Beta-lactam Antibiotics Research Articles

Characterization and transmission of plasmid-mediated multidrug resistance in foodborne Vibrio parahaemolyticus.

The purpose of this study was to determine the structural features and transferability of the multidrug-resistance (MDR) plasmid, and resistance phenotypes for the tested antimicrobials in foodborne Vibrio parahaemolyticus. Plasmids were isolated from a V. parahaemolyticus strain of seafood origin, then sequenced using the Illumina NovaSeq 6000 and PacBio Sequel II sequencing platforms to obtain the complete genome data. Characterization of the MDR plasmid pVP52-1, including determination of antimicrobial resistance genes (ARGs), plasmid incompatibility groups, and transferability, was carried out. V. parahaemolyticus strain NJIFDCVp52 contained two circular chromosomes and two circular plasmids (pVP52-1 and pVP52-2). Plasmid typing indicated that pVP52-1 belonged to the incompatibility group IncA/C2 and the sequence type pST3. pVP52-1 carried 12 different ARGs, an IS110-composite transposon consisting of aac(6')-Ib-cr, qnrVC1, aac(6')-Ib, dfrA14, and the IS26-mphA-IS6100 unit flanked by inverted sequences of IS5075 and IS4321. pVP52-2 carried no ARGs. A plasmid elimination assay showed that only pVP52-1 and its ARGs were lost, the loss of resistance to several antimicrobials, causing a change from the ampicillin-ampicillin/sulbactam-cefazolin-cefoxitin-ceftazidime-cefotaxime-imipenem-trimethoprim/sulfamethoxazole resistance pattern to the ampicillin resistance pattern. In accordance, a conjugation transfer assay showed that only pVP52-1 and its ARGs were horizontally transferred, leading to increased antimicrobial resistance in Escherichia coli strain EC600, causing a change from the ampicillin-nalidixic acid resistance pattern to the ampicillin-ampicillin/sulbactam-cefazolin-cefoxitin-ceftazidime-cefotaxime-imipenem-nalidixic acid-chloramphenicol-tetracycline-trimethoprim/sulfamethoxazole-azithromycin resistance pattern. Further transferability experiments revealed that pVP52-1 could be transferred to other enterobacterial strains of E. coli and Salmonella. This study emphasizes the urgent need for continued surveillance of resistance plasmids and changes in antimicrobial resistance profiles among the V. parahaemolyticus population.

The Immediate and Delayed Maximal Nonirritating Skin Testing Concentrations of β-Lactam Antibiotics

BackgroundMaximal skin testing (ST) nonirritant concentrations (NICs) are consistent for penicillin and aminopenicillin amongst guidelines. However, there is variability amongst guidelines for maximal ST NICs of cephalosporins. ObjectiveTo determine maximal immediate and delayed ST NICs of 15 β-lactams in β-lactam-tolerant and β-lactam-naïve participants. MethodsWe performed a single-center, nonrandomized prospective study between September 2019 and January 2022 in adult participants. Participants received skin prick testing (SPT) and intradermal test (IDT) injections at six increasing concentrations of 1 or more β-lactams. A concentration was considered irritant when more than 5% of participants had a positive test. A positive test was defined as a wheal ≥3 mm than negative control accompanied by a ≥5 mm flare for SPT/IDT and induration ≥5 mm with associated erythema at 48 hours for delayed readings (dIDT). Sensitivity analyses using 3 alternative IDT positive criteria were conducted. ResultsA total of 747 participants with a median age of 64 (IQR 54-72), 52% males, 85% White, and 92% Non-Hispanic underwent 20,858 skin tests. All undiluted SPT concentrations were nonirritant. We found the following maximal IDT/dIDT NICs (mg/ml): ampicillin (41.6/125), ampicillin-sulbactam (93.8/187.5), aztreonam (6.3/25), cefazolin (55/165), cefepime (35/140), cefoxitin (45/90), ceftaroline (7.5/15), ceftriaxone (58.3/175), cefuroxime (55/110), ertapenem (16.6/50), imipenem-cilastin (6.3/25), meropenem (8.3/25), nafcillin (31.3/62.5), oxacillin (20.9/83.5), and piperacillin-tazobactam (112.5/225). dIDTs were almost all completely non-irritant close or at undiluted concentrations. There were no differences when we applied 3 IDT positivity criteria to our raw data. ConclusionOur results suggest that SPTs with undiluted stock β-lactam antibiotic concentrations are nonirritant. Compared to previously published nonirritant concentrations, we propose a 2 to 50-fold increase to the maximal IDT and dIDT NICs of 15 β-lactam antibiotics. When performing dIDTs, a higher concentration should be used rather than the same IDT concentration.

Prevalence of Extended-Spectrum ß-Lactamases (ESBLs) and AmpC ß-Lactamases in Clinical Isolates of Multiple Drug-Resistant Escherichia coli

The current study aims to investigate the prevalence of extended-spectrum ß-lactamases (ESBLs) and AmpC β-lactamases in multiple-drug-resistant Escherichia coli (e.g., multidrug-resistant (MDR), extensively drug-resistant (XDR), and pan-drug-resistant (PDR)) collected from hospitalized patients in Baghdad. The results showed that the prevalence of ESBLs among E.coli isolates was high. From the total 113 E.coli isolates, 75 (66.37%) were ESBL-producing, while 38 (33.63%) were non-ESBL-producing. Out of 75 ESBL-positive isolates, 39 (52%) were obtained from females and 36 (48%) from males. Additionally, 43 (57.33%) isolates were collected from urine samples, and the highest production of ESBLs was obtained from the age group 41–60 years (29.33%). Moreover, out of 111 MDR E.coli, 64 (57.66%) exhibited a positive ESBL test, while 47 (42.34%) did not. Out of 24 XDR E.coli isolates, 11 (45.83%) demonstrated positive ESBLs, while 13 (54.17%) showed negative ESBLs. The antimicrobial susceptibility test results showed that positive ESBL E.coli isolates were more drug-resistant than negative ESBL isolates. The positive ESBLs of E.coli exhibited a higher resistance rate to the β-lactam antibiotics and showed a co-resistance to non-β-lactam antibiotics. Phenotypic detection of AmpC β-lactamase by the screening of cefoxitin-resistant isolates revealed that 43 (38.05%) isolates were considered positive for AmpC β-lactamase production. However, the PCR technique gives different results. In conclusion, the prevalence of ESBL and AmpC β-lactamase producing E. coli is rapidly increasing among clinical isolates of MDR, XDR, and possibly PDR E.coli.

Synergistic Interactions between Selected β-Lactam Antibiotics and Cinnamic Acid and Its Chosen Derivatives.

Staphylococcus epidermidis, a component of human microbiota, may also cause life-threatening opportunistic infections. These are becoming increasingly common infections associated with the implantation of various implants. Due to the exhaustion of antibiotic resources, new substances with antimicrobial activity are being sought. The present study examined the antibacterial effect of cinnamic acid and its derivatives and their combinations with β-lactam antibiotics on the growth of Staphylococcus epidermidis strains isolated from vascular infections. The data obtained during the research indicated that cinnamic acid and its derivatives, sinapic acid, ferulic acid, and p-coumaric acid, have weak antibacterial activity (MIC values at the level of 2048 and 4096 mg/L). The combination of cinnamic acid and its derivatives with β-lactam antibiotics increases the effectiveness of their action and may demonstrate various pharmacological effects depending on the established cutoff.

Highly Specific Voltammetric Detection of Cephalexin in Tablet Formulations and Human Urine Samples Using a Poly(2,4,6-2',4',6'-hexanitrodiphenylamine)-Modified Glassy Carbon Electrode.

β-Lactam antibiotics are employed to treat bacterial illnesses. Despite a high level of clinical success, they have encountered serious resistance that demands a high-dose regimen and a new pharmacokinetic combination. This requires continuous monitoring of their levels in pharmaceutical and biological samples. In this study, an electrochemical sensor was developed for the determination of cephalexin (CLN) in pharmaceutical formulations and biological fluid samples. The sensors were developed by modifying a glassy carbon electrode (GCE) using a conducting polymer (dipicrylamine) by potentiodynamic electropolymerization. Characterization (using cyclic voltammetry and electron impedance spectroscopy) results revealed modification of the electrode surface, leading to an enhanced effective electrode surface area and their conductivity. The appearance of an irreversible oxidative peak at much-reduced potential with 5-fold current enhancement at a poly(dipicrylamine)-modified glassy carbon electrode (poly(DPA)/GCE) verified the electrocatalytic role toward CLN. Under optimized conditions, a wider linear concentration range (5 × 10-8 to 3.0 × 10-4 M), lowest limit of detection (LoD) (2.5 nM), detected amount of each tablet brand above 97.00% of the labeled value (showing excellent agreement between the detected amount and company label), and excellent % recovery results in pharmaceutical and biological samples were obtained with an excellent interference recovery error of less than 4.05%. Its excellent accuracy, selectivity, reproducibility, and stabilities and only requiring a simple electrode modification step combined with its readily available and nontoxic modifier, which sets it apart from most previously reported methods, have validated the present method's potential applicability for determining CLN in biological and pharmaceutical samples.

Les infections urinaires chez les insuffisants rénaux chroniques hospitalisés en Néphrologie, Centre Hospitalier Universitaire Befelatanana, Antananarivo

Urinary tract infection is the leading cause of nosocomial infection worldwide. It is a factor in the progression of chronic kidney disease. To determine the epidemiological, clinical, microbiological, therapeutic and evolving profile of patients with chronic kidney disease and urinary tract infection. This was a retrospective, descriptive study lasting 5 years, from January 2014 to december 2018 in chronic kidney disease with urinary tract infection. Fifty-one patients (7.15%) were retained with a mean age of 53.03 years and a sex ratio of 0.55. Chronic kidney disease was in end-stage in 45.1% (n=23). Cystitis was found in 49.02% (n=25) and gram-negative bacilli were found in 74.50% (n=38), predominantly Escherichia coli (54.90%). Third generation of cephalosporins and fluoroquinolones were frequently prescribed as probabilistic antibiotics. Resistance to beta-lactam antibiotics was 50% for Escherichia coli. Factors influencing severe infection were: advanced age, male gender, urinary lithiasis, multiple antibiotic resistance and non-enterobacterial germs. Urinary tract infection in chronic kidney disease were frequent and particularly severe.

Epidemiological Characteristics and Drug Resistance Analysis of 187 Strains of Carbapenem-Resistant Enterobacteriaceae in a General Hospital

Background: Carbapenem antibiotics are currently the most broad-spectrum and potent β-lactam antibiotics. Without effective intervention measures, Carbapenem-Resistant Enterobacteriaceae (CRE) may become widespread in all healthcare institutions within ten years, potentially developing into an endemic issue. Objectives: To understand the epidemiological characteristics and multilocus sequence typing (MLST) of CRE infections in hospitals, and to explore critical strategies for preventing and controlling CRE hospital infections. Methods: The study focused on hospitalized patients with CRE strains isolated by the Laboratory Department of the First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine from 2020 to 2022. Patient data, bacterial isolation, culture, and drug sensitivity results were collected and analyzed to determine the epidemiological characteristics of CRE infections. Preserved Carbapenem-Resistant Klebsiella pneumoniae (CRKP) strains were reviewed, and the CRKP sequence type (ST) was obtained through MLST typing. Results: Over the past three years, 187 CRE strains were isolated in the hospital, with infections predominantly occurring in males and individuals over 60 years old. The departments with the highest detection rates were the ICU (35.29%), geriatric department (11.23%), and rehabilitation department (8.02%). The top three specimen sources were sputum (43.85%), clean midstream urine (32.09%), and secretions (13.90%). carbapenem-resistant Klebsiella pneumoniae accounted for the majority of CRE isolates (80.21%), followed by carbapenem-resistant Escherichia coli (14.44%). Carbapenem-resistant Enterobacteriaceae strains exhibited a high resistance rate to most commonly used antibiotics but were sensitive to tigecycline. Multilocus sequence typing results from 11 CRKP strains showed that 90.91% were of the ST11 type, while 9.09% were of the ST15 type. Conclusions: From 2020 to 2022, CRE infections at the hospital primarily affected elderly male patients over 60, with CRKP as the predominant pathogen and ST11 as the main sequence type. Carbapenem-resistant Enterobacteriaceae strains were highly resistant to most commonly used antimicrobial drugs. Hospitals should prioritize the prevention and control of CRE infections, emphasizing the management of antimicrobial drugs, patient identification, environmental hygiene, and infection control measures to prevent outbreaks caused by CRE.

Restoring susceptibility to β-lactam antibiotics in methicillin-resistant Staphylococcus aureus.

Infections by Staphylococcus aureus have been treated historically with β-lactam antibiotics. However, these antibiotics have become obsolete in methicillin-resistant S. aureus by acquisition of the bla and mec operons. The presence of the β-lactam antibiotic is detected by the sensor domains of BlaR and/or MecR, and the information is transmitted to the cytoplasm, resulting in derepression of the antibiotic-resistance genes. We hypothesized that inhibition of the sensor domain would shut down this response system, and β-lactam susceptibility would be restored. An in silico search of 11 million compounds led to a benzimidazole-based hit and, ultimately, to the boronate 4. The X-ray structure of 4 is covalently engaged with the active-site serine of BlaR. Compound 4 potentiates by 16- to 4,096-fold the activities of oxacillin and of meropenem against methicillin-resistant S. aureus strains. The combination of 4 with oxacillin or meropenem shows efficacy in infected mice, validating the strategy.

Biofilm Formation and Antibiotic Resistance Profiles in Carbapenemase-Producing Gram-Negative Rods-A Comparative Analysis between Screening and Pathological Isolates.

(1) Background: Carbapenem-resistant (CR) bacteria pose a significant global public health challenge due to their ability to evade treatment with beta-lactam antibiotics, including carbapenems. This study investigates the biofilm-forming capabilities of CR clinical bacterial isolates and examines the impact of serum on biofilm formation. Additionally, the study evaluates the resistance profiles and genetic markers for carbapenemase production. (2) Methods: Bacterial isolates were collected from the microbiology laboratory of Mures County Clinical Hospital between October 2022 and September 2023. Pharyngeal and rectal swabs were screened for carbapenem-resistant bacteria using selective media. Lower respiratory tract samples were also analyzed for CR Gram-negative bacteria. The isolates were tested for their ability to form biofilms in the presence and absence of fetal bovine serum at 24 and 48 h. Carbapenemase production was detected phenotypically and confirmed via PCR for relevant genes. (3) Results: Out of 846 screened samples, 4.25% from pharyngeal swabs and 6.38% from rectal swabs tested positive for CR bacteria. Acinetobacter baumannii and Klebsiella pneumoniae were the most common species isolated. Biofilm formation varied significantly between clinical isolates and standard strains, with clinical isolates generally showing higher biofilm production. The presence of serum had no significant effect on biofilm formation in Klebsiella spp., but stimulated biofilm formation for Acinetobacter spp. Carbapenemase genes blaKPC, blaOXA-48-like, and blaNDM were detected in various isolates, predominantly in Klebsiella spp., but were not the main determinants of carbapenem resistance, at least in screening isolates. (4) Conclusions: This study highlights the variability in biofilm formation among CR clinical isolates and underscores the differences between the bacteria found as carriage versus infection. Both bacterial species and environmental factors variably influence biofilm formation. These insights are crucial for the development of effective treatment and infection control strategies in clinical settings.

Evaluation of synergism effect of human glucose-dependent insulinotropic polypeptide (GIP) on Klebsiella pneumoniae carbapenemases (KPC) producer isolated from clinical samples

Antibiotic resistance is increasing among Gram-negative bacteria, prompting the development of new antibiotics as well as alternative treatment approaches. Klebsiella pneumoniae Carbapenemases (KPC) has become a major concern in the treatment of infections, since KPC-producing bacteria are resistant to a number of β -lactam and non β-lactam antibiotics in addition to hydrolyzing carbapenemases. The aim of this study is to examine the synergistic effect of human Glucose-dependent Insulinotropic Polypeptide (GIP) on KPC producer. The K. pneumoniae isolates were identified by using biochemical tests and PCR genotyping. The disc diffusion method was used to assess the antimicrobial susceptibility of each isolate, and the modified Hodge test (MHT) was used to find carbapenemases. Agar well diffusion and minimum inhibitory concentration (MIC) assays were used to validate the synergistic effect of GIP against Klebsiella species. MIC values of chosen antimicrobial compounds demonstrated a considerable synergism impact when combined with human GIP, particularly against KPC strains. The antibacterial activity of the antimicrobial compounds was boosted by 4–16 times due to human GIP, reducing the MIC values. The fractional inhibitory concentration (FIC) ranged from 0.032 to 0.25 for examined antibiotics. Thus, GIP can be considered an antibacterial adjuvant with the potential to supplement the current antibiotic spectrum.

Activity of Synthetic Peptide KP and Its Derivatives against Biofilm-Producing Escherichia coli Strains Resistant to Cephalosporins.

Bacterial resistance to β-lactam antibiotics, particularly new generation cephalosporins, is a major public health concern. In Escherichia coli, resistance to these antibiotics is mainly mediated by extended-spectrum β-lactamases (ESBL), which complicates a range of health-threatening infections. These infections may also be biofilm-related, making them more difficult to treat because of the higher tolerance to conventional antibiotics and the host immune response. In this study, we tested as potential new drug candidates against biofilm-forming ESBL-producing E. coli four antimicrobial peptides previously shown to have antifungal properties. The peptides proved to be active in vitro at micromolar concentrations against both sensitive and ESBL-producing E. coli strains, effectively killing planktonic cells and inhibiting biofilm formation. Quantitative fluorescence intensity analysis of three-dimensional reconstructed confocal laser scanning microscopy (CLSM) images of mature biofilm treated with the most active peptide showed significant eradication and a reduction in viable bacteria, while scanning electron microscopy (SEM) revealed gross morphological alterations in treated bacteria. The screening of the investigated peptides for antibacterial and antibiofilm activity led to the selection of a leading candidate to be further studied for developing new antimicrobial drugs as an alternative treatment against microbial infections, primarily associated with biofilms.

Click chemistry-based fluorescence polarization sensor for sensitive detection of ampicillin

Ampicillin (AMP) is a β-lactam antibiotic that can inhibit bacterial wall synthesis. The overuse and misuse of AMP makes it micropollutant that commonly found in food and various environmental media. In this work, a fluorescence polarization sensor was designed to sensitive detection of trace ampicillin based on click chemistry, using graphene oxide (GO) as a fluorescence polarization (FP) signal enhancement element. First, when ampicillin binds to its aptamer (apt), the adjacent alkyne and azide groups are separated, hindering the click-linking reaction. When Carboxyfluorescein (FAM) fluorophore-labeled probe (C-FAM) is added, its protruding 3-terminal FAM is recognized and cleaved by exonuclease I (EXO I), releasing fluorophores free that could not be adsorbed on GO, resulting in a lo0wer polarization signal. If there is no AMP in the system, aptamer probe is connected to its complementary chain ends by a click reaction. After C-FAM hybridizes with apt, the apt/P duplex is opened and the prominent single-stranded ends adsorb on the GO, leading a significantly enhanced FP signal. According to the relationship between the difference in FP values and the concentrations of AMP, the limit of detection of proposed method is as low as 80 pg/mL. This assay has a wide linear range plus excellent selectivity, and has been applied to detect AMP in milk and river water samples with satisfactory results, which demonstrates that the FP sensor has great potential for practical applications in food safety and environmental protection fields.

The study of honokiol as a natural product-based antimicrobial agent and its potential interaction with FtsZ protein.

Multidrug resistant bacteria have been a global health threat currently and frontline clinical treatments for these infections are very limited. To develop potent antibacterial agents with new bactericidal mechanisms is thus needed urgently to address this critical antibiotic resistance challenge. Natural products are a treasure of small molecules with high bioactive and low toxicity. In the present study, we demonstrated that a natural compound, honokiol, showed potent antibacterial activity against a number of Gram-positive bacteria including MRSA and VRE. Moreover, honokiol in combination with clinically used β-lactam antibiotics exhibits strong synergistic antimicrobial effects against drug-resistant S. aureus strains. Biochemical studies further reveal that honokiol may disrupt the GTPase activity, FtsZ polymerization, cell division. These biological impacts induced by honokiol may ultimately cause bacterial cell death. The in vivo antibacterial activity of honokiol against S. aureus infection was also verified with a biological model of G. mellonella larvae. The in vivo results support that honokiol is low toxic against the larvae and effectively increases the survival rate of the larvae infected with S. aureus. These findings demonstrate the potential of honokiol for further structural advancement as a new class of antibacterial agents with high potency against multidrug-resistant bacteria.

Ceftriaxone and MC-100093 mitigate fentanyl-induced cardiac injury in mice: Preclinical investigation of its underlying molecular mechanisms

Drug addiction is considered a worldwide concern and one of the most prevailing causes of death globally. Opioids are highly addictive drugs, and one of the most common opioids that is frequently used clinically is fentanyl. The potential harmful effects of chronic exposure to opioids on the heart are still to be elucidated. Although β-lactam antibiotics are well recognized for their ability to fight bacteria, its protective effect in the brain and liver has been reported. In this study, we hypothesize that β-lactam antibiotic, ceftriaxone, and the novel synthetic non-antibiotic β-lactam, MC-100093, are cardioprotective against fentanyl induced-cardiac injury by upregulating xCT expression. Mice were exposed to repeated low dose (0.05 mg/kg, i.p.) of fentanyl for one week and then challenged on day 9 with higher dose of fentanyl (1 mg/kg, i.p.). This study investigated cardiac histopathology and target genes and proteins in serum and cardiac tissues in mice exposed to fentanyl overdose and β-lactams. We revealed that fentanyl treatment induced cardiac damage as evidenced by elevated cardiac enzymes (troponin I). Furthermore, fentanyl treatment caused large aggregations of inflammatory cells and elevation in the areas and volumes of myocardial fibers, indicating hypertrophy and severe cardiac damage. Ceftriaxone and MC-100093 treatment, However, induced cardioprotective effects as evidenced by marked reduction in cardiac enzymes (troponin I) and changes in histopathology. Furthermore, ceftriaxone and MC-100093 treatment decreased the levels of hypertrophic genes (α-MHC & β-MHC), apoptotic (caspase-3), and inflammatory markers (IL-6 & NF-κB). This study reports for the first time the cardioprotective effect of β-lactams against fentanyl-induced cardiac injury. Further studies are greatly encouraged to completely identify the cardioprotective properties of ceftriaxone and MC-100093.

Preanalytical Stability of 13 Antibiotics in Biological Samples: A Crucial Factor for Therapeutic Drug Monitoring.

The stability of antibiotic preanalytical samples is a critical factor in therapeutic drug monitoring (TDM), a practice of undoubted importance for the proper therapeutic use of antibiotics, especially in complex management patients, such as pediatrics. This review aims to analyze the data in the literature regarding the preanalytical stability of some of the antibiotics for which TDM is most frequently requested. The literature regarding the preanalytical stability of amikacin, ampicillin, cefepime, ceftazidime, ciprofloxacin, daptomycin, gentamicin, levofloxacin, linezolid, meropenem, piperacillin, teicoplanin, and vancomycin in plasma, serum, whole blood, and dried blood/plasma spot samples was analyzed. Various storage temperatures (room temperature, 4 °C, -20 °C, and -80 °C) and various storage times (from 1 h up to 12 months) as well as subjecting to multiple freeze-thaw cycles were considered. The collected data showed that the non-beta-lactam antibiotics analyzed were generally stable under the normal storage conditions used in analytical laboratories. Beta-lactam antibiotics have more pronounced instability, particularly meropenem, piperacillin, cefepime, and ceftazidime. For this class of antibiotics, we suggest that storage at room temperature should be limited to a maximum of 4 h, storage at 2-8 °C should be limited to a maximum of 24 h, and storage at -20 °C should be limited to a maximum of 7 days; while, for longer storage, freezing at -80 °C is suggested.

New Delhi Metallo-Beta-Lactamase Inhibitors: A Systematic Scoping Review.

Background/Objectives: Among various carbapenemases, New Delhi metallo-beta-lactamases (NDMs) are recognized as the most powerful type capable of hydrolyzing all beta-lactam antibiotics, often conferring multi-drug resistance to the microorganism. The objective of this review is to synthesize current scientific data on NDM inhibitors to facilitate the development of future therapeutics for challenging-to-treat pathogens. Methods: Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Extension for Scoping Reviews, we conducted a MEDLINE search for articles with relevant keywords from the beginning of 2009 to December 2022. We employed various generic terms to encompass all the literature ever published on potential NDM inhibitors. Results: Out of the 1760 articles identified through the database search, 91 met the eligibility criteria and were included in our analysis. The fractional inhibitory concentration index was assessed using the checkerboard assay for 47 compounds in 37 articles, which included 8 compounds already approved by the Food and Drug Administration (FDA) of the United States. Time-killing curve assays (14 studies, 25%), kinetic assays (15 studies, 40.5%), molecular investigations (25 studies, 67.6%), in vivo studies (14 studies, 37.8%), and toxicity assays (13 studies, 35.1%) were also conducted to strengthen the laboratory-level evidence of the potential inhibitors. None of them appeared to have been applied to human infections. Conclusions: Ongoing research efforts have identified several potential NDM inhibitors; however, there are currently no clinically applicable drugs. To address this, we must foster interdisciplinary and multifaceted collaborations by broadening our own horizons.

2-Cinnamamido-4-Methylpentanamide and N-(2-Hydroxypropanoyl)Cinnamamide: Synthesis, Characterization, and Molecular Docking Studies Through PBP2a Protein

ABSTRACT. Cinnamic acid has been found in several types of plants and has a diverse spectrum of bioactivity. Derivatization of cinnamic acid related to the improving bioactivity of a compound. Cinnamic acid can be found as an acid or in conjugated form with amides, esters, aldehydes. This research focus on the synthesis of amide derivatives of cinnamic acid to improve the bioactivity. Two compounds namely 2-cinnamamido-4-methylpentanamide (1a) and N-(2-hydroxypropanoyl)cinnamamide (1b) were carried out through amidation reaction using carbodiimide coupling reagent for 24 hours. The synthesized target compounds were characterized using FT-IR, GCMS-MS, 1H-NMR and 13C-NMR spectroscopy. The compounds were evaluated their antibacterial activity by molecular docking simulation against PBP2a (PDB ID: 1MWT) using AutoDock4 and AutoDockTools software. PBP2a is one of the main proteins in MRSA that has evolved to resist β-lactam antibiotics and was proposed to be the most likely target of MRSA. The inhibitory process of this protein works through inhibition of the bacterial cell wall. The synthesis process of 1a and 1b produced yields of 22.13% and 25.20%. Molecular docking results showed that 1a and 1b had better energy (ΔGbinding -7.33 and -6.29 kcal/mol) than Streptomycin as the control positive. The compounds of 1a and 1b had interactions on PBP2a through hydrogen bond with Asn464, Thr600, and Tyr519. This present study showed that the synthesized compounds from cinnamic acid derivatives have a potential to be used as antibacterial agents. Keywords: Amidation, antibacterial, 2-cinnamamido-4-methylpentanamide, molecular docking, N-(2-hydroxypropanoyl) cinnamamide.

Cefepime trough levels and clinical outcomes in patients undergoing universal therapeutic drug monitoring: A prospective cohort study

BackgroundCefepime is an essential beta-lactam antibiotic for which therapeutic drug monitoring (TDM) is not performed routinely in many centers. Current literature on cefepime levels consists of retrospective reports of TDM applied selectively by clinicians, i.e., in the setting of suspected toxicity. In an effort to capture and define therapeutic plasma concentration thresholds, this prospective study applied TDM uniformly to consecutive inpatients with suspected or confirmed bacterial infections and observed their ensuing 30-day clinical course. MethodsThis single-center prospective observational study included adult patients hospitalized in the hematology, intermediate- or intensive-care units of Geneva University Hospitals between January 2019 and December 2021. Participants in steady state (receiving cefepime for ≥24 hours) uniformly underwent TDM at least once and thereafter were assessed for the primary and secondary outcomes of occurrence of adverse events and clinical response, respectively, through 30 days. ResultsAmong 151 included patients, 104 had at least one trough level. Most (95/104, 91%) experienced clinical success. Six (6%) experienced an adverse event possibly related to cefepime; no neurotoxicity was observed. Median trough level was 8.5 mg/L (IQR 5.8-13.3); trough levels of those with or without adverse events and those with or without clinical success did not differ significantly. Trough levels increased significantly with renal insufficiency and age. ConclusionCefepime TDM conducted uniformly in hospitalized patients with severe infections reveals lower trough levels than previously reported. Toxicity is rare and clinical effectiveness is high, such that the determination of a strict therapeutic range remains elusive.

Probing the interaction between the metallo-β-lactamase SMB-1 and ampicillin by multispectral approaches combined with molecular dynamics.

Metallo-β-lactamases (MβLs) hydrolyze and inactivate β-lactam antibiotics, are a pivotal mechanism conferring resistance against bacterial infections. SMB-1, a novel B3 subclass of MβLs from Serratia marcescens could deactivate almost all β-lactam antibiotics including ampicillin (AMP), which has posed a serious threat to public health. To illuminate the mechanism of recognition and interaction between SMB-1 and AMP, various fluorescence spectroscopy techniques and molecular dynamics simulation were employed. The results of quenching spectroscopy unraveled that AMP could make SMB-1 fluorescence quenching that mechanism was the static quenching; the synchronous and three-dimensional fluorescence spectra validated that the microenvironment and conformation of SMB-1 were altered after interaction with AMP. The molecular dynamics results demonstrated that the whole AMP enters the binding pocket of SMB-1, even though with a relatively bulky R1 side chain. Loop1 and loop2 in SMB-1 undergo significant fluctuations, and α2 (71-73) and local α5 (186-188) were turned into random coils, promoting zinc ion exposure consistent with circular dichroism spectroscopy results. The binding between them was driven by a combination of enthalpy and entropy changes, which was dominated by electrostatic force in agreement with the fluorescence observations. The present study brings structural insights and solid foundations for the design of new substrates for β-lactamases and the development of effective antibiotics that are resistant to superbugs.

Nafcillin-induced thrombocytopenia: An uncommon complication

Drug-induced thrombocytopenia is a challenging clinical dilemma that is often overlooked. Nafcillin is a beta-lactam anti-staphylococcal penicillin antibiotic used as a first-line treatment for methicillin-susceptible Staphylococcus aureus (MSSA) bacteremia and severe infections. Nafcillin has been associated with a higher rate of premature antibiotic discontinuation than cefazolin. Here we report a 58-year-old woman with multiple comorbid conditions who presented with a prosthetic right hip joint infection due to MSSA and was treated with nafcillin but developed profound thrombocytopenia due to a possible nafcillin side effect on the 14th day of therapy. Thrombocytopenia resolved after discontinuation of nafcillin, and the patient was treated successfully with cefazolin. Keywords: Nafcillin-induced thrombocytopenia, drug-induced thrombocytopenia, thrombocytopenia