New Antibiotics for Community-Acquired Pneumonia

Marin H. Kollef; Kevin D. Betthauser

Disclosures

Curr Opin Infect Dis. 2019;32(2):169-175. 

In This Article

Treatment Considerations for Community-acquired Pneumonia

Timely and effective management of CAP influences clinical outcomes. Prompt diagnosis through a chest radiograph within the first 4 h of presentation; early appropriate antimicrobial therapy covering the underlying etiologic agents of pneumonia; early identification of patients requiring respiratory and hemodynamic support, and thus ICU admission; and mortality risk assessment using severity scores have been linked to improved outcomes.[4] As treatment success for CAP rests on prompt delivery of antibiotics effective against the likely causative organisms, clinicians should take into consideration the severity of the disease process and the prevailing local antibiotic susceptibility patterns in their decision process. An important controversy for CAP management is whether existing antibiotics are adequate therapies and whether there is a need for new antimicrobials targeting CAP.

Several studies have demonstrated that initial antimicrobial therapy lacking activity against the offending pathogens, so called inappropriate empiric therapy (IET), is associated with greater mortality in patients with CAP.[25,26] IET in CAP is primarily because of failure to cover a specific pathogen (e.g. MRSA) or the presence of a bacterial pathogen that is resistant to the prescribed regimen (e.g. macrolide-resistant Strep. pneumoniae [MRSP]).[27–29] The need to empirically cover for both 'typical' bacterial pathogens (Strep. pneumoniae, H. influenzae, methicillin-susceptible Staph. aureus) and 'atypical' pathogens (M. pneumoniae, Legionella pneumophilia, Chlamydophila pneumoniae) is controversial with some studies showing no benefit when atypical coverage is provided whereas others suggesting outcome benefits.[30–32] Given these challenges in providing optimal treatment to patients with CAP, especially those with sCAP, new antibiotics to improve the treatment of CAP are under development. These new agents provide coverage for the currently existing limitations in empiric therapy to include macrolide-resistant species (Strep. pneumoniae, f Mycoplasma penumoniae) and MRSA (Table 2).

Lefamulin

Lefamulin is a novel semisynthetic pleuromutilin that inhibits bacterial growth by binding to the peptidyl transferase center of the 50S ribosomal subunit.[33] Lefamulin exhibits potent antibacterial activity against the most important respiratory pathogens, including MRSP, MRSA, fastidious Gram-negative organisms, such as H. influenzae, and atypical respiratory pathogens, including M. pneumoniae, C. pneumoniae, and Legionella pneumophila.[34] Lefamulin has demonstrated bacteriostatic properties against most organisms, with the exception of M. pneumoniae to which it is bacteriocidal. Lefamulin also achieves extensive penetration and accumulation in pulmonary epithelial lining fluid (ELF), with ELF exposure to lefamulin being ~5.7-fold higher than the unbound fraction in plasma.[35] These properties suggest that lefamulin could target several of the deficiencies of existing CAP therapies.

To date there are two phase 3 trials of lefamulin in CAP (LEAP 1 – intravenous to oral lefamulin; LEAP 2 – oral only) that have demonstrated comparable (noninferior) outcomes to moxifloxacin (https://investors.nabriva.com/static-files/5c34b447-99cc-4739-b9d6-d4ea4c7d13b9 accessed on 26 September 2018). Both studies demonstrated noninferiority of lefamulin to moxifloxacin across the spectrum of pneumonia severity assessed by the PORT classification. In LEAP 2, lefamulin met the primary endpoint for noninferiority (within 10%) of the European Medicines Agency (EMA) regarding an investigator assessment of clinical response rates 5–10 days following the completion of therapy in the modified intent-to-treat (mITT) and clinically evaluable at test-of-cure (CE-TOC) populations. Treatment emergent adverse events appeared to be greater with lefamulin compared with moxifloxacin, primarily for gastrointestinal complaints including diarrhea/loose stools, nausea, and vomiting. Lefamulin is undergoing evaluation by the Food and Drug Administration (FDA) and the EMA for possible approval in the United States and Europe.

Omadacycline

Omadacycline is from the aminomethylcycline class created by chemical modification of minocycline. It is bacteriostatic, inhibiting protein synthesis by binding to the 30S ribosomal subunit. Chemical modifications enable it to be active against the two main forms of bacterial resistance to the tetracyclines: efflux and ribosomal protection. Omadacycline exhibits excellent potency against staphylococci, penicillin-resistant, and macrolide-resistant Strep. pneumoniae as well as multidrug-resistant strains.[36] Omadacycline also has pharmacokinetic advantages of higher and sustained concentrations in plasma and ELF compared with those of tigecycline suggesting that it will be a promising antibacterial agent for the treatment of lower respiratory tract bacterial infections caused by susceptible pathogens.[37]

Results from the phase 3 OPTIC trial comparing once-daily intravenous to oral omadacycline to intravenous to oral moxifloxacin demonstrated noninferiority across pneumonia severity (https://paratekpharma.com/media/1571/presentation-ats-2018-a4458-ramirez-optic-ecr-by-port-17.pdf; accessed on 26 September 2018). Gastrointestinal side effects were greater with omadacycline. The FDA recently approved intravenous and oral omadacycline for the treatment of acute bacterial skin and skin structure infections and community-acquired bacterial pneumonia (CABP). The FDA also noted a concern of an imbalance in mortality seen in the CABP trial favoring moxifloxacin. However, a cause for the imbalance could not be determined from the available current data. In addition, the rate of mortality in the omadacycline group appears to be similar to the 30-day mortality observed in other recently conducted CABP trials.

Delafloxacin

Delafloxacin (Baxdela) is a novel fluoroquinolone with structural and mechanistic differences compared with currently available fluoroquinolones. Its unique chemical structure facilitates improved cellular transmembrane penetration and potency in acidic environments common to most infectious sites. Delafloxacin targets both topoisomerase IV and DNA gyrase with high and similar affinities, resulting in inhibition of bacterial DNA replication. Its potency and penetration, combined with its unique mechanism of action, give delafloxacin bactericidal activity against a broad range of Gram-positive bacteria, Gram-negative bacteria, anaerobes, and intracellular microorganisms.[38] Delafloxacin has exhibited excellent and more potent in vitro activity against the most common CAP pathogens, and penetrates well into the ELF.[38,39] The results of a phase 3 trial comparing delafloxacin to moxifloxacin for hospitalized, adult patients with CAP are awaited.

Data from clinical trials aiding the FDA approval of delafloxacin for acute bacterial skin and skin structure infections suggest delafloxacin is well tolerated.[40,41,42] Gastrointestinal disturbances are the most commonly reported adverse effects, though central nervous system effects, endocrine abnormalities, and increased serum liver function tests have also been reported.

Solithromycin

Solithromycin (Solithera) is a fourth-generation macrolide and the first fluoroketolide in clinical development. Solithromycin exerts a bactericidal effect by binding to the 50S ribosomal unit, resulting in subsequent alterations of bacterial DNA translation. Solithromycin has potent in-vitro activity against the most common CAP pathogens, including fluoroquinolone, macrolide, and penicillin-resistant isolates of Strep. pneumoniae. Further, solithromycin has exhibited adequate ELF penetration in healthy volunteers to warrant use as a treatment option in patients with respiratory infections.[43] Two phase 3 trials, SOLITAIRE-ORAL and SOLITAIRE-IV, have investigated the safety and efficacy of oral and intravenous to oral solithromycin, respectively. Both trials met their predefined margin of noninferiority for the primary endpoint of early clinical response, compared with moxifloxacin.[44]

Adverse events were comparable between groups in SOLITAIRE-ORAL; however, more than 50% of patients in the solithromycin arm of SOLITAIRE-IV experienced a treatment-emergent adverse event, compared with 35% in the moxifloxacin arm. This difference was driven by an incidence of infusion site reactions of 31.3% in solithromycin patients. Other adverse events were typical of macrolide antibiotics including gastrointestinal disturbances and asymptomatic transaminase elevations. However, because of concerns over potential hepatic toxicity, the FDA recommended that the company initiate a new clinical study to better evaluate the drug's safety profile in 9000 patients.

Nemonoxacin

Nemonoxacin is a novel, nonfluorinated fluoroquinolone with a broader spectrum of activity and reduced resistance profile compared with other fluoroquinolones. This is achieved by its targeting of both topoisomerase II and IV. Nemonoxacin has potent activity against Gram-positive cocci, Gram-negative bacilli, and atypical bacteria, including common CAP pathogens.

Published phase 2 and 3 clinical trials suggest Nemonoxacin is noninferior to levofloxacin for the treatment of mild and moderate CAP.[45–50] The most recent phase 3 trial achieved its predefined noninferiority margin for clinical cure and microbiologic success rates across all patient populations. The safety/tolerability of nemonoxacin has been comparable with levofloxacin, with gastrointestinal disturbances, neutropenia, leukopenia, dizziness, headache, and elevated serum transaminases being infrequently experienced. Results of other trials of nemonoxacin for CAP are expected in the near future.

Ceftaroline

Ceftaroline fosamil (Teflaro) is an N-phosphonoamino water-soluble prodrug cephalosporin with the active form, ceftaroline, possessing broad-spectrum in-vitro antimicrobial activity. The spectrum of activity includes typical CAP bacterial pathogens, and its high affinity for PBP2a allows coverage of MRSA.[49] A recent patient level meta-analysis of three phase 3 trials in CAP found the clinical cure rates in each trial consistently favored ceftaroline versus ceftriaxone, with no evidence of heterogeneity.[50] Ceftaroline was superior to ceftriaxone in the mITT [odds ratio (OR) 1.66; 95% CI 1.34–2.06; P < 0.001] and CE (OR 1.65; 95% CI 1.26–2.16; P < 0.001) populations. Results were consistent across various patient-related and disease-related factors including patients' age and PORT score.

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