Resistance Issues and Resistance Factors With MDR Bacteria

Jason Gallagher, PharmD, provides an overview of the resistance issues and resistance factors of specific pathogens that develop multidrug resistance.

Jason Gallagher, PharmD: Among the multidrug-resistant bacteria, gram-negatives are a most pressing concern. And, of that, there are different issues with the different species that we see causing antibiotic resistance. For example, in the Enterobacteriaceae, we’re having issues with resistance to third-generation cephalosporins, to extended-spectrum penicillins, and, most recently, to the carbapenems. So, within the Enterobacteriaceae, Klebsiella species are the ones that are most commonly resistant to carbapenems, and that has been spreading worldwide, including in the United States. In E. coli, the most significant concern is extended-spectrum beta-lactamase production, which renders them to most beta-lactams, including third-generation cephalosporins. And the problem that I’m seeing most commonly in E. coli is that we’re starting to lose our oral antibiotics to treat E. coli infections, because when E. coli expresses genes that make it, that gives it the ability to create ESBLs. It typically also has genes that give it resistance to other oral antibiotics as well, such as fluoroquinolones and trimethoprim sulfamethoxazole. So, one of the most common infections seen in the community is urinary tract infections, and, unfortunately, the resistance to these oral options in E. coli has gone up significantly. And Enterobacter species, these are a tough bug to treat altogether. They are expressing increasing amounts of carbapenem resistance as well.

Pseudomonas aeruginosa is kind of the granddaddy of resistant gram-negative rods, and this is an ever-existent problem that we’re seemingly always dealing with. Multidrug-resistant Pseudomonas, between 15% to 20% in many hospitals in the United States, has been fairly consistent and has crept up somewhat over time. However, while we often have antibiotic options to treat Pseudomonas infections, those sometimes aren’t the best options that we would like to give, where we might have a carbapenem-resistant Pseudomonas where aminoglycosides could be an option. However, those are not ideal antibiotics for some infections like pneumonia, for example.

Probably the most resistant bacteria that we see causing infections in hospitals in the United States are species of Acinetobacter. Now, Acinetobacter is extremely drug resistant in many institutions, but the degree to which an institution has a problem with Acinetobacter is very institution specific. Some places will have basically outbreaks of Acinetobacter that will come and go and others deal with the problem more consistently.

Extended-spectrum beta—lactamase producing organisms, or ESBL producers, are resistant intrinsically through the production of this mechanism of resistance to most beta-lactams, including first-, second-, third-generation cephalosporins and some beta-lactam/beta-lactamase inhibitor combinations and aztreonam. The problem with this is that kind of rules out some of our best drugs for the treatment of many infections and leaves carbapenems for us to utilize. Now, carbapenems work well against these infections; however, they are essentially the broadest spectrum class of antibiotics that we have. And overusing them can lead to resistance to them, leading to the problem that we have very little options remaining for carbapenem-resistant bacteria, which have risen in the United States.

New Delhi metallo-beta—lactamase producing organisms, or NDM producers, are really kind of a perfect storm of resistance. It’s something that is very uncommon in the United States presently, and I hope that remains uncommon because we have very few treatment options against them. Even some of the newer beta-lactam/beta-lactamase inhibitor combinations that have been approved are not active against those organisms. Most concerning is that they are endemic in the region of the world where it sounds like they would be, in India and China where they can be isolated fairly commonly. While in the United States this is very uncommon, it’s probably just a matter of time before we see these infections more frequently.

The most common mechanism of resistance to carbapenems among the Enterobacteriaceae in the United States is through Klebsiella pneumoniae carbapenemases, or KPCs. KPCs are endemic in the northeastern United States, where they can be responsible for up to 10% to 15% of Klebsiella infections in areas where it’s very bad, to other parts of the country where they’re essentially almost never seen. But they’ve been reported in just about every state in the United States at this point. Now, when an organism produces KPC, it is extremely resistant to beta-lactams and essentially resistant to all of them, except for the new beta-lactam/beta-lactamase inhibitor combinations that have been recently approved.