In vitro evaluation of the effect of linezolid and levofloxacin on Bacillus anthracis toxin production, spore formation and cell growth.

BACKGROUND: Owing to its ability to form spores and toxins, Bacillus anthracis is considered a bioterror agent. Although current therapeutic strategies can be effective, treatment does not prevent sporulation and toxin production. OBJECTIVES: To quantify the combined effect of a protein synthesis inhibitor and a bactericidal agent on B. anthracis toxin production, sporulation and cell growth. METHODS: Susceptibility and synergy titrations were conducted on B. anthracis Sterne and 03-0191 strains using linezolid and levofloxacin. The effect of antibiotic exposure on cell viability was evaluated using a continuous medium replacement model. In vitro static models were used to study the effect of linezolid and levofloxacin on sporulation and toxin production. Spores were quantified using the heat shock method. Toxin was quantified via commercial ELISA. RESULTS: Synergy titrations indicated that the combination was synergistic or indifferent; however, in all models antagonism was observed. In the spore model, linezolid resulted in the lowest sporulation rates, while combination therapy resulted in the highest. In the toxin model, linezolid prevented toxin production altogether. CONCLUSIONS: This study advances our understanding of the effects of combination therapy on B. anthracis infection. Used alone, linezolid therapy abolishes toxin production and reduces sporulation. These results suggest that studies using a step-wise approach using linezolid initially to stop sporulation and toxin production followed by levofloxacin to rapidly kill vegetative B. anthracis can be recommended.

Alternative pre-approved and novel therapies for the treatment of anthrax.

BACKGROUND: Bacillus anthracis, the causative agent of anthrax, is a spore forming and toxin producing rod-shaped bacterium that is classified as a category A bioterror agent. This pathogenic microbe can be transmitted to both animals and humans. Clinical presentation depends on the route of entry (direct contact, ingestion, injection or aerosolization) with symptoms ranging from isolated skin infections to more severe manifestations such as cardiac or pulmonary shock, meningitis, and death. To date, anthrax is treatable if antibiotics are administered promptly and continued for 60 days. However, if treatment is delayed or administered improperly, the patient's chances of survival are decreased drastically. In addition, antibiotics are ineffective against the harmful anthrax toxins and spores. Therefore, alternative therapeutics are essential. In this review article, we explore and discuss advances that have been made in anthrax therapy with a primary focus on alternative pre-approved and novel antibiotics as well as anti-toxin therapies. METHODS: A literature search was conducted using the University of Manitoba search engine. Using this search engine allowed access to a greater variety of journals/articles that would have otherwise been restricted for general use. In order to be considered for discussion for this review, all articles must have been published later than 2009. RESULTS: The alternative pre-approved antibiotics demonstrated high efficacy against B. anthracis both in vitro and in vivo. In addition, the safety profile and clinical pharmacology of these drugs were already known. Compounds that targeted underexploited bacterial processes (DNA replication, RNA synthesis, and cell division) were also very effective in combatting B. anthracis. In addition, these novel compounds prevented bacterial resistance. Targeting B. anthracis virulence, more specifically the anthrax toxins, increased the length of which treatment could be administered. CONCLUSIONS: Several novel and pre-existing antibiotics, as well as toxin inhibitors, have shown increasing promise. A combination treatment that targets both bacterial growth and toxin production would be ideal and probably necessary for effectively combatting this armed bacterium.

Potential role for telavancin in bacteremic infections due to gram-positive pathogens: focus on Staphylococcus aureus.

Staphylococcus aureus bacteremia (SAB) is one of the most common serious bacterial infections and the most frequent invasive infection due to methicillin-resistant S. aureus (MRSA). Treatment is challenging, particularly for MRSA, because of limited treatment options. Telavancin is a bactericidal lipoglycopeptide antibiotic that is active against a range of clinically relevant gram-positive pathogens including MRSA. In experimental animal models of sepsis telavancin was shown to be more effective than vancomycin. In clinically evaluable patients enrolled in a pilot study of uncomplicated SAB, cure rates were 88% for telavancin and 89% for standard therapy. Among patients with infection due to only gram-positive pathogens enrolled in the 2 phase 3 studies of telavancin for treatment of hospital-acquired pneumonia, cure rates for those with bacteremic S. aureus pneumonia were 41% (9/22, telavancin) and 40% (10/25, vancomycin) with identical mortality rates. These data support further evaluation of telavancin in larger, prospective studies of SAB.

Centers for disease control and prevention expert panel meetings on prevention and treatment of anthrax in adults.

The Centers for Disease Control and Prevention convened panels of anthrax experts to review and update guidelines for anthrax postexposure prophylaxis and treatment. The panels included civilian and military anthrax experts and clinicians with experience treating anthrax patients. Specialties represented included internal medicine, pediatrics, obstetrics, infectious disease, emergency medicine, critical care, pulmonology, hematology, and nephrology. Panelists discussed recent patients with systemic anthrax; reviews of published, unpublished, and proprietary data regarding antimicrobial drugs and anthrax antitoxins; and critical care measures of potential benefit to patients with anthrax. This article updates antimicrobial postexposure prophylaxis and antimicrobial and antitoxin treatment options and describes potentially beneficial critical care measures for persons with anthrax, including clinical procedures for infected nonpregnant adults. Changes from previous guidelines include an expanded discussion of critical care and clinical procedures and additional antimicrobial choices, including preferred antimicrobial drug treatment for possible anthrax meningitis.

Telavancin for hospital-acquired pneumonia: clinical response and 28-day survival.

U.S. Food and Drug Administration draft guidance for future antibiotic clinical trials of bacterial nosocomial pneumonia recommends the use of diagnostic criteria according to American Thoracic Society/Infectious Diseases Society of America (ATS/IDSA) guidelines and the use of a primary endpoint of 28-day all-cause mortality. The effect of applying these guidelines on outcomes of phase III nosocomial pneumonia studies of telavancin was evaluated in a post hoc analysis. ATS/IDSA criteria were applied in a blind fashion to the original all-treated (AT) group. Clinical cure rates at final follow-up were determined in the refined AT and clinically evaluable (CE) groups (ATS/IDSA-AT and ATS/IDSA-CE, respectively). The exploratory endpoint of 28-day survival was evaluated for the ATS/IDSA-AT group. Noninferiority of telavancin versus vancomycin was demonstrated, with similar cure rates in the ATS/IDSA-AT (59% versus 59%) and ATS/IDSA-CE (83% versus 80%) groups. Cure rates favored telavancin in ATS/IDSA-CE patients where Staphylococcus aureus was the sole pathogen (86% versus 75%). Overall, 28-day survival rates were similar in the telavancin (76%) and vancomycin (77%) groups but lower in telavancin-treated patients with preexisting moderate-to-severe renal impairment (creatinine clearance [CLCR] of <50 ml/min). Telavancin should be administered to patients with moderate-to-severe renal impairment only if treatment benefit outweighs the risk or if no suitable alternatives are available.

Effect of vancomycin serum trough levels on outcomes in patients with nosocomial pneumonia due to Staphylococcus aureus: a retrospective, post hoc, subgroup analysis of the Phase 3 ATTAIN studies.

BACKGROUND: Existing data are not consistently supportive of improved clinical outcome when vancomycin dosing regimens aimed at achieving target trough levels are used. A retrospective, post hoc, subgroup analysis of prospectively collected data from the Phase 3 ATTAIN trials of telavancin versus vancomycin for treatment of nosocomial pneumonia was conducted to further investigate the relationship between vancomycin serum trough levels and patient outcome. METHODS: Study patients were enrolled in 274 study sites across 38 countries. A total of 98 patients had Staphylococcus aureus nosocomial pneumonia and vancomycin serum trough levels available. These patients were grouped according to their median vancomycin trough level; < 10 µg/mL, 10 µg/mL to < 15 µg/mL, and ≥ 15 µg/mL. RESULTS: Clinical cure rates in the < 10 µg/mL, 10 µg/mL to < 15 µg/mL, and ≥ 15 µg/mL vancomycin trough level groups were 70% (21/30), 55% (18/33), and 49% (17/35), respectively (p = 0.09), and the frequencies of patient death were 10% (3/30), 15% (5/33), and 20% (7/35), respectively (p = 0.31). Renal adverse events were more frequent in the ≥ 15 µg/mL (17% [6/35]) than the < 10 µg/mL (0%) and 10 µg/mL to < 15 µg/mL (3% [1/33]) trough level groups (p < 0.01). When patients with acute renal failure or vancomycin exposure within 7 days prior to study medication were excluded, clinical cure rates in the < 10 µg/mL, 10 µg/mL to < 15 µg/mL, and ≥ 15 µg/mL vancomycin trough level groups (71% [12/17], 60% [9/15], and 27% [3/11], respectively; p = 0.04) and the number of deaths (12% [2/17], 20% [3/15], and 45% [5/11], respectively; p = 0.07) demonstrated a trend towards worse outcomes in the higher vancomycin trough level groups. CONCLUSIONS: The findings of our study suggest that higher vancomycin trough levels do not result in improved clinical response but likely increase the incidence of nephrotoxicity. TRIAL REGISTRATION: NCT00107952 and NCT00124020.

Knowledge, attitudes, beliefs and behaviours of older adults about pneumococcal immunization, a Public Health Agency of Canada/Canadian Institutes of Health Research Influenza Research Network (PCIRN) investigation.

BACKGROUND: Fewer Canadian seniors are vaccinated against pneumococcal disease than receive the influenza vaccine annually. Improved understanding of factors influencing pneumococcal vaccination among older adults is needed to improve vaccine uptake. METHODS: A self-administered survey measuring knowledge, attitudes, beliefs and behaviours about pneumococcal vaccination was administered to a cohort of seniors participating in a clinical trial of seasonal influenza vaccines at eight centers across Canada. Eligible participants were ambulatory adults 65 years of age or older, in good health or with stable health conditions, previously given influenza vaccine. The primary outcome was self-reported receipt of pneumococcal vaccination. Multi-variable logistic regression was used to determine factors significantly associated with pneumococcal vaccine receipt. RESULTS: A total of 863 participants completed questionnaires (response rate 92%); 58% indicated they had received the pneumococcal vaccine. Being offered the vaccine by a health care provider had the strongest relationship with vaccine receipt (AOR 23.4 (95% CI 13.4-40.7)). Other variables that remained significantly associated with vaccine receipt in the multivariable model included having heard of the vaccine (AOR 10.1(95% CI 4.7-21.7)), and strongly agreeing that it is important for adults > 65 to be vaccinated against pneumococcus (AOR 3.3 (95% CI 1.2-9.2)). Participants who were < 70 years of age were less likely to be vaccinated. CONCLUSIONS: These results indicate healthcare recommendation significantly influenced vaccine uptake in this population of older adults. Measures to encourage healthcare providers to offer the vaccine may help increase coverage.

Bacteremia caused by Eggerthella lenta in an elderly man with a gastrointestinal malignancy: A case report.

Eggerthella lenta is an anaerobic, Gram-positive bacillus commonly found in the human digestive tract. Occasionally, it can cause life-threatening infections. Bacteremia due to this organism is always clinically significant and is associated with gastrointestinal diseases and states of immune suppression. The authors report a case involving an elderly man with a newly diagnosed gastrointestinal malignancy who developed bacteremia caused by E lenta, treated successfully using empirical therapy with vancomycin and piperacillin-tazobactam, followed by directed therapy with metronidazole once the identity and antibiotic susceptibility of the organism was established. The present case reinforces the connection between E lenta bacteremia with gastrointestinal malignancy and highlights the importance of searching for a source of bacteremia due to this organism.

L'Eggerthella lenta est un bacille anaérobique à Gram positif présent dans le tube digestif humain. Il cause parfois des infections au potentiel mortel. La bactériémie attribuable à cet organisme est toujours grave sur le plan clinique et s'associe à des maladies gastro-intestinales et à des états immunosuppressifs. Les auteurs présentent le cas d'un homme âgé atteint d'un cancer gastro-intestinal diagnostiqué qui a souffert d'une bactériémie causée par l'E lenta et qui a reçu un traitement empirique fructueux à la vancomycine et à la pipéracilline-tazobactam, suivi d'une thérapie dirigée au métronidazole une fois l'organisme connu et la susceptibilité à l'organisme établie. Ce cas renforce le lien entre la bactériémie causée par l'E lenta et le cancer gastro-intestinal et fait ressortir l'importance d'en chercher la source.

Integrating pharmacokinetics, pharmacodynamics and MIC distributions to assess changing antimicrobial activity against clinical isolates of Pseudomonas aeruginosa causing infections in Canadian hospitals (CANWARD).

OBJECTIVES: To study antimicrobial pharmacodynamic (PD) activity over time against clinical isolates of Pseudomonas aeruginosa in Canadian hospitals. METHODS: Integrated pharmacokinetic (PK)/PD analyses with Monte Carlo simulations were used to study cefepime, meropenem, piperacillin/tazobactam, ciprofloxacin, amikacin, gentamicin and colistin. Profiles of P. aeruginosa infections were modelled using CANWARD data from January 2007 to June 2012 inclusive. The probability of target attainment (PTA) was the proportion of cases achieving a %ƒT>MIC ≥ 50% for cefepime, meropenem and piperacillin/tazobactam, an ƒAUC/MIC ≥ 90 for ciprofloxacin and the aminoglycosides, and a total AUC/MIC ≥ 60 for colistin. RESULTS: Some 2126 P. aeruginosa isolates were identified. There were no significant trends over time in the PTA for cefepime (0.93-1.0), meropenem (0.89-0.92) or piperacillin/tazobactam (0.74-0.79) (data shown for the highest recommended doses). The PD activity for ciprofloxacin (PTA 0.48-0.64) was variable. There were notable improvements in the PTA for amikacin (from 0.21 to 0.55, P = 0.027), gentamicin (from 0.10 to 0.51, P = 0.035) and colistin (from 0.04 to ~0.20, P = 0.05), which were not reliably detected by MIC indices. There was a decline over time in the PTA for piperacillin/tazobactam from 0.73 to 0.61 against P. aeruginosa isolated from intensive care units (ICUs) (Pearson correlation coefficient -0.99, P = 0.003). Neither MIC50 nor MIC90 detected this reduction in PD activity. CONCLUSIONS: The overall PD activity against P. aeruginosa was stable from 2007 to 2012 for cefepime, meropenem and piperacillin/tazobactam, was variable and unreliable for ciprofloxacin, and improved significantly but remained relatively low for the aminoglycosides and colistin. There was a progressive reduction over time in the PD activity of piperacillin/tazobactam against ICU isolates, which was not detected by simply assessing MIC indices.

Comparison of pathogens and their antimicrobial resistance patterns in paediatric, adult and elderly patients in Canadian hospitals.

OBJECTIVES: The purpose of this study was to describe the association between age groups and antimicrobial resistance in the most commonly identified pathogens in Canadian hospitals. METHODS: Between 2007 and 2011, 27,123 clinically significant isolates, comprising 3580 isolates from children ≤ 18 years old, 12,119 isolates from adults 19-64 years old and 11,424 isolates from elderly patients aged ≥ 65 years old, were collected as part of the CANWARD surveillance study from tertiary-care centres across Canada. Antimicrobial susceptibility testing was performed according to CLSI guidelines. A multifactorial logistic regression model was used to determine the impact of demographic factors, including age groups, on antimicrobial resistance. RESULTS: Staphylococcus aureus, Escherichia coli, Streptococcus pneumoniae and Pseudomonas aeruginosa were in the top five organisms for all of the age groups. The proportions of S. aureus that were methicillin resistant, enterococci that were vancomycin resistant and E. coli that produced extended-spectrum ß-lactamases were 11.2%, 0.7% and 1.0% for children, 22.8%, 4.6% and 4.3% for adults, and 28.0%, 3.8% and 4.9% for the elderly, respectively. Notable age-related differences in antimicrobial resistance patterns included the following: significantly less methicillin, clindamycin, clarithromycin and trimethoprim/sulfamethoxazole resistance in S. aureus from children; for E. coli, higher cefazolin and ciprofloxacin resistance in the elderly and less ceftriaxone, ciprofloxacin and gentamicin resistance in isolates from children; more S. pneumoniae isolates with penicillin MICs >1 mg/L in children; and for P. aeruginosa, higher resistance rates for meropenem, ciprofloxacin and levofloxacin in adults. CONCLUSIONS: The assessment of antimicrobial susceptibility patterns by age group revealed that resistance rates are often higher in the older age groups; however, considerable variability in age-specific resistance trends for different pathogen-antimicrobial combinations was noted.

Modulation of the Bi3+ 6s2 Lone Pair State in Perovskites for High-Mobility p-Type Oxide Semiconductors.

Oxide semiconductors are key materials in many technologies from flat-panel displays，solar cells to transparent electronics. However, many potential applications are hindered by the lack of high mobility p-type oxide semiconductors due to the localized O-2p derived valence band (VB) structure. In this work, the VB structure modulation is reported for perovskite Ba2 BiMO6 (M = Bi, Nb, Ta) via the Bi 6s2 lone pair state to achieve p-type oxide semiconductors with high hole mobility up to 21 cm2 V-1 s-1 , and optical bandgaps widely varying from 1.5 to 3.2 eV. Pulsed laser deposition is used to grow high quality epitaxial thin films. Synergistic combination of hard x-ray photoemission, x-ray absorption spectroscopies, and density functional theory calculations are used to gain insight into the electronic structure of Ba2 BiMO6 . The high mobility is attributed to the highly dispersive VB edges contributed from the strong coupling of Bi 6s with O 2p at the top of VB that lead to low hole effective masses (0.4-0.7 me ). Large variation in bandgaps results from the change in the energy positions of unoccupied Bi 6s orbital or Nb/Ta d orbitals that form the bottom of conduction band. P-N junction diode constructed with p-type Ba2 BiTaO6 and n-type Nb doped SrTiO3 exhibits high rectifying ratio of 1.3 × 104 at ±3 V, showing great potential in fabricating high-quality devices. This work provides deep insight into the electronic structure of Bi3+ based perovskites and guides the development of new p-type oxide semiconductors.

Reduction in antibiotic use following a cluster randomized controlled multifaceted intervention: the Israeli judicious antibiotic prescription study.

BACKGROUND: Antibiotic overuse is of great public health concern. This study assessed whether intervention among physicians and their treated population could achieve a sustained reduction in antibiotic use, specifically in classes known to promote antibiotic resistance among children in a community setting. METHODS: We performed a cluster randomized controlled multifaceted trial among 52 primary care pediatricians and the 88,000 children registered in their practices. The intervention was led by local leaders and engaged the participating physicians. It included physician focus group meetings, workshops, seminars, and practice campaigns. These activities focused on self-developed guidelines, improving parent and physician knowledge, diagnostic skills, and parent-physician communication skills that promoted awareness of antibiotic resistance. The main outcome measure was the change in annual antibiotic prescription rates (APRs) of children treated by the intervention group physicians as compared with rates among those treated by control group physicians. The study comprised a 2-year pre-intervention period, a 3-year intervention period, and a 1-year follow-up period. Mixed-effect models were used to assess risk ratios to account for the clustered study design. RESULTS: A decrease in the total APR among children treated by the intervention physicians compared with those treated by the control physicians was observed in the first intervention year (APR decrease among control physicians, 40%; APR decrease among intervention physicians, 22%; relative risk [RR], .76; 95% confidence interval [CI], .75-.78). This reduction crossed over all antibiotic classes but was most prominent for macrolides (macrolide prescription rate among control physicians, 58%; macrolide prescription rate among intervention physicians, 27%; RR, .58; 95% CI, .55-.62). The effect was sustained during the 4 following years. CONCLUSIONS. Multifaceted intervention that engages the physicians in an educational process is effective in reducing APRs and can be sustained. CLINICAL TRIALS REGISTRATION: NCT01187758.

Telavancin versus vancomycin for hospital-acquired pneumonia due to gram-positive pathogens.

BACKGROUND: Telavancin is a lipoglycopeptide bactericidal against gram-positive pathogens. METHODS: Two methodologically identical, double-blind studies (0015 and 0019) were conducted involving patients with hospital-acquired pneumonia (HAP) due to gram-positive pathogens, particularly methicillin-resistant Staphylococcus aureus (MRSA). Patients were randomized 1:1 to telavancin (10 mg/kg every 24 h) or vancomycin (1 g every 12 h) for 7-21 days. The primary end point was clinical response at follow-up/test-of-cure visit. RESULTS: A total of 1503 patients were randomized and received study medication (the all-treated population). In the pooled all-treated population, cure rates with telavancin versus vancomycin were 58.9% versus 59.5% (95% confidence interval [CI] for the difference, -5.6% to 4.3%). In the pooled clinically evaluable population (n = 654), cure rates were 82.4% with telavancin and 80.7% with vancomycin (95% CI for the difference, -4.3% to 7.7%). Treatment with telavancin achieved higher cure rates in patients with monomicrobial S. aureus infection and comparable cure rates in patients with MRSA infection; in patients with mixed gram-positive/gram-negative infections, cure rates were higher in the vancomycin group. Incidence and types of adverse events were comparable between the treatment groups. Mortality rates for telavancin-treated versus vancomycin-treated patients were 21.5% versus 16.6% (95% CI for the difference, -0.7% to 10.6%) for study 0015 and 18.5% versus 20.6% (95% CI for the difference, -7.8% to 3.5%) for study 0019. Increases in serum creatinine level were more common in the telavancin group (16% vs 10%). CONCLUSIONS: The primary end point of the studies was met, indicating that telavancin is noninferior to vancomycin on the basis of clinical response in the treatment of HAP due to gram-positive pathogens.

The responses of Aboriginal Canadians to adjuvanted pandemic (H1N1) 2009 influenza vaccine.

BACKGROUND: Because many Aboriginal Canadians had severe cases of pandemic (H1N1) 2009 influenza, they were given priority access to vaccine. However, it was not known if the single recommended dose would adequately protect people at high risk, prompting our study to assess responses to the vaccine among Aboriginal Canadians. METHODS: We enrolled First Nations and Métis adults aged 20-59 years in our prospective cohort study. Participants were given one 0.5-mL dose of ASO3-adjuvanted pandemic (H1N1) 2009 vaccine (Arepanrix, GlaxoSmithKline Canada). Blood samples were taken at baseline and 21-28 days after vaccination. Paired sera were tested for hemagglutination-inhibiting antibodies at a reference laboratory. To assess vaccine safety, we monitored the injection site symptoms of each participant for seven days. We also monitored patients for general symptoms within 7 days of vaccination and any use of the health care system for 21-28 days after vaccination. RESULTS: We enrolled 138 participants in the study (95 First Nations, 43 Métis), 137 of whom provided all safety data and 136 of whom provided both blood samples. First Nations and Métis participants had similar characteristics, including high rates of chronic health conditions (74.4%-76.8%). Pre-existing antibody to the virus was detected in 34.3% of the participants, all of whom boosted strongly with vaccination (seroprotection rate [titre ≥ 40] 100%, geometric mean titre 531-667). Participants with no pre-existing antibody also responded well. Fifty-eight of 59 (98.3%) First Nations participants showed seroprotection and a geometric mean titre of 353.6; all 30 Métis participants with no pre-existing antibody showed seroprotection and a geometric mean titre of 376.2. Pain at the injection site and general symptoms frequently occurred but were short-lived and generally not severe, although three participants (2.2%) sought medical attention for general symptoms. INTERPRETATION: First Nations and Métis adults responded robustly to ASO3-adjuvanted pandemic (H1N1) 2009 vaccine. Virtually all participants showed protective titres, including those with chronic health conditions.

Changing parents' opinions regarding antibiotic use in primary care.

Parents' wish for antibiotics is a significant determinant of antibiotic prescription for their children. The objective of the study was to assess the effect of an educational intervention on parents' attitudes towards antibiotic use. Parents accompanying their children to primary pediatric clinics of Jerusalem-Hashfela District of Maccabi Healthcare Services responded to a survey regarding their wish for antibiotic treatment. Two groups of parents were surveyed: A (control) in a pre-intervention period and B (intervention) during the intervention period. The intervention included posters, pamphlets, and drawing booklets for children in the waiting rooms. A per-protocol analysis that included from group B only parents that stated they noticed the educational material (B1) was also performed. Eight hundred and sixty-eight parents were surveyed during the pre-intervention period and 688 parents during the intervention period. Children's median age was 4 years (8 days-16 years). Most (86%) of the parents were mothers. Groups were similar in socio-demographic characteristics and children's medical complaints. Factors associated with parent's low expectation for antibiotics were a general negative attitude to antibiotics (OR 1.66, 95% CI 1.20-2.30), current upper respiratory tract symptoms (OR 0.29, 95% CI 0.21-0.39), advanced knowledge regarding antibiotics (OR 1.72, 95% CI 1.26-2.34), and being in group B (intervention) (OR 1.47, 95% CI 1.08-2.00). The effect of the intervention was greater in the per-protocol analysis (OR 1.75, 95% CI 1.20-2.55). A simple educational intervention was effective in reducing parents' expectation for antibiotics but was significantly more effective when parents reported they noticed the campaign. Improving parents' knowledge regarding antibiotics can reduce parents' wish for antibiotic treatment.

Chemokine receptor 5 △32 allele in patients with severe pandemic (H1N1) 2009.

Because chemokine receptor 5 (CCR5) may have a role in pulmonary immune response, we explored whether patients with severe pandemic (H1N1) 2009 were more likely to carry the CCR5Δ32 allele than were members of the general population. We found a large proportion of heterozygosity for the CCR5Δ32 allele among white patients with severe disease.

Influenza epidemiology--past, present, and future.

In April 2009, Mexican, American, and Canadian authorities announced that a novel influenza virus with pandemic potential had been identified in large segments of the population. Within weeks, it became apparent that the world was dealing with the first influenza pandemic in >40 yrs. Despite the unpredictable nature of influenza severity and spread in the pandemics of the 20th century, understanding the epidemiology of the past pandemics and current influenza pandemic will help prepare physicians, hospitals, and governments to predict and prepare for the subsequent waves and subsequent pandemics. We present a summary of the biology that predisposes influenza to cause sudden pandemics, as well as a summary of the epidemiology of the 20th century pandemics. We also report on the epidemiology, disease severity, and risk factors for severe disease and intensive care admission from the first wave of the current pandemic (April-August 2009). Last, we provide a mathematical model based on transmission dynamics of the H1N1 influenza virus that may provide some guidance in terms of disease incidence and hospital impact.

Pulsed moxifloxacin for the prevention of exacerbations of chronic obstructive pulmonary disease: a randomized controlled trial.

BACKGROUND: Acute exacerbations contribute to the morbidity and mortality associated with chronic obstructive pulmonary disease (COPD). This proof-of-concept study evaluates whether intermittent pulsed moxifloxacin treatment could reduce the frequency of these exacerbations. METHODS: Stable patients with COPD were randomized in a double-blind, placebo-controlled trial to receive moxifloxacin 400 mg PO once daily (N = 573) or placebo (N = 584) once a day for 5 days. Treatment was repeated every 8 weeks for a total of six courses. Patients were repeatedly assessed clinically and microbiologically during the 48-week treatment period, and for a further 24 weeks' follow-up. RESULTS: At 48 weeks the odds ratio (OR) for suffering an exacerbation favoured moxifloxacin: per-protocol (PP) population (N = 738, OR 0.75, 95% confidence interval (CI) 0.565-0.994, p = 0.046), intent-to-treat (ITT) population (N = 1149, OR 0.81, 95% CI 0.645-1.008, p = 0.059), and a post-hoc analysis of per-protocol (PP) patients with purulent/mucopurulent sputum production at baseline (N = 323, OR 0.55, 95% CI 0.36-0.84, p = 0.006).There were no significant differences between moxifloxacin and placebo in any pre-specified efficacy subgroup analyses or in hospitalization rates, mortality rates, lung function or changes in St George's Respiratory Questionnaire (SGRQ) total scores. There was, however, a significant difference in favour of moxifloxacin in the SGRQ symptom domain (ITT: -8.2 vs -3.8, p = 0.009; PP: -8.8 vs -4.4, p = 0.006). Moxifloxacin treatment was not associated with consistent changes in moxifloxacin susceptibility. There were more treatment-emergent, drug related adverse events with moxifloxacin vs placebo (p < 0.001) largely due to gastrointestinal events (4.7% vs 0.7%). CONCLUSIONS: Intermittent pulsed therapy with moxifloxacin reduced the odds of exacerbation by 20% in the ITT population, by 25% among the PP population and by 45% in PP patients with purulent/mucopurulent sputum at baseline. There were no unexpected adverse events and there was no evidence of resistance development. TRIAL REGISTRATION: ClinicalTrials.gov number, NCT00473460 (ClincalTrials.gov).

The pneumococcal pilus predicts the absence of Staphylococcus aureus co-colonization in pneumococcal carriers.

The determinants of the negative association between Streptococcus pneumoniae and Stapylococcus aureus colonization are unknown. In this matched case-control study, the odds of co-colonization with S. aureus were significantly lower for individuals carrying a piliated versus a nonpiliated S. pneumoniae strain, suggesting the pilus may be a determinant of the negative association.

Clinical consensus conference: survey on Gram-positive bloodstream infections with a focus on Staphylococcus aureus.

The increased incidence over the past decade of bloodstream infections (BSIs) caused by gram-positive bacteria, particularly methicillin-resistant Staphylococcus aureus, highlights the critical need for a consistent approach to therapy. However, there is currently no international consensus on the diagnosis and management of gram-positive BSIs. The Clinical Consensus Conference on Gram-Positive Bloodstream Infections was convened as a session at the 9th International Symposium on Modern Concepts in Endocarditis and Cardiovascular Infections held in 2007. Participants discussed various aspects of the practical treatment of patients who present with gram-positive BSI, including therapeutic options for patients with BSIs of undefined origin, the selection of appropriate empirical therapy, and treatment of complicated and uncomplicated BSIs. The opinions of participants about these key issues are reflected in this article.