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May 1, 2011 (Vol. 31, No. 9)

New Macrolides Essential to Treat CABP

Community-Acquired Bacterial Pneumonia and Other Infections Must Be Addressed Now

  • 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.

  • Other Indications

    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.

  • Conclusions

    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.

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