Andrea Baran

Bacterial Complications of Respiratory Tract Viral Illness: A Comprehensive Evaluation

Abstract Background. Respiratory tract infection is one of the most common reasons for hospitalization among adults, and recent evidence suggests that many of these illnesses are associated with viruses. Although bacterial infection is known to complicate viral infections, the frequency and impact of mixed viral-bacterial infections has not been well studied. Methods. Adults hospitalized with respiratory illness during 3 winters underwent comprehensive viral and bacterial testing. This assessment was augmented by measuring the serum level of procalcitonin (PCT) as a marker of bacterial infection. Mixed viral-bacterial infection was defined as a positive viral test result plus a positive bacterial assay result or a serum PCT level of ≥ 0.25 ng/mL on admission or day 2 of hospitalization. Results. Of 842 hospitalizations (771 patients) evaluated, 348 (41%) had evidence of viral infection. A total of 212 hospitalizations (61%) involved patients with viral infection alone. Of the remaining 136 hospitalizations (39%) involving viral infection, results of bacterial tests were positive in 64 (18%), and PCT analysis identified bacterial infection in an additional 72 (21%). Subjects hospitalized with mixed viral-bacterial infections were older and more commonly received a diagnosis of pneumonia. Over 90% of hospitalizations in both groups involved subjects who received antibiotics. Notably, 4 of 10 deaths among subjects hospitalized with viral infection alone were secondary to complications of Clostridium difficile colitis. Conclusions. Bacterial coinfection is associated with approximately 40% of viral respiratory tract infections requiring hospitalization. Patients with positive results of viral tests should be carefully evaluated for concomitant bacterial infection. Early empirical antibiotic therapy for patients with an unstable condition is appropriate but is not without risk.

Serum Procalcitonin Measurement and Viral Testing to Guide Antibiotic Use for Respiratory Infections in Hospitalized Adults: A Randomized Controlled Trial

Abstract Background. Viral lower respiratory tract illness (LRTI) frequently causes adult hospitalization and is linked to antibiotic overuse. European studies suggest that the serum procalcitonin (PCT) level may be used to guide antibiotic therapy. We conducted a trial assessing the feasibility of using PCT algorithms with viral testing to guide antibiotic use in a US hospital. Methods. Three hundred patients hospitalized with nonpneumonic LRTI during October 2013–April 2014 were randomly assigned at a ratio of 1:1 to receive standard care or PCT-guided care and viral PCR testing. The primary outcome was antibiotic exposure, and safety was assessed at 1 and 3 months. Results. Among the 151 patients in the intervention group, viruses were identified in 42% (63), and 83% (126) had PCT values of <0.25 µg/mL. There were no significant differences in antibiotic use or adverse events between intervention patients and those in the nonintervention group. Subgroup analyses revealed fewer subjects with positive results of viral testing and low PCT values who were discharged receiving antibiotics (20% vs 45%; P = .002) and shorter antibiotic durations among algorithm-adherent intervention patients versus nonintervention patients (2.0 vs 4.0 days; P = .004). Compared with historical controls (from 2008–2011), antibiotic duration in nonintervention patients decreased by 2 days (6.0 vs 4.0 days; P < .001), suggesting a study effect. Conclusions. Although antibiotic use was similar in the 2 arms, subgroup analyses of intervention patients suggest that physicians responded to viral and biomarker data. These data can inform the design of future US studies. Clinical Trials Registration. NCT01907659.

Dalteparin thromboprophylaxis in cancer patients at high risk for venous thromboembolism: A randomized trial

BACKGROUND Ambulatory cancer patients at high-risk for venous thromboembolism (VTE) can be identified using a validated risk score (Khorana score). We evaluated the benefit of outpatient thromboprophylaxis with dalteparin in high-risk patients in a multicenter randomized study. METHODS Cancer patients with Khorana score≥3 starting a new systemic regimen were screened for VTE and if negative randomized to dalteparin 5000units daily or observation for 12weeks. Subjects were screened with lower extremity ultrasounds every 4weeks on study and with chest CT at 12weeks. The primary efficacy endpoint was all VTE over 12weeks and primary safety endpoint was clinically relevant bleeding events over 13weeks. The study was terminated early due to low accrual. RESULTS Of 117 enrolled patients, 10 (8.5%) had VTE on baseline screening and were not randomized. Of 98 randomized patients, VTE occurred in 12% (N=6/50) of patients on dalteparin and 21% (N=10/48) on observation (hazard ratio, HR 0.69, 95% CI 0.23-1.89). Major bleeding was similar (N=1) in each arm but clinically relevant bleeding was higher in dalteparin arm (N=7 versus 1 on observation) (HR=7.0, 95% CI 1.2-131.6). There was no difference in overall survival. CONCLUSIONS Thromboprophylaxis is associated with a non-significantly reduced risk of VTE and significantly increased risk of clinically relevant bleeding in this underpowered study. The Khorana score successfully identifies patients with high incidence of VTE both at baseline and during treatment. Future studies should continue to focus on risk-adapted approaches to reduce the burden of VTE in cancer. TRIAL REGISTRATION clinicaltrials.gov identifier: NCT00876915.

Should clinical case definitions of influenza in hospitalized older adults include fever

Influenza is a major cause of morbidity and mortality in elderly persons. Fever is included in all standard definitions of influenza‐like illness (ILI), yet older patients may have diminished febrile response to infection. Therefore, we examined the utility of various thresholds to define fever for case definitions of influenza in persons ≥65 years of age.

Phase 2 study of imexon, a prooxidant molecule, in relapsed and refractory B-cell non-Hodgkin lymphoma

Lymphoma cells are subject to higher levels of oxidative stress compared with their normal counterparts and may be vulnerable to manipulations of the cellular redox balance. We therefore designed a phase 2 study of imexon (Amplimexon/NSC-714597), a prooxidant molecule, in patients with relapsed/refractory B-cell non-Hodgkin lymphoma (NHL). Imexon was administered at 1000 mg/m(2) IV daily for 5 days in 21-day cycles. Gene expression analysis performed on pretreatment tumor specimens included 13 transcripts used to generate a redox signature score, previously demonstrated to correlate with lymphoma prognosis. Twenty-two patients were enrolled having follicular (n = 9), diffuse large B-cell (DLBCL) (n = 5), mantle cell (n = 3), transformed follicular (n = 2), small lymphocytic (n = 2), and Burkitt (n = 1) lymphoma. The most common grade 3/4 adverse events were anemia (14%) and neutropenia (9%). The overall response rate was 30%, including responses in follicular lymphoma (4 of 9) and DLBCL (2 of 5). Gene expression analyses revealed CD68 and the redox-related genes, GPX1 and SOD2, as well as a higher redox score to correlate with clinical responses. Therefore, pretreatment markers of oxidative stress may identify patients likely to respond to this therapeutic approach. This trial was registered at www.clinicaltrials.gov as #NCT01314014.

Analysis of the risk of infection in patients with chronic lymphocytic leukemia in the era of novel therapies

Abstract We studied the risk of infections in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL). Major infections were defined as requiring hospital admission or intravenous antimicrobial treatment. Incidence rate (IR) ratios (IRR) were used to compare infection rates. Of 263 CLL patients followed for 936.9 person-years, 60% required treatment for progressive CLL (66 received ibrutinib). Infections occurred in 71.9% patients (IR 92.4/100 person-years) with 31.9% having major infections (IR 20.3/100 person-years) and infections causing 37.5% of deaths. CLL treatment was associated with significantly higher risk of major (IRR 3.31, 95% CI 2.10, 5.21) and minor (IRR 1.78, 95% CI 1.43, 2.22) infections. Compared to their previous chemoimmunotherapy patients receiving salvage ibrutinib therapy (n = 47) had a significantly increased risk of a major infection (IRR 2.35 95% CI 1.27, 4.34). The risk of infection in CLL patients remains high even with use of less immunosuppressive therapies.

Anti-CD20 monoclonal antibody-dependent phagocytosis of chronic lymphocytic leukaemia cells by autologous macrophages.

Unconjugated monoclonal antibodies (mAbs) are an important component of effective combination therapies for chronic lymphocytic leukaemia (CLL). Antibody‐dependent phagocytosis (ADP) is a major mediator of mAb cytotoxicity, but there is limited knowledge of the determinants of ADP efficacy. We used macrophages derived in vitro from autologous circulating monocytes to test the effects of mAb structure and concentration, target : effector cell ratio, duration of co‐incubation and CLL cell CD20 expression on ADP. Next‐generation anti‐CD20 mAbs (ofatumumab, ublituximab, obinutuzumab, ocaratuzumab) were significantly more effective at inducing ADP compared to rituximab, but none were as effective as the anti‐CD52 mAb alemtuzumab. Ofatumumab (10 μg/ml) used as a representative next‐generation anti‐CD20 mAb achieved an ADP plateau at 3 h co‐incubation with a target : effector ratio of 10 : 1 (mean = 2·1 CLL cells/macrophage, range = 1·5–3·5). At 0·156 μg/ml (the lowest concentration tested) ofatumumab ADP was significantly higher than alemtuzumab. However, ofatumumab‐induced ADP did not increase significantly at higher mAb concentrations. We show that anti‐CD20 mAb ADP efficacy is determined by the mAb characteristics, target : effector ratio and incubation time. We suggest that preclinical evaluation of anti‐CD20 mAbs to understand the determinants of ADP could be useful in designing future combination therapies for CLL.

Implementation of a penicillin allergy screening tool to optimize aztreonam use

PURPOSE The implementation of a penicillin allergy screening tool to optimize the use of aztreonam is described. METHODS This study was conducted at a 528-bed tertiary referral community teaching facility and compared the use of aztreonam in patients before and after the implementation of a multipronged intervention consisting of a penicillin allergy screening tool (PAST), education, order set decision support, and prospective review of aztreonam orders by the antimicrobial stewardship team and clinical pharmacists. Patients for whom aztreonam was prescribed at any time during their presentation to the hospital January 1-June 30, 2013 (preintervention period), and September 1, 2013-February 28, 2014 (postintervention period) were eligible for inclusion. Primary outcomes included total and inappropriate aztreonam usage. Secondary outcomes included cost avoidance and safety. RESULTS A total of 496 aztreonam orders were reviewed. The total number of days of therapy (DOT) with aztreonam significantly decreased from 9.5 per 1,000 patient-days in the preintervention group to 4.4 per 1,000 patient-days in the postintervention group (p < 0.0001). The number of inappropriate aztreonam DOT decreased from 4.0 per 1,000 patient days to 0.8 per 1,000 patient-days (p < 0.0001). The median number of inappropriate aztreonam doses decreased significantly in the postintervention period, as did inappropriate aztreonam DOT (p < 0.0001 for both comparisons). An estimated cost avoidance of

Can serum procalcitonin levels help interpret indeterminate chest radiographs in patients hospitalized with acute respiratory illness

60,000-

Factors associated with symptomatic rhinovirus infection in patients with COPD

100,000 was realized, depending on the alternative antibiotic selected. CONCLUSION Implementation of the PAST and provider and pharmacist education reduced the use of aztreonam by promoting the first-line use of β-lactam alternatives.