CARD9 mutations in patients with fungal infections: An update from the last 5 years.

BACKGROUND: Autosomal recessive deficiency in the caspase recruitment domain-containing protein 9 (CARD9) is a congenital immunological condition that leads to susceptibility to mucocutaneous and invasive fungal infections. There is growing incidence of fungal infections in patients with CARD9 deficiency, a phenomenon that is increasingly recognised. OBJECTIVES: This study aimed to assess the frequency, geographic distribution and nature of mutations in patients with CARD9 deficiency, based on published papers in the literature until March 2023. METHODS: We swiftly conducted a study to pinpoint every documented instance of fungal infections arising from CARD9 deficiency. We selected case reports from the databases of PubMed, Embase, Scopus and Google Scholar spanning the period from October 2009 to March 2023. RESULTS: We analysed 90 cases of fungal infections and identified 32 mutations in the CARD9 gene. Notably, the homozygous (HMZ) p.Q295X (c.883C > T) mutation was associated with an increased risk of candidiasis. In contrast, the HMZ p.Q289X (c.865C > T) mutation is linked to a higher risk of dermatophytosis. We observed differences in the geographical distribution of these mutations. The primary mutations found in African patients differ from those in Asian patients. Specifically, Asian patients exhibit a broader spectrum of CARD9 mutations than African patients. CONCLUSIONS: The diversity of mutations observed in the 90 cases revealed 32 distinct variations, emphasising the unique genetic alterations in the CARD9 gene associated with specific geographical areas and the corresponding prevalence of fungal infections.

Antimicrobial peptides against polymyxin-resistant Klebsiella pneumoniae: a patent review.

The spread of polymyxin-resistant Klebsiella pneumoniae strains represents an emerging health challenge, limiting treatment options for the patients. Thus, the development of new antimicrobials is an urgent requirement. Antimicrobial peptides (AMPs) are a large class of compounds that are part of innate immune response; these peptides are promising compounds in the field of antimicrobial resistance and are present in all organisms. The present review evaluated patents on antimicrobial peptides tested against polymyxin-resistant K. pneumoniae, available on Espacenet as of September 2022. A total of 1313 patents were examined and 1197 excluded as they were out of focus for this review; 104 patents of peptides tested against K. pneumoniae were included; of which only 14 were tested against polymyxin-resistant K. pneumoniae strains. The results indicated that all AMPs evaluated were in the experimental or pre-clinical phase; the clinical phase is pending. Furthermore, a few peptides were tested effectively against polymyxin-resistant K. pneumoniae. Although, the research and patent filing alone are not enough to develop a suitable antimicrobial therapy, they can represent good starting point upon which to develop new antimicrobials. More investment is required to push these pharmaceuticals through the stages of development to introduce them into the market.

Seroprevalence of Treponema pallidum infection among high-risk populations from Brazil.

Syphilis is a significant public health concern worldwide. According to the 2020 estimates, nearly 7.1 million new cases of syphilis have been reported globally, with over 30 % of these cases reported from American nations, particularly Brazil. Concerns have been raised regarding the susceptibility of specific groups to syphilis due to challenges and vulnerabilities that place these groups at a higher risk of infections or complications in the treatment outcomes. The present study aimed to compare the seroprevalence and the factors associated with syphilis among such high-risk groups. The study was designed as a cross-sectional one and was conducted with pregnant women, people living with HIV (PLHIV), people living with tuberculosis (PLTB), indigenous and healthy populations in Mato Grosso do Sul, Brazil. The study was conducted between June 2019 and August 2022, during which the included patients were subjected to treponemal and non-treponemal serological assays. The study also included a survey conducted through a self-reported questionnaire to collect information regarding the participants' demographics and sexual behaviors. A total of 550 samples were collected, with 110 participants in each of the five groups. The results of the study revealed that the seroprevalence of Treponema pallidum infection in pregnant women, PLHIV, PLTB, indigenous and healthy populations of the study region was 10 % (n = 11/110), 41.81 % (n = 46/110), 17.27 % (n = 19/110), 5.45 % (n = 6/110), and 8.18 % (n = 9/110), respectively. Homosexual orientation (p = 0.04) and a history of sexually transmitted infection (STI) (p = 0.01) were associated with the seroprevalence of T. pallidum infection in PLHIV. However, no such associations were noted in the remaining four groups. The seroprevalence of T. pallidum infection was observed to vary significantly among the different high-risk groups, which highlighted the persistent concern of syphilis, particularly among vulnerable populations. These findings underscore the significance of focused interventions and public health strategies customized to the specific requirements of each of the groups evaluated in the present study to decrease the number of cases of syphilis and thereby prevent future complications in patients with other serious infections.

Multidrug-resistant gram-negative bacteria in patients with COVID-19: An epidemiological and clinical study.

Epidemiological data regarding the incidence of secondary multidrug-resistant (MDR) Gram-negative infection in patients with coronavirus disease (COVID-19) in Brazil are still ambiguous. Thus, a case-control study was designed to determine factors associated with the acquisition of MDR Gram-negative bacteria (GNB) in patients with and without COVID-19 and describe the mortality rates and clinical features associated with unfavorable outcomes. In total, we assessed 280 patients admitted to Brazilian intensive care units from March/2020 to December/2021. During the study, 926 GNB were isolated. Out of those, 504 were MDR-GNB, representing 54.4% of the resistance rate. In addition, out of 871 patients positive for COVID-19, 73 had secondary MDR-GNB infection, which represented 8.38% of documented community-acquired GNB-MDR infections. The factors associated with patients COVID-19-MDR-GNB infections were obesity, heart failure, use of mechanical ventilation, urinary catheter, and previous use of ß-lactams. Several factors associated with mortality were identified among patients with COVID-19 infected with MDR-GNB, including the use of a urinary catheter; renal failure; and the origin of bacterial cultures such as tracheal secretion, exposure to carbapenem antibiotics, and polymyxin. Mortality was significantly higher in patients with COVID-19-MDR-GNB (68.6%) compared to control groups, where COVID-19 was 35.7%, MDR-GNB was 50%, and GNB was 21.4%. Our findings demonstrate that MDR-GNB infection associated with COVID-19 has an expressive impact on increasing the case fatality rate, reinforcing the importance of minimizing the use of invasive devices and prior exposure to antimicrobials to control the bacterial spread in healthcare environments to improve the prognosis among critical patients.

How Did COVID-19 Impact the Antimicrobial Consumption and Bacterial Resistance Profiles in Brazil?

The indiscriminate use of antibiotics has favored the selective pressure of multidrug resistance among microorganisms. This research evaluated the pattern of antibiotic prescriptions among the Brazilian population between January 2018 and December 2021. Additionally, the study sought to analyze the incidence rates of central line-associated bloodstream infection (CLABSI) and examine the profiles of antibiotic resistance. We assessed the hospital and community antimicrobial consumption from the National Health Surveillance Agency Database and correlated it to microorganisms. The consumption of antimicrobials in the hospital environment increased by 26% in 2021, highlighting polymyxin B, which increased by 204%. In 2021, 244,266 cases of CLABSI were reported, indicating a nosocomial infection rate of 7.9%. The rate of resistance to polymyxin B was higher in Pseudomonas aeruginosa (1400%) and Klebsiella pneumoniae (514%). Azithromycin emerged as the predominant antibiotic utilized within the community setting, accounting for 24% of the overall consumption. Pearson's correlation analysis revealed a significant and positive correlation (r = 0.71) between the elevated usage of azithromycin and the incidence of COVID-19. Our results indicate an increase in antimicrobial consumption during the COVID-19 pandemic and reinforce the fact that the misuse of antimicrobials may lead to an expansion in antimicrobial resistance.

Exploring the Bacteriome and Resistome of Humans and Food-Producing Animals in Brazil.

The epidemiology of antimicrobial resistance (AMR) is complex, with multiple interfaces (human-animal-environment). In this context, One Health surveillance is essential for understanding the distribution of microorganisms and antimicrobial resistance genes (ARGs). This report describes a multicentric study undertaken to evaluate the bacterial communities and resistomes of food-producing animals (cattle, poultry, and swine) and healthy humans sampled simultaneously from five Brazilian regions. Metagenomic analysis showed that a total of 21,029 unique species were identified in 107 rectal swabs collected from distinct hosts, the highest numbers of which belonged to the domain Bacteria, mainly Ruminiclostridium spp. and Bacteroides spp., and the order Enterobacterales. We detected 405 ARGs for 12 distinct antimicrobial classes. Genes encoding antibiotic-modifying enzymes were the most frequent, followed by genes related to target alteration and efflux systems. Interestingly, carbapenemase-encoding genes such as blaAIM-1, blaCAM-1, blaGIM-2, and blaHMB-1 were identified in distinct hosts. Our results revealed that, in general, the bacterial communities from humans were present in isolated clusters, except for the Northeastern region, where an overlap of the bacterial species from humans and food-producing animals was observed. Additionally, a large resistome was observed among all analyzed hosts, with emphasis on the presence of carbapenemase-encoding genes not previously reported in Latin America. IMPORTANCE Humans and food production animals have been reported to be important reservoirs of antimicrobial resistance (AMR) genes (ARGs). The frequency of these multidrug-resistant (MDR) bacteria tends to be higher in low- and middle-income countries (LMICs), due mainly to a lack of public health policies. Although studies on AMR in humans or animals have been carried out in Brazil, this is the first multicenter study that simultaneously collected rectal swabs from humans and food-producing animals for metagenomics. Our results indicate high microbial diversity among all analyzed hosts, and several ARGs for different antimicrobial classes were also found. As far as we know, we have detected for the first time ARGs encoding carbapenemases, such as blaAIM-1, blaCAM-1, blaGIM-2, and blaHMB-1, in Latin America. Thus, our results support the importance of metagenomics as a tool to track the colonization of food-producing animals and humans by antimicrobial-resistant bacteria. In addition, a network surveillance system called GUARANI, created for this study, is ready to be expanded and to collect additional data.

In vitro and in vivo antibacterial activity assays of carvacrol: A candidate for development of innovative treatments against KPC-producing Klebsiella pneumoniae.

Dissemination of carbapenem-resistant Klebsiella pneumoniae poses a threat to the successful treatment of bacterial diseases and increases the need for new antibacterial agents development. The objective of this study was to determine the antimicrobial activity of carvacrol against multidrug-resistant K. pneumoniae. Carbapenemase production was detected by MALDI-TOF. The PCR and sequencing showed that the blaKPC-2, blaOXA-48, blaNDM-1, blaCTX-M-8 genes were present in carbapenem-resistant K. pneumoniae strains. The polymyxin-resistant K. pneumoniae strain exhibited alterations in mgrB gene. The antimicrobial activity of carvacrol was evaluated in vitro using broth microdilution and time-kill methods. For this, carbapenem-resistant K. pneumoniae and polymyxin-resistant strains, were evaluated. The in vitro results showed that carvacrol had antimicrobial activity against all isolates evaluated. The survival curves showed that carvacrol eradicated all of the bacterial cells within 4 h. The antimicrobial effect of carvacrol in vivo was determined using a mouse model of infection with Klebsiella pneumoniae carbapenemase (KPC). The treatment with carvacrol was associated with increased survival, and significantly reduced bacterial load in peritoneal lavage. In addition, groups treated with carvacrol, had a significant reduction in the total numbers of white cell and significantly increased of platelets when compared to the untreated group. In vivo and in vitro studies showed that carvacrol regimens exhibited significant antimicrobial activity against KPC-producing K. pneumoniae, making it an interesting candidate for development of alternative treatments.