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1.
Mikrochim Acta ; 191(5): 293, 2024 05 01.
Article En | MEDLINE | ID: mdl-38691169

To address the need for facile, rapid detection of pathogens in water supplies, a fluorescent sensing array platform based on antibiotic-stabilized metal nanoclusters was developed for the multiplex detection of pathogens. Using five common antibiotics, eight different nanoclusters (NCs) were synthesized including ampicillin stabilized copper NCs, cefepime stabilized gold and copper NCs, kanamycin stabilized gold and copper NCs, lysozyme stabilized gold NCs, and vancomycin stabilized gold/silver and copper NCs. Based on the different interaction of each NC with the bacteria strains, unique patterns were generated. Various machine learning algorithms were employed for pattern discernment, among which the artificial neural networks proved to have the highest performance, with an accuracy of 100%. The developed prediction model performed well on an independent test dataset and on real samples gathered from drinking water, tap water and the Anzali Lagoon water, with prediction accuracy of 96.88% and 95.14%, respectively. This work demonstrates how generic antibiotics can be implemented for NC synthesis and used as recognition elements for pathogen detection. Furthermore, it displays how merging machine learning techniques can elevate sensitivity of analytical devices.


Anti-Bacterial Agents , Copper , Gold , Metal Nanoparticles , Silver , Metal Nanoparticles/chemistry , Anti-Bacterial Agents/analysis , Anti-Bacterial Agents/chemistry , Gold/chemistry , Copper/chemistry , Silver/chemistry , Drinking Water/microbiology , Drinking Water/analysis , Neural Networks, Computer , Spectrometry, Fluorescence/methods , Machine Learning , Bacteria/isolation & purification , Fluorescent Dyes/chemistry , Vancomycin/chemistry , Water Microbiology , Kanamycin/analysis
2.
BMC Infect Dis ; 24(1): 494, 2024 May 14.
Article En | MEDLINE | ID: mdl-38745289

BACKGROUND: Brain-heart infusion agar supplemented with 4 µg/mL of vancomycin (BHI-V4) was commonly used for the detection of heterogeneous (hVISA) and vancomycin-intermediate Staphylococcus aureus (VISA). However, its diagnostic value remains unclear. This study aims to compare the diagnostic accuracy of BHI-V4 with population analysis profiling with area under the curve (PAP-AUC) in hVISA/VISA. METHODS: The protocol of this study was registered in INPLASY (INPLASY2023120069). The PubMed and Cochrane Library databases were searched from inception to October 2023. Review Manager 5.4 was used for data visualization in the quality assessment, and STATA17.0 (MP) was used for statistical analysis. RESULTS: In total, eight publications including 2153 strains were incorporated into the meta-analysis. Significant heterogeneity was evident although a threshold effect was not detected across the eight studies. The summary receiver operating characteristic (SROC) was 0.77 (95% confidence interval [CI], 0.74-0.81). The pooled sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, diagnostic score and diagnostic odds ratio were 0.59 (95% CI: 0.46-0.71), 0.96 (95%CI: 0.83-0.99), 14.0 (95% CI, 3.4-57.1), 0.43 (95%CI, 0.32-0.57), 3.48(95%CI, 2.12-4.85) and 32.62 (95%CI, 8.31-128.36), respectively. CONCLUSION: Our study showed that BHI-V4 had moderate diagnostic accuracy for diagnosing hVISA/VISA. However, more high-quality studies are needed to assess the clinical utility of BHI-V4.


Anti-Bacterial Agents , Microbial Sensitivity Tests , Staphylococcal Infections , Staphylococcus aureus , Vancomycin , Humans , Staphylococcal Infections/microbiology , Staphylococcal Infections/diagnosis , Vancomycin/pharmacology , Anti-Bacterial Agents/pharmacology , Staphylococcus aureus/drug effects , Staphylococcus aureus/isolation & purification , Sensitivity and Specificity , Vancomycin Resistance , Culture Media , Area Under Curve
3.
Gut Microbes ; 16(1): 2342583, 2024.
Article En | MEDLINE | ID: mdl-38722061

Vancomycin and metronidazole are commonly used treatments for Clostridioides difficile infection (CDI). However, these antibiotics have been associated with high levels of relapse in patients. Fidaxomicin is a new treatment for CDI that is described as a narrow spectrum antibiotic that is minimally active on the commensal bacteria of the gut microbiome. The aim of this study was to compare the effect of fidaxomicin on the human gut microbiome with a number of narrow (thuricin CD) and broad spectrum (vancomycin and nisin) antimicrobials. The spectrum of activity of each antimicrobial was tested against 47 bacterial strains by well-diffusion assay. Minimum inhibitory concentrations (MICs) were calculated against a select number of these strains. Further, a pooled fecal slurry of 6 donors was prepared and incubated for 24 h with 100 µM of each antimicrobial in a mini-fermentation system together with a no-treatment control. Fidaxomicin, vancomycin, and nisin were active against most gram positive bacteria tested in vitro, although fidaxomicin and vancomycin produced larger zones of inhibition compared to nisin. In contrast, the antimicrobial activity of thuricin CD was specific to C. difficile and some Bacillus spp. The MICs showed similar results. Thuricin CD exhibited low MICs (<3.1 µg/mL) for C. difficile and Bacillus firmus, whereas fidaxomicin, vancomycin, and nisin demonstrated lower MICs for all other strains tested when compared to thuricin CD. The narrow spectrum of thuricin CD was also observed in the gut model system. We conclude that the spectrum of activity of fidaxomicin is comparable to that of the broad-spectrum antibiotic vancomycin in vitro and the broad spectrum bacteriocin nisin in a complex community.


Anti-Bacterial Agents , Feces , Fidaxomicin , Gastrointestinal Microbiome , Microbial Sensitivity Tests , Nisin , Vancomycin , Nisin/pharmacology , Anti-Bacterial Agents/pharmacology , Humans , Fidaxomicin/pharmacology , Vancomycin/pharmacology , Gastrointestinal Microbiome/drug effects , Feces/microbiology , Bacteria/drug effects , Bacteria/classification , Clostridioides difficile/drug effects , Clostridium Infections/drug therapy , Clostridium Infections/microbiology , Bacteriocins/pharmacology
4.
Mikrochim Acta ; 191(6): 305, 2024 05 07.
Article En | MEDLINE | ID: mdl-38713444

A multifunctional surface-enhanced Raman scattering (SERS) platform integrating sensitive detection and drug resistance analysis was developed for Gram-positive bacteria. The substrate was based on self-assembled Ti3C2Tx@Au NPs films and capture molecule phytic acid (IP6) to achieve specific capture of Gram-positive bacteria and different bacteria were analyzed by fingerprint signal. It had advantages of good stability and homogeneity (RSD = 8.88%). The detection limit (LOD) was 102 CFU/mL for Staphylococcus aureus and 103 CFU/mL for MRSA, respectively. A sandwich structure was formed on the capture substrate by signal labels prepared by antibiotics (penicillin G and vancomycin) and non-interference SERS probe molecules (4-mercaptobenzonitrile (2223 cm-1) and 2-amino-4-cyanopyridine (2240 cm-1)) to improve sensitivity. The LOD of Au NPs@4-MBN@PG to S. aureus and Au NPs@AMCP@Van to MRSA and S. aureus were all improved to 10 CFU/mL, with a wide dynamic linear range from 108 to 10 CFU/mL (R2 ≥ 0.992). The SERS platform can analyze the drug resistance of drug-resistant bacteria. Au NPs@4-MBN@PG was added to the substrate and captured MRSA to compare the SERS spectra of 4-MBN. The intensity inhomogeneity of 4-MBN at the same concentrations of MRSA and the nonlinearity at the different concentrations of MRSA revealed that MRSA was resistant to PG. Finally, the SERS platform achieved the determination of MRSA in blood. Therefore, this SERS platform has great significance for the determination and analysis of Gram-positive bacteria.


Anti-Bacterial Agents , Gold , Limit of Detection , Metal Nanoparticles , Spectrum Analysis, Raman , Staphylococcus aureus , Titanium , Spectrum Analysis, Raman/methods , Gold/chemistry , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/chemistry , Titanium/chemistry , Metal Nanoparticles/chemistry , Staphylococcus aureus/drug effects , Staphylococcus aureus/isolation & purification , Methicillin-Resistant Staphylococcus aureus/drug effects , Methicillin-Resistant Staphylococcus aureus/isolation & purification , Vancomycin/pharmacology , Vancomycin/chemistry , Drug Resistance, Bacterial , Microbial Sensitivity Tests , Penicillin G/pharmacology , Penicillin G/chemistry , Gram-Positive Bacteria/drug effects , Gram-Positive Bacteria/isolation & purification
5.
Int J Nanomedicine ; 19: 3991-4005, 2024.
Article En | MEDLINE | ID: mdl-38720939

Purpose: Surgical site infections pose a significant challenge for medical services. Systemic antibiotics may be insufficient in preventing bacterial biofilm development. With the local administration of antibiotics, it is easier to minimize possible complications, achieve drugs' higher concentration at the injured site, as well as provide their more sustained release. Therefore, the main objective of the proposed herein studies was the fabrication and characterization of innovative hydrogel-based composites for local vancomycin (VAN) therapy. Methods: Presented systems are composed of ionically gelled chitosan particles loaded with vancomycin, embedded into biomimetic collagen/chitosan/hyaluronic acid-based hydrogels crosslinked with genipin and freeze-dried to serve in a flake/disc-like form. VAN-loaded carriers were characterized for their size, stability, and encapsulation efficiency (EE) using dynamic light scattering technique, zeta potential measurements, and UV-Vis spectroscopy, respectively. The synthesized composites were tested in terms of their physicochemical and biological features. Results: Spherical structures with sizes of about 200 nm and encapsulation efficiencies reaching values of approximately 60% were obtained. It was found that the resulting particles exhibit stability over time. The antibacterial activity of the developed materials against Staphylococcus aureus was established. Moreover, in vitro cell culture study revealed that the surfaces of all prepared systems are biocompatible as they supported the proliferation and adhesion of the model MG-63 cells. In addition, we have demonstrated significantly prolonged VAN release while minimizing the initial burst effect for the composites compared to bare nanoparticles and verified their desired physicochemical features during swellability, and degradation experiments. Conclusion: It is expected that the developed herein system will enable direct delivery of the antibiotic at an exposed to infections surgical site, providing drugs sustained release and thus will reduce the risk of systemic toxicity. This strategy would both inhibit biofilm formation and accelerate the healing process.


Anti-Bacterial Agents , Chitosan , Hydrogels , Staphylococcus aureus , Vancomycin , Vancomycin/chemistry , Vancomycin/pharmacology , Vancomycin/administration & dosage , Vancomycin/pharmacokinetics , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/administration & dosage , Hydrogels/chemistry , Hydrogels/pharmacology , Staphylococcus aureus/drug effects , Humans , Chitosan/chemistry , Hyaluronic Acid/chemistry , Hyaluronic Acid/pharmacology , Drug Carriers/chemistry , Collagen/chemistry , Collagen/pharmacology , Particle Size , Drug Liberation , Surgical Wound Infection/prevention & control , Surgical Wound Infection/drug therapy , Microbial Sensitivity Tests , Biofilms/drug effects
6.
Biomacromolecules ; 25(5): 3190-3199, 2024 May 13.
Article En | MEDLINE | ID: mdl-38693753

Intracellular bacteria in dormant states can escape the immune response and tolerate high-dose antibiotic treatment, leading to severe infections. To overcome this challenge, cascade-targeted nanoplatforms that can target macrophages and intracellular bacteria, exhibiting synergetic antibiotic/reactive oxygen species (ROS)/nitric oxide (NO)/immunotherapy, were developed. These nanoplatforms were fabricated by encapsulating trehalose (Tr) and vancomycin (Van) into phosphatidylserine (PS)-coated poly[(4-allylcarbamoylphenylboric acid)-ran-(arginine-methacrylamide)-ran-(N,N'-bisacryloylcystamine)] nanoparticles (PABS), denoted as PTVP. PS on PTVP simulates a signal of "eat me" to macrophages to promote cell uptake (the first-step targeting). After the uptake, the nanoplatform in the acidic phagolysosomes could release Tr, and the exposed phenylboronic acid on the nanoplatform could target bacteria (the second-step targeting). Nanoplatforms can release Van in response to infected intracellular overexpressed glutathione (GSH) and weak acid microenvironment. l-arginine (Arg) on the nanoplatforms could be catalyzed by upregulated inducible nitric oxide synthase (iNOS) in the infected macrophages to generate nitric oxide (NO). N,N'-Bisacryloylcystamine (BAC) on nanoplatforms could deplete GSH, allow the generation of ROS in macrophages, and then upregulate proinflammatory activity, leading to the reinforced antibacterial capacity. This nanoplatform possesses macrophage and bacteria-targeting antibiotic delivery, intracellular ROS, and NO generation, and pro-inflammatory activities (immunotherapy) provides a new strategy for eradicating intracellular bacterial infections.


Anti-Bacterial Agents , Nanoparticles , Nitric Oxide , Reactive Oxygen Species , Reactive Oxygen Species/metabolism , Nitric Oxide/metabolism , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/chemistry , Mice , Animals , RAW 264.7 Cells , Nanoparticles/chemistry , Macrophages/drug effects , Macrophages/metabolism , Macrophages/immunology , Immunotherapy/methods , Vancomycin/pharmacology , Vancomycin/chemistry , Vancomycin/administration & dosage , Bacterial Infections/drug therapy , Trehalose/chemistry , Trehalose/pharmacology
7.
Cell Rep ; 43(4): 114082, 2024 Apr 23.
Article En | MEDLINE | ID: mdl-38583155

Infections caused by methicillin-resistant Staphylococcus aureus (MRSA) are alarmingly common, and treatment is confined to last-line antibiotics. Vancomycin is the treatment of choice for MRSA bacteremia, and treatment failure is often associated with vancomycin-intermediate S. aureus isolates. The regulatory 3' UTR of the vigR mRNA contributes to vancomycin tolerance and upregulates the autolysin IsaA. Using MS2-affinity purification coupled with RNA sequencing, we find that the vigR 3' UTR also regulates dapE, a succinyl-diaminopimelate desuccinylase required for lysine and peptidoglycan synthesis, suggesting a broader role in controlling cell wall metabolism and vancomycin tolerance. Deletion of the 3' UTR increased virulence, while the isaA mutant is completely attenuated in a wax moth larvae model. Sequence and structural analyses of vigR indicated that the 3' UTR has expanded through the acquisition of Staphylococcus aureus repeat insertions that contribute sequence for the isaA interaction seed and may functionalize the 3' UTR.


3' Untranslated Regions , Staphylococcal Infections , Staphylococcus aureus , Animals , 3' Untranslated Regions/genetics , Anti-Bacterial Agents/pharmacology , Bacterial Proteins/genetics , Bacterial Proteins/metabolism , Base Sequence , Gene Expression Regulation, Bacterial , Methicillin-Resistant Staphylococcus aureus/genetics , Methicillin-Resistant Staphylococcus aureus/pathogenicity , Methicillin-Resistant Staphylococcus aureus/drug effects , Moths/microbiology , Staphylococcal Infections/microbiology , Staphylococcal Infections/drug therapy , Staphylococcus aureus/genetics , Staphylococcus aureus/pathogenicity , Staphylococcus aureus/drug effects , Vancomycin/pharmacology , Virulence/genetics
9.
J Appl Microbiol ; 135(4)2024 Apr 01.
Article En | MEDLINE | ID: mdl-38587823

AIM: In this study, it was aimed to examine the antibacterial activity of the essential oil components (EOCs), carvacrol (CAR), cinnamaldehyde (CIN), thymol (TH), alpha pinene (α-PN), eucalyptol (EU), limonene (LIM), and the antibiotics, linezolid (LZD), vancomycin (VAN), gentamicin (GEN), ciprofloxacin (CIP), clindamycin (CLN), and penicillin (PEN) against 50 multidrug resistant Corynebacterium striatum strains, and the synergistic interactions of CAR and CIN with the antibiotics against 10 randomly selected Coryne. striatum strains to explore synergistic interactions to determine if their combined use could enhance antibiotic activity and potentially reduce resistance. METHODS AND RESULTS: The activity of the EOCs and the antibiotics against Coryne. striatum strains isolated from clinical specimens, was examined by broth microdilution method. The synergistic interactions of the EOCs with the antibiotics against 10 randomly selected Coryne. striatum strains were determined by checkerboard method. EOCs, CIN, and CAR and antibiotics, LZD, VAN, GEN, CIP, and CLN were detected to have antibacterial activity against Coryne. striatum strains alone and either synergistic interactions were observed in combinations of the antibiotics with EOCs. CONCLUSIONS: All Coryne. striatum strains were determined to be susceptible to VAN and LZD and resistant to GEN, PEN, CIP, and CLN. Synergistic interactions were observed in all combinations of antibiotics tested with CAR and CIN.


Acrolein , Acrolein/analogs & derivatives , Anti-Bacterial Agents , Corynebacterium , Drug Resistance, Multiple, Bacterial , Drug Synergism , Microbial Sensitivity Tests , Monoterpenes , Oils, Volatile , Anti-Bacterial Agents/pharmacology , Corynebacterium/drug effects , Oils, Volatile/pharmacology , Drug Resistance, Multiple, Bacterial/drug effects , Acrolein/pharmacology , Monoterpenes/pharmacology , Cymenes/pharmacology , Ciprofloxacin/pharmacology , Gentamicins/pharmacology , Vancomycin/pharmacology , Linezolid/pharmacology , Limonene/pharmacology , Eucalyptol/pharmacology , Thymol/pharmacology , Clindamycin/pharmacology , Humans , Penicillins/pharmacology , Terpenes/pharmacology , Cyclohexenes/pharmacology , Corynebacterium Infections/microbiology
10.
ACS Infect Dis ; 10(5): 1696-1710, 2024 May 10.
Article En | MEDLINE | ID: mdl-38577780

Treatment of microbial infections is becoming daunting because of widespread antimicrobial resistance. The treatment challenge is further exacerbated by the fact that certain infectious bacteria invade and localize within host cells, protecting the bacteria from antimicrobial treatments and the host's immune response. To survive in the intracellular niche, such bacteria deploy surface receptors similar to host cell receptors to sequester iron, an essential nutrient for their virulence, from host iron-binding proteins, in particular lactoferrin and transferrin. In this context, we aimed to target lactoferrin receptors expressed by macrophages and bacteria; as such, we prepared and characterized lactoferrin nanoparticles (Lf-NPs) loaded with a dual drug combination of antimicrobial natural alkaloids, berberine or sanguinarine, with vancomycin or imipenem. We observed increased uptake of drug-loaded Lf-NPs by differentiated THP-1 cells with up to 90% proportion of fluorescent cells, which decreased to about 60% in the presence of free lactoferrin, demonstrating the targeting ability of Lf-NPs. The encapsulated antibiotic drug cocktail efficiently cleared intracellular Staphylococcus aureus (Newman strain) compared to the free drug combinations. However, the encapsulated drugs and the free drugs alike exhibited a bacteriostatic effect against the hard-to-treat Mycobacterium abscessus (smooth variant). In conclusion, the results of this study demonstrate the potential of lactoferrin nanoparticles for the targeted delivery of antibiotic drug cocktails for the treatment of intracellular bacteria.


Anti-Bacterial Agents , Lactoferrin , Nanoparticles , Staphylococcus aureus , Lactoferrin/chemistry , Lactoferrin/pharmacology , Humans , Nanoparticles/chemistry , Staphylococcus aureus/drug effects , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/chemistry , THP-1 Cells , Macrophages/drug effects , Vancomycin/pharmacology , Drug Carriers/chemistry , Drug Delivery Systems , Microbial Sensitivity Tests
11.
J Microbiol Biotechnol ; 34(4): 828-837, 2024 Apr 28.
Article En | MEDLINE | ID: mdl-38668685

Vancomycin (VAN) and metronidazole (MTR) remain the current drugs of choice for the treatment of non-severe Clostridioides difficile infection (CDI); however, while their co-administration has appeared in clinical treatment, the efficacy varies greatly and the mechanism is unknown. In this study, a CDI mouse model was constructed to evaluate the therapeutic effects of VAN and MTR alone or in combination. For a perspective on the intestinal ecology, 16S rRNA amplicon sequencing and non-targeted metabolomics techniques were used to investigate changes in the fecal microbiota and metabolome of mice under the co-administration treatment. As a result, the survival rate of mice under co-administration was not dramatically different compared to that of single antibiotics, and the former caused intestinal tissue hyperplasia and edema. Co-administration also significantly enhanced the activity of amino acid metabolic pathways represented by phenylalanine, arginine, proline, and histidine, decreased the level of deoxycholic acid (DCA), and downregulated the abundance of beneficial microbes, such as Bifidobacterium and Akkermansia. VAN plays a dominant role in microbiota regulation in co-administration. In addition, co-administration reduced or increased the relative abundance of antibiotic-sensitive bacteria, including beneficial and harmful microbes, without a difference. Taken together, there are some risks associated with the co-administration of VAN and MTR, and this combination mode should be used with caution in CDI treatment.


Anti-Bacterial Agents , Clostridioides difficile , Clostridium Infections , Disease Models, Animal , Drug Therapy, Combination , Feces , Gastrointestinal Microbiome , Metronidazole , RNA, Ribosomal, 16S , Vancomycin , Animals , Metronidazole/administration & dosage , Vancomycin/administration & dosage , Vancomycin/pharmacology , Clostridium Infections/drug therapy , Clostridium Infections/microbiology , Gastrointestinal Microbiome/drug effects , Mice , Anti-Bacterial Agents/administration & dosage , Anti-Bacterial Agents/pharmacology , Clostridioides difficile/drug effects , Clostridioides difficile/genetics , RNA, Ribosomal, 16S/genetics , Feces/microbiology , Intestines/microbiology , Intestines/drug effects , Male , Bacteria/classification , Bacteria/genetics , Bacteria/drug effects , Metabolome/drug effects
12.
Medicine (Baltimore) ; 103(16): e37860, 2024 Apr 19.
Article En | MEDLINE | ID: mdl-38640320

Staphylococcus aureus is an important human pathogen that has a major impact on public health. The objective of the present work was to determine the prevalence and the pattern of antibiotic susceptibility in S aureus (MRSA) isolates from the King Khalid University Hospital (KKUH) in Riyadh, Saudi Arabia. The isolates were collected from different body sites of infection and the antibiotic susceptibility was confirmed on the Vitek 2 system. A total of 371 MRSA isolates from clinical samples were received over a 12-month period from January 2021 to December 2021. The results showed that infection was predominant among males (55.8%) and most of the isolates occurred in the older age groups, with a mean age of 43.7 years and an age span from <1 to 89 years old. The majority (34.5%) recovered from wound infection followed by (14.6%) from blood. We have observed peaks of MRSA infections during the autumn, especially in September and November. All MRSA isolates were resistant to Amoxicillin + clavulanic acid, Ampicillin, Imipenem, Oxacillin, Cloxacillin, and Penicillin while all isolates were sensitive to Daptomycin and Nitrofurantoin. Furthermore, Vancomycin was resistant in (0.3%) of MRSA isolates, and (2.9%) was resistant to Linezolid. The current study concluded that MRSA strains had developed resistance toward 24 tested antibiotics, including the previous effective drugs vancomycin and linezolid. Therefore, there is an urgent need for continuous review of infection control practices to prevent any further spread of resistant strains.


Methicillin-Resistant Staphylococcus aureus , Staphylococcal Infections , Male , Humans , Aged , Adult , Infant , Child, Preschool , Child , Adolescent , Young Adult , Middle Aged , Aged, 80 and over , Vancomycin/pharmacology , Linezolid/pharmacology , Saudi Arabia/epidemiology , Tertiary Care Centers , Microbial Sensitivity Tests , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/therapeutic use , Staphylococcus aureus , Staphylococcal Infections/drug therapy , Staphylococcal Infections/epidemiology , Amoxicillin-Potassium Clavulanate Combination/pharmacology
13.
Mikrobiyol Bul ; 58(2): 125-134, 2024 Apr.
Article Tr | MEDLINE | ID: mdl-38676581

The World Health Organization has included the problem of antibiotic resistance among the top 10 important health problems in the world. Treatment of infectious diseases has become more difficult due to the spread of antibiotic resistance between bacteria via transposable elements. Vancomycin-resistant enterococci (VRE) are of critical medical and public health importance due to their association with serious nosocomial infections and high risk of death. One of the most important features of VREs is that they have multiple antibiotic resistance and treatment options are reduced. Therefore, new treatment methods are needed. The vanA gene constitutes the building block of the vancomycin resistance mechanism and causes high resistance to vancomycin. In this study, it was aimed to investigate the neutralization of the vancomycin resistance mechanism by creating vanA antisense RNA (asRNA). The vanA positive VRE50 strain in our culture collection which was isolated from the clinical sample, was used to amplify the vanA gene by polymerase chain reaction (PCR). The amplified vanA amplicon was inserted inversely into the pUC19 plasmid by means of the enzyme cutting sites in the primers used. The resulting plasmid was combined with the pAT392 plasmid which can replicate in gram-positive bacteria and a fusion plasmid was created. The fusion plasmid whose orientation was confirmed, was transferred to the wild strain VRE50 by electroporation method. Minimum inhibitory concentration (MIC) values of transformed VRE (tVRE50) and wild type VRE50 strains used as control were determined by the E-Test method. The vancomycin MIC value of the wild type VRE50 strain was determined as 1024 µg/mL and that of the tVRE50 strain was 32 µg/mL and it was determined that the vancomycin resistance of the tVRE50 strain decreased with asRNA (antisense RNA). Antisense RNA technology is an important method for neutralizing the expression of genes. This study showed that neutralization of the vancomycin resistance gene may provide a lower MIC value in a vancomycin-resistant enterococcus strain and lead to increased susceptibility. This new approach provides a new method for VRE treatment by neutralizing the vancomycin resistance mechanism. The result obtained in this study needs to be supported by in vivo tests.


Bacterial Proteins , Carbon-Oxygen Ligases , RNA, Antisense , Vancomycin-Resistant Enterococci , Vancomycin , Vancomycin-Resistant Enterococci/genetics , Vancomycin-Resistant Enterococci/drug effects , Carbon-Oxygen Ligases/genetics , RNA, Antisense/genetics , Bacterial Proteins/genetics , Humans , Vancomycin/pharmacology , Plasmids/genetics , Vancomycin Resistance/genetics , Microbial Sensitivity Tests , Anti-Bacterial Agents/pharmacology , Gene Silencing
14.
Gut Microbes ; 16(1): 2337312, 2024.
Article En | MEDLINE | ID: mdl-38591915

Clostridioides difficile causes a range of debilitating intestinal symptoms that may be fatal. It is particularly problematic as a hospital-acquired infection, causing significant costs to the health care system. Antibiotics, such as vancomycin and fidaxomicin, are still the drugs of choice for C. difficile infections, but their effectiveness is limited, and microbial interventions are emerging as a new treatment option. This paper focuses on alternative treatment approaches, which are currently in various stages of development and can be divided into four therapeutic strategies. Direct killing of C. difficile (i) includes beside established antibiotics, less studied bacteriophages, and their derivatives, such as endolysins and tailocins. Restoration of microbiota composition and function (ii) is achieved with fecal microbiota transplantation, which has recently been approved, with standardized defined microbial mixtures, and with probiotics, which have been administered with moderate success. Prevention of deleterious effects of antibiotics on microbiota is achieved with agents for the neutralization of antibiotics that act in the gut and are nearing regulatory approval. Neutralization of C. difficile toxins (iii) which are crucial virulence factors is achieved with antibodies/antibody fragments or alternative binding proteins. Of these, the monoclonal antibody bezlotoxumab is already in clinical use. Immunomodulation (iv) can help eliminate or prevent C. difficile infection by interfering with cytokine signaling. Small-molecule agents without bacteriolytic activity are usually selected by drug repurposing and can act via a variety of mechanisms. The multiple treatment options described in this article provide optimism for the future treatment of C. difficile infection.


Clostridioides difficile , Clostridium Infections , Gastrointestinal Microbiome , Humans , Anti-Bacterial Agents/therapeutic use , Anti-Bacterial Agents/pharmacology , Fecal Microbiota Transplantation , Vancomycin/pharmacology , Clostridium Infections/drug therapy , Clostridium Infections/prevention & control
15.
Front Cell Infect Microbiol ; 14: 1353433, 2024.
Article En | MEDLINE | ID: mdl-38558854

Objective: To analyze the clinical epidemiological characteristics including clinical features, disease prognosis of pneumococcal meningitis (PM), and drug sensitivity of S. pneumoniae isolates in Chinese children. Methods: A retrospective analysis was performed on the clinical, laboratory microbiological data of 160 hospitalized children less than 15 years of age with PM from January 2019 to December 2020 in 33 tertiary hospitals in China. Results: A total of 160 PM patients were diagnosed, including 103 males and 57 females The onset age was 15 days to 15 years old, and the median age was 1 year and 3 months. There were 137 cases (85.6%) in the 3 months to <5 years age group, especially in the 3 months to <3 years age group (109 cases, 68.2%); S. pneumoniae was isolated from cerebrospinal fluid (CSF) culture in 95(35.6%), and 57(35.6%) in blood culture. The positive rates of S. pneumoniae detection by CSF metagenomic next-generation sequencing (mNGS)and antigen detection method were 40.2% (35/87) and 26.9% (21/78). Fifty-five cases (34.4%) had one or more predisposing factors of bacterial meningitis; and 113 cases (70.6%) had one or more extracranial infection diseases Fever (147, 91.9%) was the most common clinical symptom, followed by vomiting (61, 38.1%) and altered mental status (47,29.4%). Among 160 children with PM, the main intracranial imaging complications were subdural effusion and (or) empyema in 43 cases (26.9%), hydrocephalus in 24 cases (15.0%), cerebral abscess in 23 cases (14.4%), intracranial hemorrhage in 8 cases (5.0%), and other cerebrovascular diseases in 13 cases (8.1%) including encephalomalacia, cerebral infarction, and encephalatrophy. Subdural effusion and (or) empyema and hydrocephalus mainly occurred in children < 1 years old (90.7% (39/43) and 83.3% (20/24), respectively). 17 cases with PM (39.5%) had more than one intracranial imaging abnormality. S. pneumoniae isolates were completely sensitive to vancomycin (100.0%, 75/75), linezolid (100.0%,56/56), ertapenem (6/6); highly sensitive to levofloxacin (81.5%, 22/27), moxifloxacin (14/17), rifampicin (96.2%, 25/26), and chloramphenicol (91.3%, 21/23); moderately sensitive to cefotaxime (56.1%, 23/41), meropenem (51.1%, 23/45) and ceftriaxone (63.5, 33/52); less sensitive to penicillin (19.6%, 27/138) and clindamycin (1/19); completely resistant to erythromycin (100.0%, 31/31). The cure and improvement rate were 22.5% (36/160)and 66.3% (106/160), respectively. 18 cases (11.3%) had an adverse outcome, including 6 cases withdrawing treatment therapy, 5 cases unhealed, 5 cases died, and 2 recurrences. S. pneumoniae was completely susceptible to vancomycin (100.0%, 75/75), linezolid (100.0%, 56/56), and ertapenem (6/6); susceptible to cefotaxime, meropenem, and ceftriaxone in the order of 56.1% (23/41), 51.1% (23/45), and 63.5 (33/52); completely resistant to erythromycin (100.0%, 31/31). Conclusion: Pediatric PM is more common in children aged 3 months to < 3 years old. Intracranial complications mostly occur in children < 1 year of age with fever being the most common clinical manifestations and subdural effusion and (or) empyema and hydrocephalus being the most common complications, respectively. CSF non-culture methods can facilitate improving the detection rate of pathogenic bacteria. More than 10% of PM children had adverse outcomes. S. pneumoniae strains are susceptible to vancomycin, linezolid, ertapenem, levofloxacin, moxifloxacin, rifampicin, and chloramphenicol.


Empyema , Hydrocephalus , Meningitis, Bacterial , Meningitis, Pneumococcal , Subdural Effusion , Adolescent , Child , Female , Humans , Infant , Male , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/therapeutic use , Cefotaxime , Ceftriaxone/therapeutic use , Chloramphenicol , Empyema/drug therapy , Ertapenem/therapeutic use , Erythromycin/therapeutic use , Hydrocephalus/drug therapy , Levofloxacin , Linezolid/therapeutic use , Meningitis, Bacterial/diagnosis , Meningitis, Pneumococcal/diagnosis , Meningitis, Pneumococcal/drug therapy , Meningitis, Pneumococcal/epidemiology , Meropenem/therapeutic use , Microbial Sensitivity Tests , Moxifloxacin/therapeutic use , Retrospective Studies , Rifampin , Subdural Effusion/drug therapy , Vancomycin , Infant, Newborn , Child, Preschool
16.
J Nepal Health Res Counc ; 21(4): 616-622, 2024 Mar 31.
Article En | MEDLINE | ID: mdl-38616592

BACKGROUND: Staphylococcus aureus (S.aureus) is an emerging antibiotic resistant bacterium responsible for various infections in human. Resistance to methicillin and vancomycin are of prime concern in S. aureus. The study aims to determine the minimum inhibitory concentration (MIC) of Vancomycin and evaluate the existence of mecA and vanA genes, associated with antibiotic resistance. METHODS: Clinical specimens from three Kathmandu hospitals were processed and S. aureus was identified using conventional microbiological procedures. MRSA was phenotypically identified with cefoxitin (30µg) disc diffusion, while vancomycin susceptibility was assessed using the Ezy MICTM stripes. The mecA and vanA genes were detected by polymerase chain reaction (PCR). RESULTS: Out of 266 S. aureus samples from various clinical specimen subjected for analysis, 77 (28.9%) were found methicillin-resistant (MRSA) and 10 (3.8%) were observed vancomycin-resistant (VRSA). Vancomycin resistant isolates showed a significant correlation between resistance to ampicillin, chloramphenicol, and cefoxitin. The mecA gene was found in 39 of the MRSA isolates, having 50.64% of MRSA cases, while the vanA gene was detected in 4 of the VRSA cases, constituting 40% of VRSA occurrences. CONCLUSIONS: The strains with higher vancomycin minimum inhibitory concentration values (≥ 1.5 µg/ml) displayed increased resistance rates to various antibiotics compared to strains with lower minimum inhibitory concentration values (< 1.5 µg/ml). The presence of vanA genes was strongly associated (100%) with vancomycin resistance, while the 10.3% mecA gene was identified from MRSA having resistance towards vancomycin also.


Staphylococcal Infections , Vancomycin , Humans , Vancomycin/pharmacology , Staphylococcus aureus/genetics , Cefoxitin/pharmacology , Nepal , Staphylococcal Infections/drug therapy , Anti-Bacterial Agents/pharmacology
17.
ACS Infect Dis ; 10(4): 1327-1338, 2024 Apr 12.
Article En | MEDLINE | ID: mdl-38567846

Due to the widespread abuse of antibiotics, drug resistance in Enterococcus has been increasing. However, the speed of antibiotic discovery cannot keep pace with the acquisition of bacterial resistance. Thus, drug repurposing is a proposed strategy to solve the crises. Lusutrombopag (LP) has been approved as a thrombopoietin receptor agonist by the Food and Drug Administration. This study demonstrated that LP exhibited significant antimicrobial activities against vancomycin-resistant Enterococcus in vitro with rare resistance occurrence. Further, LP combined with tobramycin exhibited synergistic antimicrobial effects in vitro and in vivo against Enterococcus. No in vitro or in vivo detectable toxicity was observed when using LP. Mechanism studies indicated that the disrupted proton motive force may account for LP's antimicrobial activity. In summary, these results demonstrate that LP has the previously undocumented potential to serve as an antibacterial agent against refractory infections caused by Enterococcus.


Aminoglycosides , Cinnamates , Thiazoles , Vancomycin-Resistant Enterococci , United States , Aminoglycosides/pharmacology , Vancomycin/pharmacology , Pharmaceutical Preparations , Drug Repositioning , Microbial Sensitivity Tests , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/therapeutic use
18.
Lett Appl Microbiol ; 77(4)2024 Apr 08.
Article En | MEDLINE | ID: mdl-38569656

Diagnostic laboratories in Aotearoa, New Zealand (NZ) refer cultures from faecal samples positive for Shiga toxin genes to the national Enteric Reference Laboratory for isolation of Shiga toxin-producing Escherichia coli (STEC) for epidemiological typing. As there was variation in the culture media being referred, a panel of 75 clinical isolates of STEC, representing 28 different serotypes, was used to assess six commercially available media and provide guidance to clinical laboratories. Recommendations were subsequently tested for a 3-month period, where STEC isolations and confirmations were assessed by whole genome sequencing analysis against the culture media referred. CHROMagar™ STEC (CH-STEC; CHROMagar Microbiology, Paris, France) or CH-STEC plus cefixime-tellurite sorbitol MacConkey agar was confirmed inferior to CH-STEC plus blood agar with vancomycin, cefsulodin, and cefixime (BVCC). The former resulted in fewer STEC types (n = 18) being confirmed compared to those from a combination of CH-STEC and BVCC (n = 42). A significant (P < .05) association with an STEC's ability to grow on CH-STEC and the presence of the ter gene cluster, and eae was observed. Culturing screen positive STEC samples onto both CH-STEC and BVCC ensures a consistently higher recovery of STEC from all clinical samples in NZ than CH-STEC alone.


Escherichia coli Infections , Escherichia coli Proteins , Shiga-Toxigenic Escherichia coli , Humans , Shiga-Toxigenic Escherichia coli/genetics , Cefixime , Agar , New Zealand , Culture Media , Vancomycin , Cefsulodin , Escherichia coli Infections/microbiology , Escherichia coli Proteins/genetics
19.
Front Cell Infect Microbiol ; 14: 1323054, 2024.
Article En | MEDLINE | ID: mdl-38567022

The patient, a 43-year-old male, was admitted to the hospital with gradually aggravated exertional palpitations and chest tightness over a 2-day period. Upon hospital admission, a cardiac ultrasound revealed aortic valve redundancy, however multiple blood culture investigations came back negative. Blood mNGS was perfected, revealing Coxiella burnetii, and the diagnosis of Q fever (query fever) was established. The temperature and inflammatory indices of the patient were all normal with the treatment of vancomycin before cardiac surgery. But for the potential liver damage of and the Coxiella burnetii was still positive in the anti-phase II IgG titer, the doxycycline and hydroxychloroquine instead of vancomycin were applied for the patient. Despite receiving standardized anti-infective therapy of doxycycline combined with hydroxychloroquine, this patient had fever and increased leukocytes following surgery. After the addition of vancomycin as an anti-infective treatment, the temperature and leukocytes improved quickly. During the treatment of vancomycin, a discovery of liver injury may have resulted. These findings provide new therapy options for future professionals.


Coxiella burnetii , Endocarditis, Bacterial , Q Fever , Male , Humans , Adult , Q Fever/diagnosis , Q Fever/drug therapy , Vancomycin/therapeutic use , Doxycycline/therapeutic use , Hydroxychloroquine , Endocarditis, Bacterial/diagnosis , Endocarditis, Bacterial/drug therapy
20.
Sr Care Pharm ; 39(5): 185-192, 2024 May 01.
Article En | MEDLINE | ID: mdl-38685618

Objective Infections from methicillin-resistant Staphylococcus aureus are increasingly treated in longterm care facilities, but long-term care pharmacies face high costs in the provision of sterile vancomycin for intravenous administration. This study compares pharmaceutical costs of outsourced, compounded, and room temperature premixed vancomycin formulations in a long-term care pharmacy. Design This retrospective observational study reviewed 124 orders of vancomycin. Means for total pharmacy preparation time, pharmacist labor time, and extrapolated time over complete course of treatment were compared for three vancomycin preparations: outsourced, compounded by pharmacy, and room temperature premixed vancomycin formulations. Cost calculations were generated using ingredient costs as reported by the pharmacy and median pharmacist labor costs as published from national sources. Results Mean total preparation times and pharmacist preparation times were shortest for premixed vancomycin. Over full courses of treatment, mean pharmacy preparation time for compounded was 5 hours 3 minutes (mean of 28 treatments) and 2 hours 8 minutes for premixed (mean of 54 treatments). Data on pharmacist time in outsourced orders were not available. Total pharmacy costs were $993.94 for compounded vancomycin, $2220.34 for outsourced, and $809.36 for room temperature premixed vancomycin. Conclusion There were reduced preparation times for room temperature premixed vancomycin compared with compounded and outsourced formulations for skilled nursing facilities. As multiple drug-resistant organism infections are increasingly treated in long-term care, finding cost-effective approaches to medication provision from pharmacies is critical.


Anti-Bacterial Agents , Vancomycin , Vancomycin/economics , Vancomycin/administration & dosage , Vancomycin/therapeutic use , Retrospective Studies , Humans , Anti-Bacterial Agents/economics , Anti-Bacterial Agents/administration & dosage , Drug Compounding/economics , Time Factors , Methicillin-Resistant Staphylococcus aureus/drug effects , Drug Costs , Long-Term Care/economics , Pharmacists/economics
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