Some Good News in the Field of Antimicrobial Resistance

Nov. 17, 2020

It’s no secret that antimicrobial resistance (AMR) is a problem of progressively increasing scope, threatening the ability of doctors to treat people infected with pathogens that once succumbed reliably to any of a host of widely available antimicrobial agents. But as the problem of resistance has grown, so has awareness of the problem among clinicians, patients and policymakers. While we are far from turning back the tide on AMR, efforts to limit unnecessary use of antibiotics are starting to produce some encouraging results. In celebration of World Antimicrobial Awareness Week, let’s take a look at some of these examples of good news.

The Decline of mcr-1-Mediated Colistin Resistance in China

In late 2015, a report of a new gene conferring resistance to colistin, a “last-resort” antibiotic with broad-spectrum gram-negative activity that is one of the few agents with activity against most carbapenem-resistant Enterobacteriaceae, generated headlines throughout the world. The gene, named mobilized colistin resistance-1 (mcr-1), was concerning because it was spread on a plasmid, a mobile genetic element that can easily be transmitted from one bacterial isolate to another. While colistin resistance due to mutations on bacterial chromosomes had existed for years, mcr-1 had the potential for rapid, far-reaching spread as a result of its mechanism of transmission. It was soon observed in countries throughout the world.

One of the contributing factors to the emergence of mcr-1 was believed to be the large-scale use of colistin as an animal growth promoter. In response to this urgent threat, the Chinese Ministry of Agriculture and Rural Affairs banned colistin as an animal feed additive in 2017. In October 2020, scientists in China reported some encouraging news about the results of these efforts: between 2015 and 2018, production and sales of colistin sulfate in China fell by ~90%, while the mean residual concentration of colistin in animal farms fell by more than 95%. The abundance of mcr-1 and of colistin-resistant Escherichia coli in animal feces also dropped during this time period. Most importantly, the prevalence of human carriage of mcr-1-containing E. coli fell from 14.3% in 2016 to 6.3% in 2019. The effect on rates of human disease was somewhat more modest (colistin-resistant E. coli infections accounted for 1.7% of E. coli infections in 2015-2016 vs. 1.3% in 2018-2019 (p<0.0001)) and heterogeneous (some provinces actually saw an increase in colistin-resistant E. coli infections during this time period). Nevertheless, the decline in human infection and carriage following an intervention in animal husbandry is a striking demonstration of the value of One Health interventions to control antimicrobial resistance.

The Return of Penicillin-Susceptible Staphylococcus aureus (PSSA)

When penicillin was first introduced, one of its most important roles was in treatment of Staphylococcus aureus infections. Very soon, however, penicillin-resistant strains began to appear, and in time β-lactamase-resistant “antistaphylococcal” penicillins, such as oxacillin, flucloxacillin and nafcillin, supplanted penicillin for treatment of S. aureus. (Methicillin, an antistaphylococcal penicillin that is no longer available due to kidney toxicity, lives on in the designation methicillin-resistant Staphylococcus aureus (MRSA), referring to S. aureus isolates that are resistant to almost all β-lactam drugs). By the mid-1960s, over 90% of hospital-acquired S. aureus isolates causing bacteremia in Denmark were resistant to penicillin.
Figure from Rammelkamp and Keefer, 1943, demonstrating the effect of penicillin on Staphylococcus aureus.
Comparative effect of penicillin and sulfadiazine on Staphylococcus aureus. Solid dots represent original inoculum per cc. of S. aureus. Circles represent final number of organisms per cc. at the end of 48 hours incubation. Solid lines indicate killing; broken lines growth.
Source: Rammelkamp and Keefer, J Clin Invest. 1943.

In 2016, however, investigators in Montréal, Canada noted that 28% of 324 unique methicillin-susceptible S. aureus (MSSA) isolates from bloodstream infections were also susceptible to penicillin. In spite of this, none of the patients had been treated with penicillin. This may have been the result of clinicians’ unfamiliarity with penicillin as a treatment option for S. aureus or lack of comfort with S. aureus penicillin susceptibility testing in the clinical microbiology laboratory. However, penicillin may be a more effective treatment option for penicillin-susceptible S. aureus (PSSA) bloodstream infections than cephalosporins or anti-staphylococcal penicillins, and it has the distinct advantage of being a very narrow-spectrum antibiotic, and therefore less likely to contribute to ongoing rising rates of antimicrobial resistance. While the reason for the reemergence of PSSA is not certain, it may result in part from the overall fall in prescription rates of narrow-spectrum antibiotics such as penicillin (a trend that is more often cause for concern than for celebration among antimicrobial stewards - see below!). The experience in Montréal is not unique: increasing rates of PSSA have also been noted outside of Canada, in locations including western Massachusetts, Boston, New York state and Sweden.
A prescription for penicillin written on April 30, 1946.
A prescription for penicillin written on April 30, 1946, about one year after penicillin became available for civilians in the U.S. From the University of Arizona's History of Pharmacy Museum.
Source: Thea Brennan-Krohn

Brand-New Good News: Improvements in Antibiotic Prescribing

The prescription of unnecessarily broad-spectrum antibiotics is a major driver of increasing rates of antimicrobial resistance. Changing clinicians’ prescribing practices is not straightforward: old habits, fears of treating too narrowly and unfamiliarity with the risks of certain classes of antibiotics all contribute to inappropriately broad prescribing. But presentations from IDWeek 2020 suggest that recent interventions to tackle these underlying issues may be starting to pay off.

Fluoroquinolones, such as ciprofloxacin and levofloxacin, have long been a target of antimicrobial stewardship efforts because of their broad spectrum of activity and frequent use in the outpatient setting, often in scenarios when no antibiotic is needed (e.g. viral infection) or when a narrower agent would be appropriate. Fluoroquinolones also have significant potential side effects, including tendon rupture and cardiac arrhythmias, especially among older adults and people with risk factors such as obesity and steroid use. Between 2008 and 2018, the U.S. Food and Drug Administration (FDA) added several “black box” safety warnings highlighting these risks and recommending the use of fluoroquinolones only when no other option is available. It appears that the warnings (likely in addition to other educational and stewardship efforts) is having an effect: a group of epidemiologists, physicians and public health experts from the Centers for Disease Control and Prevention (CDC) reported that fluoroquinolone prescription rates decreased by 30% between 2011 and 2018, with most of that decline happening between 2015 and 2018.

Skin prick test for penicillin allergy.
Skin prick testing, a method used to test for penicillin allergy.
Numerous poster presentations at IDWeek 2020 highlighted the work of pharmacist-led interventions in “de-labeling” penicillin allergies. To de-label an allergy, a pharmacist or other health professional determines, on the basis of history-taking or allergy testing, that an allergy documented in a patient’s chart is not, in fact, a true allergy and removes that documentation from the medical record. Penicillin is one of the most common antibiotics to which people report an allergy, yet the majority of people with a documented penicillin allergy do not, in fact, have a true allergy to penicillin. Some may have been labeled with a penicillin allergy when they developed a virus-induced rash while being treated with penicillin or amoxicillin for what was thought to be a bacterial infection, while others may have had a non-allergic amoxicillin rash or have an antibiotic side effect like diarrhea. Because documented penicillin allergies lead to prescription of unnecessarily broad antibiotics to avoid the use of penicillin and related drugs, de-labeling penicillin allergies in people who can safely receive these drugs is an important step in reducing broad-spectrum antibiotic use.

In one example, a pharmacist-driven algorithm in an outpatient surgical clinic at a community hospital succeeded in de-labeling penicillin allergies in all but one patient through the use of penicillin skin testing. After the de-labeling intervention, preoperative vancomycin use in the clinic declined by 39%, providing a direct demonstration of allergy de-labeling decreasing broad-spectrum antibiotic use. A pharmacist-led intervention at Oregon Health and Science University showed success in de-labeling penicillin allergies by using either an interview or an oral graded challenge in almost all cases, thereby avoiding more costly penicillin skin testing. A comparison of 2 hospitals within the same community health system in Georgia showed that there were significantly more updates to documented penicillin allergies, including removal of the allergy from the chart, in the hospital that had an Infectious Diseases pharmacist-led penicillin allergy reconciliation program in place. The 2 hospitals are served by the same Infectious Diseases physicians, underscoring the valuable role of Infectious Diseases pharmacists in addition to physicians.

Antimicrobial resistance remains an urgent threat to human health and will only be exacerbated by the cardinal infectious diseases crisis of 2020, COVID-19. Nevertheless, without letting up in our efforts to mitigate the spread of resistance and the emergence of pan-resistant pathogens, there are reasons to celebrate the small steps we’ve taken, as a global community, in the right direction.

Author: Thea Brennan-Krohn

Thea Brennan-Krohn
Thea Brennan-Krohn is a diplomate of the American Board of Medical Microbiology at Beth Israel Deaconess Medical Center (BIDMC). She is an attending in Pediatric Infectious Diseases at Boston Children's Hospital and a postdoctoral fellow at Beth Israel Deaconess Medical Center,