Pharmacodynamic comparison of different antimicrobial regimens against Staphylococcus aureus bloodstream infections with elevated vancomycin minimum inhibitory concentration.

BACKGROUND: Staphylococcus aureus is one of the major causes of bloodstream infections (BSI) worldwide, representing a major challenge for public health due to its resistance profile. Higher vancomycin minimum inhibitory concentrations (MIC) in S. aureus are associated with treatment failure and defining optimal empiric options for BSIs in settings where these isolates are prevalent is rather challenging. In silico pharmacodynamic models based on stochastic simulations (Monte Carlo) are important tools to estimate best antimicrobial regimens in different scenarios. We aimed to compare the pharmacodynamic profiles of different antimicrobials regimens for the treatment of S. aureus BSI in an environment with high vancomycin MIC. METHODS: Steady-state drug area under the curve ratio to MIC (AUC/MIC) or the percent time above MIC (fT > MIC) were modeled using a 5000-patient Monte Carlo simulation to achieve pharmacodynamic exposures against 110 consecutive S. aureus isolates associated with BSI. RESULTS: Cumulative fractions of response (CFRs) against all S. aureus isolates were 98% for ceftaroline; 79% and 92% for daptomycin 6 mg/kg q24h and for the high dose of 10 mg/kg q24h, respectively; 77% for linezolid 600 mg q12h when MIC was read according to CLSI M100-S26 instructions, and 64% when MIC was considered at the total growth inhibition; 65% and 86% for teicoplanin, three loading doses of 400 mg q12 h followed by 400 mg q24 h and for teicoplanin 400 mg q12 h, respectively; 61% and 76% for vancomycin 1000 mg q12 h and q8 h, respectively. CONCLUSIONS: Based on this model, ceftaroline and high-dose daptomycin regimens delivered best pharmacodynamic exposures against S. aureus BSIs. Teicoplanin higher dose regimen achieved the best CFR (86%) among glycopeptides, although optimal threshold was not achieved, and vancomycin performance was critically affected by the S. aureus vancomycin MIC ≥2 mg/L. Linezolid effectiveness (CFR of 73%) is also affected by high prevalence of isolates with linezolid MIC ≥2 mg/L. These data show the need to continually evaluate the pharmacodynamic profiles of antimicrobials for empiric treatment of these infections.

S53P4 BIOACTIVE GLASS PUTTY IN THE LOCAL TREATMENT OF CAVITARY CHRONIC OSTEOMYELITIS.

Objective: Evaluating the clinical results of bioactive glass S53P4 putty for the treatment of cavitary chronic osteomyelitis. Methods: Retrospective observational study, including patients of any age with clinical and radiological diagnosis of chronic osteomyelitis, who underwent surgical debridement and implantation of bioactive glass S53P4 putty (BonAlive® Putty, Turku, Finland). Patients who underwent any plastic surgery on the soft tissues of the affected site or had segmental bone lesions or septic arthritis were excluded. Statistical analysis was performed using Excel®. Demographic data, as well as data on the lesion, treatment, and follow-up, were collected. Outcomes were classified as "disease-free survival," "failure," or "indefinite." Results: This study included 31 patients, of which 71% were men and had with a mean age of 53.6 years (SD ± 24.2). In total, 84% were followed-up for at least 12 months and 67.7% had comorbidities. We prescribed combination antibiotic therapy for 64.5% of patients. In 47.1%, Staphylococcus aureus was isolated. Finally, we classified 90.3% of cases as "disease-free survival" and 9.7% as "indefinite." Conclusion: Bioactive glass S53P4 putty is safe and effective to treat cavitary chronic osteomyelitis, including infections by resistant pathogens, such as methicillin-resistant S. aureus. Level of Evidence IV, Case Series.

Objetivo: Avaliar a atividade do vidro bioativo S53P4 em pasta no tratamento de osteomielite crônica. Métodos: Estudo observacional retrospectivo, com inclusão de indivíduos de qualquer idade com diagnóstico clínico e radiológico de osteomielite que realizaram tratamento cirúrgico com limpeza e desbridamento, seguido do preenchimento da cavidade com biovidro S53P4 em pasta (BonAlive ® Putty, Turku, Finland). Foram excluídos pacientes submetidos a procedimentos de cirurgia plástica nos tecidos moles do local afetado, com lesões ósseas segmentares e com presença de artrite séptica. A análise estatística foi realizada em Excel ® . Foram coletados dados demográficos, sobre a lesão, o tratamento e o acompanhamento. O desfecho foi classificado em "sobrevida livre de doença", "falha" ou "indeterminado". Resultados: Dos 31 pacientes analisados, 71% eram homens, com idade média de 53,6 anos (DP ± 24,26). Do total, 84% foram acompanhados por no mínimo 12 meses, e 67,7% apresentaram comorbidades. A terapia antibiótica combinada foi realizada em 64,5% dos pacientes, sendo o patógeno mais frequente o Staphylococcus aureus (47,1%). Ao final, 90,3% dos pacientes obtiveram "sobrevida livre de doenças" e 9,7% foram considerados "indeterminados". Conclusão: O vidro bioativo S53P4 em pasta é seguro e eficaz no tratamento da osteomielite cavitária e de infecções por patógenos resistentes, incluindo o S. aureus multirresistente. Nível de Evidência IV, Série de Casos.

Outcome and Predictors of Treatment Failure in Chronic Osteomyelitis Using Bioactive Glass Granules and Putty Formulations.

BACKGROUND: The aim of this study is to evaluate the outcome of patients with cavitary chronic osteomyelitis undergoing adjuvant treatment with bioactive glass (BAG) S53P4 and identify the independent risk factors (RFs) for recurrence in 6- and 12-month patient follow-up. METHODS: A retrospective, multicentre observational study conducted in tertiary specialised hospitals among patients undergoing the surgical treatment of chronic cavitary osteomyelitis using BAG-S53P4 in a granule and/or putty formulation to assess the clinical outcome and RFs for failure in 6- and 12-month patient follow-up. RESULTS: Of the 92 and 78 patients with 6-month and 12-month follow-ups, infection was eradicated in 85.9% and 87.2%, respectively. In the 6-month follow-up, BAG-S53P4 in the granule formulation presented a greater risk of recurrence compared to the bioactive glass putty formulation or combined granules and putty (prevalence ratio (PR) = 3.04; confidence interval 95% [CI95%]: 1.13-10.52) and neoplasia (PR = 5.26; CI95%: 1.17-15.52). In the 12-month follow-up cohort of 78 patients, smoking (PR = 4.0; 95% CI: 1.03-15.52) and nonfermenting GNB infection (PR = 3.87; CI95%: 1.09-13.73) presented a greater risk of recurrence. CONCLUSIONS: BAG-S53P4 is a viable option for bone-void filling and the treatment of chronic cavitary osteomyelitis. Formulations of BAG with putty or in combination with granules showed better results.

S53p4 bioactive glass putty in the local treatment of cavitary chronic osteomyelitis / Biovidro ativo s53p4 em pasta no tratamento local da osteomielite crônica cavitária

ABSTRACT Objective: Evaluating the clinical results of bioactive glass S53P4 putty for the treatment of cavitary chronic osteomyelitis. Methods: Retrospective observational study, including patients of any age with clinical and radiological diagnosis of chronic osteomyelitis, who underwent surgical debridement and implantation of bioactive glass S53P4 putty (BonAlive® Putty, Turku, Finland). Patients who underwent any plastic surgery on the soft tissues of the affected site or had segmental bone lesions or septic arthritis were excluded. Statistical analysis was performed using Excel®. Demographic data, as well as data on the lesion, treatment, and follow-up, were collected. Outcomes were classified as "disease-free survival," "failure," or "indefinite." Results: This study included 31 patients, of which 71% were men and had with a mean age of 53.6 years (SD ± 24.2). In total, 84% were followed-up for at least 12 months and 67.7% had comorbidities. We prescribed combination antibiotic therapy for 64.5% of patients. In 47.1%, Staphylococcus aureus was isolated. Finally, we classified 90.3% of cases as "disease-free survival" and 9.7% as "indefinite." Conclusion: Bioactive glass S53P4 putty is safe and effective to treat cavitary chronic osteomyelitis, including infections by resistant pathogens, such as methicillin-resistant S. aureus. Level of Evidence IV, Case Series.

RESUMO Objetivo: Avaliar a atividade do vidro bioativo S53P4 em pasta no tratamento de osteomielite crônica. Métodos: Estudo observacional retrospectivo, com inclusão de indivíduos de qualquer idade com diagnóstico clínico e radiológico de osteomielite que realizaram tratamento cirúrgico com limpeza e desbridamento, seguido do preenchimento da cavidade com biovidro S53P4 em pasta (BonAlive ® Putty, Turku, Finland). Foram excluídos pacientes submetidos a procedimentos de cirurgia plástica nos tecidos moles do local afetado, com lesões ósseas segmentares e com presença de artrite séptica. A análise estatística foi realizada em Excel ® . Foram coletados dados demográficos, sobre a lesão, o tratamento e o acompanhamento. O desfecho foi classificado em "sobrevida livre de doença", "falha" ou "indeterminado". Resultados: Dos 31 pacientes analisados, 71% eram homens, com idade média de 53,6 anos (DP ± 24,26). Do total, 84% foram acompanhados por no mínimo 12 meses, e 67,7% apresentaram comorbidades. A terapia antibiótica combinada foi realizada em 64,5% dos pacientes, sendo o patógeno mais frequente o Staphylococcus aureus (47,1%). Ao final, 90,3% dos pacientes obtiveram "sobrevida livre de doenças" e 9,7% foram considerados "indeterminados". Conclusão: O vidro bioativo S53P4 em pasta é seguro e eficaz no tratamento da osteomielite cavitária e de infecções por patógenos resistentes, incluindo o S. aureus multirresistente. Nível de Evidência IV, Série de Casos.

Pharmacodynamic profiling of commonly prescribed antimicrobial drugs against Escherichia coli isolates from urinary tract.

Since antimicrobial resistance among uropathogens against current first line agents has affected the management of severe urinary tract infection, we determined the likelihood that antibiotic regimens achieve bactericidal pharmacodynamic exposures using Monte Carlo simulation for five antimicrobials (ciprofloxacin, ceftriaxone, piperacillin/tazobactam, ertapenem, and meropenem) commonly prescribed as initial empirical treatment of inpatients with severe community acquired urinary tract infections. Minimum inhibitory concentration determination by Etest was performed for 205 Brazilian community urinary tract infection Escherichia coli strains from 2008 to 2012 and 74 E. coli bloodstream strains recovered from a surveillance study. Pharmacodynamic exposure was modeled via a 5000 subject Monte Carlo simulation. All isolates were susceptible to ertapenem and meropenem. Piperacillin/tazobactam, ceftriaxone and ciprofloxacin showed 100%, 97.5% and 83.3% susceptibility among outpatient isolates and 98.6%, 75.7% and 64.3% among inpatient isolates, respectively. Against outpatient isolates, all drugs except ciprofloxacin (82.7% in aggressive and 77.6% in conservative scenarios) achieved high cumulative fraction of response: carbapenems and piperacillin/tazobactam cumulative fraction of responses were close to 100%, and ceftriaxone cumulative fraction of response was 97.5%. Similar results were observed against inpatients isolates for carbapenems (100%) and piperacillin/tazobactam (98.4%), whereas ceftriaxone achieved only 76.9% bactericidal cumulative fraction of response and ciprofloxacin 61.9% (aggressive scenario) and 56.7% (conservative scenario) respectively. Based on this model, standard doses of beta-lactams were predicted to deliver sufficient pharmacodynamic exposure for outpatients. However, ceftriaxone should be avoided for inpatients and ciprofloxacin empirical prescription should be avoided in both inpatients and outpatients with complicated urinary tract infection.

Pandemic H1N1 illness prognosis: evidence from clinical and epidemiological data from the first pandemic wave in São Paulo, Brazil.

OBJECTIVES: The pandemic of 2009 H1N1 influenza A emerged in February 2009, with high morbidity and mortality, and rapidly spread globally. São Paulo was among the most affected areas in Brazil. This study compares the clinical and epidemiological characteristics of influenza-like illness between outpatients and hospitalized patients and evaluates the impact of oseltamivir therapy on the outcome of 2009 H1N1 influenza A patients. METHODS: This is a case series study comparing the clinical and epidemiological characteristics of influenza-like illness between outpatients attended at Hospital São Paulo in August 2009 (the peak of the first pandemic wave) and those patients hospitalized between May and September 2009 (the entire first pandemic wave). RESULTS: The 1651 patients evaluated were predominantly female (927×686, p<0.001) and aged 31.71±16.42 years, with 148 reporting chronic pulmonary disease. Dyspnea was presented by 381 (23.4%) patients and was more frequent among those aged 30 years or more (p<0.001). Hospitalization occurred at 3.73±2.85 days, and antiviral treatment started 2.27±2.97 days after the onset of first symptoms. A delay of more than 5 days in starting oseltamivir therapy was independently associated with hospitalization (p<0.001), a stay in the ICU (p<0.001) and a higher risk of dying (OR=28.1, 95% CI 2.81-280.2, p=0.007). CONCLUSION: The 2009 pandemic of H1N1 influenza A affected young adults, presented a significant disease burden and produced severe cases with a significant fatality rate. However, promptly starting specific therapy improved the outcome.

Pharmacodynamic profiling of commonly prescribed antimicrobial drugs against Escherichia coli isolates from urinary tract

Since antimicrobial resistance among uropathogens against current first line agents has affected the management of severe urinary tract infection, we determined the likelihood that antibiotic regimens achieve bactericidal pharmacodynamic exposures using Monte Carlo simulation for five antimicrobials (ciprofloxacin, ceftriaxone, piperacillin/tazobactam, ertapenem, and meropenem) commonly prescribed as initial empirical treatment of inpatients with severe community acquired urinary tract infections. Minimum inhibitory concentration determination by Etest was performed for 205 Brazilian community urinary tract infection Escherichia coli strains from 2008 to 2012 and 74 E. coli bloodstream strains recovered from a surveillance study. Pharmacodynamic exposure was modeled via a 5000 subject Monte Carlo simulation. All isolates were susceptible to ertapenem and meropenem. Piperacillin/tazobactam, ceftriaxone and ciprofloxacin showed 100%, 97.5% and 83.3% susceptibility among outpatient isolates and 98.6%, 75.7% and 64.3% among inpatient isolates, respectively. Against outpatient isolates, all drugs except ciprofloxacin (82.7% in aggressive and 77.6% in conservative scenarios) achieved high cumulative fraction of response: car-bapenems and piperacillin/tazobactam cumulative fraction of responses were close to 100%, and ceftriaxone cumulative fraction of response was 97.5%. Similar results were observed against inpatients isolates for carbapenems (100%) and piperacillin/tazobactam (98.4%), whereas ceftriaxone achieved only 76.9% bactericidal cumulative fraction of response and ciprofloxacin 61.9% (aggressive scenario) and 56.7% (conservative scenario) respectively. Based on this model, standard doses of beta-lactams were predicted to deliver sufficient pharmacodynamic exposure for outpatients. However, ceftriaxone should be avoided for inpatients and ciprofloxacin empirical prescription should be avoided in both inpatients and outpatients with complicated urinary tract infection.

Pandemic H1N1 illness prognosis: evidence from clinical and epidemiological data from the first pandemic wave in São Paulo, Brazil

OBJECTIVES: The pandemic of 2009 H1N1 influenza A emerged in February 2009, with high morbidity and mortality, and rapidly spread globally. São Paulo was among the most affected areas in Brazil. This study compares the clinical and epidemiological characteristics of influenza-like illness between outpatients and hospitalized patients and evaluates the impact of oseltamivir therapy on the outcome of 2009 H1N1 influenza A patients. METHODS: This is a case series study comparing the clinical and epidemiological characteristics of influenza-like illness between outpatients attended at Hospital São Paulo in August 2009 (the peak of the first pandemic wave) and those patients hospitalized between May and September 2009 (the entire first pandemic wave). RESULTS: The 1651 patients evaluated were predominantly female (927×686, p<0.001) and aged 31.71±16.42 years, with 148 reporting chronic pulmonary disease. Dyspnea was presented by 381 (23.4%) patients and was more frequent among those aged 30 years or more (p<0.001). Hospitalization occurred at 3.73±2.85 days, and antiviral treatment started 2.27±2.97 days after the onset of first symptoms. A delay of more than 5 days in starting oseltamivir therapy was independently associated with hospitalization (p<0.001), a stay in the ICU (p<0.001) and a higher risk of dying (OR = 28.1, 95% CI 2.81-280.2, p = 0.007). CONCLUSION: The 2009 pandemic of H1N1 influenza A affected young adults, presented a significant disease burden and produced severe cases with a significant fatality rate. However, promptly starting specific therapy improved the outcome. .