Abstract: Since the introduction into clinical practice of the aminoglycoside class of antibiotics, a number of other antimicrobial agents with improved safety profile have entered the market. Studies have failed to demonstrate the superiority of aminoglycoside-containing regimens in a number of infection settings. This has raised doubts regarding the actual clinical utility of aminoglycosides. However, the recent emergence of infections due to Gram-negative bacterial strains with advanced patterns of antimicrobial resistance has prompted physicians to reconsider these 'old' antibacterial agents. This revived interest in the use of aminoglycosides has brought back to light the debate on the two major issues related to these compounds, namely the spectrum of antimicrobial susceptibility and toxicity. Although some of the aminoglycosides retain activity against the majority of Gram-negative clinical bacterial isolates in many parts of the world, the relatively frequent occurrence of nephrotoxicity and ototoxicity during aminoglycoside treatment make physicians reluctant to use these compounds in everyday practice. We believe that recent advances in the understanding of the effect of various dosage schedules of aminoglycosides on toxicity combined with the retained (to a considerable degree) activity against the majority of Gram-negative bacterial isolates make this class of antibiotics still valuable in today's clinical practice.

Abstract: WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT * Treatment guidelines generally support that a 10-14-day antibiotic regimen should be administered to uncomplicated acute bacterial sinusitis patients. * However, the level of evidence for such a recommendation is rather weak. * Treatment of such duration may have disadvantages compared with a shorter duration but equally effective regimen, including the promotion of bacterial drug resistance, poorest patient compliance, higher toxicity, and a greater overall economic burden. WHAT THIS STUDY ADDS * The findings of this meta-analysis suggest that short-course antibiotic treatment has similar effectiveness to longer-course treatment for patients with acute uncomplicated bacterial sinusitis, when treatment is warranted. * However, we should underscore the importance of the clinician's own assessment, so that antimicrobial therapy should not inappropriately be curtailed in a patient not adequately responding to the regimen administered. We sought to evaluate the effectiveness and safety of short-course antibiotic treatment for acute bacterial sinusitis (ABS) compared with longer duration treatment. We performed a meta-analysis of randomized controlled trials (RCTs), identified by searching PubMed and the Cochrane Central Register of Controlled Trials. We included RCTs that compared short-course (up to 7 days) vs. long-course therapy (>/=2 days longer than short-course), with the same antimicrobial agent, in the same daily dosage, for patients with ABS. Twelve RCTs (10 double-blinded) involving adult patients with radiologically confirmed ABS were included. There was no difference in the comparison of short-course (3-7 days) with long-course treatment (6-10 days) regarding clinical success [12 RCTs, 4430 patients, fixed effect model (FEM), odds ratio (OR) 0.95, 95% confidence interval (CI) 0.81, 1.12]; microbiological efficacy; relapses; adverse events (10 RCTs, 4172 patients, random effects model, OR 0.88, 95% CI 0.71, 1.09); or withdrawals due to adverse events. In the sensitivity analysis comparing 5- vs. 10-day regimens, clinical success was similar, although adverse events were fewer with short-course treatment (5 RCTs, 2151 patients, FEM, OR 0.79, 95% CI 0.63, 0.98). Although antibiotics for acute sinusitis should be reserved for select patients with substantial probability of bacterial disease, accurate clinical diagnosis is often difficult to attain. Short-course antibiotic treatment had comparable effectiveness to a longer course of therapy for ABS. Shortened treatment, particularly for patients without severe disease and complicating factors, might lead to fewer adverse events, better patient compliance, lower rates of resistance development and fewer costs.

Abstract: Cross-reactivity of murine and recently human CD8(+) T cells between different viral peptides, i.e., heterologous immunity, has been well characterized. However, the directionality and quality of these cross-reactions is critical in determining their biological importance. Herein we analyzed the response of human CD8(+) T cells that recognize both a hepatitis C virus peptide (HCV-NS3) and a peptide derived from the influenza neuraminidase protein (Flu-NA). To detect the cross-reactive CD8(+) T cells, we used peptide-MHC class I complexes (pMHCs) containing a new mutant form of MHC class I able to bind CD8 more strongly than normal MHC class I complexes. T cell responses against HCV-NS3 and Flu-NA peptide were undetectable in normal donors. In contrast, some responses against the Flu-NA peptide were identified in HCV(+) donors who showed strong HCV-NS3-specific reactivity. The Flu-NA peptide was a weak agonist for CD8(+) T cells in HCV(+) individuals on the basis of novel pMHCs and functional assays. These data support the idea of cross-reactivity between the 2 peptides, but indicate that reactivity toward the Flu-NA peptide is highly CD8-dependent and occurs predominantly after priming during HCV infection. Our findings indicate the utility of the novel pMHCs in dissecting cross-reactivity and suggest that cross-reactivity between HCV and influenza is relatively weak. Further studies are needed to relate affinity and functionality of cross-reactive T cells.

Abstract: Burkholderia cepacia complex (BCC) is an important group of pathogens affecting patients with cystic fibrosis and chronic granulomatous disease as well as immunocompromised and hospitalised patients. Therapeutic options are limited owing to high levels of resistance of the organism, either intrinsic or acquired, to many antimicrobial agents. Co-trimoxazole (trimethoprim/sulfamethoxazole) has been a drug of choice. However, in some cases it cannot be administered because of allergic or hypersensitivity reactions, intolerance or resistance. We systematically searched for relevant publications including clinical data in PubMed and Scopus. The search identified 48 relevant case reports (57 cases) and 8 cohort studies or trials. Nineteen (33.3%) of 57 patients included in the case reports received ceftazidime-based regimens, 14 (73.7%) of whom were cured. Meropenem was administered in seven patients (12.3%), one (14.3%) of whom improved and five (71.4%) were cured. Seven (12.3%) of 57 cases were treated with penicillins, four of which were piperacillin (all had a favourable outcome). Based on the data reported in the eight relevant cohort studies or trials identified, favourable outcomes were observed in 68.4% (26/38) to 100% (16/16) of cases treated with ceftazidime and 66.7% (6/9) of cases treated with meropenem. Also, 9/12 (75%) of patients receiving penicillins improved. Thus, Ceftazidime, meropenem and penicillins, mainly piperacillin, either alone or in combination with other antimicrobial agents, may be considered as alternative options for BCC infections, according to the in vitro antimicrobial susceptibility patterns and clinical results. However, the available clinical data are not sufficient and further clinical experience is required to clarify the appropriateness of these antibiotics for BCC infections.

Abstract: The optimal duration of antimicrobial treatment of patients with ventilator-associated pneumonia is a major concern for clinicians. We looked for the evidence that a short course of therapy (< or =10 days) is as effective as a traditional long-course therapy (14-21 days). Unfortunately, only one trial (PneumA trial) has focused directly on this question. To further evaluate this issue, we identified trials in which the duration of anti-infective treatment was used as the outcome. Such trials, by providing data on mortality, length of intensive care unit stay and recurrence, may allow for estimating the association between duration of therapy and the aforementioned outcomes. Nine such trials were identified; all reported a decrease in the total length of antibiotic administration (statistically significant in seven) with the application of the intervention studied. Short, as opposed to long, courses of antibiotics did not adversely affect mortality, length of intensive care unit stay or recurrence rates. In conclusion, the available evidence seems to support the use of short-course antimicrobial treatments (< or =10 days) for patients with ventilator-acquired pneumonia not caused by nonfermenting Gram-negative bacilli.

Abstract: The prevalence of atopic diseases has increased abruptly in recent years in most Westernized societies, making the question why this happened the topic of a heated debate. The best paradigm available to date to explain this steep rise, the 'hygiene hypothesis', supports that it is the excess 'cleanliness' of our environments that has led to the decline in the number of infectious stimuli that are necessary for the proper development of our immune system. Recent findings support that it is the combined effect that not only pathogenic, but also non-pathogenic microorganisms, and even their structural components,can exert on the immune system that deters from the development of atopic responses. Adding to these results are intriguing new findings on the effect different gene polymorphisms can have on an individual's predisposition to allergic diseases. The most important linkages produced, to date, include those among the genes for IL-4, IL-13, HLA-DRB, TNF, LTA,FCER1B, IL-4RA, ADAM33, TCR alpha/delta, PHF11, GPRA, TIM, p40, CD14, DPP10, T-bet, GATA-3, and FOXP3 and allergic disorders. The two parallel research efforts, epidemiologic and genetic, are only recently starting to converge,producing fascinating results on the effect particular gene-environment interactions might have in the development of atopy.The most important lesson learned through this tremendous research effort is that not only a small number but thousands and millions of separate risk factors act in concordance in the production of the allergic phenotype.

Abstract: BACKGROUND: The evidence for traditionally recommended 7- to 14-day duration of antibacterial therapy for community-acquired pneumonia (CAP) is not well established. OBJECTIVES: We endeavoured to assess the effectiveness and safety of shorter than traditionally recommended antibacterial therapy for CAP. METHODS: We performed a meta-analysis of randomized controlled trials (RCTs) comparing short- (< or = 7 days) versus long- (> or = 2 days difference) course therapy for CAP with the same antibacterial regimens, in the same daily dosages. RESULTS: Five RCTs involving adults (including outpatients and inpatients who did not require intensive care) and two RCTs involving children (aged 2-59 months, residing in developing countries) were included. All RCTs were double-blind and assessed patients with CAP of mild to moderate severity. No differences were found between short- (adults 3-7 days; children 3 days) and long- (adults 7-10 days; children 5 days) course regimens (adults - amoxicillin, cefuroxime, ceftriaxone, telithromycin and gemifloxacin; children - amoxicillin) regarding clinical success at end-of-therapy (six RCTs; 5107 patients [1095 adults, 4012 children]; fixed-effect model [FEM]; odds ratio [OR] = 0.89; 95% CI 0.74, 1.07), clinical success at late follow-up, microbiological success, relapses, mortality (seven RCTs; 5438 patients; FEM; OR = 0.57; 95% CI 0.23, 1.43), adverse events (five RCTs; 3214 patients; FEM; OR = 0. 90; 95% CI 0.72, 1.13) or withdrawals as a result of adverse events. No differences were found in subset analyses of adults or children, and of patients treated with no more than 5-day short-course regimens versus at least 7-day long-course regimens. CONCLUSION: No difference was found in the effectiveness and safety of short- versus long-course antimicrobial treatment of adult and paediatric patients with CAP of mild to moderate severity.

Abstract: Despite the constantly increasing need for new antimicrobial agents, antibiotic drug discovery and development seem to have greatly decelerated in recent years. Presented with the significant problem of advancing antimicrobial resistance, the global scientific community has attempted to find alternative solutions; one of the most promising ones is the evaluation and use of old antibiotic compounds. Due to the low-level use of many of the old antibiotic compounds, these have remained active against a large number of currently prevalent bacterial isolates. Thus, clinicians are beginning to re-evaluate their use in various patient populations and infections, despite the fact that they were previously thought to be less effective and/or more toxic than newer agents. A number of old antibiotic compounds, such as polymyxins, fosfomycin, fusidic acid, cotrimoxazole, aminoglycosides and chloramphenicol, are re-emerging as valuable alternatives for the treatment of difficult-to-treat infections. The availability of novel genetic and molecular modification methods provides hope that the toxicity and efficacy drawbacks presented by some of these agents can be surpassed in the future.

Abstract: 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 beta-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 beta-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 beta-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 beta-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 beta-lactam antibiotics. The use of fluoroquinolones as first-line therapy cannot be endorsed.