FIRST OF THREE ORIGINAL OBSERVATIONS

There are advantages for a clinician personally seeing and treating many patients over a prolonged period. A prolonged period may be necessary to observe the effects of any interventions. A wise observation of that great physician Sir William Osler is relevant to the following section –

‘Medicine is to be learned by experience; and is not an inheritance; it cannot be revealed. Learn to see, learn to hear, learn to feel, learn to smell, and know that by practice alone can you become expert”.

Hence, my enthusiasm for seeing as many patients as possible in clinics where one could improve one’s knowledge of a condition and observe where improvements and changes in management were needed and the results of any interventions. Certainly in 1968, when I was first appointed as an NHS consultant paediatrician in Leeds, there was room for improvement in many areas.

To expand on and reinforce these beliefs I will describe the only three really original and important clinical observations I have made during my 40-year career as a consultant paediatrician. All were the direct result of experience gained from personally following, investigating and treating many children with a particular condition or complication over a prolonged period.  None of the observations would have been made had I only treated occasional patients. The three observations were

• That inhaled colomycin would eradicate a new growth of Pseudomonas aeruginosa from the airways of children with cystic fibrosis – contrary to all previous teaching.                                                                                                      

 Littlewood JM, Miller MG, Ghoneim AT, Ramsden CH   Nebulised colomycin for early pseudomonas colonisation in cystic fibrosis. Lancet. 1985 Apr 13;1(8433):865.  

• That inhaled corticosteroids (Becotide) could impair the growth of some children with asthma – contrary to establish teaching.                                                                         

Littlewood JM, Johnson AW, Edwards PA, Littlewood AE. Growth retardation in asthmatic children treated with inhaled beclomethasone dipropionate. Lancet. 1988 Jan 16;1(8577):115-6. 2891952

• That coeliac disease in the Yorkshire region was disappearing as judged by the numbers of children referred to me for jejunal biopsy.   

Littlewood JM, Crollick AV, Richards IDG. Childhood coeliac disease is disappearing. Lancet 1980 Dec 20/27:1359.

All three original observations were the result of accumulating considerable experience derived from personally following, investigating or treating many children with a particular condition.

The importance of significant patient numbers, careful follow-up and note-taking and particularly continuity of professional involvement are of great importance – hence my deep unwavering commitment to CF Centre Care for all people with the condition.  Good care is a team effort. The care and dedication of the nurses and other staff in the paediatric clinics and wards and the skill, interest and collaboration of people in many other departments at St James’s in Leeds was of crucial importance in providing a professional effective service.

THE FIRST ORIGINAL OBSERVATION 

That inhaled colomycin would eradicate a new growth of Pseudomonas aeruginosa from the airways of children with cystic fibrosis – contrary to all previous teaching.     

1985 Littlewood JM, Miller MG, Ghoneim AT, Ramsden CH. Nebulised colomycin for early Pseudomonas colonisation in cystic fibrosis. Lancet 1985;1:865. 

This letter to the Lancet from our CF Unit at St James’s University Hospital was the first report of the use of nebulised colomycin to eradicate early Pseudomonas infection in children with cystic fibrosis. Although only a modest letter, this was undoubtedly the most important publication of my career! Pseudomonas aeruginosa once it was isolated from respiratory cultures of a person with CF usually persisted; there followed a gradual increase in a chronic cough and sputum production and deterioration in respiratory function. Without wish to overdramatise the situation – at that stage the patient had passes the “point of no return”. Thereafter progress would be steadily downhill – the rate of decline depending on the treatment the patient received. At some stage, when the symptoms worsened the child would be treated with a course of intravenous anti-Pseudomonal antibiotics. In the majority these intermittent courses of IV antibiotics would continue to the end of the patient’s life. Until the later part of the Eighties this treatment necessitated a two week admission to hospital with a major disruption to family life. We did not introduce home intravenous antibiotics until the second half of the Eighties when oral ciprofloxacin, the first oral antibiotic effective against P. aeruginosa, also became available.

Long term nebulised anti-Pseudomonal antibiotics, such as gentamicin or tobramycin, were by no means accepted as a safe, effective treatment in the Eighties and tended to be used only when the respiratory function was deteriorating rather than to eradicate early infection.
However, in 1981, there was a seminal publication by Dr Margaret Hodson and her colleagues at the Royal Brompton Adult CF clinic in London

Hodson ME et al. Aerosol carbenicillin and gentamicin treatment of Pseudomonas aeruginosa in patients with cystic fibrosis. Lancet 1981; i: 1137-1139. [PubMed]. 

Most adults with CF had chronic Pseudomonas infection with frequent exacerbation of their chest infection requiring admission to hospital for intravenous antibiotics. Margaret Hodson’s use of long  term nebulised antibiotics significantly reduced the frequency of these exacerbations.

Margaret was to make many major contributions to the treatment of people with CF from her vast experience at the Brompton Hospital treating many hundreds of adult patients with CF. This 1981 paper of hers had a major influence on treatment in the UK of chronic Pseudomonas infection although there had been many earlier concerns about nebulised antibiotics increasing the incidence of bacterial resistance.

Although nebulised penicillin had been used in the Forties, when S. aureus was the main pathogen (di Sant’Agnese, et al, 1946), it was undoubtedly this present paper from the Brompton, that revived the interest in nebulised antibiotics for patients with chronic Pseudomonas infection who were having frequent exacerbations of their chest infection.. Although numbers were small the nebulised anti-Pseudomonal antibiotics, gentamicin and carbenicillin, obviously stabilised the condition of some patients with frequently relapsing chronic P, aeruginosa infection who were requiring increasingly frequent courses of IV antibiotics. As a result of this paper, nebulised anti-Pseudomonal antibiotics gradually became more widely used in the UK for CF patients with chronic Pseudomonas infection.

In this respect the UK was well in advance of North America where, even in 1986, McLusky and colleagues from Toronto advised that, “until additional well-controlled trials were completed their routine use (of inhaled antibiotics) was not justified because of cost, potential side effects and the propensity to select resistant organisms” (McLusky et al, 1986).

As it eventually turned out, both the routine use of nebulised anti-Pseudomonal antibiotics to suppress chronic infection, as recommended by Margaret Hodson in 1981 (also eventually in the USA by Ramsay BW et al, 1999) and the early use of colomycin to eradicate early Pseudomonal infection (Littlewood et al, 1985; Valerius et al, 1991) both proved to be effective, proven and eventually widely used treatments for people with CF on both sides of the Atlantic.

Before early eradication treatment of Pseudomonas aeruginosa

To return to our paediatric CF clinic in Leeds in the early Eighties, many of our young children with CF of the 3000 born annually in St Mary’s Maternity Hospital in East Leeds, (where I was responsible for neonatal care), had been diagnosed by neonatal screening since 1975 and were in excellent condition and free of P. aeruginosa. (Paediatricians at the other two maternity units,  (Dick Smithers and Ian Forsyth) did not agree with neonatal CF screening).

Our young CF infants received prophylactic anti-staphylococcal cloxacillin (as recommended by Dr David Lawson) which reduced the incidence of Staph. aureus infection but disappointingly sooner or later virtually all became infected with P. aeruginosa (sequence illustrated in the figure). This was invariably associated with a gradual but quite obvious increase in chronic cough and sputum production as they passed the ‘point of no return’ (stage 3) and chronic Pseudomonas infection became established and progressive. Both the clinic staff and the parents understood the serious significance of transition from intermittent infections to chronic P. aeruginosa infection; for this reason most were enthusiastic to try any treatment likely to eradicate the organism.

So as this was a major and increasing problem, I decided to examine the possibility of treating the early P. aeruginosa infections, before the organism became established.
I had been influenced by Margaret Hodson’s use of nebulised antibiotics, admittedly used in slightly different circumstances i.e to stabilise adult patients who already had chronic Pseudomonas infection. However, I was reluctant to use one of the aminoglycosides (gentamicin or tobramycin) in our young patients as eventually these would be needed for intravenous antibiotic treatment.

I found some old references reporting the successful use of nebulised colomycin in non-CF adult patients with pneumonia due to P. aeruginosa

Halliday NP. Pseudomonas infection of the respiratory tract treated with colistin sulphomethate sodium (colomycin). Clin Trials J 1967 August 771-775.

Herrell WE. Aerosolized colistimethate in the treatment of pulmonary infections. Clin Med September 1968, 18-19. Rose HD et al. Evaluation of sodium colistimethate aerosol in gram-negative infections of the respiratory tract. J Clin Pharm 1970; 19:274-281

I discussed the possibility of using nebulised colomycin in children with CF with the UK manufacturers (Pharmax at the time) from February 1981. From the information they provided it seemed reasonable to try a small dose of nebulised colomycin twice daily in an attempt to eradicate early P. aeruginosa. I’m sure this would not have been condoned by the regulatory authorities in 2022! However, it should be remembered that at that time, in the early Eighties, CF was usually fatal in childhood or adolescence. Most children suffered from progressive P. aeruginosa chest infection and and were slowly dying – most either died during childhood or in their early teens from respiratory failure after years of miserable chronic illness. There were no adult CF clinics in the early Eighties outside the one at the Royal Brompton in London as there were so few adults.

So at St James’s in Leeds we started treating a few children with nebulised colomycin 500mg twice daily after a test dose. The children seemed to tolerate the inhalations. Gradually, as more monthly cough/throat swabs became negative, it became quite obvious that the nebulised colomycin was clearing the Ps. aeruginosa from the respiratory tract (Table from the original Lancet paper). At this stage we reported our initial experience in our letter to the Lancet.

Subsequent experience –