Surgical site infections after simultaneous pancreas kidney and pancreas transplantation in the Swiss Transplant Cohort Study.

BACKGROUND: Among hospital-acquired infections, surgical site infections (SSIs) are frequent. SSI in the early post-transplant course poses a relevant threat to transplant recipients. AIM: To determine incidence, risk factors for SSI and its association with post-transplant outcomes and pancreas transplant (P-Tx) recipients. METHODS: Adult simultaneous kidney-pancreas transplantation (SPK-T) and P-Tx recipients with a follow-up of at least 90 days were identified in the Swiss Transplant Cohort Study (STCS) dataset. Except for the categorization of SSIs according to Centers for Disease Control and Prevention (CDC) criteria, all other data were prospectively collected. Risk factors for SSI were investigated with logistic regression. A Weibull accelerated failure-time model was applied to address the impact of SSI on length of stay, correcting for transplant-related complications and delayed graft function. FINDINGS: Of 130 transplant recipients, 108 SPK-Tx and 22 P-Tx, 18 (14%) individuals developed SSI within the first 90 days after transplantation. Deep incisional (seven, 38.9%) and organ/space infections (eight, 44.4%) predominated. In the majority of SSIs (11, 61.1%; two SSIs with simultaneous identification of fungal pathogens) bacteria were detected with Enterococcus spp. being most frequent. The median duration of hospitalization after transplantation was significantly longer in recipients with SSI (median: 26 days; interquartile range (IQR): 19-44) than in patients without SSI (median: 17 days; IQR: 12-25; P = 0.002). In multivariate analysis, SSI was significantly associated with increased length of stay and prolonged the duration of hospitalization by 36% (95% confidence interval: 4-79). CONCLUSION: SSI after SPK-Tx and P-Tx occurred at a frequency of 14%. Among pathogens, Enterococcus spp. predominated. SSI was independently associated with a longer hospitalization after transplantation.

Emerging echinocandin-resistant Candida albicans and glabrata in Switzerland.

Echinocandins represent the first-line therapy of candidemia. Echinocandin resistance among Candida spp. is mainly due to acquired FKS mutations. In this study, we report the emergence of FKS-mutant Candida albicans/glabrata in Switzerland and provide the microbiological and clinical characteristics of 9 candidemic episodes. All patients were previously exposed to echinocandins (median 26 days; range 15-77). Five patients received initial echinocandin therapy with persistent candidemia in 4 of them. Overall mortality was 33%.

Accuracy of Sensititre YeastOne echinocandins epidemiological cut-off values for identification of FKS mutant Candida albicans and Candida glabrata: a ten year national survey of the Fungal Infection Network of Switzerland (FUNGINOS).

OBJECTIVES: Echinocandins represent the first-line treatment of candidaemia. Acquired echinocandin resistance is mainly observed among Candida albicans and Candida glabrata and is associated with FKS hotspot mutations. The commercial Sensititre YeastOne™ (SYO) kit is widely used for antifungal susceptibility testing, but interpretive clinical breakpoints are not well defined. We determined echinocandins epidemiological cut-off values (ECV) for C. albicans/glabrata tested by SYO and assessed their ability to identify FKS mutants in a national survey of candidaemia. METHODS: Bloodstream isolates of C. albicans and C. glabrata were collected in 25 Swiss hospitals from 2004 to 2013 and tested by SYO. FKS hotspot sequencing was performed for isolates with an MIC≥ECV for any echinocandin. RESULTS: In all, 1277 C. albicans and 347 C. glabrata were included. ECV 97.5% of caspofungin, anidulafungin and micafungin were 0.12, 0.06 and 0.03 µg/mL for C. albicans, and 0.25, 0.12 and 0.03 µg/mL for C. glabrata, respectively. FKS hotspot sequencing was performed for 70 isolates. No mutation was found in the 52 'limit wild-type' isolates (MIC=ECV for at least one echinocandin). Among the 18 'non-wild-type' isolates (MIC>ECV for at least one echinocandin), FKS mutations were recovered in the only two isolates with MIC>ECV for all three echinocandins, but not in those exhibiting a 'non-wild-type' phenotype for only one or two echinocandins. CONCLUSION: This 10-year nationwide survey showed that the rate of echinocandin resistance among C. albicans and C. glabrata remains low in Switzerland despite increased echinocandin use. SYO-ECV could discriminate FKS mutants from wild-type isolates tested by SYO in this population.

Epidemiology, risk factors and outcomes of invasive aspergillosis in solid organ transplant recipients in the Swiss Transplant Cohort Study.

BACKGROUND: There is lack of recent multicenter epidemiological data on invasive aspergillosis (IA) among solid organ transplant recipient (SOTr) in the mold-acting antifungal era. We describe the epidemiology and outcomes of IA in a contemporary cohort of SOTr using the Swiss Transplant Cohort Study. METHODS: All consecutive SOTr with proven or probable IA between 01.05.2008 and 31.12.2014 were included. A case-control study to identify IA predictors was performed: 1-case was matched with 3-controls based on SOT type, transplant center, and time post-SOT. RESULTS: Among 2868 SOTr, 70 (2.4%) patients were diagnosed with proven (N: 30/70, 42.9%) or probable (N: 40/70, 57.1%) IA. The incidence of IA was 8.3%, 7.1%, 2.6%, 1.3%, and 1.2% in lung, heart, combined, kidney, and liver transplant recipients, respectively, Galactomannan immunoassay was positive in 1/3 of patients tested. Only 33/63 (52.4%) of patients presented with typical pulmonary radiographic findings. Predictors of IA included: renal insufficiency, re-operation, and bacterial and viral infections. 12-week mortality was higher in liver (85.7%, 6/7) compared to other (15.9%, 10/63; P < .001) SOTr. CONCLUSIONS: Invasive aspergillosis remains a rare complication post-SOT, with atypical radiographic presentations and low positivity rates of biomarkers posing significant diagnostic challenges. Although overall mortality has decreased in SOTr, it remains high in liver SOTr.

Detection of in vivo hepatitis B virus surface antigen mutations-A comparison of four routine screening assays.

An important requirement for a state-of-the-art hepatitis B surface antigen (HBsAg) screening assay is reliable detection of mutated HBsAg. Currently, there is a striking shortage of data regarding the detection rates of in vivo HBsAg mutations for these clinically important assays. Therefore, we compared the detection rates of four commercial HBsAg screening assays using a global cohort of 1553 patients from four continents with known HBV genotypes. These samples, which represent the broadest spectrum of known and novel HBsAg major hydrophilic region (MHR) mutations to date, were analyzed for the presence of HBsAg using the Roche Elecsys® HBsAg II Qualitative, Siemens ADVIA Centaur XP HBsAg II, Abbott Architect HBsAg Qualitative II and DiaSorin Liaison® HBsAg Qualitative assays, respectively. Of the 1553 samples, 1391 samples could be sequenced; of these, 1013 (72.8%) carried at least one of the 345 currently known amino acid substitutions (distinct HBsAg mutation) in the HBsAg MHR. All 1553 patient samples were positive for HBsAg using the Elecsys® HBsAg II Qual assay, with a sensitivity (95% confidence interval) of 99.94% (99.64%-100%), followed by the Abbott Architect 99.81% (99.44%-99.96%), Siemens ADVIA 99.81% (99.44%-99.96%) and DiaSorin Liaison® 99.36% (98.82%-99.69%) assays, respectively. Our results indicate that the Elecsys® HBsAg II Qual assay exhibits the highest sensitivity among the commercial HBsAg screening assays, and demonstrate that its capacity to detect HBV infection is not compromised by HBsAg MHR mutants.

False-positive hepatitis C virus serology after placement of a ventricular assistance device.

BACKGROUND: Ventricular assist devices (VADs) have been associated with immune activation and sensitization. We observed several cases of false-positive (FP) hepatitis C virus (HCV) antibody (Ab) tests in patients being evaluated for orthotopic heart transplant (OHT), prompting us to investigate this further. METHODS: We reviewed all VAD and OHT cases at Johns Hopkins from 2005 to 2012. FP HCV serology was defined as an equivocal or low-positive HCV Ab, plus either (i) a negative recombinant immunoblot (RIBA) and/or HCV nucleic acid test (NAT), or (ii) an indeterminate RIBA and negative NAT. RESULTS: In 53 patients with available HCV testing, nearly 40% of patients (21/53: 39.6%) developed FP HCV Ab tests after VAD placement: 4 patients had negative NAT, 12 had negative RIBA, and 5 had an indeterminate RIBA and negative NAT. All patients with indeterminate RIBA tests had isolated reactivity to the same HCV protein, c100p/5-1-1p (NS4b protein). In 3 of 4 VAD patients who had OHT and repeat HCV Ab testing after VAD removal, repeat HCV Ab was negative (699-947 days after OHT); in 1 case, FP HCV serology persisted (5 days after OHT). Thirteen patients had OHT alone and none developed a FP HCV Ab. CONCLUSIONS: FP HCV Ab results following VAD placement are very common. Reversal of FP serology in several patients after VAD removal is suggestive of a possible association with the VAD hardware. Clinicians should be aware of this phenomenon, as it could lead to delays in determining eligibility for OHT and increased costs.

Voriconazole therapeutic drug monitoring: results of a prematurely discontinued randomized multicenter trial.

BACKGROUND: Voriconazole (VOR) levels are highly variable, with potential implications to both efficacy and safety. We hypothesized that VOR therapeutic drug monitoring (TDM) will decrease the incidence of treatment failures and adverse events (AEs). METHODS: We initiated a prospective, randomized, non-blinded multicenter study to compare clinical outcomes in adult patients randomized to standard dosing (clinician-driven) vs. TDM (doses adjusted based on levels). VOR trough levels were obtained on day 5, 14, 28, and 42 (or at completion of drug; ± 3 days). Real-time dose adjustments were made to maintain a range between 1-5 µg/mL on the TDM-arm, while levels were assessed retrospectively in the standard-arm. Patient questionnaires were administered to assess subjective AEs. RESULTS: The study was discontinued prematurely, after 29 patients were enrolled. Seventeen (58.6%) patients experienced 38 AEs: visual changes (22/38, 57.9%), neurological symptoms (13/38, 34.2%), and liver abnormalities (3/38, 7.9%). VOR was discontinued in 7 (25%) patients because of an AE (4 standard-arm, 3 TDM-arm). VOR levels were frequently out of range in the standard-arm (8 tests >5 µg/mL; 9 tests <1 µg/mL). Three dose changes occurred in the TDM-arm for VOR levels <1 µg/mL. Levels decreased over time in the standard-arm, with mean VOR levels lower at end of therapy compared to TDM (1.3 vs. 4.6 µg/mL, P = 0.008). CONCLUSIONS: VOR TDM has become widespread clinical practice, based on known variability in drug levels, which impaired accrual in this study. Although comparative conclusions are limited, observations of variability and waning levels over time support TDM.

Treatment and outcomes of Candida osteomyelitis: review of 53 cases from the PATH Alliance® registry.

Candida osteomyelitis is associated with significant morbidity; however, data on the management of Candida osteomyelitis are limited. The Prospective Antifungal Therapy (PATH) Alliance® registry is a comprehensive, multicenter, prospective, observational registry that collected data on patients with invasive fungal infections between 2004 and 2008. The aim of this descriptive analysis was to evaluate the clinical characteristics, treatment, and outcomes of patients with Candida osteomyelitis. Using the PATH Alliance® registry, we performed a review of all patients with a proven diagnosis of Candida osteomyelitis who received a minimum of 14 days of antifungal treatment and/or a therapeutic surgical intervention (n = 53). The epidemiology, diagnosis, treatment, and outcomes of these patients were assessed at 12 weeks. C. albicans (56.6 %) was the most commonly identified organism, followed by C. parapsilosis (18.9 %), C. glabrata (9.4 %), and C. tropicalis (9.4 %). The mean treatment duration was 54.9 days. Multiple different treatment regimens were administered to patients. These included fluconazole (56.0 %), echinocandins (29.3 %), amphotericin B formulations (10.7 %), and voriconazole (4.0 %). Twenty-eight patients (52.8 %) also had a therapeutic surgical intervention. Clinical response was improved in 38 (71.7 %) patients (43.4 % complete and 28.3 % partial response), stable in 11 (20.8 %), and worse in one (1.9 %); three (5.7 %) patients had unknown response. The 12-week survival rate was 93.8 %. In summary, C. albicans was the predominant pathogen, and fluconazole was the most commonly administered agent. However, treatment patterns vary and remain non-standardized. Concurrent candidemia was infrequent, and 12-week survival was notably good in this series of 53 patients with Candida osteomyelitis.

Donor-derived Trypanosoma cruzi infection in solid organ recipients in the United States, 2001-2011.

Although Trypanosoma cruzi, the parasite that causes Chagas disease, can be transmitted via organ transplantation, liver and kidney transplantation from infected donors may be feasible. We describe the outcomes of 32 transplant recipients who received organs from 14 T. cruzi seropositive donors in the United States from 2001 to 2011. Transmission was confirmed in 9 recipients from 6 donors, including 3 of 4 (75%) heart transplant recipients, 2 of 10 (20%) liver recipients and 2 of 15 (13%) kidney recipients. Recommended monitoring posttransplant consisted of regular testing by PCR, hemoculture, and serology. Thirteen recipients had no or incomplete monitoring; transmission was confirmed in five of these recipients. Four of the five recipients had symptomatic disease and all four died although death was directly related to Chagas disease in only one. Nineteen recipients had partial or complete monitoring for T. cruzi infection with weekly testing by PCR, hemoculture and serology; transmission was confirmed in 4 of 19 recipients with no cases of symptomatic disease. Our results suggest that liver and kidney transplantation from T. cruzi seropositive donors may be feasible when the recommended monitoring schedule for T. cruzi infection is followed and prompt therapy with benznidazole can be administered.

Epidemiology, outcomes, and mortality predictors of invasive mold infections among transplant recipients: a 10-year, single-center experience.

BACKGROUND: The epidemiology of invasive mold infections (IMI) in transplant recipients differs based on geography, hosts, preventative strategies, and methods of diagnosis. METHODS: We conducted a retrospective observational study to evaluate the epidemiology of proven and probable IMI, using prior definitions, among all adult hematopoietic stem cell transplant (HSCT) and solid organ transplant (SOT) recipients in the era of "classic" culture-based diagnostics (2000-2009). Epidemiology was evaluated before and after an initiative was begun to increase bronchoscopy in HSCT recipients after 2005. RESULTS: In total, 106 patients with one IMI were identified. Invasive aspergillosis (IA) was the most common IMI (69; 65.1%), followed by mucormycosis (9; 8.5%). The overall rate of IMI (and IA) was 3.5% (2.5%) in allogeneic HSCT recipients. The overall incidence for IMI among lung, kidney, liver, and heart transplant recipients was 49, 2, 11, and 10 per 1000 person-years, respectively. The observed rate of IMI among human leukocyte antigen-matched unrelated and haploidentical HSCT recipients increased from 0.6% annually to 3.0% after bronchoscopy initiation (P < 0.05). The 12-week mortality among allogeneic HSCT, liver, kidney, heart, and lung recipients with IMI was 52.4%, 47.1%, 27.8%, 16.7%, and 9.5%, respectively. Among allogeneic HSCT (odds ratio [OR]: 0.07, P = 0.007) and SOT (OR: 0.22, P = 0.05) recipients with IA, normal platelet count was associated with improved survival. Male gender (OR: 14.4, P = 0.007) and elevated bilirubin (OR: 5.7, P = 0.04) were significant predictors of mortality for allogeneic HSCT and SOT recipients with IA, respectively. CONCLUSIONS: During the era of culture-based diagnostics, observed rates of IMI were low among all transplants except lung transplant recipients, with relatively higher mortality rates. Diagnostic aggressiveness and host variables impact the reported incidence and outcome of IMI and likely account for institutional variability in multicenter studies. Definitions to standardize diagnoses among SOT recipients are needed.

Histoplasmosis and subcutaneous nodules in a kidney transplant recipient: erythema nodosum versus fungal panniculitis.

Erythema nodosum (EN)-like lesions are a rare occurrence after solid organ transplantation. Differential diagnosis includes infective panniculitis, which can be a feature of progressive disseminated histoplasmosis (PDH), an uncommon but severe form affecting primarily immunocompromised hosts. We report on a fatal case of PDH, which presented as fungal panniculitis masquerading as EN in a renal allograft recipient 25 years after transplantation. We discuss the clinical, histopathological, and microbiological characteristics of this rare complication, with focus on its distinction from EN. This case emphasizes the central role of biopsy in transplant recipients presenting with cutaneous lesions, and the importance of clinicopathologic correlation and complementary microbiological investigations.

Epidemiology, risk factors, and outcomes of Clostridium difficile infection in kidney transplant recipients.

BACKGROUND: We sought to describe the epidemiology and risk factors for Clostridium difficile infection (CDI) among kidney transplant recipients (KTR) between 1 January 2008 and 31 December 2010. METHODS: A single-institution retrospective study was conducted among all adult KTR with CDI, defined as a positive test for C. difficile by a cell cytotoxic assay for C. difficile toxin A or B or polymerase chain reaction test for toxigenic C. difficile. RESULTS: Among 603 kidney transplants performed between 1 January 2008 and 31 December 2010, 37 (6.1%) patients developed CDI: 12 (of 128; 9.4%) high-risk (blood group incompatible and/or anti-human leukocyte antigen donor-specific antibodies) vs. 25 (of 475; 5.3%, P = 0.08) standard-risk patients. The overall rate of CDI increased from 3.7% in 2008 to 9.4% in 2010 (P = 0.05). The median time to CDI diagnosis was 9 days, with 27 (73.0%) patients developing CDI within the first 30 days after their transplant, and 14 (51.8%) developing CDI within 7 days. A case-control analysis of 37 CDI cases and 74 matched controls demonstrated the following predictors for CDI among KTR: vancomycin-resistant Enterococcus colonization before transplant (odds ratio [OR]: 3.6, P = 0.03), receipt of an organ from Centers for Disease Control high-risk donor (OR: 5.9, P = 0.006), and administration of high-risk antibiotics within 30 days post transplant (OR: 6.6, P = 0.001). CONCLUSIONS: CDI remains a common early complication in KTR, with rates steadily increasing during the study period. Host and transplant-related factors and exposure to antibiotics appeared to significantly impact the risk for CDI among KTR.

Donor-derived organ transplant transmission of coccidioidomycosis.

Coccidioidomycosis in solid organ transplant recipients most often occurs as a result of primary infection or reactivation of latent infection. Herein, we report a series of cases of transplant-related transmission of coccidioidomycosis from a single donor from a non-endemic region whose organs were transplanted to 5 different recipients. In all, 3 of the 5 recipients developed evidence of Coccidioides infection, 2 of whom had disseminated disease. The degree of T-cell immunosuppression and timing of antifungal therapy initiation likely contributed to development of disease and disease severity in these recipients. This case series highlights the importance of having a high index of suspicion for Coccidioides infection in solid organ transplant recipients, even if the donor does not have known exposure, given the difficulties of obtaining a detailed and accurate travel history from next-of-kin.

Epidemiology and outcome of invasive fungal infections in solid organ transplant recipients.

Contemporary epidemiology and outcomes of invasive fungal infections (IFIs) in solid organ transplant (SOT) recipients are not well described. From March 2004 through September 2007, proven and probable IFIs were prospectively identified in 17 transplant centers in the United States. A total 429 adult SOT recipients with 515 IFIs were identified; 362 patients received a single and 67 patients received >or=2 organs. Most IFIs were caused by Candida species (59.0%), followed by Aspergillus species (24.8%), Cryptococcus species (7.0%), and other molds (5.8%). Invasive candidiasis (IC) was the most frequently observed IFI in all groups, except for lung recipients where invasive aspergillosis (IA) was the most common IFI (P<0.0001). Almost half of IC cases in liver, heart, and lung transplant recipients occurred during the first 100 days post transplant. Over half of IA cases in lung recipients occurred >1 year post transplant. Overall 12-week mortality was 29.6%; liver recipients had the highest mortality (P=0.05). Organ damage, neutropenia, and administration of corticosteroids were predictors of death. These results extend our knowledge on the epidemiology of IFI in SOT recipients, emphasizing the occurrence of IC early after non-lung transplant, and late complications with molds after lung transplant. Overall survival appears to have improved compared with historical reports.

Epidemiology and outcome of invasive fungal infection in adult hematopoietic stem cell transplant recipients: analysis of Multicenter Prospective Antifungal Therapy (PATH) Alliance registry.

BACKGROUND: With use of data from the Prospective Antifungal Therapy (PATH) Alliance registry, we performed this multicenter, prospective, observational study to assess the epidemiologic characters and outcomes of invasive fungal infection (IFI) in hematopoietic stem cell transplant (HSCT) recipients. METHODS: Sixteen medical centers from North America reported data on adult HSCT recipients with proven or probable IFI during the period July 2004 through September 2007. The distribution of IFIs and rates of survival at 6 and 12 weeks after diagnosis were studied. We used logistic regression models to determine risk factors associated with 6-week mortality for allogeneic HSCT recipients with invasive aspergillosis (IA). RESULTS: Two hundred thirty-four adult HSCT recipients with a total of 250 IFIs were included in this study. IA (59.2%) was the most frequent IFI, followed by invasive candidiasis (24.8%), zygomycosis (7.2%), and IFI due to other molds (6.8%). Voriconazole was the most frequently administered agent (68.4%); amphotericin B deoxycholate was administered to a few patients (2.1%). Ninety-three (46.7%) of 199 HSCT recipients with known outcome had died by week 12. The 6-week survival rate was significantly greater for patients with IA than for those with invasive candidiasis and for those with IFI due to the Zygomycetes or other molds (P < .07). The 6-week mortality rate for HSCT recipients with IA was 21.5%. At 6 weeks, there was a trend toward a worse outcome among allogeneic HSCT recipients with IA who received myeloablative conditioning (P = .07); absence of mechanical ventilation or/and hemodialysis (P = .01) were associated with improved survival. CONCLUSIONS: IA remains the most commonly identified IFI among HSCT recipients, but rates of survival in persons with IA appear to have improved, compared with previously reported data. Invasive candidiasis and IFI due to molds other than Aspergillus species remain a significant problem in HSCT recipients.

Use of the PATH Alliance database to measure adherence to IDSA guidelines for the therapy of candidemia.

Candidemia is an increasing complication of the care of complex patients. Adherence to Infectious Diseases Society of America (IDSA) guidelines for the treatment of candidemia was investigated to assess the impact of compliance on outcomes of therapy. Data on the epidemiology, diagnosis, and treatment of patients with invasive fungal infections (IFIs) was extracted from the PATH Alliance registry, a prospective, multicenter, observational database of invasive fungal infections. Patients with proven candidemia were evaluated for adherence to the IDSA guidelines in terms of choice, dosage, and duration of antifungal therapy. Removal of central venous catheters and time to treatment initiation were assessed. Four-week survival data were compared. Of the 418 patients with candidemia who were included in the study, 361 patients with the necessary data sets were identified, of whom 262 (72.6%) were treated within the IDSA guidelines for the treatment of candidemia (IDSA group); the remaining 99 (27.4%) patients received treatment different from the guidelines (non-IDSA group). Kaplan-Meier (KM) survival analysis for patients in the IDSA and non-IDSA group showed mortality rates of 21.9 and 13.6%, respectively; the difference between the two groups was not statistically significant (P = 0.093). Following the exclusion of patients requiring mechanical ventilation or acute cardiac support, the modified survival KM curves were similar between the two groups. Significantly more patients in the IDSA group required mechanical ventilation and tunneled central catheters, had a concomitant IFI, and received caspofungin. The duration of treatment and inappropriate dosing did not appear to have had a significant impact on survival. Most of the deviations from IDSA guidelines were due to the inappropriate duration and dosing of therapy. No significant difference in mortality was noted between the IDSA and non-IDSA groups. The basis of these differences merit further study.

Emergence of staphylococcal cassette chromosome mec type IV methicillin-resistant Staphylococcus aureus as a cause of ventilator-associated pneumonia.

Staphylococcal cassette chromosome mec (SCCmec) type IV methicillin-resistant Staphylococcus aureus (MRSA) strains were identified in 8 (19.5%) of 41 consecutive patients with MRSA ventilator-associated pneumonia (VAP) in this retrospective, observational study. There were no significant differences in VAP severity and crude mortality rates between patients with SCCmec type II strains and patients with SCCmec type IV strains.