Global trends in carbapenem- and difficult-to-treat-resistance among World Health Organization priority bacterial pathogens: ATLAS surveillance program 2018-2022.

OBJECTIVES: To report trends in carbapenem resistance and difficult-to-treat resistance (DTR) among clinical isolates of Gram-negative priority pathogens collected by the ATLAS global surveillance program from 2018 to 2022. METHODS: Reference broth microdilution testing was performed in a central laboratory for 79,214 Enterobacterales, 30,504 Pseudomonas aeruginosa, and 13,500 Acinetobacter baumannii-calcoaceticus complex isolates collected by a constant set of 157 medical centres in 49 countries in Asia Pacific (APAC), Europe (EUR), Latin America (LATAM), Middle East-Africa (MEA), and North America (NA) regions. MICs were interpreted by 2023 CLSI M100 breakpoints. ß-lactamase genes were identified for meropenem-nonsusceptible (MIC ≥2 mg/L) Enterobacterales isolates. RESULTS: Carbapenem-resistant Enterobacterales (CRE) detection increased (P < 0.05) in APAC, EUR, LATAM, and MEA regions and decreased in NA, while annual DTR percentages increased in all five regions. Carbapenem-resistant P. aeruginosa (CRPA; decreased in MEA region) and carbapenem-resistant A. baumannii-calcoaceticus complex (CRAB; decreased in MEA region and increased in EUR) remained relatively stable over time in all regions, although notably, annual percentages of CRAB and DTR A. baumannii-calcoaceticus complex isolates were consistently >25 percentage points lower in NA than in other regions. For all regions except NA, the majority of changes in CRE percentages could be attributed to hospital-acquired infections. Among meropenem-nonsusceptible Enterobacterales, KPC was the most frequent carbapenemase in NA and EUR each year. NDM was the most prevalent carbapenemase detected in 2022 in other global regions. CONCLUSION: CRE, CRPA, CRAB, and DTR rates vary among global regions over time highlighting the need for continuing surveillance to inform treatment strategies and antimicrobial stewardship.

Antimicrobial Activities of Aztreonam-Avibactam and Comparator Agents against Enterobacterales Analyzed by ICU and Non-ICU Wards, Infection Sources, and Geographic Regions: ATLAS Program 2016-2020.

Increasing antimicrobial resistance among multidrug-resistant (MDR), extended-spectrum ß-lactamase (ESBL)- and carbapenemase-producing Enterobacterales (CPE), in particular metallo-ß-lactamase (MBL)-positive strains, has led to limited treatment options in these isolates. This study evaluated the activity of aztreonam-avibactam (ATM-AVI) and comparator antimicrobials against Enterobacterales isolates and key resistance phenotypes stratified by wards, infection sources and geographic regions as part of the ATLAS program between 2016 and 2020. Minimum inhibitory concentrations (MICs) were determined per Clinical and Laboratory Standards Institute (CLSI) guidelines. The susceptibility of antimicrobials were interpreted using CLSI and European Committee on Antimicrobial Susceptibility Testing (EUCAST) breakpoints. A tentative pharmacokinetic/pharmacodynamic breakpoint of 8 µg/mL was considered for ATM-AVI activity. ATM-AVI inhibited ≥99.2% of Enterobacterales isolates across wards and ≥99.7% isolates across infection sources globally and in all regions at ≤8 µg/mL. For resistance phenotypes, ATM-AVI demonstrated sustained activity across wards and infection sources by inhibiting ≥98.5% and ≥99.1% of multidrug-resistant (MDR) isolates, ≥98.6% and ≥99.1% of ESBL-positive isolates, ≥96.8% and ≥90.9% of carbapenem-resistant (CR) isolates, and ≥96.8% and ≥97.4% of MBL-positive isolates, respectively, at ≤8 µg/mL globally and across regions. Overall, our study demonstrated that ATM-AVI represents an important therapeutic option for infections caused by Enterobacterales, including key resistance phenotypes across different wards and infection sources.

The Role of the Private Sector in Advancing Antimicrobial Stewardship: Recommendations from the Global Chief Medical Officers' Network.

Antimicrobial resistance (AMR) occurs when microorganisms develop the ability to defeat the drugs designed to kill them. If allowed to increase at the current rate, AMR could kill an estimated 10 million people per year and cost society approximately 100-200 trillion USD globally by 2050. The slow development of novel antimicrobials further exacerbates the problem. Most human antibiotic use occurs in homes and workplaces, where antibiotic-resistant infections may contribute to diminished performance and loss of work productivity. Employers in the private sector have the ability to reach large populations of employees and their families, raise awareness about AMR, and promote antimicrobial stewardship (AMS) among their workforce. The authors describe 4 steps a company can take to help advance AMS: (1) sign the AMR Pledge, (2) perform a gap analysis, (3) implement and/or modify standard practices, and (4) measure and report outcomes. Real-world examples are provided, including barriers faced, in order to successfully implement initiatives to promote better AMS. Behavioral methods to influence change in the workplace are also presented. Both large and small companies can make a difference to support responsible use of antibiotics and improve the health and well-being of their employees.

The Role of Pharmaceutical Companies in Antimicrobial Stewardship: A Case Study.

Rising levels of antimicrobial resistance pose serious dangers to patients, population health, food security, and economic stability worldwide. In response to this threat, the United Nations and the World Health Organization have called for multisectoral, multidisciplinary action, recognizing that human, animal, and environmental health are interdependent. Although the pharmaceutical industry clearly has a leading role in developing novel antimicrobials and vaccines, it is also active in many areas supporting antimicrobial stewardship. This article describes why pharmaceutical companies invest in antimicrobial stewardship, outlines why they are well suited to help address this issue, and provides examples of how the pharmaceutical industry can support the responsible use of antimicrobials. Merck & Co., Inc. (Kenilworth, NJ, USA), a large, globally operating pharmaceutical company that develops and markets both human and veterinary antimicrobials and vaccines is used as a case study for illustrating industry involvement in antimicrobial stewardship efforts.

Decreasing the Peril of Antimicrobial Resistance Through Enhanced Health Literacy in Outpatient Settings: An Underrecognized Approach to Advance Antimicrobial Stewardship.

Globally, antimicrobial resistance (AMR) is a serious problem causing 700,000 deaths annually. By 2050, AMR is expected to cause approximately 10 million deaths globally each year if allowed to increase at the present rate. Many individuals have limited knowledge regarding appropriate antibiotic use and AMR. Most antibiotic use occurs in the outpatient setting, with approximately 30% of antibiotics prescribed deemed unnecessary. Antimicrobial stewardship (AMS) is a means to reduce inappropriate antibiotic use and AMR. While existing AMS efforts generally focus on the inpatient setting, a significant gap is present in the outpatient setting. A common theme across various national action plans to reduce AMR is the need for education and awareness. The importance of communicating information in a manner easily comprehended by the patient in addition to productive clinician-patient dialogue cannot be overestimated. Enhancing the public's and patients' AMS health literacy is an underrecognized approach to help address AMR. We describe Four Core Elements of Enhancing AMS Health Literacy in the Outpatient Setting, utilizing the Centers for Disease Control and Prevention's framework: (1) leadership commitment, (2) intervention/action, (3) tracking/reporting, and (4) education/expertise. We call upon leaders in outpatient settings to embrace this approach to curb inappropriate antimicrobial use.

Lack of Benefit With Combination Therapy for Clostridium difficile Infection.

Limited data exist regarding combination therapy for Clostridium difficile infection (CDI). After adjusting for confounders in a cohort of patients with CDI and≥1 year old, combination therapy was not associated with significant differences in clinical outcomes, but it was associated with prolonged duration of therapy (1.22 days; 95% confidence interval, 1.03-1.44 days; P=.02). Infect Control Hosp Epidemiol 2017;38:602-605.

A retrospective study of outcomes of device-associated osteomyelitis treated with daptomycin.

BACKGROUND: Daptomycin appears well tolerated and effective for osteomyelitis treatment. However, limited data exist regarding daptomycin use for treatment of device-associated osteomyelitis (DAO). METHODS: We used a retrospective, observational database (Cubicin® Outcomes Registry and Experience [CORE® 2007-2009]) that assessed patients treated with daptomycin to evaluate the characteristics of patients with DAO, outcomes after daptomycin treatment, and safety of daptomycin in this setting. Information from 54 institutions for patients with prosthetic joint infection (PJI) and other hardware-associated osteomyelitis (OHAO) who received daptomycin from January 2007 to December 2008 with follow-up data in 2009 was collected using a standardized data collection form. RESULTS: Eighty-two patients receiving daptomycin were identified in CORE 2007-2009; 48 patients (59 %) had follow-up data. Sixty-seven percent of patients had received a previous antibiotic. Surgical intervention was similar between the 2 groups: PJI, 22 of 27 (82 %) and OHAO, 17 of 21 (81 %). However, device removal or replacement was more frequent in the PJI patients (17 of 27, 63 %) than in the OHAO patients (8 of 21, 38 %). Clinical success was reported in 22 of 27 (82 %; 95 % confidence interval [CI], 62-94 %) patients with PJI and 18 of 21 (86 %; 95 % CI, 64-97 %) patients with OHAO at follow-up (13-402 days). Adverse events occurred in 8 of 50 (16 %) patients in the safety population and did not differ by daptomycin dose. CONCLUSION: Daptomycin appeared effective and well tolerated in patients with DAO, including PJI or OHAO.

Guidance for the knowledge and skills required for antimicrobial stewardship leaders.

Antimicrobial stewardship programs are increasingly recognized as critical in optimizing the use of antimicrobials. Consequently, more physicians, pharmacists, and other healthcare providers are developing and implementing such programs in a variety of healthcare settings. The purpose of this guidance document is to outline the knowledge and skills that are needed to lead an antimicrobial stewardship program. It was developed by antimicrobial stewardship experts from organizations that are engaged in advancing the field of antimicrobial stewardship.

Outcomes and metrics for antimicrobial stewardship: survey of physicians and pharmacists.

We conducted a survey to compare antimicrobial stewardship outcomes considered to be most important with those used in practice as metrics. Respondent opinion of important outcomes compared with those collected as metrics were antimicrobial use (15% vs 73%), antimicrobial cost (10% vs 73%), appropriateness of antimicrobial use (56% vs 51%), infection-related mortality rate (34% vs 7%), and antibiotic-associated length of stay (22% vs 12%). Patient outcomes are important to many practitioners but are rarely used as metrics.

Antimicrobial stewardship: philosophy versus practice.

To promote the judicious use of antimicrobials and preserve their usefulness in the setting of growing resistance, a number of policy-making bodies and professional societies have advocated the development of antimicrobial stewardship programs. Although these programs have been implemented at many institutions in the United States, their impact has been difficult to measure. Current recommendations advocate the use of both outcome and process measures as metrics for antimicrobial stewardship. Although patient outcome metrics have the greatest impact on the quality of care, the literature shows that antimicrobial use and costs are the indicators measured most frequently by institutions to justify the effectiveness of antimicrobial stewardship programs. The measurement of more meaningful outcomes has been constrained by difficulties inherent to these measures, lack of funding and resources, and inadequate study designs. Antimicrobial stewardship can be made more credible by refocusing the antimicrobial review process to target specific disease states, reassessing the usefulness of current metrics, and integrating antimicrobial stewardship program initiatives into institutional quality and safety efforts.

Assessing appropriateness of antimicrobial therapy: in the eye of the interpreter.

To address the increase of drug-resistant bacteria and widespread inappropriate use of antimicrobials, many healthcare institutions have implemented antimicrobial stewardship programs to promote appropriate use of antimicrobials and optimize patient outcomes. However, a consensus definition of appropriate use is lacking. We conducted a multicenter observational study to compare 4 definitions of appropriateness--a study site-specific definition, use supported by susceptibility data, use supported by electronic drug information resources (Clinical Pharmacology/Micromedex), or study site principal investigator (PI) opinion-among patients receiving 1 or more of 13 identified antimicrobials. Data were collected for 262 patients. Overall, appropriateness with the 4 definitions ranged from 79% based on PI opinion to 94% based on susceptibility data. No single definition resulted in consistently high appropriate use for all target antimicrobials. For individual antimicrobials, the definitions with the highest rate of appropriate use were Clinical Pharmacology/Micromedex support (6 of 7 antimicrobials) and susceptibility data (5 of 7 antimicrobials). For specific indications, support from susceptibility data resulted in the highest rate of appropriate use (4 of 7 indications). Overall comparisons showed that appropriateness assessed by PI opinion differed significantly compared with other definitions when stratified by either target antimicrobial or indication. The significant variability in the rate of appropriate use highlights the difficulty in developing a standardized definition that can be used to benchmark judicious antimicrobial use.

Knowledge and attitudes of doctor of pharmacy students regarding the appropriate use of antimicrobials.

Pharmacists are key partners in antimicrobial stewardship efforts, yet their degree of education on and attitudes toward this topic during training are not well documented. An electronic survey measuring knowledge and attitudes regarding antimicrobial use and resistance was administered to graduating pharmacy students at 12 US schools of pharmacy. Of 1445 pharmacy students, 579 (40%) completed the survey. The vast majority (94%) believed that strong knowledge of antimicrobials was important for their pharmacy careers, and 89% desired more education on appropriate antimicrobial use. Most students (84%) considered their pharmacy education regarding antimicrobials useful or very useful, but there was significant variability on perceptions of preparation for most antimicrobial stewardship activities according to the students' school. The mean number of correct answers on a section of 11 knowledge questions was 5.8 (standard deviation 2.0; P value for score between schools <.001). On multivariable linear regression analysis, significant predictors of a higher knowledge score were pharmacy school attended, planned postgraduate training, completion of a clinical rotation in infectious diseases, perception of pharmacy school education as useful, use of resources to answer the knowledge questions, and use of Infectious Diseases Society of America guidelines and smartphone applications as frequent resources for learning about antimicrobials. Pharmacy students perceive antimicrobial stewardship to be an important healthcare issue and desire more education on the subject. Student perceptions of antimicrobial coursework and actual antimicrobial knowledge scores significantly varied by the school of pharmacy attended. Sharing of best practices among institutions may enhance the preparation of future pharmacists to contribute to effective antimicrobial stewardship.

Breaking down the barriers: challenges with development and implementation of an industry-sponsored antimicrobial stewardship data collection and analysis tool.

Partnership between clinicians and the pharmaceutical industry with a focus on antimicrobial stewardship research initiatives is a necessary step toward meeting the shared goals of combating inappropriate antimicrobial use, improving patient outcomes, and minimizing resistance development. Achieving these goals requires outcomes-focused data collection and monitoring tools for antimicrobial stewardship programs (ASP) that consider real-world data about how antimicrobials are used to treat patients. Here we highlight the experiences and challenges associated with the development and implementation of an industry-sponsored electronic antimicrobial stewardship data collection and analysis tool (AS-DCAT). The benefits and risks of the industry-sponsored AS-DCAT from the perspectives of the sponsoring company and participating sites are discussed. Barriers encountered as well as general considerations and recommendations for preventing or overcoming those barriers for future studies and tool development are provided.

Implementation of a clinical decision support system for antimicrobial stewardship.

Clinical decision support systems (CDSSs) for antimicrobial stewardship require considerable human resources and financial investments. This pre-/postimplementation study evaluated the effect of a CDSS on performance of prospective audit with intervention and feedback and demonstrated an increase in interventions and recommendation acceptance countered by a substantial number of nonactionable alerts.

Inappropriate use of urinary catheters: a prospective observational study.

BACKGROUND: Despite the well-recognized role of urinary catheters in nosocomial urinary tract infections, data on risk factors associated with inappropriate urinary catheter use are scarce. METHODS: A prospective review of electronic medical records of 436 patients admitted to an adult medical-surgical unit between October and December 2007 was performed to examine the appropriateness of urinary catheter use. RESULTS: The use of 157 urinary catheters in 144 patients was observed. A total of 557 urinary catheter-days were recorded in these patients, of which 175 (31.4%) were found to be inappropriate based on the study criteria. The total number of catheters used and the total duration of catheterization were risk factors for inappropriate urinary catheter use (P < .05). Inappropriate catheter use was not associated with such adverse events as mortality, readmission, intensive care unit admission, catheter complications, or urine culture rates, but was associated with a trend toward longer duration of hospitalization. CONCLUSIONS: Significant rates of inappropriate urinary catheter use and a trend toward longer duration of hospitalization with inappropriate catheter use were observed. These findings underscore the importance of establishing guidelines and effective policy implementation for the appropriate use of urinary catheters in hospitalized patients.

Is there a role for oral human immunoglobulin in the treatment for norovirus enteritis in immunocompromised patients?

No treatment for NVE is available. Immunocompromised patients with NVE treated with OHIG (12 cases) were retrospectively identified and matched 1:1 by age and gender with immunocompromised patients with NVE not treated with OHIG (12 controls). Chi-squared test, t-test, bivariate conditional linear regression analyses, and Kaplan-Meier curve were performed. A total of 58.3% patients were small bowel transplant (SBT) recipients. Although not statistically significant, cases compared with controls were more likely to have had induction therapy (p = 0.25, OR = 65.3), higher peak tacrolimus levels (p = 0.43, OR = 1.04), SBT (p = 0.30, OR = 65.3), prior NVE (p = 0.42, OR = 2.0), TPN support (p = 0.42 OR = 2.0), and decrease in immunosuppression (p = 0.14, OR = 5.0). Treatment with OHIG favored resolution of diarrhea (p = 0.078, OR = 65.3) and decreased stool output seven days after treatment compared with controls (mean difference 11.95 mL/kg/day, p = 0.09). OHIG did not impact total time to resolution of diarrhea (mean 12.08 vs. 11.91 days; p = 0.63), length of hospital stay (p = 0.31, OR = 1.05), or cost of hospitalization (p = 0.32, OR = 1.0). We show a potential role of OHIG treatment for NVE. Resolution of diarrhea and decreased stool output were observed at seven days; no benefit was found for length of hospital stay or hospital cost.

Validation and comparison of clinical prediction rules for invasive candidiasis in intensive care unit patients: a matched case-control study.

INTRODUCTION: Due to the increasing prevalence and severity of invasive candidiasis, investigators have developed clinical prediction rules to identify patients who may benefit from antifungal prophylaxis or early empiric therapy. The aims of this study were to validate and compare the Paphitou and Ostrosky-Zeichner clinical prediction rules in ICU patients in a 689-bed academic medical center. METHODS: We conducted a retrospective matched case-control study from May 2003 to June 2008 to evaluate the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of each rule. Cases included adults with ICU stays of at least four days and invasive candidiasis matched to three controls by age, gender and ICU admission date. The clinical prediction rules were applied to cases and controls via retrospective chart review to evaluate the success of the rules in predicting invasive candidiasis. Paphitou's rule included diabetes, total parenteral nutrition (TPN) and dialysis with or without antibiotics. Ostrosky-Zeichner's rule included antibiotics or central venous catheter plus at least two of the following: surgery, immunosuppression, TPN, dialysis, corticosteroids and pancreatitis. Conditional logistic regression was performed to evaluate the rules. Discriminative power was evaluated by area under the receiver operating characteristic curve (AUC ROC). RESULTS: A total of 352 patients were included (88 cases and 264 controls). The incidence of invasive candidiasis among adults with an ICU stay of at least four days was 2.3%. The prediction rules performed similarly, exhibiting low PPVs (0.041 to 0.054), high NPVs (0.983 to 0.990) and AUC ROCs (0.649 to 0.705). A new prediction rule (Nebraska Medical Center rule) was developed with PPVs, NPVs and AUC ROCs of 0.047, 0.994 and 0.770, respectively. CONCLUSIONS: Based on low PPVs and high NPVs, the rules are most useful for identifying patients who are not likely to develop invasive candidiasis, potentially preventing unnecessary antifungal use, optimizing patient ICU care and facilitating the design of forthcoming antifungal clinical trials.

Vancomycin susceptibility trends and prevalence of heterogeneous vancomycin-intermediate Staphylococcus aureus in clinical methicillin-resistant S. aureus isolates.

Due to the rise in methicillin-resistant Staphylococcus aureus (MRSA) infections and widespread use of vancomycin, MRSA isolates with reduced susceptibility to vancomycin are emerging (i.e., MIC creep). However, the prevalence of heterogeneous vancomycin-intermediate S. aureus (hVISA) is unknown due to the difficulty in detecting this phenotype. Recently, Etest glycopeptide resistance detection (GRD) strips have been developed to detect hVISA. This study assessed vancomycin susceptibility in MRSA isolates and determined the prevalence of hVISA by Etest GRD and population analysis profile-area under the curve ratio (PAP-AUC). The genetic backgrounds of 167 MRSA isolates collected from 2000 to 2008 were identified by pulsed-field gel electrophoresis. Vancomycin MICs were determined using Etest and two broth microdilution assays, MicroScan and Sensititre. Etest GRD was performed on all isolates, and those exhibiting a hVISA phenotype were further tested by PAP-AUC. The vancomycin MIC modes remained consistent at 1 µg/ml, as assessed by Sensititre and MicroScan. Etest reported a significant increase (mode MIC = 1.5 µg/ml) in the MIC between 2000 and 2008 (P < 0.01); however, this increase did not reflect a ≥ 2-fold change. In addition, the slight MIC increase did not increase linearly from 2000 to 2008, suggesting biological fluctuation, and is inconsistent with the concept of MIC creep. Etest GRD identified six hVISA isolates, two of which were confirmed to be hVISA by PAP-AUC. In conclusion, reduced vancomycin susceptibility was not detected in our hospital over a 9-year period using three different MIC methodologies, and the hVISA incidence was 1.2%, as determined by Etest GRD and PAP-AUC.

Is incidental recovery of yeast from enteric pathogen stool cultures obtained from hospitalized patients clinically significant?

A matched case-control study was conducted to investigate gastrointestinal colonization with yeast as a predictor of invasive candidiasis (IC) in patients who underwent an enteric pathogen test. No significant association was detected between gastrointestinal colonization and IC. However, gastrointestinal colonization with yeast was associated with increased antimicrobial exposure and median length of hospitalization.

Linezolid versus vancomycin or teicoplanin for nosocomial pneumonia: a systematic review and meta-analysis.

INTRODUCTION: Compared with glycopeptides, linezolid achieves higher lung epithelial lining fluid concentrations, which may correlate with improved efficacy in the treatment of nosocomial pneumonia. However, clinical superiority has not been demonstrated. OBJECTIVE: To test the hypothesis that linezolid may be superior to glycopeptides. METHODS: Prospective randomized trials that tested linezolid vs. vancomycin or teicoplanin for treatment of nosocomial pneumonia were included. Heterogeneity was analyzed by I(2) and Q statistics. Meta-analysis relative risks were based on fixed and random-effects models. Outcomes evaluated consisted of clinical cure, microbiological eradication, and side effects. RESULTS: Nine linezolid trials (vancomycin [7]; teicoplanin [2]) were included (n = 2329). The linezolid vs. glycopeptide analysis shows clinical cure relative risk of 1.01 (95% confidence interval, 0.93-1.10; p = .83; I(2) = 0%) and microbiological eradication relative risk of 1.10 (95% confidence interval, 0.98 -1.22; p = .10; I(2) = 0%). Methicillin-resistant Staphylococcus aureus subgroup analysis yielded a microbiological eradication relative risk of 1.10 (95% confidence interval, 0.87-1.38; p = .44; I(2) = 16%). If linezolid is compared with vancomycin only, then clinical cure relative risk is 1.00 (95% confidence interval, 0.90-1.12), microbiological eradication and methicillin-resistant Staphylococcus aureus relative risks are 1.07 (95% confidence interval, 0.90-1.26; p = .45) and 1.05 (95% confidence interval, 0.82-1.33; p = .71). The risks of thrombocytopenia (relative risk, 1.93; 95% confidence interval, 1.30-2.87; p = .001) and gastrointestinal events (relative risk, 2.02; 95% confidence interval, 1.10-3.70; p = .02) are higher with linezolid, but no differences are seen for renal dysfunction (relative risk, 0.89; 95% confidence interval, 0.56-1.43; p = .64) or all-cause mortality (relative risk, 0.95; 95% confidence interval, 0.76-1.18; p = .63). CONCLUSIONS: Our study does not demonstrate clinical superiority of linezolid vs. glycopeptides for the treatment of nosocomial pneumonia despite a statistical power of 95%. Linezolid shows a significant two-fold increase in the risk of thrombocytopenia and gastrointestinal events. Vancomycin and teicoplanin are not associated with more renal dysfunction than linezolid.