Showing papers in "Clinical Infectious Diseases in 2013"

Diagnosis and Management of Prosthetic Joint Infection: Clinical Practice Guidelines by the Infectious Diseases Society of America

Abstract: These guidelines are intended for use by infectious disease specialists, orthopedists, and other healthcare professionals who care for patients with prosthetic joint infection (PJI). They include evidence-based and opinion-based recommendations for the diagnosis and management of patients with PJI treated with debridement and retention of the prosthesis, resection arthroplasty with or without subsequent staged reimplantation, 1-stage reimplantation, and amputation.

Case Definitions, Diagnostic Algorithms, and Priorities in Encephalitis: Consensus Statement of the International Encephalitis Consortium

Abstract: Background Encephalitis continues to result in substantial morbidity and mortality worldwide. Advances in diagnosis and management have been limited, in part, by a lack of consensus on case definitions, standardized diagnostic approaches, and priorities for research. Methods In March 2012, the International Encephalitis Consortium, a committee begun in 2010 with members worldwide, held a meeting in Atlanta to discuss recent advances in encephalitis and to set priorities for future study. Results We present a consensus document that proposes a standardized case definition and diagnostic guidelines for evaluation of adults and children with suspected encephalitis. In addition, areas of research priority, including host genetics and selected emerging infections, are discussed. Conclusions We anticipate that this document, representing a synthesis of our discussions and supported by literature, will serve as a practical aid to clinicians evaluating patients with suspected encephalitis and will identify key areas and approaches to advance our knowledge of encephalitis.

Executive summary: diagnosis and management of prosthetic joint infection: clinical practice guidelines by the Infectious Diseases Society of America.

Abstract: These guidelines are intended for use by infectious disease specialists, orthopedists, and other healthcare professionals who care for patients with prosthetic joint infection (PJI). They include evidence-based and opinion-based recommendations for the diagnosis and management of patients with PJI treated with debridement and retention of the prosthesis, resection arthroplasty with or without subsequent staged reimplantation, 1-stage reimplantation, and amputation.

10 × '20 Progress—Development of New Drugs Active Against Gram-Negative Bacilli: An Update From the Infectious Diseases Society of America

Abstract: Infections caused by antibiotic-resistant bacteria, especially the “ESKAPE” pathogens, continue to increase in frequency and cause significant morbidity and mortality. New antimicrobial agents are greatly needed to treat infections caused by gram-negative bacilli (GNB) resistant to currently available agents. The Infectious Diseases Society of America (IDSA) continues to propose legislative, regulatory, and funding solutions to this continuing crisis. The current report updates the status of development and approval of systemic antibiotics in the United States as of early 2013. Only 2 new antibiotics have been approved since IDSA's 2009 pipeline status report, and the number of new antibiotics annually approved for marketing in the United States continues to decline. We identified 7 drugs in clinical development for treatment of infections caused by resistant GNB. None of these agents was included in our 2009 list of antibacterial compounds in phase 2 or later development, but unfortunately none addresses the entire spectrum of clinically relevant GNB resistance. Our survey demonstrates some progress in development of new antibacterial drugs that target infections caused by resistant GNB, but progress remains alarmingly elusive. IDSA stresses our conviction that the antibiotic pipeline problem can be solved by the collaboration of global leaders to develop creative incentives that will stimulate new antibacterial research and development. Our aim is the creation of a sustainable global antibacterial drug research and development enterprise with the power in the short term to develop 10 new, safe, and efficacious systemically administered antibiotics by 2020 as called for in IDSA's “10 × '20 Initiative.”

Increasing Echinocandin Resistance in Candida glabrata: Clinical Failure Correlates With Presence of FKS Mutations and Elevated Minimum Inhibitory Concentrations

Abstract: Background. Fluconazole (FLC) resistance is common in C. glabrata and echinocandins are often used as firstline therapy. Resistance to echinocandin therapy has been associated with FKS1 and FKS2 gene alterations. Methods. We reviewed records of all patients with C. glabrata bloodstream infection at Duke Hospital over the past decade (2001–2010) and correlated treatment outcome with minimum inhibitory concentration (MIC) results and the presence of FKS gene mutations. For each isolate, MICs to FLC and echinocandins (anidulafungin, caspofungin, and micafungin) and FKS1 and FKS2 gene sequences were determined. Results. Two hundred ninety-three episodes (313 isolates) of C. glabrata bloodstream infection were analyzed. Resistance to echinocandins increased from 4.9% to 12.3% and to FLC from 18% to 30% between 2001 and 2010, respectively. Among the 78 FLC resistant isolates, 14.1% were resistant to 1 or more echinocandin. Twenty-five (7.9%) isolates harbored a FKS mutation. The predictor of a FKS mutant strain was prior echinocandin therapy (stepwise multivariable analysis, odds ratio, 19.647 [95% confidence interval, 7.19–58.1]). Eighty percent (8/10) of patients infected with FKS mutants demonstrating intermediate or resistant MICs to an echinocandin and treated with an echinocandin failed to respond or responded initially but experienced a recurrence. Conclusions. Echinocandin resistance is increasing, including among FLC-resistant isolates. The new Clinical and Laboratory Standards Institute clinical breakpoints differentiate wild-type from C. glabrata strains bearing clinically significant FKS1/FKS2 mutations. These observations underscore the importance of knowing the local epidemiology and resistance patterns for Candida within institutions and susceptibility testing of echinocandins for C. glabrata to guide therapeutic decision making.

The Scourge of Antibiotic Resistance: The Important Role of the Environment

Abstract: Antibiotic resistance and associated genes are ubiquitous and ancient, with most genes that encode resistance in human pathogens having originated in bacteria from the natural environment (eg, β-lactamases and fluoroquinolones resistance genes, such as qnr). The rapid evolution and spread of "new" antibiotic resistance genes has been enhanced by modern human activity and its influence on the environmental resistome. This highlights the importance of including the role of the environmental vectors, such as bacterial genetic diversity within soil and water, in resistance risk management. We need to take more steps to decrease the spread of resistance genes in environmental bacteria into human pathogens, to decrease the spread of resistant bacteria to people and animals via foodstuffs, wastes and water, and to minimize the levels of antibiotics and antibiotic-resistant bacteria introduced into the environment. Reducing this risk must include improved management of waste containing antibiotic residues and antibiotic-resistant microorganisms.

Better tests, better care: improved diagnostics for infectious diseases.

Abstract: In this IDSA policy paper, we review the current diagnostic landscape, including unmet needs and emerging technologies, and assess the challenges to the development and clinical integration of improved tests. To fulfill the promise of emerging diagnostics, IDSA presents recommendations that address a host of identified barriers. Achieving these goals will require the engagement and coordination of a number of stakeholders, including Congress, funding and regulatory bodies, public health agencies, the diagnostics industry, healthcare systems, professional societies, and individual clinicians.

Finding the “Missing 50%” of Invasive Candidiasis: How Nonculture Diagnostics Will Improve Understanding of Disease Spectrum and Transform Patient Care

Abstract: Blood cultures are limited for diagnosing invasive candidiasis by poor sensitivity and slow turn-around time. New diagnostics are needed to complement cultures, in particular to identify the "missing 50%" of patients who are blood culture-negative. Mannan/anti-mannan immunoglobulin G, β-D-glucan (BDG) and polymerase chain reaction (PCR) assays can diagnose candidemia before blood cultures and show promising sensitivity/specificity, but they are not widely investigated in blood culture-negative, deep-seated candidiasis. In a recent study, BDG and PCR were superior to blood cultures in deep-seated candidiasis, suggesting they may identify currently undiagnosed patients and expand our understanding of disease spectrum. Positive predictive values of nonculture tests are limited by the low prevalence of invasive candidiasis, which mandates that results be interpreted judiciously. When used as biomarkers that assess a patient's risk of having invasive candidiasis, tests will facilitate preemptive antifungal strategies. Because negative predictive values are excellent, tests will also be useful for ruling out invasive candidiasis and discontinuing unnecessary antifungal therapy.

A Guide to Utilization of the Microbiology Laboratory for Diagnosis of Infectious Diseases: 2013 Recommendations by the Infectious Diseases Society of America (IDSA) and the American Society for Microbiology (ASM)a

Abstract: The critical role of the microbiology laboratory in infectious disease diagnosis calls for a close, positive working relationship between the physician and the microbiologists who provide enormous value to the health care team. This document, developed by both laboratory and clinical experts, provides information on which tests are valuable and in which contexts, and on tests that add little or no value for diagnostic decisions. Sections are divided into anatomic systems, including Bloodstream Infections and Infections of the Cardiovascular System, Central Nervous System Infections, Ocular Infections, Soft Tissue Infections of the Head and Neck, Upper Respiratory Infections, Lower Respiratory Tract infections, Infections of the Gastrointestinal Tract, Intraabdominal Infections, Bone and Joint Infections, Urinary Tract Infections, Genital Infections, and Skin and Soft Tissue Infections; or into etiologic agent groups, including Tickborne Infections, Viral Syndromes, and Blood and Tissue Parasite Infections. Each section contains introductory concepts, a summary of key points, and detailed tables that list suspected agents; the most reliable tests to order; the samples (and volumes) to collect in order of preference; specimen transport devices, procedures, times, and temperatures; and detailed notes on specific issues regarding the test methods, such as when tests are likely to require a specialized laboratory or have prolonged turnaround times. There is redundancy among the tables and sections, as many agents and assay choices overlap. The document is intended to serve as a reference to guide physicians in choosing tests that will aid them to diagnose infectious diseases in their patients.

The State of Engagement in HIV Care in the United States: From Cascade to Continuum to Control

Abstract: The National HIV/AIDS Strategy and the promise of treatment as prevention have garnered considerable attention from the policy, practice, and scientific communities, with the treatment cascade becoming the sentinel image illustrating the domestic human immunodeficiency virus (HIV) epidemic. The cascade depicts prevalence estimates for sequential steps from HIV diagnosis through viral suppression, the most striking of which is that >50% of persons diagnosed with HIV are not in medical care. This heterogeneous group includes individuals not linked to medical care following HIV diagnosis and those entering care who are not retained, requiring reengagement from a range of community settings. This review synthesizes the state of engagement in HIV care in the United States, focusing on research, practice, and policy considerations. Included are conceptual frameworks, a review of health implications, measurement, monitoring, and evidence-based intervention approaches, and a look to the future in addressing the greatest challenge and opportunity facing our domestic HIV epidemic.

Impact of Rapid Organism Identification via Matrix-Assisted Laser Desorption/Ionization Time-of-Flight Combined With Antimicrobial Stewardship Team Intervention in Adult Patients With Bacteremia and Candidemia

Abstract: BACKGROUND Integration of rapid diagnostic testing via matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) with antimicrobial stewardship team (AST) intervention has the potential for early organism identification, customization of antibiotic therapy, and improvement in patient outcomes. The objective of this study was to assess the impact of this combined approach on clinical and antimicrobial therapy-related outcomes in patients with bloodstream infections. METHODS A pre-post quasi-experimental study was conducted to analyze the impact of MALDI-TOF with AST intervention in patients with bloodstream infections. The AST provided evidence-based antibiotic recommendations after receiving real-time notification following blood culture Gram stain, organism identification, and antimicrobial susceptibilities. Outcomes were compared to a historic control group. RESULTS A total of 501 patients with bacteremia or candidemia were included in the final analysis: 245 patients in the intervention group and 256 patients in the preintervention group. MALDI-TOF with AST intervention decreased time to organism identification (84.0 vs 55.9 hours, P < .001), and improved time to effective antibiotic therapy (30.1 vs 20.4 hours, P = .021) and optimal antibiotic therapy (90.3 vs 47.3 hours, P < .001). Mortality (20.3% vs 14.5%), length of intensive care unit stay (14.9 vs 8.3 days) and recurrent bacteremia (5.9% vs 2.0%) were lower in the intervention group on univariate analysis, and acceptance of an AST intervention was associated with a trend toward reduced mortality on multivariable analysis (odds ratio, 0.55, P = .075). CONCLUSION MALDI-TOF with AST intervention decreased time to organism identification and time to effective and optimal antibiotic therapy.

Mortality Attributable to Smoking Among HIV-1–Infected Individuals: A Nationwide, Population-Based Cohort Study

Abstract: Background. We assessed mortality attributable to smoking among patients with human immunodeficiency virus (HIV). Methods. We estimated mortality rates (MRs), mortality rate ratios (MRRs), life expectancies, life-years lost, and population-attributable risk of death associated with smoking and with HIV among current and nonsmoking individuals from a population-based, nationwide HIV cohort and a cohort of matched HIV-negative individuals. Results. A total of 2921 HIV patients and 10 642 controls were followed for 14 281 and 45 122 person-years, respectively. All-cause and non-AIDS-related mortality was substantially increased among smoking compared to nonsmoking HIV patients (MRR, 4.4 [95% confidence interval {CI}, 3.0–6.7] and 5.3 [95% CI, 3.2–8.8], respectively). Excess MR per 1000 person-years among current vs nonsmokers was 17.6 (95% CI, 13.3–21.9) for HIV patients and 4.8 (95% CI, 3.2–6.4) for controls. A 35-year-old HIV patient had a median life expectancy of 62.6 years (95% CI, 59.9–64.6) for smokers and 78.4 years (95% CI, 70.8–84.0) for nonsmokers; the numbers of life-years lost in association with smoking and HIV were 12.3 (95% CI, 8.1–16.4) and 5.1 (95% CI, 1.6–8.5). The populationattributable risk of death associated with smoking was 61.5% among HIV patients and 34.2% among controls. Conclusions. In a setting where HIV care is well organized and antiretroviral therapy is free of charge, HIVinfected smokers lose more life-years to smoking than to HIV. The excess mortality of smokers is tripled and the population-attributable risk of death associated with smoking is doubled among HIV patients compared to the background population.

Seven Ways to Preserve the Miracle of Antibiotics

Abstract: Antibiotic resistance is a well-acknowledged crisis with no clearly defined comprehensive, national corrective plan. We propose a number of interventions that, collectively, could make a large difference. These include collection of data to inform decisions, efforts to reduce antibiotic abuse in people and animals, great emphasis on antibiotic stewardship, performance incentives, optimal use of newer diagnostics, better support for clinical and basic resistance-related research, and novel methods to foster new antibiotic development.

Understanding the Determinants of Antimicrobial Prescribing within hospitals: The role of ‘Prescribing Etiquette’

Abstract: Background. There is limited knowledge of the key determinants of antimicrobial prescribing behavior (APB) in hospitals. An understanding of these determinants is required for the successful design, adoption, and implementation of quality improvement interventions in antimicrobial stewardship programs. Methods. Qualitative semistructured interviews were conducted with doctors (n = 10), pharmacists (n = 10), and nurses and midwives (n = 19) in 4 hospitals in London. Interviews were conducted until thematic saturation was reached. Thematic analysis was applied to the data to identify the key determinants of antimicrobial prescribing behaviors. Results. The APB of healthcare professionals is governed by a set of cultural rules. Antimicrobial prescribing is performed in an environment where the behavior of clinical leaders or seniors influences practice of junior doctors. Senior doctors consider themselves exempt from following policy and practice within a culture of perceived autonomous decision making that relies more on personal knowledge and experience than formal policy. Prescribers identify with the clinical groups in which they work and adjust their APB according to the prevailing practice within these groups. A culture of “noninterference” in the antimicrobial prescribing practice of peers prevents intervention into prescribing of colleagues. These sets of cultural rules demonstrate the existence of a “prescribing etiquette,” which dominates the APB of healthcare professionals. Prescribing etiquette creates an environment in which professional hierarchy and clinical groups act as key determinants of APB. Conclusions. To influence the antimicrobial prescribing of individual healthcare professionals, interventions need to address prescribing etiquette and use clinical leadership within existing clinical groups to influence practice.

Population Pharmacokinetics of Intravenous Polymyxin B in Critically Ill Patients: Implications for Selection of Dosage Regimens

Abstract: Background. Polymyxin B is a last-line therapy for multidrug-resistant gram-negative bacteria. There is a dearth of pharmacokinetic data to guide dosing in critically ill patients. Methods. Twenty-four critically ill patients were enrolled and blood/urine samples were collected over a dosing interval at steady state. Polymyxin B concentrations were measured by liquid chromatography–tandem mass spectrometry. Population pharmacokinetic analysis and Monte Carlo simulations were conducted. Results. Twenty-four patients aged 21–87 years received intravenous polymyxin B (0.45–3.38 mg/kg/day). Two patients were on continuous hemodialysis, and creatinine clearance in the other patients was 10–143 mL/min. Even with very diverse demographics, the total body clearance of polymyxin B when scaled by total body weight (population mean, 0.0276 L/hour/kg) showed remarkably low interindividual variability (32.4% coefficient of variation). Polymyxin B was predominantly nonrenally cleared with median urinary recovery of 4.04%. Polymyxin B total body clearance did not show any relationship with creatinine clearance (r 2 = 0.008), APACHE II score, or age. Median unbound fraction in plasma was 0.42. Monte Carlo simulations revealed the importance of initiating therapeutic regimens with a loading dose. Conclusions. Our study showed that doses of intravenous polymyxin B are best scaled by total body weight. Importantly, dosage selection of this drug should not be based on renal function.

Continuous infusion of beta-lactam antibiotics in severe sepsis: a multicenter double-blind, randomized controlled trial

Abstract: Background. Beta-lactam antibiotics are a commonly used treatment for severe sepsis, with intermittent bolus dosing standard therapy, despite a strong theoretical rationale for continuous administration. The aim of this trial was to determine the clinical and pharmacokinetic differences between continuous and intermittent dosing in patients with severe sepsis. Methods. This was a prospective, double-blind, randomized controlled trial of continuous infusion versus intermittent bolus dosing of piperacillin-tazobactam, meropenem, and ticarcillin-clavulanate conducted in 5 intensive care units across Australia and Hong Kong. The primary pharmacokinetic outcome on treatment analysis was plasma antibiotic concentration above the minimum inhibitory concentration (MIC) on days 3 and 4. The assessed clinical outcomes were clinical response 7–14 days after study drug cessation, ICU-free days at day 28 and hospital survival. Results. Sixty patients were enrolled with 30 patients each allocated to the intervention and control groups. Plasma antibiotic concentrations exceeded the MIC in 82% of patients (18 of 22) in the continuous arm versus 29% (6 of 21) in the intermittent arm (P= .001). Clinical cure was higher in the continuous group (70% vs 43%; P=.037), but ICU-free days (19.5 vs 17 days; P=.14) did not significantly differ between groups. Survival to hospital discharge was 90% in the continuous group versus 80% in the intermittent group (P=.47). Conclusions. Continuous administration of beta-lactam antibiotics achieved higher plasma antibiotic concentrations than intermittent administration with improvement in clinical cure. This study provides a strong rationale for further multicenter trials with sufficient power to identify differences in patient-centered endpoints.

Colistin and Rifampicin Compared With Colistin Alone for the Treatment of Serious Infections Due to Extensively Drug-Resistant Acinetobacter baumannii: A Multicenter, Randomized Clinical Trial

Abstract: Background Extensively drug-resistant (XDR) Acinetobacter baumannii may cause serious infections in critically ill patients. Colistin often remains the only therapeutic option. Addition of rifampicin to colistin may be synergistic in vitro. In this study, we assessed whether the combination of colistin and rifampicin reduced the mortality of XDR A. baumannii infections compared to colistin alone. Methods This multicenter, parallel, randomized, open-label clinical trial enrolled 210 patients with life-threatening infections due to XDR A. baumannii from intensive care units of 5 tertiary care hospitals. Patients were randomly allocated (1:1) to either colistin alone, 2 MU every 8 hours intravenously, or colistin (as above), plus rifampicin 600 mg every 12 hours intravenously. The primary end point was overall 30-day mortality. Secondary end points were infection-related death, microbiologic eradication, and hospitalization length. Results Death within 30 days from randomization occurred in 90 (43%) subjects, without difference between treatment arms (P = .95). This was confirmed by multivariable analysis (odds ratio, 0.88 [95% confidence interval, .46-1.69], P = .71). A significant increase of microbiologic eradication rate was observed in the colistin plus rifampicin arm (P = .034). No difference was observed for infection-related death and length of hospitalization. Conclusions In serious XDR A. baumannii infections, 30-day mortality is not reduced by addition of rifampicin to colistin. These results indicate that, at present, rifampicin should not be routinely combined with colistin in clinical practice. The increased rate of A. baumannii eradication with combination treatment could still imply a clinical benefit. Clinical trials registration NCT01577862.

A Large Multicenter Study of Methicillin–Susceptible and Methicillin–Resistant Staphylococcus aureus Prosthetic Joint Infections Managed With Implant Retention

Abstract: Background. Several series predicting the prognosis of staphylococcal prosthetic joint infection (PJI) managed with debridement, antibiotics, and implant retention (DAIR) have been published, but some of their conclusions are controversial. At present, little is known regarding the efficacy of the different antibiotics that are used or their ability to eliminate methicillin-resistant S. aureus (MRSA) infection. Methods. This was a retrospective, multicenter, observational study of cases of PJI by S. aureus that were managed with DAIR (2003–2010). Cases were classified as failures when infection persistence/relapse, death, need for salvage therapy, or prosthesis removal occurred. The parameters that predicted failure were analyzed with logistic and Cox regression. Results. Out of 345 episodes (41% men, 73 years), 81 episodes were caused by MRSA. Fifty-two were hematogenous, with poorer prognoses, and 88% were caused by methicillin-susceptible S. aureus (MSSA). Antibiotics were used for a median of 93 days, with similar use of rifampin-based combinations in MSSA- and MRSA-PJI. Failure occurred in 45% of episodes, often early after debridement. The median survival time was 1257 days. There were no overall prognostic differences between MSSA- and MRSA-PJI, but there was a higher incidence of MRSA-PJI treatment failure during the period of treatment (HR 2.34), while there was a higher incidence of MSSA-PJI treatment failure after therapy. Rifampin-based combinations exhibited an independent protective effect. Other independent predictors of outcome were polymicrobial, inflammatory, and bacteremic infections requiring more than 1 debridement, immunosuppressive therapy, and the exchange of removable components of the prosthesis. Conclusions. This is the largest series of PJI by S. aureus managed with DAIR reported to date. The success rate was 55%. The use of rifampin may have contributed to homogenizing MSSA and MRSA prognoses, although the specific rifampin combinations may have had different efficacies.

Treatment of Hepatitis C virus infection among people who are actively injecting drugs: a systematic review and meta-analysis

Abstract: Background. Although guidelines recommend that people who inject drugs (PWID) should not be excluded from hepatitis C (HCV) treatment, some services remain reluctant to treat PWID. The aim of this review was to investigate sustained virologic response (SVR), adherence, discontinuation, and HCV reinfection among PWID. Methods. A search of Medline, Embase, and Cochrane databases (between 2002 and January 2012) was conducted for primary articles/conference abstracts examining HCV treatment outcomes in PWID. Meta-analysis was used to obtain pooled estimates of SVR, adherence, discontinuation, and HCV reinfection. Results. Ten primary articles and 1 conference abstract met the inclusion criteria. Across 6 studies (comprising 314 drug users, of whom 141 [45%] were PWID), pooled SVR was 56% (95% confidence interval [CI], 50%–61%) for all genotypes, 37% (95% CI, 26%–48%) for genotypes 1/4, and 67% (95% CI, 56%–78%) for genotypes 2/3. Pooled 80/80/80 adherence was 82% (95% CI, 74%–89%) across 2 studies, and pooled treatment discontinuation was 22% (95% CI, 16%–27%) across 4 studies. Across 5 studies (comprising 131 drug users) examining reinfection, pooled risk was 2.4 (95% CI, .9–6.1) per 100 person-years. Conclusions. HCV treatment outcomes are acceptable in PWID, supporting treatment guidelines. The pooled estimate of HCV reinfection risk was low, but there was considerable uncertainty around this estimate. Further studies on the risk of reinfection are needed to assess the long-term effectiveness of HCV treatment in PWID.

Aspergillosis due to Voriconazole Highly Resistant Aspergillus fumigatus and Recovery of Genetically Related Resistant Isolates From Domiciles

Abstract: BACKGROUND: Azole resistance is an emerging problem in Aspergillus fumigatus and complicates the management of patients with Aspergillus-related diseases. Selection of azole resistance may occur through exposure to azole fungicides in the environment. In the Netherlands a surveillance network was used to investigate the epidemiology of resistance selection in A. fumigatus. METHODS: Clinical A. fumigatus isolates were screened for azole resistance in 8 university hospitals using azole agar dilution plates. Patient information was collected using an online questionnaire and azole-resistant A. fumigatus isolates were analyzed using gene sequencing, susceptibility testing, and genotyping. Air sampling was performed to investigate the presence of resistant isolates in hospitals and domiciles. RESULTS: Between December 2009 and January 2011, 1315 A. fumigatus isolates from 921 patients were screened. A new cyp51A-mediated resistance mechanism (TR46/Y121F/T289A) was observed in 21 azole-resistant isolates from 15 patients in 6 hospitals. TR46/Y121F/T289A isolates were highly resistant to voriconazole (minimum inhibitory concentration >/=16 mg/L). Eight patients presented with invasive aspergillosis due to TR46/Y121F/T289A, and treatment failed in all 5 patients receiving primary therapy with voriconazole. TR46/Y121F/T289A Aspergillus fumigatus was recovered from 6 of 10 sampled environmental sites. CONCLUSIONS: We describe the emergence and geographical migration of a voriconazole highly resistant A. fumigatus that was associated with voriconazole treatment failure in patients with invasive aspergillosis. Recovery of TR46/Y121F/T289A from the environment suggests an environmental route of resistance selection. Exposure of A. fumigatus to azole fungicides may facilitate the emergence of new resistance mechanisms over time, thereby compromising the use of azoles in the management of Aspergillus-related diseases.

Combination Interventions to Prevent HCV Transmission Among People Who Inject Drugs: Modeling the Impact of Antiviral Treatment, Needle and Syringe Programs, and Opiate Substitution Therapy

Abstract: Background. Interventions such as opiate substitution therapy (OST) and high-coverage needle and syringe programs (HCNSP) cannot substantially reduce hepatitis C virus (HCV) prevalence among people who inject drugs (PWID). HCV antiviral treatment may prevent onward transmission. We project the impact of combining OST, HCNSP, and antiviral treatment on HCV prevalence/incidence among PWID. Methods. An HCV transmission model among PWID was used to project the combinations of OST, HCNSP, and antiviral treatment required to achieve different prevalence and incidence reductions within 10 years for 3 chronic prevalence scenarios and the impact of HCV treatment if only delivered through OST programs. Multivariate and univariate sensitivity analyses were performed. Results. Large reductions (>45%) in HCV chronic prevalence over 10 years require HCV antiviral treatment. Scaling up OST and HCNSP substantially reduces the treatment rate required to achieve specific HCV prevalence reductions. If OST and HCNSP coverage were increased to 40% each (no coverage at baseline), then annually treating 10, 23, or 42 per 1000 PWID over 10 years would halve prevalence for 20%, 40%, or 60% baseline chronic HCV prevalences, respectively. Approximately 30% fewer treatments are necessary with new direct-acting antivirals. If coverage of OST and HCNSP is 50% at baseline, similar prevalence reductions require higher treatment rates for the same OST and HCNSP coverage. Conclusions. Combining antiviral treatment with OST with HCNSP is critical for achieving substantial reductions (>50%) in HCV chronic prevalence over 10 years. Empirical studies are required on how best to scale up antiviral treatment and combine treatment with other interventions.

Community-Associated Extended-Spectrum β-Lactamase–Producing Escherichia coli Infection in the United States

Abstract: (See the Editorial Commentary by Foxman on pages 649–51.) Escherichia coli that produces extended-spectrum β-lactamase (ESBL) has become widespread in hospitals around the world since the late 1980s [1]. ESBLs refer to a group of β-lactamases that have acquired the capacity to hydrolyze penicillins, cephalosporins, and aztreonam [1, 2]. Organisms that produce ESBLs are thus resistant to most broad-spectrum β-lactams with the exception of carbapenems. The genes for these ESBLs are frequently encoded on transferable plasmids that also encode resistance genes for other classes of antimicrobials [3]. Acquisition of such plasmids can thus promptly render an organism multidrug-resistant [4]. In fact, it is commonly observed that ESBL-producing organisms are resistant to multiple classes of antimicrobials including β-lactams, fluoroquinolones, aminoglycosides, and sulfonamides [1]. The global spread of community-associated methicillin-resistant Staphylococcus aureus infections has emerged as a major public concern in recent years [5]. On the other hand, infections due to resistant gram-negative organisms have largely been regarded as a healthcare-associated phenomenon. However, emergence of community-associated infections caused by ESBL-producing E. coli has been reported in multiple countries since the mid-2000s [6–8]. In each of these instances, the ESBLs associated with community-associated infection have largely been the CTX-M type, specifically CTX-M-15, distinct from the TEM and SHV types that were historically common [2]. In addition, the majority of CTX-M–producing E. coli belong to a specific clone that is defined by phylogenetic group B2, serotype O25:H4, and multilocus sequence typing (MLST) profile ST131, including in the United States [9, 10]. However, the extent and significance of community-associated infections caused by ESBL-producing E. coli in the United States have not been elucidated. The potential spread of ESBL-producing E. coli in the community poses a public health concern as well as a challenge to the management of community-associated infections, which are typically treated empirically with agents such as oral cephalosporins or fluoroquinolones without antimicrobial susceptibility testing. The main objective of this study was to describe the occurrence of ESBL-producing E. coli in the community, and to assess the clinical outcome of these patients at multiple hospitals and their affiliated clinics across the United States. We also sought to identify additional risk factors associated with healthcare-associated ESBL-producing E. coli cases in comparison with community-associated cases.

Congenital Cytomegalovirus Infection: Clinical Outcome

Abstract: Congenital cytomegalovirus (CMV) infection is a leading cause of hearing loss and neurologic disabilities in children worldwide. Infants with symptomatic congenital CMV infection at birth are at significantly increased risk for developing adverse long-term outcomes. The vast majority of infants with congenital CMV infection have no clinical findings at birth (asymptomatic infants), and about 10%-15% of these children develop long-term sequelae. Currently, predictors of adverse outcome in asymptomatic congenital CMV infection are not known, and it is important that future studies address this issue.

The Global Spread of Healthcare-Associated Multidrug-Resistant Bacteria: a Perspective from Asia

Abstract: Since antibiotics were first used, each new introduced class has been followed by a global wave of emergent resistance, largely originating in Europe and North America where they were first used. Methicillin-resistant Staphylococcus aureus spread from the United Kingdom and North America across Europe and then Asia over more than a decade. Vancomycin-resistant enterococci and Klebsiella pneumoniae carbapenemase-producing K. pneumoniae followed a similar path some 20 years later. Recently however, metallo-β-lactamases have originated in Asia. New Delhi metallo-β-lactamase-1 was found in almost every continent within a year of its emergence in India. Metallo-β-lactamase enzymes are encoded on highly transmissible plasmids that spread rapidly between bacteria, rather than relying on clonal proliferation. Global air travel may have helped facilitate rapid dissemination. As the antibiotic pipeline offers little in the short term, our most important tools against the spread of antibiotic resistant organisms are intensified infection control, surveillance, and antimicrobial stewardship.

Epidemiology, clinical presentation and antibody response to primary infection with herpes simplex virus type 1 and type 2 in young women

Abstract: Background. Herpes simplex virus infections type 1 (HSV-1) and type 2 (HSV-2) are common, but the epidemiology of HSV disease is changing. Methods. HSV-seronegative women, aged 18–30 years, who were in the control arm of the HERPEVAC Trial for Women were followed for 20 months for primary HSV infections. Results. Of the 3438 evaluable participants, 183 became infected with HSV: 127 (3.7%) with HSV-1 and 56 (1.6%) with HSV-2. The rate of infection for HSV-1 (2.5 per 100 person-years) was more than twice that for HSV-2 (1.1 per 100 person-years). Most infections (74% of HSV-1 and 63% of HSV-2) occurred without recognized signs or symptoms of herpes disease. The HSV-2 infection rate was 2.6 times higher in non-Hispanic black participants than in Hispanics and 5.5 times higher than in non-Hispanic whites (P < .001), while the HSV-1 infection rate was 1.7 times higher in non-Hispanic whites than non-Hispanic blacks. Younger participants (18–22 years) were more likely to acquire HSV-1 infections and less likely to develop recognized disease than older participants. Overall, 84% of recognized disease cases were genital. No differences were noted in the clinical manifestations of genital HSV-1 vs genital HSV-2 disease. The clinicians’ assessment that cases were caused by HSV was good when they assessed cases as clinically confirmed or unlikely (validated in 83% and 100% of cases, respectively). Conclusions. HSV-1 is now more common than HSV-2 as a cause of oral and genital mucosal infections in young women, but there are important age and race differences.

Increasing Failure of Miltefosine in the Treatment of Kala-azar in Nepal and the Potential Role of Parasite Drug Resistance, Reinfection, or Noncompliance

Abstract: Background. Miltefosine (MIL), the only oral drug for visceral leishmaniasis (VL), is currently the first-line therapy in the VL elimination program of the Indian subcontinent. Given the paucity of anti-VL drugs and the looming threat of resistance, there is an obvious need for close monitoring of clinical efficacy of MIL. Methods. In a cohort study of 120 VL patients treated with MIL in Nepal, we monitored the clinical outcomes up to 12 months after completion of therapy and explored the potential role of drug compliance, parasite drug resistance, and reinfection. Results. The initial cure rate was 95.8% (95% confidence interval [CI], 92.2−99.4) and the relapse rate at 6 and 12 months was 10.8% (95% CI, 5.2−16.4) and 20.0% (95% CI, 12.8−27.2) , respectively. No significant clinical risk factors of relapse apart from age <12 years were found. Parasite fingerprints of pretreatment and relapse bone marrow isolates within 8 patients were similar, suggesting that clinical relapses were not due to reinfection with a new strain. The mean promastigote MIL susceptibility (50% inhibitory concentration) of isolates from definite cures was similar to that of relapses. Although more tolerant strains were observed, parasite resistance, as currently measured, is thus not likely involved in MIL treatment failure. Moreover, MIL blood levels at the end of treatment were similar in cured and relapsed patients. Conclusions. Relapse in one-fifth of the MIL-treated patients observed in our study is an alarming signal for the VL elimination campaign, urging for further review and cohort monitoring.

Fourth European Conference on Infections in Leukaemia (ECIL-4): Guidelines for Diagnosis and Treatment of Human Respiratory Syncytial Virus, Parainfluenza Virus, Metapneumovirus, Rhinovirus, and Coronavirus

Abstract: Community-acquired respiratory virus (CARV) infections have been recognized as a significant cause of morbidity and mortality in patients with leukemia and those undergoing hematopoietic stem cell transplantation (HSCT). Progression to lower respiratory tract infection with clinical and radiological signs of pneumonia and respiratory failure appears to depend on the intrinsic virulence of the specific CARV as well as factors specific to the patient, the underlying disease, and its treatment. To better define the current state of knowledge of CARVs in leukemia and HSCT patients, and to improve CARV diagnosis and management, a working group of the Fourth European Conference on Infections in Leukaemia (ECIL-4) 2011 reviewed the literature on CARVs, graded the available quality of evidence, and made recommendations according to the Infectious Diseases Society of America grading system. Owing to differences in screening, clinical presentation, and therapy for influenza and adenovirus, ECIL-4 recommendations are summarized for CARVs other than influenza and adenovirus.

Clinical Outcomes With Extended or Continuous Versus Short-term Intravenous Infusion of Carbapenems and Piperacillin/Tazobactam: A Systematic Review and Meta-analysis

Abstract: We sought to study whether the better pharmacokinetic and pharmacodynamic (PK/PD) properties of carbapenems and piperacillin/tazobactam, when the duration of infusion is longer, were associated with lower mortality. PubMed and Scopus were searched for studies reporting on patients treated with extended (≥3 hours) or continuous (24 hours) versus short-term duration (20-60 minutes) infusions of carbapenems or piperacillin/tazobactam. Fourteen studies were included (1229 patients). Mortality was lower among patients receiving extended or continuous infusion of carbapenems or piperacillin/tazobactam compared to those receiving short-term (risk ratio [RR], 0.59; 95% confidence interval [CI], .41-.83). Patients with pneumonia who received extended or continuous infusion had lower mortality than those receiving short-term infusion (RR, 0.50; 95% CI, 0.26-0.96). Data for other specific infections were not available. The available evidence from mainly nonrandomized studies suggests that extended or continuous infusion of carbapenems or piperacillin/tazobactam was associated with lower mortality. Well-designed randomized controlled trials are warranted to confirm these findings before such approaches become widely used.

Extended-Spectrum β-Lactamase–Producing Escherichia coli From Retail Chicken Meat and Humans: Comparison of Strains, Plasmids, Resistance Genes, and Virulence Factors

Abstract: BACKGROUND: The worldwide prevalence of extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae is increasing rapidly both in hospitals and in the community. A connection between ESBL-producing bacteria in food animals, retail meat, and humans has been suggested. We previously reported on the genetic composition of a collection of ESBL-producing Escherichia coli (ESBL-EC) from chicken meat and humans from a restricted geographic area. Now, we have extended the analysis with plasmid replicons, virulence factors, and highly discriminatory genomic profiling methods. METHODS: One hundred forty-five ESBL-EC isolates from retail chicken meat, human rectal carriers, and blood cultures were analyzed using multilocus sequence typing, phylotyping, ESBL genes, plasmid replicons, virulence genes, amplified fragment length polymorphism (AFLP), and pulsed-field gel electrophoresis (PFGE). RESULTS: Three source groups overlapped substantially when their genetic composition was compared. A combined analysis using all variables yielded the highest resolution (Wilks lambda [Lambda]: 0.08). Still, a prediction model based on the combined data classified 40% of the human isolates as chicken meat isolates. AFLP and PFGE showed that the isolates from humans and chicken meat could not be segregated and identified 1 perfect match between humans and chicken meat. CONCLUSIONS: We found significant genetic similarities among ESBL-EC isolates from chicken meat and humans according to mobile resistance elements, virulence genes, and genomic backbone. Therefore, chicken meat is a likely contributor to the recent emergence of ESBL-EC in human infections in the study region. This raises serious food safety questions regarding the abundant presence of ESBL-EC in chicken meat.

Ampicillin Plus Ceftriaxone Is as Effective as Ampicillin Plus Gentamicin for Treating Enterococcus faecalis Infective Endocarditis

Abstract: (See the Editorial Commentary by Munita et al on pages 1269–72.) Background. The aim of this study was to compare the effectiveness of the ampicillin plus ceftriaxone (AC) and ampicillin plus gentamicin (AG) combinations for treating Enterococcus faecalis infective endocarditis (EFIE). Methods. An observational, nonrandomized, comparative multicenter cohort study was conducted at 17 Spanish and 1 Italian hospitals. Consecutive adult patients diagnosed of EFIE were included. Outcome measurements were death during treatment and at 3 months of follow-up, adverse events requiring treatment withdrawal, treatment failure requiring a change of antimicrobials, and relapse. Results. A larger percentage of AC-treated patients (n = 159) had previous chronic renal failure than AG-treated patients (n= 87) (33% vs 16%, P=.004), and AC patients had a higher incidence of cancer (18% vs 7%, P= .015), transplantation (6% vs 0%, P= .040), and healthcare-acquired infection (59% vs 40%, P= .006). Between AC and AGtreated EFIE patients, there were no differences in mortality while on antimicrobial treatment (22% vs 21%, P=.81) or at 3-month follow-up (8% vs 7%, P= .72), in treatment failure requiring a change in antimicrobials (1% vs 2%, P= .54), or in relapses (3% vs 4%, P=.67). However, interruption of antibiotic treatment due to adverse events was much more frequent in AG-treated patients than in those receiving AC (25% vs 1%, P< .001), mainly due to new renal failure (≥25% increase in baseline creatinine concentration; 23% vs 0%, P< .001). Conclusions. AC appears as effective as AG for treating EFIE patients and can be used with virtually no risk of renal failure and regardless of the high-level aminoglycoside resistance status of E. faecalis.