Acinetobacter Infections among Adult Patients in Qatar: A 2-Year Hospital-Based Study

This retrospective study was conducted at Hamad General Hospital, Qatar, to describe the demographic data, clinical features underlying diseases, antimicrobial susceptibility, and outcome of A. baumannii infection. It involved all adult patients 15 years of age or older who were managed at Hamad General Hospital for A. baumannii infection from January 1, 2012, to December 31, 2013. We identified a total of 239 patients with A. baumannii infection, of which 182 (76.2%) were males. The mean age was 49.10 ± 19.57 years. The majority of the episodes (25.1%) occurred in elderly patients (≥65 years) and the most commonly identified site of A. baumannii infection was the respiratory tract, 117 (48.9%). Most episodes of infection, 231 (96.7%), were hospital-acquired and high rate of nosocomial infections occurred in the medical intensive care unit, 66 (28.6%). All patients had underlying medical conditions. Maximum resistance was seen to cefotaxime, 147 (58.3%), and minimum resistance was seen to colistin, 2 (1.4%). Of the 239 isolates, 102 (42.7%) were susceptible and 137 (57.3%) were multidrug-resistant. The in-hospital mortality in our study was 31%. Male gender, multidrug resistance, and septic shock were found to be independent mortality predictors.


Introduction
Acinetobacter baumannii is an aerobic Gram-negative coccobacillus that has emerged as an important opportunistic pathogen, especially among debilitated patients, and a common cause of hospital-acquired infections, such as bacteremia, pneumonia, meningitis, urinary tract infection, and wound infection, especially in intensive care units [1,2]. A. baumannii is also a cause of community-acquired infections in many countries [3,4]. The epidemic potential and the clinical severity of A. baumannii infections are related to resistance of the isolates to most classes of antibiotics through multiple mechanisms [1,2].
In Qatar, the epidemiology of A. baumannii infection has not been studied in detail before. Only few reports have been published [5,6]. The aim of this study was to describe the demographic data, clinical features, underlying diseases, antimicrobial susceptibility, and outcome of A. baumannii infection at Hamad General Hospital, Qatar.

Design and Setting.
This hospital-based retrospective study was conducted at Hamad General Hospital. It involved all adult patients 15 years of age or older who were managed at Hamad General Hospital for A. baumannii infection from January 1, 2012, to December 31, 2013.

Case Definition.
Hospital-acquired infection was defined as occurrence of infection 48 hours or more after hospital admission or within 48 h after discharge or if it was preceded by an invasive procedure [6]. Community-acquired infection was considered if the positive culture was obtained within 2 Canadian Journal of Infectious Diseases and Medical Microbiology the first 48 h of hospitalization and the patient was not hospitalized in the preceding month [6]. Empirical antimicrobial therapy was defined as treatment that included at least one antibiotic and that was started no later than 24 h after the blood sample for culture had been drawn. This therapy was deemed inadequate if the antibiotics were administered after 24 h of blood sample extraction and/or when the dosage, route, and duration of treatment were not in accordance with current medical standards [7]. A. baumannii infection was defined as any patient who had A. baumannii isolated from any site in conjunction with a compatible clinical picture warranting treatment with antibiotics effective against A. baumannii [8]. Disease severity was estimated by the presence of sepsis or septic shock, which was defined according to the American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference. Sepsis was defined as the systemic inflammatory response (SIRS) to infection and septic shock was defined as sepsis-(SIRS-) induced hypotension despite adequate fluid resuscitation along with presence of perfusion abnormalities that may include, but are not limited to, lactic acidosis, oliguria, or an acute alteration in mental status. Patients receiving inotropic or vasopressor agents may no longer be hypotensive by the time they manifest hypoperfusion abnormalities or organ dysfunction, yet they would still be considered having septic (SIRS) shock [9]. A. baumannii isolates were considered multidrug resistance (MDR) if they exhibit resistance to carbapenem or resistance to at least one agent in three or more antibiotic classes [10]. The primary outcome was crude in-hospital mortality, which was defined as all causes of death during admission (i.e., infection-related mortality and mortality due to other causes).
Antibiotic Susceptibility Testing. After A. baumannii had been isolated from a range of clinical specimens, all isolates underwent susceptibility testing by the broth microdilution method (BD Phoenix; Becton Dickinson, Franklin Lakes, NJ, USA). The susceptibility breakpoints are defined by the Clinical and Laboratory Standards Institute [11].

Case Identification and Data
Collection. All cases were identified from the hospital's microbiology records. The files and the electronic records of the patients were reviewed to identify infections and to retrieve the following data: demographic information; underlying conditions such as prior MRSA colonization; type of infection (communityacquired or hospital-acquired); antimicrobial susceptibility; and the outcome.

Data Analysis.
Quantitative variables are expressed as mean ± standard deviations. In identifying the independent risk factors for in-hospital mortality, logistic regression model was used for univariate and multivariate analysis. The following variables were analyzed: age, sex, nationality, clinical picture, presence of other medical conditions, multidrug resistance isolates, and severity of infection. Univariate logistic regression was performed to determine the probable predictors of mortality among patients with A. baumannii infection. All potential risk factors significant at the 0.1 level in the univariate analysis were entered in the multiple logistic regression to identify the independent predictors of mortality at < 0.05. The data were analyzed with SPSS software (v 17; IBM Corp., Armonk, NY, USA).

Research Committee Approval.
As the study was retrospective, a waiver of informed consent was obtained from the research committee at Hamad Medical Corporation.

Results
During the period of study, a total of 372 consecutive A. baumannii isolates were collected by the microbiology department at Hamad General Hospital, which represent 2.8% (372/13286) of total isolates and 3.6% (372/10333) of Gram-negative isolates in our hospital. Based on evaluation of clinical charts, 239/372 (64.3%) isolates were classified as infection and 133/372 (35.7%) were considered colonizers. Of the 239 patients with Acinetobacter infection, 182 (76.2%) were males and 166 (66.5%) were non-Qataris. The mean age (± standard deviation (SD)) was 49.10 ± 19.57 years (range: 14-99 years). Table 1 illustrates the demographic and clinical data of the 239 patients. Sixty episodes (25.1%) occurred in elderly patients (≥65 years). Table 2 describes the distribution of the 239 infections among different age groups.
The crude in-hospital mortality in our study was 65/239 (31%). By the univariate analysis, the following variables were associated with increased in-hospital mortality: old age (>65 year), male gender, pneumonia as underlying disease, multidrug resistance, septic shock, and inadequate therapy. Only male gender, multidrug resistance, and septic shock were found to be independent predictors of in-hospital mortality by multivariate logistic regression analysis (Table 6).

Discussion
To our knowledge this is the first report detailing the demographic data, clinical features, underlying diseases,      As noted, most of our findings are consistent with several reports worldwide; for example, A. baumannii infection occurred in the elderly, mainly male patients; the vast majority of cases were hospital-acquired, affecting critically ill patients, especially those admitted into the intensive care units [1][2][3][12][13][14][15].
Our results are, however, different from other studies in antimicrobial susceptibility pattern of A. baumannii isolates. These findings are the most relevant issue in this study and deserve special attention especially resistance pattern of the isolates towards carbapenems. The emergence of multidrug-resistant (MDR) isolates significantly limits effective therapeutic options. Therefore, monitoring antibiotic resistance patterns of this organism over time may provide useful information regarding its treatment policy. In the present study the prevalence of MDR among A. baumannii isolates accounted for 57.3% of the total, and the resistance to carbapenems represented 45.6% of total cases. These findings are less than those reported in India, Pakistan, Iran, Libya, Saudi Arabia, Greece, Turkey, Spain, and Italy [12,[14][15][16][17][18][19][20][21][22][23][24]. This findings are, however, alarming, suggesting the emergence of carbapenem-resistant A. baumannii and demonstrating the potential for this pathogen to become a major cause of nosocomial infections in Qatar; in addition, since the prevalence of MDR A. baumannii in Qatar was not determined before, our data can be used as a reference to assess any increase in the prevalence of resistant Acinetobacter in the future.
It has become increasingly clear that resistance development in A. baumannii is multifactorial and could be mediated by several mechanisms including (i) decreased permeability of antibiotics due to porin loss, (ii) alterations in penicillinbinding proteins, (iii) efflux pump and integrons, and (iv) hydrolysis of -lactams by -lactamases encoded by either plasmids or chromosome [25][26][27]. As noted, our study was descriptive, and there was data lacking on molecular epidemiology. Thus, we are unable to investigate the molecular basis of resistance among our isolates.
Other finding in our study which deserves attention is susceptibility pattern of A. baumannii isolates towards colistin and tigecycline. Literature data on the in vitro activity of tigecycline and colistin against A. baumannii shows variable susceptibility. Concerning tigecycline, 3.6% of our isolates were nonsusceptible, which is less than the proportions from Italy, India, and Taiwan [15,28,29] but similar to those reported in Turkey, Greece, and Thailand [30][31][32]. On the other hand, with few exceptions [33], recent reports show high antimicrobial activities of colistin against A. baumannii isolates, in agreement with our findings [32,34]. These data suggest that tigecycline and colistin can be used effectively against MDR A. baumannii isolates in our hospital; however resistance rates should be monitored closely.
The crude mortality of A. baumannii infection varies ranging from 26 to 68% [13]. In our study, in-hospital mortality was 31% (65/239) which falls within the abovementioned range. Although drug resistance of A. baumannii is a recognized problem, the effect of MDR A. baumannii infections on patient outcomes remains controversial [35]. By univariate analysis, we recognized several clinical variables as probable predictors of in-hospital mortality; only male gender, multidrug resistance, and septic shock were found to be independent predictors of in-hospital mortality by multivariate logistic regression analysis.
This study has several limitations that need to be considered when interpreting these data. First, the study was retrospective. Second, it is small and hospital-based. Third, the study period was short. Fourth, data on molecular epidemiology of A. baumannii are lacking.
Despite these limitations, this study allowed us to reach important conclusions regarding resistance pattern among A. baumannii isolates in our hospital, which has an implication for future work. Accordingly, we suggest conducting largescale long-period prospective studies on molecular epidemiology of A. baumannii with emphasis on drug resistance, in order to determine the population structure and their antimicrobial resistance patterns.
In conclusion, our findings revealed that A. baumannii is an important human pathogen that is gradually gaining more attention as a public health threat in Qatar. The emergence of carbapenem resistance means that there is a need to look for alternatives such as colistin and tigecycline, which retained greatest activity against the A. baumannii isolates. Infection with MDR A. baumannii is independently associated with high mortality, emphasizing the need for aggressive infection control strategies to prevent MDR Acinetobacter infection and its adverse effects on hospitalized patients.