Antimicrobial Resistance—Could Less Really Be More?

In the United States, antibiotic resistance was responsible for over 2000 000 infections and more than 20000 deaths in 2013. In an effort to address this growing threat, the White House issued the National Action Plan for Combating Antibiotic-Resistant Bacteria in March 2015. The plan includes several goals, the first of which is to slow the emergence and spread of antimicrobial resistance. Similarly, in May 2015, the WHO released its Global Action Plan on Antimicrobial Resistance, calling for optimization of the use of antimicrobial agents.

Innovative approaches to successfully stem the tide of antimicrobial resistance are urgently needed. A recent feature in Science profiled one such potential approach to antimicrobial use where antibiotics are administered at lower doses, just enough to reduce the concentration of susceptible bacteria and allow the immune system to fully clear the infection (1). This approach, put forth by evolutionary biologists, is at odds with the current dogma established by Dr. Paul Ehrlich at the beginning of the 19th century, which advocates treatment of patients as aggressively as possible (i.e., highest possible dose) to kill bacteria.

So, could less be more? The proposed strategy of lower dosage is based on the idea that most infections are heterogeneous, with both susceptible and resistant organisms present, and using high doses of antibiotics destroys the susceptible population, allowing resistant organisms to flourish. Instead, an approach that maintains enough susceptible organisms to compete with resistant ones may prevent the emergence and spread of antibiotic resistance. This approach has similarities to other novel treatment concepts including fecal transplant to restore the gut microbiome and prevent Clostridium difficile overgrowth and the use of shorter courses of antimicrobials therapy to treat common infections.

Reduced dosing of antimicrobial agents may have several potential limitations. In vitro studies have shown that suboptimal levels of bactericidal antibiotics can promote antibiotic resistance through DNA damage by reactive oxygen species. Antimicrobial resistance frequently arises in patients on long-term antimicrobial therapy for prophylaxis or difficult-to-control infections. In these patients, the immune system is often highly suppressed and giving lower antimicrobial doses may be an ineffective strategy. The emergence of resistance varies among drugs (e.g., bacteriostatic vs bactericidal) and among the various drug-pathogen combinations. Finally, innate differences in host metabolism, such as differences in rates of absorption and/or clearance of drugs, may prevent a universal implementation of this strategy.

Stronger collaborative research between clinicians, scientists and pharmaceutical companies will be necessary to evaluate the effectiveness of prescribing lower doses of antibiotic and its impact on preventing antibiotic resistance. However, this approach is in line with the national and global plans to combat antibiotic resistance in that it supports the judicious use of antibiotics and provides novel ideas to achieve it.

• Received for publication August 16, 2016.
• Accepted for publication August 22, 2016.

• © 2016 American Association for Clinical Chemistry