Dalbavancin Sequential Therapy for Gram-Positive Bloodstream Infection: A Multicenter Observational Study.

INTRODUCTION: Long-acting lipoglycopeptides such as dalbavancin may have utility in patients with Gram-positive bloodstream infections (BSI), particularly in those with barriers to discharge or who require prolonged parenteral antibiotic courses. A retrospective cohort study was performed to provide further multicenter real-world evidence on dalbavancin use as a sequential therapy for Gram-positive BSI. METHODS: One hundred fifteen patients received dalbavancin with Gram-positive BSI, defined as any positive blood culture or diagnosed with infective endocarditis, from 13 centers geographically spread across the United States between July 2015 and July 2021. RESULTS: Patients had a mean (SD) age of 48.5 (17.5) years, the majority were male (54%), with many who injected drugs (40%). The most common infection sources (non-exclusive) were primary BSI (89%), skin and soft tissue infection (SSTI) (25%), infective endocarditis (19%), and bone and joint infection (17%). Staphylococcus aureus accounted for 72% of index cultures, coagulase-negative Staphylococcus accounted for 18%, and Streptococcus species in 16%. Dalbavancin started a median (Q1-Q3) of 10 (6-19) days after index culture collection. The most common regimen administered was dalbavancin 1500 mg as one dose for 50% of cases. The primary outcome of composite clinical failure occurred at 12.2%, with 90-day mortality at 7.0% and 90-day BSI recurrence at 3.5%. CONCLUSIONS: Dalbavancin may serve as a useful tool in facilitating hospital discharge in patients with Gram-positive BSI. Randomized controlled trials are anticipated to validate dalbavancin as a surrogate to current treatment standards.

Understanding vancomycin nephrotoxicity augmented by ß-lactams: a synthesis of endosymbiosis, proximal renal tubule mitochondrial metabolism, and ß-lactam chemistry.

The recent understanding that hydrophobic ß-lactams have greater affinity for organic anion transporter-3 (OAT-3) of the proximal renal tubule could provide valuable insights for anticipating ß-lactams that may exacerbate vancomycin-induced nephrotoxicity. Vancomycin alone provides oxidative stress on the highly metabolic proximal tubular cells. Hydrophobic ß-lactams (eg, piperacillin and anti-staphylococcal ß-lactams) could have greater OAT-3 mediated uptake into proximal tubular cells than hydrophilic ß-lactams (eg, most cephalosporins and carbapenems), thereby causing greater mitochondrial stress on these susceptible cells. It remains to be seen whether concomitant drugs that inhibit OAT-3 mediated cellular uptake of ß-lactams into proximal tubular cells or provide antioxidant effects might mitigate ß-lactam augmented vancomycin nephrotoxicity. Furthermore, the serum creatinine rise seen with vancomycin and hydrophobic ß-lactams might represent competition for creatinine-secreting transporters (of which OAT-3 is one), thus, indicating creatinine retention rather than renal injury. In the meantime, clinicians are advised to utilise less nephrotoxic combinations in both empirical and directed antibiotic selection settings until further research is conducted.

Eravacycline, the first four years: health outcomes and tolerability data for 19 hospitals in 5 U.S. regions from 2018 to 2022.

IMPORTANCE: The rise of multidrug-resistant (MDR) pathogens, especially MDR Gram-negatives, poses a significant challenge to clinicians and public health. These resilient bacteria have rendered many traditional antibiotics ineffective, underscoring the urgency for innovative therapeutic solutions. Eravacycline, a broad-spectrum fluorocycline tetracycline antibiotic approved by the FDA in 2018, emerges as a promising candidate, exhibiting potential against a diverse array of MDR bacteria, including Gram-negative, Gram-positive, anaerobic strains, and Mycobacterium. However, comprehensive data on its real-world application remain scarce. This retrospective cohort study, one of the largest of its kind, delves into the utilization of eravacycline across various infectious conditions in the USA during its initial 4 years post-FDA approval. Through assessing clinical, microbiological, and tolerability outcomes, the research offers pivotal insights into eravacycline's efficacy in addressing the pressing global challenge of MDR bacterial infections.

Long-term evaluation of clinical success and safety of omadacycline in nontuberculous mycobacteria infections: a retrospective, multicenter cohort of real-world health outcomes.

Infections due to nontuberculous mycobacteria (NTM) continue to increase in prevalence, leading to problematic clinical outcomes. Omadacycline (OMC) is an aminomethylcycline antibiotic with FDA orphan drug and fast-track designations for pulmonary NTM infections, including Mycobacteroides abscessus (MAB). This multicenter retrospective study across 16 U.S. medical institutions from January 2020 to March 2023 examined the long-term clinical success, safety, and tolerability of OMC for NTM infections. The cohort included patients aged ≥18 yr, who were clinically evaluable, and` had been treated with OMC for ≥3 mo without a previous diagnosis of cystic fibrosis. The primary outcome was 3 mo clinical success, with secondary outcomes including clinical improvement and mortality at 6- and 12 mo, persistence or reemergence of infection, adverse effects, and reasons for OMC utilization. Seventy-five patients were included in this analysis. Most patients were female (48/75, 64.0%) or Caucasian (58/75, 77.3%), with a median (IQR) age of 59 yr (49-67). Most had NTM pulmonary disease (33/75, 44.0%), skin and soft tissue disease (19/75, 25.3%), or osteomyelitis (10/75, 13.3%), and Mycobacterium abscessus (60/75, 80%) was the most commonly isolated NTM pathogen. The median (IQR) treatment duration was 6 mo (4 - 14), and the most commonly co-administered antibiotic was azithromycin (33/70, 47.1%). Three-month clinical success was observed in 80.0% (60/75) of patients, and AEs attributable to OMC occurred in 32.0% (24/75) of patients, leading to drug discontinuation in 9.3% (7/75).

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.

Nephrotoxicity of Vancomycin in Combination With Beta-Lactam Agents: Ceftolozane-Tazobactam vs Piperacillin-Tazobactam.

BACKGROUND: Vancomycin (VAN)-associated acute kidney injury (AKI) is increased when VAN is combined with certain beta-lactams (BLs) such as piperacillin-tazobactam (TZP) but has not been evaluated with ceftolozane-tazobactam (C/T). Our aim was to investigate the AKI incidence of VAN in combination with C/T (VAN/C/T) compared with VAN in combination to TZP (VAN-TZP). METHODS: We conducted a multicenter, observational, comparative study across the United States. The primary analysis was a composite outcome of AKI and risk, injury, failure, loss, end stage renal disease; Acute Kidney Injury Network; or VAN-induced nephrotoxicity according to the consensus guidelines. Multivariable logistic regression analysis was conducted to adjust for confounding variables and stratified Kaplan-Meir analysis to assess the time to nephrotoxicity between the 2 groups. RESULTS: We included VAN/C/T (n = 90) and VAN-TZP (n = 284) at an enrollment ratio of 3:1. The primary outcome occurred in 12.2% vs 25.0% in the VAN-C/T and VAN-TZP groups, respectively (P = .011). After adjusting for confounding variables, VAN-TZP was associated with increased odds of AKI compared with VAN-C/T; with an adjusted odds ratio of 3.308 (95% confidence interval, 1.560-6.993). Results of the stratified Kaplan-Meir analysis with log-rank time-to-nephrotoxicity analysis indicate that time to AKI was significantly shorter among patients who received VAN-TZP (P = .004). Cox proportional hazards analysis demonstrated that TZP was consistent with the primary analysis (P = .001). CONCLUSIONS: Collectively, our results suggest that the AKI is not likely to be related to tazobactam but rather to piperacillin, which is a component in VAN-TZP but not in VAN-C/T.

Clinical Outcomes of Eravacycline in Patients Treated Predominately for Carbapenem-Resistant Acinetobacter baumannii.

Forty-six patients were treated with eravacycline (ERV) for Acinetobacter baumannii infections, where 69.5% of isolates were carbapenem resistant (CRAB). Infections were primarily pulmonary (58.3%), and most patients received combination therapy (84.4%). The median (IQR) ERV duration was 6.9 days (5.1 to 11.1). Thirty-day mortality was 23.9% in the cohort and 21.9% in CRAB patients. One patient experienced an ERV-possible adverse event. IMPORTANCE Acinetobacter baumannii, particularly when carbapenem resistant (CRAB), is one of the most challenging pathogens in the health care setting. This is complicated by the fact that there is no consensus guideline regarding management of A. baumannii infections. However, the recent Infectious Diseases Society of America guidelines for treatment of resistant Gram-negative infections provided expert recommendations for CRAB management. The panel suggest using minocycline among tetracycline derivatives rather than eravacycline (ERV) until sufficient clinical data are available. Therefore, we present the largest multicenter real-world cohort in patients treated with ERV for A. baumannii, where the majority of isolates were CRAB (69.5%). Our analysis demonstrate that patients treated with ERV-based regimens achieved a 30-day mortality of 23.9% and had a low incidence of ERV-possible adverse events (2.1%). This study is important as it fills the gap in the literature regarding the use of a novel tetracycline (i.e., ERV) in the treatment of this challenging health care infection.

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.

Real-World, Multicenter Case Series of Patients Treated with Oral Omadacycline for Resistant Gram-Negative Pathogens.

INTRODUCTION: Antibiotic-resistant Gram-negative bacteria have been associated with substantial morbidity and mortality and have limited treatment options available. Omadacycline (OMC) is an aminomethylcycline antibiotic that has been shown to exhibit broad in vitro activity against antibiotic-resistant Gram-negative bacteria. Given the lack of real-world data, the primary objective of our report was to describe early experience with OMC for the treatment of resistant Gram-negative infections. METHODS: This was a real-world, multicenter, observational cases series/pilot study conducted in the USA. Inclusion criteria included any adult patient aged ≥ 18 years who received OMC for ≥ 72 h either in the inpatient and/or outpatient setting. Clinical success was defined as a composite of 90-day survival from initiation of OMC, lack of alteration in treatment/addition of other antibiotic due to concerns of OMC failure, and lack of microbiologic recurrence within 30 days from the end of therapy. RESULTS: Oral OMC was used in nine cases primarily for multidrug-resistant (MDR)/extensively drug-resistant (XDR) Gram-negative bacterial infections (55.6% XDR and/or carbapenem-resistant Acinetobacter baumannii [CRAB]). The majority of infections were of bone/joint (55.6%) origin, followed by intra-abdominal (33.3%) origin. Clinical success occurred in 66.7% of cases, with 80.0% success each in infections of bone/joint origin or those caused by CRAB. One patient experienced an adverse effect that was not treatment limiting while on therapy (gastrointestinal). CONCLUSION: The use of oral OMC in MDR/XDR Gram-negative infections exhibited a relatively high success rate with minimal adverse effects. Real-world studies with larger case numbers are needed to confirm our initial findings.

Clinical Characteristics Associated with Bacterial Bloodstream Coinfection in COVID-19.

INTRODUCTION: Inappropriate antibiotic use in COVID-19 is often due to treatment of presumed bacterial coinfection. Predictive factors to distinguish COVID-19 from COVID-19 with bacterial coinfection or bloodstream infection are limited. METHODS: We conducted a retrospective cohort study of 595 COVID-19 patients admitted between March 8, 2020, and April 4, 2020, to describe factors associated with a bacterial bloodstream coinfection (BSI). The primary outcome was any characteristic associated with BSI in COVID-19, with secondary outcomes including 30-day mortality and days of antibiotic therapy (DOT) by antibiotic consumption (DOT/1000 patient-days). Variables of interest were compared between true BSI (n = 25) and all other COVID-19 cases (n = 570). A secondary comparison was performed between positive blood cultures with true BSI (n = 25) and contaminants (n = 33) on antibiotic use. RESULTS: Fever (> 38 °C) (as a COVID-19 symptom) was not different between true BSI (n = 25) and all other COVID-19 patients (n = 570) (p = 0.93), although it was different as a reason for emergency department (ED) admission (p = 0.01). Neurological symptoms (ED reason or COVID-19 symptom) were significantly higher in the true BSI group (p < 0.01, p < 0.01) and were independently associated with true BSI (ED reason: OR = 3.27, p < 0.01; COVID-19 symptom: OR = 2.69, p = 0.03) on multivariate logistic regression. High (15-19.9 × 109/L) white blood cell (WBC) count at admission was also higher in the true BSI group (p < 0.01) and was independently associated with true BSI (OR = 2.56, p = 0.06) though was not statistically significant. Thirty-day mortality was higher among true BSI (p < 0.01). Antibiotic consumption (DOT/1000 patient-days) between true BSI and contaminants was not different (p = 0.34). True bloodstream coinfection was 4.2% (25/595) over the 28-day period. CONCLUSION: True BSI in COVID-19 was associated with neurological symptoms and nonsignificant higher WBC, and led to overall higher 30-day mortality and worse patient outcomes.

Early Multicenter Experience With Imipenem-Cilastatin-Relebactam for Multidrug-Resistant Gram-Negative Infections.

A multicenter case series of 21 patients were treated with imipenem-cilastatin-relebactam. There were mixed infection sources, with pulmonary infections (11/21,52%) composing the majority. The primary pathogen was Pseudomonas aeruginosa (16/21, 76%), and 15/16 (94%) isolates were multidrug-resistant. Thirty-day survival occurred in 14/21 (67%) patients. Two patients experienced adverse effects.

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.

Standardized Treatment and Assessment Pathway Improves Mortality in Adults With Methicillin-resistant Staphylococcus aureus Bacteremia: STAPH Study.

BACKGROUND: Methicillin-resistant Staphylococcus aureus (MRSA) bloodstream infection (BSI) management remains challenging for clinicians. Numerous in vitro studies report synergy when vancomycin (VAN) and daptomycin (DAP) are combined with beta-lactams (BLs), which has led to clinical implementation of these combinations. While shorter durations of bacteremia have often been reported, there has been no significant impact on mortality. METHODS: The Detroit Medical Center (DMC) developed and implemented a clinical pathway algorithm for MRSA BSI treatment in 2016 that included the early use of BL combination therapy with standard of care (VAN or DAP) and a mandatory Infectious Diseases consultation. This was a retrospective, quasi-experimental study at the DMC between 2013 and 2020. Multivariable logistic regression was used to assess the independent association between pathway implementation and 30-day mortality while adjusting for confounding variables. RESULTS: Overall, 813 adult patients treated for MRSA BSI were evaluated. Compared with prepathway (PRE) patients (n = 379), those treated postpathway (POST; n = 434) had a significant reduction in 30-day and 90-day mortality: 9.7% in POST vs 15.6% in PRE (P = .011) and 12.2% in POST vs 19.0% in PRE (P = .007), respectively.The incidence of acute kidney injury (AKI) was higher in the PRE compared with the POST group: 9.6% vs 7.2% (P = .282), respectively. After adjusting for confounding variables including Infectious Diseases consult, POST was independently associated with a reduction in 30-day mortality (adjusted odds ratio [aOR], 0.608; 95% CI, 0.375-0.986). CONCLUSIONS: Implementation of an MRSA BSI treatment pathway with early use of BL reduced mortality with no increased rate of AKI. Further prospective evaluation of this pathway approach is warranted.

Impact of COVID-19 pandemic on training of pharmacy residents and fellows: Results from a national survey of postgraduate pharmacy trainees.

PURPOSE: The coronavirus disease 2019 (COVID-19) pandemic has impacted the activities of healthcare workers, including postgraduate pharmacy trainees. Quality training experiences must be maintained to produce competent pharmacy practitioners and maintain program standards. METHODS: A cross-sectional survey of postgraduate pharmacy trainees in the United States was conducted to evaluate training experience changes and assess perceived impacts on residents and fellows following the COVID-19 pandemic's onset. RESULTS: From June 4 through June 22, 2020, 511 pharmacy trainees in 46 states completed the survey. Participants' median age was 26 (interquartile range [IQR], 25-28) years, with included responses from postgraduate year 1 residents (54% of sample), postgraduate year 2 residents (40%), and postgraduate fellows (6%). Compared to experiences prior to the onset of the COVID-19 pandemic, fewer trainees conducted direct patient care (38.5% vs 91.4%, P < 0.001), more worked from home (31.7% vs 1.6%, P < 0.001), and less time was spent with preceptors per day (2 [IQR, 2-6] hours vs 4 [IQR, 1-4] hours, P < 0.001). Sixty-five percent of respondents reported experiencing changes in their training program, 39% reported being asked to work in areas outside of their routine training experience, and 89% stated their training shifted to focus on COVID-19 to some degree. Most respondents perceived either major (9.6%) or minor (52.0%) worsening in quality of experience, with major and minor improvement in quality of experience reported by 5.5% and 8.4% of respondents, respectively. CONCLUSION: Pharmacy resident/fellow experiences were perceived to have been extensively impacted by the COVID-19 pandemic in varying ways. Our findings describe shifts in postgraduate training and may aid in the development of best practices for optimizing trainee experiences in future crises.

Preliminary, Real-world, Multicenter Experience With Omadacycline for Mycobacterium abscessus Infections.

Twelve patients were treated with omadacycline (OMC) as part of a multidrug regimen for Mycobacterium abscessus. The majority of infections were of pulmonary origin (7/12; 58.3%). The median (interquartile range) duration of OMC was 6.2 (4.2-11.0) months. Clinical success occurred in 9/12 (75.0%) patients. Three patients experienced a possible adverse effect while on therapy.

COVID-19: Before the Fall, An Evidence-Based Narrative Review of Treatment Options.

The 2019 novel coronavirus (COVID-19) has quickly become one of the most dire international pandemic crises since the 1918 Spanish flu. Evidence for COVID-19 pharmacological therapies has shown rapid growth and a diverse array of results, but an assessment of the value of each piece of evidence must be reinforced. This article aims to review utilized therapies, the evidence level supporting these therapies, as well as drugs under investigation for the treatment of COVID-19. Primary scrutinized therapies include antiviral regimens, such as remdesivir, hydroxychloroquine/chloroquine, lopinavir/ritonavir, immunomodulating drugs, such as corticosteroids and interleukin (IL) inhibitors, and other therapies including convalescent plasma. Only one therapy, dexamethasone, has shown a mortality benefit in randomized controlled trials and summarized evidence for other therapies show limited positive results. Reviewing these therapies in a historical way shows how limited evidence can drive therapy decisions. A broad summary of available evidence can assist clinicians in a return to hierarchical assessments of evidence which can lead to safer patient outcomes, improved distribution of resources, and better targets for appropriate therapy decisions.

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.

The Evolving Reduction of Vancomycin and Daptomycin Susceptibility in MRSA-Salvaging the Gold Standards with Combination Therapy.

Methicillin-resistant Staphylococcus aureus (MRSA) is associated with substantial morbidity and mortality. Vancomycin (VAN) has been used as the gold standard treatment for invasive MRSA infections for decades but, unfortunately, the reliance of VAN as the primary treatment option against these infections has led to a reduction in VAN susceptibility in MRSA isolates. Although daptomycin (DAP) is another common treatment option against invasive MRSA infections, it has been shown that the development of VAN resistance can lead to DAP nonsusceptibility. VAN or DAP backbone regimens in combination with other antibiotics has been advocated as an alternative approach to improve patient outcomes in VAN/DAP-susceptible infections, enhance outcomes in infections caused by isolates with reduced VAN/DAP susceptibility, and/or prevent the emergence of VAN/DAP resistance or further resistance. A peer-reviewed literature search was conducted using Medline, Google Scholar and PubMed databases. The primary purpose of this review is to describe the mechanisms and epidemiology of MRSA isolates with a reduction in VAN and/or DAP susceptibility, evaluate in vitro and in vivo literature describing combination therapy (CT) against MRSA isolates with reduced VAN and/or DAP susceptibility and describe studies involving the clinical outcomes of patients treated with CT against invasive MRSA infections.

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.