Participant Diversity in United States Randomized Controlled Trials of Antibacterials for Staphylococcus aureus Infections, 2000-2021.

BACKGROUND: Equitable representation of members from historically marginalized groups is important in clinical trials, which inform standards of care. The goal of this study was to characterize the demographics and proportional subgroup reporting and representation of participants enrolled in randomized controlled trials (RCTs) of antibacterials used to treat Staphylococcus aureus infections. METHODS: We examined randomized controlled registrational and strategy trials published from 2000-2021 to determine the sex, race, and ethnicity of participants. Participation to incidence ratios (PIRs) were calculated by dividing the percentage of study participants in each demographic group by the percentage of the disease population in each group. Underrepresentation was defined as a PIR <0.8. RESULTS: Of the 87 included studies, 82 (94.2%) reported participant sex; 69 (79.3%) reported participant race; and 20 (23.0%) included ethnicity data. Only 17 (19.5%) studies enrolled American Indian/Alaskan Native participants. Median PIRs indicated that Asian and Black participants were underrepresented in RCTs compared with the incidence of methicillin-resistant S. aureus (MRSA) infections in these subgroups. Underrepresentation of Black participants was associated with a larger study size, international sites, industry sponsorship, and Phase 2/3 trials compared with Phase 4 trials (P<0.05 for each). Black participants had over 4 times the odds of being underrepresented in Phase 2/3 trials compared with Phase 4 trials (OR 4.57; 95% CI 1.14-18.3). CONCLUSIONS: Standardized reporting methods for race and ethnicity and efforts to increase recruitment of marginalized groups would help ensure equity, rigor, and generalizability in RCTs of antibacterial agents and reduce health inequities.

Clinical Outcomes and Bacterial Characteristics of Carbapenem-resistant Acinetobacter baumannii Among Patients From Different Global Regions.

BACKGROUND: Carbapenem-resistant Acinetobacter baumannii (CRAb) is 1 of the most problematic antimicrobial-resistant bacteria. We sought to elucidate the international epidemiology and clinical impact of CRAb. METHODS: In a prospective observational cohort study, 842 hospitalized patients with a clinical CRAb culture were enrolled at 46 hospitals in five global regions between 2017 and 2019. The primary outcome was all-cause mortality at 30 days from the index culture. The strains underwent whole-genome analysis. RESULTS: Of 842 cases, 536 (64%) represented infection. By 30 days, 128 (24%) of the infected patients died, ranging from 1 (6%) of 18 in Australia-Singapore to 54 (25%) of 216 in the United States and 24 (49%) of 49 in South-Central America, whereas 42 (14%) of non-infected patients died. Bacteremia was associated with a higher risk of death compared with other types of infection (40 [42%] of 96 vs 88 [20%] of 440). In a multivariable logistic regression analysis, bloodstream infection and higher age-adjusted Charlson comorbidity index were independently associated with 30-day mortality. Clonal group 2 (CG2) strains predominated except in South-Central America, ranging from 216 (59%) of 369 in the United States to 282 (97%) of 291 in China. Acquired carbapenemase genes were carried by 769 (91%) of the 842 isolates. CG2 strains were significantly associated with higher levels of meropenem resistance, yet non-CG2 cases were over-represented among the deaths compared with CG2 cases. CONCLUSIONS: CRAb infection types and clinical outcomes differed significantly across regions. Although CG2 strains remained predominant, non-CG2 strains were associated with higher mortality. Clinical Trials Registration. NCT03646227.

In vitro activity of sulbactam-durlobactam against colistin-resistant and/or cefiderocol-non-susceptible, carbapenem-resistant Acinetobacter baumannii collected in U.S. hospitals.

The activity of a novel ß-lactamase inhibitor combination, sulbactam-durlobactam (SUL-DUR), was tested against 87 colistin-resistant and/or cefiderocol-non-susceptible carbapenem-resistant Acinetobacter baumannii clinical isolates collected from U.S. hospitals between 2017 and 2019. Among them, 89% and 97% were susceptible to SUL-DUR and imipenem plus SUL-DUR, with MIC50/MIC90 values of 2 µg/mL/8 µg/mL and 1 µg/mL/4 µg/mL, respectively. The presence of amino acid substitutions in penicillin-binding protein 3, including previously reported A515V or T526S, was associated with SUL-DUR non-susceptibility.

Current treatment options for pneumonia caused by carbapenem-resistant Acinetobacter baumannii.

PURPOSE OF REVIEW: The purpose of this review is to briefly summarize the challenges associated with the treatment of pneumonia caused by carbapenem-resistant Acinetobacter baumannii (CRAB), discuss its carbapenem-resistance, and review the literature supporting the current treatment paradigm and therapeutic options. RECENT FINDINGS: In a multicenter, randomized, and controlled trial the novel ß-lactam-ß-lactamase inhibitor sulbactam-durlobactam was compared to colistin, both in addition to imipenem-cilastatin. The drug met the prespecified criteria for noninferiority for 28-day all-cause mortality while demonstrating higher clinical cure rates in the treatment of CRAB pneumonia. In an international, randomized, double-blind, placebo controlled trial colistin monotherapy was compared to colistin combined with meropenem. In this trial, combination therapy was not superior to monotherapy in the treatment of drug-resistant gram-negative organisms including CRAB pneumonia. SUMMARY: CRAB pneumonia is a preeminent public health threat without an agreed upon first line treatment strategy. Historically, there have been drawbacks to available treatment modalities without a clear consensus on the first-line treatment regimen. CRAB pneumonia is a top priority for the continued development of antimicrobials, adjuvant therapies and refinement of current treatment strategies.

Clinical characteristics and genome epidemiology of Stenotrophomonas maltophilia in Japan.

BACKGROUND: Stenotrophomonas maltophilia is a carbapenem-resistant Gram-negative pathogen increasingly responsible for difficult-to-treat nosocomial infections. OBJECTIVES: To describe the contemporary clinical characteristics and genome epidemiology of patients colonized or infected by S. maltophilia in a multicentre, prospective cohort. METHODS: All patients with a clinical culture growing S. maltophilia were enrolled at six tertiary hospitals across Japan between April 2019 and March 2022. The clinical characteristics, outcomes, antimicrobial susceptibility and genomic epidemiology of cases with S. maltophilia were investigated. RESULTS: In total, 78 patients were included representing 34 infection and 44 colonization cases. The median age was 72.5 years (IQR, 61-78), and males accounted for 53 cases (68%). The most common comorbidity was localized solid malignancy (39%). Nearly half of the patients (44%) were immunosuppressed, with antineoplastic chemotherapy accounting for 31%. The respiratory tract was the most common site of colonization (86%), whereas bacteraemia accounted for most infection cases (56%). The 30 day all-cause mortality rate was 21%, which was significantly higher in infection cases than colonization cases (35% versus 9%; adjusted HR, 3.81; 95% CI, 1.22-11.96). Susceptibility rates to ceftazidime, levofloxacin, minocycline and sulfamethoxazole/trimethoprim were 14%, 65%, 87% and 100%, respectively. The percentage of infection ranged from 13% in the unclassified group to 86% in genomic group 6A. The percentage of non-susceptibility to ceftazidime ranged from 33% in genomic group C to 100% in genomic groups 6 and 7 and genomic group geniculate. CONCLUSIONS: In this contemporary multicentre cohort, S. maltophilia primarily colonized the respiratory tract, whereas patients with bacteraemia had the highest the mortality from this pathogen. Sulfamethoxazole/trimethoprim remained consistently active, but susceptibility to levofloxacin was relatively low. The proportions of cases representing infection and susceptibility to ceftazidime differed significantly based on genomic groups.

COVID-19 hospitalization risk after outpatient nirmatrelvir/ritonavir use, January to August 2022, North Carolina.

BACKGROUND: In the USA, nirmatrelvir/ritonavir is authorized for the treatment of mild-to-moderate COVID-19 in patients at least 12 years of age, at high risk for progression to severe COVID-19. OBJECTIVES: To estimate the impact of outpatient nirmatrelvir/ritonavir on COVID-19 hospitalization risk in a US healthcare system. METHODS: We conducted a cohort study using electronic health records among outpatients with a positive SARS-CoV-2 PCR test between January and August 2022. We evaluated the association of nirmatrelvir/ritonavir therapy with time to hospitalization by estimating adjusted HRs and assessed the impact of nirmatrelvir/ritonavir on predicted COVID-19 hospitalizations using machine-learning methods. RESULTS: Among 44 671 patients, 4948 (11%) received nirmatrelvir/ritonavir, and 201 (0.4%) were hospitalized within 28 days of COVID-19 diagnosis. Nirmatrelvir/ritonavir recipients were more likely to be older, white, vaccinated, have comorbidities and reside in areas with higher average socioeconomic status. The 28 day cumulative incidence of hospitalization was 0.06% (95% CI: 0.02%-0.17%) among nirmatrelvir/ritonavir recipients and 0.52% (95% CI: 0.46%-0.60%) among non-recipients. For nirmatrelvir/ritonavir versus no therapy, the age-adjusted HR was 0.08 (95% CI: 0.03-0.26); the fully adjusted HR was 0.16 (95% CI: 0.05-0.50). In the machine-learning model, the primary features reducing predicted hospitalization risk were nirmatrelvir/ritonavir, younger age, vaccination, female gender and residence in a higher socioeconomic status area. CONCLUSIONS: COVID-19 hospitalization risk was reduced by 84% among nirmatrelvir/ritonavir recipients in a large, diverse healthcare system during the Omicron wave. These results suggest that nirmatrelvir/ritonavir remained highly effective in a setting substantially different than the original clinical trials.

Clinical outcomes in patients infected with ertapenem-only-resistant Enterobacterales versus multi-carbapenem-resistant Enterobacterales.

BACKGROUND: Use of anti-carbapenem-resistant Enterobacterales (anti-CRE) agents such as ceftazidime/avibactam has been associated with improved clinical outcome in cohorts that primarily include patients infected with CRE that are resistant to meropenem (MCRE). OBJECTIVES: To clarify whether patients with CRE resistant to ertapenem but susceptible to meropenem (ertapenem-only-resistant Enterobacterales; EORE) benefit from therapy with anti-CRE agents. METHODS: Patients treated for CRE infection in hospitals in the USA between 2016 and 2019 and enrolled in the CRACKLE-2 study were included. The primary outcome was the desirability of outcome ranking (DOOR) assessed at 30 days after index cultures. RESULTS: The EORE group included 213 patients and the MCRE group included 643. The demographics were similar between the groups except for the patients' race and origin before admission. The MCRE group received anti-CRE agents for definitive therapy significantly more frequently compared with the EORE group (30% versus 5% for ceftazidime/avibactam). We did not observe a significant difference between the groups in the adjusted DOOR probability of a more desirable outcome for a randomly selected patient in the EORE group compared with the MCRE group (52.5%; 95% CI, 48.3%-56.7%). The MCRE group had a similar proportion of patients who died at 30 days (26% versus 21%) and who were discharged to home (29% versus 40%), compared with the EORE group. CONCLUSIONS: Patients with clinical EORE infection rarely received anti-CRE agents, but attained similar outcomes compared with patients with MCRE infection. The findings support current IDSA treatment guidance for meropenem- or imipenem-based therapy for treatment of EORE infections.

Infections Following Kidney Transplantation After Exposure to Immunosuppression for Treatment of Glomerulonephritis.

RATIONALE & OBJECTIVE: Kidney transplant patients with glomerulonephritis (GN) as their native disease commonly have received pretransplant immunosuppression (PTI). This may contribute to the immunosuppression burden potentially increasing the risk for infections after transplantation. STUDY DESIGN: Single-center, retrospective cohort study. SETTING & PARTICIPANTS: Recipients of a kidney transplant from January 2005 until May 2020 at a tertiary care university teaching hospital. EXPOSURE: Patients with GN as their native kidney disease who received PTI for treatment of GN (n=184) were compared with nondiabetic recipients of kidney transplants who did not receive PTI (n = 579). OUTCOME: First occurrence after transplantation of an infection outcome, either viral (BK or cytomegalovirus [CMV] infection) or bacterial. ANALYTICAL APPROACH: Cox regression analysis adjusted for age at transplant, sex, race, donor type, year of transplant surgery, dialysis vintage, receipt of T-cell depleting induction, and CMV transplant status. RESULTS: Over a median follow-up period of 5.7 years, patients with GN PTI were not at an increased risk for developing any first viral infection compared with controls (adjusted HR [AHR] 0.69 [95% CI, 0.52-0.91]) nor at increased risk for specific viral infections: BK infection 19.6% vs 26.3% (AHR 0.72 [95% CI, 0.50-1.05]) or CMV infection, 24.5% vs 29.0% (AHR, 0.76 [95% CI, 0.54-1.07]), respectively. There was also no increased risk of developing a first bacterial infection: 54.5% vs 57.5% (AHR, 0.90 [95% CI, 0.71-1.13]). These findings of no increased risk for infection were independent of the type of PTI used (cyclophosphamide, rituximab, mycophenolate mofetil, or calcineurin inhibitor) or the type of T-cell depleting induction therapy (alemtuzumab or antithymocyte globulin) administered. LIMITATIONS: Single-center study, no data on methylprednisone use for PTI, unmeasured confounding. CONCLUSIONS: Use of PTI for the treatment of GN was not associated with an increased risk of viral (BK or CMV) or bacterial infection after transplantation. Additional surveillance for infection after transplantation for patients who received PTI may not be necessary. PLAIN-LANGUAGE SUMMARY: Many kidney transplant patients have glomerular disease as the cause of kidney failure. These patients may be exposed to immunosuppression before transplantation, which could increase the risk for infections after receipt of a transplanted kidney. We identified kidney transplant recipients at a university teaching hospital who received immunosuppression before transplant for the treatment of glomerular kidney disease. We examined their risk for infection after transplantation by comparing it with the risk among transplant patients who were not exposed to immunosuppression before transplant. We observed no increased risk for infection after exposure to prior immunosuppression. Therefore, patients exposed to significant amounts of immunosuppression before transplantation may not require special surveillance or medication adjustment for fear of infection after their receipt of a kidney transplant.

Infectious Diseases Society of America 2023 Guidance on the Treatment of Antimicrobial Resistant Gram-Negative Infections.

BACKGROUND: The Infectious Diseases Society of America (IDSA) is committed to providing up-to-date guidance on the treatment of antimicrobial-resistant infections. This guidance document focuses on infections caused by extended-spectrum ß-lactamase producing Enterobacterales (ESBL-E), AmpC ß-lactamase-producing Enterobacterales (AmpC-E), carbapenem-resistant Enterobacterales (CRE), Pseudomonas aeruginosa with difficult-to-treat resistance (DTR-P. aeruginosa), carbapenem-resistant Acinetobacter baumannii (CRAB), and Stenotrophomonas maltophilia. This updated document replaces previous versions of the guidance document. METHODS: A panel of six infectious diseases specialists with expertise in managing antimicrobial-resistant infections formulated questions about the treatment of infections caused by ESBL-E, AmpC-E, CRE, DTR-P. aeruginosa, CRAB, and S. maltophilia. Because of differences in the epidemiology of resistance and availability of specific anti-infectives internationally, this document focuses on the treatment of infections in the United States. RESULTS: Preferred and alternative suggested treatment approaches are provided with accompanying rationales, assuming the causative organism has been identified and antibiotic susceptibility results are known. Approaches to empiric treatment, transitioning to oral therapy, duration of therapy, and other management considerations are also discussed briefly. Suggested approaches apply for both adult and pediatric populations, although suggested antibiotic dosages are provided only for adults. CONCLUSIONS: The field of antimicrobial resistance is highly dynamic. Consultation with an infectious diseases specialist is recommended for the treatment of antimicrobial resistant infections. This document is current as of December 31, 2022 and will be updated periodically. The most current version of this document, including date of publication, is available at www.idsociety.org/practice-guideline/amr-guidance/.

Transmission of Carbapenem-Resistant Klebsiella pneumoniae in US Hospitals.

BACKGROUND: Carbapenem-resistant Klebsiella pneumoniae (CRKp) is the most prevalent carbapenem-resistant Enterobacterales in the United States. We evaluated CRKp clustering in patients in US hospitals. METHODS: From April 2016 to August 2017, 350 patients with clonal group 258 CRKp were enrolled in the Consortium on Resistance Against Carbapenems in Klebsiella and other Enterobacteriaceae, a prospective, multicenter, cohort study. A maximum likelihood tree was constructed using RAxML. Static clusters shared ≤21 single-nucleotide polymorphisms (SNP) and a most recent common ancestor. Dynamic clusters incorporated SNP distance, culture timing, and rates of SNP accumulation and transmission using the R program TransCluster. RESULTS: Most patients were admitted from home (n = 150, 43%) or long-term care facilities (n = 115, 33%). Urine (n = 149, 43%) was the most common isolation site. Overall, 55 static and 47 dynamics clusters were identified involving 210 of 350 (60%) and 194 of 350 (55%) patients, respectively. Approximately half of static clusters were identical to dynamic clusters. Static clusters consisted of 33 (60%) intrasystem and 22 (40%) intersystem clusters. Dynamic clusters consisted of 32 (68%) intrasystem and 15 (32%) intersystem clusters and had fewer SNP differences than static clusters (8 vs 9; P = .045; 95% confidence interval [CI]: -4 to 0). Dynamic intersystem clusters contained more patients than dynamic intrasystem clusters (median [interquartile range], 4 [2, 7] vs 2 [2, 2]; P = .007; 95% CI: -3 to 0). CONCLUSIONS: Widespread intrasystem and intersystem transmission of CRKp was identified in hospitalized US patients. Use of different methods for assessing genetic similarity resulted in only minor differences in interpretation.

International Epidemiology of Carbapenemase-Producing Escherichia coli.

BACKGROUND: Carbapenemase-producing (CP) Escherichia coli (CP-Ec) are a global public health threat. We aimed to describe the clinical and molecular epidemiology and outcomes of patients from several countries with CP-Ec isolates obtained from a prospective cohort. METHODS: Patients with CP-Ec were enrolled from 26 hospitals in 6 countries. Clinical data were collected, and isolates underwent whole-genome sequencing. Clinical and molecular features and outcomes associated with isolates with or without metallo-ß-lactamases (MBLs) were compared. The primary outcome was desirability of outcome ranking (DOOR) at 30 days after the index culture. RESULTS: Of the 114 CP-Ec isolates in Consortium on resistance against carbapenems in Klebsiella and other Enterobacterales-2 (CRACKLE-2), 49 harbored an MBL, most commonly blaNDM-5 (38/49, 78%). Strong regional variations were noted with MBL-Ec predominantly found among patients in China (23/49). Clinically, MBL-Ec were more often from urine sources (49% vs 29%), less often met criteria for infection (39% vs 58%, P = .04), and had lower acuity of illness when compared with non-MBL-Ec. Among patients with infection, the probability of a better DOOR outcome for a randomly selected patient with MBL-Ec as compared with non-MBL-Ec was 62% (95% CI: 48.2-74.3%). Among infected patients, non-MBL-Ec had increased 30-day (26% vs 0%; P = .02) and 90-day (39% vs 0%; P = .001) mortality compared with MBL-Ec. CONCLUSIONS: Emergence of CP-Ec was observed with important geographic variations. Bacterial characteristics, clinical presentations, and outcomes differed between MBL-Ec and non-MBL-Ec. Mortality was higher among non-MBL isolates, which were more frequently isolated from blood, but these findings may be confounded by regional variations.

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.

Phage Therapy of Mycobacterium Infections: Compassionate Use of Phages in 20 Patients With Drug-Resistant Mycobacterial Disease.

BACKGROUND: Nontuberculous Mycobacterium infections, particularly Mycobacterium abscessus, are increasingly common among patients with cystic fibrosis and chronic bronchiectatic lung diseases. Treatment is challenging due to intrinsic antibiotic resistance. Bacteriophage therapy represents a potentially novel approach. Relatively few active lytic phages are available and there is great variation in phage susceptibilities among M. abscessus isolates, requiring personalized phage identification. METHODS: Mycobacterium isolates from 200 culture-positive patients with symptomatic disease were screened for phage susceptibilities. One or more lytic phages were identified for 55 isolates. Phages were administered intravenously, by aerosolization, or both to 20 patients on a compassionate use basis and patients were monitored for adverse reactions, clinical and microbiologic responses, the emergence of phage resistance, and phage neutralization in serum, sputum, or bronchoalveolar lavage fluid. RESULTS: No adverse reactions attributed to therapy were seen in any patient regardless of the pathogen, phages administered, or the route of delivery. Favorable clinical or microbiological responses were observed in 11 patients. Neutralizing antibodies were identified in serum after initiation of phage delivery intravenously in 8 patients, potentially contributing to lack of treatment response in 4 cases, but were not consistently associated with unfavorable responses in others. Eleven patients were treated with only a single phage, and no phage resistance was observed in any of these. CONCLUSIONS: Phage treatment of Mycobacterium infections is challenging due to the limited repertoire of therapeutically useful phages, but favorable clinical outcomes in patients lacking any other treatment options support continued development of adjunctive phage therapy for some mycobacterial infections.

Treatment approaches for severe Stenotrophomonas maltophilia infections.

PURPOSE OF REVIEW: Stenotrophomonas maltophilia is an emerged opportunistic pathogen. Intrinsic multidrug resistance makes treating infections caused by S. maltophilia a great clinical challenge. Herein, we provide an update on the most recent literature on treatment options for severe S. maltophilia infections. RECENT FINDINGS: Trimethoprim-sulfamethoxazole (SXT) is recognized as the first-line therapy for S. maltophilia infections. However, its clinical use is based on good in vitro activity and favorable clinical outcomes, rather than on solid minimum inhibitory concentration (MIC) correlations with pharmacokinetic/pharmacodynamics (PK/PD) and/or clinical outcomes. The same is true for other treatment options like levofloxacin (LVX) and minocycline (MIN). Recent PK/PD studies question the current clinical breakpoints for SXT, LVX, and MIN. Based on this, the latest guidance issued by the Infectious Diseases Society of America (IDSA) recommends using these agents only as part of a combination therapy. Alternatively, novel therapeutic options such as cefiderocol (FDC) and ceftazidime-avibactam plus aztreonam (CZA-ATM) are suggested, based on limited but promising clinical data. SUMMARY: PK/PD data and controlled clinical studies are needed to optimize current treatment options. Presently, combination therapy of SXT, LVX, MIN, or FDC, or monotherapy with CZA-ATM are recommended therapeutic options for severe-to-moderate S. maltophilia infections.

Society of Critical Care Medicine and the Infectious Diseases Society of America Guidelines for Evaluating New Fever in Adult Patients in the ICU.

RATIONALE: Fever is frequently an early indicator of infection and often requires rigorous diagnostic evaluation. OBJECTIVES: This is an update of the 2008 Infectious Diseases Society of America and Society (IDSA) and Society of Critical Care Medicine (SCCM) guideline for the evaluation of new-onset fever in adult ICU patients without severe immunocompromise, now using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology. PANEL DESIGN: The SCCM and IDSA convened a taskforce to update the 2008 version of the guideline for the evaluation of new fever in critically ill adult patients, which included expert clinicians as well as methodologists from the Guidelines in Intensive Care, Development and Evaluation Group. The guidelines committee consisted of 12 experts in critical care, infectious diseases, clinical microbiology, organ transplantation, public health, clinical research, and health policy and administration. All task force members followed all conflict-of-interest procedures as documented in the American College of Critical Care Medicine/SCCM Standard Operating Procedures Manual and the IDSA. There was no industry input or funding to produce this guideline. METHODS: We conducted a systematic review for each population, intervention, comparison, and outcomes question to identify the best available evidence, statistically summarized the evidence, and then assessed the quality of evidence using the GRADE approach. We used the evidence-to-decision framework to formulate recommendations as strong or weak or as best-practice statements. RESULTS: The panel issued 12 recommendations and 9 best practice statements. The panel recommended using central temperature monitoring methods, including thermistors for pulmonary artery catheters, bladder catheters, or esophageal balloon thermistors when these devices are in place or accurate temperature measurements are critical for diagnosis and management. For patients without these devices in place, oral or rectal temperatures over other temperature measurement methods that are less reliable such as axillary or tympanic membrane temperatures, noninvasive temporal artery thermometers, or chemical dot thermometers were recommended. Imaging studies including ultrasonography were recommended in addition to microbiological evaluation using rapid diagnostic testing strategies. Biomarkers were recommended to assist in guiding the discontinuation of antimicrobial therapy. All recommendations issued were weak based on the quality of data. CONCLUSIONS: The guidelines panel was able to formulate several recommendations for the evaluation of new fever in a critically ill adult patient, acknowledging that most recommendations were based on weak evidence. This highlights the need for the rapid advancement of research in all aspects of this issue-including better noninvasive methods to measure core body temperature, the use of diagnostic imaging, advances in microbiology including molecular testing, and the use of biomarkers.

Duration of antibiotic treatment for acute graft pyelonephritis: What's the standard of care?

BACKGROUND: Limited evidence is available to inform the duration of antibiotic treatment in kidney transplant recipients with bacterial acute graft pyelonephritis. Guidelines from the Infectious Diseases Community of Practice of the American Society of Transplantation suggest a 14-21 day duration. METHODS: A four-question survey was constructed to determine the current standard of practice for the duration of treatment for acute graft pyelonephritis. The survey was distributed among members of the Infectious Diseases and the Kidney Pancreas Communities of Practice of the American Society of Transplantation. RESULTS: Among 144 survey respondents, 87 (60%) were infectious disease physicians, and 36 (25%) were transplant nephrologists. Although most (55%) respondents preferred a 14-day duration, a spread between 7 and 28 days was observed. Goals of treatment and drivers for longer duration differed between infectious disease physicians and transplant nephrologists. CONCLUSIONS: Although most respondents prefer a 14-day duration of treatment for acute graft pyelonephritis, a wide range of responses was seen between 7 and 28 days. More evidence is needed to inform optimal treatment duration in this common infectious complication after transplantation.

Pay-it-forward gonorrhea and chlamydia testing among men who have sex with men and male STD patients in China: the PIONEER pragmatic, cluster randomized controlled trial protocol.

BACKGROUND: Gonorrhea and chlamydia are the most common sexually transmitted diseases (STDs) among men who have sex with men (MSM) in China. Previous studies have shown pay-it-forward (PIF) interventions to be associated with a substantial increase in gonorrhea and chlamydia test uptake compared to standard-of-care. We propose a 'pay-it-forward' gonorrhea and chlamydia testing randomized controlled trial (PIONEER). The trial would evaluate the effectiveness of two pay-it-forward strategies in promoting testing uptake compared to the standard of care (in which men pay for their tests out-of-pocket) among MSM and male STD patients in China. METHODS: PIONEER will be a three-armed, pragmatic cluster randomized controlled trial (RCT), conducted across 12 clinics (six MSM-led and six public STD clinics) to compare the effectiveness of three implementation strategies. Each facility will be randomized to a standard pay-it-forward intervention of gonorrhea/ chlamydia testing with minimal encouragement for testing, a community-engaged pay-it-forward arm, or a control arm where men pay for their tests out-of-pockets. The primary outcome will be dual gonorrhea/chlamydia test uptake. Secondary outcomes will include syphilis testing, amount donated in pay-it-forward, number of positive gonorrhea and chlamydia tests, and measures of antimicrobial resistance. A sequential transformative mixed methods design will be used to evaluate the implementation process in type 2 effectiveness-implementation hybrid design. Data sources will include survey on acceptability, and feelings and attitudes towards the interventions among participants; testing and treatment uptake data from clinic records, WeChat records, and qualitative data to gain insights into men's perceptions and attitudes towards the pay-it-forward, mechanisms driving uptake, and donating behaviors. Implementers and organizers will be interviewed about fidelity and adherence to protocol, sustainability of pay-it-forward intervention, and barriers and facilitators of implementing the intervention. DISCUSSION: PIONEER will substantially increase gonorrhea/chlamydia testing among MSM in China, providing an innovative and new financial mechanism to sustain STD screening among sexual minorities in low- and middle-income countries. This study will answer compelling scientific questions about how best to implement pay-it-forward and the individual and organizational characteristics that moderate it. TRIAL REGISTRATION: The study with identification number NCT05723263 has been registered on clinicaltrials.gov/.

Infectious Diseases Society of America 2022 Guidance on the Treatment of Extended-Spectrum ß-lactamase Producing Enterobacterales (ESBL-E), Carbapenem-Resistant Enterobacterales (CRE), and Pseudomonas aeruginosa with Difficult-to-Treat Resistance (DTR-P. aeruginosa).

BACKGROUND: The Infectious Diseases Society of America (IDSA) is committed to providing up-to-date guidance on the treatment of antimicrobial-resistant infections. The initial guidance document on infections caused by extended-spectrum ß-lactamase producing Enterobacterales (ESBL-E), carbapenem-resistant Enterobacterales (CRE), and Pseudomonas aeruginosa with difficult-to-treat resistance (DTR-P. aeruginosa) was published on 17 September 2020. Over the past year, there have been a number of important publications furthering our understanding of the management of ESBL-E, CRE, and DTR-P. aeruginosa infections, prompting a rereview of the literature and this updated guidance document. METHODS: A panel of 6 infectious diseases specialists with expertise in managing antimicrobial-resistant infections reviewed, updated, and expanded previously developed questions and recommendations about the treatment of ESBL-E, CRE, and DTR-P. aeruginosa infections. Because of differences in the epidemiology of resistance and availability of specific anti-infectives internationally, this document focuses on the treatment of infections in the United States. RESULTS: Preferred and alternative treatment recommendations are provided with accompanying rationales, assuming the causative organism has been identified and antibiotic susceptibility results are known. Approaches to empiric treatment, duration of therapy, and other management considerations are also discussed briefly. Recommendations apply for both adult and pediatric populations. CONCLUSIONS: The field of antimicrobial resistance is highly dynamic. Consultation with an infectious diseases specialist is recommended for the treatment of antimicrobial-resistant infections. This document is current as of 24 October 2021. The most current versions of IDSA documents, including dates of publication, are available at www.idsociety.org/practice-guideline/amr-guidance/.

Infectious Diseases Society of America Guidance on the Treatment of AmpC ß-Lactamase-Producing Enterobacterales, Carbapenem-Resistant Acinetobacter baumannii, and Stenotrophomonas maltophilia Infections.

The Infectious Diseases Society of America (IDSA) is committed to providing up-to-date guidance on the treatment of antimicrobial-resistant infections. A previous guidance document focused on infections caused by extended-spectrum ß-lactamase-producing Enterobacterales (ESBL-E), carbapenem-resistant Enterobacterales (CRE), and Pseudomonas aeruginosa with difficult-to-treat resistance (DTR-P. aeruginosa). Here, guidance is provided for treating AmpC ß-lactamase-producing Enterobacterales (AmpC-E), carbapenem-resistant Acinetobacter baumannii (CRAB), and Stenotrophomonas maltophilia infections. A panel of 6 infectious diseases specialists with expertise in managing antimicrobial-resistant infections formulated questions about the treatment of AmpC-E, CRAB, and S. maltophilia infections. Answers are presented as suggested approaches and corresponding rationales. In contrast to guidance in the previous document, published data on the optimal treatment of AmpC-E, CRAB, and S. maltophilia infections are limited. As such, guidance in this document is provided as "suggested approaches" based on clinical experience, expert opinion, and a review of the available literature. Because of differences in the epidemiology of resistance and availability of specific anti-infectives internationally, this document focuses on the treatment of infections in the United States. Preferred and alternative treatment suggestions are provided, assuming the causative organism has been identified and antibiotic susceptibility results are known. Approaches to empiric treatment, duration of therapy, and other management considerations are also discussed briefly. Suggestions apply for both adult and pediatric populations. The field of antimicrobial resistance is highly dynamic. Consultation with an infectious diseases specialist is recommended for the treatment of antimicrobial-resistant infections. This document is current as of 17 September 2021 and will be updated annually. The most current version of this document, including date of publication, is available at www.idsociety.org/practice-guideline/amr-guidance-2.0/.

Resistance in Enterobacterales Is Higher Among People Living With Human Immunodeficiency Virus.

BACKGROUND: Multidrug-resistant Enterobacterales (MDR-E) are important pathogens. People living with human immunodeficiency virus (HIV; PLWH) may be at greater risk for MDR-E infection given relatively high antibiotic exposure and burden of comorbidities. METHODS: We analyzed data from 36 521 patients in a healthcare system in North Carolina who had a clinical culture with growth of an Enterobacterales species from 2000 to 2018; 440 were PLWH. We used generalized linear models to estimate prevalence ratios and differences, contrasting PLWH and people not living with HIV (PNLWH) for resistance to individual antibiotic classes, as well as MDR-E. We assessed trends in prevalence over time by calculating the 5-year moving average and fitting restricted cubic spline models. RESULTS: The overall prevalence of MDR-E was higher among PLWH (21.5%; 95% confidence interval [CI], 18.2%-25.1%) vs PNLWH (16.5%; 95% CI, 16.2%-16.9%), with an adjusted prevalence ratio of 1.38 (95% CI, 1.14-1.65). PLWH had higher rates of antimicrobial resistance than PNLWH for all antibiotic classes analyzed, including penicillins, penicillin/beta lactamase inhibitor combinations, and sulfonamides. MDR-E prevalence was 3 to 10 percentage points higher among PLWH than PNLWH throughout the study period based on the 5-year moving average. CONCLUSIONS: In a large clinical study population in the southeastern United States from 2000 to 2018, the prevalence of antibacterial resistance among Enterobacterales was consistently higher among PLWH than PNLWH. These data highlight the importance of identifying and mitigating the factors that contribute to antimicrobial resistance in PLWH, given the potential clinical consequences of these resistant pathogens.