Daptomycin

Nature, use and production process

Antibiotic Daptomycin is a cyclolipopeptide antibiotic with a new structure extracted from the fermentation broth of Streptomyces Streptomyces (S.riseosporus). It was discovered by Eli Lilly in the United States in the 1980s and successfully developed by Cubist Pharmaceutical Company in 1997. It not only has a novel chemical structure, but also has a novel chemical structure. Moreover, its mode of action is different from that of any approved antibiotic: it disrupts the transport of amino acids to the cell membrane, thus impeding the biosynthesis of peptidoglycan in the bacterial cell wall, altering the properties of the cell plasma membrane, disrupting the function of the bacterial cell membrane in multiple ways, and rapidly killing gram-positive bacteria. In addition to its ability to act on most clinically relevant gram-positive bacteria, dattomycin has a strong activity in vitro against strains resistant to methicillin, vancomycin and linezolidin, which is of great clinical significance for patients with critical infections. The US Food and Drug Administration first approved daptomycin for the treatment of severe skin infections in September 2003 and for infectious diseases in March 2006. In January 2006, it was approved by the European Commission for the treatment of complex skin and soft tissue infections caused by certain Gram-positive bacteria. On September 6, 2007, Cubist Pharmaceuticals announced that the European Union has approved its antibacterial drug daptomycin for injection, Cubicin is used for the treatment of right ventricular infective endocarditis caused by Staphylococcus aureus and staphylococcus aureus bacteremia associated with right ventricular infective endocarditis or complex skin and soft tissue infections. On July 29, 2010, the U.S. Food and Drug Administration (FDA) issued information alerting patients and health care professionals to the possibility of eosinophilic pneumonia as a result of the use of the intravenously administered drug daptomycin (Cubist Pharmaceuticals, under the trade name Cubicin) during treatment. Eosinophilic pneumonia is a rare and very serious disease with symptoms that include fever, cough, shortness of breath, and difficulty breathing. Daptomycin is also known as Daptomycin. The antibacterial activity of datomycin was similar to that of vancomycin, mainly due to its strong antibacterial activity against gram-positive coccus, such as MIC=0.125 ~ 0.5μg/ml for Staphylococcus spp and MIC=0.06 ~ 0.5μg/ml for Gram-positive spp. MIC for enterococcus = 0.25 ~ 2.0 μg/ml. Daptomycin also has a broad spectrum of antibacterial activity against gram-positive anaerobic bacteria, and against peptostreptococcus spp. MIC=0.12μg/ml, spp.MIC=0.5 μg/ml for Clostridium, spp.MIC=1 μg/ml for Lactobacillus. Daptomycin has good antibacterial activity against various antibiotic resistant bacteria, such as MIC=0.06 ~ 0.5 μg/ml for methicillin-resistant Staphylococcus aureus (MRSA) and MIC=0.0625 ~ 1 μg/ml for methicillin-resistant staphylococcus. MIC=0.12 ~ 0.5 μg/ml for oxacillin-resistant surface staphylococcus, MIC=2.5μg/ml for highly aminoglycoside resistant enterococcus, MIC= 0.5 ~ 1 μg/ml for GMRBIa-resistant Enterococcus, and MIC=1 ~ 2 μg/ml for glycoleptide resistant enterococcus. Toxicology According to the data provided by Eli Lilly Pharmaceutical laboratories in the United States, dattomycin is a relatively safe and low-toxicity antibiotic. LD50= 142-159 mg/kg in mice (200 mg/kg in dogs), no death, can lead to weight loss, loss of appetite, LD50= 25-200 mg/kg in monkeys. The main symptoms are lethargy, muscle weakness, ataxia, increased creatinine phosphokinase, and mild irritation after skin and eye contact. At different doses of 25 ~ 125 mg/kg (intravenous injection) for one month, the renal cortex tubular epidermis and skeletal muscle degeneration were observed in all dose groups, and sciatic nerve degeneration was also observed in 150 mg/kg dose group, but it did not affect fertility and had no teratogenic effect. In the 6-month chronic toxicity test, dogs were given intravenous injection of daptomycin at doses of 2,10,40 mg/(kg·d) respectively. Only dogs in the 40 mg/(kg·d) dose group showed loss of knee twitch response, moderate neuroaxonal degeneration and slight decrease in neurotransmission velocity, but the function returned to normal after 2 weeks of discontinuation. A single dose of 2.0mg/kg has no effect on the human muscle and nervous system. Healthy volunteers were given six doses of 0.5-6.0 mg/kg and 1.0 mg/ kg14C-labeled daptomycin once (intravenously). The results showed that daptomycin had a longer t1/2 (t1/2 = 6-8 h) and a smaller distribution volume (V= 0.1-0.2 L/kg) in vivo. Renal clearance CLr = 0.17-0.2 ml/(min·kg). The kidney is the main metabolic organ. About 78% of daptomycin is excreted from urine. There are metabolites of daptomycin in urine. The distribution of daptomycin in the body is not completely clear. Compared with healthy volunteers, the mean peak blood concentration (cmax) was 35.45, the steady-state volume of distribution (Vss = 0.21) was increased, and the clearance rate (CL) was also increased by 22% in patients with septicemia and endocarditis who received 3mg/kg of daptomycin intravenically every 12 h. In vivo activity and clinical application This product is mainly used in the treatment of endocarditis, septicemia, peritonitis and urinary tract infection caused by staphylococcus, streptococcus and enterococcus, especially endocarditis caused by various drug-resistant strains. Animal experiments have shown that the effect of using dattomycin in the treatment of endocarditis, peritonitis, pneumonia, mylitis and other diseases caused by MRSA or other drug-resistant strains is superior to or equal to vancomycin, and dattomycin is t1 1/2 long in vivo with less toxic side effects, so it has considerable clinical application value. In October 1990, the first case of failure of dattomycin in the treatment of endocarditis caused by Staphylococcus aureus resistant strain was reported. The reasons were estimated to be the high affinity of dattomycin with protein (90%), low dose and different pharmacokinetic parameters of patients compared with healthy people. Further studies on the pharmacology and clinical application of dattomycin are still in progress. The occurrence rate of daptomycin-resistant strains was low and the drug resistance was not strong. In vitro screening of daptomycin-resistant strains from Streptococcus pneumoniae, enterococcus and staphylococcus, the occurrence rate of streptococcus pneumoniae resistant strains was the highest, which was 1.2×10-6(16MIC), and the incidence rate of drug-resistant strains from golden Vitis was the lowest, which was 7.0×10-9(8MIC). Generally, MIC is increased 8-32 times. After three passes in the culture medium without antibiotics, the resistance decreased to 1/2 ~ 1/4. In the rabbit endocarditis model, after treatment with datomycin, 13% of rabbits developed datomycin-resistant Staurococcus aureus, but the resistance was weakened, suggesting that the stability of datomycin-resistant resistance may involve multiple mutations. When combined with netimiacin, amikacin, imipenem and fosfomycin, dattomycin has a synergistic effect and can improve the antibacterial activity; when combined with teicolanin and vancomycin, it has a good antibacterial activity against Sma GMRBLA-Enterococcus; when combined with dattomycin and gentamicin, it also has a synergistic effect on Streptococcus faecalis which is resistant to glycopeptide antibiotics. This has been confirmed in animal models. When treated in combination with tobramycin, the nephrotoxicity of tobramycin is reduced, as opposed to vancomycin.

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