What is known and objective: Treatment of methicillin-resistant Staphylococcus aureus (MRSA) bacteraemia is a long-standing challenge to health care, often complicated by metastatic infections, treatment failure and mortality. When MRSA bacteraemia persists despite adequate initial treatment, current Infectious Diseases Society of America guidelines recommend evaluation and removal of possible sources of infection. In addition, a change in therapy may be considered. The objective of this review was to explore the therapeutic options for the treatment of persistent MRSA bacteraemia. Methods: A literature search of PubMed, MEDLINE and Google Scholar was performed using the following search terms: [methicillin-resistant Staphylococcus aureus OR MRSA] AND [bacteraemia OR bloodstream infection] AND [persistent OR persistence OR refractory OR treatment failure OR salvage] AND treatment. We evaluated relevant, adult, English-language, peer-reviewed studies published between 1985 and May 2018. In vitro and animal studies were considered as supportive of in vivo data. Results and discussion: Randomized, controlled trials are lacking. However, case series and case reports support multiple treatment options including high-dose daptomycin in combination with an antistaphylococcal β-lactam, ceftaroline, trimethoprim-sulfamethoxazole (TMP-SMX) or fosfomycin; ceftaroline alone or in combination with vancomycin or TMP-SMX; linezolid alone or in combination with a carbapenem, or telavancin. What is new and conclusion: Given the heterogeneity of the data, a preferred regimen has not emerged. Prescribers must take into consideration recent exposure, source control, and available synergy and clinical data. Further comparative trials are needed to establish a preferred regimen and the creation of a universal treatment algorithm.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第18163号 / 医博第3883号 / 新制||医||1003(附属図書館) / 31021 / 京都大学大学院医学研究科医学専攻 / (主査)教授 福山 秀直, 教授 富樫 かおり, 教授 増永 慎一郎 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

BACKGROUND: Evidence supporting beta-lactam plus vancomycin synergy for methicillin-resistant (MRSA) continues to grow. Current evidence demonstrates that combination therapy is associated with shorter time to blood sterilization than vancomycin monotherapy. However, this combination has not been reported as salvage therapy for persistent MRSA bacteremia. CASE REPORT: We report a case of an 81-year-old male who was successfully treated with vancomycin plus nafcillin after failing vancomycin monotherapy, daptomycin monotherapy, and daptomycin plus gentamicin combination therapy. The patient originally presented with sepsis from a suspected urinary tract infection. Blood cultures drawn on days 1, 3, 5, 15, 19, 23, and 28 remained positive for MRSA despite multiple antimicrobial therapy changes. On day 29, therapy was changed to vancomycin plus nafcillin. Blood cultures drawn on day 32 remained negative. After 11 days, nafcillin was changed to piperacillin-tazobactam due to an infected decubitus ulcer. The combination was continued for 42 days after achieving blood sterility, 71 days after the patient originally presented. Evidence regarding salvage therapy for persistent bacteremia is sparse and is limited to case reports and case series. CONCLUSION: This case report supports that vancomycin plus an anti-staphylococcal beta-lactam combination should be further studied as salvage therapy for persistent MRSA bacteremia.

Die Hochdosischemotherapie (HDCT) wurde als Therapiestrategie zur Verbesserung des Therapieansprechens bei Patienten mit rezidivierten und/oder refraktären Keimzelltumoren entwickelt. Im Zeitraum von August 1989 bis September 1995 wurden insgesamt 150 Patienten mit rezidivierten und/oder refraktären Keimzelltumoren in konsekutive Therapieprotokolle mit einer konventionell-dosierten Chemotherapie gefolgt von einem Zyklus HDCT mit Carboplatin in der Dosierung 1500-2000 mg/m², Etoposide in der Dosierung 1200-2400 mg/m² und Ifosfamid in der Dosierung 0-10 g/m² eingeschlossen und retrospektiv ausgewertet. Nach einem medianen Follow-up von 55 Monaten (Spanne 21-88 Monate) lebten 51/150 (34%) Patienten und waren tumorfrei. Das berechnete ereignisfreie Überleben lag bei 29%, das Gesamtüberleben bei 39%. Die Bedeutung von Prognosefaktoren für das Therapieansprechen auf HDCT wurden prospektiv bestätigt. Persistierende Toxizitäten traten bei gut einem Drittel der Langzeitüberlebenden auf. Die intensivierte Behandlung mit HDCT resultierte in einem signifikanten Anteil an Langzeitüberlebenden bei Patienten mit rezidivierten und/oder refraktären Keimzelltumoren. Klinische Studien zur prospektiven Evaluierung der HDCT als frühe Therapieintervention scheinen gerechtfertigt. / High-dose chemotherapy (HDCT) has evolved as a strategy to improve treatment outcome in patients with relapsed and/or refractory germ cell tumors. Between August 1989 and September 1995, 150 consecutive patients with relapsed and/or refractory germ cell tumors were treated with conventional-dose salvage chemotherapy followed by one cycle of HDCT with carboplation 1500-2000 mg/m², etoposide 1200-2400 mg/m² and ifosfamide 0-10 g/m² and were retrospetively analysed. With a median follow-up time of 55 month (range 21-88 month) 51/150 (34%) patients were alive and disease free. The projected event-free and overall survival are 29% and 39% respectively. The relevance of prognostic variables for long-term survival after HDCT were prospectively confirmed. Persisting toxicities occured in approximately one third of long-term survivors. Treatment intensification with HDCT resulted in a significant proportion of long-term survivors in patients with relapsed and/or refractory germ cell tumors. Trials to prospetively evaluate HDCT as an early intervention in these patients semm justified.

Introdução: O carcinoma epidermóide de cabeça e pescoço tem na cirurgia e na radioterapia, as principais modalidades terapêuticas iniciais. Nas recidivas loco-regionais, a cirurgia é a escolha padrão de tratamento. Objetivos: Identificação de fatores prognósticos clínicos, histopatológicos e biomoleculares e a avaliação da sobrevida após cirurgia de resgate. Casuística e Métodos: Estudo retrospectivo de pacientes submetidos a tratamento cirúrgico inicial, com revisão de variáveis histopatológicas e expressão imunohistoquímica de VEGF, ciclina d1 e EGF-R no tumor inicial e no resgate. Das recidivas, 10 eram de estádio clínico precoce (I e II) e 18, avançado (III e IV). O período de seguimento médio foi de 33,4 meses. Resultados: A comparação das variáveis histológicas e dos marcadores moleculares no tumor inicial e na recidiva não apresentou alterações estatisticamente significantes. A sobrevida global após cirurgia de resgate foi superior nas recidivas com diagnóstico após seis meses (p=0,02). Conclusões: Os achados sugerem que a expressão de VEGF superior a 75% é fator preditivo para controle da doença após a recidiva. A sobrevida entre o tempo decorrido do tratamento inicial e a recidiva foi estatisticamente significante / Introduction: The usual management of squamous cell carcinoma (SCC) head and neck is the surgery associated or not to post surgical radiotherapy. Salvage surgery is the first therapeutic option for recurrent tumors. Objective: The identification of prognostic factors and to assess survival interval after salvage surgery for SCC. Methods: Retrospective analysis of patients treated with surgery and review of histopathological variables and immunohistochemical expression of VEGF, EGF-R and Ciclina in the initial tumor and salvage surgery. Twenty eight patients were submitted salvage surgery with 10 were staged as early tumors (I and II) and 18 as advanced ones (III and IV). The average follow-up was 33.4 months. Results: The comparison of histopathologicals variables in the initial tumor and loco regional recurrence no statistically significant changes. Survival after salvage surgery was 70% in cases with recurrences diagnosed after six months of follow-up (p=0.02). Conclusions: The findings suggest that variables immunohistopathologicals in loco regional recurrence were of minor importance in prognosis. The time between the initial treatment and recurrence loco regional was independent variable of survival

Introdução: O carcinoma epidermóide de cabeça e pescoço tem na cirurgia e na radioterapia, as principais modalidades terapêuticas iniciais. Nas recidivas loco-regionais, a cirurgia é a escolha padrão de tratamento. Objetivos: Identificação de fatores prognósticos clínicos, histopatológicos e biomoleculares e a avaliação da sobrevida após cirurgia de resgate. Casuística e Métodos: Estudo retrospectivo de pacientes submetidos a tratamento cirúrgico inicial, com revisão de variáveis histopatológicas e expressão imunohistoquímica de VEGF, ciclina d1 e EGF-R no tumor inicial e no resgate. Das recidivas, 10 eram de estádio clínico precoce (I e II) e 18, avançado (III e IV). O período de seguimento médio foi de 33,4 meses. Resultados: A comparação das variáveis histológicas e dos marcadores moleculares no tumor inicial e na recidiva não apresentou alterações estatisticamente significantes. A sobrevida global após cirurgia de resgate foi superior nas recidivas com diagnóstico após seis meses (p=0,02). Conclusões: Os achados sugerem que a expressão de VEGF superior a 75% é fator preditivo para controle da doença após a recidiva. A sobrevida entre o tempo decorrido do tratamento inicial e a recidiva foi estatisticamente significante / Introduction: The usual management of squamous cell carcinoma (SCC) head and neck is the surgery associated or not to post surgical radiotherapy. Salvage surgery is the first therapeutic option for recurrent tumors. Objective: The identification of prognostic factors and to assess survival interval after salvage surgery for SCC. Methods: Retrospective analysis of patients treated with surgery and review of histopathological variables and immunohistochemical expression of VEGF, EGF-R and Ciclina in the initial tumor and salvage surgery. Twenty eight patients were submitted salvage surgery with 10 were staged as early tumors (I and II) and 18 as advanced ones (III and IV). The average follow-up was 33.4 months. Results: The comparison of histopathologicals variables in the initial tumor and loco regional recurrence no statistically significant changes. Survival after salvage surgery was 70% in cases with recurrences diagnosed after six months of follow-up (p=0.02). Conclusions: The findings suggest that variables immunohistopathologicals in loco regional recurrence were of minor importance in prognosis. The time between the initial treatment and recurrence loco regional was independent variable of survival