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Tigecycline is a last-resort drug used to treat serious infections caused by multidrug-resistant bacteria. tet(X4) is a recently discovered plasmid-mediated tigecycline resistance gene that confers high-level resistance to tigecycline and other tetracyclines. Since the first discovery of tet(X4) in 2019, it has spread rapidly worldwide, and as a consequence, tigecycline has become increasingly ineffective in the clinical treatment of multidrug-resistant infections. In this study, we identified and analyzed tet(X4)-positive Escherichia coli isolates from duck farms in Hunan Province, China. In total, 976 samples were collected from nine duck farms. Antimicrobial susceptibility testing and whole-genome sequencing (WGS) were performed to establish the phenotypes and genotypes of tet(X4)- positive isolates. In addition, the genomic characteristics and transferability of tet (X4) were determined based on bioinformatics analysis and conjugation. We accordingly detected an E. coli strain harboring tet(X4) and seven other resistance genes in duck feces. Multi-locus sequence typing analysis revealed that this isolate belonged to a new clone, and subsequent genetic analysis indicated that tet(X4) was carried in a 4608-bp circular intermediate, flanked by ISVsa3-ORF2-abh elements. Moreover, it exhibited transferability to E. coli C600 with a frequency of 10-5. The detection of tet(X4)-harboring E, coli strains on duck farms enhances our understanding of tigecycline resistance dynamics. The transferable nature of the circular intermediate of tet(X4) contributing to the spread of tigecycline resistance genes poses a substantial threat to healthcare. Consequently, vigilant monitoring and proactive measures are necessary to prevent their spread. [ABSTRACT FROM AUTHOR]

Drug repurposing (repositioning) is a dynamically-developing area in the search for effective therapy of infectious diseases. Repositioning existing drugs with a well-known pharmacological and toxicological profile is an attractive method for quickly discovering new therapeutic indications. The off-label use of drugs for infectious diseases requires much less capital and time, and can hasten progress in the development of new antimicrobial drugs, including antibiotics. The use of drug repositioning in searching for new therapeutic options has brought promising results for many viral infectious diseases, such as Ebola, ZIKA, Dengue, and HCV. This review describes the most favorable results for repositioned drugs for the treatment of bacterial infections. It comprises publications from various databases including PubMed and Web of Science published from 2015 to 2023. The following search keywords/strings were used: drug repositioning and/or repurposing and/or antibacterial activity and/ or infectious diseases. Treatment options for infections caused by multidrugresistant bacteria were taken into account, including methicillin-resistant staphylococci, multidrug-resistant Mycobacterium tuberculosis, or carbapenem-resistant bacteria from the Enterobacteriaceae family. It analyses the safety profiles of the included drugs and their synergistic combinations with antibiotics and discusses the potential of antibacterial drugs with antiparasitic, anticancer, antipsychotic effects, and those used in metabolic diseases. Drug repositioning may be an effective response to public health threats related to the spread of multidrug-resistant bacterial strains and the growing antibiotic resistance of microorganisms. [ABSTRACT FROM AUTHOR]

Purpose: Antibiotic-resistant bacterial pneumonia poses a significant therapeutic challenge. In China, Chinese herbal compound (CHC) is commonly used to treat bacterial pneumonia. We aimed to evaluate the efficacy and safety of CHC and identify core herb combinations for the treatment of multidrug-resistant or extensively drug-resistant bacterial pneumonia. Methods: Stata 16 and TSA 0.9.5.10 beta software were used for meta-analysis and trial sequential analysis (TSA), respectively. Exploring the sources of heterogeneity through meta-regression and subgroup analysis. Results: Thirty-eight studies involving 2890 patients were included in the analyses. Meta-analysis indicated that CHC combined with antibiotics improved the response rate (RR = 1.24; 95% CI: 1.19-1.28; p < 0.0001) and microbiological eradication (RR = 1.41; 95% CI: 1.27-1.57; p < 0.0001), lowered the white blood cell count (MD = -2.09; 95% CI: -2.65 to -1.53; p < 0.0001), procalcitonin levels (MD = -0.49; 95% CI: -0.59 to -0.40; p < 0.0001), C-reactive protein levels (MD = -11.80; 95% CI: -15.22 to -8.39; p < 0.0001), Clinical Pulmonary Infection Scores (CPIS) (MD = -1.97; 95% CI: -2.68 to -1.26; p < 0.0001), and Acute Physiology and Chronic Health Evaluation (APACHE)-II score (MD = -4.08; 95% CI: -5.16 to -3.00; p < 0.0001), shortened the length of hospitalization (MD = -4.79; 95% CI: -6.18 to -3.40; p < 0.0001), and reduced the number of adverse events. TSA indicated that the response rate and microbiological eradication results were robust. Moreover, Scutellaria baicalensis Georgi, Fritillaria thunbergii Miq, Lonicera japonica Thunb, and Glycyrrhiza uralensis Fisch were identified as core CHC prescription herbs. Conclusion: Compared with antibiotic treatment, CHC + antibiotic treatment was superior in improving response rate, microbiological eradication, inflammatory response, CPIS, and APACHE-II score and shortening the length of hospitalization. Association rule analysis identified four core herbs as promising candidates for treating antibiotic-resistant bacterial pneumonia. However, large-scale clinical studies are still required. [ABSTRACT FROM AUTHOR]

Drug repurposing (repositioning) is a dynamically-developing area in the search for effective therapy of infectious diseases. Repositioning existing drugs with a well-known pharmacological and toxicological profile is an attractive method for quickly discovering new therapeutic indications. The off-label use of drugs for infectious diseases requires much less capital and time, and can hasten progress in the development of new antimicrobial drugs, including antibiotics. The use of drug repositioning in searching for new therapeutic options has brought promising results for many viral infectious diseases, such as Ebola, ZIKA, Dengue, and HCV. This review describes the most favorable results for repositioned drugs for the treatment of bacterial infections. It comprises publications from various databases including PubMed and Web of Science published from 2015 to 2023. The following search keywords/strings were used: drug repositioning and/or repurposing and/or antibacterial activity and/or infectious diseases. Treatment options for infections caused by multidrug-resistant bacteria were taken into account, including methicillin-resistant staphylococci, multidrug-resistant Mycobacterium tuberculosis, or carbapenem-resistant bacteria from the Enterobacteriaceae family. It analyses the safety profiles of the included drugs and their synergistic combinations with antibiotics and discusses the potential of antibacterial drugs with antiparasitic, anticancer, antipsychotic effects, and those used in metabolic diseases. Drug repositioning may be an effective response to public health threats related to the spread of multidrug-resistant bacterial strains and the growing antibiotic resistance of microorganisms.

Purpose: Antibiotic-resistant bacterial pneumonia poses a significant therapeutic challenge. In China, Chinese herbal compound (CHC) is commonly used to treat bacterial pneumonia. We aimed to evaluate the efficacy and safety of CHC and identify core herb combinations for the treatment of multidrug-resistant or extensively drug-resistant bacterial pneumonia.Methods: Stata 16 and TSA 0.9.5.10 beta software were used for meta-analysis and trial sequential analysis (TSA), respectively. Exploring the sources of heterogeneity through meta-regression and subgroup analysis.Results: Thirty-eight studies involving 2890 patients were included in the analyses. Meta-analysis indicated that CHC combined with antibiotics improved the response rate (RR = 1.24; 95% CI: 1.19–1.28; p < 0.0001) and microbiological eradication (RR = 1.41; 95% CI: 1.27–1.57; p < 0.0001), lowered the white blood cell count (MD = −2.09; 95% CI: −2.65 to −1.53; p < 0.0001), procalcitonin levels (MD = −0.49; 95% CI: −0.59 to −0.40; p < 0.0001), C-reactive protein levels (MD = −11.80; 95% CI: −15.22 to −8.39; p < 0.0001), Clinical Pulmonary Infection Scores (CPIS) (MD = −1.97; 95% CI: −2.68 to −1.26; p < 0.0001), and Acute Physiology and Chronic Health Evaluation (APACHE)-II score (MD = −4.08; 95% CI: −5.16 to −3.00; p < 0.0001), shortened the length of hospitalization (MD = −4.79; 95% CI: −6.18 to −3.40; p < 0.0001), and reduced the number of adverse events. TSA indicated that the response rate and microbiological eradication results were robust. Moreover, Scutellaria baicalensis Georgi, Fritillaria thunbergii Miq, Lonicera japonica Thunb, and Glycyrrhiza uralensis Fisch were identified as core CHC prescription herbs.Conclusion: Compared with antibiotic treatment, CHC + antibiotic treatment was superior in improving response rate, microbiological eradication, inflammatory response, CPIS, and APACHE-II score and shortening the length of hospitalization. Association rule analysis identified four core herbs as promising candidates for treating antibiotic-resistant bacterial pneumonia. However, large-scale clinical studies are still required.Systematic Review Registration:https://www.crd.york.ac.uk/prospero/, identifier CRD42023410587.

Abstract The informal milk value chain in Uganda controls most of the raw marketed milk, albeit of poor quality. A study was conducted to assess the milk handling practices, the bacterial quality and the associated health concerns of raw milk along the informal milk value in Nakasongola District. The cross-sectional study used both qualitative and quantitative methods to obtain information from key players. The qualitative data was categorized and presented into emerging themes. Bacterial contamination of 200 milk samples was determined by morphological and biochemical tests. The antibiotic susceptibility test was done by the disc diffusion method. Hand milking was carried out mainly by men (92.5%), and most never or rarely practised hand washing (67.5%) during milking. Milk was mainly delivered to mobile milk-collecting centres located under tree shades (50%). The quality of raw milk was affected by poor hygienic, handling and transportation practices. Most participants (75%) were aware of the dangers of drinking raw milk and the requirements to transport milk in metallic cans. Viable bacterial counts above the recommended limit were recorded in 76 samples (38%) that included Staphylococcus aureus (46%), coagulase-negative Staphylococcus (29%), Escherichia coli (12%), Streptococcus agalactiae (8%) and Salmonella spp. (5%). The overall antibiotic resistance was 45% (34/76), which included resistant isolates of S. aureus (17/34), coagulase-negative Staphylococcus (11/22), S. agalactiae (3/6), Salmonella spp. (2/4) and E. coli (2/9). The raw milk contaminated with antibiotic drug-resistant bacterial pathogens is of public health concern. Thus, measures to improve the quality of milk need to be designed for the pastoral community in Nakasongola district.

The indiscriminate use of first-line drugs contributed to the spread of resistant bacteria, a major concern for both human and veterinary medicine. Methicillin resistance is acquired through the mecA gene, which encodes for the PBP2a protein and lends the resistance to β-lactams. Verifying the correspondence between gene harboring and protein expression and accelerating methicillin resistance diagnosis is critical to improve the management of antimicrobial administration and to reduce the spread of drug resistances. We tested the applicability of immunofluorescence targeting PBP2a protein to identify a new potential methicillin resistance screening test, ancillary to conventional culture methods. We collected 26 clinical Staphylococcus pseudintermedius (SP) isolates: 25 from canine pyoderma and 1 from dermatitis in a dog owner. SP is one of the most important etiological agents in canine pyoderma and can harbor the mecA gene. We performed PCR for mecA gene detection, broth microdilution (BMD) for phenotypic methicillin resistance, and immunofluorescence targeting PBP2a protein. Compared to the PCR as the gold standard, immunofluorescence showed an apparent prevalence of 34.6% vs. a true prevalence of 53.8%, with 100% specificity, 64.3% sensitivity, and 80.8% diagnostic accuracy. PBP2a expression showed isolate-dependent variability: in some isolates, most of the bacterial cells showed an intense and clearly membranous pattern, while in others only a few of them could be detected. Performing the assay in duplicate improved the diagnostic accuracy. Since the mecA gene is shared among the members of the Staphylococcus genus, the test can be applied to identify methicillin resistance independently from the staphylococcal species, both in human and animal samples. Being a rapid and easy method and providing the unique possibility to study the expression of PBP2a by directly visualizing the morphology, it could represent a new interesting tool for both research and diagnostics. To accelerate methicillin resistance diagnosis, it would be worth further testing of its performance on cytological samples.

Background:Escherichia coli (E. coli) column for one of the most common pathogens causing neonatal infections. The emergence of antibiotic-resistant bacteria is a major cause of treatment failure in infected newborns. The purpose of this study was to describe antibiotic and multidrug resistance of E. coli strains isolated from neonates with infection throughout the years 2009–2011.Methods: The antimicrobial susceptibility testing of E. coli strains to selected antibiotics was assessed using the E-test technique on the Mueller-Hinton agar. The antimicrobial tests included ceftazidime, cefuroxime, cefatriaxone, amoxicillin, amoxicillin-clavulanic acid, cefoperazone- sulbactam, meropenem, gentamicin, ciprofloxacin, and sulfonamides.Results: A total of 100 E. coli strains were isolated from sputum (n = 78), blood (n = 10), cerebrospinal fluid (n = 5), and umbilical discharge (n = 7) samples of hospitalized neonates at the Beijing Children's Hospital. The highest rate of E. coli resistance was found in amoxicillin (85%), followed by cefuroxime (65%), and cefatriaxone (60%), respectively. A total of 6 and 5% of all isolates were only resistant to amoxicillin/clavulanic acid and cefoperazone -sulbactam. The rates of resistance to ceftazidime, gentamicin, ciprofloxacin, and sulfonamides were 31, 20, 33, and 47%, respectively. All isolates were susceptible to meropenem. Approximately 26% of all E. coli isolates were multidrug-resistant. The detection rate of ESBL-Producing E. coli was 55%.Conclusions: Multi-drug-resistant E. coli has become an important and complex problem in clinical treatment, and it is thus essential to monitor E. coli resistance in neonates.

Purpose: The aim of the present study was to determine whether de-escalation guided by blood cultures for patients with a diagnosis of sepsis, severe sepsis or septic shock reduces mortality, and antimicrobial drug resistance (ADR).Methods: A prospective, single-center, cohort study was conducted with adults admitted to the ICU with a diagnosis of sepsis, severe sepsis, or septic shock at a public hospital in Sorocaba, State of São Paulo, Brazil, from January 2013 to December 2013. We excluded patients who had negative blood cultures. Patients who had replaced the initial empirical broad-spectrum antibiotic therapy (EAT) by the antibiotic therapy guided by blood cultures were compared with those who continued receiving EAT. The outcome included mortality and antimicrobial drug resistance. We used the Cox regression (proportional hazards regression) and the Poisson regression to analyze the association between antibiotic therapy guided by blood cultures (ATGBC) and outcomes. The statistical adjustment in all models included the following variables: sex, age, APACHE II (Acute Physiology And Chronic Health Evaluation II) score and SOFA (Sequential Organ Failure Assessment) score.Results: Among the 686 patients who were admitted to the intensive care unit, 91 were included in this study. The mean age of the patients was 52.7 years (standard deviation = 18.5 years) and 70.3% were male. EAT was replaced by ATGBC in 33 patients (36.3%) while 58 patients (63.7%) continued receiving EAT. Overall hospital mortality decreased from 56.9% in patients who received EAT to 48.5% in patients who received ATGBC [Hazard ratio- HR 0.44 (95% CI 0.24–0.82), p = 0.009]. There was no association between ATGBC and ADR [HR 0.90 (95% CI 0.78 – 1.03) p = 0.15].Conclusions: Although the early and appropriate empirical EAT is undoubtedly an important factor prognostic, ATGBC can reduce the mortality in these patients.

Drug-resistant tuberculosis threatens to undermine global control programs by limiting treatment options. New antimicrobial drugs are required, derived from new chemical classes. Natural products offer extensive chemical diversity and inspiration for synthetic chemistry. Here, we isolate, synthesize and test a library of 52 natural and synthetic compounds for activity against Mycobacterium tuberculosis. We identify seven compounds as antimycobacterial, including the natural products isobavachalcone and isoneorautenol, and a synthetic chromene. The plant-derived secondary metabolite damnacanthal was the most active compound with the lowest minimum inhibitory concentration of 13.07 μg/mL and a favorable selectivity index value. Three synthetic polyacetylene compounds demonstrated antimycobacterial activity, with the lowest MIC of 17.88 μg/mL. These results suggest new avenues for drug discovery, expanding antimicrobial compound chemistries to novel anthraquinone and polyacetylene scaffolds in the search for new drugs to treat drug-resistant bacterial diseases.

Drug-resistant tuberculosis threatens to undermine global control programs by limiting treatment options. New antimicrobial drugs are required, derived from new chemical classes. Natural products offer extensive chemical diversity and inspiration for synthetic chemistry. Here, we isolate, synthesize and test a library of 52 natural and synthetic compounds for activity against Mycobacterium tuberculosis. We identify seven compounds as antimycobacterial, including the natural products isobavachalcone and isoneorautenol, and a synthetic chromene. The plant-derived secondary metabolite damnacanthal was the most active compound with the lowest minimum inhibitory concentration of 13.07 μg/mL and a favorable selectivity index value. Three synthetic polyacetylene compounds demonstrated antimycobacterial activity, with the lowest MIC of 17.88 μg/mL. These results suggest new avenues for drug discovery, expanding antimicrobial compound chemistries to novel anthraquinone and polyacetylene scaffolds in the search for new drugs to treat drug-resistant bacterial diseases. [ABSTRACT FROM AUTHOR]

The informal milk value chain in Uganda controls most of the raw marketed milk, albeit of poor quality. A study was conducted to assess the milk handling practices, the bacterial quality and the associated health concerns of raw milk along the informal milk value in Nakasongola District. The cross-sectional study used both qualitative and quantitative methods to obtain information from key players. The qualitative data was categorized and presented into emerging themes. Bacterial contamination of 200 milk samples was determined by morphological and biochemical tests. The antibiotic susceptibility test was done by the disc diffusion method. Hand milking was carried out mainly by men (92.5%), and most never or rarely practised hand washing (67.5%) during milking. Milk was mainly delivered to mobile milk-collecting centres located under tree shades (50%). The quality of raw milk was affected by poor hygienic, handling and transportation practices. Most participants (75%) were aware of the dangers of drinking raw milk and the requirements to transport milk in metallic cans. Viable bacterial counts above the recommended limit were recorded in 76 samples (38%) that included Staphylococcus aureus (46%), coagulase-negative Staphylococcus (29%), Escherichia coli (12%), Streptococcus agalactiae (8%) and Salmonella spp. (5%). The overall antibiotic resistance was 45% (34/76), which included resistant isolates of S. aureus (17/34), coagulase-negative Staphylococcus (11/22), S. agalactiae (3/6), Salmonella spp. (2/4) and E. coli (2/9). The raw milk contaminated with antibiotic drug-resistant bacterial pathogens is of public health concern. Thus, measures to improve the quality of milk need to be designed for the pastoral community in Nakasongola district. [ABSTRACT FROM AUTHOR]

The widely used biocide triclosan selectively targets FabI, the NADH-dependent trans-2-enoyl-acyl carrier protein (ACP) reductase, which is also an important target for the development of narrow spectrum antibiotics. The analysis of triclosan resistant Staphylococcus aureus isolates had previously shown that in about half of the strains, the mechanism of triclosan resistance consists on the heterologous duplication of the triclosan target gene due to the acquisition of an additional fabI allele derived from Staphylococcus haemolyticus (sh-fabI). In the current work, the genomic sequencing of 10 of these strains allowed the characterization of two novel composite transposons TnSha1 and TnSha2 involved in the spread of sh-fabI. TnSha1 harbors one copy of IS1272, whereas TnSha2 is a 11.7 kb plasmid carrying TnSha1 present either as plasmid or in an integrated form generally flanked by two IS1272 elements. The target and mechanism of integration for IS1272 and TnSha1 are novel and include targeting of DNA secondary structures, generation of blunt-end deletions of the stem-loop and absence of target duplication. Database analyses showed widespread occurrence of these two elements in chromosomes and plasmids, with TnSha1 mainly in S. aureus and with TnSha2 mainly in S. haemolyticus and S. epidermidis. The acquisition of resistance by means of an insertion sequence-based mobilization and consequent duplication of drug-target metabolic genes, as observed here for sh-fabI, is highly reminiscent of the situation with the ileS2 gene conferring mupirocin resistance, and the dfrA and dfrG genes conferring trimethoprim resistance both of which are mobilized by IS257. These three examples, which show similar mechanisms and levels of spread of metabolic genes linked to IS elements, highlight the importance of this genetic strategy for recruitment and rapid distribution of novel resistance mechanisms in staphylococci. [ABSTRACT FROM AUTHOR]

Keywords: natural antimicrobial peptides; antimicrobial drug resistance; natural products; antibiotic; drug discovery EN natural antimicrobial peptides antimicrobial drug resistance natural products antibiotic drug discovery N.PAG N.PAG 1 02/19/21 20210216 NES 210216 Infectious diseases are serious global health problems as they are often difficult to control, manage or eradicate. Antimicrobial peptides (AMPs) have been reported to act as broad spectrum antibiotics that kill bacteria, viruses, fungi as well as cancerous cells and demonstrated as a potential source of new antibiotics ([1]). Natural antimicrobial peptides, antimicrobial drug resistance, natural products, antibiotic, drug discovery. [Extracted from the article]

Purpose: The aim of the present study was to determine whether de-escalation guided by blood cultures for patients with a diagnosis of sepsis, severe sepsis or septic shock reduces mortality, and antimicrobial drug resistance (ADR). Methods: A prospective, single-center, cohort study was conducted with adults admitted to the ICU with a diagnosis of sepsis, severe sepsis, or septic shock at a public hospital in Sorocaba, State of São Paulo, Brazil, from January 2013 to December 2013. We excluded patients who had negative blood cultures. Patients who had replaced the initial empirical broad-spectrum antibiotic therapy (EAT) by the antibiotic therapy guided by blood cultures were compared with those who continued receiving EAT. The outcome included mortality and antimicrobial drug resistance. We used the Cox regression (proportional hazards regression) and the Poisson regression to analyze the association between antibiotic therapy guided by blood cultures (ATGBC) and outcomes. The statistical adjustment in all models included the following variables: sex, age, APACHE II (Acute Physiology And Chronic Health Evaluation II) score and SOFA (Sequential Organ Failure Assessment) score. Results: Among the 686 patients who were admitted to the intensive care unit, 91 were included in this study. The mean age of the patients was 52.7 years (standard deviation = 18.5 years) and 70.3% were male. EAT was replaced by ATGBC in 33 patients (36.3%) while 58 patients (63.7%) continued receiving EAT. Overall hospital mortality decreased from 56.9% in patients who received EAT to 48.5% in patients who received ATGBC [Hazard ratio- HR 0.44 (95% CI 0.24–0.82), p = 0.009]. There was no association between ATGBC and ADR [HR 0.90 (95% CI 0.78 – 1.03) p = 0.15]. Conclusions: Although the early and appropriate empirical EAT is undoubtedly an important factor prognostic, ATGBC can reduce the mortality in these patients. [ABSTRACT FROM AUTHOR]