Abstract
Introduction: The aims of the study were to investigate the risk factors of tigecycline-induced hypofibrinogenemia and to evaluate the safety of tigecycline with concomitant antithrombotic drugs. Methods: We performed a retrospective analysis of patients who received tigecycline for more than 3 days between January 2015 and June 2019. Clinical and laboratory data were collected including fibrinogen concertation, tigecycline dose, duration of treatment, disease severity, complete blood count, indicators of infection, liver and renal function. Risk factors of hypofibrinogenemia were analyzed by univariate and multivariate analysis. To evaluate the safety of tigecycline and concomitant antithrombotic drugs, bleeding events were assessed by comparing the decline in hemoglobin and the amount of red blood cell transfusion in patients with antithrombotic drugs and those without. Results: This study included a total of 68 cases, 20 of which experienced hypofibrinogenemia while receiving tigecycline treatment. Duration of treatment, cefoperazone/sulbactam combination therapy, and fibrinogen levels prior to initiation of tigecycline were risk factors associated with tigecycline-induced hypofibrinogenemia. There were 26 recorded bleeding incidents, 25 of which happened before the start of tigecycline. Antithrombotic and non-antithrombotic patients did not differ in their hemoglobin decline or need for red blood cell transfusions while taking tigecycline. Conclusion: A longer treatment duration, cefoperazone/sulbactam combination therapy, and a lower level of fibrinogen before tigecycline were associated with an increased risk of tigecycline-induced hypofibrinogenemia. A combination of antithrombotic drugs and tigecycline did not aggravate the bleeding events during tigecycline treatment.
Introduction
Tigecycline is a novel glycylcycline antibiotic that has overcome tetracycline resistance mechanisms (efflux pumps and ribosomal protection) [1]. It demonstrates broad-spectrum activity against Gram-positive pathogens, Gram-negative bacteria, anaerobes, atypical organisms, and multidrug-resistant (MDR) bacteria such as methicillin-resistant Staphylococcus aureus, Klebsiella pneumoniae, and Acinetobacter baumannii [2, 3]. It is known that the indication of tigecycline includes complicated intra-abdominal infections, complicated skin and soft tissue infections, and community-acquired bacterial pneumonia in clinical practice [4]. But recently, reports of coagulopathy, one of the side effects connected to tigecycline administration, have increased and caught our attention. Several studies have shown that tigecycline can cause fibrinogen (FIB) reduction, prothrombin time, and activated partial thromboplastin time prolongation [5‒7]. It is worth noting that overt hypofibrinogenemia and subsequent severe bleeding during tigecycline treatment may even be life-threatening [8].
Antithrombotic agents, including antiplatelets and anticoagulants, are paramount therapeutic strategies to prevent stroke recurrence in patients with cerebrovascular disease [9‒11]. However, preventing bleeding complications is also a crucial component of providing these patients with the best possible medical care. There is no doubt that critically ill and bedridden patients with cerebrovascular disease are prone to nosocomial pulmonary infections, and tigecycline provides a key treatment option [12]. Considering the association of tigecycline with hypofibrinogenemia and coagulopathy, concerns about bleeding events have arisen when tigecycline is used in patients on antithrombotic drugs. To date, to our knowledge, rare studies have investigated the safety of tigecycline in patients concomitantly treated with antithrombotic drugs.
Herein, we conducted a study to evaluate the safety of tigecycline in patients on antithrombotic therapy. We analyzed risk factors for hypofibrinogenemia in tigecycline-treated patients and assessed whether the antithrombotic drug was a risk factor for tigecycline-induced hypofibrinogenemia. Additionally, we compared the prevalence of hypofibrinogenemia and evaluated bleeding incidents in patients taking antithrombotic medications versus those who were not.
Methods
Patients Selection
From January 2015 to June 2019, patients with severe infections who were receiving tigecycline treatment in the neurological intensive care unit of Nanfang Hospital, Southern Medical University, China, were screened. The inclusion criteria were as follows: tigecycline therapy ≥3 days; FIB ≥2.0 g/L before tigecycline treatment. The exclusion criteria included incomplete FIB medical records. The patients were then divided into two groups: antithrombotic and control. Patients who received antithrombotic drugs at the same time were classified as antithrombotic, while patients who did not receive antithrombotic therapy were classified as control. Hypofibrinogenemia during tigecycline treatment was defined as FIB <2.0 g/L [13]. Patients received tigecycline (Tygacil, Patheon Italia S.p.A.) at the recommended dose (a loading dose of 100 mg, followed by 50 mg q12h) or a higher dose (100 mg q12h) depending on the clinical situation.
Data Collection
We reviewed the medical records of the patients. The patients’ sociodemographic and clinical information was gathered, including primary diagnosis, infection site, tigecycline treatment time, blood transfusion status, and cefoperazone/sulbactam combined therapy. FIB level was collected before and during tigecycline treatment. FIB level before tigecycline was defined as data collected within 7 days before the first dose of tigecycline. FIB level at the end of tigecycline treatment was defined as data collected 3 days before or after the last dose of tigecycline. FIB level after tigecycline treatment was defined as data collected within 7 days after the last dose of tigecycline. FIB level was determined using the modified Claus method by an automatic coagulometer (Siemens, Munich, Germany). Additional laboratory findings were also gathered, including white blood cell, lymphocyte, neutrophil, hemoglobin (HGB), hematocrit (HCT), platelets count of complete blood count, alanine aminotransferase (ALT), aspartate transaminase, albumin, total bilirubin creatinine, C-reactive protein (CRP), and procalcitonin (PCT). Antithrombotic therapy, including antiplatelet agents and anticoagulants, was also collected for each patient. The disease severity was assessed by Sequential Organ Failure Assessment (SOFA) score. Bleeding events during hospitalization were recorded and classified as (1) life-threatening (fatal bleeding, or bleeding in critical area, or bleeding requiring surgery or vasopressors, or drop of HGB of ≥5 g/dL, or transfusion of ≥4 red blood cell units), (2) major bleeding (drop of HGB of ≥3 g/dL or transfusion of 2–3 red blood cell units and not meeting criteria of life-threatening bleeding), and (3) minor bleeding (any bleeding worthy of clinical mention but not defined as life-threatening or major bleeding) [14]. This study was approved by the Ethics Committee of Nanfang Hospital (reference number: NFEC-2022-024).
Statistical Analysis
All data were analyzed using Statistic Package for Social Science (SPSS) 17.0. Continuous variables that were normally distributed were expressed as the mean ± standard deviation and were analyzed using independent sample t test. Non-normally distributed continuous variables were expressed as median and quartiles, and rank-sum tests were conducted. Categorical parameters were expressed as frequency and percentage and were analyzed with the χ2 test. A p value <0.05 was considered statistically significant.
Results
The Sociodemographic Characteristics and Clinical Information of the Patients
There were 58 patients included in our study, among which 6 patients had two separate episodes of tigecycline administration during hospitalization and 2 patients had three. Because the half-life of tigecycline ranged from 37 to 67 h [15], we defined different episodes of tigecycline administration as interval time ≥7 days (about 5 half-lives). Hence, we finally incorporated 68 episodes into the analysis (Fig. 1).
Flowchart of patient selection. FIB, fibrinogen; NICU, neurological intensive care unit.
Flowchart of patient selection. FIB, fibrinogen; NICU, neurological intensive care unit.
The sociodemographic and clinical information of the patients is illustrated in Table 1. The median age was 55 years (30–68), with males accounting for 63.2% of all cases. The most common primary disease was cerebrovascular disease. Among these cases, all cases had pulmonary infection, and 13 cases had both pulmonary and bloodstream infection. The median of the tigecycline treatment course was 11 days (7–14). CRP value declined significantly after tigecycline therapy, while PCT demonstrated a decreased trend but did not reach a significant difference (online suppl. Fig. S1; for all online suppl. material, see https://doi.org/10.1159/000532001). A total of 20 cases developed hypofibrinogenemia, accounting for 29.4% (20/68) of the episodes. The median level of FIB before tigecycline treatment was 4.43 g/L. During tigecycline therapy, the median of the lowest FIB level was 2.63 g/L. Along with the decline of FIB, both prothrombin time and activated partial thromboplastin time increased significantly during tigecycline treatment (Fig. 2). After tigecycline treatment, FIB rebounded to a mean concentration of 3.46 ± 1.44 g/L. Forty-three patients used antithrombotic medications while receiving tigecycline, of whom 7 received antiplatelet medications, 30 received anticoagulants, and 6 received both antiplatelet and anticoagulant medications.
Characteristics of the study population (N = 68)
Variable . | . |
---|---|
Age, median (interquartile range), years | 55 (30–68) |
Gender, n (%) | |
Male | 43 (63.2) |
Female | 25 (36.8) |
Primary disease, n (%) | |
Cerebrovascular disease | 35 (51.5) |
Autoimmune disease | 16 (23.5) |
Infectious disease | 10 (14.7) |
Metabolic and nutritional disease | 4 (5.9) |
Tumor | 2 (2.9) |
Trauma | 1 (1.5) |
Infection site, n (%) | |
Pneumonia | 68 (100) |
Bacteremia | 13 (19.1) |
Intracranial infection | 8 (11.8) |
Urinary tract infection | 14 (20.6) |
Skin and soft tissue infection | 5 (7.4) |
Intra-abdominal infection | 5 (7.4) |
Catheter-related infection | 2 (2.9) |
FIB level before tigecycline treatment, median (25th–75th), g/L | 4.43 (3.50–6.23) |
The lowest level of FIB during tigecycline treatment, median (25th–75th), g/L | 2.63 (1.80–3.49) |
FIB level at the end of tigecycline treatment*, median (25th–75th), g/L | 2.70 (1.95–3.40) |
FIB level after tigecycline treatmenta, mean±SD, g/L | 3.46±1.44 |
Hypofibrinogenemia, n (%) | 20 (29.4) |
Tigecycline treatment duration, median (25th–75th), days | 11 (7–14) |
Tigecycline dose, median (25th–75th), mg/day | 108.3 (102.5–152.7) |
SOFA score, median (25th–75th) | 6.0 (4.0–7.0) |
Antithrombotic therapy, n (%) | |
None | 25 (36.8) |
Solely antiplatelet agents | 7 (10.3) |
Solely anticoagulants | 30 (44.1) |
Both antiplatelet and anticoagulants | 6 (8.8) |
Type of antiplatelet agent, n (%) | |
None | 55 (80.9) |
Solely aspirin | 5 (7.4) |
Solely clopidogrel | 6 (8.8) |
Dual antiplatelet therapy with aspirin plus clopidogrel | 2 (2.9) |
Type of anticoagulant agent, n (%) | |
None | 32 (47.1) |
Low-molecular-weight heparin | 32 (47.1) |
Novel oral anticoagulants | 4 (5.9) |
Variable . | . |
---|---|
Age, median (interquartile range), years | 55 (30–68) |
Gender, n (%) | |
Male | 43 (63.2) |
Female | 25 (36.8) |
Primary disease, n (%) | |
Cerebrovascular disease | 35 (51.5) |
Autoimmune disease | 16 (23.5) |
Infectious disease | 10 (14.7) |
Metabolic and nutritional disease | 4 (5.9) |
Tumor | 2 (2.9) |
Trauma | 1 (1.5) |
Infection site, n (%) | |
Pneumonia | 68 (100) |
Bacteremia | 13 (19.1) |
Intracranial infection | 8 (11.8) |
Urinary tract infection | 14 (20.6) |
Skin and soft tissue infection | 5 (7.4) |
Intra-abdominal infection | 5 (7.4) |
Catheter-related infection | 2 (2.9) |
FIB level before tigecycline treatment, median (25th–75th), g/L | 4.43 (3.50–6.23) |
The lowest level of FIB during tigecycline treatment, median (25th–75th), g/L | 2.63 (1.80–3.49) |
FIB level at the end of tigecycline treatment*, median (25th–75th), g/L | 2.70 (1.95–3.40) |
FIB level after tigecycline treatmenta, mean±SD, g/L | 3.46±1.44 |
Hypofibrinogenemia, n (%) | 20 (29.4) |
Tigecycline treatment duration, median (25th–75th), days | 11 (7–14) |
Tigecycline dose, median (25th–75th), mg/day | 108.3 (102.5–152.7) |
SOFA score, median (25th–75th) | 6.0 (4.0–7.0) |
Antithrombotic therapy, n (%) | |
None | 25 (36.8) |
Solely antiplatelet agents | 7 (10.3) |
Solely anticoagulants | 30 (44.1) |
Both antiplatelet and anticoagulants | 6 (8.8) |
Type of antiplatelet agent, n (%) | |
None | 55 (80.9) |
Solely aspirin | 5 (7.4) |
Solely clopidogrel | 6 (8.8) |
Dual antiplatelet therapy with aspirin plus clopidogrel | 2 (2.9) |
Type of anticoagulant agent, n (%) | |
None | 32 (47.1) |
Low-molecular-weight heparin | 32 (47.1) |
Novel oral anticoagulants | 4 (5.9) |
FIB, fibrinogen; SD, standard deviation; SOFA, Sequential Organ Failure Assessment score.
*With data available in 65 cases.
aWith data available in 26 cases.
Simultaneous prolongation of PT (a) and aPTT (b) when FIB reduced to the lowest level (c) during tigecycline treatment. PT and aPTT before tigecycline treatment were collected within 7 days before tigecycline treatment. During tigecycline treatment, when FIB reached the lowest level, simultaneous PT and aPTT values were collected and significantly increased compared with before treatment. FIB, fibrinogen; PT, prothrombin time; aPTT, activated partial thromboplastin time; ***, <0.001 compared with before treatment.
Simultaneous prolongation of PT (a) and aPTT (b) when FIB reduced to the lowest level (c) during tigecycline treatment. PT and aPTT before tigecycline treatment were collected within 7 days before tigecycline treatment. During tigecycline treatment, when FIB reached the lowest level, simultaneous PT and aPTT values were collected and significantly increased compared with before treatment. FIB, fibrinogen; PT, prothrombin time; aPTT, activated partial thromboplastin time; ***, <0.001 compared with before treatment.
Risk Factors Associated with Tigecycline-Related Hypofibrinogenemia
We divided the included cases into hypofibrinogenemia group and normal group, and then analyzed risk factors of tigecycline-related hypofibrinogenemia by univariate and multivariate analysis. In univariate analysis (Table 2), there were no significant differences in complete blood count analysis (white blood cell, lymphocyte, neutrophil, HGB, platelets count), liver, kidney function (alanine aminotransferase, aspartate transaminase, albumin, total bilirubin, creatinine), and biomarkers of infection (CRP, PCT) between hypofibrinogenemia group and the control group. Additionally, no differences were observed between the two groups with respect to antithrombotic drugs. Neither SOFA score nor tigecycline dose differed between the two groups. Notably, the hypofibrinogenemia group experienced a significantly longer tigecycline period compared with the control group. The median duration of tigecycline treatment was 14 days in the hypofibrinogenemia group and 9 days in the control group. In addition, cases who developed hypofibrinogenemia had a significantly higher percentage of cefoperazone/sulbactam combination therapy compared with the control group. Furthermore, in the multivariate analysis, in addition to the variables that were statistically significant in the univariate analysis, we also considered variables that may affect the level of FIB. Finally, the following variables were included: tigecycline treatment duration, tigecycline dose, cefoperazone/sulbactam combination therapy, FIB level before tigecycline initiation, antithrombotic therapy, and SOFA score. However, only three variables were identified as risk factors associated with the decline of FIB: tigecycline treatment duration (p = 0.005), FIB level before tigecycline initiation (p = 0.015), and cefoperazone/sulbactam therapy (p = 0.044) (Table 3).
Univariate analysis of risk factors related to tigecycline-associated hypofibrinogenemia
Variable . | Hypofibrinogenemia . | Control . | OR (95% CI) . | p value . |
---|---|---|---|---|
group (N = 20) . | group (N = 48) . | |||
Age, median (25th–75th), years | 55 (33–65) | 55 (30–75) | 0.994 (0.968–1.020) | 0.636 |
Gender, n (%) | 0.721 | |||
Male | 12 (60.0) | 31 (64.6) | 1 | |
Female | 8 (40.0) | 17 (35.4) | 0.823 (0.281–2.404) | |
Infection site, n (%) | ||||
Pneumonia | 20 (100) | 48 (100) | / | / |
Bacteremia | 5 (25.0) | 8 (16.7) | 0.600 (0.169–2.126) | 0.429 |
Intracranial infection | 4 (20.0) | 4 (8.3) | 0.364 (0.081–1.629) | 0.186 |
Urinary tract infection | 3 (15.0) | 11 (22.9) | 1.685 (0.416–6.831) | 0.465 |
Skin and soft tissue infection | 1 (5.0) | 4 (8.3) | 1.727 (0.181–16.493) | 0.635 |
Intra-abdominal infection | 1 (5.0) | 4 (8.3) | 1.727 (0.181–16.493) | 0.635 |
Catheter-related infection | 1 (5.0) | 1 (2.1) | 0.404 (0.024–6.800) | 0.529 |
Tigecycline duration, median (25th–75th), days | 14 (10–26) | 9 (6–12) | 1.144 (1.050–1.247) | 0.002 |
Tigecycline dose, median (25th–75th), mg/day | 148.0 (103.9–191.7) | 107.1 (100.6–131.0) | 1.003 (0.996–1.011) | 0.380 |
SOFA score, median (25th–75th) | 7 (5–9) | 6 (3–7) | 1.102 (0.921–1.319) | 0.287 |
WBC, median (25th–75th), ×109/L | 10.72 (8.20–14.55) | 11.33 (9.09–13.29) | 1.014 (0.908–1.133) | 0.803 |
LYM, median (25th–75th), ×109/L | 1.00 (0.69–1.80) | 1.06 (0.73–1.72) | 1.183 (0.568–2.466) | 0.654 |
NEU, median (25th–75th), ×109/L | 8.70 (5.14–12.41) | 9.27 (6.28–11.59) | 1.013 (0.902–1.136) | 0.832 |
HGB, mean±SD, g/L | 88±20 | 98±22 | 0.979 (0.954–1.004) | 0.104 |
PLT, mean±SD, ×109/L | 263±122 | 272±121 | 0.999 (0.995–1.004) | 0.771 |
CRP, median (25th–75th), mg/L | 57.60 (28.10–105.32) | 61.86 (30.17–106.83) | 0.998 (0.989–1.008) | 0.727 |
PCT, median (25th–75th), μg/L | 0.36 (0.15–1.39) | 0.27 (0.10–1.04) | 0.996 (0.975–1.016) | 0.664 |
Creatinine, median (25th–75th), µmol/L | 53.5 (35.3–82.0) | 59.0 (44.5–85.3) | 0.999 (0.996–1.002) | 0.655 |
ALT, median (25th–75th), U/L | 60.0 (21.5–89.0) | 41.5 (22.0–80.0) | 1.000 (0.995–1.005) | 0.928 |
AST, median (25th–75th), U/L | 62.5 (25.5–113.0) | 37.0 (25.5–90.5) | 1.000 (0.995–1.005) | 0.986 |
ALB, mean±SD, g/L | 33.30±5.84 | 32.25±5.13 | 1.037 (0.940–1.144) | 0.470 |
TBIL, median (25th–75th), µmol/L | 9.45 (6.35–14.80) | 8.35 (5.78–13.33) | 1.034 (0.973–1.099) | 0.286 |
FIB before tigecycline initiation, mean±SD, g/L | 4.20±1.45 | 5.03±1.90 | 0.748 (0.538–1.040) | 0.084 |
Cefoperazone/sulbactam, n (%) | 14 (70.0) | 17 (35.4) | 0.235 (0.076–0.724) | 0.012 |
Dialysis or CRRT, n (%) | 2 (10.0) | 5 (10.4) | 1.047 (0.186–5.901) | 0.959 |
Blood transfusion, n (%) | 14 (70.0) | 21 (43.8) | 0.333 (0.109–1.015) | 0.053 |
Invasive mechanical ventilation, n (%) | 19 (95.0) | 46 (95.8) | 1.211 (0.103–14.158) | 0.879 |
Antithrombotics, n (%) | ||||
None | 4 (20) | 21 (44.0) | 1 | |
Solely antiplatelet agents | 2 (10) | 5 (10.4) | 0.952 (0.087–10.483) | 0.968 |
Solely anticoagulants | 13 (65.0) | 17 (35.4) | 2.000 (0.134–29.808) | 0.615 |
Both antiplatelet and anticoagulants | 1 (5.0) | 5 (10.4) | 3.824 (0.397–36.833) | 0.246 |
Type of antiplatelet agent, n (%) | ||||
None | 17 (85.0) | 38 (79.2) | 1 | |
Solely aspirin | 1 (5.0) | 4 (8.3) | 0.447 (0.026–7.582) | 0.577 |
Solely clopidogrel | 1 (5.0) | 5 (10.4) | 0.250 (0.007–8.560) | 0.442 |
Dual antiplatelet | 1 (5.0) | 1 (2.1) | 0.200 (0.006–6.664) | 0.368 |
Type of anticoagulant agent, n (%) | ||||
None | 6 (30.0) | 26 (54.2) | 1 | |
Low-molecular-weight heparin | 11 (55.0) | 21 (43.8) | 5.727 (0.531–61.749) | 0.150 |
Novel oral anticoagulants | 3 (15.0) | 1 (2.1) | 0.441 (0.140–1.390) | 0.162 |
Vitamin K, n (%) | 8 (40.0) | 11 (16.2) | 0.446 (0.146–1.366) | 0.157 |
Variable . | Hypofibrinogenemia . | Control . | OR (95% CI) . | p value . |
---|---|---|---|---|
group (N = 20) . | group (N = 48) . | |||
Age, median (25th–75th), years | 55 (33–65) | 55 (30–75) | 0.994 (0.968–1.020) | 0.636 |
Gender, n (%) | 0.721 | |||
Male | 12 (60.0) | 31 (64.6) | 1 | |
Female | 8 (40.0) | 17 (35.4) | 0.823 (0.281–2.404) | |
Infection site, n (%) | ||||
Pneumonia | 20 (100) | 48 (100) | / | / |
Bacteremia | 5 (25.0) | 8 (16.7) | 0.600 (0.169–2.126) | 0.429 |
Intracranial infection | 4 (20.0) | 4 (8.3) | 0.364 (0.081–1.629) | 0.186 |
Urinary tract infection | 3 (15.0) | 11 (22.9) | 1.685 (0.416–6.831) | 0.465 |
Skin and soft tissue infection | 1 (5.0) | 4 (8.3) | 1.727 (0.181–16.493) | 0.635 |
Intra-abdominal infection | 1 (5.0) | 4 (8.3) | 1.727 (0.181–16.493) | 0.635 |
Catheter-related infection | 1 (5.0) | 1 (2.1) | 0.404 (0.024–6.800) | 0.529 |
Tigecycline duration, median (25th–75th), days | 14 (10–26) | 9 (6–12) | 1.144 (1.050–1.247) | 0.002 |
Tigecycline dose, median (25th–75th), mg/day | 148.0 (103.9–191.7) | 107.1 (100.6–131.0) | 1.003 (0.996–1.011) | 0.380 |
SOFA score, median (25th–75th) | 7 (5–9) | 6 (3–7) | 1.102 (0.921–1.319) | 0.287 |
WBC, median (25th–75th), ×109/L | 10.72 (8.20–14.55) | 11.33 (9.09–13.29) | 1.014 (0.908–1.133) | 0.803 |
LYM, median (25th–75th), ×109/L | 1.00 (0.69–1.80) | 1.06 (0.73–1.72) | 1.183 (0.568–2.466) | 0.654 |
NEU, median (25th–75th), ×109/L | 8.70 (5.14–12.41) | 9.27 (6.28–11.59) | 1.013 (0.902–1.136) | 0.832 |
HGB, mean±SD, g/L | 88±20 | 98±22 | 0.979 (0.954–1.004) | 0.104 |
PLT, mean±SD, ×109/L | 263±122 | 272±121 | 0.999 (0.995–1.004) | 0.771 |
CRP, median (25th–75th), mg/L | 57.60 (28.10–105.32) | 61.86 (30.17–106.83) | 0.998 (0.989–1.008) | 0.727 |
PCT, median (25th–75th), μg/L | 0.36 (0.15–1.39) | 0.27 (0.10–1.04) | 0.996 (0.975–1.016) | 0.664 |
Creatinine, median (25th–75th), µmol/L | 53.5 (35.3–82.0) | 59.0 (44.5–85.3) | 0.999 (0.996–1.002) | 0.655 |
ALT, median (25th–75th), U/L | 60.0 (21.5–89.0) | 41.5 (22.0–80.0) | 1.000 (0.995–1.005) | 0.928 |
AST, median (25th–75th), U/L | 62.5 (25.5–113.0) | 37.0 (25.5–90.5) | 1.000 (0.995–1.005) | 0.986 |
ALB, mean±SD, g/L | 33.30±5.84 | 32.25±5.13 | 1.037 (0.940–1.144) | 0.470 |
TBIL, median (25th–75th), µmol/L | 9.45 (6.35–14.80) | 8.35 (5.78–13.33) | 1.034 (0.973–1.099) | 0.286 |
FIB before tigecycline initiation, mean±SD, g/L | 4.20±1.45 | 5.03±1.90 | 0.748 (0.538–1.040) | 0.084 |
Cefoperazone/sulbactam, n (%) | 14 (70.0) | 17 (35.4) | 0.235 (0.076–0.724) | 0.012 |
Dialysis or CRRT, n (%) | 2 (10.0) | 5 (10.4) | 1.047 (0.186–5.901) | 0.959 |
Blood transfusion, n (%) | 14 (70.0) | 21 (43.8) | 0.333 (0.109–1.015) | 0.053 |
Invasive mechanical ventilation, n (%) | 19 (95.0) | 46 (95.8) | 1.211 (0.103–14.158) | 0.879 |
Antithrombotics, n (%) | ||||
None | 4 (20) | 21 (44.0) | 1 | |
Solely antiplatelet agents | 2 (10) | 5 (10.4) | 0.952 (0.087–10.483) | 0.968 |
Solely anticoagulants | 13 (65.0) | 17 (35.4) | 2.000 (0.134–29.808) | 0.615 |
Both antiplatelet and anticoagulants | 1 (5.0) | 5 (10.4) | 3.824 (0.397–36.833) | 0.246 |
Type of antiplatelet agent, n (%) | ||||
None | 17 (85.0) | 38 (79.2) | 1 | |
Solely aspirin | 1 (5.0) | 4 (8.3) | 0.447 (0.026–7.582) | 0.577 |
Solely clopidogrel | 1 (5.0) | 5 (10.4) | 0.250 (0.007–8.560) | 0.442 |
Dual antiplatelet | 1 (5.0) | 1 (2.1) | 0.200 (0.006–6.664) | 0.368 |
Type of anticoagulant agent, n (%) | ||||
None | 6 (30.0) | 26 (54.2) | 1 | |
Low-molecular-weight heparin | 11 (55.0) | 21 (43.8) | 5.727 (0.531–61.749) | 0.150 |
Novel oral anticoagulants | 3 (15.0) | 1 (2.1) | 0.441 (0.140–1.390) | 0.162 |
Vitamin K, n (%) | 8 (40.0) | 11 (16.2) | 0.446 (0.146–1.366) | 0.157 |
ALB, albumin; ALT, alanine aminotransferase; AST, aspartate transaminase; CI, confidence interval; CRP, C-reactive protein; CRRT, continuous renal replacement therapy; FIB, fibrinogen; HGB, hemoglobin; LYM, lymphocyte; NEU, neutrophil; OR, odds ratio; PCT, procalcitonin; PLT, platelets count; SD, standard deviation; TBIL, total bilirubin; WBC, white blood cell.
Multivariate analysis of risk factors for tigecycline-associated hypofibrinogenemia
Variable . | OR . | 95% CI . | p value . |
---|---|---|---|
Tigecycline duration | 1.191 | 1.055–1.344 | 0.005 |
FIB before tigecycline initiation | 0.598 | 0.395–0.906 | 0.015 |
Cefoperazone/sulbactam | 3.855 | 1.037–14.332 | 0.044 |
Variable . | OR . | 95% CI . | p value . |
---|---|---|---|
Tigecycline duration | 1.191 | 1.055–1.344 | 0.005 |
FIB before tigecycline initiation | 0.598 | 0.395–0.906 | 0.015 |
Cefoperazone/sulbactam | 3.855 | 1.037–14.332 | 0.044 |
Adjusted for antithrombotics, Sequential Organ Failure Assessment score, tigecycline dose.
CI, confidence interval; FIB, fibrinogen; OR, odds ratio.
Comparison of Bleeding Events in Antithrombotic and Non-Antithrombotic Group
Although antithrombotic drugs were not associated with an increased risk of tigecycline-induced hypofibrinogenemia based on multivariate analysis, to comprehensively assess the safety of tigecycline, we evaluated bleeding events in antithrombotic and non-antithrombotic groups (Table 4). There were 26 bleeding events recorded in a total number of 68 incorporated cases, while 25 of them occurred before the tigecycline initiation. The gastrointestinal tract and brain were the main bleeding sites. In terms of bleeding severity, the proportion of life-threatening, major, or minor bleeding did not differ between the antithrombotic and non-antithrombotic groups. We compared the changes in HGB and HCT after tigecycline treatment for these bleeding events, and neither the decrease in HGB nor the change in HCT differed between the two groups. In addition, no differences were observed in blood transfusion requirement as well as the total amount of red blood cell transfusion. Specifically, with regard to intracranial hemorrhage, there was no significant difference in the change of Glasgow coma scale scores after tigecycline treatment between antithrombotic and non-antithrombotic patients. For gastrointestinal hemorrhage, the percentage of endoscopic intervention was comparable in both groups.
Bleeding events in antithrombotic and control group
Variable . | All (N = 26) . | Bleeding events of antithrombotic . | Bleeding events of non-antithrombotic . | p value . |
---|---|---|---|---|
group (N = 13) . | group (N = 13) . | |||
Hemorrhage site, n (%) | 0.227 | |||
Solely gastrointestinal | 11 (42.3) | 7 (53.8) | 4 (30.8) | / |
Solely intracranial | 12 (46.2) | 6 (46.2) | 6 (46.2) | / |
Both gastrointestinal and intracranial | 3 (11.5) | 0 (0) | 3 (23.1) | / |
Occurrence of bleeding, n (%) | 1.000 | |||
Before tigecycline treatment | 25 (96.2) | 12 (92.3) | 13 (100) | / |
During tigecycline treatment | 1 (3.8) | 1 (7.7) | 0 (0) | / |
Bleeding severity, n (%) | 1.000 | |||
Life-threatening bleeding | 19 (73.1) | 9 (69.2) | 10 (76.9) | / |
Major bleeding | 2 (7.7) | 1 (7.7) | 1 (7.7) | / |
Minor bleeding | 5 (19.2) | 3 (23.1) | 2 (15.4) | / |
Treatment course of tigecycline, median (25th–75th), days | 9 (5–13) | 10 (7–12) | 5 (4–16) | 0.190 |
Tigecycline dose, median (interquartile range), mg/day | 116.3 (103.8–166.4) | 108.7 (105.3–172.5) | 125.0 (101.8–180.0) | 0.607 |
HGB before tigecycline treatment, mean±SD, g/L | 95.2±21.7 | 99.4±19.3 | 94.0±22.9 | 0.779 |
HGB after tigecycline treatment, mean±SD, g/L | 92.6±26.2 | 99.9±22.8 | 88.8±27.5 | 0.470 |
HCT before tigecycline treatment, mean±SD | 0.296±0.062 | 0.301±0.061 | 0.290±0.064 | 0.651 |
HCT after tigecycline treatment, mean±SD | 0.292±0.078 | 0.305±0.079 | 0.279±0.077 | 0.408 |
Change of HGB, mean±SD, g/L | −2.65±12.61 | −0.08±11.46 | −5.23±13.62 | 0.307 |
Change of HCT, mean±SD | −0.0040±0.0369 | 0.0036±0.0362 | −0.0110±0.0376 | 0.323 |
Blood transfusion requirement, n (%) | 15 (57.7) | 8 (61.5) | 7 (53.8) | 1.000 |
Red blood cell transfusion, median (25th–75th), unit | 0.5 (0.0–3.3) | 0.5 (0.0–2.0) | 0.0 (0.0–4.0) | 0.956 |
Gastrointestinal bleeding | 14 | 7 | 7 | |
Endoscopic intervention, n (%) | 2 (14.3) | 1 (14.3) | 1 (14.3) | 0.769 |
Hematochezia, n (%) | 0 (0) | 0 (0) | 0 (0) | / |
Hematemesis or bloody gastric aspirate, n (%) | 0 (0) | 0 (0) | 0 (0) | / |
Melena, n (%) | 3 (21.4) | 1 (14.3) | 2 (28.6) | 1.000 |
Positive fecal or gastric juice test, n (%) | 11 (78.6) | 6 (85.7) | 5 (71.4) | 1.000 |
Intracranial bleeding | 15 | 6 | 9 | |
Surgical intervention, n (%) | 5 (33.3) | 1 (16.7) | 4 (44.4) | 1.000 |
External ventricular drain, n (%) | 2 (13.3) | 0 (0) | 2 (22.2) | 0.343 |
GCS score on admission, mean±SD | 8±4 | 8±5 | 8±4 | 0.981 |
GCS score after tigecycline treatment, mean±SD | 8±5 | 7±5 | 9±5 | 0.544 |
Change of GCS score, mean±SD | 0.13±3.83 | −0.83±4.44 | 0.78±3.49 | 0.446 |
Variable . | All (N = 26) . | Bleeding events of antithrombotic . | Bleeding events of non-antithrombotic . | p value . |
---|---|---|---|---|
group (N = 13) . | group (N = 13) . | |||
Hemorrhage site, n (%) | 0.227 | |||
Solely gastrointestinal | 11 (42.3) | 7 (53.8) | 4 (30.8) | / |
Solely intracranial | 12 (46.2) | 6 (46.2) | 6 (46.2) | / |
Both gastrointestinal and intracranial | 3 (11.5) | 0 (0) | 3 (23.1) | / |
Occurrence of bleeding, n (%) | 1.000 | |||
Before tigecycline treatment | 25 (96.2) | 12 (92.3) | 13 (100) | / |
During tigecycline treatment | 1 (3.8) | 1 (7.7) | 0 (0) | / |
Bleeding severity, n (%) | 1.000 | |||
Life-threatening bleeding | 19 (73.1) | 9 (69.2) | 10 (76.9) | / |
Major bleeding | 2 (7.7) | 1 (7.7) | 1 (7.7) | / |
Minor bleeding | 5 (19.2) | 3 (23.1) | 2 (15.4) | / |
Treatment course of tigecycline, median (25th–75th), days | 9 (5–13) | 10 (7–12) | 5 (4–16) | 0.190 |
Tigecycline dose, median (interquartile range), mg/day | 116.3 (103.8–166.4) | 108.7 (105.3–172.5) | 125.0 (101.8–180.0) | 0.607 |
HGB before tigecycline treatment, mean±SD, g/L | 95.2±21.7 | 99.4±19.3 | 94.0±22.9 | 0.779 |
HGB after tigecycline treatment, mean±SD, g/L | 92.6±26.2 | 99.9±22.8 | 88.8±27.5 | 0.470 |
HCT before tigecycline treatment, mean±SD | 0.296±0.062 | 0.301±0.061 | 0.290±0.064 | 0.651 |
HCT after tigecycline treatment, mean±SD | 0.292±0.078 | 0.305±0.079 | 0.279±0.077 | 0.408 |
Change of HGB, mean±SD, g/L | −2.65±12.61 | −0.08±11.46 | −5.23±13.62 | 0.307 |
Change of HCT, mean±SD | −0.0040±0.0369 | 0.0036±0.0362 | −0.0110±0.0376 | 0.323 |
Blood transfusion requirement, n (%) | 15 (57.7) | 8 (61.5) | 7 (53.8) | 1.000 |
Red blood cell transfusion, median (25th–75th), unit | 0.5 (0.0–3.3) | 0.5 (0.0–2.0) | 0.0 (0.0–4.0) | 0.956 |
Gastrointestinal bleeding | 14 | 7 | 7 | |
Endoscopic intervention, n (%) | 2 (14.3) | 1 (14.3) | 1 (14.3) | 0.769 |
Hematochezia, n (%) | 0 (0) | 0 (0) | 0 (0) | / |
Hematemesis or bloody gastric aspirate, n (%) | 0 (0) | 0 (0) | 0 (0) | / |
Melena, n (%) | 3 (21.4) | 1 (14.3) | 2 (28.6) | 1.000 |
Positive fecal or gastric juice test, n (%) | 11 (78.6) | 6 (85.7) | 5 (71.4) | 1.000 |
Intracranial bleeding | 15 | 6 | 9 | |
Surgical intervention, n (%) | 5 (33.3) | 1 (16.7) | 4 (44.4) | 1.000 |
External ventricular drain, n (%) | 2 (13.3) | 0 (0) | 2 (22.2) | 0.343 |
GCS score on admission, mean±SD | 8±4 | 8±5 | 8±4 | 0.981 |
GCS score after tigecycline treatment, mean±SD | 8±5 | 7±5 | 9±5 | 0.544 |
Change of GCS score, mean±SD | 0.13±3.83 | −0.83±4.44 | 0.78±3.49 | 0.446 |
CI, confidence interval; CRP, C-reactive protein; GCS, Glasgow coma scale; HCT, hematocrit; HGB, hemoglobin; SD, standard deviation.
Discussion
In this study, we retrospectively included 68 cases and found that as high as 29.4% of the cases developed hypofibrinogenemia during tigecycline treatment. Treatment duration, cefoperazone/sulbactam combination therapy, and FIB level before tigecycline initiation were the risk factors associated with tigecycline-induced hypofibrinogenemia. There was no significant difference between patients receiving antithrombotic treatment and patients receiving no antithrombotic treatment in the decline of HGB or the number of red blood cells transfused during tigecycline treatment.
FIB, a large plasma glycoprotein as the substrate for fibrin formation, is involved in platelet aggregation and plays an important role in hemostasis [16]. However, decreased FIB level, which interferes with effective coagulation cascade and increases the risk of bleeding, is associated with poor outcomes in a variety of clinical settings [17, 18]. Therefore, hypofibrinogenemia, whether congenital or acquired, is worth our attention in clinical practice. Recently, acquired FIB disorder associated with tigecycline has been increasingly identified and reported. A few studies have shown that the level of FIB decreased under the treatment of tigecycline [8, 19‒21], which in worsening situations could cause life-threatening bleeding events. However, the FIB plasma concentrate resolved gradually and could recover to the normal reference range after the withdrawal of tigecycline. Previous studies have demonstrated that the incidence of hypofibrinogenemia during tigecycline medication varied from 19.3% to 60.8% [7, 22, 23]. In this study, only 29.4% of the cases with tigecycline treatment developed hypofibrinogenemia, probably due to a relatively younger age of the population compared with previous studies. The mechanism underlying tigecycline-associated hypofibrinogenemia has not yet been thoroughly investigated. It was proposed that the tigecycline’s inhibition of cytokines contributed to the reduced production of FIB [24, 25]. In addition, as FIB was synthetized in the liver and tigecycline could result in aminotransferase enzyme increase, the impaired hepatic function was also associated with tigecycline-induced hypofibrinogenemia [26]. Another possibility could be the increased consumption of FIB due to disseminated intravascular coagulation, but lack of platelet consumption as well as improvement of infection status during tigecycline treatment did not support this hypothesis [8]. Overall, with the limited evidence available, the mechanism of tigecycline-induced hypofibrinogenemia remained unknown and more in-depth studies are warranted.
Factors that are associated with tigecycline-induced coagulopathy have been widely explored. Zhang et al. [22] showed that patients with renal failure were more likely to experience a decline in FIB along with tigecycline therapy. Two observational studies by Juan Hu and David Campany-Herrero, respectively, have both demonstrated that treatment duration and high dose of tigecycline were associated with an increased risk of tigecycline-induced hypofibrinogenemia [7]. Similar to previous studies, our study found that the median days of tigecycline treatment were significantly longer in the hypofibrinogenemia group than in the control group. Some studies have suggested that in treating MDR A. baumannii pneumonia, a longer treatment duration of tigecycline presented with a more effective microbiological eradication and clinical resolution [27, 28]. Therefore, clinicians should be more alert about the risk of hypofibrinogenemia when considering longtime tigecycline therapy for a better clinical outcome.
Cefoperazone/sulbactam, in combination with tigecycline, reveals a synergistic effect against MDR A. baumannii [29, 30]. Our study demonstrated that patients who developed hypofibrinogenemia had a higher percentage of cefoperazone/sulbactam treatment, indicating that cefoperazone/sulbactam may deteriorate tigecycline-induced hypofibrinogenemia. There is increasing evidence that cefoperazone/sulbactam can induce vitamin K-dependent hypoprothrombinemia by impairing the intestinal synthesis of vitamin K or interfering with vitamin K activity [31, 32]. However, the exact mechanisms underlying the high percentage of cefoperazone/sulbactam in tigecycline-associated hypofibrinogenemia were unclear and more research was warranted.
Previous studies have demonstrated conflicting data on the relationship between tigecycline-induced hypofibrinogenemia and bleeding risk. In an observational retrospective cohort study involving 148 patients treated with tigecycline, the rate of bleeding events was significantly higher in the hypofibrinogenemia group compared with the normal group (13.3% vs. 1.7%) [23]. Hypofibrinogenemia was found to be a risk factor for bleeding occurrences in the logistic regression analysis. However, in the study by Zhang et al. [22], there was no significant difference in the proportion of bleeding patients between the hypofibrinogenemia group and the normal group (12.09% vs. 8.06%). Besides, a retrospective cohort study demonstrated that colistin-tigecycline treatment was not linked with an increased major bleeding risk in comparison with colistin-carbapenem therapy although the data of FIB level were lacking [33].
In our study, most bleeding events occurred before tigecycline treatment. Only 1 case of minor secondary gastrointestinal bleeding was recorded on day 7 of tigecycline use. In this case, hypofibrinogenemia was not observed and neither tigecycline was withdrawal nor blood transfusion was required due to bleeding. As the cerebrovascular disease was the common cause of neurological intensive care unit patients, we assessed whether a combination of tigecycline and antithrombotic drugs would exacerbate preexisting bleeding events. We found no difference in HGB decline or blood transfusion requirements between the antithrombotic and non-antithrombotic groups, which suggested the safety of tigecycline in combination with antithrombotic agents.
To date, there are few studies on the tigecycline-antithrombotic drug interaction. One study assessed the tigecycline-warfarin interaction and found that no dosage adjustment of tigecycline was required during coadministration with warfarin [34]. Though scant evidence is available regarding the safety of concurrent tigecycline and antithrombotics, our data tend to imply that the combination of tigecycline and antithrombotics has not increased the bleeding risk of the patients.
The study has some limitations. First, as a retrospective and observational study, this study only included patients in the neurological department. In addition, the number of patients was relatively small. Despite all these limitations, our study provided a preliminary clue about the safety of tigecycline along with antithrombotic therapy. Prospective randomized controlled studies are needed to better assess the benefit-risk balance of tigecycline in patients receiving antithrombotic concurrently.
Conclusion
As high as 29.4% of the patients developed hypofibrinogenemia during tigecycline treatment. Treatment duration, cefoperazone/sulbactam combination therapy, and FIB level before tigecycline initiation were the risk factors associated with tigecycline-induced hypofibrinogenemia. A combination of tigecycline and antithrombotic drugs did not increase the bleeding risk. More research with a larger sample size was warranted to confirm the result.
Statement of Ethics
The study proposal was approved by the Nanfang Hospital’s Ethics Committee for clinical research (approval reference number: NFEC-2022-024). Informed consent was waived by the review board because this study was retrospective, observational, and all data were fully de-identified. We confirm that we have read the journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.
Conflict of Interest Statement
The authors declare no conflict of interest.
Funding Sources
This study was supported by the National Natural Science Foundation of China (82201505 to Dongmei Wang, 82071484 to Yongming Wu), President Foundation of Baiyun Branch of Nanfang Hospital (BYYZ23007 to Shengnan Wang), President Foundation of Nanfang Hospital, Southern Medical University (No. 2019B007 to Dongmei Wang).
Author Contributions
D.W., S.W., and Y.W. are responsible for concepts and design. C.L., M.T., C.G., and Y.W. are responsible for data collecting and statistical analysis. All authors contributed intellectually. All authors acquired, analyzed, and interpreted the data. The manuscript was prepared by C.L., D.W., and S.W. All authors reviewed and made critical revisions to the manuscript.
Additional Information
Chuwen Lin and Miaoqin Tan contributed equally to this work.
Data Availability Statement
All data generated or analyzed during this study are included in this article and its online supplementary material. Further inquiries can be directed to the corresponding author.