XDR-AB infection has been reported as a significantly causative agent of nosocomial infection, while the choice of therapeutic regimen is of great interest. For some patients, the treatment outcomes of the new antibiotics, such as PMB, tigecycline, etc were not satisfactory. As a result, sulbactam, which is an old antimicrobial agent has gained more and more attention in recent years. However, it is noteworthy that only a limited number of countries, such as China offers the single-agent formulation of sulbactam. Furthermore, the majority of research on sulbactam has primarily focused on the combination dosage forms rather than the single-agent formulation. To our knowledge, this is the first clinical study focusing on sulbactam single agent in XDR-AB infection and evaluating the therapeutic efficacy of the high-dose sulbactam as a single agent formulation (≥ 6 g/day).
The all-cause mortality observe in our study was 36.5%. A study by Huang, S et al. on the treatment of pneumonia of Acinetobacter calcoaceticus-Acinetobacter baumannii complex with sulbactam (SBT) or ampicillin/sulbactam reported a similar mortality rate of 31.2% 15. Besides, Niu, T et al. conducted a comparative analysis of CR-AB infected patients with bloodstream infection, treated with Cefoperazone/Sulbactam and Tigecycline. Their finding showed that the 28-day mortality rate of patients treated by Cefoperazone/Sulbactam was significantly lower than the those treated by tigecycline, 29.3% vs. 51.9%, P = 0.00118. Similarly, Gu, S et al reported a study of CR-AB infected patients treated with Cefoperazone/Sulbactam, demonstrating a significantly lower mortality rate in the Cefoperazone/Sulbactam group (25.4% vs 53.4%, P = 0.005) 19. In recent years, more and more research has been done on sulbactam-durlobactam 20, Keith et al had conducted a phase 3, non-inferiority clinical trial involving 181 patients randomly assigned to sulbactam-durlobactam or colistin due to carbapenem-resistant Acinetobacter baumannii-calcoaceticus complex (ABC) infection. This study demonstrated a lower 28-day all-cause mortality in patients receiving sulbactam-durlobactam compared to colistin group (19% vs 32%).
Additionally, our study reported a clinical response rate of 59.6% (31 / 52) for sulbactam in the treatment of XDR-AB infected patients. In comparison, a study by G. Kalin et al. on patients with multidrug-resistant Acinetobacter baumannii ventilator-associated pneumonia indicated a 15-day clinical response of 43.2% to colistin/sulbactam treatment, but it's worth noting that their study focused on patients with severe drug-resistant Acinetobacter baumannii ventilator-associated pneumonia 21. In conclusion, sulbactam-based therapy may be a promising treatment to in improving both patient mortality and clinical response for XDR-AB infection. However, more research support is still needed for a comprehensive understanding of its effectiveness.
For the analysis of risk factors affecting 28-day mortality and 14-day unfavourable clinical response in patients with XDR-AB infections treated with sulbactam, our study firstly found that the duration of SBT therapy could affect the mortality and clinical response. This finding aligns with the study conducted by Huang, S et al, which suggested that a shorter duration of SBT-based therapy is a risk factor for clinical failure in patients 15. Furthermore, receiver operating characteristic curves modeling indicated that the optimal cutoff for the duration of SBT treatment was 8.5 days for 28-day survival and 11.5 days for 14-day favorable clinical response, which was established for the first time and necessitates further investigation and validation in subsequent studies. Secondly, our study suggested that SBT-based therapy is likely suitable for patients who got intracranial infection, which demonstrated a longer survival duration by performing a Kaplan–Meier survival analysis, P = 0.09, without a statistical difference. The reason why maybe that only 9 patients with intracranial infection were enrolled in our study. In a study by Ye Y et al. involving 91 patients with carbapenem-resistant Gram-negative bacteria-related health care-associated ventriculitis and meningitis for 9 years, therapies of polymyxin and meropenem/sulbactam were considered optional choices 22. Sun L et al. reported that ampicillin-sulbactam may be an effective therapeutic agent for meningitis caused by Acinetobacter baumannii resistant to imipenem and other β-lactam medication 23. However, the majority of research has focused on SBT-based composite preparations, research of SBT single agent formulation was rare. Our study may provide a new therapeutic option for patients with intracranial infection.
Sulbactam which possesses intrinsic antibiotic activity, could saturate PBP1a/1b and PBP3 in A. baumannii isolates at high doses 12,24. The outcomes of our current study revealed that patient treated with a high dose of SBT (≥ 6 g/day) exhibit a shorter time of response consistent with the intrinsic properties of sulbactam as described above, P = 0.03 and r = -0.381. Moreover, the result of Cox regression analyses suggested that the CrCl of patients higher, the clinical response worse, which also manifested the importance of high dosage. Previous study indicated that the antibacterial activity of SBT depends on the time of its concentration remain above the minimum inhibitory concentration (MIC) 25. A lower CrCl results in a higher likelihood of free concentration exceeding the percentage of time above MIC (%f T > MIC) of XDR-AB, therefore, potentially influences the clinical response to our antibiotics. This correlation may explain why a higher CrCl is associated with a less favorable clinical response in this study. Addtionally, Infectious Diseases Society of America (IDSA) 2023 Guidance suggested high-dose ampicillin-sulbactam (sulbactam component 6 – 9g/day) combine with at least one additional for treating CR-AB infections 16. Another study indicated that in patients with XDR-AB infected pneumonia, treatment with colistin combined with sulbactam at a dosage of 12 g/day was not superior to 9 g/day 26, aligning with IDSA guidelines. Besides, a meta-analysis demonstrated that high-dose sulbactam (≥6 g/day) combining with other antibacterial medications such as colistin might might be a potential therapy for MDR-AB or XDR-AB infections27. But limited evidence on the safety of high-dose sulbactam therapy, existing findings indicate that high-dose ampicillin-sulbactam (sulbactam component 12 g/day) has caused no relevant adverse effects 28, while, another analysis suggested that patients treated with a daily dose of sulbactam/ampicillin of ≥9 g (sulbactam component 6 g/day) were more likely to experience an increase in alanine aminotransferase grade 29. There is still a debate about safety of SBT. Moreover, in our study, no adverse events were reported despite administering the highest dose of 9g/day. Consequently, SBT emerges as a potentially new alternative for XDR-AB infection and and further investigations into high-dose sulbactam single agent formulations are warranted.
However, there are still some limitations in our study. Firstly, this is a retrospective study, although we just included 52 patients, the sample size is already relatively large for sulbactam single agent formulation in treating XDR-AB infection. Secondly, this study includes patients with co-infections due to the limited number of patients with simple XDR-AB infection, which may have impacted the results.