A. baumannii is one of the most threatening nosocomial microorganisms, characterized by its capacity to survive in various environments and to develop antibiotic resistance. Drug-resistant A. baumannii is prevalent in several healthcare facilities in China. The rapid growth of antibiotic resistance is a considerable economic and medical burden, and is associated with higher costs, longer hospital stays, and increased in-hospital mortality (22)(23). Due to the increase in the occurrence of XDR and pan drug-resistant A. baumannii strains, WHO reported that there is an urgent need of novel antibiotics (24), emphasizing the importance of preventing and treating drug-resistant A. baumannii.
This study assessed the effect of XDR-AB colonization on the prognoses of severely ill patients. We conducted the study in two mixed adult ICUs in China, where XDR-AB is the most common pathogen in nosocomial infections. The findings revealed that XDR-AB colonization had no association with the short-term (28-day) mortality of ICU patients but contributed to a 1.75-fold increase in mortality risk at 6 months.
In our study, the overall peripheral colonization rate of XDR-AB was 18%, which is higher than that published in previous reports. An XDR-AB acquisition rate of 15.6% was observed in a Lebanese ICU (25). Further, in an American study, the colonization rate of XDR-AB among solid organ transplant patients was reported as 0.9% (26). The relatively high colonization rate in our study indicates a possible regional epidemic of XDR-AB in our ICUs.
Studies have elucidated several risk factors of XDR-AB colonization, such as previous admission to long-term healthcare facilities, invasive operations, presence of comorbidities, low socioeconomic status, and previous use of carbapenems (25, 27, 28). In this study, critical patients who were admitted with suspected sepsis and required extended invasive ventilation and longer ICU stay were more likely to be colonized with XDR-AB. There are possible reasons for this finding. First, in septic patients, immune system disorders lead to poor defensive responses, making them more susceptible to opportunistic pathogens. Second, invasive operations, such as tracheal intubation and tracheostomy, provide opportunities for pathogen colonization through wounds and invasive devices due to impairments in skin and mucosal barriers. Finally, decolonization has not been adopted in ICUs in China; therefore, long-term hospitalizations coupled with poor baseline conditions and more intensive care might increase opportunities for colonization.
There is not much information on the impact of XDR-AB colonization on patient prognosis. It has been wildly accepted that A. baumannii infections can lead to higher death rates. Among critically ill patients, the estimated increase in the in-hospital mortality rate due to A. baumannii infection ranges between 7.8% and 23%, and the attributable ICU mortality ranges from 10% to 43% (29). High mortality rates have been reported in patients infected with drug-resistant A. baumannii (30, 31). However, only a few studies have elucidated the association between mortality and colonization of drug-resistant strains. In one such cohort study conducted by Dautzenberg et al., it was confirmed that there is a 1.79 times higher risk of death in ICU patients colonized with carbapenemase-producing Enterobacteriaceae than in ICU patients who are not colonized (16). Currently, the association between A. baumannii colonization and mortality is still under debate. It has been reported that colonization with multiple drug-resistant A. baumannii (MDR-AB) strains upon ICU admission is related with a 1.4-fold increase in in-hospital death rate (32). Additionally, several studies have concluded that colonization and infection with A. baumannii is an independent risk factor of mortality (27, 33-35), without distinguishing between colonization and infection. In this study, we identified colonization using nasopharyngeal and perirectal samplings, which are generally used to identify colonization (16, 36, 37). As far as we know, this is the first research to assess the effect of XDR-AB colonization on long-term mortality in critical patients. The results revealed that XDR-AB colonization has no impact on the 28-day prognosis based on the multivariate analysis findings, but it was associated with higher mortality rates at 6 months. Thus, in our study, patients with XDR-AB colonization had a 1.75 times higher risk of death at 6 months. After adjusting for severity of illness, previous medical history, intensity of care, and other factors identified in univariate analysis, XDR-AB colonization proved to be an independent risk factor of poor long-term prognoses.
The mechanisms of bacterial colonization may hold the answer to the increased mortality observed in patients with XDR-AB colonization. In general, bacterial colonization in hosts typically occurs in several steps. First, colonizers enter the nasopharynx and escape from the mucus, and following this, they attach themselves and adhere to epithelial cells. At the colonization loci, pathogens acquire the nutrition required to grow and to proliferate via various pathways of carbohydrate transportation and utilization (38, 39), and eventually evade host immune responses and achieve persistence. In the case of A. baumannii, colonization starts with pili-mediated twitching, and adherence is assisted by cell surface hydrophobicity and biofilm-associated proteins (38, 40). Insufficient nutrient availability in the upper respiratory tract promotes the transformation from motion to colonization (41). Additionally, persistent invasion of the host immune system is facilitated by capsules, immunoglobulin-targeted proteases, and the biofilm (42-44). The colonization is also dependent on the establishment of balance between hosts and pathogens: Immunocompetent hosts tend to coexist with the microorganisms, while infection occurs in deteriorated immune systems.
The association between A. baumannii colonization and mortality could be explained by several mechanisms. For example, virulence factors for A. baumannii, particularly porins, can cause cytotoxicity and induce immune responses. Porins, including OmpA, Omp34, and carO, exist on the outer membranes of A. baumannii. They have been found to be correlated with antimicrobial resistance, inflammatory responses, and cell death (45, 46). OmpA is also found in secreted membrane vesicles, and increase in the density of OmpA has been proven to be associated with high mortality (47). Additionally, spread of colonized pathogens into the lower respiratory tract, or other sterile locations, can lead to increased risk of diffuse infections (48). Moreover, interactions between colonizers can result in coinfections or induction of antibiotic resistance even without antibiotic exposure. In fact, this appears to be a prominent mechanism in bacteria with extensive drug resistance.
Increase in mortality caused by XDR-AB colonization indicates the need for essential surveillance during the early stage and efficient measures of decolonization. A meta-analysis reported that decolonization reduces infection caused by multidrug-resistant gram-negative bacteria when combined with standard care, especially in Europe, where decolonization has been widely applied as an infection prevention and control strategy (49). However, considering that there is a lack of effective antibiotics, it is challenging to eliminate XDR-AB. It has been reported that daily whole-body bathing with chlorhexidine was efficient in eliminating MDR-AB from the skin (50) and was helpful in reducing bloodstream infections in patients colonized with XDR gram-negative bacilli (51). This, this might be a feasible approach to decolonize XDR-AB. Decontamination of the alimentary tract with polymyxin E and tobramycin was effective in patients colonized with MDR-AB (37, 52-54). However, there is no clinical evidence about systematic antibiotics for the decolonization of XDR-AB. Additionally, standard nosocomial care is of vital importance, e.g., hand hygiene, exposure precautions, conventional screening, and environmental sterilization, especially in wards with highly prevalent strains (3). However, according to the guidelines established by the European Committee on Infection Control (EUCIC), there is not enough information about the decolonization of carbapenem-resistant Acinetobacter baumannii (CRAB) (55). Our data provide some evidence supporting the need for decolonization, but further interventional studies are required for strategy development and efficacy validation.
It has been acknowledged that in critical patients, colonization with gram-negative bacteria contributes to more nosocomial infections (56). The risk of developing subsequent A. baumannii infections is 8.4 times higher in patients colonized with CRAB (36). In this study, the incidence of XDR-AB infection is higher in colonized patients than in non-colonized ones. We also observed higher use of colistin or tigecycline after detection of XDR-AB colonization. Multivariate Cox regression analysis showed that XDR-AB infection is not an independent risk factor for death at 6 months. This implies that the increase in the 6-month mortality of colonized patients was not caused by subsequent XDR-AB infection during admission.
Subgroup analyses of 6-month mortality rates were performed in patients with different characteristics, and the results were consistent. Patients colonized with XDR-AB had the worse prognosis (with HR >1) in all the groups; however, some of the subgroups did not show statistically significant differences. Colonization with XDR-AB was recognized as a risk factor of 6-month mortality regardless of age, admission season, comorbidity, and APACHE II scores upon admission. In addition, XDR-AB colonization was worse in ICU patients who were hospitalized for more than 14 days (HR = 2.022, 95% CI = 1.393–2.936). This indicates the harmful effect of XDR-AB colonization on critical patients with prolonged ICU stay.
Our study had some limitations. First, there is no information on the effect of colonization with drug-sensitive A. baumannii or MDR-AB on patient prognosis. Approximately 95% of the A. baumannii strains isolated were XDR strains, and sensitive and multidrug-resistant strains were rare. Second, we assumed in colonized patients, the XDR-AB colonization persisted at discharge, because decolonization measures were not performed. Third, information about XDR-AB infection from the patients’ discharge to 6 months after discharge could not be obtained; therefore, its influence on 6-month mortality may have been underestimated. Fourth, we did not determine cause-specific survival as we were unable to obtain follow-up data for all the patients. Patients were re-admitted to other hospitals that used different information systems, so it was it was difficult to obtain their medical records after discharge.