Hyperimmune Globulins in COVID-19.

The COVID-19 pandemic, resulting from the emergence of the novel coronavirus SARS-CoV-2, posed unprecedented challenges to global health systems as no proven therapy was available. Initially, COVID-19 convalescent plasma (CCP) from recovered COVID-19 patients showed promise as a therapeutic option. However, the efficacy of this approach was closely correlated with the neutralizing antibody titer in the administered plasma and thus effectiveness was not always guaranteed. In response, hyperimmune immunoglobulins (hIG) derived from CCP obtained by apheresis from recovered or vaccinated individuals emerged as a potential alternative. hIG were purified through stringent chromatographic processing from CCP units and displayed varying results in clinical trials, although it seems likely that they improved outcomes compared to placebo or CCP at day 28, particularly in unvaccinated patients. The variability in the effect of hIG likely stems from factors such as the timing of outcome assessment, the administered dose of hIG, the patients' immunological background, and the matching between the variant infecting patients and the neutralization ability of the immunoglobulin batch, which depended on the timing of the CCP collection. Despite logistical challenges and high production costs, hIG showcase advantages over CCP, offering versatility in administration routes and eliminating the need for blood matching, thus facilitating administration in the community, and allowing for variant-specific preparations. hIG appear to be of particular importance in the treatment of immunocompromised patients and patients with persistent COVID-19, although studies in these populations are lacking. Non-human alternatives, such as equine-derived hIG and recombinant hIG, may provide a solution to the logistical challenges of large-scale hIG preparation. Further study is needed to explore these avenues. Establishing the infrastructure for large-scale hIG production independent of plasma donations emerges as a strategic approach for future pandemics, justifying exploration and promotion by health authorities.

The impact of Boric Acid tubes on quantitative urinary bacterial cultures in hospitalized patients.

INTRODUCTION: The accuracy of urine culture results can be affected by pre-analytical factors such as transport delays and storage conditions. The objectives of this study were to analyze urine collection practices and assess the impact of introducing boric acid tubes for urine collection on quantitative urinary bacterial cultures of hospitalized patients in medical wards. METHODS: A quasi-experimental pre-post study conducted in an acute care facility. In the pre-intervention phase (2020-2021), urine samples were transported without preservatives at room temperature. In 2022 (post-intervention), we transitioned to boric acid transport tubes, evaluating its effect on significant bacterial growth (≥ 105 CFU/ml). Bivariate and multivariate analyses identified predictors of culture positivity. RESULTS: Throughout the duration of the study, a total of 12,660 urine cultures were analyzed. Date and time documentation was complete for 38.3% of specimens. Culture positivity was higher with longer processing times: positivity was 21.3% (220/1034) when specimens were processed within 4 h, 28.4% (955/3364) when processed in 4-24 h, and 32.9% (137/417) when processed after 24 h (p < 0.0001). For 4-24-hour processing, positivity decreased from 30.4% (704/2317) pre-intervention to 24.0% (251/1047) post-intervention (p < 0.001), with no significant changes in < 4 or ≥ 24-hour specimens. Stratified analysis by processing time revealed that the intervention was associated with reduced positivity only in cultures processed within 4-24 h (OR 0.80, 95% CI 0.67-0.94; p = 0.008). CONCLUSION: The introduction of boric acid transport tubes predominantly influenced cultures transported within a 4-24-hour window. This presents an opportunity to improve urine tract infection diagnostic practices in healthcare settings.

Blood stream Infections in chronic hemodialysis patients - characteristics and outcomes.

INTRODUCTION: Bloodstream Infections (BSI) are a major cause of death and hospitalization among hemodialysis (HD) patients. The rates of BSI among HD patients vary and are influenced by local patient and pathogen characteristics. Modifications in local infection prevention protocols in light of active surveillance of BSI has been shown to improve clinical outcomes. The aim of this study was to further explore factors associated with BSI in a contemporary cohort of HD patients at a public teaching hospital dialysis center in Israel. METHODS: This was a retrospective cohort study of HD patients with a BSI in the years 2014 to 2018. The primary outcome was the occurrence of BSI. Secondary outcomes were to describe the causative pathogens of BSI, and to assess for risk factors for BSI, and mortality. RESULTS: Included were 251 patients. The mean age was 68.5 ± 13.4 years, 66.9% were male. The mean time from initiation of dialysis was 34.76 ± 40.77 months, interquartile range (IQR) 1-47.5 months and the follow up period of the cohort was 25.17 ± 15.9 months. During the observation period, 44 patients (17.5%) developed 54 BSI events, while 10 of them (3.9% of the whole cohort) developed recurrent BSI events. Gram-negative microorganisms caused 46.3% of all BSI events. 31.4% of these BSI were caused by resistant bacteria. In a multivariate logistic regression analysis, patients receiving dialysis through a central line had a significantly increased risk for BSI adjusted Odds Ratio (aOR) 3.907, p = 0.005, whereas patients' weight was mildly protective (aOR 0.971, p = 0.024). CONCLUSIONS: We noted an increased prevalence of gram-negative pathogens in the etiology of BSI in HD patients. Based on our findings, additional empirical antibiotics addressing gram negative bacteria have been added to our empirical treatment protocol. Our findings highlight the need to follow local epidemiology for implementing appropriate preventative measures and for tailoring appropriate empiric antibiotic therapy.

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.

A Randomized Controlled Study Assessing Convalescent Immunoglobulins vs Convalescent Plasma for Hospitalized Patients With Coronavirus 2019.

BACKGROUND: It is unknown whether convalescent immunoglobulins (cIgGs) are better than convalescent plasma (CP) for patients with coronavirus 2019 (COVID-19). METHODS: In this randomized controlled trial, we assigned high risk COVID-19 patients with ≤10 days of symptoms, to receive cIgGs or CP. The primary endpoint was improvement on day 14 according to the World Health Organization scale. Secondary endpoints were survival on day 14, and improvement, survival, and percent of ventilated patients on day 28, and treatment response in unvaccinated and vaccinated patients. RESULTS: A total of 319 patients were included: 166 received cIgGs and 153 CP. Median age was 64 to 66 years. A total of 112 patients (67.5%) in the cIgG group and 103 patients (67.3%) in the CP group reached the primary endpoint. Difference between groups was 0.1 (95% confidence interval, -10.1 to 10.4; P = .026), failing to reach noninferiority. More patients receiving cIgG improved by day 28 (136 patients [81.9%] and 108 patients [70.6%], respectively; 95% confidence interval, 1.9-20.7; P < .001; for superiority P = .018). Seventeen patients in the cIgG group (10.2%) and 25 patients (16.3%) in the CP group required mechanical ventilation (P = .136). Sixteen (9.6%) and 23 (15%) patients, respectively, died (P = .172). More unvaccinated patients improved by day 28 in the cIgG group (84.1% vs 66.1%; P = .024), and survival was better in the cIgG group (89.9% vs 77.4%; P = .066). CONCLUSIONS: cIgGs failed to reach the primary noninferiority endpoint on day 14 but was superior to CP on day 28. Survival and improvement by day 28 in unvaccinated patients treated with cIgGs were better. In the face of new variants, cIgGs are a viable option for treating COVID-19. TRIAL REGISTRATION NUMBER: My Trials MOH_2021-01-14_009667.

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.

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.

Qualifying coronavirus disease 2019 convalescent plasma donors in Israel.

BACKGROUND AND OBJECTIVES: Passive immunization using investigational COVID-19 convalescent plasma (CCP) is a promising therapeutic strategy and could improve outcome if transfused early and contain high levels of anti-SARS-CoV-2 antibodies. We report the management of a national CCP collection and distribution program in Israel. MATERIALS AND METHODS: From 1 April 2020 to 15 January 2021, 4020 volunteer donors donated 5221 CCP units and 837 (20.8%) donors donated more than once. Anti-nucleocapsid IgG antibodies were determined using chemiluminescent immunoassay method (Abbott). A statistical model based on repeated IgG tests in sequential donations was created to predict the time of antibody decline below sample/cut-off (S/CO) level of 4.0. RESULTS: Ninety-six percent of CCP donors suffered a mild disease or were asymptomatic. Older donors had higher antibody levels. Higher antibody levels (S/CO ≥4) were detected in 35.2% of the donors. Low positive (S/CO ≥1.4-3.99) were found in 37%, and 27.8% had undetectable antibodies (S/CO ≤1.4). The model predicted decrease antibody thresholds of 0.55%/day since the first CCP donation, providing guidance for the effective timing of future collections from donors with high antibody levels. CONCLUSIONS: An efficient CCP collection and distribution program was achieved, based on performing initial and repeated plasma collections, preferably from donors with higher antibody levels, and only antibody-rich units were supplied for therapeutic use. The inventory met the quantity and quality standards of the authorities, enabled to respond to the growing demand of the medical system and provide a product that may contribute to improve prognosis in patients with COVID-19.

Emergence of Mycobacterium canariasense infections in central Israel.

In 2018, Mycobacterium canariasense bloodstream infection was diagnosed in Israel. Further investigation had identified additional five cases in three medical centers, including isolates from blood (1), cornea (1), and sputum (3). Isolates were susceptible to all the antimicrobial tested. All but one isolate was related by whole-genome phylogeny.

Short- and long-term mortality in patients with urosepsis caused by Escherichia coli susceptible and resistant to 3rd generation cephalosporins.

BACKGROUND: The aim of this study was to compare short- and long-term mortality among patients with urosepsis caused by Escherichia coli susceptibile (EC-SC) and resistant (EC-RC) to 3rd generation cephalosporins. METHODS: A retrospective cohort study that included all patients with E. coli urosepsis admitted to a 700-bed hospital from January 2014 until December 2019. Mortality up to 30 days, 6 months and 1 year was assessed using logistic multivariate regression analysis and Cox regression analysis. RESULTS: A total of 313 adult were included, 195 with EC-SC and 118 patients with EC-RC. 205 were females (74%), mean age was 79 (SD 12) years. Mean Charlson score was 4.93 (SD 2.18) in the EC-SC group and 5.74 (SD 1.92) in the EC-RC group. Appropriate empiric antibiotic therapy was initiated in 245 (78.3%) patients, 100% in the EC-SC group but only 42.5% in the EC-RC group. 30-day mortality occurred in 12 (6.3%) of EC-SC group and 15 (12.7%) in the EC-RC group. Factors independently associated with 30-day mortality were Charlson score, Pitt bacteremia score, fever upon admission and infection with a EC-RC. Appropriate antibiotic therapy was not independently associated with 30-day mortality. Differences in mortality between groups remained significant one year after the infection and were significantly associated with the Charlson co-morbidity score. CONCLUSIONS: Mortality in patients with urosepsis due to E. coli is highly affected by age and comorbidities. Although mortality was higher in the EC-RC group, we could not demonstrate an association with inappropriate empirical antibiotic treatment. Mortality remained higher at 6 months and 1 year long after the infection resolved but was associated mainly with co-morbidity.

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.

Laboratory Diagnosis of 37 Cases of Bartonella Endocarditis Based on Enzyme Immunoassay and Real-Time PCR.

Bartonella spp., mostly Bartonella quintana and B. henselae, are a common cause of culture-negative endocarditis. Serology using immunofluorescence assay (IFA) and PCR performed on cardiac tissues are the mainstays of diagnosis. We developed an enzyme immunoassay (EIA) and a novel multiplex real-time PCR assay, utilizing Bartonella genus-specific, B. henselae-specific, and B. quintana-specific SimpleProbe probes, for diagnosis of Bartonella endocarditis. We aimed to evaluate the performance of these assays. Thirty-seven patients with definite endocarditis, 18 with B. henselae, 18 with B. quintana, and 1 with B. koehlerae, were studied. Diagnosis was confirmed by conventional PCR and DNA sequencing of surgical cardiac specimens. Similar to the case with IFA, anti-Bartonella IgG titers of ≥1:800 were found in 94% of patients by EIA; cross-reactivity between B. henselae and B. quintana precluded species-specific serodiagnosis, and frequent (41%) but low-titer cross-reactivity between Coxiella burnetii antibodies and B. henselae antigen was found in patients with Q fever endocarditis. Low-titer (1:100) cross-reactivity was uncommonly found also in patients with brucellosis and culture-positive endocarditis, particularly Enterococcus faecalis endocarditis. Real-time PCR performed on explanted heart valves/vegetations was in complete agreement with results of sequence-based diagnosis with characteristic melting curves. The genus-specific probe identified five additional endocarditis-associated Bartonella spp. at the genus level. In conclusion, EIA coupled with a novel real-time PCR assay can play an important role in Bartonella endocarditis diagnosis and expand the diagnostic arsenal at the disposal of the clinical microbiologist. Since serology remains a major diagnostic tool, recognizing its pitfalls is essential to avoid incorrect diagnosis.

[COVID-19 - BLOOD GROUPS, ANTIBODIES AND CONVALESCENT PLASMA].

INTRODUCTION: Israel is currently struggling with the Coronavirus Disease (COVID-19) caused by SARS CoV-2. Transmission is increasing, with higher morbidity and mortality among populations at risk. Over-representation of blood type A was reported in COVID-19 patients with increased respiratory failure, while blood type O seems to have a protective effect. This may be caused by interference of anti-A antibodies in viral binding to the ACE receptor, different neutralization antibodies potency or variations in the stability of von Willebrand factor (VWF) multimers in different blood types. Since transfusion of convalescent COVID19 Plasma (CCP) is an accepted therapeutic modality, the Ministry of Health initiated a national project whereby CCP is collected by Magen David Adom (MDA) Blood Services using apheresis procedures and transfusions are approved by an experts committee, as part of the clinical trial or as compassionate treatment. Preliminary analysis of 49/170 patients treated so far shows improvement in 49%, with important relations with the anti-SARS-CoV-2 IgG antibodies level in the transfused plasma. Anti-SARS-CoV-2 antibodies were found in 83% of 1100 CCP donors, but a 13% decrease in antibodies level was detected in repeat donations. Blood type A was more predominant among CCP donors, when compared to MDA blood donors' data. A transfusion of CCP is a feasible and relatively safe therapeutic modality, mainly for patients with moderate COVID 19. CCP also serves as a source for the production of hyperimmune globulin for the treatment of COVID 19 and for passive immunization for populations at risk.

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.

Aminoglycoside versus carbapenem or piperacillin/tazobactam treatment for bloodstream infections of urinary source caused by Gram-negative ESBL-producing Enterobacteriaceae.

OBJECTIVES: We studied the performance of aminoglycosides in treating bloodstream infections (BSIs) of urinary source caused by ESBL-producing Enterobacteriaceae (ESBL-EB). METHODS: In a retrospective study of 193 patients with a clinical diagnosis of urinary tract infection, pyelonephritis or urosepsis and blood and urine cultures positive for ESBL-EB, patients were grouped according to whether they were treated with an aminoglycoside, a carbapenem or piperacillin/tazobactam. Multivariate analysis was used to define risk factors for mortality with inverse probability of treatment weighting used to minimize confounding. The primary efficacy outcome was 30 day mortality. The primary safety outcome was acute kidney injury (AKI) at 14 days. RESULTS: Mean age was 79.3 years. Dementia, chronic kidney disease and the presence of a urinary catheter were common. Thirty-two (16.6%) patients died and risk factors for mortality included age, high Charlson score, presentation with severe sepsis/septic shock and infection with bacteria other than Escherichia coli. Aminoglycosides were non-inferior compared with other antibiotics regarding 30 day mortality [13.0% versus 21.2%, respectively; adjusted risk difference=10.29% (-0.82% to 21.41%)], but did not reach non-inferiority for bacteriuria recurrence [48.9% versus 44.7%, respectively; adjusted risk difference=-8.72% (-30.87% to 13.43%)]. AKI developed at a similar rate in both treatment groups: 12.0% versus 10.6%, respectively [OR=1.14 (0.46-2.81)]. Aminoglycosides were more efficacious in E. coli infections compared with other ESBL-EB. CONCLUSIONS: We demonstrated the efficacy and safety of aminoglycosides in treating BSI of urinary source caused by ESBL-EB. This carbapenem-sparing approach can assist in avoiding excessive carbapenem use without compromising outcomes.

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.

The synergistic effect of PDT and oxacillin on clinical isolates of Staphylococcus aureus.

BACKGROUND: Staphylococcus aureus is a major pathogen in clinical microbiology. It is known to cause infections at various body sites and can be life-threatening. The development of resistance to many well-established antibiotic treatments and the prevalence of methicillin-resistant S. aureus (MRAS) among hospital patients and the general community pose challenges in treating the pathogen. The antimicrobial effect of photodynamic therapy (PDT) has been a subject of study for a long time and can offer new strategies for dealing with resistant strains. OBJECTIVE: In our study, we searched for a positive synergistic relationship between PDT and the standard antibiotics used to treat S. aureus and MRSA infections. MATERIALS AND METHODS: The phototoxic profile of deuteroporphyrin (DP) in both resistant and susceptible clinical strains of S. aureus was determined by plating of treated and untreated broth cultures. Electron microscopy imaging was done to explore possible sites of damage and free-radical accumulation in the cells during DP-PDT. Minimal inhibitory concentration (MIC) of oxacillin, gentamicin, vancomycin, rifampin, and fusidic acid was determined using the broth dilution method, and the checkerboard method was used to detect and evaluate the synergistic potential of DP-PDT and antibiotic combinations. A synergistic combination was further characterized using broth cultures and plating. RESULTS: DP-PDT using a light dose of 15 J/cm2 showed a bactericidal effect even with a small concentration of 17 µM DP. Transmission electron microscopy indicated profound damage in the cell wall and cell membrane, and the appearance of mesosome-like structures. Free radicals tend to localize in the cell membrane and inside the mesosome. No synergistic effect was detected by combining PDT with gentamicin, vancomycin, rifampin, and fusidic acid treatments. A positive synergistic effect was observed only in DP-PDT-oxacillin combined treatment using the checkerboard method. The effect was observed in clinical antibiotic-resistant isolates after DP-PDT using a light dose of 46 J/cm2 and small concentrations of DP. Oxacillin MIC decreased below 2 µg/ml in resistant strains under such conditions. Cultures which did not undergo new cycles of DP-PDT recovered their original oxacillin resistance after a few generations. CONCLUSIONS: PDT with porphyrins shows possible new therapeutic options in treating drug-resistant S. aureus at body sites suitable for irradiation. The synergistic effect of DP-PDT with oxacillin on clinical strains illustrates the potential of PDT to augment traditional antibiotic treatment based on cell wall inhibitors. Lasers Surg. Med. 50:535-551, 2018. © 2018 Wiley Periodicals, Inc.

Multidrug-Resistant Candida haemulonii and C. auris, Tel Aviv, Israel.

Candida auris and C. haemulonii are closely related, multidrug-resistant emerging fungal pathogens that are not readily distinguishable with phenotypic assays. We studied C. auris and C. haemulonii clinical isolates from 2 hospitals in central Israel. C. auris was isolated in 5 patients with nosocomial bloodstream infection, and C. haemulonii was found as a colonizer of leg wounds at a peripheral vascular disease clinic. Liberal use of topical miconazole and close contact among patients were implicated in C. haemulonii transmission. C. auris exhibited higher thermotolerance, virulence in a mouse infection model, and ATP-dependent drug efflux activity than C. haemulonii. Comparison of ribosomal DNA sequences found that C. auris strains from Israel were phylogenetically distinct from isolates from East Asia, South Africa and Kuwait, whereas C. haemulonii strains from different countries were closely interrelated. Our findings highlight the pathogenicity of C. auris and underscore the need to limit its spread.