Skip to main content

Non-antibiotic treatments for bacterial diseases in an era of progressive antibiotic resistance

A Letter to this article was published on 03 May 2017


The emergence of multi-drug resistant (MDR) microbial pathogens threatens the very foundation upon which standard antibacterial chemotherapy is based. We must consider non-antibiotic solutions to manage invasive bacterial infections. Transition from antibiotics to non-traditional treatments poses real clinical challenges that will not be easy to solve. Antibiotics will continue to reliably treat some infections (e.g., group A streptococci and Treponema pallidum) but will likely need adjuvant therapies or will need to be replaced for many bacterial infections in the future.

Recent discoveries of plasmid-transferable genes that mediate resistance to carbapenems [1] and colistin [2] indicate that the last defensive wall against multi-drug resistant (MDR) pathogens has already been breached. We now face the uncomfortable reality that the post-antibiotic era has arrived when dealing with pan-resistant bacterial pathogens. We need to consider our remaining options and develop new ones in a world where antibiotics can no longer be counted upon to cure infections. Non-antibiotic opportunities to treat serious bacterial infections exist as possible options (Table 1).

Table 1 Summary of some non-antibiotic inhibitors of bacterial growth and/or pathogenesis

Hemofiltration devices

Extracorporeal pathogen removal filters are in development which can bind and remove an array of blood stream pathogens. Multiple device filters are being studied; two of the more interesting ones include the use of mannose binding lectins [3] or bound heparin [4]. Reduction in the bacterial load by hemofilters could theoretically allow the host innate and adaptive immune systems to remove residual pathogens despite pan-resistance to antimicrobial agents.

Quorum sensing inhibitors

Many bacteria employ some form of intercellular communication to alert pathogens about their collective bacterial concentration. If high concentrations are detected, pathogens can switch their transcription profiles to an invasive phenotype [5, 6]. An impressive array of natural and synthetic molecules can block quorum sensing and improve outcomes in experimental models of systemic infection. Whether quorum sensing inhibitors will ever be of practical clinical benefit against MDR pathogens remains the subject of considerable debate [5, 6].

Lytic bacteriophages

The use of bacteriophages (viruses that lyse specific bacteria) as a replacement for antimicrobial agents against MDR pathogens remains an attractive option despite numerous challenges [7, 8]. Phage therapy to treat bacterial infection was introduced in the early 1920s and is still in clinical use in some regions in Eastern Europe and in Georgia [8]. Phage therapy is now regaining widespread interest as antimicrobial resistance is reaching a global crisis.

Bacteriolysis by selected lytic phages is likened to the activity of a rapidly bactericidal antibiotic against susceptible bacteria. Phage invade bacteria via attachment to surface receptors on bacteria where they replicate intracellularly and kill the bacterial host by digesting the peptidoglycan cell wall. Phage are ubiquitous in nature and are harmlessly ingested in our diet by the millions each day [8]. Phage therapy can be administered topically on open wounds or surface infections [7] or given intravenously for use in systemic infections.

Despite all the theoretical advantages of phage therapy for MDR pathogens, numerous drawbacks and practical challenges exist. The major problem is their exquisite specificity. Phage infect only one strain of bacteria, thereby precluding their use as empiric therapy for acute infections. The causative bacterium responsible for the infection must be identified; then a suitable phage therapy can be fashioned from existing stocks of phage. Stocking a hospital laboratory with a complete library of phage for every conceivable bacterial pathogen will be a major challenge indeed [8].

Advanced immunotherapies

Immunotherapy to treat infectious diseases is not a new idea, but innovations in the generation of high affinity, human polyclonal or monoclonal antibodies against an array of molecular targets makes this an attractive approach. Active immunizations with adjuvanted, multi-eptitope bacterial vaccines are in development, as are monoclonal and polyclonal antibodies, as passive therapies against bacterial pathogens [911]. Transchromosomic cattle have been developed that can deliver high volumes of high quality, human polyclonal antibodies against bacterial and viral antigens [11]. Monoclonal antibodies can be designed with advantageous features and half-lives that can opsonize bacteria or inhibit virulence factors without the need for antibiotics [9, 10].

Immune adjuvants are in clinical development to booster cellular and humoral adaptive immunity of the host [12]. A number of adjuvants are under investigation, including interleukin-7, granulocyte macrophage-colony stimulating factor, programmed cell death ligand-1 antibody, among other strategies. Such immune adjuvants could benefit patients with sepsis-induced immune suppression [12].

Alternative efforts to limit virulence

Liposome-based cyto-toxin inhibitors [13] have been engineered to capture a variety of cell membrane lytic toxins produced by bacteria. These liposomes serve as cell membrane decoys to absorb cyto-toxins and thereby protect human cells from injury. This non-antibiotic defense mechanism is protective experimentally and could complement anti-microbial agents in treating exotoxin-producing bacterial infections.

Non-immune tolerance to pathogens

Non-immune tolerizing events allow the host to survive and co-exist in the presence of a potential microbial threat. This represents a novel way of approaching the problem of MDR pathogens [14, 15]. Treatments would be aimed at allowing the host to compensate for pathogen presence until immune clearance removes the pathogen. An example of non-immune tolerance is seen in the differential susceptibility of mice (and likely humans) to Ebola virus disease [15]. Mouse strains vary dramatically in their susceptibility to the same strain and dose of Ebola virus. The genetic explanation is found primarily in the variation of expression of a single gene known as Tek, the human homologue for tyrosine kinase receptor for angiopoietin-1. High levels of angiopoietin1/Tie2 promote endothelial barrier protection. Ebola viruses specifically target the endothelium and kill endothelial cells. Mouse strains with high levels of Tek are better able to defend their endothelial surfaces until the adaptive immune cells (cytotoxic CD8 cells) arrive at about 7 days into infection to clear the virus. Perhaps non-immune therapeutics against infectious diseases might provide some options against MDR pathogens in clinical medicine.


The progressive spread of antibiotic resistance genes is forcing us to reconsider our treatment options against some bacterial pathogens. Treating bacterial infections will likely become more challenging in the future. We need to protect the antibiotics we already have, develop new ones, and redouble our efforts to generate novel therapies against bacterial pathogens.


  1. Rolain JM, Parola P, Cornaglia C. New Delhi metallo-beta lactamase (NDM-1): towards a new pandemic? Clin Microbial Infect. 2010;16(12):1699–76.

    Article  CAS  Google Scholar 

  2. Liu Y-Y, Wang Y, Walsh TR, et al. Emergence of plasmid-mediated colistin resistance mechanism, MCR-1 in animals and human beings in China: a microbiological and molecular biological study. Lancet Infect Dis. 2016;16(2):160–8.

    Google Scholar 

  3. McCrea K, Ward R, LaRosa S. Removal of carbapenem-resistant Enterobacteriaceae (CRE) from blood by heparin-functional hemoperfusion media. PLoS One. 2014;9(12), e114242.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Kang JH, Super M, Yung CW, et al. An extracorporeal blood-cleaning device for sepsis therapy. Nat Med. 2014;20:1211–6.

    Article  CAS  PubMed  Google Scholar 

  5. Brackman G, Coenye T. Quorum sensing inhibitors as anti-biofilm agents. Curr Pharm Des. 2015;21(1):5–11.

    Article  CAS  PubMed  Google Scholar 

  6. Kalia V. Quorum sensing inhibitors: an overview. Biotechnol Adv. 2013;31(2):224–45.

    Article  CAS  PubMed  Google Scholar 

  7. Wright A, Hawkins CH, Anggard EE, Harper DR. A controlled clinical trial of a therapeutic bacteriophage preparation in chronic otitis due to antibiotic-resistant Pseudomonas aeruginosa; a preliminary report of efficacy. Clin Otolaryngol. 2009;34(4):349–57.

    Article  CAS  PubMed  Google Scholar 

  8. Wittebole X, De Roock S, Opal S. A historical overview of bacteriophage therapy as an alternative to antibiotics for the treatment of bacterial pathogens. Virulence. 2014;5(1):226–35.

    Article  PubMed  Google Scholar 

  9. Irani V, Guy A, Andrew D, et al. Molecular properties of human IgG subclasses and their implications for designing therapeutic monoclonal antibodies against infectious diseases. Mole Immun. 2015;67:171–82.

    Article  CAS  Google Scholar 

  10. Lu Q, Rouby JJ, Laterre PF, et al. Pharmacokinetics and safety of panobacumab: specific adjunctive immunotherapy in critical patients with nosocomial Pseudomonas aeruginosa 011 pneumonia. J Antimicrob Chemother. 2011;66(5):1110–6.

    Article  CAS  PubMed  Google Scholar 

  11. Luke T, Wu H, Zhao J, et al. Human polyclonal immunoglobulin G from transchromosomic bovines inhibits MERS-CoA in vivo. Sci Transl Med. 2016;8(326):326ra21.

    Article  PubMed  Google Scholar 

  12. Boomer J, To K, Chang K, et al. Immunosuppression in patients who die of sepsis and multiple organ failure. JAMA. 2011;306(23):2594–605.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Henry B, Neill D, Becker K, et al. Engineered liposomes sequester bacterial exotoxins and protect from severe invasive infections in mice. Nat Biotechnol. 2015;33(1):81–8.

    Article  CAS  PubMed  Google Scholar 

  14. Medzhitov R, Schneider D, Soares M. Disease tolerance as a strategy. Science. 2012;335(6071):936–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Rassmussen AL, Okumura A, Ferris MT, et al. Host genetic diversity enables Ebola hemorrhagic fever pathogenesis and resistance. Science. 2014;346(6212):987–91.

    Article  Google Scholar 

Download references


Not applicable


Not applicable.

Availability of data and materials

Not applicable.

Author’s contribution

The author conceived and prepared the manuscript and the table.

Competing interests

SO is a consultant for Aridis, Asahi-Kasei, Beckton-Dickenson, Ferring, Arsanis, Battelle, BioAegis, Cyon, and Sobi.

Consent for publication

Not applicable.

Ethics approval and consent to participate

Not applicable.

Author information

Authors and Affiliations


Corresponding author

Correspondence to Steven M. Opal.

Rights and permissions

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (, which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( applies to the data made available in this article, unless otherwise stated.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Opal, S.M. Non-antibiotic treatments for bacterial diseases in an era of progressive antibiotic resistance. Crit Care 20, 397 (2016).

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: