Base Teórica: Bacteremias causadas por Klebsiella pneumoniae produtoras de carbapenemase são infecções ameaçadoras da vida e com elevadas taxas de mortalidade. As Enterobacteriaceae são as principais reponsáveis por bacteremias nos hospitais brasileiros. Há limitadas opções terapêuticas e o melhor tratamento para essas infecções ainda não está definido. O racional teórico para a terapia combinada nesse cenário seria o aumento da ação bactericida e a diminuição da indução de resistência. A terapia combinada com colistina parece estar relacionada com maior sobrevida. Com relação a terapia combinada com polimixina B, no entanto, as evidências são exíguas. Objetivo: Avaliar a mortalidade em 30 dias de pacientes com bacteremias por KPC-KP com enfoque na terapia combinada.Métodos: Trata-se de um estudo de coorte retrospectivo e unicêntrico que incluiu pacientes maiores de 18 anos com diagnóstico de bacteremia por KPC-KP. O desfecho primário avaliado foi mortalidade em 30 dias. Bacteremia por KPC-KP foi definida como uma ou mais hemoculturas positivas para esse microorganismo. A identificação bacteriana e os testes de susceptibilidade foram realizados utilizando o sistema automatizado Vitek 2 (bioMérieux, France). A terapia antimicrobiana foi caracterizada como empírica (iniciada nas primeiras 48 horas) e definitiva (esquemas iniciados ou mantidos após 48 horas) e avaliada da seguinte forma: nenhuma droga ativa, monoterapia (apenas um agente ativo), terapia combinada entre uma droga ativa e uma ou mais drogas inativas e terapia combinada com duas ou mais drogas ativas A análise estatística foi realizada com o software SPSS para Windows, versão 18.0. As análises de sobrevivência foram realizadas com curvas de Kaplan-Meier e as diferenças foram avaliadas utilizando o log-rank test. Todos os testes foram bicaudais considerando um nível de significância de 95%. Um modelo de regressão de Cox foi realizado para identificar fatores independentemente relacionados com a mortalidade em 30 dias. Resultados: Foram incluídas 105 bacteremias por KPC-KP. A mortalidade em 30 dias foi de 63 (60%) pacientes. O tempo médio de sobrevida foi de 24 dias (95% IQR, 17-21 dias). A taxa de mortalidade em pacientes tratados com terapia combinada foi significativamente menor (16,5/1000 pacientes-dia) comparada com os pacientes recebendo outros regimes terapêuticos (57,5/1000 pacientes-dia). Terapia combinada (Hazard Ratio [HR]; 0,32; 95% IC, 0,18-0.57; p<0,01) e bacteremia urinária (HR; 0,29; 95% IC, 0,09- 0,95; p=0,04) foram independentemente associados com a sobrevida em 30 dias. Em contrapartida, neoplasias (HR; 1,98; 95% IC, 1,18-3,32; p=0,01), admissão por patologia clínica (HR; 2,91; 95% IC, 1,56-5,42; p<0.01) e necessidade de tratamento com droga vasoativa (HR; 2,94; 95% IC, 1,59- 5,29; p<0,01) foram independentemente associados com o desfecho primário. Conclusão: O presente estudo demonstrou uma mortalidade em 30 dias de 60% nas bacteremias por KPC-KP. A terapia combinada com pelo menos dois agentes ativos in vitro foi consistentemente associada com sobrevida em 30 dias. / Background: BSI for KPC-KP is a life-threatening disease and compared to other sites of infection related to higher mortality rates. Enterobacteriaceae are the leading cause of BSI in Brazilian hospitals. There are limited treatment options and the best available treatment is still unknown. Rationale for combination therapy in this setting would be increasing bactericidal action and decreasing resistance induction. Combination therapy regimens with colistin seemed to be related with higher rates of survival. Polymyxin B combinations were studied only in a few studies. Objective: In this study we aim to evaluate 30-day mortality in KPC-KP bacteremia with particular emphasis on combination therapy. Methods: This is a single center retrospective cohort study that included patients older than 18 years diagnosed with KPC-KP BSI. The primary outcome was 30-day mortality after BSI. KPC-KP BSI was defined as one or more positive blood cultures with recovery of KPC-KP. Bacterial identification and antimicrobial susceptibility tests were performed using Vitek 2 (bioMérieux, France) automatized system. Antimicrobial therapy was defined as empirical (started on first 48 hours) and definitive (schemes initiated or maintained after 48 hours) and evaluated as follows: no active agents, monotherapy (only one active agents), combination therapy between one active agent plus one or more non-active agents and combination with two or more in vitro active agents Statistical analysis was performed using SPSS for Windows, version 18.0. Kaplan-Meier survival estimates were calculated and the difference was evaluated using the log-rank test. All tests were two-tailed and a p value < 0.05 were considered statistically significant. A Cox regression model were performed to identify independent factors related to 30-day mortality. Results: A total of 105 bloodstream infections caused by KPC-KP were included. A total of 63 (60%) patients died in the first 30 days after BSI. Median time to death was 24 days (95% IQR, 17-21 days). The mortality rate in patients treated with the combination of two antibiotics with in vitro activity was significantly lower (16.5/1000 patients-day) compared with that patients receiving other regimens (57.5/1000 patients-day). Combination therapy (Hazard Ratio [HR]; 0.32; 95% CI, 0.18-0.57; p<0.01) and urinary BSI (HR; 0.29; 95% CI, 0.09- 10 0.95; p=0.04) were independently associated to 30-day survival. On the other hand, having Cancer (HR; 1.98; 95% CI, 1.18-3.32; p=0.01), non-surgical admission (HR; 2.91; 95% CI, 1.56-5.42; p<0.01) and requirement of vasoactive drugs (HR; 2.94; 95% CI, 1.59-5.29; p<0.01) were independently associated to 30-day mortality. Conclusion: This study showed a 60% 30-day mortality in KPC-KP BSI. Combination therapy with two in vitro active agents was independently associated with 30-day survival.

O uso do cateter venoso central é apontado como um importante fator de risco para infecção da corrente sanguínea, acarretando no prolongamento da internação, aumento da morbimortalidade, e elevação dos custos de hospitalização. Frente ao exposto objetivou-se avaliar as evidências científicas sobre o controle de infecção relacionada ao cateter venoso central utilizado em pacientes adultos hospitalizados. A prática baseada em evidências representou o referencial teórico-metodológico. E, como recurso para obtenção das evidências de Níveis I e II realizou-se a revisão integrativa da literatura nas bases de dados LILACS, CINAHL e MEDLINE. Totalizou-se 17 publicações nos últimos dez anos. A análise dos estudos culminou em 03 categorias temáticas: cateteres impregnados com anti-sépticos, dispositivos seguros e manutenção do cateter. Como resultado obteve-se o apontamento de diversos aspectos no controle da infecção relacionada a cateter, dentre eles: uso de cateter de lúmen único, inserção por via subclávia com técnica estéril e aplicação de anti-séptico a base de clorexidine. Acresce-se que a indicação de cateteres impregnados com anti-sépticos, bem como de sistemas valvulados sem agulha, ainda é controversa. Em geral, os estudiosos sobre a temática alertaram que a qualidade da assistência à pacientes com cateter venoso central está diretamente relacionada com o risco de infecção. Assim, esforços têm sido recomendados a fim de viabilizar a aplicação das evidências advindas das pesquisas e conseqüentemente nortear o poder de decisão na prática clínica, contribuindo para a melhoria da qualidade da assistência. / The use of central venous catheter is pointed as a factor of risk to the infection of the blood stream, which increases the hospitalization period, the morbidity and mortality, and also the hospitalization costs. Therefore, this study aimed to evaluate scientific evidences about the control of infection related to the central venous catheter used in hospitalized adult patients. The evidence based practice is the theoretical-methodological reference. To obtain evidences Level I and II, an integrative literature review was performed on the databases LILACS, CINAHL e MEDLINE. In the last ten years was found a total of 17 publications. From the analysis of these studies emerged three thematic categories: catheters impregnated with antiseptics, safe devices and maintenance of the catheter. As a result, several aspects of the control of infection related to the catheter were pointed, such as: the use of the single lumen catheter, insertion through the subclavian with sterile technique and application of clorexidine based antiseptic. It is important to mention that the indication of catheters impregnated with antiseptics, as the use of needleless valve systems are still controversy. In general, researchers alerted that the quality of assistance to patients with venous catheter is directly related to the risk of infection. Therefore, efforts are recommended in order to facilitate the implementation of evidences found in research, and consequently, guide the decision making process in the clinical practice, contributing to the improvement of the quality of assistance.

Base Teórica: Bacteremias causadas por Klebsiella pneumoniae produtoras de carbapenemase são infecções ameaçadoras da vida e com elevadas taxas de mortalidade. As Enterobacteriaceae são as principais reponsáveis por bacteremias nos hospitais brasileiros. Há limitadas opções terapêuticas e o melhor tratamento para essas infecções ainda não está definido. O racional teórico para a terapia combinada nesse cenário seria o aumento da ação bactericida e a diminuição da indução de resistência. A terapia combinada com colistina parece estar relacionada com maior sobrevida. Com relação a terapia combinada com polimixina B, no entanto, as evidências são exíguas. Objetivo: Avaliar a mortalidade em 30 dias de pacientes com bacteremias por KPC-KP com enfoque na terapia combinada.Métodos: Trata-se de um estudo de coorte retrospectivo e unicêntrico que incluiu pacientes maiores de 18 anos com diagnóstico de bacteremia por KPC-KP. O desfecho primário avaliado foi mortalidade em 30 dias. Bacteremia por KPC-KP foi definida como uma ou mais hemoculturas positivas para esse microorganismo. A identificação bacteriana e os testes de susceptibilidade foram realizados utilizando o sistema automatizado Vitek 2 (bioMérieux, France). A terapia antimicrobiana foi caracterizada como empírica (iniciada nas primeiras 48 horas) e definitiva (esquemas iniciados ou mantidos após 48 horas) e avaliada da seguinte forma: nenhuma droga ativa, monoterapia (apenas um agente ativo), terapia combinada entre uma droga ativa e uma ou mais drogas inativas e terapia combinada com duas ou mais drogas ativas A análise estatística foi realizada com o software SPSS para Windows, versão 18.0. As análises de sobrevivência foram realizadas com curvas de Kaplan-Meier e as diferenças foram avaliadas utilizando o log-rank test. Todos os testes foram bicaudais considerando um nível de significância de 95%. Um modelo de regressão de Cox foi realizado para identificar fatores independentemente relacionados com a mortalidade em 30 dias. Resultados: Foram incluídas 105 bacteremias por KPC-KP. A mortalidade em 30 dias foi de 63 (60%) pacientes. O tempo médio de sobrevida foi de 24 dias (95% IQR, 17-21 dias). A taxa de mortalidade em pacientes tratados com terapia combinada foi significativamente menor (16,5/1000 pacientes-dia) comparada com os pacientes recebendo outros regimes terapêuticos (57,5/1000 pacientes-dia). Terapia combinada (Hazard Ratio [HR]; 0,32; 95% IC, 0,18-0.57; p<0,01) e bacteremia urinária (HR; 0,29; 95% IC, 0,09- 0,95; p=0,04) foram independentemente associados com a sobrevida em 30 dias. Em contrapartida, neoplasias (HR; 1,98; 95% IC, 1,18-3,32; p=0,01), admissão por patologia clínica (HR; 2,91; 95% IC, 1,56-5,42; p<0.01) e necessidade de tratamento com droga vasoativa (HR; 2,94; 95% IC, 1,59- 5,29; p<0,01) foram independentemente associados com o desfecho primário. Conclusão: O presente estudo demonstrou uma mortalidade em 30 dias de 60% nas bacteremias por KPC-KP. A terapia combinada com pelo menos dois agentes ativos in vitro foi consistentemente associada com sobrevida em 30 dias. / Background: BSI for KPC-KP is a life-threatening disease and compared to other sites of infection related to higher mortality rates. Enterobacteriaceae are the leading cause of BSI in Brazilian hospitals. There are limited treatment options and the best available treatment is still unknown. Rationale for combination therapy in this setting would be increasing bactericidal action and decreasing resistance induction. Combination therapy regimens with colistin seemed to be related with higher rates of survival. Polymyxin B combinations were studied only in a few studies. Objective: In this study we aim to evaluate 30-day mortality in KPC-KP bacteremia with particular emphasis on combination therapy. Methods: This is a single center retrospective cohort study that included patients older than 18 years diagnosed with KPC-KP BSI. The primary outcome was 30-day mortality after BSI. KPC-KP BSI was defined as one or more positive blood cultures with recovery of KPC-KP. Bacterial identification and antimicrobial susceptibility tests were performed using Vitek 2 (bioMérieux, France) automatized system. Antimicrobial therapy was defined as empirical (started on first 48 hours) and definitive (schemes initiated or maintained after 48 hours) and evaluated as follows: no active agents, monotherapy (only one active agents), combination therapy between one active agent plus one or more non-active agents and combination with two or more in vitro active agents Statistical analysis was performed using SPSS for Windows, version 18.0. Kaplan-Meier survival estimates were calculated and the difference was evaluated using the log-rank test. All tests were two-tailed and a p value < 0.05 were considered statistically significant. A Cox regression model were performed to identify independent factors related to 30-day mortality. Results: A total of 105 bloodstream infections caused by KPC-KP were included. A total of 63 (60%) patients died in the first 30 days after BSI. Median time to death was 24 days (95% IQR, 17-21 days). The mortality rate in patients treated with the combination of two antibiotics with in vitro activity was significantly lower (16.5/1000 patients-day) compared with that patients receiving other regimens (57.5/1000 patients-day). Combination therapy (Hazard Ratio [HR]; 0.32; 95% CI, 0.18-0.57; p<0.01) and urinary BSI (HR; 0.29; 95% CI, 0.09- 10 0.95; p=0.04) were independently associated to 30-day survival. On the other hand, having Cancer (HR; 1.98; 95% CI, 1.18-3.32; p=0.01), non-surgical admission (HR; 2.91; 95% CI, 1.56-5.42; p<0.01) and requirement of vasoactive drugs (HR; 2.94; 95% CI, 1.59-5.29; p<0.01) were independently associated to 30-day mortality. Conclusion: This study showed a 60% 30-day mortality in KPC-KP BSI. Combination therapy with two in vitro active agents was independently associated with 30-day survival.

Background: The proportion of nosocomial Staphylococcus infections caused by methicillin-resistant Staphylococcus aureus (MRSA) has increased from 22% in 1995 to 63% in 2004. Blood stream infections, more commonly referred to as bacteremias, represented the majority (75.5%) of hospital-onset MRSA cases. The economic impact of Staphylococcus aureus bacteremia merits investigation. Methods: This was a retrospective cohort analysis within Cerner HealthFacts data warehouse. Eligible patients were those who had Staphylococcus aureus bacteremia and were discharged between January 1, 2000, and December 31, 2006. Inclusion criteria include age > 18 years old and onset of infection > 48 hours post admission. The crude association was measured by subtracting the total mean hospital charge for MSSA bacteremia from the MRSA charge. A generalized linear model using a gamma distribution and log link were used to determine the adjusted hospital charge and post-infection length of stay for the MRSA and MSSA groups. Path analysis was used to describe the relationships between infection susceptibility status, LOS and total hospital charge. Results: During the study period, 930 patients meet all the inclusion and exclusion criteria. The overall total hospital charge was $111,636 (MRSA = $121,713, MSSA = $97,307.) The crude difference in mean charge was $24,406. The multivariable model included predicted a MRSA patient would have an increased total charge of $22,889. MRSA had a higher total charge but when patients were more severely ill, MRSA charges decreased while MSSA charges increased. The second multivariable model predicted a MRSA patient would have an increased post-infection LOS of 1.3 days. However, the magnitude of increased post-infection LOS based on pre-infection LOS was different for MRSA and MSSA patients. The path analysis model indicated the direct and indirect effects of susceptibility status on both post-infection LOS and total charge were relatively small. Conclusion: This investigation was the first large multi-center investigation to examine the economic impact of MRSA and MSSA bacteremia. MRSA was associated with a higher total charge and longer post-infection LOS than MSSA patients. The path analysis model analyzed suggests the actually role of infection susceptibility status on post-infection LOS and total charge was minor.

A sepse é uma doença de alta mortalidade e o uso adequado de antimicrobianos no seu manuseio é essencial na obtenção de melhores resultados. O objetivo deste estudo foi avaliar o consumo de antimicrobianos em pacientes com sepse hospitalar com agente etiológico identificado no sangue, comparando a reação em cadeia da polimerase (PCR) - LightCycler® SeptiFast (SF) para a detecção rápida de microorganismos à hemocultura convencional nos primeiros 14 dias de tratamento. Os objetivos secundários incluíram descrever o percentual de positividade e a concordância entre o teste molecular e a hemocultura, o tempo de internação hospitalar, os custos diretos dos antimicrobianos utilizados e a letalidade em 10 e 28 dias. Entre outubro de 2012 e maio de 2016, foram incluídos 200 pacientes adultos com sepse hospitalar: 100 alocados no grupo intervenção onde a terapia antimicrobiana foi ajustada após a identificação do micro-organismo pelo SF (dentro de 6 a 12 horas) e 100 pacientes no grupo controle onde a terapia antimicrobiana foi ajustada após a identificação do microrganismo pela hemocultura (dentro de 48 a 72 horas). O consumo de antimicrobianos foi de 1429 (1071-2000) DOT por 1000 pacientes-dia no grupo intervenção versus 1889 (1357-2563) DOT por 1000 pacientes-dia no grupo controle (p = 0.017). O SF apresentou positividade de 25,9% enquanto a positividade da hemocultura foi de 22,9% (p = 0,452). O tempo de descalonamento antimicrobiano foi de 8 horas (7-14) versus 54 horas (38-75) (p < 0,001), enquanto a mortalidade em 10 e 28 dias foi de 21% e 36,8% no grupo de intervenção versus 37% e 44% no grupo controle, (p = 0,710 e p = 0,632), respectivamente. Não houve diferença no tempo de internação hospitalar e no custo direto dos antimicrobianos utilizados nos dois grupos. A duração média da terapia antimicrobiana em dias foi menor no grupo intervenção (12 ± 5 versus 15 ± 4, p = 0,039) em comparação com o grupo controle / Sepsis is a high mortality disease. Appropriate use of antimicrobials is essential to improve outcomes. The aim of the present study was to determine whether the use of the multiplex polymerase chain reaction LightCycler® SeptiFast (SF) assay reduces the antibiotic consumption through early de-escalation in patients with nosocomial sepsis compared with conventional blood cultures (BC) in the first 14 days of treatment. Secondary outcomes included the percentage of microorganisms identified through SF and BC (in both groups), timing of antimicrobial de-escalation, length of stay, direct costs of the antimicrobial drugs and mortality at 10 and 28 days. Between October 2012 and May 2016 adult patients with nosocomial sepsis were randomized in intervention group and control group: antimicrobial therapy was adjusted following the identification of microorganisms by SF (within 6 to 12 hours) or BCs (within 48 to 72 hours), respectively. A total of 200 patients were included (100 in each group). The median antimicrobial consumption was 1429 (1071-2000) DOT/1000 patients-day in the intervention group versus 1889 (1357-2563) DOT/1000 patients-day in the control (p = 0.017). Microorganism identification was 25.9% versus 22.9% (p = 0.452), timing of antimicrobial de-escalation was 8 hours (7-14) versus 54 hours (38-75) (p < 0.001) while the mortality rate at 10 and 28 days was 21% and 36.8% in the intervention group versus 37% and 44% in the control group, (p = 0.710 and p = 0.632), respectively. There was no difference in length of stay and antimicrobial costs between groups. The mean duration of antimicrobial therapy was lower in the SF group (12 ± 5 vs. 15 ± 4, p = 0.039) comparing to BC group. The use of a rapid molecular blood test resulted in a reduction in the antimicrobial consumption and a more rapid de-escalation in patients with nosocomial sepsis when compared to the standard management of blood culture

Sepse é a primeira causa de morte em Unidades de Terapia Intensiva. A gravidade dessa doença é considerada conseqüência de um desequilíbrio da resposta inflamatória e, apesar dos avanços em diagnóstico e tratamento, os índices de mortalidade se mantêm inalterados. O papel dos receptores Fc de immunoglobulinas nesta situação é pouco esclarecido. Tais receptores deflagram respostas imunes opostas, que dependem do receptor envolvido e podem ser tanto ativatórias, quanto inibitórias. As respostas ativatórias são atribuídas a um motivo chamado ITAM, enquanto as inibitórias são relacionadas ao motivo ITIM. Camundongos apresentam dois receptores de IgG ativatórios (Fc&#947;RI e Fc&#947;RIII), que portam motivos ITAM, associados a uma sub-unidade conhecida como cadeia gamma, assim como um receptor de IgG que apresenta um motivo ITIM na sua porção intra-citoplasmática (Fc&#947;RII). Este trabalho teve como objetivo o estudo do papel destes receptores em bacteremias e sepse. Para isso, utilizamos um modelo de peritonite induzida por ligadura e punção cecal. Este projeto descreve pela primeira vez, um papel importante do FcR&#947;II na indução de apoptose em linfócitos B, durante infecção bacteriana severa. Nossos resultados colocaram em evidência, ainda, o fato de que animais deficientes em cadeia gamma apresentam mortalidade diminuída, quando submetidos a esse modelo de peritonite, e que essa diminuição é associada a menores valores de TNF&#945; no soro e nos fluidos peritoneais, menor recrutamento peritoneal de células inflamatórias, assim como a um surpreendente aumento na fagocitose de E. coli. Hemocultura e cultura do lavado peritoneal desses animais revelaram uma flora multimicrobiana, enquanto camundongos selvagens apresentaram uma forte predominância de E. coli e um número total bastante superior de bactérias. Esse papel inibitório da cadeia gamma pode estar relacionado a mecanismos de auto-tolerância. Lisado total de células peritoneais de camundongos deficientes em cadeia gamma apresentam fosforilação aumentada de diversas proteínas, quando comparados a lisados obtidos, a partir de camundongos selvagens. Estudos semelhantes realizados com camundongos transgênicos para o receptor de IgA (Fc&#945;RI), entretanto, não demonstraram um papel crucial desse receptor nesta doença. Este trabalho abre, portanto, novas perspectivas para o tratamento de doenças infecciosas, através de intervenção sobre a cadeia gamma e coloca em rediscussão os conceitos atuais de ITAM e ITIM. / Sepsis is the first cause of death in Critical Care Units and despite the development in its diagnosis and treatment, mortality remains unaffected. The role of immunoglobulin Fc receptors in sepsis is not clearly understood. These receptors initiate opposing responses, depending on their aggregation by the ligand and can induce activating or inhibitory responses. The activating responses are attributed to a motif known as ITAM, and the inhibitory responses to another one called ITIM. Mice express two activating IgG receptors (Fc&#947;RI et Fc&#947;RIII) which have ITAM motifs in the intracytoplasmic domain of an associated subunit, called the FcR&#947; chain, as well as an inhibitory IgG receptor which possesses an ITIM motif in its intracytoplasmic domain. The objective of this work is to study the importance of these receptors in bacteremia and in sepsis. To this aim, we have used a peritonitis model, induced by cecal ligation and puncture (CLP). This project describes for the first time, an important role of Fc&#947;RII in B lymphocytes apoptosis. Moreover, our results show that FcR&#947; chain knockout mice have a decreased mortality in this model, which is associated to diminished TNF&#945; serum and peritoneal fluids levels, to a reduced recruitment of peritoneal inflammatory cells and to a surprising increase in E. coli phagocytosis. Blood and peritoneal fluid cultures have shown a polymicrobial flora 24 hours post-CLP for FcR&#947;-chain deficient mice, whereas wild-type mice present a strong predominance of E. coli in the same cultures and an increased bacteria total count. Lysates from FcR&#947;-chain deficient peritoneal cells revealed augmented phosphorylation of many proteins, as compared to wild-type cells. This FcR&#947; chain inhibitory role could be related to self-tolerance mechanisms. This work opens new perspectives for the treatment of bacterial diseases, proposing FcR&#947; chain targeting and the reexamination of the actual concepts of ITAM and ITIM.

Σκοπός της μελέτης ήταν να καθορισθεί εάν η μονοθεραπεία με σιπροφλοξασίνη σε υψηλές δόσεις (400 mg x 3φορές/ημέρα ενδοφλεβίως), είναι αποδεκτή ως αρχική εμπειρική αντιμικροβιακή θεραπεία σε εμπύρετα επεισόδια ουδετεροπενικών ασθενών με αιματολογικά νοσήματα σε σχέση με τον καθιερωμένο συνδυασμό κεφταζιντίμης+αμικασίνης, και επιπρόσθετα να διερευνηθεί εάν η χορήγηση σιπροφλοξασίνης από του στόματος (750 mg x 2 φορές/ημέρα) μπορεί αποτελεσματικά να υποκαταστήσει την ενδοφλέβια χορήγηση 72 ώρες μετά την έναρξη αυτής. Σε προοπτική τυχαιοποιημένη μελέτη μελετήθηκαν συνολικά 123 εμπύρετα ουδετεροπενικά επεισόδια, σε 61 από τα οποία χορηγήθηκε σιπροφλοξασίνη και σε 62 ο συνδυασμός κεφταζιντίμης+αμικασίνης. Επί του συνόλου σε 96 (78,1%) η υποκείμενη νόσος ήταν οξεία λευχαιμία, σε 24 (19,5%) μη-Hodgkin λέμφωμα και σε 3 (2,4%) απλαστική αναιμία. Επιτυχής κλινική ανταπόκριση στο τέλος της θεραπείας χωρίς τροποποίηση αυτής παρατηρήθηκε σε 30/61 (49,2%) επεισόδια στην ομάδα της σιπροφλοξασίνης και σε 31/62 (50%) στην ομάδα της κεφταζιντίμης+αμικασίνης (p=1,00). Σε 40/61 (65,6%) επεισόδια στην ομάδα της σιπροφλοξασίνης η ενδοφλέβια θεραπεία αντικαταστάθηκε με από του στόματος μετά από 4,3±069 ημέρες, με επιτυχή ανταπόκριση στο 75%(30/40) αυτών. Επί του συνόλου των επεισοδίων στις μικροβιολογικά αποδεδειγμένες λοιμώξεις κυριαρχούσαν οι Gram-θετικοί μικροοργανισμοί σε ποσοστό 56,8%, ενώ οι Gram-αρνητικοί αποτελούσαν το 43,2%. Η ανταπόκριση στην θεραπεία με σιπροφλοξασίνη στις μικροβιολογικά αποδεδειγμένες λοιμώξεις (βακτηριαιμίες και άλλες λοιμώξεις) ήταν 40,0%, στις κλινικά αποδεδειγμένες λοιμώξεις 50% και στα επεισόδια πυρετού αγνώστου αιτιολογίας 55,2%, έναντι 41,2%, 43,8% και 58,6% αντίστοιχα στην δεύτερη ομάδα. Ειδικότερα στις βακτηριαιμίες από gram-θετικά παθογόνα επιτυχής έκβαση παρατηρήθηκε στο 20% των επεισοδίων στην ομάδα της σιπροφλοξασίνης και στο 12,5% στην ομάδα του συνδυασμού. Στη διάρκεια της μελέτης παρατηρήθηκαν 6 επιλοιμώξεις μόνο στην ομάδα της σιπροφλοξασίνης και 4 επαναλοιμώξεις μόνο στην ομάδα του συνδυασμού κεφταζιντίμης/αμικασίνης, (p=0,006). Οι επιλοιμώξεις ήταν δύο μυκητιασικές πνευμονίες, μια λοίμωξη ουροποιητικού από P. aeruginosa, και τρεις βακτηριαιμίες από P. Aeruginosa, St. viridans και Enterococcus spp.. Οι επαναλοιμώξεις αφορούσαν δύο βακτηριαιμίες μία από P. aeruginosa και μια από St. Aureus, μία λοίμωξη ουροποιητικού από E. coli και μία γαστρεντερίτιδα από Ε. faecalis. Ο αριθμός των θανάτων στις πρώτες 72 ώρες ήταν 2 για την ομάδα της σιπροφλοξασίνης και 1 για την ομάδα κεφταζιντίμης+αμικασίνης. Επιπλέον 11 ασθενείς ακόμη (7 vs 4, p=0,363) κατέληξαν στη φάση της ουδετεροπενίας. Επί του συνόλου 12/14 θανάτους οφείλονταν σε λοίμωξη. Από τη στατιστική ανάλυση των δεδομένων προκύπτει ότι η παρατεταμένη και σοβαρή ουδετεροπενία αποτελεί σημαντικό παράγοντα για την ανταπόκριση στη θεραπεία. Στην ομάδα της σιπροφλοξασίνης ουδετεροπενία με ουδετερόφιλα <100/μl για περισσότερο από 14 ημέρες επηρεάζει εξαιρετικά ισχυρά την ανταπόκριση στη θεραπεία (p=0,003), ενώ στην ομάδα του συνδυασμού κεφταζιντίμης+αμικασίνης η διαφορά αυτή, παρότι υπάρχει, δεν εμφανίζεται στατιστικά σημαντική (p=0,07). Με ανάλυση λογαριθμικής παλινδρόμησης καθορίσθηκαν παράγοντες που κατά την έναρξη του εμπυρέτου επεισοδίου και την διάρκεια αυτού ασκούν σημαντική επίδραση στην ανταπόκριση στη θεραπεία, και επομένως είναι δυνατόν να χαρακτηρίσουν τον ασθενή ως “χαμηλού κινδύνου” για την εμφάνιση επιπλοκών. Θετική επίδραση στην ανταπόκριση στη θεραπεία κατά την έναρξη του πυρετού έχουν η απουσία κλινικής λοίμωξης, ο αριθμός των ουδετεροφίλων >100/μl, η αιματολογική κακοήθεια σε ύφεση, το διάστημα από την προηγηθείσα αντινεοπλασματική χημειοθεραπεία να είναι > από 10 ημέρες από την έναρξη αυτής και το περιβάλλον εμφάνισης της λοίμωξης να είναι αυτό της κοινότητας (εξωνοσοκομειακή λοίμωξη). Κατά τη διάρκεια του επεισοδίου οι παράγοντες αυτοί είναι η άνοδος των ουδετεροφίλων >100/μl και >500/μl, η διάρκεια της ουδετεροπενίας <100/μl να είναι <14ημέρες, καθώς και η διάρκεια της ουδετεροπενίας <500/μl να είναι επίσης <14ημέρες. Τέλος αναλύοντας τα επεισόδια με ουδετερόφιλα <100/μl για περισσότερο από 14ημέρες είχαν 2,75 φορές πιθανότητα επιτυχούς έκβασης εάν έπαιρναν το συνδυασμό κεφταζιντίμης+αμικασίνης (p=0,038, odds ratio=2,75). Ανεπιθύμητες ενέργειες παρατηρήθηκαν σε 9/61 (14,7%) επεισόδια της ομάδας της σιπροφλοξασίνης και σε 10/62 (16,1%) της ομάδας κεφταζιντίμης+αμικασίνης (p=1,00), χωρίς να απαιτηθεί σε κανένα διακοπή της θεραπείας. Συμπερασματικά φαίνεται ότι η μονοθεραπεία με υψηλές δόσεις σιπροφλοξασίνης είναι εξ’ ίσου αποτελεσματική και ασφαλής με τον καθιερωμένο συνδυασμό κεφταζιντίμης+αμικασίνης, ως εμπειρική θεραπεία ουδετεροπενικών ασθενών “χαμηλού κινδύνου” με πυρετό. Επιπρόσθετα στους ασθενείς που ανταποκρίθηκαν, έχει το πλεονέκτημα της από του στόματος χορήγησης για τη συμπλήρωση της αγωγής, ενώ συγχρόνως στερείται νεφροτοξικότητας και ωτοτοξικότητας. Παρόλα αυτά ιδιαίτερα σημαντικό είναι κατά την επιλογή της εμπειρικής αντιμικροβιακής θεραπείας, να λαμβάνεται υπόψη το μικροβιακό φάσμα που επικρατεί και η ανθεκτικότητα των μικροοργανισμών που απομονώνονται στο συγκεκριμένο νοσοκομείο. / The aim of the present study was to compare administration of ciprofloxacin, given initially at the higher intravenous dose 400 mg three times a day for at least 72 hours, followed by oral administration 750 mg twice a day, with the standard combination regimen of ceftazidime plus amikacin as empiric treatment in patients with febrile neutropenia. In a prospective study, a total of 123 febrile neutropenic patients were randomized: 61 in the ciprofloxacin group and 62 in the ceftazidime plus amikacin group. In 78,1% of the patients acute leukemia was the underlying disease, another 19,5% of the patients suffered from high-grade non-Hodgkin’s lymphoma, and the remaining 2,4% of the patients suffered from aplastic anemia. The frequency of successful clinical response without modification at the end of therapy was almost identical for ciprofloxacin [49,2% (30/61 patients)] compared with that for ceftazidime plus amikacin [50% (31/62 patients)], (p=1,00). For 40/61 (65,6%) patients, it was possible to switch from parenteral ciprofloxacin to the oral after a mean of 4,3±069 days, and the response was successful for 30/40 (75%) patients. Gram-positive organisms accounted for 56,8% of all organisms isolated. The response to therapy in ciprofloxacin group was 40,0% for the microbiologically documented infections, 50% for the clinically documented infections and 55,2% for the episodes with fever of unknown origin, compared with 41,2%, 43,8% and 58,6% respectively in ceftazidime plus amikacin group. The efficacies of the regimens against gram-positive bacteremias were 20% for the ciprofloxacin group and 12,5% for the combination group. Superinfections were seen in 6 episodes in ciprofloxacin group and 4 episodes of reinfection in ceftazidime plus amikacin group (p=0,006). 3 patients (2 of ciprofloxacin group and 1 of combination group) died within 72 hours of randomization. Another 11 patients (7 vs 4 respectively, p=0,363) died before resolution of neutropenia. Of the total 12/14 patients died because of infection. The analysis of the data shown that the prolonged and severe granulocytopenia is a critical factor for the successful outcome. In ciprofloxacin group the neutropenia with neutrophils <100/μl for 14 days or more is significantly associated with the response to treatment (p=0,003). In the combination group this association is not significant (p=0,07). Logistic regression analyses were performed to estimate the probability of success and to identify “low risk” neutropenic patients. The covariates could be assessed at the onset of fever and during treatment as well. Among the tested covariates, the following variables were significant predictors of outcome at the onset of fever: absence of signs of clinically documented infection, neutrophils >100/μl, primary disease in remission, fever developing more than 10 days from the recent course of chemotherapy and outpatients status before the onset of fever. The significant predictors of outcome during treatment were: increasing neutrophils count >100/μl, increasing neutrophils count >500/μl, neutrophils <100/μl for less than 14 days and neutrophils <500/μl for less than 14 days as well. Furthermore episodes with 14 days or more of neutropenia <100/μl treated with ceftazidime plus amikacin had response rates 2,75 times higher compared to episodes treated with ciprofloxacin (p=0,038, odds ratio=2,75). Adverse events were mostly self-limited and were observed in 9 (14,7%) ciprofloxacintreated patients and 10 (16,1%) patients who were receiving the combination. In summary, this trial suggests that high-dose ciprofloxacin is therapeutically equivalent to the routine regimen of ceftazidime plus amikacin in “low risk” febrile neutropenic patients and has the advantages of intravenous and oral administration, without nepfro- and ototoxicity. However, it is very important that before an empirical therapy is chosen each hospital determine bacteriologic predominance and perform resistance surveillance.

Diss. (sammanfattning) Stockholm : Karol. inst. / Härtill 5 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst., 2005. / Härtill 5 uppsatser.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2007. / Härtill 4 uppsatser.