Pleuromutilins are a class of antibiotics that originated from the fungus Pleurotus mutilus, first identified in 1951. These compounds were initially developed for veterinary applications before being adapted for human use. They represent a distinct group of antibacterial drugs used for treating infections in both humans and animals.
How Pleuromutilins Work
Pleuromutilins function by halting bacterial protein synthesis, a process necessary for bacteria to grow and multiply. They achieve this by binding to a specific location on the bacterial ribosome, the cellular machinery responsible for producing proteins. The specific target is the 50S subunit of the ribosome, at a region known as the peptidyl transferase center. This binding action obstructs the ribosome’s ability to link amino acids together into new proteins.
The interaction prevents transfer RNAs (tRNAs), which carry the amino acid building blocks, from properly attaching to the ribosome. This mode of action is distinct from many other classes of antibiotics that also target the ribosome. The unique binding site means that bacteria resistant to other protein synthesis inhibitors may still be susceptible to pleuromutilins.
Medical and Veterinary Uses
In veterinary practices, particularly for swine and poultry, derivatives like tiamulin and valnemulin are used. These drugs treat and control respiratory and intestinal diseases, such as swine dysentery caused by Brachyspira hyodysenteriae and pneumonia involving Mycoplasma species.
In human medicine, retapamulin is available as a topical ointment. It is prescribed for treating common bacterial skin infections, including impetigo caused by Staphylococcus aureus and Streptococcus pyogenes. Its use is restricted to the skin because it is rapidly metabolized by the liver if taken systemically.
Lefamulin is the first pleuromutilin antibiotic approved for systemic administration, available in both intravenous and oral forms. It is used to treat community-acquired bacterial pneumonia (CABP). It is effective against a range of bacteria that cause CABP, including Streptococcus pneumoniae, Haemophilus influenzae, and Mycoplasma pneumoniae.
Addressing Antibiotic Resistance
The rise of antibiotic-resistant bacteria presents a continuous challenge to public health. Pleuromutilins are significant in this context because their unique mechanism of action allows them to be effective against bacteria that have developed resistance to other drugs. This class has demonstrated effectiveness against challenging pathogens like Methicillin-resistant Staphylococcus aureus (MRSA), a cause of difficult-to-treat infections.
A key advantage of pleuromutilins is their low level of cross-resistance with other antibiotic classes. Cross-resistance occurs when a bacterium’s mechanism for resisting one antibiotic also provides resistance to others. Because the pleuromutilin binding site does not significantly overlap with those of classes like macrolides or tetracyclines, resistance to those drugs does not confer resistance to pleuromutilins.
Safety Profile and Considerations
The safety and side effects of pleuromutilins depend on the specific drug and how it is administered. For topical applications, such as with retapamulin ointment, side effects are generally mild and localized. The most common reaction is irritation at the site of application.
For systemic pleuromutilins like lefamulin, a broader range of side effects can occur. The most frequently reported adverse reactions for the oral formulation are gastrointestinal, including diarrhea, nausea, and vomiting. When administered intravenously, patients may experience reactions at the injection site.
Pleuromutilins should be used only under the guidance of a healthcare professional to ensure they are appropriate for the specific infection. Rare but more serious reactions can include Clostridium difficile-associated diarrhea and a potential for affecting the heart’s rhythm, known as QT prolongation. Patients should discuss their medical history with their doctor before starting treatment.