Impact of a real-time diagnostic and antimicrobial stewardship workflow on time to appropriate therapy for infections caused by multidrug-resistant Gram-negative organisms.

INTRODUCTION: Multidrug-resistant (MDR) Gram-negative organisms cause life-threatening infections, and the incidence is rising globally. Timely therapy for these infections has a direct impact on patient survival. This study aimed to determine the impact of a multidisciplinary diagnostic and antimicrobial stewardship (AMS) workflow on time to appropriate therapy (TAP) for these infections using novel beta-lactam/beta-lactamase inhibitors. METHODS: This was a retrospective quasi-experimental study of adult patients with carbapenem-resistant Enterobacterales (CRE) and multidrug-resistant Pseudomonas (MDR PsA) infections at a 1500 bed university hospital. Included patients who received ≥ 72 hours of ceftazidime-avibactam (CZA) or ceftolozane-tazobactam (C/T) from December 2017 to December 2019. During the pre-intervention period (December 2017 to December 2018), additional susceptibilities (including CZA and C/T) were performed only upon providers' request. In 2019, reflex algorithms were implemented for faster identification and testing of all CRE/MDR PsA isolates. Results were communicated in real-time to the AMS team to tailor therapy. RESULTS: A total of 99 patients were included, with no between-group differences at baseline. The median age was 60 years and 56 (56.7%) were in intensive care at the time of culture collection. Identified organisms included 71 (71.7%) MDR PsA and 26 CRE, of which 18 were carbapenemase producers (Klebsiella-producing carbapenemase = 12, New Delhi metallo-ß-lactamase = 4, Verona integron-encoded metallo-ß-lactamase = 2). The most common infections were pneumonia (49.5%) and bacteraemia (30.3%). A decrease was found in median TAP (103 [IQR 76.0-156.0] vs. 75 [IQR 56-100] hours; P < 0.001). Median time from culture collection to final susceptibility results was shorter in the post-intervention group (123 vs. 93 hours; P < 0.001). CONCLUSION: This study identified improvement in TAP in MDR PsA and CRE infections with implementation of a reflex microbiology workflow and multidisciplinary antimicrobial stewardship initiatives.

Genomic heterogeneity underlies multidrug resistance in Pseudomonas aeruginosa: A population-level analysis beyond susceptibility testing.

BACKGROUND: Pseudomonas aeruginosa is a persistent and difficult-to-treat pathogen in many patients, especially those with Cystic Fibrosis (CF). Herein, we describe a longitudinal analysis of a series of multidrug resistant (MDR) P. aeruginosa isolates recovered in a 17-month period, from a young female CF patient who underwent double lung transplantation. Our goal was to understand the genetic basis of the observed resistance phenotypes, establish the genomic population diversity, and define the nature of sequence evolution over time. METHODS: Twenty-two sequential P. aeruginosa isolates were obtained within a 17-month period, before and after a double-lung transplant. At the end of the study period, antimicrobial susceptibility testing, whole genome sequencing (WGS), phylogenetic analyses and RNAseq were performed in order to understand the genetic basis of the observed resistance phenotypes, establish the genomic population diversity, and define the nature of sequence changes over time. RESULTS: The majority of isolates were resistant to almost all tested antibiotics. A phylogenetic reconstruction revealed 3 major clades representing a genotypically and phenotypically heterogeneous population. The pattern of mutation accumulation and variation of gene expression suggested that a group of closely related strains was present in the patient prior to transplantation and continued to change throughout the course of treatment. A trend toward accumulation of mutations over time was observed. Different mutations in the DNA mismatch repair gene mutL consistent with a hypermutator phenotype were observed in two clades. RNAseq performed on 12 representative isolates revealed substantial differences in the expression of genes associated with antibiotic resistance and virulence traits. CONCLUSIONS: The overwhelming current practice in the clinical laboratories setting relies on obtaining a pure culture and reporting the antibiogram from a few isolated colonies to inform therapy decisions. Our analyses revealed significant underlying genomic heterogeneity and unpredictable evolutionary patterns that were independent of prior antibiotic treatment, highlighting the need for comprehensive sampling and population-level analysis when gathering microbiological data in the context of CF P. aeruginosa chronic infection. Our findings challenge the applicability of antimicrobial stewardship programs based on single-isolate resistance profiles for the selection of antibiotic regimens in chronic infections such as CF.

Effects of Tocilizumab in COVID-19 patients: a cohort study.

BACKGROUND: Due to the lack of proven therapies, we evaluated the effects of early administration of tocilizumab for COVID-19. By inhibition of the IL-6 receptor, tocilizumab may help to mitigate the hyperinflammatory response associated with progressive respiratory failure from SARS-CoV-2. METHODS: A retrospective, observational study was conducted on hospitalized adults who received intravenous tocilizumab for COVID-19 between March 23, 2020 and April 10, 2020. RESULTS: Most patients were male (66.7%), Hispanic (63.3%) or Black (23.3%), with a median age of 54 years. Tocilizumab was administered at a median of 8 days (range 1-21) after initial symptoms and 2 days (range 0-12) after hospital admission. Within 30 days from receiving tocilizumab, 36 patients (60.0%) demonstrated clinical improvement, 9 (15.0%) died, 33 (55.0%) were discharged alive, and 18 (30.0%) remained hospitalized. Successful extubation occurred in 13 out of 29 patients (44.8%). Infectious complications occurred in 16 patients (26.7%) at a median of 10.5 days. After tocilizumab was administered, there was a slight increase in PaO2/FiO2 and an initial reduction in CRP, but this effect was not sustained beyond day 10. CONCLUSIONS: Majority of patients demonstrated clinical improvement and were successfully discharged alive from the hospital after receiving tocilizumab. We observed a rebound effect with CRP, which may suggest the need for higher or subsequent doses to adequately manage cytokine storm. Based on our findings, we believe that tocilizumab may have a role in the early treatment of COVID-19, however larger randomized controlled studies are needed to confirm this.

Development and Implementation of a COVID-19 Disease Response Protocol at a Large Academic Medical Center.

In response to the rapid spread of novel coronavirus disease 2019 (COVID-19), health-care systems should establish procedures for early recognition and management of suspected or confirmed cases. We describe the various steps taken for the development, implementation, and dissemination of the interdisciplinary COVID-19 protocol at Jackson Health System (JHS), a complex tertiary academic health system in Miami, Florida. Recognizing the dynamic nature of COVID-19, the protocol addresses the potential investigational treatment options and considerations for special populations. The protocol also includes infection prevention and control measures and routine care for suspected or proven COVID-19 patients.

Where should antibiotic gradient diffusion strips be crossed to assess synergy? A comparison of the standard method with a novel method using steady-state antimicrobial concentrations.

Multi-drug resistance among Pseudomonas aeruginosa in hospitals, and particularly intensive care units, has achieved alarming rates. Some combination antimicrobial therapies have demonstrated promising synergistic effects and an ability to overcome resistance without increasing drug-related toxicities. Nevertheless, rapid and feasible methods to identify synergy have not been routinely implemented in clinical microbiology laboratories. Synergistic activity of meropenem plus tobramycin or levofloxacin against clinical P. aeruginosa isolates (N=21) was assessed by two different methods using gradient diffusion strips (GDSs). A 90° angle was created at the intersection of the minimum inhibitory concentration (MIC) of each drug by the standard method, and by a novel method, the cross was placed at clinically relevant steady-state concentrations (Css) based on recommended dosing regimens. Fractional inhibitory concentration indexes were determined to describe antibiotic interactions. Time-kill analyses were performed over 24 h in duplicate for instances of discordance between the standard cross method and the novel method. Synergy between meropenem and tobramycin by the novel method was observed in one (4.8%) isolate and between meropenem and levofloxacin in two (9.5%) isolates. Agreement with the standard method was 86-100% for meropenem plus tobramycin and meropenem plus levofloxacin combinations, respectively. Time-kill studies resulted in agreement with GDSs crossed at Css in two of three instances of discordance between GDS methods. This novel method of synergy testing that involves crossing GDSs at steady-state concentrations may be a rapid and feasible tool for routine practice. Further comparisons of this novel procedure with time-kill methods are needed.

Management of Pediatric Acute Hematogenous Osteomyelitis, Part II: A Focus on Methicillin-Resistant Staphylococcus aureus, Current and Emerging Therapies.

Methicillin-resistant Staphylococcus aureus (MRSA) has become the most prevalent cause of acute hematogenous osteomyelitis (AHO) in pediatric patients. This increase in MRSA is due to the rise in community-acquired MRSA. Therefore, it is important that clinicians are aware of the various and upcoming therapies that cover this bacterium. A literature search of the Medline database was performed from creation through January 2018. Articles chosen for the review emphasize well-established MRSA treatment options for pediatric AHO, newer therapies on the horizon, and important pharmacokinetics and pharmacodynamic concepts for treatment. Traditional therapies, including vancomycin and clindamycin, remain effective for the treatment of pediatric AHO. When these agents cannot be used, evidence in AHO has been growing for daptomycin, linezolid, and ceftaroline. Further initial pediatric data with the long-acting lipoglycopeptides show promise and in the future may provide a role in AHO treatment in children.

Management of Pediatric Acute Hematogenous Osteomyelitis, Part I: Antimicrobial Stewardship Approach and Review of Therapies for Methicillin-Susceptible Staphylococcus aureus, Streptococcus pyogenes, and Kingella kingae.

Acute hematogenous osteomyelitis (AHO), often occurring in young children, is the most frequently diagnosed type of osteomyelitis in pediatric patients. Optimizing antibiotics is essential as delays to receipt of appropriate therapy can lead to chronic osteomyelitis, as well as impairments in bone growth and development. Antimicrobial stewardship programs (ASPs) are in a key position to help improve the care of patients with AHO as they contain a pharmacist with expertise in antibiotic drug selection, optimization of dosing, and microbiologic test review. A literature search of the MEDLINE database was conducted from initiation through January 2018. Articles selected for the review focus on pathogen identification, pharmacokinetics and pharmacodynamics, efficacy and safety in children, transition from intravenous to oral therapy, duration of treatment, and antimicrobial stewardship interventions. This review will highlight the potential roles ASPs can have in improving the management of AHO in pediatric patients. These roles include the creation of clinical pathways, improving testing algorithms, antibiotic choice and dosing, intravenous to oral transitions, duration of treatment, and therapy monitoring. Overall, patients are most effectively treated by focusing treatments on age, presentation, local sensitivities, and directed therapy with pathogen identification.