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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 β-lactam-β-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.).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.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.Our results suggest that C/T is a safe and effective therapeutic regimen for patients with MDR and XDR P. aeruginosa LRTI.

Biofilm-associated infections lead to substantial morbidity. Omadacycline (OMC) is a novel aminomethylcycline with potent in vitro activity against Staphylococcus aureus and Staphylococcus epidermidis , but data surrounding its use in biofilm-associated infections are lacking.

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.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.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 × 10True 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.

Multidrug-resistant (MDR) and extensively drug-resistant (XDR) Pseudomonas aeruginosa isolates are frequent causes of serious nosocomial infections that may compromise the selection of antimicrobial therapy. The goal of this review is to summarize recent epidemiologic, microbiologic, and clinical data pertinent to the therapeutic management of patients with infections caused by MDR/XDR-P. aeruginosa. Historically, conventional antipseudomonal β-lactam antibiotics have been used for the empiric treatment of MDR/XDR-P. aeruginosa. Owing to the remarkable capacity of P. aeruginosa to confer resistance via multiple mechanisms, these traditional therapies are often rendered ineffective. To increase the likelihood of administering empiric antipseudomonal therapy with in vitro activity, a second agent from a different antibiotic class is often administered concomitantly with a traditional antipseudomonal β-lactam. However, combination therapy may pose an increased risk of antibiotic toxicity and secondary infection, notably, Clostridioides difficile. Multiple novel agents that demonstrate in vitro activity against MDR-P. aeruginosa (e.g., β-lactam/β-lactamase inhibitor combinations and cefiderocol) have been recently granted US Food and Drug Administration (FDA) approval and are promising additions to the antipseudomonal armamentarium. Even so, comparative clinical data pertaining to these novel agents is sparse, and concerns surrounding the scarcity of antibiotics active against refractory MDR/XDR-P. aeruginosa necessitates continued assessment of alternative therapies. This is particularly important in patients with cystic fibrosis (CF) who may be chronically colonized and suffer from recurrent infections and disease exacerbations due in part to limited efficacious antipseudomonal agents. Bacteriophages represent a promising candidate for combatting recurrent and refractory infections with their ability to target specific host bacteria and circumvent traditional mechanisms of antibiotic resistance seen in MDR/XDR-P. aeruginosa. Future goals for the management of these infections include increased comparator clinical data of novel agents to determine in what scenario certain agents may be preferred over others. Until then, appropriate treatment of these infections requires a thorough evaluation of patient- and infection-specific factors to guide empiric and definitive therapeutic decisions.

Background Multi-drug resistant (MDR) pathogens are a continuously evolving threat for which there are limited effective treatment modalities. Omadacycline (OMC) is a novel oral and intravenously administered aminomethylcycline with potent in-vitro activity against MDR gram-negative and gram-positive pathogens. Post-marketing data investigating its potential place in the antibiotic armamentarium is limited. This study aimed at describing the clinical success and tolerability of patients receiving OMC for various infections. Methods This was a multicenter, retrospective, observational study conducted from January 2020 to March 30, 2022. We included all patients ≥ 18 years of age that received OMC for any infection not related to Mycobacterium spp. for ≥72 hours. The primary outcome was clinical success at 30 days, defined as survival, the absence of persistence or re-emergence of infection during or after therapy, and the absence of escalation or alteration of OMC. Incidence of adverse effects while on OMC and reasons for OMC utilization were also analyzed. Results This analysis included 19 patients from 10 distinct academic centers. The median age was 50 years (IQR, 37-63), 58% were male, 63% were Caucasian, and the median APACHE II, Charlson and SOFA scores were 10 (IQR 5-12.5), 4 (IQR 2-6.3), and 1 (IQR 0 – 2.25), respectively. Most patients had a bone and joint (8/19, 42.1%) or intra-abdominal infections (4/19, 21.1%), all with positive cultures. Eight patients (44.1%) had a polymicrobial infection and 4 (22.2%) had bacteremia. The most common pathogens encountered were Carbapenem-resistant A. baumannii (5/19, 27.8%), E. coli (5/19, 27.8%), Vancomycin-resistant Enterococcus spp. (4/19, 22.2%), and K. pneumoniae (3/19, 16.7%). Clinical success was observed in 14 patients (74%) and 7 (36.8%) received combination therapy. Adverse drug reactions were reported in 3 patients (15.8%) and of those patients, none discontinued therapy. Reasons for prescribing OMC were mostly attributed to oral availability (12/14, 85.7%) and resistance to other agents (7/14, 50%). Conclusion OMC demonstrated clinical effectiveness and safety against a large number of MDR pathogens. More robust, prospective, comparative studies are needed to confirm our preliminary findings. Disclosures P. Brandon Bookstaver, PharmD, Spero Therapeutics: Advisor/Consultant.

Background Comparative effectiveness studies to guide treatment decisions for infections caused by carbapenem-resistant P. aeruginosa (CRPA) susceptible to traditional agents (non-carbapenem β-lactams and fluoroquinolones) are unavailable. This study aims to compare clinical outcomes between patients treated with traditional and alternative treatment regimens for lower respiratory tract infection (LRTI) caused by CRPA that remain susceptible to traditional agents. Methods Multi-center, retrospective cohort from January 2016 to December 2019. We included adults with CRPA (resistant to ≥ 1 carbapenem; meropenem or imipenem) that were susceptible to ≥1 traditional agent (piperacillin-tazobactam, cefepime, ceftazidime, ciprofloxacin, or aztreonam) by CLSI breakpoints isolated from an LRTI sample. All other antibiotics were considered alternative agents. We excluded patients with known colonization, cystic fibrosis, or who expired ≤24 hours after antibiotic receipt. Primary outcome was 30-day mortality and secondary outcomes included 30-day readmission and 30-day recurrence. Results In total, 87 patients, ‘traditional’ treatment (n=53) and ‘alternative’ treatment (n=34), were included from 2 institutions in Detroit, MI, USA: median(IQR) age 59(20) years, 64.4% male, and 59.8% African American. Median(IQR) APACHE II and Charlson Comorbidity index scores were 24(10) and 4(5), respectively. Most patients received traditional therapy (n=53), most commonly with cefepime (60.4%) or piperacillin-tazobactam (41.5%). While 34(39.0%) were treated with alternative agents, most commonly ceftolozane-tazobactam (64.7%) or an aminoglycoside (29.4%) alone or in combination. Thirty-day mortality was not significantly different between traditional and alternative therapy groups (22.6% and 11.8%), respectively. There was no significant difference between 30-day recurrence (17.0% and 20.6%) or 30-day readmission (22.6% and 17.6%) between groups. Conclusion Clinical outcomes did not differ significantly between patients receiving traditional vs. alternative agents for LRTI caused by CRPA susceptible to traditional agents. Traditional agents may be considered for these infections. Further comparative studies are needed to guide treatment decisions for CRPA. Disclosures All Authors: No reported disclosures.

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.

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.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.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).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.

Aims Here, we investigate the impact of phage-antibiotic combinations (PAC) on bacterial killing, resistance development and outer membrane vesicle (OMV) production in multidrug-resistant (MDR) P. aeruginosa. Methods and Results After screening 10 well-characterized MDR P. aeruginosa strains against three P. aeruginosa phages, representative strains, R10266 and R9316, were selected for synergy testing based on high phage sensitivity and substantial antibiotic resistance patterns, while phage EM was chosen based on host range. To understand the impact of phage-antibiotic combinations (PAC) against MDR P. aeruginosa, time-kill analyses, OMV quantification and phage/antibiotic resistance testing were performed. Phage and meropenem demonstrated synergistic activity against both MDR strains. Triple combination regimens, phage-meropenem-colistin and phage-ciprofloxacin-colistin, resulted in the greatest CFU reduction for strains R9316 (3.50 log10 CFU ml−1) and R10266 (4.50 log10 CFU ml−1) respectively. PAC resulted in regained and improved antibiotic susceptibility to ciprofloxacin (MIC 2 to 0.0625) and meropenem (MIC 32 to 16), respectively, in R9316. Phage resistance was prevented or reduced in the presence of several classes of antibiotics and OMV production was reduced in the presence of phage for both strains, which was associated with significantly improved bacterial eradication. Conclusions These findings support the potential of phage-antibiotic synergy (PAS) to augment killing of MDR P. aeruginosa. Systematic in vitro and in vivo studies are needed to better understand phage interactions with antipseudomonal antibiotics, to define the role of OMV production in P. aeruginosa PAC therapy and to outline pharmacokinetic and pharmacodynamic parameters conducive to PAS. Significance and Impact of Study This study identifies novel bactericidal phage-antibiotic combinations capable of thwarting resistance development in MDR and XDR P. aeruginosa strains. Furthermore, phage-mediated OMV reduction is identified as a potential mechanism through which PAC potentiates bacterial killing.

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.

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.

Coronavirus disease 2019 (COVID-19), caused by the 2019 novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is currently responsible for a global pandemic. To date, only remdesivir and dexamethasone have demonstrated a positive response in a prospective, randomized trial for the treatment of patients with COVID-19. Hydroxychloroquine (HCQ) is an agent available in an oral formulation with in vitro activity against SARS-CoV-2 that has been suggested as a potential agent. Unfortunately, results of randomized trials evaluating HCQ as treatment against a control group are lacking, and little is known about its pharmacokinetic/pharmacodynamic (PK/PD) profile against SARS-CoV-2. The objective of this review was to describe the current understanding of the PK/PD and dose selection of HCQ against SARS-CoV-2, discuss knowledge gaps, and identify future studies that are needed to optimize the efficacy and safety of treatments against COVID-19.

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).

Treatment of serious gram-positive infections presents multiple challenges. Treatment often results in prolonged hospitalization for administration of intravenous antimicrobials and presents an inefficient use of hospital resources. Prolonged hospitalization is typically also unfavorable to patient preferences and potentially subjects patients to additional health care-associated complications. Current strategies of transition to outpatient settings-outpatient parenteral antimicrobial therapy and use of oral antibiotics-often do not adequately serve vulnerable populations for whom there is often no alternative to inpatient therapy. Specifically, people who use drugs, those who cannot reliably adhere to unsupervised treatment (poor mental or physical health), people with complicating life circumstances (e.g., homelessness, incarceration, rural location), and those with inadequate health insurance remain hospitalized for weeks longer than persons without such conditions. We suspected that long-acting lipoglycopeptides (laLGP), such as dalbavancin and oritavancin, may be useful in patient transitions to outpatient settings. Thus, we conducted a search of the peer-reviewed literature using the PubMed, Google Scholar, and MEDLINE databases. Based on accumulating literature, it appears that laLGPs offer a reliable alternative therapeutic strategy that addresses many of the personal and systemic barriers to the traditional transitioning approaches. Current evidence also suggests that these agents may be cost-effective from patient, payer, and hospital perspectives. Barriers to broader use of laLGPs include, among others, a relative lack of prospective data regarding efficacy in serious infections, a narrow United States Food and Drug Administration-approved indication restricted to only acute bacterial skin and skin structure infections, and lack of reimbursement infrastructure for inpatient settings.

Background Methicillin-resistant Staphylococcus aureus (MRSA) bloodstream infections (BSI) are associated with high morbidity and mortality. More in vitro, in vivo, and clinical data suggest that vancomycin (VAN) or daptomycin (DAP) combination therapy with β-lactams (BL) improves outcomes of MRSA infections. We hypothesize that BL combination with VAN or DAP would reduce the odds of clinical failure compared to VAN or DAP monotherapy. Methods A retrospective cohort study of adult patients ≥ 18 years treated with VAN or DAP for MRSA BSI from 2006 to 2019 at Detroit Medical Center. Combination therapy (CT) was defined as VAN or DAP plus any BL for ≥ 24 h within 72 h of index culture. Monotherapy (MT) was defined as ≥ 72 h VAN or DAP within 72 h of index culture and no BL for ≥ 24 h up to 7 days following VAN/DAP initiation. Primary outcome was composite endpoint of clinical failure defined as: (1) 30-day mortality, (2) 60-day recurrence, or (3) persistent bacteremia (PB). PB was defined as bacteremia > 5 days. Multivariable logistic regression was used to evaluate the association between CT and the primary outcome. Results Overall, 597 patients were included in this analysis, 153 in the MT group and 444 in the CT group. CT was independently associated with reduced odds of clinical failure (adjusted odds ratio, 0.523; 95% confidence interval, 0.348–0.787). The composite endpoint was driven by 60-day recurrence and PB but not 30-day mortality. There were no difference in adverse events including nephrotoxicity between the two study arms. Conclusions In hospitalized adults with MRSA BSI, CT with any BL was independently associated with improved clinical outcomes and may ultimately be selected as preferred therapy.

Enterococcus faecium is a significant multidrug-resistant pathogen. Bacteriophage cocktails are being proposed to complement antibiotic therapy. After a screen of 8 E. faecium strains against 4 phages, 2 phages (113 and 9184) with the broadest host ranges were chosen for further experiments. Transmission electron microscopy, whole-genome sequencing, comparative genome analyses, and time-kill analyses were performed. Daptomycin (DAP) plus the phage cocktail (113 [myophage] and 9184 [siphopage]) showed bactericidal activity in most regimens, while DAP addition prevented phage 9184 resistance against daptomycin-nonsusceptible E. faecium.

Clinicians, researchers, and the public frequently turn to digital channels and social media for up-to-the-minute information on novel therapeutics and vaccines. The value of credible infectious diseases drug information is more apparent in the setting of the coronavirus disease 2019 (COVID-19) pandemic. This viewpoint by the Society of Infectious Diseases Pharmacists (SIDP) provides guidance on utilizing social media platforms to optimize infectious diseases pharmacotherapy. It includes tips for all levels of users but primarily serves a guide for the infectious diseases clinician who has not yet joined social media. It compares various social media platforms and suggests which to begin with based on user needs, recommends efficient curation of social media content, and outlines a stepwise approach (shown below) to increasing engagement over time. This summary will hopefully spur further quality content and engagement regarding drug information from the infectious diseases social media network.

Tedizolid has activity against Gram-positive pathogens as well as Mycobacterium spp and Nocardia spp. Real-world evidence supporting long-term tolerability and clinical success of tedizolid is lacking. Prolonged tedizolid therapy (median, 188 days; interquartile range, 62–493 days) appeared to be well tolerated in 37 patients (8.1% experienced adverse effect leading to discontinuation). Clinical success was 81.3% in those evaluated.

Exebacase is a lysin (cell wall hydrolase) with direct lytic activity against Staphylococcus aureus including methicillin-resistant S. aureus (MRSA). Time-kill analysis experiments illustrated bactericidal activity of exebacase-daptomycin against MRSA strains MW2 and 494. Furthermore, exebacase in addition to daptomycin (10, 6, and 4 mg/kg/day) in a two-compartment ex vivo pharmacokinetic/pharmacodynamic simulated endocardial vegetation model with humanized doses resulted in reductions of 6.01, 4.99, and 2.81 log(10) CFU/g (from initial inoculum) against MRSA strain MW2.

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.

Introduction: E. faecium and E. faecalis are responsible for 13.9% of hospital-acquired infections with frequent resistance to vancomycin (82.6% of E. faecium, 9.5% of E. faecalis). Medical device infections secondary to enterococci often require combination therapy due to impaired activity against biofilm embedded cells. In vitro data demonstrate synergistic activity of daptomycin combinations. Using a novel, biofilm time-kill approach, we evaluated whether daptomycin combinations maintained synergy against biofilm-producing E. faecium and E. faecalis. Methods: Broth microdilution (BMD) and biofilm MIC (bMIC) values for daptomycin, ampicillin, ceftriaxone, fosfomycin, and rifampin were determined against biofilm-producing E. faecium and E. faecalis. Daptomycin combination bMIC values were determined in the presence of biologic concentrations of other antimicrobials. Synergy was evaluated against two E. faecalis (R6981, R7808) and two E. faecium (5938 and 8019) using a previously described biofilm time-kill method. Synergy was defined as ≥2 log10 CFU/cm2 reduction over the most active agent alone. Bactericidal activity was defined as ≥3 log10 CFU/cm2 reduction. Results: Daptomycin bMICs were 2–8-fold higher than BMD. In the presence of other antimicrobials, daptomycin bMICs were reduced ≥ two-fold in dilutions. Ceftriaxone and ampicillin demonstrated the most potent combinations with daptomycin, yielding synergy against three of four strains. Daptomycin plus rifampin was synergistic against E. faecium 5938 and E. faecalis 6981 and produced bactericidal kill. The combination of daptomycin plus fosfomycin displayed synergy solely against E. faecalis 6981. Conclusions: Daptomycin combinations with beta-lactams demonstrated promising synergistic activity against both E. faecium and E. faecalis. While daptomycin plus rifampin yielded bactericidal results, the effect was not seen across all organisms. These combinations warrant further evaluation to determine the optimal dose and response.

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.

Clostridioides difficile infection (CDI) is a common complication in the hematopoietic stem cell transplantation (HSCT) and hematologic malignancy (HM) population. CDI is associated with increased hospital length of stay, health care and societal costs, morbidity, and mortality. Identifying strategies for secondary prevention of CDI is of extreme importance in the HSCT/HM population. In this study, our primary objective was to evaluate the effectiveness and safety of an oral vancomycin prophylaxis (OVP) protocol for secondary prevention of CDI in a retrospective cohort of adult autologous/allogeneic HSCT recipients and patients with HM who did not undergo HSCT with a first CDI episode treated with concomitant broad-spectrum antibiotics (BSA). Patients were diagnosed and treated for CDI as inpatients and/or outpatients and were divided into 2 groups based on a preprotocol versus postprotocol analysis: the OVP group, comprising patients who received planned monotherapy with oral vancomycin 125 mg every 6 hours for 14 days for a first episode of CDI and subsequently received OVP posttreatment and a no OVP (NOVP) group, comprising patients who received planned monotherapy with oral vancomycin 125 mg every 6 hours for 14 days for a first episode of CDI and subsequently did not receive OVP posttreatment. OVP was defined as vancomycin 125 mg every 12 hours for up to 7 days after BSA discontinuation. The primary endpoint was recurrent CDI (rCDI), defined as symptoms of loose stools/diarrhea with high clinical suspicion for CDI prompting empiric therapy within 60 days of completion of treatment/prophylaxis for the first CDI episode. The incidence of vancomycin-resistant enterococcal (VRE) infection and 60-day mortality were also compared between the 2 groups. Multivariate logistic regression was created from associated variables to identify independent associations with rCDI. A total of 50 patients were included, 21 in the OVP group (42%) and 29 in the NOVP group (58%). The mean patient age was 58 years, and the cohort was 60% male and 86% Caucasian. HSCT was performed in 60% of the patients, and 76% of CDI cases were diagnosed during hospitalization. The rate of rCDI was significantly lower in the OVP group compared with the NOVP group (5% [1 of 21] versus 35% [10 of 29]; P= .016), with no subsequent increase in VRE infection rate (14% [3 of 21] versus 10% [3 of 29]; P = .686). By multivariable logistic regression, rCDI was inversely associated with OVP (odds ratio [OR], .14; 95% confidence interval [CI], .007 to .994; P = .049) and directly associated with outpatient CDI diagnosis (OR, 8.72; 95% CI, 1.816 to 49.158; P = .007). No between-group differences were found in 60-day mortality (10% [2 of 21] for OVP versus 7% [2 of 29] for NOVP; P > 0.999). OVP appears to be safe and effective for secondary prevention of CDI in the HSCT/HM population. Prospective trials are needed to validate the effectiveness of OVP in this vulnerable population to prevent rCDI.

Background: Peritonitis remains a complication of peritoneal dialysis (PD) and contributes to morbidity. Adherence to evidence-based recommendations should resolve peritonitis within 5 days; however, hospital length of stay (LOS) for patients with PD-associated peritonitis (PDAP) varies. Factors contributing to increased LOS and vigilance with antimicrobial stewardship (ASP) in this population are not well described. Methods: This was a system-wide, retrospective cohort of adult patients presenting with PDAP from August 2012 to August 2017. Patients were divided into 2 groups based on LOS: 180 mg/dL ( P = .028). Opportunities for antimicrobial de-escalation were identified in 24 (52%) and 22 (50%) patients in the reduced and prolonged LOS groups, respectively; however, de-escalation occurred in only 5 (21%) and 6 (27%) of these patients. There were no differences in mortality or 30-day readmissions. Conclusions: Longer LOS was influenced by acuity of illness and possibly lack of enforced ASP. Improvement of ASP within the PDAP population is necessary.

Pseudomonas aeruginosa is one of the most common causes of healthcare-associated diseases and is among the top three priority pathogens listed by the World Health Organization (WHO). This Gram-negative pathogen is especially difficult to eradicate because it displays high intrinsic and acquired resistance to many antibiotics. In addition, growing concerns regarding the scarcity of antibiotics against multidrug-resistant (MDR) and extensively drug-resistant (XDR) P. aeruginosa infections necessitate alternative therapies. Bacteriophages, or phages, are viruses that target and infect bacterial cells, and they represent a promising candidate for combatting MDR infections. The aim of this review was to highlight the clinical pharmacology considerations of phage therapy, such as pharmacokinetics, formulation, and dosing, while addressing several challenges associated with phage therapeutics for MDR P. aeruginosa infections. Further studies assessing phage pharmacokinetics and pharmacodynamics will help to guide interested clinicians and phage researchers towards greater success with phage therapy for MDR P. aeruginosa infections.

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.

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. Supplementary Information The online version contains supplementary material available at 10.1007/s40121-021-00399-6.

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.

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.

Respiratory syncytial virus (RSV) is responsible for significant morbidity and mortality in the lung transplant population. Oral and aerosolized ribavirin may improve outcomes in lung transplant patients with RSV; however, data relating ribavirin concentrations in plasma and intracellular ribavirin triphosphate (iRTP) concentrations in blood and bronchoalveolar lavage (BAL) fluid cells with efficacy and safety are lacking. We describe ribavirin and iRTP concentrations within various compartments in two adult lung transplant recipients with RSV who were sampled throughout successful treatment courses with oral and inhaled ribavirin. In patient one, iRTP BAL concentrations decreased by 45% over three days after changing inhaled ribavirin to oral (6.32 to 3.43 pmol/106 cells). In patient two, iRTP BAL concentrations were 103 pmol/106 cells after five days of oral followed by five days of inhaled ribavirin. Further study is needed to describe ribavirin pharmacokinetics in the respiratory compartment to inform clinical use of ribavirin for respiratory viruses.

Concerns regarding increased prevalence of daptomycin (DAP)-resistant strains necessitate novel therapies for Enterococcus faecium infections. Obligately lytic bacteriophages are viruses that target, infect, and kill bacterial cells. Limited studies have evaluated phage-antibiotic combinations against E. faecium . After an initial screen of eight E. faecium strains, three strains with varying DAP/phage susceptibilities were selected for further experiments.

Methicillin-resistant Staphylococcus aureus (MRSA) bloodstream infections (BSI) are associated with substantial morbidity and mortality. Monotherapy with first-line antimicrobials such as vancomycin (VAN; glycopeptide) and daptomycin (DAP; lipopeptide) are inadequate in some cases due to reduced antibiotic susceptibilities or therapeutic failure. In recent years, β-lactam antibiotics have emerged as a potential option for combination therapy with VAN and DAP that may meet an unmet therapeutic need for MRSA BSI. Ceftaroline (CPT), the only commercially available β-lactam in the United States with intrinsic in vitro activity against MRSA, has been increasingly studied in the setting of VAN and DAP failures. Novel combinations of first-line agents (VAN and DAP) with β-lactams have been the subject of many recent investigations due to in vitro findings such as the "seesaw effect," where β-lactam susceptibility may be improved in the presence of decreased glycopeptide and lipopeptide susceptibility. The combination of CPT and DAP, in particular, has become the focus of many scientific evaluations, due to intrinsic anti-MRSA activities and potent in vitro synergistic activity against various MRSA strains. This article reviews the available literature describing these innovative therapeutic approaches for MRSA BSI, focusing on preclinical and clinical studies, and evaluates the potential benefits and limitations of each strategy.

IntroductionAlthough 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.MethodsThis 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.ResultsA 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).ConclusionsIn 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.

Our objective was to describe the prescribing practices, clinical characteristics, and outcomes of patients treated with ceftolozane-tazobactam (C/T) for multidrug-resistant (MDR) Gram-negative infections. This was a multicenter, retrospective, cohort study at eight U.S. medical centers (2015 to 2019). Inclusion criteria were age ≥18 years and receipt of C/T (≥72 hours) for suspected or confirmed MDR Gram-negative infection. The primary efficacy outcome, evaluated among patients with MDR Pseudomonas aeruginosa infections, was composite clinical failure, namely, 30-day all-cause mortality, 30-day recurrence, and/or failure to resolve or improve infection signs or symptoms after C/T treatment. In total, 259 patients were included, and P. aeruginosa was isolated in 236 (91.1%). The MDR and extremely drug-resistant phenotypes were detected in 95.8% and 37.7% of P. aeruginosa isolates, respectively. The most common infection source was the respiratory tract (62.9%). High-dose C/T was used in 71.2% of patients with a respiratory tract infection (RTI) overall but in only 39.6% of patients with an RTI who required C/T renal dose adjustment. In the primary efficacy population (n = 226), clinical failure and 30-day mortality occurred in 85 (37.6%) and 39 (17.3%) patients, respectively. New C/T MDR P. aeruginosa resistance was detected in 3 of 31 patients (9.7%) with follow-up cultures. Hospital-acquired infection and Acute Physiological and Chronic Health Evaluation II (APACHE II) score were independently associated with clinical failure (adjusted odds ratio [aOR], 2.472 and 95% confidence interval [CI], 1.322 to 4.625; and aOR, 1.068 and 95% CI, 1.031 to 1.106, respectively). Twenty-five (9.7%) patients experienced ≥1 adverse effect (9 acute kidney injury, 13 Clostridioides difficile infection, 1 hepatotoxicity, 2 encephalopathy, and 2 gastrointestinal intolerance). C/T addresses an unmet medical need in patients with MDR Gram-negative infections.