Antibiotic Resistance, Agriculture, and the Plague

Antibiotics have ended the uncontrollable outbreaks of plague in humans that stalked our ancestors. Today, outbreaks are usually snuffed out after a couple of cases with antibiotic treatment of patients, prophylactic treatment of contacts and vector control. Our greatest risks from plague today are a pneumonic plague outbreak/attack and the emergence of antibiotic resistance.

Beginning in 1995 several antibiotic resistant strains of Yersinia pestis emerged in Madagascar. Two strains isolated from different districts of Madagascar in 1995 were resistant to multiple antibiotics (1). Genetic analysis shows that not only are the resistance plasmids of different derivation but the ribotypes of the Yersina pestis are also different. There is no discernible connection between the development of these two strains. Strain 17/95 is resistant to multiple drugs including all of the antibiotics used to treat plague and for prophylaxis (1). The second strain isolated that year, strain 16/95, is resistant to Streptomycin the primary drug of choice but vulnerable to other drugs commonly used to treat plague. From 1996 to 1998, several more Y. pestis strains each resistant to a single antibiotic were also isolated in Madagascar in humans, rats and fleas (1).

Like the majority of microbes with antibiotic resistance, Y. pestis gained these plasmids by conjugation, a type of lateral gene transfer.  Experiments have shown that Y. pestis readily exchanges antibiotic resistance plasmids with E. coli and other species in the flea gut (1). This is believed to be the primary site where Y. pestis interacts with other plasmid bearing bacterial species. The plasmid isolated from Strain 17/95 (IP275) in 1995 has been identified as “nearly identical” to multi-drug resistant (MDR) plasmids isolated from Salmonella enterica (ser. Newport) and Yersinia ruckeri, a fish pathogen and with a similar core to MDR plasmids found in E. coli, Klebsiella species, and multiple serotypes of Salmonella isolated from agricultural products (2). These plasmids have a common plasmid backbone categorized as IncA/C.

Past interaction between Salmonella enterica and Yersinia pestis has been known for a long time. The Yersinia pestis plasmid pFra is 97% identical to the exclusively human pathogen Salmonella enterica ser. typhi’s cryptic pHMC2 plasmid (2). The pFra plasmid contains the F1 capsule protein and the murine toxin, important virulence factors. The location of transfer between Yersinia pestis and the human only Salmonella enterica ser. typhi has not been determined (2, 4).

Antibiotic resistant plasmids linked to IP275 have been found in many agricultural products — in livestock, grocery stores, and ill humans (2). It is not hard to imagine flea mediated transfer of an antibiotic resistant pathogen from livestock to rats and Yersinia pestis picking up the resistance plasmid where-ever co-infection is occurring.  Antibiotic resistance in livestock enteric pathogens must now be considered a risk for not only Y. pestis but also other similar zoonotic pathogens (2). Rats feeding on livestock feed containing antibiotics would set up a situation that favors the retention of the antibiotic resistance plasmids.

In an effort to see how wide-spread the problem is, an antibiotic resistance survey was conducted on 392 isolates Y. pestis from 17 countries (3). The survey was conducted for all eight antimicrobials commonly used for treatment or prophylaxis. The good news is that they found no resistance in human, animal or flea isolates (3). However, the survey was not as wide-spread as it sounds on the surface. The United States, Uganda and Madagascar contributed 84% of the 229 human cases, and the United States alone contributed 81.7% of animal cases and 92% of the flea isolates (3).  Known antibiotic resistant Y. pestis strains could not be included due to restricted access (3). Isolates from central Asia are meager: four each from China and India, three from Nepal, one from Iran, and eight from Kazakhstan; most collected in the 1960s or earlier (3).  Of the 229 human cases, 32 died and 10 of these had been treated with antibiotics that the strains were shown to be susceptible (3). This gives a 14% fatality rate overall with approximately a third of the deaths occurring despite antibiotic treatment. These survey results make it all the more important that we understand what happened in Madagascar in the 1990s.

Surveillance for antibiotic resistance should now be standard on all Y. pestis isolates.  Once we could begin with the belief that antibiotic resistant plague was an act of biological warfare but no longer. Active monitoring is, as always, the key, now with special attention to areas where livestock and plague foci overlap.

 

References

1. Galimand, M. ,  Carniel, E.  and Courvalin, P. Resistance of Yersinia pestis to Antimicrobial Agents. Antimicrob. Agents Chemother. 2006, 50(10):3233. DOI:10.1128/AAC.00306-06 [Mini-review]
2. Welch TJ, Fricke WF, McDermott PF, White DG, Rosso ML, Rasko DA, Mammel MK, Eppinger M, Rosovitz MJ, Wagner D, Rahalison L, Leclerc JE, Hinshaw JM, Lindler LE, Cebula TA, Carniel E, & Ravel J (2007). Multiple antimicrobial resistance in plague: an emerging public health risk. PloS one, 2 (3) PMID: 17375195
3. Urich SK, Chalcraft L, Schriefer ME, Yockey BM, & Petersen JM (2012). Lack of antimicrobial resistance in Yersinia pestis isolates from 17 countries in the Americas, Africa, and Asia. Antimicrobial agents and chemotherapy, 56 (1), 555-8 PMID: 22024826
4. Prentice MB, James KD, Parkhill J, Baker SG, Stevens K, Simmonds MN, Mungall KL, Churcher C, Oyston PC, Titball RW, Wren BW, Wain J, Pickard D, Hien TT, Farrar JJ, & Dougan G (2001). Yersinia pestis pFra shows biovar-specific differences and recent common ancestry with a Salmonella enterica serovar Typhi plasmid. Journal of bacteriology, 183 (8), 2586-94 PMID: 11274119