Antibiotics

Neonatal sepsis is an important cause of morbidity and mortality in neonatal intensive care units (NICUs). Continuous evaluation of antimicrobial resistance (AMR) profiles is advised to implement antimicrobial stewardship (AMS) programs and establish effective empiric antibiotic protocols. AMS may reduce AMR in NICUs and improve sepsis outcomes. In this retrospective observational study, we report data on culture-positive neonatal sepsis, assessing differences after the implementation of an AMS program (2011–2016 vs. 2017–2022). A total of 215 positive bacterial cultures from 169 infants were retrieved, with 79 early-onset (36.7%) and 136 late-onset (63.3%) sepsis episodes. Frequent causative agents for early-onset sepsis were S. agalactiae and E. coli, all susceptible to empiric treatment. Late-onset sepsis was mainly caused by Enterobacterales and S. aureus. Aminoglycosides, cefotaxime, and piperacillin-tazobactam resistance among Enterobacterales was substantially low; S. aureus was mostly susceptible to oxacillin and vancomycin. There were no differences in mortality and multidrug-resistant pathogens rates between the two study periods. There were five episodes of fungal late-onset sepsis, mostly due to C. albicans, of which one was fatal. The microbial distribution pattern and AMR profiles overlapped with other European studies. Because susceptibility patterns are rapidly changing worldwide, with the emerging threat of Methicillin-resistant S. aureus and extended-spectrum beta-lactamases producers, infection prevention and control practices and AMS strategies require continuous optimization to limit selection pressure and AMR escalation. Full article

Our study describes the prevalence and spectrum of enterococci isolated from one-day-old chickens in the Czech Republic, their level of antimicrobial resistance, and the occurrence of multiresistance. Over a 24-month period from 1 August 2021 to 31 July 2023, a total of 464 mixed samples of one-day-old chicken organs were examined during routine inspections at 12 randomly selected poultry farms in the Czech Republic. The samples were processed via cultivation methods and suspected strains were confirmed using the MALDI–TOF Mass Spectrometry method. Antimicrobial susceptibility was determined using the MIC method for eight antimicrobials. A total of 128 isolates (prevalence of 27.6%) representing 4 species of enterococci were isolated, including Enterococcus faecalis, Enterococcus faecium, Enterococcus gallinarum, and Enterococcus hirae, with prevalence rates of 23.3%, 1.5%, 2.2%, and 0.6%, respectively. Susceptibility tests showed a high percentage of susceptible strains among E. faecalis, E. faecium, and E. gallinarum for penicillin-based antibiotics, sulfamethoxazole with trimethoprim, and florfenicol (80–100% susceptible strains). E. hirae was an exception, displaying complete resistance to enrofloxacin (0% susceptible strains) and a high degree of resistance to other tested antimicrobials (33.3% susceptible strains). Among the isolated strains, a total of 16 isolates (12.5%) showed resistance to 3 or more antimicrobials. Complete resistance to all eight antimicrobials simultaneously was observed in four isolates (3.1%). This research shows the possible sources of pathogenic enterococci and their virulence and resistance genes. The findings hold relevance for both veterinary and human medicine, contributing to a better understanding of enterococcal circulation in the human ecosystem and food chain, as well as the development of their resistance and multiresistance. Full article

Prosthetic joint infections (PJI) present a major management challenge for practicing orthopedic surgeons and infectious disease physicians. There are few high-quality data to inform treatment guidelines. The aim of this systematic review was to report the design characteristics and recruitment rates for randomized controlled trials (RCTs) of PJI management. Trials were considered eligible for inclusion if human participants were randomized to any management intervention for PJI. We searched Medline, PubMed, Embase, Web of Science, Cochrane Database, ANZ Clinical Trials Registry, ClinicalTrials.gov, and the EU Clinical Trials Register until the end of May 2023. The systematic review was registered with PROSPERO (CRD42018112646). We identified 15 published RCTs with a total of 1743 participants with PJI. The median (interquartile range [IQR]) number of successfully recruited participants was 63 (38–140), with 0.28 (0.13–0.96) enrolments per site per month. Only four trials (36.4%) achieved the target recruitment. All RCTs applied different primary endpoints and varying definitions of a ‘good’ outcome. Despite recent improvements, PJI RCTs are characterized by slow recruitment and heterogeneous endpoint assessments, which preclude synthesis in a standard meta-analytic framework. To inform international guidelines, future PJI trials should be run as multi-country trials at high-recruiting sites. Full article

Replacement of native joints aims to restore patients’ quality of life by relieving pain and improving joint function. While periprosthetic joint infection (PJI) affects a small percentage of patients, with an estimated incidence of 1–9% following primary total joint replacement, this postoperative complication necessitates a lengthy hospitalisation, extended antibiotic treatment and further surgery. It is highlighted that establishing the correct diagnosis of periprosthetic infections is critical in order for clinicians to avoid unnecessary treatments in patients with aseptic failure. Of note, the PJI diagnosis could not purely rely upon clinical manifestations given the fact that heterogeneity in host factors (e.g., age and comorbidities), variability in infection period, difference in anatomical location of the involved joint and discrepancies in pathogenicity/virulence of the causative organisms may confound the clinical picture. Furthermore, intra-operative contamination is considered to be the main culprit that can result in early or delayed infection, with the hematogenous spread being the most prevalent mode. To elaborate, early and hematogenous infections often start suddenly, whereas chronic late infections are induced by less virulent bacteria and tend to manifest in a more quiescent manner. Last but not least, viruses and fungal microorganisms exert a role in PJI pathogenesis. Full article

Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) is a multifunctional neuropeptide that is widely distributed and conserved across species. We have previously shown that in teleost fish, PACAP not only possesses direct antimicrobial properties but also immunomodulatory effects against the bacterial pathogens Flavobacterium psychrophilum and Pseudomonas aeruginosa using in vitro and in vivo experiments. These previous results suggest PACAP can be used as an alternative to antibiotics to prevent and/or treat bacterial infections in the aquaculture industry. To accomplish this goal, more studies are needed to better understand the effect of PACAP on pathogens affecting fish in live infections. In the present study, the transcripts PACAP, PRP/PACAP, and VPAC2 receptor were examined in rainbow trout (Oncorhynchus mykiss) naturally infected with Yersinia ruckeri, which exhibited an increase in their expression in the spleen when compared to healthy fish. Synthetic Clarias gariepinus PACAP-38 has direct antimicrobial activity on Y. ruckeri and inhibits up to 60% of the bacterial growth when the peptide is at concentrations between 50 and 100 µM in TSB. The growth inhibition increased up to 90% in the presence of 12.5 µM of PACAP-38 when salt-free LB broth was used instead of TSB. It was also found to inhibit Y. ruckeri growth in a dose-dependent manner when the rainbow trout monocyte/macrophage-like cell line (RTS11) was pre-treated with lower concentrations of the peptide (0.02 and 0.1 µM) before going through infection. Differential gene expression was analyzed in this in vitro model. Overall, the results revealed new evidence to support the role of PACAP as an antimicrobial and immunomodulatory peptide treatment in teleosts. Full article

The emergence of multidrug-resistant (MDR) superbugs underlines the urgent need for innovative treatment options to tackle resistant bacterial infections. The clinical efficacy of natural products directed our efforts towards developing new antibacterial leads from naturally abundant known chemical structures. The present study aimed to explore an unusual class of phenylacylphenols (malabaricones) from Myristicamalabarica as antibacterial agents. In vitro antibacterial activity was determined via broth microdilution, cell viability, time–kill kinetics, biofilm eradication, intracellular killing, and checkerboard assays. The efficacy was evaluated in vivo in murine neutropenic thigh and skin infection models. Confocal and SEM analyses were used for mechanistic studies. Among the tested isolates, malabaricone B (NS-7) demonstrated the best activity against S. aureus with a favorable selectivity index and concentration-dependent, rapid bactericidal killing kinetics. It displayed equal efficacy against MDR clinical isolates of S. aureus and Enterococci, efficiently clearing S. aureus in intracellular and biofilm tests, with no detectable resistance. In addition, NS-7 synergized with daptomycin and gentamicin. In vivo, NS-7 exhibited significant efficacy against S. aureus infection. Mechanistically, NS-7 damaged S. aureus membrane integrity, resulting in the release of extracellular ATP. The results indicated that NS-7 can act as a naturally derived bactericidal drug lead for anti-staphylococcal therapy. Full article

The accuracy of preoperative synovial fluid microbe detection in periprosthetic joint infection (PJI) is widely reported. However, the reliability of this diagnostic modality amongst the different joints is not yet described. We aimed to compare the concordance rate between preoperative synovial fluid and intraoperative tissue cultures in shoulder, knee and hip PJIs. A total of 150 patients who met the 2018 International Consensus Meeting criteria for shoulder, hip and knee PJI were retrospectively reviewed. This cohort was divided into three groups based on the involved joint (should, hip or knee), with 50 patients in each group. Cultures were collected and held for culture for 14 days. The overall concordance rate was 56.7%. Concordance rates between preoperative and intraoperative cultures were 60%, 56% and 54% for the knee, shoulder and hip joints, respectively. The analysis of high- or low-virulence and difficult- or not-difficult-to-treat germs did not reveal any significant differences between preoperative and intraoperative cultures in any of the groups. However, even considering the higher concordance in knee PJI, the overall discordance between preoperative and intraoperative cultures should prompt surgeons not to rely solely on preoperative synovial fluid culture data in determining appropriate treatment and antibiotics. Full article

Antibiotic resistance in uropathogens has increased substantially and severely affected treatment of urinary tract infections (UTIs). Lately, some new formulations, including meropenem/vaborbactam (MEV), ceftazidime/avibactam (CZA), and ceftolozane/tazobactam (C/T) have been introduced to treat infections caused by drug-resistant pathogens. This study was designed to screen Enterobacteriales isolates from UTI patients and to assess their antimicrobial resistance pattern, particularly against the mentioned (new) antibiotics. Phenotypic screening of extended-spectrum β-lactamase (ESBL) and carbapenem resistance was followed by inhibitor-based assays to detect K. pneumoniae carbapenemase (KPC), metallo-β-lactamase (MBL), and class D oxacillinases (OXA). Among 289 Enterobacteriales, E. coli (66.4%) was the most predominant pathogen, followed by K. pneumoniae (13.8%) and P. mirabilis (8.3%). The isolates showed higher resistance to penicillins and cephalosporins (70–87%) than to non-β-lactam antimicrobials (33.2–41.5%). NDM production was a common feature among carbapenem-resistant (CR) isolates, followed by KPC and OXA. ESBL producers were susceptible to the tested new antibiotics, but NDM-positive isolates appeared resistant to these combinations. KPC-producers showed resistance to only C/T. ESBLs and carbapenemase encoding genes were located on plasmids and most of the genes were successfully transferred to recipient cells. This study revealed that MEV and CZA had significant activity against ESBL and KPC producers. Full article

Cholelithiasis has a major impact on global health and affects an average of 20% of the Western population. The main risk factors are females, age over 40 years, obesity and pregnancy. Most of the time it is asymptomatic, but when there are symptoms, they are generally nonspecific. Bile was considered sterile, but today it is known that it contains a complex bacterial flora, which causes biofilm in the gallbladder and gallstones. Among the main bacteria associated with cholelithiasis are Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumoniae, species of Enterococcus spp. and Acinetobacter spp. Antibiotic prophylaxis is used in an attempt to reduce postoperative infections, especially at the surgical site. However, some authors found no relationship between the use of antibiotic prophylaxis and a lower risk of surgical site infection. Thus, the aim of this double-blind randomized clinical trial was to compare the existence or not of bacteriobilia in patients at low anesthetic risk who underwent videolaparoscopic cholecystectomy, and its correlation with the use of prophylactic antibiotics. This study included 40 patients between 18 and 65 years old, diagnosed with cholelithiasis, symptomatic or not, with low anesthetic risk classified by the American Society of Anesthesiology in ASA I or ASA II, without complications or previous manipulation of the bile duct, who underwent elective video cholecystectomy, divided into two groups: Experimental Group A (n = 20), which received 2 g of Cephalotin (first-generation Cephalosporin, Keflin^®, ABL antibiotics, Cosmópolis, Brazil) during anesthetic induction, and Control Group B (n = 20), where no antibiotics were administered until bile collection. After the procedure, a bile sample was collected and culture and antibiogram were performed. In the sample, 22 (55%) were classified as ASA I and 18 (45%) as ASA II. It was observed that 81.8% of the patients who had a positive culture did not use antibiotics, against 18.2% of those who used prophylaxis. When comparing patients regarding anesthetic risk, ASA I patients had a positive culture in 9.1% of cases, against 90.9% in patients classified as ASA II. It was concluded that patients with higher anesthetic risk (ASA II) have a higher chance of bacteriobilia and benefit from antibiotic prophylaxis when compared to patients with lower anesthetic risk (ASA I). Full article

Urinary tract infections (UTIs) are the second most common bacterial infection with high recurrence rates and can involve biofilm formation on patient catheters. Biofilms are inherently tolerant to antimicrobials, making them difficult to eradicate. Many antibiofilm agents alone do not have bactericidal activity; therefore, linking them to antibiotics is a promising antibiofilm strategy. However, many of these hybrid agents have not been tested in relevant preclinical settings, limiting their potential for clinical translation. Here, we evaluate a ciprofloxacin di-nitroxide hybrid (CDN11), previously reported to have antibiofilm activity against uropathogenic Escherichia coli (UPEC) strain UTI89 in vitro, as a potential UTI therapeutic using multiple preclinical models that reflect various aspects of UTI pathogenesis. We report improved in vitro activity over the parent drug ciprofloxacin against mature UTI89 biofilms formed inside polyethylene catheters. In bladder cell monolayers infected with UTI89, treatment with CDN11 afforded significant reduction in bacterial titers, including intracellular UPEC. Infected mouse bladders containing biofilm-like intracellular reservoirs of UPEC UTI89 showed decreased bacterial loads after ex vivo bladder treatment with CDN11. Activity for CDN11 was reported across different models of UTI, showcasing nitroxide–antibiotic hybridization as a promising antibiofilm approach. The pipeline we described here could be readily used in testing other new therapeutic compounds, fast-tracking the development of novel antibiofilm therapeutics. Full article

By ensuring optimal dosing, therapeutic drug monitoring (TDM) improves outcomes in critically ill patients by maximizing effectiveness while minimizing toxicity. Current methods for measuring plasma drug concentrations, however, can be challenging, time-consuming, and slow to return an answer, limiting the extent to which TDM is used to optimize drug exposure. A potentially promising solution to this dilemma is provided by biosensors, molecular sensing devices that employ biorecognition elements to recognize and quantify their target molecules rapidly and in a single step. This paper reviews the current state of the art for biosensors regarding their application to TDM of antibiotics in the critically ill, both as ex vivo point-of-care devices supporting single timepoint measurements and in vivo devices supporting continuous real-time monitoring in situ in the body. This paper also discusses the clinical development of biosensors for TDM, including regulatory challenges and the need for standardized performance evaluation. We conclude by arguing that, through precise and real-time monitoring of antibiotics, the application of biosensors in TDM holds great promise for enhancing the optimization of drug exposure in critically ill patients, offering the potential for improved outcomes. Full article

The treatment of Staphylococcus aureus skin and soft tissue infections faces several challenges, such as the increased incidence of antibiotic-resistant strains and the fact that the antibiotics available to treat methicillin-resistant S. aureus present low bioavailability, are not easily metabolized, and cause severe secondary effects. Moreover, besides the susceptibility pattern of the S. aureus isolates detected in vitro, during patient treatment, the antibiotics may never encounter the bacteria because S. aureus hides within biofilms or inside eukaryotic cells. In addition, vascular compromise as well as other comorbidities of the patient may impede proper arrival to the skin when the antibiotic is given parenterally. In this manuscript, we revise some of the more promising strategies to improve antibiotic sensitivity, bioavailability, and delivery, including the combination of antibiotics with bactericidal nanomaterials, chemical inhibitors, antisense oligonucleotides, and lytic enzymes, among others. In addition, alternative non-antibiotic-based experimental therapies, including the delivery of antimicrobial peptides, bioactive glass nanoparticles or nanocrystalline cellulose, phototherapies, and hyperthermia, are also reviewed. Full article

The overuse and inappropriate use of antibiotics pose a grave threat to public health, contributing significantly to the accelerated development of antimicrobial resistance (AMR) and increased rates of morbidity and mortality, making it a leading cause of death globally. To examine the relationship between demographic variables and knowledge, attitudes, and behaviors concerning antibiotic use, a survey-based cross-sectional study was conducted involving 1158 individuals. The questionnaire included two sections: in the first section, participants’ socio-demographic characteristics were analyzed; the second investigated knowledge, attitudes, and behaviors concerning antibiotics utilization using a total of 36 questions. Descriptive statistics were used, and then a multiple linear regression analysis (MLRA) using three models was carried out. In Model I, knowledge about antibiotics exhibited correlations with smoking habits and educational attainment. In Model II, attitudes were significantly associated with gender, smoking habits, age, education, relationship status, and knowledge. In Model III, behaviors related to antibiotics were correlated with educational attainment, having children, knowledge, and attitudes. Implementing tailored public health programs could be a cost-effective intervention to enhance behaviors associated with antibiotic use in the general population. This study offers valuable insights into the determinants of knowledge, attitudes, and behaviors regarding antibiotics in the general population. Full article

Impairments in liver function lead to different complications. As chronic liver disease progresses (CLD), hypoalbuminemia and alterations in bile acid compositions lead to changes in gut microbiota and, therefore, in the host–microbiome interaction, leading to a proinflammatory state. Alterations in gut microbiota composition and permeability, known as gut dysbiosis, have important implications in CLD; alterations in the gut–liver axis are a consequence of liver disease, but also a cause of CLD. Furthermore, gut dysbiosis plays an important role in the progression of liver cirrhosis and decompensation, particularly with complications such as hepatic encephalopathy and spontaneous bacterial peritonitis. In relation to this, antibiotics play an important role in treating CLD. While certain antibiotics have specific indications, others have been subjected to continued study to determine whether or not they have a modulatory effect on gut microbiota. In contrast, the rational use of antibiotics is important, not only because of their disrupting effects on gut microbiota, but also in the context of multidrug-resistant organisms. The aim of this review is to illustrate the role of gut microbiota alterations in CLD, the use and impact of antibiotics in liver cirrhosis, and their harmful and beneficial effects. Full article

Antimicrobial resistance (AMR) has a significant impact on human, animal, and environmental health, being spread in diverse settings. Antibiotic misuse and overuse in the food chain are widely recognized as primary drivers of antibiotic-resistant bacteria. However, other antimicrobials, such as metals and organic acids, commonly present in agri-food environments (e.g., in feed, biocides, or as long-term pollutants), may also contribute to this global public health problem, although this remains a debatable topic owing to limited data. This review aims to provide insights into the current role of metals (i.e., copper, arsenic, and mercury) and organic acids in the emergence and spread of AMR in the food chain. Based on a thorough literature review, this study adopts a unique integrative approach, analyzing in detail the known antimicrobial mechanisms of metals and organic acids, as well as the molecular adaptive tolerance strategies developed by diverse bacteria to overcome their action. Additionally, the interplay between the tolerance to metals or organic acids and AMR is explored, with particular focus on co-selection events. Through a comprehensive analysis, this review highlights potential silent drivers of AMR within the food chain and the need for further research at molecular and epidemiological levels across different food contexts worldwide. Full article

The increasing interest in microbiological food safety requires the development of sensitive and reliable analyses and technologies for preserving food products’ freshness and quality. Different types of packaging systems are one of the solutions for controlling microbiological activity in foods. During the last decades, the development of biopolymer-based active packaging with essential oil incorporation systems has resulted in technologies with exceptional application potential, primarily in the food industry. There is no doubt that this principle can facilitate food status monitoring, reduce food waste, extend the shelf life, improve the overall quality of food, or indicate a larger problem during the storage, production, and distribution of foodstuffs. On the other hand, most antimicrobial packaging systems are in the development phase, while the sensitivity, selectivity, complexity, and, above all, safety of these materials are just some of the essential questions that need to be answered before they can be widely used. The incorporation of essential oils as antimicrobial substances in biopolymer-based active packaging holds significant promise for enhancing food safety, extending shelf life, and offering more sustainable packaging solutions. While challenges exist, ongoing research and innovation in this field are likely to lead to the development of effective and environmentally friendly packaging systems with enhanced antimicrobial properties. Full article

Streptococcus downii is a recently reported bacterial species of oral origin, with inhibitory capacity against Streptococcus mutans, Actinomyces naeslundii, Veillonella parvula and Aggregatibacter actinomycetemcomitans, which confers upon it the potential of being an oral probiotic. The aim of the present study was to identify the potential mechanisms by which S. downii exerts its inhibitory effect on S. mutans. To this end, the study assessed the consumption of glucose and proteins available in the culture medium, the modification of the pH, the production of short-chain fatty acids, the changes in the protein panel of the inhibition halo, the production of hydrogen peroxide and the effect of proteinase K. There were no differences in the glucose values or in the protein content of the medium, but there was a reduction in pH (with no effect on the growth of S. mutans). Significant increases were detected in the levels of lactic and formic acid (with no effect on the growth of S. mutans), as well as changes in the peptide panel (with no effect on the growth of S. mutans). The inhibitory effect was maintained in the presence of peroxidase but disappeared after adding proteinase K. Based on these results, it is suggested that the main mechanism of inhibition of S. downii against S. mutans is the production of bacteriocins. Full article

Antibiotics (ABs) have made it possible to treat bacterial infections, which were in the past untreatable and consequently fatal. Regrettably, their use and abuse among humans and livestock led to antibiotic resistance, which has made them ineffective in many cases. The spread of antibiotic resistance genes (ARGs) and bacteria is not limited to nosocomial environments, but also involves water and soil ecosystems. The environmental presence of ABs and ARGs is a hot topic, and their direct and indirect effects, are still not well known or clarified. A particular concern is the presence of antibiotics in agroecosystems due to the application of agro-zootechnical waste (e.g., manure and biosolids), which can introduce antibiotic residues and ARGs to soils. This review provides an insight of recent findings of AB direct and indirect effects on terrestrial organisms, focusing on plant and invertebrates. Possible changing in viability and organism growth, AB bioaccumulation, and shifts in associated microbiome composition are reported. Oxidative stress responses of plants (such as reactive oxygen species production) to antibiotics are also described. Full article

Oligella ureolytica is a Gram-negative bacillus, a member of the Alcaligenaceae family, that had never previously been reported as lethal. Herein, a case of fatal infection caused by Oligella ureolytica in an elderly woman with suspected bladder cancer is reported. The species identification was confirmed through Sanger sequencing of the bacterial 16S rRNA sequence and compared to published sequences for phylogenetic analysis. Initial antibiotic therapy with ceftriaxone and oxacillin was initiated but had to be switched due to resistance. Cefepime in combination with metronidazole was administered, unfortunately failing to prevent the patient’s death. Further studies are needed to explore additional factors influencing clinical outcomes in Oligella ureolytica infections. Full article