Diagnosis and Risk Factors of Prediabetes and Diabetes in People Living with HIV- Evaluation of Clinical and Microbiome Parameters.

Diabetes is more common among people living with HIV (PLWH), as compared with healthy individuals. In a prospective multicenter study (N = 248), we identified normoglycemic (48.7%), prediabetic (44.4%) and diabetic (6.9%) PLWH. HbA1c and fasting blood glucose (FBG) sensitivity in defining dysglycemia was 96.8%, while addition of oral glucose tolerance test led to reclassification of only 4 patients. Inclusion of 93 additional PLWH with known DM enabled identification of multiple independent predictors of dysglycemia or diabetes: older age, higher BMI, Ethiopian origin, HIV duration, lower integrase inhibitor exposure and advanced disease at diagnosis. Shotgun metagenomic microbiome analysis revealed 4 species that were significantly expanded with hyperglycemia/hyperinsulinemia, and 2 species that were differentially more prevalent in prediabetic/diabetic PLWH. Collectively, we uncover multiple potential host and microbiome predictors of altered glycemic status in PLWH, while demonstrating that FBG and HbA1C likely suffice for diabetes screening. These potential diabetic predictors merit future prospective validation.

Neutrophils impose strong immune pressure against PfEMP1 variants implicated in cerebral malaria.

Plasmodium falciparum, the deadliest form of human malaria, remains one of the major threats to human health in endemic regions. Its virulence is attributed to its ability to modify infected red blood cells (iRBC) to adhere to endothelial receptors by placing variable antigens known as PfEMP1 on the iRBC surface. PfEMP1 expression determines the cytoadhesive properties of the iRBCs and is implicated in severe malaria. To evade antibody-mediated responses, the parasite undergoes continuous switches of expression between different PfEMP1 variants. Recently, it became clear that in addition to antibody-mediated responses, PfEMP1 triggers innate immune responses; however, the role of neutrophils, the most abundant white blood cells in the human circulation, in malaria remains elusive. Here, we show that neutrophils recognize and kill blood-stage P. falciparum isolates. We identify neutrophil ICAM-1 and specific PfEMP1 implicated in cerebral malaria as the key molecules involved in this killing. Our data provide mechanistic insight into the interactions between neutrophils and iRBCs and demonstrate the important influence of PfEMP1 on the selective innate response to cerebral malaria.

Invasive infections caused by the recently described species Enterococcus innesii.

E. innesii is a recently described Enterococcus species which may be difficult to differentiate from the more common E. casseliflavus. We present the first clinical report of invasive E. innesii infection, featuring two cases of biliary sepsis. Whole genome sequencing confirmed the taxonomic assignment and the presence of vanC-4. Analysis of public genomes identified 13 deposited E. innesii and 13 deposited E. casselifalvus/E.gallinarum genomes which could be reassigned as E. innesii. Improved laboratory diagnosis of E. innesii is expected to generate additional data concerning its clinical relevance and support the future diagnosis and treatment of this uncommon pathogen.

High rate of adenovirus detection in gastrointestinal biopsies of symptomatic stem cell transplant recipients.

OBJECTIVES: The gastrointestinal (GI) tract is a major human adenovirus (HAdV) replication site in patients undergoing hematopoietic stem cell transplantation (HSCT), yet the prevalence and correlates of HAdV GI infection in this setting have remained poorly recognized, especially among adult HSCT recipients. DESIGN OR METHODS: We retrospectively studied the prevalence and risk factors of HAdV GI-tissue infection in HSCT recipients (73 adults and 15 children) with GI symptoms who underwent GI-tissue biopsy between January-2012 and December-2017. The presence of HAdV in the GI tissues was determined by real-time PCR. RESULTS: HAdV GI-tissue infection was detected in 21 (23.9%) patients, with similar infection rates identified in adults and children. GI-tissue detection was more common at late (>100 days) compared to early times post-transplantation (50% vs. 12.9%, p < .001). The presence of bloody diarrhea, Arab ethnicity (p = .014) and concurrent cytomegalovirus GI-tissue detection (p = .025) were significantly correlated with HAdV GI-tissue infection, while chronic graft versus host disease was of borderline association (p = .055). CONCLUSIONS: Our findings reveal a high rate and new clinical-demographic correlates of HAdV GI-tissue infection in adult and pediatric HSCT recipients with GI symptoms. The findings highlight the need for future prospective studies to assess the relatedness of HAdV infection to the GI symptoms, and the prevalence, impact, and treatment of HAdV GI infection in HSCT recipients.

Metagenomic sequencing for investigation of a national keratoconjunctivitis outbreak, Israel, 2022.

BackgroundEpidemics of keratoconjunctivitis may involve various aetiological agents. Microsporidia are an uncommon difficult-to-diagnose cause of such outbreaks.AimDuring the third quarter of 2022, a keratoconjunctivitis outbreak was reported across Israel, related to common water exposure to the Sea of Galilee. We report a comprehensive diagnostic approach that identified Vittaforma corneae as the aetiology, serving as proof of concept for using real-time metagenomics for outbreak investigation.MethodsCorneal scraping samples from a clinical case were subjected to standard microbiological testing. Samples were tested by calcofluor white staining and metagenomic short-read sequencing. We analysed the metagenome for taxonomical assignment and isolation of metagenome-assembled genome (MAG). Targets for a novel PCR were identified, and the assay was applied to clinical and environmental samples and confirmed by long-read metagenomic sequencing.ResultsFluorescent microscopy was suggestive of microsporidiosis. The most abundant species (96.5%) on metagenomics analysis was V. corneae. Annotation of the MAG confirmed the species assignment. A unique PCR target in the microsporidian rRNA gene was identified and validated against the clinical sample. The assay and metagenomic sequencing confirmed V. corneae in an environmental sludge sample collected at the exposure site.ConclusionsThe real-time utilisation of metagenomics allowed species detection and development of diagnostic tools, which aided in outbreak source tracking and can be applied for future cases. Metagenomics allows a fully culture-independent investigation and is an important modality for public health microbiology.

Prevalence of Antibiotic Tolerance and Risk for Reinfection Among Escherichia coli Bloodstream Isolates: A Prospective Cohort Study.

BACKGROUND: Tolerance is the ability of bacteria to survive transient exposure to high concentrations of a bactericidal antibiotic without a change in the minimal inhibitory concentration, thereby limiting the efficacy of antimicrobials. The study sought to determine the prevalence of tolerance in a prospective cohort of E. coli bloodstream infection and to explore the association of tolerance with reinfection risk. METHODS: Tolerance, determined by the Tolerance Disk Test (TDtest), was tested in a prospective cohort of consecutive patient-unique E. coli bloodstream isolates and a collection of strains from patients who had recurrent blood cultures with E. coli (cohorts 1 and 2, respectively). Selected isolates were further analyzed using time-dependent killing and typed using whole-genome sequencing. Covariate data were retrieved from electronic medical records. The association between tolerance and reinfection was assessed by the Cox proportional-hazards regression and a Poisson regression models. RESULTS: In cohort 1, 8/94 isolates (8.5%) were tolerant. Using multivariate analysis, it was determined that the risk for reinfection in the patients with tolerant index bacteremia was significantly higher than for patients with a nontolerant strain, hazard ratio, 3.98 (95% confidence interval, 1.32-12.01). The prevalence of tolerance among cohort 2 was higher than in cohort 1, 6/21(28.6%) vs 8/94 (8.5%), respectively (P = .02). CONCLUSIONS: Tolerant E. coli are frequently encountered among bloodstream isolates and are associated with an increased risk of reinfection. The TDtest appears to be a practicable approach for tolerance detection and could improve future patient management.

Characteristics of endovascular pneumococcal infections; a decade of nationwide surveillance study.

In order to characterize pneumococcal endovascular infection in the post-vaccination era, a retrospective nationwide study based on the Israeli Adult IPD database was conducted. Between 2010 and 2019, 0.6% (23 cases) of IPD cases were of endovascular type, occurring mainly in males (72.3%) with underlying medical conditions (78.2%). Additional pneumococcal source (10 patients) and concomitant infections were not uncommon. Penicillin and ceftriaxone susceptibility rates were 65.2% and 91.3%, respectively; 60.9% of the isolates were not covered by the pneumococcal conjugate vaccine. 21.7% of patients died during hospitalization. In conclusion, pneumococcal endovascular infections still carry significant morbidity and mortality.

Cat Scratch Disease Presenting as Fever of Unknown Origin Is a Unique Clinical Syndrome.

BACKGROUND: Fever of unknown origin (FUO) is a rare manifestation of cat scratch disease (CSD). Data regarding CSD-associated FUO (CSD-FUO), particularly in adults, are limited. We aimed to study disease manifestations and long-term clinical outcome. METHODS: A national CSD surveillance study has been conducted in Israel since 1991. Data are obtained using questionnaires, review of medical records, and telephone interviews. FUO was defined as fever of ≥14 days without an identifiable cause. CSD-FUO patients were identified in the 2004-2017 CSD national registry. Follow-up included outpatient clinic visits and telephone/e-mail surveys. RESULTS: The study included 66 CSD-FUO patients. Median age was 35.5 years (range, 3-88). Median fever duration was 4 weeks (range, 2-9). Relapsing fever pattern was reported in 52% of patients, weight loss in 57%, and night sweats in 48%. Involvement of ≥1 organs occurred in 59% of patients; hepatosplenic space-occupying lesions (35%), abdominal/mediastinal lymphadenopathy (20%), ocular disease (18%), and multifocal osteomyelitis (6%) were the most common. Malignancy, particularly lymphoma, was the initial radiological interpretation in 21% of patients; 32% underwent invasive diagnostic procedures. Of the 59 patients available for follow-up (median duration, 31 weeks; range, 4-445), 95% had complete recovery; 3 patients remained with ocular sequelae. CONCLUSION: This is the first attempt to characterize CSD-FUO as a unique syndrome that may be severe and debilitating and often mimics malignancy. Relapsing fever is a common clinical phenotype. Multiorgan involvement is common. Recovery was complete in all patients except in those with ocular disease.

The association between vegetation size and surgical treatment on 6-month mortality in left-sided infective endocarditis.

AIMS: In left-sided infective endocarditis (IE), a large vegetation >10 mm is associated with higher mortality, yet it is unknown whether surgery during the acute phase opposed to medical therapy is associated with improved survival. We assessed the association between surgery and 6-month mortality as related to vegetation size. METHODS AND RESULTS: Patients with definite, left-sided IE (2008-2012) from The International Collaboration on Endocarditis prospective, multinational registry were included. We compared clinical characteristics and 6-month mortality (by Cox regression with inverse propensity of treatment weighting) between patients with vegetation size ≤10 mm vs. >10 mm in maximum length by surgical treatment strategy. A total of 1006 patients with left sided IE were included; 422 with a vegetation size ≤10 mm (median age 66.0 years, 33% women) and 584 (median age 58.4 years, 34% women) patients with a large vegetation >10 mm. Operative risk by STS-IE score was similar between groups. Embolic events occurred in 28.4% vs. 44.3% (P < 0.001), respectively. Patients with a vegetation >10 mm was associated with higher 6-month mortality (25.1% vs. 19.4% for small vegetation, P = 0.035). However, after propensity adjustment, the association with higher mortality persisted only in patients with a large vegetation >10 mm vs. ≤10 mm: hazard ratio (HR) 1.55 (1.27-1.90); but only in patients with large vegetation managed medically [HR 1.86 (1.48-2.34)] rather than surgically [HR 1.01 (0.69-1.49)]. CONCLUSION: Left-sided IE with vegetation size >10 mm was associated with an increased mortality at 6 months in this observational study but was dependent on treatment strategy. For patients with large vegetation undergoing surgical treatment, survival was similar to patients with smaller vegetation size.

Association between the timing of surgery for complicated, left-sided infective endocarditis and survival.

BACKGROUND: In patients with active infective endocarditis (IE), the relationship between timing of surgery and survival is uncertain. The objective was to evaluate clinical characteristics associated with timing of surgery and the association between surgical timing and 6-month survival in complicated, left-sided IE. METHODS: In a prospective, multicenter, observational registry (The International Collaboration on Endocarditis-PLUS, registry from 2008 to 2012), clinical factors associated with timing of surgery during the index hospitalization were determined among 485 adult patients with definite, complicated, left-sided IE who underwent cardiac surgery during their index hospitalization. The relationship between early surgical intervention (<7 days from admission to surgery center) and outcome after surgery was analyzed. The primary end point of the study was 6-month survival. RESULTS: The median time to surgery from admission to surgical center was 7 (interquartile range 2-15) days. Patients who underwent earlier surgery were more likely transferred to the surgical center (74.2% vs 46.4%, P < .001) and had a lower percentage of preexisting heart failure (before IE diagnosis) (6.0% vs 17.3%, P < .001) but higher rate of acute heart failure (53.2% vs 38.4%, P = .001). Variables independently associated with surgery <7 days from admission were patient transfer, acute heart failure, and nonelective surgical status (C-index = 0.84), but predicted operative risk was not. Cox proportional hazards modeling with inverse probability of treatment weighting found that earlier surgery was associated with a trend toward higher 6-month mortality compared with later surgery (hazard ratio = 1.68, 95% CI 0.97-2.96; P = .065), particularly surgery within 2 days of admission or transfer. Mortality was significantly associated with operative risk and complicated IE, including Staphylococcus aureus infection and presence of abscess. CONCLUSIONS: Earlier surgery in IE is strongly associated with acute heart failure and surgical urgency. After adjustment for operative risk and IE complications, earlier surgery <7 days from admission was associated with a trend toward higher 6-month overall mortality compared with surgery later in the index hospitalization.

[ANTIBIOTIC STEWARDSHIP IN ISRAEL - WHERE ARE WE HEADED IN 2018?]

INTRODUCTION: We live in an age where antibiotic resistant pathogens are common, and we see an increase in infections caused by multidrug resistant pathogens. This arises from the broad use of antibiotics, many times inappropriately, combined with slackening in recent years of new antibiotic development. This combination of events threatens the core of modern medical care, increasing the number of patients with resistant infections resulting in prolonged illness with high morbidity and mortality. Most antibiotics are not prescribed by infectious disease specialists and inappropriate antibiotic use habits foster increased resistance. When prescribing an antibiotic to a patient, the physician impacts the society and environment, as well as his patient, hence the critical need for implementing antibiotic stewardship programs. The incorporation of electronic medical records into medical care in the last decade provides effective opportunities for implementing antibiotic stewardship. In this review we present the elements of antibiotic stewardship and suggest different methods for Israeli medical organizations to implement an antibiotic stewardship program. There are many different interventions that may be applied, and each institution or organization must evaluate their unique environment and challenges and implement a program that has the best possibility to succeed. There is no single program that fits all. The programs must be led by Infectious Disease specialists and management must prioritize the resources needed and continuously stay involved to keep the agenda in the forefront, so we may lead a change in our healthcare system, which is critical for our health and for the future of modern medicine.

Pneumococcal Meningitis in Adults after Introduction of PCV7 and PCV13, Israel, July 2009-June 20151.

The indirect effect of pneumococcal conjugate vaccine on adult pneumococcal meningitis has not been thoroughly investigated. We present data from active surveillance on pneumococcal meningitis in adults in Israel occurring during July 2009-June 2015. Pneumococcal meningitis was diagnosed for 221 patients, 9.4% of all invasive pneumococcal disease (IPD) cases. Although overall IPD incidence decreased during the study period, meningitis increased nonsignificantly from 0.66 to 0.85 cases/100,000 population. Incidence of vaccine type (VT) pneumococcal meningitis (VT13) decreased by 70%, but non-VT13 pneumococcal meningitis increased from 0.32 to 0.75 cases/100,000 population (incident rate ratio 2.35, 95% CI 1.27-4.35). Pneumococcal meningitis patients were younger and healthier than nonmeningitis IPD patients, and 20.2% had a history of previous head surgery or cerebrospinal fluid leak compared with <2.0% of nonmeningitis patients (p<0.0001). Non-VT13 types that rarely cause IPD (15B/C, 6C, 23A, 23B, 24F) seem to be emerging as common causes of meningitis.

Association between surgical indications, operative risk, and clinical outcome in infective endocarditis: a prospective study from the International Collaboration on Endocarditis.

BACKGROUND: Use of surgery for the treatment of infective endocarditis (IE) as related to surgical indications and operative risk for mortality has not been well defined. METHODS AND RESULTS: The International Collaboration on Endocarditis-PLUS (ICE-PLUS) is a prospective cohort of consecutively enrolled patients with definite IE from 29 centers in 16 countries. We included patients from ICE-PLUS with definite left-sided, non-cardiac device-related IE who were enrolled between September 1, 2008, and December 31, 2012. A total of 1296 patients with left-sided IE were included. Surgical treatment was performed in 57% of the overall cohort and in 76% of patients with a surgical indication. Reasons for nonsurgical treatment included poor prognosis (33.7%), hemodynamic instability (19.8%), death before surgery (23.3%), stroke (22.7%), and sepsis (21%). Among patients with a surgical indication, surgical treatment was independently associated with the presence of severe aortic regurgitation, abscess, embolization before surgical treatment, and transfer from an outside hospital. Variables associated with nonsurgical treatment were a history of moderate/severe liver disease, stroke before surgical decision, and Staphyloccus aureus etiology. The integration of surgical indication, Society of Thoracic Surgeons IE score, and use of surgery was associated with 6-month survival in IE. CONCLUSIONS: Surgical decision making in IE is largely consistent with established guidelines, although nearly one quarter of patients with surgical indications do not undergo surgery. Operative risk assessment by Society of Thoracic Surgeons IE score provides prognostic information for survival beyond the operative period. S aureus IE was significantly associated with nonsurgical management.

Candida infective endocarditis: an observational cohort study with a focus on therapy.

Candida infective endocarditis is a rare disease with a high mortality rate. Our understanding of this infection is derived from case series, case reports, and small prospective cohorts. The purpose of this study was to evaluate the clinical features and use of different antifungal treatment regimens for Candida infective endocarditis. This prospective cohort study was based on 70 cases of Candida infective endocarditis from the International Collaboration on Endocarditis (ICE)-Prospective Cohort Study and ICE-Plus databases collected between 2000 and 2010. The majority of infections were acquired nosocomially (67%). Congestive heart failure (24%), prosthetic heart valve (46%), and previous infective endocarditis (26%) were common comorbidities. Overall mortality was high, with 36% mortality in the hospital and 59% at 1 year. On univariate analysis, older age, heart failure at baseline, persistent candidemia, nosocomial acquisition, heart failure as a complication, and intracardiac abscess were associated with higher mortality. Mortality was not affected by use of surgical therapy or choice of antifungal agent. A subgroup analysis was performed on 33 patients for whom specific antifungal therapy information was available. In this subgroup, 11 patients received amphotericin B-based therapy and 14 received echinocandin-based therapy. Despite a higher percentage of older patients and nosocomial infection in the echinocandin group, mortality rates were similar between the two groups. In conclusion, Candida infective endocarditis is associated with a high mortality rate that was not impacted by choice of antifungal therapy or by adjunctive surgical intervention. Additionally, echinocandin therapy was as effective as amphotericin B-based therapy in the small subgroup analysis.

Reduction in incidence of invasive fungal infection in patients receiving allogeneic stem cell transplantation using combined diagnostic-driven approach and itraconazole oral solution.

Invasive fungal infections are an important cause of morbidity and mortality after allogeneic haematopoietic stem cell transplantation. We evaluated, in our allogeneic stem cell transplant patients, the effect on the incidence of invasive fungal infection during neutropenia of a strategy combining a diagnostic-driven approach with chemoprophylaxis during higher risk periods of graft vs. host disease and prolonged neutropenia, using itraconazole oral solution with parenteral voriconazole bridging. One hundred and thirty patients admitted for allogeneic stem cell transplantation within two predefined 20 month periods were included in the study. Data for all patients were collected prospectively. Implementation of the protocol resulted in the administration of more prophylactic antifungals to more patients. Following implementation, there was a non-significant decrease in the overall number of invasive fungal infections (IFI) [11 of 65 patients (17.2%) vs. 4 of 65 patients (6.2%, P = 0.051)], as well as in the occurrence of invasive mould infections [8 of 65 patients (12.5%) vs. 2 of 65 patients (3.1%, P = 0.054)]. Survival rates at three and 6 months were not significantly affected. A combined diagnostic-driven approach and antifungal prophylaxis with oral itraconazole and an intravenous voriconazole bridging protocol, was associated with a reduced, albeit non-statistically significant, number of IFI in our medical centre.

Fluoroquinolone-modifying enzyme: a new adaptation of a common aminoglycoside acetyltransferase.

Antimicrobial-modifying resistance enzymes have traditionally been class specific, having coevolved with the antibiotics they inactivate. Fluoroquinolones, antimicrobial agents used extensively in medicine and agriculture, are synthetic and have been considered safe from naturally occurring antimicrobial-modifying enzymes. We describe reduced susceptibility to ciprofloxacin in clinical bacterial isolates conferred by a variant of the gene encoding aminoglycoside acetyltransferase AAC(6')-Ib. This enzyme reduces the activity of ciprofloxacin by N-acetylation at the amino nitrogen on its piperazinyl substituent. Although approximately 30 variants of this gene have been reported since 1986, the two base-pair changes responsible for the ciprofloxacin modification phenotype are unique to this variant, first reported in 2003 and now widely disseminated. An intense increase in the medical use of ciprofloxacin seems to have been accompanied by a notable development: a single-function resistance enzyme has crossed class boundaries, and is now capable of enzymatically undermining two unrelated antimicrobial agents, one of them fully synthetic.

Real-Life Comparison of Fosfomycin to Nitrofurantoin for the Treatment of Uncomplicated Lower Urinary Tract Infection in Women.

In this study, we compared the failure rates of fosfomycin and nitrofurantoin for uncomplicated urinary tract infections. We used Meuhedet Health Services' large database to collect data on all female patients, older than 18 years, who were prescribed either antibiotic during 2013-2018. Treatment failure was a composite endpoint of hospitalization, emergency-room visit, IV antibiotic treatment, or prescription of a different antibiotic, within seven days of the initial prescription. Reinfection was considered when one of these endpoints appeared 8-30 days following the initial prescription. We found 33,759 eligible patients. Treatment failure was more common in the fosfomycin group than the nitrofurantoin group (8.16% vs. 6.87%, p-value < 0.0001). However, reinfection rates were higher among patients who received nitrofurantoin (9.21% vs. 7.76%, p-value < 0.001). Among patients younger than 40 years, patients treated with nitrofurantoin had more reinfections (8.68% vs. 7.47%, p value = 0.024). Treatment failure rates were mildly higher in patients treated with fosfomycin, despite having less reinfections. We suggest that this effect is related to a shorter duration of treatment (one vs. five days) and encourage clinicians to be more patient before declaring fosfomycin failure and prescribing another antibiotic.

Timing of midstream urine culture before endourological procedure-can we do better?-A comparative study.

Endourological procedures are the mainstay of treatment for stone disease in the upper urinary system. Infection is a common complication, and urine cultures (UC) are often obtained preoperatively. In this study, we sought to investigate the role of positive UC in the 90 days prior to surgery (90PreOp) in predicting postoperative infectious complications in comparison to a single positive preoperative UC (PreOP). We compared the correlation between positive PreOp UCs and positive 90PreOp UCs with postoperative urosepsis, and a positive UC obtain proximal to obstruction (Prox UC) during percutaneous nephrolithotomy, ureteroscopy and a placement of nephrostomy tube or ureteral stent. Data from 140 consecutive patients were collected. PreOp UCs were positive in 15 (11%) of patients versus 31 of 140 (22%) positive 90PreOp UCs. All six sepsis events had a positive 90PreOp UC, and five had a positive PreOp UC. Fourteen (93.3%) out of 15 positive Prox UC had a positive 90PreOp UC, whereas only 7 (38.9%) had a positive 90PreOp UC. Positive 90PreOp UC outperformed PreOp UC in predicting positive Prox UC, OR = 12.8 (95% CI 3.70-44.30, p < 0.001), versus OR of 88.9 (95% CI 11.0-720.7, p < 0.001); sensitivity 93%(95% CI 68-100%) versus 47%(95% CI 21-73%); as well as area under the ROC curve(AUC), 0.90 (CI 0.80-0.95) for 90PreOp versus 0.70 (CI 0.56-0.82) for positive Prox UC. Uropathogen persistence was better identified when using 90PreOp UC (27%) than using PreOp UC (12%). We suggest reviewing UCs taken within 90 days preoperatively as this was found superior to a single preoperative midstream UCs in predicting postoperative infectious sequela after stone procedure.