Multicenter Registry of Patients Receiving Systemic Mold-Active Triazoles for the Management of Invasive Fungal Infections.

INTRODUCTION: 'Real-world' data for mold-active triazoles (MATs) in the treatment of invasive fungal infections (IFIs) are lacking. This study evaluated usage of MATs in a disease registry for the management of IFIs. METHODS: Data were collected for this multicenter, observational, prospective study from 55 US centers, between March 2017 and April 2020. Eligible patients received isavuconazole, posaconazole, or voriconazole as MAT monotherapy (one MAT) or multiple/sequenced MAT therapy (more than one MAT) for prophylaxis or treatment. Patients were enrolled within 60 days of MAT initiation. The primary objective was to characterize patients receiving a MAT and their patterns of therapy. The full analysis set (FAS) included eligible patients for the relevant enrollment protocol, and the safety analysis set (SAF) included patients who received ≥ 1 MAT dose. RESULTS: Overall, 2009 patients were enrolled in the SAF. The FAS comprised 1993 patients (510 isavuconazole; 540 posaconazole; 491 voriconazole; 452 multiple/sequenced MAT therapies); 816 and 1177 received treatment and prophylaxis at study index/enrollment, respectively. Around half (57.8%) of patients were male, and median age was 59 years. Among patients with IFIs during the study, the most common pathogens were Aspergillus fumigatus in the isavuconazole (18.2% [10/55]) and voriconazole (25.5% [12/47]) groups and Candida glabrata in the posaconazole group (20.9% [9/43]); the lungs were the most common infection site (58.2% [166/285]). Most patients were maintained on MAT monotherapy (77.3% [1541/1993]), and 79.4% (1520/1915) completed their MAT therapies. A complete/partial clinical response was reported in 59.1% (591/1001) of patients with a clinical response assessment. Breakthrough IFIs were reported in 7.1% (73/1030) of prophylaxis patients. Adverse drug reactions (ADRs) were reported in 14.7% (296/2009) of patients (3.9% [20/514] isavuconazole; 11.3% [62/547] posaconazole; 14.2% [70/494] voriconazole). CONCLUSIONS: In this 'real-world' study, most patients remained on their initial therapy and completed their MAT therapy. Over half of patients receiving MATs for IFIs had a successful response, and most receiving prophylaxis did not develop breakthrough IFIs. ADRs were uncommon.

Voriconazole plus terbinafine combination antifungal therapy for invasive Lomentospora prolificans infections: analysis of 41 patients from the FungiScope® registry 2008-2019.

OBJECTIVES: Lomentospora prolificans is an emerging cause of serious invasive fungal infections. Optimal treatment of these infections is unknown, although voriconazole-containing treatment regimens are considered the treatment of choice. The objective of this study was to evaluate the role of combination antifungal therapy for L. prolificans infections. METHODS: We performed a retrospective review of medical records of patients with invasive L. prolificans infection diagnosed between 1 January 2008 and 9 September 2019 that were documented in the FungiScope® registry of rare invasive fungal infections. We compared clinical outcomes between antifungal treatment strategies. RESULTS: Over the study period, 41 individuals with invasive L. prolificans infection from eight different countries were documented in the FungiScope® registry. Overall, 17/40 (43%) had treatment response/stable disease and 21/40 (53%) had a fatal outcome attributed to invasive fungal infection. Combination antifungal therapy was associated with increased 28-day survival (15/24 survived versus 4/16 receiving monotherapy; p 0.027) and the combination voriconazole plus terbinafine trended to be associated with higher rates of treatment success (10/16, 63%, 95% CI 35%-85%) compared with other antifungal treatment regimens (7/24, 29%, 95% CI 13%-51%, p 0.053). In Kaplan-Meier survival analysis there was a higher survival probability in individuals receiving the voriconazole/terbinafine combination compared with other antifungal regimens (median survival 150 days versus 17 days). CONCLUSIONS: While overall mortality was high, combination antifungal treatment, and in particular combination therapy with voriconazole plus terbinafine may be associated with improved treatment outcomes compared with other antifungal regimens for the treatment of invasive L. prolificans infections.

Transmission of infection to liver transplant recipients from donors with infective endocarditis: lessons learned.

Donors not meeting standard criteria, such as those with bacteremia, are now being used in response to the increasing need for organs for transplantation. Recommended strategies to prevent the occurrence of donor-derived bacteremia include the use of directed antibiotic prophylaxis. However, this approach does not eliminate the risk of infection transmission. Similarly, the management of organ recipients from donors with infective endocarditis (IE) remains uncharacterized. We report 2 cases of donor-derived bacterial infections in liver transplant recipients despite pathogen-specific antibiotic prophylaxis. In both instances, the donors had documented IE treated with appropriate antimicrobial therapy and clearance of bacteremia. Recipients had very distinctive clinical outcomes likely related to pathogen virulence and the extent of donor infection. Persistent infection in the transplanted liver should be suspected in organ recipients of a liver from donors with IE, despite the absence of bacteremia at the time of death and organ procurement. For eradication, recipients may require prolonged pathogen-directed antimicrobial therapy, such as is used for endovascular infections. Prompt recognition of donors with IE, appropriate notification, and prolonged antibiotic prophylaxis are key to reducing the risk of such donor-derived infections.

Oral mucositis in myeloma patients undergoing melphalan-based autologous stem cell transplantation: incidence, risk factors and a severity predictive model.

Melphalan-based autologous stem cell transplant (Mel-ASCT) is a standard therapy for multiple myeloma, but is associated with severe oral mucositis (OM). To identify predictors for severe OM, we studied 381 consecutive newly diagnosed myeloma patients who received Mel-ASCT. Melphalan was given at 200 mg/m2 body surface area (BSA), reduced to 140 mg/m2 for serum creatinine >3 mg/dl. Potential covariates included demographics, pre-transplant serum albumin and renal and liver function tests, and mg/kg melphalan dose received. The BSA dosing resulted in a wide range of melphalan doses given (2.4-6.2 mg/kg). OM developed in 75% of patients and was severe in 21%. Predictors of severe OM in multiple logistic regression analyses were high serum creatinine (odds ratio (OR)=1.581; 95% confidence interval (CI): 1.080-2.313; P=0.018) and high mg/kg melphalan (OR=1.595; 95% CI: 1.065-2.389; P=0.023). An OM prediction model was developed based on these variables. We concluded that BSA dosing of melphalan results in wide variations in the mg/kg dose, and that patients with renal dysfunction who are scheduled to receive a high mg/kg melphalan dose have the greatest risk for severe OM following Mel-ASCT. Pharmacogenomic and pharmacokinetic studies are needed to better understand interpatient variability of melphalan exposure and toxicity.

Iron overload is a major risk factor for severe infection after autologous stem cell transplantation: a study of 367 myeloma patients.

We evaluated the risk factors for infection of 367 consecutive myeloma patients who underwent high-dose melphalan and autologous stem cell transplantation (ASCT). Examination of bone marrow iron stores (BMIS) prior to ASCT was used to evaluate body iron stores. Other variables included age, sex, active smoking, myeloma remission status, severity of mucositis and duration of severe neutropenia post-ASCT (<100 absolute neutrophils counts (ANC)/microl). Median age was 56 years; 61% of patients were males. 140 episodes of severe infections occurred in 116 patients, including bacteremia (73), pneumonia (40), severe colitis (25) and bacteremia with septic shock (two). The infection incidence per 1,000 days at risk was 45.2. Pre-ASCT risk factors for severe infection by univariate analysis were increased BMIS (OR=2.686; 95% CI 1.707-4.226; P<0.0001), smoking (OR=1.565; 95% CI 1.005-2.437; P=0.0474) and male gender (OR=1.624; 95% CI 1.019-2.589; P=0.0414). Increased BMIS (OR=2.716; 95% CI 1.720-4.287; P<0.0001) and smoking (OR=1.714; 95% CI 1.081-2.718; P=0.022) remained significant by multivariate analysis. Duration of ANC <100 micro/l (OR=1.129; 95% CI 1.039-1.226; P=0.0069 and OR=1.127; 95% CI 1.038-1.224; P=0.0045 by both univariate and multivariate analysis, respectively) was the only post-ASCT risk factor for infection. Increased pre-transplant BMIS and smoking are significant predictors of severe infection after myeloablative chemotherapy followed by ASCT in myeloma patients.

Recovery from neutropenia can be predicted by the immature reticulocyte fraction several days before neutrophil recovery in autologous stem cell transplant recipients.

The duration of neutropenia (absolute neutrophil count (ANC) < or = 100/microl) identifies cancer patients at risk for infection. A test that precedes ANC > or = 100/microl would be of clinical value. The immature reticulocyte fraction (IRF) reflects erythroid engraftment and hence a recovering marrow. We evaluated the IRF as predictor of marrow recovery among 90 myeloma patients undergoing their first and second (75 patients) melphalan-based autologous stem cell transplantation (Mel-ASCT). The time to IRF doubling (IRF-D) preceded ANC > or = 100/microl in 99% of patients after the first Mel-ASCT by (mean+/-s.d.) 4.23+/-1.96 days and in 97% of the patients after the second Mel-ASCT by 4.11+/-1.95 days. We validated these findings in a group of 117 myeloma patients and 99 patients with various disorders undergoing ASCT with different conditioning regimens. We also compared the time to hypophosphatemia and to absolute monocyte count > or = 100/microl to the time to ANC > or = 100/microl. These markers were reached prior to this ANC end point in 55 and 25% of patients but were almost always preceded by IRF-D. We conclude that the IRF-D is a simple, inexpensive and widely available test that can predict marrow recovery several days before ANC> or = 100/microl.

18F-fluorodeoxyglucose positron emission tomography contributes to the diagnosis and management of infections in patients with multiple myeloma: a study of 165 infectious episodes.

PURPOSE: Correctly identifying infection in cancer patients can be challenging. Limited data suggest that positron emission tomography (PET) using fluorine-18 fluorodeoxyglucose (FDG) may be useful for diagnosing infection. To determine the role of FDG-PET in the diagnosis of infection in patients with multiple myeloma (MM). PATIENTS AND METHODS: The medical records of 248 patients who had FDG-PET performed for MM staging or infection work-up revealing increased uptake at extramedullary sites and/or bones and joints that would be atypical for MM between October 2001 and May 2004 were reviewed to identify infections and evaluate FDG-PET contribution to patient outcome. RESULTS: One hundred sixty-five infections were identified in 143 adults with MM. Infections involved the respiratory tract [99; pneumonia (93), sinusitis (six)], bone, joint and soft tissues [26; discitis (10), osteomyelitis (nine), septic arthritis (one), cellulitis (six)], vascular system [18; septic thrombophlebitis (nine), infection of implantable catheter (eight), septic emboli (one)], gastrointestinal tract [12; colitis (seven), abdominal abscess (three), and diverticulitis and esophagitis (one each)], and dentition [periodontal abscess (10)]. Infections were caused by bacteria, mycobacteria, fungi, and viruses. FDG-PET detected infection even in patients with severe neutropenia and lymphopenia (30 episodes). The FDG-PET findings identified infections not detectable by other methods (46 episodes), determined extent of infection (32 episodes), and led to modification of work-up and therapy (55 episodes). Twenty silent, but clinically relevant, infections were detected among patients undergoing staging FDG-PET. CONCLUSION: In patients with MM, FDG-PET is a useful tool for diagnosing and managing infections even in the setting of severe immunosuppression.

Serial measurement of serum C-reactive protein levels can identify patients at risk for severe complications following autologous stem cell transplantation.

The value of serum C-reactive protein (CRP) levels as a predictor of complications in neutropenic patients needs to be further defined. We sought to identify an association between severe complications and daily CRP levels measured in 104 multiple myeloma patients during the 3 week period following high-dose melphalan and autologous transplant. Significantly higher mean CRP levels and CRP velocity of increase were observed among patients with severe complications. A cut-off point of 100 mg/l (CRP levels) and 15 mg/l/day (CRP velocity) identified patients likely to suffer severe complications with 86 and 75% sensitivity, respectively. Prospective validation of this model is currently underway.

Leaving previously implanted central venous catheters (ports) in place does not increase morbidity in patients undergoing autologous peripheral stem cell transplantation.

We sought to assess if leaving in place a previously inserted noncolonized or infected implantable catheter (IC) is associated with an increase in morbidity in patients undergoing autologous peripheral stem cell transplantation (APSCT). Medical records from all patients between March 1997 and January 2002 undergoing APSCT with an IC in place were reviewed. Case group (IC in place) was compared with a control group (no IC) from 6 days prior to 60 days after APSCT. In all, 43 cases were matched with 43 controls by underlying disease, age and sex. In both groups, duration of neutropenia and use of antimicrobial prophylaxis were comparable. Underlying malignancies were lymphoma (22/24), multiple myeloma (14/12), leukemia (3/3), and others (7/7) in case and control groups. Cases and controls had comparable rates of risk for fever, bloodstream infection, use of vancomycin and amphotericin B, and death, as well as comparable lengths of stay and readmissions. ICs were used in 20 of 43 patients. Using the IC did not significantly increase the risk of fever, bloodstream infection, length of stay, and/or readmissions after APSCT but was associated with increased use of antibacterial and antifungal agents. Leaving in place a previously inserted, noncolonized or infected IC did not increase morbidity in patients undergoing APSCT.

Loss of hepatitis A virus (HAV) antibodies after peripheral stem cell transplantation (PSCT).

The majority of patients with hepatitis A have a benign course, but some may develop fulminant hepatitis and hematological complications. Peripheral stem cell transplantation (PSCT) is associated with loss of immunity. There are no data regarding loss of HAV antibodies (anti-HAV) after PSCT. We retrospectively evaluated the persistence of anti-HAV in a nonvaccinated population that underwent PSCT. Serum detection of anti-HAV was determined before and after PSCT using a qualitative commercially available enzyme immunoassay. From January 1997 to March 2001, 136 (68%) of 201 patients tested (+) for anti-HAV prior to PSCT. Subsequent investigation of anti-HAV was possible in 36 of these patients at a median of 12 months after PSCT. The median age of patients was 47 years old; they had diagnoses of hematological malignancies (33) and solid tumors (three), and underwent autologous (31) and allogenic (five) PSCT. A total of 31 (86%) of 36 patients remained anti-HAV (+) and five (14%) became (-) after PSCT. The variables age, sex, diagnosis, type of PSCT, time of testing, and number of CD34 cells infused were not predictors of loss of anti-HAV. In conclusion, 14% of 36 nonvaccinated anti-HAV (+) patients lost their antibodies at a median of 12 months after PSCT.