ANTIBIOTICS THERAPY FOR PSEUDOMONAL INFECTION IN CF Abdullah M. Al-Olayan MBBS, SBP, ABP. Assistant Professor of Pediatrics. Pediatric Pulmonologist. Introduction. Pseudomonas (Microbiology). Acute Exacerbation. Chronic Infection. Approach. Introduction Cystic fibrosis (CF) is a multisystem disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, located on chromosome 7. Rommens JM, Iannuzzi MC, Kerem B, et al. Identification of the cystic fibrosis gene: chromosome walking and jumping. Science 1989; 245:1059. Introduction Cystic fibrosis (CF) is the most common lifeshortening autosomal recessive disease among Caucasian populations, with a frequency of 1 in 2000 to 3000 live births. Cystic Fibrosis Foundation Patient Registry: annual data report 2011. http://www.cff.org/UploadedFiles/research/ClinicalRe search/2011-Patient-Registry.pdf (Accessed on December 18, 2012). Introduction The median predicted survival for CF patients in the United States was 36.8 years according to the Cystic Fibrosis Foundation 2011 Registry Report. Cystic Fibrosis Foundation Patient Registry: annual data report 2011. http://www.cff.org/UploadedFiles/research/ClinicalRe search/2011-Patient-Registry.pdf (Accessed on December 18, 2012). Introduction Pulmonary disease remains the leading cause of morbidity and mortality in patients with CF. Ratjen F, Döring G. Cystic fibrosis. Lancet 2003; 361:681. Brennan AL, Geddes DM. Cystic fibrosis. Curr Opin Infect Dis 2002; 15:175. Introduction The usual presenting symptoms and signs include persistent pulmonary infection, pancreatic insufficiency, and elevated sweat chloride levels. Ratjen F, Döring G. Cystic fibrosis. Lancet 2003; 361:681. Introduction Symptomatic presentation in infants and children: •Meconium ileus – 20%. •Respiratory symptoms – 45%. •Failure to thrive – 28%. Introduction For infants presenting with meconium ileus, the median age of diagnosis was 2 weeks. For those presenting with other symptoms, the median age of diagnosis was 14.5 months. Accurso FJ, Sontag MK, Wagener JS. Complications associated with symptomatic diagnosis in infants with cystic fibrosis. J Pediatr 2005; 147:S37. Introduction Typical respiratory manifestations of CF include a persistent, productive cough, hyperinflation of the lung fields on chest radiograph, and pulmonary function tests that are consistent with obstructive airway disease. Introduction The onset of clinical symptoms varies widely, due to differences in CFTR genotype and other individual factors, but pulmonary function abnormalities often are detectable even in the absence of symptoms. Introduction As an example, in a cohort of infants largely identified by newborn screening, 35% had respiratory symptoms (cough, wheezing, or any breathing difficulty); mean pulmonary function scores were abnormal by six weeks of age and declined during the subsequent two years. Pillarisetti N, Williamson E, Linnane B, et al. Infection, inflammation, and lung function decline in infants with cystic fibrosis. Am J Respir Crit Care Med 2011; 184:75. Pseudomonas Pseudomonas aeruginosa: a gram-negative nonfermenting bacillus. The organism is common in the environment, especially in water, even contaminating distilled water. Warburton DW, Bowen B, Konkle A. The survival and recovery of Pseudomonas aeruginosa and its effect upon salmonellae in water: methodology to test bottled water in Canada. Can J Microbiol 1994; 40:987. Pseudomonas P. aeruginosa is the most common cause of respiratory failure in CF and is responsible for the death of the majority of these patients. Acquisition of P. aeruginosa begins early in childhood (median 1 year). Li Z, Kosorok MR, Farrell PM, et al. Longitudinal development of mucoid Pseudomonas aeruginosa infection and lung disease progression in children with cystic fibrosis. JAMA 2005; 293:581. Pseudomonas It is believed that the organism is initially acquired from environmental sources, but patient-to-patient spread may also occur in clinics and families. Kosorok MR, Jalaluddin M, Farrell PM, et al. Comprehensive analysis of risk factors for acquisition of Pseudomonas aeruginosa in young children with cystic fibrosis. Pediatr Pulmonol 1998; 26:81. Pseudomonas The initial acquisition of P. aeruginosa in the CF lung is with nonmucoid strains and occurs early in life (median 1 year). Over time (median 11 years), there is a transition to a mucoid phenotype that is associated with deterioration in cough scores, chest x-ray scores, and pulmonary function. Li Z, Kosorok MR, Farrell PM, et al. Longitudinal development of mucoid Pseudomonas aeruginosa infection and lung disease progression in children with cystic fibrosis. JAMA 2005; 293:581. Pseudomonas Early airway colonization : The organism gains access to the airways and then attaches to cells via pili and flagella, which appear to be important for initial infection. DiMango E, Zar HJ, Bryan R, Prince A. Diverse Pseudomonas aeruginosa gene products stimulate respiratory epithelial cells to produce interleukin-8. J Clin Invest 1995; 96:2204. Pseudomonas Wild-type CFTR may be a cellular receptor for P. aeruginosa; thus, the defective CFTR in CF might be unable to take up the organism and to clear it from the airways. Pier GB, Grout M, Zaidi TS. Cystic fibrosis transmembrane conductance regulator is an epithelial cell receptor for clearance of Pseudomonas aeruginosa from the lung. Proc Natl Acad Sci U S A 1997; 94:12088. Pseudomonas The CF airways show mucous hypersecretion and a defect in mucociliary clearance that worsens with age; P. aeruginosa could take advantage of this situation because it is able to bind to the mucous and thus, be protected from phagocytosis. Vishwanath S, Ramphal R. Adherence of Pseudomonas aeruginosa to human tracheobronchial mucin. Infect Immun 1984; 45:197. Pseudomonas Mucoid phenotype: During prolonged colonization, P. aeruginosa isolates often convert to a mucoid phenotype through production of the polysaccharide alginate. Alginate production contributes to biofilm growth, decreased clearance by host immune responses, and tissue damage. Song Z, Wu H, Ciofu O, et al. Pseudomonas aeruginosa alginate is refractory to Th1 immune response and impedes host immune clearance in a mouse model of acute lung infection. J Med Microbiol 2003; 52:731. ACUTE PULMONARY EXACERBATIONS ●Increased cough ●Increased sputum production or chest congestion ●Decreased exercise tolerance ●Increased fatigue ●Decreased appetite ●Increased respiratory rate ●Change in sputum appearance ●Fever ●Absence from school ●Increased nasal congestion or drainage TREATMENT OF ACUTE PULMONARY EXACERBATIONS The standard of practice has been to treat pulmonary exacerbations in patients with P. aeruginosa with two antipseudomonal antibiotics. Flume PA, Mogayzel PJ Jr, Robinson KA, et al. Cystic fibrosis pulmonary guidelines: treatment of pulmonary exacerbations. Am J Respir Crit Care Med 2009; 180:802. TREATMENT OF ACUTE PULMONARY EXACERBATIONS Duration of treatment: Antibiotic treatment is typically continued until the signs and symptoms are largely resolved. In practice, this usually entails treatment for a minimum of 10 days to as long as 3 weeks, and occasionally more. VanDevanter DR, O'Riordan MA, Blumer JL, Konstan MW. Assessing time to pulmonary function benefit following antibiotic treatment of acute cystic fibrosis exacerbations. Respir Res 2010; 11:137. TREATMENT OF CHRONIC PULMONARY INFECTION Chronic oral antibiotics : Chronic use of antibiotics frequently induces antibiotic resistance, which does not necessarily abate when antibiotic treatment is stopped. Diver JM, Schollaardt T, Rabin HR, et al. Persistence mechanisms in Pseudomonas aeruginosa from cystic fibrosis patients undergoing ciprofloxacin therapy. Antimicrob Agents Chemother 1991; 35:1538. TREATMENT OF CHRONIC PULMONARY INFECTION There is little clinical data documenting the effectiveness of intermittent prophylactic antibiotics. One study of oral Ciprofloxacin administered for 10 days every three months for one year in a small number of patients failed to show benefits in terms of (FEV1), the number of hospitalizations, or the requirement for intravenous antibiotics. Sheldon CD, Assoufi BK, Hodson ME. Regular three monthly oral ciprofloxacin in adult cystic fibrosis patients infected with Pseudomonas aeruginosa. Respir Med 1993; 87:587. Inhaled antibiotics Inhaled tobramycin : Treatment with nebulized tobramycin in patients chronically infected with P. aeruginosa improves lung function and reduces acute pulmonary exacerbations. Bowman CM. The long-term use of inhaled tobramycin in patients with cystic fibrosis. J Cyst Fibros 2002; 1:194. Inhaled antibiotics Randomized, double blind, multicenter trial in 520 patients with stable CF. Compared with a control group, subjects receiving tobramycin had a 10% higher FEV1 at 20 weeks, a decrease in the sputum density of P. aeruginosa, and a 26% decrease in the likelihood of hospitalization during the trial. Ramsey BW, Pepe MS, Quan JM, et al. Intermittent administration of inhaled tobramycin in patients with cystic fibrosis. Cystic Fibrosis Inhaled Tobramycin Study Group. N Engl J Med 1999; 340:23. Inhaled antibiotics In a two-year, follow-up of patients, ongoing use of inhaled tobramycin was associated with greater improvement in FEV1 and with an increase in (BMI). Inhaled antibiotics A powdered form of tobramycin received approval from the (FDA) in March, 2013 for CF patients 6 years of age and older. The 112 mg dose is delivered by inhaling the contents of 4 capsules using a specially designed apparatus. Parkins MD, Elborn JS. Tobramycin Inhalation Powder™: a novel drug delivery system for treating chronic Pseudomonas aeruginosa infection in cystic fibrosis. Expert Rev Respir Med 2011; 5:609. Inhaled antibiotics Inhaled aztreonam lysine: FDA approved inhaled aztreonam (Cayston) in February 2010. Aztreonam is administered using a high efficiency nebulizer (eFlow/Altera). 75 mg three times a day for one month, every other month. Inhaled antibiotics Inhaled colistin : The renal and neurotoxicity of inhaled colistin appears minimal when 150 mg of colistimethate sodium is diluted in 2 mL of sterile water and administered by nebulizer twice per day. However, bronchospasm may be induced. Alothman GA, Ho B, Alsaadi MM, et al. Bronchial constriction and inhaled colistin in cystic fibrosis. Chest 2005; 127:522. Approach The recommendations of an expert panel that all patients over 6 years of age who are colonized with P. aeruginosa should be treated chronically with inhaled tobramycin. 300 mg in 5 cc by nebulizer twice daily for one month, on alternate months. Flume PA, O'Sullivan BP, Robinson KA, et al. Cystic fibrosis pulmonary guidelines: chronic medications for maintenance of lung health. Am J Respir Crit Care Med 2007; 176:957. Approach Inhaled aztreonam instead of tobramycin : ●The patient does not tolerate inhaled tobramycin. ●The patient is deteriorating clinically despite inhaled tobramycin. ●The patient is considered more likely to be adherent to inhaled aztreonam. ●The patient is or may soon become pregnant, which makes aminoglycosides relatively contraindicated. Approach Colistin only in those patients who are not doing well despite tobramycin and/or aztreonam, or in those who do not tolerate them. Saiman L, Mehar F, Niu WW, et al. Antibiotic susceptibility of multiply resistant Pseudomonas aeruginosa isolated from patients with cystic fibrosis, including candidates for transplantation. Clin Infect Dis 1996; 23:532. Other strategies Prevention of acquisition : A randomized trial of oral cephalexin was performed in young children. Cephalexin or placebo was started at the time of CF diagnosis and administered continuously for seven years. Cephalexin was successful in reducing the prevalence of S. aureus infection, but the incidence of P. aeruginosa infection actually increased. Stutman HR, Lieberman JM, Nussbaum E, Marks MI. Antibiotic prophylaxis in infants and young children with cystic fibrosis: a randomized controlled trial. J Pediatr 2002; 140:299. Other strategies Oral ciprofloxacin and inhaled colistin. Three-week courses of these medications were administered every three months for three years. No difference between rates of initial or chronic P. aeruginosa. Tramper-Stranders GA, Wolfs TF, van Haren Noman S, et al. Controlled trial of cycled antibiotic prophylaxis to prevent initial Pseudomonas aeruginosa infection in children with cystic fibrosis. Thorax 2010; 65:915. Other strategies Early eradication of P. aeruginosa: The Cystic Fibrosis Center in Copenhagen, Denmark has adopted a policy of performing monthly sputum cultures for all patients with CF. When P. aeruginosa is first isolated, oral ciprofloxacin and aerosolized colistin are begun. The treatment is repeated and prolonged if P. aeruginosa is not eradicated or if it reappears after treatment. Johansen HK, Nørregaard L, Gøtzsche PC, et al. Antibody response to Pseudomonas aeruginosa in cystic fibrosis patients: a marker of therapeutic success?--A 30-year cohort study of survival in Danish CF patients after onset of chronic P. aeruginosa lung infection. Pediatr Pulmonol 2004; Other strategies Current evidence supports the use of inhaled tobramycin alone to treat patients for newly acquired P. aeruginosa. In a multicenter trial, 304 children with newly acquired P. aeruginosa were treated with inhaled tobramycin for 28 days, with or without concomitant oral ciprofloxacin. Treggiari MM, Retsch-Bogart G, Mayer-Hamblett N, et al. Comparative efficacy and safety of 4 randomized regimens to treat early Pseudomonas aeruginosa infection in children with cystic fibrosis. Arch Pediatr Adolesc Med 2011; 165:847. Other strategies Perform cultures of expectorated sputum or throat swabs every three months during routine clinic visits. When P. aeruginosa is first detected, we recommend treatment with inhaled tobramycin alone (300 mg in 5 mL, administered twice daily) for 28 days. Thank You