Dose Of Tigecycline Research Articles

Impact of Tigecycline on Coagulation in Severe Infections and Effect of Vitamin K1 Intervention: A Retrospective Single-Center Analysis.

BACKGROUND Tigecycline is a tetracycline antibiotic used to treat gram-positive and gram-negative bacterial infections, and bleeding is a dose-dependent adverse effect. Vitamin K1 is a fat-soluble vitamin used to treat hemorrhagic conditions. This retrospective study from a single center included 920 patients treated with tigecycline for bacterial infections between January 2017 and December 2022 and aimed to evaluate the incidence of coagulopathy and the use of vitamin K1. MATERIAL AND METHODS A total of 220 patients were included and divided into a high-dose group (100 mg, every 12 h) and normal-dose group (50 mg, every 12 h) according to the treatment dose of tigecycline. Clinical characteristics and changes in coagulation indicators during tigecycline treatment were collected. Seventy-two patients were treated with vitamin K1, and the changes in coagulation indicators before and after treatment were compared. ANOVA and t test were used to analyze the effects of different doses of tigecycline on coagulation function and the intervention of vitamin K1. RESULTS Among 920 patients, the incidence of coagulopathy was 23.91%. In both groups, coagulopathy occurred on days 5 to 7 after administration, and the high-dose group had worse coagulation function than the normal-dose group, including activated partial thrombin time, prothrombin time, and fibrinogen (P<0.05). After treatment with vitamin K1, fibrinogen increased and activated partial thrombin time and prothrombin time were shortened in both groups (P<0.05 or P<0.01). CONCLUSIONS Tigecycline caused coagulopathy with dose and time dependence. Vitamin K1 can improve tigecycline-induced coagulopathy.

Incidence, characteristics, and risk factors of hypofibrinogenemia induced by generic tigecycline: a retrospective study.

The objective of this study was to evaluate the incidence, clinical features, and risk factors of generic tigecycline-associated hypofibrinogenemia. A single-center retrospective study was conducted in adult patients treated with generic tigecycline. Clinical data were extracted from the electronic medical records. The endpoint was tigecycline-related hypofibrinogenemia, defined as a condition with no abnormality in fibrinogen before tigecycline application, but developing hypofibrinogenemia upon prescription. The risk factors were determined by logistic regression analysis, and the ROC curve was subsequently established. A total of 240 adults prescribed generic tigecycline from May 1st to November 30th 2023 were included. It was shown that hypofibrinogenemia is a frequent side effect of generic tigecycline, with an adverse reaction rate of 42.9% (103/240). However, the incidence of adverse reactions to generic drugs was lower than in previous studies. The cumulative dose of tigecycline (OR:1.002, 95%CI 1.001-1.002, P < 0.001), baseline FIB (OR:0.995, 95%CI 0.992-0.997, P < 0.001), baseline PT (OR:1.247, 95%CI 1.071-1.452, P = 0.004) and baseline ALB (OR:0.931, 95%CI 0.879-0.986, P = 0.025) were identified as independent prognostic factors of tigecycline-related hypofibrinogenemia. We recommend intensive monitoring of coagulation function in patients exhibiting the aforementioned risk factors for generic tigecycline-associated hypofibrinogenemia to ensure patients safety.

Treatment of infections caused by carbapenem-resistant Acinetobacter baumannii.

Patients with severe carbapenem-resistant Acinetobacter baumannii (CRAB) infections currently face significant treatment challenges. When patients display signs of infection and the clinical suspicion of CRAB infections is high, appropriate treatment should be immediately provided. However, current treatment plans and clinical data for CRAB are limited. Inherent and acquired resistance mechanisms, as well as host factors, significantly restrict options for empirical medication. Moreover, inappropriate drug coverage can have detrimental effects on patients. Most existing studies have limitations, such as a restricted sample size, and are predominantly observational or non-randomized, which report significant variability in patient infection severity and comorbidities. Therefore, a gold-standard therapy remains lacking. Current and future treatment options of infections due to CRAB were described in this review. The dose and considerable side effects restrict treatment options for polymyxins, and high doses of ampicillin-sulbactam or tigecycline appear to be the best option at the time of initial treatment. Moreover, new drugs such as durlobactam and cefiderocol have substantial therapeutic capabilities and may be effective salvage treatments. Bacteriophages and antimicrobial peptides may serve as alternative treatment options in the near future. The advantages of a combination antimicrobial regimen appear to predominate those of a single regimen. Despite its significant nephrotoxicity, colistin is considered a primary treatment and is often used in combination with antimicrobials, such as tigecycline, ampicillin-sulbactam, meropenem, or fosfomycin. The Infectious Diseases Society of America (IDSA) has deemed high-dose ampicillin-sulbactam, which is typically combined with high-dose tigecycline, polymyxin, and other antibacterial agents, the best option for treating serious CRAB infections. A rational combination of drug use and the exploration of new therapeutic drugs can alleviate or prevent the effects of CRAB infections, shorten hospital stays, and reduce patient mortality.

Pharmacokinetic/pharmacodynamic evaluation of tigecycline dosing in a hollow fiber infection model against clinical bla-KPC producing Klebsiella Pneumoniae isolates

The FDA announced a boxed warning for tigecycline due to progression of infections caused by Gram-negative bacteria and increased risk of mortality during treatment. Plasma exposure of tigecycline might not prevent bacteraemia in these cases from the focuses. Hence, we evaluated intensified dosing regimens and breakpoints that might suppress bloodstream infections, caused by progression of infection by e.g., Gram-negatives. A pharmacometric model was built from tigecycline concentrations (100–600 mg daily doses) against clinical Klebsiella pneumoniae isolates (MIC 0.125–0.5 mg/L). Regrowth occurred at clinically used doses and stasis was only achieved with 100 mg q8h for the strain with the lowest studied MIC of 0.125 mg/L. Stasis at 24 h was related to fAUC/MIC of 38.5. Our study indicates that even intensified dosing regimens might prevent bloodstream infections only for MIC values ≤0.125 mg/L for tigecycline. This indicates an overly optimistic breakpoint of 1 mg/L for Enterobacterales, which are deemed to respond to the tigecycline high dose regimen (EUCAST Guidance Document on Tigecycline Dosing 2022).

Clinical efficacy and safety of tigecycline based on therapeutic drug monitoring for carbapenem-resistant Gram-negative bacterium pneumonia in intensive care units

BackgroundWe investigated the associations between the different doses of tigecycline, its efficacy and safety, and the role of tigecycline therapeutic drug monitoring for patients in the intensive care unit.MethodsThis study was a single-center cohort including patients infected with multidrug-resistant Acinetobacter baumannii (MDR-AB) and multidrug-resistant Klebsiella pneumoniae (MDR-KP) causing pulmonary infections. The steady-state plasma concentration after tigecycline administration was determined by High-Performance Liquid Chromatography (HPLC) in patients admitted to the ICU between October 2020 and December 2021. Multivariate analyses of tigecycline’s clinical efficacy and safety were performed to control confounding factors.ResultsFor this study, we included 45 patients and 45 blood samples to determine steady-state trough concentrations of tigecycline. All patients were divided into the High Dose (HD) and Standard Dose (SD) groups. The median trough concentration of tigecycline was 0.56 μg/mL in the HD group, which was higher than in the SD group (0,21 μg/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 the ICU days were 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 in the SD group (-3.05 ± 1.67 vs -1.75 ± 1.90), p = 0.038. We identified that age and tigecycline treatment duration influenced fibrinogen decline.ConclusionsTigecycline 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 the patient’s age and days of tigecycline. Large sample data are still needed to confirm the clinical guidance significance of tigecycline TDM.

Safety of Tigecycline in Patients on Antithrombotic Therapy: A Single-Center Retrospective Study

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.

The Spectrum of Tigecycline-Induced Pancreatitis in Clinical Characteristics, Diagnosis, and Management.

Tigecycline-induced acute pancreatitis (AP) has been frequently increasingly reported in solid organ transplant patients. This review aimed to summarize the characteristics, possible mechanisms, and management of tigecycline-induced AP. Case reports of tigecycline-induced AP published in Chinese or English were collected until February 2023 for retrospective analysis. Thirty-four patients from 29 articles were included. Fifteen patients (46.9%) had solid organ transplantation, and 4 patients (12.5%) had malignant tumors. Twenty-five patients (89.3%) received a recommended maintenance dose of tigecycline (50 mg q12 h). The median age was 50 years (range 9-87). Compared to the nontransplant patients, the median age of the transplant patients was significantly younger, 44 years (range 12.5-61) versus 57.5 years (range 9-87) (P=0.03). The median time of symptom onset was 7 days (range 2-29), and 91.2% (31/34) were less than 14 days. Typical initial symptoms included abdominal pain (90.6%), nausea (46.9%), vomiting (43.8%), and abdominal distention (21.9%). Most cases were accompanied by elevated levels of pancreatic enzymes. The main radiological features included edematous infiltrate and acute pancreatitis on computed tomography (CT) scan and abdominal ultrasound. Except for one patient who continued tigecycline treatment, all patients discontinued treatment and received symptomatic support such as fasting, acid suppression, and enzyme suppression. The median time to recover pancreatic enzymes to the normal range was 5 days (range 1-43), and the median time to relieve symptoms was 4 days (range 1-12). Four patients died, of whom two died of severe pancreatitis complications and two of cardiogenic shock and septicemia. Tigecycline-induced AP was a rare and serious complication that occurred mainly within two weeks of the medication. This serious side effect should be kept in mind while treating severe infections especially in transplant recipients.

Systematic evaluation and Meta-analysis of the efficacy and safety of different doses of tigecycline in ventilator-associated pneumonia caused by multiple resistant bacteria

IntroductionIn this study, we conducted a systematic review and meta-analysis to evaluate the efficacy and safety of different doses of tigecycline in the treatment of VAP caused by multi-resistant bacteria.Material and methodsTo identify relevant studies, we conducted a comprehensive search of multiple databases including theThrough Cochrane libraryLibrary, Embase, PubMed, Chinese biomedical literature database, CNKI, Chinese JP, and WP, covering the period up to the database until December 2022. We assessed the quality of the included studies using the Jadad quality score, and performed a meta-analysis of the data using Stata software.ResultsThere was no clinical heterogeneity or statistical heterogeneity between studies, and a fixed-effect model was used to incorporate the effect size. The incidence of adverse effects in the observed group was not different from that of the control group. The clinical effect of the observation group was significantly better than that of the control group . Meta-analysis of the adverse effects showed that there was no clinical heterogeneity or statistical heterogeneity between studies, and a fixed-effect model was used to incorporate the effect size. The incidence of adverse effects in the observed group was not different fromsimilar to that of the control group.The included articles were tested for publication bias using funnel plot and Egger's test, and none of the four articles had adverse effects as effect indicators.ConclusionsHigh-dose duration of tigecycline treatment for ventilator-related pneumonia caused by multi-resistant bacteria has is associated with improved better clinical efficacy with noout an increase in adverse effectsand high safety.

Pharmacokinetic/Pharmacodynamic Target Attainment of Tigecycline in Patients with Hepatic Impairment in a Real-World Setting.

This study aimed to investigate the pharmacokinetic/pharmacodynamic (PK/PD) target attainment of various tigecycline dosing regimens in real-world patients with impaired liver function. The clinical data and serum concentrations of tigecycline were extracted from the patients' electronic medical records. Patients were classified into Child-Pugh A, Child-Pugh B, and Child-Pugh C groups, according to the severity of liver impairment. Furthermore, the minimum inhibition concentration (MIC) distribution and PK/PD targets of tigecycline from the literature were used to obtain a proportion of PK/PD targets attainment of various tigecycline dosing regimens at different infected sites. The pharmacokinetic parameters revealed significantly higher values in moderate and severe liver failure (groups Child-Pugh B and Child-Pugh C) than those in mild impairment (Child-Pugh A). Considering the target area under the time-concentration curve (AUC 0-24 )/MIC ≥4.5 for patients with pulmonary infection, most patients with high-dose (100 mg, every 12 hours) or standard-dose (50 mg, every 12 hours) for tigecycline achieved the target in groups Child-Pugh A, B, and C. Considering the target AUC 0-24 /MIC ≥6.96 for patients with intra-abdominal infection, when MIC ≤1 mg/L, more than 80% of the patients achieved the target. For an MIC of 2-4 mg/L, only patients with high-dose tigecycline in groups Child-Pugh B and C attained the treatment target. Patients experienced a reduction in fibrinogen values after treatment with tigecycline. In group Child-Pugh C, all 6 patients developed hypofibrinogenemia. Severe hepatic impairment may attain higher PK/PD targets, but carries a high risk of adverse reactions.

Population pharmacokinetics of tigecycline in critically ill patients.

Objective: In critically ill patients, the change of pathophysiological status may affect the pharmacokinetic (PK) process of drugs. The purpose of this study was to develop a PK model for tigecycline in critically ill patients, identify the factors influencing the PK and optimiz dosing regimens. Method: The concentration of tigecycline was measured LC-MS/MS. We established population PK model with the non-linear mixed effect model and optimized the dosing regimens by Monte Carlo simulation. Result: A total of 143 blood samples from 54 patients were adequately described by a one-compartment linear model with first-order elimination. In the covariate screening analysis, the APACHEII score and age as significant covariates. The population-typical values of CL and Vd in the final model were 11.30 ± 3.54L/h and 105.00 ± 4.47L, respectively. The PTA value of the standard dose regimen (100mg loading dose followed by a 50mg maintenance dose at q12h) was 40.96% with an MIC of 2mg/L in patients with HAP, the ideal effect can be achieved by increasing the dosage. No dose adjustment was needed for Klebsiella pneumoniae for AUC0-24/MIC targets of 4.5 and 6.96, and the three dose regimens almost all reached 90%. A target AUC0-24/MIC of ≥17.9 reached 100% in patients with cSSSI in the three tigecycline dose regimens, considering MIC ≤ 0.25mg/L. Conclusion: The final model indicated that APACHEII score and age could affect the Cl and Vd of tigecycline, respectively. The standard dose regimen of tigecycline was often not able to obtain satisfactory therapeutic effects for critically ill patients. For patients with HAP and cIAI caused by one of three pathogens, the efficacy rate can be improved by increasing the dose, but for cSSSI infections caused by Acinetobacter baumannii and K. pneumoniae, it is recommended to change the drug or use a combination of drugs.

Risk factors of tigecycline-associated fibrinogen reduction in patients with renal transplantation: a case-control study.

Hypofibrinogenemia is a serious adverse reaction related to tigecycline administered against multidrug-resistant (MDR) bacteria and can lead to therapy termination. High dose and prolonged tigecycline therapy, renal failure, and base level of fibrinogen (FIB) were reported risk factors of tigecycline-associated FIB reduction. But results are unknown in patients with renal transplantation. A single-center and a case-control study involving renal transplantation patients was conducted. From January, 2017 to January, 2020, patients with a tigecycline course more than 2 days and a baseline FIB level greater than 2 g/L were enrolled. Hypofibrinogenemia was defined as plasma FIB <2.0 g/L. The extent of FIB reduction was calculated based on the baseline of FIB level before tigecycline administration. FIBRO was defined as the extent of FIB reduction over 50%, and FIBRB referred to the extent of FIB reduction below 50%. Univariate and multivariate analyses were performed by logistic regression models to identify independent risk factors of tigecycline-associated FIB reduction. In total, 120 patients were enrolled. A total of 114 patients (95.00%) developed with hypofibrinogenaemia. Hypofibrinogenemia mainly occurred 3 days after tigecycline administration. Of them, 79 (65.83%) developed FIBRO with a median occurrence of 3 [2-4] days after initiation of tigecycline. Multivariable regression analysis demonstrated that the FIB level before tigecycline use [odds ratio (OR): 3.225, 95% confidence interval (CI): 1.801-5.772] and total tigecycline dose (OR: 4.930, 95% CI: 1.433-16.959) were risk factors for FIBRO. The FIB level before tigecycline use and total tigecycline dose were significantly associated with FIBRO, suggesting that FIB level and coagulation-related indicators should be closely monitored during tigecycline treatment to avoid life-threatening bleeding events.

Population Pharmacokinetics of Tigecycline: A Systematic Review.

Although tigecycline is widely used in clinical practice, its efficiency and optimal dosage regimens remain controversial. The purpose of this article was to help guide tigecycline dosing in different patient subpopulations through comparing the published population pharmacokinetic models of tigecycline, as well as summarizing and determining the potential covariates that markedly influence tigecycline pharmacokinetics. In this review, literature was systematically searched from the PubMed database from inception to March 2022. The articles focusing on population pharmacokinetics for tigecycline in healthy volunteers or patients were included; finally, a total of eight studies were included in this review. NONMEM methods were used in five studies to generate the population pharmacokinetic models. Tigecycline pharmacokinetics were mostly described by a two-compartment model in these included studies. Estimated clearance and volumes of distribution of tigecycline at steady state (Vss) varied widely in different target patient populations, with a range of 7.5–23.1 L/h and 212.7–1087.7 L, respectively. Body-weight and creatinine clearance were the most important predictors of clearance in these studies, while other predictors include age, gender, bilirubin and aspartate aminotransferase. In conclusion, this review showed the large variability of tigecycline population pharmacokinetics, which can provide guide dosing in different target populations. For clinicians, the individual dosing adjustment should be based not only on the indication and pathogen susceptibility but also on the potential important predictors. However, more studies were needed to confirm the necessity of modified dosage regimens in different patient subpopulations.

A case report of drug-induced liver injury after tigecycline administration: histopathological evidence and a probable causality grading as assessed by the updated RUCAM diagnostic scale

BackgroundThere have been no reports of tigecycline-associated drug-related liver injury (DILI) identified by histopathological assistance and causal assessment method. We reported the histopathological manifestations for the first time and described tigecycline-associated liver injury’s pattern, severity, duration, and outcome.Case presentationA 68-year-old male with post-liver transplantation was given high-dose tigecycline intravenously (loading dose 200 mg, followed by 100 mg every 12 h) combined with polymyxin B (50,000 units by aerosol inhalation every 12 h) for hospital-acquired pneumonia caused by carbapenem-resistant Klebsiella pneumoniae. At the same time, tacrolimus was discontinued. Liver function was initially normal but started to decline on day 4 of tigecycline. Reducing the dose of tigecycline and resuming tacrolimus could not reverse the deterioration. Therefore, a liver puncture biopsy was performed for further diagnosis, with histopathological findings being cytotoxic injury. The updated RUCAM scale was used to evaluate the causal relationship between tigecycline and liver injury, with the result of 7 points indicating a “probable” causality grading. Methylprednisolone was initiated to treat DILI that was determined to be Grade 1 cholestatic injury. Total bilirubin and transaminase levels returned to normal on day 4 and 11 after tigecycline withdrawal, respectively. Monthly outpatient follow-up showed that the patient’s liver function stayed normal.ConclusionsThis case possessed a significant reference value for differential diagnosis and treatment prognosis of tigecycline-associated DILI. With early diagnosis and timely management, the tigecycline-associated DILI of this patient was successfully reversed.

Comparison of the Efficacy and Safety of Standard versus High Dose Tigecycline

Comparison of the Efficacy and Safety of Standard versus High Dose Tigecycline

Tigecycline population pharmacokinetics in critically ill patients with decompensated cirrhosis and severe infections.

Physiopathological changes in advanced cirrhosis could alter tigecycline pharmacokinetics (PK), thus affecting serum drug concentrations and compromising target attainment. We aimed to describe tigecycline PK in patients with decompensated cirrhosis and severe bacterial infections, identify the sources of PK variability and assess the performance of different dosing regimens to optimize the PK/pharmacodynamic (PD) target. Serum concentrations and covariates were obtained from patients with severe infections under tigecycline treatment. A population PK analysis was performed using non-linear mixed-effects modelling and the final model was used to simulate tigecycline exposure to assess the PTA. Twenty critically ill patients were enrolled in the study. Data were best described by a two-compartment linear model. Mean ± SD parameter estimates for clearance (CL), intercompartmental clearance (Q), central and peripheral volumes of distribution (V1 and V2) were 14.8 ± 11 L/h, 38.4 ± 24 L/h, 63.7 ± 14 L and 233 ± 30 L, respectively. MELD score significantly influenced tigecycline CL, and total serum proteins significantly affected V1. Monte Carlo simulations showed that tigecycline elimination is hampered as MELD score values increase, consequently requiring lower drug doses. Patients with hypoproteinaemia would have lower peak tigecycline concentrations but similar steady-state concentrations compared with patients with normoproteinaemia. Our study confirms that tigecycline dose adjustment is needed in severe hepatic dysfunction and suggests using the MELD score for dose optimization since it is identified as a covariate that significantly influences tigecycline CL. Dosing regimens are recommended to reach several PK/PD targets considering this clinical variable and any MIC within the susceptibility range.

Intrapulmonary pharmacokinetics of high doses of tigecycline in patients with ventilator-associated pneumonia

Tigecycline is commonly used for infections by multidrug-resistant bacteria. However, it is not approved for ventilator-associated pneumonia (VAP) as increased mortality has been reported in VAP patients treated with conventional doses. The purpose of this study was to prospectively evaluate the intrapulmonary pharmacokinetics of off-label high-dose tigecycline in patients with VAP. Nine mechanically ventilated patients received tigecycline intravenously (loading dose 200 mg followed by 100 mg every 12 h). After ≥5 doses, two bronchoscopies were performed in each patient on consecutive days and eight blood samples were collected. Tigecycline concentrations in plasma and bronchoalveolar lavage fluid were determined by liquid chromatography. The urea dilution method was used to calculate epithelial lining fluid (ELF) concentrations. A two-compartmental pharmacokinetic (PK) model with linear elimination was used to estimate PK parameters. Mean patient age was 69 ± 11.86 years and mean APACHE II score was 21. The estimated population mean PK parameters (relative standard error) were: clearance, 11.64 L/h (54%); volume of distribution in central compartment, 79.01 L (37%); volume of distribution in peripheral compartment, 92.95 L (17%); intercompartmental clearance, 62.81 L/h (34%); and ELF penetration ratio, 2.41 (40%). Cmax, Cmin, plasma AUC0-12, plasma fAUC0-12 and ELF AUC0-12 were 1.99 ± 1.82 μg/mL, 0.81 ± 1.27 μg/mL, 12.89 ± 17.25 μg•h/mL, 3.24 ± 3.09 μg•h/mL and 7.13 ± 2.61 μg•h/mL, respectively. The increased plasma and ELF AUC0-12 achieved with a 200 mg daily tigecycline dose, combined with high ELF penetration, support the effectiveness of off-label high-dose tigecycline in VAP.

Progression of Fibrinogen Decrease during High Dose Tigecycline Therapy in Critically Ill Patients: A Retrospective Analysis.

Tigecycline is a novel glycylcycline broad-spectrum antibiotic offering good coverage for critically ill patients experiencing complicated infections. A known side effect is a coagulation disorder with distinct hypofibrinogenemia. To date, the information on possible risk factors and outcomes is sparse. Therefore, the aim of this study is to examine the time course of fibrinogen level changes during tigecycline therapy in critically ill patients. Moreover, we sought to identify risk factors for coagulopathy and to report on clinically important outcomes. We retrospectively reviewed all intensive care patients admitted to our General and Surgical Intensive Care Unit receiving tigecycline between 2010 and 2018. A total of 130 patients were stratified into two groups based on the extent of fibrinogen decrease. Patients with a greater fibrinogen decrease received a higher dose, a longer treatment and more dose changes of tigecycline, respectively. In regard to the underlying pathology, these patients showed higher inflammation markers as well as a slightly reduced liver synthesis capacity. We, therefore, conclude that such a fibrinogen decrease may be based upon further impairment of liver synthesis during severe inflammatory states. To decrease the risk of bleeding, cautious monitoring of coagulation in critically ill patients treated with high-dose tigecycline is warranted.

High-Dose versus Standard-Dose Tigecycline Treatment of Secondary Bloodstream Infections Caused by Extensively Drug-Resistant Acinetobacter baumannii: An Observational Cohort Study.

BackgroundExtensively drug-resistant Acinetobacter baumannii (XDR-AB) infections have become difficult to treat and are associated with a high mortality rate. Tigecycline is one of the most effective agents used to treat XDR-AB infections, but data from treating bloodstream infection (BSI) in standard dose do not look promising, because of its low plasma concentration. Secondary BSI with primary infection source may indicate tigecycline treatment with a higher dose. Currently, little is known about the application of high-dose tigecycline among patients with secondary BSI caused by XDR-AB. We aimed to investigate the outcomes for high-dose (HD) tigecycline treatment versus standard-dose (SD) treatment of these patients.MethodsAn observational cohort study was conducted at four university affiliated hospitals in mainland China. Adult inpatients who were confirmed as having secondary BSI caused by XDR-AB and received definitive tigecycline treatment were consecutively included. Patients who were treated with 50 mg every 12 h were defined as the SD group, and a twice dose was defined as the HD group.ResultsOf the enrolled patients, 63 received SD and 88 received HD tigecycline treatment. Patients in the two groups had similar with regard to baseline clinical conditions. The 30-day survival was affected by the source of the primary infection. Survival was significantly better in patients with non-pulmonary-infection-related BSI than in patients with pulmonary-infection-related BSI. Multivariate Cox regression confirmed that HD had a protective effect only observed in patients with non-pneumonia-related BSI.ConclusionA tigecycline dose that is twice its standard dose is better for the treatment of XDR-AB infection only in BSI associated with non-pulmonary infection.

Tigecycline in the Treatment of Ventilator-Associated Pneumonia Due to Stenotrophomonas maltophilia: A Multicenter Retrospective Cohort Study.

IntroductionTigecycline is a potential alternative to trimethoprim–sulfamethoxazole in treating Stenotrophomonas maltophilia infections due to its potent in vitro antimicrobial activity. Clinical evidence regarding the use of tigecycline in the treatment of S. maltophilia infections is scarce. In this study, we assessed the efficacy of tigecycline treating ventilator-associated pneumonia (VAP) due to S. maltophilia in comparison with fluoroquinolones.MethodsThis is a multicenter retrospective cohort study of patients admitted between January 2017 and December 2020 with the diagnosis of VAP caused by S. maltophilia receiving either tigecycline or fluoroquinolones as the definitive therapy ≥ 48 h. Clinical outcomes including 28-day mortality, clinical cure and microbiological cure were analyzed.ResultsOf 82 patients with S. maltophilia VAP included, 46 received tigecycline, and 36 received fluoroquinolones; 70.7% of patients had polymicrobial pneumonia, and the appropriate empiric therapy was applied to only 14.6% of patients. The overall 28-day mortality was 39%. Compared with patients receiving fluoroquinolones, tigecycline therapy resulted in worse clinical cure (32.6% vs. 63.9%, p = 0.009) and microbiological cure (28.6% vs. 59.1%, p = 0.045), while there was no statistical difference between 28-day mortality (47.8% vs. 27.8%, p = 0.105) in the two groups. Similar results were also shown in the inverse probability of treatment weighted univariable regression model and multivariable regression model.ConclusionsThe standard dose of tigecycline therapy was associated with a lower clinical and microbiological cure rate but not associated with an increased 28-day mortality in patients with S. maltophilia VAP compared with fluoroquinolones. Considering the unfavorable clinical outcomes, we therefore recommend against using the standard dose of tigecycline in treating S. maltophilia VAP unless new clinical evidence emerges.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40121-021-00516-5.

The Synergistic Activity and Optimizing Doses of Tigecycline in Combination with Aminoglycosides against Clinical Carbapenem-Resistant Klebsiella pneumoniae Isolates.

Carbapenem-resistant Enterobacteriaceae (CRE), especially carbapenem-resistant Klebsiella pneumoniae (CRKP), are among the largest pathogenic threats to humans. The available antibiotic treatment options for combating CRKP are limited. Colistin-resistant Enterobacteriaceae (CoRE) have also been reported worldwide, including in Thailand. Therefore, this study aimed (1) to determine minimum inhibitory concentrations (MICs) and synergistic activities of antibiotics of CRKP, and (2) to determine the probability target of attainment (PTA) and cumulative fraction of response (CFR) using pharmacokinetic/pharmacodynamic (PK/PD) data. Clinical CRKP isolates were obtained from Phramongkutklao Hospital (June to November 2020). Broth microdilution and checkerboard techniques were used to determine the mono- and synergistic activities of antibiotics. Carbapenemase and mcr-1 genes were also identified by polymerase chain reaction (PCR). The optimal antibiotic regimens were evaluated using Monte Carlo simulations. Forty-nine CRKP isolates were collected, 40 of which were CoRKP strains. The MIC50 and MIC90 of tigecycline, amikacin, and gentamicin were 1 and 2 µg/mL, 4 and 16 µg/mL, and 0.25 and 4 µg/mL, respectively. None of any isolates expressed the mcr-1 gene, whereas blaOXA-48 (53.1%) and blaOXA-48 plus blaNDM (42.9%) were detected. Synergistic activity was observed in 8.2% of isolates for tigecycline combined with amikacin or gentamicin. Additive activity was observed in 75.5% of isolates for tigecycline-amikacin and 69.4% for tigecycline-gentamicin, and no antagonism was observed. High-dose antibiotic regimens achieved the PTA target. The general recommended dose of combination regimens began with 200 mg tigecycline and 25 mg/kg amikacin, or 7 mg/kg gentamicin, followed by 100 mg tigecycline every 12 h and 15 mg/kg amikacin or 5 mg/kg gentamicin every 24 h. In conclusion, tigecycline plus aminoglycosides might be a potential regimen against CRKP and CoRKP. The appropriate combination regimen based on MIC-based dose adjustment can improve optimal antibiotic dosing. Further research via clinical studies will be necessary to confirm these results.