Evaluation of hospital-onset bacteraemia and fungaemia in the USA as a potential healthcare quality measure: a cross-sectional study.

BACKGROUND: Hospital-onset bacteraemia and fungaemia (HOB) is being explored as a surveillance and quality metric. The objectives of the current study were to determine sources and preventability of HOB in hospitalised patients in the USA and to identify factors associated with perceived preventability. METHODS: We conducted a cross-sectional study of HOB events at 10 academic and three community hospitals using structured chart review. HOB was defined as a blood culture on or after hospital day 4 with growth of one or more bacterial or fungal organisms. HOB events were stratified by commensal and non-commensal organisms. Medical resident physicians, infectious disease fellows or infection preventionists reviewed charts to determine HOB source, and infectious disease physicians with training in infection prevention/hospital epidemiology rated preventability from 1 to 6 (1=definitely preventable to 6=definitely not preventable) using a structured guide. Ratings of 1-3 were collectively considered 'potentially preventable' and 4-6 'potentially not preventable'. RESULTS: Among 1789 HOB events with non-commensal organisms, gastrointestinal (including neutropenic translocation) (35%) and endovascular (32%) were the most common sources. Overall, 636/1789 (36%) non-commensal and 238/320 (74%) commensal HOB events were rated potentially preventable. In logistic regression analysis among non-commensal HOB events, events attributed to intravascular catheter-related infection, indwelling urinary catheter-related infection and surgical site infection had higher odds of being rated preventable while events with neutropenia, immunosuppression, gastrointestinal sources, polymicrobial cultures and previous positive blood culture in the same admission had lower odds of being rated preventable, compared with events without those attributes. Of 636 potentially preventable non-commensal HOB events, 47% were endovascular in origin, followed by gastrointestinal, respiratory and urinary sources; approximately 40% of those events would not be captured through existing healthcare-associated infection surveillance. DISCUSSION: Factors identified as associated with higher or lower preventability should be used to guide inclusion, exclusion and risk adjustment for an HOB-related quality metric.

Amoxicillin-clavulanate Breakpoints Against Enterobacterales: Rationale for Revision by the Clinical and Laboratory Standards Institute.

Amoxicillin-clavulanate (AMC) is among the most frequently prescribed antibiotics globally. It has broad antibacterial activity against gram-positive, gram-negative, and anaerobic bacteria, and has been utilized to treat infections caused by a broad range of pathogens. AMC breakpoints against Enterobacterales were initially set in the 1980s but since then increases in antibiotic resistance, advances in pharmacokinetic (PK)/pharmacodynamic (PD) analyses, and publication of additional clinical data prompted a reassessment by the Clinical and Laboratory Standards Institute (CLSI) Subcommittee on Antimicrobial Susceptibility Testing. Based on this contemporary reappraisal, the CLSI retained the Enterobacterales breakpoints but revised comments regarding dosing associated with use of the AMC breakpoints in the 2022 supplement of M100. This viewpoint provides insight into the CLSI breakpoint reevaluation process and summarizes the data and rationale used to support these revisions to the AMC Enterobacterales breakpoint.

Assessment of antibiotic release and antibacterial efficacy from pendant glutathione hydrogels using ex vivo porcine skin.

Acute bacterial skin and skin structure infections (ABSSSIs) confer a substantial burden on the healthcare system. Local antibiotic delivery systems can provide controlled drug release directly to the site of infection to maximize efficacy and minimize systemic toxicity. The purpose of this study was to examine the antibacterial activity of antibiotic-loaded glutathione-conjugated poly(ethylene glycol) hydrogels (GSH-PEG) against ABSSSIs utilizing an ex vivo porcine dermal explant model. Vancomycin- or meropenem-loaded GSH-PEG hydrogels at 3 different dose levels were loaded over 1 h. Drug release was monitored in vitro under submerged conditions, by the Franz cell diffusion method, and ex vivo utilizing a porcine dermis model. Antibacterial activity was assessed ex vivo on porcine dermis explants inoculated with Staphylococcus aureus or Pseudomonas aeruginosa isolates treated with vancomycin- or meropenem-loaded GSH-PEG hydrogels, respectively. Histological assessment of the explants was conducted to evaluate tissue integrity and viability in the context of the experimental conditions. A dose-dependent release was observed from vancomycin and meropenem hydrogels, with in vitro Franz cell diffusion data closely representing ex vivo vancomycin release, but not high dose meropenem release. High dose vancomycin-loaded hydrogels resulted in a >3 log10 clearance against all S. aureus isolates at 48 h. High dose meropenem-loaded hydrogels achieved 6.5, 4, and 2 log10 reductions in CFU/ml against susceptible, intermediate, and resistant P. aeruginosa isolates, respectively. Our findings demonstrate the potential application of GSH-PEG hydrogels for flexible, local antibiotic delivery against bacterial skin infections.

Pharmacokinetics and dialytic clearance of baricitinib during in vivo continuous venovenous haemodialysis in a patient with COVID-19.

OBJECTIVES: To date, there are no published pharmacokinetic (PK) data for baricitinib in critically ill patients requiring continuous renal replacement therapy. This paper describes in detail the plasma PK and dialytic clearance of baricitinib in a patient infected with coronavirus disease 2019 (COVID-19) requiring continuous renal replacement therapy in order to suggest dosing strategies in this population. METHODS: Baricitinib 2 mg daily was used for the treatment of COVID-19 in a critically ill patient on continuous venovenous haemodialysis (CVVHD). Prefiltration plasma drug concentrations of baricitinib were measured at hours 1, 2, 12, and 24 after drug administration. Postfiltration and ultrafiltrate concentrations were collected at hour 24. RESULTS: Plasma PK parameters of baricitinib in this patient were as follows: maximum plasma concentration (Cmax), 20.98 ng/mL; minimum plasma concentration (Cmin), 9.84 ng/mL; half-life (t1/2), 23.85 h; apparent volume of distribution at the steady state (Vss), 99.42 L; total clearance at the steady state (CLss), 2.89 L/h; and area under the concentration-time curve (AUC0-∞), 692.14 ng · h/mL. The saturation coefficient for baricitinib at 24 h after administration was 0.607. The transmembrane clearance of baricitinib by CVVHD running at a flow rate of 2 L/h was 1.21 L/h, representing 41.9% of the total clearance of baricitinib. CONCLUSIONS: In a critically ill COVID-19 patient on CVVHD, a 2-mg dose of baricitinib achieves a Cmax comparable with healthy subjects, but total clearance was reduced to about 20%. Larger studies exploring multiple patients and dialysis modes are needed to determine the optimal dosing strategy for baricitinib in this patient population.

Comparison of thrombotic and clinical outcomes in SARS-CoV-2-pneumonia versus other viral pneumonia in an urban academic medical center.

BACKGROUND: Infection with viral pneumonia (PNA) is known to offset the coagulation cascade. Recent studies assessing novel SARS-CoV-2 infection observed a high frequency of systemic thrombotic events resulting in ambiguity if severity of infection or specific viral strain drive thrombosis and worsen clinical outcomes. Furthermore, limited data exists addressing SARS-CoV-2 in underrepresented patient populations. OBJECTIVES: Assess clinical outcomes events and death in patients diagnosed with SARS-CoV-2 pneumonia compared to patients with other types of viral pneumonia. METHODS: Retrospective cohort study evaluated electronic medical records in adult patients admitted to University of Illinois Hospital and Health Sciences System (UIHHSS) with primary diagnosis of SARS-CoV-2 PNA or other viral (H1N1 or H3N2) PNA between 10/01/2017 and 09/01/2020. Primary composite outcome was the following event incidence rates: death, ICU admission, infection, thrombotic complications, mechanical ventilation, renal replacement therapy, and major bleeding. RESULTS: Of 257 patient records, 199 and 58 patients had SARS-CoV-2 PNA and other viral PNA, respectively. There was no difference in primary composite outcome. Thrombotic events (n = 6, 3%) occurred solely in SARS-CoV-2 PNA patients in the ICU. A significantly higher incidence of renal replacement therapy (8.5% vs 0%, p=0.016) and mortality (15.6% vs 3.4%, p=0.048) occurred in the SARS-CoV-2 PNA group. Multivariable logistic regression analysis revealed age, presence of SARS-CoV-2, and ICU admission, aOR 1.07, 11.37, and 41.95 respectively, was significantly associated with mortality risk during hospitalization; race and ethnicity were not. CONCLUSION: Low overall incidence of thrombotic events occurred only in the SARS-CoV-2 PNA group. SARS-CoV-2 PNA may lead to higher incidence of clinical events than those observed in H3N2/H1N1 viral pneumonia, and that race/ethnicity does not drive mortality outcomes.

Rapid Diagnostic Test Value and Implementation in Antimicrobial Stewardship Across Low-to-Middle and High-Income Countries: A Mixed-Methods Review.

Despite technological advancements in infectious disease rapid diagnostic tests (RDTs) and use to direct therapy at the per-patient level, RDT utilisation in antimicrobial stewardship programmes (ASPs) is variable across low-to-middle income and high-income countries. Key insights from a panel of seven infectious disease experts from Colombia, Japan, Nigeria, Thailand, the UK, and the USA, combined with evidence from a literature review, were used to assess the value of RDTs in ASPs. From this, a value framework is proposed which aims to define the benefits of RDT use in ASPs, separate from per-patient benefits. Expert insights highlight that, to realise the value of RDTs within ASPs, effective implementation is key; actionable advice for choosing an RDT is proposed. Experts advocate the inclusion of RDTs in the World Health Organization Model List of essential in vitro diagnostics and in iterative development of national action plans.

Multicenter Evaluation of an MIC-Based Aztreonam and Ceftazidime-Avibactam Broth Disk Elution Test.

Due to limited therapeutic options, there is a clinical need to assess the in vitro activity of the combination of aztreonam (ATM) and ceftazidime-avibactam (CZA) to guide the therapeutic management of multidrug-resistant (MDR) Gram-negative organism infections. We set out to develop a practical MIC-based broth disk elution (BDE) method to determine the in vitro activity of the combination ATM-CZA using readily available supplies and compare it to reference broth microdilution (BMD). For the BDE method, a 30-µg ATM disk, a 30/20-µg CZA disk, both disks in combination, and no disks were added to 4 separate 5-mL cation-adjusted Mueller-Hinton broth (CA-MHB) tubes, using various manufacturers. Three testing sites performed both BDE and reference BMD testing of bacterial isolates in parallel from a single 0.5 McFarland standard inoculum and after overnight incubation, assessed them for growth (not susceptible) or no growth (susceptible) at a final concentration of 6/6/4 µg/mL ATM-CZA. During the first phase, the precision and accuracy of the BDE were analyzed by testing 61 Enterobacterales isolates at all sites. This testing yielded 98.3% precision between sites, with 98.3% categorical agreement and 1.8% major errors (ME). During the second phase, at each site, we evaluated unique, clinical isolates of metallo-ß-lactamase (MBL)-producing Enterobacterales (n = 75), carbapenem-resistant Pseudomonas aeruginosa (n = 25), Stenotrophomonas maltophilia (n = 46), and Myroides sp. (n = 1). This testing resulted in 97.9% categorical agreement, with 2.4% ME. Different results were observed for different disk and CA-MHB manufacturers, requiring a supplemental ATM-CZA-not-susceptible quality control organism to ensure the accuracy of results. The BDE is a precise and effective methodology for determining susceptibility to the combination ATM-CZA.

Antimicrobial susceptibility testing: An updated primer for clinicians in the era of antimicrobial resistance: Insights from the Society of Infectious Diseases Pharmacists.

Antimicrobial susceptibility testing (AST) is a critical function of the clinical microbiology laboratory and is essential for optimizing care of patients with infectious diseases, monitoring antimicrobial resistance (AMR) trends, and informing public health initiatives. Several methods are available for performing AST including broth microdilution, agar dilution, and disk diffusion. Technological advances such as the development of commercial automated susceptibility testing platforms and the advent of rapid diagnostic tests have improved the rapidity, robustness, and clinical application of AST. Numerous accrediting and regulatory agencies are involved in the process of AST and setting and revising breakpoints, including the U.S. Food and Drug Administration and the Clinical and Laboratory Standards Institute. Challenges to optimizing AST include the emergence of new resistance mechanisms, the development of new antimicrobial agents, and generation of new data requiring updates and revisions to established methods and breakpoints. Together, the challenges in AST methods and their interpretation create important opportunities for well-informed clinicians to improve patient outcomes and provide value to antimicrobial stewardship programs, especially in the setting of rapidly changing and increasing AMR. Addressing AST challenges will involve continued development of new technologies along with collaboration between clinicians and the laboratory to facilitate optimal antimicrobial use, combat the increasing burden of AMR, and inform the development of novel antimicrobials. This updated primer serves to reinforce important principles of AST, and to provide guidance on their implementation and optimization.

Breaking Down the Breakpoints: Rationale for the 2022 Clinical and Laboratory Standards Institute Revised Piperacillin-Tazobactam Breakpoints Against Enterobacterales.

Piperacillin-tazobactam (PTZ) is one of the most common antibiotics administered to hospitalized patients. Its broad activity against gram-negative, gram-positive, and anaerobic pathogens; efficacy in clinical trials across diverse infection types and patient populations; and generally favorable toxicity profile make it a particularly appealing antibiotic agent. PTZ susceptibility interpretive criteria (ie, breakpoints) for the Enterobacterales were initially established in 1992, as the drug was undergoing approval by the US Food and Drug Administration. In the ensuing 30 years, changes in the molecular epidemiology of the Enterobacterales and its impact on PTZ susceptibility testing, mounting pharmacokinetic/pharmacodynamic data generated from sophisticated techniques such as population pharmacokinetic modeling and Monte Carlo simulation, and disturbing safety signals in a large clinical trial prompted the Clinical Laboratory and Standards Institute (CLSI) to review available evidence to determine the need for revision of the PTZ breakpoints for Enterobacterales. After an extensive literature review and formal voting process, the susceptibility criteria were revised in the 2022 CLSI M100 document to the following: ≤8/4 µg/mL (susceptible), 16/4 µg/mL (susceptible dose-dependent), and ≥32/4 µg/mL (resistant). Herein, we provide a brief overview of the CLSI process of antibiotic breakpoint revisions and elaborate on the available data that ultimately led to the decision to revise the PTZ breakpoints.

The importance of pharmacokinetics and pharmacodynamics in antimicrobial drug development and their influence on the success of agents developed to combat resistant gram negative pathogens: A review.

A deep understanding of an antimicrobial's critical pharmacokinetic and pharmacodynamic properties is crucial towards optimizing its use in patients and bolstering the drug development program. With the growing threat of antimicrobial resistance and decline in antimicrobial development, the advancement of complex and rigorous pharmacokinetic and pharmacodynamic studies over a short time span has renewed confidence in the value of pharmacokinetic and pharmacodynamic studies and allowed it to become fundamental component of a robust drug development program with high chances of successful approval. In addition, recent guidance by various regulatory bodies have reinforced that a strong and dedicated focus on pharmacokinetics and pharmacodynamics throughout research and development lead to the use of an optimized dosing regimen in Phase 3 trials, improving the probability of drug approval. The objective of this review is to demonstrate the importance of pharmacokinetic and pharmacodynamic studies in the drug development decision-making process by highlighting the developments in pharmacokinetic and pharmacodynamic methods and discuss the role of pharmacokinetic and pharmacodynamic studies in antimicrobial successes and failures.

Activity of Delafloxacin and Levofloxacin against Stenotrophomonas maltophilia at Simulated Plasma and Intrapulmonary pH Values.

Fluoroquinolones have become a popular treatment option for Stenotrophomonas maltophilia infections. Although levofloxacin is most commonly used, delafloxacin demonstrates comparable in vitro activity when evaluated under standard susceptibility testing conditions at neutral pH. At acidic pH, the activity of the anionic delafloxacin is improved, while the activity of the zwitterionic levofloxacin is reduced. Because the human respiratory tract has a pH of ~6.6 and is the most common site of S. maltophilia infection, it is vital to understand the activity of these agents in this environment. Therefore, levofloxacin and delafloxacin were tested against clinical S. maltophilia isolates via broth microdilution testing (n = 37) and time-kill analysis (n = 5) in neutral cation-adjusted Mueller-Hinton broth (CAMHB) (pH 7.3) and acidic CAMHB (aCAMHB) (pH 6.5). In CAMHB, MIC50 values were similar between levofloxacin and delafloxacin (8 mg/L versus 8 mg/L). In aCAMHB, levofloxacin MICs did not change, while delafloxacin MICs decreased by a median of 4 log2 dilutions (MIC50 values of 8 mg/L versus 0.25 mg/L). In time-kill analyses, levofloxacin and delafloxacin at the maximum drug concentration for the free drug (fCmax) were bactericidal against 3 and 2 isolates in CAMHB, respectively. In aCAMHB, levofloxacin was not bactericidal against any isolate, while delafloxacin was bactericidal against the same 2 isolates. Relative to CAMHB, levofloxacin activity was reduced by 2.5 log10 CFU/mL in aCAMHB, whereas delafloxacin activity was increased 2.7 log10 CFU/mL. Although the bactericidal activity of levofloxacin against S. maltophilia was attenuated in an acidic environment in this study, the increased potency of delafloxacin at pH 6.5 did not translate into improved bactericidal activity in time-kill analyses, compared to pH 7.3. IMPORTANCE Stenotrophomonas maltophilia most often infects the lungs, where the physiologic environment is naturally slightly acidic (pH ~6.6), compared to most parts of the body (such as the bloodstream), which have neutral pH values (~7.4). Pneumonia due to S. maltophilia is often treated with the antibiotic levofloxacin, despite the activity of levofloxacin being known to be impaired at acidic pH. Unfortunately, currently available methods for susceptibility testing of levofloxacin against S. maltophilia are performed at a neutral pH and therefore may not accurately represent the activity of levofloxacin at the site of infection in the lungs. A similar but newer antibiotic in the same class as levofloxacin, namely, delafloxacin, is not affected by being in an acidic environment and may actually work better at lower pH values. Therefore, the purpose of this study was to investigate whether one drug might be better than the other in this setting by testing each agent's ability to kill S. maltophilia at pH 7.3 and pH 6.5. These findings could then be used to design confirmatory studies that may ultimately impact which drug is given to patients with lung infections due to S. maltophilia.

Activity of Omadacycline Alone and in Combination against Carbapenem-Nonsusceptible Acinetobacter baumannii with Varying Minocycline Susceptibility.

Tetracycline-based combinations are increasingly used for serious carbapenem-nonsusceptible Acinetobacter baumannii (CNSAb) infections given their potent in vitro activity, synergism with other agents, and acceptable toxicity profile. Omadacycline is a novel aminomethylcycline with activity against minocycline-resistant pathogens, once daily oral dosing, and favorable pharmacokinetic properties. Given these potential advantages, the in vitro potency and antibacterial activity of omadacycline were evaluated alone and in combination against CNSAb with varying minocycline susceptibility. Broth microdilution testing of 41 CNSAb revealed that omadacycline (MIC50/90: 4/8 mg/L) inhibited 68.3% (28/41) of isolates at ≤4 mg/L and its activity was unaffected by minocycline nonsusceptibility (MIC50/90: 4/8 mg/L; 74.2% [23/31] inhibited at ≤4 mg/L). Ten (5 minocycline susceptible and 5 nonsusceptible) of the 41 CNSAb isolates were then evaluated in time-kill analyses against omadacycline and comparator agents alone and in dual- and triple-drug combinations at the free maximum concentration of drug in serum (fCmax). Amikacin, meropenem, and polymyxin B alone were each bactericidal against 4 of 10 (40%) isolates while omadacycline and sulbactam were bactericidal against 0 (0%) and 1 (10%), respectively. In dual-drug combinations with omadacycline, synergy was observed against 80% of isolates with sulbactam followed by 30% with amikacin or polymyxin B and 0% with meropenem or rifampin. The triple-drug combination of omadacycline, sulbactam, and polymyxin B achieved synergy against just one additional strain over the omadacycline-sulbactam dual combination but significantly reduced the time to 99.9% kill by more than 6 h (4.6 ± 2.8 h vs. 11.3 ± 5.9 h, P < 0.01). These results support the continued investigation into tetracycline-based combinations against CNSAb, particularly those including sulbactam, and suggest that omadacycline may have in vitro advantages over existing tetracycline-derivatives. IMPORTANCE Treatment of infections due to Acinetobacter baumannii often involves the use of multiple antibiotics simultaneously as combination therapy, but it is unknown which antibiotics are best used together. Tetracycline agents such as minocycline and tigecycline maintain good activity against A. baumannii and are often used with one or more other agents to achieve better killing of the bacteria. Omadacycline is a new tetracycline that may have a role in the treatment of A. baumannii, but no data are available evaluating its interaction with other commonly used drugs such as polymyxin B and sulbactam. Therefore, the purpose of this study was to investigate the antibacterial activity of omadacycline when combined with one or more other agents against carbapenem-resistant strains of A. baumannii. These findings may then be used to design confirmatory studies that could help decide what drugs work best together and what combination of agents should be used for patients.

Use of Novel Antibiograms to Determine the Need for Earlier Susceptibility Testing and Administration for New ß-Lactam/ß-Lactamase Inhibitors in the United States.

Antimicrobial resistance is a global public health threat, and gram-negative bacteria, such as Enterobacterales and Pseudomonas aeruginosa, are particularly problematic with difficult-to-treat resistance phenotypes. To reduce morbidity and mortality, a reduction in the time to effective antimicrobial therapy (TTET) is needed, especially among critically ill patients. The antibiogram is an effective clinical tool that can provide accurate antimicrobial susceptibility information and facilitate early antimicrobial optimization, decrease TTET, and improve outcomes such as mortality, hospital length of stay, and costs. Guidance is lacking on how to validate the susceptibility to new antibacterial agents. Commonly used traditional and combination antibiograms may not adequately assist clinicians in making treatment decisions. Challenges with the current susceptibility testing of new ß-lactam/ß-lactamase inhibitor combinations persist, impacting the appropriate antibacterial choice and patient outcomes. Novel antibiograms such as syndromic antibiograms that incorporate resistant gram-negative phenotypes and/or minimum inhibitory concentration distributions may assist in determining the need for earlier susceptibility testing or help define an earlier optimal use of the new ß-lactam/ß-lactamase inhibitors. The purpose of this review is to emphasize novel antibiogram approaches that are capable of improving the time to susceptibility testing and administration for new ß-lactam/ß-lactamase inhibitors so that they are earlier in a patient's treatment course.

Overcoming Stenotrophomonas maltophilia Resistance for a More Rational Therapeutic Approach.

Stenotrophomonas maltophilia is an underappreciated source of morbidity and mortality among gram-negative pathogens. Effective treatment options with acceptable toxicity profiles are limited. Phenotypic susceptibility testing via commercial automated test systems is problematic and no Food and Drug Administration breakpoints are approved for any of the first-line treatment options for S maltophilia. The lack of modern pharmacokinetic/pharmacodynamic data for many agents impedes dose optimization, and the lack of robust efficacy and safety data limits their clinical utility. Levofloxacin has demonstrated similar efficacy to trimethoprim-sulfamethoxazole, although rapid development of resistance is a concern. Minocycline demonstrates the highest rate of in vitro susceptibility, however, evidence to support its clinical use are scant. Novel agents such as cefiderocol have exhibited promising activity in preclinical investigations, though additional outcomes data are needed to determine its place in therapy for S maltophilia. Combination therapy is often employed despite the dearth of adequate supporting data.

Aztreonam in combination with imipenem-relebactam against clinical and isogenic strains of serine and metallo-ß-lactamase-producing enterobacterales.

OBJECTIVE: The objective of this study was to evaluate the in vitro activity of aztreonam plus imipenem-relebactam against clinical and isogenic strains of Escherichia coli and Klebsiella pneumoniae co-harboring NDM and >1 serine ß-lactamase. METHODS: Thirteen isolates were included: 4 clinical E. coli, 4 clinical K. pneumoniae, and 5 isogenic E. coli. Drugs were tested in time-kill analyses alone, in dual ß-lactam combinations, and in triple drug combinations against all strains. RESULTS: All isolates were resistant to imipenem and imipenem-relebactam, and 85% were aztreonam-resistant. Neither imipenem nor imipenem-relebactam was bactericidal alone while aztreonam was bactericidal against 54% of isolates. The combination of aztreonam+imipenem was bactericidal and synergistic against 7/13 and 10/13 isolates. The addition of relebactam to this combination resulted in synergy against all 11 aztreonam-resistant clinical isolates. CONCLUSION: Aztreonam plus imipenem-relebactam may be a viable treatment option for aztreonam-non-susceptible NDM and serine ß-lactamase-producing E. coli and K. pneumoniae.