02/08/2017
🔰The Antibiotic Course Has Had Its Day ~
With little evidence that failing to complete a prescribed antibiotic course contributes to antibiotic resistance, it’s time for policy makers, educators, and doctors to drop this message.
Antibiotics are vital to modern medicine and antibiotic resistance is a global, urgent threat to human health. The relation between antibiotic exposure and antibiotic resistance is unambiguous both at the population level and in individual patients. Reducing unnecessary antibiotic use is therefore essential to mitigate antibiotic resistance.
Avoiding overuse requires healthcare professionals and the public to be well informed about antibiotic treatment, as set out in the first objective of the World Health Organization Global Action Plan. Public communication about antibiotics often emphasises that patients who fail to complete prescribed antibiotic courses put themselves and others at risk of antibiotic resistance. For example, in materials supporting Antibiotic Awareness Week 2016 WHO advised patients to “always complete the full prescription, even if you feel better, because stopping treatment early promotes the growth of drug-resistant bacteria.”
Similar advice appears in national campaigns in Australia,5 Canada,6 the United States,7and Europe.8 And in the United Kingdom it is included as fact in the curriculum for secondary school children.9
However, the idea that stopping antibiotic treatment early encourages antibiotic resistance is not supported by evidence, while taking antibiotics for longer than necessary increases the risk of resistance. Without explicitly contradicting previous advice, current public information materials from the US Centers for Disease Control and Prevention (CDC) and Public Health England have replaced “complete the course” with messages advocating taking antibiotics “exactly as prescribed.”
We explore the evidence for antibiotic duration, clinical effectiveness, and resistance, and encourage policy makers, educators, and doctors to stop advocating “complete the course” when communicating with the public. Further, they should publicly and actively state that this was not evidence-based and is incorrect.
🔰Origin of the idea
Concern that giving too little antibiotic treatment could select for antibiotic resistance can be traced back to the dawn of the antibiotic era. When Howard Florey’s team treated Albert Alexander’s staphylococcal sepsis with penicillin in 1941 they eked out all the penicillin they had (around 4 g, less than one day’s worth with modern dosing) over four days by repeatedly recovering the drug from his urine. When the drug ran out, the clinical improvement they had noted reversed and he subsequently succumbed to his infection. There was no evidence that this was because of resistance, but the experience may have planted the idea that prolonged therapy was needed to avoid treatment failure.
Fleming’s early work showed that sensitive bacteria could be “acclimatised” to penicillin in the laboratory. In his 1945 Nobel prize acceptance speech, Fleming painted a vivid clinical vignette in which an imagined patient with a streptococcal throat infection who takes insufficient penicillin, transmits the infection—now in resistant form—to his wife, and is thus responsible for her subsequent death from antibiotic resistant disease. Fleming advised, “If you use penicillin, use enough!” Ironically, Streptococcus pyogenes has never developed resistance to penicillin, and we now know that for most forms of antibiotic resistance that currently threaten patients, selection of resistance in the bacteria being treated is of limited importance.
Antibiotic treatment drives resistance
The scenario envisaged by Fleming was of target selected resistance. Infections typically begin when a small population of microorganisms gain access to the host and replicate. Genetic mutations conferring antibiotic resistance may arise spontaneously during replication and be selected for during treatment. Target selected resistance can occur with inadequate antimicrobial dosing or with monotherapy for infections for which spontaneous resistant mutations arise on treatment, such as tuberculosis, gonorrhoea, and HIV.
Early trials of tuberculosis treatment showed resistance emerging during monotherapy and underpin the need for combination therapy for this disease. Transmission of such pathogens during or following inadequate treatment may allow resistant strains to spread from person to person.
However, most of the bacterial species now posing the greatest problems do not develop resistance through target selection. The clinical threat comes mainly from species such as Escherichia coli and the so called ESKAPE organisms (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter spp, Pseudomonas spp, Enterobacter spp), which are all found harmlessly in us, on us, or in our environment. They can also act as “opportunistic” pathogens.
When a patient takes antibiotics for any reason, antibiotic sensitive species and strains present among commensal flora on their skin or gut or in the environment are replaced by resistant species and strains ready to cause infection in the future. This collateral selection is the predominant driver of the important forms of antibiotic resistance affecting patients today. The longer the antibiotic exposure these opportunist bacteria are subjected to, the greater the pressure to select for antibiotic resistance.
Importantly for these opportunistic pathogens, resistant strains are transmitted between asymptomatic carriers rather than people with disease. Furthermore, many resistance conferring genes can pass easily between bacterial strains or species. Thus antibiotic selection may drive outbreaks of resistant infections independently of transmission of a specific strain or species.
From fear of undertreatment to harm from overtreatment.
Traditionally, antibiotics are prescribed for recommended durations or courses. Fundamental to the concept of an antibiotic course is the notion that shorter treatment will be inferior. There is, however, little evidence that currently recommended durations are minimums, below which patients will be at increased risk of treatment failure.
The key argument for changing how we discuss antibiotic courses with patients is that shorter treatment is clearly better for individual patients. Not only does an individual patient’s risk of resistant infection depend on their previous antibiotic exposure but reducing that exposure by shorter treatment is associated with reduced risk of resistant infection and better clinical outcome. In hospital acquired pneumonia, for example, randomised controlled trial data indicate that short treatment strategies have equivalent clinical outcomes to longer courses and are associated with lower rates of infection recurrence and antibiotic resistance.
There are reasons to be optimistic that the public will accept that completing the course to prevent resistance is wrong if the medical profession openly acknowledges that this is so, rather than simply substituting subtle alternatives such as “exactly as prescribed.” Completing the course goes against one of the most fundamental and widespread medication beliefs people have, which is that we should take as little medication as necessary. Concerted and consistent efforts have successfully educated the public that antibiotics do not treat viral infections, for example.
Research is needed to determine the most appropriate simple alternative messages, such as stop when you feel better. Until then, public education about antibiotics should highlight the fact that antibiotic resistance is primarily the result of antibiotic overuse and is not prevented by completing a course. The public should be encouraged to recognise that antibiotics are a precious and finite natural resource that should be conserved. This will allow patient centred decision making about antibiotic treatment, where patients and doctors can balance confidence that a complete and lasting cure will be achieved against a desire to minimise antibiotic exposure unimpeded by the spurious concern that shorter treatment will cause antibiotic resistance.