An Open-Label, Randomized Trial Comparing Fidaxomicin With Oral Vancomycin for the Treatment of Clostridioides difficile Infection in Hospitalized Patients Receiving Concomitant Antibiotics for Concurrent Infections.

BACKGROUND: Recurrent Clostridioides difficile infection (rCDI) occurs frequently, and concomitant antibiotic (CA) during the initial episode for treatment of non-CDI is a major risk factor. We sought to address the comparative efficacy of fidaxomicin versus vancomycin in the setting of CA during the initial CDI episode. METHODS: We conducted a randomized, controlled, open-label trial at 2 hospitals in Ann Arbor, Michigan. We consecutively consented and enrolled hospitalized patients ≥18 years old with diarrhea, a positive test for C. difficile, and ≥1 qualifying CA. Complicated CDI, CDI treatment for >24 hours prior to enrollment, and planned long-term (>12 weeks) CA use were notable exclusions. Clinical cure was defined as resolution of diarrhea for 2 consecutive days maintained until 2 days after therapy, and rCDI as recurrent diarrhea with positive testing ≤30 days after initial treatment. Patients were randomized to fidaxomicin or vancomycin. RESULTS: Baseline characteristics were similar in the 2 groups of 144 patients. Rates of clinical cure (73% vs 62.9%, P = .195) and rCDI (3.3% vs 4.0%; P > .99) were similar for fidaxomicin and vancomycin in the intention-to-treat and per-protocol cohorts, respectively. Only 4 patients developed rCDI. CONCLUSIONS: In this study of patients with CDI receiving CA, a numerically higher proportion were cured with fidaxomicin versus vancomycin, but this result did not reach statistical significance. Overall recurrence was lower than anticipated in both arms compared with previous studies that did not extend duration of CDI treatment during CA. CLINICAL TRIALS REGISTRATION: www.clinicaltrials.gov (NCT02692651).

Cytomegalovirus infection is associated with impaired myocardial flow reserve after heart transplantation.

BACKGROUND: Cardiac allograft vasculopathy (CAV) limits long-term survival after heart transplantation (HT). This study evaluates the relationship between clinically significant cytomegalovirus infection (CS-CMVi) and CAV using cardiac positron emission tomography (PET). METHODS: We retrospectively evaluated HT patients from 2005 to 2019 who underwent cardiac PET for CAV evaluation. Multivariable linear and logistic regression models were used to evaluate the association between CS-CMVi and myocardial flow reserve (MFR). Kaplan-Meier and Cox regression analyses were used to assess the relationship between CS-CMV, MFR, and clinical outcomes. RESULTS: Thirty-two (31.1%) of 103 HT patients developed CS-CMVi at a median 9 months after HT. Patients with CS-CMVi had a significantly lower MFR at year 1 and 3, driven by reduction in stress myocardial blood flow. Patients with CS-CMVi had a faster rate of decline in MFR compared to those without infection (-0.10 vs -0.06 per year, p < 0.001). CS-CMVi was an independent predictor of abnormal MFR (<2.0) (odds ratio: 3.8, 95% confidence intervals (CI): 1.4-10.7, p = 0.001) and a lower MFR (ß = -0.39, 95% CI: -0.63 to -0.16, p = 0.001) at year 3. In adjusted survival analyses, both abnormal MFR (log-rank p < 0.001; hazard ratio [HR]: 5.7, 95% CI: 4.2-7.2) and CS-CMVi (log-rank p = 0.028; HR: 3.3, 95% CI: 1.8-4.8) were significant predictors of the primary outcome of all-cause mortality, retransplantation, heart failure hospitalization, and acute coronary syndrome. CONCLUSIONS: CS-CMVi is an independent predictor of reduced MFR following HT. These findings suggest that CMV infection is an important risk factor in the development and progression of CAV.

Real-World Data Collection from Expanded Access Case Studies for the Treatment of Nontuberculous Mycobacterial Infection with Clofazimine.

Background: Due to its indolent nature, nontuberculous mycobacteria (NTM) are increasing in global prevalence as a cause of pulmonary infections and are difficult to treat with traditional antibiotics. Here, we study the repurposing of clofazimine (CFZ) to treat NTM through expanded access in a single health system. Our main objectives are to describe the feasibility of accessing and analyzing expanded access data and to generate hypotheses regarding CFZ use in NTM treatment. Methods: A retrospective chart review was performed on patients within a single health system who had been approved for expanded access of clofazimine or who received it through an outside hospital for NTM treatment. Data were collected on patients' baseline demographics, details of their NTM infection, concomitant therapies, and results as of 30 June 2021. Results: A total of 55 patients were identified upon initial review as potentially receiving CFZ for NTM infection. After excluding 19 patients who did not initiate CFZ, data from the remaining 36 patients were collected and summarized. The median age at which patients were diagnosed with NTM was 51.3 years old, with a median BMI of 21.2 kg/m2. Patients were more likely to be female (64%), have a baseline lung disease (72%), and 52% were current or former smokers at the time of their diagnosis. The most common species isolated was M. avium complex (47%) followed by M. abscessus (36%), with the most common site of infection being the lung (78%). The majority of patients presented with productive cough with excess sputum production followed by pulmonary nodules and bronchiectasis present on radiograph. Conclusions: This study demonstrated the difficulty of collecting retrospective real-world data via electronic healthcare records on symptoms, side effects, and radiography from patients who obtained a drug through expanded access. Based on the findings of this study, we recommend further research into the potential use of CFZ in patients with M. abscessus pulmonary infections.

Successful Treatment of Prolonged Severe Acute Respiratory Syndrome Coronavirus 2 Infection in Patients With Immunodeficiency With Extended Nirmatrelvir/Ritonavir: Case Series.

Immunocompromised patients with B-cell deficiencies are at risk for prolonged symptomatic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We describe 4 patients treated for B-cell malignancies with B-cell-depleting therapies who developed persistent SARS-CoV-2 infection and had resolution of symptoms following an extended course of nirmatrelvir/ritonavir.

Defibrotide Therapy for SARS-CoV-2 ARDS.

BACKGROUND: SARS-CoV-2-related ARDS is associated with endothelial dysfunction and profound dysregulation of the thrombotic-fibrinolytic pathway. Defibrotide is a polyanionic compound with fibrinolytic, antithrombotic, and antiinflammatory properties. RESEARCH QUESTION: What is the safety and tolerability of defibrotide in patients with severe SARS-CoV-2 infections? STUDY DESIGN AND METHODS: We report a prospective, open-label, single-center safety trial of defibrotide for the management of SARS-CoV-2-related ARDS. Eligible participants were 18 years of age or older with clinical and radiographic signs of ARDS, no signs of active bleeding, a serum D-dimer of more than twice upper limit of normal, and positive polymerase chain reaction-based results for SARS-CoV-2. Defibrotide (6.25 mg/kg/dose IV q6h) was administered for a planned 7-day course, with serum D-dimer levels and respiratory function monitored daily during therapy. RESULTS: Twelve patients (median age, 63 years) were treated, with 10 patients receiving mechanical ventilation and 6 receiving vasopressor support at study entry. The median D-dimer was 3.25 µg/ml (range, 1.33-12.3) at study entry. The median duration of therapy was 7 days. No hemorrhagic or thrombotic complications occurred during therapy. No other adverse events attributable to defibrotide were noted. Four patients met the day 7 pulmonary response parameter, all four showing a decrease in serum D-dimer levels within the initial 72 h of defibrotide therapy. Three patients died of progressive pulmonary disease 11, 17, and 34 days after study entry. Nine patients (75%) remain alive 64 to 174 days after initiation of defibrotide. Day 30 all-cause mortality was 17% (95% CI, 0%-35%). All patients with a baseline Pao2 to Fio2 ratio of ≥ 125 mm Hg survived, whereas the three patients with a baseline Pao2 to Fio2 ratio of < 125 mm Hg died. INTERPRETATION: The use of defibrotide for management of SARS-CoV-2-related ARDS proved safe and tolerable. No hemorrhagic or thrombotic complications were reported during therapy, with promising outcomes in a patient population with a historically high mortality rate. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT04530604; URL: www. CLINICALTRIALS: gov.

Early Antibiotic Discontinuation or De-escalation in High-Risk Patients With AML With Febrile Neutropenia and Prolonged Neutropenia.

BACKGROUND: There is minimal data evaluating the safety of antibiotic de-escalation in patients with acute myeloid leukemia (AML) with fever and ongoing neutropenia. Therefore, this study evaluated antibiotic prescribing, infection-related outcomes, and patient outcomes of an antibiotic de-escalation initiative. PATIENTS AND METHODS: This pre-post quasiexperimental study included adult patients with AML hospitalized with febrile neutropenia. An antibiotic de-escalation guideline was implemented in January 2017, which promoted de-escalation or discontinuation of intravenous antipseudomonal ß-lactams. The primary outcome assessment was the incidence of bacterial infection in a historical control group before guideline implementation compared with an intervention group after guideline implementation. RESULTS: A total of 93 patients were included. Antibiotic de-escalation occurred more frequently in the intervention group (71.7% vs 7.5%; P<.001), which resulted in fewer days of therapy for intravenous antipseudomonal ß-lactams (14 vs 25 days; P<.001). Thirty-day all-cause mortality and length of hospitalization were not different between groups. However, the intervention group had significantly fewer episodes of Clostridioides difficile colitis (5.7% vs 27.5%; P=.007). CONCLUSIONS: Implementation of an antibiotic de-escalation guideline resulted in decreased use of intravenous antipseudomonal ß-lactams and fewer episodes of C difficile colitis, without adversely impacting patient outcomes. Additional studies are needed, preferably in the form of randomized controlled trials, to confirm these results.

Coronavirus-19-Associated Retinopathy.

Background: To describe the first case of Coronavirus disease-2019 (COVID-19) vision loss from an acute outer retinopathy.Methods: A retrospective case report from a tertiary referral center using multimodal retinal imaging and clinical examination findingsFindings: A 40-year-old female developed significant vision loss in her right eye shortly after developing fever and myalgias. She was found to be COVID positive, while her systemic laboratory evaluation was otherwise unremarkable. Multimodal imaging was consistent with a white-dot-like outer retinopathy and she was started on systemic prednisone. Within 10 days of starting steroids, her vision, symptoms, and outer retinal changes on multimodal imaging were improving.Interpretation: While exceedingly rare, COVID-19 can cause inflammatory-associated changes of the outer retina and significant vision loss.

Tocilizumab for Treatment of Mechanically Ventilated Patients With COVID-19.

BACKGROUND: Severe coronavirus disease 2019 (COVID-19) can manifest in rapid decompensation and respiratory failure with elevated inflammatory markers, consistent with cytokine release syndrome for which IL-6 blockade is an approved treatment. METHODS: We assessed effectiveness and safety of IL-6 blockade with tocilizumab in a single-center cohort of patients with COVID-19 requiring mechanical ventilation. The primary endpoint was survival probability postintubation; secondary analyses included an ordinal illness severity scale integrating superinfections. Outcomes in patients who received tocilizumab compared with tocilizumab-untreated controls were evaluated using multivariable Cox regression with propensity score inverse probability of treatment weighting (IPTW). RESULTS: 154 patients were included, of whom 78 received tocilizumab and 76 did not. Median follow-up was 47 days (range, 28-67). Baseline characteristics were similar between groups, although tocilizumab-treated patients were younger (mean: 55 vs 60 years), less likely to have chronic pulmonary disease (10% vs 28%), and had lower D-dimer values at time of intubation (median: 2.4 vs 6.5 mg/dL). In IPTW-adjusted models, tocilizumab was associated with a 45% reduction in hazard of death (HR, .55; 95% CI, .33-.90) and improved status on the ordinal outcome scale [OR per 1-level increase, .58; .36-.94). Although tocilizumab was associated with an increased proportion of patients with superinfections (54% vs 26%; P < .001), there was no difference in 28-day case fatality rate among tocilizumab-treated patients with versus without superinfection (22% vs 15%; P = .42). Staphylococcus aureus accounted for ~50% of bacterial pneumonia. CONCLUSIONS: In this cohort of mechanically ventilated COVID-19 patients, tocilizumab was associated with lower mortality despite higher superinfection occurrence.

Tocilizumab for treatment of mechanically ventilated patients with COVID-19.

BACKGROUND: Severe COVID-19 can manifest in rapid decompensation and respiratory failure with elevated inflammatory markers. This presentation is consistent with cytokine release syndrome in chimeric antigen receptor T cell therapy, for which IL-6 blockade is approved treatment. METHODS: We assessed effectiveness and safety of IL-6 blockade with tocilizumab in a single-center cohort of patients with COVID-19 requiring mechanical ventilation. The primary endpoint was survival probability post-intubation; secondary analyses included an ordinal illness severity scale integrating superinfections. Outcomes in patients who received tocilizumab compared to tocilizumab-untreated controls were evaluated using multivariable Cox regression with propensity score inverse probability weighting (IPTW). FINDINGS: 154 patients were included, of whom 78 received tocilizumab and 76 did not. Median follow-up was 47 days (range 28-67). Baseline characteristics were similar between groups, although tocilizumab-treated patients were younger (mean 55 vs. 60 years), less likely to have chronic pulmonary disease (10% vs. 28%), and had lower D-dimer values at time of intubation (median 2.4 vs. 6.5 mg/dL). In IPTW-adjusted models, tocilizumab was associated with a 45% reduction in hazard of death [hazard ratio 0.55 (95% CI 0.33, 0.90)] and improved status on the ordinal outcome scale [odds ratio per 1-level increase: 0.59 (0.36, 0.95)]. Though tocilizumab was associated with an increased proportion of patients with superinfections (54% vs. 26%; p<0.001), there was no difference in 28-day case fatality rate among tocilizumab-treated patients with versus without superinfection [22% vs. 15%; p=0.42]. INTERPRETATION: In this cohort of mechanically ventilated COVID-19 patients, tocilizumab was associated with a decreased likelihood of death despite higher superinfection occurrence. Randomized controlled trials are urgently needed to confirm these findings.

Coronavirus Disease 2019 (COVID-19) Clinical Trial Oversight at a Major Academic Medical Center: Approach of Michigan Medicine.

Clinicians, eager to offer the best care in the absence of guiding data, have provided patients with coronavirus disease 2019 (COVID-19) diverse clinical interventions. This usage has led to perceptions of efficacy of some interventions that, while receiving media coverage, lack robust evidence. Moving forward, randomized controlled clinical trials are necessary to ensure that clinicians can treat patients effectively during this outbreak and the next. To do so, academic medical centers must address 2 key research issues: (1) how to effectively and efficiently determine which trials have the best chance of benefiting current and future patients and (2) how to establish a transparent and ethical process for subject recruitment while maintaining research integrity and without overburdening patients or staff. We share here the current methods used by Michigan Medicine to address these issues.

Acquired hypogammaglobulinemia and pathogen-specific antibody depletion after solid organ transplantation in human immunodeficiency virus infection: A brief report.

Hypogammaglobulinemia (HGG) frequently occurs in recipients after types of (SOT). The incidence and significance of HGG in HIV+ recipients of SOT are just being explored. We reported that 12% of the recipients in the SOT in multi-center HIV-TR (HIV-TR) Study developed moderate or severe HGG at 1 year. In LT recipients, this was associated with serious infections and death. We have now further characterized the decreased antibodies in HIV+ SOT recipients who developed HGG. We measured the levels of pathogen-specific antibodies and poly-specific self-reactive antibodies (PSA) in relation to total IgG levels from serial serum samples for 20 HIV+ SOT recipients who developed moderate to severe HGG following SOT. Serum antibody levels to measles, tetanus toxoid, and HIV-1 were determined by EIA. Levels of PSAs were determined by incubating control lymphocytes with patient serum, staining with anti-human IgG Fab-FITC, and analysis by flow cytometry. Levels of PSA were higher compared to healthy, HIV-uninfected controls at pre-transplant baseline and increased by weeks 12 and 26, but the changes were not significant. Likewise, anti-HIV antibody levels remained unchanged over time. In contrast, antibody levels against measles and tetanus were significantly reduced from baseline by week 12, and did not return to baseline, even after 2 years. For HIV patients who develop moderate to severe HGG after transplant, the reduction in IgG levels is associated with a significant decrease in pathogen-specific antibody titers, while PSA levels and anti-HIV antibodies are unchanged. This may contribute to infectious complications and other clinical endpoints.

A Randomized, Placebo-controlled Trial of Fidaxomicin for Prophylaxis of Clostridium difficile-associated Diarrhea in Adults Undergoing Hematopoietic Stem Cell Transplantation.

Background: Clostridium difficile-associated diarrhea (CDAD) is common during hematopoietic stem-cell transplantation (HSCT) and is associated with increased morbidity and mortality. We evaluated fidaxomicin for prevention of CDAD in HSCT patients. Methods: In this double-blind study, subjects undergoing HSCT with fluoroquinolone prophylaxis stratified by transplant type (autologous/allogeneic) were randomized to once-daily oral fidaxomicin (200 mg) or a matching placebo. Dosing began within 2 days of starting conditioning or fluoroquinolone prophylaxis and continued until 7 days after neutrophil engraftment or completion of fluoroquinolone prophylaxis/clinically-indicated antimicrobials for up to 40 days. The primary endpoint was CDAD incidence through 30 days after study medication. The primary endpoint analysis counted confirmed CDAD, receipt of CDAD-effective medications (for any indication), and missing CDAD assessment (for any reason, including death) as failures; this composite analysis is referred to as "prophylaxis failure" to distinguish from the pre-specified sensitivity analysis, which counted only confirmed CDAD (by toxin immunoassay or nucleic acid amplification test) as failure. Results: Of 611 subjects enrolled, 600 were treated and analyzed. Prophylaxis failure was similar in fidaxomicin and placebo recipients (28.6% vs 30.8%; difference 2.2% [-5.1, 9.5], P = .278). However, most failures were due to non-CDAD events. Confirmed CDAD was lower in fidaxomicin vs placebo recipients (4.3% vs 10.7%; difference 6.4% [2.2, 10.6], P = .0014). Drug-related adverse events occurred in 15.0% of fidaxomicin recipients and 20.0% of placebo recipients. Conclusions: While no difference was demonstrated between arms in the primary analysis, results of the sensitivity analysis demonstrated that fidaxomicin significantly reduced the incidence of CDAD in HSCT recipients. Clinical Trials Registration: NCT01691248.

Unique characteristics of cryptococcosis identified after death in patients with liver cirrhosis: comparison with concurrent cohort diagnosed antemortem.

Characteristics of cirrhosis-associated cryptococcosis first diagnosed after death are not fully known. In a multicenter study, data generated as standard of care was systematically collected in 113 consecutive patients with cirrhosis and cryptococcosis followed for 80 patient-years. The diagnosis of cryptococcosis was first established after death in 15.9% (18/113) of the patients. Compared to cases diagnosed while alive, these patients had higher MELD score (33 vs. 22, P = .029) and higher rate of cryptococcemia (75.0% vs. 41.9%, P = .027). Cases diagnosed after death, in comparison to those diagnosed during life were more likely to present with shock (OR 3.42, 95% CI 1.18-9.90, P = .023), require mechanical ventilation at admission (OR 8.5, 95% CI 2.74-26.38, P = .001), less likely to undergo testing for serum cryptococcal antigen (OR 0.07, 95% CI 0.02-0.21, P < .001) and have positive antigen when the test was performed (OR 0.07, 95% CI 0.01-0.60, P = .016). In a subset of cirrhotic patients with advanced liver disease cryptococcosis was first recognized after death. These patients had the characteristics of presenting with fulminant fungemia, were less likely to have positive serum cryptococcal antigen and posed a diagnostic challenge for care providers.

Bacterial and viral co-infections complicating severe influenza: Incidence and impact among 507 U.S. patients, 2013-14.

BACKGROUND: Influenza acts synergistically with bacterial co-pathogens. Few studies have described co-infection in a large cohort with severe influenza infection. OBJECTIVES: To describe the spectrum and clinical impact of co-infections. STUDY DESIGN: Retrospective cohort study of patients with severe influenza infection from September 2013 through April 2014 in intensive care units at 33 U.S. hospitals comparing characteristics of cases with and without co-infection in bivariable and multivariable analysis. RESULTS: Of 507 adult and pediatric patients, 114 (22.5%) developed bacterial co-infection and 23 (4.5%) developed viral co-infection. Staphylococcus aureus was the most common cause of co-infection, isolated in 47 (9.3%) patients. Characteristics independently associated with the development of bacterial co-infection of adult patients in a logistic regression model included the absence of cardiovascular disease (OR 0.41 [0.23-0.73], p=0.003), leukocytosis (>11K/µl, OR 3.7 [2.2-6.2], p<0.001; reference: normal WBC 3.5-11K/µl) at ICU admission and a higher ICU admission SOFA score (for each increase by 1 in SOFA score, OR 1.1 [1.0-1.2], p=0.001). Bacterial co-infections (OR 2.2 [1.4-3.6], p=0.001) and viral co-infections (OR 3.1 [1.3-7.4], p=0.010) were both associated with death in bivariable analysis. Patients with a bacterial co-infection had a longer hospital stay, a longer ICU stay and were likely to have had a greater delay in the initiation of antiviral administration than patients without co-infection (p<0.05) in bivariable analysis. CONCLUSIONS: Bacterial co-infections were common, resulted in delay of antiviral therapy and were associated with increased resource allocation and higher mortality.

Invasive Aspergillosis: Epidemiology, Clinical Aspects, and Treatment.

Invasive aspergillosis remains an often fatal, difficult-to treat infection in immunocompromised patients. Patients not classically defined as immunocompromised, especially those in an intensive care unit setting, also develop invasive aspergillosis. Clinical clues suggesting angioinvasion and radiographic modalities, especially computed tomographic scans, combined with newer non-culture-based diagnostic techniques, have allowed earlier recognition of invasive aspergillosis. Although mortality remains high, it has greatly decreased over the past 15 years. Voriconazole has supplanted amphotericin B, with its various toxicities, as primary treatment for invasive aspergillosis. Combination therapy with voriconazole and an echinocandin for initial therapy, based on results from a recent controlled clinical trial, could become the standard of care in high-risk patients.

Severe Influenza in 33 US Hospitals, 2013-2014: Complications and Risk Factors for Death in 507 Patients.

BACKGROUND: Influenza A (H1N1) pdm09 became the predominant circulating strain in the United States during the 2013-2014 influenza season. Little is known about the epidemiology of severe influenza during this season. METHODS: A retrospective cohort study of severely ill patients with influenza infection in intensive care units in 33 US hospitals from September 1, 2013, through April 1, 2014, was conducted to determine risk factors for mortality present on intensive care unit admission and to describe patient characteristics, spectrum of disease, management, and outcomes. RESULTS: A total of 444 adults and 63 children were admitted to an intensive care unit in a study hospital; 93 adults (20.9%) and 4 children (6.3%) died. By logistic regression analysis, the following factors were significantly associated with mortality among adult patients: older age (>65 years, odds ratio, 3.1 [95% CI, 1.4-6.9], P=.006 and 50-64 years, 2.5 [1.3-4.9], P=.007; reference age 18-49 years), male sex (1.9 [1.1-3.3], P=.031), history of malignant tumor with chemotherapy administered within the prior 6 months (12.1 [3.9-37.0], P<.001), and a higher Sequential Organ Failure Assessment score (for each increase by 1 in score, 1.3 [1.2-1.4], P<.001). CONCLUSION: Risk factors for death among US patients with severe influenza during the 2013-2014 season, when influenza A (H1N1) pdm09 was the predominant circulating strain type, shifted in the first postpandemic season in which it predominated toward those of a more typical epidemic influenza season.

Cryptococcosis in Patients With Cirrhosis of the Liver and Posttransplant Outcomes.

BACKGROUND: The outcomes and optimal management of cirrhotic patients who develop cryptococcosis before transplantation are not fully known. METHODS: We conducted a multicenter study involving consecutive patients with cirrhosis and cryptococcosis between January 2000 and March 2014. Data collected were generated as standard of care. RESULTS: In all, 112 patients were followed until death or up to 9 years. Disseminated disease and fungemia were present in 76.8% (86/112) and 90-day mortality was 57.1% (64/112). Of the 39 patients listed for transplant, 20.5% (8) underwent liver transplantation, including 2 with active but unrecognized disease before transplantation. Median duration of pretransplant antifungal therapy and posttransplant therapy was 43 days (interquartile range, 8-130 days) and 272 days (interquartile range, 180-630 days), respectively. Transplantation was associated with lower mortality (P = 0.002). None of the transplant recipients developed disease progression during the median follow-up of 3.5 years with a survival rate of 87.5%. CONCLUSIONS: Cryptococcosis in patients with cirrhosis has grave prognosis. Our findings suggest that transplantation after recent cryptococcal disease may not be a categorical exclusion and may be cautiously undertaken in liver transplant candidates who are otherwise deemed clinically stable.

Risk factors for piperacillin/tazobactam-resistant Gram-negative infection in hematology/oncology patients with febrile neutropenia.

PURPOSE: Febrile neutropenia (FN) is a life-threatening complication of cancer therapy, and initial ineffective therapy is associated with poor outcomes. Piperacillin/tazobactam (PTZ) is a commonly used empiric antibiotic for the treatment of FN, but resistance among Gram-negative pathogens is well described. We conducted a retrospective case-control study to identify risk factors for PTZ-resistant (PTZ-R) Gram-negative isolates. METHODS: Hematology/oncology patients with FN from November 2007 to November 2013 with a positive culture for Gram-negative bacilli were divided into two groups: PTZ-sensitive (PTZ-S) and PTZ-R. A multivariable model using logistic regression was constructed to identify risk factors for PTZ-R. RESULTS: A total of 171 patients were included (25 PTZ-R, 146 PTZ-S), yielding a 14.6 % resistance rate. Thirty-day all-cause mortality was significantly higher in the PTZ-R group (29 vs 11 %, P = 0.024). Multivariable analysis yielded intensive care unit (ICU) status (odds ratio (OR) 20.18; 95 % confidence interval (CI) 1.03-397.35; P = 0.048), antibiotics for > 14 days in the previous 90 days (OR 6.02; CI 1.17-30.93; P = 0.032), and respiratory source (OR 13.65; CI 1.14-163.57; P = 0.039) as significant risk factors for PTZ-R, and the receiver operating characteristic area under the curve of the model was 0.894. Among PTZ-R isolates, 88 % were sensitive to meropenem and 100 % were sensitive to amikacin. CONCLUSIONS: Given the high mortality rates in the PTZ-R group, a risk-factor-guided approach driven by this multivariable model may help identify patients that could benefit from amikacin combination therapy to help optimize empiric therapy in this setting.