Drug Monograph
Tobramycin
tobramycin sulfate — aminoglycoside antibacterial
Pharmacokinetic Profile
Half-Life
2–3 h (normal renal function)
Metabolism
None — excreted unchanged
Protein Binding
Practically none
Bioavailability
100% (IV/IM); negligible oral
Volume of Distribution
~0.25 L/kg (extracellular fluid)
Clinical Information
Drug Class
Aminoglycoside
Available Forms
40 mg/mL vials (injection); 300 mg/5 mL ampule (nebulisation)
Route
IV (20–60 min infusion), IM, or inhaled
Renal Adjustment
Required — dose/interval by CrCl & levels
Hepatic Adjustment
None required
Pregnancy
May cause fetal harm — irreversible ototoxicity reported with aminoglycosides
Lactation
Present in breast milk; low oral absorption limits systemic infant exposure
Schedule
Prescription only (not scheduled)
Generic Available
Yes (injection and inhalation solution)
Therapeutic Index
Narrow — TDM mandatory (parenteral)
Black Box Warning
Yes — Nephrotoxicity, Ototoxicity, Neuromuscular Blockade, Fetal Harm
Indications
| Indication | Approved Population | Therapy Type | Status |
|---|---|---|---|
| Septicaemia (P. aeruginosa, E. coli, Klebsiella) | Adults & paediatrics | Monotherapy or combination | FDA Approved |
| Lower respiratory tract infections (P. aeruginosa, Klebsiella, Enterobacter, Serratia, E. coli, S. aureus) | Adults & paediatrics | Combination (usually + beta-lactam) | FDA Approved |
| CNS infections (meningitis) | Adults & paediatrics | Combination | FDA Approved |
| Intra-abdominal infections / peritonitis (E. coli, Klebsiella, Enterobacter) | Adults & paediatrics | Combination | FDA Approved |
| Skin, bone, and soft tissue infections (P. aeruginosa, Proteus, E. coli, Klebsiella, Enterobacter, S. aureus) | Adults & paediatrics | Monotherapy or combination | FDA Approved |
| Complicated urinary tract infections (P. aeruginosa, Proteus, E. coli, Klebsiella, Enterobacter, Serratia, S. aureus, Providencia, Citrobacter) | Adults & paediatrics | Monotherapy or combination | FDA Approved |
| Cystic fibrosis — chronic P. aeruginosa pulmonary infection (inhaled tobramycin 300 mg BID, 28 on/28 off) | Adults & paediatrics ≥6 years | Adjunctive (inhaled) | FDA Approved (TOBI) |
Tobramycin is an aminoglycoside with concentration-dependent bactericidal activity against aerobic gram-negative bacilli. It closely parallels gentamicin in its antibacterial spectrum but has notably superior in vitro activity against Pseudomonas aeruginosa, making it the preferred aminoglycoside when pseudomonal infection is suspected or confirmed. Like all aminoglycosides, tobramycin lacks reliable activity against streptococci, enterococci (when used alone), and anaerobes. Inhaled tobramycin (TOBI) achieves high airway concentrations with minimal systemic absorption and is a cornerstone of P. aeruginosa suppressive therapy in cystic fibrosis.
Off-Label / Extended Uses
Extended-interval (once-daily) dosing for serious gram-negative infections: 5–7 mg/kg IV q24h with Hartford nomogram monitoring is widely adopted in clinical practice, supported by meta-analyses demonstrating equivalent efficacy and potentially reduced nephrotoxicity. Evidence quality: High.
Synergy with beta-lactams for enterococcal endocarditis: Low-dose tobramycin (1 mg/kg q8h) used similarly to gentamicin for synergistic killing, though gentamicin is more commonly referenced in guidelines. Evidence quality: Moderate.
Dosing
Adult Dosing by Clinical Scenario (Parenteral)
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| Serious gram-negative infection — extended-interval (once-daily) dosing | 5–7 mg/kg IV q24h | Guided by Hartford nomogram | 7 mg/kg/dose | Draw random level 6–14 h post-dose; plot on nomogram to set interval (q24, q36, q48h). Use for patients with normal renal function Not recommended for endocarditis, burns >20% BSA, CF, pregnancy, ascites, or CrCl <20 mL/min |
| Serious infection — traditional (multiple-daily) dosing | 1 mg/kg IV/IM q8h | Adjusted by TDM | 5 mg/kg/day | 3 mg/kg/day for serious infections; up to 5 mg/kg/day in 3–4 divided doses for life-threatening infections, reduced to 3 mg/kg/day ASAP (FDA PI) Peak 4–6 µg/mL (at 1 mg/kg dose); trough <2 µg/mL. Avoid peak >12 µg/mL |
| Cystic fibrosis — parenteral acute exacerbation | 10 mg/kg/day IV in 4 divided doses | Guided by serum levels | Per TDM | CF patients have increased Vd and faster clearance; initial dose of 10 mg/kg/day recommended by FDA PI as starting guide Wide inter-patient variability; monitor levels closely. Extended-interval 10 mg/kg q24h also used (CF Foundation consensus) |
| Cystic fibrosis — chronic P. aeruginosa suppression (inhaled) | 300 mg nebulised BID | 300 mg nebulised BID | 300 mg BID | 28 days on / 28 days off alternating cycles. Not weight-adjusted. Use PARI LC PLUS or equivalent nebuliser Average serum level ~1 µg/mL post-inhalation; routine TDM not required unless renal impairment or concurrent parenteral aminoglycoside |
| Renal impairment — any indication | Loading dose 1 mg/kg | Reduce dose or extend interval per CrCl and serum levels | Per TDM | Interval (h) ≈ serum creatinine (mg/dL) × 6 (FDA PI guideline). Removed by haemodialysis; poorly removed by peritoneal dialysis Supplement after dialysis sessions; redose when level <1 µg/mL |
| Obesity (BMI ≥30) — weight adjustment | Use adjusted body weight: ABW = IBW + 0.4 × (TBW − IBW). The FDA PI states dosing weight should be estimated using lean body weight plus 40% of excess weight (FDA PI Section 2.7) Tobramycin distributes into extracellular fluid; does not penetrate adipose tissue proportionally | |||
Paediatric & Neonatal Dosing (Parenteral)
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| Premature or full-term neonates (≤1 week of age) | Up to 4 mg/kg/day in 2 equal doses q12h | Guided by levels | 4 mg/kg/day | FDA PI dosing; extended-interval approaches (4–5 mg/kg q24–48h) also used in clinical practice Neonates have larger Vd and prolonged half-life; adjust by GA and postnatal age |
| Children (>1 week of age) — serious infection | 2–2.5 mg/kg IV q8h | Adjusted by levels | 7.5 mg/kg/day | FDA PI: 6–7.5 mg/kg/day in 3–4 equally divided doses Alternative: 1.5–1.9 mg/kg q6h. Duration 7–10 days |
Clinical Pearl: TDM for Parenteral Tobramycin
Tobramycin has a narrow therapeutic index and TDM is mandatory for all parenteral use. The FDA PI recommends measuring serum levels after 2–3 doses, then every 3–4 days during therapy. For traditional dosing, draw peak 30 min after IV infusion (target: avoid >12 µg/mL; typical therapeutic range 4–6 µg/mL at 1 mg/kg) and trough just before next dose (target: <2 µg/mL). Rising trough levels >2 µg/mL indicate tissue accumulation and increased toxicity risk. For extended-interval dosing, a single random level at 6–14 hours is plotted on the Hartford nomogram. Inhaled tobramycin achieves average serum levels of ~1 µg/mL and does not routinely require TDM unless concurrent parenteral aminoglycoside use or renal impairment is present.
Pharmacology
Mechanism of Action
Tobramycin is a bactericidal aminoglycoside that irreversibly binds to the bacterial 30S ribosomal subunit, causing misreading of mRNA and disrupting protein synthesis. This leads to production of aberrant proteins that are incorporated into the bacterial cell membrane, increasing its permeability and accelerating cell death. Tobramycin exhibits concentration-dependent killing: bactericidal activity correlates with the peak serum concentration relative to the organism’s MIC (Cmax:MIC ratio). It also produces a clinically important post-antibiotic effect (PAE) of 1–3 hours against gram-negative organisms, which supports extended-interval dosing strategies that maximise peak concentrations while allowing prolonged drug-free periods to reduce toxicity. Tobramycin has enhanced activity against P. aeruginosa compared with gentamicin, which is the principal clinical differentiator within the aminoglycoside class.
ADME Profile
| Parameter | Value | Clinical Implication |
|---|---|---|
| Absorption | Negligible oral bioavailability; 100% via IV/IM. Inhaled: sputum levels ~1200 µg/g at 10 min; serum ~1 µg/mL at 1 h (300 mg nebulised dose) | Parenteral administration mandatory for systemic infections; inhaled route achieves high airway levels with minimal systemic exposure |
| Distribution | Vd ~0.25 L/kg; extracellular fluid distribution; renal cortex concentrations several-fold higher than serum; minimal biliary excretion; poor CSF penetration; crosses placenta | Vd increased in burns, sepsis, ascites (higher doses may be needed); low CSF levels may require intrathecal dosing for CNS infections |
| Metabolism | Not metabolised; excreted as unchanged drug | No hepatic dose adjustment needed; no CYP450 interactions |
| Elimination | t½ 2–3 h (normal renal function); primarily renal via glomerular filtration; practically no protein binding; removed by haemodialysis; poorly removed by peritoneal dialysis | Half-life directly proportional to renal impairment; small amounts retained in renal cortex for weeks (basis for nephrotoxicity); supplement dose post-haemodialysis |
Side Effects
≥10%
Very Common (Parenteral)
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Nephrotoxicity (rising BUN/SCr, proteinuria, oliguria, electrolyte wasting) | ~10–15% | Primarily acute tubular necrosis; risk factors include trough >2 µg/mL, peak >12 µg/mL, cumulative dose, advanced age, dehydration, concurrent nephrotoxins, and diabetes (FDA PI). Generally reversible with early detection |
| Ototoxicity (auditory and/or vestibular) | ~2–14% | Auditory damage is usually irreversible; vestibular toxicity may manifest as dizziness, vertigo, nystagmus. Risk increased with high peak/trough levels, prolonged therapy, renal impairment, concurrent ototoxins, extremes of age, and MT-RNR1 mitochondrial DNA variants (FDA PI) |
1–10%
Common
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Nausea / vomiting | 1–5% | GI effects reported in clinical studies and post-marketing (FDA PI Section 6) |
| Diarrhoea | 1–5% | Evaluate for C. difficile if persistent or bloody; CDAD can present up to 2 months post-therapy (FDA PI Section 5.6) |
| Elevated transaminases (SGOT/SGPT) | 1–5% | Usually transient and isolated; monitor LFTs (FDA PI Section 6) |
| Eosinophilia / leukopenia / anaemia / thrombocytopenia | 1–3% | Haematological changes reported; usually reversible (FDA PI Section 6) |
| Electrolyte wasting (Mg, Ca, K, Na, PO4) | 1–10% | Renal tubular losses; hypomagnesaemia may cause tetany, arrhythmias (FDA PI Section 5.1) |
| Rash / injection site pain | 1–3% | Local irritation uncommon; serious dermatological reactions reported rarely (FDA PI Section 5.4) |
Inhaled
Common Adverse Effects — Inhaled Tobramycin (>5%)
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Increased cough | >5% | Most common inhaled side effect; usually mild |
| Pharyngitis | >5% | Throat irritation from nebulised drug |
| Increased sputum | >5% | Related to mucus mobilisation |
| Dyspnoea / bronchospasm | >5% | Pre-treatment with bronchodilator recommended for patients with reactive airways |
| Voice alteration / taste perversion | >5% | Dysgeusia reported; usually temporary |
| Haemoptysis | >5% | Common in CF patients; distinguish from disease progression |
| Decreased lung function | >5% | Transient decreases in FEV1 may occur post-inhalation; pre-treatment with bronchodilator recommended |
| Rash | >5% | Monitor for progression; discontinue if severe dermatological reaction suspected |
Serious
Serious Adverse Effects (Regardless of Frequency)
| Adverse Effect | Estimated Frequency | Typical Onset | Required Action |
|---|---|---|---|
| Irreversible sensorineural hearing loss | 2–14% (class data) | Days to weeks; may manifest after therapy ends | Baseline and serial audiometry in high-risk patients; discontinue immediately at first sign. Consider MT-RNR1 variant testing if maternal history of aminoglycoside ototoxicity (FDA PI Section 5.2) |
| Vestibulotoxicity (vertigo, ataxia, nystagmus) | Variable | Days to weeks | Discontinue tobramycin; deficit may be permanent |
| Acute kidney injury / renal failure | ~10–15% | 3–7 days into therapy | Monitor SCr daily; reduce dose or discontinue if rising; ensure hydration; generally reversible if detected early (FDA PI Section 5.1) |
| Neuromuscular blockade / respiratory paralysis | Rare | During or shortly after administration | IV calcium salts to reverse; mechanical ventilation if needed; avoid in myasthenia gravis / Parkinson’s disease (FDA PI Section 5.5) |
| Anaphylaxis / SJS / TEN / exfoliative dermatitis | Rare (post-marketing) | Variable | Discontinue immediately; emergency treatment; cross-allergenicity among aminoglycosides (FDA PI Section 5.4) |
| Macular necrosis (intraocular/subconjunctival use) | Reported | Post-administration | Tobramycin injection is NOT approved for intraocular or subconjunctival use (FDA PI Section 5.8) |
| Clostridioides difficile-associated diarrhoea | Uncommon | During or up to 2 months post-treatment | Test for C. difficile toxin; discontinue tobramycin if confirmed; initiate appropriate therapy (FDA PI Section 5.6) |
Discontinuation
Discontinuation Rates
Parenteral Tobramycin
Nephrotoxicity & Ototoxicity
Key point: The FDA PI does not provide pooled discontinuation rates. Treatment duration is typically 7–10 days. Discontinuation is driven by rising creatinine, hearing changes, or completion of planned course. Therapy beyond 10 days significantly increases toxicity risk.
Inhaled Tobramycin (TOBI)
Bronchospasm & Tinnitus
Key point: Tinnitus occurred in 8 tobramycin-treated vs 0 placebo patients in clinical studies and may be a sentinel symptom of ototoxicity. Bronchospasm should be managed with pre-treatment bronchodilator.
Managing Nephrotoxicity
Tobramycin nephrotoxicity results from drug accumulation in proximal tubular cells leading to acute tubular necrosis. The FDA PI (Section 5.1) identifies key risk factors: rising trough levels above 2 µg/mL, peak concentrations above 12 µg/mL, total cumulative dose, advanced age, volume depletion, diabetes, and concurrent use of nephrotoxic drugs. Extended-interval dosing may reduce nephrotoxicity by allowing a drug-free interval that limits tubular accumulation. Maintaining adequate hydration, monitoring daily serum creatinine, electrolytes (Mg, Ca, K, Na, PO4), urinalysis, and urine output during the first week are essential.
Drug Interactions
Tobramycin is not metabolised and has practically no protein binding, so CYP450-mediated or protein displacement interactions are absent. Clinically significant interactions are pharmacodynamic (additive toxicity) and involve concurrent nephrotoxic, ototoxic, or neuromuscular blocking agents. In vitro inactivation by beta-lactam antibiotics occurs, particularly relevant in severe renal impairment.
MajorOther Nephrotoxic / Ototoxic Drugs (Vancomycin, Amphotericin B, Cisplatin, other aminoglycosides)
MechanismAdditive nephrotoxicity and/or ototoxicity via independent tubular and cochlear damage pathways
EffectSubstantially increased risk of acute kidney injury and irreversible hearing loss
ManagementAvoid concurrent or sequential use when possible; if essential, monitor renal function daily, serum levels frequently, and perform serial audiometry (FDA PI Section 7.1)
FDA PI (Boxed Warning)MajorLoop Diuretics (Furosemide, Ethacrynic Acid)
MechanismIndependent ototoxic potential; IV diuretics may alter aminoglycoside tissue concentrations
EffectEnhanced risk of irreversible ototoxicity
ManagementAvoid concurrent use when possible; if unavoidable, monitor hearing closely (FDA PI Section 7.2)
FDA PI (Boxed Warning)MajorNeuromuscular Blocking Agents (Succinylcholine, Tubocurarine)
MechanismAminoglycosides have intrinsic curare-like neuromuscular blocking activity
EffectProlonged respiratory depression and paralysis, especially in patients with myasthenia gravis or Parkinson’s
ManagementUse with extreme caution; have IV calcium available for reversal; mechanical ventilation may be needed (FDA PI Section 5.5)
FDA PIModerateBeta-Lactam Antibiotics (Penicillins, Cephalosporins)
MechanismIn vitro inactivation of tobramycin by beta-lactam ring opening; clinically relevant mainly in severe renal impairment where both drugs accumulate
EffectReduced tobramycin serum levels, subtherapeutic concentrations possible
ManagementNever mix in same IV line or syringe; administer separately. In renal failure, monitor tobramycin levels more frequently. Therapeutic synergy with separate administration remains beneficial (FDA PI Section 5.9)
FDA PIMonitoring
-
Serum Drug Levels (TDM)
After 2–3 doses, then q3–4 days
Routine Traditional: peak 30 min post-IV (target: avoid >12 µg/mL), trough just before next dose (target: <2 µg/mL). Extended-interval: random level at 6–14 h on Hartford nomogram. Inhaled: routine TDM not required (avg serum ~1 µg/mL) unless renal impairment or concurrent parenteral aminoglycoside (FDA PI Section 2.9). -
Renal Function (BUN, SCr, CrCl, electrolytes)
Baseline, then daily for first week; twice weekly thereafter
Routine Monitor SCr, BUN, urine output, urinalysis. Also monitor serum Mg, Ca, K, Na, PO4 as renal tubular losses occur (FDA PI Section 5.1). Rising SCr ≥0.5 mg/dL above baseline warrants dose adjustment or discontinuation. -
Auditory Function
Baseline audiometry; serial testing if therapy >2 weeks or high-risk
Trigger-based High-frequency hearing loss occurs first and may be initially subclinical. Tinnitus is a sentinel symptom. For inhaled tobramycin, tinnitus occurred in 8 vs 0 placebo patients in clinical studies. Patients with MT-RNR1 variants at greatly increased risk (FDA PI Section 5.2). -
Vestibular Function
Assess clinically throughout therapy
Routine Monitor for dizziness, vertigo, nystagmus, and ataxia. Vestibular damage may be independent of cochlear damage. -
Pulmonary Function (inhaled only)
Baseline FEV1; monitor for bronchospasm
Routine Bronchospasm may occur with nebulised tobramycin. Pre-treatment with a bronchodilator is recommended. Monitor spirometry in CF patients as clinically indicated. -
Neuromuscular Function
In operative/ICU settings
Trigger-based Particularly in patients receiving NMBAs or with neuromuscular disorders. Have IV calcium available (FDA PI Section 5.5).
Contraindications & Cautions
Absolute Contraindications
- Known hypersensitivity to tobramycin or any aminoglycoside — cross-allergenicity exists across the class; serious reactions including anaphylaxis, SJS, and TEN have been reported (FDA PI Section 4).
Relative Contraindications (Specialist Input Recommended)
- Pre-existing significant renal impairment — dramatically increased nephrotoxicity risk; requires intensified TDM and dose individualisation.
- Pre-existing auditory or vestibular impairment — baseline audiometry essential before therapy.
- Known MT-RNR1 mitochondrial DNA variants (m.1555A>G) — greatly increased susceptibility to permanent hearing loss even at therapeutic levels (FDA PI Section 5.2).
- Pregnancy — aminoglycosides cross the placenta and can cause fetal harm including irreversible congenital deafness (FDA PI Section 5.3).
- Myasthenia gravis or Parkinson’s disease — may precipitate or worsen neuromuscular blockade (FDA PI Section 5.5).
Use with Caution
- Elderly patients — reduced renal function may not be reflected by SCr alone; use CrCl-based dosing (FDA PI Section 8.5).
- Dehydration or volume depletion — increases nephrotoxicity risk; ensure adequate hydration.
- Concurrent nephrotoxic or ototoxic agents — avoid concurrent or sequential use when possible.
- Extensive burns — altered PK with reduced serum concentrations; higher doses may be required guided by TDM (FDA PI Section 2.5).
- Cystic fibrosis — altered PK with increased clearance; use higher initial doses (10 mg/kg/day) with close TDM (FDA PI Section 2.5).
- Obesity — use adjusted body weight (lean BW + 40% of excess); do not dose on total body weight (FDA PI Section 2.7).
FDA Boxed Warning
Nephrotoxicity, Ototoxicity, Neuromuscular Blockade, and Embryo-Fetal Toxicity
Tobramycin can cause acute kidney injury including renal failure. Risk factors include rising trough levels above 2 µg/mL, peak concentrations above 12 µg/mL, cumulative dose, advanced age, volume depletion, and concurrent nephrotoxic drugs. Tobramycin can cause irreversible auditory and vestibular toxicity that may continue to develop after discontinuation. Aminoglycosides have been associated with neuromuscular blockade and respiratory paralysis. Tobramycin can cause fetal harm when administered to pregnant women. Monitor renal function and serum tobramycin levels in all patients. Reduce dose or discontinue if renal impairment or ototoxicity occurs.
Patient Counselling
Purpose of Therapy
Tobramycin is a powerful antibiotic used to treat serious bacterial infections, particularly those caused by Pseudomonas and other gram-negative bacteria. It is given through a vein, as a muscle injection, or inhaled through a nebuliser (for cystic fibrosis patients). It requires regular blood tests to monitor drug levels and kidney function. It does not treat viral infections.
How to Take
Parenteral tobramycin is administered by healthcare professionals in a clinical setting. Inhaled tobramycin (for CF) is self-administered at home using a nebuliser, twice daily for 28 days followed by 28 days off, in alternating cycles. Complete the full course as prescribed even if symptoms improve early.
Hearing Changes
Tell patientTobramycin can rarely cause hearing problems, including ringing in the ears or difficulty hearing, which may be permanent. Hearing tests may be performed before and during treatment.
Call prescriberImmediately if you notice ringing in your ears, muffled hearing, or difficulty understanding speech.
Dizziness and Balance
Tell patientThis medication may affect the balance centres in your inner ear. You may experience dizziness, unsteadiness, or a spinning sensation.
Call prescriberIf you develop new dizziness, difficulty walking, or a sensation that the room is spinning.
Kidney Function
Tell patientTobramycin can affect the kidneys. Your care team will monitor kidney function with regular blood and urine tests. Staying well hydrated helps protect your kidneys.
Call prescriberIf you notice a significant decrease in urine output, swelling, or unusually dark urine.
Inhaled Tobramycin — Breathing Difficulty
Tell patientInhaled tobramycin may cause temporary coughing, throat irritation, or wheezing. Your doctor may recommend using a bronchodilator before each nebuliser session. Do not mix tobramycin with dornase alfa in the same nebuliser.
Call prescriberIf you experience severe shortness of breath, chest tightness, or wheezing that does not improve after using your bronchodilator.
Pregnancy
Tell patientTobramycin may harm an unborn baby, including causing permanent hearing loss. Inform your doctor before starting treatment if you are pregnant, think you may be pregnant, or are planning a pregnancy.
Call prescriberIf you become pregnant during treatment.
Allergic Reactions
Tell patientSerious allergic reactions can occur, including skin rashes, swelling, and difficulty breathing. Inform your care team of any known allergies to antibiotics, especially aminoglycosides.
Call prescriberImmediately for fever, swelling, difficulty breathing, wheezing, decreased blood pressure, severe skin rash, or blistering.
Sources
Regulatory (PI / SmPC)
- Tobramycin for Injection, USP — Full Prescribing Information (Fresenius Kabi). Revised 2/2023. FDA Label (NDA 050789) Primary FDA label source for all parenteral dosing, indications, boxed warnings, adverse reactions, PK data, and drug interactions in this monograph.
- TOBI (tobramycin inhalation solution) — Full Prescribing Information. FDA Label (NDA 050753) FDA label for inhaled tobramycin; source for CF dosing, inhalation PK data, and inhaled-specific adverse effects.
Key Clinical Trials / Meta-Analyses
- Ramsey BW, Pepe MS, Quan JM, et al. Intermittent administration of inhaled tobramycin in patients with cystic fibrosis. N Engl J Med. 1999;340(1):23–30. doi:10.1056/NEJM199901073400104 Pivotal RCT establishing the 28-on/28-off inhaled tobramycin regimen for CF patients with P. aeruginosa.
- Hatala R, Dinh T, Cook DJ. Once-daily aminoglycoside dosing in immunocompetent adults: a meta-analysis. Ann Intern Med. 1996;124(8):717–725. doi:10.7326/0003-4819-124-8-199604150-00003 Meta-analysis supporting extended-interval aminoglycoside dosing as at least as effective and no more toxic than traditional multiple-daily dosing.
- Barza M, Ioannidis JPA, Cappelleri JC, Lau J. Single or multiple daily doses of aminoglycosides: a meta-analysis. BMJ. 1996;312(7027):338–345. doi:10.1136/bmj.312.7027.338 Independent meta-analysis confirming similar efficacy and possible reduced nephrotoxicity with once-daily aminoglycoside dosing.
- Nicolau DP, Freeman CD, Belliveau PP, Nightingale CH, Ross JW, Quintiliani R. Experience with a once-daily aminoglycoside program administered to 2,184 adult patients. Antimicrob Agents Chemother. 1995;39(3):650–655. doi:10.1128/AAC.39.3.650 Landmark study validating the Hartford nomogram for extended-interval aminoglycoside dosing in a large adult cohort.
Guidelines
- Mogayzel PJ Jr, Naureckas ET, Robinson KA, et al. Cystic Fibrosis Foundation pulmonary guideline: pharmacologic approaches to prevention and eradication of initial Pseudomonas aeruginosa infection. Ann Am Thorac Soc. 2014;11(10):1640–1650. doi:10.1513/AnnalsATS.201404-166OC CFF guideline positioning inhaled tobramycin for eradication and suppressive therapy of P. aeruginosa in cystic fibrosis.
- Baddour LM, Wilson WR, Bayer AS, et al. Infective endocarditis in adults: diagnosis, antimicrobial therapy, and management of complications: a scientific statement from the AHA. Circulation. 2015;132(15):1435–1486. doi:10.1161/CIR.0000000000000296 AHA guideline providing aminoglycoside synergy dosing context for infective endocarditis.
Mechanistic / Basic Science
- Moore RD, Lietman PS, Smith CR. Clinical response to aminoglycoside therapy: importance of the ratio of peak concentration to minimal inhibitory concentration. J Infect Dis. 1987;155(1):93–99. doi:10.1093/infdis/155.1.93 Established the Cmax:MIC ratio as the primary pharmacodynamic predictor of aminoglycoside efficacy.
- Lacy MK, Nicolau DP, Nightingale CH, Quintiliani R. The pharmacodynamics of aminoglycosides. Clin Infect Dis. 1998;27(1):23–27. doi:10.1086/514620 Key review of concentration-dependent killing and post-antibiotic effect principles underpinning extended-interval dosing strategies.
Pharmacokinetics / Special Populations
- Smyth AR, Bhatt J, Nevitt SJ. Once-daily versus multiple-daily dosing with intravenous aminoglycosides for cystic fibrosis. Cochrane Database Syst Rev. 2017;3:CD002009. doi:10.1002/14651858.CD002009.pub6 Cochrane review of aminoglycoside dosing in CF, supporting once-daily dosing as safe and effective in this population.
- Traynor AM, Nafziger AN, Bertino JS Jr. Aminoglycoside dosing weight correction factors for patients of various body sizes. Antimicrob Agents Chemother. 1995;39(2):545–548. doi:10.1128/AAC.39.2.545 Established the 0.4 correction factor for adjusted body weight dosing in obese patients receiving aminoglycosides.
- Rybak MJ, Abate BJ, Kang SL, Ruffing MJ, Lerner SA, Drusano GL. Prospective evaluation of the effect of an aminoglycoside dosing regimen on rates of observed nephrotoxicity and ototoxicity. Antimicrob Agents Chemother. 1999;43(7):1549–1555. doi:10.1128/AAC.43.7.1549 Prospective study comparing extended-interval vs traditional dosing for nephrotoxicity and ototoxicity outcomes.
- Touw DJ, Westerman EM, Sprij AJ. Therapeutic drug monitoring of aminoglycosides in neonates. Clin Pharmacokinet. 2009;48(2):71–88. doi:10.2165/0003088-200948020-00001 Comprehensive review of neonatal aminoglycoside PK and TDM strategies informing age- and weight-based dosing.