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Oral 5-Day Lefamulin for Outpatient Management of Community-Acquired Bacterial Pneumonia: Post-hoc Analysis of the Lefamulin Evaluation Against Pneumonia (LEAP) 2 Trial
Reprint Address: Frank LoVecchio, do, mph, facep, ASU, U of AZ, Creighton, Valleywise Medical Center, University of Arizona, 1012 Willetta Street, Floor 2, Phoenix, AZ 85006
Affiliations
ASU, U of AZ, Creighton, Valleywise Medical Center, University of Arizona, Phoenix, Arizona
Safe and effective oral antibiotics are needed for outpatient management of moderate to severe community-acquired bacterial pneumonia (CABP).
Objective
We describe a post-hoc analysis of adults with CABP managed as outpatients from the Lefamulin Evaluation Against Pneumonia (LEAP) 2 double-blind, noninferiority, phase 3 clinical trial.
Methods
LEAP 2 compared the efficacy and safety of oral lefamulin 600 mg every 12 h (5 days) vs. oral moxifloxacin 400 mg every 24 h (7 days) in adults (inpatients and outpatients) with Pneumonia Outcomes Research Team (PORT) risk classes II‒IV.
Results
Overall, 41% (151 of 368) of patients receiving lefamulin and 43% (159 of 368) of patients receiving moxifloxacin started treatment as outpatients—44% and 40%, respectively, were PORT risk class III/IV, and 21% in both groups had CURB-65 scores of 2‒3. Early clinical response (at 96 ± 24 h) and investigator assessment of clinical response success rates at test of cure (5‒10 days after last study drug dose) were high and similar in both groups among all (lefamulin, 91% vs. moxifloxacin, 89‒90%), PORT risk class III/IV (89‒91% vs. 88‒91%), and CURB-65 score 2‒3 (87‒90% vs. 82‒88%) outpatients. Few outpatients (lefamulin, 2.6%; moxifloxacin, 2.5%) discontinued the study drug because of treatment-emergent adverse events (TEAEs). No outpatient in the lefamulin group was hospitalized for a TEAE, compared with 5 patients (3%), including two deaths, in the moxifloxacin group.
Conclusions
These data suggest that 5 days of oral lefamulin can be given in lieu of fluoroquinolones for outpatient treatment of adults with CABP and PORT risk class III/IV or CURB-65 scores of 2‒3.
). Disposition decisions, which revolve around an initial assessment of severity and may involve the use of tools to stratify patients based on the risk of short-term mortality, are dependent on the availability of treatment options appropriate for outpatients (
). Examples of tools that aid in this decision-making include the Pneumonia Outcomes Research Team (PORT) risk class and the CURB-65 score (confusion of new onset, blood urea nitrogen > 19 mg/dL, respiratory rate ≥ 30 breaths/min, systolic blood pressure < 90 mm Hg or diastolic blood pressure ≤ 60 mm Hg, and age 65 years or older) (
). Although these tools provide useful guidance for patient management, a given PORT risk class or CURB-65 score can result in variable site-of-care decisions, depending on the clinician's subjective assessment of the individual patient (
). For example, patients with PORT risk class III or a CURB-65 score of 2 could be admitted for a short hospitalization or observation or treated as outpatients. Studies have shown that physicians may overestimate the risk of death in patients with pneumonia, potentially leading to unnecessary hospitalizations and increased costs for patients who could be treated effectively and safely in the outpatient setting (
Reasons why emergency department providers do not rely on the pneumonia severity index to determine the initial site of treatment for patients with pneumonia.
). Furthermore, physicians may choose inpatient rather than outpatient care because of concerns related to possible adverse events that are commonly associated with some of the most frequently used CABP therapies (e.g., fluoroquinolones) (
Diagnosis and treatment of adults with community-acquired pneumonia: an official clinical practice guideline of the American Thoracic Society and Infectious Diseases Society of America.
Lefamulin is a first-in-class systemic pleuromutilin antibiotic approved for i.v. and oral use in adults with CABP and has been shown to selectively inhibit bacterial protein synthesis by binding the 50S ribosomal subunit at the peptidyl transferase center and preventing peptide bond formation (
Inhibition of peptide bond formation by pleuromutilins: the structure of the 50S ribosomal subunit from Deinococcus radiodurans in complex with tiamulin.
). This unique mechanism at a highly conserved ribosomal site suggests that development of bacterial resistance to lefamulin and cross-resistance to other antibacterial classes are unlikely (
Antibacterial activity of lefamulin against pathogens most commonly causing community-acquired bacterial pneumonia: SENTRY antimicrobial surveillance program (2015-2016).
Antimicrobial activity of the pleuromutilin antibiotic BC-3781 against bacterial pathogens isolated in the SENTRY Antimicrobial Surveillance Program in 2010.
In vitro activities of lefamulin and other antimicrobial agents against macrolide-susceptible and macrolide-resistant Mycoplasma pneumoniae from the United States, Europe, and China.
). This in vitro activity translated to clinical efficacy in the Lefamulin Evaluation Against Pneumonia (LEAP) 1 and LEAP 2 phase 3 clinical trials, which demonstrated that lefamulin was noninferior to moxifloxacin in adults with CABP based on standard early and post-treatment clinical response endpoints (
Efficacy and safety of intravenous-to-oral lefamulin, a pleuromutilin antibiotic, for the treatment of community-acquired bacterial pneumonia: the phase III Lefamulin Evaluation Against Pneumonia (LEAP 1) trial.
Oral lefamulin vs moxifloxacin for early clinical response among adults with community-acquired bacterial pneumonia: the LEAP 2 randomized clinical trial.
Efficacy and safety of intravenous-to-oral lefamulin, a pleuromutilin antibiotic, for the treatment of community-acquired bacterial pneumonia: the phase III Lefamulin Evaluation Against Pneumonia (LEAP 1) trial.
Post hoc assessment of time to clinical response among adults hospitalized with community-acquired bacterial pneumonia who received either lefamulin or moxifloxacin in 2 phase III randomized, double blind, double-dummy clinical trials.
). In the LEAP 2 trial, patients were stratified by PORT risk class II vs. III/IV, and a substantial proportion of patients began treatment in the outpatient setting (
Oral lefamulin vs moxifloxacin for early clinical response among adults with community-acquired bacterial pneumonia: the LEAP 2 randomized clinical trial.
Post hoc assessment of time to clinical response among adults hospitalized with community-acquired bacterial pneumonia who received either lefamulin or moxifloxacin in 2 phase III randomized, double blind, double-dummy clinical trials.
). The objective of this post-hoc analysis of the LEAP 2 trial was to evaluate whether patients with moderate to severe CABP (i.e., patients who might be considered for either hospital admission or outpatient treatment) could be effectively managed as outpatients using a 5-day regimen of oral lefamulin therapy.
Materials and Methods
Methods for the LEAP 2 trial (ClinicalTrials.gov Identifier: NCT02813694) were previously described in detail and are briefly summarized here (
Oral lefamulin vs moxifloxacin for early clinical response among adults with community-acquired bacterial pneumonia: the LEAP 2 randomized clinical trial.
). The trial protocol was approved by the Ethics Committee or Institutional Review Board at each site, and the trial was conducted in accordance with Good Clinical Practice guidelines and the ethical principles of the Declaration of Helsinki. All patients provided written informed consent.
Patients
Eligible patients were aged 18 years and older, with PORT risk class II through IV (≥50% of patients were required to have PORT risk class III or IV), radiographically documented pneumonia (lung infiltrates or diffuse opacities on chest x-ray study or computed tomography scan consistent with acute bacterial pneumonia), acute illness for ≤ 7 days with three or more CABP symptoms (e.g., dyspnea, cough, sputum production, or chest pain), two or more vital sign abnormalities (e.g., fever or hypothermia, hypotension, tachycardia, or tachypnea), and one or more other clinical signs or laboratory findings of CABP (e.g., hypoxemia). Patients were excluded if they received more than one dose of a short-acting oral or i.v. antibacterial for CABP within 72 h before randomization; were hospitalized for ≥ 2 days within 90 days before symptom onset; had confirmed or suspected methicillin-resistant Staphylococcus aureus; were at risk of major cardiac events or dysfunction; had severe renal impairment (estimated creatinine clearance, ≤ 30 mL/min); or had evidence of significant hepatic, hematologic, or immunologic disease.
Assessments
The U.S. Food and Drug Administration (FDA) primary efficacy endpoint was early clinical response (ECR) at 96 ± 24 h after the first dose of study drug, and the European Medicines Agency primary (FDA secondary) efficacy endpoint was investigator assessment of clinical response (IACR) at test of cure (TOC; 5‒10 days after last study drug dose). Patients were programmatically classified as ECR responders if they were alive, showed improvement in two or more CABP symptoms, had no worsening of any CABP symptom, and received no nonstudy antibiotic for the treatment of CABP. Investigator assessment classified patient response as a success if CABP signs or symptoms were resolved or improved such that no additional antibiotic was administered for the current CABP episode. This post-hoc analysis reports ECR, IACR at TOC and at late follow-up (day 30 ± 3 days), and ECR plus IACR at TOC. Additional analyses included ECR and IACR at TOC by baseline pathogen or by comorbidity. Treatment-emergent adverse events (TEAEs) were evaluated by category and preferred term (Medical Dictionary for Regulatory Activities, version 20.0; www.meddra.org). TEAE severity was defined as mild if the TEAE was generally transient, required minimal therapeutic intervention, and did not interfere with usual activities of daily living; as moderate if the TEAE was usually alleviated with specific therapeutic intervention, interfered with usual activities of daily living, and caused discomfort without disrupting function; and as severe if the TEAE interrupted the usual activities of daily living, significantly affected clinical status, or required intensive therapeutic intervention. TEAEs were assessed through TOC and serious TEAEs (defined as an AE that was life-threatening, resulted in persistent or significant disability or incapacity, required hospitalization or prolongation of existing hospitalization, or resulted in death) were assessed through late follow-up.
Statistical Methods
For this post-hoc analysis, descriptive statistics were generated to characterize demographics and baseline clinical characteristics, efficacy outcomes, and safety outcomes. Treatment differences (lefamulin minus moxifloxacin) and corresponding 95% confidence intervals were calculated for those efficacy outcomes in which each treatment group included at least 20 patients. All analyses were conducted in the outpatient cohort, which was defined as randomized patients from the LEAP 2 trial who received any amount of study drug and were treated on an outpatient basis for the current CABP episode. However, the efficacy outcomes of ECR and IACR by baseline pathogen were assessed within a subset of the outpatient cohort in only those patients who also had one or more baseline bacterial pathogens known to cause CABP.
Results
Patients
Overall, 42% of patients (310 of 736) started treatment as outpatients (lefamulin, 41% [151 of 368]; moxifloxacin, 43% [159 of 368]). Patient demographics and baseline clinical characteristics were generally similar between treatment groups (Table 1) and were broadly reflective of the patient population with CABP. In the overall cohort, 30% of outpatients were aged 65 years or older, and approximately 15% were aged 75 years or older. A PORT risk class of III/IV was reported in 42% of outpatients, and a CURB-65 score of 2‒3 was reported in 21% of outpatients. Lung infiltrates were present in most outpatients (90%) at baseline and were unilobar and multilobar in 60% and 29% of patients, respectively. Among outpatients, the majority (lefamulin, 77%; moxifloxacin, 76%) entered the study with at least one comorbid condition or risk factor (i.e., age 65 years or older, smoking history, history of hypertension, baseline liver enzyme elevation, moderate to severe renal impairment, history of asthma or chronic obstructive pulmonary disease, diabetes mellitus, or history of dysrhythmia), and 25% of patients in the lefamulin group and 29% in the moxifloxacin group had at least three comorbid conditions or risk factors (Table 1).
Table 1Patient Demographics and Baseline Clinical Characteristics in Outpatients
PORT risk class was calculated programmatically using data obtained at the site and reported in the electronic case report form and was not always consistent with the site-reported PORT risk class used for enrollment or stratification; as a result, 1 outpatient with PORT risk class I in the moxifloxacin group and 2 outpatients with PORT risk class V (lefamulin, n = 1; moxifloxacin, n = 1) were enrolled in the LEAP 2 trial.
Medical history terms were defined as follows: hypertension included patients with medical history terms of hypertension (n = 59) or arterial hypertension (n = 28); baseline liver enzyme elevation was defined as aspartate aminotransferase or alanine aminotransferase greater than the upper limit of normal; moderate or severe renal impairment was defined as creatinine clearance < 60 mL/min; asthma/COPD included patients with medical history terms of asthma (n = 22), COPD (n = 21), chronic bronchitis (n = 5), or both asthma and COPD (n = 1); diabetes mellitus included patients with medical history terms of diabetes mellitus (n = 12) or type 2 diabetes mellitus (n = 17); and dysrhythmia included patients with the medical history terms of atrial fibrillation (n = 3), atrial flutter (n = 1), bundle branch block left (n = 1), bundle branch block right (n = 1), or ventricular extrasystoles (n = 1).
Conditions included age 65 years or older, smoking history, history of hypertension, baseline liver enzyme elevation, moderate to severe renal impairment, history of COPD or asthma, history of diabetes mellitus, or history of dysrhythmia.
Conditions included age 65 years or older, smoking history, history of hypertension, baseline liver enzyme elevation, moderate to severe renal impairment, history of COPD or asthma, history of diabetes mellitus, or history of dysrhythmia.
n (%)
0 conditions
35 (23.2)
38 (23.9)
1 conditions
52 (34.4)
55 (34.6)
2 conditions
27 (17.9)
20 (12.6)
3 or more conditions
37 (24.5)
46 (28.9)
Met SIRS criteria,
Defined as meeting two or more of the following four criteria at baseline: temperature < 36°C or > 38°C; heart rate > 90 beats/min; respiratory rate >20 breaths/min; and white blood cell count < 4000 cells/mm3, white blood cell count > 12,000 cells/mm3, or immature polymorphonuclear neutrophils > 10%.
BMI = body mass index; COPD = chronic obstructive pulmonary disease; LEAP = Lefamulin Evaluation Against Pneumonia; PORT = Pneumonia Outcomes Research Team; SD = standard deviation; SIRS = systemic inflammatory response syndrome.
∗ PORT risk class was calculated programmatically using data obtained at the site and reported in the electronic case report form and was not always consistent with the site-reported PORT risk class used for enrollment or stratification; as a result, 1 outpatient with PORT risk class I in the moxifloxacin group and 2 outpatients with PORT risk class V (lefamulin, n = 1; moxifloxacin, n = 1) were enrolled in the LEAP 2 trial.
† Patients received a single dose of short-acting systemic antibacterial medication within 72 h before randomization.
‡ Medical history terms were defined as follows: hypertension included patients with medical history terms of hypertension (n = 59) or arterial hypertension (n = 28); baseline liver enzyme elevation was defined as aspartate aminotransferase or alanine aminotransferase greater than the upper limit of normal; moderate or severe renal impairment was defined as creatinine clearance < 60 mL/min; asthma/COPD included patients with medical history terms of asthma (n = 22), COPD (n = 21), chronic bronchitis (n = 5), or both asthma and COPD (n = 1); diabetes mellitus included patients with medical history terms of diabetes mellitus (n = 12) or type 2 diabetes mellitus (n = 17); and dysrhythmia included patients with the medical history terms of atrial fibrillation (n = 3), atrial flutter (n = 1), bundle branch block left (n = 1), bundle branch block right (n = 1), or ventricular extrasystoles (n = 1).
§ Conditions included age 65 years or older, smoking history, history of hypertension, baseline liver enzyme elevation, moderate to severe renal impairment, history of COPD or asthma, history of diabetes mellitus, or history of dysrhythmia.
|| Defined as meeting two or more of the following four criteria at baseline: temperature < 36°C or > 38°C; heart rate > 90 beats/min; respiratory rate >20 breaths/min; and white blood cell count < 4000 cells/mm3, white blood cell count > 12,000 cells/mm3, or immature polymorphonuclear neutrophils > 10%.
Nearly one-half of outpatients (49%; 153 of 310) had at least one baseline pathogen, including 55% (83 of 151) in the lefamulin group and 44% (70 of 159) in the moxifloxacin group. Polymicrobial infections were identified in 28% (23 of 83) and 33% (23 of 70) of outpatients in the lefamulin and moxifloxacin groups, respectively, and were most frequently caused by a combination of gram-positive and fastidious gram-negative pathogens (i.e., Haemophilus influenzae or Moraxella catarrhalis), predominantly Streptococcus pneumoniae plus H. influenzae or M. catarrhalis (lefamulin, 48% [11 of 23]; moxifloxacin, 65% [15 of 23]). Of the identified polymicrobial infections, 9% (2 of 23) of infections in the lefamulin group and 13% (3 of 23) in the moxifloxacin group were caused by a combination of S. pneumoniae plus an atypical pathogen (Legionella pneumophila or Mycoplasma pneumoniae).
Efficacy
The rates for ECR and IACR success at TOC were high and similar in both treatment groups among all outpatients, including those with PORT risk class III/IV and CURB-65 scores of 2‒3 (Figure 1). Among outpatients with PORT risk class III, ECR rates were 88% (45 of 51; lefamulin) and 94% (46 of 49; moxifloxacin) and IACR success rates at TOC were 92% (47 of 51) and 94% (46 of 49), respectively. Similarly, in outpatients with a CURB-65 score of 2, ECR rates were 86% (24 of 28) in each treatment group and IACR success rates at TOC were 92% (47 of 51) with lefamulin and 94% (46 of 49) with moxifloxacin. Among all outpatients, the IACR success rate was maintained through late follow-up (day 30 ± 3 days) in both the lefamulin (91% [137 of 151]) and moxifloxacin (90% [143 of 159]) groups.
Figure 1Early clinical response (ECR) and investigator assessment of clinical response (IACR) at test of cure (TOC) in outpatients. PORT = Pneumonia Outcomes Research Team.
Lefamulin also demonstrated high response rates among the subgroups of outpatients infected by typical (S. pneumoniae, S. aureus, H. influenzae, and M. catarrhalis) and atypical (M. pneumoniae, L. pneumophila, and Chlamydophila pneumoniae) CABP pathogens (Figure 2), including those with polymicrobial infections (ECR: lefamulin, 78% [18 of 23]; moxifloxacin, 91% [21 of 23]; IACR at TOC: 87% [20 of 23] and 83% [19 of 23], respectively). Similarly, high response rates with lefamulin were generally demonstrated among the subgroups of outpatients with advanced age (those 65 years or older or 75 years or older), smoking history, and other comorbidities and risk factors (Figure 3).
Figure 2Early clinical response (A) and investigator assessment of clinical response at test of cure (B) by baseline pathogen in outpatients. Baseline pathogen is assessed within a subset of the outpatient cohort with one or more baseline bacterial pathogens known to cause community-acquired bacterial pneumonia. A patient could have had more than one baseline pathogen. CI = confidence interval; NA = not applicable.
Figure 3Early clinical response (A) and investigator assessment of clinical response at test of cure (B) by comorbidity in outpatients. A patient could have had more than one comorbidity. CI = confidence interval; COPD = chronic obstructive pulmonary disease; NA = not applicable.
TEAE rates were similar in both treatment groups, with few TEAEs leading to study drug discontinuation (Table 2). In the lefamulin group, no outpatient had a TEAE resulting in hospital admission during the study or any other serious TEAE. In the moxifloxacin group, 5 outpatients (3%) had serious TEAEs (Table 3), including two deaths and one hospital admission due to relapse. The most frequently reported TEAEs in the lefamulin group were gastrointestinal events (Table 4), which were all mild to moderate in severity. Three outpatients discontinued study drug owing to a gastrointestinal TEAE (vomiting [lefamulin, n = 1; moxifloxacin, n = 1], upper abdominal pain [lefamulin, n = 1]). Related TEAEs were generally reflective of overall TEAEs.
Table 2Overview of Treatment-Emergent Adverse Events in Outpatients
A TEAE was defined as an AE that started or worsened at or after the start time of the first dose of study drug. AEs with unknown start date or partial date such that it could not be determined if they started on or after first study drug administration, were categorized as TEAEs; AEs were classified using the Medical Dictionary for Regulatory Activities, version 20.0 (www.meddra.org).
Related TEAEs were defined as TEAEs that were considered by the investigator to be “definitely,” “probably,” or “possibly” related to study drug. If the relationship for a TEAE was missing, it was considered “related.”
A TEAE was classified as serious if it was life-threatening, resulted in death or persistent or significant disability or incapacity, required inpatient hospitalization or prolongation of existing hospitalization, was a congenital anomaly or birth defect, or was an important medical event that jeopardized the patient or required medical or surgical intervention.
∗ A TEAE was defined as an AE that started or worsened at or after the start time of the first dose of study drug. AEs with unknown start date or partial date such that it could not be determined if they started on or after first study drug administration, were categorized as TEAEs; AEs were classified using the Medical Dictionary for Regulatory Activities, version 20.0 (www.meddra.org).
† Related TEAEs were defined as TEAEs that were considered by the investigator to be “definitely,” “probably,” or “possibly” related to study drug. If the relationship for a TEAE was missing, it was considered “related.”
‡ A TEAE was classified as serious if it was life-threatening, resulted in death or persistent or significant disability or incapacity, required inpatient hospitalization or prolongation of existing hospitalization, was a congenital anomaly or birth defect, or was an important medical event that jeopardized the patient or required medical or surgical intervention.
Patient's pneumonia symptoms were absent by the end-of-treatment visit on day 8 (1 day after the last study drug dose) and clinical response was documented as success. On day 12, patient collapsed at home and did not recover consciousness; on arrival, paramedics confirmed that the patient had already died. The death certificate confirmed death from natural causes, and no autopsy was performed.
BMI = body mass index; DM = diabetes mellitus; GERD = gastroesophageal reflux disease; HTN = hypertension; PORT = Pneumonia Outcomes Research Team; TEAE = treatment-emergent adverse event.
∗ No serious TEAEs or deaths occurred in outpatients treated with lefamulin.
† Patient's pneumonia symptoms were absent by the end-of-treatment visit on day 8 (1 day after the last study drug dose) and clinical response was documented as success. On day 12, patient collapsed at home and did not recover consciousness; on arrival, paramedics confirmed that the patient had already died. The death certificate confirmed death from natural causes, and no autopsy was performed.
Diarrhea was the most frequently reported TEAE among outpatients and was more frequent in the lefamulin group (19% [29 of 151]) than the moxifloxacin group (2% [3 of 159]). The 29 outpatients treated with lefamulin who experienced diarrhea as a TEAE reported a total of 31 episodes (20 mild and 11 moderate in severity). Of these, 28 episodes (20 mild; 8 moderate) occurred in 1 outpatient each and 3 moderate episodes occurred in 1 outpatient. The 3 outpatients treated with moxifloxacin who experienced diarrhea as a TEAE each experienced one mild episode. Among diarrhea TEAE episodes with reported start and stop times (lefamulin, n = 30; moxifloxacin, n = 3), the mean (standard deviation) duration of diarrhea was 2.9 (2.7) days with lefamulin and 2.7 (2.9) days with moxifloxacin. No patient in either treatment group in the LEAP 2 trial (inpatient or outpatient) experienced diarrhea that was severe, serious, or that led to study drug discontinuation.
Discussion
This post-hoc analysis of data from the LEAP 2 trial suggests that patients with CABP and PORT risk class III/IV or CURB-65 score of 2‒3, including those with advanced age (those 65 years and older or 75 years and older), comorbidities associated with CABP, polymicrobial infections, or difficult-to-treat pathogens, such as L. pneumophila, can be effectively managed as outpatients using a 5-day regimen of oral lefamulin as an alternative to fluoroquinolones. The outpatient population examined here was broadly reflective of the CABP population treated in clinical practice or real-world setting, as evidenced by the substantial proportions of outpatients who entered the study with multilobar pneumonia (30%) or at least one comorbid condition (72%) typically associated with CABP (
). Among outpatients who responded early (i.e., achieved ECR), > 90% continued to respond (i.e., achieved IACR success) at both 5‒10 days after the last dose of study drug (i.e., at TOC) and at day 30 ± 3 days (i.e., at late follow-up), with only 1 patient in the moxifloxacin group admitted to the hospital because of relapse. These results demonstrate that lefamulin therapy can provide sustained efficacy in outpatients.
Initiating appropriate empiric antimicrobial therapy and preventing unnecessary hospital admissions can have significant economic benefits and infection control implications (
Society for Healthcare Epidemiology of America, Infectious Diseases Society of America, Pediatric Infectious Diseases Society Policy statement on antimicrobial stewardship by the Society for Healthcare Epidemiology of America (SHEA), the Infectious Diseases Society of America (IDSA), and the Pediatric Infectious Diseases Society (PIDS).
Implementing an antibiotic stewardship program: guidelines by the Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America.
Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America guidelines for developing an institutional program to enhance antimicrobial stewardship.
). A retrospective analysis of claims data for approximately 2 million individuals aged 65 years or older found that the burden of community-acquired pneumonia (CAP) was greater than that of other serious medical conditions (
). Furthermore, the numbers of hospitalizations and readmissions, length of stay per hospitalization or readmission, and mortality rate within 30 days of discharge were all greater in patients with CAP compared with those who experienced myocardial infarction, stroke, or osteoporotic fractures (
). One retrospective study of claims data from a large U.S. health plan found that the overall cost for an episode of CAP was $27,661 for inpatients compared with $2212 for outpatients (
). Increased rates of nosocomial infection and exposure to second- and third-line antimicrobials may also lead to higher mortality rates in the hospital setting, providing further incentive for outpatient treatment of CABP when possible (
Managing patients with CABP in the outpatient setting may also result in better patient satisfaction and a timelier return to work and usual activities. Among patients with a PORT risk class of II or III, 91% of those treated in the outpatient setting reported satisfaction with their overall care compared with 79% of those treated in the hospital (p = 0.03) (
). In a separate analysis of low-risk patients (i.e., PORT risk class of I‒III) with CAP, outpatients were more likely to return to work or their usual activities and did so 6‒9 days earlier compared with inpatients; these differences were not explained by inpatient length of stay (
The fact that initiating lefamulin therapy in the outpatient setting resulted in sustained efficacy throughout the LEAP 2 trial suggests that expensive health care resource use (e.g., hospitalization) may be able to be largely avoided in some patients. This is supported by the observation that no patient who began lefamulin treatment as an outpatient required hospital admission at any point during the LEAP 2 trial. Although selecting the appropriate treatment approach and setting may be challenging with many patients presenting with CABP, these data may reassure physicians that some patients with PORT risk class III/IV or a CURB-65 score of 2‒3 may be safely and effectively managed as outpatients with lefamulin therapy.
In this analysis, 5 days of therapy with oral lefamulin was generally well tolerated, with low rates of study drug discontinuation due to TEAEs. No outpatient treated with lefamulin had a serious TEAE, and no new safety concerns were identified. Diarrhea was reported more frequently in outpatients treated with lefamulin than with moxifloxacin, but all cases were mild or moderate in severity, none were treatment limiting, and no cases of Clostridium difficile were observed.
Limitations
This analysis is limited by its post-hoc nature and was not powered for subgroup analyses; therefore, the presented statistical analyses should be interpreted with caution. Second, participants in the LEAP 2 trial, including outpatients, were predominantly from outside of North America. Although this may limit the generalizability of these results, this pattern of enrollment is consistent with that of other contemporary phase 3 clinical trials evaluating CABP, and broad similarities in demographic, clinical, and microbiological characteristics have been demonstrated across geographic regions in a recent analysis of antimicrobial clinical trials conducted between 2001 and 2017 (
SOLITAIRE-IV: a randomized, double-blind, multicenter study comparing the efficacy and safety of intravenous-to-oral solithromycin to intravenous-to-oral moxifloxacin for treatment of community-acquired bacterial pneumonia.
FOCUS 1: a randomized, double-blinded, multicentre, phase III trial of the efficacy and safety of ceftaroline fosamil versus ceftriaxone in community-acquired pneumonia.
FOCUS 2: a randomized, double-blinded, multicentre, phase III trial of the efficacy and safety of ceftaroline fosamil versus ceftriaxone in community-acquired pneumonia.
). Third, this analysis was also limited by being smaller in size than originally expected. Because enrollment of patients with PORT risk class III and IV was limited to 50% of LEAP 2 participants, the anticipated study population subset starting treatment as outpatients was expected to be much higher than the 42% that was observed. However, instead of being treated as outpatients, as recommended by treatment guidelines (
Oral lefamulin vs moxifloxacin for early clinical response among adults with community-acquired bacterial pneumonia: the LEAP 2 randomized clinical trial.
). Because LEAP 2 participants were predominantly from outside North America, the low proportion of outpatients may be attributed to geographic differences in reimbursement structures around site-of-care decisions that may encourage physicians to choose inpatient care more often than outpatient care in this population (
). However, because lefamulin was approved in the United States for the treatment of adults with CABP in 2019, further data on outpatients will continue to accumulate (
These data suggest that patients with CABP and PORT risk class III/IV or CURB-65 scores of 2‒3, including those aged 65 years or older or with typical comorbidities in this population, can be managed effectively as outpatients using a 5-day regimen of oral lefamulin as an alternative to fluoroquinolones. Lefamulin is a promising new monotherapy option for the outpatient treatment of CABP regardless of advanced age or typical comorbidities.
Article Summary
1. Why is this topic important?
Management of community-acquired bacterial pneumonia (CABP) is associated with significant inpatient health care costs and oral antibiotic options that safely and effectively treat patients in the outpatient setting are needed.
2. What does this study attempt to show?
The objective of this post-hoc analysis of the Lefamulin Evaluation Against Pneumonia (LEAP) 2 trial was to evaluate whether patients with moderate to severe CABP (i.e., patients who might be considered for either hospital admission or outpatient treatment) could be managed effectively as outpatients using a 5-day course of oral lefamulin.
3. What are the key findings?
Early clinical response (at 96 ± 24 h) and investigator assessment of clinical response success rates at test of cure (5‒10 days after the last study drug dose) were high and similar in both treatment groups among all outpatients (lefamulin, 91% vs. moxifloxacin, 89‒90%), including those with Pneumonia Outcomes Research Team (PORT) risk class III/IV (89‒91% vs. 88‒91%) and CURB-65 scores of 2‒3 (87‒90% vs. 82‒88%). Few outpatients (lefamulin, 2.6%; moxifloxacin, 2.5%) discontinued study drug because of treatment-emergent adverse events (TEAEs). No outpatient in the lefamulin group was admitted to the hospital due to a TEAE or worsening pneumonia.
4. How is patient care impacted?
These data suggest that a 5-day regimen of oral lefamulin can be used in lieu of fluoroquinolones for outpatient treatment of adults with CABP and PORT risk class III/IV or CURB-65 scores of 2‒3.
Acknowledgments
The LEAP 2 trial was funded by Nabriva Therapeutics. Editorial and medical writing support for manuscript development was provided by Morgan C. Hill, PhD, and Michael S. McNamara, MS, employees of ICON (North Wales, PA), and funded by Nabriva Therapeutics.
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Inhibition of peptide bond formation by pleuromutilins: the structure of the 50S ribosomal subunit from Deinococcus radiodurans in complex with tiamulin.
Antibacterial activity of lefamulin against pathogens most commonly causing community-acquired bacterial pneumonia: SENTRY antimicrobial surveillance program (2015-2016).
Antimicrobial activity of the pleuromutilin antibiotic BC-3781 against bacterial pathogens isolated in the SENTRY Antimicrobial Surveillance Program in 2010.
In vitro activities of lefamulin and other antimicrobial agents against macrolide-susceptible and macrolide-resistant Mycoplasma pneumoniae from the United States, Europe, and China.
Efficacy and safety of intravenous-to-oral lefamulin, a pleuromutilin antibiotic, for the treatment of community-acquired bacterial pneumonia: the phase III Lefamulin Evaluation Against Pneumonia (LEAP 1) trial.
Oral lefamulin vs moxifloxacin for early clinical response among adults with community-acquired bacterial pneumonia: the LEAP 2 randomized clinical trial.
Post hoc assessment of time to clinical response among adults hospitalized with community-acquired bacterial pneumonia who received either lefamulin or moxifloxacin in 2 phase III randomized, double blind, double-dummy clinical trials.
Society for Healthcare Epidemiology of America, Infectious Diseases Society of America, Pediatric Infectious Diseases Society
Policy statement on antimicrobial stewardship by the Society for Healthcare Epidemiology of America (SHEA), the Infectious Diseases Society of America (IDSA), and the Pediatric Infectious Diseases Society (PIDS).
Implementing an antibiotic stewardship program: guidelines by the Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America.
Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America guidelines for developing an institutional program to enhance antimicrobial stewardship.
SOLITAIRE-IV: a randomized, double-blind, multicenter study comparing the efficacy and safety of intravenous-to-oral solithromycin to intravenous-to-oral moxifloxacin for treatment of community-acquired bacterial pneumonia.
FOCUS 1: a randomized, double-blinded, multicentre, phase III trial of the efficacy and safety of ceftaroline fosamil versus ceftriaxone in community-acquired pneumonia.
FOCUS 2: a randomized, double-blinded, multicentre, phase III trial of the efficacy and safety of ceftaroline fosamil versus ceftriaxone in community-acquired pneumonia.
Frank LoVecchio has served on an advisory board for Nabriva Therapeutics. Jennifer Schranz and David Mariano are employees of/stockholders in Nabriva Therapeutics plc. Elizabeth Alexander and Andrew Meads were employees of/stockholders in Nabriva Therapeutics at the time of the analysis. Christian Sandrock has served as a consultant for Nabriva Therapeutics; served as a speaker for Allergan, Merck, and Pfizer; received grants from the National Institutes of Health and the Health Resources and Services Administration; and received salary support from the State of California. Gregory J. Moran has received grants from Allergan, ContraFect, and Nabriva Therapeutics. Philip A. Giordano has served on advisory boards for Nabriva Therapeutics and Paratek.
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