MDR-AB increases the mortality rate of nosocomial pneumonia. Our study found that admission to the intensive care unit, age > 75 years, invasive catheterization, and mechanical ventilation increased the mortality of patients with severe MDR-AB pneumonia, which was consistent with the results of other studies . Early removal of invasive catheters and reducing the time on mechanical ventilation might reduce the mortality of critically ill patients diagnosed with severe MDR-AB pneumonia. Table 1 shows that there were age differences in clinical outcomes in the study population, but no differences by gender. This may be related to factors such as more complications, more co-morbidities, difficulty in weaning from ventilator, and longer ICU stay in older adults with severe pneumonia.
In our study, the main drugs that affect the mortality of patients with severe MDR-AB pneumonia or CRAB pneumonia included tigecycline, carbapenem, and sulbactam. Although Abs had good sensitivity to colistin in vitro, the MIC of colistin was less than 1 in China. But colistin was not widely used in the treatment of CRAB because of its high cost and not being covered by general health insurance in our country. There were only 2 patients were treated with colistin for CRAB, and they could not be included in the study due to uncertainty of clinical data and co-infection of fungal.
Although tigecycline was recommended as a first-line drug for CRAB pneumonia, there were different opinions on whether its use was beneficial to reduce mortality. The resistance rate of tigecycline in vitro was low in China (about 2.9%) , which ranges from 0.2 to 74.2% in other countries and regions . The concentration of tigecycline was higher in tissue, and it has suitable antibacterial activity and was safe for use against local tissue infections. Therefore, it has been theorized that tigecycline was an effective antibiotic for the treatment of CRAB and can reduce mortality [10. A previous meta-analysis showed that patients treated with tigecycline for CRAB infection had a higher mortality rate, longer hospital stay, and lower microbial clearance rate as compared with other drugs . Another prospective study demonstrated that tigecycline increases the mortality rate in patients with CRAB infection when the tigecycline MIC > 2 mg/L . The results of our study showed that tigecycline could significantly reduce the mortality rate of hospital-acquired pneumonia when CRAB was the main pathogen and treatment was not delayed. Because of Abs isolated in this study was sensitive to tigecycline (Mean MIC = 1.5 mg/L) in vitro, and the therapeutic effect of tigecycline might be related to drug sensitivity. Even if these patients had higher APACHE II scores, some of them were prescribed tigecycline alone, there were still good clinical outcomes, if tigecycline was sensitive in vitro.
Most MDR-AB produce carbapenemases in previous study . We also found that the resistance rate of carbapenem reached 94.6%. Continued use of carbapenem did not reduce the mortality of patients with CRAB pneumonia. It was not recommended to use only carbapenem for theses patients, but it might be effective as one of the combined treatment options, especially the MIC of carbapenem was less than 8. It was worth noting that, the combination of other drugs may reduce the carbapenem MIC value. The most common combination was sulbactam and or tigecycline in clinical practice. Carbapenem and sulbactam had been shown to have a synergistic effect and could reduce mortality . Sulbactam, a β-lactamase inhibitor, has a suitable clinical therapeutic effect, and most of Abs has a low rate of resistance to sulbactam. Sulbactam enhanced the antibacterial effect of carbapenem by acting on the penicillin-binding protein. A previous study suggested that, compared with a single drug, carbapenem combined with sulbactam enhanced the antibacterial effect on CRAB in vitro and decreased the MIC value of carbapenem . Our study found that although Abs was resistant to carbapenem, the 28-day mortality rate of patients after the addition of sulbactam was significantly reduced, which might be related to a mechanism by which sulbactam reduced the MIC value of carbapenem.
In addition, the combined dose of sulbactam needs to be further explored. A previous study found that when patients were given sulbactam 2 g q6h or 3 g q8h intravenously, the T > MIC (above 60%) was 98.83% and 95.59% respectively, if the sulbactam MIC was 16 µg/ml. Therefore, high-dose sulbactam was beneficial to controlling MDR-AB infection . Another study recommended that a high-dose sulbactam (9 g/d) was also beneficial in controlling MDR-AB infection . Our study found that the mortality rate of patients with CRAB pneumonia was lower in the high-dose sulbactam group as compared with the low-dose group, but the difference was not statistically significant. This might be related to the small number of cases in the high-dose sulbactam group. Thus, future studies regarding the dose of sulbactam need to include a larger number of cases.
Our research has many limitations. First, we followed 1,823 clinical cases with positive AB culture results. Most of the cases were excluded because clinicians were not sure whether AB was the causative bacterium of severe pneumonia or only colonization in the lower respiratory tract. Especially at the same time, other bacterial and or fungal pathogens were cultivated from the lower respiratory tract. Second, only 166 cases were identified as severe MDR-AB pneumonia. After grouping, some data results did not reach statistical differences, for example, comparison of the clinical effects of high- and low-dose sulbactam for CRAB. Then, further mechanistic studies were needed, including the paper diffusion method or the antibiotic concentration gradient method (E-test method), to detect whether there was a synergistic effect between carbapenem and sulbactam, and different resistance mechanism in these CRAB strains.
In summary, despite the above shortcomings, ICU status, an extended period of invasive catheter retention time and mechanical ventilation time, and not using the appropriate antibacterial treatment increased the mortality in patients with severe hospital-acquired MDR-AB pneumonia. Although MDR-AB was resistant to many antibiotics, most of the MDR-AB strains in western China were still sensitive to tigecycline. The inclusion of tigecycline in the combined treatment plan could significantly reduce the 28-day mortality of patients. In addition, the inclusion of sulbactam in the treatment plan could also reduce the mortality of patients with carbapenemase-producing AB pneumonia on the basis of tigecycline. High-dose sulbactam might improve the clinical prognosis of patients by reducing the MIC of carbapenem drugs especially.