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Burkholderia pseudomallei Infection in a Child With Cystic FibrosisBurkholderia pseudomallei in Cystic Fibrosis: Acquisition in the Western Hemisphere FREE TO VIEW

Brian P. O’Sullivan, MD; Brenda Torres, BS; Giuseppe Conidi, MPH; Sandra Smole, PhD; Cheryl Gauthier, MA; Kendra E. Stauffer, DVM; Mindy B. Glass, BS; Jay E. Gee, PhD; David Blaney, MD, MPH; Theresa L. Smith, MD, MPH
Author and Funding Information

From the Department of Pediatrics (Dr O’Sullivan), University of Massachusetts Medical School and UMass Memorial Health Care; and the Department of Laboratory Sciences (Ms Torres), UMass Memorial Health Care, Worcester, MA; the Division of Epidemiology and Immunization, Bureau of Infectious Diseases (Mr Conidi), and the Bureau of Laboratory Sciences, William A. Hinton State Laboratory Institute (Dr Smole and Ms Gauthier), Massachusetts Department of Public Health, Jamaica Plain, MA; the US Department of Agriculture, Animal Plant Health Inspection Service/Veterinary Service (Dr Stauffer), Gainesville, FL; and the Bacterial Special Pathogens Branch (Ms Glass and Drs Gee, Blaney, and Smith), Division of High-Consequence Pathogens and Pathology, National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, GA.Some of the authors are employees of the US Government, and this work was prepared as part of their official duties.

Correspondence to: Brian P. O’Sullivan, MD, Department of Pediatrics, UMass Memorial Health Care, 55 Lake Ave, Worcester, MA 01655; e-mail: osullivb@ummhc.org


Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml).


© 2011 American College of Chest Physicians


Chest. 2011;140(1):239-242. doi:10.1378/chest.10-3336
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Melioidosis, an infection caused by the bacterium Burkholderia pseudomallei, is endemic to Southeast Asia and northern Australia but is only very rarely seen in patients in the United States. We report pulmonary B pseudomallei infection in a young girl with cystic fibrosis (CF) who had never traveled to Asia or Australia. Biochemical and epidemiologic investigation determined Aruba as the likely site of disease acquisition. This report highlights the ability of patients with CF to acquire this organism outside of Southeast Asia and describes an aggressive treatment regimen that has kept this patient culture-negative for the organism over a long period of time.

Figures in this Article

Patients with cystic fibrosis (CF) have chronic airways infection due to abnormalities in airway hydration, mucociliary clearance, and innate immunity.1 Many organisms are opportunistic infectious agents in patients with CF, including members of the Burkholderia cepacia complex (Bcc). Bcc infection can lead to an acute, severe deterioration in lung function and even to overwhelming sepsis.2

Melioidosis is a disease caused by infection with Burkholderia pseudomallei, a human and animal pathogen endemic to tropical areas, which is distinct from but closely related to Bcc.3,4 Melioidosis is an exceedingly rare disease outside of the endemic areas of Southeast Asia and northern Australia. Despite its relatedness, B pseudomallei infection is not commonly seen in patients with CF, presumably because there is little overlap between the geographic distribution of the pathogen and CF prevalence.1,3 Although not a common occurrence, B pseudomallei infection has been reported in patients with CF who have spent time in Southeast Asia and northern Australia.5-8 We report a case of pulmonary B pseudomallei infection in a young patient with CF who has never been to Asia or Australia but who does have a travel history to tropical islands in the Americas.

In March 2009, a 7-year-old female patient with CF presented with a history of increased cough, increased sputum production, and fever for 5 days. Auscultation of the chest revealed new crackles throughout her left lung. An oropharyngeal culture was obtained, from which the microbiology laboratory results showed growth of a gram-negative organism on oxidation-fermentation-polymyxin-bacitracin-lactose medium. Subculture on selective media led to a presumptive identification of B pseudomallei on a VITEK 2 (bioMérieux; Durham, North Carolina) automated instrument. Additional oropharyngeal and induced sputum samples were obtained on March 31, 2009, and April 1, 2009, respectively, and each grew organisms identified as B pseudomallei by VITEK 2. BAL was not considered necessary at this time because of three positive throat and sputum cultures and new findings on auscultation. The bacterium was susceptible to imipenem, ceftazidime, and doxycycline. The original isolate was categorized as resistant to trimethoprim/sulfamethoxazole (TMP/SMX) with a minimal inhibitory concentration (MIC) of 4/76. Subsequently this isolate was reported as sensitive by the US Centers for Disease Control and Prevention (CDC) (MIC, 2/38).

An extensive travel and exposure history was obtained. The family had never traveled to Australia or Southeast Asia, but had vacationed in Puerto Rico in 2003, northern Portugal in 2005, and Aruba, off the coast of Venezuela, several times, most recently 3 months prior to isolation of B pseudomallei from this patient. It rained the entire week of this visit; however, the patient stayed on the resort property and did not explore wet, muddy areas. No other family member reported fever, cough, or other signs of localized or systemic infection.

A chest radiograph obtained at the time of the positive sputum culture demonstrated a new infiltrate in the left lower lobe (Fig 1). The patient was admitted to the hospital and treated with imipenem and ceftazidime IV for 14 days. The crackles in the left chest persisted throughout the hospitalization, although the patient did not appear ill and was afebrile. Abdominal ultrasonography results were normal with no evidence of splenic or hepatic abscess. She was discharged to home on a regimen of oral TMP/SMX (160 mg trimethoprim, 800 mg sulfamethoxazole bid) and inhaled meropenem (500 mg IV solution bid via nebulizer). The patient was treated with inhaled meropenem for a total of 28 days and has remained on oral TMP/SMX continuously since that time. Subsequent sputum and throat cultures were negative for B pseudomallei (Fig 2). Therefore, BAL was performed 4 months after completion of IV antimicrobial agents and 3 months after finishing inhaled meropenem to assess possible eradication of the organisms. Multiple BAL samples from the left lower lobe, lingula, and right middle lobe were negative for B pseudomallei. Analysis of the lavage fluid showed inflammatory changes consistent with CF. At a visit 12 months after the discovery of B pseudomallei, the left lower lobe crackles were decreased and cultures of respiratory secretions remained negative for B pseudomallei.

Figure Jump LinkFigure 1. Chest radiograph at the time of admission demonstrates patchy opacity at the left-sided heart border (arrow), which was not present on previous radiographs. A repeat study 2 weeks later showed no change in the infiltrate.Grahic Jump Location
Figure Jump LinkFigure 2. Timeline of cultures and therapy. Three specimens (one oropharyngeal and two sputa) were positive for Burkholderia pseudomallei prior to institution of therapy. Numerous throat, sputum, and BAL cultures have been negative for B pseudomallei since starting antimicrobial therapy. + = culture positive for B pseudomallei; − = culture negative for B pseudomallei; inh = inhaled; IV abx = period of time treated in-hospital with IV antimicrobial agents; OP = oropharyngeal culture; TMP/SMX = trimethoprim/sulfamethoxazole; tsp = teaspoonfuls.Grahic Jump Location

The original patient isolate was sent to the Massachusetts Public Health Laboratory, where it was tested using real-time detection polymerase chain reaction and culture. The isolate was polymerase chain reaction-positive by four of four genetic markers specific for B pseudomallei and forwarded by the Massachusetts Public Health Laboratory to the CDC for biochemical characterization, antimicrobial susceptibility testing, and multilocus sequence typing (MLST). The organism was confirmed as B pseudomallei by biochemical testing and genetically characterized by MLST and eBURST (electronic based upon related sequence types) analysis.9,10 The MLST sequence type (ST 698) most closely matched that of a Venezuelan strain (ST 12) in the B pseudomallei MLST database (http://bpseudomallei.mlst.net/) with six alleles out of seven identical and the seventh allele (ndh) differing by only one nucleotide. This is a new ST number; the isolate is archived at CDC.

B pseudomallei lives in soil and ground water; human infection is most common during the rainy season when it is leached from the soil and can be aerosolized by heavy winds, causing infection by cutaneous inoculation or inhalation.4,11 It can live in low-nutrient environments or within human cells for years before causing disease.11,12 When disease does occur, sepsis, pneumonia, joint infection, and splenic or hepatic abscesses may be seen. Melioidosis is more common in patients with underlying health problems, such as diabetes mellitus, a common comorbidity of CF but one that this patient did not have.

B pseudomallei is endemic to Southeast Asia and northern Australia and is responsible for a large proportion of community-acquired pneumonia, sepsis, and sepsis-related mortality, particularly in Thailand.4,12 With the exception of imported cases, B pseudomallei infection has generally been reported in tropical areas between latitudes 20°N and 20°S, but it is not exclusively limited to Southeast Asia and northern Australia. The organism has been found in Africa and Central and South America,3,13,14 and an epizootic outbreak of B pseudomallei was reported in sheep, goats, and pigs on Aruba in 1957.15 Biochemical testing and MLST of this patient’s original throat culture isolate confirmed its identity and demonstrated that it had close homology (six alleles matching out of seven) to a clinical isolate from Venezuela. The Venezuelan strain (ST 12) also differs by a single locus from strains from Thailand, Ecuador, and Puerto Rico.

It is most likely that this patient acquired her infection while in Aruba, which at its closest point is no more than 20 miles from Venezuela. Her presumed acquisition of B pseudomallei during a rainy period is consistent with the epidemiology of this disease. Unfortunately, no isolates from Aruba were available for comparison. Currently, the B pseudomallei MLST database is heavily weighted by strains from Thailand and Australia and, therefore, lacks sufficient representative data from Western Hemisphere isolates to fully interpret the relatedness of this CF isolate. Genetic characterization of additional Western Hemisphere isolates will enhance knowledge of the geographic distribution of B pseudomallei. Of note, B pseudomallei infection has been reported in a patient with CF who never traveled outside of Brazil.16

It is not surprising that patients with CF could become infected with an organism such as B pseudomallei if exposed to it, given their susceptibility to other unusual pathogens.1 Infection with this organism can be extremely difficult to treat because of its inherent resistance to multiple antimicrobial agents, including aminoglycosides. The treatment regimen we chose was somewhat unconventional. Ceftazidime has been shown to lower mortality in melioidosis,3 but carbapenems, such as imipenem and meropenem, have even lower MICs than ceftazidime and have been shown to be superior in time-kill studies in vitro.17 Given the known morbidity and mortality of infection with the related Bcc in patients with CF, and that multidrug antibiotic therapy is routine for patients with CF with pulmonary exacerbations, we opted to use an aggressive combination of IV ceftazidime and imipenem for short-term management. Because of this patient’s underlying lung disease and persistent crackles even after 2 weeks of IV therapy, we decided to use a “consolidation phase” combining the typical eradication agent TMP/SMX with inhaled meropenem, an agent known to have very good anti-B pseudomallei activity. Administering IV antimicrobial agents via the inhaled route is not unusual in CF care, and we believed we could achieve good airway concentrations of this agent without risking undue systemic side effects.

Repeated oropharyngeal and sputum cultures have been negative for B pseudomallei. Unfortunately, despite a very high specificity, the sensitivity of oropharyngeal cultures is only 79% for patients with sputum-positive B pseudomallei infection.18 Therefore, BAL was performed 5 months and 18 months after the initial isolation of the organism. All BAL specimens were negative for B pseudomallei. We have continued TMP/SMX therapy beyond the usual eradication phase because eradication of other pulmonary pathogens in CF (eg, Pseudomonas aeruginosa, Bcc) is almost impossible once infection is well established, the child continues to have lung findings not present before the initial positive culture, and the organism is known to be able to lie dormant in cells for years. However, eradication of Pseudomonas and Bcc can be achieved in CF with early, aggressive therapy; therefore, if this patient remains culture-negative at 2 years from her last positive culture we will discontinue TMP/SMX and observe her closely with frequent airway cultures.

Patients with CF and their caregivers need to be aware of the risk of acquiring this organism from areas outside of Southeast Asia and the need to culture for it in order to make an accurate diagnosis of melioidosis. Identification of antimicrobial susceptibility and aggressive, multimodal therapy with appropriate agents can keep infection quiescent and may be able to eradicate the organism from the airways.

Bcc

Burkholderia cepacia complex

CDC

US Centers for Disease Control and Prevention

CF

cystic fibrosis

MIC

minimum inhibitory concentration

MLST

multilocus sequence typing

TMP/SMX

trimethoprim/sulfamethoxazole

Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Other contributions: We thank David Lonsway, MMedSci, for performing antimicrobial susceptibility testing.

Additional information: The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention/the Agency for Toxic Substances and Disease Registry. Names of vendors or manufacturers are provided as examples of available product sources; inclusion does not imply endorsement of the vendors, manufacturers, or products by the US Government. Burkholderia pseudomallei is a select agent and its possession, use, and transfer is regulated by the US Department of Health and Human Services, Centers for Disease Control and Prevention, and the US Department of Agriculture, Animal, and Plant Health Inspection Service. The select agent regulations have mandatory reporting requirements for identification of select agents in diagnostic specimens.

O’Sullivan BP, Freedman SD. Cystic fibrosis. Lancet. 2009;3739678:1891-1904. [CrossRef] [PubMed]
 
Lipuma JJ. Update on the Burkholderia cepacia complex. Curr Opin Pulm Med. 2005;116:528-533. [CrossRef] [PubMed]
 
Cheng AC, Currie BJ. Melioidosis: epidemiology, pathophysiology, and management [published correction appears inClin Microbiol Rev. 2007;20(3):533]. Clin Microbiol Rev. 2005;182:383-416. [CrossRef] [PubMed]
 
Wiersinga WJ, van der Poll T, White NJ, Day NP, Peacock SJ. Melioidosis: insights into the pathogenicity ofBurkholderia pseudomalleiNat Rev Microbiol. 2006;44:272-282. [CrossRef] [PubMed]
 
Visca P, Cazzola G, Petrucca A, Braggion C. Travel-associatedBurkholderia pseudomallei infection(Melioidosis) in a patient with cystic fibrosis: a case report. Clin Infect Dis. 2001;321:E15-E16. [CrossRef] [PubMed]
 
Holland DJ, Wesley A, Drinkovic D, Currie BJ. Cystic fibrosis andBurkholderia pseudomalleiinfection: an emerging problem? Clin Infect Dis. 2002;3512:e138-e140. [CrossRef] [PubMed]
 
O’Carroll MR, Kidd TJ, Coulter C, et al. Burkholderia pseudomallei: another emerging pathogen in cystic fibrosis. Thorax. 2003;5812:1087-1091. [CrossRef] [PubMed]
 
Schülin T, Steinmetz I. Chronic melioidosis in a patient with cystic fibrosis. J Clin Microbiol. 2001;394:1676-1677. [CrossRef] [PubMed]
 
Godoy D, Randle G, Simpson AJ, et al. Multilocus sequence typing and evolutionary relationships among the causative agents of melioidosis and glanders,Burkholderia pseudomalleiandBurkholderia malleiJ Clin Microbiol. 2003;415:2068-2079. [CrossRef] [PubMed]
 
Feil EJ, Li BC, Aanensen DM, Hanage WP, Spratt BG. eBURST: inferring patterns of evolutionary descent among clusters of related bacterial genotypes from multilocus sequence typing data. J Bacteriol. 2004;1865:1518-1530. [CrossRef] [PubMed]
 
Adler NR, Govan B, Cullinane M, Harper M, Adler B, Boyce JD. The molecular and cellular basis of pathogenesis in melioidosis: how doesBurkholderia pseudomalleicause disease? FEMS Microbiol Rev. 2009;336:1079-1099. [CrossRef] [PubMed]
 
Aldhous P. Tropical medicine: melioidosis? Never heard of it. Nature. 2005;4347034:692-693. [CrossRef] [PubMed]
 
Dance DA. Melioidosis: the tip of the iceberg? Clin Microbiol Rev. 1991;41:52-60. [PubMed]
 
Inglis TJJ, Rolim DB, Sousa AdeQ. Melioidosis in the Americas. Am J Trop Med Hyg. 2006;755:947-954. [PubMed]
 
Sutmoller P, Kraneveld FC, Van Der Schaaf A. Melioidosis (Pseudomalleus) in sheep, goats, and pigs on Aruba (Netherland Antilles). J Am Vet Med Assoc. 1957;1309:415-417. [PubMed]
 
Barth AL, de Abreu E Silva FA, Hoffmann A, et al. Cystic fibrosis patient withBurkholderia pseudomalleiinfection acquired in Brazil. J Clin Microbiol. 2007;4512:4077-4080. [CrossRef] [PubMed]
 
Currie BJ. Melioidosis: an Australian perspective of an emerging infectious disease. Rec Advan Microbiol. 2000;8:1-75
 
Wuthiekanun V, Suputtamongkol Y, Simpson AJH, Kanaphun P, White NJ. Value of throat swab in diagnosis of melioidosis. J Clin Microbiol. 2001;3910:3801-3802. [CrossRef] [PubMed]
 

Figures

Figure Jump LinkFigure 1. Chest radiograph at the time of admission demonstrates patchy opacity at the left-sided heart border (arrow), which was not present on previous radiographs. A repeat study 2 weeks later showed no change in the infiltrate.Grahic Jump Location
Figure Jump LinkFigure 2. Timeline of cultures and therapy. Three specimens (one oropharyngeal and two sputa) were positive for Burkholderia pseudomallei prior to institution of therapy. Numerous throat, sputum, and BAL cultures have been negative for B pseudomallei since starting antimicrobial therapy. + = culture positive for B pseudomallei; − = culture negative for B pseudomallei; inh = inhaled; IV abx = period of time treated in-hospital with IV antimicrobial agents; OP = oropharyngeal culture; TMP/SMX = trimethoprim/sulfamethoxazole; tsp = teaspoonfuls.Grahic Jump Location

Tables

References

O’Sullivan BP, Freedman SD. Cystic fibrosis. Lancet. 2009;3739678:1891-1904. [CrossRef] [PubMed]
 
Lipuma JJ. Update on the Burkholderia cepacia complex. Curr Opin Pulm Med. 2005;116:528-533. [CrossRef] [PubMed]
 
Cheng AC, Currie BJ. Melioidosis: epidemiology, pathophysiology, and management [published correction appears inClin Microbiol Rev. 2007;20(3):533]. Clin Microbiol Rev. 2005;182:383-416. [CrossRef] [PubMed]
 
Wiersinga WJ, van der Poll T, White NJ, Day NP, Peacock SJ. Melioidosis: insights into the pathogenicity ofBurkholderia pseudomalleiNat Rev Microbiol. 2006;44:272-282. [CrossRef] [PubMed]
 
Visca P, Cazzola G, Petrucca A, Braggion C. Travel-associatedBurkholderia pseudomallei infection(Melioidosis) in a patient with cystic fibrosis: a case report. Clin Infect Dis. 2001;321:E15-E16. [CrossRef] [PubMed]
 
Holland DJ, Wesley A, Drinkovic D, Currie BJ. Cystic fibrosis andBurkholderia pseudomalleiinfection: an emerging problem? Clin Infect Dis. 2002;3512:e138-e140. [CrossRef] [PubMed]
 
O’Carroll MR, Kidd TJ, Coulter C, et al. Burkholderia pseudomallei: another emerging pathogen in cystic fibrosis. Thorax. 2003;5812:1087-1091. [CrossRef] [PubMed]
 
Schülin T, Steinmetz I. Chronic melioidosis in a patient with cystic fibrosis. J Clin Microbiol. 2001;394:1676-1677. [CrossRef] [PubMed]
 
Godoy D, Randle G, Simpson AJ, et al. Multilocus sequence typing and evolutionary relationships among the causative agents of melioidosis and glanders,Burkholderia pseudomalleiandBurkholderia malleiJ Clin Microbiol. 2003;415:2068-2079. [CrossRef] [PubMed]
 
Feil EJ, Li BC, Aanensen DM, Hanage WP, Spratt BG. eBURST: inferring patterns of evolutionary descent among clusters of related bacterial genotypes from multilocus sequence typing data. J Bacteriol. 2004;1865:1518-1530. [CrossRef] [PubMed]
 
Adler NR, Govan B, Cullinane M, Harper M, Adler B, Boyce JD. The molecular and cellular basis of pathogenesis in melioidosis: how doesBurkholderia pseudomalleicause disease? FEMS Microbiol Rev. 2009;336:1079-1099. [CrossRef] [PubMed]
 
Aldhous P. Tropical medicine: melioidosis? Never heard of it. Nature. 2005;4347034:692-693. [CrossRef] [PubMed]
 
Dance DA. Melioidosis: the tip of the iceberg? Clin Microbiol Rev. 1991;41:52-60. [PubMed]
 
Inglis TJJ, Rolim DB, Sousa AdeQ. Melioidosis in the Americas. Am J Trop Med Hyg. 2006;755:947-954. [PubMed]
 
Sutmoller P, Kraneveld FC, Van Der Schaaf A. Melioidosis (Pseudomalleus) in sheep, goats, and pigs on Aruba (Netherland Antilles). J Am Vet Med Assoc. 1957;1309:415-417. [PubMed]
 
Barth AL, de Abreu E Silva FA, Hoffmann A, et al. Cystic fibrosis patient withBurkholderia pseudomalleiinfection acquired in Brazil. J Clin Microbiol. 2007;4512:4077-4080. [CrossRef] [PubMed]
 
Currie BJ. Melioidosis: an Australian perspective of an emerging infectious disease. Rec Advan Microbiol. 2000;8:1-75
 
Wuthiekanun V, Suputtamongkol Y, Simpson AJH, Kanaphun P, White NJ. Value of throat swab in diagnosis of melioidosis. J Clin Microbiol. 2001;3910:3801-3802. [CrossRef] [PubMed]
 
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