Evaluating duration of antimicrobial therapy for community-acquired pneumonia in clinically stable patients

"In the United States, community-acquired pneumonia (CAP) results in an estimated 2 to 3 million diagnoses each year, 10 million physician visits, and 600,000 hospitalizations resulting in a total cost of over 20 billion dollars annually. Common causative organisms of CAP include Streptococcus pneumoniae, Haemophilus influenzae, Mycoplasma pneumoniae, Chlamydia pneumoniae, and Legionella pneumophila. Identifying the etiologic organism helps guide therapeutic decisions, however, the pathogen remains unknown in about 50 percent of cases. Therefore, optimal empiric therapy relies on a physician's experience and clinical judgment. The Infectious Diseases Society of America (IDSA) guidelines for treatment of community-acquired pneumonia (CAP) recommend a minimum 5-day course of antibiotics for patients who achieve clinical stability within 48 to 72 hours from initiation of appropriate therapy. A multicenter, cohort study of 686 patients hospitalized with CAP found that most were treated for 7 to 10 days despite median time to clinical stability of 3 days, indicating that a shorter duration of therapy is often not favored by clinicians despite guideline recommendations. Moreover, although many patients receive active antimicrobial therapy while hospitalized, additional courses of antimicrobials are often prescribed upon discharge resulting in excessive antibiotic use. While many patients are given prolonged courses of therapy for CAP, shorter durations of antibiotics in patients eligible for such courses of treatment offer a number of advantages such as minimizing the emergence and selection of resistant organisms, increasing patient compliance, and reducing the risk of medication adverse effects. The objective of this study was to assess the percentage of hospitalized patients diagnosed with uncomplicated CAP receiving antimicrobial therapy in excess of the guideline-recommended duration, evaluate subsequent thirty-day all-cause readmission rates, and determine if select co-morbidities influenced the length of antimicrobial therapy prescribed."--Introduction.Lucy Hahn (Parkland Health and Hospital System, Dallas, Texas), Anita Hegde (University of Texas Southwestern Medical Center, Dallas, Texas), Norman Mang (Parkland Health and Hospital System, Dallas, Texas, University of Texas Southwestern Medical Center, Dallas, Texas), Jessica K. Ortwine (Parkland Health and Hospital System, Dallas, Texas, University of Texas Southwestern Medical Center, Dallas, Texas), Wenjing Wei (Parkland Health and Hospital System, Dallas, Texas, University of Texas Southwestern Medical Center, Dallas, Texas), Bonnie Chase Prokesch (University of Texas Southwestern Medical Center, Dallas, Texas)Includes bibliographical reference

A Multicenter Evaluation of Vancomycin-Associated Acute Kidney Injury in Hospitalized Patients with Acute Bacterial Skin and Skin Structure Infections

BACKGROUND: We sought to determine the real-world incidence of and risk factors for vancomycin-associated acute kidney injury (V-AKI) in hospitalized adults with acute bacterial skin and skin structure infections (ABSSSI). METHODS: Retrospective, observational, cohort study at ten U.S. medical centers between 2015 and 2019. Hospitalized patients treated with vancomycin (≥ 72 h) for ABSSSI and ≥ one baseline AKI risk factor were eligible. Patients with end-stage kidney disease, on renal replacement therapy or AKI at baseline, were excluded. The primary outcome was V-AKI by the vancomycin guidelines criteria. RESULTS: In total, 415 patients were included. V-AKI occurred in 39 (9.4%) patients. Independent risk factors for V-AKI were: chronic alcohol abuse (aOR 4.710, 95% CI 1.929-11.499), no medical insurance (aOR 3.451, 95% CI 1.310-9.090), ICU residence (aOR 4.398, 95% CI 1.676-11.541), Gram-negative coverage (aOR 2.926, 95% CI 1.158-7.392) and vancomycin duration (aOR 1.143, 95% CI 1.037-1.260). Based on infection severity and comorbidities, 34.7% of patients were candidates for oral antibiotics at baseline and 39.3% had non-purulent cellulitis which could have been more appropriately treated with a beta-lactam. Patients with V-AKI had significantly longer hospital lengths of stay (9 vs. 6 days, p = 0.001), higher 30-day readmission rates (30.8 vs. 9.0%, p \u3c 0.001) and increased all-cause 30-day mortality (5.1 vs. 0.3%, p = 0.024) CONCLUSIONS: V-AKI occurred in approximately one in ten ABSSSI patients and may be largely prevented by preferential use of oral antibiotics whenever possible, using beta-lactams for non-purulent cellulitis and limiting durations of vancomycin therapy

Real-world, Multicenter Experience With Meropenem-Vaborbactam for Gram-Negative Bacterial Infections Including Carbapenem-Resistant Enterobacterales and Pseudomonas Aeruginosa

Background: We aimed to describe the clinical characteristics and outcomes of patients treated with meropenem-vaborbactam (MEV) for a variety of gram-negative infections (GNIs), primarily including carbapenem-resistant Enterobacterales (CRE). Methods: This is a real-world, multicenter, retrospective cohort within the United States between 2017 and 2020. Adult patients who received MEV for ≥72 hours were eligible for inclusion. The primary outcome was 30-day mortality. Classification and regression tree analysis (CART) was used to identify the time breakpoint (BP) that delineated the risk of negative clinical outcomes (NCOs) and was examined by multivariable logistic regression analysis (MLR). Results: Overall, 126 patients were evaluated from 13 medical centers in 10 states. The most common infection sources were respiratory tract (38.1%) and intra-abdominal (19.0%) origin, while the most common isolated pathogens were CRE (78.6%). Thirty-day mortality and recurrence occurred in 18.3% and 11.9%, respectively. Adverse events occurred in 4 patients: nephrotoxicity (n = 2), hepatoxicity (n = 1), and rash (n = 1). CART-BP between early and delayed treatment was 48 hours (P = .04). MEV initiation within 48 hours was independently associated with reduced NCO following analysis by MLR (adusted odds ratio, 0.277; 95% CI, 0.081-0.941). Conclusions: Our results support current evidence establishing positive clinical and safety outcomes of MEV in GNIs, including CRE. We suggest that delaying appropriate therapy for CRE significantly increases the risk of NCOs

Nafcillin versus cefazolin for the treatment of methicillin-susceptible Staphylococcus aureus bacteremia

Background: Anti-staphylococcal penicillins have long been the first-line treatment option for methicillin-susceptible Staphylococcus aureus (MSSA) infections. Recent retrospective data comparing nafcillin and cefazolin report similar clinical efficacy despite concerns about high inoculum MSSA infections. Methods: This was a retrospective, non-inferiority, cohort study comparing treatment failure rates between nafcillin and cefazolin in patients with MSSA bacteremia from any source, other than meningitis. Multiple logistic regression was used to adjust for confounding variables. Results: A total of 142 patients were included in the study. The overall treatment failure rate among patients receiving cefazolin was non-inferior to nafcillin (11.3% versus 8.5%; 90% confidence interval −5.2% to 10.8%). Rates of adverse drug events were significantly higher in the nafcillin arm (19.7% versus 7%; p = 0.046). After adjustment for confounding variables, no difference between treatment groups was found in treatment failure (adjusted odds ratio (OR) = 1.2; 95% CI, 0.3–4.5), but nafcillin was associated with significantly higher nephrotoxicity (adjusted odds ratio (OR) = 5.4; 95% CI, 1.1–26.8). Conclusion: Cefazolin was associated with lower nephrotoxicity and similar treatment failure rates compared to nafcillin suggesting that cefazolin is an appealing first line agent for most MSSA bloodstream infections. Keywords: Nafcillin, Cefazolin, Methicillin-susceptible Staphylococcus aureus, MSSA, Bacteremi

Efficacy and Safety of Eravacycline: A Meta-analysis

INTRODUCTION: Eravacycline is a recently approved fluorocycline for treatment of complicated intra-abdominal infections (cIAIs). We conducted this study to evaluate its efficacy and safety.METHODS: PubMed, EMBASE, and three trial registries were searched for randomized controlled trials (RCTs) comparing the efficacy and safety of eravacycline versus comparators. Odds ratios (ORs) with 95% confidence intervals (CIs) were estimated using random-effects models. The study outcomes included clinical response, all-cause mortality, and adverse events (AEs).RESULTS: Three RCTs (1,128 patients) with cIAIs were included. There were no significant differences in clinical response in the modified intention-to-treat (ITT) population (OR, 0.91; 95% CI, 0.62 to 1.35; I2=0%), microbiological ITT population (OR, 0.93; 95% CI, 0.62 to 1.41; I2=0%) and clinically evaluable population (OR, 0.98; 95% CI, 0.55 to 1.75; I2=0%) or all-cause mortality (OR, 1.18; 95% CI, 0.16 to 8.94; I2=0%). Eravacycline was associated with significantly greater odds of total AEs (OR, 1.55; 95% CI, 1.20 to 1.99; I2=0%) and nausea (OR, 5.29; 95% CI, 1.77 to 15.78; I2=1.70%) but the increase in vomiting was not significant (OR, 1.44; 95% CI, 0.73 to 2.86; I2=1.70%). There were no significant differences in serious AEs or discontinuation due to AEs.CONCLUSIONS: This meta-analysis of RCTs found similar clinical efficacy and mortality with eravacycline compared to carbapenems for the treatment of cIAI. However, the odds of total AEs and specifically nausea occurred more with eravacycline, while no significant differences were observed in vomiting (although numerically higher), serious AEs, or drug discontinuation due to AEs

Optimizing the Management of Uncomplicated Gram-Negative Bloodstream Infections: Consensus Guidance Using a Modified Delphi Process

Abstract Background Guidance on the recommended durations of antibiotic therapy, the use of oral antibiotic therapy, and the need for repeat blood cultures remain incomplete for gram-negative bloodstream infections. We convened a panel of infectious diseases specialists to develop a consensus definition of uncomplicated gram-negative bloodstream infections to assist clinicians with management decisions. Methods Panelists, who were all blinded to the identity of other members of the panel, used a modified Delphi technique to develop a list of statements describing preferred management approaches for uncomplicated gram-negative bloodstream infections. Panelists provided level of agreement and feedback on consensus statements generated and refined them from the first round of open-ended questions through 3 subsequent rounds. Results Thirteen infectious diseases specialists (7 physicians and 6 pharmacists) from across the United States participated in the consensus process. A definition of uncomplicated gram-negative bloodstream infection was developed. Considerations cited by panelists in determining if a bloodstream infection was uncomplicated included host immune status, response to therapy, organism identified, source of the bacteremia, and source control measures. For patients meeting this definition, panelists largely agreed that a duration of therapy of ~7 days, transitioning to oral antibiotic therapy, and forgoing repeat blood cultures, was reasonable. Conclusions In the absence of professional guidelines for the management of uncomplicated gram-negative bloodstream infections, the consensus statements developed by a panel of infectious diseases specialists can provide guidance to practitioners for a common clinical scenario

1575. Predictors of Negative Clinical Outcomes among Patients treated with Meropenem-Vaborbactam for Serious Gram-Negative Bacterial Infections: Impact of Delayed Appropriate Antibiotic Selection

Abstract Background Numerous number of studies have found a positive correlation between delayed appropriate antibiotic therapy and negative clinical outcomes (NCO) in Gram-negative bacterial infections (GNBI). The combination of meropenem with vaborbactam (MVB) received Food and Drug Administration approval for the treatment of complicated urinary tract infections and acute pyelonephritis caused by susceptible organisms in August 2017. We sought to determine the impact of delayed appropriate therapy with MVB on NCO among patients with GNBI. Methods Multi-center, retrospective cohort study from October 2017 to March 2020. We included adult patients treated with MVB for >72 hours. We excluded patients who received alternative appropriate antibiotics for GNB prior to MVB and patients with unknown dates for index culture. NCO were defined as 30-day mortality and/or microbiological recurrence. All outcomes were measured from MVB start date. Classification and regression tree analysis (CART) was used to identify the time breakpoint (BP) that delineates the risk of NCO. Multivariable logistic regression analysis (MLR) was used to examine the independent association between the CART-derived-BP and NCO. Variables were retained in the model if P< 0.2 and removed in a backward stepwise approach. Results A total of 86 patients were included from 13 institutions in the United States: median(IQR) age 55 (37-67) years, 67% male, and 48% Caucasian. Median(IQR) APACHE II and Charlson Comorbidity index scores were 18(11-26) and 4(2-6), respectively. Common sources of infection were respiratory (37%) and intra-abdominal (21%). The most common pathogens were carbapenem-resistant Enterobacterales (83%). CART-derived BP between early and delayed treatment was 48 hours, where NCO was increased (36% vs.7%; P=0.04). Delayed MVB initiation was independently associated with NCO in the MLR (aOR=7.4, P=0.02). Results of Regression Analysis of Variables Associated With Negative Clinical Outcomes and Delayed Appropriate Therapy with Meropenem-vaborbactam Conclusion Our results suggest that delaying appropriate antibiotic therapy with MVB for >48 hours significantly increases the risk of NCO in patients with GNBI. Clinicians must ensure timely administration of MVB to assure best outcomes in patients with GNBI. Disclosures Kevin W. Garey, PharMD, MS, FASHP, Merck & Co. (Grant/Research Support, Scientific Research Study Investigator) Michael J. Rybak, PharmD, MPH, PhD, Paratek (Grant/Research Support

Real-world, Multicenter Experience With Meropenem-Vaborbactam for Gram-Negative Bacterial Infections Including Carbapenem-Resistant Enterobacterales and Pseudomonas aeruginosa

Abstract Background We aimed to describe the clinical characteristics and outcomes of patients treated with meropenem-vaborbactam (MEV) for a variety of gram-negative infections (GNIs), primarily including carbapenem-resistant Enterobacterales (CRE). Methods This is a real-world, multicenter, retrospective cohort within the United States between 2017 and 2020. Adult patients who received MEV for ≥72 hours were eligible for inclusion. The primary outcome was 30-day mortality. Classification and regression tree analysis (CART) was used to identify the time breakpoint (BP) that delineated the risk of negative clinical outcomes (NCOs) and was examined by multivariable logistic regression analysis (MLR). Results Overall, 126 patients were evaluated from 13 medical centers in 10 states. The most common infection sources were respiratory tract (38.1%) and intra-abdominal (19.0%) origin, while the most common isolated pathogens were CRE (78.6%). Thirty-day mortality and recurrence occurred in 18.3% and 11.9%, respectively. Adverse events occurred in 4 patients: nephrotoxicity (n = 2), hepatoxicity (n = 1), and rash (n = 1). CART-BP between early and delayed treatment was 48 hours (P = .04). MEV initiation within 48 hours was independently associated with reduced NCO following analysis by MLR (adusted odds ratio, 0.277; 95% CI, 0.081–0.941). Conclusions Our results support current evidence establishing positive clinical and safety outcomes of MEV in GNIs, including CRE. We suggest that delaying appropriate therapy for CRE significantly increases the risk of NCOs