Episode 9- Carbapenem-resistant but cephalosporin-sensitive pseudomonas

Hello and welcome to Episode 9 of ER-Rx. A few days ago when I was reviewing cultures for patients discharged from the ER, I came across a very interesting strain of pseudomonas. Come to think of it, I also saw this strain one other time during my PGY-1 pharmacy residency training. This pseudomonas strain was carbapenem-resistant but was sensitive to all other antibiotics (namely cefepime, ceftazidime, fluoroquinolones (FQs), Zosyn, and tobramycin). In This week’s Pharmacy Consult episode, we’ll take a little dive into this interesting pseudomonas phenotype.

It is well known that drug-resistant bacteria are on the rise. Non-fermenting gram-negative bacilli (such as pseudomonas) are especially problematic due to the many resistance mechanisms that they possess or that they can acquire. Typically, pseudomonas can be treated by using beta-lactams, FQs, aminoglycosides (AGs), and we also have some less favorable options such as colistin, and Zerbaxa. We typically stick to agents such as Zosyn (piperacillin/tazobactam), cefepime, and ceftazidime. Carbapenems are the first-line agent against multi-drug resistant pseudomonas, but should not routinely be used for strains that are sensitive to other antibiotics mentioned. However, we have even seen an increasing rate of pseudomonas resistant to carbapenems, likely due to the increasing global use of these agents. These carbapenem-resistant strains are typically also resistant to other classes of antibiotics such as cephalosporins, FQs, and AGs. This is because pseudomonas can have several resistance mechanisms such as AmpC Beta-lactamases, cephalosporinases, carbapenemases, a change to their penicillin-binding proteins, over-expression of efflux pumps, and a decrease or absence of the OprD protein. The increase in efflux pumps and the OprD porin deserves some special attention as we will see shortly. The OprD porin in the outer membrane of pseudomonas facilitates the diffusion of carbapenems to their site of action. If we have less of this porin, or none of it at all, the carbapenem can’t get to its site of action.

The topic of today’s episode is carbapenem-resistant but cephalosporin-sensitive pseudomonas strains. This seems like such an odd entity because one would assume that if the organism is carbapenem-resistant, it is also resistant to many other antibiotics. We will look at 2 studies, one published in 2018 from Hungary and the other published in 2020 from China that looked at these particular pseudomonal strains in patients with UTIs and bacteremia, respectively.

In the 2018 UTI study, a total of 57 of these strains were reported over a 10-year period, so this is a fairly rare thing. About 60% of these strains were also resistant to FQs and 60% were resistant to the AGs gentamicin and tobramycin. Phenotypically, over-expression of efflux pumps was present in 50% of the strains and was the most common mechanism of resistance detected in this study. Only a minority of strains had both carbapenemases OR AmpC beta-lactamases in combination with efflux pump over-expression. Unfortunately, in 1/4 of the strains they were not able to verify the resistance mechanism, which was a limitation to this study. The authors assume that the down-regulation or deletion of the OprD porin was likely the mechanism of resistance in these other cases.

In the 2020 bacteremia study, a total of 63 such cases were reported over an 8-year period. 24% were resistant to FQs and 22% were resistant to AGs. None of the isolates possessed carbapenemases or extended-spectrum beta-lactamase (ESBL) genes–the over-expression of efflux pumps and decrease expression of OprD porin was likely the cause of this resistance pattern per the authors.

Who is at risk of getting these odd strains? The most prominent risk factors included 30-day readmission, total parenteral nutrition (TPN) use, central venous catheterization, hematologic malignancy, and prior exposure to carbapenems. The average age of these patients was in the low 60s and most of them were males with comorbid conditions. These strains are also associated with longer (lengths of stay) LOS and mortality rates; The median LOS was 30 days and the 30-day mortality rate was high at 27%.

In multiple studies, including the two we reviewed, cephalosporins such as ceftazidime and cefepime were recommended as viable treatment options. The authors stress avoiding jumping to other broad agents such as colistin due to its adverse event profile including neuro and nephrotoxicity and its difficult dosing strategies. Also highlighted is something that I am a very strong proponent of in my ER, which is to stop using carbapenems for patients that do not need them! This is especially an issue peri-operatively where providers will order carbapenems for intra-abdominal infections or as pre-operative prophylaxis. Giving one or two doses of carbapenems, although it may seem benign, can lead to the breeding of these particular strains which can impact our patients’ lives in the future- please be mindful of this.

In conclusion, although a rare occurrence, you may encounter this strain of pseudomonas in your practice site. These strains typically don’t possess beta-lactamases and remain sensitive to ceftazidime and cefepime. Possibly, they could also be sensitive to FQs, Zosyn, and AGs, as they were in my patient, but this will greatly depend on your site or your region’s antibiogram. The patients with these strains of pseudomonas are typically older and more complex with high mortality rates, so appropriate treatment with an agent showing sensitivity is very important; there is no need to jump to colistin or other newer agents such as Zerbaxa in this situation. Consultation with an ID pharmacist or ID physician in these cases is also appropriate, especially in more serious infectious such as bacteremia.

As always, thank you so much for your time. If you have any questions, comments, or anything to add to my discussion for this episode please leave a comment. We are now available on Apple Podcasts/ iTunes, Google Podcasts, Spotify, and even YouTube with more options coming shortly.