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