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• The POSY-TEICO study assessed the safety of HLD teicoplanin in a real-world setting. • Incidence of nephrotoxicity with HLD of teicoplanin was determined. • Nephrotoxicity of HLD of teicoplanin was compared with historical data of vancomycin. • Nephrotoxicity was 11.0% and 6.9% in loading and maintenance dose periods, respectively. • Nephrotoxicity certainly/possibly related to teicoplanin was 12.4% in complete study period. Teicoplanin is used for treating infections caused by Gram-positive bacteria. The POSY-TEICO study assessed the safety of a high loading dose (HLD) of teicoplanin (12 mg/kg twice daily) in a real-world setting. This prospective study was conducted across six countries in Europe and enrolled adults prescribed HLD of teicoplanin between 2016 and 2019. The primary objective was to determine the incidence of nephrotoxicity following HLD of teicoplanin over loading dose period. An independent clinical adjudication committee (ICAC) assessed all study outcomes related to nephrotoxicity. The study included 300 patients (males, 68.3%), with a mean age of 63.1 years and median teicoplanin treatment duration of 16 days (interquartile range: 9–38). The number of patients with bone and joint infection, infective endocarditis, and other severe infections was 176, 36, and 80, respectively. During the loading dose period, 41 (13.8%) patients received 3 HLDs and 246 (82.8%) received ≥4 HLDs. Overall, 28 (11.0%) patients (95% CI, 7.4–15.5) experienced nephrotoxicity during loading, and 10 (6.9%) patients (95% CI, 3.4–12.4) during maintenance dose periods. The number of patients who experienced nephrotoxicity certainly or possibly related to teicoplanin according to the ICAC was 20 (7.9%; 95% CI, 4.9–11.9), 8 (5.6%; 95% CI, 2.4–10.7) and 33 (12.4%; 95% CI, 8.7–16.9) across three study periods. HLD of teicoplanin had an acceptable safety profile in patients treated for bone and joint infection, infective endocarditis, and other severe infections, and no increased risk of nephrotoxicity was observed. However, patients should be closely monitored when HLDs are administered. [ABSTRACT FROM AUTHOR]

Highlights • Teicoplanin (TEC) can be used as an alternative first-line treatment in E. faecium infective endocarditis (IE). • TEC may be salvage therapy in select E. faecalis IE patients having adverse events with standard regimens or to allow OPAT. • There were no relapses when using TEC in this cohort of 22 episodes of enterococcal IE. ABSTRACT This study aimed to evaluate the effectiveness and safety of teicoplanin for treating enterococcal infective endocarditis (EIE). A retrospective analysis of a prospective cohort of definite EIE patients treated with teicoplanin in a Spanish referral centre (2000–2017) was performed. The primary outcome was mortality during treatment. Secondary outcomes were mortality during 3-month follow-up, adverse effects and relapse. A total of 22 patients received teicoplanin, 9 (40.9%) as first-line (8 Enterococcus faecium and 1 Enterococcus faecalis) and 13 (59.1%) as salvage therapy (13 E. faecalis). Median (IQR) age was 71.5 (58.3–78) years and Charlson comorbidity index was 4.5 (3–7). Five (22.7%) affected prosthetic valves. Median duration of treatment in survivors was 53 (42.5–61) days for antibiotics and 27 (17–41.5) days for teicoplanin [median dose 10 (10–10.8) mg/kg/day]. Reasons for teicoplanin use were resistance to β-lactams (40.9%), adverse events with previous regimens (31.8%) and outpatient parenteral antimicrobial therapy (OPAT) (27.3%). Teicoplanin was withdrawn due to adverse events in 2 patients (9.1%). Five patients (22.7%) died during treatment: four in the first-line (three with surgery indicated but not performed) and one in the salvage therapy group (surgery indicated but not performed). Two deaths (11.8%) occurred over the 3-month follow-up. There were no relapses during a median of 43.2 (22.1–69.1) months. Teicoplanin can be used as an alternative treatment for susceptible E. faecium IE and as a salvage therapy in selected patients with E. faecalis IE when adverse events develop with standard regimens or to allow OPAT. [ABSTRACT FROM AUTHOR]

Highlights • Antimicrobial protein LL-37 synergizes with teicoplanin against Staphylococcus aureus. • Synthetic antimicrobial and antibiofilm peptide (SAAP)-148, SAAP-276 and TC84 also synergize with teicoplanin. • Teicoplanin and synthetic peptides synergize in the eradication of S. aureus biofilms. • dltABCD and mprF in S. aureus confer resistance to LL-37, but not to SAAP-148. • Loss of synergy compared with Δ dlt A strain, suggesting teicoplanin interaction with teichoic acids. ABSTRACT Antibiotic resistance and biofilm formation are the main reasons for failure in treatment of bacterial infections. This study aimed to identify synergistic combinations of conventional antibiotics and novel synthetic antimicrobial and antibiofilm peptides (SAAPs) inspired by the structures of the natural human cationic peptides LL-37 and thrombocidin-1 (TC-1). The LL-37-inspired lead peptide SAAP-148 was combined with antibiotics of different classes against Staphylococcus aureus , and showed synergy with teicoplanin. Synergy with teicoplanin was also observed with LL-37, the LL-37-inspired SAAP-276 and the TC-1-inspired TC84. Interestingly, no synergy was observed against Staphylococcus epidermidis. Furthermore, teicoplanin combined with SAAP-148 or SAAP-276 showed strong interaction against S. aureus biofilms. The dltABCD operon and the mprF gene in S. aureus conferred resistance to LL-37, but SAAP-148 proved to be indifferently potent against wild-type, Δ dltA and Δ mprF S. aureus strains. When used alone, relatively high concentrations of both LL-37 and teicoplanin (30–120 µM and 4–32 mg/L, respectively) were required to kill S. aureus. Resistance to LL-37 in S. aureus was overcome by combined use of teicoplanin and LL-37. Thus, teicoplanin potentiates peptide LL-37, enhancing the efficacy of the innate defence, and combining the novel peptides with teicoplanin offers potential for enhanced efficacy of treatment of S. aureus infections, including biofilms. [ABSTRACT FROM AUTHOR]

Highlights • Different STs carrying the same chromosomal integrated Tn 1549 -like transposon, with a highly mutated vanB 2 -operon associated to teicoplanin resistance were detected in Vietnam. • Two unusual vanA/vanB 2 - type strains were detected within the vanB 2 -type ST17 population, harboring a Tn 1546-vanA -like transposon in pJEG40-like plasmids in Vietnam. • Microevolution among ST17 isolates, including the vanA/vanB 2 -type strains, and inter-wards VREf transmission were highlighted. Abstract Enterococcus faecium has become a globally disseminated nosocomial pathogen mainly because of acquisition and diffusion of virulence factors and multidrug resistance determinants, including glycopeptides, which are some of the last resort antimicrobials used to treat more serious infections common in high-risk patients. In this study we investigated and characterized hospital-associated (HA) E. faecium isolates collected at Hue Central Hospital, Vietnam. Our results highlighted the spread among hospital wards of a surprisingly heterogeneous multidrug-resistant E. faecium population comprising five different CC17-related sequence types (STs), of which 46% VREf carry the vanB gene. Whole genome sequencing of selected E. faecium isolates showed that VREf from different STs carried the same chromosomal integrated Tn1549-like transposon, with a highly mutated vanB2-operon, showing an increased level of vancomycin resistance (VanB phenotype) and able, in one isolate, to confer resistance to teicoplanin (VanA incongruent phenotype). Two unusual vanA/vanB 2 -type strains were detected within the vanB 2 -type ST17 population, harbouring a Tn 1546- vanA-like transposon in pJEG40-like plasmids. Wg-SNPs-based analysis showed the genetic relatedness of VSEf/VREf of the same STs and indicated lateral exchange of the Tn 1549 -like element among isolates followed by clonal expansion. Microevolution among ST17 isolates, including the vanA/vanB 2 -type strains, and inter-wards VREf transmission, were highlighted. The use of teicoplanin is strongly discouraged in the study hospital because of the spreading of Tn 1549 – vanB 2 associated to teicoplanin resistance. A rational use of glycopeptides and effective surveillance measures are required to reduce nosocomial VSEF/VREf spread and to avoid the rise of unusual and misleading VREf genotypes. [ABSTRACT FROM AUTHOR]

• ST1421 VVE E. faecium are associated with vanHAX and lack vanRS and vanZ. • Resistance reversion was due to increased vanA plasmid copy number and 44-bp deletion in vanHAX -promoter region. • Reversion occurred at a frequency below the detection limit of standard AST. • The reversion is initially associated with an increased fitness cost. Vancomycin variable enterococci (VVE) are van -positive enterococci with a vancomycin-susceptible phenotype (VVE-S) that can convert to a resistant phenotype (VVE-R) and be selected for during vancomycin exposure. VVE-R outbreaks have been reported in Canada and Scandinavian countries. The aim of this study was to examine the presence of VVE in whole genome sequenced (WGS) Australian bacteremia Enterococcus faecium (Efm) isolates collected through the Australian Group on Antimicrobial resistance (AGAR) network. Eight potential VVE Aus isolates, all identified as Efm ST1421, were selected based on the presence of vanA and a vancomycin-susceptible phenotype. During vancomycin selection, two potential VVE-S harboring intact vanHAX genes, but lacking the prototypic vanRS and vanZ genes, reverted to a resistant phenotype (VVE Aus -R). Spontaneous VVE Aus -R reversion occurred at a frequency of 4-6 × 10−8 resistant colonies per parent cell in vitro after 48 h and led to high-level vancomycin and teicoplanin resistance. The S to R reversion was associated with a 44-bp deletion in the vanHAX promoter region and an increased vanA plasmid copy number. The deletion in the vanHAX promoter region enables an alternative constitutive promoter for the expression of vanHAX. Acquisition of vancomycin resistance was associated with a low fitness cost compared with the corresponding VVE Aus -S isolate. The relative proportion of VVE Aus -R vs. VVE Aus -S decreased over time in serial passages without vancomycin selection. Efm ST1421 is one of the predominant VanA- Efm multilocus sequence types found across most regions of Australia, and has also been associated with a major prolonged VVE outbreak in Danish hospitals. [ABSTRACT FROM AUTHOR]

• Dalbavancin is a long-acting glycopepetide, approved for use in skin and soft tissue infections. • Limited data are currently available regarding the use of dalbavancin in deeper seated infections, such as infective endocarditis. • This article reviews the literature on the use of dalbavancin in infective endocarditis. • The data suggest that dalbavancin could be used as sequential treatment for infective endocarditis. Dalbavancin is a parenteral lipoglycopeptide antibiotic derived from teicoplanin, an analogue of vancomycin. It is mainly used for skin and soft tissue infections. The sustained half-life of approximately 14 days makes dalbavancin a novel option for potential use as sequential treatment in infections such as infective endocarditis, which require prolonged antibiotic courses. However, only a few studies have been reported in the literature, and the use of dalbavancin remains limited. This article is a review of the currently available literature using dalbavancin for the treatment of infective endocarditis due to Gram-positive organisms. Almost all patients received dalbavancin as sequential therapy following standard-of-care antibiotics. The overall clinical efficacy of dalbavancin was approximately 90%, and it appeared to be well tolerated. [ABSTRACT FROM AUTHOR]

In 2010, our hospital introduced a higher target teicoplanin trough concentration of ≥20 mg/L by Day 3 for haematological malignancy patients. This study aimed to explore whether target trough concentrations were achieved, to identify factors associated with trough concentrations attained, and to assess clinical efficacy with teicoplanin treatments and nephrotoxicity. This was a retrospective, single-centre, cohort study of 172 teicoplanin treatments in 104 adults with haematological malignancy. Mixed-effects regression was used to evaluate factors affecting trough concentrations, and logistic regression was used to assess the relationship between trough concentrations and treatment outcomes. Nephrotoxicity was assessed using the RIFLE criteria. Considerable variability in trough concentrations was observed, with trough concentrations ≥20 mg/L rarely achieved early in therapy. A mixed-effects regression model explaining 52% of the variation in trough concentrations was developed. Dose and day of therapy were positively associated with trough concentration, whilst estimated renal function and, interestingly, acute myeloid leukaemia diagnosis were negatively associated (P < 0.05). Results suggested a positive relationship between trough concentration and the likelihood of a favourable outcome for coagulase-negative staphylococcal central line-associated bloodstream infections. Elucidation of a specific target concentration requires further investigation. Teicoplanin was well tolerated renally. Findings suggest a risk of underexposure if conventional teicoplanin doses are used in haematological malignancy patients. Given the variability in trough concentrations observed, the identified factors affecting trough concentrations attained and the suggested link with clinical outcome, individualised initial dosing followed by therapeutic drug monitoring is recommended to ensure early adequate exposure in this vulnerable patient group. [ABSTRACT FROM AUTHOR]

There is large interindividual variability in serum teicoplanin (TEIC) concentrations after administration of a loading dose, and the factors that influence the pharmacokinetics of TEIC are disputed. The aim of this study was to clarify changes in the pharmacokinetics of TEIC that occur in patients with hyperglycaemia as well as the impact of albumin glycosylation on the pharmacokinetics of TEIC. This study consisted of retrospective and prospective investigations. The pharmacokinetic parameters of TEIC were retrospectively compared between patients receiving TEIC treatment. Ninety-four patients were divided into four groups according to their serum albumin and blood glucose concentrations [(i) hyperglycaemic hypoalbuminaemia (albumin < 3.0 g/dL) ( n = 16); (ii) non-hyperglycaemic hypoalbuminaemia ( n = 29); (iii) hyperglycaemic normoalbuminaemia (albumin ≥ 3.0 g/dL) ( n = 9); and (iv) non-hyperglycaemic normoalbuminaemia ( n = 40)]. In addition, the concentration of glycosylated albumin was prospectively determined in 28 patients. At 12 h after administration of a loading dose, patients with hyperglycaemic hypoalbuminaemia displayed significantly lower serum TEIC concentrations ( P < 0.05) and higher TEIC volume of distribution ( V d ) ( P < 0.05) than the other three groups, whereas TEIC clearance did not differ significantly among the groups. In addition, the percentage of glycosylated albumin was significantly correlated with the association constant ( K a ) of TEIC for albumin ( r = 0.53, P = 0.004) and the V d ( r = 0.41, P = 0.031). These results suggest that hyperglycaemic hypoalbuminaemia lowers the serum TEIC concentration, which is attributable to the decreased K a and increased V d of TEIC by albumin glycosylation. [ABSTRACT FROM AUTHOR]

The impact of decreased serum albumin concentrations on free antibiotic concentrations in non-critically ill patients is poorly described. This study aimed to describe the pharmacokinetics of a high-dose regimen of teicoplanin, a highly protein-bound antibiotic, in non-critically ill patients with hypoalbuminaemia. Ten patients with chronic bone sepsis and decreased serum albumin concentrations (<35 g/L) receiving teicoplanin 12 mg/kg 12-hourly intravenously for 48 h followed by 12 mg/kg once daily were enrolled. Surgical debridement was performed on Day 3. Samples of venous blood were collected pre-infusion and post-infusion during the first 4 days of therapy. Total and free teicoplanin concentrations were assayed using validated chromatographic methods. The median serum albumin concentration for the cohort was 18 (IQR 15–24) g/L. After 48 h, the median (IQR) free trough ( f C min ) and total trough ( t C min ) concentrations were 2.90 (2.67–3.47) mg/L and 15.54 (10.28–19.12) mg/L, respectively, although trough concentrations declined thereafter. Clearance of the free concentrations was significantly high relative to the total fraction at 38.6 (IQR 29.9–47.8) L/h and 7.0 (IQR 6.8–9.8) L/h, respectively ( P < 0.001). Multiple linear regression analysis demonstrated that whereas total teicoplanin concentration did not impact on free concentrations ( P = 0.174), albumin concentration did ( P < 0.001). This study confirms the significant impact of hypoalbuminaemia on free concentrations of teicoplanin in non-critically ill patients, similar to that in critically ill patients. Furthermore, the poor correlation with total teicoplanin concentration suggests that therapeutic drug monitoring of free concentrations should be used in these patients. [ABSTRACT FROM AUTHOR]

Biofilm-associated bacteria display a decreased susceptibility towards antibiotics. Routine assessment of antibiotic susceptibility of planktonic bacteria therefore offers an insufficient prediction of the biofilm response. In this study, in vitro biofilms of eight clinical Staphylococcus epidermidis strains were subjected to treatment with vancomycin, teicoplanin, oxacillin, rifampicin and gentamicin. In addition, the biofilms were subjected to combinations of an antibiotic with rifampicin. The effects on the biofilms were assessed by crystal violet staining to determine the total biofilm biomass, staining with XTT to determine bacterial cell viability, and microscopy. Combining these methods showed that treatment of S. epidermidis biofilms with glycopeptides increased the total biofilm biomass and that these antibiotics were not effective in killing bacteria embedded in biofilms. The decreased killing efficacy was more pronounced in biofilms produced by strains that were classified as ‘strong’ biofilm producers. Rifampicin, oxacillin and gentamicin effectively killed biofilm-associated bacteria of all tested strains. Combining antibiotics with rifampicin increased the killing efficacy without influencing the total biofilm biomass. When vancomycin or teicoplanin were combined with rifampicin, the increase in biofilm biomass was neutralised and also the killing efficacy was influenced in a positive way. We conclude that the combined methodology used in this study showed that glycopeptides were not effective in eradicating S. epidermidis biofilms but that combination with rifampicin improved the killing efficacy in vitro. [ABSTRACT FROM AUTHOR]

The aims of this study were (i) to evaluate the relationship between teicoplanin (TEIC) dosage and subsequent trough concentration, (ii) to investigate factors that affect TEIC serum concentration fluctuations and (iii) to examine the association between serum concentration of TEIC and adverse reactions in neonates. A total of 37 eligible neonates (<28 days of age) treated with TEIC from 2008–2012 were included in this study. The median trough concentration in the loading dose regimen of >12–16 mg/kg on Day 1, followed by >6–8 mg/kg every 24 h (q24 h) was 19.6 μg/mL on Day 3 or 4, and the median trough concentration in the maintenance dose regimen of >6–8 mg/kg q24 h was 18.5 μg/mL at steady-state. There were significant correlations between serum creatinine and concentration/dose ( C / D ) ratio ( r = 0.475, P = 0.019), body weight and C / D ratio ( r = −0.425, P = 0.038) and corrected gestational age and C / D ratio ( r = −0.482, P = 0.017) after administering the loading dose. The incidence of hepatic dysfunction, renal impairment and thrombocytopenia was 14.8%, 20.0% and 14.8%, respectively. There was no significant difference in the incidence of adverse reactions between the trough concentration <20 μg/mL and ≥20 μg/mL groups. These data suggest that the recommended TEIC dosage for neonates is appropriate to achieve and maintain a trough concentration range of 15–30 μg/mL, and it is possible to set the target trough concentration at ≥20 μg/mL for deep-seated infections such as endocarditis, bone and joint infections, and osteomyelitis. [ABSTRACT FROM AUTHOR]

Seven high-risk clones of vancomycin-resistant Enterococcus faecium (VREF) belonging to clonal complex 17 were identified using multilocus sequence typing (MLST) among clinical isolates from Saudi Arabia. Among these isolates, a new hospital-associated sequence type (ST795), VanB 2 -type teicoplanin-resistant strain was detected. Its unusual phenotype resulted from a new combination of mutations in the ddl , vanS and vanW genes, which confirmed the trend of evolution in VanB-type resistance. Furthermore, characteristics of adaptation and persistence in the hospital environment of ST795 were emphasised by the presence of genes and clusters recognised to be specific for hospital-associated VREF. [ABSTRACT FROM AUTHOR]

Abstract: The aims of this study were to describe the variability in protein binding of teicoplanin in critically ill patients as well as the number of patients achieving therapeutic target concentrations. This report is part of the multinational pharmacokinetic DALI Study. Patients were sampled on a single day, with blood samples taken both at the midpoint and the end of the dosing interval. Total and unbound teicoplanin concentrations were assayed using validated chromatographic methods. The lower therapeutic range of teicoplanin was defined as total trough concentrations from 10 to 20mg/L and the higher range as 10–30mg/L. Thirteen critically ill patients were available for analysis. The following are the median (interquartile range) total and free concentrations (mg/L): midpoint, total 13.6 (11.2–26.0) and free 1.5 (0.7–2.5); trough, total 11.9 (10.2–22.7) and free 1.8 (0.6–2.6). The percentage free teicoplanin for the mid-dose and trough time points was 6.9% (4.5–15.6%) and 8.2% (5.5–16.4%), respectively. The correlation between total and free antibiotic concentrations was moderate for both the midpoint (ρ =0.79, P =0.0021) and trough (ρ =0.63, P =0.027). Only 42% and 58% of patients were in the lower and higher therapeutic ranges, respectively. In conclusion, use of standard dosing for teicoplanin leads to inappropriate concentrations in a high proportion of critically ill patients. Variability in teicoplanin protein binding is very high, placing significant doubt on the validity of total concentrations for therapeutic drug monitoring in critically ill patients. [Copyright &y& Elsevier]

Abstract: Teicoplanin and polymyxin E (colistin) are antibiotics consisting of multiple, closely related subcomponents, produced by fermentation. The principal components comprise a complex mixture of chemically related, active substances (teicoplanin A2-1–A2-5 and polymyxin E1–2, respectively), which might be required to be present in specific ratios to ensure optimal antibacterial and clinical efficacy. These subcomponents differ in their fatty acid and amino acid composition and, as such, the lipophilic and protein binding characteristics differ between components. This has therapeutic implications for critically ill patients, as the volume of distribution of the teicoplanin A2 and polymyxin E analogues at the onset of an intravenous infusion may impact on expected pharmacokinetics and influence outcome. [Copyright &y& Elsevier]

The activity of dalbavancin, a representative of the lipoglycopeptide antibiotics, alone and in combination with rifampicin, was investigated against meticillin-resistant Staphylococcus aureus (MRSA) in a foreign-body infection model in guinea pigs. The MIC, MBC and time–kill profile of dalbavancin were determined for MRSA ATCC 43300 in the logarithmic (MBClog) and stationary (MBCstat) growth phases. The pharmacokinetic profile of dalbavancin was determined in sterile cage fluid in guinea pigs. The activity of intraperitoneal dalbavancin (40, 60 or 80mg/kg as a single dose), rifampicin (12.5mg/kg/12h for 4 days) and their combination was assessed against planktonic and biofilm MRSA. The MIC of dalbavancin was 0.078mg/L; MBClog and MBCstat were both >128× MIC. In time–kill studies, bacterial reduction of 3log10 CFU/mL was achieved after 48h at ≥32× MIC (logarithmic growth) and at ≥1× MIC (stationary growth). Dalbavancin was neither synergistic nor antagonistic with rifampicin, and prevented the emergence of rifampicin resistance in vitro. The half-life of dalbavancin in cage fluid was 35.8–45.4h and the concentration remained above the MIC of MRSA during 7 days after a single dose. Dalbavancin reduced planktonic MRSA in cage fluid at high dose (60mg/kg and 80mg/kg) but failed to eradicate biofilm MRSA from cages. In combination with rifampicin, dalbavancin at 80mg/kg cured 36% of infected cages, and emergence of rifampicin resistance was completely prevented. Dalbavancin at 80mg/kg and in combination with rifampicin eradicated approximately one-third of cage-associated MRSA infections and prevented emergence of rifampicin resistance. [ABSTRACT FROM AUTHOR]

Abstract: Vancomycin minimum inhibitory concentration (MIC) creep has recently been demonstrated by many countries but is rarely reported in China. In this study, a total of 1411 meticillin-resistant Staphylococcus aureus (MRSA) isolates were collected from six hospitals in China during the period 2006–2011 and the MICs of vancomycin, teicoplanin and linezolid were determined by broth microdilution according to Clinical and Laboratory Standards Institute (CLSI) guidelines. MIC50 and MIC90 values (MICs required to inhibit the growth of 50% and 90% of organisms, respectively) as well as geometric mean (GM) MICs were calculated for all isolates in each year, and MIC creep for the drugs was evaluated. All of the MRSA isolates were susceptible to vancomycin and linezolid. Overall, the vancomycin GM MIC of MRSA isolates was 0.906, 0.952, 0.956, 0.947, 1.013 and 1.040mg/L, with a significantly increasing trend over the years (P <0.001). Percentages of MRSA isolates with a vancomycin MIC above 1μg/mL (2μg/mL≥MIC>1μg/mL) were 26.0%, 23.5%, 21.6%, 27.8%, 30.6% and 42.8% from 2006–2011, respectively, and increased over time (P <0.005). The teicoplanin GM MIC increased rapidly from 0.749mg/L in 2008 to 0.973mg/L in 2011, and ca. 5% of isolates were resistant to teicoplanin in the period according to European Committee on Antimicrobial Susceptibility Testing (EUCAST) criteria. MIC shifts were not found for linezolid (P >0.05). In conclusion, a tendency towards decreasing susceptibility to glycopeptides in MRSA has emerged in China. [Copyright &y& Elsevier]

Abstract: Current treatment for Staphylococcus aureus infections relies heavily upon the cell wall synthesis inhibitor antibiotics such as penicillin, oxacillin, vancomycin and teicoplanin. Increasing antibiotic resistance requires the development of new approaches to combating infection. Autoinducer-2 (AI-2) exists widely both in Gram-negative and Gram-positive pathogens and is suggested as a universal language for intraspecies and interspecies communication. This study demonstrates the association between AI-2 signalling and cell wall synthesis inhibitor antibiotic susceptibility in S. aureus. In addition, a luxS mutant exhibited decreased autolysis and upregulated vancomycin resistance-associated VraRS two-component regulatory system. This finding may provide novel clues for antimicrobial therapy in S. aureus infection. [Copyright &y& Elsevier]

Abstract: The purpose of this study was (i) to determine the optimal dosage of teicoplanin for each patient group stratified by renal function and weight based on a population pharmacokinetic model and observed distribution of patient characteristics and (ii) to develop new simplified dosing regimens designed to achieve 15–30μg/mL. Patient data were collected retrospectively from routine therapeutic drug monitoring files of adult patients who were given the standard loading dose regimen of teicoplanin (400mg twice on Day 1, followed by 400mg once daily for 2 days) and whose trough concentration was measured just before administration on Day 4. Monte Carlo simulation was conducted to estimate the trough concentration at 72h after the initial loading dose (C min 72h) and at steady state (C ss min). The percentage of observed C min 72h in patients who received the standard loading dose regimen outside the non-parametric 90% prediction interval (from 5th to 95th percentile) of the simulated C min 72h was <10%. Simplified loading dose and maintenance dose regimens for each group stratified by renal function and weight were created to achieve C min 72h and C ss min of 15μg/mL and 20–25μg/mL, respectively. The percentage of C min 72h and C ss min in the range 15–30μg/mL was 43–65% and 61–82% across each renal function and weight strata, respectively. These new simplified dosing regimens of teicoplanin could be helpful in individual adjustment of the loading and maintenance doses to achieve 15–30μg/mL. [Copyright &y& Elsevier]

Abstract: Glycopeptides have been considered the antimicrobials of choice for serious meticillin-resistant Staphylococcus aureus (MRSA) and meticillin-resistant coagulase-negative staphylococci (MR-CoNS) infections for several years. Daptomycin is a new option for the treatment of these infections, including those exhibiting reduced susceptibility to glycopeptides. The aim of this study was to compare glycopeptides and daptomycin for the treatment of infections caused by MRSA or MR-CoNS. Data for 106 patients with bloodstream infections (bacteraemia or infective endocarditis) or skin and soft-tissue infections (SSTIs) were retrospectively reviewed, of which 43 were treated with daptomycin (DAP group) and 63 were treated with vancomycin or teicoplanin (GLYCO group). Patients included in the two comparison groups were homogeneous in terms of age, risk factors and clinical severity. Aetiology was mainly represented by MRSA in both groups, followed by various species of MR-CoNS. Daptomycin was used more frequently in patients with central venous catheter-associated bacteraemia or pacemaker-associated infection. Patients with SSTIs included in the GLYCO group had a longer mean duration of antibiotic therapy (18.2 days vs. 14.6 days; P =0.009) and a longer mean length of hospital stay (28.2 days vs. 19.6 days; P =0.01) compared with those included in the DAP group. A longer mean duration of antibiotic therapy was also observed in patients with bloodstream infections receiving glycopeptide therapy (25.6 days vs. 18 days; P =0.004). In conclusion, the good clinical efficacy of daptomycin is associated with a more rapid resolution of the clinical syndrome and a reduced length of hospitalisation. This latter aspect may have important pharmacoeconomic implications, promoting the use of daptomycin in the clinical setting. [Copyright &y& Elsevier]

Abstract: This study was designed to identify factors associated with adverse outcomes and increased duration of parenteral therapy in patients with skin and soft-tissue infections (SSTIs) managed with outpatient parenteral antibiotic therapy (OPAT). A retrospective cohort study interrogating variables recorded prospectively in an electronic OPAT patient database was performed. ‘OPAT failure’ was defined as hospitalisation following initiation of OPAT, or adverse event or progression of infection necessitating a change in antibiotic therapy. Variables associated with failure or increased duration of therapy were identified via univariate and multiple logistic regression analyses. In total, 963 first patient episodes of OPAT-treated SSTIs were observed; 84% were treated with daily ceftriaxone and 15% with teicoplanin (three daily loading doses then three times per week). Progression of infection was observed in 2.8% of cases, inpatient management was required in 6% and significant adverse events occurred in 7.1%. Overall OPAT success was 87.1%. Female sex, diabetes and treatment with teicoplanin were independently associated with OPAT failure. A significant reduction in duration of OPAT therapy was observed over time. A longer duration of intravenous therapy was associated with meticillin-resistant Staphylococcus aureus (MRSA), older age, vascular disease, a diagnosis of bursitis, and treatment with teicoplanin. Non-inpatient referrals, management via a nurse-led patient group direction, and treatment with ceftriaxone were associated with reduced duration of OPAT. For selected patients with SSTIs, OPAT was generally safe and effective, but specific patient groups were identified with more complex management pathways and poorer outcomes. [Copyright &y& Elsevier]

Abstract: An initial loading dose of teicoplanin is required to reach the optimal trough concentration (≥10μg/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 15μg/mL, was defined. Among 70 patients, 33 patients received the individual loading dose regimen, 33 patients received the conventional loading dose regimen (200mg or 400mg every 12h on Day 1 followed by 200mg 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 800mg to 1800mg. These findings suggest that individual adjustment of the initial loading dose of teicoplanin is potentially useful to attain the optimal concentration rapidly. [Copyright &y& Elsevier]

Abstract: The aim of this study was to analyse the effectiveness of teicoplanin versus vancomycin lock therapy in the treatment of coagulase-negative staphylococci (CoNS) venous access port-related bloodstream infection (BSI). The study included 44 consecutive patients during a 36-month prospective case-series study. The primary endpoint was failure to cure. Treatment was successful in 39 patients. At the end of the study, the cumulative port survival rate was 100% in the teicoplanin lock group compared with 77% in the vancomycin lock group (P =0.06). In the Cox regression analysis, fever beyond 48h of treatment was a significant predictor of treatment failure (P =0.02). Use of vancomycin or teicoplanin locks had an effectiveness of 88.6% in the treatment of CoNS port-related BSI. Teicoplanin locks reduced the failure rate from 18.5% to 0% compared with vancomycin locks. The presence of fever after beginning antimicrobial lock therapy was associated with treatment failure. [Copyright &y& Elsevier]

Abstract: Following an initial response to vancomycin therapy, a patient with meticillin-resistant Staphylococcus aureus (MRSA) bacteraemia developed endocarditis, failed a second course of vancomycin and then failed daptomycin therapy. An increase in the vancomycin minimum inhibitory concentrations of four consecutive MRSA blood isolates from 2μg/mL to 8μg/mL was shown by Etest. Population analysis of four successive blood culture isolates recovered over the 10-week period showed that the MRSA strain became progressively less susceptible to both vancomycin and daptomycin. Retrospectively, the macro Etest method using teicoplanin indicated a decrease in vancomycin susceptibility in the second blood isolate. The patient improved after treatment with various courses of trimethoprim/sulfamethoxazole, quinupristin/dalfopristin and linezolid. Early detection of vancomycin-heteroresistant S. aureus isolates, which appeared to have clinical significance in this case, continues to be a challenge for the clinical laboratory. Development of suitable practical methods for this should be given priority. Concurrent development of resistance to vancomycin and daptomycin, whilst rare, must be considered in a patient who is unresponsive to daptomycin following vancomycin therapy. [Copyright &y& Elsevier]

Abstract: A prospective randomised study was conducted in three centres to evaluate the efficacy of teicoplanin as antimicrobial prophylaxis for arthroplasties. From a total of 616 patients undergoing total hip or knee arthroplasty, 278 patients operated on in one centre were administered a single dose of 10mg/kg teicoplanin upon introduction of anaesthesia and the remaining 338 patients operated on in the other two centres were administered multiple doses of comparators for 4–6 days as decided by the attending physicians. Follow-up was done for 24 months. No differences were found between the two groups regarding gender, underlying diseases and duration of the operation. Surgical site infections (SSIs) were present in two patients in the teicoplanin arm (0.78%) and in 11 patients in the comparator arm (3.53%) (P =0.025 between groups). These were deep SSIs in four patients (two in each arm). Two cases of severe allergic reaction occurred, one in the teicoplanin arm and another in the comparator arm. It is concluded that single-dose teicoplanin was more effective as prophylaxis for total hip or knee arthroplasty compared with multiple doses of broad-spectrum antimicrobials. [Copyright &y& Elsevier]

Abstract: The optimum teicoplanin loading dose and duration of therapy required for rapid attainment of a therapeutic trough plasma concentration (C min) (≥10mg/L for serious Gram-positive infections and ≥20mg/L for deep-seated infections) are not known. In this open-label, multicentre, observational study, teicoplanin levels were determined following administration of loading doses of 6mg/kg every 12h on Day 1 followed by 6mg/kg once or twice daily to hospitalised patients with suspected or diagnosed Gram-positive infections. C min levels for the first 4 days of treatment were collected 15min prior to drug administration. Levels were determined with an Abbott TDx®/FLx® Analyzer and Seradyn Teicoplanin Innofluor Assay Kit. The two target trough values (≥10mg/L and ≥20mg/L) were only achieved by Day 4 in the once-daily group (n =34; mean 9.55mg/L, 95% confidence interval (CI) 8.17–10.94mg/L) and in the twice-daily group (n =40; mean 21.8mg/L, 95% CI 17.21–26.39mg/L), respectively. However, the mean C min in the twice-daily group was ≥10mg/L (11.03mg/L) by Day 2. To achieve rapid therapeutic C min concentrations targeted for the majority of serious Gram-positive infections, we recommend teicoplanin loading doses of 6mg/kg every 12h for 48h followed by once-daily for infections other than infective endocarditis, septic arthritis and osteomyelitis. Regarding the latter infections, higher loading doses might be warranted to reach rapid steady-state concentrations. [Copyright &y& Elsevier]

Abstract: Glycopeptides are among the most widely used agents for the treatment of serious infections caused by Gram-positive bacteria, with vancomycin recommended for the treatment of infections caused by β-lactam-resistant Staphylococcus aureus (MRSA). However, the utility of glycopeptides against MRSA has come into question owing to their poor tissue penetration, slow bactericidal activity and the emergence of strains with reduced susceptibility. A number of single-centre studies have demonstrated incremental increases in glycopeptide MICs for S. aureus strains over time – a phenomenon known as glycopeptide creep. High MICs have long been known to correlate with poorer clinical outcomes, but recent studies have shown that even small increases in MIC below the susceptibility breakpoint can affect the clinical efficacy of glycopeptides. The accurate measurement and ongoing surveillance of glycopeptide MICs at individual sites is therefore recommended to assist clinicians in their choice of empiric therapy for suspected serious S. aureus infections. [Copyright &y& Elsevier]

Abstract: Medical centres in eight countries in the Asia–Pacific region provided 2391 isolates for the SENTRY Antimicrobial Surveillance Program during 2003–2004 to determine their susceptibility to several antimicrobial classes, including daptomycin. Daptomycin, vancomycin and teicoplanin minimum inhibitory concentrations (MICs) and minimum bactericidal concentrations (MBCs) were determined for 120 isolates of Staphylococcus aureus, which included wild-type (WT) methicillin-resistant S. aureus (MRSA) and strains with decreased susceptibility to vancomycin (hetero-vancomycin-intermediate S. aureus (hVISA)). Oxacillin-resistant staphylococcal isolates were much less susceptible to the other tested agents compared with oxacillin-susceptible strains. Vancomycin resistance was higher among Enterococcus faecium (10.3%) than Enterococcus faecalis (0.4%), and macrolide resistance was high both for β-haemolytic (17.7%) and viridans group (48.7%) streptococci. Daptomycin (MIC for 90% of the organisms (MIC90)=0.5–1mg/L) was two-fold more potent than vancomycin, with >99% susceptibility when tested against staphylococci. All tested isolates of E. faecalis (MIC90 =2mg/L) and β-haemolytic streptococci (MIC90 =0.5mg/L) were susceptible to daptomycin. Daptomycin MIC and MBC values were slightly higher for the hVISA isolates compared with WT-MRSA, with MBC/MIC ratios of only 1–2 for both groups. The MBC/MIC ratio for vancomycin was often greater when tested against these strains, particularly hVISA. In contrast, teicoplanin MBC/MIC ratios were significantly higher, with many of the strains showing values consistent with tolerance (≥32). Daptomycin was demonstrated to have excellent in vitro activity when tested against Gram-positive isolates collected from Asia–Pacific countries, including hVISA strains. [Copyright &y& Elsevier]

Abstract: The aim of this study was to determine the effect of multifactorial, multidisciplinary educational interventions over a 3-year period on the appropriate use of teicoplanin. Teicoplanin was considered a valid surrogate marker of good antibiotic use in clinical practice owing to its peculiar pharmacokinetics (i.e. necessity for an initial loading dose regardless of the patient''s renal function for early achievement of optimal exposure, namely C min ≥10mg/L) and to the opportunity of comparing current routine therapeutic drug monitoring (TDM) results with those of a historical retrospective study. A significantly higher proportion of patients received appropriate loading doses of teicoplanin in the present prospective study than in the retrospective study, both when considered as a whole (66.6% versus 38.6%, respectively; P <0.001) or when stratified according to the degree of estimated renal function (78.4% versus 60.4% for creatinine clearance (CLCr) >50mL/min; 59.8% versus 26.8% for CLCr 20–50mL/min; and 27.7% versus 5.5% for CLCr <20mL/min). The highest adherence was observed in haematological wards (97.7%). The percentages of patients with teicoplanin C min ≥10mg/L during the treatment period in the present and retrospective study, respectively, were: 61.4% versus 3.2% on Day 2; 88% versus 35% on Day 4; 94% versus 70% on Day 7; and 99% versus 90% on Day 11. Our findings suggest that continuous application of a multifactorial educational programme including active TDM may be efficacious in improving and maintaining over time the appropriate use in a hospital setting of a theoretically difficult-to-use drug such as teicoplanin. [Copyright &y& Elsevier]

Abstract: The population analysis profile (PAP) method as well as analysis of autolytic activity and cellular ultrastructure by transmission electron microscopy (TEM) were used to characterise Staphylococcus epidermidis, Staphylococcus haemolyticus and Staphylococcus warneri clinical strains with reduced susceptibility to glycopeptides. All strains showed heterogeneous profiles to vancomycin and teicoplanin by the PAP method. Subpopulations that grew in the presence of high concentrations of each drug were selected from the PAP as derivative strains. Their glycopeptide minimal inhibitory concentrations (MICs) were determined and subsequently all parental and derivative strains were grown in one-half of the MIC of vancomycin or teicoplanin. An increase in cell wall thickness of all derivative strains was seen by TEM, with statistically significant values (P <0.01) compared with their respective parental strains. In general, variable rates of autolysis among the strains were observed. Cell wall thickness is an important factor involved in glycopeptide resistance and, in association with PAP results, confirmed the Brazilian coagulase-negative staphylococci clinical isolates as being heteroresistant to glycopeptides. Detection of these heteroresistant organisms is important in order to achieve more judicious use of vancomycin and teicoplanin in hospitals. [Copyright &y& Elsevier]

Abstract: A prospective, two-arm, open study assessing plasma exposure to teicoplanin with two different prophylactic regimens (Group A (n =23), 800mg pre-operatively versus Group B (n =24), 400mg pre-operatively plus two doses of 200mg 24h apart) was carried out in patients undergoing major vascular surgery. The intent was to define the feasibility and the possible advantages of the single pre-operative high dose in ensuring therapeutically effective plasma concentrations (>10mg/L) of teicoplanin even during long-lasting operations. At the end of the intervention, mean teicoplanin concentrations (±S.D.) were 14.05±5.13mg/L and 5.39±2.13mg/L in Groups A and B, respectively. At 24h, average teicoplanin levels were 5.10±1.25mg/L and 2.08±0.73mg/L in Groups A and B, respectively; at 48h they declined to 2.86±0.70mg/L in Group A, whereas they rose to 2.67±0.82mg/L after administration of 2.63±0.51mg/kg at 24h in Group B. Single pre-operative high-dose teicoplanin may ensure effective plasma levels even in cases of very long-lasting operations (>8h) with no need for intraoperative re-dosing and may enable more appropriate prophylactic exposure than that achievable with the same total dose given in three administrations 24h apart. [Copyright &y& Elsevier]

Abstract: The aim of this study was to compare the antibacterial activity of teicoplanin and vancomycin in the treatment of methicillin-resistant Staphylococcus aureus (MRSA) meningitis using a rabbit meningitis model. The MRSA strain ATCC 43300 was used to infect the rabbits. The vancomycin group received 20mg/kg vancomycin every 12h (q12h), the teicoplanin group received 6mg/kg teicoplanin q12h and the control group did not receive any treatment. Drug levels were measured using a bioassay technique. Bacterial counts in the treatment groups were significantly lower (P <0.05) than those of the control group at 12h and 24h after treatment. When the treatment groups were compared, the bacterial counts after 12h or 24h of treatment were similar (P >0.05). These data suggest that the antibacterial activity of vancomycin and teicoplanin are similar in experimental MRSA meningitis of rabbits. [Copyright &y& Elsevier]

Abstract: We evaluated retrospectively, 10 MRSA meningitis cases in our hospital that occurred between January 1999 and June 2004. All were post-neurosurgical and were considered to have hospital-acquired meningitis. Fever, leukocytosis, variable conscious levels were the most common findings. Six patients were treated with regimens including teicoplanin, and four with vancomycin. Mean duration of treatment was 23.5±18.8 days (range, 3–60 days). One patient died. In cases of MRSA meningitis, intravenous vancomycin is the mainstay of therapy. However, six of these 10 patients were successfully treated with regimens including teicoplanin, suggesting that this agent may be an alternative to vancomycin in the therapy of these cases. [Copyright &y& Elsevier]

We developed a simple method that can replace the polymerase chain reaction (PCR) to distinguish between vancomycin-resistant enterococci (VRE) with the vanA, vanB and vanC genes. The method is based on induction of teicoplanin resistance by vancomycin in vanB-VRE, while the two compounds have a synergistic effect in vanC-VRE. In addition, vanA-VRE shows resistance to both vancomycin and teicoplanin, and both the compounds can induce resistance to vanA-VRE. Utilising these properties, we attempted to develop a simple method to distinguish between vanA, vanB and vanC. We compared our simple method with the PCR method in 43 strains of vanA-VRE, 35 strains of vanB-VRE and 37 strains of vanC-VRE. The results were 100% consistent with that obtained by PCR. [Copyright &y& Elsevier]

In a recent multinational trial, hospital resource use and total cost of treatment were compared between linezolid and teicoplanin for severe Gram-positive bacterial infections among 227 European hospitalised patients. The results show that the linezolid group had a 3.2-day (6.3 for linezolid versus 9.5 for teicoplanin groups) shorter mean intravenous antibiotic treatment duration. Certain baseline variables, particularly the inpatient location at enrolment and the presence of outpatient/home parenteral antibiotic therapy (OHPAT), had substantial effects on length of stay (LOS) and cost of treatment. After adjusting for the between-treatment difference in these two variables and other baseline variables, the results showed non-significant shorter LOS and lower mean total cost of treatment for the linezolid group among patients with no access to OHPAT. [Copyright &y& Elsevier]

The synergy between two glycopeptides, vancomycin (Vm) and teicoplanin (Tec) and streptomycin (Sm) was studied by time-kill method. Five clinical vanB resistant Enterococcus faecalis (ENC) isolates with variable Vm-susceptibility were used. Different concentrations of Vm, Tec and Sm representing therapeutic concentrations were combined. Antibacterial activity was related to the concentrations of Vm and Sm, and Vm susceptibility to ENC. For strains with Vm MIC up to 64 mg/l, synergy was achieved with higher concentrations of Vm and Sm, while all combinations of Tec and Sm were synergistic against all strains except ENC 29. For ENC 29 with Vm MIC of 512 mg/l and Tec MIC of <1 mg/l, none of the combinations was synergistic. The significance of these in vitro results needs further investigation in vivo. [Copyright &y& Elsevier]

In order to define a dose regimen of teicoplanin for patients undergoing chronic haemodialysis so that they achieved trough drug serum levels above 10 mg/l, two single doses of 5 and 10 mg/kg were administered intravenously in seven anuric patients immediately after the end of haemodialysis. Concentrations of teicoplanin were determined by a microbiological assay in samples collected from peripheral veins via the arterial and the venous lines of the fistulae and from the dialysate during haemodialysis. The administration of a 5 and 10 mg/kg dose gave mean Cmax of 62.80 and 122.43 mg/l, mean AUC of 526.43 and 1103.98 mg h/l, mean half life (t1/2) of 109.09 and 107.06 h, mean clearance rates of 12.85 and 12.44 ml/min, mean apparent volumes of distribution of 1.68 and 1.68 l/kg and mean volumes of distribution at steady state of 0.31 and 0.28 l/kg, respectively. Trough serum levels above 10 mg/l were found for 24 h after the administration of the 5 mg/kg dose and for 48 h after the administration of the 10 mg/kg dose. Teicoplanin was not detected in the dialysate. Its concentrations in both the arterial and the venous lines of the fistulae were similar. Based on the time period after the administration of teicoplanin where the desired trough serum levels were found and on the observed t1/2, it is proposed that teicoplanin should be administered at a dose of 10 mg/kg at 48–72 h intervals, in patients undergoing chronic haemodialysis for the therapy of infections caused by Gram-positive cocci. [Copyright &y& Elsevier]