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

INTRODUCTION: 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. PATIENTS AND METHODS: We present a case series of children and adolescents treated with dalbavancin for osteoarticular, catheter-related and other non-ABSSSI infections. RESULTS: 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). CONCLUSIONS: Dalbavancin was a safe, effective and convenient alternative in selected paediatric patients with complicated non-ABSSSI infections caused by Gram-positive bacteria.

Dalbavancin as consolidation therapy for infective endocarditis in patients with comorbidity. A real world experience.

OBJECTIVE: Infective endocarditis (IE) is a potentially life-threatening infection, the incidence of which has in creased in recent decades, particularly among elderly patients with comorbidity. The primary objective of this study was to evaluate the effectiveness of dalbavancin in the consolidation therapy of IE in patients with comorbidity six months after the end of treatment (EOT). METHODS: An observational and retrospective study was conducted on patients with a Charlson Comorbidity Index (CCI) ≥ 3 who were diagnosed with IE and received consolidation therapy with dalbavancin. RESULTS: Forty-eight patients were included, 58.3% were male, mean age of 76.2 years (IQR: 66-88), and a mean age adjusted CCI of 6.5 (IQR: 5-7.5). Definite IE was diagnosed in 77% of cases. The most frequently isolated microorganisms were Staphylococcus aureus (45.8%) followed by Enterococcus spp. (31.3%). Complications of IE were observed in 67.7% of cases, and cardiac surgery was performed in 27% of patients. The primary reason for using dalbavancin was outpatient parenteral antibiotic therapy in 85.4% of cases. The effectiveness at EOT was 93.8%. At six months, six IE-related deaths, four unrelated deaths, and two IE relapses were observed. The effectiveness was 77%. Adverse effects related to DBV were reported in 4.2% of cases, of which 2% were considered serious. CONCLUSIONS: Dalbavancin has proven to be an effective alternative as consolidation antibiotherapy for IE in elderly patients with comorbidity. Moreover, a very favorable safety profile with few associated adverse effects has been observed in this population.

Single Intravenous Dose Dalbavancin Pathway for the Treatment of Acute Bacterial Skin and Skin Structure Infections: Considerations for Emergency Department Implementation and Cost Savings.

BACKGROUND: A pathway for the treatment of acute bacterial skin and skin structure infections (ABSSSI) with a single intravenous (IV) dose of dalbavancin was previously shown to reduce hospital admissions and shorten inpatient length of stay (LOS). OBJECTIVES: To describe pathway implementation at the emergency department (ED) and evaluate cost-effectiveness of a single-dose dalbavancin administered to ED patients who would otherwise be hospitalized to receive usual care with multidose IV antibiotics. METHODS: The dalbavancin pathway was previously implemented at 11 U.S. EDs (doi:10.1111/acem.14258). Patients with ABSSSI, without an unstable comorbidity or infection complication requiring complex management, were treated with a single dose of dalbavancin. At the emergency physicians' discretion, patients were either discharged and received outpatient follow-up or were hospitalized for continued management. A decision analytic cost-effectiveness model was developed from the U.S. healthcare's perspective to evaluate costs associated with the dalbavancin pathway compared with inpatient usual care. Costs (2021 USD) were modeled over a 14-day horizon and included ED visits, drug costs, inpatient stay, and physician visits. One-way and probabilistic sensitivity analyses examined input parameter uncertainty. RESULTS: Driven largely by the per diem inpatient cost and LOS for usual care, the dalbavancin pathway was associated with savings of $5133.20 per patient and $1211.57 per hospitalization day avoided, compared with inpatient usual care. The results remained robust in sensitivity and scenario analyses. CONCLUSION: The new single-dose dalbavancin ED pathway for ABSSSI treatment, which was previously implemented at 11 U.S. EDs, offers robust cost savings compared to inpatient usual care.

Dalbavancin as suppressive therapy for implant-related infections: a case series with therapeutic drug monitoring and review of the literature.

Implant-related infections may need suppressive antibiotic therapy (SAT). We describe a SAT strategy using dalbavancin with therapeutic drug monitoring (TDM). This is a retrospective bicentric study of patients with implant-related infection who received dalbavancin SAT between January 2021 and September 2023. Fifteen patients were included. Median number of injections was 4 (IQR: 2-7). Median time between two reinjections was 57 days (IQR 28-82). Dalbavancin plasma concentrations were above 4 mg/L for 97.9% of dosages (93/95) and above 8 mg/L for 85% (81/95). These results support the use of dalbavancin SAT for implant-related infections.

Early Therapeutic Drug Monitoring Optimizes Teicoplanin Use in Febrile Neutropenic Patients with Hematological Malignancies.

INTRODUCTION: A target trough concentration (Cmin) of teicoplanin ≥ 15-20 mg/L between the fourth and sixth day has been suggested for severe infections or management of febrile neutropenia (FN). Owing to no reports discussing the impact of early target attainment on treatment outcomes, this study aimed to evaluate the dose-Cmin relationship and clinical outcome and estimate the optimal early target Cmin for FN in patients with hematological malignancies. METHODS: This single-center, prospective study enrolled patients with hematological malignancies who were treated with teicoplanin either as an empirical antibiotic for FN or as targeted treatment for Gram-positive bacteria. Blood samples were collected on day three (48 h) post-loading doses, day 5 (96 h), and day 8 (when applicable) and determined by ultrahigh-pressure liquid chromatography-triple quadruple mass spectrometry. A total of 117 samples from 47 patients with FN (27 men, 20 women) were consecutively analyzed. A two-tailed α value of 0.05 was considered statistically significant. RESULTS: The mean Cmin values at 48 h, 96 h, and on day 8 were 23.4, 21.4, and 27.8 mg/L, respectively. The patients achieving Cmin ≥ 20 mg/L at 48 h had a higher likelihood of treatment success. The areas under the receiver operating characteristic curves were 0.71 for clinical efficacy and the cutoff value of Cmin at 48 h was 18.85 mg/L (95% confidence interval 0.55-0.87; P = 0.018). CONCLUSIONS: The Cmin of teicoplanin after completion of loading doses could predict the treatment response, with a target concentration ≥ 18.85 mg/L.

Head-to-head comparison of multi-dose oritavancin and dalbavancin for complicated infections: A propensity score-matched analysis.

BACKGROUND: Oritavancin and dalbavancin are long-acting lipoglycopeptide antibiotics approved for the treatment of skin and skin structure infections. Recently, they have been used for outpatient antimicrobial therapy for complicated infections. No head-to-head studies exist for this purpose. OBJECTIVE: To compare outcomes of patients treated with multiple doses of oritavancin or dalbavancin for complicated infections. PATIENTS AND METHODS: This was a single-centre, retrospective cohort study evaluating adult patients who received two or more doses of lipoglycopeptides for complicated infections from February 2019 through December 2022. Patients receiving oritavancin were compared to dalbavancin after propensity score-matching. The primary endpoint was clinical success at 90 days. Other endpoints included: 30-day re-admission, 30-day mortality, adverse drug reactions (ADRs), and changes in white blood cell count and inflammatory markers after the first dose. RESULTS: After exclusions and propensity score-matching, 131 matched pairs (N = 262) were included in the analysis. Most patients were receiving lipoglycopeptide therapy for osteomyelitis. There was no significant difference in clinical success at 90 days in patients who received oritavancin compared to those who received dalbavancin (99 [76%] vs. 103 [79%], respectively; P = 0.556). There was no significant difference in secondary endpoints, however, there was a trend towards higher incidence of ADRs oritavancin compared to dalbavancin (9 [7%] vs. 2 [2%], respectively; P = 0.060) which led to more treatment discontinuation. CONCLUSION: There was no significant difference in efficacy between multi-dose oritavancin and dalbavancin for the treatment of complicated infections. Both agents were generally well tolerated; however, dalbavancin may be better tolerated when long-term treatment is warranted.

Cost evaluation of continuation of therapy with dalbavancin compared to standard-of-care antibiotics alone in hospitalized persons who inject drugs with severe gram-positive infections.

PURPOSE: Persons who inject drugs (PWID) are at risk for severe gram-positive infections and may require prolonged hospitalization and intravenous (IV) antibiotic therapy. Dalbavancin (DBV) is a long-acting lipoglycopeptide that may reduce costs and provide effective treatment in this population. METHODS: This was a retrospective review of PWID with severe gram-positive infections. Patients admitted from January 1, 2017, to November 1, 2019 (standard-of-care [SOC] group) and from November 15, 2019, to March 31, 2022 (DBV group) were included. The primary outcome was the total cost to the healthcare system. Secondary outcomes included hospital days saved and treatment failure. RESULTS: A total of 87 patients were included (37 in the DBV group and 50 in the SOC group). Patients were a median of 34 years old and were predominantly Caucasian (82%). Staphylococcus aureus (82%) was the most common organism, and bacteremia (71%) was the most common type of infection. Compared to the SOC group, the DBV group would have had a median of 14 additional days of hospitalization if they had stayed to complete their therapy (P = 0.014). The median total cost to the healthcare system was significantly lower in the DBV group than in the SOC group ($31,698.00 vs $45,093.50; P = 0.035). The rate of treatment failure was similar between the groups (32.4% in the DBV group vs 36% in the SOC group; P = 0.729). CONCLUSION: DBV is a cost-saving alternative to SOC IV antibiotics for severe gram-positive infections in PWID, with similar treatment outcomes. Larger prospective studies, including other patient populations, may demonstrate additional benefit.

Proactive therapeutic monitoring of dalbavancin concentrations in the long-term management of chronic osteoarticular/periprosthetic joint infections.

Here, we describe the use of proactive therapeutic drug monitoring (TDM) to individualize the optimal timing of drug injections in 16 adult patients with chronic osteoarticular infections receiving a median of 7 injections of dalbavancin (up to 12 injections in 15 months). Dalbavancin injections were repeated at medians of 39-47 days, with infusion intervals ranging from 26 to 69 days. TDM can facilitates a precise, targeted use of dalbavancin for infections requiring prolonged treatments.

In-label, off-label prescription, efficacy and tolerability of dalbavancin: report from a National Registry.

PURPOSE: Although dalbavancin is currently approved for the treatment of ABSSIs, several studies suggest its efficacy and tolerance as long-term therapy for other off-label indications requiring prolonged intravenous antibiotic administration. METHODS: We conducted a prospective nationwide study of dalbavancin use in real-life settings for both approved and off-label indications analysing for each case the clinical and microbiological characteristics of infection the efficacy and safety of treatments. RESULTS: During the study period (from December 2018 to July 2021), the ID specialists from 14 different centres enrolled 223 patients treated with dalbavancin [141 males (63%) and 82 females (37%); male/female ratio 1.72; mean age 59 (SD 17.2) years, (range 15-96). Most patients in the study population (136/223; 61.0%) came from community rather than health care facilities and most of them were visited in Infectious Diseases wards (93/223; 41.7%) and clinics (55/223; 24.7%) even though some patients were cured in other settings, such as surgery wards (18/223; 8.1%), orthopaedic wards (11/223; 4.9%), Emergency Rooms (7/223; 3.1%) and non-surgical other than ID wards (6/223; 2.7%). The most common ID diagnoses were osteomyelitis (44 cases/223; 19.7%; of which 29 acute and 15 chronic osteomyelitis), cellulitis (28/223; 12.5%), cutaneous abscess (23/223; 10.3%), orthopaedic prosthesis-associated infection (22/223; 9.9%), surgical site infection (20/223; 9.0%) and septic arthritis (15/223; 6.7%). CONCLUSION: In conclusion, by virtue of its PK/PD properties, dalbavancin represents a valuable option to daily in-hospital intravenous or outpatient antimicrobial regimens also for off-label indications requiring a long-term treatment of Gram-positive infections.

Prevalence and molecular characteristics of heterogeneous vancomycin intermediate Staphylococcus aureus in a tertiary care center of northern China.

The use of glycopeptide medications may decline in line with the annual decline in methicillin-resistant Staphylococcus aureus (MRSA) detection rates in China. The rate of heterogeneous vancomycin-intermediate Staphylococcus aureus (hVISA)detection may be impacted by this. However, there is currently a dearth of information on the incidence of hVISA in China. This study aims to analyze the recent epidemiology and molecular characteristics of hVISA strains in Beijing, China. A total of 175 non-duplicate MRSA strains from various infection sites were collected from a medical center between January 2018 and May 2023 and underwent molecular typing and susceptibility testing (Vitek2). Vancomycin and teicoplanin MICs were also evaluated by standard broth microdilution method and agar dilution method, respectively. Isolates growing on screening agar (BHIV4 and BHIT5, brain heart infusion agar containing 4 µg/ml vancomycin and 5 µg/ml teicoplanin, respectively) were characterized further by analysis of macro-Etest (MET) and population analysis profiling with area under the curve (PAP-AUC). The proportion of hVISA among MRSA isolates was 8.6 %. BHIT5 could select all hVISA strains while BHIV4 and MET only selected two hVISA strains. Compared with vancomycin- susceptible Staphylococcus aureus (VSSA), hVISA isolates were less susceptible to erythromycin and clindamycin. In addition, hVISA frequency was MIC-independent despite using different detection methods. In total, 11 types of STs, 28 types of spa typing, four types of SCCmec typing, and two types of agr typing were identified and the predominant type in both MRSA and hVISA isolates was ST239-t030-SCCmecIII-agr I. The analysis of biofilm formation, growth, and virulence genes in hVISA strains revealed sparse information. The dataset presented in this study provided the prevalence and molecular characteristics of hVISA in hospital settings and the combination of BHIT5 and PAP-AUC may identify hVISA efficiently. The result of genotyping suggested the genotype of hVISA was mainly consistent with that of local MRSA. Additional studies on the characteristics of hVISA strains were necessary.

High prevalence of heteroresistance in Staphylococcus aureus is caused by a multitude of mutations in core genes.

Heteroresistance (HR) is an enigmatic phenotype where, in a main population of susceptible cells, small subpopulations of resistant cells exist. This is a cause for concern, as this small subpopulation is difficult to detect by standard antibiotic susceptibility tests, and upon antibiotic exposure the resistant subpopulation may increase in frequency and potentially lead to treatment complications or failure. Here, we determined the prevalence and mechanisms of HR for 40 clinical Staphylococcus aureus isolates, against 6 clinically important antibiotics: daptomycin, gentamicin, linezolid, oxacillin, teicoplanin, and vancomycin. High frequencies of HR were observed for gentamicin (69.2%), oxacillin (27%), daptomycin (25.6%), and teicoplanin (15.4%) while none of the isolates showed HR toward linezolid or vancomycin. Point mutations in various chromosomal core genes, including those involved in membrane and peptidoglycan/teichoic acid biosynthesis and transport, tRNA charging, menaquinone and chorismite biosynthesis and cyclic-di-AMP biosynthesis, were the mechanisms responsible for generating the resistant subpopulations. This finding is in contrast to gram-negative bacteria, where increased copy number of bona fide resistance genes via tandem gene amplification is the most prevalent mechanism. This difference can be explained by the observation that S. aureus has a low content of resistance genes and absence of the repeat sequences that allow tandem gene amplification of these genes as compared to gram-negative species.

Model-based dosing optimization and therapeutic drug monitoring practices of teicoplanin in patients with complicated or non-complicated methicillin-resistant staphylococcus aureus infection.

AIMS: This study aims to establish a population pharmacokinetic (PK) model of teicoplanin in Chinese adult patients to evaluate the dosing regimen in the label sheet and optimize it. METHODS: Nonlinear mixed-effects modelling was used to estimate PK parameters. Monte Carlo simulations were used to evaluate the attainment of various dosing regimens in achieving the target trough concentrations in patients with normal or decreased renal function. RESULTS: A total of 115 patients were enrolled in this retrospective study. Creatinine clearance (CrCL) and albumin (ALB) were identified as covariates on the clearance of teicoplanin. For the treatment of non-complicated methicillin-resistant Staphylococcus aureus (MRSA) infections in patients with normal renal function and serum ALB concentration, the recommended dosing regimen was 600 mg q12h with five administrations as the loading dose followed by 600 mg qd as the maintenance dose; for the treatment of serious and/or complicated MRSA infections, the recommended dosing regimen was 800 mg q12h with five administrations as the loading dose followed by 800 mg qd as the maintenance dose. It is worth noting that both the loading and maintenance doses ought to be modified based on the patient's renal function and serum ALB concentration. In addition, trough concentrations of teicoplanin were significantly increased every other week. CONCLUSIONS: Both loading dosing and maintenance dosing regimens were recommended to be adjusted according to patient's renal function and serum ALB concentration. In addition, it is necessary to perform follow-up therapeutic drug monitoring of teicoplanin at least once every week.

Implementation and validation of a Bayesian method for accurately forecasting duration of optimal pharmacodynamic target attainment with dalbavancin during long-term use for subacute and chronic staphylococcal infections.

Dalbavancin is increasingly being used for long-term treatment of subacute and chronic staphylococcal infections. In this study, a new Bayesian model was implemented and validated using MwPharm software for accurately forecasting the duration of pharmacodynamic target attainment above the efficacy thresholds of 4.02 mg/L or 8.04 mg/L against staphylococci. Forecasting accuracy improved substantially with the a posteriori approach compared with the a priori approach, particularly when two measured concentrations were used. This strategy may help clinicians to estimate the duration of optimal exposure with dalbavancin in the context of long-term treatment.

Molecular and Clinical Features of Heterogeneous Vancomycin-Intermediate Staphylococcus aureus in Tertiary Care Hospitals in South India.

Objectives: This study aimed to detect heterogeneous vancomycin-intermediate Staphylococcus aureus (hVISA) among methicillin-resistant S. aureus (MRSA) isolated from healthcare-associated infections and identify staphylococcal cassette chromosome mec (SCCmec) types. Methods: This study was conducted from February 2019 to March 2020 and included patients admitted in 4 tertiary care hospitals in Karnataka, India. Isolation and identification of MRSA were done using standard bacteriological methods. Antimicrobial susceptibility testing was done using Kirby-Bauer disc diffusion; macrolide-lincosamide-streptogramin B phenotypes were identified using the D test. The minimum inhibitory concentration (MIC) of vancomycin was determined using agar dilution. hVISA were confirmed by the modified population analysis profile-area under the curve test. SCCmec types and the Panton-Valentine leukocidin (pvl) gene were detected using multiplex polymerase chain reaction. Results: Of 220 MRSA stains, 14 (6.4%) were hVISA. None of the MRSA isolates was vancomycin-intermediate or -resistant and all hVISA were susceptible to linezolid and teicoplanin. The macrolide-streptogramin B phenotype was present in 42.9% of hVISA; 92.9% of the hVISA strains had vancomycin MIC in the range of 1-2 µg/mL. Majority of the hVISA and vancomycin-susceptible MRSA were isolated from patients with skin and soft tissue infections. SCCmec III and IV were present in 50% and 35.7% of hVISA, respectively; 14.3% of the hVISA harboured SCCmec V. Conclusion: The prevalence rate of hVISA among MRSA was 6.4%. Therefore, MRSA strains should be tested for hVISA before starting vancomycin treatment. None of the isolates was vancomycin-intermediate or -resistant and all the hVISA strains were susceptible to linezolid and teicoplanin. The majority of the hVISA were isolated from patients with skin and soft tissue infections and harboured SCCmec III and IV.

Successful Outpatient Treatment of Severe Diabetic-Foot Myositis and Osteomyelitis Caused by Extensively Drug-Resistant Enterococcus faecalis with Teicoplanin plus Rifampicin: A Case Report.

BACKGROUND Foot ulcers are high-morbidity and debilitating complications of diabetes mellitus, and carry significantly increased rates of associated major amputations. They contribute to significantly worse quality of life. Osteomyelitis is a frequent complication of diabetic foot ulcers, since bacteria can contiguously spread from soft tissues to the bone, involving the cortex first and then the bone marrow. Unfortunately, clinically unsuspected osteomyelitis is frequent in persisting diabetic foot ulcers. It is associated with limb amputations and increased mortality. CASE REPORT We describe a 76-year-old man with long-standing insulin-treated type 2 diabetes, who experienced extensively drug-resistant Enterococcus faecalis diabetic foot myositis and osteomyelitis associated with sepsis. He was successfully treated with surgical debridement combined with the administration of teicoplanin plus rifampicin in the outpatient setting, completing, in total, a twelve-week course of antibiotic therapy. CONCLUSIONS Clinically unsuspected osteomyelitis in patients with persisting diabetic foot ulcers has been associated with infections from highly resistant bacteria. Early and accurate diagnosis of diabetic foot osteomyelitis, as well as proper therapeutic approach (antimicrobial and surgical), is of great importance to reduce the risk of minor and major amputations, septic shock leading to multiple organ failure, and overall mortality.

Oral teicoplanin administration suppresses recurrence of Clostridioides difficile infection: Proof of concept.

OBJECTIVES: Teicoplanin is a potential antimicrobial candidate for Clostridioides difficile infection (CDI) treatment. However, the therapeutic potential of teicoplanin against severe CDI has not been clinically proven. In the present study, we investigated the efficacy of oral teicoplanin administration against severe CDI and the recurrence of severe CDI after teicoplanin treatment in a mouse model. METHODS: A lethal CDI mouse model was established by colonizing the mice with C. difficile ATCC® 43255; they were orally administered teicoplanin (128 mg/kg/d) or vancomycin (160 mg/kg/d) for 10 d, 24 h after C. difficile spore challenge, and physiological and biological responses were monitored for 20 d after the initial antibiotic treatment. We also performed the in vitro time-kill assay and determined minimum inhibitory concentration (MIC), post-antibiotic effect, and toxin production with antibiotic exposure. RESULTS: The therapeutic response (survival rates, body weight change, clinical sickness score grading, C. difficile load, and toxin titer in feces) of oral teicoplanin administration was comparable to that of oral vancomycin administration in the lethal CDI mouse model. Moreover, teicoplanin treatment suppressed the re-onset of diarrhea and re-increase in toxin titer 10 d after treatment compared with that by vancomycin treatment. In in vitro experiments, teicoplanin exhibited time-dependent antibacterial activity and possessed lower MIC and longer post-antibiotic effect than vancomycin against C. difficile. C. difficile toxin production was numerically lower with teicoplanin exposure than with vancomycin exposure. CONCLUSIONS: The results obtained from the present basic experiments could suggest that teicoplanin is a potential antibiotic for the treatment of severe CDI with recurrence-prevention activity.

Efficacy of boric acid used to treat experimental vascular graft infection by methicillin-resistant Staphylococcus aureus.

INTRODUCTION: We aimed to investigate the efficacy of local boric acid (BA) and teicoplanin in prosthetic vascular graft infection (PVGI) caused by methicillin-resistant Staphylococcus aureus (MRSA) in a rat model. METHODOLOGY: Fourty rats were divided into five groups. Group 1 received no treatments (control group); group 2 was uncontaminated polytetrafluoroethylene (PTFE) graft group; group 3 was untreated and the PTFE graft was contaminated with 2×107 CFU/mL MRSA; group 4 received local BA (8 mg/kg) and was contaminated with with 2×107 CFU/mL MRSA; group 5 received local BA (8 mg/kg) and intraperitoneal teikoplanin (10 mg/kg), and was contaminated with 2×107 CFU/mL MRSA; On the 3rd day, grafts and serums were removed for microbiological, histological and serological tests. RESULTS: The amounts of culture growth in groups 4 and 5 were significantly lower compared to group 3 (p < 0.001). TNF-α was significantly higher in Group 3 than the other groups (p = 0.001). There was no significant difference between the groups in serum IL-1 levels (p = 0.138). Monocyte chemotactic protein-1 (MCP-1) was not significantly different between groups 3, 4, and 5, but it was significantly higher than groups 1 and 2 (p < 0.001). The severity of inflammation was significantly higher in group 3 than the other groups, and fibroblastic proliferation, granulation tissue and collagen synthesis were significantly lower (p < 0.05). CONCLUSIONS: Our study showed that local BA and combined teicoplanin treatment is effective in preventing PVGI.