Evaluation of outbreak persistence caused by multidrug-resistant and echinocandin-resistant Candida parapsilosis using multidimensional experimental and epidemiological approaches.

Candida parapsilosis is known to cause severe and persistent outbreaks in clinical settings. Patients infected with multidrug-resistant C. parapsilosis (MDR Cp) isolates were identified in a large Turkish hospital from 2017-2020. We subsequently identified three additional patients infected with MDR Cp isolates in 2022 from the same hospital and two echinocandin-resistant (ECR) isolates from a single patient in another hospital. The increasing number of MDR and ECR isolates contradicts the general principle that the severe fitness cost associated with these phenotypes could prevent their dominance in clinical settings. Here, we employed a multidimensional approach to systematically assess the fitness costs of MDR and ECR C. parapsilosis isolates. Whole-genome sequencing revealed a novel MDR genotype infecting two patients in 2022. Despite severe in vitro defects, the levels and tolerances of the biofilms of our ECR and MDR isolates were generally comparable to those of susceptible wild-type isolates. Surprisingly, the MDR and ECR isolates showed major alterations in their cell wall components, and some of the MDR isolates consistently displayed increased tolerance to the fungicidal activities of primary human neutrophils and were more immunoevasive during exposure to primary human macrophages. Our systemic infection mouse model showed that MDR and ECR C. parapsilosis isolates had comparable fungal burden in most organs relative to susceptible isolates. Overall, we observed a notable increase in the genotypic diversity and frequency of MDR isolates and identified MDR and ECR isolates potentially capable of causing persistent outbreaks in the future.

Adjunctive glucocorticoid therapy for Pneumocystis jirovecii pneumonia in solid organ transplant recipients: A multicenter cohort, 2015-2020.

Solid organ transplant recipients (SOTRs) frequently receive adjunctive glucocorticoid therapy (AGT) for Pneumocystis jirovecii pneumonia (PJP). This multicenter cohort of SOTRs with PJP admitted to 20 transplant centers in Canada, the United States, Europe, and Australia, was examined for whether AGT was associated with a lower rate of all-cause intensive care unit (ICU) admission, 90-day death, or a composite outcome (ICU admission or death). Of 172 SOTRs with PJP (median [IQR] age: 60 (51.5-67.0) years; 58 female [33.7%]), the ICU admission and death rates were 43.4%, and 20.8%, respectively. AGT was not associated with a reduced risk of ICU admission (adjusted odds ratio [aOR] [95% CI]: 0.49 [0.21-1.12]), death (aOR [95% CI]: 0.80 [0.30-2.17]), or the composite outcome (aOR [95% CI]: 0.97 [0.71-1.31]) in the propensity score-adjusted analysis. AGT was not significantly associated with at least 1 unit of the respiratory portion of the Sequential Organ Failure Assessment score improvement by day 5 (12/37 [32.4%] vs 39/111 [35.1%]; P = .78). We did not observe significant associations between AGT and ICU admission or death in SOTRs with PJP. Our findings should prompt a reevaluation of routine AGT administration in posttransplant PJP treatment and highlight the need for interventional studies.

Recent Advances in Adult Post-Transplant Lymphoproliferative Disorder.

PTLD is a rare but severe complication of hematopoietic or solid organ transplant recipients, with variable incidence and timing of occurrence depending on different patient-, therapy-, and transplant-related factors. The pathogenesis of PTLD is complex, with most cases of early PLTD having a strong association with Epstein-Barr virus (EBV) infection and the iatrogenic, immunosuppression-related decrease in T-cell immune surveillance. Without appropriate T-cell response, EBV-infected B cells persist and proliferate, resulting in malignant transformation. Classification is based on the histologic subtype and ranges from nondestructive hyperplasias to monoclonal aggressive lymphomas, with the most common subtype being diffuse large B-cell lymphoma-like PTLD. Management focuses on prevention of PTLD development, as well as therapy for active disease. Treatment is largely based on the histologic subtype. However, given lack of clinical trials providing evidence-based data on PLTD therapy-related outcomes, there are no specific management guidelines. In this review, we discuss the pathogenesis, histologic classification, and risk factors of PTLD. We further focus on common preventive and frontline treatment modalities, as well as describe the application of novel therapies for PLTD and elaborate on potential challenges in therapy.

The Pathogenesis and Diagnosis of Pneumocystis jiroveci Pneumonia.

Pneumocystis jiroveci remains an important fungal pathogen in immunocompromised hosts. The environmental reservoir remains unknown. Pneumonia (PJP) results from airborne transmission, including in nosocomial clusters, or with reactivation after an inadequately treated infection. Pneumocystis pneumonia most often occurs within 6 months of organ transplantation, with intensified or prolonged immunosuppression, notably with corticosteroids and following cytomegalovirus (CMV) infections. Infection may be recognized during recovery from neutropenia and lymphopenia. Invasive procedures may be required for early diagnosis and therapy. Despite being a well-established entity, aspects of the pathogenesis of PJP remain poorly understood. The goal of this review is to summarize the data on the pathogenesis of PJP, review the strengths and weaknesses of the pertinent diagnostic modalities, and discuss areas for future research.

Clinical Features and Multimodal Imaging in Atypical Posterior Uveitis Secondary to Bartonella Henselae Infection.

PURPOSE: To characterize an unusual presentation of infectious posterior uveitis using multimodal imaging, and discuss the clinical decision-making involved in diagnosis and treatment. METHODS: Wide-field fundus photography, swept-source optical coherence tomography (OCT), swept-source OCT angiography, fluorescein angiography, and indocyanine green angiography. RESULTS: This patient presented with cyclical fevers and blurry vision. Fundus examination revealed bilateral optic disc edema, macular intraretinal white spots and many scattered yellow-white chorioretinal lesions. Multimodal imaging characteristics suggested that many of these lesions represent choroidal granulomas. Extensive systemic workup was only notable for borderline elevated Bartonella henselae IgG titers (1:128), however convalescent IgG titers were elevated at 38 days (1:512) supporting the diagnosis of Bartonella chorioretinitis. CONCLUSION: Ocular manifestations of Bartonella henselae infection are varied and may include choroidal granulomas. Multimodal imaging characteristics may help identify etiologies of infectious uveitis. Convalescent titers are important when evaluating patients with suspected Bartonellosis, especially patients with atypical presentations.

Invasive Pulmonary Aspergillosis Complicating Noninfluenza Respiratory Viral Infections in Solid Organ Transplant Recipients.

BACKGROUND: Invasive pulmonary aspergillosis (IPA) is increasingly recognized as a complication of severe influenza and coronavirus disease 2019. The extent to which other respiratory viral infections (RVIs) predispose to IPA is unclear. METHODS: We performed a retrospective review of IPA occurring within 90 days of respiratory syncytial virus (RSV), parainfluenza, or adenovirus infections (noninfluenza respiratory viral infections [NI-RVIs]) in patients who underwent solid organ transplant between 1/15/2011 and 12/19/2017. RESULTS: At a median post-transplant follow-up of 43.4 months, 221 of 2986 patients (7.4%) developed 255 RSV, parainfluenza, or adenovirus infections. IPA complicating these NI-RVIs was exclusively observed in lung and small bowel transplant recipients, in whom incidence was 5% and 33%, respectively. Cumulative prednisone doses >140mg within 7 days and pneumonia at the time of NI-RVI were independent risk factors for IPA (odds ratio [OR], 22.6; 95% CI, 4.5-112; and OR, 7.2; 95% CI, 1.6-31.7; respectively). Mortality at 180 days following NI-RVI was 27% and 7% among patients with and without IPA, respectively (P = .04). CONCLUSIONS: In conclusion, IPA can complicate RSV, parainfluenza, and adenovirus infection in lung and small bowel transplant recipients. Future research is needed on the epidemiology of IPA complicating various RVIs. In the interim, physicians should be aware of this complication.

End-of-life cost for lung cancer patients in Greece: a hospital-based retrospective study.

Objective: The aim of the present study was to estimate the cost of treating patients with lung cancer at their end-of-life (EOL) phase of care in Greece. Materials & methods: A hospital-based retrospective study was conducted in the Oncology Unit of 'Sotiria' Hospital, in Athens, Greece. All lung cancer patients who died between 1 January 2015 and 31 December 2018 with at least 6 months follow-up were enrolled in the study. Healthcare resource utilization data, including inpatient and outpatient ones, during the last 6 months before death was extracted from a registry kept in the unit. This data were combined with the corresponding local unit costs to calculate the 6, 3 and 1-month EOL cost in €2019 values. Results: A total of 122 patients met the inclusion criteria. The mean (standard deviation) age at diagnosis was 67.8 (8.9) years with 78.7% of patients being male and 55.0% diagnosed at stage IV. About 52.5% of patients had been diagnosed with adenocarcinoma, 28.7% with squamous non-small-cell lung cancer types and 18.9% with small-cell-lung cancer. The median overall survival of these patients was 10.8 months. During the EOL periods, the mean cost/patient in the last 6, 3 and 1 month were €7665, €3351 and €1009, respectively. Pharmaceutical cost was the key driver of the total cost (75% of the total 6-month) followed by radiation therapy (16.2%). The median EOL 6-month cost was marginally statistically significantly higher among patients with adenocarcinoma (€9031) compared with squamous (€6606) and to small-cell-lung cancer (€5474). Conclusion: The findings of the present study indicate that lung cancer treatment incurs high costs in Greece, mainly attributed to pharmaceutical expenses, even at the EOL phase.

Invasive Pulmonary Aspergillosis in Patients with SARS-CoV-2 Infection: A Systematic Review of the Literature.

In this systematic review, we investigate the epidemiology, pathogenesis, risk factors, clinical manifestations, diagnosis and treatment of COVID-19-associated pulmonary aspergillosis (CAPA). We identified 85 cases from 22 studies. The frequency of CAPA is currently unknown but ranges between <5% to >30% in different case series; the possibility of colonization rather than invasive disease is the most important confounder. The vast majority of patients with CAPA did not have any of the classic host risk factors, such as immunosuppression from organ transplant or neutropenia, although a significant proportion (46%) had received corticosteroids. Age, pulmonary comorbidities and male sex were associated with higher mortality. Patients treated with voriconazole had numerically lower case-fatality rate. Clinical vigilance for CAPA is advisable in critically ill patients with COVID-19 who are not improving, even those who do not meet classic host criteria for invasive mycoses, especially if they are receiving corticosteroids. A thorough, multi-faceted diagnostic work-up and early initiation of a mold-active triazole may be lifesaving. Further research studies using standardized, uniform definitions of invasive disease and colonization are urgently needed.

A Retrospective Comparative Study of Different Methods of Blood Management in Total Knee Replacement.

Perioperative blood management is essential to minimize allogeneic blood transfusion in total knee replacement. The effect of preoperative administration of erythropoietin, intraoperative cell saver, tranexamic acid, and restrictive transfusion strategies on allogeneic transfusion is studied in total knee replacement. A retrospective comparative study of 106 patients who underwent total knee replacement in different time periods was performed. Group A (n 1 = 45) underwent restrictive strategies of transfusion between 2009 and 2010. Group B (n 2 = 24) includes patients where erythropoietin of either 10.000 IU or 20.000 IU was given preoperatively. Patients of Group C (n 3 = 21) underwent autologous washed erythrocytes transfusion through a cell saver. Lastly, in Group D (n 4 = 15) tranexamic acid dose of 1 gr IV was given intraoperatively. The preoperative and discharge hemoglobin together with total units of blood transfusion and creatinine levels was studied. Tranexamic acid noted the least units of blood transfusion (mean = 0.82 units/patient, p < 0.001, CI 95%) in contrast to the two regimens of erythropoietin (1.16 units/patient) OrthoPAT (1.43 units/patient) and restrictive strategies (1.92 units/patient). The mean preoperative hemoglobin was 13.37 g/dL with no statistical difference among the groups of patients. The postoperative mean hemoglobin was 10.59 with no statistical difference among the groups of patients too. Additionally, the mean creatinine level was 0.93 mg/dL; however, no statistical difference among the groups of patients was noted. Finally, tranexamic acid seemed to be the most cost-effective regime. In our study, tranexamic acid proved its superiority concerning the postoperative blood transfusion on patients undergoing total knee replacement, in comparison with the other existing methods of perioperative blood management. This is a Level III, retrospective comparative study.

The Dose-Dependent Efficacy of Cefepime in the Empiric Management of Febrile Neutropenia: A Systematic Review and Meta-Analysis.

BACKGROUND: Despite reports questioning its efficacy, cefepime remains a first-line option in febrile neutropenia. We aimed to re-evaluate the role of cefepime in this setting. METHODS: We searched the PubMed and EMBASE databases to identify randomized comparisons of (1) cefepime vs alternative monotherapy or (2) cefepime plus aminoglycoside vs alternative monotherapy plus aminoglycoside, published until November 28, 2016. RESULTS: Thirty-two trials, reporting on 5724 patients, were included. Clinical efficacy was similar between study arms (P = .698), but overall mortality was greater among cefepime-treated patients (risk ratio [RR] = 1.321; 95% confidence interval [CI], 1.035-1.686; P = .025). Also of note, this effect seemed to stem from trials using low-dose (2 grams/12 hours, 100 mg/kg per day) cefepime monotherapy (RR = 1.682; 95% CI, 1.038-2.727; P = .035). Cefepime was also associated with increased mortality compared with carbapenems (RR = 1.668; 95% CI, 1.089-2.555; P = .019), a finding possibly influenced by cefepime dose, because carbapenems were compared with low-dose cefepime monotherapy in 5 of 9 trials. Treatment failure in clinically documented infections was also more frequent with cefepime (RR = 1.143; 95% CI, 1.004-1.300; P = .043). Toxicity-related treatment discontinuation was more common among patients that received high-dose cefepime (P = .026), whereas low-dose cefepime monotherapy resulted in fewer adverse events, compared with alternative monotherapy (P = .009). CONCLUSIONS: Cefepime demonstrated increased mortality compared with carbapenems, reduced efficacy in clinically documented infections, and higher rates of toxicity-related treatment discontinuation. The impact of cefepime dosing on these outcomes is important, because low-dose regimens were associated with lower toxicity at the expense of higher mortality.

Fever of unknown origin (FUO) due to miliary BCG: The diagnostic importance of morning temperature spikes and highly elevated ferritin levels.

Fever of unknown origin (FUO) is defined as prolonged fever of >101 °F for at least 3 weeks that remains undiagnosed after a focused inpatient or outpatient workup. One of the most elusive FUO diagnoses is miliary tuberculosis (TB) which typically has few/no localizing signs/symptoms. Since the introduction of intravesicular Bacille Calmette-Guerin (BCG) treatment for bladder carcinoma, miliary BCG has only rarely been reported as a cause of FUO. As with miliary TB, there are few/no clues to suspect miliary BCG. We present an interesting case of FUO due to miliary BCG without any localizing signs, i.e., no lung, liver or prostate involvement. The only clues to the diagnosis of this FUO due to disseminated BCG were morning temperature spikes and otherwise unexplained highly elevated ferritin levels.

Model studies on acrylamide generation from glucose/asparagine in aqueous glycerol.

Acrylamide formation from asparagine and glucose in different ratios in neutral glycerol/water mixtures was found to increase with decreasing water activity (0.33 < or = aw < or = 0.71 investigated) and increasing temperature (120 degrees C < or = T < or = 160 degrees C investigated). The initial rate of acrylamide formation was found to be approximately proportional to the asparagine concentration for an excess of asparagine, but less dependent on an excess of glucose. A steady-state concentration of acrylamide was established at 160 degrees C after 1 h for aw = 0.33 (30 microg x L-1 for GLU:ASN = 10:1, 11 microg x L-1 for GLU:ASN = 1:1, and 130 microg x L-1 for GLU:ASN = 1:10) and for aw = 0.47 (15 microg x L-1 for GLU:ASN = 10:1 and 80 microg x L-1 for GLU:ASN = 1:10), suggesting a protection by glucose against acrylamide degradation. The energy of activation, as estimated from the temperature dependence of the initial rate, increased with decreasing aw despite a higher rate of formation of acrylamide at low aw. For high aw, water elimination from a reaction intermediate is suggested to be rate determining. For low aw, the increase in energy of activation (and enthalpy of activation) is accordingly counteracted by a more positive entropy of activation, in agreement with decarboxylation as rate determining at low aw.