Healthcare Resource Utilization and Discharge Readiness in Adult Hospitalized Patients With Candidemia or Invasive Candidiasis Who Received an Echinocandin: An Analysis of United States Hospitals.

Background: Scant real-world outcomes data are available among hospitalized patients with candidemia (C) or invasive candidiasis without candidemia (IC) who were treated with an echinocandin and few have assessed if there is an opportunity to accelerate the transition of their care to the outpatient setting. This study described the outcomes associated with echinocandin therapy for C/IC and determined the proportion of patients on an echinocandin at hospital discharge (HD) who were potentially eligible for an earlier HD. Methods: A retrospective, multicenter observational study was performed using the PINC AI Healthcare Database (January 2016-April 2019) of hospitalized adult patients with C/IC who received ≥3 days of an echinocandin. Outcomes included post-index culture hospital costs and discharge location. Patients were considered potentially dischargeable earlier than actual HD day if they met the following 3 criteria prior to their actual HD day: resided on a non-intensive care unit hospital ward until HD, received any oral medications, and had no diagnostic/therapeutic interventions. Results: A total of 1865 patients met study criteria. Mean (standard deviation) post-index culture hospital costs for patients with C and IC were 50 196 (64 630) US dollars and 61 551 (73 080) US dollars, respectively. Of the 1008 patients on an echinocandin near HD and discharged alive, 432 (42.9%) were potentially dischargeable prior to their actual hospital day. Most patients (35.8%) were discharged to a long-term care facility. Conclusions: The findings suggest that a high proportion of hospitalized C/IC patients receiving an echinocandin near the time of HD were potentially dischargeable earlier. Like all studies of this nature, the findings need to be prospectively validated.

Machine Learning-Led Optimization of Combination Therapy: Confronting the Public Health Threat of Extensively Drug Resistant Gram-Negative Bacteria.

Developing optimized regimens for combination antibiotic therapy is challenging and often performed empirically over many clinical studies. Novel implementation of a hybrid machine-learning pharmacokinetic/pharmacodynamic/toxicodynamic (ML-PK/PD/TD) approach optimizes combination therapy using human PK/TD data along with in vitro PD data. This study utilized human population PK (PopPK) of aztreonam, ceftazidime/avibactam, and polymyxin B along with in vitro PDs from the Hollow Fiber Infection Model (HFIM) to derive optimal multi-drug regimens de novo through implementation of a genetic algorithm (GA). The mechanism-based PD model was constructed based on 7-day HFIM experiments across 4 clinical, extensively drug resistant Klebsiella pneumoniae isolates. GA-led optimization was performed using 13 different fitness functions to compare the effects of different efficacy (60%, 70%, 80%, or 90% of simulated subjects achieving bacterial counts of 102 CFU/mL) and toxicity (66% of simulated subjects having a target polymyxin B area under the concentration-time curve [AUC] of 100 mg·h/L and aztreonam AUC of 1,332 mg·h/L) on the optimized regimen. All regimens, except those most heavily weighted for toxicity prevention, were able to achieve the target efficacy threshold (102 CFU/mL). Overall, GA-based regimen optimization using preclinical data from animal-sparing in vitro studies and human PopPK produced clinically relevant dosage regimens similar to those developed empirically over many years for all three antibiotics. Taken together, these data provide significant insight into new therapeutic approaches incorporating ML to regimen design and treatment of resistant bacterial infections.

Incidence of acute kidney injury (AKI) and its impact on patient outcomes among adult hospitalized patients with carbapenem-resistant Gram-negative infections who received targeted treatment with a newer ß-lactam or ß-lactam/ß-lactamase inhibitor-, polymyxin- or aminoglycoside-containing regimen.

BACKGROUND: Limited comparative data exist on acute kidney injury (AKI) risk and AKI-associated outcomes in hospitalized patients with carbapenem-resistant Gram-negative infections (CR-GNIs) treated with a newer ß-lactam/ß-lactam-ß-lactamase inhibitor (BL/BL-BLI)-, polymyxin (PB)- or aminoglycoside (AG)-containing regimen. This study quantified the risk of AKI and AKI-related outcomes among patients with CR-GNIs treated with a newer BL/BL-BLI-, PB- or AG-containing regimen. METHODS: A multicentre, retrospective, observational study was performed (2016-20). The study included adult hospitalized patients with (i) baseline estimated glomerular filtration rates ≥30 mL/min/1.73 m2; (ii) CR-GN pneumonia, complicated urinary tract infection or bloodstream infection; and (iii) receipt of newer BL/BL-BLI, PG or AG within 7 days of index CR-GN culture for ≥3 days. Outcomes included AKI, in-hospital mortality and hospital costs. RESULTS: The study included 750 patients and most (48%) received a newer BL/BL-BLI. The median (IQR) treatment duration was 8 (5-11), 5 (4-8) and 7 (4-8) days in the newer BL/BL-BLI group, AG group and PB group, respectively. The PB group had the highest adjusted AKI incidence (95% CI) (PB: 25.1% (15.6%-34.6%) versus AG: 8.9% (5.7%-12.2%) versus newer BL/BL-BLI: 11.9% (8.1%-15.7%); P = 0.001). Patients with AKI had significantly higher in-hospital mortality (AKI: 18.5% versus 'No AKI': 5.6%; P = 0.001) and mean hospital costs (AKI: $49 192 versus 'No AKI': $38,763; P = 0.043). CONCLUSIONS: The AKI incidence was highest among PB patients and patients with AKI had worse outcomes. Healthcare systems should consider minimizing the use of antibiotics that augment AKI risk as a measure to improve outcomes in patients with CR-GNIs.

Impact of a Purified Microbiome Therapeutic on Abundance of Antimicrobial Resistance Genes in Patients With Recurrent Clostridioides difficile Infection.

BACKGROUND: The gastrointestinal microbiota is an important line of defense against colonization with antimicrobial resistant (AR) bacteria. In this post hoc analysis of the phase 3 ECOSPOR III trial, we assessed impact of a microbiota-based oral therapeutic (fecal microbiota spores, live; VOWST Oral Spores [VOS], formerly SER-109]; Seres Therapeutics) compared with placebo, on AR gene (ARG) abundance in patients with recurrent Clostridioides difficile infection (rCDI). METHODS: Adults with rCDI were randomized to receive VOS or placebo orally for 3 days following standard-of-care antibiotics. ARG and taxonomic profiles were generated using whole metagenomic sequencing of stool at baseline and weeks 1, 2, 8, and 24 posttreatment. RESULTS: Baseline (n = 151) and serial posttreatment stool samples collected through 24 weeks (total N = 472) from 182 patients (59.9% female; mean age: 65.5 years) in ECOSPOR III as well as 68 stool samples obtained at a single time point from a healthy cohort were analyzed. Baseline ARG abundance was similar between arms and significantly elevated versus the healthy cohort. By week 1, there was a greater decline in ARG abundance in VOS versus placebo (P = .003) in association with marked decline of Proteobacteria and repletion of spore-forming Firmicutes, as compared with baseline. We observed abundance of Proteobacteria and non-spore-forming Firmicutes were associated with ARG abundance, while spore-forming Firmicutes abundance was negatively associated. CONCLUSIONS: This proof-of-concept analysis suggests that microbiome remodeling with Firmicutes spores may be a potential novel approach to reduce ARG colonization in the gastrointestinal tract.

Priorities and Progress in Gram-negative Bacterial Infection Research by the Antibacterial Resistance Leadership Group.

Addressing the treatment and prevention of antibacterial-resistant gram-negative bacterial infections is a priority area of the Antibacterial Resistance Leadership Group (ARLG). The ARLG has conducted a series of observational studies to define the clinical and molecular global epidemiology of carbapenem-resistant and ceftriaxone-resistant Enterobacterales, carbapenem-resistant Pseudomonas aeruginosa, and carbapenem-resistant Acinetobacter baumannii, with the goal of optimizing the design and execution of interventional studies. One ongoing ARLG study aims to better understand the impact of fluoroquinolone-resistant gram-negative gut bacteria in neutropenic patients, which threatens to undermine the effectiveness of fluoroquinolone prophylaxis in these vulnerable patients. The ARLG has conducted pharmacokinetic studies to inform the optimal dosing of antibiotics that are important in the treatment of drug-resistant gram-negative bacteria, including oral fosfomycin, intravenous minocycline, and a combination of intravenous ceftazidime-avibactam and aztreonam. In addition, randomized clinical trials have assessed the safety and efficacy of step-down oral fosfomycin for complicated urinary tract infections and single-dose intravenous phage therapy for adult patients with cystic fibrosis who are chronically colonized with P. aeruginosa in their respiratory tract. Thus, the focus of investigation in the ARLG has evolved from improving understanding of drug-resistant gram-negative bacterial infections to positively affecting clinical care for affected patients through a combination of interventional pharmacokinetic and clinical studies, a focus that will be maintained moving forward.

Priorities and Progress in Gram-positive Bacterial Infection Research by the Antibacterial Resistance Leadership Group: A Narrative Review.

The Antibacterial Resistance Leadership Group (ARLG) has prioritized infections caused by gram-positive bacteria as one of its core areas of emphasis. The ARLG Gram-positive Committee has focused on studies responding to 3 main identified research priorities: (1) investigation of strategies or therapies for infections predominantly caused by gram-positive bacteria, (2) evaluation of the efficacy of novel agents for infections caused by methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci, and (3) optimization of dosing and duration of antimicrobial agents for gram-positive infections. Herein, we summarize ARLG accomplishments in gram-positive bacterial infection research, including studies aiming to (1) inform optimal vancomycin dosing, (2) determine the role of dalbavancin in MRSA bloodstream infection, (3) characterize enterococcal bloodstream infections, (4) demonstrate the benefits of short-course therapy for pediatric community-acquired pneumonia, (5) develop quality of life measures for use in clinical trials, and (6) advance understanding of the microbiome. Future studies will incorporate innovative methodologies with a focus on interventional clinical trials that have the potential to change clinical practice for difficult-to-treat infections, such as MRSA bloodstream infections.

Clinical Risk Scores to Predict Nonsusceptibility to Trimethoprim-Sulfamethoxazole, Fluoroquinolone, Nitrofurantoin, and Third-Generation Cephalosporin Among Adult Outpatient Episodes of Complicated Urinary Tract Infection.

Background: Clinical risk scores were developed to estimate the risk of adult outpatients having a complicated urinary tract infection (cUTI) that was nonsusceptible to trimethoprim-sulfamethoxazole (TMP-SMX), fluoroquinolone, nitrofurantoin, or third-generation cephalosporin (3-GC) based on variables available on clinical presentation. Methods: A retrospective cohort study (1 December 2017-31 December 2020) was performed among adult members of Kaiser Permanente Southern California with an outpatient cUTI. Separate risk scores were developed for TMP-SMX, fluoroquinolone, nitrofurantoin, and 3-GC. The models were translated into risk scores to quantify the likelihood of nonsusceptibility based on the presence of final model covariates in a given cUTI outpatient. Results: A total of 30 450 cUTIs (26 326 patients) met the study criteria. Rates of nonsusceptibility to TMP-SMX, fluoroquinolone, nitrofurantoin, and 3-GC were 37%, 20%, 27%, and 24%, respectively. Receipt of prior antibiotics was the most important predictor across all models. The risk of nonsusceptibility in the TMP-SMX model exceeded 20% in the absence of any risk factors, suggesting that empiric use of TMP-SMX may not be advisable. For fluoroquinolone, nitrofurantoin, and 3-GC, clinical risk scores of 10, 7, and 11 predicted a ≥20% estimated probability of nonsusceptibility in the models that included cumulative number of prior antibiotics at model entry. This finding suggests that caution should be used when considering these agents empirically in patients who have several risk factors present in a given model at presentation. Conclusions: We developed high-performing parsimonious risk scores to facilitate empiric treatment selection for adult outpatients with cUTIs in the critical period between infection presentation and availability of susceptibility results.

Real-world effectiveness of omadacycline and impact of unapproved omadacycline prescription claims among adult outpatients with community-acquired bacterial pneumonia or acute bacterial skin and skin structure infections.

BACKGROUND: Omadacycline is an amino-methylcycline antibiotic that is indicated for the treatment of adults with community-acquired bacterial pneumonia (CABP) and acute bacterial skin and skin structure infections (ABSSSI). Like many new antibiotics, there are scant real-world effectiveness data for omadacycline. There is also a high potential that an omadacycline prescription is rejected or reversed, and it is not known whether patients who have an unapproved omadacycline claim are at higher risk for 30-day emergency department (ED)/inpatient (IP) visits. OBJECTIVE: To describe the real-world effectiveness of omadacycline and assess the impact of unapproved omadacycline claims among adult outpatients with CABP or ABSSSIs. METHODS: The study population included patients who received 1 or more omadacycline outpatient prescriptions from a large US claims database (October 2018 to September 2020) and had a diagnosis for CABP or ABSSSI. The approval status of omadacycline claims was determined. The proportion of all-cause 30-day ED/IP visits among patients with an approved vs unapproved claim was compared. RESULTS: 404 patients met the inclusion criteria (CABP: 97; ABSSSI: 307). Of the 404 patients, 146 (36%) had an unapproved claim (CABP: 28; ABSSSI: 118). Overall, the proportion of 30-day ED/IP visits (yes/no) for those with an unapproved and approved claim was 28% vs 17%, respectively (P < 0.05). The overall adjusted 30-day ED/IP visits incidence difference was 11% (95% CI = 2 - 19), corresponding to an adjusted number needed to treat of 9 (95% CI = 5 - 43). CONCLUSIONS: A high incidence (36%) of unapproved omadacydine claims was observed in this study. Patients with unapproved daims had an 11% higher incidence of 30-day all-cause ED/IP visits than patients with approved claims. DISCLOSURES This study was funded by Paratek Pharmaceuticals, Inc (King of Prussia, PA). Dr Lodise is a consultant to Paratek Pharmaceuticals, Inc, and has received consultancy payments. Drs Gunter, Sandor, and Berman are employees and shareholders of Paratek Pharmaceuticals, Inc. Dr Mu, Ms Gao, Ms Yang, and Ms Yim are employees of Analysis Group. Analysis Group has received payment from Paratek Pharmaceuticals, Inc, to conduct part of this study.

Treatment of critically ill patients with cefiderocol for infections caused by multidrug-resistant pathogens: review of the evidence.

Appropriate antibiotic treatment for critically ill patients with serious Gram-negative infections in the intensive care unit is crucial to minimize morbidity and mortality. Several new antibiotics have shown in vitro activity against carbapenem-resistant Enterobacterales (CRE) and difficult-to-treat resistant Pseudomonas aeruginosa. Cefiderocol is the first approved siderophore beta-lactam antibiotic with potent activity against multidrug-resistant, carbapenem-resistant, difficult-to-treat or extensively drug-resistant Gram-negative pathogens, which have limited treatment options. The spectrum of activity of cefiderocol includes drug-resistant strains of Acinetobacter baumannii, P. aeruginosa, Stenotrophomonas maltophilia, Achromobacter spp. and Burkholderia spp. and CRE that produce serine- and/or metallo-carbapenemases. Phase 1 studies established that cefiderocol achieves adequate concentration in the epithelial lining fluid in the lung and requires dosing adjustment for renal function, including patients with augmented renal clearance and continuous renal-replacement therapy (CRRT); no clinically significant drug-drug interactions are expected. The non-inferiority of cefiderocol versus high-dose, extended-infusion meropenem in all-cause mortality (ACM) rates at day 14 was demonstrated in the randomized, double-blind APEKS-NP Phase 3 clinical study in patients with nosocomial pneumonia caused by suspected or confirmed Gram-negative bacteria. Furthermore, the efficacy of cefiderocol was investigated in the randomized, open-label, pathogen-focused, descriptive CREDIBLE-CR Phase 3 clinical study in its target patient population with serious carbapenem-resistant Gram-negative infections, including hospitalized patients with nosocomial pneumonia, bloodstream infection/sepsis, or complicated urinary tract infections. However, a numerically greater ACM rate with cefiderocol compared with BAT led to the inclusion of a warning in US and European prescribing information. Cefiderocol susceptibility results obtained with commercial tests should be carefully evaluated due to current issues regarding their accuracy and reliability. Since its approval, real-world evidence in patients with multidrug-resistant and carbapenem-resistant Gram-negative bacterial infections suggests that cefiderocol can be efficacious in certain critically ill patient groups, such as those requiring mechanical ventilation for COVID-19 pneumonia with subsequently acquired Gram-negative bacterial superinfection, and patients with CRRT and/or extracorporeal membrane oxygenation. In this article, we review the microbiological spectrum, pharmacokinetics/pharmacodynamics, efficacy and safety profiles and real-world evidence for cefiderocol, and look at future considerations for its role in the treatment of critically ill patients with challenging Gram-negative bacterial infections.

Examining the clinical impact of rapid multiplex polymerase chain reaction-based diagnostic testing for bloodstream infections in a national cohort of the Veterans Health Administration.

STUDY OBJECTIVE: Bloodstream infections (BSIs) are a significant cause of mortality. Use of a rapid multiplex polymerase chain reaction-based blood culture identification panel (BCID) may improve antimicrobial utilization and clinical outcomes by shortening the time to appropriate therapy and de-escalating antibiotics among patients on overly broad-spectrum empiric therapy. The effect of BCID on clinical outcomes across varying institutional antimicrobial stewardship program (ASP) practices is unclear. This study evaluated clinical outcomes associated with the "real-world" implementation of BCID in a national health system with varying ASP practices. DESIGN: National, multicenter, retrospective, pre-post quasi-experimental study of hospitalized patients admitted from 2015 to 2020 to VHA facilities, which introduced the BCID for ≥1 year. SETTING: United States Veterans Health Administration (VHA) hospitals with BCID. PATIENTS: Hospitalized VHA patients with ≥1 blood culture positive for bacteria featured on the BCID panel. INTERVENTION: Comparison of outcomes between the pre- and post-BCID implementation groups. MEASUREMENTS: Outcomes evaluated included early antimicrobial de-escalation within 48 h, defined as reduction in antimicrobial spectrum scores, time to appropriate therapy, and 30-day mortality. MAIN RESULTS: A total of 4138 patients (pre-BCID, n = 2100; post-BCID, n = 2038) met the study criteria. Implementation of BCID was associated with significant improvements in early antimicrobial de-escalation (34.6%: pre-BCID vs. 38.1%: post-BCID; p = 0.022), which persisted after adjusting for other covariates (adjusted risk ratio [aRR], 1.11; 95% confidence interval [CI], 1.02-1.20; p = 0.011). Median time to appropriate therapy was shorter in the post-BCID implementation group relative to the pre-BCID group (9 h: pre-BCID vs. 8 h: post-BCID, respectively, p = 0.005), and a greater percentage of patients received early appropriate antimicrobial therapy within 48 h in the post-BCID implementation group (91.7%: pre-BCID vs. 93.8%: post-BCID; p = 0.008). In the multivariable regression analysis, BCID implementation was significantly associated with a higher likelihood of appropriate therapy within 48 h (aRR, 1.02; 95% CI, 1.01-1.08; p = 0.020). There was no difference in 30-day mortality between groups overall (12.6% pre-BCID vs. 11.2% post-BCID; p = 0.211). CONCLUSIONS: In a "real-world" clinical setting, the implementation of BCID was associated with clinical improvements in antimicrobial utilization. The BCID platform may serve as a useful adjunct for BSI management in facilities with ASP.

Safety and microbiological activity of phage therapy in persons with cystic fibrosis colonized with Pseudomonas aeruginosa: study protocol for a phase 1b/2, multicenter, randomized, double-blind, placebo-controlled trial.

BACKGROUND: Bacteriophages (phages) are a promising anti-infective option for human disease. Major gaps remain in understanding their potential utility. METHODS: This is a randomized, placebo-controlled, double-blind study of a single dose of intravenous phage in approximately 72 clinically stable adult cystic fibrosis volunteers recruited from up to 20 US sites with Pseudomonas aeruginosa airway colonization. The single dose of phage consists of a mixture of four anti-pseudomonal phages. Six sentinel participants will be sequentially enrolled with dose escalation of the phage mixture by one log10 beginning with 4 × 107 plaque-forming units in an unblinded stage 1. If no serious adverse events related to the study product are identified, the trial will proceed to a double-blinded stage 2. In stage 2a, 32 participants will be randomly assigned to one of three phage dosages or placebo in a 1:1:1:1 allocation. An interim analysis will be performed to determine the phage dosage with the most favorable safety and microbiological activity profile to inform phage dosing in stage 2b. During stage 2b, up to 32 additional volunteers will be randomized 1:1 to the phage or placebo arm. Primary outcomes include (1) the number of grade 2 or higher treatment-emergent adverse events, (2) change in log10 P. aeruginosa total colony counts in sputum, and (3) the probability of a randomly selected subject having a more favorable outcome ranking if assigned to receive phage therapy versus placebo. Exploratory outcomes include (1) sputum and serum phage pharmacokinetics, (2) the impact of phage on lung function, (3) the proportion of P. aeruginosa isolates susceptible to the phage mixture before and after study product administration, and (4) changes in quality of life. DISCUSSION: This trial will investigate the activity of phages in reducing P. aeruginosa colony counts and provide insights into the safety profile of phage therapy. TRIAL REGISTRATION: ClinicalTrials.gov NCT05453578. Registered on 12 July 2022.

Safety of Ceftazidime-Avibactam in Combination with Aztreonam (COMBINE) in a Phase I, Open-Label Study in Healthy Adult Volunteers.

This phase I study evaluated the safety of the optimal ceftazidime-avibactam (CZA) with aztreonam (ATM) regimens identified in hollow fiber infection models of MBL-producing Enterobacterales. Eligible healthy subjects aged 18 to 45 years were assigned to one of six cohorts: 2.5 g CZA over 2 h every 8 h (approved dose), CZA continuous infusion (CI) (7.5 g daily), 2 g ATM over 2 h every 6 h, ATM CI (8 g daily), CZA (approved dose) with 1.5 g ATM over 2 h every 6 h, and CZA (approved dose) with 2 g ATM over 2 h every 6 h. Study drug(s) were administered for 7 days. The most frequently observed adverse events (AEs) were hepatic aminotransferase (ALT/AST) elevations (n = 19 subjects). Seventeen of the 19 subjects with ALT/AST elevations received ATM alone or CZA-ATM. The incidence of ALT/AST elevations was comparable between the ATM-alone and CZA-ATM cohorts. Two subjects in the ATM CI cohort experienced severe ALT/AST elevation AEs. All subjects with ALT/AST elevations were asymptomatic with no other findings suggestive of liver injury. Most other AEs were of mild to moderate severity and were similar across cohorts, except for prolonged prothrombin time (more frequent in CZA-ATM cohorts). These results suggest that CZA-ATM administered as 2-h intermittent infusions is safe and that some caution should be exercised with the use of ATM CI at an ATM dose of 8 g daily. If CZA-ATM is prescribed, clinicians are advised to monitor liver function, hematologic, and coagulation parameters. Future controlled studies are required to better define the safety and efficacy of the CZA-ATM regimens evaluated in this phase I study.

Pharmacokinetics of Ceftazidime-Avibactam in Combination with Aztreonam (COMBINE) in a Phase 1, Open-Label Study of Healthy Adults.

Scant pharmacokinetic (PK) data are available on ceftazidime-avibactam (CZA) and aztreonam (ATM) in combination, and it is unknown if CZA-ATM exacerbates alanine aminotransferase (ALT)/aspartate aminotransferase (AST) elevations relative to ATM alone. This phase 1 study sought to describe the PK of CZA-ATM and assess the associations between ATM exposures and ALT/AST elevations. Subjects (n = 48) were assigned to one of six cohorts (intermittent infusion [II] CZA, continuous infusion [CI] CZA, II ATM, CI ATM [8 g/daily], II CZA with II ATM [6 g/daily], and II CZA with II ATM [8 g/daily]), and study product(s) were administered for 7 days. A total of 19 subjects (40%) had ALT/AST elevations, and most (89%) occurred in the ATM/CZA-ATM cohorts. Two subjects in the CI ATM cohort experienced severe ALT/AST elevations, which halted the study. All subjects with ALT/AST elevations were asymptomatic with no other signs of liver injury, and all ALT/AST elevations resolved without sequalae after cessation of dosing. In the population PK (PopPK) analyses, CZA-ATM administration reduced total ATM clearance by 16%, had a negligible effect on total ceftazidime clearance, and was not a covariate in the avibactam PopPK model. In the exposure-response analyses, coadministration of CZA-ATM was not found to augment ALT/AST elevations. Modest associations were observed between ATM exposure (maximum concentration of drug in serum [Cmax] and area under the concentration-time curve [AUC]) and ALT/AST elevations in the analysis of subjects in the II ATM/CZA-ATM cohorts. The findings suggest that administration of CZA-ATM reduces ATM clearance but does not exacerbate AST/ALT elevations relative to ATM alone. The results also indicate that CI ATM should be used with caution.

Gut microbiome health and dysbiosis: A clinical primer.

The gut microbiome has been referred to as the "forgotten organ." Although much about the gut microbiome remains incompletely understood, data on its clinical importance is emerging at rapid speed. Many practicing clinicians may be unaware of the essential role that the microbiome plays in both health and disease. This review aims to improve clinical understanding of the gut microbiome by discussing key terminology and foundational concepts. The role of a healthy microbiome in normal host function is described, as well as the consequences of a disrupted microbiome (i.e., dysbiosis). Management strategies to restore the gut microbiome from a disrupted to a healthy state are also briefly discussed. Lastly, we review emerging areas for therapeutic potential and opportunity to bring determinants of microbiome health from the bench to bedside.

Retrospective Cohort Study of the 12-Month Epidemiology, Treatment Patterns, Outcomes, and Health Care Costs Among Adult Patients With Complicated Urinary Tract Infections.

Background: Limited data are available in the United States on the 12-month epidemiology, outpatient (OP) antibiotic treatment patterns, outcomes, and costs associated with complicated urinary tract infections (cUTIs) in adult patients. Methods: A retrospective observational cohort study of adult patients with incident cUTIs in IBM MarketScan Databases between 2017 and 2019 was performed. Patients were categorized as OP or inpatient (IP) based on initial setting of care for index cUTI and were stratified by age (<65 years vs ≥65 years). OP antibiotic treatment patterns, outcomes, and costs associated with cUTIs among adult patients over a 12-month follow-up period were examined. Results: During the study period, 95 322 patients met inclusion criteria. Most patients were OPs (84%) and age <65 years (87%). Treatment failure (receipt of new unique OP antibiotic or cUTI-related ED visit/IP admission) occurred in 23% and 34% of OPs aged <65 years and ≥65 years, respectively. Treatment failure was observed in >38% of IPs, irrespective of age. Across both cohorts and age strata, >78% received ≥2 unique OP antibiotics, >34% received ≥4 unique OP antibiotics, >16% received repeat OP antibiotics, and >33% received ≥1 intravenous (IV) OP antibiotics. The mean 12-month cUTI-related total health care costs were $4697 for OPs age <65 years, $8924 for OPs age >65 years, $15 401 for IPs age <65 years, and $17 431 for IPs age ≥65 years. Conclusions: These findings highlight the substantial 12-month health care burden associated with cUTIs and underscore the need for new outpatient treatment approaches that reduce the persistent or recurrent nature of many cUTIs.

Epidemiology of Complicated Urinary Tract Infections due to Enterobacterales Among Adult Patients Presenting in Emergency Departments Across the United States.

In this multicenter study of adult patients who presented to the emergency department with an Enterobacterales complicated urinary tract infection (cUTI), high rates of resistance and co-resistance to commonly used oral antibiotics (fluoroquinolones, trimethoprim-sulfamethoxazole, nitrofurantoin, and third-generation cephalosporins) were observed.

New Perspectives on Antimicrobial Agents: Imipenem-Relebactam.

Imipenem (IMI)/cilastatin/relebactam (REL) (I/R) is a novel ß-lactam/ß-lactamase inhibitor combination with expanded microbiologic activity against carbapenem-resistant non-Morganellaceae Enterobacterales (CR-NME) and difficult-to-treat (DTR) Pseudomonas aeruginosa. Relebactam, a bicyclic diazabicyclooctane, has no direct antimicrobial activity but provides reliable inhibition of many Ambler class A and class C enzymes. It is currently approved for the treatment of adult patients with hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia (HABP/VABP) and those with complicated urinary tract infections (cUTIs) and complicated intra-abdominal infections (cIAIs) when limited or no alternative treatments are available. Given the number of recently approved ß-lactams with expanded activity against highly resistant Gram-negative pathogens, this review summarizes the published literature on I/R, with a focus on its similar and distinguishing characteristics relative to those of other recently approved agents. Overall, available data support its use for the treatment of patients with HABP/VABP, cUTI, and cIAI due to CR-NME and DTR P. aeruginosa. Data indicate that I/R retains some activity against CR-NME and DTR P. aeruginosa isolates that are resistant to the newer ß-lactams and vice versa, suggesting that susceptibility testing be performed for all the newer agents to determine optimal treatment options for patients with CR-NME and DTR P. aeruginosa infections. Further comparative PK/PD and clinical studies are warranted to determine the optimal role of I/R, alone and in combination, for the treatment of patients with highly resistant Gram-negative infections. Until further data are available, I/R is a potential treatment for patients with CR-NME and DTR P. aeruginosa infections when the benefits outweigh the risks.

The 30-Day Economic Burden of Newly Diagnosed Complicated Urinary Tract Infections in Medicare Fee-for-Service Patients Who Resided in the Community.

INTRODUCTION: Scant data are available on the 30-day financial burden associated with incident complicated urinary tract infections (cUTIs) in a cohort of predominately elderly patients. This study sought to examine total and cUTI-related 30-day Medicare spending (MS), a proxy for healthcare costs, among Medicare fee-for-service (FFS) beneficiaries who resided in the community with newly diagnosed cUTIs. METHODS: A retrospective multicenter cohort study of adult beneficiaries in the Medicare FFS database with a cUTI between 2017 and 2018 was performed. Patients were included if they were enrolled in Medicare FFS and Medicare Part D from 2016 to 2019, had a cUTI first diagnosis in 2017-2018, no evidence of any UTI diagnoses in 2016, and residence in the community between 2016 and 2018. RESULTS: During the study period, 723,324 cases occurred in Medicare beneficiaries who met the study criteria. Overall and cUTI-related 30-day MS were $7.6 and $4.5 billion, respectively. The average overall and cUTI-related 30-day MS per beneficiary were $10,527 and $6181, respectively. The major driver of cUTI-related 30-day MS was acute care hospitalizations ($3.2 billion) and the average overall and cUTI-related 30-day MS per hospitalizations were $16,431 and $15,438, respectively. CONCLUSION: Overall 30-day MS for Medicare FSS patients who resided in the community with incident cUTIs was substantial, with cUTI-related MS accounting for 59%. As the major driver of cUTI-related 30-day MS was acute care hospitalizations, healthcare systems should develop well-defined criteria for hospital admissions that aim to avert hospitalizations in clinically stable patients and expedite the transition of patients to the outpatient setting to complete their care.

Determination of plasma protein binding of dalbavancin.

OBJECTIVES: Dalbavancin is a lipoglycopeptide with a long half-life, making it a promising treatment for infections requiring prolonged therapy, such as complicated Staphylococcus aureus bacteraemia. Free drug concentration is a critical consideration with prolonged treatment, since free concentration-time profiles may best correlate with therapeutic effect. In support of future clinical trials, we aimed to develop a reliable and reproducible assay for measuring free dalbavancin concentrations. METHODS: The ultracentrifugation technique was used to determine free dalbavancin concentrations in plasma at two concentrations (50 and 200 mg/L) in duplicate. Centrifuge tubes and pipette tips were treated for 24 h before use with Tween 80 to assess adsorption. Dalbavancin concentrations were analysed from the plasma samples (total) and middle layer samples (free) by LC/MS/MS with isotopically labelled internal standard. Warfarin served as a positive control with known high protein binding. RESULTS: Measurement of free dalbavancin was sensitive to adsorption onto plastic. Treatment of tubes and pipette tips with ≥2% Tween 80 effectively prevented drug loss during protein binding experiments. By the ultracentrifugation method, dalbavancin's protein binding was estimated to be approximately 99%. CONCLUSIONS: Dalbavancin has very high protein binding. Given dalbavancin's high protein binding, accurate measurement of free dalbavancin concentrations should be a key consideration in future exposure-response studies, especially clinical trials. Future investigations should confirm if the active fraction is best predicted by the free or total fraction.

In vitro activity of imipenem/relebactam plus aztreonam against metallo-ß-lactamase-producing, OprD-deficient Pseudomonas aeruginosa with varying levels of Pseudomonas-derived cephalosporinase production.

BACKGROUND: Treatment options for metallo-ß-lactamase (MBL)-producing Pseudomonas aeruginosa infections are limited. Imipenem/relebactam (I/R) plus aztreonam (ATM) may be an option. METHODS: Ten OprD(-) P. aeruginosa isolates (3 parent strains; 7 MBL-producers) were evaluated using checkerboard methodology and Fractional Inhibitory Concentration Index (FICI). Isolates exhibiting synergy in checkerboard studies (FICI ≤0.5) were evaluated using 24-h static concentration time-kill. Bacteria in late log-phase growth were diluted to 1 × 106 cfu/mL and incubated at 37°C for 24 h. Samples were drawn at 0, 2, 4, 6 and 24 h. Physiological fCmax, fCss,avg and fCmin of imipenem (26.7, 5.6, 0.5 mg/L), relebactam (REL; 13.1, 4, 0.8 mg/L) and ATM (62, 29, 8 mg/L) were used. Synergy in time-kill studies was defined as >2 log10 cfu/mL reduction compared with the most active individual agent. RESULTS: Synergy was observed in five isolates in checkerboard studies, including three of seven MBL-producing isolates. Isolates that were OprD(-) and harbored inducible Pseudomonas-derived cephalosporinases (PDCs) did not show synergy as defined by FICI; however, ATM minimum inhibitory concentrations (MICs) were significantly reduced with the combination. In time-kill studies, ATM alone was as active as combination regimens for MBL-producing isolates with deleted or inducible PDC production. For strains exhibiting constitutive PDC production, I/R plus ATM was synergistic at fCss,avg concentrations but exhibited similar activity to ATM at fCmin and fCmax concentrations. CONCLUSIONS: I/R plus ATM appears to exhibit synergy for some MBL-producing P. aeruginosa at physiological concentrations. Further study of the effect of dynamic concentrations is needed to fully understand the utility of this combination.