High dose aminoglycosides in septic shock

nephappl said:

Hi all,
Had a pt in ICU (ARF - dialysis dependent in septic shock maybe line was the source) . Line removed, all cultures negative so far, he is anuric and dependent on dialysis. He was in shock, 4 pressors and our new Pulm / CCM doc from Cleveland gave him a gigantic dose of gentamycin (400 mg around 5 mg / kg) I was initially shocked given the docummented ototoxicity then he explained that it has shown to improve mortality in refractory septic shock and actually pt is doing better this am.
He did not provide the evidence, I looked @ pubmed and did not find that either.
Any thoughs about that??
Thanks
N/A

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Some of the stuff that gets done may not be written into a formal paper. Could be abstract presentations or stuff currently being looked at and unpublished but talked about at meetings.

Though worry about hearing loss in a patient that is going to die from septic shock seems a bit misplaced with regards to priorities.

You know what else is a well documented cause of ototoxicity? Death. Sorry for the snark, but dont loose the forest for the trees.

5 mg/kg isn't a huge dose, especially if it is a single dose. Many places will give a 7mg/kg loading dose then do maintaince dosing based off of gfr.

I'm not aware of the data for refractory septic shock per say, but there is data for use of combos with aminioglycocides such as this http://www.ncbi.nlm.nih.gov/pubmed/20160050

I always thought that the aminoglycoside thing came from this paper http://www.ncbi.nlm.nih.gov/pubmed/2816969. It showed mortality benefit for pseudomonas bacteremia with combination therapy predominantly with beta-lactam.

When I looked this stuff up couple of years ago when our medicine attendings would do double coverage (with any 2 Abx) for gram -ve bacteremia (even if not psuedomonas) or psuedomonas UTI or even gram -ve UTI, I found that it was a common practice extrapolated from that original paper. I would only do it for psuedomonas bacteremia or initially when I see profound septic shock.

The big single dose is pretty standard now for treatment of Gram-negative infections - 5-7mg/kg. In theory it maximizes pharmacodynamics (peak drug concentration/MIC) and minimizes toxicity (which are dependent on sustained trough concentrations). The 7mg/kg dose is based on what's called the Hartford nomogram. The 1mg/kg q8h dosing should only be used for synergy in Gram-positive infections, but even then there's data showing that 3mg/kg once daily is just as effective and potentially less toxic - although this depends on whether you think AG synergy is useful in the first place.

What was he covering? I presume septic shock culture negative he was already on vanc which was hurting the beans....what are you covering with vanc/gent that your not covering with vanc/merrem or vanc/aztreonam/flagyl? I know gent has some synergistic effects but I almost never use it nor see it used, especially in a renal failure pt

Bostonredsox said:

What was he covering? I presume septic shock culture negative he was already on vanc which was hurting the beans....what are you covering with vanc/gent that your not covering with vanc/merrem or vanc/aztreonam/flagyl? I know gent has some synergistic effects but I almost never use it nor see it used, especially in a renal failure pt

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You don't use gent for synergy

You use it because its just like an AK47, when you absolutely, positively, got to kill every mother****er in the room.

Bostonredsox said:

What was he covering? I presume septic shock culture negative he was already on vanc which was hurting the beans....what are you covering with vanc/gent that your not covering with vanc/merrem or vanc/aztreonam/flagyl? I know gent has some synergistic effects but I almost never use it nor see it used, especially in a renal failure pt

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AGs tend to have the highest % coverage on any given institutions antibiogram (not including colistin), so when you're truly worried about an MDR bug, they're the go-to. I'll use them in septic shock folks who have been on a carbapenem for weeks at the local LTACH before they get transferred in. You have to have a high index of suspicion, because as has been mentioned, they're not benign drugs.

The synergy data is mostly in vitro. All of the clinical studies done recently have shown no benefit in double coverage once you have a known organism with known sensitivities. This again, is excluding the MDR/XDR bugs where all bets are off and you just dump out the toolbox. My go-to for them is carbapenem/colistin.

Synergy is also shown for Gram-positives, but again, the recent data shows that AG adds nothing to standard practice for S. aureus beyond nephrotoxicity. Enterococcus has more limited data, and its still routine practice for that - although the ampicillin/cephalosporin combo data coming out more recently may change that practice down the road.

Agree with this. Hospital acquired septic shock gets MRSA coverage (Vanc) and double coverage for GNR. We usually do cefepime/tobra based on local biograms. For the simpletons, we have an electronic order entry called the sepsis bundle which helps speed up the delivery of optimal care in hospital sepsis.

Wait so every hospital-acquired septic shock who has not been on abx previously gets up front double-coverage for gram-neagatives at your shop? Do you cover for C. diff empirically, and why cefepime over carbepenems if you are trying to cover every organism up front and we think carbepenems are broader in term's of coverage of anaerobes and ESBL(maybe?).

I guess there is no one-size fits all approach, and at my shop we do not routinely give double GN coverage for newly admitted ICU patients with undifferentiated septic shock (espeically if we think the urine is the source). We will sometimes give upfront an echinocandin, flagyl, carbepenems, or AG's for different scenarios.

ORL10 said:

Wait so every hospital-acquired septic shock who has not been on abx previously gets up front double-coverage for gram-neagatives at your shop? Do you cover for C. diff empirically, and why cefepime over carbepenems if you are trying to cover every organism up front and we think carbepenems are broader in term's of coverage of anaerobes and ESBL(maybe?).

I guess there is no one-size fits all approach, and at my shop we do not routinely give double GN coverage for newly admitted ICU patients with undifferentiated septic shock (espeically if we think the urine is the source). We will sometimes give upfront an echinocandin, flagyl, carbepenems, or AG's for different scenarios.

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There is actual evidence that his approach improves inappropriate antibiotic selection in sepsis, which is a huge issue,

ORL10 said:

Wait so every hospital-acquired septic shock who has not been on abx previously gets up front double-coverage for gram-neagatives at your shop? Do you cover for C. diff empirically, and why cefepime over carbepenems if you are trying to cover every organism up front and we think carbepenems are broader in term's of coverage of anaerobes and ESBL(maybe?).

I guess there is no one-size fits all approach, and at my shop we do not routinely give double GN coverage for newly admitted ICU patients with undifferentiated septic shock (espeically if we think the urine is the source). We will sometimes give upfront an echinocandin, flagyl, carbepenems, or AG's for different scenarios.

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I think the context was sepsis *acquired in the hospital*.

And in that setting there is a rationale for double covering until you can get culture results back - pick your two poisons based on experience with your local bad ass bugs.

Aminoglycosides got a bad rap for awhile, for various reasons, some more legit than others, but they are a more predictable killer of all bacterial types gram+ or gram- so if you've got a sicker than crap septic patient and the hospital gave it to them, go tactical nuke. At least that is the thought process.

ORL10 said:

Wait so every hospital-acquired septic shock who has not been on abx previously gets up front double-coverage for gram-neagatives at your shop? Do you cover for C. diff empirically, and why cefepime over carbepenems if you are trying to cover every organism up front and we think carbepenems are broader in term's of coverage of anaerobes and ESBL(maybe?).

I guess there is no one-size fits all approach, and at my shop we do not routinely give double GN coverage for newly admitted ICU patients with undifferentiated septic shock (espeically if we think the urine is the source). We will sometimes give upfront an echinocandin, flagyl, carbepenems, or AG's for different scenarios.

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Yes, we cover hospital-acquired sepsis landing you in the ICU with two different GNR antibiotics as well as empiric coverage for MRSA. The choice of cefepime and an amino is based on our local bug resistance patterns. We don't empirically cover C dif unless there's a story that includes diarrhea, abdominal pain, etc. We also don't cover VRE empirically, which is a whole different interesting conversation.

I disagree with there not being a one size fits all approach. I believe that bundled antibiotics based on local resistance pattens will get it right more often than a heterogenous collection of physicians. Fine with style tailoring after 48 hours based on sensitivity patterns, etc - but initial coverage is too important to not have a systematic approach/rationale.

Agree with all the above comments. For patients with community-acquired sepsis and no healthcare exposure, single-drug GNR coverage is still probably fine in most epidemiologic settings in the U.S. At other places, all bets are off - for example, my institution has ~80% coverage with cefepime for Pseudomonas, and that's not something I like to take a chance with. LTACHs are also a huge problem, because they seem to be black holes of unnecessary broad-spectrum antibiotic use. A standardized approach overcomes individual practice and provides rational, data-driven care - every hospital can, and should, have some sort of standardized bundle for this.

And specifically in regards to the comment about why not carbapenems over cefepime or pip/tazo, it all depends on your institutions antibiogram. At my place, cefepime actually has a higher % coverage than the carbapenems for Pseudomonas. The difference for other GNRs is negligible, and recent data shows that as long as dosed appropriately, cefepime and meropenem are no different when used in the treatment of AmpC- or ESBL-producing organisms.

They key is for individual prescribers to be willing to modify therapy once culture results are in and in many cases, this would end up stopping the aminoglycoside. Antibiotic stewardship services help with this, but it is ultimately up to the treating service to buy in.

nephappl said:

Hi all,
Had a pt in ICU (ARF - dialysis dependent in septic shock maybe line was the source) . Line removed, all cultures negative so far, he is anuric and dependent on dialysis. He was in shock, 4 pressors and our new Pulm / CCM doc from Cleveland gave him a gigantic dose of gentamycin (400 mg around 5 mg / kg) I was initially shocked given the docummented ototoxicity then he explained that it has shown to improve mortality in refractory septic shock and actually pt is doing better this am.
He did not provide the evidence, I looked @ pubmed and did not find that either.
Any thoughs about that??
Thanks
N/A

Click to expand...

I'm a critical care pharmacist and see it quite frequently. It's called extended duration dosing. 5-7mg/kg is typical, but not recommended in certain patient populations (renal failure being one of them). It takes advantage of the high Peak to enhance killing. In terms of whether it improves mortality in refractory septic shock depends on whats going on and what has been isolated. Further, your institutional antibiogram should be reviewed and taken into consideration. Anyway, these doses are typically daily (vs multiple daily doses with conventional therapy) and can be adjust based upon a certain adjustment graph. There was a person that mentioned Vancomycin and its effects on the "beans." Vanc. has been notoriously given this ADE of nephrotoxicity, but much of it was actually linked to older formulations that led to such nephrotoxicity due to impurities within the formulation. I don't consider it as hard on the kidneys and obviously will depend upon levels. Hope this helps!