Patient Demographics and Characteristics of Infection with Carbapenem-Resistant <i>Acinetobacter baumannii</i> in a Teaching Hospital from the United States

doi:10.4236/aid.2013.31002

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Advances in Infectious Diseases, 2013, 3, 10-16

http://dx.doi.org/10.4236/aid.2013.31002 Published Online March 2013 (http://www.scirp.org/journal/aid)

Patient Demographics and Characteristics of Infection

with Carbapenem-Resistant Acinetobacter baumannii in a

Teaching Hosp i ta l fr om t he United States*

Nachiket D. Vaze, Christopher L. Emery, Richard J. Hamilton, Ari D. Brooks, Suresh G. Joshi#

Surgical & Nosocomial Infection Research and Bacterial Pathogenesis Program, Drexel University College of Medicine, Hahnemann

University Hospital, Philadelphia, USA

Email: #[email protected]

Received November 13th, 2012; revised December 15th, 2012; accepted January 18th, 2013

ABSTRACT

A characterization of the clinical demographic features of patients with infection caused Acinetobacter baumannii, and

the antibiotyping of the isolates recovered from these patients was undertaken, with a special reference to carbapenem-

resistant variants, and their risk factors. This study was conducted retrospectively from January 2010 to March 2011 at a

616-bed tertiary care university hospital. Sixty-four patients were identified. Clinical and microbiological data were

analyzed for risk factors and demographic features to derive relative risk and odds ratio. We identified 100 A. bauman-

nii from 64 patients during 15 months period. Significant risk factors were working age (18 - 60 years), male gender,

hospital stay (>1 week but <1 month), prior hospitalization, in a progressive care nursing units, respiratory/mechanical

ventilation, polymicrobial infections and prior antibiotic therapy. Methicillin-resistant staphylococcus aureus (MRSA),

Pseudomonas aeruginosa, and Klebsiella pneumoniae were the significant co-infecting agents. The antibiogram dem-

onstrated multidrug resistance in a majority of the isolates. Relative risk associated with ventilator, diabetes, and sur-

gery was higher in repeat isolates than in first isolates and were multidrug resistant. Repeat isolates were more resistant

that the first isolates to most anti-acinetobacter agents, but the overall crude mortality was not significant during this

study period, and couldn’t correlated to the choice of treatment. In conclusion, a resistance against all clinically used

carbapenems, and colistin is rapidly increasing in repeat isolates of A. baumannii; leaves narrow therapeutic options to

treat multidrug-resistant and pandrug-resistant A. baumannii infection. For the first time we report rising incidence of

colistin resistance by 20 percent in repeat isolates, and is worrisome for healthcare centers. A combination therapy

should be adopted to treat such infection to avoid the emergence of colistin-resistant phenotypes in the United States.

Keywords: Acinetobacter ba um anni i ; Carbapenem Resistance; Colistin, Imipenem; Meropenem; Multidrug Resistance;

Risk Factor

1. Introduction

Acinetobacter baumannii is a third most prevalent noso-

comial pathogenic species. It has been isolated from

various hospital environments and has been shown to

colonize patients. Until recently, this pathogen was found

primarily outside the United States, mainly in Europe and

Asia [1,2], but it is emerging in the United States [3]. In

addition, A. baumann ii infections have been identified in

troops returning from military engagements in the Mid-

dle East [4]. A. baumannii has been identified as the cau-

sative agent in many serious medical conditions such as

sepsis and nosocomial pneumonia [5,6]. Although in

general the virulence of this species is low; its coloniza-

tion poses a threat in a health care setting. Pneumonia

caused by A. baumannii is associated with contaminated

or colonized surgical and respiratory equipment. Out-

breaks of A. baumannii have been reported in hospitals;

especially in intensive care units (ICUs) [7]. Its status as

an opportunistic organism makes it an unpredictable no-

socomial pathogen that can cause significant mortality in

such cases [8-10].

A. baumannii is inherently resistant to many antim-

icrobials and can further acquire resistance to additional

antimicrobials to become multidrug resistant (MDR).

MDR- A. ba umannii is a major cause of concern in heal-

th care settings, and the infections are extremely difficult

to treat [11,12]. MDR- A. baumannii is usually treated

with broad-spectrum antibiotics, including carbapenems.

Carbapenems such as imipenem and meropenem are of-

ten the antibiotics of last resort for such infection, and

*All authors report no conflict of interest related to this manuscript.

#Corresponding author.

Patient Demographics and Characteristics of Infection with Carbapenem-Resistant Acinetobacter baumannii in

a Teaching Hospital from the United States

resistance against them is considered an alarming situa-

tion [13,14]. Many risk factors are associated with the

prevalence of A. baumannii and the development of MDR-

A. baumannii [15]. Environmental risk factors such as

intubation [16], prior surgery [17], and length of stay in

the ICU [18] can lead to the development of MDR in A.

baumannii.

In this study, the sensitivity of the isolates to imipe-

nem and meropenem was determined; imipenem-resis-

tant and meropenem-resistant isolates were further ana-

lyzed for the presence of risk factors. One of the major

reasons for antibiotic resistance is the persistence of in-

fection and recolonization with the variants that can lead

to repeat isolation of the same strain or a related strain

[19]. This phenomenon was also analyzed in the present

study. The repeat isolates are often much more virulent

and more likely to be MDR [20,21]. Because obtaining

repeat isolates is specifically related to hospital environ-

ments and therapy, a risk analysis was performed on

these isolates for resistance to imipenem and merope-

nem.

2. Materials, Methodology, and Set up

The study was conducted during Jun 2010 through Dec

2011 at a 616 bed tertiary care university hospital. Pa-

tients with Acinetobacter-positive cultures were identi-

fied from the microbiology laboratory database, and the

cases of A. baumannii infection were considered. The

isolates were identified using standard microbiological

laboratory tests and the API 20E and VITEK systems

(bioMérieux, Durham, NC). Antibiotic susceptibility data

were obtained using the VITEK 2 system (bioMérieux)

and minimum inhibitory concentrations (MICs) carried

out using agar microdilution technique, following the

Clinical and Laboratory Standards Institute (CLSI) gui-

delines. For each patient and each sample, clinical data

were accessed through the hospital online patient data-

base. The criterion for infection versus colonization was

interpreted as per Center for Disease Control and Preven-

tion (CDC) guidelines [22]. The isolate was considered

as multidrug resistant, if resistant to more than two class-

es of antimicrobials or to carbapenems. The first isolate

was defined as the organism that was first isolated from

the sample during hospital admission and the repeat iso-

late as the one that was obtained from the same patient

after the isolation of the first isolate (usually after an in-

terval of a week). Statistical analysis was carried out us-

ing GraphPad version 3.0 (GraphPad Software, LaJolla,

CA). Fisher’s exact test was applied, and odds ratios (OR)

and risk ratios (RR) with 95% confidence interval (CI)

values were calculated. A P value < 0.05 was considered

significant.

3. Results

Total 100 isolates were recovered from 64 cases of infec-

tion with A. baumannii were considered, having distinct

episodes of hospitalization. Table 1 demonstrates analy-

sis of the demographic features. The patients were group-

ed into two broad categories according to age to enable

comparison for analysis. Patients of working age (18 - 60

years) had a significantly higher chance of A. baumannii

infection than seniors (65 and older). More men than

women had infections with A. baumannii (OR = 2.78; CI

= 1.36 - 5.68; P = 0.0078). There was significant associa-

tion between a stay in the hospital of less than 1 month

but longer than 1 week and isolation of A. baumannii

compared to a longer stay in the hospital (OR = 3.51, CI

= 1.71 - 7.20; P = 0.0009). However, there was no sig-

nificant correlation between the samples collected during

the hospital stay, and culture positivity in regard to rela-

tive risk.

A source of sample is the important epidemiological

indicator. Almost half (49%) of the isolates were from

sputum and tracheal secretion; 36 (73%) of the patients

with A. baumannii isolated from sputum were on a me-

chanical ventilator. Sputum was a more likely source of

A. baumannii infection than bronchial wash (OR = 12.76,

CI = 5.39 - 30.24; P = 0.0001). Most of the samples col-

lected from ventilated patients had at least one other

bacterium. The most prevalent co-isolated organisms

were P. aeruginosa (25%) and methicillin-resistant S. au-

reus (19%) (Data is not shown).

The isolates were tested using the VITEK 2 system for

susceptibility against commonly used antibiotics and ca-

tegorized as resistant and susceptible groups according to

the results, interpreted as per the CLSI criteria. Figure 1

is a graphical presentation of antibiogram using common

antimicrobial agents, and indicates high levels of resis-

tance across drug classes. More than 50% of the isolates

were resistant to seven different antibiotics. Levofloxacin

was the most ineffective antibiotic. Even a combination

of piperacillin-tazobactam was ineffective. Both imipe-

nem and meropenem showed resistance to 44% and 49%

of the isolates, respectively. The only antibiotics that

were relatively effective against A. baumannii infections

were amikacin and colistin, and showed 30% and 11% of

the isolates as resistant phenotypes (respectively), during

studies of first isolates. Total 36 repeat isolates were in-

cluded in this study. Some patients had no repeat isolates

whereas some cases had more than two. A separate anal-

ysis was performed on these two groups, and their anti-

biogram and risk factor analysis were compared. The

comparison demonstrates an increase in resistance in the

repeat isolates against almost all antibiotics tested (Fig-

ure 1). The levels of resistance have increased by 30%

for levofloxacin, by 32% for trimethoprim-sulfamethoxa-

Patient Demographics and Characteristics of Infection with Carbapenem-Resistant Acinetobacter baumannii in

a Teaching Hospital from the United States

Table 1. Clinical demographic characteristics of Acinetobacter baumannii infections.

Characteristic Number of patients

(n = 64) Total (%)Groups to compare OR 95% CI RRP value

Age

18 to 40 years 18 28 Working group vs seniors6.01 2.82 - 13.0 2.50.0001

41 to 64 years 27 42

65 years and older 18 28

Infant 1 3

Gender

Female 24 37

Male 40 63

Male vs female 2.78 1.36 - 5.68 1.670.0078

Duration of hospital stay

Same-day discharge 4 6

1 week 15 23

More than 1 week but less than 1

month 26 39

More than 1 month 21 32 <1 month vs >1 month 3.51 1.71 - 7.20 1.950.0009

Characteristic Number of cases

(n = 100) Total (%) OR CI RRP value

Time to culture of samples

Day of admission 29 29

Less than 1 week of hospitalization 22 22

More than 1 week but less than 1

month 31 31

More than 1 month 18 18

Source of sample

Anerobe 9 9

Blood 10 10

Sputum vs blood 8.65 4.03 - 18.53 4.90.0001

Bronchi 7 7

Tissue 1 1

Urine 13 13

Wound 11 11

Sputum vs wound 7.77 3.71 - 16.28 4.450.0001

Sputum 49 49

Sputum vs bronchial wash12.76 5.39 - 30.24 7 0.0001

oxazole (Bactrim), and colistin to 22%. There was an

increase in the levels of resistance to imipenem (44% to

77%) and meropenem (49% to 71%).

Table 2 demonstrates the risk factor analysis for resis-

tance to carbapenem. Risk factors for resistant isolates

were determined through clinical data analysis, and the

odds ratios were calculated. Prior hospitalization was a

major risk factor for development of resistance to both

drugs. Significantly higher odds of developing a resistant

isolate were observed for carbapenem (OR = 5.56, CI =

2.7 - 11.47; P ≤ 0.05). Samples from the ventilated pa-

tients had an odds ratio of 1.9 for resistance to carba-

penem (OR = 1.9, CI = 1.01 - 3.52; P ≤ 0.05). A greater

number of resistant samples were taken from patients

who were hospitalized for less than a month compared to

patients with longer hospital stays (OR = 3.58, CI = 1.78

- 7.2; P ≤ 0.05). Sputum samples did not have a statisti-

cally significant risk for development of resistance to

either carbapenem. Diabetes was not associated with risk

of resistance in this analysis. Carbapenem here includes

Patient Demographics and Characteristics of Infection with Carbapenem-Resistant Acinetobacter baumannii in

a Teaching Hospital from the United States

100

Levofloxacin

Piperacilin/Tazobactam

Cefepime

Trimeth-Sulfametho

Meropenem

Gentamicin

Imipenem

Tobramycin

Ampicillin/Sulbact

Amikacin

C olis tin

Resistant Isolates (%)

Antimicrobial agents

Figure 1. A comparative antibiogram of the first and repeat (second) isolates (white bar, first isolates, n = 64; black bar, re-

peat isolate, n = 36).

Table 2. Risk factor analysis for carbapenem*.

Risk Factor Resistant Susceptible OR CI RR P value

Prior hospitalization 43 25 5.562.70 - 11.47 3.58 <0.05

Less than 1 month of hospitalization 43 38 3.581.78 - 7.20 2.8 <0.05

Polymicrobial infection 35 22 2.161.14 - 4.1 1.75 <0.05

Ventilator 36 27 1.9 1.01 - 3.52 1.65 <0.05

Sputum 26 22 0.8960.49 - 1.63 0.91 >0.05

Diabetes 19 11 0.4150.22 - 0.79 0.52 <0.05

*Carbapenem here includes imipenem and meropenem; and p values were similar on both cases.

imipenem and meropenem. A significance of risk factors

for both these agents are similar (P < 0.05), and separate

data is not shown.

A comparative study of the risk factors associated with

first and repeat isolates for carbapenem-resistance was

performed (Table 3). Association of the development of

resistance with certain risk factors was statistically sig-

nificant for repeat isolates. Although ventilator use was

Patient Demographics and Characteristics of Infection with Carbapenem-Resistant Acinetobacter baumannii in

a Teaching Hospital from the United States

Table 3. First and repeat isolate comparison of risk factors for carbapenem*.

First Isolates Repeat Isolates

Risk Factor OR 95% CI RR P value OR 95% CI RR P value

Ventilator 1 0.45 - 2.23 1 >0.05 5.37 1.94 - 14.85 4.4 <0.05

Diabetes 1.18 0.53 - 2.63 1.15 >0.05 4.17 1.60 - 10.86 3.5 <0.05

Surgery NA NA NA NA 2.7 1.12 - 6.51 2.37 <0.05

*Carbapenem here includes imipenem and meropenem, and p values were similar in both cases.

not a significant factor for all isolates when considered

together, it significantly increased the odds of resistance

for repeat isolates for carbapenem (OR = 5.37, CI = 1.94

- 14.85; P ≤ 0.05). Diabetes, which was not seen as a

major factor for overall development of resistance, was a

risk factor for resistance development when studied re-

peat isolate from the specimen. This observation was

evident from the increase in the odds ratio and statistical

significance of the results (OR = 4.17, CI = 1.6 - 10.86; P

≤ 0.05). The risk factor was considered only when it was

applied to repeat isolates. Invasive procedures in the

hospital were considered for their association with the

resistant isolates. For the purpose of this study, debride-

ment, biopsies, and major surgeries were considered as

part of this category. Invasive procedures were an im-

portant risk factor for the development of resistance in

repeat isolates.

4. Discussion

The findings demonstrate the occurrence of Acinetobac-

ter infections in an urban hospital setting from the United

States. Analysis of the clinical data provided information

about the sources of the infections, with predominant risk

factors associated with identified Acinetobacter infec-

tions. Age has been discussed as a major factor associ-

ated with the acquisition of Acinetobacter [23]. Although

our sample size is smaller, a recent report on the analysis

of 55,000 US surveillance samples indicates that people

of working age have a higher risk of developing A.

baumannii than do elderly people [24]. Men had a rela-

tively higher risk of developing this infection. The higher

occurrence of A. baumannii infection in working men

could not be explained, but similar findings have been

reported from other countries [25]. Duration of hospi-

talization is an important factor associated with nosoco-

mial infections and hospital outbreaks. In the present

study, shorter stay (>1 week but <1 month) in the hospi-

tal contributed more to the incidence of infection. Prior

and prolonged hospitalization and antibiotic therapy are

established risk factors [10,18,26,27]. Therefore, the

finding is difficult to explain. The possibilities, such as

community acquisition or health care provider-associated

dissemination, remain to be demonstrated. Sputum was a

major source of A. baumannii, and the organism was

associated with ventilator-associated pneumonia [28] and

may indicate respiratory colonization and subsequent in-

vasion [29]. A. baumannii was also isolated in conjunc-

tion with other nosocomial pathogens such as methicil-

lin-resistant S. aureus and P. aeruginosa and denotes a

dangerous combination of polymicrobial infections, of-

fering more collective resistance.

Multidrug-resistant A. baumannii has been reported

worldwide. In the present study, the large-scale occur-

rence of MDR- A. baumannii indicates increased preva-

lence in urban US hospital. The carbapenem-resistant A.

baumannii isolates are increasingly reported from other

US hospitals too and narrows the therapeutic options to

control these superbugs. The large number of MDR- A.

baumannii isolates prompted us to determine and sys-

tematically analyze the associated risk factors. Common

risk factors suspected in previous studies [30], such as

patient’s time on a ventilator, were confirmed. The big-

gest risk factor for developing carbapenem-resistant A.

baumannii was prior hospitalization. This risk factor has

also been reported by other group [5] and could be in-

dicative of exposures in the hospital environment or of

the use of antibiotics that leads to development of resis-

tance. Samples from the patients on respiratory ventila-

tors and from those with polymicrobial infections [31]

also had high odds of developing carbapenem resistant A.

baumannii and suggest that cross contamination and co-

lonization of respiratory equipment could be a concern.

We also observed many repeat isolates among the total

isolates and risk factors associated with resistance among

them. Separate risk analysis between first and repeat iso-

lates indicated the association of certain risk factors that

were not significant in the overall analysis of all samples.

The risk of developing repeat isolate resistant to carbap-

enems increased significantly with ventilator use. Inva-

sive procedures have been associated with the multidrug

resistance [7]. Diabetes and prior surgery, which were

not significantly associated with overall resistance, were

major risk factors in developing resistance in a second

(or repeat) isolate. In our studies, many elderly patients

who were hospitalized had a sacral decubitus ulcer, and

Patient Demographics and Characteristics of Infection with Carbapenem-Resistant Acinetobacter baumannii in

a Teaching Hospital from the United States

were subsequently found to be infected [32]. These pa-

tients had come for a debridement procedure. The majo-

rity of these patients were ventilated, but a clear correla-

tion could not be established in the acquisition of A.

baumannii. These patients are usually given broad-spec-

trum antibiotics to control infection and are sent back to

their long-term care facility and may be subsequently

contributing to dissemination of A. baumannii in such

health care facilities and the community at large. Further

follow-up is required in such cases to gain more insight.

We did not analyzed patient outcome and therapy evalua-

tion analysis, which are beyond the scope of the present

study. These analyses will require a manual data mining

as not all the documents are retrievable.

In conclusion, a multidrug resistance was observed in

a majority of the isolates. The repeat isolates displayed

an increased level of antibiotic resistance. The resistance

against all carbapenems and colistin is rapidly increasing;

and the resistance was double in many of the repeat

(second) isolates compared to initial (first) isolates against

colistin, the drug of choice for such infections. A combi-

nation therapy is strongly advisable against such infec-

tions to avoid the emergence of colistin-resistant pheno-

types in the United States hospitals.

5. Acknowledgements

This research work was partly supported by intramural

funds from Drexel University College of Medicine, and

partly, by the grant from Merck & Co. Authors thank Ms.

Pamela Fried for critical input in the manuscript. The

study has IRB approval from the Drexel University Col-

lege of Medicine.

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Abbreviations

ICU: Intensive care unit;

MRSA: Methicillin-resistant Staphylococcus aureus;

DR: Multi drug resistance;

MIC: Minimum inhibitory concentration;

OR: Odds ratio;

RR: Relative risk;

CI: Confidence interval.