Gram-positive Infections Research Articles

Detection of linezolid resistance cfr gene among MRSA isolates

BackgroundLinezolid (Oxazolidinones) is commonly used against a variety of Gram-positive infections, especially methicillin-resistant Staphylococcus aureus (MRSA). The emerging resistance to linezolid curtail the treatment of infections caused by MRSA and other Gram-positive bacteria. Presence of cfr gene plays a crucial role in Linezolid resistance. ObjectivePresent study was aimed to detect cfr gene among clinical MRSA isolates. Materials and methodsThe suspected Staphylococcus aureus isolates were processed through Kirby Bauer disc diffusion methods for the confirmation of MRSA strains. Phenotypic Linezolid resistance was determined through broth micro-dilution method. The plasmid and DNA of Linezolid resistant isolates were subjected to molecular characterization for the presence of cfr gene. ResultsAmong 100 Staphylococcus aureus isolates, 85 of them were confirmed as MRSA isolates. Categorically, 65% MRSA isolates were sensitive to linezolid with MIC lower than 8 µg/ml, whereas, 35% of them were resistant to linezolid having MIC greater than 8 µg/ml. MIC level of 128 µg/ml was observed among 3.5% of the resistant isolates. Similarly, MIC level of 64 µg/ml, 32 µg/ml, 16 µg/ml and 8 µg/ml were noted for 3.5%, 4.7%, 8.2% and 15.3% isolates respectively. Linezolid resistance cfr gene was detected only in 9.4% of the resistant isolates. ConclusionMulti drug resistance among MRSA isolates is keenly attributed to the presence of cfr gene as evident in the present study, and horizontal dissemination of cfr gene among MRSA strains is accredited to cfr-carrying transposons and plasmids.

A lipoglycopeptide antibiotic for Gram-positive biofilm-related infections.

Drug-resistant Gram-positive bacterial infections are still a substantial burden on the public health system, with two bacteria (Staphylococcus aureus and Streptococcus pneumoniae) accounting for over 1.5 million drug-resistant infections in the United States alone in 2017. In 2019, 250,000 deaths were attributed to these pathogens globally. We have developed a preclinical glycopeptide antibiotic, MCC5145, that has excellent potency (MIC90 ≤ 0.06 μg/ml) against hundreds of isolates of methicillin-resistant S. aureus (MRSA) and other Gram-positive bacteria, with a greater than 1000-fold margin over mammalian cell cytotoxicity values. The antibiotic has therapeutic in vivo efficacy when dosed subcutaneously in multiple murine models of established bacterial infections, including thigh infection with MRSA and blood septicemia with S. pneumoniae, as well as when dosed orally in an antibiotic-induced Clostridioides difficile infection model. MCC5145 exhibited reduced nephrotoxicity at microbiologically active doses in mice compared to vancomycin. MCC5145 also showed improved activity against biofilms compared to vancomycin, both in vitro and in vivo, and a low propensity to select for drug resistance. Characterization of drug action using a transposon library bioinformatic platform showed a mechanistic distinction from other glycopeptide antibiotics.

Ion Exchange Biomaterials to Capture Daptomycin and Prevent Resistance Evolution in Off-Target Bacterial Populations.

Daptomycin (DAP), a cyclic anionic lipopeptide antibiotic, is among the last resorts to treat multidrug-resistant Gram-positive bacterial infections, caused by vancomycin-resistant Enterococcus faecium or methicillin-resistant Staphylococcus aureus. DAP is administered intravenously, and via biliary excretion, ∼5-10% of the intravenous DAP dose arrives in the gastrointestinal (GI) tract where it drives resistance evolution in the off-target populations of E. faecium bacteria. Previously, we have shown in vivo that the oral administration of cholestyramine, an ion exchange biomaterial (IXB) sorbent, prevents DAP treatment from enriching DAP resistance in the populations of E. faecium shed from mice. Here, we investigate the biomaterial-DAP interfacial interactions to uncover the antibiotic removal mechanisms. The IXB-mediated DAP capture from aqueous media was measured in controlled pH/electrolyte solutions and in the simulated intestinal fluid (SIF) to uncover the molecular and colloidal mechanisms of DAP removal from the GI tract. Our findings show that the IXB electrostatically adsorbs the anionic antibiotic via a time-dependent diffusion-controlled process. Unsteady-state diffusion-adsorption mass balance describes the dynamics of adsorption well, and the maximum removal capacity is beyond the electric charge stoichiometric ratio because of DAP self-assembly. This study may open new opportunities for optimizing cholestyramine adjuvant therapy to prevent DAP resistance, as well as designing novel biomaterials to remove off-target antibiotics from the GI tract.

Oral pharmacokinetic profile and withdrawal time estimation for tylosin tartrate in the cultured olive flounder Paralichthys olivaceus

The Korean government regulates pharmaceutical parameters and withdrawal times for antimicrobials in aquaculture. Tylosin tartrate (TT) is a bacteriostatic antibacterial agent mainly used in veterinary medicine for the prevention and treatment of gram-positive bacterial infections. However, pharmacokinetic (PK) and drug withdrawal reports in aquatic animals, including olive flounder (Paralichthys olivaceus), are limited. This study aimed to determine the PK profile and drug withdrawal time following oral TT administration (10 or 20 mg/kg) in olive flounder. The concentrations of tylosin in the serum and muscle plus skin were analyzed using liquid chromatography and tandem mass spectrometry. PK parameters were calculated for serum samples using the PKSolver software based on a non-compartmental model. The PK parameters after a single oral dose of 10 (or 20) mg/kg were as follows: Cmax, 0.7 (1.49) μg/mL; Tmax, 12 h; t1/2, 22.83 (19.44) h; area under the concentration curve, 10.58 (33.17) μg/mL h; and mean residence time, 20.53 (25.62) h. Oral administration of TT at a dose of 10 mg/kg at 24–48 h intervals may help achieve efficacy comparable to that obtained with antimicrobials at minimum inhibitory concentration values of ≤ 1 μg/mL. After a 5-day oral administration of TT in olive flounder (water temperature, 22 ℃), a withdrawal time of 17.8 (rounded up to 18 days) days was required to achieve muscle plus skin TT residue levels below 100 μg/kg, which is the European limit; the corresponding value at a lower water temperature (13 ℃) was 20 days. Overall, this study not only serves as a reference for authorizing the clinical use of TT in olive flounder but also provides valuable data for evaluating the safety of food derived from aquatic animals.

Epidemiology of early infections and predictors of mortality after autologous hematopoietic stem-cell transplantation among multiple myeloma, Hodgkin, and non-Hodgkin lymphoma: the first experience from Palestine

BackgroundAutologous hematopoietic stem-cell transplantation (HSCT) is the standard of care in many relapsed and refractory lymphoid malignancy, neuroblastoma, and multiple myeloma (MM). This study was conducted to describe the epidemiology of early infections that occurred within the first 100 days among patients who received HSCT for MM, Hodgkin (HL), and non-Hodgkin lymphoma (NHL) in Palestine.MethodsThis study was conducted in a retrospective cohort design in the only autologous HSCT in Palestine in the period between 2014 and 2021. The medical records of the patients were reviewed to identify and collect demographic, clinical, and microbiological data on bacterial, viral, fungal, and parasitic infections as diagnosed by cultures, polymerase chain reaction, and fluorescent antibody testing.ResultsA total of 145 patients were included in this study (median age = 44.0 [28.0, 53.5] years). Of those, 8 (5.5%) were younger than 18 years, 69 (47.6%) had MM, 53 (36.6%) had HL, and 23 (15.9%) had NHL. The source of fever had no focus in the majority of the cases 82 (56.6%), 12 (8.3%) had bloodstream infections, 8 (5.5%) had colitis, and 7.6 (5.0%) had pneumonia. Patients from whom gram-negative bacteria were isolated stayed in the hospital for longer duration compared to the other patients (median = 21.0 [19.0, 25.0] vs. 18.0 [15.0, 22.0] days, p-value = 0.043, respectively). The cumulative incidence of death in the first 100 days after infusion of stem cells was 3.4%. The cumulative incidence of death in the first 100 days post-transplantation was higher for patients with NHL compared to those with HL and MM (p-value = 0.017). Gram-negative and fungal infections were strong predictors of mortality.ConclusionBacterial gram-positive and gram-negative infections were the most common early infections among patients who underwent autologous HSCT for hematological malignancies (HM) in the only center in Palestine. The findings of this study are informative to healthcare providers and planners of care for patients who are scheduled to receive autologous HSCT for HM.

Genome-wide post-transcriptional regulation of bovine mammary gland response to Streptococcus uberis.

MicroRNAs (miRNAs) as post-transcriptionally regulators of gene expression have been shown to be critical regulators to fine-tuning immune responses, besides their criteria for being an ideal biomarker. The regulatory role of miRNAs in responses to most mastitis-causing pathogens is not well understood. Gram-positive Streptococcus uberis (Str. uberis), the leading pathogen in dairy herds, cause both clinical and subclinical infections. In this study, a system biology approach was used to better understand the main post-transcriptional regulatory functions and elements of bovine mammary gland response to Str. uberis infection. Publicly available miRNA-Seq data containing 50 milk samples of the ten dairy cows (five controls and five infected) were retrieved for this current research. Functional enrichment analysis of predicted targets revealed that highly confident responsive miRNAs (4 up- and 19 downregulated) mainly regulate genes involved in the regulation of transcription, apoptotic process, regulation of cell adhesion, and pro-inflammatory signaling pathways. Time series analysis showed that six gene clusters significantly differed in comparisons between Str. uberis-induced samples with controls. Additionally, other bioinformatic analysis, including upstream network analysis, showed essential genes, including TP53 and TGFB1 and some small molecules, including glucose, curcumin, and LPS, commonly regulate most of the downregulated miRNAs. Upregulated miRNAs are commonly controlled by the most important genes, including IL1B, NEAT1, DICER1 enzyme and small molecules including estradiol, tamoxifen, estrogen, LPS, and epigallocatechin. Our study used results of next-generation sequencing to reveal key miRNAs as the main regulator of gene expression responses to a Gram-positive bacterial infection. Furthermore, by gene regulatory network (GRN) analysis, we can introduce the common upregulator transcription factor of these miRNAs. Such milk-based miRNA signature(s) would facilitate risk stratification for large-scale prevention programs and provide an opportunity for early diagnosis and therapeutic intervention.

Clinical Effectiveness and Pharmacokinetics of Dalbavancin in Treatment-Experienced Patients with Skin, Osteoarticular, or Vascular Infections.

Dalbavancin (DBV) is a lipoglycopeptide approved for the treatment of Gram-positive infections of the skin and skin-associated structures (ABSSSIs). Currently, its off-label use at different dosages for other infections deserves attention. This work aimed to study the clinical effectiveness and tolerability of DBV in outpatients with ABSSSIs, osteoarticular (OA), or other infections, treated with either one or two 1500 mg doses of dalbavancin, for different scheduled periods. A liquid chromatography–tandem mass spectrometry method was used to measure total DBV concentrations. PK/PD parameters and the clinical and microbiological features of this cohort were evaluated in order to investigate the best predictors of treatment success in real-life settings. Of the 76 screened patients, 41 completed the PK study. Long-term PK was comparable to previous studies and showed significant differences between genders and dosing schedules. Few adverse events were observed, and treatment success was achieved in the vast majority of patients. Failure was associated with lower PK parameters, particularly Cmax. Concluding, we were able to describe DBV PK and predictors of treatment success in selected infections in this cohort, finding DBV Cmax as a possible candidate for therapeutic drug-monitoring purposes, as well as highlighting the dual-dose one-week-apart treatment as the optimal choice for OA infections.

Application of the clearance rate of inflammatory markers for evaluation of the therapeutic effect in adult bacterial bloodstream infection.

Bloodstream infection (BSI) is a serious systemic infectious disease. This study aimed to investigate the application of the clearance rate of interleukin-6, procalcitonin, and C-reactive protein for the evaluation of antimicrobial efficacy in adult bacterial BSI without other inflammatory factors. Patients with positive blood culture and without other inflammatory factors in The First Hospital of Hebei Medical University from January 2017 to December 2019, who received continuous detection interleukin-6, procalcitonin, and C-reactive protein, were selected. The clearance rate of these inflammatory markers was calculated, and the consistency test (kappa test) was performed to analyze the clinical outcomes (cure, improvement, delay, deterioration, or death). For adult patients with bacterial BSI without other inflammatory factors, the testing speculation based on the clearance rate of interleukin-6 and C-reactive protein was consistent with the clinical outcome of the patients, with kappa values of 0.784 and 0.714, respectively (P=0.000). The testing speculation based on the procalcitonin clearance rate was generally consistent with the clinical outcome, with a kappa value of 0.685 (P=0.000). The testing speculation based on the procalcitonin clearance rate showed good consistency with the clinical outcome of patients with Gram-positive cocci infection, kappa =0.813 (P=0.000); for patients with gram-negative bacilli infection, the consistency of clinical outcomes was general, kappa =0.649 (P=0.000). In adult patients with bacterial BSI without other inflammatory factors, the clearance rate of interleukin-6, procalcitonin, and C-reactive protein can predict the clinical outcome within 24 hours, among which the procalcitonin clearance rate can better predict the clinical outcome of patients with Gram-negative bacilli infection. This approach can be used to evaluate the effectiveness of anti-infection treatment in early-stage BSI.

Retention of Minocycline Susceptibility When Gram-Positive Periprosthetic Joint Infection Isolates Are Non-Susceptible to Doxycycline.

Background: The treatment of hardware infections often utilizes chronic oral suppression antibiotics to prevent infection recurrence. However, when methicillin-resistant Staphylococcus aureus and other bacteria are non-susceptible to doxycycline, limited oral antibiotic options can be available that do not cause significant side effects and drug–drug interactions. Consequently, the purpose of this study was to evaluate the ability of Gram-positive clinical prosthetic joint infection isolates that were non-susceptible to doxycycline and to retain susceptibility to minocycline. Methods: Twenty-six Gram-positive prosthetic joint infection isolates that were not susceptible to doxycycline were evaluated for retained minocycline susceptibility with the use of minocycline gradient diffusion test strips. Results: All five of the coagulase-negative staphylococcal isolates and eight of the eleven methicillin-resistant S. aureus isolates were susceptible to minocycline, despite being doxycycline non-susceptible. None of the five Enterococcus faecium PJI isolates retained susceptibility to minocycline and only two of the five E. faecalis isolates (n = 5) were susceptible to minocycline. Conclusions: The findings have direct clinical implications supporting minocycline susceptibility testing for patients with PJI and other hardware-associated infections, which have isolates that are doxycycline non-susceptible to thereby provide alternative suppression antibiotic options.

Daptomycin exerts differential immunomodulatory effects on host responses against methicillin-resistant Staphylococcus aureus biofilms

Daptomycin (DAP) is indicated for difficult-to-treat Gram-positive infections, especially those caused by methicillin-resistant Staphylococcus aureus (MRSA). Exposure of S. aureus to subinhibitory antimicrobial concentrations (sub-MICs) has been shown to alter cell morphology and biofilm formation. This study aimed to investigate the influence of DAP biofilm sub-MICs on the damage caused by human polymorphonuclear neutrophils (PMNs) against MRSA biofilms and the potential immunomodulatory activity of DAP on human monocytes (MNCs) exposed to MRSA biofilms. DAP activity against biofilms and the impact of DAP on PMN-induced biofilm damage were evaluated by the XTT reduction assay, whereas pathogen recognition, signal transduction and cytokine modulation of DAP on MNCs in response to MRSA biofilms were assessed by RT-PCR and ELISA methodology. The MIC50 of DAP to MRSA biofilms was 16-32 mg/L. Pre-treatment of MRSA with 1, 2 or 4 mg/L DAP caused a synergistic effect on PMN-mediated biofilm damage, being dependent on the effector-to-target ratio. MNCs responded to MRSA biofilms and DAP through Toll like receptor 2 (TLR2) upregulation and increased NLRP3 inflammasome production. DAP caused 2.5-fold greater TLR2 mRNA levels than those caused by MRSA biofilms. A predominantly inflammatory response was induced by either component, causing the release of significantly increased IFN-γ, TNF-α, IL-8 and IL-6 levels by MNCs exposed to the combination treatment. MRSA biofilms alone or combined with DAP caused low amounts of IL-10 production, but increased IL-1β levels. DAP may condition MNCs towards an inflammatory response through TLR2 engagement and NLRP3 inflammasome activation, possibly controlling biofilm-associated pathogenicity.

234. Does nasal screening for methicillin resistant Staphylococcus aureus (MRSA) prevent deep surgical site infections for elective cervical spinal fusion?

<h3>BACKGROUND CONTEXT</h3> Preoperative MRSA screening and decolonization has demonstrated success for some orthopaedic subspecialties in prevention of surgical site infections (SSIs). Spine surgery, however, has seen varied results, potentially secondary to the anatomic and surgical heterogeneity of the patients included in prior studies. Given that prior research has demonstrated greater propensity for gram positive SSIs in the cervical spine, we sought to investigate if MRSA screening would be more impactful in the cervical spine. <h3>PURPOSE</h3> The purpose of this study was to determine the relationship between nasal MRSA testing and SSI rates specifically in the setting of primary posterior cervical instrumented spine surgery. <h3>STUDY DESIGN/SETTING</h3> Retrospective cohort study. <h3>PATIENT SAMPLE</h3> Adult patients undergoing primary instrumented posterior cervical procedures from January 2015-December 2019 at two tertiary academic referral centers in an urban setting <h3>OUTCOME MEASURES</h3> Physiologic measures: subfascial presumed infected collection or abscess within 90 days of the index operation. <h3>METHODS</h3> Adult patients undergoing primary instrumented posterior cervical procedures from January 2015-December 2019 were reviewed for MRSA testing < 90-days before surgery, preoperative mupirocin, perioperative antibiotics and SSI defined as operative incision and drainage (I&D) < 90-days after surgery. Trauma, tumor and infection cases were excluded. Logistic regression modeling was used with SSI the primary outcome and MRSA screening the primary predictor with clinical and demographic factors as covariates. <h3>RESULTS</h3> This study included 668 patients, of whom MRSA testing was performed in 212 patients (31.7%) and 6 (2.8%) were colonized with MRSA. Twelve patients (1.8%) underwent an I&D. On adjusted analysis, preoperative MRSA testing was not associated with postoperative I&D risk. Perioperative vancomycin similarly had no association with postoperative I&D risk. Notably, six patients (50%) grew MSSA from intraoperative cultures, with no cases of MRSA. <h3>CONCLUSIONS</h3> There was no association between preoperative nasal MRSA screening and SSIs in primary posterior cervical instrumented procedures, nor was there any association between vancomycin or infection rate. Furthermore, there was a preponderance of gram-positive infections but none caused by MRSA. Given these findings, the considerable cost and effort associated with MRSA testing in the setting of primary posterior cervical instrumentation may not be justified. Further research should investigate if higher-risk scenarios demonstrate greater utility of preoperative testing. <h3>FDA DEVICE/DRUG STATUS</h3> This abstract does not discuss or include any applicable devices or drugs.

Physiologically based pharmacokinetic modeling of daptomycin dose optimization in pediatric patients with renal impairment.

Background and Objective: Daptomycin is used to treat Gram-positive infections in adults and children and its dosing varies among different age groups. We focused on the pharmacokinetics of daptomycin in children with renal impairment, which has not been evaluated. Methods: A physiologically based pharmacokinetic (PBPK) model of daptomycin was established and validated to simulate its disposition in healthy populations and adults with renal impairment, along with a daptomycin exposure simulated in pediatric patients with renal impairment. Results: The simulated PBPK modeling results for various regimens of intravenously administered daptomycin were consistent with observed data according to the fold error below the threshold of 2. The Cmax and AUC of daptomycin did not differ significantly between children with mild-to-moderate renal impairment and healthy children. The AUC increased by an average of 1.55-fold and 1.85-fold in severe renal impairment and end-stage renal disease, respectively. The changes were more significant in younger children and could reach a more than 2-fold change. This scenario necessitates further daptomycin dose adjustments. Conclusion: Dose adjustments take into account the efficacy and safety of the drug; however, the steady-state Cmin of daptomycin may be above 24.3 mg/L in a few instances. We recommend monitoring creatine phosphokinase more than once a week when using daptomycin in children with renal impairment.

Diagnostic Value and Prognostic Significance of Procalcitonin Combined with C-Reactive Protein in Patients with Bacterial Bloodstream Infection.

Objective To study the clinical values and implications for the prognosis of procalcitonin (PCT) combined with C-reactive protein (hs-CRP) in patients with bacterial bloodstream infection. Methods One hundred and twenty patients with infection hospitalized from Mar. 2020 to Jun. 2021 were chosen as subjects. All participants were tested for serum PCT, hs-CRP, and blood culture. According to the types of pathogenic bacteria, they were divided into the gram-negative bacteria bloodstream infection group (n = 53) and the gram-positive bacteria bloodstream infection group (n = 31). Depending on the prognostic outcome of the participants after 28 days, they were categorized into survival and fatality cohorts. The PCT and hs-CRP levels were compared to explore diagnostic value implications for the prognosis of the cases with bacterial bloodstream infection. Results Serum PCT and hs-CRP values in the positive cohort were higher than those in the negative cohort. The levels of serum PCT and hs-CRP in pulmonary infection were higher than those in the group with negative cases, and the difference was statistically significant (P < 0.05). There were 27 gram-positive participants and 9 gram-negative cases in the positive cohort. The serum PCT value of gram-negative bacterial infection was greater than that of gram-positive bacterial infection. The value of serum PCT in the gram-negative bacterial infection group was higher than that in the gram-positive bacterial infection group, and the difference was statistically significant (P < 0.05). The areas under the curve (AUCs) of PCT, combination of hs-CRP and PCT, and hs-CRP were 0.946, 0.783, and 0.991, respectively. The combined examination of PCT and hs-CRP was the largest, PCT was the second, and hs-CRP was the lowest. These results indicated that the accuracy of combined detection of PCT and hs-CRP in the diagnostic bloodstream infection was the highest (0.991), followed by PCT (0.946) and the lowest (0.783). The PCT and hs-CRP levels of the survival cohort were lower than those in the death cohort. AUCs of PCT, hs-CRP and PCT, and hs-CRP were 0.848, 0.826, and 0.934, respectively. The combined examination of PCT and hs-CRP was the largest, followed by PCT and hs-CRP. The accuracy of the combination of PCT and hs-CRP was the highest (0.934), followed by PCT (0.848), and the diagnostic accuracy of hs-CRP was the lowest (0.826). Conclusion There were significant differences in the levels of PCT and CRP between the gram-positive bacteria group and the gram-positive bacteria group. PCT and CRP have high diagnostic values in predicting the short-term prognosis of patients. PCT and CRP assist clinical diagnosis and guide treatment and play a positive role in early treatment and prognosis evaluation of patients.

Gram-Positive Bacterial Infections and Antibiotics Resistance in Jordan: Current Status and Future Perspective

Background: Antibiotic resistance is expanding worldwide at alarming rates. Middle East countries including Jordan have high prevalence of antibiotic resistance.&#x0D; Aims: The main aims of this review are to summarize the situation with Gram-positive bacterial infections and antibiotic resistance in Jordan, identify areas where further investigation is required, and suggest strategies to combat antibiotic resistance.&#x0D; Methods: A systematic literature search was conducted by two independent researchers using general and specific combinations of MeSH search terms using Embase, PubMed, Web of Science, and Google Scholar databases.&#x0D; Results: Staphylococci and Streptococci were commonly isolated from environmental, animal, and human samples, while Staphylococci, Enterococci, and Listeria were commonly isolated from food. Staphylococci, Streptococci, and Enterococci human colonization were documented at variable but high rates. Methicillin-resistant S. aureus (MRSA) and methicillin-resistance coagulase-negative Staphylococci (MR-CoNS) infections were common with high rates of antibiotic resistance. S. pneumoniae showed increased resistance rates to most antimicrobials. Enterococci and C. difficile resistance rates were moderate, while group B Streptococci (GBS), viridans group streptococci (VGS), C. perfringens and L. monocytogenes antibiotic susceptibility patterns were not reported. All MRSA and vancomycin-resistant Enterococci (VRE) isolates were mec-A positive, while resistance genes among CoNS, S. pneumoniae, S. pyogenes, S. agalactia, C. perfringens, and L. monocytogenes were not investigated.&#x0D; Conclusions: Gram-positive bacterial infections and antibiotic resistance rates were high in Jordan. Molecular epidemiology studies, a nationwide surveillance program, and action plans are urgently required to combat antibiotic resistance.

NCD64 index as a novel inflammatory indicator for the early prediction of prognosis in infectious and non-infectious inflammatory diseases: An observational study of febrile patients

BackgroundGenerally, febrile patients admitted to the Department of Infectious Diseases, Fudan University Affiliated Huashan Hospital, China may eventually be diagnosed as infectious (ID) or non-infectious inflammatory diseases (NIID). Furthermore, mortality from sepsis remains incredibly high. Thus, early diagnosis and prognosis evaluation of sepsis is necessary. Here, we investigated neutrophil (n)CD64 index profile in a cohort of febrile patients and explored its diagnostic and prognostic value in ID and NIID.MethodsThis observational cohort study enrolled 348 febrile patients from the Emergency Department and Department of Infectious Diseases. nCD64 index were detected using flow cytometry, and dynamically measured at different timepoints during follow-up. Procalcitonin (PCT), C-reactive protein (CRP), and ferritin levels were measured routinely. Finally, the diagnostic and prognostic value of nCD64 index were evaluated by receiver operating characteristic (ROC) analysis and Kaplan-Meier curve analysis.ResultsOf included 348 febrile patients, 238, 81, and 29 were categorized into ID, NIID, and lymphoma groups, respectively. In ID patients, both SOFA score and infection site had impact on nCD64 index expression. In NIID patients, adult-onset Still’s disease patients had the highest nCD64 index value, however, nCD64 index couldn’t distinguish between ID and NIID. Regardless of the site of infection, nCD64 index was significantly higher in bacterial and viral infections than in fungal infections, but it could not discriminate between bacterial and viral infections. In bloodstream infections, gram-negative (G-) bacterial infections showed an obvious increase in nCD64 index compared to that of gram-positive (G+) bacterial infections. nCD64 index has the potential to be a biomarker for distinguishing between DNA and RNA virus infections. The routine measurement of nCD64 index can facilitate septic shock diagnosis and predict 28-day hospital mortality in patients with sepsis. Serial monitoring of nCD64 index in patients with sepsis is helpful for evaluating prognosis and treatment efficacy. Notably, nCD64 index is more sensitive to predict disease progression and monitor glucocorticoid treatment in patients with NIID.ConclusionsnCD64 index can be used to predict 28-day hospital mortality in patients with sepsis and to evaluate the prognosis. Serial determinations of nCD64 index can be used to predict and monitor disease progression in patients with NIID.

Flap sub-domain dynamics of serine-threonine phosphatase (Stp1) of Staphylococcus aureus: an accelerated molecular dynamics simulation study

Vancomycin and daptomycin are commonly used glycopeptide antibiotics to cure Gram-positive staphylococcal infections. The clinical isolates of mutant Staphylococcus aureus strains, Methicillin-Resistant (MRSA) and Vancomycin-Resistant (VRSA), have developed resistance against these antibiotics. A recently discovered Serine/threonine phosphatase (Stp1) is an Mn+2 containing protein at the active site with a flap sub-domain that participates in the phospho-signaling system of bacterial cell wall formation. The flap sub-domain probably regulates substrates recruitment and release with an extra Mn+2, possibly highly flexible as in the other homologous family of proteins. In this study, the flap sub-domain has been sampled with conventional and accelerated molecular dynamics (cMD and aMD) simulations to get other sub-optimal conformational states of the protein that are nearly impossible to observe through experimental methods. Trajectory analysis has shown that protein remained static in cMD while dynamic in aMD with RMSD of ∼2Å and ∼3Å, respectively. Accelerated MD has shown greater flexibility of ∼4 Å in the flap sub-domain, while cMD only captured a deviation of ∼ 2 Å. Later, the dynamic cross-correlation map (DCCM) confirmed that the flap sub-domain is significantly more flexible than the other part of the structure, indicating its role in substrate regulation. Secondary structure transition in the flap sub-domain, i.e. 3-10 helix and turn (PRO159 - ILE163) region of the flap sub-domain shifted into α-helix, which is a more stable structure. Further, the trajectory has been clustered, and conformational states extracted, which may be exploited in structure-based antibiotics discovery.

Recent Advances in the Development of Semisynthetic Glycopeptide Antibiotics: 2014-2022.

The accelerated appearance of drug-resistant bacteria poses an ever-growing threat to modern medicine’s capacity to fight infectious diseases. Gram-positive species such as methicillin-resistant Staphylococcus aureus (MRSA) and Streptococcus pneumoniae continue to contribute significantly to the global burden of antimicrobial resistance. For decades, the treatment of serious Gram-positive infections relied upon the glycopeptide family of antibiotics, typified by vancomycin, as a last line of defense. With the emergence of vancomycin resistance, the semisynthetic glycopeptides telavancin, dalbavancin, and oritavancin were developed. The clinical use of these compounds is somewhat limited due to toxicity concerns and their unusual pharmacokinetics, highlighting the importance of developing next-generation semisynthetic glycopeptides with enhanced antibacterial activities and improved safety profiles. This Review provides an updated overview of recent advancements made in the development of novel semisynthetic glycopeptides, spanning the period from 2014 to today. A wide range of approaches are covered, encompassing innovative strategies that have delivered semisynthetic glycopeptides with potent activities against Gram-positive bacteria, including drug-resistant strains. We also address recent efforts aimed at developing targeted therapies and advances made in extending the activity of the glycopeptides toward Gram-negative organisms.

Pathogens of bovine mastitis and their sensitivity to antimicrobials

Mastitis is the most important disease in the dairy industry. Antibiotics are considered to be the first choice in the treatment of the disease. However, the problem of antibiotic residue and antimicrobial resistance, leads to many restrictions on antibiotic therapy in the dairy sector worldwide.The work is devoted to the study and analysis of the sensitivity of pathogens of acute mastitis in cows to different antibacterial drugs. Bacteriological studies were carried out according to the generally accepted methods. Antibiotic sensitivity was determined by the disk diffusion method.The dynamics of isolation of the main pathogens of acute mastitis in cows and their antibiotic sensitivity within a 5-year period (2017-2021) in the central region of Russia was analyzed. It has been established that in recent years gram-positive infections became predominant, while coagulase-negative staphylococci are increasingly replacing S. aureus. Representatives of the genus Enterococcus were predominant causative agents of the disease. High-level multidrug resistance of all isolated strains of pathogens was determined (97%).The improvement of laboratory diagnosis and strict control over the use of antimicrobials need to reduce the level of resistance and the spread of multi-resistant pathogens of pyo-inflammatory diseases.

Lanthanide/Cu2-xSe Nanoparticles for Bacteria-Activated NIR-II Fluorescence Imaging of Infection.

A material system enabling specific NIR-II fluorescence imaging of Gram-positive bacteria is described. The material system is based on the electrostatic binding of Cu2-xSe and vancomycin-modified NaGdF4:Nd,Yb@NaGdF4 downconversion nanoparticles (DCNPs), the fluorescence of which is weak owing to the spectral overlap of Cu2-xSe absorption with the DCNP NIR emission. The presence of Gram-positive bacteria precisely disconnects the bond between vancomycin-modified DCNPs and Cu2-xSe, thus enabling a strong fluorescent signal. In vivo studies show that the material system can be specifically activated at the site of Gram-positive bacterial infection but is essentially nonfluorescent in the area of Gram-negative bacterial infection.

Recent advances in oxazolidinones as antituberculosis agents.

Tuberculosis (TB) is an infectious and fatal disease caused by Mycobacterium tuberculosis (Mtb) and remains a serious public health threat; therefore, the development of new antitubercular agents is a priority for the World Health Organization's End TB strategy and the United Nations' Sustainable Development Goals to eradicate TB. Oxazolidinones are a class of synthetic antibacterial agents with a distinct mode of action developed for the treatment of Gram-positive bacterial infections. Many oxazolidinones exhibit good activity against Mtb, and some are currently in clinical trials for multidrug-resistant TBand extensively drug-resistant TBtherapy. In this review, the mechanism of action, activityand toxicity of oxazolidinonesand recent progress in the research and development of oxazolidinones as anti-TB agentsare summarized.