Retrospective study of teicoplanin loading regimen that rapidly achieves target 15-30 µg/mL serum trough concentration.

OBJECTIVES: There are several studies of assessment for teicoplanin loading dose regimen. However, the optimal loading dose achieving the target range 15-30 µg/mL has been still unclear. We investigated the probability of target attachment as teicoplanin concentration 15-30 µg/mL at the 3rd day after teicoplanin therapy started, clinical efficacy and safety in retrospective study. METHODS: In total, 42 patients treated with teicoplanin from January 2010 to July 2014 at Aichi Medical University Hospital were divided into three groups; group 1 (about 40 mg/kg for 2 days), group 2 (about 35 mg/kg for 2 days) and group 3 (about 30 mg/kg for 2 days; the previous regimen). The probability of target attachment as teicoplanin concentration, efficacy and toxicity were compared among three groups. RESULTS: The proportion of patients achieving the target range was 100% in group 1, 57.9% in group 2, and 38.9% in group 3 (p = 0.05). The percentage of patients that showed hepatotoxicity and nephrotoxicity was not different from three groups (hepatotoxicity: group 1, 20%; group 2, 21.1%; group 3, 16.7%: p = 0.48; nephrotoxicity: group 1, 0%; group 2, 5.3%; group 3, 16.7%: p = 0.38). Finally, there were not significant differences of clinical efficacy among three regimens, but CRP 4-7 day after teicoplanin therapy in group 1 and group 2 exhibited a significant lower value, compared with group 3. CONCLUSIONS: We suggested that 35-40 mg/kg for 2 days as a loading does would be needed for the early achieving target range (15-30 µg/mL) and improvement of infection.

TIGAR Protects Cochlear Hair Cells against Teicoplanin-Induced Damage.

Teicoplanin is a glycopeptide antibiotic used to treat severe staphylococcal infections. It has been claimed that teicoplanin possesses ototoxic potential, although its toxic effects on cochlear hair cells (HCs) remain unknown. The TP53-induced glycolysis and apoptosis regulator (TIGAR) plays a crucial role in promoting cell survival. Prior research has demonstrated that TIGAR protects spiral ganglion neurons against cisplatin damage. However, the significance of TIGAR in damage to mammalian HCs has not yet been investigated. In this study, firstly, we discovered that teicoplanin caused dose-dependent cell death in vitro in both HEI-OC1 cells and cochlear HCs. Next, we discovered that HCs and HEI-OC1 cells treated with teicoplanin exhibited a dramatically decrease in TIGAR expression. To investigate the involvement of TIGAR in inner ear injury caused by teicoplanin, the expression of TIGAR was either upregulated via recombinant adenovirus or downregulated by shRNA in HEI-OC1 cells. Overexpression of TIGAR increased cell viability, decreased apoptosis, and decreased intracellular reactive oxygen species (ROS) level, whereas downregulation of TIGAR decreased cell viability, exacerbated apoptosis, and elevated ROS level following teicoplanin injury. Finally, antioxidant therapy with N-acetyl-L-cysteine decreased ROS level, prevented cell death, and restored p38/phosphorylation-p38 expression levels in HEI-OC1 cells injured by teicoplanin. This study demonstrates that TIGAR may be a promising novel target for the prevention of teicoplanin-induced ototoxicity.

Are the leading drugs against Staphylococcus aureus really toxic to cartilage?

Many studies have shown that the toxic effects of local antibiotics on bone and cartilage limit orthopedic surgeons. In this study, we evaluated three antibacterial agents used locally to treat highly mortal and morbid diseases in the field of orthopedics, such as septic arthritis. Are vancomycin, teicoplanin, and linezolid, which are archenemies of Staphylococcus aureus, really toxic to chondrocytes? The purpose of the study was to investigate the effects of antibiotics, which are used against S. aureus, on human chondrocytes in vitro. Primary cell cultures obtained from gonarthrosis patients were divided into two main groups. One of these groups was designated as the control chondrocyte culture. The other group was divided into three subgroups, and each group was exposed to vancomycin, teicoplanin, or linezolid. Cell culture samples were characterized by immunophenotyping following incubation with the three different antibiotics. Before and after the agents were administered, the cultures were subjected to inverted and environmental scanning electron microscopy. The number of live cells and the proliferation rate were monitored with the MTT-assay. We found that vancomycin, teicoplanin, and linezolid do not have chondrotoxic effects. Vancomycin, teicoplanin, and linezolid had no chondrotoxic activity during in vitro culture, which supports the argument that these agents can safely be used in orthopedic surgery, especially against methicillin-resistant S. aureus agents.

Aerosol Route to Administer Teicoplanin in Mechanical Ventilation: In Vitro Study, Lung Deposition and Pharmacokinetic Analyses in Pigs.

BACKROUND: Glycopeptides given intravenously achieve low airway concentrations. Nebulization of teicoplanin may be an efficient way of delivering a high concentration of this antibiotic to the lung. This multistep study assessed the feasibility of teicoplanin nebulization during mechanical ventilation by evaluating: the stability of its antibiotic effect; epithelial tolerance; lung deposition and systemic absorption in ventilated pigs. METHODS: Nebulized and non-nebulized teicoplanin activity was tested on Staphylococcus aureus cultures. The cytotoxic effect of teicoplanin on human respiratory epithelial cells was assessed by measuring lactate dehydrogenase activity released, cell viability, and transepithelial electrical resistance. Volume median diameter of particles of nebulized teicoplanin was measured by laser diffraction during mechanical ventilation. The deposited mass of teicoplanin nebulized with a vibrating mesh nebulizer in ventilated piglets was assessed by scintigraphy. Blood pharmacokinetics of teicoplanin administered either intravenously or by nebulization was compared. RESULTS: No decrease of antibiotic activity was observed after nebulization. In vitro cytotoxicity of teicoplanin was only observed with 1000 times the dose recommended for intravenous administration. Volume median diameter of particles was 2.5±0.1 µm. Of the initial nebulizer charge of teicoplanin, 24±7% was present in the lungs of ventilated pigs after the nebulization. Amount absorbed in blood was low (3.4%±0.9%) after nebulization, and blood stream elimination half-life value was 25.4 h. CONCLUSIONS: Teicoplanin was administered efficiently by nebulization during mechanical ventilation, without any effect on its pharmacological properties or any cytotoxicity. The pharmacokinetic parameters are promising in view of its time-dependent killing process. All the results of our multi-step study highlighted the potential of teicoplanin to be nebulized during mechanical ventilation.

Impact of the agar medium and disc type on disc diffusion susceptibility testing against teicoplanin and vancomycin.

Susceptibility to teicoplanin and vancomycin was assessed by three disc types: two commercially available discs (NeoSensitabs and PDM disc (30 micrograms)) and one locally prepared 30 micrograms disc (SS disc) on four different medium types: Mueller-Hinton agar (MH medium), MH medium and PDM agar II supplemented with 5% horse blood (HMB medium and PDM medium, respectively), and Danish blood agar (DBA medium). Two previously studied groups of Gram-positive bacteria were tested: group B (N = 75) comprised miscellaneous cocci, and group C (N = 59) mostly rods. With NeoSensitabs, mean zone diameters were larger than with PDM and SS discs on all medium types, and mean zone diameters were larger on DBA medium than on MHB and PDM medium with all disc types. The impact of the medium type on the zone diameter was evaluated for 121 strains growing on MHB medium, PDM medium, and DBA medium. Bacterial groups B and C each divided into three MIC groups were analysed separately. We compared mean zone diameters for each specific group with the average zone diameter, i.e. the mean value for all zone diameters obtained. The smallest deviations from the average zone diameters were observed on PDM medium for both teicoplanin and vancomycin. Thirty-seven percent of strains failed to grow on MH medium, but supplementation of MH medium with horse blood significantly reduced the zone diameter for group B strains both for teicoplanin and vancomycin. Poor predictability of MIC from the zone diameter was found especially for strains with MICs < or = 1 microgram/ml. The medium type hardly affected the results of regression analysis. In contrast, the medium type markedly affected the results of error-rate bounded analysis. No errors were recorded with the SS disc on MHB medium for either teicoplanin or vancomycin, but no strains with MICs of vancomycin within the intermediate group could be correctly classified on DBA medium.

Nephrotoxicity of teicoplanin in rats.

Teicoplanin, a glycopeptide antibiotic, is marketed in a number of European countries and has recently been put on the market in Japan. The spectrum of antibacterial activity of teicoplanin is equivalent or superior to that of vancomycin. The aim of the present study is to examine the nephrotoxicity of teicoplanin compared with vancomycin in rats. Wistar male rats, housed in a light-controlled room at room temperature for 1 week, were used. They were injected with either 15 or 50 mg/kg/day of teicoplanin or 50 or 200 mg/kg/day of vancomycin at 13:00 daily for 14 days. The rats were randomly assigned to groups of five rats each and were housed individually in metabolic cages to collect urine. Urine samples were collected 24 hours prior to the drug treatment and every 24 hours thereafter for 14 days. N-Acetyl-beta-D-glucosaminidase (NAG) activity was determined in the supernatant and expressed in international units per total urine collected for 24 hours. The group which was given vancomycin 200 mg/kg/day had significantly elevated urinary NAG levels compared with the other groups (p < 0.05). No significant differences were observed in the NAG levels in urine among the remaining three groups. These results suggest that the nephrotoxicity of teicoplanin may be only one-fourth that of vancomycin in rats. It appears that by extrapolating the dose amount required for the treatment in humans to rats, the high dose of teicoplanin was set at 50 mg/kg/day and that of vancomycin, 200 mg/kg/day. The recommended dose for teicoplanin will probably be 200 mg/day compared to 2 g/day of vancomycin. If the teicoplanin dose is only one-tenth that of the vancomycin dose, then teicoplanin should be better tolerated than vancomycin in terms of nephrotoxicity.

Participation of GABA-ergic system in epileptogenic activity induced by teicoplanin in mice.

PURPOSE: The present study was undertaken to clarify the participation of the GABA-ergic system in epileptogenic activity induced by teicoplanin. METHODS: Under pentobarbital anesthesia, mice were fixed to a stereotaxic apparatus, and stainless steel electrodes were implanted into the frontal cortex (FCOR), hippocampus (HPC) and amygdala (AMG). Behavioral and electroencephalographic (EEG) changes were observed for 60min following teicoplanin intracerebroventricular (i.c.v.) injection. RESULTS: I.c.v. injection of teicoplanin caused dose-related behavioral and EEG seizures. MK-801 (N-methyl-d-aspartate receptors antagonist) had no significant influence on either behavioral or EEG seizures induced by teicoplanin (500microg, i.c.v.). On the other hand, NNC-711 (GABA transporters inhibitor) dose-dependently antagonized behavioral and EEG seizures induced by teicoplanin (500microg, i.c.v.). The inhibitory effect of NNC-711 (10mg/kg, i.p.) on teicoplanin-induced epileptogenic activity was antagonized by bicuculline (GABA(A) receptor antagonist) but not by TPMPA (GABA(C) receptor antagonist). CONCLUSIONS: It is reasonable to presume that teicoplanin-induced epileptogenic seizures are closely related with GABA-ergic mechanisms through GABA(A) receptors rather than GABA(C) receptors.

Epileptogenic activity induced by teicoplanin and effects of some antiepileptics in mice.

The present study was undertaken to clarify the epileptogenic activity induced by intracerebroventricular injection (i.c.v.) of methicillin-resistant Staphylococcus aureus (MRSA) antibiotics in mice. Teicoplanin (200 microg, i.c.v.) caused dose-related behavioral seizures such as head twitch and forelimb clonus. At the same time, the drug caused electroencephalographic (EEG) seizures characterized by spike-and-wave complex and a continuous spike with high amplitude. At a high dose (500 microg, i.c.v.), the drug caused a severe clonic convulsion followed by continuous spike and spike-and-wave complex on EEG. On the other hand, vancomycin caused no or almost no epileptogenic activity in both behavior and on EEG. Diazepam and sodium valproate dose-dependently antagonized epileptic seizures in behavior and on EEG induced by teicoplanin (500 microg, i.c.v.). In contrast, carbamazepine and ethosuximide caused no significant changes in both behavioral and EEG seizures induced by teicoplanin. From these findings, it can be concluded that teicoplanin may cause potent epileptogenic activity different from vancomycin when used clinically at extremely high doses. In addition, it may be that teicoplanin-induced seizure is closely related with the gamma-amino butyric acid (GABA)-ergic mechanism.

Epileptogenic activity of methicillin-resistant Staphylococcus aureus (MRSA) antibiotics in rats.

The present study was undertaken to clarify the epileptogenic activity induced by intracerebroventricular injection (i.c.v.) of antibiotics effective in methicillin-resistant Staphylococcus aureus (MRSA) in chronically electrode implanted rats. Teicoplanin (10-100 microg, i.c.v.) caused dose-related electroencephalographic (EEG) seizure characterized by an uninterrupted high voltage and wave complex. At the same time, the rats showed forelimb clonus, head nodding, jumping and severe convulsion. At a high dose (100 microg, i.c.v.), the drug caused a severe twisting immediately after the intracerebroventricular injection (i.c.v.) followed by jumping and violent convulsion with a continuous rhythmic spike and wave complex in EEG. On the other hand, vancomycin (30-1000 microg, i.c.v.) caused no or almost no epileptogenic activity in terms of behavior and in EEG. However, at a high dose (1000 microg, i.c.v.), the drug caused an occasional spike from the hippocampus without showing any behavioral changes in the rats. Fosfomycin (30-1000 microg, i.c.v.), cefazolin (10-100 microg, i.c.v.) and penicillin G (30-300 microg, i.c.v.), used as reference drugs, caused dose-dependent epileptogenic activity in both EEG. From these findings, it was found that teicoplanin caused a potent epileptogenic activity, different to vancomycin. Therefore, it can be concluded that vancomycin may be safety on epileptogenic activity used for the clinical purpose of infections caused by MRSA.

Statistical analysis of the adverse effects of glycopeptide antibiotics, based on pharmacokinetics and toxicokinetics (PK/TK).

The effects of vancomycin hydrochloride (VCM) and teicoplanin complex (TEIC) on hepatic function and renal function were evaluated in rats. VCM was injected via the jugular vein at doses of 40, 100, and 250 mg/kg, and TEIC was injected via the jugular vein at doses of 10, 30, 40, 50, and 60 mg/kg, both after being dissolved in 1 ml of saline solution. Increased doses of VCM significantly increased the integrated plasma concentrations, from 0 to 8 h, for blood urea nitrogen (BUN(0-8)) and serum creatinine (SCr(0-8)). TEIC gave rise to a slight increase in both BUN(0-8) and SCr(0-8) as its dose was increased. On the other hand, TEIC significantly increased the integrated plasma concentrations, from 0 to 8 h, for aspartate aminotransferase (AST(0-8)), and alanine aminotransferase (ALT(0-8)), at doses from 40 mg/kg to 60 mg/kg, though VCM did not increase these concentrations. This study suggests the importance of paying attention to hepatic function--in addition to renal function--when TEIC is administered to patients with methicillin-resistant Staphylococcus aureus (MRSA).

A comparative study of enzymuria, in the rat, of the drug combinations amikacin/vancomycin and amikacin/teicoplanin.

The aim of this study was to compare nephrotoxicity of the combinations amikacin/vancomycin and amikacin/teicoplanin. Eighteen male Wistar rats were divided into 3 groups of 6 animals each. The first group received 50 mg.kg-1 of amikacin (i.m. route) and 100 mg.kg-1 of vancomycin (i.p. route). The second group received 50 mg.kg-1 of amikacin (i.m. route) and 40 mg.kg-1 of teicoplanin (i.p. route). The third group received an isotonic solution of sodium chloride. The antibiotics were injected for a period of 6 days. Urine samples of animals were taken 24 h before the beginning of the experiment, then every day, throughout the duration of the treatment (6 days), continuing for an additional 3 days following completion of the administration of the drugs. There were no significant modifications in the urinary excretions of alanine aminopeptidase and the creatinine between the 3 groups; but in the group receiving amikacin/teicoplanin, we observed between days 3 and 8 an increase in the excretion of N-acetyl-beta-D- glucosaminidase when compared to the group receiving amikacin/vancomycin (p < or = 0.05) and to the control group (p < or = 0.01).

Endothelial cell compatibility of glycopeptide antibiotics for intravenous use.

The use of human venous endothelial cells for testing antibiotic solutions for intravenous compatibility provides a valuable alternative to animal models. In order to evaluate the effect of vancomycin and teicoplanin on the viability of human umbilical venous endothelial cells, intracellular ATP levels were measured by a luciferin-luciferase assay. Prostacyclin (PGI2) and thromboxane A2 (TXA2) were determined by direct radioimmunoassay. Vancomycin at concentrations of 5 and 10 mg/mL reduced the intracellular ATP content by 18.7% and 69.9%, respectively, within 60 min. In contrast, cellular energy charge remained significantly higher after incubation with teicoplanin at 5 and 10 mg/mL (reduction 8.7% and 15.5%, respectively). Neither vancomycin nor teicoplanin at a concentration of 2 mg/mL led to significant ATP decline. However, endothelial cells incubated with vancomycin resulted in significantly lower release of PGI2 and TXA2 compared with teicoplanin. These results show that teicoplanin is more compatible with endothelial cells than vancomycin, and that both antibiotics are well tolerated if diluted to a final concentration of 2 mg/mL.