Synthesis of biologically active cefpodoxime and vanillin-based schiff base metal complexes with the detailed biological evaluations.

Schiff bases of existing antimicrobial drugs are an area, which is still to be comprehensively explored to improve drug efficiency against consistently resisting bacterial species. In this study, we have targeted a new and eco-friendly method of condensation reaction that allows the "green synthesis" as well as improved biological efficacy. The transition metal complexes of cefpodoxime with well-enhanced biological activities were synthesized. The condensation reaction product of cefpodoxime and vanillin was further reacted with suitable metal salts of [Mn (II), Cu (II), Fe (II), Zn (II), and Ni (II)] with 1:2 molar ratio (metal: ligand). The characterization of all the products were carried out by using UV-Visible, elemental analyzer, FTIR, 1H-NMR, ICP-OES, and LC-MS. Electronic data obtained by UV-Visible proved the octahedral geometry of metal complexes. The biological activities Schiff base ligand and its transition metal complexes were tested by using in-vitro anti-bacterial analysis against various Gram-negative, as well as Gram-positive bacterial strains. Proteinase and protein denaturation inhibition assays were utilized to evaluate the products in-vitro anti-inflammatory activities. The in vitro antioxidant activity of the ligand and its complexes was evaluated by utilizing the 2,2-diphenyl-1-picrylhydrazyl (DPPH) in-vitro method. The final results proved metal complexes to be more effective against bacterial microorganisms as compared to respective parent drug as well as their free ligands. Patch Dock, a molecular docking tool, was used to dock complexes 1a-5e with the crystal structure of GlcN-6-P synthase (ID: 1MOQ). According to the docking results, complex 2b exhibited a highest score (8,882; ACE = -580.43 kcal/mol) that is well correlated with a high inhibition as compared to other complexes which corresponds to the antibacterial screening outcomes.

Effectiveness of cephalosporins in hydrolysis and inhibition of Staphylococcus aureus and Escherichia coli biofilms.

IMPORTANCE: Staphylococcus aureus and Escherichia coli contribute to global health challenges by forming biofilms, a key virulence element implicated in the pathogenesis of several infections. OBJECTIVE: The study examined the efficacy of various generations of cephalosporins against biofilms developed by pathogenic S. aureus and E. coli. METHODS: The development of biofilms by both bacteria was assessed using petri-plate and microplate methods. Biofilm hydrolysis and inhibition were tested using first to fourth generations of cephalosporins, and the effects were analyzed by crystal violet staining and phase contrast microscopy. RESULTS: Both bacterial strains exhibited well-developed biofilms in petri-plate and microplate assays. Cefradine (first generation) showed 76.78% hydrolysis of S. aureus biofilm, while significant hydrolysis (59.86%) of E. coli biofilm was observed by cefipime (fourth generation). Similarly, cefuroxime, cefadroxil, cefepime, and cefradine caused 78.8%, 71.63%, 70.63%, and 70.51% inhibition of the S. aureus biofilms, respectively. In the case of E. coli, maximum biofilm inhibition (66.47%) was again shown by cefepime. All generations of cephalosporins were more effective against S. aureus than E. coli, which was confirmed by phase contrast microscopy. CONCLUSIONS AND RELEVANCE: Cephalosporins exhibit dual capabilities of hydrolyzing and inhibiting S. aureus and E. coli biofilms. First-generation cephalosporins exhibited the highest inhibitory activity against S. aureus, while the third and fourth generations significantly inhibited E. coli biofilms. This study highlights the importance of tailored antibiotic strategies based on the biofilm characteristics of specific bacterial strains.

Comparison of the Efficacy of Cephalosporins and Non-cephalosporins in Preventing Surgical Site Infections in Colorectal Surgery Patients: An Updated Systematic Review and Meta-Analysis.

OBJECTIVE: This study aims to compare the efficacy of cephalosporin and non-cephalosporin antibiotics in preventing surgical site infections (SSIs) in patients undergoing colorectal surgery, providing a scientific basis for the selection of perioperative antibiotics through systematic review and meta-analysis. METHODS: Adhering to the PRISMA guidelines, this research employed an extensive literature search strategy across multiple databases to identify relevant studies, including randomized controlled trials (RCTs) and observational studies. Inclusion criteria were studies on adults undergoing colorectal surgery who received preoperative prophylaxis with either cephalosporin or non-cephalosporin antibiotics. Exclusion criteria included preoperative diagnosis of infectious diseases and preoperative use of antimicrobial agents. Meta-analysis was conducted using RevMan 5.3 software to assess the effectiveness of both antibiotic classes in preventing SSIs, including subgroup analyses. RESULTS: Eight studies met the inclusion criteria, comprising 872 patients. Meta-analysis revealed that the incidence of SSI in the cephalosporin group was lower than in the non-cephalosporin group (14.8% vs 25.1%), with statistical significance (OR = 1.94, 95% CI: 1.38-2.74, PP = =0.0001). However, no significant difference in SSI risk was observed between the groups within 30 days (OR = =1.92, 95% CI: 1.08-3.42). Subgroup analysis indicated that higher-quality studies were associated with larger effect sizes. CONCLUSION: This study suggests that cephalosporin antibiotics may be superior to non-cephalosporins in preventing SSIs following colorectal surgery, especially in the short term. However, their long-term efficacy in SSI prevention may be similar. The selection of perioperative antibiotics should consider factors such as the antimicrobial spectrum, pharmacokinetic properties, and bacterial resistance.

The prevalence of antimicrobial drug resistance of non-typhoidal Salmonella in human infections in sub-Saharan Africa: a systematic review and meta-analysis.

INTRODUCTION: Non-typhoidal Salmonella (NTS) bacteremia is common in sub-Saharan Africa. We examined the prevalence of antibiotic resistance to fluoroquinolones, third-generation cephalosporins, and multi-drug resistance (MDR) in NTS human isolates from sub-Saharan Africa. METHODS: A systematic review was conducted using a search in Ovid Medline, Embase, and African Index Medicus of publications between 2000 and 2021. A random-effects model meta-analysis was performed using data from 66 studies that included 29,039 NTS blood and 1,065 stool isolates. RESULTS: The pooled prevalence proportions of MDR were 0.685 (95% CI 0.574-0.778) and 0.214 (0.020-0.785) in blood vs. stool isolates. The corresponding estimates of fluoroquinolones resistance were 0.014 (0.008-0.025) vs. 0.021 (0.012-0.036) and third-generation cephalosporins resistance 0.019 (0.012-0.031) vs. 0.035 (0.006-0.185). Similar results were found for children and adults. Resistance prevalence to these antibiotics in blood isolates increased between 2000-2010 and 2011-2021. The guidelines employed to determine antimicrobial resistance and epidemiological characteristics (e.g. sample size, study duration) correlated with the resistance prevalence. CONCLUSIONS: The prevalence of MDR and resistance to fluoroquinolones and third-generation cephalosporins in NTS in sub-Saharan Africa is alarming. EXPERT OPINION: Standardized surveillance of antimicrobial drug resistance in NTS in sub-Saharan Africa is warranted to guide healthcare policymaking and antibiotic stewardship programs.

Non-typhoidal Salmonella (NTS) usually causes diarrheal disease, but some patients might develop bloodstream infection. The occurrence and case fatality of bloodstream infections caused by NTS are high in sub-Saharan Africa. However, the information on antibiotic resistance of these bacteria in this region is scarce. We performed a systematic review and meta-analysis to examine the prevalence of multi-drug resistance (MDR) and resistance to antibiotics used to treat NTS bloodstream infection: fluoroquinolones and third-generation cephalosporins in NTS isolates from patients from sub-Saharan Africa.We used data from 66 studies. In NTS blood isolates, the combined prevalence was 1.4% for fluoroquinolones resistance, 1.9% for resistance to third-generation cephalosporins, and 68.5% for MDR. These estimates were 2.1%, 3.5%, and 21.4% in stool isolates. The prevalence of resistance to fluoroquinolones and third-generation cephalosporins in blood isolates has increased in the past 2 decades. The guidelines employed to determine antimicrobial resistance and the study epidemiological characteristics were related to the resistance prevalence.The high prevalence of MDR in NTS raises concerns, and the emergence of resistance to fluoroquinolones and third-generation cephalosporins is worrisome. Strengthening the monitoring of antimicrobial drug resistance in NTS is essential to guide patients' care and policymaking in sub-Saharan Africa.

Accumulation of resistance genes in Salmonella Typhimurium transmitted between poultry and dairy farms increases the risk to public health.

Salmonella Typhimurium is a zoonotic pathogen that poses a major threat to public health. This generalist serotype can be found in many hosts and the environment where varying selection pressures may result in the accumulation of antimicrobial resistance determinants. However, the transmission of this serotype between food-producing hosts, specifically between poultry layer flocks and nearby dairy herds, was never demonstrated. We investigated an outbreak at a dairy in Israel to determine the role of nearby poultry houses to be sources of infection. The 2-month outbreak resulted in a 47% mortality rate among 15 calves born in that period. Routine treatment of fluid therapy, a nonsteroidal anti-inflammatory, and cefquinome was ineffective, and control was achieved by the introduction of vaccination of dry cows against Salmonella (Bovivac S, MSD Animal Health) and a strict colostrum regime. Whole genome sequencing and antimicrobial sensitivity tests were performed on S. Typhimurium strains isolated from the dairy (n = 4) and strains recovered from poultry layer farms (n = 10). We identified acquired antimicrobial-resistant genes, including the blaCTX-M-55 gene, conferring resistance to extended-spectrum cephalosporins, which was exclusive to dairy isolates. Genetic similarity with less than five single nucleotide polymorphism differences between dairy and poultry strains suggested a transmission link. This investigation highlights the severe impact of S. Typhimurium on dairy farms and the transmission risk from nearby poultry farms. The accumulation of potentially transferable genes conferring resistance to critically important antimicrobials underscores the increased public health risk associated with S. Typhimurium circulation between animal hosts.IMPORTANCESalmonella Typhimurium is one of the major causes of food-borne illness globally. Infections may result in severe invasive disease, in which antimicrobial treatment is warranted. Therefore, the emergence of multi-drug-resistant strains poses a significant challenge to successful treatment and is considered one of the major threats to global health. S. Typhimurium can be found in a variety of animal hosts and environments; however, its transmission between food-producing animals, specifically poultry layers flocks and dairy herds, was never studied. Here, we demonstrate the transmission of the pathogen from poultry to a nearby dairy farm. Alarmingly, the multi-drug-resistant strains collected during the outbreak in the dairy had acquired resistance to extended-spectrum cephalosporins, antibiotics critically important in treating Salmonellosis in humans. The findings of the study emphasize the increased risk to public health posed by zoonotic pathogens' circulation between animal hosts.

Multidrug resistance in Salmonella isolates of swine origin: mobile genetic elements and plasmids associated with cephalosporin resistance with potential transmission to humans.

The emergence of foodborne Salmonella strains carrying antimicrobial resistance (AMR) in mobile genetic elements (MGE) is a significant public health threat in a One Health context requiring continuous surveillance. Resistance to ciprofloxacin and cephalosporins is of particular concern. Since pigs are a relevant source of foodborne Salmonella for human beings, we studied transmissible AMR genes and MGE in a collection of 83 strains showing 9 different serovars and 15 patterns of multidrug resistant (MDR) previously isolated from pigs raised in the conventional breeding system of Northern Spain. All isolates were susceptible to ciprofloxacin and three isolates carried blaCMY-2 or blaCTX-M-9 genes responsible for cefotaxime resistance. Filter mating experiments showed that the two plasmids carrying blaCTX-M-9 were conjugative while that carrying blaCMY-2 was self-transmissible by transformation. Whole-genome sequencing and comparative analyses were performed on the isolates and plasmids. The IncC plasmid pSB109, carrying blaCMY-2, was similar to one found in S. Reading from cattle, indicating potential horizontal transfer between serovars and animal sources. The IncHI2 plasmids pSH102 in S. Heidelberg and pSTM45 in S. Typhimurium ST34, carrying blaCTX-M-9, shared similar backbones and two novel "complex class 1 integrons" containing different AMR and heavy metal genes. Our findings emphasize the importance of sequencing techniques to identify emerging AMR regions in conjugative and stable plasmids from livestock production. The presence of MGE carrying clinically relevant AMR genes raises public health concerns, requiring monitoring to mitigate the emergence of bacteria carrying AMR genes and subsequent spread through animals and food.IMPORTANCEThe emergence of foodborne Salmonella strains carrying antimicrobial resistance (AMR) in mobile genetic elements (MGE) is a significant public health threat in a One Health context. Since pigs are a relevant source of foodborne Salmonella for humans, in this study, we investigate different aspects of AMR in a collection of 83 Salmonella showing nine different serovars and 15 patterns of multidrug resistant (MDR) isolated from pigs raised in the conventional breeding system. Our findings emphasize the importance of sequencing techniques to identify emerging AMR regions in conjugative and stable plasmids from livestock production. The presence of MGE carrying clinically relevant AMR genes raises public health concerns, requiring monitoring to mitigate the emergence of bacteria carrying AMR genes and subsequent spread through animals and food.

Online-Assisted Survey on Antibiotic Use by Pet Owners in Dogs and Cats.

The aim of the study was two-fold: first, to collect data on the use of antibiotics in Germany for dogs and cats and, second, their owners' experiences and opinions. Using an anonymous online survey, dog and cat owners were asked about the last antibiotic administration in their pet. The inclusion criterion was any antibiotic administration within the last year. A total of 708 questionnaires from 463 dogs and 245 cats could be evaluated. Diarrhea was reported as the most common reason for antibiotic administration in dogs (18.4%). Wound infection/abscess/bite injury was the second most common reason in dogs (16.0%). In cats wound infection/abscess/bite injury was the most common reason (23.3%), followed by dental treatment (21.2%) and upper respiratory tract infections (16.7%). The most common antibiotics used systemically in both species were amoxicillin/clavulanic acid (32.5%), amoxicillin (14.8%), metronidazole (6.9%), and doxycycline (6.8%). While efficacy (99.9%) and tolerability (94.8%) were rated as most important for the choice of antibiotics, costs (51.6%) were cited as predominantly unimportant. First-line antibiotics were used significantly more often than critically important antibiotics. The majority of animal owners show awareness for avoidance of antibiotic resistance and the use of critically important antibiotics.

Phenotypic and molecular characterization of ß-lactamase-producing Klebsiella species among children discharged from hospital in Western Kenya.

BACKGROUND: The emergence and spread of ß-lactamase-producing Klebsiella spp. has been associated with a substantial healthcare burden resulting in therapeutic failures. We sought to describe the proportion of phenotypic resistance to commonly used antibiotics, characterize ß-lactamase genes among isolates with antimicrobial resistance (AMR), and assess the correlates of phenotypic AMR in Klebsiella spp. isolated from stool or rectal swab samples collected from children being discharged from hospital. METHODS: We conducted a cross-sectional study involving 245 children aged 1-59 months who were being discharged from hospitals in western Kenya between June 2016 and November 2019. Whole stool or rectal swab samples were collected and Klebsiella spp. isolated by standard microbiological culture. ß-lactamase genes were detected by PCR whilst phenotypic antimicrobial susceptibility was determined using the disc diffusion technique following standard microbiology protocols. Descriptive analyses were used to characterize phenotypic AMR and carriage of ß-lactamase-producing genes. The modified Poisson regression models were used to assess correlates of phenotypic beta-lactam resistance. RESULTS: The prevalence of ß-lactamase carriage among Klebsiella spp. isolates at hospital discharge was 62.9% (154/245). Antibiotic use during hospitalization (adjusted prevalence ratio [aPR] = 4.51; 95%CI: 1.79-11.4, p < 0.001), longer duration of hospitalization (aPR = 1.42; 95%CI: 1.14-1.77, p < 0.002), and access to treated water (aPR = 1.38; 95%CI: 1.12-1.71, p < 0.003), were significant predictors of phenotypically determined ß-lactamase. All the 154 ß-lactamase-producing Klebsiella spp. isolates had at least one genetic marker of ß-lactam/third-generation cephalosporin resistance. The most prevalent genes were blaCTX-M 142/154 (92.2%,) and blaSHV 142/154 (92.2%,) followed by blaTEM 88/154 (57.1%,) and blaOXA 48/154 (31.2%,) respectively. CONCLUSION: Carriage of ß-lactamase producing Klebsiella spp. in stool is common among children discharged from hospital in western Kenya and is associated with longer duration of hospitalization, antibiotic use, and access to treated water. The findings emphasize the need for continued monitoring of antimicrobial susceptibility patterns to inform the development and implementation of appropriate treatment guidelines. In addition, we recommend measures beyond antimicrobial stewardship and infection control within hospitals, improved sanitation, and access to safe drinking water to mitigate the spread of ß-lactamase-producing Klebsiella pathogens in these and similar settings.

Ceftiofur in swine manure contributes to reducing pathogens and antibiotic resistance genes during composting.

Aerobic composting is a common way for the disposal of feces produced in animal husbandry, and can reduce the release of antibiotic resistance genes (ARGs) from feces into the environment. In this study, we collected samples from two distinct treatments of swine manure compost with and without ceftiofur (CEF), and identified the ARGs, mobile genetic elements (MGEs), and bacterial community by metagenomic sequencing. The impacts of CEF on the bacterial community composition and fate of ARGs and MGEs were investigated. With increasing composting temperature and pH, the concentration of CEF in the manure decreased rapidly, with a degradation half-life of 1.12 d and a 100% removal rate after 10 d of aerobic composting. Metagenomics demonstrated that CEF in the manure might inhibit the growth of Firmicutes and Proteobacteria, thereby reducing some ARGs and MGEs hosted by these two bacteria, which was further confirmed by the variations of ARGs and MGEs. A further redundancy analysis suggested that pH and temperature are key environmental factors affecting ARG removal during composting, and intI1 and bacterial communities also have significant influence on ARG abundance. These results are of great significance for promoting the removal of some ARGs from animal manure by controlling some key environmental factors and the type of antibiotics used in animals.

Perioperative Cefazolin for Total Joint Arthroplasty Patients Who Have a Penicillin Allergy: Is It Safe?

BACKGROUND: Cefazolin is the standard of care for perioperative antibiotic prophylaxis in total joint arthroplasty (TJA) in the United States. The potential allergic cross-reactivity between cefazolin and penicillin causes uncertainty regarding optimal antibiotic choice in patients who have a reported penicillin allergy (rPCNA). The purpose of this study was to determine the safety of perioperative cefazolin in PCNA patients undergoing primary TJA. METHODS: We identified all patients (n = 49,842) undergoing primary total hip arthroplasty (n = 25,659) or total knee arthroplasty (n = 24,183) from 2016 to 2022 who received perioperative intravenous antibiotic prophylaxis. Patients who had an rPCNA (n = 5,508) who received cefazolin (n = 4,938, 89.7%) were compared to rPCNA patients who did not (n = 570, 10.3%), and to patients who did not have an rPCNA (n = 43,359). The primary outcome was the rate of allergic reactions within 72 hours postoperatively. Secondary outcomes included the rates of superficial infections, deep infections, and Clostridioides difficile infections within 90 days. RESULTS: The rate of allergic reactions was 0.1% (n = 5) in rPCNA patients who received cefazolin, compared to 0.2% (n = 1) in rPCNA patients who did not (P = .48) and 0.02% (n = 11) in patients who have no rPCNA (P = .02). Allergic reactions were mild in all 5 rPCNA patients who received cefazolin and were characterized by cutaneous symptoms (n = 4) or dyspnea in the absence of respiratory distress (n = 1) that resolved promptly with antibiotic discontinuation and administration of antihistamines and/or corticosteroids. We observed no differences in the rates of superficial infections (0.1 versus 0.2%, P = .58), deep infections (0.3 versus 0.4%, P = .68), or C difficile infections (0.04% versus 0%, P = .99) within 90 days in rPCNA patients who received cefazolin versus alternative perioperative antibiotics. CONCLUSIONS: In this series of more than 5,500 patients who had an rPCNA undergoing primary TJA, perioperative prophylaxis with cefazolin resulted in a 0.1% incidence of allergic reactions that were clinically indolent. Cefazolin can be safely administered to most patients, independent of rPCNA severity. LEVEL OF EVIDENCE: III.

Cefazolin as the mainstay for antibiotic prophylaxis in patients with a penicillin allergy in obstetrics and gynecology.

Cefazolin is the most common antibiotic used for prophylaxis in obstetrics and gynecology. Among those with a penicillin allergy, alternative antibiotics are often chosen for prophylaxis, given fears of cross-reactivity between penicillin and cefazolin. Alternative antibiotics in this setting are associated with adverse sequelae, including surgical site infection, induction of bacterial resistance, higher costs to the healthcare system, and possible Clostridium difficile infection. Given the difference in R1 side chains between penicillin and cefazolin, cefazolin use is safe and should be recommended for patients with a penicillin allergy, including those who experience Immunoglobulin E-mediated reactions such as anaphylaxis. Cefazolin should only be avoided in those who experience a history of a severe, life-threatening delayed hypersensitivity reaction manifested as severe cutaneous adverse reactions (Steven-Johnson Syndrome), hepatitis, nephritis, serum sickness, and hemolytic anemia in response to penicillin administration. In addition, >90% of those with a documented penicillin allergy do not have true allergies on skin testing. Increased referral for penicillin allergy testing should be incorporated into routine obstetric care and preoperative assessment to reduce suboptimal antibiotic prophylaxis use. More education is needed among providers surrounding penicillin allergy assessment and cross-reactivity among penicillins and cephalosporins to optimize antibiotic prophylaxis in obstetrics and gynecology.

Cefazolin as a predictor of urinary cephalosporin activity in indicated Enterobacterales.

Traditionally, cephalothin susceptibility results were used to predict the susceptibility of additional cephalosporins; however, in 2013-2014, the Clinical and Laboratory Standards Institute (CLSI) revisited this practice and determined that cefazolin is a more accurate proxy than cephalothin for uncomplicated urinary tract infections (uUTIs). Therefore, a cefazolin surrogacy breakpoint was established to predict the susceptibility of seven oral cephalosporins for Escherichia coli, Klebsiella pneumoniae, and Proteus mirabilis in the context of uUTIs. Clinical microbiology laboratories face several operational challenges when implementing the cefazolin surrogacy breakpoint, which may lead to confusion for the best path forward. Here, we review the historical context and data behind the surrogacy breakpoints, review PK/PD profiles for oral cephalosporins, discuss challenges in deploying the breakpoint, and highlight the limited clinical outcome data in this space.

Ceftriaxone-Induced Encephalopathy in a Patient With Chronic Kidney Disease.

Neurotoxicity is an acknowledged side effect of third and fourth-generation cephalosporins, but its occurrence with ceftriaxone is not widely recognized. This article presents a case involving a 56-year-old woman with multiple comorbidities who sought medical attention after experiencing lipothymia. The initial diagnosis suggested a urinary tract infection with acute kidney failure, leading to the initiation of ceftriaxone and hemodialysis. Subsequently, the patient exhibited a progressive deterioration of her neurological state, characterized by agitation and chorea. Metabolic encephalopathy, seizure/nonconvulsive status epilepticus, and acute central nervous system lesions were considered primary differential diagnoses, all of which were subsequently ruled out through thorough investigations. Days later, a remarkable recovery of the patient's neurological state was observed. A retrospective analysis revealed a correlation between the improvement and the fourth day of antimicrobial suspension. Consequently, a presumptive diagnosis of ceftriaxone-induced encephalopathy was made. This unusual case underscores the importance of recognizing the potential for pharmacological encephalopathy, particularly with ceftriaxone, and emphasizes its reversibility upon discontinuation of the implicated drug. Clinicians should remain vigilant to this uncommon adverse effect, promoting timely intervention and improved patient outcomes.

Wild-Type AmpC Beta-Lactamase-Producing Enterobacterales Are a Risk Factor for Empirical Treatment Failure in Patients with Bloodstream Infection.

Introduction: Beta-lactamases are frequently prescribed for Gram-negative bloodstream infections (BSIs). However, chromosomally encoded AmpC-producing Enterobacterales (AE) could overproduce beta-lactamases when exposed to third-generation cephalosporins (3GCs), with a risk of clinical failure. There are few available in vivo data on the subject. Our goal was to assess the potential role of AE as a predictive factor for clinical failure in patients with BSIs. Materials and Methods: We retrospectively analyzed patients admitted to Cannes hospital between 2021 and 2022 for BSIs due to Enterobacterales. Patient demographics, comorbidities, and main clinical and laboratory parameters during hospitalization were collected. The risk factors for clinical instability after 48 h or death, as well as for ineffective initial empirical therapy, were assessed using univariate and multivariate analyses. Results: From January 2021 to December 2022, 101 subjects were included (mean age 79 years, 60% men, 97% with comorbidities, 17% with healthcare-associated infection, 13% with septic shock, 82% with qPitt severity score < 2, 58% with urinary tract infection, and 18% with AE). Septic shock [adjusted odds ratio (ORadj) = 5.30, 95% confidence interval (CI): 1.47-22.19, p = 0.014] and ineffective initial empirical therapy [ORadj 5.54, 95% CI: 1.95-17.01, p = 0.002] were independent predictive factors for clinical instability or death. Extended-spectrum beta-lactamases [ORadj 9.40, 95% CI: 1.70-62.14, p = 0.012], AE group [ORadj 5.89, 95% CI: 1.70-21.40, p = 0.006], and clinical instability or death [ORadj 4.71, 95% CI: 1.44-17.08, p = 0.012] were independently associated with ineffective empirical therapy. Conclusions: Infection with AE was associated with treatment failure. Empirical therapy may result in failure if restricted to 3GC.

penA profile of Neisseria gonorrhoeae in Guangdong, China: Novel penA alleles are related to decreased susceptibility to ceftriaxone or cefixime.

BACKGROUND: Resistance to extended-spectrum cephalosporins (ESCs) has become a public health concern with the spread of Neisseria gonorrhoeae and increasing antimicrobial resistance. Mutation of penA, encoding penicillin-binding protein 2, represents a mechanism of ESC resistance. This study sought to assess penA alleles and mutations associated with decreased susceptibility (DS) to ESCs in N. gonorrhoeae. MATERIALS AND METHODS: In 2021, 347 gonococci were collected in Guangdong, China. Minimum inhibitory concentations (MICs) of ceftriaxone and cefixime were determined, and whole-genome sequencing and phylogenetic analysis were performed. Multi-locus sequence typing (MLST) and conventional resistance determinants such as penA, mtrR, PonA and PorB were analysed. penA was genotyped and sequence-aligned using PubMLST. RESULTS: Genome-wide phylogenetic analysis revealed that the prevalence of DS to ESCs was highest in Clade 11.1 (100.0%), Clade 2 (66.7%) and Clade 0 (55.7%), and the leading cause was strains with penA-60.001 or new penA alleles in clades. The penA phylogenetic tree is divided into two branches: non-mosaic penA and mosaic penA. The latter contained penA-60.001, penA-10 and penA-34. penA profile analysis indicated that A311V and T483S are closely related to DS to ESCs in mosaic penA. The new alleles NEIS1753_2840 and NEIS1753_2837 are closely related to penA-60.001, with DS to ceftriaxone and cefixime of 100%. NEIS1753_2660, a derivative of penA-10 (A486V), has increased DS to ceftriaxone. NEIS1753_2846, a derivative of penA-34.007 (G546S), has increased DS to cefixime. CONCLUSION: This study identified critical penA alleles related to elevated MICs, and trends of gonococcus-evolved mutated penA associated with DS to ESCs in Guangdong.

Comprehensive stability analysis of 13 ß-lactams and ß-lactamase inhibitors in in vitro media, and novel supplement dosing strategy to mitigate thermal drug degradation.

Non-clinical antibiotic development relies on in vitro susceptibility and infection model studies. Validating the achievement of the targeted drug concentrations is essential to avoid under-estimation of drug effects and over-estimation of resistance emergence. While certain ß-lactams (e.g., imipenem) and ß-lactamase inhibitors (BLIs; clavulanic acid) are believed to be relatively unstable, limited tangible data on their stability in commonly used in vitro media are known. We aimed to determine the thermal stability of 10 ß-lactams and 3 BLIs via LC-MS/MS in cation-adjusted Mueller Hinton broth at 25 and 36°C as well as agar at 4 and 37°C, and in water at -20, 4, and 25°C. Supplement dosing algorithms were developed to achieve broth concentrations close to their target over 24 h. During incubation in broth (pH 7.25)/agar, degradation half-lives were 16.9/21.8 h for imipenem, 20.7/31.6 h for biapenem, 29.0 h for clavulanic acid (studied in broth only), 23.1/71.6 h for cefsulodin, 40.6/57.9 h for doripenem, 46.5/64.6 h for meropenem, 50.8/97.7 h for cefepime, 61.5/99.5 h for piperacillin, and >120 h for all other compounds. Broth stability decreased at higher pH. All drugs were ≥90% stable for 72 h in agar at 4°C. Degradation half-lives in water at 25°C were >200 h for all drugs except imipenem (14.7 h, at 1,000 mg/L) and doripenem (59.5 h). One imipenem supplement dose allowed concentrations to stay within ±31% of their target concentration. This study provides comprehensive stability data on ß-lactams and BLIs in relevant in vitro media using LC-MS/MS. Future studies are warranted applying these data to antimicrobial susceptibility testing and assessing the impact of ß-lactamase-related degradation.

Carbapenem-producing Enterobacteriaceae in mothers and newborns in southeast Gabon, 2022.

Introduction: Infections caused by carbapenemase-producing Enterobacteriaceae (CPE) pose a significant threat, leading to severe morbidity and mortality among newborns. Methods: This study, conducted at Franceville hospital's maternity and neonatology wards from February 22nd to June 20th, 2022, investigated the prevalence of CPE in 197 parturients and 203 newborns. Rectal swabs were taken from parturients before delivery and from newborns 30 minutes after birth. Blood culture samples were collected if signs of infection were observed in newborns during a 28-day follow-up. A total of 152 environmental samples were obtained, comprising 18 from sinks, 14 from incubators, 27 from cradles, 39 from maternal beds, 14 from tables and desks, four from the two baby scales and 36 from bedside furniture. Results: None of the 203 newborns were found to be CPE carriers 30 minutes after delivery. CPE carriage was found in 4.6% of mothers. When comparing colonized and uncolonized parturients, well-established risk factors for CPE carriage, such as recent hospitalization and antibiotic therapy, were more frequently observed among CPE carriers (33.3 vs 10.6% for hospitalization in the past 15 days; 55.5 vs 30.3% for hospitalization during pregnancy, and 55.5 vs 35.1% for antibiotic therapy during pregnancy). Notably, the prevalence of treatment with amoxicillin and clavulanic acid was 44.4% in CPE carriers compared to 17.0% in non-carriers. The incidence density of CPE-associated bloodstream infection was 0.49 per 100 newborns, accounting for a fatal case of CPE-associated bacteremia identified in one of the 203 newborns. Seven environmental samples returned positive for CPE (5 sinks and two pieces of furniture). Whole genome sequencing, performed on the 25 CPE isolates, revealed isolates carrying blaNDM-7 (n=10), blaNDM-5 (n=3), blaOXA181 (n=10), blaOXA48 (n=2) or blaOXA244 (n=1), along with genetic traits associated with the ability to cause severe and difficult-to-treat infections in newborns. Core genome comparison revealed nine CPE belonging to three international high-risk clones: E. coli ST410 (four mothers and a sink), two E. coli ST167 (a mother and a piece of furniture), and K. pneumoniae ST307 (a sink and a piece of furniture), with highly similar genetic backgrounds shared by maternal and environmental isolates, suggesting maternal contamination originating from the environment. Discussion: Our study reveals key findings may guide the implementation of infection control measures to prevent nosocomial infections in newborns: the prevalence of CPE carriage in one out of 20 parturients, an infection occurring in one out of 400 newborns, substantial contamination of the care environment, clinical and environmental CPE isolates possessing genetic traits associated with the ability to cause severe and challenging infections, and clonal relationships between clinical and environmental isolates suggesting CPE spread within the wards, likely contributing to the acquisition and colonization of CPE by parturients during pregnancy.

Prolonged versus intermittent ß-lactam infusion in sepsis: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: The two latest studies on prolonged versus intermittent use of ß-lactam antibiotics in patients with sepsis did not reach consistent conclusions, further contributing to the controversy surrounding the effectiveness of the prolonged ß-lactam antibiotics infusion strategy. We conducted a systemic review and meta-analysis to evaluate the efficacy and safety of prolonged and intermittent ß-lactam infusion in adult patients with sepsis. METHODS: We systematically searched PubMed, EMBASE, and Cochrane Library databases for original randomized controlled trials comparing prolonged and intermittent ß-lactam infusion in sepsis patients. A random-effects model was used to evaluate mortality, clinical success, microbiological success, and adverse events. We also conducted subgroup analyses to explore the impact of various factors on the mortality rates. Relative risk (RR) and corresponding 95% confidence intervals (CIs) were used to calculate the overall effect sizes for dichotomous outcomes. This meta-analysis was registered in PROSPERO (CRD42023463905). RESULTS: We assessed 15 studies involving 2130 patients. In our comprehensive assessment, we found a significant reduction in all-cause mortality (RR, 0.83; 95% CI 0.72-0.97; P = 0.02) and a notable improvement in clinical success (RR, 1.16; 95% CI 1.03-1.31; P = 0.02) in the prolonged infusion group compared to the intermittent infusion group, whereas microbiological success did not yield statistically significant results (RR, 1.10; 95% CI 0.98-1.23; P = 0.11). No significant differences in adverse events were observed between the two groups (RR, 0.91; 95% CI 0.64-1.29; P = 0.60). Additionally, remarkable conclusions were drawn from subgroup analyses including studies with sample sizes exceeding 20 individuals per group (RR, 0.84; 95%CI 0.72-0.98; P = 0.03), research conducted post-2010 (RR, 0.84; 95%CI 0.72-0.98; P = 0.03), cases involving infections predominantly caused by Gram-negative bacteria (RR, 0.81; 95%CI 0.68-0.96; P = 0.02), as well as the administration of a loading dose (RR, 0.84; 95% CI 0.72-0.97; P = 0.02) and the use of penicillin (RR, 0.61; 95% CI 0.38-0.98; P = 0.04). CONCLUSIONS: Compared to intermittent infusion, prolonged infusion of ß-lactam antibiotics significantly decreases all-cause mortality among patients with sepsis and enhances clinical success without increasing adverse events.

Cefdinir vs cephalexin for the treatment of urinary tract infections: A retrospective evaluation.

PURPOSE: Cefdinir and cephalexin are cephalosporin antibiotics commonly used in the treatment of urinary tract infections (UTIs). Their efficacy depends on achieving sufficient time with concentrations exceeding the minimum inhibitory concentration (MIC). Despite being frequently prescribed for UTIs, cefdinir has markedly lower urine penetration compared to cephalexin. It is possible that differences in pharmacokinetics could result in dissimilar efficacy between these agents; however, comparative studies of cephalosporins in UTIs are lacking. METHODS: This was a retrospective comparative study of patients discharged from emergency departments within a community health system with a diagnosis of acute cystitis who were prescribed cefdinir or cephalexin. Treatment failure rates at 7 and 14 days were compared between the 2 agents using a χ2 or Fisher's exact test, as appropriate. RESULTS: There were no differences in overall treatment failure between the cefdinir and cephalexin groups. Treatment failure at 7 days occurred in 11.6% (n = 14) of patients in the cefdinir group and 8.3% (n = 10) of patients in the cephalexin group (P = 0.389). Treatment failure at 14 days was higher for cefdinir at 20.7% (n = 25) than for cephalexin at 11.8% (n = 14), but this difference was not statistically significant (P = 0.053). There were no differences in the rate of treatment failure in subgroup analyses of uncomplicated or complicated UTIs. CONCLUSION: The results of this study suggest that cefdinir and cephalexin have comparable efficacy for the treatment of lower UTIs. While there was a numerically higher rate of treatment failure with cefdinir, there were no significant differences in treatment failure between the agents.

Subacute Neurotoxicity as an Adverse Reaction to Ceftazidime: A Case Report.

Neurotoxicity associated with cephalosporins is an increasingly recognized complication, although among cephalosporins, ceftazidime is rarely reported for such an adverse reaction. Moreover, subacute, rather than acute, presentation of neurotoxicity associated with cephalosporins is rare. A 77-year-old female patient with stage 4 chronic renal disease was admitted due to cellulitis in her right lower limb, multiorgan dysfunction complicated by oliguric acute kidney injury, and a need for hemodialysis via a central venous catheter. On the 13th day after admission, she became febrile, and bacteremia associated with a central venous catheter was identified, which prompted the initiation of empirical antibiotic therapy with vancomycin and ceftazidime. After 13 days of antibiotic therapy with vancomycin and ceftazidime, the patient became confused, with temporal-spatial disorientation and myoclonus, especially in the upper limbs, with worsening renal function. Ceftazidime was discontinued, and the patient's condition improved with complete remission of symptoms on the 8th day after symptom onset. Neurotoxicity associated with ceftazidime is a rare but probably underdiagnosed adverse reaction. It is more frequent in elderly patients with previous neurological dysfunction and end-stage kidney disease and/or acute kidney injury, and it usually manifests soon after starting treatment. Early identification and monitoring of risk factors and symptoms should lead the physician to a rapid withdrawal of the offending drug.