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Introduction Vancomycin remains first-line therapy for methicillin-resistant Staphylococcus aureus (MRSA) blood stream infections (BSI); however, its toxicity and reported clinical failures are well established. Binary efficacy endpoints evaluating alternative anti-MRSA therapies leave clinicians deciphering between segregated clinical and safety outcomes and do not provide a comprehensive patient-centered picture of comparative therapies. This study aimed to apply a novel methodology, desirability of outcomes ranking (DOOR), to compare anti-MRSA therapies. Methods This was a single-centered, retrospective, cohort of adult patients with MRSA BSI that received vancomycin, daptomycin, or ceftaroline. A previously developed DOOR for S. aureus BSI was adjusted and applied to this cohort to compare vancomycin-treated versus daptomycin/ceftaroline-treated patients. The DOOR had five mutually exclusive ranks: (1) alive without treatment failure, infectious complications, or grade 4 adverse events (AEs); (2) alive with any one of treatment failure, infectious complications, or grade 4 AE; (3) alive with two of treatment failure, infectious complications, or grade 4 AE; (4) alive with all three treatment failure, infectious complications, or grade 4 AE; or (5) deceased. Results A total of 43 vancomycin-treated and 13 daptomycin/ceftaroline-treated patients were included. Baseline clinical characteristics were similar, except for higher median serum creatinine in the daptomycin/ceftaroline cohort (0.76 [IQR 0.57, 1.11] vs 1.36 [IQR 1.09, 1.91] mg/dL, P = 0.03). Patients in the daptomycin/ceftaroline cohort had a 92% probability of better outcome using DOOR methodology. Patients treated with daptomycin/ceftaroline experienced less MRSA BSI persistence (0% vs 13.9%), MRSA BSI recurrence (7.8% vs 25.6%), grade 4 AEs (23.1% vs 46.5%), and in-hospital mortality (0% vs 9.3%). Conclusions Although limited by sample size, this study demonstrates the potential of DOOR to produce valuable, patient-centered results. Clinicians are encouraged to become familiar with appropriate use and interpretation of DOOR methodology as it will become an increasingly common endpoint in clinical trials.

Introduction Acute bacterial skin and skin structure infections (ABSSSIs) remain among the most common infectious processes seen in the clinical setting. For patients with complicated ABSSSIs deemed to require intravenous antibiotics, vancomycin remains the mainstay therapy. Ceftaroline has been shown to be non-inferior to vancomycin and may result in faster resolution of signs of infection. Methods Multicenter, prospective, open-label, randomized trial of ceftaroline versus vancomycin for the treatment of adult patients admitted for management of ABSSSIs from April 2012 to May 2016; 166 patients in the clinically evaluable (CE) group were needed to determine a 20% difference in primary outcome of clinical response at day 2 or 3 of antibiotics. Clinical response was defined as cessation of spread of lesion and improvement in systemic signs/symptoms of infection. A secondary outcome was a ≥ 20% reduction in lesion size at day 2 or 3 of antibiotics. Results One hundred seventy-four patients were enrolled in the intention-to-treat (ITT) group and 108 were CE. Among CE patients, 54 were randomized to ceftaroline and 54 to vancomycin. Baseline characteristics were similar except patients in the ceftaroline arm were older and had a non-significantly higher degree of comorbidities (median Charlson score 2 vs. 4, respectively). Cellulitis was the most common type of ABSSSI (85.2% vs. 79.6%, respectively). Rapid diagnostic testing of available cultures (n = 55) demonstrated high agreement with clinical microbiology for identification of Staphylococcus aureus (100%) and MRSA (100%). There was no significant difference in primary outcome of day 2 or 3 clinical response (50.0% vs. 51.9%). Conclusion Early clinical response between vancomycin- and ceftaroline-treated ABSSSIs was similar. Patients with ABSSSIs rarely remained hospitalized for > 2–3 days, thus limiting our ability to critically assess clinical outcomes. Trial Registration ClinicalTrials.gov identifier, NCT02582203. Funding Allergan plc.

Introduction Acute bacterial skin and skin structure infections (ABSSSIs) represent a large burden to the US healthcare system. There is little evidence-based guidance regarding the appropriate level of care for ABSSSIs. This study aimed to develop a prediction model and risk-scoring tool to determine appropriate levels of care. Methods This was a single-center observational cohort study of adult patients treated for ABSSSIs from 2012 to 2015 at the Detroit Medical Center. The predictive model used to create a novel risk-scoring tool was derived using multinomial regression analysis. The overall accuracy of this tool was compared to the Clinical Resource Efficacy Support Team (CREST) Classification and Standardized Early Warning Score (SEWS) using area-under-the- receiver-operator-curve (AUROC) analysis and Z-statistic. Results Final patient disposition was 230 (45.5%) home from the emergency department (ED), 65 (12.8%) observation unit (OU), and 211 (41.7%) initial inpatient. IV antibiotic therapy was used in 358 (70.8%) patients. CREST and SEWS were not accurate in the determination of ED versus OU disposition [AUROC CREST 0.0.682 (95% CI 0.640–0.724), AUROC SEWS 0.686 (95% CI 0.641–0.731)], but performed better in determining ED/OU versus inpatient [AUROC CREST = 0.678 (95% CI 0.630–0.725), AUROC SEWS 0.693 (95% CI 0.645–0.740)]. These scores were also not accurate in determining IV versus PO antibiotic therapy [AUROC CREST = 0.586 (95% CI 0.530–0.624), AUROC SEWS = 0.630 (95% CI 0.576–0.684)]. A risk-scoring tool ranging from 0 to 10 points was derived incorporating WBC, temperature, site of infection, and past medical history of diabetes, liver disease, PVD, AKI, and/or CKD. The AUROC of the new model was 0.675 (95% CI 0.611–0.739) ED versus OU, 0.789 (95% CI 0.748–0.829) ED/OU versus inpatient, and 0.742 (95% CI 0.694–0.789) IV versus oral antibiotics. The new score had a significantly higher AUROC compared to both the CREST and SEWS for determining ED/OU versus inpatient (p

Introduction Vancomycin remains the standard of care for invasive methicillin-resistant Staphylococcus aureus (MRSA) infections. Treatment failures from heteroresistant vancomycin-intermediate subpopulations (hVISA) are challenging to detect. Minimum inhibitory concentrations (MIC) identified by modified population analysis profile (PAP) is an alternative testing method. The aim of this study was to evaluate the role of PAP MIC on vancomycin failures in two high inoculum infections: MRSA infective endocarditis and pneumonia. Methods Retrospective, observational study at Detroit Medical Center from 2008 to 2016. Adults ≥ 18 years with ≥ 1 positive MRSA blood culture from IE or pneumonia source and received ≥ 48 h vancomycin were included. The primary outcome was composite failure: MRSA bacteremia ≥ 7 days or 30-day all-cause mortality. Results A total of 191 patients were included; 47.6% IE and 52.4% pneumonia. About 19% were hVISA isolates, median vancomycin PAP MIC of 3 (2, 3). More than half (54.5%) experienced composite failure with a larger proportion of PAP MIC ≥ 4 mg/L in this group (25 vs. 15%, p = 0.086). Patients with IE experienced prolonged bacteremia whereas patients with pneumonia experienced higher 30-day mortality. On logistic regression analysis, age [adjusted odds ratio (aOR), 1.026; 95% confidence interval (CI), 1.005–1.047; p = 0.014] and APACHE II score (aOR 1.039; 95% CI, 1.004–1.076; p = 0.029) independently predicted composite failure. Conclusion Vancomycin PAP MIC may be a more relevant predictor of patient outcomes in persistent bacteremic MRSA infections (e.g., IE). This susceptibility method is less applicable in other high inoculum infections with shorter bacteremia durations and higher mortality rates (e.g., pneumonia).

Introduction Lower respiratory tract infections (LRTIs) are a major cause of morbidity and death. Because of changes in how LRTIs are defined coupled with the increasing prevalence of drug resistance, there is a gap in knowledge regarding the current burden of antimicrobial use for Centers for Disease Control and Prevention (CDC)-defined LRTIs. We describe the infection characteristics, antibiotic consumption, and clinical and economic outcomes of patients with Gram-negative (GN) LRTIs treated in intensive care units (ICUs). Methods This was a retrospective, observational, cross-sectional study of adult patients treated in ICUs at two large academic medical centers in metropolitan Detroit, Michigan, from October 2013 to October 2015. To meet the inclusion criteria, patients must have had CDC-defined LRTI caused by a GN pathogen during ICU stay. Microbiological assessment of available Pseudomonas aeruginosa isolates included minimum inhibitory concentrations for key antimicrobial agents. Results Four hundred and seventy-two patients, primarily from the community (346, 73.3%), were treated in medical ICUs (272, 57.6%). Clinically defined pneumonia was common (264, 55.9%). Six hundred and nineteen GN organisms were identified from index respiratory cultures: P. aeruginosa was common (224, 36.2%), with 21.6% of these isolates being multidrug resistant. Cefepime (213, 45.1%) and piperacillin/tazobactam (174, 36.8%) were the most frequent empiric GN therapies. Empiric GN therapy was inappropriate in 44.6% of cases. Lack of in vitro susceptibility (80.1%) was the most common reason for inappropriateness. Patients with inappropriate empiric GN therapy had longer overall stay, which translated to a median total cost of care of $79,800 (interquartile range $48,775 to $129,600) versus $68,000 (interquartile range $38,400 to $116,175), p = 0.013. Clinical failure (31.5% vs 30.0%, p = 0.912) and in-hospital all-cause mortality (26.4% vs 25.9%, p = 0.814) were not different. Conclusion Drug-resistant pathogens were frequently found and empiric GN therapy was inappropriate in nearly 50% of cases. Inappropriate therapy led to increased lengths of stay and was associated with higher costs of care.

Introduction Acute bacterial skin and skin structure infections (ABSSSIs) are frequently treated in emergency departments (EDs) or observation units (OUs) initially with intravenous (IV) antibiotics before discharge on oral therapy. This study aims to describe ABSSSI patients discharged directly from EDs/OUs. Methods This is a retrospective cohort study of patients with ABSSSIs treated in EDs/OUs of the Detroit Medical Center from 2012 to 2014. Adults with less than 24 h of IV antibiotics without hospital admission were included. Demographics, clinical characteristics, and severity were compared between ED and OU patients. Resource utilization, including tissue and blood cultures, and use of radiographic analysis was also collected. The primary outcome was 96-h ED revisit/hospitalization. Results Analysis included 308 patients; 219 ED and 89 OU. OU patients were significantly more likely to be obese, have COPD/asthma, be diagnosed with cellulitis, and meet at least one systemic inflammatory response syndrome (SIRS) criterion. Tissue cultures were obtained in 21.7% of abscesses in the ED; 67.9% were in uncomplicated abscesses. In the OU tissue cultures were obtained in 48.8% of abscesses and 37.5% were uncomplicated cases. Blood cultures were drawn in 18.3% of ED patients and 56.2% of OU patients, not significantly associated with the presence of SIRS criteria. Radiology was used in the diagnosis of ABSSSIs in 33.5% of ED versus 69.5% OU patients (p

As antibiotic resistance continues to increase among Gram-negative organisms such as Acinetobacter baumannii there is a growing need for novel therapies to overcome these resistance mechanisms. Antibiotics active against multidrug-resistant A. baumannii (MDRAB) are few, and agents in development are primarily active against other multidrug-resistant Gram-negative organisms. The combinations of colistin and antimicrobials such as glycopeptides and lipopeptides are unique potential treatment modalities against MDRAB. For both lipopeptides and glycopeptides in vitro data have demonstrated significant synergy, resulting in rapid bactericidal activity in time-kill curves. Several invertebrate in vivo models have also demonstrated increased survival compared to colistin alone. Currently, very little clinical data have focused on using these combinations for infections caused exclusively by multidrug-resistant Gram-negatives. The combination of vancomycin and colistin has been studied with conflicting results regarding both improved outcomes and risk of nephrotoxicity. Although in vitro and in vivo models have proved promising, further investigation is required to provide clinical data necessary to support the use of these combinations. The objective of this review is to summarize literature currently available for the novel combination of lipopeptides or glycopeptides with colistin for the treatment of A. baumannii, in particular MDRAB. Electronic supplementary material The online version of this article (doi:10.1007/s40121-014-0051-9) contains supplementary material, which is available to authorized users.