Burkholderia cepacia in cystic fibrosis children and adolescents: overall survival and immune alterations.

Background: In current literature there are only scarce data on the host inflammatory response during Burkholderia cepacia complex (Bcc) persistence. The primary objective of the present research was to carry out cross-sectional analyses of biomarkers and evaluate disease progression in cystic fibrosis (CF) patients with chronic Bcc infection and pathogen-free ones. The secondary aim was to assess prospectively overall survival of the study participants during up to 8 years of follow-up. Methods: The study included 116 paediatric patients with CF; 47 CF patients were chronically infected with Bcc, and 69 individuals were Bcc free. Plasma and sputum biomarkers (neutrophil elastase, MMP-8, MMP-9, MMP-12, IL-2, IL-4, IL-6, IL-8, IL-10, IL-18, IL-22, IL-23, IL-17, IFN-γ, TGFß1, TNF-α) were analysed using commercially available kits. Besides, inhibitory effect of dexamethasone on proliferative response of PHA-stimulated peripheral blood lymphocytes had been assessed. Results: Bcc infected patients did not differ from Bcc free ones in demographic and clinical parameters, but demonstrated an increased rate of glucose metabolism disturbances and survival disadvantage during prolong follow-up period. Biomarkers analyses revealed elevated TNF-α and reduced IL-17F levels in sputum samples of Bcc infected patients. These patients also demonstrated improvement of peripheral blood lymphocyte sensitivity to steroid treatment and reduction in plasma pro-inflammatory (IL-17F and IL-18) and anti-inflammatory (TGFß1 and IL-10) cytokine concentrations. Conclusions: Reduction in IL-17F levels may have several important consequences including increase in steroid sensitivity and glycemic control disturbances. Further investigations are needed to clarify the role of IL-17 cytokines in CF complication development. Low plasma TGFß1 and IL-10 levels in Bcc infected group may be a sign of subverted activity of regulatory T cells. Such immune alterations may be one of the factors contributing to the development of the cepacia syndrome.

Mortalidad en niños con bacteriemia por Burkholderia cepacia: una revisión sistemática / Mortality in children with bacteremia due to Burkholderia cepacia: a systematic review

INTRODUCCIÓN: En los niños, la bacteriemia debida a Burkholderia cepacia, es considerada una complicación grave y conducente a una elevada mortalidad. Con el objetivo de conocer la mortalidad asociada a esa condición, se realizó una revisión sistemática de la literatura médica. MATERIAL Y MÉTODOS: Se aplicó una estrategia de búsqueda bibliográfica con las palabras claves: "bacteriemia por B. cepacia", "humanos", "niños" y "adolescentes", como únicos filtros. Se informan la mediana y los valores intercuartílicos de la frecuencia de la mortalidad reportada por los estudios incluidos. RESULTADOS: Se identificaron 92 estudios potencialmente útiles. De ellos, se descartaron 81, incluyéndose finalmente, 11 estudios. Se trató de descripciones retrospectivas de casos, salvo uno de ellos, que respondió a un diseño analítico caso-control. La mediana de la mortalidad reportada por esta revisión, fue 0 (Q25 = 0 y Q75 = 28,57%). INTERPRETACIÓN: Si bien la evidencia disponible es escasa y de baja calidad, sugiere que el curso clínico de esta afección no siempre resulta en una elevada mortalidad.

BACKGROUND: Bacteremia due to Burkolderia cepacia in children is considered a severe complication and associated with high mortality incidence. In order to know the level of mortality associated with it, this systematic review of the literature was carried out. METHODS: A search strategy was carried out with the keywords: "bacteremia by B cepacia and human" and "children" and "adolescents" as filters. Global frequency of mortality reported by the included studies was calculated and informed as median (Q2) and its interquartile values (Q1 and Q3). RESULTS: The search identified 92 potentially useful studies. Of these, 81 were discarded, and then remained 11 studies to be included. One out of 11 studies is an analytic case-control design. Rest are retrospective case series. Related mortality median was 0 (Q25 = 0 and Q75 = 28,57%). CONCLUSION: Although the available evidence is scarce and of low quality, it suggests that clinical course of this condition does not always lead to high mortality rates.

Prevalence, Etiology, and Outcome of Sepsis among Critically Ill Patients in Malawi.

There are scarce data describing the etiology and clinical sequelae of sepsis in low- and middle-income countries (LMICs). This study describes the prevalence and etiology of sepsis among critically ill patients at a referral hospital in Malawi. We conducted an observational prospective cohort study of adults admitted to the intensive care unit or high-dependency unit (HDU) from January 29, 2018 to March 15, 2018. We stratified the cohort based on the prevalence of sepsis as defined in the following three ways: quick sequential organ failure assessment (qSOFA) score ≥ 2, clinical suspicion of systemic infection, and qSOFA score ≥ 2 plus suspected systemic infection. We measured clinical characteristics and blood and urine cultures for all patients; antimicrobial sensitivities were assessed for positive cultures. During the study period, 103 patients were admitted and 76 patients were analyzed. The cohort comprised 39% male, and the median age was 30 (interquartile range: 23-40) years. Eighteen (24%), 50 (66%), and 12 patients (16%) had sepsis based on the three definitions, respectively. Four blood cultures (5%) were positive, two from patients with sepsis by all three definitions and two from patients with clinically suspected infection only. All blood bacterial isolates were multidrug resistant. Of five patients with urinary tract infection, three had sepsis secondary to multidrug-resistant bacteria. Hospital mortality for patients with sepsis based on the three definitions ranged from 42% to 75% versus 12% to 26% for non-septic patients. In summary, mortality associated with sepsis at this Malawi hospital is high. Bacteremia was infrequently detected, but isolated pathogens were multidrug resistant.

Outbreak of Burkholderia cepacia complex infections associated with contaminated octenidine mouthwash solution, Germany, August to September 2018.

Three German patients developed nosocomial pneumonia after cardiac surgery and had Burkholderia cepacia complex detected in respiratory specimens. Two patients died of septic multi-organ failure. Whole-genome sequencing detected genetically identical B. cepacia complex strains in patient samples, from a batch of octenidine mouthwash solution, which had been used for nursing care, as well as in samples obtained from the manufacturer during production. Contamination of medical products during manufacturing may lead to international outbreaks.

Burkholderia cepacia, cystic fibrosis and outcomes following lung transplantation: experiences from a single center in Brazil.

OBJECTIVES: To evaluate the impact of Burkholderia cepacia complex colonization in cystic fibrosis patients undergoing lung transplantation. METHODS: We prospectively analyzed clinical data and respiratory tract samples (sputum and bronchoalveolar lavage) collected from suppurative lung disease patients between January 2008 and November 2013. We also subtyped different Burkholderia cepacia complex genotypes via DNA sequencing using primers against the recA gene in samples collected between January 2012 and November 2013. RESULTS: From 2008 to 2013, 34 lung transplants were performed on cystic fibrosis patients at our center. Burkholderia cepacia complex was detected in 13 of the 34 (38.2%) patients. Seven of the 13 (53%) strains were subjected to genotype analysis, from which three strains of B. metallica and four strains of B. cenocepacia were identified. The mortality rate was 1/13 (7.6%), and this death was not related to B. cepacia infection. CONCLUSION: The results of our study suggest that colonization by B. cepacia complex and even B. cenocepacia in patients with cystic fibrosis should not be considered an absolute contraindication to lung transplantation in Brazilian centers.

Survival after lung transplantation of cystic fibrosis patients infected with Burkholderia dolosa (genomovar VI).

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

Clinical characteristics of bacteraemia caused by Burkholderia cepacia complex species and antimicrobial susceptibility of the isolates in a medical centre in Taiwan.

This study investigated the clinical characteristics and outcomes of bacteraemia due to Burkholderia cepacia complex (BCC) species among 54 patients without cystic fibrosis from January 2013 to February 2015. BCC isolates were identified to the species level by the Bruker Biotyper MALDI-TOF MS system and by sequencing analysis of the 16S rRNA and recA genes. Antimicrobial susceptibilities of the isolates were determined by the agar dilution method. Sequencing of the recA gene in the 54 blood isolates revealed 37 (68.5%) isolates of B. cenocepacia, 9 (16.7%) of B. cepacia, 4 (7.4%) of B. multivorans and one isolate each of B. arboris, B. pseudomultivorans, B. seminalis, and B. vietnamiensis. The overall performance of the Bruker Biotyper MALDI-TOF MS system for correctly identifying the 54 BCC isolates to the species level was 79.6%, which was better than that (16.7%) by 16S RNA sequencing analysis. Bacteraemic pneumonia (n = 23, 42.6%) and catheter-related bacteraemia (n = 21, 38.9%) were the most common types of infection. Higher rates of ceftazidime and meropenem resistance were found in B. cepacia isolates (33.3% and 22.2%, respectively) than in isolates of B. cenocepacia (21.6% and 10.8%, respectively) and other species (12.5% and 12.5%, respectively). Overall, the 30-day mortality rate was 38.9% (21/54). Bacteraemia caused by BCC species other than B. cenocepacia and B. cepacia (adjusted odds ratio [aOR] 20.005, P = 0.024) and high SOFA score (aOR 1.412, P = 0.003) were predictive of higher 30-day mortality. Different BCC species are associated with different outcomes of bacteraemia and exhibit different susceptibility patterns.

Burkholderia cepacia, cystic fibrosis and outcomes following lung transplantation: experiences from a single center in Brazil

OBJECTIVES: To evaluate the impact of Burkholderia cepacia complex colonization in cystic fibrosis patients undergoing lung transplantation. METHODS: We prospectively analyzed clinical data and respiratory tract samples (sputum and bronchoalveolar lavage) collected from suppurative lung disease patients between January 2008 and November 2013. We also subtyped different Burkholderia cepacia complex genotypes via DNA sequencing using primers against the recA gene in samples collected between January 2012 and November 2013. RESULTS: From 2008 to 2013, 34 lung transplants were performed on cystic fibrosis patients at our center. Burkholderia cepacia complex was detected in 13 of the 34 (38.2%) patients. Seven of the 13 (53%) strains were subjected to genotype analysis, from which three strains of B. metallica and four strains of B. cenocepacia were identified. The mortality rate was 1/13 (7.6%), and this death was not related to B. cepacia infection. CONCLUSION: The results of our study suggest that colonization by B. cepacia complex and even B. cenocepacia in patients with cystic fibrosis should not be considered an absolute contraindication to lung transplantation in Brazilian centers.

Human Infection with Burkholderia thailandensis, China, 2013.

Burkholderia thailandensis infection in humans is uncommon. We describe a case of B. thailandensis infection in a person in China, a location heretofore unknown for B. thailandensis. We identified the specific virulence factors of B. thailandensis, which may indicate a transition to a new virulent form.

Survival after lung transplantation for cystic fibrosis in Sweden.

Objectives: In Sweden, lung transplantation has been performed in patients with end-stage lung disease since 1990. We assessed survival after lung transplantation for cystic fibrosis (CF) with focus on early mortality and outcome for patients infected with certain multiresistant bacteria, considered a relative contraindication for lung transplantation. Methods: Review of CF and transplant databases and patient charts. The Kaplan-Meier method and log-rank test were used for survival analysis and group comparison. Results: From November 1991 to December 2014, 115 transplantations were performed in 106 CF patients (9 retransplantations): 3 heart-lung, 106 double lung-, 1 double lobar- and 5 single lung transplantations, constituting 13% (115/909) of all lung-transplant procedures performed in Sweden. The mean age at surgery was 31 (SD 10, range 10-61) years and there were 48% females. Overall 1-year survival after lung transplantation for CF was 86.4%, 5-year survival was 73.7% and 10-year survival was 62.4%. The mean and median survival after transplantation were 13.1 (95% confidence interval (CI): 11-15.3) and 14.6 (95% CI: 9.3-19.8) years, respectively, and there was no significant difference for gender or transplant centre. Extracorporeal membrane oxygenation was used as a bridge to transplantation in 11 cases and five patients received reconditioned lungs. Vascular and infectious complications contributed to eight deaths within the first three postoperative months. The mean survival for 14 patients infected pretransplant with Mycobacterium abscessus or Burkholderia cepacia complex was 8.8 (95% CI: 6.1-11.6) years compared to 13.2 (95% CI: 10.9-15.8) years for patients negative for these bacteria. Nineteen patients (14% of all listed), of whom three were listed for retransplantation, died while waiting a median time of 94 days (range 4 days-2.5 years) after listing. Conclusions: Survival after lung transplantation in Sweden is good, also for patients with pretransplant infection with M. abscessus or B. cepacia complex, and comparable to international data.

Lung transplantation in patients with cystic fibrosis: special focus to infection and comorbidities.

Despite advances in medical care, patients with cystic fibrosis still face limited life expectancy. The most common cause of death remains respiratory failure. End-stage cystic fibrosis can be treated with lung transplantation and is the third most common reason for which the procedure is performed. Outcomes for cystic fibrosis are better than most other lung diseases, but remain limited (5-year survival 60%). For patients with advanced disease lung transplantation appears to improve survival. Outcomes for patients with Burkholderia cepacia remain poor, although they are better for patients with certain genomovars. Controversy exists about Mycobacterium abscessus infection and appropriateness for transplant. More information is also becoming available for comorbidities, including diabetes and pulmonary hypertension among others. Extra-corporeal membrane oxygenation is used more frequently for end-stage disease as a bridge to lung transplantation and will likely be used more in the future.

Characteristics and outcome predictors of patients involved in an outbreak of Burkholderia cepacia complex.

A Burkholderia cepacia complex outbreak occurred among ventilated non-cystic fibrosis patients in an intensive care unit (ICU) in Italy: 33 colonized and 13 infected patients were included in a retrospective study aimed at investigating factors related to clinical infection and mortality. Demographic/clinical conditions and mortality did not vary significantly between colonized and infected patients, both groups showing high mortality rates compared with the overall ICU population and similar to that observed in patients with other infections. In multivariate regression analysis, disease severity (defined by the Simplified Acute Physiology Score II) and age were the only independent predictors of early mortality (odds ratio: 1.12; 95% confidence interval: 1.02-1.26; and 1.07; 1.01-1.15, respectively).

Burkholderia gladioli sepsis in newborns.

UNLABELLED: Burkholderia gladioli is a rare cause of bacteremia and sepsis in the absence of such predisposing factors as chronic granulomatous disease, cystic fibrosis, and immunosuppression. Little is known about B. gladioli infection in newborns. The aim of this study was to present the features of B. gladioli infection in newborns. Clinicopathological characteristics, patterns of antimicrobial susceptibility, predisposing factors, and outcomes of B. gladioli bloodstream infection were retrospectively analyzed in newborns treated between 2008 and 2011. During the 3-year study period, B. gladioli was isolated from the blood cultures of 14 patients (3.7 per 1,000 admissions). In all, 5 (35.7 %) of the 14 cases had a positive blood culture at the time of initial admission. Primary diagnoses in the neonates were severe major congenital anomalies, congenital leukemia, prematurity with respiratory distress syndrome, pneumonia, and parapneumonic pleural effusion. In total, 10 (71.4 %) of the patients underwent ≥2 invasive procedures. The overall in-hospital mortality rate was 21.4 %, whereas the mortality rate due to B. gladioli infection was 7 %. CONCLUSION: B. gladioli might be a causative microorganism of both early neonatal and nosocomial sepsis in newborns. To the best of our knowledge, this is the first study on B. gladioli infection in newborns. Invasive procedures and severe major congenital anomalies may be predisposing factors for B. gladioli bloodstream infection in neonates. Although it appears to have low pathogenic potential and an insidious clinical course in newborns, resistance to antibiotics may be a potential problem. Mortality was primarily associated with underlying diseases.

Exposing the third chromosome of Burkholderia cepacia complex strains as a virulence plasmid.

The Burkholderia cepacia complex (Bcc) consists of 17 closely related species of opportunistic bacterial pathogens, which are particularly problematic for cystic fibrosis patients and immunocompromised individuals. Bcc genomes consist of multiple replicons, and each strain sequenced to date has three chromosomes. In addition to genes thought to be essential for survival, each chromosome carries at least one rRNA operon. We isolated three mutants during a transposon mutagenesis screen that were non-pathogenic in a Caenorhabditis elegans infection model. It was demonstrated that these mutants had lost chromosome 3 (c3), and that the observed attenuation of virulence was a consequence of this. We constructed a c3 mini-replicon and used it to cure c3 from strains of several Bcc species by plasmid incompatibility, resulting in nine c3-null strains covering seven Bcc species. Phenotypic characterization of c3-null mutants revealed that they were attenuated in virulence in multiple infection hosts (rat, zebrafish, C. elegans, Galleria mellonella and Drosophila melanogaster), that they exhibited greatly diminished antifungal activity, and that c3 was required for d-xylose, fatty acid and pyrimidine utilization, as well as for exopolysaccharide production and proteolytic activity in some strains. In conclusion, we show that c3 is not an essential chromosomal element, rather a large plasmid that encodes virulence, secondary metabolism and other accessory functions in Bcc bacteria.

Risk factors for mortality in patients with Burkholderia cepacia complex bacteraemia.

BACKGROUND: Over the last 2 decades, Burkholderia cepacia complex has emerged as a serious human pathogen, especially in critically ill patients. B. cepacia complex has been associated with increased morbidity and mortality in intensive care unit patients. However, in our literature search, we could not find studies on risk factors for mortality in patients with B. cepacia complex bacteraemia. Therefore, we investigated risk factors for mortality in B. cepacia complex bacteraemia. METHODS: Clinical characteristics and laboratory parameters of 27 patients with 1 or more blood cultures positive for B. cepacia complex from January 2006 to October 2010 in Severance Hospital, Yonsei University College of Medicine, Korea were retrospectively analyzed. The main outcome measure was overall 28-day mortality. Appropriate initial empirical antimicrobial use was defined as administration of agent(s) to which the organism was susceptible within 24 h of obtaining blood for culture. RESULTS: The overall 28-day mortality rate was 41% (11/27). In univariate analysis, underlying diabetes mellitus (p = 0.033), inappropriate initial empirical antimicrobial therapy (p = 0.033), and an elevated Sequential Organ Failure Assessment (SOFA) score (p = 0.002) were significantly associated with mortality. In multivariate analysis, inappropriate initial empirical antimicrobial therapy and an elevated SOFA score were independent risk factors for increased mortality (p = 0.032 and p = 0.028, respectively). CONCLUSIONS: An elevated SOFA score and inappropriate initial empirical antimicrobial therapy were significantly associated with adverse outcome in patients with B. cepacia complex bacteraemia.

Should cystic fibrosis patients infected with Burkholderia cepacia complex be listed for lung transplantation?

A best evidence topic was constructed according to a structured protocol. The question addressed was whether lung transplantation remained a beneficial treatment for cystic fibrosis (CF) patients infected or colonized with Burkholderia cepacia complex (BCC) prior to lung transplantation (LTx). Of the 25 papers found using a report search, five presented the best evidence to answer the clinical question. The authors, journal, date and country of publication, study type, group studied, relevant outcomes and results of these papers are given. We conclude that, on the whole, the five studies were clearly in favor of maintaining access to LTx lists for BCC infected or colonized CF patients. In other words, access to LTx should not be denied to BCC infected CF patients in that the beneficial effects of LTx do not differ with respect to non-infected patients: comparison showed neither a difference in survival nor a higher mortality risk. However, results would differ for Burkholderia cenocepacia infected CF patients prior to LTx: both short- and long-term survival are significantly lower when B. cenocepacia infected patients are compared to other BCC infected patients or non-infected patients. Hence, current evidence shows that careful screening of all BCC suspected CF patients and risk-aware multidisciplinary management should be achieved before listing patients for LTx. This would allow identification of different bacterial species (in particular, B. cenocepacia) present and optimize lung transplantation survival outcomes.

Clinical characteristics and outcomes of patients with Burkholderia cepacia bacteremia in an intensive care unit.

The purpose of this study was to investigate a cohort of patients with Burkholderia cepacia bacteremia in the intensive care unit (ICU) at our institution. A large outbreak of B. cepacia bacteremia involving 95 patients lasted for 4 years in an ICU in northern Taiwan. The clinical characteristics and antimicrobial treatment responses of these patients were analyzed. Minimal inhibitory concentrations were determined and pulse-field gel electrophoresis was performed for the 73 available isolates. Overall, the in-hospital mortality rate was 53.8% and the 14-day mortality rate was 16.8%. Most patients (95.6%) had several underlying diseases and all but 1 patient had tracheal intubation. Malignancy (37.5% versus 13.9%, P = 0.02) and higher Sequential Organ Failure Assessment (SOFA) scores at the onset of bacteremia (11.9 ± 4.7 versus 7.9 ± 3.6, P < 0.001) were significant risk factors for 14-day mortality. In contrast, treatment with ceftazidime (76.0% versus 43.7%, P = 0.02) and diabetes (51.9% versus 13.8%, P = 0.01) were associated with decreased mortality. In the multivariate analysis, malignancy and higher SOFA score were significant risk factors for mortality [odds ratio (OR) 12.45, 95% confidence interval (CI) 2.35-65.94; OR 1.20, 95% CI 1.00-1.45, respectively]. Meropenem, ceftazidime, and piperacillin-tazobactam were the most active agents (susceptible rate 100%, 97.3%, and 97.3%, respectively). Pulsed-field gel electrophoresis results indicated 49 of the 73 isolates could be classified as outbreak-related strains. There was no significant difference in the clinical characteristics and outcomes of patients with bacteremia due to outbreak-related and non-outbreak-related strains. In conclusion, malignancy and a higher SOFA score at onset of bacteremia predicted increased mortality, but the clinical presentation and outcome of patients with outbreak and non-outbreak strains were similar.

Lung transplantation for patients with cystic fibrosis and Burkholderia cepacia complex infection: a single-center experience.

BACKGROUND: Pre-operative infection with organisms from the Burkholderia cepacia complex (BCC), particularly B cenocepacia, has been linked with a poorer prognosis after transplantation compared to patients with cystic fibrosis (CF) without this infection. Therefore, many transplant centers do not list these patients for transplantation. METHODS: We report the early and long-term results of a cohort of lung transplant recipients with CF and pre-operative BCC infection. Patients with pre-transplantation BCC infection were identified by case-note review. BCC species status was assigned by polymerase chain reaction (PCR)-based techniques. Survival rates were compared to recipients with CF without BCC infection. Survival rates in BCC subgroups were also compared, and then further analyzed pre- and post-2001, when a new immunosuppressive and antibiotic regime was introduced for such patients. RESULTS: Two hundred sixteen patients with CF underwent lung transplantation and 22 had confirmed pre-operative BCC infection, with 12 of these being B cenocepacia. Nine B cenocepacia-infected recipients died within the first year, and in 8 BCC sepsis was considered to be the cause of death. Despite instituting a tailored peri-operative immunosuppressive and microbiologic care approach for such patients, post-transplantation BCC septic deaths occurred frequently in those with pre-transplantation B cenocepacia infection. In contrast, recipients infected with other BCC species had significantly better outcomes, with post-transplantation survival comparable to other recipients with CF. CONCLUSIONS: Mortality in patients with B cenocepacia infection was unacceptably high and has led to our center no longer accepting patients with this condition onto the lung transplant waiting list. Long-term survival in the non-B cenocepacia BCC group was excellent, without high rates of acute rejection or bronchiolitis obliterans syndrome (BOS) longer term, and these patients continue to be considered for lung transplantation.

Survival of Burkholderia cepacia sepsis following lung transplantation in recipients with cystic fibrosis.

Cystic fibrosis (CF) lung transplant recipients infected with Burkholderia cenocepacia have a worse survival rate after lung transplantation than those who are not infected with this organism. The decreased survival is predominantly due to recurrent B. cenocepacia infection, with the majority of affected recipients succumbing within 3 months after transplant. B. cepacia complex (BCC) sepsis is one of the defining criteria for cepacia syndrome, an almost universally fatal necrotizing pneumonic illness. We report 2 CF patients who were long-term survivors of B. cenocepacia sepsis after lung transplantation. The aim of this report is to demonstrate that, although survival of B. cenocepacia sepsis after lung transplantation is extremely uncommon, with aggressive multidisciplinary management, long-term survival remains a realistic objective.

Antisense phosphorodiamidate morpholino oligomers targeted to an essential gene inhibit Burkholderia cepacia complex.

BACKGROUND: Members of the Burkholderia cepacia complex (Bcc) cause considerable morbidity and mortality in patients with chronic granulomatous disease and cystic fibrosis. Many Bcc strains are antibiotic resistant, which requires the exploration of novel antimicrobial approaches, including antisense technologies such as phosphorodiamidate morpholino oligomers (PMOs). METHODS: Peptide-conjugated PMOs (PPMOs) were developed to target acpP, which encodes an acyl carrier protein (AcpP) that is thought to be essential for growth. Their antimicrobial activities were tested against different strains of Bcc in vitro and in infection models. RESULTS: PPMOs targeting acpP were bactericidal against clinical isolates of Bcc (>4 log reduction), whereas a PPMO with a scrambled base sequence (scrambled PPMO) had no effect on growth. Human neutrophils were infected with Burkholderia multivorans and treated with AcpP PPMO. AcpP PPMO augmented killing, compared with neutrophils alone and compared with neutrophils alone plus scrambled PPMO. Mice with chronic granulomatous disease that were infected with B. multivorans were treated with AcpP PPMO, scrambled PPMO, or water at 0, 3, and 6 h after infection. Compared with water-treated control mice, the AcpP PPMO-treated mice showed an approximately 80% reduction in the risk of dying by day 30 of the experiment and relatively little pathology. CONCLUSION: AcpP PPMO is active against Bcc infections in vitro and in vivo.