ORIGINAL ARTICLE
Utility of Ampicillin-Sulbactam for Empiric Treatment of
Ventilator-Associated Pneumonia in a Trauma Population
Wesley D. McMillian, PharmD, Jayde L. Bednarik, PharmD, Joseph J. Aloi, PharmD, John W. Ahern, PharmD,
and Bruce A. Crookes, MD, FACS
Background: Ampicillin-sulbactam is guideline-recommended treatment
for early-onset ventilator-associated pneumonia (VAP). However, in-
tensive care unit clinicians are encountering increasing resistance to
ampicillin-sulbactam. We sought to analyze the time period for early-
onset VAP in our trauma population by using daily evaluation of
resistance to ampicillin-sulbactam.
Methods: A retrospective cohort study was completed on all mechanically
ventilated trauma patients admitted to a rural level-1 trauma center from
January 2003 to December 2008 who were diagnosed with VAP. Daily
bacterial resistance to ampicillin-sulbactam ⬎15% was defined as the thresh-
old for early empiric antibiotic failure for the first episode of VAP. A
univariate analysis of risk factors for multi-drug resistant pathogens
(MDRPs) and comorbidities was completed to assess for predisposing factors
for ampicillin-sulbactam resistance.
Results: One hundred sixty-three pathogens were identified in 121 trauma
patients diagnosed with VAP. Of these isolates, 71% were gram-negative,
28% were gram-positive, and 1% was fungal. Methicillin-susceptible Staph-
ylococcus aureus (23.9%), H aemophilus influenzae (20.9%), and Pseudo-
monas aeruginosa (11.7%) were the most common infecting organisms.
Daily ampicillin-sulbactam resistance was 40%, 26%, 32%, 43%, 50%, and
60% on days 3 to 7 and ⱖ8 days, respectively. Only the presence of MDRP
risk factors (89% vs. 65%, p ⬍ 0.01) and hospital LOS (36.8 [22.8 – 49.0]
vs. 25.7 days [19.0 –32.5], p ⬍ 0.01) was different between ampicillin-
sulbactam resistant and ampicillin-sulbactam susceptible VAP groups. On
univariate analysis, hospital length of stay ⬎4 days and antibiotic use within
90 days were associated with ampicillin-sulbactam resistant VAP (p ⬍ 0.01).
Conclusions: Ampicillin-sulbactam is not an effective empiric therapy for
early-onset VAP in our rural trauma population. The utility of ampicillin-
sulbactam should be reviewed at other institutions to assess for appropriate
empiricism.
Key Words: Ventilator-associated pneumonia, Trauma, Early-onset pneu-
monia, Pneumonia, Intensive care unit.
(J Trauma. 2010;69: 861– 865)
Submitted for publication March 2, 2010.
Accepted for publication May 17, 2010.
Copyright © 2010 by Lippincott Williams & Wilkins
From the Department of Surgery (W.D.M., B.A.C.), Department of Pharmacy
(W.D.M., J.L.B., J.J.A., J.W.A.), and Department of Medicine (J.J.A.,
J.W.A.), Fletcher Allen Health Care, Burlington, Vermont.
Abstract presented at the Society of Critical Care Medicine, 39th Critical Care
Congress Miami, FL, January 2010.
Address for reprints: Wesley D. McMillian, Fletcher Allen Health Care, 111
Colchester Avenue, Mailstop 272BA1 Burlington, VT 05401; email: wes.
mcmillian@vtmednet.org.
DOI: 10.1097/TA.0b013e3181e83f8b
The Journal of TRAUMA® Injury, Infection, and Critical Care • Volume 69, Number 4, October 2010
V entilator-associated pneumonia (VAP) is a leading infection-
related cause of death of patients in the intensive care unit
(ICU) and causes significant increases in duration of mechan-
ical ventilation (MV), ICU and hospital length of stay (LOS),
and associated healthcare costs.1– 6 Approximately 70% of
VAP cases are contracted within the first 4 days of MV and
are described as “early-onset.”1 Patients with early-onset
VAP have a better prognosis and generally lack infection
with multidrug-resistant pathogens (MDRPs), whereas VAP
that occurs ⱖ5 days after initial intubation are generally
caused by MDRPs and are associated with significant mor-
bidity and mortality.1
The American Thoracic Society and Infectious Diseases
Society of America (ATS/IDSA)1 guidelines recommend em-
piric antimicrobial treatment of VAP dependent on the presence
or absence of risk factors for MDRPs (Table 1). Potential
pathogens in patients without risk factors for MDRP (i.e., early-
onset) include Streptococcus pneumoniae, Haemophilus influ-
enzae, methicillin-susceptible Staphylococcus aureus (MSSA),
and gram-negative bacilli such as Escherichia coli and Kleb-
siella pneumoniae. The recommended empiric antibiotic therapy
for these patients include ceftriaxone, levofloxacin, moxifloxa-
cin, ciprofloxacin, ampicillin-sulbactam, or ertapenem.1 Patients
with risk factors for MDRPs require broad-spectrum antimicro-
bials to ensure appropriate coverage for pathogens such as
Pseudomonas aeruginosa, Acinetobacter species, and methicillin-
resistant S. aureus.1
The Surviving Sepsis Campaign from the Society of
Critical Care Medicine along with the ATS/IDSA guidelines
for the management of hospital-acquired pneumonia (HAP),
healthcare-associated pneumonia, and VAP stress the impor-
tance of early and appropriate empiric antimicrobial therapy.1,7
Local pathogen and sensitivity patterns along with standard-
ized empiric antibiotic regimens should be used to avoid
inappropriate therapy. Initial therapy should be broad enough
to cover all suspected pathogens to reduce morbidity, mor-
tality, and associated healthcare costs.5,8,9 However, overuse
of antimicrobial therapy or use of preemptive antibiotic
therapy may promote MDRP colonization and the develop-
ment of severe pulmonary infections.5,10 –13
Previous studies by Croce et al.14 and Wood et al.15
using an ICU specific empiric antibiotic protocol for the
treatment of VAP in trauma patients found low rates of
antibiotics resistance over a 3-year period. Empiric therapy
with ampicillin-sulbactam for early-onset VAP (⬍7 days)
was appropriate for ⬎85% of isolated bacteria. The aim of
861
McMillian et al. The Journal of TRAUMA® Injury, Infection, and Critical Care • Volume 69, Number 4, October 2010

considered positive if an organism ⱖ100,000 colony forming

TABLE 1. Risk Factors for Multidrug-Resistant Pathogens*
units (cfu)/mL were isolated or heavy growth was docu-
Antimicrobial therapy in preceding 90 d mented. If cultures returned with ⬍100,000 cfu/mL of an
Current hospitalization of ⱖ5 d organism or if ETT cultures returned negative, the patient
Immunosuppressive disease and/or therapy was deemed to have systemic inflammatory response syn-
Hospitalization for ⱖ2 d in the preceding 90 d drome and were not included in the final analysis. Treatment
Home infusion therapy (including antibiotics) of VAP was defined as intravenous antibiotic therapy for ⱖ72
Chronic dialysis within 30 d hours. Early-onset VAP was defined as the number of days
Home wound care after endotracheal intubation on which daily pathogen resistance
Family member with multidrug-resistant pathogen was ⱕ15% to empiric therapy, ampicillin-sulbactam.15,18
*Adapted from Am J Resp Crit Care Med. 2005;171:388 – 416. Late-onset VAP was defined as the day on which pathogen
resistance, not total cumulative resistance, to empiric ampi-
cillin-sulbactam was ⬎15%. Empiric therapy was defined as
this study was to define the time period for early-onset VAP an antibiotic regimen used from diagnostic sample attainment
in our trauma population using a daily evaluation of resis- until the reporting of the final culture results.
tance to empiric ampicillin-sulbactam. Statistical Analysis
The primary objective of determining the breakpoint of
PATIENTS AND METHODS early- versus late-onset VAP and microbiology was charac-
Study Design and Patient Selection terized using descriptive statistics. Comparison of patients
with risk factors for MDRPs and those without risk factors
Fletcher Allen Health Care (FAHC) is a level I trauma
were compared using ␹2 analysis or Fisher’s exact test where
center and rural academic medical center, which serves
appropriate. Statistical analyses were performed using SAS/
⬎150,000 patients annually from Vermont and Upstate New
STAT software version 9.1 of the SAS system for Windows
York. A retrospective chart review approved by the Univer-
(Cary, NC).
sity of Vermont Committee on Human Research was per-
formed on all trauma patients admitted to the FAHC surgical
ICU between January 1, 2003, and December 31, 2008. RESULTS
Patients on MV ⱖ48 hours with an International Classification Patients
of Diseases, ninth revision (ICD-9: 480 – 488 and 997.31) code A total of 6,474 trauma patients were admitted to the
by the Centers for Medicare and Medicaid Services for pneu- surgical ICU in the 6-year study period. Four hundred sev-
monia were identified through the FAHC hospital trauma data- enty patients (7.3%) were on MV for at least 48 hours of
base. Patients were included if they had a clinical diagnosis of whom 257 (54.7%) had an ICD-9 code for pneumonia during
VAP, positive bronchoalveolar lavage (BAL), or endotracheal their hospital stay. We excluded 136 patients due to reasons
tube (ETT) aspirate culture while on MV, and treated with such as culture-negative pneumonia (n ⫽ 73), HAP (n ⫽ 27),
intravenous antibiotics. We excluded patients younger than 18 or diagnosis of community-acquired pneumonia (MV ⬍48
years of age or those who developed HAP. hours, n ⫽ 24). One hundred twenty-one patients were
To ensure consistency, all data were reviewed and included in the final analysis. This is an overall VAP rate of
recorded into a computer database by a single investigator 25.7%. Patients with documented VAP when compared with
(J.B.). The following data were recorded for patients who met trauma patients who were excluded, but on MV for at least 48
inclusion criteria: baseline characteristics (age, sex, weight, hours, experienced prolonged MV, ICU, and hospital LOS
smoking history, and comorbidities), cause of injury, Acute (Table 2). Fifty-nine (48.8%) patients were diagnosed with
Physiology and Chronic Health Evaluation (APACHE) II16 VAP within the first 5 days of MV (Fig. 1).
score within 24 hours of admission, Injury Severity Score
(ISS),17 duration of MV, hospital and ICU LOS, presence of
risk factors for MDRPs, microbiological culture results, an- TABLE 2. VAP and Non-VAP Outcomes
tibiotic use (type and duration), and in-hospital mortality. No VAP VAP
(n ⴝ 349) (n ⴝ 121) p
Definitions
Definitions for VAP were derived from the ATS/IDSA 1 Age, years, mean (SD) 49.3 (19.8) 44.6 (18.7) 0.02
guidelines for the management of adults with HAP, VAP, and Sex, male, n (%) 244 (70.0) 106 (88.0) 0.11
healthcare-associated pneumonia. Clinical diagnosis of VAP ISS, mean (SD) 23.7 (11.9) 27.2 (13.3) ⬍0.0001
was defined as the presence of new or progressive radio- Length of MV, days, 4 (2.0–7.0) 14.4 (10.6–23.0) ⬍0.0001
median (IQR)
graphic infiltrate plus two of three clinical features as follows:
ICU LOS, days, 7 (4.0–11.0) 20 (15.3–29.6) ⬍0.0001
fever ⬎38°C, leukocytosis or leukopenia, or purulent secre- median (IQR)
tions. Per institutional practice, bacterial cultures are obtained Hospital LOS, days, 12 (7.0–22.0) 27.8 (20.0–43.6) ⬍0.0001
and empirical antimicrobial therapy is initiated once the median (IQR)
clinical diagnosis of VAP is made. HAP was defined as Mortality, n (%) 52 (15.0) 11 (9.0) 0.01
patients who developed pneumonia but were not on MV at
IQR, intraquartile range.
the time cultures were drawn. BAL and ETT cultures were

862 © 2010 Lippincott Williams & Wilkins

The Journal of TRAUMA® Injury, Infection, and Critical Care • Volume 69, Number 4, October 2010 Empiric Ampicillin-Sulbactam for VAP in Trauma

70 aeruginosa became the most frequently isolated pathogen

60 responsible for gram-negative VAP. S. aureus (39 isolates)
Ampicillin-Sulbactam (%)

was the major gram-positive pathogen regardless of the day

50
of diagnosis. Thirty-two (82%) of these isolates were MSSA.
Resistance to

40 Mixed gram-positive and gram-negative VAP occurred in

30
14.8% of patients.
Baseline characteristics of patients with ampicillin-
20
sulbactam resistant bacteria (43.8%) were compared with
10 those who had susceptible pathogens (56.2%) (Table 4).
0
Forty-eight (91%) patients with ASRP had risk factors for
3 4 5 6 7 8+ MDRP, whereas 76% of patients had MDRP risk factors but
Ventilation Time (days) ultimately did not develop ASRP VAP (p ⬍ 0.01). There
were no differences between the ASRP and non-ASRP
Figure 1. Development of ventilator-associated pneumonia groups with respect to outside intubation, aspiration, duration
and daily resistance to empiric ampicillin-sulbactam therapy.
The black boxes indicate the trend (%) of overall VAP devel-
of MV, ICU LOS, development of multiple VAPs, or mor-
opment. The white boxes represent the percent daily resis- tality. However, patients with ASRP VAP required prolonged
tance to empiric ampicillin-sulbactam by VAP episode. hospitalization (36.8 [intraquartile range 22.8 – 49.0] vs. 25.7
[intraquartile range 19.0 –35.2] days; p ⬍ 0.01).

Primary Outcome Sensitivities

Resistance to empiric ampicillin-sulbactam ranged
from 26% on day 4 to 61% for cases occurring after 7 days
(Fig. 1). Overall, 43.8% of all patients were documented with
ampicillin-sulbactam resistant pathogens (ASRP). A high
level of resistance to ampicillin-sulbactam was found in
patients with the strict ATS/IDSA definition of early-onset
VAP (no risk factors for MDRP and on day 3 or 4 of MV);
four (33%) patients had resistant pathogens on day 3 and 1
(11%) on day 4.
Pathogens
A total of 163 pathogens (29% gram-positive and 71%
gram-negative) were documented in the 121 included cases
(Table 3). Thirty-nine (32%) patients had multiple organisms
in significant quantities on BAL or ETT aspirate cultures. The
most prevalent gram-negative pathogen isolated between
days 3 and 6 was H. influenzae. On day 7 and after, P.
In a univariate analysis of MDRP risk factors and
comorbidities, only antibiotic use within the preceding 90
days (including prophylactic antibiotics used for 24 hours and
longer) and hospital LOS ⬎4 days were found to be inde-
pendent risk factors for the development of ASRP VAP (p ⬍
0.01, both risk factors). No specific comorbid condition was
associated with the development of ASRP VAP.
DISCUSSION
The IDSA/ATS guidelines divide VAP into early- and
late-onset and by the presence or absence of MDRP risk
factors.1 These distinctions guide the selection of empiric
antibiotic therapy to cover the most likely pathogens produc-
ing infection. Empiric ampicillin-sulbactam, as recommended
by the guidelines for the treatment early-onset VAP, has been
shown to be effective in ⬎80% of trauma patients with VAP

TABLE 3. Incidence of Pathogen by Day

Pathogens N (%) Day 3 Day 4 Day 5 Day 6 Day 7 Day 8ⴙ
Gram-negative 116 (71.2)
Haemophilus influenzae 34 (20.9) 6 (17.6) 7 (20.6) 9 (26.5) 5 (14.7) 2 (5.9) 5 (14.7)
Pseudomonas aeruginosa 19 (11.7) 1 (5.3) 1 (5.3) 1 (5.3) 1 (5.3) 2 (10.6) 13 (68.4)
Enterobacter spp. 17 (10.4) 1 (5.9) 1 (5.9) 3 (17.6) 4 (23.5) 2 (11.8) 6 (35.3)
Klebsiella spp. 13 (8.0) 0 (0) 4 (30.8) 5 (38.5) 1 (7.7) 1 (7.7) 2 (15.4)
Serratia spp. 10 (6.1) 2 (20.0) 0 (0) 4 (40.0) 1 (10.0) 1 (10.0) 2 (20.0)
Escherichia coli 9 (5.5) 1 (11.1) 1 (11.1) 3 (33.3) 2 (22.2) 1 (11.1) 1(11.1)
Citrobacter spp. 7 (4.3) 1 (14.3) 3 (42.9) 0 (0) 1 (14.3) 0 (0) 2 (28.6)
Other 7 (4.3) 0 (0) 2 (28.6) 2 (28.6) 0 (0) 0 (0) 3 (42.9)
Gram-positive 46 (28.2)
Staphylococcus aureus 39 (23.9)
MSSA 32 (19.6) 5 (15.6) 6 (18.8) 6 (18.8) 4 (12.5) 1 (3.1) 10 (31.3)
MRSA 7 (4.3) 1 (14.3) 0 (0) 1 (14.3) 1 (14.3) 1 (14.3) 3 (42.9)
Streptococcus pneumoniae 6 (3.7) 0 (0) 3 (50.0) 1 (16.7) 1 (16.7) 1 (16.7) 0 (0)
Corynebacterium spp 1 (0.6) 0 (0) 0 (0) 1 (100) 0 (0) 0 (0) 0 (0)
Aspergillus fumigatus 1 (0.6) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 1 (100)
Other gram-negative pathogens included Neisseria spp., Acinetobacter bumanii, Hafnia alvei, and Moraxella catarrhalis.

© 2010 Lippincott Williams & Wilkins 863

McMillian et al. The Journal of TRAUMA® Injury, Infection, and Critical Care • Volume 69, Number 4, October 2010

MSSA were the most frequently encountered pathogens in

TABLE 4. Baseline Characteristics in Patients With and
Without ASRP VAP our trauma patients. However, because of a mix of other
gram-negative pathogens such as S. marcescens and P.
ASRP VAP Non-ASRP VAP aeruginosa, our empiric therapy failure rate was higher than
(n ⴝ 53) (n ⴝ 68) p
our predefined breakpoint of ⬎15% starting on day 3 and
Age, years, mean (SD) 46.3 (20.5) 43.2 (17.2) 0.38 continuing throughout the subsequent days. These results
Sex, male, n (%) 45 (85) 62 (91) 0.28 indicate a potential need for expanded empiric antimicrobial
Organ system injury, n (%) therapy. Theoretically, using ampicillin-sulbactam as our
Pulmonary 25 (47) 35 (51) 0.77 empiric regimen, we would have lacked coverage in 40% of
Spine 24 (45) 31 (46) 0.79 patients on day 3 after endotracheal intubation.
Head 22 (42) 34 (50) 0.43 Overall, the rate of VAP at our institution is equivalent
Liver 7 (13) 4 (5.6) 0.20 to previously reported estimates between 6% and 39%.1,6,14,19
Burn 6 (11) 5 (7) 0.36 As similarly described in other studies, patients at our insti-
Cardiovascular 5 (9) 5 (7) 0.74 tution who developed VAP had longer length of MV and ICU
Kidney 1 (2) 6 (9) 0.24 and hospital LOS compared with those who were not diag-
Other 6 (11) 9 (12.7) 0.91 nosed with VAP.2–5
Smoking, n (%) 21 (40) 27 (40) 0.99 Our trauma population characteristics and overall out-
CrCl, ml/min, mean (SD) 92.2 (40.8) 96.7 (34.8) 0.52 comes mimic patients in previously published VAP literature
ISS, mean (SD) 29.2 (13.1) 25.6 (12) 0.12 are young, relatively healthy men, with low mean ISS and
APACHE II score, 22.8 (6.7) 23.6 (5.3) 0.47 APACHE II scores.14,15,19 We found no difference between
mean (SD)
the groups with ASRPs and those without ASRPs in regards
MDRP risk factors, n (%) 48 (91) 52 (76) ⬍0.01
to mechanism of injury, smoking history, ISS, APACHE II
Outside intubation, n (%) 27 (51) 42 (62) 0.23
score, length of MV, or ICU LOS. However, patients with
Aspiration, n (%) 1 (2) 4 (6) 0.27
ASRP VAP had a longer hospital LOS.
Length of MV, days, 17.1 (10.4–24.2) 13.8 (10.6–22.1) 0.35
median (IQR)
Our trial is not without limitations. The results of this
ICU LOS, days, 21.1 (14.5–26.1) 18.7 (16.2–34.1) 0.08
single-center retrospective study may not be directly appli-
median (IQR) cable to other ICU or trauma populations because of our ICU
Hospital LOS, days, 36.8 (22.8–49.0) 25.7 (19.0–35.2) ⬍0.01 specific microbiology and antimicrobial sensitivities. Another
median (IQR) limitation of our trial includes confounders such as incom-
Mortality, n (%) 7 (13) 4 (6) 0.16 plete or inaccurate medical history and unidentified risk
Multiple VAP, n (%) 8 (15) 19 (28) 0.09 factors for the development of MDRP VAP. We attempted to
ASRP, ampicillin-sulbactam resistant pathogen; CrCl, creatinine clearance; ISS,
assess other potential risk factors for MDRP VAP and the
injury severity score. IDSA/ATS guideline risk factors to surface any potential con-
founders. A third limitation is the use of semi-quantitative ETT
aspirates and the frequent occurrence of aseptic pneumonia. A
in a single center regardless of the presence of MDRP risk unique attribute of our study is that it was completed in a rural
factors.14,15 However, in another study, trauma patients were academic medical center, which shed light on the incidence of
shown to develop more gram-negative VAP, with resistant VAP and the microbiology in this population.
pathogens in ⬎30% of early-onset pneumonia when com- The IDSA/ATS guidelines recommend use of ampicillin-
pared with their nontrauma comparators.19 In other ICU sulbactam, ceftriaxone, levofloxacin, moxifloxacin, ciprofloxa-
patients with early-onset VAP (ⱕ4 days of MV) up to 52% cin, or ertapenem as empiric treatment for patients without risk
have pathogens potentially resistant to multiple antibiotics.20 factors for MDRPs. We chose to assess the utility of ampicillin-
In our study, ⬎30% of our patients had isolates that were sulbactam because it has the narrowest spectrum of activity
resistant to ampicillin-sulbactam regardless of MDRP risk of these agents. At our institution, we found a high rate of
factors or day of diagnosis. Unfortunately, the acceptable resistance to empiric ampicillin-sulbactam for treatment of
failure rate for empiric antibiotic therapy has not been de- VAP starting on day 3 of MV. Future analyses of resistance
fined. In a study by Magnotti et al.21, the first episode of to other antibiotics will aid in our quest to create an institution
inappropriate empiric antimicrobial therapy for treatment of specific ICU VAP algorithm. However, using broad-spectrum
VAP in the trauma population was found to be inconsequen- antibiotics empirically introduces additional risk of creating
tial. However, in other ICU populations, inappropriate MDRPs. Therefore, we must weigh the benefits and risk of
empiric antimicrobial therapy has been associated with sig- using a broader spectrum antibiotic, such as levofloxacin,
nificant morbidity and mortality.22 against the risk of introducing resistant P. aeruginosa into our
H. influenzae and MSSA have been documented in ICU. Other institutions should review their bacterial isolates
multiple studies as the most prevalent VAP pathogens in to assess the utility of ampicillin-sulbactam for empiric treat-
trauma patients.14,15,19,23–25 The antibiotic spectrum of ment of VAP.
ampicillin-sulbactam extends to both of these pathogens and
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