Pseudomonas aeruginosa ventilator associated pneumonia: improved outcomes with earlier follow-up

doi:10.4236/health.2010.22014

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Vol.2, No.2, 82-89 (2010)

doi:10.4236/health.2010.22014

SciRes

Health

Pseudomonas aeruginosa ventilator assoc iated

pneumonia: improved outcomes with earlier follow-up

Elpis Giantsou1,2, N ikolaos L iratzopoulo s1, Eleni Efraimidou 1, Konstanti nos I. Manolas1, J.

Duncan You ng2

1Intensive Care Unit, Demokritus University of Thrace, Greece

2Adult intensive Care Unit, John Radcliffe Hospital, Oxford, United Kingdom; [email protected]

Received 27 October 2009; revised 16 December 2009; accepted 17 December 2009.

ABSTRACT

It is not clear what is the appropriate timing to

follow-up patients with ventilator-associated

pneumonia (VAP) and Clinical Pulmonary Infe-

ction Score >6 between days 3-5 of an appro-

priate antibiotic treatment. We studied 122

patients with Pseudomonas aeruginosa VAP. A

follow-up respiratory sample was collected on

days three or five ( “day-three” and “day-five”

group ) and treatment was modified 48h later.

Molecular typing identified super-infections or

persistence. For serial data another respiratory

sample was collected, on day three from the

“day-five” group and on day five from the

“day-three” group. Sixty patients, in the “day-

three” group compared to 62 in the “day-five”

group, had reduced fourteen-day mortality

( 18.3% and 38.7%; p=0.01 ) and fewer days in

intensive care unit (17.2 ± 4.3 compared to 27.3

± 4.7, p<0.05 ). Eighteen patients of the “day-

five” group were diagnosed with super-infec

tion and 22 with persistence on day five, of

whom 14 and 19 had b een havi ng these patterns

since day three. For patients with Pseudomonas

aeruginosa VAP and Clinical Pulmonary Infe-

ction Score >6, improved fourteen-day mortality

and shorter duration of stay in health-care

facilities were observed with earlier follow-up.

Keywords: Ventilator-Associated Pneumonia;

Clinical Pulmonary Infection Score; Pseudomonas

Aeruginosa

1. INTRODUCTION

In addition to its value in diagnosing ventilator-associa-

ted pneumonia (VAP), the Clinical Pulmonary Infection

Score (CPIS) has other uses [1]. Initial values of CPIS

may guide the duration of antibiotic therapy for patients

with VAP [2], while serial measurements may identify

patients as potentially un-responsive to antibiotic therapy,

when the value of the score is above six from day three

to day five of antibiotic treatment [3]. Further invest-

tigation of patients identified as potentially

un-responsive should ensure that the administered an-

timicrobials are appropriate and that extra-pulmonary

infections and non-infectious conditions are not involved

[4,5]. When the lung remains the suspected focus of in-

fection, the next step should involve a follow-up respi-

ratory sample to investigate treatment failure [6]. How-

ever, it is not clear from the data available [3,7] what is

the appropriate timing to collect a follow-up respiratory

sample from patients with VAP, in whom CPIS remains

>6, between days three to five of antibiotic treatment.

Should the follow-up respiratory sample be collected on

day three or a little later?

The objective was to evaluate an earlier compared

with a later timing to retrieve respiratory pathogens and

determine treatment failure, for patients with initially

appropriately treated Pseudomonas aeruginosa (P. A er-

uginosa) VAP, in whom the simplified CPIS [3]

remained >6 between days 3-5 of antibiotic therapy.

2. MATERIALS AND METHODS

The study was conducted at the University Hospital of

Thrace, during a 48-month period. Patients were entered

into the study if they met all the following: clinical sus-

picion for VAP [1]; two identical positive solely for P.

aeruginosa quantitative cultures, one of tracheal aspirate

and one of bronchoalveolar lavage (BAL) (thresholds of

>106 and >104 colony–forming units/ml, respectively);

and simplified CPIS>6 [3] between days 3-5 of treat-

ment. Patients were excluded if they had received solid

organ or bone marrow transplant or had evidence of

rapid deterioration within 72hr of treatment [8]. The

diagnostic and therapeutic approach is presented in Fig-

ure 1. Initial antibiotic treatment for P. aeruginosa with

daily infusion of Amikacin (20mg/kg per day) combined

with 6h bolus administration of Piperacillin- Tazobactam

4.5gm) was instigated within 6h of bronchoscopy. (

E. Giantsou et al. / HEALTH 2 (2010) 82-89

Figure 1. Schematic presentation of the diagnostic and therapeutic approach. VAP, ventilator-associated pneumonia; BAL,

bronchoalveolar-lavage; P.aeruginosa, Pseudomonas aeruginosa; CPIS, Clinical Pulmonary Infection Score.

E. Giantsou et al. / HEALTH 2 (2010) 82-89

Figure 2. Schematic representation of the approach used for serial microbiology and molecular typing.

The follow-up BAL was collected by the endoscopy

group on days three or five as determined by the avail-

ability of service and patients shall be referred to as the

“day-three” and the “day-five” group respectively. The

follow-up BAL cultures and sensitivity tests results re-

turned to the Intensive Care Unit (ICU) 48hr later and

were used to modify the antimicrobials. The duration of

treatment was 14 days [9].

Pulsed gel electrophoresis was applied to the BAL

samples at study entry and follow-up, to identify

whether P. aeruginosa isolated at follow-up was super-

infection or persistence of the initial isolate. The DNA

fragment patterns were interpreted as genetically indis-

tinguishable, closely related or unrelated [10,11]. Iso-

lates genetically unrelated to those grown at study entry

were considered super-infections, whereas isolates ge-

netically indistinguishable or closely related, were con-

sidered persistence.

For serial microbiologic and molecular typing data

two independent investigators performed BAL on day

three at the “day-five” group and on day five at the

“day-three” group (Figure 2). For cost reasons, no

sensitivity testing was undertaken for these samples,

when P. aeruginosa was isolated, because it was

previously tested from the same source. If growth, other

than P. aeruginosa, was isolated, then patients were

excluded and sensitivity was tested. The outcomes

evaluated were mortality, SAPS II [12] and SOFA [13]

on day 14, mortality on day 28, mortality in ICU and

hospital, duration of mechanical ventilation and duration

of stay in ICU and hospital after VAP. CPIS and organ

failures [13] were assessed on day 14.

3. STATISTICS

Data were expressed as mean ± standard deviation (SD)

or as percentages of total. Continuous data were com-

pared using Student’s t-test. The chi-square test with

Yates correction for proportions was used for categorical

variables. All tests were two sided. Significance was

accepted for p<.05. Data were analyzed using SPSS 11

(SPSS, Chicago, IL).

4. RESULTS

The admission and study entry characteristics of 122

patients with P.aeruginosa VAP appear in Table 1. The

CPIS score for the “day-three” and the “day-five” group

respectively it was 7.33 ( ± 0.47 ) vs 7.32 ( ± 0.59 ),

p=0.9 on day three and 7.08 ( ± 0.27 ) vs 7.1 ( 0.42 ) ,

p=0.46 on day five .

Super-infection and persistence rates of P. aeruginosa

as revealed by the follow-up BAL are presented in Table

2 and schematically in Figure 3. For both study groups,

the strains of P. aeruginosa identified at follow-up as

super-infection or persistence at significant counts were

resistant to Piperacillin-Tazobactam and sensitive to

Meropenem and Amikacin which replaced the initial

combination of Piperacillin-Tazobactam with Amikacin.

P. aeruginosa strains persistent at insignificant counts at

follow-up remained sensitive to the initial antibiotics

which remained unchanged.

Significantly lower mortality, SAPS II and SOFA

were noted on day 14 for the “day-three” group (Table

3). Schematic presentation of mortality and length of

E. Giantsou et al. / HEALTH 2 (2010) 82-89

Table 1. Admission and study entry characteristics.

Characteristics

“day-three”

group

n=60

“day-five”

group

n=62

P value

On admission

Age, mean ( SD )

Men, n (% )

SAPS II, mean, SD

SOFA, mean, SD

Admission, n (% )

Medical

Emergency surgery

Elective surgery

Reason for MV, n ( % )

Status asthmaticus

COPD

CAP

Drug overdose

Abdominal Surgery

Other surgery

CHF

Neurological emergency

On study entry

MV before VAP, mean ( SD ), d

Antibiotics before VAP, n(%)

SAPS II, mean ( SD )

SOFA, mean ( SD )

CPIS, mean ( SD )

55.4 ( 11.9 )

39 ( 65 )

43.3 ( 5.8 )

6.7 ( 2.2 )

33 ( 55 )

14 ( 23 )

13 ( 22 )

7 ( 12 )

11 ( 18 )

9 ( 15 )

4 ( 7 )

5 ( 8 )

10 ( 17 )

6.9 ( 1.2 )

47 ( 78 )

45.3 ( 5.8 )

6.8 ( 2.1 )

7.68 ( 0.85 )

55.6 ( 13 )

40 ( 64 )

45.7 ( 6 )

6.5 ( 2.1 )

31 ( 50 )

16 ( 26 )

15 ( 24 )

8 ( 13 )

10 ( 16 )

7 ( 11 )

8 ( 13 )

5 ( 8 )

6 ( 10 )

12 ( 19 )

7 (1.2 )

46 ( 74 )

46 ( 6.3 )

6.7 ( 2.3 )

7.6 ( 0.7 )

0.2

0.9

0.7

0.8

0.9

0.8

0.1

0.7

0.8

Abbreviations: SAPS, Simplified Acute Physiology Score; SOFA, Sequential Organ Failure Assessment; MV, Mechanical Ventilation; COPD,

Chronic Obstructive Pulmonary Disease; CAP, Community Acquired Pneumonia; CHF, Congestive Heart Failure; VAP, Ventilator-associated

pneumonia.

Day-3

group Day-5

group

Persista n ce at insign ific an t

c ounts on follow-up

Persis tenc e a t s ig nific a nt counts

on follow-up

Super-infe c tions on follow-up

Figure 3. Schematic presentation of P.aeruginosa patterns on follow-up.

E. Giantsou et al. / HEALTH 2 (2010) 82-89

Table 2. P.aeruginosa patterns on follow-up.

“Day- three” group on follow-upa, n=60 Patients

n ( % ) Final antibiotics

Super-infectionb

Persistencec at significant counts

Persistencec at insignificant counts

15 ( 25 )

18 ( 30 )

27 ( 45 )

M / A

PT / A

“Day- five” group on follow-upa, n=62

Super-infectionb

Persistencec at significant counts

Persistencec at insignificant counts

18 ( 29 )

22 ( 35.5 )

M / A

PT / A

Abbreviations: M, Meropenem; A, Amikacin; PT,Piperacillin-Tazobactam.

aThe follow-up BAL was performed on day three of therapy for the “day-three” group and on day five of therapy for the “day-five” group.

bThese Pseudomonas aeruginosa strains were identified as super-infections, because they were genetically unrelated to the clone isolated at

study entry.

cThese Pseudomonas aeruginosa strains were identified as persistence, because they were closely related or indistinguishable to the clone

isolated at study entry.

Table 3. Study outcomes.

End Point

“day-three”

group

( n=60 )

“day-five”

group

( n=62 )

p value

Mortality on day 14, n ( % )

SAPSb on day 14

SOFAb on day 14

Mortality on day 28, n (% )

Mortality in ICU, n ( % )

Mortality in hospital, ( n % )

MV after VAP, d

ICU stay after VAP, d

Hospital stay after VAP, d

CPIS on day-14

Οrgan failure on day- 14 b, n (% )

Cardiovascular

Renal

Central nervous

Hepatic

Coagulation

11 ( 18.3 )

42.1 ( 5.8 )

5.9 ( 1.6 )

17 ( 28.3 )

16 ( 26.6 )

18 ( 30 )

14.3 (2 )

17.2 ( 4.3 )

23.1 ( 3.7 )

4.2 ( 1.7 )

19 ( 38.7 )

17 ( 34.6 )

10 ( 20.4 )

2 ( 4 )

24 ( 38.7 )

49.5 ( 9.7 )

8.1 ( 2 )

39 ( 62.9 )

40 ( 64.5 )

42 ( 67.7 )

22.7 ( 2.6 )

27.3 ( 4.7 )

35.5 ( 4.5 )

4.4 ( 1.5 )

24 ( 63.1 )

23 ( 60.5 )

14 ( 36.8 )

4 ( 10.5 )

0.01

<0.05

0.59

Abbreviations: SAPS, Simplified Acute Physiology Score; SOFA, Sequential Organ Failure Assessment Score; MV, mechanical ventilation; CPIS,

Clinical Pulmonary Infection Score bFor patients alive on day 14. Values are expressed as mean ( SD ) unless otherwise indicated. Organ failures

may not sum up to hundred as some patients may have >1.

stay in health care facilities appear in Figur e 4.

Eighteen patients of the “day-five” group were diag-

nosed with super-infection with a new strain of P.

aeruginosa at follow-up on day five. Of them 14 had

been having super-infection and required treatment

change, since day three, as it was diagnosed by the in-

dependent investigators on day three (Ta b le 4 ). Five of

the 14 (35.7%) P. aeruginosa strains that were respo-

nsible for super-infections in the” day-five” group, were

present at insignificant concentrations in the BAL that

was performed initially to diagnose VAP. Similarly, for

the “day-three” group six of the 15 (40%) superinfec-

tions on day 3 were due to overgrowth of P. aeruginosa,

that was present in insignificant concentrations in the

BAL performed initially to diagnose VAP. The evolution

over time of superinfection is presented schematically in

Figure 5 for both groups.

Twenty two patients of the “day-five” group were

diagnosed at follow-up on day five with persistence at

significant counts, of the initially isolated P. aeruginosa

E. Giantsou et al. / HEALTH 2 (2010) 82-89

Mortalit y on day 14

Morta lity on d a y 2 8

Mort ality in ICU

Morta lity in ho spital

MV afte r VAP

ICU sta y a fter V AP

Hospit al stay after VAP

Da y- thre e g roup

Da y- five g roup

Figure 4. Schematic presentation of mortality and length of stay in health care facilities

Table 4. Super-infection and persistence over time.

Patients, n ( % )

“day-three”

groupa

( n=60 )

“day-five”

groupb

( n=62 )

Super-infections on

Day three of therapy

Day five of therapy

Persistence at significant counts on

Day three of therapy

Day five of therapy

15 ( 25 )

20 ( 33.3 )

18 ( 30 )

22 ( 36.6 )

14 ( 22.5 )

18 ( 29 )

19 ( 30.6 )

22 ( 35.4 )

0.7

0.8

0.9

0.8

aFor the “day-three” group super-infections and persistence at significant counts on day three of therapy were derived from the follow-up BAL

and on day five of therapy from the BAL collected by the independent investigators.

bFor the “day-five” group super-infections and persistence at significant counts on day three of therapy were derived from the BAL collected

by the independent investigators and on day five of therapy from the follow-up BAL.

(Table 4).Of them 19 had been having this pattern and

required treatment adjustment, since day three. Fourteen-day

mortality for patients of the “day-five” group, who had

super-infection or persistence at significant counts since

day three and in whom treatment was adjusted on day

seven, was 8 of 14 (57.1%) and 11 of 19 (58%)

respectively. By contrast, fourteen-day mortality for

patients of the “day-three” group, who had super-

infection or persistence at significant counts on day three

and in whom treatment was adjusted on day five was 3 of

15 (20%) and 4 of 18 (22%) respectively. The evolution

over time of persistence at significant counts is presented

schematically in Figure 5 for both groups.

5. DISCUSSION

In this study, improved fourteen-day mortality, severity

scores and duration of stay in ICU and hospital were

observed with earlier follow-up and re-institution of an

appropriate antibiotic regimen for patients with P.

aeruginosa VAP, who were initially appropriately treated

and in whom CPIS remained >6 six between days 3-5 of

treatment.

Few data are available, on clinical outcomes with an

earlier or a later recognition of treatment failure for pa-

tients with initially appropriately treated VAP. Our study

showed mortality of 18.3% for patients re-evaluated on

day three and 38.7% for patients re-evaluated on day five.

Montravers et al. reported 35% mortality, for patients,

who on clinical suspicion for VAP were treated appropri-

ately and on day three were microbiologically re-evaluated,

to identify and treat super-infections and persistence [7].

E. Giantsou et al. / HEALTH 2 (2010) 82-89

Figure 5. Schematic presentation of super-infection and persistence at significant counts over time

The American Thoracic Society guidelines suggest

that the earliest time point to re-assess the antibiotic

regimen is day three of treatment [9]. Although, BAL

data can optimize antibiotic therapy in VAP, this is

translated to improved clinical outcomes when the anti-

biotics administered on clinical suspicion for VAP are

adequate and BAL data become available in a timely

manner [14-17]. In our data, both groups had received an

appropriate antibiotic therapy on clinical suspicion for

VAP, which by day-three became inappropriate due to

super-infections and persistence at significant counts.

We observed improved outcomes with early recognition

and treatment of non-response to therapy. Appropriate

antibiotic therapy administered in a timely manner is

suggested to be one of the primary determinants of hos-

pital outcome [18] and our data reinforce this view.

Our study has limitations. First, we used the availabil-

ity of service to determine assignment and not randomi-

zation because we could not ensure endoscopy support

on the assigned day. This would introduce bias if the

availability correlated with aspects of clinical care. Sec-

ond, the study was necessarily un-blinded, but bias

should not have occurred from this as the primary out-

come was mortality. Third, it was conducted within a

single ICU and a relatively large number of patients

were excluded. Therefore the results cannot necessarily

be extended to other populations. Fourth, patients in the

“day-five” group had CPIS >6 from day three of therapy

and treatment were modified on day seven. However, the

CPIS provided no evidence for deterioration because it

was continuously dropping. Finally, our study was not

specifically designed to test whether an earlier follow-up

is superior to a later one. To answer this question we

need a double blind randomized trial.

Although clearly important, an accurate diagnostic

technique and an appropriate initial empirical therapy

may not be sufficient to reduce mortality in patients with

P.aeruginosa VAP [19,20]. In our data, improved morta-

lity and shorter duration of stay in health–care facilities

were observed with earlier follow-up for patients with

P.aeruginosa VAP. This finding suggest that clinicians

should have low threshold to re-sample early and if ne-

cessary to revise therapy for patients with P. aeruginosa

VAP, who failed to reduce CPIS to values below six

between days three to five of antibiotic treatment.

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