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 –

An example of long term prevention of chronic P. aeruginosa infection 

A boy with CF had early eradication therapy for P. aeruginosa with colomycin having grown the organism on six cultures during his 5th year (blue-green shaded area). His cultures became negative (– along lower graph), the colistin (colomycin) was eventually stopped at the age of 10 years and he passed into adulthood free of chronic infection.

The Copenhagen CF centre started to use inhaled colomycin first to reduce relapses in chronic Pseudomonas infection

The Danish group in Copenhagen, were undoubtedly the leading CF clinic at the time in Europe (Professor Niels Hoiby and Dr Christian Koch).
Apparently as a result of our letter to the Lancet reporting the  successful use of colomycin in eradicating early Pseudomonas infection, they started to use nebulised colomycin in the first instance to stabilise the condition of their chronically infected CF patients – suppression rather than eradication.

1987 Jensen T, Pedersen SS, Garne S, Heilmann C, Hoiby N, Koch C. Colistin inhalation therapy in cystic fibrosis patients with chronic aeruginosa lung infection. J Antimicrob Chemother 1987; 19:831-838. 

In this Jensen paper one million units of inhaled colistin twice daily were compared with inhaled isotonic saline over three months in patients already chronically infected with P. aeruginosa. More patients in the colistin group completed the study (18 vs.11). In terms of symptom scores, maintenance of pulmonary function (but only limited to the FVC) and inflammatory parameters, colistin was superior to placebo.
Although the results in this Copenhagen study were not impressive, nevertheless inhaled colistin came into widespread use in the UK and Europe to stabilise patients with chronic Pseudomonas chest infection – as it turned out, on the relatively modest published evidence in this Jensen paper!
Eventually subsequent studies showed colistin to be somewhat less effective than inhaled tobramycin (TOBI) but both treatments were definitely associated with a significant fall in the numbers of bacteria in the sputum (Hodson ME et al. Eur Respir J 2002; 20:658-664). However, in this comparison study the patients had received colistin previously but were TOBI (tobramycin) naive and hence were more likely to improve with the latter.

The Copenhagen CF Centre group then trialed inhaled colomycin to eradicate early P. aeruginosa

Valerius NH, Koch C, Hoiby N. Prevention of chronic Pseudomonas aeruginosa infection in cystic fibrosis by early treatment. Lancet 1991; 338:7245-726 

Subsequently, after the Jensen trial, apparently as a result of our short letter to the Lancet according to Niels Hoiby, the Copenhagen team performed a controlled trial using nebulised colomycin as early eradication therapy (Valerius et al, 1991). They reported that their results “confirm and extend the preliminary report by Littlewood and colleagues”.

The results of this Copenhagen trial were impressive (Valerius et al, 1991). In summary from the paper – “To assess whether chronic pulmonary colonisation with Pseudomonas aeruginosa in cystic fibrosis is preventable, 26 patients who had never received anti-pseudomonas chemotherapy were randomly allocated to groups receiving either no anti-pseudomonas chemotherapy or oral ciprofloxacin and aerosol inhalations of colistin twice daily for 3 weeks, whenever Ps aeruginosa was isolated from routine sputum cultures. 

During the 27 months of the trial, infection with Ps aeruginosa became chronic in significantly fewer treated than untreated subjects (2 [14%] vs 7 [58%]; p <0.05) and there were significantly fewer Ps aeruginosa isolates in routine sputum cultures in the treated group (49/214 [23%] vs 64/158 [41%]; p = 0.0006). Thus, chronic colonisation with Ps aeruginosa can be prevented in cystic fibrosis by early institution of anti-pseudomonas chemotherapy”

Henrik Valerius kindly supplied the photo and told me he first presented this data as a poster at the International CF Conference in Washington in 2000. It was by far the least studied poster by the participants at the conference! As he recalled none at all stopped by to read it or discuss it- the only reaction he recalls was head shaking!! Indeed he was surprised when the Lancet accepted the paper!!

 

The widespread introduction of Pseudomonas aeruginosa eradication therapy was painfully slow

The slow introduction of early eradication therapy for P. aeruginosa, particularly in North America, is difficult to understand although perhaps one reason was that, in the early Eighties, the serious long term consequences of chronic Pseudomonas infection were only just being clearly described; most publications documenting the unfavourable outlook for patients with chronic Pseudomonas infection did not appear until the early Nineties (Kerem E et al, 1990.; Henry et al, 1992; Hudson et al, 1993; Pamucku et al, 1995; Frederiksen et al, 1996; Kosorok et al, 2001).
However, most clinicians treating patients were well aware of the downward course of the patient’ condition following the onset of chronic P. aeruginosa infection.

However, it is surprising that in a Cochrane Systematic Review of early Pseudomonas eradication treatment even as late as 2017, the reviewers, while noting that the organism was eradicated in some patients, were still reluctant to admit that eradicating the organism had a favourable long term effect – presumably ignoring a great deal of published work attesting to the adverse effects of chronic P. aeruginosa infection mentioned above?
The other lesson to take from this episode is that if the clinical course following a new intervention is so very different from the usual expected course, it is very likely to be a significant effect. To ignore such an occurrence, just because there is no “randomised controlled trial”, is not in the patients’ best interest.

In this context it is interesting to recall the relaxed attitude of many UK CF centre directors to P. aeruginosa (UK CF Trust’s ‘CF Centre Directors Meeting’, Autumn, 2001) and their vigorous reaction to proposals for patient segregation when this was suggested by the UK CF Trust in 2001 to prevent cross infection with the organism.

• “Draconian measures ..very little evidence in this document.  It ought to be removed..no evidence that segregation is beneficial”
• The laboratories will be flooded out and it would cost thousands of pounds
• It would ruin shared clinics as you could only see one type of patient (i.e. Pseudomonas + or Pseudomonas -)
• No logic in seeing them on a separate day
• I don’t think it right that such a document should be available in the public demain
• Most Pseudomonas comes from the environment – what are you going to gain from this?  You are going to stigmatise, you are going to increase fear
• You may blow apart CF centres ..being considered bad places for patients to go
• I strongly suggest that we consider the whole thing and see if we aren’t doing more harm than good

In contrast some centre directors already appreciated the cross infection was indeed a significant risk in CF centres and clinics (UK CF Trust’s Centre Directors Meeting, Autumn, 2000)

• CF centres, whether you like it or not, do have problems with cross infection – it is one of the big downsides of a centre
• There is evidence of cross infection ..more is emerging”v“We found 3 patients had the same genotype … we now practice segregation
• Whatever the professionals think, parents are starting to ask these questions
• I think we should be segregating in anticipating
• To sit back and say ‘I’m alright I have not got the same strain’is naïve. You can wait for it to happen and you cannot get rid of it once it is there
• I came onto the (Cross Infection) Committee for the first year adamant that we would not be segregating. I have been converted, worn down!
• With due respect, to say there is no evidence (of cross infection) is just rubbish!

Obviously the situation and attitudes changed radically during the new Millenium.

In a recent Cochrane Systematic Review of early Pseudomonas eradication treatment as late as 2017, the reviewers Simon Langton-Hewer and Alan Smyth, found “that nebulised antibiotics, alone or in combination with oral antibiotics, were better than no treatment for early infection with Pseudomonas aeruginosa. Eradication may be sustained for up to two years”. Surprisingly they consider “There is insufficient evidence to determine whether antibiotic strategies for the eradication of early Pseudomonas aeruginosa decrease mortality or morbidity, improve quality of life, or are associated with adverse effects compared to placebo or standard treatment. Four trials comparing two active treatments have failed to show differences in rates of eradication of Pseudomonas aeruginosa. There have been no published randomised controlled trials that investigate the efficacy of intravenous antibiotics to eradicate Pseudomonasaeruginosa in cystic fibrosis. Overall, there is still insufficient evidence from this review to state which antibiotic strategy should be used for the eradication of early Pseudomonas aeruginosa infection in cystic fibrosis.’

Langton Hewer  SC, Smyth  AR. Antibiotic strategies for eradicating Pseudomonas aeruginosa in people with cystic fibrosis. Cochrane Database of Systematic Reviews 2017, Issue 4. Art. No.: CD004197. DOI: 10.1002/14651858.CD004197.pub5.

It was predictable that these varied approaches to early treatment of Pseudomonas were reflected gradually in the markedly different prevalence of chronic Pseudomonas infection in different CF centres- this difference in the prevalence of chronic infection became increasingly obvious first in paediatric patients as time progressed (Frederiksen et al, 1996; Lee et al, 2003; Lebecque et al, 2006 all below).

The Copenhagen CF team regarded early eradication as a major advance

In 1997 I had the good fortune to visit the Copenhagen CF centre to make a video of their work and interview the late Dr Christian Koch, then the Medical Director of the Copenhagen CF centre, Brigitte Frederiksen and Niels Hoiby. At the end of the day when I asked Dr Koch what aspect of CF treatment he regarded as the most important, he thought for some time and then replied –

When I look back on what we’ve done all through the years that I’ve been involved with cystic fibrosis, I would say that the early treatment of Pseudomonas is probably the best thing that we have done for the patients. It becomes more and more clear that really what determines the long term course is whether you get Pseudomonas or not” .

It is of interest, but difficult to understand, that even in 1998, reviewing the history of Pseudomonas infection in people with CF, a highly regarded US CF centre director wrote –“early administration with aerosol colistin may delay colonisation with P. aeruginosa. This intriguing observation has not been verified by prospective controlled studies”(Ramsey BW. Pediatrics 1998; Supplement: 210-213) – even though by this time early eradication of P. aeruginosa was widespread practice in Europe and already supported by many publications in addition to that of Valerius et al, 1991 from Copenhagen (Brett MM et al. Arch Dis Child 1992; 67:1086-1088]; Frederiksen B et al, Pediatr Pulmonol 1997; 23:330-335; Weisemann HG, et al. Pediatr Pulmonol 1998; 25:88-92; and later Munck A et al. Pediatr Pulmonol 2001; 32:288-292).

In conclusion there is now no doubt that avoidance of chronic Pseudomonas aeruginosa infection by eradication using inhaled antibiotics at an early stage, in some centres from the late Eighties, has been one of the major advances in management. There are now numerous trials to that effect and even cautious support of a Cochrane Review!

In 2021 treatment with intravenous antibiotics was shown to be equivalent but not superior to inhaled antibiotic treatment of early P. aeruginosa infection in cystic fibrosis.

Simon C Langton Hewer. Alan R Smyth, Michaela Brown, Ashley P Jones, Helen Hickey, Dervla Kenna, Deborah Ashby, Alexander Thompson, Paula R Williamson, on behalf of the TORPEDO-CF study group† Intravenous versus oral antibiotics for eradication of Pseudomonas aeruginosa in cystic fibrosis (TORPEDO-CF): a randomised controlled trial. Lancet Respir Med 2020; 8:975-986

This formidable protracted trial certainly shows there is no advantage in using intravenous antibiotics for first infections with P. aeruginosa. With the already known effectiveness of oral ciprofloxacin and nebulised colistin, shown many years ago, it was unlikely that using intravenous antibiotics for first infections would prove superior. It is disappointing that the eradication success rate of both treatments was so modest in this trial– perhaps the multiplicity of sites and fine details of treatment delivery where the patients were treated may have contributed to the modest results.

Addendum

“Pseudomonas aeruginosa eradication: Finally moving the needle?” An editorial by Jonathan Cogen and Margaret Rosenfield of Seattle in the Journal of Cystic Fibrosis 2017; 16:309-310.

“One of the major advances in the treatment of pseudomonas aeruginosa in CF patients over the past 10 to 20 years has been the the widespread adoption of eradication regimens as standard of care for new isolation of P. aeruginosa from respiratory cultures in an effort to delay or prevent chronic P. aeruginosa infection with the associated negative effects on lung health and survival. First pioneered by the Copenhagen CF Clinic in the 1980s, the efficacy of different eradication regimens has been demonstrated in prospective clinic trials, reporting 70-90% eradication rates”.

It was good for our team at St James’s in Leeds to realise that our modest letter to the Lancet in 1985 reporting only 7 children, stimulated the expert Copenhagen CF team and subsequently many others to trial and introduce early antibiotic eradication treatment of P. aeruginosa in people with cystic fibrosis.