Acinetobacter 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. In our present study, the incidence density of MDR/XDR- Acinetobacter baumannii at our facility was 0.48 cases/1000 patient-days, which approximated to the incidence of 0.47 cases/1000 patient-days from reported in ICU patients but lower than the incidence of another PICU that literature reports. Patients in PICU always characterized by more severe underlying diseases, immune dysfunction and more complex medical history, all of these conditions will cause severe infection of Acinetobacter baumannii while MDR/XDR Acinetobacter baumannii strains appeared.
From our single-center data, ventilator-associated pneumonia (VAP) occupied the major complication in pediatric critically ill patients who MDR/XDR Acinetobacter baumannii infection with an incidence rate of 54.9% (56/102). Both blood stream and CNS infection caused relative high mortality, in our research, 12 in 28 bloodstream infection patients and all 4 meningitis patients died. Due to increased invasive operations as well as the severity of primary conditions of critically ill patients, the overall incidence of MDR/XDR Acinetobacter baumannii infection increased.
MDR/XDR Acinetobacter baumannii is resistant to most pediatric antimicrobial agents, including penicillins, most cephalosporins, carbapenems, aminoglycosides, and sulfa drugs. XDR Acinetobacter baumannii tends to develop resistance to multiple antimicrobial agents through degrading enzymes targeting β- lactams, increasing the expression of Ampc enzyme, modifying enzymes targeting aminoglycosides and alteration to the binding sites for quinolones, producing OXA-23 carbapenem enzyme, decreasing the expression of outer membrane pore channel protein, efflux pump system hyperactivity, and loss of PBPs. Additionally, MDR/XDR Acinetobacter baumannii could induce drug resistance through plasmid integration, while causing multiple drug resistance plasmids[20,21]. In our study, the susceptibility results showed that the drug resistance rates of MDR/XDR Acinetobacter baumannii to beta-lactam antibiotics were more than 75% except for cefoperazone/sulbactam (42%). When it came to the in vitro activities of beta-lactamase inhibitors, sulbactam was superior to clavulanic acid and tazobactam. Sulbactam has good intrinsic antimicrobial activity against multidrug-resistant acinetobacter strains at concentrations readily achievable in human serum. As the contribution of sulbactam, another antibiotic contains sulbactam-ampicillin/sulbatan, showed lower drug resistance rate (79%) than other beta-lactam antibiotics. During the period of neither tigecycline nor polymyxin was available, a combination therapy of cefoperazone/sulbactam or fosfomycin and carbapenems was applied.
Since the safety of children's medication has been put in an important place, our choice of antibiotics faced a lot of limitations. Although no evidence in the literature that combination therapy is prior to single drug for infection with MDR/XDR Acinetobacter baumannii, some in vitro studies have shown that certain drug combinations are synergistic[23,24].In the study by Singkham-In U et al, the combination of 1× MIC of imipenem (16-64 mg/L, and 128mg/L of isolate A10) and 1× MIC of fosfomycin (128-256 mg/L) showed synergism and bactericidal effect against most Acinetobacter baumannii isolates. Fosfomycin, when combined with imipenem, may enhance the inhibition of bacterial cell wall synthesis. So, from this point of view, the combination of fosfomycin and carbapenems in the past few years benefited a number of our patients.
Acinetobacter baumannii was transported together by infiltrating neutrophils. Go Kamoshida et al. found that Acinetobacter baumannii exploits human neutrophils by adhering to and inducing IL-8 release for bacterial portage. Acinetobacter baumannii stimulation IL-8 plays a critical role in enhancing the migration of Acinetobacter baumannii -adhering neutrophils, the migration of Acinetobacter baumannii was suppressed when the infiltration of neutrophils was suppressed by inhibiting IL-8. Through Toll-like receptor 4 (TLR4) and CD14, Acinetobacter baumannii lipopolysaccharide leads the production of the neutrophil chemotactic factor IL-8 and the proinflammatory cytokine TNF-α. In our MDR/XDR Acinetobacter baumannii infected patients, a higher serum level of IL-8 (15.25 (1.62, 47.215)pg/mL vs. 0.1(0.1, 22.99)pg/mL ) was detected in the non-survival group, this phenomenon might explain that Acinetobacter baumannii in this group seems to spread throughout the body more easily.
Studies have shown that purified TLR2 ligands from Acinetobacter baumannii are immunostimulatory. CD4+ T cells play important role in the Th1/Th2 paradigm, participate in inflammation, AbOmpA of Acinetobacter baumannii (AbOmpA) is a major porin protein in the outer membrane and is partly responsible for apoptosis of eukaryotic cells. Jun SikLee et al co-cultured CD4+ splenic T cells with AbOmpA-treated DCs, and found AbOmpA directs CD4+ T cell differentiation towards a Th1 response. 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. 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.
Critically ill patients had increased oxygen consumption, when these patients accompanied with capillary leak syndrome, they often had hydration status resulting in increasing reabsorption of urea by the kidneys, and reduction of ALB, elevation of BUN level can be frequently observed. Current studies highlighted BUN/ALB level as a predictor of 30-day mortality in a large sample of adult patients with hospital acquired pneumonia , and in our research, we also find that high BUN/ALB level associate with worse clinical outcome ( 0.09（0.06, 0.16）vs. 0.17（0.09, 0.27）, p= 0.001), which coincide with the results in adult patients.
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- Acinetobacter baumannii is an important opportunistic pathogen that causes nosocomial infection in PICU with a rather high mortality. The incidence increased these years. Bloodstream and central nervous infection accounted for high risk of death. Increased invasive operations, IL-8 releasing, and persistent neutrophil activation contributed to the risk of death.