Epidemiology of autoimmune encephalitis and comparison to infectious causes-Experience from a tertiary center.

OBJECTIVES: The incidence of autoimmune encephalitis (AIE) has risen in the last decade, yet recent studies are lacking. We compared the epidemiology of autoimmune and infectious encephalitis cases in Tel-Aviv Sourasky Medical Center (TASMC) between 2010 and 2020. METHODS: All encephalitis cases, aged 18 and above, admitted to TASMC between the years 2010 and 2020 were reviewed for demographic, clinical, laboratory, and imaging data and categorized based on etiology. RESULTS: Two hundred and twenty-five patients with encephalitis were identified. The most common identifiable cause was viral (42%), followed by autoimmune encephalitis (35%), bacterial (18%), and fungal/parasitic (5%). The incidence of AIE cases out of the yearly admitted cases increased substantially, from 3.8/100 K in 2010 to 18.8/100 K in 2020. The incidence of viral cases also increased while those of bacterial and fungal/parasitic infections remained stable. Patients with AIE were younger compared to infectious patients (p-value <0.001) and had lower markers of systemic and cerebrospinal fluid inflammation (p-value for all <0.001). Seizures were more common among AIE patients (p-value <0.001), yet one-year mortality rates were higher among infectious patients (p-value <0.001). INTERPRETATION: AIE incidence has risen significantly in our institution during the past decade, with current rates comparable to those of all infectious causes combined. Based on this cohort, clinical clues for an autoimmune etiology include a non-inflammatory cerebrospinal fluid profile, the presence of seizures, and temporal lobe imaging abnormalities (also common in herpetic encephalitis). In light of its rising incidence and the importance of early treatment, AIE should be considered in the differential diagnosis of all encephalitis cases.

Dual anti-viral treatment for persistent COVID-19 in immunocompromised hemato-oncological patients is associated with a favorable prognosis and minor side effects.

In hemato-oncological patients, COVID-19 can present as a persistent infection with ongoing symptoms and viral replication over a prolonged period of time. Data are scarce on the preferred treatment options for these patients. We describe our experience with a five-day course of dual anti-viral treatment with remdesivir and nirmatrelvir/ritonavir for hemato-oncological immunocompromised patients with persistent COVID-19. Fifteen patients with a history of lymphoma, CLL, and MM were included. Eight were male, median age was 74. All patients had an immediate clinical and virological response. In 73 % of patients, PCR for SARS-CoV-2 became negative at the end of treatment and the rest had an increase in PCR cycle threshold (CT) values, with a median increase of 6 cycles. After a follow-up of three months, 60 % of patients remained in full clinical and virological remission. None required invasive mechanical ventilation or died. The side effects we observed, neutropenia, lactatemia and elevated transaminases, were mild and almost all transient in nature. We conclude that dual anti-viral treatment appears to be a valid treatment option for persistent COVID-19.

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.

The Effect of Macrolides on Mortality in Bacteremic Pneumococcal Pneumonia: A Retrospective, Nationwide Cohort Study, Israel, 2009-2017.

BACKGROUND: Previous cohort studies of pneumonia patients reported lower mortality with advanced macrolides. Our aim was to characterize antibiotic treatment patterns and assess the role of quinolones or macrolides in empirical therapy. MATERIALS: An historical cohort, 1 July 2009 to 30 June 2017, included, through active surveillance, all culture-confirmed bacteremic pneumococcal pneumonia (BPP) among adults in Israel. Cases without information on antibiotic treatment were excluded. Logistic regression analysis was used to assess independent predictors of in-hospital mortality. RESULTS: A total of 2016 patients with BPP were identified. The median age was 67.2 years (interquartile range [IQR] 53.2-80.6); 55.1% were men. Lobar pneumonia was present in 1440 (71.4%), multi-lobar in 576 (28.6%). Median length of stay was 6 days (IQR 4-11). A total of 1921 cases (95.3%) received empiric antibiotics with anti-pneumococcal coverage: ceftriaxone, in 1267 (62.8%). Coverage for atypical bacteria was given to 1159 (57.5%), 64% of these, with macrolides. A total of 372 (18.5%) required mechanical ventilation, and 397 (19.7%) died. Independent predictors of mortality were age (odds ratio [OR] 1.051, 95% confidence interval [CI] 1.039, 1.063), being at high-risk for pneumococcal disease (OR 2.040, 95% CI 1.351, 3.083), multi-lobar pneumonia (OR 2.356, 95% CI 1.741, 3.189). Female sex and macrolide therapy were predictors of survival: (OR 0.702, 95% CI .516, .955; and OR 0.554, 95% CI .394, .779, respectively). Either azithromycin or roxithromycin treatment for as short as two days was predictor of survival. Quinolone therapy had no effect. CONCLUSIONS: Empirical therapy with macrolides reduced odds for mortality by 45%. This effect was evident with azithromycin and with roxithromycin. The effect did not require a full course of therapy.

Hospital-onset adult invasive pneumococcal disease in Israel: Sicker patients, different pathogens.

OBJECTIVES: Invasive pneumococcal disease (IPD) usually has its onset in the community (CO-IPD), but it can commence following hospitalization (HO-IPD). This study compared HO-IPD and CO-IPD cases during the implementation of the pneumococcal conjugate vaccine (PCV) program for children in Israel. METHODS: This was a nationwide retrospective cohort study of adult (age >18 years) IPD patients covering the period from the implementation of the PCV7/13 program in 2009/2010 through 2015. HO-IPD and CO-IPD were defined as IPD with onset ≥4 and ≤2 days from admission, respectively. Patient characteristics, outcome measures, serotypes, and antimicrobial susceptibility were compared for the entire cohort, followed by a matched case-control analysis. RESULTS: The study included 114 patients with HO-IPD and 2180 with CO-IPD. After matching HO-IPD to CO-IPD patients by age, sex, and comorbidities, the mortality rate and discharge to long-term care facility rate were significantly higher for HO-IPD patients than for CO-IPD patients (44.6% vs. 26.3% and 26.5% vs. 8.2%, respectively). HO-IPD isolates were less often covered by PCV13 (39.6% vs. 49.0%) and pneumococcal polysaccharide vaccine PPSV23 (56.6% vs. 71.3%) and more often resistant to penicillin (9.3% vs. 3.6%), ceftriaxone (3.8% vs. 0.75%), and levofloxacin (9.3% vs. 0.8%). CONCLUSIONS: HO-IPD was associated with higher morbidity and mortality than CO-IPD and was more often caused by non-vaccine serotypes (primarily non-PCV13 types) and antibiotic-resistant strains.

Invasive pneumococcal disease (IPD) in HIV infected patients in Israel since the introduction of pneumococcal conjugated vaccines (PCV): Analysis of a nationwide surveillance study, 2009-2014.

STUDY AIM: to assess the incidence, risk factors and outcome of invasive pneumococcal disease (IPD) among the Israeli HIV population. A matched case-control study nested in a nationwide, prospective, population-based, cohort of adult IPD was performed. In addition, the HIV-IPD patients were compared to the general adult HIV population in Israel. STUDY PERIOD: from the introduction of PCV into the national immunization program (NIP) in July 2009 to June 2014. Each HIV patient within the IPD cohort was matched to 4 non-HIV controls. Serotyping was performed by a central laboratory using the Quellung reaction. Thirty-five IPD episodes in 33 HIV patients were identified, with a median annual incidence of 128/100,000 HIV+ persons compared to 5.1/100,000 in the age-matched, non-HIV population. Compared to the general HIV population, HIV-IPD patients practiced intravenous drug use more frequently and originated from a country with generalized epidemic (OGE), mainly non-citizens lacking medical insurance. The proportion of men who have sex with men (MSM) was lower than in the general HIV population. Pneumonia was the most common clinical presentation (81%), while meningitis occurred in only one patient. Outcomes were similar to those of the IPD non-HIV population. Nineteen serotypes were identified, of which only 42% were covered by PCV13 vaccine. By 2014, none of the HIV-IPD cases belonged to serotypes covered by PCV13. In conclusion, most HIV IPD cases were from marginalized populations with poor access to health services. A decrease in IPD cases covered by PCV 13 was observed.

Bacteroides fragilis-stimulated interleukin-10 contains expanding disease.

Commensal symbionts may become pathogens upon escaping their habitat. In the gut, Bacteroides fragilis protects against colitis through induction of interleukin 10 (IL-10) by CD4(+) T cells. When intestinal integrity is disrupted, B. fragilis and colonic contents escape into the peritoneum, causing abscesses and bacteremia. Whether the virulence mechanisms employed by B. fragilis during infections differ from those employed for symbiosis during commensalism is unknown. We demonstrate T cell-independent IL-10 production in response to B. fragilis during its pathogenic interactions with the host, and demonstrate the ability of the whole organism to activate Toll-like receptor 2-mediated MyD88 signaling in macrophages. Upon challenge with B. fragilis, mortality rates and serum proinflammatory cytokine levels were higher among IL-10(-/-) mice than among wild-type mice. Deaths were due to exuberant proinflammatory responses, not increased bacterial burden. During infection or commensalism, induction of IL-10 by B. fragilis is critical to this microbe's interactions with the immune system.

Implications on emergence of antimicrobial resistance as a critical aspect in the design of oral sustained release delivery systems of antimicrobials.

PURPOSE: To assess the effects of the unabsorbed fraction of an orally administered antimicrobial drug which enters the colon on the emergence of resistance among the natural microflora, a phenomenon largely overlooked so far despite its clinical importance, especially when sustained release formulations are used. METHODS: Effects of an orally administered model beta-lactam antibiotic (amoxicillin) on emergence of resistant bacteria were assessed using a microbiological assay for qualitative and quantitative determination of resistant bacteria in fecal samples of rats following gastric administration of the drug to rats for 4 consecutive days. Time- and site-controlled administration of a beta-lactamase to the rat colon was assessed as a potential strategy for prevention the emergence of resistant bacteria following oral administration of incompletely absorbed antimicrobials. RESULTS: Emergence of resistant bacteria was demonstrated following oral administration of amoxicillin to rats, whereas de-activation of the beta-lactam prior to entering the colon, by infusion of a beta-lactamase into the lower ileum, was shown to prevent the emergence of resistant colonic bacteria. CONCLUSIONS: This study illustrates the need to consider the emergence of antimicrobial resistance as a goal equally important to microbiological and clinical cure, when designing oral sustained-release delivery systems of antimicrobial drugs.

Macrolide, lincosamide and tetracycline susceptibility and emm characterisation of invasive Streptococcus pyogenes isolates in Israel.

Group A beta-haemolytic streptococcus (GAS) causes a variety of infections, including life-threatening illnesses. Although the species is uniformly penicillin susceptible, resistance to other antibiotics is becoming more common. We studied the prevalence of resistance and associated factors in a nationwide, prospective, population-based study of invasive infections in Israel. Isolates were collected in collaboration with 24 hospitals in Israel during 1996-1999. Minimal inhibitory concentrations (MICs) of erythromycin (ERY), clindamycin (CLI) and tetracycline (TET) were determined as well as ERY and TET resistance phenotypes and genotypes. Five hundred isolates were examined: 136 (27.2%) were not susceptible to TET, 10 (2.0%) to ERY and 5 (1%) to CLI. ERY resistance was associated with emm types 12 and 83 (P<0.001 for both). MICs of TET had a bimodal distribution distinguishing sensitive and resistant populations. Non-susceptibility to TET was mainly due to the presence of tet(M) and was associated with T types 3, 3/13/B3624 and 9 and emm types 9, 33, 64, 73, 74, 76, 77 and 83. TET susceptibility was associated with T types 1, 2 and 11, emm types 1-4, 11, 12, 22, 26 and 75 and the presence of speA and speC. In Israel, resistance of invasive GAS isolates to ERY remains low and is associated with specific T and emm types, as is TET resistance. TET resistance is less frequent than previously reported in Israel and is associated with a lower prevalence of speA and speC.

Group G streptococcal bacteremia in Jerusalem.

Group G Streptococcus (GGS) can cause severe infections, including bacteremia. These organisms often express a surface protein homologous to the Streptococcus pyogenes M protein. We retrospectively studied the characteristics of patients from the Hadassah Medical Center with GGS bacteremia from 1989 to 2000. Ninety-four cases of GGS bacteremia were identified in 84 patients. The median age was 62 years, 54% were males, and 92% had underlying diseases (35% had a malignancy, and 35% had diabetes mellitus). The most frequent source for bacteremia was cellulitis (61%). emm typing of 56 available isolates disclosed 13 different types, including 2 novel types. Six patients had recurrent bacteremia with two to four bacteremic episodes, five had chronic lymphatic disorders, and two had emm type stG840.0 in every episode. Recurrent bacteremia has not been described for invasive group A Streptococcus. We describe an entity of recurrent GGS bacteremia, which is associated with lymphatic disorders and possibly with emm stG840.0.

Infective endocarditis due to Moraxella lacunata: report of 4 patients and review of published cases of Moraxella endocarditis.

Moraxella is an aerobic, oxidase-positive, Gram-negative coccobacillus, which is rarely associated with serious and invasive infections. We describe 4 cases of Moraxella lacunata endocarditis and review 12 previously published cases of Moraxella endocarditis, including 1 further case with M. lacunata, 5 with M. catarrhalis, 2 with M. phenylperuvica and the remainder consisting of 1 case each of M. liquefaciens, M. osloensis, M. nonliquefaciens and 1 non-specified. Of these 16 patients, 5 had prosthetic valves, 5 suffered from an underlying heart abnormality, and the other 6 had normal hearts. Therapy consisted of a beta-lactam antimicrobial and, in several instances, an aminoglycoside as well. The mean duration of antibiotic treatment was 35+/-13 d. Four patients (25%) underwent surgery and 4 out of 16 (25%) died. Moraxella should be added to the growing list of organisms which may occasionally cause infective endocarditis, even in patients without preexisting valvular abnormality.

emm typing of M nontypeable invasive group A streptococcal isolates in Israel.

We performed emm typing of M nontypeable invasive group A streptococcal (GAS) isolates collected in a prospective population-based study in Israel. One hundred twenty of 131 isolates (92%) had emm sequences compatible with GAS, consisting of 51 different emm types. Eleven isolates were found to be group G streptococcus. Of the 120 isolates, 55 (46%) belonged to 32 types for which there were no typing sera available in the Streptococcal Reference Laboratory in Israel. The other 65 (64%) isolates, consisting of 19 types, had sera available and therefore could have been serotyped. Forty-three isolates had T and emm types which were not correlated according to standard M-typing protocols and were therefore missed. The principal effect of emm typing was the addition of 32 types not previously identified in Israel and the discovery of new associations between emm and T types. emm typing did not significantly change the proportion of M types; the five most common types were 3, 28, 2, 62, and 41. Twenty different types comprised 80% of all isolates. No new emm sequences were discovered. emm typing emphasized the unusually low incidence of M1 strains causing severe disease in Israel. As serological typing of GAS becomes more problematic due to lack of sera and the appearance of new emm types, reference laboratories should replace M typing with emm sequence typing. Development of a GAS vaccine relies on the emm type distributions in different geographical locations. In our study, 7% of isolates (types 41 and 62) are not included in a 26-valent vaccine that is being studied.