Aerosolized colistin as adjunctive treatment of ventilator-associated pneumonia due to multidrug-resistant Gram-negative bacteria: a prospective study

BACKGROUND: Ventilator-associated pneumonia (VAP) remains the leading cause of death in patients with intensive care unit (ICU) acquired infections associated with an attributable mortality around 30%. Increasing antimicrobial resistance in patients with VAP challenges intensivists to search for alternative therapeutic options. There is scarcity of data in the literature concerning the administration of aerosolized colistin in critically ill patients with VAP due to multidrug-resistant (MDR) Gram-negative pathogens. METHODS: To assess the safety and effectiveness of aerosolized colistin as an adjunctive to the intravenous antimicrobial therapy for the treatment of VAP due to MDR Gram-negative pathogens, we prospectively examined all patients, who received inhaled colistin. RESULTS: Sixty critically ill patients with a mean APACHE II score 16.7, received aerosolized colistin for the treatment of VAP due to MDR pathogens [Acinetobacter baumannii (37/60 cases), Pseudomonas aeruginosa (12/60 cases) and Klebsiella pneumoniae strains (11/60 cases)]. Half of the isolated pathogens were susceptible only to colistin. Mean (+/-SD) daily dosage of aerosolized colistin was 2.2 (+/-0.7) million international units (IU). All patients received 2946 inhalations of colistin and the mean duration of administration was 16.4 days. Fifty-seven patients received concomitant intravenous treatment with colistin or other antimicrobial agents. Bacteriological and clinical response of VAP was observed in 50/60 (83.3%) patients. No adverse effects related to inhaled colistin were recorded. All cause hospital mortality was 25% while mortality attributable to VAP was 16.7%. CONCLUSIONS: Aerosolized colistin may be considered as adjunctive to intravenous treatment in patients with VAP due to MDR Gram-negative bacteria susceptible to colistin in critically ill patients. Although colistin is safe and effective, the best route of administration remains unclear. In addition, controlled comparative studies are needed to establish its effectiveness and safety.     

Elevated Tissue Kallikrein Activity in Airway Secretions from Patients with Tracheobronchitis Associated with Prolonged Mechanical Ventilation

The clinical course of patients undergoing prolonged mechanical ventilation is often complicated by the development of purulent tracheobronchitis. The purpose of this study was to assess whether ventilator-associated hypersecretion is associated with elevated levels of tissue kallikrein (TK) activity. TK can induce marked bronchial inflammation in animal models and TK activity is increased in the airway secretions of symptomatic asthmatics. It has not been studied in conditions with predominantly neutrophilic bronchial secretions, although animal data indicate that neutrophil elastase may stimulate TK activity. We measured TK activity in airway secretions of patients undergoing mechanical ventilation for more than 4 weeks (PMV group) and in two comparator groups: patients with cystic fibrosis, who were colonized with Pseudomonas aeruginosa (CF group) and patients undergoing mechanical ventilation for less than one week who did not have clinical evidence of purulent airway secretions (acute mechanical ventilation, AMV group). We also compared the level of neutrophil elastase (NE) activity, an index of neutrophil activation, in the three patient groups. TK and NE activity in the sol phase were measured by the degradation of chromogenic substrates (DL Val-Leu-Arg pNA and N-Methoxy Succinyl Ala-Ala-Pro-Val pNA, respectively). Intergroup differences in cell counts were not significant. However, TK activity was significantly less in the AMV group than in the PMV and cystic fibrosis patients (Kruskal-Wallis ANOVA, p < 0.05). Elastase activity was significantly greater in the CF group (p < 0.05) than in the other two groups. Compared to patients undergoing short-term mechanical ventilation (AMV group), TK activity was elevated in patients with purulent tracheobronchitis associated with prolonged mechanical ventilation (PMV group). The elevation in TK activity in these patients is comparable to levels in sputum from patients with cystic fibrosis (CF group), although the latter had a significantly higher level of NE activity. The observation of increased TK activity in patients with neutrophilic airway inflammation suggests that TK may play a role in modulating inflammation in ventilator-associated tracheobronchitis and may be worthy of further study to determine its source and significance.     

Fatal Burkholderia gladioli infection misidentified as Empedobacter brevis in a lung transplant recipient with cystic fibrosis

Data describing the risk of lung transplantation (LT), clinical features, and outcomes of patients with cystic fibrosis (CF) infected with Burkholderia gladioli are limited. Herein, we report a case of disseminated B. gladioli infection characterized by bacteremia, necrotizing pneumonia, lung abscess, and empyema in a lung transplant recipient with CF, highlight the importance of accurate microbiological identification, and review published outcomes of LT in CF patients infected with B. gladioli, which include cases of pneumonia, tracheobronchitis, bacteremia, and abscesses, and demonstrate an all‐cause 1‐year mortality of approximately 23%, often after combined medical and surgical treatment.     

Effect of long-term nebulized colistin on lung function and quality of life in patients with chronic bronchial sepsis

Recurrent Gram-negative bacterial infection is a significant cause of death in patients with bronchiectasis and severe chronic obstructive pulmonary disease (COPD). Nebulized colistin in cystic fibrosis has shown maintenance of pulmonary function and improved symptom scores. We prospectively followed 18 patients with chronic bronchial sepsis treated with nebulized colistin 30 mg daily. Mean decline in forced expiratory volume in 1 s was significantly slower following commencement of inhaled colistin (44 mL/year vs 104 mL/year, P = 0.035). Mean decline in forced vital capacity was also significantly slower following commencement of colistin (48 mL/year vs 110 mL/year, P = 0.033). Patient-reported quality of life improved following commencement of colistin (3.6 vs 6.2, P = 0.001). No patient had isolates resistant to colistin. No side-effects were reported by patients in the cohort. Use of inhaled colistin in the treatment of bronchiectasis and severe (COPD) in patients with recurrent Gram-negative infections is safe. Inhaled colistin may improve quality of life and slow decline in forced expiratory volume in 1 s and forced vital capacity.     

Sputum induction in young cystic fibrosis patients.

A culture from the lower airway secretions is the optimal sample to guide antibiotic therapy in cystic fibrosis (CF) lung disease. The authors therefore examined whether sputum induction is an efficient, safe and acceptable procedure in CF children without spontaneous expectorations. Nineteen patients were studied. Their mean age (range) was 8.6 yrs (4.3-15.2 yrs). Their mean forced expiratory volume in one second (FEV1) was 88% predicted (46-122%). NaCl solutions from 0.9-6% were inhaled, after baseline lung function tests before and after salbutamol. All patients did produce secretions. Alveolar macrophages were present in 16/19 induced samples. The procedure induced minor but significant bronchoconstriction: the mean change (range) in postsalbutamol FEV1 (% pred) was -7 (-24-16). Percutaneous oxygen saturation remained above 90% in all children. The test had to be discontinued in one child because of cough and wheeze. Acceptability of the procedure evaluated using a visual analogue scale from -7-7 showed a mean value (range) at the final concentration of -1.23 (-6.16-5.88). It is concluded that sputum induction is possible, safe and acceptable in cystic fibrosis children who do not expectorate spontaneously.     

Fibronectin-cleaving activity in bronchial secretions of patients with cystic fibrosis

In cystic fibrosis, colonization of the airways with Pseudomonas aeruginosa follows colonization with Staphylococcus aureus and is related to accelerated deterioration of pulmonary function. Because P. aeruginosa adheres better to cell surfaces devoid of fibronectin, we searched for fibronectin-cleaving activity in bronchial secretions and saliva from 24 patients with cystic fibrosis who were followed up for 4.5 y and from two control groups. Proteolytic activity against 125I-labeled fibronectin was continuously present in cystic fibrosis bronchial secretions; significantly higher fibronectin-cleaving activity was found in older vs. younger patients, in patients with advanced disease stages determined by a five-stage scoring system, and in those colonized with P. aeruginosa. The fibronectin-cleaving activity was due to neutrophil elastase and cathepsin G. Cystic fibrosis bronchial secretions had proteolytic activity against surface fibronectin of airway mucosal cells. Thus fibronectin-cleaving activity of bronchial secretions rather than of saliva may favor P. aeruginosa colonization of the upper respiratory tract in individuals with cystic fibrosis.     

The interrupter technique to assess airway responsiveness in children with cystic fibrosis

The aim of this study was to assess the validity of the interrupter technique (Rint) in measuring airway responsiveness in children with cystic fibrosis. Fifty children (aged 6-16 years) with cystic fibrosis performed six Rint measurements followed by three acceptable forced expiratory maneuvers. Each child then inhaled 5 mg of nebulized salbutamol by facemask. After 20 min the Rint and forced expiratory measurements were repeated. In the population as a whole a moderate but significant correlation between inverse Rint and FEV1 values was observed, both before and after inhaled bronchodilator (r=0.71 and 0.72, respectively, P < 0.001). However, when changes in Rint and FEV1 readings following inhaled bronchodilator were examined, no relationship was seen. Indeed, the two methods identified completely different subsets of children as being bronchodilator responsive. These results indicate that although a relationship exists between Rint and FEV1 in the whole population, this is not the case in individual children. Rint and FEV1 reflect different aspects of lung function. It is not appropriate to use Rint as a simple alternative for FEV1 in children with cystic fibrosis when assessing airway responsiveness.     

Inhaled Anti-infective Agents: Emphasis on Colistin

The administration of antibiotics by the inhaled route is a widely recognized treatment in patients with cystic fibrosis (CF) and bronchiectasis. Tobramycin solution for inhalation (TOBI) has been available for many years and is licensed in the USA and Europe. While strong data support the use of aerosolized antibiotics for the treatment of respiratory infections in patients with CF or bronchiectasis, only a few clinical studies have examined the role of aerosolized antibiotics in the treatment of pneumonia, including ventilator-associated pneumonia (VAP) in these patients. During the last decade increasing interest has been directed towards alternative treatments to the systemic administration of antimicrobial agents for the treatment of patients with hospital-acquired pneumonia or VAP due to multidrug-resistant (MDR) Gram-negative bacteria. Recent publications demonstrate the clinical benefits from administering inhaled aminoglycosides or polymyxins in patients with hospitalacquired pneumonia or VAP. In addition to antibiotics, antifungals, and antivirals have been administered by inhalation to specific groups of critically ill patients. However, randomized controlled trials dealing with the administration of anti-infective agents via the respiratory tract are necessary in order to validate the efficacy, safety, advantages, and disadvantages of this therapeutic approach for the treatment of nosocomial pneumonia.     

Recombinant human deoxyribonuclease shortens ventilation time in young, mechanically ventilated children

Recombinant human deoxyribonuclease I (dornase alfa) is currently used as an inhaled mucoactive agent in the treatment of cystic fibrosis. In a randomized, placebo-controlled, double-blind clinical study in 100 infants, we investigated whether the therapeutic use of dornase alfa can be extended to ventilated, fluid-restricted children to reduce reintubation rate, ventilation duration, pediatric intensive care unit (PICU) stay, and ventilation complications. While reintubation rates were similar for dornase alfa 7% vs. placebo 9% (odds ratio, 0.77; confidence interval, 0.11-4.9), the incidence of atelectasis (6 vs. 17, respectively; P-value 0.051), median ventilation time (2.2 vs. 3.4 days, respectively; P-value 0.043), median length of PICU stay (7 vs. 8 days, respectively; P-value 0.051), and mean costs (4,830 vs. 6,320, respectively) were lower in the dornase alfa group. No adverse effects were observed, even in critically ill patients. We found that dornase alfa was beneficial and safe. Our findings also indicate that dornase alfa is possibly of value from the first day of mechanical ventilation onward, particularly when longer ventilation (>3 days) is expected in fluid-restricted children after cardiac surgery.     

Transmission of colistin-resistant Pseudomonas aeruginosa between patients attending a pediatric cystic fibrosis center

We report on an outbreak of colistin-resistant Pseudomonas aeruginosa (CRPA) that occurred in a United Kingdom pediatric cystic fibrosis (CF) unit and involved six children over a period of 5 years. All CRPA-positive children had received aerosolized colistin therapy before first isolation of resistant organisms (mean duration, 3.1 years). Four of the 6 had also received courses of intravenous colistin in the year before the first isolation of CRPA. No impact of CRPA acquisition on respiratory function, clinical condition, or radiological parameters could be demonstrated. Four of the 6 children carried isolates of CRPA indistinguishable on genotyping. Two of these 4 children were sisters. The other 2 were on the same ward together at time of first isolation, and subsequently shared overlapping admissions with one of the sisters.While there is no conclusive evidence for the route of transmission, the frequency of overlapping in-patient admissions between 3 of these patients is suggestive of patient-to-patient transfer in the nosocomial setting.CF clinicians should be aware that colistin resistance can occur in P. aeruginosa, and some of these strains are capable of spread within CF units.     

The clinical use of colistin in patients with cystic fibrosis.

Colistin is a cationic polypeptide antibiotic from the polymyxin family that was first introduced in 1962 but abandoned in the early 1970s because of initial reports of severe toxicities. However, a recent increase in the prevalence of multidrug resistant (MDR) Pseudomonas aeruginosa and the lack of novel agents in development calls for a need to re-examine the role of colistin therapy in patients with cystic fibrosis. Current data supports the use of intravenous colistimethate for the treatment of acute pulmonary exacerbations involving MDR P. aeruginosa and inhaled therapy for initial colonization. The frequency of nephrotoxicity and severity of neurotoxicity seem to be substantially less than previously believed. In addition, recent pharmacokinetic and pharmacodynamic data suggests new intravenous dosing regimens may enhance efficacy while minimizing toxicities; such regimens deserve further evaluation. Pre- and post-treatment spirometry is recommended at initiation of inhaled colistin therapy to identify sensitized individuals. Judicious use of colistin where the benefits have been clearly documented will retain this as a useful agent in the management of P. aeruginosa infections in patients with cystic fibrosis.     

Proteases of Pseudomonas aeruginosa in patients with cystic fibrosis

Radioimmunoassays were used to determine titers of antibody to alkaline protease (AP) and elastase (Ela) produced by Pseudomonas aeruginosa in sera and bronchial secretions, in vitro production of AP and Ela by P. aeruginosa isolates, and occurrence of these enzymes in bronchial secretions from patients with cystic fibrosis. Titers of serum antibodies to AP ranging from 1:10 to 1:545 and to Ela ranging from 1:10 to 1:725 were found in 83%-88% of patients with cystic fibrosis and chronic lung infections due to P. aeruginosa. Antibody titers in liquified bronchial secretions were approximately 10% of the serum titers. Thirty-one (93%) of 34 isolates produced both proteases in vitro in comparable amounts (concentration of protease in culture supernatant: AP, 0.01-480 micrograms/ml; Ela, 0.02-490 micrograms/ml). AP and Ela were detected in vivo when antibodies to the enzymes were absent. The results suggest that specific immune responses in patients with cystic fibrosis neutralize proteases of P. aeruginosa.     

儿童甲型H1N1流行性感冒病毒相关性肺炎的临床特征

目的 了解儿童甲型H1N1流行性感冒(流感)病毒相关性肺炎的临床流行特征.方法 通过描述性研究对2009年上海复旦大学附属儿科医院收治的30例甲型H1N1流感病毒所致肺炎的患儿做临床及流行病学分析.中位数比较采用秩和检验,率的比较采用精确卡方检验.结果 30例确诊为甲型H1N1流感合并肺炎的患儿中,年龄中位数为5.9岁,5例有基础疾病史,占16.7%.有明确发热病例暴露史的20例,占66.7%.所有患儿均有发热和咳嗽,11例伴气促,占36.7%,10例伴喘息,占33.3%.11例患儿WBC＜4.0×109/L,占36.7%,2例PLT减少,占6.7%.所有患儿入院时胸部X线片提示肺部有单侧或双侧片状渗出性病灶,4例危重症患儿肺部多处大片状渗出伴肺水肿,占13.3%,1例危重症肺炎患儿发病后3个月和9个月复查胸部CT提示不同程度肺纤维化,占3.3%,3例同时伴纵隔积气和皮下积气,占10.0%,6例并发急性呼吸衰竭,占20.0%,3例伴支气管哮喘急性发作,占10.0%,1例合并脑炎,占3.3%.所有患儿均给予奥司他书和抗菌药物治疗,4例接受机械通气,均治愈或好转出院.发病2 d内和2 d后接受奥司他韦治疗的患儿的热程中位数比较差异有统计学意义(2 d比5 d,Z=-8.015,P＜0.01).结论 学龄前和学龄儿童易感染甲型H1N1流感病毒,可并发严重的肺部疾病.在发病早期采用奥司他韦治疗,可缩短热程,降低危重并发症的发生.     

A regional cohort study of the treatment of critically ill children with bronchiolitis

Objective: To describe the treatment practices in critically ill children with RSV bronchiolitis across four regional PICUs in the northeastern United States, and to determine the factors associated with increased ICU length of stay in this population. Methods: We conducted a retrospective cohort study of children who were admitted with RSV bronchiolitis between July 2009 and July 2011 to the PICUs of Connecticut Children's Medical Center, Yale-New Haven Children's Hospital, Maria Fareri Children's Hospital, and Baystate Children's Hospital. Data were collected regarding clinical characteristics and intensive care course among these hospitals. Results: During the study period, 323 children were admitted to one of the four ICUs with RSV bronchiolitis. Despite similar mortality risk scores among ICUs, there was considerable variation in the use of therapies, particularly intubation and mechanical ventilation, in which there was greater than a 3.5-fold increased risk of intubation between sites with the highest and lowest frequency of intubation (odds ratio: 3.8; 95% confidence interval: 2.2–6.4). Albuterol was the most commonly used respiratory treatment, followed by chest physiotherapy, high-flow nasal cannula, and hypertonic saline. Longer stays in the ICU were associated with more frequent use of therapies, specifically invasive mechanical ventilation, inhaled corticosteroids, intrapulmonary percussive ventilation, and chest physiotherapy. Conclusions: Even within a close geographic region, there is significant variation in the treatment provided to critically ill children with RSV bronchiolitis. None of these treatments were associated with shorter durations of hospitalization in this population and some, such as mechanical ventilation, were associated with longer ICU lengths of stay.     

Paediatric problems of cough

All children cough, but most children are normal. In a child with isolated cough, a detailed history and examination, followed in a small number of cases by targeted investigations, should allow the child to be placed in one of five diagnostic categories. These are normal child; the child with a serious illness such as cystic fibrosis, tuberculosis etc. the child with non-serious, but treatable causes of cough and wheeze, for example gastro-oesophageal reflux or postnasal drip; the child with an asthma syndrome and an overestimation of symptoms for psychological or other reasons by either or both of child or family. Treatment is of the underlying condition if appropriate. Non-specific treatment with cough syrups are not useful. Attention to environmental factors such as active and passive smoking, and exposure to dust and pets is important. The diagnosis of cough variant asthma should only be made in older children after variable airflow obstruction and response to bronchodilator has been demonstrated physiologically. In younger children, rational diagnostic criteria are an abnormally increased cough, with no evidence of any non-asthma diagnosis, a clear-cut response to a therapeutic trial of asthma medication, usually moderate dose inhaled corticosteroids, and relapse on stopping medications with second response to recommencing them. Some such children go on to develop more typical asthma, with wheeze and bronchial hyper-reactivity. It is important however, not to over-diagnose asthma in children who in fact have a chronic non-specific cough. Such children require no treatment, get better with time, and have normal long-term lung function.     

Community‐acquired,methicillin‐resistant Staphylococcus aureus isolated from children with community‐onset pneumonia in China

Community‐acquired, methicillin‐resistant Staphylococcus aureus (CA‐MRSA) has been associated with morbidity and mortality in various countries. In this study, we characterized the molecular and clinical features of pediatric CA‐MRSA pneumonia in China. Between June 2006 and February 2008, 55 previously healthy children confined in eight hospitals countrywide were found to be afflicted with CA‐MRSA pneumonia. A total of 55 strains collected from these children were analyzed by multilocus sequence typing (MLST), Staphylococcus cassette chromosome mec (SCCmec) typing, and spa typing. The Panton–Valentine leukocidin (PVL) gene was also detected. Overall, nine STs were obtained, with ST59 (40.4%) established to be the most prevalent type. We first registered the new ST1409 from a child with necrotizing pneumonia. SCCmecIVa was the most predominant type, followed by SCCmec type V. Twelve spa types were identified, of which one new spa type, t5348, was first detected and registered. One typical livestock‐associated spa type, t034, was found in a 4‐month‐old girl living in the countryside. We also found that 40% of those isolates were PVL‐positive. In addition, the median age of the children in this study was 10 months. A total of 69% (38/55) of the children with community‐acquired pneumonia (CAP) had preceding influenza or influenza‐like illness, and three ST910‐MRSA‐IV strains (PVL gene‐positive) were associated with severe necrosis. The results indicated that the recent CA‐MRSA found in Chinese children with CAP was largely associated with the spread of the ST59‐MRSA‐IV clone, and most of the PVL‐positive strains in this study did not cause necrotic cases. Pediatr Pulmonol. 2010; 45:387–394. © 2010 Wiley‐Liss, Inc.     

Promoting the young child's development in the intensive care unit

Young children are much more emotionally vulnerable to hospitalization than are adults. The admission of a child to an intensive care unit (ICU) is stress-producing and can affect the child's ability to develop at an optimal level. This article provides the ICU nurse with a working knowledge of normal growth and developmental patterns of infants and toddlers. Internal strengths of the child, external supports, and environmental manipulation that the nurse can use to promote the critically ill child's growth and development and support the child in coping with hospitalization are presented. Discussion centers on the child experiencing an acute crisis that requires long-term intensive monitoring, rather than on the chronically ill child.     

The feasibility of conducting clinical trials in infants and children with acute respiratory failure

Designing robust clinical trials in critically ill, mechanically ventilated children requires an understanding of the epidemiology and course of pediatric respiratory failure. As part of a clinical trial, we screened all mechanically ventilated children in nine large pediatric intensive care units (ICUs) across North America for 6 consecutive months. Of 6,403 total ICU admissions, 1,096 (17.1%) required mechanical ventilator support for a minimum of 24 hours. Of these, 701 (64%) met one or more exclusion criteria for trial enrollment. Common reasons for exclusion were upper airway obstruction (13.5%) and cyanotic congenital heart disease (11.5%). Life support interventions were restricted for 9.7% of patients, and 5.5% were chronically ventilator dependent. In the patients who were eligible for respiratory failure studies, 62.4% had an acute primary diagnosis of pulmonary disease, 14.2% neurologic disease, and 8.9% cardiac disease. Chronic underlying conditions were present in 43.2% of the patients. The most common acute diagnosis was bronchiolitis in infants (43.6%) and pneumonia in children 1 year old and older (24.5%). Mortality was rare (1.6%), and the median duration of ventilation was 7 days. The design of clinical trials in critically ill children is feasible but must account for the diverse population, infrequent mortality, and short duration of mechanical ventilation.     

Interfacility transport of the critically ill pediatric patient

Care of the critically ill and injured child has evolved over the last 20 years, with growth of regional pediatric critical care services, attendant subspecialties, and the proliferation of pediatric critical care training programs nationally. Concurrent with this evolution has been recognition of the need for specialty care of the critically ill child during air or ground transport to a regional pediatric center. The American Academy of Pediatrics Section on Transport Medicine has provided standards that have been adopted by many neonatal and pediatric transport teams. Team composition varies, but all share the mission of specialized transport for critically ill and injured children in a safe and expeditious process while ultimately improving patient outcome. Specialized pediatric transport teams are costly to maintain. Declining reimbursement for specialized care and reduced profit margins have resulted in extended roles for transport team members within children's hospitals. More stringent budgetary constraints have created challenges for pediatric transport teams in our constantly changing medical environment.