Butyrate Differentiates Permissiveness to Clostridioides difficile Infection and Influences Growth of Diverse C. difficile Isolates.

A disrupted "dysbiotic" gut microbiome engenders susceptibility to the diarrheal pathogen Clostridioides difficile by impacting the metabolic milieu of the gut. Diet, in particular the microbiota-accessible carbohydrates (MACs) found in dietary fiber, is one of the most powerful ways to affect the composition and metabolic output of the gut microbiome. As such, diet is a powerful tool for understanding the biology of C. difficile and for developing alternative approaches for coping with this pathogen. One prominent class of metabolites produced by the gut microbiome is short-chain fatty acids (SCFAs), the major metabolic end products of MAC metabolism. SCFAs are known to decrease the fitness of C. difficile in vitro, and high intestinal SCFA concentrations are associated with reduced fitness of C. difficile in animal models of C. difficile infection (CDI). Here, we use controlled dietary conditions (8 diets that differ only by MAC composition) to show that C. difficile fitness is most consistently impacted by butyrate, rather than the other two prominent SCFAs (acetate and propionate), during murine model CDI. We similarly show that butyrate concentrations are lower in fecal samples from humans with CDI than in those from healthy controls. Finally, we demonstrate that butyrate impacts growth in diverse C. difficile isolates. These findings provide a foundation for future work which will dissect how butyrate directly impacts C. difficile fitness and will lead to the development of diverse approaches distinct from antibiotics or fecal transplant, such as dietary interventions, for mitigating CDI in at-risk human populations. IMPORTANCE Clostridioides difficile is a leading cause of infectious diarrhea in humans, and it imposes a tremendous burden on the health care system. Current treatments for C. difficile infection (CDI) include antibiotics and fecal microbiota transplant, which contribute to recurrent CDIs and face major regulatory hurdles, respectively. Therefore, there is an ongoing need to develop new ways to cope with CDI. Notably, a disrupted "dysbiotic" gut microbiota is the primary risk factor for CDI, but we incompletely understand how a healthy microbiota resists CDI. Here, we show that a specific molecule produced by the gut microbiota, butyrate, is negatively associated with C. difficile burdens in humans and in a mouse model of CDI and that butyrate impedes the growth of diverse C. difficile strains in pure culture. These findings help to build a foundation for designing alternative, possibly diet-based, strategies for mitigating CDI in humans.

Predictors of Coronavirus Disease 2019 Hospitalization After Sotrovimab in Patients With Hematologic Malignancy During the BA.1 Omicron Surge.

BACKGROUND: Sotrovimab is an anti-spike neutralization monoclonal antibody developed to reduce the risk of coronavirus disease 2019 (COVID-19) progression and advancement to hospitalization in high-risk patients. Currently, there is limited research describing the association of sotrovimab treatment in patients with hematologic malignancy and the predictive factors of hospitalization. METHODS: We performed an observational study of 156 consecutive cancer patients who received sotrovimab at Memorial Sloan Kettering Cancer Center in New York City during the BA.1 Omicron surge. We evaluated the demographic, clinical, and laboratory characteristics of the patients who had subsequent COVID-19-related hospitalization(s) compared to those who did not. RESULTS: Among the 156 study patients, 17 (11%) were hospitalized, of whom 4 were readmitted for COVID-19-related complications; 3 deaths were attributed to COVID-19. Results from multivariable logistic regression show that significant factors associated with hospitalization include patients on anti-CD20 therapy (adjusted odds ratio [aOR], 5.59 [95% confidence interval {CI}, 1.73-18.12]; P = .004) and with relapse/refractory disease (aOR, 5.69 [95% CI, 1.69-19.16]; P = .005). Additionally, whole genome sequencing of severe acute respiratory syndrome coronavirus 2 detected high occurrences of mutations in the spike gene associated with treatment-related resistance longitudinal samples from 11 patients treated with sotrovimab. CONCLUSIONS: While sotrovimab is effective at reducing COVID-19 hospitalization and disease severity in patients with hematologic malignancy when administered early, patients who received anti-CD20 antibodies showed substantial morbidity. Due to the high potential for resistance mutation to sotrovimab and increased morbidity in patients on anti-CD20 therapy, combination treatment should be explored to determine whether it provides added benefits compared to monotherapy.

Predictors of SARS-CoV-2 Omicron breakthrough infection after receipt of AZD7442 (tixagevimab-cilgavimab) for pre-exposure prophylaxis among hematologic malignancy patients.

AZD7442 (tixagevimab-cilgavimab) is a combination of two human monoclonal antibodies for pre-exposure prophylaxis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection among high-risk patients who do not mount a reliable vaccine response. Foremost among these are hematologic malignancy patients with limited clinical trial or realworld experience to assess the effectiveness of this combination treatment since the emergence of Omicron and its subvariants. We performed a retrospective study of 892 high-risk hematologic malignancy patients who received AZD7442 at Memorial Sloan Kettering Cancer Center in New York City from January 1, 2022 to July 31, 2022. We evaluated demographic, clinical, and laboratory characteristics and performed regression analyses to evaluate risk factors for breakthrough infection. We also evaluated the impact of updated AZD7442 dosing regimens on the risk of breakthrough infection. Among 892 patients, 98 (10.9%) had a breakthrough infection during the study period. A majority received early outpatient treatment (82%) and eventually eight (8.2%) required hospitalization for management of Coronavirus Disease 2019 (COVID-19), with a single instance of severe COVID-19 and death. Patients who received a repeat dose or a higher firsttime dose of AZD7442 had a lower incidence of breakthrough infection. Univariate analyses did not reveal any significant predictors of breakthrough infection. While AZD7442 is effective at reducing SARS-CoV-2 breakthrough infection in patients with hematologic malignancies, no risk factors reliably predicted risk of infection. Patients who received updated dosing regimens as per Food and Drug Administration guidelines had better protection against breakthrough infection.

Cefiderocol: A New Cephalosporin Stratagem Against Multidrug-Resistant Gram-Negative Bacteria.

Cefiderocol is a novel injectable siderophore cephalosporin that hijacks the bacterial iron transport machinery to facilitate cell entry and achieve high periplasmic concentrations. It has broad in vitro activity against gram-negative bacteria, including multidrug-resistant (MDR) organisms such as carbapenem-resistant Enterobacterales, carbapenem-resistant Pseudomonas aeruginosa, and Acinetobacter baumannii. It was approved by the US Food and Drug Administration for the treatment of complicated urinary tract infections and nosocomial pneumonia based on clinical trials that demonstrated noninferiority to comparators. In this review, we summarize the available in vitro and clinical data, including recent evidence from 2 phase 3 clinical trials (APEKS-NP and CREDIBLE-CR), and discuss the place of cefiderocol in the clinician's armamentarium against MDR gram-negative infections.

Risk of Healthcare-Associated Transmission of Sever Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) in Hospitalized Cancer Patients.

BACKGROUND: There is limited information on the risk of hospital-acquired coronavirus disease 2019 (COVID-19) among high-risk hospitalized patients after exposure to an infected patient or healthcare worker (HCW) in a nonoutbreak setting. METHODS: This study was conducted at a tertiary care cancer center in New York City from 10 March 2020 until 28 February 2021. In early April 2020, the study institution implemented universal severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) testing at admission and retesting every 3 days through the hospital stay. Contact tracing records were reviewed for all exposures to SARS-CoV-2 positive patients and HCWs. RESULTS: From 10 March 2020 to 28 February 2021, 11 348 unique patients who were SARS-CoV-2 polymerase chain reaction (PCR) negative at the time of admission underwent 31 662 postadmission tests during their hospitalization, and 112 tested positive (0.98%). Among these, 49 patients housed in semiprivate rooms during admission resulted in 74 close contacts and 14 secondary infections within 14 days, for an overall attack rate of 18.9%. Among those exposed to a roommate undergoing an aerosol-generating procedure (AGP), the attack rate was 35.7%. Whole genome sequencing (WGS) corroborated transmission in 6/8 evaluated pairs. In addition, three transmission events occurred in 214 patients with significant exposure to 105 COVID-19 positive healthcare workers (1.4%). CONCLUSIONS: The overall risk of hospital-acquired COVID-19 is low for hospitalized cancer patients, even during periods of high community prevalence. However, shared occupancy with an unrecognized case is associated with a high secondary attack rate in exposed roommates.

Clinical and Genomic Characterization of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS CoV-2) Infections in mRNA Vaccinated Health Care Personnel in New York City.

BACKGROUND: Vaccine-induced clinical protection against severe acute respiratory syndrome coronavirus 2 (SARS CoV-2) variants is an evolving target. There are limited genomic level data on SARS CoV-2 breakthrough infections and vaccine effectiveness (VE) since the global spread of the B.1.617.2 (Delta) variant. METHODS: In a retrospective study from 1 November 2020 to 31 August 2021, divided as pre-Delta and Delta-dominant periods, laboratory-confirmed SARS CoV-2 infections among healthcare personnel (HCP) at a large tertiary cancer center in New York City were examined to compare the weekly infection rate-ratio in vaccinated, partially vaccinated, and unvaccinated HCP. We describe the clinical and genomic epidemiologic features of post-vaccine infections to assess for selection of variants of concern (VOC)/variants of interest (VOI) in the early post-vaccine period and impact of B.1.617.2 (Delta) variant domination on VE. RESULTS: Among 13658 HCP in our cohort, 12379 received at least 1 dose of a messenger RNA (mRNA) vaccine. In the pre-Delta period overall VE was 94.5%. Whole genome sequencing (WGS) of 369 isolates in the pre-Delta period did not reveal a clade bias for VOC/VOI specific to post-vaccine infections. VE in the Delta dominant phase was 75.6%. No hospitalizations occurred among vaccinated HCP in the entire study period, compared to 17 hospitalizations and 1 death among unvaccinated HCP. CONCLUSIONS: Findings show high VE among HCP in New York City in the pre-Delta phase, with moderate decline in VE post-Delta emergence. SARS CoV-2 clades were similarly distributed among vaccinated and unvaccinated infected HCP without apparent clustering during the pre-Delta period of diverse clade circulation. Strong vaccine protection against hospitalization was maintained through the entire study period.

Severe Acute Respiratory Syndrome Coronavirus 2 Surveillance and Exposure in the Perioperative Setting With Universal Testing and Personal Protective Equipment Policies.

BACKGROUND: New York City (NYC) experienced a surge of coronavirus disease 2019 (COVID-19) cases in March and April 2020. Since then, universal polymerase chain reaction (PCR)-based surveillance testing and personal protective equipment (PPE) measures are in wide use in procedural settings. There is limited published experience on the utility and sustainability of PCR-based surveillance testing in areas with receding and consistently low community COVID-19 rates. METHODS: The study was conducted at a tertiary care cancer center in NYC from 22 March to 22 August 2020. Asymptomatic patients underwent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) testing before surgeries, interventional radiology procedures, and endoscopy. Contact tracing in procedural areas was done if a patient with an initial negative screen retested positive within 48 hours of the procedure. RESULTS: From March 22 until August 22, 2020, 11 540 unique patients underwent 14 233 tests before surgeries or procedures at Memorial Sloan Kettering Cancer Center. Overall, 65 patients were positive, with a peak rate of 4.3% that fell below 0.3% after April 2020. Among the 65 positive cases, 3 were presymptomatic and 38 were asymptomatic. Among asymptomatic test-positive patients, 76% had PCR cycle threshold >30 at first detection. Five patients tested newly positive in the immediate postoperative period, exposing 82 employees with 1 case of probable transmission (1.2%). CONCLUSIONS: The prevalence of SARS-CoV-2 infection identified on preprocedural surveillance was low in our study, which was conducted in an area with limited community spread at the later stage of the study. Universal PPE is protective in procedural settings. Optimal and flexible diagnostic strategies are needed to accomplish and sustain the goals of comprehensive preprocedure surveillance testing.

Protective Factors in the Intestinal Microbiome Against Clostridium difficile Infection in Recipients of Allogeneic Hematopoietic Stem Cell Transplantation.

Background: Clostridium difficile infection (CDI) is a frequent complication in recipients of allogeneic hematopoietic stem cell transplantation (allo-HSCT), who receive intensive treatments that significantly disrupt the intestinal microbiota. In this study, we examined the microbiota composition of allo-HSCT recipients to identify bacterial colonizers that confer protection against CDI after engraftment. Methods: Feces collected from adult recipients allo-HSCT at engraftment were analyzed; 16S ribosomal RNA genes were sequenced and analyzed from each sample. Bacterial taxa with protective effects against development of CDI were identified by means of linear discriminant analysis effect size analysis and then further assessed with clinical predictors of CDI using survival analysis. Results: A total of 234 allo-HSCT recipients were studied; postengraftment CDI developed in 53 (22.6%). Within the composition of the microbiota, the presence of 3 distinct bacterial taxa was correlated with protection against CDI: Bacteroidetes, Lachnospiraceae, and Ruminococcaceae. Colonization with these groups at engraftment was associated with a 60% lower risk of CDI, independent of clinical factors. Conclusions: Colonization with these 3 bacterial groups is associated with a lower risk of CDI. These groups have been shown to be vital components of the intestinal microbiota. Targeted efforts to maintain them may help minimize the risk of CDI in this at-risk population.

Feasibility and applicability of antimicrobial stewardship in immunocompromised patients.

PURPOSE OF REVIEW: Antimicrobial stewardship is the primary intervention in the battle against antimicrobial resistance, but clinicians do not always apply many key antimicrobial stewardship principles to patients with significant immune defects due to lack of data and fear of bad outcomes. We review evidence regarding the application of stewardship principles to immunocompromised patients, with a focus on solid organ and hematopoietic stem cell transplant recipients. RECENT FINDINGS: Antimicrobial stewardship programs (ASPs), targeting immunocompromised patient populations such as oncology and transplant, are gaining traction. Emerging literature suggests that several stewardship interventions can be adapted to immunocompromised hosts and improve antimicrobial utilization, but data supporting improved outcomes is very limited. SUMMARY: The application of antimicrobial stewardship principles to immunocompromised patients is feasible, necessary, and urgent. As antimicrobial stewardship programs gain momentum across a diverse range of healthcare settings more immunocompromised patients will fall under their purview. It is imperative that centers applying antimicrobial stewardship principles share their experience and establish collaborative research efforts to advance our knowledge base in applying antimicrobial stewardship initiatives to immunocompromised host populations, both in terms of programmatic success and patient outcomes.

Norovirus.

Norovirus, an RNA virus of the family Caliciviridae, is a human enteric pathogen that causes substantial morbidity across both health care and community settings. Several factors enhance the transmissibility of norovirus, including the small inoculum required to produce infection (<100 viral particles), prolonged viral shedding, and its ability to survive in the environment. In this review, we describe the basic virology and immunology of noroviruses, the clinical disease resulting from infection and its diagnosis and management, as well as host and pathogen factors that complicate vaccine development. Additionally, we discuss overall epidemiology, infection control strategies, and global reporting efforts aimed at controlling this worldwide cause of acute gastroenteritis. Prompt implementation of infection control measures remains the mainstay of norovirus outbreak management.

Integration of whole-genome sequencing into infection control practices: the potential and the hurdles.

Microbial whole-genome sequencing (WGS) is poised to transform many of the currently used approaches in medical microbiology. Recent reports on the application of WGS to understand genetic evolution and reconstruct transmission pathways have provided valuable information that will influence infection control practices. While this technology holds great promise, obstacles to full implementation remain. Two articles in this issue of the Journal of Clinical Microbiology (S. Octavia, Q. Wang, M. M. Tanaka, S. Kaur, V. Sintchenko, and R. Lan, J Clin Microbiol 53:1063-1071, 2015, doi:10.1128/JCM.03235-14, and S. J. Salipante, D. J. SenGupta, L. A. Cummings, T. A. Land, D. R. Hoogestraat, and B. T. Cookson, J Clin Microbiol 53:1072-1079, 2015, doi:10.1128/JCM.03385-14) describe the breadth of application of WGS to the field of clinical epidemiology.

Economic evaluation of laboratory testing strategies for hospital-associated Clostridium difficile infection.

Clostridium difficile infection (CDI) is the most common cause of infectious diarrhea in health care settings, and for patients presumed to have CDI, their isolation while awaiting laboratory results is costly. Newer rapid tests for CDI may reduce this burden, but the economic consequences of different testing algorithms remain unexplored. We used decision analysis from the hospital perspective to compare multiple CDI testing algorithms for adult inpatients with suspected CDI, assuming patient management according to laboratory results. CDI testing strategies included combinations of on-demand PCR (odPCR), batch PCR, lateral-flow diagnostics, plate-reader enzyme immunoassay, and direct tissue culture cytotoxicity. In the reference scenario, algorithms incorporating rapid testing were cost-effective relative to nonrapid algorithms. For every 10,000 symptomatic adults, relative to a strategy of treating nobody, lateral-flow glutamate dehydrogenase (GDH)/odPCR generated 831 true-positive results and cost $1,600 per additional true-positive case treated. Stand-alone odPCR was more effective and more expensive, identifying 174 additional true-positive cases at $6,900 per additional case treated. All other testing strategies were dominated by (i.e., more costly and less effective than) stand-alone odPCR or odPCR preceded by lateral-flow screening. A cost-benefit analysis (including estimated costs of missed cases) favored stand-alone odPCR in most settings but favored odPCR preceded by lateral-flow testing if a missed CDI case resulted in less than $5,000 of extended hospital stay costs and <2 transmissions, if lateral-flow GDH diagnostic sensitivity was >93%, or if the symptomatic carrier proportion among the toxigenic culture-positive cases was >80%. These results can aid guideline developers and laboratory directors who are considering rapid testing algorithms for diagnosing CDI.

Biosafety and biohazard considerations of HSV-1-based oncolytic viral immunotherapy.

Oncolytic viral immunotherapies are agents which can directly kill tumor cells and activate an immune response. Oncolytic viruses (OVs) range from native/unmodified viruses to genetically modified, attenuated viruses with the capacity to preferentially replicate in and kill tumors, leaving normal tissue unharmed. Talimogene laherparepvec (T-VEC) is the only OV approved for patient use in the United States; however, during the last 20 years, there have been a substantial number of clinical trials using OV immunotherapies across a broad range of cancers. Like T-VEC, many OV immunotherapies in clinical development are based on the herpes simplex virus type 1 (HSV-1), with genetic modifications for tumor selectivity, safety, and immunogenicity. Despite these modifications, HSV-1 OV immunotherapies are often treated with the same biosafety guidelines as the wild-type virus, potentially leading to reduced patient access and logistical hurdles for treatment centers, including community treatment centers and small group or private practices, and healthcare workers. Despite the lack of real-world evidence documenting possible transmission to close contacts, and in the setting of shedding and biodistribution analyses for T-VEC demonstrating limited infectivity and low risk of spread to healthcare workers, barriers to treatment with OV immunotherapies remain. With comprehensive information and educational programs, our hope is that updated biosafety guidance on OV immunotherapies will reduce logistical hurdles to ensure that patients have access to these innovative and potentially life-saving medicines across treatment settings. This work reviews a comprehensive collection of data in conjunction with the opinions of the authors based on their clinical experience to provide the suggested framework and key considerations for implementing biosafety protocols for OV immunotherapies, namely T-VEC, the only approved agent to date.

Comparison of coronavirus disease 2019 (COVID-19) symptoms at diagnosis among healthcare personnel before and after the emergence of the omicron variant.

We used a self-reporting system to compare symptom frequency of hospital personnel with coronavirus disease 2019 before and after the emergence of the Omicron variant. Omicron was more likely to result in asymptomatic carriage (7% vs 12%; P = .009), and fewer symptoms were observed in those with booster vaccination.

COVID-19 severity and cardiovascular outcomes in SARS-CoV-2-infected patients with cancer and cardiovascular disease.

Background: Data regarding outcomes among patients with cancer and co-morbid cardiovascular disease (CVD)/cardiovascular risk factors (CVRF) after SARS-CoV-2 infection are limited. Objectives: To compare Coronavirus disease 2019 (COVID-19) related complications among cancer patients with and without co-morbid CVD/CVRF. Methods: Retrospective cohort study of patients with cancer and laboratory-confirmed SARS-CoV-2, reported to the COVID-19 and Cancer Consortium (CCC19) registry from 03/17/2020 to 12/31/2021. CVD/CVRF was defined as established CVD or no established CVD, male ≥ 55 or female ≥ 60 years, and one additional CVRF. The primary endpoint was an ordinal COVID-19 severity outcome including need for hospitalization, supplemental oxygen, intensive care unit (ICU), mechanical ventilation, ICU or mechanical ventilation plus vasopressors, and death. Secondary endpoints included incident adverse CV events. Ordinal logistic regression models estimated associations of CVD/CVRF with COVID-19 severity. Effect modification by recent cancer therapy was evaluated. Results: Among 10,876 SARS-CoV-2 infected patients with cancer (median age 65 [IQR 54-74] years, 53% female, 52% White), 6253 patients (57%) had co-morbid CVD/CVRF. Co-morbid CVD/CVRF was associated with higher COVID-19 severity (adjusted OR: 1.25 [95% CI 1.11-1.40]). Adverse CV events were significantly higher in patients with CVD/CVRF (all p<0.001). CVD/CVRF was associated with worse COVID-19 severity in patients who had not received recent cancer therapy, but not in those undergoing active cancer therapy (OR 1.51 [95% CI 1.31-1.74] vs. OR 1.04 [95% CI 0.90-1.20], pinteraction <0.001). Conclusions: Co-morbid CVD/CVRF is associated with higher COVID-19 severity among patients with cancer, particularly those not receiving active cancer therapy. While infrequent, COVID-19 related CV complications were higher in patients with comorbid CVD/CVRF. (COVID-19 and Cancer Consortium Registry [CCC19]; NCT04354701).

The spike gene target failure (SGTF) genomic signature is highly accurate for the identification of Alpha and Omicron SARS-CoV-2 variants.

The Alpha (B.1.1.7) and Omicron (B.1.1.529, BA.1, BA.4 and BA.5) variants of concern (VOC) share several mutations in their spike gene, including mutations resulting in the deletion of two amino acids at position 69 and 70 (del 69-70) in the Spike protein. Del 69-70 causes failure to detect the S gene target on a widely used, commercial test, the TaqPath SARS-CoV-2 RT-PCR (Thermo Fisher). The S gene target failure (SGTF) signature has been used to preliminarily infer the presence of Alpha and Omicron VOC. We evaluated the accuracy of the SGTF signature in identifying these two variants through analysis of all positive SARS-CoV-2 samples tested on the TaqPath RT-PCR and sequenced by next generation sequencing between December 2020 to July 2022. 2324 samples were successfully sequenced including 914 SGTF positive samples. The sensitivity and specificity of the SGTF signature was 99.6% (95% CI 96.1-99.9%) and 98.6% (95% CI 99.2-99.8%) for the Alpha variant and 99.6% (95% CI 98.9-99.9%) and 99.8% (95% CI 99.4-99.9%) for the Omicron variant. At the peak of their corresponding wave, the positive predictive value of the SGTF was 98% for Alpha and 100% for Omicron. The accuracy of the SGTF signature was high, making this genomic signature a rapid and accurate proxy for identification of these variants in real-world laboratory settings.

Variable duration of viral shedding in cancer patients with coronavirus disease 2019 (COVID-19).

In this retrospective study of 105 severe acute respiratory coronavirus virus 2 (SARS-CoV-2)-infected cancer patients with longitudinal nasopharyngeal sampling, the duration of viral shedding and time to attain cycle threshold >30 was longer in patients with hematologic malignancy than in those with solid tumors. These findings have important public health implications.

Effectiveness of MRNA booster vaccine among healthcare workers in New York City during the Omicron surge, December 2021 to January 2022.

OBJECTIVE: To describe effectiveness of mRNA vaccines by comparing 2-dose (2D) and 3-dose (3D) healthcare worker (HCW) recipients in the setting of Omicron variant dominance. Performance of 2D and 3D vaccine series against SARS-CoV-2 variants and the clinical outcomes of HCWs may inform return-to-work guidance. METHODS: In a retrospective study from December 15, 2020 to January 15, 2022, SARS-CoV-2 infections among HCWs at a large tertiary cancer centre in New York City were examined to estimate infection rates (aggregated positive tests / person-days) and 95% CIs over the Omicron period in 3D and 2D mRNA vaccinated HCWs and were compared using rate ratios. We described the clinical features of post-vaccine infections and impact of prior (pre-Omicron) COVID infection on vaccine effectiveness. RESULTS: Among the 20857 HCWs in our cohort, 20,660 completed the 2D series with an mRNA vaccine during our study period and 12461 had received a third dose by January 15, 2022. The infection rate ratio for 3D versus 2D vaccinated HCWs was 0.667 (95% CI 0.623, 0.713) for an estimated 3D vaccine effectiveness of 33.3% compared to two doses only during the Omicron dominant period from December 15, 2021 to January 15, 2022. Breakthrough Omicron infections after 3D + 14 days occurred in 1,315 HCWs. Omicron infections were mild, with 16% of 3D and 11% 2D HCWs being asymptomatic. DISCUSSION: Study demonstrates improved vaccine-derived protection against COVID-19 infection in 3D versus 2D mRNA vaccinees during the Omicron surge. The advantage of 3D vaccination was maintained irrespective of prior COVID-19 infection status.

Coinfections in Patients With Cancer and COVID-19: A COVID-19 and Cancer Consortium (CCC19) Study.

BACKGROUND: The frequency of coinfections and their association with outcomes have not been adequately studied among patients with cancer and coronavirus disease 2019 (COVID-19), a high-risk group for coinfection. METHODS: We included adult (≥18 years) patients with active or prior hematologic or invasive solid malignancies and laboratory-confirmed severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) infection, using data from the COVID-19 and Cancer Consortium (CCC19, NCT04354701). We captured coinfections within ±2 weeks from diagnosis of COVID-19, identified factors cross-sectionally associated with risk of coinfection, and quantified the association of coinfections with 30-day mortality. RESULTS: Among 8765 patients (hospitalized or not; median age, 65 years; 47.4% male), 16.6% developed coinfections: 12.1% bacterial, 2.1% viral, 0.9% fungal. An additional 6.4% only had clinical diagnosis of a coinfection. The adjusted risk of any coinfection was positively associated with age >50 years, male sex, cardiovascular, pulmonary, and renal comorbidities, diabetes, hematologic malignancy, multiple malignancies, Eastern Cooperative Oncology Group Performance Status, progressing cancer, recent cytotoxic chemotherapy, and baseline corticosteroids; the adjusted risk of superinfection was positively associated with tocilizumab administration. Among hospitalized patients, high neutrophil count and C-reactive protein were positively associated with bacterial coinfection risk, and high or low neutrophil count with fungal coinfection risk. Adjusted mortality rates were significantly higher among patients with bacterial (odds ratio [OR], 1.61; 95% CI, 1.33-1.95) and fungal (OR, 2.20; 95% CI, 1.28-3.76) coinfections. CONCLUSIONS: Viral and fungal coinfections are infrequent among patients with cancer and COVID-19, with the latter associated with very high mortality rates. Clinical and laboratory parameters can be used to guide early empiric antimicrobial therapy, which may improve clinical outcomes.