Dalbavancin is a long-lasting parenteral lipoglycopeptide antibiotic1 that mainly exerts its antimicrobial activity through interaction with the terminal D-alanyl-D-alanine residues of peptidoglycan precursors,2 thereby inhibiting the activity of transpeptidase and transglycosylase enzymes.3,4 It was approved by the US Food and Drug Administration (FDA) in 2014 and by the European Medicines Agency (EMA) in 2015 for the treatment of acute bacterial skin and skin structure infections (ABSSSI).3,5

Its off-label use is becoming increasingly common in the treatment of complex chronic infections caused by Gram-positive bacteria, including osteoarticular infections, periprosthetic joint infections, and endocarditis.5–7

Dalbavancin exhibits unique pharmacokinetic and pharmacodynamic (PK/PD) properties. Its long half-life means that a single 1500 mg dose is sufficient for the treatment of ABSSSI.Alternatively, a two-dose regimen of 1000 mg followed by 500 mg 1 week later can be used.6–9 This extended half-life of at least 8.5 days9 is attributable to its high plasma protein binding (mainly to albumin), which reaches 93% in humans.8,9 Its volume of distribution is greater than 10 L,8,9 with a clearance of 0.0473 mL/min.9 It is widely distributed in the extracellular fluid of soft tissues,8 and its elimination is both renal (up to 45%) and extrarenal.8,9 No dose adjustment is recommended in cases of mild or moderate renal impairment or in hepatic impairment; however, a dose reduction is necessary in cases of severe renal impairment.8 In addition, dalbavancin does not interfere with the activity of cytochrome P450 enzymes.10–14 All these factors contribute to its ease of use.

Dalbavancin is effective against Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA), Staphylococcus aureus with intermediate sensitivity to vancomycin, multidrug-resistant coagulase-negative staphylococci, and vancomycin-resistant enterococci with the VanB phenotype.11,15,16 Some complex infections, including bone and joint infections (BJI), prosthetic joint infections (PJI), and infective endocarditis (IE), are caused by S. aureus and other species of staphylococci and streptococci.17,18 These infections are more difficult to treat due to biofilm formation and the variable penetration of antibiotics into bone and joint structures. This penetration can be particularly limited in bone tissue and in the presence of biofilms.19 This challenge necessitates long-term treatment with drugs that have good tissue distribution, as has been demonstrated for dalbavancin in tissue distribution studies.20 Therefore, dalbavancin has great potential as an antibiotic in these cases. However, these indications are not included in the current authorisation for use.

Due to its activity against Gram-positive cocci—including MRSA—its prolonged half-life, and favourable safety profile, dalbavancin is considered a potential alternative to the daily IV administration of other antibiotics, which typically necessitates prolonged hospitalisation for patients with osteoarticular, periprosthetic, and vascular graft infections.11–13,15–19,21

There is growing evidence supporting the prolonged use of dalbavancin in complex chronic infections, with published case series demonstrating favourable clinical outcomes.13,18,20,22–26 However, dosing strategies vary widely between studies, and there are no clear recommendations or published guidelines on extended dosing regimens. Therefore, dosing is frequently informed by therapeutic drug monitoring (TDM).

Because of this unmet need, we conducted a systematic review to identify existing studies proposing dalbavancin administration guidelines based on TDM for complex infections. The aim was to find potential regimens that extend treatment beyond the approved dosing regimen for ABSSSI.3,4

In a mouse model of S. aureus infection, the mean free-drug area under the concentration-time curve at 24 h/minimum inhibitory concentration (24-h fAUC/MIC) required to achieve a 2-log reduction in S. aureus bacterial load (equivalent to a 100-fold decrease in the number of bacteria, or 99% reduction of the initial inoculum) was 111.1 ± 51.81.27 This indicates that, in infected mice, the drug needed to maintain a 24-h AUC/MIC ratio greater than 111.1 is necessary to achieve a significant reduction in bacterial load. Subsequently, using population pharmacokinetic simulations, it was determined that a 24-h AUC/MIC ratio greater than 111.1 corresponded to a trough concentration of 8.04 mg/L for a MIC of 0.125 mg/L. This value was derived from the previously calculated 24-h fAUC/MIC thresholds in order to achieve the optimal PK/PD target against S. aureus, based on the most commonly observed MIC values (0.0625 mg/L and 0.125 mg/L). The 24-h fAUC/MIC thresholds were 6.94 mg·h/L and 13.89 mg·h/L. Taking into account the high plasma protein binding of dalbavancin, these values corresponded to total 24-h AUC values of 99.2 mg·h/L and 198.3 mg·h/L, respectively. Plasma concentrations were validated as a reliable estimate of 24-h AUC values, enabling the determination of trough thresholds of 4.02 mg/L and 8.04 mg/L for MICs of 0.0625 mg/L and 0.125 mg/L, respectively.28

To date, there are no systematic reviews have analysed the optimal dosing regimen for dalbavancin in treating complex chronic infections caused by Gram-positive microorganisms. Our objective was to review the current literature in order to summarise the most common dosing regimens for dalbavancin in treating this type of infection, assess whether the PK/PD objectives reported in the literature are achieved with these regimens, and explore TDM-based strategies used to optimise treatment. In addition, we aimed to describe the interindividual variability observed in plasma concentrations and the patient characteristics that may influence it.

The protocol for this review was registered in the PROSPERO database (registration number: CRD42024622177).29 The study was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)30 statement (see Fig. 1).

Figure 1.

PRISMA flow diagram illustrating the study selection process.

The initial search yielded a total of 241 articles. After removing duplicates, 112 unique articles remained. The titles and abstracts of these 112 articles were reviewed, of which 102 were excluded for not meeting the inclusion criteria. Of these 102 articles, 83 were excluded because they were unrelated to the aims of this review: 77 did not primarily analyse the pharmacokinetics of dalbavancin, while 6 analysed the pharmacokinetics of dalbavancin alongside those of other drugs. Thirteen articles were excluded because they involved studies conducted in paediatric patients, and 6 because they focused on the development of analytical techniques for determining dalbavancin concentrations in blood. Finally, 10 studies were included in the systematic review (Fig. 1).

Studies with variability in both design and sample size were included. Six of the included studies were retrospective observational,31–36 and 4 were prospective observational37–40 (Table 1). Nine of these were single-centre studies, and 1 was conducted in 2 centres.36Table 1 presents the characteristics of the reviewed studies.

A total of 1298 samples from 457 patients were included in the analysed studies. The number of samples per study ranged from 34 to 336, and the number of patients per study ranged from 14 to 133. However, some studies did not provide this information.

The reviewed studies addressed various complex infections, the most frequent of which wereosteoarticular infections (such as osteomyelitis, septic arthritis, prosthetic infections, and spondylodiscitis). These infections were reported in 9 of the 10 studies. They accounted for all (100%) infections in 532–34,38,40 of the studies, and 79%,37 76.8%,31 and 80%36 of infections in 3 other studies. One other study did not report the percentage of osteoarticular infections.39

Other types of complex infection included vascular prosthetic infections and endocarditis. However, these studies also described patients with osteoarticular infections, which were generally more prevalent.31,36,37,39

The main objectives of the studies included in this systematic review were to evaluate the appropriate dosage of dalbavancin for treating complex infections (particularly osteoarticular infections), describe actual dalbavancin plasma concentrations, and determine whether these concentrations exceed the therapeutic targets established in the literature. Our review also aimed to assess the usefulness of TDM in achieving PK/PD targets and optimising dosing regimens, and to describe interindividual variability in dalbavancin plasma concentrations.

This systematic review is the most comprehensive analysis to date of dalbavancin plasma concentration monitoring in patients with complex infections. It includes 10 observational studies, comprising 1298 samples from 457 patients. The results highlight the usefulness of TDM in optimising dalbavancin dosing regimens and achieving pharmacokinetic/pharmacodynamic goals, particularly in settings characterised by high inter-individual variability in plasma concentrations.

Most of the reviewedstudies used a 2-dose regimen of 1500 mg administered 1 week apart. This regimen, which is based on population pharmacokinetic models, maintains adequate concentrations for 5 weeks.38 However, considerable flexibility in dosing regimens was observed, with TDM being used to determine the optimal timing of additional doses,33–36,40 and dose adjustments being made in patients with renal impairment.31,33

Based on studies by Lepak27 and Cojutti,28 the most common PK/PD targets were maintaining trough concentrations greater than 8 μg/mL31,33–35,40 or achieving an AUC/MIC ratio greater than 111.1. However, although 1 study proposed a more restrictive threshold of 10 μg/mL,36 no justification was provided for this, raising questions about its clinical relevance.

While most of the reviewed studies used Cmin or the AUC/MIC ratio as PK/PD targets, some evaluated Cmax as an exposure parameter, justifying its use as an alternative for assessing dalbavancin pharmacokinetics and predicting its behaviour.33,39 This parameter has been shown to be related to early clinical response, with a correlation was found between values of less than 313 mg/mL after the first dose and a higher risk of therapeutic failure.39 In addition, patients who received two 1500 mg doses administered 1 week apart achieved significantly higher Cmax, which translated into greater cumulative exposure (AUC 0–4 weeks).39 Another study used Cmax as an alternative to Cmin to guide TDM and adjust dosing intervals.33 However, the AUC/MIC ratio and Cmin remain the most well-established PK/PD targets for assessing the long-term effectiveness of dalbavancin.

Another study set an AUC/MIC ratio threshold of greater than 1000,37 based on a dalbavancin pharmacokinetic model.41 This threshold was determined using Monte Carlo simulations and PK/PD models, and represents the cumulative exposure to dalbavancin throughout the course of treatment. It complements the 24-h AUC/MIC ratio threshold greater than 111.1, as maintaining this value over time enables a total AUC/MIC ratio greater than 1000 to be achieved.41

Most of the studies reviewed found that administering two 1500 mg doses 1 week apart was an effective regimen for achieving PK/PD targets.31,33–35,40

Five studies used TDM to adjust the dalbavancin dosing regimen following the initial doses,33–36,40 using strategies such as Monte Carlo simulations or adjustments based on trough or Cmax concentrations. These strategies enabled therapeutic concentrations to be maintained for prolonged periods and reduced the frequency of dalbavancin administration, particularly in patients with renal impairment.33,38,40 It was also demonstrated that administering additional doses at specific times could extend the period during which trough concentrations remain above the therapeutic target. This suggests that TDM can be used to to extend the interval between doses without compromising clinical outcomes. These results are important because standard regimens approved for treating ABSSSI maintain adequate plasma concentrations for approximately 3 weeks. While this timeframe is generally sufficient for treating these infections, it is insufficient for treating complex or chronic infections.

Although no statistically significant differences in clinical success were found between patients with and without TDM,35 this result may be due to the small sample size. Further research is needed to confirm this finding.

Another key finding of the reviewed studies was that plasma dalbavancin concentrations varied between individuals and were influenced by factors including renal function, weight, and body surface area.31,32,37,39 Patients with a GFR of less than 60 mL/min showed significantly higher concentrations, while those weighing more than 75 kg or with a larger body surface area—for which no specific threshold was identified—showed lower exposure to the drug. These findings reinforce the importance of individualised dose adjustment for patients with significant variations in renal function or body weight.

Based on the available evidence, we recommend therapeutic monitoring of dalbavancin between 3 and 5 weeks after the initial treatment, depending on renal function, to determine whether a further dose is required.

For patients with a GFR of 60 mL/min or more, trough concentrations greater than 8 μg/mL are usually maintained for 4–5 weeks after two 1500 mg doses have been administered 1 week apart. If TDM is unavailable and treatment requires extension, an additional 500 mg, 1000 mg, or 1500 mg dose may be administered at week 5. This will prolong exposure by 1, 2 or 3 additional weeks, respectively, depending on the expected duration of treatment.

If TDM is available, management can be adjusted according to plasma concentrations:

• •

  Adequate concentrations (greater than 8 μg/mL): If treatment needs to be extended, continue clinical monitoring and consider repeating TDM in 2 weeks.

• •

  Concentrations 6–8 μg/mL: repeat TDM in 1 week. Consider a 500 mg dose if concentrations fall or there are signs of therapeutic failure. Repeat TDM in 2 weeks.

• •

  Concentrations 4–6 μg/mL: administer 1000 mg and repeat TDM in 2 weeks.

• •

  Concentrations of less than 4 μg/mL: administer 1500 mg and repeat TDM in 2 weeks.

As the effects of additional doses has not been studied in patients with a ClCr of less than 60 mL/min, their empirical administration is not recommended. If subtherapeutic concentrations are detected, redosing should be based exclusively on TDM; therefore, monitoring may be performed at 5 or 6 weeks. If a significant decrease in concentrations is confirmed and an additional dose is deemed necessary, the most prudent option may be to administer a 500 mg dose with reassessment using TDM at 2 weeks.

In patients with severe renal impairment (a ClCr <30 mL/min), administering two 1000 mg doses on days 1 and 8 may be an appropriate strategy.

These recommendations are based on the best available evidence to date, but they should be interpreted with caution and adapted to each patient's individual clinical situation. The final decision on redosing should take clinical progress into account and, whenever possible, be supported by TDM.

Larger sample size studies and randomised designs are essential to validate and develop dosing recommendations for complex Gram-positive infections treated with dalbavancin. It would also be desirable to standardise PK/PD endpoints and evaluate the impact of TDM on broader clinical parameters, such as infection clearance.

In summary, this review demonstrates that a TDM-based approach not only ensures adequate drug exposure but also enables personalised dosing according to patient characteristics. Although the results are promising, further evidence from clinical trials is needed to establish these strategies as standard clinical practice.

This review has the following limitations:

• •

  Study design: all of the reviewed studies were observational, which introduces potential biases and limits the possibility of establishing causal relationships.

• •

  Small sample size: the results of several studies are difficult to generalise due to their small sample size.

• •

  Heterogeneity in methods and objectives: the results are difficult to compare due to a lack of consensus on PK/PD cut-off points.

• •

  Single-centre setting: most studies were conducted in a single centre, which limits the applicability of the findings to different clinical settings.

This review provides a comprehensive and up-to-date overview of studies published on the therapeutic monitoring of dalbavancin since 2021, emphasising its relevance and novelty in the clinical context of treating infections that require prolonged management with this antibiotic.

Despite the limitations inherent to observational studies, this review represents a significant advance in understanding the pharmacokinetics of dalbavancin and its application in complex infections.

This review also identifies emerging areas of research that could address gaps in the current literature. Although the sample size of the included studies is limited, this issue has been addressed through detailed analysis and a focus on consistent patterns within the samples analysed.

None declared.

None declared.

Laura Moñino-Dominguez: Writing – review & editing, Writing – original draft, Visualization, Validation, Supervision, Project administration, Methodology, Investigation, Formal analysis, Data curation, Conceptualization. Alicia Aguado-Paredes: Writing – review & editing, Writing – original draft, Visualization, Validation, Supervision, Methodology, Investigation, Data curation, Conceptualization. Jaime Cordero-Ramos: Writing – review & editing, Writing – original draft, Visualization, Validation, Supervision, Project administration, Methodology, Investigation, Data curation, Conceptualization.