Showing papers in "Clinical Infectious Diseases in 2008"
Radboud University Nijmegen1, National Institutes of Health2, Stanford University3, University of California, Los Angeles4, University of Lausanne5, University of Alabama6, University of Paris7, University of Michigan8, University of Texas Health Science Center at San Antonio9, University of Strasbourg10, University of Manchester11, University College London12, Oregon Health & Science University13, Complutense University of Madrid14, University of Aberdeen15, Duke University16, Charité17, University at Buffalo18, Wayne State University19, University of Sydney20, University of Genoa21, University of Florida22, University of Pennsylvania23
TL;DR: These revised definitions of invasive fungal disease are intended to advance clinical and epidemiological research and may serve as a useful model for defining other infections in high-risk patients.
Abstract: BACKGROUND: Invasive fungal diseases are important causes of morbidity and mortality. Clarity and uniformity in defining these infections are important factors in improving the quality of clinical studies. A standard set of definitions strengthens the consistency and reproducibility of such studies. METHODS: After the introduction of the original European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group definitions, advances in diagnostic technology and the recognition of areas in need of improvement led to a revision of this document. The revision process started with a meeting of participants in 2003, to decide on the process and to draft the proposal. This was followed by several rounds of consultation until a final draft was approved in 2005. This was made available for 6 months to allow public comment, and then the manuscript was prepared and approved. RESULTS: The revised definitions retain the original classifications of "proven," "probable," and "possible" invasive fungal disease, but the definition of "probable" has been expanded, whereas the scope of the category "possible" has been diminished. The category of proven invasive fungal disease can apply to any patient, regardless of whether the patient is immunocompromised, whereas the probable and possible categories are proposed for immunocompromised patients only. CONCLUSIONS: These revised definitions of invasive fungal disease are intended to advance clinical and epidemiological research and may serve as a useful model for defining other infections in high-risk patients.
4,389 citations
National Institutes of Health1, University of Arkansas for Medical Sciences2, University of Manchester3, University of Strasbourg4, Oregon Health & Science University5, Veterans Health Administration6, University of Minnesota7, Roswell Park Cancer Institute8, Duke University9, Stanford University10, Santa Clara Valley Medical Center11, University of Florida12, University of Texas Health Science Center at San Antonio13
TL;DR: This research presents a novel, scalable, scalable and scalable approach that allows for real-time evaluation of the impact of Epstein-Barr virus on the development and management of childhood cancer in rats.
Abstract: Aspergillus species have emerged as an important cause of life-threatening infections in immunocompromised patients. This expanding population is composed of patients with prolonged neutropenia, advanced HIV infection, and inherited immunodeficiency and patients who have undergone allogeneic hematopoietic stem cell transplantation (HSCT) and/or lung transplantation. This document constitutes the guidelines of the Infectious Diseases Society of America for treatment of aspergillosis and replaces the practice guidelines for Aspergillus published in 2000 [1]. The objective of these guidelines is to summarize the current evidence for treatment of different forms of aspergillosis. The quality of evidence for treatment is scored according to a standard system used in other Infectious Diseases Society of America guidelines. This document reviews guidelines for management of the 3 major forms of aspergillosis: invasive aspergillosis, chronic (and saprophytic) forms of aspergillosis, and allergic forms of aspergillosis. Given the public health importance of invasive aspergillosis, emphasis is placed on the diagnosis, treatment, and prevention of the different forms of invasive aspergillosis, including invasive pulmonary aspergillosis, sinus aspergillosis, disseminated aspergillosis, and several types of single-organ invasive aspergillosis. There are few randomized trials on the treatment of invasive aspergillosis. The largest randomized controlled trial demonstrates that voriconazole is superior to deoxycholate amphotericin B (D-AMB) as primary treatment for invasive aspergillosis. Voriconazole is recommended for the primary treatment of invasive aspergillosis in most patients (A-I). Although invasive pulmonary aspergillosis accounts for the preponderance of cases treated with voriconazole, voriconazole has been used in enough cases of extrapulmonary and disseminated infection to allow one to infer that voriconazole is effective in these cases. A randomized trial comparing 2 doses of liposomal amphotericin B (L-AMB) showed similar efficacy in both arms, suggesting that liposomal therapy could be considered as alternative primary therapy in some patients (A-I). For salvage therapy, agents include lipid formulations of amphotericin (LFAB; A-II), posaconazole (B-II), itraconazole (B-II), caspofungin (B-II), or micafungin (B-II). Salvage therapy for invasive aspergillosis poses important challenges with significant gaps in knowledge. In patients whose aspergillosis is refractory to voriconazole, a paucity of data exist to guide management. Therapeutic options include a change of class using an amphotericin B (AMB) formulation or an echinocandin, such as caspofungin (B-II); further use of azoles should take into account host factors and pharmacokinetic considerations. Refractory infection may respond to a change to another drug class (B-II) or to a combination of agents (B-II). The role of combination therapy in the treatment of invasive aspergillosis as primary or salvage therapy is uncertain and warrants a prospective, controlled clinical trial. Assessment of patients with refractory aspergillosis may be difficult. In evaluating such patients, the diagnosis of invasive aspergillosis should be established if it was previously uncertain and should be confirmed if it was previously known. The drug dosage should be considered. Management options include a change to intravenous (IV) therapy, therapeutic monitoring of drug levels, change of drug class, and/or combination therapy. Antifungal prophylaxis with posaconazole can be recommended in the subgroup of HSCT recipients with graft-versus-host disease (GVHD) who are at high risk for invasive aspergillosis and in neutropenic patients with acute myelogenous leukemia or myelodysplastic syndrome who are at high risk for invasive aspergillosis (A-I). Management of breakthrough invasive aspergillosis in the context of mould-active azole prophylaxis is not defined by clinical trial data. The approach to such patients should be individualized on the basis of clinical criteria, including host immunosuppression, underlying disease, and site of infection, as well as consideration of antifungal dosing, therapeutic monitoring of drug levels, a switch to IV therapy, and/or a switch to another drug class (B-III). Certain conditions of invasive aspergillosis warrant consideration for surgical resection of the infected focus. These include but are not limited to pulmonary lesions contiguous with the heart or great vessels, invasion of the chest wall, osteomyelitis, pericardial infection, and endocarditis (B-III). Restoration of impaired host defenses is critical for improved outcome of invasive aspergillosis (A-III). Recovery from neutropenia in a persistently neutropenic host or reduction of corticosteroids in a patient receiving high-dose glucocorticosteroids is paramount for improved outcome in invasive aspergillosis. A special consideration is made concerning recommendations for therapy of aspergillosis in uncommon sites, such as osteomyelitis and endocarditis. There are very limited data on these infections, and most involve D-AMB as primary therapy simply because of its long-standing availability. Based on the strength of the randomized study, the panel recommends voriconazole for primary treatment of these very uncommon manifestations of invasive aspergillosis (B-III). Management of the chronic or saprophytic forms of aspergillosis varies depending on the condition. Single pulmonary aspergillomas may be best managed by surgical resection (B-III), whereas chronic cavitary and chronic necrotizing pulmonary aspergillosis require long-term medical therapy (B-III). The management of allergic forms of aspergillosis involves a combination of medical and anti-inflammatory therapy. For example, management of allergic bronchopulmonary aspergillosis (ABPA) involves the administration of itraconazole and corticosteroids (A-I). © 2008 by the Infectious Diseases Society of America. All rights reserved.
2,463 citations
TL;DR: If the antimicrobial resistance crisis is to be addressed, a concerted, grassroots effort led by the medical community will be required and could mean a literal return to the preantibiotic era for many types of infections.
Abstract: The ongoing explosion of antibiotic-resistant infections continues to plague global and US health care. Meanwhile, an equally alarming decline has occurred in the research and development of new antibiotics to deal with the threat. In response to this microbial “perfect storm,” in 2001, the federal Interagency Task Force on Antimicrobial Resistance released the “Action Plan to Combat Antimicrobial Resistance; Part 1: Domestic” to strengthen the response in the United States. The Infectious Diseases Society of America (IDSA) followed in 2004 with its own report, “Bad Bugs, No Drugs: As Antibiotic Discovery Stagnates, A Public Health Crisis Brews,” which proposed incentives to reinvigorate pharmaceutical investment in antibiotic research and development. The IDSA’s subsequent lobbying efforts led to the introduction of promising legislation in the 109th US Congress (January 2005–December 2006). Unfortunately, the legislation was not enacted. During the 110th Congress, the IDSA has continued to work with congressional leaders on promising legislation to address antibiotic-resistant infection. Nevertheless, despite intensive public relations and lobbying efforts, it remains unclear whether sufficiently robust legislation will be enacted. In the meantime, microbes continue to become more resistant, the antibiotic pipeline continues to diminish, and the majority of the public remains unaware of this critical situation. The result of insufficient federal funding; insufficient surveillance, prevention, and control; insufficient research and development activities; misguided regulation of antibiotics in agriculture and, in particular, for food animals; and insufficient overall coordination of US (and international) efforts could mean a literal return to the preantibiotic era for many types of infections. If we are to address the antimicrobial resistance crisis, a concerted, grassroots effort led by the medical community will be required.
1,523 citations
TL;DR: General aspects of staphylococcal pathogenesis are addressed, with emphasis on methicillin-resistant strains and factors or genetic backgrounds that may enhance their virulence or may enable them to cause particular clinical syndromes.
Abstract: Staphylococcus aureus is a versatile pathogen capable of causing a wide range of human diseases. However, the role of different virulence factors in the development of staphylococcal infections remains incompletely understood. Some clonal types are well equipped to cause disease across the globe, whereas others are facile at causing disease among community members. In this review, general aspects of staphylococcal pathogenesis are addressed, with emphasis on methicillin-resistant strains. Although methicillin-resistant S. aureus (MRSA) strains are not necessarily more virulent than methicillin-sensitive S. aureus strains, some MRSA strains contain factors or genetic backgrounds that may enhance their virulence or may enable them to cause particular clinical syndromes. We examine these pathogenic factors.
977 citations
TL;DR: The development or discovery of new therapies, well-controlled clinical trials of existing antimicrobial regimens and combinations, and greater emphasis on the prevention of health care-associated transmission of multidrug-resistant Acinetobacter infection are essential.
Abstract: Multidrug-resistant Acinetobacter baumannii is recognized to be among the most difficult antimicrobial-resistant gram-negative bacilli to control and treat. Increasing antimicrobial resistance among Acinetobacter isolates has been documented, although definitions of multidrug resistance vary in the literature. A. baumannii survives for prolonged periods under a wide range of environmental conditions. The organism causes outbreaks of infection and health care-associated infections, including bacteremia, pneumonia, meningitis, urinary tract infection, and wound infection. Antimicrobial resistance greatly limits the therapeutic options for patients who are infected with this organism, especially if isolates are resistant to the carbapenem class of antimicrobial agents. Because therapeutic options are limited for multidrug-resistant Acinetobacter infection, the development or discovery of new therapies, well-controlled clinical trials of existing antimicrobial regimens and combinations, and greater emphasis on the prevention of health care-associated transmission of multidrug-resistant Acinetobacter infection are essential.
938 citations
TL;DR: In the absence of a specific routine diagnostic test for P. knowlesi malaria, patients who reside in or have traveled to Southeast Asia and who have received a "P. malariae" hyperparasitemia diagnosis by microscopy receive intensive management as appropriate for severe falciparum malaria.
Abstract: Background. Until recently, Plasmodium knowlesi malaria in humans was misdiagnosed as Plasmodium malariae malaria. The objectives of the present study were to determine the geographic distribution of P. knowlesi malaria in the human population in Malaysia and to investigate 4 suspected fatal cases. Methods. Sensitive and specific nested polymerase chain reaction was used to identify all Plasmodium species present in (1) blood samples obtained from 960 patients with malaria who were hospitalized in Sarawak, Malaysian Borneo, during 2001-2006; (2) 54 P. malariae archival blood films from 15 districts in Sabah, Malaysian Borneo (during 2003-2005), and 4 districts in Pahang, Peninsular Malaysia (during 2004-2005); and (3) 4 patients whose suspected cause of death was P. knowlesi malaria. For the 4 latter cases, available clinical and laboratory data were reviewed. Results. P. knowlesi DNA was detected in 266 (27.7%) of 960 of the samples from Sarawak hospitals, 41 (83.7%) of 49 from Sabah, and all 5 from Pahang. Only P. knowlesi DNA was detected in archival blood films from the 4 patients who died. All were hyperparasitemic and developed marked hepatorenal dysfunction. Conclusions. Human infection with P. knowlesi, commonly misidentified as the more benign P. malariae, are widely distributed across Malaysian Borneo and extend to Peninsular Malaysia. Because P. knowlesi replicates every 24 h, rapid diagnosis and prompt effective treatment are essential. In the absence of a specific routine diagnostic test for P. knowlesi malaria, we recommend that patients who reside in or have traveled to Southeast Asia and who have received a "P. malariae" hyperparasitemia diagnosis by microscopy receive intensive management as appropriate for severe falciparum malaria.
875 citations
TL;DR: The guideline includes data on the epidemiology, clinical features, diagnosis, and treatment of many viral, bacterial, fungal, protozoal, and helminthic etiologies of encephalitis and provides information on when specific etiologic agents should be considered in individual patients with encephalopathy.
Abstract: Guidelines for the diagnosis and treatment of patients with encephalitis were prepared by an Expert Panel of the Infectious Diseases Society of America. The guidelines are intended for use by health care providers who care for patients with encephalitis. The guideline includes data on the epidemiology, clinical features, diagnosis, and treatment of many viral, bacterial, fungal, protozoal, and helminthic etiologies of encephalitis and provides information on when specific etiologic agents should be considered in individual patients with encephalitis.
858 citations
TL;DR: The trends in both nosocomial and community-associated MRSA infections are examined and recent studies of the mechanisms that allow S. aureus to become resistant to currently available drugs are explored.
Abstract: The frequency of methicillin-resistant Staphylococcus aureus (MRSA) infections continues to grow in hospital-associated settings and, more recently, in community settings in the United States and globally. The increase in the incidence of infections due to S. aureus is partially a consequence of advances in patient care and also of the pathogen's ability to adapt to a changing environment. Infection due to S. aureus imposes a high and increasing burden on health care resources. A growing concern is the emergence of MRSA infections in patients with no apparent risk factors. MRSA infection in community settings involves considerable morbidity and mortality, as does nosocomial MRSA infection. For community-associated MRSA, person-to-person transmission has been reported, and several factors have been shown to predict disease. We examine the trends in both nosocomial and community-associated MRSA infections and explore recent studies of the mechanisms that allow S. aureus to become resistant to currently available drugs.
857 citations
TL;DR: Voriconazole therapeutic drug monitoring improves the efficacy and safety of therapy in severely ill patients with invasive mycoses and aids in prompt and complete neurological recovery.
Abstract: Background Voriconazole is the therapy of choice for aspergillosis and a new treatment option for candidiasis. Liver disease, age, genetic polymorphism of the cytochrome CYP2C19, and comedications influence voriconazole metabolism. Large variations in voriconazole pharmacokinetics may be associated with decreased efficacy or with toxicity. Methods This study was conducted to assess the utility of measuring voriconazole blood levels with individualized dose adjustments. Results A total of 181 measurements with high-pressure liquid chromatography were performed during 2388 treatment days in 52 patients. A large variability in voriconazole trough blood levels was observed, ranging from 5.5 mg/L (a level possibly associated with toxicity) in 31% of cases. Lack of response to therapy was more frequent in patients with voriconazole levels 1 mg/L (15 [12%] of 39 patients; P=.02). Blood levels >1 mg/L were reached after increasing the voriconazole dosage, with complete resolution of infection in all 6 cases. Among 16 patients with voriconazole trough blood levels >5.5 mg/L, 5 patients (31%) presented with an encephalopathy, including 4 patients who were treated intravenously with a median voriconazole dosage of 8 mg/kg per day, whereas none of the patients with levels Conclusions Voriconazole therapeutic drug monitoring improves the efficacy and safety of therapy in severely ill patients with invasive mycoses.
796 citations
TL;DR: Mortality associated with MRSA bacteremia was significantly higher when the empirical antibiotic was inappropriate and when vancomycin was empirically used for treatment of infection with strains with a high vancomYcin MIC (>1 microg/mL).
Abstract: Background Vancomycin treatment failure in methicillin-resistant Staphylococcus aureus (MRSA) bacteremia is not uncommon, even when MRSA is susceptible to vancomycin. The aim of our study was to evaluate whether vancomycin minimum inhibitory concentration has any influence on the mortality associated with MRSA bacteremia. Methods A total of 414 episodes of MRSA bacteremia were prospectively followed-up from 1991 through 2005. MIC of vancomycin for the first isolate was determined by E-test. Clinical variables recorded were age, comorbidity, prior administration of vancomycin, use of corticosteroids, prognosis of underlying disease, source of bacteremia, the need for mechanical ventilation, shock, and mortality. A "treatment group" variable was created and defined as follows: (1) receipt of empirical vancomycin and an isolate with a vancomycin MIC of 1 microg/mL (38 episodes), (2) receipt of empirical vancomycin and an isolate with a vancomycin MIC of 1.5 microg/mL (90 episodes), (3) receipt of empirical vancomycin and an isolate with a vancomycin MIC of 2 microg/mL (40 episodes), and (4) receipt of inappropriate empirical therapy (246 episodes). Univariate and multivariate analyses were performed. Results Episodes caused by strains with a vancomycin MIC of 2 microg/mL were independently associated with a lower risk of shock (odds ratio [OR], 0.33; 95% confidence interval [CI], 0.15-0.75). Multivariate analysis selected receipt of empirical vancomycin and an isolate with a vancomycin MIC of 2 microg/mL (OR, 6.39; 95% CI, 1.68-24.3), receipt of inappropriate empirical therapy (OR, 3.62; 95% CI, 1.20-10.9), increasing age (OR, 1.02; 95% CI, 1.00-1.04), use of corticosteroids (OR, 1.85; 95% CI, 1.04-3.29), an ultimately (OR, 10.2; 95% CI, 2.85-36.8) or rapidly (OR, 1.81; 95% CI, 1.06-3.10) fatal underlying disease, high-risk (OR, 3.60; 95% CI, 1.89-6.88) and intermediate-risk (OR, 2.18; 95% CI, 1.17-4.04) sources of bacteremia, and shock (OR, 7.38; 95% CI, 4.11-13.3) as the best predictors of mortality. Conclusions Mortality associated with MRSA bacteremia was significantly higher when the empirical antibiotic was inappropriate and when vancomycin was empirically used for treatment of infection with strains with a high vancomycin MIC (>1 microg/mL).
770 citations
TL;DR: Correlates of protection after vaccination are sometimes absolute quantities but often are relative, such that most infections are prevented at a particular level of response but some will occur above that level because of a large challenge dose or deficient host factors.
Abstract: The immune system is redundant, and B and T cells collaborate. However, almost all current vaccines work through induction of antibodies in serum or on mucosa that block infection or interfere with microbial invasion of the bloodstream. To protect, antibodies must be functional in the sense of neutralization or opsonophagocytosis. Correlates of protection after vaccination are sometimes absolute quantities but often are relative, such that most infections are prevented at a particular level of response but some will occur above that level because of a large challenge dose or deficient host factors. There may be >1 correlate of protection for a disease, which we term "cocorrelates." Either effector or central memory may correlate with protection. Cell-mediated immunity also may operate as a correlate or cocorrelate of protection against disease, rather than against infection. In situations where the true correlate of protection is unknown or difficult to measure, surrogate tests (usually antibody measurements) must suffice as predictors of protection by vaccines. Examples of each circumstance are given.
TL;DR: Malnutrition and nutritional alterations, common complications of human immunodeficiency virus infection, include disorders of food intake, nutrient absorption, and intermediary metabolism and play a significant and independent role in morbidity and mortality.
Abstract: Infection and malnutrition have always been intricately linked. Malnutrition is the primary cause of immunodeficiency worldwide, and we are learning more and more about the pathogenesis of this interaction. Five infectious diseases account for more than one-half of all deaths in children aged <5 years, most of whom are undernourished. Micronutrient deficiencies have effects such as poor growth, impaired intellect, and increased mortality and susceptibility to infection. The worldwide magnitude of parasite infection is enormous. It is understood that parasites may lead to malnutrition, but the extent to which malnutrition causes increased parasite infestation is not known; thus, the conditions need to be addressed together. Nutritional deficiencies associated with pregnancy are associated with poor immune response to infection. Because this immune deficiency is partially compensated by breast-feeding, this is the single best way to protect infants from infection. Malnutrition and nutritional alterations, common complications of human immunodeficiency virus infection, include disorders of food intake, nutrient absorption, and intermediary metabolism and play a significant and independent role in morbidity and mortality. The 21st century provides new information and new challenges. With new technologies and political changes, it is hoped that a healthier, more disease-free, and better-nourished population will emerge.
TL;DR: C. difficile type 078 isolates from humans and pigs are highly genetically related and presents with similar severity, but CDI due totype 078 affects a younger population and is more frequently community associated.
Abstract: BACKGROUND: Since 2005, an increase in the prevalence of Clostridium difficile infection (CDI) due to polymerase chain reaction ribotype 078 has been noticed in The Netherlands. This strain has also been identified as the predominant strain in pigs and calves. METHODS: CDI caused by type 078 was studied in relation to CDI caused by the hypervirulent type 027 and by types other than 027 and 078. Human and porcine isolates were further investigated and characterized by multilocus variable number tandem repeat analysis. RESULTS: From February 2005 through February 2008, the incidence of type 078 among isolates obtained from 1687 patients increased from 3% to 13%. Compared with patients infected with type 027, patients infected with type 078 were younger (67.4 vs. 73.5 years; P < .01) and more frequently had community-associated disease (17.5% vs. 6.7%; odds ratio, 2.98; 95% confidence interval, 2.11-8.02); rates of severe diarrhea (38.9% vs. 40.0%) and attributable mortality (3.8% vs. 4.0%) were similar in both groups. Compared with patients infected with other types, patients infected with type 078 more frequently received fluoroquinolone therapy (29.4% vs. 19.8%; odds ratio, 2.17; 95% confidence interval, 1.06-4.44). Type 078 isolates contained genes for toxin A, toxin B, binary toxin, and a 39-base pair deletion in toxin regulator gene (tcdC), as well as a point mutation at position 184, resulting in a stop codon. Multilocus variable number tandem repeat analysis of 54 human and 11 porcine isolates revealed 4 clonal complexes containing both porcine and human isolates. CONCLUSIONS: CDI due to type 078 and CDI due to type 027 present with similar severity, but CDI due to type 078 affects a younger population and is more frequently community associated. C. difficile type 078 isolates from humans and pigs are highly genetically related.
TL;DR: Systematic education and serological screening of pregnant women are the most reliable and currently available strategies for the prevention, diagnosis, and early treatment of the infection in the offspring; this is largely because toxoplasmosis in pregnant women most often goes unrecognized.
Abstract: Acute infection with Toxoplasma gondii during pregnancy and its potentially tragic outcome for the fetus and newborn continue to occur in the United States, as well as worldwide, despite the fact that it can be prevented. The infection can be acquired through ingestion of infected, undercooked meat or contaminated food or water. Transmission to the fetus occurs almost solely in women who acquire their primary infection during gestation and can result in visual and hearing loss, mental and psychomotor retardation, seizures, hematological abnormalities, hepatosplenomegaly, or death. Systematic education and serological screening of pregnant women are the most reliable and currently available strategies for the prevention, diagnosis, and early treatment of the infection in the offspring; this is largely because toxoplasmosis in pregnant women most often goes unrecognized. Treatment of the infection in the fetus and infant during the first year of life has been demonstrated to significantly improve the clinical outcome.
TL;DR: Investigations involving animal models and studies performed in vitro suggest that inhibitory activity against C. difficile and differences in the propensity to stimulate toxin production may also influence the likelihood that particular drugs may cause CDI.
Abstract: Antimicrobial therapy plays a central role in the pathogenesis of Clostridium difficile infection (CDI), presumably through disruption of indigenous intestinal microflora, thereby allowing C. difficile to grow and produce toxin. Investigations involving animal models and studies performed in vitro suggest that inhibitory activity against C. difficile and differences in the propensity to stimulate toxin production may also influence the likelihood that particular drugs may cause CDI. Although nearly all antimicrobial classes have been associated with CDI, clindamycin, third-generation cephalosporins, and penicillins have traditionally been considered to harbor the greatest risk. Recent studies have also implicated fluoroquinolones as high-risk agents, a finding that is most likely to be related in part to increasing fluoroquinolone resistance among epidemic strains (i.e., restriction-endonuclease analysis group BI/North American PFGE type 1 strains) and some nonepidemic strains of C. difficile. Restrictions in the use of clindamycin and third-generation cephalosporins have been associated with reductions in CDI. Because use of any antimicrobial has the potential to induce the onset of CDI and disease caused by other health care-associated pathogens, antimicrobial stewardship programs that promote judicious use of antimicrobials are encouraged in concert with environmental and infection control-related efforts.
TL;DR: Delayed amphotericin B-based therapy resulted in a 2-fold increase in mortality rate at 12 weeks after diagnosis, compared with early treatment, and the pursuit of aggressive diagnostic strategies and prompt initiation of antifungal agents with activity against Zygomycetes should be considered for patients with hematological malignancy who are at an increased risk for zygomyCosis.
Abstract: Background Zygomycosis is an emerging opportunistic mycosis among immunocompromised patients with a particularly poor prognosis. Methods We analyzed the impact of delaying effective amphotericin B-based therapy on outcome among 70 consecutive patients with hematologic malignancy who had zygomycosis in our institution during the period 1989-2006. We used classification and regression tree analysis to identify the mortality breakpoint between early and delayed treatment. Results Delayed amphotericin B-based therapy (i.e., initiating treatment >/=6 days after diagnosis) resulted in a 2-fold increase in mortality rate at 12 weeks after diagnosis, compared with early treatment (82.9% vs. 48.6%); this remained constant across the years of the study and was an independent predictor of poor outcome (odds ratio, 8.1; 95% confidence interval, 1.7-38.2; P = .008) in multivariate analysis. Active malignancy (P = .003) and monocytopenia (P =.01) at the time of diagnosis of infection were also independently associated with a poor outcome, whereas salvage posaconazole-based therapy (P=.01) and neutrophil recovery (P = .009) were predictive of a favorable outcome. Conclusions Because discriminating between zygomycosis and aspergillosis in a timely fashion is difficult, the pursuit of aggressive diagnostic strategies and prompt initiation of antifungal agents with activity against Zygomycetes should be considered for patients with hematological malignancy who are at an increased risk for zygomycosis.
TL;DR: This work counted daily unique queries originating in the United States that contained influenza-related search terms from the Yahoo! search engine from March 2004 through May 2008, and estimated linear models, using searches with 1-10-week lead times as explanatory variables to predict the percentage of cultures positive for influenza and deaths attributable to pneumonia and influenza in the US.
Abstract: The Internet is an important source of health information. Thus, the frequency of Internet searches may provide information regarding infectious disease activity. As an example, we examined the relationship between searches for influenza and actual influenza occurrence. Using search queries from the Yahoo! search engine ( http://search.yahoo.com ) from March 2004 through May 2008, we counted daily unique queries originating in the United States that contained influenza-related search terms. Counts were divided by the total number of searches, and the resulting daily fraction of searches was averaged over the week. We estimated linear models, using searches with 1-10-week lead times as explanatory variables to predict the percentage of cultures positive for influenza and deaths attributable to pneumonia and influenza in the United States. With use of the frequency of searches, our models predicted an increase in cultures positive for influenza 1-3 weeks in advance of when they occurred (P < .001), and similar models predicted an increase in mortality attributable to pneumonia and influenza up to 5 weeks in advance (P < .001). Search-term surveillance may provide an additional tool for disease surveillance.
TL;DR: These updated guidelines replace the previous management guidelines published in the April 2000 issue of Clinical Infectious Diseases and are intended for use by health care providers who care for patients who have blastomycosis.
Abstract: Evidence-based guidelines for the management of patients with blastomycosis were prepared by an Expert Panel of the Infectious Diseases Society of America. These updated guidelines replace the previous management guidelines published in the April 2000 issue of Clinical Infectious Diseases. The guidelines are intended for use by health care providers who care for patients who have blastomycosis. Since 2000, several new antifungal agents have become available, and blastomycosis has been noted more frequently among immunosuppressed patients. New information, based on publications between 2000 and 2006, is incorporated in this guideline document, and recommendations for treating children with blastomycosis have been noted.
TL;DR: A panel of physicians and scientists with expertise in drug-resistant HIV-1, drug management, and patient care is convened to review recently published data and presentations at scientific conferences and to provide updated recommendations on resistance testing.
Abstract: Resistance to antiretroviral drugs remains an important limitation to successful human immunodeficiency virus type 1 (HIV-1) therapy. Resistance testing can improve treatment outcomes for infected individuals. The availability of new drugs from various classes, standardization of resistance assays, and the development of viral tropism tests necessitate new guidelines for resistance testing. The International AIDS Society-USA convened a panel of physicians and scientists with expertise in drug-resistant HIV-1, drug management, and patient care to review recently published data and presentations at scientific conferences and to provide updated recommendations. Whenever possible, resistance testing is recommended at the time of HIV infection diagnosis as part of the initial comprehensive patient assessment, as well as in all cases of virologic failure. Tropism testing is recommended whenever the use of chemokine receptor 5 antagonists is contemplated. As the roll out of antiretroviral therapy continues in developing countries, drug resistance monitoring for both subtype B and non-subtype B strains of HIV will become increasingly important.
TL;DR: Several characteristics commonly presumed to be essential to probiotics, such as human origin and the ability to improve the balance of the intestinal microbiota, are discussed.
Abstract: Interest in probiotics is at an all-time high in the United States, driven in part by new products emerging in the market, by US researchers eager to evaluate efficacy claims rigorously, and by consumers interested in potential therapeutic and preventive health benefits. The US marketplace is a mixed bag of products, some well-defined and properly evaluated in controlled clinical studies and others with unsubstantiated claims of efficacy. Validation of probiotic contents in commercial products is needed to ensure consumer confidence. The term "probiotic" should be used only for products that meet the scientific criteria for this term-namely, products that contain an adequate dose of live microbes that have been documented in target-host studies to confer a health benefit. Probiotics must be identified to the level of strain, must be characterized for the specific health target, and must be formulated into products using strains and doses shown to be efficacious. Several characteristics commonly presumed to be essential to probiotics, such as human origin and the ability to improve the balance of the intestinal microbiota, are discussed.
TL;DR: Endoscopy and computed tomography are less sensitive than stool toxin assays but may be useful when immediate results are important or other confounding conditions rank high in the differential diagnosis.
Abstract: Prompt and precise diagnosis is an important aspect of effective management of Clostridium difficile infection (CDI). CDI causes 15%-25% of all cases of antibiotic-associated diarrhea, the severity of which ranges from mild diarrhea to fulminant pseudomembranous colitis. Several factors, especially advanced age and hospitalization, should be considered in the diagnosis of CDI. In particular, nosocomial diarrhea arising >72 hours after admission among patients receiving antibiotics is highly likely to have resulted from CDI. Testing of stool for the presence of C. difficile toxin confirms the diagnosis of CDI. However, performance of an enzyme immunoassay is the usual method by which CDI is confirmed, but this test appears to be relatively insensitive, compared with the cell cytotoxicity assay and stool culture for toxigenic C. difficile on selective medium. Endoscopy and computed tomography are less sensitive than stool toxin assays but may be useful when immediate results are important or other confounding conditions rank high in the differential diagnosis. Often overlooked aspects of this diagnosis are high white blood cell counts (which are sometimes in the leukemoid range) and hypoalbuminemia.
University of California, Los Angeles1, Johns Hopkins University2, University of Michigan3, National Institutes of Health4, University of Colorado Denver5, Yale University6, Harvard University7, Duke University8, American Geriatrics Society9, Infectious Diseases Society of America10, Wake Forest University11
TL;DR: Researchers in infectious diseases, geriatrics, immunology, and gerontology met to review what is known about HIV infection and aging, to identify research gaps, and to suggest high priority topics for future research.
Abstract: Highly active antiretroviral treatment has resulted in dramatically increased life expectancy among patients with HIV infection who are now aging while receiving treatment and are at risk of developing chronic diseases associated with advanced age. Similarities between aging and the courses of human immunodeficiency virus (HIV) infection and acquired immunodeficiency syndrome suggest that HIV infection compresses the aging process, perhaps accelerating comorbidities and frailty. In a workshop organized by the Association of Specialty Professors, the Infectious Diseases Society of America, the HIV Medical Association, the National Institute on Aging, and the National Institute on Allergy and Infectious Diseases, researchers in infectious diseases, geriatrics, immunology, and gerontology met to review what is known about HIV infection and aging, to identify research gaps, and to suggest high priority topics for future research. Answers to the questions posed are likely to help prioritize and balance strategies to slow the progression of HIV infection, to address comorbidities and drug toxicity, and to enhance understanding about both HIV infection and aging.
TL;DR: In this paper, the authors discuss the molecular mechanisms of antifungal resistance and the concept of clinical resistance, which is critical to the understanding of treatment failure in patients with invasive fungal infections.
Abstract: Despite advances in preventive, diagnostic, and therapeutic interventions, invasive fungal infections cause significant morbidity and mortality in immunocompromised patients. The burden of antifungal resistance in such high-risk patients is becoming a major concern. A better understanding of the mechanisms and clinical impact of antifungal resistance is essential to the prompt and efficient treatment of patients with invasive mycoses and to improving the outcome of such infections. Although recent guidelines have attempted to standardize antifungal susceptibility testing, limitations still exist as a result of the incomplete correlation between in vitro susceptibility and clinical response to treatment. Four major mechanisms of resistance to azoles have been identified, all of which rely on altered gene expression. Mechanisms responsible for polyene and echinocandin resistance are less well understood. In addition to discussing the molecular mechanisms of antifungal resistance, this article elaborates on the concept of clinical resistance, which is critical to the understanding of treatment failure in patients with invasive fungal infections.
TL;DR: In both populations, an unequivocal correlation between the number of culture-positive tissue samples and positive results of histologic analysis was noted, which corroborated the evidence that true infections were detected over the entire cultivation period.
Abstract: BACKGROUND: The value of microbiological culture to diagnose late periprosthetic infection is limited, especially because standard methods may fail to detect biofilm-forming sessile or other fastidious bacteria. There is no agreement on the appropriate cultivation period, although this period is a crucial factor. This study was designed to assess the duration of culture that is necessary for reliable detection. PATIENTS AND METHODS: Ten periprosthetic tissue specimens each were obtained during revision from 284 patients with suspected late hip or knee arthroplasty infection. Five samples were examined by microbiological culture over a 14-day period, and 5 were subjected to histologic analysis. To define infection, a pre-established algorithm was used; this included detection of indistinguishable organisms in >/=2 tissue samples or growth in 1 tissue sample and a positive result of histologic analysis (>5 neutrophils in at least 10 high-power fields). The time to detection of organisms was monitored. RESULTS: Infection was diagnosed in 110 patients. After 7 days (the longest incubation period most frequently reported), the detection rate via culture was merely 73.6%. Organisms indicating infection were found for up to 13 days. "Early"-detected species (mostly staphylococci) emerged predominantly during the first week, whereas "late"-detected agents (mostly Propionibacterium species) were detected mainly during the second week. In both populations, an unequivocal correlation between the number of culture-positive tissue samples and positive results of histologic analysis was noted, which corroborated the evidence that true infections were detected over the entire cultivation period. CONCLUSIONS: Prolonged microbiological culture for 2 weeks is promising because it yields signs of periprosthetic infection in a significant proportion of patients that would otherwise remain unidentified.
TL;DR: Minimizing unnecessary antibiotic use by even a small percentage could significantly reduce the immediate and direct risks of drug-related adverse events in individual patients.
Abstract: (See the editorial commentary by Linder on pages 744–6) Background. Drug-related adverse events are an underappreciated consequence of antibiotic use, and the national magnitude and scope of these events have not been studied. Our objective was to estimate and compare the numbers and rates of emergency department (ED) visits for drug-related adverse events associated with systemic antibiotics in the United States by drug class, individual drug, and event type. Methods. We analyzed drug-related adverse events from the National Electronic Injury Surveillance System– Cooperative Adverse Drug Event Surveillance project (2004–2006) and outpatient prescriptions from national sample surveys of ambulatory care practices, the National Ambulatory Medical Care Survey and the National Hospital Ambulatory Medical Care Survey (2004–2005). Results. On the basis of 6614 cases, an estimated 142,505 visits (95% confidence interval [CI], 116,506–168,504 visits) annually were made to US EDs for drug-related adverse events attributable to systemic antibiotics. Antibiotics were implicated in 19.3% of all ED visits for drug-related adverse events. Most ED visits for antibiotic-associated adverse events were for allergic reactions (78.7% of visits; 95% CI, 75.3%–82.1% of visits). One-half of the estimated ED visits were attributable to penicillins (36.9% of visits; 95% CI, 34.7%–39.2% of visits) and cephalosporins (12.2%; 95% CI, 10.9%–13.5%). Among commonly prescribed antibiotics, sulfonamides and clindamycin were associated with the highest rate of ED visits (18.9 ED visits per 10,000 outpatient prescription visits [95% CI, 13.1–24.7 ED visits per 10,000 outpatient prescription visits] and 18.5 ED visits per 10,000 outpatient prescription visits [95% CI, 12.1–25.0 ED visits per 10,000 outpatient prescription visits], respectively). Compared with all other antibiotic classes, sulfonamides were associated with a significantly higher rate of moderate-to-severe allergic reactions (4.3% [95% CI, 2.9%–5.8%] vs. 1.9 % [95% CI, 1.5%–2.3%]), and sulfonamides and fluoroquinolones were associated with a significantly higher rate of neurologic or psychiatric disturbances (1.4% [95% CI, 1.0%– 1.7%] vs. 0.5% [95% CI, 0.4%–0.6%]). Conclusions. Antibiotic-associated adverse events lead to many ED visits, and allergic reactions are the most common events. Minimizing unnecessary antibiotic use by even a small percentage could significantly reduce the immediate and direct risks of drug-related adverse events in individual patients.
TL;DR: In this paper, the authors compared the clinical characteristics, epidemiologic investigations, infection-control evaluations, and microbiologic findings of all 7 cases of vancomycin-resistant Staphylococcus aureus (VRSA) infection in the United States during the period 2002-2006.
Abstract: BACKGROUND This report compares the clinical characteristics, epidemiologic investigations, infection-control evaluations, and microbiologic findings of all 7 of the cases of vancomycin-resistant Staphylococcus aureus (VRSA) infection in the United States during the period 2002-2006. METHODS Epidemiologic, clinical, and infection-control information was collected. VRSA isolates underwent confirmatory identification, antimicrobial susceptibility testing, pulsed-field gel electrophoresis, and typing of the resistance genes. To assess VRSA transmission, case patients and their contacts were screened for VRSA carriage. RESULTS Seven cases were identified from 2002 through 2006; 5 were reported from Michigan, 1 was reported from Pennsylvania, and 1 was reported from New York. All VRSA isolates were vanA positive and had a median vancomycin minimum inhibitory concentration of 512 microg/mL. All case patients had a history of prior methicillin-resistant S. aureus and enterococcal infection or colonization; all had several underlying conditions, including chronic skin ulcers; and most had received vancomycin therapy prior to their VRSA infection. Person-to-person transmission of VRSA was not identified beyond any of the case patients. Infection-control precautions were evaluated and were consistent with established guidelines. CONCLUSIONS Seven patients with vanA-positive VRSA have been identified in the United States. Prompt detection by microbiology laboratories and adherence to recommended infection control measures for multidrug-resistant organisms appear to have prevented transmission to other patients.
TL;DR: SMART-COP is a simple, practical clinical tool for accurately predicting the need for IRVS that is likely to assist clinicians in determining CAP severity.
Abstract: BACKGROUND: Existing severity assessment tools, such as the pneumonia severity index (PSI) and CURB-65 (tool based on confusion, urea level, respiratory rate, blood pressure, and age >or=65 years), predict 30-day mortality in community-acquired pneumonia (CAP) and have limited ability to predict which patients will require intensive respiratory or vasopressor support (IRVS). METHODS: The Australian CAP Study (ACAPS) was a prospective study of 882 episodes in which each patient had a detailed assessment of severity features, etiology, and treatment outcomes. Multivariate logistic regression was performed to identify features at initial assessment that were associated with receipt of IRVS. These results were converted into a simple points-based severity tool that was validated in 5 external databases, totaling 7464 patients. RESULTS: In ACAPS, 10.3% of patients received IRVS, and the 30-day mortality rate was 5.7%. The features statistically significantly associated with receipt of IRVS were low systolic blood pressure (2 points), multilobar chest radiography involvement (1 point), low albumin level (1 point), high respiratory rate (1 point), tachycardia (1 point), confusion (1 point), poor oxygenation (2 points), and low arterial pH (2 points): SMART-COP. A SMART-COP score of >or=3 points identified 92% of patients who received IRVS, including 84% of patients who did not need immediate admission to the intensive care unit. Accuracy was also high in the 5 validation databases. Sensitivities of PSI and CURB-65 for identifying the need for IRVS were 74% and 39%, respectively. CONCLUSIONS: SMART-COP is a simple, practical clinical tool for accurately predicting the need for IRVS that is likely to assist clinicians in determining CAP severity.
TL;DR: Analysis of the complete profile of the pharmacological activities and molecular modes of action of artemisinin and artesunate and their performance in clinical trials will further elucidate the full antimicrobial potential of these versatile pharmacological tools from nature.
Abstract: Traditional Chinese medicine commands a unique position among all traditional medicines because of its 5000 years of history. Our own interest in natural products from traditional Chinese medicine was triggered in the 1990s, by artemisinin-type sesquiterpene lactones from Artemisia annua L. As demonstrated in recent years, this class of compounds has activity against malaria, cancer cells, and schistosomiasis. Interestingly, the bioactivity of artemisinin and its semisynthetic derivative artesunate is even broader and includes the inhibition of certain viruses, such as human cytomegalovirus and other members of the Herpesviridae family (e.g., herpes simplex virus type 1 and Epstein-Barr virus), hepatitis B virus, hepatitis C virus, and bovine viral diarrhea virus. Analysis of the complete profile of the pharmacological activities and molecular modes of action of artemisinin and artesunate and their performance in clinical trials will further elucidate the full antimicrobial potential of these versatile pharmacological tools from nature.
TL;DR: Combination polyene-caspofungin therapy represents a promising potential alternative to polyene monotherapy for patients with ROCM and a randomized, prospective investigation of these findings is warranted.
Abstract: Rhino-orbital-cerebral mucormycosis (ROCM) is a life-threatening infection that occurs most frequently in patients with diabetic ketoacidosis or in patients who are immunocompromised as a result of neutropenia or immunosuppressive drugs [1, 2]. Unfortunately, despite disfiguring surgical debridement and polyene antifungal therapy, the overall mortality of ROCM remains ≥50%, particularly in the presence of CNS extension. Because of the increasing incidence of mucormycosis [3–5] and the unacceptably high mortality rate associated with it, novel antifungal therapies are urgently needed.
Amphotericin B deoxycholate (AmB) and its lipid formulations remain the only antifungal agents approved for the treatment of invasive mucormycosis. Echinocandins have had no activity in in vitro susceptibility assays against the Mucorales [6–8]. Therefore, it has been axiomatic that echinocandins are ineffective in treating mucormycosis. However, traditional susceptibility testing may not reflect the true activity of echinocandins against molds in general and against the agents of mucormycosis in particular [9–11]. We recently reported that Rhizopus oryzae, the most common pathogen causing mucormycosis, expressed the target enzyme for echinocandins (1,3-β-glucan synthase, encoded by the FKS gene); that caspofungin inhibited the enzyme's activity in vitro; and that caspofungin had activity in the diabetic mouse model of disseminated mucormycosis [12]. Furthermore, combination therapy with caspofungin and amphotericin B lipid complex (ABLC) was synergistic in the same model [13].
On the basis of these data, we recently began treating ROCM with combination polyene-caspofungin therapy. We retrospectively reviewed cases of ROCM to compare outcomes of patients treated with combination therapy with those of patients not treated with combination therapy. In addition, we sought to determine whether outcomes differed by the initial polyene used for treatment.
TL;DR: Although reduced within the past decade, the delay of diagnosis of common variable immunodeficiency remains unacceptable and recurrence of upper respiratory tract infection or pneumonia should lead to systematic evaluation of serum immunoglobulin.
Abstract: Background. Common variable immunodeficiency is characterized by recurrent infections and defective immunoglobulin production. Methods. The DEFI French national study prospectively enrolled adult patients with primary hypogammaglobulinemia. Clinical events before inclusion were retrospectively analyzed at that time. Results. From April 2004 through April 2007, 341 patients were enrolled, 252 of whom had received a diagnosis of common variable immunodeficiency; of those, 110 were male, 142 were female, and 228 were white. The median age at first symptoms was 19 years. The median age at common variable immunodeficiency diagnosis was 33.9 years. The median delay for diagnosis was 15.6 years for the 138 patients with initial symptoms before 1990 and 2.9 years for the 114 patients with initial symptoms from 1990 to the time of the study. The most frequent initial symptoms were upper respiratory tract infections: bronchitis (in 38% of patients), sinusitis (36%), pneumonia (31%), and/or bronchiectasis (14%). Overall, 240 patients had respiratory symptoms. Pneumonia was reported in 147 patients; Streptococcus pneumoniae and Haemophilus influenzae were documented in 46 and 17 cases, respectively. Recurrent or chronic diarrhea was reported in 118 patients. Giardia (35 cases), Salmonella (19), and Campylobacter (19) infections were more frequent in patients with undetectable serum immunoglobulin A (P< .001). Sixteen patients developed opportunistic infections. Persistent infections and requirement for antibiotics despite immunoglobulin substitution correlated with severe defect of memory switched B cells (P =.003) but not with immunoglobulin G trough levels (P =.55). Conclusion. Although reduced within the past decade, the delay of diagnosis of common variable immunodeficiency remains unacceptable. Recurrence of upper respiratory tract infection or pneumonia should lead to systematic evaluation of serum immunoglobulin.