Antimicrobial drugs constitute a fundamental part of modern medicine. The global rise in antimicrobial resistance poses a major threat to global health. Optimising antimicrobial treatment... Show moreAntimicrobial drugs constitute a fundamental part of modern medicine. The global rise in antimicrobial resistance poses a major threat to global health. Optimising antimicrobial treatment strategies in patients offers an important direction to address this challenge. In this thesis, we describe how quantitative characterisation of the drug, the pathogen, and the patients, and how these three factors interact, can help to achieve this goal. To this end, we used a combination of state-of-the-art in silico model-based approaches to analyse and integrate experimental data from in vitro models, and clinical data from healthy volunteers and patients. We developed models describing infection site drug exposure, antimicrobial resistance evolution, and host response biomarker dynamics. We explored the impact of infection on pulmonary pharmacokinetics, evolutionary-based treatment strategies, and the utility host response biomarker for treatment monitoring. The work in this thesis builds towards developing novel strategies to optimise antimicrobial treatments and showcases the importance on interdisciplinary collaborations. Show less
Willems, S.A.; Brouwers, J.J.W.M.; Eefting, D. 2022
Objective: Brucellosis is the most common zoonosis worldwide. Although cardiovascular complications in human brucellosis comprise only 3% of morbidity, they are the principal cause of death.... Show moreObjective: Brucellosis is the most common zoonosis worldwide. Although cardiovascular complications in human brucellosis comprise only 3% of morbidity, they are the principal cause of death. Endocarditis covers the majority of these cases. Infected aneurysms and ulcerative processes of the aorta are rare but can be life threatening as well. Currently, limited information is available about aortic and iliac involvement in brucellosis.Methods: A PubMed, Web of Science, and AccessMedicine search (without restriction on language or year of publication) was performed to identify relevant articles on aortic and iliac involvement in brucellosis. Case reports were eligible for inclusion if they reported on thoracic, abdominal, or iliac aortic pathology caused by Brucella.Results: Seventy-one cases were identified over the last 70 years, with an overall mortality rate of 22%. Most of the patients were male (86%) and had a history of Brucella exposure (66%). Approximately one quarter (23%) contracted Brucella while travelling in a (hyper)endemic region. Almost half of the infections were located in the abdominal aorta (49%), followed by the ascending (37%) and descending (13%) thoracic aorta. Infected aneurysms (61%) and ulcerative processes (16%) were seen most frequently. Aortic rupture was present in 31% of cases and occurred mainly in the abdominal (49%) and descending thoracic aorta (44%). The majority of all patients (59%) underwent open surgery combined with long term antibiotics. Over the past 15 years, a trend towards endovascular treatment was observed.Conclusion: Although aortic and iliac involvement in brucellosis is rare, it can be a life threatening manifestation. Due to low awareness, this infection may represent an under reported disease. The therapeutic cornerstone in these cases remains open surgery combined with antibiotics. The role of endovascular treatment is yet to be decided, in which the condition of the patient and the risks of long term complications need to be considered. Show less
The research described in this thesis has, using the zebrafish as a model system, shed new light on the intricate relationship between TB and DM2, in particular on the role of leptin, SHP-1 and... Show moreThe research described in this thesis has, using the zebrafish as a model system, shed new light on the intricate relationship between TB and DM2, in particular on the role of leptin, SHP-1 and glucocorticoids.Leptin plays an important role during TB infection and has a huge impact on insulin sensitivity in zebrafish larvae. Similarly to what has been observed in the murine model, leptin deficiency in zebrafish increased the bacterial burden and mortality during the infection, leading to hyperglycemia and the development of insulin resistance. In addition, a novel SHP-1/SHP-2 inhibitor, NSC-87877, was shown to represent a promising anti-diabetic drug that can be used for further DM2 research, as it is able to rescue the phenotype of the leptin-deficient zebrafish and to restore glucose transport to the tissues. In contrast to metformin, NSC-87877 can act at very early developmental stages and inhibits the function of SHP-1 and factors that underlay impaired glucose metabolism, whereas metformin is mostly known to improve insulin sensitivity. Additionally, treatment with the glucocorticoid beclomethasone attenuates the metabolic changes associated with the infection, and transcriptional alterations induced by beclomethasone treatment suggest that genes involved in glucose metabolism, insulin and leptin signaling all play an important role in the modulation of the metabolism.Our data show that zebrafish larvae represent an interesting model system to investigate the complex pathology of TB, and the studies described in this thesis in which this model has been used have provided novel insights into the molecular mechanisms underlying wasting syndrome and the possibilities for adjunctive glucocorticoid therapy to alleviate this metabolic state. Show less
Our research group recently published a positive association between early postoperative pain and 30-day postoperative complications in a broad surgical population. To investigate whether... Show moreOur research group recently published a positive association between early postoperative pain and 30-day postoperative complications in a broad surgical population. To investigate whether heterogeneity of the population and surgical procedures influenced these results, we explored this association in a homogenous surgical population. A secondary analysis of the LEOPARD-2 (NCT02146417) and RELAX-1 study (NCT02838134) in laparoscopic donor nephrectomy patients (n = 160) was performed. Pain scores on the postanesthesia care unit and postoperative day (POD) 1 and 2 were compared between patients with infectious, noninfectious, and no complications 30 days after surgery. Patients who developed infectious complications had significantly higher pain scores on POD1 and 2 (6.7 +/- 2.1 and 6.4 +/- 2.8) than patients without complications (4.9 +/- 2.2 and 4.1 +/- 1.9), respectively (P= 0.006 andP= 0.000). Unacceptable pain (numeric rating scale [NRS] >= 6) on POD1 was reported by 72% of patients who developed infectious complications, compared to 38% with noninfectious complications and 30% without complications (P= 0.018). This difference was still present on POD2 at 67% with infectious complications, 21% with noninfectious, and 40% without complications (P= 0.000). Multiple regression analysis identified unacceptable pain (numeric rating scale >= 6) on POD2 as a significant predictor for 30-day infectious complications (odds ratio 6.09,P= 0.001). Results confirm the association between early postoperative pain and 30-day infectious complications in a separate, homogenous surgical population. Further clinical trials should focus on finetuning of postoperative analgesia to elucidate the effects on the endocrine and immune response, preserve immune homeostasis, and prevent postoperative infectious complications. Show less
AimsInduction heating is a noninvasive, nonantibiotic treatment modality that can potentially be used to cause thermal damage to the bacterial biofilm on the metal implant surface. The purpose of... Show moreAimsInduction heating is a noninvasive, nonantibiotic treatment modality that can potentially be used to cause thermal damage to the bacterial biofilm on the metal implant surface. The purpose of this study was to determine the effectiveness of induction heating on killing Staphylococcus epidermidis from biofilm and to determine the possible synergistic effect of induction heating and antibiotics.MethodsS. epidermidis biofilms were grown on titanium alloy (Ti6Al4V) coupons for 24 hours (young biofilm) and seven days (mature biofilm). These coupons with biofilm were heated to temperatures of 50 degrees C, 55 degrees C, 60 degrees C, 65 degrees C, 70 degrees C, 80 degrees C, and 90 degrees C for 3.5 minutes and subsequently exposed to vancomycin and rifampicin at clinically relevant concentrations.ResultsFor the young biofilm, total eradication was observed at 65 degrees C or higher for 3.5 minutes followed by 24 hours of vancomycin 10 mg/l and rifampicin 1 mg/l. For the mature biofilm, total eradication was observed at 60 degrees C for 3.5 minutes followed by 24 hours of vancomycin 10 mg/l and rifampicin 1 mg/l. Total eradication was also observed at 60 degrees C for 3.5 minutes followed by 24 hours of vancomycin 1 mg/l and rifampicin 1 mg/l followed by anotherthermal shock of 60 degrees C for 3.5 minutes (two thermal shocks).ConclusionInduction heating of Ti6Al4V coupons is effective in reducing bacterial load in vitro for S. epidermidis biofilms. Induction heating and antibiotics have a synergistic effect resulting in total eradication of the biofilm at 60 degrees C or higher for clinically relevant concentrations of vancomycin and rifampicin. Show less
Background: Non-contact induction heating (NCIH) is a noninvasive treatment modality that can be used to cause thermal damage to bacterial biofilms on a metal implant surface in the context of a... Show moreBackground: Non-contact induction heating (NCIH) is a noninvasive treatment modality that can be used to cause thermal damage to bacterial biofilms on a metal implant surface in the context of a prosthetic joint infection. The purpose of this study was (1) to determine the effectiveness of NCIH on killing Staphylococcus aureus from biofilm and (2) to determine the possible synergistic effect of NCIH and cocktails of antibiotics and N-acetylcysteine (NAC). Methods: Staphylococcus aureus biofilms were grown on titanium alloy (Ti6Al4V) coupons. These coupons were heated to 50 degrees C, 60 degrees C, 70 degrees C, 80 degrees C, and 90 degrees C for 3.5 min and subsequently exposed to cocktails of vancomycin, rifampicin and NAC at clinically relevant concentrations over 24 h. Results: In the control group without induction heating, 2.2*10(7) colony forming units (CFU)/cm(2) were observed. At 50 degrees C, 60 degrees C, 70 degrees C, 80 degrees C, and 90 degrees C, a reduction of 0.3-log, 3.9-log, 4.2-log, 4.3-log, and 6.6-log CFU/cm(2) were observed, respectively. There was synergy between antibiotics and induction heating that resulted in less than 100 CFU/cm(2) remaining after 3.5 min at 60 degrees C, and exposure to vancomycin and rifampicin. Total eradication was observed at 80 degrees C. Total eradication was also observed at 60 degrees C and a cocktail of antibiotics with NAC. Conclusion: Induction heating of titanium alloy coupons is effective for the reduction of bacterial load in vitro in S. aureus biofilms. Induction heating and cocktails of antibiotics and NAC have a synergistic effect that results in the total eradication of the biofilm at 60 degrees C and higher for clinically relevant concentrations of vancomycin, rifampicin and NAC. Show less
The most common complications that are associated with bilateral sagittal split osteotomy are: bad splits, postoperative infection, removal of osteosynthesis material, and neurosensory disturbances... Show moreThe most common complications that are associated with bilateral sagittal split osteotomy are: bad splits, postoperative infection, removal of osteosynthesis material, and neurosensory disturbances of the lower lip. Particularly in elective orthognathic surgery, it is important that surgeons inform their patients about the risk of these complications and attempt to minimize these risks. The purpose of this literature review and meta-analysis is to provide an overview of these common complications and their risk factors.After a systematic electronic database search, 59 studies were identified and included in this review. For each complication, a pooled mean incidence was computed. Both the pooled study group and the pooled 'complication group' were analysed.The mean incidences for bad split (2.3% per SSO), postoperative infection (9.6% per patient), removal of the osteosynthesis material (11.2% per patient), and neurosensory disturbances of the lower lip (33.9% per patient) are reported. Regularly reported risk factors for complications were the patient's age, smoking habits, presence of third molars, the surgical technique and type of osteosynthesis material. This information may help the surgeon to minimize the risk of these complications and inform the patient about the risks of complications associated with bilateral sagittal split osteotomy. (C) 2016 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved. Show less
General significance: Histo-blood group glycans have a unique linking position in the complex network of genes, oncodevelopmental biological processes, and disease mechanisms. Thus, they are highly... Show moreGeneral significance: Histo-blood group glycans have a unique linking position in the complex network of genes, oncodevelopmental biological processes, and disease mechanisms. Thus, they are highly promising targets for novel approaches in the field of personalized medicine. This article is part of a Special Issue entitled "Glycans in personalised medicine" Guest Editor: Professor Gordan Lauc. (C) 2015 Elsevier B.V. All rights reserved. Show less
Preface: The content of this thesis is based on research that was conducted at the travel and vaccination clinic at Leiden University Medical Centre (LUMC). This clinic provides pre-travel care to... Show morePreface: The content of this thesis is based on research that was conducted at the travel and vaccination clinic at Leiden University Medical Centre (LUMC). This clinic provides pre-travel care to the general population, and to special groups of travellers, such as patients who use immunosuppressants or who have chronic diseases. The clinic is closely connected to the department of Infectious Diseases at LUMC. The setting of a travel clinic within an academic medical hospital, provides unique circumstances for medical research, like an experienced team of nurses, expertise regarding immunization, a constant flux of travellers and the knowledge and infrastructure that is required for research into microbiology, virology and parasitology. Examples of research that stem from this clinic are projects on immunization against malaria, yellow fever, travellers' diarrhea, poliomyelitis and hepatitis B, vaccination of immunocompromised patients, and projects on travel related acquisition of extended spectrum ß-lactamase producing Enterobacteriacae and on the utility of post-travel screening of asymptomatic travellers for parasites. Show less
Insects are the most diverse group of animals on earth. They inhabit nearly all terrestrial habitats. One of the factors underlying this success is the ability of insect eggs to survive in adverse... Show moreInsects are the most diverse group of animals on earth. They inhabit nearly all terrestrial habitats. One of the factors underlying this success is the ability of insect eggs to survive in adverse conditions. For a long time the ability to survive these adverse conditions has been attributed to maternal investment in the form of a protective eggshell. In this thesis, I show that contrary to common belief, insect eggs are far from helpless. The insect egg itself develops a cellular layer around the egg called the serosa. This serosa protects the developing embryo from dehydration which enables it to survive in dry habitats. The serosa furthermore protects against infection, mounting an impressive immune response upon the entry of bacteria in the egg. The data presented in this thesis show the importance of the serosa in the survival of the insect egg. I propose that this multifunctional serosa contributed to the great success of insects. Show less
This thesis is focused on the innate immune defence mechanisms responsible for controlling mycobacterial growth after infection. To provide a detailed description of the host__s innate immune... Show moreThis thesis is focused on the innate immune defence mechanisms responsible for controlling mycobacterial growth after infection. To provide a detailed description of the host__s innate immune response to M. marinum infection, zebrafish gene expression levels were analysed by RNA sequencing at various time points during infection and correlated with imaging data of the process of pathogenesis. We demonstrate that the scavenger receptor Marco (macrophage receptor with collagenous structure) is a key player in the rapid phagocytosis of M. marinum and we use gene expression analysis in combination with gene knockdown studies to show that it is also essential in the establishment of an initial transient pro-inflammatory response to M. marinum infection. Once phagocytosed, M. marinum is capable of avoiding killing mechanisms of the host cell and can continue to grow within macrophages. This is the period when Membrane Attack Complex/Perforin proteins are involved in killing intracellular bacteria by their pore-forming activities. We reveal the regulatory mechanisms and function of two macrophage specific genes, mpeg1 and mpeg1.2 (macrophage expressed gene 1.2). The results from this thesis complement knowledge obtained from other model organisms by providing new insights into both counteracting and supporting mechanisms underlying the innate immune response. Show less
