, these pathogens have acquired various degrees of resistance to many traditional antibiotics.⁸The benefit of older antibiotics over placebo in the treatment of acute bacterial sinusitis appears limited, mostly because of the high success rate achieved with placebo.^9,10 However, newer, third-and fourth-generation fluoroquinolones possess excellent in vitro activity against the most common respiratory pathogens,¹¹ and for this reason these drugs are often designated as “respiratory.” Based on analysis of the available laboratory data, current guidelines give the newer fluoroquinolones the highest ranking, in terms of expected clinical effectiveness, among the antimicrobials used to treat acute bacterial sinusitis (although admittedly the difference is marginal).⁷The presumed clinical advantage of the respiratory fluoroquinolones over other classes of antimicrobials has not been clearly demonstrated in comparative clinical trials or meta-analyses.^9,10 We aimed to comprehensively reassess the role of fluoroquinolones in the treatment of acute bacterial sinusitis, in terms of effectiveness and safety, by performing a meta-analysis of relevant randomized controlled trials.     

Crystal structure of the inclusion complex of the antibacterial agent triclosan with cyclomaltoheptaose and NMR study of its molecular encapsulation in positively and negatively charged cyclomaltoheptaose derivatives

The inclusion complexes of triclosan with native cyclomaltoheptaose (beta-cyclodextrin, betaCD) as well as with negatively and positively charged derivatives are studied. The structure of the inclusion complex betaCD/triclosan in the crystalline state [P1, a=15.189(5), b=15.230(6), c=16.293(6), alpha=91.07(4), beta=91.05(3) gamma=100.71(3)] comprises two crystallographically independent host macrocycles A and B. The packing results in betaCD dimers that align head-to-head and form infinite channels along the c-axis. Only one guest molecule statistically disordered over two positions, (the dichlorophenyl ring in the cavities of either A or B) corresponds to each dimer (a 2:1 host/guest complex). The enclosed dichlorophenyl ring enters the dimer through the primary side, whereas the hydrophilic chlorophenol ring extends in the space between dimers. Water molecules in five positions are also enclosed in the intradimer region, arranged on a plane perpendicular to the sevenfold axis of betaCD. The NMR spectroscopic studies in aqueous solution show the presence of both 1:1 and 2:1 betaCD/triclosan complexes. In the first case, two different 1:1 complexes are simultaneously present, each with either ring entering the narrow primary side of one betaCD molecule. In the 2:1 complex both rings of triclosan are included in two independent betaCD hosts, a precursor to the supramolecular arrangement found in the crystalline form. In the case of the negatively charged sodium heptakis[6-deoxy-6-(3-thiopropionate)]-betaCD, the NMR studies at pH 7.9 show a complete inclusion of triclosan inside the host in two orientations, one for the non-ionized (phenol) and reverse for the ionized (phenolate) form. Finally, for the positively charged heptakis(6-aminoethylamino-6-deoxy)-betaCD, inclusion of triclosan is possible only when the pH is raised to 10 and it is concluded that both aromatic rings are alternatively inside the cavity. However in that case also, inclusion of the entire guest in the elongated cavity is suggested.     

The endocytic recycling protein EHD2 interacts with myoferlin to regulate myoblast fusion

Skeletal muscle is a multinucleated syncytium that develops and is maintained by the fusion of myoblasts to the syncytium. Myoblast fusion involves the regulated coalescence of two apposed membranes. Myoferlin is a membrane-anchored, multiple C2 domain-containing protein that is highly expressed in fusing myoblasts and required for efficient myoblast fusion to myotubes. We found that myoferlin binds directly to the eps15 homology domain protein, EHD2. Members of the EHD family have been previously implicated in endocytosis as well as endocytic recycling, a process where membrane proteins internalized by endocytosis are returned to the plasma membrane. EHD2 binds directly to the second C2 domain of myoferlin, and EHD2 is reduced in myoferlin null myoblasts. In contrast to normal myoblasts, myoferlin null myoblasts accumulate labeled transferrin and have delayed recycling. Introduction of dominant negative EHD2 into myoblasts leads to the sequestration of myoferlin and inhibition of myoblast fusion. The interaction of myoferlin with EHD2 identifies molecular overlap between the endocytic recycling pathway and the machinery that regulates myoblast membrane fusion.     

An improvement of the diffusion model for assessment of drought stress in plant tissues

The article discusses an improvement of a previously developed method for assessment of ion leakage from plant tissues as a gauge of membrane and cell wall performance under stressful environment. It employs conductometric measurements of the ion efflux from leaves and their quantitative interpretation by a theoretical model based on the laws of diffusion. Experimental data are readily fit with the model and results are in accordance with relative water content of dehydrated barley (Hordeum vulgare) seedlings of two distinct cultivars. Some new parameters obtained from fitting are proposed as reliable indicators of the leaf status. They appear to be helpful in further distinguishing the behavior of two separate cellular structures with respect to their electrolyte permeability. It is concluded that the established method based on the kinetics of ion leakage is adequate for evaluation of contrasting genotypes under normal and stress conditions. Furthermore, it could be used as a simple and powerful tool for routine analysis and screening for drought tolerance in crops.     

FGF23 Deficiency Leads to Mixed Hearing Loss and Middle Ear Malformation in Mice

Fibroblast growth factor 23 (FGF23) is a circulating hormone important in phosphate homeostasis. Abnormal serum levels of FGF23 result in systemic pathologies in humans and mice, including renal phosphate wasting diseases and hyperphosphatemia. We sought to uncover the role FGF23 plays in the auditory system due to shared molecular mechanisms and genetic pathways between ear and kidney development, the critical roles multiple FGFs play in auditory development and the known hearing phenotype in mice deficient in klotho (KL), a critical co-factor for FGF23 signaling. Using functional assessments of hearing, we demonstrate that Fgf mice are profoundly deaf. Fgf mice have moderate hearing loss above 20 kHz, consistent with mixed conductive and sensorineural pathology of both middle and inner ear origin. Histology and high-voltage X-ray computed tomography of Fgf mice demonstrate dysplastic bulla and ossicles; Fgf mice have near-normal morphology. The cochleae of mutant mice appear nearly normal on gross and microscopic inspection. In wild type mice, FGF23 is ubiquitously expressed throughout the cochlea. Measurements from Fgf mice do not match the auditory phenotype of Kl ^−/− mice, suggesting that loss of FGF23 activity impacts the auditory system via mechanisms at least partially independent of KL. Given the extensive middle ear malformations and the overlap of initiation of FGF23 activity and Eustachian tube development, this work suggests a possible role for FGF23 in otitis media.     

Psychosocial distress and functioning of Greek youth with cystic fibrosis: a cross-sectional study

Background

To assess psychosocial functioning and distress of children and adolescents with cystic fibrosis compared to healthy controls.

Methods

Thirty-six patients with cystic fibrosis aged 8–18 years (24 boys, mean age?±?SD: 11.5?±?2.6 years) and 31 sex- and age-matched healthy control subjects (18 boys, mean age?±?SD: 12?±?2.5 years) were enrolled in the study. In order to assess the self-esteem, social adjustment, and family functioning of these young people, the Culture-free Self-esteem Inventory, the Social Adjustment Scale–Self-Report, and the Family Assessment Device were administered. Emotional/ behavioral problems were assessed through the Youth Self Report and the Child Behavior Checklist given to both the subjects and their parents.

Results

No significant differences were found for self-esteem between the two study groups. Regarding social adjustment, children with cystic fibrosis reported significantly worse friendship and overall adjustment (P?<?0.05). Moreover, no difference was found in the levels of family functioning between the two groups. No significant differences between the groups were found in emotional/ behavioral problems from the self-reports. On the contrary, parents of children with cystic fibrosis reported significantly higher levels of withdrawal/ depression, thought problems, and delinquent behavior (P?≤?0.01) as compared to controls.

Conclusions

Children and adolescents with cystic fibrosis appear to be a psychosocially vulnerable group. A biopsychosocial approach should emphasize the assessment and treatment of the psychosocial distress of these patients alongside multiple somatic treatments.

     

Towards analyzing the potential of exosomes to deliver microRNA therapeutics

Exosome selectivity mechanisms underlying exosome–target cell interactions and the specific traits affecting their capability to communicate still remain unclear. Moreover, the capacity of exosomes to efficiently deliver their molecular cargos intracellularly needs precise investigation towards establishing functional exosome‐based delivery platforms exploitable in the clinical practice. The current study focuses on: (a) exosome production from normal MRC‐5 and Vero cells growing in culture, (b) physicochemical characterization by dynamic light scattering (DLS) and cryo‐transmission electron microscopy; (c) cellular uptake studies of rhodamine‐labeled exosomes in normal and cancer cells, providing to exosomes either “autologous” or “heterologous” cellular delivery environments; and (d) loading exogenous Alexa Fluor 488‐labeled siRNA into exosomes for the assessment of their delivering capacity by immunofluorescence in a panel of recipient cells. The data obtained thus far indicate that MRC‐5 and Vero exosomes, indeed exhibit an interesting delivering profile, as promising “bio‐shuttles,” being pharmacologically exploitable in the context of theranostic applications.     

Reproductive responses to photoperiod and temperature by diapausing and nondiapausing populations of Sesamia nonagrioides Lef. (Lepidoptera − Noctuidae)

Abstract.  The influence of long- and short-day cycles on ovipostion and egg hatch of the corn stalk borer, Sesamia nonagrioides were investigated at a range of temperatures. Oviposition was suppressed when insects are exposed to long days through their immature stages and then transferred to short days after mating. Moreover, mean oviposition and egg hatch increased from 15 to 27.5 °C, whereas oviposition declined significantly at 30 °C at both photoperiodic regimes. Females derived from a diapausing population exposed to long days after mating showed a significantly higher egg production compared to females derived from a nondiapausing population. However, when females from a diapausing population were left to oviposit under short days, fewer eggs were produced compared to those exposed to long days after mating. Thus, photoperiod appears to affect reproductive traits of this species in a quantitative manner. Larval diapause duration is positively correlated with fecundity of the adults. There is also a positive correlation between pupal weight of individuals derived from a diapausing population and the postdiapause fecundity of adults.     

NMR-based metabolic profiling of children with premature adrenarche

Metabolomics - The effects of lipopolysaccharides (i.e., endotoxin; LPS) on metabolism are poorly defined in lactating dairy cattle experiencing hyperlipidemia. Our objective was to explore the...     

R-Loops Enhance Polycomb Repression at a Subset of Developmental Regulator Genes

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