(Aust Prescr 1997;20:57-60)
The Editorial Executive Committee welcomes letters, which should be less than 250 words. Before a decision to publish is made, letters which refer to a published article may be sent to the author for a response. Any letter may be sent to an expert for comment. Letters are usually published together with their responses or comments in the same issue. The Editorial Executive Committee screens out discourteous, inaccurate or libellous statements and sub-edits letters before publication. The Committee's decision on publication is final.
Doses of selected emergency drugs
Editor, – Australian Prescriber Vol. 19 No. 4 1996 was accompanied by a card entitled 'Doses of selected emergency drugs'. Aminophylline was recommended for asthma not responding to nebulised salbutamol. The Canadian Medical Association Journal recently published guidelines for the emergency management of asthma.1 These guidelines were developed using an evidence-based medicine approach. The recommendation not to use aminophylline in the setting of the emergency department was grade A based on a meta-analysis of the results of 9 level I trials and 4 level II trials.2 The use of aminophylline appears to be associated with an increased risk of adverse effects. Aminophylline may have a role in the treatment of patients with severe acute asthma once the initial crisis in the emergency department has passed.
Joel Lexchin
Doctor of Medicine
Toronto, Ontario
Canada
References
1 . Beveridge RC, Grunfeld AF, Hodder RV, Verbeek PR. Guidelines for the emergency management of asthma in adults. CAEP/CTS Asthma Advisory Committee. Canadian Association
of Emergency Physicians and the Canadian Thoracic Society. Can Med Assoc J 1996;155:25-37.
2 . Littenberg B. Aminophylline treatment in severe acute asthma. A meta-analysis. JAMA 1988;259:1678-84.
Editorial note:
Dr Lexchin's letter was referred to Professor J.P. Seale who represents the Thoracic Society of Australia and New Zealand on the Advisory Editorial Panel of
Australian Prescriber. Professor Seale concurs with Dr Lexchin. He also points out that the guidelines of the National Asthma Campaign1 state that the benefits of
aminophylline are uncertain and so it should be reserved for adults who are unresponsive to maximal doses of beta2 agonists. The guidelines consider
aminophylline to be unnecessary in the treatment of acute asthma in children.
Reference
1 . National Asthma Campaign. Asthma management handbook.3rd ed. Melbourne: National Asthma Campaign, 1996.
Antibiotic prophylaxis of endocarditis
Editor, – With regard to the article 'Antibiotic prophylaxis of endocarditis'(Aust Prescr1997;20:11), it is stated that high-risk patients, i.e. prosthetic valve and previous endocarditis, now only need a single (adult) oral dose of 3 gamoxycillin one hour pre-operatively or clindamycin 600 mg (adult) oral dose one hour pre-operatively.
This is a considerable change from the previously recommended antibiotic cover for high-risk patients prior to dental or other procedures, i.e. intravenous amoxycillin 1 g and intravenous gentamicin 1.5 mg/kg with a follow-up oral dose of 500 mg amoxycillin 6 hours later or intravenous vancomycin1 g and intravenous gentamicin 1.5 mg/kg.
Is this change of antibiotic prophylaxis the result of scientific research or a move to provide an easier and cheaper antibiotic cover for these patients? If the latter is the case, this should be of some concern as some cardiologists at St Vincent's Hospital have indicated there is documented evidence of failure of endocarditis protection with oral antibiotic cover.
Ian Hewson
VMO (Dental)
Royal Melbourne Hospital and St Vincent's Hospital
Fitzroy, Vic.
Benafsha Khariwala, the Managing Editor of the Therapeutic Guidelines, comments:
The article which appeared in Australian Prescriber
Vol.20 No. 1 1997 on antibiotic prophylaxis of endocarditis only mentioned the standard regimen, i.e. an oral dose of amoxycillin 3 g or clindamycin 600mg, for
non-high risk patients undergoing dental procedures without a general anaesthetic.
Dr Hewson's concerns are valid. The 9th edition of the 'Antibiotic Guidelines' (1996) also recommends that `Because the consequences are severe, for high risk patients, i.e. with prosthetic valve or previous infective endocarditis, add gentamicin to the standard or one of the alternative regimens' (intravenous amoxycillin/ampicillin, intravenous vancomycin, intravenous or intramuscularteicoplanin or intravenous clindamycin). For doses, refer to pages 94-5 of the 'Antibiotic Guidelines'.
I hope I have managed to clarify the issue for your readers.
Dr R.G. Woods, Australian Dental Association,
comments:
The position of the Australian Dental Association regarding antibiotic prophylaxis for infective endocarditis is that it endorses in principle there commendations set out in
the 'Antibiotic Guidelines', 9th edition.
Although different regimens have been recommended in North America and Britain, in Australia we should observe the Australian recommendations.
Editor, – The article on proton pump inhibitors (Aust Prescr 1997;20:16) contains unfortunate special pleading which detracts from the impact which was clearly to support the restrictions on proton pump inhibitors.
The writer raises the possibility of cancer by saying 'Carcinogenesisis a long lasting adverse reaction to drugs'. This is truly a definition of the word. To then imply that the prescribing, presumably of proton pump inhibitors, could lead to 'setting in place a drug disaster' is unscientific scaremongering without something to back the assertion. Or is this meant to be a warning against all new drugs?
There is also an unfortunate phrasing in 'are these drugs honestly necessary'. The writer appears overwhelmed by high technology tests and ignores the patient even while admitting 'the poor correlation between symptoms and diagnostic tests'.
The result of the recent restrictions will be an increase in activity for the endoscopists and some more suffering for those who cannot afford these tests or who just have to wait.
R.J. Burn
General Practitioner
Chippendale, N.S.W.
Professor J. Marley, the author of the article, comments:
Treatment of reflux oesophagitis should follow the stepped care approach which starts with lifestyle measures
('Gastrointestinal drug guidelines' pages29-31). It would clearly not be advisable to deny patients who have failed treatment at earlier stepped care points, the use of proton pump inhibitors.
Neither is it desirable to use these drugs for patients who have not tried more simple treatments. I stated that carcinogenesis is a long latency adverse reaction, meaning that it takes many
years to become apparent, not a long lasting reaction. There is a biologically plausible mechanism which might mean an increased risk of gastric cancer through the use of these drugs, which
unfortunately cannot be dismissed as unscientific scaremongering.
The article does not contain support for the current restrictions, or endoscopy, but it does contain support for safe and rational prescribing.
Editor, – The stated therapeutic range for lithium of 0.6-1.2 in the article 'Therapeutic drug monitoring' (Aust Prescr 1997;20:9-11) may give a wrong message to non-psychiatrists who are managing patients on lithium.
Although patients with an acute manic episode may be given doses of lithium carbonate which produce levels of up to 1.2 mmol/L, the recommended serum levels in the maintenance phase have, for many years, been between 0.5and 0.8.1,2
I have had occasion in the past to inform clinical pathology laboratories of their out-of-date recommended range, which on one occasion was 0.8-1.5 mmol/L, the higher figure liable to result in lithium toxicity in some patients.
I treat over 120 patients with lithium, and in only one current patient do I need to keep the serum level above 0.8 mmol/L.
The issue is not an academic one, for adverse effects, and perhaps nephrotoxicity, are dose-related. Because the vast majority of your readers are not psychiatrists, they may be encouraged by your
article to maintain patients on higher lithium doses than necessary, and at some cost.
David Grounds
Psychiatrist
Richmond, Vic.
References
1 . Johnson G. The role of lithium in the affective disorders. Aust NZ J Psychiatry 1996;30:715-9.
2 . Jefferson JW. Lithium encyclopedia for clinical practice. 2nd ed. Washington, DC: American Psychiatric Press, 1987:600.
Editor, – This article contains some figures which are not congruent with modern literature and practice in the area of antibiotic levels and therapeutic monitoring.
In Table 2, the following antibiotics and their therapeutic ranges are listed:
| Gentamicin, tobramycin, netilmicin | trough <2 2; peak >5 |
| Amikacin | trough <5 2; peak >15 |
| Vancomycin | trough <10; peak 20-40 |
2 for 8-hourlydosing
The administration of 8-hourly aminoglycosides has been recognised as being associated with nephrotoxicity, particularly in patients with impairment of glomerular filtration.
High peak levels of aminoglycosides have been shown to beassociated with a better therapeutic outcome and the recognition of the post-antibiotic effect associated with aminoglycoside levels below the MIC of the target antibiotic have led to a shift away from 3 times daily dosing with these drugs to once daily dosing of up to 7 mg/kg of the drug. This allows a high post-dose peak and time for excretion of the antibiotic to minimise nephrotoxicity.
The 9th edition of the 'Antibiotic Guidelines' recommends the aminoglycoside levels quoted for non-respiratory infections only with a recommended peak level for respiratory infections of >8 mg/L.
The post-dose amikacin peak level quoted by Professor Birkettof >15 mg/L is not congruent with the 9th edition of the 'Antibiotic Guidelines' which recommends >25 mg/L.
Amikacin is usually administered twice daily and not 3 times daily, so the information in the superscript in the Table above is also erroneous for this antibiotic.
Vancomycin is a bacterio static drug and, in contrast to the aminoglycosides, a trough level of between 5 and 10 or 15 mg/L must be maintained for efficacy. Allowing the vancomycin level to fall lower than 5 mg/L will ensure lack of efficacy of the treatment regimen.
I am surprised that in this important area of drug monitoring, there was not a more careful evaluation of the data quoted and a more thoughtful analysis of the need for monitoring and the
appropriate levels to achieve a cost efficient and therapeutically effective outcome.
J.L. Faoagali
Director of Microbiology
Royal Brisbane Hospital
Herston, Qld
Editor, – I read with interest the informative article by Professor Birkett. He lists and gives a therapeutic range for a number of drugs the use of which 'without monitoring would be difficult and often dangerous'.
For many patients, vancomycin can now be removed from this list. Recent reviews have described the lack of toxicity of current formulations of the drug, and the lack of correlation between serum levels and either toxicity or clinical efficacy.1
Professor Birkett gives a therapeutic range for aminoglycosides, such as gentamicin, based on 8-hourly dosing. Such therapeutic ranges are meaningless for once daily dosing. A number of monitoring methods for once daily dosing have been developed in Australasia, including at least two computer-based methods('Aladdin' and 'Dosecalc') and one nomogram.2 These are generally based on performance of one or two sets of levels after the dose has been given, rather than the traditional 'peak and trough' collections. While theoretically attractive, these methods have yet to be compared with each other to determine which approach is most useful clinically and most appealing financially.
Finally, Professor Birkett omits tacrolimus (FK-506) from his list of essential drugs to monitor. Tacrolimus is an immunosuppressive agent, rapidly replacing cyclosporin as the key immunosuppressant for transplant recipients in Australia. There is a clear correlation between elevated tacrolimus levels and nephrotoxicity and neurotoxicity.3 While the correlation between low tacrolimus concentrations and acute rejection is less clear-cut, it has been demonstrated in at least one study.4
David L. Paterson
Infectious Diseases Physician
Department of Veterans' Affairs Medical Centre
Pittsburgh, Pennsylvania
U.S.A.
References
1 . Cantu TG, Yamanaka-Yuen NA, Lietman PS. Serum vancomycin concentrations: re-appraisal of their clinical value. Clin Infect Dis 1994;18:533-43.
2 . Victorian Drug Usage Advisory Committee. Antibiotic Guidelines. 9th ed. Melbourne: Victorian Medical Postgraduate Foundation,1996.
3 . Backman L, Nicar M, Levy M, Distant D, Eisenstein C, Renard T, et al. FK506 trough levels in whole blood and plasma in liver transplant recipients. Correlation with clinical events and side effects. Transplantation 1994;57:519-25.
4 . Jain AB, Todo S, Fung JJ, Venkataramanan R, Day R, Bryant J, et al. Correlation of rejection episodes with FK506 dosage,FK506 level, and steroids following primary orthotopic liver transplant. Transplant Proc 1991;23:3023-5.
Professor D. Birkett, the author of the article, comments:
These letters reveal the complexities and sometimes lack of good data in the use of therapeutic drug concentration ranges.
For example, Dr Paterson states that therapeutic drug monitoring for vancomycin is not useful, whereas Dr Faoagali considers that a 'trough level between 5 and 10 or 15 mg/L must be maintained for
efficacy'. With the move to once daily dosing for aminoglycosides, the best method of monitoring to avoid toxicity is not clear, and the current uncertainties are well discussed in the 9th edition of
the 'Antibiotic Guidelines'. As noted by Dr Paterson, a number of methods for monitoring of once daily dosing have been proposed on pharmacokinetic grounds, but the clinical relevance of these
has yet to be established. It does seem clear that a trough concentration of 2 mg/mL for patients with normal renal function is too high, but the situation is less clear for patients with reduced
renal function where the dose size and peak concentrations are reduced. Also, once daily dosing is not suitable for all situations as noted in the 'Antibiotic Guidelines'.
Dr Grounds has taken me to task over the therapeutic range for lithium. In preparing the article, I found as many therapeutic ranges for lithium as there are laboratories and reference sources. There are several general points that are relevant. The first is that reference ranges are often established by small studies with small numbers of patients and often many years ago. The extrapolation to the wider patient population needs some caution. The second is that drug concentrations need to be interpreted in the clinical context of individual patients - there is substantial interindividual variability in the relationship between drug concentration and therapeutic response or adverse effects. Finally, as noted in the article, the concentration-response relationship is not all or nothing, but is a continuum (see 'Pharmacodynamics- the concentration-effect relationship' Aust Prescr 1995;18:102-4). The therapeutic range represents an attempt to choose a drug concentration range which optimises the chance in a patient population of having a therapeutic effect with an acceptable incidence of adverse effects.
I thank your correspondents for their remarks which draw attention to the need to consider therapeutic concentration ranges as a guide to be interpreted in the context of the individual patient.
