Febrile neutropenia is a potentially life-threatening oncologic emergency characterized by a dangerously low neutrophil count that places the patient at great risk. In these patients, fever may be the only sign of infection, which requires prompt treatment. With the increasing focus in shifting health care from inpatient centers to outpatient arenas, home health care clinicians will likely have an increased role in the care of neutropenic fever patients in the future. The article describes both the pharmacologic treatment and nonpharmacologic support required of these patients with particular attention to treatment that may be required in the patient?s home.

In the first part of my thesis I focus on mapping problems associated with antibiotic therapy and subsequent development of antibiotic resistance. Tracking resistance is based primarily on data collection and evaluation of the results set sensitivity from around the world. Antibiotic resistance is a natural phenomenon that can be observed in the evolution of microbes as one of the mechanisms of adaptation to new conditions in the environment. For this work I have chosen the following research questions. Do the incidence of ESBL strains in the České Budějovice Hospital a.s. increase over time? Are these values comparable to those achieved in another region, namely in Moravian hospitals the University Hospital of Olomouc, Ostrava University Hospital and Regional University Hospital of T. Bata in Zlin? The data collection I made in collaboration with the laboratory technicians and doctors at Hospital?s Bacteriology Laboratory in České Budějovice. Bacteries tested for the detection of ESBL production originated from biological materials, witch came from patients of hospital in České Budějovice. The first objective was to compare the results achieved in the České Budějovice Hospital in the period of 2007 to 2012. If we look at the total number of ESBL strains that have been isolated since 2007, values have upward trend. While in 2007 there were only 64 strains a year later, the number more than doubled. In 2010, the value soared to 281 tribes and in the year 2012, the number was 321 tribes. The incidence of ESBL strains in 2007 increased about five times. In the long term we can say the numbers have increasing tendency and the range of each species in the production of ESBL has significantly changed. In 2007, it was K. pneumoniae strains that dominated the statistics, but over time the strains of E. coli came forefront. Values of 2012 suggest that the presence of ESBL strains of K. pneumoniae is again almost equal to the number of E. coli strains. The second objective was to compare the results of the 2012 with study of the Prevalence of ESBL-positive Enterobacteriaceae in large Moravian hospitals. In the general overview of ESBL producers values in Hospital České Budějovice (5.23%) are comparable to those in Ostrava (4.9%) and in Zlín (4.3%). Number of strains in the Hospital in Olomouc (11.8%) is about twice as high as the numbers in České Budějovice. In this comparison the České Budějovice Hospital is one of the hospitals with a lower incidence of ESBL producers. The České Budějovice Hospital is below the national average, which originate from an elaborate system of care for patients with colonization or infection with ESBL strains, and from therapy control system using antibiotic center. These results may serve to the Hospital in České Budějovice for statistical purposes, and also for proposals for improving patient care. In the discussion, I pointed out the danger of the spread of resistant strains of bacteria in the community and also the associated risks that mentioned bacteria mean for patients injured in mass accidents or disasters. In these cases, number of infections including ESBL producers can penetrate through open wounds into the affected body. Unlike conventional sensitive bacteria those strains are resistant to commonly used antibiotics and thereby endanger the lives of people affected by the accident.

Pneumonia is one of the leading causes of death worldwide. The course of the disease is often highly dynamic with unforeseen critical deterioration within hours in a relevant proportion of patients. Besides antibiotic treatment, novel adjunctive therapies are under development. Their additive value needs to be explored in preclinical and clinical studies and corresponding therapy schedules require optimization prior to introduction into clinical practice. Biomathematical modeling of the underlying disease and therapy processes might be a useful aid to support these processes. We here propose a biomathematical model of murine immune response during infection with Streptococcus pneumoniae aiming at predicting the outcome of different treatment schedules. The model consists of a number of non-linear ordinary differential equations describing the dynamics and interactions of the pulmonal pneumococcal population and relevant cells of the innate immune response, namely alveolar- and inflammatory macrophages and neutrophils. The cytokines IL-6 and IL-10 and the chemokines CCL2, CXCL1 and CXCL5 are considered as major mediators of the immune response. We also model the invasion of peripheral blood monocytes, their differentiation into macrophages and bacterial penetration through the epithelial barrier causing blood stream infections. We impose therapy effects on this system by modelling antibiotic therapy and treatment with the novel C5a-inactivator NOX-D19. All equations are derived by translating known biological mechanisms into equations and assuming appropriate response kinetics. Unknown model parameters were determined by fitting the predictions of the model to time series data derived from mice experiments with close-meshed time series of state parameters. Parameter fittings resulted in a good agreement of model and data for the experimental scenarios. The model can be used to predict the performance of alternative schedules of combined antibiotic and NOX-D19 treatment. We conclude that we established a comprehensive biomathematical model of pneumococcal lung infection, immune response and barrier function in mice allowing simulations of new treatment schedules. We aim to validate the model on the basis of further experimental data. We also plan the inclusion of further novel therapy principles and the translation of the model to the human situation in the near future.

Operationen an der Bauchspeicheldrüse stellen anspruchsvolle abdominalchirurgische Eingriffe dar. Trotz rückläufiger Mortalität in den vergangenen Jahrzehnten persistiert die Morbidität weiterhin bei 40-60% selbst an ausgewiesenen High-Volume Zentren (Hartwig et al., 2009). Pankreaskopfresektionen werden zum überwiegenden Anteil aufgrund eines malignen Prozesses im Bereich des Pankreaskopfes durchgeführt. Die komplette Tumorentfernung stellt die einzig kurative Therapieoption für diese Patienten:innen dar (AWMF Leitlinienprogramm Exokrines Pankreaskarzinom, 2021). Postoperative Komplikationen können den Beginn einer adjuvanten Therapie verzögern oder gar unmöglich machen und damit das mediane Überleben negativ beeinflussen. Maßgeblich sind hierfür septische Komplikationen verantwortlich (Vollmer et al., 2012; De Pastena et al., 2017). Eine Bakterobilie, die durch eine präoperative ERCP oder eine tumorbedingte Gallengangsobstruktion induziert werden kann korreliert mit einer erhöhten Rate an postoperativen Komplikationen insbesondere mit einer signifikant erhöhten Rate an Wundinfektionen (Surgical site infection [SSI]) (van der Gaag et al. 2007). In den intraoperativ entnommenen Gallenwegsabstrichen dominieren häufig Enterobacter- und Enterococcus-Spezies, welche in der Regel eine Resistenz gegenüber Cephalosporinen der ersten und zweiten Generation aufweisen (Ohgi et al. 2016, Sugiura et al. 2012). Vorangegangene Studien haben bereits einen positiven Effekt auf die SSI-Rate sowie auf das Auftreten weiterer septischer Komplikationen nach Pankreasresektion durch die Gabe einer an das Keimspektrum der Gallenwege angepassten Antibiotikatherapie nachweisen können (De Pastena et al., 2021). Der Einsatz einer Extensive intraoperative peritoneal lavage (EIPL) in der onkologischen Magenchirurgie führte zu einer signifikanten Reduktion der Mortalität, der Morbidität und der postoperativen Schmerzen. Zudem zeigte sich eine geringere Inzidenz für das Auftreten von septischen Komplikationen und eine höhere 5-Jahres-Überlebensrate (Jing Guo et.al., 2019, Kuramoto et.al., 2009). Vor diesem Hintergrund haben wir in dieser retrospektiven Studie untersucht ob durch den Einsatz einer EIPL und der Gabe einer an das biliäre Keimspektrum angepassten perioperativen Antibiotikaprophylaxe die Rate an septischen Komplikationen nach Pankreaskopfresektionen reduziert werden kann. Zudem sollte untersucht werden inwieweit diese Maßnahmen Einfluss auf die Morbidität und die Mortalität nehmen. Wir führten eine retrospektive Datenanalyse von 163 Patienten:innen durch, die im Zeitraum vom 24.05.2018 bis 20.05.2021 eine Pankreatikoduodenektomie in der Klinik für Viszeral-, Thorax- und Gefäßchirurgie am Universitätsklinikum Carl Gustav Carus in Dresden erhielten. Die Kontrollgruppe wurde durch 100 Patienten:innen gebildet, welche im Zeitraum vom 24.05.2018 bis zum 29.02.2023 operiert wurden. Diese Probanden:innen erhielten eine perioperative Antibiotikaprophylaxe mit einem Cephalosporin der Zweiten Generation (Cefuroxim) in Kombination mit einem Nitroimidazol (Metronidazol). Die Interventionsgruppe wurde durch 63 Probanden:innen gebildet, welche im Zeitraum vom 01.03.2020 bis zum 20.05.2021 operiert wurden. Diese Patienten:innen wurden perioperativ mit Piperazillin/ Tazobactam behandelt. Zudem erfolgte eine EIPL vor dem Verschluss der Abdominalhöhle. 46 Patienten:innen (28,2%) entwickelten postoperativ eine Wundinfektion. Vier fünftel dieser Patienten:innen waren Probanden aus der Kontrollgruppe (37,0%), wohingegen nur neun Patienten:innen (14,3%) aus der Interventionsgruppe eine SSI entwickelten. Sowohl in der univariaten als auch in der multivariaten Analyse bestätigte sich, dass der Einsatz einer an das Keimspektrum des Gallenwegssystem angepassten perioperativen Antibiotikaprophylaxe in Kombination mit einer EIPL ein protektiver Faktor für das Auftreten von SSI darstellt (OR=0,374; 95% KI=0,149-0,935; p=0,035). Ein hohes Patientenalter bestätigte sich als unabhängiger Risikofaktor für das Auftreten von SSIs (OR=2,607; 95% KI=1,107-6,142). Ein arterieller Hypertonus, ein hoher intraoperativer Blutverlust, eine Magenentleerungsstörung und eine Pankreasfistel waren in der univariaten Analyse ebenfalls als Risikofaktoren für das Auftreten von SSIs zu werten. In der multivariaten Analyse zeigten sich für diese Variablen jedoch keine signifikanten Ergebnisse. Weiterhin zeigte sich, dass die präoperative Gabe einer selektiven Darmdekontaminations (SDD)-Lösung zu einer signifikant niedrigeren SSI-Rate führte. Die Durchführung einer EIPL nimmt auf dieses Ergebnis keinen Einfluss. Inwiefern die SDD alleine ohne EIPL effektiv zur Senkung der SSI-Rate beiträgt, kann die vorliegende Studie nicht abschließend klären. Trotz unserer Ergebnisse kann keine generelle Empfehlung zur Gabe von Piperazillin/ Tazobactam gegeben werden. Es fehlen weiterführende randomisierter Studienergebnisse.:Inhalt I Abkürzungsverzeichnis III Abbildungsverzeichnis V Tabellenverzeichnis VI 1 Einleitung 1 1.1 Historische Entwicklung der Pankreaschirurgie 1 1.2 Indikationen für eine Pankreaskopfresektion 2 1.2.1 Exokrines Pankreaskarzinom 2 1.2.2 Chronische Pankreatitis 5 1.2.3 Zystische Pankreasraumforderungen 6 1.2.4 Neuroendokrine Pankreastumore 6 1.2.5 Raumforderungen der Papilla vateri 7 1.2.6 Raumforderungen des Duodenums 7 1.2.7 Distales Gallengangskarzinom 8 1.2.8 Metastasen 8 1.3 OP-Verfahren 8 1.3.1 Pylorus-erhaltende Pankreaskopfresektion 9 1.3.2 Operation nach Whipple-Kausch 11 1.3.3 Mesenteriko-portale Resektion 12 1.3.4 Arterielle Resektion 12 1.4 Perioperative Morbidität und Mortalität 13 1.5 Septische Komplikationen 13 1.6 Perioperatives Management 14 1.7 Zielsetzung 16 2 Material und Methoden 17 2.1 Einschlusskriterien 17 2.2 Ausschlusskriterien 17 2.3 Ethik und Datenmanagement 17 2.4 Datenerhebungen 17 2.4.1 Retrospektive Datenerhebung 17 2.4.2 Prospektive Datenerhebung 18 2.5 Statistische Analyse 22 3 Ergebnisse 23 3.1 Patientencharakteristika 23 3.2 Komorbiditäten 24 3.3 Perioperative Antibiotikaprophylaxe 26 3.4 Perioperative Charakteristika 27 3.5 Morbidität und Mortalität 28 3.6 Univariate Analyse der Risikofaktoren für SSI 31 3.7 Multivariate Analyse der Risikofaktoren für SSI 35 3.8 Einfluss von EIPL und SDD auf SSI 36 4 Diskussion 37 4.1 Patientencharakteristika 37 4.1.1 Geschlecht, Patientenalter und BMI 37 4.1.2 Komorbiditäten 38 4.1.3 Diagnose 39 4.1.4 Präoperative ERCP und neoadjuvante Chemotherapie 40 4.2 Perioperative Charakteristika 41 4.2.1 Operative Details 41 4.2.2 Operationslänge, intraoperativer Blutverlust, Operationserweiterungen 41 4.3 Septische Komplikationen 42 4.3.1 POPF 42 4.3.2 PPH und DGE 43 4.3.3 SSI und weitere septische Komplikationen 44 4.3.4 Reoperation, Krankenhausverweildauer, Mortalität 45 4.4 Weitere Risikofaktoren 46 4.5 Modifizierte Antibiotikaprophylaxe 46 4.6 Effekt der EIPL auf SSI 49 4.7 Auswirkung der SDD auf SSI 49 5 Schlussfolgerung 50 5.1 Limitation 50 5.2 Ausblick 51 6 Zusammenfassung 52 7 Summary 55 8 Literaturverzeichnis 57

The purpose of this thesis was to quantify the prevalence, measure the severity, and describe treatment patterns in patients who present to medical clinics in Texas with community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) skin and soft-tissue infections (SSTI). Ten clinics participated in this prospective, community-based study. Clinicians consented patients and collected clinical information, pictures, and wound swabs; data were processed centrally. MRSASelect[trademark] was used for identification. Susceptibilities were determined via Etest[registered sign]. The results are as follows. Overall, 73/119 (61%) patients had CA-MRSA. Among these, 49% were male, 79% were Hispanic, and 30% had diabetes. Half (56%) of the lesions were [greater than or equal to] 5 cm in diameter. Most patients had abscesses (82%) and many reported pain scores of [greater than or equal to] 7/10 (67%). Many presented with erythema (85%) or drainage (56%). Most received incision and drainage (I&D) plus an antibiotic (64%). Antibiotic monotherapy was frequently prescribed: sulfamethoxazole/ trimethoprim (SMX/TMP) (78%), clindamycin (4%), doxycycline (2%), and mupirocin (2%). The rest frequently received SMX/TMP in combination with other antibiotics. SMX/TMP was commonly administered as one double-strength tablet twice daily. Isolates were 93% susceptible to clindamycin and 100% susceptible to vancomycin, doxycycline, SMX/TMP, and linezolid. We report a predominance of CA-MRSA SSTIs, favorable susceptibilites, and frequent prescribing of SMX/TMP in primary care clinics located in South Texas. / text

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Submitted by biblioteca unifenas (biblioteca@unifenas.br) on 2018-03-05T22:29:58Z No. of bitstreams: 1 Moisés Soares_prot.pdf: 532244 bytes, checksum: ec9e5e02f20bf1dd5a397cdc7723b712 (MD5) / Made available in DSpace on 2018-03-05T22:29:58Z (GMT). No. of bitstreams: 1 Moisés Soares_prot.pdf: 532244 bytes, checksum: ec9e5e02f20bf1dd5a397cdc7723b712 (MD5) Previous issue date: 2015-04-29 / It aimed to evaluate, the effectiveness of two antibiotics, associated or not to the sodium cloprostenol in treatment of retention of cows’ placenta. The animals have been randomly divided into the following treatments: Treat. 1: cefquinoma (n=25) 1ml/25kg PV (25 mg/ml) – Intramuscular – once a day, during three days; Treat. 2: cefquinoma (n=25) 1ml/25kg PV (25 mg/ml) – Intramuscular – once a day, during three days, plus 2ml of sodium cloprostenol (0,250 mg/ml) in the 1st and 3rd day of treatment (n=25) animals; Treat. 3: oxytetracycline (n=25), 20mg/kg PV of oxytetracycline hydrochloride – Intramuscular – during two days with a gap of 48h; and Treat. 4: oxytetracycline associated to the sodium cloprostenol (n=25), 20 mg/kg PV of oxytetracycline hydrochloride – Intramuscular – during two days with a gap of 48h, plus 2ml of sodium cloprostenol (0,250 mg/ml). In the 1st and 3rd day of treatment. After the treatments, the animals have been evaluated relating to the increase of temperature (over 39,0 ºC) and the need of supportive care through the 1st week after the birth. The animals were re-evaluated between the 3rd and 5th postpartum weeks, by the rectal palpation, ultrasonography and vaginoscopy, to measure the presence and level of the uterine infection. It has evaluated the rate of conception at the 1st insemination, the number of pregnant animals on the 60, 90, 120 and 180 postpartum days, the average number of labors/conceptions and labor periods. The experiments were organized in DIC. The variables were submitted to a normality test and the averages were compared by Chi-square or Tuckey’s tests. The treatments with cefquinoma associated or not to the sodium cloprostenol presented better results (P<0,05) relating to the increase of temperature. The need of additional treatments and presence of uterine infection were bigger in the animals that received only oxytetracycline (P<0,05). For the same antibiotic, the association with cloprostenol has not interfered into these variables (P>0,05). There was not effect of treatments in the % of pregnant animals in the 1st IA and into the numbers of births by conception (P>0,05). The animals treated only with oxytetracycline presented worst period of births (P<0,05). It concludes that the treatment with cefquinoma is more efficient. The oxytetracycline applied alone, not associated to the cloprostenol gives the worst results. / Objetivou-se avaliar a eficácia de dois antibióticos, associados ou não ao cloprostenol sódico, no tratamento de retenção da placenta de vacas. Os animais foram aleatoriamente divididos nos seguintes tratamentos: Tratamento 1: cefquinoma (n=25) 1ml/25kg PV (25 mg/ML) – Intramuscular – 1x dia, durante 3 dias. Tratamento 2: cefquinoma 1ml/25kg PV (25 mg/ML) – Intramuscular – 1x dia, durante 3 dias, acrescido de 2ml de cloprostenol sódico (0,250 mg/ML). No 1º e 3º dias de tratamento (n=25) animais. Tratamento 3: oxitetraciclina (n=25), 20 mg/kg PV de cloridrato de oxitretraciclina – Intramuscular – durante dois dias com intervalo de 48h. Tratamento 4: oxitetraciclina associada ao cloprostenol sódico (n=25), 20 mg/kg PV de cloridrato de oxitretraciclina – Intramuscular – durante dois dias com intervalo de 48h, acrescido de 2ml de cloprostenol sódico (0,250 mg/ML). No 1º e 3º dias de tratamento. Após os tratamentos, os animais foram avaliados em relação ao aumento de temperatura (acima de 39,0 ºC) e a necessidade de tratamento de suporte dentro da 1a semana após o parto. Os animais foram reavaliados entre a 3ª e 5ª semanas pós-parto por meio de palpação transretal, ultrassonografia e vaginoscopia para avaliar a presença e grau da infecção uterina. Avaliou-se a taxa de concepção à 1ª inseminação, o número de animais gestantes aos 60, 90, 120 e 180 dias pós-parto, o número médio de serviços/concepções e período de serviços. Os experimentos foram organizados em DIC. As variáveis foram submetidas a teste de normalidade e as médias foram comparadas por Qui-Quadrado ou testes de Tuckey. Os tratamentos com cefquinoma, associada ou não ao cloprostenol sódico, apresentaram melhores resultados (P<0,05) em relação ao aumento de temperatura. A necessidade de tratamentos adicionais e presença de infecção uterina foram maiores nos animais que receberam apenas oxitetraciclina (P<0,05). Para um mesmo antibiótico a associação com o cloprostenol não interferiu nestas variáveis (P>0,05). Não houve efeito de tratamento na porcentagem de animais gestantes na 1ª IA e no número de serviços por concepção (P>0,05). Os animais tratados apenas com oxitetraciclina apresentaram pior período de serviços (P<0,05). Conclui-se que o tratamento com cefquinoma é mais eficiente. A oxitetraciclina, aplicada sozinha, não associada ao cloprostenol, fornece os piores resultados.