Novel long acting lipoglycopeptides oritavancin and dalbavancin
Acute bacterial skin and skin structure infections (ABSSSIs) are among the most frequent indications for antimicrobial therapy. The causative agents are usually Gram-positive bacteria including MRSA for which there are a number of treatment options that may be quite demanding with respect to application, dosing frequency, monitoring requirements, and duration of treatment. With the advent of novel lipoglycopeptides (in addition to teicoplanin, which has been available in Europe since 1992 and telavancin, which has received FDA approval in 2009), characterized by a concentration-dependent bactericidal activity and an extended elimination half-life, therapy of ABSSSI may become more easily manageable.
Oritavancin has (at least) three distinct mechanisms of action, namely inhibition of transglycosylation (like vancomycin), inhibition of transpeptidation (like beta-lactams), and disruption of cell membrane integrity (like telavancin) [
3]. These result in rapid bactericidal activity against a number of Gram-positive pathogens. It also has a very long terminal half-life of >300 h [
4] and demonstrated potent bactericidal activity of a single 1200 mg dose in an in vitro PK/PD model [
5]. It is not metabolized, and there is no need for dose adjustment for renal or moderate hepatic impairment. This set of characteristics allows for very easy administration especially in an outpatient setting. Following a phase II study that did not support the daily administration of oritavancin [
6], the recent phase III SOLO I trial involving 954 patients in the mITT population demonstrated non-inferiority of a single 1200 mg i.v. dose of oritavancin versus 7–10 days of twice daily i.v. vancomycin for ABSSSI with respect to all three efficacy end points including cure [
7]. This held true for a variety of subgroup analyses. While nausea was somewhat more common in the oritavancin group (11 vs. 8.9 %), there was no statistically significant difference with respect to safety or tolerability in general. Oritavancin therefore has the potential to be used as single-shot treatment for ABSSSIs virtually eliminating adherence issues. As stated for the SOLO I as well as the SOLO II trial, the prolonged half-life of oritavancin was not associated with any safety issues including the 60 day follow-up period [
7].
Dalbavancin is another semisynthetic lipoglycopeptide and has been evaluated for skin and soft tissue/skin structure infections [
8,
9] as well as catheter-associated blood stream infections [
10] already since the early 2000s. It has been shown to have only a minor impact on the gut flora [
11]. Its terminal half-life of about 2 weeks [
12] also allows for extended dosing intervals. Recently, the twin-phase III DISCOVER-1 and DISCOVER-2 trials for ABSSSI with 1312 patients in the pooled analysis were published. They demonstrated non-inferiority of two single doses of dalbavancin given 1 week apart compared to a standard twice-daily treatment regimen of i.v. vancomycin followed by an optional switch to p.o. linezolid for a total of 10–14 days [
13]. This was true for both the primary end point of early clinical success and end of treatment success, independent of causative pathogen or comorbidity. Non-inferiority of a two-dose regimen is even more remarkable when considering that about half the patients met the criteria for systemic inflammatory response syndrome (SIRS). Dalbavancin had a favorable safety profile with both fewer adverse events and fewer patients experiencing adverse events. Nausea was noted to be the most frequent adverse event in the dalbavancin group occurring in 2.5 % of patients. Notably, the use of dalbavancin was associated with a significantly lower mortality (0.2 vs. 1.1 %). This has led to the FDA approval of dalbavancin for ABSSSI caused by
S. aureus and
S. pyogenes in May 2014.
Tedizolid
Tedizolid phosphate is a new oxazolidinone compound. Its mechanism of action is similar to that of linezolid, which was the first drug in this class: It acts by inhibition of the ribosomal protein synthesis of bacteria. The exact mechanism of blockade is located at the 50S subunit of the bacterial ribosome, which is directly targeted by oxazolidinones in a way that inhibits binding of the tRNA by a conformational change in the binding moiety. Thereby, the protein synthesis chain is terminated [
14,
15]. The active compound of tedizolid emerges by cleavage of the phosphate moiety of the prodrug. Tedizolid is active against Gram-positive bacteria, including MRSA. Vancomycin-resistant organisms and even linezolid-resistant MRSA have been found to be susceptible to the new drug [
15‐
17].
Substantial pharmacological data on tedizolid show its suitability for clinical use as an antibiotic. Pooled analyses of intravenous and oral application have shown correlations of drug levels with clinical success. The absolute bioavailability of tedizolid is higher than 80 % which is comparable to linezolid [
14,
17‐
20]. More positive pharmacological data show a lower interaction potential of tedizolid as compared to linezolid, e.g., no interaction with inhibitors of the monoamino-oxidase (MAO-inhibitors). The long half-life of tedizolid in combination with a high bioavailability offers the realistic rationale for once daily administration. With a 10- to 12-h half-life, drug levels of tedizolid above the MIC can still be accomplished at the end of a 24-h dose interval. About 80 % of the drug is eliminated via the gut and about 20 % renally.
Because the compound has good tissue penetration, one clinical area of use is ABSSSI.
The two-phase III ESTABLISH 1 and ESTABLISH 2 trials showed non-inferiority compared to linezolid, leading to approval of the new drug by the FDA in June 2014 [
15,
16]. In ESTABLISH 2, a total of 666 patients with ABSSSI were recruited in nine countries with 58 participating treatment sites. A 1:1 randomization allocated patients in a double-blind manner to either tedizolid 200 mg intravenously followed by oral medication over 6 days or to linezolid at a dose of 600 mg by mouth twice daily over a period of 10 days. Stepdown from intravenous to oral medication could take place if the criteria of early clinical response were fulfilled. Early clinical response was defined as a reduction in the inflamed area by at least 20 % in the first 3 days. This criterion was reached roughly with equal frequency in both trial arms: In the tedizolid arm 85 % and in the linezolid arm 83 % of all patients had early clinical response. Regarding adverse events and safety issues, there was a significantly lower incidence of gastrointestinal adverse reactions in the tedizolid group (16 vs. 23 %) [
16,
17,
21].
In addition to clinical efficacy data, there have been studies investigating pharmacological issues in special populations: Patients with renal failure and with hepatic insufficiency have been subject to pharmacokinetic sampling. The results show that no dose adjustment is necessary in patients with chronic renal failure with and without hemodialysis treatment. Only 10 % of the antibiotics were removed by dialysis. In patients with hepatic impairment, a moderate increase in drug levels in the range of 22–34 % was observed [
19].