Clinical Efficacy and Safety of Tigecycline Based on Therapeutic Drug Monitoring for Carbapenem- Resistant Gram Negative Bacterium Pneumonia in Intensive Care Units

doi:10.21203/rs.3.rs-3140601/v1

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Research Article

Clinical Efficacy and Safety of Tigecycline Based on Therapeutic Drug Monitoring for Carbapenem- Resistant Gram Negative Bacterium Pneumonia in Intensive Care Units

https://doi.org/10.21203/rs.3.rs-3140601/v1

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Journal Publication

published 27 Nov, 2023

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Background

We investigated the associations between the different dose of tigecycline, its efficacy and safety, and the role of tigecycline therapeutic drug monitoring for patients in intensive care unit.

Methods

This was a single-center cohort study including patients with Multidrug-Resistant Acinetobacter baumannii, (MDR-AB)and Multidrug-Resistant Klebsiella pneumoniae(MDR-KP) pulmonary infections admitted to the ICU between October 2020 and December 2021. The steady-state plasma concentration after tigecycline administration was determined by the High Performance Liquid Chromatography (HPLC) method. Multivariate analysis of the clinical efficacy and safety of tigecycline were performed to control cofounding factors.

Results

This study included 45 patients, and a total of 45 blood samples were collected to determine steady-state trough concentrations of tigecycline. All patients were divided into High Dose (HD) group and Standard Dose (SD) group. The median trough concentration of tigecycline was 0.56µg/mL in the HD group, which was higher than in the SD group(0,21µg/mL),p = 0.000. There was no significant difference between the two groups of patients in terms of bacterial eradication rate, mortality rate and clinical efficacy. Multiple regression analysis showed that ICU days was correlated with mortality OR 1.030(1.005–1.056), p = 0.017. APACHE II was significantly associated with clinical efficacy OR 0.870(0.755–1.002),p = 0.045. The level of fibrinogen decline in the HD group was significantly higher than that in the SD group(-3.05 ± 1.67 vs -1.75 ± 1.90),p = 0.038. Age and tigecycline treatment duration were identified as influencing factors for fibrinogen decline.

Conclusions

Tigecycline plasma concentrations are significantly increased when using a high dose. However, the plasma concentration of tigecycline is not correlated with clinical efficacy and adverse reactions. Fibrinogen decline appears to be related to patient age and days of tigecycline. Large sample data are still needed to confirm the clinical guidance significance of tigecycline TDM.

Tigecycline

Therapeutic Drug Monitoring

Multidrug-Resistant Negative Bacteria

Fibrinogen Decline

Pneumonia

The incidence of pneumonia caused by gram-negative organisms has significantly increased in the ICU^[1]. Multidrug-resistant (MDR) bacteria gram-negative organisms, especially P. aeruginosa, Acinetobacter baumannii, and the Enterobacteriaceae, are predominant. Multidrug-resistant Acinetobacter baumannii((MDR-AB) and Klebsiella pneumoniae carbapenemase-producing K. pneumoniae (KPC-KP) infections are major causes of mortality in intensive care unit^[2]. Managing these infections is difficult due to their resistance to antibiotics, particularly carbapenems. Broad-spectrum antibiotics, including tigecycline, are considered for treating pneumonia caused by these organisms.

Tigecycline has been approved for the treatment of various infections and is widely used for multi-drug resistant bacteria, including MDR-AB and KPC-KP^[3]. It is off-label used in ventilator-associated pneumonia, hospital-acquired pneumonia (HAP) caused by MDR pathogens, especially carbapenem-resistant(CR) bacteria^[4]. The recommended initial dose of tigecycline for injection is 100 mg, followed by 50 mg every 12 hours. A meta-analysis study indicated that higher doses of tigecycline lead to lower all-cause mortality and higher clinical cure and microbiological eradication rates. ^[5]. Nowadays, the IDSA guidelines recommend high-dose tigecycline (initial dose of 200 mg, followed by 100 mg every 12 hours) as an alternative option^[6].

Gastrointestinal symptoms, including nausea, vomiting and diarrhea, are the most common adverse reactions in all-case post-marketing surveillance studies^[7]. Some studies showed that high-dose tigecycline treatment in ICU patients may result in a decrease in plasma fibrinogen levels and activated partial thromboplastin time (APTT) values^[8–10]. Coagulopathy has been reported as a side effect of high-dose tigecycline in the FDA adverse event reporting systems.^[10] A study indicated that age, days of medication, and baseline fibrinogen levels were associated with hypofibrinogenemia^[11]. Therefore, it is crucial to prevent coagulation abnormalities or detect them in time, especially for ICU patients.

Therapeutic drug monitoring (TDM) of antibiotics was recommended for critically ill patients to optimize drug effectiveness and adjust the dosage ^[12]. One study found that trough concentrations of tigecycline can predict hepatotoxicity^[13]. However, there is limited clinical experience with tigecycline TDM, and no evidence exists to determine whether tigecycline TDM can predict the risk of hypofibrinogenemia. Therefore, we evaluate the clinical efficacy by monitoring the plasma concentration of tigecycline, and provide a reference for early prediction of coagulation abnormalities.

Study Design and Participants

This was a retrospective cohort study conducted in a single health system from October 2020 to December 2021 at a tertiary-care teaching hospital in China. The study included patients who were over 18 years old and diagnosed with pulmonary infection, and were treated with tigecycline. Blood samples were collected from the patients had to fulfill the following mandatory criteria: samples were taken from patients who had received tigecycline therapy for >72 hours (2) adult patients (>18 years) who needed treatment with tigecycline which bronchoalveolar lavage fluid culture was MDR-AB and KPC-KP. Respiratory tract secretion test was performed daily. Exclusion criteria were pregnancy (2) liver or kidney failure (3) non-compliance with the dosing regimen (4) infection in other sites. All patients were divided into two groups, High Dose (HD) (loading dose 200mg, maintenance dose 100mg q12h) group and Standard Dose (SD) (loading dose 100mg, maintenance dose 50mg q12h) group, based on their tigecycline dosage. The follow up time for all patients was transition from the ICU or discharge. Hospital-Acquired Pneumonia was diagnosis based on IDSA guideline^[14].

Blood Sampling and Analytical Assays

To obtain total tigecycline concentration samples for analysis, 0.5–1.0 mL of peripheral vein blood was collected from patients at trough concentration points or at other times after tigecycline administration. The collected blood was placed in vacutainer tubes without anticoagulant and then centrifuged at 3,000 rpm for 10 minutes at 10◦C, and the serum was collected and stored at −40◦C until analysis. To determine the concentration of tigecycline in the serum, an HPLC method was used, with a calibration curve ranging from 0.10-5.00μg/mL showing good linearity. The intraday and interday precision RSD for low, medium, and high-dose quality control samples were all less than 10%, while the extraction recovery was found to range from 99.43% to 116.68%^[15].

Data collection:

Patient demographic characteristics, including gender, age, Charlson Comorbidity Index, mechanical ventilation, catheter indwelling, and steroid use during treatment, were collected. Data on the usage, dosage, course of treatment, and combination of tigecycline were also collected. Changes in body temperature (T), respiration (R), pulse (P), chest imaging and laboratory indexes were collected before and after treatment. Laboratory tests, including White blood cell count (WBC), Albumin(ALB), platelet(PLT), procalcitonin (PCT), C-reactive protein (CRP),Albumin, Fibrinogen level(Fib), Prothrombin time (PT), and Activated partial prothrombin time (APTT), were also collected before tigecycline initiation and within one week after discontinuation.

Microbiological Analysis：

All the MDR-KP and MDR-AB were isolated for evaluation with 13 different antibiotics using the VITEK-2 compact system (bioMérieux, France). The minimum inhibitory concentration (MIC) was routinely determined in accordance with Clinical and Laboratory Standards Institute (CLSI) guidelines. The results for CR A. baumannii and CRKP were interpreted as susceptible (S), intermediate (I), or resistant (R), based on the breakpoints for Enterobacteriaceae strains released by the US Food and Drug Administration (FDA) (S ≤ 2, I = 4, and R ≥ 8 mg/L for minimum inhibitory concentration (MIC) testing by using the E-test method (BIO-KONT, Wenzhou, China)^[16].

Clinical Outcomes：

All-cause death in the ICU: The patient died during the whole following-up period.

Clinical efficacy was divided into effective clinical treatment (improvement of body temperature, symptoms and signs, and improvement or no progress of pulmonary imaging) and ineffective clinical treatment (lack of improvement or aggravation in body temperature and vital signs, progress of pulmonary imaging or death of patients due to infection).

Eradication of pathogens: The microbiology efficacy was divided into eradication (negative bacterial culture results),hypothetical eradication (clinically effective but not confirmed due to the inability to obtain respiratory specimens), and replacement (MDR-AB and KPC-KP were clear, while other bacteria were detected) and re-infection (MDR-AB and KPC-KP were still detected in the culture). The microbiology eradication rate = (number of cleared cases + assumed number of cleared cases + number of replacement cases)/total number of cases ×100%^[17]. The duplicated cases (multiple isolates in the same patient) were not included..

Safety：

Changed of coagulation values: The changes values of platelet (PLT), fibrinogen level (Fib), prothrombin time (PT), and activated partial prothrombin time (APTT) were collected before and after the administration of tigecycline.

Decline of fibrinogen: (< 1.0~0.75 times the lower limit of normal value; If the baseline value is abnormal, it is lower than the baseline<25% according to the Common Terminology Criteria for Adverse Event (CTCAE) v.5.0 guidelines.^[18]

Confirmation of clinical and safety outcomes were performed by two independent investigators.

Statistical Analysis:

Continuous variables were described using mean and standard deviation or median with interquartile range, while categorical variables were described using frequency or percentage. The Student t-test or a nonparametric test was used to compare continuous variables, and the X² test or Fisher’s exact test was used to compare categorical variables. Covariates with p<0.05 in the univariate analysis were included in the multivariate analysis. IBM SPSS Statistics (version 25.0, IBM, Armonk, NY) was used for statistical analyses, and a two-sided p < 0.05 was considered statistically significance. All graphs were created using GraphPad Prism (version 9.0, GraphPad Software, La Jolla, CA).

Baseline demographics:

Between October 2020 and December 2021, we identified 139 patients who met the inclusion criteria. After applying the exclusion criteria, a total of 45 patients were included in the study , with 13 in the high-dose group and 32 in the standard-dose group. See the flow chat in supplement file Figure 1. Baseline characteristics of the two groups are presented in Table 1, and all patients were consistent at baseline. The media concentrations of tigecycline differed significantly between the two groups (0.56μg/mL vs 0.21μg/mL). The distribution of tigecycline plasma concentration in two groups of patients are presented in supplement file Figure 2. All 45 patients were treated with a combination of tigecycline regimens, with 27 patients being carbapenem-resistant Acinetobacter baumannii and 18 patients being carbapenem-resistant Klebsiella pneumoniae, which were sensitive to tigecycline. However, there was no significant difference in bacterial eradication, mortality, or clinical efficacy between the two groups.

Table 1 Baseline demographics

Demographic	HD group N =13	SD group N=32	p value
Gender, male/female	11/2	25/7	0.622
Age (yr)	62.09±15.57	63.62±15.79	0.770
BMI	25.24±3.94	25.12±6.52	0.951
CCI median (IQR)	1(0.5-3)	1(0.0-2.75)	0.219
APACHE II	20.94±5.72	19.91±5.58	0.659
CPIS median (IQR)	8(6.5-8.5)	7(7-8)	0.614
SOFA median (IQR)	5(3-5.5)	3(2-5)	0.673
Mechanical ventilation	11	25	1.000
Duration of tigecycline treatment (d)	12.31±5.63	16.63±10.02	0.152
Trough concentration (μg/mL), media(IQR)mean	0.56(0.43-0.81)	0.21(0.15-0.36)	0.000
ICU days median (IQR)	38（25-63）	40（22.5-59）	0.981
bacterial eradication	2	3	0.617
Mortality	2	9	0.467
Clinical efficacy	12	20	0.070
Combination with tigecycline
Carbapenems	4	16	0.336
Aminoglycosides	3	12	0.492
Polymyxin B	4	0	-
Cefoperazone sulbactam	2	3	0.617
Ceftadine	0	1	-

HAP: Hospital acquired pneumonia ; CAP: Community acquired pneumonia ;BMI：Body Mass Index; CCI: Charlson Comorbidity Index; APACHE II: Acute Physiology and Chronic Health Disease Classification System II; SOFA: Sequential Organ Failure Assessment; CPIS: The Clinical Pulmonary Infection Score.

Baseline labs

Before using tigecycline, there was no statistically significant differences in coagulation indicators such as PT, APTT, and Fib between the two groups. Similarly, there were no statistically significant differences in inflammatory response indicators such as CRP and PCT. Please refer to Table 2 for further details.

Table 2 Labs value in both groups

Lab value	High dose N =13	SD dose N=32	p value
WBC(10⁹/L)	9.71±4.68	11.18±5.28	0.302
ALB	27.73±2.77	29.39±3.06	0.993
Fib(g/L)	5.5±1.67	6.0±1.79	0.445
APTT(s)	42.43±8.86	40.16±6.91	0.329
PLT(10⁹/L)	269.9±140.71	247.06±147.37	0.861
PT(s)	13.92±1.34	13.7±0.81	0.084
PCT (ng/mL)	0.2(0.09-0.46)	0.22(0.12-0.72)	0.494
CRP(mg/L)	39(18-104)	46(16-67)	0.897
ALT (IU/L)	29(19-97)	37(16-42)	0.841
AST (IU/L)	37(25-84)	37(25-41)	0.520
ALP(IU/L)	71(60-125)	80(65-101)	0.743
TB (μmol/L)	7.35(5.7-9.15)	9.31(5.6-13.2)	0.340

WBC: white blood cell; ALB: Albumin; Fib：Fibrinogen；APTT: Activated partial prothrombin time; PT:Prothrombin time; PLT: platelet ;PCT:procalcitonin; CRP:C-reactive protein ALT:Alanine transaminase; AST:Aspartate aminotransferase ALP:Alkaline phosphatase ;TB：Total bilirubin

Logistic regression analysis of mortality in ICU

Multivariate logistic regression analysis was performed to evaluate the mortality in the ICU (Table 3). The results indicated that ICU days were a risk factor, after adjusting for these variables (OR 1.030 95% CI 1.005-1.056 p=0.017).

Table 3 Univariate and Multivariate analysis of the mortality in the ICU

Variable	Univariate analysis			Multivariate analysis
Variable	OR	95% CI	p value	OR	95% CI	p value
Age	0.986	0.912-1.067	0.732
Gender（female）	1.417	0.137-14.626	0.770
BMI	0.909	0.700-1.181	0.475
CCI	1.504	0.797-2.835	0.208
APACHE II	1.157	0.916-1.463	0.222
CPIS	1.389	0.563-3.417	0.474
SOFA	1.215	0.855-1.727	0.278
Duration of tigecycline treatment	0.326	0.813-1.071	0.326
Trough concentration	0.254	0.536-10.573	0.254
ICU days	1.079	1.000-1.164	0.051	1.030	1.005-1.056	0.017
mechanical ventilation	0.476	0.048-4.699	0.525

BMI：Body Mass Index ;CCI: Charlson Comorbidity Index; APACHE II: Acute Physiology and Chronic Health Disease Classification System II; SOFA: Sequential Organ Failure Assessment; CPIS: The Clinical Pulmonary Infection Score; TG: tigecycline; CI: Confidence Interval

Logistic regression analysis of clinical efficacy

Multivariate logistic regression analysis was performed to evaluate the clinical efficacy of tigecycline (Table 4 ). The results showed that APACHE II were significantly associated with clinical efficacy, after adjusting for potential confounding variables (OR 0.870 95% CI 0.755-1.002 p=0.045).

Table 4 Univariate and Multivariate analysis of clinical efficacy

Variable	Univariate analysis			Multivariate analysis
Variable	OR	95% CI	p value	OR	95% CI	p value
Age	0.938	0.904-1.067	0.230
Gender（female）	0.408	0.003-0.845	0.038	0.213	0.038-1.197	0.079
BMI	1.566	0.984-2.493	0.058
CCI	1.080	0.592-1.972	0.802
APACHE II	0.720	0.543-0.955	0.023	0.870	0.755-1.002	0.045
CPIS	0.889	0.348-2.274	0.807
SOFA	1.021	0.584-1.784	0.942
Duration of TG treatment	1.195	0.965-1.480	0.102
Trough TG concentration	1.084	0.955-18.858	0.956
ICU days	1.030	0.955-1.113	0.460
Mechanical ventilation	18.79	0.570-619.68	0.100

BMI：Body Mass Index; CCI: Charlson Comorbidity Index; APACHE II: Acute Physiology and Chronic Health Disease Classification System II; SOFA: Sequential Organ Failure Assessment; CPIS: The Clinical Pulmonary Infection Score; TG: tigecycline；CI: Confidence Interval

Safety:

Changes in coagulation

This study revealed that the decrease in fibrinogen levels was significantly higher among high-dose patients compared to the standard-dose group, with statistical significance (p=0.038). Please refer to Table 5 for further details.

Table 5 Changes in coagulation in two groups after tigecycline discontinuation

Lab value changed	HD group (N =13)	SD group(N=32)	p value
ΔFib	-3.05±1.67	-1.75±1.90	0.038
ΔAPTT	7.25±9.32	6.93±9.19	0.918
ΔPT	0.95±1.53	1.07±1.52	0.860
ΔPLT	47.15±152.01	-7±144.9	0.374

Δ=changed; Fib：Fibrinogen；APTT: Activated partial prothrombin time; PT:Prothrombin time; PLT: platelet

Logistic regression analysis of fibrinogen decline

After conducting a multivariate regression analysis on the decline of fibrinogen, the study revealed that age (OR 0.231, 95% CI 0.086-0.616, p=0.003) and the duration of tigecycline treatment (OR 1.115, 95% CI 1.006-1.235, p=0.038) were the primary influencing factors. However, no significant correlation was found between the trough concentration of tigecycline in the blood and the decline of fibrinogen , as demonstrated in Table 6.

Table 6 Univariate and Multivariate analysis of tigecycline induced fibrinogen decline

Variable	Univariate analysis			Multivariate analysis
Variable	OR	95% CI	p value	OR	95% CI	p value
Age	0.986	0.897-1.083	0.467	0.231	0.086-0.616	0.003
BMI	1.175	0.706-1.954	0.535
CCI	5.869	0.703-48.992	0.102
APACHE II	1.131	0.897-1.083	0.438
CPIS	1.122	0.427-2.951	0.815
SOFA	0.772	0.348-1.499	0.722
Duration of TG treatment	0.820	0.844-1.046	0.011	1.115	1.006-1.235	0.038
Trough TG concentration	5.89	0.004-8.502	0.146
ICU days	1.013	0.941-1.090	0.730

In this study, we used an established HPLC method to evaluate the concentration of tigecycline in ICU patients. All patients had consistent at baselines, and there was no significant difference observed between the two groups. Our study found that patient mortality and clinical efficacy were associated with APACHE II sore and ICU days respectively. However, the blood concentration of tigecycline was not correlated with clinical efficacy and mortality. In terms of safety, the fibrinogen decline was not related to the blood concentration of tigecycline, except for the patient's age and days of tigecycline. It suggests that close monitor of the days of treatment is necessary for ICU patients.

Some studies found that the clinical efficacy of tigecycline for multiple drug-resistant Gram-negative bacteria was 57.57%-71.43%, and the bacterial eradication rate was 25%-56.5% ^[19]. Our study also demonstrated a clinical treatment efficacy of 71%, which was consistent with the literature. However, the bacterial eradication rate observed in our study was 11%, which was lower than reported in previous studies. The ICU mortality rate of 24.4% was comparable to a meta-analysis study with a mortality rate of 31.4%^[20]. There is a tendency of higher mortality in the HD group with decreased fibrinogen, but it is not statistically significant. This was also consistent with Zhang’s study, who found that hospital mortality was higher in patients with hypofibrinogenemia than those with normal fibrinogen. Nevertheless, these patients in this study were not critically ill ^[21].

Critically ill patients can experience a range of pathophysiological changes that complicate antibiotic dosing. Therefore, knowledge of the pharmacokinetic and pharmacodynamic properties of the antibiotics used for the management of critically ill patients is essential for selecting the antibiotic dosing regimens. AUC/MIC was the main pharmacodynamic factor for tigecycline^[22].However, calculating AUC usually requires multiple consecutive sampling, which is difficult to achieve in clinical ICU patients. Hence, therapeutic drug monitoring (TDM) is necessary to evaluate the clinical efficacy of tigecycline. In ICU patients, steady-state blood drug concentration monitoring plays a crucial role due to the possibility of one-time sampling. Currently, TDM studies of tigecycline use a standard dose, and there are no studies on high doses^[23]. Our study found that the drug concentration of tigecycline in HD groups patients was significantly higher than SD group. Up to now, it is the first time reported that the blood concentration of high-dose tigecycline is significantly increased. However, there was no significant association between the plasma concentration of tigecycline and clinical efficacy in our study. This was also consistent with another study^[13].

Recent studies have shown that a combination of the Acute Physiology and Chronic Health Evaluation II (APACHE II) score ≥ 24 and AUC0–12h × V/MIC ≥ 100 (where V is the apparent distribution volume of the central compartment) is also closely related to the clinical efficacy of tigecycline^[24]. Our research found that APACHE II was also a factor affecting drug efficacy, which was consistent with the results of previous studies.

In terms of mortality, ICU days is an influential factor. A meta-analysis suggest that high-dose use of tigecycline can reduce the mortality rate of HAP ^[5]. This contrasts with the results of our studies, which may be due to factors such as drug combination, patient age, and so on.

Studies have shown that the albumin also affects the clinical efficacy of tigecycline. For every 10.3 g/L increasing in the albumin, the odds of microbiological success increased 8–21 times compared to the albumin ≤ 26.00g/L^[25]. This observation may be due to the high protein-binding rate of tigecycline, which may increase the free plasma concentration, and further associated with clinical efficacy. Therefore, during tigecycline treatment, if the albumin value is below the normal limited, the albumin can be supplemented appropriately to obtain a greater curative effect. Due to the small number of patients in our study and most patients of the albumin value are ≥ 26.00 g/L, it is not analyzed the correlation between the albumin and PK parameters.

Literature research found that the adverse reactions of tigecycline was diarrhea, coagulation abnormalities, and thrombocytopenia in a real-world study^[26]. Whether TDM monitoring can prevent adverse reactions is still unclear. A study reported that blood tigecycline concentration was related to hepatotoxicity ^[13]. Our study find that there is no significant difference in ALT,AST, ALP and Total bilirubin before or after tigecycline treatment in both groups. However, in the HD group, there was a significant decrease in fibrinogen levels, but no significant changes in APTT and PT. A retrospective study of 55 cases found that albumin level and weight-adjusted tigecycline dosage were factors affecting PT and APTT prolongation^[27].However, this study did not indicate whether patients used large doses of tigecycline. Retrospective studies suggested that large doses of tigecycline lead to fibrinogen decline^[28]. Beside age, our study indicated that tigecycline treatment duration may also lead to a decrease in fibrinogen levels, which has not been reported in other studies. Lastly, our study found that the trough concentration of tigecycline in the blood did not predict the level of fibrinogen decline. Literature reported that Fibrinogen fall to critically low levels (< 1.0 g/L) during major hemorrhage was clinical significant.^[29]. However, early detection of fibrinogen decline can reduce the risk of bleeding in ICU, and further large sample size is still needed to confirm it.

The exact mechanism by which tigecycline causes a decline in fibrinogen levels is not fully understood. It is believed that tigecycline is supposed to inhibit interleukin six (IL-6) expression, which normally stimulates gene expression and increases fibrinogen levels^[30]. Recently, a study found that inhibition of mitochondrial DNA translation was a potential molecular mechanism^[31]. A study found that Multidrug-resistant Acinetobacter baumannii can bind fibrinogen, through two domain tip adhesins, Abp1D and Abp2D, respectively ^[32].Plasminogen bound to CipA, which mediates complement resistance of Acinetobacter baumannii, could be activated to plasmin to degradation fibrinogen^[33]. This may explain that there were no differences in APTT and PT. Several methods have been proposed for preventing or minimizing fibrinogen decline. These includes monitoring fibrinogen levels before and during treatment with tigecycline; adjusting doses based on patient characteristics such as age and underlying medical conditions; avoiding concomitant use of other medications known to affect clotting. Additionally, it has been suggested that prophylactic administration of vitamin K may be beneficial for some patients receiving long-term tigecycline therapy due to its role in clotting factor synthesis.

Our study had some limitations. Firstly, the study cohort is small, which is a common issue in studies evaluating tigecycline. This limitation makes it challenging to draw definitive conclusions about the drug's safety and efficacy. Secondly, our study lack pharmacokinetic/pharmacodynamic (PK/PD) data on tigecycline, which can result in suboptimal dosing regimens that are ineffective or may cause adverse effects due to drug toxicity. Third, The blood drug concentration of tigecycline is the total drug concentration, not free drug concentration. At last, further analysis is not conducted about effect of albumin on clinical efficacy.

Our study found that patients receiving high-dose tigecycline exhibited significantly higher blood concentrations compared to those receiving low doses. There were no significant differences in mortality, clinical efficacy, and bacterial eradication rates between the two groups. High doses of tigecycline were found to reduce the level of fibrinogen. Nevertheless, additional research is needed to better understand the mechanism behind this reduction and identify potential preventive measures for patients experiencing this complication during tigecycline therapy. Furthermore, further investigation is required to evaluate the efficacy of prophylactic administration of vitamin K in preventing this complication during tigecycline treatment. Based on our findings, we recommend monitoring fibrinogen levels in patients who receive high doses of tigecycline.

Ethics approval and consent to participate

The study was carried out in accordance with the Declaration of Helsinki criteria and received approval the Ethics Committee of Xuanwu Hospital Capital Medical University (IRB, protocol number: 2020038 6/20/2020). All methods were carried out in accordance with relevant guidelines and regulations. Informed consent was obtained from all study participants prior to the start of the study.

Consent for publication

Not applicable

Data availability

The datasets are not publicly available due to privacy or ethical restrictions but are available from the corresponding author on reasonable request.

Competing interests

The authors declare no competing interests

Author Contributions:

Xiang-rong Bai: Conceptualization, Resources, Data Curation,

Writing-Original Draft, Writing-Reviewing and Editing

Zhi-zhou Wang: Data collection

Wen-chao Li: Data collection

Yan-gai Wang:Resources, Data Curation

Ran Lou: Resources, Data Curation

Xin Qu: Resources, Data Curation,

Fan linlin: Resources, Data Curation

Zhang wei: Resources, Data Curation

Yan-chuan Wu:Visualization, Project Administration

Su-ying Yan: Supervision, Project Administration

Lan Zhang: Resources, Supervision, Project Administration

Funding

This study was funded by National Key R&D Program of China (2020YFC2008305) ;Beijing Municipal Science and Technology Commission Special Funding Project(D181100000218002); National Clinical Research Center for Geriatric Disorders, Beijing, China. Beijing Municipal Commission of Health and Family Planning, No. PXM2018_026283_000002; Beijing Municipal Administration of Hospitals Incubating Program (PX2020038)

Acknowledgements

The authors would like to thank all participants for giving data, analyzing data as well as the hospital administration for granted access to all patients.

Gaynes R, Edwards JR. Overview of nosocomial infections caused by gram-negative bacilli. Clin Infect Dis. 2005;41:848–54.
Jernigan JA, Hatfield KM, Wolford H, et al. Multidrug-Resistant Bacterial Infections in U.S. Hospitalized Patients, 2012–2017. N Engl J Med. 2020;382:1309–19. https://doi.org/10.1056/NEJMoa1914433.
Stein GE, Craig WA. Tigecycline: a critical analysis. Clin Infect Dis. 2006;43:518–24.
Frampton JE, Curran MP. Tigecycline Drugs. 2005;65:2623–35. discussion 2636-7.
Zha L, Pan L, Guo J, et al. Effectiveness and Safety of High Dose Tigecycline for the Treatment of Severe Infections: A Systematic Review and Meta-Analysis. Adv Ther. 2020;37:1049–64.
Tamma PD, Aitken SL, Bonomo RA, et al. 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. 2022;75:187–212.
Ohashi T, Sugiyama N, Watanabe T, et al. Drug use investigation on the safety and efficacy of tigecycline in Japan (all-case post-marketing surveillance). J Infect Chemother. 2022;28:866–74.
Pieringer H, Schmekal B, Biesenbach G, et al. Severe coagulation disorder with hypofibrinogenemia associated with the use of tigecycline. Ann Hematol. 2010;89:1063–4.
Routsi C, Kokkoris S, Douka E, et al. High-dose tigecycline-associated alterations in coagulation parameters in critically ill patients with severe infections. Int J Antimicrob Agents. 2015;45:90–3.
Guo M, Liang J, Li D, et al. Coagulation dysfunction events associated with tigecycline: a real-world study from FDA adverse event reporting system (FAERS) database. Thromb J. 2022;20:12.
Liu J, Yan Y, Zhang F. Risk Factors for Tigecycline-Associated Hypofibrinogenemia. Ther Clin Risk Manag. 2021;17:325–32. https://doi.org/10.2147/TCRM.S302850.
Abdul-Aziz MH, Alffenaar JC, Bassetti M, et al. Antimicrobial therapeutic drug monitoring in critically ill adult patients: a Position Paper(). Intensive Care Med. 2020;46:1127–53.
Fan G, Jin L, Bai H, et al. Safety and Efficacy of Tigecycline in Intensive Care Unit Patients Based on Therapeutic Drug Monitoring. Ther Drug Monit. 2020;42:835–40.
Kalil AC, Metersky ML, Klompas M, et al. Management of Adults With Hospital-acquired and Ventilator-associated Pneumonia: 2016 Clinical Practice Guidelines by the Infectious Diseases Society of America and the American Thoracic Society. Clin Infect Dis. 2016;63:e61–1111.
Wen-chao, L, YW, Qian. S, SS, Xiao-ling. L XB. Establishment and application of a HPLC method for determination of tigecycline in human serum. Chin J Drug Application Monit. 2022;19:16–20.
Yin D, Guo Y, Li M, et al. Performance of VITEK 2, E-test, Kirby-Bauer disk diffusion, and modified Kirby-Bauer disk diffusion compared to reference broth microdilution for testing tigecycline susceptibility of carbapenem-resistant K. pneumoniae and A. baumannii in a multicenter study in China. Eur J Clin Microbiol Infect Dis. 2021;40:1149–54.
Kwon SH, Ahn HL, Han OY, et al. Efficacy and safety profile comparison of colistin and tigecycline on the extensively drug resistant Acinetobacter baumannii. Biol Pharm Bull. 2014;37:340–6.
Freites-Martinez A, Santana N, Arias-Santiago S, et al. Using the Common Terminology Criteria for Adverse Events (CTCAE - Version 5.0) to Evaluate the Severity of Adverse Events of Anticancer Therapies. Actas Dermosifiliogr (Engl Ed). 2021;112:90–2.
Wang J, Pan Y, Shen J, et al. The efficacy and safety of tigecycline for the treatment of bloodstream infections: a systematic review and meta-analysis. Ann Clin Microbiol Antimicrob. 2017;16:24.
Ni W, Han Y, Liu J, et al. Tigecycline Treatment for Carbapenem-Resistant Enterobacteriaceae Infections: A Systematic Review and Meta-Analysis. Med (Baltim). 2016;95:e3126.
Zhang Q, Wang J, Liu H, et al. Risk factors for tigecycline-induced hypofibrinogenaemia. J Clin Pharm Ther. 2020;45:1434–41.
Singh R, Mukker JK, Drescher SK, et al. A need to revisit clinical breakpoints of tigecycline: effect of atypical non-linear plasma protein binding. Int J Antimicrob Agents. 2017;49:449–55.
Shao R, Li X, Hu Y et al. Determination of tigecycline in human plasma by LC-MS/MS and its application to population pharmacokinetics study in Chinese patients with hospital-acquired pneumonia. Biomed Chromatogr 2018; 32.
Zhou Y, Xu P, Li H, et al. Population pharmacokinetics and exposure-response analysis of tigecycline in patients with hospital-acquired pneumonia. Br J Clin Pharmacol. 2021;87:2838–46.
Bhavnani SM, Rubino CM, Hammel JP, et al. Pharmacological and patient-specific response determinants in patients with hospital-acquired pneumonia treated with tigecycline. Antimicrob Agents Chemother. 2012;56:1065–72.
Shi X, Zuo C, Yu L, et al. Real-World Data of Tigecycline-Associated Drug-Induced Liver Injury Among Patients in China: A 3-year Retrospective Study as Assessed by the Updated RUCAM. Front Pharmacol. 2021;12:761167.
Wang D, Lin C, Gu C, et al. Tigecycline-Associated Coagulopathy: A Single-Center Retrospective Analysis. Pharmacology. 2022;107:524–36.
Campany-Herrero D, Larrosa-Garcia M, Lalueza-Broto P, et al. Tigecycline-associated hypofibrinogenemia in a real-world setting. Int J Clin Pharm. 2020;42:1184–9.
Levy JH, Welsby I, Goodnough LT. Fibrinogen as a therapeutic target for bleeding: a review of critical levels and replacement therapy. Transfusion 2014; 54: 1389 – 405; quiz 1388.
Vasse M, Paysant I, Soria J, et al. Down-regulation of fibrinogen biosynthesis by IL-4, IL-10 and IL-13. Br J Haematol. 1996;93:955–61.
Vandecasteele SJ, Seneca S, Smet J, et al. Tigecycline-induced inhibition of mitochondrial DNA translation may cause lethal mitochondrial dysfunction in humans. Clin Microbiol Infect. 2018;24:431e1–3.
Tamadonfar KO, Di Venanzio G, Pinkner JS, et al. Structure-function correlates of fibrinogen binding by Acinetobacter adhesins critical in catheter-associated urinary tract infections. Proc Natl Acad Sci U S A. 2023;120:e2212694120.
Ries JI, Heß M, Nouri N, et al. CipA mediates complement resistance of Acinetobacter baumannii by formation of a factor I-dependent quadripartite assemblage. Front Immunol. 2022;13:942482.

No competing interests reported.

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Clinical Efficacy and Safety of Tigecycline Based on Therapeutic Drug Monitoring for Carbapenem- Resistant Gram Negative Bacterium Pneumonia in Intensive Care Units

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