BURKHOLDERIA CEPACIA COMPLEX and SOME SIMILAR ORGANISMS –

(previously known as Pseudomonas cepacia and Burkholderia cepacia) See also cross infection section of Topic.

There are numerous publications (over 3000 by 2019) on the both the clinical and laboratory aspects of Pseudomonas cepacia/Burkholderia cepacia/Burkholderia cepacia complex in cystic fibrosis. Only a few of the more clinically relevant publications are reviewed in this Topic.

The realisation that both hospital and community acquired infection were major factors in acquisition and spread of the organism and the subsequent introduction of patient segregation have reduced the incidence and numbers of affected patients in CF clinics. However, the treatment remains difficult and the infection, particularly with certain strains, significantly worsens the prognosis.

* Some abstracts included in this Topic do not appear in the main text

1977 Lararya-Cuasay LR, Lipstein M, Huang NN. Pseudomonas cepacia in the respiratory flora of patients with cystic fibrosis. Pediatr Res 1977; 11:502.
One of the earliest reports of Pseudomonas cepacia (later called first Burkholderia cepacia, then Burkholderia cepacia complex) isolated between 1973 and 1976 from 54 patients with cystic fibrosis; many were severely affected and 14 children died. The presence of the organism made treatment more difficult.

This was a very early report of P. cepacia which did not appear cause concern at the time – perhaps somewhat obscured by the generally very poor outlook for children with cystic fibrosis. In fact in John Lloyd-Still’s 1983 Textbook of Cystic Fibrosis there is only very brief mention of P. cepacia as one of the “other gram-negative rods that may infect people with cystic fibrosis”.

Later Rosenstein & Hall reported pneumonia and septicemia due to Pseudomonas cepacia in a patient with CF (Johns Hopkins Med J 1980; 147:188-189.[PubMed]) before the first report from Toronto describing major problems in treating the infection (Gold R et al. J Antimicrob Chemother 1983; 12 Suppl A: 331-336.[PubMed]) and before the other major publication from Toronto (Isles A, et al. Pseudomonas cepacia infection in cystic fibrosis: an emerging problem. J Pediatr 1984; 104:206-210.[PubMed] below).

The first report from the UK was from our Leeds centre and did not appear until 1990 by which time we had identified 11 cases since 1984 (Simmonds EJ et al. Arch Dis Child 1990; 65:874-877 below). The tendency for B. cepacia to spread between patients was not generally appreciated in the UK until 1993 when John Govan from Edinburgh published definite evidence of patient to patient spread (Govan et al, 1993 below)

1984 Isles A, McLuskey I, Corey M. Pseudomonas cepacia infection in cystic fibrosis: an emerging problem. J Pediatr 1984; 104:206-210.[PubMed]
The prevalence of Pseudomonas cepacia infection in a population of approximately 500 patients with CF in the Toronto CF centre, increased from 10% in 1971 to 18% by 1981. The carriage of P. aeruginosa had remained unchanged at 70% to 80% over the same period. Patients infected with P. cepacia had greater impairment of pulmonary function than those with P. aeruginosa alone. A syndrome characterized by high fever, severe progressive respiratory failure, leukocytosis, and elevated erythrocyte sedimentation rate (“cepacia syndrome”) had occurred in eight patients over the previous three years, with a 62% fatality rate. Because P. cepacia strains are uniformly resistant to ticarcillin, piperacillin, and aminoglycosides, and because ceftazidime is ineffective despite in vitro activity, treatment of these infections was very difficult. Prevention of acquisition and effective treatment of P. cepacia in patients with cystic fibrosis had become a major problem in the Toronto clinic.

This paper, which describes the devastating effect of the introduction of B. cepacia into a CF clinic population very clearly, heralded a new era in CF care and was to have a profound permanent effect on the treatment and social life of people with CF and their families.

The potential for spread between people with CF and the serious, often fatal, consequences (the so-called “cepacia syndrome”) were not fully appreciated in the UK until the early Nineties when John Govan’s publication documented definite person to person spread (Govan et al, 1993 below). From 1993 there was a general introduction of infection control measures in CF Centres in the UK; also there was an end to the North American CF holiday camps which were an important source of acquisition of the B. cepacia infection.

In Leeds three of our patients developed serious B. cepacia infections some months after visiting Canadian CF camps. In 1990 we published the first UK paper on B. cepacia in CF, having identified 11 patients with the infection over 6 years since 1984 but we found no evidence of obvious cross infection between our patients when we first identified the infection (Simmonds EJ, et al. Pseudomonas cepacia: a new pathogen in patients with cystic fibrosis referred to a large centre in the United Kingdom Arch Dis Child 1990; 65:874-877).

*1986 Thomassen MJ, Demko CA, Doershuk CF, Stern RC, Klinger JD. Pseudomonas cepacia: decrease in colonization in patients with cystic fibrosis. Am Rev Respir Dis 1986; 134:669-671.[PubMed]
Previous work had indicated a greater prevalence among siblings of patient colonised by P. cepacia, also an association of initial positive cultures with hospitalisation. So the authors instituted precautionary measures in 1983 including physical separation of hospitalised patients colonised by P. cepacia for non-colonised patients, re-education of staff reinfection control, explanation to families and institution of separate summer camps.  Hospital cultures were repeatedly negative. following these measures the incidence in 1984 fell from 8.2% in 1983 to 1.7% in 1984.

The authors suggest (quite correctly as it turned out) that these results are suggestive of patient-to-patient transmission. Because P. cepacia infections have been associated with shorter survival in some patients with CF, they intended to continue their current segregation measures.

So this is an early report of patient segregation and we now know that the fall in incidence they reported was almost certainly due to their segregation measures. One could ask why we did not take more notice of these findings in the UK; this is discussed in our 1990 report from Leeds (Simmonds EJ et al, 1990 below).

*1990 Simmonds EJ, Conway SP, Ghoneim AT, Ross H, Littlewood JM. Pseudomonas cepacia: a new pathogen in patients with cystic fibrosis referred to a large centre in the United Kingdom.  Arch Dis Child 1990; 65:874-877.[PubMed]
In a large cystic fibrosis centre in the United Kingdom 11 cases P. cepacia infection have been identified during the last six years, with a maximum prevalence of 7% in 1988. Three patients died, two of whom deteriorated rapidly shortly after acquisition of the organism despite intensive treatment with appropriate antibiotics.

We analysed the possible causes of the increase in P. cepacia infection and found no evidence of patient to patient transmission in our clinic nor was the use of nebulised antibiotics associated with an increased risk of infection. In the discussion we noted that nosocomial spread of infection had been suggested as an important factor (LiPuma JJ et al, 1988) but the role of patient to patient transmission remained controversial. Separation of cases infected with P. cepacia  from non-infected patients during hospital admissions and summer camps led to a fall in incidence of new cases at one centre (Thomassen MJ et al, 1986. above) but cultures from settle plates failed to show that there is appreciable contamination of the environment of infected patients with P. cepacia. Moreover sputum cultures from non-infected patients after contact with infected patient at summer camps (Buchdahl RM et al, 1988. Proc 10th Internat CF Congress, Australia) or as inpatients (Hardy KA et al, 1986.[PubMed]) showed no new P. cepacia infection suggesting that the organism in not transmitted from patient to patient.

So in 1990 there was still considerable doubt as the whether patient to patient transmission did occur.

1993 Govan JR, Brown PH, Maddison J, Doherty CJ, Nelson JW, Dodd M, Greening AP, Webb AK. Evidence for transmission of Pseudomonas cepacia by social contact in cystic fibrosis. Lancet 1993; 342(8862):15-19.[PubMed]

                         John Govan

Pulmonary colonisation with Pseudomonas cepacia in patients with cystic fibrosis can be associated with increased morbidity and mortality. The modes of transmission of P cepacia are, however, unclear. The authors used selective media and phenotypic and genomic typing systems to investigate the acquisition of P. cepacia by adults with cystic fibrosis. An analysis of isolates from 210 patients attending regional clinics in Edinburgh and Manchester between 1986 and 1992 showed that the main cause of increased isolations of P. cepacia from 1989 was the emergence of an epidemic strain that had spread between patients in both clinics. Epidemiological evidence indicated that social contact was important in spread of the epidemic strain within and between clinics.

The authors suggested that guidelines to limit the acquisition of P. cepacia should not be restricted to patients in hospital, and that intimate or frequent social contact is associated with a high risk of cross-infection.

Following this important publication, the UK CF Trust advised that all patients with B. cepacia be segregated from other patients in the clinics and also that they avoid social contact with other patients outside the hospitals

1993 Smith DL, Gumery LB, Smith EG, Stableforth DE, Kaufmann ME, Pitt TL. Epidemic of Pseudomonas cepacia in an adult cystic fibrosis Unit: Evidence of person-to-person transmission. J Clin Microbiol 1993; 31:3017-3022.[PubMed]
Report of transmission between patients in the Birmingham Adult CF Centre investigated in collaboration with Dr Ty Pitt of the Central Public Health Laboratory, London. Prevalence rose from 1.4% in 1988 to 8.3% in 1992. At the time of writing five (30%) of the 17 affected patients had died. In only two of the six patients referred to the CF centre had P. cepacia been identified before referral.

Dr Ty Pitt has been a central figure in understanding the microbiological aspects of cystic fibrosis collaborating closely with clinicians both at the Brompton Hospital in London and also with national studies. Of particular importance was the national survey of CF centres revealing widespread evidence of cross infection both within and between CF Centres in the UK (Scott and Pitt, 2003).

1994 Humphreys H, Peckham D, Patel P, Knox A. Airborne dissemination of Burkholderia (Pseudomonas) cepacia from adult patients with cystic fibrosis. Thorax 1994; 49:1157-9. [PubMed]
A study was undertaken to determine whether B. cepacia could be recovered from room air occupied by colonised adult patients with cystic fibrosis. Air samples were obtained consecutively from an enclosed room or isolation cubicle before, during, and after occupation by six patients on nine occasions using a surface air sampler incorporating contact plates with selective medium. Settle plates were also used and sputum from five patients was cultured. B. cepacia was recovered from room air during occupation by five of six patients, the number of bacteria ranging from 1 to 158 cfu/m3 (mean 32 cfu/m3). The number of bacteria isolated was greater when patients were coughing. B. cepacia persisted in room air on four occasions after the patient left the room, on one occasion for up to 45 minutes.

The authors concluded that the isolation of B. cepacia from the air of rooms occupied by colonised patients suggests that dissemination might occur by aerosol as well as by direct physical contact with patients or contaminated environmental sites.

Subsequently a similar study from Nottingham showed that there was significant air contamination after a physiotherapy session (Ensor E et al, 1996 [PubMed])

2001 Moore JE, McIlhatton B, Shaw A, Murphy PG, Elborn JS. Occurrence of Burkholderia cepacia in foods and waters: clinical implications for patients with cystic fibrosis. J Food Protect 2001; 64:1076-1078. [PubMed]

          John Moore

Two hundred forty-eight retail “ready-to-eat” foodstuffs in eight food categories and 134 waters categorized into nine types were analyzed for the presence of the Burkholderia cepacia complex of organisms. Of these, 14 of 26 (53.8%) samples of raw unpasteurized bovine milk were positive for this organism.

Consumption of raw unpasteurized milk may therefore act as a potential source of infection with this organism, which is of particular concern for patients with cystic fibrosis, where colonization and infection can lead to a fatal necrotising pneumonia and premature death. In addition to the associated risk of infection from faecal pathogens, patients with cystic fibrosis should therefore avoid the consumption of raw unpasteurized milk to minimize the risk of becoming infected with this organism.

Important information for people with CF as unpasteurized milk is still available in some parts of the UK.

2001 Mahenthiralingam E, Vandamme P, Campbell ME, Henry DA, Gravelle AM, Wong LT, Davidson AG, Wilcox PG, Nakielna B, Speert DP. Infection with Burkholderia cepacia complex genomovars in patients with cystic fibrosis: virulent transmissible strains of genomovar III can replace Burkholderia multivorans. Clin Infect Dis 2001; 33:1469-1475.[PubMed]
Infection with Burkholderia cepacia complex in patients with cystic fibrosis (CF) results in highly variable clinical outcomes. The purpose of this study was to determine if there are genomovar-specific disparities in transmission and disease severity. B. cepacia complex was recovered from 62 patients with CF on > or =1 occasions (genomovar III, 46 patients; genomovar II [B. multivorans], 19 patients; genomovar IV [B. stabilis], 1 patient; genomovar V [B. vietnamiensis], 1 patient; and an unclassified B. cepacia complex strain, 1 patient). Patient-to-patient spread was observed with B. cepacia genomovar III, but not with B. multivorans. Genomovar III strains replaced B. multivorans in 6 patients. Genomovar III strains were also associated with a poor clinical course and high mortality. Infection control practices should be designed with knowledge about B. cepacia complex genomovar status; patients infected with transmissible genomovar III strains should not be cohorted with patients infected with B. multivorans and other B. cepacia genomovars.

E Mahenthiralingam. Author’s photo.

An important paper regarding the management of people with CF who are infected with organisms in the B. cepacia complex from experts in this area. Prof. Mahenthiralingam (figure 10) is a leading CF microbiologist and now at Cardiff University in the UK.

2002 Moore JE, McIlhatton B, Buchanan J, Gilpin D, Shaw A, Hall V, Murphy PG, Elborn JS. Occurrence of Burkholderia cepacia in the hospital environment. Irish J Med Sci 2002; 171:131-133.[PubMed]
To determine the prevalence of Burkholderia cepacia from the environment in a regional adult cystic fibrosis care centre. B. cepacia was not detected from commonly shared items of equipment, staff hands, staff uniforms or toilets. In addition, the organism was not detected in toilet bowls, even in the B. cepacia unit. With regard to positive environments for B. cepacia, 4/10 (40%) of the outside surfaces and inner rims of patients’ plastic disposable sputum collection containers and 4/17 (23.5%) of air from patients’ rooms, following physiotherapy, were positive. All positive samples originated in the B. cepacia segregation area of the inpatient wards and B. cepacia was not detected in the non-cepacia area of the CF centre. Consequently, these two positive sites should therefore be treated as high risk, where organisms may be potentially transmitted from environment to patient

A useful study confirming that B.cepacia only appeared to be a potential problem in areas inhabited by CF patients already infected by the organism.

2004 The Burkholderia cepacia complex – Suggestions for Prevention and Infection Control. Cystic Fibrosis Trust Infection Control Group. Second edition. London. Cystic Fibrosis Trust, September 2004. 

2004 Jones AM, Dodd ME, Govan JR, Barcus V, Doherty CJ, Morris J, Webb AK. Burkholderia cenocepacia and Burkholderia multivorans: influence on survival in cystic fibrosis. Thorax 2004; 59:948-951.[PubMed]

            Andy Jones

Forty nine patients had an initial infection with either B. multivorans (n = 16) or B. cenocepacia (n = 33); 8/16 and 31/33, respectively, developed chronic infection (p<0.001). Deaths from “cepacia syndrome” occurred in both BCC groups. Patients with B. cenocepacia infection had a shorter survival than patients with P. aeruginosa infection (p = 0.01). There was no difference in survival between CF patients infected with B. multivorans and P. aeruginosa. There were no observed differences in changes in spirometry and BMI or treatment requirements between the BCC groups and respective controls. In CF, the genomovar status of BCC may influence both the likelihood of progression from initial to chronic infection and the overall survival of the patients.

This study from a large CF centre in Manchester confirms the more serious prognosis for patients infected with B. cenocepacia than for those infected with B. multivorans.

2004 Courtney JM, Dunbar KE, McDowell A, Moore JE, Warke TJ, Stevenson M, Elborn JS. Clinical outcome of Burkholderia cepacia complex infection in cystic fibrosis adults. J Cyst Fibros 2004; 3:93-98. [PubMed]
Nineteen CF adults infected with Burkholderia cepacia complex (BCC) and 19 controls infected with Pseudomonas aeruginosa were studied over a 4-year period at the Adult CF Centre in Belfast. The BCC infected group displayed a significantly greater reduction of FEV(1) and BMI compared to the P. aeruginosa infected group. Sixteen patients infected with a single Burkholderia cenocepacia strain had a significantly greater rate of FEV(1) decline compared to those infected with Burkholderia multivorans (n=3) or P. aeruginosa (p=0.01 and p<0.0001, respectively). The rate of BMI decline was significantly greater in patients infected with B. cenocepacia compared to those with P. aeruginosa (p=0.007), but not significantly different in those with B. multivorans (p=0.29). BCC infection is associated with an accelerated decline in pulmonary function and BMI. Infection with a single B. cenocepacia strain was associated with a more rapid decline in lung function than those infected with either B. multivorans or P. aeruginosa.

A further report indicating the more serious nature of infections with B. cenocepacia comfirming the findings in the Manchester CF centre (Jones et al. 2004 above).

2004 Blackburn L,, Brownlee K, Conway S, Denton M. ‘Cepacia syndrome’ with Burkholderia multivorans, 9 years after initial colonization. J Cyst Fibros 2004; 3:133-134.[PubMed]
A 16-year-old boy with cystic fibrosis developed ‘cepacia syndrome’ 9 years after the first isolation of Burkholderia multivorans. The authors stress that it is important to recognise that ‘cepacia syndrome’ is not restricted to those infected with genomovar type III strains and that rapid, irreversible clinical decline can occur many years after the 1st isolation of Burkholderia cepacia complex.

2004 Scott FW, Pitt TL. Identification and characterization of transmissible Pseudomonas aeruginosa strains in cystic fibrosis patients in England and Wales. J Med Microbiol 2004; 53:609-615.[PubMed]

                    Ty Pitt

Most previous studies of cross-infection with P. aeruginosa (PA) among patients with CF in the UK suggested that it is a rare occurrence. However, two recent UK reports of highly transmissible strains of PA in patients in regional centres in Liverpool (Cheng et al, 1996 above) and Manchester (Jones et al, 2001 above) raised questions as to the extent of the problem. These reports prompted the UK CF Trust to fund this nationwide survey to establish the distribution of PA genotypes among these patients. Isolates of PA were requested from over 120 hospitals in England and Wales and a sample size of approximately 20% of the CF patient population in each centre was recommended. In total, 1225 isolates were received from 31 centres (range 1 to 330). Single patient isolates were typed by SpeI macrorestriction and PFGE. A panel of strains of the common genotypes including representatives of reported transmissible strains was assembled and further characterized by fluorescent amplified fragment length polymorphism (FAFLP) genotyping.

The important findings were as follows:-
– At least 72% of all patients harboured strains with unique genotypes.
– Small clusters of related strains were evident in some CF centres, presumably indicating limited transmission of local strains.
– The most prevalent strain was indistinguishable from that previously described as the ‘Liverpool’ genotype, and accounted for approximately 11% of patient isolates from 15 centres in England and Wales.
– The second most common genotype (termed Midlands 1) was recovered from 86 patients in nine centres
– The third genotype, which matched closely the PFGE profile of Clone C, a genotype originally described in Germany, was found in eight centres and was isolated from 15 patients.
– A fourth genotype, identical to the published Manchester strain, was found in three centres.

Fluorescent amplified fragment length polymorphism (FAFLP) genotyping revealed some microheterogeneity among strains of the Liverpool genotype but all isolates of this genotype were positive by PCR for a strain-specific marker.

These data are mentioned in detail in view of their great importance for clinic routines and suggest that cross-infection with PA has occurred both within and widely between CF centres in England and Wales. The two most common genotypes accounted for more than one-fifth of patients’ isolates examined and transmissible genotypes were found in all but three of the 31 CF centres studied. These results emphasize the need for continued surveillance of P. aeruginosa genotypes in CF patients to provide informed infection control policy in treatment centres

2008 Mahenthiralingam E, Baldwin A, Dowson CG. Burkholderia cepacia complex bacteria: opportunistic pathogens with important natural biology. J Appl Microbiol 2008; 104:1539-1551.[PubMed]
Interaction with plants around their roots and foliage forms the natural habitat for a wide range of gram-negative bacteria such as Burkholderia, Pseudomonas and Ralstonia. During these interactions many of these bacteria facilitate highly beneficial processes such as the breakdown of pollutants or enhancement of crop growth. All these bacterial species are also capable of causing opportunistic infections in vulnerable individuals, especially people with cystic fibrosis (CF).

Here the authors review the current understanding of the Burkholderia cepacia complex (Bcc) as a group of model opportunistic pathogens, contrasting their clinical epidemiology with their ecological importance. Currently, the B. cepacia complex is composed of nine formally named species groups which are all difficult to identify using phenotypic methods. Genetic methods such as 16S rRNA and recA gene sequence analysis have proven useful for Bcc species identification. Multilocus sequence typing (MLST) is also emerging as a very useful tool for both Bcc strain and species identification. Historically, Burkholderia cenocepacia was the most dominant Bcc pathogen in CF, however, probably as a result of strict infection control practices introduced to control the spread of this species, its prevalence has been reduced. Burkholderia multivorans is the now the most dominant Bcc infection encountered in the UK CF population, a changing epidemiology that also appears to be occurring in the US CF population. The distribution of Bcc species residing in the natural environment may vary considerably with the type of environment examined. Clonally identical Bcc strains have been found to occur in the natural environment and cause infection. The contamination of medical devices, disinfectants and pharmaceutical formulations has also been directly linked to several outbreaks of infection. In the last 10 years considerable progress has been made in understanding the natural biology and clinical infections caused by this fascinating group of bacteria.

An up to date clear review of the B. cepacia complex by Esch Malhenthiralingam of Cardiff, an expert on the subject of BC complex. The summary is reproduced in full.

2008 Jacobs JL, Fasi AC, Ramette A, Smith JJ, Hammerschmidt R, Sundin GW. Identification and onion pathogenicity of Burkholderia cepacia complex isolates from the onion rhizosphere and onion field soil. Appl & Environ Microbiol 2008; 74:3121-3129.[PubMed]
Genotypic identification and pathogenicity characterization were performed on B. cepacia complex isolates from the rhizosphere of onion and organic soils in Michigan. A total of 1,290 isolates, 980 rhizosphere and 310 soil isolates, were assigned to the species B. cepacia (160), B. cenocepacia (480), B. ambifaria (623), and B. pyrrocinia (27). The majority of isolates identified as B. cepacia (85%), B. cenocepacia (90%), and B. ambifaria (76%) were pathogenic in a detached onion bulb scale assay and caused symptoms of water soaking, maceration, and/or necrosis.

This study confirmed that multiple B. cepacia complex species colonize the onion rhizosphere and have the potential to cause sour skin rot disease of the onion. In addition, the onion rhizosphere is a natural habitat and a potential environmental source of B. cenocepacia. Following the introduction of segregation of patients growing B. cepacia most new infections were with such environmentally acquired organisms.

2009 Wainwright CE, France MW, O’Rourke P, Anuj S, Kidd TJ, Nissen MD, Sloots TP, Coulter C, Ristovski Z, Hargreaves M, Rose BR, Harbour C, Bell SC, Fennelly KP. Cough-generated aerosols of Pseudomonas aeruginosa and other Gram-negative bacteria from patients with cystic fibrosis. Thorax. 2009; 64:926-931.[PubMed]

     Claire Wainwright

P. aeruginosa was isolated in cough aerosols of 25 subjects (89%), 22 of whom produced sputum samples. P. aeruginosa from sputum and paired cough aerosols were indistinguishable by molecular typing. In four cases the same genotype was isolated from ambient room air. Approximately 70% of viable aerosols collected during voluntary coughing were of particles <or=3.3 microm aerodynamic diameter. P aeruginosa, Burkholderia cenocepacia, Stenotrophomonas maltophilia and Achromobacter xylosoxidans were cultivated from respiratory particles in this size range. Positive room air samples were associated with high total counts in cough aerosols (p = 0.003). The magnitude of cough aerosols was associated with higher forced expiratory volume in 1 s (r = 0.45, p = 0.02) and higher quantitative sputum culture results (r = 0.58, p = 0.008).

One of a number of recent studies showing that during coughing, patients with CF produce viable aerosols of P. aeruginosa and other Gram-negative bacteria of respirable size range, suggesting the potential for airborne transmission.

2012 Skurnik D, Davis MR Jr, Benedetti D, Moravec KL, Cywes-Bentley C, Roux D, Traficante DC, Walsh RL, Marylander T, Cassidy SK, Harems CR, Martin TR, Assaultable EL, Vargas SO, Macadam AJ, Lie berm an TD, Cushion R, Li puma JJ, Pier GB, Goldberg JB, Probe GP. Targeting pan-resistant bacteria with antibodies to a broadly conserved surface polysaccharide expressed during infection. J Infect Dis 2012; 205:1709-1718.[PubMed]
The bacterial surface polysaccharide poly-beta-(1-6)-N-acetyl-glucosamine (PNAG) mediates biofilm formation by some bacterial species, and antibodies to PNAG can confer protective immunity. By analyzing sequenced genomes, the authors found that potentially multidrug-resistant bacterial species such as Klebsiella pneumoniae, Enterobacter cloacae, Stenotrophomonas maltophilia, and the Burkholderia cepacia complex (BCC) may be able to produce PNAG.

The presence of PNAG on BCC was assessed and antibodies to PNAG were tested using opsonophagocytic assays and for protective efficacy against lethal peritonitis in mice. PNAG is expressed in vitro and in vivo by the BCC, and cystic fibrosis patients infected by the BCC species B. dolosa mounted a PNAG-specific opsonophagocytic antibody response.

Antisera to PNAG mediated opsonophagocytic killing of BCC and were protective against lethal BCC peritonitis even during coinfection with methicillin-resistant Staphylococcus aureus. The authors concluded this was a potential new therapeutic options against PNAG-producing bacteria, including even pan-resistant pathogen.

This is an interesting approach for it is likely that pan-resistant bacteria will become an ever increasing problem as the age of people with CF increases and they receive repeated courses of antibiotics. BCC remains a serious and often intractable problem. So this different approach is to be welcomed.

2012 Gilchrist FJ, Webb AK, Bright-THomas RJ, Jones AM. Successful treatment of cepacia syndrome with a combination of intravenous cyclosporin, antibiotics and oral corticosteroids. J Cyst Fibros 2012; 11:458-460.[PubMed]
The clinical manifestations of BCC infection are varied but can include cepacia syndrome, which is a rapidly progressing necrotising pneumonia with an almost universally fatal outcome. These authors from Manchester report the case of a 38 year old man, known to have chronic infection with the ET12 strain of Burkholderia cenocepacia who developed cepacia syndrome 26 years after initial infection. Aggressive treatment with a combination of 4 intravenous antibiotics, oral corticosteroids and cyclosporin brought about clinical, radiological and biochemical resolution of his cepacia syndrome.

The authors suggest that this case highlights the possible role of cyclosporin in the treatment of cepacia syndrome. However, it may also suggest that the patient had unusual resistance to B.cepacia as he had tolerated the infection for so many years.

Geake JB, Reid DW, Currie BJ, Bell SC et al. An international  multicentre evaluation and description of Burkholderia pseudomallei infection in cystic fibrosis.  Pulm Med. 2015 Oct 9;15:116. doi: 10.1186/s12890-015-0109-9.    Free PMC article [PubMed]
25 culture-confirmed cases of B. pseudomallei infection were identified. The median age at acquisition was 21years, mean FEV1 % predicted was 60%, and mean BMI was 19.5kg/m(2). The location of acquisition was northern Australia or Southeast Asia for most. 19 patients (76%) developed chronic infection, which was usually associated with clinical decline.
Successful eradication strategies included a minimum of two weeks of intravenous ceftazidime, followed by a consolidation phase with trimethoprim/sulfamethoxazole, and this resulted in a higher chance of success when instituted early. Three cases of lung transplantation have been recorded in the setting of chronic B. pseudomallei infection.
The authors concluded chronic carriage of B. pseudomallei in patients with CF appears common after infection, in contrast to the non-CF population. This is often associated with an accelerated clinical decline.

–  A useful review of all the published cases of Burkholderia pseudomallei, an infection which seems to be associated with people with CF visiting Thailand in the rainy season – to the extent that some would advise people with CF to avoid such visits in the rainy season.

2015 Radhakrishna N, Morton J. Burkholderia pseudomallei in cystic fibrosis and treatment complications. Respirol Case Rep. 2015 Mar;3(1):1-2. doi: 10.1002/rcr2.86. Epub 2014 Nov 30. [PubMed] Full article available.
A healthy 29-year-old Australian man with cystic fibrosis (CF) grew Burkholderia pseudomallei on a routine sputum culture 1 month after returning from holiday in Thailand. He underwent a 12-month treatment regime with multiple antibiotics resulting in a number of adverse events. Sputum cultures were cleared of the pathogen and remain negative 8 years post-treatment. There were no clinical sequelae and no deterioration in lung function. Few reports have been published to date on melioidosis in CF patients. The proposed management for this infection includes multiple antibiotics regimens for prolonged periods of time, which may result in adverse events. Optimal treatment and length of treatment are currently determined on an individual basis.

Quon BSSykes JStanojevic SMarshall BCPetren KOstrenga JFink AElbert AFaro AGoss CHStephenson AL.Clinical characteristics of cystic fibrosis patients prior to lung transplantation: An international comparison between Canada and the United States.Clin Transplant. 2018 Jan 2. doi: 10.1111/ctr.13188. [Epub ahead of print]  [PubMed] 

         Bradley Quon

Between 1986 and 2013, 607 (10.2%) CF patients underwent lung transplantation in Canada and 3428 (7.5%) in the United States. A lower proportion of recipients had growth of B. cepacia complex prior to transplant in the United States compared to Canada (0.8% vs 4.3%). Lung function was similar between recipients from the two countries. The proportion of patients classified as underweight was significantly higher in the United States compared to Canada (39.8% vs 28.0%; SD 26.1) despite higher rates of feeding tube use (42.5% vs 28.6%; SD 29.0).

CF lung transplant recipients from the United States have similar lung function, lower rates of B. cepacia complex, and worse nutritional parameters prior to transplant compared to counterparts in Canada. Future studies are necessary to evaluate the impact of these differences on post-transplant survival.

Dr. Bradley S Quon is Assistant Professor in the Department of Medicine University of British Columbia. He is a Staff Respirologist and CF Physician at St. Paul’s Hospital in Vancouver

– Presumably the better nutrition and higher B. cepacia rates are a reflection of the patients’ previous experience – the Canadians being better nourished for decades from the time of Douglas Crozier in the Seventies but more likely to have B. cepacia which became a common pathogen in Toronto patients from the Eighties.

2018 Abdallah MAbdallah HAMemish ZA.Burkholderia cepacia complex outbreaks among non-cystic fibrosis patients in the intensive care units: A review of adult and pediatric literature. Infez Med. 2018 Dec 1;26(4):299-307.  Free full text [PubMed] 
Burkholderia cepacia complex (Bcc) is a Gram-negative bacterium commonly found in moist environments and soil. Bcc species are associated with many outbreaks in intensive care units (ICUs). In this review, we describe the sources of Bcc outbreaks among non-cystic fibrosis (CF) patients in various ICUs that include neonatal intensive care units, pediatric intensive care units and adult ICUs. Also we summarize the risk factors and outcome predictors of Bcc infection or colonization in non-CF critically ill patients. Finally, we describe the infection control measures that are used to manage and prevent the spread of Bcc outbreaks. PubMed was searched from 1 January 1994 and 31 December 2017. We found 30 outbreaks of Bcc among non-cystic fibrosis patients in ICUs; 17 outbreaks occurred in adult ICUs. The source was identified in 22 outbreaks. B. cepacia was the most common Bcc species causing outbreaks in ICUs; it was detected in 21 outbreaks. Indwelling central lines, presence of renal failure on hemodialysis, multiple bronchoscopic procedures, and recent abdominal surgery are independently associated with the development of B. cepacia bacteremia, while prolonged duration on a mechanical ventilator, a large number of nebulized albuterol therapies delivered, and prescription of beta-lactam, aztreonam, or macrolide-vancomycin antibiotics are risk factors for respiratory tract acquisition of B. cepacia. Disease severity and age were the main significant independent predictors of 14-day mortality in adult ventilated non-CF patients with Bcc acquisition. Bcc species have been linked to many outbreaks in non-CF patients in ICUs. Strict application of infection control standards is critical to limit the emergence and spread of Bcc in ICU settings.

From the King Saud Medical City, Riyadh Saudi Arabia

2018 Cantón-Bulnes MLHurtado Martínez ÁLópez-Cerero LArenzana Seisdedos ÁMerino-Bohorquez VGarnacho-Montero J. A case of pan-resistant Burkholderia cepacia complex bacteremic pneumonia, after lung transplantation treated with a targeted combination therapy. Transpl Infect Dis. 2018 Dec 12:e13034. doi: 10.1111/tid.13034. [Epub ahead of print] [PubMed] 
The authors describe a case of one patient with cystic fibrosis who developed a pan-resistant Burkholderia cepacia complex rapidly progressive bacteraemic pneumonia, following bilateral lung transplantation. The patient was treated with a targeted combination antibiotic therapy (meropenem plus ceftazidime/avibactam plus high doses of nebulized colistimethate sodium). Evolution of the disease was complicated by multiple organ system dysfunction. Finally, clinical improvement and microbiological cure was achieved.

From Hospital Universitario Virgen Macarena, Sevilla, Spain

2018 Ho SSC, Nashid N, Waters VJ, LiPuma JJZlosnik JEAOtley ASomers GRKamath BMYau YCW.Burkholderia multivorans septicemia in a pediatric liver transplant patient.Am J Transplant. 2018 Aug 9. doi: 10.1111/ajt.15065. [Epub ahead of print]  [PubMed]
“Cepacia syndrome”, caused by Burkholderia cepacia complex and often associated with cystic fibrosis, carries a high mortality rate. It is rare for Burkholderia multivorans, a species within the B. cepacia complex, to cause cepacia syndrome even among patients with cystic fibrosis. This is the first reported fatal case of cepacia syndrome caused by B. multivorans occurring in a pediatric liver transplant recipient who does not have cystic fibrosis. We describe the unique characteristics of this pathogen among the non-cystic fibrosispopulation and the importance of early recognition and treatment.

A report from Toronto.

2018 Van Dalem AHerpol MEchahidi FPeeters CWybo IDe Wachter EVandamme PPiérard D. In Vitro Susceptibility of Burkholderia cepacia Complex Isolated from Cystic Fibrosis Patients to Ceftazidime-Avibactam and Ceftolozane-Tazobactam.  Antimicrob Agents Chemother. 2018 Aug 27;62(9). pii: e00590-18. doi: 10.1128/AAC.00590-18. Print  2018 Sep. [PubMed] 
The authorstested the in vitro susceptibility of ceftazidime-avibactam and ceftolozane-tazobactam and 13 other antibiotics against 91 Burkholderia cepacia complex (BCC) strains isolated from cystic fibrosis patients since 2012. The highest susceptibility (82%) was found for trimethoprim-sulfamethoxazole. Eighty-one and 63% of all BCC strains were susceptible to ceftazidime-avibactam and ceftolozane-tazobactam, respectively. For temocillin, ceftazidime, piperacillin-tazobactam, and meropenem, at least 50% of the strains were susceptible. B. stabilis seems to be more resistant than other BCC species.

Rojas-Rojas FULópez-Sánchez DMeza-Radilla GMéndez-Canarios AIbarra JAEstrada-de Los Santos P.[The controversial Burkholderia cepacia complex, a group of plant growth promoting species and plant, animals and human pathogens]. Rev Argent Microbiol. 2018 Apr 21. pii: S0325-7541(18)30003-8. doi: 10.1016/j.ram.2018.01.002. [Epub ahead of print]   [Article in Spanish]  [PubMed]
The Burkholderia cepacia complex is a group of 22 species, which are known as opportunistic pathogens in immunocompromised people, especially those suffering from cystic fibrosis. It is also found in nosocomial infections and is difficult to eradicate due to intrinsic resistance to several antibiotics. The species have large genomes (up to 9 Mbp), distributed into 2-5 replicons. These features significantly contribute to genome plasticity, which makes them thrive in different environments like soil, water, plants or even producing nodules in legume plants. Some B. cepacia complex species are beneficial in bioremediation, biocontrol and plant-growth promotion. However, because the B. cepacia complex is involved in human infection, its use in agriculture is restricted. B. cepacia complex is being constantly studied due to the health problems that it causes and because of its agricultural potential. In this review, the history of B. cepacia complex and the most recently published information related to this complex are revised.

From the Instituto Politécnico Nacional, Escuela Nacional de Ciencias Biológicas, Departamento de Microbiología, Ciudad de México, México

2018 Wang RWelsh SKBudev MGoldberg HNoone PGGray AZaas DBoyer D. Survival after lung transplantation of cystic fibrosis patients infected with Burkholderia dolosa (genomovar VI).  Clin Transplant. 2018 May;32(5):e13236. doi: 10.1111/ctr.13236.[PubMed]
Cystic fibrosis (CF) with severe lung disease is a well-recognized indication for lung transplantation. Colonization with various organisms in CF patients may impact post-transplant morbidity and mortality. Burkholderia cepacia complex (BCC) is made up of distinct genomovars with significant morbidity and mortality associated with B. cenocepacia (genomovar III) following lung transplant. The outcomes of patients infected with genomovar B. dolosa (genomovar VI) have yet to be described in the literature. We performed a retrospective chart review of all cystic fibrosis patients colonized with B. dolosa from our center who underwent lung transplantation (n = 11) at various medical centers across the US between 2000 and 2014. Survival rates were 73%, 53%, and 30% for 1, 3, and 5 years, respectively. Median survival was 44 months (95% CI = 11.1-76.8). CF patients with B. dolosa that have undergone lung transplantation have decreased one-year survival when compared to all patients transplanted with cystic fibrosis. Conditional 5-year survival for B. dolosa-infected patients was 43% in patients that survived the first year post-transplant, suggesting that this first year is crucial in managing the infection. Importantly, the survival of the B. dolosa patients was higher than compared to previously reported survival rates of B. cenocepacia patients post-transplant.

Dr. Ruobing Wang is a pediatric pulmonologist in Boston, Massachusetts and is affiliated with the Division of Respiratory Diseases Boston Children’s Hospital

2018 Cogen JDOnchiri FEmerson JGibson RLHoffman LRNichols DPRosenfeld MChronic Azithromycin Use in Cystic Fibrosis and Risk of Treatment-Emergent Respiratory Pathogens. Ann Am Thorac Soc. 2018 Jun;15(6):702-709. doi: 10.1513/AnnalsATS.201801-012OC. [PubMed]

Johnathan Cogen

Azithromycin has been shown to improve lung function and reduce the number of pulmonary exacerbations in patients with cystic fibrosis. Concerns remain, however, regarding the potential emergence of treatment-related respiratory pathogens.    A study to determine whether chronic azithromycin use (defined as three-times weekly administration) is associated with increased rates of detection of eight specific respiratory pathogens.

The authors performed a new-user, propensity score-matched retrospective cohort study utilizing data from the Cystic Fibrosis Foundation Patient Registry. Incident azithromycin users were propensity score matched 1:1 with contemporaneous nonusers. Kaplan-Meier curves and Cox proportional hazards regression were used to evaluate the association between chronic azithromycin use and incident respiratory pathogen detection. Analyses were performed separately for each pathogen, limited to patients among whom that pathogen had not been isolated in the 2 years before cohort entry.

After propensity score matching, the mean age of the cohorts was approximately 12 years. Chronic azithromycin users had a significantly lower risk of detection of new methicillin-resistant Staphylococcus aureus, non-tuberculous mycobacteria, and Burkholderia cepacia complex compared with nonusers. The risk of acquiring the remaining five pathogens was not significantly different between users and nonusers.

The authors concluded using an innovative new-user, propensity score-matched study design to minimize indication and selection biases, they found in a predominantly pediatric cohort that chronic azithromycin users had a lower risk of acquiring several cystic fibrosis-related respiratory pathogens. They suggest these results may ease concerns that chronic azithromycin exposure increases the risk of acquiring new respiratory pathogens among pediatric patients with cystic fibrosis.

Dr Jonathan D Cogen is Pulmonary and Sleep medicine specialist ay Seattle Children’s

Costabile G, Provenzano R, Azzalin A, Scoffone V, Chiarelli LR, Rondelli V, Grillo I, Zinn T, Lepioshkin A, Savina S, Miro A, Quaglia F, Makarov V, Coenye T, Brocca P, Riccardi G, Buroni S, Ungaro F.  PEGylated mucus-penetrating nanocrystals for lung delivery of a new FtsZ inhibitor against Burkholderia cenocepacia infection.   Nanomedicine. 2019 Oct 25;23:102113. doi: 10.1016/j.nano.2019.102113. [Epub ahead of print]    [Pubmed]
C109 is a potent but poorly soluble FtsZ inhibitor displaying promising activity against Burkholderia cenocepacia, a high-risk pathogen for cystic fibrosis (CF) sufferers. To harness C109 for inhalation, we developed nanocrystal-embedded dry powders for inhalation suspension consisting in C109 nanocrystals stabilized with D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) embedded in hydroxypropyl-β-cyclodextrin (CD). The powders could be safely re-dispersed in water for in vitro aerosolization. Owing to the presence of a PEG shell, the rod shape and the peculiar aspect ratio, C109 nanocrystals were able to diffuse through artificial CF mucus. The promising technological features were completed by encouraging in vitro/in vivo effects. The formulations displayed no toxicity towards human bronchial epithelial cells and were active against planktonic and sessile B. cenocepacia strains. The efficacy of C109 nanosuspensions in combination with piperacillin was confirmed in a Galleria mellonella infection model, strengthening their potential for combined therapy of B. cenocepacia lung infections.

From the Department of Pharmacy, University of Napoli “Federico II”, Napoli, Italy.

Blanchard AC, Tang L, Tadros M, Muller M, Spilker T, Waters VJ, LiPuma JJ, Tullis E.Burkholderia cenocepacia ET12 transmission in adults with cystic fibrosis.   Thorax.2019 Nov 15. pii: thoraxjnl-2019-214098. doi: 10.1136/thoraxjnl-2019-214098. [Epub ahead of print][Pubmed]

        Ana Blanchard

This report describes transmission of a Burkholderia cenocepacia ET12 strain (ET12-Bc) at the Toronto Adult Cystic Fibrosis (CF) Centre occurring from 2008 to 2017. Epidemiological and genomic data from 11 patients with CF were evaluated. Isolates were analysed using whole genome sequencing (WGS). Epidemiological investigation and WGS analysis suggested nosocomial transmission, despite enhanced infection control precautions. This was associated with subsequent deaths in 10 patients. ET12-Bc positive patients are no longer cared for on the same unit as ET12-Bc negative patients.

Ana C Blanchard is a research fellow in the Dept of Pediatrics, Infectious Diseases, Hospital for Sick Children, Toronto, Ontario, Canada

Spoletini G, Etherington C, Shaw N, Clifton IJ, Denton M, Whitaker P, Peckham DG. Use of ceftazidime/avibactam for the treatment of MDR Pseudomonas aeruginosa and Burkholderia cepacia complex infections in cystic fibrosis: a case series. J Antimicrob Chemother. 2019 Jan 11. doi: 10.1093/jac/dky558. [Epub ahead of print] [Pubmed]

Miles Denton & Daniel Peckham

The efficacy of antibiotic treatment in pulmonary and systemic infections in cystic fibrosis (CF) is limited by the increased prevalence of MDR strains of Pseudomonas aeruginosa and Burkholderia cepacia complex. Ceftazidime/avibactam is a new combination which, in vitro, appears to have good activity against MDR strains of P. aeruginosa and B. cepacia complex.

A retrospective analysis was performed including adult patients with CF who received at least one course of ceftazidime/avibactam owing to pulmonary exacerbations not responding to conventional antibiotic treatment. Treatment with ceftazidime/avibactam was associated with reduction in inflammatory markers and improvement in lung function. No episodes of acute kidney injury or elevation in transaminase were observed.

The authors conclude Ceftazidime/avibactam appeared to be well tolerated and improved patients’ outcomes. Further studies are needed to better assess the role of this new combination in CF.

Dr Miles Denton is consultant microbiologist and Professor Daniel Peckham is Director of the Leeds Adult Cystic Fibrosis Centre

Bartley BL, Gardner KJ, Spina S, Hurley BP, Campeau D, Berra L, Yonker LM, Carroll RW.    High-Dose Inhaled Nitric Oxide as Adjunct Therapy in Cystic Fibrosis Targeting Burkholderia multivorans.   Case Rep Pediatr. 2020 Jun 24;2020:1536714. doi: 10.1155/2020/1536714. eCollection 2020. Free PMC article.[Pubmed]
Background: Individuals with cystic fibrosis (CF) have persistent lung infections, necessitating the frequent use of antibiotics for pulmonary exacerbations. Some respiratory pathogens have intrinsic resistance to the currently available antibiotics, and any pathogen may acquire resistance over time, posing a challenge to CF care. Gaseous nitric oxide has been shown to have antimicrobial activity against a wide variety of microorganisms, including common CF pathogens, and offers a potential inhaled antimicrobial therapy. Case Presentation. Here, we present the case of a 16-year-old female with CF who experienced a precipitous decline in lung function over the prior year in conjunction with worsening antibiotic resistance of her primary pathogen, Burkholderia multivorans. She received 46 intermittent inhalations of 160 parts-per-million nitric oxide over a 28-day period. The gas was administered via a mechanical ventilator fitted with nitrogen dioxide scavenging chambers.

Conclusions: High-dose inhaled nitric oxide was safe, well tolerated, and showed clinical benefit in an adolescent with cystic fibrosis and pulmonary colonization with Burkholderia multivorans. Inhaled high-dose NO therapy, utilized as an anti-infective adjunct therapy, improved pathogen antibiotic resistance patterns and clinical outcomes in our patient.    Inhaled high-dose NO therapy, utilized as an anti-infective adjunct therapy, improved pathogen antibiotic resistance patterns and clinical outcomes in our patient. Mechanistic studies in vitro and larger randomized controlled clinical trials are needed to better understand the bactericidal efficacy and biofilm dispersal properties of high-dose NO on Bmultivorans. To our knowledge, this is the first report of high-dose inhaled NO therapy in an individual with CF and pulmonary colonization with Bmultivorans. In follow-up, the patient continues to require frequent courses of antibiotics for pulmonary exacerbations though much less frequent inpatient admissions. During inpatient stays, we continue to offer high-dose inhaled NO therapy as an adjunct therapy to intravenous antibiotics. The patient’s genotype qualifies for the newly available, highly effective, triple combination CFTR modulator, elexacaftor-ivacaftor-tezacaftor (Vertex Pharmaceuticals) which has improved her lung function but has not yet altered her sputum microbiota. Recalcitrant infection with multidrug-resistant pathogens will likely continue to be a major problem in CF despite the advent of CFTR modulators [2223], and high-dose inhaled NO may help those who continue to struggle with difficult to treat respiratory pathogens.

Dr Bethany L Bartley is at the Department of Pediatric Pulmonology, Massachusetts General Hospital, Boston, USA