Lefamulin - An Overview

Drug Overview

Lefamulin injection is a parenteral antibiotic utilized in the management of bacterial pneumonia of the community-acquired type in adult patients. It is a member of pleuromutilin antibiotics which possess the ability to inhibit bacterial protein synthesis. Lefamulin has antimicrobial activity against Gram-positive and Gram-negative bacteria such as Streptococcus pneumoniae, Haemophilus influenzae, and methicillin-resistant Staphylococcus aureus. The vein gives it and provides a solution to patients who cannot tolerate or are unresponsive to other medication. The FDA (U.S. Food and Drug Administration) approved it in 2019.

For Patients:

What Are the Clinical Indications of Lefamulin?

Lefamulin injection is indicated for use in the treatment of community-acquired pneumonia, a type of pneumonia caused by specific types of bacteria that affect patients who are not in the hospital.

What Is the Dosage of Lefamulin?

The dosage is 150 milligrams (mg) every 12 hours, infused over 60 minutes.

What Are the Things to Inform the Doctor Before Taking the Drug?

The patient must inform the doctor if they are on other medications before starting this drug. They should also inform them about the below-mentioned conditions:

• Pregnancy.

• Heart disease.

• Liver disease.

• Kidney diseases.

• Stroke.

• Cancer.

• Breastfeeding.

• Diabetes.

How Is Lefamulin Administered?

The method of administration of Lefamulin injection is a sterile solution infused via a vein over 60 minutes. This regimen is employed every 12 hours for about five to seven days.

What Are the Side Effects of Lefamulin?

• Nausea.

• Headache.

• Difficulty falling asleep or staying asleep.

• Swelling near the spot where the medication was injected.

• Diarrhea.

Missed Dose:

If the patient forgets to take Lefamulin, they should take it as soon as they remember. In general, if the next scheduled dose is within a reasonable time frame, the dose to be given may be skipped, and dosing may be continued as prescribed. Do not take two doses simultaneously to cover the missed dose.

Overdose:

Management of an overdose with Lefamulin consists of monitoring the patient and offering supportive management. Neither Lefamulin nor its primary metabolite is dialyzable.

Storage:

When diluted, Lefamulin injection can be kept outside or at room temperature for a maximum of 24 hours. If refrigerated at two to eight degrees Celsius, it can be kept for 48 hours.

For Doctors:

Indication:

Lefamulin is a pleuromutilin antibiotic approved to treat adults suffering from community-acquired bacterial pneumonia (CABP) due to susceptible organisms.

Dose:

• In adults with community-acquired bacterial pneumonia (CABP), the optimum dose of Lefamulin is 150 milligrams (mg) intravenously every 12 hours over a 60-minute infusion for five to seven days.

• Alternatively, this drug can be taken in the oral form at 600 mg every twelve hours for five days.

• For severe hepatic impairment, an adjustment of the standard dosage is required.

Dosing Considerations:

• It is recommended that all the dilutable contents of a 15-milliliter (ml) vial of Lefamulin injection be diluted into the provided diluent bag, which contains 250 ml of 10 millimolar sodium citrate, buffered saline containing 0.9 % sodium chloride.

• Use an aseptic technique when increasing the volume of Lefamulin injection in the diluent bag and mix well.

• Parenteral preparations should be examined for contamination and changes in color before being given to the patient, as far as the drug and its packaging permit.

• Use the diluent bag only if the solution is clear and the container is intact.

• Do not use any other additives with the diluent bag, as the compatibility with Lefamulin injection has not been proven.

What Are the Pharmacological Aspects of Lefamulin?

Mechanism of Action

Lefamulin is a new member of pleuromutilins, an antibiotic that has a different way of working since it interferes with bacterial protein synthesis. It has a functional selectivity towards the 50S ribosomal subunit, one of the cellular machinery used by the organism to make proteins. This attachment stops the elongation of the polypeptide chain during the translation stage, which is also of great importance to the protein synthesis process required for the average growth and survival of bacteria. In this way, Lefamulin invites the bacteria into an inactive phase where they cannot manufacture the proteins necessary for cellular activity and, as a result, cellular replication is blocked. As a result, the bacterial cells cannot survive, and the infection is cleared. When bacterial ribosomal RNA is the target, the problem of cross-resistance with other antibiotics is minimal, which is an advantage in the current era when other drug resistance is an issue.

Lefamulin appears to have a relatively broad spectrum of activity against over 99 % of common bacteria, as it works against both Gram-positive and Gram-negative bacteria. It is effective against important pathogens such as Streptococcus pneumoniae and Haemophilus influenzae, two common pathogens associated with community-acquired bacterial pneumonia (CABP). Furthermore, Lefamulin has shown effectiveness against resistant pathogens, notably methicillin-resistant Staphylococcus aureus (MRSA), which is known to be the primary agents of infections acquired in hospitals and the community. This widespread activity profile illustrates the utility of Lefamulin in treating serious bacterial infections, especially where other antibiotics would be ineffective due to resistance. The availability of such new classes of drugs that act strategically and target resistant strains of bacteria opens new avenues in treating difficult bacterial diseases.

Pharmacokinetics

• Absorption: The bioavailability of Lefamulin upon oral administration is moderate, which indicates that the drug reaches the circulation to some extent, which is quite promising. In terms of plasma concentration, the drug generally attains maximum concentration following oral ingestion within about one to four hours. This quick absorption is critical for therapeutic action because it is important to achieve the appropriate level of the drug in the blood for the antibacterial activities to be initiated. The oral form is useful for patients who are not warranted to IV treatment because it is most probably in the latter part of the therapy or for those with less severe disease.

• Distribution: After administration, Lefamulin is found to spread rapidly over the entire body with a high penetration into the tissues. More than that, it is present in the highest amounts in the lungs, which is very important in treating bacterial community-acquired pneumonia (CABP). The attainment of effective levels of Lefamulin in the lungs means that it works in the area of need and, thus, enhances the treatment of pneumonia. This also suggests that the drug might help treat other types of infections located in some other tissues but is mainly indicated against respiratory infection.

• Metabolism: Once taken, Lefamulin is metabolized, primarily within the liver, mainly by the action of the cytochrome P450 (CYP3A4) enzyme. The particular focus of this enzyme is the metabolism of drugs into their respective metabolites. Besides the CYP3A4-dependent metabolism, the Lefamulin drug is also metabolized by non-CYP enzymes, making it possible for the drug metabolism to be complex, involving several routes. The dependence on CYP3A4 implies that drug metabolism can be compromised by substances that inhibit or induce the activity of the particular enzyme, thereby affecting its concentrations in the body and its effectiveness in curing the condition.

• Excretion: Lefamulin and its metabolites are mainly eliminated from the body via feces, which is close to 70 %. This poses a concern as about 13 % of the drug reaches urine and is excreted out. The present excretion pattern indicates that the clearance of Lefamulin is highly dependent on the liver, while the kidney makes a minor contribution. The drug has an elimination half-life of eight to ten hours, which translates to the time taken to reduce the blood concentration of Lefamulin by 50 %. This half-life is good enough to warrant a 12-hour drug dosing schedule so that adequate plasma levels of the drug for bacterial infections are maintained over time, extending the anti-infection therapeutic window.

Pharmacodynamics

Lefamulin exerts its antibacterial effect through the pharmacodynamic profile. In other words, the concentration of the drug that matters is not the maximum therapeutic level reached in the blood but somewhat how long the concentration of the antibiotic exceeds a certain threshold, called the minimum inhibitory concentration (MIC), which is defined as the lowest concentration of an antibiotic that prevents visible growth of a bacterial culture. The anti-bacterial action of Lefamulin has to consider that the drug level above the MIC has to be held for a duration over a specific time. This is usually an important pharmacodynamic property when managing an infection, as it helps to value recurrent bacterial activity over a period, allowing for adequate clearance of the infection by the patient’s body immunity.

More specifically, Lefamulin exerts a bacteriostatic or bactericidal effect depending on the bacterial organism and the drug concentration employed. Bacteriostatic activity is the ability of the drug to arrest bacterial division so that the bacteria remains non-replicating while the host’s defense takes care of the infection. This phenomenon is most seen when the concentration of the drug is low, or the bacteria under consideration are not very susceptible to the drug. In the case of bactericidal activity, Lefamulin cures the infection by killing the bacteria, as opposed to only preventing their reproductive processes. In this case, although high antibiotic doses are needed, this bactericidal activity is rapidly achieved among specific organisms, and therefore, the infection is quickly controlled.

Lefamulin has shown therapeutic success because it sustains optimal drug concentrations over time. This is more important when it comes to managing serious infections such as community-acquired bacterial pneumonia (CABP) because, in such circumstances, the underlying bacterial infection needs to be successfully controlled at all times to prevent its further progress or distribution that may worsen the infection. CABP is mainly caused by micro-organisms like Streptococcus pneumoniae and Haemophilus influenzae, and hence, safe drug concentrations have to be maintained to effect a total cure to the infection, particularly in severe cases or in the presence of drug-resistant strains, for example, methicillin resistant Staphylococcus aureus (MRSA).

Moreover, Lefamulin exhibits time-dependent pharmacokinetics and can, therefore, be administered every 12 hours, enabling continuous exposure throughout the treatment. Lefamulin targets the ribosomes of bacterial cells. The antibacterial activity is accompanied by less development of resistance, so it is useful in treating CABP and other bacterial infections.

Clinical Studies And Efficacy:

• Lefamulin clinical trials were carried out in different settings; therefore, the adverse reaction rates recorded in these studies are not comparable to those of other drugs and do not apply in real life.

• Two clinical studies were conducted to evaluate Lefamulin for the treatment of CABP utilizing different treatment duration approaches. This included a switch from intravenous dosing followed by oral dosing (Trial 1) to this one, which only involves oral dosing (Trial 2).

• In Trial 1551, adult patients were enrolled, 276 of whom were randomized to Lefamulin and 275 to Moxifloxacin. In Trial 2738, 370 patients were randomized to Lefamulin and 368 to Moxifloxacin.

• Trial 1 included patients presenting with more severe pneumonia. The average duration of IV treatment was six days, with seven days being the total treatment duration. In Trial 2, which comprised patients with PORT Risk Class II-IV, the duration of therapy was five days for Lefamulin and seven days for Moxifloxacin.

• The median age of all patients treated with Lefamulin was 61 years, comprising more than half the number of patients aged 65 years or older. The patients were predominantly male and white, with a median body mass index (BMI) of 26.

• Serious adverse events were recorded in relatively few patients during the two trials, and very few patients withdrew from treatment because of these adverse reactions. The death rate in the first 28 days of treatment was low and comparable in patients treated with Lefamulin and Moxifloxacin.

• Lefamulin and Moxifloxacin's efficacy was comparable in managing CABP with tolerable safety issues, including adverse events and treatment dropouts.

What Are the Contraindications of Lefamulin?

• Patients with known hypersensitivity to Lefamulin, other pleuromutilin-class drugs, or non-active medicine components should not be given Lefamulin.

• It is not appropriate to coadminister Lefamulin tablets and any CYP3A drugs that prolong QT interval.

Warnings and Precautions:

• QT Prolongation: Lefamulin is known to cause QT interval prolongation on ECG in some patients. This should be avoided in the following situations:

  • The patients with a known prolonged QT interval.

  • The patients with ventricular arrhythmias.

  • The patients on other antiarrhythmic drugs, class IA, for example, Quinidine, Procainamide, and class III drugs, for example, Amiodarone and Sotalol.

  • The patients are on other drugs that may cause QT prolongation, for example, antipsychotic drugs, Erythromycin, Pimozide, Moxifloxacin, and tricyclic antidepressants. Similarly, in patients with mild, moderate, or severe hepatic impairment, metabolic derangement associated with hepatic impairment may predispose the patients to QT prolongation.

  • If Lefamulin has to be used in patients at risk of developing QT prolongation or those on drugs with known QT effects, then monitoring should be performed by ECG during the course of therapy. The risk of developing QT prolongation may rise at the peak concentrations or rapid infusion of the drug, thus risking the patient if the recommended dosage or infusion rate is surpassed.

• Embryo-Fetal Toxicity: The available animal data suggests that Lefamulin may be associated with fetal toxicity when given to pregnant women. In these studies, Lefamulin treatment resulted in increased post-implantation fetal wastage or stillbirths in organically dosed rats and rabbits. Low fetal weight and its ossification related delay were noted in rats and rabbits while incurring the risk of delaying sexual maturation in rats. Evidence of malformation was observed in rats following systemic concentrations of this agent that were lower than those attained in CABP patients, showing the likelihood of embryo-fetal toxicity. Before the use of Lefamulin, the pregnancy status of women of childbearing age should be ascertained. Instruct women who are of childbearing age and may become pregnant while being treated with the drug, not to engage in unprotected sexual intercourse for two days after the last dose. It is important to inform not only pregnant women but also women of childbearing potential about the possibilities of use and potential effects on a fetus.

• Clostridium difficile-Associated Diarrhea (CDAD): There is a lot of clinical evidence linking the use of antibiotics to developing pseudomembranous colitis. There are increasing instances of infection with C. difficile, likely due to increased antibiotic use. This abnormality affects around seventy percent of the patients who have been infected with C. difficile. New reproductive and homosexual relationships with multiple new constructs may give rise to new socio-cultural systems.

• Development of Drug-Resistant Bacteria: Clostridium difficile-associated diarrhea (CDAD) has been reported with nearly all antibiotics, including Lefamulin, and may vary from mild diarrhea to life-threatening colitis. Antibiotics can disrupt the normal gut flora, leading to an overgrowth of C. difficile. This bacterium produces toxins A and B, which contribute to CDAD. Hypertoxin-producing strains of C. difficile can cause more severe illness, with higher morbidity and mortality, often requiring more aggressive treatment, including surgery. CDAD should be considered in all patients who develop diarrhea after using antibacterial drugs, even if it occurs up to two months after treatment. If CDAD is suspected or confirmed, ongoing antibiotic treatment not directed at C. difficile may need to be discontinued. Proper management may include fluid and electrolyte replenishment, protein supplementation, specific antibiotic treatment for C. difficile, and surgical intervention when necessary.

Specific Population

• Pregnancy: It has been suggested, and some animal studies confirm that Lefamulin is likely to be harmful to the fetus if used by expectant mothers. There is no clinical information available regarding Lefamulin use in pregnant women that includes its risks for major birth defects, miscarriages, or any other negative impacts on the mother and the child. Lefamulin administration by way of IV drug during the organogenesis period has been witnessed in studies to lead to higher foeticide in near clinical maternal exposure while also causing a reduction in fetal body weight and prevention of sexual maturity, which denotes the possible presence of developmental lags, and stunted organs in animals at less than average patient exposure for people with CABP. Furthermore, lowered ossification occurred in a dose-response fashion, implying some aspects of developmental abnormality. The absence of Lefamulin –associated baseline incidence of major malformations and fetal wastage in clinical pregnancy is unknown. However, for non-drug-treated women of the general population, the background risk of fetal defects is estimated in the two to four percent range, and for miscarriages in 15-20 % for biologically proven pregnancies. A pregnancy exposure registry for Lefamulin is provided.

• Lactation: There is no information available regarding the presence of Lefamulin in human breast milk and its effects on breastfed infants. Animal studies have indicated that Lefamulin accumulates in the milk of nursing rats and may be the same for lactating humans. Because of the likelihood of a significant risk of adverse effects in infants, such as QT prolongation, women should neither pump nor breastfeed milk during treatment with Lefamulin for 48 hours after the last dose.

• Females and Males of Reproductive Potential: In women of childbearing age, pregnancy status has to be verified before starting Lefamulin treatment. Women should be advised to use contraception to cover the treatment period with Lefamulin effectively and for two days post the last dose, owing to the possible risk of an adverse effect on the fetus.

• Pediatric Use: Lefamulin is statistically appropriate for people aged 18 and above. Apart from this, no data is available for children.

• Geriatric Use: 646 patients were treated with Lefamulin in the clinical trials, and 268 were aged 65 or older. There were no major differences in clinical response rates between patients 65 years and older and those under 65 years and between the Lefamulin and Moxifloxacin treatment groups. The incidence of adverse reactions was also comparable across age groups, with 30 percent of elderly subjects 65 years and older and 38% of younger patients reporting at least one adverse reaction.

• Hepatic Impairment: There is no need to adjust the dose of Lefamulin for patients with mild or moderate hepatic function impairment. The safety or use of Lefamulin tablets has not been tested in patients with hepatic impairment, and they are not indicated for moderate to severe hepatic impairment.

• Renal Impairment: No dose revisions were required in renally impaired patients, including patients on hemodialysis.