Can Lefamulin Decrease the Burden of Community-Acquired Pneumonia?

A diagnosis of community-acquired pneumonia is associated with high costs and significant morbidity and mortality, yet currently available treatment options have high levels of failure and associated adverse event risks.

In fact, according to an analysis published in 2016, pneumonia ranks as the eighth most expensive condition treated in US hospitals with an estimated annual cost of $16 billion.

Each year there are between 5 and 6 million cases of community-acquired pneumonia, accounting for about $10 billion in inpatient treatment costs, with the remainder being spent on the outpatient side. Mortality rates fluctuate between 12% for patients admitted to the hospital and 30% for those who require ICU admission, making community-acquired pneumonia the eighth leading cause of death in the United States.

“If there is interest in reducing the economic burden of patients with pneumonia, the single most important thing to do is deflect hospitalizations in appropriate patients,” Thomas Lodise, PharmD, PhD, professor of pharmacy practice at Albany College of Pharmacy and Health Sciences, told Contagion® in an interview.

Dr. Lodise explained this further, citing a 2013 retrospective analysis that found that between 2006 and 2008, the mean all-cause cost for pneumonia patients treated in the hospital ranged from $11,148 to $51,219 depending on the associated risks and age of the patient.

He also pointed out that drug costs “pales in comparison to the cost of care,” explaining that the cost of drugs used to treat the infections only makes up 1.5% of the total treatment cost. So how can treatment costs be reduced? For one, it’s important not to make split-second decisions on admitting patients.

“We can either divert a hospitalization or reduce length of stay in a patient who is inappropriate,” Dr. Lodise said, explaining that hospitalized patients often remain in the hospital following resolution of their infection even when it is possible to discharge the patients without compromising overall outcomes.

While community-acquired pneumonia has significant cost burdens, Dr. Lodise also noted that several of the currently available therapies also have significant concerns associated with overall outcomes.

According to the Infectious Disease Society of America/American Thoracic Society’s 2007 guidelines on managing community-acquired pneumonia, clinicians should first risk stratify patients to determine if their infection can be treated as an outpatient or if hospital admission is necessary.

For outpatient treatment, the guidelines recommend macrolides for healthy individuals with no severe risk factors for drug-resistance. But for individuals with comorbidities or risks for resistance, a respiratory fluoroquinolone or a beta-lactam + a macrolide can be used. Additionally, the guidelines recommend avoiding macrolides for patients in regions with a high rate of infection with high-level macrolide-resistant Streptococcus pneumoniae.

However, there are several concerns associated with these recommended therapies, and an estimated 22.1% of all community-acquired pneumonia patients reported antibiotic treatment failure. Reasons for failure included antibiotic refill, changes to new antibiotics, emergency room visits, and/or hospitalization. Treatment failures are often costly and leave patients at an increased risk of death, especially patients over the age of 65.

Treatment failure was associated with 25.7% of patients taking a beta-lactam, 22.9% of patients taking macrolides, and 20.8% of patients on fluoroquinolones.

Dr. Lodise emphasizes that just because patients taking fluoroquinolones had less occurrences of treatment failure, does not mean that the option is safe. In fact, Lodise recommends limiting use of quinolones.

“[Although] you have lower potential failures in quinolones, there is a lot of increased baggage,” Dr. Lodise said, referencing the growing number of warnings and the US Food and Drug Administration’s (FDA) black box indication, which estimates that there is about 1 aortic aneurysm event per 300 people per year in individuals at highest risk.

How can the risk of treatment failure and aortic aneurysm events be reduced? Implementing new agents, Dr. Lodise says.

In particular, he discusses lefamulin, a first-in-class option being developed by Nabriva Therapeutics, which could be an alternative to currently available therapies. The drug has been found to be well tolerated with a favorable safety profile in 2 Phase 3 trials of patients with community-acquired pneumonia.

In the LEAP 1 trial, intravenous (IV) to oral lefamulin was found to be non-inferior to IV to oral moxifloxacin with or without linezolid. In LEAP 2, lefamulin again successfully met the FDA primary endpoint of non-inferiority compared with moxifloxacin for early clinical response, which was evaluated in the intent-to-treat patient population 72 to 120 hours after treatment was initiated.

Additionally, the drug does not have fasting requirements, which is a bonus for patients with comorbidities who need to take antibiotics that need to be taken with food.

“We have limited trial experience, but so far we have a drug with no food effects, good safety profile, demonstrated efficacy both IV and oral, and unique in class that will not carry the side effects that we see in fluoroquinolones and macrolides,” Dr. Lodise said.

The ease of transition from IV to oral, in combination with the lack of food restrictions, can result in streamlining care by avoiding inappropriate admissions to the hospital and reducing the duration of hospitalization for patients who need to be admitted.

“This is an unmet need and this drug will help fulfill that need,” Dr. Lodise said, summarizing the implications of lefamulin. “We want to deliver the highest quality of care at the lowest cost. In pneumonia the cost is driven up by admitting patients. We can avoid hospitalization in appropriate patients, we can shorten hospitalization in appropriate patients, and we can also give a drug with a low propensity for an adverse event so that patient doesn’t come back with a drug-related bad experience.”

In December, Nabriva announced the submission of 2 New Drug Applications to the FDA for the oral and IV formulations of lefamulin for the treatment of community-acquired pneumonia. The drug was also granted Qualified Infectious Disease Product and Fast Track designation by the FDA, enabling potential Priority Review of the applications.