A Retrospective Analysis of the Effect of Tigecycline on Coagulation Function

Abstract

A number of clinical trials demonstrated that tigecycline was effective and well tolerated in the treatment of patients with various bacterial infections, but few literatures had shown the coagulopathy induced by tigecycline. To address this concern, we performed a retrospective analysis to assess the impact of tigecycline treatment on coagulation parameters in 50 patients with bacterial infections in our hospital (Shandong Provincial Hospital, China). These patients were treated with tigecycline at Shandong Provincial Hospital in 2015–2016 at either a recommended (50 mg q12h) or a higher dose (100 mg q12h). Coagulation parameters, including Fibrinogen (FIB) levels, prothrombin time (PT), activated partial thromboplastin time (aPTT), platelet count (PLT) and D-dimer, were evaluated in order to assess the impact of tigecycline treatment in these severely infected patients. What we found was that the plasma fibrinogen (FIB) level was 4.63 ± 1.56 g/L before tigecycline treatment, and decreased to 2.92 ± 1.23 g/L during treatment, which was statistically significant (p < 0.001). The mean values of aPTT and PT were significantly increased from 39.58 ± 8.72 to 44.05 ± 10.45 s (p = 0.002), and from 15.37 ± 1.53 to 16.37 ± 2.64 s (p = 0.004), respectively. This study demonstrates that treatment of tigecycline could reduce FIB, prolong aPTT and PT. In conclusion, we advise that it is necessary for practitioners routinely monitor coagulation level in at-rick patient populations treated with tigecycline.

Introduction

Tigecycline, as the first representative of glycylcyclines class of antimicrobial, is structurally similar to tetracyclines, which inhibits the synthesis of bacterial protein by binding to the 30s ribosomal subunit and obstructing the entry of aminoacylated tRNA molecules into the A site of the ribosome.¹⁾ Tigecycline has a very broad spectrum of antibacterial activity, which includes Gram-positive, Gram-negative, anaerobic bacteria and atypical pathogens. It also has effect towards Multi-Drug Resistant (MDR) pathogens, such as Mmethicillin-Resistant Staphylococcus aureus (MRSA), Vancomycin-Resistant Enterococci (VRE), Extended-Spectrum β-lactamase-producing Enterobacteriaceae, Carbapenem-Resistant Enterobacteriaceae, and MDR Acinetobacter spp., but it has no activity against Pseudomonas aeruginosa, Proteus spp. or Providentia spp.^2–6) Tigecycline is currently used for complicated skin and skin structure infections (cSSSI), complicated intra-abdominal infections (cIAIs), and community-acquired bacterial pneumonia (CAP).⁷⁾ A number of clinical trials had demonstrated tigecycline was effective and well tolerated in the treatment of patients with connected infections.^8–10) The common adverse reactions of tigecycline are digestive symptoms, such as nausea and vomiting.^11–13) Moreover, a few case reports showed that tigecycline seems to induce coagulation disorders, which manifested through bleeding and abnormal coagulation parameters.^14–21) Therefore, we performed a retrospective analysis to assess the impact of tigecycline treatment on coagulation parameters in 50 patients with bacterial infections admitted to our hospital.

Methods

Study Population

All 50 patients enrolled in this study were admitted to Shandong Provincial Hospital affiliated to Shandong University in 2015–2016 with bacterial infection and subsequently treated with tigecycline. The exclusion criteria were: severe liver disease, kidney disease, pre-existing coagulopathy and severe bleeding, age <18 years, pregnancy, lactation, duration of tigecycline treatment <3 d, and patients with severe incomplete clinical documents. In this study, 50 patients presented with a normal or higher level of fibrinogen before tigecycline treatment. They were treated with tigecycline at recommended dose (an initial dose of 100 mg, followed by 50 mg q12h), or a higher dose (100 mg q12h). The course of treatment depended on the severity and location of the infection, the clinical and bacteriological progression of the patients.

Observation and Monitoring

The characteristics of the subjects were listed. Fibrinogen (FIB) levels, prothrombin time (PT), activated partial thromboplastin time (aPTT), platelet count (PLT), D-dimer, alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatinine (Cr) were monitored before, during and after the treatment of tigecycline in order to measure the effects of treatment.

Statistical Analysis

All data were analyzed using Statistic Package for Social Science (SPSS) 17.0. Continuous parameters were expressed as the mean ± standard deviation and analyzed with Student’s t-test or ANOVA. The correlations of the coagulation abnormality with age, the baseline level (the level before treatment), liver and kidney parameters were identified by Pearson correlation analysis where appropriate. p value of ≤0.05 was considered statistically significant.

Results

Subject Demographics

The mean age of 50 patients was 57.20 ± 17.58 years, with the youngest patient was 18 years old and the oldest was 78 years old. In addition, there were 27 patients ≥60 years of age (54%), including 7 who were ≥75 years (14%). In total, we included 40 male and 10 female patients. Among them, 33 patients had pulmonary infections, 7 patients had intra-abdominal, 5 patients had sepsis, 3 had complicated skin and soft tissue infections, and 2 had intracranial infections. Forty eight patients were treated with tigecycline based on antibiotic susceptibility tests that showed that 46 of these patients were infected by MDR-Acinetobacter baumannii while the other 2 were infected by Enterococcus faecium. Only 2 patients accepted treatment as empiric antibiotic. Thirty nine out of 50 patients had received treatment at the recommended dose, while the others received a higher dose. The duration of treatment was 3 to 51 d, and the mean duration was 12.36 d.

Tigecycline Effects on Coagulation

During the treatment, the plasma FIB level decreased significantly from 4.63 ± 1.56 g/L to 2.93 ± 1.24 g/L (p < 0.001). The mean values of aPTT and PT were significantly increased between before and during treatment (p = 0.002 and p = 0.004, respectively) (Table 1). There was no significant difference in the level of D-dimer (p = 0.960) (Table 1). The FIB level showed a trend of significant decline during tigecycline treatment and rebounded after withdrawal, while the aPTT and PT values increased during treatment, then decreased after discontinuation (Fig. 1). The mean level of FIB reduced by 36.72% and the mean level of aPTT and PT increased by 11.29 and 6.51%, respectively.

Table 1. The Values of FIB, aPTT, PT and D-Dimer at Different Treatment Periods

Period	Cases	FIB (g/L)	aPTT (s)	PT (s)	D-Dimerc)
Before treatment	50	4.63 ± 1.56	39.58 ± 8.72	15.37 ± 1.53	6.80 ± 5.75
During treatment	50	2.92 ± 1.23	44.05 ± 10.45	16.37 ± 2.64	6.56 ± 11.63
After treatmenta)	18b)	3.40 ± 1.54	41.80 ± 9.47	15.55 ± 1.97	2.75 ± 2.19

a) Monitoring data within 20 d after discontinuation. b) Only 18 patients were monitored coagulation after discontinuation. c) Because of missing data, only 46 cases of D-dimer data were analyzed before and during medication.

Fig. 1. (a) FIB Levels of 50 Cases Treated with Tigecycline, the FIB Level Showed a Trend of Significant Decline during Tigecycline Treatment and Rebounded after Withdrawal

(b) aPTT levels of 50 cases treated with tigecycline, (c) PT levels of 50 cases treated with tigecycline. The aPTT and PT values increased during treatment, then decreased after discontinuation. (Dotted lines were used to separate three conditions (Before, During and After treatment).)

In all patients, 46 cases showed that FIB levels decreased during the treatment while 25 had more dramatic decrease of >50%. There were 25 patients with FIB levels of <2.0 g/L, including 6 who had levels of <1.0 g/L. Pearson correlation coefficients revealed a strong positive association between FIB differences and the baseline level of this parameter (r = 0.769, p < 0.001) (Fig. 2). No significant correlation was found when comparing FIB differences to age, AST, ALT and Cr separately (p = 0.565, 0.772, 0.278, and 0.525, respectively). All data of aPTT and PT values were processed by the same method. The aPTT and PT levels maintain the daily downward trend seen in Table 2, but with some volatility. Compared with the pre-medication, the FIB value decreased significantly on the 3rd day during the treatment, and continued to decrease with the prolongation of the medication time. After withdrawal, the FIB value gradually increased, and there was no significant difference in FIB value between pre-medication and the 4th day after discontinuation. There was no significant correlation when comparing aPTT differences and PT differences to age, the baseline levels, AST, ALT, and Cr separately.

Fig. 2. The Liner Correlation between FIB Difference and FIB Baseline Level

Pearson correlation coefficients revealed a strong positive association between them.

Table 2. The Values of FIB, aPTT, PT in Different Time Points^a)

Time (d)	FIB (g/L)		aPTT (s)		PT (s)
	Mean ± standard deviation	p* Value	Mean ± standard deviation	p* Value	Mean ± standard deviation	p* Value
Before treatment	4.63 ± 1.56	—	39.58 ± 8.72	—	15.37 ± 1.53	—
D1 during treatment	4.05 ± 1.32	0.133	45.83 ± 9.47	0.043	16.24 ± 2.71	.202
D2 during treatment	4.12 ± 1.82	0.154	41.42 ± 7.57	0.52	16.27 ± 2.72	.160
D3 during treatment	3.73 ± 1.19	0.028	45.17 ± 13.30	0.082	16.66 ± 3.48	.067
D4 during treatment	2.94 ± 0.93	<0.001	45.87 ± 10.94	0.042	16.96 ± 4.26	.024
D5 during treatment	2.86 ± 1.09	<0.001	46.07 ± 10.46	0.044	16.48 ± 1.79	.124
D6 during treatment	2.27 ± 1.06	<0.001	51.33 ± 20.65	0.001	16.90 ± 2.52	.050
D7 during treatment	2.47 ± 1.30	<0.001	49.86 ± 15.86	0.002	17.07 ± 2.30	.019
D1 after treatment	2.53 ± 0.96	0.003	45.27 ± 6.38	0.239	17.02 ± 0.42	.127
D2 after treatment	2.29 ± 1.11	<0.001	43.77 ± 5.15	0.325	16.64 ± 2.60	.183
D3 after treatment	3.48 ± 2.06	0.04	41.42 ± 11.30	0.665	15.14 ± 1.87	.808
D4 after treatment	3.44 ± 1.13	0.173	39.57 ± 4.01	0.998	15.40 ± 0.72	.983
D5 after treatment	3.43 ± 2.70	0.082	43.96 ± 10.71	0.404	15.66 ± 1.15	.803

a) Due to the different course of treatment and the amount of data used in our case, this table only shows the values for the first 7 d of the medication period and the first 5 d after the withdrawal of the drug. *p value means statistical differences between the lever of FIB, aPTT, PT in different time points and baseline level before medication.

Among the 50 cases, 22 received tigecycline combined with cefoperazone sulbactam in the treatment. There was no significant difference in the baseline levels of FIB, aPTT, and PT between the tigecycline group and tigecycline + cefoperazone/sulbactam group (p = 0.667 for FIB, p = 0.587 for aPTT, p = 0.950 for PT, respectively) (Table 3). Both of two groups had significant decrease in the FIB levels, with before and during treatment being 4.72 ± 1.46 g/L (before) and 2.86 ± 1.01 g/L (during) (p < 0.001) in the tigecycline group, and 4.52 ± 1.72 g/L (before) and 3.00 ± 1.48 g/L (during) (p < 0.001) in the tigecycline + cefoperazone/sulbactam group. Between the two groups, there was no significant difference in the FIB mean level during treatment (p = 0.693) (Table 3). The levels of aPTT and PT during treatment also showed no significant difference between the tigecycline group and tigecycline + cefoperazone/sulbactam group (p = 0.210 for aPTT, p = 0.693 for PT, respectively) (Table 3, Fig. 3). In Table 4, 50 patients were divided into recommended dose group (39 patients) and higher dose (11 patients) group according to the single dose of tigecycline. We found no statistical difference in the levels of FIB, aPTT and PT before the treatment between the two groups (p = 0.159 for FIB, p = 0.815 for aPTT, p = 0.539 for PT, respectively) (Table 4). Similarly, no statistical difference in levels of the three coagulation indexes during the treatment was observed between the two groups (p = 0.832, 0.087 and 0.247, respectively) (Table 4, Fig. 4).

Table 3. Differences in FIB, aPTT, PT between Tigecycline Group and Tigecycline + Cefoperazone/Sulbactam Group at Different Treatment Periods

Group period	Tigecycline group		Tigecycline + cefoperazone/sulbactam group
	Before treatment	During treatment	Before treatment	During treatment
FIB (g/L)	4.72 ± 1.46	2.86 ± 1.01	4.52 ± 1.72	3.00 ± 1.48
aPTT (s)	40.18 ± 8.97	45.71 ± 11.75	38.81 ± 8.53	41.95 ± 8.29
PT (s)	15.38 ± 1.43	16.53 ± 2.53	15.35 ± 1.69	16.16 ± 2.82

Fig. 3. (a) FIB Differences between Tigecycline Group and Tigecycline + Cefoperazone/Sulbactam Group, (b) aPTT Differences between Tigecycline Group and Tigecycline + Cefoperazone/Sulbactam Group, (c) PT Differences between Tigecycline Group and Tigecycline + Cefoperazone/Sulbactam Group

Table 4. Differences in FIB, aPTT, PT between Recommended Dose Group and Higher Dose Group of Tigecycline at Different Treatment Periods

Group period	Recommended dose group (50 mg)		Higher dose group (100 mg)
	Before treatment	During treatment	Before treatment	During treatment
FIB (g/L)	4.75 ± 1.70	2.94 ± 1.12	4.20 ± 0.87	2.85 ± 1.61
aPTT (s)	39.74 ± 8.60	45.71 ± 11.25	39.03 ± 9.52	39.29 ± 4.70
PT (s)	15.44 ± 1.48	16.60 ± 2.73	15.11 ± 1.75	15.54 ± 2.23

Fig. 4. Fifty Patients Were Divided into Recommended Dose Group (50 mg) and Higher Dose Group (100 mg) According to the Single Dose of Tigecycline

(a) FIB differences between the <65 and ≥65 years age groups, (b) aPTT differences between the <65 and ≥65 years age groups, (c) T differences between the <65 and ≥65 years age groups.

The PLT level was 203.31 ± 105.45 (× 10⁹/L) before tigecycline treatment, 203.64 ± 104.11 (× 10⁹/L) during treatment, and 199.39 ± 97.31 (× 10⁹/L) after cessation of treatment. We also found that the differences among the three periods were not statistically significant (p > 0.05).

Among the 50 cases, only one patient developed active gastrointestinal bleeding with FIB 1.93 g/L, aPTT 35.2 s, PT19s, and PLT 119 × 10⁹/L at the 13th day of treatment with tigecycline. Tigecycline was withdrawn and this patient was then treated for four days until the bleeding had stopped with supportive plasma and plasma cryoprecipitate treatment. All patients had no other adverse drug reaction symptoms.

Tigecycline Effects on Liver and Kidney Function

Based on our analysis, we found no significant changes in AST, ALT, and Cr levels associated with treatment (p > 0.05) (Table 5).

Table 5. Differences in AST, ALT, Cr at Different Treatment Periods

Period	AST (U/L)	ALT (U/L)	Cr (μmoI/L)
Before treatment	55.39 ± 99.59	52.42 ± 56.31	82.90 ± 75.24
During treatment	46.00 ± 60.86	41.44 ± 33.18	77.49 ± 67.44
After treatmenta)	55.14 ± 50.17	62.94 ± 127.81	74.09 ± 77.98

a) Monitoring data within 20 d after discontinuation.

Discussion

In recent years, tigecycline, being an excellent antibacterial drug, has been used against of Gram-positive Cocci, Gram-negative Bacilli, anaerobic bacteria and a variety of MDR pathogens has very high activity (including MDR A. baumannii, MDR Enterobacteriaceae and VRE). According to the data of Adverse Event reporting system from 2004 to 2009 announced by Food and Drug Administration (FDA), the uncommon adverse reactions of tigecycline included cholestasis, jaundice, and increased international normalized ratio (INR).²²⁾ On the clotting effect of tigecycline, there are two small clinical studies in addition to a few cases reports. Routsi et al. found that high doses of this drug lead to hypofibrinogenemia,²³⁾ while Zhang et al. described hypofibrinogenemia induced by tigecycline seemed to depend on dose, not on patient age.²⁴⁾

We collected and analyzed clinical and laboratory data, including coagulation parameters (FIB, aPTT, PT, and PLT), liver and kidney parameters (ALT, AST, and Cr) from 50 patients with bacterial infections treated with tigecycline in 2015–2016.

Our study showed that the patients treated with tigecycline experienced a reduction in plasma FIB levels, and a prolongation in aPTT and PT values which were all statistically significant between before and during treatment. The value changes on FIB were more remarkable than those of aPTT and PT. Among the 50 patients, 92% cases had decreased FIB values during the treatment, in which 25 cases of FIB value decreased more than 50%. From this result we deduced that the change of FIB has a positive correlation with the baseline level of it before medication whereby a higher the baseline level of FIB is associated with higher decline. We also found that the FIB, aPTT and PT have obvious changes 3–4 d after medication and these changes continued to expand significantly afterwards. However, the levels of coagulation parameters returned to normal gradually after discontinuation of treatment, where there was no striking difference between FIB baseline levels and those 4 d after drug withdrawal.

Twenty two patients were later found to have severe multidrug-resistant A. baumannii infections in this study, and were treated by tigecycline combined with cefoperazone/sulbactam. To identify the drugs that affected coagulation in the study, we compared the levels of coagulation parameters between tigecycline group and tigecycline + cefoperazone/sulbactam group. There was no significant difference in the levels of FIB, aPTT, and PT during treatment between these two groups, suggesting that the observed changes in coagulation was due to tigecycline alone, and not through cefoperazone/sulbactam. We further divided these patients into a recommended dose (50 mg q12h) and a higher dose (100 mg q12h) of tigecycline and found that the levels of FIB, aPTT, and PT levels had no statistical significance between two dose groups. The result showed that changes of coagulation were not significantly influenced with dosage.

In our study, the PLT level during treatment of tigecycline was similar to the one before treatment. And the mean value continued to decline after treatment discontinuation. The scatter plot of platelet count decreased slightly during the treatment. The PLT level was then slowly recovered after the treatment discontinuation. We found the decrease and reversal of the platelet count was gradual and delayed, when compared with the changes observed in plasma fibrinogen.

As we all know, the coagulation parameters abnormality is one of the clinical manifestations of coagulopathy. The reduction of clotting factors is likely due to increased consumption and impaired biosynthesis. These patients did not have the risk factors for increased consumption, such as disseminated intravascular coagulation (DIC), primary active bleeding, and clotting factors degradation accelerated by acidosis.²⁵⁾ Based on the change of D-dimer which was a product of fibrin degradation, subsequently was used as a means of assessing hemostasis and active fibrinolysis,²⁶⁾ and there was also no significant difference in D-dimer between before and during treatment in our results, we therefore concluded that the reduction of FIB has no obvious relationship with clotting factors consumption. We also found no change of AST, ALT, and Cr levels in these patients during the treatment, excluding that hepatic and renal function could be implicated in the effect of FIB in our patients. As vitamin K deficiency usually exhibited prolonged PT level, which is the consequence of deficiencies of factors II, VII, IX.^27,28) Cefoperazone/sulbactam can cause a decrease of vitamin K dependent factors (II, VII, IX, X), leading to coagulation disorder.²⁹⁾ However, we found no significant difference between tigecycline group and tigecycline + cefoperazone/sulbactam group. Based on our analysis, we speculated that tigecycline is able to induce reduction of FIB that is associated with the pathologic prolongation of aPTT and PT, and this deficiency in FIB is probably localized in a yet-unknown step of FIB synthesis in the hepatic cell. Also, we know that there are many factors which can cause PT and aPTT to change. APTT can be used to evaluate the clotting factors of the intrinsic pathway. It could be increased in coagulation factor deficiencies (factors II, V, VIII, IX, X, XI, XII), hypofibrinogenemia, increased fibrinolytic activity and presence of anticoagulants.³⁰⁾ PT can be used to evaluate the clotting factors of the exterior pathway, which could be affected by factors II, V, VII, X, dysfibrinogenemia, DIC, cirrhosis, vitamin K deficiency, and in drug therapy—e.g., heparin and aspirin.³¹⁾ Fibrinogen is the final essential building block of the clotting process, while aPTT, PT is determined at a certain time and many factors could affect the time of this determination, such as II, V, VII, X, fibrinogen content.³²⁾ The reduction of FIB alone does not lead to the prolongation of PT to a corresponding extent, and other factors are uncontrollable and have a buffer effect. It is maybe the reason that the value changes on FIB were more remarkable than those of aPTT and PT.

There were certain limitations associated in this study, such as a relatively low patient population where a larger scale should be warranted in the future. Also, these results were all based on the retrospective analysis of existing cases. Furthermore, we cannot exclude other factors, such as different monitoring time and possible missing data, which may affect the accuracy of the study. In addition, some patients were given multiple antimicrobials at the same time, such as carbapenems and caspofungin, which although found were not connected with coagulopathy, but might still affect the underlying physiological parameters measured here. Patients with more severe illness were not included in this study due to the reduced glutathione and other Hepatoprotective drugs given once in ICU that aims to modulate the systemic hepatic level to normal level. We need to do prospective study or a lager sample retrospective study to identify the risk factors of reduction of FIB, prolong aPTT and PT in patients in the further time.

Conclusion

In conclusion, we found that patients with tigecycline had statistically significant difference in FIB reduction, and aPTT and PT prolongation. These changes generally occurred within 3–4 d of tigecycline treatment. Based on these results, we suggest that the patients with severe, traumatic, hepatic, and renal impairment, and the history of coagulation disease, should be routinely monitored within 1 week and adjusted the treatment plan according to the results after using tigecycline. It is also necessary to examine the patients’ oral mucosa, skin, and digestive tract carefully to make sure that there is no bleeding. It is necessary for patients with tigecycline to examine coagulation parameters and whether there is a tendency to bleed before trachea, indwelling catheters and surgery. Hemorrhages, hematomas, petechiae, bruising and prolonged bleeding time are indications for withdrawal and the injection of blood products that contain coagulation factors.

Acknowledgments

This research was supported by Shandong Medical and Health Science and Technology Development Program (Project No. 2017WS201 and No. 2017WS029).

Conflict of Interest

The authors declare no conflict of interest.

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