Minimizing Resistance

“We can’t do away with antibiotics,” says Christian Coles, PhD, MPH. “But is there a better way to use them?”

It’s a common question, with antimicrobial resistance on the rise around the globe. But for Coles, an assistant professor of International Health, it is especially pressing.

Coles recently helped analyze data from a study of the ancillary benefits of distributing the antibiotic azithromycin on a mass basis in Tanzania in order to eliminate trachoma. Funded by the Bill & Melinda Gates Foundation and led by Sheila West, PhD, PharmD, the El-Maghraby Professor of Preventive Ophthalmology at the Johns Hopkins School of Medicine, the study was designed to shed light on the side benefits of treating entire communities with azithromycin in order to stamp out an infectious eye disease that is the leading cause of blindness worldwide.

If left untreated, infection by Chlamydia trachomatis causes scarring of the eyelid and rubbing of the eyelashes against the eyeball, scarring the cornea. The disease disproportionately affects women and children in the developing world.

WHO, which aims to eliminate trachoma globally by 2020, recommends that all individuals in a community be given repeated annual doses of oral azithromycin when prevalence among children exceeds 10 percent. When combined with other measures such as face washing, the drug can break the cycle of infection.

Since azithromycin is effective against a wide variety of pathogens, it seemed likely that mass distribution might have other positive effects. Coles did find that mass treatment of young children in rural Tanzania also lowered the risk of diarrhea and acute respiratory infection. But he discovered something else, too: Mass distribution of azithromycin (MDA) also caused a “huge jump” in antibiotic resistance—specifically, in Streptococcus pneumoniae, a leading cause of severe childhood infections such as pneumonia and meningitis and a major global public health problem in its own right.

In a paper published online in Clinical Infectious Diseases in March, Coles and his colleagues report that the prevalence of azithromycin resistance within treated communities continued to rise at one-, three-, and six-month intervals after mass distribution, peaking at 82 percent, more than double what it had been prior to treatment. At that point, the odds of carrying azithromycin-resistant S. pneumoniae were five times higher in treated communities than in untreated ones. While the clinical significance of such a spike has yet to be demonstrated, those numbers only heighten the need to establish whether or not such a rise in resistance reduces the efficacy of antibiotics in treating severe pediatric infections.

Coles suspects that repeated administration of azithromycin in MDA programs may increase the circulation of macrolide- and multidrug-resistant bacteria and therefore have the potential to reduce the efficacy of antibiotics against childhood infectious diseases over time. Moreover, resistance to azithromycin implies resistance to all antibiotics in the same class, known as macrolides; and Coles also found signs of resistance to the common sulfa drug trimethoprim/sulfamethoxazole, raising the troubling possibility that mass treatment with azithromycin might contribute to multidrug resistance as well.

In a commentary on the paper, researchers at the Vaccine & Infectious Disease Institute at the University of Antwerp say that the community-wide rise of resistant S. pneumoniae “highlights the need to monitor the long-term impact of MDA on treatment options for pediatric infections.”

Coles will soon participate in a new study to examine the impact of MDA programs on childhood mortality in Tanzania, Malawi and Niger that will investigate the clinical significance of associated antibiotic resistance. And he wants to examine the genetic, social, and environmental factors that influence azithromycin resistance to see if there might be ways of using the drug that will maintain its efficacy but limit its adverse effects.

“I’m not saying don’t use it,” Coles says. “I’m saying, let’s figure out if we can minimize the effects on resistance so that we can use it better.”