As scientists around the globe wage war against a novel, deadly virus, one University of Colorado Boulder lab is working on new weapons to battle a different microbial threat: a rising tide of antibiotic-resistant bacteria which, if left unchecked, could kill an estimated 10 million people annually by 2050.
“The COVID-19 situation is definitely putting us at risk for increasing resistance to antibiotics, so it’s more important now than ever that we come up with alternative treatments,” said Corrie Detweiler, a professor of molecular, cellular and developmental biology who has spent her career seeking those alternatives.
In a paper published Friday in the journal PLOS Pathogens, Detweiler and her research team unveil their latest discovery – a chemical compound that works with a host’s innate immune response to push past cellular barriers that help bacteria resist antibiotics.
Along with their other recently published discoveries, the authors say, the finding could lead to a new arsenal for fighting what could be the next big public health threat.
“If we don’t solve the problem of finding new antibiotics or somehow making old antibiotics work again, we are going to see sharply increasing deaths from bacterial infections we thought we had beaten decades ago,” said Detweiler.
“This study offers a totally new approach and could point the way toward new drugs that work better and have fewer side effects.”
In the United States alone, 35,000 people die annually from bacterial infections that could not be treated because they’ve grown resistant to existing drugs. Countless others suffer life-threatening bouts with once-easily treatable illnesses like strep throat, urinary tract infections and pneumonia. By 2050, the authors note, there could be more deaths from antibiotic resistance than from cancer.
“As our existing antibiotics adapt and work less, we risk essentially going back to a period 100 years ago, when even a minor infection could mean death,” said Detweiler.
The pandemic has shone even more light on the problem, she notes, as many patients die not from the virus itself but from hard-to-treat secondary bacterial infections.
Meanwhile, she and other scholars worry that heightened use of antibiotics to prevent or treat those secondary infections, while at times necessary, may be exacerbating resistance.
Most antibiotics in use today were developed in the 1950s, and pharmaceutical companies have since scaled back on research in the field in favor of more profitable ventures.
To feed the pipeline, Detweiler’s lab developed a technique called SAFIRE for screening for new small molecules which work differently than older drugs.
Of 14,400 candidates screened from a library of existing chemicals, SAFIRE identified 70 that hold promise.
The new paper centers around “JD1,” which appears to be particularly effective at infiltrating what are known as “Gram-negative bacteria.”
With a tough exterior membrane that prevents antibiotics from accessing the cell, and another interior membrane providing a buffer, these bacteria (including Salmonella and E. coli) are inherently difficult to treat.
But unlike other drugs, JD1 takes advantage of the host’s initial immune assault on that outer bacterial membrane, then slips inside and goes after the inner membrane too.
“This is the first study to show that you can target a Gram-negative bacteria’s inner membrane by exploiting the innate immune response of the host,” Detweiler said.
In laboratory and rodent experiments, JD1 reduced survival and spread of Gram-negative bacteria called Salmonella enterica by 95%.
But while it damaged the bacterial cell membranes, it couldn’t penetrate the fine layer of cholesterol that lined its mammalian host’s cell membranes.
“Bacteria are vulnerable to JD1 in a way that our cells are not,” said Detweiler, noting that for this reason, side-effects would likely be minimal.
Further studies are underway to explore JD1 and other compounds like it.
Meanwhile, Detweiler has formed a spin-off company to help commercialize other compounds which work by inhibiting pumps, called “efflux pumps,” that bacteria use to pump out antibiotics.
“The reality is, evolution is way smarter than all of the scientists put together and these bacteria will continue to evolve to resist what we throw at them,” she said. “We cannot rest on our laurels. We have to keep feeding the pipeline.”
COVID-19 and AMR: what do we know?
Detailed information on secondary bacterial or fungal infections among patients hospitalized with COVID-19 is sparse.3 Most reports of COVID-19 that have mentioned secondary infections have done so in passing, without providing case definitions, diagnostic criteria or methods for distinguishing colonization from disease. Secondary infections have been reported in ∼10% of COVID-19 patients included in published series from hospitals in China, Europe and the USA, with incidence as high as 35% among ICU residents.3,5
The most common type of infection was pneumonia (especially ventilator-associated pneumonia), followed by bloodstream and urinary tract infections. Certain centres, mostly in Europe, have reported incidence of invasive aspergillosis as high as 20%–30% among critically ill COVID-19 patients.6 In autopsy studies of SARS-CoV-2-infected persons, histopathologic findings consistent with bacterial bronchopneumonia have been reported in about 30% of cases but, with rare exception, culture data were lacking.6–8
Antibiotics were administered to most hospitalized COVID-19 patients in reports to date, including 75%–100% of those in ICUs.3 Most commonly used agents have been fluoroquinolones, cephalosporins, carbapenems, azithromycin, vancomycin and linezolid.
The impact of COVID-19 on overall antibiotic use within hospitals, healthcare systems and regions is unclear, as cancellation of non-essential medical services, surgeries and outpatient clinic visits has led to sharp decreases in the numbers of non-COVID-19 patients seeking care. Sparse data since the onset of the pandemic suggest significant reductions in antibiotic prescriptions.
A news report cited unpublished data from IQVIA (Durham, NC, USA) that described a 45% drop in antibiotic purchases in the USA between the start of January and mid-April 2020.7 Estimated total prescription fills for amoxicillin and azithromycin, the most commonly prescribed antibiotics in the USA, were each down nationally by over 60% in the week of 19–25 April 2020 compared with the same week in 2019.8
In our healthcare system in western Pennsylvania, removed from a disease epicentre, in-hospital antibiotic days of therapy (DOT) and outpatient antibiotic prescriptions decreased by an average of 5.1% and 6.1% per week, respectively, between 1 March and 2 May 2020 (Figure 1) (D. J. Buehrle, B. K. Decker, M. M. Wagener, A. A. Adalja, N. Singh, M. C. McEllistrem, M. H. Nguyen and C. J. Clancy, unpublished data). In-hospital antibiotic use lagged behind reductions in bed days of care (BDOC) by a week.
Limited microbiological data published during the COVID-19 pandemic suggest that causative organisms and AMR patterns for secondary infections were consistent with institutional ecology. In reports from China, organisms included pandrug-resistant (PDR) Acinetobacter baumannii, KPC-producing Klebsiella pneumoniae, ESBL-producing K. pneumoniae, ESBL-producing Pseudomonas aeruginosa, MRSA, Aspergillus fumigatus, Aspergillus flavus, Candida albicans and Candida glabrata.3
Anecdotal evidence for the potential of COVID-19 to accelerate AMR appeared in a British Medical Journal news feature, in which a stewardship director described ‘a slow but steady increase in multi-drug resistance (MDR)’ at a large New York City health system.9 In contrast, an online viewpoint from Geneva, the canton in Switzerland with the highest incidence of COVID-19, reported that weekly screening of ICU patients showed decreased asymptomatic colonization and disease by MDR organisms.10 Data were not presented in either of these pieces.
Why might AMR arise?
Clearly, no conclusions about relationships between COVID-19 and AMR can be drawn from published reports. There are several reasons, however, that we expect AMR to emerge during the pandemic.
Broad-spectrum antibiotic use has been widespread among hospitalized COVID-19 patients, and in excess of reported secondary infection rates. Therefore, much of the use to date has been unnecessary. Antibiotic therapy will likely remain common owing to difficulties in conclusively excluding secondary pneumonia or nosocomial superinfections in many cases.
A large percentage of patients admitted to hospitals with COVID-19 are from congregated living facilities such as nursing homes, prisons and psychiatric hospitals.11 Patients from nursing homes, in particular, are more likely to have altered microbiomes and to be colonized with ESBL- and carbapenemase-producing organisms, MRSA, VRE and Candida.
This population may drive high rates of broad-spectrum antibiotic use, especially since empiric therapy upon hospital admission will likely be directed against healthcare-associated pathogens.
COVID-19 strained hospital capacity to breaking point in hard-hit epicentres globally. As such, overall antibiotic use in these locations and at facilities in other locations that cared for large numbers of COVID-19 patients was likely up sharply, even if non-emergency hospital services were suspended or regional antibiotic trends were down.
For many hospitals outside of epicentres, antibiotic use within ICUs or wings that converted into COVID-19 units was likely increased, particularly if normalized to BDOC (Figure 1). Therefore, it is reasonable to assume that there will be significant AMR selection pressure in COVID-19 units, regardless of patterns elsewhere in a facility.
Hospitals and regions with high AMR prevalence that have moderate-to-high numbers of COVID-19 patients should be prepared for potential upswings in nosocomial infections by these pathogens. Risk factors and comorbidities that increase the likelihood of hospitalization or poor outcomes among COVID-19 patients, such as advanced age, debilitation, diabetes and cardiopulmonary or other underlying systemic diseases, also predispose to development of AMR infections.
Worry for emergence of AMR is heightened by the fact that first-wave COVID-19 epicentres were also AMR epicentres. As of 31 May 2020, countries with the largest numbers of diagnosed COVID-19 cases were the USA, Brazil, Russia, the UK, Spain and Italy,12 each of which face significant challenges with MDR Gram-negative and other AMR bacteria.
New York and Lombardy, regions within the USA and Italy, respectively, that were hit disproportionately hard by COVID-19, are both AMR hotspots,13 as are China (where the pandemic began) and India and Mexico (large nations with among the most rapid growth in newly diagnosed COVID-19 cases at the time of writing).
Local selection pressure for AMR during COVID-19 will be overlaid on larger, ongoing and highly dynamic regional trends, such as the remarkable growth of PDR A. baumannii and MBL-producing Enterobacteriaceae in Asia and ESBL-producing Enterobacteriaceae in the USA.14,15
While antibiotic exposure is undeniably a major risk factor for AMR,16 it is simplistic to conclude that the reductions in overall antibiotic prescriptions reported thus far will lessen the likelihood of AMR during the COVID-19 pandemic.
Reduced antibiotic use has correlated with suspensions of healthcare services during a time of stay-at-home and other extreme protective measures. As restrictions are lifted and healthcare activities resume, it is likely that antibiotic prescribing will rebound.
It is also notable that peaks of COVID-19 in Europe and North America occurred at the end of the 2019–20 influenza season. It is unclear what pressures will be placed on healthcare and antibiotic utilization if COVID-19 resurges during the upcoming influenza season.
If antibiotics are prescribed liberally in outpatient settings, particularly as SARS-CoV-2 and influenza cocirculate, AMR may also emerge in communities. It is important to understand that any changes in human antibiotic use are small in the face of global antibiotic use, over 80% of which occurs in animal husbandry and agriculture.17
These sectors have generally been designated as essential and not restricted by COVID-19. Non-human antibiotic use is clearly linked to AMR in humans.17 As one example, Escherichia coli with colistin resistance due to plasmid-borne mcr1 arose in pigs in China, which led to worldwide human dissemination in 2015 and horizontal gene transfer to other Enterobacteriaceae.15,18
Risks of animal-to-human transmission of novel AMR will remain and COVID-19 may increase the pool of potentially vulnerable hosts.
The volume of human antibiotic consumption has an inconsistent impact on AMR rates.16,19 Models using human population-based data do not reliably show causal relationships between antibiotic exposure and AMR, even if such relationships exist at the level of individual patients.20
Therefore, active surveillance of SARS-CoV-2-infected individuals for newly emergent AMR pathogens will be crucial. Once AMR arises (as, for example, might happen in COVID-19 patients in hospital units facing increased selection pressure, or in animals due to husbandry practices), socioeconomic and anthropological factors that drive spread are often more important determinants of prevalence than overall antibiotic consumption.16
In this regard, disruptive direct or indirect effects of COVID-19 on economic systems, governance, sanitation and water safety, and public health expenditures, infrastructure and regulation may fuel increasing AMR.
What can we expect?
We anticipate that the impact of COVID-19 on AMR will be uneven, varying between epicentres and non-epicentres, by geographic region, hospital-to-hospital within regions and within specific hospital units. Initially, local AMR patterns are likely to be exacerbated. As travel resumes, the risk of dissemination of novel resistance determinants will increase.
AMR screening programmes should be implemented for asymptomatic hosts and livestock following antibiotic exposure. Research protocols can evaluate the impact of antibiotic use on microbiota and resistomes, as part of more sensitive surveillance.
1 Osterholm MT. Preparing for the next pandemic. N Engl J Med 2005; 352: 1839–42.
2 Talbot GH , Jezek A , Murray BE et al. The Infectious Diseases Society of America’s 10 × ’20 Initiative (10 new systemic antibacterial agents US Food and Drug Administration approved by 2020): is 20 × ’20 a possibility? Clin Infect Dis 2019; 69: 1–11.
3 Clancy CJ , Nguyen MH. COVID–19, superinfections and antimicrobial development: what can we expect? Clin Infect Dis 2020; doi:10.1093/cid/ciaa524.
4 O’Neill J. Review on antimicrobial resistance: tackling a crisis for the health and wealth of nations. 2014. https://amr-review.org/sites/default/files/AMR%20Review%20Paper%20-%20Tackling%20a%20crisis%20for%20the%20health%20and%20wealth%20of%20nations_1.pdf.
5 Rawson TM , Moore LSP , Zhu N et al. Bacterial and fungal co-infection in individuals with coronavirus: a rapid review to support COVID-19 antimicrobial prescribing. Clin Infect Dis 2020; doi:10.1093/cid/ciaa530.
6 Thompson G , Cornely O , Pappas P et al. Invasive aspergillosis as an under-recognized superinfection in COVID-19? Open Forum Infect Dis 2020; doi: 10.1093/ofid/ofaa242.
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8 Vaduganathan M , van Meijgaard J , Mehra M et al. Prescription fills patterns for commonly used drugs during the COVID-19 pandemic in the United States. JAMA 2020; doi:10.1001/jama.2020.9184.
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11 McMichael TM , Currie DW , Clark S et al. Epidemiology of Covid-19 in a long-term care facility in King County, Washington. N Engl J Med 2020; 382: 2005–11.
12 Johns Hopkins Coronavirus Resource Center. COVID-19 Dashboard by the Center for Systems Science and Engineering (CSSE) at Johns Hopkins University (JHU). https://coronavirus.jhu.edu/map.html.
13 Satlin MJ , Chen L , Patel G et al. Multicenter clinical and molecular epidemiological analysis of bacteremia due to carbapenem-resistant Enterobacteriaceae (CRE) in the CRE epicenter of the United States. Antimicrob Agents Chemother 2017; 61: e02349–16
14 Jernigan JA , Hatfield KM , Wolford H et al. Multidrug-resistant bacterial infections in U.S. hospitalized patients, 2012-2017. N Engl J Med 2020; 382: 1309–19.
15 Hsu L-Y , Apisarnthanarak A , Khan E et al. Carbapenem-resistant Acinetobacter baumannii and Enterobacteriaceae in South and Southeast Asia. Clin Microbiol Rev 2017; 30: 1–22.
16 Collignon P , Beggs JJ , Walsh TR et al. Anthropological and socioeconomic factors contributing to global antimicrobial resistance: a univariate and multivariable analysis. Lancet Planet Health 2018; 2: e398–405.
17 McEwen SA , Collignon PJ. Antimicrobial resistance: a one health perspective. Microbiol Spectr 2018; doi:10.1128/microbiolspec.ARBA-0009-2017.
18 Gao R , Hu Y , Li Z et al. Dissemination and mechanism for the MCR-1 colistin resistance. PLoS Pathog 2016; 12: e1005957.
19 Olesen SW , Barnett ML , MacFadden DR et al. The distribution of antibiotic use and its association with antibiotic resistance. eLife 2018; 7: e39435.
20 Harbarth S , Harris AD , Carmeli Y et al. Parallel analysis of individual and aggregated data on antibiotic exposure and resistance in gram-negative bacilli. Clin Infect Dis 2001; 33: 1462–8.
More information: Jamie L. Dombach et al, A small molecule that mitigates bacterial infection disrupts Gram-negative cell membranes and is inhibited by cholesterol and neutral lipids, PLOS Pathogens (2020). DOI: 10.1371/journal.ppat.1009119