Burkholderia cepacia complex

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MICROBIOLOGY

The taxonomy of Burkholderia (formerly Pseudomonas) cepacia complex currently consists of 18 distinct bacterial species with a wide environmental distribution in soil and plants, especially the underground stem (rhizome) (Table 1) (63, 73) . B. cepaciacomplex species are obligate aerobic gram-negative rods that do not ferment glucose and are catalase positive. The organism can proliferate under conditions of minimal nutrition and can survive in the presence of certain disinfectants.

EPIDEMIOLOGY

Although B. cepacia complex strains are frequently isolated from the natural environment, common environmental species are infrequently associated with human infection. Historically regarded as an organism of low pathogenicity, B. cepacia complex can be transmitted person to person in both healthcare and non-healthcare settings, and both direct and indirect contact with infectious secretions and droplet spread have been implicated in transmission (25, 31, 32, 39, 63). B. cepacia complex can survive for long periods in water or disinfectants, and healthcare-associated outbreaks of B. cepacia complex infection have been linked to contaminated nebulized and intravenous medications and solutions, including compounded and commercially distributed products, skin care products, disinfectants, and to inadequate disinfection of reusable medical devices (20, 47, 49, 58).

B. cepacia complex emerged in the late 1970s as a cystic fibrosis respiratory pathogen, associated with accelerated decline in pulmonary functions and reduced survival, especially among those with more advanced lung disease or who had undergone lung transplantation (16, 19, 34). According to the U.S. Cystic Fibrosis Foundation’s 2012 National Patient Registry, 2.6 percent of all persons with cystic fibrosis were infected with B. cepacia complex compared to 3.1% in 2005 (1). The prevalence increases with age and varies widely between cystic fibrosis centers. In the United States, B. multivorans and B. cenocepacia account for ~70% of patient isolates, and the incidence of new infection with B. multivorans relative to B. cenocepacia has increased in recent years (40). In comparison, in Canada and some European countries, B. cenocepacia is the predominant species. Molecular typing and epidemiologic investigations support person-to-person transmission of B. cepacia complex during hospitalization, while attending ambulatory clinics, and during social gatherings (25, 40, 57). Transmission is facilitated by prolonged close contact between cystic fibrosis patients, sharing of equipment and personal care items, and by bacterial virulence factors. Transmission of B. cepacia complex among cystic fibrosis patients has been reduced in recent years by stringent infection prevention and control efforts, supported by the finding that the majority of new B. cepacia complex infections involve acquisition of unique strains likely from independent environmental sources (63).

CLINICAL MANIFESTATIONS

B. cepacia complex has been associated with both sporadic infections and outbreaks in hospitals and other health-care settings, including device-associated bloodstream infection in immunocompromised patients (45, 47, 56), lower respiratory tract infection, particularly associated with nebulized medications and mechanical ventilation (27, 38, 55), urinary tract infection, neonatal meningitis and brain abscess (29), wound infection, peritonitis, septic arthritis, and ocular infections. B. cepacia complex is an important cause of chronic respiratory infection among persons with cystic fibrosis (40) and of pneumonia, septicemia, and soft tissue abscesses among persons with chronic granulomatous disease (52, 59). Among persons with cystic fibrosis, B. cepacia complex is associated with five clinical syndromes: transient colonization; persistent colonization without clinical deterioration; persistent infection with clinical deterioration similar to that seen with Pseudomonas aeruginosa infection; persistent infection with frequent exacerbations and marked clinical deterioration; and the “cepacia” syndrome with persistently positive blood cultures and death.

LABORATORY DIAGNOSIS

B. cepacia complex grow well on standard laboratory media, and isolation from clinical specimens with mixed respiratory flora is enhanced by use of selective media, such as BCSA, OFPBL and PC agar ). Of these, BCSA agar is the most useful in supporting the growth of B. cepacia complex and suppressing the growth of other organisms. B. cepacia complex isolates are frequently misidentified in the clinical laboratory by conventional manual biochemical or automated testing methods. In contrast, MALDI-ToF instruments can correctly identify most B. cepacia complex isolates to the species level, although 23.1% of isolates were not correctly identified related, in part, to close genetic homology (21) . Confirmation of identification, speciation, and molecular typing of epidemiologically important B. cepacia complex isolates should be performed at a reference laboratory.

PATHOGENESIS

B. cepacia complex form biofilms in vitro and in vivo in the lungs of cystic fibrosis patients, potentially contributing to reduced antimicrobial susceptibility, treatment failure and persistent infection (9, 50) . Compared to MICs for planktonic B. cepacia complex isolates, biofilm inhibitory concentrations are substantially higher for most β-lactam agents (9). Other putative virulence factors, include regulated gene expression by quorum sensing, exopolysaccharide production associated with the mucoid phenotype that promotes evasion of the host response and persistence, and lipopolysaccharide that contributes to immune-mediated tissue damage. There is an inverse correlation between the quantity of mucoid exopolysaccharide production by B. cepacia strains and rate of decline in cystic fibrosis lung function, likely related to increased surface expression of virulence factors in non-mucoid strains (76) . Epidemic transmission of B. cenocepacia strains among both cystic fibrosis and non-cystic fibrosis patients has been associated with two genetic markers, cable pilin subunit (cblA) that promotes respiratory colonization by binding the abnormal cystic fibrosis respiratory mucin (66) and the transcriptional regulator Burkholderia cepacia epidemic strain marker (BCESM) (43). However, the low frequency of both markers suggests that other factors are involved in B. cepacia complex virulence and transmissibility.

The pathogenicity of B. cepacia complex in persons with chronic granulomatous disease appears due to the ability of the organism to resist neutrophil-mediated non-oxidative killing and to induce neutrophil necrosis (8, 59). Clinical isolates from the same B. cepacia complex species display different virulence phenotypes likely related to differential expression of virulence factors that promote intracellular survival. In contrast to chronic B. cepacia complex infection in persons with cystic fibrosis that typically is associated with persistence of a single strain type, recurrent B. cepacia complex infection in persons with chronic granulomatous disease is usually caused by a new strain (26).

SUSCEPTIBILITY IN VITRO AND IN VIVO

Single Drug

B. cepacia complex strains are intrinsically resistant to a wide range of antimicrobial agents, including aminoglycosides, polymyxin, first and second generation cephalosporins, and carboxypenicillins (51, 54) . Antimicrobial agents that are effective against B. cepacia complex in vitro include trimethoprim-sulfamethoxazole, ceftazidime, carbapenems, ureidopenicillins, fluoroquinolones, minocyline, and chloramphenicol. The antibacterial activity of cefoperazone/sulbactam is comparable to that of ceftazidime against B. cepacia complex and both compounds are more active than cefepime or cefaperazone (22). Meropenem and doripenem have greater activity in vitro against B. cepacia complex than imipenem or ertapenam (11, 12, 67). Temocillin, a 6-a-methoxy derivative of ticarcillin, has orphan drug status for the treatment of B. cepacia complex infection in Europe and is more active in vitro than meropenem and ceftazidime (72). Aztreonam is poorly active in vitro against B. cepacia with MIC50 values ranging from 32 mg/mL to128 mg/mL (24, 40). Of fluoroquinolones, clinafloxacin has the greatest activity against susceptible and efflux-mediated multidrug-resistant B. cepacia complex strains (74) . Tigecycline is variably active in vitro due to efflux-mediated resistance and clinical experience is limited (12, 48).

Resistance to β-lactam agents is most commonly mediated by constitutively expressed or inducible chromosomal β lactamases or efflux pumps (68). The variable ability of novel b-lactamase inhibitors to restore the in vitro activity of ceftazidime may be related to the relative prevalence of b lactamase- versus efflux-mediated resistance in clinical B. cepacia complex isolates (50). Less commonly, resistance is due to plasmid-mediated β-lactamases of the TEM class (cephalosporinases) or to alterations in the penicillin-binding proteins that confer piperacillin resistance. Resistance to β-lactam drugs also can be increased in vitro by incubation in 5% CO2, a condition that may mimic the milieu of the cystic fibrosis lung (17).

Emerging resistance to carbapenems and trimethoprim-sulfamethoxazole are of increasing clinical concern, especially among cystic fibrosis patients with B. cepacia complex respiratory infection where only 26% and 5% of over 2600 strains tested were susceptible to these two agents, respectively (75). Carbapenem resistance is conferred metallo-β-lactamses that are particularly effective in hydrolyzing imipenem or to efflux pumps (68). Resistance to trimethoprim is mediated by production of dyhydrofolate reductase or acquisition of outer membrane antibiotic efflux pumps that confer cross resistance to chloramphenicol and fluoroquinolones (7).

Intrinsic resistance of B. cepacia complex strains to aminoglycosides and polymyxin results from decreased site-specific drug binding of these cationic drugs to lipopolysaccharide, reduced outer membrane permeability, and efflux pumps. One specific species,B. vietnamiensis, is susceptible to aminoglycosides but resistant to other polycationic antimicrobials. In cystic fibrosis patients with B. vietnamiensis pulmonary infection, aminoglycoside or azithromycide therapy has been associated with emergence of aminoglycoside resistance via induction of active drug efflux (33). Efflux-mediated tobramycin resistance can potentially be overcome in the lung alveoli by efficient delivery of tobramycin inhalation powder by a podhaler device (21).

B. cepacia complex isolates from patients with cystic fibrosis are generally substantially more resistant than are isolates from non-cystic fibrosis patients, a finding that likely reflects the both prior parenteral, oral, and nebulized antimicrobial exposure and differences in the distribution of the B. cepacia complex species among the patient populations (41). In the few studies that compared B. cepacia complex isolates from cystic fibrosis and non-cystic fibrosis patients, the cystic fibrosis isolates were less susceptible to all antibiotics tested, including carbapenems, ceftazidime, chloramphenicol, fluoroquinolones, piperacillin, and trimethoprim-sulfamethoxazole (37, 65). Meropenem, ceftazidime, minocycline, temocillin, and piperacillin/tazobactam appear to have the greatest activity in vitro against B. cepacia complex isolates from patients with cystic fibrosis (Table 2) (75). Among cystic fibrosis patients, pan-resistant B. cepacia complex isolates are of increasing concern. In a study of 119 multidrug-resistant B. cepacia complex isolates from 59 patients in 17 geographically dispersed cystic fibrosis centers, 50% of the isolates were resistant to all single drug and 8% to all two-drug combinations tested (3). In a larger and more generalizable study of approximately one-third of US cystic fibrosis patients harboring B. cepacia complex, 18% of strains were resistant to all single agents tested (75).

Despite in vitro susceptibility, antimicrobial agents are very ineffective in eradicating chronic B. cepacia complex pulmonary infection from patients with cystic fibrosis (62). This discrepancy between in vitro susceptibility and the clinical response may be due to a variety of factors in cystic fibrosis patients including: altered pharmacokinetics, failure to deliver drug to the bronchiectatic lung, failure to penetrate across the bronchial mucosa in sufficient concentration into abnormally viscous bronchial secretions, high colony counts of organisms (>107 cfu/mL), biofilm resistance, and local factors such as decreased pH and increased concentration of divalent cations that impair phagocytic activity in the lung. Attempts to eradicate new B. cepacia pulmonary infection, typically with a combination of intravenous and nebulized antimicrobials, are increasingly used, particularly at UK adult cystic fibrosis centers (30). These efforts are unsuccessful in the majority of cases, and spontaneous clearance of early infection can also occur, confounding interpretation of early eradication therapy.

Combination Drugs

Because of intrinsic and acquired resistance of B. cepacia complex strains from cystic fibrosis patients, combination antimicrobial susceptibility testing has become widely performed although evidence of clinical efficacy is lacking (3, 75). Typically, broth micro- or macrodilution checkerboard MIC testing has been utilized to identify synergistic and bactericidal antimicrobial combinations against B. cepacia complex strains. Checkerboard MIC testing using two-drug combinations appears to have limited utility in designing treatment regimens for cystic fibrosis patients with multiply-resistant B. cepacia complex (18, 75). Among 2,621 B. cepacia complex isolates from US cystic fibrosis patients, synergy was uncommon (range, 1% to 15% of isolates per two-drug combination) and antagonistic combinations were identified for up to 9% of isolates (75). The use of combinations of e-test strip and breakpoint combination susceptibility testing are simpler and more rapid methods to assess synergy for two-drug combinations against B. cepaciacomplex and have good correlation with but also the same potential clinical limitations as checkerboard MIC testing (46, 70).

Multiple-combination bactericidal testing (MCBT) allows rapid bactericidal determination for up to three drug combinations using 12 antibiotics arranged in 298 total combinations in microtiter trays (2). The triple antimicrobial combination of meropenem, high-dose tobramycin (200 µg/mL, achievable by aerosol administration), and a third antibiotic were bactericidal against 81%-93% of 191 multidrug-resistant B. cepacia complex isolates from cystic fibrosis patients (2). Using this method, antagonism was common (47%) for two drug combinations, especially meropenem-tobramycin, but could be overcome by adding a third drug. Instructions on how to ship bacterial isolates for MCBT can be obtained by emailing cheomcbt@cheo.on.ca. In a more recent report, the three-drug combination of high-dose tobramycin, meropenem, and a third agent—either piperacillin-tazobactam, ceftazidime, trimethoprim-sulfamethoxazole, or amikacin, was active in vitro against half of 47 multidrug-resistant biofilm-grown B. cepacia complex isolates (18,).

ANTIMICROBIAL THERAPY

Drug of Choice

Clinical studies comparing the various agents in the treatment of B. cepacia complex infection are largely limited to uncontrolled case series, especially among patients who do not have cystic fibrosis (4, 38). A recent systematic review of patients with B. cepacia complex infection treated with systemic antimicrobials other than trimethoprim-sulfamethoxazole included 8 cohort studies with 125 patients both with and without cystic fibrosis found that ceftazidime and meropenem were the most effective agents (4). Cure was reported in 77.8% (42/54) of patients receiving ceftazidime [4 studies; monotherapy (33 patients), combination therapy (21 patients)] and 66.7% (11/15) of patients treated with a carbapenem [2 studies; meropenem monotherapy (9 patients); imipenem + ceftazidime (6 patients)]. Given the many methodological limitations of the primary studies, data is insufficient to determine the relative clinical efficacy of these agents or the benefit of combination therapy for serious B. cepaciacomplex infection.

Based upon in vitro susceptibility data, meropenem, ceftazidime, piperacillin, temocillin, and trimethoprim-sulfamethoxazole have the greatest activity against B. cepacia (Table 2). Data from synergy studies and the potential for emergence of resistance while on monotherapy suggest that therapy of serious B. cepacia complex infection should include at least two parenteral antimicrobial agents administered at standard doses. The choice of agents should be guided by results of in vitro susceptibility testing, and the duration of therapy should be based upon assessment clinical and microbiologic response. For serious infection with susceptible strains, a two-drug combination of parenteral trimethoprim-sulfamethoxazole (5 mg/kg trimethoprim component every 6-12 hr) plus a β-lactam (e.g., ceftazidime, piperacillin, meropenem) or a fluoroquinolone should be utilized. For serious infection with trimethoprim-sulfamethoxazole-resistant strains or sulfa drug allergy, combination therapy guided by in vitro susceptibility results should be administered.

Special Situations

Cystic Fibrosis

Each year, approximately 3% of all US patients with cystic fibrosis have B. cepacia isolated from respiratory secretions, almost all of whom are previously colonized with mucoid Pseudomonas aeruginosa (63). Pulmonary infection of cystic fibrosis patients with B. cepacia complex most often results in chronic endobronchial colonization with a large numbers of organisms (107cfu/mL). Despite the low prevalence of B. cepacia complex infection among cystic fibrosis patients, the organism has a major impact on morbidity and mortality (1, 39), especially when associated with epidemic strains that may be enhanced in virulence (34).

Patients with cystic fibrosis experience periodic exacerbations of pulmonary infections that are typically manifested by increased pulmonary symptoms and sputum production and decline in pulmonary function. A 2011 systematic review did not identify any randomized trials of therapies for treating pulmonary exacerbations in cystic fibrosis patient chronically infected with B. cepaciacomplex, concluding that clinicians must continue to assess each patient individually, taking into consideration in vitrosusceptibility results, previous clinical response, and clinical experience (73). Typical therapy for exacerbations associated with B. cepacia complex includes 14-21 days of parenteral therapy with at least two antimicrobials, intensified chest physiotherapy to promote airway clearance, and bronchodilator administration (60). For treatment of pulmonary exacerbations for susceptible strains of B. cepacia complex two-drug therapy is recommended with meropenem (40 mg/kg IV every 8 hours) plus one of the following: tobramycin (10 mg/kg IV once daily) or amikacin (20 mg/kg IV once daily); ceftazidime (50 mg/kg IV every 8 hours; or trimethoprim-sulfamethoxazole (5 mg/kg trimethoprim component every 12 hours) (13).

The clinical impact of combination antimicrobial therapy against B. cepacia complex has been studied most commonly in small, uncontrolled series of cystic fibrosis patients and assessment of clinical response potentially was confounded by co-infection with P. aeruginosa (4). In a prospective open-label study of combination therapy, 14 cystic fibrosis patients with pulmonary exacerbations associated with B. cepacia complex were treated with 14 days of meropenem 40 mg/kg IV up to 2 gm every 8 hours and tobramycin every eight hours (adjusted to achieve a peak >8 mcg/mL and trough <2 mcg/mL) (6). Treatment was associated with a small but significant improvement from baseline in pulmonary function (13% improvement in FEV1% predicted), clinical status, and a mean 1.8 log reduction in sputum bacterial burden. No meropenem resistant B. cepacia complex strains were cultured at the end of treatment compared to 5 of 14 strains resistant to meropenem before therapy. This study emphasizes that antimicrobials to which B. cepacia complex strains are resistant as single agent in vitro may have clinical benefit in treating chronic endobronchial infection when used in combination.

In a large, prospective randomized trial, use of MCBT to guide combination antimicrobial therapy did not result in better clinical and bacteriologic response compared to standard culture and sensitivity testing in a group of 251 patients with routine exacerbations of cystic fibrosis associated with multiply-resistant bacteria, including 21.5% with B. cepacia complex (3). Whether MCBT is of benefit for guiding therapy in the subset of the sickest patients who have failed to improve after a course of empiric antimicrobial therapy cannot be determined from this trial. Despite these findings, based upon the goals of reducing bacterial density, virulence factor production, and airway inflammation and potentially limiting the risk of emergence of resistance on therapy, cystic fibrosis patients with pulmonary exacerbations associated with B. cepacia complex should receive combination therapy. For patients with multidrug- or pan-resistant B. cepacia complex strains, two- or three-drug combination bactericidal therapy should be utilized, especially for severe infections. Drug selection should be guided by MCBT testing to avoid the substantial risk of antagonism with two-drug combinations (2) . Temocillin has been used as salvage therapy for multidrug-resistant B. cepacia infection. In an uncontrolled, retrospective study, combination therapy with temocillin (mean dose 4 gm/day) and an aminoglycoside for 14 days resulted in objective improvement in clinical status and pulmonary functions in 18 (56.2%) of 32 treatment courses administered to 20 cystic fibrosis patients with B. cepacia complex infection (36). However, eight patients died during therapy, including three in whom the strain had become resistant during therapy.

The role of maintenance oral therapy in reducing the incidence of exacerbations of pulmonary infections associated with B. cepacia complex has not been defined. Trimethoprim-sulfamethoxazole (children: 4-5 mg/kg trimethoprim component every 12 hours; adults: 160 mg trimethoprim and 800 mg sulfamethoxazole every 12 hours) has been recommended when oral therapy is used (23, 60). For patients colonized with trimethoprim-sulfamethoxazole-resistant strains, oral minocycline (4 mg/kg initial dose followed by 2 mg/kg twice a day) or doxycycline (5 mg/kg initial dose followed by 2.5 mg/kg twice a day) may have some clinical benefit, but emergence of resistance and toxicity, including dental and skin discoloration, are of concern (35, 59).

Chronic Granulomatous Disease

B. cepacia complex also has emerged as an important cause of infection among patients with chronic granulomatous disease, in part related to the ability of the organism to resist neutrophil-mediated non-oxidative killing (59). Because B. cepacia survives intracellularly, it may be difficult to isolate and to identify early in the course of invasive infection in patients with chronic granulomatous disease. It is important to consider B. cepaciacomplex, especially in cases of culture-negative pneumonia. The initial empiric antimicrobial regimen for with invasive infections in a patient with chronic granulomatous disease should include trimethoprim-sulfamethoxazole (5 mg/kg trimethoprim component every 6 hours) and ceftazidime or a similar agent with broad spectrum antimicrobial activity. Prophylactic antimicrobial therapy benefits patients with chronic granulomatous disease, and oral trimethoprim-sulfamethoxazole (children: 4-5 mg/kg trimethoprim component every 12 hours; adults: 160 mg trimethoprim and 800 mg sulfamethoxazole every 12 hours) is the regimen of choice.

Other Special Situations

Data is limited on the treatment of central nervous system infections with B. cepacia complex, but based upon in vitro susceptibility and pharmacokinetics, meropenem may be a particularly useful agent for this indication. Optimal management of B. cepacia complex infection associated with indwelling medical devices, including central venous catheters and central nervous system shunts, requires removal of the device in addition to directed antimicrobial therapy (53, 56).

B. cepacia complex is often resistant in vitro (MIC >256 mg/mL) to concentrations of tobramycin achieved by nebulization of solution (54). Although high-dose nebulized tobramycin is often synergistic in vitro with one- or two-additional drugs based on MCBT results, evidence of clinical efficacy is lacking (2). Delivery of tobramycin inhalation powder by the podhaler device results very high sputum concentrations (up to 2000 mg/gm), which may overcome some of this resistance (61). A clinical trial of tobramycin inhalational powder in cystic fibrosis patients infected with B. cepacia complex is pending enrollment as of August 2014 (clinicaltrials.gov identifier NCT02212587).

A recent placebo, controlled trial of 24 weeks of continuous nebulized aztreonam for chronic B. cepacia complex pulmonary infection in cystic fibrosis found no benefit in improving pulmonary function tests or other clinical or microbiologic endpoint (69). In addition, at 24 weeks the B. cepacia MIC50 increased 4 fold compared to baseline in the nebulized aztreonam arm but was unchanged in the placebo arm. Although the concomitant use of non-study antibiotics in both arms may have confounded the results, current evidence does not support the use of nebulized aztreonam for prevention or treatment of pulmonary exacerbations associated with B. cepacia complex respiratory infections in cystic fibrosis.

Strategies that alter membrane permeability or decrease drug efflux have been investigated for the potential treatment of B. cepacia complex infection. Nebulized amiloride or verapamil inhibit the B. cepacia multidrug-resistance efflux pump, and both appear to potentiate the effect of tobramycin in vitro (14, 15). However, in two small, uncontrolled series, the continuous use of nebulized amiloride four times daily and nebulized tobramycin twice daily for up to 6 months eradicated B. cepacia complexin only 1 of 29 cystic fibrosis patients with chronic pulmonary infection (5, 71). Fosmidomycin is an antibacterial and antiparasitic agent that inhibits isoprenoid biosynthesis, a precursor to hopanoids that are involved in membrane stability. Although B. cepacia complex are highly resistant to both fosmidomycin and colistin in vitro, fosmidomycin decreased the colistin MIC up to 64-fold to as low as 8 mg/mL in checkerboard MIC assays, a concentration achievable by inhalational therapy (44).

Two recent studies examined the efficacy of B. cenocepacia-specific phage therapy in a mouse model of pulmonary infection. In the first, systemic phage therapy delivered intraperitoneally was more effective than intranasal delivery in reducing pulmonary bacterial density and inflammatory markers (10). In contrast, other investigators found aerosol phage delivery was associated with significant reductions in pulmonary bacterial loads whereas intraperitoneal delivery was not (64). These differences potentially were related to the more widespread and uniform particle delivery to the lungs by aerosolization compared to intranasal administration and to the aspiration of intranasal phage particles into the stomach. Aerosol phage therapy warrants additional study in the treatment of multidrug-resistant B. cepacia complex pulmonary infection.

ENDPOINTS OF THERAPY

Among cystic fibrosis patients, objective response to therapy for exacerbations of pulmonary infection associated with B. cepaciacan be monitored by improved pulmonary functions, decreased inflammatory markers such as white blood count, ESR, and c-reactive protein, and weight gain. Compared to treatment of exacerbations associated with P. aeruginosa, a decrease in of the density of B. cepacia in the sputum is limited, and eradication of chronic endobronchial B. cepacia infection is rarely achieved. Although information about the treatment of pulmonary B. cepacia infection in cystic fibrosis therapy is limited, several conclusions can be drawn: 1) multidrug-resistant strains and frequent in vitro antagonism between agents make empiric therapy problematic; 2) bactericidal, two-or three-drug antimicrobial combinations should be administered with choice of agents guided by a combination susceptibility testing method; and 3) clinical response may be observed in the absence of bacteriologic response.

PREVENTION AND INFECTION CONTROL

Epidemic transmission of B. cepacia complex among persons with cystic fibrosis has most commonly been associated with B. cenocepacia strains, including ET12 (dominant in eastern Canada and the United Kingdom), PHDC (prevalent in the US mid-Atlantic region) and the Midwestern clone (39). Recently, B. delosa strain SLC6 caused a large outbreak of B. cepacia complex infection among pediatric and adult patients at a large US cystic fibrosis care center (34). These epidemic strains may be more transmissible or better adapted to cause human infection and have been associated with poorer clinical outcome (17, 34).

Recommendations to prevent transmission of epidemiologically important pathogens among patients with cystic fibrosis were updated recently (63). In addition to observing contact and standard precautions when caring for a cystic fibrosis patient who is coughing and infected with B. cepacia complex, segregation of patients with B. cepacia complex from other cystic fibrosis patient in inpatient, ambulatory care, and social settings is recommended.

CONTROVERSIES, CAVEATS, AND COMMENTS

Although much has been learned recently about the taxonomy, epidemiology and pathogenicity of B. cepacia complex, particularly among cystic fibrosis patients, further investigation is needed to define differences in pathogenicity, transmissibility, and antimicrobial susceptibility of B. cepacia complex, the relationship between in vitro susceptibility and clinical response to therapy, the role of novel parenteral and inhaled agents and local host factors in treating endobronchial infection, and the optimal selection of agents for two- and three-drug combination therapy. Development of new agents with in vitro and in vivo activity against B. cepacia complex remain an important goal in advancing the management of patients with B. cepacia complex infection.

REFERENCES

1. Cystic Fibrosis Patient Registry, 2012 Annual Data Report Bethesda, MD: Cystic Fibrosis Foundation; 2013.

2. Aaron SD, Ferris W, Henry DA, Speert DP, Macdonald NE. Multiple combination bactericidal antibiotic testing for patients with cystic fibrosis infected with Burkholderia cepacia. American journal of respiratory and critical care medicine 2000;161:1206-12. [PubMed]

3. Aaron SD, Vandemheen KL, Ferris W, Fergusson D, Tullis E, Haase D, Berthiaume Y, Brown N, Wilcox P, Yozghatlian V, Bye P, Bell S, Chan F, Rose B, Jeanneret A, Stephenson A, Noseworthy M, Freitag A, Paterson N, Doucette S, Harbour C, Ruel M, MacDonald N. Combination antibiotic susceptibility testing to treat exacerbations of cystic fibrosis associated with multiresistant bacteria: a randomised, double-blind, controlled clinical trial. Lancet 2005;366:463-71. [PubMed]

4. Avgeri SG, Matthaiou DK, Dimopoulos G, Grammatikos AP, Falagas ME. Therapeutic options for Burkholderia cepacia infections beyond co-trimoxazole: a systematic review of the clinical evidence. International Journal of Antimicrobial Agents 2009;33:394-404. [PubMed]

5. Ball R, Brownlee KG, Duff AJ, Denton M, Conway SP, Lee TW. Can Burkholderia cepacia complex be eradicated with nebulised amiloride and TOBI? J Cyst Fibros 2010;9:73-4. [PubMed]

6. Blumer JL, Saiman L, Konstan MW, Melnick D. The efficacy and safety of meropenem and tobramycin vs ceftazidime and tobramycin in the treatment of acute pulmonary exacerbations in patients with cystic fibrosis. Chest 2005;128:2336-46. [PubMed]

7. Burns JL, Lien DM, Hedin LA. Isolation and characterization of dihydrofolate reductase from trimethoprim-susceptible and trimethoprim-resistant Pseudomonas cepacia. Antimicrob Agents Chemother 1989;33:1247-51. [Pub Med]

8. Bylund J, Campsall PA, Ma RC, Conway BA, Speert DP. Burkholderia cenocepacia induces neutrophil necrosis in chronic granulomatous disease. J Immunol 2005;174:3562-9. [PubMed]

9. Caraher E, Reynolds G, Murphy P, McClean S, Callaghan M. Comparison of antibiotic susceptibility of Burkholderia cepacia complex organisms when grown planktonically or as biofilm in vitro. Eur J Clin Microbiol Infect Dis 2007;26:213-6. [PubMed]

10. Carmody LA, Gill JJ, Summer EJ, Sajjan US, Gonzalez CF, Young RF, LiPuma JJ. Efficacy of bacteriophage therapy in a model of Burkholderia cenocepacia pulmonary infection. J Infect Dis 2010;201:264-71. [PubMed]

11. Chen Y, Garber E, Zhao Q, Ge Y, Wikler MA, Kaniga K, Saiman L. In vitro activity of doripenem (S-4661) against multidrug-resistant gram-negative bacilli isolated from patients with cystic fibrosis. Antimicrob Agents Chemother 2005;49:2510-1.[PubMed]

12. Cheng NC, Hsueh PR, Liu YC, Shyr JM, Huang WK, Teng LJ, Liu CY. In vitro activities of tigecycline, ertapenem, isepamicin, and other antimicrobial agents against clinically isolated organisms in Taiwan. Microb Drug Resist 2005;11:330-41. [PubMed]

13. Chernish RN, Aaron SD. Approach to resistant gram-negative bacterial pulmonary infections in patients with cystic fibrosis. Curr Opin Pulm Med 2003;9:509-15. [PubMed]

14. Cohn RC, Rudzienski L. In vitro suppression of Pseudomonas cepacia after limited exposure to subinhibitory concentrations of amiloride and 5-(N,N-hexamethylene) amiloride. Pediatric Pulmonology 1994;17:366-9. [PubMed]

15. Cohn RC, Rudzienski L, Putnam RW. Verapamil-tobramycin synergy in Pseudomonas cepacia but not Pseudomonas aeruginosa in vitro. Chemotherapy 1995;41:330-3. [PubMed]

16. Corey M, Farewell V. Determinants of mortality from cystic fibrosis in Canada, 1970-1989. Amer J Epidemiol 1996;143:1007-17. [PubMed]

17. Corkill JE, Deveney J, Pratt J, Shears P, Smyth A, Heaf D, Hart CA. Effect of pH and CO2 on in vitro susceptibility of Pseudomonas cepacia to beta-lactams. PediatricRes 1994;35:299-302. [PubMed]

18. Dales L, Ferris W, Vandemheen K, Aaron S. Combination antibiotic susceptibility of biofilm-grown <i>Burkholderia cepacia</i> and <i>Pseudomonas aeruginosa</i> isolated from patients with pulmonary exacerbations of cystic fibrosis. European Journal of Clinical Microbiology & Infectious Diseases 2009;28:1275-9. [PubMed]

19. De Soyza A, McDowell A, Archer L, et al. Burkholderia cepacia complex genomovars and pulmonary transplantation outcomes in patients with cystic fibrosis. Lancet 2001;358:1780-1. [PubMed]

20. Dolan SA, Dowell E, LiPuma JJ, Valdez S, Chan K, James JF. An outbreak of Burkholderia cepacia complex associated with intrinsically contaminated nasal spray. Infect Control Hosp Epidemiol 2011;32:804-10. [PubMed]

21. Fehlberg LC, Andrade LH, Assis DM, Pereira RH, Gales AC, Marques EA. Performance of MALDI-ToF MS for species identification of Burkholderia cepacia complex clinical isolates. Diagnostic microbiology and infectious disease 2013;77:126-8. [PubMed]

22. Fu W, Demei Z, Shi W, Fupin H, Yingyuan Z. The susceptibility of non-fermentative Gram-negative bacilli to cefperazone and sulbactam compared with other antibacterial agents. Int J Antimicrob Agents 2003;22:444-8. [PubMed]

23. Gibson RL, Burns JL, Ramsey BW. Pathophysiology and management of pulmonary infections in cystic fibrosis. American journal of respiratory and critical care medicine 2003;168:918-51. [PubMed]

24. Gibson RL, Retsch-Bogart GZ, Oermann C, Milla C, Pilewski J, Daines C, Ahrens R, Leon K, Cohen M, McNamara S, Callahan TL, Markus R, Burns JL. Microbiology, safety, and pharmacokinetics of aztreonam lysinate for inhalation in patients with cystic fibrosis. Pediatric Pulmonology 2006;41:656-65. [PubMed]

25. 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;342:15-9. [PubMed]

26. Guide SV, Stock F, Gill VJ, Anderson VL, Malech HL, Gallin JI, Holland SM. Reinfection, rather than persistent infection, in patients with chronic granulomatous disease. J Infect Dis 2003;187:845-53. [PubMed]

27. Hamill RJ, Houston ED, Georghiou PR, Wright CE, Koza MA, Cadle RM, Goepfert PA, Lewis DA, Zenon GJ, Clarridge JE. An outbreak of Burkholderia (formerly Pseudomonas) cepacia respiratory tract colonization and infection associated with nebulized albuterol therapy. Ann Intern Med 1995;122:762-6. [PubMed]

28. Henry D, Campbell M, McGimpsey C, Clarke A, Louden L, Burns JL, Roe MH, Vandamme P, Speert D. Comparison of isolation media for recovery of Burkholderia cepacia complex from respiratory secretions of patients with cystic fibrosis. J Clin Microbiol 1999;37:1004-7. [PubMed]

29. Hobson R, Gould I, Govan J. Burkholderia (Pseudomonas) cepacia as a cause of brain abscesses secondary to chronic suppurative otitis media. Eur J Clin Microbiol Infect Dis 1995;14:908-11. [PubMed]

30. Horsley A, Webb K, Bright-Thomas R, Govan J, Jones A. Can early Burkholderia cepacia complex infection in cystic fibrosis be eradicated with antibiotic therapy? Frontiers in cellular and infection microbiology 2011;1:18. [PubMed]

31. 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]

32. Jarvis WR, Olson D, Tablan O, Martone WJ. The epidemiology of nosocomial Pseudomonas cepacia infections: endemic infections. European journal of epidemiology 1987;3:233-6. [PubMed]

33. Jassem AN, Zlosnik JE, Henry DA, Hancock RE, Ernst RK, Speert DP. In vitro susceptibility of Burkholderia vietnamiensis to aminoglycosides. Antimicrob Agents Chemother 2011;55:2256-64. [PubMed]

34. Kalish LA, Waltz DA, Dovey M, Potter-Bynoe G, McAdam AJ, Lipuma JJ, Gerard C, Goldmann D. Impact of Burkholderia dolosa on Lung Function and Survival in Cystic Fibrosis. Am J Respir Crit Care Med 2006;173:421-5. [PubMed]

35. Kurlandsky LE, Fader RC. In vitro activity of minocycline against respiratory pathogens from patients with cystic fibrosis. Pediatric Pulmonology 2000;29:210-2. [PubMed]

36. Lekkas A, Gyi KM, Hodson ME. Temocillin in the treatment of Burkholderia cepacia infection in cystic fibrosis. J Cyst Fibros 2006;5:121-4. [PubMed]

37. Lewin C, Doherty C, Govan J. In vitro activities of meropenem, PD 127391, PD 131628, ceftazidime, chloramphenicol, co-trimoxazole, and ciprofloxacin against Pseudomonas cepacia. Antimicrob Agents Chemother 1993;37:123-5. [PubMed]

38. Liao CH, Chang HT, Lai CC, Huang YT, Hsu MS, Liu CY, Yang CJ, Hsueh PR. Clinical characteristics and outcomes of patients with Burkholderia cepacia bacteremia in an intensive care unit. Diagnostic Microbiol Infect Dis 2011;70:260-6. [PubMed]

39. Lipuma JJ. Update on the Burkholderia cepacia complex. Curr Opin Pulm Med 2005;11:528-33. [PubMed]

40. Lipuma JJ. The changing microbial epidemiology in cystic fibrosis. Clinical Microbiol Rev 2010;23:299-323. [PubMed]

41. LiPuma JJ, Spilker T, Gill LH, Campbell PW, 3rd, Liu L, Mahenthiralingam E. Disproportionate distribution of Burkholderia cepacia complex species and transmissibility markers in cystic fibrosis. Amer J Respir Crit Care Med 2001;164:92-6. [PubMed]

42. Livermore DM, Mushtaq S, Ge Y, Warner M. Activity of cephalosporin CXA-101 (FR264205) against Pseudomonas aeruginosa and Burkholderia cepacia group strains and isolates. International J Antimicrobial Agents 2009;34:402-6. [PubMed]

43. Mahenthiralingam E, Simpson DA, Speert DP. Identification and characterization of a novel DNA marker associated with epidemic Burkholderia cepacia strains recovered from patients with cystic fibrosis. J Clin Microbiol 1997;35:808-16. [PubMed]

44. Malott RJ, Wu CH, Lee TD, Hird TJ, Dalleska NF, Zlosnik JE, Newman DK, Speert DP. Fosmidomycin decreases membrane hopanoids and potentiates the effects of colistin on Burkholderia multivorans clinical isolates. Antimicrob Agents Chemother 2014;58:5211-9. [PubMed]

45. Mann T, Ben-David D, Zlotkin A, Shachar D, Keller N, Toren A, Nagler A, Smollan G, Barzilai A, Rahav G. An outbreak of Burkholderia cenocepacia bacteremia in immunocompromised oncology patients. Infection 2010;38:187-94. [PubMed]

46. Manno G, Ugolotti E, Belli ML, Fenu ML, Romano L, Cruciani M. Use of the E test to assess synergy of antibiotic combinations against isolates of Burkholderia cepacia-complex from patients with cystic fibrosis. Eur J Clin Microbiol Infect Dis 2003;22:28-34. [PubMed]

47. Martone WJ, Tablan OC, Jarvis WR. The epidemiology of nosocomial epidemic Pseudomonas cepacia infections. European journal of epidemiology 1987;3:222-32. [PubMed]

48. Milatovic D, Schmitz FJ, Verhoef J, Fluit AC. Activities of the glycylcycline tigecycline (GAR-936) against 1,924 recent European clinical bacterial isolates. Antimicrob Agents Chemother 2003;47:400-4. [PubMed]

49. Moehring RW, Lewis SS, Isaacs PJ, Schell WA, Thomann WR, Althaus MM, Hazen KC, Dicks KV, Lipuma JJ, Chen LF, Sexton DJ. Outbreak of bacteremia due to Burkholderia contaminans linked to intravenous fentanyl from an institutional compounding pharmacy. JAMA Intern Med 2014;174:606-12. [PubMed]

50. Mushtaq S, Warner M, Livermore DM. In vitro activity of ceftazidime+NXL104 against Pseudomonas aeruginosa and other non-fermenters. J Antimicrob Chemother 2010;65:2376-81. [PubMed]

51. Nzula S, Vandamme P, Govan JR. Influence of taxonomic status on the in vitro antimicrobial susceptibility of the Burkholderia cepacia complex. J Antimicrob Chemother 2002;50:265-9. [PubMed]

52. O'Neil KM, Herman JH, Modlin JF, Moxon ER, Winkelstein JA. Pseudomonas cepacia: an emerging pathogen in chronic granulomatous disease. J Pediatr 1986;108:940-2. [PubMed]

53. Panlilio AL, Beck-Sague CM, Siegel JD, Anderson RL, Yetts SY, Clark NC, Duer PN, Thomasson KA, Vess RW, Hill BC. Infections and pseudoinfections due to povidone-iodine solution contaminated with Pseudomonas cepacia. Clin Infect Dis 1992;14:1078-83. [PubMed]

54. Peeters E, Nelis HJ, Coenye T. In vitro activity of ceftazidime, ciprofloxacin, meropenem, minocycline, tobramycin and trimethoprim/sulfamethoxazole against planktonic and sessile Burkholderia cepacia complex bacteria. J Antimicrob Chemother 2009;64:801-9. [PubMed]

55. Pegues CF, Pegues DA, Ford DS, et al. Burkholderia cepacia respiratory tract acquisition: epidemiology and molecular characterization of a large nosocomial outbreak. Epidemiol Infect 1996;116:309-17. [PubMed]

56. Pegues DA, Carson LA, Anderson RL, Anderson RL, Norgard MJ, Argent TA, Jarvis WR, Woernle CH. Outbreak of Pseudomonas cepacia bacteremia in oncology patients. Clin Infect Dis 1993;16:407-11. [PubMed]

57. Pegues DA, Carson LA, Tablan OC, FitzSimmons SC, Roman SB, Miller JM, Jarvis WR. Acquisition of Pseudomonas cepacia at summer camps for patients with cystic fibrosis. Summer Camp Study Group. J Pediatr 1994;124:694-702. [PubMed]

58. Pegues DA, Schidlow DV, Tablan OC, Carson LA, Clark NC, Jarvis WR. Possible nosocomial transmission of Pseudomonas cepacia in patients with cystic fibrosis. Arch Pediatr Adolesc Med 1994;148:805-12. [PubMed]

59. Porter LA, Goldberg JB. Influence of neutrophil defects on Burkholderia cepacia complex pathogenesis. Frontiers Cellular Infect Microbiol 2011;1:9. [PubMed]

60. Ramsey BW. Management of pulmonary disease in patients with cystic fibrosis. N Engl J Med 1996;335:179-88. [PubMed]

61. Ratjen A, Yau Y, Wettlaufer J, Matukas L, Zlosnik JE, Speert DP, LiPuma J J, Tullis E, Waters V. In vitro efficacy of high dose tobramycin against Burkholderia cepacia complex and Stenotrophomonas maltophilia isolates from cystic fibrosis patients. Antimicrob Agents Chemother 2015;59:711-3. [PubMed]

62. Regan KH, Bhatt J. Eradication therapy for Burkholderia cepacia complex in people with cystic fibrosis. The Cochrane database of systematic reviews 2014;10:CD009876. [PubMed]

63. Saiman L, Siegel JD, LiPuma JJ, et al. Infection prevention and control guideline for cystic fibrosis: 2013 update. Infect Control Hosp Epidemiol 2014;35 Suppl 1:S1-S67. [PubMed]

64. Semler DD, Goudie AD, Finlay WH, Dennis JJ. Aerosol phage therapy efficacy in Burkholderia cepacia complex respiratory infections. Antimicrob Agents Chemother 2014;58:4005-13. [PubMed]

65. Spangler SK, Visalli MA, Jacobs MR, Appelbaum PC. Susceptibilities of non-Pseudomonas aeruginosa gram-negative nonfermentative rods to ciprofloxacin, ofloxacin, levofloxacin, D-ofloxacin, sparfloxacin, ceftazidime, piperacillin, piperacillin-tazobactam, trimethoprim-sulfamethoxazole, and imipenem. Antimicrob Agents Chemother 1996;40:772-5. [PubMed]

66. Sun L, Jiang RZ, Steinbach S, et al. The emergence of a highly transmissible lineage of cbl+ Pseudomonas (Burkholderia) cepacia causing CF centre epidemics in North America and Britain. Nat Med 1995;1:661-6. [PubMed]

67. Traczewski MM, Brown SD. In vitro activity of doripenem against Pseudomonas aeruginosa and Burkholderia cepacia isolates from both cystic fibrosis and non-cystic fibrosis patients. Antimicrob Agents Chemother 2006;50:819-21. [PubMed]

68. Tseng SP, Tsai WC, Liang CY, Lin YS, Huang JW, Chang CY, Tyan YC, Lu PL. The contribution of antibiotic resistance mechanisms in clinical Burkholderia cepacia complex isolates: an emphasis on efflux pump activity. PLoS One 2014;9:e104986. [PubMed]

69. Tullis DE, Burns JL, Retsch-Bogart GZ, Bresnik M, Henig NR, Lewis SA, Lipuma JJ. Inhaled aztreonam for chronic Burkholderia infection in cystic fibrosis: a placebo-controlled trial. J Cyst Fibros 2014;13:296-305. [PubMed]

70. Tunney MM, Scott EM. Use of breakpoint combination sensitivity testing as a simple and convenient method to evaluate the combined effects of ceftazidime and tobramycin on Pseudomonas aeruginosa and Burkholderia cepacia complex isolates in vitro. Journal of microbiological methods 2004;57:107-14. [PubMed]

71. Uluer AZ, Waltz DA, Kalish LA, Adams S, Gerard C, Ericson DA. Inhaled amiloride and tobramycin solutions fail to eradicate Burkholderia dolosa in patients with cystic fibrosis. J Cyst Fibros 2013;12:54-9. [PubMed]

72. Van Acker H, Van Snick E, Nelis HJ, Coenye T. In vitro activity of temocillin against planktonic and sessile Burkholderia cepacia complex bacteria. J Cyst Fibros 2010;9:450-4. [PubMed]

73. Vandamme P, Dawyndt P. Classification and identification of the Burkholderia cepacia complex: Past, present and future. Systematic and applied microbiology 2011;34:87-95. [PubMed]

74. Zhang L, Li XZ, Poole K. Fluoroquinolone susceptibilities of efflux-mediated multidrug-resistant Pseudomonas aeruginosa, Stenotrophomonas maltophilia and Burkholderia cepacia. J Antimicrob Chemother 2001;48:549-52. [PubMed]

75. Zhou J, Chen Y, Tabibi S, Alba L, Garber E, Saiman L. Antimicrobial susceptibility and synergy studies of Burkholderia cepacia complex isolated from patients with cystic fibrosis. Antimicrob Agents Chemother 2007;51:1085-8. [PubMed]

76. Zlosnik JE, Costa PS, Brant R, Mori PY, Hird TJ, Fraenkel MC, Wilcox PG, Davidson AG, Speert DP. Mucoid and nonmucoid Burkholderia cepacia complex bacteria in cystic fibrosis infections. American journal of respiratory and critical care medicine 2011;183:67-72. [PubMed]

Tables

Table 1. Taxonomy and Sources of Isolation of Burkholderia cepacia Complex Species. Adapted from (63,73)

Species	Former genomovar designation	Habitat
B ubonensis		Human (non CF), soil
B. ambifaria	VII	Human (CF and non CF), soil
B. anthina	VIII	Human (CF), turtle, soil, plant, water, industrial contaminant
B. arboris		Human (CF), turtle, soil, water, industrial contaminant
B. cenocepacia	III	Human (CF and non CF), soil, plant, water, industrial contaminant
B. cepacia	I	Human (CF and non CF), soil, plant, water
B. contaminans		Human (CF and non CF), sheep, plant
B. diffusa		Human (CF and non CF), soil
B. delosa	VI	Human (CF), soil, plant
B. lateens		Human (CF)
B. lata		Human (CF and non CF), soil, plant, water, industrial contaminant
B. metallica		Human (CF)
B. multivorans	II	Human (CF and non CF), soil, plant, water
B. pyrrocinia	IX	Human (CF and non CF), soil, water
B. seminalis		Human (CF and non CF), soil, plant
B. stabilis	IV	Human (CF and non CF), plant, hospital contaminant
B. uronensis		Human (non CF), soil
B. vietnamiensis	V	Human (CF and non CF), soil, plant, water, industrial contaminant

CF = cystic fibrosis

Table 2. Summary of Data From Selected Studies of the In Vitro Activity of Selected Antimicrobial Agents for Isolates of B. cepacia Complex from Non-Cystic Fibrosis and Cystic Fibrosis Patients.

			MIC (mg/mL)
Agent	Isolate Source	Number tested	MIC50	MIC90	MIC Range	Ref
Amikacin	Cystic fibrosis	59	128	>256	4->256	(42)
Ceftazidime	Cystic fibrosis	59	2	>256	0.5->256	(42)
	Non-cystic fibrosis	66	8	64	2-128	(68)
	Reference strains*	38	8	32	2->128	(54)
Chloramphenicol	Non-cystic fibrosis	66	16	64	4-128	(68)
Ciprofloxacin	Cystic fibrosis	59	128	>256	8->256	(42)
	Reference strains	38	1	16	<0.25-128	(54)
Colistin	Cystic fibrosis	59	>256	>256	16->256	(42)
Gentamicin	Cystic fibrosis	59	128	>256	4->256	(42)
Imipenem	Cystic fibrosis	59	16	64	<0.25-128	(42)
Levofloxacin	Non-cystic fibrosis	66	2	4	0.25-64	(54)
Meropenem	Cystic fibrosis	59	2	8	<0.25-128	(42)
	Non-cystic fibrosis	66	4	16	1-128	(68)
	Reference strains	38	4	16	0.5-32	(54)
Minocycline	Non-cystic fibrosis	66	1	4	0.5-64	(68)
	Reference strains	38	2	8	<0.25-16	(54)
Piperacillin	Reference strains	38	4	>256	0.5->256	(54)
Ticarcillin-clavulanic acid	Non-cystic fibrosis	66	128/2	>128/2	>128/2	(68)
Tobramycin	Reference strains	38	64	256	2-1024	(54)
Trimethoprim-sulfamethoxazole	Cystic fibrosis	59	<0.5/9.5	4	2/38-32/608	(42)
	Non-cystic fibrosis	66	<0.5/9.5	1/19	<0.5/9.5-4/76	(68)
	Reference strains	38	4/76	32/608	0.25/4.75->128/2432	(54)

*Reference strains of 17 different B. cepacia complex species

What's New

King P, Lomovskaya O, et al. In vitro Pharmacodynamics of Levofloxacin and Other Aerosolized Antibiotics Under Multiple Conditions Relevant to Chronic Pulmonary Infection in Cystic Fibrosis. Antimicrob Agents Chemother. 2010 Jan;54:143-8.

Dales L, et al. Combination Antibiotic Susceptibility of Biofilm-grown Burkholderia cepacia and Pseudomonas aeruginosa Isolated from Patients with Pulmonary Exacerbations of Cystic Fibrosis. Eur J Clin Microbiol Infect Dis 2009;28:1275-1279.

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