Lefamulin: A Novel Semisynthetic Pleuromutilin Antibiotic for Community-acquired Bacterial Pneumonia

Abstract

Community-acquired bacterial pneumonia (CABP) remains a significant cause of morbidity and mortality worldwide. Antimicrobial resistance, including in pathogens that cause CABP, continues to spread at an alarming rate. Because of these factors, the development of new antibiotic classes is urgently needed. Lefamulin, previously known as BC-3781, is a semisynthetic pleuromutilin antibiotic that was approved by the Food and Drug Administration for the treatment of CABP in adults. Available in both oral and intravenous formulations, lefamulin has potent in vitro activity against both typical and atypical CABP pathogens. The first pleuromutilin to be used systemically in humans, lefamulin has a unique mechanism of action that inhibits protein synthesis by preventing the binding of tRNA for peptide transfer. This review summarizes the available data on lefamulin, including recent evidence from 2 phase III clinical trials (LEAP 1 and LEAP 2), and discusses its potential role in the treatment of CABP.

Pneumonia remains a significant cause of morbidity and mortality, especially in children and the elderly. Indeed, the World Health Organization lists pneumonia as the fourth leading cause of death and the leading cause of death due to infection worldwide [1]. This is despite the widespread use of modern and effective antibiotics. The ongoing global threat of antimicrobial resistance (AMR) has also spread to the pathogens that commonly cause pneumonia [2, 3]. Therefore, it is a cause for optimism whenever a new antibiotic class is added to our antibiotic armamentarium, especially for community-acquired bacterial pneumonia (CABP). Lefamulin is a novel semisynthetic pleuromutilin antibiotic with oral and intravenous (IV) formulations approved by the Food and Drug Administration (FDA) on 19 August 2019 for the treatment of CABP in adult patients.

Pleuromutilins were first discovered in the 1950s after being isolated from the edible mushroom Clitophilus scyphoides [4]. The first agent developed was tiamulin, which was approved in 1979 for pulmonary and intestinal infections in animals, followed by valnemulin in 1999. Neither has been used for growth promotion or feed efficiency, which likely explains why there is no widespread resistance to the drugs. The first pleuromutilin developed for human use was retapamulin, a topical agent approved in 2007 for the treatment of impetigo or wounds caused by Staphylococcus aureus and Streptococcus pyogenes. Toxicity previously limited efforts to develop pleuromutilins for systemic use in humans. However, increasing AMR in gram-positive organisms led to renewed interest in the pleuromutilins, which culminated in the synthesis of lefamulin in 2006. In this article we review the chemistry, mechanism of action, antimicrobial activity, pharmacodynamics, pharmacokinetics, clinical experience, and adverse events (AEs) of lefamulin. Finally, we discuss formulary issues involving lefamulin and its potential place among the treatment options for CABP.

We performed a systematic literature review using PubMed that included the terms “lefamulin,” “pleuromutilin,” and “BC-3781.” Results were limited to articles published in English. Clinical trials focused on lefamulin were identified using https://clinicaltrials.gov. Additional information was found on the Nabriva Therapeutics website (https://www.nabriva.com).

CHEMIS TRY AND MECHANISM OF ACTION

Lefamulin has a molecular formula of C₂₈H₄₅NO₅S and a molecular weight of 567.79 g (Figure 1). The key structure is the C(14) side chain, which is largely responsible for the antimicrobial properties and pharmacokinetics of the compound, as well as the ability to be used systemically in humans. An inhibitor of protein synthesis, lefamulin binds to the peptidyl transferase center of the 50S subunit of the bacterial ribosome [5].This unique interaction accounts for the lack of cross-resistance to other protein synthesis inhibitors including tetracyclines, macrolides, ketolides, fusidic acid, oxazolidinones, and lincosamides [6].

IN VITRO ACTIVITY

The antibacterial spectrum of lefamulin is broad. It has potent bactericidal activity against many gram-positive aerobic organisms including staphylococcus (eg, methicillin-susceptible S. aureus and methicillin-resistant S. aureus [MRSA] and coagulase-negative staphylococcus), streptococcus (eg, multidrug-resistant Streptococcus pneumoniae, β-hemolytic streptococci, and viridans group streptococci), and Enterococcus faecium including vancomycin-resistant enterococcus (VRE), but not against E. faecalis [7]. The SENTRY surveillance program collected resistance data on lefamulin between 2015 and 2016 and included 2919 S. aureus, 276 coagulase-negative staphylococci, 3923 S. pneumoniae, 389 β-hemolytic streptococcus, and 178 viridans group streptococci isolates [8]. Over 99% of the isolates exhibited minimum inhibitory concentrations (MICs) of ≤0.008 to 0.25 µg/mL. Certainly, it is necessary to continue to monitor MICs over time as the use of lefamulin in human medicine increases.

Lefamulin has activity against atypical bacteria associated with CABP such as Chlamydophila pneumoniae, Mycoplasma pneumoniae, and Legionella pneumophila. It has activity against several anaerobes including Clostridium perfringens, Cutibacterium acnes, Fusobacterium spp., Peptostreptococcus, and Prevotella spp., but not Clostridiodes difficile or Bacteroides fragilis [7]. The activity of lefamulin against gram-negative aerobes is more limited. While it has activity against the CABP pathogens Haemophilus influenzae and Moraxella catarrhalis, lefamulin lacks activity against Pseudomonas aeruginosa, Acinetobacter baumanii, and Enterobacterales due to the action of AcrAB-TolC efflux pumps [7].

The efficacy of lefamulin against common sexually transmitted pathogens appears promising. These include Neisseria gonorrhoeae (MIC_50/90 of 0.12/0.5 mg/L), Chlamydia trachomatis (MIC_50/90, 0.02/0.04 mg/L), and Mycoplasma genitalium (MIC range, 0.002–0.063 mg/L) [9]. Notably, Jacobsson et al [10] reported that lefamulin has activity against multidrug-resistant (MDR) and extensively drug-resistant strains of N. gonorrhoeae. With the ongoing spread of MDR N. gonorrhoeae and the increasing reports of failure with currently available therapy, these data provide hope that lefamulin will be an option in the future for the treatment of gonorrhea and other sexually transmitted diseases (STDs).

PHARMACOKINETICS AND PHARMACODYNAMICS

The oral and IV formulations of lefamulin are bioequivalent. In a phase I study of healthy male volunteers between 18 and 55 years old, Zeitlinger et al [11] measured the concentration of lefamulin in plasma, skeletal muscle, adipose tissue, and pulmonary epithelial lining fluid (ELF) after administration of a single 150-mg IV infusion. Concentration-time curves of lefamulin in plasma, skeletal muscle, adipose tissue, and ELF are shown in Figure 2. Exposure to unbound drug in adipose and skeletal muscle tissue was 98% and 87%, respectively. This suggests that the unbound drug diffuses freely into the interstitial spaces in these tissues. Furthermore, the ELF concentration of unbound drug was 5.7 times higher than unbound plasma levels, indicating a high penetration of lefamulin into ELF. This is similar to the known accumulation effects in ELF of macrolides and quinolones, drugs widely used for treating pneumonia. The authors posited that lefamulin concentrates in the ELF due to a P-glycoprotein–mediated active transport mechanism from the plasma [11]. Using a mouse model of neutropenic pneumonia from S. pneumoniae or S. aureus, investigators demonstrated that lefamulin penetrates rapidly into lung macrophages and is active in the presence of surfactant [12].

The metabolism of lefamulin occurs by CYP450 enzymes, specifically as a substrate and inhibitor of CYP3A. Therefore, concomitant administration of lefamulin with CYP3A inducers (eg, phenobarbital, phenytoin, rifampicin, St John’s wort, and glucocorticoids) or inhibitors (eg, clarithromycin, erythromycin, diltiazem, itraconazole, ketoconazole, ritonavir, verapamil, and grapefruit) could affect serum concentrations of lefamulin. Oral, but not IV, lefamulin increases serum concentrations of midazolam. Lefamulin is primarily excreted in the feces (77.3–88.5%).

The area under the curve (AUC):MIC is the pharmacodynamic parameter that best predicts lefamulin activity in animal infection models. Bhavnani et al [13] reported that the percentage probability of attaining the total-drug ELF AUC:MIC ratio target associated with a 2 log₁₀ colony-forming unit (cfu) reduction from baseline for S. aureus was 100% at the MIC value of 0.03 mg/L for the IV dosing regimen. Percentage probabilities of pharmacokinetics/pharmacodynamics (PK/PD) target attainment were 98.4% and 99.9% for the fed and fasted oral dosing regimens, respectively, at the same MIC value. Similarly, the percentage probability of attaining the total-drug ELF AUC:MIC ratio target associated with a 2 log₁₀ cfu reduction from baseline for S. pneumoniae was 99.2% at an MIC₉₀ value of 0.12 mg/L for the IV dosing regimen [13]. Percentage probabilities were 92.3% and 99.2% for the fed and fasted oral dosing regimens, respectively, at the same MIC value.

Given its unique mechanism of action and low spontaneous mutation frequency (≤10⁻⁹), the development of antibiotic resistance to lefamulin is likely to be slow. However, antibiotic resistance has been described in vitro, mainly due to alterations in the target site [6]. The primary resistance mechanism is mutations in 23S rRNA, rplC, and rplD genes that encode ribosomal proteins L3 and L4 [6]. Notably, lefamulin resistance from mutational changes in rplC and 23S rRNA develops gradually and in a stepwise manner, which suggests that multiple mutations are necessary for high-level resistance to develop [6].

DOSAGE AND ADMINISTRATION

The recommended dosing for lefamulin is 150 mg IV over 60 minutes every 12 hours or 600 mg orally every 12 hours for 5 to 7 days [14]. Tablets should be swallowed whole with 6 to 8 ounces of water at least 1 hour before or 2 hours after a meal. A missed dose of oral lefamulin can be taken up to 8 hours before the next scheduled dose. For patients with severe hepatic impairment (Child-Pugh class C), the IV dose should be decreased to 150 mg every 24 hours. However, lefamulin is not recommended for patients with moderate to severe hepatic impairment, and alternative agents should be used. There is no dosage adjustment needed for patients with renal impairment, including those on dialysis.

CLINICAL EXPERIENCE

The clinical efficacy and safety of lefamulin have been studied in 2 phase III randomized clinical trials for CABP, Lefamulin Evaluation Against Pneumonia (LEAP) 1 [15] and LEAP 2 [16], and 1 phase II trial for skin and skin-structure infections [17].

Community-acquired Bacterial Pneumonia

LEAP 1 and LEAP 2

The LEAP 1 and LEAP 2 trials were both double-blind, double-dummy, parallel-group, randomized trials that evaluated lefamulin versus moxifloxacin in adults with moderate to severe CABP. In both studies, randomization (1:1) was stratified by PORT risk class (III vs IV/V in LEAP 1; II vs III/IV in LEAP 2), geographic region (United States vs outside the United States), and receipt of a single dose of a short-acting antibacterial for CABP before randomization.

In LEAP 1, patients received IV lefamulin 150 mg every 12 hours for 5 to 7 days or IV moxifloxacin 400 mg every 24 hours for 7 days. Moxifloxacin-treated patients received alternating doses of a placebo to maintain blinding (also linezolid if MRSA was suspected); in which case a placebo was also administered if in the lefamulin group). Patients could switch to oral therapy (lefamulin 600 mg every 12 hours or moxifloxacin 400 mg every 24 hours) after 6 IV doses of the study drug (~3 days) if predefined improvement criteria were met. In both treatment groups, patients with CABP due to MRSA received 10 days of treatment. In LEAP 2, patients received oral lefamulin 600 mg every 12 hours for 5 days or oral moxifloxacin 400 mg every 24 hours for 7 days. Patients in the lefamulin group received an oral moxifloxacin placebo every 24 hours for 7 days, and patients in the moxifloxacin group received an oral lefamulin placebo every 12 hours for 5 days.

In both trials, the primary efficacy endpoint for the FDA was early clinical response (ECR) at 96 ± 24 hours after the first study drug dose in the intent-to-treat (ITT) population. The European Medicines Agency (EMA) coprimary endpoints (FDA secondary endpoints) were investigator assessment of clinical response (IACR) at test of cure in the microbiologic ITT population and clinically evaluable populations. Safety was assessed in all randomized patients who received any amount of study drug (safety analysis set).

Lefamulin was noninferior to moxifloxacin in the rates of ECR as well as the EMA test-of-cure populations in both trials (Table 1). The most common baseline CABP-causing pathogens identified were S. pneumoniae, S. aureus (methicillin-susceptible), and H. influenzae. “Atypical pathogens” (M. pneumoniae, L. pneumophila, C. pneumoniae) were also commonly detected in both studies. In subpopulation analysis, lefamulin and moxifloxacin demonstrated high ECR responder and IACR success rates across all CABP pathogens and severities. There were 2 patients with MRSA in LEAP 2 and both had clinical success at both EMA and IACR. For patients aged less than 65 years and those meeting modified American Thoracic Society (ATS) severity criteria, treatment differences favored moxifloxacin. Further analyses indicated that the lower response rate among patients younger than 65 years was confounded by minor, not major, ATS severity criteria. The findings in this subgroup likely reflect the effect of chance in a small subgroup, combined with observed imbalances in study drug discontinuations prior to the ECR assessment for reasons unrelated to efficacy [19].

Skin and Skin-structure Infections

In a phase II clinical trial, 2 doses of lefamulin were compared with vancomycin for IV treatment of acute bacterial skin and skin-structure infections known or suspected to be caused by gram-positive bacteria. In total, 90.8% of patients in the modified ITT population had S. aureus infection; 69.1% of patients had MRSA. The clinical success rate was comparable with lefamulin 100 mg (90%) or 150 mg (89%) and vancomycin 1 g (92%) in the clinically evaluable population, all administered IV every 12 hours [17].

Other Infections

Phase I clinical trials have been initiated in the pediatric population. Based on antimicrobial activities against STD pathogens, lefamulin may be an option for such infections in the future; presently, clinical trials have not been performed for this indication.

ADVERSE EVENTS

Clinical trial data examining the safety of lefamulin indicated that it is general well tolerated. The most common AEs of lefamulin in the CABP clinical trials were infusion-site reactions and diarrhea. Hepatic enzyme elevations, nausea, hypokalemia, insomnia, and headache also occurred with use of lefamulin; these occurred at similar rates as moxifloxacin (Table 2). In the Acute Bacterial Skin and Skin-Structure Infection trial, the most common adverse effects of lefamulin, occurring in 2% or more of patients on either dose of lefamulin and at a higher rate than with vancomycin, were infusion-site reactions, increases in creatinine phosphokinase, vulvovaginal mycotic infection, abdominal pain, and tinnitus. Lefamulin can prolong the QT interval. In the LEAP 1 trial there were 8 patients (n = 3 lefamulin, n = 5 moxifloxacin) who had nonserious treatment-emergent AEs of prolonged QT intervals; in 4 patients (n = 1 lefamulin; n = 3 moxifloxacin) the event led to study drug discontinuation. No lefamulin-treated patient and 2 moxifloxacin-treated patients had a postbaseline increase of more than 60 ms that resulted in a value greater than 480 ms; no patient in either group had a postbaseline increase of more than 60 ms that resulted in a value more than 500 ms.

The use of lefamulin in pregnant women has not been studied. In animal models, lefamulin use in pregnancy was associated with fetal loss, malformations of bones and the heart, decreased fetal weight, and decreased or no ossification of skeletal elements [14]. The animal models also demonstrated that lefamulin crosses the placenta and is found in fetal tissues. Therefore, lefamulin should not be used during pregnancy and women of childbearing potential who take it should use effective contraception for 2 days after stopping it. There are no data on the presence of lefamulin in human milk, its effects on breastfed infants, or its effects on milk production. Animal studies have shown that lefamulin concentrates in the milk of lactating rats, so it is likely to have a similar effect in human milk [14]. Breastfeeding women taking lefamulin should be advised to pump and discard breast milk, and to continue this for 2 days after taking the last dose.

Patients with liver or kidney injury prescribed lefamulin have an increased risk of QT prolongation. Lefamulin should be avoided in patients with QT prolongation at baseline, who have a known ventricular arrhythmia, are taking class IA or IIIA antiarrhythmic drugs, or are taking other drugs that are known to prolong the QT interval. If lefamulin is prescribed in these circumstances, then electrocardiogram monitoring is recommended during the course of therapy.

PLACE IN THERAPY

Lefamulin provides an additional option for treatment of CABP. It is the first systemic antibacterial of a new antibiotic class with favorable clinical data in the treatment of CABP in more than 15 years. As an IV and oral empiric monotherapy it provides targeted antimicrobial activity against the most prevalent CABP pathogens, providing clinicians a potential CABP treatment option that aligns with the principles of antimicrobial stewardship. Considerations for the use of lefamulin should take into account antimicrobial activity against key CABP pathogens, safety, cost, and impact of disruption of the microbiome. Lefamulin has minimal activity against Enterobacteriales and B. fragilis and likely will have less impact on the gastrointestinal microbiome compared with other treatment regimens with broader spectrum of activity, and avoids many of the adverse effects of the fluoroquinolones. It also provides an option to patients who are unable to tolerate β-lactams or macrolides.

For patients receiving lefamulin, the ability to step down from the IV to the oral formulation could theoretically lead to a reduced length of stay and lower healthcare costs. However, the wholesale cost in the United States per day is $205 for the IV formulation and $275 for tablets. Thus, the cost for a 7-day course of oral therapy is $1925 and for the IV formulation is $1435. Because of the high cost, more detailed pharmacoeconomic analyses will be necessary to define the high-risk patient subgroups for which lefamulin can provide cost-effective, quinolone- and macrolide-sparing CABP therapy. Furthermore, the high cost will likely be a limiting factor if lefamulin is approved for the treatment of STDs.

Conclusions

Lefamulin is a novel pleuromutilin antibiotic with an excellent PK/PD profile that is generally well tolerated and has a low risk of AEs. It has broad-spectrum antimicrobial coverage, with clinical trial data showing it to be an effective therapy for CABP. While promising, questions remain over its place in therapy due its high cost and the availability of other well-established and far less expensive antibiotic options.

Notes

Acknowledgments. The authors thank Dr Markus Zeitlinger for kindly allowing us to use Figure 2 and Dr Tracy Lemonovich for her helpful comments about the manuscript.

Potential conflicts of interest. R. R. W. has received research grant support and serves on an advisory board and speaker’s bureau for Allergan. T. M. F. has served as a consultant for Motif BioSciences, Merck, Nabriva Therapeutics, Paratek, GlaxoSmithKline, Melinta, and Shionogi. Both authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

References