Thread by @DrH_flu

Mandell ch. 25:
There are so many more aminoglycosides than I ever thought 😅

AGs are characterized by concentration-dependent killing (high peak/MIC is desirable), the post-antibiotic effect, and synergism
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#IDtwitter #idmeded

The higher the external (to the 🦠) concentration of AG, the more AG gets inside the 🦠 and the quicker it induces death...hence higher peak/MIC and AUC/MIC

Many many trials have shown once-daily dosing is = or superior to BID/TID in many different diseases/populations
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Synergy has been shown in vitro and in animal models for many different abx with AGs in many different 🦠 ...but it doesn't translate into all clinical situations with Pseudomonas or Enterobacteriaceae

Synergy does not work for MRSA
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Enterococci are intrinsically resistant to AGs because they are facultatively anaerobic, thus they have less transmembrane intake of AGs. However, b-lactams or vanc act on cell wall, creating openings for AGs to get in, resulting in classic synergy
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However, acquisition of one of many enzymes that inactivate AGs can confer resistance and also ruin synergy

These enzymes are often carried on plasmids that also confer resistance to other drug classes
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Plazomicin is generally not inactivated by the AG-modifying enzymes, but another form of resistance, 16S RNA methyltransferases, which alter the drug target, not the drug, do render plazomicin inactive
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This chapter cites several studies from 2010 and stated that combo AG + beta-lactam had improved outcomes in Gm- bacteremia and septic shock and apparently this was endorsed in 2016 Surviving Sepsis update? I wonder why I haven't seen this used in practice? 🤔🤷🏻‍♀️
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AG-impregnated cement is being used more and more in arthroplasties, both primary and revisions for PJI, but there hasn't really been data to show improved outcomes.

Also AGs can induce biofilm formation, sooo...that might be concerning
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Nephrotoxicity is due to AG-induced necrosis of renal proximal tubular cells. The cells regenerate after a few days, even if the AG is continued, and the new cells have a reduced capacity to take up AG 🙅‍♀️
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Uptake of AG by renal tubular cells is saturatable, therefore high daily doses cause less nephrotoxicity than multiple smaller daily doses

By contrast, ototoxicity is due to cumulative effects, so the same total daily dose has same risk, regardless of dosing pattern
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While nephrotoxicity is reversible, ototoxicity is irreversible and can appear after the end of therapy. Either cochlear or vestibular damage can occur; vestibular is more common. It is rare to have both cochlear & vestibular damage or both oto & nephrotoxicity
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Finally, fun fact:
Gentamicin can be used as one-time injection into the middle ear to destroy hair cells and thus treat Meniere disease, controlling vertigo in 75% of patients! Pretty cool!
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