Pleiotropy Might Help Slow The Evolution Of Antibiotic Resistance

Well, there’s a silver lining in a recently-discovered dark cloud.

Before we get started, let’s do a quick biology review. A serious health problem are carbapenem-resistant enterobacteriaceae (‘CRE’)–E. coli and relatives that are resistant to all antibiotics that start with ceph-, cef-, or end with -cillin or -penem (the beta-lactam antibiotics). To make things worse, these bacteria are usually resistant to most or even all other classes of antibiotics.

In the U.S., the most common form of carbapenem resistance is encoded by the KPC gene (‘blaKPC’), which confers resistance to all beta-lactams. The one weakness blaKPC has is when it’s faced with an inhibitor, such as ampicillin-sulbactam: the sulbactam inhibits KPC, so the beta-lactam ampicillin can kill the host. So, you might ask, why not use inhibitor combinations like ampicillin-sulbactam or amoxicllin-clavulanic acid (augmentin)? The problem is that most strains with blaKPC also carry genes that protect the bacterium from these combinations (such as blaTEM).

So the last-line treatment is a newer beta-lactam with an inihibitor, such as ceftazidime-avibactam. But then there’s that damn thing known as evolution. Which (finally) brings us to this recent article–don’t worry, I’ll translate it into English (boldface mine):

Ceftazidime-avibactam is a novel β-lactam/β-lactamase inhibitor with activity against carbapenem-resistant Enterobacteriaceae (CRE) that produce Klebsiella pneumoniae carbapenemase (KPC). We report the first cases of ceftazidime-avibactam resistance to develop during treatment of CRE infections and identify resistance mechanisms. Ceftazidime-avibactam-resistant K. pneumoniae emerged in three patients after ceftazidime-avibactam treatment for 10 to 19 days. Whole-genome sequencing (WGS) of longitudinal ceftazidime-avibactam-susceptible and -resistant K. pneumoniae isolates was used to identify potential resistance mechanisms. WGS identified mutations in plasmid-borne blaKPC-3, which were not present in baseline isolates. blaKPC-3 mutations emerged independently in isolates of a novel sequence type 258 sublineage and resulted in variant KPC-3 enzymes. The mutations were validated as resistance determinants by measuring MICs of ceftazidime-avibactam and other agents following targeted gene disruption in K. pneumoniae, plasmid transfer, and blaKPC cloning into competent Escherichia coli. In rank order, the impact of KPC-3 variants on ceftazidime-avibactam MICs was as follows: D179Y/T243M double substitution > D179Y > V240G. Remarkably, mutations reduced meropenem MICs ≥4-fold from baseline, restoring susceptibility in K. pneumoniae from two patients. Cefepime and ceftriaxone MICs were also reduced ≥4-fold against D179Y/T243M and D179Y variant isolates, but susceptibility was not restored. Reverse transcription-PCR revealed that expression of blaKPC-3 encoding D179Y/T243M and D179Y variants was diminished compared to blaKPC-3 expression in baseline isolates. In conclusion, the development of resistance-conferring blaKPC-3 mutations in K. pneumoniae within 10 to 19 days of ceftazidime-avibactam exposure is troubling, but clinical impact may be ameliorated if carbapenem susceptibility is restored in certain isolates.

The bad news is that resistance to ceftazidime-avibactam evolved, in one or two mutational steps. Worse, these changes occurred in the blaKPC gene (the particular variant of the gene, or allele, was blaKPC-3), meaning the last ditch therapy would fail. This is where pleiotropy–when one mutation alters multiple traits–turns out to be our friend. Most of the blaKPC-3 mutant alleles, while gaining ceftazidime-avibactam resistance, no longer confer resistance to carbapenems–they are no longer CREs (there also appears to be decreased production of the KPC protein as well). While it’s possible that we will see the emergence of ceftazidime-avibactam and carbapenem resistant blaKPC alleles, it appears pleiotropy might be holding that at bay for now: there currently might be a tradeoff between ceftazidime-avibactam resistance and carbapenem resistance.

And we need every break we can catch.

Article: Shields, R.K., et al. 2017. Emergence of Ceftazidime-Avibactam Resistance Due to Plasmid-Borne blaKPC-3 Mutations during Treatment of Carbapenem-Resistant Klebsiella pneumoniae Infections. Antimicrob. Agents Chemother. March 2017 vol. 61 no. 3 e02097-16. doi: 10.1128/AAC.02097-16

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