Pharmacology and toxicology of tigecycline for injection

Pharmacological action: Tigecycline is an antibacterial agent of glycylcycline. By binding with the 30S subunit of ribosome, it prevents aminoacylated tRNA molecules from entering the A position of ribosome, thus inhibiting bacterial protein synthesis. This prevents the peptide chain from extending by combining amino acid residues. Tigecycline contains a glycylamino group, which is substituted in the 9- position of minocycline. This substitution form is not found in any natural or semi-synthetic tetracycline compound, which gives tigecycline unique microbiological characteristics. Tigecycline is not affected by two mechanisms of tetracycline resistance (ribosome protection and efflux mechanism). Therefore, in vitro and in vivo experiments confirmed that tigecycline has broad-spectrum antibacterial activity. No cross-resistance between tigecycline and other antibiotics was found. Tigecycline is not affected by drug resistance mechanisms such as β -lactamases (including extended-spectrum β -lactamases), target modification, macrolide efflux pump or enzyme target change (such as gyrase/topoisomerase). In vitro studies have not confirmed that tigecycline has antagonistic effect with other commonly used antibacterial drugs. Generally speaking, tigecycline is an antibacterial drug. Whether in vitro test or clinical infection study described in [indications], Tigecycline has antibacterial activity against most of the following bacterial strains: aerobic and facultative Gram-positive bacteria Enterococcus faecalis (vancomycin-sensitive strains only), Staphylococcus aureus (methicillin-sensitive and drug-resistant strains), Streptococcus agalactiae (including Streptococcus pharyngis), Streptococcus intermedia and Streptococcus constellation aerobic and facultative Gram-negative bacteria Citrobacter freundii, Enterobacter cloacae, Escherichia coli, Klebsiella pneumoniae, anaerobic bacteria, Bacteroides fragilis, and at least 90% of these bacteria. However, the safety and effectiveness of tigecycline in the treatment of clinical infections caused by these bacteria have not been confirmed by enough well-controlled clinical trials. Aerobic and facultative Gram-positive bacteria include Enterococcus avium, Enterococcus casei (vancomycin-resistant strain), Enterococcus faecalis (vancomycin-sensitive and drug-resistant strain), Enterococcus gallinarum, Listeria monocytogenes, Staphylococcus epidermidis (methicillin-sensitive and drug-resistant strain), Staphylococcus haemolyticus, aerobic and facultative Gram-negative bacteria, Acinetobacter baumannii, Aeromonas hydrophila, Citrobacter krylov, Enterobacter aerogenes, Pasteurella marcescens. Stenotrophomonas maltophilia and anaerobic bacteria If possible, the clinical microbiology laboratory should regularly provide clinicians with drug sensitivity reports of hospital-acquired and community-acquired pathogens, which should be a summary of the results of in vitro drug sensitivity tests of antibiotics used in local hospitals and practice fields. These reports help clinicians choose the most effective antibacterial drugs. The minimum inhibitory concentration (MIC) of antibacterial drug dilution method was determined by quantitative method. These MICs can be used to evaluate the sensitivity of bacteria to antimicrobial agents. The mic should be determined by standardized operation based on dilution method (broth dilution method, agar dilution method or microdilution method) or by equivalent standardized inoculum and tigecycline concentration. In order to monitor aerobic bacteria by broth dilution method, mic must be carried out in freshly prepared test medium (within 12 hours). MICs values should be interpreted according to the standards provided in Table 5. Diffusion method needs to measure the diameter of bacteriostatic circle, and can also be used to repeatedly estimate the sensitivity of bacteria to antibacterial drugs. Its standard operation requires the use of standardized inoculum concentrations. In this operation, the paper was impregnated with 15μg of tigecycline to detect the sensitivity of microorganisms to tigecycline. The explanation of the results includes the correlation between the diameter measured by disk diffusion method and the MIC result of tigecycline. The results of standard single-sheet drug sensitivity test provided by 15μg tigecycline test paper used in the laboratory should be interpreted according to Table 5. Because the quality control parameters of broth dilution method have not been established, agar dilution method should be used in the anaerobic drug sensitivity test of tigecycline. If the report is "sensitive", it suggests that if the antibacterial compound reaches the concentration that can usually be achieved, it is likely to inhibit the pathogenic bacteria. If the report is "intermediate", the result is suspicious. If microorganisms are not sensitive enough to alternative drugs and clinically available drugs, the experiment should be repeated. This classification means that this drug has clinical applicability in the body parts where drugs are physiologically concentrated or in the case where drugs can be used in high doses. This classification also provides a buffer zone to avoid large deviations in interpretation caused by small uncontrollable technical factors. The report "Drug Resistance" suggests that even the concentration of antibacterial compounds that can usually be achieved is not enough to inhibit pathogenic bacteria, so other therapeutic drugs should be selected at this time. Quality control is similar to other drug sensitivity testing techniques. In order to control the technical level of standardized operation in the laboratory, it is necessary to control strains in the laboratory. Standard tigecycline powder should be able to provide the MIC value shown in Table 6. The diffusion technology using 15 μg tigecycline paper should meet the standards shown in Table 6. Toxicological study: Toxicity of repeated administration: In the two-week study, rats and dogs were exposed to tigecycline at a daily dose of 8 times and 10 times, respectively, and red blood cells, reticular cells, white blood cells and platelets related to bone marrow suppression could all decrease. After 2 weeks of administration, these changes were reversible. No signs of photosensitivity were observed in rats after taking tigecycline. Genotoxicity: In a series of tests (including chromosome aberration test of China hamster ovary (CHO) cells in vitro, positive mutation test of CHO cells (HGRPT site) in vitro, positive mutation test of mouse lymphoma cells in vitro and micronucleus test in mice), tigecycline was not found to have mutagenic effect. Reproductive toxicity: According to AUC calculation, even if the exposure dose of tigecycline reaches 5 times of human daily dose, it will not affect the mating or fertility of rats, and there is no drug-related effect on the ovaries or estrous cycle of female rats. Carcinogenicity: No animal lifetime study has been conducted to evaluate the carcinogenicity of tigecycline. Others: In preclinical studies, it was found that a large amount of intravenous tigecycline was related to histamine reaction.