May 1, 2011 (Vol. 31, No. 9)
Prabhavathi Fernandes, Ph.D.
Jennifer Schranz, M.D.
Community-Acquired Bacterial Pneumonia and Other Infections Must Be Addressed Now
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.
Analysis & Insight: In the Battle of the Bugs, Antibiotic R&D Needs to Be Re-Incentivized
On April 7, World Health Day, the Infectious Diseases Society of America (IDSA) issued a report that recommended ways to encourage pharmaceutical companies to reinvigorate anemic pipelines. During the past three decades, IDSA’s report points out, the number of new antibacterials approved by the FDA has dwindled from 29 between 1980 and 1989 to 9 between 2000 and 2009. It noted that in 2003, of 89 approved drugs, none were antibiotics. For our full story about how regulatory constraints and lower ROI has been impeding investment and thus development, click here.
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.
The Need for New Antibiotics
The failure of PPV to demonstrate efficacy for prevention of CABP or a significant reduction in adult mortality has stimulated interest in the medical community for a better universal pneumococcal vaccine strategy. In the meantime, an antibiotic that provides reliable, effective and safe treatment is required.
The broad spectrum and the anti-inflammatory properties of macrolides, as well as their safety, have also made this class useful in pediatrics. Mycoplasma infections in children can be severe, and since these organisms are not routinely cultured, empiric treatment is routinely practiced. As with pneumococcus, macrolide resistance in mycoplasma has also risen—up to 33% in Japan and as high as 78% in China.
Macrolides are also used for treating urethritis and nongonococcal urethritis. Erythromycin and, more recently, azithromycin have been prescribed for the therapy of certain pelvic infections, usually those caused by Chlamydia trachomatis. Multidrug resistant gonococci have increased in prevalence. Fluoroquinolones are no longer recommended and recently high levels of resistance to azithromycin have been reported.
Macrolides have an added benefit for treating urethritis, as Chlamydia are frequently identified as co-pathogens or can also be found as the sole pathogen. Azithromycin has been used as a single dose of one gram but resistance is a growing problem. A dose of two grams of azithromycin is recommended except in the case of penicillin-allergic patients. Side effects such as nausea and vomiting due to this higher dose have led to compliance problems, and importantly the emergence of resistance is of concern.
Macrolides have been useful historically for treating the spectrum of organisms involved in gonococcal and nongonococcal urethritis including Ureaplasma and Mycoplasma species. Some Ureaplasma species have also gained macrolide and quinolone resistance. A well-tolerated new antibiotic with activity against these pathogens, specifically azithromycin and fluoroquinolone-resistant strains, would be well received.
Untreated syphilis during pregnancy can have devastating consequences such as stillbirth, neonatal death, or infant morbidity such as deafness or other significant neurologic sequelae. Congenital syphilis among infants less than one year old also increased 23% from 8.2 cases/100,000 live births in 2005 to 10.1 in 2008. Women of color and those living in the southern U.S. are disproportionately affected. Azithromycin has been used as a two gram single dose; however, resistance has been documented in California and elsewhere.
Critical and Urgent
New antibiotics against Mycobacterium avium complex (MAC) infection in AIDS, COPD, and cystic fibrosis (CF) are urgently needed. Patients with cystic fibrosis are colonized with staphylococci and an oral agent with activity against CA-MRSA would be a useful addition to the limited available drugs. MRSA infection in CF patients has been shown to shorten life expectancy and contribute to significant morbidity. Additionally, patients with chronic lung disease or AIDS who have MAC are in need of new bactericidal antibiotics. Clarithromycin resistance in M. avium is now more than 15%.
H. pylori infection has become less common since the approval of clarithromycin in combination with amoxicillin and proton pump inhibitors for treating Helicobacter gastritis. Clarithromycin resistance is approximately 20% and reports of combination therapy failure have been noted.
New treatments for malaria, multidrug, and extensively drug-resistant tuberculosis are urgently needed. Macrolides have been only weakly active in treating these infections. Although the return on the research investment may be limited from these indications, the benefit of a new macrolide that is active in these infections could be leveraged for approval and priority regulatory review as well as a priority voucher.
CABP continues to be a serious public health problem. Bacterial resistance has been increasing against previously effective antibiotics. Pneumococcal conjugate vaccines have helped, especially for pediatric infections. However, protection of adults, particularly seniors, with polysaccharide vaccines has not been very effective, and vaccine-driven selection pressure is selecting for previously less frequent pneumococcal strains. In addition, a number of serious infections, many for which macrolides have been effective antibiotics, are losing effectiveness due to increasing rates of resistance. For all of the above reasons, a new potent macrolide/ketolide is urgently needed.