An ongoing dialogue on HIV/AIDS, infectious diseases,
June 6th, 2013
ID Learning Unit — Aminoglycosides
You young whippersnappers out there may not believe it, but we once used aminoglycosides all the time — literally every day on inpatient medical and surgical services, especially in the ICUs.
They were an inevitable part of “triples” (e.g., amp/gent/clinda), a broad-spectrum combination given to almost every critically ill patient way back when — think right around the time Pac-Man was state-of-the-art and George Bush Senior was President, saying he didn’t like broccoli.
(It’s just an association with the 1980s/early 1990s I’m after. How’d I do?)
Over the years, aminoglycoside prescribing has rapidly and progressively declined — there are other less toxic antibiotics that do the same thing — so these drugs are unfamiliar to many clinicians today.
But they still have their place, so here is brief refresher unit.
Let’s start with a table comparing the four agents in most common use, and finish with some factoids that could be clinically relevant — or at the very least quite helpful when trying to impress your friends. First, the table:
| Drug | Principal Indication | Distinguishing Characteristic Compared with Others |
| Gentamicin | Used in combination with ampicillin or penicillin or vancomycin for treatment of serious infections due to enterococcal (and some streptococcal) infections. | Least expensive. |
| Tobramycin | Used as inhalational therapy in patients with cystic fibrosis, bronchiectasis, and other conditions associated with recurrent bacterial respiratory tract infections. | Most active in vitro versus Pseudomonas aeruginosa. |
| Amikacin | Used as part of empiric broad therapy in patients with known highly resistant GNR infections, or in urinary tract infections with no oral alternatives. | Broadest antibacterial spectrum. |
| Streptomycin | Used as part of second-line combination therapy for tuberculosis and other mycobacterial infections. | Vestibular toxicity a particular problem. |
Now for the factoids:
- These are relatively toxic antibiotics, and patients receiving them should always be monitored closely. Renal, cochlear (hearing), and vestibular (balance) toxicity are the main concerns, and the big problem is that the side effects may be irreversible if the drugs are not stopped promptly.
- The risk factors for these toxicities are exactly what you’d predict. Older age. Impaired renal function. Other nephrotoxic drugs. Critical illness. Higher doses. Higher levels (especially trough concentrations). Longer duration of therapy. Genetic predisposition. You get the idea — can you say “multifactorial”? There, now you can charge for the renal consult you just did on that 87-year-old woman with diabetes and hypertension, taking NSAIDs, who received a course of gentamicin and now has a creatinine increase.
- Monitoring drug levels is essential. The problem is that even when they are “perfect,” end-organ toxicity still occurs. Oh well, it’s at least less likely to happen when toxic drug levels are averted.
- Extended-interval dosing is probably more effective than multiple-day dosing. It might be less toxic, too. (Data are mixed.) The killing of bacteria with aminoglycosides is concentration-dependent, and there’s also a nice post-antibiotic effect even after the drugs are cleared. As a result, we preferentially employ extended-interval dosing when treating serious GNR infections, under the careful guidance of our hospital pharmacy which uses the Hartford nomogram method. Note it’s not appropriate for several patient groups, including those with changing renal function, CF with pseudomonas (see below for clarification), or for endocarditis. [Edit: Extended interval dosing IS used for CF, but the doses are way higher, and the nomogram does not apply.]
- When aminoglycosides are used for endocarditis, use low-dose “synergy” dosing. In enterococcal and certain streptococcal endocarditis cases, you just need low levels of gentamicin — just enough to be detectable on trough measurements. You know, the vermouth in the very dry martini.
- With Staph aureus infections, resist the urge to “just add gent.” Every ID doctor has been there — consulted on a case of Staph aureus bacteremia that won’t go away, despite what should be appropriate therapy. In vitro, Staph aureus is killed faster by combining a beta-lactam with gentamicin than with the beta-lactam alone, so adding gentamicin sounds like a good idea. The problem is that people are vastly more complex than these lab experiments — for example, humans have kidneys and ears — and there has never been a clinical study showing a net clinical benefit from this practice to “just add gent.” With MRSA, we even have the opposite — that adding gentamicin to vancomycin worsens outcomes. So don’t do it. (Possible exception: Staph aureus prosthetic valve endocarditis. Maybe. But call the surgeons anyway.)
- Some gentamicin-resistant enterococci are still sensitive to streptomycin. But faced with using streptomycin for this indication over the past few years, I’ve gone with the ampicillin/ceftriaxone alternative combination instead of amp/streptomycin because: 1) Data are accumulating that this combination actually works; 2) Monitoring streptomycin levels in real-time is all but impossible in most hospitals today.
- Neuromuscular blockade is another complication of this drug class. It’s rare, but it happens — particularly a concern for patients with Parkinson’s or myasthenia gravis, or who received certain paralyzing anesthesia agents. Think of this when, in the ICU, a previously critically ill patient who was paralyzed for intubation is slow to regain muscle strength after receiving an aminoglycoside.
- The only indication for systemic aminoglycoside monotherapy is treatment of urinary tract infections resistant to other antibiotics. This has become a relatively common indication for these drugs, in particular amikacin, due to rising rates of quinolone resistance in GNR. But these are infamously poor drugs for treatment of pneumonia and abscesses, as low pH environments reduce aminoglycoside activity; in addition, single-drug therapy with aminoglycosides in fever and neutropenia was suboptimal. You wouldn’t do these things anyway.
- A trivia question: What rare infections still list aminoglycosides among preferred first-line treatments? Answer: tularemia, brucellosis, plague. Now you’re prepared!
Last, an observation with no apparent explanation: Back when we used quite a bit of gentamicin at our hospital, the doctors all abbreviated it by saying “gent” (one syllable), while most of the nurses said “genta” (two syllables).
Figure that one out.
24 Responses to “ID Learning Unit — Aminoglycosides”
Paul E. Sax, MD
Contributing Editor
NEJM Journal Watch
Infectious Diseases
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And do not forget amikacin is a second line anti tuberculous drug
A urologist I know uses aminoglycosides, including gent, on an outpatient basis when urine C&S indicates nothing else will work. But she uses a very extended interval, usually every 3-5 days. For example, she will inject 80 mg of gent IM on this schedule, and it apparently does the job. Any thoughts, Paul? Thanks so much for this learning unit, by the way. I always learn so much from your posts.
Sounds like an interesting strategy. Given the “post-antibiotic effect” of aminoglycosides, and the high urinary concentrations, not surprised that it works.
Paul
Gent vs genta, my guess: likely because physicians often referred to gent as the middle of a series of abx so further abbreviated- like amp/gent/flagyl and nurses more likely to use as a single- like I just started the genta, or, can you go get the genta? (days before CPOE!)
-and I enjoyed the 80s/90s reminders:)
Still widely used cost effective antibiotic class in third world
Countries such as India. Risk of toxicity is clearly exagerated
Although one needs to be careful.
Yes, I am one of those ancient enough to remember when gentamycin was our “big gun” antibiotic. We used it in adults with Keflin (the predecessor to Ancef) and in newborns and infants with ampicillin. This was all done without (gasp!) the availability of gentamycin levels. We did monitor renal function via creatinine and I do remember watching in trepidation as the level rose in one adult patient before it subsequently returned to normal range. Ototoxicity was a “crapshoot” as we didn’t have a good way to monitor this.
When gentamicin was used for urinary tract infection, simultaneous alkalinisation achieved:
1. Better urine levels of gentamicin
2. Less need for high doses and high systemic levels and therefore lower risk of ototoxicity.
Dr. Sax
Many many thanks for your blog and all the good updates. As one well past being a WhipperSnapper I am reminded of an experience I had in 1937. I had a Strep Throat. I was taken to a Clinic at the University of Illinois Research and Education Hospital in Chicago where my infection was treated. My throat was swabbed with Merthiolate. Antibiotics were yet to come. For being a good boy I was allowed to buy an orange ice ice cream cone and I passed over the two cents myself.
What happened to Kanamycin (Kantrex)? Gent (no a) was just replacing it when I was a student.
Thanks very much Paul for that primer on Aminoglycosides, you always give me very nice pearls for my Residents during rounds.
“Genta” is the female form of the word “gent”.
the “patient is on triples” was a refrain often heard from surgery residents…seemingly to imply that the patient was OK, but scared the heck out of us on Medicine services!!
thanx for the blast from the past..
my observations & experiences…
#1. a single dose of gent120/Rocephin500 works miracles for the OP treatment pf pyelo..
#2. “no one ever died from a single dose of gent”…
#3. I always gave gent q12 hours @ 5-6 g/kg/day…peak & trough after 48 hours…with consistently good #s!!
Loved your blog. Two things:
1) surprised you commented on the abbreviation of gent but not the notorious misspellings
2) Anyone that was educated at Hopkins Med in the 30 (if not 40 year) era of pharmacology taught by Paul Lietman (just recently passed: http://articles.baltimoresun.com/2013-04-24/news/bs-md-ob-paul-lietman-20130424_1_johns-hopkins-children-pediatrics-george-dover)
was tested on one key fact about gent…never give it with X or it precipitates rapid ototoxicity.
The answer on the test was ethacrinic acid…and when we all reached the wards we were disappointed by knowing the fact and never being able to use it. Why, because no one ever prescribed ethacrinic acid…ever.
RW
Why do some of the ID respondents continue to spell it “gentamycin”. I recall that it is gentamicin because of it’s parental streptomyces species is spelled streptomices or some such. Like the harmless drudges at the OED, we should use and spell words in ways that are consistent, make sense to all and can be remembered. If we did, then my pedantic comment on spelling would be even more irrelevant than it is! I can also endorse the outpatient use of IM gent with a several day interval if administration when broad resistance is in play.
In areas where brucellosis is common Gentamicin and Streptomycin are widely used espicially when there is focal brucellosis.
I think useful to also note the niche of amikacin for treating mycobacterial infections. In practice, seems that we use amikacin more than streptomycin for MAC and M.abscessus. Nebulized amikacin is used not uncommonly in certain pulmonary NTM patients. One also questions when dosing IV amikacin in these pts, dose MTW, M Th, M-F?? Seems that for the non-daily IV amikacin treatment in these patients, it is part science and part personal experience and opinion as how to dose . . .
And a burning question: why is streptomycin more commonly administered IM rather than IV? Could never recall the toxicity risk and issues that call for IM administration to be the preferred route.
Question from an ignoramus — but one not young enough, sadly, to have never used AGs routinely. I love your blogs. What about empiric AG for neutropenic febrile patients with sepsis and suspected or possible GNRs to not rely on beta-lactam coverage alone until cultures return? I still do that every once in a while. Is it crazy?
Thanks for the instructive blog on AG. Clearly, toxicity issues have relegated aminoglycosides to third line or fourth line in many indications. One situation I find difficult is the healthy and young (<50 yrs) woman with acute pyelonephritis due to an ESBL strain susceptible only to carbapenems and aminoglycosides. Should we favor gentamicin or ertapenem for OPAT in this case? Many of my colleagues will give the carbapenem. I like the aminoglycoside for cost and spectrum issues. Any thoughts?
Aside from the fact that I’ve found a bunch of these ESBLs to be resistant to gentamicin, so need to use amikacin, I agree with you that the AG option is one that should be considered more often.
Paul
Up to date recommends once daily dosing of aminoglycosides for CF and references guidelines by the CF foundation
Stu,
You are absolutely right — but the dosing is very different. Have edited post to clarify.
Paul
The pearl to teach in order to get people to spell them correctly: those derived from Streptomyces end in -ycin (e.g. tobramycin, streptomycin)and those derived from Micromonospora end in -icin (e.g. gentamicin, netilmicin). It can have relevance for cross resistance patterns. So what’s up with amikacin?? It’s the only one that is synthetic and not found in nature.
It’s one of the trivia I cover on Day 1 of every rotation. 24 years of former fellows and residents and students spell gentamicin correctly.