Microbiology · Year 2 · from Microbiology
Case 2: Aminoglycoside Toxicity
Presentation
A 72-year-old woman with a prosthetic aortic valve is admitted with fever and positive blood cultures growing Enterococcus faecalis. She is started on ampicillin plus gentamicin for synergistic bactericidal therapy for presumed infective endocarditis. Baseline audiometry is performed. After 10 days of therapy, she reports new onset of tinnitus and difficulty hearing her family members during visits. Repeat audiometry shows bilateral high-frequency hearing loss. Her serum creatinine has also risen from 0.9 mg/dL at admission to 1.8 mg/dL.
Clinical Image
Diagram illustrating the mechanism of aminoglycoside action (binding to 30S ribosomal subunit causing protein mistranslation) and the mechanisms of ototoxicity and nephrotoxicity.
Image Source: Lecture image - aminoglycoside pharmacology
Questions
- Why is ampicillin combined with an aminoglycoside for enterococcal endocarditis?
- What is the mechanism of aminoglycoside ototoxicity?
- What is the mechanism of aminoglycoside nephrotoxicity, and what are its clinical characteristics?
- How should this patient's antibiotic regimen be modified?
Answers
- Rationale for combination therapy: Enterococci are inherently tolerant to beta-lactam antibiotics - ampicillin inhibits cell wall synthesis and is bacteriostatic, but it does not kill enterococci. For serious enterococcal infections like endocarditis, bactericidal therapy is required to eradicate the infection from the valve vegetation. The combination of a cell wall-active agent (ampicillin) plus an aminoglycoside (gentamicin or streptomycin) achieves synergistic bactericidal activity. The mechanism is that the cell wall damage from ampicillin allows increased aminoglycoside uptake into the bacterial cell, where it causes lethal mistranslation of proteins. This synergism does not occur if the enterococcus has high-level aminoglycoside resistance (HLAR), which must be tested before initiating combination therapy.
- Mechanism of ototoxicity: Aminoglycoside ototoxicity results from damage to the hair cells of the cochlea (causing hearing loss) and vestibular apparatus (causing vertigo and imbalance). Aminoglycosides are taken up by hair cells and persist in the inner ear long after serum levels decline. The drugs cause:
- Formation of reactive oxygen species (ROS)
- Disruption of mitochondrial function in hair cells
- Activation of apoptotic pathways leading to irreversible hair cell death
Hearing loss typically begins in the high-frequency range (perceived first as difficulty understanding speech) and progresses to lower frequencies with continued exposure. A mitochondrial DNA mutation (A1555G) markedly increases susceptibility to aminoglycoside ototoxicity.
- Mechanism of nephrotoxicity: Aminoglycosides are freely filtered at the glomerulus and accumulate in proximal tubular epithelial cells via megalin-mediated endocytosis. Intracellular accumulation leads to:
- Disruption of phospholipid metabolism
- Mitochondrial dysfunction
- Proximal tubular cell necrosis
Clinical characteristics include:
- Nonoliguric acute kidney injury (urine output is often preserved)
- Rise in serum creatinine typically after 5-7 days of therapy
- Usually reversible upon drug discontinuation (unlike ototoxicity)
- Risk factors: prolonged therapy, high trough levels, concurrent nephrotoxins (NSAIDs, contrast), volume depletion, and advanced age
- Modification of antibiotic regimen: Given the documented ototoxicity and nephrotoxicity, gentamicin should be discontinued. Options for completing therapy include:
- Ampicillin plus ceftriaxone - this double beta-lactam combination has been shown to be as effective as ampicillin-gentamicin for E. faecalis endocarditis and is now preferred by many experts, especially for patients at high risk of aminoglycoside toxicity
- If the isolate is susceptible, daptomycin may be considered as an alternative (though its use in left-sided endocarditis is controversial)
- The aminoglycoside should not be restarted due to the irreversible nature of ototoxicity
- Audiology follow-up and nephrology consultation are warranted