Showing papers in "Clinical Infectious Diseases in 2011"

Clinical Practice Guidelines by the Infectious Diseases Society of America for the Treatment of Methicillin-Resistant Staphylococcus aureus Infections in Adults and Children

Abstract: Evidence-based guidelines for the management of patients with methicillin-resistant Staphylococcus aureus (MRSA) infections were prepared by an Expert Panel of the Infectious Diseases Society of America (IDSA). The guidelines are intended for use by health care providers who care for adult and pediatric patients with MRSA infections. The guidelines discuss the management of a variety of clinical syndromes associated with MRSA disease, including skin and soft tissue infections (SSTI), bacteremia and endocarditis, pneumonia, bone and joint infections, and central nervous system (CNS) infections. Recommendations are provided regarding vancomycin dosing and monitoring, management of infections due to MRSA strains with reduced susceptibility to vancomycin, and vancomycin treatment failures.

Clinical Practice Guideline for the Use of Antimicrobial Agents in Neutropenic Patients with Cancer: 2010 Update by the Infectious Diseases Society of America

Abstract: This document updates and expands the initial Infectious Diseases Society of America (IDSA) Fever and Neutropenia Guideline that was published in 1997 and first updated in 2002. It is intended as a guide for the use of antimicrobial agents in managing patients with cancer who experience chemotherapy-induced fever and neutropenia. Recent advances in antimicrobial drug development and technology, clinical trial results, and extensive clinical experience have informed the approaches and recommendations herein. Because the previous iteration of this guideline in 2002, we have a developed a clearer definition of which populations of patients with cancer may benefit most from antibiotic, antifungal, and antiviral prophylaxis. Furthermore, categorizing neutropenic patients as being at high risk or low risk for infection according to presenting signs and symptoms, underlying cancer, type of therapy, and medical comorbidities has become essential to the treatment algorithm. Risk stratification is a recommended starting point for managing patients with fever and neutropenia. In addition, earlier detection of invasive fungal infections has led to debate regarding optimal use of empirical or preemptive antifungal therapy, although algorithms are still evolving. What has not changed is the indication for immediate empirical antibiotic therapy. It remains true that all patients who present with fever and neutropenia should be treated swiftly and broadly with antibiotics to treat both gram-positive and gram-negative pathogens. Finally, we note that all Panel members are from institutions in the United States or Canada; thus, these guidelines were developed in the context of North American practices. Some recommendations may not be as applicable outside of North America, in areas where differences in available antibiotics, in the predominant pathogens, and/or in health care-associated economic conditions exist. Regardless of venue, clinical vigilance and immediate treatment are the universal keys to managing neutropenic patients with fever and/or infection.

International clinical practice guidelines for the treatment of acute uncomplicated cystitis and pyelonephritis in women: A 2010 update by the Infectious Diseases Society of America and the European Society for Microbiology and Infectious Diseases

Abstract: A Panel of International Experts was convened by the Infectious Diseases Society of America (IDSA) in collaboration with the European Society for Microbiology and Infectious Diseases (ESCMID) to update the 1999 Uncomplicated Urinary Tract Infection Guidelines by the IDSA. Co-sponsoring organizations include the American Congress of Obstetricians and Gynecologists, American Urological Association, Association of Medical Microbiology and Infectious Diseases-Canada, and the Society for Academic Emergency Medicine. The focus of this work is treatment of women with acute uncomplicated cystitis and pyelonephritis, diagnoses limited in these guidelines to premenopausal, non-pregnant women with no known urological abnormalities or co-morbidities. The issues of in vitro resistance prevalence and the ecological adverse effects of antimicrobial therapy (collateral damage) were considered as important factors in making optimal treatment choices and thus are reflected in the rankings of recommendations.

The Spectrum of Engagement in HIV Care and its Relevance to Test-and-Treat Strategies for Prevention of HIV Infection

Abstract: For individuals with human immunodeficiency virus (HIV) infection to fully benefit from potent combination antiretroviral therapy, they need to know that they are HIV infected, be engaged in regular HIV care, and receive and adhere to effective antiretroviral therapy. Test-and-treat strategies for HIV prevention posit that expanded testing and earlier treatment of HIV infection could markedly decrease ongoing HIV transmission, stemming the HIV epidemic. However, poor engagement in care for HIV-infected individuals will substantially limit the effectiveness of test-and-treat strategies. We review the spectrum of engagement in care for HIVinfected individuals in the United States and apply this information to help understand the magnitude of the challenges that poor engagement in care will pose to test-and-treat strategies for HIV prevention.

The Management of Community-Acquired Pneumonia in Infants and Children Older Than 3 Months of Age: Clinical Practice Guidelines by the Pediatric Infectious Diseases Society and the Infectious Diseases Society of America

Abstract: Evidenced-based guidelines for management of infants and children with community-acquired pneumonia (CAP) were prepared by an expert panel comprising clinicians and investigators representing community pediatrics, public health, and the pediatric specialties of critical care, emergency medicine, hospital medicine, infectious diseases, pulmonology, and surgery. These guidelines are intended for use by primary care and subspecialty providers responsible for the management of otherwise healthy infants and children with CAP in both outpatient and inpatient settings. Site-of-care management, diagnosis, antimicrobial and adjunctive surgical therapy, and prevention are discussed. Areas that warrant future investigations are also highlighted.

Premature Age-Related Comorbidities Among HIV-Infected Persons Compared With the General Population

Abstract: Background Human immunodeficiency virus (HIV)‐infected patients may have a greater risk of noninfectious comorbidities (NICMs) compared with the general population We assessed the prevalence and risk factors for NICMs in a large cohort of HIV-infected adults and compared these findings with data from matched control subjects Methods We performed a case-control study involving antiretroviral therapy (ART)‐experienced HIVinfected patients treated at Modena University, Italy, from 2002 through 2009 These patients were compared with age-, sex-, and race-matched adults (control subjects) from the general population included in the CINECA ARNO database NICMs included cardiovascular disease, hypertension, diabetes mellitus, bone fractures, and renal failure Polypathology (Pp) was defined as the concurrent presence of $2 NICMs Logistic regression models were constructed to evaluate associated predictors of NICMs and Pp Results There were 2854 patients and 8562 control subjects The mean age was 46 years, and 37% were women Individual NICM and Pp prevalences in each age stratum were higher among patients than among controls (all P ,001) Pp prevalence among patients aged 41‐50 years was similar to that among controls aged 51‐60 years (P value was not statistically significant); diabetes mellitus, cardiovascular disease, bone fractures, and renal failure were statistically independent after adjustment for sex, age, and hypertension Logistic regression models showed that independent predictors of Pp in the overall cohort were (all P , 001) age (odds ratio [OR], 111), male sex (OR, 177), nadir CD4 cell count ,200 cells/lL (OR, 446), and ART exposure (OR, 101) Conclusions Specific age-related NICMs and Pp were more common among HIV-infected patients than in the general population The prevalence of Pp in HIV-infected persons anticipated Pp prevalence observed in the general population among persons who were 10 years older, and HIV-specific cofactors (lower nadir CD4 cell count and more prolonged ART exposure) were identified as risk factors These data support the need for earlier screening for NICMs in HIV-infected patients

“Herd Immunity”: A Rough Guide

Abstract: The term "herd immunity" is widely used but carries a variety of meanings. Some authors use it to describe the proportion immune among individuals in a population. Others use it with reference to a particular threshold proportion of immune individuals that should lead to a decline in incidence of infection. Still others use it to refer to a pattern of immunity that should protect a population from invasion of a new infection. A common implication of the term is that the risk of infection among susceptible individuals in a population is reduced by the presence and proximity of immune individuals (this is sometimes referred to as "indirect protection" or a "herd effect"). We provide brief historical, epidemiologic, theoretical, and pragmatic public health perspectives on this concept.

Systematic review of intestinal microbiota transplantation (fecal bacteriotherapy) for recurrent Clostridium difficile infection.

Abstract: Clostridium difficile infection (CDI) is a gastrointestinal disease believed to be causally related to perturbations to the intestinal microbiota. When standard treatment has failed, intestinal microbiota transplantation (IMT) is an alternative therapy for patients with CDI. IMT involves infusing intestinal microorganisms (in a suspension of healthy donor stool) into the intestine of a sick patient to restore the microbiota. However, protocols and reported efficacy for IMT vary. We conducted a systematic literature review of IMT treatment for recurrent CDI and pseudomembranous colitis. In 317 patients treated across 27 case series and reports, IMT was highly effective, showing disease resolution in 92% of cases. Effectiveness varied by route of instillation, relationship to stool donor, volume of IMT given, and treatment before infusion. Death and adverse events were uncommon. These findings can guide physicians interested in implementing the procedure until better designed studies are conducted to confirm best practices.

Executive Summary: Clinical Practice Guideline for the Use of Antimicrobial Agents in Neutropenic Patients with Cancer: 2010 Update by the Infectious Diseases Society of America

Abstract: This document updates and expands the initial Infectious Diseases Society of America (IDSA) Fever and Neutropenia Guideline that was published in 1997 and first updated in 2002. It is intended as a guide for the use of antimicrobial agents in managing patients with cancer who experience chemotherapy-induced fever and neutropenia. Recent advances in antimicrobial drug development and technology, clinical trial results, and extensive clinical experience have informed the approaches and recommendations herein. Because the previous iteration of this guideline in 2002, we have a developed a clearer definition of which populations of patients with cancer may benefit most from antibiotic, antifungal, and antiviral prophylaxis. Furthermore, categorizing neutropenic patients as being at high risk or low risk for infection according to presenting signs and symptoms, underlying cancer, type of therapy, and medical comorbidities has become essential to the treatment algorithm. Risk stratification is a recommended starting point for managing patients with fever and neutropenia. In addition, earlier detection of invasive fungal infections has led to debate regarding optimal use of empirical or preemptive antifungal therapy, although algorithms are still evolving. What has not changed is the indication for immediate empirical antibiotic therapy. It remains true that all patients who present with fever and neutropenia should be treated swiftly and broadly with antibiotics to treat both gram-positive and gram-negative pathogens. Finally, we note that all Panel members are from institutions in the United States or Canada; thus, these guidelines were developed in the context of North American practices. Some recommendations may not be as applicable outside of North America, in areas where differences in available antibiotics, in the predominant pathogens, and/or in health care-associated economic conditions exist. Regardless of venue, clinical vigilance and immediate treatment are the universal keys to managing neutropenic patients with fever and/or infection.

Carbapenem-Resistant Enterobacteriaceae: Epidemiology and Prevention

Abstract: Over the past 10 years, dissemination of Klebsiella pneumoniae carbapenemase (KPC) has led to an increase in the prevalence of carbapenem-resistant Enterobacteriaceae (CRE) in the United States. Infections caused by CRE have limited treatment options and have been associated with high mortality rates. In the previous year, other carbapenemase subtypes, including New Delhi metallo-β-lactamase, have been identified among Enterobacteriaceae in the United States. Like KPC, these enzymes are frequently found on mobile genetic elements and have the potential to spread widely. As a result, preventing both CRE transmission and CRE infections have become important public health objectives. This review describes the current epidemiology of CRE in the United States and highlights important prevention strategies.

Combating antimicrobial resistance: policy recommendations to save lives.

Abstract: Antimicrobial resistance is recognized as one of the greatest threats to human health worldwide [1]. Drugresistant infections take a staggering toll in the United States (US) and across the globe. Just one organism, methicillin-resistant Staphylococcus aureus (MRSA), kills more Americans every year ( 19,000) than emphysema, HIV/AIDS, Parkinson’s disease, and homicide combined [2]. Almost 2 million Americans per year develop hospital-acquired infections (HAIs), resulting in 99,000 deaths [3], the vast majority of which are due to antibacterial (antibiotic)-resistant pathogens. Indeed, two common HAIs alone (sepsis and pneumonia) killed nearly 50,000 Americans and cost the US health care system more than $8 billion in 2006 [4]. In a recent survey, approximately half of patients in more than 1,000 intensive care units in 75 countries suffered from an infection, and infected patients had twice the risk of dying in the hospital as uninfected patients [5]. Based on studies of the costs of infections caused by antibiotic-resistant pathogens versus antibiotic-susceptible pathogens [6–8], the annual cost to the US health care system of antibioticresistant infections is $21 billion to $34 billion and more than 8 million additional hospital days. The discovery of antibiotics in the 1930s fundamentally transformed the way physicians care for patients, shifting their approach from a focus on diagnoses without means to intervene to a treatment-focused approach that saves lives. Seven decades of medical advances enabled by antibiotics are now seriously threatened by the convergence of relentlessly rising antibiotic resistance and the alarming and ongoing withdrawal of most major pharmaceutical companies from the antibiotic market. Without effective antibiotics, diverse fields of medicine will be severely hampered, including surgery, the care of premature infants, cancer chemotherapy, care of the critically ill, and transplantation medicine, all of which are feasible only in the context of effective antibiotic therapy. Our ability to respond to national security threats (e.g., bioterrorism and pandemics) also is in serious jeopardy. Ultimately, the loss of effective antibiotics will result in a great increase in morbidity and mortality from infections. Antimicrobial resistance is of such tremendous global concern that the World Health Organization (WHO) has proclaimed it the central focus of World Health Day 2011 (April 7). This policy paper summarizes the Infectious Diseases Society of America’s (IDSA) recommendations about how best to address the synergistic crises of rising rates of antibiotic resistance and waning approvals of new antibiotics. IDSA’s goal is to represent the best interests of patients and health care professionals by recommending public policy strategies and research activities that reverse antibiotics’ decline and save lives. Specific recommendations for Congress related to legislative action and funding needs are summarized in Tables 1 and 2, Received 14 February 2011; accepted 15 February 2011. *This policy paper, written by Brad Spellberg, Martin Blaser, Robert J. Guidos, Helen W. Boucher, John S. Bradley, Barry I. Eisenstein, Dale Gerding, Ruth Lynfield, L. Barth Reller, John Rex, David Schwartz, Edward Septimus, Fred C. Tenover, and David N. Gilbert, was developed for and approved by the IDSA Board of Directors on February 9, 2011. IDSA represents more than 9300 physicians, scientists and other health care professionals who specialize in infectious diseases. IDSA seeks to improve the health of individuals, communities, and society by promoting excellence in patient treatment and care, education, research, public health, and prevention relating to infectious diseases. Correspondence: Robert J. Guidos, 1300 Wilson Boulevard, Suite 300, Arlington, VA 22209 (rguidos@idsociety.org). Clinical Infectious Diseases 2011;52(S5):S397–S428 The Author 2011. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com. 1058-4838/2011/52S5-0001$37.00 DOI: 10.1093/cid/cir153

Convalescent plasma treatment reduced mortality in patients with severe pandemic influenza A (H1N1) 2009 virus infection

Abstract: Background: Experience from treating patients with Spanish influenza and influenza A(H5N1) suggested that convalescent plasma therapy might be beneficial. However, its efficacy in patients with severe pandemic influenza A(H1N1) 2009 virus (H1N1 2009) infection remained unknown. Methods: During the period from 1 September 2009 through 30 June 2010, we conducted a prospective cohort study by recruiting patients aged ≥ 18 years with severe H1N1 2009 infection requiring intensive care. Patients were offered treatment with convalescent plasma with a neutralizing antibody titer of ≥ 1:160, harvested by apheresis from patients recovering from H1N1 2009 infection. Clinical outcome was compared with that of patients who declined plasma treatment as the untreated controls. Results: Ninety-three patients with severe H1N1 2009 infection requiring intensive care were recruited. Twenty patients (21.5%) received plasma treatment. The treatment and control groups were matched by age, sex, and disease severity scores. Mortality in the treatment group was significantly lower than in the nontreatment group (20.0% vs 54.8%; P = .01). Multivariate analysis showed that plasma treatment reduced mortality (odds ratio [OR], .20; 95% confidence interval [CI], .06-.69; P = .011), whereas complication of acute renal failure was independently associated with death (OR, 3.79; 95% CI, 1.15-12.4; P = .028). Subgroup analysis of 44 patients with serial respiratory tract viral load and cytokine level demonstrated that plasma treatment was associated with significantly lower day 3, 5, and 7 viral load, compared with the control group (P < .05). The corresponding temporal levels of interleukin 6, interleukin 10, and tumor necrosis factor α (P < .05) were also lower in the treatment group. Conclusions: Treatment of severe H1N1 2009 infection with convalescent plasma reduced respiratory tract viral load, serum cytokine response, and mortality.

Morbidity and Aging in HIV-Infected Persons: The Swiss HIV Cohort Study

Abstract: Results. Overall,8444(96%)of8848participantscontributeddatafrom40720semiannualvisits;2233individuals (26.4%) were aged 50‐64 years, and 450 (5.3%) were aged $65 years. The median duration of HIV infection was 15.4 years (95% confidence interval [CI], 9.59‐22.0 years); 23.2% had prior clinical AIDS. We observed 994 incident nonAIDS events in the reference period: 201 cases of bacterial pneumonia, 55 myocardial infarctions, 39 strokes, 70 cases of diabetes mellitus, 123 trauma-associated fractures, 37 fractures without adequate trauma, and 115 non-AIDS malignancies. Multivariable hazard ratios for stroke (17.7; CI, 7.06‐44.5), myocardial infarction (5.89; 95% CI, 2.17‐ 16.0), diabetes mellitus (3.75; 95% CI, 1.80‐7.85), bone fractures without adequate trauma (10.5; 95% CI, 3.58‐30.5), osteoporosis (9.13; 95% CI, 4.10‐20.3), and non‐AIDS-defining malignancies (6.88; 95% CI, 3.89‐12.2) were elevated for persons aged $65 years. Conclusions. Comorbidity and multimorbidity because of non-AIDS diseases, particularly diabetes mellitus, cardiovascular disease, non‐AIDS-defining malignancies, and osteoporosis, become more important in care of HIV-infected persons and increase with older age.

β-D-Glucan Assay for the Diagnosis of Invasive Fungal Infections: A Meta-analysis

Abstract: We aimed to assess the accuracy of measuring serum or plasma (1→3)-β-D-glucan (BDG) for the diagnosis of invasive fungal infections (IFIs) by means of a meta-analysis of relevant studies. We searched in bibliographic databases for relevant cohort or case-control studies. We primarily compared BDG between patients with proven or probable IFIs (excluding Pneumocystis jirovecii infections), according to the criteria of the European Organization for Research and Treatment of Cancer/Mycoses Study Group or similar criteria, and patients without IFIs (excluding healthy individuals as controls). A total of 2979 patients (594 with proven or probable IFIs), included in 16 studies, were analyzed. The pooled sensitivity of BDG was 76.8% (95% confidence interval [CI], 67.1%-84.3%), and the specificity was 85.3% (95% CI, 79.6%-89.7%). The area under the summary receiver operating characteristic curve was 0.89. Marked statistical heterogeneity was noted. BDG has good diagnostic accuracy for distinguishing proven or probable IFIs from no IFIs. It can be useful in clinical practice, if implemented in the proper setting and interpreted after consideration of its limitations.

Summary of recommendations: Guidelines for the Prevention of Intravascular Catheter-related Infections.

Abstract: These guidelines have been developed for healthcare personnel who insert intravascular catheters and for persons responsible for surveillance and control of infections in hospital, outpatient, and home healthcare settings. This report was prepared by a working group comprising members from professional organizations representing the disciplines of critical care medicine, infectious diseases, healthcare infection control, surgery, anesthesiology, interventional radiology, pulmonary medicine, pediatric medicine, and nursing. The working group was led by the Society of Critical Care Medicine

Impact of Vancomycin Exposure on Outcomes in Patients With Methicillin-Resistant Staphylococcus aureus Bacteremia: Support for Consensus Guidelines Suggested Targets

Abstract: Background. High rates of vancomycin failure in methicillin-resistant Staphylococcus aureus (MRSA) infections have been increasingly reported over time. The primary objective of our study was to determine the impact of vancomycin exposure and outcomes in patients with MRSA bacteremia initially treated with vancomycin. Methods. This was a single-center retrospective analysis of 320 patients with documented MRSA bacteremia initiallytreatedwithvancomycinfromJanuary2005 throughApril2010.Twomethodsofsusceptibility,Etestandbroth microdilution, were performed for all isolates to determine the correlation of susceptibility testing to patient outcomes. Results. Among a cohort of 320 patients, more than half (52.5%) experienced vancomycin failure. Independent predictors of vancomycin failure in logistic regression included infective endocarditis (adjusted odds ratio [AOR], 4.55; 95% confidence interval [CI], 2.26‐9.15), nosocomial-acquired infection (AOR, 2.19; 95% CI, 1.21‐3.97), initial vancomycin trough ,15 mg/L (AOR, 2.00; 95% CI, 1.25‐3.22), and vancomycin minimum inhibitory concentration (MIC) .1 mg/L by Etest (AOR, 1.52; 95% CI, 1.09‐2.49). With use of Classification and Regression Tree (CART) analysis, patients with vancomycin area under the curve at 24 h (AUC24h) to MIC ratios ,421 were found to have significantly higher rates of failure, compared with patients with AUC24h to MIC ratios .421 (61.2% vs 48.6%; P 5 .038) Conclusions. In light of the high failure rates associated with this antimicrobial, optimizing the pharmacokinetic/pharmacodynamic properties of vancomycin by targeting higher trough values of 15‐20 mg/L and AUC24h/MIC ratios >400 in selected patients should be considered.

Estimating the Burden of 2009 Pandemic Influenza A (H1N1) in the United States (April 2009–April 2010)

Abstract: To calculate the burden of 2009 pandemic influenza A (pH1N1) in the United States, we extrapolated from the Centers for Disease Control and Prevention's Emerging Infections Program laboratory-confirmed hospitalizations across the entire United States, and then corrected for underreporting. From 12 April 2009 to 10 April 2010, we estimate that approximately 60.8 million cases (range: 43.3-89.3 million), 274,304 hospitalizations (195,086-402,719), and 12,469 deaths (8868-18,306) occurred in the United States due to pH1N1. Eighty-seven percent of deaths occurred in those under 65 years of age with children and working adults having risks of hospitalization and death 4 to 7 times and 8 to 12 times greater, respectively, than estimates of impact due to seasonal influenza covering the years 1976-2001. In our study, adults 65 years of age or older were found to have rates of hospitalization and death that were up to 75% and 81%, respectively, lower than seasonal influenza. These results confirm the necessity of a concerted public health response to pH1N1.

Containment of a Country-wide Outbreak of Carbapenem-Resistant Klebsiella pneumoniae in Israeli Hospitals via a Nationally Implemented Intervention

Abstract: Background During 2006, Israeli hospitals faced a clonal outbreak of carbapenem-resistant Klebsiella pneumoniae that was not controlled by local measures A nationwide intervention was launched to contain the outbreak and to introduce a strategy to control future dissemination of antibiotic-resistant bacteria in hospitals Methods In March 2007, the Ministry of Health issued guidelines mandating physical separation of hospitalized carriers of carbapenem-resistant Enterobacteriaceae (CRE) and dedicated staffing and appointed a professional task force charged with containment The task force paid site visits at acute-care hospitals, evaluated infection-control policies and laboratory methods, supervised adherence to the guidelines via daily census reports on carriers and their conditions of isolation, provided daily feedback on performance to hospital directors, and intervened additionally when necessary The initial intervention period was 1 April 2007-31 May 2008 The primary outcome measure was incidence of clinically diagnosed nosocomial CRE cases Results By 31 March 2007, 1275 patients were affected in 27 hospitals (175 cases per 1 million population) Prior to the intervention, the monthly incidence of nosocomial CRE was 555 cases per 100,000 patient-days With the intervention, the continuous increase in the incidence of CRE acquisition was halted, and by May 2008, the number of new monthly cases was reduced to 117 cases per 100,000 patient-days (P < 001) There was a direct correlation between compliance with isolation guidelines and success in containment of transmission (P = 02) Compliance neutralized the effect of carrier prevalence on new incidence (P = 03) Conclusions A centrally coordinated intervention succeeded in containing a nationwide CRE outbreak after local measures failed The intervention demonstrates the importance of strategic planning and national oversight in combating antimicrobial resistance

Potent CD8+ T-Cell Immunogenicity in Humans of a Novel Heterosubtypic Influenza A Vaccine, MVA−NP+M1

Abstract: Licensed influenza vaccines, whether inactivated or live attenuated, are designed to induce humoral immunity to hemagglutinin (HA). Seasonal influenza vaccines are a mixture of A/H1N1, A/H3N2, and B antigens. Vaccine effectiveness is 70%–90% when the circulating virus is well matched to the vaccine, but may fall below 50% when the circulating strain has drifted significantly from the vaccine strain [ 1], particularly in people over 60 years of age [ 2]. Annual revaccination is required to maintain immunity against seasonal influenza viruses. Fears of an H5N1 pandemic resulted in the generation and testing of H5-specific vaccines, which may require the use of an adjuvant or multiple doses to achieve a protective level of immunity following vaccination [ 3]. H5N1 viruses have continued to mutate in avian populations, and in clinical trials of an unadjuvanted H5 vaccine, serological cross-reactivity to variant H5 viruses even within the same clade was only 20%–30% [ 4], although use of an adjuvant may improve this. Since swine origin H1N1 began to circulate in humans in April 2009, vaccine manufacturers have produced pandemic-specific vaccines, and the first doses became available in October 2009, 6 months after the virus was first identified. Clearly, a vaccine that could provide heterosubtypic protection against all influenza A viruses would be of great benefit, and, if effective and widely used, could prevent another pandemic from occurring. The efficacy of influenza vaccines designed to induce subtype cross-reactive T cells to internal influenza antigens such as nucleoprotein (NP), which is highly conserved between all influenza A subtypes, has been demonstrated in many species of animal model [ 5– 8], and this approach has the potential to replace or supplement seasonal and pandemic-specific vaccination in humans. Influenza challenge studies in humans with low neutralizing antibody titers to the challenge virus (measured by the HA inhibition assay) have demonstrated a negative correlation between T-cell response to viral antigens and influenza disease and virus shedding [ 9]. Protection is thought to be mediated chiefly by CD8+ T cells, but protective immunity is short-lived [ 10], although reexposure to influenza virus within a few years of the first infection may result in a subclinical infection and boosting of the T-cell response. Lee et al [ 11] reported that memory T cells recognizing influenza antigens were detected in over 90% of those tested, and showed cross-recognition of at least one H5N1 internal protein. The magnitude of the responses varied considerably, and is presumably related to the time elapsed since the most recent exposure to influenza virus. However, low-level memory T-cell responses to influenza antigens have the potential to be boosted to protective levels, by further exposure to the virus or by vaccination. Live attenuated influenza vaccines have been shown to induce modest T-cell responses in children, but did not significantly boost T-cell responses to influenza in adults with T-cell responses induced by natural exposure [ 12]. Modified Vaccinia virus Ankara (MVA) is a highly attenuated virus that has been used to boost T-cell responses to recombinant antigens encoded by the virus in many clinical studies aimed at developing new vaccines for malaria, human immunodeficiency virus (HIV), and tuberculosis (TB). MVA has an excellent safety profile, and has been tested in children [ 13] as well as HIV-positive [ 14] and latently TB-infected individuals [ 15]. MVA has been used to boost both CD4+ and CD8+ responses primed by prior DNA, fowlpox [ 16], adenovirus [ 17], or Bacille Calmette-Guerin immunization [ 18], or HIV infection [ 14]. Since adults have been primed by prior exposure to influenza, MVA expressing conserved internal antigens of influenza such as NP and matrix protein 1 (M1) could be used to boost cross-reactive T-cell responses to protective levels, providing broad immunity to all subtypes of influenza A. An illustration of the conservation of the vaccine antigens is given in Table 1, showing the identity and divergence of the amino acid sequences of NP and M1 in the vaccine MVA−NP+M1 and human isolates of H3N2, H1N1, H5N1, and swine origin H1N1. The identity and divergence of HA are given for comparison. The high degree of identity with H3N2 is not surprising since the vaccine antigens are derived from the H3N2 virus A/Panama/2007/99, but both antigens are more than 90% identical with homologues from seasonal H1N1, swine origin H1N1, and H5N1 viruses, whereas identity drops as low as 43% between the HA proteins of the same 4 viruses. Table 1. Sequence Identity (top) and Divergence (Bottom) Between Antigens in MVA-NP+M1 and Other Influenza A Viruses We now report on the safety and immunogenicity of MVA−NP+M1, a vaccine designed to boost preexisting T-cell responses to conserved influenza antigens in a Phase I clinical study in healthy adult volunteers.

Cumulative Antibiotic Exposures Over Time and the Risk of Clostridium difficile Infection

Abstract: Background Clostridium difficile infection (CDI) is a major cause of hospital-acquired diarrhea and is most commonly associated with changes in normal intestinal flora caused by administration of antibiotics. Few studies have examined the risk of CDI associated with total dose, duration, or number of antibiotics while taking into account the complex changes in exposures over time. Methods A retrospective cohort study conducted from 1 January to 31 December 2005 among hospitalized patients 18 years or older receiving 2 or more days of antibiotics. Results The study identified 10,154 hospitalizations for 7,792 unique patients and 241 cases of CDI, defined as the detection of C. difficile toxin in a diarrheal stool sample within 60 days of discharge. We observed dose-dependent increases in the risk of CDI associated with increasing cumulative dose, number of antibiotics, and days of antibiotic exposure. Compared to patients who received only 1 antibiotic, the adjusted hazard ratios (HRs) for those who received 2, 3 or 4, or 5 or more antibiotics were 2.5 (95% confidence interval [CI] 1.6-4.0), 3.3 (CI 2.2-5.2), and 9.6 (CI 6.1-15.1), respectively. The receipt of fluoroquinolones was associated with an increased risk of CDI, while metronidazole was associated with reduced risk. Conclusions Cumulative antibiotic exposures appear to be associated with the risk of CDI. Antimicrobial stewardship programs that focus on the overall reduction of total dose as well as number and days of antibiotic exposure and the substitution of high-risk antibiotic classes for lower-risk alternatives may reduce the incidence of hospital-acquired CDI.

A Novel Risk Factor for a Novel Virus: Obesity and 2009 Pandemic Influenza A (H1N1)

Abstract: Background many critically ill patients with 2009 pandemic influenza A (H1N1) (2009 H1N1) infection were noted to be obese, but whether obesity, rather than its associated co-morbidities, is an independent risk factor for severe infection is unknown. Methods using public health surveillance data, we analyzed demographic and clinical characteristics of California residents hospitalized with 2009 H1N1 infection to assess whether obesity (body mass index [BMI] ≥ 30) and extreme obesity (BMI ≥ 40) were an independent risk factor for death among case patients ≥ 20 years old. Results during the period 20 April-11 August 2009, 534 adult case patients with 2009 H1N1 infection for whom BMI information was available were observed. Two hundred twenty-eight patients (43%) were ≥ 50 years of age, and 378 (72%) had influenza-related high-risk conditions recognized by the Advisory Committee on Immunization Practices as risk factors for severe influenza. Two hundred and seventy-four (51%) had BMI ≥ 30, which is 2.2 times the prevalence of obesity among California adults (23%) and 1.5 times the prevalence among the general population of the United States (33%). Of the 92 case patients who died (17%), 56 (61%) had BMI ≥ 30 and 28 (30%) had BMI ≥ 40. In multivariate analysis, BMI ≥ 40 (odds ratio [OR], 2.8; 95% confidence interval [CI], 1.4-5.9) and BMI ≥ 45 (OR, 4.2; 95% CI, 1.9-9.4), age ≥ 50 years (OR, 2.1; 95% CI, 1.2-3.7), miscellaneous immunosuppressive conditions (OR, 3.9; 95% CI, 1.6-9.5), and asthma (OR, 0.5; 95% CI, 0.3-0.9) were associated with death. Conclusion half of Californians ≥ 20 years of age hospitalized with 2009 H1N1 infection were obese. Extreme obesity was associated with increased odds of death. Obese adults with 2009 H1N1 infection should be treated promptly and considered in prioritization of vaccine and antiviral medications during shortages.

Randomized, Placebo-controlled Phase 2 Trial of a Lactobacillus crispatus Probiotic Given Intravaginally for Prevention of Recurrent Urinary Tract Infection

Abstract: Background. Urinary tract infections (UTIs) are common among women and frequently recur. Depletion of vaginal lactobacilli is associated with UTI risk, which suggests that repletion may be beneficial. We conducted a double-blind placebo-controlled trial of a Lactobacillus crispatus intravaginal suppository probiotic (Lactin-V; Osel) for prevention of recurrent UTI in premenopausal women. Methods. One hundred young women with a history of recurrent UTI received antimicrobials for acute UTI and then were randomized to receive either Lactin-V or placebo daily for 5 d, then once weekly for 10 weeks. Participants were followed up at 1 week and 10 weeks after intervention and for UTIs; urine samples for culture and vaginal swabs for real-time quantitative 16S ribosomal RNA gene polymerase chain reaction for L. crispatus were collected. Results. Recurrent UTI occurred in 7/48 15% of women receiving Lactin-V compared with 13/48 27% of women receiving placebo (relative risk [RR], .5; 95% confidence interval, .2‐1.2). High-level vaginal colonization with L. crispatus (>10 6 16S RNA gene copies per swab) throughout follow-up was associated with a significant reduction in recurrent UTI only for Lactin-V (RR for Lactin-V, .07; RR for placebo, 1.1; P , .01). Conclusions. Lactin-V after treatment for cystitis is associated with a reduction in recurrent UTI. Larger efficacy trials of this novel preventive method for recurrent UTI are warranted. Clinical Trials Registration. NCT00305227.

Clinical Applications of DNA Vaccines: Current Progress

Abstract: It was discovered almost 20 years ago that plasmid DNA, when injected into the skin or muscle of mice, could induce immune responses to encoded antigens. Since that time, there has since been much progress in understanding the basic biology behind this deceptively simple vaccine platform and much technological advancement to enhance immune potency. Among these advancements are improved formulations and improved physical methods of delivery, which increase the uptake of vaccine plasmids by cells; optimization of vaccine vectors and encoded antigens; and the development of novel formulations and adjuvants to augment and direct the host immune response. The ability of the current, or second-generation, DNA vaccines to induce more-potent cellular and humoral responses opens up this platform to be examined in both preventative and therapeutic arenas. This review focuses on these advances and discusses both preventive and immunotherapeutic clinical applications.

Clinical and Microbiologic Outcomes in Patients Receiving Treatment for Mycobacterium abscessus Pulmonary Disease

Abstract: Background Mycobacterium abscessus can produce a chronic pulmonary infection for which little is known regarding optimal treatment and long-term outcomes. Methods We performed a retrospective observational study (2001-2008) including all patients who met American Thoracic Society criteria for M. abscessus pulmonary disease. Our aim was the evaluation of clinical and microbiologic outcomes in patients treated with combined antibiotic and surgical therapy, compared with antibiotic therapy alone. Results A total of 107 patients were included in the analysis. Patients were predominantly female (83%) and never-smokers (60%), with a mean age of 60 years. Fifty-nine (55%) of 107 patients had coexistent or previous history of Mycobacterium avium complex pulmonary infection. High-resolution chest CT showed bronchiectasis and nodular opacities in 98% of patients and cavities in 44%. Sixty-nine (46 medical, 23 surgical) patients were followed up for a mean duration of 34 months (standard deviation, 21.1 months, range, 2-82 months). Cough, sputum production, and fatigue remained stable, improved, or resolved in 80%, 69%, and 59% of patients, respectively. Twenty (29%) of 69 patients remained culture positive, 16 (23%) converted but experienced relapse, 33 (48%) converted to negative and did not experience relapse, and 17 (16%) died during the study period. There were significantly more surgical patients than medical patients whose culture converted and remained negative for at least 1 year (57% vs 28%; P = .022). Conclusions Patients with M. abscessus pulmonary disease who are treated with multidrug antibiotic therapy and surgery or antibiotic therapy alone had similar clinical outcomes. However, surgical resection, in addition to antibiotics, may offer a prolonged microbiologic response.

Clinical Importance of Streptococcus gallolyticus Infection Among Colorectal Cancer Patients: Systematic Review and Meta-analysis

Abstract: Background. Streptococcus bovis has long been associated with colorectal cancer (CRC). However, not all genospecies are as closely related to CRC. With this systematic review, we aim to increase the awareness of the association between S. bovis biotype I (Streptococcus gallolyticus) and CRC and urge for uniform molecular microbiological classification. Methods. In January 2011, the PubMed database was searched for all studies that investigated the association between S. bovis, infective endocarditis (IE), and CRC. A total of 191 studies were screened for eligibility and yielded 52 case reports and 31 case series, of which 11 were used for meta-analysis on the association between S. bovis biotype, IE, and adenomas/carcinomas (CRC). Results. Among the S. bovis‐infected patients who underwent colonic evaluation, the median percentage of patients who had concomitant adenomas/carcinomas was 60% (interquartile range, 22%), which largely exceeds the disease rate reported in the general asymptomatic population. Meta-analysis showed that patients with S. bovis biotype I infection had a strongly increased risk of having CRC (pooled odds ratio [OR], 7.26; 95% confidence interval [CI], 3.94‐13.36) and IE (pooled OR, 16.61; 95% CI, 8.85‐31.16), compared with S. bovis biotype II‐infected patients. Notably, CRC occurred more often among patients with S. bovis IE than among patients with S. bovis infection at other sites (pooled OR, 3.72; 95% CI, 2.03‐6.81). Conclusions. Our meta-analysis clearly indicates that S. bovis should no longer be regarded as a single species in clinical practice, because S. gallolyticus (S. bovis biotype I) infection, in particular, has an unambiguous association with CRC.

Viral Infections of the Lower Respiratory Tract: Old Viruses, New Viruses, and the Role of Diagnosis

Abstract: Viral infections of the lower respiratory tract cause an enormous disease burden in children, and the role of respiratory viruses in serious lower respiratory tract infections (LRTIs) in older adults is increasingly appreciated. Although viruses are responsible for a large proportion LRTIs, antibiotics are often prescribed. New diagnostic platforms have the potential to detect a wider range of established and newly discovered viruses with greater sensitivity. This will create additional challenges. Although it is clear that influenza, parainfluenza, respiratory syncytial virus, human metapneumovirus, and adenovirus are important causes of pneumonia, the role of rhinoviruses and some of the newly described viruses, including human coronaviruses and bocavirus, is harder to determine. Better diagnostic tests that establish the cause of LRTIs in children have the potential to both reduce overall antibiotic use and to improve the targeted use of antibiotics. In addition, rapid identification of viral infections can help control nosocomial transmission.

A Multicenter Evaluation of Tests for Diagnosis of Histoplasmosis

Abstract: Background. The sensitivity of the MVista Histoplasma antigen enzyme immunoassay (MiraVista Diagnostics) has been evaluated in disseminated histoplasmosis in patients with AIDS and in the ‘‘epidemic’’ form of acute pneumonia. Moreover, there has been no evaluation of the sensitivity of antigenemia detection in disseminated histoplasmosis after the implementation of methods to dissociate immune complexes and denature released antibodies. The goal of this study was to determine the sensitivity of the current antigen assay in different categories of histoplasmosis. Methods. Urine and serum specimens obtained from 218 patients with histoplasmosis and 229 control subjects, including 30 with blastomycosis, were tested. Results. Antigenuria was detected in 91.8% of 158 patients with disseminated histoplasmosis, 83.3% of 6 patients with acute histoplasmosis, 30.4% of 46 patients with subacute histoplasmosis, and 87.5% of 8 patients with chronic pulmonary histoplasmosis; antigenemia was present in 100% of 31 tested cases of disseminated histoplasmosis. Among patients with disseminated cases, antigenuria was detected more often and at higher concentrations in immunocompromised patients and those with severe disease. Specificity was 99.0% for patients with nonfungal infections (n 5 130) and in healthy subjects (n 5 69), but cross-reactivity occurred in 90% of patients with blastomycosis. Conclusions. The sensitivity of antigen detection in disseminated histoplasmosis is higher in immunocompromised patients than in immunocompetent patients and in patients with more severe illness. The sensitivity for detection of antigenemia is similar to that for antigenuria in disseminated infection.

High-frequency Triazole Resistance Found In Nonculturable Aspergillus fumigatus from Lungs of Patients with Chronic Fungal Disease

Abstract: BACKGROUND: Oral triazole therapy is well established for the treatment of invasive (IPA), allergic (ABPA), and chronic pulmonary (CPA) aspergillosis, and is often long-term. Triazole resistance rates are rising internationally. Microbiological diagnosis of aspergillosis is limited by poor culture yield, leading to uncertainty about the frequency of triazole resistance. METHODS: Using an ultrasensitive real-time polymerase chain reaction (PCR) assay for Aspergillus spp., we assessed respiratory fungal load in bronchoalveolar lavage (BAL) and sputum specimens. In a subset of PCR-positive, culture negative samples, we further amplified the CYP51A gene to detect key single-nucleotide polymorphisms (SNPs) associated with triazole resistance. RESULTS: Aspergillus DNA was detected in BAL from normal volunteers (4/11, 36.4%) and patients with culture or microscopy confirmed IPA (21/22, 95%). Aspergillus DNA was detected in sputum in 15 of 19 (78.9%) and 30 of 42 (71.4%) patients with ABPA and CPA, compared with 0% and 16.7% by culture, respectively. In culture-negative, PCR-positive samples, we detected triazole-resistance mutations (L98H with tandem repeat [TR] and M220) within the drug target CYP51A in 55.1% of samples. Six of 8 (75%) of those with ABPA and 12 of 24 (50%) with CPA had resistance markers present, some without prior triazole treatment, and in most despite adequate plasma drug concentrations around the time of sampling. CONCLUSIONS: The very low organism burdens of fungi causing infection have previously prevented direct culture and detection of antifungal resistance in clinical samples. These findings have major implications for the sustainability of triazoles for human antifungal therapy.

Multidrug-Resistant Staphylococcus aureus in US Meat and Poultry

Abstract: We characterized the prevalence, antibiotic susceptibility profiles, and genotypes of Staphylococcus aureus among US meat and poultry samples (n = 136). S. aureus contaminated 47% of samples, and multidrug resistance was common among isolates (52%). S. aureus genotypes and resistance profiles differed significantly among sample types, suggesting food animal–specific contamination.

Comparison of Staphylococcus aureus From Skin and Soft-Tissue Infections in US Emergency Department Patients, 2004 and 2008

Abstract: Background In the past decade, new methicillin-resistant Staphylococcus aureus (MRSA) strains have emerged as a predominant cause of community-associated skin and soft-tissue infections (SSTIs). Little information exists regarding trends in MRSA prevalence and molecular characteristics or regarding antimicrobial susceptibility profiles of S. aureus isolates. Methods We enrolled adults with acute, purulent SSTIs presenting to a US network of 12 emergency departments during August 2008. Cultures and clinical information were collected. S. aureus isolates were characterized by antimicrobial susceptibility testing, pulsed-field gel electrophoresis, and toxin genes detection. The prevalence of S. aureus and MRSA and isolate genetic characteristics and susceptibilities were compared with those from a similar study conducted in August 2004. Results The prevalence of MRSA was 59% among all SSTIs during both study periods; however, the prevalence by site varied less in 2008 (38%-84%), compared with 2004 (15%-74%). Pulsed-field type USA300 continued to account for almost all MRSA isolates (98%). Susceptibility to trimethoprim-sulfamethoxazole, clindamycin, and tetracycline among MRSA isolates remained greater than 90% in 2008. A higher proportion of MRSA infections were treated with an agent to which the infecting isolate was susceptible in vitro in 2008 (97%), compared with 2004 (57%). Conclusions Similar to 2004, MRSA remained the most common identifiable cause of purulent SSTIs among patients presenting to a network of US emergency departments in 2008. The infecting MRSA isolates continued to be predominantly pulsed-field type USA300 and susceptible to recommended non-β-lactam oral agents. Clinician prescribing practices have shifted from MRSA-inactive to MRSA-active empirical antimicrobial regimens.