Procalcitonin for sepsis management: Implementation within an antimicrobial stewardship program.

PURPOSE: Clinical trials of procalcitonin (PCT)-based algorithms for antibacterial therapy have shown a reduction in antimicrobial use and improved survival. Translation of PCT algorithms to clinical settings has often been unsuccessful. We hypothesized that appropriate utilization of PCT could be improved by implementing an antimicrobial stewardship team (AST) approach to PCT testing. METHODS: We completed a pre-post intervention evaluation of adult patients admitted to the intensive care unit with a diagnosis of sepsis. The standard PCT algorithm period (SPAP) cohort included patients enrolled before dedicated AST involvement. During the AST-supported PCT algorithm period (ASPAP), the AST reviewed and provided feedback for all appropriate patients. The primary outcome was adherence to the PCT algorithm. RESULTS: Thirty-five and 57 patients were evaluated in the SPAP and ASPAP cohorts, respectively. There were no differences in demographics or infection site between the groups. Baseline PCT assessment was ordered in a larger proportion of patients in the ASPAP cohort (90% vs 57%; P = 0.0006). Follow-up PCT measurement was performed in more patients in the ASPAP cohort (76% vs 23%; P < 0.0001). Antibiotics were discontinued per algorithm in more patients in the ASPAP cohort (25/57 [44%] vs 2/35 [7%]; P < 0.0001). Patients in the ASPAP cohort experienced a shorter total duration of antibiotics (5 vs 7 days; P = 0.02), with no significant difference in length of stay or 30-day readmission or mortality between the cohorts. CONCLUSION: A PCT algorithm successfully implemented by an AST was associated with a significant decrease in total antibiotic days with no differences in mortality or length of stay.

Enoxaparin augments alpha-1-antitrypsin inhibition of TMPRSS2, a promising drug combination against COVID-19.

The cell surface serine protease Transmembrane Protease 2 (TMPRSS2) is required to cleave the spike protein of SARS-CoV-2 for viral entry into cells. We determined whether negatively-charged heparin enhanced TMPRSS2 inhibition by alpha-1-antitrypsin (AAT). TMPRSS2 activity was determined in HEK293T cells overexpressing TMPRSS2. We quantified infection of primary human airway epithelial cells (hAEc) with human coronavirus 229E (HCoV-229E) by immunostaining for the nucleocapsid protein and by the plaque assay. Detailed molecular modeling was undertaken with the heparin-TMPRSS2-AAT ternary complex. Enoxaparin enhanced AAT inhibition of both TMPRSS2 activity and infection of hAEc with HCoV-229E. Underlying these findings, detailed molecular modeling revealed that: (i) the reactive center loop of AAT adopts an inhibitory-competent conformation compared with the crystal structure of TMPRSS2 bound to an exogenous (nafamostat) or endogenous (HAI-2) TMPRSS2 inhibitor and (ii) negatively-charged heparin bridges adjacent electropositive patches at the TMPRSS2-AAT interface, neutralizing otherwise repulsive forces. In conclusion, enoxaparin enhances AAT inhibition of both TMPRSS2 and coronavirus infection. Such host-directed therapy is less likely to be affected by SARS-CoV-2 mutations. Furthermore, given the known anti-inflammatory activities of both AAT and heparin, this form of treatment may target both the virus and the excessive inflammatory consequences of severe COVID-19.

Effectiveness of Shorter Versus Longer Durations of Therapy for Common Inpatient Infections Associated With Bacteremia: A Multicenter, Propensity-Weighted Cohort Study.

BACKGROUND: National guidelines for pneumonia (PNA), urinary tract infection (UTI), and acute bacterial skin and skin structure infection (ABSSSI) do not address treatment duration for infections associated with bacteremia. We evaluated clinical outcomes of patients receiving shorter (5-9 days) versus longer (10-15 days) duration of antibiotics. METHODS: This was a multicenter retrospective cohort study of inpatients with uncomplicated PNA, UTI, or ABSSSI and associated bacteremia. The primary outcome was clinical failure, a composite of rehospitalization, reinitiation of antibiotics, or all-cause mortality within 30 days of antibiotic completion. Secondary outcomes included individual components of the primary outcome, Clostridioides difficile infection, and antibiotic-related adverse effects necessitating change in therapy. A propensity score-weighted logistic regression model was used to mitigate potential bias associated with nonrandom assignment of treatment duration. RESULTS: Of 408 patients included, 123 received a shorter treatment duration (median 8 days) and 285 received a longer duration (median 13 days). In the propensity-weighted analysis, the probability of the primary outcome was 13.5% in the shorter group and 11.1% in the longer group (average treatment effect, 2.4%; odds ratio [OR], 1.25; 95% confidence interval [CI], .65-2.40; P = .505). However, shorter courses were associated with higher probability of restarting antibiotics (OR, 1.62; 95% CI, 1.01-2.61; P = .046) and C. difficile infection (OR, 4.01; 95% CI, 2.21-7.59; P < .0001). CONCLUSIONS: Shorter courses of antibiotic treatment for PNA, UTI, and ABSSSI with bacteremia were not associated with increased overall risk of clinical failure; however, prospective studies are needed to further evaluate the effectiveness of shorter treatment durations.

A 27-Year-Old Man With Acute Severe Low Back Pain and Bilateral Leg Swelling That Prompted Renting a Wheelchair for Mobility.

A 27-year-old man with OSA, posttraumatic stress disorder, and chronic mechanical back pain presented with a 3-day history of acute atraumatic worsening of his low back pain as well as right groin numbness that was exacerbated by walking. He also complained of bilateral leg "heaviness," pain, and swelling, all becoming so severe that he rented a wheelchair for mobility.

Antimicrobial Stewardship Programs: Comparison of a Program with Infectious Diseases Pharmacist Support to a Program with a Geographic Pharmacist Staffing Model.

BACKGROUND: Stewardship of antimicrobial agents is an essential function of hospital pharmacies. The ideal pharmacist staffing model for antimicrobial stewardship programs is not known. OBJECTIVE: To inform staffing decisions for antimicrobial stewardship teams, we aimed to compare an antimicrobial stewardship program with a dedicated Infectious Diseases (ID) pharmacist (Dedicated ID Pharmacist Hospital) to a program relying on ward pharmacists for stewardship activities (Geographic Model Hospital). METHODS: We reviewed a randomly selected sample of 290 cases of inpatient parenteral antibiotic use. The electronic medical record was reviewed for compliance with indicators of appropriate antimicrobial stewardship. RESULTS: At the hospital staffed by a dedicated ID pharmacist, 96.8% of patients received initial antimicrobial therapy that adhered to local treatment guidelines compared to 87% of patients at the hospital that assigned antimicrobial stewardship duties to ward pharmacists (P < .002). Therapy was modified within 24 hours of availability of laboratory data in 86.7% of cases at the Dedicated ID Pharmacist Hospital versus 72.6% of cases at the Geographic Model Hospital (P < .03). When a patient's illness was determined not to be caused by a bacterial infection, antibiotics were discontinued in 78.0% of cases at the Dedicated ID Pharmacist Hospital and in 33.3% of cases at the Geographic Model Hospital (P < .0002). CONCLUSION: An antimicrobial stewardship program with a dedicated ID pharmacist was associated with greater adherence to recommended antimicrobial therapy practices when compared to a stewardship program that relied on ward pharmacists.

The risk of overanticoagulation with antibiotic use in outpatients on stable warfarin regimens.

BACKGROUND: Medication interactions account for a significant proportion of overanticoagulation in warfarin users. However, little is known about the incidence or degree of interaction with commonly used oral antibiotics. OBJECTIVE: To investigate the incidence and degree of overanticoagulation associated with commonly used oral antibiotics. DESIGN: Retrospective cohort study of patients using warfarin who initiated an antibiotic (azithromycin, levofloxacin, or trimethoprim/sulfamethoxazole (TMP/SMX)) or terazosin for clinical indications between January 1998 and December 2002. The incidence of international normalized ratio (INR) elevation and the degree of change and bleeding events after institution of either medication type was recorded. SUBJECTS: Patients at a university-affiliated Veteran's Affairs Medical Center. RESULTS: The mean change in INR was -0.15 for terazosin, 0.51 for azithromycin, 0.85 for levofloxacin, and 1.76 for TMP/SMX. These mean INR changes in the antibiotic groups were all statistically different from the terazosin group. The incidence of supratherapeutic INR was 5% for terazosin, 31% for azithromycin, 33% for levofloxacin, and 69% for TMP/SMX. The incidence of absolute INR >4.0 was 0% for terazosin, 16% for azithromycin, 19% for levofloxacin, and 44% for TMP/SMX. CONCLUSIONS: Among acutely ill outpatients, oral antibiotics (azithromycin, levofloxacin, and TMP/SMX) increase the incidence and degree of overanticoagulation.

Role of antiplatelet therapy in cardiovascular disease I: Acute coronary syndromes.

The acute coronary syndromes (ACS), consisting of ST-segment elevation myocardial infarction (STEMI), non-STEMI (NSTEMI), and unstable angina, remain a leading cause of death in the United States. Through the process of atherothrombosis, underlying atherosclerosis can progress to an acute ischemic coronary event. This disease mechanism is also common to ischemic stroke and peripheral arterial disease. As ACS is a heterogeneous disease, accurate patient diagnosis and risk categorization is essential. Treatment approaches for both STEMI and NSTEMI ACS consist of a combination of surgical intervention and pharmacotherapy, with antiplatelet agents such as clopidogrel, aspirin and glycoprotein IIb/IIIa receptor antagonists playing an essential role.