First US detection of bacteria with gene causing resistance to last-ditch antibiotic

A woman from Pennsylvania is the first US person found carrying bacteria with a gene which causes resistance to the last-ditch antibiotic colistin, according to the journal Antimicrobial Agents and Chemotherapy. Researchers at the Walter Reed National Military Medical Center reported that E. coli from the woman’s urinary tract infection contained the mcr-1 gene, first discovered in China in 2015.

 

Dr. Gerry Wright, Director of the Michael G. DeGroote Institute for Infectious Disease Research, McMaster University (webpage): 

Expertise: Combating antibiotic resistance and treating infectious diseases; discovering new antibiotics; duplicating antibiotics in the lab for research purposes.

This is something we expected, the mcr-1 gene has been reported across the globe (including Canada) since it was first reported in November of last year. The US was actually an anomaly in not finding it until now. I expect it’s been around for some time, just not detected. Because the patient has no reported travel history, you can predict with certainty that mcr-1 is established in the USA.

mcr-1 is increasingly found on plasmids (mobile mini-chromosomes) that carry additional resistance genes, or found in bacteria with multiple plasmids with many resistance elements. In this case, another plasmid in the cell (it contained 2) had a gene that codes for an enzyme (ctx-m) that is notorious for degrading penicillin and cephalosporin antibiotics (front line drugs). The organism is consequently resistant to all these drugs. So bad news all around. This strain of E. coli was sensitive pretty much to only one class of drugs, the carbapenems, so one step away from pan-resistance. There have been reports in the literature recently of mcr-1 strains with genes that encode enzymes that inactivate carbapenems, and these are particularly grim.”

 

Dr. Nasia Safdar, Associate Professor of Infectious Diseases, University of Wisconsin School of Medicine and Public Health (webpage):

Expertise: Healthcare-associated infections and novel interventions to reduce healthcare-associated infection.

The results are very concerning because the first description of a colistin resistant organism in the US is what the entire infectious diseases community was worried about. E. coli is a member of the Enterobacteriaceae family, and ever since carbapenem-resistant Enterobacteriaceae (CRE) made an appearance we have been using more colistin as the go-to agent for treatment of multi-drug resistant infections. I don’t even know what we would use to treat an infection if it was colistin resistant.

“We were a little bit relieved and surprised that colistin resistance hasn’t already happened in the US. So while we had been anticipating this news, it is nonetheless a huge concern to hear about the first case. It is particularly concerning that the individual reported no travel history. There are places in the world where highly multi-drug resistant bacteria are more common than in the US, but this case seems completely home-grown.

“It is almost inevitable that more cases will come to light. It’s just a matter of how quickly things spread. With CRE, soon after the initial description it became fairly widespread and not just in the US but globally. It wouldn’t be a stretch to say that we are towards the end of effective antimicrobial therapy for antibiotic resistant bacteria.” 

 

Dr. Bruce Lee, Associate Professor of International Health, Johns Hopkins Bloomberg School of Public Health (webpage):

Expertise: Developing computational models to help decision makers prevent and control infectious diseases throughout the world, including antibiotic-resistant bacteria.

This is quite concerning. Colistin is a last line of defense against bacteria, an antibiotic that you turn to when other antibiotics fail.  This along with the issue that there are relatively few new antibiotics in the development pipeline makes you wonder whether we may re-enter a time when many, many more people will die from infections. People today do not recall the time before antibiotics when millions more were dying from simple infections because there was no treatment. Resistant bacteria can multiply and spread quickly. For example, penicillin-resistant Staphylococcus strains emerged and became a major problem within a decade of penicillin being used to treat Staphylococcus.  Similarly, methicillin-resistant Staphylococcus aureus (MRSA) emerged within a decade of widespread use of methicillin in the early 1960s.   

Everyone needs to be much more careful about unnecessary antibiotic use.  A recent study showed that about one third of antibiotic prescriptions from doctors are not necessary. And this does not count the antibiotics used by dentists as well as the antibiotics put in animal feed.  There needs to be more aggressive antibiotic stewardship programs, more efforts to develop new antibiotics, and better ways of tracking and controlling the spread of antibiotic resistance.  An example is more regional, collaborative approaches to preventing and controlling the spread of antibiotic-resistant bacteria.”

 

Dr. Nirav Patel, Assistant Professor of Infectious Diseases, Saint Louis University (webpage):

Expertise: Transplant infectious diseases, nosocomial/ICU infections, infections due to multi-drug resistant organisms, and in the appropriate utilization of antibiotics in the ICU.

The discovery of the case of this particular resistance mechanism in the US is extremely concerning.  It has been described elsewhere in the world previously, but the use of colistin in the US is relatively low, and thus it is concerning that even in this environment, the resistance gene has been identified.  Unfortunately, this revelation is likely to herald further cases in the US as well, and it will only be a matter of time when a patient gets a truly serious infection for which we have no viable antibiotics to treat them with.

The concern for pan-drug-resistant antibiotics is real.  The more antibiotics are used, both for the treatment of patients as well as in the environment, for the growth promotion of farm animals, the more likely infections will occur due to resistant organisms.  As the overall rate of resistance in the community increases, doctors to have to use antibiotics that previously would have been reserved for the most difficult-to-treat infections.  This becomes a self-perpetuating cycle, and at some point, we run out of antibiotics that remain active.  Colistin is considered by many experts to be an extremely toxic drug, one that we wouldn’t use regularly, but we saved since it continued to work for some highly resistant infections.  However, with increasing resistance, we’ve had to use it more frequently.  This is has led to selective pressure in favor of resistance to colistin.  Eventually, as in this case, a human has become infected with a colistin-resistant organism.  Now there are no other drugs to turn to.

Even worse however, is that all of this resistance has occurred in a relatively short time period.  It has only been 88 years since penicillin was first described.  We have developed hundreds of new antibiotics, but all of them have been countered by resistance.  Studies have been done looking at bacteria trapped beneath the permafrost in Canada that are 30,000 years old, as well as a cave system isolated for over 4 million years.  In both of these sequestered environments multiple antibiotic resistance mechanisms were noted to modern antibiotics.  And since many antibiotics are derived from natural sources (like Penicillium mold from which penicillin was synthesized), bacteria have had a chance to evolve novel mechanisms of resistance for eons.  Taken in total, the data suggest that bacteria are already resistant to antibiotics humans haven’t even invented yet.”

 

Dr. Yun (Wayne) Wang, Associate Professor of Pathology & Laboratory Medicine, Emory University School of Medicine (webpage):

Expertise: Rapid laboratory diagnosis of infectious diseases; antimicrobial susceptibility testing and resistance surveillance.

Resistance to antibiotics such as colistin and or polymyxin B developed by bacteria, especially Gram-negative organisms, is concerning.  There are not that many new antibiotics out there.  The report on finding the plasmid associated resistance gene (mcr-1) in Extended Spectrum Beta-Lactamase (ESBL)-producing E. coli in the US is of great interest.

“According to the study published, this isolate was recovered from a patient with a urinary tract infection who presented to a clinic in Pennsylvania.  The patient had no travel history in the past five months, was not admitted to hospital and was not on medications such as colistin. Though the E. coli isolate was an ESBL-producing bacterium, it was not carbapenem-resistant and it was susceptible to other antibiotics such amikacin and piperacillin/tazobactam.”

 

Dr. Guy Loneragan, Professor of Food Safety and Public Health, Texas Tech University (webpage):

Expertise: Animal and public health; controlling food-borne pathogens and antimicrobial drug resistance.

McGann et al’s report of an mcr-1 harboring E. coli isolate recovered from a patient with no recent travel history is concerning.  It is, however, not overly surprising.  Given the burgeoning reports of its global dissemination – with prevalence estimates likely associated with total colistin use – it should be expected that US reports would emerge. This report does not change the fact that its prevalence in the US is much less than that reported elsewhere.

“The isolate was broadly resistant to many important drugs.  It was, however, not pan-resistant and therapeutic options remain.  However, there is a real possibility that some isolates will soon assemble the genes necessary to resist all known antibiotics and that has dire implications.  It also highlights the need for accelerating discover and approval of novel antibiotics and alternative antibiotics, and adoption of stewardship practices the limit the selection and spread of resistant organisms.”

 

Declared interests (see GENeS register of interests policy):

Dr. Guy Loneragan: “G.H.L. has provided scientific advice to various pharmaceutical companies that market antimicrobial drugs for administration to animals. He has on occasion billed for his service. G.H.L. has also received honoraria and travel support for service on advisory boards and presentations from pharmaceutical companies.”

No further interests declared.

 

Reference:

Escherichia coli Harboring mcr-1 and blaCTX-M on a Novel IncF Plasmid: First report of mcr-1 in the USA‘ by McGann et al, published in Antimocrobial Agents and Chemotherapy on Thursday, May 26, 2016.

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