Pediatric Pulmonology 46:60–66 (2011)

Safety in Treatment of Ventilator-Associated Pneumonia

Due To Extensive Drug-Resistant Acinetobacter
Baumannii With Aerosolized Colistin in Neonates:
A Preliminary Report
Narongsak Nakwan, MD,1,2* Jeerawan Wannaro, MD,2 Tipaporn Thongmak, MD,2
Pornpat Pornladnum, MD,2 Ratchanee Saksawad, MD,2 Narongwit Nakwan, MD,3
and Kulkanya Chokephaibulkit, MD4
Summary. Background: Infections caused by extensive drug-resistant Acinetobacter baumannii
(XDR-AB) have been increasingly observed and are associated with a high mortality rate. We
present our experience using aerosolized colistin for the treatment of ventilator-associated
pneumonia (VAP) due to XDR-AB in neonates. Methods: The clinical data of neonates who
received aerosolized 4 mg per kg of colistin base twice daily as an adjunctive therapy for VAP
caused by XDR-AB between July 2008 and September 2009 were retrospectively reviewed. The
outcomes were compared with the neonates with VAP from XDR-AB in October 2006–September
2007 who did not receive aerosolized colistin. Results: During the study period, eight neonates
(three preterm and five term neonates) with VAP caused by XDR-AB received aerosolized colistin.
All isolated pathogens from the tracheobronchial specimens of the eight patients were XDR-AB
susceptible to colistin only. Six patients received aerosolized colistin without concomitant
intravenous colistin. All children were cured with eradication of XDR-AB from respiratory
secretions. Seven patients survived and were discharged from the hospital, and one died from
bacterial sepsis unrelated to the VAP episode. There were no clinical or laboratory adverse events
related to aerosolized colistin. Compared to the seven neonates in the earlier period, the neonates
who received aerosolized colistin had higher birth weight and gestational age, and lower mortality
rate (13% vs. 71%, P ¼ 0.04). Conclusions: Aerosolized colistin may be a useful adjunctive therapy
in VAP due to XDR-AB. The use of aerosolized colistin in neonates should be investigated in a
larger controlled study. Pediatr Pulmonol. 2011; 46:60–66. ß 2010 Wiley-Liss, Inc.

Key words: Acinetobacter baumannii; aerosolized colistin; neonates; pneumonia.

Funding source: none reported.

INTRODUCTION
Extensive drug resistant Acinetobacter baumannii
(XDR-AB), the isolates that resist to all available
antimicrobial drugs except for colistin and tigecycline,
has emerged as an important cause of nosocomial
infection worldwide,1,2 and is causing an increase in
mortality and complications in pediatric intensive care
units.3 Due to the lack of new effective antimicrobial
agents, older agents such as colistin has been used
widely to treat infections from this extensively resistant
pathogen.4,5
Colistin, a polymyxin E, exerts its effect through a
concentration-dependent bactericidal mechanism. It binds
with the anionic lipopolysaccharide molecule by displac-
ing calcium and magnesium in the outer cell membrane of
Gram-negative bacteria (GNB), leading to outer mem-
brane disruption and cell death, and also reduces the
production of endotoxins and cytokines.4,6 Colistin has
1
Neonatal Intensive Care Unit, Hat Yai Medical Education Center, Hat Yai
Hospital, Songkhla, Thailand.
2
Department of Pediatrics, Hat Yai Medical Education Center, Hat Yai
Hospital, Songkhla, Thailand.
3
Department of Medicine, Hat Yai Medical Education Center, Hat Yai
Hospital, Songkhla, Thailand.
4
Division of Infectious Diseases, Department of Pediatrics, Faculty of
Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
*Correspondence to: Narongsak Nakwan, MD, Neonatal Intensive Care
Unit, Department of Pediatrics, Hat Yai Medical Education Center, Hat Yai
Hospital, Songkhla 90110, Thailand. E-mail: nnakwan@hotmail.com
Received 5 March 2010; Revised 31 May 2010; Accepted 22 June 2010.
DOI 10.1002/ppul.21324
Published online 1 September 2010 in Wiley Online Library
(wileyonlinelibrary.com).

ß 2010 Wiley-Liss, Inc.

 VAP Treated With Aerosolized Colistin in Neonates
good in vitro efficacy against XDR-AB but has potential
toxicity, including nephrotoxicity (20%) or neurotoxicity
(7%).7–9 Moreover, the efficacy of this drug in treating
pneumonia may be limited due to low penetration of the
drug into lung tissue.10 Aerosolized administration may be
an appropriate route to deliver the drug and also to reduce
systemic toxicity. Aerosolized colistin has been used in
chronically infected cystic fibrosis patients to stabilize
lung function and reduce bacterial colonization in the
respiratory tract.11 Recently, there have been reports of
treating ventilator-associated pneumonia (VAP) due to
XDR-GNB with aerosolized colistin.12–15 To our knowl-
edge, there has been no report on using aerosolized colistin
for adjuctive therapy of VAP in the neonatal population.
We report our experience of using aerosolized colistin for
the treatment of VAP due to XDR-AB in neonates.
MATERIALS AND METHODS
Study Design and Data Collection
At our neonatal intensive care unit (NICU), a level III
12-beds unit at Hat Yai, Southern Thailand, from October
2006 to September 2007, there were 670 neonates
admitted. Of the 276 cases who were mechanically
ventilated, 39 (14%) had VAP, and 7 were due to XDR-
AB with 71% of mortality at VAP episode. Because of the
emergence of this resistant bacteria with high mortality
rate, and the concern about systemic side effects of colistin
with the potential benefit of aerosolized colistin reported
from some studies in adults, we offered aerosolized
colistin as adjunctive treatment to neonates who had VAP
caused by XDR-AB starting in July 2008. No other
treatment intervention was instituted. Infectious control
measures were stringent, including hand hygiene and
contact isolation. The environment culture to search for
reservoir of the XDR-AB was performed.
This presenting study aimed to report our experience of
using aerosolized colistin in neonates. We performed a
retrospective review of medical records of neonates who
received aerosolized colistin for more than 72 hr for
treatment of XDR-AB VAP. For each case of XDR-AB
VAP, we collected data regarding the basal characteristics,
the clinical and laboratory characteristics of the infection,
and the outcome. The study was approved by the Hat Yai
Ethics Committee.
Administration of Aerosolized Colistin
Colistimethate sodium (CMS; Colistate 1501; Atlantic
Pharmaceutical Co. Ltd, Thailand) used for aerosol
preparation has been approved for intravenous use in
Thailand since 2004. Each vial contained 360 mg of CMS,
which is equivalent to about 4.5 million IU or 150 mg of
colistin base activity. The parents were informed about the
drug options and were required to give approval before the
61
aerosolized colistin was started. CMS dry powder of
150 mg colistin was prepared for inhalation by NICU
nurses by dissolving in 2 ml of sterile normal saline 0.9%.
The 4 mg per kg of colistin of this solution was then diluted
with 3 ml of sterile normal saline 0.9%. Each preparation
took approximately 5 min with sterile technique. The final
suspension was aerosolized by a Servo Ultra Nebulizer in
the SERVO-i ventilator (Maquet, Solna, Sweden) for
15 min every 12 hr. The patients who received the
treatment were monitored for outcomes (e.g., survival,
and duration of mechanical ventilation after treatment)
and toxicity. The heart rate, respiratory rate, blood
pressure, and oxygen saturation were monitored during
each aerosol therapy. The renal functions including
creatinine clearance, using Schwartz formula,16 were
checked before and within 3 days after finishing treatment.
The use of intravenous antibiotics was not restricted for
patients receiving aerosol therapy.
Definitions
The criteria for diagnosis of VAP followed U.S. Centers
for Disease Control and Prevention (CDC) guidelines, that
is, the patient was required to have received mechanical
ventilation for 48 hr or more and to have a new or
progressive infiltrate, consolidation, cavitation, or pleural
effusion as shown on chest radiograph. In addition, the
patient had to have one or more of the following: new
purulent sputum or a change in the character of the
sputum; an organism isolated from a blood culture that
was not related to another source of infection; isolation of
pathogens from a specimen obtained by transtracheal
aspirate.17
XDR-AB was defined as an A. baumannii isolate that
was resistant to all cephalosporins, carbapenems, amino-
glycosides, quinolones, and ceperazone/sulbactam. Sus-
ceptibilities of A. baumannii were determined by the disk
diffusion method. Because the 2010 Clinical and Labo-
ratory Standards Institute (CLSI) guidelines does not
define the cut-off for disk diffusion test of colistin for A.
baumannii,18 we followed the National Committee for
Clinical Laboratory Standards in 1981,19 which was
similar to the cut-off recommended for Pseudomonas
aerugenosa in the current CLSI guidelines.18 The 10 mg
colistin disks (Benex Limited, Shannon, County Clare,
Ireland) was used for the test. Isolates were considered
sensitive if the inhibition zone was
11 mm and resistant
if the inhibition zone was <11 mm.7,19 The minimum
inhibitory concentration (MIC) was not determined.
Statistical Analysis
Data were evaluated using descriptive statistics
(median (range: minimum–maximum), and proportion
(%)). To evaluate the effect of aerosolized colistin on the
outcome, the seven neonates with XDR-AB VAP during
Pediatric Pulmonology
62 Nakwan et al.
October 2006 to September 2007, before we started to
offer this treatment, were compared with those who
received treatment. The variables were gestational age,
sex, birth weight, Apgar score, duration of mechanical
ventilation before VAP onset, antibiotic treatment, and
mortality. The Mann–Whitney U-test was used for
continuous variables, and Fisher’s exact test was used
for comparisons of categorical data. A P-value of <0.05
was considered statistically significant. Data analyses
were performed using SPSS 13.0 (SPSS, Inc., Chicago,
IL).
RESULTS
Patient Characteristics
From July 2008 to September 2009, 697 were admitted
to our NICU. Of the 288 cases who were mechanically
ventilated, 15 (5%) developed VAP while receiving
mechanical ventilation. Of these, eight (53%) had VAP
due to XDR-AB, three premature and five full-term, and
all received aerosolized colistin therapy. Characteristics
and outcomes of the eight patients are presented in Table 1.
The median gestational age and median birth weight
were 38 (range: 28–41) weeks, and 2,595 (range: 940–
3,825) g, respectively. All patients were mechanically
ventilated with the SERVO-i ventilator. The median onset
of VAP caused by XDR-AB was 10 (range: 3–36) days of
age. The median time from onset of VAP to start of
aerosolized colistin was 2 (range: 1–5) days.
Drug Administration
The median duration of aerosolized colistin was 9
(range: 4–14) days. Two neonates (Cases 1 and 2)
received intravenous colistin at the onset of VAP due to
XDR-AB with the duration of 5 and 3 days, respectively,
but they did not improve until aerosolized colistin was
given. The other six patients were successfully treated
with aerosolized colistin without intravenous colistin.
The intravenous antimicrobial agents given concurrently
were colistin plus cefoperazone/sulbactam plus vanco-
mycin (1 case), colistin plus meropenem plus vancomycin
(1 case), ceftazidime plus cefoperazone/salbactam plus
amikacin (1 case), and meropenem plus vancomycin
(5 cases). None of patients received steroid or broncho-
dilator during aerosol therapy with colistin.
Isolated Pathogens and Susceptibility
XDR-AB was isolated from endotracheal aspirates
from all eight neonates at least two separate times before
starting aerosolized colistin therapy. All XDR-AB isolates
were susceptible to colistin. At 72 hr after starting
aerosolized colistin, all of the follow-up cultures of
tracheobronchial aspirates revealed no growth.
Pediatric Pulmonology
Outcome, Safety, and Tolerability of Aerosolized
Colistin
All eight patients were cured from VAP caused by
XDR-AB. Seven patients were discharged from the
hospital, and one died from subsequent clinical sepsis
17 days after resolving from the VAP episode.
There were no clinical or laboratory adverse events
related to aerosolized colistin administration. Heart and
respiratory rate, blood pressure, and oxygen saturation
were stable during each aerosol therapy with colistin.
Serum creatinine and blood urea nitrogen remained within
normal limits during and within 72 hr after discontinued
aerosolized colistin therapy (median: 0.4, range: 0.3–
0.5 mg/dl; and 14, range: 6–27 mg/dl, respectively). The
median (range) creatinine clearance before and after
aerosolized colistin therapy were 38 (14–80) and 58 (28–
81) ml/min/1.73 m2, respectively.
Comparison With the 7 Neonateas Who Had VAP
Due To XDR-AB and Did Not Receive Aerosolized
Colistin in the Earlier Period (Control Group)
The basic characteristic data of the control group is
presented in Table 2. The most common used antimicro-
bial agents of the five dead cases from VAP were
ceperazone/sulbactam (three cases), meropenem (one
case), and ceftazidime plus amikacin (one case). The
other two cases who survived were treated with ceper-
azone/sulbactam (one case), and meropenem plus piper-
acillin/tazobactam plus vancomycin (one case). In
comparison with the eight infants that received aerosol-
ized colistin, the control group had lower median gesta-
tional age (29 vs. 38 weeks, P ¼ 0.03), lower median birth
weight (1,210 vs. 2,595 g, P ¼ 0.03), and higher mortality
rate (71% vs. 13%, P ¼ 0.04). Also, there was a significant
difference in the mortality between the control and the
aerosolized colistin group (Table 2).
DISCUSSION
Colistin (or Polymyxin E) is an antibiotic discovered
from Bacillus polymyxa subspecies colistinus in Japan in
1949.20 There are two forms of colistin commercially
available: colistin sulfate for oral and topical use, and
CMS for parenteral use. In early clinical practice, colistin
was used for treatment of infections caused by GNB.
Colistin was gradually withdrawn from clinical practice
because of its reported nephrotoxicity and neuro-
toxicity.7–9 In recent years, however, XDR-AB nosoco-
mial infections have emerged which are causing mortality
in intensive care units worldwide. Neonates in intensive
care units have an even a higher risk of mortality due to
their immature host immunity. The lack of safe and
effective antimicrobial agent available for treatment has
 TABLE 1— Clinical and Laboratory Characteristics and Outcome of Eight Patients Receiving Aerosolized Colistin for Treatment XDR A. baumannii VAP

Case 1 Case 2 Case 3 Case 4 Case 5 Case 6 Case 7 Case 8

Gestational age (weeks) 31 28 39 38 38 41 41 31

Sex Male Male Male Male Female Female Male Female
Birth weight (g) 1,485 940 3,880 3,825 2,310 2,880 3,420 1,240
Apgar scores (1, 5 min) 3, 5 9, 9 0, 2 5, 9 10, 10 7, 8 1, 2 9, 9
Underlying diseases RDS, BPD RDS, BPD HIE TTNB, PPHN MAS, PPHN MAS, PPHN MAS, PPHN RDS
Age of pneumonia onset (days) 3 36 6 14 6 8 12 22
Clinical manifestations of pneumonia Fever, tachypnea Hypothermia, Fever, tachypnea Fever, tachynea, Fever, tachypnea Fever, tachypnea Fever, tachypnea Fever, tachypnea
onset tachypnea irritable
Duration of MV before pneumonia onset 3 36 6 14 6 8 12 22
(days)
Time from pneumonia onset to time 2 2 5 1 1 3 2 3
aerosolized colistin was given (days)
Site of infection VAP VAP VAP VAP VAP VAP VAP VAP
Duration of aerosolized colistin (days) 4 14 14 10 7 7 7 10
Duration of concurrent intravenous anti- Colistin: 15 days Colistin: 9 days Ceftazidime: 5 days, Meropenem: Meopenam: Meropenem: Meropenem: 14 days Meropenem:
microbial treatment Amikacin: 5 days 21 days 7 days 10 days 14 days
Cep/Sul: 14 days Meropenem: Cep/Sul: 14 days Vancomycin: Vancomycin: Vancomycin: Vancomycin: 14 days Vancomycin:
18 days 21 days 10 days 10 days 10 days
Vancomycin: Vancomycin:
14 days 10 days
Investigations at pneumonia onset
White blood cells count (cells/mm3) 2,200 31,700 6,500 23,800 29,900 4,200 25,300 18,600
Hemoglobin (g/dl) 14 11 14 15 17 15 12 10
Hematocrit (%) 43 32 42 44 50 47 36 29
Platelets count (cells/mm3) 140,000 63,000 171,000 230,000 94,000 110,000 106,000 412,000
Blood culture Negative Negative Negative Negative Negative Negative Negative Negative
Outcome:
Outcome of infection Cure Cure Cure Cure Cure Cure Cure Cure
Outcome of patient Died from 2nd Discharge Discharge Discharge Discharge Discharge Discharge Discharge
episode of sep-
sis
Duration of MV after pneumonia 31 35 21 10 7 1 1 12
onset (days)
Safety
Renal function on the first day/within
3 days after finishing aerosolized
colistin therapy
Blood urea nitrogen (mg/dl) 18/8 14/12 24/12 29/27 7/15 18/17 29/19 8/6
Creatinine (mg/dl) 1.0/0.5 0.4/0.3 0.5/0.3 0.3/0.4 0.4/0.3 0.8/0.3 0.5/0/4 0.8/0.4
Creatine clearance (ml/min/ 14/28 31/42 49/81 80/60 59/69 27/72 45/56 17/33
1.73 m2)

XDR, extentive drug-resistant; VAP, ventilator-associated pneumonia; RDS, respiratory distress syndrome; BPD, bronchopulmonary dysplasia; HIE, hypoxic ischemic encephalopathy; PPHN,
VAP Treated With Aerosolized Colistin in Neonates

persistent pulmonary hypertension of the newborn; MAS, meconium aspiration syndrome; MV, mechanical ventilation; Cep/Sul, ceperazone/sulbactam.
63

Pediatric Pulmonology
64 Nakwan et al.
TABLE 2— Comparison of Demographic and Clinical Characteristics Between the Infants With XDR- A. baumannii VAP
Who Received Aerosolized Colistin and Those Who Did Not Received Colistin
Variables Received aerosolized colistin (n ¼ 8)
Gestation age (weeks), median (range) 38 (28–41)
Birth weight (g), median (range) 2,595 (940–3,880)
Male (%) 5 (63%)
Apgar score at 1 min, median (range) 6 (0–10)
Apgar score at 5 min, median (range) 8 (2–10)
Duration of MV before VAP onset 10 (3–36)
(days), median (range)
Death (%) 1 (13%)
XDR, extensive drug-resistant; VAP, ventilator-associated pneumonia; MV, mechanical ventilation.
been a serious problem.1–3 An in vitro study found that
most XDR-AB isolates remained susceptibility to coli-
stin.7 Therefore, colistin seems to be one of the few
effective and available drugs for these infections. More-
over, colistin is a relatively low-cost drug, which as been
commonly used for resistant GNB infections in resource
limited settings, despite the concerns about toxicity.4–10 In
studies in adults, aerosolized colistin was effective in
treating 83% of VAP.13 In children, the experience with
colistin has been limited. Goverman et al.21 reported using
colistin in 14 pediatric burn patients for treatment of XDR-
GNB infections with a 79% cure rate, and three of the
patients were successfully treated with an aerosolized
colistin.
Colistin has been reported to poorly penetrate into lung
tissue.10 Because aerosolized administration directly
delivers drugs to the lungs, aerosolized colistin has
been used widely to prevent and treat pneumonia in
patients with cystic fibrosis, resulting in less systemic
toxicity.22–23 Moreover, several studies have described
successful treatment using this drug via aerosol therapy in
nosocomial pneumonia in adult patients.12–15 To our
knowledge, the present report is the first published case
series on the use of aerosolized colistin as an adjuvant
therapy for the treatment of VAP caused by XDR-AB in
neonates.
Our report suggests that aerosolized colistin could be a
helpful adjunctive therapy in VAP due to XDR-AB in
neonates. In comparison to the patients with similar
infection earlier who did not receive aerosolized colistin,
we found the mortality rate of XDR-AB VAP was
significantly reduced after using an aerosolized colistin.
However, significant lower gestational age and birth
weight of the control group could be explained a higher
morality rate. There has been no recommended dose of
colistin for use by this route in neonates. The dosage of
colistin used in the present study (4 mg/kg twice daily)
was extrapolated from the dosage of 80 mg twice daily that
was used in children > 6 years old with cystic fibrosis.23 A
pharmacokinetic study of aerosolized colistin in cystic
fibrosis patients22 revealed that the maximum observed
serum colistin concentration was 0.178 mg/L, <10% of
Pediatric Pulmonology
Not received aerosolized colistin (n ¼ 7) P-value
29 (28–34) 0.03
1,210 (760–1,980) 0.03
5 (71%) 1.00
5 (3–8) 0.93
7 (5–9) 0.62
5 (5–32) 0.89
5 (71%) 0.04
the level in sputum, and much less than the maximal level
of 2.8–13.9 mg/L achieved by the intravenous route24–25
and was undetectable 12 hr after inhalation. We did not
measure the plasma level of colistin in our patients, and it
is unknown how much systemic absorption of colistin
would occur via this route in neonates, but it is reasonable,
based on the experience with older patients, to assume
low-serum levels and therefore lower risk of systemic side
effects.
Our experience suggests that aerosolized colistin for
VAP may offer advantages over systemic administration.
Two patients in our report (Cases 1, and 2) did not respond
to treatment with intravenous colistin until aerosolized
colistin was added. The other six cases were successfully
treated with aerosolized colistin without intravenous
colistin. It has been reported that colistin is active against
certain growths of pathogens inside biofilms.26 Aerosol-
ized delivery yields high concentration in the airways22
and may be able to inhibit growth of bacteria inside the
biofilm in intubated patients. Follow-up cultures from
endotracheal aspirates revealed eradication of the patho-
gen after aerosol therapy, which would not be possible by
systemic antimicrobial therapy. However, because colistin
is absorbed poorly via topical treatment, aerosolized
administration will not be able to treat pneumonia that is
associated with systemic infection.22
One of the arguments against aerosolized administra-
tion of antibiotics therapy for pneumonia has been that the
aerosol may be concentrated or stuck in the proximal
airway and not able to reach alveoli. We used Servo Ultra
Nebulizer in the SERVO-i ventilator (ultrasonic nebulizer)
that was expected to deliver aerosolized particles of
<5 mm.27 This ultrasonic nebulizer was also used by
Michalopoulos et al.13 to successfully treat adult patients
with VAP. This nebulizer device could be an important
factor of success in aerosolized delivery to alveoli and
contribute to good outcomes. Traditional nebulization
with high-flow oxygen yields various sizes of aerosol and
may not reach alveoli, although it was used successfully in
the study by Michalopoulos et al.12 Other nebulizers used
with satisfactory results in patients with cystic fibrosis
were PARI LC Star jet nebulizer (PARI, Sternberg,
 VAP Treated With Aerosolized Colistin in Neonates
Germany) and Ventstream jet nebulizer (Medi-Aid,
Bognor Regis, UK).23,24,28
Nephrotoxicity and neurotoxicity are the most common
potential toxicities with parenteral administration of CMS
in early clinical studies.7–9 For aerosolized CMS, there
have been reported side effects in adult and pediatric
patients, such as bronchospasm, chest tightness, or renal
insufficiency.28,29 In this report, none of our eight patients
experienced clinical adverse events during or after
aerosolized colistin therapy. There were no abnormalities
in the laboratory parameters of renal function.
Our study was limited by the small sample size and
presence of many confounders. The results of environ-
mental cultures showed there was 32 isolates from 20
specimens and 3 isolates were XDR-AB. These were from
nurse counters, radiant warmers, and tourniquet rubber.
With the rid of reservoir of infection and strict infectious
control measures, it was likely to get additional infection,
and may affect a better outcome during the period that
aerosolized colistin was used. All patients received other
intravenous antimicrobial agents, which might have
influenced the outcome. Ideally, susceptibility testing of
colistin to isolated pathogens should be confirmed with the
broth and agar dilution method, because the disk diffusion
method may reveal false-susceptibility.30 However, if this
was the isolates that resistant to colistin, it would be even
more impressive that aerosolized colistin was able to
eradicate colonization with a favorable clinical outcome.
In summary, we found that aerosolized colistin was
well-tolerated, safe, and may be an effective alternative or
adjunctive treatment for XDR-AB pneumonia in neo-
nates. The appropriate dose of aerosolized colistin
remains to be determined. A larger prospective, controlled
study is warranted.
ACKNOWLEDGMENTS
We thank the pediatric staffs, pediatric residents, and
nurses for caring for all patients. The authors thank
Dr. Chulalak Komonti, Department of Developmental
Research, Siriraj Hospital Faculty of Medicine, Mahidol
University, Bangkok, Thailand, for important statistical
assistance, and also thank Dr. Simonds RJ for critical
reviewing the manuscript.
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