National epidemiology of culture-confirmed brucellosis in Israel, 2004-2022.

Brucellosis, a global zoonosis, is endemic in Israel. We used a national database of culture-confirmed cases (2004-2022) to analyse the trends of brucellosis. Of 2,489 unique cases, 99.8% were bacteraemic, 64% involved males, and the mean age was 30.5 years. Brucella melitensis was the dominant species (99.6%). Most cases occurred among the Arab sector (84.9%) followed by the Jewish (8.5%) and Druze (5.5%) sectors. The average annual incidence rates overall and for the Arab, Druze, and Jewish sectors were 1.6/100,000, 6.6/100,000, 5.5/100,000, and 0.18/100,000, respectively. The annual incidence rates among the Arab (incidence rate ratio (IRR) = 36.4) and the Druze (IRR = 29.6) sectors were significantly higher than among the Jewish sector (p < 0.001). The highest incidence rates among the Arab sector occurred in the South District, peaking at 41.0/100,000 in 2012. The frequencies of B. melitensis isolated biotypes (biotype 1 - 69.1%, biotype 2 - 26.0%, and biotype 3 - 4.3%) differed from most Middle Eastern and European countries. A significant switch between the dominant biotypes was noted in the second half of the study period. Efforts for control and prevention should be sustained and guided by a One Health approach mindful of the differential trends and changing epidemiology.

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.

Spotted Fever Group Rickettsioses in Israel, 2010-2019.

In a multicenter, nationwide, retrospective study of patients hospitalized with spotted fever group rickettsiosis in Israel during 2010-2019, we identified 42 cases, of which 36 were autochthonous. The most prevalent species was the Rickettsia conorii Israeli tick typhus strain (n = 33, 79%); infection with this species necessitated intensive care for 52% of patients and was associated with a 30% fatality rate. A history of tick bite was rare, found for only 5% of patients; eschar was found in 12%; and leukocytosis was more common than leukopenia. Most (72%) patients resided along the Mediterranean shoreline. For 3 patients, a new Rickettsia variant was identified and had been acquired in eastern, mountainous parts of Israel. One patient had prolonged fever before admission and clinical signs resembling tickborne lymphadenopathy. Our findings suggest that a broad range of Rickettsia species cause spotted fever group rickettsiosis in Israel.

Healthcare-associated Pneumocystis jirovecii Pneumonia (PJP) Infection in HIV-negative Adults: a Multicenter Study.

BACKGROUND: Pneumocystis jirovecii pneumonia (PJP) is an opportunistic infection in immunocompromised patients. Clusters of PJP, especially among organ transplant recipients in clinic settings were described. Data regarding nosocomial PJP infection among inpatients are limited. OBJECTIVES: To assess the magnitude and characteristics of inpatient healthcare-associated PJP infection (HCA-PJP) in HIV-negative patients. METHODS: A retrospective chart review of hospitalized PJP patients was performed to identify HCA-PJP. The study was performed at six medical centers in Israel from 2006 to 2016. HCA-PJP was defined as cases of hospital-onset or those with documented contact with a PJP patient. We reviewed and cross-matched temporal and spatial co-locations of patients. Clinical laboratory characteristics and outcomes were compared. RESULTS: Seventy-six cases of PJP were identified. Median age was 63.7 years; 64% men; 44% hematological malignancies; 18% inflammatory diseases; and 61% steroid usage. Thirty-two patients (42%) were defined as HCA-PJP: 18/32 (23.6%) were hospitalized at onset and 14/32 (18.4%) had a previous encounter with a PJP patient. Time from onset of symptoms to diagnosis was shorter in HCA-PJP vs. community-PJP (3.25 vs. 11.23 days, P = 0.009). In multivariate analysis, dyspnea at presentation (odds ratio [OR] 16.79, 95% confidence interval [95%CI] 1.78-157.95) and a tendency toward higher rate of ventilator support (72% vs. 52%, P = 0.07, OR 5.18, 95%CI 0.7-30.3) were independently associated with HCA-PJP, implying abrupt disease progression in HCA-PJP. CONCLUSIONS: HCA-PJP was common. A high level of suspicion for PJP among selected patients with nosocomial respiratory infection is warranted. Isolation of PJP patients should be considered.

Antibiotic treatment for invasive nonpregnancy-associated listeriosis and mortality: a retrospective cohort study.

Little evidence exists addressing the clinical value of adding gentamicin to ampicillin for invasive listeriosis. A multicenter retrospective observational study of nonpregnant adult patients with invasive listeriosis (primary bacteremia, central nervous system (CNS) disease, and others) in 11 hospitals in Israel between the years 2008 and 2014 was conducted. We evaluated the effect of penicillin-based monotherapy compared with early combination therapy with gentamicin, defined as treatment started within 48 h of culture results and continued for a minimum of 7 days. Patients who died within 48 h of the index culture were excluded. The primary outcome was 30-day all-cause mortality. A total of 190 patients with invasive listeriosis were included. Fifty-nine (30.6%) patients were treated with early combination therapy, 90 (46.6%) received monotherapy, and 44 (22.8%) received other treatments. Overall 30-day mortality was 20.5% (39/190). Factors associated with mortality included lower baseline functional status, congestive heart failure, and higher sequential organ failure assessment score. Source of infection, treatment type, and time from culture taken date to initiation of effective therapy were not associated with mortality. In multivariable analysis, monotherapy was not significantly associated with increased 30-day mortality compared with early combination therapy (OR 1.947, 95% CI 0.691-5.487). Results were similar in patients with CNS disease (OR 3.037, 95% CI 0.574-16.057) and primary bacteremia (OR 2.983, 95% CI 0.575-15.492). In our retrospective cohort, there was no statistically significant association between early combination therapy and 30-day mortality. A randomized controlled trial may be necessary to assess optimal treatment.

[WHO'S AFRAID OF INFECTIOUS DISEASES - A DISCIPLINE WITH BROAD IMPACT].

INTRODUCTION: The Infectious Diseases discipline is diverse, dynamic, vibrant, ever-changing, exciting and fascinating. The Infectious Diseases specialists have a major contribution both to the successful outcome of the individual patient with an infectious episode and to public health on multiple levels. The involvement of infectious diseases specialist in complex infections has shown to reduce mortality by about 50%. On the background of the global antimicrobial resistance crisis, the infectious diseases specialists have assumed another important role: to guard antibiotics and fight resistance. As a response to the crisis, guidelines to balance between the need for high quality treatment for the individual patient and sensible use of antibiotics were issued. These were named antibiotic stewardship programs. The Israeli Society of Infectious Diseases, instituted in 1979, has risen to the challenge and undertaken leadership in promoting antibiotic stewardship programs in Israel. This edition of Harefuah, dedicated to the disciple of Infectious Diseases, includes several original articles and reviews representing a selection of the major activities of the Israeli Infectious Diseases specialists. The topic of antibiotic stewardship is emphasized in this edition; it is covered by two original articles, a review and an editorial. Other topics covered are antibiotic resistance, vaccine effects, travel medicine and international medicine. The field of infectious diseases is facing important challenges, among them responses to the global antibiotic crisis and the development of efficient vaccines to fight life-threatening endemic and emerging infections, as well as future epidemics. The Israeli Infectious Diseases specialists are also committed to these important tasks.

[PRINCIPLES OF APPROPRIATE ANTIBIOTIC USAGE IN ISRAELBY THE ISRAELI SOCIETY FOR INFECTIOUS DISEASES: TO WHOM ARE THEY DIRECTED?]

INTRODUCTION: In this issue of Harefuah Nesher and Strahilevitz discuss the principles of appropriate antibiotic guidelines based on a position paper by the Israeli Society for Infectious Diseases (ISID). This editiorial discusses for whom this position paper was intended. The first and most obvious target would be the Infectious Disease (ID) physicians themselves. Since the setup of ID units in Israeli hospitals in the 1970s and 1980s, all have engaged in antibiotic control and infection control. Antibiotic control in Israel has always consisted of antibiotic restriction, development of guidelines for the most commonly encountered infections, and oversight of adherence to guidelines (including computer applications). In comparison, antibiotic control was not an ID priority in US hospitals until the concept of antibiotic stewardship emerged in the last decade. Second, the position paper could have been intended for hospital managements, in order to provide the resources necessary to make appropriate antibiotic use an attainable goal, in particular: allocation of highly skilled manpower (physicians, clinical microbiologists, pharmacists) and development of relevant computer applications. Third, the position paper could have been intended as a response to the initiatives by Ministry of Health National Center for Infection Control and Antibiotic Use. The latter was set up more than a decade ago to deal with emerging multi-drug resistant pathogens and to provide professional leadership. Unfortunately, a professional conflict has emerged between the ISID and the National Center, when the latter was trying to impose professional guidelines regarding antibiotic stewardship unilaterally. While Nesher and Strahilevitz outline the ISID view on antibiotic stewardship in Israeli hospitals, they also call for cooperation and joining forces to combat the huge problem of antibiotic resistance in Israel. Forth, the position paper was probably also intended for all physicians who prescribe antimicrobials, to engage them in the responsibility of guarding antibiotics for us and the next generations.

Ambient temperature and age-related notified Campylobacter infection in Israel: A 12-year time series study.

BACKGROUND: Campylobacter spp. are the leading cause of foodborne infection worldwide, with a seasonal disease peak that might be affected by temperature increase. We studied the relationship between ambient temperature and weekly notified Campylobacter spp.infections. METHODS: Data on 29,762 laboratory-confirmed cases of Campylobacter infection for the period, January, 1999 to December, 2010 were retrieved from the Ministry of Health registry. To estimate the association between the number of weekly cases of Campylobacter infection and the national average temperature at lags 0-3 weeks, firstly, we used GAM models, and secondly two-segment piecewise linear Poisson regressions. The effect of temperature was adjusted for seasonality, long-term trends and holidays. RESULTS: We found a J-shaped relationship between ambient temperature and notified Campylobacter spp. CASES: For C. jejuni in all ages, the curve below the threshold was constant and the percent increase in cases for 1 °C above a threshold of 27 °C was 15.4% (95%CI: 6.7-24.1%). For ages 3-10 yr and > =26 yr the curve was constant below the threshold and positive above it; the percent increase in cases for 1 °C was 17.7%(95%CI: 6.0-29.4%) and 23.7%(95%CI: 11.6-35.8%), respectively. For ages 0-2 yr the curve was linear with no threshold and the percent increase for 1 °C was 5.1%(95%CI: 2.1-8.1%). For ages 11-25 yr the curve was always constant. Results for C. coli were similar. CONCLUSION: Our findings indicate that higher temperatures throughout the year affect Campylobacter spp. morbidity, especially in younger children. This should be taken into consideration in public education and health system preparedness for temperature increases as a result of climate change.

Plasmodium malariae in Israeli Travelers: A Nationwide Study.

BACKGROUND: Little is known about Plasmodium malariae, a relatively rare cause of malaria in returned travelers. Recently, polymerase chain reaction (PCR) use for malaria diagnosis has enhanced specificity of P. malariae detection. The study objective was to describe the unique aspects of P. malariae diagnosis and clinical course in travelers. METHODS: Malaria is a reportable disease in Israel. All PCR-proven P. malariae monoinfections in Israeli travelers between January 2008 and January 2017 were retrieved from the Ministry of Health Reference Parasitology Laboratory. Data regarding method and timing of diagnosis, clinical characteristics, and laboratory testing were collected from patient charts. RESULTS: Eighteen patients with P. malariae were included. All cases were acquired in Africa. During the study period, the relative proportion of P. malariae increased (2%-10% of all malaria cases). Malaria was identified by blood smear in 10 of 18 patients (56%) on admission, and by rapid antigen test in 5 of 18 (29%) patients only, while P. malariae speciation was correctly identified by smear in 2 of 18 (11%) patients. Though all patients reported fever, only 4 of 18 (22%) described a quartan fever course. In 7 of 18 (39%) patients, malaria was contracted despite prophylactic treatment. Five patients had prolonged prepatent periods (median, 55 days), all of whom received prior prophylaxis. CONCLUSIONS: The relative proportion of P. malariae is on the rise. Diagnosis in routine clinical settings is inadequate due to the low sensitivity and specificity of blood smears. PCR should be considered when clinical suspicion is high. Prophylaxis failure, which caused delayed clinical presentation, was documented.

Travel-Related Tick-Borne Encephalitis, Israel, 2006-2014.

During 2006-2014, four tick-borne encephalitis (TBE) cases occurred among Israeli travelers. We calculated TBE incidence at 321.0, 45.0, 13.2, and 7.5 cases/100,000 travelers/year of travel to Sweden, Switzerland, Austria, and Germany, respectively. TBE incidence among travelers to these destinations appears to justify TBE vaccination in accordance with World Health Organization recommendations.

Complex clinical and microbiological effects on Legionnaires' disease outcone; A retrospective cohort study.

BACKGROUND: Legionnaires' disease (LD) is associated with high mortality rates and poses a diagnostic and therapeutic challenge. Use of the rapid urinary antigen test (UAT) has been linked to improved outcome. We examined the association between the method of diagnosis (UAT or culture) and various clinical and microbiological characteristics and outcome of LD. METHODS: Consecutive patients with pneumonia and confirmation of Legionella infection by a positive UAT and/or a positive culture admitted between the years 2006-2012 to a university hospital were retrospectively studied. Isolated L. pneumophila strains were subject to serogrouping, immunological subtyping and sequence-based typing. Variables associated with 30-day all-cause mortality were analyzed using logistic regression as well as cox regression. RESULTS: Seventy-two patients were eligible for mortality analyses (LD study group), of whom 15.5 % have died. Diagnosis based on positive L. pneumophila UAT as compared to positive culture (OR = 0.18, 95 % CI 0.03-0.98, p = 0.05) and administration of appropriate antibiotic therapy within 2 hospitalization days as compared to delayed therapy (OR = 0.16, 95 % CI 0.03-0.90, p = 0.04) were independently associated with reduced mortality. When controlling for intensive care unit (ICU) admissions, the method of diagnosis became non-significant. Survival analyses showed a significantly increased death risk for patients admitted to ICU compared to others (HR 12.90, 95 % CI 2.78-59.86, p = 0.001) and reduced risk for patients receiving appropriate antibiotic therapy within the first two admissions days compared to delayed therapy (HR 0.13, 95 % CI 0.04-0.05, p = 0.001). Legionella cultures were positive in 35 patients (including 29 patients from the LD study group), of whom 65.7 % were intubated and 37.1 % have died. Sequence type (ST) ST1 accounted for 50.0 % of the typed cases and ST1, OLDA/Oxford was the leading phenon (53.8 %). Mortality rate among patients in the LD study group infected with ST1 was 18.2 % compared to 42.9 % for non-ST1 genotypes (OR = 0.30, 95 % CI 0.05-1.91, p = 0.23). CONCLUSIONS: The study confirms the importance of early administration of appropriate antibiotic therapy and at the same time highlights the complex associations of different diagnostic approaches with LD outcome. Infection with ST1 was not associated with increased mortality. Genotype effects on outcome mandate examination in larger cohorts.

Increased incidence of Campylobacter spp. infection and high rates among children, Israel.

During 1999-2010, the annual incidence of Campylobacter spp. infection in Israel increased from 31.04 to 90.99 cases/100,000 population, a yearly increase of 10.24%. Children <2 years of age were disproportionally affected; incidence in this age group (356.12 cases/100,000 population) was >26-fold higher than for the 30-<50 age group.

Antibiotic exposure as a risk factor for fluconazole-resistant Candida bloodstream infection.

Recent exposure to azoles is an important risk factor for infection with fluconazole-resistant Candida spp., but little is known about the role of antibacterial drug exposure in the emergence of drug-resistant Candida. We did a prospective nationwide surveillance study of candidemia in Israel and analyzed the propensity score-adjusted association between antifungal and antibacterial drug exposure and bloodstream infection with C. glabrata and fluconazole-resistant Candida isolates. Four hundred forty-four episodes of candidemia (450 Candida isolates, 69 [15%] C. glabrata isolates, and 38 [8.5%] fluconazole-resistant isolates) from 18 medical centers in Israel were included. C. glabrata bloodstream infection was strongly associated with recent metronidazole exposure (odds ratio [OR], 3.2; P < 0.001). Infection with a fluconazole-resistant isolate was associated with exposure to carbapenems, trimethoprim-sulfamethoxazole, clindamycin, and colistin (odds ratio, 2.8; P = 0.01). The inclusion of antibacterial drug exposure in a multivariable model significantly enhanced the model's predictive accuracy for fluconazole-resistant Candida bloodstream infection. Our findings may be relevant to the selection of empirical antifungal treatment and broaden the scope of antibiotic-associated collateral damage.

The role of readily available clinical, laboratory and radiologic findings in distinguishing a/H1N1/2009 influenza from other causes of acute febrile respiratory illness under pandemic conditions.

BACKGROUND: During an influenza pandemic, clinicians need easily available clinical and laboratory criteria to distinguish influenza from similar respiratory illnesses. We compared A/H1N1/2009-polymerase chain reaction (PCR)-positive and matched PCR-negative hospitalized patients with suspected H1N1 influenza to identify factors that could assist physicians at patient admission. OBJECTIVES: To identify factors significantly associated with A/ H1N1/2009 infection. METHODS: A group of 145 patients with PCR-confirmed A/H1N1 2009 influenza admitted between 27 May 2009 and 3 December 2009 was matched with 145 PCR-negative patients by age, epidemiological week and pregnancy status. Epidemiological and clinical parameters and radiological findings on initial chest X-ray were compared between the two groups. RESULTS: Asthma (PCR+ 26%, PCR- 12%, P = 0.006) and military service (PCR+ 13%, PCR- 4%, P = 0.15) were associated with PCR-positive status in non-pregnant patients. At presentation, fever, cough, myalgia and fulfilling the pandemic influenza case definition were significantly more frequent in nonpregnant PCR+ patients (62/90/43/59% in PCR+ versus 38/69/30/35% in PCR-). In pregnant patients, fever and fulfilling the case definition were significantly associated with PCR-positive status. Mean leukocyte and absolute lymphocyte counts were significantly lower in both pregnant and nonpregnant PCR-positive patients. Significantly more PCR-negative non-pregnant patients (43% vs. 22% PCR+, P = 0.004) had abnormal chest X-ray (CXR) findings on presentation. In PCR-positive patients, patchy consolidation and interstitial infiltrates were the most common abnormalities. CONCLUSIONS: Under the conditions generated by the A/ H1 1/2009 pandemic, radiological findings did not distinguish reliably between influenza and other febrile respiratory illnesses. Asthma, military service, the pandemic case definition (particularly fever, cough and myalgia)

Predictors of mortality in COVID-19 patients treated with convalescent plasma therapy.

Several options to treat hospitalized severe COVID-19 patients have been suggested. The study aimed to describe survival in patients treated with convalescent COVID plasma (CCP) and to identify in-hospital mortality predictors. This prospective cohort study examined data from 112 severe COVID-19 patients hospitalized in the Corona Departments in an acute care hospital who received two units of CCP (at least one of them high-titer). Demographic and medical data was retrieved from the patients' electronic health records (EHR). Possible predictors for in-hospital mortality were analyzed in a univariate analysis and those found to be clinically significant were further analyzed in a multivariable analysis. Median age was 67 years (IQR 55-74) and 66 (58.9%) of them were males. Of them, 20 (17.9%) died in hospital. On multivariable analysis diabetes mellitus (p = 0.004, OR 91.54), mechanical ventilation (p = 0.001, OR 59.07) and lower albumin levels at treatment (p = 0.027, OR 0.74) were significantly associated with increased in-hospital mortality. In our study, in-hospital mortality in patients receiving CCP is similar to that reported for the general population, however certain variables mentioned above were associated with increased in-hospital mortality. In the literature, these variables were also associated with a worse outcome in patients with COVID-19 who did not receive CCP. As evidence points toward a benefit from CCP treatment in immunocompromised patients, we believe the above risk factors can further define COVID-19 patients at increased risk for mortality, enabling the selection of candidates for early treatment in an outpatient setting if possible.

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.

Multidrug-resistant Salmonella enterica serovar Infantis, Israel.

To determine whether rapid emergence of Salmonella enterica serovar Infantis in Israel resulted from an increase in different biotypes or spread of 1 clone, we characterized 87 serovar Infantis isolates on the genotypic and phenotypic levels. The emerging strain comprised 1 genetic clone with a distinct pulsed-field gel electrophoresis profile and a common antimicrobial drug resistance pattern.

WGS-Based Prediction and Analysis of Antimicrobial Resistance in Campylobacter jejuni Isolates From Israel.

Rapid developments in the field of whole genome sequencing (WGS) make in silico antimicrobial resistance (AMR) a target within reach. Campylobacter jejuni is a leading cause of foodborne infections in Israel with increasing rates of resistance. We applied WGS analysis to study the prevalence and genetic basis of AMR in 263 C. jejuni human and veterinary representative isolates retrieved from a national collection during 2003-2012. We evaluated the prediction of phenotypic AMR from genomic data. Genomes were screened by the NCBI AMRFinderPlus and the BioNumerics tools for acquired AMR genes and point mutations. The results were compared to phenotypic resistance determined by broth microdilution. The most prevalent resistant determinants were the multi-drug efflux transporter gene cmeABC (100%), the tetracycline resistance tet(O) gene (82.1%), the quinolone resistance gyrA T861 point mutation (75.7%), and the aadE streptomycin resistance gene. A variety of 12 known ß lactam resistance genes (blaOXA variants) were detected in 241 (92%) isolates, the most prevalent being blaOXA-193, blaOXA-461, and blaOXA-580 (56, 16, and 7%, respectively). Other aminoglycoside resistance genes and the macrolide resistance point mutation were rare (<1%). The overall correlation rate between WGS-based genotypic prediction and phenotypic resistance was 98.8%, sensitivity, specificity, positive, and negative predictive values being 98.0, 99.3, 99.1, and 98.5%, respectively. wgMLST-based phylogeny indicated a high level of clonality and clustering among the studied isolates. Closely related isolates that were part of a genetic cluster (single linkage distance ≤ 15 alleles) based on wgMLST phylogeny mostly shared a homogenous AMR determinant profile. This was observed in 18 of 20 (90.0%) clusters within clonal complex-21, suggesting clonal expansion of resistant isolates. Strong association to lineage was noted for the aadE gene and the various blaOXA genes. High resistance rates to tetracycline and quinolones and a low resistance rate to macrolides were detected among the Israeli C. jejuni isolates. While a high genotypic-phenotypic correlation was found, some resistance phenotypes could not be predicted by the presence of AMR determinants, and particularly not the level of resistance. WGS-based prediction of antimicrobial resistance in C. jejuni requires further optimization in order to integrate this approach in the routine workflow of public health laboratories for foodborne surveillance.

Rituximab identified as an independent risk factor for severe PJP: A case-control study.

OBJECTIVE: Pneumocystis jirovecii pneumonia (PJP) was reported among immunosuppressed patients with deficits in cell-mediated immunity and in patients treated with immunomodulatory drugs. The aim of this study was to identify risk-factors for PJP in noninfected HIV patients. METHODS: This retrospective, test negative, case-control study was conducted in six hospitals in Israel, 2006-2016. Cases were hospitalized HIV-negative patients with pneumonia diagnosed as PJP by bronchoalveolar lavage. Controls were similar patients negative for PJP. RESULTS: Seventy-six cases and 159 controls were identified. Median age was 63.7 years, 65% males, 34% had hematological malignancies, 11% inflammatory diseases, 47% used steroids and 9% received antilymphocyte monoclonal antibodies. PJP was independently associated with antilymphocyte monoclonal antibodies (OR 11.47, CI 1.50-87.74), high-dose steroid treatment (OR 4.39, CI 1.52-12.63), lymphopenia (OR 8.13, CI 2.48-26.60), low albumin (OR 0.15, CI 0.40-0.54) and low BMI (OR 0.80, CI 0.68-0.93). CONCLUSION: In conclusion, rituximab, which is prescribed for a wide variety of malignant and inflammatory disorders, was found to be significant risk-factor for PJP. Increased awareness of possible PJP infection in this patient population is warranted.

High Morbidity Due to Murine Typhus Upsurge in Urban Neighborhoods in Central Israel.

The incidence of murine typhus in Israel has decreased substantially since 1950 to a low of 0.04/100,000 population in 2010. We present the experience of a single university medical center in central Israel. Hospitalized patients serologically positive for Rickettsia typhi by indirect immunofluorescence antibody assay during 2006-2016 were retrospectively identified. Clinical and laboratory data from patients' charts were used to analyze disease trends and distribution. Seventy-eight patients were studied (mean age: 27.9 years), mostly of Arab ethnicity (68, 87.2%). Seventy-one (91%) patients resided in two large mixed Jewish-Arab cities-Lod and Ramla. The incidence of murine typhus among the Arab population in Lod increased 8.4-fold from 6.4/100,000 in 2006 to a peak of 53.4/100,000 in 2013. The average annual incidence among Arabs in Ramla was 10.1/100,000. Among Jews, incidences were 0.8/100,000 in Lod and 0.4/100,000 in Ramla. The classical triad of fever, headache, and rash was noted in 20.8% patients. Substantial morbidity included prolonged fever before hospitalization and hospital stay (mean of 8.4 and 5.1 days, respectively), and severe complications in six patients, including pneumonitis in three patients, and splenic infarctions, pericardial effusion, and retinitis, each in one. One previously healthy patient died of multiorgan failure. The study describes a high incidence of murine typhus with a recent upsurge in an urban setting in central Israel. High morbidity and a single fatal outcome challenge the concept of murine typhus being a mild disease. The study calls for better rodent control and sanitation measures in the affected neighborhoods.