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.

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.

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.

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.

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.

[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.

Preserving the efficacy of front-line fluoroquinolones through selective use to optimise clinical outcomes.

As antibiotic resistance is increasing worldwide, it is important to prescribe fluoroquinolone (FQ) antibiotics appropriately for a given infection to preserve class efficacy. Clinical studies reveal good efficacy and tolerability of the currently approved FQs (ciprofloxacin, levofloxacin and moxifloxacin) in a wide range of community- and hospital-acquired infections. However, certain features supporting their clinical efficacy suggest a rationale for inclusion of moxifloxacin and ciprofloxacin with complementary clinical benefit on a formulary rather than levofloxacin alone; it may also be more cost-effective. Ciprofloxacin has advantages over levofloxacin in the treatment of Gram-negative infections, whilst moxifloxacin has certain efficacy and ease of use advantages over levofloxacin in respiratory tract infections. To preserve the potential of FQs and to minimise the risk of resistance selection, agents with the highest in vitro activity and supportive pharmacokinetic/pharmacodynamic profiles should be used first-line, as appropriate for local guidelines and prescribing information.

Risks associated with the therapeutic use of fluoroquinolones.

INTRODUCTION: Quinolones are among the most often prescribed antimicrobial agents. Some types of toxicity observed during therapy with these drugs have gained much attention. AREAS COVERED: Here, we review the potential of the most widely used fluoroquinolones, ciprofloxacin, levofloxacin and moxifloxacin for adverse reactions. The rates of adverse events are similar for quinolones and other antibacterial agents. However, quinolone therapy can be associated with specific risks, which must be weighed against their benefit. In some studies, use of quinolones was associated with Clostridium difficile-associated diarrhea. Patients with impairments of the CNS (e.g., epilepsy or arteriosclerosis) should not be treated with quinolones. They should be avoided in patients with known prolongation of the QT interval or other risk factors for tachyarrhythmia. The risk for quinolone-associated tendinopathy is more pronounced among elderly persons, non-obese patients and individuals with concurrent use of glucocorticoids or chronic renal diseases. Quinolones are contraindicated in children because they cause destruction of the immature joint cartilage in animals. The use in paediatrics is restricted to life-threatening infections. EXPERT OPINION: Changes in the resistance situation and newly recognized adverse reactions require a continuing adjustment of therapeutic recommendations and constant educational efforts in the field of antimicrobial therapy.

Pneumococcal infection--low awareness as a potential barrier to vaccination: results of a European study.

INTRODUCTION: Elderly people and adults with chronic disease or compromised immune status are at increased risk of pneumococcal infection, with pneumonia being the most common serious presentation and a significant cause of morbidity and mortality. Most European countries have recommendations for pneumococcal vaccination but vaccination rates have remained low. In the present article, the authors present the results of a European survey that investigated the current level of awareness of pneumococcal infection among primary care physicians and specialists, and attitudes to vaccination in these physicians and members of the general public aged >50 years. METHODS: Primary care physicians (n = 1,300) and specialists (n = 926) from 13 Western European countries participated in online/face-to-face interviews, and a further 6,534 individuals aged >50 years from a population sample reflecting local socio-demographic structure participated in telephone/face-to-face interviews. RESULTS: Pneumonia was the most well-known of the pneumococcal infections amongst primary care physicians and specialists. However, there was a relatively low awareness of the term invasive pneumococcal disease (IPD), with only 50% of primary care physicians and 71% of specialists reporting knowledge of the term IPD. Key factors influencing a physician's decision to prescribe pneumococcal vaccination were the patient's health condition, recommendations from health authorities, and the tolerability of the vaccine. Perceptions regarding vaccination were good amongst the members of the general public; individuals did not fear vaccines or their side effects. The main drivers for vaccination were recommendations from a healthcare professional and, to a lesser extent, that vaccination provides reassurance against contracting a disease. CONCLUSION: These findings highlight the low awareness of the term IPD in comparison with individual pneumococcal conditions. Given the importance of physician recommendations in encouraging patients to be vaccinated, primary care physicians need to be vigilant of patients at risk of pneumococcal infections in order to increase vaccination rates.

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.

Epidemiology, microbiology, and treatment considerations for bacterial pneumonia complicating influenza.

Post-influenza bacterial pneumonia is a major cause of morbidity and mortality associated with both seasonal and pandemic influenza virus illness. However, despite much interest in influenza and its complications in recent years, good clinical trial data to inform clinicians in their assessment of treatment options are scant. This paucity of evidence needs to be addressed urgently in order to improve guidance on the management of post-influenza bacterial pneumonia. The objectives of the current article are to evaluate the emergence of the 2009 H1N1 influenza pandemic and use this information as background for an in-depth review of the epidemiology of bacterial pneumonia complicating influenza, to review the bacterial pathogens most likely to be associated with post-influenza bacterial pneumonia, and to discuss treatment considerations in these patients. When determining optimal management approaches, both antiviral and antibacterial agents should be considered, and their selection should be based upon a clear understanding of how their mechanisms of action intervene in the pathogenesis of post-influenza acute bacterial pneumonia.

A European care bundle for prevention of ventilator-associated pneumonia.

BACKGROUND: One recent approach to facilitating guideline implementation involves the use of care bundles. METHODS: This document presents a care bundle package addressing VAP prevention in an attempt to promote guideline-compliant practices. Uniquely, the development of these care bundles used a formalized methodology to assess the supporting data, based on multi-criteria decision analysis. RESULTS: The resulting VAP care bundles for prevention were: non-ventilatory circuit changes unless specifically indicated, alcohol hand hygiene, appropriately educated and trained staff, incorporation of sedation control and weaning protocols into patient care, and oral care with clorhexidine. CONCLUSION: Adoption of these care bundles should rationalise VAP prevention practises and improve outcomes, such as length of stay.

Safety considerations of fluoroquinolones in the elderly: an update.

The fluoroquinolones ciprofloxacin, levofloxacin, moxifloxacin and gemifloxacin are widely used for the treatment of various types of bacterial infections. Overall, these antibacterial agents can be considered safe and well tolerated drugs. Comparative studies have evaluated the use of quinolones in elderly and younger populations. Although age per se does not seem to decrease their tolerability, specific adverse effects of the quinolones must be considered when they are chosen for antibacterial treatment. Renal function declines consistently with age and doses of renally excreted quinolones (e.g. ofloxacin, levofloxacin, gatifloxacin) need to be adjusted if a clinically relevant reduction of creatinine clearance is identified. Reactions of the gastrointestinal tract, such as nausea, dyspepsia, vomiting or diarrhoea, are among the most often registered adverse drug reactions during therapy with fluoroquinolones. Treatment with a quinolone causes diarrhoea less frequently than treatment with other classes of antimicrobials. Conflicting data have been published with respect to the incidence of Clostridium difficile-associated diarrhoea in quinolone-treated patients. Hypersensitivity reactions, often manifested on the skin, occur less commonly during therapy with quinolones than, for example, during therapy with beta-lactam antibacterials. Adverse reactions of the CNS are of particular concern in the elderly population. Given the CNS excitatory effects of quinolones, elderly patients should be monitored carefully for such symptoms. It is likely that many signs of possible adverse reactions, such as confusion, weakness, loss of appetite, tremor or depression, are often mistakenly attributed to old age and remain unreported. Quinolones should be used with caution in patients with known or suspected CNS disorders that predispose to seizures (e.g. severe cerebral arteriosclerosis or epilepsy). Quinolones can cause QT interval prolongation. They should be avoided in patients with known prolongation of the QT interval, patients with uncorrected hypokalaemia or hypomagnesaemia and patients receiving class IA (e.g. quinidine, procainamide) or class III (e.g. amiodarone, sotalol) antiarrhythmic agents. Tendinitis and tendon ruptures are recognized as quinolone-induced adverse effects that can occur during treatment or as late as several months after treatment. Chronic renal diseases, concomitant use of corticosteroids and age >60 years are known risk factors for quinolone-induced tendopathies. Overall, the specific adverse-effect profile of quinolones must be considered when they are chosen for treatment of bacterial infections. Because of physiological changes in renal function and when certain co-morbidities are present, some special considerations are necessary when elderly patients are treated with these drugs.

Safety and tolerability of commonly prescribed oral antibiotics for the treatment of respiratory tract infections.

Recent data suggest that adverse events (AEs) associated with the use of antimicrobial drugs are a major safety concern, with antibiotics implicated in a significant proportion (approximately 20%) of all drug-related emergency department visits in the United States. Although most of these visits are attributable to allergic reactions (79%), certain commonly prescribed antibiotics are notable contributors to conditions that range in nature from gastrointestinal to neurologic and/or psychiatric--particularly after ED visits are adjusted per outpatient prescription visits. This article reviews medically significant AEs of agents included in the major antimicrobial classes--AEs that may be underappreciated by general practitioners. Considerable attention is devoted to the fluoroquinolone agents. Also discussed are the assessment procedures of regulatory agencies in Europe and the United States that are in place to evaluate antimicrobial safety more accurately. Offsetting potential risks and benefits associated with currently available antimicrobials in a climate in which new agents are desperately needed to combat continually evolving multiresistant pathogens remains an interesting dilemma in antimicrobial therapy.

Synergistic effects of dexamethasone and quinolones on human-derived tendon cells.

Quinolones and glucocorticoids are frequently used drugs that may cause tendinopathy as a rare adverse effect. We exposed human tenocyte cultures to the steroid dexamethasone alone or in combination with either ciprofloxacin or levofloxacin at concentrations of 3mg/L and 10mg/L. At concentrations corresponding to peak levels in plasma and tissues during therapy (ca. 3-10mg/L), ciprofloxacin caused a significant decrease in collagen type I and the beta(1)-integrin receptor. In contrast, no corresponding effect was induced by 3mg/L levofloxacin. With both quinolones at 3mg/L and 10mg/L, the amount of matrix metalloproteinase-1 (MMP-1) and MMP-13 was increased. In addition, 3mg/L ciprofloxacin and 10mg/L levofloxacin activated caspase-3. Apoptotic changes were confirmed by electron microscopy. Incubation of human tenocytes with dexamethasone decreased the main matrix protein collagen type I, the transmembrane beta(1)-integrin receptor and the cytoskeleton protein vinculin, but only at the high concentrations tested (0.1 microM or 10 microM). Concentrations of 0.1 microM and 10 microM dexamethasone increased the amount of MMPs and activated caspase-3 as an indicator of apoptosis. Combined exposure to quinolones and dexamethasone led to more pronounced effects in tenocyte cultures at most of the analysed endpoints. The clinical observations of an increased risk of quinolone-induced tendinopathy by glucocorticoids are supported by these in vitro data.

Quinolone-induced arthropathy: an update focusing on new mechanistic and clinical data.

Quinolones possess favourable antibacterial and pharmacokinetic characteristics and are often used as anti-infective agents in adults. They are contraindicated in children and adolescents because they damage weight-bearing joints in juvenile animals. In addition, they possess a tendotoxic potential. Since ciprofloxacin has been used off-label for decades in children and adolescents, it is known today that no pronounced risks for arthropathies or tendinopathies exist in humans. Recently published clinical studies with gatifloxacin in children support this clinical experience. However, a low risk for joint disorders cannot be excluded and tendinopathies are a generally accepted rare adverse effect of quinolones at least in adults. Isolated case reports of arthralgia in children following quinolone therapy have been published and in studies with levofloxacin the incidence of musculoskeletal disorders was significantly greater in levofloxacin-treated patients than in control patients treated with comparator antibiotics. As a consequence, only life-threatening infections for which other antimicrobials cannot be used are possible indications for quinolones in children, for example the use of ciprofloxacin in cystic fibrosis patients with a bronchopulmonary exacerbation, chronic suppurative otitis media caused by Pseudomonas sp., complicated urinary tract infections and enteritis caused by invasive multidrug-resistant pathogens (e.g. Salmonella, Shigella).

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.

Gemifloxacin for community-acquired pneumonia.

BACKGROUND: Newer fluoroquinolones have become an important therapeutic choice in the treatment of community-acquired pneumonia (CAP). Gemifloxacin is one of the newest members of this class of antibiotics and has performed favourably in this indication. OBJECTIVE: To analyse the microbiological activity, pharmacokinetic/pharmacodynamic properties and clinical activity of gemifloxacin in CAP, as well as the safety reported in controlled clinical studies. METHODS: Literature research of English publications in the last 10 years addressing all aspects of gemifloxacin in CAP. RESULTS/CONCLUSIONS: Gemifloxacin is microbiologically the most active fluoroquinolone against Streptococcus pneumoniae--the leading pathogen of CAP. In several comparative studies gemifloxacin was highly effective and well tolerated in the treatment of mild-to-moderate severe CAP.