Losing the War on Resistant Gram Negatives

Extended spectrum beta-lactamases (ESBLs) have been a challenge to antimicrobial therapy since the 1980s. Enterobacteriaceae, Pseudomonas aeruginosa, Acinetobacter baumanii and many other Gram negative bacteria carrying ESBLs have disseminated globally. To compound problems, these organisms often carry multiple resistance genes. First detected as nosocomial infectious agents, much like MRSA, they are increasingly a cause of community acquired infections.

Resistance initially comes with a fitness cost. However, in the intestinal tract, all organisms with the exception of those inherently resistant bear this. A new equilibrium is established, resistant organisms in this environment aren’t competing against bacteria that are fully fit. Without the inherent risk of being outcompeted, resistant strains have time to evolve. Farmed animals are continuously exposed to sub-clinical doses of oxyimino-cephalosporins. The evolution of resistant strains in farm animals has resulted in the restoration of virulence and fitness. Laboratory produced resistant organisms are outcompeted by the host resistant flora. This has human health consequences. Salmonella Typhimurium DT-104 was a virulent and resistant organism transmitted via unpasteurised milk. With the raw food movement in America (and associated outbreaks) could this lead to the emergence fitter human strains?

Contrary to what is thought, efficient genetic mechanisms of carriage may protect MR-GNBs from losing acquired resistances. The most important mechanism is the integron. This should be thought of in lay terms as a resistance Swiss army knife. It’s costly to carry a tool box, but shared architecture allows efficient carriage. The shared architecture in this case is not a handle etc, but one that allows for sharing a common regulatory sequence. Similarly to the knife example, the most frequently used of these tools is located closer to the top. This sequence contains commonly useful tools like resistance to quaternary ammonium compounds and sulfamethoxazole. It is also flexible, allowing for new useful tools to be added, and less useful tools moved down.

Enterobacteriaceae which carry these integrons are more capable of acquiring ESBLs. One study found in E. coli there was a stepwise progression from ampicillin and sulphamethoxazole resistance (integron carried) to ESBL production. Community abuse of antimicrobials selects for these organisms and indirectly for multi-resistant nosocomial pathogens. ESBLs are transmissible. CTX- M producing organisms are observed to colonise entire families. Colonisation the intestine may last for up to 33 months, however knowledge is limited. Chronic antibiotic use may allow persistent colonisation with ESBLs. Improper use of antimicrobials in the community is a driving factor. We must make a culture of following sensitivity. However, the use of antimicrobials in agriculture will ultimately render this strategy alone ineffective. Dense, high antimicrobial use environments in hospitals will be reservoirs for ESBLs. Integron bearing Enterobacteriaceae will stably maintain resistance determinants, often alongside virulence factors. Without an integrated approach (human and animal health), the best that can be achieved is outbreak mitigation.

References

• Multiresistant CTX-M-15 ESBL-producing Escherichia coli in southern Sweden: Description of an outbreak. [PMID 19396721]
• Selection and Persistence of CTX-M-Producing Escherichia coli in the Intestinal Flora of Pigs Treated with Amoxicillin, Ceftiofur, or Cefquinome [PMC 2565910]
• The superbugs: evolution, dissemination and fitness [PMID 10066531]
• Multidrug Resistance among Enterobacteriaceae Is Strongly Associated with the Presence of Integrons and Is Independent of Species or Isolate Origin [PMID 12552449]