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The utility of obtaining screening urine cultures for febrile neutropenia (FN) during hematopoietic stem cell transplant (HCT) is unknown. In 667 adult HCT patients with FN, only 40 (6%) were found with bacteriuria. Antibiotics were modified in 3 patients (0.4%) based on urine cultures and none developed urinary-associated infectious complications.

The global burden of infection from MDR organisms (MDROs) disproportionately affects children residing in low- and middle-income countries and those with increased healthcare exposure. These populations have high rates of malnutrition making them increasingly vulnerable to infection with intestinal-derived pathogens. Malnourished children experience increased incidence of intestinal carriage and invasive infection with intestinal-derived MDROs including ESBL- and carbapenemase-producing Enterobacterales. However, the relationship between malnutrition and MDRO infection remains to be clearly defined. Impairment in intestinal barrier function and innate and adaptive immunity in malnutrition increases the risk for infection with intestinal-derived pathogens, and there is an increasing appreciation of the role of the intestinal microbiota in this process. Current evidence from human studies and animal models suggests that diet and the intestinal microbiota influence each other to determine nutritional status, with important implications for infectious outcomes. These insights are crucial to developing microbiota-targeted strategies aimed at reversing the growing burden of MDRO infections in malnourished populations worldwide.

Summary Background Carbapenem-resistant Klebsiella pneumoniae (CRKP) is a global threat. We therefore analysed the bacterial characteristics of CRKP infections and the clinical outcomes of patients with CRKP infections across different countries. Methods In this prospective, multicentre, cohort study (CRACKLE-2), hospitalised patients with cultures positive for CRKP were recruited from 71 hospitals in Argentina, Australia, Chile, China, Colombia, Lebanon, Singapore, and the USA. The first culture positive for CRKP was included for each unique patient. Clinical data on post-hospitalisation death and readmission were collected from health records, and whole genome sequencing was done on all isolates. The primary outcome was a desirability of outcome ranking at 30 days after the index culture, and, along with bacterial characteristics and 30-day all-cause mortality (a key secondary outcome), was compared between patients from China, South America, and the USA. The desirability of outcome ranking was adjusted for location before admission, Charlson comorbidity index, age at culture, Pitt bacteremia score, and anatomical culture source through inverse probability weighting; mortality was adjusted for the same confounders, plus region where relevant, through multivariable logistic regression. This study is registered at ClinicalTrials.gov , NCT03646227 , and is complete. Findings Between June 13, 2017, and Nov 30, 2018, 991 patients were enrolled, of whom 502 (51%) met the criteria for CRKP infection and 489 (49%) had positive cultures that were considered colonisation. We observed little intra-country genetic variation in CRKP. Infected patients from the USA were more acutely ill than were patients from China or South America (median Pitt bacteremia score 3 [IQR 2–6] vs 2 [0–4] vs 2 [0–4]) and had more comorbidities (median Charlson comorbidity index 3 [IQR 2–5] vs 1 [0–3] vs 1 [0–2]). Adjusted desirability of outcome ranking outcomes were similar in infected patients from China (n=246), South America (n=109), and the USA (n=130); the estimates were 53% (95% CI 42–65) for China versus South America, 50% (41–61) for the USA versus China, and 53% (41–66) for the USA versus South America. In patients with CRKP infections, unadjusted 30-day mortality was lower in China (12%, 95% CI 8–16; 29 of 246) than in the USA (23%, 16–30; 30 of 130) and South America (28%, 20–37; 31 of 109). Adjusted 30-day all-cause mortality was higher in South America than in China (adjusted odds ratio [aOR] 4·82, 95% CI 2·22–10·50) and the USA (aOR 3·34, 1·50–7·47), with the mortality difference between the USA and China no longer being significant (aOR 1·44, 0·70–2·96). Interpretation Global CRKP epidemics have important regional differences in patients’ baseline characteristics and clinical outcomes, and in bacterial characteristics. Research findings from one region might not be generalisable to other regions. Funding The National Institutes of Health.

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.

Background Carbapenemase-producing (CP) Escherichia coli (CPEc) are a global public health threat. We describe the epidemiology and outcomes of patients with CPEc isolates obtained in CRACKLE 2, a prospective cohort study of hospitalized patients with positive cultures for CP Enterobacteriaceae. Methods In CRACKLE-2, patients with CPEc were enrolled from 26 hospitals in 6 countries (ClinicalTrials.gov NCT03646227). Clinical data were collected, and bacterial isolates underwent whole genome sequencing (WGS). Here, we included unique patients with CPEc by WGS (n=114). The primary outcome was desirability of outcome ranking (DOOR) at 30 days after index culture. Chi squared tests with alpha = 0.05 were used to evaluate differences in culture source and outcomes between metallo-beta-lactamase (MBL) and non-MBL isolates. Results Of 114 CPEc isolates, 57 (50%) represented infection (Table 1). Isolates primarily arose from urine (34%) and blood (21%). Compared to non-MBL isolates, isolates containing MBL were more often from urine (41% vs 29%) and less frequently from blood (6% vs 32%); p=0.02. We observed strong regional variations in CP (Figure 1) and MBL (p < 0.0001). Sequence type (ST) 167 was more common among MBL than non-MBL isolates (31% vs 2%, p< 0.0001); non-MBL isolates were more often ST410 and ST131 (17% and 20%). Extended-spectrum beta-lactamases (ESBL) were present in 52% of isolates; most commonly, CTX-M-15 in both MBL (33%) and non-MBL isolates (34%). Phylogenetic analysis of the isolates and corresponding region, bacterial characteristics, and DOOR outcomes are in Figure 1. Death at 30 days occurred in 18 (16%) of patients, more commonly among non-MBL than MBL CPEc (23% vs 6%; p=0.01). The probability of a better DOOR outcome for a randomly selected MBL was 58% [95% CI: 48.2, 67.4], indicating no significant difference between the groups. Figure 1:Phylogenetic population structures of Carbapenemase-producing Escherichia coli (CPEc) isolates Legend: Infection = categorization as infection or colonization. ST = sequence type. BlaCarb = Carbapenemase gene. BlaESBL = acquired ESBL enzymes. DOOR = desirability of outcome ranking. DOOR rankings: 1 = Alive without events; DOOR 2 = Alive with 1 event; DOOR 3 = Alive with 2 or 3 events; DOOR 4 = dead. Conclusion Emergence of carbapenem resistance with important geographic variations was observed in E coli including among high-risk clones such as ST131. Mortality was higher among non-MBL isolates, which were more frequently from blood, but these findings may be confounded by region. Disclosures Vance G. Fowler, Jr, MD, MHS, Affinergy: Grant/Research Support|Affinergy: Honoraria|Affinium: Honoraria|Amphliphi Biosciences: Honoraria|ArcBio: Stocks/Bonds|Basilea: Grant/Research Support|Basilea: Honoraria|Bayer: Honoraria|C3J: Honoraria|Cerexa/Forest/Actavis/Allergan: Grant/Research Support|Contrafect: Grant/Research Support|Contrafect: Honoraria|Cubist/Merck: Grant/Research Support|Debiopharm: Grant/Research Support|Deep Blue: Grant/Research Support|Destiny: Honoraria|Genentech: Grant/Research Support|Genentech: Honoraria|Integrated Biotherapeutics: Honoraria|Janssen: Grant/Research Support|Janssen: Honoraria|Karius: Grant/Research Support|Medicines Co.: Honoraria|MedImmune: Grant/Research Support|MedImmune: Honoraria|NIH: Grant/Research Support|Novartis: Grant/Research Support|Novartis: Honoraria|Pfizer: Grant/Research Support|Regeneron: Grant/Research Support|Regeneron: Honoraria|Sepsis diagnostics: Sepsis diagnostics patent pending|UpToDate: Royalties|Valanbio: Stocks/Bonds Cesar A. Arias, MD, PhD, Entasis Phramceuticals: Grant/Research Support|MeMed Diagnostics: Grant/Research Support|Merck: Grant/Research Support David Paterson, MBBS, Accelerate: Honoraria|bioMerieux: Honoraria|Entasis: Advisor/Consultant|Janssen-Cilag: Grant/Research Support|MSD: Advisor/Consultant|MSD: Grant/Research Support|MSD: Honoraria|Pfizer: Grant/Research Support|Pfizer: Honoraria|PPD: Grant/Research Support|Shionogi: Grant/Research Support|VenatoRx: Advisor/Consultant Karen M. Ordonez, MD, AstraZeneca: Expert Testimony|Biomerieux: Expert Testimony|Farma de Colombia: Expert Testimony|MSD: Expert Testimony|Pfizer: Expert Testimony Souha S. Kanj, Pr, MSD, Pfizer, Gilead, Menarini, Astellas: Advisor/Consultant|MSD, Pfizer, Gilead, Menarini, Astellas: Honoraria Robert Bonomo, MD, Cystic Fibrosis Foundation: Grant/Research Support|Merck: Grant/Research Support|NIH: Grant/Research Support|VA: Grant/Research Support|VenatoRx: Grant/Research Support|Wockhardt: Grant/Research Support David van Duin, MD, PhD, Achaogen: Advisor/Consultant|Allergan: Advisor/Consultant|Astellas: Advisor/Consultant|MedImmune: Advisor/Consultant|Melinta: Advisor/Consultant|Merck: Advisor/Consultant|Merck: Grant/Research Support|NeuMedicine: Advisor/Consultant|Pfizer: Advisor/Consultant|Qpex: Advisor/Consultant|Roche: Advisor/Consultant|Sanofi-Pasteur: Advisor/Consultant|Shionogi: Advisor/Consultant|Shionogi: Grant/Research Support|T2 Biosystems: Advisor/Consultant|Tetraphase: Advisor/Consultant.

Background Multidrug resistance (MDR) in Enterobacterales is common; the impact of socioeconomic status (SES) on MDR prevalence is unclear. Methods Data from 2014–2021 was obtained from UNC Hospitals for all cultures with Enterobacterales growth (N=90129). ZIP-code level socioeconomic data for North Carolina was sourced from the 2020 5-Year American Community Survey and combined into an SES factor score assigned to each ZIP code (N=790). Prevalence ratios from generalized linear models were used to compare the relative MDR occurrence between SES quartiles. Results A significant inverse relationship between MDR and SES was observed (16%, 16.5%, 19.5%, and 20.7% MDR in the highest, medium-high, medium-low, and lowest quartiles, respectively; Table 1). The prevalence of MDR in Enterobacterales from patients residing in lowest-quartile ZIP codes was 32% higher (Table 1) relative to those from the highest quartile. This effect was significant across all measured antibiotic classes, with the largest absolute difference in penicillins (40.1% and 50.6% in the highest and lowest quartiles, respectively), and the smallest in aminoglycosides (5.6% and 7.3%; Figure 1). Temporally, the lowest quartile had the highest prevalence of MDR in all measured years. Conclusion Our findings show that in North Carolina from 2014–2021, MDR was consistently more prevalent in Enterobacterales from patients residing in lowest-quartile ZIP codes. These data emphasize the need to address the societal causes for disparities in clinical outcomes and can inform further study of the relationship between SES and MDR. Disclosures David van Duin, MD, PhD, Achaogen: Advisor/Consultant|Actavis: Advisor/Consultant|Allergan: Advisor/Consultant|Astellas: Advisor/Consultant|Entasis: Advisor/Consultant|Karius: Advisor/Consultant|MedImmune: Advisor/Consultant|Merck: Advisor/Consultant|Merck: Grant/Research Support|Neumedicine: Advisor/Consultant|Pfizer: Advisor/Consultant|Pfizer: Honoraria|Qpex: Advisor/Consultant|Roche: Advisor/Consultant|Sanofi-Pasteur: Advisor/Consultant|Shionogi: Advisor/Consultant|Shionogi: Grant/Research Support|T2Biosystems: Advisor/Consultant|Tetraphase: Advisor/Consultant|Utility: Advisor/Consultant|Wellspring: Advisor/Consultant.

Background Eravacycline, a novel synthetic fluorocycline, is structurally similar to tigecycline. Cases of tigecycline associated hyperfibrinogenemia have been reported in the literature, however the mechanism is not currently well described. At this time it is unknown if this is a class effect. Methods Two cases of patients on eravacycline for treatment of Mycobacterium abscessus (M.abscessus) who received regular fibrinogen monitoring are described. Results Patient 1 received a kidney transplant (2010) and was admitted for acute hypoxic respiratory failure secondary to COVID-19. Their course was complicated by multiple infections including disseminated M.abscessus with positive cultures from the lung and blood. Eravacycline 1 mg/kg BID (80 mg) was started on D1 and continued through D24. Fibrinogen levels on D1 was 448 mg/dl and on D23 were 120 mg/dl. Eravacycline was stopped and fibrinogen returned to normal range (228 mg/dl) in 5 days. Eravacycline was re-trialed at 80 mg BID and fibrinogen level on D1 was 310 mg/dl and 147 mg/dl on D8. No repeat fibrinogen levels were obtained. Patient 2 was a lung transplant recipient (2019) admitted for treatment of M.abscessus skin and soft tissue infection. The patient was started on eravacycline 1 mg/kg BID (90 mg) due to concerns of hypofibrinogenemia from tigecycline. On D1 of eravacycline fibrinogen was 167 mg/dl , on D19 of therapy fibrinogen was 64 mg/dl and eravacycline was stopped. Fibrinogen level returned to normal 3 days after eravacycline discontinuation (212 mg/dl). Conclusion Similar to tigecycline, we observed eravacycline related hypofibrinogenemia. Time to onset was variable in the two cases presented. Hypofibrinogenemia was readily reversible, within 3-5 days, with drug withdrawal and reproducible in one patient with re-challenge of eravacycline. Further analysis into eravacycline related hypofibrinogenemia and its impact on coagulation outcomes are warranted based on these reports. Disclosures David van Duin, MD, PhD, Achaogen: Advisor/Consultant|Allergan: Advisor/Consultant|Astellas: Advisor/Consultant|MedImmune: Advisor/Consultant|Melinta: Advisor/Consultant|Merck: Advisor/Consultant|Merck: Grant/Research Support|NeuMedicine: Advisor/Consultant|Pfizer: Advisor/Consultant|Qpex: Advisor/Consultant|Roche: Advisor/Consultant|Sanofi-Pasteur: Advisor/Consultant|Shionogi: Advisor/Consultant|Shionogi: Grant/Research Support|T2 Biosystems: Advisor/Consultant|Tetraphase: Advisor/Consultant.

BackgroundMultidrug-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.MethodsWe 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.ResultsThe 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.ConclusionsIn 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.

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.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.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.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.

Antimicrobial resistance is a global threat. As “proof-of-concept,” we employed a system-based approach to identify patient, bacterial, and drug variables contributing to mortality in patients with carbapenem-resistant Klebsiella pneumoniae (CR Kp ) bloodstream infections exposed to colistin (COL) and ceftazidime-avibactam (CAZ/AVI) as mono- or combination therapies.

Patients with burn injuries are at high risk for infectious complications, and infections are the most common cause of death after the first 72 h of hospitalization. Hospital-acquired infections caused by multidrug resistant (MDR) Gram-negative bacteria (GNB) in this population are concerning. Here, we evaluated carriage with MDR GNB in patients in a large tertiary-care burn intensive care unit. Twenty-nine patients in the burn unit were screened for intestinal carriage. Samples were cultured on selective media. Median time from admission to the burn unit to first sample collection was 9 days (IQR 5 – 17 days). In 21 (72%) patients, MDR GNB were recovered; the most common bacterial species isolated was Pseudomonas aeruginosa, which was found in 11/29 (38%) of patients. Two of these patients later developed bloodstream infections with P. aeruginosa. Transmission of KPC-31-producing ST22 Citrobacter freundii was detected. Samples from two patients grew genetically similar C. freundii isolates that were resistant to ceftazidime-avibactam. On analysis of whole-genome sequencing, bla(KPC-31) was part of a Tn4401b transposon that was present on two different plasmids in each C. freundii isolate. Plasmid curing experiments showed that removal of both copies of bla(KPC-31) was required to restore susceptibility to ceftazidime-avibactam. In summary, MDR GNB colonization is common in burn patients and patient-to-patient transmission of highly resistant GNB occurs. These results emphasize the ongoing need for infection prevention and antimicrobial stewardship efforts in this highly vulnerable population.

BackgroundMedically vulnerable individuals are at increased risk of acquiring multidrug-resistant Enterobacterales (MDR-E) infections. People with HIV (PWH) experience a greater burden of comorbidities and may be more susceptible to MDR-E due to HIV-specific factors.MethodsWe performed an observational study of PWH participating in an HIV clinical cohort and engaged in care at a tertiary care center in the Southeastern United States from 2000 to 2018. We evaluated demographic and clinical predictors of MDR-E by estimating prevalence ratios (PRs) and employing machine learning classification algorithms. In addition, we created a predictive model to estimate risk of MDR-E among PWH using a machine learning approach.ResultsAmong 4734 study participants, MDR-E was isolated from 1.6% (95% CI, 1.2%–2.1%). In unadjusted analyses, MDR-E was strongly associated with nadir CD4 cell count ≤200 cells/mm3 (PR, 4.0; 95% CI, 2.3–7.4), history of an AIDS-defining clinical condition (PR, 3.7; 95% CI, 2.3–6.2), and hospital admission in the prior 12 months (PR, 5.0; 95% CI, 3.2–7.9). With all variables included in machine learning algorithms, the most important clinical predictors of MDR-E were hospitalization, history of renal disease, history of an AIDS-defining clinical condition, CD4 cell count nadir ≤200 cells/mm3, and current CD4 cell count 201–500 cells/mm3. Female gender was the most important demographic predictor.ConclusionsPWH are at risk for MDR-E infection due to HIV-specific factors, in addition to established risk factors. Early HIV diagnosis, linkage to care, and antiretroviral therapy to prevent immunosuppression, comorbidities, and coinfections protect against antimicrobial-resistant bacterial infections.

The term difficult-to-treat resistance has been recently coined to identify Gram-negative bacteria exhibiting resistance to all fluoroquinolones and all β-lactam categories, including carbapenems. Such bacteria are posing serious challenges to clinicians trying to identify the best therapeutic option for any given patient. Delayed appropriate therapy has been associated with worse outcomes including increase in length of stay, increase in total in-hospital costs and ∼20% increase in the risk of in-hospital mortality. In addition, time to appropriate antibiotic therapy has been shown to be an independent predictor of 30 day mortality in patients with resistant organisms. Improving and anticipating aetiological diagnosis through optimizing not only the identification of phenotypic resistance to antibiotic classes/agents, but also the identification of specific resistance mechanisms, would have a major impact on reducing the frequency and duration of inappropriate early antibiotic therapy. In light of these considerations, the present paper reviews the increasing need for rapid diagnosis of bacterial infections and efficient laboratory workflows to confirm diagnoses and facilitate prompt de-escalation to targeted therapy, in line with antimicrobial stewardship principles. Rapid diagnostic tests currently available and future perspectives for their use are discussed. Early appropriate diagnostics and treatment of MDR Gram-negative infections require a multidisciplinary approach that includes multiple different diagnostic methods and further consensus of algorithms, protocols and guidelines to select the optimal antibiotic therapy.

Carbapenem-resistant Enterobacterales (CRE) are a growing threat to human health worldwide. CRE often carry multiple resistance genes that limit treatment options and require longer durations of therapy, are more costly to treat, and necessitate therapies with increased toxicities when compared with carbapenem-susceptible strains. Here, we provide an overview of the mechanisms of resistance in CRE, the epidemiology of CRE infections worldwide, and available treatment options for CRE. We review recentlyapproved agents for the treatment of CRE, including ceftazidime-avibactam, meropenem-vaborbactam, imipenem-relebactam, cefiderocol, and novel aminoglycosides and tetracyclines. We also discuss recent advances in phage therapy and antibiotics that are currently in development targeted to CRE. The potential for the development of resistance to these therapies remains high, and enhanced antimicrobial stewardship is imperative both to reduce the spread of CRE worldwide and to ensure continued access to efficacious treatment options.

Ceftriaxone-resistant (CRO-R)This is a prospective cohort of patients withNotable differences between patients infected with CRO-R and CRO-SPatients with CRO-R

Globally disseminated carbapenem-resistant Enterobacterales is an urgent threat to public health. The most common carbapenem resistance mechanism is the production of carbapenemases.

OBJECTIVE To examine recent trends and differences in all-cause and cause-specific hospitalization rates by race, ethnicity, and gender among persons with HIV (PWH) in the United States and Canada. DESIGN HIV clinical cohort consortium. METHODS We followed PWH at least 18 years old in care 2005-2015 in six clinical cohorts. We used modified Clinical Classifications Software to categorize hospital discharge diagnoses. Incidence rate ratios (IRR) were estimated using Poisson regression with robust variances to compare racial and ethnic groups, stratified by gender, adjusted for cohort, calendar year, injection drug use history, and annually updated age, CD4+, and HIV viral load. RESULTS Among 27 085 patients (122 566 person-years), 80% were cisgender men, 1% transgender, 43% White, 33% Black, 17% Hispanic of any race, and 1% Indigenous. Unadjusted all-cause hospitalization rates were higher for Black [IRR 1.46, 95% confidence interval (CI) 1.32-1.61] and Indigenous (1.99, 1.44-2.74) versus White cisgender men, and for Indigenous versus White cisgender women (2.55, 1.68-3.89). Unadjusted AIDS-related hospitalization rates were also higher for Black, Hispanic, and Indigenous versus White cisgender men (all P

Treatment options for Achromobacter xylosoxidans are limited. Eight cystic fibrosis patients with A. xylosoxidans were treated with 12 cefiderocol courses. Pretreatment in vitro resistance was seen in 3 of 8 cases. Clinical response occurred after 11 of 12 treatment courses. However, microbiologic relapse was observed after 11 of 12 treatment courses, notably without emergence of resistance.

Stenotrophomonas maltophilia is a non-fermenting, Gram-negative bacillus that has emerged as an opportunistic nosocomial pathogen. Its intrinsic multidrug resistance makes treating infections caused by S. maltophilia a great clinical challenge. Clinical management is further complicated by its molecular heterogeneity that is reflected in the uneven distribution of antibiotic resistance and virulence determinants among different strains, the shortcomings of available antimicrobial susceptibility tests and the lack of standardized breakpoints for the handful of antibiotics with in vitro activity against this microorganism. Herein, we provide an update on the most recent literature concerning these issues, emphasizing the impact they have on clinical management of S. maltophilia infections.

Carbapenem-resistant Klebsiella pneumoniae (CRKp) is the most prevalent carbapenem-resistant Enterobacterales in the United States. We evaluated clustering of CRKp in hospitalized patients in US hospitals.From April 2016 to August 2017, 350 patients with clonal group 258 were included as part of the Consortium on Resistance Against Carbapenems in Klebsiella and other Enterobacteriaceae (CRACKLE-2), 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.Most patients were admitted from home (n = 150, 43%) or a long-term care facility (n = 115, 33%). Urine (n = 149, 43%) was the most common site of isolation. In total, 55 static and 47 dynamics clusters were identified involving 210/350 (60%) and 194/350 (55%) patients, respectively. About half of static clusters were identical to dynamic clusters. Static clusters consisted of 33 (60%) intra-system and 22 (40%) inter-system clusters. Dynamic clusters consisted of 32 (68%) intra-system and 15 (32%) inter-system clusters and had fewer SNP differences compared to static clusters (8 versus 9, P= 0.045, 95% CI: [-4, 0]). Dynamic inter-system clusters contained more patients than dynamic intra-system clusters (median [IQR]: 4 [2, 7] vs 2 [2, 2], P= 0.007, 95% CI: [-3, 0]).Widespread intra-system and inter-system transmission of CRKp was identified in hospitalized US patients. Employing different methods for assessing genetic similarity resulted in only minor differences in interpretation.

Stenotrophomonas maltophilia is a non-fermenting, Gram-negative bacillus that has emerged as an opportunistic nosocomial pathogen. Its intrinsic multidrug resistance makes treating infections caused by S. maltophilia a great clinical challenge. Clinical management is further complicated by its molecular heterogeneity that is reflected in the uneven distribution of antibiotic resistance and virulence determinants among different strains, the shortcomings of available antimicrobial susceptibility tests and the lack of standardized breakpoints for the handful of antibiotics with in vitro activity against this microorganism. Herein, we provide an update on the most recent literature concerning these issues, emphasizing the impact they have on clinical management of S. maltophilia infections.

BackgroundCOVID-19 Convalescent Plasma (CCP) was an early and widely adopted putative therapy for severe COVID-19. Results from randomized control trials and observational studies have failed to demonstrate a clear therapeutic role for CCP for severe SARS-CoV-2 infection. Underlying these inconclusive findings is a broad heterogeneity in the concentrations of neutralizing antibodies (nAb) between different CCP donors. The present study was designed to evaluate nAb titer threshold for clinically effective CCP.MethodsWe conducted a double-blind, phase 2 study to evaluate the safety and effectiveness of nAb titer-defined CCP in adults admitted to an academic referral hospital. Patients positive on a SARS-CoV-2 nucleic acid amplification test and with symptoms for < 10 days were eligible. Participants received either CCP with nAb titers ≥1:160-1:640 (standard titer group) or >1:640 (high titer group) in addition to standard of care treatments. Adverse events were contrasted by CCP titer. The primary clinical outcome was time to hospital discharge, with mortality and respiratory support evaluated as secondary outcomes.FindingsBetween August 28 and December 4, 2020, 316 participants were screened, 55 received CCP, with 41 and 14 receiving standard versus high titer CCP, respectively. Participants were a median of 61 years of age (IQR 52-67), 36% women, 25% Black and 33% Hispanic. Severe adverse events (SAE) (≥ grade 3) occurred in 4 (29%) and 23 (56%) of participants in the high versus standard titer groups, respectively by day 28 (Risk Difference -0.28 [95% CI -0.56, 0.01]). There were no observed treatment-related AEs. By day 55, time to hospital discharge was shorter among participants receiving high versus standard titer, accounting for death as a competing event (hazard ratio 1.94 [95% CI 1.05, 3.58], Gray’s p=0.02).InterpretationIn this phase 2 trial in a high-risk population of patients admitted for Covid-19, we found earlier time to hospital discharge and lower occurrences of life-threatening SAEs among participants receiving CCP with nAb titers >1:640 compared with participants receiving CCP with lower nAb titer CCP. Though limited by a small study size these findings support further study of high-nAb titer CCP defined as >1:640 in the treatment of COVID-19.FundingThis clinical study was supported by the UNC Health Foundation and the North Carolina Policy Collaboratory at the University of North Carolina at Chapel Hill with funding from the North Carolina Coronavirus Relief Fund established and appropriated by the North Carolina General Assembly. The laboratory assays for neutralizing antibody titers and SARS-CoV-2 specific antibody-binding assays were partially supported by The NIH NCI/NIAID SeroNet Serocenter of Excellence Award U54 CA260543.Research in ContextEvidence before this studyCOVID-19 Convalescent Plasma (CCP) has emergency use authorization from the FDA for early treatment of COVID-19 in either outpatient or inpatient settings. Evidence supporting the use of CCP for severe COVID-19 is mixed and still emerging. One major limitation in interpreting published clinical trials and the clinical role of CCP is incomplete understanding of necessary neutralizing antibody (nAb) titer for clinically effective CCP. Observational studies suggest that higher antibody-content CCP is more effective than lower antibody-content CCP, or that very low antibody-content CCP is harmful. We searched PubMed articles published between February 1, 2020, and April 15, 2022, using the terms “COVID-19”, “convalescent plasma”, “SARS-CoV-2”, and “CCP” alone and in combination. Our search yielded 6,468 results which we filtered to 280 and 162 by selecting ‘Clinical Trial’ and ‘Randomized Controlled Trial’ article types, respectively. Among these, we identified 25 open-label or blinded efficacy or effectiveness studies in hospitalized patients that were relevant to our study. Preliminary reports show wide variability in the antibody content of CCP used in clinical trials, the assays used to define CCP antibody content, and the estimates of clinical outcomes following CCP therapy for hospitalized patients. Only one study deliberately infused CCP with nAb > 1:640. Post-hoc analyses of potent monoclonal antibody therapy in hospitalized patients in the UK showed survival benefit when monoclonal antibody was infused to patients who had not yet seroconverted by spike antibody ELISA, suggesting that if dosed appropriately, antibody-based therapies may have a role in improving outcomes of severe COVID-19.Added value of this studyThis phase 2 study showed that CCP with high nAb titer (>1:640) provided more rapid recovery to hospital discharge and fewer COVID-19 attributable AEs than CCP with nAb titer between the FDA-recommended minimum standard and 4-fold higher (≥1:160-1:640). The hazard ratio of time to hospital discharge from baseline through day 55, accounting for death as a competing event, contrasting patients receiving high versus standard CCP titer was 1.94 (95% CI 1.05-3.58). Adjusted hazard ratios of high versus standard titer CCP receipt for time to hospital discharge were consistent with the primary unadjusted findings. Mortality through 55 days was lower in the high titer group, but with a wide confidence interval that did not reach statistical significance.Implications of all available evidenceOur data that CCP with nAb >1:640 expedites recovery of patients admitted with COVID-19 compared with CCP with nAb ≥1:160-1:640 suggests that a threshhold of nAb ≥1:160 may be too low to define CCP as ‘high titer’. Analyses in larger CCP trials should consider full reporting of nAb in CCP units administered at individual study participant level, and specifically whether CCP contained nAb >1:640. Further investigation of CCP with nAb >1:640 is warranted given that raising the threshhold of nAb, or a correlative specific anti-spike antibody assay, used to qualify ‘high titer’ CCP in clinical trials could inform policy guidance and clinical use of CCP.

Background People with HIV (PWH) may be at increased risk for MDR Enterobacterales (MDR-E) infection or colonization, relative to individuals without HIV, due to a greater burden of comorbidities as well as HIV-related intestinal inflammation and microbiota alterations. Objectives To characterize antibiotic susceptibility of enteric Enterobacterales and risk factors for antimicrobial-resistant bacterial infections in a sample of PWH attending routine clinic visits. Methods Participants provided self-administered rectal swabs and completed questionnaires regarding healthcare, travel and occupational exposures for the prior 12 months. Rectal samples were processed to identify Enterobacterales species, and susceptibility testing was performed. Results Among 82 participants, 110 Enterobacterales isolates were obtained. Non-susceptibility was common for penicillins, sulphonamides and first-generation cephalosporins. MDR-E was present in 20% of participants. HIV-related characteristics, including current or nadir CD4 cell count, viral suppression, or AIDS-defining clinical conditions, were not associated with MDR-E. Conclusions MDR-E colonization is common in this population of PWH. Further research evaluating risk factors for MDR-E in PWH may inform infection prevention approaches to better protect at-risk populations from these difficult-to-treat infections.

BACKGROUND: Carbapenem-resistant Enterobacteriaceae (CRE) are a global threat. Here, we describe the clinical and molecular characteristics of Centers for Disease Control and Prevention (CDC)-defined CRE in the US. METHODS: The second Consortium on Resistance Against Carbapenems in Klebsiella and other Enterobacteriaceae (CRACKLE-2, ClinicalTrials.gov: NCT03646227) is a prospective, multicenter, cohort study. Patients hospitalized in 49 US hospitals, with clinical cultures positive for CDC-defined CRE between 30 April 2016 and 31 August 2017 were included. Primary outcome was desirability of outcome ranking (DOOR) at 30 days. Clinical data and bacteria were collected, and whole genome sequencing (WGS) was performed. FINDINGS: 1,040 patients with unique isolates were included; 449 (43%) with infection and 591 (57%) with colonization. CDC-defined CRE admission rate was 57 CDC-defined CRE admissions/100,000 admissions (95% CI: 45–71). Three subsets of CDC-defined CRE were identified: carbapenemase-producing Enterobacteriaceae (618/1,040, 59%); non-carbapenemase-producing CRE (194/1,040, 19%); and unconfirmed CRE (228/1,040, 22%; initially reported as CRE, but susceptible to carbapenems in two central laboratories). Klebsiella pneumoniae carbapenemase (KPC)-producing clonal group 258 K. pneumoniae was the most common carbapenemase-producing Enterobacteriaceae. In 449 patients with CDC-defined CRE infections, DOOR outcomes were not significantly different in patients with carbapenemase-producing Enterobacteriaceae, non-carbapenemase-producing CRE, and unconfirmed CRE. At 30 days 107/449 (24%, 95% CI 20–28%) patients had died. INTERPRETATION: Among patients with CDC-defined CRE, similar outcomes were observed among three subgroups, including the novel unconfirmed CRE group. CDC-defined CRE represent diverse bacteria, whose spread may not respond to interventions directed to carbapenemase-producing Enterobacteriaceae. FUNDING: National Institutes of Health

Daptomycin (DAP) is key in treating multidrug-resistant Staphylococcus infections. Diminished susceptibility to DAP is emerging among Staphylococcus epidermidis strains although mechanisms for non-susceptibility (NS) remain poorly understood. We report a case of persistent S. epidermidis bacteremia in which loss of DAP susceptibility arose during prolonged treatment. Whole genome sequencing identified two mutations, Q371del and P415L, in a single-affected gene, WalK, that coincided with the emergence of DAP-NS. Protein modeling of the mutations predicted a disruption of WalK protein configuration. The emergence of mutations in a single-gene during DAP exposure raises concerns in an era of increasingly treatment-resistant infections. Lay summary: Daptomycin is an important antibiotic for fighting Staphylococcus infections. We identified variants in the WalK gene that were coincident with resistance in a clinical Staphylococcus epidermidis infection. Clinicians, hospital epidemiologists, and microbiology laboratories need to be aware of the potential for the evolution of drug resistance during prolonged daptomycin therapy.

Introduction Most studies of solid organ transplant (SOT) recipients with COVID-19 focus on outcomes within one month of illness onset. Delayed mortality in SOT recipients hospitalized for COVID-19 has not been fully examined. Methods We used data from a multicenter registry to calculate mortality by 90 days following initial SARS-CoV-2 detection in SOT recipients hospitalized for COVID-19 and developed multivariable Cox proportional-hazards models to compare risk factors for death by days 28 and 90. Results Vital status at day 90 was available for 936 of 1117 (84%) SOT recipients hospitalized for COVID-19: 190 of 936 (20%) died by 28 days and an additional 56 of 246 deaths (23%) occurred between days 29 and 90. Factors associated with mortality by day 90 included: age > 65 years [aHR 1.8 (1.3-2.4), p = Conclusions In SOT recipients hospitalized for COVID-19, >20% of deaths occurred between 28 and 90 days following SARS-CoV-2 diagnosis. Future investigations should consider extending follow-up duration to 90 days for more complete mortality assessment

Objectives:To describe the epidemiology of patients with nonintestinal carbapenem-resistant Enterobacterales (CRE) colonization and to compare clinical outcomes of these patients to those with CRE infection.Design:A secondary analysis of Consortium on Resistance Against Carbapenems in Klebsiella and other Enterobacteriaceae 2 (CRACKLE-2), a prospective observational cohort.Setting:A total of 49 US short-term acute-care hospitals.Patients:Patients hospitalized with CRE isolated from clinical cultures, April, 30, 2016, through August 31, 2017.Methods:We described characteristics of patients in CRACKLE-2 with nonintestinal CRE colonization and assessed the impact of site of colonization on clinical outcomes. We then compared outcomes of patients defined as having nonintestinal CRE colonization to all those defined as having infection. The primary outcome was a desirability of outcome ranking (DOOR) at 30 days. Secondary outcomes were 30-day mortality and 90-day readmission.Results:Of 547 patients with nonintestinal CRE colonization, 275 (50%) were from the urinary tract, 201 (37%) were from the respiratory tract, and 71 (13%) were from a wound. Patients with urinary tract colonization were more likely to have a more desirable clinical outcome at 30 days than those with respiratory tract colonization, with a DOOR probability of better outcome of 61% (95% confidence interval [CI], 53%–71%). When compared to 255 patients with CRE infection, patients with CRE colonization had a similar overall clinical outcome, as well as 30-day mortality and 90-day readmission rates when analyzed in aggregate or by culture site. Sensitivity analyses demonstrated similar results using different definitions of infection.Conclusions:Patients with nonintestinal CRE colonization had outcomes similar to those with CRE infection. Clinical outcomes may be influenced more by culture site than classification as “colonized” or “infected.”