A systematic review was conducted to evaluate the safety and efficacy of drugs approved by the United States Food and Drug Administration for the treatment of complicated urinary tract infections between 2016 and 2023. The primary endpoint for all drugs used in treating complicated urinary tract infections was the cure rate. Among the drugs used for treating complicated urinary tract infections, meropenem had the highest cure rate at 91.4%, followed by plazomicin at 88% and cefiderocol at 73% when used as monotherapy. In combination therapy, meropenem-vaborbactam had the highest cure rate at 98.4%, followed by piperacillin-tazobactam at 94%, and ceftazidime-avibactam at 87.5%. The safety profiles of the drugs indicated that almost all drugs caused gastrointestinal symptoms, with imipenem-relebactam and colistin-imipenem combinations having the most serious adverse events. Cefiderocol had a low magnitude of adverse events, with most side effects being mild gastrointestinal symptoms.

Bone and joint infections (BJIs) caused by multidrug-resistant bacteria are becoming more frequent. However, data on the use of novel β-lactam/β-lactamase inhibitors, such as imipenem/cilastatin/relebactam (I-R) and meropenem/vaborbactam (MVB), to treat BJIs is lacking. Furthermore, prolonged infusions of these β-lactams should theoretically optimize pharmacokinetic/pharmacodynamics target in these indications, but there are currently no reports on these types of infusions, especially in the setting of BJI. A case of a vertebral osteomyelitis caused by carbapenem-resistant Enterobacter cloacae successfully treated with extended-infusion of I-R (1.25 g q6h over 2 h), then with continuous infusion of MVB (2 g q4h as over 4 h) is recently reported. The favourable outcome of this patient treated for a vertebral osteomyelitis caused by carbapenem-resistant E. cloacae suggest that extended- and continuous infusions of I-R and MVB, are promising regimens for treatment of BJIs caused by carbapenem-resistant Enterobacterales.

Recently, an increase in cases of multidrug-resistant Gram-negative bacteria post-neurosurgical ventriculitis and meningitis has been reported. Treating these infections has become challenging due to the limited availability of antibiotics and the need to select those with optimal pharmacodynamic and pharmacokinetic profiles. There is limited evidence regarding the use of meropenem-vaborbactam in treating carbapenem-resistant Enterobacterales infections of the central nervous system. The authors report 2 new cases of shunt-related ventriculitis due to carbapenem-resistant K. pneumoniae with a favourable microbiological evolution after IV only combination therapy with meropenem-vaborbactam. The first case was of a 41-year-old man hospitalized for a ruptured arteriovenous malformation managed with the placement of an external ventricular drain (EVD). Forty-eight hours after EVD placement, fever arose, and blood, urine, and cerebrospinal fluid (CSF) samples were collected, all resulting positive for KPC-Kp. According to antibiotic susceptibility profile MVB was used instead of empirical ceftazidime-avibactam therapy. The first control sample of CSF was collected and tested negative for culture 72 h after the initiation of MVB therapy. The second case was a 64-year-old female patient hospitalized for ischemic stroke complicated by cerebral oedema, who underwent a decompressive craniotomy. The postoperative course was complicated by craniotomy wound infection, so surgical debridement was performed. Pus samples collected during surgery were positive for ESBL-producing K. pneumoniae, so empirical therapy already started with meropenem was continued. Ten days later, obstructive hydrocephalus appeared, so an external spinal drain (ESD) was placed, and intra-operative CSF samples were collected. Cultural examination was positive for K. pneumoniae, which showed increased minimal inhibitory concentrations (MIC) for carbapenems despite carbapenemases not being detected by the immunochromatographic assay. Based on the antibiotic susceptibility profile, meropenem was replaced by combined therapy with MVB (administered as for patient 1) plus IV ciprofloxacin (400 mg q8h), according to an eGFR of 95 ml/min. After 48 h, the initial CSF sample was obtained and tested negative for culture, as did subsequent CSF samples collected on days + 4, +6, + 9, and + 11. These case reports add knowledge to the effectiveness of MVB in combination IV therapy or the treatment of shunt-related ventriculitis and emerge in selected cases as a possible intrathecal-sparing regimen if administered with an extended infusion time.

To evaluate the susceptibility profiles of regional meropenem-resistant (MEM-R) potential non-class B carbapenemase-producing Enterobacterales (CPE) isolates (without confirmation by phenotypic tests) against important antibiotics, the authors extracted data from the 2018-2022 Antimicrobial Testing Leadership and Surveillance. This data included susceptibility information of MEM-R potential non-class B CPE isolates against indicated antibiotics – amikacin [AMK], gentamicin [GM], ceftazidime-avibactam [CZA], colistin [CST], meropenem-vaborbactam [MVB], and tigecycline [TGC] – from sepsis patients hospitalized in ICUs across six major regions. Carbapenemase-encoding genes of the tested CPE isolates, determined by multiplex PCR and Sanger sequencing, were also analysed. Susceptibility breakpoints recommended by CLSI 2024 and US FDA criteria (for TGC only) against Enterobacterales were employed. A total of 1,500 potential non-class B CPE isolates (89% of which were K. pneumoniae) were tested globally. Resistance rates to AMK and GM against the evaluated isolates were statistically higher in Africa/the Middle East, Europe, and India compared to other regions. A similar pattern was observed in the susceptibility of these potential CPE isolates to CZA and MVB. High CST resistance rates were noted in Asia, Latin America, and Europe (29%-35%). Furthermore, the proportions of potential CPE isolates carrying genes encoding bla_OXA variants were notably higher among the tested CPE isolates in India, Europe, and Africa/the Middle East regions (99.2%, 53.3%, and 96.7%, respectively) compared to other regions.

This study aimed to outline dosing strategies and therapeutic drug monitoring protocols for new β-lactam antibiotics effective against MDR-GNB in critically ill patients undergoing extracorporeal life support techniques at a national level. Additionally, the study sought to develop a consensus document, based on the available evidence, through a National Survey. The antimicrobials included was meropenem, ceftazidime/avibactam, ceftolozane/tazobactam, cefiderocol, meropenem/vaborbactam, imipenem/relebactam, and aztreonam. Extracorporeal life support techniques included continuous renal replacement therapy, conventional intermittent haemodialysis, and extracorporeal membrane oxygenation. The availability of extracorporeal life support techniques has expanded significantly in recent years, alongside a rise in the prevalence of infections caused by multidrug-resistant gram-negative bacilli (MDR-GNB). There is a need to develop evidence-based tools of high quality to standardize dosing and monitoring strategies for new β-lactam antibiotics.

This study aimed to elucidate the resistance mechanisms and assess the combined synergistic and bactericidal activities of aztreonam in combination with ceftazidime/avibactam (CZA), meropenem/vaborbactam (MEV), and imipenem/relebactam (IMR) against Enterobacterales strains producing dual carbapenemases. In vitro synergistic and bactericidal activities of the combination of aztreonam with CZA, MEV and IMR against these strains were determined using checkerboard assay and time-kill curve assay. A total of 12 Enterobacterales strains producing dual-carbapenemases were collected, including nine K. pneumoniae, two P. rettgeri, and one E. hormaechei. The most common dual-carbapenemase gene pattern observed was bla _{(KPC-2+NDM-5)} (n=4), followed by bla _KPC-2+IMP-26 (n=3), bla _{(KPC-2+NDM-1)} (n=2), bla _{(KPC-2+IMP-4)} (n=1), bla _{(NDM-1+IMP-4)} (n=1) and bla _{(KPC-2+KPC-2)} (n=1). The results of the checkerboard synergy analysis consistently revealed good synergistic effects of the combination of ATM with CZA, MEV and IMR.

This study aimed to describe the initial uses and efficacy of MVB for compassionate treatment during the first 21 months following its early access in France. Ultimately, 21 patients from 15 French hospitals were included in this national multicentre retrospective study. The main indication for MVB treatment was respiratory tract infections (n = 9). The targeted bacteria included P. Aeruginosa (n = 12), K. pneumoniae (n = 3), Enterobacter spp (n = 3), Citrobacter freundii (n = 1), E. coli (n = 1), and Burkholderia multivorans (n = 1). Overall, no significant advantage of vaborbactam over meropenem alone was observed across all strains of P. aeruginosa in terms of in vitro susceptibility. However, MVB demonstrated a notable impact, compared to carbapenem alone, on the MIC for the two KPC-3-producing K. pneumoniae and B. multivorans.

In this study, the authors discovered bla_KPC-90 in ceftazidime-avibactam resistant clinical isolates of K. pneumoniae from a patient with multiple comorbidities. KPC-90 isolates had an insertion of two amino acids (Thr180_Ser181 ins Tyr Thr) compared to the wildtype KPC-2. Antimicrobial susceptibility testing of isolates with KPC-90 vs. KPC-2 showed ceftazidime-avibactam MICs of >128 vs. 1-2 mg/L, meropenem-vaborbactam MICs of 4 vs. 1 mg/L, meropenem MICs of 4-8 vs. >128 mg/L and imipenem MICs of 0.5-1 vs. 64 mg/L. Analysis of kinetic parameters of KPC-90 compared to KPC-2 showed decreased hydrolysis of carbapenems and increased IC50 of avibactam. Genetic characterization of the plasmid revealed that IS26 could mediate the intramolecular inversion, translocation and truncation of the resistance determinant region.

Authors conducted a retrospective, observational study at 17 Italian haematological wards that included patients with haematological malignancies (HMs) receiving ceftazidime/avibactam for the treatment of suspected or proven infections. Of 198 patients enrolled, 66 had fever of unknown origin and 132 had microbiologically proven infections (MPIs). Enterobacterales were responsible for 98 MPIs, with KPC producers accounting for 75% of these, and carbapenem-resistant Pseudomonas aeruginosa caused 25% of MPIs. The overall 30-day mortality rate was 17.7%. Infection relapse occurred in four patients with MPI. Patients who died within 30 days of infection onset tended to have pre-existing cerebrovascular diseases, a Charlson Comorbidity Index > 4 and septic shock at infection onset and had received inadequate initial antibiotic therapy. Thirty-day mortality was independently associated with septic shock at infection onset and inappropriate initial antibiotic therapy. This study provides further evidence about the effectiveness of ceftazidime/avibactam in treating infections in patients with HMs.

The aim of this study was to perform a pharmacokinetic–pharmacodynamic (PK/PD) evaluation of recommended dosing regimens of ceftazidime–avibactam (CAZ–AVI) in ICU patients with different degrees of renal function for a specific strain of P. aeruginosa. A semi-mechanistic PK/PD model has been developed, that it allows for the simulation of CAZ–AVI steady-state plasma level curves and the evolution of bacterial growth curves. The percentage of bacterial load reduction and the value of the recommended PK/PD indices have been considered to define the success or failure of the regimens. In both populations, dosing regimens endorsed for patients with clearance of creatinine (CLcr) higher than 10 mL/min reach the PK/PD indices recommended, T > MIC > 90% and C_min/MIC > 1.3. While dosage regimens endorsed for patients with CLcr of 10 mL/min or lower fail (T > MIC < 60% and C_min/MIC < 0.35). However, proposed dosing regimens based on shortening dosing intervals for these patients would be successful, increasing bacterial load reduction by almost 50% and reaching the proposed PK/PD indices. Therefore, CAZ–AVI dosing strategies based on model-informed precision dosing (MIPD) could directly influence the efficacy of results in ICU patients with renal insufficiency.

Study’s aim was to identify variables associated with treatment failure during the use of ceftazidime/avibactam for CRE infections and assess the effect of combining an aminoglycoside with ceftazidime/avibactam. Retrospective study of 303 CRE-infected patients treated with ceftazidime/avibactam between 2015 and 2021 in 134 Veterans Affairs (VA) facilities. The overall 30-day and in-hospital mortality rates were 12.5% and 24.1%, respectively. In the subgroup of patients that received an aminoglycoside (n=77), their use in combination with ceftazidime/avibactam had a 30-day mortality a OR of 0.321. In veterans treated with ceftazidime/avibactam for CRE infections, increased age, receipt of an empiric aminoglycoside, and presence in the ICU at the time of index culture were associated with higher 30-day mortality. Among patients who received an aminoglycoside, their use in combination with ceftazidime/avibactam trended toward protectiveness of 30-day mortality, suggesting a potential role for this combination to treat CRE infections in patients who are more severely ill.

Study conducted to investigate decreased susceptibility (minimum inhibitory concentrations [MICs] 0.25–4 mg/L) and resistance (MICs > 4 mg/L) to aztreonam-avibactam (ATM-AVI); contemporary non-replicate clinical isolates of carbapenemase-producing E.coli (CP-EC) (n=90) and ESBL-producing E. coli (EP-EC) (n=12) were used. The EUCAST epidemiological cut-off value of 0.125 mg/L was used to define the wild type (WT). Among 102 isolates, 40 (39%) and 62 (61%) were WT and non-WT, respectively. Resistance was observed among 14/47 New Delhi metallo-β-lactamase (NDM)-producers, 5/43 OXA-48 group producers, and 1/12 EP-EC. Resistance to ATM-AVI is observed across NDM-, OXA-48 group- and ESBL- producing isolates of E. coli. Decreased susceptibility/resistance to ATM-AVI is mediated by alterations in penicillin-binding protein (PBP) 3. resistance to ATM-AVI is a result of interplay of various determinants, including target alterations, deactivating enzymes, and decreased permeability.

This hospital-based, single-centre retrospective study was conducted between April 2020 and March 2022 using data from inpatient records. Data from 46 patients (mean age = 65.2 ± 14.5 years, 73.9% male) were included. Ceftazidime–avibactam treatment was initiated within 5 days of hospitalization in 51.2% of patients. The median duration of treatment was 8 days, and the average daily dose was 4.6 g. Inpatient and 30-day all-cause mortality rates were 41.5% and 17.1%, respectively. Authors observed clinical success, predefined by day 14, in 58.5% of patients and microbiological cure in 61.3%. 97.0% patients did not have recurrent infections. The median length of hospitalization and ICU admission was 15.5 days and 11 days, respectively. Most patients (85.7%) utilized various healthcare resources during hospitalization. Among patients with available data, most showed clinical success (58.5%) and microbiological cure (61.3%) within 14 days of treatment initiation with ceftazidime–avibactam, with nearly no recurrence of infection, indicating treatment effectiveness in patients with intra-abdominal sepsis or urosepsis in an Indian hospital setting

This observational prospective study aimed to describe the use and outcome of CAZ-AVI in a pediatric intensive care unit (PICU). Ten patients were included, with 12 episodes of clinical suspicion or confirmed multidrug-resistant (MDR) bacterial infections treated with CAZ-AVI for surgical prophylaxis, suspicion of sepsis, pneumonia, and surgical wound infection. Of these patients, 80% received empirical treatment because of previous MDR bacterial colonization, and 60% were administrated combination therapy with aztreonam for Metallo-β-Lactamases (MBL)strains. No bacteria were resistant to CAZ-AVI. The average duration of the treatment was 3 days when cultures turned negative and 7 days when MDR bacteria were isolated. The most frequent use of CAZ-AVI in our PICU was the short-term empirical treatment for patients with previous MDR bacterial colonization and clinical suspicion of bacteremia or sepsis.

Tolerance/persistence to CAZ-AVI was detected with Tolerance Disk Test (TDtest) in 48/80 (60%) isolates, all extensively drug-resistant (XDR) or multidrug-resistant, carbapenem-resistant K. pneumoniae (CRKp), KPC producers, and previously categorized as susceptible (not resistant) to CAZ-AVI. No heteroresistance was detected. CAZ-AVI tolerance/persistence occurred due to ceftazidime tolerance/persistence and was not related to CAZ-AVI in the CZA combination. Among the K. pneumoniae bloodstream isolates studied, 60%, previously categorized as susceptible to CAZ-AVI, were, actually, tolerant/persistent to this antibiotic, all these KPC producers. All the CAZ-AVI-tolerant/persistent isolates harboured the carbapenemase-encoding gene blaKPC−2. Mutation in only two genes (rpoS and degQ) related to beta-lactam tolerance/persistence was found in only 7/49 CAZ-AVI-tolerant/persistent isolates, suggesting the presence of yet unknown beta-lactam tolerance/persistence genes

This study aimed to design an artificial intelligence-clinical decision support system (AI-CDSS) using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) and machine learning for the rapid detection of ceftazidime-avibactam (CZA) resistance in KP to improve clinical decision-making processes. Out of 107,721 bacterial samples, 675 specimens of KP with suspected multi-drug resistance were selected. Authors used MALDI-TOF MS and machine learning to develop an AI-CDSS with enhanced speed of resistance detection. The study confirms that MALDI-TOF MS, integrated with machine learning, can swiftly detect CZA resistance. Incorporating this insight into an AI-CDSS could transform clinical workflows, giving healthcare professionals immediate, crucial insights for shaping treatment plans.

Four commercial tests EUMDROXFÒ Sensititre microplates, MTS gradient strips, and disc diffusion were evaluated for imipenem-relebactam susceptibility in 148 ceftazidime and imipenem-resistant P. aeruginosa strains, using broth microdilution (BMD) as the reference. EUMDROXF^Ò Sensititre microplates showed the highest accuracy (CA=93.2%, EA=93.9%, and bias difference +21.8%). While the MTS gradient strips showed acceptable performance (CA= 84.5%; EA=89.9%, and difference of bias =21.0%), the disc method misclassed 25.8% (16/62) of the resistant strains. Given these results, considering an Area of Technical Uncertainty (ATU) for disc diffusion (21-24 mm) in imipenem-relebactam testing is recommended for P. aeruginosa strains.

The authors report a case of pneumonia induced by multiple Gram-negative pathogens including a carbapenem-resistant Klebsiella pneumoniae developing cefiderocol resistance within 32 days of cefiderocol therapy. Whole genome sequencing of 3 consecutive K. pneumoniae isolates revealed the bacteria were isogenic and were carrying several broad-spectrum β-lactamases (bla_NDM5 and bla_CTX-M-15) and 2 isolates with elevated MIC against cefiderocol harbored mutations in genes encoding siderophore. The combination of a metallo-β-lactamase background and mutations in siderophore receptors was associated with phenotypic resistance to cefiderocol.

A 72-year-old female patient with sepsis caused by KP NDM, OXA 48 was admitted to the ICU, immediately after an emergency graftectomy (of a recently transplanted kidney) complicated with bleeding. Because of suspicion of intra-abdominal infection, a broad-spectrum empirical antibiotic therapy was initiated (meropenem, vancomycin, colistin). The patient underwent an abdominal revision 48h after admission. On the 3rd day of hospitalization, diagnosis of a septic shock with aetiology of KP NDM, OXA 48 was made. The strain had sensitivity to colistin and cefiderocol (CFDC). On 13th day in the ICU a relaparotomy was performed. Again, KP strains with sensitivity to CFDC only, were cultured from intra-abdominal fluid. Aztreonam, in combination with meropenem/vaborbactam, were included in the treatment and were used together with colistin and tigecycline. In the following days, the inflammatory markers decreased slightly, but the patient’s general condition did not improve. On day 27 ceftazidime/avibactam and aztreonam were added, while colistin, meropenem/vaborbactam and fosfomycin were discontinued. On 37th day of hospitalization, CFDC became available in hospital and was included in the treatment. CFDC monotherapy was continued for 8 days. After 4 days of CFDC treatment, the inflammatory markers CRP and PCT decreased and a significant improvement in patient’s condition were observed. On day 56, the patient was transferred to another department. A surgical debridement of a source infection, and usage of meropenem/vaborbactam or ceftazidime/avibactam together with aztreonam and colistin allowed survival of the patient but not full recovery. Ultimately, only the CFDC monotherapy was effective in treatment of the patient with septic shock of KP NDM OXA 48 aetiology.

This study compared the in vitro activity of delafloxacin (with other fluoroquinolones against bacterial pathogens recovered from inpatients with osteomyelitis, Acute Bacterial Skin and Skin-Structure Infections (ABSSSI). Total 100 bacterial isolates (58 % Gram-negative and 42 % Gram-positive) recovered from inpatients. AST conducted using the broth microdilution method and the detection of biofilm formation was assessed through the microtiter plate assay and the screening for mecA was carried out by PCR. Results showed that delafloxacin exhibited greater in vitro potency (at least 64-times) than the other tested fluoroquinolones (levofloxacin and ciprofloxacin) when evaluating Staphylococcus aureus (MIC50 ≤0.008 mg/L) and coagulase-negative Staphylococcus (MIC50 0.06 mg/L). Furthermore, delafloxacin (MIC50 0.25 mg/L) was at least 4 times more potent than other tested fluoroquinolones (MIC50 1 mg/L) against P. aeruginosa. No difference in delafloxacin activity (MIC50 0.03 mg/L) was observed against Enterobacter cloacae when compared with ciprofloxacin (MIC50 0.03 mg/L). Despite presenting low activity against K. pneumoniae isolates (22.2 %), delafloxacin exhibited twice the activity compared to both levofloxacin and ciprofloxacin. Delafloxacin also exhibited a strong activity (71.4 %‒85.7 %.) against biofilm producing bacterial pathogens tested in this study. Interestingly, 82.14 % of the staphylococci tested in this study harboured mecA gene.

Susceptibility of delafloxacin on 199 osteoarticular levofloxacin-resistant staphylococci strains was reported in 49% and 1% using SSTI S. aureus breakpoint (0.25 mg/L) and general S. aureus breakpoint (0.016 mg/L) respectively. Fifty percents levofloxacin-resistant staphylococci showed resistance to delafloxacin using CA-SFM/EUCAST recommendations.

This is a report of a case of a 48-year-old male with haematological malignancy and graft failure post hematopoietic stem cell transplantation complicated by dialysis-dependent acute kidney injury and recurrent neutropenic fevers due to vancomycin-resistant Enterococcus faecium (VREf) bacteraemia. Despite central line changes, and strict aseptic precautions, the bacteraemia returned, showing resistance to daptomycin and linezolid after the second recurrence. As a final effort, using limited clinical data and in vitro studies, authors utilized oritavancin (ORI) off-label as salvage therapy for refractory VREf bacteraemia, with subsequent clearance of blood cultures. This is a rare case of successful off-label use of ORI for recurrent multidrug-resistant VREf bacteraemia in a patient with haematological malignancy after undergoing hematopoietic stem cell transplantation. Patients with haematological malignancies, especially those who undergo hematopoietic stem cell transplantation (HSCT), are at a particularly high risk for VRE infection, with mortality ranging from 40-100%. SO, it’s important to increase awareness of the potential use of this novel antibiotic with increasing resistance of VREf to first-line agents.

This study describes the clinical outcomes and adverse reactions related to ORI. This was a retrospective study conducted over a 5-year period at a tertiary care medical centre. Ninety-five adult patients were included in this study and were followed for 1 year after the last dose of ORI. The most common indication for ORI at our institution was osteomyelitis, followed by ABSSSI. Other indications were vertebral infection, hardware-associated infection, bacteraemia and infective endocarditis. Fourteen percent (13/95) of patients developed an adverse reaction to ORI during the study period. Cure with no recurrence up to 1 year after the last dose of ORI was achieved in 74% (53/71) of patients, and the treatment failure rate was 19% (14/71 patients). ORI is an effective agent that can be used to treat invasive Gram-positive bacterial infections other than ABSSSI. Adverse events requiring drug discontinuation were common

Authors reported a case of a man in his eighties with a late shoulder PJI caused by methicillin resistant S. epidermidis (MRSE) with contraindications for surgical replacement and few oral therapeutic options for a long term suppressive antibiotic therapy. The prosthesis was retained, and the patient received ten outpatient sequential doses of 1200 mg of ORI for 28 weeks, based on therapeutic drug monitoring (TDM) as a guide for correct timing of administration of each dose. During ORI administration, the patient achieved clinical cure, with disappearance of the pain and regaining pre-infection joint mobility, with no side effects reported and no further surgery or hospitalization needed. The treatment is ongoing as a long-lasting suppressive antimicrobial therapy. ORI could represent an excellent solution for treating PJI caused by MR organism, especially in patients who need a long-term suppressive therapy.

Vascular graft infections (VGIs) represent a life-threatening complication, occurring in 0.2-6% of patients following aortic prosthetic placements. Historically, the primary focus for reducing VGIs has been on prevention. Currently, antimicrobial grafts are not available on the market. This study aimed to evaluate the efficacy of combining two antibiotics, fosfomycin and oritavancin, impregnated into the commercially available Gelweave^TM vascular graft as a prophylactic alternative against the most commonly implicated bacteria responsible for VGI. The antimicrobial activity of fosfomycin and oritavancin was assessed using the broth microdilution method, and a synergistic effect was demonstrated using the checkerboard assay against Staphylococcus epidermidis, methicillin-resistant Staphylococcus aureus, and vancomycin-resistant Enterococcus faecium. Eradication of all microorganisms tested was achieved using impregnation solutions with concentrations of 40 mg/mL of fosfomycin and 256 µg/mL of oritavancin. Impregnation with the combination of fosfomycin/oritavancin proved to be a promising approach to prevent VGIs.

The aim of this study was to elucidate possible molecular targets of ORI in human and microbes in relevance to its mechanism of action and model its pharmacokinetics for optimal dose selection in clinical practice. Computational methods were used in this study which include target prediction, molecular docking, molecular dynamics simulation, pharmacokinetics prediction, and physiological-based pharmacokinetics (PBPK) modelling. ORI was moderately soluble in water and did not permeate the blood-brain barrier. Seven molecular targets were identified in humans. Molecular docking results showed highest binding affinity of ORI with PI3-kinase p110-gamma subunit, followed by Acyl-CoA desaturase and Cytochrome P450 2C19. ORI PBPK modelling in adult human showed that infusion has lower peak concentrations (C_max) compared to bolus administration, with 1200 mg dose yielded C_max of 16.559 mg/L, 800 mg dose yielded C_max of 11.258 mg/L, and 200 mg over 3 days dose yielded C_max of 7.526 mg/L. Notably, infusion gave extended half-life (t1/2) for all doses and slightly higher clearance rates compared to bolus, particularly for the 1200 mg and 800 mg doses. The results corroborated existing clinical pharmacokinetic data and confirmed the model’s accuracy and predictive capability. This comprehensive computational study has provided invaluable insights into the pharmacological profile of ORI, aiding its further development and optimization for clinical use.

Authors conducted a systematic review to describe the clinical efficacy and the safety of dalbavancin in for infective endocarditis (IE) treatment. in fact, they searched for available evidence using the MEDLINE (PubMed), Embase, Scopus, Cochrane Library and Web of Science libraries, with no restrictions regarding the publication year. The risk of bias was performed using the Cochrane ROBINS-I tool for the comparative studies and the Newcastle-Ottawa Scale for descriptive studies. Nine observational studies were included. Native valve endocarditis was the most common kind of IE found in the studies’ populations (128/263, 48.7%), followed by prosthetic valve endocarditis, and cardiovascular implantable electronic device-related endocarditis. Coagulase-negative Staphylococci were the most common pathogens isolated (83/269, 30.1%), followed by S. aureus, Enterococci spp and Streptococci spp. Five out of nine studies documented a clinical failure rate of less than 10%. Dalbavancin showed a favourable safety profile and appears to be a promising option for the consolidation therapy of IE. However, further studies comparing dalbavancin with standard of care are needed.

The aim of this retrospective analysis is to evaluate the safety and efficacy of dalbavancin in real life settings for both in-label and off-label indications. It enrolled 100 consecutive patients treated with dalbavancin between May 2017 and September 2021 and followed up for 6 months after treatment (58% male; median age 63.5 years, median Charlson Comorbidity Index CCI = 2.7, 28% inpatients). Infection type were acute bacterial skin and skin structure infections (22%), bone and prosthetic infections (57%), and cardiovascular infections (19%). Infections were caused by MSSA (30%), MRSA (5%), MR-CoNS (20%), and Streptococcus spp. (8%). The overall clinical success rate was 84%-91% for registered and 82% for unregistered indications. The prescription of higher loading doses was the only predictor independently associated with better outcomes in multivariate models (OR: 5.2, 95%CI: 1.5-17.9, p < 0.01).