Pleuromutilins are antibiotics that selectively inhibit bacterial translation 
and are semisynthetic derivatives of the naturally occurring tricyclic 
diterpenoid pleuromutilin, which received its name from the 
pleuromutilin-producing fungus Pleurotus mutilus Tiamulin and valnemulin are two 
established derivatives in veterinary medicine for oral and intramuscular 
administration. As these early pleuromutilin drugs were developed at a time when 
companies focused on major antibacterial classes, such as the β-lactams, and 
resistance was not regarded as an issue, interest in antibiotic research 
including pleuromutilins was limited. Over the last decade or so, there has been 
a resurgence in interest to develop this class for human use. This has resulted 
in a topical derivative, retapamulin, and additional derivatives in clinical 
development. The most advanced compound is lefamulin, which is in late-stage 
development for the intravenous and oral treatment of community-acquired 
bacterial pneumonia and acute bacterial skin infections. Overall, pleuromutilins 
and, in particular, lefamulin are characterized by potent activity against 
Gram-positive and fastidious Gram-negative pathogens as well as against 
mycoplasmas and intracellular organisms, such as Chlamydia spp. and Legionella 
pneumophila Pleuromutilins are unaffected by resistance to other major 
antibiotic classes, such as macrolides, fluoroquinolones, tetracyclines, 
β-lactam antibiotics, and others. Furthermore, pleuromutilins display very low 
spontaneous mutation frequencies and slow, stepwise resistance development at 
sub-MIC in vitro. The potential for resistance development in clinic is 
predicted to be slow as confirmed by extremely low resistance rates to this 
class despite the use of pleuromutilins in veterinary medicine for >30 years. 
Although rare, resistant strains have been identified in human- and 
livestock-associated environments and as with any antibiotic class, require 
close monitoring as well as prudent use in veterinary medicine. This review 
focuses on the structural characteristics, mode of action, antibacterial 
activity, and resistance development of this potent and novel antibacterial 
class for systemic use in humans.