Risk factors and new markers of pulmonary fungal infection

Outline of the Thesis Part I Pneumocystis in kidney transplant recipients: transmission, risk factors , new diagnostic and chemo-prophylactic strategies. Chapter 2 describes the characteristics of a large outbreak of Pneumocystis pneumonia among kidney transplant recipients. By performing a classical outbreak investigation and by application of new molecular genotyping techniques, the potential of the __interhuman transmission hypothesis__ is addressed and discussed. In Chapter 3 all currently available data on reported outbreaks of Pneumocystis pneumonia is systematically reviewed with the emphasis on mortality data, clinical risk factors and transmission analyses. In the case-control study described in Chapter 4, we performed a detailed risk factor analysis for development of PCP in kidney transplant recipients and used the multivariate output data to estimate the effects of several chemoprophylactic strategies by modeling the expected incidence and number-needed-to-treat to provide efficient PCP chemoprophylaxis over a 2-year period post transplantation. Chapter 5 reports the data of a prospective study on the serum markers S-adenosylmethionine and (1-->3)-_-D-glucan serum levels and correlation with clinical parameters in HIVnegative immunocompromised patients __ the majority kidney transplant recipients - with Pneumocystis pneumonia. Potential applicability for treatment monitoring and assessment of P. jirovecii pulmonary load is also discussed. Part II Genetic predisposition for development of invasive aspergillosis in stem cell transplant recipients Chapter 6 describes a multicenter study on the impact of the Y238X stop mutation in the human Dectin-1 receptor (which senses and attaches to glucan moieties of the fungal cell wall) on the risk of development of invasive aspergillosis in stem cell transplant recipients. In Chapter 7 a retrospective study of the influence of genetic variation in the macrophage activation route with respect to the relative additional risk for development of invasive aspergillosis is presented. Part III Experimental markers for detection of fungal infection: scintigraphic imaging. In Chapter 8 the clinical applicability of radiolabeled antimicrobial peptides and antifungal drugs for the diagnosis of invasive fungal infections is reviewed, together with a concise discussion about how promising agents should be further developed. The results of the thesis are summarized and discussed in Chapter 9.UBL - phd migration 201

Antibioticaresistentie en de zoektocht naar de grenzen tussen onder- en overbehandeling met antibiotica

Oratie uitgesproken door prof. dr. Mark G.J. de Boer bij de aanvaarding van het ambt van hoogleraar Infectieziekten, in het bijzonder antimicrobiële resistentie en antibioticabeleid aan de Universiteit Leiden op vrijdag 9 juni 2023Oratie uitgesproken door prof. dr. Mark G.J. de Boer bij de aanvaarding van het ambt van hoogleraar Infectieziekten, in het bijzonder antimicrobiële resistentie en antibioticabeleid aan de Universiteit Leiden op vrijdag 9 juni 2023LUMC / Geneeskund

Rifampin for staphylococcal prosthetic joint infection: do we still need a randomized controlled trial?

Immunogenetics and cellular immunology of bacterial infectious disease

Characteristics and Mortality of Pneumocystis Pneumonia in Patients With Cushing's Syndrome: A Plea for Timely Initiation of Chemoprophylaxis

Diabetes mellitus: pathophysiological changes and therap

Outcome of debridement, antibiotics, and implant retention for staphylococcal hip and knee prosthetic joint infections, focused on rifampicin use: a systematic review and meta-analysis

The treatment of staphylococcal prosthetic joint infection (PJI) with debridement, antibiotics, and retention of the implant (DAIR) often results in failure. An important evidence gap concerns the treatment with rifampicin for PJI. A systematic review and meta-analysis were conducted to assess the outcome of staphylococcal hip and/or knee PJI after DAIR, focused on the role of rifampicin. Studies published until September 2, 2020 were included. Success rates were stratified for type of joint and type of micro-organism. Sixty-four studies were included. The pooled risk ratio for rifampicin effectiveness was 1.10 (95% confidence interval, 1.00-1.22). The pooled success rate was 69% for Staphylococcus aureus hip PJI, 54% for S aureus knee PJI, 83% for coagulase-negative staphylococci (CNS) hip PJI, and 73% for CNS knee PJI. Success rates for MRSA PJI (58%) were similar to MSSA PJI (60%). The metaanalysis indicates that rifampicin may only prevent a small fraction of all treatment failures.Orthopaedics, Trauma Surgery and Rehabilitatio

Диференційна діагностика жінок з полікістозною та мультіфолікулярною стукрурою яєчників

Синдром полікістозних яєчників (СПКЯ) є найчастішою ендокринопатією у жінок репродуктивного віку як в Україні ,так і за кордоном і становить гетерогенну групу порушень із широкою клінічною і біохімічною варіабельністю. Частота СПКЯ в популяції складає від 4 до 15 % і зустрічається однаково часто в різних етнічних групах: в Україні – від 0,6 до 11 %, у країнах ближнього зарубіжжя -1,8-11%, в Європі - 15-20%, в США - 6-10%.Більшість пацієнток репродуктивного віку з СПКЯ страждають на безпліддя, частота якого складає 35-74%

Early action on Paris Agreement allows for more time to change energy systems

The IMAGE integrated assessment model was used to develop a set of scenarios to evaluate the Nationally Determined Contributions (NDCs) submitted by Parties under the Paris Agreement. The scenarios project emissions and energy system changes under (i) current policies, (ii) implementation of the NDCs, and (iii) various trajectories to a radiative forcing level of 2.8 W/m2 in 2100, which gives a probability of about two thirds to limit warming to below 2 °C. The scenarios show that a cost-optimal pathway from 2020 onwards towards 2.8 W/m2 leads to a global greenhouse gas emission level of 38 gigatonne CO2 equivalent (GtCO2eq) by 2030, equal to a reduction of 20% compared to the 2010 level. The NDCs are projected to lead to 2030 emission levels of 50 GtCO2eq, which is still an increase compared to the 2010 level. A scenario that achieves the 2.8 W/m2 forcing level in 2100 from the 2030 NDC level requires more rapid transitions after 2030 to meet the forcing target. It shows an annual reduction rate in greenhouse gas emissions of 4.7% between 2030 and 2050, rapidly phasing out unabated coal-fired power plant capacity, more rapid scale-up of low-carbon energy, and higher mitigation costs. A bridge scenario shows that enhancing the ambition level of NDCs before 2030 allows for a smoother energy system transition, with average annual emission reduction rates of 4.5% between 2030 and 2050, and more time to phase out coal capacity

SAAP-148 eradicates MRSA persisters within mature biofilm models simulating prosthetic joint infection

Prosthetic joint infection (PJI) is a severe complication of arthroplasty. Due to biofilm and persister formation current treatment strategies often fail. Therefore, innovative anti-biofilm and anti-persister agents are urgently needed. Antimicrobial peptides with their broad antibacterial activities may be such candidates. An in vitro model simulating PJI comprising of rifampicin/ciprofloxacin-exposed, mature methicillin-resistant Staphylococcus aureus (MRSA) biofilms on polystyrene plates, titanium/aluminium/niobium disks, and prosthetic joint liners were developed. Bacteria obtained from and residing within these biofilms were exposed to SAAP-148, acyldepsipeptide-4, LL-37, and pexiganan. Microcalorimetry was used to monitor the heat flow by the bacteria in these models. Daily exposure of mature biofilms to rifampicin/ciprofloxacin for 3 days resulted in a 4-log reduction of MRSA. Prolonged antibiotic exposure did not further reduce bacterial counts. Microcalorimetry confirmed the low metabolic activity of these persisters. SAAP-148 and pexiganan, but not LL-37, eliminated the persisters while ADEP4 reduced the number of persisters. SAAP-148 further eradicated persisters within antibiotics-exposed, mature biofilms on the various surfaces. To conclude, antibiotic-exposed, mature MRSA biofilms on various surfaces have been developed as in vitro models for PJI. SAAP-148 is highly effective against persisters obtained from the biofilms as well as within these models. Antibiotics-exposed, mature biofilms on relevant surfaces can be instrumental in the search for novel treatment strategies to combat biofilm-associated infections.Orthopaedics, Trauma Surgery and Rehabilitatio

Liver and kidney function in patients with Covid-19 treated with remdesivir

For the treatment of Covid-19 patients with remdesivir, poor renal and liver function were both exclusion criteria in randomized clinical trials and contraindication for treatment. Also, nephrotoxicity and hepatotoxicity are reported as adverse events. We retrospectively reviewed renal and liver functions of Covid-19 103 patients who received remdesivir in the 15 days after treatment initiation. Approximately 20% of the patient population met randomized clinical trial exclusion criteria. In total, 11% of the patients had a decrease in estimated glomerular filtration rate >10 mL/min/1.73m(2). Also, 25 and 35% had increased alanine transaminase and aspartate transaminase levels, respectively. However, serious adverse events were limited. Therefore, based on these preliminary results, contraindications based on kidney and liver function should not be absolute for remdesivir treatment in patients with Covid-19 if these functions are monitored regularly. A larger patient cohort is warranted to confirm our results.Immunogenetics and cellular immunology of bacterial infectious disease

Complicated carriage with methicillin-resistant Staphylococcus aureus: evaluation of the effectiveness of decolonization regimens advised in the Dutch national guideline

Methicillin-resistant Staphylococcus aureus (MRSA) colonization leads to increased infection rates and mortality. Decolonization treatment has been proven to prevent infection and reduce transmission. As the optimal antimicrobial strategy is yet to be established, different regimens are currently prescribed to patients. This study aimed to evaluate the efficacy of the decolonization treatments recommended by the Dutch guideline. A retrospective multicenter cohort study was conducted in five Dutch hospitals. All patients who visited the outpatient clinic because of complicated MRSA carriage between 2014 and 2018 were included. We obtained data on patient characteristics, clinical and microbiological variables relevant for MRSA decolonization, environmental factors, decolonization regimen, and treatment outcome. The primary outcome was defined as three negative MRSA cultures after treatment completion. Outcomes were stratified for the first-line treatment strategies. A total of 131/224 patients were treated with systemic antibiotic agents. Treatment was successful in 111/131 (85%) patients. The success rate was highest in patients treated with doxycycline-rifampin (32/37; 86%), but the difference from any of the other regimens did not reach statistical significance. There was no difference in the success rate of a 7-day treatment compared to that with 10 to 14 days of treatment (odds ratio [OR], 0.99; 95% confidence interval [CI], 0.39 to 253; P= 1.00). Side effects were reported in 27/131 (21%) patients and consisted mainly of mild gastrointestinal complaints. In a multivariable analysis, an immunocompromised status was an independent risk factor for failure at the first treatment attempt (OR, 4.65; 95% CI, 125 to 17.25; P =0.02). The antimicrobial combinations recommended to treat complicated MRSA carriage yielded high success rates. Prolonged treatment did not affect treatment outcome. A randomized trial is needed to resolve whether the most successful regimen in this study (doxycycline plus rifampin) is superior to other combinations.Immunogenetics and cellular immunology of bacterial infectious disease