Teicoplanin Concentrations Research Articles

The persistence of drug-induced fever by teicoplanin – a case report

It was reported that the drug-induced fever of teicoplanin tended to persist after cessation of treatment. It is considered that the long half-life of teicoplanin causes the phenomenon. However there was no detailed report regarding plasma concentration of teicoplanin during onset of drug induced-fever. Therefore we investigated the relation between persistence of drug-induced fever and plasma concentration of teicoplanin. A 38-year-old male patient on the Left Ventricular Assist System (LVAS) was treated with teicoplanin for methicillin-resistant Staphylococcus aureus (MRSA) and he experienced drug-induced fever. Plasma concentrations of teicoplanin were measured not only during the treatment with the drug but also after it was discontinued. As such, plasma concentration was measured even when the fever had subsided. On Day 9 of treatment, the dose was increased from 400 to 600 mg, but the patient had a fever of about 38 - 39 °C. When the treatment was discontinued, it took 9 days for the fever to subside to a temperature of about 37 °C. The half-life of elimination of teicoplanin in the elimination phase is about 108 h, which is long. The fever persisted until the plasma concentration decreased to below 10 µg/ml, which is the effective trough concentration, and subsided when the estimated blood concentration was 7.5 µg/ml. We suggest that there is the possibility that the drug-induced fever due to teicoplanin persisted until the plasma concentration had decreased adequately. Close monitoring of plasma concentration is necessary, particularly when teicoplanin clearance is decreased such as in patients with renal dysfunction.

Long-term stability of teicoplanin in dialysis fluid: Implications for the home-treatment of CAPD peritonitis

Abstract The long-term stability of teicoplanin in dialysis solution was determined at various storage temperatures. The investigation was undertaken using dialysis solution (1.36 per cent glucose) containing 25mg/L teicoplanin. Stability under refrigerated conditions (4°C), room temperature (representing typical home storage conditions of 20°C) and body temperature (37°C) was determined in triplicate over a 42 day period. Samples (5ml) from each dialysis bag were taken at 0, 1, 2, 5, 7, 10, 14, 21, 28 and 42 days. Measurement of teicoplanin was by stability-indicating bioassay involving a standard plate technique using spore suspensions of Bacillus subtilis. All bioanalyses were performed in triplicate. Loss of teicoplanin activity of more than 10 per cent was indicative of instability. At 4°C, the mean concentration (±SD) of teicoplanin over the 42-day period was 24.05±1.53mg/L with a coefficient of variation of 6.36 per cent. However, loss in antibiotic activity was observed at the higher temperature storage conditions. At 20°C, a 10 per cent reduction in activity occurred after 25 days' storage; at 37°C it occurred after seven days. Therefore, teicoplanin is stable in dialysis fluid but the storage conditions have a marked effect on shelf-life.

Induction kinetics of the Staphylococcus aureus cell wall stress stimulon in response to different cell wall active antibiotics

BackgroundStaphylococcus aureus activates a protective cell wall stress stimulon (CWSS) in response to the inhibition of cell wall synthesis or cell envelope damage caused by several structurally and functionally different antibiotics. CWSS induction is coordinated by the VraSR two-component system, which senses an unknown signal triggered by diverse cell wall active agents.ResultsWe have constructed a highly sensitive luciferase reporter gene system, using the promoter of sas016 (S. aureus N315), which detects very subtle differences in expression as well as measuring > 4 log-fold changes in CWSS activity, to compare the concentration dependence of CWSS induction kinetics of antibiotics with different cell envelope targets. We compared the effects of subinhibitory up to suprainhibitory concentrations of fosfomycin, D-cycloserine, tunicamycin, bacitracin, flavomycin, vancomycin, teicoplanin, oxacillin, lysostaphin and daptomycin. Induction kinetics were both strongly antibiotic- and concentration-dependent. Most antibiotics triggered an immediate response with induction beginning within 10 min, except for tunicamycin, D-cycloserine and fosfomycin which showed lags of up to one generation before induction commenced. Induction characteristics, such as the rate of CWSS induction once initiated and maximal induction reached, were strongly antibiotic dependent. We observed a clear correlation between the inhibitory effects of specific antibiotic concentrations on growth and corresponding increases in CWSS induction kinetics. Inactivation of VraR increased susceptibility to the antibiotics tested from 2- to 16-fold, with the exceptions of oxacillin and D-cycloserine, where no differences were detected in the methicillin susceptible S. aureus strain background analysed. There was no apparent correlation between the induction capacity of the various antibiotics and the relative importance of the CWSS for the corresponding resistance phenotypes.ConclusionCWSS induction profiles were unique for each antibiotic. Differences observed in optimal induction conditions for specific antibiotics should be determined and taken into account when designing and interpreting CWSS induction studies.

An assessment of teicoplanin use and monitoring serum levels in a Chinese teaching hospital

To validate a high performance liquid chromatography (HPLC) method for serum teicoplanin measurement and use the method for clinical monitoring of teicoplanin levels to analyze the clinical application of teicoplanin. 55 patient profiles were collected and analyzed for the clinical teicoplanin application. 10 critically ill patients of the 55 cases were monitored for teicoplanin trough concentration using the HPLC method. The modified HPLC method exhibited excellent linearity, with correlation coefficient r = 0.9995. The intra-day and inter-day coefficients of variation were less than 10%. The lower limit of detection of teicoplanin was 5.63 mg/l. The recovery of teicoplanin was above 90%. Of the 55 patients in this study, there were 42 patients without load-dosing. There were only 29 patients treated with teicoplanin documented Gram-positive infections by etiological diagnoses. In the 10 patients with teicoplanin serum trough concentration monitoring, all cases received a loading dose of 400 mg every 12 h for 3 doses, and the mean trough concentration of teicoplanin was 10.82 ± 4.51 mg/l. The mean trough levels were 13.04 ± 6.23 mg/l in 4 patients with microbiological eradication and improvement of symptoms of diseases and 9.34 ± 2.61 mg/l in 6 patients with persistence of previous clinical infectious symptoms, respectively. The modified HPLC method is robust, highly reproducible and suited to monitor the concentration of teicoplanin. In critically ill Chinese patients, we should consider more appropriate loading doses and evaluate the relationship between teicoplanin trough concentration and the efficacy using microbiological and clinical parameters.

Analyses of teicoplanin concentrations from 1994 to 2006 from a UK assay service

Objectives An analysis of the trough serum concentrations sent to the UK Antimicrobial Reference Laboratory for teicoplanin therapeutic drug monitoring (TDM). Methods All trough concentrations over a 13 year period were analysed and the percentages were calculated for the following: <10 mg/L (a sub-optimal concentration for all); ≥10-<20 mg/L (the target used for ordinary Gram-positive infections); ≥20-<60 mg/L (the target for all severe staphylococcal infections including endocarditis); and ≥60 mg/L (the concentration associated with toxicity). Results The percentage of patients with concentrations of <10 mg/L decreased each year to 13% in 2006. Almost 40% of the samples each year were in the ≥10-<20 mg/L range. In 1996, the percentage of samples in the ≥20-<60 mg/L range reached a study high of ∼70%. That percentage then fell to 30% and increased slowly to 50% at the end of the study. Fewer than 5% of the samples were ≥60 mg/L. Conclusions Our study shows that there is a need to increase the initial dose or extend the number of days that the loading dose is used in a significant number of patients. With such a wide optimal range and a low potential for toxicity, it is unclear why optimal therapy is not achieved in a higher percentage of patients.

Significance of individual adjustment of initial loading dosage of teicoplanin based on population pharmacokinetics

An initial loading dose of teicoplanin is required to reach the optimal trough concentration (≥10 μg/mL) rapidly. To attain the optimal teicoplanin concentration efficiently, an individual loading dose regimen based on population pharmacokinetics, in which the target trough concentration was set to 15 μg/mL, was defined. Among 70 patients, 33 patients received the individual loading dose regimen, 33 patients received the conventional loading dose regimen (200 mg or 400 mg every 12 h on Day 1 followed by 200 mg once daily) and 4 patients received no loading dose. The proportion of patients showing an optimal plasma concentration was 88% in the individual loading dose regimen but only 33% in the conventional loading dose regimen. No patient without a loading dose showed the optimal concentration. Both total loading dose and plasma concentration were significantly ( P < 0.001) higher in the individual loading dose group than in the conventional loading dose group. Notably, the trough concentration was almost constant in patients with individual loading doses ranging from 800 mg to 1800 mg. These findings suggest that individual adjustment of the initial loading dose of teicoplanin is potentially useful to attain the optimal concentration rapidly.

Methicillin resistant Staphylococcus aureus in a Japanese community hospital: 5-year experience

Methicillin resistant Staphylococcus aureus (MRSA) is exceptionally critical to infection treatment and control in the health-care setting. MRSA has been detected at high levels in Japan, and the frequency of MRSA infection must be ascertained to provide a baseline with which to assess various infection control efforts. We studied MRSA infection rate at a general hospital in Japan in all 65,135 inpatients of Sendai Kousei Hospital from January 2004 to December 2008. MRSA's prevalence among strains of S. aureus and the rate of MRSA detection were studied. Identification of MRSA infection is according to the laboratory-based ward liaison surveillance. The minimal inhibitory concentrations (MICs) of vancomycin, teicoplanin, and arbekacin for the various isolates were determined. During the period studied, there were 621 MRSA-positive patients. MRSA prevalence among strains of S. aureus was 45.5% (621/1,365). The rate of MRSA detection in inpatients was 0.953/100 inpatients. Of the 621 patients from whom MRSA was isolated, 51 (8.2%) had an MRSA infection (MRSA infection rate 0.078/100 inpatients). MRSA was often detected from the respiratory tract, but this seldom led to infection, since many of those affected were merely carriers. MICs against MRSA was 0.5-4μg/ml for vancomycin, 0.5-16μg/ml for teicoplanin, and 0.5 to >16μg/ml for arbekacin, with no tendency for tolerance observed for these drugs. Findings suggest that whereas MRSA remains prevalent, there is a low incidence of infection in a general hospital in Japan.

Did local teicoplanin delivery systems inhibit or aggravate implant-related infection?

Dear Editor, We read with great interest the article by Sener et al. [1] and would like to bring four issues to your attention. First, the authors analysed the difference in the bacterial density between four groups with repetitive Mann-Whitney U test. Unavoidably, type I error (α) would be magnified [2]. It would be appropriate to calibrate the P value as: [2]. Thus, we made a second statistical analysis (Table 1). The data showed, however, no difference was found between group 2 and group 3 nor between group 3 and group 4. Combined with the inferior performance of group 3 in both radiological findings and macroscopic findings, antibiotic-loaded bone cement did not show superiority over other treatment modalities. Table 1 Statistical results of subgroup comparison in microbiological evaluation Second, the results showed that teicoplanin-loaded bone graft could not help, and could even interfere, with the infection control. Apart from the mechanisms discussed by the authors, other interpretations may be considered (Fig. 1). For example, local subacute inflammation was assumed two weeks after the bacterial inoculation. Less encapsulation of granulation tissue and bone callus, more osteolysis and exudation, and greater hyperemia were anticipated compared with chronic osteomyelitis [3]. Also, teicoplanin releasing systems were placed at the fracture site, a more open space than the medullary cavity. As a result, the adopted model of implant-related infection might present greater dilution, absorption, distribution, and elimination of teicoplanin than that of chronic osteomyelitis [4]. Some hidden or distant bacteria might be spared from the locally compromised teicoplanin level and account for recurrence of infection. Moreover, it was reported that the length of time during which the local antibiotic level exceeded minimal inhibition concentration (T>MIC) highly predicted antimicrobial potency of glycopeptide releasing systems [4]. Applying morselised cancellous bone, lengthening the duration of immersion in antibiotic solution, and the technique of iontophoresis would facilitate the teicoplanin impregnation into bone and prolong the T>MIC [5]. The authors simply immersed the corticocancellous grafts in teicoplanin solution for only one hour. The adsorption was possibly far below the saturation threshold, which may underestimate the antimicrobial efficacy of teicoplanin-loaded bone grafts. To our disappointment, no in vivo investigation was attempted on the kinetics of antibiotic release from bone. Also, implant removal is a prerequisite for thorough debridement; however, the authors retained the infected implant, where bacteria colonised and biofilm probably developed (Fig. 1). It was difficult to reach effective antibiofilm concentrations of teicoplanin around the implant. Fig. 1 Schematic diagram of osteomyelitis models of subacute infection (a) and chronic infection (b). In comparison with the model of chronic osteomyelitis (b), the subacute animal model (a) had less encapsulation of granulation tissue and bone callus, more ... Third, substantial details concerning the fabrication of teicoplanin-loaded bone grafts and acrylic beads [5], such as the concentration and pH of teicoplanin solution, the surface area, the bulk volume and the weight of bone grafts and acrylic beads, were not mentioned, which made comparison on antimicrobial efficacy impossible. Fourth and finally, the authors indicated that use of antibiotic-loaded beads was superior to debridement and systematic antibiotic treatment while antibiotic-loaded autogenous bone was not. This did not seem reasonable. In fact, debridement and systematic teicoplanin treatment were also offered in groups 3 and 4. What differed from group 2 was additional teicoplanin-loaded beads and teicoplanin-loaded autogenous bone in groups 3 and 4, respectively. It seems more appropriate to conclude that the inhibition by both antibiotic delivery systems was inferior to their aggravation of infection.

Development of teicoplanin dosage guidelines for patients treated within an outpatient parenteral antibiotic therapy (OPAT) programme

The long elimination half-life of teicoplanin facilitates outpatient parenteral antibiotic therapy (OPAT) with thrice-weekly dosing. This study aimed to develop teicoplanin dosage guidelines for OPAT use from routine clinical data. Patients received 15-25 mg/kg/day for 3 days, then 15-25 mg/kg thrice weekly. Trough concentrations were measured weekly and doses adjusted to maintain 20-30 or 10-20 mg/L according to clinical condition. Concentration-time data were analysed using the pharmacokinetic package NONMEM and the final model was used to develop new dosage guidelines. Data from 94 and 36 patients were used for model development and validation, respectively. Patient ages ranged from 15 to 94 years, weights from 43 to 146 kg and estimated CL(CR) from 9 to 195 mL/min. Teicoplanin concentrations (n = 670) ranged from 6.7 to 66.9 mg/L and a one-compartment model adequately described the data. The typical estimate of CL was 0.542 L/h and changed by 10.6% for every 10 mL/min difference from a CL(CR) of 66 mL/min. V was 1.62 L/kg. Dosage guidelines based on body weight and CL(CR) can be expected to lead to a significant improvement in the proportion of concentrations in the range 20-30 mg/L. Alternative doses aimed at lower target concentrations have also been developed. New dosage guidelines have been developed to support thrice-weekly administration of teicoplanin in an OPAT setting.

Concentration and Bioavailability of Ciprofloxacin and Teicoplanin in the Cornea

To investigate the concentration and bioavailability of ciprofloxacin and teicoplanin in the cornea. A biological assay was developed with corneal tissue used as a carrier for the antimicrobial. Concentration and biological activity were determined with a chemical assay and zone of inhibition (ZOI) around corneal samples with epithelial and endothelial surfaces in contact with the indicator organism. Patients undergoing penetrating keratoplasty received ciprofloxacin 0.3% or teicoplanin 1%. There were good correlations between antimicrobial concentration and ZOI, when either filter paper or corneal discs were used (R(2) > 92%). Of 33 patients, the mean (median) concentration of ciprofloxacin in the cornea was 1.37 mg/L (0.46 mg/L) and 1.89 mg/L (1.44 mg/L; bioassay) in the epithelial and endothelial orientations, respectively, and 14.87 mg/L (7.41) in the cornea and 0.51 mg/L (0.42) in the aqueous (chemical assay). For teicoplanin, the mean (median) concentration in the cornea was 9.58 mg/L (0 mg/L) in the epithelial and 4.78 mg/L (0 mg/L) in the endothelial orientations (bioassay). In the chemical assay, teicoplanin could not be detected in the cornea or aqueous at the lower limit of detection of 3.6 mg/L. The ZOI produced by corneal tissue provides a potential bioassay of antimicrobial activity and concentration. Although in contrast to teicoplanin ciprofloxacin shows good corneal penetration, with high endothelial-to-epithelial levels, only approximately 10% of measured levels in a chemical assay are available, according to a bioassay. Teicoplanin shows relatively poor corneal penetration through intact epithelium. These methods may be useful in evaluating the biological activity across the cornea of antimicrobials introduced into ophthalmic practice to deal with changing bacterial resistance.

In Vitro Release of Fusidic Acid and Teicoplanin from Cancellous Bone Allografts

The characteristics of cancellous bone allografts as carriers of fusidic acid and teicoplanin are described. Particles of cancellous bone were compressed into a wire-mesh cylinder; five replicas were impregnated for one hour into fusidic acid; and another five for one hour into teicoplanin. Elution was estimated daily. Concentrations of fusidic acid and teicoplanin were determined by a microbiological assay. Both antibiotics were eluted at very high concentrations within the first days. Allografts impregnated in fusidic acid provided concentrations above 20 μg/ml for 20 days. Eluted teicoplanin after day 4 was below 10 μg/ml. It is concluded that cancellous bone allografts may allow adequate In Vitro elution of fusidic acid but not of teicoplanin. The latter results support their application in experimental models of osteomyelitis.

Method development for the determination of teicoplanin in patient serum by solid phase extraction and micellar electrokinetic chromatography

In-hospital deaths caused by the infection of methicillin-resistant Staphylococcus aureus (MRSA) are on the increase worldwide. Teicoplanin is a potent glycopeptide antibiotic against MRSA. A rapid and cost-saving micellar electrokinetic chromatography (MEKC) method combined with solid phase extraction (SPE) was developed and then validated to quantify teicoplanin in patient serum in this work. The method includes the following steps: (1) pretreatment of the serum samples with 10 M urea to denature proteins, (2) application of SPE by using an OASIS HLB cartridge to clean up and concentrate the serum samples, and (3) use of MEKC for sample analysis. Under the optimized conditions, the SPE recovery of teicoplanin is higher than 90%. The six major components of teicoplanin could be baseline-separated from one another and endogenous materials in 12 min with a background electrolyte composed of 20 mM sodium tetraborate buffer pH 8.8, 40 mM sodium dodecyl sulfate, and 11% (v/v) ACN. The relative standard deviation (R.S.D.) of the peak area ratios for method repeatability ( n = 6) and intermediate precision (inter-day, n = 3) were found to be lower than 4.18% and 5.30%, respectively. The calibration curves were linear between the chromatographic response and total teicoplanin concentration over the range of 5 μg/mL to 55 μg/mL. Limit of detection (LOD) for each of the six components was found to be lower than 0.06 μg/mL. Pearson’s correlation revealed that a good correlation ( r = 0.98) was obtained between the SPE–MEKC method and the fluorescence polarization immunoassay (FPIA) method. The developed method can be used to quantitatively determine serum teicoplanin concentration in patients for dose monitoring and clinical research.

Endophthalmitis: Gram Positive Ethiological Agents and Susceptibility to Glycopeptides

Endophthalmitis is a serious sight-threatening condition, with a postoperative incidence of 0.13 -0.7%. This study aimed to investigate the spectrum of Gram-positive bacteria causing culture-proven endophthalmitis and their susceptibility to teicoplanin and vancomycin. At this purpose, minimum inhibitory concentrations of teicoplanin and vancomycin of Gram-positive bacteria isolated in the period 2001--2007 from vitreous cultures were determined. Staphylococcus epidermidis was the most common organisms identified (31,8 %), followed by Staphylococcus aureus, Peptococcus spp. e Bacillus spp. All bacteria were susceptible to teicoplanin and vancomycin. The two drugs showed a comparable activity against staphylococci and bacilli, while teicoplanin was more potent against streptococci and anaerobes. In conclusion, teicoplanin showed a spectrum of activity similar or even better that of vancomycin against the most common ethiological agents of postoperative endophthalmitis.

A comparative in-vitro evaluation of resistance selection after exposure to teicoplanin, vancomycin, linezolid and quinupristin–dalfopristin in Staphylococcus aureus and Enterococcus spp.

The ability of breakpoint and serum concentrations of teicoplanin, vancomycin, linezolid and quinupristin-dalfopristin to select resistance was compared for isolates of methicillin-susceptible Staphylococcus aureus (MSSA), methicillin-resistant S. aureus (MRSA), Enterococcus faecalis and Enterococcus faecium. Mutation frequencies were always <10(-10), except for two isolates grown in the presence of teicoplanin at the trough serum concentration. After multistep selection, linezolid selected for resistance in staphylococci and enterococci, and serial exposure to certain concentrations of linezolid was more likely to select for stable resistance in MRSA, MSSA and enterococci than was exposure to glycopeptides and quinupristin-dalfopristin.

Bioluminescence imaging to study the promoter activity of hla of Staphylococcus aureus in vitro and in vivo

Alpha-toxin (Hla, encoded by hla) is a major virulence factor of Staphylococcus aureus. The activity of the hla promoter was analyzed using luxABCDE on an integration vector. The p hla– lux construct was introduced in S. aureus Newman and its isogenic sae and sigB regulator mutants. Promoter activity was monitored by bioluminescence in vitro and in the murine tissue-cage model. Hla promoter activity could be followed in real time at repeated time points of infection. The activation of hla in the sigB-deficient strain and the repression to background levels in a sae-deficient strain relative to hla expression in the wild type could be demonstrated in vivo. Subinhibitory concentrations of teicoplanin, imipenem and ciprofloxacin enhanced hla promoter activity in vitro whereas clindamycin and rifampicin did not. Our approach proved to be rapid and adequate to study promoter activity in vitro and in vivo under conditions where high bacterial numbers are reached.

Distribution and genetic relatedness of vancomycin-resistant enterococci (VRE) isolated from healthy slaughtered chickens in Hungary from 2001 to 2004

The presence of the vanA gene was determined in enterococci from healthy poultry, originating from the Hungarian resistance monitoring system between 2001 and 2004. Enterococci (n = 562) were collected from intestinal samples of slaughtered broiler chickens. The presence of van genes was detected by polymerase chain reaction (PCR). The vancomycin-resistant enterococcus (VRE) strains carried only the vanA gene. Genus- and species-level identification of the vanA gene carrier strains was carried out by PCR using specific primers. In 2001, 25 out of the 289 isolated strains (8.6%) were vanA carriers (1 Enterococcus mundtii, 13 E. durans and 11 E.faecium). In 2002 (n = 87), 20 (23%) strains were vanA positive (11 E. durans and 9 E. faecium). In 2003 and 2004, none of the strains (n = 95 and 91, respectively) were positive for the most common van genes. In 2003, there was only one strain for which higher minimum inhibitory concentrations (MIC) of vancomycin (4 mg/L) and teicoplanin (8 mg/L) were found. In 2004 there were three strains for which the MIC of vancomycin was 8 mg/L, and 2 strains and 1 strain with teicoplanin MICs of 4 mg/L and 8 mg/L, respectively. The potential similarity of these strains was studied by pulsed-field gel electrophoresis (PFGE). The VRE strains were not closely related to one another. The annual data of vancomycin resistance indicate an association between the recovery of vancomycin-resistant enterococci and the use of avoparcin in animal feeds. This study indicates that with the reduced use of antibiotics in food animals, it is possible to decrease the rate of resistant bacteria. Although the use of avoparcin had been banned in 1998, the VRE strains disappeared only five years later.

Comparative bactericidal activities of daptomycin, glycopeptides, linezolid and tigecycline against blood isolates of Gram-positive bacteria in Taiwan

In-vitro MICs and minimum bactericidal concentrations (MBCs) of daptomycin, linezolid, tigecycline, vancomycin and teicoplanin against Gram-positive bacteria were determined using the broth microdilution method for ten blood isolates each of methicillin-susceptible Staphylococcus aureus (MSSA), methicillin-resistant S. aureus (MRSA), including two vancomycin-intermediate S. aureus (VISA), vancomycin-resistant Enterococcus faecium and Enterococcus faecalis. One strain of VISA was tested in a time-kill synergism assay of daptomycin combined with oxacillin, imipenem, rifampicin and isepamicin. Daptomycin showed excellent in-vitro bactericidal activity against all the isolates tested, with no tolerance or synergism effects when combined with other agents, except with rifampicin against VISA. Vancomycin had better bactericidal activity against MRSA and MSSA than did teicoplanin. Linezolid had the poorest bactericidal activity against the isolates tested, with 100% tolerance by the MSSA and VRE isolates, and 80% tolerance by the MRSA isolates. Tolerance towards tigecycline was exhibited by 40% of the MRSA isolates, 100% of the MSSA and vancomycin-resistant E. faecalis isolates, and 90% of the vancomycin-resistant E. faecium isolates.

Glycopeptide Bone Penetration in Patients with Septic Pseudoarthrosis of the Tibia

In the treatment of bone infections, a major determinant of the clinical response is the active drug concentration at the infected site. Because of the high prevalence of meticillin (methicillin)-resistant staphylococci and enterococci, glycopeptides are widely used for the treatment of bone and joint infections, but data on their penetration into human bone are lacking. The aim of our study was to measure vancomycin and teicoplanin concentrations in infected human bone under steady-state conditions and verify their relationship with inflammatory markers, patient demographic characteristics and pharmacodynamic microbiological markers. Twenty-seven adult orthopaedic patients undergoing surgical debridement for septic pseudoarthrosis of the tibia and receiving either intravenous vancomycin (Vancocina) 1 g twice daily) or teicoplanin (Targosid) 10 mg/kg/day) were studied from January 2004 to January 2008. Plasma and bone specimens were simultaneously collected during surgery for pharmacokinetic and microbiological assays at a variable interval after antimicrobial administration. Bone samples were dissected into cortical and cancellous bone, cleaned of soft tissues, crushed and eluted into phosphate buffer. Necrotic samples and sequestra were not analysed.Plasma and bone antimicrobial concentrations were measured by a validated method of high-performance liquid chromatography with UV detection, and bone/plasma concentration ratios were calculated. Cortical and cancellous bone area under the concentration-time curve (AUC) over 24 hours (AUC(24)) values were measured by the linear-log trapezoidal rule, using WinNonlin) software, and were compared with the minimum inhibitory concentrations (MICs) of the infecting agents. For vancomycin, the mean +/- SD concentrations were 2.66 +/- 1.2 mg/L in cortical bone and 11.53 +/- 7.8 mg/L in cancellous bone (corresponding to 20.67% and 89.39% of intraoperative plasma concentrations), and the mean +/- SD tissue AUC(24) values were 55.15 +/- 25.26 h . mg/L for cortical bone and 299.16 +/- 299.54 h . mg/L for cancellous bone. For teicoplanin, the mean +/- SD concentrations were 2.01 +/- 1.7 and 7.51 +/- 7.0 mg/L in cortical and cancellous bone, respectively (12.35% and 48.6% of intraoperative plasma concentrations), and the mean +/- SD teicoplanin tissue AUC(24) values were 34.08 +/- 23.6 h . mg/L and 155.17 +/- 132.8 h . mg/L for cortical bone and cancellous bone, respectively. The mean vancomycin AUC(24)/MIC ratios were 215.02 for plasma, 47.14 for cortical bone and 268.95 for cancellous bone. The mean teicoplanin AUC(24)/MIC ratios were 336.48, 36.27 and 197.21 for plasma, cortical bone and cancellous bone, respectively. Bone penetration of both glycopeptides ranged from poor (<15%) to satisfactory (15-30%) in the cortical compartment, while it was far higher into the highly vascularized cancellous tissue. Vancomycin bone penetration was slightly higher than with teicoplanin, but the difference was not statistically significant. Higher bone concentrations were observed with higher inflammatory markers, possibly as a result of increased vascularization and vascular permeability under inflammatory conditions. Bone concentrations over the MIC and AUC/MIC ratios suggested that both glycopeptides achieve a satisfactory pharmacokinetic exposure in the cancellous bone, as far as Gram-positive pathogens are concerned. On the other hand, cortical bone exposure was suboptimal in most patients. Furthermore, as antimicrobial penetration may be affected by impaired blood supply, the role of radical surgical removal of purulent and necrotic tissues appears to be essential in order to shorten treatment duration and to reduce the risk of treatment failure.

Variability in Teicoplanin Protein Binding and Its Prediction Using Serum Albumin Concentrations

The impact of lower serum albumin levels on teicoplanin pharmacokinetics has not been previously determined. The authors assessed the relationship between total and free concentrations of teicoplanin in serum samples obtained from patients receiving teicoplanin therapy for Gram-positive bacterial infections. In addition, the authors determined the contribution of serum albumin concentrations to the unbound fraction of teicoplanin. One hundred ninety-eight serum samples were obtained from 65 patients undergoing routine therapeutic drug monitoring of teicoplanin. Free serum teicoplanin was separated by ultrafiltration, and total and free serum concentrations of teicoplanin were determined by a fluorescence polarization immunoassay. Regression analysis was then performed to build a prediction model for the free serum teicoplanin concentration from the total serum teicoplanin concentration and the serum albumin level using the first 132 samples. The predictive performance of this model was then tested using the next 66 samples. Free serum teicoplanin concentrations (Cf) (mug/mL) were predicted using a simple model constructed using total serum teicoplanin (Ct) (mug/mL) and albumin concentrations (ALB) (g/dL): Cf = Ct/(1 + 1.78 * ALB). This model could estimate free serum teicoplanin concentrations with a small bias and an acceptable error. The measured free level of teicoplanin will lie between 0.63 and 1.38 times the predicted concentration in 95% of cases. Serum albumin level plays a major role in the variability of the fraction unbound of teicoplanin. This model can reliably estimate free serum teicoplanin concentrations more easily than by using direct measurements.

A post-authorization survey to evaluate plasma concentrations of teicoplanin in adult hospitalized patients treated for sepsis in Gauteng, South Africa

A post-authorization survey to evaluate plasma concentrations of teicoplanin in adult hospitalized patients treated for sepsis in Gauteng, South Africa