Efficacy and safety of Lianhua Qingwen capsules combined with standard of care in the treatment of adult patients with mild to moderate COVID-19 (FLOSAN): protocol for a randomized, double-blind, international multicenter clinical trial.

Background: Effective anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) drugs are not only the next defense after vaccines but also the key part of establishing a multi-tiered coronavirus disease 2019 (COVID-19) prevention and control system. Previous studies had indicated that Lianhua Qingwen (LHQW) capsules could be an efficacious Chinese patent drug for treating mild to moderate COVID-19. However, pharmacoeconomic evaluations are lacking, and few trials have been conducted in other countries or regions to evaluate the efficacy and safety of LHQW treatment. So, this study aims to explore the clinical efficacy, safety, and economy of LHQW for treating adult patients with mild to moderate COVID-19. Methods: This is a randomized, double-blind, placebo-controlled, international multicenter clinical trial protocol. A total of 860 eligible subjects are randomized at a 1:1 ratio into the LHQW or placebo group to receive two-week treatment and follow-up visits on days 0, 3, 7, 10, and 14. Clinical symptoms, patient compliance, adverse effects, cost scale, and other indicators are recorded. The primary outcomes will be the measured median time to sustained improvement or resolution of the nine major symptoms during the 14-day observation period. Secondary outcomes regarding clinical efficacy will be evaluated in detail on the basis of clinical symptoms (especially body temperature, gastrointestinal symptoms, smell loss, and taste loss), viral nucleic acid, imaging (CT/chest X-ray), the incidence of severe/critical illness, mortality, and inflammatory factors. Moreover, we will assess health care cost, health utility, and incremental cost-effectiveness ratio (ICER) for economic evaluation. Discussion: This is the first international multicenter randomized controlled trial (RCT) of Chinese patent medicine for the treatment of early COVID-19 in accordance with WHO guidelines on COVID-19 management. This study will help clarify the potential efficacy and cost-effectiveness of LHQW in the treatment of mild to moderate COVID-19, facilitating decision-making by healthcare workers. Registration: This study is registered at the Chinese Clinical Trial Registry, with registration number: ChiCTR2200056727 (date of first registration: 11/02/2022).

In vitro and in vivo synergistic effects of tigecycline combined with aminoglycosides on carbapenem-resistant Klebsiella pneumoniae.

OBJECTIVES: Carbapenem-resistant Klebsiella pneumoniae (CR-KP) infections represent severe threats to public health worldwide. The aim of this study was to assess potential synergistic interaction between tigecycline and aminoglycosides via in vitro and in vivo studies. METHODS: Antibiotic resistance profiles and molecular characteristics of 168 CR-KP clinical isolates were investigated by susceptibility testing, PCR and MLST. Chequerboard tests and time-kill assays were performed for 20 CR-KP isolates to evaluate in vitro synergistic effects of tigecycline combined with aminoglycosides. A tissue-cage infection model of rats was established to evaluate in vivo synergistic effects. Different doses of tigecycline and aminoglycosides alone or in combination were administered for 7 days via tail vein injection. Antibiotic efficacy was evaluated in tissue-cage fluid and emergence of resistance was screened. RESULTS: The chequerboard tests showed that this combination displayed synergistic or partial synergistic activity against CR-KP. The time-kill assays further demonstrated that strong synergistic effects of such a combination existed against isolates that were susceptible to both drugs but for resistant isolates no synergy was observed if clinical pharmacokinetics were taken into consideration. The in vivo study showed that the therapeutic effectiveness of combination therapies was better than that of monotherapy for susceptible isolates, suggesting in vivo synergistic effects. Furthermore, combinations of tigecycline with an aminoglycoside showed significant activity in reducing the occurrence of tigecycline-resistant mutants. CONCLUSIONS: Compared with single drugs, tigecycline combined with aminoglycosides could exert synergistic effects and reduce the emergence of tigecycline resistance. Such a combination might be an effective alternative when treating CR-KP infections in clinical practice.

Evidence-based Guideline for Therapeutic Drug Monitoring of Vancomycin: 2020 Update by the Division of Therapeutic Drug Monitoring, Chinese Pharmacological Society.

BACKGROUND: Clinical practice guidelines or recommendations often require timely and regular updating as new evidence emerges, because this can alter the risk-benefit trade-off. The scientific process of developing and updating guidelines accompanied by adequate implementation can improve outcomes. To promote better management of patients receiving vancomycin therapy, we updated the guideline for the therapeutic drug monitoring (TDM) of vancomycin published in 2015. METHODS: Our updated recommendations complied with standards for developing trustworthy guidelines, including timeliness and rigor of the updating process, as well as the use of the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. We also followed the methodology handbook published by the National Institute for Health and Clinical Excellence and the Spanish National Health System. RESULTS: We partially updated the 2015 guideline. Apart from adults, the updated guideline also focuses on pediatric patients and neonates requiring intravenous vancomycin therapy. The guideline recommendations involve a broadened range of patients requiring TDM, modified index of TDM (both 24-hour area under the curve and trough concentration), addition regarding the necessity and timing of repeated TDM, and initial dose for specific subpopulations. Overall, 1 recommendation was deleted and 3 recommendations were modified. Eleven new recommendations were added, and no recommendation was made for 2 clinical questions. CONCLUSIONS: We updated an evidence-based guideline regarding the TDM of vancomycin using a rigorous and multidisciplinary approach. The updated guideline provides more comprehensive recommendations to inform rational and optimized vancomycin use and is thus of greater applicability.

Frequency and Genetic Determinants of Tigecycline Resistance in Clinically Isolated Stenotrophomonas maltophilia in Beijing, China.

Stenotrophomonas maltophilia is an emerging nosocomial pathogen with high resistance to most clinically used antimicrobials. Tigecycline is a potential alternative antimicrobial for S. maltophilia infection treatment, but its resistance mechanism in clinical isolates is not fully elucidated. We investigated the antimicrobial susceptibility of 450 S. maltophilia isolated during 2012-2015 from three university hospitals in Beijing, China. These strains exhibited high susceptibility to minocycline (98.44%), sulfamethoxazole/trimethoprim (87.56%), tigecycline (77.78 %), doxycycline (81.33%), levofloxacin (67.56%), and ticarcillin/clavulanate (73.00%). The susceptibility of tigecycline-nonsusceptible strains (TNS) to doxycycline and levofloxacin was much lower than that of tigecycline-susceptible strains (TSS) (25.00% vs. 97.71% for doxycycline, P < 0.001; 17.00% vs. 82.00% for levofloxacin, P < 0.001). We further selected 48 TNS and TSS and compared the detection rate of eight tetracycline-specific genes by PCR and the expression level of six intrinsic multidrug resistance efflux pumps by real-time PCR. Only one tetB and two tetH genes in TNS and three tetH genes in TSS were detected, and the detection rate had no difference. The average expression level of smeD in TNS was higher than that in TSS [20.59 (11.53, 112.54) vs. 2.07 (0.80, 4.96), P < 0.001], while the average expression levels of smeA, smeI, smeO, smeV, and smrA were not significantly different, indicating that smeDEF was the predominant resistance genetic determinant in clinical S. maltophilia. Higher smeD expression was also observed in levofloxacin- and doxycycline-nonsusceptible isolates than in their corresponding susceptible isolates [16.46 (5.83, 102.24) vs. 2.72 (0.80, 6.25) for doxycycline, P < 0.001; 19.69 (8.07, 115.10) vs. 3.01(1.00, 6.03), P < 0.001], indicating that smeDEF was also the resistance genetic determinant to levofloxacin and doxycycline. The consistent resistance profile and common resistance genetic determinant highlight the importance of rational use of tigecycline for preventing the occurrence and spread of multidrug resistance.

Use of Monte Carlo simulation to evaluate the efficacy of tigecycline and minocycline for the treatment of pneumonia due to carbapenemase-producing Klebsiella pneumoniae.

BACKGROUND: Pneumonia caused by carbapenemase-producing Klebsiella pneumoniae (CP-KP) are increasingly encountered in hospitals worldwide, causing high mortality due to lack of treatment options. The goal of this study was to assess the efficacy of tigecycline and minocycline for CP-KP hospital-acquired pneumonia (HAP) by using Monte Carlo simulation. METHODS: A total of 164 non-duplicated CP-KP strains were collected from sputum or blood in patients with HAP. The MICs for antimicrobials were determined by the agar dilution method. A 10,000-patient Monte Carlo Simulation based on a PK/PD model incorporating the MICs and population pharmacokinetic parameters were conducted to calculate probability of target attainment (PTA) at each MIC value and total cumulative fraction of response (CFR). RESULTS: The susceptibility rate of tigecycline and minocycline were 79.9% and 41.5%, respectively. At recommended doses, an optimal PTA of 90% was obtained for treating HAP caused by CP-KP with MICs of tigecycline ≤0.5 mg/L or minocycline ≤4 mg/L. The CFR of tigecycline at the recommended dose and double dose (100 mg q12h) were 71.2% and 90.2%, respectively. The CFR of minocycline at recommended dose and double dose (200 mg q12h) was 53.4% and 77.2%, respectively. CONCLUSIONS: The findings of this study suggest that the recommended dose of tigecycline was not effective in HAP caused by CP-KP, and a higher CFR indicating a better clinical efficacy can be gained by doubling the dose (100 mg q12h). minocycline (200 mg q12h) might be a potential alternative of tigecycline to against strains with MICs ≤ 8 mg/L.

Diagnosis and treatment of community-acquired pneumonia in adults: 2016 clinical practice guidelines by the Chinese Thoracic Society, Chinese Medical Association.

Community-acquired pneumonia (CAP) in adults is an infectious disease with high morbidity in China and the rest of the world. With the changing pattern in the etiological profile of CAP and advances in medical techniques in diagnosis and treatment over time, Chinese Thoracic Society of Chinese Medical Association updated its CAP guideline in 2016 to address the standard management of CAP in Chinese adults. Extensive and comprehensive literature search was made to collect the data and evidence for experts to review and evaluate the level of evidence. Corresponding recommendations are provided appropriately based on the level of evidence. This updated guideline covers comprehensive topics on CAP, including aetiology, antimicrobial resistance profile, diagnosis, empirical and targeted treatments, adjunctive and supportive therapies, as well as prophylaxis. The recommendations may help clinicians manage CAP patients more effectively and efficiently. CAP in pediatric patients and immunocompromised adults is beyond the scope of this guideline. This guideline is only applicable for the immunocompetent CAP patients aged 18 years and older. The recommendations on selection of antimicrobial agents and the dosing regimens are not mandatory. The clinicians are recommended to prescribe and adjust antimicrobial therapies primarily based on their local etiological profile and results of susceptibility testing, with reference to this guideline.

Macrolide-resistant Mycoplasma pneumoniae prevalence and clinical aspects in adult patients with community-acquired pneumonia in China: a prospective multicenter surveillance study.

BACKGROUND: Drug resistant Mycoplasma pneumoniae (MP) is a rising issue in the management of community-acquired pneumonia (CAP). Epidemiological monitoring is essential for identifying resistant patterns of MP isolates against various antibiotics in adult CAP patients. METHODS: This is a prospectively designed multicenter study conducted on adult patients with CAP visiting six teaching hospitals in the cities of Beijing, Shanghai and Guangzhou between September 2010 and June 2012. RESULTS: A total of 520 adult patients (mean age: 45.7±26.2 years) with CAP visiting teaching hospitals in the cities of Beijing, Shanghai and Guangzhou were included. Of the 520 patients, only 75 (14.42%) were confirmed MP positive by means of culture and real-time PCR methods. Quinolones were the most common initially prescribed antimicrobial, followed by ß-lactams and ß-lactams plus quinolones. Macrolide resistance was as high as 80% and 72% against erythromycin (ERY) and azithromycin (AZM) respectively, which were associated with the A2063G transition mutation in domain V of the 23S ribosomal RNA (rRNA) gene. Six strains with mild to moderate ERY-resistant level were still susceptible to AZM. Tetracycline (TET), minocycline (MIN) and quinolones [moxifloxacin (MOX) and fluoroquinolones] had no signs of resistance. CONCLUSIONS: High resistance was observed with macrolides, whereas, none of the MP strains were resistant to fluoroquinolones and TET. Hence, macrolide resistant MP (MRMP)_infections could be well treated with fluoroquinolones. However, few isolated strains had minimal inhibitory concentration (MIC) values on the edge of resistance to quinolones, alarming a quinolone-resistant MP in the near future.

Penetration of Ciprofloxacin and Amikacin into the Alveolar Epithelial Lining Fluid of Rats with Pulmonary Fibrosis.

We determined the concentration-time profiles of ciprofloxacin and amikacin in serum and alveolar epithelial lining fluid (ELF) of rats with or without pulmonary fibrosis and investigated the effect of pulmonary fibrosis on the capacity for penetration of antimicrobials into the ELF of rats. Pulmonary fibrosis was induced in rats with a single intratracheal instillation of bleomycin. After intravenous injection of ciprofloxacin or amikacin, blood and bronchoalveolar lavage fluid samples were collected. Urea concentrations in serum and lavage fluid were determined using an enzymatic assay. Ciprofloxacin and amikacin concentrations were determined by high-performance liquid chromatography and liquid chromatography-tandem mass spectrometry, respectively. The mean ratio of ELF to plasma concentrations of ciprofloxacin at each time point in the normal group did not significantly differ from that in the pulmonary fibrosis group. However, the ratio of the ciprofloxacin area under the concentration-time curve from 0 to 24 h (AUC0-24) in ELF to the AUC0-24 in plasma was 1.02 in the normal group and 0.76 in the pulmonary fibrosis group. The mean ELF-to-plasma concentration ratios of amikacin at each time point in the normal group were higher than those in the pulmonary fibrosis group, reaching a statistically significant difference at 1, 2, and 4 h. The ratio of the AUC0-24 in ELF to the AUC0-24 in plasma was 0.49 in the normal group and 0.27 in the pulmonary fibrosis group. In conclusion, pulmonary fibrosis can influence the penetration of antimicrobials into the ELF of rats and may have a marked effect on the penetration of amikacin than that of ciprofloxacin.

Serum soluble urokinase-type plasminogen activator receptor as a biological marker of bacterial infection in adults: a systematic review and meta-analysis.

The serum concentration of soluble urokinase-type plasminogen activator receptor (suPAR) reflects immune activation. We performed a meta-analysis to evaluate the usefulness of suPAR for the diagnosis and prognosis of bacterial infections. PubMed, Embase and Cochrane Library databases were searched for studies reporting the detection of suPAR in adult patients with bacterial infections. Seventeen studies were selected from 671 studies. The pooled sensitivity and specificity of suPAR for diagnosing infection were 0.73 and 0.79, respectively, and the area under the summary receiver operating characteristic curve (AUC) was 0.82. Subgroup analyses revealed suPAR showed similar AUC values for diagnosing sepsis and bacteremia, but the AUC for differentiating sepsis from systemic inflammatory response syndrome (SIRS) was only 0.68. Elevated suPAR levels were significantly associated with a high risk of death, with a pooled risk ratio of 3.37 (95% confidence interval, 2.60-4.38). The pooled sensitivity and specificity for predicting mortality were 0.70 and 0.72, respectivfely, with an AUC of 0.77. Serum suPAR could be a biomarker for the diagnosis and prognosis of bacterial infection, but it is relatively ineffective for differentiating sepsis from SIRS. Further investigation is required to evaluate whether using of suPAR in combination with other biomarkers can improve diagnostic efficacy.

Surveillance of Dihydropteroate Synthase Genes in Stenotrophomonas maltophilia by LAMP: Implications for Infection Control and Initial Therapy.

Stenotrophomonas maltophilia is a common nosocomial pathogen that causes high morbidity and mortality. Because of its inherent extended antibiotic resistance, therapeutic options for S. maltophilia are limited, and sulfamethoxazole/trimethoprim (SXT) is the only first-line antimicrobial recommended. However, with the spread of dihydropteroate synthase (sul1 and sul2) genes, global emergence of SXT resistance has been reported. There is an urgent need to develop a rapid and sensitive but cost-efficient method to monitor the dissemination of sul genes. In this study, we developed loop-mediated isothermal amplification (LAMP) assays for sul1 and sul2 using real-time turbidity and hydroxy naphthol blue coloration methods. The assays could quickly detect sul genes with high sensitivity and specificity. The LAMP detection limit was 0.74 pg/reaction of extracted genomic DNA for sul1 and 2.6 pg/reaction for sul2, which were both 10-fold more sensitive than the corresponding traditional PCR assays. Additionally, the LAMP assays could positively amplify DNA from sul1-producing strains, but not from the negative controls. We then used the LAMP assays to investigate the dissemination of sul genes among S. maltophilia isolates from patients in three hospitals in Beijing, China. Among 450 non-duplicated samples collected during 2012-2014, 56 (12.4%) strains were SXT-resistant. All these SXT-resistant strains were positive for sul genes, with 35 (62.5%) carrying sul1, 17 (30.4%) carrying sul2, and 4 (7.1%) carrying both sul1 and sul2, which indicated that sul genes were the predominant resistance mechanism. Of 394 SXT-susceptible strains, 16 were also sul-positive. To provide epidemiological data for the appropriate choice of antimicrobials for treatment of sul-positive S. maltophilia, we further tested the susceptibility to 18 antimicrobials. Among these, sul-positive strains showed the highest susceptibility to tetracycline derivatives, especially minocycline (MIC50/MIC90, 0.5/4; susceptibility rate, 95.4%). Ticarcillin-clavulanate and new fluoroquinolones (moxifloxacin and levofloxacin) also showed some in vitro activity. Apart from these three kinds of antimicrobials, other agents showed poor activity against sul-positive strains.

A randomized, open, multicenter clinical study on the short course of intravenous infusion of 750 mg of levofloxacin and the sequential standard course of intravenous infusion/oral administration of 500 mg of levofloxacin for treatment of community-acquired pneumonia.

BACKGROUND: To compare 5-day regimen of levofloxacin 750 mg IV daily with 7-14-day conventional regimen of levofloxacin 500 mg intravenous to oral (IV/PO) daily for treatment of community-acquired pneumonia (CAP) in Chinese population. METHODS: This was a non-inferiority study to assess the difference of clinical efficacy at the end of treatment (EOT) between two regimens. Adult CAP patients with CURB-65 score 0-2 were enrolled from 17 hospitals in China from November 2012 to July 2014. The subjects were randomized into levofloxacin 750 or 500 mg group and the clinical data were collected. Sputum and blood specimens were sent for bacterial culture. The urinary antigen of Streptococcus pneumoniae (S. pneumoniae) was detected as well. At EOT, the clinical efficacy (primary endpoint), microbiological efficacy and safety were evaluated. RESULTS: A total of 457 patients were enrolled. Intent-to-treat (ITT) for primary endpoint analysis and per-protocol set (PPS) populations were 448 and 427 patients respectively. The therapeutic durations were 4.86 and 10.35 days and the mean drug exposure was 3,641.4 and 5,169.6 mg in 750 and 500 mg groups respectively. The clinical efficacy rate was 91.40% (202/221) in 750 mg group and 94.27% (214/227) in 500 mg group (ITT, P=0.2449). The difference in clinical efficacy rate was -2.87 (95% CI: -7.64, 1.90) between the two groups. The non-inferiority hypothesis of two groups was tenable (Δ=10%). The bacterial eradication rate was 100.00% in both groups. The most common drug-related clinical adverse events were injection site and gastrointestinal reactions. The most common drug-related laboratory abnormalities were WBC decrease and ALT/AST elevation. No statistical difference was found between two groups (P>0.05). CONCLUSIONS: The 5-day regimen of levofloxacin 750 mg daily is non-inferior to 7-14-day conventional regimen of 500 mg daily in clinical efficacy for treatment of mild to moderate Chinese CAP population. The short course regimen allows the reduction of antimicrobial drug exposure and is well tolerated.

Tigecycline-Amikacin Combination Effectively Suppresses the Selection of Resistance in Clinical Isolates of KPC-Producing Klebsiella pneumoniae.

By far, only tigecycline, colistin, and some aminoglycosides still show favorable in vitro activities against carbapenem-resistant Enterobacteriaceae. However, rapid emergence of resistance often occurs during long-term treatment in clinic, challenging these last resort antimicrobials. In this study, we measured mutant prevention concentration (MPC) and mutant selection window (MSW) of tigecycline, colistin and amikacin alone and in combination for clinical isolates of KPC-producing K. pneumoniae, and characterized the resistant mutants recovered. The MPC90 of 30 tested isolates for tigecycline, colistin, and amikacin were 16, >128, and 128 mg/L, respectively. The average MSW of tigecycline-amikacin, tigecycline-colistin, and amikacin-colistin combinations for four representative strains were 11.99, 200.13, and 372.38, respectively. A strong correlation was found between the MSW combination and the product of MSW of each single drug. Combinations of 1 minimal inhibitory concentration (MIC) multiple tigecycline and 1 MIC multiple amikacin could result in 1000- to 10000-fold reduction in mutational frequency relative to their individual mutational frequencies, and combinations of 1 MIC multiple amikacin and 1.5-2 MIC multiple tigecycline could successfully restrict the recovery of resistant mutants on agar plates. However, 2 MIC multiple colistin in combination with 2 MIC multiple tigecycline or amikacin merely resulted in approximately 10-fold decrease in the mutational frequency. In conclusion, this study showed tigecycline-amikacin combination could effectively suppress the selection of resistance at low concentrations compared with the colistin-tigecycline and colistin-amikacin combinations, suggesting that this combination may be useful in clinical therapy.

Therapeutic drug monitoring of vancomycin: a guideline of the Division of Therapeutic Drug Monitoring, Chinese Pharmacological Society.

BACKGROUND: Guideline development should be based on the quality of evidence, balance of benefits and harms, economic evaluation and patients' views and preferences. Therefore, these factors were considered in the development of a new guideline for therapeutic drug monitoring (TDM) of vancomycin. OBJECTIVES: To develop an evidence-based guideline for vancomycin TDM and to promote standardized vancomycin TDM in clinical practice in China. METHODS: We referred to the WHO Handbook for Guideline Development and used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system to rate the quality of evidence and grade the strength of recommendations, according to economic evaluation and patients' views and preferences. We used the GRADE Grid method to formulate the recommendations. RESULTS: The guideline presents recommendations about who should receive vancomycin TDM, how to monitor vancomycin efficacy and renal safety, therapeutic trough concentrations, time to start initial vancomycin TDM, loading dose and how to administer and adjust the vancomycin dose. CONCLUSIONS: We developed an evidence-based guideline for vancomycin TDM, which provides recommendations for clinicians and pharmacists to conduct vancomycin TDM in China.

Effects of Efflux Pump Inhibitors on Colistin Resistance in Multidrug-Resistant Gram-Negative Bacteria.

We tested the effects of various putative efflux pump inhibitors on colistin resistance in multidrug-resistant Gram-negative bacteria. Addition of 10 mg/liter cyanide 3-chlorophenylhydrazone (CCCP) to the test medium could significantly decrease the MICs of colistin-resistant strains. Time-kill assays showed CCCP could reverse colistin resistance and inhibit the regrowth of the resistant subpopulation, especially in Acinetobacter baumannii and Stenotrophomonas maltophilia These results suggest colistin resistance in Gram-negative bacteria can be suppressed and reversed by CCCP.

Tigecycline Treatment for Carbapenem-Resistant Enterobacteriaceae Infections: A Systematic Review and Meta-Analysis.

Carbapenem-resistant Enterobacteriaceae (CRE) infections are prevalent worldwide; they have few effective treatments and this jeopardizes public health. Clinicians often use tigecycline to combat CRE, but its clinical efficacy remains controversial. Therefore, to compare the efficacy and safety of tigecycline in treating CRE infections compared with that of other antimicrobial agents, and to evaluate whether combination therapy and high-dose regimens are beneficial, we performed a systematic review and meta-analysis. PubMed and Embase were searched for controlled trials or cohort studies reporting the efficacy and/or safety of tigecycline-based regimens to treat CRE infections. Statistical analyses were performed using the Comprehensive Meta-Analysis V2.2. All meta-analyses were performed based on fixed- or random-effects model, and the I method was used to assess heterogeneity. Twenty-one controlled studies and 5 single-arm studies were included in this systematic review. With regard to the controlled studies, the tigecycline groups did not differ significantly from the control groups in terms of overall mortality (Odds ratio (OR) = 0.96 [95% confidence interval (CI) = 0.75-1.22; P = 0.73]), clinical response rate (OR = 0.58 [95% CI = 0.31-1.09; P = 0.09]), or microbiological response rate (OR = 0.46 [95% CI = 0.15-1.44; P = 0.18]). Subgroup analyses showed that 30-day mortality was significantly lower in patients who received tigecycline combination therapy than in those who received monotherapy (OR = 1.83 [95% CI = 1.07-3.12; P = 0.03]) and other antibiotic regimens (OR = 0.59 [95% CI = 0.39-0.88; P = 0.01]), respectively. In addition, high-dose tigecycline regimens differed significantly from standard dose schedules in terms of ICU mortality (OR = 12.48 [95% CI = 2.06-75.43; P = 0.006]). The results of the 5 single-arm studies corroborated the findings of the controlled studies. Our results indicated that the efficacy of tigecycline in treating CRE infections is similar to that of other antibiotics. Tigecycline combination therapy and high-dose regimens may be more effective than monotherapy and standard-dose regimens, respectively. Nonetheless, considering that the current available evidence is limited, well-designed randomized controlled trials are urgently needed to clarify the comparative efficacy of tigecycline in treating CRE infections.

Tigecycline treatment experience against multidrug-resistant Acinetobacter baumannii infections: a systematic review and meta-analysis.

The role of tigecycline in treating multidrug-resistant Acinetobacter baumannii (MDR-AB) infections remains controversial. A systematic review and meta-analysis was performed to assess the efficacy and safety of tigecycline in treating MDR-AB infections. PubMed, Embase and Cochrane Library databases were searched up to 20 September 2015. Studies evaluating the efficacy and/or safety of tigecycline in treating MDR-AB infections were included. PRISMA guidelines were followed and the I(2) method was used for heterogeneity. Seven controlled and seventeen single-arm studies were included. No significant difference was noted when tigecycline was compared with control groups in terms of all-cause mortality (OR=0.87, 95% CI 0.50-1.52; P=0.63) and clinical response (OR=1.58, 95% CI 0.61-4.05; P=0.34). Subgroup analysis indicated that treatment with tigecycline was associated with higher in-hospital mortality (OR=1.57, 95% CI 1.04-2.35; P=0.03). Compared with controls, tigecycline had a significantly lower microbial eradication rate (OR=0.20, 95% CI 0.07-0.59; P=0.003) and trend for longer hospital stay (mean difference, 4.69 days, 95% CI -0.17 to 9.55 days; P=0.06). In comparison with monotherapy, tigecycline combination therapy did not affect mortality, clinical response or microbiological response. Tigecycline was well tolerated in the patient populations studied. The pooled rates of resistance emergence and superinfection during treatment were 12.47% and 19.11%, respectively. These findings disfavour the use of a tigecycline-based regimen for the treatment of MDR-AB infections. Well-designed RCTs are needed to clarify the role of tigecycline for MDR-AB infections.

The accuracy of presepsin (sCD14-ST) for the diagnosis of sepsis in adults: a meta-analysis.

INTRODUCTION: The early diagnosis of sepsis remains a challenge. Recently, soluble cluster of differentiation 14 subtype (sCD14-ST), also known as presepsin, has been identified as a potential biomarker of sepsis. We performed a meta-analysis to assess the diagnostic accuracy of presepsin for sepsis in patients with systemic inflammation. METHODS: We systematically searched the PubMed, Embase, Web of Knowledge and Cochrane databases. Studies were included if they assessed the diagnostic accuracy of presepsin for sepsis in adult patients with systemic inflammatory response syndrome (SIRS). Furthermore, a 2 × 2 contingency table was constructed based on these results. Two authors independently judged the studies and extracted the data. The diagnostic accuracy of presepsin in sepsis was calculated using a bivariate meta-analysis model. The Q-test and I (2) index were used to test the heterogeneity. RESULTS: Eight studies involving a total of 1,815 patients were included in the present study. The pooled sensitivity, specificity, diagnostic odds ratio, positive likelihood ratio and negative likelihood ratio were 0.86 (95% CI: 0.79-0.91), 0.78 (95% CI: 0.68-0.85), 22 (95% CI: 10-48), 3.8 (95% CI: 2.6-5.7), and 0.18 (95% CI: 0.11-0.28), respectively. The area under the summary receiver operator characteristic curve was 0.89 (95% CI: 0.86-0.92). Meta-regression analysis revealed that consecutive patient selection, sample size and setting significantly accounted for the heterogeneity of sensitivity. CONCLUSIONS: Our findings suggest that presepsin exhibits very good diagnostic accuracy (AUC=0.89) for the diagnosis for sepsis. Nevertheless, an overall assessment of all the clinical indexes for sepsis diagnosis and continual re-evaluation of presepsin during the course of the disease are needed.