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Rapid responses are electronic letters to the editor. They enable our users to debate issues raised in articles published on thebmj.com. Although a selection of rapid responses will be included online and in print as readers' letters, their first appearance online means that they are published articles. If you need the url (web address) of an individual response, perhaps for citation purposes, simply click on the response headline and copy the url from the browser window. Letters are indexed in PubMed.

Re: The antibiotic course has had its day Cliff Gorton, John Paul, Tim E A Peto, Lucy Yardley, et al. 358:doi 10.1136/bmj.j3418

Dear Editors

I am very disturbed by the discussion that has arisen from the publication of Llewelyn et al's opinion piece.

My concerns are, however, not with the thought challenge Llewelyn et al has laid down upon years of mantra based on conventional wisdom mostly formulated prior the availability of current technology in molecular and genetic microbiology. The idea that there is a set duration of antibiotics treatment to prevent bacterial resistance should be reviewed

Neither did the rapid responses published so far offer adequate reassurance that many experts (who wrote the responses) have a holistic perspective of dealing with infection in a clinical setting.

Llewelyn et al and other clinicians wanting to join in this discussion should be reminded that in our daily work setting we are dealing with infection in a human being in the hospital or at home rather than playing chess on a big petri dish in the lab.

Thus the issue of whether antibiotic duration should be reviewed based on the evidence from a study population is fundamentally flawed built on false assumption.

Different people have different body weights. They have different comorbidities which influenced antimicrobial therapy; some have renal or liver dysfunction which affects drug pharmacokinetics and pharmacodynamics whereas others have genetic susceptibility to certain infections or weakened defense mechanism as in poorly-controlled diabetics.

Antibiotics are only part of the armamentarium available to health professionals in their fight against clinical infection in patients (albeit an important constituent in modern medicine). Improving hygiene and living conditions, improving 'host' health, debulking microbial load, etc, are also important considerations.

A few generations ago doctors and nurses at the coalface of medicine would have been more proactive in toileting/cleaning wounds or draining abscesses, giving basic good advice on skin infection management and organising timely review to monitor progress. I fear nowadays that we are too complacent in our trust and reliance on antibiotics to do the job, in which wounds receive a cursory wash and just handing out a script for a broad-spectrum antibiotic constitute acceptable care in a 6-minute consultation.

Clinicians should also not forget about risk management in the treatment of infection. While many infections may not result in major co-morbidity if treated poorly, other infections in privileged regions of the human body will result in catastrophic outcome if not managed correctly in a timely manner. Bacterial meningitis, meningococcal septicaemia, prosthetic infection, etc, are life changing diagnoses for individuals and communities, and if there is reasonable suspicion or likelihood of occurrence, the drive in anti-microbial stewardship and "evidence-based" practice should not trump individual risk management in the mindless demand for "proof" before weighing in risk-benefit analysis.

Sometimes we may never get the level 1 or 2 evidence that some opinion-makers demand because it is simply no-longer ethical to deny conventional treatment in a randomised control trial.

Therefore the debate on antibiotic therapy is not just about bacterial resistance: it is only one part of multifaceted approach to looking after people who have infections; we should not assume that this debate about dosing or duration can be resolved without addressing the issue of host health and hygiene, microbial debulking and wound toileting, risk management as well as ethical considerations.

Competing interests: No competing interests

28 July 2017
Shyan Goh
Orthopaedic Surgeon
Sydney, Australia
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Re: Courts can decide that vaccine has caused harm despite lack of evidence Clare Dyer. 357:doi 10.1136/bmj.j3081

Response to comment by Andrew Deas, Principal Information Analyst (http://www.bmj.com/content/357/bmj.j3081/rr)

I would have thought that in your position at ISD you would know that the cervical cancer cases reported each year prior to and post HPV vaccination. When I quoted in my earlier comment an increase of “4 times higher than they were before” I was referring to years 2006 to 2008 when there were only 10 cases of cervical cancer in the age group 20-24 in Scotland (average 3 per year). Whilst in years 2012 to 2014 there were 35 cases of cervical cancer (average 12 per year). As I previously reported most of these women (approx. 90%) should have been vaccinated in the national programme/catch-up programme. By the way the rates from 1994 to 2005 averaged just 6 per year. You don’t need a degree in statistics to know that this is statistically significant. ONS data in England also shows an increase in cervical cancers in the 20-24 age group but not such an alarming increase. However, neither of them show the expected dramatic decrease.

What is also important is the overall trend in cervical cancer cases in Scotland (all age groups). I am sure that you are aware that ISD data for all age groups – from 1990 to 2003 cases of cervical cancer reduced from 497 to 267 per annum – this was very consistent and progressive, year on year, and almost certainly due to the increase in Pap screening rates. From 2004 to 2014 the cervical cancer rates have consistently and progressively increased to reach 385 cases per annum, as the Pap screening rates have decreased (down from 77% to 69%). This again is statistically very significant and consistent. Pap screening may not be perfect but it is safe and very effective and, more important, recommended by the vaccine manufacturers even after vaccination.

Given your position in ISD I would hope that you are sharing these significant statistics with the NHS and Scottish Government as well as the public that deserve the opportunity to make an INFORMED consent when deciding on immunisation with this vaccine. Remembering also that it has never been proven to prevent a single case of cancer and the manufacturer’s clinical trials did not include assessment of carcinogenicity!

P.S. Scotland cervical cancer rates for 2015 have now been published and the number of cervical cancers in the 20-24 age group is 8, a slight reduction on the previous 3 years but still not down to just 3 cases /annum. Also the all age group cases remain at a high of 379 cases with another, albeit slight, reduction in Pap screening rates.

P.P.S. I note that you didn't challenge my quotes from the WHO global database for reported adverse drug reactions to the HPV vaccine. There are over 272,000 adverse reactions reported including 378 deaths with a acknowledged reporting rate of just 10%. Of course some of these could be coincidental but all were reported contemporaneously and suspected of being caused by the vaccine.

Competing interests: No competing interests

28 July 2017
Steve Hinks
Retired health Professional
AHVID
Drumburgh
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Re: Stimulant medication to treat attention-deficit/hyperactivity disorder Paramala Santosh. 358:doi 10.1136/bmj.j2945

I published this rapid response at http://www.bmj.com in 2004. No lessons seem to have been learned since then.

Essential nutrients needed to treat ADHD
21 October 2004

For decades the incidence of attention deficit hyperactivity disorder (ADHD) has been increasing.1 It is therefore a pity that neither Coghill nor Markovich, in their debate about psychoactive drug use,2,3 mention the “burgeoning” clinical and basic research finding significant deficits of zinc and essential fatty acids (EFAs) in affected children.4-7 Recent randomised controlled trials demonstrate that nutritional supplements improve children’s brain function and behaviour.

Ward et al found significantly lower zinc levels in the urine, scalp hair, serum, 24-hour urine and fingernails of hyperactive children.8 Tartrazine induced a reduction in serum and saliva zinc and increase in urinary zinc, with a corresponding deterioration in behaviour/ emotional responses of the hyperactive children.

In our study, among dyslexic children, who also usually had attention difficulties and hyperactivity, all were zinc deficient in their passive sweat.9 Each dyslexic child had a lower sweat zinc level than their age and sex matched control partner from the same school and neighbourhood. Repletion of deficient nutrients cannot undo developmental damage to a child’s brain caused by maternal zinc deficiency in early pregnancy, and is therefore vitally important to allow affected children to have greater mental concentration and improved brain function with monitored nutritional repletion.10 If zinc is deficient, EFA pathways are likely to be blocked and B vitamins are likely to be deficient.11

Rather than give drugs to one in six of all children why not simply ensure children’s brains and lymphocytes are fed? Impaired brain function and adverse allergic, behavioural or mental reactions to common foods and chemicals can be prevented physiologically. Repletion of essential co- factors and high protein-low allergy-additive-free diets allow maintenance of normal homeostatic mechanisms, with adequate levels of endogenous psychoactive amines and unblocked amine pathways, which can respond flexibly to all types of stress. There is no excuse for ignoring this work and continuing to prescribe ever more drugs to children with undiagnosed and therefore untreated deficiencies.

1 Grant ECG. Re: A rise in the prevalence of ADHD.http://bmj.com/cgi/eletters/329/7467/643-c#75351, 23 Sep 2004
2 Coghill D. Education and debate Use of stimulants for attention deficit hyperactivity disorder: FOR. BMJ 2004 329: 907-908.
3 Marcovitch H. Education and debate Use of stimulants for attention deficit hyperactivity disorder. AGAINST BMJ 2004;329:908-909.
4 Bilici M, Yildirim F, Kandil S, et al. Double-blind, placebo- controlled study of zinc sulfate in the treatment of attention deficit hyperactivity disorder. Prog Neuropsychopharmacol Biol Psychiatry. 2004; 28: 181-90.
5 Akhondzadeh S, Mohammadi MR, Khademi M. Zinc sulfate as an adjunct to methylphenidate for the treatment of attention deficit hyperactivity disorder in children: a double blind and randomized trial [ISRCTN64132371]. BMC Psychiatry. 2004;4 : 9.
6 Hallahan B, Garland MR. Essential fatty acids and their role in the treatment of impulsivity disorders. Prostaglandins Leukot Essent Fatty Acids. 2004; 71: 211-6.
7 Arnold LE, Pinkham SM, Votolato N. Does zinc moderate essential fatty acid and amphetamine treatment of attention-deficit/hyperactivity disorder? J Child Adolesc Psychopharmacol. 2000 ;10:111-7.
8 Ward NI, Soulsbury KA, Zettel VH, et al. The influence of the chemical additive tartrazine on the zinc-status of hyperactive children – a double-blind placebo-controlled study. J Nutr Med 1990;1:51-57.
9 Grant ECG, Howard JM ,Davies S, Chasty H, Hornsby B, Galbraith J. Zinc deficiency in children with dyslexia: concentrations of zinc and other minerals in sweat and hair. BMJ 1989;296:607-9.
10 Grant ECG. Developmental dyslexia and zinc deficiency. Lancet 2004; 364: 247-8.
11 Colquhoun I, Bunday S. Med Hypotheses. A lack of essential fatty acids as a possible cause of hyperactivity in children. Med Hypotheses. 1981; 7: 673-9.

Competing interests: No competing interests

Competing interests: No competing interests

28 July 2017
Ellen C G Grant
Physician and medical gynaecologist
Retired
Kingston-upon-Thames. KT2 7JU. UK
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Re: Community hospitals: still a viable option? Gareth Iacobucci. 358:doi 10.1136/bmj.j3581

Yes of course they are, and many commissioners/providers/commentators accept that is the case. In the absence of suitable beds for intermediate care, for example, the problem of delayed transfers of care from acute hospital settings becomes harder to solve. And sub-acute care for elderly patients with dementia, who don't always need to be in an acute hospital, is made more difficult to provide. There is not, however, a strong evidence base for the retention of community hospitals, so I suppose the zombie of closure will continue to threaten their survival.

Competing interests: No competing interests

28 July 2017
John G Gooderham
locum lollipop lady
none
Billinghsurst
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Re: The antibiotic course has had its day Cliff Gorton, John Paul, Tim E A Peto, Lucy Yardley, et al. 358:doi 10.1136/bmj.j3418

We welcome the healthy debate sparked by Llewelyn et al’s opinion piece [1], and strongly support the principle of safely reducing antibiotic course lengths. However, the British Society for Antimicrobial Chemotherapy (BSAC) is unable to currently support a call to drop the ‘complete the course of antibiotics’ recommendation. This is because the evidence in support of this call remains sparse and such advice is potentially confusing for patients.

BSAC highlight the critical importance of considering whether an antibiotic is required in situations when the clinical benefit is likely to be marginal or an effective non-antibiotic treatment is available. This decision should be made before a healthcare professional decides upon the length of an antibiotic course to prescribe. We agree that, in general, course lengths may be too long and hope that research initiatives such as the Antibiotic Reduction and Konservation (ARK) in Hospitals (ARK-Hospital), a project aimed at safely reducing antibiotic use in hospitals [http://modmedmicro.nsms.ox.ac.uk/ark/] that Llewelyn et al lead will illuminate the debate. We strongly encourage hospitals across the UK to participate.

In dropping the existing paradigm now with little evidence to do so, there is a risk that ‘it is OK not to complete the course’ could give an unintended licence to patients not to adhere with other dosage instructions (for example, taking an antibiotic once a day instead of twice a day). This may result in treatment failure and encourage drug resistance. Furthermore, the suggestion that patients should stop taking antibiotics ‘when they feel better’ is too subjective and could lead to patients stockpiling unused antibiotics for future use without first seeking the advice of a doctor. A recent UK study showed that more than one-quarter of 732 patients disagreed with disposing of unwanted antibiotics [2]; any inappropriate subsequent use will contribute to resistance.

As we enter the era of personalised medicine, for any one individual with a bacterial infection we do not know how long the course of antibiotics should be. Higher-quality evidence is required before prescribing policy changes are implemented. This includes studies that assess the harm that stopping antibiotics early might cause in higher risk or vulnerable patients such as the very young, elderly and those unable to make decisions about their treatment, and how to individualise course lengths to minimise antibiotic exposure whilst maximising clinical benefit. Doctors and patients should always discuss the pros and cons of antibiotics and, if prescribed, what course length is appropriate.

BSAC recommends that the message to the public should remain “follow the advice of the healthcare professional”. Prescribers in hospitals should stop antibiotics when it is clinically safe to do so and base the decision on available evidence, national guidance and clinical judgement. This is also true for prescribers in outpatient and primary care settings where the clinical challenge and monitoring of patients is difficult. We recommend that the current approach of fixed, but generally short course lengths for most bacterial infections should remain. The society welcomes opportunities to continue the debate and work collaboratively with those seeking the robust evidence on which policies and practice should be based.

1 The antibiotic course has had its day: BMJ 2017; 358 doi: https://doi.org/10.1136/bmj.j3418 (Published 26 July 2017) Cite this as: BMJ 2017;358:j3418
2 Seriously resistant: Leeds Citywide Insight Summary Report: 17 July 2017

Competing interests: No competing interests

28 July 2017
Michael Corley
Senior Policy and Public Affairs Officer
Tracey Guise (BSAC Chief Executive), Dr Gavin Barlow (Infectious Diseases Consultant), Professor Laura Piddock (BSAC Chair in Public Engagement, Director of Antibiotic Action, and Professor of Microbiology), Philip Howard (Vice President of BSAC and Consultant Antimicrobial Pharmacist), Dr Nick Brown (Consultant Medical Microbiologist), Professor Dilip Nathwani OBE (President of BSAC, Consultant Physician, and Honorary Professor of Infection)
British Society for Antimicrobial Chemotherapy (BSAC)
53 Regent Place, Birmingham B1 3NJ
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Re: Increase in life expectancy in England has halted, new figures show Gareth Iacobucci. 358:doi 10.1136/bmj.j3473

Iacobucci1 and Public Health England2 recently reported that the trend of increasing life expectancy has slowed and highlighted possible links to austerity. Whilst there is no indication of the statistical significance of the turnover in this trend2, even if we accept it on face value, it still leaves the question of what do we really mean by life expectancy?

Life expectancy indicators can easily be misunderstood. They are created by taking account of the mortality rates today and asking, if they didn’t change, how long would a child born today live. As such it does not actually represent the number of years a person could expect to live, but reflects mortality among those living in a specific area and time-period3. Therefore, it is simply a summary population health measure giving an overview of the current mortality of an area. It is this subtle distinction that is often missed and one that makes life expectancy estimates not particularly helpful to health and social care planners.

An alternative approach might be to look at trends in the actual ages people die and project them forward. This is different to life expectancy in that the age of death is a real measurement of a persons end state incorporating their whole life experience, whereas the life expectancy estimate is simply a number representing a snapshot of the current health of the population. If life expectancy increases then we can say the current overall health of the population today has increased, but not that we would realistically expect a child born to live any longer. However, a projection of the average age of death would incorporate historical data and use it to estimate future trends.

We have used ten years of mortality (2006-2016) and demographic data to estimate and model trends in the average recorded age of death, taking into account expected deprivation and sex inequalities. We then use this model to project the average age of death into the future to give a more easily interpretable estimate of the likely burden of an aging population on health and social care services.

Looking at the data, we find that, across the Dorset, Bournemouth & Poole authorities (population of around 750,000), the average age of death has been steadily increasing over the last 10 years and is higher for women (83 years) than men (78 years). Additionally, there exists a gap in the average age of death between the most and least deprived areas (9 years for men, 6 years for women). There has been little change in this gap from 2006 – 2016.

After applying a simple linear regression model, we are able to confirm the significance of the above findings. We also uncover and quantify an interaction between males and deprivation, indicating deprivation has a more profound effect on men (13 years between most deprived males and least derived females). Examining the data-model residuals, we note they are not significantly different from zero (R2=0.92), indicating the model fits the data well and allowing us to project the average age of death into the future. By 2036 we estimate a female and male average age of death at 88-82 years and 85-79 years respectively (least to most deprived quintile, 95%CI±2 years). The most recent data from PHE4 suggests that, across Dorset, Bournemouth & Poole, the average life expectancy at 65 is 19 and 22 years for males and females respectively. This gives a theoretical life expectancy of 84 for males (dying in 2034), compared to a projected average age of death of 81, and 87 for females (dying in 2037) with a projected average age of death of 86.

The average age of death is in essence a retrospective health measure representing the impact a lifetime of accumulated risks/behaviours and the associated social-demographic status has on a populations final years. This suggests that without the possibility of social-mobility, of those spending most of their time in more deprived areas, the impact of deprivation on health will be felt most severely by men. Any policies that increase poverty and further restrict social-mobility will only serve to exacerbate this phenomenon. In this respect, we are in agreement with Marmot on the potential harmful effects of austerity.

Finally, this alternative average age of death population health indicator is potentially more easily interpretable and meaningful to health and social care planners than the traditional life expectancy measure.

Yours faithfully,
David Lemon & David Phillips
Public Health Dorset

References
1. Iacobucci, G. Increase in life expectancy in England has halted, new figures show. BMJ 2017;358:j3473

2. Public Health England, Health profile for England, July 2017, https://www.gov.uk/government/publications/health-profile-for-england

3. ONS, National Life Tables, United Kingdom: 2012-214, 2017 https://www.ons.gov.uk/peoplepopulationandcommunity/birthsdeathsandmarri...

4. Public Health England, Public Health Outcome Framework, http://www.phoutcomes.info/

Competing interests: No competing interests

28 July 2017
David J Lemon
Senior Public Health Analyst
David Phillips, Director of Public Health
Public Health Dorset
Princes House, Princes Street
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Re: Charlie Gard case: an ethicist in the courtroom Daniel Sokol. 358:doi 10.1136/bmj.j3451

Mr Sokol's piece is persuasive and compelling. However, the Hippocratic oath is a professional code of conduct for doctors. It is not a general ethical code of conduct for society at large. Being so iatrocentric, it is difficult to see how it can be an arbiter in this case as to what constitutes the best interests for the child. Having said this, even when viewed as a professional code of practice, "Hippocratic principles" are pro-life and have a strong inclination toward the preservation of life. It is often overlooked that the oath also contains the passages:

"Neither will I administer a poison to anybody when asked to do so, nor will I suggest such a course. Similarly I will not give to a woman a pessary to cause abortion"(1)

This preference for the preservation of life in some ways tessellates with the considerations the court had to engage in the present case, when determining the best interests of the child. The High Court judge cites the test case ruling, Wyatt v. Portsmouth NHS Trus 2005:

"The judge must decide what is in the child's best interests... There is a strong presumption in favour of a course of action which will prolong life, but that presumption is not irrebuttable."

Hippocratic principles can be evoked to support both sides. However, depending on what we intuit it is tempting to see only one side and not the obverse.

(1) Hippocrates of Cos (1923). "The Oath". Loeb Classical Library. 147: 298 299. doi:10.4159/DLCL.hippocrates_cos-oath.1923

(2) http://www.bailii.org/cgi-bin/format.cgi?doc=/ew/cases/EWHC/Fam/2017/972...(Great)+AND+(Ormond)+AND+(Street) -April 11 2017 Paragraph 13.

Competing interests: No competing interests

28 July 2017
C E Uzoigwe
Doctor
J Mehet
Harcourt House
Sheffield
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Re: The antibiotic course has had its day Cliff Gorton, John Paul, Tim E A Peto, Lucy Yardley, et al. 358:doi 10.1136/bmj.j3418

Though my medical experience has me taught that is always dangerous to diverge from the antibiotic treatment scheme, I do believe that a short course of antibiotics can actually have the same outcome in certain circumstances.

Competing interests: No competing interests

28 July 2017
vincenzo anello
medical manager Italian NHS
ASL ROMA 1
Piaza Istria 20, 00198, Rome ,Italy
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Re: The antibiotic course has had its day Cliff Gorton, John Paul, Tim E A Peto, Lucy Yardley, et al. 358:doi 10.1136/bmj.j3418

Llewelyn et al. are concernet about antibiotic resistance caused by drug misuse.

However, studies suggest that bacteria do not need exposure to antibiotics to gain resistance. Indeed, Bhullar et al. (2012) discovered bacteria at the bottom of a 1,000 feet deep cave (Lechuguilla Cave, New Mexico) that, although isolated from humans and antibiotic drugs for four million years, are resistant to 14 different commercially available antibiotics. This finding negates the theory that bacteria only develop resistance to antibiotics when directly exposed to them. Therefore, antibiotic resistance did not evolve in the clinic just through our use, rather it is natural, ancient and hard wired in the microbial pangenome. Environmental organisms have reservoirs of resistance genes that can be vehicled to other bacteria through simple horizontal transmission.

REFERENCE:
Bhullar K, Waglechner N, Pawlowski A, Koteva K, Banks ED, et al. Antibiotic Resistance Is Prevalent in an Isolated Cave Microbiome. PLoS One. 2012; 7(4): e34953. doi: 10.1371/journal.pone.0034953

Competing interests: No competing interests

28 July 2017
Arturo Tozzi
pediatrician
ASL Napoli 2 Nord
via Amendola 5, Caivano
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Re: The antibiotic course has had its day Cliff Gorton, John Paul, Tim E A Peto, Lucy Yardley, et al. 358:doi 10.1136/bmj.j3418

Prolific and horrific, parasites are Mother Nature's army of mini-monsters that invade our lives and trap us in a morbid Möbius loop and biphasic food chain, in which we're both victor and vector, predator and prey, chef and buffet, diner and dinner, and winner and loser. To combat parasites, we need personal prevention with merciful intervention.*

*Parasites include viruses, bacteria, fungi, protozoa, worms, insects, and arachnids. The best antiparasitics are hygiene, nutrition, and aerobic exercise, since vaccines are vexed, and we're in the post-antibiotic era of antibiotic-resistant superbugs and superinfections. To quote GB Shaw, "Science never solves one problem without creating ten more."

Competing interests: No competing interests

27 July 2017
Hugh Mann
Physician
Retired
New York, NY, USA
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