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Pediatric Pulmonology 45:11351140 (2010)

Inhaled Colistin for the Treatment of Tracheobronchitis


and Pneumonia in Critically Ill Children
Without Cystic Fibrosis
Matthew E. Falagas, MD, MSc, DSc,1,2,3* Georgia Sideri, MD,4 Ioanna P. Korbila, MD,1
Evridiki K. Vouloumanou, MD,1 John H. Papadatos, MD, PhD,4 and Dimitris A. Kafetzis, MD, PhD5
Summary. Data regarding the role of inhaled colistin in critically ill pediatric patients without cystic
fibrosis are scarce. Three children (one female), admitted to the intensive care unit (ICU) of a
tertiary-care pediatric hospital in Athens, Greece, during 20042009 received inhaled colistin as
monotherapy for tracheobronchitis (two children), and as adjunctive therapy for necrotizing
pneumonia (one child). Colistin susceptible Acinetobacter baumannii and Pseudomonas
aeruginosa were isolated from the cases bronchial secretions specimens. All three children
received inhaled colistin at a dosage of 75 mg diluted in 3 ml of normal saline twice daily
(1,875,000 IU of colistin daily), for a duration of 25, 32, and 15 days, respectively. All three children
recovered from the infections. Also, a gradual reduction, and finally total elimination of the microbial
load in bronchial secretions was observed during inhaled colistin treatment in the reported cases.
All three cases were discharged from the ICU. No bronchoconstriction or any other type of toxicity of
colistin was observed. In conclusion, inhaled colistin was effective and safe for the treatment of two
children with tracheobronchitis, and one child with necrotizing pneumonia. Further studies are
needed to clarify further the role of inhaled colistin in pediatric critically ill patients without cystic
fibrosis. Pediatr Pulmonol. 2010; 45:11351140. 2010 Wiley-Liss, Inc.

Key words: Gram-negative infections; polymyxins; Pseudomonas; Acinetobacter; inten-


sive care unit.

Funding source: none reported.

INTRODUCTION both ventilator-associated tracheobronchitis (VAT) and


ventilator-associated pneumonia (VAP).12,13 Recent data
The use of inhaled antibiotics for the prevention and
provide preliminary evidence of inhaled colistins value to
treatment of difficult-to-treat infections of the respiratory
cure difficult-to-treat infections of the respiratory tract
tract has been investigated over the past years. Inhaled
tobramycin and colistin are recommended as an early 1
eradication and maintenance therapy in patients with Alfa Institute of Biomedical Sciences (AIBS), Athens, Greece.
cystic fibrosis and chronic Pseudomonas aeruginosa 2
Department of Medicine, Henry Dunant Hospital, Athens, Greece.
infection.13 Inhaled pentamidine is suggested as an
alternative prophylactic regimen against Pneumocystis 3
Department of Medicine, Tufts University School of Medicine, Boston,
jirovecii pneumonia in immunocompromised patients.4 Massachusetts.
Inhaled ribavirin is also used to treat severe infections of 4
Pediatric Intensive Care Unit, P. & A. Kyriakou Childrens Hospital,
the lower respiratory tract, caused by respiratory syncytial Athens, Greece.
virus (RSV), in children.5 Inhaled zanamivir is considered
to be effective for the treatment of influenza infection and 5
Second Department of Pediatrics, University of Athens, P. & A. Kyriakou
the prevention of influenza outbreaks.6,7 Childrens Hospital, Athens, Greece.
The strategy of antimicrobial drug delivery through
*Correspondence to: Matthew E. Falagas, MD, MSc, DSc, Alfa Institute of
inhalation has been tested in adult and children popula- Biomedical Sciences (AIBS), 9 Neapoleos Street, 151 23 Marousi, Athens,
tion. Specifically, regarding colistin, several studies in Greece. E-mail: m.falagas@aibs.gr
adult and pediatric patients with cystic fibrosis have
investigated the role of inhaled colistin to eradicate Received 1 February 2010; Revised 19 March 2010; Accepted 13 April
P. aeruginosa, which chronically colonizes the respiratory 2010.
tract, as well as its adverse events.811 Patients on DOI 10.1002/ppul.21302
mechanical ventilation constitute a high-risk group Published online 23 July 2010 in Wiley Online Library
for difficult-to-treat respiratory infections, including (wileyonlinelibrary.com).

2010 Wiley-Liss, Inc.


1136 Falagas et al.

caused by multi-drug resistant Gram-negative pathogens pattern of these isolates is presented in the Table 1). In this
such as P. aeruginosa, A. baumannii, and Klebsiella regard, inhaled colistin was administered alone at a dosage
pneumoniae in the intensive care unit (ICU) setting in of 75 mg diluted in 3 ml of normal saline twice daily (this
patients without cystic fibrosis.1418 On the other hand, in equals to a daily dosage of 1,875,000 IU of colistin,
the field of pediatric critical care medicine there is a lack of administered in two divided doses) for 25 days.
evidence regarding the role of inhaled colistin to treat such At day 21 of inhaled colistin treatment, a culture of
infections.19,20 tracheobronchial secretions with normal flora was
In this regard, in this small case series we present data obtained. Bronchoconstriction, attributed to the tracheo-
regarding critically ill pediatric patients hospitalized in the bronchitis, was present before the initiation of inhaled
ICU of a tertiary care pediatric hospital in Athens, Greece, colistin and was unsuccessfully treated with bronchodi-
who did not suffer from cystic fibrosis and received lators (specifically, salbutamol and ipratropium). Bron-
inhaled colistin for infections of the lower respiratory choconstriction did not worsen during treatment. The
tract. outcome of the infection was favorable. However, the
child exhibited serious neurological deficiencies that led
to the need of permanent tracheostomy and gastrostomy.
Case Description
Children who received inhaled colistin (colistimethate
Case 2
sodium) [1 mg equals 12,500 international units (IU) of
colistin base activity] in the ICU of the P. & A. Kyriakou Case 2 was a 7.5-month-old female with no underlying
tertiary-care pediatric hospital during 20042009, were disease, nor immunodeficiencies, who was admitted at the
identified by reviewing ICU records. Data presented in this ICU with septic shock due to necrotizing pneumonia
study were extracted from medical charts. Specifically, caused by P. aeruginosa, which was isolated in blood and
data regarding the demographical characteristics, under- bronchial secretions cultures obtained at the day of
lying disease, reason for ICU admission, length of stay in admission in the ICU. The susceptibility pattern of the
the ICU and duration of ventilation, type of infection, site P. aeruginosa is presented at the Table 1. The child
of isolation, and susceptibility pattern of each isolated received various intravenous antibiotic agents. Inhaled
pathogen, whether intravenous colistin was administered colistin was initiated 3 days after the acquisition of the
prior to inhaled colistin, the device used to deliver inhaled index cultures at a dosage of 75 mg diluted in 3 ml of
colistin, the type of the ventilator used, and presence of normal saline twice daily (a daily dosage of 1,875,000 IU
humidification, as well as time of institution, dosage and of colistin), administered in two divided doses) for
duration of inhaled colistin treatment, any concomitantly 32 days. Concomitant to inhaled colistin administration
administered antibiotics, quantitative measures of the of intravenous antibiotic regimens included piperacillin/
microbial load, the outcome and any adverse event tazobactam and gentamicin for the first 10 days of
reported are presented in the Table 1. The collection and administration of colistin and meropenem plus vancomy-
report of the data presented in our study was approved cin (due to the isolation of Staphylococcus coagulase-
from the hospitals ethical committee. Specifically, this negative from blood culture) for the following 11 days.
report on inhaled colistin constitutes a nested study within During the course of the infection the child developed
a larger one regarding the toxicity of rarely administered bilateral pleural effusions. Culture of the pleural fluid led
(either intravenously or through inhalation) antimicrobial to P. aeruginosa isolation, as well. At day 32 after the
agents in children. institution of inhaled colistin a culture consisting of
normal flora was obtained. Bronchoconstriction was not
observed at anytime during treatment. The child was cured
Case 1
from the infection, extubaded, and discharged from the
Case 1 was a 10-year-old male suffering from acute ICU.
disseminated encephalomyelitis attributed to infection
with influenza B virus. This child stayed in the ICU for
Case 3
7 months and developed five episodes of septicemia and
two episodes of septic shock for which he received various Case 3 was a 4-year-old female with no underlying
antibiotics. Polymyxin-only-susceptible A. baumannii disease who was admitted in the ICU with acute
was isolated in one blood culture, and the infection was respiratory distress syndrome due to thermal burn of the
cured with the administration of intravenous colistin. The airway requiring tracheostomy. The child received a
childs clinical manifestations were suggestive of tracheo- variety of intravenous antibiotics before the administra-
bronchitis and it also had a high microbial load, with a tion of inhaled colistin because of three episodes of
high microbial load of A. baumannii and P. aeruginosa in septicemia due to P. aeruginosa, Escherichia coli, and
cultures of tracheobronchial secretions (the susceptibility coagulase negative Staphylococcus spp., respectively.
Pediatric Pulmonology
Inhaled Colistin in Critically Ill Children 1137
TABLE 1 Characteristics and Outcomes of Critically Ill Children Without Cystic Fibrosis Who Received Inhaled Colistin
(Colistimethate Sodium) for the Treatment of Tracheobronchitis and Pneumonia

Patient 1 Patient 2 Patient 3

Age 10 y 7.5 mo 4y
Sex M F F
Underlying disease ADEM None None
Reason for ICU admission Encephalomyelitis Septic shock, necrotizing Respiratory burn, respiratory
pneumonia distress
Length of stay (LOS) in the ICU &7 mo &1.5 mo &3 mo
Length of time on the ventilator &1.5 mo (followed by &1.5 mo 11 d (followed by
tracheostomy) tracheostomy)
Type of infection Tracheobronchitis Necrotizing pneumonia Tracheobronchitis
Isolated pathogen(s) Acinetobacter baumannii, Pseudomonas aeruginosa Pseudomonas aeruginosa
Pseudomonas aeruginosa
Site of isolation Bronchial culture Bronchial culture Bronchial culture
Susceptibility pattern of the Acinetobacter baumannii Pseudomonas aeruginosa Pseudomonas aeruginosa
isolated pathogen(s) Amoxicillin-clavulanic acid: Piperacillin: S, piperacillin- Piperacillin: S, piperacillin-
S, minocycline: tazobactam: S, cefotaxime: tazobactam: S, ticarcillin-
I, doxycycline: I, and R, aztreonam: S, imipenem: clavulanate: S, cefotaxime:
colistin: S S, ciprofloxacin: R, aztreonam:
Pseudomonas aeruginosa S, gentamicin: I, tobramycin: S, ciprofloxacin:
Piperacillin: S, ciprofloxacin: I, netilmicin: I, and colistin: S S, gentamicin: I, tobramycin:
S, ticarcillin-clavulanate: S, I, netilmicin: I, and colistin: S
aztreonam: S, piperacillin-
tazobactam: S, imipenem: S,
gentamicin: R, tobramycin: R,
netilmicin: R, and colistin: S
Prior administration of Yes2 No Yes4
intravenous colistin
Concomitant antibiotic None i.v. (piperacillin-tazobactam None
treatment to inhaled colistin plus gentamicin for 10 d,
meropenem plus vancomycin
for the following 11 d)
Time of institution of inhaled Day 206 after ICU admission Day 3 after ICU admission Day 27 after ICU admission
colistin (while on tracheostomy) (while on intubation) (while on tracheostomy)
Dosage of inhaled colistin 75 mg diluted in 3 ml of normal 75 mg diluted in 3 ml of normal 75 mg diluted in 3 ml of normal
saline twice daily saline twice daily saline twice daily
Duration of treatment 25 d 32 d 15 d
with inhaled colistin
Delivery of inhaled colistin Via a nebulizer apparatus Via a nebulizer apparatus Via a nebulizer apparatus
connected to the connected to the connected to the
tracheostomy circuit ventilation system tracheostomy circuit
Type of ventilator Siemens Servo-i Ventilator3 Siemens Servo-i Ventilator5 Siemens Servo-i Ventilator3
Humidification On On On
Quantitative change of the Acinetobacter baumannii Pseudomonas aeruginosa Pseudomonas aeruginosa
microbial burden of the Day 1: >100,000 1 day prior to colistin Day 1: >100,000
isolated pathogen(s) institution: >100,000
(cfu/ml)/days after institution Day 4: 95,000 Day 3: 100,000 Day 4: 80,000
of inhaled colistin Day 11: 75,000 Day 10: 75,000 Day 8: Rare microbes found
Day 17: rare microbes found Day 16: 70,000 Day 11: natural flora
Day 21: natural flora Day 28: 5,000
Day 32: natural flora
Pseudomonas aeruginosa
Day 1: >100,000
Day 4: 75,000
Day 11: 45,000
Day 17: 6,000
Day 21: natural flora
Outcome Cured from the infection Cured from the infection Cured from the infection
Discharged from the ICU/ Discharged from the ICU Discharged from the ICU/
still with tracheostomyno still with tracheostomyno
colonization colonization

(Continued )

Pediatric Pulmonology
1138 Falagas et al.
TABLE 1 (Continued )

Patient 1 Patient 2 Patient 3

Adverse events
Nephrotoxicity No No No
Urea/creatinine1 (before (23/0.725/0.6) (47/715/0.3) (30/0.535/0.5)
colistin treatment after
colistin treatment)
Other toxicity No No No

F, female; M, male; ADEM, acute disseminated encephalomyelitis; y, year(s); mo, month(s); d, days; S, susceptibility; I, intermediate susceptibility;
R, resistant; i.v., intravenous.
1
mg/dl.
2
Administered for the treatment of Acinetobacter baumannii bacteremia.
3
Prior to colistin treatment.
4
Administered for the treatment of Pseudomonas aeruginosa bacteremia.
5
While on colistin treatment.

P. aeruginosa septicemia was treated successfully with pathogen was confirmed by quantitative cultures of
intravenous colistin. P. aeruginosa was also isolated from tracheobronchial secretions in all three cases.
cultures of tracheobronchial secretions. The susceptibility The rationale justifying the choice of inhaled colistin or
pattern of this isolate is presented in the Table 1. However, other appropriate inhaled antibiotics as monotherapy
due to the childs clinical manifestations, that were for the treatment of patients with tracheobronchitis is
suggestive of tracheobronchitis, and the persistence of a that tracheobronchitis represents a topical inflammatory
high microbial load of P. aeruginosa in tracheo- process that could be controlled with locally administered
bronchial secretions (>100,000 cfu/ml), inhaled colistin antibiotics.12 A placebo-controlled study in critically ill
alone was administered at a dosage of 75 mg diluted in patients with VAT showed that inhaled antibiotics
3 ml of normal saline twice daily for 15 days (a daily decreased the signs of respiratory infection and the use
dosage of 1,875,000 IU of colistin, administered in two of systemic antibiotics.21 In our cases the only active
divided doses). At day 11 of the administration of inhaled antibiotic agent for inhalation was colistin based on the
colistin a culture of tracheobronchial secretions consisting in vitro susceptibility pattern of the isolates. In addition,
of normal flora was obtained. Bronchoconstriction, based on preliminary evidence, adjunctive inhaled colistin
attributed to the tracheobronchitis, was present before to intravenous antibiotic treatment improved the outcome
the initiation of inhaled colistin and was unsuccessfully of pneumonia.17,22 On this ground, inhaled colistin was
treated with bronchodilators (specifically, salbutamol and selected as a therapeutic regimen for case 2.
ipratropium). Bronchoconstriction did not worsen during The dosage administered to the three children presented
treatment. The child recovered from the infection but in our study was 75 mg of colistimethate sodium diluted in
could not overcome the need for permanent tracheostomy 3 ml of normal saline, twice daily. This equals to a daily
and tracheal dilatations. dosage 1,875,000 IU of colistin, administered in two
divided doses. According to the national formulary, the
recommended dosage of inhaled colistimethate sodium
for children older than 2 years and adults with cystic
DISCUSSION
fibrosis is 12,000,000 IU, 23 times a day. Regarding the
We report a case series of pediatric critically ill patients 7.5-month-old infant in our report, the dosage of the
who received inhaled colistin for the treatment of 1,875,000 IU per day was chosen due to her critical
tracheobronchitis (two children) and pneumonia (one condition. All three children were closely monitored for
infant). Cases 1 and 3 of tracheobronchitis were caused by adverse events. No adverse event related to colistin
P. aeruginosa, while case 1 was co-infected with a multi- treatment was noted in our cases.
drug resistant A. baumannii isolate. Both these two cases In order to achieve the most of the benefits conferred by
recovered from the infections with the administration of inhaled antibiotics in mechanical ventilated patients
inhaled colistin alone. The remaining child had pneumo- several conditions should be met. The device used for
nia caused by P. aeruginosa. This patient was treated inhalation (nebulizer), the ventilator and the ventilator
concurrently with intravenous antibiotics depending on circuit, the inhaled agent and patient characteristics are
susceptibility results for the 2/3 of the total duration of aspects of major significance. Nebulizers are placed at a
inhaled colistin treatment. The outcome was cure for this distance from the endotracheal tube in the inspiratory limb
case also. Bacteriological eradication of the responsible of the ventilator circuit and their deliverance of small
Pediatric Pulmonology
Inhaled Colistin in Critically Ill Children 1139

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