Objectives mRNA 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 get infected and suffer 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 multicenter cohort study of 17 hospitals included Pfizer/BioNTech's BNT162b2 fully-vaccinated patients 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 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). Notable, the cohort was characterized by a high rate of comorbidities predisposing to severe COVID-19, including hypertension (108, 71%), diabetes (73, 48%), CHF (41, 27%), chronic kidney and lung diseases (37, 24% each), dementia (29, 19%), and cancer (36, 24%), and only 6 (%) had no comorbidities. Sixty (40%) of the patients were immunocompromised. Higher SARS-CoV-2 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 titers 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 comorbidities. Our patients had a higher rate of comorbidities and immunosuppression compared to previously reported non-vaccinated hospitalized COVID-19 patients. 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.
Tuberculosis treatment is shortened to six months by the indispensable addition of pyrazinamide (PZA) to the drug regimen that includes isoniazid and rifampin. PZA is a pro-drug of pyrazinoic acid (POA) (ref. 3), whose target of action has never been identified. Although PZA is active only against Mycobacterium tuberculosis, the PZA analog 5-chloro-pyrazinamide (5-Cl-PZA) displays a broader range of anti-mycobacterial activity. We have found that the eukaryotic-like fas1 gene (encoding fatty acid synthetase I, FASI) from M. avium, M. bovis BCG or M. tuberculosis confers resistance to 5-Cl-PZA when present on multi-copy vectors in M. smegmatis. 5-Cl-PZA and PZA markedly inhibited the activity of M. tuberculosis FASI, the biosynthesis of C16 to C24/C26 fatty acids from acetyl-CoA (ref. 6). Importantly, PZA inhibited FASI in M. tuberculosis in correlation with PZA susceptibility. These results indicate that FASI is a primary target of action for PZA in M. tuberculosis. Further characterization of FASI as a drug target for PZA may allow the development of new drugs to shorten the therapy against M. tuberculosis and may provide more options for treatment against M. bovis, M. avium and drug resistant M. tuberculosis.
Candida species have emerged as frequent causes of nosocomial bloodstream infection (BSI) in association with well-defined risk factors, including prolonged hospitalization, abdominal surgery, antibiotic treatment, neutropenia and central venous catheterization (14). Candidemia is associated with high rates of attributable mortality, prolongation of hospital stay, and excessive costs (28). In recent years, there has been a shift in the distribution of Candida species causing invasive infection, with non-albicans species now surpassing Candida albicans in many institutions (14,25). Of particular concern is the rising incidence of the azolenonsusceptible species C. glabrata and the inherently fluconazoleresistant species C. krusei (11,25,27).Fluconazole is often used as empirical treatment of candidemia. However, given the correlation between the survival rate and the timely initiation of appropriate treatment for candidemia (8), accurate assessment of the risk of fluconazole-resistant Candida (FRC) BSI is of prime importance. Patients who were recently treated with an azole drug are at increased risk of infection with FRC (9) and should be treated initially with an echinocandin agent according to current guidelines (18). However, experimental and clinical data support the notion that nonantifungal antimicrobial agents also affect the risk of colonization and infection with FRC (15,17,22). Since exposure to antibacterial drugs among at-risk patients far exceeds exposure to antifungal agents, even modest effects of individual antibacterials could translate into significant overall changes in the susceptibility patterns of Candida spp. Nevertheless, the collateral effects of antibacterial drugs on Candida spp. are poorly understood. To address this question, we analyzed prospectively collected data from a nationwide study of candidemia in Israel and examined the association between exposure to antifungal and antibacterial agents and the risk of infection with FRC. MATERIALS AND METHODS Study design.We performed a prospective nationwide study of candidemia in Israel from November 2005 through June 2007. Eighteen medical centers, which together account for 75% of the hospital beds in Israel, were included. All candidemia episodes that occurred in the participating centers during the study period were eligible for inclusion in this study. Clinical data were prospectively entered into standardized data forms by on-site investigators at each of the centers. The Candida sp. clinical isolates underwent preliminary identification and susceptibility testing in each center according to local practices. Subsequently, the isolates were transferred together with the corresponding data forms to the central study site, where species identification and susceptibility testing were performed as detailed below. The data forms were collected by the study coordinator, reviewed by the principal investigator, and entered into a computerized database. The study was approved by the ethics committee of each of the participating centers.Data...
Bartonella koehlerae is reported for the first time to be a human pathogen that causes culture-negative endocarditis. It is also shown that this species, isolated twice before from domestic cats, can be recovered as well from a stray cat population in Israel. This work follows a recent report of the same case in which the causative agent was misidentified as B. henselae, based on serology and PCR-restriction fragment length polymorphism (
From Allium stipitatum, three pyridine-N-oxide alkaloids (1-3) possessing disulfide functional groups were isolated. The structures of these natural products were elucidated by spectroscopic means as 2-(methyldithio)pyridine-N-oxide (1), 2-[(methylthiomethyl)dithio]pyridine-N-oxide (2), and 2,2′-dithio-bis-pyridine-N-oxide (3). The proposed structure of 1 was confirmed by synthetic S-methylthiolation of commercial 2-thiopyridine-N-oxide. Compounds 1 and 2 are new natural products, and 3 is reported for the first time from an Allium species. All compounds were evaluated for activity against fast-growing species of Mycobacterium, methicillin-resistant Staphylococcus aureus, and a multidrug-resistant (MDR) variants of S. aureus. Compounds 1 and 2 exhibited minimum inhibitory concentrations (MICs) of 0.5-8 μg/mL against these strains. A small series of analogues of 1 were synthesized in an attempt to optimize antibacterial activity, although the natural product had the most potent in vitro activity. In a whole-cell assay at 30 μg/mL, 1 was shown to give complete inhibition of the incorporation of 14C-labeled acetate into soluble fatty acids, indicating that it is potentially an inhibitor of fatty acid biosynthesis. In a human cancer cell line antiproliferative assay, 1 and 2 displayed IC50 values ranging from 0.3 to 1.8 μM with a selectivity index of 2.3 when compared to a human somatic cell line. Compound 1 was evaluated in a microarray analysis that indicated a similar mode of action to menadione and 8-quinolinol by interfering with the thioredoxin system and up-regulating the production of various heat shock proteins. This compound was also assessed in a mouse model for in vivo toxicity.
Background: We assessed outcome of patients with moderate and severe COVID-19 following treatment with convalescent plasma (CP) and the association with IgG levels in transfused CP. Methods: A prospective cohort study. Primary outcome was improvement at day 14 defined as alive, not on mechanical ventilation, and moderate, mild, or recovered from COVID-19. Antibody levels in CP units were unknown at the time of treatment. IgG against the spike protein S1 was subsequently measured by ELISA. Neutralizing antibodies titers were determined in a subset. Outcome was assessed in relation to the mean antibody level transfused to the patients (4.0 versus >4.0). Findings: Of 49 patients, 11 (22.4%) had moderate, 38 (77.6%) had severe disease, 28 were ventilated. At day 14, 24 (49.0%) patients improved, 9 (18.4%) died, and 13 (26.5%) were ventilated. In 14/98 (14.3%) CP units
An analog of pyrazinamide (PZA), 5-chloropyrazinamide (5-Cl-PZA), has previously been shown to inhibit mycobacterial fatty acid synthase I (FASI). FASI has been purified from a recombinant strain of M. smegmatis (M. smegmatis ⌬fas1 attB::M. tuberculosis fas1). Following purification, FASI activity and inhibition were assessed spectrophotometrically by monitoring NADPH oxidation. The observed inhibition was both concentration and structure dependent, being affected by both substitution at the 5 position of the pyrazine nucleus and the nature of the ester or N-alkyl group. Under the conditions studied, both 5-Cl-PZA and PZA exhibited concentration and substrate dependence consistent with competitive inhibition of FASI with K i s of 55 to 59 M and 2,567 to 2,627 M, respectively. The results were validated utilizing a radiolabeled fatty acid synthesis assay. This assay showed that FASI was inhibited by PZA and pyrazinoic acid as well as by a series of PZA analogs.
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