Cascade-Targeted Nanoplatforms for Synergetic Antibiotic/ROS/NO/Immunotherapy against Intracellular Bacterial Infection.

Intracellular bacteria in dormant states can escape the immune response and tolerate high-dose antibiotic treatment, leading to severe infections. To overcome this challenge, cascade-targeted nanoplatforms that can target macrophages and intracellular bacteria, exhibiting synergetic antibiotic/reactive oxygen species (ROS)/nitric oxide (NO)/immunotherapy, were developed. These nanoplatforms were fabricated by encapsulating trehalose (Tr) and vancomycin (Van) into phosphatidylserine (PS)-coated poly[(4-allylcarbamoylphenylboric acid)-ran-(arginine-methacrylamide)-ran-(N,N'-bisacryloylcystamine)] nanoparticles (PABS), denoted as PTVP. PS on PTVP simulates a signal of "eat me" to macrophages to promote cell uptake (the first-step targeting). After the uptake, the nanoplatform in the acidic phagolysosomes could release Tr, and the exposed phenylboronic acid on the nanoplatform could target bacteria (the second-step targeting). Nanoplatforms can release Van in response to infected intracellular overexpressed glutathione (GSH) and weak acid microenvironment. l-arginine (Arg) on the nanoplatforms could be catalyzed by upregulated inducible nitric oxide synthase (iNOS) in the infected macrophages to generate nitric oxide (NO). N,N'-Bisacryloylcystamine (BAC) on nanoplatforms could deplete GSH, allow the generation of ROS in macrophages, and then upregulate proinflammatory activity, leading to the reinforced antibacterial capacity. This nanoplatform possesses macrophage and bacteria-targeting antibiotic delivery, intracellular ROS, and NO generation, and pro-inflammatory activities (immunotherapy) provides a new strategy for eradicating intracellular bacterial infections.

Regional antibiotic delivery for sternal wound infection prophylaxis a systematic review and meta-analysis of randomized controlled trials.

Despite evidence suggesting the benefit of prophylactic regional antibiotic delivery (RAD) to sternal edges during cardiac surgery, it is seldom performed in clinical practice. The value of topical vancomycin and gentamicin for sternal wound infections (SWI) prophylaxis was further questioned by recent studies including randomized controlled trials (RCTs). The aim of this systematic review and meta-analysis was to comprehensively assess the safety and effectiveness of RAD to reduce the risk of SWI.We screened multiple databases for RCTs assessing the effectiveness of RAD (vancomycin, gentamicin) in SWI prophylaxis. Random effects meta-analysis was performed. The primary endpoint was any SWI; other wound complications were also analysed. Odds Ratios served as the primary statistical analyses. Trial sequential analysis (TSA) was performed.Thirteen RCTs (N = 7,719 patients) were included. The odds of any SWI were significantly reduced by over 50% with any RAD: OR (95%CIs): 0.49 (0.35-0.68); p < 0.001 and consistently reduced in vancomycin (0.34 [0.18-0.64]; p < 0.001) and gentamicin (0.58 [0.39-0.86]; p = 0.007) groups (psubgroup = 0.15). Similarly, RAD reduced the odds of SWI in diabetic and non-diabetic patients (0.46 [0.32-0.65]; p < 0.001 and 0.60 [0.44-0.83]; p = 0.002 respectively). Cumulative Z-curve passed the TSA-adjusted boundary for SWIs suggesting adequate power has been met and no further trials are needed. RAD significantly reduced deep (0.60 [0.43-0.83]; p = 0.003) and superficial SWIs (0.54 [0.32-0.91]; p = 0.02). No differences were seen in mediastinitis and mortality, however, limited number of studies assessed these endpoints. There was no evidence of systemic toxicity, sternal dehiscence and resistant strains emergence. Both vancomycin and gentamicin reduced the odds of cultures outside their respective serum concentrations' activity: vancomycin against gram-negative strains: 0.20 (0.01-4.18) and gentamicin against gram-positive strains: 0.42 (0.28-0.62); P < 0.001. Regional antibiotic delivery is safe and effectively reduces the risk of SWI in cardiac surgery patients.

Antibiotic cement-coated rigid locked nails in infected femoral and tibial nonunion. Reoperation rates of commercial versus custom-made nails.

INTRODUCTION: The objective of this study is to assess bone union, infection control, and reoperation rates in a series of patients with infected femoral or tibial nonunion treated with antibiotic-cement-coated rigid nails and to compare the results obtained with custom-made nails versus commercial nails. METHODS: We retrospectively analyzed a series of consecutive patients with infected nonunion of the femur or the tibia treated with antibiotic-cement-coated rigid nails between January 2010 and 2020. We assessed patients' distinctive characteristics, initial injury, type of nail used (custom-made nail with vancomycin or commercial nail with gentamicin), success rate (bone union + infection control), reoperation rate, and failure rate. Comparative analyses were conducted between reoperated and non-reoperated patients regarding the type of nail used. A multivariate regression analysis was performed to assess the risk variables that impacted reoperation rates. RESULTS: We included 54 patients with 22 (40.74%) infected femoral nonunions and 32 (59.25%) tibial nonunions, who were treated with 38 (70.37%) custom-made antibiotic-cement coated nails and 16 (29.62%) commercial nails. Bone union and infection control were achieved in 51 (94.44%) cases. The reoperation rate was 40.74% (n = 22), and the failure rate was 5.55% (n = 3). The use of custom-made nails was associated with a higher risk of reoperation (Odds Ratio 4.71; 95% Confidence Interval 1.10 - 20.17; p = 0.036). CONCLUSION: Antibiotic-cement-coated nails reached a 94.44% success rate. Nails manufactured in the OR coated with vancomycin cement were associated with a higher risk of reoperation than commercial nails loaded with gentamicin cement. LEVEL OF EVIDENCE: III comparative, observational, non-randomized.

Vancomycin powder embedded in collagen sponge decreases the rate of prosthetic shoulder infection.

BACKGROUND: Shoulder arthroplasty is a successful procedure to treat degenerative and traumatic diseases of the glenohumeral joint. Periprosthetic infection represents an infrequent but dreaded complication (2%-4%). Application of intrawound vancomycin powder seems to reduce periprosthetic infections, but limited information is available on its efficiency in shoulder arthroplasty. The purpose of this study was to evaluate if the vancomycin powder embedded in a collagen sponge could decrease the rate of prosthetic shoulder infection. METHODS: A retrospective analysis of 827 patients undergoing total shoulder arthroplasty was performed. The study involved a control group of 405 patients and a group of 422 with the intraoperative insertion of intrawound vancomycin powder. Incidence of periprosthetic infection was evaluated comparing the 2 groups at a minimum follow-up of 12 months. Patient demographics, comorbidities, and perioperative information were compared between the 2 groups. RESULTS: No infection was observed in the group treated with intrawound vancomycin, and 13 cases of infection were observed in the control group (3.2%) (P value <.001) without subacromial vancomycin application. No wound complications requiring revision were observed as a result of intrawound vancomycin application. DISCUSSION AND CONCLUSION: Intrawound vancomycin powder significantly reduces the rate of periprosthetic shoulder infections without any increase in local and systemic aseptic complications at a minimum follow-up of 12 months. Our results support the use of intrawound local vancomycin for prophylaxis of shoulder periprosthetic infections.

Vancomycin therapeutic monitoring by measured trough concentration versus Bayesian-derived area under the curve in critically ill patients with cancer.

The updated vancomycin guideline and recent studies suggested that trough concentrations may result in underestimation of the actual area under the curve (AUC), leading to excessive dosing and nephrotoxicity. With limited data available on critically ill cancer patients, this study aimed to compare the two methods in this patient population. This was a 5-year retrospective study on patients treated with vancomycin in the intensive care unit (ICU) of a comprehensive cancer center. The measured trough concentration was compared to Bayesian-derived AUC/minimum-inhibitory-concentration (MIC), considering MIC as 1. Trough concentrations of 15-20 mg/L and AUC of 400-600 mg h/L were considered the targeted goal. Multivariate analysis was performed to identify factors associated with an AUC below the targeted goal. During the study period, 316 patients were included. The mean age was 54 years ±16 (SD); most patients had solid tumors (75%), and 11% had neutropenia. A targeted goal AUC and trough were recorded in 128 (41%) patients and in 64 (20%) patients, respectively. Of the 128 patients with targeted goal AUC, 31 (24%) had targeted goal trough concentrations and 91 (71%) had trough concentrations below 15 mg/L. Furthermore, among the patients with targeted goal trough concentration (n = 64), 33 (52%) had higher than targeted goal AUC. Augmented renal clearance (ARC), defined as a calculated creatinine-clearance ≥130 ml/min, was associated with an AUC below the targeted goal. In a cohort of critically ill patients with cancer, over two-thirds of the patients with a targeted goal Bayesian AUC/MIC had trough concentrations below the targeted goal. ARC was associated with AUC below the targeted goal.

Use of Topical Vancomycin Powder to Reduce Surgical Site Infections after Deep Brain Stimulation Surgery: UCSF Experience and Meta-Analysis.

OBJECTIVE: Surgical site infection (SSI) is the most common serious complication of deep brain stimulation (DBS) implantation surgery. Here, we report a single-surgeon experience on the efficacy of topical, intrawound vancomycin powder (VP) in reducing SSI for DBS surgery and present the first systematic review and meta-analysis examining the effect of topical vancomycin on SSI in patients after DBS surgery. METHODS: For the retrospective review, all unique patients undergoing DBS surgery at UCSF for new hardware implantation or internal pulse generator (IPG) replacement by a single surgeon from September 2013 to March 2019, with at least 1 year of follow-up data, were included. For the meta-analysis, we included all primary studies that compared SSIs with and without application of topical vancomycin in DBS surgeries. RESULTS: 368 unique patients met inclusion criteria; 195 patients received topical VP (VP group) and 173 did not (control). 99/195 patients in the VP group underwent new DBS implantation and 96/195 had IPG replacement. 71/173 patients in the control group had new DBS implantation and 102/173 had IPG replacement. There were 10 total cases of SSI: 4 patients from the VP group (3 new implants and 1 IPG replacement) and 6 patients from the control group (3 new implants and 3 IPG replacements), resulting in SSI rates of 2.1 and 3.5%, respectively (p value = 0.337). Including our retrospective analysis, 6 studies met inclusion criteria for the systematic review and meta-analysis. In the 4 studies that examined primary DBS implants, 479 total patients received topical VP and 436 did not; mean odds ratio for SSI with topical vancomycin was 0.802 (95% confidence interval [CI] 0.175-3.678). Across the 5 studies that examined IPG implantations or replacements, 606 total patients received topical VP while 1,173 patients did not; mean odds ratio for SSI with topical vancomycin was 0.492 (95% CI 0.164-1.475). In either case, topical VP application did not significantly decrease risk of SSI. CONCLUSION: Surgical infections after DBS surgery are uncommon events, with studies demonstrating mixed results on whether topical vancomycin reduces this risk. Our single-institution retrospective analysis and systematic review of prior studies both demonstrated no significant SSI rate reduction with topical VP. This is likely due to low baseline SSI rates, resulting in a small effect size for prevention. Given the cost-effectiveness, simplicity, and low risk, topical, intrawound VP remains a treatment option to further reduce risk of SSI, particularly in settings with higher baseline infection rates.

Intra-wound vancomycin powder for the eradication of periprosthetic joint infection after debridement and implant exchange: experimental study in a rat model.

BACKGROUND: Intra-wound vancomycin powder (VP) has been used in clinical practice to prevent periprosthetic joint infection (PJI) after primary knee/hip arthroplasty. The role of intra-wound VP in the setting of debridement and implant exchange after PJI remains undefined. This study aimed to explore the efficacy and safety of intra-wound VP in the control of methicillin-resistant S. aureus (MRSA) infection after debridement and implant exchange. METHODS: PJI modeling by knee prosthesis implantation and MRSA inoculation, debridement and implant exchange were performed in Wistar rats successively to mimic the one-stage exchange arthroplasty of PJI patients. Two weeks of systemic vancomycin (SV) or/and intraoperative intra-wound VP of single dosage were applied after revision surgery. RESULTS: No post-surgery deaths, incision complications and signs of drug toxicity were observed. The microbial counts of SV or intra-wound VP group were significantly reduced compared with the control group, while bacteria were still detected on the bone, soft-tissue and prosthesis. The elimination of bacterial counts, along with improvement of tissue inflammation and serum inflammatory markers, were observed in the rats with SV plus intra-wound VP. Serum levels of vancomycin in all groups were lower than that of causing nephrotoxicity, while no statistic difference was observed in the serum biochemical marker among the groups. CONCLUSIONS: Intra-wound VP is effective after debridement and implant exchange in our current rat PJI model. Neither SV nor intra-wound VP alone could eradicate the bacteria within a two-weeks treatment course, while SV plus intra-wound VP could eliminate the MRSA infection, without notable hepatic or renal toxicity and any incision complications.

Biomarkers in neonates receiving potential nephrotoxic drugs.

OBJECTIVE: Novel biomarkers, such as kidney injury molecule-1 (KIM-1), cystatin, and neutrophil gelatinase-associated lipocalin (NGAL) were shown to predict acute kidney injury (AKI) earlier than serum creatinine in critically ill. We carried out the present study to evaluate these biomarkers in addition to conventional in our neonates. PATIENTS AND METHODS: We recruited 70 neonates of various gestational age groups receiving one or more potential nephrotoxic drug/s. Daily urine samples were collected for estimating KIM-1, cystatin, and NGAL. Modified neonatal kidney disease improving global outcomes (mKDIGO) classification was used in defining AKI. RESULTS: A significant trend in increased urine concentrations of KIM-1, cystatin, and NGAL were observed as we proceed from term to preterm categories. Strong positive correlation was observed between urine albumin and urine albumin creatinine ratio (ACR), and strong negative correlations between urine creatinine and urine cystatin, and between urine creatinine with urine NGAL. A moderate positive correlation was observed between urine KIM-1 and urine cystatin, between urine KIM-1 and urine NGAL, and between urine cystatin and urine NGAL; and a moderate negative correlation was observed between urine creatinine and urine KIM-1. Seven neonates met the mKDIGO criteria for AKI and ROC plot revealed that baseline KIM-1 and NGAL can significantly predict possible drug-induced AKI in neonates. CONCLUSIONS: Urine KIM-1, cystatin, and NGAL are significantly correlated with several other conventional biomarkers that reflect renal function in critically ill neonates. Baseline urine KIM-1 and NGAL concentrations can predict the AKI following potential nephrotoxic drug use in this population.

Elution and Biomechanical Properties of Meropenem-Loaded Bone Cement.

OBJECTIVE: To investigate the biomechanical and elution properties of meropenem-loaded bone cement. METHODS: Bone cement (Palacos LV) with 5% (2 g/4 0g), 10% (4 g/40 g), and 15% (6 g/40 g) meropenem; 5% (2 g/40 g) and 10% (4 g/40 g) vancomycin; and blank bone cement were prepared in a total of six groups named A2, A4, A6, B2, B4, and A0 (antibiotic-free). 36 cylinder specimens (6-mm diameter and 12-mm height) of all six groups were molded for a compression test. After the compression test, because of mechanical properties below the ISO standard requirements, groups B2, B4 were not subjected to a bending test. So a total of 24 rectangular strip specimens (10-mm width, 75-mm length, and 3.3-mm thickness) for groups A2, A4, A6 and A0 were molded for the bending test. Between-group differences of compressive strength, bending strength and bending modulus were analyzed. The meropenem standard was prepared as a series of standard solutions to calculate the standard curve. At a constant temperature of 37 °C, separately, meropenem-loaded bone cement cylinder specimens (12 mm in diameter and 17 mm in length) of A2, A4 and A6 were serially immersed in saline solution without stirring. The eluent drug concentration at 24, 48, 72 h and 6, 12, 24 days was measured and the drug concentration-time curve of meropenem was constructed. RESULTS: With the exception of groups B2 and B4, all cements compressive strength values were well above the minimum requirement of the ISO 5833 standard (70 MPa). The compressive strength and bending strength values of group A4 were higher than those of group A0 (P < 0.05), but no difference was found between the A0, A2 and A6 groups (P > 0.05). There were no intergroup differences of bending modulus between the A0, A2, A4 and A6 groups (P > 0.05). A standard curve of meropenem was obtained and a regression equation was constructed: Y = 15.0265 X + 13.5218, r = 1.00. At 37 °C, the release of meropenem was rapid during the first 48 h for all A2, A4, A6 samples, and subsequent release continued to decrease. CONCLUSION: When adding up to 15% (6 g/40 g) meropenem to the bone cement, the biomechanical properties were not reduced, and bone cement with 10% (4 g/40 g) meropenem had the best performance. At a constant temperature of 37°C, meropenem can be released from bone cement for up to 24 days.

Effectiveness and antimicrobial susceptibility profiles during primary antimicrobial prophylaxis for pediatric acute myeloid leukemia.

Limited data are available on antimicrobials exposure and microbiology evolution in pediatric acute myeloid leukemia (AML) patients underwent antimicrobials prophylaxis. To assess the effectiveness of antimicrobials prophylaxis, antibiotic susceptibilities of bacteria, and exposure of antimicrobials during intensive chemotherapy for AML patients, 90 consecutive de novo AML patients aged 0-18 years between January 1, 1997 and March 31, 2018 were enrolled. Vancomycin, ciprofloxacin and voriconazole prophylaxis was administered from January 1, 2010. During the preprophylaxis period, January 1997 to December 2009, 62 patients experienced a total of 87 episodes of bloodstream infection (BSI) and 17 episodes of invasive fungal infection (IFI) among 502 courses of chemotherapy. In contrast, 16 episodes of BSI occurred and no IFIs were reported to occur in 28 patients who received 247 courses of chemotherapy in the prophylaxis period. Patients who received antimicrobial prophylaxis had a significant reduction of BSI, IFI, and febrile neutropenia in comparison with patients without prophylaxis. Exposure to amikacin, carbapenem, amphotericin B was reduced in the prophylaxis period. Imipenem susceptibility of Enterobacter cloacae as well as vancomycin susceptibility of Enterococcus species were reduced in the prophylaxis period. At the time of the last follow up, patients with prophylaxis had a better subsequent 5-year overall survival rate than those without prophylaxis. Prophylactic antimicrobials administration in children with AML who undergo chemotherapy can significantly reduce the rates of life-threatening infection, exposure to antimicrobials, and might result in a better outcome.

Effectiveness of topical vancomycin in the prevention of spinal surgical site infections: a retrospective cohort study.

BACKGROUND: The risk of surgical site infections (SSIs), particularly methicillin-resistant Staphylococcus aureus (MRSA) SSIs, after spinal surgeries is one of the most daunting experiences to patients and surgeons. Some authors suggest applying vancomycin powder on the wound before skin closure to minimize the risk of SSIs; however, this practice is not supported by well-established evidence. This study sought to assess the effectiveness of topical (i.e. intra-wound) vancomycin in minimizing the risk of SSIs in patients who underwent spinal surgeries at a Saudi hospital. METHODS: A retrospective cohort study was conducted using the hospital database. Patients who underwent spinal surgeries from the period of 09/2013 to 09/2019 were included and followed up (observed from the time of the surgery) to 30 days (surgeries without implants) or 90 days (with implants). The odds ratio (OR) of the primary outcome between vancomycin treated versus non-treated patients was estimated using a logistic regression model adjusting for the measured confounders. A sensitivity analysis was conducted using propensity score analysis (inverse probability of treatment weighting [IPTW] with stabilized weights) to control for confounding by indication. All study analyses were completed using RStudio Version 1.2.5033. RESULTS: We included 81 vancomycin treated vs. 375 untreated patients with 28 infections (8/81 vs. 20/375; respectively). The adjusted OR of SSIs between the two groups was 0.40 (95% confidence interval [CI] 0.11 to 1.34). The result of the propensity score analysis was consistent (OR: 0.97 [95% CI 0.35 to 2.68]). CONCLUSIONS: We could not find a lower association of SSIs with intra-wound vancomycin in patients who underwent spinal surgeries. Further studies are needed to assess benefits of using topical vancomycin for this indication vs. the risk of antimicrobial resistance.

The Role of Vancomycin Powder During Spinal Cord Stimulator Implantation: A Case Series and Review of the Literature.

OBJECTIVE: We examined the role of intrawound vancomycin powder as prophylaxis against postoperative surgical site infection (SSI) after spinal cord stimulator (SCS) implantation. METHODS: We performed a retrospective analysis of 153 consecutive patients who had undergone permanent SCS implantation surgery via open laminectomy between 2014 and 2020. We queried the patients' medical records for patient age, sex, relevant medical history, and whether intrawound vancomycin had been administered. We compared the rates of SSI (primary outcome) and seroma (secondary outcome) within 3 months after surgery between the vancomycin and no-vancomycin groups. Finally, we conducted multivariable logistic regression analyses to identify independent predictors of postoperative SSI or seroma. RESULTS: Of the 153 patients, 59% were women, and the average age was 65.4 years. Overall, 3 patients (2%) had developed an SSI: 2 (methicillin-resistant Staphylococcus aureus, Klebsiella) in the vancomycin group and 1 (methicillin-sensitive Staphylococcus aureus) in the no-vancomycin group. This difference in SSI rate between the 2 groups was insignificant (P = 0.73). Three seromas, all in the no-vancomycin group, accounted for a statistically significant difference in seroma formation between the 2 groups (P = 0.04). Multivariate logistic regression failed to identify any perioperative characteristics as independent predictors of postoperative SSI or seroma. CONCLUSIONS: Our experience suggests open laminectomy for SCS implantation surgery can be performed with a low postoperative SSI rate, with or without the use of powdered vancomycin. We found no evidence suggesting that the use of powdered vancomycin is unsafe or related to postoperative seroma formation. We failed to draw any definitive conclusions regarding its efficacy, despite referencing the largest single case series of SCS implantation to date.

The therapeutic effect of Cilastatin on drug-induced nephrotoxicity: a new perspective.

OBJECTIVE: By creating nephrotoxicity models with cisplatin, vancomycin, and gentamicin in HK-2 (human renal proximal tubule cell) and HEK293T (human embryonic kidney epithelial cells) cell lines, we aimed to evaluate the effect of cilastatin on recovery of cell damage after toxicity had occurred. MATERIALS AND METHODS: In the first phase of the study, the doses of cisplatin, vancomycin, and gentamicin (50% inhibitive concentration; IC50) were determined. In the second phase, the effective dose of cilastatin against these drugs was determined, and IC50 doses of nephrotoxic agents were administered simultaneously. In the third phase of our study, to evaluate the possible therapeutic effect of cilastatin after toxicity had occurred, the analyses of cell viability, apoptosis, oxidative stress, expression of kidney injury molecule-1 (KIM-1), and neutrophil gelatinase-associated lipocalin (NGAL) were performed. RESULTS: In the second phase of the study, it was observed that cilastatin increased cell viability when treated simultaneously with a nephrotoxic agent. In the third phase, cilastatin provided a significant increase in cell viability. After treatment with each agent for 24 hours, we determined that adding cilastatin to the medium had an effect on the recovery of cell damage by increasing cell viability and reducing apoptosis and oxidative stress. The expression of KIM-1 and NGAL increased when nephrotoxicity occurred and decreased with the addition of cilastatin to the medium. CONCLUSIONS: The findings of the study suggest that cilastatin may have a healing effect after the development of nephrotoxicity.

Dual Topical Antibiotic Application Prior to Sternotomy Closure Reduces Sternal Wound Infection Rates: A Simple Solution to a Grave Morbidity.

BACKGROUND: A significant cohort of patients who undergo cardiac surgery suffer from diabetes and atherosclerosis. These patients have impaired tissue perfusion, hence a reduction in antibiotic concentration in the subcutaneous tissues at the side of the mammary artery harvesting. Topical application of gentamicin and vancomycin before wound closure broadens the antibiotic spectrum and reduces the incidence of deep sternal wound infection. In this article, we compare the use of single versus dual application of vancomycin and/or gentamicin in sternotomy wounds in a single tertiary center. METHODS: An observational cohort analysis with three sequential patient groups (N = 2550) was performed at Ain Shams University Hospital in Cairo. A control group (N = 850), vancomycin only group (N = 850), and vancomycin plus gentamicin group (N = 850) were included in the study, during the three-year period from January 2017 to December 2019. Patients who had minimal access surgery were excluded from this study. The presence of an infected postoperative sternotomy wound was assessed in all patients. RESULTS: The presence of an infected sternotomy wound (El Oakley class 2B) was present in 38 patients (4.5%) in the control group, in 19 patients (2.2%) in the vancomycin group, and in nine patients (1.1%) in the dual antibiotic group, respectively (P < .001). In contrast to the usual, we had a proliferous growth of gram-negative organisms 29 (3.4%) in the control group, 10 (1.2%) in the vancomycin group, and five (0.6%) in the dual antibiotic group, respectively (P < .001). CONCLUSION: Deep sternal wound infection is a major cause of post-cardiac surgery morbidity and prolonged hospital stay. Adding the simple step of topical application of vancomycin and gentamicin to the sternotomy wound at the end of the procedure appeared to significantly reduce deep wound infection rates.

Antibacterial Poly(ε-CL)/Hydroxyapatite Electrospun Fibers Reinforced by Poly(ε-CL)-b-poly(ethylene phosphoric acid).

In bone surgery and orthopedics, bioresorbable materials can be helpful in bone repair and countering post-op infections. Explicit antibacterial activity, osteoinductive and osteoconductive effects are essential to achieving this objective. Nonwoven electrospun (ES) fibers are receiving the close attention of physicians as promising materials for wound dressing and tissue engineering; potentially, in high contrast with dense materials, ES mats hamper regeneration of the bone extracellular matrix to a lesser extent. The use of the compositions of inherently biodegradable polyesters (poly(ε-caprolactone) PCL, poly(lactoglycolide), etc.), calcium phosphates and antibiotics is highly prospective, but the task of forming ES fibers from such compositions is complicated by the incompatibility of the main organic and inorganic ingredients, polyesters and calcium phosphates. In the present research we report the synthesis of hydroxyapatite (HAp) nanoparticles with uniform morphology, and demonstrate high efficiency of the block copolymer of PCL and poly(ethylene phosphoric acid) (PEPA) as an efficient compatibilizer for PCL/HAp mixtures that are able to form ES fibers with improved mechanical characteristics. The materials obtained in the presence of vancomycin exhibited incremental drug release against Staphylococcus aureus (St. aureus).

Optimization of dosing regimens of vancomycin, teicoplanin, linezolid and daptomycin against methicillin-resistant Staphylococcus aureus in neutropenic patients with cancer by Monte Carlo simulations.

The objective of this study was to evaluate the efficacy of various dosing regimens of vancomycin, teicoplanin, linezolid and daptomycin against methicillin-resistant Staphylococcus aureus (MRSA) in neutropenic patients with cancer. Monte Carlo simulations were conducted using pharmacokinetic parameters and pharmacodynamic data to determine cumulative fraction of response (CFRs) in terms of area under the concentration-time curve/minimum inhibition concentration target. Currently clinical standard dosing regimens of vancomycin, teicoplanin, linezolid and daptomycin were insufficient to provide expected CFRs against MRSA for neutropenic patients with cancer. The high dosing regimens of vancomycin (3500 mg/d), teicoplanin (800 mg/d) and daptomycin (8 mg/kg/d) could provide CFRs of ≥ 80%, showing a higher treatment success. However, the majority of CFRs with linezolid simulated dosing regimens reached < 80% against MRSA. Therefore, a strategy of high dosages of vancomycin, teicoplanin and daptomycin may be needed to attain optimal therapeutic efficacy against MRSA in neutropenic patients with cancer.

Effect of Local Delivery of Vancomycin and Tobramycin on Bone Regeneration.

OBJECTIVE: A bone defect rat model was established to investigate the osteogenic effect of local delivery two antibiotics (vancomycin and tobramycin powder) on bone regeneration. METHODS: Twenty-four Sprague-Dawley (SD) male rats (6 to 8 weeks, 200 to 250 g) were used in this study. All these rats were randomly divided into four groups. Based on dose conversion between rat and human via body surface area, the rat dose of two antibiotics was 88µg/g and 176 µg/g for vancomycin and tobramycin, respectively. Con group (no antibiotic), Van group (vancomycin, 88 µg/g), Tob group (tobramycin 176 µg/g), and Van+Tob group (vancomycin 88µg/g combined with tobramycin 176 µg/g). A 5.0-mm full-thickness standardized mandibular bone defect was performed with a drill in each rat and different antibiotic powders were placed over the bone defect space, respectively. All these animals were sacrificed after 12 weeks post-operation. The mandible bones were harvested for further radiographic and histologic analysis. The bone volume/total volume (BV/TV) ratio, bone volume (BV), and bone fractional area (BFA) in the defect area via micro-computed tomography (µCT scanning) were further analyzed. Then, we performed a histological assessment via hematoxylin and eosin (H&E) and Masson's trichrome staining to analyze bone regeneration and also analyze the number of osteoblasts per filed. RESULTS: There were no postoperative deaths, signs of vancomycin-related or tobramycin-related toxicity, or signs of systemic illness in any of the four groups. All wounds healed well, and no complications or surgical site infection were observed in all rats. From the µCT scans analyses, there was less bone regeneration in the Van group than in the Con group (BV/TV: F = 64.29, R2  = 0.9602; P = 0.0052; BFA: F = 76.17, R2  = 0.9662, P = 0.0007; BV: F = 194.4, R2  = 0.9865, P = 0.0022). However, when the tobramycin and vancomycin were combined, an increase in bone defect re-ossification was found in the Van+Tob group than in the Van group (BV/TV: F = 64.29, R2  = 0.9602, P = 0.0033; BFA: F = 76.17, R2  = 0.9662, P = 0.0006; BV: F = 194.4, R2  = 0.9865, P = 0.0033). Routine H&E and Masson staining supported the finding of µCT scanning. Quantitative indices confirmed that both the bone regeneration and the number of osteoblasts per filed in the defect area was higher in the Van+Tob group than in the Van group (percentage of bone tissue: F = 145.7, R2  = 0.9562, P = 0.0008; number of osteoblasts per file; F = 67.3, R2  = 0.9098, P < 0.0001). There was no significant difference between the Con group and the Van+Tob group on the number of osteoblasts each field (F = 145.7, R2  = 0.9562, P > 0.9999). CONCLUSION: For bone defect, local application of vancomycin combined with tobramycin was recommended over vancomycin alone. This animal study presents data suggesting that the use of local delivery of vancomycin and tobramycin should be investigated further in clinical studies.

Impacto del monitoreo terapéutico de vancomicina y amikacina en la optimización de dosis de antimicrobianos en pacientes pediátricos / Impact of the vancomycin and amikacin therapeutic monitoring in the optimization of antimicrobial dose in pediatric patients

INTRODUCCIÓN: La monitorización de antimicrobianos mediante sus concentraciones plasmáticas permite determinar la posología óptima de éstos, conducta esencial en pediatría. OBJETIVOS: Describir la monitorización de concentraciones plasmáticas de antimicrobianos y el ajuste de dosis en población pediátrica para determinar si las dosis utilizadas alcanzan rangos terapéuticos. PACIENTES Y MÉTODOS: Estudio descriptivo, retrospectivo, utilizando una base de datos con medición de concentraciones plasmáticas de amikacina y vancomicina en pacientes pediátricos del Hospital San Borja Arriarán, entre 2015-2018. Se determinó el número de pacientes que alcanzó rango terapéutico con dosis inicial, cuántos requirieron ajuste y sus características. RESULTADOS: Se monitorizó 104 concentraciones totales. Para vancomicina 65 concentraciones plasmáticas eran basales encontrándose fuera de rango terapéutico 56,5%; de los que requirieron ajuste, 25% fueron neonatos con mayor probabilidad de estar fuera de rango versus otros (p = 0,022). Para amikacina la Cpeak estuvo en rango en 60% de mediciones; 15,4% requirió ajuste incluyendo pacientes con fibrosis quística y oncológicos. No fue necesario efectuar ajustes en pacientes sin co-morbilidad. CONCLUSIÓN: La medición de concentraciones plasmáticas es necesaria para ajustar de forma individualizada la dosis, especialmente en pacientes pediátricos con fibrosis quística, oncológicos y en neonatología, donde es más probable no alcanzar rango terapéutico con las dosis iniciales.

BACKGROUND: The monitoring of antimicrobial therapy through plasma levels makes it possible to determine the optimal dosage of antimicrobials, an essential approach in pediatrics. AIM: To describe the monitoring of plasma antimicrobial levels and dose adjustment in the pediatric population to determine if the doses used reach therapeutic ranges. METHODS: Retrospective, descriptive study using a database with measurement of plasma levels of amikacin and vancomycin in pediatric patients at San Borja Arriarán Hospital between 2015-2018. The number of patients who reached the therapeutic range with the initial dose, how many required adjustment and their characteristics were determined. RESULTS: 104 total levels were monitored. For vancomycin 65 plasmatic levels were baseline, being outside the therapeutic range 56.5%; 25% of those requiring adjustment were neonates with a higher probability of being out of range versus others (p = 0.022). For amikacin, Cpeak was in range in 60% of measurements; 15.4% required adjustment, including patients with cystic fibrosis and cancer, without adjustments in patients without comorbidity. CONCLUSION: Measurement of plasma levels is necessary to individually adjust the dose, especially in pediatric patients with cystic fibrosis, oncology and in neonatology where it is more likely not to reach a therapeutic range with initial doses.

Evaluation of dosing strategies and trough concentrations of vancomycin in patients undergoing continuous venovenous hemofiltration.

STUDY OBJECTIVE: Recommendations regarding vancomycin dosing in critically ill patients on continuous venovenous hemofiltration (CVVH) are limited. The purpose of this study was to evaluate current dosing practices of pharmacists for patients treated with CVVH, develop guidelines for optimal dosing and monitoring of vancomycin to improve target trough attainment, and reduce pharmacist workload. DESIGN: A retrospective cohort study. was performed of critically ill adult patients from January 2015 to December 2018. Patients were included if they received vancomycin during CVVH for at least 48 h. Patients with significant residual kidney function, defined as daily urine output >400 ml or significant fluctuations (≥1000 ml/h in a 24-h period) in their hemofiltration rates, were excluded. Interruptions in CVVH up to 6 h/day were permitted. Dosing strategies with two dosing categories were defined: (1) dosing based on random serum levels (dosing by level, DBL) or (2) scheduled vancomycin dosing (SD). SETTING: Academic medical center in Detroit, Michigan. PATIENTS: Critically ill adult patients. MEASUREMENTS AND MAIN RESULTS: During the study period, 942 patients were evaluated and 200 met inclusion criteria, for a total of 586 serum vancomycin levels. There were 141 patients with 443 random vancomycin serum levels in the DBL group and 59 patients with143 vancomycin trough levels in the SD group. Mean vancomycin trough levels were similar between groups (17.1 ± 6 vs. 16.5 ± 4 mcg/ml) for the DBL and SD groups, respectively. For the primary end point of overall target trough achievement of 15-20 mcg/ml, significantly more trough levels in the SD group were in the 15-20 mcg/ml range compared with the DBL group, 50% vs. 38%; p < 0.001, respectively. When target trough range was extended to 10-20 mcg/ml, success rates were similar between groups (74% DBL vs. 82% SD, p = 0.021). The number of interventions required by the pharmacist, including notes per day and orders per day, were reduced by approximately 50% when the SD strategy was utilized. Scheduled vancomycin dosing regimens of 15-22 mg/kg every 12-24 h were required to yield trough levels in the 15-20 mcg/ml range. CONCLUSIONS: Target vancomycin trough achievement of 15-20 mcg/ml occurred more frequently when vancomycin was scheduled at a dose of 15-22 mg/kg every 12-24 h based on ultrafiltration rate and may alleviate the time and cost associated with frequent vancomycin serum monitoring.