Skin Structure Infections Research Articles

Ceftobiprole Medocaril: A New Fifth-Generation Cephalosporin.

The objective was to review the pharmacology, efficacy, and safety of intravenous ceftobiprole in the treatment of bloodstream infections, acute bacterial skin and skin structure infections (ABSSSIs), community-acquired pneumonia (CAP), and hospital-acquired pneumonia (HAP), or ventilator-associated pneumonia (VAP). PubMed and ClinicalTrials.gov were searched using the following terms: ceftobiprole, ceftobiprole medocaril, ceftobiprole medocaril sodium, Zevtera, and BAL5788. Articles published in English between January 1985 and August 15, 2024, related to pharmacology, safety, efficacy, and clinical trials were reviewed. Ceftobiprole has shown similar efficacy to comparator antibiotics in CAP, ABSSSIs, and bloodstream infections. Overall treatment success in patients with bacteremia was 69.8% and 68.7%; 91.3% and 88.1% with ABSSSIs and 86.6% and 87.4% with CAP in ceftobiprole and comparator groups, respectively. Finally, in the management of HAP and VAP, ceftobiprole was inferior in the VAP population. Ceftobiprole had a favorable safety profile with gastrointestinal adverse effects occurring more frequently than comparators. Clinicians have limited options to treat multidrug-resistant infections. Ceftobiprole has demonstrated efficacy against causative pathogens in specific infections including methicillin-resistant Staphylococcus aureus bacteremia (SAB), ABSSSI, and CAP and may be considered a viable alternative. However, ceftobiprole's impact on HAP, VAP, and febrile neutropenia needs to be further delineated. Ceftobiprole's broad-spectrum activity makes it a viable option for treating patients hospitalized with CAP, ABSSSI, and SAB. Further studies are needed in severely ill HAP or VAP, febrile neutropenia, and pediatric patients.

Pharmacokinetic/pharmacodynamic analysis of tedizolid phosphate against Staphylococcus aureus and Streptococcus pneumoniae in children, adolescents, and adults by Monte Carlo simulation

The objective of this study was to investigate the cumulative fraction of response of various dosage regimens of tedizolid phosphate against Staphylococcus aureus and Streptococcus pneumoniae in children, adolescents, and adults. Monte Carlo simulations (MCSs) were performed using previously published pharmacokinetic parameters and pharmacodynamic data to evaluate the efficacy of the simulated dosage strategies in terms of area under the concentration-time curve/minimum inhibitory concentration targets of tedizolid. According to the results of the MCSs, currently approved dosage regimens of tedizolid phosphate were effective in the treatment of acute bacterial skin and skin structure infections (ABSSSIs) caused by methicillin-susceptible Staphylococcus aureus (MSSA) and methicillin-resistant Staphylococcus aureus (MRSA) including vancomycin intermediate, heterogeneous vancomycin intermediate, and daptomycin-non-susceptible MRSA in adult and pediatric patients aged 12 years and older. However, high-dose regimens of tedizolid phosphate should be the preferred option to optimize efficacy against ABSSSIs caused by linezolid-resistant MRSA, particularly cfr-mediated isolates. Furthermore, the dosage regimens of 3 and 4 mg/kg/day of tedizolid phosphate were appropriate to treat ABSSSIs caused by MSSA and MRSA in children aged 2 to 6 and 6 to 12 years, respectively. Moreover, approved dosage regimens of tedizolid phosphate for patients older than 12 years may be sufficient against Streptococcus pneumoniae pneumonia but insufficient for Staphylococcus aureus pneumonia. For neutropenic patients, almost all the simulated regimens of tedizolid phosphate were ineffective against Staphylococcus aureus and Streptococcus pneumoniae. These pharmacokinetics/pharmacodynamics-based simulations rationalize and optimize the dosage regimens of tedizolid phosphate against Staphylococcus aureus and Streptococcus pneumoniae in children, adolescents, and adults.

Safety and Efficacy of Dalbavancin in Real Life: Retrospective Analysis of a Large Monocentric Case Series of Patients Treated for Skin/Soft Tissue and Other Difficult-to-Treat Infections.

Background: Dalbavancin is a long-acting lipoglycopeptide, approved for treatment of skin and skin structure infections. Its PK/PD profile and safety allow for short hospital stays even in the case of difficult-to-treat infections requiring long courses of therapy, e.g., osteomyelitis, cardiovascular, and prosthetic infections. Objectives: We aimed to evaluate the safety and efficacy of dalbavancin in real life settings for both in-label and off-label indications. Methods: retrospective evaluation of all consecutive patients treated with dalbavancin at our site between May 2017 and September 2021. Results: A total of 100 patients treated with dalbavancin and followed up for 6 months after treatment (58% male; median age 63.5 years, median Charlson Comorbidity Index CCI = 2.7, 28% inpatients) were included with the following indications: 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%). In 32 cases, no isolate was obtained. The average number of infusions was 5 (s.d. = 3). Neither ensuing alteration of renal function nor neutropenia or thrombocytopenia were observed during treatment and follow-up. Two self-limiting skin rashes occurred. 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). Conclusions: Dalbavancin proved to be effective for skin and skin structure infections, as well as for difficult-to-treat infections in highly comorbid patients. Regarding tolerability, our results support the use of dalbavancin for long-lasting treatments of deep-seated infections.

Evaluating omadacycline dosing regimens against drug-resistant pathogens including Staphylococcus aureus, Streptococcus pneumoniae and Haemophilus influenzae in adults: a pharmacokinetic/pharmacodynamic analysis using Monte Carlo simulation.

The objective of this study was to evaluate the efficacy of various dosing regimens of omadacycline against main drug-resistant pathogens in the treatment of acute bacterial skin and skin structure infections (ABSSSI) and community-acquired bacterial pneumonia (CABP). Monte Carlo simulations were conducted using pharmacokinetic parameters and pharmacodynamic data to calculate cumulative fractions of response (CFRs) in terms of drug area under the concentration curve/minimum inhibition concentration targets.CFR ≥ 90% was considered optimal for a dosage regimen. CFR of any approved oral/intravenous regimen with loading-dose was ≥ 90% against methicillin-resistant Staphylococcus aureus (MRSA) for ABSSSI and penicillin-resistant Streptococcus pneumonia, tetracycline-resistant Streptococcus pneumonia, MRSA and β-lactamase positive Haemophilus influenzae for CABP. In conclusion, approved oral/intravenous loading and maintenance doses of omadacycline showed enough efficacy in the treatment of ABSSI and CABP caused by the main drug-resistant pathogens.

Serum Pharmacokinetics and Bone Penetration of Novel Broad-Spectrum Anti-MRSA Agent Levonadifloxacin in Wistar Rats.

Objectives: Levonadifloxacin (IV) and alalevonadifloxacin (oral) are novel broad-spectrum anti-methicillin-resistant Staphylococcus aureus (S. aureus) agents based on novel benzoquinolizine core. Both are recently approved in India for the treatment of acute bacterial skin and skin structure infections, including diabetic foot infections and concurrent bacteremia. The present investigation reports the findings from preclinical pharmacokinetic (PK) studies that support the development of levonadifloxacin as a treatment option for bone and joint infections (BJIs). Methods: PK profiles of levonadifloxacin were obtained in serum, and/or various anatomical segments of femoral bone such as whole bone (WB), hard bone (HB), and bone marrow (BM) following subcutaneous administration of levonadifloxacin single doses at 50, 100, 200, and 400 mg/kg, as well as multiple doses at 200 mg/kg (BID (two times a day), 6 hours apart) for 5 days in Wistar rats. Results: The distribution of levonadifloxacin in bone was rapid, and the extent of distribution (B/S ratio; bone-to-serum area under the concentration-time curve ratio) was nearly comparable across bone segments. In single-dosage PK studies, the mean B/S ratio in WB, HB, and BM was 0.40, 0.33, and 0.34, respectively; however, in 5 days' repeated dose studies, it increased to 1.01, 1.14, and 0.61, respectively. Conclusions: On the basis of bone PK data in Wistar rat and ever-growing clinical experience in terms of safety and efficacy, levonadifloxacin has the potential to offer a well-differentiated therapy for the treatment of BJIs.

Complicated skin and skin structure infections in alcoholics, a retrospective cohort study

Background Alcoholism increases the risk of skin and skin structure infections (SSSIs). Furthermore, in complicated SSSIs (cSSSIs) alcoholism is associated with delayed treatment response and a higher risk of blood culture positivity, suggesting poor outcomes. In pneumonia and bacteremia alcoholism is linked with higher mortality, longer hospital treatment and more ICU treatment. Methods We conducted a population-based retrospective cohort study including all cases of complicated skin and skin structure infections (n = 460) treated in Gothenburg, Sweden and Helsinki, Finland from 2008 − 2011. Patients were stratified as alcoholics (9%) and non-alcoholics (91%) and patient and disease factors, treatment, and outcomes were compared. Results Alcoholics were comparatively younger and more often male, with more liver diseases. We observed higher rates of bacteraemia, intensive care unit admission, surgical intervention, and clinical failure in alcoholics. Alcoholism was associated with longer length of stay and more interdepartmental transfers. We did not observe differences in infection type or time from symptom onset to diagnosis. Mortality was low and equivalent in alcoholics and non-alcoholics. Conclusions Alcoholism is associated with increased cSSSI disease severity and resource utilisation.

Intravenous Versus Oral Omadacycline or Linezolid for Acute Bacterial Skin and Skin Infections: A post hoc Analysis of the OASIS Trials.

Appropriate oral antibiotic therapy for the treatment of acute bacterial skin and skin structure infections (ABSSSI) is a challenge, as current oral treatment guidelines do not fully cover the most common skin pathogens. Both linezolid and omadacycline are available as intravenous or bioequivalent oral formulations. This post hoc analysis of the OASIS-1 (ClinicalTrials.gov identifier NCT02378480) and OASIS-2 (ClinicalTrials.gov identifier NCT02877927) phase 3 trials assessed safety and clinical efficacy of intravenous (IV)-start versus oral (PO)-start therapy in patients treated with omadacycline or linezolid for ABSSSI. In OASIS-1, patients were randomized to IV omadacycline or linezolid, with optional switch to oral therapy, while patients in OASIS-2 received oral omadacycline or linezolid. Treatment was provided for 7-14days in both studies. The primary endpoint was an early clinical response (ECR) at 48 to 72h, defined as survival and ≥ 20% reduction in lesion size, without rescue antibacterial therapy. A total of 645 IV-start inpatients and 735 PO-start outpatients were assessed. Median age was 47years for the IV-start group and 44years for the PO-start group. Most patients had solely gram-positive infections (97% in each group; ECR [85.2% IV-start and 85.0% PO-start]), and the incidence of treatment-emergent adverse events (AEs) was similar between the groups. The most frequent AEs observed were nausea (11.2% [IV-start] versus 18.9% [PO-start]) and subcutaneous abscess (5.6% [IV-start] versus 1.9% [PO-start]). Discontinuation due to AEs was infrequent in both groups (2% [IV-start] versus 1.2% [PO-start]). Oral therapy is equally efficacious to IV therapy when omadacycline or linezolid is used to treat ABSSSIs. These data strengthen the evidence for oral omadacycline as a therapeutic option for ABSSSI, particularly for patients who have experienced treatment failure because of the limitations of other therapies. Clinicaltrials.gov, NCT02378480 and NCT02877927.

Population pharmacokinetics/pharmacodynamics of minocycline plus rifampicin in patients with complicated skin and skin structure infections caused by MRSA.

The population pharmacokinetics/pharmacodynamics (PK/PD) of minocycline, rifampicin and linezolid in patients with complicated skin and soft tissue infections (cSSTIs) caused by MRSA are described. Samples were collected in a Phase 4 study of oral minocycline plus rifampicin versus linezolid showing minocycline plus rifampicin to be non-inferior to linezolid. Antibiotics were assayed by HPLC or LC-MS, and a population PK model was developed using Pmetrics. The association between PK/PD indices and patient outcomes was explored. A three-compartment model (with an absorption compartment) with first-order input and elimination best described the data for the three drugs. No covariates were included in the final model. The population median values (95% credibility limits) of the clearance and volume of distribution were 7.412 L/h (5.121-8.361) and 14.155 L (6.799-33.901) for minocycline, 5.683 L/h (3.703-7.726) and 7.736 L (6.031-8.948) for rifampicin, and 1.970 L/h (1.326-2.499) and 20.169 L (12.857-32.629) for linezolid, respectively. Maximum a posteriori probability-Bayesian estimation plots of observed versus predicted had a slope of 0.999 r20.967 for minocycline, slope 0.998 r20.769 for rifampicin and slope 0.998 r20.895 for linezolid. PK/PD indices were not related to clinical outcome. Taking a translational minocycline fAUC24h/MIC target of >0.5 for minocycline in the presence of rifampicin, 96% (49/51) of patients reached the target. Population PK models of minocycline, rifampicin and linezolid were developed in patients with MRSA cSSTI and almost all patients reached the predefined PD index targets. As a result, neither AUC, MIC nor the AUC/MIC ratio could be related to clinical outcome.

Efficacy and Safety of Antibiotics in the Treatment of Methicillin-Resistant Staphylococcus aureus (MRSA) Infections: A Systematic Review and Network Meta-Analysis.

Vancomycin is a first-line drug for the treatment of MRSA infection. However, overuse of vancomycin can cause bacteria to become resistant, forming resistant strains and making infections more difficult to treat. This study aimed to evaluate the efficacy and safety of different antibiotics in the treatment of MRSA infections and to compare them, mainly with vancomycin, to find better vancomycin alternatives. All studies were obtained from the PubMed and Embase databases from inception to 13 April 2023. The three comprehensive indicators of clinical cure success rate, clinical microbiological success rate, and adverse reactions were evaluated, and the clinical cure success rates of three disease types, complex skin and skin structure infections (cSSSIs), complex skin and soft tissue infections (cSSTIs), and pneumonia, were analyzed in subgroups. All statistical analyses were performed using R and STATA 14.0 software for network meta-analysis. A total of 38 trials with 6281 patients were included, and 13 drug treatments were evaluated. For MRSA infections, the results of network meta-analysis showed that the clinical success rates of linezolid, the combination of vancomycin and rifampin, and the combination of minocycline and rifampin were better than that of vancomycin (RR 1.71; 95%-CI 1.45-2.02), (RR 2.46; 95%-CI 1.10-5.49) (RR, 2.77; 95%-CI 1.06-7.21). The success rate of clinical microbiological treatment with vancomycin was inferior to that with telavancin (RR 0.74; 95%-CI 0.55-0.99). Linezolid had a higher rate of adverse reactions than teicoplanin (RR 5.35; 95%-CI 1.10-25.98). Subgroup analysis showed that vancomycin had a lower clinical success rate than linezolid in the treatment of MRSA-induced cSSSIs, cSSTIs, and pneumonia (RR 0.59; 95%-CI 0.44-0.80) (RR 0.55; 95%-CI 0.35-0.89) (RR 0.55; 95%-CI 0.32-0.93). This systematic review and NMA provide a new comparison framework for the clinical treatment of MRSA infection. The NMA suggests that linezolid may be the antibiotic of choice for the treatment of MRSA infections, with the ability to improve clinical and microbiological success rates despite its disadvantage in terms of adverse effects. At the same time, the combination of minocycline and rifampicin may be the most effective drug to treat MRSA-induced cSSSIs, tedizolid may be the best drug to treat MRSA-induced cSSTIs, and the combination of vancomycin and rifampicin may be the most effective treatment for MRSA-induced pneumonia. More high-quality studies are still needed in the future to further identify alternatives to vancomycin. PROSPERO registration number CRD42023416788.

Infectious Foci, Comorbidities and Its Influence on the Outcomes of Septic Critically Ill Patients.

Sepsis is among the most frequent diagnoses on admission to the intensive care unit (ICU). A systemic inflammatory response, activated by uncontrolled infection, fosters hypoperfusion and multiorgan failure and often leads to septic shock and mortality. These infections arise from a specific anatomic source, and how the infection foci influence the outcomes is unknown. All patients admitted to the ICU of Hospital de Vila Franca de Xira, between 1 January 2017 and 31 June 2023, were screened for sepsis and categorized according to their infection foci. During the study period, 1296 patients (32.2%) had sepsis on admission. Their mean age was 67.5 ± 15.3 and 58.1% were male; 73.0% had community-acquired infections. The lung was the main focus of infection. Septic shock was present in 37.9% of the patients and was associated with hospital mortality. Severe imbalances were noted in its incidence, and there was lower mortality in lung infections. The hospital-acquired infections had a slightly higher mortality but, after adjustment, this difference was non-significant. Patients with secondary bacteremia had a worse prognosis (one-year adjusted hazard ratio of 1.36, 95% confidence interval 1.06-1.74, p = 0.015), especially those with an isolated non-fermenting Gram-negative infection. Lung, skin, and skin structure infections and peritonitis had a worse prognosis, whilst urinary, biliary tract, and other intra-abdominal infections had a better one-year outcome.

Excessive prescription duration is a major contributor of inappropriate antibiotic use in primary care

ObjectivesIn France, 75% of systemic antibiotics are prescribed by general practitioners (GPs) in primary care. We aimed to estimate the burden of inappropriate use related to excessive prescription duration. Patients and methodsIn 2021, we performed a cross-sectional and pharmaco-economic study of a network of six GPs. The references for optimal durations were those of the French national guidelines for antibiotic prescription. ResultsOut of 196 antibiotic prescriptions, 33.7 % were of excessive duration, with a mean excess of 0.9 [0.86–0.94] to 1.6 [1.45–1.72] days per prescription. Ear, nose, and throat, respiratory tract, and skin and skin structure infections were the main infections associated with excessive prescription. The pharmaco-economic analysis showed that the cost of excessive prescription duration would range from an estimated 151 to 262 million € in France in 2021. ConclusionAddressing excessive antibiotic prescription duration by GPs may represent a powerful and cost-saving tool in antimicrobial stewardship programs.

Assessment of pharmacokinetics-pharmacodynamics to support omadacycline dosing regimens for the treatment of patients with acute bacterial skin and skin structure infections.

Pharmacokinetic-pharmacodynamic (PK-PD) relationships for efficacy were evaluated using data from omadacycline-treated patients with acute bacterial skin and skin structure infections (ABSSSI) enrolled in two phase 3 studies. Patients received omadacycline 100 mg intravenously (IV) every 12 hours for two doses, followed by 100 mg IV every 24 hours (q24h), with the option to switch to 300 mg oral (PO) q24h after 3 days or 450 mg PO q24h for two doses, followed by 300 mg PO q24h for a total duration of 7-14 days. Clinical response was evaluated at 48-72 hours [early clinical response (ECR)], end of treatment (EOT), and 7-14 days after EOT. Using a population pharmacokinetic (PK) model and PK data from patients with Staphylococcus aureus at baseline, omadacycline free-drug plasma area under the concentration-time curve (AUC) values were determined, and the relationships between free-drug plasma AUC:MIC ratio and dichotomous efficacy endpoints were evaluated. Using these relationships, the population PK model, simulation, and an omadacycline MIC distribution for S. aureus, mean percent probabilities of response were evaluated. Statistically significant PK--PD relationships were identified for ECR (P = 0.016 and 0.013 for optimized two- and three-group free-drug plasma AUC:MIC ratios, respectively). At an MIC value of 0.5 µg/mL, percent probabilities of model-predicted success for ECR based on the univariable PK-PD relationships using continuous and two-group free-drug plasma AUC:MIC ratio variables were 91.9 and 95.6%, respectively, for the IV-to-PO dosing regimen and 89.3 and 88.4%, respectively, for the PO-only dosing regimen. These data support for omadacycline IV-to-PO and PO-only dosing regimens for ABSSSI and an omadacycline susceptibility breakpoint of 0.5 µg/mL for S. aureus.

Usefulness of dalbavancin in early discharge and nonhospitalization. It's time to throw your heart over the obstacle?

Dalbavancin is a semisynthetic lipoglycopeptide long-acting antibiotic approved for the treatment of acute bacterial skin and skin structure infections (ABSSSIs). Its features can be useful in the current healthcare scenario characterized by the shortage of available hospital beds. We implemented several actions in order to optimize the use of dalbavancin allowing an improvement strategy both from the healthcare system and the patient's perspective in two hospital settings. In the Emergency Department we hospitalized only patients who met the clinical criteria and not the logistic criteria (i.e., the need for antibiotic therapy infusion). During the years 2017-2023, this strategy was applied in 40 cases, thus avoiding 40 hospitalizations for a total saving of 280 days of hospitalization.In the Internal Medicine ward and surgery department when there was no longer any need for hospitalization, we discharged the patient as early as possible. During the years 2017-2023, this strategy was applied in 189 cases, saving at least 1,134 days of hospitalization. The outcome of the treated patients was favorable in 228 out of 229 patients (99.5%). Our experience using dalbavancin in ABSSSI has been very satisfactory overall. The efficacy was close to 100%. Minor adverse events of slight severity occurred rarely. At the same time, this strategy allowed a more efficient allocation of hospital beds. Dalbavancin presents an ideal pharmacodynamic/pharmacokinetic profile for the management of ABSSSI especially in settings where shortage of hospital beds is critical.

Analysis of bacteraemia caused by group C and G Streptococcus (Streptococcus dysgalactiae subsp. equisimilis) in Western Sydney over a 6-year period (2015-2020).

Streptococcus dysgalactiae subsp. equisimilis (SDSE) has increasingly been recognised as a significant pathogen that causes a myriad of infections, ranging from cellulitis to invasive infections, including bacteraemia and even toxic shock syndrome. The aim of this study was to examine the epidemiology and disease manifestations of bacteraemia caused by SDSE. We retrospectively reviewed cases of SDSE bacteraemia in adults aged ≥ 18 years admitted to four public hospitals in Western Sydney, Australia, between January 2015 and December 2020. We reviewed demographics, comorbidities, disease manifestations, management, and outcomes. There were 108 patients with SDSE bacteraemia over a six-year period. The median age of individuals with SDSE bacteraemia was 70 years (interquartile range, IQR, 58-85 years). Cardiovascular disease (46%), chronic skin conditions (44%) and diabetes (37%) were the most common comorbidities. Ten patients (9%) with SDSE bacteraemia had healthcare-acquired infections. Skin and skin structure infections (SSTIs) were the most common presentations (59%), while bone and joint infections (BJIs) represented 13% of the cases. Twenty patients (19%) had septic shock on presentation. Fifteen patients (14%) were prescribed clindamycin, while one patient received intravenous immunoglobulin (IVIg). Infective endocarditis (IE) was present in 3% of patients; however, only 44% of the total patients had an echocardiogram. The 30-day mortality rate was 13%, but it was greater in those aged > 75 years (21%). The average length of hospital stay for patients who survived was 15 days, and the average duration of intravenous therapy was 12 days. SDSE bacteraemia is typically a community-onset infection with a fifth of patients in our cohort presenting with septic shock. Though complications such as BJI (13%) and IE (3%) are infrequent, 30-day mortality is high at 21% in those aged > 75 years.

Off-label use of dalbavancin in children: a case series.

Dalbavancin is an antibiotic active against most Gram-positive bacteria approved for acute bacterial skin and skin structure infections (ABSSSI). Owing to its long half-life, it is being increasingly used for other indications. We present a case series of children and adolescents treated with dalbavancin for osteoarticular, catheter-related and other non-ABSSSI infections. Dalbavancin was prescribed to 15 patients. Six (40%) were female and median age at prescription was 11.9 (IQR 1.3-18.0) years. Most of them (12/15) had significant comorbidities. Patients presented mainly with deep surgical site infections, osteoarticular infections and central-line-associated bloodstream infections. The most common isolate was Staphylococcus aureus followed by Staphylococcus epidermidis. Major reasons to prescribe dalbavancin were to ensure compliance and patients' convenience. Two patients discontinued the drug due to adverse events possibly related to it. The rest of the patients completed the treatment with dalbavancin, with a median duration of 56 days (IQR 17.5, 115.5). All achieved complete resolution and present no relapse after a median follow-up of 9.9 months (IQR 4.8, 16.6). Dalbavancin was a safe, effective and convenient alternative in selected paediatric patients with complicated non-ABSSSI infections caused by Gram-positive bacteria.

Check of APpropriaTeness of Antimicrobial therapy In Nursing homes (CAPTAIN):a point prevalence study in Belgium.

The overall prevalence of antimicrobial therapy (AMT) in nursing homes is well described. However, less is known about the appropriateness of AMT in nursing home residents. Therefore, the Check of APpropriaTeness of antimicrobial therapy in nursing homes (CAPTAIN) study aimed to assess both prevalence and appropriateness of AMT in Belgian nursing homes. In a prospective, observational, point prevalence study, researchers documented prevalence and identified potentially inappropriate prescriptions (PIPs) by evaluating accordance of AMT with national guidelines. The severity of inappropriateness was assessed by a modified Delphi expert panel. Eleven nursing homes, including 1178 residents, participated in this study. On the survey day, 8.0% of residents took systemic AMT, primarily for urinary tract infections (54.2%), respiratory tract infections (36.5%), and skin and skin-structure infections (6.3%). About half of these prescriptions were used in prophylaxis (52.1%). Registration of indication and stop date was missing in 58.3% and 56.3% of AMTs, respectively. In 89.6% of the systemic AMTs, at least one discordance with national guidelines was identified, resulting in a total of 171 PIPs, with 49 unique PIPs. Of all unique PIPs, 26.5% were assessed with a high severity score (≥4). According to the expert panel, most inappropriate practice was starting AMT for cough without other symptoms. Inappropriate timing of time-dependent AMTs was common, but assessed as 'moderately severe'. One-third of systemic AMT exceeded the recommended duration. AMT in nursing homes is often not prescribed according to national guidelines, highlighting the need for future interventions to promote the rational use of AMT in this setting.

Ceftazidime-Avibactam as a Salvage Treatment for Severely Infected Immunosuppressed Children.

Multidrug-resistant Gram-negative bacteria (MDR-GNB) are becoming increasingly common around the world, with carbapenems frequently serving as a last resort but being threatened by the growing incidence of carbapenemase-producing bacteria. Ceftazidime-avibactam (CAZ/AVI) is a potential agent against MDR-GNB but with limited clinical experience, particularly in critically ill immunosuppressed children. This study analyzed the use of CAZ/AVI as salvage treatment in severely infected immunosuppressed children from September 2019 to July 2022. Patients with confirmed GNB infection who received CAZ/AVI were matched with patients who received other antibiotics. Twenty-five critically ill immunosuppressed children treated with CAZ/AVI were included. The majority had hematologic diseases. All patients presented with sepsis in all 30 courses. Septic shock presented in 36.7% of these courses. The primary sites of infection included bloodstream infection (20.0%), skin and skin structure infection (20.0%), intra-abdominal infection (13.3%) and hospital-acquired pneumonia (10.0%). Twelve of the 25 (48.0%) patients had positive microbiological cultures, mainly Pseudomonas aeruginosa and Klebsiella pneumoniae, including 5 carbapenem-resistant GNB-infected cases. Fifteen (50.0%) courses presented clinical improvement. For the initial course of each patient, the clinical response rate of the GNB recovered group was significantly higher than that of the group without GNB recovery (66.7% vs 23.1%, P = 0.047). The 14-day and 30-day mortality rates were 24.0% and 28.0%, respectively, which were significantly correlated with the absence of GNB recovery (P = 0.004 and 0.024, respectively) and hospital-acquired pneumonia as the primary site of infection (P = 0.001 and 0.006, respectively). There was no significant difference in major outcomes between patients who received CAZ/AVI and matched patients who received other antibiotics. CAZ/AVI could be considered a salvage strategy for immunosuppressed children with confirmed GNB infection. Caution should be taken when CAZ/AVI is applied to these patients in the absence of GNB recovery.

Real-life experience with IV dalbavancin in Canada; results from the CLEAR (Canadian LEadership on Antimicrobial Real-life usage) registry

We report the use of IV dalbavancin in Canadian patients using data captured by the national CLEAR registry. The CLEAR registry uses the web-based data management program, REDCap™ (online survey https://rcsurvey.radyfhs.umanitoba.ca/surveys/?s=TPMWJX98HL) to facilitate clinicians entering details associated with their clinical experiences using IV dalbavancin. Data were available for 40 patients. The most common infections treated were acute bacterial skin and skin structure infection (ABSSSI) (62.5% of patients), bone/joint infection (22.5%), bloodstream/vascular infection (7.5%) and endocarditis (5.0%). Dalbavancin was used as directed (75.0%) and empiric therapy (25.0%). MRSA was the most common identified pathogen (70.0%). Dalbavancin was used both in outpatient (e.g., emergency department) (65.0%), and inpatient treatment settings (e.g., hospital ward) (35.0%). Dalbavancin was used due to the convenience of a single dose treatment (77.5%) as well as to facilitate hospital discharge (7.5%). Dalbavancin was primarily used alone (90.0%), and most commonly using a single 1500 mg dose (77.5%). Microbiological success (pathogen eradicated or presumed eradicated) occurred in 88.2% of known cases, while clinical success (cure and/or improvement) occurred in 93.3% of known cases. No adverse events were reported. In Canada, IV dalbavancin is used as both directed and empiric therapy to treat ABSSSI as well as off-label (bone/joint, bacteremia/vascular, endocarditis, device-related) infections. It is used in both outpatient and inpatient settings due primarily to its convenience as a single-dose treatment regimen and to facilitate early hospital discharge. Dalbavancin use is associated with high microbiological and clinical cure rates along with an excellent safety profile.

Dalbavancin, a Second Generation Lipoglycopeptide is a New Addition to Therapy Armamentarium

Gram-positive infections with widespread developing resistance have posed considerable challenges to the long stay of antimicrobials in the market. Also, there has been a dearth in the provision of a suitable antimicrobial to treat the evolving resistance. Dalbavancin a 2nd generation lipoglycopeptide has shown its activity against gram-positive and multidrug resistant isolates. Owing to a favorable pharmacokinetic profile and supporting evidence this drug moiety has been used as long-term therapy for various indications. These indications include infective endocarditis (IE), osteomyelitis, bloodstream infections, and prosthetic joint infections. However, it is approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) only for acute bacterial skin and skin structure infections (ABSSSIs). Dalbavancin can be a valuable alternative to daily in-hospital intravenous or outpatient antimicrobial regimens in the treatment of long-term Gram-positive infections and ‘niche’ but important indications. This systematic review demonstrates comparative microbiology, chemistry, in vitro susceptibility, pharmacokinetics, clinical efficacy, safety, tolerability, dosage, and administration of dalbavancin. Additionally, it highlights past, present, and upcoming evidence of real-world use of dalbavancin alone or in combination with different indications. Keywords: Dalbavancin, Acute bacterial skin and skin structure infections, Gram-positive, Long-term, and pharmacokinetics.

ER-mitochondria association negatively affects wound healing by regulating NLRP3 activation

Methicillin-resistant Staphylococcus aureus (MRSA) is the most common causative agent of acute bacterial skin and skin-structure infections (ABSSSI), one of the major challenges to the health system worldwide. Although the use of antibiotics as the first line of intervention for MRSA-infected wounds is recommended, important side effects could occur, including cytotoxicity or immune dysregulation, thus affecting the repair process. Here, we show that the oxazolidinone antibiotic linezolid (LZD) impairs wound healing by aberrantly increasing interleukin 1 β (IL-1β) production in keratinocytes. Mechanistically, LZD triggers a reactive oxygen species (ROS)-independent mitochondrial damage that culminates in increased tethering between the endoplasmic reticulum (ER) and mitochondria, which in turn activates the NLR family pyrin domain-containing 3 (NLRP3) inflammasome complex by promoting its assembly to the mitochondrial surface. Downregulation of ER-mitochondria contact formation is sufficient to inhibit the LZD-driven NLRP3 inflammasome activation and IL-1β production, restoring wound closure. These results identify the ER-mitochondria association as a key factor for NLRP3 activation and reveal a new mechanism in the regulation of the wound healing process that might be clinically relevant.