A Hemoglobin-Based Nanoparticle Delivery System Enhances the Pharmacokinetics and Efficacy of Tigecycline in Klebsiella pneumoniae Infections

To evaluate the efficacy and safety of tigecycline in treating secondary infections of patients with hematological diseases. A total of 85 cases of hematological patients with secondary infections were classified into empirical and targeted therapy groups. Empirical therapy group was composed of patients receiving tigecycline as an alternative due to ineffective anti-infection treatment for 3-5 days in the absence of microbiological evidence while those taking tigecycline based on microbiological evidence belonged to targeted therapy group. Dosage regimen of tigecycline: loading dose 100 mg, 50 mg every 12 hours as maintenance therapy for 2-4 weeks. Among them, except for 11 cases of bloodstream infections and 2 cases of fever for unknown reasons, the most common site for infection was lower respiratory tract. Among 45 isolated bacterial strains, Stenotrophomonas maltophilia (40%) was the most commonly seen while extended spectrum beta-lactamases (ESBLS)+ multidrug resistant gram negative bacilli 15.6%. Among 5 bacterial strains, there were 3 methicillin-resistant Staphylococcus aureus+golden staphylococci strains and 2 excrement enterococci. The total effective rate of tigecycline was 72.9%. And the bacterial clearance rates of acinetobacter baumannii, ESBLS+ gram-negative bacillus and stenotrophomonas maltophilia were 85%, 70% and 55% respectively. The effect of tigecycline was equivalent for two groups. Pneumonia patients obtained an effective rate of 71%, compared to those with bloodstream infections (54.5%). For patients whose absolute neutrophil counts were less than 0.2 × 10⁹/L, the effective rate decreased obviously (45% vs 81.5%, P = 0.003). Adverse reaction was mild due to mostly gastrointestinal symptoms. Tigecycline is a new treatment choice in treating secondary multidrug resistant infections of patients with hematological diseases. Empirical therapy of tigecycline may improve the therapeutic efficacy of patients non-responding favorably to conventional anti-infectives.

The emergence of multidrug-resistant bacteria in companion animals is an increasing concern in view of the concept of One Health. The antimicrobials linezolid (LZD) and tigecycline (TGC) are effective against multidrug-resistant bacteria isolated from humans; however, thus far, no previous study has evaluated the efficacy of these drugs against bacteria isolated from companion animals. This study aimed to evaluate the efficacy of LZD and TGC against bacteria that were isolated from companion dogs and showed resistance to all classes of antimicrobial agents. Clinical samples (auditory channel, eye, skin, and urine) were collected from dogs that visited the Veterinary Medical Teaching Hospital of Konkuk University (Seoul, South Korea) from October 2017 to September 2020. In total, 392 bacterial isolates were obtained, of which 85 were resistant to all classes of antimicrobial agents tested and were, therefore, considered potentially pan-drug resistant (PDR). The susceptibility of isolates to LZD and TGC was determined by the disk diffusion method and interpreted using the Clinical Laboratory Standards Institute guidelines. In total, 95.6% (43/45) and 97.8% (44/45) of gram-positive isolates were susceptible to LZD and TGC, respectively, whereas 82.5% (33/40) of gram-negative isolates were sensitive to TGC. In conclusion, both agents showed favorable efficacy, with the susceptibility rates for all potential PDR bacteria, except Pseudomonas spp., ranging from 72.7 to 100%. Thus, these drugs may serve as excellent antimicrobial options for veterinary medicine in the future.

Objective To explore the usage of the treatment and evaluate the safety and efficacy of tigecycline in the treatment of infections secondary to burn injury. Methods This was a non-controlled, multicenter, open-label clinical tria1. Intravenous tigecycline was administered with a loading dose of 100 mg for the first time followed by 50 mg/12 hours during the remaining treatment, which lasted for 30-60 minutes every time. The drug was evaluated by 4 aspects: initial treatment effect, clinical efficacy, bacteriological efficacy, and safety. Results A total of 77 patients were recruited, the initial effective rate was 81.82%, and the clinical effective rate was 84.42% (cured 9.09%, markedly effective 50.65%, improved 24.68%). There was one adverse event related to the drug, the incidence of adverse reaction was 1.31%. The bacterial clearance rate was 46.75%. Conclusions Tigecycline is mostly mild in the treatment of infections secondary to burn injury and the clinical incidence of adverse reactions is low. Tigecycline can be an effective and safe treatment for infections secondary to burn injury. Key words: Burns; Infection; Treatment outcome; Tigecycline; Safety

Efficacy of Tigecycline Against Worldwide Levofloxacin-Resistant Pathogens

There is existing controversy regarding the efficacy of tigecycline (TG) in treating complicated urinary tract infections (cUTIs) because of its pharmacokinetic concerns. We present three patients with cUTIs caused by carbapenem-resistant gram-negative (GN) pathogens successfully treated with high-dose tigecycline (HDT)-based regimens, as cefiderocol and aztreonam were not available in our country. The first case describes a 67-year-old patient with diabetes, prostate cancer, and double J ureteral stenting who was hospitalized with a febrile, complicated urinary tract infection (cUTI). Urine and blood cultures were positive for metallo-beta-lactamases (MBL)-producing extensively drug-resistant (XDR) Klebsiella pneumoniae(cefiderocol-susceptible). The synergy between TG and colistin using thein vitro E-test was demonstrated, and the patient was started on this regimen using HDT. Clinical and microbiological cures were achieved, and the patient was discharged home. The second case presents a 70-year-old patient with urethral pathology who was hospitalized with the diagnosis of a lower cUTI caused by an MBL-producing pan-drug-resistant (PDR) Klebsiella pneumoniae.Thein vitro E-test showed synergy between TG and colistin, and our patient was successfully treated with this HDT-based combination. The third case emphasizes a 63-year-old patient with insulin-dependent diabetes, Child B cirrhosis, and a right double J ureteral stent who was hospitalized with a febrile cUTI. Urine and blood cultures were positive for carbapenem-resistant XDR Acinetobacter baumannii(susceptible to colistin and TG). Colistin was administered for only 96 hours because of stage II acute kidney injury, and we continued the treatment with HDT in monotherapy. The patient was discharged home, and no urinary tract infection relapse was seen for six months. Favorable clinical and microbiological outcomes were achieved with TG-based regimens in our cUTI cases. We highlight the role of antibiotic synergy determined by the in vitroE-test in two cases of MBL-producing XDR/PDRKlebsiella pneumoniae.

Tigecycline (TGC), a first-in-class glycylcycline that has been approved for treating complicated skin and skin structure infections and complicated intra-abdominal infections, has an expanded spectrum of activity against Gram-positive, Gram-negative, anaerobic, and atypical bacteria, including resistant strains. The purpose of this study was to compare the efficacy and safety of TGC with levofloxacin (LEV) in adult hospitalized patients with community-acquired pneumonia (CAP) in a randomised, doubleblind, phase 3 multinational trial. This analysis evaluated TGC efficacy and safety in the European region. Hospitalised patients from 53 centres in 18 countries received 7-14 days of i.v. TGC (100-mg loading dose followed by 50 mg every 12 hours) or i.v. LEV (500 mg once or twice daily). Co-primary efficacy endpoints were clinical response in clinically evaluable (CE) and clinical modified intent-to-treat (c-mITT) populations at test-of-cure (TOC).Results indicated that 358 patients received at least 1 dose of study medication (mITT: TGC 177, LEV 181), 245 were CE (TGC 125, LEV 120). Demographics were similar in both groups and the majority of patients had a Fine Pneumonia Severity Index of II to IV (84.4% TGC, 78.2% LEV, mITT). At TOC (CE), TGC cured 112/125 patients (89.6%; 95% CI 82.9, 94.3) and LEV cured 103/120 patients (85.8%; 95% CI 78.3, 91.5), absolute difference of TGC-LEV 3.8% (95% CI -5.3, 12.8; test for noninferiority p<0.001). For those CE patients with a Fine score of <III or III/IV, TGC cured 90.0% and 88.9%, and LEV cured 88.5% and 83.6%, respectively. In c-mITT, TGC cured 146/173 patients (84.4%; 95% CI 78.1, 89.5) and LEV cured 142/173 patients (82.1%; 95% CI 75.5, 87.5), absolute difference of TGC-LEV 2.3% (95% CI 6.1, 10.8; test for noninferiority p<0.001). In c-mITT patients with a Fine score of <III or III/IV, TGC cured 86.3% and 81.9%, and LEV cured 80.7% and 83.1%, respectively. Both regimens were generally well tolerated with only a few patients being withdrawn from the study because of any adverse event (3; 1.6% TGC versus 2, 1.1% LEV). The authors concluded that TGC was safe and efficacious in patients hospitalised with CAP, achieving similar efficacy to that of the comparator.

Staphylococcal biofilms on surgical implants are the underlying cause of a lack of response to antimicrobial treatment. We investigated the effects of vancomycin (VAN), daptomycin (DAP), fosfomycin (FOS), tigecycline (TGC), and ceftriaxone (CRX), alone and in combination with azithromycin (AZI), on established biofilms of Staphylococcus epidermidis. Biofilms were studied using the static microtiter plate model with established S. epidermidis biofilms, with an initial inoculum of 10(6)/ml in 96-well polystyrene flat-bottom microtiter plates. Biofilms were inoculated with VAN, DAP, FOS, TGC, or CRX at two concentrations, alone or in combination with AZI (2, 512, or 1,024 mg/liter). To assess the reduction in biomass, the optical density ratio (ODr), calculated as (optical density [OD] of the treated biofilm)/(OD of the untreated biofilm, taken as 1), was used. For antibacterial efficacy, the viable bacterial count was used. Reductions in the biofilm ODr were observed for VAN (15 and 40 mg/liter) and FOS (200 mg/liter) only (ODr [mean +/- standard deviation] for VAN at 15 and 40 mg/liter, 0.77 +/- 0.32 and 0.8 +/- 0.35, respectively; ODr for FOS at 200 mg/liter, 0.78 +/- 0.26; P < 0.05), but not for DAP (2 and 5 mg/liter), TGC (0.2 and 2 mg/liter), or CRX (600 and 2,400 mg/liter). The addition of AZI had no further effect on the ODr, but a significant reduction of bacterial growth was achieved with high doses of AZI plus TGC or AZI plus CRX (a 3-log count reduction for AZI at 1,024 mg/liter plus CRX at 600 mg/liter and for AZI at 512 or 1,024 mg/liter plus CRX at 2,400 mg/liter; a 2-log count reduction for AZI at 512 or 1,024 mg/liter plus TGC at 2 mg/liter [P < 0.05]). No significant reduction in bacterial growth was observed for FOS (50 and 200 mg/liter), DAP (2 and 5 mg/liter), or TGC (0.2 mg/liter) in combination with AZI. None of the antibiotics at either concentration reduced the bacterial count of the biofilms when used alone. Thus, the use of a combination of AZI plus TGC, FOS, or CRX at high concentrations has little effect on biofilm density but significantly reduces bacterial growth.

Introduction:This study was conducted to evaluate the efficacy of tigecycline (TGC) versus levofloxacin (LEV) in hospitalized patients with community-acquired pneumonia (CAP) using pooled data and to perform exploratory analyses of risk factors associated with poor outcome.Materials and Methodology:Pooled analyses of 2 phase 3 studies in patients randomized to intravenous (IV) TGC (100 mg, then 50 mg q12h) or IV LEV (500 mg q24h or q12h). Clinical responses at test of cure visit for the clinically evaluable (CE) and clinical modified intention to treat populations were assessed for patients with risk factors including aged ≥65 years, prior antibiotic failure, bacteremia, multilobar disease, chronic obstructive pulmonary disease, alcohol abuse, altered mental status, hypoxemia, renal insufficiency, diabetes mellitus, white blood cell count >30 x 109/L or <4 x 109/L, CURB-65 score ≥2, Fine score category of III to V and at least 2 clinical instability criteria on physical examination.Results:In the CE population of 574 patients, overall cure rates were similar: TGC (253/282, 89.7%); LEV (252/292, 86.3%). For all but one risk factor, cure rates for TGC were similar to or higher than those for LEV. For individual risk factors, the greatest difference between treatment groups was observed in patients with diabetes mellitus (difference of 22.9 for TGC versus LEV; 95% confidence interval, 4.8 - 39.9).Conclusions:TGC achieved cure rates similar to those of LEV in hospitalized patients with CAP. For patients with risk factors, TGC provided generally favorable clinical outcomes.

Tigecycline (TIG) is a Food and Drug Administration (FDA)-approved antibiotic that has recently demonstrated its anti-cancer properties in diverse tumour types. This review will discuss current research findings and future directions pertaining to the use of TIG in mitigating acute myeloid leukemia (AML), non-small cell lung cancer (NSCLC), gastric cancer, hepatocellular carcinoma (HCC), breast cancer, melanoma, cervical squamous cell carcinoma (CSCC), and glioblastoma (GM). TIG exerts its therapeutic effects via inhibition of mitochondrial functionality, interference of various signal transduction pathways, and acting synergistically with pre-existing chemotherapy drugs, all of which contribute to cell death. In comparison to conventional treatments such as chemotherapy, TIG may result in less severe and reduced side effects; this may be attributed to its selectivity and non-invasiveness. Upon evaluation of TIG’s efficacy in targeting multiple cancer-types, future efforts should aim to validate findings through human trials, broadening the scope of cancers targeted, establishing novel TIG derivatives, and assessing its performance when used in combination with other treatments.

A relevant bacterial load in cutaneous wounds significantly interferes with the normal process of healing. Vitamin E (VE) is a known immunomodulator and immune enhancer. Here, it was shown that administration of VE before infection was effective at increasing the antimicrobial activity of daptomycin (DAP) or tigecycline (TIG) in a mouse model of wound infection caused by meticillin-resistant Staphylococcus aureus (MRSA). A wound was established through the panniculus carnosus of mice and inoculated with MRSA. Mice were assigned to six groups: a VE pre-treated group with no antibiotics given after MRSA challenge; two VE pre-treated groups with DAP or TIG given after MRSA challenge; two groups treated with DAP or TIG only after MRSA challenge; and a control group that did not receive any treatment. Mice receiving each antibiotic alone showed a 3 log decrease in the number of c.f.u. recovered compared with the control group, mice treated with VE plus TIG had a 4 log decrease, whilst mice treated with VE plus DAP had the largest decrease in c.f.u. recovered (5 logs). The increased antimicrobial effect seen from treatment with VE plus antibiotics was associated with increased levels of natural killer cell cytotoxicity, with a more pronounced increase in leukocyte populations in mice treated with VE plus DAP. These data suggest that treatment with VE prior to infection and subsequent antibiotic treatment act in synergy.

This randomized, open-label, multi-center trial compared tigecycline (TGC), a broad-spectrum glycylcycline, with ceftriaxone-metronidazole (CTX/MET) for the treatment of complicated intra-abdominal infections (cIAI). Eligible subjects were randomized to receive TGC 100 mg followed by 50 mg q 12 h or CTX 2 g qd plus MET 1-2 g daily for 4-14 days. Subjects were stratified by Acute Physiology and Chronic Health Evaluation (APACHE) II score ≤10 or >10 and could not receive oral therapy. The primary endpoint was clinical response in the clinically evaluable (CE) population at the test of cure (TOC) assessment 8-44 days after the last drug dose. Clinical responses in the CE population were 81.8% (162/198) vs. 79.4% (150/189) for TGC and CTX/MET, respectively; a weighted estimate of the difference of 1.6 (95% confidence interval [CI] -6.4, 9.6). In the microbiologically evaluable (ME) population, microbiological eradication rates were 82.4% (98/119) for TGC vs. 79.6% (86/108) for CTX/MET: a difference of 2.7 (95% CI -7.9, 13.3). Common adverse events were nausea (21.6% TGC vs. 21.3% CTX/MET) and vomiting (17.7% TGC vs. 13.2% CTX/MET). Discontinuation rates because of adverse events were 7.8% for TGC and 6.4% for CTX/MET. Tigecycline was effective in the treatment of cIAI and was non-inferior to CTX/MET for the treatment of cIAI in hospitalized adults. Clinical Trials Identifier: NCT00230971.

Activité in vitro de la tigécycline vis-à-vis des germes pathogènes isolés d’infections respiratoires en Europe. Le Programme TEST 2004–2007

Cell-material interactions play an essential role in the development of scaffold-based tissue engineering strategies. Cell therapies are still limited in treating injuries when severe damage causes irreversible loss of muscle cells. Electroactive biomaterials and, in particular, piezoelectric materials offer new opportunities for skeletal muscle tissue engineering since these materials have demonstrated suitable electroactive microenvironments for tissue development. In this study, the influence of the surface charge of piezoelectric poly(vinylidene fluoride) (PVDF) on cell adhesion was investigated. The cytoskeletal organization of C2C12 myoblast cells grown on different PVDF samples was studied by immunofluorescence staining, and the interactions between single live cells and PVDF were analyzed using an atomic force microscopy (AFM) technique termed single-cell force spectroscopy. It was demonstrated that C2C12 myoblast cells seeded on samples with net surface charge present a more elongated morphology, this effect being dependent on the surface charge but independent of the poling direction (negative or positive surface charge). It was further shown that the cell deadhesion forces of individual C2C12 cells were higher on PVDF samples with an overall negative surface charge (8.92 ± 0.45 nN) compared to those on nonpoled substrates (zero overall surface charge) (4.06 ± 0.20 nN). These findings explicitly demonstrate that the polarization/surface charge is an important parameter to determine cell fate as it affects C2C12 cell adhesion, which in turn will influence cell behavior, namely, cell proliferation and differentiation.

Overview: In this study, the physical and chemical properties of curcumin are extensively examined when it is incorporated into liposome nanoparticles, to enhance its therapeutic potency and bioavailability. Curcumin, a plant-derived polyphenol, has garnered attention for its anti-inflammatory, antioxidant, and anti-cancer activities. However, its clinical utility is hindered by several limitations, including poor water solubility, inadequate absorption, and rapid metabolism. By leveraging the potential of liposome nanoparticles to improve drug delivery and efficacy, this research aims to overcome these obstacles and unlock the full therapeutic potential of curcumin. Methods: Curcumin-loaded liposome nanoparticles (CLLNs) were fabricated employing a thin-film hydration method, after sonication. The physicochemical attributes of CLLNs were subsequently characterized, encompassing particle size and zeta potential assessment utilizing dynamic light scattering (DLS), encapsulation efficiency (EE%) and drug loading efficiency (DLE%) determination through high-performance liquid chromatography (HPLC), investigation of in vitro drug release patterns in simulated biological fluids. Results: The CLLNs optimized in this study had a mean particle diameter of less than 250 nm and a negative surface charge, implying good stability and potential for cellular uptake. The encapsulation efficiency and drug loading efficiency were both found to be high, indicating that curcumin was effectively loaded into the liposomes. In vitro release testing showed a sustained release pattern of curcumin from the CLLNs. Conclusion: The research offered important observations about the advantageous physicochemical features of curcumin-loaded liposome nanoparticles, highlighting their potential as a cutting-edge delivery system for curcumin. The study demonstrated that CLLNs have high encapsulation and drug loading efficiencies, as well as controlled release and improved stability, which suggests their ability to enhance the therapeutic benefits of curcumin. These findings set the stage for future in vivo and clinical trials to fully investigate the potential of CLLNs in medical applications.

Human serum albumin (HSA) has a very significant role in the transport of drugs, in their pharmacokinetic and pharmacodynamic properties, as well as the unbound concentration of drugs in circulating plasma. The aim of this study was to look into the competition between tigecycline (TGC) and alkaloid (ALK) (caffeine (CAF)), and flavonoids (FLAVs) (catechin (CAT), quercetin (QUE), and diosmin (DIO)) in binding to HSA in simulated physiological conditions using multiple spectroscopic measurements and docking simulations. Fluorescence analysis was used to find the binding and quenching properties of double HSA-TGC and triple HSA-TGC-CAF/FLAV systems. The conformational change of the HSA was analyzed using synchronous fluorescence spectroscopy, Fourier transform infrared spectroscopy, and circular dichroism. Obtained results of spectroscopic analyses indicate that triple complexes of HSA-TGC-CAF/FLAVs are formed without problems and have higher binding affinities than double HSA-TGC. In addition, TGC does not change the microenvironments around the tryptophan (Trp) and tyrosine (Tyr) residues in the presence of ALK and FLAVs. Ultimately, the binding affinity, competition, and interaction nature were explored by docking modeling. Computational outcomes are in good accordance with experimentally obtained results. Accordingly, concluding remarks may be very useful for potential interactions between common food components and drugs.