Lefamulin

Nature of the antibiotic

Semi-synthetic, pleuromutilin class.
Molecular weight – 567.79 gm/mole

Pleuromutilins

Pleuromutilins (produced by Pleurotus sp.), discovered in the 1950s, have a tricyclic mutilin core.
Tiamulin – the first member of this group, was approved for veterinary use in 1979.
Retapamulin – topical pleuromutilin was approved for human use in 2007.

Mechanism of action

It inhibits protein synthesis by preventing the binding of tRNA for peptide transfer.

It interacts with the A- and P-sites of the peptidyl transferase centre in domain V of the 23s rRNA of the
50S subunit. It interacts by hydrogen bonds, hydrophobic interactions, and Van der Waals forces.

Mechanism of resistance

• Protection or modification of the ribosomal target: by ABC-F proteins such as vga (A, B, E), lsa(E), sal(A), Cfr methyl transferase,
• Mutations of ribosomal proteins L3 and L4

There is potential for cross-resistance with chloramphenicol, lincosamides, oxazolidinones, and
streptogramin A.

PK/PD

• Best PK-PD index – The 24 h free-drug AUC to minimal inhibitory concentration (MIC) ratio.
• oral bioavailability – 25%
• Food (esp high fat, high calorie) reduce bioavailability – tablets should be taken 1 hour before or 2 hours after food.
• Plasma protein binding >/= 95%
• T1/2 (in patients with community-acquired bacterial pneumonia patients – 8 hours.
• Lefamulin is primarily metabolized by CYP3A4.
• Hepatic impairment: IV – dose reduction in severe liver derangement (Child-Pugh C); PO – not recommended in moderate-severe (Child-Pugh B and C).
• Excretion – mainly in faeces (>705), and urine (approx 15%)

Use

• FDA approval in 2019 to treat adults with community-acquired bacterial pneumonia (caused by Streptococcus pneumoniae, methicillin-susceptible Staphylococcus aureus, Haemophilus influenzae, Legionella pneumophila, Mycoplasma pneumoniae, and Chlamydophila pneumonia).
• Other potential uses (trial, as per the manufacturer Nabriva) – Acute bacterial skin and skin structure infections (ABSSSI), sexually transmitted infections (STIs), ventilator-associated bacterial pneumonia (VABP), hospital-acquired bacterial pneumonia (HABP), osteomyelitis, and prosthetic joint infections.

Adverse effect

Gastrointestinal adverse effects (diarrhoea, nausea, vomiting), administration site reactions, hepatic enzyme elevation, hypokalemia, insomnia, headache, QT Prolongation.

Caution/contraindication

• Avoid use in patients with known QT prolongation, ventricular arrhythmias including torsades de pointes, and patients receiving drugs that prolong the QT interval.
• May cause fetal harm (Females of reproductive age may need effective contraception).
• C difficile-associated diarrhoea.
• Avoid in hypersensitivity to lefamulin/Pleuromutilin.
• Avoid concurrent use with strong or moderate CYP3A inducers or P-gp inducers.
• Avoid concurrent use of Lefamulin tablets with strong CYP3A inhibitors or P-gp inhibitors.

Spectrum

Gram-positive: Methicillin sensitive Staph aureus (Not MRSA – not evaluated), Streptococcus pneumonia.
Gram-negative: H influenzae
Atypicals: Mycoplasma pneumonia, Chlamydophila pneumonia, Legionella pneumophila.

It is not active against Enterobacteriaceae and Pseudomonas aeruginosa.
The safety and efficacy have not been assessed in the trial for – group A Streptococcus, group B Streptococcus, alpha haemolytic Streptococcus, MRSA.
It is bacteriostatic against MSSA and group A Streptococcus; bacteriocidal against S. pneumoniae, H. influenzae and M. pneumoniae.

Papers/ref:

• https://www.nature.com/articles/srep39004
• https://academic.oup.com/cid/article/69/11/1856/5306243?searchresult=1
• LEAP – Study to Compare Lefamulin to Moxifloxacin (With or Without Linezolid) for the Treatment of Adults With Pneumonia
• LEAP2 – Study to Compare Lefamulin to Moxifloxacin for the Treatment of Adults With Pneumonia
• Bioavailability and Pharmacokinetics of Lefamulin When Administered to Fed and Fasted Healthy Subjects