Department of Microbiology and Infectious Diseases, Women's and Children's Hospital, 72 King William Road, North Adelaide, S.A. 5006, Australia
Sir,
Antibiotic resistance is now accepted as a major global problem, and recent years have seen an exponential increase in this problem in common pathogens, such as penicillin resistance in Streptococcus pneumoniae.1 Despite the global publicity given to antibiotic resistance by microbiologists, infectious diseases experts and public health authorities, it is still common to hear our clinical colleagues say that they have not noticed any significant effect of this resistance on patient outcomes. It is then hardly surprising that resistance does not rate highly in prescribers' clinical decision-making about individual patients, and more importantly, that they are slow to change their practice of unnecessary prescribing because of their wish to fulfil patient expectations.1
A seemingly unrelated issue is that of clinical response rates in clinical trials. There are a range of new agents in development or recently released that are designed specifically to overcome emerging resistances. Yet it is uncommon to see significant differences in clinical or bacteriological efficacy between these new agents and their comparators in phase III studies, even when patients with isolates resistant to the comparator agent are included in the intention-to-treat analysis. If resistance is such a problem, why does it not show up in these studies?
The key to both paradoxes is the natural resolution rate of the common infections. In this context, the natural resolution rate is the proportion of untreated patients who resolve as rapidly as those patients treated with antibiotics, and without complications. Through the modern tools of evidence-based medicine, meta-analysis and critical review, we now have much more information about the natural response rate to many common infections, especially respiratory tract infections, from pooled placebo-controlled trials. Documented rates include those for acute otitis media (8186%),2 acute sinusitis (69%),3 acute pharyngitis (>90%),4 acute bronchitis (85%)5 and acute exacerbations of chronic bronchitis (high but not quantified).6 It is therefore obvious that resistance can have an impact on outcomes in only the residual percentage of patients. It is possible to quantify the rate of resistance required to reduce the response rate of the whole treatment group with the following formula:
![]() |
The formula involves the assumption that all patients with resistant isolates will fail treatment, and all those with susceptible isolates will be cured. Although this is an oversimplification, the application of the formula still provides a quantitative view of the impact of resistance. This is depicted graphically in the Figure, which examines the resistance required at different overall reductions in efficacy, and with an expected efficacy rate of 100%.
|
These same figures can equally be applied to comparative clinical studies. Thus, an overall resistance rate of 17% to the comparator is required to demonstrate a 5% difference in efficacy between the new agent and the comparator, assuming that patients with isolates that are resistant to the comparator are included in the analysis, and that the response rate to the new agent is 100%. More typical response rates in clinical studies, at the end of therapy, are in the range 8090%. Assuming a rate of 85% and a natural response of 75% the margin for resistance to make an impact is 10%, and resistance to the comparator would have to be 50% to reduce efficacy in that group to 80%. The evaluable sample size for this study (assuming an error of 0.05 and a ß error of 0.20) would have to be 1426 patients. In addition, I am aware of studies where the outcomes of both arms of treatment have not shown significant differences from natural response rates, consistent with the hypothesis that neither agent had significant efficacy, rather than the usual sponsor and regulator hypothesis that the new agent was at least as efficacious as the comparator.
It is vital that natural resolution rates are routinely considered in clinical thinking, undergraduate and postgraduate teaching, patient education and regulatory considerations. Where the data on rates are not currently available, strenuous efforts should be made to define these through meta-analysis, critical review or prospective placebo-controlled studies.
Notes
J Antimicrob Chemother 2000;45: 925926
* Tel: +61-8-8204-8873; Fax: +62-8-8204-6051; E-mail: turnidgej{at}wch.sa.gov.au
References
1
.
Butler, C. C., Rollnick, S., Pill, R., Maggs-Rapport, F. & Stott, N. (1998). Understanding the culture of prescribing: qualitative study of general practitioners' and patients' perceptions of antibiotics for sore throats. British Medical Journal 317, 63742.
2
.
Del Mar, C., Glasziou, P. & Hayem, M. (1997). Are antibiotics indicated as initial treatment for children with acute otitis media? A meta-analysis. British Medical Journal 314, 15269.
3
.
de Ferranti, S. D., Ioannidis, J. P., Lau, J., Anninger, W. V. & Barza, M. (1998). Are amoxycillin and folate inhibitors as effective as other antibiotics for acute sinusitis? A meta-analysis. British Medical Journal 317, 6327.
4 . Del Mar, C. B., Glasziou, P. P. & Spinks, A. B. (1999). Antibiotics for sore throat (Cochrane Review). In The Cochrane Library, Issue 4, 1999. Update Software, Oxford.
5 . Smucny, J. J., Becker, L. A., Glazier, R. H. & McIsaac, W. (1998). Are antibiotics effective treatment for acute bronchitis? A metaanalysis. Journal of Family Practice 47, 45360.[ISI][Medline]
6 . Saint, S., Bent, S., Vittinghoff, E. & Grady, D. (1995). Antibiotics in chronic obstructive pulmonary disease exacerbations. A meta-analysis. Journal of the American Medical Association 273, 95760.[Abstract]