Emerging treatments

Newer antibiotics

Given the concerns over increasing drug resistance and safety issues (e.g., fluoroquinolones) with existing antibiotics, there is a need for further research on new therapeutic agents. Newer antibiotic agents are detailed in this section. Current guidelines do not recommend them yet as they require further validation. Therefore, these agents are still considered to be emerging. Despite this, some of these newer antibiotics are approved by the European Medicines Agency (EMA) for the treatment of CAP and may be considered under specialist guidance.

Lefamulin

A first-in-class pleuromutilin antibiotic available in oral and intravenous formulations. It inhibits bacterial protein synthesis via interactions with the A- and P- sites of the peptidyl transferase centre of the 50S subunit. Lefamulin offers a unique spectrum of activity covering Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, Legionella pneumophila, Chlamydia pneumoniae, Mycoplasma pneumoniae, Staphylococcus aureus (including methicillin-resistant S aureus [MRSA]), beta-haemolytic streptococci (including S pyogenes and S agalactiae), and Enterococcus faecium (including vancomycin-resistant enterococci). It lacks cross-resistance with other antibiotic classes for S pneumoniae and S aureus.[221][222][223] The safety and efficacy of lefamulin has been evaluated in two phase 3 clinical trials where it was found to be non-inferior to moxifloxacin (with or without linezolid) in terms of primary efficacy endpoints (early clinical response, investigator assessment of clinical response). It was considered safe and well tolerated.[224][225] However, it has the potential to cause QT interval prolongation and should not be used in patients with known prolongation of the QT interval, ventricular arrhythmias, or who are on other drugs that prolong the QT interval. Lefamulin is approved by the EMA for the treatment of CAP in adults; however, its exact place in management is not clear as yet. One systematic review suggests a role for lefamulin as an alternative agent to beta-lactams and macrolides in bacterial CAP and an alternative to amoxicillin and doxycycline in the outpatient setting.[226]

Delafloxacin

A new fluoroquinolone antibiotic approved by the EMA for the treatment of adults with CAP when it is considered inappropriate to use other antibiotics that are commonly recommended for the treatment of CAP. One phase 3 study that found delafloxacin was non-inferior to moxifloxacin.[227]

Omadacycline

A new modernised tetracycline antibiotic with broad-spectrum activity, designed to overcome tetracycline resistance. Like other antibiotics in the tetracycline class, omadacycline may cause discolouration of deciduous teeth, and inhibition of fetal bone growth when administered during pregnancy.[228] It has been found to be noninferior to moxifloxacin in terms of efficacy in adults with CAP.[228] Omadacycline is approved in the US by the FDA for the treatment of CAP in adults; however, it was refused approval for this indication in Europe in October 2018.

Ceftobiprole

A broad-spectrum parenteral cephalosporin that has microbiological activity against most typical bacterial pathogens causing CAP, including MRSA. A phase III study found that ceftobiprole was non-inferior to ceftriaxone with or without linezolid for the treatment of CAP.[229]

Nemonoxacin

A non-fluorinated, broad-spectrum quinolone. It has greater antimicrobial activity than the fluoroquinolones (e.g., levofloxacin) against MRSA, methicillin-sensitive Staphylococcus epidermidis (MSSE), methicillin-resistant S epidermidis (MRSE), S pneumoniae, and Enterobacter faecalis. One systematic review found that it is as effective and well tolerated as levofloxacin in patients with CAP.[230] Nemonoxacin is not currently approved in Europe or the US, but may be available in other countries.

Solithromycin

A fluoroketolide with antimicrobial activity against gram-positive and gram-negative bacteria commonly associated with CAP. A completed phase II study showed that solithromycin had similar efficacy to that of levofloxacin in adults with bacterial CAP with pneumonia severity index scores of II to IV.[231] It has also been found to be non-inferior to moxifloxacin.[232] Solithromycin is currently in phase III development for the treatment of bacterial CAP.

Statins

There is evidence to suggest that statins may reduce the risk of CAP and its complications due to their immunomodulatory effects. Data suggest that patients with CAP who are taking a statin on hospital admission have a reduced risk of inpatient mortality.[233] One meta-analysis found that statins may decrease mortality associated with CAP, as well as reduce the need for mechanical ventilation or intensive care unit admission.[234] However, whether statin use can reduce the risk of pneumonia is unclear and further studies are required. It is important to note that statins interact with macrolides, an antibiotic class commonly used for the treatment of CAP. These drugs should not be used in combination as macrolides inhibit the metabolism of statins via the CYP3A4 pathway and therefore increase the risk of myopathy and rhabdomyolysis.

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