Cepacia Infection Research Articles

Lung transplantation for cystic fibrosis

To examine recent publications on lung transplantation for cystic fibrosis for changes in surgical techniques, selection criteria of patients, and impact on quality of life. Recent evidence focuses on cystic fibrosis patient subsets enabling better decisions about listing for lung transplantation as a therapeutic option. There is information about Burkholderia cepacia infection, ventilator dependence, young age, and arthropathy. In the US, the United Network for Organ Sharing has addressed perceived inequities in organ distribution by allocating organs by illness severity rather than time on the waiting list. A Lung Allocation Score ranks severity for patients 12 years of age and older for transplantation based on variables including lung function, oxygen and ventilatory needs, diabetes, weight and physical performance. Some recently studied important variables that influence survival in cystic fibrosis and after lung transplantation, including airway infections, pancreatic exocrine function and acute exacerbations, are not included in the Lung Allocation Score. Few publications have examined quality of life after transplantation, and a definitive work has yet to appear. New information has refined decision-making about lung transplantation for patients with cystic fibrosis. We examine recent findings and make recommendations for patients, families and medical providers.

Trasplante pulmonar en la fibrosis quística: complicaciones infecciosas

Lung transplantation is the only treatment for end-stage lung disease in patients with cystic fibrosis (CF). The presence of pathogens in the airways prior to transplantation is a risk factor for infections in the post-transplantation period; in fact, infections account for 80% of deaths within the first year. Our goal was to analyze the incidence of infectious complications in patients who underwent a lung transplantation due to cystic fibrosis. Descriptive transversal study of CF transplanted lung patients since the beginning of the transplantation programme (1991 to September 2004). We evaluated data regarding opportunistic infections, demographical information, lung function, mortality causes and survival. We used descriptive statistics and Kaplan Meier for survival. 267 lung transplants were done, 57 were due to CF, 30 men and 27 women, with an average age of 21 years (7.8 years. The average time on waiting list was 96 days (range 1-407). 57 bilateral lung transplants, 3 heart-lung transplants and one combined liver-lung transplant were performed. All patients received triple immunosuppression (tacrolimus/cyclosporine, azathioprine and prednisone). 16 patients (28%) died: 4 in early postoperative period (7%), 5 at 6 months after transplantation, and the remaining 7 patients died several years post transplantation. Survival was 82% at one year, 76% at three years, and 65% at five years; 75% of our patients survived a mean of 3.56 years. Cytomegalovirus (CMV) infections occurred in 26% of patients and were associated with chronic rejection (p < 0.05). Purulent bronchitis was the most frequent bacterial infection: 59% of cases were caused by multiresistant pathogens. There was a 8.77% cases of B cepacia infection with 2 patients dying because of it. There were 7 cases of airway infection due to Aspergillus fumigatus, and 5 fungal invasive forms that were associated with chronic rejection (p < 0.05). Two cases of tuberculosis (Mycobacterium tuberculosis) were registered, 1 case of M. abcessus lung disease and 1 case of visceral leishmaniosis. Infectious diseases accounted for 19% of early and 12% of late mortality. Although serious infections were seen after transplantation in our series, infectious events did not represent a high risk of postoperative mortality rate. Fungal disease was the only late relevant infectious complication, mainly associated with chronic rejections. Close CMV monitoring, and even pre-emptive antifungal therapy, are recommended for patients with chronic rejection.

Combination aerosol therapy to treatBurkholderia cepaciacomplex: Fig. 1—

Burkholderia cepacia infection in cystic fibrosis (CF) patients is associated with significant morbidity and mortality, yet no definitive treatment is currently available. This report describes a new approach to treat B. cepacia infection in CF patients, using a combination of amiloride and tobramycin aerosols. Four adults with the typical clinical syndrome of CF were recruited after repeated positive sputum cultures for B. cepacia. Aerosols of amiloride and tobramycin were given three times daily for 1-6 months, and repeated sputum cultures were collected to assess efficacy. Three of the four patients treated with the combined therapy eradicated B. cepacia from their sputum cultures for at least 2 yrs, and there were no adverse events. This novel combination may provide a new therapeutic option for Burkholderia cepacia infections. Furthermore, the strategy of combining antibiotics with ion transport agents may have ramifications for the treatment of other multi-resistant organisms.

A National Guard outbreak of Burkholderia Cepacia infection and colonization secondary to intrinsic contamination of Albuterol nebulization solution

Burkholderia cepacia, a gram-negative pathogen, has been a known cause of hospital outbreaks because of a contaminated common source such as multidose medications. We describe an outbreak with Burkholderia cepacia infection in 2 major hospitals affiliated to the National Guard, related to an intrinsic contamination of a locally manufactured, multidose Albuterol nebulization solution (Tabouk Pharmaceutical Company, Tabouk, Saudi Arabia) and we report the interventions taken to interrupt this outbreak.During the outbreak period between May 2003 and March 2004, a combined prospective surveillance and a retrospective chart and microbiologic data review were conducted in 4 major hospitals affiliated to the National Guard. Microbiologic cultures were also performed on environmental objects of concern, as well as certain medications. In addition, a questionnaire was distributed to the respiratory therapy staff to evaluate the process of administering respiratory medications and their adherence to sound infection control practices.An intrinsic contamination of a locally manufactured brand of multidose Albuterol nebulization with B cepacia was identified. Two of the 4 hospitals were found to be involved: hospital A a 700-bed tertiary care center and Hospital B a 150-bed hospital. A total of 2121 patients were exposed to Albuterol nebulization as inpatients at hospital A and 318 as outpatients. For hospital B, a total of 283 inpatients and 34 outpatients were exposed to the Albuterol nebulization. Forty and 12 patients, from hospital A and hospital B, respectively, were found to have at least 1 positive culture for B cepacia. From hospital A, most samples were respiratory, and, from hospital B, most were from blood. Molecular typing of 34 available isolates showed that 23 cases were of a single strain of B cepacia that matched the strain isolated from the 3 different batches of multidose Albuterol nebulization. Three culture-positive patients never received Albuterol nebulization of that brand but were in the same room of a patient who had been receiving the medication.We identified a large outbreak of B cepacia in 2 major hospitals affiliated with the National Guard, linked to an intrinsic contamination of a multidose Albuterol nebulization solution. During the period of prospective surveillance, only a few cases were identified as a result of nosocomial transmission. Immediate notification of the Ministry of Health and withdrawal of the medication and revisiting the respiratory therapy practices were necessary to halt this outbreak.

Use of Lung Transplantation Survival Models to Refine Patient Selection in Cystic Fibrosis

Lung transplantation in cystic fibrosis may improve survival for patients with low 5-year predicted survival. Identifying characteristics that affect post-transplantation survival may improve patient selection and survival benefit. Using Cystic Fibrosis Foundation Patient Registry and United Network for Organ Sharing data, we identified 845 lung transplant recipients from 1991-2001, and 12,826 control patients from 1997. We used Cox proportional hazards models to identify variables that influence post-transplantation survival. To estimate the survival benefit of transplantation for patients affected by identified variables, we compared Kaplan-Meier survival curves of transplanted and control patients stratified by 5-year predicted survival. Post-transplantation survival improved annually. Youth, Burkholderia cepacia, and cystic fibrosis-related arthropathy increased the post-transplantation hazard of death. Compared with control subjects, transplanted adults with a 5-year predicted survival of less than 50% without B. cepacia or arthropathy have improved survival. Transplanted adults with B. cepacia, arthropathy, or a 5-year predicted survival of greater than 50% have decreased survival. Transplantation never improves survivorship for pediatric patients. Patients with arthropathy, B. cepacia infection, or younger age derive no aggregate survival benefit and must appraise carefully the high risk of decreased post-transplantation survival. Adult patients with low 5-year predicted survival without B. cepacia infection should receive priority for lung transplantation.

134 Transient non-genomovar III Burkholderia cepacia infection is not uncommon in adults with cystic fibrosis

134 Transient non-genomovar III Burkholderia cepacia infection is not uncommon in adults with cystic fibrosis

Hemophagocytic Syndrome and Burkholderia cepacia Splenic Microabscesses in a Child With Chronic Granulomatous Disease

Hemophagocytic syndrome, splenic microabscesses and pulmonary cavitary lesions were presented in a 17-month-old boy with prolonged fever, hepatosplenomegaly and a history of tuberculous lymphadenitis. Clinical course mimicked tuberculosis. Blood cultures were negative. Ultrasound-guided, percutaneous aspiration from splenic microabscesses grew Burkholderia cepacia. He was treated successfully with trimethoprim-sulfamethoxazole. This child with chronic granulomatous disease had an unusual clinical manifestation of B. cepacia infection.

Twenty-year experience of lung transplantation at a single center: influence of recipient diagnosis on long-term survival

Objectives The objective of this study was to examine the long-term patient outcomes of lung transplantation in a single center. Methods Between 1983 and 2003, 521 lung transplants were performed in 501 patients. Major indications were cystic fibrosis (n = 124), chronic obstructive pulmonary disease (n = 88), alpha-1 antitrypsin deficiency (n = 63), pulmonary fibrosis (n = 97), primary pulmonary hypertension (n = 35), Eisenmenger syndrome (n = 21), and miscellaneous end-stage lung diseases (n = 93). Results The 5-, 10-, and 15-year survivals for all recipients were 55.1% (95% confidence interval: ±5%), 35.3% (±6%), and 26.5% (±11%), respectively. The most common causes of death were sepsis and bronchiolitis obliterans syndrome. Despite an increased postoperative mortality rate, patients with primary pulmonary hypertension achieved the best long-term survival (10-year survival: 59%). Recipients with cystic fibrosis without Burkholderia cepacia infection achieved significantly better long-term survival (10-year survival: 52%) than those with Burkholderia cepacia infection (10-year survival: 15%). The 10-year survival was also significantly better in recipients with chronic obstructive pulmonary disease (43%) than in recipients with alpha-1 antitrypsin deficiency (23%). Although the incidence of bronchiolitis obliterans syndrome was similar between recipients with chronic obstructive pulmonary disease (39%) and alpha-1 antitrypsin deficiency (46%), recipients with alpha-1 antitrypsin deficiency died of sepsis more frequently than recipients with chronic obstructive pulmonary disease (27% vs 6%, respectively; P = .0003). Conclusions Although bronchiolitis obliterans syndrome and sepsis still limit the durability of the benefit, lung transplantation returns many patients with end-stage lung disease to active and productive lives. Differences in the complications and long-term survival show the important contribution of the recipient diagnosis to the success of lung transplantation.

Control of Burkholderia (Pseudomonas) bacteraemia in the intensive care and paediatric units.

Investigation and control of nosocomial bacteraemia caused by Burkholderia (Pseudomonas) cepacia in the Intensive Care and Paediatric Units of a general care hospital. A cross-sectional analytical study. Departments of Pathology, Intensive Care and Paediatrics, Kahota Research Laboratory Hospital, Islamabad from January 1998 to June 2002. Blood cultures from patients admitted to Intensive Care Unit and Paediatric Ward were inoculated into brain heart infusion broth and incubated for upto 10 days. Any Gram-negative rods isolated were characterized by API-20E. Environmental samples were inoculated on blood and MacConkey's agars and isolates, if any, were identified as above. Intensive intervention in the form of hand washing, strict adherence to aseptic practices and standard sterilization techniques were adopted and then cultures were again carried out with similar methodology. Cultures yielded 58 strains of Burkholderia cepacia, 52 from blood cultures and 6 from hospital environment, including 1 from the washbasin of the ICU. Thirty- four of these were isolated before intervention measures were adopted, mainly during 1998. Findings suggested a strong probability of nosocomial transmission, with washbasin as the common source. After a lapse of about a year, B. cepacia infection re-emerged in a sporadic form but remaining confined to paediatric unit. Only 18 isolates were yielded over the next two and-a-half years. The intervention measures for Burkholderia bacteraemia within the hospital, proved effective in stopping the nosocomial transmission leading to disappearance of B. cepacia from blood cultures. We emphasize the crucial role of hand hygienic practices in the hospital setting, especially in critical care units.

First cases of animal diseases published since 2000. 5. Sheep1

Summary In this fifth article of a series of papers listing first case reports of animal diseases published since 2000, the following five cases of sheep diseases are discussed: - Ependymoma. - Mastitis caused by Burkholderia cepacia infection. - Meningoencephalitis associated with Globicatella sanguinis infection. - Neospora caninum infection in an adult sheep and her twin fetuses. - Plasma cell tumor. After a short introduction, the bibliographical data, the abstract of the author(s), and some additional information derived from the article are given. The article will be regularly updated adding overlooked as well as new first reports.

Épidémie nosocomiale à Burkholderia cepacia dans une unité de réanimation infantile

Backgroung. – We report an outbreak of Burkholderia cepacia respiratory tract infection and colonization in an intensive pediatric care unit. Patients and methods. – Between February and December 1999, B. cepacia was isolated from five children hospitalized in this unit. We reviewed the charts of the patients, evaluated the antiseptics use and the disinfection practices for reusable patient care equipment. An environmental study was conducted and comparison of B. cepacia was performed with genotypic method (RAPD). Results. – All patients were mechanically ventilated and had received large spectrum antibiotics. The disinfection procedure for reusable equipment was not respected and some single-dose of antiseptics solutions were used for several patients. B. cepacia was not found in 34 environmental samples. The RAPD assay revealed that all five isolates had identical DNA profiles. Conclusion. – Despite the investigation the source of the B. cepacia clone in this nosocomial outbreak remained unknown, but antiseptics use and disinfection practices were revised. No new B. cepacia infections were identified after control measures were implemented.

Epidemiologic investigation of Burkholderia cepacia acquisition in two pediatric intensive care units.

To investigate and describe an outbreak of Burkholderia cepacia in a neonatal intensive care unit (NICU) and a pediatric intensive care unit (PICU), and to report the interventions leading to the cessation of the outbreak. We conducted an epidemiologic investigation of an outbreak of B. cepacia colonization or infection in two clinical wards during a 35-month period (December 1998 to October 2001). A 500-bed, university hospital-affiliated, tertiary-care pediatric institution in Paris, France, with a 22-bed PICU and 31-bed NICU. Ribotyping was used to determine the genotypes of B. cepacia isolates. Procedures for the maintenance and disinfection of respiratory therapy devices were reviewed. Thirty-two children were colonized (n = 14) or infected (n = 18) by B. cepacia in 2 wards (28 in the PICU and 4 in the NICU). In the PICU, a single ribotype was found among the isolates obtained from all of the patients except 1, and from the 6 isolates obtained from respiratory therapy devices (ie, heated humidifier water). In the NICU, the isolates obtained from the patients harbored a single ribotype unrelated to that of the epidemic strain isolated in the PICU; no environmental source of infection was found. Two different outbreaks appeared to be associated with 2 ribotypes, 1 of which was linked to patient-to-patient transmission via respiratory therapy devices. Complete elimination of the outbreak was achieved only when disposable, sterilizable, or easy-to-disinfect materials were used in the PICU. The source of infection in the NICU was not found.

Pulmonary transplantation for cystic fibrosis: pre-transplant recipient characteristics in patients dying of peri-operative sepsis

Background: Pulmonary transplantation has emerged as a successful treatment for end-stage cystic fibrosis. Despite the chronic bronchial sepsis and often multi-resistant organisms seen in this group of recipients, death due to post-operative sepsis is relatively scarce. Identifying potential recipient risk factors for poor outcome may further improve the utilization of a scarce donor pool. Methods: We assessed the role of pre-operative clinical measures of sepsis, microbial characteristics and recipient characteristics on post-transplant outcome in 85 cystic fibrosis patients who underwent pulmonary transplantation. Ten percent of patients died in the early post-operative period due to sepsis. The prognostic role of recipient factors including markers of sepsis, such as white cells and C-reactive protein (CRP), and the influence of multi-resistant organisms, in particular organisms from the Burkholderia cepacia complex, on outcomes were investigated. Results: We found no prognostic effect of gender, pre-transplant CRP, forced expiratory volume in 1 second (FEV 1), weight, diabetic status or infection with multi-resistant Pseudomonas organisms. A raised white cell count or temperature or a pre-transplant infection with B cepacia was, however, associated with a significantly poorer prognosis at p = 0.03, 0.03 and 0.001, respectively. Conclusions: Pre-operative B cepacia complex infection, leukocytosis and pyrexia, but not CRP, weight, diabetes or lung function, were found to be associated with poorer post-transplant outcome. The most clinically relevant of these to the subsequent risk of post-operative death from sepsis appear to be B cepacia infection and pyrexia.

Burkholderia cepacia infection and lung transplantation.

Burkholderia cepacia has emerged as an important pathogen in patients with cystic fibrosis (CF) undergoing lung transplantation. Taxonomic analyses have divided B. cepacia into 7 closely related species called genomovars. The prevalence of B. cepacia infection ranges from 2% to 13% in CF patients with genomovar III being most prevalent. Risk factors for the acquisition of B. cepacia include greater severity of underlying CF, increasing age, having a sibling colonized with B. cepacia, and previous hospitalizations. One-year survival in patients with CF undergoing lung transplantation usually have been reported to be less than 70%. The antimicrobial resistance pattern of B. cepacia has correlated with inconsistent effect on survival. Presence of genomovar III also has been linked with survival of B. cepacia-infected patients; the survival rates were inferior for genomovar III as compared with non-genomovar III patients. Standard infection control techniques including isolation of both colonized and noncolonized individuals with frequent sputum culture have been recommended to prevent CF patients from acquiring B. cepacia infection. B. cepacia is inherently resistant to antipseudomonal antibiotics, colistin, and polymyxin. The combination of 2 or more antibiotics usually is recommended for the treatment of B. cepacia infections. Studies delineating the epidemiology and influence of B. cepacia infection on lung transplantation are warranted. This is a US government work. There are no restrictions on its use.

Pharmacokinetics and efficacies of liposomal and conventional formulations of tobramycin after intratracheal administration in rats with pulmonary Burkholderia cepacia infection.

The objective of the present study was to determine the pharmacokinetics and efficacies of liposomal and conventional formulations of tobramycin against Burkholderia cepacia in a model of chronic lung infection. Male Sprague-Dawley rats were inoculated intratracheally with 10(6) CFU of a very resistant strain of B. cepacia (strain BC 1368; MIC, 128 micro g/ml) to establish lung infection. A 1,200- micro g dose of tobramycin was administered intratracheally as a liposomal formulation and as a conventional formulation. Rats were anesthetized and exsanguinated by cardiac puncture at different times over 24 h to assess pulmonary tobramycin concentrations and the number of residual CFU. Pharmacokinetic parameters were calculated by using a two-compartment model with NONMEM. The mean half-life at the beta phase (t(1/2beta)) and the pulmonary exposure (the area under the concentration-time curve [AUC]) of liposomal tobramycin were 19.7 h (coefficient of variation [CV], 24.2%) and 6,811 micro g. h/lungs (CV, 19.7%), respectively. The pharmacokinetics of conventional tobramycin were statistically different, with a t(1/2beta) and AUC of 12.9 h (CV, 31.4%) and 821 micro g. h/lungs (CV, 15.0%), respectively. Pearson chi-square analyses were performed on residual CFU data distributed in the following categories: <10(3), 10(3) to 10(5), and >10(5). Differences in CFU data between formulations showed a statistical trend (P < 0.10) when data from all time points were used, and statistically significant differences were found after 12 h (P < 0.05), with greater eradication achieved with the liposomal formulation. In conclusion, intratracheal administration of tobramycin in liposomes was associated with marked changes in the pharmacokinetics of the drug in the lung and an apparent trend for a prolonged efficacy against B. cepacia. These results support the hypothesis that inhalation of liposomal tobramycin may improve the management of chronic pulmonary infections caused by resistant bacteria in patients with cystic fibrosis.

Preventing Burkholderia cepacia complex infection in cystic fibrosis: Is there a middle ground?

Preventing Burkholderia cepacia complex infection in cystic fibrosis: Is there a middle ground?

Risk factors for Burkholderia cepacia complex colonization and infection among patients with cystic fibrosis

Objectives: To determine risk factors for acquiring Burkholderia cepacia complex among patients with cystic fibrosis (CF). Study design: A case-control study was conducted with active surveillance for B cepacia complex colonization/infection among patients at 21 CF centers from April 1986 to March 1989 (study period). A case-patient was defined as any CF patient with B cepacia complex colonization for the first time during the study period. Control patients were patients with CF not B cepacia complex colonized during the study period. For each patient, a questionnaire was completed semiannually. Results: In multivariate analyses, hospitalization for pulmonary exacerbations, living with a B cepacia complex-positive person, attending a CF summer camp, and direct contact with a B cepacia complex-colonized CF person outside of camp and home were associated with B cepacia complex acquisition. Receiving antimicrobial aerosol therapy or cleaning and drying a home-used nebulizer between uses were associated with a decrease in B cepacia complex acquisition. Conclusions: Numerous factors inside and outside the health care setting are associated with person-to-person transmission of B cepacia complex among patients with CF. Prevention programs should reduce direct or indirect contact between noncolonized and B cepacia complex-colonized/infected patients with CF. (J Pediatr 2002;141:512-7)

Differential persistence among genomovars of the Burkholderia cepacia complex in a murine model of pulmonary infection.

Cystic fibrosis patients infected with strains from different genomovars of the Burkholderia cepacia complex can experience diverse clinical outcomes. To identify genomovar-specific determinants that might be responsible for these differences, we developed a pulmonary model of infection in BALB/c mice. Mice were rendered leukopenic by administration of cyclophosphamide prior to intranasal challenge with 1.6 x 10(4) bacteria. Five of six genomovar II strains persisted at stable numbers in the lungs until day 16 with minimal toxicity, whereas zero of seven genomovar III strains persisted but resulted in variable toxicity. We have developed a chronic pulmonary model of B. cepacia infection which reveals differences among genomovars in terms of clinical infection outcome.

Differential invasion of respiratory epithelial cells by members of the Burkholderia cepacia complex

To investigate whether there are differences between members of the Burkholderia cepacia complex in their ability to invade human respiratory epithelial cells, 11 strains belonging to genomovars I-V were studied in an antibiotic protection assay using the A549 cell line. Strains belonging to genomovars II and III were more invasive than those of genomovars I, IV and V. There was also intra-genomovar variation in invasiveness. No correlation between invasiveness and other putative virulence factors of importance in B. cepacia infection in individuals with cystic fibrosis, cable pilus and B. cepacia epidemic strain marker was identified.

Adherence of Burkholderia cepacia to respiratory tract epithelial cells and inhibition with dextrans

Adherence of Burkholderia cepacia to cells of the respiratory tract of patients with cystic fibrosis (CF) appears to be a necessary precondition for colonization and infection. To date, no effective anti-adhesive strategy has been devised for preventing B. cepacia infection in CF patients. It was found in this study that B. cepacia adhered to respiratory epithelial cells both in vitro and in vivo. However, strains with cable-like pili (Cbl) exhibited the typical clump formation on pneumocytes, whereas non-cable piliated strains predominantly showed single-cell adherence. Dextrans (nominally 4000-10000 Da) significantly inhibited adhesion of B. cepacia to A549 pneumocytes. When compared on an equal weight basis, the nominally 10000 Da dextran was most inhibitory. A dose-dependent inhibitory effect (up to 80 mg ml(-1)) was observed for most strains. Dextran exerted less of an anti-adhesive effect on the two Cbl+ strains than on the others which were Cbl-. Dextrans appeared to block the adherence in a non-specific fashion, as shown by the observations that the inhibitory effect was readily reversible and oligosaccharides composed of 2-4 glucose units with the same alpha-1,6 linkage were not inhibitory. The mean molecular masses of dextrans used in this study, as determined by gel filtration and MS, were approximately 10-fold lower than those indicated by the manufacturers. Our data suggest that dextran of nominal molecular mass 4000 Da at a concentration of 40 mg ml(-1) (10 mM according to manufacturer's quoted molecular mass) or more may be useful in patients with CF to prevent colonization and infection with B. cepacia.