'Little point taking antibiotics for coughs'

‘The winter may be peak season for coughs and colds but there is no point in taking antibiotics to shift them’, The Independent reports. Its story comes from a large trial looking at whether a commonly used antibiotic, amoxicillin, can relieve symptoms of acute lower respiratory tract infections such as coughs and bronchitis.

The study found that antibiotics didn’t shorten the time people had symptoms for, nor did they reduce the severity of respiratory symptoms. This is unsurprising as the majority of coughs and cases of bronchitis are thought to be caused by viral, not bacterial, infection – and antibiotics are useless against viral infections.

If anything, as the Daily Mail points out, antibiotics may be doing more harm than good in these types of infection, as they carry a small risk of side effects such as nausea and rash.

This large, well-designed trial provides firm evidence that taking antibiotics for self-limiting conditions, such as the cough or bronchitis, has little benefit, even for older people.

Where did the story come from?

The study was carried out by researchers from a number of institutions in Europe including the University of Southampton and Cardiff University in the UK. It was funded by the European Commission, UK National Institute for Health Research, Barcelona Ciber de Enfermadades Respiratorias, and Research Foundation Flanders.

The study was published in the peer-reviewed medical journal The Lancet Infectious Diseases.

The media reported the story accurately, though The Independent’s use of the term “coughs and colds” was a little misleading. The study looked at the use of antibiotics for all lower respiratory tract infections (LRTIs), commonly known as chest infections. A cold usually only affects the upper respiratory tract (nose and throat), although some viruses can affect both the upper and lower airways.

What kind of research was this?

This was an international randomised placebo controlled trial (RCT) that aimed to look at both the benefits and harms of giving people amoxicillin for lower respiratory tract infections (LRTIs), one of the most common acute (short-term) illnesses seen by GPs.

LRTIs are those that affect the windpipe and the lungs (upper infections affect the nose and throat). Symptoms may include cough, fever, fatigue and general sense of feeling unwell. LRTIs may be caused by viruses (such as those known to be associated with the cold, including rhinoviruses) or bacteria.

The researchers point out that most patients with LRTIs receive antibiotics, partly because they worry about the symptoms and also because some doctors may give antibiotics as a precaution to try to prevent complications, such as pneumonia (a more severe type of lung infection), even if there is uncertainty of a bacterial infection being present.The researchers argue that prescribing antibiotics in this way is costly and is one of the main causes of antibiotic resistance.

In 2009, a systematic review of the use of antibiotics for acute bronchitis showed moderate benefits and no significant short-term harm, so the debate about their use for LRTIs has continued, with little data from placebo controlled trials, say the researchers.

Most doctors tend to prescribe antibiotics for older patients who also have other illnesses (as they are more vulnerable to the harmful effects of infection), but their role for healthier older people with coughs is unclear.

What did the research involve?

Between 2007 and 2010, researchers recruited patients attached to primary care practices in 12 countries; Belgium, England, France, Germany, Italy, the Netherlands, Poland, Slovakia, Slovenia, Spain, Sweden, and Wales.

Eligible patients were aged 18 or over and had seen their doctor for the first time with either an acute cough (one which had lasted 28 days or less) or an illness in which cough was the main symptom but which the doctor thought due to an LRTI.

Patients who had been diagnosed with pneumonia were excluded, as were patients whose cough was found to be caused by conditions other than infection (such as a clot on the lung or allergy), or who had been prescribed antibiotics in the previous month. Patients were also excluded if they couldn’t provide informed consent, were pregnant, allergic to penicillin, or had immune system deficiencies.

Using computer-generated random numbers, the researchers randomly assigned participants to one of two groups. The first group were given amoxicillin (dosage 1g three times a day for seven days) and the second a placebo drug (dummy treatment), identical to amoxicillin in appearance, taste and texture, for the same period. Neither patients nor the doctors involved knew which participants were allocated to which group (double-blinded).

The researchers wanted to see whether taking antibiotics affected the duration of symptoms that were described as “moderately bad” or worse (see description of symptom scale below). They also looked at whether antibiotics had any effect on the severity of symptoms in days two to four, or on the development of new or worsening symptoms, such as:

a return visit to the doctor with worsening symptoms
new symptoms or signs
illness requiring hospital admission

The patients’ doctors recorded the severity of symptoms at baseline and rated them as:

no problem
mild problem
moderate problem
severe problem

The patients were asked to complete a daily symptom diary for the duration of the illness, recording the severity of cough, phlegm, shortness of breath, wheeze, blocked or runny nose, chest pain, muscle aches, headaches, disturbed sleep, general feeling of being unwell, fever and interference with normal activities. Symptoms were scored on a scale of 0 to 6, with 0 being “no problem” and 6 “as bad as it could be”.

Patients also recorded non-respiratory symptoms such as diarrhoea, skin rash and vomiting. The symptom diary used in the research is considered reliable.

Researchers telephoned participants after three days to offer support and answer any questions about completion of the diary. If the diary was not returned after four weeks, they collected information about symptom duration and severity with either a short questionnaire or a telephone call.

The patients’ doctors registered all contacts with patients for four weeks after the initial consultation including referral to hospital and out-of-hours contacts.

Using patients’ diaries, the researchers analysed the results using standard statistical methods. They also completed a separate analysis of patients aged 60 or over and for patients aged 70 or older.

What were the basic results?

The study had 3,108 patients agree to take part, though 1,047 were ineligible, mostly because they refused to be randomly assigned to an antibiotic or placebo. After exclusions, 2,061 patients were randomly assigned to one of the two groups:

1,038 to the amoxicillin group
1,023 to the placebo group

The researchers found:

There was no significant difference between the amoxicillin and placebo groups in how long “moderately bad” or worse symptoms lasted (hazard ratio 1.06, 95% confidence interval [CI] 0.96 to 1.18).
There was no significant difference between the two groups in the average severity of symptoms (1.69 with placebo versus 1.62 with amoxicillin, difference –0.07 [95% CI 0.15 to 0.007]).
New or worsening symptoms were significantly less common in the amoxicillin group than in the placebo group (162 [15.9%] of 1,021 patients versus 194 [19.3%] of 1,006, p=0.043, number needed to treat 30).
Cases of nausea, rash, or diarrhoea were significantly more common in the amoxicillin group than in the placebo group (28.7% versus 24%, number needed to harm 21, 95% CI 11 to 174), and one case of anaphylaxis (severe allergic reaction) was noted with amoxicillin.
Two patients in the placebo group and one in the amoxicillin group needed to be admitted to hospital.
No-one died.
There was no evidence of any benefit for amoxicillin in patients aged 60 years or older (n=595) or in those aged 70 or over (n=266).

How did the researchers interpret the results?

If pneumonia and other complications are not suspected, amoxicillin has little benefit for acute lower respiratory tract infections overall or for patients aged 60 or over, and has a slight risk of side effects, they say.

Any mild short-term benefits of antibiotic treatment should be balanced against the risk of side effects and in the long term of fostering antibiotic resistance.

Conclusion

This large international trial provides convincing evidence that for most patients with an uncomplicated, acute cough where pneumonia is not suspected, antibiotics do not shorten how long symptoms last or their severity.

Antibiotics did reduce the risk of new or worsening symptoms. However, as the researchers point out, 30 people needed to be treated with amoxicillin to prevent just one case of new or worsening symptoms. This is called the ‘number needed to treat’ and is a useful way for researchers to compare the effectiveness of treatments.

This ‘number needed to treat’ of 30 has to be balanced against the increased rate of side effects. In this study, the ‘number needed to harm’ was 21. The fact that the number need to harm is lower than the number needed to treat means that more people would get side effects from the treatment than might be helped by it. However, the severity and duration of these side effects has to be weighed up against the symptoms that are being eased.

Even if there was a more favourable trade-off between number needed to treat and the number needed to harm, doctors, health policymakers, and even us ordinary punters, have to consider the wider (and growing) problem of antibiotic resistance. Every time we use an antibiotic to treat a trivial, self-limiting condition, such as a bacterial chest infection, we increase the risk of that antibiotic subsequently failing to treat a life-threatening condition such as bacterial meningitis. However, as the authors point out, the results may not apply to older people with other serious illnesses or weakened immune systems, where antibiotic treatment could be warranted.

There are a few limitations in this study that are worth noting, including :

About a third of patients recruited chose not to be randomly assigned, so did not take part in the study. This could lead to “recruitment bias”, although the researchers say there is no evidence of this.
Only one type of antibiotic was used in the trial. It is possible that other types might be more effective, although this is unlikely and some others may also have more side-effects.
The small number of patients aged 70 or over (266) may mean the study did not have the power to detect any benefit for antibiotics in this group.
Poor adherence may have affected the results, although more than 90% of patients in both groups reported taking the study drugs by day five.