Tedizolid in skin and skin structure infections: brave new world?

KEYWORDS:

• Antibiotics
• MRSA
• skin and skin structure infections
• tedizolid

1. Introduction

Skin and soft tissue infections (SSTIs) encompass a wide spectrum of clinical manifestations, depending on the anatomical site of infection. They range in severity from mild superficial forms to severe life-threatening infections, which penetrate into the deep subcutaneous tissues. The definition of complicated SSTIs (cSSTIs) identifies patients who need complex management including surgical procedures and antibiotic treatment and/or who have significant underlying comorbidities, such as diabetes mellitus, systemic immunosuppression, or neurological diseases.

Recently, updated guidelines have tried to simplify the management of localized purulent staphylococcal infections, notably skin abscesses, furuncles, and carbuncles in the era of methicillin-resistant Staphylococcus aureus (MRSA) [1]. In this context, the US Food and Drug Administration (FDA) has issued guidelines to assist sponsors in the clinical development of drugs for the treatment of acute bacterial skin and skin structure infections (ABSSSIs). An ABSSSI is defined as: (1) bacterial infection of the skin with a lesion size area of at least 75 cm²; (2) cellulitis/erysipelas, wound infection, and major cutaneous abscess [2].

2. Etiology

Worldwide, the most common cause of SSTI is Staphylococcus aureus. However, Streptococcus pyogenes and other streptococci, enterococci, and Gram-negative bacteria can also be involved in ABSSSI. Recent epidemiological data of the European Antimicrobial Resistance Surveillance (EARS) Network from 28 participating countries suggested that overall MRSA accounted for 16.7% of all staphylococcus isolates, and rates of >25% were reported from Cyprus, Greece, Italy, and Malta [3]. One of the new therapeutic options for MRSA infections is linezolid, with both oral and parenteral administration, shown to be effective for SSTIs, osteomyelitis, and pneumonia [4]. Nonetheless, multifocal outbreaks of linezolid-resistant staphylococcus (LRS) have been documented [4]. Linezolid resistance occurs by mutations in the linezolid 23S rRNA binding site, the ribosomal proteins L3, and/or L4 of the peptide translocation center of the ribosome or by acquisition of the plasmid-borne ribosomal methyltransferase gene cfr [4]. Additionally, L3-coding gene mutations have been recorded in Staphylococcus epidermidis clinical isolates, showing high-level linezolid resistance and causing bacteraemia in critically ill patients in Greece [5]. Moreover, the common adverse event of bone marrow suppression often observed after long-term treatment with linezolid is an obstacle for the specific antibiotic. Fortunately, new agents are in the pipeline, enabling single-dose administration, such as dalbavancin (1000 mg intravenous infusion followed by a 500 mg intravenous infusion after a week) or oritavancin (as a single dose treatment) and may improve the outlook of patients with ABSSSI [6,7].

3. Tedizolid

Tedizolid phosphate is a novel, potent oxazolidinone pro-drug, which is rapidly converted in vivo to microbiologically active tedizolid. This specific molecule interacts with the bacterial 23S ribosome initiation complex to inhibit translation. The efficacy and safety of this new antibacterial agent have been studied in the Efficacy and Safety of 6-day Oral Tedizolid in Acute Bacterial Skin and Skin Structure Infections vs. 10-day Oral Linezolid Therapy-1 (ESTABLISH-1) trial, whereby a 6-day oral tedizolid regimen was compared with a 10-day oral linezolid therapy in ABSSSIs [8]. Tedizolid was statistically noninferior to linezolid in early clinical response at 48-72 h after initiating therapy [8]. A further trial, Efficacy and Safety of 6-day Oral Tedizolid in Acute Bacterial Skin and Skin Structure Infections vs. 10-day Oral Linezolid Therapy-2 (ESTABLISH-2), randomized patients to either intravenous tedizolid phosphate 200 mg once daily for 6 days or intravenous linezolid 600 mg twice daily for 10 days, with optional oral step-down [9]. Once again, noninferiority was documented for tedizolid [9].

Taken together, these two trials [8,9] have demonstrated the noninferiority of tedizolid (early clinical responses 81.6% vs. 79.4%, respectively) along with its improved tolerability and safety profile compared with linezolid, particularly in terms of gastrointestinal adverse events and hematological parameters. The most frequently reported adverse event was nausea (tedizolid 8.2%; linezolid 12.2%; p = 0.02), whereas fewer tedizolid-treated than linezolid-treated patients exhibited low platelet counts [10]. A phase I study in healthy volunteers comparing five treatments (tedizolid at 200, 300, or 400 mg once daily; tedizolid at 600 mg twice daily) over 21 days showed that mean platelet counts decreased over time in a dose-dependent manner for tedizolid, with higher doses being similar to linezolid [11]. Of note, pharmacokinetic analysis in specific populations suggested that estimated tedizolid exposure measures in Latino patients versus non-Latino patients were similar [12]. Additionally, no dosage adjustment would be required when switching administration routes in Chinese population.

Not to be underestimated, there are still many queries on the efficacy of tedizolid in other serious infections, such as catheter-related biofilm infections and respiratory tract infections [13]. In a recent animal-model study employing the model of infection by methicillin-sensitive Staphylococcus aureus (MSSA) and MRSA strains, the tedizolid-treated group exhibited significantly improved efficacy versus the linezolid-treated and vancomycin-treated groups [13]. Cubist Pharmaceuticals LLC is currently recruiting participants in a 1:1, randomized, double-blind, double-dummy, multicenter, global, phase III study of tedizolid 200 mg intravenous once daily for 7 days versus linezolid 600 mg every 12 h for 10 days for the treatment of ventilated participants with presumed gram-positive hospital-acquired bacterial pneumonia (HABP) or ventilator-associated bacterial pneumonia (VABP) [14]. We should also take into account that tedizolid in vitro was highly active against multidrug resistance (MDR) Streptococci pneumoniae isolates from Asian areas, showing at least fourfold greater potency compared to linezolid and maintained activity regardless of resistance phenotypes to other commonly utilized agents [15].

Another interesting clinical implication relates to infected diabetic foot ulcers, in which ongoing research is still trying to improve isolation of pathogens, antibiotic treatment, and promotion of healing. Experience with tedizolid in this setting is more than eagerly awaited.

Finally, antibiotic cost is an increasingly serious problem in our era, whereas recently marketed drugs are more expensive than their trial comparators. This could be a limitation for their usage especially in countries with financial problems affecting health care.

4. Conclusion

Tedizolid has been shown to be safe and efficacious in ABSSSIs. Its efficacy and convenient dosing render it a very promising alternative to linezolid.

5. Expert opinion

Tedizolid has demonstrated excellent activity against broad-spectrum aerobic and facultative anaerobic gram-positive bacteria. Other advantages include the availability of both oral and intravenous routes of administration, the short course of therapy, the convenient dosing scheme, and the trend toward less hematological toxicity [8–12]. Taken these advantages into consideration, tedizolid appears increasingly preferable to linezolid in ABSSSIs.

Nonetheless, further evidence is required before its use in other more serious infections can be safely recommended. Relevant ongoing trials will increase our awareness in this area. Overall, further use of tedizolid, perhaps with increased number of therapeutic indications, is expected during the next 5 years.

Declaration of interest

P. Panagopoulos has been an advisory board member of Gilead Science and Merck Sharp and Dohme, has received honoraria by AbbVie, Gilead Science, Merck Sharp and Dohme and Novartis and attended conferences sponsored by Actelion, Janssen, Bristol-Myers Squibb, Merck Sharp and Dohme and Gilead. N Papanas has been an advisory board member of Astra-Zeneca, Boehringer Ingelheim, MSD, Novo Nordisk, Pfizer, Takeda and TrigoCare International; has participated in sponsored studies by Astra-Zeneca, Eli-Lilly, GlaxoSmithKline, Merck Sharp and Dohme, Novo Nordisk, Novartis and Sanofi-Aventis; has received honoraria as a speaker for Astra-Zeneca, Boehringer Ingelheim, Eli-Lilly, ELPEN, Merck Sharp and Dohme, Mylan, Novo Nordisk, Pfizer, Sanofi-Aventis and Vianex; and attended conferences sponsored by TrigoCare International, Eli-Lilly, Galenica, Novo Nordisk, Pfizer and Sanofi-Aventis. E Maltezos has participated in sponsored studies by Astra-Zeneca, GlaxoSmithKline, Novo Nordisk, Novartis and Sanofi-Aventis; and attended conferences sponsored by Wyeth, Pfizer, and Bayer. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

This paper was not funded.