An observational study of Pseudomonas aeruginosa in adult long-term ventilation

Discussion

Pseudomonas aeruginosa is a ubiquitous organism found in the natural environment but is frequently associated with both acute and chronic infections of the respiratory tract [6]. Recent paediatric research suggested a 15% prevalence of Pa in children with complex neuromuscular disorders and cerebral palsy [7]. The pathogen colonised 11% of a paediatric LTV cohort and reached a prevalence of 63% in LTV paediatric patients with a tracheostomy [7].

The current study is, to our knowledge, the first extensive work on Pa isolates in an adult LTV cohort. Our key findings are that Pa colonisation is frequent in adults on LTV, affecting nearly 1 in 5 (17.6%). Consistent with previous data [7], we found that tracheostomy is a significant factor influencing Pa positive culture. Patients with CF and bronchiectasis also had high Pa culture rates, an expected result as this pathogen is associated with these diseases. It is therefore expected to be intensified in a population with high disease severity requiring LTV [2]. Lastly, patients with a tracheostomy who were colonised with Pa were more likely to receive treatment in the form of a nebulised antibiotic and have samples positive for copathogens (Serratia, Proteus species, Stenotrophomonas, Burkholderia cepacia complex and NTM).

The frequency of Pa in the tracheostomy population was 71.7%, a higher rate than documented in previous paediatric studies [7]. Consistent with previous data [7], we also observed high rates of Pa in the cohort with cerebral palsy, but these results were not significant. This likely reflects the small sample size in this group (19). Interestingly no patients with cerebral palsy had a tracheostomy.

Patients with OSA/OHS and MND were associated with a statistically significantly lower probability of culturing Pa isolates. This outcome is not unexpected. LTV for OHS is associated with a reduced mortality (5-year survival 77.3%) than in untreated OHS [8]. High NIV adherence results in less hospital admission, and improved mortality [9]. We postulate that due to the rapid progression and reduced life expectancy in MND, the time period on LTV may be short, with lower lifetime antibiotic exposure and less time for acquisition of Pa. Further research into the reduced frequency of Pa in these disease categories is welcomed.

LTV services care for a diverse number of aetiologies. Since tracheostomy is associated with increased rates of Pa, a useful tool for home ventilation clinicians is to understand which disease categories have higher rates of tracheostomy. We found patients with spinal cord injury had the highest prevalence of tracheostomy, followed by the groups “other” and DMD.

Nearly half of Pa positive patients received treatment in the form of a long-term macrolide, and over a third received a nebulised antibiotic. Macrolide and nebulised antibiotic use are recommended in guidelines for preventing Pa-associated respiratory exacerbations for both bronchiectasis and CF. These agents are not specifically recommended in neuromuscular disease guidelines, and hence treatment is often empirical [10, 11]. There is a potential for these modalities to cause harm; colistin has been associated with respiratory arrest in myasthenia gravis [12] but also potential benefit, i.e. reducing/preventing Pa infections [12]. The clinical rationale for commencing antibiotic treatment in our cohort was not analysed, nor was exacerbation rate secondary to Pa infection, or the prevalence of Pa-associated pneumonia. A recent paediatric series [7] showed there was no immediate treatment benefit to acute anti-pseudomonals versus empirical antibiotics, highlighting the need for further research and understanding in this area.

There has been limited research regarding the prognostic significance of Pa in those with long-term tracheostomies [13, 14]. Pa has been shown to colonise tracheostomy tubes, forming biofilms [15]. Biofilms are recognised to cause an inherent resistance to antimicrobial treatment as well as bacterial persistence [7, 15]. Furthermore there is evidence of transmission to the lower airways resulting in complications such as pneumonia [16, 17]. As there are no clear guidelines for the management of Pa in long-term tracheostomy, treatment is guided by the patient's clinical presentation and physicians’ acumen. In the acute ventilation setting there is a tendency to treat, reflecting the critical illness of these patients and the priority to prevent ventilator-associated pneumonia. We recorded a significant increase in treatment with a nebulised antibiotic in our Pa tracheostomy population (54.1%) but are unable to conclude whether this was guided by patients’ clinical deterioration/biochemical markers or solely triggered by the presence of tracheostomy. Another important variable to consider is sampling bias, and that tracheostomised patients may have sputum cultures sent more frequently as part of secretion management or for intentional surveillance.

There was a wide range in treatment modalities used in the management of these patients. This included combinations of and isolated use of long-term macrolides, nebulised colistin, nebulised aminoglycosides, cyclical nebulised antibiotic, e.g. tobramycin/colistin, and widespread use of carbocisteine as a mucolytic agent. It is important to recognise that prescription does not reflect adherence to treatment. Adherence to long-term nebulised antibiotic therapy can be challenging, and patients requiring LTV already have a significant treatment burden.

Within the Pa isolate cohort requirement for LTOT and/or AOT was not independent of diagnostic group. 80% of patients on LTOT and/or AOT had a respiratory diagnosis.

The exact date of commencement of a nebulised antibiotic had limited documentation, which hindered assessment of Pa suppression or effects on emerging pathogens. Similarly the COVID-19 pandemic has limited sputum sample collections as clinics carried out more remote consultations in 2020–2021. Within the cohort of Pa positive isolates, we had hoped to record the infective exacerbation rate pre- and post-treatment with Pa eradication antimicrobials. However, a key limitation to our study, reflecting the retrospective design, was the lack of documentation of this.

We found that Serratia, Proteus species, Stenotrophomonas, Burkholderia cepacia complex or NTM were isolated in 33.3% of the Pa cohort, and patients with a tracheostomy and Pa isolates were at increased risk of culturing a copathogen. This reflects the known association between tracheostomy and bacterial colonisation. A limitation to this research is we did not record the time period between isolating Pa and the copathogen. We recognise that the two isolates may have a significant time period between them. It is also possible the copathogen predates the first Pa isolate. NTM prevalence may be underestimated as growth requires rapid-growing mycobacteria medium to be specifically requested. The regional nature of the study resulted in samples being accessed across multiple sites and microbiology laboratories. These naturally will have slight variation in their approach to sample preparation.

An important question requiring further assessment is whether long-term antibiotics in LTV and LTV tracheostomy results in increased rates of virulent copathogens (i.e. multiple drug-resistant bacteria). Secondly, do long-term antimicrobials suppress Pa and/or exacerbation rates in this cohort? This is a point of major interest for the home ventilation community and also for antibiotic stewardship. It is important to balance treating infection against the potential future harm from antibiotic resistance.

The strengths of this study are the large sample size, data collection across multiple organisations and the description of treatment modalities applied. There are, however, limitations that need to be recognised, predominantly related to the retrospective design. Firstly, we cannot conclude that the prevalence described here is truly representative – if a sample has not been requested as part of routine clinical assessment, we cannot confirm the absence of Pa. Secondly, from the data gathered we do not know what proportion of Pa isolates represent asymptomatic colonisation versus a pathogen driving clinical deterioration. However, a degree of pragmatism is required when studying patients receiving LTV, acknowledging the reduced life expectancy seen in some subgroups which can make prospective study design challenging. Thirdly, although this was a regional study, we still encountered multiple aetiologies with small (n=1) cohorts (see supplementary material). This reflects the diversity of aetiologies managed by LTV services. In order to overcome this barrier a multicentre approach to data collection would be required. Additionally, we acknowledge that a valued piece of data would be the time period on LTV and/or tracheostomy to the first isolate of Pa. Lastly, although infrequent, our service has patients who require home ventilation following a failed wean and level 3 intensive care. In the immediate period following discharge these patients may be colonised with hospital acquired bacteria. However, the mean number of days before the first episode of ventilator-associated pneumonia in home ventilation is 345 days suggesting a complex relationship between culture status and major infection episodes [5].

We conclude that Pa positive culture is common within the adult LTV population and is significantly associated with the presence of tracheostomy. This is an important consideration, adding to the high rates of healthcare burden already seen in this population [18] Patients managed with LTV, particularly those with a tracheostomy, should be considered for surveillance sputum culture as is already applied in other at-risk groups such as bronchiectasis. Research is required into whether Pa isolated in the adult LTV population drives morbidity and/or mortality, as seen in other diseases such as COPD and bronchiectasis [1, 2, 19]. This evidence will help formulate international guidelines on long-term antimicrobial management. Finally, when considering whether to proceed with tracheostomy in a LTV setting, the higher risk of Pa isolates and attendant treatment burden (i.e. limited oral or enteral antibiotic choices) should be discussed during multidisciplinary team meetings and shared decision making with the patient.