CFDB - Cystic Fibrosis DataBase

Antibiotics for prevention of respiratory exacerbations

Antibiotic treatment of early pseudomonas aeruginosa

Background

The chronic presence of Pseudomonas aeruginosa (PA) in respiratory secretions is a major predictor of morbidity and mortality in children with CF. The first PA colonization episode can occur very early in life. After a first ever colonization episode, patients may go through different episodes of colonization (intermittent colonization), preceding chronic colonization by months to years, eventually resulting in chronic infection. PA strains causing early colonization have usually a non-mucoid phenotype, whereas PA strains in chronically colonized patients are mucoid and form biofilms. While the emergence of chronic and mucoid Pseudomonas aeruginosa (Pa) infection are both associated with poorer outcomes among CF patients, their relationship is poorly understood. US researchers, evaluating data from the CFF registry, examined the longitudinal relationship of incident, chronic and mucoid Pa in a contemporary, young CF cohort in the current era of Pa eradication therapy (Heltshe SL, 2018).

PA strains causing early infection are usually antibiotic sensitive and have low bacterial density in the airways. As a result, the treatment strategy has shifted from suppressive therapy in patients chronically colonized by PA to attempts at early eradication therapy as soon as PA is detected. A review on this topic was published (Schelstraete P, 2013).

Reviews on the role, the pathophysiology and the therapeutic approach of PA infection in people with CF have been recently published (Talwakar JS, 2016 and Lund-Palau H, 2016)

There are differences in the approach to detection and management of early P. aeruginosa infection. Some CF centres advocate frequent microbiological surveillance with attempts to eradicate PA when it first appears in the lung whereas others treat only when clinical or radiological signs of pulmonary infection are present. There is evidence that, when PA is cleared from respiratory secretions it is not simply suppressed because, when infection recurs, this is with a genetically distinct organism in most cases.

A consensus document (Döring G, 2012), considering that a risk/benefit ratio favors antibiotic eradication therapy (AET), suggests to initiate AET as soon as possible after a positive Pa respiratory culture, although there is currently no specific treatment strategy for the eradication of PA that has been recommended. However, the current data suggest that: “28 days of Tobramycin Inhaled Solution, when there is a positive culture, is a recommended treatment strategy for the purpose of eradication of P. aeruginosa. However, because a number of treatment protocols have been shown to be of similar effectiveness including oral, inhalation and intravenous therapy, and there are only few comparative studies available, the optimal antibiotic regimen is not known.”

The US CF Foundation strongly recommends, in its guidelines (Mogayzel PJ, 2014), inhaled antibiotic therapy for the treatment of initial or new growth of PA from an airway culture, stating that the favored antibiotic regimen is inhaled tobramycin (300 mgtwice daily) for 28 days.

Finally, another possible approach to the prevention of PA infection could be represented by vaccines and it is important to know whether vaccination against PA can prevent lung infection.

Issues

  • It is uncertain whether eradication strategies result in increased survival or improved quality of life for people with CF.
  • It is uncertain which eradication strategies result in successful eradication of early PA infection.
  • The cost-effectiveness of these strategies remains undetermined.
  • The effectiveness of vaccination againstPA in cystic fibrosis.
  • The potential correlation between paranasal sinus and lower airway bacteriology.

What is known

One CDSR review examined this issue (Langton Hewer SC, 2017). It identified seven eligible trials of antibiotic strategies for the eradication of P. aeruginosa infection in CF, with data from 744 participants.

Cumulative data from 43 participants in two of the four included trials indicate that PA was more frequently eradicated from the respiratory secretions in the participants receiving inhaled tobramycin than from those receiving placebo (Gibson 2003; Wiesemann 1998). This reduction in the number of isolates of PA was noted at both one month and two months, after the start of treatment. The available case analysis revealed a reduction in the odds of a positive culture for PA in the group treated with tobramycin inhalation when compared to the odds in the placebo group at both one and two months from the start of treatment. There are relevant differences in the type and dose of drug administered to the treatment groups in the two trials where nebulised tobramycin was compared to placebo, that is a potential source of heterogeneity between the trials.

Oral ciprofloxacin and inhaled colistin versus no treatment was the intervention included in one trial recruiting 26 participants (Valerius 1991). This trial suggests that the onset of chronic infection with PA is delayed in those individuals who have received antibiotic therapy compared to those receiving no therapy.

In one trial oral ciprofloxacin and inhaled colistin versus inhaled tobramycin were evaluated (Proesmans M, 2008), but the numbers of participants in each group were too low to allow comparisons of superiority between the two eradication regimens to be made.

The ELITE trial (Ratjen F, 2010) showed that treatment with Tobramycin Inhaled Solution (TIS) for 28 days was an effective and well tolerated therapy for early PA infection in patients with CF.

A trial [the EPIC trial] (Treggiari MM, 2011) investigated the efficacy and safety of 4 anti–PA treatments in children with CF and recently acquired PA infection. No difference in the rate of exacerbation or prevalence of PA positivity was detected between cycled and culture-based therapies. Adding ciprofloxacin produced no benefits.

Moreover, another trial (Taccetti G, 2012) studying the superiority of inhaled tobramycin/oral ciprofloxacin compared with inhaled colistin/oral ciprofloxacin (reference treatment) over 28 days, showed no superiority of treatment under study in comparison to the reference treatment.

Similar results were obtained by a further Belgian trial comparing inhaled tobramycin with inhaled colistin/oral ciprofloxacin (Proesmans M, 2013).

In conclusion, this review was updated with the inclusion of more recent trials, but the conclusions remain the same of the past.

A recent CDSR review examined strategies to delay the time to PA recurrence in people with CF (Palser S, 2019). The authors evaluated the medical literature to establish whether secondary prevention strategies, using antibiotics or other therapies, increase the chances of people with CF remaining free from PA infection following successful eradication therapy. The main conclusion is that cycled TIS therapy may be beneficial in prolonging the time to recurrence of PA after successful eradication, but further trials are required, specifically addressing this question and in both adults and children.

 

One single-arm, open-label study was conducted to evaluate the safety and efficacy of a 28-day treatment course of Aztreonam Lysine (AZLI) to eradicate newly acquired PA infection in pediatric CF patients (Tiddens HAWM, 2015). The study showed that AZLI was effective and well tolerated in eradicating PA from newly infected pediatric patients with CF. These eradication rates were consistent with success rates reported in the literature for various antibiotic regimens, including other inhaled antibiotics studied for eradication.

Canadian authors (Blanchard AC, 2017) provided a multi-step eradication protocol. This study, although retrospective and limited to the experience of a single center, is however very interesting, trying to optimize the eradication strategy by a multi-step approach. The study is accompanied by an editorial (Cogen J, 2017), that examines and evaluates the issue of the PA eradication.

Recently, a double-blind, placebo-controlled trial randomised CF patients <7 years (N = 51) with early Pa-infection to tobramycin inhalation solution (TOBI 300 mg) or placebo (twice daily) for 28 days with an optional cross-over on Day 35. Primary endpoint was proportion of patients having throat swabs/sputum free of Pa on Day 29 (Ratjen F, 2019). The authors conclude that TOBI was effective in eradicating early Pa-infection (on Day 29, 84.6% patients in the TOBI versus 24.0% in the placebo group were Pa-free) with a favourable safety profile in young CF patients.

Several economic evaluation were available (Baumann U, 2003; Iles R, 2003). They agree that the implementation of early eradication treatment, decreasing the prevalence of patients chronically infected by PA, might bring a notable decrease in costs by means of the reduction in hospital attendance and intravenous (IV) antibiotic administration, which would be expected to improve the patients' quality of life and reduce interference to schooling and work. Use of TNS would reduce the use of health care services, particularly hospital days, and lead to substantial savings in direct medical costs that would offset its acquisition price.

Another CDSR review (Krogh Johansen H, 2015) aimed to study whether vaccination against PA is beneficial in CF, and to compare the effects of different vaccines. The results of the three trials included in the review did not suggest that the vaccines tested for preventing infection against P. aeruginosa were effective.

Significantly more children with CF show clearance of PA from their respiratory secretions two months after commencing antibiotic therapy aimed at eradication of the organism from their lower respiratory tract when compared to placebo. This effect may last for several months. No improvement in clinical outcome measures following treatment was shown. However, the small numbers of participants in the eligible trials could mean that statistical power to detect changes in clinical outcomes was insufficient. There was no significant difference in the rate of common adverse effects nor in the isolation of micro-organisms other than PA.

The aim of antibiotic therapy for early PA infection in CF should be both eradication of the micro-organism and improvement in (or slowing in the rate of decline of) clinical parameters, whilst minimising adverse effects and the isolation of new micro-organisms. If PA is successfully eradicated, but there is no measurable clinical benefit then, either PA is less important than many clinicians believe it to be, or (which is more likely) current measures of clinical status are not sufficiently sensitive to small but important changes in the condition of an individual with CF.

Recently, US researchers tested the hypothesis that the addition of azithromycin to tobramycin inhalation solution in children with CF and early Pa decreases the risk of pulmonary exacerbation and prolongs the time to Pa recurrence (Mayer-Hamblett N, 2018). Azithromycin was associated with a significant reduction in the risk of pulmonary exacerbation and a sustained improvement in weight, but had no impact on microbiological outcomes in children with early Pa.

All results should be interpreted with caution. Reporting of the presence of organisms in respiratory secretions is difficult to standardise, dependent on the sampling methods used and on the number of samples taken. The trials used a heterogeneous mix of methods to sample respiratory secretions from both the lower and upper respiratory tracts.

Overall, there is insufficient evidence to state which antibiotic strategy should be used for the eradication of early PA infection in CF.

Recently, several studies provide support to the hypothesis that paranasal sinuses are potential areas for bacteria growth and evolution before infecting the lower airways in CF patients. Limited evidence exists to suggest optimum treatment methods in the eradication of microorganisms in the paranasal sinus of CF patients (Wilson P, 2014).

 

Unresolved questions

There is an urgent need for trials, which are specifically designed to examine the hypothesis that antibiotic treatment of early PA infection will prevent or delay chronic infection, and result in appreciable clinical benefit to patients, without causing them harm. A recent observational study (Mayer-Hamblett N, 2015), based on the follow up data of the EPIC trial, showed no association between eradication status and clinical outcomes including the  rate of exacerbations and lung function decline.

Eradication treatment is part of routine clinical practice in many CF centres and clinical trials comparing alternative eradication regimens may be preferable for pragmatic or ethical reasons.

It is important to establish whether secondary prevention strategies, using antibiotics or other therapies, increase the chances of patients with CF remaining free from PA infection following successful eradication therapy. A protocol for a CDSR is ongoing (Palser S, 2016).

Consideration should be given to appropriate outcome measures particularly spirometric lung function, nutritional status, socio-economic outcomes including quality of life and duration of follow up.

Long-term follow-up trials with careful clinical and bacteriological surveillance are required.

Additional basic research is needed to further increase our understanding of those elements of the immune response to PA that could potentially have a protective effect. 

The influence of the upper airways on the general health of CF patients has been the object of investigation to verify the hypothesis that sinonasal involvement may function as a reservoir for pulmonary infection and influence the results of eradication strategies.

Keywords: Bacterial Infections; Burkholderia cepacia; Colonization; Exacerbation; Infection; Pneumonia; Pseudomonas aeruginosa; Respiratory Tract Infections; Aminoglycosides; Anti-Bacterial Agents; Carbapenems; Cephalosporins; Macrolides; Monobactams; Others anti-bacterial agents; Penicillins; Quinolones; Tetracyclines;