Evidence map›Paper›PMID 28477626›Full record

ArticleBMC microbiology2017

When more is less: Emergent suppressive interactions in three-drug combinations.

Casey Beppler, Elif Tekin, Cynthia White, Zhiyuan Mao, Jeffrey H Miller, Robert Damoiseaux, Van M Savage, Pamela J Yeh

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in BMC microbiology, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.

0numbers the graph read from it
0cells of the map it votes in
16citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

16 citing papers in PubMed.

  1. Article
  2. Drug combinations targeting antibiotic resistance.npj antimicrobials and resistance · 2024
    Review
  3. Article
  4. Article
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  6. Article
  7. Article
  8. Review
  9. Article
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  12. Review
  13. Article
  14. Prevalence and patterns of higher-order drug interactions inNPJ systems biology and applications · 2018
    Article
  15. Article
  16. Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

8 authors.

Casey BepplerDepartment of Ecology and Evolutionary Biology, University of California, Los Angeles, CA, USA.
Elif TekinDepartment of Biomathematics, University of California, David Geffen School of Medicine, Los Angeles, CA, USA.
Cynthia WhiteDepartment of Ecology and Evolutionary Biology, University of California, Los Angeles, CA, USA.ORCID 0000-0002-3111-6140
Zhiyuan MaoDepartment of Ecology and Evolutionary Biology, University of California, Los Angeles, CA, USA.
Jeffrey H MillerDepartment of Microbiology, Immunology, and Molecular Genetics, and the Molecular Biology Institute, University of California, David Geffen School of Medicine, Los Angeles, CA, USA.
Robert DamoiseauxDepartment of Medical and Molecular Pharmacology, University of California, Los Angeles, CA, USA.
Van M SavageDepartment of Ecology and Evolutionary Biology, University of California, Los Angeles, CA, USA.
Pamela J YehDepartment of Ecology and Evolutionary Biology, University of California, Los Angeles, CA, USA. pamelayeh@ucla.edu.

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

backgroundIn drug-drug interactions, there are surprising cases in which the growth inhibition of bacteria by a single antibiotic decreases when a second antibiotic is added. These interactions are termed suppressive and have been argued to have the potential to limit the evolution of resistance. Nevertheless, little attention has been given to suppressive interactions because clinical studies typically search for increases in killing efficiency and because suppressive interactions are believed to be rare based on pairwise studies.

resultsHere, we quantify the effects of single-, double-, and triple-drug combinations from a set of 14 antibiotics and 3 bacteria strains, totaling 364 unique three-drug combinations per bacteria strain. We find that increasing the number of drugs can increase the prevalence of suppressive interactions: 17% of three-drug combinations are suppressive compared to 5% of two-drug combinations in this study. Most cases of suppression we find (97%) are "hidden" cases for which the triple-drug bacterial growth is less than the single-drug treatments but exceeds that of a pairwise combination.

conclusionsWe find a surprising number of suppressive interactions in higher-order drug combinations. Without examining lower-order (pairwise) bacterial growth, emergent suppressive effects would be missed, potentially affecting our understanding of evolution of resistance and treatment strategies for resistant pathogens. These findings suggest that careful examination of the full factorial of drug combinations is needed to uncover suppressive interactions in higher-order combinations.

Indexed as

Drug CombinationsDrug InteractionsAnti-Bacterial AgentsBacteriaDrug Resistance, Multiple, BacterialEscherichia coliMicrobial Sensitivity TestsModels, BiologicalStaphylococcus epidermidisAnti-Bacterial AgentsDrug CombinationsAntagonismAntibioticsDrug resistanceHigher-order interactionsMultiple stressors

Identifiers

PMID28477626
PMCPMC5420147

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LicenceCC BY
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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.