The upper respiratory tract is colonized by several bacterial species that make up the normal flora. Although these commensal organisms can cause disease in certain situations (e.g., in immunocompromised persons), they generally serve a protective function by limiting the growth of other pathogenic bacteria in the respiratory tract. In the lower respiratory tract (LRT), macrophages that can clear foreign particles reside within the alveoli and serve as the final defense against infection.
Common Etiologic Pathogens
Many bacteria have been shown to cause community-acquired pneumonia, but researchers and clinicians identify several bacterial species as the most common causes of the disease. However, epidemiological studies investigating the etiology of the disease show that in the majority of cases, pathogen identification is not readily attainable. Pathogens are classified as typical or atypical based on the spectrum of symptoms associated with them (described in the preceding section). In most studies, five pathogens (discussed in the following sections) have been found to account for approximately 90% of all community-acquired pneumonia.
Fluoroquinolones: Garenoxacin, Sitafloxacin
The fluoroquinolones have proven to be one of the most commercially and clinically successful antibacterial classes for the treatment of acute exacerbations of chronic bronchitis.
Gemifloxacin
Gemifloxacin, as a member of the fluoroquinolone class, acts by inhibiting bacterial topoisomerase IV and DNA gyrase. These enzymes are required for DNA replication, transcription, repair, and recombination.
Acute Exacerbations of Chronic Bronchitis: Emerging therapies
Despite the large patient populations with respiratory tract infections (RTIs), in recent years, many biopharmaceutical companies have shifted development effort away from RTIs to pursue other disease areas with perceived higher unmet need (e.g., resistant hospital-acquired infections). Likewise, many companies have shifted away from antibacterial drug development in favor of chronic disease markets perceived to have higher return on investment.
Cephalosporins: Ceftizoxime
Cephalosporins have traditionally been one of the most commonly used antibacterial classes for the treatment of respiratory tract infections. In recent years, drug development within this class has been limited owing to competitiveness, the lack of novel candidates, and high development costs relative to return. Cephalosporins differ widely in their spectrum of activity, susceptibility to β-lactamases produced by bacteria, and serum half-life. Dong-A pharmaceuticals in South Korea is developing DA-7101, indicated for the potential treatment of respiratory and urinary tract infections.
Ketolides: Cethromycin
Ketolides are a new class of antibacterials specially designed to combat respiratory tract pathogens that have acquired resistance to macrolides. The ketolides are derivatives of the macrolide erythromycin A.
Streptogramins
Streptogramins are produced by streptomycetes and are classified as A or B compounds, based on their mechanism of action as outlined below. As a class, streptogramin A and B compounds are bacteriostatic when used separately.
Peptide Deformylase Inhibitors
Peptide deformylase is an essential bacterial metalloenzyme required for protein synthesis and thus represents a good target for antibacterial therapy. Peptide deformylase inhibitors act on the peptide deformylase enzyme, disrupting protein maturation and inhibiting protein synthesis.
Dihydrofolate Reductase Inhibitors
The dihydrofolate reductase (DHFR) inhibitors target bacterial DHFR, an enzyme involved in the folic acid pathway, thereby disrupting bacterial replication. DHFR inhibitors target both gram-positive and gram negative-bacteria and hence could serve as broad-spectrum antibacterials.