MDR/XDR Acinetobacter baumannii hospital infection associated with high mortality: A retrospective study in the PICU

Multiple drug-resistant (MDR) and extensively drug-resistant (XDR) Acinetobacter baumannii presents challenges for clinical treatment and causes high mortality in children. We aimed to assess the risk factors for MDR/XDR Acinetobacter baumannii (MDR/XDR-AB) infection and for 28-day mortality in this patient population. This retrospective study included 102 pediatric patients who developed MDR/XDR-AB infection in the pediatric intensive care unit (PICU) of Shanghai Children’s Hospital in China from January 2015 to December 2017. Clinical presentations and outcome of the patients were analyzed.

system infection. Acute kidney injury is associated with high risk of mortality. Early use of tigarecycline might be involved in improving MDR/XDR-AB bacteremia.

Introduction
Acinetobacter baumannii is a Gram-negative coccobacillus that has a remarkable Ability to acquire antibiotic resistance which embarrassed for decades for causing persistent nosocomial infections. (1,2) The propensity of A. baumannii to be multidrug-resistant (MDR) or extensively drug-resistant (XDR) presents therapeutic challenges. (3,4) Invasive operations such as intra trachea mechanical ventilation, inserted invasive devices, intensive care unit stay, recent surgery, use of broadspectrum antibiotics, ineffective management, and septic shock at diagnosis are reported as risk factors for colonization or infection by MDR A. baumannii and higher mortality (5,6).
The incidence of MDR/XDR-AB is higher in children in pediatric intensive care unit (PICU) than in other patients on concern of severe underlying diseases, immune deficiency, and invasive operations.(7) the mortality rate varies from 18. 26-88.7% depending on the infection source. (7)(8)(9) The problems for pediatrician in China are polymyxins cannot be obtained, tigecycline only became available in late 2016, and had limited experience in manage these young patients. (10) (11) Few studies have evaluated the risk factors for A. baumannii infection in Chinese pediatric patients. The objective of our study was to describe severe infections with MDR/XDR AB, as well as to investigate risk factors for mortality, in PICU patients.

Material and Methods
This retrospective study included pediatric patients who developed MDR/XDR-AB infection in the pediatric intensive care unit (PICU) of Shanghai Children's Hospital in China.
Identification of MDR/XDR-AB was confirmed by positive blood, sputum, aseptic fluid or catheter culture as well as symptoms and signs of infection. Susceptibility testing to the tested antibiotics was determined according to the Clinical and Laboratory Standards Institute (CLSI) interpretive criteria for disk diffusion method (12). MDR was defined as acquired non-susceptibility to at least one agent in three or more antimicrobial categories, XDR was defined as non-susceptibility to at least one agent in all but two or fewer antimicrobial categories (i.e. bacterial isolates remain susceptible to only one or two categories) and PDR was defined as nonsusceptibility to all agents in all antimicrobial categories. (13). Diagnosis of ventilation-associated-pneumonia (VAP) was made according to the recommendation by the American Thoracic Society (ATS) and Infectious Diseases Society of America (IDSA). VAP involving XDR AB was defined as clinical evidence of pneumonia along with a positive bronchoalveolar lavage fluid (BALF) or tracheal aspiration culture of XDR AB from 48 h after intra-tracheal intubated mechanical ventilation. Tracheal aspirate specimens were qualified for performing cultures as at least 25 neutrophils and less than 10 epithelial cells per low-power field on Gram staining.

Clinical conditions and outcomes
Clinical, biological and treatment data were obtained retrospectively from the patients' medical records. Underlying illnesses at the time of admission to the PICU were classified and pediatric risk of mortality Ⅲ (PRISM Ⅲ) scores were measured at the time of PICU admission. The 28-day mortality was defined as the mortality within 28days stay or left PICU.

Statistical analysis
Continuous variables were presented as mean ± standard deviation, and comparative analysis was conducted using an independent sample nonparametric test. The chi-square test or Fisher's exact test was conducted. The Mann-Whitney test was used for continuous variables. Variables showing p < 0.05 in a univariate analysis were included in a multivariate analysis, which was performed by stepwise logistic regression. All statistical analyses were performed with the Statistical Package for the Social Sciences, version 17.0 (SPSS Inc., Chicago, IL, USA).

Clinical manifestations
During the study period of January 1, 2015 and December 31, 2017, a total of 102 episodes of MDR/XDR Acinetobacter baumannii in 102 patients were identified, their demographics and clinical features were summarized in Table 1. The overall incidence of MDR/XDR AB was 0.48 cases/1000 patient-days, and we observed a continually increased distribution of cases during the study period. Both the incidence and mortality were growing higher in the latest 6 months ( patients had surgery (50%) and 70 treated with corticosteroids (68.6%), all these patients received broad-spectrum antibiotics treatment for more than one week.  Organ function and immune status of MDR/XDR A B . i n f e c t e d p a t i e n t s Table 3. listed the organ function of patients at diagnose of MDR/XDR AB infection, as the concern of the importance of immunologic function in the process of antiinflammatory pathophysiological, the indicators of immune function as well as serum cytokine levels were recorded in Table 4. It seems that no significant differences lies in the organ functions at diagnose of MDR/XDR AB infection, but non-survival patients appeared to have a lower NK cell activity (5.23%±3.62% vs.

Discussion
A. baumannii, an aerobic, gram-negative bacillus which is widely distributed in nature, is notorious for its remarkable Ability to acquire antibiotic resistance. As a result, it causes persistent hospital-acquired infections (1,2). In our present study, the incidence of MDR/XDR-AB at our facility was 0.48 cases/1000 patient-days, which was consistent with the incidence range from 0 to 58 cases/1000 patientdays (15) and lower than the incidence of another PICU that literature reports (7).  (2,16,17). In our study, the susceptibility results showed that the drug resistance rates of MDR/XDR AB to beta-lactam antibiotics were more than 75% except for cefoperazone/sulbactam (44%). This phenomenon could be explained that Most biofilms provide a mechanical barrier to phagocytosis much like a capsule. A small number of bacteria become biologically active by migration from the biofilm or by shearing forces that remove small clumps of the biofilm. These bacteria released from the biofilm can induce not only host responses but also act as the seeding colony for the establishment of another infectious focus (28). In our research, the patients in non-survival group appeared a higher CD4 + T cell ratio than survival patients, which revealed that a persistent neutrophil activation and accumulation in tissue that caused inflammation spread.
Our study had several limitations. First, because data were collected retrospectively from medical records, some parameters had to be inferred from the charts.
Susceptibility testing had limitations, fosfomycin was not included, which resulted in a lack of antibiotic susceptibility evidence when we made treatment decisions.
In conclusion, our study suggests that MDR/XDR-AB is an important opportunistic pathogen that causes nosocomial infection in PICU with a rather high mortality. The incidence increased in the last six months, ineffective management, immune dysfunction, co-infected with other pathogen contributed to the risk of death.

Declarations
Ethical approval and consent to participate: Not applicable

Conflict of Interest:
On behalf of all authors, the corresponding author states that there is no conflict of interest.

Competing interests:
On behalf of all authors, the corresponding author states that there is no conflict of interest.