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Rapid Responses: Rapid Responses published:
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"Aminoglycosides in the UK are only used in hospitals"
- Michael G Bamber (20 October 2007)
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How practical is this genetic screening test?
- Thomas Rourke (26 October 2007)
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Aminoglycoside vestibulotoxicity
- Barry M. Seemungal, Adolfo M. Bronstein, Professor of Clinical Neurology and Neuro-Otology, Imperial College. (29 October 2007)
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Ototoxicity caused by aminoglycosides- A neonatal perspective
- Hugh Bishop, Richard Hansen, Sumesh Thomas, and Ian M. Gould (7 November 2007)
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Aminoglycosides: putting risk in perspective
- Zahir O.E Babiker, John S Cheesbrough, Consultant Microbiologist, Department of Microbiology, Royal Preston Hospital, Sharoe Green Lane North, Preston PR2 9HT (10 November 2007)
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Michael G Bamber, general practitioner Colsterworth Medical Practice, Back Lane, Colsterworth, Grantham Lincolnshire NG33 5NJ
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The interesting editorial by Bitner-Glindzicz and Rahman on the rare group of people sensitive to ototoxicity from aminoglycosides could be expanded with respect to their dogmatic statement, "..aminoglycosides in the UK are only used in hospitals". Are the authors aware of the availability of both gentamicin and neomycin drops used on their own or in combination with corticosteroids for treatment of otitis externa? My consultant ENT colleagues have suggested on occasion that I prescribe these preparations to patients with otitis media with perforation and copious aural discharge, reassuring me that my concerns are without foundation. It is interesting that those same colleagues use aminoglycosides topically to destroy vestibular activity. Michael G Bamber Competing interests: None declared |
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Thomas Rourke, ST2 ENT St Georges Hospital, Tooting, London, SW17 0QT
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This article highlights an important side-effect associated with aminoglycoside administration and a possible screening method to reduce this potential risk. It does however fail to point out the lack of clinical practicality of the genetic test described. In a recent case of acute mastoiditis complicated by a lateral sinus thrombosis it was decided to commence IV Gentamicin following mastoidectomy. It was suggested that this genetic screening test be performed prior to administration. On contacting the genetics department, we were informed that the test could not be performed at our own hospital and would be referred elsewhere for analysis. We were also informed that a result would take between 2-3 days. The decision was then made to commence the gentamicin prior to obtaining the result of the genetic test based on the clinical severity of the case. Although this form of screening could potentially reduce the rates of ototoxicity secondary to aminoglycoside admnistration, its widespread use is somewhat limited by its practicality. The commencement of aminoglycoside therapy is used most commonly in the acute setting where witholding treatment for 2-3 days for the results of a genetic screening test would not be in the best interests of the patient. As the author points out, this test needs to be more readily available and quicker, in order to justify its use in conjunction with aminoglycoside therapy. Competing interests: None declared |
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Barry M. Seemungal, Honorary Research Clinician Neuro-otology Unit, Dep't of Clin Neuroscience, Imperial College, Charing Cross Hosp, London W6 8RF, Adolfo M. Bronstein, Professor of Clinical Neurology and Neuro-Otology, Imperial College.
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Bitner-Glindzicz and Rahman are to be commended for raising awareness of aminoglycoside ototoxicity and focus on their special interest in hearing loss with special reference to mitochondrial mutations. We are however, concerned to correct a common misconception, i.e. ototoxicity is synonymous with deafness. In fact, except for the rare cases of mitochondrial mutations discussed by these authors, vestibular function is much more sensitive to aminoglycosides than hearing function. Thus in patients with gentamicin-associated vestibular loss, the majority (90%) will not be deaf[1]. Sadly, most cases of aminoglycoside vestibulotoxicity with preserved hearing will not be diagnosed[2]. The typical patient with aminoglycoside vestibular failure will have been in critical care often with renal failure. If not sedated, a minority (20%) experience spontaneous episodic vertigo[1] for a few days, with episodes lasting minutes to hours; an unexplained phenomenon as simultaneous, bilateral vestibular loss should not cause vertigo (since vertigo implies a right-left vestibular imbalance). Whatever their origin, the vertiginous episodes wane after a few days as the vestibular function is ablated. In all patients with aminoglycoside vestibulotoxicity however, attempts to rehabilitate and mobilise are severely compromised due to gait imbalance and disabling oscillopsia on head movement. Occasionally, vestibular sedatives (e.g. stemetil) are administered which further compromises balance. Some patients are labelled as having had a cerebellar stroke. The diagnosis of vestibulotoxicity must be considered in patients with a history of aminoglycoside administration who develop head-movement- induced oscillopsia and gait imbalance. The diagnosis is easily made clinically via the head-impulse test[3] and confirmed by caloric testing. Aminoglycoside vestibular failure, which is permanent, can have devastating consequences for a patient’s mobility and functional independence. Functional recovery, which is never complete, is slow (over years). Graded physical activity is important in aiding the recovery of gait and balance function. 1. Shiyama G, Ishiyama A, Kerber K, Baloh RW. Gentamicin ototoxicity: clinical features and the effect on the human vestibulo-ocular reflex. Acta Otolaryngol 2006; 126(10):1057-61. 2. Rinne T, Bronstein AM, Rudge P, Gresty MA, Luxon LM. Bilateral loss of vestibular function. Acta Otolaryngol Suppl 520, Pt 2:247-50 (1995). 3. Halmagyi GM, Curthoys IS. A clinical sign of canal paresis. Arch Neurol 1988; 45(7):737-9. Competing interests: None declared |
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Hugh Bishop, Specialist Registrar in Paediatrics Royal Aberdeen Children's Hospital, Richard Hansen, Sumesh Thomas, and Ian M. Gould
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We read with interest Bitner-Glindzicz and Rahmans editorial on Ototoxixcity caused by aminoglycosides (1). We would like to comment on their conclusions with specific reference to the neonatal population, in particular the suggestion that genetic testing be performed in babies requiring aminoglycosides and that an alternative antibiotic regimen be considered pending the results thereof. It seems to us that there are two competing imperatives, one that a single course of aminoglycosides within the therapeutic dose range may be enough to cause severe hearing impairment (1), and the other that newborn babies with suspected early-onset sepsis require prompt antimicrobial therapy, which must include cover for both Group B Streptococci and Escherichia coli, the two commonest infecting organisms in this patient group. Three antibiotic regimens which fulfil the latter need are combined penicillin and aminoglycoside, monotherapy with a third-generation cephalosporin or monotherapy with a carbapenem. A Cochrane review of empirical treatment of suspected early onset neonatal sepsis reveals that there are no RCTs showing benefit of one regimen over another. (2) Further reading of the literature reveals that third-generation cephalosporins are known to select extended spectrum Beta-lactamase (ESBL) -producing Gram-negative organisms, as well as derepressed Gram-negatives, Enterococci and methicillin-resistant Staphylococcus aureus (MRSA), Clostridium difficile and yeasts.(3). One study comparing empirical treatment with amoxicillin and cefotaxime vs. penicillin and tobramycin for early-onset sepsis in neonates showed an 18 times Relative Risk of becoming colonised with bacteria resistant to the empirical regimen assigned for the amoxycillin-cefotaxime regimen(4). Carbapenems too, are known to select ESBL-producing Gram-negatives (5) as well as carbapenemase -producing organisms. In the absence of accurate data on prevalence of this mutation, and the relatively small numbers of patients in high quality studies looking at ototoxicity of gentamicin in the neonatal age group (210 babies in 4 studies) (6), we suggest that babies requiring empirical antibiotic therapy deserve to have their family history of hearing impairment in maternal relatives elucidated by their paediatrician, prior to a discussion with parents of the relative benefits and risks of any given antibiotic regimen, as retrospective analysis has shown that this simplest of medical interventions could help identify patients at risk of aminoglycoside induced deafness secondary to mitochondrial gene mutation.(7) Pending the availability of further information regarding the prevalence of the m.1555A>G gene and the safety of alternative empirical antibiotic regimens for early-onset neonatal sepsis, we suggest that all pregnant women with sensorineural deafness or a family history of hearing impairment in maternal relatives should have genetic screening for the m.1555A>G mutation prior to delivery. This would enable obstetricians and midwives to highlight newborns at particular risk of ototoxicity caused by aminoglycoside. We would welcome comment from our obstetric colleagues as to the practicality of this suggestion. Finally, it would be useful to retrospectively screen the notes of neonatal unit graduates with sensorineural deafness and perform a genetic screen in those infants who had received aminoglycosides. This would enable us to assess the contribution of this particular gene mutation to deafness in a population who are well known to be exposed to a number of factors associated with the development of deafness. References 1 Bitner-Glindzicz M, Rahman S. Ototoxicity caused by aminoglycosides is severe and permanent in genetically susceptible people. BMJ 2007; 335:784-5 2 Mtitimila E I, Cooke R W I. Antibiotic regimens for suspected early neonatal sepsis. Cochrane Database of Systematic Reviews 2004, Issue 4. Art. No.: CD 004495. 3 Gould I M. A review of the role of antibiotic policies in the control of antibiotic resistance. Journal of Antimicrobial Chemotherapy 1999; 43: 459-465 4 De Man P, Verhoeven B A N, Verbrugh H A et al. An antibiotic policy to prevent emergence of resistant bacilli. Lancet 2000; 355: 973- 78 5 Mart¨ªnez JA, Aguilar J, Almela M et al. Prior use of carbapenems may be a significant risk factor for extended-spectrum beta-lactamase- producing Escherichia coli or Klebsiella spp. in patients with bacteraemia. J Antimicrob Chemother 2006; 58(5):1082-1085 6 Nestaas E, Bangstad H-J, Sandvik L et al. Aminoglycoside extended interval dosing in neonates is safe and effective: a meta-analysis. Arch Dis Child Fetal Neonatal Ed 2005;90: F294-F300 7 Fischel-Ghodsian N, Prezant T R, Chaltraw W E et al. Mitochondrial Gene Mutation Is a Significant Predisposing Factor in Aminoglycoside Ototoxicity. American Journal of Otolaryngology 1997;18(3): 173-178 Competing interests: None declared |
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Zahir O.E Babiker, Specialist Registrar in Infectious Diseases & Virology Department of Microbiology, Royal Preston Hospital, Sharoe Green Lane North, Preston PR2 9HT, John S Cheesbrough, Consultant Microbiologist, Department of Microbiology, Royal Preston Hospital, Sharoe Green Lane North, Preston PR2 9HT
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The appearance of the Bitner-Glindzicz and Rahman article on aminoglycosides ototoxicity and Adrian O’Dowd’s item on the Maidstone and Tunbridge Wells outbreak of Clostridium difficile in the same edition of the BMJ brings into focus the tensions inherent in delivering safe health care. 1,2 Bitner-Glindzicz and Rahman highlight the issue of a sub-group of patients who are highly susceptible to aminoglycoside-associated ototoxicity due to genetic mutations (principally m.1555A>G). Such patients may be rendered deaf by a single dose and they recommend using alternative antibiotics until this has been excluded by genetic testing. 1 As infection specialists, we are concerned that raising this alarm will jeopardise our attempts to promote the use of aminoglycosides, a group of antibiotics which not only continue to retain good activity against many of the multi-resistant strains of Escherichia coli now endemic in the United Kingdom but also avoids the increased risk of acquiring C. difficile or methicillin-resistant staphylococcus aureus (MRSA) inherent in using alternative agents such as fluroquinolones or cephalosporins. 3 This is mainly an issue for patients over the age of 65 years who account for the majority of both MRSA and C. difficile infections. An accurate estimate of the frequency, penetrance and clinical impact of genetic mutations responsible for deafness is required to put aminoglycoside-related ototoxicity into perspective. The prevalence of the m.1555A>G mutation has been estimated to be in the region of 1 in 40 000. 1 However, this estimate is in a similar order of magnitude as the risks encountered with other commonly used antibiotics. For example, the generally deemed acceptable risk of fatal anaphylaxis associated with penicillin use is about 1 in 100 000. 4 Furthermore, Bitner-Glindzicz and Rahman indicated that the probability of deafness by the age of 30 years for an individual with the genetic mutation who has been exposed to aminoglycosides was 96.5% compared to 39.9% if never been exposed to them. Therefore among patients over 65 years (who currently account for more than half of all bed days in our Trust) it is likely that deafness due to gene mutations would have occurred before hospital admission. In view of the above, we question the benefit of offering genetic screening for such groups of patients. We are concerned that the article by Bitner-Glindzicz and Rahman might result in swaying clinicians from using aminoglycosides when they are genuinely indicated for the treatment of serious infections on the basis of a rare untoward reaction. However, the continued use of aminoglycosides for prophylaxis against infective endocarditis, an intervention for which there is little evidence of benefit, may need to be re-examined and at risk patients may need to be have their options carefully appraised. 5 References: 1. Bitner-Glindzicz M, Rahman. S. Ototoxicity caused by aminoglycosides is severe and permanent in genetically susceptible people. BMJ 2007; 335:784-785 2. O’Dowd A. Doctors need a “sea change” in their attitude to C. difficile. BMJ 2007; 335:790 3. Saving Lives: reducing infection, delivering clean and safe care. 2007. Department of Health, United Kingdom 4. Lin RY. A perspective on penicillin allergy. Arch Intern Med 1992;152:930-937 5. Gould FK, Elliott TSJ, Foweraker J, et al. Guidelines for the prevention of endocarditis: report of the Working Party of the British Society for Antimicrobial Chemotherapy. J Antimicrob Chemother 2006; 57:1035-1042 Competing interests: None declared |
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