Citations

Abstract Background: Neutropenia is the most common predisposing factor that increases the susceptibility of cancer patients (pts) to infection. The use of fluoroquinolones (FQs) as prophylaxis during chemotherapy-induced neutropenia has been shown to decrease the frequency of gram-negative (GN) infections (Cullen et al. NEJM 2005) with the benefit of reduced infection-related mortality in neutropenic pts with cancer (Bucaneve et al. NEJM 2005) and was instituted as part of our institution-wide standard clinical practice in January 2006. The widespread use of FQs for prophylaxis of pts with neutropenia and hematologic malignancies raises concerns about the evolving resistance of organisms. Methods: This retrospective observational study compared acute myeloid leukemia (AML) and acute lymphoid leukemia (ALL) pts, ages 18 and older who were admitted to the hematology service and received levofloxacin prophylaxis (LEVP) within 60 days of admission with those who were admitted but did not receive LEVP during the period of chemotherapy-induced neutropenia. Pts had to have a positive sterile site culture up to 96 hours prior to admission excluding Staphylococcus coagulase negative, Propionibacterium, Corynebacterium, and other common colonizing organisms. Analysis also compared the rates of Methicillin-resistant Staphylococcus aureus (MRSA) infections, positive Vancomycin-resistant Enterococci (VRE) swabs, and positive Clostridium difficile cultures and evaluated them for a correlation LEVP. Results: A total of 213 pts were evaluated between September 2004 and May 2007. Ninety-four pts received LEVP and 119 did not. Patient characteristics were similar between groups. There was a shift from almost equal incidence of gram-positive (GP) and GN cultures in the group without prophylaxis (51% vs 49%, respectively) to a predominance of GP cultures with LEVP (68% vs 32%, respectively). There was a significant decrease in the number of sterile site cultures of GN organisms (n = 94 vs 37, respectively), while cultures of GP organisms remained similar (n = 98 vs. 77, respectively). GN organisms in sterile site cultures occurred less often in the LEVP group, however; the incidence of resistance to levofloxacin in GN was higher (32% vs 15%), particularly the susceptibility profiles of Pseudomonas sp., Escherichia coli, and Stenotrophomonas maltophilia. Both groups had equal cultures of Staphylococcus aureus, but the group receiving LEVP had a greater incidence of MRSA (55% vs 30%). Rates of positive VRE swabs declined and had no apparent correlation with the use of levofloxacin as prophylaxis. There were more documented positive Clostridium difficile cultures in the pts receiving LEVP (29% vs 22%, respectively), but rates of Clostridium difficile have shown a constant increase throughout the institution; therefore, LEVP should not be considered the sole contributing factor to an increased rate of positive cultures. Conclusions: The epidemiology and microbial susceptibility profile of positive sterile site cultures of acute leukemia pts receiving LEVP during chemotherapy-induced neutropenia differed from those that did not. The LEVP group had a decrease in the absolute number of sterile site cultures, number and percent of GN sterile site cultures. There was an increase in GN organism resistance to levofloxacin and the incidence of several GP organisms increased with the number of GP organisms remaining constant.

Abstract Ulceration of the skin of the legs may occur in Mediterranean disease. Such ulceration cannot be distinguished grossly from that occurring in sickle cell anemia and congenital hemolytic icterus. The outstanding histologic feature (noted at biopsy of one of these ulcers) is the prominent deposition of iron in the cutis.

Background: The CACNA1C -encoded cardiac L-type calcium channel (Cav1.2) is essential for cardiocyte action potential duration (APD). We previously reported the CACNA1C-p.R518C variant associated with prolonged QT intervals, cardiomyopathy, and sudden cardiac death in several pedigrees. Methods: To characterize a patient-derived human induced pluripotent stem cell–derived cardiomyocyte (hiPSC-CM) CACNA1C-p.R518C model, CACNA1C-p.R518C hiPSC-CMs were generated from a 13-year-old man (QTc, >480 ms) with a family history of sudden cardiac death. An isogenic hiPSC-CM gene-corrected control was created using CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/clustered regularly interspaced short palindromic repeat–associated 9). APD and calcium handling were assessed by live cell imaging with Arclight voltage and Fluo-4 calcium indicators, respectively. The APD and L-type calcium channel biophysical properties were further assessed by whole-cell patch clamp technique. Results: The Bazett formula-corrected, Arclight-measured APD 90 of CACNA1C-p.R518C hiPSC-CMs was significantly longer (622±11 ms; n=92) than the isogenic control hiPSC-CMs (453±5 ms; n=62; P <0.0001). Patch clamp assessment of CACNA1C-p.R518C hiPSC-CMs paced at 1 Hz confirmed a prolonged APD 90 (689±29 ms; n=10) compared with the patient’s isogenic control hiPSC-CMs (434±30 ms; n=8; P <0.05). Fluo-4–measured calcium transient decay time suggested calcium mishandling in CACNA1C-p.R518C. Patch clamp analysis revealed increased L-type calcium channel window current, slow decay time at various voltages, and increased late calcium current for CACNA1C-p.R518C hiPSC-CMs when compared with isogenic control hiPSC-CMs. Conclusions: Using patient-specific hiPSC-CM mutant and isogenic control lines, we demonstrate that the CACNA1C-p.R518C variant is the self-sufficient, monogenetic substrate for the patient’s long-QT syndrome phenotype. These data further bolster the conclusion that CACNA1C is a bona fide, definite evidence long-QT syndrome susceptibility gene.

Abstract Background Limited data exist to evaluate safety-related outcomes in Outpatient Parenteral Antimicrobial Therapy (OPAT) patients treated with antimicrobial agents for Gram-positive infections. Methods This retrospective, single-center study enrolled Mayo Clinic OPAT patients between 2013 and 2017. The primary objective of the study compared rates of therapy modification due to drug-related toxicity for staphylococcal infections treated with ceftriaxone, cefazolin, nafcillin, oxacillin, vancomycin, daptomycin, ceftaroline, linezolid, or ertapenem. Secondary objectives included determination of the frequency and type of adverse drug events (ADEs) attributed to OPAT and rate of readmission due to ADEs attributed to OPAT. Results One hundred seventy-two patients were identified (cefazolin n = 54, ceftriaxone n = 49, vancomycin n = 30, daptomycin n = 16, nafcillin n = 9, ertapenem n = 6, ceftaroline n = 4, oxacillin n = 3, linezolid n = 1). The overall treatment completion rates were high (153/172, 89.0%). Patients completed an average of 35.3 days (7 to 95) of therapy with their original antibiotic. Fourteen patients required change to a different antibiotic due to antimicrobial toxicity (ceftriaxone=5; vancomycin=2; cefazolin = 2; daptomycin = 2; ceftaroline = 1; nafcillin = 1; oxacillin = 1) and five patients experienced treatment failure required an additional agent (ceftriaxone = 2; nafcillin = 2; linezolid = 1). Adverse drug events (ADEs) were the most common reason for antimicrobial adjustment (14/19, 73.7%). The most common ADEs were hypokalemia (28/172, 16.3%) and diarrhea (25/172, 14.5%). There were only two cases of Clostridium difficile. Thirty-day readmissions due to antimicrobial therapy were low with 11 patients. Conclusion OPAT with Gram-positive agents used for staphylococcal infections is effective, but antimicrobial modifications still occur. Clinicians should be aware of the risk of ADEs and readmissions in OPAT patients. A multidisciplinary approach may enhance management of ADEs and possibly preventing readmissions Disclosures All authors: No reported disclosures.

SummaryDue to the introduction of newer, more efficacious treatment options, there is a pressing need for policy makers and public health officials to develop or adapt national hepatitis C virus (HCV) control strategies to the changing epidemiological landscape. To do so, detailed, country‐specific data are needed to characterize the burden of chronic HCV infection. In this study of 17 countries, a literature review of published and unpublished data on HCV prevalence, viraemia, genotype, age and gender distribution, liver transplants and diagnosis and treatment rates was conducted, and inputs were validated by expert consensus in each country. Viraemic prevalence in this study ranged from 0.2% in Hong Kong to 2.4% in Taiwan, while the largest viraemic populations were in Nigeria (2 597 000 cases) and Taiwan (569 000 cases). Diagnosis, treatment and liver transplant rates varied widely across the countries included in this analysis, as did the availability of reliable data. Addressing data gaps will be critical for the development of future strategies to manage and minimize the disease burden of hepatitis C.

SummaryFactors influencing the morbidity and mortality associated with viremic hepatitis C virus (HCV) infection change over time and place, making it difficult to compare reported estimates. Models were developed for 17 countries (Bahrain, Bulgaria, Cameroon, Colombia, Croatia, Dominican Republic, Ethiopia, Ghana, Hong Kong, Jordan, Kazakhstan, Malaysia, Morocco, Nigeria, Qatar and Taiwan) to quantify and characterize the viremic population as well as forecast the changes in the infected population and the corresponding disease burden from 2015 to 2030. Model inputs were agreed upon through expert consensus, and a standardized methodology was followed to allow for comparison across countries. The viremic prevalence is expected to remain constant or decline in all but four countries (Ethiopia, Ghana, Jordan and Oman); however, HCV‐related morbidity and mortality will increase in all countries except Qatar and Taiwan. In Qatar, the high‐treatment rate will contribute to a reduction in total cases and HCV‐related morbidity by 2030. In the remaining countries, however, the current treatment paradigm will be insufficient to achieve large reductions in HCV‐related morbidity and mortality.

SummaryThe hepatitis C virus (HCV) epidemic was forecasted through 2030 for 17 countries in Africa, Asia, Europe, Latin America and the Middle East, and interventions for achieving the Global Health Sector Strategy on viral hepatitis targets—“WHO Targets” (65% reduction in HCV‐related deaths, 90% reduction in new infections and 90% of infections diagnosed by 2030) were considered. Scaling up treatment and diagnosis rates over time would be required to achieve these targets in all but one country, even with the introduction of high SVR therapies. The scenarios developed to achieve the WHO Targets in all countries studied assumed the implementation of national policies to prevent new infections and to diagnose current infections through screening.