New Antibiotics in the Management of Acute Bacterial Skin and Skin Structure Infections

Kristyna Gleghorn, BS¹; Emily Grimshaw, MD²; Erica Kelly, MD²

¹School of Medicine, ² Department of Dermatology, The University of Texas Medical Branch, Galveston, TX, USA

ABSTRACT
Acute bacterial skin and skin-structure infections (ABSSSIs), often caused by aerobic gram-positive cocci, are most often mild-tomoderate infections that can easily be treated in an outpatient setting. With the rates of these infections substantially increasing in the past decade, owing in part to the emergence of community acquired methicillin-resistant Staphylococcus aureus (CA-MRSA), alternative options for the treatment of ABSSSIs are necessary. This editorial reviews the mechanism of action, efficacy, bacterial coverage, and potential side effect profiles for dalbavancin and oritavancin, both semisynthetic lipoglycopeptide antibiotics, and tedizolid, an oxazolidinone. Dalbavancin, oritavancin, and tedizolid have been extremely valuable additions to treatment options for ABSSSIs due to the convenient dosing regimen and the fact that there are fewer resistant organisms to these therapies at this time.

Key Words:
acute bacterial skin and skin-structure infections, antibiotics, glycopeptide, dalbavancin, oritavancin, tedizolid

Introduction

Acute bacterial skin and skin-structure infections (ABSSSIs), often caused by aerobic gram-positive cocci, are estimated to cause more than 15 million infections and 870,000 hospital admissions annually in the United States.1 SSSIs are most often mild-to-moderate infections that can easily be treated in an outpatient setting. Rates of these infections have substantially increased in the past decade, owing in part to the emergence of community acquired methicillin-resistant Staphylococcus aureus (CA-MRSA).² The economic burden of SSSIs remains substantial and is driven by the high costs of hospitalization, which is often required for severe SSSIs since the agents used to treat these infections require daily intravenous (IV) administration for multiple days.³ Early clinical detection of severe or necrotizing SSSIs is difficult because the disease is often indistinguishable from its milder counterparts early in the disease course. Signs of a severe infection include pain disproportionate to the clinical findings, violaceous bullae, cutaneous hemorrhage, skin sloughing, skin anesthesia, rapid progression, and gas in the tissue.⁴ Additionally, it is recommended that patients with SSSIs accompanied by signs and symptoms of systemic toxicity, such as hypotension, fever, hypothermia, tachycardia, increased creatinine level, decreased serum bicarbonate, increased creatinine phosphokinase, marked left shift, or C-reactive protein >13 mg/L, be considered for hospitalization.⁴

Glycopeptide antibiotics, such as vancomycin, have been used in treatment of SSSIs for over half a century and are still used extensively today; however, reduced vancomycin susceptibility in CA-MRSA strains as well as difficulty in therapeutic drug monitoring compromise the clinical efficacy of vancomycin.^2,5 Second generation semisynthetic lipoglycopeptide derivatives such as dalbavancin and oritavancin, which possess a broader spectrum of activity and improved pharmacokinetic properties, will be discussed in this article. The new glycopeptide antibiotics provide efficacious alternatives for the treatment of complicated ABSSSIs.¹ A major benefit is management in an outpatient setting, which could significantly decrease or omit the costs and risks of hospitalization, as well as eliminating the need for laboratory monitoring.¹

Oxazolidinones are another important class of antibiotics used in the treatment of ABSSSIs, particularly vancomycin resistant Enterococcus(VRE) infections. Historically, linezolid has been the antibiotic of choice; however, tedizolid is a novel oxazolidinone that offers enhanced antimicrobial potency, low rates of bacterial resistance, and potential safety advantages. Additionally, the recommended dosing of once per day may be more convenient and is associated with higher compliance than twice per day dosing for linezolid.⁶

To maintain effectiveness of new antibiotics, their use should be limited to ABSSSIs where the bacteria are susceptible to the new medication and are resistant to other more cost effective options. Although tedizolid, dalbavancin, and oritavancin have been approved for SSSIs caused by MRSA, they probably should not be used as a first-line treatment when there are less expensive and more easily accessible antibiotics, such as trimethoprimsulfamethoxazole or doxycycline, that are very effective for MRSA infections.⁷

Glycopeptide Therapeutics – Dalbavancin and
Oritavancin

Dalbavancin is a long-acting IV semisynthetic lipoglycopeptide antibiotic with bactericidal activity against gram-positive cocci, including MRSA.^6-10 It is the first US FDA approved drug for adults with ABSSSIs that requires only 2 IV doses administered 1 week apart: the first dose is 1000 mg IV infused over 30 minutes, followed 1 week later by the second dose of 500 mg IV.^6-10

Dalbavancin is effective for treatment of adult patients with ABSSSI caused by susceptible isolates of gram-positive organisms. Susceptible gram-positive organisms include Staphylococcus aureus (S. aureus), including MRSA and MSSA, and Streptococcus groups (S. pyogenes, S. agalactiae, and S. anginosus).^6-11 In vitro studies suggest it may also be effective against vancomycinsusceptible Enterococcus faecium and Enterococcus faecalis (E. faecalis), as well as vancomycin-intermediate S. aureus; however, clinical importance has not been established.^6,11 The safety and efficacy in pediatric patients 18 years of age and younger has not been demonstrated.^8,11 However, vancomycin has been successfully used in treating these bacterial infections in the pediatric patient population.11 Dalbavancin is pregnancy category C meaning there has been some fetal toxicity in animals, but no adequate human studies.^6,8,11

The adverse effects most commonly experienced include nausea, diarrhea, and headaches, reported in 5% or less of patients.^6-8,10,11 Infrequent serious hypersensitivity reactions, including anaphylaxis, have been reported and caution should be exercised with patients who have a known allergy to other glycopeptides.^8,10 Additionally, rapid IV infusion could cause infusion-related reactions (pruritus, urticaria, and flushing).^6-8,10 Slowing or interrupting the infusion may be helpful if this occurs.⁷

Oritavancin is a long-acting IV semisynthetic lipoglycopeptide antibiotic with potent activity against gram-positive pathogens, including MRSA.³ Oritavancin is bactericidal and has an extended plasma half-life.^3,11,12 It is the first single-dose antibacterial drug approved by the US FDA for treatment of adult patients with ABSSIs.¹² The recommended single dose is 1200 mg IV infused over 3 hours.^7,11 Dose adjustment for advanced age, decreased renal function, or moderate hepatic impairment is not required.^3,7

Oritavancin is approved for use in adults with ABSSSIs caused by susceptible gram-positive microorganisms. Susceptible grampositive microorganisms include S. aureus (including MRSA and MSSA), various Streptococcus groups (S. pyogenes, S. agalactiae, S. dysgalactiae, and S. anginosus), and E. faecalis (vancomycinsusceptible isolates only).¹¹ The safety and efficacy have not been established in patients 18 years of age and younger.¹¹ Oritavancin is pregnancy category C.¹¹

The adverse effects most often reported include nausea, headache, vomiting and diarrhea, all occurring in less than 10% of patients.^3,7,11,12Osteomyelitis is a rare adverse event occurring in 0.3% of patients.^11,12 If osteomyelitis is suspected an antibacterial agent other than oritavancin should be used.^11,12 Infrequent reports of serious hypersensitivity reactions have occurred.^3,11 It is important to be aware of patients who have a history of allergies to other glycopeptides, including vancomycin.¹¹ Additionally, infusion-related reactions (pruritus, urticaria, flushing) have been experienced, as with other glycopeptides.^3,11,12 If this occurs, slowing or interrupting the infusion should be considered.¹¹

The current therapeutic options for the treatment of ABSSSIs require multidose and multiday regimens, with some patients requiring dosage adjustments for renal insufficiency or monitoring of plasma drug concentration.³ Multiday regimens may require patients to be hospitalized over their course of treatment, which increases the risk of nosocomial complications.³ Additionally, oral antibiotic regimens have an increased rate of noncompliance, which increases the potential for pathogen resistance. Oritavancin achieves a sustained clinical response with a single dose and does not require dosage adjustments for renal insufficiency. Oritavancin and dalbavancin could potentially reduce or eliminate hospital stays, improve treatment compliance, reduce utilization of health care resources, and add flexibility to the treatment of these serious infections. Despite the advantages, other more cost effective antibiotics with a history of effective use in treatment of ABSSSIs should be considered before deciding to treat with dalbavancin or oritavancin.

Oxazolidinone Therapeutic – Tedizolid Phosphate

The oxazolidinones are a synthetic class of agents now commonly relied on for the treatment of ABSSSIs, including more serious infections like MRSA and VRE.¹³ With increasing utilization of linezolid, resistant pathogens have begun to emerge.¹³ Tedizolid phosphate is a second-generation oxazolidinone antibiotic that offers enhanced antimicrobial potency and low rates of bacterial resistance.^13-15 Available in both IV and oral forms, tedizolid exhibits bacteriostatic activity by binding the 50S subunit of the bacterial ribosome, resulting in inhibition of bacterial protein synthesis.^11,13-15 The recommended dosage is 200 mg once daily for 6 days,^6,7,14,16 which may offer increased convenience and compliance when compared to twice daily linezolid.

Clinical studies have proven tedizolid phosphate to be effective against susceptible isolates of gram-positive organisms including S. aureus (including MRSA and MSSA), various Streptococcus groups (S. pyogenes, S. agalactiae, and S. anginosus), and E. faecalis (including VRE).^6,7,11,13-16 In vitro studies have suggested it may also exhibit activity against some strains of Staphylococci and Enterococci that are not susceptible to vancomycin or linezolid; however, the clinical importance of this data has not been established.^{6,11,13,14,16} The safety and effectiveness in pediatric patients 18 years of age or younger has not been demonstrated; whereas, linezolid is indicated for use in pediatric patients.^11,16 Tedizolid phosphate is pregnancy category C.^6,11,16

Structural differences between tedizolid and linezolid are thought to contribute to tedizolid’s decreased rates of resistance and enhanced potency.^13,14 Bacteria confer resistance to linezolid by acquiring the chloramphenicol-florfenicol resistance gene, which can be horizontally transferred.^13,15 However, because of structural distinctions, tedizolid has decreased vulnerability to this resistance mechanism.^13,15 Interactions with the ribosomal subunit are thought to contribute to the increased potency of tedizolid.^13,15

Another potential advantage of tedizolid compared to linezolid is an improved safety profile.^14,15 The most common adverse effects are similar to those seen with linezolid and include nausea, headache, diarrhea, vomiting, and dizziness, each occurring in less than 8% of patients.^6,7,14-16 Toxicity linked to duration of treatment with linezolid includes peripheral and optic neuropathy as well as hematologic toxicity and thrombocytopenia.^13,16 Tedizolid has not had reports of peripheral and optic neuropathy.^13,16 Although tedizolid exposure has been limited to 21 days or less in patients, a rat study using tedizolid doses up to 10-fold greater than human doses did not induce a neuropathy.¹³ This data indicates a possible safety advantage of tedizolid. Additionally, at recommended doses, tedizolid has not been associated with hematologic toxicity or thrombocytopenia¹³; however, higher doses or longer treatment durations might increase the risk. Linezolid has been associated with the occurrence of myelosuppression, especially in patients who have underlying hematologic abnormalities or renal insufficiency, which requires complete blood counts to be monitored weekly.¹³ An additional concern exists for the oxazolidinone class, which has been shown to act as weak, reversible monoamine oxidase (MAO) inhibitors in some in vitro studies.^6,13 However, based on two randomized, double-blind, placebo-controlled crossover studies, as well as another study including both humans and animals, tedizolid failed to interact with serotonergic drugs, adrenergic agents, or result in MAO inhibitor activity.^6,13,16 Data from post marketing experience will be beneficial to confirm the encouraging results that are currently available.

Conclusion

Dalbavancin, oritavancin, and tedizolid have been extremely valuable additions to treatment options for ABSSSIs due to the convenient dosing regimen and the fact that there are fewer resistant organisms to therapy at this time. In practice, other antibiotics with a history of effective use for ABSSSIs, which also cost less, should be considered first in order to prevent bacterial resistance.

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