Mg Of Vancomycin Research Articles

Intraosseous Versus Intravenous Vancomycin in Tourniquetless Primary Total Knee Arthroplasty: A Randomized Trial

BackgroundIntraosseous (IO) administration of vancomycin at the time of total knee arthroplasty (TKA) has been shown to be safer and more effective than intravenous (IV) administration at preventing early periprosthetic joint infection. Previous studies have relied on tourniquet inflation to enhance local tissue concentrations and mitigate systemic release. MethodsA single-blinded, randomized clinical trial was performed on 20 patients (10 IV, 10 IO) undergoing primary TKA. The control (IV) group received weight-dosed vancomycin approximately 1 hour prior to the incision and weight-dosed cefazolin immediately prior to the incision. The interventional (IO) group received weight-dosed cefazolin immediately prior to the incision and 500 mg of vancomycin delivered via the IO technique at the time of the incision. Systemic samples for vancomycin levels were taken prior to the incision and at closure. During the procedure, tissue samples were taken from the distal femur, proximal tibia, and suprapatellar synovium. There were no differences in patient demographics or changes in serum creatinine from preoperative to postoperatively between groups. ResultsSignificant differences in systemic vancomycin levels (ug/mL) were found at the start of the case (IV = 27.9 ± 4.9 versus IO = 0 ± 0, P = .0004) and at the end of the case (IV = 19.6 ± 2.6 versus IO = 7.8 ± 1.0, P = .001). No significant differences were seen in the average vancomycin concentration in the distal femur (IV = 61.0 ± 16.0 versus IO = 66.2 ± 12.3, P = .80), proximal tibia (IV = 52.8 ± 13.5 versus IO = 57.1 ± 17.0, P = .84), or suprapatellar synovial tissue (IV = 10.7 ± 5.3 versus IO = 9.0 ± 3.3, P = .80). There were no complications associated with vancomycin administration in either group. ConclusionsThis study demonstrates the utility of IO vancomycin in tourniquetless TKA with similar local tissue and significantly lower systemic concentrations than IV administration. Level of EvidenceLevel 1 therapeutic randomized trial.

Defensive antibacterial coating (DAC) hydrogel with gentamycin and vancomycin for the therapy of achilles tendon infection after surgical repair without massive soft-tissue defect. Results in 8 cases

Abstract Introduction We report the results of revision surgery in postoperative infection after Achilles tendon (AT) suturing consisting of debridement of AT together with a local application of hyaluronic acid and polylactic acid hydrogel with an addition of gentamicin and vancomycin in suture canals and into an operative wound. Materials and Methods A retrospective study included eight patients operated due to a postoperative and unsuccessfully treated infection after AT suture. Before revision with defensive antibacterial coating (DAC) hydrogel, all patients underwent an unsuccessful antibiotic therapy, removal of sutures via the sinus tract. In none of the cases was there a skin defect due to a previous surgery and infection. In all cases, the AT healed at revision surgery, residual stiches were removed, and suture canals and adjacent soft tissue and anchor canals in the bone were debrided and filled with 5 ml DAC hydrogel with an addition of gentamicin and vancomycin. Results During the follow-up ranging from 6 to 43 months, all patients obtained a complete resolution of inflammation. No side effects related to DAC hydrogel were observed. Conclusion The use of 5 ml antibacterial DAC® hydrogel containing 160 mg gentamycin and 50 mg of vancomycin applied during revision surgery on the surface of AT and in suture canals in AT as an adjunct to surgical debridement for infection complicating repair of AT without a massive soft-tissue defect proved to be safe and effective. Level of Evidence: IV (case series).

Drug monitoring of the antibacterial drug Vancomycin in patients with purulent-inflammatory diseases of the maxillofacial region

To evaluate the change in the level of concentration of the antibacterial drug Vancomycin registered in the purulent focus area (facial vein) and in the peripheral blood flow (cubital vein) in patients with phlegmon of the maxillofacial region (MFR). The clinical material of the study was 12 patients with phlegmon of MFR who were being treated in the maxillofacial department of the N.I. Pirogov State Clinical Hospital No. 1 of the Moscow Medical Center. The drainage of phlegmons was performed on the day of admission of the patient 2-3 days after the onset of the disease. The phlegmons involved two or more spaces of the MFR. As an antimicrobial drug, 500 mg of Vancomycin in 400 ml of saline solution was used intravenously. Quantitative registration of Vancomycin was carried out 2 hours after intravenous infusion. Blood sampling was carried out from the cubital and facial veins in an amount of 7-8 ml intraoperatively at the opening of the phlegmon, under endotracheal anesthesia. The concentration of the antibiotic was determined by high-performance liquid crystal chromatography. The study found that the concentration of Vancomycin in the facial vein exceeds similar indicators obtained from the cubital vein. The difference in the percentage ratio averaged 19.2±7.3%. In 10 patients with phlegmons of various localization, it was found that the penetration of the antibacterial drug into the tissues of the inflammatory focus is higher compared to the periphery. However, in a number of patients, the concentration of the drug did not exceed the minimum suppressive concentration recommended for obtaining a therapeutic effect (for Vancomycin, it is at least 2 mcg / ml). To achieve the therapeutic effect of phlegmon treatment, it is necessary to select an individual dose of the drug for each patient.

2312. Utility of Intrathecal Antibiotic Administration in the Reduction of Ventriculoperitoneal (VP) Shunt Infections in our Urban Referral Health Center

Abstract Background Infection is one of the primary causes of VP shunt failure, with an incidence rate of 7%-14%. Systemic antibiotics, administered intravenously (IV), are considered the standard of care (SOC) for perioperative prophylaxis. Prophylactic intrathecal (IT) administration of antibiotics, in addition to SOC, is practiced by some surgeons at our institution. Our objective was to study the impact of this modality on VP shunt infections. Methods A retrospective review of all VP shunt procedures at our institution from 2018–2020 was performed. Patients with active VP shunt infection were excluded. We compared the incidence of 90-day postoperative shunt infection in patients who received IT and SOC antibiotics (intervention group) to patients who only received SOC IV antibiotics (control group). Data collection included demographics, comorbidities, prophylactic antibiotics used, and pathogens implicated in shunt infections. T-test or Mann-Whitney U test was used for comparison of continuous variables; chi-square or Fisher’s exact test was used to assess the relationship between categorical variables. A value of p < 0.05, on two-tailed testing, was considered statistically significant. Results A total of 112 patients were included in the study. Control and intervention arms comprised 54 (48.2%) and 58 patients (51.8%), respectively. All patients received parenteral perioperative antibiotics. The most commonly used agent was cefazolin (83.9%). Patients in the intervention arm received 4 mg of gentamicin and 5 mg of vancomycin intrathecally. Baseline characteristics were not statistically different between the groups. Among the 112 patients, 12 (10.7%) developed shunt infection; 4 in the intervention and 8 in the control arm. Infection rates were not statistically different in these groups (χ2 (1) =1.83, p= 0.176). However, there was a statistically significant association between history of prior shunt (uninfected) placement and post-operative shunt infection (Fisher’s exact test, p = 0.025). Conclusion Our study did not reveal additional benefit of prophylactic IT antibiotic use in decreasing VP shunt infections. History of prior shunt placement was identified as risk factor, however. Limitations include relatively small sample size, retrospective, and a single-center study. Disclosures All Authors: No reported disclosures.

Impact of a vancomycin loading dose on the achievement of target vancomycin exposure in the first 24 h and on the accompanying risk of nephrotoxicity in critically ill patients.

BackgroundThe advocated pharmacokinetic/pharmacodynamic (PK/PD) target for vancomycin, AUC/MIC ≥ 400 mg·h/L, may not be reached with a conventional fixed starting dose of 1000 mg in critically ill patients, but increasing the dose may cause nephrotoxicity.ObjectivesTo evaluate the effect of a weight-based loading dose of 25 mg/kg vancomycin on PK/PD target attainment in the first 24 h (AUC0–24) in critically ill patients and to evaluate whether this increases the risk of acute kidney injury (AKI).Patients and methodsA prospective observational before/after study was performed in ICU patients, comparing the percentage of vancomycin courses with AUC0–24 ≥ 400 mg·h/L and the incidence of AKI, defined as worsening of the risk, injury, failure, loss of kidney function and end-stage kidney disease (RIFLE) score. The conventional dose group received 1000 mg of vancomycin as initial dose; the loading dose group received a weight-based loading dose of 25 mg/kg. A population PK model developed using non-linear mixed-effects modelling was used to estimate AUC0–24 in all patients.ResultsOne hundred and four courses from 82 patients were included. With a loading dose, the percentage of courses achieving AUC0–24 ≥ 400 mg·h/L increased significantly from 53.8% to 88.0% (P = 0.0006). The percentage of patients with new-onset AKI was not significantly higher when receiving a 25 mg/kg loading dose (28.6% versus 37.8%; P = 0.48). However, the risk of AKI was significantly higher in patients achieving AUC0–24 > 400 mg·h/L compared with patients achieving AUC < 400 mg·h/L (39.0% versus 14.8%; P = 0.031).ConclusionsA weight-based loading dose of 25 mg/kg vancomycin led to significantly more patients achieving AUC0–24 ≥ 400 mg·h/L without increased risk of AKI. However, some harm cannot be ruled out since higher exposure was associated with increased risk of AKI.

Effect of Vancomycin on the Gut Microbiome and Plasma Concentrations of Gut-Derived Uremic Solutes

IntroductionDeclining renal function results in the accumulation of solutes normally excreted by healthy kidneys. Data suggest that some of the protein-bound solutes mediate accelerated cardiovascular disease. Many of the poorly dialyzable protein-bound uremic retention solutes are products of gut bacterial metabolism.MethodsWe performed a blinded-randomized controlled trial comparing the changes in plasma concentrations of a panel of protein-bound solutes and microbiome structure in response to the once-weekly oral administration of 250 mg of vancomycin or placebo over a period of 12 weeks in a cohort of stable patients with end-stage kidney disease. We also examined the pattern of recovery of the solutes and gut microbiome over 12 weeks of placebo administration following vancomycin.ResultsWe enrolled 15 subjects. Ten subjects provided sufficient plasma and stool samples to permit us to examine the effect of vancomycin on plasma solute levels. We showed that a weekly dose of vancomycin resulted in a reduction in the plasma concentration of 7 colon-derived solutes. We described a significant effect of vancomycin on the microbiome structure with a decrease in alpha diversity and change in beta diversity. Multiple taxa decreased with vancomycin including genera Clostridium and Bacteroides. We demonstrated microbiome recovery after stopping vancomycin. However, recovery in the solutes was highly variable between subjects.ConclusionsWe demonstrated that microbiome suppression using vancomycin resulted in changes in multiple gut-derived uremic solutes. Future studies are needed to address whether reduction in those uremic solutes results in improvement of cardiovascular outcomes in ESKD patients.

P0554IN VITRO ASSESSMENT OF HA330 CARTRIDGE ADSORPTION CAPACITY REALTED TO VANCOMYCIN

Abstract Background and Aims The rationale for blood purification as adjunctive therapy during sepsis involved the capacity in removing endogenous and exogenous toxins, but currently no recommendations exists [1]. A critical point may be the potential interaction with antimicrobial therapy, which remains the mainstay of sepsis treatment. HA330 cartridge (Jafron, Zhuhai City, China), widely used in China and actually available in Europe, is used in hemoperfusion for blood purification in septic patients.The aim of this in vitro study was to investigate the adsorptive capacity of HA330 related to vancomycin (VAN). Reference: 1. Rhodes A et al. Crit Care Med 45:486-552. 2017 Method This is an experimental study, simulating an hemoperfusion treatment with HA330. We circulated (250 ml/min) in a closed loop 500 ml of normal saline solution enriched with VAN, stirred and maintained at 37°C. We spiked 100 mg of VAN every 15 minutes to increase the antibiotic load until reaching 1500 mg, the last injection was 500 mg to get a total amount of 2 g. Samples were collected from the inlet line at each VAN adjunct, after system stabilization. Measured VAN concentrations were used to get the adsorption isotherm: for each VAN load, the adsorbed amount of VAN was obtained by multiplying VAN reduction ratio and the quantity of VAN injected. Results Figure 1 shows VAN adsorption isotherm obtained with HA330 cartridge. We observed that, at each injection, after 15 minutes VAN was almost entirely adsorbed by the cartridge, with an average reduction ratio of 0.96. Interestingly, this was confirmed even adding 500 mg at once. Even increasing the VAN load to 500 mg at once, the reduction ratio was maintained. Conclusion In our study, simulating hemoperfusion using HA330, a rapid and clinically relevant removal of VAN has been shown. A significant amount of VAN (2g) was adsorbed without reaching membrane saturation nor reducing its adsorptive capacity. In a clinical setting, we recommend a therapeutic drug monitoring to optimize VAN levels during blood purification with HA330 and a VAN loading dose may be considered. Further in vivo studies are warranted to confirm these findings.

Vancomycin- and Poly(simvastatin)-Loaded Scaffolds with Time-Dependent Development of Porosity

Biodegradable scaffolds are widely use in drug delivery and tissue engineering applications. The scaffolds can be modified to provide the necessary mechanical support for tissue formation and to deliver one or more drugs to stimulate tissue formation or for the treatment of a specific condition. In the current study, we developed biodegradable scaffolds that have the potential for dual drug delivery. The scaffolds consisted of simvastatin-containing prodrug, poly(simvastatin) entrapped in poly(β-amino ester) (PBAE) porogen particles and vancomycin encapsulated in poly(lactic-co-glycolic acid) (PLGA) microspheres, which were fused together around the PBAE porogens to create a slow-degrading matrix. Upon hydrolysis, poly(simvastatin) releases simvastatin acid, which has angiogenic and osteogenic properties, while the PLGA microspheres release vancomycin as an antibacterial agent. Degradation of PBAE porogens through hydrolysis of ester linkages led to the development of porosity in a controlled manner and led to water penetration that facilitated hydrolysis of PLGA. Higher porogen loading (~60% by weight) gave rise to ~70% interconnected porosity with pore spacing of ~180 μm. This open volume facilitated simvastatin acid release upon hydrolysis and entrapped vancomycin release via diffusion through and degradation of PLGA. During the study, ~162 μg of simvastatin acid and ~18 mg vancomycin were released from the highest porosity scaffolds. Bioactivity studies showed that released simvastatin acid stimulated preosteoblastic activity, indicating that scaffold fabrication did not damage the polymeric prodrug. Regarding mechanical properties, compressive modulus, failure strain, and failure stress decreased with increasing PBAE porogen content. These dual drug releasing scaffolds with controlled development of microarchitecture can be useful in bone tissue engineering applications.

The effect of local release antibiotic beads on in-vitro bacterial growth from tissue taken from infected diabetic foot ulcers

Diabetic foot infection is the main reason for diabetes-related hospitalisation and is a major cause of diabetes-related amputation. Recent figures published by Public Health England show that there are more than 163 diabetes related amputations in England every week. This study investigates the effect of antibiotic loaded calcium sulfate (Stimulan® Rapid Cure) beads on in-vitro bacterial growth from tissue taken from diabetic foot infections. Patients were recruited from the Macleod Diabetes and Endocrine Centre at the Royal Devon and Exeter Hospital. Inclusion in the study was based on clinical recognition of an infected foot ulcer requiring wound debridement. Debrided tissue was homogenised and 50 µl spread over the surface of Columbia blood agar and fastidious anaerobe agar. Three replicate calcium sulfate beads containing a combination of vancomycin and gentamicin were then placed on the surface of the agar. Each bead contained approximately 3.4 mg and 1.6 mg of vancomycin and gentamicin respectively. Plates were incubated aerobically or anaerobically as appropriate. Zones of inhibition were recorded at 1 and 4 days. Calcium sulfate beads containing vancomycin and gentamicin were able to inhibit bacterial growth in all tissue homogenates tested with zone diameters ranging from 16 to 40 mm. Local release of antibiotics could have the benefit of achieving high local concentrations within poorly vascularised tissue which may inhibit bacterial growth at the wound site. By improving treatment of diabetic foot infections, it may be possible to prevent amputation, maintain mobility and conserve quality of life.

Vancomycin Enema in the Treatment of Clostridium difficile Infection.

Background: Current guidelines for the treatment of Clostridium difficile infections (CDIs) recommend vancomycin enemas for patients with adynamic ileus. There is significant variability in guideline recommendations for vancomycin dose and enema volume and whether a retention enema should be used. The most recent (2017) guidelines from the Infectious Diseases Society of America/Society for Healthcare Epidemiology of America recommend rectal instillation of 500 mg of vancomycin in 100 mL of physiologic saline every 6 hours as a retention enema. Methods: Published studies regarding vancomycin enema use in CDI (1990-present) were reviewed to compare drug dose, volume, and whether a retention enema was used in order to determine the efficacy and make recommendations for optimal dosing. Results: Case series with higher vancomycin dose, higher enema volume, and use of retention enema demonstrated greater efficacy. Use of smaller volumes and lower doses (100 mL; 125-250 mg q 6 hours) demonstrated no efficacy of intracolonic vancomycin. Conclusion: We recommend revision of the current CDI guideline recommendations for patients with adynamic ileus to the following: Vancomycin per rectum (500 mg in a volume of 500 mL q 6 hours) by retention enema (18F Foley catheter with 30-cc balloon inserted into the rectum, balloon inflated, solution instilled, and catheter clamped for 60 minutes) for optimal efficacy.

Vancomycin elution from a biphasic ceramic bone substitute.

ObjectivesThe aim of this study was to analyze drain fluid, blood, and urine simultaneously to follow the long-term release of vancomycin from a biphasic ceramic carrier in major hip surgery. Our hypothesis was that there would be high local vancomycin concentrations during the first week with safe low systemic trough levels and a complete antibiotic release during the first month.MethodsNine patients (six female, three male; mean age 75.3 years (sd 12.3; 44 to 84)) with trochanteric hip fractures had internal fixations. An injectable ceramic bone substitute, with hydroxyapatite in a calcium sulphate matrix, containing 66 mg of vancomycin per millilitre, was inserted to augment the fixation. The vancomycin elution was followed by simultaneously collecting drain fluid, blood, and urine.ResultsThe antibiotic concentration in the drain reached a peak during the first six hours post-surgery (mean 966.1 mg/l), which decreased linearly to a mean value of 88.3 mg/l at 2.5 days. In the urine, the vancomycin concentration reached 99.8 mg/l during the first two days, followed by a logarithmic decrease over the next two weeks to reach 0 mg/l at 20 days. The systemic concentration of vancomycin measured in blood serum was low and decreased linearly from 2.17 mg/l at one hour post-surgery to 0 mg/l at four days postoperatively.ConclusionThis is the first long-term pharmacokinetic study that reports vancomycin release from a biphasic injectable ceramic bone substitute. The study shows initial high targeted local vancomycin levels, sustained and complete release at three weeks, and systemic concentrations well below toxic levels. The plain ceramic bone substitute has been proven to regenerate bone but should also be useful in preventing bone infection.Cite this article: M. Stravinskas, M. Nilsson, A. Vitkauskiene, S. Tarasevicius, L. Lidgren. Vancomycin elution from a biphasic ceramic bone substitute. Bone Joint Res 2019;8:49–54. DOI: 10.1302/2046-3758.82.BJR-2018-0174.R2.

Incidence and risk factors for potentially suboptimal serum concentrations of vancomycin during cardiac surgery.

AIMTo investigate the incidence and risk factors for vancomycin concentrations less than 10 mg/L during cardiac surgery.METHODSIn this prospective study, patients undergoing cardiac surgery received a single dose of 1000 mg of vancomycin. Multiple arterial samples were drawn during surgery. Exclusion criteria were hepatic dysfunction; renal dysfunction; ongoing infectious diseases; solid or hematologic tumors; severe insulin-dependent diabetes; body mass index of < 17 or > 40 kg/m2; pregnancy or lactation; antibiotic, corticosteroid, or other immunosuppressive therapy; vancomycin or nonsteroidal anti-inflammatory drug therapy in the previous 2 wk; chemotherapy or radiation therapy in the previous 6 mo; allergy to vancomycin or cefazolin; drug abuse; cardiac surgery in the previous 6 mo; previous or scheduled organ transplantation; preoperative stay in the intensive care unit for more than 24 h; emergency procedure or lack of adequate preparation for surgery; and participation in another trial.RESULTSOver a 1-year period, 236 patients were enrolled, and a total of 1682 serum vancomycin concentrations (median 7/patient) were measured. No vancomycin levels under 10 mg/L were recorded in 122 out of 236 patients (52%), and 114 out of 236 patients (48%) were found to have at least 1 serum sample with a vancomycin level < 10 mg/L; 54 out of 236 patients (22.9%) had at least 5 serum samples with a vancomycin level lower than 10 mg/L. Vancomycin infusion was administered for 60 min in 97 out of 236 patients (41%). In 47 patients (20%), the duration of infusion was longer than 60 min, and in 92 patients (39%) the duration of infusion was shorter than 60 min. The maximum concentration and area under the concentration-time curve were significantly higher in patients with no vancomycin levels less than 10 mg/L (P < 0.001). The multivariate analysis identified female gender, body mass index (BMI) > 25 kg/m2, and creatinine clearance above 70 mL/min as risk factors for vancomycin levels less than 10 mg/L.CONCLUSIONResults of this study identified female gender, BMI > 25 kg/m2, and creatinine clearance above 70 mL/min as risk factors for suboptimal vancomycin serum concentration during cardiac surgery; no relationship was found between infusion duration and vancomycin levels less than 10 mg/L. These findings call attention to the risk of facilitating the emergence of vancomycin-resistant methicillin-resistant Staphylococcus aureus strains.

Vancomycin concentrations in the cervical spine after intravenous administration: results from an experimental pig study

Background and purpose — Vancomycin may be an important drug for intravenous perioperative antimicrobial prophylaxis in spine surgery. We assessed single-dose vancomycin intervertebral disc, vertebral cancellous bone, and subcutaneous adipose tissue concentrations using microdialysis in a pig model.Material and methods — 8 female pigs received 1,000 mg of vancomycin intravenously as a single dose over 100 minutes. Microdialysis probes were placed in the C3–C4 intervertebral disc, C3 vertebral cancellous bone, and subcutaneous adipose tissue, and vancomycin concentrations were obtained over 8 hours. Venous blood samples were obtained as reference.Results — Ranging from 0.24 to 0.60, vancomycin tissue penetration, expressed as the ratio of tissue to plasma area under the concentration-time curve from 0 to the last measured value, was incomplete for all compartments. The lowest penetration was found in the intervertebral disc. The time to a mean clinically relevant minimal inhibitory concentration (MIC) of 4 µg/mL was 3, 17, 25, and 156 min for plasma, subcutaneous adipose tissue, vertebral cancellous bone, and the intervertebral disc, respectively. In contrast to the other compartments, a mean MIC of 8 µg/mL was not reached in the intervertebral disc. An approximately 3-times longer elimination rate was observed in the intervertebral disc in comparison with all the other compartments (p < 0.001), and the time to peak drug concentration was higher for all tissues compared with plasmaInterpretation — Preoperative administration of 1,000 mg of vancomycin may provide adequate vancomycin tissue concentrations with a considerable delay, though tissue penetration was incomplete. However, in order also to achieve adequate intervertebral disc concentrations in all individuals and accommodating a potentially higher MIC target, supplemental application of vancomycin may be necessary.

Single-dose bone pharmacokinetics of vancomycin in a porcine implant-associated osteomyelitis model.

The increasing incidence of orthopaedic methicillin-resistant Staphylococcus aureus (MRSA) infections represents a significant therapeutic challenge. Being effective against MRSA, the role of vancomycin may become more important in the orthopaedic setting in the years to come. Nonetheless, vancomycin bone and soft tissue penetration during infection remains unclear. In eight pigs, implant-associated osteomyelitis was induced on day 0, using a Staphylococcus aureus strain. Following administration of 1,000 mg of vancomycin on day 5, vancomycin concentrations were obtained with microdialysis for 8 h in the implant bone cavity, in cancellous bone adjacent to the implant cavity, in subcutaneous adipose tissue (SCT) adjacent to the implant cavity, and in healthy cancellous bone and healthy SCT in the contralateral leg. Venous blood samples were also obtained. The extent of infection and inflammation was evaluated by post-mortem computed tomography scans, C-reactive protein serum levels and cultures of blood and swabs. In relation to all the implant cavities, bone destruction was found. Ranging from 0.20 to 0.74, tissue penetration, expressed as the ratio of the area under the concentration-time curve from 0 to the last measured value, was incomplete for all compartments except for healthy SCT. The lowest penetration was found in the implant cavity. In conclusion, Staphylococcus aureus implant-associated osteomyelitis was found to reduce vancomycin bone penetration, especially in the implant cavity. These findings suggest that it may be unsafe to rely solely on vancomycin therapy when treating acute osteomyelitis. Particularly when metaphyseal cavities are present, surgical debridement seems necessary. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1093-1098, 2018.

Bone and subcutaneous adipose tissue pharmacokinetics of vancomycin in total knee replacement patients

Background and purpose — The incidence of orthopedic methicillin-resistant Staphylococcus aureus (MRSA) infections is increasing. Vancomycin may therefore play an increasingly important role in orthopedic perioperative antimicrobial prophylaxis. Studies investigating perioperative bone and soft tissue concentrations of vancomycin are sparse and challenged by a lack of appropriate methods. We assessed single-dose plasma, subcutaneous adipose tissue (SCT) and bone concentrations of vancomycin using microdialysis in male patients undergoing total knee replacement.Methods — 1,000 mg of vancomycin was administered postoperatively intravenously over 100 minutes to 10 male patients undergoing primary total knee replacement. Vancomycin concentrations in plasma, SCT, cancellous, and cortical bone were measured over the following 8 hours. Microdialysis was applied for sampling in solid tissues.Results — For all solid tissues, tissue penetration of vancomycin was significantly impaired. The time to a mean clinically relevant minimal inhibitory concentration (MIC) of 2 mg/L was 3, 36, 27, and 110 min for plasma, SCT, cancellous, and cortical bone, respectively. As opposed to the other compartments, a mean MIC of 4 mg/L could not be reached in cortical bone. The area under the concentration-time curve from 0 to the last measured value and peak drug concentrations (Cmax) for SCT, cancellous, and cortical bone was lower than that of free plasma. The time to Cmax was higher for all tissues compared with free plasma.Interpretation — Postoperative penetration of vancomycin to bone and SCT was impaired and delayed in male patients undergoing total knee replacement surgery. Adequate perioperative vancomycin concentrations may not be reached using standard prophylactic dosage.

ВЛИЯНИЕ ПЕРФТОРОРГАНИЧЕСКИХ СОЕДИНЕНИЙ НА РОСТ STAPHYLOCOCCUS EPIDERMIDIS

In order to analyze the influence of perfluororganic compounds (perfluorodecalin) on growth of Staphylococcus epi-dermidis there was an invitro experiment conducted. During 24hours St.epidermidis cell crop was grown on meat-peptone agar in the Petri dishes: 1.1 water-salt BSS+ solution, 1.2–3,5ml BSS+ solution and 1mg of vancomycin in 0,1ml of 0.9% sodium chloride solution, 1.3 perfluororganic compound, 1.4 the mixture of perfluororganic compound and 1mg of vancomycin in 0,1ml of 0.9% sodium chloride solution. Similarly the Petri dishes were numbered and the second experiment was conducted when the initial Staphilococcusepidermidis concentration was two times reduced. To hold control the pure crop of bacteria was cultivated without adding any additional materials in cups 1.0 and 1.2. No growth of colonies were detected in cups 1,2, 2,2, local absence of growth was found in 1.4, 2,4. In cups 1.1 and 2.1 there was more intensive growth detected and approximately the same intensive growth of crop was found in cups 1.3, 2.3. comparing to the controlled crop. The findings confirm the effectiveness of vancomycin regarding Staphylococcus epidermidis and the possibility of its use together with perfluororganic compounds. This fact can be used in the process of treatment of postoperative endophthalmitis.

Single-dose pharmacokinetics of vancomycin in porcine cancellous and cortical bone determined by microdialysis

High treatment failure rates and the need for prolonged antimicrobial therapy for osteomyelitis and implant-associated infections suggest that antimicrobial bone penetration may be incomplete. Assessment of the bone pharmacokinetics of antimicrobials is challenged by a lack of validated methods. In this study, 1000mg of vancomycin was administered as a single dose over 100min to eight female pigs. Plasma, subcutaneous adipose tissue (SCAT) and bone pharmacokinetics were investigated over 12h. Microdialysis was applied for collection of samples in bone and SCAT. The vancomycin concentration in microdialysates was determined using ultra-high performance liquid chromatography, whilst the free plasma concentration was determined using Cobas c501. The mean (95% CI) area under the concentration–time curve (AUC0–last; minμg/mL) was 9375 (7445–11304), 9304 (7374–11233), 5998 (3955–8040) and 3451 (1522–5381) for plasma, SCAT, and cancellous and cortical bone, respectively (ANOVA P-value <0.001). Both cortical and cancellous bone AUC0–last were lower than that of free plasma (P<0.01). Peak drug concentrations (Cmax) in cortical and cancellous bone were also significantly lower than that of free plasma (P<0.001). Moreover, both AUC0–last and Cmax were significantly lower in cortical bone than in cancellous bone (P<0.025). Bone penetration of vancomycin was found to be incomplete and delayed. Significant differences in pharmacokinetics between cancellous and cortical bone suggest that bone may not be considered as one compartment. Future studies should focus on validating the applicability of microdialysis for assessment of antimicrobial bone pharmacokinetics.

Pharmacokinetics of LFF571 and Vancomycin in Patients with Moderate Clostridium difficile Infections

Clostridium difficile infection causes diarrheal disease with potentially fatal complications. Although treatments are available, including vancomycin, metronidazole, and fidaxomicin, the recurrence of disease after therapy remains a problem. LFF571 is a novel thiopeptide antibacterial that shows in vitro potency against C. difficile that is comparable to or greater than that of other clinically used antibiotics. Here, we compare the pharmacokinetics (PK) of LFF571 and vancomycin in patients with C. difficile infection as part of an early efficacy study. This multicenter, randomized, evaluator-blind, and active-controlled study evaluated the safety, efficacy, and pharmacokinetics of LFF571 in adults with primary episodes or first relapses of moderate C. difficile infections. Patients were randomized to receive 200 mg of LFF571 or 125 mg of vancomycin four times daily for 10 days. The PK parameters were calculated from drug concentrations measured in serum and fecal samples. The systemic exposure following oral administration of 200 mg of LFF571 four times per day for 10 days in patients with C. difficile infection was limited. The highest LFF571 serum concentration observed was 41.7 ng/ml, whereas the levels in feces at the end of treatment were between 107 and 12,900 μg/g. In comparison, the peak vancomycin level observed in serum was considerably higher, at 2.73 μg/ml; the levels of vancomycin in feces were not measured. Similar to healthy volunteers, patients with C. difficile infections exhibited high fecal concentrations and low serum levels of LFF571. These results are consistent with the retention of LFF571 in the lumen of the gastrointestinal tract. (This study has been registered at ClinicalTrials.gov under registration no. NCT01232595.).

Evaluation of a dosing regimen for continuous vancomycin infusion in critically ill patients: An observational study in intensive care unit patients

PurposeWe aimed to evaluate a dosing algorithm for continuous vancomycin administration in intensive care unit patients. Materials and MethodsThis observational study was conducted in a medical intensive care unit (German university hospital; June 2012-February 2013). Following a loading dose of 20 mg per kg actual body weight, vancomycin was administered continuously (20 or 30 mg of vancomycin per kg actual body weight over 24 hours depending on renal function). The vancomycin infusion rate was adjusted to achieve a target serum vancomycin concentration of 20-30 mg/L. ResultsVancomycin was administered for a median (interquartile range) of 7 (5-9) days. The median vancomycin dose given as an initial bolus was 1750 (1400-2000) mg. The median daily vancomycin dose ranged from 480 (180–960) mg (day 6) to 3.120 (2596-3980) mg (day 1). Altogether, the achieved median serum vancomycin concentration was 29.0 (25.2-33.2) mg/L. On treatment days 1 to 7, we observed target serum vancomycin levels (20-30 mg/L) in 48%, 39%, 33%, 26%, 43%, 57%, and 69% of patients. Supra-therapeutic serum vancomycin concentrations (>30 mg/L) were observed in 36%, 52%, 61%, 63%, 39%, 19%, and 15% of patients on treatment days 1 to 7. ConclusionsThe evaluated vancomycin dosing regimen for continuous infusion allowed rapid achievement of sufficient vancomycin serum levels. However, we frequently observed supra-therapeutic serum vancomycin concentrations in the first days of vancomycin treatment.

Efficacy of Intravitreal Administrations of Linezolid in an Experimental Model ofS. aureus–Related Endophthalmitis

To evaluate the efficacy of intravitreal administration of linezolid (LZD) in a rabbit model of Staphylococcus aureus endophthalmitis. Of 40 rabbits studied, 36 of them received 10(2) colony-forming units (CFU) of S. aureus in their right eye before being randomly assigned to the following groups: four groups of 8 animals received 24 hours after the bacterial inoculation, 1, 10, 30 mg of LZD (LZD 1, LZD 10, and LZD 30) or 1 mg of vancomycin (V1), respectively. Four other animals had a sham injection in their infected eye. The 4 remaining animals were used as negative controls. Clinical, bacterial, and histologic assessments were conducted at different endpoints. Animals were euthanized at day 8. The safety profile of intravitreal LZD was assessed by electroretinography in 5 more animals by comparing the recordings in eyes injected with 30 mg of LZD and contralateral control eyes injected with a solution of sterile saline water. At day 5, the mean inflammatory clinical scores of Nussenblatt were 7.0 ± 1.0, 3.6 ± 0.7, and 3.1 ± 0.8, in the LZD 1, LZD 10, and LZD 30 groups and 3.4 ± 1.7 and 7.5 ± 0 in the V1 and BSS+ groups, respectively (P < 0.05, ANOVA). The corresponding mean bacterial counts in the vitreous (log 10 CFU/mL) were 6.2 ± 6.5, 3.5 ± 3.8, 0, 3.8 ± 4.2, and 7.8 ± 4.9, respectively (P < 0.05, ANOVA). A 30 mg dose of LZD sterilized all the eyes at day 5 and displayed the lowest (best) histologic score (1.5 ± 0.6). Residual LZD concentrations 24 hours after the administration were between 0.1 and 7.2 mg/L LZD 30 group. The half-time of linezolid in the vitreous was 2 hours. There were no differences in the electroretinogram recordings between control eyes and eyes injected with 30 mg of linezolid at days 1 and 14 after the intravitreal injection. This is the first evidence of the effectiveness of linezolid for the treatment of experimental staphylococcal endophthalmitis. High ocular concentrations of LZD were needed to obtain a satisfactory bactericidal effect. Linezolid displayed a concentration-dependent killing activity in the eye. Such doses of intravitreal linezolid appeared to be safe for the retinal function.