The pleuromutilins are a relatively ‘old’ class of antibiotics that have seen much use in veterinary but not in human medicine. According to EMA, Tiamulin is an “essential antibiotic” for the control of dysentery in pigs which is caused by Brachyspira hyodysenteriae, a macrolide-resistant pathogen. Retapamulin / Altabax® was introduced by GSK into the clinic a few years ago; it is a topical antibiotic approved for the treatment of impetigo. A systemically absorbed pleuromutilin is as yet unavailable.
The pleuromutilin furthest advanced in development is BC-3781, a compound developed by Nabriva. Its Phase 2 program in ABSSSI was conducted between 2010-2012, with results published first in abstract form and then as a full publication by Prince and colleagues.
Because the drug class is unfamiliar to most clinicians, here a quick summary:
- The target of pleuromutilins is the 23 sRNA bacterial ribosome subunit; hence, the MoA is bacteriostatic
- The antimicrobial spectrum includes mainly Gram-positive bacteria, MRSA, PRSP, E. faecium (but not other enterococci), with MIC90 in the 0.12 -0.5 µg/mL range
- Activity against H. influenzae is adequate but MIC90s are 2-3 dilution steps lower than for S. aureus
- Excellent activity against M. pneumoniae, C. pneumophila, Legionella and M. catarrhalis
- activity against M. tuberculosis
- benign overall safety profile but some earlier compounds have shown liver toxicity in animal studies.
Hence, BC-3781 should work very well for ABSSSI and CABP, in cases of atypical pneumonia and possibly as an agent for E. faecium.
The paper by Prince  is of interest as it is the first large well-designed clinical trial of a systemic pleuromutilin in humans. Given the novelty of the compound class, we were curious about the safety / tolerability of BC-3781 in the 141 patients receiving either 100 or 150 mg PO q12h compared to vancomycin which was administered as 1g q12h.
Most patients received treatment for 4-7 days. BC-3781 caused more infusion site reactions than the comparator, a finding already noticed in earlier Phase 1 dose-escalation trials. The frequency of GI related adverse events was low overall and not more than seen with vancomycin. Vancomycin, as would be expected, was associated with a higher incidence of pruritus. There was no signals pointing to any other system organ class (SOC), and LFTs were unremarkable. There were no deaths. Numbers of patients with severe AEs or prematurely discontinued were too small to draw conclusions.
The authors mention QTc prolongation of 7, 11, and 12 msec in the vancomycin, BC-3781 100mg and BC-3781 150 mg dosing arms, respectively. These are relatively small changes that do not raise undue concerns but probably warrant monitoring in the next set of studies just to put the issue at rest.
There is an oral intermediate release formulation of BC-3781 in development which would allow a convenient step-down treatment. For competitive reasons (oxazolidinones have a similar ribosomal MoA, bacterial spectrum, and list of indications), having a IV / PO pleuromutilin would be a big plus.
Bottom line: With few new market entries expected in the coming years, a broad-spectrum drug like BC-3781 will have little competition and high share of voice while addressing a significant medical need. Not a bad place to be.
 Prince. Antimicrob Agents Chemother 2013; 57: 2087