An evaluation of vancomycin pharmacokinetics was performed in 2 phases. In phase I, a vancomycin population pharmacokinetic model was developed based on data from 126 patients using a two-compartment model. Variables tested for inclusion in the model were creatinine clearance (Crcl), age, total body weight (wt) ICU status, gender, body surface area, ideal weight and height. Variables were included at the P < _ 0. 05 level. The final population pharmacokinetic model was as follows: Cl (L/hr) = (0.025 * Crcl) * (1 + 0.0165 *age), V1 (L) = 29.5, V2 (L) = 8.17 + 0.349 * Crcl and Q (L/hr.kg) = 0. 0639 * wt. For ICU patients, V2 was larger than the non ICU patients and it was V2 (L) = 16.258 + 0.694 * Crcl. In phase II, the performance of the derived model was evaluated and compared to the Moellering, Matzke, Birt & Chandler and Rodvold Methods. Predictability of .52 vancomycin serum concentrations was assessed in 3 0 new patients. In predicting all concentration types, mean prediction error (MPE) with 95% CI for Moellering,. Matzke, Birt & Chandler, Rodvold and current methods were -0.1 (-1.6, 1.4), -0.8 (-0.7, 2. 4) , o. o ( -1.5, 1. 6) , -2. 0 ( -3. 4, -o. 5) , and 2. 1 ( o. 9, 3. 4) mg/L respectively. When considering only troughs, MPE with 95% CI were 1.8 (0.2, 3.4), 2.7 (0.9, 4.6), -1.5 (-3.5, 0.5), -1.5 (-3.2, 0.1), and 0.8 (-0.8, 2.4) mg/L respectively. MPE with 95% for the peaks were -2.5 (-5.0, 0.0), -1.6 (-4.1, 1.0), 2.0 (-0.4, 4.4), -2.5 (-5.3, 0.3) and 3.8 (1.8, 5.8) mg/L respectively. Median absolute prediction error (MABPE) , 5% and 95% quantiles for all concentration types for Moellering, Matzke, Birt & Chandler, Rodvold and current methods were 3.4 (0.2, 10.1), 4.1 (0.3, 10.9), 3.9 (0.4, 11.7), 3.1 (0.2, 13.0) and 2.3 (0.1, 9.5) mg/L respectively. MABPE, 5% and 95% quantiles for the troughs were 2. 6 ( o. 2, 9. 4) , 4. o ( o. 4, 10. 3) , 4. 1 (0.7, 10.2), 2.9 (0.2, 9.4) and 2.0 (0.1, 9.2) mg/L respectively. MABPE, 5% and 95% quantiles for the peaks were 5.0 (0.7, 11.5·), 4.2 (0.3, 10.9), 3.8 (0.4, 11.7), 4.9 (0.6, 13.0) and 5.0 (1.1, 9.5) mg/L respectively. It is recommended that the current method be used while setting initial target peak at 30 mg/L with the initial target trough at 6 mgjL. This should frequently result in serum vancomycin concentration within the therapeutic window. Individualization of therapy should then be done when the measured concentrations are available.

Indiana University-Purdue University Indianapolis (IUPUI) / This study was undertaken to investigate histologically the effect of a combination of a potent antibiotic and calcium hydroxide when used as a medication in direct pulp therapy. The pulps of 74 teeth in one Macaca Speciosa monkey and two Macaca Nemestrina monkeys were exposed and left open to the oral environment for 48 hours to insure contamination. These pulps received direct treatment with one of four experimental medications: 1) starch and water; 2) vancomycin, starch and water; 3) calcium hydroxide, methyl cellulose and water; and 4) vancomycin, calcium hydroxide, methyl cellulose and water. In 30 days the teeth were removed from two animals and at 90 days from the other for histologic evaluation. A satisfactory response was observed in all the teeth treated with vancomycin, calcium hydroxide, methyl cellulose and water; in 94.4 per cent of the teeth treated with calcium hydroxide, methyl cellulose and water; in 33.3 per cent of those treated with vancomycin and starch; and in 11.2 per cent of those receiving starch and water. Complete bridging was seen in all teeth treated with vancomycin, calcium hydroxide, methyl cellulose and water. This was confirmed by the use of Procion brilliant red H-8BS dye and the study of serial sections. Under the conditions of this investigation, vancomycin in combination with calcium hydroxide and methyl cellulose was effective in controlling infection and promoting reparative dentin formation in monkeys.

No description available.

Diss. (sammanfattning) Stockholm : Karol. inst., 2003. / Härtill 6 uppsatser.

Class of 2012 Abstract / Specific Aims: The primary purpose of this study was to evaluate the time of vancomycin pre-operative surgical site infection prophylaxis administration relative to other scheduled antibiotic therapy at a tertiary care, academic medical center. The secondary purpose was to characterize the incidence of adverse events post-surgery that were associated with vancomycin therapy in patients who received both pre- operative scheduled vancomycin therapy and vancomycin for surgical site infection prophylaxis Methods: This descriptive study was a retrospective medical chart review of all patients over the age of 28 days who received vancomycin for surgical site infection prophylaxis between February 2011 and May 2011 at a tertiary care, academic medical center. This study was approved be the Institutional Review Board. The subject population included patients admitted to the hospital for at least 72 hours who received at least 48 hours of scheduled vancomycin (IV), daptomycin or linezolid therapy before index surgery and subsequently received surgical site infection prophylaxis with vancomycin. Main Results: Of the 20 subjects who meet the study inclusion criteria, 18 (90%) subjects received scheduled vancomycin doses within 48 hours prior to surgery, 5 (25%) subjects within 4 hours, and 4 (20%) subjects within 2 hours. No surgical site infections were reported. Conclusions: This was a pilot study to evaluate the timing of vancomycin surgical site infection prophylaxis doses with scheduled vancomycin, linezolid, and daptomycin. No adverse effects associated with surgical site infection prophylaxis were reported but the sample size is small and likely inadequate to detect this potential issue.

Thesis advisor: Steven D. Bruner / Thesis advisor: Mary Roberts / The dioxygenase DpgC performs a key step in the biosynthesis of 3,5-dihydroxyphenylglycine (DPG), a nonproteogenic amino acid found in the vancomycin family of antibiotics. Remarkably, DpgC performs a 4-electron oxidation without the use of metals or cofactors. The tools of synthetic organic chemistry, enzymology and structural biology were used to study this enzyme. We have solved the first structure of an enzyme of this oxygenase class, in complex with a bound substrate mimic. The structure confirms the absence of cofactors, and electron density consistent with molecular oxygen is located adjacent to the site of oxidation on the substrate. The use of a designed, synthetic substrate analog allowed us to gain unique insights into the chemistry of oxygen activation. We systematically probed the importance of active site residues by engineering conservative changes using site-directed mutagenesis. The kinetic parameters of these constructs imply that the phenolic hydroxyls of the substrate are of particular importance. These conclusions were verified by kinetic evaluation of synthetic substrate analogs. We have synthesized cyclopropyl substrate derivatives to probe the electron transfer step. The single electron oxidation should produce a radical species capable of opening the cycloproyl ring, thus providing a handle of detection. Our results resolve the unique and complex chemistry of DpgC, a key enzyme in the biosynthetic pathway of an important class of antibiotics. / Thesis (PhD) — Boston College, 2009. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

Enterococcus faecium is a leading cause of hospital-acquired infection, disproportionally affecting immunocompromised and critically ill patients. Despite infection control measures, rates of vancomycin-resistant E. faecium (VREfm) bacteraemias have failed to decline in the United Kingdom, and Cambridge University Hospitals (CUH) report the highest numbers nationally. The aims of my PhD were to use epidemiological and genomic surveillance data to establish risk factors for acquisition and infection with E. faecium in patients at CUH, and to use a One Health approach to consider possible sources for hospital patients by relating bloodstream-associated isolates with those cultured from livestock and the environment in the same geographic region. A retrospective matched nested case control study was performed to determine risk factors for VRE bacteraemia relating to antibiotic exposure. 235 cases were matched to 220 controls for length of admission, year, specialty and ward type. Multivariable analysis demonstrated that duration of exposure to parenteral vancomycin, fluoroquinolones and meropenem were independently associated with VRE bacteraemia. This provides evidence for the importance of antimicrobial stewardship targeting high-risk antibiotics in patients at risk of VRE bacteraemia. VREfm bacteraemia may be complicated by disease recurrence. Whole genome sequencing was used to distinguish between relapse and reinfection in 14 episodes of recurrent VREfm bacteraemia. This demonstrated that 10 (71%) episodes were due to reinfection with a new strain, with reinfection being more likely with increasing time between two positive cultures. This study also evaluated 9 patients with blood cultures positive for both VREfm and vancomycin-susceptible E. faecium (VSEfm), the majority (78%) of which were found to be unrelated strains. More than half of all study isolates from these two patient groups were closely related to another isolate causing bacteraemia at CUH, suggesting that hospital acquisition of VREfm is a driver for infection and recurrence. A cross-sectional study of E. faecium in raw and treated wastewater from 20 municipal water treatment plants across the East of England revealed widespread dissemination of healthcare-associated lineages of VREfm in all sampled locations including rural areas, and environmental release in treated wastewater in 17/20 locations. Wastewater isolates were genetically intermixed with isolates causing bacteraemia at CUH, including highly related isolates indicating recent transmission between the two reservoirs. These findings are consistent with widespread distribution of healthcare-associated VREfm in community populations. A One Health approach incorporating sampling from livestock (10 pork, 10 cattle, 9 poultry farms) detected no VREfm in animals whilst 2 independent meat surveys demonstrated VREfm in 1-2% of uncooked products. Genomic comparison of >1400 E. faecium isolates from livestock, meat, wastewater and almost 800 people with bloodstream infection demonstrated that livestock and human isolates were genetically distinct. Analysis of the accessory genome added further evidence for distinct gene content associated with niche adaptation. An analysis of mobile genes encoding antibiotic resistance revealed limited evidence of sharing between human and animal populations. A prospective longitudinal study in haematology patients at CUH over 6 months revealed high rates of VREfm carriage (63% of cases) and environmental contamination (49% of samples). Genomic analysis elucidated complex colonisation dynamics with frequent loss and acquisition of subtypes, including unsuspected acquisition of new VREfm subtypes in patients already colonised with VREfm, and multiple transmission chains involving patients and the environment, including some leading to bacteraemia. These findings highlight the shortcomings of infection control and environmental cleaning and provide the basis for revised interventions.

A vancomicina é um antimicrobiano de escolha para o tratamento de microrganismos gram-positivos multirresistentes, como Staphylococcus aureus resistente à meticilina (MRSA). Apesar da importância ouso indiscriminado gera preocupação em relação à resistências bacteriana, além de ser considerado nefrotóxico e haver carência de dados em pediatria.Objetivo:Avaliar o perfil de utilização de vancomicina, a presença de eventos adversos, nefrotoxicidade e o desfecho clínico pacientes de uma Unidade de Terapia Intensiva. Método: Estudo transversal, retrospectivo, conduzido entre pacientes pediátricos internados em unidade de terapia intensiva que receberam vancomicina durante o período de abril de 2013 a junho de 2014. Os dados foram coletados de fontes secundárias como prontuário, prescrições e exames laboratoriais. Resultados: De 94 pacientes selecionados, 53,2% eram lactentes e o CID mais prevalente foi bronquiolite aguda devido a outros microrganismos especificados. A duração do tratamento com vancomicina teve uma média de 13±6,7 dias e uma dose média inicial de 51,2±14,7 mg/kg/dia. Entre os eventos adversos observados, edema foi o mais prevalente, seguido de toxicidade renal. Dos doze pacientes que tiveram MRSA identificado em hemocultura ou cultura de secreções, três tiveram infecção persistente e um foi a óbito em menos de 30 dias. Dos pacientes com nefrotoxicidade, 63,6% utilizaram vancomicina por mais de 14 dias e todos tiveram níveis séricos ≥15 μg/ml. Conclusão: As faixas de doses de vancomicina usadas estão dentro do que tem sido recomendado na literatura, contudo o aparecimento de toxicidade renal parece ter relação significativa não somente com o nível sérico de vancomicina, mas também com o tempo de tratamento. Sugere-se a realização de estudos que consigam confirmar essa tendência associativa entre tempo, concentração sérica de vancomicina e aparecimento de nefrotoxicidade. / Vancomycin is an antibiotic of choice for the treatment of multidrug-resistant grampositive microorganisms, as methicillin-resistant Staphylococcus aureus (MRSA). Despite the importance their indiscriminately use causes concern regarding the bacterial resistance, besides being nephrotoxic agent and there are few studies in pediatric patients. Objective: To evaluate the profile of use of vancomycin, the presence of adverse events, nephrotoxicity and clinic outcome in children admitted to the Intensive Care Unit. Method: Cross-sectional and retrospective study, with pediatric patients admitted to the intensive care unit who received vancomycin during the period from April 2013 to June 2014. Data were collected from secondary sources such as patient records, prescriptions and laboratory tests. Results: 94 selected patients, 53.2% were aged infants and the most prevalent CID was acute bronchiolitis due to other specified microorganism. The duration of vancomycin treatment averaged 13±6.7 days and an initial mean dose was 51.2±14.7 mg/kg/day. Among the adverse events observed edema was the most prevalent, followed by renal toxicity. Of the twelve patients who had MRSA identified in blood or secretions culture, three had persistent infection and one died in less than 30 days. Of patients with nephrotoxicity, 63.6% used vancomycin for more than 14 days and all had vancomycin serum levels ≥15 μg/mL. Conclusion: Vancomycin doses used are in agreement with recommended in literature, however the onset of renal toxicity seems to be related with serum level and the duration of vancomycin treatment. It is suggested to conduct studies to confirm this associative tendency among treatment duration, vancomycin serum levels and appearance of nephrotoxicity.

published_or_final_version / Microbiology / Master / Master of Medical Sciences

Thesis (Ph.D.)--Tufts University, 2004. / Adviser: Krishna Kumar. Submitted to the Dept. of Chemistry. Includes bibliographical references (leaves 190-197). Access restricted to members of the Tufts University community. Also available via the World Wide Web;