This StAR episode features the CID State-of-the-Art Review on ##.

Our guest stars this episode are:

Arsheena Yassin (Robert Wood Johnson University Hospital)

Mariya Huralska (Robert Wood Johnson University Hospital)

Journal article link: Yassin A, Huralska M, Pogue JM, Dixit D, Sawyer RG, Kaye KS. State of the Management of Infections Caused by Multidrug-Resistant Gram-Negative Organisms. Clin Infect Dis. 2023;77(9):e46-e56. doi:10.1093/cid/ciad499

Journal companion article - Executive summary link: https://academic.oup.com/cid/article/77/9/1223/7408674

From Clinical Infectious Diseases

Episodes | Consult Notes | Subscribe | Twitter | Merch | febrilepodcast@gmail.com

Febrile is produced with support from the Infectious Diseases Society of America (IDSA)

Hi, everyone.

Welcome to Febrile, a cultured podcast about all things infectious disease.

We use consult questions to dive into ID clinical reasoning, diagnostics,

and antimicrobial management.

I'm Sara Dong, your host and a MedPeds ID doc.

I hope everyone is settling into the new academic year nicely.

I just thought I'd put out a quick call for volunteers message.

As a little reminder, Febrile is a pretty small operation and it is always improved

by our guests who come to talk about ID.

I am looking to highlight people on the show.

I welcome any ideas that you have and I am definitely in need of new cases and topics

for us to cover in the coming months.

It is really just as simple as emailing me at febrilepodcast@gmail.com.

If you want to be on an episode, have a recommendation or another idea,

especially for fellows, trainees and junior faculty, I think this is a really

great way to make your work count twice.

If you have a topic that you've previously presented on and it helps support

Febrile to keep us running , and if you're interested, but you don't have

an idea, I can brainstorm with you.

Thanks for letting me make that little plug.

Okay.

So back to business.

We are here with another Febrile StAR episode.

These feature topics and authors from the CID, Clinical Infectious Diseases

journal, State of the Art Reviews.

We've been spending the past few months getting caught up and still have a few

upcoming episodes, including this one.

Today, we have two guest stars here to discuss multidrug

resistant gram negative infections.

Hello, everyone.

I'm Arsheena Yassin.

I'm an ID pharmacist at the Robert Wood Johnson University Hospital in New

Jersey, and I'm excited to be here today.

Hi, everyone.

My name is Mariya Huralska.

I am an infectious disease fellow at Robert Wood Johnson,

and I work with Arsheena.

I'm also really excited to be here.

I really love the Febrile podcast.

As everyone's favorite cultured podcast, we always start off by asking

if you'd be willing to share a little piece of culture or something that,

uh, brings you joy or happiness.

You know, as the weather is getting warm, I actually saw a lot of sunlight

yesterday, so I'm looking forward to being outside more, but the music

is something that I really enjoy and something that I, you know, listen to

on my downtime, whenever I'm coming home from work or on the weekend.

And I like all types of music, depending upon my mood that day.

Yeah yeah it's nice, well depending on when this gets released, it's

flower blooming season outside, even though it's raining for me today.

It's very nice.

Mariya, what about you?

So one of my favorite shows right now that I'm watching with my mom, it's

called Servant of the People, and it's on Netflix, and it stars President Zelensky

from Ukraine and it's about a teacher who goes on a rant about politics and

corruption and his video goes viral and then he becomes president and then he

actually becomes president in real life.

And I just really love it.

It's a very satirical commentary on the disconnect between corrupt

politicians and the people that they're supposed to be serving.

So I really love it and I highly recommend it.

Nice.

So we're gonna walk through a case that also is featured in the review as well,

but just to talk through some of the key concepts that you covered in the article.

So I'll jump in with our case today.

We have an 82 year old female with hypertension, diabetes, CKD,

and a recent ruptured cerebral aneurysm, status post embolization,

so that was about 2 months ago.

She is transferred from a nursing home to the emergency department due to

hypotension and fevers, as well as one week of coughing and pleuritic pain.

She had received five days of piperacillin tazobactam at the nursing facility

without improvement in her symptoms.

And we'll note that that recent admission related to her cerebral aneurysm, she

was admitted for 10 days in the ICU and was overall in the hospital for 18 days.

And so during this time, she was treated for a ceftriaxone resistant E.

coli UTI with seven days of pip-tazo [piperacillin-tazobactam].

And then in the interim, she has also had one other reported UTI that was

treated with seven days of levofloxacin.

This time she's dyspnic, she's hypotensive, 80s over 40s, heart

rate's 120 and is febrile to 101.

2.

Her oxygen saturation is 86 percent on room air and she has

crackles at the left lung base.

For a little more objective info, her lab showed a leukocytosis

to 18, lactate of 4, and a serum creatinine of 3 from a baseline of 1.

5.

Her chest x ray demonstrates a dense infiltrate on the left side and she's

continuing to deteriorate and now is intubated and requiring a norepi drip.

Two sets of blood cultures and respiratory cultures are cooking in the lab.

So this is a pretty common scenario, the ICU or ED calls you, they're

asking, what empiric therapy to start.

So I was hoping you could walk us through how to approach this type of case,

and then what gram negative targeted antimicrobial you'd want to start?

For us in ID, it's getting a really good history on our patients is really key

because we're thinking about how to tie this into what pathogens we need to be

concerned about, and also how likely this patient is to have resistant organisms and

then be able to tailor our antimicrobials to the pathogens we are concerned about.

When we are seeing these patients that are coming in, and especially

when you are concerned about resistant gram negatives, is really trying

to see where that patient has been.

So some of this was also presented in the case, but really looking to see

what antibiotics this patient has been exposed to, which facilities and exposure

this patient has had, what infections this patient has, had past micro.

When I'm evaluating a patient that's coming in with a suspected resistant

organism infection, there's a systematic way that I evaluate high

risk risk factors, is what I call them.

So, firstly, where's the patient coming from?

Is the patient coming from the community, meaning from home?

or are they coming from another facility and the facility is also important.

So are they coming from a different hospital and they were only in that

hospital for a couple of days or are they coming from an ICU part of that

hospital where they were already trached or ventilated for a month and now they're

being transferred to your hospital.

Or are they coming from a long term care facility, which that in itself is

a pretty strong risk factor for having a resistant organism, especially if

they have foreign indwelling devices.

So a trach is a big one, chronic indwelling catheters,

long term PICC or midlines.

Those are all risk factors for having resistant organisms,

especially in the bloodstream.

I always review the prior culture results, I usually look about a year out.

You don't have to go a year out, but it is important to look at least within the past

30 days, I would say, to see if they've ever been in that hospital and if they've

ever grown anything resistant in the past.

Now that doesn't mean necessarily if they've grown a resistant organism

in the urine, let's say six months ago, that that is the exact same

organism that is presenting in our patient as a cause of her pneumonia.

However, knowing that this patient has grown a very resistant organism

even in the urine six months ago tells you that this patient is

colonized with this organism or could be colonized with this organism.

And so again might push you into starting broader therapy early.

And lastly, travel history, I think could be an overlooked risk factor, but

it's also really important, especially when we're talking about NDM organisms.

So recent travel to India is a really big risk factor that you

don't want to miss finding out about.

Other MDR Enterobacterales have been observed in southern Asia, South

America, and northern Africa as well.

Getting a good travel history, especially within the past month, I would say, um,

and if that patient is then coming in with a severe infection, you want to know the

epidemiology of the resistant organisms to the relevant country that they've traveled

to because that again may increase your pre test probability of this patient

being sick with something very resistant.

Yeah, and then just piggybacking off of the risk factors, the two that the

IDSA's AMR document really highlights is previous antibiotic exposure and

the past cultures, like Mariya said.

And then there are others that have been studied, such as advanced age,

other comorbidities, such as being immunosuppressed, being bedridden,

et cetera, that may put these patients at high risk for infections.

When you look at the studies that were done to look at which risk

factors we can use to really estimate the probability of a patient having,

whether it be a carbapenem resistant Enterobacterales or a difficult to

treat Pseudomonas, they've all been very different, including various patient

populations, various infection source.

So just being aware of the other risk factors that may play a role

in that patient presenting with drug resistance is important.

Locally at one of my previous hospitals, we really tried to see of the models

that were published, how we can use them in our patient population to

distinguish who will have a carbapenem resistant Enterobacterales or not.

And they really sort of varied in how they were able to predict those

infections in our patient population.

As ID fellows, we're usually the ones kind of seeing the patient first.

So when you're seeing a patient who potentially might have a resistant

gram negative infection, especially based on their history, it's really

important to figure out where their source might be because the source

will then change what antibiotics you use with respect to locations.

For example, if you're thinking that it might be a CNS

infection, you need CNS dosing.

If you're thinking that it might be a GU infection, then you need

an antibiotic that has good renal penetration and so on and so forth.

So in this case, she's coming in dyspneic.

She is hypoxic and eventually becomes intubated.

So I'm thinking that it's probably a respiratory source.

We already have a chest x ray.

We know that she has a left infiltrate, and so she gets intubated.

When you're working someone up, it's always really, really important

to get a good sample from wherever you think the infection is.

So if she's getting intubated and she has a lot of secretions, I would either

hope to get secretions to culture at that time or maybe down the line

when she's a little bit more stable.

We already have a CBC and I would want to get a CMP to look at

her kidney and liver function.

That will be helpful also in the future for antibiotic dosing, Say she has an AKI

or shock liver or something like that.

We would want to know that information for the future.

Lastly, you know, when choosing an empiric antibiotic, especially

when it's broad, you want to look at how sick is the patient.

So, you know, is the patient coming in with a diabetic foot ulcer and

you have some time to think about it and maybe even hold antibiotics

before you can get cultures?

Or in this case, she's coming in very sick, intubated almost right

away, and she started on pressers.

We don't have a lot of margin of error in this case.

We can't afford to be wrong.

And so if I were to have a patient like this where I'm asked what I start,

I would be more inclined to allow myself the freedom to go more broad

because again, we don't have the luxury of being wrong in this situation.

Now, specifically looking at when we're choosing an empiric regimen for

our patients, Where we're concerned about multidrug resistant infections.

Here I'm mainly talking about those gram negative infections where

you have resistance to one or more antibiotics in three or more classes.

When we're thinking about these patients, and as Mariya highlighted

, just looking at these three factors, looking at the local epidemiology,

looking at the patient specific risk factors and then also looking at the

acuity of illness for that patient.

So now I'll go into briefly, just more focusing on the local epi.

So when we're looking particularly at multi drug resistant gram negatives,

resistance really varies locally, globally, even within a hospital.

It's really important when you're looking at your patient, where

did that patient infection start?

Because the way we approach that patient is going to be different from whether

they're coming from the community versus coming from a facility versus

someone that's sick in your ICU or the floors, because again, the resistance

pathogens, the exposure that the patient has really varies from that location.

And one helpful tool that we in ID love to use are our antibiograms.

Most hospital has a local antibiogram.

It's not always easy to get antibiograms from a facility or somewhere else

that the patient's coming from.

And if you're so lucky, you may also have antibiograms that are syndrome

specific or even unit specific.

And all of this information is just very helpful.

Because it sort of gives you an idea as how well your agents

are against that particular pathogen you're concerned about.

So let's say we want to cover for Pseudomonas, for example.

And generally, you're thinking about using your backbone drug, cefepime.

You can look at your antibiogram and say, hey, how well does cefepime cover

this pathogen that I'm concerned about?

And depending upon the susceptibility rates in your antibiograms, you may

lean towards choosing cefepime or using something else, depending upon

that susceptibility rates within your antibiogram, if you're able to

get the nursing home antibiogram.

So this is all just very helpful information for us to use when we're

trying to choose which empiric regimen to use for that particular patient.

Just something to note, depending upon your hospital, and I think

this is probably true for most hospitals here within the U.

S., our antibiograms are almost always outdated.

It's usually based on microbiology results from the year prior.

So, for example, at our hospital, we're now creating our 2023 antibiogram.

It's not the most up to date information.

It's helpful, but it's just really important to be aware of some of these

downsides with using your antibiograms.

Also, another thing is that when you're looking at your antibiograms, you may

have changes in certain breakpoints.

So, the Clinical and Laboratory Standard Institutes, they're normally the ones that

review and set a lot of breakpoints for various antibiotics for various pathogens.

But there's often a lag from when they would suggest breakpoint changes to

when that actually happens in the lab, just updating all of those panels.

So when there are changes in breakpoints, it's just really important to communicate

to your micro lab to come up with a game plan on how to report those

susceptibility results and also how to incorporate that maybe when you're

creating your antibiogram as well.

And just briefly talking about specifically looking

at gram negative infections.

Here within the U.

S.

You know, most of the gram negative resistance that we see, it's

usually, you know, ESBL organisms.

So, 2020 CDC data shows about over 20 percent of hospital E.

coli are resistant to third generation cephalosporin and also Pseudomonas.

Those are, you know, two major pathogens that most hospitals would commonly see.

But when it comes to carbapenem resistant Acinetobacter, or difficult to treat

Pseudomonas, so these are pseudomonal strains that are resistant to most of

the commonly used antibiotics . This is often very rare that we would need to

cover empirically for patients, unless you're in an area where there is a

recent outbreak, for example, maybe a nursing home has a recent outbreak of

one of these pathogens, or even locally as well, or if they're just endemic

to maybe the area that you're in.

So, it's really important just know your local epi and also be

aware of trends that are happening within your community as well.

But most of the time, we usually do not have to cover these agents

empirically, unless you have a really strong suspicion for those pathogens.

But other than that, it's really covering those ESBL organisms,

Pseudomonas, and when it comes to CRE, it really depends upon the

area in the United States you're in.

I know the resistance that we see here in New Jersey may be different from

other places within the country, and then also the various strains within the U.

S.

It's mainly KPC right now.

But they're also, this is really changing as well.

And then also, this sort of ties in especially for your travelers.

So, in our example case, just based on her risk factors and her previous cultures,

we decided to cover for Pseudomonas just because she has previous hospitalization,

a recent past antibiotic use.

Also decided to cover for MRSA just based on those risk factors as well, following

the latest IDSA pneumonia guidelines.

And also because she's coming in pretty sick and has past cultures

with ESBL E coli, it was decided to cover for those as well.

And just based on the antibiogram, the empiric regimen that

was chosen was meropenem.

Based on the antibiotic, we're making sure we're covering for susceptible, usually

susceptible, not difficult to treat Pseudomonas and also that ESBL pathogen.

Vancomycin to cover a risk for MRSA and also just adding on an aminoglycoside

to help increase just based on meropenem susceptibility patterns in the hospital

and in the nursing home to really help expand that gram negative coverage

for better coverage of Pseudomonas.

Now, if for example, we chose not to cover and start this patient out

on one of the the newer agents, and here newer, I'm talking about

agents that we'll generally be using for carbapenem resistant pathogens.

And this is mainly because she did not present with past

cultures for these pathogens.

If for example, she, she did, we had a urine culture with a carbapenem resistant

Enterobacterales or she's coming from a facility that has recent outbreak or,

this is very common within their facility to have patients with these pathogens.

Or she's coming, maybe had a recent travel to an area where these pathogens

are endemic, then we would generally have a much lower threshold to start these

patients on one of the more targeted agents to cover those resistant pathogens.

And Arsheena kind of already touched on this, but let's say I have a septic

patient and she's coming in on pressors.

, is being intubated.

Maybe she's coming in from a long term nursing home facility,

but she has no history of resistant organisms in the past.

I've reviewed her micro cultures, I don't see anything.

Or let's say she's really never even been hospitalized.

I really would not be reaching for the newer agents in this case right away.

I would be relying on my local antibiogram that I always carry in my pocket.

And so in our cases, we have choices of antibiotics that we can

use based on whether the patient is in the ICU or whether the

patient is somewhere on the floor.

So in our case, a patient that's in the ICU that I would like to cover for a

severe infection, I would choose cefepime based on our local antibiogram, . but

I still would like to go broad because of how sick she is, tying it back to

what we talked about before, where the margin of error is small and I

can't afford to guess incorrectly.

Yeah, and, especially in these cases where patients have no real risk factors for

resistant pathogens, it's really helpful to use your local antibiogram to see how

well your backbone therapy is working.

For example, your backbone gram negative is the cefepime for your

hospital, and cefepime covers more than 90 percent of your gram negatives,

including Pseudomonas, depending upon how sick the patient is, you may

be okay with using one agent or not.

But it really depends on the patient as to what margin you're okay with,

but let's say you have maybe cefepime susceptibilities are in the 70s.

That's really when you want to consider adding on a second agent

to really increase that gram negative spectrum for that patient.

And then the opposite spectrum of the scenarios, you have a patient coming

in with, let's say, a diabetic foot ulcer and that ulcer's been there for

many weeks and the only reason the patient's coming in is because his sister

said, you're going to the hospital.

Meaning there weren't any preceding signs of sepsis, the patient wasn't

having chills or rigors at home, there wasn't increased drainage, it's

mainly a just situational admission to the hospital for a long term,

probably diabetic osteomyelitis in a patient who's otherwise stable.

Um, but, I review his cultures and I see that previously he's been admitted

for this ulcer before and he's had debridements before and he actually has

grown carbapenem resistant Klebsiella.

Am I reaching for a newer agent?

Probably not, at least not at this stage, because again, the overarching theme

here is that the patient is stable.

He's not having fevers, he's not having chills, rigors, he's hemodynamically

stable, and I have time to wait until we consult our surgical colleagues

so that they can get us really good specimens, and then we can send that off

to the lab and tailor our antibiotics based on what grows this time.

Um, so I may consider not starting anything despite the fact that

I know that he's grown very resistant organisms in the past.

So, I can briefly talk about optimizing the dosing for patients when we're

looking at Gram negative infections, and, the IDSA's AMR document is a

readlly helpful tool based on the resistance that you're seeing to

help choose the empiric regimen.

And also, it has a helpful table there on how to dose these

antibiotics for the resistant pathogens that you're concerned about.

Now, oftentimes, when we have patients and we're starting them on an antibiotic,

it usually involves beta lactams.

And especially in our very sick patients, really we just want to be careful on

how we're dosing to make sure we're using appropriate dose, especially

in our ICU patients where there may be altered volume distribution, their

clearance may be changing, they may be on continuous renal replacement therapy, etc.

So just taking all of these things into consideration when we're dosing

antibiotics and just making sure that we're using the appropriate dose

for a particular patient based on the pathogen we're concerned about.

Now, oftentimes specifically when we're using beta lactams, we can

either give them intermittent, so for example, infuse over 30 minutes, or we

can give it by a prolonged infusion.

So most of our beta lactams, after you give a dose, you have this high

concentration and peak, and usually with that short half life, you may have

a decrease in concentration eventually leading to concentrations below the MIC

of the pathogen you're concerned about, and this may lead to decreased efficacy

of the drug and even regrowth of those organisms and potential resistance.

If we prolong that infusion of the antibiotics, so giving piperacillin

tazobactam instead of 30 minutes over 4 hours, you're having a more constant

concentration in the blood above the minimum inhibitory concentration, and

really it's a way to help enhance the efficacy of that drug, decreasing the

resistance based on specific parameters.

And this is something, especially when we're looking at resistant gram negatives

that maybe have higher MICs, using this prolonged infusion to really help target

those higher MICs are useful tools.

Now, when it comes to clinical outcomes and use of prolonged infusion antibiotics,

mainly it's been retrospective studies that have shown mortality benefits,

particularly in really sick patients with documented Gram negative bacteremia.

It really has not shown in a lot of more retrospective studies.

But just based on the pharmacokinetic properties of the medications, the

international consensus guidelines on prolonged infusion beta lactams

really recommends using prolonged infusion if possible, especially for

those patients where you're looking at resistant gram negatives, especially

in patients that are critically ill.

Now, for in our example patient, that patient will also be started

on usually vancomycin, as you mentioned, as well as aminoglycoside.

And part of the monitoring for these antibiotics, as a lot of

our pharmacists like, will involve therapeutic drug monitoring.

And this involves measuring a concentration of the drug within the body.

And then being able to really calculate to see if your drug is

reaching its efficacy target and also as a way to help decrease toxicity.

So, very commonly in most hospitals, this is done for

aminoglycosides and vancomycin.

Not really done for beta lactams, but it is done in certain centers within the U.

S.

But I do think if you are using a beta lactam in a patient that's just you know,

their, their clearance may be different.

So patients with extremes of body weight, our CF patients, if your

patients are on ECMO or continuous renal replacement therapy, if your

patients are having side effects from some of these medications, for

example, of neurotoxicity from cefepime.

Or, if you're using, you know, you're stuck using beta lactam for a pathogen

with a higher MIC, this may be an area to incorporate using therapeutic

drug monitoring with our beta lactams to make sure we're reaching our

efficacy and as well as safety targets for those particular antibiotics.

And, we're getting more and more resistant pathogens.

We now have a large amount of various antibiotics to use and which

one to use for certain resistance genes will just become more and

more confusing in the future.

But really just involving an ID or maybe a stewardship specialist within

your hospital to really help guide that we're using these drugs for the

appropriate indication, and we're using it for the appropriate pathogen as well.

That's a great summary.

I mean, I think some of the points that you guys made of general considerations,

are obviously good for this case, but they're probably good for everything in

ID, like what's the source of infection?

What bugs do we think are there?

And like Mariya talked about the consequences if we don't have the

correct combo of antibiotics initially.

So at this point in our case, let's say, we have a working diagnosis

that our patient has a pneumonia.

The patient was empirically placed on vancomycin, meropenem, and tobramycin.

We mentioned some risk factors for MDR gram negative infection, so recent

antibiotic exposure and hospitalization.

And after some chart review, you also learn that she has had previous cultures

or colonization with the likely ESBL E.

coli.

You are lucky enough to get a little bit of information from her local nursing

facility antibiogram, which showed that Pseudomonas susceptibility to meropenem in

the ICU is 75 percent on that antibiogram.

So again, another, another place that we're often called, empiric therapy

has been started in this patient.

You have sort of pending partially returned diagnostic results.

And we are asked to help think about how do we adjust the antibiotic regimen?

Can you talk a little bit about some of the cautions or things

to think about related to sort of traditional testing and whether or

not we may have rapid diagnostics that can help impact our management?

Yeah, I can sort of start here, you know, especially when we're starting

broad antibiotics for our patients.

I'm wearing my stewardship hat right now.

It's really important for us to get additional testing, utilizing

rapid diagnostic testing, if you have that available, so you're

able to get your answers quickly.

And this really allows us to be broad when we need to be broad and then

be able to taper and streamline our antibiotics in a timely manner,

so we're not giving these patients unnecessarily broad antimicrobials.

Now specifically looking at our traditional culture methods, right now,

most laboratories in the United States, if you obtain blood cultures, those blood

cultures will then go to lab, has to be incubated, and then maybe within a couple

hours or a day or so may become positive.

And then, the techs are able to do gram stain results, and you're able to see

the gram stain and be able to tailor results based on the gram stain results,

which are negative or gram positive.

Then, that culture is then plated out and then further incubated for growth.

And once there's growth, usually most laboratories use susceptibility testing

panels such as Phoenix or Microscan to do identification susceptibilities.

Overall, for even a susceptible pathogen, it takes about three

days to get ID and susceptibility.

Now just think about that for resistant pathogens.

It's going to be much longer, especially, for example, if you are treating

a difficult to treat Pseudomonas.

So, on day three, when you have all your results returning, then there's

additional testing that has to be done on other antimicrobials, the newer

antimicrobials, and then that again delays that time to final susceptibility results

and really for us to be able to know if we're treating this patient appropriately.

Now, there have been some panels that are updated with some of the newer agents, so

when I say newer, it's really relative, but more of those agents that we use

for carbapenem resistant gram negatives.

So, some panels include ceftolozane tazobactam, ceftazidime avibactam at

this point, and it's really important to know what your micro lab has.

So when you have a patient that's coming in or you're in a hospital

that sees a lot of resistance, just so you're able to really decrease that

time to final susceptibility results.

For us, we, we do have some cases where we do see quite a

number of resistant pathogens.

So we worked with our micro lab to have reflex testing done.

So if there's a pathogen that tests resistant to particular antimicrobials,

certain antimicrobials are automatically tested without us even having to call the

lab and that just helps us with decreasing our time to final susceptibility

results and hopefully decreasing that time to appropriate antibiotic use.

And then to expand a little bit more on what Arsheena said, so she talked

about traditional culture testing and rapid diagnostics is a way that we can

test for possibly resistant organisms and then can get resistance patterns

in these organisms a lot quicker than traditional culture methods.

Like Arsheena said, with culturing, it might take 24, 48 hours or longer

to grow an organism, but with rapid diagnostics such as Accelerate Pheno or

Maldi TOF or Varigene for Gram Positives, we can get those results much quicker.

So one to eight hours.

Our lab, we can get the identification of an organism within three hours, and

we're usually expecting to get some kind of susceptibility results, at least

the earliest ones, within six hours.

So much quicker than with traditional culture results.

And so in these cases where patients are coming in septic, very sick,

intubated, and we're concerned for septic shock, losing time is detrimental,

waiting for cultures to grow, especially if you don't know how broad

you should go with your antibiotics.

So from the infectious disease fellow standpoint, I'm already

calling the micro lab pretty much as soon as I see the patient.

And firstly, I'm telling them, Hey, I have a concern for a

multi drug resistant organism.

Could you please, in addition to the early susceptibility antibiotics on the

standard panel, could you also please add the newer agent as well so that I'm not

losing time waiting for them to then add it on once it does come back resistant.

Yeah, and luckily for us, we have a lot of rapid diagnostic tools that we're

able to use for our patients, and I think this is just going to be more

and more common as we're seeing more resistant pathogens and using more of

these tools, I think it's really important to tie these results with some sort

of ID or stewardship feedback as well.

It's very difficult for frontline providers to understand the

results of these rapid diagnostic tools and how to use them.

So, for example, we have CARBA 5 that's being done for patients where

isolates test carbapenem resistant.

As you can tell, if something comes back, OXA positive, the primary team usually,

they don't understand how they should be tailoring regimens for these patients.

So currently, at our institution, when these results are positive, the

ID stewardship team, the ID fellows are made aware, and we sort of have

a schedule to call the team and make them aware to adjust antimicrobials.

So we're really utilizing the rapid diagnostic tools to decrease that

time to appropriate antibiotics.

And I know like multiple studies that have been done in the past,

really showing mortality benefits in using these tools in this way.

And it's also important when we talk about resistant gram negatives, how to

interpret an ESBL pattern in a isolate of E.coli that is ceftriaxone resistant or

pathogens with inducible AmpC resistance.

Because again, it's, it's something that may be familiar to us in ID, but

the teams will you know, not aware of what the meaning of these and usually

choose something that says susceptible on the panel that's being released.

Later in that day, after antibiotics have been started, we learned that the blood

cultures have returned positive for gram negative bacilli in two of two sets.

The rapid diagnostic results one hour after this showed Klebsiella

pneumoniae with the KPC gene detected.

So the patient was adjusted to meropenem vaborbactam.

So, about two days after this, the susceptibility results confirmed the

organism was resistant to standard antimicrobials, including meropenem,

but susceptible to tobramycin based on updated CLSI breakpoints.

Reflex susceptibility testing was done due to the resistant meropenem

result and showed us susceptibility to ceftazidime avibactam, imipenem

relebactam, and meropenem vaborbactam.

And in addition to these, our respiratory cultures also did show a carbapenem

resistant Kleb pneumoniae as well.

The patient has defervesced.

They are extubated over the course of the next 72 hours.

And so now we are being asked, well, what should we do for a duration of therapy?

Okay, so I can I can get started on kind of monitoring the patient first.

Well, when we start the broad spectrum antibiotic, so mero-vabor in this case,

we always want to make sure that we monitor and see signs of improvement

as in most infectious diseases.

So in her case, her fever curve improved and most importantly,

she was able to be extubated.

So, in our case, we picked the site of infection correctly.

We picked the right antibiotic and very quickly she was

able to come off of the vent.

However in other cases, especially in let's say intra abdominal

infections, which become a lot more complicated situations where duration

of therapy is not defined and it's really dependent on source control.

In those instances and or in cases where patients are intubated on top

of that and can't tell you any signs and symptoms, you're stuck kind of

monitoring things like, again, fever curve, but also sometimes lactate

and procalcitonin can be helpful.

Although those markers can be a little bit controversial and they're more

taken in the context of the patient.

So in this case, she's getting better and duration of therapy.

It's important to understand that with resistant gram negatives, IDSA

does not recommend extending duration of therapy just based on the fact

that the organism is resistant.

What's most important in terms of duration is, is the patient getting

better, and is the patient responding to the antibiotic that we've chosen.

Another key part of your review and really all of these state of the art reviews

that I wanted us to end on is how to use multidisciplinary approaches to not

only manage patients in the hospital, but also to help ensure they have a safe

transition to the outpatient setting.

So in our example in this case, the patient is ready for

discharge back to her facility.

It's about hospital day five, but you get a call that the facility

does not have meropenem vaborbactam.

They're not sure if they can get it.

So maybe as you talk about how you might handle the situation, you could

give us some insight into who is part of this multidisciplinary team that

is trying to help the patient get to a safe discharge from the hospital.

So from the clinical side, when we've said as consultants, okay, we would

like for this patient to go on this newer agent, probably the very first

people that we're consulting is, of course, case management, and I mean,

we always have our ID pharmacist on board with us, but I think those two

people early in the discharge process are really important because, you have

to make sure that the place that you're sending this patient to on this newer

agent or any really broad agent spectrum agent is available at the facility.

And so the social worker and the case manager, and in some cases, ID

pharmacist can help ensure that when the patient gets to the facility,

there is no delay in treatment because the antibiotic is or isn't available.

Additionally, we always want to send patients on an antibiotic that is

given the least amount of times.

If anybody's had to take antibiotics multiple times a day can appreciate that,

in theory, it doesn't sound like a big deal, but in practice, it can be very

challenging, especially for patients who already have other comorbidities going on.

So we really try to minimize the amount of times that the patient

receives the antibiotic per day.

Less frequent dosings are favorable.

There are studies that have found that OPAT regimens that are dosed once or twice

daily are closely associated with better adherence, than more frequent regimens.

And then, of course, whenever possible, we always try to consider oral agents.

Now, in very resistant organisms, that's almost never an option, but if we can,

we always consider sending the patient on an oral agent to minimize complications

from PICC lines or midlines that may further downline cause more infections.

Yeah, just just piggybacking off of the multidisciplinary team it's

really important to get ID involved, especially early in these cases

to really see and help determine the duration of antibiotics.

So, does that patient really need an additional 7 days of these agents outside

at a hospital and really determine what the correct duration is and if

those patients can switch to oral.

And then also to, especially if you're going to be on, for example, 6 weeks

of antibiotics after discharge, really making sure that we have the appropriate

labs are done and someone is following that patient outside to make sure

that you're having no toxicity and you're having clinical improvements.

And, the usual monitoring, especially for most antibiotics

is usually weekly CBC and CMP.

if you're giving maybe vancomycin, also therapeutic drug monitoring is needed.

So, I really think it's key to, to really have a broad team involved

when discharging these patients to make sure all of that is

really communicated on discharge.

And other members, if you have these in your hospital are OPAT liaisons,

your transition to care pharmacist that can work magic to help you get

some of these antimicrobials that you really need for your patients

at home, or even at a facility.

Looking at various formulary options, and again, just involving case management,

social work, and also the bedside nurse is going to be the one that's educating

that patient and their family member on how to, if it's an IV antibiotic, how

to administer that antibiotic, because most of the time, if they're going

home, they'll likely be administering those antimicrobials themselves.

When we do have these patients admitted to the hospital, I do

think this multidisciplinary approach also holds through.

So when we have these patients, especially that have these resistant pathogens and

intra abdominal infection, it's really important to get a multidisciplinary team

to really help ensure you have source control, because especially when we're

reaching for, agents such as, ceftazidime avbactam, the more likely that patient

still has that remaining source, the more likely that patient is going to develop

further and further resistance later on.

So I think just having that multidisciplinary approach involving

key stakeholders, that's important for that patient care, helping appropriate

antibiotic use in the hospital, appropriate source control if needed, and

then appropriate discharge is really key.

I want to add to what Arsheena just mentioned.

So, source control, especially in situations where source

control may never be achieved.

So, a good example is in a patient who has an LVAD infection, and that LVAD is a, is

destination therapy, and has, let's say, a drive live infection with an organism like

Pseudomonas, where the more antibiotics you give this patient, the more

resistant the Pseudomonas will become.

So, I think it's really important to start planning early in these

kinds of situations where source control is, may not be feasible.

What, what will be the plan once that Pseudomonas becomes so resistant

where there are no options available.

And, of course, involving the patient as well and making the patient

understand, there may come a time where we may run out of antibiotics.

And so these are one of the times where you want to involve the patient, the

surgeon, ID, the pharmacist, so that we have a plan for when that time arrives.

Awesome.

And then I just want to open it up just to see if there's any other

closing thoughts that you guys have.

Thank you so much , it's a huge topic that we can't always condense

into these episodes, but I think you've given people really valuable

initial steps to get started.

So closing thoughts would be that treating multi drug resistant gram

negative infections is certainly challenging, but it's exciting that

we have new agents that we can use.

It's encouraging, but I think it's really important to understand the

appropriate time of when to use them.

, it's really important to understand that just because these newer agents

are novel, we shouldn't be afraid to use them, especially if we have

strong risk factors, strong indications to reach for them, and especially

if the patient is very, very sick.

So don't be afraid of them, but also use them thoughtfully.

And just adding to what Mariya said, just really considering the whole

patient, their risk factors, how ill they are, your local epi, to really

determine which one of these agents to start, because now we have several.

And then also really utilizing, I think, rapid diagnostic testing

has really changed how we will be approaching these patients.

Really just taking advantage of those.

If you have them to really be able to modify therapy in an appropriate manner

based on the resistance, based on the results . And then also just adding the

duration should really just focus on the clinical improvement, how that patient is

doing versus just maybe this is resistant pathogen, we need to treat them longer.

And then also just involving a multidisciplinary team, and be

able to facilitate those patients leaving the hospital safely and

hopefully being able to prevent them from having further readmissions.

And just closing thoughts, this was an exciting article that we

did with some amazing co authors.

I just wanted to give them a shout out.

So shout out to co authors, Drs.

Jason Pogue, Deepali Dixit, Robert Sawyer, and Dr.

Keith Kaye.

Thanks to Arsheena and Mariya for joining today.

You can find their article linked in the episode description and Consult Notes

from CID entitled State of the Management of Infections Caused by Multidrug

Resistant Gram Negative Organisms.

Don't forget to check out the website, febrilepodcast.

com, where you'll find the Consult Notes, which are written complements to

the episodes with links to references, our library of ID infographics,

and a link to our merch store.

Febrile is produced with support from the Infectious Diseases Society of America.

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Thanks for listening.

Stay safe and I'll see you next time.