Why ….. do we use intravenous antibiotics in the way we do?

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Professor Alan Smyth, University of Nottingham, UK.

Many people with cystic fibrosis have chronic lung infection with the germ Pseudomonas aeruginosa and will need regular treatment with intravenous antibiotics. These courses of treatment will often include an aminoglycoside antibiotic – for instance tobramycin – and one other antibiotic.  Two antibiotics are given, rather than one, so that the bacteria have less of an opportunity to become resistant.  Also it is likely that the combination of two antibiotics produces a greater effect than if they were given alone.  However, while these antibiotics are good at treating the exacerbation, they also have the potential to cause kidney damage so they are carefully monitored to minimise this risk.

Identifying a problem

We became aware that our local children’s kidney dialysis unit had been referred a number of children with CF who had suffered temporary kidney failure – acute kidney injury – and we were concerned to work out what was causing it.

We carried out a national survey to see how common this problem was. We wrote to all CF Centres (paediatric and adult) in the UK and asked if they had ever been involved in looking after a patient with CF who had acute kidney injury.  55 cases were identified and these involved both children and adults. This meant that there were between 5 and 11 cases of acute kidney injury per 10,000 patients with CF per year.

In order to identify factors that made these patients more at risk of acute kidney injury, we randomly identified two ‘control’ patients who were both of a similar age and sex to the patient with kidney injury.  We compared risk factors for kidney injury in the patient with kidney injury with the two comparison patients who had remained well.  Patients who developed acute kidney injury were eighty times more likely to be on an aminoglycoside at the time of their acute kidney injury than controls. Gentamicin was frequently used in the patients who developed acute kidney injury and almost never in the control patients. The increased exposure to gentamicin was statistically significant and so is unlikely to be a chance finding.

As a result of this research, we recommended that gentamicin is not used for people with CF and the UK treatment guidelines were amended to reflect this. Tobramycin is now recommended as the antibiotic of first choice for treating Pseudomonas.  As ever, aminoglycoside therapy should be carefully monitored.

An opportunity for improvement

Evidence from the laboratory and from other patients suggested that a once a day dose of tobramycin might be safer and cause less damage to the kidneys than if it was given three times a day, as was the norm at the time.

We conducted a clinical trial (called the TOPIC trial) which compared once-a-day and three times-a-day dosing of tobramycin. This involved 244 patients with CF (children and adults) in the UK.

We found that both approaches were equally effective.  We saw the same improvement in lung function – forced expiratory volume in 1 sec (FEV1) of around 10% in both groups. One marker of early kidney damage – N-acetyl Beta D glucosaminidase (NAG) – went up in both groups but much less in the once daily group. In children, there was a much greater difference in favour of once daily treatment when we measured another, more common marker of kidney function – serum creatinine.

As a result we now recommend once daily tobramycin for the treatment of Pseudomonas chest infections in patients with CF. These recommendations have been included in treatment guidelines in the UK and the US.  The use of once daily treatment has increased from 17% of UK CF Centres in 2002 to 86% today. However, it is too early to tell if this has reduced the rates of acute kidney injury.