The Assessment of Anti-Melanoma Potential of Tigecycline-Cellular and Molecular Studies of Cell Proliferation, Apoptosis and Autophagy on Amelanotic and Melanotic Melanoma Cells.

High mortality, aggressiveness, and the relatively low effectiveness of therapy make melanoma the most dangerous of skin cancers. Previously published studies presented the promising therapeutic potential of minocycline, doxycycline, and chlortetracycline on melanoma cells. This study aimed to assess the cytotoxicity of tigecycline, a third-generation tetracycline, on melanotic (COLO 829) and amelanotic (A375) melanoma cell lines. The obtained results showed that tigecycline, proportionally to the concentration and incubation time, efficiently inhibited proliferation of both types of melanoma cells. The effect was accompanied by the dysregulation of the cell cycle, the depolarization of the mitochondrial membrane, and a decrease in the reduced thiols and the levels of MITF and p44/42 MAPK. However, the ability to induce apoptosis was only found in COLO 829 melanoma cells. A375 cells appeared to be more resistant to the treatment with tigecycline. The drug did not induce apoptosis but caused an increase in LC3A/B protein levels-an autophagy marker. The observed differences in drug action on the tested cell lines also involved an increase in p21 and p16 protein levels in melanotic melanoma, which was related to cell cycle arrest in the G1/G0 phase. The greater sensitivity of melanotic melanoma cells to the action of tigecycline suggests the possibility of considering the use of the drug in targeted therapy.

Large-Scale Analysis of Fitness Cost of tet(X4)-Positive Plasmids in Escherichia coli.

Tigecycline is one of important antimicrobial agents for the treatment of infections caused by multidrug-resistant (MDR) Gram-negative bacteria. However, the emergence and prevalence of plasmid-mediated tigecycline resistance gene tet(X4) are threatening human and animal health. Fitness cost elicited by resistance plasmids is a key factor affecting the maintenance and transmission of antibiotic resistance genes (ARGs) in the host. A comparative analysis of the fitness cost of different types of tet(X4)-positive plasmids is helpful to understand and predict the prevalence of dominant plasmids. In this study, we performed a large-scale analysis of fitness cost of tet(X4)-positive plasmids origin from clinical isolates. These plasmids were successfully electroporated into a reference strain Escherichia coli TOP10, and a series of transformants carrying the tet(X) gene were obtained. The effects of tet(X4)-positive plasmids on the growth rate, plasmid stability, relative fitness, biofilm formation, and virulence in a Galleria mellonella model were evaluated. Consequently, we found that these plasmids resulted in varying degrees of fitness cost on TOP10, including delayed bacterial growth and attenuated virulence. Out of these plasmids, tet(X4)-harboring IncFII plasmids showed the lowest fitness cost on the host. Furthermore, by means of experimental evolution in the presence of commonly used drugs in clinic, the fitness cost of tet(X4)-positive plasmids was substantially alleviated, accompanied by increased plasmid stability. Collectively, our data reveal the differential fitness cost caused by different types of tet(X4)-positive plasmids and suggest that the wide use of tetracycline antibiotics may promote the evolution of plasmids.

In-Vitro Assessment Of The Therapeutic Potential Of Polymyxins And Tigecycline Against Multidrugresistant Acinetobacter Isolates From Infected Wounds.

BACKGROUND: The incidence of multidrug-resistant (MDR), extreme drug resistant (XDR), and pan drug-resistant (PDR) Acinetobacter are increasing throughout the world. The therapeutic management and control of Acinetobacter are difficult due to the emergence of drug resistance and its enduring capacity to survive in the environment. The present study was designed to appraise the efficacy of Polymyxins and Tigecycline against multidrugresistant Acinetobacter isolates from surgical and burn wounds. METHODS: During the study, the specimens were collected from various types of wounds from inpatients and outpatients of the tertiary care hospitals of Lahore, Pakistan in 2017 and 2018. The bacterial pathogens were isolated and identified using standard microbiological procedures and molecular confirmation of Acinetobacter species was examined by PCR using specific primers. The antibiotic susceptibility profiling of Acinetobacter isolates was studied against 18 antibiotics as per Clinical and Laboratory Standards Institute (CLSI) guidelines. RESULTS: The Acinetobacter isolates demonstrated extreme resistance especially to ampicillin/sulbactam, piperacillin/tazobactam, cephalosporins, carbapenems, fluoroquinolones, and aminoglycosides. However, the colistin, polymyxin, and tigecycline remained the most effective antimicrobial agents against Acinetobacter isolates. CONCLUSIONS: The results highlight the extent of drug resistance and therapeutic potential of Polymyxins and Tigecycline for wound infections caused by MDR and XDR Acinetobacter species. The wiser use of antimicrobials, incessant surveillance of antimicrobial resistance, and stringent adherence to infection control guidelines are critical to reducing major outbreaks in the future.

Optimization of tigecycline dosage regimen for different infections in the patients with hepatic or renal impairment.

OBJECTIVE: The objective of this study was to investigate the cumulative fraction of response (CFR) of various tigecycline dosing regimens in patients with hepatic or renal impairment. METHODS: Monte Carlo simulations were performed using pharmacokinetic parameters and microbiological data to evaluate various tigecycline regimens in patients with hepatic or renal impairment. RESULTS: For HAP and cIAI, the regimen of 25 mg q12h achieved CFR values of >90% in Child-Pugh C patients against Gram-positive bacteria and partial Gram-negative bacteria (Escherichia coli and Klebsiella oxytoca). However, dose increases of tigecycline was mostly required for Enterobacter cloacae, Klebsiella pneumoniae and Acinetobacter baumanni. The conventional tigecycline regimen (50 mg q12h) was effective for HAP and cIAI caused by Gram-positive bacteria and Escherichia coli in patients with renal impairment. For HAP caused by Klebsiella pneumoniae and Enterobacter cloacae, patients with severe renal failure can use the standard dose regimen 50 mg q12h, and other patients need to increase the dose of tigecycline. However, when treating cSSSI caused by Acinetobacter baumannii, Enterobacter cloacae and Klebsiella pneumoniae, all tigecycline maintenance doses have a CFR <90%. CONCLUSIONS: It is necessary to optimize tigecycline dosage regimens in patients with hepatic or renal impairment in order to maximise clinical response and minimise the probability of exposure-related toxicity.

Assessment of the in vitro activity of ceftazidime/avibactam against a global collection of multidrug-resistant Klebsiella spp. from the INFORM surveillance programme (2015-2017).

Infections caused by Klebsiella spp. are difficult to treat when these pathogens exhibit multidrug resistance (resistance to ≥3 drug classes). This study determined rates of multidrug-resistant (MDR) Klebsiella spp. among clinical isolates collected globally (Africa/Middle East, Asia, Oceania, Europe and Latin America, but not the USA) as part of the INFORM surveillance programme (2015-2017). In vitro antimicrobial activities of ceftazidime/avibactam (CAZ/AVI) and comparator antimicrobials against these MDR isolates were determined using CLSI broth microdilution methodology. MICs were interpreted using EUCAST 2019 breakpoints. By species, 38.4% (4555/11 864) of Klebsiella pneumoniae isolates were MDR, followed by 28.3% (452/1598) of Klebsiella aerogenes. The majority (69.5%) of MDR K. pneumoniae isolates were extended-spectrum ß-lactamase (ESBL)-positive and carbapenemase-negative compared with 1.3% of MDR K. aerogenes. Globally, >92% of MDR K. pneumoniae isolates were resistant to amoxicillin/clavulanic acid, aztreonam, cefepime, ceftazidime or ceftriaxone. CAZ/AVI, colistin and tigecycline MIC90 values were 1-2 mg/L against the global collection of MDR K. pneumoniae and MDR K. aerogenes. Approximately 5% (216/4555) of all MDR K. pneumoniae isolates and 1.1% (5/452) of all MDR K. aerogenes isolates were resistant to CAZ/AVI. Rates of resistance to CAZ/AVI and colistin were low for MDR, ESBL-positive, carbapenemase-negative K. pneumoniae (0.1% and 3.0%, respectively). Resistance to CAZ/AVI was highest among MDR, carbapenemase-positive, metallo-ß-lactamase (MBL)-positive K. pneumoniae (98.0%), whereas colistin resistance was highest among MDR, carbapenemase-positive, MBL-negative isolates (30.2%). The results of this study suggest that CAZ/AVI, colistin and tigecycline are potential treatment options for nosocomial infections caused by MDR Klebsiella spp. isolates.

In vitro activity of tigecycline and comparators (2014-2016) among key WHO 'priority pathogens' and longitudinal assessment (2004-2016) of antimicrobial resistance: a report from the T.E.S.T. study.

We report contemporary (2014-2016) Tigecycline Evaluation and Surveillance Trial (T.E.S.T.) global data on activity of tigecycline and comparators against WHO 'priority pathogens', and global trends (2004-2016) in antimicrobial resistance. MICs were determined using CLSI broth microdilution methodology. Antimicrobial resistance was determined using CLSI breakpoints (FDA breakpoints for tigecycline). Data are reported for Africa, Asia, Europe, North America and South America. From 2014-2016, Africa, Asia and South America reported highest resistance rates among Acinetobacter baumannii; North America lowest (all antimicrobials tested). The tigecycline MIC90 against A. baumannii was 2 mg/L in all regions except South America (1 mg/L). Among Enterobacteriaceae, meropenem resistance was low and tigecycline resistance was ≤1.3% in all regions (Escherichia coli, 0.0-0.3%; Klebsiella pneumoniae 0.0-1.3%; Enterobacter spp. 0.5-1.1%; Serratia marcescens 0.0-1.3%). Ceftriaxone resistance among E. coli ranged from 14.5% (North America) to 54.7% (Asia), and among K. pneumoniae from 9.1% (North America) to 54.0% (South America). North America reported highest rates of vancomycin-resistant Enterococcus faecium (64.6%); Europe lowest (17.7%). The tigecycline MIC90 against methicillin-resistant Staphylococcus aureus (MRSA) ranged from 0.12 mg/L (Africa and North America) to 0.5 mg/L (Asia). From 2004-2016, carbapenem resistance increased among A. baumannii (all regions), reaching 92.3% in Africa and 85.7% in South America (2016). Rates of ceftriaxone-resistant E. coli increased in all regions except Asia. Ceftriaxone resistance in K. pneumoniae increased in Europe. Rates of vancomycin-resistant E. faecium and MRSA were highest in North America and South America (and Asia for MRSA); lowest in Europe.

The tigecycline evaluation and surveillance trial; assessment of the activity of tigecycline and other selected antibiotics against gram-positive and gram-negative pathogens from France collected between 2004 and 2016.

Background: A high level of antibiotic consumption in France means antimicrobial resistance requires rigorous monitoring. The Tigecycline Evaluation and Surveillance Trial (T.E.S.T.) is a global surveillance study that monitors the in vitro activities of tigecycline and a panel of marketed antimicrobials against clinically important Gram-positive and Gram-negative isolates. Methods: Annually clinically relevant strains were prospectively included in the survey through a national network of hospital-based laboratories. MICs were determined locally by broth microdilution using CLSI guidelines. Antimicrobial susceptibility was assessed using European Committee on Antimicrobial Susceptibility Testing breakpoints. Results: Thirty-three centres in France collected 26,486 isolates between 2004 and 2016. Enterococcus species were highly susceptible (≥94.4%) to linezolid, tigecycline and vancomycin. Staphylococcus aureus, including methicillin-resistant S. aureus (MRSA), were susceptible (≥99.9%) to tigecycline, vancomycin and linezolid. Between 2004 and 2016, 27.7% of S. aureus isolates were MRSA, decreasing from 28.0% in 2013 to 23.5% in 2016. Susceptibility of Streptococcus pneumoniae isolates was 100% to vancomycin, and > 99.0% to levofloxacin, linezolid and meropenem; 3.0% were penicillin-resistant S. pneumoniae (100% susceptibility to vancomycin and linezolid). Escherichia coli isolates were highly susceptible (> 98.0%) to meropenem, tigecycline and amikacin. The rate of extended-spectrum ß-lactamase (ESBL) positive E. coli increased from 2004 (3.0%), but was stable from 2012 (23.1%) to 2016 (19.8%). Susceptibility of Klebsiella pneumoniae isolates was 99.4% to meropenem and 96.5% to amikacin. The proportion of ESBL-positive K. pneumoniae isolates increased from 2004 (7.5%) to 2012 (33.3%) and was highest in 2016 (43.6%). A. baumannii was susceptible to meropenem (81.0%) and amikacin (74.9%); none of the 6.2% of isolates identified as multidrug-resistant (MDR) was susceptible to any agents with breakpoints. P. aeruginosa isolates were most susceptible to amikacin (88.5%), and MDR rates were 13.6% in 2013 to 4.0% in 2016; susceptibility of MDR isolates was no higher than 31.4% to amikacin. Conclusions: Rates of MRSA decreased slowly, while rates of ESBL-positive E. coli and K. pneumoniae increased from 2004 to 2016. Susceptibility of Gram-positive isolates to vancomycin, tigecycline, meropenem and linezolid was well conserved, as was susceptibility of Gram-negative isolates to tigecycline and meropenem. The spread of MDR non-fermentative isolates must be carefully monitored.