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Ciprofloxacin ear drops ototoxicity gentamicin

Since their introduction in 1944, multiple aminoglycoside preparations have become available, including streptomycin, dihydrostreptomycin, kanamycin, gentamicin, neomycin, tobramycin, netilmicin, and amikacin. The aminoglycosides are bactericidal antibiotics that bind to the 30S ribosome and inhibit bacterial protein synthesis. They are active only against aerobic gram-negative bacilli and cocci.

Although the ototoxic effects of aminoglycosides are well documented, this class of drugs is still widely used today. Aminoglycosides may be used in combination with penicillin in staphylococcal, streptococcal, and, especially, enterococcal endocarditis. An aminoglycoside is often added to a beta-lactam antibiotic when serious Pseudomonas aeruginosa infections are treated. Aminoglycosides can also be effective in the treatment of tuberculosis. Particular groups of patients, including those with cystic fibrosis, immune dysfunction, and certain chronic infectious disease, are more likely to be treated with this class of antibiotics.

Of all ototoxic drugs, the aminoglycosides are the most vestibulotoxic, although they vary greatly in their differential effects on the vestibular and cochlear systems. [2] Kanamycin, amikacin, neomycin, and dihydrostreptomycin are preferentially cochleotoxic. Gentamicin affects both cochlear and vestibular systems; however, most authors include gentamicin as primarily ciprofloxacin ear drops ototoxicity gentamicin vestibulotoxic. Streptomycin, tobramycin, and netilmicin are also primarily vestibulotoxic.

Pathophysiology

Aminoglycoside toxicity primarily targets renal and cochleovestibular systems; however, no clear correlation exists between degree of nephrotoxicity and ototoxicity. Cochlear toxicity that results in hearing loss usually begins in the high frequencies and is secondary to irreversible destruction of outer hair cells in the organ of Corti, predominantly at the basal turn of the cochlea. In the vestibular apparatus, type I hair cells are more sensitive than type II hair cells. [3]

Aminoglycosides are cleared more slowly from inner ear fluids than from serum and therefore a latency exists to the ototoxic affects of aminoglycosides. This latency can result in progression of hearing loss or onset of hearing loss after cessation of aminoglycoside treatment. Continuing to monitor the patient for cochleotoxic and vestibulotoxic effects up to 6 months after cessation of aminoglycoside treatment is important.

The exact mechanisms of aminoglycoside ototoxicity remain unknown. Many cellular processes have been implicated, and this continues to be an active area of research. [4] It does appear that aminoglycoside agents must enter hair cells to induce cell death. [5] After entry into hair cells, many cellular mechanisms and processes may be involved. Disruption of mitochondrial protein synthesis, formation of free oxygen radicals, activation of c-Jun N-terminal kinase (JNK), and activation of caspases and nucleases can ensue. Aminoglycosides have also been shown to have direct effects on cellular membrane potentials through interactions with potassium channels. [6] In addition, aminoglycoside interaction with transition metals such as iron and copper potentiate the formation of free radicals and further cell damage.

Ultimately, some interaction of these many processes leads to permanent loss of sensory hair cells in both the cochlea and vestibular apparatus, resulting in permanent hearing loss or balance dysfunction. [7, 8]

Aminoglycoside ototoxicity is likely multifactorial, and further investigation continues. Some studies are investigating iron chelators and antioxidants as possible agents to prevent hearing loss during therapy, while other studies are exploring forms of gene therapy as future treatment options. Currently, no treatment is available apart from amplification and cochlear implantation; therefore, prevention is paramount.

Epidemiology

In certain countries, antibiotics are prescribed freely or are available without prescription. In these areas, aminoglycosides cause as many as 66% of cases of deaf mutism. Depending on agent and dosing, up to 33% of adult patients may have audiometric changes with aminoglycoside treatment. Vestibular toxicity is also well documented; it occurs in as many as 4% of adult patients. The incidence of patients who experience toxicity due to aminoglycosides may be decreasing because of improvements in monitoring and heightened awareness.

Studies indicate that cochlear toxicity from aminoglycosides is less common in neonates and children than in adults. The incidence of aminoglycoside-induced cochlear toxicity in neonates has been estimated at around 2%. [9]

Risk factors

Certain factors may put patients at increased risk for ototoxicity. Aminoglycoside ototoxicity is more likely to occur with larger doses, higher blood levels, or longer duration of therapy. Other high-risk patients include elderly patients, those with renal insufficiency, those with preexisting hearing problems, those with a family history of ototoxicity, and those receiving loop diuretics or other ototoxic or nephrotoxic medications.

A genetic predisposition exists in mitochondrial RNA mutation 1555A>G, which has been found to be associated with nonsyndromic and aminoglycoside-induced hearing loss. [10] The defect creates an alteration in mitochondrial protein synthesis. Chinese patients with this defect have more rapid and severe effects of aminoglycoside ototoxicity. Careful evaluation of family history is important and may prevent many cases. In addition, some have suggested that high-risk populations (eg, patients with cystic fibrosis, a family history, and immune dysfunction) should be screened for this mutation. [11, 8]

Signs and symptoms

Clinically, acute cochlear damage may present as tinnitus. Early hearing loss may go unrecognized by the patient and initially manifest as an increase in the threshold of highest frequencies (>4000 Hz). With progression, lower speech frequencies are affected and the patient may become profoundly deaf if the drug is continued. If the drug is stopped early in the course of damage, further loss may be prevented, and partial recovery of auditory thresholds may be possible. However, the loss is usually permanent.

Symptoms of vestibular toxicity typically include imbalance and visual symptoms. The imbalance is worse in the dark or in situations in which footing is uncertain. Spinning vertigo is unusual. The visual symptoms, called oscillopsia, occur only when the head is moving. Quick movements of the head are associated with transient visual blurring. This can cause difficulties with seeing signs while driving or recognizing people's faces while walking. Clinically, nystagmus may be present as an early sign.

Prevention

Prevention of aminoglycoside ototoxicity involves careful monitoring of serum drug levels and renal function as well as hearing evaluations before, during, and after therapy. Measure baseline audiometric function before therapy; however, this is not always possible in acute situations. Daily administration decreases incidence of ototoxicity and should be considered whenever possible. Conscientiously identify high-risk patients and select alternative antibiotics for them. Lastly, because aminoglycosides remain in the cochlea long after therapy has ended, instruct patients to avoid noisy environments for 6 months after therapy completion because they remain more susceptible to noise-induced cochlear damage.

Recent animal studies have involved the administration of free-radical scavengers, iron chelators, and inhibitors of cell death pathways as possible mechanisms to prevent ototoxicity. Several promising agents, including vitamin E, alpha lipoic acid, Ebselen, and ginkgo biloba, have been found to be otoprotective and effective in some animal studies. Further clinical trials are needed to determine if the protective mechanisms demonstrated in animal studies can be replicated in patients while maintaining therapeutic effects of the aminoglycosides. [7, 12]

A study by Kocyigit et al suggested that the antioxidant N-acetyl-cysteine (NAC) can protect against amikacin ototoxicity. The study involved 46 patients who received amikacin for peritoneal dialysis-related peritonitis, with NAC being administered to half of the patients and a placebo being given to the other half. Otoacoustic emission measurements in the NAC and placebo groups indicated that NAC protected cochlear function, particularly at higher frequencies. In addition, oxidative stress measurements indicated that antioxidant status significantly improved in the NAC patients. [13]

A literature review by Kranzer et al also indicated that NAC has an otoprotective effect when administered with aminoglycosides. The review included 146 patients with end-stage renal failure who showed reduced ototoxicity with NAC administration while undergoing aminoglycoside treatment. [14]

Specific aminoglycosides

See the list below:

  • Streptomycin: Streptomycin was the first clinically applied aminoglycoside and was used successfully against gram-negative bacteria in the past. Streptomycin preferentially affects the vestibular system rather than the auditory system. Vestibular damage due to streptomycin is common with prolonged use and in patients with impaired renal function. Because of its toxicity, and because of widespread resistance, this agent is used infrequently today. However, streptomycin use has risen for treatment of tuberculosis.

  • Gentamicin: As with streptomycin, gentamicin has a predilection for the vestibular system. Therapeutic peak serum levels of 10-12 mcg/mL are generally considered safe but may still be toxic in some patients. Carefully adjust dosing in patients with renal disease.

  • Neomycin: This agent is one of the most cochleotoxic aminoglycosides when administered orally and in high doses; therefore, systemic use generally is not recommended. Neomycin is among the slowest aminoglycosides to clear from the perilymph; consequently, delayed toxicity (1-2 wk) may ensue after discontinuation of therapy. Neomycin is mainly used as an effective otic and ototopical agent. Although neomycin is generally considered safe when used topically in the ear canal or on small skin lesions, equally effective alternatives are available.

  • Kanamycin: Although less toxic than neomycin, kanamycin is quite ototoxic. Kanamycin has a propensity to cause profound cochlear hair cell damage, marked high-frequency hearing loss, and complete deafness. The damaging effect is primarily to the cochlea, while the vestibular system is usually spared injury. Kanamycin has limited clinical use today. As with neomycin, parenteral administration is generally not recommended.

  • Amikacin: Amikacin is a derivative of kanamycin and has very little vestibular toxicity. Its adverse effects primarily involve the auditory system; however, it is considered less ototoxic than gentamicin. In the treatment of severe infections, amikacin is mainly indicated on the basis of results of susceptibility tests and patient response.

  • Tobramycin: Ototoxicity of tobramycin is similar to that of amikacin; high-frequency hearing loss results. As with kanamycin, vestibular toxicity is less common. Tobramycin is frequently used in otic and topical preparations. Topical use, although not without controversy, is generally considered safe.


Source: http://emedicine.medscape.com/article/857679-overview


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