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Microbiology Department, Hospital Universitari Germans Trias i Pujol, Institut d’Investigació Germans Trias i Pujol, Universitat Autònoma de Barcelona, Ctra del Canyet s/n, 08916 Badalona, Barcelona, SpainCIBER Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain
Microbiology Department, Hospital Universitari Germans Trias i Pujol, Institut d’Investigació Germans Trias i Pujol, Universitat Autònoma de Barcelona, Ctra del Canyet s/n, 08916 Badalona, Barcelona, SpainCIBER Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain
The clinical and microbiological challenges for establishing the clinical role of bacteria in the respiratory tract are listed.
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The available diagnostic methods and studies needed to help in treatment decisions are highlighted.
•
A review of novel therapeutic options is provided.
Summary
Background
Acute and chronic respiratory tract infections are a common cause of inappropriate antimicrobial prescription. Antimicrobial therapy leads to the development of resistance and the emergence of opportunistic pathogens that substitute the indigenous microbiota.
Methods
This review explores the major challenges and lines of research to adequately establish the clinical role of bacteria and the indications for antimicrobial treatment, and reviews novel therapeutic approaches.
Results
In patients with chronic pulmonary diseases and structural disturbances of the bronchial tree or the lung parenchyma, clinical and radiographic signs and symptoms are almost constantly present, including a basal inflammatory response. Bacterial adaptative changes and differential phenotypes are described, depending on the clinical role and niche occupied. The respiratory tract has areas that are potentially inaccessible to antimicrobials. Novel therapeutic approaches include new ways of administering antimicrobials that may allow intracellular delivery or delivery across biofilms, targeting the functions essential for infection, such as regulatory systems, or the virulence factors required to cause host damage and disease. Alternatives to antibiotics and antimicrobial adjuvants are under development.
Conclusions
Prudent treatment, novel targets, and improved drug delivery systems will contribute to reduce the emergence of antimicrobial resistance in lower respiratory tract infections.
1. Introduction—a daily clinical and microbiological challenge
As a medical microbiologist, reporting the results of susceptibility testing of a non-primary pathogenic microorganism isolated from the respiratory tract may be discouraging, both when it is susceptible and when it is multidrug-resistant (MDR). The clinical consequence of such a report is often the prescription of antimicrobial treatment, even without clinical symptoms. Therapeutic decisions are a daily clinical challenge. What is the clinical role of a MDR Pseudomonas aeruginosa or a methicillin-resistant Staphylococcus aureus (MRSA) isolated from the sputum of a chronic pulmonary obstructive disease (COPD) patient with a moderate exacerbation, or when isolated from the endotracheal aspirate of a ventilated patient who simultaneously presents Escherichia coli bacteremia?
Huge progress has been made in imaging and bronchoscopic techniques and these have improved the diagnosis of neoplasia, lower respiratory tract infections (LRTI), and tuberculosis. In addition, the development of highly sensitive molecular biology assays and mass spectrometry have increased the detection of respiratory pathogens. However, the clinical role of bacteria whose normal ecological niche is the airways, where healthy carriage dominates over disease, is still an unresolved issue,
and very sensitive techniques need to be interpreted with caution. Many efforts have also been directed at identifying novel therapeutic approaches, but it is first crucial to clearly establish when it is really necessary to treat and what the adequate duration of treatment is. The unnecessary use of extended-spectrum antibiotics in patients infected with non-resistant organisms and the inappropriate use of first-line antibiotics in patients infected with resistant organisms contribute to the emergence and spread of resistance.
National Institute for Health and Clinical Excellence
Respiratory tract infections—antibiotic prescribing: prescribing of antibiotics for self-limiting respiratory tract infections in adults and children in primary care.
Acute and chronic respiratory tract infections are the most frequent causes of antimicrobial prescription in primary care, the hospital setting, and health care facilities.
The respiratory tract has become one of the biggest reservoirs of MDR variants of microorganisms such as S. aureus and P. aeruginosa.
Antibiotic resistance is the evolutionary response to the strong selective pressure that results from exposure to the use of these drugs in the clinic and in livestock feed, and it needs to be curtailed.
The availability of antibiotics has enabled revolutionary medical interventions such as cancer chemotherapy, organ transplantation, and all major invasive surgeries,
but patients are exposed to infections by MDR bacteria, which impacts on morbidity and mortality. The presence of a MDR microorganism is troublesome even when only colonizing, because of its social and economic impact due to the required contact isolation measures.
Antimicrobial usage in LRTI also leads to the emergence of opportunistic pathogens that substitute the indigenous microbiota, such as constitutively resistant non-glucose-fermenting Gram-negative bacilli, Aspergillus, Actinomycetales, and environmental mycobacteria.
Finally, even when an apparently appropriate therapy is prescribed, the respiratory tract has areas that are potentially inaccessible to antimicrobial entry due to collapse or oedema, but also because of microbial adaptation mechanisms such as biofilm formation and intracellular persistence. Considering all the aforementioned reasons, respiratory tract infections are often mismanaged regarding the correct diagnosis, indication, dosage, and duration of antimicrobial treatment. In addition, the immunity of several opportunistic pathogens adapted to the respiratory tract is not completely understood, so vaccine development remains challenging.
and the composition of the indigenous microbiota evolves in relation to factors such as the hormonal environment, ecological disturbances, and antimicrobial use.
The resident microbiome includes microorganisms that are also potential aetiological agents of respiratory tract infections, such as Streptococcus pneumoniae, non-typeable Haemophilus influenzae, and S. aureus. Airway inflammation, altered mucus production, and diminished mucociliary clearance contribute to colonization in several situations. S. aureus carriage in the upper airways may be occasional or persistent,
and its success as a component of the respiratory flora is determined by its ability to scavenge iron and coordinate gene expression, as well as the horizontal acquisition of useful genetic elements.
are present in the nasopharynx (a highly oxygen-exposed region) of up to 60% of preschool children, as well as in patients with underlying pulmonary diseases. The establishment of colonization is a prerequisite for the development of pneumococcal disease through a combination of virulence factor activity and the ability to evade the early components of the host immune response to compete with other microorganisms.
Quantitative measurements of bacterial load have failed to clear up the situation: respiratory samples are heterogeneous and often not comparable one to another, although bacteriological response is a parameter used in clinical trials to assess efficacy. The validity of microbiological tests is improved by strict case definition and adequate radiographic review, but in the absence of positive blood cultures, a gold standard is lacking and the variability of sputum quality and contamination with oropharyngeal bacteria is still determinant, even when molecular detection is positive.
Comprehensive molecular testing including bacterial load quantitation significantly improves pathogen detection and may improve early antimicrobial de-escalation,
but PCR is able to detect dead as well as viable bacteria and a clinical improvement is sometimes observed without a decrease in the bacterial inoculum. The recently published hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP) guidelines recommend non-invasive sampling with semiquantitative cultures, since the evidence suggests that clinical outcomes are similar regardless of whether specimens are obtained invasively or non-invasively, and whether cultures are performed quantitatively or semiquantitatively, although a lower risk of inadequate initial antibiotic coverage may be observed and facilitates antibiotic de-escalation.
Management of adults with hospital-acquired and ventilator-associated pneumonia: 2016 clinical practice guidelines by the Infectious Diseases Society of America and the American Thoracic Society.
Microorganisms may persist in the respiratory tract for a long time even when prescribed antimicrobials have been expected to be active based on conventional in vitro susceptibility testing.
at least temporarily, to the anatomical site and nutrient environment where they secure a niche. A hypothesis is that lymphatic tissue associated with the respiratory tract allows the immune system to contain pathogens and confine them to their carrier niche, and occasional failure and disturbances in homeostasis result in disease.
Infection is the establishment of a microorganism within a host, while infectious disease applies when the interaction causes damage or an altered physiology resulting in clinical signs and symptoms.
The distinction is particularly difficult in patients with chronic pulmonary diseases and structural disturbances of the bronchial tree (bronchiectasis) or the lung parenchyma (pulmonary neoplasia, lobectomy/pneumonectomy, or tuberculosis scars) in whom clinical and radiographic signs and symptoms are almost constantly present, including a persistent systemic inflammation.
Several new assays and technologies have come into clinical use, such as matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) and gene expression profiling.
This last approach using microarrays has potential value as a diagnostic test, once validated through multi-cohort analyses to identify diagnostic gene sets,
since it uses the host response to pathogens as a means of diagnosing infection, rather than direct pathogen detection, or response through a specific biomarker, generating a snapshot of the immune response.
For opportunistic pathogens that can either reside asymptomatically or cause symptomatic infections, the definition of success becomes increasingly complex.
Bacteria develop adaptative mechanisms to the respiratory tract in order to survive in hostile environments related to factors such as co-infecting species and antimicrobial therapies, as well as lung conditions such as inflammatory response, hypoxia, or nutrient deficiency
(Figure 1). Adaptation mechanisms include exopolysaccharide production (mucoid phenotypes), loss in motility, formation of small colony variants (SCV), and an increased mutation rate, as well as changes in quorum sensing (QS) and in the consequent production of virulence factors.
Figure 1Key host, microorganism, and drug factors during colonization and infection in respiratory tract infections.
In many cases, especially those associated with indwelling medical devices such as an orotracheal tube, the formation of biofilm may explain the persistent isolation of S. aureus, H. influenzae, or P. aeruginosa. In fact, the natural state of many bacteria is one where they are associated with surfaces, in which acting as a ‘community’ increases their possibility of survival. Biofilm-associated bacteria tend to be less susceptible to treatments with standard chemical antibacterial agents than planktonic bacteria. It is considered that mixed species biofilms are the dominant form and that the cell–cell communication (i.e., QS) may condition changes in the composition of extracellular polymeric substances, biofilm resistance to antimicrobial agents, and environmental stress conditions.
In addition, there is accumulating evidence that aside from the classically defined intracellular pathogens, microorganisms like S. aureus and P. aeruginosa are also able to survive within eukaryotic host cells and might be termed opportunistic intracellular pathogens, constituting a reservoir for recurrence and infection,
This immune-evasive strategy shields microorganisms from many of the humoral and cellular defence mechanisms and also protects them from antimicrobial treatment. Treatment with antibiotics that act poorly intracellularly may foster the selection of resistant mutants,
Several studies have suggested that circulating macrophages or neutrophils could act as a ‘Trojan horse’ for pathogenic bacteria, allowing their dissemination in systemic infections.
Cell models employing non-professional phagocytes (i.e. airway epithelial and endothelial cells) and professional phagocytes (neutrophils and macrophages) have documented different strategies, such as escape from the phagosome into the cytoplasm or survival in phagolysosomes.
Intracellular replication of Staphylococcus aureus in mature phagolysosomes in macrophages precedes host cell death, and bacterial escape and dissemination.
Effects of subinhibitory concentrations of antibiotics on virulence factor expression by community-acquired methicillin-resistant Staphylococcus aureus.
Acute LRTI is defined as an acute illness (present for 21 days or less), usually with cough as the main symptom, and with at least one other lower respiratory tract symptom (fever, sputum production, breathlessness, wheeze, or chest discomfort or pain) and no alternative explanation (such as sinusitis or asthma). Pneumonia, acute bronchitis, and exacerbations of chronic obstructive airway disease are included in this definition.
National Institute for Health and Clinical Excellence
Respiratory tract infections—antibiotic prescribing: prescribing of antibiotics for self-limiting respiratory tract infections in adults and children in primary care.
Chest radiography has become an imperfect gold standard for the diagnosis of pneumonia, since it may be distorted by co-existing co-morbidities and there is inter-observer variability.
In a recent study, early multidetector computed tomography chest scans led to changes in the initial diagnosis and in patient management, both excluding and revealing pulmonary involvement.
Systematic reviews do not conclude on the real benefit of antibiotic use in exacerbations, and a randomized double-bind placebo controlled study is ongoing to demonstrate that antibiotics are not needed in moderate acute exacerbations of COPD.
ABACOPD study group Randomized double blind placebo-controlled study to demonstrate that antibiotics are not needed in moderate acute exacerbations of COPD—the ABACOPD study.
Regarding patients undergoing mechanical ventilation through an orotracheal tube or carrying a tracheostomy, surveillance endotracheal aspirate cultures are used to guide antimicrobial therapy.
In patients with ventilator-associated tracheobronchitis (VAT), antibiotic treatment has been reported to be associated with significantly lower intensive care unit (ICU) mortality and subsequent VAP rates, as well as more mechanical ventilator-free days, but this could be explained by the reduction in secretion volume and tracheobronchial inflammation,
without a significant impact on the total duration of mechanical ventilation or ICU stay. Therefore, current guidelines even suggest not providing antibiotic therapy in VAT.
Management of adults with hospital-acquired and ventilator-associated pneumonia: 2016 clinical practice guidelines by the Infectious Diseases Society of America and the American Thoracic Society.
Substantial efforts have been made to develop short-course therapies and antibiotic de-escalation.
4.2 Inflammatory biomarkers and severity scores
The inflammatory response and acute lung injury evoked by the microorganisms are determinant in the pathogenesis and outcome of LRTI. The use of systemic biomarkers has been evaluated extensively in different settings.
Single and serial measurements can be seen as a complementary tool for diagnosis, assessment of the prognosis, and antibiotic therapy decisions (use and duration),
Use of serum C reactive protein and procalcitonin concentrations in addition to symptoms and signs to predict pneumonia in patients presenting to primary care with acute cough: diagnostic study.
In addition, there are some factors that can influence biomarker secretion, such as the presence of specific co-morbidities (mostly cardiac and renal) or the use of previous antibiotic and steroid treatment. The National Institute for Health and Care Excellence guidelines recommend using the results of C-reactive protein (CRP) testing to guide antibiotic prescription in people without a clinical diagnosis of pneumonia. However, the inflammatory response may be different depending on whether the aetiology is bacterial or viral,
HAP and VAP guidelines do not include CRP, procalcitonin, or soluble triggering receptor expressed on myeloid cells 1 (sTREM-1) in algorithms for treatment decisions, although levels are used when guiding antibiotic discontinuation.
Management of adults with hospital-acquired and ventilator-associated pneumonia: 2016 clinical practice guidelines by the Infectious Diseases Society of America and the American Thoracic Society.
Severity assessed by oxygen level is not necessarily related to infection in patients with pneumopathy. Severity scores are based on clinical, radiological, and biochemical abnormalities, and relate to the risk of death, but they are not necessarily related to the infection process itself. An approach combining biomarker levels with scores
Enhancement of CURB65 score with proadrenomedullin (CURB65-A) for outcome prediction in lower respiratory tract infections: derivation of a clinical algorithm.
does improve sensitivity and specificity for the identification of high-risk patients, and thus provides a more accurate stratification.
4.3 Detection of virulence factors
Whether the infecting microorganism has to be eliminated or just become unharmful by reducing disease severity is a clinical challenge. Successful infection depends on a vast array of microbial virulence factors that are not essential for viability but are required for pathogenesis. Each physiological niche comprises specific environmental characteristics, which differentially affect bacterial gene expression, orchestrated by regulatory systems based on the QS. Some virulence factors have been considered determinant in the pathogenesis of infection, and assays including point-of-care tests have been developed to detect them.
Measurement of Pseudomonas aeruginosa phenazine pigments in sputum and assessment of their contribution to sputum sol toxicity for respiratory epithelium.
However, the role of Panton–Valentine leukocidin from S. aureus in necrotizing pneumonia caused by USA300 strains has been the subject of controversy, since other factors from the core genome, such as phenol soluble modulins (PSM) or alpha-haemolysin, may contribute to virulence.
Co-expression of several factors simultaneously or sequentially is most likely.
Virulence factors from S. pneumoniae that have been used for the development of diagnostic methods or as vaccine antigens include pneumolysin, essential for the survival of the microorganism in both the upper and lower respiratory tract,
but also lectins, exotoxins, or elastase. Lipopolysaccharide is the most important immune-stimulator in Gram-negative bacteria and tests to detect endotoxin have been developed.
Endotoxin activity levels as a prediction tool for risk of deterioration in patients with sepsis not admitted to the intensive care unit: a pilot observational study.
has been associated with an improved outcome. All of these virulence factors could be regarded as potential targets for treatment, but the diagnostic role of serum antibody detection is still not clear.
5. Studies needed to understand the host–pathogen interaction
Daily clinical observation is the first step when assessing a patient's response to infection. Large observational studies are required to clearly define the epidemiology and natural history of respiratory infections and to assess whether microbial factors in combination with clinical and epidemiological features correlate with asymptomatic carriage or increase the risk of an adverse outcome. In this sense, the New Drugs for Bad Bugs (ND4BB) programme, an Innovative Medicines Initiative, has the ultimate goal of boosting the fight against antimicrobial resistance through basic science and drug discovery, as well as clinical development and the responsible use of antibiotics.
The Innovative Medicines Initiative's New Drugs for Bad Bugs programme: European public–private partnerships for the development of new strategies to tackle antibiotic resistance.
The genetic variations among individual isolates and variations in susceptibility among different individuals creates a spectrum of interactive events that may shift the balance towards commensalism or towards disease.
Adequate in vitro cell models and animal models close to the clinical situation are critical, including real-time imaging within specific organs, such as the lungs, and mathematical modelling.
Novel high-throughput sequencing technologies (next-generation sequencing, NGS), although producing copious ‘big data’, open up new possibilities for analysis of genome-wide associations and functional genomic approaches and provide insights into bacterial evolution and disease aetiology.
Persistent Staphylococcus aureus isolates from two independent cases of bacteremia display increased bacterial fitness and novel immune evasion phenotypes.
Our capacity to acquire ‘omics’ data about infections is increasing exponentially, and substantial efforts in bioinformatic and systems biology approaches are needed to connect data into a pipeline and make it manageable. The objective would be to integrate NGS with electronic medical records, immune profiling data, and other datasets to create multiscale predictive models that may help not only to combine properties associated with disease, but also to improve antimicrobial stewardship.
. Metabolomics and secretomics in accessible clinical samples may assess host–pathogen interactions, because metabolites are seen as terminal downstream end products, whose presence and concentration reflect changes occurring at the gene, transcription, and translation level.
Systematic review regarding metabolic profiling for improved pathophysiological understanding of disease and outcome prediction in respiratory infections.
and should help in understanding the switch from carriage to infection.
6. Novel therapeutic approaches
Over-prescription of antibiotics in respiratory tract infections must be reduced by identifying the correct indications, as discussed above, but also optimizing the antimicrobial of choice and the duration of treatment. Also, pharmacokinetic/pharmacodynamic (PK/PD) optimized dosing and de-escalation are strategies to combat resistance.
Management of adults with hospital-acquired and ventilator-associated pneumonia: 2016 clinical practice guidelines by the Infectious Diseases Society of America and the American Thoracic Society.
In terms of novel developments, the pharmaceutics pipeline is becoming less productive. However, there is better knowledge of natural product biosynthesis and new approaches for the development of synthetic compounds with improved antibiotic properties,
Furthermore, there is a need for more imaginative ways of administering treatment. Figure 2 summarizes key factors for the improvement of antimicrobial options in LRTI.
Figure 2Future approaches for the treatment of respiratory tract infections: description of alternatives.
As a general principle, the antimicrobial of choice has to be appropriate (pathogen is susceptible) and adequate (high enough level of the drug at the site of infection). For the first aspect, pathogen-directed therapy guided by in vitro microbiological data is a safe approach;
as an example, penicillins are still the first option for S. pneumoniae in many settings. For the second aspect, as is obvious, a prerequisite for antimicrobial activity is that the bacteria and antibiotics come into contact in the same compartment. Due to the unique structure of the lung, it is not always possible to deliver microbiologically active concentrations of antimicrobials to the appropriate parts.
pH, or enzymes. Activity studies are based on serum concentrations, but distribution into the pulmonary tissue may be insufficient. This may also be the case in anatomical cavities and areas of collapse or oedema, as well as in bacterial infections with evidence of biofilm formation and co-localization in intracellular compartments, where it will depend on cellular drug accumulation and subcellular distribution.
An adequate duration of therapy is crucial not only to prevent the development of resistance, but also the development of persistent phenotypes, which have a different in vitro susceptibility profile.
6.2 Intracellular targeting
Because of potential simultaneous intracellular and extracellular bacterial foci and different metabolic states, targeting the mechanisms of bacterial adaptation to the intracellular environment represents a novel therapeutic strategy. Combined therapies may have a role, in a similar way as in tuberculosis and as hypothesized for systemic
Intracellular proliferation of S. aureus in osteoblasts and effects of rifampicin and gentamicin on S. aureus intracellular proliferation and survival.
There are substantial differences in PK/PD properties of the different classes of antibiotics. In general, beta-lactams, aminoglycosides, and vancomycin have restricted cellular penetration owing to their high hydrophobicity. On the other hand, although fluoroquinolones and macrolides diffuse well into cells, they display low intracellular retention.
Study of macrophage functions in murine J774 cells and human activated THP-1 cells exposed to oritavancin, a lipoglycopeptide with high cellular accumulation.
and, interestingly, MRSA can become methicillin-susceptible when intracellular because penicillin binding protein 2a (PBP2a) is modified by an acidic pH.
Restoration of susceptibility of methicillin-resistant Staphylococcus aureus to beta-lactam antibiotics by acidic pH: role of penicillin-binding protein PBP 2a.
Nowadays it is possible to encapsulate, incorporate, or even conjugate biologically active molecules into different families of nanocarriers such as liposomes or nanoparticles. The encapsulation of antibiotics may allow directed therapy preventing the disruption of the commensal microbiota. Optimal nanocarriers need to be biocompatible and biodegradable and able to deliver the drug to the correct place and at a therapeutic concentration, and must not burst and release the encapsulated drug before reaching the target site. Drug delivery platforms include among others liposomes, micelles, and nanotubes and polymeric nanoparticles.
Among nanodevices, liposomal formulations are the best known and most widely investigated. It is feasible to manipulate the composition: indeed it is possible to change the size, surface charge, sensitivity to pH or temperature, and even make them more suitable for hydrophobic or water-soluble molecules, respectively. Delivery may be through inhalation, such as liposomal amikacin for P. aeruginosa in cystic fibrosis
and mycobacterial infections. Alternatively, passive targeting may be preferred, such as blood long circulating nanocarriers that delay hepatosplenic clearance in order to favour extravasation towards infected tissues, such as the lungs, as well as reaching optimal intracellular concentrations (i.e., vancomycin).
Another approach is functionalized nanoparticles with on–off demand drug release, which occurs only when the loaded nanoparticle comes into contact with the specific bacterial secreted toxins,
The most important advantages are a reduction in side effects, improved drug solubility for intravenous administration, and reduced frequency of administration.
Among polymeric compounds, the copolymers of poly(lactide-co-glycolide) are of particular interest since they are biologically tolerable, may be able to cross the intestinal barrier, and are metabolized via normal metabolic pathways.
Alfaro S, Larrea A, Mendoza G, Lacoma A, Sebastian V, Ainsa J, et al. Oral administration of antibiotic loaded nanoparticles able to cross the intestinal barrier to treat intracellular pathogens. Poster Communication. 49th Congress of the Spanish Society of Pneumology and Thoracic Surgery; 2016.
Management of adults with hospital-acquired and ventilator-associated pneumonia: 2016 clinical practice guidelines by the Infectious Diseases Society of America and the American Thoracic Society.
Colistin, discovered more than 50 years ago, has been almost forgotten for decades due to its high toxicity, inducing neuronal or kidney damage in up to half of patients, but nebulized therapy has allowed its resurgence.
Important issues are the optimal method of drug delivery and the different interpretation of minimum inhibitory concentration.
Not all types of nebulizer deliver aerosol particles with the same efficiency. There are several approaches, mostly in the treatment of cystic fibrosis, where treatment with inhaled antibiotics (tobramycin, colistin, or aztreonam lysine) is indicated for chronic lung infection with P. aeruginosa, as well as the use of azithromycin and ciprofloxacin dry powder.
The Innovative Medicines Initiative's New Drugs for Bad Bugs programme: European public–private partnerships for the development of new strategies to tackle antibiotic resistance.
Use of adjunctive aerosolized antimicrobial therapy in the treatment of Pseudomonas aeruginosa and Acinetobacter baumannii ventilator-associated pneumonia.
Management of adults with hospital-acquired and ventilator-associated pneumonia: 2016 clinical practice guidelines by the Infectious Diseases Society of America and the American Thoracic Society.
Inflammation of the airways and/or the lung tissue is crucial for the secondary damage that determines signs and symptoms and defines the switch from colonization to infection. The use of systemic bactericidal drugs may not be superior to bacteriostatic agents because bacterial lysis releases large amounts of cell wall and cytosolic toxins with a consequent excessive inflammatory reaction. For instance, inhibitors of protein synthesis such as clindamycin, rifampicin, and linezolid also inhibit toxin production and could become beneficial
Linezolid dampens neutrophil-mediated inflammation in methicillin-resistant Staphylococcus aureus-induced pneumonia and protects the lung of associated damages.
Effects of subinhibitory concentrations of antibiotics on virulence factor expression by community-acquired methicillin-resistant Staphylococcus aureus.
an alternative approach to conventional antimicrobials, aimed at killing the bacteria (as are almost all available antibiotics), is based on targeting the functions essential for infection, such as virulence factors required to cause host damage and disease, without impairing microbial growth. Although antibody therapies in the form of serum were the first effective antimicrobials, the use of purified monoclonal antibodies (mAb) has only recently reached the field of infectious diseases.
This approach expands the repertoire of bacterial targets, preserving the host endogenous microbiome, and exerting less selective pressure, which may result in a decreased development of antibiotic resistance,
Antibodies binding virulence factors are considered one of the alternative approaches most likely to have a major clinical impact and there are already several products undergoing clinical evaluation in phase 2 trials, mostly targeting S. aureus and P. aeruginosa.
mAbs towards alginate, a cell surface polysaccharide, have been used for hospital-acquired VAP. Finally, a multifunctional bispecific antibody against type III secretion system virulence factor PcrV and persistence factor Psl exopolysaccharide is also under evaluation.
They can be used alone or as adjuncts to current antimicrobial therapy and will be effective in hosts with different states of immunity, so could be used as immunoprophylaxis or adjunctive therapy.
Adjuvants can be used in conjunction with antibiotics used to potentiate the effects of antimicrobials and also include anti-resistance drugs such as novel beta-lactamase inhibitors, efflux pump inhibitors, and outer membrane permeabilizers.
Bacteriophages were used extensively to treat bacterial infections in the former Soviet Union. A resurgence of phage development is now being observed as a result of many antimicrobials being less useful due to the emergence of multidrug resistance.
Phage therapy for pulmonary infections is interesting because delivery can be topical and/or systemic.
Topical application avoids the losses associated with absorption and distribution, increasing the potential for local achievement, including delivery as aerosols into the lungs.
that cleave the major bond types in the peptidoglycan by specific cell wall hydrolysis. Currently available evidence still supports the notion that even lysins with a wider range of antimicrobial activity would exert a less dramatic effect on the normal microbiota than conventional antibiotics. It is feasible to construct new and more lethal phage lysins from modified pre-existing enzymes that are active against Gram-positive species, which lack the impermeable lipopolysaccharide layer surrounding their cell wall.
Recently, endolysins have been modified by protein engineering to create outer membrane-penetrating endolysins (artilysins), rendering them highly bactericidal against Gram-negative pathogens, including P. aeruginosa and Acinetobacter baumannii.
There is also a second category of phage-encoded enzymes (EPS depolymerases) that digest the extracellular polymeric substance (EPS), a particularly notable component of bacterial biofilms, so they act by reducing bacterial density of a diversity of biofilms.
Surfactant can assist in the delivery of an antimicrobial peptide into the lung, as recently tested against MRSA and P. aeruginosa as proof of concept,
The management of infections, as for many other pathologies, requires a multidisciplinary approach. Such an approach is better established in other clinical situations such as oncology. For the management of respiratory tract infections including tuberculosis, the role of the medical specialist in charge of the patient has to be complemented by adequate communication with radiologist and microbiologist experts. Nowadays novel diagnostic methods allow the rapid and accurate detection and identification of microorganisms in most cases, but careful interpretation is needed. The role of the clinical microbiologist includes giving advice regarding the selection of adequate samples to be drawn and the diagnostic method to be used, the interpretation of results, and a consensus for the optimal treatment. In times of laboratory centralization, fluent communication between specialists is even more crucial, and working teams to elaborate protocols and to discuss conflicting results are needed, reaching not only hospital specialists but also general practitioners. A permanent exchange of knowledge between the different specialists is crucial to acquire expertise and finally to improve management.
There is increasing evidence that treatment is only required when the microorganism is really causing airway or tissue injury. Understanding the host–pathogen interaction that contributes to persistence and dissemination during colonization and infection has to result in the proposal of a prudent treatment indication. In our opinion, the option not to treat has to be one of the potential decisions based on clinical, radiographic, and microbiological data, as well as data obtained from novel diagnostic methods based on the detection of the inflammatory response and virulence pathogenesis. Regarding how to treat, novel therapeutic targets based on virulence factors, as well as new means of administration, dosages, and combinations of antimicrobials and adjuvants, will contribute to reduce the adverse side effects and the emergence of drug resistance and provide an effective delivery to the site of infection.
Acknowledgements
We would like to acknowledge Vicente Ausina (Servei de Microbiologia, Hospital Universitari Germans Trias i Pujol, Badalona, Spain), Manuel Arruebo (Nanostructured Films and Particles Group, Instituto de Nanociencia de Aragón, Universidad de Zaragoza, Spain), and Iñigo Lasa (Laboratory of Microbial Biofilms, Instituto de Agrobiotecnología, Universidad Pública de Navarra/CSIC, Spain) for a critical review of the manuscript. We thank Carlos Rodrigo (Paediatrics), Montse Gimenez (Microbiology), Juan Ruiz-Manzano (Pneumology), Pere Tudela (Internal Medicine), Alicia Marin (Pneumology), and Fernando Arméstar (Intensive Care) for daily clinical discussions and knowledge exchange that contribute to the management of respiratory tract infections.
Funding: This work has been funded by the project PI13/01418 which is part of “Plan Nacional de I+D +I” and co-funded by ISCIII- Subdirección General de Evaluación and “Fondo Europeo de Desarrollo Regional” (FEDER). This work also received a grant of the Spanish Society of Pneumology and Thoracic Surgery (SEPAR 054/2011). None of the funding entities had a role in the study design, in the collection, analysis, and interpretation of data, in the writing of the manuscript, or in the decision to submit the manuscript for publication.
Ethical approval: Ethical approval was not required.
Conflict of interest: Both authors declare no competing interests.
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Commensal pathogens, with a focus on Streptococcus pneumoniae, and interactions with the human host.
National Institute for Health and Clinical Excellence
Respiratory tract infections—antibiotic prescribing: prescribing of antibiotics for self-limiting respiratory tract infections in adults and children in primary care.
Management of adults with hospital-acquired and ventilator-associated pneumonia: 2016 clinical practice guidelines by the Infectious Diseases Society of America and the American Thoracic Society.
Intracellular replication of Staphylococcus aureus in mature phagolysosomes in macrophages precedes host cell death, and bacterial escape and dissemination.
Effects of subinhibitory concentrations of antibiotics on virulence factor expression by community-acquired methicillin-resistant Staphylococcus aureus.
Randomized double blind placebo-controlled study to demonstrate that antibiotics are not needed in moderate acute exacerbations of COPD—the ABACOPD study.
Use of serum C reactive protein and procalcitonin concentrations in addition to symptoms and signs to predict pneumonia in patients presenting to primary care with acute cough: diagnostic study.
Enhancement of CURB65 score with proadrenomedullin (CURB65-A) for outcome prediction in lower respiratory tract infections: derivation of a clinical algorithm.
Measurement of Pseudomonas aeruginosa phenazine pigments in sputum and assessment of their contribution to sputum sol toxicity for respiratory epithelium.
Endotoxin activity levels as a prediction tool for risk of deterioration in patients with sepsis not admitted to the intensive care unit: a pilot observational study.
The Innovative Medicines Initiative's New Drugs for Bad Bugs programme: European public–private partnerships for the development of new strategies to tackle antibiotic resistance.
Persistent Staphylococcus aureus isolates from two independent cases of bacteremia display increased bacterial fitness and novel immune evasion phenotypes.
Systematic review regarding metabolic profiling for improved pathophysiological understanding of disease and outcome prediction in respiratory infections.
Intracellular proliferation of S. aureus in osteoblasts and effects of rifampicin and gentamicin on S. aureus intracellular proliferation and survival.
Study of macrophage functions in murine J774 cells and human activated THP-1 cells exposed to oritavancin, a lipoglycopeptide with high cellular accumulation.
Restoration of susceptibility of methicillin-resistant Staphylococcus aureus to beta-lactam antibiotics by acidic pH: role of penicillin-binding protein PBP 2a.
Alfaro S, Larrea A, Mendoza G, Lacoma A, Sebastian V, Ainsa J, et al. Oral administration of antibiotic loaded nanoparticles able to cross the intestinal barrier to treat intracellular pathogens. Poster Communication. 49th Congress of the Spanish Society of Pneumology and Thoracic Surgery; 2016.
Use of adjunctive aerosolized antimicrobial therapy in the treatment of Pseudomonas aeruginosa and Acinetobacter baumannii ventilator-associated pneumonia.
Linezolid dampens neutrophil-mediated inflammation in methicillin-resistant Staphylococcus aureus-induced pneumonia and protects the lung of associated damages.
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