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.

A Systems-Based Analysis of Mono- and Combination Therapy for Carbapenem-Resistant Klebsiella pneumoniae Bloodstream Infections.

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 (CRKp) bloodstream infections exposed to colistin (COL) and ceftazidime-avibactam (CAZ/AVI) as mono- or combination therapies. Patients (n = 49) and CRKp isolates (n = 22) were part of the Consortium on Resistance Against Carbapenems in Klebsiella and other Enterobacteriaceae (CRACKLE-1), a multicenter, observational, prospective study of patients with carbapenem-resistant Enterobacterales (CRE) conducted between 2011 and 2016. Pharmacodynamic activity of mono- and combination drug concentrations was evaluated over 24 h using in vitro static time-kill assays. Bacterial growth and killing dynamics were estimated with a mechanism-based model. Random Forest was used to rank variables important for predicting 30-day mortality. Isolates exposed to COL+CAZ/AVI had enhanced early bacterial killing compared to CAZ/AVI alone and fewer incidences of regrowth compared to COL and CAZ/AVI. The mean coefficient of determination (R2) for the observed versus predicted bacterial counts was 0.86 (range: 0.75 - 0.95). Bacterial subpopulation susceptibilities and drug mechanistic synergy were essential to describe bacterial killing and growth dynamics. The combination of clinical (hypotension), bacterial (IncR plasmid, aadA2, and sul3) and drug (KC50) variables were most predictive of 30-day mortality. This proof-of-concept study combined clinical, bacterial, and drug variables in a unified model to evaluate clinical outcomes.

The Pitt Bacteremia Score Predicts Mortality in Nonbacteremic Infections.

BACKGROUND: Predicting mortality risk in patients is important in research settings. The Pitt bacteremia score (PBS) is commonly used as a predictor of early mortality risk in patients with bloodstream infections (BSIs). We determined whether the PBS predicts 14-day inpatient mortality in nonbacteremia carbapenem-resistant Enterobacteriaceae (CRE) infections. METHODS: Patients were selected from the Consortium on Resistance Against Carbapenems in Klebsiella and Other Enterobacteriaceae, a prospective, multicenter, observational study. We estimated risk ratios to analyze the predictive ability of the PBS overall and each of its components individually. We analyzed each component of the PBS in the prediction of mortality, assessed the appropriate cutoff value for the dichotomized score, and compared the predictive ability of the qPitt score to that of the PBS. RESULTS: In a cohort of 475 patients with CRE infections, a PBS ≥4 was associated with mortality in patients with nonbacteremia infections (risk ratio [RR], 21.9; 95% confidence interval [CI], 7.0, 68.8) and with BSIs (RR, 6.0; 95% CI, 2.5, 14.4). In multivariable analysis, the hypotension, mechanical ventilation, mental status, and cardiac arrest parameters of the PBS were independent risk factors for 14-day all-cause inpatient mortality. The temperature parameter as originally calculated for the PBS was not independently associated with mortality. However, a temperature <36.0°C vs ≥36°C was independently associated with mortality. A qPitt score ≥2 had similar discrimination as a PBS ≥4 in nonbacteremia infections. CONCLUSIONS: Here, we validated that the PBS and qPitt score can be used as reliable predictors of mortality in nonbacteremia CRE infections.

Early infectious complications after autologous hematopoietic cell transplantation for multiple myeloma.

BACKGROUND: The spectrum of infectious complications in autologous hematopoietic cell transplant recipients (AHCT) with multiple myeloma has not been well described in the recent era of novel agent induction and improved supportive care. METHODS: We conducted a retrospective cohort study of 413 adult myeloma AHCT recipients at our institution from 2007-2016 to describe the cumulative incidence and risk factors for various infections and FN occurring within the first 100 days after AHCT. Additionally, landmark analysis was done among 404 patients who survived at least 100 days after transplant admission to estimate the association of infections with subsequent non-relapse mortality (NRM), overall survival (OS), and relapse-free survival (RFS). RESULTS: Cumulative incidences (95% CI) of infection events by day 100 were: FN 43% (38-48), any infection 21% (17-25), bacterial 17% (14-21), viral 4% (3-7) and fungal 1% (0.5-3), central line-associated blood stream infection 3% (2-6), and Clostridium difficile colitis 6% (4-8). Patients with infection had a longer initial transplant hospitalization (median 17 vs 16 days, P < 0.01), more readmissions (31% vs 8%, P < 0.01), and spent more days in hospital in first 100 days (median 18 vs 16 days, P < 0.01). A 100-day mortality was low and similar between groups (2% vs 1%, P = 0.28). In landmark analysis of 404 100-day survivors, OS was worse among patients with early infections (hazard ratio 1.54 [1.03-2.30], P = 0.03), although there was no difference in NRM and RFS. CONCLUSIONS: Notwithstanding advances in supportive care, early infectious complications remain a relevant source of morbidity and require attention in myeloma AHCT recipients.

Colistin Versus Ceftazidime-Avibactam in the Treatment of Infections Due to Carbapenem-Resistant Enterobacteriaceae.

Background: The efficacy of ceftazidime-avibactam-a cephalosporin-ß-lactamase inhibitor combination with in vitro activity against Klebsiella pneumoniae carbapenemase-producing carbapenem-resistant Enterobacteriaceae (CRE)-compared with colistin remains unknown. Methods: Patients initially treated with either ceftazidime-avibactam or colistin for CRE infections were selected from the Consortium on Resistance Against Carbapenems in Klebsiella and other Enterobacteriaceae (CRACKLE), a prospective, multicenter, observational study. Efficacy, safety, and benefit-risk analyses were performed using intent-to-treat analyses with partial credit and the desirability of outcome ranking approaches. The ordinal efficacy outcome was based on disposition at day 30 after starting treatment (home vs not home but not observed to die in the hospital vs hospital death). All analyses were adjusted for confounding using inverse probability of treatment weighting (IPTW). Results: Thirty-eight patients were treated first with ceftazidime-avibactam and 99 with colistin. Most patients received additional anti-CRE agents as part of their treatment. Bloodstream (n = 63; 46%) and respiratory (n = 30; 22%) infections were most common. In patients treated with ceftazidime-avibactam versus colistin, IPTW-adjusted all-cause hospital mortality 30 days after starting treatment was 9% versus 32%, respectively (difference, 23%; 95% bootstrap confidence interval, 9%-35%; P = .001). In an analysis of disposition at 30 days, patients treated with ceftazidime-avibactam, compared with those treated within colistin, had an IPTW-adjusted probability of a better outcome of 64% (95% confidence interval, 57%-71%). Partial credit analyses indicated uniform superiority of ceftazidime-avibactam to colistin. Conclusions: Ceftazidime-avibactam may be a reasonable alternative to colistin in the treatment of K. pneumoniae carbapenemase-producing CRE infections. These findings require confirmation in a randomized controlled trial.

Colistin Resistance in Carbapenem-Resistant Klebsiella pneumoniae: Laboratory Detection and Impact on Mortality.

Background: Polymyxins including colistin are an important "last-line" treatment for infections caused by carbapenem-resistant Klebsiella pneumoniae (CRKp). Increasing use of colistin has led to resistance to this cationic antimicrobial peptide. Methods: A cohort nested within the Consortium on Resistance against Carbapenems in Klebsiella pneumoniae (CRACKLE) was constructed of patients with infection, or colonization with CRKp isolates tested for colistin susceptibility during the study period of December, 2011 to October, 2014. Reference colistin resistance determination as performed by broth macrodilution was compared to results from clinical microbiology laboratories (Etest) and to polymyxin resistance testing. Each patient was included once, at the time of their first colistin-tested CRKp positive culture. Time to 30-day in-hospital all-cause mortality was evaluated by Kaplan-Meier curves and Cox proportional hazard modeling. Results: In 246 patients with CRKp, 13% possessed ColR CRKp. ColR was underestimated by Etest (very major error rate = 35%, major error rate = 0.4%). A variety of rep-PCR strain types were encountered in both the ColS and the ColR groups. Carbapenem resistance was mediated primarily by blaKPC-2 (46%) and blaKPC-3 (50%). ColR was associated with increased hazard for in-hospital mortality (aHR 3.48; 95% confidence interval, 1.73-6.57; P < .001). The plasmid-associated ColR genes, mcr-1 and mcr-2 were not detected in any of the ColR CRKp. Conclusions: In this cohort, 13% of patients with CRKp presented with ColR CRKp. The apparent polyclonal nature of the isolates suggests de novo emergence of ColR in this cohort as the primary factor driving ColR. Importantly, mortality was increased in patients with ColR isolates.

NDM-5 and OXA-181 Beta-Lactamases, a Significant Threat Continues To Spread in the Americas.

Among Gram-negative bacteria, carbapenem-resistant infections pose a serious and life-threatening challenge. Here, the CRACKLE network reports a sentinel detection and characterization of a carbapenem-resistant Klebsiella pneumoniae ST147 isolate harboring blaNDM-5 and blaOXA-181 from a young man who underwent abdominal surgery in India. blaNDM-5 was located on an IncFII plasmid of ≈90 kb, whereas blaOXA-181 was chromosomally encoded. Resistome and genome analysis demonstrated multiple copies of the transposable element IS26 and a "hot-spot region" in the IncFII plasmid.

Comparison of serum concentrations between different dosing strategies of posaconazole delayed-release tablet at a large academic medical centre.

It is unclear if the prophylaxis dose of 300 mg/day is sufficient for achieving serum concentrations targeting the treatment of invasive fungal infections. To evaluate differences between PCZ serum concentrations in patients receiving the DRT vs the OS and in patients receiving higher doses than 300 mg/day of the DRT, a retrospective review was conducted on inpatients who received PCZ for either treatment or prophylaxis. Baseline demographics including comorbid conditions, indication and dose of therapy were collected. Serum trough concentrations were collected at steady state. Fifty-seven patients received PCZ during the study period. A total of 35 levels were collected (DRT n = 18, OS n = 17). Patients receiving the DRT had levels >0.7 mcg/mL 100% of the time compared to 58.8% in those receiving the OS. No significant difference was seen in serum concentrations at 300 mg/day (n = 14) vs 400 mg/day (n = 8) of the DRT (1.55 mcg/mL (1.08-2.50) vs 2.5 mcg/mL (1.85-2.70), P = .19). The DRT leads to more consistent levels in the therapeutic range than the OS. Standard dosing of 300 mg/day with DRT achieves adequate concentrations for prophylaxis and treatment of IFIs, although further data are needed to determine optimal serum concentrations for treatment.

Carbapenem-resistant Klebsiella pneumoniae urinary tract infection following solid organ transplantation.

Carbapenem-resistant Klebsiella pneumoniae (CRKP) is an emerging pathogen with a devastating impact on organ transplant recipients (OTRs). Data describing urinary tract infections (UTIs) due to CRKP, compared to extended-spectrum ß-lactamase (ESBL)-producing and susceptible K. pneumoniae, are lacking. We conducted a retrospective cohort study comparing OTRs with a first episode of UTI due to CRKP, ESBL-producing K. pneumoniae, or susceptible K. pneumoniae. We identified 108 individuals; 22 (20%) had UTIs due to CRKP, 22 (20%) due to ESBL-producing K. pneumoniae, and 64 (60%) due to susceptible K. pneumoniae. Compared to susceptible K. pneumoniae (27%), patients with UTIs due to CRKP or ESBL-producing K. pneumoniae were more likely to have a ≥ 24-hour stay in the intensive care unit (ICU) before or after development of the UTI (64% and 77%, respectively; P < 0.001). Among 105/108 hospitalized patients (97%), the median lengths of stay prior to UTI with CRKP or ESBL-producing K. pneumoniae (7 and 8 days, respectively) were significantly longer than that for susceptible K. pneumoniae (1 day; P < 0.001). Clinical failure was observed for 8 patients (36%) with CRKP, 4 (18%) with ESBL-producing K. pneumoniae, and 9 (14%) with susceptible K. pneumoniae (P = 0.073). Microbiological failure was seen for 10 patients (45%) with CRKP, compared with 2 (9%) with ESBL-producing K. pneumoniae and 2 (3%) with susceptible K. pneumoniae (P < 0.001). In multivariable logistic regression analyses, CRKP was associated with greater odds of microbiological failure (versus ESBL-producing K. pneumoniae: odds ratio [OR], 9.36, 95% confidence interval [CI], 1.94 to 72.1; versus susceptible K. pneumoniae: OR, 31.4, 95% CI, 5.91 to 264). In conclusion, CRKP is associated with ICU admission, long length of stay, and microbiological failure among OTRs with UTIs. Greater numbers are needed to determine risk factors for infection and differences in meaningful endpoints associated with carbapenem resistance.

Impact of therapy and strain type on outcomes in urinary tract infections caused by carbapenem-resistant Klebsiella pneumoniae.

OBJECTIVES: Carbapenem-resistant Klebsiella pneumoniae (CRKP) is an important healthcare-associated pathogen. We evaluated the impact of CRKP strain type and treatment on outcomes of patients with CRKP bacteriuria. PATIENTS AND METHODS: Physician-diagnosed CRKP urinary tract infection (UTI)-defined as those patients who received directed treatment for CRKP bacteriuria-was studied in the multicentre, prospective Consortium on Resistance against Carbapenems in Klebsiella pneumoniae (CRaCKle) cohort. Strain typing by repetitive extragenic palindromic PCR (rep-PCR) was performed. Outcomes were classified as failure, indeterminate or success. Univariate and multivariate ordinal analyses to evaluate the associations between outcome, treatment and strain type were followed by binomial analyses. RESULTS: One-hundred-and-fifty-seven patients with physician-diagnosed CRKP UTI were included. After adjustment for CDC/National Healthcare Safety Network (NHSN)-defined UTI, critical illness and receipt of more than one active antibiotic, patients treated with aminoglycosides were less likely to fail therapy [adjusted OR (aOR) for failure 0.34, 95% CI 0.15-0.73, P=0.0049]. In contrast, patients treated with tigecycline were more likely to fail therapy (aOR for failure 2.29, 95% CI 1.03-5.13, P=0.0425). Strain type data were analysed for 55 patients. The predominant clades were ST258A (n=18, 33%) and ST258B (n=26, 47%). After adjustment for CDC/NHSN-defined UTI and use of tigecycline and aminoglycosides, infection with strain type ST258A was associated with clinical outcome in ordinal analysis (P=0.0343). In multivariate binomial models, strain type ST258A was associated with clinical failure (aOR for failure 5.82, 95% CI 1.47-28.50, P=0.0113). CONCLUSIONS: In this nested cohort study of physician-diagnosed CRKP UTI, both choice of treatment and CRKP strain type appeared to impact on clinical outcomes.

Population structure of KPC-producing Klebsiella pneumoniae isolates from midwestern U.S. hospitals.

Genome sequencing of carbapenem-resistant Klebsiella pneumoniae isolates from regional U.S. hospitals was used to characterize strain diversity and the bla(KPC) genetic context. A phylogeny based on core single-nucleotide variants (SNVs) supports a division of sequence type 258 (ST258) into two distinct groups. The primary differences between the groups are in the capsular polysaccharide locus (cps) and their plasmid contents. A strict association between clade and KPC variant was found. The bla(KPC) gene was found on variants of two plasmid backbones. This study indicates that highly similar K. pneumoniae subpopulations coexist within the same hospitals over time.

Surveillance of carbapenem-resistant Klebsiella pneumoniae: tracking molecular epidemiology and outcomes through a regional network.

Carbapenem resistance in Gram-negative bacteria is on the rise in the United States. A regional network was established to study microbiological and genetic determinants of clinical outcomes in hospitalized patients with carbapenem-resistant (CR) Klebsiella pneumoniae in a prospective, multicenter, observational study. To this end, predefined clinical characteristics and outcomes were recorded and K. pneumoniae isolates were analyzed for strain typing and resistance mechanism determination. In a 14-month period, 251 patients were included. While most of the patients were admitted from long-term care settings, 28% of them were admitted from home. Hospitalizations were prolonged and complicated. Nonsusceptibility to colistin and tigecycline occurred in isolates from 7 and 45% of the patients, respectively. Most of the CR K. pneumoniae isolates belonged to repetitive extragenic palindromic PCR (rep-PCR) types A and B (both sequence type 258) and carried either blaKPC-2 (48%) or blaKPC-3 (51%). One isolate tested positive for blaNDM-1, a sentinel discovery in this region. Important differences between strain types were noted; rep-PCR type B strains were associated with blaKPC-3 (odds ratio [OR], 294; 95% confidence interval [CI], 58 to 2,552; P < 0.001), gentamicin nonsusceptibility (OR, 24; 95% CI, 8.39 to 79.38; P < 0.001), amikacin susceptibility (OR, 11.0; 95% CI, 3.21 to 42.42; P < 0.001), tigecycline nonsusceptibility (OR, 5.34; 95% CI, 1.30 to 36.41; P = 0.018), a shorter length of stay (OR, 0.98; 95% CI, 0.95 to 1.00; P = 0.043), and admission from a skilled-nursing facility (OR, 3.09; 95% CI, 1.26 to 8.08; P = 0.013). Our analysis shows that (i) CR K. pneumoniae is seen primarily in the elderly long-term care population and that (ii) regional monitoring of CR K. pneumoniae reveals insights into molecular characteristics. This work highlights the crucial role of ongoing surveillance of carbapenem resistance determinants.

Early de-escalation of antibiotic therapy in hospitalized cellular therapy adult patients with febrile neutropenia.

Febrile neutropenia (FN) is an oncologic emergency frequently encountered in hematopoietic cell transplant (HCT) and chimeric antigen receptor (CAR) T-cell therapy patients, which requires immediate initiation of broad-spectrum antibiotics. Data regarding antibiotic de-escalation (DE) in neutropenic patients are limited, and guideline recommendations vary. A clinical protocol for antibiotic DE of broad-spectrum agents was implemented if patients were afebrile after 72 hours and had no clinical evidence of infection. The primary endpoint was the difference in the number of antibiotic therapy days between the pre-and post-DE protocol implementation group. Secondary endpoints included rates of subsequent bacteremia during index hospitalization, 30-day mortality, and hospital length of stay. Retrospective chart reviews were conducted to assess outcomes for patients who received allogeneic HCT, autologous HCT, or CAR T-cell therapy under the antibiotic de-escalation protocol (post-DE) compared to those who did not (pre-DE). The pre-DE group underwent HCT/CAR T-cell from February 2018 through September 2018 (n=64), and the post-DE group from February 2019 through September 2019 (n=67). The median duration of antibiotics was significantly lower in the post-DE group (6 days; range 3-60 days) compared to the pre-DE group (8 days; range 3-31 days) (p=0.034). There were no differences in any secondary endpoints. We conclude that antibiotic DE in neutropenic HCT or CAR T-cell therapy patients treated with broad-spectrum antibiotics for at least three days who are afebrile and without documented infection appears to be a safe and effective practice. Adopting it significantly reduces the number of days of antibiotics without compromising patient outcomes.

Global epidemiology and clinical outcomes of carbapenem-resistant Pseudomonas aeruginosa and associated carbapenemases (POP): a prospective cohort study.

BACKGROUND: Carbapenem-resistant Pseudomonas aeruginosa (CRPA) is a global threat, but the distribution and clinical significance of carbapenemases are unclear. The aim of this study was to define characteristics and outcomes of CRPA infections and the global frequency and clinical impact of carbapenemases harboured by CRPA. METHODS: We conducted an observational, prospective cohort study of CRPA isolated from bloodstream, respiratory, urine, or wound cultures of patients at 44 hospitals (10 countries) between Dec 1, 2018, and Nov 30, 2019. Clinical data were abstracted from health records and CRPA isolates were whole-genome sequenced. The primary outcome was 30-day mortality from the day the index culture was collected. We compared outcomes of patients with CRPA infections by infection type and across geographic regions and performed an inverse probability weighted analysis to assess the association between carbapenemase production and 30-day mortality. FINDINGS: We enrolled 972 patients (USA n=527, China n=171, south and central America n=127, Middle East n=91, Australia and Singapore n=56), of whom 581 (60%) had CRPA infections. 30-day mortality differed by infection type (bloodstream 21 [30%] of 69, respiratory 69 [19%] of 358, wound nine [14%] of 66, urine six [7%] of 88; p=0·0012) and geographical region (Middle East 15 [29%] of 52, south and central America 20 [27%] of 73, USA 60 [19%] of 308, Australia and Singapore three [11%] of 28, China seven [6%] of 120; p=0·0002). Prevalence of carbapenemase genes among CRPA isolates also varied by region (south and central America 88 [69%] of 127, Australia and Singapore 32 [57%] of 56, China 54 [32%] of 171, Middle East 27 [30%] of 91, USA ten [2%] of 527; p<0·0001). KPC-2 (n=103 [49%]) and VIM-2 (n=75 [36%]) were the most common carbapenemases in 211 carbapenemase-producing isolates. After excluding USA patients, because few US isolates had carbapenemases, patients with carbapenemase-producing CRPA infections had higher 30-day mortality than those with non-carbapenemase-producing CRPA infections in both unadjusted (26 [22%] of 120 vs 19 [12%] of 153; difference 9%, 95% CI 3-16) and adjusted (difference 7%, 95% CI 1-14) analyses. INTERPRETATION: The emergence of different carbapenemases among CRPA isolates in different geographical regions and the increased mortality associated with carbapenemase-producing CRPA infections highlight the therapeutic challenges posed by these organisms. FUNDING: National Institutes of Health.

Accessory Genomes Drive Independent Spread of Carbapenem-Resistant Klebsiella pneumoniae Clonal Groups 258 and 307 in Houston, TX.

Carbapenem-resistant Klebsiella pneumoniae (CRKp) is an urgent public health threat. Worldwide dissemination of CRKp has been largely attributed to clonal group (CG) 258. However, recent evidence indicates the global emergence of a CRKp CG307 lineage. Houston, TX, is the first large city in the United States with detected cocirculation of both CRKp CG307 and CG258. We sought to characterize the genomic and clinical factors contributing to the parallel endemic spread of CG258 and CG307. CRKp isolates were collected as part of the prospective, Consortium on Resistance against Carbapenems in Klebsiella and other Enterobacterales 2 (CRACKLE-2) study. Hybrid short-read and long-read genome assemblies were generated from 119 CRKp isolates (95 originated from Houston hospitals). A comprehensive characterization of phylogenies, gene transfer, and plasmid content with pan-genome analysis was performed on all CRKp isolates. Plasmid mating experiments were performed with CG307 and CG258 isolates of interest. Dissection of the accessory genomes suggested independent evolution and limited horizontal gene transfer between CG307 and CG258 lineages. CG307 contained a diverse repertoire of mobile genetic elements, which were shared with other non-CG258 K. pneumoniae isolates. Three unique clades of Houston CG307 isolates clustered distinctly from other global CG307 isolates, indicating potential selective adaptation of particular CG307 lineages to their respective geographical niches. CG307 strains were often isolated from the urine of hospitalized patients, likely serving as important reservoirs for genes encoding carbapenemases and extended-spectrum ß-lactamases. Our findings suggest parallel cocirculation of high-risk lineages with potentially divergent evolution. IMPORTANCE The prevalence of carbapenem-resistant Klebsiella pneumoniae (CRKp) infections in nosocomial settings remains a public health challenge. High-risk clones such as clonal group 258 (CG258) are particularly concerning due to their association with blaKPC carriage, which can severely complicate antimicrobial treatments. There is a recent emergence of clonal group 307 (CG307) worldwide with little understanding of how this successful clone has been able to adapt while cocirculating with CG258. We provide the first evidence of potentially divergent evolution between CG258 and CG307 with limited sharing of adaptive genes. Houston, TX, is home to the largest medical center in the world, with a large influx of domestic and international patients. Thus, our unique geographical setting, where two pandemic strains of CRKp are circulating, provides an indication of how differential accessory genome content can drive stable, endemic populations of CRKp. Pan-genomic analyses such as these can reveal unique signatures of successful CRKp dissemination, such as the CG307-associated plasmid (pCG307_HTX), and provide invaluable insights into the surveillance of local carbapenem-resistant Enterobacterales (CRE) epidemiology.

Carbapenem-Resistant Acinetobacter baumannii in U.S. Hospitals: Diversification of Circulating Lineages and Antimicrobial Resistance.

Carbapenem-resistant Acinetobacter baumannii (CRAb) is a major cause of health care-associated infections. CRAb is typically multidrug resistant, and infection is difficult to treat. Despite the urgent threat that CRAb poses, few systematic studies of CRAb clinical and molecular epidemiology have been conducted. The Study Network of Acinetobacter as a Carbapenem-Resistant Pathogen (SNAP) is designed to investigate the clinical characteristics and contemporary population structure of CRAb circulating in U.S. hospital systems using whole-genome sequencing (WGS). Analysis of the initial 120 SNAP patients from four U.S. centers revealed that CRAb remains a significant threat to hospitalized patients, affecting the most vulnerable patients and resulting in 24% all-cause 30-day mortality. The majority of currently circulating isolates belonged to ST2Pas, a part of clonal complex 2 (CC2), which is the dominant drug-resistant lineage in the United States and Europe. We identified three distinct sublineages within CC2, which differed in their antibiotic resistance phenotypes and geographic distribution. Most concerning, colistin resistance (38%) and cefiderocol resistance (10%) were common within CC2 sublineage C (CC2C), where the majority of isolates belonged to ST2Pas/ST281Ox. Additionally, we identified ST499Pas as the most common non-CC2 lineage in our study. Our findings suggest a shift within the CRAb population in the United States during the past 10 years and emphasize the importance of real-time surveillance and molecular epidemiology in studying CRAb dissemination and clinical impact. IMPORTANCE Carbapenem-resistant Acinetobacter baumannii (CRAb) constitutes a major threat to public health. To elucidate the molecular and clinical epidemiology of CRAb in the United States, clinical CRAb isolates were collected along with data on patient characteristics and outcomes, and bacterial isolates underwent whole-genome sequencing and antibiotic susceptibility phenotyping. Key findings included emergence of new sublineages within the globally predominant clonal complex 2 (CC2), increased colistin and cefiderocol resistance within one of the CC2 sublineages, and emergence of ST499Pas as the dominant non-CC2 CRAb lineage in U.S. hospitals.

Clinical outcomes and bacterial characteristics of carbapenem-resistant Klebsiella pneumoniae complex among patients from different global regions (CRACKLE-2): a prospective, multicentre, cohort study.

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.

Itraconazole vs. posaconazole for antifungal prophylaxis in patients with acute myeloid leukemia undergoing intensive chemotherapy: A retrospective study.

OBJECTIVE: The objective of this study was to compare itraconazole with posaconazole for antifungal prophylaxis in acute myeloid leukemia (AML) patients undergoing intensive chemotherapy. METHODS: Adult patients with AML received either itraconazole or posaconazole for antifungal prophylaxis while undergoing intensive chemotherapy. The primary endpoint was incidence of prophylaxis failure (change in antifungal agent due to suspected invasive fungal infection [IFI], drug intolerance, drug interaction, or adverse event). RESULTS: From February 2016 to January 2018, 90 patients were included in the itraconazole group and 45 patients in the posaconazole group. Prophylaxis failure occurred in 88% of itraconazole recipients compared with 33% of posaconazole recipients (P<0.001). The primary reason for prophylaxis failure with itraconazole was suspected IFI (58%) whereas for posaconazole, failure predominantly related to drug interaction (60%). An antifungal regimen was continued upon discharge in 47% of itraconazole recipients compared with 9% of posaconazole recipients (P<0.001). The use of breakthrough IFI diagnostic tests was not significantly different in the two groups. A larger proportion of drug concentrations were collected in the posaconazole group. CONCLUSIONS: In AML patients undergoing intensive chemotherapy, posaconazole was associated with significantly lower rates of prophylaxis failure and less need for continued antifungal therapy on discharge compared with itraconazole.