Skip to main content
Dr. Tony Bai

Medical Grand Rounds featuring Dr. Tony Bai

Pierce Colpman, MSc Candidate (Translational Medicine)


Attendees to last week’s Medical Grand Rounds had the privilege of hearing from Dr. Tony Bai surrounding non-inferiority trials of new antibiotics. Dr. Bai firstly described the context and rationale for non-inferiority trials in approving antibiotics. It was explained that between 1990 to 2010, there was a void of new discoveries. Dr. Bai attributes this to the incentive for big pharma companies to invest their money elsewhere.  The average cost of bringing a drug to market is similar across all diseases, approximately $500,000,000. However, there are vast differences in the return that companies will see. A cardiology drug can be broadly prescribed, and its use continued for weeks to years after it is developed. In contrast, an antibiotic drug will be restricted to one to two cases a year for a resistant organism, drastically limiting potential profits and deterring investors from seeing antibiotic drugs as a worthwhile financial investment (1).
 

Dr. Bai highlighted how this is changing with IDSAs commitment in 2010 to discover 10 new antibiotics prioritized against the ESKAPE pathogens that are effective and safe by 2020, along with regulatory and policy incentives associated with increasing antibiotic development. In 2010 The FDA published guidelines on how to approve new antibiotics for new common infectious diseases, and since then, there has been an explosion of non-inferior antibiotic trials. Infectious disease researchers believe that the efficacy of current antibiotics is adequate, and they are focusing their efforts largely on antibiotic conveniences, such as getting drugs into oral forms or creating drugs with a shorter duration. With this as the aim, non-inferiority trials are the perfect design, as the goal of infectious disease researchers is to prove that they are not compromising efficacy while increasing convenience.
 

A standard non-inferiority trial has two arms, both a treatment and comparison arm, to establish that the treatment arm is not inferior to the comparison arm. Once data is collected, a confidence interval is constructed around the point estimate. If this interval lies wholly to the right of the non-inferiority margin, then the trial has been deemed a success. When critically appraising non-inferiority trials, Dr. Bai suggests watching out for ways in which trialists cheat to obtain significance. Examples of this include using an inferior comparison arm, a larger non-inferiority margin, or a shorter confidence interval. Dr. Bai studied 227 non-inferiority trials for new antibiotics and measured them against quality markers of what a methodologically sound trial should contain. He concluded that there is much room for improvement and that many things we do to treat infections are propagated by tradition and not always supported by evidence (2). For example, Dr. Bai was taught that the intention to treat model (ITT) does not work for non-inferiority trials and instead per-protocol analysis (PP) should be used. However, in 2021 he investigated the empirical evidence and found that the point estimate of ITT and PP are the same. ITT yields a more conservative estimate based on the confidence interval in the majority of non-inferiority trials (3). Dr. Bai was also interested in the statistical methods used to determine the confidence interval, as the entire theory of the trial design is based on this calculation. He compared the 5 most common statistical methods used to calculate the confidence interval and concluded that the most conservative method is the Miettinen-Nurminen method, with the Wald method being the worst (4).
 

Dr. Bai then spoke to us about bio creep, the phenomenon where a small amount of absolute risk reduction is introduced that lies within the confidence interval. The treatment arm becomes the comparison arm through this mechanism, and a slow erosion of effectiveness is thought to be seen. Dr. Bai published a paper that tested to see if this was the case for antibiotics in non-inferiority trials. They found that in 227 non-inferiority trials for new antibiotics, bio creep was rare and is not occurring yet. Finally, Dr. Bai summarized the most useful new antibiotics that we can use in KGH and implored us to challenge traditional practices as sometimes they aren’t necessarily supported by recent evidence.
 

The TMED graduate students were lucky enough to continue talking to Dr. Bai about his research following his talk. We discussed how Dr. Bai’s research on non-inferiority trials could benefit patients as well as how antibiotics and their associated trials have been represented in the lay press. Finally, Dr. Bai outlined his education and career path, including how his clinical experience influenced his research passions, and ended with some wise advice for us surrounding skills for a great career, the forefront of which was an ability to be a nice person! On behalf of myself and my peers, I would like to thank Dr. Bai for presenting at Grand Rounds and for taking the extra time to discuss with myself and my peers.

 

  1. Silver, L. L. (2011). Challenges of antibacterial discovery. Clinical Microbiology Reviews, 24(1), 71–109. https://doi.org/10.1128/cmr.00030-10
  2. Bai, A. D., Komorowski, A. S., Lo, C. K., Tandon, P., Li, X. X., Mokashi, V., Cvetkovic, A., Kay, V. R., Findlater, A., Liang, L., Loeb, M., & Mertz, D. (2020). Methodological and reporting quality of noninferiority randomized controlled trials comparing antibiotic therapies: A systematic review. Clinical Infectious Diseases, 73(7). https://doi.org/10.1093/cid/ciaa1353
  3. Bai, A. D., Komorowski, A. S., Lo, C. K., Tandon, P., Li, X. X., Mokashi, V., Cvetkovic, A., Findlater, A., Liang, L., Tomlinson, G., Loeb, M., & Mertz, D. (2021). Intention-to-treat analysis may be more conservative than per protocol analysis in antibiotic non-inferiority trials: A systematic review. BMC Medical Research Methodology, 21(1). https://doi.org/10.1186/s12874-021-01260-7
  4. Bai, A. D., Komorowski, A. S., Lo, C. K., Tandon, P., Li, X. X., Mokashi, V., Cvetkovic, A., Findlater, A., Liang, L., Tomlinson, G., Loeb, M., & Mertz, D. (2021). Confidence interval of risk difference by different statistical methods and its impact on the study conclusion in antibiotic non-inferiority trials. Trials, 22(1). https://doi.org/10.1186/s13063-021-05686-8

 

 

Comments

Name
Alyssa Burrows

Wed, 02/23/2022 - 15:01

Hi Pierce,

Thank you for facilitating a vibrant discussion last week with Tony and good job on summarising his lecture.

You have highlighted that the IDSA commitment to discovering 10 new antibiotics by 2020 helped bring incentives to antibiotic drug discovery and development however antimicrobial-resistant infections are still of high concern. Combination therapy has emerged as a common treatment strategy, they can exhibit independent, antagonistic or synergistic effects (1). Several screening strategies have been proposed to assess the efficacy of combinatorial drugs specifically, manual plate assays, microfluidic systems, and in silico methods, hit quality and throughput must be balanced (1). Given the lack of financial incentives for pharmaceutical companies to pursue antibiotic discovery as you have discussed, Nielsen et al., proposed that a non-profit approach may help stating that an “alternative model for sustaining discovery of antibiotics is overdue” (2). With the advancements of artificial intelligence and machine learning, it is predicted that these tools will help open up new regions of chemical space to exploration, the repurposing of non-antibiotic pharmaceuticals could also be a promising avenue for antibiotic discovery and will be facilitated by deep learning (3).

Are there any other antibiotic drug discovery initiatives that you have come across that could help address antimicrobial resistance? Do you think one approach may be more successful than another? Or will a combination of approaches be needed?

Looking forward to hearing your thoughts,

Alyssa

Reference
1) Zhu M, Tse MW, Weller J, Chen J, Blainey PC. The future of antibiotics begins with discovering new combinations. Annals of the New York Academy of Sciences. 2021 Jul;1496(1):82-96.
2) Nielsen TB, Brass EP, Gilbert DN, Bartlett JG, Spellberg B. Sustainable discovery and development of antibiotics—is a nonprofit approach the future?. The New England journal of medicine. 2019 Aug 8;381(6):503.
3) Melo MC, Maasch JR, de la Fuente-Nunez C. Accelerating antibiotic discovery through artificial intelligence. Communications biology. 2021 Sep 9;4(1):1-3.

Name
Alyssa Burrows

Hi Pierce and Alyssa,

I thoroughly enjoyed the discussion we had about antibiotic discovery especially due to the ever so becoming importance with the emergence of antimicrobial resistance! From some quick research, I learned that bacteria develop resistance through a few main mechanisms: enzymatic inactivation, overexpression of efflux pumps, decreased permeability and modifications that change biding of the antibiotics (1). To address your comment Alyssa, it seems like the use of non-essential target inhibitors as antibiotics adjuvants that increase susceptibility of bacteria to antibiotics are becoming commonly used. While these methods could be considered a form of combination therapy, I too am wondering if this might be the most feasible way to fight antimicrobial resistance. Does anyone know if focusing on developing drugs that increase permeability and stop the efflux of antibiotics from bacteria would be "easier" than looking at new antibiotics through inferiority trials? My thoughts are that developing these drugs could target similar traits of bacteria and be more widely used, but I would love to hear the thoughts of others!

Cassie

(1) Annunziato, G. (2019). Strategies to overcome antimicrobial resistance (AMR) making use of non-essential target inhibitors: A review. International journal of molecular sciences, 20(23), 5844.

Name
Cassie Brand

Hi Alyssa! Thank you so much for your detailed question! The repurposing of nonantibiotic pharmaceuticals, AI advancements, and combination therapy all have promise in developing new ways to combat antimicrobial resistance. However, I think the point you raised about a non-profit approach is the most important and relevant to Dr. Bai’s talk. It has been well established through our learning and through the knowledge Dr. Bai imparted on us, that the current entrepreneurial development model for antibiotics is broken and needs to be fundamentally transformed. Dr. Bai mentioned that the most relevant factor which is impeding the development of new antimicrobials is the lack of incentive for large pharmaceutical companies. Nonprofit organizations have substantial advantages over for-profit companies as nonprofit companies can choose to not enter markets in favor of addressing unmet needs, as they face no pressure to continually generate revenue growth and drive-up shareholder value. As nonprofits lack shareholders, they face less pressure to increase drug prices and are better positioned to control post-approval antibiotic use. A drug with tens of millions of dollars in annual sales is considered a failure for large for-profit companies but could be very impactful for nonprofits, who can reinvest this revenue to sustain research and development efforts in the future. An improved system would encourage discovery and development of truly needed antibiotics that improve patient outcomes, rather than continued development of “me too” drugs for profits. This would make the development of antibiotics with low peak sales economically feasible and would permit more effective control over the post-approval use of antibiotics to prolong their effectiveness. To specifically answer your question, based on my research I believe that this non-profit approach which I have outlined would be more successful than the other new potential avenues which you mentioned as in my opinion they would most likely fall prey to the same issues we see in large pharmacological companies today with antimicrobials. I do not know if these new therapies would be susceptible to the ”me too” drug movement we see in antimicrobials however the directly profit-oriented agenda of these companies would undoubtedly have an effect on which new therapies are pursued which I believe could be lessened through a non-profit system.

Name
Pierce Colpman

Name
Nolan Breault

Wed, 02/23/2022 - 18:31

Hi Pierce,

Thanks for the summary of last week's MGR! This is my first time learning about non-inferiority study design, and I think the concept addresses a bunch of interesting themes related to the current state and future of medical research. These include how the funding of drug development is handled (you identify that the progress of health care is heavily dictated by how profitable a certain venture is -- should/how could this be altered to be more ethical?) and the "limits" of what medicine can achieve. I wanted to address this latter topic.

As I understand it, non-inferiority studies have gained traction in the last few decades due to incrementally smaller and smaller improvements in standards of care and outcomes -- a sort of diminishing returns scenario (while the discussion's centred around antibiotics, it would be interesting to quantify the prevalence of non-inferiority trials in other major markets of drug research, like cardiovascular and depression/anxiety medications, chemotherapeutics, etc). While I have a somewhat better-than-lay understanding of the drug development process for antibiotics, I'm not sure that I've grasped the reasons behind why our ability to develop new therapies is particularly limited. With drugs for non-infectious disease, we're typically dealing with a static adversary. That is, if we can identify what's causing a patient's ailment, the disease doesn't reflexively adapt and counteract whatever medication we prescribe (outside of some cancers). Thus, hypertension, anxiety, etc, can be managed for decades on one or two therapies. As such, the number of ways we can design an effective seems clearly finite (until precision medicine and patient-specific treatments become mainstream). We might, as you described, find ways to improve quality of life/compliance by converting an intravenous medication into an orally-administered one, but there isn't a tug-of-war with the disease.

Contrast this with a bacterial infection, where there's an entirely independent genome that experiences natural selection just like we do. As I understand it, most of our antibiotics are derived from molecules that we find in nature, as they exist as part of other organisms' immune systems. There's inherently then an arms race between the ability of bacteria to infect and propagate within a host, as well as the host's ability to stave off the infection. These forces are underlaid by proteins, which have defined structures and functions. If we throw in the capacity for favourable mutations to occur and become common in a strain of bacteria, as well as the host, could we not theoretically have many more potential molecules to draw antibiotics from? Further, many medicines are compounds that don't occur in nature, so perhaps we could use synthetics as antibiotics as well (further reading in the Nature review below).

Looking forward to everyone's thoughts on this!

Nolan

References
Mitcheltree, M.J., Pisipati, A., Syroegin, E.A. et al. A synthetic antibiotic class overcoming bacterial multidrug resistance. Nature 599, 507–512 (2021). https://doi.org/10.1038/s41586-021-04045-6

Name
Nolan Breault

Name
Kiera Liblik

Wed, 02/23/2022 - 18:44

Hello Pierce,
Thank you for a wonderful discussion of last week's MGR. I was doing some reading about the World Health Organization's response to antibiotic resistance.(1) As Dr. Bai discussed, there is a critical need for new and novel ways to counteract antibiotic resistance. Accordingly, governments and global health organizations are providing financial incentives for development in this area.(2)
Interestingly, it seems that one of the barriers to preventing antibiotic resistance in the first place is the inconsistent prescription practices across different medical centres. In Ontario alone, it's been found that types and volume of antibiotics differ greatly between regions. (3) I wonder if you think that it would be worthwhile for the government to put together a committee to decide on definitive antibiotic prescribing practices to be followed at all centres (unless a special case which goes through an appeal). Or, do you think this would be too much paperwork for an insufficient amount of benefit?
Warm regards,
Kiera

1) Tacconelli, E., Carrara, E., Savoldi, A., Harbarth, S., Mendelson, M., Monnet, D. L., ... & Zorzet, A. (2018). Discovery, research, and development of new antibiotics: the WHO priority list of antibiotic-resistant bacteria and tuberculosis. The Lancet Infectious Diseases, 18(3), 318-327.
2) Outterson, K. (2019). A shot in the arm for new antibiotics. Nature biotechnology, 37(10), 1110-1112.
3) Schwartz, K. L., Achonu, C., Brown, K. A., Langford, B., Daneman, N., Johnstone, J., & Garber, G. (2018). Regional variability in outpatient antibiotic use in Ontario, Canada: a retrospective cross-sectional study. Canadian Medical Association Open Access Journal, 6(4), E445-E452.

Name
Kiera Liblik

Hi Kiera, thank you so much for your kind words and response. To answer your question, yes, I do believe that it would be worthwhile for the government to put together a committee to decide on definitive antibiotic prescribing practices to be followed at all centers, for many different reasons. A study from the United Kingdom estimates that in the absence of significant intervention, deaths from drug-resistant infections will surpass deaths from cancer by 2050, resulting in 10 million deaths annually (1). As you mentioned, and this fact supports, antimicrobial resistance is an urgent public health threat and there is a critical need for novel ways to counteract antibiotic resistance before it gets out of hand. I believe that developing a program to combat inappropriate prescription practices would be effective due to the following factors. Firstly, antibiotic use has been seen to be the most important modifiable risk factor associated with the development of antimicrobial resistance at both the individual and population levels (2). In Canada, approximately 92% of antibiotics are used outside of the acute care hospital setting and in the United States it is estimated that 30% of all antibiotics prescribed in the community are unnecessary (3). In addition, a recent study from Canada found that almost 50% of Ontario seniors with upper respiratory infections inappropriately receive antibiotics (4). As improper antimicrobial prescription is a large contributing factor to the development of antimicrobial resistance, these facts suggest that there are opportunities to reduce inappropriate community antibiotic use and help lessen the increasing antimicrobial resistance which I believe would be well tolerated through a committee-style design as you mentioned. Thanks again for your response!

1. O’Neill J (2016) Tackling drug-resistant infections globally: final report and recommendations (Wellcome Trust & HM Government, London (UK)).
2. Costelloe, C., Metcalfe, C., Lovering, A., Mant, D., & Hay, A. D. (2010). Effect of antibiotic prescribing in primary care on antimicrobial resistance in individual patients: Systematic review and meta-analysis. BMJ, 340(may18 2), c2096–c2096. https://doi.org/10.1136/bmj.c2096
3. Fleming-Dutra, K. E., Hersh, A. L., Shapiro, D. J., Bartoces, M., Enns, E. A., File, T. M., Finkelstein, J. A., Gerber, J. S., Hyun, D. Y., Linder, J. A., Lynfield, R., Margolis, D. J., May, L. S., Merenstein, D., Metlay, J. P., Newland, J. G., Piccirillo, J. F., Roberts, R. M., Sanchez, G. V., … Hicks, L. A. (2016). Prevalence of inappropriate antibiotic prescriptions among us ambulatory care visits, 2010-2011. JAMA, 315(17), 1864. https://doi.org/10.1001/jama.2016.4151
4. Silverman, M., Povitz, M., Sontrop, J. M., Li, L., Richard, L., Cejic, S., & Shariff, S. Z. (2017). Antibiotic prescribing for nonbacterial acute upper respiratory infections in elderly persons. Annals of Internal Medicine, 166(11), 765. https://doi.org/10.7326/m16-1131

Name
Pierce Colpman

Dear Pierce and Kiera,

Thank you so much for facilitating our discussion and for this summary! I agree with Kiera’s point regarding the importance of identifying novel ways to counteract antibiotic resistance. As Kiera pointed out, one of the ways of mitigating antibiotic resistance is by improving antibiotic prescribing/stewardship. Another way to mitigate antibiotic resistance is by continually allocating efforts to tracking and gathering data on antibiotic resistant infections, causes of infections and whether there are risk factors for resistance infection. This information and data can provide quality insights for preventative measures that can be taken in order avoid infection to begin with. Furthermore, avoiding infections will ultimately reduce the amount of antibiotics that have to be used and reduces likelihood of resistance development during therapy. Finally, the tracking of this data would experts to develop specific strategies to mitigate the spread of resistant bacteria. Do you think there are other ways that can be taken to prevent antibiotic resistance?

Name
Dilakshan Srikanthan

Name
Georgia Kersche

Wed, 02/23/2022 - 21:01

Hi Pierce,
Great summary of Dr. Bai's talk last week! It was great to hear from someone still at the beginning of their career as a physician to get a different perspective, as you mentioned during the discussion.

Annually, fewer and fewer antibiotics are effective against ESKAPE pathogens. As I believe someone pointed out during class, bacteria are outsmarting us! ESKAPE pathogens are associated with a high mortality and significantly increase healthcare costs when attempting to treat resistant infections (1). While the development of novel antibiotics is finally picking up speed, some investigation into alternatives is also warranted . One of the several strategies I have read about is silver nanoparticles. Silver nanoparticles are used as antibiofilms to protect surgical implants and also show promising antimicrobial activity in vivo (2). Silver nanoparticles release ions that disrupt the electron transport chain and signal transduction pathways that leads to damage in cellular structures (3). While toxic to bacteria, they have so far demonstrated good safety profiles in animal models and humans (3). Photodynamic therapy has also shown promise. A beam of light of the right wavelength transfers electrons create radical oxygen species that are toxic to cells. In vitro studies on blue light treat topical wounds, and an ideal wavelength of 415nm causes minimal harm to healthy underlying tissue (4). However, pathogens that overexpress efflux pumps limit the potential of photodynamic therapy, and is limited mostly to topical applications (2). These and other alternatives made me wonder how Dr. Bai's discussion of noninferiority trials extends to these types of therapies. Do you think that direct comparisons of these alternatives between each other and traditional antibiotics are our future? I look forward to hearing your thoughts, or hearing about other alternatives folks come across!

References
1. Founou, R., Founou, L., & Essack, S. (2017). Clinical and economic impact of antibiotic resistance in developing countries: A systematic review and meta-analysis. PLOS ONE, 12(12), e0189621. https://doi.org/10.1371/journal.pone.0189621
2. Mulani, M., Kamble, E., Kumkar, S., Tawre, M., & Pardesi, K. (2019). Emerging Strategies to Combat ESKAPE Pathogens in the Era of Antimicrobial Resistance: A Review. Frontiers In Microbiology, 10. https://doi.org/10.3389/fmicb.2019.00539
3. Munger, M., Radwanski, P., Hadlock, G., Stoddard, G., Shaaban, A., & Falconer, J. et al. (2014). In vivo human time-exposure study of orally dosed commercial silver nanoparticles. Nanomedicine: Nanotechnology, Biology And Medicine, 10(1), 1-9. https://doi.org/10.1016/j.nano.2013.06.010
4. Halstead, F., Thwaite, J., Burt, R., Laws, T., Raguse, M., & Moeller, R. et al. (2016). Antibacterial Activity of Blue Light against Nosocomial Wound Pathogens Growing Planktonically and as Mature Biofilms. Applied And Environmental Microbiology, 82(13), 4006-4016. https://doi.org/10.1128/aem.00756-16

Name
Georgia Kersche

Hello, Pierce and Georgia,

I wanted to start off by saying what a wonderful job, Pierce, summarizing and expanding on this talk. I think you did an incredible job capturing the key takeaways.

I wanted to discuss the ESKAPE pathogens as well with you, as these pathogens are the leading cause of nosocomial infectious throughout the world [1]. These pathogens are known to be multidrug resistant and although antibodies are the gold-standard/ go to for treating these infectious, I wondered if we are approaching them appropriately. My personal research looks at antimicrobial peptides, using a nanoparticle release system, as we are seeing sexually transmitted infectious such as Neisseria gonorrhoea become antibiotic resistant [2]. My question coincides with Georgia, do you think we will see a comparison in our future for these alternate treatment methods? And do you think there will be a focus on alternate methods to avoid this ongoing issue, antibiotic resistant organisms?

References:
[1] Santajit, S., & Indrawattana, N. (2016). Mechanisms of Antimicrobial Resistance in ESKAPE Pathogens. BioMed research international, 2016, 2475067. https://doi.org/10.1155/2016/2475067

[2] Tshokey T, Tshering T, Pradhan AR, Adhikari D, Sharma R, Gurung K, Dorji T, Wangmo S, Dorji U, Wangdi K. Antibiotic resistance in Neisseria gonorrhoea and treatment outcomes of gonococcal urethritis suspected patients in two large hospitals in Bhutan, 2015. PLoS One. 2018 Aug 1;13(8):e0201721. doi: 10.1371/journal.pone.0201721. PMID: 30067836; PMCID: PMC6070275.

Name
Kyla

Name
Katie Lindale

Wed, 02/23/2022 - 22:15

Thanks for the fantastic summary Pierce! Dr. Bai's discussion was thoroughly enjoyable and enlightening. I found the discussion on intention to treat (ITT) analysis particularly interesting, considering its utility in managing noncompliance and its inherent shortcomings in assessing treatment efficacy (1). I'm intrigued by the idea of taking ITT analysis' utility a step further and identifying patterns in study participants who end up with changes in their planned treatment course after randomization. From a translational lens, protocol-deviating real-world clinical data can be as informative as it is complicated. Especially in the world of Infectious Disease research, learning about how patients fare on treatments and adapt course could highlight important research areas otherwise overlooked in the search for highly effective therapeutics. I'm curious to know what the class thinks about the pros and cons of using ITT analysis, and what our responsibilities are as translational researchers in capturing patterns in the real-world data that this strategy can provide us with.

Many thanks,

Katie

(1) Gupta SK. Intention-to-treat concept: a review. Perspectives in clinical research. 2011 Jul;2(3):109.

Name
Katie Lindale

Name
Emmanuel Fagbola

Thu, 02/24/2022 - 14:25

Excellent summary Pierce!

I am curious to hear your thoughts about how patient compliance may play a foundational role in the minute investment prospects that antibiotic drug development holds.

According to the example and supporting details you mentioned, it seems clear that investors are keen on spending money on drugs for cardiovascular ailments and diseases. Going into the average person's mind, I would expect anything concerning cardiovascular health to be taken seriously. In turn, I would expect a resultant high level of compliance independent of medication frequency, length, and convenience.

However, my expectation looking at the same concept for antibiotic drug compliance would be quite different. Omission of doses, taking more doses than prescribed in the hopes to relieve symptoms quicker, premature discontinuation of antibiotic therapy at the first sign of symptom relief, and the preconception that relief will be seen in a short period are factors that contribute to patient non-compliance, according to the article attached below.

In closing, do you think that increasing patient compliance through something like public health campaigns would serve to support more antibiotic research? By improving public knowledge about the gravity of infection to an individual and, by extension, the general public, will more individuals seek out emergency or primary care to receive the appropriate antibiotics when needed?

https://academic.oup.com/jac/article/49/6/897/712911

Emmanuel

Name
Emmanuel Fagbola

Name
Pierce Colpman

Sun, 02/27/2022 - 23:49

In reply to by Emmanuel Fagbola (not verified)

Hey Emmanuel thanks for this great question!
I do think that increasing awareness through something like a public health campaign or equivalent would be a good idea to support antibiotic research. However, I don't know if this would necessarily be enough to impact the large financial barriers that are in place. The points you made regarding omitting doses and the improper usage of antibiotic drugs are major issues, especially in terms of antibiotic resistance, but the lack of support in their development is mostly due to limited profits after they are created. Cardiology drugs can be used by every patient which may benefit from their effects and continued for weeks to years after they are developed. Antibiotic drugs on the other hand are restricted to a small number of cases for resistant organisms. Because of this, the potential profits even from a very successful antibiotic, are shadowed by the initial investment required and even more dwarfed by the potential profits from developing other classes of drugs. I think that more awareness always has the potential to bring more support to a cause but before we see any real change in the support seen for antibiotic research we need to make it a more attractive target for investors, or alternatively, as Alyssa mentioned in her comment, move to a more publicly funded system.

Name
Pierce Colpman

Name
Trinity Vey

Thu, 02/24/2022 - 14:34

Hi Pierce,

Thanks for a great summary of last week’s MGR! I really enjoyed our discussion with Dr. Bai and I think you did an excellent job describing non-inferiority trials and some of the current challenges with antibiotics.

I wanted to expand on what Dr. Bai highlighted as one of the main contributors to antibiotic resistance - antibiotic use in agriculture. With increasing demand for animal protein, antibiotics have become commonly used in livestock for the treatment of diseases, as well as prophylactically and for growth promotion (Manyi-Loh et al., 2018). This usage has supported the development of resistant bacterial strains in animals. In many countries, particularly developing countries, the use of non-essential antibiotics in animal feed to support growth is largely unregulated. Increased antibiotic usage in both humans and animals ultimately results in antibiotic pollution from waste streams, creating selective pressure for antibiotic resistance in the environment (Manyi-Loh et al., 2018). Furthermore, animal products including meat, eggs, and milk can be contaminated with antibiotic residues, which contribute to resistance in human gut flora upon consumption (Manyi-Loh et al., 2018). As such, I’m wondering if anyone has thoughts on how the use of antibiotics can be better regulated in agriculture globally, to help combat the antibiotic resistance crisis?

Thank you again for a great discussion and summary, looking forward to continuing this conversation!

Trinity

Manyi-Loh, C., Mamphweli, S., Meyer, E., & Okoh, A. (2018). Antibiotic Use in Agriculture and Its Consequential Resistance in Environmental Sources: Potential Public Health Implications. Molecules (Basel, Switzerland), 23(4), E795. https://doi.org/10.3390/molecules23040795

Name
Trinity Vey

Great summary, Pierce, and intriguing discussion point, Trinity!

It appears that the topic of regulation of antibiotics used in agriculture varies country by country, each with slightly differing policies. In the US, the US Department of Agriculture (USDA) is the monitoring body to ensure that antibiotic levels do not exceed standards set by the FDA and USDA. The European Union has even banned the use of antibiotics in a country-specific manner. Despite these measures, antibiotic resistance is still of concern. Newer strategies of addressing this problem focus on using alternatives to antibiotics, such as peptide antibiotics/antimicrobial peptides (AMPs), carbohydrate-modified compounds, and even bacteriophage therapy (1).

Especially with these new strategies, do you think we may ever be able to completely eradicate resistance?

Lubnaa

(1) https://www.sciencedirect.com/science/article/pii/S2666517421000110#sec…

Name
Lubnaa Hossenbaccus

Hi Pierce and Trinity,

Thank you for leading the discussion and writing a great summary of the MGR last week.

The role of antibiotics in agriculture contributing to antibiotic resistance was something that stood out to me in the MGR last week. The federal government recently created regulations requiring farmers to obtain a prescription from a veterinarian for medically important antibiotics for livestock. 1 Medically important antibiotics include those used to treat human infections, and importance is also affected by whether alternatives exist for the antibiotic. 1 This regulation aims to increase veterinarian oversight of agricultural antibiotic use and reduce the use of antibiotics in livestock, especially those important for treating human disease. Interestingly, lab-grown meat would likely require significantly less antibiotics compared to livestock. 2 Risk of exposure to bacteria is reduced by sterile lab conditions and cellular agriculture is much faster, reducing the potential for bacterial exposure. 3 Additionally, a widespread shift from traditional to lab-grown meat would decrease the number of livestock and reduce contact between humans and animals, lowering the risk of zoonotic diseases. 3 I’m not sure if lab-grown meat will be popular, but it sounds like it would help combat agriculture-related antibiotic resistance! I look forward to hearing everyone’s thoughts on other methods to reduce antibiotic use in agriculture.

All the best,

Samantha

References
1. Farmers play ‘societal’ role with tighter antibiotic rules in 2018, says prof. 2018. CBC News. https://www.cbc.ca/news/canada/kitchener-waterloo/prescription-agricult….
2. The food safety advantages of lab-grown meat. 2022. Food in Canada. https://www.foodincanada.com/features/the-food-safety-advantages-of-lab…
3. Lab-grown meat tackles the looming threat of antibiotic resistance. 2020. Lab grown meat. https://labgrownmeat.com/lab-grown-meat-antibiotics/

Name
Samantha Ables

Hi Trinity thanks so much for this question, I think that this is a really important topic and I am glad someone brought it up. The unscrupulous use of antibiotics in farm animals has drastically exacerbated the problems of antibiotic resistance and experts argue that implementing measures that will help to reduce the abuse of antibiotics in livestock farming will help with lessening antibiotic resistance (1). Christy Manyi-Loh and her colleagues did a study on antibiotic use in agriculture and its consequential resistance in environmental sources and had the following recommendations: Firstly, it was found that there is a general lack of knowledge among farmers regarding antibiotic use, storage, its abuse, and consequent hazards to public health and the environment (1). Other sources also corroborate that educating both the farmers and the general population on the dangers of misusing antibiotics, and its consequences on public health will have the greatest effect in reducing antibiotic resistance due to agriculture (2). Furthermore, the indiscriminate use of antibiotics in animal farming should be avoided. Veterinary officers and pharmacists should adhere strictly to the policies governing prescriptions of antibiotics used in animal farming. They should ensure that the farmers adhere to the dosage, length, and administration of treatment and withdrawal periods of antibiotics prescribed for a purpose, as well as the causative agent of the disease, be diagnosed and antibiotic susceptibility testing conducted against the disease causative agent prior to prescription and employment of the antibiotics (3).

(1) Manyi-Loh, C., Mamphweli, S., Meyer, E., & Okoh, A. (2018). Antibiotic Use in Agriculture and Its Consequential Resistance in Environmental Sources: Potential Public Health Implications. Molecules (Basel, Switzerland), 23(4), 795. https://doi.org/10.3390/molecules23040795

(2) Islam, K. S., Shiraj-Um-Mahmuda, S., & Hazzaz-Bin-Kabir, M. (2016). Antibiotic usage patterns in selected broiler farms of Bangladesh and their public health implications. Journal of Public Health in Developing Countries, 2(3), 276-284.

(3) Osei Sekyere J. (2014). Antibiotic Types and Handling Practices in Disease Management among Pig Farms in Ashanti Region, Ghana. Journal of veterinary medicine, 2014, 531952. https://doi.org/10.1155/2014/531952

Name
Pierce Colpman

Name
Bethany Wilken

Fri, 02/25/2022 - 14:20

Hi Emmanuel,

I regrettably had to miss last week’s grand rounds but Pierce’s summary and the insightful discussion that is taking place has definitely sparked my interest. Up until recently, I had never heard the medical community expressing major concerns over antibiotic resistance. As highlighted in various comments, there could be many contributing factors to resistance including antibiotic use in agriculture, inconsistent prescription and as you emphasized, patient compliance.

Antibiotics are considered relatively safe, with mild side effects. Perhaps due to their safety profile, patients are more lenient with their usage. In being critical of patients, I believe we should also be critical of the doctors prescribing the antibiotics. Antibiotic overprescribing is a longstanding clinical concern. The Center for Disease Control and Prevention (CDC) estimates that 30% of antibiotics prescribed in an outpatient setting are unnecessary (1), while up to 40% of antibiotic prescription for acute respiratory tract infections are unnecessary (2). Considering the implications of antibiotic resistance, we must lower the number of unnecessary prescriptions. One idea I had to modify physician antibiotic prescribing is to have a prompt on electronic medical records. The prompt would require the physician to provide a note for antibiotic justification. Interestingly, patient demand is the major reason that physicians feel pressured to overprescribe (3). Thus, pamphlets or other educational tools focused on the potential harms of overprescribing could be distributed to patients. Does anyone else have ideas on how to combat antibiotic overprescribing to help address antibiotic resistance?

Best,
Bethany

1. Harris AM, Hicks LA, Qaseem A, for the High Value Care Task Force of the American College of Physicians and for the Centers for Disease Control and Prevention. Appropriate antibiotic use for acute respiratory tract infection in adults: advice for highvalue care from the American College of Physicians and the Centers for Disease Control and Prevention. Ann Intern Med. 2016;164:425-434
2. Barlam TF, Soria-Saucedo R, Cabral HJ, et al. Unnecessary antibiotics for acute respiratory tract infections: association with care setting and patient demographics. Open Forum Infect Dis. 2016;3:1-7.
3. Dempsey PP, Businger AC, Whaley LE, et al. Primary care clinicians’ perceptions about antibiotic prescribing for acute bronchitis: a qualitative study. BMC Fam Pract. 2014;15:194.

Name
Bethany Wilken

Hi Bethany,
I wanted to chime in and provide my thoughts on other factors that may contribute to overprescription as well as possible solutions. I think you have hit on an incredibly important problem that is contributing to the antibiotic resistance crisis. One study estimated that doctors in the U.S. prescribed antibiotics for sore throats in 60% of visits (for sore throat), despite streptococcal pharyngitis being the only cause of sore throat that warrants antibiotic prescription and this condition represents about 10% of sore throat visits (1,2). Factors that might contribute to physician antibiotic overprescription include lack of sleep, hunger, hurried environment, and lack of attention (among others) (3). I completely agree that patient education is an important factor. 88% of studies on patient expectations with antibiotics found that patients overestimate the benefits of antibiotics and 67% of these studies found patients underestimate the harms (4). I think one factor that could lead to this perception is the marketing of drugs in media which leads to a culture that believes that every ailment requires a pill (3). Regulating the pharmaceutical industry-patient relationship in media may help change the culture. In 2013, the CDC recommended antibiotic stewardship which is when physicians only prescribe antibiotics when they are needed for treatment or to prevent disease (5). Furthermore, prescribing the correct antibiotic and dose are also essential (5). In conclusion, I think that patient, physician, and societal factors contribute to antibiotic overprescription. Physicians should take the lead on this issue and help to change the culture of antibiotic overprescription and educate patients on the real harms and benefits of antibiotics.
Thanks for starting the discussion,
James

1. Barnett M. L., Linder J. A. 2014. Antibiotic prescribing to adults with sore throat in the United States, 1997-2010. JAMA Intern Med.
2. Wessels M. R. 2011. Clinical practice. Streptococcal pharyngitis. N Engl J Med.
3. Feller E. 2019. Why do doctors overprescribe antibiotics? Rhode Island Med J
4. Hoffmann T. C., Mar C. D. 2015. Patients' expectations of the benefits and harms of treatments, screening, and tests: a systematic review. JAMA Intern Med.
5. CDC. 2013. Antibiotic resistance threats in the united stated, 2013.

Name
James King

Add new comment

Plain text

  • No HTML tags allowed.
  • Lines and paragraphs break automatically.
  • Web page addresses and email addresses turn into links automatically.