Multi-Drug Resistant Gram-Negative Bacteria and Novel Treatment Approaches - Episode 8
Ryan Shields, PharmD, MS: A prime example of institutional-specific prescribing is with the carbapenems. We’ve known for several years now that when we overuse or use a lot of carbapenems, we tend to select for more resistant pathogens, specifically carbapenem-resistant pathogens. Now, our carbapenem-resistant threats now include the Enterobacteriaceae, Acinetobacter baumannii, and Pseudomonas aeruginosa. Among each of these pathogens, the mechanism of carbapenem-resistance varies. Let’s start with the Enterobacteriaceae.
Predominately, we see carbapenem-resistance among Klebsiella pneumoniae. Here, like other Enterobacteriaceae, resistance is mediated by beta-lactamases. Specifically, carbapenemases, which not only hydrolyze carbapenem antibiotics, but they also hydrolyze other beta—lactam types of antibiotics. Now, a worrisome feature of carbapenemases is they exist on bacterial plasmids, which are mobile genetic elements that not only carry genes conferring resistance to beta-lactams, but oftentimes carry genes that confer resistance to other antibiotic classes. Because of this, we see multidrug-resistant pathogens. The other worrisome part about plasmids is they can be transmitted from bacteria to bacteria through horizontal gene transfer. So resistance can spread quickly by that mechanism as well.
Carbapenemases are also a major contributor of carbapenem resistance in Acinetobacter baumannii. But unlike the types of carbapenemases we see in Enterobacteriaceae, we see different types in Acinetobacter. These are predominantly called oxacillinases, or OXA-type enzymes, which also hydrolyze carbapenem and can be both found on the plasmid and the chromosome of the organism. Now, like the Enterobacteriaceae, carbapenem resistance in Acinetobacter is oftentimes associated with resistance to other antibiotic classes as well.
The final carbapenem-resistant thread is Pseudomonas aeruginosa, which varies from the previous two. Pseudomonas aeruginosa, keep in mind, has this outer cell membrane that’s much less permeable than, say, E. coli. Because of this, drugs like the carbapenems have to use porin channels to gain access into the periplasmic space of the bacteria. Decreased expression, or loss of these porin channels, can then mediate resistance to carbapenems because they can’t gain access to their target sites in the periplasmic space.
Pseudomonas is unique because there are many types of resistance that we find. So other contributors of carbapenem resistance could include increased expression of transmembrane efflux pumps, which pump the drug back out of the bacterial cell once it’s in. And a lesser contributor is derepression of AmpC beta-lactamases, which hydrolyze other beta-lactams and, to a lesser extent, carbapenems. Each of these factors then contribute to carbapenem resistance as a whole and in Pseudomonas, which makes this a very unique organism to treat.
Until recently, we’ve had very few options to treat multidrug-resistant gram-negative infections, including carbapenem-resistant infections. The agents we do have available to us are salvage agents like the polymyxins and colistin, the aminoglycosides, and tigecycline. We consider these agents salvage agents because they’re limited by at least one of the following factors:
No. 1, poor pharmacokinetics, the inability to reach adequate drug concentrations at the site of infection. No. 2, inferior efficacy, which we’ve seen now in meta-analyses data with tigecycline, specifically for the treatment of hospital-acquired pneumonia. No. 3, high rates of toxicity. We know the polymyxins and aminoglycosides are associated with nephrotoxicity to our patients. And finally, no. 4 is the emergence of resistance to these salvage agents. As we began to use them more often, we’re seeing increasing rates of resistance to them and also the emergence of resistance following therapy for our patients. This has resulted in several infections, which have now been documented in the literature, that are essentially untreatable, even with these salvage agents, because of the way we’ve used them. In the best-case scenario, we’re able to use these salvage agents as infrequently as possible and for as short of a duration as possible to treat our patients.
For carbapenem-resistant infections specifically, we’ve been forced to use them because of the lack of alternative agents. And what we’ve learned in doing that is that monotherapy with one of these salvage agents is largely ineffective. Through the studies that have been published thus far, combination therapy with salvage agents appears to be superior to monotherapy with one of these agents. Combinations, including a carbapenem plus one of these salvage agents, may be the best combination, but patient responses are still suboptimal. So, we truly need new antibiotics to treat these very resistant infections.
Now that we have new antibiotics available to us, it’s important that we’re able to use these new agents judiciously and as effectively as possible. One of the ongoing challenges we have in infectious diseases is the timely identification of resistant pathogens in the microbiology laboratory. Through standard microbiology procedures, oftentimes it’s 2, 3, or even 4 days into the infection course where we first identify a resistant pathogen and start the appropriate therapy for that patient.
Now, what’s exciting and moving forward is there’s a number of new rapid diagnostic tests that have been made available that will identify these resistant bacteria much earlier in the infection course. So, what’s really exciting is that we’re able then to use new drugs with new and improved diagnostics to tailor both of these methods to treat patients optimally, sooner, and with better antibiotics.
If history has taught us anything, once we introduce new antibiotics, we know bacteria will evolve and generate mechanisms of resistance even to the best new antibiotics we can introduce. So, it’s incumbent upon us as a community to be able to use these antibiotics only for the patients who can most benefit from them. In order to do that, these drugs are best regulated by antimicrobial stewardship programs and by infectious diseases clinicians who have the expertise to identify patients who benefit from them and who use these drugs most effectively for the right durations of time for the right patients.
My final take to the audience today is that we’re in a much better position today than we were 5 years ago. But moving forward, we have to make sure that we continue these efforts to use these drugs as effectively as possible, and for the right indications, so we don’t find ourselves cycling back into an era where we’re out of options once again.
My final take-home message to health care providers is that we’re in a much better position today than we were 5 or 10 years ago because of a number of efforts to develop new antibiotics and new rapid diagnostic tests to identify resistant bacteria sooner. Moving forward, it’s important for us as health care providers to use these drugs for the right patients and the right indication and also partner them with rapid diagnostic tests to identify infections sooner so that the longevity of both the test and the drugs can be preserved for future patients.
Transcript edited for clarity.