Antimicrobial stewardship programs and facility antibiograms help clinicians choose effective therapies and slow the development of antibiotic resistance. Sometimes mutations occur during a patient’s treatment that protect the organism from antibiotics that worked just days earlier. In a recent article in the Proceedings of the National Academy of Sciences (PNAS), researchers documented one such case and provided some insights into how increased understanding of mutations can enable other researchers and clinicians to select therapies that will continue to work.1
In the case profiled, the patient suffered a leaking abdominal aortic aneurysm graft and received treatment for a disseminated Salmonella typhimurium infection. The Salmonella strain developed resistance to ciprofloxacin. The team studied isolates taken over a 20 week period and sequenced the genome to find the mutation that enabled the organism to develop resistance.
“We cannot know for sure when this mutation happened within this strain. What we do know is that it developed soon after this patient was given ciprofloxacin to treat the infection,” said lead author Jessica Blair, PhD, of the Antimicrobials Research Group in a news release. 2 "It’s further evidence that, when it comes to the issue of antibiotic resistance, we are coming up against a very capable and complex adversary.”
The specific novel mutation affected the efflux pump gene, acrB. The alteration decreased susceptibility to ciprofloxacin, to devastating effect: the treatment failed and the patient subsequently died of bacteremia.
In laboratory tests on strains of E. coli and Salmonella, researchers found that the mutation that conferred resistance to ciprofloxacin also reduced the organisms’ ability to pump out doxorubicin and minocycline, increasing the intracellular concentration of these drugs and their effectiveness.
“Understanding mechanisms of resistance at the genomic and structural level will not only inform clinicians treating such infections, but provide the basis for rational drug design, including new agents that are either unaffected by [the mutation] or become more active when this substitution is present,” noted the authors.
The findings may provide more support for the increased use of antibiotic cocktails or alternating regimens of antibiotics to treat resistant organisms. Recent research published in PLOS Biology found that alternating erythromycin and doxycycline provided an effective treatment against a strain of E. coli that was resistant to both drugs. 3
“Our study finds a complex relationship between dose, bacterial population densities and drug resistance,” said lead author Robert Beardmore, PhD, of the University of Exeter in Exeter, UK. “As we demonstrate, it is possible to reduce bacterial load to zero at dosages that are usually said to be sub lethal and, therefore, are assumed to select for increased drug resistance.”
In that study, the researchers found that one drug would make the bacteria more susceptible to the second, reducing the risk of resistance. Although sequential treatments didn’t suppress the rise of all drug resistance mutations in the bacteria, one drug would “sensitize” the bacteria to the second drug, reducing the risk of resistance occurring.
Does your hospital prescribe antibiotic cocktails? What strategies have you implemented to reduce resistance?
1. New insight into antibiotic resistance strengthens call for increased focus on research. University of Birmingham. 3 March 2015. http://www.birmingham.ac.uk/news/latest/2015/03/New-insight-into-antibiotic-resistance-030315.aspx
2. Blair JMA, Bavro VN, Ricci V, Modi N, Cacciotto P, et al. AcrB Drug-binding pocket substitution confers clinically relevant resistance and altered substrate specificity. PNAS. March 17, 2015;112(11):3511-3516.3. Fuentes-Hernandez A, Plucain J, Gori F, Pena-Miller R, Reding C, Jansen G. Schulenburg H, Gudej I, Beardmore R. Using a Sequential Regimen to eliminate Bacteria at Sublethal Antibiotic Dosages. PLOS Biology. April 8, 2015. DOI: 10.1371/journal.pbio.1002104