In temperate regions, influenza typically arrives with the onset of colder weather. Seasonal waves travel over large spaces covering many climatic zones in a relatively short period of time. The precise mechanism for this striking seasonal pattern is still not well understood and the interplay of factors that influence the spread of infection and the emergence of new strains is largely unknown. The study of influenza seasonality has been fraught with problems. One of these is the ever shifting description of illness due to influenza and the use of both the historical definitions and new definitions based on actual isolation of the virus. The compilation of records describing influenza oscillations on a local and global scale is massive, but the value of these data is a function of the definitions used. In this review we argue that both observations of seasonality and deviation from the expected pattern stem from the nature of this disease. Heterogeneity in seasonal patterns may arrive from differences in behavior of specific strains, emergence of a novel strain or cross-protection from previously observed strains. Most likely the seasonal patterns emerge from interactions of individual factors behaving as coupled resonators. We emphasize that both seasonality and deviations from it may merely be a reflection of our inability to disentangle signal from noise, be it due to ambiguity in measurement and/or terminology. We conclude the review with suggestions for new promising and realistic directions with tangible consequences to model complex influenza dynamics in order to effectively control infection.
Although Clostridium difficile (C. difficile) is the leading cause of infectious diarrhoea in hospitalized patients, the economic burden of this major nosocomial pathogen for hospitals, third-party payers and society remains unclear. We developed an economic computer simulation model to determine the costs attributable to healthcare-acquired C. difficile infection (CDI) from the hospital, third-party payer and societal perspectives. Sensitivity analyses explored the effects of varying the cost of hospitalization, C. difficile-attributable length of stay, and the probability of initial and secondary recurrences. The median cost of a case ranged from $9179 to $11 456 from the hospital perspective, $8932 to $11 679 from the third-party payor perspective, and $13 310 to $16 464 from the societal perspective. Most of the costs incurred were accrued during a patient’s primary CDI episode. Hospitals with an incidence of 4.1 CDI cases per 100 000 discharges would incur costs ≥$3.2 million (hospital perspective); an incidence of 10.5 would lead to costs ≥$30.6 million. Our model suggests that the annual US economic burden of CDI would be ≥$496 million (hospital perspective), ≥$547 million (third-party payer perspective) and ≥$796 million (societal perspective). Our results show that C. difficile infection is indeed costly, not only to third-party payers and the hospital, but to society as well. These results are consistent with current literature citing C. difficile as a costly disease.
Burden; Clostridium difficile; cost; economics; stochastic model
A multicenter, case-control study was conducted to assess risk factors and patient outcomes from bacteremia due to Enterobacteriaceae producing extended-spectrum β-lactamases (ESBL) and Klebsiella pneumoniae carbapenemases (KPCs). One hundred five and 20 patients with bacteremia due to ESBL and KPC-producing organisms were matched to controls that had bacteremia with non-ESBL/KPC-producing organisms, respectively. Independent risk factors for ESBL production included admission from a nursing home (odds ratio [OR], 4.64; 95% confidence interval [CI], 2.64–8.16), chronic renal failure (OR, 2.09; 95% CI, 1.11–3.92), the presence of a gastrostomy tube (OR, 3.36; 95% CI, 1.38–8.18), length of hospital stay before infection (OR, 1.02; 95% CI, 1.01–1.03), transplant recipients (OR, 2.48; 95% CI, 1.24–4.95) and receipt of antibiotics with Gram-negative activity in the preceding 30 days (OR, 1.76; 95% CI, 1.00–3.08). 28-day crude mortality rates for patients infected with ESBL or KPC-producing organisms and controls were 29.1% (34/117) and 19.5% (53/272), respectively (OR 1.70; 95% CI 1.04–2.80). On multivariate analysis, inadequate empiric therapy (OR, 2.26; 95% CI, 1.18–4.34), onset of bacteremia while in ICU (OR, 2.74; 95% CI, 1.47–5.11), Apache II score (OR, 1.17; 95% CI, 1.12–1.23), and malignancy (OR, 2.66; 95% CI, 1.31–5.41) were independent risk factors for mortality. CTX-M was the most common ESBL type in E. coli, whereas SHV predominated in Klebsiella spp. and Enterobacter spp.
Enterobacteriaceae; bacteremia; extended-spectrum β-lactamase (ESBL); Klebsiella pneumoniae carbapenemase (KPC); carbapenem
Comparison of genome-wide, high-resolution restriction maps of Klebsiella pneumoniae clinical isolates, including an NDM-1 producer, and in silico-generated restriction maps of sequenced genomes revealed a highly heterogeneous region we designated the “high heterogeneity zone” (HHZ). The HHZ consists of several regions including a “hot spot” prone to insertions and other rearrangements. The HHZ is a characteristic genomic area that can be used in the identification and tracking of outbreak-causing strains.
Klebsiella pneumoniae; Genomic analysis; optical map; NDM-1; ICE
The Entamoeba histolytica infections result from asymptomatic colonization to variable disease outcomes. However, markers that may predict infection outcomes are not known. Here, we investigated sequence types of a non-coding tRNA-linked locus R-R to identify surrogate markers that may show association with infection outcomes. Among 112 clinical samples -21 asymptomatic, 20 diarrhea/dysentery, and 71 liver abscesses (LA), we identified 11 sequence types. Sequence type 5RR mostly associated with asymptomatic samples, and sequence type 10RR predominantly associated with the symptomatic (diarrhea/dysentery and LA) samples. This is the first report that identifies markers that may predict disease outcomes in E. histolytica.
Enterococci are organisms with a remarkable ability to adapt to the
environment and acquire antibiotic resistance determinants. The evolution of
antimicrobial resistance in these organisms poses enormous challenges for
clinicians when faced with patients affected with severe infections. The
increased prevalence and dissemination of multidrug-resistant
Enterococcus faecium worldwide has resulted in a major
decrease in therapeutic options because the majority of E.
faecium isolates are now resistant to ampicillin and vancomycin,
and exhibit high-level resistance to aminoglycosides, which are three of the
traditionally most useful anti-enterococcal antibiotics. Newer antibiotics such
as linezolid, daptomycin and tigecycline have good in vitro
activity against enterococcal isolates, although their clinical use may be
limited in certain clinical scenarios as a result of reduced rates of success,
possible underdosing for enterococci and low serum levels, respectively, and
also by the emergence of resistance. The experimental agent oritavancin may
offer some hope for the treatment of vancomycin-resistant enterococci but
clinical data are still lacking. Thus, optimal therapies for the treatment of
multidrug-resistant enterococcal infections continue to be based on empirical
observations and extrapolations from in vitro and animal data.
Clinical studies evaluating new strategies, including combination therapies, to
treat severe vancomycin-resistant E. faecium infections are
Antibiotics; enterococci; resistance; review; vancomycin
Human milk oligosaccharides (HMO) constitute the third most abundant class of molecules in breast milk. Since infants lack the enzymes required for milk glycan digestion, this group of carbohydrates passes undigested to the lower part of the intestinal tract, where they can be consumed by specific members of the infant gut microbiota. We review proposed mechanisms for the depletion and metabolism of HMO by two major bacterial genera within the infant intestinal microbiota, Bifidobacterium and Bacteroides
Bacteroides; Bifidobacterium; human milk oligosaccharides; infant gut
The kinetics of serum (1→3)-β-D-glucan (BG) following the diagnosis of invasive fungal disease and administration of antifungal therapy are poorly characterized. It is unknown whether early BG changes have prognostic implications. We assessed the post-diagnostic kinetics of BG in patients with an initial serum BG ≥80 pg/mL and at least one additional post-diagnostic BG value in the setting of invasive aspergillosis (IA, n=69), invasive candidiasis (IC, n=40), or Pneumocystis jirovecii pneumonia (PCP, n=18), treated with antifungal therapy. Clinical failure of antifungal therapy and mortality were assessed at 6 and 12 weeks, and Cox modeling was used to assess the hazard of initial BG and change in BG at 1 or 2 weeks for these outcomes. In patients with ≥2 BG values, median initial BG was >500 pg/mL (IQR (interquartile range) 168, >500; range 80, >500) in IA, 136 pg/mL (IQR 88, >500; range 31, >500) in IC, and >500 pg/mL (IQR 235, >500; range 86, >500) in PCP. In patients with ≥2 BG values through one week after diagnosis, overall one-week decline in BG was 0 pg/mL (IQR 0, 53) in IA, 0 (IQR −65, 12) in IC, and 17 (IQR 0, 82) in PCP. Most patients with BG values through 6 and 12 weeks had persistent levels >80 pg/mL. Initial BG and the early trajectory of BG were not predictive of 6 or 12-week clinical failure or mortality. While BG eventually declines in patients with IA, IC, and PCP, it lacks prognostic value within a clinically meaningful time frame.
beta-glucan; invasive aspergillosis; candidiasis; Pneumocystis jirovecii; invasive fungal disease; galactomannan; kinetics
Antibody detection is a safely applied method at wide scale in diagnosis of Visceral Leishmaniasis (VL). Towards further advancement of serodiagnosis, rK28 antigen has been recently introduced as a candidate for diagnosis of VL. We evaluated sensitivity and specificity of rK28 antigen in a micro-ELISA format in comparison to rk39 antigen. The test was conducted on 252 parasitologically confirmed VL cases, 103 endemic healthy controls, 95 non endemic healthy controls, 88 other infectious disease and 53 follow-up cases. Of 252 parasitologically confirm VL cases, 251 cases were reported positive by rK28 antigen yielding 99.6% sensitivity (95% CI, 0.97–0.99) which was similar to sensitivity of rK39 ELISA (99.6%) (95% CI, 0.97–0.99). Specificity of rK28 antigen in non-endemic and endemic healthy controls was 100% (95%CI 0.96–1) and 94.17% (95% CI, 0.88–0.97), respectively. In 88 different diseases, specificity was 95.45% (95% CI, 0.84–0.96). With rK39 antigen, specificity of non-endemic and endemic controls, and different diseases was 100% (95%CI 0.96–1) and 92.23% (95% CI 0.85–0.96), and 96.59% (95% CI 0.90–0.98) respectively. Our results show that rK39 and rK28 antigens have similar sensitivity and specificity and rK28 can also be used as a serodiagnostic tool in endemic population of Bihar.
Visceral Leishmaniasis; rk-28; serodiagnosis; ELISA
We and others have previously isolated influenza B viruses with reduced sensitivity to neuraminidase (NA) inhibitors (oseltamivir and zanamivir) from patients who were never exposed to these drugs. It was unclear whether the NA substitutions found in these influenza B isolates arose spontaneously or were due to selective pressure. Here, we obtained influenza B viruses with reduced neuraminidase inhibitor sensitivity by in vitro selection with NA inhibitors. We found that these viruses possessed the same NA substitutions as those previously found in viruses isolated from untreated patients. These results suggest that these NA substitutions were selected in patients who were treated with an NA inhibitor and the resistant variants were then transmitted to others.
Influenza B virus; neuraminidase; NA inhibitor; drug-resistant mutation; in vitro selection
A serological survey for antibodies to influenza viruses was performed in China on a group of people without a history of influenza vaccination. Using the hemagglutination inhibition (HI) assay, we found seropositivity rates for seasonal H3N2 to be significantly higher than for seasonal H1N1. Samples positive for antibodies to pandemic (H1N1) 2009 virus increased from 0.6% pre-outbreak to 4.5% (p<0.01) at one year post-outbreak. Interestingly, HI and neutralization tests showed that 1.4% of people in the group have antibodies recognizing H9N2 avian influenza viruses, suggesting that infection with this subtype may be more common than previously thought.
influenza; prevalence; antibody; pandemic H1N1; H9N2
A previous meta-analysis determined that the effects of steroids during sepsis were dose-dependent; since then, additional trials have been published. The current analysis updates our previous analysis examining the effects of steroids during sepsis. A literature search from 2004 to 2008 identified seven randomized controlled trials in adult patients; these were added to 14 previously identified trials. The effects of steroids on mortality were highly variable among the 21 trials (p <0.001, I2 = 60%). In trials published before 1989, which involved short courses of high-dose steroids, steroids increased mortality (n = 8, I2 = 14%, OR of death 1.39 (95% CI 1.04–1.86), p 0.03). In trials published after 1997, which involved longer courses of lower-dose steroids, steroids consistently improved shock reversal (n = 7, I2 = 0%, OR of shock reversal 1.66 [95% CI 1.25–2.20), p <0.001), but demonstrated a more heterogeneous beneficial effect on mortality (n = 12, I2 = 25%, OR of death 0.64 (95% CI 0.45–0.93), p 0.02). An inverse linear relationship between severity of illness and the effects of steroids on mortality was identified across all trials (p 0.03) and within the subgroup of trials published after 1997 (p 0.03); steroids were harmful in less severely ill patient populations and beneficial in more severely ill patient populations. There was no effect of response to adrenocorticotrophic hormone (ACTH) stimulation testing concerning the effects of steroids and no increase in steroid-associated adverse events. Low-dose steroids appear to improve mortality rates in patients with septic shock who are at high risk of death; however, additional trials in this subpopulation are necessary to definitively determine the role of low-dose steroids during sepsis.
Corticosteroids; glucocorticoids; meta-analysis; review; sepsis; septic shock; steroids
Mycobacterium tuberculosis harbours little DNA sequence diversity compared to other bacteria. However, there is mounting evidence that strain-to-strain variation in this organism has been underestimated. Here we review our current understanding of the genetic diversity among M. tuberculosis clinical strains and discuss the relevance of this diversity for the ongoing global epidemics of drug-resistant tuberculosis. Based on findings in other bacteria, we propose that epistatic interactions between pre-existing differences in strain genetic background, acquired drug resistance-conferring mutations and compensatory changes could play a role in the emergence and spread of drug-resistant M. tuberculosis.
Mycobacterium avium subsp hominissuis, hereafter referred to as M. avium, forms biofilm, a property that, in mice, is associated with lung infection via aerosol. As M. avium might co-inhabit the respiratory tract with other pathogens, treatment of the co-pathogen-associated infections, such as in bronchiectasis, would expose M. avium to therapeutic compounds which may have their origin in other organisms sharing the natural environments. Incubation of M. avium with two compounds produced by environmental organisms, streptomycin and tetracycline in vitro at sub-inhibitory concentrations increased biofilm formation in a number of M. avium strains, although exposure to ampicillin, moxifloxacin, rifampin, and TMP/SMX had no effect on biofilm. No selection of genotypically resistant clones was observed. While bacteria incubation in presence of streptomycin upregulates the expression of biofilm-associated genes, the response to the antibiotics had no association with a regulation of a regulator (LysR) linked to the formation of biofilm in M. avium.
Biofilms are made of planktonic and sessile bacteria. While planktonic M. avium is susceptible to clarithromycin and ethambutol (clinically used antimicrobials), sessile bacteria are at least 3- to 4-fold more resistant to antibiotics. The sessile phenotype, though, is reversible, and no selection of resistant clones was observed. Mice infected through the airway with both phenotypes were infected with a similar number of bacteria, demonstrating no phenotype advantage.
M. avium biofilm formation is enhanced by commonly used compounds and, in the sessile bacterial phenotype, is resistant to clarithromycin and ethambutol, in a reversible manner.
M. avium; biofilm; gene expression; antibiotics
Enterobacter species are the fourth most common cause of gram-negative bloodstream infection (BSI). We examined temporal changes and seasonal variation in the incidence rate of Enterobacter spp. BSI, estimated 28-day and 1-year mortality, and determined in vitro antimicrobial resistance rates of Enterobacter spp. bloodstream isolates in Olmsted County, Minnesota, from 1/1/1998 to 12/31/2007. Multivariable Poisson regression was used to examine temporal changes and seasonal variation in incidence rate and Kaplan-Meier method to estimate 28-day and 1-year mortality. The median age of patients with Enterobacter spp. BSI was 58 years and 53% were female. The overall age- and gender-adjusted incidence rate of Enterobacter spp. BSI was 3.3/100,000 person-years (95% confidence interval [CI]: 2.3-4.4). There was a linear trend of increasing incidence rate from 0.8 (95% CI: 0-1.9) to 6.2 (95% CI: 3.0-9.3) per 100,000 person-years between 1998 and 2007 (p=0.002). There was no significant difference in the incidence rate of Enterobacter spp. BSI during the warmest four months compared to the remainder of the year (incidence rate ratio 1.06 [95% CI: 0.47-2.01]). The overall 28-day and 1-year mortality rates of Enterobacter spp. BSI were 21% (95% CI: 8-34%) and 38% (95% CI: 22-53%), respectively. Up to 13% of Enterobacter spp. bloodstream isolates were resistant to third-generation cephalosporins. To our knowledge, this is the first population-based study to describe the epidemiology and outcome of Enterobacter spp. BSI. The increase in incidence rate of Enterobacter spp. BSI over the past decade, coupled with its associated antimicrobial resistance, dictate more investigation of this syndrome.
bacteremia; epidemiology; mortality; seasonal variation; incidence; Enterobacter; antimicrobial resistance
Although norovirus is a significant cause of nosocomial viral gastroenteritis, the economic value of hospital outbreak containment measures following identification of a norovirus case is currently unknown. We developed computer simulation models to determine the potential cost-savings from the hospital perspective of implementing the following norovirus outbreak control interventions: (1) increased hand hygiene measures, (2) enhanced disinfection practices, (3) patient isolation, (4) use of protective apparel, (5) staff exclusion policies, and (6) ward closure. Sensitivity analyses explored the impact of varying intervention efficacy, number of initial norovirus cases, the norovirus reproductive rate (R), and room and ward size and occupancy. Implementing increased hand hygiene, using protective apparel, staff exclusion policies, or increased disinfection separately or in bundles provided net cost-savings, even when the intervention was only 10% effective in preventing further norovirus transmission. Patient isolation or ward closure was cost-saving only when transmission prevention efficacy was very high (≥90%), and their economic value decreased as the number of beds per room and the number of empty beds per ward increased. Increased hand hygiene, using protective apparel, or increased disinfection practices separately or in bundles are the most cost-saving interventions for the control and containment of a norovirus outbreak.
Norovirus; Hospital; Economics; Infection Control; Outbreak; Interventions
Former illegal blood donation in the past decade has caused HIV outbreaks in some rural areas in China. Other HIV associated virus infections, such as human herpesvirus 8 (HHV8) in such areas are still not well defined. In order to explore HHV8 and HCV seroprevalence and potential risk factors in such areas, a cross-sectional study with 305 HIV positive and 315 HIV negative subjects recruited from a rural county in Shanxi province was conducted, where illegal blood collection was reported. Interview questionnaires and serum testing were carried out with these participants. HCV and HHV8 seroprevalence were found to be higher in HIV positive than negative group (76.4% vs. 2.5%; 15.4% vs. 4.8% respectively), while the difference in HBV seroprevalence was not significant. Co-infection with HCV and HHV8 was also more prevalent in the HIV positive group. HIV status (odds ratio [OR], 2.71; 95% confidence interval [CI], 1.16–6.30) and HBV status (OR, 2.56; 95%CI: 1.14–5.75) were independently associated with HHV8 infection. HIV status (OR, 23.03; 95%CI: 9.95–53.27) and blood/plasma selling history (OR, 14.57; 95%CI: 7.49–28.23) were strongly associated with HCV infection. These findings demonstrate that both HHV8 and HCV infections are prevalent in this community. HIV infection is an important risk factor for both HHV8 and HCV infection. HBV infection is associated with HHV8 infection but not with HCV infection. It is possible that HHV8 and HBV, but not HCV, may have similar mode of transmission in this population.
HIV; HHV8; HCV; Illegal blood donor; Seroprevalence
Helicobacter pylori strains from different geographic areas exhibit clear phylogeographical differentiation; therefore, the genotypes of H. pylori strains can serve as markers for the migration of human populations. Currently, the genotypes of two virulence factors of H. pylori, cagA and vacA, and multilocus sequence typing (MLST) are widely used markers for genomic diversity within H. pylori populations. There are two types of cagA: the East Asian type and the Western type. In addition, the right end of the cag pathogenicity island is divided into five subtypes and there are distinct mosaic structures at the signal region and the middle region of vacA. Using combinations of the cagA, cag right end junction, and vacA genotypes, five major groups (East Asia type, South/Central Asia type, Iberian/Africa type and Europe type) have been defined according to geographical associations. MLST has revealed seven modern population types and six ancestral population types of H. pylori, and is a useful tool for mapping human migration patterns. Serial studies of large numbers of H. pylori strains, including strains isolated from aboriginal populations, show that MLST analysis provides more detailed information on human migration than does the analysis of human genetics. H. pylori infection is rapidly declining as a result of improvements in personal hygiene and quality of life. The molecular epidemiology of H. pylori infection has much to tell us and should be studied before it disappears entirely.
cagA; house keeping genes; MLST; vacA
In the populations of Western countries, particular genotypes of the vacuolating cytotoxin gene, vacA (vacA s, signal region variants; vacA m, middle region variants) of Helicobacter pylori are believed to be risk factors for the development of peptic ulcers and gastric cancer. However, it was unclear whether these vacA gene variants are associated with the development of gastrointestinal diseases in developing nations. The relationship between vacA genotypes and H. pylori-related disease development in Latin American and African populations was investigated using meta-analysis of 2612 patients from Latin America (2285 strains) and 520 patients from Africa (434 strains). The frequencies of vacA s and m genotypes differed between strains from Latin America (77.2% for s1 and 68.1% for m1) and Africa (83.9% for s1 and 56.7% for m1). Latin American strains with s1 and m1 genotypes increased the risk of gastric cancer (OR 4.17, 95% CI 2.49–6.98 for s1, and 3.59, 2.27–5.68 for m1) and peptic ulcers (e.g. 1.73, 1.37–2.20 for s1). African strains with the s1 or m1 genotypes also increased the risk of peptic ulcers (8.69, 1.16–64.75 for s1) and gastric cancer (10.18, 2.36–43.84 for m1). The cagA-positive genotype frequently coincided with s1 and m1 genotypes in both populations. Overall, the vacA s and m genotypes were related to gastric cancer and peptic ulcer development and might be useful markers of risk factors for gastrointestinal disease, especially in Latin America. Further studies will be required to evaluate the effects of vacA genotypes in African populations because of the small sample number currently available.
Developing country; gastric cancer; Helicobacter pylori; middle region; peptic ulcer; signal region; VacA
Group A streptococcal (GAS) pharyngeal colonization rates were determined among 1061 asymptomatic students in Hawaii and American Samoa where acute rheumatic fever rates are high. All GAS isolates were emm sequence typed. Although pharyngeal colonization rates were low in Hawaii (3.4%), Pacific Islander children had significantly higher colonization rates (5.7% versus 1.2% in other ethnic groups, p<0.05). The colonization rate was higher in American Samoa (13%). Few emm types that were infrequently observed in symptomatic infections in Hawaii were repeatedly identified in both sites. These emm types were previously described among asymptomatic children suggesting a type-specific association with pharyngeal colonization.
Streptococcus pyogenes; epidemiology; asymptomatic colonization; emm typing; Pacific Islander
Improved detection and isolation of rickettsial agents from naturally infected dogs would facilitate understanding the epidemiologic roles of these hosts. In this study, current methods were refined for rapid screening of carrier blood and ticks for Ehrlichia canis, and the feasibility of blood culture after PCR screening was addressed.
Ehrlichia canis; Rhipicephalus sanguineus; blood culture; PCR assay
Infections as a result of community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) are an issue of increasing global healthcare concern. In Europe, this principally involves strains of multi-locus sequence type clonal complex 80 sequence type 80 with methicillin resistance in a staphylococcal chromosomal cassette (SCCmec) type IV arrangement (CC80:ST80-IV). As with other CA-MRSA strains, CC80:ST80-IV isolates tend to appear uniform when analysed by common molecular typing methods (e.g. pulsed field gel electrophoresis, multi-locus sequence type, SCCmec). To explore whether DNA sequence-based differences exist, we compared the genetic composition of six CC80:ST80-IV isolates of diverse chronological and geographic origin (i.e. Denmark and the Middle East) using an Affymetrix high-density microarray that was previously used to analyse CA-MRSA USA300 isolates. The results revealed a high degree of homology despite the diversity in isolation date and origin, with isolate differences primarily in conserved hypothetical open reading frames and intergenic sequences, but also including regions of known function. This included the confirmed loss of SCCmec recombinase genes in two Danish isolates representing potentially new SCCmec types. Microarray analysis grouped the six isolates into three relatedness pairs, also identified by pulsed field gel electrophoresis, which were consistent with both the clinical and molecular data.
Community; microarray; ST80; Staphylococcus aureus