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Pathogens (Basel, Switzerland) Apr 2023A case of severe mortality in farmed was investigated to characterize the causative agent. We identified the bacterial strain as isolated from the gut of infected by...
A case of severe mortality in farmed was investigated to characterize the causative agent. We identified the bacterial strain as isolated from the gut of infected by biochemical assay, scanning electron microscopy and 16S rRNA gene sequence analysis. The in vivo challenge experiment showed that the LD of was 2.2 × 10 CFU/fish. Virulence gene investigation revealed that the isolated possesses Aerolysin, Cytotoxic enterotoxin, Serine protease, Dnase and Type III secretion system genes. The isolated strain was resistant to two antibiotics (ampicillin and dicloxacillin) while susceptible to 22 other antibiotics. The study further revealed that induced both stresses along with non-specific and specific immune responses marked by elevated cortisol HSP70, HSP90 and IgM levels in the treated fingerlings. Although the bacterial pathogen enhances the immune response, the negative effect on fish, including stress, and high mortality, create concern and a need for management in farms. The knowledge gained from this study would facilitate future research aimed at assessing the pathogenicity of , with an emphasis on microbial disease management in other farmed fish species.
PubMed: 37111485
DOI: 10.3390/pathogens12040598 -
British Journal of Clinical Pharmacology Aug 2023Dicloxacillin is used to treat staphylococcal infections and we have previously shown that dicloxacillin is an inducer of cytochrome P450 enzymes (CYPs). Here, we...
AIMS
Dicloxacillin is used to treat staphylococcal infections and we have previously shown that dicloxacillin is an inducer of cytochrome P450 enzymes (CYPs). Here, we employed a translational approach to investigate the effect of a treatment with dicloxacillin on warfarin efficacy in Danish registries. Furthermore, we assessed dicloxacillin as an inducer of CYPs in vitro.
METHODS
We conducted a register-based study and analysed international normalized ratio (INR) levels in chronic warfarin users before and after short- and long-term use of dicloxacillin (n = 1023) and flucloxacillin (n = 123). Induction of CYPs were investigated in a novel liver model of 3D spheroid primary human hepatocytes at the level of mRNA, and protein and enzyme activity.
RESULTS
Short- and long-term dicloxacillin treatments decreased INR levels by -0.65 (95% confidence interval [CI]: -0.57 to -0.74) and -0.76 (95% CI: -0.50 to -1.02), respectively. More than 90% of individuals experienced subtherapeutic INR levels (below 2) after long-term dicloxacillin treatment. Flucloxacillin decreased INR levels by -0.37 (95% CI: -0.14 to -0.60). In 3D spheroid primary human hepatocytes, the maximal induction of CYP3A4 mRNA, protein and enzyme activity by dicloxacillin were 4.9-, 2.9- and 2.4-fold, respectively. Dicloxacillin also induced CYP2C9 mRNA by 1.7-fold.
CONCLUSION
Dicloxacillin induces CYPs and reduces the clinical efficacy of warfarin in patients. This effect is substantially exacerbated during long-term treatment with dicloxacillin. The in vitro results corroborated this drug-drug interaction and correlated to the clinical findings. Caution is warranted for warfarin patients that initiate dicloxacillin or flucloxacillin, especially for a long-term treatment of endocarditis.
Topics: Humans; Warfarin; Dicloxacillin; Anticoagulants; Floxacillin; International Normalized Ratio; Cytochrome P-450 Enzyme System; Hepatocytes; Drug Interactions
PubMed: 37021780
DOI: 10.1111/bcp.15738 -
Clinical Infectious Diseases : An... Jul 2023In the POET (Partial Oral Endocarditis Treatment) trial, oral step-down therapy was noninferior to full-length intravenous antibiotic administration. The aim of the...
BACKGROUND
In the POET (Partial Oral Endocarditis Treatment) trial, oral step-down therapy was noninferior to full-length intravenous antibiotic administration. The aim of the present study was to perform pharmacokinetic/pharmacodynamic analyses for oral treatments of infective endocarditis to assess the probabilities of target attainment (PTAs).
METHODS
Plasma concentrations of oral antibiotics were measured at day 1 and 5. Minimal inhibitory concentrations (MICs) were determined for the bacteria causing infective endocarditis (streptococci, staphylococci, or enterococci). Pharmacokinetic/pharmacodynamic targets were predefined according to literature using time above MIC or the ratio of area under the curve to MIC. Population pharmacokinetic modeling and pharmacokinetic/pharmacodynamic analyses were done for amoxicillin, dicloxacillin, linezolid, moxifloxacin, and rifampicin, and PTAs were calculated.
RESULTS
A total of 236 patients participated in this POET substudy. For amoxicillin and linezolid, the PTAs were 88%-100%. For moxifloxacin and rifampicin, the PTAs were 71%-100%. Using a clinical breakpoint for staphylococci, the PTAs for dicloxacillin were 9%-17%.Seventy-four patients at day 1 and 65 patients at day 5 had available pharmacokinetic and MIC data for 2 oral antibiotics. Of those, 13 patients at day 1 and 14 patients at day 5 did only reach the target for 1 antibiotic. One patient did not reach target for any of the 2 antibiotics.
CONCLUSIONS
For the individual orally administered antibiotic, the majority reached the target level. Patients with sub-target levels were compensated by the administration of 2 different antibiotics. The findings support the efficacy of oral step-down antibiotic treatment in patients with infective endocarditis.
Topics: Humans; Rifampin; Dicloxacillin; Linezolid; Moxifloxacin; Anti-Bacterial Agents; Endocarditis; Endocarditis, Bacterial; Amoxicillin; Microbial Sensitivity Tests
PubMed: 36947131
DOI: 10.1093/cid/ciad168 -
Clinical Pharmacology and Therapeutics Jun 2023Primary human hepatocytes (PHHs) have been the gold standard in vitro model for the human liver and are crucial to predict hepatic drug-drug interactions. The aim of...
Primary human hepatocytes (PHHs) have been the gold standard in vitro model for the human liver and are crucial to predict hepatic drug-drug interactions. The aim of this work was to assess the utility of 3D spheroid PHHs to study induction of important cytochrome P450 (CYP) enzymes and drug transporters. The 3D spheroid PHHs from three different donors were treated for 4 days with rifampicin, dicloxacillin, flucloxacillin, phenobarbital, carbamazepine, efavirenz, omeprazole, or β-naphthoflavone. Induction of CYP1A1, CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4, and transporters P-glycoprotein (P-gp)/ABCB1, multidrug resistance-associated protein 2 (MRP2)/ABCC2, ABCG2, organic cation transporter 1 (OCT1)/SLC22A1, SLC22A7, SLCO1B1, and SLCO1B3 were evaluated at mRNA and protein levels. Enzyme activity of CYP3A4, CYP2B6, CYP2C19, and CYP2D6 were also assessed. Induction of CYP3A4 protein and mRNA correlated well for all donors and compounds and had a maximal induction of five- to sixfold for rifampicin, which closely correlates to induction observed in clinical studies. Rifampicin induced the mRNA of CYP2B6 and CYP2C8 by 9- and 12-fold, whereas the protein levels of these CYPs reached 2- and 3-fold induction, respectively. Rifampicin induced CYP2C9 protein by 1.4-fold, whereas the induction of CYP2C9 mRNA was over 2-fold in all donors. Rifampicin induced ABCB1, ABCC2, and ABCG2 by 2-fold. In conclusion, 3D spheroid PHHs is a valid model to investigate mRNA and protein induction of hepatic drug-metabolizing enzymes and transporters, and this model provides a solid basis to study induction of CYPs and transporters, which translates to clinical relevance.
Topics: Humans; Cytochrome P-450 CYP2C8; Cytochrome P-450 CYP2C19; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP2B6; Rifampin; Cytochrome P-450 CYP2D6; Cytochrome P-450 CYP2C9; Cells, Cultured; Cytochrome P-450 Enzyme System; Hepatocytes; Membrane Transport Proteins; Carrier Proteins; RNA, Messenger; Liver-Specific Organic Anion Transporter 1
PubMed: 36906857
DOI: 10.1002/cpt.2887 -
Euro Surveillance : Bulletin Europeen... Mar 2023From October 2022 through January 2023, nine patients with NDM-5/OXA-48-carbapenemase-producing ST79 were detected in Denmark and subsequently one patient in Iceland....
From October 2022 through January 2023, nine patients with NDM-5/OXA-48-carbapenemase-producing ST79 were detected in Denmark and subsequently one patient in Iceland. There were no nosocomial links between patients, but they had all been treated with dicloxacillin capsules. An NDM-5/OXA-48-carbapenemase-producing ST79, identical to patient isolates, was cultured from the surface of dicloxacillin capsules in Denmark, strongly implicating them as the source of the outbreak. Special attention is required to detect the outbreak strain in the microbiology laboratory.
Topics: Humans; Iceland; Dicloxacillin; Disease Outbreaks; Denmark
PubMed: 36862098
DOI: 10.2807/1560-7917.ES.2023.28.9.2300108 -
BMJ Open Feb 2023Lesional skin of atopic dermatitis (AD) is often colonised by and the bacterial abundance increases during a flare. However, the role of and the skin microbiome in the...
Defining the temporal relationship between the skin microbiome, immune response and skin barrier function during flare and resolution of atopic dermatitis: protocol of a Danish intervention study.
INTRODUCTION
Lesional skin of atopic dermatitis (AD) is often colonised by and the bacterial abundance increases during a flare. However, the role of and the skin microbiome in the pathogenesis of AD, including its influence on the dysfunctional skin barrier and immune response, remains to be elucidated. In this study, the temporal relationship between alterations in the skin barrier function, inflammation and microbiome is examined in adults with AD.
METHODS AND ANALYSIS
This clinical study consists of 81 adult patients with AD, as defined by the Hanifin and Rajka criteria, and 41 age and sex-matched controls. The objectives are to examine alterations in the skin microbiome, skin barrier and immune response during (1) an untreated AD flare, (2) an AD flare treated with topical corticosteroids (TCS), (3) an AD flare treated with systemic dicloxacillin/placebo and TCS or (4) cutaneous exposure to either autologous , staphylococcal enterotoxin B or a vehicle. Skin biopsies, tape strips, skin and nasal swabs are collected and analysed using RNA sequencing, multiplex immunoassays, liquid chromatography-mass spectrometry and 16S rDNA. Blood samples are analysed for filaggrin gene mutations and leucocyte gene expression.
ETHICS AND DISSEMINATION
The scientific Ethical Committee of the Capital Region in Denmark (phases I and II: H-20011047, phases III and IV: H-21079287), the local data protection agency (phases I and II: P-2020-165, phases III and IV: P-2022-250) and the Danish Medicines Agency (phases III and IV: EudraCT 2021-006883-25, ClinicalTrials.gov: NCT05578482) have approved the studies. Participants will give written informed consent prior to study initiation. The study is conducted in accordance with the Helsinki Declaration. Outcomes will be presented at national and international conferences and in international peer-reviewed publications.
TRIAL REGISTRATION NUMBER
NCT05578482, EudraCT 2021-006883-2.
Topics: Adult; Humans; Dermatitis, Atopic; Staphylococcus aureus; Skin; Immunity; Denmark
PubMed: 36806068
DOI: 10.1136/bmjopen-2022-068395 -
Cureus Jan 2023Linear immunoglobulin A (IgA) bullous dermatosis (LABD) is an autoimmune disease affecting children or adults that leads to subepithelial vesiculobullous lesions on the...
Linear immunoglobulin A (IgA) bullous dermatosis (LABD) is an autoimmune disease affecting children or adults that leads to subepithelial vesiculobullous lesions on the skin and/or mucosa. Due to the histologic and clinical appearance of the disease with tense and pruritic blisters, direct immunofluorescence is required for diagnosis, which features the characteristic linear deposition of IgA autoantibodies along the basement membrane zone. LABD can be idiopathic, drug-induced, or associated with a systemic disease such as inflammatory bowel disease. Many drugs have been implicated, such as antibiotics, anti-hypertensives, anti-epileptics, analgesics, and immunosuppressive medications. Treatment of LABD centers on discontinuation of the offending drug, if applicable, as well as pharmacotherapy with dapsone as the first-line treatment. Adjunctive therapy with sulphonamides, systemic corticosteroids, cyclosporine, colchicine, intravenous immunoglobulins, tetracyclines, erythromycin, and dicloxacillin has also shown benefits. We report the case of a young adult patient who developed LABD with a background of recent initiation of treatment with imipramine and newly diagnosed ulcerative colitis.
PubMed: 36751220
DOI: 10.7759/cureus.33448 -
Antibiotics (Basel, Switzerland) Dec 2022In this study, we report the performance improvement of wound dressings by covering them with magnetite-based nanostructured coatings. The magnetite nanoparticles (FeO...
In this study, we report the performance improvement of wound dressings by covering them with magnetite-based nanostructured coatings. The magnetite nanoparticles (FeO NPs) were functionalized with () powder/essential oil and dicloxacillin and were synthesized as coatings by matrix assisted pulsed laser evaporation (MAPLE). The expected effects of this combination of materials are: (i) to reduce microbial contamination, and (ii) to promote rapid wound healing. The crystalline nature of FeO NPs and coatings was determined by X-ray diffraction (XRD). Differential Scanning Calorimetry (DSC) and Thermo Gravimetric Analysis (TGA) have been coupled to investigate the stability and thermal degradation of nanoparticle components. The coatings' morphology was examined by scanning electron microscopy (SEM). The distribution of chemical elements and functional groups in the resulting coatings was evidenced by Fourier transform infrared (FTIR) spectrometry. In order to simulate the interaction between wound dressings and epithelial tissues and to evaluate the drug release in time, the samples were immersed in simulated body fluid (SBF) and investigated after different durations of time. The antimicrobial effect was evaluated in planktonic (free-floating) and attached (biofilms) bacteria models. The biocompatibility and regenerative properties of the nanostructured coatings were evaluated , at cellular, biochemical, and the molecular level. The obtained results show that magnetite-based nanostructured coatings functionalized with and dicloxacillin are biocompatible and show an enhanced antimicrobial effect against Gram positive and Gram negative opportunistic bacteria.
PubMed: 36671260
DOI: 10.3390/antibiotics12010059 -
Experimental and Therapeutic Medicine Jan 2023Diabetic foot ulcers infected with microorganisms increase the risk of amputation. The presence of drug-resistant bacteria in diabetic foot ulcers creates a big...
Diabetic foot ulcers infected with microorganisms increase the risk of amputation. The presence of drug-resistant bacteria in diabetic foot ulcers creates a big challenge during the treatment. The objective of the present study was to determine the bacterial prevalence and antibiotic resistance among bacteria isolated from Chinese patients with diabetic foot ulcers. The present study studied the microbial colonization of diabetic foot ulcers of patients from a single center in China. Wound swabs from 89 patients with diabetic foot ulcers were collected and the presence of microorganisms detected. The isolated microorganisms were subjected to antibiotic susceptibility testing by the disk diffusion method. Of 89 patients, 56 (62.9%) were male and 33 (37.1%) were female, the mean age of patients was 53.2±5.4 years, the mean duration of diabetes was 14.8±2.9 years, the mean random blood sugar was 301±87 mg/dl, mean HbA1c was 7.9±1.4%. Patients with Wanger ulcer grade III (36.0%; P=0.034) and patients within the weight range of 51-75 kg (59.6%; P=0.012) were significantly higher. The prevalence rate of diabetic foot ulcers was 11.3%. Among 153 microorganisms, gram-positive bacteria (52.3%) were more prevalent than gram-negative bacteria (44.4%). Most of the patients with polymicrobial infection were classified to have Wanger III ulcer grade diabetic foot ulcers. (38.2%) was the most predominant bacteria isolated followed by (29.2%) and (28.1%). Most of the gram-positive and gram-negative bacteria were resistant to dicloxacillin (73.8%, P=0.021) and cefotaxime (50%), respectively and ~53.4% of the isolates were multi-drug resistance isolates, 61.8% of the were identified as methicillin-resistant and 61.8% of the gram-negative bacteria were extended-spectrum -lactamase producers. and were the predominant gram-positive and gram-negative bacteria isolated, respectively. Penicillin resistance was significantly higher among the gram-negative bacteria (P=0.019). and were the predominant gram-positive and gram-negative bacteria isolated and levofloxacin and nitrofurantoin were the most effective antibiotics among the gram-positive and gram-negative bacterial isolates, respectively.
PubMed: 36588808
DOI: 10.3892/etm.2022.11752 -
Microbiology Spectrum Feb 2023New strategies are urgently needed to address the public health threat of antimicrobial resistance. Synergistic agent combinations provide one possible pathway toward...
New strategies are urgently needed to address the public health threat of antimicrobial resistance. Synergistic agent combinations provide one possible pathway toward addressing this need and are also of fundamental mechanistic interest. Effective methods for comprehensively identifying synergistic agent combinations are required for such efforts. In this study, an FDA-approved drug library was screened against methicillin-resistant Staphylococcus aureus (MRSA) (ATCC 43300) in the absence and presence of sub-MIC levels of ceftobiprole, a PBP2a-targeted anti-MRSA β-lactam. This screening identified numerous potential synergistic agent combinations, which were then confirmed and characterized for synergy using checkerboard analyses. The initial group of synergistic agents (sum of the minimum fractional inhibitory concentration ∑FIC ≤0.5) were all β-lactamase-resistant β-lactams (cloxacillin, dicloxacillin, flucloxacillin, oxacillin, nafcillin, and cefotaxime). Cloxacillin-the agent with the greatest synergy with ceftobiprole-is also highly synergistic with ceftaroline, another PBP2a-targeted β-lactam. Further follow-up studies revealed a range of ceftobiprole synergies with other β-lactams, including with imipenem, meropenem, piperacillin, tazobactam, and cefoxitin. Interestingly, given that essentially all other ceftobiprole-β-lactam combinations showed synergy, ceftaroline and ceftobiprole showed no synergy. Modest to no synergy (0.5 < ∑FIC ≤ 1.0) was observed for several non-β-lactam agents, including vancomycin, daptomycin, balofloxacin, and floxuridine. Mupirocin had antagonistic activity with ceftobiprole. Flucloxacillin appeared particularly promising, with both a low intrinsic MIC and good synergy with ceftobiprole. That so many β-lactam combinations with ceftobiprole show synergy suggests that β-lactam combinations can generally increase β-lactam effectiveness and may also be useful in reducing resistance emergence and spread in MRSA. Antimicrobial resistance represents a serious threat to public health. Antibacterial agent combinations provide a potential approach to combating this problem, and synergistic agent combinations-in which each agent enhances the antimicrobial activity of the other-are particularly valuable in this regard. Ceftobiprole is a late-generation β-lactam antibiotic developed for MRSA infections. Resistance has emerged to ceftobiprole, jeopardizing this agent's effectiveness. To identify synergistic agent combinations with ceftobiprole, an FDA-approved drug library was screened for potential synergistic combinations with ceftobiprole. This screening and follow-up studies identified numerous β-lactams with ceftobiprole synergy.
Topics: Humans; Methicillin-Resistant Staphylococcus aureus; Floxacillin; Staphylococcal Infections; Anti-Bacterial Agents; beta-Lactams; Cloxacillin; Microbial Sensitivity Tests; Ceftaroline
PubMed: 36519895
DOI: 10.1128/spectrum.03726-22