The antibiotic course has had its day | The BMJ – July 2017
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, argue Martin Llewelyn and colleagues.
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.
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.
This seems unlikely because such long-held “wisdoms” are ingrained in institutions, guidelines, standard procedures, doctors’ education, and patients’ minds.
Origins 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
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.
Antibiotic treatment drives 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.
Many bacterial species that live harmlessly in the gut, on our skin and mucus membranes, or in the environment can also cause disease as opportunist pathogens.
For such organisms, resistance selection occurs predominantly during antibiotic treatment of other infections.
Resistance in opportunists may be passed easily to other strains of the same species of bacteria or to different species.
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
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.
Historically, antibiotic courses were set by precedent, driven by fear of undertreatment, with less concern about overuse.
For many indications, recommended durations have decreased as evidence of similar clinical outcomes with shorter courses has been generated.
For most indications, studies to identify the minimum effective treatment duration simply have not been performed.
For the opportunist pathogens for which antimicrobial resistance poses the greatest threat, no clinical trials have shown increased risk of resistance among patients taking shorter treatments.
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.
Is the concept of an antibiotic course still valid?
The concept of an antibiotic course ignores the fact that patients may respond differently to the same antibiotic, depending on diverse patient and disease factors.
Currently, we largely ignore this fact and instead make indication specific recommendations for antibiotic duration that are based on poor evidence.
patients might be best advised to stop treatment when they feel better, in direct contradiction of WHO advice.
Of note, a recent clinical trial found that using fever resolution to guide stopping antibiotics in community acquired pneumonia halved the average duration of antibiotic treatment without affecting clinical success.
“Complete the course”: a barrier to antibiotic conservation
The fallacious belief that antibiotic courses should always be completed to minimise resistance is likely to be an important barrier to reducing unnecessary antibiotic use.
The idea is deeply embedded, and both doctors and patients currently regard failure to complete a course of antibiotics as irresponsible behaviour.
strategies to reduce overuse aim to change, or ideally stop, antibiotics 48-72 hours after they are started, but these are challenging to implement.
Designing trials of antibiotic sparing treatment is notoriously difficult,
What should we advise patients?
The “complete the course” message has persisted despite not being supported by evidence and previous arguments that it should be replaced.
Daily review of the continued need for antibiotics is a cornerstone of antibiotic stewardship in hospitals, but in primary care, where 85% of antibiotic prescriptions are written, no such ongoing assessment is attempted.
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.
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.
- Patients are put at unnecessary risk from antibiotic resistance when treatment is given for longer than necessary, not when it is stopped early
- For common bacterial infections no evidence exists that stopping antibiotic treatment early increases a patient’s risk of resistant infection
- Antibiotics are a precious and finite natural resource which should be conserved by tailoring treatment duration for individual patients
- Clinical trials are required to determine the most effective strategies for optimising duration of antibiotic treatment