Epidemiology and outcomes of Clostridium difficile infection in allogeneic hematopoietic cell and lung transplant recipients.

BACKGROUND: Clostridium difficile infection (CDI) is a common complication of lung and allogeneic hematopoietic cell (HCT) transplant, but the epidemiology and outcomes of CDI after transplant are poorly described. METHODS: We performed a prospective, multicenter study of CDI within 365 days post-allogeneic HCT or lung transplantation. Data were collected via patient interviews and medical chart review. Participants were followed weekly in the 12 weeks post-transplant and while hospitalized and contacted monthly up to 18 months post-transplantation. RESULTS: Six sites participated in the study with 614 total participants; 4 enrolled allogeneic HCT (385 participants) and 5 enrolled lung transplant recipients (229 participants). One hundred and fifty CDI cases occurred within 1 year of transplantation; the incidence among lung transplant recipients was 13.1% and among allogeneic HCTs was 31.2%. Median time to CDI was significantly shorter among allogeneic HCT than lung transplant recipients (27 days vs 90 days; P = .037). CDI was associated with significantly higher mortality from 31 to 180 days post-index date among the allogeneic HCT recipients (Hazard ratio [HR] = 1.80; P = .007). There was a trend towards increased mortality among lung transplant recipients from 120 to 180 days post-index date (HR = 4.7, P = .09). CONCLUSIONS: The epidemiology and outcomes of CDI vary by transplant population; surveillance for CDI should continue beyond the immediate post-transplant period.

Management of an Outbreak of Exophiala dermatitidis Bloodstream Infections at an Outpatient Oncology Clinic.

We report the presentation and management of 17 cases of Exophiala dermatitidis and Rhodotorula mucilaginosa bloodstream infections caused by a compounded parenteral medication at an oncology clinic. Twelve patients were asymptomatic. All central venous catheters were removed and antifungal therapy, primarily voriconazole, was administered to patients. Three patients died.

Investigation of the First Seven Reported Cases of Candida auris, a Globally Emerging Invasive, Multidrug-Resistant Fungus-United States, May 2013-August 2016.

November 11, 2016/65(44);1234-1237. What is already known about this topic? Candida auris is an emerging pathogenic fungus that has been reported from at least a dozen countries on four continents during 2009-2015. The organism is difficult to identify using traditional biochemical methods, some isolates have been found to be resistant to all three major classes of antifungal medications, and C. auris has caused health care-associated outbreaks. What is added by this report? This is the first description of C. auris cases in the United States. C. auris appears to have emerged in the United States only in the last few years, and U.S. isolates are related to isolates from South America and South Asia. Evidence from U.S. case investigations suggests likely transmission of the organism occurred in health care settings. What are the implications for public health practice? It is important that U.S. laboratories accurately identify C. auris and for health care facilities to implement recommended infection control practices to prevent the spread of C. auris. Local and state health departments and CDC should be notified of possible cases of C. auris and of isolates of C. haemulonii and Candida spp. that cannot be identified after routine testing.

Opportunistic infections and biologic therapies in immune-mediated inflammatory diseases: consensus recommendations for infection reporting during clinical trials and postmarketing surveillance.

No consensus has previously been formed regarding the types and presentations of infectious pathogens to be considered as 'opportunistic infections' (OIs) within the setting of biologic therapy. We systematically reviewed published literature reporting OIs in the setting of biologic therapy for inflammatory diseases. The review sought to describe the OI definitions used within these studies and the types of OIs reported. These findings informed a consensus committee (infectious diseases and rheumatology specialists) in deliberations regarding the development of a candidate list of infections that should be considered as OIs in the setting of biologic therapy. We reviewed 368 clinical trials (randomised controlled/long-term extension), 195 observational studies and numerous case reports/series. Only 11 observational studies defined OIs within their methods; no consistent OI definition was identified across studies. Across all study formats, the most numerous OIs reported were granulomatous infections. The consensus group developed a working definition for OIs as 'indicator' infections, defined as specific pathogens or presentations of pathogens that 'indicate' the likelihood of an alteration in host immunity in the setting of biologic therapy. Using this framework, consensus was reached upon a list of OIs and case-definitions for their reporting during clinical trials and other studies. Prior studies of OIs in the setting of biologic therapy have used inconsistent definitions. The consensus committee reached agreement upon an OI definition, developed case definitions for reporting of each pathogen, and recommended these be used in future studies to facilitate comparison of infection risk between biologic therapies.

Evaluation of screening and treatment of cryptococcal antigenaemia among HIV-infected persons in Soweto, South Africa.

OBJECTIVES: We retrospectively evaluated clinic-based screening to determine the prevalence of cryptococcal antigenaemia and management and outcome of patients with antigenaemia. METHODS: Cryptococcal antigen (CrAg) screening of HIV-infected adults who attended the HIV clinic at Chris Hani Baragwanath Hospital was conducted over 19 months. Data collected from CrAg-positive patients included CD4 T-lymphocyte count at screening, prior or subsequent cryptococcal meningitis (CM), antifungal and antiretroviral treatment and outcome after at least 8 months. RESULTS: Of 1460 patients with no prior CM, 30 (2.1%) had a positive CrAg test. The prevalence of antigenaemia among patients with a CD4 count < 100 cells/µl and no prior CM was 2.8% (20 of 708). Of 29 evaluable CrAg-positive patients with no prior CM, 14 (48%) did not return for post-screening follow-up. Of these 14, five developed CM and one (7%) was known to be alive at follow-up. Of 15 patients who returned for follow-up, two already had evidence of nonmeningeal cryptococcosis. Overall, 11 received fluconazole, one did not and fluconazole treatment was unknown for three. Among these 15, one developed CM and 10 (67%) were known to be alive at follow-up. Overall, 18 (62%) of 29 CrAg-positive patients died or were lost to follow-up. Seven (0.5%) of 1430 CrAg-negative patients developed CM a median of 83 days post-screening (range 34 to 219 days). CONCLUSIONS: Loss to follow-up is the major operational issue relevant to scale-up of screen-and-treat. Patient outcomes may be improved by rapid access to CrAg results and focus on linkage to and retention in HIV care.

Endemic fungal infections in solid organ and hematopoietic cell transplant recipients enrolled in the Transplant-Associated Infection Surveillance Network (TRANSNET).

BACKGROUND: Invasive fungal infections are a major cause of morbidity and mortality among solid organ transplant (SOT) and hematopoietic cell transplant (HCT) recipients, but few data have been reported on the epidemiology of endemic fungal infections in these populations. METHODS: Fifteen institutions belonging to the Transplant-Associated Infection Surveillance Network prospectively enrolled SOT and HCT recipients with histoplasmosis, blastomycosis, or coccidioidomycosis occurring between March 2001 and March 2006. RESULTS: A total of 70 patients (64 SOT recipients and 6 HCT recipients) had infection with an endemic mycosis, including 52 with histoplasmosis, 9 with blastomycosis, and 9 with coccidioidomycosis. The 12-month cumulative incidence rate among SOT recipients for histoplasmosis was 0.102%. Occurrence of infection was bimodal; 28 (40%) infections occurred in the first 6 months post transplantation, and 24 (34%) occurred between 2 and 11 years post transplantation. Three patients were documented to have acquired infection from the donor organ. Seven SOT recipients with histoplasmosis and 3 with coccidioidomycosis died (16%); no HCT recipient died. CONCLUSIONS: This 5-year multicenter prospective surveillance study found that endemic mycoses occur uncommonly in SOT and HCT recipients, and that the period at risk extends for years after transplantation.

Cryptococcus gattii in the United States: clinical aspects of infection with an emerging pathogen.

BACKGROUND: Cryptococcus gattii (Cg) has caused increasing infections in the US Pacific Northwest (PNW) since 2004. We describe this outbreak and compare clinical aspects of infection in the United States among patients infected with different Cg genotypes. METHODS: Beginning in 2005, PNW state health departments conducted retrospective and prospective passive surveillance for Cg infections, including patient interviews and chart reviews; clinical isolates were genotyped at the US Centers for Disease Control and Prevention (CDC). We examined symptom frequency and underlying conditions in US patients with Cg infection and modeled factors associated with death. RESULTS: From 1 December 2004 to July 2011, 96 Cg infections were reported to the CDC. Eighty-three were in patients in or travelers to the PNW, 78 of which were genotypes VGIIa, VGIIb, or VGIIc (outbreak strains). Eighteen patients in and outside the PNW had other molecular type Cg infections (nonoutbreak strains). Patients with outbreak strain infections were more likely than those with nonoutbreak-strain infections to have preexisting conditions (86% vs 31%, respectively; P < .0001) and respiratory symptoms (75% vs 36%, respectively; P = .03) and less likely to have central nervous system (CNS) symptoms (37% vs 90%, respectively; P = .008). Preexisting conditions were associated with increased pneumonia risk and decreased risk of meningitis and CNS symptoms. Nineteen (33%) of 57 patients died. Past-year oral steroid use increased odds of death in multivariate analysis (P = .05). CONCLUSIONS: Clinical differences may exist between outbreak-strain (VGIIa, VGIIb, and VGIIc) and nonoutbreak-strain Cg infections in the United States. Clinicians should have a low threshold for testing for Cg, particularly among patients with recent travel to the PNW.

Investigation of a cluster of cutaneous aspergillosis in a neonatal intensive care unit.

Between December 2007 and July 2008, three neonates in a neonatal intensive care unit (NICU) in Salford, UK, were diagnosed with primary cutaneous aspergillosis (PCA) due to Aspergillus fumigatus. The first PCA case, in December 2007, developed multi-organ failure leading to death within a short time frame: the other two cases survived after treatment with intravenous antifungal therapy followed by oral posaconazole. Air, surface, and water samples were collected within the NICU and from the incubators that were occupied by the neonates. All recovered fungal isolates were confirmed as A. fumigatus by sequencing the beta-tubulin region. Microsatellite strain typing demonstrated genotypically related A. fumigatus isolates from the neonates and the humidity chambers (HCs) of the neonates' incubators, suggesting that the source of the infection may have been the HCs/incubators used in the NICU. Aspergillus strain typing may be a useful tool in clinical outbreak settings to help understand the source of exposure and to design targeted environmental interventions to prevent future infections.

Daily trimethoprim-sulfamethoxazole prophylaxis rapidly induces corresponding resistance among intestinal Escherichia coli of HIV-infected adults in Kenya.

BACKGROUND: Trimethoprim-sulfamethoxazole (TMP-SMZ) has been recommended by World Health Organization (WHO) as daily prophylaxis for Africans with AIDS to prevent opportunistic infections. Daily TMP-SMZ may reduce its susceptibility to commensal intestinal Escherichia coli (E coli), increasing the burden of TMP-SMZ-resistant pathogens. METHODS: Participants received either daily TMP-SMZ (CD4 <350 cells/mm(3)) or daily multivitamins (MVIs; CD4 > or =350 cells/mm(3)) for 6 months. Stool was collected at baseline, 2 weeks, 2 months, and 6 months. A random E coli was tested for susceptibility. RESULTS: Baseline prevalence of TMP-SMZ resistance ranged from 71% to 81% and was not different across CD4 strata. At 2 weeks, prevalence of TMP-SMZ-resistant E coli increased significantly from 78% to 98% (P < .001) among persons taking daily TMP-SMZ and did not change among persons taking MVIs. CONCLUSIONS: Daily prophylaxis with TMP-SMZ induced in vivo resistance to the drug after 2 weeks. Empiric therapy for diarrhea with agents other than TMP-SMZ should be considered for HIV-infected persons receiving daily TMP-SMZ prophylaxis.

Sporadic paediatric diarrhoeal illness in urban and rural sites in Nyanza Province, Kenya.

OBJECTIVE: Investigate differences in the infectious aetiology, health seeking behaviour, and provider practices with regard to diarrhoeal illness among children presenting to urban versus rural clinics in Western Kenya. DESIGN: Laboratory-based, passive surveillance. SETTING: The urban portion of the study was conducted at the paediatric outpatient clinic of Nyanza Provincial Hospital in Kisumu. The rural portion of the study was conducted at four outpatient clinics in the Asembo Bay community approximately 20 kilometers west of Kisumu. SUBJECTS: Children aged less than five years presenting to medical facilities for the treatment of diarrhoea from October 2001-October 2003 at the urban site and May 1997-April 2003 for the rural sites. RESULTS: Among the 1303 urban and 1247 rural specimens collected, 24% of specimens yielded a bacterial pathogen (24% urban, 25% rural). Campylobacter was the predominant bacterial pathogen (17% urban, 15% rural), followed by Shigella and nontyphoidal Salmonella (both 4% urban and 5% rural). In both communities, susceptibilities of these pathogens to the most commonly prescribed antibiotics was low (< or = 50%); 70% of all episodes of diarrhoea were prescribed antibiotic treatment. Urban health practitioners prescribed fewer antibiotics, chose drugs more likely to be effective, and were more likely to prescribe oral rehydration therapy for bloody diarrhoea. CONCLUSION: Most characteristics of diarrhoeal disease and their causes were similar in paediatric patients presenting to urban and rural clinics. Urban providers were more compliant with WHO recommendations.

Antimicrobial resistance and genetic relatedness among Salmonella from retail foods of animal origin: NARMS retail meat surveillance.

Salmonella isolates were recovered from a monthly sampling of chicken breasts, ground turkey, ground beef, and pork chops purchased from selected grocery stores in six participating FoodNet sites (Connecticut, Georgia, Maryland, Minnesota, Oregon, and Tennessee) in 2002 and an additional two sites in 2003 (California and New York). In 2002 and 2003, a total of 6,046 retail meats were examined, including 1,513 chicken breasts, 1,499 ground turkey samples, 1,522 ground beef samples, and 1,502 pork chops. Retail meat samples tested increased to 3,533 in 2003 as compared to 2,513 in 2002. Overall, six percent of 6,046 retail meat samples (n = 365) were contaminated with Salmonella, the bulk recovered from either ground turkey (52%) or chicken breast (39%). Salmonella isolates were serotyped and susceptibility tested using a panel of 16 antimicrobial agents. S. Heidelberg was the predominant serotype identified (23%), followed by S. Saintpaul (12%), S. Typhimurium (11%), and S. Kentucky (10%). Overall, resistance was most often observed to tetracycline (40%), streptomycin (37%), ampicillin (26%), and sulfamethoxazole (25%). Twelve percent of isolates were resistant to cefoxitin and ceftiofur, though only one isolate was resistant to ceftriaxone. All isolates were susceptible to amikacin and ciprofloxacin; however, 3% of isolates were resistant to nalidixic acid and were almost exclusive to ground turkey samples (n = 11/12). All Salmonella isolates were analyzed for genetic relatedness using pulsed-field gel electrophoresis (PFGE) patterns generated by digestion with Xba1 or Xba1 plus Bln1. PFGE fingerprinting profiles showed that Salmonella, in general, were genetically diverse with a total of 175 Xba1 PFGE profiles generated from the 365 isolates. PFGE profiles showed good correlation with serotypes and in some instances, antimicrobial resistance profiles. Results demonstrated a varied spectrum of antimicrobial resistance and PFGE patterns, including several multidrug resistant clonal groups among Salmonella isolates, and signify the importance of sustained surveillance of foodborne pathogens in retail meats.

Evidence of an association between use of anti-microbial agents in food animals and anti-microbial resistance among bacteria isolated from humans and the human health consequences of such resistance.

Several lines of evidence indicate that the use of anti-microbial agents in food animals is associated with anti-microbial resistance among bacteria isolated from humans. The use of anti-microbial agents in food animals is most clearly associated with anti-microbial resistance among Salmonella and Campylobacter isolated from humans, but also appears likely among enterococci, Escherichia coli and other bacteria. Evidence is also accumulating that the anti-microbial resistance among bacteria isolated from humans could be the result of using anti-microbial agents in food animals and is leading to human health consequences. These human health consequences include: (i) infections that would not have otherwise occurred and (ii) increased frequency of treatment failures and increased severity of infection. Increased severity of infection includes longer duration of illness, increased frequency of bloodstream infections, increased hospitalization and increased mortality. Continued work and research efforts will provide more evidence to explain the connection between the use of anti-microbial agents in food animals and anti-microbial-resistant infections in humans. One particular focus, which would solidify this connection, is to understand the factors that dictate spread of resistance determinants, especially resistant genes. With continued efforts on the part of the medical, veterinary and public health community, such research may contribute to more precise guidelines on the use of anti-microbials in food animals.

Effect of granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor on polymorphonuclear neutrophils, monocytes or monocyte-derived macrophages combined with voriconazole against Cryptococcus neoformans.

The antifungal activity of voriconazole (VCZ) was tested against Cryptococcus neoformans (Cn) with and without the addition of polymorphonuclear neutrophils (PMN), monocytes or monocyte-derived macrophages (MDM) in vitro. Human effector cells with and without the addition of VCZ were incubated with Cn for 24 h. PMN, mono and MDM alone resulted in 61%, 34% and 23% inhibition of Cn, respectively (n = 3, P<0.01). VCZ at 0.01 and 0.05 microg ml(-1) alone resulted in 48% inhibition and 19% killing (n = 6). The addition of VCZ at 0.01 and 0.05 microg ml(-1) to human effector cells enhanced killing of Cn by 51% and 71% for the PMN, 41% and 58% for the mono, and 14% and 34% for the MDM, respectively. The addition of either granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage colony stimulating factor (GM-CSF) significantly enhanced the ability of human effector cells to kill Cn. G-CSF and GM-CSF plus PMN resulted in 47% and 46% killing, respectively; GM-CSF plus monocytes or MDM resulted in 31% or 22% killing, respectively. G-CSF and GM-CSF further enhanced the collaborative killing effect of human effector cells and VCZ. At 0.01 and 0.05 microg ml(-1) of VCZ, G-CSF or GM-CSF enhanced PMN killing to 92% and 93% or 87% and 94%, respectively. GM-CSF enhanced both mono and MDM with VCZ at 0.01 and 0.05 microg ml(-1) in killing Cn to 62% and 86%, and 61% and 84%, respectively. These results suggest that VCZ would have good efficacy in the treatment of Cn infection in humans. Furthermore, VCZ would have enhanced efficacy in clinical settings where either G-CSF or GM-CSF was being used.

Protease inhibitor therapy is associated with markedly prolonged time to relapse and improved survival in AIDS patients with cytomegalovirus retinitis.

Prior to the use of highly active antiretroviral therapy (HAART), cytomegalovirus retinitis (CMV-R) in AIDS patients was characterized by multiple relapses and decreased survival. Recent data suggest that CMV-R in patients treated with HAART may remain relapse-free for long periods. We performed a study of the effects of HIV protease inhibitors (PIs) on the incidence of relapse and time to death in AIDS patients with CMV-R treated with anti-CMV therapy. Medical records of all AIDS patients with CMV-R at Parkland Memorial Health and Hospital System treated with anti-CMV agents were reviewed for date of diagnosis of CMV-R, date of CMV-R relapse, type and duration of anti-CMV therapy, and duration of PI therapy. Relapse rates in subjects treated with PIs were compared with the relapse rates in those who were not treated with PIs. The primary endpoint was the time to relapse and death as determined by Kaplan-Meier analysis. Multivariate analysis was performed by Cox proportional hazard model. One hundred and nine cases of CMV-R were identified in 75 patients. Median follow-up time was 247 days (range 31-1818 days). There were 0.54 relapses per 1000 patient days in the group treated with PIs compared with 1.83 relapses per 1000 patient days in the non-PI treatment group (relative risk [RR]=0.29, P<0.01). Time to relapse was increased in the PI treatment group compared with the non-PI treatment group (endpoint not reached vs 182 days, P<0.001, log-rank). Similarly, the time to relapse or death was increased in the PI group compared with the non-PI group (543 days vs 103 days, P<0.001, log-rank). Multivariate analysis utilizing the Cox proportional hazards model demonstrated that only PI therapy but not anti-CMV therapy was associated with decreased risk of CMV-R relapse or death. Only 3 patients with an undetectable HIV viral load and one patient with a CD4 count >120 cells/microl had a relapse. We conclude that patients with CMV-R treated with HAART containing a PI have increased time to relapse and have prolonged survival.

The interaction of human monocytes, monocyte-derived macrophages, and polymorphonuclear neutrophils with caspofungin (MK-0991), an echinocandin, for antifungal activity against Aspergillus fumigatus.

The collaboration between human effector cells and caspofungin (MK-0991), a 1,3-beta-D glucan synthase inhibitor, was studied for antifungal activity against Aspergillus fumigatus. Caspofungin was co-cultured for 24h with either human monocytes (Monos), monocyte-derived macrophages (MDM), or polymorphonuclear neutrophils (PMN) against germlings of A. fumigatus and antifungal activity assessed using the XTT metabolic assay. Caspofungin at 0.1 micorg/ml and 0.05 microg/ml or Monos alone against germlings caused significant inhibition. Microscopically this was correlated with less growth and stunted malformed hyphae. The addition of caspofungin at 0.1 microg/ml and 0.05 microg/ml to the monocyte cultures increased antifungal activity. The inhibition of the combination was significantly greater than drug alone (P <.01) and Monos alone (P <.01). MDM against Aspergillus germlings inhibited hyphal growth. The combination of caspofungin at 0.1 microg/ml and 0.05 microg/ml to the macrophage cultures increased antifungal activity. The growth inhibition by the combination was significantly greater than drug alone (P <.01) and MDM alone (P <.01). There was no significant interference with or enhancement of PMNs and caspofungin. These data support the activity of caspofungin against A. fumigatus in vitro, and indicates a cooperative activity with human effector cells. This suggests caspofungin in vivo would have increased efficacy as it combines with host defenses against A. fumigatus.

Influence of human sera on the in vitro activity of the echinocandin caspofungin (MK-0991) against Aspergillus fumigatus.

There have been several reports that the activity of echinocandin antifungal agents is not affected or decreased in the presence of human sera. It is known that these drugs are bound >80% in animal and human sera. The activity of the echinocandin caspofungin (MK-0991), a 1,3-beta-D-glucan synthase inhibitor, against Aspergillus fumigatus with and without human sera was studied. Conidia of A. fumigatus in microtest plate wells formed germlings after overnight culture in RPMI 1640. Caspofungin was then added with or without serum, and the germlings were incubated at 37 degrees C for 24 h. Human serum (5%) in RPMI 1640 alone did not significantly inhibit the growth of A. fumigatus in vitro. Caspofungin in RPMI 1640 exhibited dose-dependent inhibition, with concentrations of 0.1 and 0.05 microg/ml inhibiting 24.9% +/- 10.4% and 11.7% +/- 3.6%, respectively (n = 10; P < 0.01). The addition of 5% human serum to caspofungin at 0.1 or 0.05 microg/ml increased the inhibition to 78.6% +/- 5.8% or 58.3% +/- 19.2%, respectively (n = 10; P < 0.01 versus controls and versus the drug without serum). Lower concentrations of serum also potentiated drug activity. The effect of human sera was further seen when using caspofungin that had lost activity (e.g., by storage) against A. fumigatus at 0.1 microg/ml. Inactive caspofungin alone demonstrated no significant inhibition of hyphal growth, whereas the addition of 5% human serum to the inactive drug showed 83% +/- 16.5% inhibition (n = 5; P < 0. 01). The restoration of activity of caspofungin was seen at concentrations as low as 0.05% human serum. In contrast to prior reports, this study suggests that human serum acts synergistically with caspofungin to enhance its inhibitory activity in vitro against A. fumigatus.