Increased rates of resistance of Streptococcus pneumoniae to currently available macrolides such as azithromycin and clarithromycin have increased the challenges of treating community-acquired bacterial pneumonia (CABP). In addition, despite the decrease in pneumococcal disease in infants and young children due to the introduction of pneumococcal conjugate vaccines, the prevalence of strains not covered by these vaccines is increasing.
Pneumococcal polysaccharide vaccines have not been very effective in protecting vulnerable adults, particularly seniors. There are also a number of other indications for which macrolides have been the antibiotic of choice, but rising resistance rates have reduced their effectiveness. Thus, there is a need for the continued investment in the development and launch of new antibiotics, particularly macrolides, to treat bacterial pneumonia.
In the U.S., pneumonia and influenza combined are the greatest causes of death due to an infectious disease. Macrolides have historically been the treatments of choice for CABP as they cover the broad spectrum of pathogens involved including S. pneumoniae, Mycoplasma pneumoniae, Hemophilus influenzae, and atypical bacteria such as Legionella pneumophila and Chlamydophila pneumoniae. Overall, pneumococcal pneumonia has been shown to carry 12% mortality. This level of mortality is exceeded only by Legionella species among community-acquired pathogens.
CABP is associated with substantial morbidity and mortality in patients 65 years and older. In the U.S., CABP is the sixth most common cause of death, the leading cause of death from infectious diseases, and affects about 1% of patients over 65 each year. Pneumococcal macrolide resistance has shown a significant increase since 2000. In the PROTEKT study (2005–2006), of 6,747 Streptococcus pneumoniae isolates collected at 119 centers in the U.S., macrolide resistance was as high as 35.3%. Macrolide resistance has continued to increase in the U.S. and worldwide.
Pneumococcal Polysaccharide Vaccines
Currently, only a 23-valent polysaccharide pneumococcal vaccine (PPV) for use in adults and a 13-valent conjugate pneumococcal vaccine (PCV, Prevnar 13®) for use in infants are available. However, the existence of more than 90 distinct serotypes, differing in their chemical compositions, potential immunogenicity, and epidemiological impact on different population groups has largely complicated the development and evaluation of antipneumococcal vaccines. Nonvaccine serotypes appear to replace vaccine strains and continue to cause infections.
Use of the 7-valent PCV has resulted in a dramatic decrease in invasive pneumococcal disease (IPD) in infants and young children and a decrease in spread to unvaccinated infants, children, and adults. However, the gap between the protection of adults and that of infants has widened, although IPD rates in un-immunized infants and adults over age 65 have dropped in the U.S. Despite widespread use of PPV23 (Pneumovax®) and indirect benefits of Prevnar vaccination of young children, there remains a significant clinical and economic burden of pneumococcal disease among older U.S. adults. It has been reported that among the 91.5 million U.S. adults aged ≥50 years, there were:
• 24,801 cases of IPD (bacteremia: 23,342; meningitis: 1,459),
• 1,089,152 cases of nonbacteremic pneumococcal pneumonia. Of these, 165,113 required inpatient care, and 924,039 required outpatient care only,
• 57,335 pneumococcal-related deaths are estimated to occur yearly.
Annual direct and indirect costs are estimated to total $4.1 billion and $628.8 million, respectively.
The 23-valent pneumococcal polysaccharide vaccine is only 60–70% effective against invasive pneumococcal disease, has poor efficacy in high-risk groups, has had limited impact on mortality, and has not shown efficacy in adult pneumonia. A meta-analysis of 22 studies by the Cochrane Collaboration concluded that there was no evidence to support routine use of the 23-valent pneumococcal polysaccharide vaccine (Pneumovax) for prevention of all-cause pneumonia or mortality.