| Abstract |
Introduction. Mortality and prolonged hospitalization among patients who have been
submitted to major surgical operations is often attributed to infections that occur in the
early postoperative period. During the last decade, there has been considerable change in
the epidemiology of hospital acquired infections; Gram-negative surpassed Gram-positive
bacteria as leading pathogens. Furthermore, the emergence of Gram-negative bacteria
resistant to most of the commonly used antibiotics makes treatment of such infections a
clinical challenge. Identification of the risk factors for the development of infections caused
by multi-drug-resistant Gram-negative bacteria (MDR-GNB) may help clinicians prevent
nosocomial infection. This becomes even more important, if we consider the slow pace of
development of new effective antimicrobial agents and the constantly rising prevalence
rates of MDR-GNB, especially in intensive care units (ICUs).
Multi-drug-resistance (MDR) has received various definitions in regard to the number of
classes of antimicrobial agents of pathogen’s resistance. MDR defined as resistance to all
but 3 classes of antibiotics has not been extensively investigated, especially in surgical
patients. Based on the above, the aim of this study was to identify risk factors for the
development of infections, caused by MDR-GNB, in a cohort of patients hospitalized in the
ICU for more than 5 days following general surgical operations. We sought to investigate
numerous factors that have been related, by previous studies, to the development of
resistance to antibiotics, both in vitro and in special patient populations. In addition, this
cohort study may permit to attribute mortality and length of hospital stay of patients with
such infections to the resistance pattern of the pathogen or to the various other comorbidity
conditions and complicating factors.
Methods.
Study design
A retrospective cohort study at a general, 450-bed, tertiary-care hospital in Athens,
Greece. The study was approved by the hospital's ethics review board.
Cohort description
Patients hospitalized in the ICU for more than 5 days following general surgical operations
during a 7 year period from the first day of hospital operation, in November 2001, to May
2007, were identified. The cohort included only patients without any infection on ICU
admission. All cases of infection included were clinically and microbiologically
documented. Patients who had a clinical infection that was not microbiologically
documented were eliminated from the study.
Group comparison
Patients who had an infection, caused by MDR-GNB, were assigned to the case group
(group A). The rest were included in the comparison group (group B). Moreover, there
were three comparison subgroups; patients who did not develop any microbiologically
documented infection (sub-group B1), patients who developed infection caused by a
Gram-positive pathogen during the hospital and ICU stay (sub-group B2), and patients
who developed infection caused by Gram-negative bacteria susceptible to more than 3 of
the tested antibiotics (sub-group B3).
It should be noted that only one infection per patient was taken into account for this study.
Thus, only the first infection caused by MDR-GNB was studied as case. Respectively, for
the comparison group, only the first infection caused by pathogens other than MDR-GNB
was included. Furthermore, for cases of multi-microbial infection, patients were assigned
to Group A if at least one of the isolated microbes was an MDR-GNB.
Data analysis
The chi square and Fisher’s exact tests were used to compare groups for dichotomous
variables, as appropriate. The t-test and the Mann-Whitney signed-rank test were used to
compare groups for normally and non-normally distributed continuous variables,
respectively. Variables found to be significantly associated with the development of
infection caused by MDR-GNB, in the bi-variable analyses, were entered in a multivariable
forward, stepwise, logistic regression model and the adjusted odds ratio (OR) and
95% confidence intervals (CIs) were calculated. The probability for removal in the logistic
regression model was set at p>0,1. For all tests, two-tailed p values lower than 0.05
denoted statistical significance. Furthermore, variables’ colinearity was tested. Tolerance
<0.1 indicated that the variable was redundant and highly correlated with other variables
that were already in the model. Summary measures of goodness of fit were performed
using the Hosmer-Lemeshow test. Additional checks were performed by entering the same
variables in relevant backward, stepwise, logistic regression models.
Results. During the study period, 100 patients (54 males) fulfilled the inclusion criteria.
Patients were submitted to one or more operations, the mean total operative time was 278
minutes (range 45-665) and 42% of patients were re-operated. The range of operations
included colorectal (38%), small bowel (19%), stomach (9%), liver (9%), pancreas (6%),
and other general surgical operations (19%). Among the studied patients, 48 had clinically
and microbiologically documented infections caused by MDR-GNB (32 cases of
Acinetobacter baumannii, 8 cases of Pseudomonas aeruginosa, and 8 cases of Klebsiella
pneumoniae) (group A), 14 patients had infections caused by Gram-positive bacteria (5
cases of Streptococcus faecalis, 3 cases of Staphylococcus aureus and 6 cases of other
Gram-positive pathogens) (sub-group B2), and 6 had infections caused by Gram-negative
bacteria susceptible to more than 3 of the tested antibiotics (5 cases of Pseudomonas
aeruginosa and 1 case of Klebsiella pneumoniae) (sub-group B3). Furthermore, there
were 2 patients who had infection caused by Candida albicans. Finally, there were 30
patients that did not have any clinically diagnosed nosocomial infection during
hospitalization (sub-group B1). It should be noted that there were 14 cases of multimicrobial
infections (23% of infections were multi-microbial).
First, we compared patients that developed infection caused by MDR-GNB (n=48) (group
A) with patients that did not (n=52) (group B). In Table 2, we present the findings of the
multi-variable logistic regression model for infection caused by MDR-GNB (dependent
variable). The adjusted odds ratios provided by the final model equation showed that every
minute of operative time, use of special treatments during hospitalization (anti-neoplastic,
immunosuppressive or immunomodulating therapies), every day of metronidazole, and
every day of carbapenems use, increased patients’ odds to acquire an infection caused by
MDR-GNB by 0.7%, 8.9 times, 9%, and 9%, respectively [OR (95% CIs): 1.007 (1.003-
1.011); p=0.001, 8.9 (1.8-17.3); p=0.004, 1.09 (1.04-1.18); p=0.039, 1.09 (1.01-1.18);
p=0.023, respectively). The above predictors were adjusted for admission in the first year
of hospital operation [OR (95% CIs): 0.1 (0.03-0.43); p=0.002]. The overall test for the
model was statistically significant (p<0.001) and successfully measured for goodness of fit.
Secondly, we compared patients that developed infection caused by MDR-GNB (n=48)
(group A) with patients that did not develop any infection (n=30) (sub-group B1). In Table 3,
we present the findings of the multi-variable logistic regression model for infection caused
by MDR-GNB (dependent variable). The adjusted odds ratios provided by the final model
equation showed that every minute of operative time, and use of antibiotics, within
3months prior to admission, increased patients’ odds to acquire an infection caused by
MDR-GNB by 0.7% and 3.8 times, respectively [OR (95% CIs): 1.007 (1.003-1.011);
p=0.001, 3.8 (1.07-13.2); p=0.002, respectively]. The above predictors were adjusted for
admission in the first year of hospital operation [OR (95% CIs): 0.07 (0.01-0.4); p=0.03].
The overall test for the model was statistically significant (p<0.001) and successfully
measured for goodness of fit.
Conclusions. The main finding of this retrospective cohort analysis, in patients
hospitalized in the ICU for more than 5 days following general surgical operations, is that
postoperative infection caused by MDR-GNB is independently associated with the total
operative time, special treatments during hospitalization (anti-neoplastic,
immunosuppressive or immunomodulating therapies), carbapenems and metronidazole
use duration, and prior antibiotics use (within 3 months prior to admission). Furthermore,
the study showed that, during the first year of hospital operation, cases of infection caused
by MDR-GNB were considerably lower. The above would have been a significant
confounder if not adjusted for. This may be attributed to the fact that the hospital was a
newly built facility and hospital microbial ecology changed over the first year of operation,
to meet local patterns of resistance, as patients from the national health system were also
admitted. Finally, patients with infection caused by MDR-GNB were hospitalized and
treated in the ICU for considerably longer time and had lower survival rates compared to
other patient groups.
In conclusion, this study describes the magnitude of postoperative infectious complications
that are often devastating for patients' survival, in a cohort of patients hospitalized in the
ICU for more than 5 days following general surgical operations. Furthermore, it depicts
certain, potentially modifiable, risk factors that may be associated with the development of
infections caused by MDR-GNB. Based on evidence, provided by this study, specific
actions may be taken to improve nosocomial infection prevention in patients submitted to
general surgical operations. The presented data may help surgeons and intensivists, who
treat such patients, decide to what extent they are able to modify their therapeutic
strategies to achieve the best possible clinical result. Specifically, we believe that surgeons
and intensivists may consider adding to their clinical strategies a more prudent use of
carbapenems and metronidazole, consider minimizing unnecessary surgical intervention
that prolongs total operative time, and avoid, where possible, the use of special treatments
such as anti-neoplastic, immunosuppressive or immunomodulating therapies especially
during the first post-operative days.
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