What are the concerns and considerations for using amikacin in patients with central nervous system (CNS) infections, particularly those with impaired renal function or hearing loss?

CNS Penetration of Amikacin

Amikacin has extremely poor CNS penetration and should not be used for CNS infections via systemic administration alone. The blood-brain barrier severely limits penetration of aminoglycosides, making them inadequate for treating meningitis, brain abscesses, or other CNS infections when given intravenously or intramuscularly 1.

CNS Penetration Characteristics

• Amikacin achieves negligible CSF concentrations when administered systemically, even in the presence of inflamed meninges 1
• The blood-brain barrier limits penetration of systemically administered aminoglycosides to the site of CNS infection 1
• For comparison, vancomycin achieves only 1-5% CSF penetration (inflamed vs uninflamed meninges), and amikacin penetration is similarly poor or worse 1

Alternative Routes for CNS Infections

Intraventricular administration is the only viable route if amikacin must be used for CNS infections:

• Four pediatric patients with Gram-negative meningitis/ventriculitis resistant to multiple drugs were successfully treated with combined parenteral and intraventricular amikacin 2
• All four patients were cured without nephrotoxicity, ototoxicity, or persistent infection on follow-up 2
• Treatment continued for 14 days after CSF cultures became negative 2

Critical Considerations in Patients with Renal Impairment

Renal dysfunction dramatically increases both nephrotoxicity and ototoxicity risk 1, 3:

• For patients over 59 years or with stage 3 CKD, reduce dose to 10 mg/kg per day (maximum 750 mg) 3
• In renal insufficiency, maintain the 12-15 mg/kg dose but reduce frequency to 2-3 times weekly rather than daily 3
• Never reduce the milligram dose below 12-15 mg/kg when extending intervals, as smaller doses reduce efficacy by failing to achieve adequate peak concentrations 3
• Monitor renal function twice weekly during month 1, weekly during month 2, then fortnightly thereafter 1

Dosing Adjustments

• Target trough levels must remain <5 mg/L for amikacin 3
• Peak levels above 35 mcg/mL and trough levels above 10 mcg/mL should be avoided 4
• In one study, 57% of patients with peak levels exceeding 32 mcg/mL and 55% with trough levels exceeding 10 mcg/mL developed cochlear damage 5

Ototoxicity Concerns and Monitoring

Hearing loss from amikacin is typically irreversible and occurs in 11-24% of patients 5, 6:

• Obtain baseline audiometry before initiating therapy in all patients who can be tested 3
• Perform monthly audiometry until aminoglycoside treatment ceases 1, 3
• Ototoxicity is defined as 20 dB loss from baseline at any one test frequency OR 10 dB loss at any two adjacent test frequencies 1, 3

Immediate Action Required

If ototoxicity is detected on audiogram, discontinue amikacin immediately 1, 3:

• The hearing loss that has already occurred is likely permanent 1
• Alternative option: reduce dosing frequency if discontinuation is not feasible, though this does not reverse existing damage 3
• Patients should stop treatment immediately if they develop tinnitus, vertigo, loss of balance, hearing loss, or auditory disturbances 3

Risk Factors for Ototoxicity

• Larger total dose (mean 24g vs 9.6g in those without hearing loss) 5
• Longer duration of therapy (19 days vs 9 days) 5
• Previous aminoglycoside exposure 5
• Elderly age 1
• Concurrent loop diuretics (furosemide, ethacrynic acid) which potentiate ototoxicity 1, 3

Preferred Alternatives for CNS Infections

For Gram-negative CNS infections, consider these alternatives with superior CNS penetration 1:

• Linezolid: 66% CSF penetration with peak concentrations of 7-10 mcg/mL 1
• TMP-SMX: 13-53% penetration for TMP, 17-63% for SMX 1
• Rifampin: 22% CSF penetration with bactericidal concentrations achievable 1
• Meropenem: Significantly lower nephrotoxicity risk than amikacin 7

Critical Pitfalls to Avoid

• Never combine multiple aminoglycosides (amikacin with kanamycin, streptomycin, or capreomycin) as there is no clinical benefit and increased toxicity 1, 3
• Avoid concurrent loop diuretics as they potentiate ototoxicity 1, 3
• Do not delay audiometry until symptoms appear, as damage may already be irreversible 3
• Never use amikacin in second or third trimester of pregnancy due to risk of vestibular or auditory nerve damage to the fetus 1
• In dialysis patients with recognized toxicity, immediately cease amikacin—do not attempt dose reduction 7
• Patient-reported symptoms alone are not reliable for monitoring; objective audiometry is essential 3