Risk Factors for Carbapenem-Resistant Enterobacterales Clinical Treatment Failure.

The Centers for Disease Control and Prevention (CDC) categorized carbapenem-resistant Enterobacterales (CRE) infections as an "urgent" health care threat requiring public attention and research. Certain patients with CRE infections may be at higher risk for poor clinical outcomes than others. Evidence on risk or protective factors for CRE infections are warranted in order to determine the most at-risk populations, especially with newer beta-lactam/beta-lactamase inhibitor (BL/BLI) antibiotics available to treat CRE. We aimed to identify specific variables involved in CRE treatment that are associated with clinical failure (either 30-day mortality, 30-day microbiologic recurrence, or clinical worsening/failure to improve throughout antibiotic treatment). We conducted a retrospective, observational cohort study of hospitalized patients with CRE infection sampled from 2010 to 2020 at two medical systems in Detroit, Michigan. Patients were included if they were ≥18 years old and culture positive for an organism in the Enterobacterales order causing clinical infection with in vitro resistance by Clinical and Laboratory Standards Institute (CLSI) breakpoints to at least one carbapenem. Overall, there were 140 confirmed CRE infections of which 39% had clinical failure. The most common infection sources were respiratory (38%), urinary (20%), intra-abdominal (16%), and primary bacteremia (14%). A multivariable logistic regression model was developed to identify statistically significant associated predictors with clinical failure, and they included Sequential Organ Failure Assessment (SOFA) score (adjusted odds ratio [aOR], 1.18; 95% confidence interval [CI], 1.06 to 1.32), chronic dialysis (aOR, 5.86; 95% CI, 1.51-22.7), and Klebsiella pneumoniae in index culture (aOR, 3.09; 95% CI, 1.28 to 7.47). Further research on CRE infections is needed to identify best practices to promote treatment success. IMPORTANCE This work compares carbapenem-resistant Enterobacterales (CRE) infections using patient, clinical, and treatment variables to understand which characteristics are associated with the highest risk of clinical failure. Knowing which risk factors are associated with CRE infection failure can provide clinicians better prognostic and targeted interventions. Research can also further investigate why certain risk factors cause more clinical failure and can help develop treatment strategies to mitigate associated risk factors.

Impact of Ceftolozane-Tazobactam vs. Best Alternative Therapy on Clinical Outcomes in Patients with Multidrug-Resistant and Extensively Drug-Resistant Pseudomonas aeruginosa Lower Respiratory Tract Infections.

INTRODUCTION: Infections caused by multidrug-resistant (MDR), extensively drug-resistant (XDR), and difficult-to-treat (DTR) Pseudomonas aeruginosa are increasingly challenging to combat. Ceftolozane-tazobactam (C/T) is a novel ß-lactam-ß-lactamase inhibitor combination now commonly used to treat MDR and XDR P. aeruginosa. Lower respiratory tract infections (LRTIs) remain the most common source of infection caused by MDR/XDR P. aeruginosa. Comparative effectiveness studies to date have been limited by the type of comparator agents (i.e., aminoglycosides and polymyxins) and the inclusion of multiple infection sources (i.e., urinary tract, abdominal, skin and soft tissue, etc.). METHODS: We performed a multicenter, retrospective analysis of adults with LRTI caused by MDR or XDR P. aeruginosa admitted from January 2014 to December 2019. We aimed to compare clinical outcomes between patients who received C/T (n = 118) versus best alternative therapy (n = 88). The primary outcome was clinical failure, defined as 30-day mortality and/or an adverse drug reaction on antibiotic therapy. RESULTS: Two hundred and six patients met inclusion criteria. The C/T group had a significantly higher proportion of XDR P. aeruginosa and ventilator-associated bacterial pneumonia (VABP). After multivariable logistic regression, C/T treatment was independently associated with a 73.3% reduction in clinical failure compared to those who received best alternative therapy (P < 0.001). The number needed to harm with best alternative therapy was 3. CONCLUSION: Our results suggest that C/T is a safe and effective therapeutic regimen for patients with MDR and XDR P. aeruginosa LRTI.

Vancomycin Area Under the Curve to Predict Timely Clinical Response in the Treatment of Methicillin-resistant Staphylococcus aureus Complicated Skin and Soft Tissue Infections.

INTRODUCTION: Although recent guidelines have recommended monitoring vancomycin (VAN) area under the curve (AUC)/minimum inhibitory concentration (MIC) to ensure clinical efficacy and minimize toxicity in methicillin-resistant Staphylococcus aureus (MRSA) for various infections, there are no recommendations regarding complicated skin and soft tissue infections (cSSTIs). We aimed to evaluate the association between VAN AUC and clinical outcomes in MRSA cSSTIs. METHODS: This was a retrospective cohort study of adult patients treated with ≥72 hours of VAN for MRSA cSSTI from 2008 to 2013 at Detroit Medical Center. The primary outcome was timely clinical success (TCS) defined as (1) resolution of signs and symptoms of infection within 72 hours, (2) stabilization and/or reduction in lesion size, (3) alternative agents not required due to VAN failure or toxicity as elected by the prescribing clinician. Classification and regression tree (CART) analysis was performed to determine the AUC associated with TCS in the cohort. Multivariable logistic regression was used to evaluate the association between VAN-AUC and the primary outcome. RESULTS: A total of 154 patients were included in this analysis. CART identifed an AUC ≥435 mg*hr/L for TCS. Overall, 60.9% of patients experienced TCS; 69.7% in the target-AUC group versus 52.5% in the below-target AUC group, (P = .013). Target-AUC attainment was independently associated with increased odds of TCS (adjusted odds ratio [aOR], 2.208; 95% confidence interval [CI], 1.047-4.659). CONCLUSIONS: In adults treated with VAN for MRSA cSSTI, target-AUC attainment was independently associated with improved clinical outcomes and maybe most warranted for patients at high risk of VAN failure or VAN-associated toxicity.

Cefiderocol: A Novel Siderophore Cephalosporin against Multidrug-Resistant Gram-Negative Pathogens.

Cefiderocol (CFDC), (formerly S-649266), is a novel injectable siderophore cephalosporin developed by Shionogi & Co., Ltd., with potent in vitro activity against Gram-negative pathogens including multidrug-resistant (MDR) Enterobacteriaceae and non-fermenting organisms, such as Pseudomonas aeruginosa, Acinetobacter baumannii, Burkholderia cepacia, and Stenotrophomonas maltophilia. Characterized by its siderophore catechol-moiety, CFDC uses a "trojan-horse approach" to navigate through the bacterial periplasmic space, thus evading various beta-lactam degrading enzymes and other mechanisms of resistance present in Gram-negative bacteria. More specifically in carbapenem-resistant Enterobacteriaceae, CFDC has been shown to have activity against extended spectrum beta-lactamases (ESBLs), such as CTX-type, SHV-type, and TEM-type, as well as the Ambler classes of beta-lactamases, including class A (KPC), class B (NDM, IMP, and VIM), class C (AmpC), and class D (OXA, OXA-24, OXA-48, and OXA-48-like). In addition to the strong activity that CFDC has been shown to have against MDR P. aeruginosa, it has also displayed activity against the OXA-23, OXA-24, and OXA-51, beta-lactamases commonly found in MDR A. baumannii. Cefiderocol was recently approved by the US Food and Drug Administration (FDA) for use in complicated urinary tract infections (cUTI), including pyelonephritis, for use in patients 18 years or older with limited or no alternative options for treatment, and is currently being evaluated in a phase III trial for use in nosocomial pneumonia caused by Gram-negative pathogens. The unique features and enhanced activity of CFDC suggest that it is likely to serve as a viable therapeutic option in the treatment of MDR Gram-negative infections. The purpose of this review is to provide an overview of previously published literature explaining CFDC's pharmacology, pharmacokinetic / pharmacodynamic (PK / PD) properties, microbiologic activity, resistance mechanisms, safety parameters, dosing and administration, clinical data, and potential place in therapy.

A comparison of daptomycin alone and in combination with ceftaroline fosamil for methicillin-resistant Staphylococcus aureus bacteremia complicated by septic pulmonary emboli.

The use of daptomycin (DAP) in septic pulmonary emboli (SPE) remains controversial. We analyzed 29 cases of MRSA bacteremia complicated by SPE treated with DAP (n = 14) or DAP-ceftaroline fosamil (CPT; n = 15). Initial treatment with DAP monotherapy was found to have a success rate comparable with DAP-CPT (71% vs. 80%; p = 0.68).