The Clinical Outcomes and Safety of Tigecycline in Monotherapy or Combination with Cefoperazone/sulbactam for Carbapenem-Resistant Acinetobacter baumannii-Associated Pneumonia: A Multicenter Retrospective Study

doi:10.21203/rs.3.rs-4176720/v1

Objective

We aimed to evaluate clinical outcomes and safety in tigecycline (TGC) monotherapy or in combination with cefoperazone/sulbactam (CPS) treatment for patients with hospital-acquired pneumonia (HAP) infected by carbapenem-resistant Acinetobacter baumannii(CRAB).

Methods

This was a retrospective analysis of multicenter data from patients with CRAB HAP in 62 Chinese hospitals. Risk factors of receiving TGC with CPS therapy and predictors of mortality were used multivariate logistic and Cox regression analyses, respectively. Propensity score matching (PSM) evaluated the efficacies and safety of antimicrobial regimens.

Results

180 patients included in our study, 95 used TGC monotherapy, and 85 used TGC with CPS therapy. The multivariate logistic regression analysis revealed that the risk factors were significantly associated with TGC with CPS therapy included the older age [P = 0.011], intensive care unit (ICU) admission[P = 0.007]. The multivariate Cox regression demonstrated that there was a significantly higher risk of 90-day mortality [P = 0.031] among subjects in TGC-CPS group. The subgroup of patients who received Standard dose TGC (SDT) plus CPS had a significantly higher rate of SOFA score ≧ 7(P = 0.009), and the 30/90-day mortality rate of patients was also higher. The variation of ALT, TBIL, Cr, Hb, and PLT did not differ between different antimicrobial regimens after PSM.

Conclusion

The severity of patient conditions and TGC doses were significantly associated with mortality. HDT combined with CPS was the prior treatment option for patients with CRAB HAP who were elderly, had ICU admission. We observed that different antimicrobial regimens had similar safety in liver/kidney/coagulation.

Tigecycline

Cefoperazone/Sulbactam

Carbapenem-Resistant Acinetobacter baumannii

Hospital Acquired Pneumonia

The gram-negative bacilli [1] were primary pathogens of HAP in our country, among which AB [2] was the most common, accounting for 25.6%. AB was limited in the availability of antimicrobial agents, due to increasing resistance to various antibiotics, especially carbapenems, as well as had the ability to survive long-term in vitro, which spread widely in the hospital. Besides, the conditions for patients with AB infections were severe, resulting in longer lengths of hospital stay (LOS), more medical costs, and worse prognosis[3]. It was why AB, as a priority on the global priority list for research and development of new antibiotics, has been classified by the World Health Organization(WHO) [4]. Accordingly, AB infection has long become a focus issue of global public health, bringing a heavy challenge to the safety of the international medical and health environment. It was critical to strengthen surveillance and control AB spread.

In 2020, Chen CH et al. [5] conducted a study on the in vitro activity of multiple antimicrobials against AB in the Asia-Pacific region, including novel β-lactam combination agents, TGC and colistin, which showed that drug-resistant strains of AB in China exceeded 70.0%, being third only after South Korea and India. According to the China Antimicrobial Surveillance Network (CHINET) continuous drug resistance monitoring program in 2021, it was also reported that among clinical isolates of CRAB amounted to 71.5% [6], a rising trend over the years. Although CRAB had greater than 88.0% susceptibility to polymyxin B and tigecycline [7], which were considered the last resource antibiotics currently used in CRAB infection, a superior treatment for CRAB infection is still a matter of debate. For severe CRAB infections, TGC monotherapy may lead to higher mortality, especially in the case of bacteremia or pneumonia[8]. According to the Infectious Diseases Society of America (IDSA) guidelines and the European Society for Clinical Microbiology and Infectious Diseases (ESCMID) guidelines for AMR treatment for the antimicrobial resistance (AMR) treatment, as well as 2023 IDSA Guidelines for the treatment of drug-resistant gram-negative bacterial infections, which were recommended that patients with severe CRAB infections should receive a combination of at least two in vitro active drugs[9–11]. Moreover, it also mentioned that ampicillin-sulbactam combined with TGC or cefiderocol was the preferred treatment for CRAB-associated pneumonia. Likewise, the Chinese Expert Consensus on Diagnosis, Treatment, Prevention, and Control of AB Infections also proposed that the two-drug combination therapy for CRAB was suggested sulbactam compound (or sulbactam)-based, with CPS being the mainly used in China [12], followed by polymyxin E and TGC. However, colistin with additional antibacterial agents was associated with a higher risk of nephrotoxicity [13]. Even both TGC-based combination therapy and polymyxin-based combination therapy are equally preferable for the treatment of pulmonary infection caused by CRAB.

However, there are currently only well-controlled, unsampled clinical case studies or case reports regarding the treatment of AB pneumonia with TGC, which had low quality of evdience monotherapy or combination therapy [9, 10, 14, 15], and there remains a need for further validation concerning the clinical efficacy and safety of regimens. Therefore, it is essential and of significant clinical value to explore the treatment of CRAB-infected patients with hospital-acquired pneumonia based on different doses of TGC in monotherapy or combination with CPS.

Study design and patients population

We performed a multicenter retrospective study in 62 hospitals in China from October 2019 to June 2021. We selected 180 hospitalized adult patients with CRAB pneumonia who received either TGC monotherapy or combination with CPS.

The inclusion criteria were as fllowed: (1) patients were infected with CRAB HAP; (2) patients who received either TGC monotherapy or combined with CPS. The exclusion criteria included the following: (1) pathogenic bacteria other than CRAB; (2) pathology not derived from sputum or BALF; (3) treatment for fewer than two days [16]. (Figs. 1)

Data Collection

The collected data were as follows: demographic characteristics (Gender, Age, BMI), history of chronic illness (Charlson comorbidity index score, CCI), the severity of the condition (Sequential Organ Failure Assessment score, SOFA), comorbid conditions (septic shock), intensive care unit (ICU) admission, Mechanical Ventilation (MV), Continuous Renal Replacement Therapy (CRRT), laboratory findings, and follow-up.

The primary clinical outcome was defined as all-cause 30/90-day mortality.

The secondary outcomes included length of hospital stays (LOS), variations in white blood cell (WBC), C-reactive protein (CRP), and procalcitonin (PCT) within 1 week of antibiotic use.

To assess the incidence of adverse events, we calculated the variation in ALT/TBIL/Cr/PLT/Hb( maximum minus minimum of alanine aminotransferase (ALT)/total bilirubin (TBIL)/creatinine (Cr)/platelet (PLT)/ hemoglobin (Hb)within 1 week of antibiotic use).

Definitions

Pneumonia caused by CRAB was defined as clinical evidence of HAP with a qualified sample positive for CRAB [17].

Patients were treated with an intravenous 100mg dose, followed after 12 h by a maintenance dose of 50 mg every 12 hours, defined as Standard-dose-TGC(SDT), while High-Dose-TGC(HDT) was an initial dose of 200 mg followed by 100 mg every 12 hrs(q12h). Cefoperazone/Sulbactam(cefoperazone: sulbactam, 1:1/ 2:1) at a dose of 6-9g administered intravenously one day.

Statistical analysis

All statistical analyses were performed using SPSS software (version 26.0). Continuous variables were assessed for normality with the Shapiro-Wilk test. The data that conformed to normal distribution were presented as the mean and standard deviation (SD) and analyzed using a t-test. Otherwise, data would be presented as the median and interquartile range (IQR) with the Mann-Whitney U test. Categorical Data were presented as the number and proportions (%). The chi-square test or Fisher's exact test was used to test comparisons between groups for categorical variables. The relative efficacies and adverse effects of the different antimicrobial regimens were assessed by conducting propensity score matching (PSM). Multi-logistic regression analysis and ROC curves were used to predict the independent risk factors for different antibiotic regiments. The Kaplan-Meier product-limit method was used to estimate the survival distribution function. The predictors of 30-day and 90-day mortality for CRAB Pneumonia were identified using Cox regression analysis. P values less than 0.05 were considered statistically significant.

We included data from 180 patients with CRAB HAP and analyzed their characteristics, including 95 receiving TGC monotherapy, and 85 receiving TGC combined with CPS therapy.

Patients with TGC monotherapy were defined as the control group, and TGC combined with CPS therapy as the observation group. The age(73(63,85) vs 65(56.5,76) , P = 0.009)、BMI (23.0(21.3,24.8) vs 21.6(20.1,24.4), P = 0.049)、CCI score(2(1,4)vs1(0,2),P = 0.002)、SOFA score(9(6,11)vs5(4,9), P = 0.000) were significantly higher in observation group. In subsequent analysis, a significant increase was found in patients receiving TGC plus CPS combination compared to those with TGC monotherapy, including the SOFA score ≥7(72.9% vs 35.8%, P = 0.000) and ≥65yr(68.2% vs 52.6%, P = 0.033); however, there were no significant differences in the BMI subgroup(P > 0.05). The ICU admission, used MV, and CRRT rates of patients given TGC with CPS were also higher than that of patients given TGC monotherapy (91.8% vs 56.8%, 87.1% vs 45.3%, 25.9% vs 5.3%; respectively, P = 0.000). Additionally, a similar difference was noticed in the incidence of shock (57.6% vs 34.7%, P = 0.002). (Table 1)

There was a significant difference in the primary outcomes of all-cause 30-day mortality when comparing TGC monotherapy and TGC combined with CPS therapy ( 6.3% vs 16.5%, P = 0.03). Additionally, the all-cause 90-day mortality of patients receiving TGC combined with CPS regimen was also higher; however, no statistical difference was observed (25.9% vs 15.8%, P = 0.094). Despite these circumstances, the LOS was similar in both two groups (26(21,41) vs 30(20,42), P = 0.627). The PSM was performed to adjust the WBC, PCT, ALT, TBIL, Hb, and PLT; it demonstrated that TGC plus CPS therapy was superior to those with TGC monotherapy in reducing CRP level(88.2(36.2,152) vs 22.6(9.5,71), P = 0.009). Furthermore, TGC plus CPS therapy did not differ in adverse effects when compared to TGC monotherapy(P > 0.05). (Table 2)

The multivariate logistic regression analysis revealed that independent risk factors associated with TGC plus CPS therapy included age [P = 0.011; odds ratio, OR(95% CI): 1.083 (1.018–1.152)], ICU [P = 0.007; OR(95% CI): 12.801 (1.980–82.747)], WBC [P = 0.023; OR(95% CI): 0.877 (0.784–0.982)], and Hb [P = 0.047; OR(95% CI): 0.951 (0.904–0.999)] (Table 3), with the AUC of 0.931 and 95% confidence interval of 0.887-0.975. The validation of this risk model demonstrated that the model had good prediction ability. In addition, the cut-off value was 0.3, and the sensitivity and specificity were 100% and 75.4%, respectively (Supplementary Figure 1).

A significant increase in the all-cause 30-day mortality (X²=4.202, P=0.04) in patients with CRAB HAP receiving TGC with CPS, according to the Kaplan-Meier survival curve(Figures 2a). The 90-day mortality of patients receiving TGC with CPS was also higher than that of patients with TGC monotherapy; however, the difference was not significant (Figures 2b).

The multivariate Cox regression analysis showed that shock and PLT were independent predictors of 30-day and 90-day mortality (P < 0.05). After adjusting for confounding factors, it revealed that TGC with CPS therapy was also an independent predictor of the 90-day mortality[P = 0.031, HR (95% CI): 2.934(1.104–7.802)]. The data were presented in Table 4.

We included data from 43 receiving SDT and 52 receiving HDT monotherapy. Similar baseline characteristics were shown between both groups, including gender、age、BMI、CCI score、SOFA score, ICU stay, MV, CRRT, and shock(P > 0.05). (Supplementery Table 1)

There was no significant difference between primary and secondary outcomes in those patients(P > 0.05). Regarding adverse events, the variation of ALT, TBIl, Cr, Hb, and PLT was not statistically significant when comparing the SDT and HDT groups(P > 0.05). (Supplementery Table 2)

We included data from 59 receiving SDT with CPS, and 26 receiving HDT with CPS. Some baseline characteristics in both groups were similar, including gender, age, BMI, CCI score, SOFA score, ICU stay, CRRT, and shock (P > 0.05); however, the used MV was higner in the SDT combined with CPS group (93.2% vs 73.1%, P = 0.028). In subsequent analysis, the BMI≧28 of patients was significantly lower rate in the SDT combined with CPS group (0% vs 15.4%, P = 0.006); however, The SOFA score≧7 for patients in SDT combined with CPS was higher than it was for those in HDT combined with CPS (81.4% vs 53.8%, P = 0.009). (Supplementery Table 3)

No significant difference was found between the SDT and HDT combined with CPS groups in primary and secondary outcomes (P > 0.05). Similarly, the variation of ALT、TBIl、Cr、Hb、PLT were not statistically significant in terms of adverse events(P > 0.05). (Supplementery Table 4)

CRAB HAP has become a challenging clinical dilemma worldwide due to its high antimicrobial resistance, limited availability of regimens, and high mortality[18]. There were controversial treatments for patients with CRAB HAP, according to previous research. We summarized the clinical features, treatment effectiveness, and safety of various TGC doses in monotherapy or combined with CPS treatment for CRAB pneumonia. Moreover, we evaluated the independent predictors of all-cause 30/90-day mortality and risk factors of different antibiotic regimens in patients with CRAB pneumonia. The followings were the primary findings of this study.

We found a significant increase in all-cause 30/90-day mortality in TGC plus CPS therapy, which was an independent predictor of all-cause 90-day mortality following adjustment of compound factors. Meanwhile, we noticed that shock was significantly associated with 30-day and 90-day mortality. Notably, patients receiving TGC with CPS therapy were significantly superior to those with TGC monotherapy in reducing CRP levels; however, similar safety was shown in different antimicrobial regimens, including liver/kidney/coagulation. The subgroup analysis indicated that HDT combined with CPS therapy was a prior treatment option for patients with CRAB HAP who were the older age, ICU admissions particularly. In addition, the primary and secondary outcomes were similar in SDT and HDT monotherapy or combination with CPS therapy group. It first demonstrated the difference between TGC monotherapy and TGC combined with CPS in large-scale real-world data to offer the optimal drug regimens for CRAB HAP in the clinic.

Our research showed that TGC combined with CPS treatment had different clinical features when compared to TGC monotherapy for CRAB HAP. Patients with TGC plus CPS therapy had significantly higher rates than those with TGC monotherapy with a history of hospital exposure, including ICU admission, used MV and CRRT. In addition, multivariate logistic regression analysis showed that older age and ICU admission were independent risk factors for TGC plus CPS treatment for CRAB HAP. ICU patients were usually critically ill and immunocompromised, most of whom underwent invasive operations, which therefore increased the chance of contracting CRAB. However, in our study, invasive operations were not an independent risk factor for receiving tigecycline combined with cefoperazone sulbactam therapy. This might be because almost all patients experienced invasive practices during their hospitalization in the ICU, and some patients had more than one simultaneously installed invasive device. Thus, these factors could interfere with and influence each other. In conclusion, the treatment regimen for patients in the combination therapy group is under guideline and expert consensus recommendations [9-11], and the TGC in combination with CPS therapy is the preferred treatment for infections in patients with severe CRAB.

We observed an increase in the all-cause 30/90 mortality (16.5% VS 6.3%, P=0.03; 25.9% VS 15.8%, P = 0.094; respectively) in patients receiving TGC-CPS combination therapy in comparison to TGC monotherapy; however, the difference in 90-day mortality was not significant. The further multivariate Cox regression demonstrated that shock and TGC-CPS combination treatment were independent predictors of 30/90 mortality and 90-day mortality, respectively. Attributing to older age (73 VS 65, P = 0.009) and more comorbidities among TGC with CPS treatment of patients with CRAB HAP, who had a worse condition and more susceptible to multiple organ failure and septic shock, after severe infections, resulting in higher SOFA scores(9 (6, 11) VS 5 (4, 9), P = 0.000) and mortality. Although we noticed that Food and Drugs Administration (FDA)-approved indications were only for cIAI, cSSSI, and CAP, not including HAP, due to ascended multidrug-resistant infections, TGC had been widely used for non-approved indications, among whom used in research related to CRAB HAP accounted for 1/3 [8]. A previous meta-analysis of 5 trials [19] analyzed the prognosis of patients with CRAB HAP receiving TGC monotherapy compared to those with TGC combination, no significant difference was from two prospective cohort studies (OR = 2.22, 95% CI 0.79–6.20, P = 0.13). Except for in-hospital mortality, Li Y et al. [20] found that regimens containing TGC-CPS combination therapy patients with CRAB HAP were not superior to those with TGC monotherapy in clinical and microbiological efficacies. However, we only found in some laboratory findings that patients with TGC plus CPS therapy had higher CRP decline compared with TGC monotherapy, which indicated better outcomes in reducing inflammatory response, consistent with previous results[21]. Therefore, the efficacy of patients with CRAB HAP receiving TGC monotherapy or combination regimens was controversial.

In addition, the mortality and efficacy of various doses of TGC monotherapy were also unclear [22,23]. As a previous Systematic Review and Meta-Analysis[24] reported, although the microbiological eradication rate in those given HDT did not differ from SDT monotherapy for CR pathogens (OR 1.07, 95% CI 0.44-2.60, P = 0.87), mortality was reduced（OR 0.20，95% CI 0.09-0.45，p = 0.0001). And Shields RK [25] also found that HDT combined with in-vitro active antibiotics in improving prognosis was superior to SDT. Accordingly, we supposed that the high mortality in patients with severe infection might be related to tigecycline dose. In our study, subgroup analysis showed that mortality and laboratory findings of infections in SDT and HDT monotherapy or combination were no statistical difference, although lack of microbiological data. Notably, the 30/90-day mortality and SOFA scores in patients receiving SDT with CPS were also higher than those receiving HDT with CPS, which indicated that more severe infection occurred in patients with SDT combination CPS. TGC, as a bacteriostatic agent, inevitably resulted in delayed bacterial clearance and higher mortality when the organism had severely infection, if the concentration of the drug in the tissues was low and the bacteriostatic activity was descend. The difference in mortality between the two groups of patients in this study was not statistical significant, which may be due to insufficient sample size. Accordingly, There is a great need for well-designed studies to evaluate the effectiveness of various doses of TGC in monotherapy when compared to combination therapies.

On the other hand, the safety needed to be taken into consideration when prescribing TGC or CPS. TGC[26,27] and CPS[38-30]could cause coagulation disorders, raising safety concerns. Besides, severe infection could lead to coagulation factors and PLT heavier consumption, and bleeding events occurred commonly. Notably, there was controversy about whether TGC-CPS combination treatment would increase bleeding events[31-33]. Despite lack of coagulation data, we found no difference in the variation of PLT and HGB between the TGC monotherapy and TGC-CPS combination group, and no bleeding events occurred in our retrospective study. Our study revealed that TGC-CPS treatment did not increase bleeding risk compared to TGC monotherapy. TGC was eliminated from the body through biliary excretion in the feces (59%) and urine (22%), leading to a lower prevalence of abnormal liver/kidney function[34]. It showed that the variation of ALT, TBIL, and Cr did not differ between TGC monotherapy and TGC combination with CPS therapy groups, indicating without increasing liver/kidney adverse events rates for combination treatments. In general, TGC plus CPS therapy would significantly reduce inflammation levels for patients with HAP infected by CRAB, not increasing adverse effects in clinics.

The several limitations of our study were as follows. Firstly, it was a retrospective study with small sample sizes and high risks of bias. Secondly, subcenters had missed details such as subjective symptoms, pulmonary signs, imaging, microbiological, and coagulation data, affecting the assessment of treatment efficacy, which were not in our analysis.

The mortality associated with the severity of patient condition and TGC dose for patients with CRAB HAP. HDT combined with CPS was the prior treatment option for patients with CRAB HAP who were elderly, had ICU admission, and used MV. What was more significant, the TGC plus CPS combination group significantly could reduce inflammation levels, and different antimicrobiotical regiments had similar safety in liver/kidney/coagulation. It is the first study to compare the clinical outcomes and safety of TGC in monotherapy or combination with CPS therapy for CRAB infections. Considering high rates of mortality and the lack of effective treatment options for CRAB infection, we feel that there is an emerging need to be further confirmed in greater sample prospective studies for our results.

Acknowledgements

Funding

This research was supported by grants from Beijing Medical Award Foundation (grant number: 2019-1002 and grant number: YXJL-2021-0385), and National High Level Hospital Clinical Research Funding (grant number: 2022-PUMCH-B-043).

Contribution

XT T acquired the data, drafted and revised the manuscript. ZY L and LZ designed the study, provided supervision and critically revised the manuscript. All authors approve the final version of the manuscript and agree to be accountable for all aspects of the study.

Ethics approval and consent to participate

This study was approved by Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College (Protocol No. JS-3029B) and has been performed in accordance with the ethical standards laid down in "Declaration of Helsinki 1964" and its later amendments or comparable ethical standards. Our multicenter study used only one ethics committee; as the content and procedure were based on muticenter research.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Availability of data and materials

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Yin K, Liu L, Fan G (2022) Classification and Drug Resistance Analysis of Pathogenic Bacteria in Patients with Bacterial Pneumonia in Emergency Intensive Care Unit. Contrast Media Mol Imaging 30(9):6980091
Yin Y, Zhao C, Li H et al (2021) Clinical and microbiological characteristics of adults with hospital-acquired pneumonia: a 10-year prospective observational study in China. Eur J Clin Microbiol Infect Dis 40(4):683–690
Kanj SS, Bassetti M, Kiratisin P et al (2022) Clinical data from studies involving novel antibiotics to treat multidrug-resistant Gram-negative bacterial infections. Int J Antimicrob Agents 60(3):106633
Tacconelli E, Carrara E, Savoldi A et al (2018) Discovery, research, and development of new antibiotics: the WHO priority list of antibiotic-resistant bacteria and tuberculosis. Lancet Infect Dis 18(3):318–327
Chen CH, Wu PH, Lu MC et al (2023) Geographic patterns of carbapenem-resistant, multi-drug-resistant and difficult-to-treat Acinetobacter baumannii in the Asia-Pacific region: results from the Antimicrobial Testing Leadership and Surveillance (ATLAS) program, 2020. Int J Antimicrob Agents 61(2):106707
Li DING, Baiyi CHEN, Min LI et al (2023) Expert consensus on antimicrobial synergy testing and reporting of carbapenemresistant Gram-negative bacteria. Chin J Infect Chemother 23(1):80–90
Chen YB, Ji JR, Liu ZY et al (2023) BRICS report of 2021: The distribution and antimicrobial resistance profile of clinical bacterial isolates from blood stream infections in China. Chin J ClinInfect Dis 16(1):33–47
Yaghoubi S, Zekiy AO, Krutova M et al (2022) Tigecycline antibacterial activity, clinical effectiveness, and mechanisms and epidemiology of resistance: narrative review. Eur J Clin Microbiol Infect Dis 41(7):1003–1022
Tamma PD, Aitken SL, Bonomo RA et al (2022) Infectious Diseases Society of America guidance on the treatment of AmpC beta-lactamase-producing Enterobacterales, carbapenem-resistant Acinetobacter baumannii, and Stenotrophomonas maltophilia infections. Clin Infect Dis 74(12):2089–2114
Paul M, Carrara E, Retamar P et al (2022) European Society of Clinical Microbiology and Infectious Diseases (ESCMID) guidelines for the treatment of infections caused by multidrug-resistant Gram-negative bacilli (endorsed by European society of intensive care medicine). Clin Microbiol Infect 28(4):521–547
Tamma PD, Aitken SL, Bonomo RA et al (2023) Infectious Diseases Society of America 2023 Guidance on the Treatment of Antimicrobial Resistant Gram-Negative Infections. Clin Infect Dis. :ciad428
Zeng M, Xia J, Zong Z, Society of Bacterial Infection and Resistance of Chinese Medical Association; Expert Committee on Clinical Use of Antimicrobial Agents and Evaluation of Antimicrobial Resistance of the National Health Commission; Infectious Diseases Society of Chinese Medical Education Association et al (2023) Guidelines for the diagnosis, treatment, prevention and control of infections caused by carbapenem-resistant gram-negative bacilli. J Microbiol Immunol Infect 56(4):653–671
Liu J, Shu Y, Zhu F et al (2021) Comparative efficacy and safety of combination therapy with high-dose sulbactam or colistin with additional antibacterial agents for multiple drug-resistant and extensively drug-resistant Acinetobacter baumannii infections: A systematic review and network meta-analysis. J Glob Antimicrob Resist 24(3):136–147
Tamma PD, Aitken SL, Bonomo RA et al (2022) Infectious Diseases Society of America 2022 Guidance on the Treatment of Extended-Spectrum β-lactamase Producing Enterobacterales (ESBL-E), Carbapenem-Resistant Enterobacterales (CRE), and Pseudomonas aeruginosa with Difficult-to-Treat Resistance (DTR-P. aeruginosa). Clin Infect Dis 75(2):187–212
Sy CL, Chen PY, Cheng CW et al (2022) Recommendations and guidelines for the treatment of infections due to multidrug resistant organisms. J Microbiol Immunol Infect 55(3):359–386
Wang SH, Yang KY, Sheu CC et al (2021) Efficacies of Colistin-Carbapenem versus Colistin-Tigecycline in Critically Ill Patients with CR-GNB-Associated Pneumonia: A Multicenter Observational Study. Antibiot (Basel) 10(9):1081
Infectology Group of Respiratory Diseases Branch of Chinese Medical Association (CMA) (2018) Guidelines for the diagnosis and treatment of hospital-acquired pneumonia and ventilator-associated pneumonia in Chinese adult hospitals (2018 edition). Chin J Tuberc Respir Dis 41:255–280
Du X, Xu X, Yao J et al (2019) Predictors of mortality in patients infected with carbapenem-resistant Acinetobacter baumannii: A systematic review and meta-analysis. Am J Infect Control 47(9):1140–1145
Bai XR, Liu JM, Jiang DC et al (2018) Efficacy and safety of tigecycline monotherapy versus combination therapy for the treatment of hospital-acquired pneumonia (HAP): a meta-analysis of cohort studies. J Chemother 30(3):172–178
Li Y, Xie J, Chen L et al (2020) Treatment efficacy of tigecycline in comparison to cefoperazone/ sulbactam alone or in combination therapy for carbapenenm-resistant Acinetobacter baumannii infections. Pak J Pharm Sci 33(1):161–168
Duan WW, Qin C (2023) Clinical effect of cefoperazone sulbactam combined with tegacyclin in the treatment of pan-drug-resistant acinetobacter baumannii pulmonary infection. Qingdao Med 55(2):123–125
Yao F, Wang XP, Wang YF et al (2021) The clinical efficacy of high-dose tigecycline in ICU patients with pulmonary infections[J]. Pharm Today 31(6):449–453
Han H, Qin W, Zheng Y et al (2021) High-Dose versus Standard-Dose Tigecycline Treatment of Secondary Bloodstream Infections Caused by Extensively Drug-Resistant Acinetobacter baumannii: An Observational Cohort Study. Infect Drug Resist 14(9):3837–3848
Liu J, Yan Y, Zhang F (2021) Risk Factors for Tigecycline-Associated Hypofibrinogenemia. Ther Clin Risk Manag 17(4):325–332
Shields RK, Paterson DL, Tamma PD (2023) Navigating Available Treatment Options for Carbapenem-Resistant Acinetobacter baumannii-calcoaceticus Complex Infections. Clin Infect Dis 76(5):S179–S193
Lei H, Liu X, Li Z et al (2023) Analysis of the clinical characteristics of tigecycline-induced hypofibrinogenemia. J Chemother 35(4):292–297
Wang W, Liu Y, Yu C et al (2020) Cefoperazone-sulbactam and risk of coagulation disorders or bleeding: a retrospective cohort study. Expert Opin Drug Saf 19(3):339–347
Guclu E, Kaya G, Ogutlu A et al (2020) The effect of cefoperazone sulbactam and piperacillin tazobactam on mortality in Gram-negative nosocomial infections. J Chemother 32(3):118–123
Wang W, Liu Y, Yu C et al (2020) Cefoperazone-sulbactam and risk of coagulation disorders or bleeding: a retrospective cohort study. Expert Opin Drug Saf 19(3):339–347
Lin C, Tan M, Wang D et al (2023) Safety of Tigecycline in Patients on Antithrombotic Therapy: A Single-Center Retrospective Study. Pharmacology 108(6):540–549
Zhang L, Cai X, Peng F et al (2023) Comparison of bleeding risk and hypofibrinogenemia-associated risk factors between tigecycline with cefoperazone/sulbactam therapy and other tigecycline-based combination therapies. Front Pharmacol 14(6):1182644
Miao W, Guo J, Cheng H et al (2023) Risk Factors for Cefoperazone/Sulbactam-Induced Coagulation Disorder. Infect Drug Resist 16(9):6277–6284
LaPlante KL, Dhand A, Wright K et al (2022) Re-establishing the utility of tetracycline-class antibiotics for current challenges with antibiotic resistance. Ann Med 54(1):1686–1700
Zha L, Pan L, Guo J et al (2020) Effectiveness and Safety of High Dose Tigecycline for the Treatment of Severe Infections: A Systematic Review and Meta-Analysis. Adv Ther 37(3):1049–1064

Table 1 Characteristics of Patients with CRAB HAP Receiving TGC Monotherapy and TGC Combined with CPS Therapy

Characteristics	TGC n = 95	TGC + CPS n = 85	P value
Gender, male, n (%)	65(68.4)	63(74.1)	0.4
Age/years (IQR)	65(56.5,76)	73(63,85)	0.009
Age/years, n (%)
<65	45(47.4)	27(31.8)	0.033
≧65	50(52.6)	58(68.2)
BMI (M±SD)	21.6(20.1,24.4)	23.0(21.3,24.8)	0.049
BMI, n (%)
<24	69(72.6)	55(64.7)	0.433
[24,27.9]	21(22.1)	26(30.6)
≧28	5(5.3)	4(4.7)
CCI score (IQR)	1(0,2)	2(1,4)	0.002
CCI score, n (%)
<2	50(52.6)	33(38.8)	0.064
≧2	45(47.4)	52(61.2)
SOFA score (IQR)	5(4,9)	9(6,11)	0.000
SOFA acore, n (%)
<7	61(64.2)	23(27.1)	0.000
≧7	34(35.8)	34(62,72.9)
ICU admission, n (%)	54(56.8)	78(91.8)	0.000
MV, n (%)	43(45.3)	74(87.1)	0.000
CRRT, n (%)	5(5.3)	22(25.9)	0.000
Shock, n (%)	33(34.7)	49(57.6)	0.002

Abbreviations: BMI, Body Mass Index; CCI, Charlson comorbidity index; SOFA, Sequential Organ Failure Assessment; ICU, ntensive care unit; MV, Mechanical Ventilation; CRRT, Continuous Renal Replacement Therapy.

Table 2 The Clinical Outcome and Adverse Effect of TGC Monotherapy and TGC Combined with CPS Regimens

Variable	Before PSM		P value	After PSM		P value
Variable	TGC n = 95	TGC + CPS n = 85	P value	TGC n = 35	TGC + CPS n = 35	P value
Baseline(IQR)
WBC, ×10⁹/L	26.8(22,35)	18.7(16,22.4)	0.000	20.4±6.4	20.5±7.5	0.975
CRP, mg/dL	70.9(45.9,120)	139(93,198)	0.127	68(26,214.8)	139(86.5,245.9)	0.097
PCT, ng/mL	4.97(3.9,11.4)	3.4(0.6,18.8)	0.004	5.4(2.2,11.0)	3(0.6,20.9)	0.452
ALT, U/L	8.9(7.9,12)	18.4(9,32)	0.017	11(7.6,35)	16(9,28)	0.851
TBIL, μmol/L	1.3(1.2,2.5)	4.3(1.8,7.2)	0.000	2.5(1.2,11.8)	2.2(1.7,5.4)	0.991
Cr, μmol/L	64(54,67.4)	48(38,71)	0.146	55(42.5,66.2)	45(38.2,73.5)	0.551
Hb, g/L	96(90,106)	116(101,127)	0.007	116.5±25.2	121.2±24.1	0.435
PLT,×10⁹/L	301(144,345)	323(266,410)	0.045	326.6±152.5	296.3±126.9	0.370
Variation (IQR)
WBC, ×10⁹/L	9(3.7,11.6)	7.5(4.1,9.9)	0.726	7.3(4.6,10.0)	7.8(5.5,12.3)	0.466
CRP, mg/dL	46(14,70)	85(16,127.2)	0.003	22.6(9.5,71)	88.2(36.2,152)	0.009
PCT, ng/mL	2.8(1.7,7)	2.4(0.8,7.0)	0.009	1.95(1.02,6.62)	2.44(0.42,14.3)	0.934
ALT, U/L	25.8(12.1,38.1)	27.3(8.7,52)	0.851	35(23.5,61.7)	20(6,37.5)	0.114
TBIL, μmol/L	0.2(0.14)	2.4(0.8,7.0)	0.000	1.18(0.18,8.4)	1(0.3,3.5)	0.643
Cr, μmol/L	96(42,125)	25.1(12,59)	0.001	52(31.5,111)	132(68.5,223)	0.366
Hb, g/L	16(12,21)	16(7,26)	0.472	16(9.5,25)	18(7,26)	0.533
PLT, ×10⁹/L	80(75,110)	132(55,220)	0.004	84(72,110)	132(68.5,223)	0.175
LOS, days (IQR)	26(21,41)	30(20,42)	0.627	31(20.5,50.5)	35(23,44.5)	0.869
Thirty,Mortality,N(%)	(6,6.3)	(14,16.5)	0.03	(2,5.7)	(7,20)	0.153
Ninety,Mortality,N(%)	(15,15.8)	(22,25.9)	0.094	(6,17.1)	(10,28.6)	0.255

Abbreviations: WBC, white blood cell; CRP, C-reactive protein; PCT,procalcitonin; ALT, alanine aminotransferase; TBIL, total bilirubin; Cr, creatinine; Hb, hemoglobin; PLT, procalcitonin; LOS, length of hospital stays.

Table 3 Risk Factors for Patients with TGC plus CPS Therapy

Variable	Multivariable Analysis
Variable	OR (95% CI)	P value
age	1.083 (1.018-1.152)	0.011
BMI	1.225 (0.951-1.578)	0.117
CCI score	1.009 (0.595-1.713)	0.972
SOFA score	1.123 (0.843-1.496)	0.427
ICU admission	12.801 (1.980-82.747)	0.007
MV	1.340 (0.145-12.358)	0.796
CRRT	14.404 (0.498-416.385)	0.120
Shock	1.051 (0.241-4.581)	0.947
WBC	0.877 (0.784-0.982)	0.023
CRP	1.004 (0.997-1.011)	0.255
PCT	1.013 (0.983-1.044)	0.399
ALT	1.027 (0.989-1.066)	0.167
TBIL	0.913 (0.821-1.014)	0.089
Cr	0.998 (0.979-1.018)	0.871
Hb	0.951 (0.904-0.999)	0.047
PLT	1.001 (0.996-1.007)	0.679

Abbreviations: BMI, Body Mass Index; CCI, Charlson comorbidity indexi; SOFA, Sequential Organ Failure Assessment; ICU, ntensive care unit; MV, Mechanical Ventilation; CRRT, Continuous Renal Replacement Therapy; WBC, white blood cell; CRP, C-reactive protein; PCT,procalcitonin; ALT, alanine aminotransferase; TBIL, total bilirubin; Cr, creatinine; Hb, hemoglobin; PLT, procalcitonin.

Table 4 Analysis of the Risk Factors for 30-Day and 90-Day Mortality in Patients with CRAB HAP

Variable	30-day mortality Cox regression				90-day mortality Cox regression
	Univariate		Multivariate		Univariate		Multivariate
	OR(95% CI)	P value	OR(95% CI)	P value	OR(95% CI)	P value	OR(95% CI)	P value
Gender,male,n (%)	1.356 (0.541-3.399)	0.516			0.968 (0.478-1.961)	0.927
Age, years	1.023 (0.992-1.054)	0.144	-	0.521	1.025 (1.002-1.049)	0.030	-	0.151
BMI	0.93 (0.821-1.052)	0.249			0.962 (0.884-1.046)	0.365
CCI score	1.208 (1.022-1.429)	0.027	-	0.271	1.186 (1.038-1.356)	0.012	-	0.268
SOFA score	1.290 (1.144-1.454)	0.000	-	0.470	1.270 (1.158-1.393)	0.000	-	0.156
ICU admission	33.216(0.515-2144.2)	0.099	-	0.110	2.882 (1.020-8.138)	0.046	-	0.194
MV	37.902(0.742-1936.0)	0.070	-	0.157	7.186(1.725-29.933)	0.007	-	0.086
CRRT	6.398 (1.874-21.847)	0.003	-	0.979	2.963 (1.482-5.926)	0.002	-	0.550
Shock	2.388(0.918-6.217)	0.074	18.845(2.484-142.935)	0.005	5.704(2.378-13.682)	0.000	15.690(3.672-67.053)	0.000
WBC	0.941(0.882-1.003)	0.061	-	0.568	0.960(0.917-1.005)	0.081	-	0.834
CRP	1.0 (0.994-1.006)	0.980	-		1.002(0.998-1.007)	0.270
PCT	0.997(0.983-1.011)	0.655	-		0.998(0.991-1.005)	0.599
ALT	0.982(0.944-1.021)	0.362	-		0.982(0.956-1.008)	0.178
TBIL	1.008(0.999-1.018)	0.090	-	0.923	1.008(1.002-1.015)	0.014	-	0.472
Cr	1.005(0.996-1.014)	0.255	-		1.003(0.995-1.010)	0.476
Hb	0.990(0.946-1.035)	0.647	-		0.986(0.954-1.019)	0.394
PLT	0.995(0.991-0.999)	0.014	0.995(0.991-0.999)	0.017	0.994(0.991-0.997)	0.000	0.994 (0.991-0.997)	0.000
TGC+CPS	2.615(1.004-6.808)	0.049	-	0.114	1.603(0.831-3.090)	0.159	2.934 (1.104-7.802)	0.031

Abbreviations: BMI, Body Mass Index; CCI, Charlson comorbidity indexi; SOFA, Sequential Organ Failure Assessment; ICU, ntensive care unit; MV, Mechanical Ventilation; CRRT, Continuous Renal Replacement Therapy; WBC, white blood cell; CRP, C-reactive protein; PCT,procalcitonin; ALT, alanine aminotransferase; TBIL, total bilirubin; Cr, creatinine; Hb, hemoglobin; PLT, procalcitonin;TGC, Tigecycline; CPS, Cefoperazone/Sulbactam.

No competing interests reported.

Supplementarymaterials.docx

The Clinical Outcomes and Safety of Tigecycline in Monotherapy or Combination with Cefoperazone/sulbactam for Carbapenem-Resistant Acinetobacter baumannii-Associated Pneumonia: A Multicenter Retrospective Study

Status:

Version 1

Abstract

Objective

Methods

Results

Conclusion

Figures

Introduction

Methods

Study design and patients population

Data Collection

Definitions

Statistical analysis

Results

Discussion

Conclusion

Declarations

References

Tables

Additional Declarations

Supplementary Files

Status:

Version 1