Strategies for isoniazid preventive therapy in HIV-positive patients who consume alcohol.

WHO guidance to defer isoniazid preventive therapy (IPT) among those with regular alcohol use because of hepatotoxicity concerns may exclude many people living with HIV (PLWH) at high TB risk in these settings.To evaluate hepatotoxicity during TB preventive therapy (TPT) in PLWH who report alcohol use in Uganda over 10 years.We developed a Markov model of latent TB infection, isoniazid preventive therapy (IPT - a type of TPT), and TB disease using data from the Alcohol Drinkers' Exposure to Preventive Therapy for TB (ADEPTT) study. We modeled several treatment scenarios, including no IPT, IPT with liver enzyme monitoring (AST/ALT) during treatment, and IPT with pre-screening using the tuberculin skin test (TST).The no IPT scenario had 230 TB deaths/100,000 population over 10 years, which is more than that seen in any IPT scenario. IPT, even with no monitoring, was preferred over no IPT when population TB disease incidence was >50 in 100,000.For PLWH who report alcohol use in high TB burden settings, IPT should be offered, ideally with regular AST/ALT monitoring. However, even if regular monitoring is not possible, IPT is still preferable to no IPT in almost every modeled scenario..

Retrospective genome-oriented analysis reveals low transmission rate of multidrug-resistant Pseudomonas aeruginosa from contaminated toilets at a bone marrow transplant unit.

BACKGROUND: Prevention of toilet-to-patient transmission of multidrug-resistant Pseudomonas aeruginosa (MDR PA) poses management-related challenges at many bone marrow transplant units (BMTUs). AIM: To conduct a longitudinal retrospective analysis of the toilet-to-patient transmission rate for MDR PA under existing infection control (IC) measures at a BMTU with persistent MDR PA toilet colonization. METHODS: The local IC bundle comprised: (1) patient education regarding IC; (2) routine patient screening; (3) toilet flushing volume of 9 L; (4) bromination of toilet water tanks, and (5) toilet decontamination using hydrogen peroxide. Toilet water was sampled periodically between 2016 and 2021 (minimum every three months: 26 intervals). Upon MDR PA detection, disinfection and re-sampling were repeated until ≤3 cfu/100 mL was reached. Whole-genome sequencing (WGS) was performed retrospectively on all available MDR PA isolates (90 out of 117 positive environmental samples, 10 out of 14 patients, including nine nosocomial). FINDINGS: WGS of patient isolates identified six sequence types (STs), with ST235/CT1352/FIM-1 and ST309/CT3049/no-carbapenemase being predominant (three isolates each). Environmental sampling consistently identified MDR PA ST235 (65.5% ST235/CT1352/FIM-1), showing low genetic diversity (difference of ≤29 alleles by core-genome multi-locus sequence typing (cgMLST)). This indicates that direct toilet-to-patient transmission was infrequent although MDR PA was widespread (detection on 79 occasions, detection in every toilet). Only three MDR PA patient isolates can be attributed to the ST235/CT1352/FIM-1 toilet MRD PA population over six years. CONCLUSION: Stringent targeted toilet disinfection can reduce the potential risk for MDR PA acquisition by patients.

[Chronic rhinosinusitis with nasal polyposis : A retrospective analysis of therapeutic approaches in 463 patients]. / Chronische Rhinosinusitis mit Polyposis nasi : Retrospektive Analyse des therapeutischen Vorgehens bei 463 Patienten.

BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a multifactorial inflammatory disease, the treatment of which has undergone significant changes in recent years. In addition to surgical approaches, topical and systemic steroids, and adaptive acetylsalicylic acid (ASA) desensitization, three specific antibodies have complemented the therapeutic portfolio since 2019. METHODS: A retrospective evaluation of all patients who presented as outpatients for the first time due to CRSwNP in 2007 and 2008 (collective A) and 2017 and 2018 (collective B) was performed, up to and including June 2023. RESULTS: The clinical courses of 463 patients (mean age 49.1 years, range 5-82 years; 65.9% male) were included in the analysis. Conservative treatment with nasal corticosteroids started before initial presentation was more frequent in collective B (collective A 43.9% vs. collective B 72.2%). In 278 of the 463 patients (60%; A: 62%, B: 58%), at least one operation on the nasal sinuses had been performed after initial presentation; in 101 of these patients (36.3%) recurrent polyposis (within mean follow-up of 2.4 years) required further treatment. The indication for ASA provocation/desensitization was applied less frequently in collective B, also due to a high discontinuation rate (at least 38%) of the maintenance therapy. Of the total cohort, 16 patients (3.5%; A: n = 8, B: n = 8) were meanwhile switched to antibody therapy at recurrence. CONCLUSION: A step-by-step guideline-orientated approach is recommended in the treatment of CRSwNP. Systemic antibodies as an add-on to nasal corticosteroids are a relatively new therapeutic option for treatment-refractory CRSwNP, which reduces the indication for ASA desensitization, which is associated with a relatively high incidence of side effects and poor compliance.

[Chronic rhinosinusitis with nasal polyps-extension of dupilumab treatment intervals]. / Chronische Rhinosinusitis mit nasalen Polypen ­ Verlängerung der Dupilumab-Therapieintervalle.

BACKGROUND: In patients with severe, uncontrolled chronic rhinosinusitis with nasal polyps (CRSwNP), dupilumab 300 mg every 2 weeks can completely resolve nasal polys, sinus disease, and symptoms. In this case, patients ask for de-escalation. Although trials have demonstrated recurrence after stopping the biologic at 24 weeks, reducing the dose of dupilumab to once every 4 weeks did not result in deterioration of control. An extension of the treatment intervals would, however, diverge from the approval text, and is currently not recommended. METHODS: The course of 29 patients with severe CRSwNP, type­2 inflammation-associated comorbidities, and an indication for biologic was retrospectively analyzed. After resolution of CRSwNP and symptoms under biweekly dupilumab 300 mg, the dupilumab interval had been prolonged individually, initially up to 4 weeks, thereafter up to 6 weeks, if applicable. Control was assessed via quality of life (22-item sinonasal outcome test, SNOT-22), nasal polyp score, and smell identification test (Sniffin' Sticks; Burghart Messtechnik, Holm, Germany). RESULTS: All patients showed an excellent improvement within the first 3 months. The dupilumab application interval was extended to 4 weeks after 7-31 months (median 13 months) and to 6 weeks (n = 9) after 17-35 months (median 23 months). No recurrent polyps or symptoms were subsequently observed. CONCLUSION: In case of maximal regression of polyps and discomfort, extension of dupilumab injection intervals to 4 and potentially 6 weeks is possible without clinical worsening. Further studies on de-escalation or termination of biologic treatment when CRSwNP control is achieved are essential.

Case report: Sustained complete remission with all-oral MEPED therapy in a patient with Hodgkin's disease developing resistance to pembrolizumab.

Targeted chemotherapy and immune checkpoint inhibitors (ICPi) have expanded the spectrum of therapies for patients with relapsed/refractory (r/r) Hodgkin's disease and significantly improved the proportion of patients with long-term disease control. However, there is no standardized therapeutic option in case of further progression. Recently, we demonstrated that therapy with MEPED (metronomic chemotherapy, everolimus, pioglitazone, etoricoxib, dexamethasone) is highly effective in patients with r/r Hodgkin's disease. The benefit after pre-treatment with ICPi has not been studied, yet. Here, we report a patient with progressive Hodgkin's disease on Pembrolizumab for the first time who achieved sustained complete remission (CR) after initiation of MEPED therapy. A 57-year-old patient was pre-treated with brentuximab vedotin for relapsed advanced Hodgkin's disease and had received Pembrolizumab for progression from November 2020 to July 2022. Due to further progression, MEPED therapy was started in August 2022 and continued until May 2023. It consisted of a strictly oral daily (28-day cycle) application of low-dose treosulfan 250 mg, everolimus 15 mg, pioglitazone 45 mg, etoricoxib 60 mg, and dexamethasone 0.5 mg. Treatment response was evaluated by F-18 FDG-PET/CT (PET/CT). CR was defined by a negative Deauville score (DS) of 1-3. Already 3 months after starting MEPED, a CR (DS: 3) was confirmed by PET/CT in November 2022. The next follow-up in May 2023 continued to show CR (DS: 3). The therapy was very well tolerated. No hematological or other organ toxicity was observed. However, in May 2023 the patient presented with leg edema and weight gain, most likely due to pioglitazone and the PET/CT revealed suspected everolimus-induced pneumonitis, so MEPED was discontinued and diuretic therapy and treatment with prednisolone was started with gradual dose reduction. This resulted in a rapid complete resolution of the symptoms. The next PET-CT in July 2023 continued to show CR (DS: 3) without evidence of pneumonitis. Currently, therapy with MEPED has not been resumed. In conclusion, we demonstrate for the first time that MEPED therapy is highly effective in a patient with Hodgkin's disease who has been refractory to ICPi. Sustained CR was achieved over 11 months after initiation of MEPED therapy. Further studies on a larger patient cohort should be performed.

Continuous investigation of the nasal cycle over 48 hours.

BACKGROUND: Previous results on the nasal cycle refer to measurements over up to 24h. The long-term rhinoflowmetry (LRFM) allows continuous observations over a longer period. The aim of the study was to observe the nasal cycle for the first time over 48h under everyday conditions. METHODOLOGY: The LRFM was continuously applied to 30 rhinologically healthy subjects (20 female, 10 male) over 48h. The different types of nasal cycle were classified as follows: "classic", "in concert", "one-sided", "no-cycle" and "mixed". The focus of this study was on the results over the entire 48 hours. The comparison of the two consecutive days was also made. RESULTS: A nasal cycle could be detected in 100% of the subjects over 48h. With 97%, the mixed type most commonly occurred as a combination of classical and in concert components. In all subjects, classical cycle components could be detected at least once. The no-cycle type was not observed. In the awake state, the mixed type dominated (80%), as a combination of classical and in concert parts. In the sleep state, the classical type was the most common type (97%). The average phase duration was 206 ± 83 minutes. CONCLUSIONS: In the very first continuous 48-hour study on the nasal cycle, 100% of the subjects presented a nasal cycle. The LRFM method is the only one that offers the possibility to perform continuous measurements over a longer period during daily routine. The results of previous single-stage examination methods should thus be questioned.

Accuracy of heart rate measured by military-grade wearable ECG monitor compared with reference and commercial monitors.

INTRODUCTION: Physiological monitoring of soldiers can indicate combat readiness and performance. Despite demonstrated use of wearable devices for HR monitoring, commercial options lack desired military features. A newly developed OMNI monitor includes desired features such as long-range secure data transmission. This study investigated the accuracy of the OMNI to measure HR via accuracy of R-R interval duration relative to research-grade ECG and commercial products. METHODS: 54 healthy individuals (male/female=37/17, age=22.2±3.6 years, height=173.0±9.1 cm, weight=70.1±11.2 kg) completed a submaximal exercise test while wearing a reference ECG (Biopac) and a randomly assigned chest-based monitor (OMNI, Polar H10, Equivital EQ-02, Zephyr Bioharness 3). All participants also wore two wrist-based photoplethysmography (PPG) devices, Garmin fenix 6 and Empatica E4. Bland-Altman analyses of agreement, concordance correlation coefficient (CCC) and root-mean-squared error (RMSE) were used to determine accuracy of the OMNI and commercial devices relative to Biopac. Additionally, a linear mixed-effects model evaluated the effects of device and exercise intensity on agreement. RESULTS: Chest-based devices showed superior agreement with Biopac for measuring R-R interval compared with wrist-based ones in terms of mean bias, CCC and RMSE, with OMNI demonstrating the best scores on all metrics. Linear mixed-effects model showed no significant main or interaction effects for the chest-based devices. However, significant effects were found for Garmin and Empatica devices (p<0.001) as well as the interaction effects between both Garmin and Empatica and exercise intensity (p<0.001). CONCLUSIONS: Chest-based ECG devices are preferred to wrist-based PPG devices due to superior HR accuracy over a range of exercise intensities, with the OMNI device demonstrating equal, if not superior, performance to other commercial ECG monitors. Additionally, wrist-based PPG devices are significantly affected by exercise intensity as they underestimate HR at low intensities and overestimate HR at high intensities.

Prevalence of, and factors associated with, alcohol use disorder among young adults (aged 15-24 years) living with HIV/AIDS in low-income and middle-income countries: protocol for a systematic review.

INTRODUCTION: Alcohol use is a global driver of HIV infection and disease progression, mediated through risky behaviour and poor antiretroviral adherence. Most studies about the burden of alcohol use among people living with HIV (PLWH)/AIDS have been done in adult populations, but less is known about young people with HIV, especially in low-income and middle-income countries (LMICs), despite the high level of alcohol use in these settings. The aim of this review is to collate evidence on the prevalence of, and factors associated with, alcohol use disorder (AUD) among young adults (aged 15-24 years) living with HIV/AIDS in LMICs. METHODS AND ANALYSIS: Two experienced librarians will conduct an independent article search in PubMed, PsycINFO, Embase and Web of Science databases, using relevant Medical Subject Headings terms and Boolean operators ('AND', 'OR'). We will include English-language articles that were published in peer-reviewed journals from 1 January 2000, to 25 July 2022, that documented the prevalence of AUD among young people (15-24 years) living with HIV in LMICs. We shall exclude systematic review articles and qualitative studies. Two independent reviewers will screen the articles for eligibility and data will be extracted onto a preset Excel spreadsheet. Data analysis will be done using Stata V.14.0. Heterogeneity will be assessed by use of the I2 statistic and data will be pooled in meta-analyses where appropriate. Publication bias will be assessed using the funnel plot. ETHICS AND DISSEMINATION: Ethical approval is not needed as this systematic review will be based on published studies. Findings from this study will be disseminated via submission for publication in a peer-reviewed journal, at conference presentations, and made available to health professionals, scientists and policy makers. Our data set can be made available on request. REGISTRATION DETAILS: PROSPERO, CRD42022308955.

[Typical emergencies in otorhinolaryngology-a monocentric analysis of the seasonal course]. / Typische Notfälle in der Hals-Nasen-Ohren-Heilkunde ­ eine monozentrische Evaluation über den jahreszeitlichen Verlauf.

BACKGROUND: The incidence of acute ear, nose, and throat (ENT) diagnoses is influenced by multiple parameters, for example meteorological and seasonal influences. By better understanding the triggering factors, prophylactic approaches can be developed. MATERIALS AND METHODS: A retrospective analysis was performed over 6 years of all patients who presented to the university hospital because of typical and minor ENT emergencies. The diagnoses impacted cerumen, acute otitis media, acute otitis externa, nasal bone fracture, epistaxis, acute tonsillitis, acute rhinosinusitis, and peritonsillar abscess were analyzed. RESULTS: A total of 32,968 cases were analyzed. Epistaxis was the most common of the investigated emergency diagnoses, accounting for 24.5% (8082 cases). Epistaxis, acute otitis media, and acute rhinosinusitis occurred significantly more frequently in the colder half of the year. There was no significant correlation of the incidence of nasal bone fracture with public holidays. Acute otitis externa correlated significantly with the local summer vacations. In calendar week 38, the fewest total emergency presentations occurred, whereas in calendar week 52, the most emergency presentations occurred. CONCLUSION: Seasonal and meteorological factors play a significant role in the pathogenesis of many emergency ENT diagnoses.

Evaluation of at-home methods for N95 filtering facepiece respirator decontamination.

N95 filtering facepiece respirators (FFRs) are essential for the protection of healthcare professionals and other high-risk groups against Coronavirus Disease of 2019 (COVID-19). In response to shortages in FFRs during the ongoing COVID-19 pandemic, the Food and Drug Administration issued an Emergency Use Authorization permitting FFR decontamination and reuse. However, although industrial decontamination services are available at some large institutions, FFR decontamination is not widely accessible. To be effective, FFR decontamination must (1) inactivate the virus; (2) preserve FFR integrity, specifically fit and filtering capability; and (3) be non-toxic and safe. Here we identify and test at-home heat-based methods for FFR decontamination that meet these requirements using common household appliances. Our results identify potential protocols for simple and accessible FFR decontamination, while also highlighting unsuitable methods that may jeopardize FFR integrity.

Unveiling the neuromechanical mechanisms underlying the synergistic interactions in human sensorimotor system.

Motor synergies are neural organizations of a set of redundant motor effectors that interact with one another to compensate for each other's error and ensure the stabilization of a performance variable. Recent studies have demonstrated that central nervous system synergistically coordinates its numerous motor effectors through Bayesian multi-sensory integration. Deficiency in sensory synergy weakens the synergistic interaction between the motor effectors. Here, we scrutinize the neuromechanical mechanism underlying this phenomenon through spectral analysis and modeling. We validate our model-generated results using experimental data reported in the literature collected from participants performing a finger force production task with and without tactile feedback (manipulated through injection of anesthetic in fingers). Spectral analysis reveals that the error compensation feature of synergies occurs only at low frequencies. Modeling suggests that the neurophysiological structures involving short-latency back-coupling loops similar to the well-known Renshaw cells explain the deterioration of synergy due to sensory deprivation.

[Radicality of maxillary sinus surgery and size of the maxillary sinus ostium]. / Radikalität der Kieferhöhlenoperation und Größe des Kieferhöhlenfensters.

Until the 1990s, radical sinus surgery was considered a standard procedure for maxillary sinus diseases, but it is no longer favored due to the high morbidity. Today, functional endoscopic sinus surgery (FESS) is considered the gold standard in sinus surgery. Modifications of surgical approaches also allow access to regions of the maxillary sinus that were previously difficult to reach. Depending on anatomy and pathology, different methods for widening the maxillary ostium can be selected. In type I sinusotomy, the natural ostium is widened dorsally by a maximum of 1 cm. Sinusotomy type II involves widening the natural ostium up to a maximum diameter of 2 cm. In sinusotomy type III, the natural ostium is widened dorsally to the posterior wall of the maxillary sinus and caudally to the base of the inferior turbinate. Beside the prelacrimal approach, more invasive approaches are the medial maxillectomy, in which the dorsal part of the inferior turbinate and the adjacent medial wall of the maxillary sinus is resected, as well as its modifications "mega antrostomy" and "extended maxillary antrostomy." Correct selection of the size of the maxillary sinus window is prerequisite for successful treatment and long-term postoperative success. Isolated purulent maxillary sinusitis can usually be treated by a type I sinusotomy. Sinusotomy type II addresses nasal polyps with involvement of the mucosa of the ostium, recurrent stenosis after previous surgery, chronic maxillary sinusitis due to cystic fibrosis, and purulent maxillary sinusitis with involvement of other adjacent sinuses. Sinusotomy type III is required for choanal polyps with attachment to the floor of the maxillary sinus, for extensive polyposis and fungal sinusitis, and for inverted papilloma. Particularly for (recurrent) disease and extensive interventions in the maxillary sinus, medial maxillectomy or a modification thereof may be required.

[Oncoimmunology in old age]. / Onkoimmunologie im Alter.

Physiological aging processes of the immune system are associated with an increased susceptibility to infectious, autoimmune and tumor diseases. In accordance with the general demographic development the number of tumor patients in advanced age also increases. An end to this development is not yet foreseeable. In tumor treatment, immunotherapy with checkpoint inhibitors is becoming increasingly more important; however, only a few studies on the efficacy and side-effect profiles in older patients exist so far. In this review article the changes in the immune system in old age and the influence on carcinogenesis are discussed. In addition, the current state of research on the immunotherapy of patients in advanced age who suffer from head and neck cancer is presented.

[The ulm emergency algorithm for the acute treatment of drug-induced, bradykinin-mediated angioedema]. / Ulmer Notfallalgorithmus: die Akuttherapie von medikamenteninduzierten bradykininvermittelten Angioödemen.

BACKGROUND: Bradykinin-mediated, drug-induced edema like ACE-inhibitor-induced angioedema (ACEi AE) is almost exclusively located in the head and neck region and is potentially life threatening. To date, there are no guidelines or officially-approved treatments available for this pathology. OBJECTIVES: We sought to provide a structured therapeutic algorithm for the acute treatment of drug-induced bradykinin-mediated angioedema. MATERIALS AND METHODS: We analyzed data (especially the course of disease and therapy) of all patients with acute angioedema, who presented to the Department of Otorhinolaryngology, Head and Neck Surgery at the University of Ulm (2010-2015). We also conducted a literature review on PubMed with the terms "acute angioedema", "angioedema emergency", "ACE angioedema", "bradykinin angioedema" and "angioedema therapy". Other fundamental references were the recent German guidelines "hereditary angioedema", "anaphylaxis" and "airway management". RESULTS: An emergency algorithm was generated as a flowchart for the acute therapy of bradykinin-mediated drug-induced angioedema was generated. We focused on the decision criteria for intubation/airway management and pharmacological therapy: antihistamines and glucocorticoids versus anti-bradykinin treatment. Furthermore, recommendations for inpatient monitoring have been derived. CONCLUSION/DISCUSSION: To date, therapy of drug-induced bradykinin-mediated angioedema is performed according to an "off-label" use and without officially-approved guidelines. The presented emergency algorithm provides a first approach for a structured therapeutic concept for a potentially life-threatening pathology.

A hippocampus to prefrontal cortex neural pathway inhibits food motivation through glucagon-like peptide-1 signaling.

The hippocampus and the medial prefrontal cortex (mPFC) are traditionally associated with regulating memory and executive function, respectively. The contribution of these brain regions to food intake control, however, is poorly understood. The present study identifies a novel neural pathway through which monosynaptic glutamatergic ventral hippocampal field CA1 (vCA1) to mPFC connectivity inhibits food-motivated behaviors through vCA1 glucagon-like peptide-1 receptor (GLP-1R). Results demonstrate that vCA1-targeted RNA interference-mediated GLP-1R knockdown increases motivated operant responding for palatable food. Chemogenetic disconnection of monosynaptic glutamatergic vCA1 to mPFC projections using designer receptors exclusively activated by designer drugs (DREADDs)-mediated synaptic silencing ablates the food intake and body weight reduction following vCA1 GLP-1R activation. Neuropharmacological experiments further reveal that vCA1 GLP-1R activation reduces food intake and inhibits impulsive operant responding for palatable food via downstream communication to mPFC NMDA receptors. Overall these findings identify a novel neural pathway regulating higher-order cognitive aspects of feeding behavior.

Features of haptic and tactile feedback in TORS-a comparison of available surgical systems.

Sustained interest and an increase of possible indications endorse the role of robot-assisted surgery of the head and neck region. However, broad clinical application is impeded by substantial extra cost, time exposure and a supposed deficit of haptic and tactile feedback. The role of haptic feedback has barely been examined in this context, and literature provides only limited objective validation. This point of criticism applies to all commercially available systems. We created an experimental setup to evaluate, quantify and compare the performance of surgical systems. The daVinci system (Intuitive Surgical), the Flex system (Medrobotics) and standard rigid instruments (23 cm laryngoscopic grasper, Karl Storz) were compared with the human hand by head and neck surgeons (n = 15), performing a variety of surgical tasks. Specific samples with different rigidity were sorted with all devices, and the resulting orders were analyzed by permutation analysis, indicating differences in precision and accuracy of haptic and tactile feedback. The human hand was superior in all trials, acting as reference modality. The flexible instruments of the Flex system performed better than the electro-mechanically decoupled instruments of the daVinci system for the majority of measures recorded, suggesting a benefit in terms of haptic and tactile feedback in this context. While not all aspects of haptic and tactile feedback were accessible, this first objective comparison endorses the inferiority of robot-assisted surgery in terms of haptic and tactile feedback, compared to the human sense or standard surgical tools. Furthermore, the immediate force transmission of the Flex system seems to be superior to the electro-mechanical transformation of the daVinci system, indicating an advantage in terms of haptic and tactile feedback in immediate comparison. This study is providing a basis for further experiments and the development of robotic surgery towards an implementation in clinical routine.

Pharmacokinetic changes of antibiotic, antiviral, antituberculosis and antifungal agents during extracorporeal membrane oxygenation in critically ill adult patients.

WHAT IS KNOWN AND OBJECTIVE: Extracorporeal membrane oxygenation (ECMO) is a life-saving system used for critically ill patients with cardiac and/or respiratory failure. The pharmacokinetics (PK) of drugs can change in patients undergoing ECMO, which can result in therapeutic failure or drug toxicity requiring further management of drug complications. In this review, we discussed changes in the PK of antibiotic, antiviral, antituberculosis and antifungal agents administered to adult patients on ECMO. These drugs are crucial for managing infections, which commonly occur during ECMO. METHODS: A literature search was conducted using the PubMed and EMBASE databases with the following keywords: "extracorporeal membrane oxygenation OR extracorporeal membrane oxygenations OR ECMO" and "PK OR pharmacokinetics OR pharmacokinetic*" and "anti infective* OR antibiotic* OR antiviral* OR antituberculosis OR antifungal*." RESULTS AND DISCUSSION: Generally, the volume of distribution (Vd) increases and drug clearance (CL) and elimination decrease during ECMO. Highly significant changes in drug PK can occur by interactions with the ECMO device itself, drug characteristics, pathological changes and patient characteristics. This may affect the blood concentrations of drugs, which influence the success of therapy. The PK of vancomycin, piperacillin-tazobactam, meropenem, azithromycin, amikacin and caspofungin did not change significantly in adult patients receiving ECMO. However, there were significant changes in the PK of imipenem, oseltamivir, rifampicin and voriconazole. The trough concentrations of imipenem were highly variable; oseltamivir had a decreased CL and increased Vd, and rifampicin concentrations were below therapeutic levels, even when a higher-than-standard dose was used in patients treated with ECMO. Additionally, voriconazole exhibited high mean peak concentrations during ECMO. WHAT IS NEW AND CONCLUSION: The impact of ECMO on PK varies among drugs in adult patients, and there is no consistent correlation between the effects observed in adult and infant studies. This review suggested that doses of imipenem, oseltamivir, rifampicin and voriconazole should be adjusted and therapeutic drug monitoring is needed when ECMO is used in adult patients. In the future, large PK trials in adults on ECMO are needed to provide optimal dosing guidelines. A PK/PD modelling approach will be useful for determining the precise impact of ECMO and other factors that contribute to PK changes for each drug. Finally, it is important to develop dosing guidelines based on PK/PD modelling studies that can be used in clinical practice.

Diagnosis of invasive fungal infections in haematological patients by combined use of galactomannan, 1,3-ß-D-glucan, Aspergillus PCR, multifungal DNA-microarray, and Aspergillus azole resistance PCRs in blood and bronchoalveolar lavage samples: results of a prospective multicentre study.

High mortality rates of invasive fungal disease (IFD), especially invasive aspergillosis (IA), in immunocompromised haematological patients and current diagnostic limitations require improvement of detection of fungal pathogens by defining the optimal use of biomarkers and clinical samples. Concurrent bronchoalveolar lavage (BAL) and peripheral blood samples of 99 haematological patients with suspected IFD were investigated within a multicentre prospective study. Diagnostic performance of a galactomannan (GM) enzyme immune assay (EIA), a 1,3-ß-D-glucan assay (BDG), an Aspergillus PCR, and a multifungal DNA-microarray (Chip) alone or in combination were calculated. IFD were classified as proven (n=3), probable (n=34), possible (n=33), and no IFD (n=29) according to EORTC/MSG criteria. GM, PCR, and Chip showed superior diagnostic performance in BAL than in blood, whereas specificity of BDG in BAL was poor (48% (14/29)). The combination of GM (BAL) with BDG (blood) showed sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and DOR (diagnostic odds ratio) of 92% (34/37), 93% (27/29), 94%, 90%, and 153.0, respectively. Combining GM (BAL) with PCR (BAL) showed convincing diagnostic potential for diagnosing IA with sensitivity, specificity, PPV, NPV, and DOR of 85% (17/20), 97% (28/29), 94%, 90%, and 158.7. Addition of the DNA-microarray resulted in further detection of two mucormycetes infections. In 1 out of 15 Aspergillus DNA-positive samples a triazole resistance-mediating Cyp51A mutation was found. Combination of biomarkers is superior to their sole use in diagnosing IFD, particularly IA. Integrating blood and BAL samples into a diagnostic algorithm is an advantageous approach.