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Apocalypse now! We can’t afford to wait to take action on antibiotic resistance

By Kieran Hand

The carefully measured warnings on antibiotics resistance of Chief Medical Officer Dame Sally Davies cannot be as easily dismissed as a recent article suggests

Kieran Hand Consultant pharmacist anti-infectives, University Hospital Southampton NHS Foundation Trust

Sir Frank MacFarlane Burnet, winner of the Nobel Prize for Medicine in 1960, wrote of the decline of infectious diseases in 1962, saying: “One can think of the middle of the 20th century as the end of one of the most important social revolutions in history, the virtual elimination of the infectious diseases as a significant factor in social life.”1

Readers of last week’s PJ will have noted that Robin Walsh felt that the best response to the Chief Medical Officer’s call to action on antibiotic resistance “would be to take a chill pill”.2

As someone who is directly involved with the Chief Medical Officer’s report, I can assure you that chapters and recommendations were written by practising clinicians and scientists with minimal editorial interference from the Department of Health and no attempt was made to sensationalise or “spin” the report content. Dame Sally Davies drafted the summary chapter based upon personal conviction formed by her interpretation of the factual content provided by the chapter authors and she was quite understandably disturbed by the emerging narrative, as any reasonable and responsible clinician should be.3

If anything, infectious diseases specialists have been guilty of not drawing sufficient attention to this insidious threat to public health sooner. It is estimated that bloodstream infections caused by multidrug-resistant bacteria caused more than 8,000 deaths and an additional €62m in excess costs in Europe in 2007, and prevailing trends indicate that the number of infections caused by multidrug-resistant Gram-negative bacteria is rapidly increasing.4

To death and taxes, one could confidently add antibiotic resistance as one of life’s few certainties: a natural consequence of the evolutionary response of micro-organisms to antibiotic selection pressure.

This phenomenon continues to challenge our brightest research scientists, driving the perpetual quest for new antibiotics capable of circumventing nature’s latest ingenious resistance mechanism. Declaring confidence in human innovation and creativity to overcome this challenge is sanguine but such hubris is of little comfort to the patients comprising the “still only . . . ­hundreds of cases” affected by multidrug-resistant infections or for that matter their families and dependants. With the cost of discovery and development of new antibiotics running into the hundreds of millions of pounds, the option of resorting to science to come to the rescue is increasingly incompatible with the concept of affordable public healthcare.

To illustrate this point, at University Hospital Southampton, restricted use of just one of the few remaining patented antibiotics, representing less than 1 per cent of all antibiotic treatment courses, accounts for almost 20 per cent of the entire annual hospital expenditure on antibiotics. To the less informed observer, taking the simple step of sweeping away the expensive nuisance of so-called regulatory hurdles may appear attractive but at what cost? Without the necessary pharmacovigilance, who will accept responsibility when the next thalidomide disaster unfurls?

Although the emergence of resistance is inevitable, the pace and extent of propagation of resistant pathogens is to a large extent dictated by human behaviour — most importantly consumption of antibiotics by humans and animals, as well as hygiene, sanitation and infection control. The Government provides a convenient scapegoat but the inconvenient truth for all healthcare professionals remains the regrettable over-prescribing of antibiotics. Rates of inappropriate prescribing in secondary care remain depressingly unchanged over the decades, stubbornly fixed at around 50 per cent.5-8

In primary care in the UK, an unexplained twofold variation in prescribing rate is evident between GP practices on the 10th and 90th percentiles for antibiotic prescribing volumes.9 Over-prescribing of broad-spectrum antibiotics is frequently described, with such “defensive prescribing” attributed to the precedence of treatment success in current patients at the expense of loss of antibiotic effectiveness in future patients due to resistance.10,11

A recent study of over 1.5 million patient visits to UK GPs with a diagnosis of acute respiratory infection reported the sobering statistic that the number needed to treat with antibiotics to prevent one admission to hospital with pneumonia was 12,255.12 Sixty-five per cent of patient visits resulted in a prescription for antibiotics with prescribing rates varying from 3 per cent to 95 per cent by practice. Perhaps what is most remarkable about this study is that instead of concluding that antibiotics can seldom be justified for acute respiratory infection in primary care, the authors interpreted the findings as posing a dilemma for doctors because of the lack of adverse events detected in the patients prescribed antibiotics and the resulting implications for risk-benefit assessment. The cost to society in terms of selection pressure for antibiotic resistance and the financial cost of prescribing antibiotics to one million patients unnecessarily did not merit a mention.

Let us be under no illusions that antibiotics are harmless to individual patients. Exposure to antibiotics in primary care is consistently found to be associated with a subsequent increased risk of antibiotic resistance in respiratory and urinary bacteria in individual patients.13 Antibiotic prescribing in hospitals has also been shown to select for resistant micro-organisms at the individual patient level and at the institution level.14–17 The risk of acquiring meticillin-resistant Staphylococcus aureus was found to be increased 1.8-fold in patients exposed to antibiotics.18

On closer scrutiny of the pertinent research literature, a deficit of education is often cited as a factor influencing poor prescribing. A survey of doctors in a US university hospital reported that 90 per cent wanted more education about antibiotics with only 21 per cent of doctors feeling very confident they were using antibiotics optimally.19

A more recent survey of junior doctors in a Scottish hospital suggested that 75 per cent (47/63) were confident to choose the correct antibiotic but only 36 per cent felt confident to plan the duration of treatment.20

Another recent study, set in two university hospitals in Paris, used brief case studies to explore doctors’ knowledge of antibiotic prescribing.21 The median test score left considerable room for improvement at 11.4/20 (interquartile range 8.9–14.3), comparable for junior and senior doctors, and 86 per cent of the 206 doctors who participated thought they had insufficient knowledge. Assessment of pharmacist knowledge of antibiotics would doubtless reveal similar deficiencies.

What should pharmacists do?

In primary care, clinical commissioning group pharmacists are encouraged to order and distribute the excellent patient and carer literature produced by Nick Francis and colleagues in Cardiff explaining the natural history of common infections and warning signs of more severe illness.22

Benchmarking ePACT prescribing data by practice and individual GP for overall burden of antibiotic prescribing (with appropriate case mix adjustments), as well as proportion of broad-spectrum antibiotic prescribing, is a powerful tool for driving behaviour change.

Promoting alternatives to antibiotics such as information prescriptions or delayed prescribing and emphasising narrow-spectrum agents for first-line therapy is imperative, deploying incentives where available and appropriate.
In community pharmacy, promoting symptomatic relief of viral upper respiratory tract infections and raising awareness of the natural history of such conditions (see National Institute of Health and Care Excellence clinical guideline 69) and the lack of benefit of antibiotics is vital to manage patient expectations and reduce pressure on GP colleagues. Emphasising respect for antibiotics and the importance of protecting normal commensal flora must also be encouraged.

In secondary care, working with clinical microbiology and infectious diseases colleagues to promote prescribing of narrow-spectrum antibiotics at adequate doses and timely review of broad-spectrum antibiotic prescriptions with appropriate de-escalation is key.

Prepare to be confronted by warnings of the dire unintended consequences of prescribing narrow-spectrum antibiotics inadvertently for patients unfortunate enough to be affected by antibiotic-resistant pathogens. Although this certainly holds true for patients with severe or life-threatening sepsis — ineffective antibiotic prescribing is associated with a greater risk of prolonged hospital stay and a 1.6-fold increased risk of death from infection23 — the evidence simply does not stack up for the vast majority of patients with less severe infection, for whom starting with narrow-spectrum antibiotics and escalating to broader-spectrum agents in the event of failure to respond or microbiological evidence of resistance is a safe and proportionate response.24,25 Junior hospital doctors and pharmacists must be supported with safe systems of practice around antibiotic prescribing and adequate training.

Finally, ongoing surveillance and benchmarking of antibiotic consumption and resistance in the hospital environment is essential to provide assurance to clinical directors of high-quality prescribing.

Together, these initiatives form the foundations of effective antibiotic stewardship programmes that, combined with antibiotic avoidance strategies including vaccination and development of rapid point-of-care diagnostic tests, may just be enough to avert the predicted return to the pre-antibiotics era.
When fossil fuels are exhausted, forests decimated and the oceans despoiled, will we hang our heads in shame yet again as we tell our grandchildren that their antibiotic heritage has been squandered? Mr Walsh invites us to “take a chill pill”. May I suggest a draught of humility to add to that prescription? Behaving as ostriches, burying our collective heads in the sand with the prevailing “Keep calm and carry on prescribing” attitude, will be the humiliating legacy of a complacent generation if we elect to dismiss the carefully measured warnings of the Chief Medical Officer. We must ask ourselves: is the status quo ethically or morally defensible?

 

References

1     Pier GB. On the greatly exaggerated reports of the death of infectious diseases. Clinical Infectious Diseases 2008;47:1113–4.
2     Walsh R. It’s the antibiotics apocalypse! Again... Pharmaceutical Journal 2013;290:340.
3     Davies SC. Annual Report of the Chief Medical Officer, Vol 2, 2011, Infections and the rise of antimicrobial resistance. London: Department of Health; 2013.
4     de Kraker ME, Davey PG, Grundmann H. Mortality and hospital stay associated with resistant Staphylococcus aureus and Escherichia coli bacteremia: estimating the burden of antibiotic resistance in Europe. PLoS Med 2011;8(10):e1001104.
5     Cusini A, Rampini SK, Bansal V et al. Different patterns of inappropriate antimicrobial use in surgical and medical units at a tertiary care hospital in Switzerland: a prevalence survey. PLoS One 2010;5(11):e14011.
6     Hecker MT, Aron DC, Patel NP, et al. Unnecessary use of antimicrobials in hospitalized patients: current patterns of misuse with an emphasis on the antianaerobic spectrum of activity. Archives of Internal Medicine 2003;163:972–8.
7     Kumarasamy Y, Cadwgan T, Gillanders IA, et al. Optimizing antibiotic therapy — the Aberdeen experience. Clinical Microbiology and Infection 2003;9:406–11.
8     Pulcini C, Cua E, Lieutier F, et al. Antibiotic misuse: a prospective clinical audit in a French university hospital. European Journal of Clinical Microbiology and Infectious Diseases 2007;26:277–80.
9     Wang KY, Seed P, Schofield P, et al. Which practices are high antibiotic prescribers? A cross-sectional analysis. British Journal of General Practice 2009;59:e315–e320.
10     Schouten JA, Hulscher ME, Natsch S, et al. Barriers to optimal antibiotic use for community-acquired pneumonia at hospitals: a qualitative study. Quality and Safety in Health Care 2007;16:143–9.
11     Mol PG, Denig P, Gans RO, et al. Limited effect of patient and disease characteristics on compliance with hospital antimicrobial guidelines. European Journal of Clinical Pharmacology 2006;62:297–305.
12     Meropol SB, Localio AR, Metlay JP. Risks and benefits associated with antibiotic use for acute respiratory infections: a cohort study. Annals of Family Medicine 2013;11:165–72.
13     Costelloe C, Metcalfe C, Lovering A, et al. Effect of antibiotic prescribing in primary care on antimicrobial resistance in individual patients: systematic review and meta-analysis. BMJ 2010;340:c2096.
14     Aldeyab MA, Monnet DL, Lopez-Lozano JM, et al. Modelling the impact of antibiotic use and infection control practices on the incidence of hospital-acquired methicillin-resistant Staphylococcus aureus: a time-series analysis. Journal of Antimicrobial Chemotherapy 2008;62:593–600.
15     Lopez-Lozano JM, Monnet DL, Yague A, et al. Modelling and forecasting antimicrobial resistance and its dynamic relationship to antimicrobial use: a time series analysis. International Journal of Antimicrobial Agents 2000;14:21–31.
16     Monnet DL, MacKenzie FM, Lopez-Lozano JM, et al. Antimicrobial drug use and methicillin-resistant Staphylococcus aureus, Aberdeen, 1996–2000. Emerging Infectious Diseases 2004;10:1432–41.
17     Tacconelli E, De AG, Cataldo MA, et al. Antibiotic usage and risk of colonization and infection with antibiotic-resistant bacteria: a hospital population-based study. Antimicrob Agents Chemother 2009; 53(10):4264-4269.
18     Tacconelli E, De AG, Cataldo MA, Pozzi E, Cauda R. Does antibiotic exposure increase the risk of methicillin-resistant Staphylococcus aureus (MRSA) isolation? A systematic review and meta-analysis. Journal of Antimicrobial Chemotherapy 2008;61:26–38.
19     Srinivasan A, Song X, Richards A, et al. A survey of knowledge, attitudes, and beliefs of house staff physicians from various specialties concerning antimicrobial use and resistance. Archives of Internal Medicine 2004;164:1451–6.
20     Pulcini C, Williams F, Molinari N, et al. Junior doctors’ knowledge and perceptions of antibiotic resistance and prescribing: a survey in France and Scotland. Clinical Microbiology and Infection 2011;17:80–87.
21     Lucet JC, Nicolas-Chanoine MH, Roy C, et al. Antibiotic use: knowledge and perceptions in two university hospitals. Journal of Antimicrobial Chemotherapy 2011;66:936–40.
22     Francis NA, Butler CC, Hood K, et al. Effect of using an interactive booklet about childhood respiratory tract infections in primary care consultations on reconsulting and antibiotic prescribing: a cluster randomised controlled trial. BMJ 2009;339:b2885.
23     Paul M, Shani V, Muchtar E, et al. Systematic review and meta-analysis of the efficacy of appropriate empiric antibiotic therapy for sepsis. Antimicrobial Agents and Chemotherapy 2010;54:4851–63.
24     Corona A, Bertolini G, Lipman J, et al. Antibiotic use and impact on outcome from bacteraemic critical illness: the BActeraemia Study in Intensive Care (BASIC). Journal of Antimicrobial Chemotherapy 2010;65:1276–85.
25     Thom KA, Schweizer ML, Osih RB, et al. Impact of empiric antimicrobial therapy on outcomes in patients with Escherichia coli and Klebsiella pneumoniae bacteremia: a cohort study. BMC Infectious Diseases 2008; 8:116.

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Citation: The Pharmaceutical JournalURI: 11119473

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