Though limited to 5 of the 40 French CF Centres following Burkholderia-positive patients, our retrospective study demonstrated a great diversity in the management of initial colonisations with BCC or B. gladioli.
Should eradication therapy be systematically implemented?
In the present series, eradication was not systematically attempted, as related by Horsley et al. in their survey of adult CF Centres in UK [26]. Indeed, while in the epidemic era, most infections with BCC persisted over years, nowadays infection is transient in about 50% of French patients [6]. As regards B. gladioli, Kennedy et al. showed a transient colonisation rate of 60% in a series of 30 North American patients [16], similar to that observed in France [17]. In the present study, spontaneous clearance was observed in 4 out of 6 untreated patients, and in the 3 treated patients with only one positive sputum culture, we cannot be sure that the bacterium would not have been cleared without antibiotic therapy, as pointed out by Horsley et al. in their study [26]. These observations could lead to discuss a short follow-up of sputum cultures before introducing eradication therapy in some patients whose characteristics have yet to be defined in greater detail.
Some risk factors for progressing towards chronic colonisation have been proposed. In a study including 64 patients in Australia, Ramsay et al. reported a significantly higher risk of chronic infection in adults than in children [27]. However, in our small cohort, patients in the «persistence» group were not significantly older than those in the “eradication” group. Folescu et al. studied BCC infections in 27 Brazilian patients chronically colonised with P. aeruginosa and pointed out a correlation between a low BMI and chronic colonisation [28]. The major difference, though not statistically significant, between our two groups was a lower FEV1 value in case of “persistence”, which agrees with the poorer lung function at PC observed in adult patients with chronic infection by Ramsay et al. [27]. Thus, age and degree of severity of the disease (FEV1 and BMI) at the time of Burkholderia acquisition may have an influence on the success of BCC eradication treatment.
Burkholderia species and outcomes
Another question is whether approaches to new infections ought to be adjusted according to the species detected, with regard to the ability to be involved in chronic infection, as well as to potential virulence. In Canada, Zlosnik et al. reported a higher rate of transient infection in patients harbouring B. multivorans (55%) or B. vietnamiensis (44%), than in patients harbouring B. cenocepacia (19%). In the present study, the effect of the Burkholderia species on progression to chronic colonisation could not be established given the considerable diversity of the species and the limited number of patients. As regards the clinical impact of infection, the poor outcomes generally associated with B. cenocepacia may be partly due to the spread of highly virulent clones in the 1990s, and B. multivorans, which is considered to be less virulent than B. cenocepacia in most countries, was also responsible for severe infections in French patients (OBC data), [29]. Thus, species-adjusted eradication therapy implementation should take account of national, or even local epidemiology, and defining the attitude to infection with rare species is expected to be difficult. Concerning transplantation-associated risks, B. cenocepacia and B. gladioli are considered to be the most problematic species and constitute a relative contraindication to lung transplantation. However, we also observed post-transplant bloodstream infections due to B. multivorans and B. vietnamiensis (OBC data), which does not allow to rule out any risk in case of colonisation with other species. In our study, eradication was attempted in 4 out of 4 patients with B. cenocepacia, but in only 1 out of 3 patients with B. gladioli, and in 6 out of 10 patients with other species. To-date, there is no evidence clearly establishing the benefit of early eradication therapy [18] and our study failed to demonstrate the superiority of attempted eradication over therapeutic abstention. Nevertheless, as discussed above, it can be assumed that eradication treatment is relevant in patients whose infection is most likely to become chronic, namely those with the most severe forms of the disease at detection, and/or in patients colonised by given species.
Is in vitro antibiotic susceptibility testing useful to choose an eradication protocol?
Antibiotic regimens were heterogeneous, including IV, oral and nebulised antibiotics. Such heterogeneity was also reported in the UK survey by Horsley et al. [26], and within published studies. Kitt et al. successfully proposed tobramycin, temocillin and ceftazidime IV combination therapy for 14 days followed by a switch to tobramycin aerosols for 3 months in 2 children (1 B. gladioli and 1 B. cepacia) [30]. Uluer et al. reported 12 failed attempts at eradication of B. dolosa following the administration of amiloride and tobramycin aerosols for 6 months [31]. Using the same treatment, Ball et al. recorded 6 therapeutic failures in 7 children treated (eradication of B. stabilis, persistence of 3 B. multivorans and 3 B. cenocepacia) [32]. Among 14 treated patients, Horsley et al. reported 4 successful eradications based on 14 days of IV antibiotic therapy comprising tobramycin and meropenem with the addition of trimethoprim–sulfamethoxazole (n=4), ceftazidime (n=5) and chloramphenicol (n=2). Antibiotics were also administered via a nebuliser (tobramycin or meropenem) on 13 occasions, generally for 12 weeks [26]. Lastly, Garcia et al. proposed a standardized aggressive protocol comprising a 21-day induction stage (IV + inhaled tobramycin, cetazidime, trimethoprim–sulfamethoxazole) and a 2 months consolidation stage (trimethoprim–sulfamethoxazole, inhaled tobramycin), combined with long-term azithromycin as anti-inflammatory [33]. However, due to the low numbers of patients and the diversity of patient populations and treatment protocols, the best antibiotic strategy is not defined to date [18]. Burkholderia species are innately resistant to many antibiotics including some of those used to treat Pseudomonas aeruginosa such as aminoglycosides and colistine, and additional resistance may appear during antibiotic therapy, as observed in 2 of our 11 treated patients. Hence, the treatment of colonisations and infections with Burkholderia is particularly difficult and based on a small number of molecules mostly used in combination to limit resistance selection. These currently comprise meropenem, ceftazidime, temocillin, cotrimoxazole, ciprofloxacin or cyclines [34]. BCC is usually considered to be resistant to aztreonam, but some strains are susceptible, and Iglesias et al. reported successful eradication of BCC in two patients with bronchiectasis following inhaled aztreonam lysine courses [35]. The latest ceftazidime-avibactam combination therapy seems promising but insufficient clinical experience has been acquired to date [36]. In spite of the natural resistance to aminoglycosides, the use of inhaled tobramycin which allows the delivery of high doses are considered to be of interest in BCC infections [24], [25]. B. gladioli is generally slightly more susceptible than BCC, especially to piperacillin-tazobactam and aminoglycosides [17]. The European Committee on Antimicrobial Susceptibility Testing (EUCAST) does not currently advocate Burkholderia susceptibility testing as a guideline for antibiotic therapy given the lack of any obvious correlation between in vitro susceptibility and the patient’s clinical course [19]. Conversely, both the Clinical and Laboratory Standards Institute (CLSI) and the antibiogram committee of the French Society for Microbiology provide specific guidelines for a limited number of molecules. In our study, consistency between treatment and antibiotic susceptibility appears to be associated with improved microbiological efficacy, since eradication was achieved in 5/6 cases (83.3%) of antibiogram consistency versus 1/5 cases (20%) of inconsistency.
Limitations and perspectives
The present study has several limitations, due to the low number of patients, the diversity of species involved as well as of therapeutic approaches, leading to insufficient statistical power. Thus, the positive impact of successful eradication on lung function did not reach statistical significance. Though our results suggest that the antibiogram may be of interest in order to guide therapeutic choices on a case-by-case basis, establishing the relevance of in vitro testing suffers from poor and controversial definition of clinical breakpoints, and from insufficient data. Therefore, we plan to launch a nation-wide retrospective study, which is expected to provide further information and improve statistical relevance.
Moreover, the lack of standardisation in retrospective studies is a potential source of bias. Due to the heterogeneity of the population of CF patients, clinical trials assessing different treatment protocols will probably be required to determine management algorithms taking into account all clinical and microbiological situations (extent of pulmonary impairment, Burkholderia species, co-pathogens). Based on our results and the literature, testing a triple therapy comprising an IV beta-lactam (ceftazidime or meropenem), an oral or IV fluoroquinolone (ciprofloxacin or levofloxacin) plus an inhaled aminoglycoside (tobramycin), and checking for consistency between this protocol and the resistance profile of the isolated strain should be considered when designing such trials. In case of B. gladioli colonisation, piperacillin-tazobactam or meropenem could be preferred to ceftazidime owing to their higher in vitro activity [17, 36]. In children, trimethoprim-sulfamethoxazole represents an alternative to quinolones. IV/ PO treatments could be administered during 2 to 3 weeks whereas longer durations (8 to 12 weeks) could be proposed for inhaled treatments [26, 33]. Lastly, given the specific pharmacodynamic profile of CF subjects, antibiotic assays should be encouraged for the purpose of dose optimisation. Given the low incidence of the Burkholderia infection in CF patients, only large-scale multicentre studies can shed light on this issue.