Regional advisory board position statement on optimal pneumococcal vaccination in adults. Update to 2011 consensus on adult pneumococcal disease: update on optimal pneumococcal vaccination in adults.

BACKGROUND: An important development in the field of adult pneumococcal vaccination since the last Consensus Statement, published by the Expert Panel of Central and Eastern Europe and Israel (the Region) in September 2012, was the licensure of the 13-valent pneumococcal conjugate vaccine (PCV13) for adults aged 50 years and older. DISCUSSION: The Expert Panel has developed this Position Statement as an update to its previous Consensus to address the following topics which are likely to be on the agenda of national scientific societies during the ongoing updates of vaccination recommendations in the Region: the availability of a pneumococcal conjugate vaccine for adults over 50 years of age, the available clinical evidence on its use in adults, and the future place of conjugate vaccines in adult pneumococcal vaccination. The Expert Panel concluded that there is sufficient epidemiologic immunogenicity and safety evidence to use PCV 13 in adults over 50 years of age. RESULTS: The use of conjugate vaccine induces immunological memory and can overcome some limitations associated with the plain polysaccharide vaccine (PPV). It was also agreed that, if the use of PPV is considered appropriate, PCV13 should be administered first, regardless of prior pneumococcal vaccination status.

Opportunity for healthy ageing: lessening the burden of adult pneumococcal disease in Central and Eastern Europe, and Israel.

The population of the Region (Central Europe, Eastern Europe, and Israel) is ageing, necessitating preventative programmes to maintain a healthy and active lifestyle in older age groups. Invasive pneumococcal disease (including bacteremic pneumonia, bacteremia without a focus, and meningitis) has higher incidence, morbidity and mortality in older adults and is a substantial public health burden in the ageing population. Surveillance in the Region establishes a significant burden in older adults of invasive pneumococcal disease (IPD), which still appears to be under-estimated as compared with other countries, and this warrants an improvement in surveillance systems. The largest proportion of IPD in adults is bacteremic pneumonia. Community-acquired pneumonia (CAP), largely attributable to S. pneumoniae, can be bacteremic or non-bacteremic; the non-bacteremic forms of CAP also represent a significant burden in the Region. The burden of pneumococcal disease can be reduced with programmes of effective vaccination. Recommendations on pneumococcal vaccination in adults vary widely across the Region. The main barrier to implementation of vaccination programmes is low awareness among healthcare professionals on serious heatlh consequences of adult pneumococcal disease and of vaccination options. The Expert Panel calls on healthcare providers in the Region to improve pneumococcal surveillance, optimize and disseminate recommendations for adult vaccination, and support awareness and education programmes about adult pneumococcal disease.

Community-acquired pneumonia - An EFIM guideline critical appraisal adaptation for internists.

BACKGROUND: In real-life settings, guidelines frequently cannot be followed since many patients are multimorbid and/or elderly or have other complicating conditions which carry an increased risk of drug-drug interactions. This document aimed to adapt recommendations from existing clinical practice guidelines (CPGs) to assist physicians' decision-making processes concerning specific and complex scenarios related to acute CAP. METHODS: The process for the adaptation procedure started with the identification of unsolved clinical questions (PICOs) in patients with CAP and continued with critically appraising the updated existing CPGs and choosing the recommendations, which are most applicable to these specific scenarios. RESULTS: Seventeen CPGs were appraised to address five PICOs. Twenty-seven recommendations were endorsed based on 7 high, 9 moderate, 10 low, and 1 very low-quality evidence. The most valid recommendations applicable to the clinical practice were the following ones: Respiratory virus testing is strongly recommended during periods of increased respiratory virus activity. Assessing the severity with a validated prediction rule to discriminate where to treat the patient is strongly recommended along with reassessing the patient periodically for improvement as expected. In adults with multiple comorbidities, polypharmacy, or advanced age, it is strongly recommended to check for possible drug interactions before starting treatment. Strong graded recommendations exist on antibiotic treatment and its duration. Recommendations on the use of biomarkers such as C-reactive protein or procalcitonin to improve severity assessment are reported. CONCLUSION: This document provides a simple and reliable updated guide for clinical decision-making in the management of complex patients with multimorbidity and CAP in the real-life setting.

Medication for COVID-19-an Overview of Approaches Currently Under Study.

BACKGROUND: With the worldwide spread of SARS-CoV-2 infection, it is becoming increasingly urgent to develop a vaccine to prevent COVID-19, as well as effective drugs to treat it. METHODS: This article is based on a selective literature search in PubMed and ClinicalTrials.gov, followed by an assessment of the ongoing clinical trials that were revealed by the search. RESULTS: A number of substances have been found to prevent the reproduction of SARS-CoV-2 in vitro. These include virustatic agents that have already been approved for the treatment of other types of viral infection, as well as drugs that are currently used for entirely different purposes. High in vitro activity has been found for the nucleotide analogue remdesivir, for the antimalarial drug chloroquine, and for nitazoxanide, a drug used to treat protozoan infections. Because the virus enters human cells by way of the membrane-associated angiotensin converting enzyme 2 (ACE2), keeping the virus from docking to this receptor is a conceivable treatment approach. Transmembrane protease serine 2 (TMPRSS2) plays a role in the fusion of the virus with cells; inhibitors of this enzyme are known as well. The potential therapeutic efficacy and tolerability of these and other active substances remain to be investigated in clinical trials. At present, more than 80 trials on COVID-10 have already been registered with Clinical- Trials.gov. Some initial findings should already be available in late April 2020. CONCLUSION: Clinical trials are now indispensable in order to determine the true clinical benefits and risks of the substances that have been found to be active against SARSCoV- 2 in vitro. There is not yet any recommendation for the therapeutic use of any particular agent beyond standard supportive treatment.

Calculated initial parenteral treatment of bacterial infections: Safety and tolerabilty.

This is the fourth chapter of the guideline "Calculated initial parenteral treatment of bacterial infections in adults - update 2018" in the 2nd updated version. The German guideline by the Paul-Ehrlich-Gesellschaft für Chemotherapie e.V. (PEG) has been translated to address an international audience. Safety and tolerability of antimicrobial agents will be discussed in this chapter. Toxic, allergic and biological effects can be differentiated on the basis of their pathogenesis. The question of differences in the tolerability of specific antibiotics is of particular importance. However, due to limitations of the available data, it cannot be answered for most agents with the desired accuracy. For an assessment of rare side effects, results from the postmarketing surveillance have to be used.

Calculated parenteral initial treatment of bacterial infections: Respiratory infections.

This is the fifth chapter of the guideline "Calculated initial parenteral treatment of bacterial infections in adults - update 2018" in the 2nd updated version. The German guideline by the Paul-Ehrlich-Gesellschaft für Chemotherapie e.V. (PEG) has been translated to address an international audience. It provides recommendations for the empirical and targeted antimicrobial treatment of lower respiratory tract infections, with a special emphasis on the treatment of acute exacerbation of COPD, community-acquired pneumonia and hospital-acquired pneumonia.

Impact of Bacterial Toxins in the Lungs.

Bacterial toxins play a key role in the pathogenesis of lung disease. Based on their structural and functional properties, they employ various strategies to modulate lung barrier function and to impair host defense in order to promote infection. Although in general, these toxins target common cellular signaling pathways and host compartments, toxin- and cell-specific effects have also been reported. Toxins can affect resident pulmonary cells involved in alveolar fluid clearance (AFC) and barrier function through impairing vectorial Na+ transport and through cytoskeletal collapse, as such, destroying cell-cell adhesions. The resulting loss of alveolar-capillary barrier integrity and fluid clearance capacity will induce capillary leak and foster edema formation, which will in turn impair gas exchange and endanger the survival of the host. Toxins modulate or neutralize protective host cell mechanisms of both the innate and adaptive immunity response during chronic infection. In particular, toxins can either recruit or kill central players of the lung's innate immune responses to pathogenic attacks, i.e., alveolar macrophages (AMs) and neutrophils. Pulmonary disorders resulting from these toxin actions include, e.g., acute lung injury (ALI), the acute respiratory syndrome (ARDS), and severe pneumonia. When acute infection converts to persistence, i.e., colonization and chronic infection, lung diseases, such as bronchitis, chronic obstructive pulmonary disease (COPD), and cystic fibrosis (CF) can arise. The aim of this review is to discuss the impact of bacterial toxins in the lungs and the resulting outcomes for pathogenesis, their roles in promoting bacterial dissemination, and bacterial survival in disease progression.

Moxifloxacin monotherapy is effective in hospitalized patients with community-acquired pneumonia: the MOTIV study--a randomized clinical trial.

BACKGROUND: The aim of this study was to show that sequential intravenous and oral moxifloxacin monotherapy (400 mg once per day) is as efficacious and safe as a combination regimen (intravenous ceftriaxone, 2 g once per day, plus sequential intravenous and oral levofloxacin, 500 mg twice per day) in patients hospitalized with community-acquired pneumonia. METHODS: We conducted a prospective, multicenter, randomized, double-blind noninferiority trial. Patients with a Pneumonia Severity Index (PSI) of III-V were stratified on the basis of PSI risk class before randomization. The primary efficacy end point was clinical response at test of cure (4-14 days after the completion of treatment). Secondary efficacy end points were clinical and bacteriological response at end of treatment (days 7-14) and at follow-up assessment (21-28 days after the end of treatment), overall mortality, and mortality attributable to pneumonia. RESULTS: Seven hundred thirty-three patients were enrolled in the study (368 in the moxifloxacin arm and 365 in the comparator arm); 49% had a PSI of IV, and 10% had a PSI of V. Of 569 patients (291 in the moxifloxacin arm and 278 in the comparator arm) valid for per-protocol analysis, the overall clinical cure rates at test of cure were 86.9% for moxifloxacin and 89.9% for the comparator regimen (95% confidence interval, -8.1% to 2.2%). Bacteriological success at test of cure was 83.3% for moxifloxacin and 85.1% for the comparator regimen (95% confidence interval, -15.4% to 11.8%). There were no significant differences between moxifloxacin and comparator treatments in the incidence of treatment-emergent adverse events or in mortality. CONCLUSIONS: Monotherapy with sequential intravenous/oral moxifloxacin was noninferior to treatment with ceftriaxone plus levofloxacin combination therapy in patients with community-acquired pneumonia who required hospitalization.

Rational antibiotic therapy and the position of ampicillin/sulbactam.

In the current context of increasing antimicrobial resistance, it is important to use antibiotics rationally and to re-assess regularly the clinical usefulness of commonly used agents. This review focuses on the efficacy of the beta-lactam ampicillin co-administered with the beta-lactamase inhibitor sulbactam, either parenterally (ampicillin/sulbactam) or orally (sultamicillin), for the treatment of bacterial infections. Clinical findings from the past decade confirm the results of numerous older studies and together provide good evidence to support the continued use of ampicillin/sulbactam and sultamicillin in hospital- and community-acquired infections both in adults and children. This is also recognised in recent published national and international guidelines, many of which recommend ampicillin/sulbactam as first-line therapy for various respiratory and skin infections.

Pneumococcal vaccines: mechanism of action, impact on epidemiology and adaption of the species.

Pneumococcal infections elicited by Streptococcus pneumoniae (pneumococcus) (pneumonia, otitis media, sinusitis, meningitis) are frequently occurring diseases that are associated with considerable morbidity and mortality even in developed countries. Pneumococci colonise the nasopharynx of up to 50% of children, and up to 5% of adults are pneumococcal carriers. Two pneumococcal vaccines are currently in clinical use. One of them contains 23 capsular polysaccharides of the as yet known 91 different pneumococcal serotypes. Because polysaccharide vaccines primarily induce a B-cell-dependent immune response, this type of vaccine prevents bacteraemia but does not efficiently protect the host against pneumococcal infection. In 2000, a vaccination programme was launched in the USA making use of a novel pneumococcal conjugate vaccine containing capsular polysaccharides derived from the seven most frequent pneumococcal serotypes causing pneumococcal disease in children <2 years of age. Conjugation of capsular polysaccharides with a highly immunogenic protein, i.e. a non-toxic diphtheria toxoid, induces a B- and T-cell response resulting in mucosal immunity and thus effectively protects against vaccine serotypes that induce invasive pneumococcal disease, thereby at the same time reducing vaccine serotype carrier rates. Pronounced herd immunity resulted in a decrease in invasive pneumococcal diseases in vaccinees and non-vaccinees as well as reduced antibiotic resistance rates. However, recent studies report that serotypes eradicated by the vaccine are being replaced by non-vaccine pneumococcal serotypes. This so-called 'replacement' might soon threaten the success of vaccine use.

What drives our choices? Evidence, guidelines or habit?

Physicians' treatment choices are influenced by a number of factors, including guidelines, evidence-based medicine, past experience and, to a certain extent, habit. Evidence-based medicine is the foundation of clinical practice guidelines. This article reviews the influence of evidence and guidelines on physicians' treatment choices. As examples, the role of evidence in guiding treatment decisions in chronic obstructive pulmonary disease is explored, and the impact of guidelines on treatment choices in community-acquired pneumonia is discussed. When choosing the most appropriate treatment for a patient, physicians need to continuously evaluate new evidence, in addition to implementing clinical practice guidelines. Additional factors that should also influence this decision are physicians' prior experience and the individual patient's circumstances.

Managing community-acquired pneumonia: a European perspective.

Community-acquired pneumonia (CAP) is a common disease and a frequent cause of morbidity and mortality worldwide. It puts an enormous burden on medical and economic resources, particularly if hospitalization is required. Initial antibacterial therapy for CAP is usually empirical, as culture and antibacterial sensitivity test results are rarely available at initial diagnosis. Any agent selected for empirical therapy should have good activity against the pathogens commonly associated with CAP, a favorable tolerability profile, and be administered in a simple dosage regimen for good compliance. Streptococcus pneumoniae remains the most common causative pathogen, although the incidence of this organism varies widely. Streptococcus pneumoniae strains with decreased susceptibility to penicillin have become increasingly prevalent over the past 30 years and are now a serious problem worldwide. In addition, an increase in the prevalence of pneumococci resistant to macrolides has been observed in Europe over recent years. Mycoplasma pneumoniae and Chlamydia pneumoniae are among the most common atypical pathogens isolated from patients with CAP. Haemophilus influenzae, Staphylococcus aureus and Moraxella catarrhalis are less commonly identified as causative organisms. The emergence and spread of resistance to commonly used antibiotics has challenged the management of CAP. Multiple sets of CAP guidelines have been published to address the continued changes in this complex disease.

Ultrastructural types of alveolar macrophages in bronchoalveolar lavages from patients with pulmonary sarcoidosis.

By routine applied quantitative BAL methods are particularly helpful for the diagnosis of pulmonary sarcoidosis. Here the morphology of the alveolar cells does not play a role. However, morphological and especially electron microscopic investigations might contribute to the clarification of the aetiology of this disease. In a prospective study we investigated the bronchoalveolar lavages (BALs) from 10 patients with recently histologically diagnosed, untreated pulmonary sarcoidosis. Commonly applied cytological and immunological BAL diagnostic techniques were accompanied by morphological investigations of alveolar cells, especially alveolar macrophages, using light and electron microscopy. All patients showed lymphocytic alveolitis with an increased number of CD4 positive lymphocytes as well as an increased CD4/CD8 ratio. A striking light microscopic finding was the great morphological variety of the alveolar macrophages. Electron microscopy revealed typical lymphocytes, neutrophils, and eosinophils as well as three different types of alveolar macrophages in all 10 patients: type I (approx. 30%) with a normal macrophage morphology, a vacuole-rich type II (approx. 30%) with myelin-like structures and type III (approx. 40%) with electron-dense inclusions. The occurrence of intracellular myelin figures in type II macrophages is a hint for increased phagocytotic processes of surfactant with or without its overproduction in the sense of a secondary alveolar proteinosis. Numerous electron-dense inclusions in type III also indicate an increased macrophage activity that leads to an increased release of cytokines, which in turn can trigger an inflammatory reaction.

Apoptosis of peripheral blood neutrophils in COPD exacerbation does not correlate with serum cytokines.

The study investigated the relationship between apoptosis of peripheral blood neutrophils during exacerbation of chronic obstructive pulmonary disease (COPD) and the inflammatory response that characterises this condition. Twenty-six hospitalised patients with COPD exacerbation and 13 controls were included. Three sequential blood and sputum samples were obtained from patients at admission, after 3 days and at discharge. Blood apoptotic neutrophils were measured by flow-cytometry and light microscopy. Serum and sputum levels of IL-6, IL-8 and TNF-alpha were determined by an immunoassay technique. We found a significantly reduced percentage of apoptotic neutrophils at the onset of COPD exacerbation which increased over time (1.1+/-0.4% at admission vs. 2.4+/-0.4% at discharge, P<0.0001). Patients presented no changes in serum cytokines neither during exacerbation nor in comparison to controls. In contrast, sputum levels of cytokines were significantly increased compared to serum levels. There was no significant correlation between the apoptotic neutrophils and the cytokine concentrations in serum or sputum. None of the clinical parameters, such as smoking, microbial infection, corticosteroids or hypoxemia showed a correlation with neutrophil apoptosis. No relationship could be found between the reduced percentage of apoptotic neutrophils in blood and serum concentration of IL-6, IL-8 and TNF-alpha or other clinical parameters in patients with COPD exacerbation.

Treatment and vaccines for severe acute respiratory syndrome.

The causative agent of severe acute respiratory syndrome (SARS), which affected over 8000 individuals worldwide and was responsible for over 700 deaths in the 2002-2003 outbreak, is a coronavirus that was unknown before the outbreak. Although many different treatments were used during the outbreak, none were implemented in a controlled fashion. Thus, the optimal treatment for SARS is unknown. Since the outbreak, much work has been done testing new agents against SARS using in-vitro methods and animal models. In addition, global research efforts have focused on the development of vaccines against SARS. Efforts should be made to evaluate the most promising treatments and vaccines in controlled clinical trials, should another SARS outbreak occur.

[Pharmacokinetics of antibiotics in obese and critical care patients]. / Pharmakokinetik von Antibiotika bei Übergewichtigen und kritisch Kranken.

Against the background of reduced susceptibility of many pathogens to available antibacterial agents an optimized dosing of antibiotics is of increasing importance to avoid therapeutic failures and / or microbial resistance. Consideration of the individual body weight, as well as kidney and liver function of a patient and the pharmacodynamics and pharmacokinetic properties of the antibiotic should enable an individualized dosing. An optimized approach could increase efficacy and safety of an antimicrobial therapy significantly. Aimed studies in overweight patients during the clinical development of a new antibiotic are necessary as a substantial prerequisite for a pharmacokinetically based optimized dosing. Intensive care patients also exhibit major changes in pharmacokinetics of antibiotics due to pathophysiological changes. An increased volume of distribution, an increased clearance and reduced protein binding require treatment with increased doses. On the other hand, in patients with acute renal failure often doses have to be reduced and / or the dosing interval has to be prolonged. Renal function should be assessed on the basis of the creatinine clearance. An estimation with the often applied plasma creatinine-based equations can lead to wrong results in critically ill patients, a directly measured urinary creatinine clearance is a more reasonable procedure. However, so far only few prospective studies which investigated the effect of alternative dosing strategies on the therapeutic outcome have been published. Certainly, further comprehensive studies are necessary.

The clinical positioning of telavancin in Europe.

Telavancin was the first marketed lipoglycopeptide. Although licensed in Europe in 2011 for the treatment of nosocomial pneumonia caused by meticillin-resistant Staphylococcus aureus (MRSA), it did not become clinically available until March 2014. Given the limited clinical experience with telavancin in Europe, this review provides an overview of its antimicrobial and clinical activity as well as its position among today's antimicrobials, with particular focus on the implications of its licensing requirements. Telavancin has potent in vitro activity against isolates of Gram-positive pathogens, including MRSA and glycopeptide-intermediate S. aureus strains. In addition, at clinically attainable doses telavancin inhibits Gram-positive isolates of antibiotic-resistant strains from biofilm models. The in vitro potency of telavancin has been corroborated in the clinical setting. Comparative clinical studies of telavancin demonstrate non-inferiority compared with vancomycin in the treatment of hospital-acquired Gram-positive pneumonia, with high cure rates for telavancin-treated patients with monomicrobial S. aureus infection, including isolates with reduced vancomycin susceptibility. These studies also demonstrate an overall similar safety profile for telavancin and vancomycin, although importantly, patients with moderate-to-severe renal impairment at baseline are at greater risk for mortality with telavancin and this feature must be taken into account when selecting patients for its usage. In Europe, telavancin is a useful alternative for patients with difficult-to-treat, hospital-acquired MRSA pneumonia when there are very few alternatives. For example, it should be considered in such patients when vancomycin and linezolid are not suitable and where renal function permits.

Efficacy and safety of voriconazole in the treatment of acute invasive aspergillosis.

To evaluate the efficacy and safety of voriconazole in acute invasive aspergillosis (IA), an open, noncomparative multicenter study was conducted. Immunocompromised patients with IA were treated with intravenously administered voriconazole 6 mg/kg twice a day (b.i.d.) twice and then 3 mg/kg b.i.d. for 6-27 days, followed by 200 mg b.i.d. administered orally for up to 24 weeks. Response was assessed by clinical and radiographic change. A total of 116 patients were assessable. IA was proven in 48 (41%) and probable in 68 patients. Voriconazole was given as primary therapy in 60 (52%). Good responses were seen in 56 (48%); 16 (14%) showed complete response and 40 (34%) partial response. A stable response was seen in 24 patients (21%), and 36 (31%) of the infections failed to respond to therapy. Good responses were seen in 60% of those with pulmonary or tracheobronchial IA (n=84), 16% with cerebral IA (n=19), 58% with hematologic disorders (n=67), and 26% of allogeneic stem cell transplant recipients (n=23). Voriconazole is efficacious in treating acute IA.

Nosocomial pneumonia: epidemiology, pathogenesis, diagnosis, treatment and prevention.

Nosocomial pneumonia is the second most common nosocomial infection and the leading cause of death from hospital-acquired infection. Supine body position in mechanically ventilated patients, and cardiopulmonary resuscitation and continuous sedation are significant risk factors for developing nosocomial pneumonia. During the past 2 years some new therapeutic approaches for nosocomial pneumonia and modifications to established therapies have been described, such as optimal pharmacodynamic evaluations, monotherapy versus combination therapy, computer-assisted management programmes and antibiotic rotations.

Electron microscopic findings in BAL of a fire-eater after petroleum aspiration.

Hydrocarbon pneumonitis, known also as fire-eater pneumonia, always develops after aspiration of low-viscosity, volatile hydrocarbides. Despite the presence of clear-cut indicators for an infection, it is considered to be an acute pseudoinfectious lung disease. In this article, we report on a relatively rare clinical picture of a 30-year-old man after accidental petroleum aspiration. In addition to the usual clinical and instrumental examinations, we also performed, for the first time, electron microscopic investigations of the BAL specimen. A striking finding was the occurrence of macrophages (40%) with numerous lipoid inclusions that exhibited all morphologic signs of an activation as well as neutrophil granulocytes (33%), lymphocytes (21%), and eosinophils (6%). Despite a large and necrotizing infiltration of the right lower lobe, the clinical course was uneventful with complete recovery.