Active Tuberculosis After Solid Organ Transplantation in Individuals With Negative Pretransplant QuantiFERON-TB Gold Testing: A Case Series.

Active tuberculosis (TB) in solid organ transplant (SOT) recipients most commonly occurs due to reactivation of latent infection and is associated with poor clinical outcomes, including allograft loss and death. National transplant societies, including the American Society of Transplantation, recommend screening for latent TB prior to transplant, with treatment in the peritransplant setting to reduce the subsequent risk of TB reactivation. Though screening is traditionally conducted using laboratory-based assays, such as the QuantiFERON-TB Gold, false negatives may occur in SOT candidates due to anergy from end-stage organ dysfunction, highlighting the need for a multimodal diagnostic approach. In this case series, we describe the clinical characteristics and outcomes of 3 SOT recipients at the University of Pennsylvania with negative pretransplant QuantiFERON-TB Gold testing who subsequently developed active TB in the posttransplant setting, contributing to a growing body of knowledge regarding this challenging population. Each patient experienced a complicated clinical course that arose in part from the lack of diagnosis of TB prior to transplant. Because all had epidemiologic risk factors for TB, the findings of our study highlight the need for more individualized approaches to pretransplant TB screening.

HIV and organ transplantation.

PURPOSE OF REVIEW: This review summarizes the advances that have occurred over the past 2 years in organ transplantation in the setting of HIV. RECENT FINDINGS: Although HIV+ organ transplantation is both safe and effective, recent studies show that HIV+ patients continue to experience barriers to transplantation. In the United States, the HOPE Act is not only expected to increase the donor pool for HIV+ transplant candidates, but to also allow for the use of donors with false-positive HIV+ tests, which had previously been banned under the US National Organ Transplant Act. More effective HCV treatment, increased experience with heart and lung transplantation and the potential for increased organ availability with the inclusion of HIV+ organ donors have provided for significant advances in the care of these patients. SUMMARY: There continues to be progress in the field of organ transplantation in persons living with HIV. Future efforts should continue aiming to limit barriers to transplantation and improving the understanding of immunologic derangements seen in transplant recipients with HIV infection.

Inactivated varicella zoster vaccine in autologous haemopoietic stem-cell transplant recipients: an international, multicentre, randomised, double-blind, placebo-controlled trial.

BACKGROUND: Recipients of autologous haemopoietic stem-cell transplants (auto-HSCT) have an increased risk of herpes zoster and herpes zoster-related complications. The aim of this study was to establish the efficacy and safety of an inactivated varicella zoster vaccine for the prevention of herpes zoster after auto-HSCT. METHODS: In this randomised, double-blind, placebo-controlled phase 3 trial, participants were recruited from 135 medical centres (ie, stem-cell transplant centres and hospitals) in North America, South America, Europe, and Asia. Patients were eligible if they were aged 18 years or older, scheduled to receive an auto-HSCT within 60 days of enrolment, and had a history of varicella infection or were seropositive for antibodies to varicella zoster virus, or both. Exclusion criteria included a history of herpes zoster within the previous year of enrolment, and intended antiviral prophylaxis for longer than 6 months after transplantation. Participants were randomly assigned according to a central randomisation schedule generated by the trial statistician, to receive either the inactivated-virus vaccine from one of three consistency lots, a high-antigen lot, or placebo, stratified by age (<50 vs ≥50 years) and intended duration of antiviral prophylaxis after transplantation (≤3 months vs >3 to ≤6 months). Participants, investigators, trial staff, and the funder's clinical and laboratory personnel were masked to group assignment. Participants were given four doses of inactivated vaccine or placebo, with the first dose 5-60 days before auto-HSCT, and the second, third, and fourth doses at about 30, 60, and 90 days after transplantation. The primary efficacy endpoint was the incidence of herpes zoster, confirmed by PCR or adjudication by a masked clinical committee, or both, assessed in all participants randomly assigned to the vaccine consistency lot group or placebo group who received at least one dose of vaccine and had auto-HSCT. Safety was assessed in all randomised participants who received at least one dose of vaccine and had follow-up data. A prespecified vaccine efficacy success criterion required the lower bound of the 95% CI be higher than 25% for the relative reduction of the hazard ratio of herpes zoster infection in participants given the vaccine from one of the consistency lots compared with those given placebo. This trial is registered on ClinicalTrials.gov (NCT01229267) and EudraCT (2010-020150-34). FINDINGS: Between Dec 7, 2010, and April 25, 2013, 560 participants were randomly assigned to the vaccine consistency lot group, 106 to the high-antigen lot group, and 564 to the placebo group. 249 (44%) of patients in the vaccine consistency lot group, 35 (33%) in the high-antigen lot group, and 220 (39%) in the placebo group discontinued before study end, mostly because of death or withdrawal. 51 participants were excluded from the primary efficacy endpoint analyses because they did not undergo auto-HSCT or were not vaccinated, or both (22 [4%] in the vaccine consistency lot group, and 29 [5%] in the placebo group). Mean follow-up for efficacy was 2·4 years (SD 1·3) in the vaccine consistency lot group and 2·3 years (SD 1·3) in the placebo group. 42 (8%) of 538 participants in the vaccine consistency lot group (32·9 per 1000 person-years) and 113 (21%) of 535 in the placebo group (91·9 per 1000 person-years) had a confirmed case of herpes zoster. The estimated vaccine efficacy was 63·8% (95% CI 48·4-74·6), meeting the pre-specified success criterion. For the combined vaccine groups versus the placebo group, the proportion of patients with serious adverse events (216 [33%] of 657 vs 181 [33%] of 554; risk difference 0·2%, 95% CI -5·1 to 5·5) and serious vaccine-related adverse events (five [1%] vs five [1%]; risk difference 0·1%, -1·4 to 1·1) were similar. Vaccine-related injection-site adverse events occurred more frequently in participants given vaccine than those given placebo (191 [29%] vs 36 [7%]; risk difference 22·6%, 95% CI 18·5-26·6; p<0·0001). INTERPRETATION: This study shows for the first time in a large phase 3 trial that early vaccination of auto-HSCT recipients during the peri-transplant period can be effective for the prevention of an opportunistic infection like herpes zoster and that the vaccine is well tolerated. FUNDING: Merck & Co., Inc.

Herpes Zoster in Autologous Hematopoietic Cell Transplant Recipients in the Era of Acyclovir or Valacyclovir Prophylaxis and Novel Treatment and Maintenance Therapies.

The epidemiology of herpes zoster (HZ) in contemporary autologous hematopoietic cell transplant (HCT) recipients, and the impact of acyclovir (ACV)/valacyclovir (VACV) prophylaxis, is not well described. In this observational study from 2002 to 2010, we retrospectively identified 1000 varicella zoster virus (VZV)-seropositive autologous HCT recipients with up to 5 years of follow-up. The incidence of HZ and use of ACV/VACV prophylaxis were determined through review of medical records and mailed questionnaires. Risk factors for HZ were determined by multivariable Cox regression. Over a period of 5 years after autologous HCT, 194 patients developed at least 1 HZ episode, with a cumulative incidence of 21%; 159 of 194 (82%) were not on prophylaxis at the time of HZ. A second episode of HZ occurred in 31 of 194 (16%) patients. Patients taking ACV/VACV had reduced risk for HZ (adjusted hazard ratio [aHR], .59; 95% confidence interval [CI], .37 to .91), whereas those older than the median age (≥55.5 years) had increased risk (aHR, 1.42; 95% CI, 1.05 to 1.9). Disseminated VZV was reported in 8% and postherpetic neuralgia in 13% of patients. We demonstrate a high burden of HZ late after autologous HCT, despite long-term antiviral prophylaxis. Improved prevention strategies are needed to provide sustained protection against HZ after autologous HCT.

Successful control of a norovirus outbreak among attendees of a hospital teaching conference.

We report an outbreak of norovirus gastroenteritis after a hospital teaching conference, and describe the specific measures instituted by the infection control team. No secondary cases of norovirus infection were identified among hospital staff or patients. In a case-control study, we identified multiple food source contamination as the source of the outbreak. Our report highlights the potential success of a multifaceted infection control strategy in preventing the transmission of norovirus in health care settings.

Decreased post-transplant survival among heart transplant recipients with pre-transplant hepatitis C virus positivity.

BACKGROUND: Transplant centers are reluctant to perform heart transplantation in patients with hepatitis C virus (HCV) infection because augmented immunosuppression could potentially increase mortality. However, there have been few studies examining whether HCV infection reduces survival after heart transplantation. METHODS: We used data from the the U.S. Scientific Registry of Transplant Recipients to perform a multicenter cohort study evaluating the association between recipient pre-transplant HCV status and survival after heart transplantation. Adults undergoing heart transplantation between January 1, 1993 and December 31, 2007 were eligible to participate. RESULTS: Among 20,687 heart transplant recipients (443 HCV-positive and 20,244 HCV-negative) at 103 institutions followed for a mean of 5.6 years, mortality was higher among HCV-positive than HCV-negative recipients (177 [40%] vs 6,367 [31.5%]; p = 0.0001). After matching on propensity score, hospital and gender, the hazard ratio (HR) of death for HCV-positive heart transplant recipients was 1.32 (95% confidence interval [CI] 1.08 to 1.61). Mortality rates were higher among HCV-positive heart transplant recipients at 1 year (9.4% vs 8.2%), 5 years (26.3% vs 22.9%), 10 years (53.1% vs 43.4%) and 15 years (74.8% vs 62.3%) post-transplantation. HRs did not vary by gender or overall number of heart transplantations performed at the center. CONCLUSIONS: Pre-transplant HCV positivity is associated with decreased survival after heart transplantation.

Economic value of dispensing home-based preoperative chlorhexidine bathing cloths to prevent surgical site infection.

OBJECTIVE: To estimate the economic value of dispensing preoperative home-based chlorhexidine bathing cloth kits to orthopedic patients to prevent surgical site infection (SSI). METHODS: A stochastic decision-analytic computer simulation model was developed from the hospital's perspective depicting the decision of whether to dispense the kits preoperatively to orthopedic patients. We varied patient age, cloth cost, SSI-attributable excess length of stay, cost per bed-day, patient compliance with the regimen, and cloth antimicrobial efficacy to determine which variables were the most significant drivers of the model's outcomes. RESULTS: When all other variables remained at baseline and cloth efficacy was at least 50%, patient compliance only had to be half of baseline (baseline mean, 15.3%; range, 8.23%-20.0%) for chlorhexidine cloths to remain the dominant strategy (ie, less costly and providing better health outcomes). When cloth efficacy fell to 10%, 1.5 times the baseline bathing compliance also afforded dominance of the preoperative bath. CONCLUSIONS: The results of our study favor the routine distribution of bathing kits. Even with low patient compliance and cloth efficacy values, distribution of bathing kits is an economically beneficial strategy for the prevention of SSI.

The use of antimicrobial agents after diagnosis of viral respiratory tract infections in hospitalized adults: antibiotics or anxiolytics?

OBJECTIVE: Because extensive antibiotic use by inpatients has been associated with the development of multidrug-resistant organisms, we aimed to determine which variables were associated with the use of antibiotics after viral respiratory tract infection diagnosis among adult patients admitted to the hospital with respiratory symptoms. METHODS: A retrospective cohort study was conducted at 2 affiliated urban hospitals in Pennsylvania. We identified all adult patients admitted to the hospital during the period from November 1, 2005, through August 1, 2007, with a viral assay positive for influenza A or B, parainfluenza, adenovirus, or respiratory syncytial virus. Among these patients, we identified those who received antibiotics after the diagnosis of viral RTI. Data on demographics; comorbidities; and physical examination, laboratory, and radiographic findings were ascertained to identify risk factors for antimicrobial use among these patients. RESULTS: A total of 196 hospitalized patients with positive viral assay results were included; 125 of 131 patients administered antibiotics continued to receive them after viral RTI diagnosis. Among 52 patients with an abnormal chest radiograph, 46 continued antibiotic therapy. An abnormal chest radiograph was independently associated with continued antibiotic use (adjusted odds ratio, 4.28 [95% confidence interval, 1.71-10.77]; P = .002). However, the majority of patients (79 of 125 [63%]) who continued antibiotic therapy had normal chest imaging findings. Eight patients (6%) who continued antibiotic therapy and no patients who stopped developed C. difficile infection (95% CI, 1.5-∞; P = .05), but there was no significant difference in length of stay or mortality. CONCLUSIONS: Antibiotics are commonly used to treat hospitalized patients with known acute viral RTIs. Continued use is strongly associated with abnormal radiograph findings at admission. However, the reasons for continuation of antibiotics in the treatment of the majority of patients with normal radiographs are unclear and may represent inappropriate use.

Systematic review and cost analysis comparing use of chlorhexidine with use of iodine for preoperative skin antisepsis to prevent surgical site infection.

OBJECTIVE: To compare use of chlorhexidine with use of iodine for preoperative skin antisepsis with respect to effectiveness in preventing surgical site infections (SSIs) and cost. METHODS: We searched the Agency for Healthcare Research and Quality website, the Cochrane Library, Medline, and EMBASE up to January 2010 for eligible studies. Included studies were systematic reviews, meta-analyses, or randomized controlled trials (RCTs) comparing preoperative skin antisepsis with chlorhexidine and with iodine and assessing for the outcomes of SSI or positive skin culture result after application. One reviewer extracted data and assessed individual study quality, quality of evidence for each outcome, and publication bias. Meta-analyses were performed using a fixed-effects model. Using results from the meta-analysis and cost data from the Hospital of the University of Pennsylvania, we developed a decision analytic cost-benefit model to compare the economic value, from the hospital perspective, of antisepsis with iodine versus antisepsis with 2 preparations of chlorhexidine (ie, 4% chlorhexidine bottle and single-use applicators of a 2% chlorhexidine gluconate [CHG] and 70% isopropyl alcohol [IPA] solution), and also performed sensitivity analyses. RESULTS: Nine RCTs with a total of 3,614 patients were included in the meta-analysis. Meta-analysis revealed that chlorhexidine antisepsis was associated with significantly fewer SSIs (adjusted risk ratio, 0.64 [95% confidence interval, [0.51-0.80]) and positive skin culture results (adjusted risk ratio, 0.44 [95% confidence interval, 0.35-0.56]) than was iodine antisepsis. In the cost-benefit model baseline scenario, switching from iodine to chlorhexidine resulted in a net cost savings of $16-$26 per surgical case and $349,904-$568,594 per year for the Hospital of the University of Pennsylvania. Sensitivity analyses showed that net cost savings persisted under most circumstances. CONCLUSIONS: Preoperative skin antisepsis with chlorhexidine is more effective than preoperative skin antisepsis with iodine for preventing SSI and results in cost savings.

Clinical and economic outcomes of decreased fluconazole susceptibility in patients with Candida glabrata bloodstream infections.

BACKGROUND: The impact of reduced fluconazole susceptibility on clinical and economic outcomes in patients with Candida glabrata bloodstream infections (BSI) is unknown. METHODS: A retrospective cohort study was conducted to evaluate 30-day inpatient mortality and postculture hospital charges in patients with C glabrata BSI with decreased fluconazole susceptibility (minimum inhibitory concentration [MIC] ≥ 16 µg/mL) versus fluconazole-susceptible C glabrata BSI (MIC ≤ 8 µg/mL). These analyses were adjusted for demographics, comorbidities, and time at risk. Secondary analyses limited the C glabrata group with decreased fluconazole susceptibility to MIC ≥ 64 µg/mL. RESULTS: There were 45 (31%) deaths among 144 enrolled patients: 19 deaths (25%) among 76 patients with C glabrata BSI with decreased fluconazole susceptibility and 26 deaths (38%) among 68 patients with fluconazole-susceptible C glabrata BSI. Decreased fluconazole susceptibility was not independently associated with increased 30-day inpatient mortality (adjusted odds ratio, .60; 95% confidence interval (CI): .26-1.35; P = 0.22) or hospital charges (multiplicative change in hospital charges, .93; 95% CI: .60-1.43; P = 0.73). Older age was associated with increased mortality and increased time at risk was associated with increased hospital charges. CONCLUSION: Crude mortality rates remain high in patients with C glabrata BSI. However, decreased fluconazole susceptibility was not associated with increased mortality or hospital charges.

Virologic characterization of multidrug-resistant cytomegalovirus infection in 2 transplant recipients treated with maribavir.

The experimental cytomegalovirus UL97 kinase inhibitor maribavir was used to treat 2 cases of infection in which viral mutations that conferred ganciclovir and foscarnet resistance had evolved sequentially. In one case, viral shedding was cleared without evidence of maribavir resistance in an isolate obtained after therapy. In the other case, a high-grade viremia was initially reduced 50-fold but rebounded 2 months later, coincident with the emergence of viral UL97 mutations T409M and H411Y, which confer maribavir resistance. The relatively rapid onset of maribavir resistance probably resulted from incomplete viral suppression in an immunosuppressed host with a high viral load.

A systematic review to inform institutional decisions about the use of extracorporeal membrane oxygenation during the H1N1 influenza pandemic.

OBJECTIVES: To systematically evaluate the effect of extracorporeal membrane oxygenation on survival in adults with acute respiratory failure and to help inform institutional decisions about implementing an extracorporeal membrane oxygenation program or transferring patients to experienced extracorporeal membrane oxygenation centers during the H1N1 influenza pandemic. DATA SOURCES: National Guideline Clearinghouse, MEDLINE, EMBASE, Agency for Healthcare Research and Quality Evidence-based Practice reports, National Institute for Health and Clinical Excellence, Cochrane Library, International Network of Agencies for Health Technology Assessment, and citation review. STUDY SELECTION: Studies of extracorporeal membrane oxygenation in adult acute respiratory failure, reporting mortality rates for at least 10 patients in extracorporeal membrane oxygenation and nonextracorporeal membrane oxygenation groups. DATA EXTRACTION: Mortality rates were abstracted for all patients and for patients with influenza. Risk ratios were meta-analyzed using random-effects methods and assessed for heterogeneity. DATA SYNTHESIS: There are no evidence-based clinical guidelines on the use of extracorporeal membrane oxygenation in patients with influenza. Three randomized controlled trials and three cohort studies evaluated extracorporeal membrane oxygenation in patients with acute respiratory failure; none reported specifically on patients with influenza. Meta-analysis of the randomized controlled trials revealed significant heterogeneity in risk of mortality. The summary risk ratio found by the meta-analysis was 0.93 (95% confidence interval, 0.71 to 1.22). The most recent trial found a reduction in mortality and severe disability at 6 months among patients in whom extracorporeal membrane oxygenation was considered. Observational studies suggest that extracorporeal membrane oxygenation for acute respiratory failure resulting from viral pneumonia is associated with improved mortality compared with other etiologies of acute respiratory failure. CONCLUSIONS: The best evidence to guide decisions regarding the use of extracorporeal membrane oxygenation for patients with influenza stems from trials of extracorporeal membrane oxygenation for acute respiratory failure of all etiologies, among which significant heterogeneity exists, and from case series describing outcomes of extracorporeal membrane oxygenation in patients with influenza. Thus, there is insufficient evidence to provide a recommendation for extracorporeal membrane oxygenation use among patients with respiratory failure resulting from influenza. However, clinicians should consider extracorporeal membrane oxygenation within the context of other salvage therapies for acute respiratory failure.

Risk factors for fluconazole resistance in patients with Candida glabrata bloodstream infection: potential impact of control group selection on characterizing the association between previous fluconazole use and fluconazole resistance.

BACKGROUND: Although Candida glabrata is an emerging infection, risk factors for fluconazole resistance in patients with C glabrata bloodstram infection (BSI) have not been well elucidated. METHODS: A case-control study was conducted to evaluate the primary risk factor of interest, previous fluconazole use, adjusting for demographics, comorbidities, time at risk, and antimicrobial exposure and assessing for effect modification. Secondary analyses were performed limiting the case group to C glabrata BSIs with a minimum inhibitory concentration (MIC) > or =64 microg/mL. RESULTS: Previous fluconazole use was not a significant risk factor for fluconazole-resistant C glabrata BSI in primary analysis (adjusted odds ratio [aOR], 1.5; 95% confidence interval [CI], 0.7-3.2) but was borderline significant in secondary analysis (aOR, 3.2; 95% CI, 0.9-11.3). Increased time at risk was an independent risk factor in primary (aOR, 1.02; 95% CI, 1.002-1.04) and secondary analyses (aOR, 1.03; 95% CI, 1.004-1.06). CONCLUSION: Increased time at risk was the only significant risk factor for fluconazole resistance. Future studies are needed to further evaluate the relationship between previous fluconazole use and fluconazole-resistant C glabrata BSI isolates with MIC > or =64 microg/mL.

Treating viral respiratory tract infections with antibiotics in hospitals: no longer a case of mistaken identity.

Widespread use of antibiotics in hospitalized patients contributes to the development of multidrug resistant organisms that make many infections increasingly difficult to treat. Despite calls to prescribe antibiotics judiciously, many physicians continue to order antibiotics for inpatients who do not need them. This Issue Brief investigates antibiotic use in hospitalized adults with a confirmed viral infection, a group of patients that may not benefit from such therapy. Understanding the factors that lead to inappropriate antibiotic use may help change clinical practice and limit antibiotic resistance.

Role of matching in case-control studies of antimicrobial resistance.

Of 57 case-control studies of antimicrobial resistance, matching was used in 23 (40%). Matched variables differed substantially across studies. Of these 23 matched case-control studies, 12 (52%) justified the use of matching, and 9 (39%) noted the strengths or limitations of this approach. Analysis that accounted for matching was performed in only 52% of the case-control studies.

Risk factors for fluconazole-resistant Candida glabrata bloodstream infections.

BACKGROUND: Bloodstream infections (BSIs) caused by Candida glabrata have increased substantially. Candida glabrata is often associated with resistance to fluconazole therapy. However, to our knowledge, risk factors for fluconazole-resistant C glabrata BSIs have not been studied. METHODS: A case-case-control study was conducted at 3 hospitals from January 1, 2003, to May 31, 2007. The 2 case groups included patients with fluconazole-resistant C glabrata BSIs (minimum inhibitory concentration > or =16 microg/mL) and patients with fluconazole-susceptible C glabrata BSIs (minimum inhibitory concentration < or =8 microg/mL). Hospitalized patients without C glabrata BSIs were randomly selected for inclusion in the control group and were frequency matched to cases on the basis of time at risk. Two case-control studies were performed using this shared control group. The primary risk factor of interest, previous fluconazole use, was evaluated at multivariate analyses, adjusting for demographic data, comorbid conditions, and antimicrobial exposures. RESULTS: We included 76 patients with fluconazole-resistant C glabrata BSIs, 68 patients with fluconazole-susceptible C glabrata BSIs, and 512 control patients. Previous fluconazole use (adjusted odds ratio [95% confidence interval], 2.3 [1.3-4.2]) and linezolid use (4.6 [2.2-9.3]) were independent risk factors for fluconazole-resistant C glabrata BSIs; previous cefepime use (2.2 [1.2-3.9]) and metronidazole use (2.0 [1.1-3.5]) were independent risk factors for fluconazole-susceptible C glabrata BSIs. CONCLUSIONS: Previous fluconazole use is a significant risk factor for health care-associated fluconazole-resistant C glabrata BSIs. Future studies will be needed to evaluate the effect of decreasing fluconazole use on rates of fluconazole-resistant C glabrata BSIs.