The Newest Superbug to Reach the US: The Final Threshold Crossed?

Reports have been recently published of the first isolation and identification of the first colistin resistant bacteria in the US[i]. While we may be getting used to hearing of antibiotic resistance, this report indicates the last threshold on the pathway to complete antibiotic resistance being crossed.

How did we cross that threshold? 

• Colistin is the current standard of therapy for multiply antibiotic resistance bacteria, especially members of the Carbapenem Resistant Enterobacteriacea (CRE)
• While the organism isolated ( E. coli) happened to not be resistant to a number of antibiotics and could therefore be treated, E. coli strains do exist that are also Carbapanem resistant
• The colistin resistance gene (mcr1) was found on a mobile genetic element, meaning on DNA that can be shared from bacteria to bacteria, spreading the resistance further.

What is colistin?

Colistin is a complex polypetide antibiotic in the polymixin class of antibiotics. This means it is a mix of two rings of biologically occurring amino acids.

As an antibiotic, colistin declined in clinical use in the 1970s as other antibiotics with less toxicity (especially renal and neurological) became available. However, colistin was reintroduced to treat multi-drug resistant bacteria in the 2000s.

The reintroduction of Colistin has led researchers to scrutinize thousands of historic samples, as well as to set up routine screening programs in order to find examples of resistance to colistin due its specialized nature in being one of the few antibiotics left to fight multi-drug resistance bacteria.

Where else in the world has this been found?

One of the screening programs conducted around the world is responsible for locating the most current strain, found in a 49-year-old women seeking treatment for a urinary tract infectionⁱ. The screening program of the Walter Reed National Military Medical Center (only established in May 2016) detected the colistin resistant E. coli after the isolate was sent to the center from Pennsylvania due to its unusual nature.

In addition to this most recent isolate, colistin resistance was noted in E. coli in 2015 from both animals and humans and in Klebsiella pneumoniae from humans by a screening program in China[ii]. More worryingly, the mobile DNA for colistin resistance was shown to be able to move between bacterial species-not just to “offspring” but also other relatives (horizontal gene transfer: like if you could pass your gene for eye color to a friend by shaking hands).   

Since the first finding in China, the gene for colistin resistance has been shown in animal, environmental and human samples from a number of countries and continents including Europe (Great Britain[iii], Spain[iv], Netherlands[v], Greece[vi], France[vii], Belgium[viii]) Latin America[ix], South Africa [x], Egypt[xi], Asia (Malaysia[xii], Japan[xiii], Thailand and Laos[xiv], ), Switzerland[xv], North America (Canada[xvi],  USA ⁱ).

How did we get here?

Antibiotic resistance has numerous causes and there is not a single event that led to colistin resistance. Some of the major causes of antibiotic resistance in general include:

• Livestock use of antibiotics: Widespread use of antibiotics in animal feed to promote animal health has been a long noted concern.
• Inadequate diagnosis: The ability to diagnose an infection and determine the best antibiotic choice would be preferred than using an empirically chosen broad spectrum antibiotic which often is the case currently.
• Inadequate prescribing: An estimated 20 to 50 per cent of antibiotics in hospital and around a third of physician office prescriptions have been found to be unnecessary or inappropriate.
• Resistance generation: Prior to the introduction of penicillin as a medicine, resistance to penicillin[xvii] was reported by scientists. Since then we have been playing catch up with the bacteria, cyclically introducing new antibiotics to combat resistance, while the bacteria evolve resistance requiring new antibiotics. Take these examples: Tetracycline was released in the 1950s and resistant Shigella was found in the same decade. Erythromycin was introduced in 1953 and resistance was noted in 1968, while gentamicin was developed in 1967 and saw resistance in 1979. Vancomycin, one of the front line antibiotics to treat resistant organisms, was released in 1985 and resistance was first noted in 1998.
• New antibiotic approval has been dropping: The number of antibiotics developed and approved by regulators has fallen due to a number of reasons, including that the most effective classes were the earliest found and used antibiotics. In addition, there is a poor return on investment for antibiotic drug manufacturers, as antibiotics do not generate the same kind of profit as other lines of pharmaceuticals. One of the reasons for this profit issue is that front line antibiotics that are newly approved will be used sparingly in order to maintain their effectiveness, further lowering the potential return on investment.

Should we panic?

No, not yet. Yes, the colistin resistance gene has been found in numerous bacterial species and on different mobile genetic elements, and has reportedly been able to be transferred between species with high efficiency. However, to date, the colistin gene has not been found on the same mobile DNA elements that CRE bacteria typically carry that confer broad antibiotic resistance. Added to this, while CRA can have a devastating impact (up to 50% mortality in some cases) the rate of CRE organisms are very low (around 600 deaths a year), and the incidence of CRE, while present in most states, is not particularly high[xviii] and typically confined to patients in hospitals or nursing homes.

What can we do about it?

There is a lot of focus around this issue currently and collectively action is all ready underway;

• Phasing out antibiotic utilization in food production: Voluntary action taken by the food industry and the FDA to remove antibiotics from food production, as well as movement by well known restaurants to remove antibiotics from the food supply chain should assist in reducing the chances of antibiotic resistance.
• Budget: The Federal budget provided an increase in spending in this area by more than $375 million, of which almost half went to the CDC to prevent and monitor this area.
• Screening for immediate action: As noted in the detection of the latest organism in the US, prompt screening and detection is key. Screening is already underway to locate and monitor these organisms to provide timely interventions.
• Research funding: The NIH received $100 million for antibiotic resistance research, and the Biomedical Advanced Research and Development Authority received $96 million to explore new antibiotics.
• Regulation: In 2012 the Generating Antibiotics Incentives Now Act (GAIN) was passed which sped up the FDA review for antibiotics with the SPLMU pathway, and provided additional patent exclusivity for antibiotic companies.
• Stewardship: Antibiotic stewardship is increasing in hospitals, that is, the prudent use of antibiotics. Most of the leading hospital or infections related organisms have guidelines around implementation including the CDC. In addition unnecessary prescriptions from primary care physicians should be reduced.
• Alternate medicines: A range of other anti-infective medicines could be utilized to assist in treating antibiotic resistant bacteria. These include bacteriophages (viruses that attack only bacteria, not humans), CRISPR-gene editing enzymes that could cut out or remove the resistance genes, antimicrobial peptides (small protein chains that exhibit antibiotic-like properties) including proteins isolated from alligators, frogs and other animals.

The problem of antibiotic resistance is not going to go away, and ultimately this is a story 70 years in the making. There is not a single answer. But collective action by the consumer, medical professionals, regulators, governments and research scientists is required to stop this looming threat.

Dr. Monk is the Director for Clinical and Scientific Affairs for Cupron Inc, a biotech firm based in the Richmond , VA area focusing on utilizing its novel proprietary platform technology involving the use of copper compounds in synthetic polymers for consumer, medical, industrial and military applications. Dr. Monk’s area of expertise is microbiology and antimicrobial’s mode of action and resistance, and he is responsible for managing clinical and research trials in the United States, and executing regulatory strategy in the United States for Cupron Inc.  Prior to joining Cupron, Dr. Monk was Head Scientist at Biocontrol Ltd developing novel antibacterial solutions for antibiotic resistant bacteria.  Dr. Monk received his PhD in Microbiology and Molecular Epidemiology from Bath University and B.Sc. in Biology and Microbiology from the University of Birmingham.  Dr. Monk performed his post doctoral studies at Virginia Commonwealth University focused on antimicrobial’s mode of action and resistance. 

[i] McGann P, Snesrud E, Maybank R, Corey B, Ong AC, Clifford R, Hinkle M, Whitman T, Lesho E, Schaecher KE. Escherichia coli Harboring mcr-1 and blaCTX-M on a Novel IncF Plasmid: First report of mcr-1 in the USA. Antimicrob Agents Chemother. 2016 May 26.

[ii] Liu YY, Wang Y, Walsh TR, Yi LX, Zhang R, Spencer J, Doi Y, Tian G, Dong B, Huang X, Yu LF, Gu D, Ren H, Chen X, Lv L, He D, Zhou H, Liang Z, Liu JH, Shen J. 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 Feb;16(2):161-8.

[iii] Anjum MF, Duggett NA, AbuOun M, Randall L, Nunez-Garcia J, Ellis RJ, Rogers J, Horton R, Brena C, Williamson S, Martelli F, Davies R, Teale C. Colistin resistance in Salmonella and Escherichia coli isolates from a pig farm in Great Britain. J Antimicrob Chemother. 2016 May 4

[iv] Quesada A, Ugarte-Ruiz M, Iglesias MR, Porrero MC, Martínez R, Florez-Cuadrado D, Campos MJ, García M, Píriz S, Sáez JL, Domínguez L. Detection of plasmid mediated colistin resistance (MCR-1) in Escherichia coli and Salmonella enterica  isolated from poultry and swine in Spain. Res Vet Sci. 2016 Apr;105:134-5.

[v] Presence of mcr-1-positive Enterobacteriaceae in retail chicken meat but not in humans in the Netherlands since 2009. Kluytmans-van den Bergh MF, Huizinga P, Bonten MJ, Bos M, De Bruyne K, Friedrich AW, Rossen JW, Savelkoul PH, Kluytmans JA. Euro Surveill. 2016;21(9).

[vi] Mavroidi A, Katsiari M, Likousi S, Palla E, Roussou Z, Nikolaou C, Maguina A, Platsouka ED. Characterization of ST258 Colistin-Resistant, blaKPC-Producing Klebsiella pneumoniae in a Greek Hospital. Microb Drug Resist. 2016 Feb 3.

[vii] Haenni M, Poirel L, Kieffer N, Châtre P, Saras E, Métayer V,  et al.  Co-occurrence of extended spectrum β lactamase and MCR-1 encoding genes on plasmids. Lancet Infect Dis. 2016;16(3):281-2.

[viii] Malhotra-Kumar S, Xavier BB, Das AJ, Lammens C, Butaye P, Goossens H. Colistin resistance gene mcr-1 harboured on a multidrug resistant plasmid.Lancet Infect Dis. 2016;16(3):283-4

[ix] Rapoport M, Faccone D, Pasteran F, Ceriana P, Albornoz E, Petroni A; MCR-Group, Corso A. mcr-1-mediated colistin resistance in human infections caused by Escherichia coli: First description in Latin America. Antimicrob Agents Chemother. 2016 Apr 18.

[x]  Perreten V, Strauss C, Collaud A, Gerber D. Colistin resistance gene mcr-1 in avian pathogenic Escherichia coli in South Africa. Antimicrob Agents Chemother. 2016 May 9.

[xi] Khalifa HO, Ahmed AM, Oreiby AF, Eid AM, Shimamoto T, Shimamoto T. Characterisation of the plasmid-mediated colistin resistance gene mcr-1 in Escherichia coli isolated from animals in Egypt. Int J Antimicrob Agents. 2016 May;47(5):413-4.

[xii]  Yu CY, Ang GY, Chin PS, Ngeow YF, Yin WF, Chan KG. Emergence of mcr-1-mediated colistin resistance in Escherichia coli in Malaysia. Int J Antimicrob Agents. 2016 Apr 22.

[xiii] Suzuki S, Ohnishi M, Kawanishi M, Akiba M, Kuroda M. Investigation of a plasmid genome database for colistin-resistance gene mcr-1.Lancet Infect Dis. 2016;16(3):284-5.

[xiv] Olaitan AO, Chabou S, Okdah L, Morand S, Rolain JM. Dissemination of the mcr-1 colistin resistance gene.Lancet Infect Dis. 2016;16(2):147

[xv] Nordmann P, Lienhard R, Kieffer N, Clerc O, Poirel L. Plasmid-Mediated Colistin-Resistant Escherichia coli in Bacteremia in Switzerland. Clin Infect Dis. 2016 May 15;62(10):1322-3

[xvi] Mulvey MR, Mataseje LF, Robertson J, Nash JHE, Boerlin P, Toye B,  et al.  Dissemination of the mcr-1 colistin resistance gene. Lancet Infect Dis. 2016;16(3):289-90.

[xvii] Abraham, E. P., and E. Chain. 1940. An enzyme from bacteria able to destroy penicillin. Rev. Infect. Dis. 10:677-678

[xviii] http://www.cdc.gov/hai/organisms/cre/TrackingCRE.html