Gentamicin

Mechanism of Action

Gentamicin, an aminoglycoside antibiotic, is bactericidal. Gentamicin passes through the gram-negative membrane in an oxygen-dependent active transport. As oxygen is required, this is why aminoglycosides are not effective against anaerobic bacteria. Once in the cytoplasm, gentamicin and other aminoglycosides bind to the 16s rRNA at the 30s ribosomal subunit, disturbing mRNA translation and, thus, leading to the formation of truncated or non-functional proteins.[5] The mechanism of gentamicin's bactericidal activity has not yet been fully elucidated. Still, some propose that truncated proteins are placed at the cell wall, compromising its impermeability. At the same time, others suggest that the accumulation of reactive oxygen species, as a consequence of the depletion of proteins involved in redox reactions, may lead to bacterial death.[6]

Gentamicin, like all aminoglycosides, exhibits concentration-dependent killing. Higher concentrations correlate with greater antimicrobial killing. For these reasons, clinicians should closely monitor peaks and troughs during systemic use. Additionally, research has noted that the synergistic effects of aminoglycosides on Gram-positive bacteria, when combined with other medications, have been reported, but the mechanism remains unknown.

Pharmacokinetics

When administered as an intramuscular injection, gentamicin achieves peak serum concentrations after 30 to 90 minutes. Because of its polar nature, penetration into the central nervous system and general cells is minimal, and it binds to plasma albumin. Most gentamicin is excreted unmetabolized by glomerular filtration, enabling a urinary concentration almost 100-fold higher than the serum concentration.[7]

Administration

Gentamicin is generally available in parenteral, ophthalmic, and topical preparations.

• The ophthalmic gentamicin preparations are available as ointment and solution at a concentration of 0.3%. They are typically used for bacterial eye infections, such as keratitis and conjunctivitis.[8]
• The topical gentamicin ointment and cream have a concentration of 0.1% and are restricted to specific skin and subcutaneous tissue infections, which usually are secondary to abrasions, cuts, and burns.
• The parenteral route mainly encompasses intramuscular and intravenous administration, with doses for both calculated based on the patient's weight. For moderate and morbidly obese patients, the weight for dose calculation equals 0.4 multiplied by excess body weight plus estimated ideal body weight.
  • The dose of 5 to 7 mg/kg daily given intravenously (infused over 30 to 120 minutes) is the preferred way for gentamicin application in most systemic infections by sensitive germs, even though the traditional dosing of 3 to 5 mg/kg/day divided into doses every 8 hours is still an option in certain scenarios.
  • The daily dose may be administered intramuscularly for some non-serious infections, such as pelvic inflammatory disease without sepsis.
  • Infectious endocarditis caused by staphylococci or enterococci was previously treated with gentamicin and beta-lactams, although this therapy has been abandoned due to increasing rates of bacterial resistance.[5]
  • Usually combined with an anaerobicidal antibiotic, Gentamicin can be administered as a single dose of 5 mg/kg 60 minutes before surgical incision in gastrointestinal, urologic, and gynecologic procedures for prophylaxis against surgical infection.[9]

Gentamicin and other aminoglycosides have specific characteristics in their antibacterial activity. The bactericidal capacity of aminoglycosides correlates with their peak concentration; the higher the concentration, the greater the bacterial killing. The postantibiotic effect (PAE), another feature of aminoglycosides, is the suppression of bacterial regrowth that persists for a few hours after the antibiotic concentration falls below the minimum inhibitory concentration (MIC); a high peak concentration also enhances the PAE.[10] Therefore, these properties explain why gentamicin is preferable for high-dose regimens with extended-interval dosing.

Pregnancy/Breastfeeding Considerations

It belongs to the FDA pregnancy category D medicine. Gentamicin is minimally excreted into human milk. There is a lack of data for maternal single daily doses of gentamicin. Newborn infants and older infants absorb small amounts of gentamicin, but their serum levels with maternal 3-times-daily dosing are far below the therapeutic range used to treat newborn infections. Hence, systemic effects of gentamicin are unlikely in infants. Nevertheless, monitoring the infant for possible adverse effects on the gastrointestinal flora, such as thrush, diaper rash, diarrhea, or blood in the stool, as well as for antibiotic-associated colitis, is recommended.[11]

Adverse Effects

Characteristically, gentamicin reaches high concentrations in the renal cortex and the inner ear. The latter may be injured, leading to auditory and, especially, vestibular dysfunction. The first manifestation of cochlear damage is often high-pitched tinnitus, which may last a few weeks after the gentamicin is interrupted. A high-frequency hearing loss may be present in almost two-thirds of patients receiving aminoglycosides, including gentamicin, but only a small number report hearing impairment.[12] The vestibular toxicity manifests as nausea, vomiting, balance disorder, and vertigo within the first 2 weeks. A chronic phase, which may persist for about 2 months, is marked by ataxia and, not infrequently, leaves residual dysfunction. Gentamicin tends to accumulate in renal proximal tubular cells and can cause damage. Hence, mild proteinuria and a reduction in glomerular filtration rate are potential consequences of gentamicin use, with 14% of users experiencing these effects in a review.[13] Once proximal tubular cells retain regenerative capacity, renal injury and its consequences are often reversible. Compared with the high-dose and extended-interval dosing approach, the divided-dose scheme implies a longer duration of gentamicin serum concentrations above the toxicity threshold, resulting in a higher risk of ototoxicity and nephrotoxicity.

Although rare, neuromuscular blockade is a serious adverse effect of virtually all aminoglycosides. The known risk factors include concurrent conditions (eg, myasthenia gravis) or medications (eg, vecuronium) that interfere with the neuromuscular junction. The blockade probably results from a reduction in presynaptic acetylcholine release and interference with the function of acetylcholine postsynaptic receptors, both effects mediated by aminoglycosides. The intravenous administration of calcium can overcome this toxicity.[14]

Contraindications

According to the manufacturer's label, an absolute contraindication to gentamicin use is a history of hypersensitivity to it or other aminoglycosides, although this is rare. In cases of renal impairment, dosing adjustments should be made based on the glomerular filtration rate (GFR). For a high-dose, extended-interval dosing approach, the dose can be preserved, but the interval between doses should increase in line with the decrease in GFR. In burn patients, systemic absorption of topical gentamicin may be enhanced, and one should be vigilant for potential complications. Systemic gentamicin belongs to category D of the FDA pregnancy risk classification (ie, although there is evidence of human fetal risk, its use is acceptable if the possible benefits overcome the risks).

Drug Interactions

Avoid the concomitant administration of gentamicin with potent diuretics (ie, ethacrynic acid or furosemide) as diuretics may cause ototoxicity. Additionally, when diuretics are administered intravenously, they enhance gentamicin toxicity by increasing the drug concentration in serum and tissues.[15] 

Monitoring

Serum gentamicin concentration monitoring is often unnecessary for brief treatment durations (less than 6 days) in noncritical patients with adequate renal function. On the other hand, in case of long periods of treatment or high risk for aminoglycoside toxicity (eg, older age, concomitant use of other nephrotoxins, preexisting renal disease), serum monitoring is well indicated. In traditional dosing, the concentration measurement should occur after the patient has received at least 3 maintenance doses; the trough concentration is measured within 30 minutes before the next dose, and the peak concentration is measured 30 minutes after the end of the intravenous infusion (in the case of intramuscular injection, 60 minutes after the application). For extended-interval dosing, a single serum concentration obtained between 6 and 14 hours after the first dose is sufficient to assess and readjust subsequent doses using a nomogram-based approach.[16] It is recommended to avoid prolonged peak plasma concentrations of gentamicin exceeding 12 mcg/mL and trough concentrations exceeding 2 mcg/mL.

Renal function should be evaluated twice weekly in patients without prior renal disease using serum creatinine and blood urea nitrogen. Periodic microscopic urinalysis is also vital to detect proteinuria and casts, which may indicate kidney injury. Hearing tests must be considered in patients with a high risk for toxicity or those receiving prolonged therapy. Patients with preexisting neuromuscular disorders or undergoing anesthetic procedures should have monitoring due to the risk of neuromuscular blockade.

Toxicity

The main toxicity that occurs from gentamicin systemic use is nephrotoxicity. Although a rare event, hypersensitivity reactions secondary to gentamicin administration can be severe, to the extent that cases requiring intensive care unit admissions exist in the literature.[17] There is no antidote for gentamicin toxicity, and the approach for gentamicin-induced hypersensitivity reaction is drug suspension combined with supportive treatment. The possible hypersensitivity manifestations are urticaria, eosinophilia, delayed-type hypersensitivity reaction (Stevens-Johnson syndrome and toxic epidermal necrolysis), angioedema, and anaphylactic shock. The clinical manifestations should guide the treatment strategy. In case of hypotension or even anaphylactic shock, intravenous fluids and vasoactive agents are the primary therapeutic options. Oxygen supplementation or mechanical ventilation may be necessary if respiratory distress occurs. When Stevens-Johnson syndrome or toxic epidermal necrolysis develops, the mainstay of treatment includes wound care, pain control, fluid and electrolyte management, and monitoring of superinfections. Nephrotoxicity, one of the most common adverse effects of gentamicin use, is associated with the therapy duration and not with serum concentrations. Generally, the glomerular filtration rate decrement is small and transient, and rarely progresses to oliguric-anuric renal failure. Likewise, ototoxicity is more common in long-term gentamicin therapy. Furthermore, cochlear and vestibular damage sometimes is irreversible and can be accumulated after repetitive gentamicin exposure; aspirin use may attenuate this ototoxicity risk.[18]

Enhancing Healthcare Team Outcomes

Gentamicin is a widely used antibiotic that has been an important part of medical practice since the 1940s. Although antimicrobial resistance is increasing, gentamicin remains a powerful option for many gram-negative infections, including severe cases. Clinicians must always try to determine whether the pathogen responsible for the infection is susceptible to gentamicin, enabling more accurate use of the antibiotic. Current evidence indicates that a high-dose, extended-interval dosing approach is at least as efficacious as traditional multiple-dose regimens but is less nephrotoxic and ototoxic and, therefore, should be used whenever possible. Doses must be calculated based on patient weight and adjusted according to the GFR. Nurses should remember that the infusion time must be at least 30 minutes and remain vigilant for hypersensitivity reactions. Pharmacists are essential for checking the prescribed dose, ensuring the necessary items for administration are available, and reviewing possible medication interactions. The healthcare team should be prepared to recognize and manage acute kidney injury and inner ear lesions, both potential adverse effects of gentamicin use. Open communication and collaborative work of all interprofessional team members can improve patient care and enhance treatment outcomes with gentamicin.