Modeling Control of HIV Infection Through Structured Treatment Interruptions with Recommendations for Experimental Protocol

Highly Active Anti-Retroviral Therapy (HAART) of HIV infection has significantly reduced morbidity and mortality in developed countries. However, since these treatments can cause side effects and require strict adherence to treatment protocol, questions about whether or not treatment can be interrupted or discontinued with control of infection maintained by the host immune system remain to be answered. We present sensitivity analysis of a compartmental model for HIV infection that allows for treatment interruptions, including the sensitivity of the compartments themselves to our parameters as well as the sensitivity of the cost function used in parameter estimation. Recommendations are made about collecting data in order to best estimate the most sensitive parameters in the model. Furthermore, we present parameter estimates using simulated data

Genetic heterogeneity of the Spy1336/R28-Spy1337 virulence axis in Streptococcus pyogenes and effect on gene transcript levels and pathogenesis.

Streptococcus pyogenes is a strict human pathogen responsible for more than 700 million infections annually worldwide. Strains of serotype M28 S. pyogenes are typically among the five more abundant types causing invasive infections and pharyngitis in adults and children. Type M28 strains also have an unusual propensity to cause puerperal sepsis and neonatal disease. We recently discovered that a one-nucleotide indel in an intergenic homopolymeric tract located between genes Spy1336/R28 and Spy1337 altered virulence in a mouse model of infection. In the present study, we analyzed size variation in this homopolymeric tract and determined the extent of heterogeneity in the number of tandemly-repeated 79-amino acid domains in the coding region of Spy1336/R28 in large samples of strains recovered from humans with invasive infections. Both repeat sequence elements are highly polymorphic in natural populations of M28 strains. Variation in the homopolymeric tract results in (i) changes in transcript levels of Spy1336/R28 and Spy1337 in vitro, (ii) differences in virulence in a mouse model of necrotizing myositis, and (iii) global transcriptome changes as shown by RNAseq analysis of isogenic mutant strains. Variation in the number of tandem repeats in the coding sequence of Spy1336/R28 is responsible for size variation of R28 protein in natural populations. Isogenic mutant strains in which genes encoding R28 or transcriptional regulator Spy1337 are inactivated are significantly less virulent in a nonhuman primate model of necrotizing myositis. Our findings provide impetus for additional studies addressing the role of R28 and Spy1337 variation in pathogen-host interactions

Working Together to Define Antibiotic Appropriateness: Point Prevalence Survey in 47 Intensive Care Units from 12 US Hospitals, Partnership for Quality Care, March 2017

Abstract Background: A national assessment of antibiotic appropriateness in intensive care units (ICUs) with benchmarking was performed to assist antibiotic stewardship programs (ASPs) identify improvement opportunities. Methods: A Centers for Disease Control and Prevention tool was adapted by an expert panel from the Partnership for Quality Care (PQC), a coalition dedicated to high quality care in US hospitals, to validate appropriate antibiotic use measurement via a point prevalence survey on a single day. Data were collected by ASP personnel at each hospital, de-identified and submitted in aggregate to PQC for benchmarking. Hospitals identified reasons for inappropriate antibiotic use by category and antibiotics misused. Results: Forty-seven ICUs from 12 PQC hospitals participated: California (2), Florida (2), Massachusetts (3), Minnesota (1), and New York (4). Most hospitals identified as teaching (83%) with 252-1550 bed size (median: 563) and 20–270 licensed ICU beds (median: 70). All hospitals reported a formal ASP. On March 1, 2017, 362 (54%) of 667 patients in participating ICUs were on antibiotics (range: 8-81 patients); 1 patient was not assessed. Of the remaining 361 antibiotic regimens, 112 (31%) were identified as inappropriate from among all 12 hospitals (range: 9-82%) (figure). The table displays inappropriate antibiotic use by ICU type. Reasons for inappropriate use included unnecessarily broad spectrum of activity (29%), duration longer than necessary (21%), and treatment of a non-infectious syndrome (19%). The antibiotic most commonly misused was vancomycin in 7 (58%) hospitals. Conclusion: Up to 80% of antibiotic use in some ICUs is inappropriate, underscoring the need for ASP interventions, standardized assessment tools and benchmarking. Strategies should focus on de-escalation of broad-spectrum antibiotics and reducing duration of therapy. Disclosures D. W. Kubiak, Shionogi: Consultant, Consulting fee. Astellas Pharma: Consultant, Consulting fe