anti-MRSA Agents Research Articles

Community-Acquired Skin and Soft Tissue Infections: Epidemiology and Management in Patients Presenting to the Emergency Department of a Tertiary Care Hospital.

Skin and soft tissue infections are one of the most common diseases presenting to the emergency department (ED). There is no study available on the management of Community-Acquired Skin and Soft Tissue Infections (CA-SSTIs) in our population recently.This study aims to describe the frequency and distribution ofCA-SSTIs as well as their medical and surgical management among patients presenting to our ED. We conducted a descriptive cross-sectional study on patients presenting with CA-SSTIs to the EDof a tertiary care hospital in Peshawar, Pakistan. The primary objective was to estimate the frequency of common CA-SSTIs presenting to the ED and to assess the management of these infections in terms of diagnostic workup and treatment modalities used. The secondary objectives were to study the association of different baseline variables, diagnostic modalities,treatment modalities, and improvement with the surgical procedure performancefor these infections. Descriptive statistics were obtained for quantitative variables like age. Frequencies and percentages were derived for categorical variables. The chi-square test was used to compare different CA-SSTIs in terms of categorical variables like diagnostic and treatment modalities. We divided the data into two groups based on the surgical procedure. A chi-square analysis was conducted to compare these two groups in terms of categorical variables. Out of the 241 patients, 51.9% were males and the mean age was 34.2 years. The most common CA-SSTIs were abscesses, infected ulcers, and cellulitis. Antibiotics were prescribed to 84.2% of patients. Amoxicillin + Clavulanate was the most frequently prescribed antibiotic. Out of the total, 128 (53.11%) patients received some type of surgical intervention. Surgical procedures were significantly associated with diabetes mellitus, heart disease, limitation of mobility, or recent antibiotic use. There was a significantly higher rate of prescription of any antibiotic and anti-methicillin-resistant Staphylococcus aureus (anti-MRSA) agents in the surgical procedure group. This group also saw a higher rate of oral antibiotics prescription, hospitalization, wound culture, and complete blood count. This study shows a higher frequency of purulent infections in our ED. Antibiotics were prescribed more frequently for all infections. Surgical procedures like incision and drainage were much lower even in purulent infections. Furthermore, beta-lactam antibiotics like Amoxicillin-Clavulanate were commonly prescribed. Linezolid was the only systemic anti-MRSA agent prescribed. We suggest physicians should prescribe antibiotics appropriate to the local antibiograms and the latest guidelines.

UHPLC-MS/MS method for simultaneous quantification of doripenem, meropenem, ciprofloxacin, levofloxacin, pazufloxacin, linezolid, and tedizolid in filtrate during continuous renal replacement therapy.

Since severe infections frequently cause acute kidney injury (AKI), continuous renal replacement therapy (CRRT) is often initiated for regulation of inflammatory mediators and renal support. Thus, it is necessary to decide the antibiotic dosage considering the CRRT clearance in addition to residual renal function. Some of the hemofilters used in CRRT are known to adsorb antibiotics, and clearance of antibiotics may differ depending on the adsorptive characteristics of hemofilters. Although assay systems for blood and CRRT filtrate concentrations are required, no method for measuring antibiotics concentrations in filtrate has been reported. We developed a UHPLC-MS/MS method for simultaneous quantification of antibiotics commonly used in ICU, comprising carbapenems [doripenem (DRPM) and meropenem (MEPM)], quinolones [ciprofloxacin (CPFX), levofloxacin (LVFX) and pazufloxacin (PZFX)] and anti-MRSA agents [linezolid (LZD), and tedizolid (TZD)] in CRRT filtrate samples. Filtrate samples were pretreated by protein precipitation. The analytes were separated with an ACQUITY UHPLC CSH C18 column under a gradient mobile phase consisting of water and acetonitrile containing 0.1% formic acid and 2 mM ammonium formate. The method showed good linearity over wide ranges. Within-batch and batch-to-batch accuracy and precision for each drug fulfilled the criteria of the US Food and Drug Administration guidance. The recovery rate was more than 87.20%. Matrix effect ranged from 99.57% to 115.60%. Recovery rate and matrix effect did not differ remarkably between quality control samples at different concentrations. This is the first report of a simultaneous quantification method of multiple antibiotics in filtrate of CRRT circuit.

539. Impact of a Rapid Diagnostic Assay for the Detection of Bacterial and Viral Agents on Antimicrobial use in Critically Ill Patients with Pneumonia

Abstract Background Conventional diagnostic methods for pneumonia have a long turnaround time, and a pathogen is isolated in only 33% of cases. As a result, empiric therapy with broad-spectrum antimicrobials often becomes definitive therapy. Rapid molecular diagnostics paired with antimicrobial stewardship intervention have the potential to improve outcomes for patients with lower respiratory tract infections (LRTIs). However, data to support this hypothesis are scarce. This study examined the influence of a rapid multiplex polymerase-chain-reaction (PCR) test on antimicrobial use in critically ill patients with LRTIs. Methods This single-center study consisted of pre-implementation (PrIP, December 1, 2018, to February 28, 2019) and post-implementation periods (PoIP, December 1, 2021, to February 28, 2022). Both groups included intensive-care unit (ICU) patients with respiratory cultures from bronchoalveolar lavage (BAL), mini-BAL, or tracheal aspirates. Interventions during the PoIP included concurrent testing of specimens with the BioFire® Pneumonia Panel and clinical decision support tools to streamline treatment recommendations from ICU pharmacists. The primary outcome was the difference in time to optimal therapy (TTOT). Secondary outcomes included time to effective therapy (TTET) and duration of therapy (DOT) for antipseudomonal and anti-MRSA agents. Results A total of 163 patients were included (n = 80, PrIP; n = 83, PoIP). The mean age was 57 + 16 years, and medical ICU patients accounted for 60% (n = 97) of cases. The median APACHE II score was the only significant baseline difference between the two arms (22 vs. 18, interquartile range [IQR] 16, 28 vs. 12, 25, p = 0.01). The median TTOT was 38 hours in the PrIP and 21 hours in the PoIP (p < 0.001). TTET was 5.7 hours in the PrIP and 4.9 hours in the PoIP (p = 0.106). The median DOT for antipseudomonal agents decreased by 52% (4.4 days in the PrIP and 2.1 days in the PoIP, p < 0.001), and anti-MRSA agent DOT was 53% shorter in the PoIP (1.9 days vs. 0.9 days, p < 0.001). Conclusion Implementation of a rapid multiplex PCR panel for lower respiratory-tract pathogens significantly reduced the time to optimal therapy in critically ill patients with pneumonia. Clinically meaningful reductions in anti-MRSA and anti-pseudomonal agent duration were also noted. Disclosures Blake W. Buchan, PhD, Accelerate: Advisor/Consultant|Accelerate: Honoraria|BioFire: Honoraria|ChromaCode: Advisor/Consultant|ChromaCode: Honoraria|Pattern: Advisor/Consultant|Pattern: Honoraria.

176. Evaluation of the Predictive Value of Methicillin-Resistant Staphylococcus aureus (MRSA) Nares Polymerase Chain Reaction (PCR) Screening within Hospitalized Patients

Abstract Background While MRSA nares PCR screening utilization has established evidence for de-escalation of anti-MRSA agents in pneumonia, its utility in other sites of infection is not well studied. The purpose of this study was to evaluate the utility of MRSA nares PCR screening within a wide range clinical specimens and its impact on antimicrobial stewardship. Methods This retrospective study was conducted at a 446-bed academic medical center. Patients ≥ 18 years old with an in-house MRSA nares PCR ordered between 1 November 2021 and 1 February 2022 were included in the primary analysis. Negative predictive value (NPV), positive predictive value (PPV), sensitivity, and specificity were calculated using cultures obtained within 7 days of nares screening. Vancomycin duration, de-escalation, and incidence of acute kidney injury were collected pre- and post- implementation of the in-house MRSA PCR screening. The pre-intervention cohort observed patients admitted from 1 November 2020 to 1 February 2021 screened by send out MRSA nares PCR. Results At baseline, patients were a mean age of 55 years old, 55% black, and required ICU care in 50% of cases. A total of 665 cultures from 308 patients were included in the primary analysis (131 respiratory, 282 blood, 154 urine, 61 wound, 22 sterile fluid, 15 bone, and 12 spinal fluid specimens). The overall NPV of the MRSA nares PCR screening was 99.8% and the PPV was 21.1%. The sensitivity and specificity were 96.8% and 81.67%, respectively. Duration of vancomycin was a median of 3 days in both the pre- and post- intervention cohorts. However, rates of vancomycin de-escalation increased at day 3 from 31.5% to 48.1% and at day 5 from 69.9% to 80.0% post implementation on an in-house MRSA PCR screening. Incidence of acute kidney injury decreased from 45.2% to 21.6%. Conclusion Based on its high NPV among cultures of different sites, MRSA nares PCR screening may be utilized to de-escalate anti-MRSA agents within tertiary care facilities. Disclosures All Authors: No reported disclosures.

936. Antimicrobial Stewardship Assessments in De-labeling Beta-lactam Allergies

Abstract Background Unnecessary use of broad-spectrum antibiotics due to false antibiotic allergy labels leads to an increase in drug resistant and health care associated infections. Therefore, allergy assessments to de-label patients not truly allergic is an important antimicrobial stewardship (AMS) tool. The purpose of this study was to assess the effectiveness of a pharmacy-led questionnaire and AMS rounds in improving the accuracy of beta-lactam allergy labels (BLA). Methods AMS piloted BLA de-labeling rounds three times a week from November 1, 2021 to April 1, 2022. Rounds consisted of an infectious disease physician and an AMS pharmacist that reviewed allergy questionnaires conducted by trained pharmacy personnel. The questionnaire was provided to patients 18 years or older with a documented BLA and an admission stay of two or more nights. Patients were excluded if unable to participate or did not have a representative available for interview. The primary outcomes evaluated were: (i) direct de-labelling (ii) future de-labeling upon patient consent (iii) allergy profile changes. The secondary outcomes were potential days of therapy (DOTs) saved for anti-MRSA agents (vancomycin, linezolid, clindamycin) and fluoroquinolones (ciprofloxacin, levofloxacin) and PEN-FAST scores for those with a penicillin-specific allergy. Results 93 of 96 patients interviewed (96.9%) had their allergy profile updated to include type, severity, or timing of reaction. 82 of 96 patients (85.4%) were classified as low-risk allergies in which 11 patients (13.4%) were successfully de-labeled and 18 patients (22.0%) were eligible for de-labeling upon patient consent. The remaining patients were eligible for further interrogation with an oral challenge (Figure 1). Potential DOTs saved were 131 and 67 days for anti-MRSA agents and fluoroquinolones, respectively. Average PEN-FAST scores for those de-labeled and eligible for oral challenge was 0.5 (SD 0.85) and 1.08 (SD 1.20), respectively. Conclusion AMS BLA assessments can decrease the prevalence of false BLA labels and prescribing of unnecessary broad-spectrum agents. PEN-FAST scores less than 2 suggests that allergy assessments help identify patients with low-risk penicillin allergies. Disclosures All Authors: No reported disclosures.

165. Biofire pneumonia panel use in severe pneumonia and antibiotic treatment in COVID-19 patients

Abstract Background Hospitalized COVID-19 patients with severe pneumonia are commonly treated for secondary bacterial pneumonia. The Biofire pneumonia panel, a rapid molecular diagnostic tool with 18 bacterial, 8 viral and 7 resistance gene targets, was made available to critical care and infectious disease clinicians in May 2020 at our institution. We sought to describe its utilization and influence on antibiotic use in patients hospitalized with COVID-19 lower respiratory tract infection (LRTI). Methods Eligible patients with COVID-19 LRTI (positive PCR test and abnormal chest imaging) had sputum or bronchoalveolar lavage pneumonia panel (PNP) paired with a respiratory tract culture between May 4 and Dec. 8, 2020, were included. Demographics, comorbidities, clinical data including microbiologic testing, PNP indication(s), and antibiotic use after testing were abstracted through chart review. Descriptive statistics were utilized. Results Characteristics of 133 patients are provided in Table 1. Median age was 61 years, 93 (70%) were male, 93 (70%) were mechanically ventilated, and 68 (51%) died within 30 days on PNP testing. PNP results, including culture results are listed in Table 2. No target was identified in 63 (47%) patients. Staphylococcus aureus was the most common bacterial isolate identified (MSSA in 32 [24%], MRSA in 8 [6%]) with culture growth in 21 specimens. More than 1 target was identified in 29 patients (22%). Empiric antibiotics and subsequent modifications within 24h hours of pneumonia panel are provided in Table 3. Vancomycin and cefepime were most frequently prescribed. Antibiotic modifications were made in 71/133 patients. Cessation of the anti-MRSA agent occurred in 39/72 (54%) of eligible patients and the anti-Pseudomonal agent in 21/78 (27%). Conclusion The PNP is a useful tool to evaluate secondary bacterial pneumonia in critically ill COVID-19 patients and may assist clinicians and antimicrobial stewardship programs in expedited antibiotic discontinuation or de-escalation particularly where rates of secondary bacterial infection are low, such as COVID-19 LRTI. Disclosures Erica J. Stohs, MD, MPH, bioMerieux: Grant/Research Support Paul D. Fey, PhD, BioFire: Advisor/Consultant|BioFire: Grant/Research Support|Merck: Grant/Research Support Trevor C. Van Schooneveld, MD, bioMerieux: Advisor/Consultant|bioMerieux: Grant/Research Support|Insmed: Grant/Research Support|Merck: Grant/Research Support|Thermo-Fischer: Advisor/Consultant.

Discovery of New Anti-MRSA Agents Based on Phenoxyethanol and Its Mechanism.

Methicillin-resistant Staphylococcus aureus (MRSA) poses a severe threat to public health and safety. The discovery and development of novel anti-MRSA drugs with a new mode of action are a challenge. In this study, a class of novel aryloxyethyl propiolates and their homologues as anti-MRSA agents have been designed and synthesized based on phenoxyethanol, of which compound II-39 showed high inhibitory activity against MRSA with an MIC of 0.78 μg/mL and an MBC of 3.13 μg/mL, which was better than that of vancomycin. Compound II-39 could destroy the cell wall and cell membrane, inhibited the formation of a biofilm, and bound to the DNA of MRSA through the electrostatic and groove interaction. Proteomic and metabolomic studies revealed that compound II-39 affected multiple intracellular metabolic pathways of MRSA. Notably, compound II-39 could effectively inhibit the expression of CrtPQMN proteins and block the biosynthesis of virulence factor (staphyloxanthin). Thus, aryloxyethyl propiolates and their homologues are promising anti-MRSA agents with multiple targets.

Bioprospecting of Endophytic Fungi as Promising Anti-MRSA Agents

Methicillin-resistant Staphylococcus aureus (MRSA) is a serious threat to the global healthcare system. Ineffective and resistance to antibiotic treatments have increased morbidity and mortality rates worldwide. New and effective antibiotics are needed to combat against bacterial resistance. Endophytic fungi are crucial reservoirs of novel bioactive metabolites. In particular, the secondary metabolites show promising therapeutic potential, notably, antibacterial. This review discussed the emerging potential of endophytic fungi as anti-MRSA agents. The ecological sources of endophytic fungi were discussed with the synthesis of bioactive metabolites. The mode of antibacterial actions was elucidated to give a better understanding of the mechanisms involved. This review may serve as an important reference for future discovery and developments of anti-MRSA agents from endophytic fungi.

Proposed Mechanism for Emodin as Agent for Methicillin Resistant Staphylococcus Aureus: In Vitro Testing and In Silico Study.

In the search for a new anti-MRSA lead compound, emodin was identified as a good lead against methicillin-resistant Staphylococcus aureus (MRSA). Emodin serves as a new scaffold to design novel and effective anti-MRSA agents. Because rational drug discovery is limited by the knowledge of the drug target, α-hemolysin of Staphylococcus aureus was used in this study because it has an essential role in Staphylococcus infections and because emodin shares structural features with compounds that target this enzyme. In order to explore emodin’s interactions with α-hemolysin, all possible ligand binding pockets were identified and investigated. Two ligand pockets were detected based on bound ligands and other reports. The third pocket was identified as a cryptic site after molecular dynamics (MD) simulations. MD simulations were conducted for emodin in each pocket to identify the most plausible ligand site and to aid in the design of potent anti-MRSA agents. Binding of emodin to site 1 was most stable (RMSD changes within 1 Å), while in site 2, the binding pose of emodin fluctuated, and it left after 20 ns. In site 3, it was stable during the first 50 ns, and then it started to move out of the binding site. Site 1 is a possible ligand binding pocket, and this study sheds more light on interaction types, binding mode, and key amino acids involved in ligand binding essential for better lead design. Emodin showed an IC50 value of 6.3 μg/mL, while 1, 6, and 8 triacetyl emodin showed no activity against MRSA. A molecular modeling study was pursued to better understand effective binding requirements for a lead.

Influence of pharmacists and infection control teams or antimicrobial stewardship teams on the safety and efficacy of vancomycin: A Japanese administrative claims database study.

Methicillin-resistant Staphylococcus aureus (MRSA) has a high mortality and requires effective treatment with anti-MRSA agents such as vancomycin (VCM). Management of the efficacy and safety of VCM has been implemented with the assignment of pharmacists in hospital wards and the establishment of teams related to infectious diseases. However, there are no reports evaluating the association between these factors and the efficacy and safety of VCM in large populations. This study used the Japanese administrative claims database accumulated from 2010 to 2019. The population was divided into two groups, therapeutic drug monitoring (TDM) group and non-TDM group, and adjusted by propensity score matching. We performed multivariate logistic regression analysis to determine the influence of pharmacists and infection control teams or antimicrobial stewardship teams on acute kidney injury (AKI) and 30-day mortality. The total number of patients was 73 478 (TDM group, n = 55 269; non-TDM group, n = 18 209). After propensity score matching, 18 196 patients were matched in each group. Multivariate logistic regression analysis showed that pharmacological management for each patient contributed to the reduction of AKI (odds ratio [OR]: 0.812, 95% confidence interval [CI]: 0.723‒0.912) and 30-day mortality (OR: 0.538, 95% CI: 0.503‒0.575). However, the establishment of infectious disease associated team in facilities and the assignment of pharmacists in the hospital wards had no effect on AKI and 30-day mortality. In addition, TDM did not affect the reduction in AKI (OR: 1.061, 95% CI: 0.948‒1.187), but reduced 30-day mortality (OR: 0.873, 95% CI: 0.821‒0.929). Pharmacologic management for individual patients, rather than assignment systems at facilities, is effective to reduce AKI and 30-day mortality with VCM administration.

Diversity of endophytic fungi in Coptis chinensis Franch. and their activity against methicillin-resistant Staphylococcus aureus

This study aimed at investigating the diversity of endophytic fungi from Coptis chinensis and their activity against methicillin-resistant Staphylococcus aureus (MRSA). Seventy-nine fungal isolates obtained from C. chinensis were identified to belong to 27 species based on morphological features and internal transcript spacer (ITS) gene sequencing analysis. Comparing relative frequency values, the most frequent genera were Colletotrichum and Fusarium, while most frequent species were C. gloeosporioides and F. avenaceum. Analysis of diversity indices indicated that C. chinensis harbored abundant fungal resources. Methanol extracts of fungal endophyte cultures were evaluated for antibacterial activity against S. aureus ATCC 25923 and two other MRSA clinical strains. Nine of 27 endophytic fungi exhibited inhibitory activities against S. aureus ATCC 25923. Among them, Paraboeremia litseae HL-17, Fusarium sp. HL-23, and Fusarium sp. HL-27 exhibited obvious inhibition against the three S. aureus strains. Our findings suggest that the endophytic fungi in C. chinensis have a high diversity and an obvious tissue specificity, and could be of potential interest in screening anti-MRSA agents. To the best of our knowledge, this is the first report on the diversity and anti-MRSA activity of fungal endophytes from C. chinensis.

Prospective audit and feedback implementation by a multidisciplinary antimicrobial stewardship team shortens the time to de-escalation of anti-MRSA agents.

Prospective audit and feedback (PAF) is considered an effective procedure for appropriate antibiotic use. However, its effect on the time to de-escalation is unclear. We aimed to evaluate the effect of daily PAF implementation, focusing on the time to de-escalation of anti-methicillin‐resistant Staphylococcus aureus (MRSA) agents as an outcome measure. To this end, a single-center, retrospective, quasi-experimental study including patients treated with intravenous anti-MRSA agents during pre-PAF (April 1, 2014 to March 31, 2015) and post-PAF (April 1, 2015 to March 31, 2016) periods was conducted. The time to de-escalation was estimated using the Kaplan–Meier method, and Cox proportional hazard analysis was performed to assess the effect of daily PAF implementation on the time to de-escalation. Interrupted time series analysis was used to evaluate the relationship between daily PAF implementation and anti-MRSA agent utilization data converted to defined daily dose (DDD) and days of therapy (DOT) per 1,000 patient days. The median time to de-escalation was significantly shorter in the post-PAF period than in the pre-PAF period (6 days vs. 7 days, P < 0.001). According to multivariate analysis, PAF implementation was independently associated with a shorter time to de-escalation (hazard ratio [HR], 1.18; 95% confidence interval [CI], 1.02 to 1.35). There were no significant differences in hospital mortality, 30-day mortality, and length of stay between the two periods. Interrupted time series analysis showed significant reductions in the trends of DDD (trend change, –0.65; 95% CI, –1.20 to –0.11) and DOT (trend change, –0.74; 95% CI, –1.33 to –0.15) between the pre-PAF and post-PAF periods. Daily PAF implementation for patients treated with intravenous anti-MRSA agents led to a shorter time to de-escalation and lower consumption of anti-MRSA agents without worsening the clinically important outcomes.

Synthesis, biological evaluation and structure-activity relationship of 2-(2-hydroxyaryl)alkenylphosphonium salts with potency as anti-MRSA agents

Here we report the synthesis, in vitro antimicrobial activity, preliminary toxicity and mechanism study of a new series of 2-(2-hydroxyaryl)alkenylphosphonium salts with the variation of phosphonium moiety obtained by a two-step synthetic method from phosphine oxides. The salts showed pronounced activity against Gram-positive bacteria, including MRSA strains, and some fungi. Mechanism of action against S. aureus was studied by CV test, TEM and proteomic assay. No cell wall integrity loss was observed while proteomic assay results suggested interference in different metabolic processes of S. aureus. For this series, lipophilicity was determined as a key factor for the inhibition of Gram-positive bacteria growth and S. aureus killing. Biological properties of methylated derivatives were notably different with manifested action against Gram-negative bacteria.

Antibacterial action of Silver Nanoparticles against Staphylococcus aureus Isolated from wound infection

This study aimed to assess antibiotics resistance and antibacterial action of silver nanoparticles against Staphylococcus aureus isolated from wound infection. A total of 100 samples of wound swab existed calm since wound patients who stayed the Al-Hillah, Teaching Hospital (wound unit) in, Babylon province, Iraq. S aureus was recognized biochemically and morphologically. A whole of 30(30%) of the whole specimens tested confident for S.aureus. Available of 30 S.aureus isolates, 8(26.6 percent) were MRSA. Antibiotic susceptibility for 8 antibiotics for MRSA that appeared to Penicillin G and Cefoxitin was tested, and all isolates were resistant (100percent), Were susceptible to Rifampin, Tetracycline, and Ciprofloxacin (62.5percent) Clindamycin sensitivity remained experimental in 75% isolates. Resistance to Erythromycin remained establish in approximately 62.5 percent of the population. Gentamycin resistance was found in 50% of the isolates. The antibacterial activity of silver nanoparticles (AgNPs) alongside S.aureus demonstrates extreme broad-range antibacterial act in contradiction of recognized bacteria, with an rise inhibition zone diameter related to nanoparticle concentration The MIC of Ag NPs ranged from 50 to 100g/ml, while the MBC ranged from 100 to 200g/ml. Ag NPs is suggested as an effective anti-MRSA alternative. This experiment discovered that Ag NPs is highly recommended as an alternative anti-MRSA agent with significant inhibitory and antibacterial effect due to the methicillin resistant strains' high rate of resistance to Penicillin G and Cefoxitin (100%), Erythromycin (62.5%), and Gentamycin resistance (50%).

Disulfiram: A Repurposed Drug in Preclinical and Clinical Development for the Treatment of Infectious Diseases.

This article reviews preclinical and clinical studies on the repurposed use of disulfiram (Antabuse) as an antimicrobial agent. Preclinical research covered on the alcohol sobriety aid includes uses as an anti-MRSA agent, a carbapenamase inhibitor, antifungal drug for candidiasis, and treatment for parasitic diseases due to protozoa (e.g., giardiasis, leishmaniasis, malaria) and helminthes (e.g., schistosomiasis, trichuriasis). Past, current, and pending clinical studies on disulfiram as a post-Lyme disease syndrome (PTLDS) therapy, an HIV latency reversal agent, and intervention for COVID-19 infections are also reviewed..

Polycyclic Phenol Derivatives from the Leaves of Spermacoce latifolia and Their Antibacterial and α-Glucosidase Inhibitory Activity

Three new polycyclic phenol derivatives, 2-acetyl-4-hydroxy-6H-furo [2,3-g]chromen-6-one (1), 2-(1′,2′-dihydroxypropan-2′-yl)-4-hydroxy-6H-furo [2,3-g][1]benzopyran-6-one (2) and 3,8,10-trihydroxy-4,9-dimethoxy-6H-benzo[c]chromen-6-one (8), along with seven known ones (3–7, 9 and 10) were isolated for the first time from the leaves of Spermacoce latifolia. Their structures were determined by spectroscopic analysis and comparison with literature-reported data. These compounds were tested for their in vitro antibacterial activity against four Gram-(+) bacteria: Staphyloccocus aureus (SA), methicillin-resistant Staphylococcus aureus (MRSA), Bacillus cereus (BC), Bacillus subtilis (BS), and the Gram-(−) bacterium Escherichia coli. Compounds 1, 2, 5 and 8 showed antibacterial activity toward SA, BC and BS with MIC values ranging from 7.8 to 62.5 µg/mL, but they were inactive to MRSA. Compound 4 not only showed the best antibacterial activity against SA, BC and BS, but it further displayed significant antibacterial activity against MRSA (MIC 1.95 µg/mL) even stronger than vancomycin (MIC 3.9 µg/mL). No compounds showed inhibitory activity toward E. coli. Further bioassay indicated that compounds 1, 4, 5, 6, 8 and 9 showed in vitro α-glucosidase inhibitory activity, among which compound 9 displayed the best α-glucosidase inhibitory activity with IC50 value (0.026 mM) about 15-fold stronger than the reference compound acarbose (IC50 0.408 mM). These results suggested that compounds 4, 8 and 9 were potentially highly valuable compounds worthy of consideration to be further developed as an effective anti-MRSA agent or effective α-glucosidase inhibitors, respectively. In addition, the obtained data also supported that S. latifolia was rich in structurally diverse bioactive compounds worthy of further investigation, at least in searching for potential antibiotics and α-glucosidase inhibitors.

Linearized teixobactin is inactive and after sequence enhancement, kills methicillin-resistant Staphylococcus aureus via a different mechanism.

Staphylococcus aureus is a highly adaptable pathogen that can rapidly develop resistance to conventional antibiotics such as penicillin. Recently, teixobactin was discovered from uncultivated soil bacteria by using the i-chip technology. This depsipeptide forms an ester bond between the backbone C-terminal isoleucine carboxylic acid and the hydroxyl group of threonine at position 8. Also, it contains multiple nonstandard amino acids, making it costly to synthesize. This study reports new peptides designed by linearizing teixobactin. After linearization and conversion to normal amino acids, teixobactin lost its antibacterial activity. Using this inactive template, a series of peptides were designed via hydrophobic patching and residue replacements. Three out of the five peptides were active. YZ105, only active against Gram-positive bacteria, however, showed the highest cell selectivity index. Different from teixobactin, which inhibits cell wall synthesis, YZ105 targeted the membranes of methicillin-resistant S. aureus (MRSA) based on kinetic killing, membrane permeation, depolarization, and scanning electron microscopy studies. Moreover, YZ105 could kill nafcillin-resistant MRSA, Staphylococcal clinical strains, and disrupted preformed biofilms. Taken together, YZ105, with a simpler sequence, is a promising lead for developing novel anti-MRSA agents.

Effect of Gram Stain–Guided Initial Antibiotic Therapy on Clinical Response in Patients With Ventilator-Associated Pneumonia

Gram staining should provide immediate information for detecting causative pathogens. However, the effect of Gram staining on restricting the initial antibiotic choice has not been investigated in intensive care units (ICUs). To compare the clinical response to Gram stain-guided restrictive antibiotic therapy vs guideline-based broad-spectrum antibiotic treatment in patients with ventilator-associated pneumonia (VAP). This multicenter, open-label, noninferiority randomized clinical trial (Gram Stain-Guided Antibiotics Choice for VAP) was conducted in the ICUs of 12 tertiary referral hospitals in Japan from April 1, 2018, through May 31, 2020. Patients aged 15 years or older with a VAP diagnosis and a modified Clinical Pulmonary Infection Score of 5 or higher were included. The primary analysis was based on the per-protocol analysis population. Patients were randomized to Gram stain-guided antibiotic therapy or guideline-based antibiotic therapy (based on the 2016 Infectious Disease Society of America and American Thoracic Society clinical practice guidelines for VAP). The primary outcome was the clinical response rate; clinical response was defined as completion of antibiotic therapy within 14 days, improvement or lack of progression of baseline radiographic findings, resolution of signs and symptoms of pneumonia, and lack of antibiotic agent readministration, with a noninferiority margin of 20%. Secondary outcomes were the proportions of antipseudomonal agents and anti-methicillin-resistant Staphylococcus aureus (MRSA) agents as initial antibiotic therapies; 28-day mortality, ICU-free days, ventilator-free days; and adverse events. In total, 206 patients (median [IQR] age, 69 [54-78] years; 141 men [68.4%]) were randomized to the Gram stain-guided group (n = 103) or guideline-based group (n = 103). Clinical response occurred in 79 patients (76.7%) in the Gram stain-guided group and 74 patients (71.8%) in the guideline-based group (risk difference, 0.05; 95% CI, -0.07 to 0.17; P < .001 for noninferiority). Reduced use of antipseudomonal agents (30.1%; 95% CI, 21.5%-39.9%; P < .001) and anti-MRSA agents (38.8%; 95% CI, 29.4%-48.9%; P < .001) was observed in the Gram stain-guided group vs guideline-based group. The 28-day cumulative incidence of mortality was 13.6% (n = 14) in the Gram stain-guided group vs 17.5% (n = 18) in the guideline-based group (P = .39). Escalation of antibiotics according to culture results was performed in 7 patients (6.8%) in the Gram stain-guided group and 1 patient (1.0%) in the guideline-based group (P = .03). There were no significant differences between the groups in ICU-free days, ventilator-free days, and adverse events. Results of this trial showed that Gram stain-guided treatment was noninferior to guideline-based treatment and significantly reduced the use of broad-spectrum antibiotics in patients with VAP. Gram staining can potentially ameliorate the multidrug-resistant organisms in the critical care setting. ClinicalTrials.gov Identifier: NCT03506113.

Risk of acute kidney injury associated with anti-pseudomonal and anti-MRSA antibiotic strategies in critically ill patients.

An increased risk of acute kidney injury (AKI) with the widely prescribed piperacillin-tazobactam(PTZ)-vancomycin combination in hospitalized patients has recently been reported, but evidence in ICU patients remain uncertain. This study evaluates the association between the exposure of various broad-spectrum antibiotic regimens with Pseudomonas and/or methicillin-resistance Staphylococcus aureus (MRSA) coverage and the risk of AKI in critically ill patients. A retrospective cohort study based on the publicly available MIMIC-III database reporting hospitalization data from ICU patients from a large academic medical center between 2001 and 2012. Adult patients receiving an anti-pseudomonal or an anti-MRSA agent in the ICU for more than 24-hours were included. Non-PTZ anti-pseudomonal agents were compared to PTZ; non-vancomycin agents covering MRSA were compared to vancomycin; and their combinations were compared to the PTZ-vancomycin combination. The primary outcome was defined as new or worsening AKI within 7 days of the antibiotic exposure using an adjusted binomial generalized estimating equation. Overall, 18 510 admissions from 15 673 individual patients, cumulating 169 966 days of antibiotherapy were included. When compared to PTZ, exposure to another anti-pseudomonal agent was associated with lower AKI risk (OR, 0.85; 95% CI, 0.80-0.91; p < .001). When compared to vancomycin, exposure to another anti-MRSA was also associated with lower AKI risk (OR, 0.71; 95% CI, 0.64-0.80; p < .001). Finally, when compared to the PTZ-vancomycin combination, exposure to another regimen with a similar coverage was associated with an even lower risk (OR, 0.63; 95% CI; 0.54-0.73; p < .001). A sensitivity analysis of patients with high illness severity showed similar results. These results suggest that the risk of AKI in ICU patients requiring antibiotherapy may be partially mitigated by the choice of antibiotics administered. Further clinical trials are required to confirm these findings.

Potential Fluorinated Anti-MRSA Thiazolidinone Derivatives with Antibacterial, Antitubercular Activity and Molecular Docking Studies.

MRSA infection is one of the alarming diseases in the current scenario. Identifying newer molecules to treat MRSA infection is of urgent need. In the present study, we have designed fluorinated thiazolidinone derivatives with various aryl/heteroaryl units at 5th position of the thiazolidinone core as promising anti-MRSA agents. All the compounds were screened for antibacterial activity against four bacterial strains. Among the tested compounds, the halogenated compounds with simple arylidene ring, (5Z)-5-[(3-chloro-2-fluorophenyl)methylidene]-2-[(1,3-thiazol-2-yl)amino]-1,3-thiazol-4(5H)-one (4b), (5Z)-5-[(4-chloro-2-fluorophenyl)methylidene]-2-[(1,3-thiazol-2-yl)amino]-1,3-thiazol-4(5H)-one (4c), (5Z)-5-[(3-fluoro-4-methylphenyl)methylidene]-2-[(1,3-thiazol-2-yl)amino]-1,3-thiazol-4(5H)-one (4f) and (5Z)-5-[(3,5-difluorophenyl)methylidene]-2-[(1,3-thiazol-2-yl)amino]-1,3-thiazol-4(5H)-one (4g) showed excellent activity with MIC 3.125-6.25 μg/mL against S. aureus and P. aeruginosa organism. Furthermore, these potent compounds were screened against MRSA strains, ESKAPE panel organism, and H37Rv mycobacterium strain. Compounds 4c (MIC 0.39 μg/mL), and 4f (MIC 0.39 and 0.79 μg/mL) displayed promising activity against MRSA strains (ATCC and clinical isolates, respectively). The most potent compounds, 4c and 4f eradicated the growth of bacterial colonies in a time-kill assay indicated that these are bactericidal in nature. The preliminary toxicity study of the potent molecules revealed that these compounds are non-hemolytic in nature as they did not induce lysis in human RBCs. In addition, the molecular docking and dynamics studies of compounds 4b, 4c, 4f and 4g were carried out on MurB protein of S. aureus (PDB code: 1HSK). Docking results demonstrated remarkable hydrogen bonding interaction with key amino acids ARG310, ASN83, GLY79 and π-π interactions with TYR149 which confirm the mode of action of the molecules.