An ongoing dialogue on HIV/AIDS, infectious diseases,
June 6th, 2013
ID Learning Unit — Aminoglycosides
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.