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Lung transplant recipients are at greater risk of respiratory viral infections as compared to other solid organ transplant recipients due to constant exposure of the allograft to the external environment. There are no standardized methods for surveillance, prevention, or treatment of these infections despite their association with increased morbidity and mortality. Various studies have linked respiratory viral infections with acute cellular rejection and chronic allograft dysfunction, and emerging data indicates a role in antibody mediated rejection. This paper will review the prevalence and impact of community acquired respiratory viruses in lung transplant recipients, review the evidence linking these viral infections to long term graft dysfunction and rejection, describe existing strategies for surveillance and prevention, and list the currently available, and promising investigational therapies.

Macrophage migration inhibitory factor (MIF) is an immune mediator encoded in a functionally polymorphic locus. We found the genotype conferring low expression of MIF to be enriched in a cohort of 180 patients with gram-negative bacteremia, compared with 229 healthy controls (odds ratio [OR], 2.4; P = .04), an association that was more pronounced in older adults (OR, 4.6; P = .01). Among older subjects, those with low expression of MIF demonstrated 20% reduced MIF production from lipopolysaccharide-stimulated peripheral blood monocytes and 30% lower monocyte surface Toll-like receptor 4, compared with those with high expression. Our work suggests that older adults with low expression of MIF may be predisposed to hyporesponsiveness to lipopolysaccharide and gram-negative bacterial infection.

The emergence of carbapenem resistance in Enterobacteriaceae is an important threat to global health. Reported outcomes of infections with carbapenem-resistant Enterobacteriaceae (CRE) are poor. Very few options remain for the treatment of these virulent organisms. Antibiotics which are currently in use to treat CRE infections include aminoglycosides, polymyxins, tigecycline, fosfomycin, and temocillin. In addition, the role of combination therapy, including carbapenem containing regimens, remains to be defined. There are several important concerns regarding all of these treatment options such as limited efficacy, increasing reports of resistance, and specific toxicities. Data from retrospective studies favor combination therapy over single-agent therapy for the treatment of CRE bloodstream infections. In summary, new antibiotics are greatly needed, as is additional prospective research.

Purpose Case reports of treatment failure with standard-dose daptomycin (6 mg/kg) have recently surfaced in vancomycin-resistant Enterococcus (VRE) bloodstream infection (BSI) episodes with daptomycin MICs of 3 to 4 mg/L. The clinical implications of daptomycin MICs of 3 to 4 mg/L in VRE BSIs have not been elucidated. Methods We performed a single institutional retrospective analysis of adult stem cell transplant recipients and patients with hematologic malignancies diagnosed with VRE BSI from 2006 to 2014 and compared outcomes between those with daptomycin MICs of 3 to 4 mg/L those with 2 mg/L, as determined by Etest. Findings Forty-two daptomycin-treated VRE BSI episodes, all due to Enterococcus faecium were identified; 19 episodes with daptomycin MICs of 3 to 4 mg/L and 23 episodes with a daptomycin MIC of 2 mg/L. Patients in the higher daptomycin MIC group were more likely to be male, to be stem cell transplant recipients, and to have received high-dose daptomycin treatment (>6 mg/kg). In unadjusted analyses, microbiological failure in the daptomycin MICs 3 to 4 mg/L versus 2 mg/L groups (odds ratio=1.79, 95% CI, 0.52–6.11; P = 0.35), the median duration of bacteremia (4 days in daptomycin MICs 3–4 mg/L vs 3 days in daptomycin MIC 2 mg/L; P = 0.18) and all-cause 30-day mortality (21% in daptomycin MICs 3–4 mg/L vs 35% in daptomycin MIC 2 mg/L group; P = 0.49) were not different. In adjusted analyses, the association between higher Pitt bacteremia scores and all-cause 30-day mortality was statistically significant ( P = 0.0006), whereas the association between daptomycin MICs of 3 to 4 mg/L and all-cause 30-day mortality approached statistical significance ( P = 0.06). Implications Duration of bacteremia and microbiological failure rates did not differ by daptomycin MICs in VRE BSI episodes in our patients, composed of adult stem cell transplant recipients and patients with hematologic malignancies. There was a nonsignificant trend in multivariable analysis suggesting that all-cause 30-day mortality was lower in patients whose VRE bloodstream isolates were with daptomycin MICs of 3 to 4 mg/L.

Background: Polymyxins including colistin are an important "last-line" treatment for infections caused by carbapenem-resistant Klebsiella pneumoniae (CRKp). Increasing use of colistin has led to resistance to this cationic antimicrobial peptide. Methods: A cohort nested within the Consortium on Resistance against Carbapenems in Klebsiella pneumoniae (CRACKLE) was constructed of patients with infection, or colonization with CRKp isolates tested for colistin susceptibility during the study period of December, 2011 to October, 2014. Reference colistin resistance determination as performed by broth macrodilution was compared to results from clinical microbiology laboratories (Etest) and to polymyxin resistance testing. Each patient was included once, at the time of their first colistin-tested CRKp positive culture. Time to 30-day in-hospital all-cause mortality was evaluated by Kaplan-Meier curves and Cox proportional hazard modeling. Results: In 246 patients with CRKp, 13% possessed ColR CRKp. ColR was underestimated by Etest (very major error rate = 35%, major error rate = 0.4%). A variety of rep-PCR strain types were encountered in both the ColS and the ColR groups. Carbapenem resistance was mediated primarily by blaKPC-2 (46%) and blaKPC-3 (50%). ColR was associated with increased hazard for in-hospital mortality (aHR 3.48; 95% confidence interval, 1.73-6.57; P < .001). The plasmid-associated ColR genes, mcr-1 and mcr-2 were not detected in any of the ColR CRKp. Conclusions: In this cohort, 13% of patients with CRKp presented with ColR CRKp. The apparent polyclonal nature of the isolates suggests de novo emergence of ColR in this cohort as the primary factor driving ColR. Importantly, mortality was increased in patients with ColR isolates.

Ceftolozane/tazobactam and ceftazidime/avibactam are 2 novel β-lactam/β-lactamase combination antibiotics. The antimicrobial spectrum of activity of these antibiotics includes multidrug-resistant (MDR) gram-negative bacteria (GNB), including Pseudomonas aeruginosa. Ceftazidime/avibactam is also active against carbapenem-resistant Enterobacteriaceae that produce Klebsiella pneumoniae carbapenemases. However, avibactam does not inactivate metallo-β-lactamases such as New Delhi metallo-β-lactamases. Both ceftolozane/tazobactam and ceftazidime/avibactam are only available as intravenous formulations and are dosed 3 times daily in patients with normal renal function. Clinical trials showed noninferiority to comparators of both agents when used in the treatment of complicated urinary tract infections and complicated intra-abdominal infections (when used with metronidazole). Results from pneumonia studies have not yet been reported. In summary, ceftolozane/tazobactam and ceftazidime/avibactam are 2 new second-generation cephalosporin/β-lactamase inhibitor combinations. After appropriate trials are conducted, they may prove useful in the treatment of MDR GNB infections. Antimicrobial stewardship will be essential to preserve the activity of these agents.

Multidrug resistant (MDR) bacteria are one of the most important current threats to public health. Typically, MDR bacteria are associated with nosocomial infections. However, some MDR bacteria have become quite prevalent causes of community-acquired infections. The spread of MDR bacteria into the community is a crucial development, and is associated with increased morbidity, mortality, healthcare costs and antibiotic use. Factors associated with community dissemination of MDR bacteria overlap but are distinct from those associated with nosocomial spread. Community-associated (CA) MDR bacteria have an antibiotic resistance phenotype that is stable in the absence of antibiotic pressure of the type normally observed in hospitals or nursing homes. An exception to this rule may be those CA-MDR bacteria, of which the prevalence is driven by the presence of antibiotics in the food chain. Additionally, the colonization of otherwise healthy hosts is a common characteristic of CA-MDR bacteria. However, subtle immune deficiencies may still be present in the subjects colonized with specific CA-MDR bacteria. Methicillin-resistant S. aureus (MRSA) is the most prevalent of CA-MDR bacteria. CA-MRSA also has the greatest impact on morbidity and mortality. The main threat on the horizon is represented by Enterobacteriaceae. The production of extended spectrum β-lactamases in Enterobacteriaceae encountered in the community is becoming increasingly prevalent. Of great concern is the potential for the acquisition of carbapenemase genes in CA-Enterobacteriaceae. Prevention of further community spread of MDR bacteria is of the utmost importance, and will require a multi-disciplinary approach involving all stakeholders.

Next-generation sequencing (NGS) analysis has emerged as a promising molecular epidemiological method for investigating health care-associated outbreaks. Here, we used NGS to investigate a 3-year outbreak of multidrug-resistant Acinetobacter baumannii (MDRAB) at a large academic burn center. A reference genome from the index case was generated using de novo assembly of PacBio reads. Forty-six MDRAB isolates were analyzed by pulsed-field gel electrophoresis (PFGE) and sequenced using an Illumina platform. After mapping to the index case reference genome, four samples were excluded due to low coverage, leaving 42 samples for further analysis. Multilocus sequence types (MLST) and the presence of acquired resistance genes were also determined from the sequencing data. A transmission network was inferred from genomic and epidemiological data using a Bayesian framework. Based on single-nucleotide variant (SNV) differences, this MDRAB outbreak represented three sequential outbreaks caused by distinct clones. The first and second outbreaks were caused by sequence type 2 (ST2), while the third outbreak was caused by ST79. For the second outbreak, the MLST and PFGE results were discordant. However, NGS-based SNV typing detected a recombination event and consequently enabled a more accurate phylogenetic analysis. The distribution of resistance genes varied among the three outbreaks. The first- and second-outbreak strains possessed a bla OXA-23-like group, while the third-outbreak strains harbored a bla OXA-40-like group. NGS-based analysis demonstrated the superior resolution of outbreak transmission networks for MDRAB and provided insight into the mechanisms of strain diversification between sequential outbreaks through recombination.

Klebsiella pneumoniae carbapenemase (KPC)-producing Enterobacter cloacae has been recently recognized in the United States. Whole-genome sequencing (WGS) has become a useful tool for analysis of outbreaks and for determining transmission networks of multidrug-resistant organisms in health care settings, including carbapenem-resistant Enterobacteriaceae (CRE). We experienced a prolonged outbreak of CRE E. cloacae and K. pneumoniae over a 3-year period at a large academic burn center despite rigorous infection control measures. To understand the molecular mechanisms that sustained this outbreak, we investigated the CRE outbreak isolates by using WGS. Twenty-two clinical isolates of CRE, including E. cloacae ( n = 15) and K. pneumoniae ( n = 7), were sequenced and analyzed genetically. WGS revealed that this outbreak, which seemed epidemiologically unlinked, was in fact genetically linked over a prolonged period. Multiple mechanisms were found to account for the ongoing outbreak of KPC-3-producing E. cloacae and K. pneumoniae . This outbreak was primarily maintained by a clonal expansion of E. cloacae sequence type 114 (ST114) with distribution of multiple resistance determinants. Plasmid and transposon analyses suggested that the majority of bla KPC-3 was transmitted via an identical Tn 4401 b element on part of a common plasmid. WGS analysis demonstrated complex transmission dynamics within the burn center at levels of the strain and/or plasmid in association with a transposon, highlighting the versatility of KPC-producing Enterobacteriaceae in their ability to utilize multiple modes to resistance gene propagation.

Fosfomycin has shown promising in vitro activity against multidrug-resistant (MDR) urinary pathogens; however, clinical data are lacking. We conducted a retrospective chart review to describe the microbiological and clinical outcomes of urinary tract infections (UTIs) with MDR pathogens treated with fosfomycin tromethamine. Charts for 41 hospitalized patients with a urine culture for an MDR pathogen who received fosfomycin tromethamine from 2006 to 2010 were reviewed. Forty-one patients had 44 urinary pathogens, including 13 carbapenem-resistant Klebsiella pneumoniae (CR-Kp), 8 Pseudomonas aeruginosa , and 7 vancomycin-resistant Enterococcus faecium (VRE) isolates, 7 extended-spectrum beta-lactamase (ESBL) producers, and 9 others. In vitro fosfomycin susceptibility was 86% (median MIC, 16 μg/ml; range, 0.25 to 1,024 μg/ml). Patients received an average of 2.9 fosfomycin doses per treatment course. The overall microbiological cure was 59%; failure was due to either relapse (24%) or reinfection UTI (17%). Microbiological cure rates by pathogen were 46% for CR-Kp, 38% for P. aeruginosa , 71% for VRE, 57% for ESBL producers, and 100% for others. Microbiological cure ( n = 24) was compared to microbiological failure ( n = 17). There were significantly more solid organ transplant recipients in the microbiological failure group (59% versus 21%; P = 0.02). None of the patients in the microbiological cure group had a ureteral stent, compared to 24% of patients within the microbiological failure group ( P = 0.02). Fosfomycin demonstrated in vitro activity against UTIs due to MDR pathogens. For CR-KP, there was a divergence between in vitro susceptibility (92%) and microbiological cure (46%). Multiple confounding factors may have contributed to microbiological failures, and further data regarding the use of fosfomycin for UTIs due to MDR pathogens are needed.

Context.—Endovascular infection is an uncommon but devastating manifestation of histoplasmosis, which is often diagnosed late in disease. Objectives.—To evaluate the clinical and pathologic characteristics of patients with endovascular infections caused by Histoplasma capsulatum. Design.—All cases of patients with documented endovascular histoplasmosis at a single tertiary care center in an endemic region during the period 1993–2010 were reviewed. Results.—Patients presented with a subacute febrile illness and a history of endovascular devices. All patients had positive Histoplasma serology. Routine bacterial culture results were negative for all patients. In addition to yeast forms typical of histoplasmosis, pathologic findings also revealed mycelial forms in 4 of 5 patients. Inflammation was scant. Urinary antigen detection was positive in 4 of 5 patients and Histoplasma blood culture results were positive for 3 of 5 patients. Four patients were treated with a combination of surgical and medical therapy, which consisted of amphotericin B followed by itraconazole; these 4 patients had complete resolution of symptoms and no documented relapse. One patient died before planned surgery. Conclusions.—Histoplasma capsulatum endovascular infections are clinically characterized by a subacute febrile illness with negative bacterial cultures in patients with prosthetic endografts or valves. Noninvasive diagnostics are often the initial clue to the diagnosis. Combined medical and surgical treatment is associated with survival. On histopathologic examination both mycelial and yeast forms are often observed, with absent to minimal tissue inflammatory reaction.

Objectives: To describe the influence of age on clinical features of histoplasmosis. Design: Retrospective single-center cohort study. Setting: Large tertiary care center. Participants: All individuals who met criteria for probable or proven histoplasmosis between 1998 and 2008. Measurements: Participants were divided into the following categories of histoplasmosis: acute pulmonary, chronic pulmonary, asymptomatic, disseminated, and other. Correcting for immune status, the influence of age at diagnosis on presentation, diagnosis, imaging, treatment, and all-cause mortality was evaluated. Results: In 347 participants with histoplasmosis, a number of characteristics were associated with age when evaluating participants according to diagnostic category. An age-associated increase in asymptomatic histoplasmosis was observed (P < .001). In symptomatic pulmonary histoplasmosis, older adults were less likely to present with chest pain (P < .001) and less likely to have hilar lymphadenopathy on imaging (P = .04). Lower rates of seropositivity with older age were seen in asymptomatic (P = .04) but not other forms of histoplasmosis. Cavitary disease was associated with older age in chronic pulmonary histoplasmosis (P = .05). Treatment did not change with age. All-cause mortality at 6 months was 4% and was associated with older age (P = .02). Conclusion: Although most studied characteristics of histoplasmosis were similar, notable age-related differences were present. Chronic cavitary disease and asymptomatic histoplasmosis were more common with older age. In acute histoplasmosis, the lack of chest pain and hilar lymphadenopathy may hinder diagnosis in older adults.

Burn injuries are a common source of morbidity and mortality in the United States, with an estimated 450,000 burn injuries requiring medical treatment, 40,000 requiring hospitalization, and 3,400 deaths from burns annually in the United States. Patients with severe burns are at high risk for local and systemic infections. Furthermore, burn patients are immunosuppressed, as thermal injury results in less phagocytic activity and lymphokine production by macrophages. In recent years, multidrug-resistant (MDR) pathogens have become major contributors to morbidity and mortality in burn patients.Since only limited data are available on the incidence of both device- and nondevice-associated healthcare-associated infections (HAIs) in burn patients, we undertook this retrospective cohort analysis of patients admitted to our burn intensive care unit (ICU) from 2008 to 2012.

Nontuberculous mycobacteria rarely cause bacteremia in HIV-negative patients. We describe 16 cases, including the first Mycobacterium neoaurum endocarditis. Nine cases were line related. Most patients were immunocompromised secondary to hematologic malignancy or other comorbid conditions. Amikacin had the most reliable in vitro activity. Combination therapy was frequently used. Mortality was 25%.

We evaluated TLR function in primary human dendritic cells (DCs) from 104 young (age 21–30 y) and older (≥65 y) individuals. We used multicolor flow cytometry and intracellular cytokine staining of myeloid DCs (mDCs) and plasmacytoid DCs (pDCs) and found substantial decreases in older compared with young individuals in TNF-α, IL-6, and/or IL-12 (p40) production in mDCs and in TNF-α and IFN-α production in pDCs in response to TLR1/2, TLR2/6, TLR3, TLR5, and TLR8 engagement in mDCs and TLR7 and TLR9 in pDCs. These differences were highly significant after adjustment for heterogeneity between young and older groups (e.g., gender, race, body mass index, number of comorbid medical conditions) using mixed-effect statistical modeling. Studies of surface and intracellular expression of TLR proteins and of TLR gene expression in purified mDCs and pDCs revealed potential contributions for both transcriptional and posttranscriptional mechanisms in these age-associated effects. Moreover, intracellular cytokine production in the absence of TLR ligand stimulation was elevated in cells from older compared with young individuals, suggesting a dysregulation of cytokine production that may limit further activation by TLR engagement. Our results provide evidence for immunosenescence in DCs; notably, defects in cytokine production were strongly associated with poor Ab response to influenza immunization, a functional consequence of impaired TLR function in the aging innate immune response.

Carbapenem-resistant Klebsiella pneumoniae strains that produce K. pneumoniae carbapenemase (KPC) have spread globally in the last decade. Colistin is a key agent in treating infections caused by this pathogen. In this issue of the Journal of Clinical Microbiolog y, Giani et al. (T. Giani, F. Arena, G. Vaggelli, V. Conte, A Chiarell, L. H. De Angelis, R. Fornaini, M. Grazzini, F. Niccolini, P. Pecile, and G. M. Rossolini, J Clin Microbiol 53:3341–3344, 2015, http://dx.doi.org/10.1128/JCM.01017-15 ) describe a sustained outbreak of colistin-resistant KPC-producing K. pneumoniae .

Carbapenem-resistant Enterobacteriaceae (CRE) usually infect patients with significant comorbidities and health care exposures. We present a case of a pregnant woman who developed community-acquired pyelonephritis caused by KPC-producing Klebsiella pneumoniae . Despite antibiotic treatment, she experienced spontaneous prolonged rupture of membranes, with eventual delivery of a healthy infant. This report demonstrates the challenge that CRE may pose to the effective treatment of common infections in obstetric patients, with potentially harmful consequences to maternal and neonatal health.

OBJECTIVETo determine the rates of and risk factors for tigecycline nonsusceptibility among carbapenem-resistant Klebsiella pneumoniae (CRKPs) isolated from hospitalized patientsDESIGNMulticenter prospective observational studySETTINGAcute care hospitals participating in the Consortium on Resistance against Carbapenems in Klebsiella pneumoniae (CRaCKle)PATIENTSA cohort of 287 patients who had CRKPs isolated from clinical cultures during hospitalizationMETHODSFor the period from December 24, 2011 to October 1, 2013, the first hospitalization of each patient with a CRKP during which tigecycline susceptibility for the CRKP isolate was determined was included. Clinical data were entered into a centralized database, including data regarding pre-hospital origin. Breakpoints established by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) were used to interpret tigecycline susceptibility testing.RESULTSOf 287 patients included in the final cohort, 155 (54%) had tigecycline-susceptible CRKPs. Of all index isolates, 81 (28%) were tigecycline-intermediate and 51 (18%) were tigecycline resistant. In multivariate modeling, independent risk factors for tigecycline nonsusceptibility were (1) admission from a skilled nursing facility (OR, 2.51; 95% CI, 1.51–4.21; P=.0004), (2) positive culture within 2 days of admission (OR, 1.82; 95% CI, 1.06–3.15; P=.03), and (3) receipt of tigecycline within 14 days (OR, 4.38, 95% CI, 1.37–17.01, P=.02).CONCLUSIONSIn hospitalized patients with CRKPs, tigecycline nonsusceptibility was more frequently observed in those admitted from skilled nursing facilities and occurred earlier during hospitalization. Skilled nursing facilities are an important target for interventions to decrease antibacterial resistance to antibiotics of last resort for treatment of CRKPs.Infect Control Hosp Epidemiol 2015;36(8):942–948

Objectives Carbapenem-resistant Klebsiella pneumoniae (CRKP) is an important healthcare-associated pathogen. We evaluated the impact of CRKP strain type and treatment on outcomes of patients with CRKP bacteriuria. Patients and methods Physician-diagnosed CRKP urinary tract infection (UTI)—defined as those patients who received directed treatment for CRKP bacteriuria—was studied in the multicentre, prospective Consortium on Resistance against Carbapenems in Klebsiella pneumoniae (CRaCKle) cohort. Strain typing by repetitive extragenic palindromic PCR (rep-PCR) was performed. Outcomes were classified as failure, indeterminate or success. Univariate and multivariate ordinal analyses to evaluate the associations between outcome, treatment and strain type were followed by binomial analyses. Results One-hundred-and-fifty-seven patients with physician-diagnosed CRKP UTI were included. After adjustment for CDC/National Healthcare Safety Network (NHSN)-defined UTI, critical illness and receipt of more than one active antibiotic, patients treated with aminoglycosides were less likely to fail therapy [adjusted OR (aOR) for failure 0.34, 95% CI 0.15–0.73, P = 0.0049]. In contrast, patients treated with tigecycline were more likely to fail therapy (aOR for failure 2.29, 95% CI 1.03–5.13, P = 0.0425). Strain type data were analysed for 55 patients. The predominant clades were ST258A (n = 18, 33%) and ST258B (n = 26, 47%). After adjustment for CDC/NHSN-defined UTI and use of tigecycline and aminoglycosides, infection with strain type ST258A was associated with clinical outcome in ordinal analysis (P = 0.0343). In multivariate binomial models, strain type ST258A was associated with clinical failure (aOR for failure 5.82, 95% CI 1.47–28.50, P = 0.0113). Conclusions In this nested cohort study of physician-diagnosed CRKP UTI, both choice of treatment and CRKP strain type appeared to impact on clinical outcomes.

Whipple’s disease is a rare disease that often remains undiagnosed for long periods because of difficulties on culture of the organism and the need for advanced polymerase chain reaction techniques. For these reasons, oftentimes it is initially treated as a rheumatologic disease based on presenting symptoms. There are increasing numbers of patients who require immunosuppressive medications, and little is known about the natural history of the disease in this population. This article is a follow-up to a previously published report on a patient with Whipple’s disease hip arthritis (Arthritis Rheum 1999;42:812–817). After a kidney transplantation, he went on to develop Whipple’s endocarditis 14 years after his initial diagnosis.

Melanin is made by several important pathogenic fungi and is implicated in the pathogenesis of a number of mycoses. This study investigates whether the thermally dimorphic fungal pathogen Blastomyces dermatitidis produces melanin. Using techniques developed to study melanization in other fungi, we demonstrate that B. dermatitidis conidia and yeast produce melanin in vitro and that yeast cells synthesize melanin or melanin-like pigment in vivo. Melanization reduced susceptibility to amphotericin B, but not to itraconazole or voriconazole. Since melanin is an important virulence factor in other pathogenic fungi, this pigment may affect the pathogenesis of blastomycosis.

Voriconazole is a broad-spectrum triazole that offers extended activity against molds and yeasts that are not susceptible to earlier azole-type drugs. Recent studies indicate that melanization can severely reduce the susceptibility of certain antifungal drugs, but there is no information as to whether voriconazole is vulnerable to this effect. The activity of voriconazole on C. neoformans was assessed by MIC analysis and time-kill assays for melanized and nonmelanized cells. Cell morphology, capsule release, and phagocytosis of C. neoformans were studied in the presence or absence of subinhibitory concentrations of voriconazole. Voriconazole was fungicidal at concentrations of ≥8 μg/ml in vitro against the strains of C. neoformans examined, and its efficacy was not diminished by melanization. Cells grown in subinhibitory concentrations of voriconazole had smaller cellular and capsular volumes than cells grown in the absence of drug. The induction of the capsule by serum was not affected by voriconazole. Cells grown in subinhibitory concentrations of voriconazole released their capsule and were phagocytosed at rates comparable with yeast grown without the antifungal. The high activity of voriconazole against both melanized and nonmelanized cells results suggest that voriconazole may be a particularly valuable drug for cryptococcosis.

INTRODUCTION: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are part of the same clinical syndrome that represents a medication-induced desquamation disorder. In 1922 Drs. Stevens and Johnson first described SJS as an acute mucocutaneous syndrome presenting in two young boys. 1, 2 Patients admitted to a burn center suffering from the Stevens-Johnson syndrome to Toxic Epidermal Necrolysis (SJS-TEN) spectrum are typically considered to have high hospital morbidity and mortality. Little is known about patients admitted to a burn center suffering from non-bullous Skin Disorders (SD). This group includes severe rashes, non-healing wounds, erythema multiforme, and unknown skin lesions requiring hospitalizations. We compared these two group’s costs, mortality, and the effect of Healthcare-Associated Infections (HAI) on outcomes to better define this patient population.

The fungal pathogensCryptococcus neoformansandHistoplasma capsulatumproduce melanin-like pigments in the presence ofl-dopa in vitro and during mammalian infection. We investigated whether melanization affected the susceptibilities of the fungi to amphotericin B, caspofungin, fluconazole, itraconazole, or flucytosine (5FC). Using the standard macrodilution MIC protocol (the M27A protocol) of the National Committee for Clinical Laboratory Standards for yeast, we found no difference in the susceptibilities of melanized and nonmelanizedC. neoformansandH. capsulatumisolates. Killing assays demonstrated that melanization reduced the susceptibilities of both fungi to amphotericin B and caspofungin. Laccase-deficientC. neoformanscells grown withl-dopa were significantly more susceptible than congenic melanin-producing yeast to killing by amphotericin B or caspofungin. Preincubation of amphotericin B or caspofungin with melanins decreased their antifungal activities. Elemental analysis of melanins incubated with amphotericin B or caspofungin revealed an alteration in the C:N ratios of the melanins, which indicated binding of these drugs by the melanins. In contrast, incubation of fluconazole, itraconazole, or 5FC with melanins did not significantly affect the antifungal efficacies of the drugs or the chemical composition of the melanins. The results suggest a potential explanation for the inefficacy of caspofungin againstC. neoformansin vivo, despite activity in vitro. Furthermore, the results indicate that fungal melanins protectC. neoformansandH. capsulatumfrom the activities of amphotericin B and caspofungin and that this protection is not demonstrable by standard broth macrodilution assays.

To the Editor: Tocilizumab is a monoclonal antibody that competitively inhibits binding of interleukin-6 (IL-6) to its receptor. It is approved for treatment of rheumatoid arthritis (RA) as monotherapy or with methotrexate. We report a case of cytomegalovirus (CMV) disease complicating treatment with an IL-6 receptor antagonist. A 41-year-old man who had a diagnosis of nonerosive RA (seronegative for rheumatoid factor and anticyclic citrillinated peptide antibody) in 1994 had fevers in May 2010. Previous treatment included etanercept, methotrexate, and various doses of prednisone (highest dose 40 mg/day). Because of uncontrolled RA, he was treated with monthly infusions of tocilizumab, 600 mg (≈4 mg/kg, first infusion in March 2010 and the second in April 2010), methotrexate (7.5 mg/week), and prednisone (5 mg/day from April 2010 onwards). Fever, a productive cough with white sputum, and wheezing developed ≈3 weeks after his second infusion of tocilizumab, which resulted in RA symptom resolution (Figure). Tapering of steroid treatment and levofloxacin resulted in some improvement. However, after 1 week, persistent fever led to hospitalization. Worsening shortness of breath, nausea, and vomiting developed. Results of computed tomography (CT) scans of the chest, abdomen, and pelvis were unremarkable. He was transferred to the Cleveland Clinic because of hypotension and intravenous dye–induced renal failure. Figure Timeline of events for a 41-year-old man with rheumatoid arthritis. CMV, cytomegalovirus; IV, intravenous. Daily fever (

Klebsiella pneumoniae , an ESKAPE group ( Enterococcus faecium , Staphylococcus aureus , Klebsiella pneumoniae , Acinetobacter baumannii , Pseudomonas aeruginosa , and Enterobacter species) pathogen, has acquired multiple antibiotic resistance genes and is becoming a serious public health threat. Here, we report the genome sequences of two representative strains of K. pneumoniae from the emerging K. pneumoniae carbapenemase (KPC) outbreak in northeast Ohio belonging to sequence type 258 (ST258) (isolates Kb140 and Kb677, which were isolated from blood and urine, respectively). Both isolates harbor a bla KPC gene, and strain Kb140 carries bla KPC-2 , while Kb677 carries bla KPC-3 .

Selected-ion flow-tube mass spectrometry, SIFT-MS, technology seems nowadays very promising to be utilized for the discovery and profiling of biomarkers such as volatile compounds, trace gases, and proteins from biological and clinical samples. A high performance biomarker detection method for identifying biomarkers across experimental groups is proposed for the analysis of SIFT-MS mass spectrometry data. Analysis of mass spectrometry data is often complex due to experimental design. Although several methods have been proposed for the identification of biomarkers from mass spectrometry data, there has been only a handful of methods for SIFT-MS data. Our detection method entails a three-step process that facilitates a comprehensive screening of the mass spectrometry data. First, raw mass spectrometry data are pre-processed to capture true biological signal. Second, the pre-processed data are screened via a random-forest-based screening tool. Finally, a visualization tool is complementing the findings from the previous step. In this paper, we present two applications of our method; a control-asthma case study and an H1N1 Flumist time-course case study.

Antimicrobial therapies for Carbapenem-resistant Klebsiella pneumoniae (CR-KP) infections are limited. We examine the presentation of and response to therapy in CR-KP osteomyelitis and soft tissue infections. Tigecycline monotherapy cured mild infections; the addition of amikacin and colistimethate did not increase survival in dire cases. The 45% mortality rate underscores the gravity of these infections.

Selection of the appropriate donor is essential to a successful allograft recipient outcome for solid organ transplantation. Multiple infectious diseases have been transmitted from the donor to the recipient via transplantation. Donor-transmitted infections cause increased morbidity and mortality to the recipient. In recent years, a series of high-profile transmissions of infections have occurred in organ recipients prompting increased attention on the process of improving the selection of an appropriate donor that balances the shortage of needed allografts with an approach that mitigates the risk of donor-transmitted infection to the recipient. Important advances focused on improving donor screening diagnostics, using previously excluded high-risk donors, and individualizing the selection of allografts to recipients based on their prior infection history are serving to increase the donor pool and improve outcomes after transplant. This article serves to review the relevant literature surrounding this topic and to provide a suggested approach to the selection of an appropriate solid organ transplant donor.

Use of antibiotics among livestock contributes to the selection and dissemination of multidrug resistant (MDR) bacteria ([1][1]). Olaquindox and carbadox are quinoxaline derivatives with antibacterial properties that prevent dysentery and enhance weight gain in suckling pigs ([2][2]). Resistance to

Background: Influenza vaccination may be less immunogenic in transplant recipients than in healthy people. Influenza A (H1N1) and B circulating viruses during the 2007-2008 epidemic were different from those contained in that season’s vaccine. In that epidemic, influenza vaccine effectiveness against culture-confirmed influenza was 44%. Objective: To describe clinical, immunological, and virological characteristics of 18 transplant recipients who developed influenza during the 2007-08 epidemic despite influenza vaccination (tx-vac-flu), and compare them to 6 transplant recipients who developed influenza in the absence of influenza vaccination (tx-no vac-flu), 12 previously healthy people who developed influenza (healthy-flu), and 13 transplant recipients who received influenza vaccination and did not develop influenza (tx-vac-no flu). Methods: Case ascertainment was through microbiology and electronic medical records. A case of influenza was defined by a clinical presentation of an influenza-like illness, plus a positive influenza A or B multiplex real time polymerase chain reaction (Prodesse, Inc. Waukesha, WI) on a nasopharyngeal swab. Results: Of the 36 patients with influenza, 22 had influenza A, and 15 had influenza B (1 transplant recipient had both serotypes simultaneously). Types of transplant were lung (11), hematopoietic stem cell (8), heart (7), liver (3), kidney (3), kidney + pancreas (3), liver + kidney (1), and liver + pancreas (1). Patients in the tx-vac-flu group were significantly older than patients in the tx-no vac-flu group [median 61 vs. 50.5 year, (P=0.02), the healthy-flu group [median 49.5 years (P=0.04)], and the tx-vac-no flu group [median 53 years (P=0.02)]. Influenza occurred 1,410 (261-3,467) days {median [interquartile (IQR) range]} after transplant in the tx-vac-flu group, compared to 175 (40-1,064] days in the tx-no vac-flu group (P=0.18). Influenza occurred 114 days (median [IQR 99-137]) after vaccination in the tx-vac-flu group. Immunoglobulin G levels and immune function assay levels were not significantly different between the 3 transplant groups. There were no statistically significant differences in the incidence of fever, headache, cough, rhinorrhea, sore throat, malaise, shortness of breath, exposure to contacts with similar symptoms, presence of infiltrates on chest roentgenograms, or the estimated influenza viral loads among the 3 groups who had influenza. Patients in the tx-vac-flu group were treated with oseltamivir significantly more frequently than the healthy-flu group [94% vs. 50% (P=0.0006)], but not the tx-no vac-flu group [100% (P=0.7)]. Duration of treatment with oseltamivir was not significantly different among the 3 groups who had influenza. Patients in the tx-vac-flu group had concomitant infections significantly more frequently than the healthy-flu group [44% vs. 8% (P=0.043)], but not the tx-no vac-flu group. Patients in the tx-vac-flu group developed pneumonia, and were hospitalized for management of influenza significantly more frequently than patients in the healthy-flu group (P=0.031 and P=0.00007; respectively). Only one patient (6%) in the tx-vac-flu group and none in the tx-no vac-flu or healthy-flu groups required admission to an intensive care unit and mechanical ventilation following influenza. No patients died as a result of influenza. Conclusions: Influenza vaccination did not alter clinical presentation of influenza in transplant recipients, but these patients were hospitalized and developed pneumonia more frequently than healthy people. Transplant recipients who developed influenza despite influenza vaccination were not more immunosuppressed than transplant recipients who were vaccinated and did not develop influenza. Transplant recipients who developed influenza despite influenza vaccination were more likely to have concomitant infections than healthy people with influenza.

Fluoroquinolone (FQ) antibiotics have been shown to reduce mortality and the number of febrile episodes when used as prophylaxis during neutropenia. Prior studies suggest that prophylaxis may result in increasing rates of FQ resistance. Fluoroquinolone non-susceptibility trends in Escherichia coli isolated from blood and urine cultures were evaluated over a 16-year period during which prophylaxis was initiated in patients with hematologic malignancies and stem cell transplants. Non-susceptibility rates increased after the introduction of prophylaxis, with yearly non-susceptibility rates rising from 30%­–33% to 40%–88% in blood isolates. The high rates of non-susceptibility now observed raise concerns about the continued efficacy of FQ prophylaxis. This concern exists particularly in those patients undergoing stem cell transplants where the total FQ non-susceptibility rates over the study period were 82.3%. Further evaluation of the effect of FQ prophylaxis on antibiotic resistance and its efficacy in the setting of increased rates of resistance is warranted.

Background Clinical data with use of serial interferon-γ release assay (IGRA) testing in US health-care workers (HCWs) are limited. Methods A single-center, retrospective chart review was done from 2007 to 2010 of HCWs who underwent preemployment QuantiFERON-TB Gold In-Tube testing. Demographic data, bacille Calmette-Guerin history, prior tuberculin skin test result if done, and baseline and serial IGRA values were obtained. The number of IGRA converters and reverters and their subsequent management by infectious disease physicians were reviewed. Quantitative IGRA-negative values were not available. Results A total of 7,374 IGRAs were performed on newly hired HCWs. Of these tests, 486 (6.6%) were positive at baseline, 305 (4.1%) were indeterminate, and 6,583 (89.3%) were negative. From 2007 to 2010, 52 of 1,857 HCWs (2.8%) with serial IGRA tests were identified as converters, with a serial IGRA median value of 0.63 IU/mL. Seventy-one percent of HCWs with IGRA conversion had values ≤ 1 IU/mL. None of the converters had active TB or were part of an outbreak investigation. Conclusions Clinical significance of most QuantiFERON-TB Gold In-Tube conversions in serial testing remains a challenging task for clinicians. The use of a single cutoff point criterion for IGRA may lead to overdiagnosis of new TB infections. Clinical assessment and evaluation may help to prevent unnecessary therapy in these cases. The criteria for defining conversions and reversions by establishing new cutoffs needs to be evaluated further, especially in HCWs.

Postoperative infections remain an important source of perioperative morbidity and mortality. These infections include surgical site infections but also intravenous catheter-associated bloodstream infections and Foley catheter–associated urinary tract infections.

BACKGROUND Staphylococcus aureus bacteremia (SAB) is an important cause of morbidity and mortality. Herein, we describe the incidence, clinical characteristics, and outcomes of SAB after solid organ transplantation (SOT) and compare these features with non-SOT controls. METHODS In a single-center retrospective study, blood cultures positive for S. aureus were obtained from January 1, 2000, to December 31, 2008. Chart review was performed on all SOT recipients with SAB. The social security death index was used to determine all-cause mortality. RESULTS Seventy of 2959 patients with SAB were SOT recipients (26 lung, 19 liver, 18 kidney, and seven heart). The overall attack rate of SAB in SOT was 22.9/1000 transplant patients. Early-onset SAB (≤ 90 days) was more frequent in liver recipients (79%), when compared with kidney recipients (17%). All-cause 30-day and 1-year mortality rates were 6% and 28% in SOT, respectively. Pneumonia as a source was associated with an increased 30-day mortality (18% vs. 2%, P = 0.04). Comparing SOT versus non-SOT controls, methicillin resistance was more frequent (86% vs. 52%, P < 0.0001), and duration of bacteremia was longer (mean 3.8 vs. 1.6 days, P < 0.01). SOT status was independently associated with lower risk of 30-day mortality (risk ratio [RR]: 0.37, P = 0.02). CONCLUSIONS In our cohort of SOT recipients, SAB was less common than previously reported and surprisingly had lower 30-day mortality, when compared with non-SOT. In SOT recipients, pneumonia as a source of SAB in SOT is associated with an increased 30-day mortality.