Primer registro de avance

Despite the resulting ototoxicity from aminoglycosides, these agents are utilised widely in developing countries because they are cost effective. The various aminoglycosides differ with regards to their toxicity profiles (Rybak & Ramkumar, 2007) and the prevalence of this cochleotoxicity differs in various populations and with different drugs (Petersen &

Rogers, 2015, Davidson, Brish, Rein & Rubinstein, 1980; Youw, Tengg, Bangs, Bangs &

Stephenson, 1962; Waterstrom, Bredberg, Lindquist,Lyttkens & Rask-Andersen, 1986; Al-Malky, Suri, Dawson, Sirimanna & Kemp D., 2011; Black, Lau, Weinstein, Young & Hewitt, 1976; Fausti et al., 1993). Some peptide antibiotics, despite having evidence of ototoxicity (Petersen & Rogers, 2015; Forouzesh, Moise & Sakoulas, 2009) have been studied in less detail, yet are also used to treat bacteria, such as in TB (Sagwa, 2017).

Aminoglycosides, including kanamycin, amikacin, tobramycin, netilmicin,

streptomycin and gentamicin have different reports of ototoxicity (Petersen & Rogers, 2015, Davidson et al., 1980; Youw et al., 1962; Waterstrom et al., 1986; Al-Malky et al., 2011;

Black et al., 1976; Fausti et al., 1993). Peptide antibiotics are numerous (Hancock & Chapple, 1999), and so only three specific peptides will be mentioned, namely capreomycin and

triethanolamine (polypeptide) and vancomycin (glycopeptide) as they have indicated some ototoxicity (Forouzesh et al., 2009; Akorn, Inc. Package Insert, 2015; Daniel, Sahmkow, Munguia, Schloss & Akache, 2008). However, according to Peterson & Rogers (2015), capreomycin, a polypeptide, can have a similar effect on the auditory system as

aminoglycosides.

The prevalence of cochlear damage due to aminoglycosides ranges from seven to 90%

(Petersen & Rogers, 2015). This variability could be due to a potential of underreporting, as

well as the lack of distinct parameters for monitoring ototoxicity (Edson & Terrell, 1991;

Petersen & Rogers, 2015). Different studies also detail different dosages and methods of monitoring, which could account for the difference in incidence (Arslan, Orzan & Santarelli, 1999). Furthermore, there are very few human and animal studies using kanamycin and capreomycin when not treating TB.

Studies with kanamycin have shown diverse results when used to treat infections (not TB). In a paediatric study, kanamycin at a relatively low dose (15 mg/kg daily for less than 17 days or a total dose of 280 mg) did not result in hearing loss (Davidson et al., 1980). This hearing loss was defined as a 20 dB decrease in hearing thresholds above 4 kHz and up to and including 8 kHz. Although, kanamycin did cause hearing loss in a much smaller case study of two infants who received dosages of more than 500 mg/kg (Youw et al., 1962). This small case study did not take other perinatal factors into account which could have contributed to the hearing loss. Kanamycin ototoxicity was further illustrated in an animal study with Guinea pigs, (Waterstrom et al., 1986) where ototoxicity was noted in the group that received 200 mg/kg per day for 21 days as well as in the group that received 60 mg/kg per days for 90 days. This study indicated how kanamycin, on raised dosages or increased periods can result in ototoxicity (Waterstrom et al., 1986).

Ototoxicity, from aminoglycosides, has been observed in various other studies (Fausti et al. 1993; Moore, Smith & Lietman, 1984). These studies, in some instances, investigated aminoglycosides in general and did not separate the different drugs (Fausti et al. 1993; Moore et al., 1984). Amikacin, an aminoglycoside often used to treat DR-TB (Sagwa, 2017), has demonstrated ototoxicity through a variety of studies. Black et al. (1976) looked at amikacin at dosages of ≥7.5 mg/kg every eight hours in patients who were leukopenic, infected with gentamicin-resistant organisms or had cystic fibrosis. They found, using pure tone

audiometry (PTA), that 24% were associated with the development of high-frequency hearing

loss, which was usually bilateral. Also, the onset of cochlear damage occurred in one patient after therapy was stopped (Black et al., 1976). Hotz, Harris and Probst (1994) found a higher incidence of amikacin induced ototoxicity, at 90%, when used for more than 12 days.

However, this was a small sample (10 ears), and Transient Evoked Otoacoustic Emissions (TEOAEs) were utilised in contrast to Black et al. (1976), where the use of audiometry.

Lerner and Matz (1979), with a larger group using gentamicin or amikacin, found a hearing loss in 7% of those taking gentamicin and 9% on amikacin. However, as per Black et al.

(1976), PTA was used in contrast to TEOAEs.

Moore et al. (1984) investigated incidence as well as risk factors for the expansion of auditory toxicity in patients receiving aminoglycosides, specifically gentamicin, tobramycin and amikacin. Ototoxicity, found in 22.3%, was found to be associated with drug therapy for a more extended period, patients who were more likely to be bacteremic, and had a higher temperature on average. The factors that did not significantly associate with hearing loss included plasma aminoglycoside levels, aminoglycoside type, furosemide use, diabetes, age, sex, renal function, initial auditory acuity, hematocrit value and shock (Moore et al., 1984).

Fee (1980), while investigating tobramycin and gentamicin, found only 16.4% ototoxicity in the gentamicin sample, which also showed more toxicity than tobramycin. The hearing loss from gentamicin progressed after the discontinued drug. This incidence of gentamicin

toxicity is less than Moore et al. (1984) of 22.3%, yet Moore et al. (1984) did not separate the drugs. As with Moore et al. (1984), associations between ototoxicity with high temperature and duration of therapy, and well as no associations with serum levels and age occurred. In contrast to Moore et al. (1984), Fee (1980) showed positive associations with ototoxicity with renal function and hematocrit value.

There is significantly more research on aminoglycoside ototoxicity than polypeptides, such as capreomycin. Yet, polypeptide ototoxicity, with capreomycin has been shown

through a human study (Akorn, Inc. Package Insert, 2015), and with ototopic triethanolamine polypeptide oleate-condensate in an animal (chinchilla) study (Daniel et al., 2008).

Capreomycin (injectable Capastat Sulfate) resulted in a subclinical auditory loss in approximately 11% of 722 healthy patients (5 – 10 dB loss in the 4 – 8 kHz range) and a clinically apparent hearing loss in 3% of the subjects. Some audiometric changes were reversible, and cases with permanent loss were not gradual following withdrawal of Capastat Sulfate. Tinnitus and vertigo were also reported (Akorn, Inc. Package Insert, 2015). However, these losses from capreomycin were in healthy individuals, where sick patients, such as those with TB, may have other risk factors, for example, previous exposure to ototoxic

medications, which would perhaps make them more at risk and susceptible to ototoxicity (Wang et al., 1999). Additionally, ototopic triethanolamine polypeptide oleate-condensate 10% was investigated in chinchillas (Daniel et al., 2008) as this composition is utilised as cerumenex, an earwax softener used in humans. Mean DPOAEs (between 1 kHz and 9 kHz) in the chinchillas were reduced from the first day of the study. This study demonstrated the possible ototoxic effects of another polypeptide other than capreomycin, however, has so far only been investigated in an animal model (Daniel, 2008).

Furthermore, vancomycin, a glycopeptide, has resulted in ototoxicity (Forouzesh et al., 2009), when investigated through a retrospective case-control analysis of audiometry results for patients on vancomycin therapy. Results showed a pattern of high-frequency hearing loss in 12% of the sample, with a trend in univariate analysis toward a higher rate with advanced age (Forouzesh et al., 2009). Although there are few human studies on

peptides and polypeptides, specifically on capreomycin and vancomycin, results do indicate a relationship to ototoxicity.

There is some controversy regarding the incidence of hearing loss in various human and animal studies, yet it is evident that ototoxicity occurs. Further investigation to

understand the cause and risk factors to predict an overall definitive incidence of the hearing loss with the various aminoglycosides and polypeptides is necessary. Also, the method the monitor and define ototoxicity needs to be established in order for consistent statistics and studies.