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      Characteristics of an ideal nebulized antibiotic for the treatment of pneumonia in the intubated patient

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          Abstract

          Gram-negative pneumonia in patients who are intubated and mechanically ventilated is associated with increased morbidity and mortality as well as higher healthcare costs compared with those who do not have the disease. Intravenous antibiotics are currently the standard of care for pneumonia; however, increasing rates of multidrug resistance and limited penetration of some classes of antimicrobials into the lungs reduce the effectiveness of this treatment option, and current clinical cure rates are variable, while recurrence rates remain high. Inhaled antibiotics may have the potential to improve outcomes in this patient population, but their use is currently restricted by a lack of specifically formulated solutions for inhalation and a limited number of devices designed for the nebulization of antibiotics. In this article, we review the challenges clinicians face in the treatment of pneumonia and discuss the characteristics that would constitute an ideal inhaled drug/device combination. We also review inhaled antibiotic options currently in development for the treatment of pneumonia in patients who are intubated and mechanically ventilated.

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          Most cited references 57

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          What the pulmonary specialist should know about the new inhalation therapies.

          A collaboration of multidisciplinary experts on the delivery of pharmaceutical aerosols was facilitated by the European Respiratory Society (ERS) and the International Society for Aerosols in Medicine (ISAM), in order to draw up a consensus statement with clear, up-to-date recommendations that enable the pulmonary physician to choose the type of aerosol delivery device that is most suitable for their patient. The focus of the consensus statement is the patient-use aspect of the aerosol delivery devices that are currently available. The subject was divided into different topics, which were in turn assigned to at least two experts. The authors searched the literature according to their own strategies, with no central literature review being performed. To achieve consensus, draft reports and recommendations were reviewed and voted on by the entire panel. Specific recommendations for use of the devices can be found throughout the statement. Healthcare providers should ensure that their patients can and will use these devices correctly. This requires that the clinician: is aware of the devices that are currently available to deliver the prescribed drugs; knows the various techniques that are appropriate for each device; is able to evaluate the patient's inhalation technique to be sure they are using the devices properly; and ensures that the inhalation method is appropriate for each patient.
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            Ventilator-associated pneumonia in the ICU

            Introduction Ventilator-associated pneumonia (VAP) is defined as pneumonia that occurs 48-72 hours or thereafter follow¬ing endotracheal intubation, characterized by the pre¬sence of a new or progressive infiltrate, signs of systemic infection (fever, altered white blood cell count), changes in sputum characteristics, and detection of a causative agent [1]. VAP contributes to approximately half of all cases of hospital-acquired pneumonia [1], [2]. VAP is estimated to occur in 9-27 % of all mechanically ventilated patients, with the highest risk being early in the course of hospitalization [1], [3]. It is the second most common nosocomial infection in the intensive care unit (ICU) and the most common in mechanically ventilated patients [4], [5]. VAP rates range from 1.2 to 8.5 per 1,000 ventilator days and are reliant on the definition used for diagnosis [6]. Risk for VAP is greatest during the first 5 days of mechanical ventilation (3 %) with the mean duration between intubation and development of VAP being 3.3 days [1], [7]. This risk declines to 2 %/day between days 5 to 10 of ventilation, and 1 %/day thereafter [1], [8]. Earlier studies placed the attributable mortality for VAP at between 33-50 %, but this rate is variable and relies heavily on the underlying medical illness [1]. Over the years, the attributable risk of death has decreased and is more recently estimated at 9-13 % [9], [10], largely because of implementation of preventive strategies. Approximately 50 % of all antibiotics adminis¬tered in ICUs are for treatment of VAP [2], [4]. Early onset VAP is defined as pneumonia that occurs within 4 days and this is usually attributed to antibiotic sensitive pathogens whereas late onset VAP is more likely caused by multidrug resistant (MDR) bacteria and emerges after 4 days of intubation [1], [4]. Thus, VAP poses grave implications in endotracheally intubated adult patients in ICUs worldwide and leads to increased adverse outcomes and healthcare costs. Independent risk factors for development of VAP are male sex, admission for trauma and intermediate underlying disease severity, with odds ratios (OR) of 1.58, 1.75 and 1.47-1.70, respectively [7]. Pathogenesis The complex interplay between the endotracheal tube, presence of risk factors, virulence of the invading bacteria and host immunity largely determine the development of VAP. The presence of an endotracheal tube is by far the most important risk factor, resulting in a violation of natural defense mechanisms (the cough reflex of glottis and larynx) against micro aspiration around the cuff of the tube [4], [11]. Infectious bacteria obtain direct access to the lower respiratory tract via: (1) micro aspiration, which can occur during intubation itself; (2) development of a biofilm laden with bacteria (typically Gram-negative bacteria and fungal species) within the endotracheal tube; (3) pooling and trickling of secretions around the cuff; and (4) impairment of mucociliary clearance of secretions with gravity dependence of mucus flow within the airways [11-13]. Pathogenic material can also collect in surrounding anatomic structures, such as the stomach, sinuses, nasopharynx and oropharynx, with replacement of normal flora by more virulent strains [11], [12], [14]. This bacterium-enriched material is also constantly thrust forward by the positive pressure exerted by the ventilator. Whereas reintubation following extubation increases VAP rates, the use of non-invasive positive pressure ventilation has been associated with significantly lower VAP rates [4]. Host factors such as the severity of underlying disease, previous surgery and antibiotic exposure have all been implicated as risk factors for development of VAP [1]. In addition, it has recently been noted that critically ill patients may have impaired phagocytosis and behave as functionally immunosuppressed even prior to emergence of nosocomial infection [4], [15], [16]. This effect is attributed to the detrimental actions of the anaphylatoxin, C5a, which impairs neutrophil phagocytic activity and impairs phagocytosis by neutrophils [15]. More recently, a combined dysfunction of T-cells, monocytes, and neu¬trophils has been noted to predict acquisition of noso¬comial infection [16]. For example, elevation of regula¬tory T-cells (Tregs), monocyte deactivation (measured by monocyte HLA-DR expression) and neutrophil dysfunc¬tion (measured by CD88 expression), have cumulatively shown promise in predicting infection in the critically ill population, as compared to healthy controls [16]. Microbiology The type of organism that causes VAP usually depends on the duration of mechanical ventilation. In general, early VAP is caused by pathogens that are sensitive to anti¬biotics, whereas late onset VAP is caused by multi-drug resistant and more difficult to treat bacteria. However, this is by no means a rule and merely a guide to initiate antibiotic therapy until further clinical information is available. Typically, bacteria causing early-onset VAP include Streptococcus pneumoniae (as well as other streptococcus species), Hemophilus influenzae, methicillin-sensitive Staphylococcus aureus (MSSA), antibiotic-sensitive enteric Gram-negative bacilli, Escherichia coli, Klebsiella pneumonia, Enterobacter species, Proteus species and Serratia marcescens. Culprits of late VAP are typically MDR bacteria, such as methicillin-resistant S. aureus(MRSA), Acinetobacter, Pseudomonas aeruginosa, and extended-spectrum beta-lactamase producing bacteria (ESBL) [4]. The exact prevalence of MDR organisms is variable between institutions and also within institutions [1]. Patients with a history of hospital admission for ≥ 2 days in the past 90 days, nursing home residents, patients receiving chemotherapy or antibiotics in the last 30 days and patients undergoing hemodialysis at out¬patient centers are susceptible to drug resistant bacteria [1], [4]. Commonly found bacteria in the oropharynx can attain clinically significant numbers in the lower airways. These bacteria include Streptococcus viridans, Coryne-bacterium, coagulase-negative staphylococcus (CNS) and Neisseria species. Frequently, VAP is due to polymicrobial infection. VAP from fungal and viral causes has a very low incidence, especially in the immunocompetent host [1]. Pathogens causing VAP, their frequency (in paren¬thesis) and their possible mode of multi-drug resistance, if any, are listed below [1-3]: 1. Pseudomonas (24.4 %): Upregulation of efflux pumps, decreased expression of outer membrane porin channel, acquisition of plasmid-mediated metallo-beta-lactamases. 2. S. aureus (20.4 %, of which > 50 % MRSA): Production of a penicillin-binding protein (PBP) with reduced affinity for beta-lactam antibiotics. Encoded by the mecA gene. 3. Enterobacteriaceae (14.1 % -includes Klebsiella spp., E. coli, Proteus spp., Enterobacter spp., Serratia spp., Citrobacter spp.): Plasmid mediated production of ESBLs, plasmid-mediated AmpC-type enzyme. 4. Streptococcus species (12.1 %). 5. Hemophilus species (9.8 %). 6. Acinetobacter species (7.9 %): Production of metallo-enzymes or carbapenemases. 7. Neisseria species (2.6 %). 8. Stenotrophomonas maltophilia (1.7 %). 9. Coagulase-negative staphylococcus (1.4 %). 10. Others (4.7 % -includes Corynebacterium, Moraxella, Enterococcus, fungi). Diagnosis At the present time, there is no universally accepted, gold standard diagnostic criterion for VAP. Several clinical methods have been recommended but none have the needed sensitivity or specificity to accurately identify this disease [17]. Daily bedside evaluation in conjunction with chest radiography can only be suggestive of the presence or absence of VAP, but not define it [18]. Clinical diagnosis of VAP can still miss about a third of VAPs in the ICU compared to autopsy findings and can incorrectly diagnose more than half of patients, likely due to poor interobserver agreement between clinical criteria [8], [18], [19]. Postmortem studies comparing VAP diag¬nosis with clinical criteria showed 69 % sensitivity and 75 % specificity, in comparison to autopsy findings [20]. The American Thoracic Society (ATS) and the Infectious Diseases Society of America (IDSA) guidelines recommend obtaining lower respiratory tract samples for culture and microbiology [1]. Analysis of these samples can be quantitative or qualitative. This guideline also allows use of tracheal aspirates for their negative predictive value (94 % for VAP). Johanson et al. described clinical criteria for diagnosis of VAP as follows [21]: The clinical pulmonary infection score (CPIS) takes into account clinical, physiological, microbiological and radiographic evidence to allow a numerical value to predict the presence or absence of VAP (Table 1) [18], [22]. Scores can range between zero and 12 with a score of ≥ 6 showing good correlation with the presence of VAP [22]. Despite the clinical popularity of the CPIS, debate continues regarding its diagnostic validity. One meta¬analysis of 13 studies evaluating the accuracy of CPIS in diagnosing VAP reported pooled estimates for sensitivity and specificity for CPIS as 65 % (95 % CI 61-69 %) and 64 % (95 % CI 60-67 %), respectively [23]. Despite its apparent straightforward calculation, the inter-observer variability in CPIS calculation remains substantial, jeopardizing its routine use in clinical trials [24]. Of all the criteria used to calculate the CPIS, only time-dependent changes in the PaO2/FiO2 ratio early in VAP may provide some predictive power for VAP outcomes in clinical trials, namely clinical failure and mortality [25]. However, a trial by Singh and colleagues [26] demonstrated that the CPIS is an effective clinical tool for determining whether to stop or continue antibiotics for longer than 3 days. In that study, antibiotics were discontinued at day 3 for patients who had been random¬ized to receive ciprofloxacin instead of standard of care, if their CPIS remained ≤ 6. Mortality and length of ICU stay did not differ despite a shorter duration (p = 0.0001) and lower cost (p = 0.003) of antimicrobial therapy in the experimental as compared with the standard therapy arm, and the development of antimicrobial resistance was lower among patients whose antibiotics were discontinued compared to those who received standard of care. 1. New or progressive radiographic consolidation or infiltrate. In addition, at least 2 of the following: 2. Temperature > 38 °C 3. Leukocytosis (white blood cell count ≥ 12,000 cells/ mm3) or leukopenia (white blood cell count 11,000/mm3 1 ≥ 500 Band cells 2 Tracheal secretions (subjective visual scale) None 0 Mild/non-purulent 1 Purulent 2 Radiographic findings (on chest radiography, excluding CHF and ARDS) No infiltrate 0 Diff use/patchy infiltrate 1 Localized infiltrate 2 Culture results (endotracheal aspirate) No or mild growth 0 Moderate or florid growth 1 Moderate or florid growth AND pathogen consistent with Gram stain 2 Oxygenation status (defined by PaO2:FiO2) > 240 or ARDS 0 ≤ 240 and absence of ARDS 2 ARDS: acute respiratory distress syndrome; CHF: congestive heart failure Respiratory samples can be obtained using several techniques: The ATS/IDSA guidelines note that use of a bronchoscopic bacteriologic strategy has been shown to reduce 14-day mortality when compared with a clinical strategy (16.2 % vs. 25.8 %, p = 0.02) [1]. When samples are obtained by BAL techniques (BAL, mini-BAL or PSB), the diagnostic threshold is 103 colony forming units (cfu)/ml for protected specimen brushing and 104 cfu/ml for BAL. In one multicenter study, BAL-and PSB-based diagnosis was associated with significantly more antibiotic-free days (11.5 ± 9.0 vs. 7.5 ± 7.6, p 4 days) requires broad spectrum antibiotics whereas early onset (≤ 4 days) can be treated with limited spectrum antibiotics [1]. An updated local antibiogram for each hospital and each ICU based on local bacteriological patterns and susceptibilities is essential to guide optimally dosed initial empiric therapy [1]. With any empiric antibiotic regimen, de-escalation is the key to reduce emergence of resistance [33]. Delays in initiation of antibiotic treatment may add to the excess mortality risk with VAP [1]. Tables 2 and 3 highlight the recom¬mended treatment regimens for VAP. Owing to the high rate of resistance to monotherapy observed with P .aeruginosa, combination therapy is always recommended. Acinetobacter species respond best to carbapenems (also active against ESBL positive Enterobacteriaceae), colistin, polymyxin B and ampicillin/sulbactam [36], [37]. Although MDR organisms are usually associated with late-onset VAP, recent evidence suggests that they are increasingly associated with early-onset VAP as well [37], [38]. The role of inhaled antibiotics in the setting of failure of systemic antibiotics is unclear [1]. The usual duration of treatment for early-onset VAP is 8 days and longer in the case of late-onset VAP or if MDR organisms are suspected or identified [39-41]. Table 2 Comparison of recommended initial empiric therapy for ventilator-associated pneumonia (VAP) according to time of onset [1], [34], [41] Early-onset VAP Late-onset VAP Second or third generation cephalosporin: e. g., ceftriaxone: 2 g daily; Cephalosporin cefuroxime: 1.5 g every 8 hours; e. g., cefepime: 1-2 g every 8 hours; cefotaxime: 2 g every 8 hours ceftazidime 2 g every 8 hours OR OR Fluoroquinolones Carbepenem e. g., levofloxacin: 750 mg daily; e. g., imipenem + cilastin: 500 mg every 6 hours or 1 g every 8 hours; moxifloxacin: 400 mg daily meropenem: 1 g every 8 hours OR OR Aminopenicillin + beta-lactamase inhibitor e. g., ampicillin + sulbactam: 3 g Beta-lactam/beta-lactamase inhibitor every 8 hours e. g., piperacillin + tazobactam: 4.5 g every 6 hours OR PLUS Ertapenem Aminoglycoside 1 g daily e. g., amikacin: 20 mg/kg/day; gentamicin: 7 mg/kg/day; tobramycin: 7 mg/kg/day OR Antipseudomonal fluoroquinolone e. g., ciprofloxacin 400 mg every 8 hours; levofloxacin 750 mg daily PLUS Coverage for MRSA e. g., vancomycin: 15 mg/kg every 12 hours OR linezolid: 600 mg every 12 hours Optimal dosage includes adjusting for hepatic and renal failure. Trough levels for vancomycin (15-20 mcg/ml), amikacin ( 6 may correlate with VAP, the sensitivity, specificity and inter-rater agreement of this criterion alone are not encouraging. Microbiological data should be used for tailoring antibiotic therapy and not be restricted only to diagnosis. The pitfall in using empiric antibiotics for suspicion of VAP is the potential for antibiotic overuse, emergence of resistance, unnecessary adverse effects and potential toxicity. The major goals of VAP management are early, appropriate antibiotics in adequate doses followed by de-escalation based on microbiological culture results and the clinical response of the patient. Antimicrobial stewardship programs involving pharmacists, physicians and other healthcare providers optimize antibiotic selection, dose, and duration to increase efficacy in targeting causative pathogens and allow the best clinical outcome. List of abbreviations used ARDS: acute respiratory distress syndrome; ATS: American Thoracic Society; BAL: Bronchoalveolar lavage; CDC: Centers for Disease Control and Prevention; CHF: congestive heart failure; CI: confidence interval; CNSL coagulase-negative staphylococcus; CPIS: clinical pulmonary infection score; ESBL: extended-spectrum beta-lactamase producing bacteria (ESBL); FiO2: fraction of inspired oxygen; ICU: intensive care unit; IVAC: infection-related ventilator-associated complication; IDSA: Infectious Diseases Society of America; MDR: multi drug resistant; Mini-BAL-mini-bronchoalvelolar lavage; MRSA: methicillin-resistant Staphylococcus aureus; MSSA: methicillin-senstive Staphylococcus aureus; OR: odds ratios; PBP: penicillin-binding protein; PEEP: positive end-expiratory pressure; PSB: protected specimen brush; Tregs: regulatory T-cells; VAP: ventilator-associated pneumonia. Competing interests The authors declare that they have no competing interests.
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              The effect of pathophysiology on pharmacokinetics in the critically ill patient--concepts appraised by the example of antimicrobial agents.

              Critically ill patients are at high risk for development of life-threatening infection leading to sepsis and multiple organ failure. Adequate antimicrobial therapy is pivotal for optimizing the chances of survival. However, efficient dosing is problematic because pathophysiological changes associated with critical illness impact on pharmacokinetics of mainly hydrophilic antimicrobials. Concentrations of hydrophilic antimicrobials may be increased because of decreased renal clearance due to acute kidney injury. Alternatively, antimicrobial concentrations may be decreased because of increased volume of distribution and augmented renal clearance provoked by systemic inflammatory response syndrome, capillary leak, decreased protein binding and administration of intravenous fluids and inotropes. Often multiple conditions that may influence pharmacokinetics are present at the same time thereby excessively complicating the prediction of adequate concentrations. In general, conditions leading to underdosing are predominant. Yet, since prediction of serum concentrations remains difficult, therapeutic drug monitoring for individual fine-tuning of antimicrobial therapy seems the way forward.
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                Author and article information

                Contributors
                +39 0432 559353 , mattba@tin.it
                +33 (0)1 42 16 38 24 , charles-edouard.luyt@psl.aphp.fr
                +1 860-972-3941 , david.nicolau@hhchealth.org
                +41 22 372 9236 , jerome.pugin@unige.ch
                Journal
                Ann Intensive Care
                Ann Intensive Care
                Annals of Intensive Care
                Springer Paris (Paris )
                2110-5820
                18 April 2016
                18 April 2016
                2016
                : 6
                Affiliations
                [ ]Infectious Diseases Clinic, Santa Maria Misericordia University Hospital, Udine, Italy
                [ ]Service de Réanimation, Institut de Cardiologie, Groupe Hospitalier Pitié–Salpêtrière, Assistance Publique–Hôpitaux de Paris, Paris, France
                [ ]Sorbonne Universités, UPMC Université Paris 06, INSERM, UMRS_1166-ICAN Institute of Cardiometabolism and Nutrition, Paris, France
                [ ]Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, USA
                [ ]Service des Soins Intensifs, University Hospitals of Geneva and Faculty of Medicine, University of Geneva, Geneva, Switzerland
                Article
                140
                10.1186/s13613-016-0140-x
                4835402
                27090532
                © Bassetti et al. 2016

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

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