H2S-driven chemotherapy and mild photothermal therapy induced mitochondrial reprogramming to promote cuproptosis.

The elevated level of hydrogen sulfide (H2S) in colon cancer hinders complete cure with a single therapy. However, excessive H2S also offers a treatment target. A multifunctional cascade bioreactor based on the H2S-responsive mesoporous Cu2Cl(OH)3-loaded hypoxic prodrug tirapazamine (TPZ), in which the outer layer was coated with hyaluronic acid (HA) to form TPZ@Cu2Cl(OH)3-HA (TCuH) nanoparticles (NPs), demonstrated a synergistic antitumor effect through combining the H2S-driven cuproptosis and mild photothermal therapy. The HA coating endowed the NPs with targeting delivery to enhance drug accumulation in the tumor tissue. The presence of both the high level of H2S and the near-infrared II (NIR II) irradiation achieved the in situ generation of photothermic agent copper sulfide (Cu9S8) from the TCuH, followed with the release of TPZ. The depletion of H2S stimulated consumption of oxygen, resulting in hypoxic state and mitochondrial reprogramming. The hypoxic state activated prodrug TPZ to activated TPZ (TPZ-ed) for chemotherapy in turn. Furthermore, the exacerbated hypoxia inhibited the synthesis of adenosine triphosphate, decreasing expression of heat shock proteins and subsequently improving the photothermal therapy. The enriched Cu2+ induced not only cuproptosis by promoting lipoacylated dihydrolipoamide S-acetyltransferase (DLAT) heteromerization but also performed chemodynamic therapy though catalyzing H2O2 to produce highly toxic hydroxyl radicals ·OH. Therefore, the nanoparticles TCuH offer a versatile platform to exert copper-related synergistic antitumor therapy.

Soft wetting: Substrate softness- and time-dependent droplet/bubble adhesion.

HYPOTHESIS: The droplet/bubble adhesion characteristics depend on the length of the droplet/bubble three-phase contact line. Since the deformation caused by the liquid-gas interfacial tension on the soft substrate, referred as to the wetting ridge, retards contact line spreading and retraction, we conjecture that the droplet/bubble adhesion characteristics depend also on the substrate softness. EXPERIMENTS: Soft substrates with various shear moduli are prepared and characterized by the spreading and receding dynamics of water droplets and underwater bubbles. Snap-in and normal adhesion forces of droplets/bubbles on such soft substrates are directly measured along with the visualized droplet/bubble shape profiles. FINDINGS: The droplet/bubble snap-in force, which corresponds to the short-time spreading dynamics, decreases with a decrease in the substrate shear modulus because of the retarded contact line spreading. The droplet maximal adhesion force on a soft substrate can be counterintuitively either smaller or larger than its counterpart on the rigid substrate depending on different dwelling times, i.e., the droplet/bubble-substrate contact time before droplet/bubble-substrate separation. The former is attributed to the retarded contact line spreading, whereas the latter is attributed to the retarded contact line retraction. The substrate softness- and dwelling time-dependent droplet/bubble adhesion reported in this study will benefit various applications related to soft substrates.

A Superhydrophobicity-Slipperiness Switchable Surface with Magneto- and Thermo-responsive Wires for Repelling Complex Droplets.

The inefficacy of repelling water droplets laden with macromolecules (complex droplets or diluted polymer solution) is a long-standing shortcoming of superhydrophobic surfaces, which severely limits their reliability in practical applications. Here, we design a surface termed the superhydrophobicity-slipperiness switchable surface (3S surface), which demonstrates superhydrophobicity at room temperature and slipperiness when heated. The 3S surface is composed of magneto-responsive wires coated with superhydrophobic nanoparticles and impregnated with thermoresponsive paraffin, exhibiting lotus leaf-inspired passive water repellency and respiratory cilia-inspired active water repellency at room temperature. When heated, the impregnated paraffin melts and forms a lubricant layer atop the surface structures, exhibiting the pitcher-plant-inspired removal of complex droplets that remain pinned on conventional superhydrophobic surfaces. The counterintuitive integration of superhydrophobicity (a liquid-solid-gas composite system) and slipperiness (a liquid-lubricant-gas system) into a surface and the on-demand switch between them are not only important to the applicability of self-cleaning surfaces to real-world environments, where complex liquids are inevitable, but also provide insights into various interface-related applications.

A chemodynamic nanoenzyme with highly efficient Fenton reaction for cancer therapy.

Chemodynamic therapy (CDT) is a rising technology for cancer therapy by converting intracellular hydrogen peroxide (H2O2) into hydroxyl radical (•OH) via transition-metal-containing nanoparticles (NPs) catalysis reaction (i.e. Fenton reaction) to kill tumor cells. Highly efficient Fenton reaction and favorable delivery of the catalytic NPs 'nanoenzyme' are the key for successful treatment of cancer. In this work, we developed a novel nanoenzyme MnFe2O4@GFP forin vitroandin vivoantitumor therapy. A new MnFe2O4nanoparticle containing two transition-metal-element Fe and Mn was synthesized for enhanced Fenton reaction and used to co-deliver protein with high biocompatibility through post-modification with dopamine polymerization, green fluorescent protein adsorption, and PEG coating. The enrichment of H2O2and glutathione (GSH) in tumor tissue provided a favorable microenvironment forin situgeneration of toxic free radicals. Fe3+and GSH triggered a redox reaction to produce Fe2+, which in turn catalyzed H2O2into •OH, with the consumption of antioxidant GSH. By combining Fe3+with another catalyzer, the catalytic efficiency of the nanoenzyme were greatly improved. Consequently, the nanoenzyme showed efficient antitumor ability bothin vitroandin vivo. Thus, the multifunctional CDT nanoenzyme platform shows great promising for antitumor therapy through the combination of catalyzers Fe3+and Mn2+and codelivery of protein cargo.

Bioinspired Wire-on-Pillar Magneto-Responsive Superhydrophobic Arrays.

Versatile surfaces demonstrating multiple interfacial functionalities are highly demanded as a surface typically serves various duties and faces multiple challenges in real practice. However, such versatile surfaces are rarely reported mainly due to the challenges in integrating multiple structural characteristics. Here, by mimicking lotus leaves, butterfly wing, and respiratory cilia, we develop a surface termed wire-on-pillar magneto-responsive superhydrophobic arrays (WP-MRSA), which possess interfacial properties of structural superhydrophobicity, anisotropicity, stimuli responsiveness, and flexibility. By combining soft lithography and self-alignment of iron-laden aerosols under a magnetic field, iron-laden wires are planted atop prefabricated pillar arrays, resulting in well-ordered, sparse, high-aspect-ratio, flexible, and superhydrophobic wires, which largely deflect in response to a magnetic field. This unique integration of structural properties and configurations enables various functionalities, such as on-demand control of droplet impact dynamics, real-time regulation of surface lateral adhesion force, fast removal and sorting of objects, and precise manipulation of droplets for selective reactions. Those functionalities benefit various applications especially droplet-based microfluidics and active self-cleaning surfaces.

Birt-Hogg-Dubé syndrome with c.1579_1580insA variant in a Chinese family: a case report.

Birt-Hogg-Dubé (BHD) syndrome, is a rare genetic disease with heterogeneous manifestations in different populations. In this study, we reported a Chinese female BHD case and her family members with c.1579_1580insA variant in FLCN gene, who were characterized by diffused pulmonary cysts/bulla, and reviewed another five familial BHD cases in China. Based on these cases, recurrent spontaneous pneumothorax is likely to be the first symptom for BHD in Chinese patients, with particularly but not limited to c.1579_1580insA variant. Therefore, attention to the early diagnosis of BHD in China should focus on pulmonary signs, but skin or kidney lesions still can not be neglected.

Molecular characterization of pulmonary defenses against bacterial invasion in allergic asthma: The role of Foxa2 in regulation of ß-defensin 1.

Allergic asthma, characterized by chronic airway Th2-dominated inflammation, is associated with an increased risk of infection; however, the underlying mechanisms are unclear. Forkhead box protein A2 (Foxa2) plays a critical role in Th2 inflammation and is associated with pulmonary defenses. To determining the role of Foxa2 in Th2-dominated lung inflammation against the invading bacteria, we established a mouse OVA-sensitized model, an Escherichia coli lung invasion model, and mice with conditional deletion of Foxa2 in respiratory epithelial cells. The number of bacteria in the lung tissue was counted to assess clearance ability of lung. Lung inflammation and histopathology was evaluated using HE and PAS staining. It was found that OVA-sensitized mice had decreased E. coli clearance, reduced Foxa2 expression, and decreased DEFB1 secretion. Conditional deletion of Foxa2 in respiratory epithelial cells led to decreased clearance of E. coli and impaired secretion of DEFB1, similar to the OVA-induced allergic condition. The impaired secretion of DEFB1 may be responsible for the increased risk of infection in the Th2-dominated airway inflammation. Dual luciferase assay demonstrated that Foxa2 regulates DEFB1 expression by affecting its promoter activity in HBE cells. Our study indicated that Foxa2 plays an important role in Th2-dominated airway inflammation against invading bacteria. Conditional deletion of Foxa2 in respiratory epithelial cells can reduce pulmonary's defense against bacterial invasion by inhibiting DEFB1expression.

A Higher Rate of Pulmonary Fungal Infection in Chronic Obstructive Pulmonary Disease Patients with Influenza in a Large Tertiary Hospital.

BACKGROUND: Influenza is considered a self-limiting disease. However, in patients with chronic obstructive pulmonary disease (COPD), it may result in serious outcomes during the flu season. OBJECTIVES: The aims of this retrospective study were to explore the characteristics of hospitalized patients with COPD complicated by influenza and determine the factors affecting the prognosis of these patients. METHOD: Demographic and clinical data were collected for 278 patients totally from the West China Hospital between January 1, 2016 and February 28, 2018. RESULTS: Among the patients with influenza, the positive fungal culture rate, and the rates of antifungal drug and systemic corticosteroids use were higher for those with COPD than for those without COPD. Respiratory failure was more common in patients with influenza and COPD than in patients with influenza only, while the proportion of severe cases was higher among the former than among the latter. Among the patients with COPD, the positive fungal culture rate, particularly for Aspergillus, and the rate of systemic corticosteroids use were higher for those with influenza than for those without influenza. Multivariate analysis revealed that a COPD history of >20 years and smoking for >20 pack-years were independent factors for susceptibility of COPD patients to influenza. CONCLUSIONS: Aspergillus infection seems to be more common in patients with influenza and COPD. In addition, COPD complicated by influenza during the seasonal outbreak can easily progress to a severe disease state. Heavy smokers and patients with a prolonged COPD history are more likely to be infected by influenza.

Dupilumab treatment in moderate-to-severe atopic dermatitis: A systematic review and meta-analysis.

BACKGROUND: Dupilumab, a fully human monoclonal antibody against the interleukin-4-receptor α subunit, has been developed and used in clinical trials to treat atopic dermatitis (AD). OBJECTIVE: We aimed to assess the overall efficacy and safety of dupilumab treatment in AD. METHODS: PubMed, Embase, Cochrane library databases, and the Chinese Biological Medicine (CBM) published up to September 2017 were searched. All randomized controlled trials (RCTs) of dupilumab treatment on adult patients with AD were included. Fixed- or random-effects models were used to calculate pooled standard mean differences or relative risks (SMD or RR, respectively). RESULTS: Six trials involving 2447 patients were identified. Pooled analysis revealed significant improvements in Eczema Area and Severity Index (EASI) score (SMD = -0.89, 95% CI: -1.0 to -0.78), percentage of body surface area (BSA) (SMD = -0.83, 95% CI: -0.90 to -0.75), pruritus numeric rating scale (NRS) scores (SMD = -0.81, 95% CI: -0.96 to -0.66), and Dermatology Life Quality Index (DLQI) scores (SMD = -0.78, 95% CI: -0.89 to -0.66). Dupilumab treatment was also associated with a significant increase in the proportion of patients achieving Investigator's Global Assessment (IGA) response (RR = 3.82; 95% CI: 3.23 to 4.51) and a similar incidence of adverse events (RR = 1.0; 95% CI: 0.96 to 1.04). CONCLUSIONS: Our analysis provided evidence that dupilumab had an acceptable safety profile and resulted in clinically relevant improvements in signs and symptoms of AD. Dose regimens of 300 mg qw and q2 w seemed to have similar benefits. Further long-term trials are required for confirmation.

Pharmacodynamics of tigecycline alone and in combination with colistin against clinical isolates of multidrug-resistant Acinetobacter baumannii in an in vitro pharmacodynamic model.

The objectives of this study, which were based on the hypothesis of mutant prevention concentration (MPC), were to compare tigecycline and colistin monotherapy and combination therapy against multidrug-resistant Acinetobacter baumannii (MDR-AB) and to identify changes in the susceptibility of the organism using an in vitro pharmacodynamic model. Human free-drug concentration profiles of colistin and tigecycline used alone and in combination were simulated against four clinical MDR-AB isolates over 24 h. Pharmacodynamic activity was measured as log10 CFU/mL and as the area under the bactericidal curve (AUBC). The minimum inhibitory concentration (MIC) for all isolates was determined in triplicate by the broth microdilution method. All isolates grew to control levels in the tigecycline and colistin monotherapy conditions, and the combination of colistin plus tigecycline 100 mg every 12 h (q12h) or 50 mg q12h achieved a greater reduction in bacterial density than colistin alone (-2.65 ± 1.73 or -2.09 ± 1.47 vs. 0.98 ± 0.64 log10 CFU/mL; P <0.01). Likewise, both combinations significantly reduced the AUBC compared with that achieved using colistin alone (106.9 ± 24.5 or 117.7 ± 23.5 vs. 168.1 ± 14.2 log10 CFU⋅h/mL; P <0.05). When tigecycline or colistin monotherapy concentrations were below MPC, tigecycline MICs increased 4-32-fold and colistin MICs increased >16-fold. No loss in susceptibility to tigecycline was found with combination therapy. A combination of tigecycline (high dose) and colistin may be an effective therapy to synergistically prevent the emergence of resistance during treatment of MDR-AB (tigecycline MIC < 2 mg/L) infections.

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.

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.

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.

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.

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.

A Monte Carlo pharmacokinetic/pharmacodynamic simulation to evaluate the efficacy of minocycline, tigecycline, moxifloxacin, and levofloxacin in the treatment of hospital-acquired pneumonia caused by Stenotrophomonas maltophilia.

BACKGROUND: Stenotrophomonas maltophilia has emerged as an important opportunistic pathogen in recent years. Increasing antimicrobial resistance and other contraindications have greatly compromised trimethoprim/sulfamethoxazole (SXT) as the first-line therapeutic option. The objective of this study was to explore other options for treating hospital-acquired pneumonia (HAP) caused by S. maltophilia. METHODS: A total of 102 strains of S. maltophilia were isolated from sputum and bronchoalveolar lavage (BAL) specimens of patients with HAP in our institution. The minimum inhibitory concentration (MIC) values of minocycline, tigecycline, moxifloxacin, and levofloxacin were determined by the agar dilution method. Based on the MICs and the population pharmacokinetic parameters of the investigated antimicrobials, a Monte Carlo simulation was performed to simulate the pharmacokinetic/pharmacodynamic (PK/PD) indices of different regimens. The probability of target attainment (PTA) was estimated at each MIC value and the cumulative fraction of response (CFR) was calculated to evaluate the efficacy of these regimens. RESULTS: The susceptibility rates to minocycline, tigecycline, moxifloxacin, and levofloxacin were 96.1%, 80.4%, 74.5%, and 69.6%, respectively. The estimated CFRs were 96.2% for minocycline 100 mg twice daily; 50.8%/67.1%/75.4% for tigecycline 50/75/100 mg twice daily; 34.3%/48.0%/56.6% for levofloxacin 500/750/1000 mg once daily; and 45.7% for moxifloxacin 400 mg once daily. CONCLUSIONS: The simulation results suggest that minocycline may be a proper choice for treatment of HAP caused by S. maltophilia, while tigecycline, moxifloxacin, and levofloxacin may not be optimal as monotherapy.

Efficacy of polymyxins in the treatment of carbapenem-resistant Enterobacteriaceae infections: a systematic review and meta-analysis

In recent years, carbapenem-resistant Enterobacteriaceae has become endemic in many countries. Because of limited treatment options, the abandoned "old antibiotics", polymyxins, have been reintroduced to the clinic. To evaluate the clinical efficacy of polymyxins in the treatment of infections caused by carbapenem-resistant Enterobacteriaceae, we systemically searched the PubMed, Embase, and Cochrane Library databases and analyzed the available evidence. The Preferred Reporting Items for Systematic reviews and Meta-Analysis statement were followed, and the I2 method was used for heterogeneity. Nineteen controlled and six single-arm cohort studies comprising 1086 patients met the inclusion criteria. For controlled studies, no significant difference was noted for overall mortality (OR, 0.79; 95% CI, 0.58-1.08; p = 0.15), clinical response rate (OR, 1.24; 95% CI, 0.61-2.54; p = 0.55), or microbiolog- ical response rate (OR, 0.59; 95% CI, 0.26-1.36; p = 0.22) between polymyxin-treated groups and the control groups. Subgroup analyses showed that 28-day or 30-day mortality was lower in patients who received polymyxin combination therapy than in those who received monotherapy (OR, 0.36; 95% CI, 0.19-0.68; p < 0.01) and the control groups (OR, 0.49; 95% CI, 0.31-0.75; p < 0.01). The results of the six single-arm studies were in accordance with the findings of controlled studies. One controlled and two single-arm studies that evaluated the occurrence of nephrotoxicity reported a pooled incidence rate of 19.2%. Our results suggest that polymyxins may be as efficacious as other antimicrobial therapies for the treatment of carbapenem-resistant Enterobacteriaceae infection. Compared to polymyxin monotherapy, combination regimens may achieve lower 28-day or 30-day mortality. Future large-volume, well-designed randomized control trials are required to determine the role of polymyxins in treating carbapenem-resistant Enterobacteriaceae infections.

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.

Efficacy of polymyxins in the treatment of carbapenem-resistant Enterobacteriaceae infections: a systematic review and meta-analysis.

In recent years, carbapenem-resistant Enterobacteriaceae has become endemic in many countries. Because of limited treatment options, the abandoned "old antibiotics", polymyxins, have been reintroduced to the clinic. To evaluate the clinical efficacy of polymyxins in the treatment of infections caused by carbapenem-resistant Enterobacteriaceae, we systemically searched the PubMed, Embase, and Cochrane Library databases and analyzed the available evidence. The Preferred Reporting Items for Systematic reviews and Meta-Analysis statement were followed, and the I(2) method was used for heterogeneity. Nineteen controlled and six single-arm cohort studies comprising 1086 patients met the inclusion criteria. For controlled studies, no significant difference was noted for overall mortality (OR, 0.79; 95% CI, 0.58-1.08; p=0.15), clinical response rate (OR, 1.24; 95% CI, 0.61-2.54; p=0.55), or microbiological response rate (OR, 0.59; 95% CI, 0.26-1.36; p=0.22) between polymyxin-treated groups and the control groups. Subgroup analyses showed that 28-day or 30-day mortality was lower in patients who received polymyxin combination therapy than in those who received monotherapy (OR, 0.36; 95% CI, 0.19-0.68; p<0.01) and the control groups (OR, 0.49; 95% CI, 0.31-0.75; p<0.01). The results of the six single-arm studies were in accordance with the findings of controlled studies. One controlled and two single-arm studies that evaluated the occurrence of nephrotoxicity reported a pooled incidence rate of 19.2%. Our results suggest that polymyxins may be as efficacious as other antimicrobial therapies for the treatment of carbapenem-resistant Enterobacteriaceae infection. Compared to polymyxin monotherapy, combination regimens may achieve lower 28-day or 30-day mortality. Future large-volume, well-designed randomized control trials are required to determine the role of polymyxins in treating carbapenem-resistant Enterobacteriaceae infections.

Diagnostic value of the serum galactomannan and (1, 3)-ß-D-glucan assays for invasive pulmonary aspergillosis in non-neutropenic patients.

OBJECTIVE: Galactomannan (GM) and (1, 3)-ß-D-glucan (BG) are considered useful seromarkers for the diagnosis of invasive pulmonary aspergillosis (IPA) in patients with neutropenia. However, there is still limited data on these seromarkers for testing non-neutropenic patients who are at the risk of IPA. The aim of this study was to evaluate the value of these two serum antigen assays for the early diagnosis of IPA in patients without neutropenia. METHODS: Between January 2011 and December 2012, 97 patients with suspected IPA admitted to the department of respiratory diseases and the respiratory intensive care unit were prospectively monitored. Serum GM and BG assays were performed before the patients received antifungal therapy. RESULTS: Patients were classified as proven IPA (n=11), probable IPA (n=16), possible IPA (n=4), or non-IPA (n=66). The most common underlying disease of patients with IPA was chronic obstructive pulmonary disease (18.5%), and 22.2% patients with IPA had no known diseases. The sensitivities, specificities, and positive and negative predictive values of the GM and BG assays and at least one positive on both assays were 40.7%/89.4%/61.1%/78.7%, 48.1%/78.8%/48.1%/78.8%, and 70.4%/75.8%/54.3%/86.2%, respectively. CONCLUSION: Compared with the testing of neutropenic patients, the serum GM or BG assay alone was less useful for the diagnosis of IPA in non-neutropenic patients. However, at least one positive result of the two serum assays appeared to be useful in the diagnosis of IPA in non-neutropenic patients.