Learn the reasoning, not just the number.

Concentration-dependent killing & the post-antibiotic effect

Aminoglycosides are concentration-dependent killers: raise the peak concentration and bacteria die faster and more completely, in contrast to beta-lactams, whose kill rate depends on time spent above the MIC rather than how far above it the drug climbs. A single large dose therefore does more killing than the same total amount split into several smaller doses — the opposite of the intuition that "more frequent" means "more effective."

That single large dose is safe to give because of the post-antibiotic effect (PAE): bacterial regrowth stays suppressed for roughly 0.5–8 hours after the concentration falls back below the MIC — the range reported across Craig and Ebert's and Zhanel and colleagues' post-antibiotic-effect reviews of aminoglycosides. The PAE is what lets levels fall — even to near-undetectable troughs — between doses without the infection rebounding in that gap. Together, concentration-dependent killing and the PAE are the pharmacodynamic rationale for extended-interval dosing (EIAD): one large, high-peak dose per interval outperforms the traditional multiple-smaller-doses approach on efficacy grounds, while the long drug-free window between doses works in the toxicity ledger's favor too (see Toxicity below).

The PK/PD indices — Cmax:MIC and AUC₂₄:MIC

The single best-validated efficacy driver for aminoglycosides is the peak-to-MIC ratio, Cmax:MIC 8–10: hit a peak eight to ten times the pathogen's MIC and the regimen is doing what concentration- dependent killing predicts it should. The number comes from Moore and colleagues' 1987 analysis linking peak:MIC to clinical outcome, and was sharpened by Kashuba and colleagues (Antimicrobial Agents and Chemotherapy, 1999): achieving Cmax:MIC ≥ 10 within the first 48 hours of therapy predicted roughly 90% clinical response by day 7 in Gram-negative pneumonia. It is why every target in this tool is expressed as a peak (not a trough) range, and why a low-MIC isolate can be treated to a lower peak and still hit the same ratio — the target moves with the organism, not the other way around.

A complementary index, AUC₂₄:MIC, captures total exposure over the dosing interval rather than the single peak moment. Bland, Pai, and Lodise's 2018 reappraisal (Pharmacotherapy 2018;38(12):1229–38) argues the target is context-dependent rather than one flat number: roughly 30–50 for lower-risk infections, rising to roughly 80–100 for critically ill patients or aminoglycoside monotherapy — an efficacy range of about 75–100 overall. The two indices usually point the same direction — a regimen built to hit Cmax:MIC 8–10 typically clears the AUC₂₄:MIC threshold too — but AUC₂₄:MIC is the index the Bayesian fit (see the method ladder) reports directly, since it falls naturally out of a fitted clearance and volume rather than needing a separately-timed peak sample.

Toxicity — trough, cumulative dose, ototoxicity

Where the peak governs efficacy, the trough governs toxicity — it is the single monitoring number most tightly linked to accumulation-driven harm, which is why every target table in this tool pairs a peak range with a trough ceiling rather than a peak alone. Nephrotoxicity is usually reversible; ototoxicity is the toxicity that dominates prolonged courses and is often permanent — cohorts of patients on extended amikacin for nontuberculous mycobacterial (NTM) disease report roughly 30–39% developing permanent hearing change (Peloquin and colleagues, Clinical Infectious Diseases 2004;38(11): 1538–44). Risk tracks with age and, above all, with cumulative dose: the aminoglycoside ototoxicity cumulative-dose / predictive-model literature (e.g. a 2024 predictive model for aminoglycoside-induced ototoxicity published in Frontiers in Neurology) places estimated thresholds near 50 mg/kg ("absolute") and 120 mg/kg ("clinical") total exposure, with risk rising roughly 7% per additional gram of cumulative exposure.

A common and consequential misconception: thrice-weekly dosing does not reduce ototoxicity risk compared to daily dosing (Peloquin and colleagues, Clinical Infectious Diseases 2004;38(11): 1538–44) — the ear does not "reset" between doses the way the drug-free interval lets the MIC-vs-regrowth balance reset. Toxicity tracks cumulative exposure, not dosing frequency, so switching a patient to TIW dosing to protect their hearing is not supported by the evidence; it is a real dose-schedule decision, not a toxicity-mitigation one.

Because ototoxicity is often insidious and can outlast the course itself, courses expected to run long — NTM therapy above all — warrant a baseline audiogram before starting and periodic audiometry through treatment, not just serum-level monitoring. A stable trough does not rule out a rising cumulative dose; both need tracking.

When to draw levels

The right draw time depends on which method a regimen is being individualized by, and none of the three below require waiting for steady state:

Hartford / extended-interval nomogram — a single random level drawn 6–14 hours after the start of the first dose's infusion; the level and its exact draw time are plotted against the nomogram's boundary lines to read off the interval (see the method ladder and the instrument below).

Extended-interval, high-peak individualization — two levels drawn after the first dose, timed to capture the elimination slope directly, again without waiting for steady state; this is the two-level (Sawchuk-Zaske) approach applied at the very start of therapy rather than after several doses have accumulated.

Traditional (multiple-daily-dose) monitoring — a peak drawn 30 minutes after the infusion ends and a trough drawn immediately before the next dose, both at steady state (typically after the third or fourth dose) — the one approach here where waiting matters, because traditional dosing's smaller, more frequent doses take longer to reach a stable peak/trough pattern.

The method ladder

Tod, Padoin, and Petitjean's 2001 review (Clinical Pharmacokinetics) frames aminoglycoside individualization as a ladder, not a single method — climb only as far as the patient's data and the clinical stakes require:

1. Linear dose adjustment — the simplest rung: a single level plus the assumption that concentration scales linearly with dose, enough to nudge an already-close regimen. 2. Nomogram (ODA / Hartford) — one random level at a validated draw time maps directly to an interval, no PK math required by the user. 3. Non-Bayesian two-level (Sawchuk-Zaske) — two levels let the elimination rate and volume of distribution be back-calculated directly, individualizing Ke and Vd rather than assuming population values. 4. Bayesian / MAP — population priors (informed by age, weight, renal function) combine with whatever levels exist, however sparse or early, to produce the most defensible individual fit; unlike the two-level method it works from a single level and does not require steady state.

Each rung relaxes an assumption the one below it depends on. Use the simplest method that actually fits the patient in front of you — reach for the next rung only when that assumption breaks (an unstable renal function, a level drawn off-nomogram, or too few levels for a reliable two-point slope).

NTM amikacin — daily vs thrice-weekly

For nontuberculous mycobacterial (NTM) pulmonary disease, the 2020 ATS/ERS/ESCMID/IDSA guideline (Daley and colleagues) sets IV amikacin targets that depend on the regimen, not just the drug:

Daily — 10–15 mg/kg → peak 35–45 mcg/mL, trough <5 mcg/mL.
Thrice-weekly (TIW) — 15–25 mg/kg → peak 65–80 mcg/mL, trough <5 mcg/mL.

Applying the wrong regimen's target to the wrong schedule — daily's 35–45 to a TIW patient, or the reverse — is a real, clinically consequential mix-up, which is why this tool checks the stated target against the selected regimen and warns on a mismatch rather than silently accepting either number.

Two caveats worth holding onto: first, these targets are pulmonary-derived — the 2020 guideline sets no separate target for extrapulmonary or rapidly-growing-mycobacteria (RGM) disease, so applying them outside pulmonary NTM is an extrapolation, not a validated target. Second, the TIW peak of 65–80 is not an arbitrary higher number — it reflects the same Cmax:MIC 8–10 target evaluated at the susceptibility breakpoint MIC of 8 mcg/mL; an isolate with a lower MIC reaches that same ratio at a proportionally lower peak.