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Staphylococcus aureus (SA) is a leading cause of bloodstream infection. The liver represents the sentinel immune organ for clearance of bloodstream pathogens and eradication of intracellular SA from liver-resident macrophages (Kupffer cells, KCs) eliminates the likely pathogenic reservoir that contributes to persistent bacteraemia. Objectives We assessed antimicrobial activity at phagolysosome-mimicking pH, intracellular penetration, and SA eradication within KCs in vitro for clinically prescribed antistaphylococcal agents alone or in combination: vancomycin, daptomycin, ceftaroline, ceftobiprole, oritavancin, oxacillin, cefazolin; rifampin and fosfomycin. Methods pH-adjusted broth microdilution assays, intracellular bioaccumulation assays, and intracellular killing assays against clinical bloodstream isolates were performed using a murine KC line with study agents. Results Rifampin and β-lactams exhibited enhanced activity [2- to 16-fold minimum inhibitory concentrations (MIC) decrease] at phagolysosomal pH while vancomycin, oritavancin, daptomycin and fosfomycin demonstrated reduced activity (2- to 32-fold MIC increase in order of least to greatest potency reduction). All agents evaluated had poor to modest intracellular to extracellular concentration ratios (0.024–7.8), with exceptions of rifampin and oritavancin (intracellular to extracellular ratios of 17.4 and 78.2, respectively). Finally, we showed that the first-line treatment for SA bacteraemia (SAB), vancomycin, performed worse than all other tested antibiotics in eradicating intracellular SA at human C max concentration (0.20 log cfu decrease), while oritavancin performed better than all other agents alone (2.05 versus 1.06–1.36 log cfu decrease). Conclusions Our findings raise concerns about the efficacy of commonly prescribed antibiotics against intracellular SA reservoirs and emphasize the need to consider targeting pathogen eradication from the liver to achieve early control of SAB. [ABSTRACT FROM AUTHOR]

Background: We report the final results of the clinical usage of ceftobiprole in patients in Canada from data in the national CLEAR (Canadian Le adership on Antimicrobial Real-Life Usage) registry. Research design and methods: The authors review the final data using the national ethics approved CLEAR study. Thereafter, the literature is surveyed regarding the usage of ceftobiprole to treat patients with infectious diseases via PubMed (up to March 2024). Results: In Canada, ceftobiprole is primarily used as directed therapy to treat a variety of severe infections caused by MRSA. It is primarily used in patients failing previous antimicrobials, is frequently added to daptomycin and/or vancomycin with high microbiological and clinical cure rates, along with an excellent safety profile. Several reports attest to the microbiological/clinical efficacy and safety of ceftobiprole. Ceftobiprole is also reported to be used empirically in select patients with community-acquired bacterial pneumonia (CABP), as well as hospital-acquired bacterial pneumonia (HABP). Conclusions: In Canada, ceftobiprole is used mostly as directed therapy to treat a variety of severe infections caused by MRSA, in patients failing previous antimicrobials. It is frequently added to, and thus used in combination with daptomycin and/or vancomycin with high microbiological/clinical cure rates, and an excellent safety profile. [ABSTRACT FROM AUTHOR]

Introduction: Nosocomial meningitis may occur after procedures affecting the central nervous system or following traumatic injury. The causative infectious organism is commonly Staphylococcus aureus, a Gram-positive bacterium. The aim of the present study was to compare the effectiveness of two antibacterial agents, ceftobiprole and vancomycin, in an animal model of methicillin-resistant S. aureus (MRSA) meningitis. Method: The strain of MRSA used was ATCC 43300. The animals were divided into three groups and infected intracisternally with MRSA. Controls received no antibiotherapy while the ceftobiprole group received 25 mg/kg and the vancomycin group received 20 mg/kg intravenously. Blood and cerebrospinal fluid (CSF) samples were collected at three time points. All animals were euthanized at 73 h after start of treatment. Results: There was a significant difference (p < 0.05) between both treatment groups and the control animals at 24 h (drug trough) and 73 h (1 h after third dose) after start of treatment in terms of CSF bacterial levels. At 73 h, there was a significant difference in survival between the control group and the two treatment groups but no difference between the treated animal survival rates. Conclusion: Intravenous treatment with ceftobiprole and vancomycin appears to be equally effective in a rabbit model of MRSA meningitis. [ABSTRACT FROM AUTHOR]

Despite advancements in health systems and intensive care unit (ICU) care, along with the introduction of novel antibiotics and microbiologic techniques, mortality rates in severe community-acquired pneumonia (sCAP) patients have not shown significant improvement. Delayed admission to the ICU is a major risk factor for higher mortality. Apart from choosing the appropriate site of care, prompt and appropriate antibiotic therapy significantly affects the prognosis of sCAP. Treatment regimens involving ceftaroline or ceftobiprole are currently considered the best options for managing patients with sCAP. Additionally, several other molecules, such as delafloxacin, lefamulin, and omadacycline, hold promise as therapeutic strategies for sCAP. This review aims to provide a comprehensive summary of the key challenges in managing adults with severe CAP, focusing on essential aspects related to antibiotic treatment and investigating potential strategies to enhance clinical outcomes in sCAP patients. [ABSTRACT FROM AUTHOR]

Ceftobiprole is a fifth-generation cephalosporin approved by European and American regulatory agencies for the treatment of community-acquired pneumonia (CAP) and hospital-acquired pneumonia (HAP). Ceftobiprole administration is useful in severe CAP as well as HAP where the potential is to save other β-lactams including carbapenems or linezolid/vancomycin in clinical practice. The aim of this study was to report the real-world evidence of ceftobiprole in patients with CAP and HAP in a single center. In this retrospective study, we included 159 patients with CAP or HAP: 105 (66%) had CAP and 54 (34%) had HAP. The median age was 70 years (IQR 60–77), the median Charlson Comorbidity Index was 5 (IQR 3–7.5) and baseline INCREMENT ESBL score was 8 (IQR 6–11). Ceftobiprole was mostly given as a combination treatment (77%) or as a carbapenem-sparing strategy (44%). There were no differences in mortality between shorter and longer duration of treatment (<7 days compared with ≥7 days (HR 1.02, C.I. 0.58–1.77, p = 0.93) or between first-line (HR 1.00, C.I. 0.46–2.17, p = 0.989) and second-line therapy. Ceftobiprole use in CAP or HAP in the real world is effective as a first- and second-line treatment as well as a carbapenem-sparing strategy. Further studies are needed to explore the full potential of ceftobiprole, including its real-world use in antimicrobial stewardship programs. [ABSTRACT FROM AUTHOR]

Bloodstream infections by bacteria, especially multidrug-resistant bacteria, remain a worldwide public health concern. We evaluated the antibacterial activity of ceftobiprole and comparable drugs against different bloodstream isolates and different sequence types of methicillin-resistant Staphylococcus aureus (MRSA) in China. We found that MRSA, methicillin-susceptible Staphylococcus aureus (MSSA), and methicillin-susceptible coagulase-negative Staphylococcus (MSCNS) displayed ceftobiprole sensitivity rates of >95%, which are similar to the rates for linezolid, daptomycin, and vancomycin. Of the tested MRCNS strains, 90.4% were sensitive to ceftobiprole. The sensitivities of ST59, ST398, and ST22 MRSA to ceftobiprole were higher than that of ST239. Ceftobiprole's MIC50/90 value against Enterococcus faecalis was 0.25/2 mg/L, whereas Enterococcus faecium was completely resistant to this drug. Ceftobiprole exhibited no activity against ESBL-positive Enterobacterales, with resistance rates between 78.6% and 100%. For ESBL-negative Enterobacterales, excluding Klebsiella oxytoca, the sensitivity to ceftobiprole was comparable to that of ceftazidime, ceftriaxone, and cefepime. The MIC50/90 value of ceftobiprole against Pseudomonas aeruginosa was 2/16 mg/L, and for Acinetobacter baumannii, it was 32/>32 mg/L. Thus, ceftobiprole shows excellent antimicrobial activity against ESBL-negative Enterobacterales and Pseudomonas aeruginosa (comparable to that of ceftazidime, ceftriaxone, and cefepime); however, it is not effective against ESBL-positive Enterobacterales and Acinetobacter baumannii. These results provide important information to clinicians. [ABSTRACT FROM AUTHOR]

Low-affinity PBP4, historically linked to penicillin resistance in Enterococcus faecalis, may still have affinity for novel cephalosporins. Ceftobiprole (BPR) is a common therapeutic choice, even with PBP4-related overexpression and amino acid substitution due to mutations. Our study aims to explore the interaction between BPR and High-Molecular-Mass (HMM) low-reactive PBPs in Penicillin-Resistant-Ampicillin-Susceptible/Ceftobiprole Non-Susceptible (PRAS/BPR-NS) E. faecalis clinical isolates. We conducted competition assays examining class A and B HMM PBPs from four PRAS/BPR-NS E. faecalis strains using purified membrane proteins and fluorescent penicillin (Bocillin FL), in treated and untreated conditions. Interaction strength was assessed calculating the 50% inhibitory concentration (IC50) values for ceftobiprole, by analyzing fluorescence intensity trends. Due to its low affinity, PBP4 did not display significant acylation among all strains. Moreover, both PBP1a and PBP1b showed a similar insensitivity trend. Conversely, other PBPs showed IC50 values ranging from 1/2-fold to 4-fold MICs. Upon higher BPR concentrations, increased percentages of PBP4 inhibition were observed in all strains. Our results support the hypothesis that PBP4 is necessary but not sufficient for BPR resistance, changing the paradigm for enterococcal cephalosporin resistance. We hypothesize that cooperation between class B PBP4 and at least one bifunctional class A PBP could be required to synthesize peptidoglycan and promote growth. [ABSTRACT FROM AUTHOR]

Antibiotic resistance in Gram-positive pathogens is a relevant concern, particularly in the hospital setting. Several antibiotics are now available to treat these drug-resistant pathogens, such as daptomycin, dalbavancin, linezolid, tedizolid, ceftaroline, ceftobiprole, and fosfomycin. However, antibiotic resistance can also affect these newer molecules. Overall, this is not a frequent phenomenon, but it is a growing concern in some settings and can compromise the effectiveness of these molecules, leaving few therapeutic options. We reviewed the available evidence about the epidemiology of antibiotic resistance to these antibiotics and the main molecular mechanisms of resistance, particularly methicillin-resistant Sthaphylococcus aureus, methicillin-resistant coagulase-negative staphylococci, vancomycin-resistant Enterococcus faecium, and penicillin-resistant Streptococcus pneumoniae. We discussed the interpretation of susceptibility tests when minimum inhibitory concentrations are not available. We focused on the risk of the emergence of resistance during treatment, particularly for daptomycin and fosfomycin, and we discussed the strategies that can be implemented to reduce this phenomenon, which can lead to clinical failure despite appropriate antibiotic treatment. The judicious use of antibiotics, epidemiological surveillance, and infection control measures is essential to preserving the efficacy of these drugs. [ABSTRACT FROM AUTHOR]

In this paper, we describe the case of a patient admitted to our hospital because of a brain abscess due to Streptococcus intermedius. The management of brain abscess is challenging given the limited potential drug options with effective penetration into both the central nervous system and the abscess capsule to achieve adequate therapeutic concentrations. Due to the high anti-streptococcal activity of ceftobiprole and the availability of ceftobiprole therapeutic drug monitoring in our hospital, we decided to treat the patient with ceftobiprole. To maximize the antimicrobial effect of ceftobiprole, we chose a prolonged intravenous infusion, and we monitored its concentrations in both plasma and cerebrospinal fluid.

The overall low-quality evidence concerning the clinical benefits of different antibiotic regimens for the treatment of infective endocarditis (IE), which has made it difficult to strongly support or reject any regimen of antibiotic therapy, has led to a discrepancy between the available guidelines and clinical practice. In this complex scenario, very recently published guidelines have attempted to fill this gap. Indeed, in recent years several antimicrobials have entered the market, including ceftobiprole, ceftaroline, and the long-acting lipoglycopeptides dalbavancin and oritavancin. Despite being approved for different indications, real-world data on their use for the treatment of IE, alone or in combination, has accumulated over time. Furthermore, an old antibiotic, fosfomycin, has gained renewed interest for the treatment of complicated infections such as IE. In this narrative review, we focused on new antimicrobials and therapeutic strategies that we believe may provide important contributions to the advancement of Gram-positive IE treatment, providing a summary of the current in vitro, in vivo, and clinical evidence supporting their use in clinical practice. [ABSTRACT FROM AUTHOR]

This paper presents the theoretical calculations of the inclusion complex formation between native ceftobiprole, a promising antibiotic from the cephalosporin group, and selected cyclodextrins (CDs) approved by the European Medicines Agency. Ceftobiprole was studied in three protonation states predicted from pKa calculations, along with three selected CDs in a stoichiometric ratio of 1:1. It was introduced into the CD cavity in two opposite directions, resulting in 18 possible combinations. Docking studies determined the initial structures of the complexes, which then served as starting structures for molecular dynamics simulations. The analysis of the obtained trajectories included the spatial arrangement of ceftobiprole and CD, the hydrogen bonds forming between them, and the Gibbs free energy (ΔG) of the complex formation, which was calculated using the Generalised Born Surface Area (GBSA) equation. Among them, a complex of sulfobutyl ether- (SBE-) β-CD with protonated ceftobiprole turned out to be the most stable (ΔG = −12.62 kcal/mol = −52.80 kJ/mol). Then, experimental studies showed changes in the physiochemical properties of the ceftobiprole in the presence of the CDs, thus confirming the validity of the theoretical results. High-performance liquid chromatography analysis showed that the addition of 10 mM SBE-β-CD to a 1 mg/mL solution of ceftobiprole in 0.1 M of HCl increased the solubility 1.5-fold and decreased the degradation rate constant 2.5-fold. [ABSTRACT FROM AUTHOR]

Ceftobiprole is a fifth-generation cephalosporin used for different Gram-positive bacterial infections. A population pharmacokinetic analysis was conducted in real-life clinical patients to assess the adequacy of current dosages. Population pharmacokinetics was conducted using non-linear mixed effect modeling. Monte Carlo simulations were performed to determine the probability of target attainment (PTA) of free trough or steady-state concentration over MIC (fCtrough/MIC or fCss/MIC) ≥ 1 or ≥4 associated with both the standard and intensified dosing regimens adjusted for renal function. Cumulative fraction of response (CFR) against methicillin-resistant Staphylococcus aureus (MRSA) and Staphylococcus epidermidis (MRSE) were also calculated. A total of 132 patients with 503 concentrations were included. Most of them (107/132, 81.1%) had hospital- or community-acquired pneumonia, endocarditis, and bacteremia. A three-compartment model adequately fitted ceftobiprole concentration-time data. Estimated glomerular filtration rate significantly affected drug clearance. Monte Carlo simulations showed that the optimal target of fCtrough/MIC or fCss/MIC ≥ 4 is achieved only with the use of the standard dosages administered by continuous infusion (CI) against MRSA infections in patients with preserved renal function. Intensified dosages administered by CI are needed in patients with impaired renal function and/or augmented renal clearance against MRSA and in patients with preserved renal functions against MRSE. [ABSTRACT FROM AUTHOR]

Introduction: Hospital-acquired bacterial pneumonia (HABP) and ventilator-associated bacterial pneumonia (VABP) continue to be common infections causing significant morbidity and mortality worldwide. The timely initiation of empiric antimicrobial therapy is essential. In this paper, we provide a focused expert opinion on the current and potential empiric antimicrobial treatment options in HABP and VABP in Canada influenced by antimicrobial resistance impacting the use of older agents as well as available new intravenous (IV) antimicrobials. Areas covered: The authors discuss treatment options for HABP and VABP in Canada. In addition, we focus on the potential role of new IV antimicrobials recently introduced to Canada. A literature search of HABP and VABP treatments was performed via PubMed (up to March 2023), using the following key words: monotherapy, combination therapy, aminoglycosides, carbapenems, cephalosporins, fluoroquinolones, penicillins as well as amoxicillin/clavulanate, ceftobiprole, ceftolozane/tazobactam, dalbavancin, and fosfomycin. Expert opinion: Empiric antimicrobial treatment for HABP and VABP in Canada continues to focus on both the severity of illness and the presence/absence of patient risk factors for antimicrobial resistance. The role of new IV antimicrobials in the empiric treatment for HABP and VABP depends on their antimicrobial activity and published data on efficacy and safety and influenced by Health Canadaapproved indications. [ABSTRACT FROM AUTHOR]

Objectives: In the context of COVID-19, patients with a severe or critical illness may be more susceptible to developing secondary bacterial infections. This study aims to investigate the relationship between the use of prophylactic antibiotic therapy and the occurrence of bacterial or fungal isolates following the administration of tocilizumab in hospitalized COVID-19 patients who had previously received steroids during the first and second waves of the pandemic in Spain. Methods: This retrospective observational study included 70 patients hospitalized with COVID-19 who received tocilizumab and steroids between January and December 2020. Data on demographics, comorbidities, laboratory tests, microbiologic results, treatment, and outcomes were collected from electronic health records. The patients were divided into two groups based on the use of antibiotic prophylaxis, and the incidence of bacterial and fungal colonizations/infections was analyzed. Results: Among the included patients, 45 patients received antibiotic prophylaxis. No significant clinical differences were observed between the patients based on prophylaxis use regarding the number of clinically diagnosed infections, ICU admissions, or mortality rates. However, the patients who received antibiotic prophylaxis showed a higher incidence of colonization by multidrug-resistant bacteria compared to that of the subgroup that did not receive prophylaxis. The most commonly isolated microorganisms were Candida albicans, Enterococcus faecalis, Staphylococcus aureus, and Staphylococcus epidermidis. Conclusions: In this cohort of hospitalized COVID-19 patients treated with tocilizumab and steroids, the use of antibiotic prophylaxis did not reduce the incidence of secondary bacterial infections. However, it was associated with an increased incidence of colonization by multidrug-resistant bacteria. [ABSTRACT FROM AUTHOR]

Ceftobiprole is a fifth-generation cephalosporin approved by European and American regulatory agencies for the treatment of community-acquired pneumonia (CAP) and hospital-acquired pneumonia (HAP). Ceftobiprole administration is useful in severe CAP as well as HAP where the potential is to save other β-lactams including carbapenems or linezolid/vancomycin in clinical practice. The aim of this study was to report the real-world evidence of ceftobiprole in patients with CAP and HAP in a single center. In this retrospective study, we included 159 patients with CAP or HAP: 105 (66%) had CAP and 54 (34%) had HAP. The median age was 70 years (IQR 60–77), the median Charlson Comorbidity Index was 5 (IQR 3–7.5) and baseline INCREMENT ESBL score was 8 (IQR 6–11). Ceftobiprole was mostly given as a combination treatment (77%) or as a carbapenem-sparing strategy (44%). There were no differences in mortality between shorter and longer duration of treatment (p = 0.93) or between first-line (HR 1.00, C.I. 0.46–2.17, p = 0.989) and second-line therapy. Ceftobiprole use in CAP or HAP in the real world is effective as a first- and second-line treatment as well as a carbapenem-sparing strategy. Further studies are needed to explore the full potential of ceftobiprole, including its real-world use in antimicrobial stewardship programs.

Background: Ceftobiprole is a fifth-generation cephalosporin that has been approved in Europe solely for the treatment of community-acquired and nosocomial pneumonia. The objective was to analyze the use of ceftobiprole medocaril (Cefto-M) in Spanish clinical practice in patients with infections in hospital or outpatient parenteral antimicrobial therapy (OPAT). Methods: This retrospective, observational, multicenter study included patients treated from 1 September 2021 to 31 December 2022. Results: A total of 249 individuals were enrolled, aged 66.6 ± 15.4 years, of whom 59.4% were male with a Charlson index of four (IQR 2–6), 13.7% had COVID-19, and 4.8% were in an intensive care unit (ICU). The most frequent type of infection was respiratory (55.8%), followed by skin and soft tissue infection (21.7%). Cefto-M was administered to 67.9% of the patients as an empirical treatment, in which was administered as monotherapy for 7 days (5–10) in 53.8% of cases. The infection-related mortality was 11.2%. The highest mortality rates were identified for ventilator-associated pneumonia (40%) and infections due to methicillin-resistant Staphylococus aureus (20.8%) and Pseudomonas aeruginosa (16.1%). The mortality-related factors were age (OR: 1.1, 95%CI (1.04–1.16)), ICU admission (OR: 42.02, 95%CI (4.49–393.4)), and sepsis/septic shock (OR: 2.94, 95%CI (1.01–8.54)). Conclusions: In real life, Cefto-M is a safe antibiotic, comprising only half of prescriptions for respiratory infections, that is mainly administered as rescue therapy in pluripathological patients with severe infectious diseases. [ABSTRACT FROM AUTHOR]

Ceftobiprole, a fifth-generation cephalosporin, exhibits a broad-spectrum activity against common pathogens causing pneumonia, including multidrug-resistant organisms (MDROs), such as penicillin-resistant S. pneumoniae (PRSP) and methicillin-resistant Staphylococcus aureus (MRSA) and non-extended-spectrum β -lactamase (non-ESBL) producing Enterobacterales strains. Therefore, ceftobiprole should be considered as a potential alternative for the empirical treatment of pneumonia in patients with high risk for MDROs. In this review, we discussed the role of ceftobiprole in the treatment of patients with pneumonia. Ceftobiprole has several advantages in the treatment of pneumonia. First, ceftobiprole exerts its bactericidal activity by inhibiting transpeptidases, especially showing strong affinities to penicillin-binding protein (PBP) 2a, PBP2× and PBP3. Second, its plasma protein binding is minimal, allowing it to penetrate lung tissue and achieve high concentrations in epithelial lung fluid. Third, ceftobiprole exhibits potent in vitro activity against a wide range of susceptible pathogens, including S. aureus, S. pneumoniae, Viridans streptococci, H. influenzae, M. catarrhalis, Enterobacterales, and particularly, MRSA and P. aeruginosa. Finally, several randomized controlled trials have demonstrated the clinical efficacy and safety of ceftobiprole in the treatment of pediatric and adult patients with community-acquired pneumonia and hospital-acquired pneumonia (excluding ventilator-associated pneumonia). [ABSTRACT FROM AUTHOR]

Skin and soft tissue infections (SSTIs) are associated with significant morbidity and healthcare costs, especially when caused by methicillin-resistant Staphylococcus aureus (MRSA). Vancomycin is a preferred antimicrobial therapy for the management of complicated SSTIs (cSSTIs) caused by MRSA, with linezolid and daptomycin regarded as alternative therapeutic options. Due to the increased rates of antimicrobial resistance in MRSA, several new antibiotics with activity against MRSA have been recently introduced in clinical practice, including ceftobiprole, dalbavancin, and tedizolid. We evaluated the in vitro activities of the aforementioned antibiotics against 124 clinical isolates of MRSA obtained from consecutive patients with SSTIs during the study period (2020–2022). Minimum inhibitory concentrations (MICs) for vancomycin, daptomycin, ceftobiprole, dalbavancin, linezolid and tedizolid were evaluated by the MIC Test Strip using Liofilchem strips. We found that when compared to the in vitro activity of vancomycin (MIC90 = 2 μg/mL), dalbavancin possessed the lowest MIC90 (MIC90 = 0.094 μg/mL), followed by tedizolid (MIC90 = 0.38 μg/mL), linezolid, ceftobiprole, and daptomycin (MIC90 = 1 μg/mL). Dalbavancin demonstrated significantly lower MIC50 and MIC90 values compared to vancomycin (0.064 vs. 1 and 0.094 vs. 2, respectively). Tedizolid exhibited an almost threefold greater level of in vitro activity than linezolid, and also had superior in vitro activity compared to ceftobiprole, daptomycin and vancomycin. Multidrug-resistant (MDR) phenotypes were detected among 71.8% of the isolates. In conclusion, ceftobiprole, dalbavancin and tedizolid exhibited potent activity against MRSA and are promising antimicrobials in the management of SSTIs caused by MRSA. [ABSTRACT FROM AUTHOR]

Background: Enterococcus faecalis is responsible for a large variety of severe infections. This study is a case series reporting our experience in the treatment of E. faecalis invasive infections with ampicillin in combination with ceftobiprole (ABPR). Methods: We retrospectively analyzed all the medical records of patients admitted to the University Hospital of Udine from January to December 2020 with a diagnosis of infective endocarditis or primary or non-primary complicated or uncomplicated bacteremia caused by E. faecalis. Results: Twenty-one patients were included in the final analysis. The clinical success rate was very high, accounting for 81% of patients, and microbiological cure was obtained in 86% of patients. One relapse was recorded in one patient who did not adhere to the partial oral treatment prescribed. Therapeutic drug monitoring (TDM) was always performed for ampicillin and ceftobiprole, and serum concentrations of both drugs were compared to the MICs of the different enterococcal isolates. Conclusions: ABPR is a well-tolerated antimicrobial regimen with anti-E. faecalis activity. TDM can help clinicians optimize medical treatments to achieve the best possible efficacy with fewer side effects. ABPR might be a reasonable option for the treatment of severe invasive infections caused by E. faecalis due to the high level of enterococcal penicillin-binding protein (PBP) saturation. [ABSTRACT FROM AUTHOR]

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Bloodstream infections by bacteria, especially multidrug-resistant bacteria, remain a worldwide public health concern. We evaluated the antibacterial activity of ceftobiprole and comparable drugs against different bloodstream isolates and different sequence types of methicillin-resistant Staphylococcus aureus (MRSA) in China. We found that MRSA, methicillin-susceptible Staphylococcus aureus (MSSA), and methicillin-susceptible coagulase-negative Staphylococcus (MSCNS) displayed ceftobiprole sensitivity rates of >95%, which are similar to the rates for linezolid, daptomycin, and vancomycin. Of the tested MRCNS strains, 90.4% were sensitive to ceftobiprole. The sensitivities of ST59, ST398, and ST22 MRSA to ceftobiprole were higher than that of ST239. Ceftobiprole’s MIC50/90 value against Enterococcus faecalis was 0.25/2 mg/L, whereas Enterococcus faecium was completely resistant to this drug. Ceftobiprole exhibited no activity against ESBL-positive Enterobacterales, with resistance rates between 78.6% and 100%. For ESBL-negative Enterobacterales, excluding Klebsiella oxytoca, the sensitivity to ceftobiprole was comparable to that of ceftazidime, ceftriaxone, and cefepime. The MIC50/90 value of ceftobiprole against Pseudomonas aeruginosa was 2/16 mg/L, and for Acinetobacter baumannii, it was 32/>32 mg/L. Thus, ceftobiprole shows excellent antimicrobial activity against ESBL-negative Enterobacterales and Pseudomonas aeruginosa (comparable to that of ceftazidime, ceftriaxone, and cefepime); however, it is not effective against ESBL-positive Enterobacterales and Acinetobacter baumannii. These results provide important information to clinicians.

Low-affinity PBP4, historically linked to penicillin resistance in Enterococcus faecalis, may still have affinity for novel cephalosporins. Ceftobiprole (BPR) is a common therapeutic choice, even with PBP4-related overexpression and amino acid substitution due to mutations. Our study aims to explore the interaction between BPR and High-Molecular-Mass (HMM) low-reactive PBPs in Penicillin-Resistant-Ampicillin-Susceptible/Ceftobiprole Non-Susceptible (PRAS/BPR-NS) E. faecalis clinical isolates. We conducted competition assays examining class A and B HMM PBPs from four PRAS/BPR-NS E. faecalis strains using purified membrane proteins and fluorescent penicillin (Bocillin FL), in treated and untreated conditions. Interaction strength was assessed calculating the 50% inhibitory concentration (IC50) values for ceftobiprole, by analyzing fluorescence intensity trends. Due to its low affinity, PBP4 did not display significant acylation among all strains. Moreover, both PBP1a and PBP1b showed a similar insensitivity trend. Conversely, other PBPs showed IC50 values ranging from 1/2-fold to 4-fold MICs. Upon higher BPR concentrations, increased percentages of PBP4 inhibition were observed in all strains. Our results support the hypothesis that PBP4 is necessary but not sufficient for BPR resistance, changing the paradigm for enterococcal cephalosporin resistance. We hypothesize that cooperation between class B PBP4 and at least one bifunctional class A PBP could be required to synthesize peptidoglycan and promote growth.

Coagulase-negative staphylococci (CoNS) and especially Staphylococcus epidermidis are responsible for health care infections, notably in the presence of foreign material (e.g., venous or central-line catheters). Catheter-related bacteremia (CRB) increases health care costs and mortality. The aim of our study was to evaluate the impact of 15 days of antibiotic exposure (ceftobiprole, daptomycin, linezolid and vancomycin) at sub-inhibitory concentration on the resistance, fitness and genome evolution of 36 clinical strains of S. epidermidis responsible for CRB. Resistance was evaluated by antibiogram, the ability to adapt metabolism by the Biofilm Ring test® and the in vivo nematode virulence model. The impact of antibiotic exposure was determined by whole-genome sequencing (WGS) and biofilm formation experiments. We observed that S. epidermidis strains presented a wide variety of virulence potential and biofilm formation. After antibiotic exposure, S. epidermidis strains adapted their fitness with an increase in biofilm formation. Antibiotic exposure also affected genes involved in resistance and was responsible for cross-resistance between vancomycin, daptomycin and ceftobiprole. Our data confirmed that antibiotic exposure modified bacterial pathogenicity and the emergence of resistant bacteria. [ABSTRACT FROM AUTHOR]

ABSTRACT: Objectives: Ceftobiprole is approved for use in treatment of hospital-associated and community-acquired pneumonia in 16 different European countries and is currently undergoing clinical trials in the United States. Methods: Isolates were collected from hospital laboratories from 16 European countries during 2019 as part of an ongoing post-marketing surveillance study. MICs were determined using EUCAST broth microdilution methodology and interpreted using 2020 EUCAST breakpoints. Results: Ceftobiprole was active (MIC, ≤2 mg/L) against 100% and 99.3% of methicillin-susceptible Staphylococcus aureus and MRSA isolates collected in 2019. Against Streptococcus pneumoniae, ceftobiprole was active (MIC, ≤0.5 mg/L) against 98.4% of isolates. Overall, 77.4% of Enterobacterales were susceptible though isolate numbers in certain countries were notably low. In addition, based on non-species-related PK/PD breakpoints, 69.7% of Pseudomonas aeruginosa isolates were susceptible to ceftobiprole. Analysis of data by geographical regions showed that susceptibility to ceftobiprole by region or country was not significantly varied though MRSA, S. pneumoniae, Enterobacterales and P. aeruginosa. Isolates from Italy had lower susceptibilities to ceftobiprole: 98% of MRSA, 94% of S. pneumoniae and 61% of Enterobacterales isolates were susceptible to ceftobiprole. Conclusion: The data for ceftobiprole for isolates from 2019 are encouragingly very similar to studies performed on isolates from earlier years showing that susceptibility to ceftobiprole has not changed and, importantly, that resistance emergence remains low throughout Europe.

Ceftobiprole is a fifth-generation cephalosporin used for different Gram-positive bacterial infections. A population pharmacokinetic analysis was conducted in real-life clinical patients to assess the adequacy of current dosages. Population pharmacokinetics was conducted using non-linear mixed effect modeling. Monte Carlo simulations were performed to determine the probability of target attainment (PTA) of free trough or steady-state concentration over MIC (fCtrough/MIC or fCss/MIC) ≥ 1 or ≥4 associated with both the standard and intensified dosing regimens adjusted for renal function. Cumulative fraction of response (CFR) against methicillin-resistant Staphylococcus aureus (MRSA) and Staphylococcus epidermidis (MRSE) were also calculated. A total of 132 patients with 503 concentrations were included. Most of them (107/132, 81.1%) had hospital- or community-acquired pneumonia, endocarditis, and bacteremia. A three-compartment model adequately fitted ceftobiprole concentration-time data. Estimated glomerular filtration rate significantly affected drug clearance. Monte Carlo simulations showed that the optimal target of fCtrough/MIC or fCss/MIC ≥ 4 is achieved only with the use of the standard dosages administered by continuous infusion (CI) against MRSA infections in patients with preserved renal function. Intensified dosages administered by CI are needed in patients with impaired renal function and/or augmented renal clearance against MRSA and in patients with preserved renal functions against MRSE.

Objectives: In the context of COVID-19, patients with a severe or critical illness may be more susceptible to developing secondary bacterial infections. This study aims to investigate the relationship between the use of prophylactic antibiotic therapy and the occurrence of bacterial or fungal isolates following the administration of tocilizumab in hospitalized COVID-19 patients who had previously received steroids during the first and second waves of the pandemic in Spain. Methods: This retrospective observational study included 70 patients hospitalized with COVID-19 who received tocilizumab and steroids between January and December 2020. Data on demographics, comorbidities, laboratory tests, microbiologic results, treatment, and outcomes were collected from electronic health records. The patients were divided into two groups based on the use of antibiotic prophylaxis, and the incidence of bacterial and fungal colonizations/infections was analyzed. Results: Among the included patients, 45 patients received antibiotic prophylaxis. No significant clinical differences were observed between the patients based on prophylaxis use regarding the number of clinically diagnosed infections, ICU admissions, or mortality rates. However, the patients who received antibiotic prophylaxis showed a higher incidence of colonization by multidrug-resistant bacteria compared to that of the subgroup that did not receive prophylaxis. The most commonly isolated microorganisms were Candida albicans, Enterococcus faecalis, Staphylococcus aureus, and Staphylococcus epidermidis. Conclusions: In this cohort of hospitalized COVID-19 patients treated with tocilizumab and steroids, the use of antibiotic prophylaxis did not reduce the incidence of secondary bacterial infections. However, it was associated with an increased incidence of colonization by multidrug-resistant bacteria.

Ceftobiprole is a novel β-lactam antibiotic, active against methicillin-resistant Staphylococcus aureus, vancomycin-resistant S. aureus and penicillin-resistant Streptococcus pneumoniae. To artificially generate potential degradation products (DPs) of ceftobiprole that may be formed under relevant storage conditions, acidic, alkaline, oxidative, photolytic and thermolytic stress tests were performed in both solution and solid state. A novel selective HPLC method was developed for the separation of ceftobiprole from its DPs and synthesis by-products (SBPs) using Kinetex Biphenyl column, ammonium acetate buffer pH 5.8 and acetonitrile. The kinetic studies demonstrated the low stability of ceftobiprole in alkaline solution, in the presence of an oxidising agent and under irradiation with near UV. In the solid state, ceftobiprole underwent oxidation when the powder was irradiated with visible light and UV. Based on mass spectroscopic analysis, 13 new structural formulas of SBPs and DPs were proposed, along with molecular formulas for three other DPs obtained in solution and four oxidative DPs characteristic of solid-state degradation. [ABSTRACT FROM AUTHOR]

Background: Ceftobiprole is a fifth-generation cephalosporin which has been reported to have broad antibacterial spectrum when tested against bacteria collected from other countries except China. This study evaluated the in vitro activity of ceftobiprole in comparison with other comparators against clinically significant isolates collected across from China. Results: Susceptibility testing of ceftobiprole and comparators against 1163 clinically isolated Gram-positive and Gram-negative bacteria was performed with broth micro dilution method following the CLSI guidelines. All 110 S. aureus were susceptible to ceftobiprole with MIC50/90 of 1/2 mg/L for MRSA and 0.5/1 mg/L for MSSA. For Coagulase-negative staphylococci (CNS), MIC50/90 of ceftobiprole for MRCNS and MSCNS was 1/2 mg/L and 0.25/0.5 mg/L. Ceftobiprole demonstrated good potency against E. faecalis (MIC50/90 of 0.5/1 mg/L) but limited activity against E. faecium (MIC50/90 of > 32/ > 32 mg/L). Ceftobiprole demonstrated potent activity against all 39 β-hemolytic Streptococcus spp. with MIC50/90 ≤ 0.015/ ≤ 0.015–2 mg/L and 110 of PSSP with 98.2% susceptibility. Ceftobiprole inhibited all isolates of H. influenzae and M. catarrhalis at ≤ 1 mg/L. 91.8% and 98.2% of the ESBL-negative E. coli and K. pneumoniae were susceptible to ceftobiprole, but most of the ESBL-positive or carbapenem-resistant strains were also resistant to ceftobiprole. Ceftobiprole inhibited 84.2% of carbapenem-susceptible P. aeruginosa and 94.1% of carbapenem-susceptible A. baumannii at ≤ 8 mg/L, but only 52.6% of carbapenem-resistant P. aeruginosa and 5.3% of carbapenem-resistant A. baumannii. Conclusion: Ceftobiprole demonstrated good in vitro activity against a broad range of clinically relevant contemporary Gram-positive and Gram-negative bacterial isolates. [ABSTRACT FROM AUTHOR]

A quick and accurate chromatographic–densitometric method for the determination of ceftobiprole in biological material (whole blood and urine) was developed. Preparation of the test sample required extraction of the drug from the matrix and was carried out by testing methanol or acetone as extracting agents, which were successfully used to isolate ceftobiprole from biological material. Under optimization of the procedure, various stationary and mobile phases were tested. Lastly, HPTLC cellulose plates and a mixture containing ethanol, 2-propanol, glacial acetic acid, and water in the ratio 4:4:1:3 (v/v/v/v) were chosen. Densitometric detection was made at a maximum absorbance of 316 nm. The developed method was validated; a linear function of the ceftobiprole concentration was obtained in the range of 2.4–72 µg/mL (r > 0.99) for both methanol and acetone solutions. The average accuracy of the devised method was measured at nearly 100%; nevertheless, the limit of the quantification was at 8.92 for methanol and 9.14 µg/mL for acetone solution. Therefore, the above method can be successfully used to ceftobiprole in biological material. [ABSTRACT FROM AUTHOR]

The time of re-implantation of removed CIED for local infection or endocarditis has been debated because no randomized studies are available. Many authors prefer to delay reimplantation to the time of blood culture negative or clinical stability. In this case report we describe the case of E. faecalis CIED endocarditis treated with the combination ampicillin plus ceftobiprole and one-stage removal and re-implantation with early follow-up without relapse of infection. In case of E. faecalis infection, we hypothesize that ampicillin plus ceftobiprole combination might have bactericidal and anti-biofilm activity, therefore allowing one state re-implantation without relapse.

There is an increasing need for new synergistic antimicrobial combinations against multidrug-resistant bacteria. Our objective was to evaluate the activity of ceftaroline, ceftobiprole and their combination with trimethoprim/sulfamethoxazole against methicillin-resistant Staphylococcus aureus (MRSA) isolates recovered at two centers in Turkey. Activities of ceftaroline and ceftobiprole were tested against 100 MRSA isolates using gradient diffusion method. Activities of ceftaroline and ceftobiprole in combination with trimethoprim/sulfamethoxazole against 20 selected isolates (including all isolates that were non-susceptible to ceftaroline or ceftobiprole, and randomly selected isolates) were investigated using MIC:MIC ratio method. Antimicrobial interactions were interpreted using the fractional inhibitory concentration (FIC) index. The MIC 50 /MIC 90 values for ceftaroline and ceftobiprole were 0.75/1 and 1/1.5 mg/L, respectively. Ceftaroline and ceftobiprole susceptibility rates among 100 MRSA isolates were 94% and 96%, respectively. Ceftaroline, ceftobiprole and trimethoprim/sulfamethoxazole MICs of isolates were not increased when ceftaroline or ceftobiprole was combined with trimethoprim/sulfamethoxazole. Ceftobiprole- trimethoprim/sulfamethoxazole combination demonstrated additivity against 35%, whereas ceftaroline- trimethoprim/sulfamethoxazole combination demonstrated additivity against 10% of 20 MRSA isolates. The remaining interactions for MRSA isolates were indifference. Three (75%) of four ceftobiprole-resistant isolates became susceptible to ceftobiprole after adding trimethoprim/sulfamethoxazole. None of the ceftaroline non-susceptible isolates became susceptible to ceftaroline after adding trimethoprim/sulfamethoxazole. Ceftobiprole- trimethoprim/sulfamethoxazole combination may be a better treatment option than ceftaroline- trimethoprim/sulfamethoxazole combination for MRSA infections. Clinical studies are needed to confirm the results of our in vitro study.

Background: Ceftobiprole is a fifth-generation cephalosporin that has been approved in Europe solely for the treatment of community-acquired and nosocomial pneumonia. The objective was to analyze the use of ceftobiprole medocaril (Cefto-M) in Spanish clinical practice in patients with infections in hospital or outpatient parenteral antimicrobial therapy (OPAT). Methods: This retrospective, observational, multicenter study included patients treated from 1 September 2021 to 31 December 2022. Results: A total of 249 individuals were enrolled, aged 66.6 ± 15.4 years, of whom 59.4% were male with a Charlson index of four (IQR 2–6), 13.7% had COVID-19, and 4.8% were in an intensive care unit (ICU). The most frequent type of infection was respiratory (55.8%), followed by skin and soft tissue infection (21.7%). Cefto-M was administered to 67.9% of the patients as an empirical treatment, in which was administered as monotherapy for 7 days (5–10) in 53.8% of cases. The infection-related mortality was 11.2%. The highest mortality rates were identified for ventilator-associated pneumonia (40%) and infections due to methicillin-resistant Staphylococus aureus (20.8%) and Pseudomonas aeruginosa (16.1%). The mortality-related factors were age (OR: 1.1, 95%CI (1.04–1.16)), ICU admission (OR: 42.02, 95%CI (4.49–393.4)), and sepsis/septic shock (OR: 2.94, 95%CI (1.01–8.54)). Conclusions: In real life, Cefto-M is a safe antibiotic, comprising only half of prescriptions for respiratory infections, that is mainly administered as rescue therapy in pluripathological patients with severe infectious diseases.

ABSTRACT: Objectives: Ceftobiprole is approved for the treatment of hospital-acquired and community-acquired pneumonia in 17 different European countries and is currently undergoing clinical trials in the USA. Methods: In this study, isolates were collected from hospital laboratories from 15 European countries during 2018 as part of an ongoing post-marketing surveillance study. Minimum inhibitory concentrations (MICs) were determined using European Committee on Antimicrobial Susceptibility Testing (EUCAST) broth microdilution methodology and were interpreted using 2019 EUCAST breakpoints. Results: Ceftobiprole was active (MIC, ≤2 mg/L) against 100% and 98.9% of methicillin-susceptible Staphylococcus aureus and methicillin-resistant S. aureus (MRSA) from 2018, respectively. Only six MRSA isolates (1.1%) were resistant to ceftobiprole and originated from four countries. Against Streptococcus pneumoniae, ceftobiprole was active (MIC, ≤0.5 mg/L) against 98.7% of isolates. Overall, 75.6% of Enterobacterales were susceptible, although isolate numbers in certain countries were notably low. In addition, based on non-species-related pharmacokinetic/pharmacodynamic breakpoints, 63.2% of Pseudomonas aeruginosa isolates were susceptible to ceftobiprole. Conclusion: Data for ceftobiprole for isolates from 2018 are very similar to studies performed on isolates from earlier years, showing that susceptibility to ceftobiprole has remained high.

Background: Enterococcus faecalis is responsible for a large variety of severe infections. This study is a case series reporting our experience in the treatment of E. faecalis invasive infections with ampicillin in combination with ceftobiprole (ABPR). Methods: We retrospectively analyzed all the medical records of patients admitted to the University Hospital of Udine from January to December 2020 with a diagnosis of infective endocarditis or primary or non-primary complicated or uncomplicated bacteremia caused by E. faecalis. Results: Twenty-one patients were included in the final analysis. The clinical success rate was very high, accounting for 81% of patients, and microbiological cure was obtained in 86% of patients. One relapse was recorded in one patient who did not adhere to the partial oral treatment prescribed. Therapeutic drug monitoring (TDM) was always performed for ampicillin and ceftobiprole, and serum concentrations of both drugs were compared to the MICs of the different enterococcal isolates. Conclusions: ABPR is a well-tolerated antimicrobial regimen with anti-E. faecalis activity. TDM can help clinicians optimize medical treatments to achieve the best possible efficacy with fewer side effects. ABPR might be a reasonable option for the treatment of severe invasive infections caused by E. faecalis due to the high level of enterococcal penicillin-binding protein (PBP) saturation.

Skin and soft tissue infections (SSTIs) are associated with significant morbidity and healthcare costs, especially when caused by methicillin-resistant Staphylococcus aureus (MRSA). Vancomycin is a preferred antimicrobial therapy for the management of complicated SSTIs (cSSTIs) caused by MRSA, with linezolid and daptomycin regarded as alternative therapeutic options. Due to the increased rates of antimicrobial resistance in MRSA, several new antibiotics with activity against MRSA have been recently introduced in clinical practice, including ceftobiprole, dalbavancin, and tedizolid. We evaluated the in vitro activities of the aforementioned antibiotics against 124 clinical isolates of MRSA obtained from consecutive patients with SSTIs during the study period (2020–2022). Minimum inhibitory concentrations (MICs) for vancomycin, daptomycin, ceftobiprole, dalbavancin, linezolid and tedizolid were evaluated by the MIC Test Strip using Liofilchem strips. We found that when compared to the in vitro activity of vancomycin (MIC90 = 2 μg/mL), dalbavancin possessed the lowest MIC90 (MIC90 = 0.094 μg/mL), followed by tedizolid (MIC90 = 0.38 μg/mL), linezolid, ceftobiprole, and daptomycin (MIC90 = 1 μg/mL). Dalbavancin demonstrated significantly lower MIC50 and MIC90 values compared to vancomycin (0.064 vs. 1 and 0.094 vs. 2, respectively). Tedizolid exhibited an almost threefold greater level of in vitro activity than linezolid, and also had superior in vitro activity compared to ceftobiprole, daptomycin and vancomycin. Multidrug-resistant (MDR) phenotypes were detected among 71.8% of the isolates. In conclusion, ceftobiprole, dalbavancin and tedizolid exhibited potent activity against MRSA and are promising antimicrobials in the management of SSTIs caused by MRSA.

• Ceftobiprole is a 5th generation cephalosporin with antibacterial activity against a large range G+ and G− bacteria • TDM helps to maintain plasma concentrations of antibiotics well above the MIC , thus preventing the resistant strain diffusion • TDM is already recommended for other cephalosporins as it reasonably contributes to the safety and efficacy of these drugs • The set up of a routine HPLC-UV method validated for quantification of ceftobiprole supports its TDM as clinical stardard. Ceftobiprole is a recent 5th generation parenteral cephalosporin with antibacterial activity against a large range Gram+ and Gram− bacteria. Therapeutic drug monitoring (TDM) is an essential tool for maintaining plasma concentrations of antibiotics above the MIC by the end of the dosing interval, thus preventing the resistant strain diffusion. TDM is already recommended for other cephalosporins, and it is a reasonable tool contributing to the safety and efficacy of these drugs. During the treatment of patients in real-life, a number of pharmacokinetic (PK) changes not normally seen in healthy volunteers can occur which can impair the pharmacokinetic/pharmacodynamic target attainment. We aimed to develop simple and rapid HPLC-UV method for determination of ceftobiprole in human serum to implement TDM in clinical practice and support PKs and pharmacokinetic/pharmacodynamic (PK/PD) studies. Samples preparation of calibration standards, QC, and anonymous patients serum samples was performed by protein precipitation by adding 0.01 ml of sulphosalicylic acid at 30 % to 0.1 ml of each sample. Then samples were vortexed and the centrifuged at 12,000 rpm for 10 min at 4 °C. Fifty microlitres of clear supernatant were diluted 1:1 with mobile phase and transferred into HPLC autosampler held at 8 °C. Chromatographic separation was carried out in a gradient mode at 35 °C on an ultra-Biphenyl column using a Thermo Scientific chromatographic system with a Diode array. Data management was performed with Chromeleon 7.4 software. The HPLC-UV method proved to be linear over wide concentration ranges (0.5–50.0 mg/L) and was accurate and reproducible in the absence of matrix effects, allowing for robust, specific, and rapid quantification of ceftobiprole from a low amount of serum (0.1 mL). The mean steady state C trough and C end values measured in the anonymous patients' samples were 6.26 ± 3.81 mg/L and 22.56 ± 15.69 mg/L, respectively. We report a broadened simple and fast HPLC with UV detection method for quantification of ceftobiprole in human serum to implement ceftobiprole TDM as clinical routine, and support future (PK/PD) studies in special patients' population. [ABSTRACT FROM AUTHOR]

• A wide range of clinically important bacteria can cause complicated infections, leading to sepsis or septic shock. • Increased resistance makes treatment of these infections more challenging. • At least two antimicrobial agents are required to treat MRSA and aerobic Gram-negative bacilli, as no commercial antibiotic is effective against both strains. • Ceftobiprole (the novel advanced-generation cephalosporin) is the first agent in its class that exhibit in vitro activity against MRSA and P. aeruginosa. Various bacteria produce complicated infections that are difficult to treat worldwide. Ceftobiprole is effective against resistant Gram-positive and Gram-negative bacteria. This review assessed effectiveness and safety of ceftobiprole monotherapy for severe infections. A systematic review and meta-analysis of randomized controlled trials comparing clinical cure, microbiological cure, and safety of ceftobiprole alone to a combination or non-combination antibiotic regimen was conducted. Until December 20, 2022, we searched a major databases. This study includes 4168 patients from six trials. Ceftobiprole and comparator-received patients had similar clinical responses for all patient population. Also, the eradication rate of all organisms and specific pathogenic bacteria in microbiologically examined patients was comparable between the groups. Ceftobiprole induced more gastrointestinal side events than comparable drugs, mostly nausea [OR 1.91 (1.26-2.90), p = < 0.01 ]. While skin-related adverse events were significantly associated with comparator antibiotics [6 trials, 4062 patients; OR 0.77 (0.60-0.99), p =0.03]. Conclusion: Ceftobiprole monotherapy is effective and safe for severe infections caused by Gram-positive or Gram-negative bacteria. [ABSTRACT FROM AUTHOR]

• When tcaA was deleted, all selected strains were more susceptible to β-lactams. • Ceftobiprole susceptibility was restored when tcaA was deleted. • tcaA knockout caused abnormal MRSA division. • The expression of tcaA is necessary for the upregulation of mecA when MRSA faces OXA pressure. • tcaA , which was discovered by machine learning, is a potential resistance breaker target for β-lactams in MRSA. Using a random forest algorithm, we previously found that teicoplanin-associated gene A (tcaA) might play a role in resistance of methicillin-resistant Staphylococcus aureus (MRSA) to β-lactams, which we have investigated further here. Representative MRSA strains of prevalent clones were selected to identify the role of tcaA in the MRSA response to β-lactams. tcaA genes were deleted by homologous recombination in the selected MRSA strains, and antibiotic susceptibility tests were applied to evaluate the effect of tcaA on the minimum inhibitory concentrations (MICs) of glycopeptides and β-lactams. Scanning electron microscopy, RNA sequencing, and quantitative reverse transcription-polymerase chain reaction were performed to explore the mechanism of tcaA in MRSA resistance to β-lactams. The MIC of penicillin plus clavulanate decreased from 3 mg/L to 0.064 mg/L and that of oxacillin decreased from 16 to 0.5 mg/L when tcaA was knocked out in the LAC strain. Compared with wild-type MRSA isolates, when tcaA was deleted, all selected strains were more susceptible to β-lactams. Susceptibility to ceftobiprole was restored in the ceftobiprole-resistant strain when tcaA was deleted. tcaA knockout caused "log-like" abnormal division of MRSA, and tcaA deficiency mediated low expression of mecA, ponA , and murA2. Machine learning is a reliable tool for identifying drug resistance-related genes. tcaA may be involved in S. aureus cell division and may affect mecA, ponA, and murA2 expression. Furthermore, tcaA is a potential resistance breaker target for β-lactams, including ceftobiprole, in MRSA. [Display omitted] [ABSTRACT FROM AUTHOR]

(Z)-2-(5-Amino-1,2,4-thiadiazole-3-yl)-2-(methoxyimino)acetic acid, an important intermediate prod-uct in the synthesis of Ceftobiprole, was prepared from cyanoacetamide via oximation, methylation, dehydration, oxidation, etherification, bromination, and cyclization with an overall yield of 57%. The structures of the target product and intermediates in each step were characterized by mass spectrometry and 1H NMR. [ABSTRACT FROM AUTHOR]