Dear All (and with thanks to Patricia Bradford for taking the lead on this newsletter):
Today, this paper in Nature takes us on a trip to the land of unintended consequences:
- Turner, A.M., Li, L., Monk, I.R. et al. Rifaximin prophylaxis causes resistance to the last-resort antibiotic daptomycin. Nature 635, 969–977 (2024). https://doi.org/10.1038/s41586-024-08095-4.
A wonkish summary is found below our signatures, but here’s the high-level version:
- Rifaximin is a non-absorbable oral antibiotic used to manage both traveler’s diarrhea and the CNS derangements that can be seen in advanced liver failure (hepatic encephalopathy).
- See this review (J Antibiotics 2014) and this Medscape summary.
- Daptomycin is a last-resort antibiotic (WHO AWaRe category of Reserve) used for Gram-positive infections, most notably serious infections due to Staphylococcus aureus and Enterococcus species.
- It is especially valued for its activity on vancomycin-resistant Enterococcus (Turnidge et al. 2020 CMI, https://doi.org/10.1016/j.cmi.2020.04.027).
- FDA labeling is here and note also this FDA rationale that extends the breakpoints for Enterococcus species from E. faecalis to also include E. faecium.
- Daptomycin and rifaximin are totally different classes of antibiotics and would not be expected to have any effects on each other.
- Daptomycin is a cyclic lipopeptide that acts by binding to (and disturbing) bacterial cell membranes.
- Rifaximin is related to rifampin and acts deep within bacteria by inhibiting RpoB, an enzyme involved in RNA synthesis.
- But (and now we have the unintended consequences), a group in Australia has observed that resistance to daptomycin in vancomycin-resistant Enterococcus faecium began to emerge shortly after rifaximin was introduced in the early 2000s.
- Oddly, the mutation driving resistance was in the gene for the RpoB enzyme, so not obviously linked to the bacterial cell membrane.
- Upon deeper exploration, it turns out that the RpoB mutation indirectly leads to a change in the charge of the bacterial cell membrane in a way that reduces daptomycin binding and hence creates resistance.
Ouch! As the authors observe (emphasis is ours):
- “Coordinated global efforts are underway to preserve last-resort antimicrobials through stringent stewardship protocols, limiting the use of these critically important medicines.
- “This strategy assumes that restricted antibiotic use correlates with reduced opportunities for pathogens to develop resistance.
- “Our findings challenge this assumption, demonstrating that exposure to prophylactic rifaximin can lead to daptomycin-resistant, vancomycin-resistant E. faecium emergence without direct DAP exposure.”
Unintended consequences, indeed … biologic systems are so complex! The authors observe that the benefit/risk of rifaximin may need to be reconsidered (e.g., its use in stem cell transplantation). And as the authors finally conclude, “Our research reinforces the need for judicious use of all antibiotics, and emphasizes the delicate balance required in managing AMR while meeting clinical needs.” Agreed!
With all best wishes, Patricia & John
Patricia Bradford, PhD | Antimicrobial Development Specialists, LLC | pbradford@antimicrobialdev.com. All opinions are my own.
John H. Rex, MD | Chief Medical Officer, F2G Ltd. | Operating Partner, Advent Life Sciences. Follow me on Twitter: @JohnRex_NewAbx. See past newsletters and subscribe for the future: https://amr.solutions/blog/. All opinions are my own.
14 Mar 2024 addendum: PS: Jared Silverman, part of the team who collectively discovered and developed daptomycin, wrote in response to this newsletter saying,
- “Note that while the finding is unexpected, it is not unprecedented.
- “In our original paper on daptomycin resistance in S. aureus in 2006 (Friedman et al., https://pubmed.ncbi.nlm.nih.gov/16723576/), we reported isolating RpoB and RpoC mutations in strains undergoing serial passage in daptomycin.
- “We never fully characterized the mutations (choosing to focus on the novel membrane changes) but assumed that some changes in global transcription pattern might be influencing resistance development.
- “Similarly, in our first paper on DAP resistance in Enterococci (Palmer, et al, 2011 https://pubmed.ncbi.nlm.nih.gov/21502617/), one of the strains carried a mutation in a sigma factor.
- “Again, we never characterized it but it was consistent with the same model that global transcriptional changes might facilitate resistance selection.”
Hmm! Makes one think of the comment about the most interesting statement in science being “That’s odd…”!
A deep, wonkish dive into the details:
Turner, A.M., Li, L., Monk, I.R. et al. Rifaximin prophylaxis causes resistance to the last-resort antibiotic daptomycin. Nature 635, 969–977 (2024). https://doi.org/10.1038/s41586-024-08095-4.
This Australian research group performed a multi-year survey of VREfm (vancomycin-resistant Enterococcus faecium) and noted that 19.4% of 998 VREfm isolates were also resistant to daptomycin (DAP). Some notable characteristics of these isolates:
- The isolates belonged to many different ST (sequence types) and showed no other phylogenetic clustering, suggesting that the phenotype developed independently on multiple occasions.
- There was no association of DAP-R with other mutations known to be linked to DAP resistance (mutations in the lia system regulatory genes, cls, or divIVA).
If not the usual suspects, what was the cause of DAP-R in these VREfm?
- A genome-wide association study identified 142 mutations in 73 genes significantly associated with DAP resistance. The top five were (1) an uncharacterized ABC efflux protein, (2) an uncharacterized permease protein, (3) a mannitol dehydrogenase protein, and (4, 5) genes encoding the RNA polymerase subunits RpoB (S491F mutation) and RpoC (T634K).
- Each of these mutations were introduced into a DAP-S isolate of VREF. Only one mutation — the S491F substitution in RpoB — increased the DAP MIC (from 2 to 8 mg/L).
- In further studies, other RpoB mutations (G482D and H486Y) increased the DAP MIC as well as the rifampicin MIC:
- Interestingly, every clinical isolate with the RpoB S491F substitution (n = 105) also contained a T634K substitution RpoC, which was found to provide fitness compensation for the mutations in RpoB.
- To test the notion that treatment with rifaximin resulted in the selection of DAP-R, they used a mouse gastrointestinal colonization model with VREF and found that treatment with either rifampin or rifaximin caused de novo emergence of rpoB mutations that confer cross-resistance to DAP.
How can a mutation in RNA polymerase cause resistance to DAP? The authors used a multiomics approach to show that G482D, H486Y, and S491F RpoB substitutions led to transcriptional dysregulation of a previously uncharacterized genetic locus that they named the phenotypic resistance to DAP, or prd, operon. Upregulation of the prd operon led to VREfm cell membrane remodeling and a decreased negative cell surface charge that reduced DAP binding and, ultimately, rendered VREfm resistant to DAP.
Is this problem limited to Australia? The team searched genomic databases and found the S491F substitution was identified in VREfm genomes from 20 countries and across 21 different STs.
Why is this resistance emerging now? The authors used an evolutionary clock analysis to determine that the year of emergence for the most recent common ancestor of each cluster with S491F was around 2006, which coincides with the first clinical use of rifaximin in Australia. The expansion of the resistance has increased since 2010 when it was approved for the prevention of hepatic encephalopathy.
Yikes! This emergence of resistance was completely unexpected and unpredictable. It is a stark reminder about how the evolution of antimicrobial resistance is a continuing problem.