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01.12.2015 | Research article | Ausgabe 1/2015 Open Access

BMC Pulmonary Medicine 1/2015

An international, multicentre evaluation and description of Burkholderia pseudomallei infection in cystic fibrosis

Zeitschrift:
BMC Pulmonary Medicine > Ausgabe 1/2015
Autoren:
James B. Geake, David W. Reid, Bart J. Currie, Scott C. Bell, MelioidCF Investigators
Wichtige Hinweise

Electronic supplementary material

The online version of this article (doi:10.​1186/​s12890-015-0109-9) contains supplementary material, which is available to authorized users.

Competing interests

All authors declare they have no competing interests.

Authors’ contributions

JBG participated in design of the study, collated clinical data, and drafted the manuscript. DWR participated in the design of the study and edited the manuscript. BJC participated in design of the study, provided clinical data on study subjects, and edited the final manuscript. SCB conceived the study, participated in design of the study, and edited the final manuscript. The Melioid CF Group provided clinical data on study subjects and edited the final manuscript. All authors read and approved the final manuscript.

Authors' information

Not applicable

Availability of data and materials

Not applicable
Abbreviations
BMI
Body mass index
B. pseudomallei
Burkholderia pseudomallei
CF
Cystic fibrosis
CFTR
Cystic Fibrosis Transmembrane Conductance Regulator
FEV1
Forced expiratory volume in 1 second
TMP/SMX
Trimethoprim/sulfamethoxazole

Background

Burkholderia pseudomallei is a gram-negative environmental bacterium found in soil and surface water that causes melioidosis, which most commonly occurs in south-east Asia and northern Australia [ 1]. Melioidosis has been increasingly recognised to occur in diverse tropical locations globally, including the Americas and Africa [ 2]. B. pseudomallei is now classified by the US CDC as a tier-1 select agent because of its aerosolized biothreat potential ( http://​www.​selectagents.​gov/​). Infection can occur through inhalation, aspiration and ingestion, although transmission most commonly occurs via percutaneous inoculation [ 3]. Pneumonia is the most common clinical manifestation (presumably via haematogenous spread to the lungs), with a spectrum including mild self-limiting infection, subacute pulmonary disease mimicking tuberculosis, rapidly progressive multifocal pneumonia and systemic sepsis which confers a high mortality of over 50 % [ 4]. Melioidosis is often reported in people returning to their home country after travelling to an endemic region. At-risk tourists include those with diabetes and cystic fibrosis (CF) exposed to soil and surface water or monsoonal storms where aerosolization of B. pseudomallei may occur [ 1, 2].
Generally patients who survive infection clear the organism and rarely relapse following an adequate duration of therapy [ 5]. In the 25-year Darwin Prospective Melioidosis Study [ 6], only one of over 750 consecutive melioidosis patients had evidence of long-term persisting infection with B. pseudomallei. This patient with non-CF bronchiectasis has continued to have positive sputum culture results for B. pseudomallei 14 years after diagnosis and treatment of melioidosis. Whole genome sequencing of isolates obtained from this patient over a 12-year period demonstrates loss of virulence and immunogenic factors, as well as deletion of pathways involved in environmental survival [ 7]. There have been a number of published case reports of patients with CF who have acquired B. pseudomallei infection and a number of these cases have demonstrated chronic carriage of B. pseudomallei in patients with CF [ 817].
In this study, we aimed to describe the international experience of infection with B. pseudomallei in patients with CF. We have examined potential risk factors for acquisition and persistence of infection, summarised global experience of effective antibiotic strategies, and assessed the long-term clinical sequelae of infection.

Methods

The study was conducted in accordance with the amended Declaration of Helsinki, and was approved by the local human research ethics committee. (Metro North Hospital and Health Service Human Research Ethics Committee, Queensland, HREC/13/QPCH/51). A literature search (utilising Medline, Embase, CINAHL, AustHealth and ScienceDirect databases and by Google Scholar) was performed to identify all published cases of B. pseudomallei infection in patients with CF in July 2013 and repeated in August 2014 (Additional file 1). Case reports were hand-searched and clinicians from European, North American, and Australasian CF centres that had either reported B. pseudomallei in CF patients, or were experts from CF microbiology laboratories, were contacted to locate additional cases not previously reported. Data entry sheets were provided to the clinicians that had supervised the care of the identified cases, and results including contemporaneous clinical metrics were compiled (Additional file 2). Where supervising clinicians could not be contacted, information was extracted from the published reports [ 8, 9, 11, 14]. Chronic infection was defined as persistent cultures of B. pseudomallei from sputa or endobronchial washings for 12 months or more.

Results

Case identification

Twenty-five culture-proven cases between 1987 and 2015 were identified (Table  1). 16 cases were identified by literature search. A further nine cases were identified through international consultation with experts of CF and infectious disease that had experience in the diagnosis and management of B. pseudomallei infection. Of the 25 cases, detailed clinical data were made available by the treating clinicians for 21 cases, and in the remaining four cases details were extracted from published reports. An additional two cases were identified where melioidosis was suspected based on positive B. pseudomallei serology, although culture confirmation was elusive. Both cases died from progressive refractory respiratory infection after being presumptively infected while travelling overseas; these cases were not included further in this analysis. Three additional possible cases from Mexico were identified through hand-searching references of published articles [ 18]. There were insufficient data available and the accuracy of bacterial identification was uncertain, therefore these cases were also excluded.
Table 1
Cases of culture confirmed B. pseudomallei infection in CF
Patient
Year isolated
Location of acquisition
Country of residence
Age
Gender
CFTR Mutation
FEV 1%
BMI
Co-pathogens
ETOH >40 g daily
Diabetes
1 (O’Carroll, 2003) [ 12]
1987
Northern Australia
Australia
21
M
F508del/F508del
49
21
Pseud
No
No
2
Early 1990’s
Northern Australia
Australia
40
M
F508del/R117
44.5
23
Pseud
Yes
No
Mycobacterium intracellulare
3 (Schülin, 2001) [ 14]
1992
Likely Thailand
Germany
31
M
Unknown
Unknown
Unknown
Unknown
Unknown
Unknown
4 (Visca, 2001) [ 15]
1998
South-East Asia
Italy
25
F
Unknown
Unknown
Unknown
Pseud
Unknown
Unknown
BCp
5 (Dance, 1999) [ 11]
1998
Malaysia
England
20
M
Unknown
Unknown
Unknown
Unknown
Unknown
Unknown
6 (Holland, 2002) [ 16]
1999
Northern Australia
New Zealand
8.5
M
G551D/1717-16 > A
46
15
Pseud
No
No
Aspergillus fumigatus
7 (Holland, 2002) [ 16]
2000
Northern Australia
New Zealand
7
F
G551D/1717-16 > A
Unknown
19
Haemophilus influenzae
No
No
Staph A
8 (O’Carroll, 2003) [ 12]
2000
Northern Australia
Australia
21
M
F508del/F508del
35
22
Pseud
No
Yes
Staph A
BCp
9 a (Holland, 2002) [ 16]
2000
Northern Australia
Australia
18
M
F508del/F508del
45
21
Pseud
Yes
No
Staph A
BGl
Mycobacterium intracellulare
Other
10 (O’Carroll, 2003) [ 12]
2001
Northern Australia
Australia
14
M
F508del/G542X
80
17
Pseud
No
No
Staph
11 (Holland, 2002) [ 16]
2001
Northern Australia
New Zealand
38
M
F508del/F508del
36
19
Pseud
No
IFG
Staph A
12 (O’Carroll, 2003) [ 12]
2001
Northern Australia
Australia
25
F
Unknown
80
20
Pseud
No
No
Staph A
BCp
13 (Asiah, 2006) [ 8]
2004
Malaysia
Malaysia
17
M
Unknown
Unknown
Unknown
Pseud
Unknown
Unknown
Staph A
14 (Barth, 2007) [ 9]
2005
Brazil
Brazil
17
F
Unknown
Unknown
Unknown
Pseud
Unknown
Unknown
Staph A
15
2005
Thailand
England
30
F
Unknown
56
21
Pseud
No
Yes
Staph A
Aspergillus fumigatus
16 (Corral, 2008) [ 10]
2006
British Virgin Islands
England
17
M
F508del/E60X
63
22
Pseud
Unknown
No
Staph A
Canada
17
2007
Northern Australia
Australia
38
M
F508del/F711 + 5G > A
29
19
Pseud
No
No
Staph A
Aspergillus terreus
18
2007
Thailand
New Zealand
10
F
F508del/17aa + IG74
107
16
Pseud
No
No
Staph A
Other
19
2008
Thailand
Australia
22
F
F508del/F508del
85
23
Pseud
Yes
Yes
20 (O’Sullivan, 2011) [ 13]
2009
Aruba
USA
7
F
F508del/F508del
88
13
None
No
No
21
2010
Vietnam/Cambodia
England
23
F
F508del/F508del
44
19
Pseud
No
No
Haemophilus influenzae
22 (Radhakrishna, 2014) [ 17]
2011
Thailand
Australia
25
M
Unknown
95
24
Pseud
Unknown
No
Aspergillus fumigatus
23
2012
Malaysia/Philippines
Malaysia
19
M
R553X/unknown
18
17
Pseud
No
No
24
2013
Thailand/Japan
England
30
M
F508del/E60X
67
23
Pseud
No
No
25
2015
Thailand
England
21
F
F508del/F508del
71
18
Pseud
No
No
Staph A
Pseud Pseudomona aeruginosa, Staph A Staphylococcus aureus, BCp Burkholderia cepacia complex, BGl Burkholderia gladioli, IFG impaired fasting glucos
a3 distinct B. pseudomallei infections were recorded in this patient over 8 years

Epidemiology and risk factors for B. Pseudomallei acquisition

Of the 25 cases, 15 (62.5 %) were males, and ten females. The median age at acquisition was 21 years (range 7–38 years). The presumptive location of acquisition for the majority was either northern Australia or South-east Asia. There was one case each of presumed acquisition in Brazil, Aruba and the British Virgin Islands, respectively. The mean forced expiratory volume in 1 s (FEV 1) was 60 % predicted (range 38-107 %) and mean body mass index (BMI) was 19.5 kg/m 2 (range 13–24). Two cases were siblings. Specific Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) mutations were documented in 17 of the 25 patients. Of these, 47 % (8) were F508del homozygotes and 35 % (6) were F508del heterozygotes. Having CF (pulmonary disease) was the apparent major risk factor in all patients. Of the 19 patients where data were available, CF-related diabetes was present in three (16 %) and there was impaired glucose tolerance in one. Other common risk factors for infection with B. pseudomallei such as hazardous alcohol use, chronic renal disease, congestive cardiac failure, rheumatic heart disease and immunosuppressive therapy were not reported in any of the cases.

Clinical and radiological manifestations of infection with B. Pseudomallei

Of the 25 patients, clinical manifestations at the presumed time of acquisition were available in 24. In ten (42 %), isolation of B. pseudomallei was an incidental finding on routine sputum surveillance and in the remaining 14 patients (61 %), isolation of B. pseudomallei was associated with symptoms of increased cough and sputum. Systemic features (either one or a combination of the following: fever, weight loss or deteriorating glycemic control) were reported in 10 patients. New radiological changes were documented in eight patients, with patchy areas of consolidation being the most common abnormality reported. Lobar consolidation, progressive lobar destruction, increased bronchiolectasis with “tree-in-bud” opacities and progressive bronchiectasis were also reported.

Long-term outcomes following infection with B. Pseudomallei

In five patients, acquisition of B. pseudomallei did not result in chronic infection (≥12 months). In one of these patients (patient 9), there were three different B. pseudomallei infections over an eight-year period, each with distinct organisms as confirmed by multilocus sequence typing, [ 6] and each episode was successfully cleared with 2 to 3 week courses of intravenous ceftazidime and oral trimethoprim/sulfamethoxazole (TMP/SMX) followed by consolidation with three months of oral TMP/SMX. This case was considered to have been infected with distinct B. pseudomallei strains on three occasions [ 6]. Two patients presented with acute pneumonia and the organism was eradicated after a combination of intravenous followed by consolidation nebulized and oral antibiotics (patient 16 and 20). One further patient who was not unwell at the time of isolation of the organism spontaneously cleared the infection without specific antibiotics directed at B. pseudomallei (patient 19).
In 19 patients (79 %) , initial infection was followed by evidence of chronic infection (range 1 – 11 years) (Table  2). Of these patients, 14 were thought to have had an accelerated decline in pulmonary status by their physician, although in one case the reported decline occurred after a four-year period of clinical stability despite evidence of persistent infection. Markers of clinical deterioration that were reported included increased exacerbation frequency, reduced response to intravenous antibiotics and an accelerated decline in lung function. Six patients had died by August 2014, between two and six years after the first isolation of B. pseudomallei (patients 6, 7, 8, 11, 15 and 18). In two, septicemia was documented and complicated by respiratory failure and death (patients 7 and 15). In one recurrent bacteraemia occurred and oral corticosteroids appeared to precipitate an episode (patient 15). Tigecycline controlled bacteremia despite progressive resistance to TMP/SMX and ceftazidime.
Table 2
Cases of chronic infection
Patient
Duration of infection
Year of acquisition
Eradication attempted
Eradication successful
Outcome
1 (O’Carroll, 2003) [ 12]
>15 years
1987
No
N/A
Slow decline in lung health consistent with CF; transplant 2004
10 (O’Carroll, 2003) [ 12]
11 years
2001
No
N/A
Slow decline in lung health consistent with CF
3 (Schülin, 2001) [ 14]
>9 years
1992
Yes
No
Increased frequency of exacerbations
15
>8 years
2005
Yes
No
Accelerated decline; transplant declined due to B. pseudomallei infection; B. pseudomallei septicaemia; a died 2009
22 (Radhakrishna, 2014) [ 17]
7 years
2011
Yes
Yes
No obvious clinical impact
2
7 years
Early 1990’s
No
N/A
Spontaneously clearance of infection after approx. 7 years; 11 years later died of neutropenic sepsis complicating treatment of Duke’s C colon cancer.
7 (Holland, 2002) [ 16]
>6 years
2000
Yes
No
Accelerated decline with increased frequency of exacerbations; B. pseudomallei septicaemia; died 2009
17
6 years
2007
No
N/A
Slow decline in lung health consistent with CF
18
6 years
2007
Yes
No
Accelerated decline; transplant declined due to B. pseudomallei; died 2013
11 (Holland, 2002) [ 15]
5 years
2001
Yes
No
Accelerated decline; transplant 2006; died 2011
23
>12 months
2012
Yes
No
Progressive destruction right upper lobe
6 (Holland, 2002) [ 16]
>4 years
1999
Yes
No
After presumed latency of 4 years developed accelerated decline with pneumonia; died 2004
24
4 years
2009
Yes
Unknown
Fall in lung function; stable after targeted antimicrobial therapy
14 (Barth, 2007) [ 9]
>2 years
2005
Yes
No
Accelerated decline with rapid decrease in lung function and recurrent exacerbations over 2 years; long term outcome unknown
8 (O’Carroll, 2003) [ 12]
2 years
2000
Yes
No
Rapid decline post infection; died 2 years after initial infection
21
2 years
2010
Yes
No
Accelerated decline; transplant 2012 with persistent infection post-transplant
12 (O’Carroll, 2003) [ 12]
2 years
2001
Yes
Yes
Repeated admissions with pneumonia, treated with 3 week courses of ceftazidime, meropenem, tobramycin; infection ultimately spontaneously cleared
4 (Visca, 2001) [ 15]
1 year
1998
Yes
Yes
Deteriorating pulmonary sepsis, increasingly refractory to anti-pseudomonal antibiotics; cleared infection with antimicrobial therapy; still alive 2013
13 (Asiah, 2006) [ 8]
1 year
2004
Yes
Yes
Increased pulmonary sepsis during infection with B. pseudomallei; remained well 5 months after completing targeted anti-microbial therapy
aRecurrent episodes of B. pseudomallei bacteremia
bIn patient 5 the duration of infection and long term outcome was unknown
In five patients, evidence of chronic infection (duration 5–17 years) was not associated with clinical deterioration (patients 1, 2, 10, 17 and 22).
In one patient duration of infection and outcome was unknown (patient 5), and another one patient was identified shortly prior to publication (patient 25). Initial sputa have been clear after three weeks of intravenous antibiotics. The patient continues on suppressive oral antibiotics, and long term outcomes are awaited.

Eradication strategies

Specific eradication strategies were documented in 19 of the 25 patients. Six patients (including patient 9 - multiple episodes of infection) achieved clearance of B. pseudomallei. Eradication attempts were unsuccessful in 11 patients and there was an unknown outcome in two patients (patient 24, patient 25, Table  3). For cases of successful eradication, the period of known infection was usually less than 12 months, whereas failed eradication usually occurred where long-term infection was evident. Ceftazidime was a key component of induction therapy in all but one of the patients with successful eradication, and all had consolidation therapy from one to four months after completion of intravenous antibiotics and in most cases, oral TMP/SMX was used. In select cases, antibiotic regimens also included combinations of oral amoxicillin/clavulanic acid, doxycycline and chloramphenicol, and nebulized meropenem (250–500 mg twice daily in 4 ml of sterile water).
Table 3
Eradication strategies
Patient
Duration of infection prior to treatment
Induction
Consolidation
   
Treatment
Duration
Treatment
Duration
Successful eradication
16 (Corral, 2008) [ 10]
Unknown – lived in BVI
Meropenem 2 g tds
19 days
TMP/SMX 960 mg bd
19 days
Minocycline 100 mg bd
Minocycline 100 mg bd
Tobramycin (neb) a 80 mg bd
20 (O’Sullivan, 2011) [ 13]
3 months
Imipenem
14 days
Meropenem (neb)
28 days
Ceftazidime
TMP/SMX 960 mg bd
2 years
4 (Visca, 2001) [ 15]
12 months
Ceftazidime
42 days
TMP/SMX 960 mg bd
210 days
TMP/SMX 960 mg bd
Doxycycline
Chloramphenicol
13 (Asiah, 2006) [ 8]
12 months
Ceftazidime
56 days
TMP/SMX 960 mg bd
112 days
TMP/SMX 960 mg bd
Doxycycline
22 (Radhakrishna, 2014) [ 17]
7 years
Meropenem 2 g tds
Approx 56 days
Doxycycline followed by amoxycillin/clavulanic acid (doxycycline allergy)
12 months
Ceftazidime 3 g tds
Tobramycin (neb) 80 mg bd
TMP/SMX 960 mg bd
9 (Holland, 2002) [ 16] Infection 1
Unknown
Ceftazidime
14 days
TMP/SMX 960 mg bd
90 days
TMP/SMX 960 mg bd
9 (Holland, 2002) [ 16] Infection 2
1 month
Ceftazidime
21 days
TMP/SMX 960 mg bd
90 days
TMP/SMX 960 mg bd
9 (Holland, 2002) [ 16] Infection 3
1-2 months
Ceftazidime
14 days
TMP/SMX 960 mg bd
90 days
TMP/SMX 960 mg bd
Failed Eradication
8 (O’Carroll, 2003) [ 12]
4 months
Meropenem 2 g tds
56 days
None
 
Ceftazidime 3 g tds
17
6-12 months
Ceftazidime 3 g tds
14 days
TMP/SMX 960 mg bd
84 days
TMP/SMX 960 mg bd
23
>10 months
Ceftazidime 3 g tds
21 days
Unknown (patient moved to Malaysia)
 
TMP/SMX 960 mg bd
Tobramycin 5 mg/kg
3 (Schülin, 2001) [ 14]
6 years
Unspecified antipseudomonal antibiotics
14 days
No (exacerbations directed against PsA)
 
14 (Barth, 2007) [ 9]
>18 months
Pipracillin/clavulanate
21 days
Meropenem 2 g tds
21 days
Tobramycin 5 mg/kg
Ceftazidime 3 g tds
Amikacin
TMP/SMX 960 mg bd
15
>8 years
Meropenem 2 g tds
14 days
TMP/SMX 960 mg bd
126 days
Tobramycin
Minocycline 100 mg bd
Meropenem (neb)
18 (1 st attempt)
2 months
Ceftazidime 1.5 g tds
14 days
Infection not cleared therefore 2 nd course of IV antibiotics
 
Tobramycin 300 mg
Amoxycillin/Clavulanic acid 900 mg
18 (2 nd attempt)
2 months
Meropenem
84 days
TMP/SMX 960 mg bd
Long term
Ceftazidime
Doxycycline
Amoxycillin/Clavulanic acid
6 (Holland, 2002) [ 16]
>4 years
Ceftazidime 50 mg/kg
120 days
None (exacerbations directed against B. pseudomallei)
 
Piperacillin 50 mg/kg
Amoxycillin/Clavulanic acid
7 (Holland, 2002) [ 16]
>5 years
   
TMP/SMX 960 mg bd
4 years
1 st isolation
7 (Holland, 2002) [ 16]
>9 years
Imipenem
20 days
TMP/SMX 960 mg bd
19 days
2 nd isolation
Piperacillin/Clavulanic acid
42 days
Tetracycline
30 days
Meropenem/TMP/SMX
>30 days
11 (Holland, 2002) [ 16]
3 months
Ceftazidime
14 days
TMP/SMX 960 mg bd
330 days
Tobramycin
21
1 month
Meropenem 2 g tds
42 days
Tobramycin (neb) 300 mg bd
42 days
Ceftazidime 3 g tds
TMP/SMX 960 mg bd
Tobramycin 7 mg/kg
Success of eradication for patient 24 and patient 25 unknown
aneb = nebulized
Two patients spontaneously cleared infection without specific eradication strategies (patients 2 and 19) (Table  2). Whilst not a formal approach at eradication of B. pseudomallei, patient 12 was treated with 3-week courses of ceftazidime, meropenem and tobramycin over a 15-month period for repeated episodes of pneumonia, after which time B. pseudomallei was no longer cultured from sputum.

Transplantation with B. pseudomallei

Transplantation was considered for six patients but two patients were not listed due to concerns about the potential risk of B. pseudomallei graft infection after transplantation (patient 15, patient 18). One patient was listed for transplant but deteriorated very rapidly and died several months later without transplant (patient 8). Three patients have undergone lung transplants (patients 1, 11 and 21) and immediate post-transplant results have been satisfactory. One patient (patient 1) remains well 10 years post-transplant with normal lung function despite endobronchial washings remaining positive for B. pseudomallei; another patient (patient 12) died five years after transplantation, and post-transplant endobronchial washings were positive; and the third patient (patient 21) is alive two years after transplantation also with B. pseudomallei recurrently isolated from post-transplant respiratory samples. Chronic B. pseudomallei suppression has been used in all cases (either TMP/SMX or doxycycline).

Discussion

CF is a disease that predominates in people of Caucasian descent and most patients do not live in tropical or sub-tropical regions where B. pseudomallei is endemic. As survival has increased, CF patients have increasingly had the opportunity to travel, and as a consequence over the past two decades there have been a number of reports of infection with B. pseudomallei in CF patients [ 817].
We have identified 25 cases of B. pseudomallei in CF patients and the vast majority of CF patients who have become infected with B. pseudomallei have acquired the organism through travel to endemic areas such as Southeast Asia and northern Australia. Most patients already had significant structural lung disease and low BMI, which suggests these factors are likely to be important risk factors for acquisition of the organism in CF. However severe CF disease per se was not an obvious prerequisite for acquisition. Some patients were also diabetic but other risk factors for melioidosis such as hazardous alcohol use, chronic renal disease, heart disease and immunosuppressive therapy were not present in this cohort.
In contrast with the general population, acquisition of B. pseudomallei in CF appeared to be more likely to result in chronic infection, which is problematic given how difficult it can be to eradicate this pathogen even with targeted antimicrobial therapy. Whilst the clinical manifestations of infection were varied in the CF patients, and a chronic quiescent disease state can obviously occur, the establishment of chronic infection in most patients usually heralded further clinical deterioration, with progressively refractory bronchopulmonary sepsis being a common feature. Delayed diagnosis may contribute to chronic infection and early attempts to eradicate are recommended. This requires expeditious recognition of the infection in travellers returning from endemic areas. The identification of B. pseudomallei can be challenging, and it is possible that isolates may be confused with other more common CF pathogens including other Burkholderia species, particularly if laboratories are not familiar with in vitro characteristics of B. pseudomallei [ 8, 14, 15]. Furthermore, infection with B. pseudomallei does not always result in immediate onset of symptoms as it often would in patients without CF, and symptoms may masquerade as those typical of pulmonary exacerbation. It is therefore important that CF clinicians have a high index of suspicion for patients returning from endemic areas.
Whilst not universally successful, approaches that utilise a 2–3 week course of parenteral ceftazidime, followed by a 3-month consolidation course of oral.
TMP/SMX, appear to be the most effective. This approach is similar to that recommended for melioidosis therapy [ 1, 2, 19]. If initial response does not successfully result in persistently negative sputum cultures for B. pseudomallei, then a longer course of parenteral ceftazidime or meropenem (≥4 weeks) should be considered [ 2]. If patients are allergic to or intolerant of TMP/SMX, consolidation with several months of doxycycline or amoxycillin/clavulanic acid have also been successfully used. When eradication is not possible, and a progressive decline in health ensues, lung transplantation may be considered. To date, early post-transplant outcomes have been acceptable despite persistence of B. pseudomallei.
This case series has several limitations. Firstly, it is likely other cases have not been identified, either because they have not been reported, or the infection was not recognised. For example, we excluded three possible cases from Mexico because of insufficient details [ 18]. Secondly, outcomes were not available for some patients, we were unable to access data (patients 5, 13 and 14), or cases lost to follow-up (patients 16 and 23). Interestingly, two patients were reported by two CF centres, by two UK-based centres, and by centres in the UK and Canada, respectively (patients 15 and 16). After further investigation we noted they were the same persons, highlighting the mobility of CF patients.

Conclusion

The international experience with B. pseudomallei described here demonstrates that this organism has the potential to exhibit novel behaviours in the CF host, including the development of chronic infection. Further analysis of B. pseudomallei isolates from those CF patients with persisting infection may inform on the key mechanisms contributing to bacterial persistence [ 7]. As a result of this analysis suggest the following recommendations:
1.
Clinicians should have a high index of suspicion for B. pseudomallei infection for CF patients living in or returning from areas where it is endemic. Suspicion should be heightened when fever and or pneumonia occurs. Close liaison with the CF microbiology laboratory is important.
 
2.
Eradication of B. pseudomallei infection should be attempted for CF patients when this pathogen is first isolated.
 
3.
Initial intravenous therapy should include a minimum of two weeks intravenous ceftazidime (and or meropenem if severe sepsis). Consideration should be given to extending the duration of intravenous in those CF patients who are persistently culture-positive on therapy. We also recommend addition of oral/intravenous TMP/SMX from the onset of therapy and this should continue where possible for three months, with regular clinical monitoring for potential adverse effects including renal and hepatic dysfuntion, bone marrow toxicity and potentially life-threatening skin reactions including DRESS syndrome (drug reaction with eosinophilia and systemic symptoms).
 
4.
Travel should be avoided to northern Australia or south-east Asia during the monsoonal season, with particular care to minimise exposure to wet season soils and rain in resident patients [ 20].
 
5.
Person-to-person transmission of B. pseudomallei is generally thought not to occur. However one case of siblings who developed infection with identical strains raises the possibility of cross-infection in CF and should carefully consider the risks and benefits of segregation of patients who have isolated this organism.
 

Acknowledgments

There was no external funding body involved in the design of the study, data collection and analysis, or manuscript preparation. JBG was an employee of Queensland Health, Australia. DWR is an employee of Queensland Health and the recipient of a research fellowship with the Queensland Institute of Medical Research, Australia. BJC is employed by the Northern Territory Department of Health and Families and the Menzies School of Health Research, Australia. SCB is an employee of Queensland Health and the recipient of a research fellowship with the Queensland Institute of Medical Research, Australia.

Collaborators

Writing Committee Members for the MelioidCF Group.
Rowland Bright-Thomas, Manchester Adult Cystic Fibrosis Centre
University Hospital South Manchester 1, University of Manchester Institute of Inflammation and Repair 2.
Jane Dewar, Wolfson Adult Cystic Fibrosis Unit, Nottingham University Hospitals NHS Trust, Nottingham, United Kingdom.
Steve Holden, Department of Clinical Microbiology, Nottingham University Hospitals NHS Trust, Nottingham, United Kingdom.
Nicholas Simmonds Department of Cystic Fibrosis Royal Brompton Hospital/Imperial College London, UK, SW3 6NP.
Khin Gyi, Department of Cystic Fibrosis, Royal Brompton Hospital and Imperial College, London SW3 6NP, United Kingdom.
Dervla Kenna, Antimicrobial Resistance and Healthcare Associated Infections Reference Unit, Public Health, England, London, United Kingdom.
Valerie Waters, Division of Infectious Diseases, Department of Pediatrics, Hospital for Sick Children, University of Toronto, Toronto.
Mary Jackson, Adult CF Clinic St Mary's Hospital, Kitchener, Ontario Canada.
Brian O’Sullivan, Professor of Pediatrics, CF Center Director, Director, Bioethics Core, UMass Medical School, 55 Lake Ave Worcester, MA 01655.
Giovanni Taccetti, Cystic Fibrosis Centre, Department of Paediatric Medicine, Anna Meyer Children’s University Hospital, Florence, Italy.
John Kolbe, Respiratory Services, Auckland City Hospital, New Zealand 1, School of Medicine, Auckland City Hospital, New Zealand 2.
Mark O’Carroll, Respiratory Services, Auckland City Hospital.
Catherine Byrnes Starship Children’s Health, ADHB, Auckland, New Zealand.
Dee Campbell, Clinical Nurse Specialist, Waikato Hospital, Private Bag 3200, Hamilton, New Zealand.
Mirjana Jaksic, Starship Children’s Health, ADHB, Auckland, New Zealand 1, School of Medicine and Health Science, University of Auckland, New Zealand.
Naghmeh Radhakrishna, Allergy, Immunology and Respiratory Medicine, The Alfred Hospital, Melbourne, 3004.
Timothy J. Kidd, Centre for Infection and Immunity, Queen’s University, Belfast, Belfast, Northern Ireland, United Kingdom.
William Flight, Oxford Centre for Respiratory Medicine, Churchill Hospital, Oxford, United Kingdom.
Summary At A Glance: We confirmed that Burkholderia pseudomallei commonly behaves in novel ways in the CF host, frequently establishing chronic infection, which often results in poor long-term outcomes. Eradication should be attempted early where possible, but if unsuccessful, transplantation can be carefully considered despite chronic infection.
Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://​creativecommons.​org/​licenses/​by/​4.​0/​), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://​creativecommons.​org/​publicdomain/​zero/​1.​0/​) applies to the data made available in this article, unless otherwise stated.

Competing interests

All authors declare they have no competing interests.

Authors’ contributions

JBG participated in design of the study, collated clinical data, and drafted the manuscript. DWR participated in the design of the study and edited the manuscript. BJC participated in design of the study, provided clinical data on study subjects, and edited the final manuscript. SCB conceived the study, participated in design of the study, and edited the final manuscript. The Melioid CF Group provided clinical data on study subjects and edited the final manuscript. All authors read and approved the final manuscript.

Authors' information

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Availability of data and materials

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