Nationwide Outbreak of Candida auris Infections Driven by COVID-19 Hospitalizations, Israel, 2021-2022

We report an outbreak of Candida auris across multiple healthcare facilities in Israel. For the period of May 2014-May 2022, a total of 209 patients with C. auris infection or colonization were identified. The C. auris incidence rate increased 30-fold in 2021 (p = 0.00015), corresponding in time with surges of COVID-19-related hospitalization. Multilocus sequence typing revealed hospital-level outbreaks with distinct clones. A clade III clone, imported into Israel in 2016, accounted for 48.8% of typed isolates after January 2021 and was more frequently resistant to fluconazole (100% vs. 63%; p = 0.00017) and voriconazole (74% vs. 5.2%; p<0.0001) than were non-clade III isolates. A total of 23% of patients had COVID-19, and 78% received mechanical ventilation. At the hospital level, outbreaks initially involved mechanically ventilated patients in specialized COVID-19 units and then spread sequentially to ventilated non-COVID-19 patients and nonventilated patients.

Exposure to Non-Antimicrobial Drugs and Risk of Infection with Antibiotic-Resistant Enterobacteriaceae.

Antimicrobial resistance (AMR) has consistently been linked to antibiotic use. However, the roles of commonly prescribed non-antimicrobial drugs as drivers of AMR may be under-appreciated. Here, we studied a cohort of patients with community-acquired pyelonephritis and assessed the association of exposure to non-antimicrobial drugs at the time of hospital admission with infection with drug-resistant organisms (DRO). Associations identified on bivariate analyses were tested using a treatment effects estimator that models both outcome and treatment probability. Exposure to proton-pump inhibitors, beta-blockers, and antimetabolites was significantly associated with multiple resistance phenotypes. Clopidogrel, selective serotonin reuptake inhibitors, and anti-Xa agents were associated with single-drug resistance phenotypes. Antibiotic exposure and indwelling urinary catheters were covariates associated with AMR. Exposure to non-antimicrobial drugs significantly increased the probability of AMR in patients with no other risk factors for resistance. Non-antimicrobial drugs may affect the risk of infection with DRO through multiple mechanisms. If corroborated using additional datasets, these findings offer novel directions for predicting and mitigating AMR.

Diagnosis of Monkeypox infection: Validation of two diagnostic kits for viral detection using RT-PCR.

Monkeypox virus, a zoonotic Orthopox DNA virus was rarely reported outside of African regions until April 2022. Since then, thousands of cases have been reported worldwide. In order to cope with the increasing need for laboratory diagnosis, the availability of reliable commercial PCR assays is of paramount importance. In this study we compared the diagnostic performance of two commercial real-time (RT)-PCR assays, the Novaplex™ MPXV Assay and the Bio-Speedy® Monkeypox Virus qPCR Kit, for the detection of Monkeypox virus (MPXV) DNA from 154 human samples. These assays were compared to a recently published in-house assay that included a general MPXV target (G2T) and a West African specific target (genericWA). All assays demonstrated 100% specificity. While sensitivity of the Novpalex assay was 100% the sensitivity of the other assays was lower; 94% for the Bio-speedy assay and G2R assay and 88% for the genericWA assay. The sensitivity differences between the methods manifested almost entirely in those pharyngeal samples in which the Ct values were high (≥35). The Novaplex™ MPXV Assay showed higher Ct values compared with the other methods with a median of 27.1 compared with the Bio-Speedy assay (median 15.8, p < 0.001), the G2R assay (median 23.5, p < 0.001) and the genericWA assay (median 23.6, p < 0.001). For all 4 methods, the Ct values were higher in samples taken from oropharynx compared with samples from rectal and pustule swabs.

Hospitalized Patients With Severe Coronavirus Disease 2019 During the Omicron Wave in Israel: Benefits of a Fourth Vaccine Dose.

BACKGROUND: Waning immunity and an increased incidence of coronavirus disease 2019 (COVID-19) during the Omicron outbreak led the Israeli Ministry of Health to recommend a fourth vaccine dose for high-risk individuals. In this study, we assessed its effect for hospitalized patients with severe breakthrough COVID-19. METHODS: In this multicenter cohort study of hospitalized adults with severe COVID-19 in Israel, from 15 to 31 January 2022, cases were divided according to the number of vaccinations received. Poor outcome was defined as mechanical ventilation or in-hospital death and was compared between 3- and 4-dose vaccinees using logistic regression. RESULTS: Included were 1049 patients, median age 80 years. Among them, 394 were unvaccinated, 386 and 88 had received 3 or 4 doses, respectively. The 3-dose group was older, included more males, and immunosuppressed patients but with similar outcomes, 49% vs 51% compared with unvaccinated patients (P = .72). Patients who received 4 doses were similarly older and immunosuppressed but had better outcomes compared with unvaccinated patients, 34% vs 51% (P < .01). We examined independent predictors for poor outcome in patients who received either 3 or 4 doses a median of 161 days or 14 days before diagnosis, respectively. Receipt of the fourth dose was associated with protection (odds ratio, 0.51; 95% confidence interval, .3-.87), as was remdesivir. Male sex, chronic renal failure, and dementia were associated with poor outcomes. CONCLUSIONS: Among hospitalized patients with severe breakthrough COVID-19, a recent fourth dose was associated with significant protection against mechanical ventilation or death compared with 3 doses.

Invasive Fungal Diseases in Hospitalized Patients with COVID-19 in Israel: A Multicenter Cohort Study.

Highly variable estimates of COVID-19-associated fungal diseases (IFDs) have been reported. We aimed to determine the incidence of clinically important fungal diseases in hospitalized COVID-19 patients during the first year of the pandemic. We performed a multicenter survey of IFDs among patients hospitalized with COVID-19 in 13 hospitals in Israel between February 2020 and May 2021. COVID-19-associated pulmonary mold disease (PMD) and invasive candidiasis (IC) were defined using ECMM/ISHAM and EORTC/MSG criteria, respectively. Overall rates of IC and PMD among patients with critical COVID-19 were 10.86 and 10.20 per 1000 admissions, respectively, with significant variability among medical centers. PMD rates were significantly lower in centers where galactomannan was a send-out test versus centers with on-site testing (p = 0.035). The 30-day mortality rate was 67.5% for IC and 57.5% for PMD. Treatment with an echinocandin for IC or an extended-spectrum azole for PMD was associated with significantly lower mortality rates (adjusted hazard ratio [95% confidence interval], 0.26 [0.07-0.91] and 0.23 [0.093-0.57], respectively). In this multicenter national survey, variable rates of PMD were associated with on-site galactomannan testing, suggesting under-detection in sites lacking this capacity. COVID-19-related IFDs were associated with high mortality rates, which were reduced with appropriate antifungal therapy.

Hospitalised patients with breakthrough COVID-19 following vaccination during two distinct waves in Israel, January to August 2021: a multicentre comparative cohort study.

BackgroundChanging patterns of vaccine breakthrough can clarify vaccine effectiveness.AimTo compare breakthrough infections during a SARS-CoV-2 Delta wave vs unvaccinated inpatients, and an earlier Alpha wave.MethodsIn an observational multicentre cohort study in Israel, hospitalised COVID-19 patients were divided into three cohorts: breakthrough infections in Comirnaty-vaccinated patients (VD; Jun-Aug 2021) and unvaccinated cases during the Delta wave (ND) and breakthrough infections during an earlier Alpha wave (VA; Jan-Apr 2021). Primary outcome was death or ventilation.ResultsWe included 343 VD, 162 ND and 172 VA patients. VD were more likely older (OR: 1.06; 95% CI: 1.05-1.08), men (OR: 1.6; 95% CI: 1.0-2.5) and immunosuppressed (OR: 2.5; 95% CI: 1.1-5.5) vs ND. Median time between second vaccine dose and admission was 179 days (IQR: 166-187) in VD vs 41 days (IQR: 28-57.5) in VA. VD patients were less likely to be men (OR: 0.6; 95% CI: 0.4-0.9), immunosuppressed (OR: 0.3; 95% CI: 0.2-0.5) or have congestive heart failure (OR: 0.6; 95% CI: 0.3-0.9) vs VA. The outcome was similar between all cohorts and affected by age and immunosuppression and not by vaccination, variant or time from vaccination.ConclusionsVaccination was protective during the Delta variant wave, as suggested by older age and greater immunosuppression in vaccinated breakthrough vs unvaccinated inpatients. Nevertheless, compared with an earlier post-vaccination period, breakthrough infections 6 months post-vaccination occurred in healthier patients. Thus, waning immunity increased vulnerability during the Delta wave, which suggests boosters as a countermeasure.

Frequency and Clinical Features of Candida Bloodstream Infection Originating in the Urinary Tract.

The urinary tract is considered an uncommon source of Candida bloodstream infection (CBSI). We aimed to determine the source of CBSI in hospitalized patients, and to compare clinical and microbiological features of CBSI originating in the urinary tract (U-CBSI) and non-urinary CBSI (NU-CBSI). Of 134 patients with CBSI, 28 (20.8%) met criteria for U-CBSI, 34 (25.3%) had vascular catheter-related CBSI and 21 (15.6%) had a gastrointestinal origin. Compared to NU-CBSI patients, patients with U-CBSI were older with higher rates of dementia. Bladder catheterization for urinary retention and insertion of ureteral stents or nephrostomies were risk factors for U-CBSI. Fifty percent of U-CBSI cases occurred within 48 h of hospital admission, versus 16.9% of NU-CBSI (p < 0.0001). The mortality rate was lowest for CBSI originating in the urinary tract and highest for CBSI of undetermined origin. CBSI of undetermined origin remained associated with higher mortality in a Cox regression model that included age, Candida species, Pitt bacteremia score and neutropenia as explanatory variables. U-CBSI may be increasing in frequency, reflecting extensive use of bladder catheters and urologic procedures in elderly debilitated patients. Distinct clinical features are relevant to the diagnosis, treatment and prevention of U-CBSI.

Association of a Third Dose of BNT162b2 Vaccine With Incidence of SARS-CoV-2 Infection Among Health Care Workers in Israel.

Importance: Administration of a BNT162b2 booster dose (Pfizer-BioNTech) to fully vaccinated individuals aged 60 years and older was significantly associated with lower risk of SARS-CoV-2 infection and severe illness. Data are lacking on the effectiveness of booster doses for younger individuals and health care workers. Objective: To estimate the association of a BNT162b2 booster dose with SARS-CoV-2 infections among health care workers who were previously vaccinated with a 2-dose series of BNT162b2. Design, Setting, and Participants: This was a prospective cohort study conducted at a tertiary medical center in Tel Aviv, Israel. The study cohort included 1928 immunocompetent health care workers who were previously vaccinated with a 2-dose series of BNT162b2, and had enrolled between August 8 and 19, 2021, with final follow-up reported through September 20, 2021. Screening for SARS-CoV-2 infection was performed every 14 days. Anti-spike protein receptor binding domain IgG titers were determined at baseline and 1 month after enrollment. Cox regression with time-dependent analysis was used to estimate hazard ratios of SARS-CoV-2 infection between booster-immunized status and 2-dose vaccinated (booster-nonimmunized) status. Exposures: Vaccination with a booster dose of BNT162b2 vaccine. Main Outcomes and Measures: The primary outcome was SARS-CoV-2 infection, as confirmed by reverse transcriptase-polymerase chain reaction. Results: Among 1928 participants, the median age was 44 years (IQR, 36-52 years) and 1381 were women (71.6%). Participants completed the 2-dose vaccination series a median of 210 days (IQR, 205-213 days) before study enrollment. A total of 1650 participants (85.6%) received the booster dose. During a median follow-up of 39 days (IQR, 35-41 days), SARS-CoV-2 infection occurred in 44 participants (incidence rate, 60.2 per 100 000 person-days); 31 (70.5%) were symptomatic. Five SARS-CoV-2 infections occurred in booster-immunized participants and 39 in booster-nonimmunized participants (incidence rate, 12.8 vs 116 per 100 000 person-days, respectively). In a time-dependent Cox regression analysis, the adjusted hazard ratio of SARS-CoV-2 infection for booster-immunized vs booster-nonimmunized participants was 0.07 (95% CI, 0.02-0.20). Conclusions and Relevance: Among health care workers at a single center in Israel who were previously vaccinated with a 2-dose series of BNT162b2, administration of a booster dose compared with not receiving one was associated with a significantly lower rate of SARS-CoV-2 infection over a median of 39 days of follow-up. Ongoing surveillance is required to assess durability of the findings.

BNT162b2 vaccine breakthrough: clinical characteristics of 152 fully vaccinated hospitalized COVID-19 patients in Israel.

OBJECTIVES: The mRNA coronavirus disease 2019 (COVID-19) vaccines have shown high effectiveness in the prevention of symptomatic COVID-19, hospitalization, severe disease and death. Nevertheless, a minority of vaccinated individuals might become infected and experience significant morbidity. Characteristics of vaccine breakthrough infections have not been studied. We sought to portray the population of Israeli patients, who were hospitalized with COVID-19 despite full vaccination. METHODS: A retrospective multicentre cohort study of 17 hospitals included patients fully vaccinated with Pfizer/BioNTech's BNT162b2 vaccine who developed COVID-19 more than 7 days after the second vaccine dose and required hospitalization. The risk for poor outcome, defined as a composite of mechanical ventilation or death, was assessed. RESULTS: A total of 152 patients were included, accounting for half of hospitalized fully vaccinated patients in Israel. Poor outcome was noted in 38 patients and mortality rate reached 22% (34/152). Notably, the cohort was characterized by a high rate of co-morbidities predisposing to severe COVID-19, including hypertension (108; 71%), diabetes (73; 48%), congestive heart failure (41; 27%), chronic kidney and lung diseases (37; 24% each), dementia (29; 19%) and cancer (36; 24%), and only six (4%) had no co-morbidities. Sixty (40%) of the patients were immunocompromised. Higher viral load was associated with a significant risk for poor outcome. Risk also appeared higher in patients receiving anti-CD20 treatment and in patients with low titres of anti-Spike IgG, but these differences did not reach statistical significance. CONCLUSIONS: We found that severe COVID-19 infection, associated with a high mortality rate, might develop in a minority of fully vaccinated individuals with multiple co-morbidities. Our patients had a higher rate of co-morbidities and immunosuppression compared with previously reported non-vaccinated hospitalized individuals with COVID-19. Further characterization of this vulnerable population may help to develop guidance to augment their protection, either by continued social distancing, or by additional active or passive vaccinations.

Effectiveness and safety of an institutional aminoglycoside-based regimen as empirical treatment of patients with pyelonephritis.

OBJECTIVES: To determine clinical outcomes associated with aminoglycosides versus other antimicrobial agents as empirical treatment of hospitalized patients with pyelonephritis. PATIENTS AND METHODS: An institutional programme promoting aminoglycosides as empirical treatment of pyelonephritis was implemented in 2016. We reviewed the hospital records of patients with pyelonephritis from January 2017 to April 2019. The primary outcome was death within 30 days of index culture. Initial treatment with aminoglycoside-based regimens was compared with non-aminoglycoside antibiotics. Propensity score matching was performed to adjust for between-group differences in baseline covariates. RESULTS: The study cohort included 2026 patients, 715 treated with aminoglycosides and 1311 treated with non-aminoglycoside drugs (ceftriaxone, n = 774; piperacillin/tazobactam, n = 179; carbapenems, n = 161; and fluoroquinolones, n = 133); 589 patients (29%) had bloodstream infections. Treatment with aminoglycosides was associated with a higher likelihood of in vitro activity against clinical isolates (OR = 2.0; P < 0.001). Death at 30 days occurred in 55 (7.6%) versus 145 (11%) patients treated with aminoglycosides and non-aminoglycoside drugs, respectively (adjusted HR = 0.78; P = 0.013). Aminoglycosides were either superior or similar to comparator drugs in all patient subgroups, stratified according to age, glomerular filtration rate, bacteraemia, haemodynamic shock and infection with third-generation cephalosporin-resistant Enterobacteriaceae. The incidence of acute kidney injury was similar for aminoglycosides and comparators (2.5% versus 2.9%, respectively; P = 0.6). CONCLUSIONS: Within the context of an institutional programme, initial empirical treatment of pyelonephritis with aminoglycosides was associated with higher rates of in vitro activity and lower overall mortality compared with non-aminoglycoside drugs, without excess nephrotoxicity.

HbA1c Levels and Long-Term Mortality in Patients Undergoing Coronary Angiography.

OBJECTIVES: Previous studies investigating the prognostic value of HbA1c in patients undergoing coronary angiography reported a mixed pattern of results. Therefore, we aimed to better define the prognostic power of HbA1c among coronary catheterized patients. METHODS: Patients undergoing coronary angiography (n = 3,749) were divided into four groups according to HbA1c levels (<5, 5-6, 6-7 and >7%). Cox regression models assessed long-term mortality after adjusting for multiple covariates. RESULTS: Baseline clinical profiles differed in HbA1c groups, with a higher prevalence of comorbidities in the groups with higher HbA1c levels. Median follow-up was 1,745 days (interquartile range 1,007-2,171). A J-shaped association curve was observed between HbA1c levels and all-cause mortality rates, with patients in the lowest and highest HbA1c groups suffering from significantly higher mortality rates compared to in-between groups (hazard ratio 1.9, 95% CI 1.32-2.74, p = 0.001, and hazard ratio 1.58, 95% CI 1.29-1.95, p < 0.001, for the lowest and highest HbA1c groups, respectively). This association persisted after adjustment for anemia, nutritional status, renal function, cardiovascular risk factors and inflammatory biomarkers. CONCLUSIONS: HbA1c levels <5 or >7% are predictors of all-cause mortality in patients undergoing coronary angiography.

Immunisation led to a major reduction in paediatric patients hospitalised because of the varicella infection in Israel.

AIM: The varicella-zoster virus causes infections that are often mild but can cause substantial morbidity and mortality in otherwise healthy children. We examined trends in varicella-related hospitalisations before and after the implementation of a national two-dose varicella vaccination programme in Israel in September 2008. METHODS: This retrospective chart review, performed at three tertiary care paediatric hospitals in greater Tel Aviv, compared data from 2004 to 2008 and 2009 to 2012, before and after the varicella programme was launched. It included all children to the age of 18 who were hospitalised for conditions associated with the varicella infection. RESULTS: After the vaccination programme was introduced, the number of children hospitalised for varicella fell by 63% (p < 0.5), from 38.9 to 14.5 per 10 000, and there was a 75% reduction in children aged one to six. During the same period, the percentage of hospitalised children who were immunocompromised rose from 9.7% to 18.4% (p < 0.05). The most common complications were soft-tissue infections (60%), and the most prevalent pathogens were Group A ß-haemolytic streptococcus (53%) and Staphylococcus aureus (32%). CONCLUSION: The introduction of a two-dose immunisation programme dramatically decreased the varicella burden in Israel, leading to a major reduction in hospitalisation admissions linked to the infection.

High red blood cell distribution width is associated with the metabolic syndrome.

OBJECTIVES: High values of Red Blood Cell Distribution Width (RDW) have been associated with adverse outcome in various clinical settings. The mechanism behind this association is not clear. The Metabolic Syndrome (MetS) is a chronic inflammatory disorder that increases the risk for cardiovascular disease and death. The aim of our study was to evaluate the association between high RDW and the MetS in a relatively large cohort of patients. METHODS: A cohort of 3,529 consecutive patients undergoing coronary angiography was used to evaluate the association between RDW and the MetS. The association was assessed by using a logistic regression. Cox's regression analysis was used to evaluate the impact of RDW on long term mortality. RESULTS: The mean age was 65 years (range 24-97), with 27% women. Overall, 30% were diagnosed with metabolic syndrome. The prevalence of MetS was 29% in patients with RDW <14% and 34% in patients with RDW ≥14% (P = 0.003).Using multivariate analysis, RDW values above 14% were independently associated with MetS (odds ratio 1.2 [95% CI 1.0-1.4], P = 0.043). Among all the criteria of the metabolic syndrome, hypertension, elevated glucose levels and abdominal obesity were associated with high RDW, with hypertension being the strongest criteria, with an increased risk of 1.8 fold ([95% CI 1.5-2.1]; P = 0.001). During follow up (1614 ± 709 days, 2-2763 days), long term mortality was 8% in the low RDW group and 28% in the high RDW group (p < 0.001). CONCLUSION: RDW ≥14% is independently associated with higher rates of metabolic syndrome and long-term all-cause mortality.