What is the clinical effectiveness of once daily intravenous (IV) amikacin compared to divided doses in an elderly patient with stage 3 prostate cancer and a pseudomonas infection, particularly with regards to minimizing nephrotoxicity and ototoxicity?

Once-Daily IV Amikacin is Equally Effective and Likely Safer Than Divided Dosing

Once-daily amikacin dosing at 15 mg/kg should be the preferred regimen for most patients, including elderly patients with Pseudomonas infections, as it achieves superior peak concentrations for concentration-dependent bacterial killing while demonstrating equivalent or reduced nephrotoxicity compared to divided dosing. 1

Efficacy Evidence

Clinical outcomes are equivalent between once-daily and divided dosing regimens:

• A large randomized controlled trial of 316 patients with serious gram-negative infections demonstrated 90% satisfactory clinical response with both once-daily (15 mg/kg) and twice-daily (7.5 mg/kg q12h) amikacin regimens, with no significant differences in efficacy 1

• Once-daily dosing achieves mean peak serum concentrations of 40.9 mg/L (approximately 10× MIC for most gram-negative bacteria), compared to only 24.4 mg/L (6× MIC) with twice-daily dosing 1

• These higher peaks are pharmacodynamically advantageous because aminoglycosides exhibit concentration-dependent killing—higher peak-to-MIC ratios correlate with better bacterial eradication 1

Safety Profile: Nephrotoxicity

Once-daily dosing demonstrates equal or potentially lower nephrotoxicity:

• In the pivotal 316-patient trial, nephrotoxic events occurred in 9 patients (once-daily) versus 11 patients (twice-daily), with multivariate analysis showing low correlation between dosing frequency and nephrotoxicity 1

• A smaller study of 45 elderly patients found that once-daily dosing at 15 mg/kg did not increase nephrotoxicity risk 2

• Trough concentrations were actually lower with once-daily dosing (1.8 mg/L at 24h) compared to twice-daily dosing (3.1 mg/L at 12h), which is clinically important since sustained elevated troughs drive nephrotoxicity 1

Safety Profile: Ototoxicity

Ototoxicity rates are comparable between regimens:

• Five ototoxic events total were observed: 3 with once-daily versus 2 with twice-daily dosing—no statistically significant difference 1

• Baseline audiometry should be performed before initiating therapy, with monthly monitoring during treatment 3

• Patients must be instructed to report tinnitus, hearing loss, vertigo, or balance disturbances immediately, as aminoglycoside-induced hearing loss is typically permanent and irreversible 3

Special Considerations for Elderly Patients with Renal Impairment

For patients >59 years or with stage 3 CKD, dose adjustments are mandatory:

• Reduce the dose to 10 mg/kg per day (maximum 750 mg) for patients over 59 years of age 4

• In renal insufficiency, maintain the 12-15 mg/kg dose but reduce frequency to 2-3 times weekly rather than daily to preserve concentration-dependent killing while avoiding accumulation 4

• Critical pitfall: Do not reduce the milligram dose below 12-15 mg/kg when extending intervals, as smaller doses may reduce efficacy by failing to achieve adequate peak concentrations 4

• Monitor serum drug concentrations to target peak levels >64 µg/mL and trough levels <5 mg/L 3, 5

Practical Dosing Algorithm

For elderly patients with Pseudomonas infection and stage 3 CKD:

1. Initial dose: 10 mg/kg IV once daily (not to exceed 750 mg) 4

2. Measure baseline: Serum creatinine, audiometry, and vestibular testing 3

3. Check levels: Obtain peak (1 hour post-infusion) and trough (just before next dose) on day 3 3

4. Adjust frequency if needed: If creatinine clearance continues to decline or trough >5 mg/L, extend interval to 2-3 times weekly while maintaining the 10-15 mg/kg dose 4

5. Monitor monthly: Renal function, audiometry, and patient-reported symptoms 3

Duration and Combination Therapy

• For Pseudomonas infections, consider 2-3 months of intermittent amikacin (2-3 times weekly) in combination with other agents for extensive or drug-refractory disease 4

• Combination therapy with amikacin and beta-lactams (e.g., imipenem, piperacillin) demonstrates synergistic killing against Pseudomonas, including resistant strains 6

Critical Pitfalls to Avoid

• Never continue aminoglycosides after development of ototoxicity or significant nephrotoxicity without expert infectious disease consultation 7, 3

• Never combine multiple aminoglycosides due to additive toxicity without clinical benefit 3

• Avoid concurrent loop diuretics (furosemide, ethacrynic acid) as they potentiate ototoxicity 4, 3

• Do not rely on patient-reported symptoms alone for monitoring—objective audiometry is essential as damage may be irreversible before symptoms appear 3