Plague gives clue to transmission of drug resistance in food borne bacteria

In the 1940's polymath (and subsequently Nobel Prize) winner Josh Lederburg was trying to find how bacteria produced progeny that were not clones. Avery had demontrated the genetic importance of DNA and Lederberg with Tatum described the process of genetic transfer in conjugation and later with Zinder the importance of bacteriophages in the same process which they called transduction.

In 1952 Lederberg proposed the idea of DNA carrying bodies called plasmids ... which we now know are DNA molecules separate from the chromosomal DNA and equally capable of autonomous replication, and also sequencing. It is now realised that these plasmids represent a rapid and simple form of horizontal gene transfer.

Plague is now regarded as a re-emerging disease, with small outbreaks all over the world. Therefore when a multiple drug resistant strain of Yersina pestis (the cause of bubonic plague) was identified in 1995 in a single patient in Madagascar , who exhibited high-level resistance to at least eight drugs used for treating plague, including streptomycin, tetracycline, chloramphenicol, and sulfonamides ... some scientists looked up quizically (especially those curious people who study bio-warfare, as plague kills quickly).

The antibiotic reesistance in this case was traced to a self-transmissible plasmid. What really excited attention was that this plasmid showed common elements in the gene sequences of multi drug resistant (MDR) plasmids of Salmonella enterica , a globally spread foodborne pathogen; and Yersina ruckeri, a fish pathogen.

It is a common experience that Salmonella is widespread and the incidence of MDR Salmonella is on the increase. Craig Venters Institute of Genomic Research (TIGR) Rockville MD set to, using rapid gene sequencing techniques to analyze the occurrence and distribution of the common plasmid background in three sets of samples:

1. 125 MDR Salmonella strains recovered from retail meats from 2002 to 2005 through the National Antimicrobial Resistance Monitoring System (NARMS)
2. A small collection of E coli strains recovered from food samples
3. Klebsiella isolates from ground turkey meat from Iowa.

The authors detected the common MDR plasmid backbone in multiple Salmonella serotypes, nine samples of Klebsiella from ground turkey, and E coli isolated from a calf and from ground turkey.

This implies recent recent genetic exchange, either directly between species or through bacterial intermediates, and that the overlapping ranges of these organisms could have aided past transmission, and perhaps future transmission between bacteria.

Whilst it is too soon to start writing headlines about global Plague threats - the massive overuse of antibacterials in agriculture may trigger the rapid spread of such MDR plasmids . If an outbreak of MDR plague developed in an area well-connected to the rest of the world such a method of resistance transmission could pose a serious global public health problem.

It does of course identify possible transmission methods for drug resistance in other infectious organisms, especially those that are rapidly spreading in healthcare centres.

Professor Trevor Jones gave the Health Protection Agency Annual Lecture on Infectious Diseases on Thursday and gave special emphasis to the increasing problem of extensively drug-resistant TB or XDR tuberculosis . XDR TB is almost always fatal and it is reported that severely resistant strains have spread into Europe and North America . “ We are seeing the emergence ... or re-emergence… of a number of significant infectious diseases in both the developed and the developing world e.g. influenza, malaria, tuberculosis, HIVAIDS. The causes of this varies from neglect, poor healthcare infrastructure, poverty and the absence of funding to the development of resistance and the mutation of infectious parasites and micro-organisms."

He then went on to stake the claim for more funding having previously reminded the audience that the New York XDTB outbreaks cost US$1 Bn . Ahead of World TB day on 24th March UK (not inlcuding Scotland) figures were released showing TB cases reported declined slightly from 3,541 in 2005 to 3445 in 2006 , but case numbers been rising steadily for the last 10 years with over 40% of them in London. Countries that have huge resevoirs of HIV/AIDS have been showing astonishing levels of XDTB - Russia has reported 41 percent drug resistance among patients requiring re-treatment , levels of 20% are also being found in India and South Africa

DR Salmonella spp. with resistance to antimicrobial drugs are widespread.
In developed countries such strains are zoonotic in origin and acquire their resistance in the food-animal host before onward transmission to humans through the food chain. A major problem is Salmonella typhimurium definitive phage type (DT) 104, displaying resistance to up to six commonly used antimicrobials, and some with low susceptibility to ciprofloxacin.

Multiple drug resistance ( MDR to 4 or more antimicrobials) is also common in the poultry-associated pathogens Salmonella virchow and Salmonella hadar, with an increasing number of strains of these serotypes exhibiting decreased susceptibility to ciprofloxacin.

For Salmonella typhi, multiple drug resistance is common in strains originating in the Indian subcontinent and south-east Asia often associated many with low susceptibility to ciprofloxacin.

A study published in 2005 showed that in Turkey, MDR was particularly high among Salmonella Typhimurium isolates (76.7%), and resistance or decreased susceptibility to ciprofloxacin was seen in Salmonella Paratyphi B, Salmonella Typhimurium and Salmonella Enteritidis strains.

In 2000 in a study of 27 000 cases of human salmonellosis in 10 European countries showed 40% of isolates were resistant to at least one antimicrobial, with 18% multiresistant. Resistance to ampicillin, streptomycin, sulphonamides and tetracyclines was common. In England and Wales multiple resistance was also prevalent in S. Virchow and S. Hadar

In 1998 a well known US study showed that Salmonella typhimurium with five-drug pattern of resistance increased from 0.6 percent in 1979–1980 to 34 percent in 1996. leading them to conclude . Multidrug-resistant typhimurium DT104 has become a widespread pathogen in the United States. More recent figures do not seem to be available but Danish studies show a an elevated mortality from patients with DT104 strains - 4.8 times more likely to die than the general Danish population, compared with 2.3 patients with non drug resistant strains.