The Antibiotic Resistance Trade-off: A Hospital Outbreak
A hospital ICU experiences an outbreak of carbapenem-resistant Klebsiella pneumoniae (CRKP). The strain carries a plasmid with the blaKPC gene, which encodes a carbapenemase. The plasmid also carries genes for resistance to aminoglycosides and fluoroquinolones. In the absence of antibiotics, the CRKP strain grows 15% slower than the susceptible strain in culture. The hospital implements a policy to restrict carbapenem use and instead uses colistin, to which the CRKP is susceptible. After six months, the incidence of CRKP infections drops by 50%, but a new colistin-resistant strain emerges. The new strain has a mutation in the mgrB gene, which modifies lipopolysaccharide, reducing colistin binding. However, this mutation also increases susceptibility to human defensins. The infection control team asks: (1) Why did CRKP decline when carbapenems were restricted? (2) What is the likely fate of the colistin-resistant strain, and how should the hospital respond?
1. Explain the decline in CRKP infections after carbapenem restriction, using the concept of fitness cost and selection.
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The CRKP strain carries a plasmid with resistance genes that impose a fitness cost; in the absence of carbapenems, it grows 15% slower than susceptible strains. When carbapenems are used, they kill susceptible strains, giving CRKP a strong selective advantage. When carbapenems are restricted, the selective pressure is removed, and the susceptible strains, which grow faster, can outcompete CRKP. This reduces the CRKP population and thus the incidence of infections. The decline is due to the reversal of selection: without the antibiotic, the fitness cost of resistance reduces the bacterium's competitiveness. However, the plasmid may be maintained if it also carries other resistance genes that are selected for by other antibiotics (e.g., aminoglycosides, fluoroquinolones), so the decline might not be complete if those antibiotics are still used.
2. What is the likely fate of the colistin-resistant strain? Consider the trade-off between colistin resistance and susceptibility to defensins. How should the hospital respond?
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The colistin-resistant strain has a mutation (mgrB) that reduces colistin binding but also increases susceptibility to human defensins, which are part of the innate immune system. This creates a trade-off: in the presence of colistin, the mutant is favored, but in the absence of colistin, it may be less fit because defensins can kill it more effectively. If colistin use is reduced, the mutant's advantage disappears, and it may be outcompeted by strains that are susceptible to colistin but more resistant to defensins. However, if colistin is the only available treatment and is used heavily, the mutant could spread. The hospital should avoid overuse of colistin, use combination therapy, and implement strict infection control to prevent transmission. They should also monitor for the emergence of colistin resistance and consider alternative strategies, such as phage therapy or new antibiotics. The key is to balance the use of last-resort antibiotics to minimize selection for resistance while ensuring effective treatment.