These new antibiotics can treat community-based pneumonia

Community-acquired pneumonia (CAP) is still an important infection, which has an impact on the prognosis of patients, especially the elderly and immunocompromised patients.

New antibiotics have increased opportunities for empiric treatment of CAP-related drug-resistant pathogen infections.

The etiology of CAP The cause of CAP is most often classified as bacteria.
Streptococcus pneumoniae is the most common bacterial pathogen, followed by Haemophilus influenzae, Mycoplasma pneumoniae, Legionella, Chlamydia pneumoniae and Moraxella catarrhalis.

However, with the emergence of molecular diagnostic technology, it has been determined that the inhalation virus is an increasingly important cause of CAP.

The causes of pneumonia, including CAP, may also vary depending on the patient population examined and potential comorbidities.

For example, a recent study of tuberculosis combined with stroke found that most pneumonia occurred within 1 week (78%) after the onset of stroke.
The main pathogens were Gram-negative bacteria (38%) and Gram-positive cocci (16%).
), including Enterobacter, Staphylococcus aureus (10%), Pseudomonas aeruginosa (6%), Acinetobacter baumannii (5%) and Streptococcus (4%).

However, this population may include patients with aspiration pneumonia and hospital-acquired pneumonia (HAP), depending on when the infection occurred.

The etiology of CAP in patients with chronic obstructive pulmonary disease is also different.
Streptococcus pneumoniae is the main one, followed by respiratory viruses, Pseudomonas aeruginosa, atypical pathogens and Haemophilus influenzae.

Clinicians should also be aware that patients with pneumonia admitted to the hospital may have specific risk factors (recent intravenous antibiotics, admission from a long-term care facility) that make them susceptible to bacterial pathogens in the hospital, including Pseudomonas aeruginosa and methicillin-resistant gold Staphylococcus aureus, although these patients come from outside the hospital, there has been controversy regarding classification, empiric therapy, and frequent failure of initial antibacterial therapy.

Severe pulmonary and extrapulmonary complications of community-acquired pneumonia, including sepsis, septic shock, acute respiratory distress syndrome, and acute cardiovascular events, often complicate CAP, leading to a significant increase in mortality and the need for ICU admission.

A large active population monitoring study of hospitalized CAP patients in the United States concluded that 21% of these patients require ICU admission, and 26% of them require mechanical ventilation, thus constituting a subgroup of patients with severe community-acquired pneumonia (sCAP).

The hospital mortality rate of sCAP is still as high as 25% to more than 50%.

Although there is no consensus on its definition, the most commonly used sCAP definition standard comes from the 2007 American Academy of Infectious Diseases/American Thoracic Society consensus guidelines on the treatment of adult CAP.

The definition of sCAP is that there is at least one main criterion: severe acute respiratory failure requires invasive mechanical ventilation and/or septic shock.

Other criteria that require intensive monitoring and treatment are also proposed to define sCAP.

sCAP represents the individuals who need ICU care and are at the highest risk of death and failure of initial antibiotic treatment due to an increased risk of infection by drug-resistant pathogens.

Treatment of CAP Timely and effective treatment of CAP will affect the clinical prognosis.

Taking a chest radiograph within 4 hours of the onset of symptoms is helpful for diagnosis; early and appropriate antibiotic treatment (covering possible pathogens); early identification of patients requiring respiratory and hemodynamic support; use of severity scores for mortality risk assessment and improved prognosis Related.

Since the success of CAP treatment depends on the effective and timely use of antibiotics against possible pathogens, clinicians should consider the severity of the disease and local antibiotic susceptibility patterns in their decision-making process.

An important controversy in the treatment of CAP is whether the existing antibiotics are appropriate and whether new antibacterial drugs for CAP are needed.

Some studies have shown that the initial antibacterial treatment cannot effectively target the pathogen, that is, inappropriate empirical treatment (IET) is related to the increased mortality of CAP patients.

The IET in CAP is mainly due to the failure to cover specific pathogens (such as MRSA) or the presence of pathogens that are resistant to prescribed protocols (such as the macrolide-resistant Streptococcus pneumoniae [MRSP]).

Is it necessary to empirically cover "typical" pathogens (Streptococcus pneumoniae, Haemophilus influenzae, methicillin-sensitive Staphylococcus aureus) and "atypical" pathogens (Mycoplasma pneumoniae, Legionella pneumophila, Chlamydia pneumoniae) are Controversially, some studies have shown benefits, and some studies have shown no benefits.

In view of these challenges in providing the best treatment for CAP patients, especially for sCAP patients, new antibiotics to improve the treatment of CAP are being developed.

Lefamulin Lefamulin is a new type of semi-synthetic pleuromutilin that inhibits bacterial growth by binding to the peptidyl transferase center of the 50S ribosomal subunit.

Lefamulin has effective antibacterial activity against most important respiratory pathogens, including MRSP, MRSA, nutritionally demanding gram-negative bacteria, such as Haemophilus influenzae and atypical respiratory pathogens, including Mycoplasma pneumoniae, Chlamydia pneumoniae and Legionella pneumophila .

Lefamulin has been proven to have antibacterial properties against most organisms, but has a bactericidal effect against Mycoplasma pneumoniae.

Lefamulin can also achieve extensive penetration and accumulation in the lung epithelial lining fluid (ELF), where the lefamulin in the ELF is about 5.
7 times higher than the unbound part in the plasma.

These characteristics show that lefamulin can address some of the shortcomings of existing CAP therapies.

So far, there have been two phase 3 lefamulin trials in CAP, which have proven to have a prognosis comparable to moxifloxacin (non-inferiority).

Both studies have shown that lefamulin is non-inferior to moxifloxacin within the range of pneumonia severity assessed by the PORT classification.

Compared with moxifloxacin, lefamulin treatment seems to have more emergency adverse events, mainly gastrointestinal diseases, including diarrhea/loose stool, nausea and vomiting.

Lefamulin is being evaluated by the U.
S.
Food and Drug Administration (FDA) and EMA, and may be approved in the U.
S.
and Europe.

Omadacycline Omadacycline is a new type of aminomethylcycline antibiotic that can be administered intravenously or orally once a day.
It can reach a higher concentration in lung tissue and has antibacterial activity against common pathogens that cause CAP.

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).

For community-acquired bacterial pneumonia and hospitalized non-ICU adult patients, once a day intravenous administration of omadacycline (can be converted to oral administration) is not inferior to moxifloxacin.

But omadacycline has greater gastrointestinal side effects.

Delafloxacin Delafloxacin (Baxdela) is a new type of fluoroquinolone, which has structural and mechanical differences compared with currently available fluoroquinolone drugs.

Delafloxacin targets topoisomerase IV and DNA gyrase, resulting in inhibition of bacterial DNA replication.

Due to its own characteristics and permeability, combined with its unique mechanism of action, delafloxacin has antibacterial activity against a wide range of Gram-positive bacteria, Gram-negative bacteria, anaerobic bacteria and intracellular microorganisms.

Delafloxacin has good and more effective in vitro activity against the most common CAP pathogens, and it penetrates well into ELF.

Currently waiting for the results of the Phase 3 trial of delafloxacin and moxifloxacin in the treatment of hospitalized adult CAP patients.

The data from clinical trials help the FDA to approve delafloxacin for acute bacterial skin and skin structure infections, which shows that delafloxacin is well tolerated.

Disorders of the gastrointestinal tract are the most common adverse reactions, despite central nervous system effects, endocrine abnormalities, and elevated serum liver function tests have also been reported.

Solithromycin Solithromycin is the fourth-generation macrolide and the first-generation fluoroketolactone.

Solithromycin has effective antibacterial activity against the most common CAP pathogens.

Two phase 3 trials, SOLITAIRE-ORAL and SOLITAIRE-IV, studied the safety and effectiveness of oral and intravenous conversion of Solithromycin.

Compared with moxifloxacin, both trials met their pre-determined primary endpoint of early clinical response, namely non-inferiority.

Adverse events between the SOLITAIRE-ORAL groups are comparable; however, more than 50% of patients in the SOLITAIRE-IV Solithromycin group experienced post-treatment adverse events, compared with 35% in the moxifloxacin group.

This difference is due to the 31.
3% incidence of infusion site reactions in Solithromycin patients.

Other adverse events are typical macrolide antibiotic reactions, including gastrointestinal disorders and asymptomatic elevated transaminases.

However, due to concerns about potential liver toxicity, the FDA recommended that the company initiate a new clinical study to better evaluate the safety of the drug in 9,000 patients.

Nemonoxacin Nemonoxacin is a non-fluoroquinolone antibacterial drug.
Compared with other fluoroquinolone drugs, it has a wider antibacterial spectrum and lower drug resistance.

This is achieved by targeting topoisomerase II and IV.

Nemonoxacin has strong antibacterial activity against Gram-positive cocci, Gram-negative bacilli and atypical bacteria (including common CAP pathogens).

Published Phase 2 and Phase 3 clinical trials show that Nemonoxacin is not inferior to levofloxacin in the treatment of mild and moderate CAP.

The most recent phase 3 trial achieved a pre-defined non-inferiority of clinical cure and microbiological success rate in all patient populations.

The safety/tolerability of nemonoxacin is comparable to that of levofloxacin, gastrointestinal disorders, neutropenia, leukopenia, dizziness, headache and elevated serum transaminases are rare.

The most recent phase 3 trial achieved predefined non-inferiority differences in clinical cure and microbiological success rates across all patient populations.

The safety/tolerability of nemonoxacin is comparable to levofloxacin.

Literature: Marin H.
Kollef; Kevin D.
Betthauser.
New Antibiotics for Community-Acquired Pneumonia.
Curr Opin Infect Dis.
2019;32(2):169-175.