Aminoglycosides — Gentamicin, Tobramycin, Amikacin & the Three Toxicities

Overview & definition

The aminoglycosides (the gentamicin, the tobramycin, the amikacin) are the bactericidal, the concentration-dependent Gram-negative cover. Once the ICU first-line for the empirical Gram-negative sepsis, now the largely the second-line (the safer beta-lactams) or the synergy — but the still the important. The three toxicities (the nephro, the oto, the neuromuscular) are the defining constraint, and the once-daily dosing is the design to minimise them while the maximising the efficacy.[1]

The mechanism and the spectrum

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• The mechanism — the bind the 30S ribosomal subunit → the misread the genetic code → the faulty proteins → the bactericidal. The oxygen-dependent uptake → the NO activity in the anaerobes.[1]
• The pharmacodynamics — the concentration-dependent killing (the higher the peak, the better) plus the post-antibiotic effect (PAE) — the persistent killing after the drug falls below the MIC. These two drive the once-daily dosing.[1]
• The spectrum — the Gram-negative aerobes (the Enterobacteriaceae — the E. coli, the Klebsiella). The pseudomonas (the tobramycin the better than the gentamicin; the amikacin the broadest). The enterococcus synergy (the ampicillin plus the gentamicin for the endocarditis). The NO anaerobes (the oxygen-dependent uptake). The NO atypicals. The amikacin for the mycobacteria (the TB, the MAC).[1]

The dosing — the once-daily extended-interval

• The once-daily (the extended-interval) — the Cmax over the MIC of the 8 to 10 (the high peak for the efficacy) AND the low trough (the time below the threshold to reduce the renal-cortical and the cochlear accumulation → the less the nephro and the oto-toxicity).[1]
• The gentamicin 5 to 7 mg per kg once-daily (the weight-based; the dose-adjust the obese by the adjusted body weight).[1]
• The Hartford nomogram (the 6 to 14-hour post-dose level) to determine the interval (the 24, 36, or 48 hours). The Bayesian software the alternative.[1]
• The endocarditis synergy — the traditional low-dose (the 1 mg per kg TDS or the once-daily 3 mg per kg) per the local protocol; the lower peak acceptable for the synergy.[1]
• The renal adjustment — the renal excretion → the dose-adjust for the AKI and the dialysis (the prolonged interval).[1]

The three toxicities

The nephrotoxicity

• The proximal-tubule accumulation → the acute tubular necrosis. The usually reversible (on the cessation).[1]
• The risk factors: the prolonged course (over the 5 to 7 days), the high trough, the pre-existing renal disease, the hypovolaemia, the concurrent nephrotoxins (the vancomycin — the 'VANCO-GENT' AKI, the contrast, the loop diuretics).[1]
• The monitor the daily creatinine and the trough (or the Bayesian).[1]

The ototoxicity

• The cochlear (the hearing loss) and the vestibular (the balance, the vertigo).[1]
• The often IRREVERSIBLE (the hair-cell damage); the cumulative (the total dose).[1]
• The audiology and the vestibular monitoring for the prolonged courses.[1]

The neuromuscular blockade

• The potentiates the non-depolarising muscle relaxants; the worsens the myasthenia gravis (a relative contra-indication).[1]
• The rare but the ICU-relevant — the post-operative or the myasthenic patient with the aminoglycoside → the respiratory failure.[1]
• The hypomagnesaemia and the hypokalaemia (the renal wasting) accompany.[1]

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Red flags

The class — the four clinically relevant aminoglycosides

All aminoglycosides share a streptamine-containing aminocyclitol core linked to amino sugars (hence "amino-glycoside"). They differ in the number and position of the aminated groups, which drives their spectrum and their liability to inactivating enzymes.[1]

• Streptomycin (a strepidine core) — the oldest (Waksman, 1943). Now used second-line for tuberculosis, for plague (Yersinia pestis) and tularemia (Francisella tularensis), and for enterococcal endocarditis synergy when the isolate is high-level resistant to gentamicin. The least nephrotoxic; the most vestibulotoxic.
• Gentamicin (a 2-deoxystreptamine core) — the cheapest and the most studied. The ICU synergy agent for enterococcal and viridans-streptococcal endocarditis and the Gram-negative empirical cover where local pseudomonal resistance is low. A mixture of C1, C1a, C2 components.
• Tobramycin (also a 2-deoxystreptamine) — the best intrinsic activity against Pseudomonas aeruginosa (2–4× more potent than gentamicin in vitro) and the inhaled agent (TOBI, Bethkis, Kitabis Pak) for chronic Pseudomonas airway infection in cystic fibrosis and bronchiectasis. Slightly less nephrotoxic than gentamican in some head-to-head studies.
• Amikacin (a semi-synthetic derivative of kanamycin, with an L-HABA side chain at the N-1 position) — the broadest aminoglycoside because the bulky side chain sterically shields it from most aminoglycoside-modifying enzymes (acetyltransferases, phosphotransferases, nucleotidyltransferases). The agent of choice where the local GNR aminoglycoside-resistance rate is high, and the only aminoglycoside reliably active against Mycobacterium tuberculosis, M. avium complex and other non-tuberculous mycobacteria (used in the short-course MDR-TB regimen, BEAT-TB).
• Neomycin — too nephrotoxic and ototoxic for parenteral use; given orally (poorly absorbed, <3%) for gut decontamination and hepatic encephalopathy adjunct (lactulose is now first-line). Topically for skin/eye. The "neo- in nephro-" mnemonic links neomycin to its renal toxicity. [1]

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The mechanism in molecular detail — the three-step energy-dependent uptake

The aminoglycosides cross the Gram-negative outer membrane through porins, then the inner (cytoplasmic) membrane by an unusual three-step energy-dependent process (EDP-I, EDP-II, EDP-III) that absolutely requires aerobic respiration and a membrane potential. This is the single fact that explains their entire spectrum.[1]

• EDP-I — a small amount of cationic aminoglycoside displaces the divalent Mg²⁺/Ca²⁺ that bridge adjacent lipopolysaccharide molecules, creating outer-membrane perturbation and self-promoted uptake.
• EDP-II — slow, rate-limiting transport across the inner membrane driven by the electron-transport chain (requires O₂). This is the bottleneck that anaerobes cannot overcome (no aerobic respiration → no EDP-II → no uptake → intrinsic resistance).
• EDP-III — rapid, energy-driven accumulation to very high intracellular concentrations, irreversibly committing the cell to death. [1]

Inside the cytoplasm the aminoglycoside binds irreversibly to the 30S ribosomal subunit, specifically the 16S rRNA at the A-site decoding region, causing: [1]

1. Misreading of the genetic code — faulty (mis-sense) proteins insert into the cytoplasmic membrane, increasing its permeability, which accelerates further aminoglycoside uptake — a positive-feedback "autocidal" loop.
2. Ribosome stalling / inhibition of translocation — premature termination, blocking the elongation cycle.
3. Inhibition of ribosome assembly (especially streptomycin, which binds the S12 protein rather than the rRNA A-site). [1]

The result is rapid bactericidal killing (not merely bacteriostatic, unlike linezolid or tetracyclines which bind the same 30S subunit but reversibly) — the aminoglycosides are the most rapidly bactericidal cell-membrane-disrupting ribosomal inhibitors in clinical use.[1]

Pharmacodynamics — concentration-dependent killing and the post-antibiotic effect

Three pharmacodynamic properties define the aminoglycosides and together justify once-daily dosing:[1]

1. Concentration-dependent killing. The higher the peak (Cmax) relative to the MIC, the faster and the more complete the kill. The Cmax/MIC ratio of 8–10 is the validated pharmacodynamic target — a peak of 8–10× MIC produces ≥2-log₁₀ killing and reliably suppresses resistant sub-populations. Below ~4–6× MIC the kill is submaximal and resistance emerges.
2. A robust post-antibiotic effect (PAE). After the drug concentration falls below the MIC, the bacterial kill continues for 1–8 hours against Gram-negatives (longer still against staphylococci). The PAE is concentration-dependent — the higher the peak, the longer the PAE — so a high once-daily dose buys a long PAE that covers the rest of the dosing interval.
3. Adaptive resistance (first-exposure effect). After a first exposure, the bacterium transiently down-regulates aminoglycoside uptake for several hours (post-exposure down-regulation of the inner-membrane transport). This is adaptive, not mutational, and reverses when the drug is washed out — which is exactly what once-daily dosing does. Multiple daily doses that keep the level in the "sub-MIC-but-non-zero" range prolong adaptive resistance and paradoxically reduce net kill — one of the biological reasons the once-daily strategy outperforms traditional TDS dosing. [1]

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Dosing strategies — extended-interval once-daily vs traditional vs individualised

Three dosing philosophies have been used; the extended-interval once-daily (EIAD) is now standard for empirical Gram-negative cover in adults with normal-to-moderately-impaired renal function. The exception is enterococcal endocarditis synergy, where low-dose traditional or single-daily low-dose regimens persist.[1][2][3]

• Traditional (multiple-daily) dosing — 1–1.7 mg/kg TDS (gentamicin/tobramycin) targeting a peak 5–10 mg/L and a trough <2 mg/L. Largely historical for empirical cover, but still the regimen for enterococcal endocarditis synergy in many units (low steady exposure is enough for the cell-wall-synergy hypothesis; high peaks add nephrotoxicity without synergy benefit). Still used in pregnancy and endocarditis by some Australian/UK units.
• Extended-interval once-daily dosing (EIAD) — 5–7 mg/kg gentamicin or tobramycin once daily (amikacin 15 mg/kg once daily). The high dose reliably achieves Cmax/MIC ≥8–10 against typical GNR MICs (0.5–2 mg/L). Dose on adjusted body weight in obesity (Vd in sepsis/obesity is large) and ideal body weight if underweight.
• Individualised / Hartford nomogram dosing — give a flat 7 mg/kg, then draw a single randomised level at 6–14 hours post-dose, and read the dosing interval (q24h, q36h, or q48h) off the Hartford nomogram (Nicolau 1995). The Hartford method does not need a steady state — it uses a Bayesian-free lookup table validated on 2184 patients. [1]

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Therapeutic drug monitoring — peak, trough, and the ICU nuances

TDM is mandatory whenever an aminoglycoside is continued beyond 48–72 h. The trough is the toxicity guard (renal cortical accumulation; keep it low) and the peak is the efficacy guard (the Cmax/MIC ratio). Targets:[1]

ICU-specific pharmacokinetic distortions

The ICU population deranges every assumption built into nomograms derived from ward patients:[1]

• Augmented renal clearance (ARC). Young septic, traumatised, burned and post-neurosurgical patients often run CrCl >130 mL/min. ARC accelerates aminoglycoside clearance → subtherapeutic peaks → microbiological failure and resistance emergence. Suspect ARC in any hyperdynamic ICU patient and either up-titrate (some units use 8 mg/kg) or check a peak early.
• Capillary leak / expanded Vd. Severe sepsis, burns, post-major-surgery and pancreatitis expand the extracellular fluid volume by 30–50%, dropping the peak by an equivalent fraction. The standard 5–7 mg/kg may not achieve Cmax/MIC ≥8. Consider a higher mg/kg (or a loading-dose mentality) and verify with a measured peak.
• Hypoalbuminaemia. Free-fraction rises (good for the kill) but Vd expands (bad for the peak) — net effect unpredictable, so measure, don't guess.
• CRRT. CVVHDF at 25–35 mL/kg/h clears aminoglycoside at near-normal rates; dose q24–36 h guided by a level. CVVHD with high effluent rates may require near-normal dosing.
• Intermittent haemodialysis (IHD). Aminoglycoside t½ stretches to 30–60 h. Give a full maintenance dose after each dialysis session and check a pre-dialysis level to confirm wash-out; on non-dialysis days hold.
• ECMO. Aminoglycosides are hydrophilic and have a small Vd, so ECMO circuit sequestration is modest (unlike lipophilic agents). Vd still expands with critical illness — dose on weight and check a level.
• Obesity. Aminoglycoside Vd does not scale linearly with total body weight. Use adjusted body weight (IBW + 0.4 × excess) for dosing.
• Pregnancy. Vd rises and renal clearance rises — aminoglycoside levels fall. Streptomycin is avoided (ototoxic to the fetus, classic 8th-nerve injury); gentamicin is generally considered acceptable in severe infection. [1]

Synergy — enterococcal endocarditis and the high-level-resistance screen

The classic ICU synergy use of gentamicin is enterococcal endocarditis, where ampicillin (or vancomycin) alone is bacteriOSTATIC and a brief course of gentamicin provides a bactericidal synergy by facilitating cell-wall entry of the aminoglycoside. The cell-wall-active agent (ampicillin) opens the door; the aminoglycoside walks through it.[5][6]

The catch — high-level aminoglycoside resistance (HLR). ~30–50% of enterococci (especially E. faecium) carry acquired aminoglycoside-modifying enzymes that abolish the synergy at any clinically achievable concentration. Before adding gentamicin you MUST screen the isolate for HLR by plate-based testing: [1]

• HLR to gentamicin (gentamicin synergy plate, ≥500 mg/L) — positive in ~30–60% of E. faecium. If positive, gentamicin synergy is useless; the only useful aminoglycoside is streptomycin (if the HLR-streptomycin screen is negative).
• HLR to streptomycin (streptomycin synergy plate, ≥2000 mg/L) — positive in ~30–50%.
• HLR to BOTH gentamicin AND streptomycin — no aminoglycoside synergy is possible; treat with prolonged (≥6 weeks) high-dose ampicillin ± ceftriaxone (the ceftriaxone-ampicillin double-β-lactam regimen, which achieves additive cell-wall activity without aminoglycoside synergy and is less nephrotoxic — the standard modern approach in elderly/renal-impaired patients). [1]

The 2015 AHA and ESC endocarditis guidelines recommend a short 2-week gentamicin synergy course (1 mg/kg TDS, or 3 mg/kg OD by some protocols) only when the isolate is HLR-negative; the modern trend is toward NO gentamicin (or only 3–5 days) in older/renal-impaired patients because of the nephrotoxicity — the ceftriaxone-ampicillin regimen achieves equivalent cure without it.[5][6]

• Viridans-streptococcal endocarditis — the classic 2-week regimen of ceftriaxone + gentamicin (1 mg/kg TDS × 2 weeks) is for penicillin-susceptible strains in non-elderly patients with normal renal function; only a 2-week course, not 6 weeks.
• Staphylococcal endocarditis — gentamicin synergy is NOT recommended in either AHA or ESC 2015 guidelines: the classic "anti-staphylococcal penicillin + gentamicin" was associated with more renal toxicity and no mortality benefit (the Staphylococcal Endocarditis study, Working Group on Infective Endocarditis). Leave gentamicin out of staphylococcal endocarditis. [1]

Synergy — Gram-negative sepsis and the modern question of whether to add an aminoglycoside

In empirical septic-shock bundles, an aminoglycoside is sometimes added to a β-lactam for broad Gram-negative coverage and the synergy hypothesis (different ribosomal target + cell-wall disruption). The evidence is equivocal:[1]

• GNR bacteraemia observational data — a meta-analysis of β-lactam ± aminoglycoside for Gram-negative bacteraemia found no mortality benefit and more nephrotoxicity with the combination. The aminoglycoside adds toxicity without outcome benefit when an active β-lactam is on board.
• Pseudomonas bacteraemia — two-beta-lactam or beta-lactam + aminoglycoside "double coverage" is variably advocated; the largest cohort data suggest no mortality benefit from empiric aminoglycoside addition but a real AKI cost.
• Severe septic shock from a MDR organism — the empiric addition of tobramycin/amikacin to a β-lactam (especially if carbapenem-resistant Pseudomonas, Klebsiella with carbapenemase, or Acinetobacter) is reasonable as a 48–72 h bridge pending susceptibilities, then de-escalate. [1]

The pragmatic ICU position: empiric aminoglycosides are short-course (≤72 h), additive therapy for severe septic shock or known MDR Gram-negative infection, not routine co-therapy for every bacteraemia. Always stop at 72 h unless culture results demand otherwise. [1]

Inhaled aminoglycosides — VAP adjunct and chronic Pseudomonas airway infection

Inhaled aminoglycosides achieve epithelial-lining-fluid concentrations 10–100× higher than the same IV dose while keeping systemic absorption (and toxicity) low. This makes them attractive for MDR ventilator-associated pneumonia (VAP) and for chronic Pseudomonas airway infection in cystic fibrosis and bronchiectasis.[7][10][11]

• Cystic fibrosis — inhaled tobramycin (TOBI, Bethkis, Kitabis Pak, TIPPI). Ramsey 1999 NEJM established that alternating 28 days on / 28 days off inhaled tobramycin 300 mg BID in chronically Pseudomonas-colonised CF patients improves FEV₁ by ~10% and reduces sputum Pseudomonas density. Now a cornerstone of CF chronic suppressive therapy; inhaled aztreonam (Cayston) and inhaled colistin are alternatives.[7]
• Bronchiectasis / non-CF — inhaled tobramycin and inhaled colistin have RCT evidence of reduced exacerbation frequency in chronic Pseudomonas-colonised bronchiectasis.
• VAP adjunct — the IASIS and BAY41-6551 trials. The amikacin-fosfomycin inhalation system (AMIKAF / BAY41-6551) delivers aerosolised amikacin + fosfomycin via a vibrating-mesh nebuliser synchronised to inspiration. Niederman 2012 showed bactericidal tracheal-aspirate amikacin concentrations in mechanically ventilated patients with Gram-negative pneumonia.[8] Kollef 2017 (the IASIS trial) randomised patients with Gram-negative VAP to standard IV therapy ± inhaled amikacin-fosfomycin for 7–14 days.[9] The trial did not meet its primary endpoint of a favourable microbiological outcome (driven largely by a high ventilator/off-treatment rate in the control arm and enrolment issues), but showed a strong signal toward fewer clinical recurrences in the inhaled arm and a good safety profile with no excess nephrotoxicity. The ESCMID 2017 position paper (Rello et al) supports inhaled antibiotics as adjunctive therapy for VAP caused by MDR Gram-negatives that are poorly susceptible to IV agents — i.e. where the achievable IV concentration is sub-MIC.[10]

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Nephrotoxicity in depth — proximal tubule, megalin, and the lysosomal phospholipidosis

The aminoglycoside is freely filtered at the glomerulus, then a fraction is reabsorbed in the proximal tubule by the apical membrane transporter megalin (an LDL-receptor family member). Inside the proximal tubular cell the aminoglycoside accumulates in lysosomes, where it binds acidic phospholipids and inhibits phospholipidases → lysosomal phospholipidosis (myeloid-body formation) → tubular cell necrosis. The lesion is the non-oliguric, slowly progressive AKI of aminoglycoside nephrotoxicity.[1]

Key clinical features: [1]

• Incubation period of 5–7 days — the AKI usually appears after 5–10 days of therapy (correlates with the cortical-accumulation threshold), and is delayed further by once-daily dosing (the wash-out period clears cortical drug).
• Non-oliguric (typically) — urine output is maintained; the SCr climbs slowly. Distinguish from ATN of shock (which is typically oliguric and abrupt).
• Usually reversible — on cessation, the SCr typically returns toward baseline over 1–3 weeks. The histology is acute tubular necrosis without interstitial infiltrate (distinguish from acute interstitial nephritis of β-lactams).
• Risk factors — prolonged course (>5–7 days), high trough, concurrent nephrotoxins (vancomycin, amphotericin B, IV contrast, loop diuretics, NSAIDs, calcineurin inhibitors), pre-existing renal impairment, hypovolaemia, age, hepatic dysfunction (ascites), hypokalaemia, hypomagnesaemia.
• Biomarker opportunity — KIM-1, NGAL and cystatin C rise earlier than SCr; not yet routine. [1]

The vancomycin-gentamicin combination and the older vancomycin + piperacillin-tazobactam interaction share the proximal-tubular target; the addition of an aminoglycoside to vancomycin roughly doubles the rate of AKI. The modern trend of avoiding aminoglycoside co-therapy whenever an active β-lactam is available reflects this. [1]

Ototoxicity in depth — cochlear and vestibular hair cells, ROS, and the A1555G mutation

Aminoglycoside ototoxicity is dose-cumulative, often irreversible, and mechanistically distinct from the nephrotoxicity. The aminoglycoside enters the inner-ear hair cell via a mechanotransduction channel at the stereocilia tip, generates reactive oxygen species (ROS) via an iron-aminoglycoside complex, and triggers apoptosis of the outer hair cells of the cochlea (cochlear toxicity → high-frequency hearing loss) and/or the type I hair cells of the cristae ampullares and maculae (vestibular toxicity → imbalance, oscillopsia, vertigo).[12]

• Cochlear — high-frequency sensorineural hearing loss that progresses to lower frequencies; tinnitus is the early symptom. The loss is permanent (mammalian cochlear hair cells do not regenerate). Amikacin is more cochleotoxic; streptomycin and gentamicin more vestibulotoxic.
• Vestibular — gait ataxia, oscillopsia (the visual world bobs with head movement), imbalance especially in the dark. Gentamicin and streptomycin are more vestibulotoxic than cochleotoxic — gentamicin is in fact used therapeutically (intratympanic) for Ménière's disease precisely because of this vestibulotoxicity. The ICU patient may not complain of vertigo while bed-bound; vestibular toxicity declares itself on mobilisation.
• Genetic susceptibility — the mitochondrial A1555G mutation. A maternally inherited mutation in the 12S rRNA gene (m.1555A>G) confers extreme hypersensitivity to aminoglycoside ototoxicity — a single dose can cause profound irreversible bilateral hearing loss. The mutation is enriched in some East Asian populations. A family history of aminoglycoside-induced deafness is an absolute contraindication.
• Cumulative — the risk rises with the total cumulative dose (number of courses) and with concurrent ototoxins (loop diuretics — furosemide, ethacrynic acid; cisplatin; macrolides; vancomycin).
• Monitoring — baseline + weekly audiometry and vestibular testing (Romberg, head-impulse test) for any course >5–7 days. A patient on a prolonged course should be warned that imbalance, oscillopsia, or tinnitus mandates immediate review.[12]

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Neuromuscular blockade — the third toxicity

Rare in clinical practice but ICU-relevant and exam-classic. Aminoglycosides inhibit the pre-junctional calcium-dependent acetylcholine release and reduce post-synaptic receptor sensitivity → a myasthenic-like neuromuscular blockade. The mechanism is identical to (and additive with) magnesium sulphate, calcium-channel blockers and the non-depolarising neuromuscular blockers.[1]

• Magnify in myasthenia gravis, Lambert-Eaton, botulism, and the post-operative patient. An aminoglycoside given to a myasthenic patient (or after a non-depolarising block has not fully worn off) can precipitate acute respiratory failure — sometimes the presenting feature of previously undiagnosed myasthenia.
• High-dose IV bolus in renal failure — historical cases of acute paralysis after rapid IV gentamicin/amikacin bolus in uraemia; modern slow infusion (30 min) avoids this.
• Treatment — calcium gluconate (reverses the pre-junctional calcium block) ± neostigmine with glycopyrrolate; ventilatory support as needed. The aminoglycoside potentiates the non-depolarising neuromuscular blocker — ICU patients on long-term aminoglycoside courses often need lower rocuronium/vecuronium doses. [1]

Drug interactions

The aminoglycoside-toxicity portfolio is amplified by a defined list of co-administered agents:[1]

ICU syndromes where the aminoglycoside still earns its place

• Empirical Gram-negative septic shock — gentamicin/tobramycin 5–7 mg/kg OD as a 48–72 h empirical adjunct to a β-lactam, then de-escalate on culture and sensitivity. The aminoglycoside adds a second ribosomal target and a high peak — useful if the pathogen proves MDR.
• Pyelonephritis / complicated UTI with urosepsis — gentamicin retains excellent renal/urinary concentrations and is a classic single-agent cover for empirical urosepsis in the β-lactam-allergic.
• Enterococcal endocarditis — short-course gentamicin synergy (or streptomycin if HLR-gent positive) per the unit's protocol; the modern trend avoids gentamicin in the elderly/renal-impaired in favour of ampicillin + ceftriaxone.
• Viridans-streptococcal endocarditis — 2-week ceftriaxone + gentamicin course (penicillin-susceptible, non-elderly, normal renal function).
• Plague (Yersinia pestis) — streptomycin or gentamicin are first-line. Tularemia (Francisella tularensis) — streptomycin or gentamicin first-line.
• MDR Pseudomonas / Acinetobacter / carbapenemase-producing Klebsiella — amikacin (or plazomicin where available) is often one of the few remaining active agents; inhaled colistin or inhaled amikacin may supplement.
• Mycobacterial disease — amikacin for MDR-TB (BEAT-TB regimen), for M. avium complex refractory to macrolide-ethambutol-rifampicin, and for rapid growers (M. abscessus, M. fortuitum).
• Inhalational anthrax adjunct — not standard but historically described.
• Listeria meningitis — gentamicin synergy with ampicillin for Listeria rhombencephalitis/meningitis in immunocompromised (the traditional teaching; some modern ID guidance is moving away). [1]

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Clinical pearls — high-yield CICM/FFICM/EDIC points

Additional red flags

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References

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2. [2]Hatala R, Dinh T, Cook DJ Once-daily aminoglycoside dosing in immunocompetent adults: a meta-analysis Ann Intern Med, 1996.PMID 8633831
3. [3]Barza M, Ioannidis JP, Cappelleri JC, Lau J Single or multiple daily doses of aminoglycosides: a meta-analysis BMJ, 1996.PMID 8611830
4. [4]Bhatt J, Jahnke N, Smyth AR Once-daily versus multiple-daily dosing with intravenous aminoglycosides for cystic fibrosis Cochrane Database Syst Rev, 2019.PMID 31483853
5. [5]Baddour LM, Wilson WR, Bayer AS, Fowler VG Jr, Tleyjeh IM, Rybak MJ, Barsic B, Lockhart PB, Gewitz MH, Levison ME, Bolger AF, Steckelberg JM, Baltimore RS, Fink AM, O'Gara P, Taubert KA, American Heart Association Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease of the Council on Cardiovascular Disease in the Young, Council on Clinical Cardiology, Council on Cardiovascular Surgery and Anesthesia, and Stroke Council Infective Endocarditis in Adults: Diagnosis, Antimicrobial Therapy, and Management of Complications: A Scientific Statement for Healthcare Professionals From the American Heart Association Circulation, 2015.PMID 26373316
6. [6]Habib G, Lancellotti P, Antunes MJ, Bongiorni MG, Casalta JP, Del Zotti F, Dulgheru R, El Khoury G, Erba PA, Iung B, Miro JM, Mulder BJ, Plonska-Gosciniak E, Price S, Roos-Hesselink J, Sgyng-Martin U, Thuny F, Tornos Mas P, Vilacosta I, Zamorano JL, ESC Scientific Document Group 2015 ESC Guidelines for the management of infective endocarditis: The Task Force for the Management of Infective Endocarditis of the European Society of Cardiology (ESC). Endorsed by: European Association for Cardio-Thoracic Surgery (EACTS), the European Association of Nuclear Medicine (EANM) Eur Heart J, 2015.PMID 26320109
7. [7]Ramsey BW, Pepe MS, Quan JM, Otto KL, Montgomery AB, Williams-Warren J, Vasiljev-K M, Borowitz D, Bowman CM, Marshall BC, Marshall S, Smith AL Intermittent administration of inhaled tobramycin in patients with cystic fibrosis. Cystic Fibrosis Inhaled Tobramycin Study Group N Engl J Med, 1999.PMID 9878641
8. [8]Niederman MS, Chastre J, Corkery K, Fink JB, Luyt CE, Garcia MS BAY41-6551 achieves bactericidal tracheal aspirate amikacin concentrations in mechanically ventilated patients with Gram-negative pneumonia Intensive Care Med, 2012.PMID 22147112
9. [9]Kollef MH, Ricard JD, Roux D, Francois B, Ischaki E, Rozgonyi Z, Bui H, Montgomery AB, Luyt CE, ASTRA-ASPIRE Study Group A Randomized Trial of the Amikacin Fosfomycin Inhalation System for the Adjunctive Therapy of Gram-Negative Ventilator-Associated Pneumonia: IASIS Trial Chest, 2017.PMID 27890714
10. [10]Rello J, Sole-Lleonart C, Rouby JJ, Chastre J, Blot S, Luyt CE, Riera J, Vos MC, Monsel A, Dhanani J, Franci P, Brüggemann R, Tóth I, Artigas A, European Society of Clinical Microbiology and Infectious Diseases Use of nebulized antimicrobials for the treatment of respiratory infections in invasively mechanically ventilated adults: a position paper from the European Society of Clinical Microbiology and Infectious Diseases Clin Microbiol Infect, 2017.PMID 28412382
11. [11]Ehrmann S, Luyt CE Optimizing aerosol delivery of antibiotics in ventilated patients Curr Opin Infect Dis, 2020.PMID 31990813
12. [12]Selimoglu E Aminoglycoside-induced ototoxicity Curr Pharm Des, 2007.PMID 17266591