Junchang Cui

The Mutant Selection Window in Rabbits Infected with Staphylococcus aureus

BACKGROUND The mutant selection window hypothesis, originally based on agar plate assays, may lead to new antimicrobial dosing strategies that severely restrict the acquisition of resistance. However, it has not been directly tested in an animal model of infection. METHODS Local infection with Staphylococcus aureus was established in rabbits, and the infected animals were treated orally with various doses of levofloxacin. Changes in levofloxacin concentration, levofloxacin susceptibility, and counts of total and resistant viable bacteria were monitored at the site of infection. RESULTS S. aureus lost levofloxacin susceptibility when drug concentrations at the site of infection fluctuated between the lower and upper boundaries of the window, defined in vitro as the minimum inhibitory concentration (MIC)(99) and the mutant prevention concentration (MPC), respectively. The upper boundary of the selection window in vivo was estimated as an AUC(24)/MPC value of ~25 h, where AUC(24) is the area under the drug concentration time curve in a 24-h interval. The lower boundary was estimated as an AUC(24)/MIC value of ~20 h. CONCLUSIONS The mutant selection window exists in vivo, and its boundaries fit well with those determined in vitro. Maintenance of antimicrobial concentrations above the window is expected to suppress the outgrowth of resistant mutant subpopulations.

In vitro synergy of polymyxins with other antibiotics for Acinetobacter baumannii: A systematic review and meta-analysis

In order to provide preliminary guidance for rational antibiotic combination therapy in the clinic, a systematic review and meta-analysis was performed to evaluate the in vitro synergistic activity of polymyxins combined with other antibiotics against Acinetobacter baumannii. An extensive literature search was undertaken without restriction according to region, publication type or language. All available in vitro synergy tests on antibiotic combinations consisting of polymyxins were included. The primary outcome assessed was the in vitro activity of combination therapy on bacterial kill or inhibition. In total, 70 published studies and 31 conference proceedings reporting testing of polymyxins in combination with 11 classes consisting of 28 antibiotic types against 1484 A. baumannii strains were included in the analysis. In time-kill studies, high in vitro synergy and bactericidal activity were found for polymyxins combined with several antibiotic classes such as carbapenems and glycopeptides. Carbapenems or rifampicin combination could efficiently suppress the development of colistin resistance and displayed a >50% synergy rate against colistin-resistant strains. Synergy rates of chequerboard microdilution and Etest methods in most antibiotic combinations were generally lower than those of time-kill assays. The benefits of these antibiotic combinations should be further demonstrated by well-designed clinical studies.

Prophylactic Use of Macrolide Antibiotics for the Prevention of Chronic Obstructive Pulmonary Disease Exacerbation: A Meta-Analysis

Background Acute exacerbations of chronic obstructive pulmonary disease (AECOPDs) can lead to high frequencies and rates of hospitalization and mortality. Macrolides are a class of antibiotics that possess both antimicrobial and anti-inflammatory properties. Since the occurrence of AECOPDs is associated with aggravation of airway inflammation and bacterial infections, prophylactic macrolide treatment may be an effective approach towards the prevention of AECOPDs. Methods We systemically searched the PubMed, Embase and Cochrane Library databases to identify randomized controlled trials (RCTs) that evaluated the effect of prophylactic macrolide therapy on the prevention of AECOPDs. The primary outcomes were the total number of patients with one or more exacerbations as well as the rate of exacerbations per patient per year. Results Nine RCTs comprising 1666 patients met the inclusion criteria. Pooled evidence showed macrolides could reduce the frequency of exacerbations in patients with COPD by both unweighted (RR = 0.70; 95% CI: 0.56–0.87; P < 0.01) and weighted approaches (RR = 0.58, 95% CI: 0.43–0.78, P < 0.01). Subgroup analysis showed only 6–12 months of erythromycin or azithromycin therapy could be effective. Moreover, among studies with 6–12 months of azithromycin therapy, both the daily dosing regimen and the intermittent regimen significantly reduced exacerbation rates. The overall number of hospitalizations and the all-cause rate of death were not significantly different between the treatment and control groups. A tendency for more adverse events was found in the treatment groups (OR = 1.55, 95%CI: 1.003–2.39, P = 0.049). Conclusions Our results suggest 6-12 months erythromycin or azithromycin therapy could effectively reduce the frequency of exacerbations in patients with COPD. However, Long-term treatment may bring increased adverse events and the emergence of macrolide-resistance. A recommendation for the prophylactic use of macrolide therapy should weigh both the advantages and disadvantages.

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.

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

ABSTRACT 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.

In vitro effects of tigecycline in combination with colistin (polymyxin E) and sulbactam against multidrug-resistant Acinetobacter baumannii

The lack of active antimicrobial agents against multidrug-resistant (MDR) Acinetobacter baumannii has posed great threat to the public health. Combination therapies with antibiotics owning different antimicrobial mechanisms have been proposed as good options for treating MDR A. baumannii infections. This study was aimed to investigate the in vitro effects of tigecycline in combination with colistin and sulbactam against MDR A. baumannii. A total of 70 strains from two hospitals in China were examined in the study. The checkerboard method was used for determining synergistic activity of different antibiotic combinations. Tigecycline/colistin combination displayed synergistic and partial synergistic activity in 24.3% of the isolates, whereas the tigecycline/sulbactam combination showed synergistic and partial synergistic activity in 64.3% of the isolates. Neither of the combinations showed antagonism in this study. In addition, for evaluating the ability of combinations on resistance prevention, mutant prevention concentrations (MPCs) of tigecycline, colistin, sulbactam alone and tigecycline in combination with colistin and sulbactam were studied against MDR A. baumannii. Compared with tigecycline used alone, combination therapies could achieve lower MPCs of tigecycline. However, when the MPCs of dual-drug therapy were in conjunction with clinical pharmacokinetic profiles, combinations may not strictly curb the occurrence of resistance at current dosage regimen. In summary, this study suggested that combination therapy was a good option for treating MDR A. baumannii infections. But the finding that combination with these drugs at current dosage regimen may not prevent emergence of resistance warranted further studies on dosage of combined antibiotics required for achieving resistance prevention.

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

AbstractCarbapenem-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 I2 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.

Evaluation of Trimethoprim/Sulfamethoxazole (SXT), Minocycline, Tigecycline, Moxifloxacin, and Ceftazidime Alone and in Combinations for SXT-Susceptible and SXT-Resistant Stenotrophomonas maltophilia by In Vitro Time-Kill Experiments.

Background The optimal therapy for infections caused by Stenotrophomonas maltophilia (S. maltophilia) has not yet been established. The objective of our study was to evaluate the efficacy of trimethoprim/sulfamethoxazole (SXT), minocycline, tigecycline, moxifloxacin, levofloxacin, ticarcillin-clavulanate, polymyxin E, chloramphenicol, and ceftazidime against clinical isolated S. maltophilia strains by susceptibility testing and carried out time-kill experiments in potential antimicrobials. Methods The agar dilution method was used to test susceptibility of nine candidate antimicrobials, and time-killing experiments were carried out to evaluate the efficacy of SXT, minocycline, tigecycline, moxifloxacin, levofloxacin, and ceftazidime both alone and in combinations at clinically relevant antimicrobial concentrations. Results The susceptibility to SXT, minocycline, tigecycline, moxifloxacin, levofloxacin, ticarcillin-clavulanate, chloramphenicol, polymyxin E, and ceftazidime were 93.8%, 95.0%, 83.8%, 80.0%, 76.3%, 76.3%, 37.5%, 22.5%, and 20.0% against 80 clinical consecutively isolated strains, respectively. Minocycline and tigecycline showed consistent active against 22 SXT-resistant strains. However, resistance rates were high in the remaining antimicrobial agents against SXT-resistant strains. In time-kill experiments, there were no synergisms in most drug combinations in time-kill experiments. SXT plus moxifloxacin displayed synergism when strains with low moxifloxacin MICs. Moxifloxacin plus Minocycline and moxifloxacin plus tigecycline displayed synergism in few strains. No antagonisms were found in these combinations. Overall, compared with single drug, the drug combinations demonstrated lower bacterial concentrations. Some combinations showed bactericidal activity. Conclusions In S. maltophilia infections, susceptibility testing suggests that minocycline and SXT may be considered first-line therapeutic choices while tigecycline, moxifloxacin, levofloxacin, and ticarcillin-clavulanate may serve as second-line choices. Ceftazidime, colistin, and chloramphenicol show poor active against S. maltophilia. However, monotherapy is inadequate in infection management, especially in case of immunocompromised patients. Combination therapy, especially SXT plus moxifloxacin, may benefit than monotherapy in inhibiting or killing S. maltophilia.

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.

Treatment of community-acquired pneumonia with moxifloxacin: a meta-analysis of randomized controlled trials

Abstract Community-acquired pneumonia (CAP) is a leading cause of morbidity and mortality throughout the world. To investigate whether moxifloxacin monotherapy is associated with better clinical outcomes than other antibiotics recommended for CAP among adults with mild-to-moderate or severe CAP, we performed a meta-analysis. MEDLINE, EMBASE, Web of Science, and the Cochrane Library were searched for randomized control trials (RCTs). The efficacy and safety of moxifloxacin were compared with other antimicrobial agents used to treat CAP. Fourteen RCTs, consisting of 6923 total patients, were included in the meta-analysis. No difference was found regarding the incidence of adverse events and mortality between moxifloxacin and the compared regimens. We found that moxifloxacin is as effective and well-tolerated as other recommended antibiotics for the treatment of CAP and possesses a better pathogen eradication rate than beta-lactam-based therapy.