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To evaluate the in vitro activity of ampicillin-sulbactam and cefoperazone-sulbactam against A. baumannii using the broth disk elution testing, a total of 150 A. baumannii isolates were collected from across China between January 2019 and January 2021, including 51 carbapenem-susceptible and 99 carbapenem-resistant isolates. Broth disk elution (BDE) and the broth microdilution (BMD) method were performed for all strains. The concentration range of the BDE was 10/10 µg/mL, 20/20 µg/mL, and 30/30 µg/mL for ampicillin-sulbactam, and 37.5/15 µg/mL, 75/30 µg/mL, 112.5/45 µg/mL, and 150/60 µg/mL for cefoperazone-sulbactam, respectively. Compared with BMD, the BDE results of ampicillin-sulbactam and cefoperazone-sulbactam showed a categorical agreement of 83.3% (125/150) and 95.3% (143/150), with minor errors of 16.7% (25/150) and 4.7% (7/150), respectively. No major error or very major errors were detected. The sensitivity differences by BDE of carbapenem-resistant A. baumannii (CRAb) to different concentrations of ampicillin-sulbactam showed statistically significant (p < 0.017), while those to cefoperazone-sulbactam at 37.5/15 µg/mL, 75/30 µg/mL, and 112.5/45 µg/mL were significant (p < 0.008). However, no significant difference in sensitivity was observed between 112.5/45 µg/mL and 150/60 µg/mL (p > 0.008). In conclusion, the BDE is a reliable and convenient method to detect the in vitro activity of cefoperazone-sulbactam against A. baumannii, and the results could serve as a clinical reference value when deciding whether or not to use high-dose sulbactam for the treatment of A. baumannii infections., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Antibiotics are widely used to treat bacterial infection and reduce the mortality rate, while antibiotic overuse can cause gut microbiota dysbiosis. The impact of antibiotics on gut microbiota is not fully understood. In our study, four commonly used antibiotics (ceftazidime, cefoperazone-sulbactam, imipenem-cilastatin, and moxifloxacin) were given subcutaneously to mice, and their impacts on the gut microbiota composition and serum cytokine levels were evaluated through 16S rRNA analysis and a multiplex immunoassay. Antibiotic treatment markedly reduced gut microbiota diversity and changed gut microbiota composition. Antibiotic treatment significantly increased and decreased the abundance of Firmicutes and Bacteroidota, respectively. The antibiotic treatments increased the abundance of opportunistic pathogens such as Enterococcus and decreased that of Lachnospiraceae and Muribaculaceae . For moxifloxacin, the significantly high abundance of Enterococcus and Klebsiella was observed after 14 and 21 days of treatment. However, a relatively low abundance of opportunistic pathogens was found after 14 days of imipenem-cilastatin treatment. Additionally, the serum levels of various pro-inflammatory cytokines, such as IL-1β, IL-12 (p70), and IL-17, significantly increased after 21 days of antibiotic treatments. Overall, these results provide a guide for rational use of antibiotics in clinical settings: short-term use of moxifloxacin is recommended with regard to gut microbiota health, and the 14-day use of imipenem-cilastatin may have a less severe impact than other antibiotics.IMPORTANCEAntibiotic treatments are directly associated with changes in gut microbiota and are effective against both pathogens and beneficial bacteria. Gut microbiota dysbiosis induced by antibiotic treatment could increase the risk of some diseases. Therefore, an adequate understanding of gut microbiota changes after antibiotic use is crucial. In this study, we investigated the effects of continuous treatment with antibiotics on gut microbiota, serum cytokines, and intestinal inflammatory response. Our results suggest that short-term use of moxifloxacin is recommended, and the 14-day use of imipenem-cilastatin may have a less severe effect on gut microbiota health than cefoperazone-sulbactam. These results provide useful guidance on the rational use of antibiotics with regard to gut microbiota health., Competing Interests: The authors declare no conflict of interest.

Morganella morganii is a Gram-negative bacterial pathogen that causes bacteremia, urinary tract infections, intra-abdominal infections, chorioamnionitis, neonatal sepsis, and newborn meningitis. To control this bacterial pathogen a total of 3565 putative proteins targets in Morganella morganii were screened using comparative subtractive analysis of biochemical pathways annotated by the KEGG that did not share any similarities with human proteins. One of the targets, D-alanyl-D-alanine carboxypeptidase DacB [ Morganella ] was observed to be implicated in the majority of cell wall synthesis pathways, leading to its selection as a novel pharmacological target. The drug that interacted optimally with the identified target was observed to be Cefoperazone (DB01329) with the estimated free energy of binding -8.9 Kcal/mol. During molecular dynamics simulations; it was observed that DB01328-2exb and DB01329-2exb complexes showed similar values as the control FMX-2exb complex near 0.2 nm with better stability. Furthermore, MMPBSA total free energy calculation showed better binding energy than the control complex for DB01329-2exb interaction i.e. -31.50 (±0.93) kcal/mol. Our presented research suggested that D-alanyl-D-alanine carboxypeptidase DacB could be a therapeutic target and cefoperazone could be a promising ligand to inhibit the D-alanyl-D-alanine carboxypeptidase DacB protein of Morganella morganii . To identify prospective therapeutic and vaccine targets in Morganella morganii , this is the first computational and subtractive genomics investigation of various metabolic pathways exploring other therapeutic targets of Morganella morganii. In vitro/in vivo experimental validation of the identified target D-alanyl-D-alanine carboxypeptidase and the design of its inhibitors is suggested to figure out the best dose, the drug's effectiveness, and its toxicity.Communicated by Ramaswamy H. Sarma.

Background: To establish a method to induce Campylobacter jejuni colonization in the intestines of C57BL/6 mice through antibiotic-induced microbiome depletion., Results: Fifty-four female C57BL/6 mice were divided into the normal, control, and experimental groups. The experimental group was administered intragastric cefoperazone sodium and sulbactam sodium (50 mg/mL) for 2 days; then, the experimental and control mice were intragastrically administered 200 µL C. jejuni, which was repeated once more after 2 days. Animal feces were collected, and the HipO gene of C. jejuni was detected using TaqMan qPCR from day 1 to day 14 after modeling completion. Immunofluorescence was used to detect intestinal C. jejuni colonization on day 14, and pathological changes were observed using hematoxylin and eosin staining. Additionally, 16S rDNA analyses of the intestinal contents were conducted on day 14. In the experimental group, C. jejuni was detected in the feces from days 1 to 14 on TaqMan qPCR, and immunofluorescence-labeled C. jejuni were visibly discernable in the intestinal lumen. The intestinal mucosa was generally intact and showed no significant inflammatory-cell infiltration. Diversity analysis of the colonic microbiota showed significant inter-group differences. In the experimental group, the composition of the colonic microbiota differed from that in the other 2 groups at the phylum level, and was characterized by a higher proportion of Bacteroidetes and a lower proportion of Firmicutes., Conclusions: Microbiome depletion induced by cefoperazone sodium and sulbactam sodium could promote long-term colonization of C. jejuni in the intestines of mice., (© 2024. The Author(s).)

Aims: Drug repurposing is an attractive strategy to control biofilm-related infectious diseases. In this study, two drugs (montelukast and cefoperazone) with well-established therapeutic applications were tested on Pseudomonas aeruginosa quorum sensing (QS) inhibition and biofilm control., Methods and Results: The activity of montelukast and cefoperazone was evaluated for Pqs signal inhibition, pyocyanin synthesis, and prevention and eradication of Ps. aeruginosa biofilms. Cefoperazone inhibited the Pqs system by hindering the production of the autoinducer molecules 2-heptyl-4-hydroxyquinoline (HHQ) and 2-heptyl-3-hydroxy-4(1H)-quinolone (the Pseudomonas quinolone signal or PQS), corroborating in silico results. Pseudomonas aeruginosa pyocyanin production was reduced by 50%. The combination of the antibiotics cefoperazone and ciprofloxacin was synergistic for Ps. aeruginosa biofilm control. On the other hand, montelukast had no relevant effects on the inhibition of the Pqs system and against Ps. aeruginosa biofilm., Conclusion: This study provides for the first time strong evidence that cefoperazone interacts with the Pqs system, hindering the formation of the autoinducer molecules HHQ and PQS, reducing Ps. aeruginosa pathogenicity and virulence. Cefoperazone demonstrated a potential to be used in combination with less effective antibiotics (e.g. ciprofloxacin) to potentiate the biofilm control action., (© The Author(s) 2024. Published by Oxford University Press on behalf of Applied Microbiology International.)

Effective treatment of gonorrhea is threatened by the increasing prevalence of Neisseria gonorrhoeae strains resistant to the extended-spectrum cephalosporins (ESCs). Recently, we demonstrated the promise of the third-generation cephalosporin cefoperazone as an antigonococcal agent due to its rapid second-order rate of acylation against penicillin-binding protein 2 (PBP2) from the ESC-resistant strain H041 and robust antimicrobial activity against H041. Noting the presence of a ureido moiety in cefoperazone, we evaluated a subset of structurally similar ureido β-lactams, including piperacillin, azlocillin, and mezlocillin, for activity against PBP2 from H041 using biochemical and structural analyses. We found that the ureidopenicillin piperacillin has a second-order rate of acylation against PBP2 that is 12-fold higher than cefoperazone and 85-fold higher than ceftriaxone and a lower MIC against H041 than ceftriaxone. Surprisingly, the affinity of ureidopenicillins for PBP2 is minimal, indicating that their inhibitory potency is due to a higher rate of the acylation step of the reaction compared to cephalosporins. Enhanced acylation results from the combination of a penam scaffold with a 2,3-dioxopiperazine-containing R 1 group. Crystal structures show that the ureido β-lactams overcome the effects of resistance mutations present in PBP2 from H041 by eliciting conformational changes that are hindered when PBP2 interacts with the weaker inhibitor ceftriaxone. Overall, our results support the potential of piperacillin as a treatment for gonorrhea and provide a framework for the future design of β-lactams with improved activity against ESC-resistant N. gonorrhoeae .

Antibiotic resistance is a recognized and concerning public health issue. Gram-negative bacilli, such as Pseudomonas aeruginosa ( P. aeruginosa ), are notorious for their rapid development of drug resistance, leading to treatment failures. TanReQing injection (TRQ) was chosen to explore its pharmacological mechanisms against clinical multidrug-resistant P. aeruginosa (MDR-PA), given its antibacterial and anti-inflammatory properties. We revealed the expression of proteins and genes in P. aeruginosa after co-culture with TRQ. This study developed an assessment method to evaluate clinical resistance of P. aeruginosa using MALDI-TOF MS identification and Biotyper database searching techniques. Additionally, it combined MIC determination to investigate changes in MDR-PA treated by TRQ. TRQ effectively reduced the MICs of ceftazidime and cefoperazone and enhanced the confidence scores of MDR-PA as identified by mass spectrometry. Using this evaluation method, the fingerprints of standard P. aeruginosa and MDR-PA were compared, and the characteristic peptide sequence (Seq-PA No. 1) associated with flagellum was found. The phenotypic experiments were conducted to confirm the effect of TRQ on the motility and adhesion of P. aeruginosa . A combination of co-immunoprecipitation and proteome analysis was employed, and 16 proteins were significantly differentially expressed and identified as potential candidates for investigating the mechanism of inhibiting resistance in P. aeruginosa treated by TRQ. The candidates were verified by quantitative real-time PCR analysis, and TRQ may affect these core proteins (MexA, MexB, OprM, OprF, OTCase, IDH, and ASL) that influence resistance of P. aeruginosa . The combination of multiple methods helps elucidate the synergistic mechanism of TRQ in overcoming resistance of P. aeruginosa .IMPORTANCE Pseudomonas aeruginosa is an opportunistic pathogen closely associated with various life-threatening acute and chronic infections. The presence of antimicrobial resistance and multidrug resistance in P. aeruginosa infections significantly complicates antibiotic treatment. The expression of β-lactamase, efflux systems such as MexAB-OprM, and outer membrane permeability are considered to have the greatest impact on the sensitivity of P. aeruginosa . The study used a method to assess the clinical resistance of P. aeruginosa using matrix-assisted laser desorption ionization time of flight mass spectrometry identification and Biotyper database search techniques. TanReQing injection (TRQ) effectively reduced the MICs of ceftazidime and cefoperazone in multidrug-resistant P. aeruginosa (MDR-PA) and improved the confidence scores for co-cultured MDR-PA. The study found a characteristic peptide sequence for distinguishing whether P. aeruginosa is resistant. Through co-immunoprecipitation and proteome analysis, we explored the mechanism of TRQ overcoming resistance of P. aeruginosa ., Competing Interests: The authors declare no conflict of interest.

Background: The drug resistance of carbapenem-resistant Acinetobacter baumannii bloodstream infections (CRAB-BSI), especially hospital-acquired infections, has promoted their rapid and vast spread. It is necessary to use reliable methods to establish better prediction models. According to Cox proportional hazards regression, a nomogram was established., Methods: A retrospective cohort study among patients who were diagnosed with CRAB-BSI was performed from January 2020 to December 2022. Univariate and multivariate Cox proportional hazards regression analyses were used to determine independent prognostic factors regarding CRAB-BSI. Then, nomograms were used to calculate the area under the curve (AUC), C-index, and calibration curve to determine the predictive accuracy and dis-criminability. Decision curve analysis (DCA) was employed to further confirm the clinical effectiveness of the nomogram., Results: A total of 98 cases were included in the comparison between the 28-day mortality group consisting of 32 patients and the 28-day survival group with 66 patients. The use of cefoperazone-sulbactam was significantly higher among patients who survived than among those who died. Univariable analysis revealed that factors such as primary diagnosis, time to inadequate antimicrobial therapy, and high serum creatinine and procalcitonin (PCT) levels were more prevalent in the mortality group. However, only primary diagnosis, time to inadequate antimicrobial therapy, and high PCT levels emerged as statistically significant risk factors for death in multivariate analysis and were used to construct the nomogram. The nomogram validation exhibited excellent performance., Conclusions: The nomogram was sufficiently accurate to predict the risk and prognostic factors of CRAB-BSI, allowing for individualized clinical decisions for future clinical work. The cefoperazone-sulbactam did have an effect, but more studies are needed to interpret it.

The interaction of lysozyme with cefoperazone was studied by means of spectroscopic and computational approaches. The change in the UV-visible spectrum of lysozyme in presence of cefoperazone was an indication of the complex formation between them. Fluorescence spectroscopy suggested that there was a fair interaction between the protein and drug which was taken place via dynamic quenching mechanism and the binding ratio was approximately 1:1. The binding was energetically feasible and principally supported by the hydrophobic forces. CD spectroscopic studies have shown that cefoperazone induced the secondary structure of lysozyme by increasing the α-helical contents of the latter. In silico studies revealed that the large nonpolar cavity was the preferred binding site of cefoperazone within lysozyme and the interaction was taken place mainly through hydrophobic forces with small involvement of hydrogen bonding and electrostatic interactions which is in good agreement with the experimental analyses. Effect of paracetamol was also seen on the binding and it was found that paracetamol had a negative influence on the binding between cefoperazone and lysozyme., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Candida auris , an emerging multi-drug resistant fungal pathogen, causes invasive infections in humans. The factors regulating the colonization of C. auris in host niches are not well understood. In this study, we examined the effect of antibiotic-induced gut dysbiosis on C. auris intestinal colonization, dissemination, microbiome composition and the mucosal immune response. Our results indicate that mice treated with cefoperazone alone had a significant increase in C. auris intestinal colonization compared to untreated control groups. A significant increase in the dissemination of C. auris from the intestine to internal organs was observed in antibiotic-treated immunosuppressed mice. Intestinal colonization of C. auris alters the microbiome composition of antibiotic-treated mice. Relative abundance of firmicutes members mainly Clostridiales and Paenibacillus were considerably increased in the cefoperazone-treated mice infected with C. auris compared to cefoperazone-treated uninfected mice. Next, we examined the mucosal immune response of C. auris infected mice and compared the results with Candida albicans infection. The number of CD11b+ CX3CR1+ macrophages was significantly decreased in the intestine of C. auris infected mice when compared to C. albicans infection. On the other hand, both C. auris and C. albicans infected mice had a comparable increase of the number of Th17 and Th22 cells in the intestine. A significant increase in Candida -specific IgA was observed in the serum of C. auris but not in the C. albicans infected mice. Taken together, treatment with broad-spectrum antibiotic increased the colonization and dissemination of C. auris from the intestine. Furthermore, findings from this study for the first time revealed the microbiome composition, innate and adaptive cellular immune response to intestinal infection with C. auris ., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Das, HogenEsch and Thangamani.)

Objective: to characterize the antibiotic resistance of gram-positive cocci strains isolated from the prostate secretion in men with chronic bacterial prostatitis at the level of phenotype and genotype., Materials and Methods: Bacteria were isolated from the prostate secretion of men of reproductive age (20-45 years) with chronic bacterial prostatitis by conventional bacteriological method. The type of microorganisms was determined by MALDI-TOF mass spectrometry. Resistance to 16 antibiotics of 31 strains of E. faecalis and 91 cultures of coagulase-negative staphylococci (CoNS) was determined by the disk diffusion method. Antibiotic resistance genes (mecA; blaZ; aac(6)- aph (2); ant (4)-Ia; aph (3)-IIIa; gyrA, grlA) were detected using polymerase chain reaction (PCR ) using selected primers., Results: A high resistance of enterococci to antibacterial drugs was revealed: fluoroquinolones, carbapenens, cephalosporins (with the exception of cefoperazone), gentamicin and oxacillin. It has been established that CoNS are characterized by variable antibiotic resistance, while: isolates of S. epidermidis and S. haemolyticus are resistant to all studied fluoroquinolones and carbapenems; S. warneri to carbapenems and the vast majority of studied cephalosporins; S. saprophyticus - to aminoglycosides. Amoxiclav and cefoperazone are characterized by the highest activity against clinical isolates. Using PCR, the presence of genetic determinants of resistance to aminoglycosides and -lactams was established in the isolates, with a predominance of the studied genes in CoNS., Conclusion: For effective antibiotic therapy in chronic bacterial prostatitis, it is necessary to conduct regional monitoring of the resistance of microorganisms to antibacterial drugs.

Background: Ventilator-associated pneumonia (VAP) is one of the major hospital-acquired infections and the emergence of bacterial resistance is common among patients in the intensive care units (ICUs). The aim of the study is to identify the common bacterial pathogen isolated from an endotracheal (ET) aspirate and its antibiotic susceptibility pattern., Materials and Methods: A prospective analytical study was carried out in a tertiary care hospital for a period of 1 year. All ET aspirate sample sent to the microbiology laboratory was processed and identified by standard biochemical tests and antibiotic sensitivity was by disk diffusion method as per Clinical and Laboratory Standards Institute (CLSI) guidelines., Results: Of the total 217 samples studied, 85 (39.17.1%) were culture sterile and 132 (60.82%) showed culture positive. Among 132 isolates, the predominant organism was Acinetobacter baumannii (36.36%) followed by Klebsiella pneumoniae (24.24%) and Pseudomonas aeruginosa (20.45%). We have reported a higher percentage of resistance among the isolated gram-negative bacilli to carbapenems, aminoglycosides, and third-generation cephalosporins, with increased sensitivity to piperacillin-tazobactam and cefoperazone-sulbactam., Conclusion: In our study, A. baumannii was the predominantly isolated gram-negative bacilli followed by K. pneumoniae and P. aeruginosa. One of the rising concerns to hospital-acquired respiratory pathogens is the surge of multidrug resistance patterns. Hence, strict adherence to antibiotic policy and appropriate use according to the guidelines will save the use of drugs in the future in life-threatening conditions., (© Journal of the Association of Physicians of India 2011.)

The aim of this study was to determine the resistance mechanism of Pseudomonas aeruginosa to cefoperazone sodium/sulbactam sodium. We retrospectively analyzed the drug resistance of P.a isolated at the First Affiliated Hospital of Guangxi Medical University. Drug-resistant P.a strains were constructed, then wild-type (WT) and drug-resistant (DR) strains were compared using protein and gene microarrays to determine differences between DR and WT strains. The resistance rates of P. aeruginosa during 2013, 2014 and 2015 were 21.2%, 21.4%, and 24.6% respectively. Among 242 protein peaks of WT and DR bacteriophage proteins, 41 were differentially expressed between the two groups. The expression of 26 and 15 proteins were respectively upregulated and downregulated in the DR compared with the WT group. Gene microarray results revealed 679 mutant loci in the DR group, of which 42 with the top 50 Q values were found in the NCBI database. The rate of P.a resistance to cefoperazone sodium/sulbactam sodium remained high between 2013 and 2015. The numbers of different proteins and genetic variations in the DR strains suggested that the resistance mechanism of P.a to cefoperazone sodium/sulbactam sodium involves multiple genes and proteins that might be key to controlling P.a resistance to cefoperazone sodium/sulbactam sodium.

Cefoperazone-sulbactam (SCF)-resistant Pseudomonas aeruginosa poses a big challenge in the use of SCF to treat infection caused by the pathogen. We have recently shown exogenous nitrite-enabled killing of naturally and artificially evolved Pseudomonas aeruginosa strains (AP-R CLIN-EVO and AP-R LAB-EVO , respectively) by SCF. However, the underlying mechanism is unknown. Here, reprogramming metabolomics was adopted to investigate how nitrite enhanced the SCF-mediated killing efficacy. Nitrite-reprogrammed metabolome displayed an activated pyruvate cycle (P cycle), which was confirmed by elevated activity of pyruvate dehydrogenase (PDH), α-ketoglutarate dehydrogenase, succinate dehydrogenase, and malate dehydrogenase. The activated P cycle provided NADH for the electron transport chain and thereby increased reactive oxygen species (ROS), which potentiated SCF to kill AP-R CLIN-EVO and AP-R LAB-EVO . The nitrite-enabled killing of AP-R CLIN-EVO and AP-R LAB-EVO by SCF was inhibited by PDH inhibitor furfural and ROS scavenger N-Acetyl-L-cysteine but promoted by ROS promoter Fe 3+ . SCF alone could not induce ROS, but SCF-mediated killing efficacy was enhanced by ROS. In addition, the present study demonstrated that nitrite repressed antioxidants, which were partly responsible for the elevated ROS. These results reveal a nitrite-reprogrammed metabolome mechanism by which AP-R CLIN-EVO and AP-R LAB-EVO sensitivity to SCF is elevated. IMPORTANCE Antibiotic-resistant Pseudomonas aeruginosa has become a real concern in hospital-acquired infections, especially in critically ill and immunocompromised patients. Understanding antibiotic resistance mechanisms and developing novel control measures are highly appreciated. We have recently shown that a reduced nitrite-dependent NO biosynthesis contributes to cefoperazone-sulbactam (SCF) resistance, which is reverted by exogenous nitrite, in both naturally and artificially evolved P. aeruginosa strains (AP-R CLIN-EVO and AP-R LAB-EVO , respectively). However, the mechanism is unknown. The present study reports that the nitrite-enabled killing of AP-R CLIN-EVO and AP-R LAB-EVO by SCF is attributed to the promoted production of reactive oxygen species (ROS). Nitrite activates the pyruvate cycle to generate NADH for the electron transport chain, which in turn promotes ROS generation. Nitrite-potentiated SCF-mediated killing is decreased by pyruvate dehydrogenase inhibitor furfural and ROS scavenger N-Acetyl-L-cysteine but increased by ROS promoter Fe 3+ . Furthermore, SCF-mediated killing is promoted by H 2 O 2 in a dose-dependent manner. In addition, the combination of nitrite and H 2 O 2 greatly enhances SCF-mediated killing. These results not only disclose a nitrite-ROS-potentiated SCF-mediated killing, but also show SCF-mediated killing is dependent upon ROS.

Fecal communities transplanted into individuals can eliminate recurrent Clostridioides difficile infection (CDI) with high efficacy. However, this treatment is only used once CDI becomes resistant to antibiotics or has recurred multiple times. We sought to investigate whether a fecal community transplant (FCT) pretreatment could be used to prevent CDI altogether. We treated male C57BL/6 mice with either clindamycin, cefoperazone, or streptomycin and then inoculated them with the microbial community from untreated mice before challenge with C. difficile. We measured colonization and sequenced the V4 region of the 16S rRNA gene to understand the dynamics of the murine fecal community in response to the FCT and C. difficile challenge. Clindamycin-treated mice became colonized with C. difficile but cleared it naturally and did not benefit from the FCT. Cefoperazone-treated mice became colonized by C. difficile, but the FCT enabled clearance of C. difficile. In streptomycin-treated mice, the FCT was able to prevent C. difficile from colonizing. We then diluted the FCT and repeated the experiments. Cefoperazone-treated mice no longer cleared C. difficile. However, streptomycin-treated mice colonized with 1:10 2 dilutions resisted C. difficile colonization. Streptomycin-treated mice that received an FCT diluted 1:10 3 became colonized with C. difficile but later cleared the infection. In streptomycin-treated mice, inhibition of C. difficile was associated with increased relative abundance of a group of bacteria related to Porphyromonadaceae and Lachnospiraceae . These data demonstrate that C. difficile colonization resistance can be restored to a susceptible community with an FCT as long as it complements the missing populations. IMPORTANCE Antibiotic use, ubiquitous with the health care environment, is a major risk factor for Clostridioides difficile infection (CDI), the most common nosocomial infection. When C. difficile becomes resistant to antibiotics, a fecal microbiota transplant from a healthy individual can effectively restore the gut bacterial community and eliminate the infection. While this relationship between the gut bacteria and CDI is well established, there are no therapies to treat a perturbed gut community to prevent CDI. This study explored the potential of restoring colonization resistance to antibiotic-induced susceptible gut communities. We described the effect that gut bacterial community variation has on the effectiveness of a fecal community transplant for inhibiting CDI. These data demonstrated that communities susceptible to CDI can be supplemented with fecal communities but that the effectiveness depended on the structure of the community following the perturbation. Thus, a reduced bacterial community may be able to recover colonization resistance in patients treated with antibiotics.

We evaluated the in vitro activity of eravacycline and cefoperazone/sulbactam against 42 XDR and 58 PDR Acinetobacter baumannii isolates from blood and bronchoalveolar infections. The minimum and maximum MICs for eravacycline were 0.125 and 4 mg/L, respectively. The MIC50 was 2 mg/L and the MIC90 was 3 mg/L. The minimum and maximum MICs for cefoperazone/sulbactam were 24 and >256 mg/L, respectively. The MIC50 and MIC90 were both >256 mg/L. These novel agents were not adequate for the treatment of A. baumannii infections in our hospital and we recommend that mi- crobiology laboratories perform their own evaluations before including them in clinical practice.

What Is Known and Objective: Sulbactam and sulbactam-containing β-lactam antibiotics are often used in the treatment of Acinetobacter baumannii. We aimed to further examine the clinical efficacy of a cefoperazone/sulbactam anti-infective regimen in multidrug-resistant A. baumannii (MDRAB) lung infections., Methods: We conducted a retrospective analysis among patients with MDRAB lung infection and complete data who were treated at the geriatric intensive care unit of Jiangsu Province Hospital from January 2018 to December 2020. We collected general information, including age, sex, APACHE II score, anti-infective course, comorbid infections in other sites, other pathogens, cefoperazone/sulbactam regimen and concomitant medications, and adverse reactions. We used microbiological changes before and after treatment to assess microbiological efficacy, defined as microbial eradication and reduction., Results and Discussion: 121 patients were included, among which 96 (79.34%) were men and 25 (20.66%) were women. The median age was 76 (interquartile range [IQR] 62.5-83) years, median APACHE II score was 22 (IQR 19-26), and median treatment course was 8 (IQR 5-12.5) days. Among these patients, tigecycline was concomitantly used in 52 patients and the sulbactam dose was increased to 4 g and above in 27 patients. The microbiological efficacy of conventional cefoperazone/sulbactam with/without tigecycline in MDRAB decreased with each consecutive year and a reduction in efficacy was linearly correlated with year, which was both statistically significant (p = 0.039, 0.030, respectively). In 2020, the microbiological efficacy of a higher sulbactam dose combined with tigecycline was 75%, which was a significant improvement over the conventional dose (p = 0.028). The 3-year data showed that the microbiological efficacy of conventional cefoperazone/sulbactam 3 g eight hourly (q8h) without tigecycline was 32% and efficacy increased to 57.9% when the sulbactam dose was increased. Hence, the increased sulbactam dose significantly improved efficacy in MDRAB lung infection (p = 0.049). Different doses of sulbactam combined with tigecycline increased the microbiological efficacy of MDRAB but the differences were not statistically significant., What Is New and Conclusion: A cefoperazone/sulbactam-based anti-infective regimen showed some efficacy in MDRAB lung infection, but the microbiological efficacy of a cefoperazone/sulbactam 3 g q8h regimen decreased over time. Increasing the sulbactam dose to 4 g or more can improve efficacy. Minimum inhibitory concentration (MIC)-guided personalized medicine may be a future research direction., (© 2022 John Wiley & Sons Ltd.)

Cefoperazone/sulbactam (CSL) and piperacillin/tazobactam (TZP) are commonly used in clinical practice in China because of their excellent antimicrobial activity. CSL and TZP-nonsusceptible Enterobacteriaceae are typically resistant to extended-spectrum cephalosporins such as ceftriaxone (CRO). However, 11 nonrepetitive Enterobacteriaceae strains, which were resistant to CSL and TZP yet susceptible to CRO, were collected from January to December 2020. Antibiotic susceptibility tests and whole-genome sequencing were conducted to elucidate the mechanism for this rare phenotype. Antibiotic susceptibility tests showed that all isolates were amoxicillin/clavulanic-acid resistant and sensitive to ceftazidime, cefepime, cefepime/tazobactam, cefepime/zidebactam, ceftazidime/avibactam, and ceftolozane/tazobactam. Whole-genome sequencing revealed three of seven Klebsiella pneumoniae strains harbored bla SHV-1 only, and four harbored bla SHV-1 and bla TEM-1B . Two Escherichia coli strains carried bla TEM-1B only, while two Klebsiella oxytoca isolates harbored bla OXY-1-3 and bla OXY-1-1 , respectively. No mutation in the β-lactamase gene and promoter sequence was found. Outer membrane protein (Omp) gene detection revealed that numerous missense mutations of OmpK36 and OmpK37 were found in all strains of K. pneumoniae . Numerous missense mutations of OmpK36 and OmpK35 and OmpK37 deficiency were found in one K. oxytoca strain, and no OmpK gene was found in the other. No Omp mutations were found in E. coli isolates. These results indicated that narrow spectrum β-lactamases, TEM-1, SHV-1, and OXY-1, alone or in combination with Omp mutation, contributed to the resistance to CSL and TZP in CRO-susceptible Enterobacteriaceae . Antibiotic susceptibility tests Antibiotics Breakpoint, (μg/ml) Klebsiella pneumoniae Escherichia cou Klebriehd axyoca E1 E3 E4 E7 E9 E10 E11 E6 E8 E2 E5 CRO ≤1≥4 ≤0.5 ≤0.5 ≤0.5 ≤0.5 1 ≤0.5 1 ≤0.5 ≤0.5 1 1 CAZ 4 ≥16 1 2 1 4 4 4 4 2 4 1 1 FEP ≤2 216 1 1 0.25 1 2 2 2 0.5 2 1 1 AMC ≤8 ≥32 ≥128 ≥128 ≥128 ≥128 ≥128 ≥128 ≥128 ≥128 ≥128 ≥128 ≥128 CSL ≤16 ≥64 64 64 64 64 ≥128 128 ≥128 64 128 128 ≥128 TZP ≤16 ≥128 ≥256 ≥256 ≥256 ≥256 2256 2256 ≥256 ≥256 ≥256 ≥256 ≥256 FPT ≤2 ≥16 1 0.5 0.06 0.125 2 1 2 0.25 1 0.125 0.25 FPZ ≤2 216 0.25 0.25 0.06 0.125 0.25 0.25 1 0.125 0.25 0.125 0.125 CZA ≤8 216 1 0.5 0.25 0.25 1 0.25 1 0.5 0.5 0.5 0.25 CZT ≤2 28 2 1 0.5 1 2 2 2 1 1 2 2 CROceftriaxone, CAZceftazidime, FEPcefepime, AMC:amoxicillin clavulanic-acid, CSLcefoperazone/sulbactam, TZP:piperadllin/tazobactam, FPT:cefepime tazobactam, FPZ:cefepime/zidebactam, CZA:ceftazidime/avibactam, CZTceftolozane/tazobactam Gene sequencing results Number Strain ST p-Lactamase gene Promoter sequence mutation Omp mutation El Kpn 45 blaSHV-1, blaTEM-lB none OmpK36, OmpK3 7 E3 Kpn 45 blaSHV-1, blaTEM-lB none OmpK36. OmpK3 7 E4 Kpn 2854 blaSHV-1 none OmpK36, OmpK3 7 E7 Kpn 2358 blaSHV-1 - blaTEM-lB none OmpK36, OmpK3 7 E9 Kpn 2358 blaSHV-1. blaTEM-lB none OmpK36. OmpK3 7 E10 Kpn 18 9 blaSHV-1 none OmpK36. OmpK3 7 Ell Kpn 45 blaSHV-1 none OmpK36, OmpK3 7 E6 Eco 88 blaTEM-lB none none ES Eco 409 blaTEM-1B none none E2 Kox 194 blaOXY-1-3 none OmpK36 mutations. OmpK35 and OmpK 37 deficiency E5 Kox 11 blaOXY-1-1 none no OmpK (OmpK3 5, OmpK36 and OmpK37) gene found ., (© 2022 Fengzhen Yang et al., published by Sciendo.)

Pediatric sepsis syndrome is one of the most common reasons for pediatric intensive care unit hospitalization (PICU). Cefoperazone/sulbactam is a time-dependent beta-lactamase inhibitor combination which has been widely used in the treatment of sepsis. But the pharmacokinetic (PK) and pharmacodynamic (PD) data of cefoperazone/sulbactam are unknown in children with sepsis. The present work aimed to determine whether the usual dosing regimens of cefoperazone/sulbactam (1 hour infusion, 50 mg kg -1 , every 12 hours) were suitable for these patients in PICU. A total of fourteen patients were enrolled and the PK parameters were estimated by non-compartmental analysis using WinNonlin software. The t 1/2 and AUC 0-12 of cefoperazone and sulbactam were 3.60 and 1.77 h, and 900.97 and 67.68 h μg mL -1 , respectively. The Vd and CL of cefoperazone and sulbactam were 1.65 L and 5.16 L, and 17.41 mL min -1 and 122.62 mL min -1 , respectively. The probability of target attainments (PTAs) of cefoperazone at different minimum inhibitory concentrations (MICs) based on the percentage time that concentrations exceed the minimum inhibitory concentration (% T > MIC) value were performed by Monte Carlo simulation and PTA was >90% at MICs ≤16 μg mL -1 . The PK/PD profile of dosing regimens tested will assist in selecting the appropriate cefoperazone/sulbactam regimens for these patients. At a target of 80% T > MIC, the usual dosing regimens can provide good coverage for pathogens with MICs of ≤32 μg mL -1 . The ratio between cefoperazone and sulbactam at 1 : 1 may be more suitable in pediatric sepsis. Individual dose and therapeutic drug monitoring in clinical practice will help achieve the best therapeutic effect while minimizing toxicity.

To provide direction for clinical application and pharmaceutical exploitation, the in vitro activity of sulbactam compounds and PIP/TAZ 8 : 1 against clinical isolates of Gram-negative bacteria (GNB, n = 976) was evaluated according to Clinical and Laboratory Standards Institute (CLSI) 2019. By minimal inhibitory concentrations (MICs), the resistance rate of all GNB to AMP/SBT 2 : 1 (56.9-100%) was significantly higher than other drugs, except the resistance rate of Acinetobacter baumannii ( Aba , n = 204) to piperacillin/tazobactam (PIP/TAZ 8 : 1, 78.4%) which was close to it (76.5%). Additionally, the resistance rate of Aba to other compounds except AMP/SBT 2 : 1 differed greatly, but that of Klebsiella pneumonia ( Kpn , n = 205) varied rarely. In addition, Escherichia coli ( Eco , n = 204) and Kpn demonstrated low and high resistance rates, respectively. Compared with cefoperazone/sulbactam (CPZ/SBT 2 : 1), PIP/TAZ 8 : 1 had advantage in anti- Eco (RR = 0.5and OR = 2.17) and anti- Kpn activity (RR = 0.88and OR = 1.27), while its activity against Pseudomonas aeruginosa ( Pae : n = 194, RR = 0.91, and OR = 1.12), Aba (RR = 1.31 and OR = 0.41), and other Enterobacteriaceae (other Ebc : n = 169, RR = 1.40, and OR = 0.62) was not better than CPZ/SBT 2 : 1. Although it had advantage against Eco (RR = 0.60 and OR = 1.78), Pae (RR = 0.67 and OR = 1.63), and Aba (RR = 0.70 and OR = 2.05), the inhibition effect of piperacillin/sulbactam (PIP/SBT 2 : 1) against Kpn (RR = 0.94 and OR = 1.12) and other Ebc was just similar with CPZ/SBT 2 : 1 (RR = 0.93 and OR = 1.10). Furthermore, the anti- Eco (RR = 0.70 and OR = 1.50), anti- Kpn (RR = 0.89 and OR = 1.24), and anti- Pae (RR = 0.74 and OR = 1.46) activities of ceftazidime/sulbactam (CAZ/SBT 1 : 1) had a weak advantage, while its activity against Aba (RR = 0.94 and OR = 1.15) and other Ebc (RR = 0.79 and OR = 1.36) was just close to CPZ/SBT 2 : 1. Moreover, the inhibitory effect of PIP/SBT 1 : 1 against all tested clinical species was more active than CPZ/SBT 2 : 1, while that of CAZ/SBT 2 : 1 against all species of bacteria analyzed was weaker than the controls., Competing Interests: The authors declared no conflict of interest., (Copyright © 2021 Shunian Xiao et al.)

The last decade has witnessed a massive increase in the rate of mortalities caused by multidrug-resistant Pseudomonas aeruginosa . Therefore, developing new strategies to control virulence factors and pathogenicity has received much attention. One of these strategies is quorum sensing inhibition (QSI) which was developed to control Pseudomonas infection. This study aims to validate the effect of one of the most used β-lactam antibiotics; cefoperazone (CFP) and its metallic-derivatives on quorum sensing (QS) and virulence factors of P. aeruginosa. Assessment of quorum sensing inhibitory activity of CFP, cefoperazone Iron complex (CFPF) and cefoperazone Cobalt complex (CFPC) was performed by using reporter strain Chromobacterium violaceum ATCC 12472. Minimal inhibitory concentration (MIC) was carried out by the microbroth dilution method. The influence of sub-MICs (1/4 and 1/2 MICs) of CFP, CFPF and CFPC on virulence factors of P. aeruginosa was evaluated. Data was confirmed on the molecular level by RT-PCR. Also, molecular docking analysis was conducted to figure out the possible mechanisms of QSI. CFP, CFPF, and CFPC inhibited violacein pigment production of C. violaceum ATCC 12472. Sub-MICs of CFP (128- 256 μg/mL), and significantly low concentrations of CFPC (0.5- 16 μg/mL) and CFPF (0.5- 64 μg/mL) reduced the production of QS related virulence factors such as pyocyanin, protease, hemolysin and eliminated biofilm assembly by P. aeruginosa standard strains PAO1 and PA14, and P. aeruginosa clinical isolates Ps1, Ps2, and Ps3, without affecting bacterial viability. In addition, CFP, CFPF, and CFPC significantly reduced the expression of lasI and rhlI genes. The molecular docking analysis elucidated that the QS inhibitory effect was possibly caused by the interaction with QS receptors. Both CFPF and CFPC interacted strongly with LasI, LasR and PqsR receptors with a much high ICM scores compared to CFP that could be the cause of elimination of natural ligand binding. Therefore, CFPC and CFPF are potent inhibitors of quorum sensing signaling and virulence factors of P. aeruginosa ., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Naga, El-Badan, Rateb, Ghanem and Shaaban.)

Broad spectrum antibiotics cause both transient and lasting damage to the ecology of the gut microbiome. Antibiotic-induced loss of gut bacterial diversity has been linked to susceptibility to enteric infections. Prior work on subtherapeutic antibiotic treatment in humans and non-human animals has suggested that entire gut communities may exhibit tolerance phenotypes. In this study, we validate the existence of these community tolerance phenotypes in the murine gut and explore how antibiotic treatment duration or a diet enriched in antimicrobial phytochemicals might influence the frequency of this phenotype. Almost a third of mice exhibited whole-community tolerance to a high dose of the β-lactam antibiotic cefoperazone, independent of antibiotic treatment duration or dietary phytochemical amendment. We observed few compositional differences between non-responder microbiota during antibiotic treatment and the untreated control microbiota. However, gene expression was vastly different between non-responder microbiota and controls during treatment, with non-responder communities showing an upregulation of antimicrobial tolerance genes, like efflux transporters, and a down-regulation of central metabolism. Future work should focus on what specific host- or microbiome-associated factors are responsible for tipping communities between responder and non-responder phenotypes so that we might learn to harness this phenomenon to protect our microbiota from routine antibiotic treatment.

Sulbactam, a class A β-lactamase inhibitor, added to cefoperazone either at a fixed 8 mg/L level of sulbactam or at a level of fixed cefoperazone: sulbactam ratio (2:1) would constitute a combination form of cefoperazone/sulbactam, which has better activities against Enterobacteriaceae, Pseudomonas aeruginosa and Acinetobacter baumannii than cefoperazone alone. Cefoperazone/sulbactam (1:1 or 1:2) has greater in-vitro activity against most multidrug-resistant organisms (ESBL- and AmpC-producing Enterobacteriaceae and carbapenem-resistant A. baumannii except for carbapenem-resistant P. aeruginosa) than a 2:1 ratio. However, increased sulbactam concentration may induce AmpC production. Besides, sulbactam concentration might not be readily achievable in serum if the susceptibility rates were defined by the breakpoints of higher sulbactam composites, such as ≤16/16 (1:1) or 16/32 (1:2) mg/L. Carbapenemases (KPC-, OXA-type enzymes and metallo-β-lactamases) can't be inhibited by sulbactam. Some in-vitro studies showed that increasing sulbactam composites of cefoperazone/sulbactam had no effect on carbapenem-resistant P. aeruginosa, suggesting the presence of carbapenemases or AmpC overproduction that could not be overcome by increasing sulbactam levels to recover cefoperazone activity. Sulbactam alone has good intrinsic activity against carbapenem-resistant Acinetobacter strains sometimes even in the presence of carbapenemase genes, suggesting unsteady levels of carbapenemases. In conclusion, appropriate composites of cefoperazone and β-lactamase inhibitor sulbactam may expand the clinical use if the pharmacokinetic optimization could be achieved in the human serum., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Inositol-requiring enzyme 1 (IRE1) is a bifunctional serine/threonine kinase and endoribonuclease that is a major mediator of the unfolded protein response (UPR) during endoplasmic reticulum (ER) stress. Tumour cells experience ER stress due to adverse environmental cues such as hypoxia or nutrient shortage and high metabolic/protein-folding demand. To cope with those stresses, cancer cells utilise IRE1 signalling as an adaptive mechanism. Here, we report the discovery of the FDA-approved compounds methotrexate, cefoperazone, folinic acid and fludarabine phosphate as IRE1 inhibitors. These were identified through a structural exploration of the IRE1 kinase domain using IRE1 peptide fragment docking and further optimisation and pharmacophore development. The inhibitors were verified to have an impact on IRE1 activity in vitro and were tested for their ability to sensitise human cell models of glioblastoma multiforme (GBM) to chemotherapy. We show that all molecules identified sensitise glioblastoma cells to the standard-of-care chemotherapy temozolomide (TMZ)., (© 2020 The Authors. The FEBS Journal published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Deferasirox, ExJade, is an FDA-approved iron chelator used for the treatment of iron overload. In this work, we report several fluorescent deferasirox derivatives that display unique photophysical properties, i.e., aggregation-induced emission (AIE), excited state intramolecular proton transfer, charge transfer, and through-bond and through-space conjugation characteristics in aqueous media. Functionalization of the phenol units on the deferasirox scaffold afforded the fluorescent responsive pro-chelator ExPhos, which enabled the detection of the disease-based biomarker alkaline phosphatase (ALP). The diagnostic potential of these deferasirox derivatives was supported by bacterial biofilm studies.

Conventional therapies for chronic inflammation with high dose application of active agents are often accompanied with severe side effects so that other therapeutical strategies shall be developed to be less physically demanding but still highly efficient. Locally applied Layer-by-Layer (LbL) microcarriers transporting a low, but efficient dosage of active agents directly into the inflamed tissue offer a gentle therapy option. Here, the inhibition of highly degradative enzyme human neutrophile elastase (HNE) is adressed, which is produced and secreted by neutrophile granulocytes (PMNs) in the progress of inflammation. The protected transport and release of its natural inhibitor α1-antitrypsin (AT) as a constituent of the microcarrier's biopolymer multilayer allows for an efficient inhibition of extra- and intracellular elastase. The HOCl scavenger molecule cefoperazone, which preserves AT activity, as an additional multilayer constituent induces a much higher efficacy of the inhibitor. The successful assembly of both agents in different layers of the multilayer and the subsequent HNE inhibition in PMNs is investigated. The parallel application of cefoperazone leads to an enhanced inhibitory effect even with reduced AT amount and reduced carrier:cell ratio. It is demonstrated that the modular assembly strategy of LbL carriers allows for efficient synergistic effect of active agents in inflammatory process., (© 2020 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Candida albicans hyphal morphogenesis in the gastrointestinal (GI) tract is tightly controlled by various environmental signals, and plays an important role in the dissemination and pathogenesis of this opportunistic fungal pathogen. However, methods to visualize fungal hyphae in the GI tract in vivo are challenging which limits the understanding of environmental signals in controlling this morphogenesis process. The protocol described here demonstrates a novel ex vivo method for visualization of hyphal morphogenesis in gut homogenate extracts. Using an ex vivo assay, this study demonstrates that cecal contents from antibiotic treated mice, but not from untreated control mice, promote C. albicans hyphal morphogenesis in the gut content. Further, adding back specific groups of gut metabolites to the cecal contents from antibiotic-treated mice differentially regulates hyphal morphogenesis ex vivo. Taken together, this protocol represents a novel method to identify and investigate the environmental signals that control C. albicans hyphal morphogenesis in the GI tract.

The aim of this study was to investigate the in vitro interactions of ambroxol hydrochloride (ABH) or amlodipine (AML) with commonly used antibacterial agents, including meropenem, imipenem-cilastatin sodium, biapenem, cefoperazone-sulbactam, polymyxin B, and tigecycline, against six carbapenem-resistant Acinetobacter baumannii (CRAB) clinical isolates. Drug interactions were interpreted using two models, that is, the fractional inhibitory concentration index (FICI) model and the percentage of growth difference (ΔE) model. The results show that a majority of the combination groups exhibited partial synergy and additive interactions, such as the combinations of carbapenems and cefoperazone-sulbactam (SCF) with ABH or AML. While the combination of PB/AML exhibited synergistic interactions against all tested isolates, and PB/ABH exhibited synergistic interactions against two isolates. The FICI and ΔE model correlated very well for the combinations of PBABH and PB/AML against AB2. The combinations of TGC with ABH or AML mainly exhibited additive and indifferent interactions. There were no antagonistic interactions observed in any of the combinations. In conclusion, this study revealed that the non-antibacterial agents ABH or AML can work synergistically or partial synergistically with antibacterial agents against CRAB. This finding is crucial for overcoming the carbapenem resistance of A. baumannii. SIGNIFICANCE AND IMPACT OF THE STUDY: Drug combination is an effective approach for the treatment of resistant bacterial infection. The significance of using drug combination is that it can reduce drug dosage requirements, reduce the toxic effects of agents and prevent or delay the emergence of drug resistance. This study measured the in vitro interactions between non-antimicrobial agents and antibacterial agents against carbapenem-resistant Acinetobacter baumannii and the results of this study provide new insight to find strategies to overcome the carbapenem resistance in A. baumannii., (© 2019 The Society for Applied Microbiology.)

Objectives: To evaluate the antimicrobial activities of cefoperazone-sulbactam and comparator agents tested against a large collection of clinical isolates of Gram-negative organisms., Methods: A total of 19545 Gram-negative organisms were collected from medical centers located in western Europe (W-EUR; n=10626), eastern Europe and the Mediterranean region (E-EUR; n=4029), the Asia-Pacific region (APAC; n=2491), and Latin America (LATAM; n=2399) in 2015-2016 and susceptibility tested by reference broth microdilution methods., Results: Overall, 91.5% of Enterobacterales were susceptible (≤16mg/L) to cefoperazone-sulbactam, with susceptibility rates ranging from 82.0% (E-EUR) to 94.4% (W-EUR); overall susceptibility to cefoperazone-sulbactam, piperacillin-tazobactam, imipenem, and ceftriaxone was 91.5%, 85.4%, 90.5%, and 72.1%, respectively. Among Pseudomonas aeruginosa isolates, cefoperazone-sulbactam susceptibility rates were higher in W-EUR, APAC, and LATAM (83.0-84.6%) compared to E-EUR (59.5%). Susceptibility to piperacillin-tazobactam, imipenem, and ceftazidime was 78.3%, 76.2%, and 82.0% in W-EUR; 52.3%, 43.5%, and 57.4% in E-EUR; 83.5%, 80.1%, and 84.5% in APAC; and 81.5%, 72.8%, and 83.0% in LATAM, respectively. Acinetobacter spp. susceptibility rates varied from 43.0% in E-EUR to 75.8% in LATAM (53.2% overall) for cefoperazone-sulbactam and from 19.8% in E-EUR to 40.2% in W-EUR (26.4% overall) for imipenem., Conclusions: Susceptibility rates varied widely among geographic regions and were generally lowest in E-EUR. Based on the potency and activity spectrum, cefoperazone-sulbactam remains among the most active compounds in vitro at published breakpoints., (Copyright © 2019 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

The occurrence of antibiotic resistance bacteria has become a major threat to public health. We have recently discovered a transcriptional activator that belongs to MarR family, EstR, and an esterase B (EstB) with a newly proposed de-arenethiolase activity from Sphingobium sp. SM42. De-arenethiolase activity involves the removal of the small aromatic side chain of cephalosporin antibiotics as an excellent leaving group by the enzymatic CS bond cleavage. Here, we report the regulation of estB through EstR as an activator in response to a third generation cephalosporin, cefoperazone, antibiotic. Cefoperazone induced the expression of estB in wild type Sphingobium sp., but not in the estR knockout strain, and the induction was restored in the complemented strain. Moreover, we revealed the importance of EstB localization in periplasm. Since EsB has the ability to inactivate selected β-lactam antibiotics in vitro, it is possible that the enzyme works at the periplasmic space of Gram negative bacteria similar to β-lactamases. EstB was genetically engineered by incorporating NlpA binding motif, or OmpA signal sequence, or SpyTag-SpyCatcher to the estB gene to mobilize it to different compartments of periplasm; inner membrane, outer membrane, and periplasmic space, respectively. Surprisingly, we found that Sphingobium sp. SM42 and E. coli expressing EstB at the periplasm were more sensitive to cefoperazone. The possible drug enhancement mechanism by enzyme was proposed. This work might lead to a novel strategy to tackle antibiotic resistance problem., (Copyright © 2020 The Author(s). Published by Elsevier GmbH.. All rights reserved.)

Antioxidant enzymes play an important role in body defense and free radical removal. Cephalosporins are β-lactam antibiotics. In this work, the effects of cefazolin, cefuroxime and cefoperazone which are cephalosporins on some selected antioxidant enzyme and levels of malondialdehyde (MDA) as lipid peroxidation product were investigated in kidney, liver, and brain tissues of albino female rats. Ninety-six albino rats were randomly divided into 16 groups of equal number ( n  = 6). 50 mg/kg cefazolin, 25 mg/kg cefuroxime, and 100 mg/kg cefoperazone were injected intraperitoneally to the groups (5th-8th and 9th-12th, and 13th-16th groups), respectively. The changes in glutathione reductase (GR), glutathione S-transferase (GST), superoxide dismutase (SOD), peroxidase (POD), and glutathione peroxidase (GSH-Px) levels were studied in each time point group and a time-dependent manner (at the 1st, 3rd, 5th and 7th hour). In addition, MDA levels were examined in all the tissues. The drugs evaluated in this study had different effects on the same enzyme in different tissues depending on time. MDA levels especially in cefazolin and cefoperazone experiments were lower in all the tissues; however, MDA levels were higher in brain and kidney tissues in the cefuroxime groups in a time-dependent manner ( p  < 0.05). These results revealed the complex effects of the tested drugs on different tissues at different time points. Therefore, the dose and use of these drugs should be adjusted correctly.

Tigecycline (TGC) and cefoperazone/sulbactam (CPS) both have been shown good in vitro activity against carbapenem-resistant Acinetobacter baumannii (CRAB) isolates. We aim to compare the efficacy of TGC versus CPS for CRAB infections. We conducted a retrospective cohort study of patients with CRAB at a single center in China from 2013 to 2015. Outcomes comprised in-hospital mortality, clinical and microbiological response. The method of inverse probability of treatment weighting and multivariable logistic regression analysis incorporated with propensity score were employed to estimate the effect of treatment groups. There were 130 subjects included in our study. The patients in TGC, CPS and TGC plus CPS combination group were 42, 66, and 22, respectively. After adjustment, in-hospital mortality was lower in CPS group than TGC group (weighted OR 0.173; 95% CI 0.06-0.497; P=0.001) but without differences in clinical success and microbiological eradication (P>0.05). TGC monotherapy had a similar outcome with TGC plus CPS combination group. This is the first study comparing the efficacy of tigecycline and cefoperazone/sulbactam for CRAB infections. Cefoperazone/sulbactam appears to be more efficacious than tigecycline during treatment.

Objectives: Cefoperazone/sulbactam trough concentration (C min ) varies widely in cirrhotic patients. The objective of this study was to describe the characteristics of C min and to identify factors associated with the pharmacokinetic/pharmacodynamic (PK/PD) target attainment of cefoperazone/sulbactam in cirrhotic patients., Methods: Data were collected retrospectively from cirrhotic patients who received cefoperazone/sulbactam treatment. The C min was measured using a validated liquid chromatography-tandem mass spectrometry. The PK/PD target of 100% fT > MIC was used for cefoperazone/sulbactam. Multivariate logistic regression and classification and regression tree (CART) analysis were performed to identify the factors affecting the PK/PD target attainment in these patients., Results: Cefoperazone and sulbactam C min were measured simultaneously in 103 plasma samples from 70 cirrhotic patients. Cefoperazone and sulbactam C min were 89.27 ± 44.38 mg/L and 10.09 ± 13.01 mg/L, respectively. The PK/PD target of 100% fT > MIC was achieved in 47.1% (33/70) patients for cefoperazone and in 28.6% (20/70) patients for sulbactam. The CART analysis revealed that cefoperazone C min was likely to reach the PK/PD target in patients with serum bilirubin levels between 26.15 μmol/L and 99.15 μmol/L. Inversely, lower cefoperazone C min was observed in patients with bilirubin levels ≤26.15 μmol/L and serum albumin >38.45 g/L or in patients with bilirubin levels >99.15 μmol/L and creatinine clearance (CrCl) >139.13 mL/min. Additionally, patients had higher sulbactam C min when CrCl was below 62.85 mL/min., Conclusions: This study shows that current cefoperazone/sulbactam dosage regimens may result in inadequate plasma concentrations in cirrhotic patients. We recommend monitoring the C min of cefoperazone/sulbactam to ensure efficacy of cefoperazone/sulbactam treatment., (© 2019 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).)

Background and Objective: Macrolides are the recommended antibiotics for treating pertussis and preventing transmission. The causative bacterium, Bordetella pertussis, has high macrolide resistance and has recently circulated in China. The objective of this study was to find effective alternative antibiotics for treatment by assessing the in vitro activity and clinical efficacy of antibiotics against Bordetella pertussis., Methods: Bordetella pertussis was confirmed by agglutination with specific antisera and mass spectrometry. The MICs of antibiotics against isolates were determined using the Etest method. Treatment outcomes were clinically and microbiologically evaluated., Results: A total of 126 pertussis patients were diagnosed based on culture, 69.8% of whom were aged ≤6 months and 72.1% were treated with previous macrolides. Leucocytosis and lymphocytosis were observed in 29.4% and 54.8% of all patients, respectively. Both MIC 50 and MIC 90 of erythromycin, azithromycin, and clindamycin were >256mg/L, and 75.4% were highly macrolide resistant. The MIC 90 of trimethoprim-sulfamethoxazole, ampicillin, ampicillin-sulbactam, cefuroxime, ceftriaxone and cefoperazone-sulbactam were 0.38mg/L, 0.25mg/L, 0.19mg/L, 12mg/L, 0.19mg/L and 0.047mg/L, respectively. The MICs of piperacillin in all of the isolations were <0.016mg/L. Of the patients treated with single cefoperazone-sulbactam or piperacillin-tazobactam, 30 of 32 (93.8%) had significantly improved clinical symptoms and 24 of 25 (96%) had negative culture results after 2 weeks of therapy., Conclusion: Macrolide resistance in Bordetella pertussis is a serious problem in Zhejiang Province, China. Piperacillin/piperacillin-tazobactam and cefoperazone-sulbactam have potent antibacterial activity in vitro and in vivo, and may become the alternative choice for treating pertussis caused by macrolide-resistant isolates., (Copyright © 2019 International Society for Chemotherapy of Infection and Cancer. Published by Elsevier Ltd. All rights reserved.)

Objectives: The aim of this study was to investigate whether some of the cephalosporin group antibiotics have inhibition effects on GR and GST enzymes with important functions in the metabolic pathway., Methods: In this study, some selected cephalosporin group antibiotics on GST and GR enzyme was carried out using 96 rats. 16 groups (16 × 6) were created from these rats, divided to another 4 groups (4 × 24). The resulting groups were named as sham groups, cefazolin groups, cefuroxime groups and cefoperazone groups, respectively. The antibiotics used were injected to cefazolin, cefuroxime and cefoperazone groups. The inhibition effects of the antibiotics were measured in the different time intervals (1st, 3th, 5th, 7th). The statistical investigation of the results was performed using the SPSS software program., Results: Results revealed the complex effects of the tested substances on GR and GST activity at different time intervals and in different tissues (p < 0.05). This indicated that the tested substances could be exposed to different interactions in vivo., Conclusion: The tested antibiotics showed some significant inhibition effects on the GST and GR enzyme activity in some tissues of brain, eye and muscle. The interaction of enzyme - the drug is a key factor to highlight the toxicological mechanism. For this reason, the results obtained from in vivo experiments are crucial to explane the physiological properties of the enzymes., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The mineralization of 125 mL of 50-300 mg L -1 cefoperazone (CFPZ) has been comparatively studied by electrochemical advanced oxidation processes (EAOPs) like anodic oxidation (AO), electro-Fenton (EF) and photoelectro-Fenton (PEF) with a RuO 2 /Ti or boron-doped diamond (BDD) anode and an activated carbon fiber (ACF) cathode. A microwave discharge electrodeless lamp (MDEL) was used as the UV source in PEF process. CFPZ decays always followed pseudo-first-order kinetics and their constant rates increased in the order: AO < EF < MDEL-PEF, regardless of anode types. Higher mineralization was achieved in all methods using BDD instead of RuO 2 /Ti, while the most potent BDD-MDEL-PEF gave 88% mineralization under its optimum conditions of 0.36 A, pH 3.0 and 1.0 mmol L -1 Fe 2+ . The synergistic mechanisms were explored by quantifying the electrogenerated H 2 O 2 and formed • OH, in which 2.27 and 2.58 mmol L -1 H 2 O 2 were accumulated in AO-H 2 O 2 with RuO 2 /Ti or BDD anode, respectively, while 92.0 and 263.5 μmol L -1 • OH were generated in EF with RuO 2 /Ti or BDD anode, respectively. The oxidation power of EAOPs with different anodes was also compared by measuring the evolutions of NO 3 - and NH 4 + as well as four generated carboxylic acids including oxalic, oxamic, formic and fumaric acids., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: We retrospectively analyzed the effect of tigecycline and cefoperazone/sulbactam therapies on the prognosis of patients with carbapenem-resistant Acinetobacter baumannii bloodstream infection (CRAB-BSI)., Methods: CRAB-BSI patients receiving tigecycline therapy or cefoperazone/sulbactam therapy between January 2012 and December 2017 was enrolled, and strict exclusion criteria were followed. The 28-day mortality of patients was analyzed. The impact of cefoperazone/sulbactam therapy on prognosis was evaluated using Cox multivariate regression analysis. The 28-day mortality of patients receiving cefoperazone/sulbactam monotherapy and cefoperazone/sulbactam-based combination therapy was also compared., Results: Three hundred forty eight patients with CRAB-BSI were enrolled in the study. Two hundred ten patients were included after applying the exclusion criteria. Of these, 135 patients received tigecycline therapy and 75 patients received cefoperazone/sulbactam therapy. The 28-day mortality of patients in the latter group was, significantly lower than that of the tigecycline group [29.3% vs. 51.9%; P  = 0.001]. Cox multivariate regression analysis revealed that cefoperazone/sulbactam therapy exerted a protective effect on the prognosis of patients [hazard ratio 0.566, 95% confidence interval (0.342-0.940); P  = 0.028]. Kaplan-Meier survival curve analysis indicated that the 28-day mortality of patients receiving cefoperazone/sulbactam therapy was lower than that of patients receiving cefoperazone/sulbactam monotherapy, but the difference was not significant (22.2% vs. 40%; P  = 0.074). However, the mortality of patients receiving cefoperazone/sulbactam with imipenem/cilastatin was significantly lower than that of patients receiving cefoperazone/sulbactam monotherapy ( P  = 0.048)., Conclusions: Patients treated with cefoperazone/sulbactam therapy had a better clinical outcome. The mortality of patients receiving cefoperazone/sulbactam with imipenem/cilastatin seems to be the lowest., Competing Interests: Ethics approval for this study was submitted and approved through Research Ethics. Committee of the First Affiliated Hospital, College of Medicine, Zhejiang University. (Reference Number 2017–699).Not applicable.The authors declare that they have no competing interestsSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Burkholderia pseudomallei is the causative agent of meliodosis, and the cases in China are gradually increasing. The present retrospective study aimed to surveil the molecular epidemiological characteristics and antibiotic resistance of B pseudomallei isolates. B pseudomallei strains were isolated and verified from meliodosis patients with relevant epidemiological information from 2004 to 2016 in Hainan, China. Pulsed-field gel electrophoresis based on Spe I digestion was carried out, and antimicrobial resistance of B pseudomallei strains was observed against 9 frequently-used antimicrobials. A total of 164 B pseudomallei isolates were successfully divided into 60 pulsed-field gel electrophoresis (PFGE) patterns, including 33 clusters and 27 single types, at an 85% similarity level. The isolates also exhibited a high level of ceftazidime resistance rate (12.8%, 21/164). B pseudomallei strains were mainly heterogenous with no predominant type, but there were some clonal populations, dominate clusters prevalent and the resistance rates of cephems antimicrobial increased significantly between 2004 and 2016 along with the number of melioidosis cases collected in Hainan (cefoperazone-sulbactam [SCF], rs = 0.96, P = .04; ceftazidime [CAZ], rs = 0.98, P = .01). In conclusion, this study will help to enhance our understanding of molecular characteristics and antibiotic resistance of B pseudomallei.

Background: Carbapenem-resistant Pseudomonas aeruginosa (CRPA) has become a major therapeutic problem worldwide. Combination therapy may be an alternative chemotherapeutic option., Methods: Bioluminescent CRPA Xen5-D9 was developed in the present study. Minimum inhibitory concentration of amikacin (AMK) or cefoperazone/sulbactam (SCF) against CRPA Xen5-D9 was determined by microdilution method. CRPA Xen5-D9 was intraperitoneally injected to establish a mouse model of intraperitoneal infection. In vivo bioluminescence imaging was applied at 2 and 5 h after treatment to dynamically evaluate bactericidal effects of AMK alone or in combination with SCF. After 5 h of treatment, ex vivo bacterial colony counts from liver, kidney, spleen, lung, and blood were also determined., Results: CRPA Xen5-D9 was AMK sensitive and SCF intermediate. In vivo imaging showed that AMK alone significantly decreased bioluminescent signals compared with the control, while signals from the SCF-alone group barely changed. Moreover, the AMK-SCF combination did not show greater bactericidal effect compared with AMK alone. Results of ex vivo bacterial counts confirmed that AMK alone significantly decreased the colony counts from different tissues. Although SCF also decreased the colony counts in liver, kidney, spleen, and lung compared with the control, the counts were still higher than those of the AMK-alone group. In addition, AMK-SCF combination resulted in significantly lower numbers of colony-forming units in blood compared with individual antibiotics., Conclusions: AMK-SCF combination did not show better bactericidal effect on AMK-sensitive CRPA-caused infections compared with AMK alone. Although further studies are needed, these results suggest that this combination does not seem to be indicated for treatment of CRPA-caused infections., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objective: To determine the burden of AmpC beta-lactamase producing Klebsiella pneumoniae and its antimicrobial profile among paediatric patients., Methods: This cross-sectional study was conducted at the Microbiology Department of The Children's Hospital and the Institute of Child Health in Lahore, Pakistan, from May 2014 to April 2015, in which isolates of Klebsiella pneumoniae were screened by using the cefoxitin disc. Confirmation was done by inhibitor-based method using 400 micro grams of boronic acid dispensed on the cefoxitin discs. The zone sizes of cefoxitin with and without the boronic acid were compared. The antimicrobial susceptibility testing was performed using Kirby Bauer disc diffusion method., Results: Positive cultures yielded 585 Klebsiella pneumoniae out of which 220(37.6%) strains were AmpC beta-lactamase-positive on the basis of cefoxitin screening and 126(21.53%) were positive on the basis of inhibitor-based confirmatory method. Most of the infected patients 73(57.9%) were neonates. All AmpC beta-lactamase-producing strains were resistant to cephalosporins. They also exhibited resistance to ciprofloxacin 109(86.5%), amikacin 98(77.8%), levofloxacin 8(77.8%), cefoperazone-sulbactam 81(64.3%), piperacillin-tazobactam 82(65.1%), meropenem, 56(44.4%) and imipenem 32(25.4%)., Conclusions: Prompt identification of AmpC beta-lactamases using inhibitor-based confirmatory test can help reduce the burden of these pathogens.

Objectives: This study aims to assess the in vitro activity of cefoperazone alone and different cefoperazone-sulbactam ratios against different inoculum sizes of multidrug resistant organisms., Methods: Minimum inhibitory concentrations (MICs) of cefoperazone, cefoperazone-sulbactam at fixed ratio of 1:1 and 2:1 against a normal inoculum size of 5 × 10 5  CFU/ml and a high inoculum size of 5 × 10 7  CFU/ml were measured., Results: Each 33 isolates of extended-spectrum β-lactamases (ESBL)-producing Escherichia coli, ESBL-producing Klebsiella pneumoniae, carbapenem-resistant E. coli, and carbapenem-resistant Pseudomonas aeruginosa and a total of 122 isolates of carbapenem-resistant Acinetobacter baumannii were collected. After the addition of sulbactam at a 1:1 ratio, most MIC 50 and MIC 90 values decreased. Cefoperazone-sulbactam at a 1:1 ratio had a higher susceptibility rate against ESBL-producing E. coli, carbapenem-resistant E. coli, and carbapenem-resistant A. baumannii than cefoperazone-sulbactam at a 2:1 ratio (all P < 0.05). For ESBL-producing E. coli, the susceptibility rate of cefoperazone-sulbactam at ratios of (1:1) and (2:1) decreased from 97.0 to 87.9% and 90.9 to 60.6%, for normal to high inoculum, respectively. For ESBL-producing K. pneumoniae, both susceptibility rate of cefoperazone-sulbactam at ratios of (1:1) and (2:1) decreased from 75.8%, and 63.6% at normal inoculum to 51.5% and 42.4% at high inoculum., Conclusions: Cefoperazone-sulbactam at a 1:1 ratio has greater in vitro activity against most multidrug resistant organisms than cefoperazone-sulbactam at a 2:1 ratio. Such combinations were not influenced by the inoculum size of ESBL-producing E. coli and K. pneumoniae and could be a therapeutic option for treating severe infections., (Copyright © 2017. Published by Elsevier B.V.)

In this paper, the in vivo effects of some antibiotics including cefazolin, cefuroxime, and cefoperazon, on the activity of the carbonic anhydrase enzyme (CA) in heart, brain, eye, liver, and kidney tissues of rats were evaluated. For this purpose, 16 different groups, which each containing six rats (n = 6), were formed (control group, cefazolin groups, cefuroxime groups, and cefoperazon groups). The rats were necropsied 60 min after the intraperitoneal injection of the chemicals into the rats. The CA activities were measured for each tissue using esterase activity methods. The activity values for each tissue obtained were statistically calculated. The CA activities in the liver tissue were assessed, and the activities of the cefoperazon groups were decreased compared to the sham groups from the third hour (p < 0.05). In the cefuroxime and cefoperazon groups, the CA activities in the eye tissue were decreased during the first 3 h and then increased (p < 0.05)., (© 2018 Wiley Periodicals, Inc.)

Sulbactam is a plausible option for treating Acinetobacter infections because of its intrinsic antibacterial activity against the members of the Acinetobacter genus, but the mechanisms of sulbactam resistance have not been fully studied in Acinetobacter baumannii In this study, a total of 2,197 clinical A. baumannii isolates were collected from 27 provinces in China. Eighty-eight isolates with various MICs for sulbactam were selected on the basis of their diverse clonality and underwent multilocus sequence typing (MLST), antimicrobial susceptibility testing, and resistance gene screening. The copy number and relative expression of bla TEM-1D and ampC were measured via quantitative PCR and quantitative reverse transcription-PCR, respectively. The genetic structure of multicopy bla TEM-1D was determined using the whole-genome sequencing technology. The cefoperazone-sulbactam resistance rate of the 2,197 isolates was 39.7%. The rate of positivity for bla TEM-1D or IS Aba1-ampC in the sulbactam-nonsusceptible group (64.91% and 78.95%, respectively) was significantly higher than that in the sulbactam-susceptible group (0% and 0%, respectively; P < 0.001). The MIC of sulbactam ( P < 0.001) varied considerably between the groups expressing ampC with or without upstream IS Aba1 Notably, the genetic structure of the multicopy bla TEM-1D gene in strain ZS3 revealed that bla TEM-1D was embedded within four tandem copies of the cassette IS 26-bla TEM-1D -Tn 3 -IS 26 Therefore, bla TEM-1D and IS Aba1-ampC represent the prevalent mechanism underlying sulbactam resistance in clinical A. baumannii isolates in China. The structure of the four tandem copies of bla TEM-1D first identified may increase sulbactam resistance., (Copyright © 2018 American Society for Microbiology.)

Context: Cephalosporins are derived from the fungus Acremonium. Due to their strong bactericidal ability, these drugs have to a wide usage in medicine., Objective: An investigation of the effects on sheep renal aldose reductase (AR) and sorbitol dehydrogenase (SDH) of cefoperazone, cefazolin, cefuroxime, ceftazidime and ceftriaxone as cephalosporin drugs was carried out in the present study., Methods: AR and SDH were purified from sheep kidney by ion exchange, gel filtration and affinity methods with approximately 219- and 484-fold, respectively. Some kinetic properties of the enzymes were determined such as optimal pH, optimal ionic strength, optimal temperature, stable pH, K m and V max . IC 50 values of the drugs were found for each enzyme., Results: While the AR was inhibited by all drugs, SDH enzyme was inhibited by only CXM (IC 50 8.10 mM). Interestingly, CZO activated SDH enzyme. This result was evaluated as important for the flow of the polyol reactions. K i values and inhibition types were determined for AR. However, these values could not have determined for SDH, due to insufficient inhibition., Conclusions: From these results, it was concluded that cephalosporins may have an important effect on flow of the polyol metabolism.

With the growing emergence of pan-drug-resistant Acinetobacter baumannii (PDR-Ab) strains in clinical, new strategies for the treatment of PDR-Ab infections are urgently needed. Egg yolk immunoglobulin (IgY) as a convenient and inexpensive antibody has been widely applied to the therapy of infectious diseases. The aim of this study was to produce IgY specific to PDR-Ab and investigate its antibacterial effects in vitro and in vivo. IgYs specific to two PDR-Ab strains were produced by immunizing hens with formaldehyde inactivated PDR-Ab cells and isolated from yolks with a purity of 90% by water dilution, salt precipitations and ultrafiltration. IgYs showed high titers when subjected to an ELISA and inhibited the growth of PDR-Ab in a dose-dependent manner in liquid medium. Scanning electron microscopy assay showed structural modification and aggregation of PDR-Ab treated with specific IgYs. Freshly cultured PDR-Ab cells were nasally inhaled in BALB/c mice to induce acute pneumonia. The infected mice were intraperitoneally injected with specific IgYs using cefoperazone/sulbactam and dexamethasone as positive controls. The IgYs specific to PDR-Ab lowered the mortality of mice with PDR-Ab-induced acute pneumonia, decreased the level of TNF-α and IL-1β in serum and reduced inflammation in lung tissue. Specific IgY has the potential to be used as a new therapeutic approach for the treatment of A. baumannii-induced infections., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

The prevalence of infections caused by metallo-β-lactamase (MBL) expressing Gram-negative bacteria has grown at an alarming rate in recent years. Despite the fact that MBLs can deactivate virtually all β-lactam antibiotics, there are as of yet no approved drugs available that inhibit their activity. We here examine the ability of previously reported thiol-based MBL inhibitors to synergize with meropenem and cefoperazone against a panel of Gram-negative carbapenem-resistant isolates expressing different β-lactamases. Among the compounds tested, thiomandelic acid 3 and 2-mercapto-3-phenylpropionic acid 4 were found to efficiently potentiate the activity of meropenem, especially against an imipenemase (IMP) producing strain of K. pneumoniae. In light of the zinc-dependent hydrolytic mechanism employed by MBLs, biophysical studies using isothermal titration calorimetry were also performed, revealing a correlation between the synergistic activity of thiols 3 and 4 and their zinc-binding ability with measured K d values of 9.8 and 20.0 μM, respectively.

Cefoperazone is most popularly used in the treatment of complicated infections clinically. Concomitant ingestion of ethnaol and cefoperazone may cause a disulfiram-like reaction. However, very little is known about the possible interactions between cefoperazone treatment and an alcohol with regard to the induction of disulfiram-like reaction. Study of the metabolic impact of cotreatment with cefoperazone and alcohol on animals can facilitate the identification of markers relevant to disulfiram-like reaction. In this study, the serum and cerebrospinal fluid (CSF) metabolites from Sprague-Dawley rats were profiled using gas chromatography mass spectrometry. Serum levels of valine, leucine, glycine, palmitelaidic acid, and 2-hydroxyisobutyrate in combination application group were significantly higher than those in the control; while alanine and pyruvate deceased in cotreatment group. Most TCA intermediates, glutamate and aspartate had lower CSF level in combination application group, except citrate. In addition, most carbohydrates, ethylmalonate and N-acetylaspartate had higher level compared with control group. These results highlight concomitant ingestion of alcohol and cefoperazone generated disulfiram-like reaction by way of disrupting normal metabolic pathway. Cefoperazone magnifes ethanol-induced impairment of TCA cycle and aspartate metabolism, thereby affects energy metabolism and neural transmission., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objective: To evaluate the reliability of using imipenem, meropenem, cefoperazone-sulbactam, piperacillin-tazobactam in the treatment of hospital-acquired Gram-negative bacterial infections with Monte Carlo simulation(MCS). Methods: The MIC of the four agents collected from hospital-acquired infections were detected in accordance with broth dilution method of Clinical and Laboratory Standard Institute (CLSI). MCS were conducted with MICs and the pharmacokinetics parameters of the four agents based on conventional dose regimens.The cumulative fraction of response (CFR) of time over MIC target attainment in different dosing regimen were generated. Results: A total of 2 541 strains, including 2 093 strains of Enterobacteriaceae and 448 strains of glucose non - fermentative bacilli were collected.The MIC(90) of imipenem and meropenem against Enterobacteriaceae were less than 1 mg/L in general, whereas MIC(90) of two agents with β-lactamase inhibitors was around 64 mg/L.As to glucose non - fermenting bacteria, MICs of all the four agents were very high, especially to Acinetobacter baumannii, which indicated MIC(50) more than 32 mg/L.MCS revealed that carbapenems had significantly higher CFR than those with β-lactamase inhibitors.Imipenem and meropenem (1 g, q8 h) obtained CFRs of 74.69% and 81.42%, respectively.The CFR of cefoperazone-sulbactam (2 g, q8 h) and piperacillin-tazobactam (4 g, q6 h) (both excluding β-lactamase inhibitors) were just 49.59% and 27.66% respectively, which increased after excluding A . baumannii in piperacillin-tazobactam. Conclusions: The conventional dose regimens of imipenem and meropenem are reliable for the empiric therapy of Gram-negative hospital-acquired bacterial infections.Piperacillin-tazobactam is suggested to use with higher doses or prolonged infusion time to satisfy the time of drug concentration exceeded the MIC(T>MIC)requirement.More clinical studies of cefoperazone-sulbactam should be conducted to optimize its regimen and guarantee its efficacy.

Background/purpose: The aim of this study was to investigate the cefoperazone-sulbactam (CFP-SUL) susceptibilities of important Gram-negative bacteria (GNB) by agar dilution (reference method), disk diffusion, and two automated methods., Methods: A total of 799 GNB isolates, including Enterobacteriaceae (n = 500) and nonfermentative GNB (NFGNB, n = 299), were recovered from various clinical specimens collected at National Taiwan University Hospital, Taipei, Taiwan from November 2013 to December 2014. The agar dilution method, disk diffusion method, and two automated susceptibility systems (Phoenix and Vitek 2) were used for testing susceptibility of the isolates to CFP-SUL. Categories of susceptibility (susceptible, intermediate, or resistant) to CFP-SUL yielded from each method were interpreted according to CFP-SUL interpretive breakpoints proposed previously. The results of categorical agreement and errors obtained between the agar dilution method and the other three methods were analyzed., Results: The Vitek 2 system had the highest error rates against Escherichia coli (n = 150) and Enterobacter cloacae (n = 77) isolates, i.e., 6.7% and 11.7% minor errors, 8.5% and 1.7% major errors, and 40% and 20% very major errors, respectively. Additionally, the Vitek 2 system was also found to have a significantly lower sensitivity (44.4%) and lower positive predictive value (18.2%) for detecting CFP-SUL nonsusceptible E. coli isolates than other methods. For carbapenem-nonsusceptible Enterobacteriaceae isolates, the Vitek 2 system failed to detect correct susceptibility to CFP-SUL. The three methods failed to correctly detect CFP-SUL susceptibility categories against all NFGNB isolates except Pseudomonas aeruginosa., Conclusion: The Vitek 2 system is a suboptimal method in correctly detecting CFP-SUL susceptibility categories for E. coli, E. cloacae, and carbapenem-nonsusceptible Enterobacteriaceae isolates., (Copyright © 2015. Published by Elsevier B.V.)

Objective: To identify frequency of uropathogenic Escherichia coli and its antibiotic susceptibility pattern., Methods: This cross-sectional study was conducted at Khyber Teaching Hospital, Peshawar, Pakistan, from January 2014 to September 2015, and comprised urine specimens. Biochemical techniques were used to identify Escherichia coli and antibiotic susceptibility was determined by Kirby-Bauer disk diffusion and minimum inhibitory concentration methods. SPSS 23 was used for data analysis., Results: Of the 787 urine samples, 458(58.2%) grew significant positive growths. Escherichia coli growths were present in 351(76.6%) positive cultures of which 108(30.8%) came from males and 243(69.2%) from female patients. Resistance to fluoroquinolones tested was almost similar (p>0.05). Escherichia coli was highly sensitive to imipenem (98.6%), meropenem (97.8%), tazobactum (96.2%), cefoperazone+sulbactam (93.9%) and amikacin(92.5%)., Conclusions: Escherichia coli was a common pathogen causing urinary tract infections and was highly sensitive to imipenem, meropenem, tazobactum, cefoperazone+sulbactam and amikacin.