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. 2025 Jan 15;38(2):128–135. doi: 10.1097/QCO.0000000000001092

The future approach for the management of acute bacterial skin and skin structure infections

Giusy Tiseo 1, Marco Falcone 1
PMCID: PMC12036772  PMID: 39831591

Abstract

Purpose of review

To discuss the new available options for the treatment of acute bacterial skin and skin structure infections (ABSSSIs) and how to implement in the clinical practice innovative approaches for their management.

Recent findings

The availability of long-acting antibiotics, including dalbavancin and oritavancin, changed the approach to patients with ABSSSI. Direct discharge from the emergency department and early discharge from the hospital should be considered in patients with ABSSSI. Despite limited data about different bactericidal properties, the choice between dalbavancin and oritavacin is usually based on patients’ characteristics and comorbidities. Delafloxacin and omadacycline are other options and have the advantage to be available for both intravenous and oral formulations, allowing a sequential therapy and switch from intravenous to oral treatment in clinically stable patients. Further studies should elucidate the profile of patients who may beneficiate from these drugs.

Summary

Early discharge from the hospital should be considered in patients with ABSSSI at a high risk of methicillin-resistant Staphylococcus aureus and in vulnerable patients for which hospitalization may have detrimental consequences. In elderly individuals, patients with diabetes mellitus, oncological people who need for continuing their healthcare pathway, this approach may reduce complications and costs related to hospitalization.

Keywords: acute bacterial skin and skin structure infection, dalbavancin, delafloxacin, omadacycline, oritavancin

INTRODUCTION

Acute bacterial skin and skin structure infections (ABSSSIs) are a leading cause of morbidity and are listed among the most common infections encountered in both ambulatory and hospital settings [1]. During the last decade, ABSSSIs dramatically increased, partially due to the progressive aging of the population [2,3]. A recent study from Spain, Italy, and Austria estimated a total annual expense for ABSSSI of 13.5 million EUR, 9.9 million EUR, and 3.4 million EUR, respectively [4]. The global ABSSSIs market size was valued at USD 1.22 billion in 2022 and is expected to grow at a compound annual growth rate of 4.84% from 2023 to 2030, when it is expected to reach USD 18.79 billion [5].

The burden of ABSSSIs and their complications are considerable, resulting in hospitalization, surgery, bacteraemia, and, occasionally, fatal outcome. Management of patients with ABSSSI is challenging due to the wide heterogeneity in etiology, disease severity, and patients’ characteristics [6]. Vulnerable populations are at high risk of treatment failure or recurrence and their management may be challenging [7,8]. Particular attention should be paid in frail patients hospitalized in internal medicine wards or residing in nursing homes, who appear to be at an increased risk of infection due to multidrug-resistant pathogens [9]. Patients with diabetes mellitus represent another category at risk for poor outcome. In this population, ABSSSIs (other than diabetic foot infections) are common and drug-drug interactions or drug-related adverse events (such as nephrotoxicity) should be considered in the choice of antibiotic therapy [10].

Microbiological diagnosis represents a significant challenge in ABSSSI. In the majority of cases, obtaining a microbiologic sample is difficult and when a culture is obtained, the probability of isolating an organism is low. Thus, antibiotic therapy is usually based on an empiric approach. Severe infections due to Staphylococcus aureus are associated with poor outcome, especially in frail patients [11]. Methicillin-resistant S. aureus (MRSA) should be suspected in patients with typical risk factors and may lead to unfavourable outcome [12]. Although S. aureus and beta-haemolytic streptococci represent the most common causes of ABSSSIs, Gram-negative bacilli may be also detected and polymicrobial infections may occur, especially in specific cases including (but not limited to) diabetic foot infections [13–16]. In a previous experience including patients with bacteraemic skin infections, S. aureus accounted for 42.8% of isolates pathogens, but about 15% of cases were caused by Gram-negative bacilli [17].

Due to advance in drug development and the availability of new treatment options, management of patients with ABSSSIs changed over time. In this review, we discuss the innovative approaches in the management of ABSSSIs that can be implemented in the clinical practice. 

Box 1.

Box 1

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no caption available

CLINICAL VIGNETTE

A 69-year-old man was admitted to the emergency department (ED) for the appearance of painful and erythematous area in the right leg. At home, he was treated with doxycycline with no clinical response. His medical history was significant for arterial hypertension, ischemic cardiomiopathy, and chronic renal disease. He recently underwent a colon resection for colon cancer, and he was on adjuvant chemotherapy. He recently started escitalopram to treat a generalized anxiety disorder.

On admission, he had no fever, but he complained pain of the right leg. Physical examination showed a poorly demarcated, warm, erythematous area with associated oedema, and tenderness to palpation in the anterior face of the right leg. The lesion surface area was 105 cm2, including the area of oedema and induration. WBC count was 13.000/mcL, C-reactive protein (CRP) 14 mg/dl, procalcitonin (PCT) 1.5 ng/dl, serum sodium 137 mEq/l, glucose 136 mg/dl, creatinine 2 mg/dl (estimated glomerular filtration rate 36 ml/min). The LRINEC score was 2. A Doppler ultrasound excluded vein thrombosis. He was worried about the discontinuation of chemotherapy in case of infection and/or prolonged hospitalization.

Which of the following therapeutic options would you consider to treat this patient?

  • A.

    Long-acting antibiotic (dalbavancin or oritavancin)

  • B.

    Oral linezolid

  • C.

    Oral trimethoprim-sulfamethoxazole

  • D.

    Oral delafloxacin

  • E.

    Hospitalization and intravenous (i.v.) antibiotic therapy active against MRSA

IDENTIFYING PATIENTS WITH ACUTE BACTERIAL SKIN AND SKIN STRUCTURE INFECTION WHO CAN BE MANAGED AS OUTPATIENTS

A modern approach to patients with ABSSSIs should include the evaluation of outpatient management. Figure 1 summarizes a potential approach to patients with ABSSSI to favour direct discharge from ED or early discharge from the hospital. The first step is to explore the possibility to directly discharge patients from the ED or to early discharge them when ABSSSI developed during hospitalization. Unfortunately, there are no clinical scores developed and validated to this purpose. Some parameters could be taken into account:

FIGURE 1.

FIGURE 1

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Innovative management of patients with acute bacterial skin and skin structure infections with or without risk factors for methicillin-resistant S. aureus cause.

  • (1)

    clinical stability

  • (2)

    exclusion of potential life-threatening conditions (i.e. necrotizing fasciitis)

  • (3)

    stable social situations

  • (4)

    no systemic signs (no fever, no suspicion of bloodstream infection)

  • (5)

    possibility to complete the follow-up during the subsequent weeks

Conversely, patients with clinical instability, systemic signs (such as fever), and high risk for having positive blood cultures, hospitalization should be considered. Hospital admission is required to provide appropriate care for ABSSSI patients with septic shock or at risk of acute deterioration. In these patients, therapeutic management is more challenging and requires multiple considerations about choice and dosages of i.v. antibiotics [18–20].

OUTPATIENT MANAGEMENT

Long-acting antibiotics: dalbavancin and oritavancin

The availability of long-acting antibiotics may ensure a direct discharge from ED or an early discharge from the hospital [21]. This approach may be of great interest to reduce hospitalization and its potential associated complications. Characteristics of long-acting antibiotics available for the management of patents with ABSSSI are summarized in Table 1.

Table 1.

Summary of new available therapeutic options for the treatment of acute bacterial skin and soft tissue infections

Antibiotic Class Route of administration Spectrum of activity Advantages Disadvantages
Dalbavancin Long-acting lipoglycopeptide derived from teicoplanin Iv Staphylococcus aureus (MSSA and MRSA)
Streptococcus pyogenes
Streptococcus agalactiae
Streptococcus dysgalactiae
Streptococcus anginosus group
Enterococcus faecalis
Vancomycin-susceptible Enterococcus faeciuma (no activity against VRE expressing vanA)		 PK profile

Short time of infusion

Volume needed for dilution

Available real-world data		 No activity against VRE expressing vanA

Need for renal adjustment
Oritavancin Long-acting lipoglycopeptide derived from chloroeremomycin (analogue of vancomycin) Iv Staphylococcus aureus (MSSA, MRSA, VISA, VRSA)
Streptococcus pyogenes
Streptococcus agalactiae
Streptococcus dysgalactiae
Streptococcus anginosus group
Enterococcus faecalis
Enterococcus faecium, including VREb 		PK profile

Activity against VRE
(including vanA)

No need for renal adjustment		 High volume for dilution

Time of infusion (3-h)

Suggested glucose monitoring (HGT) during administration

Potential false increase in aPTT values within 120 h from administration
Delafloxacin Fluoroquinolone (FQ) Both i.v. and oral Staphylococcus aureus (MSSA, MRSA)
Streptococcus pneumoniae (including levofloxacin-resistant strains)
Streptococcus pyogenes
Enterococci
Gram-negative bacilli (E. coli, K. pneumoniae)
Quinolone-susceptible P. aeruginosa
Anaerobes and atypical bacteria (e.g., Legionella, Chlamydia, Mycoplasma)		 Unlike traditional FQ, lower risk of side effects and better safety profile

Oral administration

Broad spectrum of activity		 Despite better safety profile compared to traditional FQ, caution should be paid in patients at a high risk of arrhythmia or cardiac events.
Omadacycline Tetracycline Both i.v. and oral Staphylococcus aureus (MSSA, MRSA)
S. pneumoniae (including penicillin- and macrolide-resistant strains)
Streptococcus pyogenes
Enterococcus faecalis
Enterococcus faecium, including VRE
Anaerobes and atypical bacteria, e.g., Legionella, Chlamydia, Mycoplasma)
Gram-negative bacilli (Enterobacterales, including ESBL, and some A. baumannii isolates)
Mycobacterium abscessus 		Unlike traditional tetracyclines, omadacycline is active against bacterial isolates that express tetracycline-specific efflux pumps and/ or ribosomal protection resistance mechanisms

Oral administration

Broad spectrum of activity
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FQ, fluoroquinolones; HGT, hemo gluco test; MRSA, methocillin-resistant Staphylococcus aureus; MSSA, methicillin-susceptible Staphylococcus aureus; PK, pharmacokinetic; VISA, vancomycin intermediate Staphylococcus aureus; VRE, vancomycin-resistant Enterococci; VRSA, vancomycin-resistant Staphylococcus aureus.

a

Reported in-vitro activity against some isolates of VRE expressing vanB and vanC but inactive against VRE expressing vanA.

b

Reported in-vitro activity against VRE expressing vanA and vanB.

Dalbavancin and oritavancin are authorized in patients with ABSSSI caused by methicillin-susceptible S. aureus (MSSA), MRSA, and multiple Streptococcus species [22,23]. Oritavancin has also been authorized for vancomycin-susceptible Enterococcus faecalis[23]. Recent data suggested that dalbavancin retains in-vitro activity against vancomycin-susceptible and vancomycin-resistant Enterococci (VRE) (vanB and vanC) and other uncommon Gram-positive pathogens including methicillin-resistant coagulase negative staphylococci [24]. Unlike dalbavancin, oritavancin retains activity vancomycin-susceptible and VRE, including both vanA and vanB [25,26], due to the peculiar mechanisms of direct interaction with cell membrane [27]. Efficacy and safety of the two long-acting antibiotics have been demonstrated in randomized clinical trials (RCTs), DISCOVER 1/DISCOVER 2 and SOLO 1/SOLO2, respectively [28–30]. Real-life data confirmed these favourable findings both for dalbavancin [31,32] and oritavancin [33].

Differences between dalbavancin and oritavancin are mainly represented by route of administration. Dalbavancin at the dosage of 1500 mg should be diluted with 5% Dextrose Injection, to a final concentration of 1–5 mg/ml (possible infusion volume of 500 ml) and may be administered via i.v. infusion using an infusion time of (at least) 30 min [24] Conversely, oritavancin 1200 mg needs to be diluted with 5% Dextrose Injection using a volume of 1000 mL (yielding a concentration of 1.2 mg/ml) over 3-h infusion time [23]. The need for a higher volume of infusion of oritavancin as well as the 3-h infusion time might represent a limitation in patients at risk of fluid overload, including patients with renal impairment and those with congestive heart failure. A new oritavancin formulation has been developed to simplify preparation of the solution for infusion, reduce the volume of the infusion, shorten the infusion time to 1 h and giving the flexibility to prepare in D5W or sterile water for injection [34]. The shorter infusion times with this latter formulation decreases the time patients spend receiving the infusion, which decreases chair time and allows for more patients to receive antimicrobial therapies. Moreover, these modifications may allow a well tolerated administration in patients who are volume-restricted, have poorly controlled diabetes mellitus or are at risk for dysglycaemia. It was approved by the FDA on March 2021 [35], but is not available in Europe, yet.

However, it should be considered that in-vitro studies showed that – unlike dalbavancin – oritavancin exerts bactericidal activity against MRSA isolates [36]. Further studies should better explore this aspect.

The use of long-acting antibiotics has several advantages. First, vulnerable patients, including elderly, patients with multiple comorbidities and oncological patients who need chemotherapy, may have important benefit by this approach. In fact, they represent a frail population in which prolonged hospitalization should be avoided [37]. Moreover, long-acting use has a positive impact on patients’ quality of life. A recently published study demonstrated greater satisfaction of patients with ABSSSI treated with dalbavancin over other antibiotic treatments [38]. Second, pharmacoeconomic data showed that both dalbavancin and oritavancin are associated with a shorter length of stay and lower costs compared to standard i.v. antibiotics for the treatment of ABSSSI [39▪▪,40–42]. The use of oritavancin directly at the ED reduced treatment duration by 0.8 days and led to cost savings also when compared to dalbavancin [40]. According to a recently published meta-analysis focusing on the costs of treatments for ABSSSI in the United States, dalbavancin reduce ABSSSI costs of 1442$ to 4803$ [43]. It has been also demonstrated that the use of oritavancin reduces healthcare costs of more than 1000$ for each patient with ABSSSI [44] and of 3571$ to 6932$ for patients with complicated ABSSSI [44].

NEW INTRAVENOUS/ORAL OPTIONS: DELAFLOXACIN AND OMADACYCLINE

Some new molecules, including delafloxacin and omadacycline, represent promising oral options for patients with ABSSSI (Table 1). Delafloxacin is an anionic fluoroquinolone characterized by activity at low pH, increased intracellular accumulation, and similar affinity in binding to both DNA topoisomerase IV and DNA gyrase [45]. Delafloxacin displays contemporary activity against both Gram-positive and Gram-negative bacteria with lower MICs when compared to other floroquinolones [45]. In-vitro data demonstrated excellent antibacterial potency, with a retained activity against fluoroquinolones-resistant Gram-positive bacteria, including MRSA [45], and a low probability for the selection of resistant mutants [46]. It also retains susceptibility towards certain Pseudomonas aeruginosa strains resistant to ciprofloxacin and levofloxacin [47,48]. Phase-3 RCTs demonstrated the noninferiority of i.v. delafloxacin compared to vancomycin/aztreonam [49,50]. Thus, delafloxacin has been approved for ABSSSI by the FDA in 2017 and by the European Medicines Agency (EMA) in 2019 at a dosage of 300 mg i.v. q12 h or 450 mg orally q12 h [51,52]. Advantages of delafloxacin for the treatment of ABSSSI include the availability of both parenteral (300 mg q12 h) and oral (450 mg q12 h) formulations, a low potential for drug–drug interactions and reassuring clinical and experimental data about the class-adverse effects. Unlike traditional fluoroquinolones, it has weak interactions with cytochrome P-450 and glucuronosyltransferase, reducing the risk of drug–drug interactions [53]. Compared to fluoroquinolones, it has also a better safety profile (adverse events reported in less than 1% of patients), with a limited impact on QT interval, atrioventricular conduction, or cardiac depolarization [54] and no reported cases of severe aortic aneurysms and dissection [55]. Renal dose adjustment is necessary only for the i.v. formulation in severe renal impairment, while no dose adjustment is needed for oral delafloxacin [56].

A potential limitation related to its use may be represented by authorities’ call for more restricted use of fluoroquinolones. However, in people with multiple allergies and intolerances (including severe penicillin allergy), people taking other medicines that interact with the standard antibiotic options, or in people who develop myelosuppression with linezolid, delafloxacin may be considered a suitable oral option. Moreover, in patients with severe disease, the availability of both parenteral and oral formulations may allow a switch from i.v. infusion to delafloxacin tablets as soon as patients are clinically stable and able to take oral drugs.

Omadacycline is an aminomethylcycline antibiotic, semisynthetic tetracycline derivative, that inhibits ribosomal synthesis by blocking the interaction between the 30 s ribosomal subunits and aminoacyl tRNA [57]. The specific structure of omadacycline determines resistance towards many bacterial mechanisms that cause tetracycline resistance, such as hyperexpression of efflux pumps or the production of ribosomal protective proteins, such as protection protein Tet(O) that interacts with the 70S ribosome and determines resistance to other tetracycline [58]. Omadacycline remains active against many tetracycline-resistant strains. It displays in-vitro activity against Gram-positive bacteria, including MRSA and VRE strains resistant to tetracycline, Panton-Valentine leucocidin producing MRSA, penicillin or macrolide-resistant Streptococcus pneumoniae and β-haemolytic streptococci [57,59▪]. It is also active against Gram-negative bacteria, including ESBL-producing Enterobacterales and approximately 50% of carbapenem-resistant Acinetobacter baumannii (CRAB), but has no activity against Proteus spp [60–62]. Finally, it is active against anaerobes and Mycobacterium abscessus[63]. Like delafloxacin, omadacycline is available both as oral (300 mg daily) and i.v. (100 mg daily) formulation. The oral bioavailability is approximately 34.5% [64]. Two recent meta-analyses showed that both oral and i.v. omadacycline had better clinical cure rates and microbiological eradication compared to linezolid, moxifloxacin, levofloxacin [65,66]. A post hoc analysis of three Phase 3 RCT of patients with ABSSSI and secondary bacteraemia suggested omadacycline as a possible therapeutic option in this subset [67].

Omadacycline is not metabolized by the cytochrome P450 enzyme and, at the recommended dosage, it does not interact with drug transporters, with subsequent low risk of drug interactions [68]. Omadacycline has a good safety profile, and the risk of antibiotic discontinuation was lower for omadacycline than for other molecules [65]. However, due to its peculiar binding with the M2 subtype of the muscarinic acetylcholine receptor, omadacycline may be related with increased risk of cardiovascular adverse events, mainly increased arterial blood pressure and heart rate, while no effect of QTc intervals has been demonstrated by available studies [69].

Real-world experience of these new molecules for the treatment of ABSSSI is limited.

CLINICAL VIGNETTE: MANAGEMENT OF THE PATIENT

Considering the clinical stability of the patient, he was managed directly in the ED, after the evaluation by the infectious disease consultant. Despite the absence of fever, considering that the patient received chemotherapy, blood cultures were collected before the antibiotic administration.

Oritavancin 1200 mg i.v. was administered over 3-h infusion. Follow-up ambulatory visits were scheduled. After 1 week, the patient had a clinical improvement, the pain disappeared, the erythema reduced as well as the induration area. CRP decreased (6 mg/dl), while PCT remained stable (1.3 ng/dl, in relation to chronic renal disease). Lesion size was 69 cm2. Blood cultures collected in the ED were negative. After 2 weeks from the long-acting antibiotic administration, there was a complete clinical resolution and he underwent chemotherapy.

This choice gave the patient the opportunity to turn back home, avoid hospitalization, and its related complications (i.e. acquisition of multidrug-resistant organisms). This latter is of importance considering the frailty of the patient who was receiving chemotherapy. His quality of life was substantially improved with this approach. This management had also impact on hospitalization-related costs.

CONCLUSION

ABSSSI management represents a significant challenge for infectious disease specialists. The availability of long-acting antibiotics represented a revolution in the management of these patients. A single administration of dalbavancin or oritavancin may allow efficacy and outpatient management of vulnerable patients who may benefit from an early hospital discharge. Considering the safety profile of the two molecules and the available data about their pharmacokinetics, therapeutic drug monitoring may be avoided in patients with ABSSSIs, while should be implemented in other off-label use [70▪▪]. Their use directly in the ED should be evaluated in patients without clinical instability or risk of rapid disease progression. Future studies should better define characteristics of patients with ABSSSI who can beneficiate from this approach. Clinical scores may be helpful to this purpose. Delafloxacin and omadacycline are two new antibiotics suitable for patients with ABSSSI and are available for both i.v. and oral formulations, allowing an early shift from i.v. to oral therapy.

These new approaches should be taken into considerations in patients at a high risk of MRSA cause and in those who can be safely managed as outpatient. Future studies are needed to better elucidate their optimal place-in-therapy and profile of patients who can better benefit from their use.

Acknowledgements

The authors thank Dr Valentina Galfo (University of Pisa) for her help in the literature search.

Financial support and sponsorship

None.

Conflicts of interest

M.F. received unconditional grants from Gilead and speaker honoraria from Pfizer, Menarini, Gilead, GSK, and TermoFisher. G.T. received speaker honoraria for educational meetings by Shionogi and honoraria for participation to scientific board by MSD and speaker honoraria by Menarini.

REFERENCES AND RECOMMENDED READING

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • ▪ of special interest

  • ▪▪ of outstanding interest

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