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 Food and Drug Administration (FDA) 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 center 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.[137][138][139] The safety and efficacy of lefamulin has been evaluated in two phase 3 clinical trials where it was found to be noninferior 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.[140][141] 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 FDA for the treatment of CAP in adults; however, its exact place in management is not clear as yet.

Delafloxacin

A new fluoroquinolone antibiotic approved by the FDA for the treatment of adults with CAP caused by designated susceptible bacteria. The approval is based on results from a phase 3 study that found it was noninferior to moxifloxacin.[142]

Omadacycline

A new modernized tetracycline antibiotic (aminomethylcycline) with broad-spectrum activity, designed to overcome tetracycline resistance. It is available in oral and intravenous formulations. Like other antibiotics in the tetracycline class, omadacycline may cause discoloration of deciduous teeth, and inhibition of fetal bone growth when administered during pregnancy. It has been found to be noninferior to moxifloxacin in terms of efficacy in adults with CAP.[143] Omadacycline is approved 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 3 study found that ceftobiprole was noninferior to ceftriaxone with or without linezolid for the treatment of CAP.[144]

Nemonoxacin

A nonfluorinated, 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. A systematic review found that it is as effective and well tolerated as levofloxacin in patients with CAP.[145] Nemonoxacin is approved in Taiwan for the treatment of CAP in adults, but it is not currently approved in the US, UK, or Europe.

Solithromycin

A fluoroketolide with antimicrobial activity against gram-positive and gram-negative bacteria commonly associated with CAP. A completed phase 2 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.[146] It has also been found to be noninferior to moxifloxacin.[147] Solithromycin is currently in phase 3 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.[148] A 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.[149] 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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