Nebulized Colistin in Ventilator-Associated Pneumonia and Tracheobronchitis: Historical Background, Pharmacokinetics and Perspectives

Colistin; Phramacokinetic; Technique of nebulizationColistina; Farmacocinètica; Tècnica de nebulitzacióColistina; Farmacocinético; Técnica de nebulizaciónClinical evidence suggests that nebulized colistimethate sodium (CMS) has benefits for treating lower respiratory tract infections caused by multidrug-resistant Gram-negative bacteria (GNB). Colistin is positively charged, while CMS is negatively charged, and both have a high molecular mass and are hydrophilic. These physico-chemical characteristics impair crossing of the alveolo-capillary membrane but enable the disruption of the bacterial wall of GNB and the aggregation of the circulating lipopolysaccharide. Intravenous CMS is rapidly cleared by glomerular filtration and tubular excretion, and 20–25% is spontaneously hydrolyzed to colistin. Urine colistin is substantially reabsorbed by tubular cells and eliminated by biliary excretion. Colistin is a concentration-dependent antibiotic with post-antibiotic and inoculum effects. As CMS conversion to colistin is slower than its renal clearance, intravenous administration can lead to low plasma and lung colistin concentrations that risk treatment failure. Following nebulization of high doses, colistin (200,000 international units/24h) lung tissue concentrations are > five times minimum inhibitory concentration (MIC) of GNB in regions with multiple foci of bronchopneumonia and in the range of MIC breakpoints in regions with confluent pneumonia. Future research should include: (1) experimental studies using lung microdialysis to assess the PK/PD in the interstitial fluid of the lung following nebulization of high doses of colistin; (2) superiority multicenter randomized controlled trials comparing nebulized and intravenous CMS in patients with pandrug-resistant GNB ventilator-associated pneumonia and ventilator-associated tracheobronchitis; (3) non-inferiority multicenter randomized controlled trials comparing nebulized CMS to intravenous new cephalosporines/ß-lactamase inhibitors in patients with extensive drug-resistant GNB ventilator-associated pneumonia and ventilator-associated tracheobronchitis.This research received no external funding

Pharmacokinetic Characteristics of Nebulized Colistimethate Sodium Using Two Different Types of Nebulizers in Critically Ill Patients with Ventilator-Associated Respiratory Infections

Colistin pharmacokinetics; Critically ill; Inhaled colistinFarmacocinética de la colistina; Enfermo crítico; Colistina inhaladaFarmacocinètica de la colistina; Malalt crític; Colistina inhaladaBackground: Rising antimicrobial resistance has led to a revived interest in inhaled colistin treatment in the critically ill patient with ventilator-associated respiratory infection (VARI). Nebulization via vibrating mesh nebulizers (VMNs) is considered the current standard-of-care, yet the use of generic jet nebulizers (JNs) is more widespread. Few data exist on the intrapulmonary pharmacokinetics of colistin when administered through VMNs, while there is a complete paucity regarding the use of JNs. Methods: In this study, 18 VARI patients who received 2 million international units of inhaled colistimethate sodium (CMS) through a VMN were pharmacokinetically compared with six VARI patients who received the same drug dose through a JN, in the absence of systemic CMS administration. Results: Surprisingly, VMN and JN led to comparable formed colistin exposures in the epithelial lining fluid (ELF) (median (IQR) AUC0–24: 86.2 (46.0–185.9) mg/L∙h with VMN and 91.5 (78.1–110.3) mg/L∙h with JN). The maximum ELF concentration was 10.4 (4.7–22.6) mg/L and 7.4 (6.2–10.3) mg/L, respectively. Conclusions: Based on our results, JN might be considered a viable alternative to the theoretically superior VMN. Therapeutic drug monitoring in the ELF can be advised due to the observed low exposure, high variability, and appreciable systemic absorption.This research was funded by Norma Hellas S.A., grant number 06797/2017, managed by the Special Research Account of the National and Kapodistrian University of Athens (ELKE)

Efficacy of tigecycline in a rabbit model of experimental enterococcal endocarbitis

Enterococci are among the most frequent etiologic agents of infective endocarditis, and therapeuticproblems arise from its inherent trend to accumulate resistance mechanisms. We evaluated the efficacy oftigecycline alone and in combination with gentamicin in a rabbit model of endocarditis caused by a linezolidand vancomycin resistant strain of Enterococcus faecium.Rabbits with induced enterococcal endocarditis were randomized to 4 groups: control group (n=14),gentamicin 6mg/kg subcutaneously once daily (n=15), tigecycline 4mg/kg intravenously twice daily (n=15),tigecycline plus gentamicin at the same dosing regimens (n=15). Treatment duration was five days. In orderto test the possibility of relapse another two groups were studied that received tigecycline (n=13) ortigecycline plus gentamicin (n=12). These animals were sacrificed 5 days after the end of antimicrobialtreatment. Post sacrifice, qualitative and quantitative cultures of excised vegetations and peripheral tissuespecimens (lung, liver, spleen and kidney) were performed.Tigecycline MIC for the selected strain was 0.06 mg/L and proved bactericidal in time-kill study.Tigecycline-treated animals had less microbial counts in excised vegetations compared with control andgentamicin-treated animals (log10cfu/g: 5.21 vs. 8.02 and 8.12, respectively, p<0.001). Addition of gentamicincaused a further, statistically non-significant, reduction in colony counts (log10 cfu/g: 3.93, p=0.23 vs.tigecycline). No strains recovered from vegetations exhibited resistance to tigecycline. Analogous results Enterococci are among the most frequent etiologic agents of infective endocarditis, and therapeuticproblems arise from its inherent trend to accumulate resistance mechanisms. We evaluated the efficacy oftigecycline alone and in combination with gentamicin in a rabbit model of endocarditis caused by a linezolidand vancomycin resistant strain of Enterococcus faecium.Rabbits with induced enterococcal endocarditis were randomized to 4 groups: control group (n=14),gentamicin 6mg/kg subcutaneously once daily (n=15), tigecycline 4mg/kg intravenously twice daily (n=15),tigecycline plus gentamicin at the same dosing regimens (n=15). Treatment duration was five days. In orderto test the possibility of relapse another two groups were studied that received tigecycline (n=13) ortigecycline plus gentamicin (n=12). These animals were sacrificed 5 days after the end of antimicrobialtreatment. Post sacrifice, qualitative and quantitative cultures of excised vegetations and peripheral tissuespecimens (lung, liver, spleen and kidney) were performed.Tigecycline MIC for the selected strain was 0.06 mg/L and proved bactericidal in time-kill study.Tigecycline-treated animals had less microbial counts in excised vegetations compared with control andgentamicin-treated animals (log10cfu/g: 5.21 vs. 8.02 and 8.12, respectively, p<0.001). Addition of gentamicincaused a further, statistically non-significant, reduction in colony counts (log10 cfu/g: 3.93, p=0.23 vs.tigecycline). No strains recovered from vegetations exhibited resistance to tigecycline. Analogous results were documented regarding lung, liver, spleen and kidney tissue cultures. No increase in bacterial load wasdocumented in the two test-of-relapse groups.In conclusion, tigecycline proved effective in reducing vegetation bacterial load and sterilizing peripheralorgans in a rabbit model of endocarditis, caused by linezolid and vancomycin resistant E.faecium, even fivedays after completion of therapy. In vitro or in vivo synergy or antagonism with gentamicin was not shown.Tigecycline could be part of a combination regimen for the treatment of clinical infective endocarditis due tomultiresistant strains of enterococci.Οι εντερόκοκκοι συγκαταλέγονται μεταξύ των συχνότερων αιτίων λοιμώδους ενδοκαρδίτιδας, τη στιγμή που θεραπευτικά προβλήματα ανακύπτουν από την εγγενή τους τάση να συσσωρεύουν μηχανισμούς αντοχής. Στη διδακτορική αυτή διατριβή αξιολογήθηκε η αποτελεσματικότητα της τιγεκυκλίνης, τόσο ως μονοθεραπεία, όσο και σε συνδυασμό με γενταμικίνη σε ζωικό πρότυπο ενδοκαρδίτιδας, σε κονίκλους,από στέλεχος Enterococcus faecium ανθεκτικό στη βανκομυκίνη και τη λινεζολίδη. Τα ζωικά πρότυπα στα οποία προκλήθηκε πειραματική λοιμώδης ενδοκαρδίτιδα τυχαιοποιήθηκαν σε 4 ομάδες: ομάδα ελέγχου (n=14), γενταμικίνη 6 mg/kg υποδορίως, άπαξ ημερησίως (n=15), τιγεκυκλίνη 4mg/kg ενδοφλεβίως, δις ημερησίως (n=15) και τιγεκυκλίνη σε συνδυασμό με γενταμικίνη στα προαναφερθέντα δοσολογικά σχήματα (n=15). Η διάρκεια της θεραπείας ήταν 5 ημέρες. Με σκοπό τον έλεγχο του ενδεχομένου υποτροπής της λοίμωξης μετά το τέλος της θεραπείας μελετήθηκαν άλλες δύο ομάδες, στις οποίες χορηγήθηκε τιγεκυκλίνη (n=13) ή συνδυασμός (n=12). Τα ζωικά αυτά πρότυπα θυσιάσθηκαν 5 ημέρες μετά το τέλος της αντιμικροβιακής θεραπείας. Όλα τα ζωικά πρότυπα υποβλήθηκαν σε νεκροτομή, και πραγματοποιήθηκε ποσοτική καλλιέργεια των αφαιρεθέντων εκβλαστήσεων, όπως επίσης και ιστικών τεμαχιδίων πνεύμονος, ήπατος, σπληνός και νεφρού.Η ελάχιστη ανασταλτική πυκνότητα της τιγεκυκλίνης του υπό μελέτη στελέχους ήταν 0,06 μg/ml.Χρησιμοποιώντας τη μέθοδο των καμπυλών θανάτωσης με την πάροδο του χρόνο, αναδείχθηκε η βακτηριοκτόνος της δράση. In vivo, παρατηρήθηκε στατιστικά σημαντική μείωση του βακτηριακού φορτίου των εκβλαστήσεων στα ζωικά πρότυπα που έλαβαν τιγεκυκλίνη, σε σύγκριση με την ομάδα ελέγχου και την ομάδα της γενταμικίνης (log10 cfu/g: 5,21 vs 8,02 και 8,12 αντίστοιχα, p<0.001). Η προσθήκη γενταμικίνης οδήγησε σε περαιτέρω, μη στατιστικά σημαντική, μείωση στον αριθμό των αποικιών (log10 cfu/g: 3,93,p=0.23 συγκριτικά με την ομάδα της τιγεκυκλίνης). Κανένα στέλεχος δεν ανέπτυξε in vivo αντοχή στην τιγεκυκλίνη. Ανάλογα αποτελέσματα παρατηρήθηκαν και στις ιστικές καλλιέργειες. Στις ομάδες ελέγχου υποτροπής, δεν παρατηρήθηκε αύξηση του βακτηριακού φορτίου.Συμπερασματικά, η τιγεκυκλίνη αποδείχθηκε αποτελεσματική στη μείωση του βακτηριακού φορτίου των εκβλαστήσεων και την αποστείρωση των περιφερικών ιστών, σε πειραματικό πρότυπο λοιμώδους ενδοκαρδίτιδας σε κονίκλους από στέλεχος E.faecium ανθεκτικό στη βανκομυκίνη και τη λινεζολίδη, ακόμη και πέντε ημέρες μετά τη διακοπή της θεραπείας. Δεν παρατηρήθηκε in vitro ή in vivo συνέργεια ή ανταγωνισμός με τη γενταμικίνη. Η τιγεκυκλίνη, θα μπορούσε να αποτελεί τμήμα ενός θεραπευτικούσυνδυασμού για την αντιμετώπιση της ανθρωπείου, πολυανθεκτικής, εντεροκοκκικής λοιμώδους ενδοκαρδίτιδας

Immune Response to Mycobacterial Infection: Lessons from Flow Cytometry

Detecting and treating active and latent tuberculosis are pivotal elements for effective infection control; yet, due to their significant inherent limitations, the diagnostic means for these two stages of tuberculosis (TB) to date remain suboptimal. This paper reviews the current diagnostic tools for mycobacterial infection and focuses on the application of flow cytometry as a promising method for rapid and reliable diagnosis of mycobacterial infection as well as discrimination between active and latent TB: it summarizes diagnostic biomarkers distinguishing the two states of infection and also features of the distinct immune response against Mycobacterium tuberculosis (Mtb) at certain stages of infection as revealed by flow cytometry to date

Clostridium subterminale septicemia in an immunocompetent patient

Clostridium subterminale is a Clostridium species that has been rarely isolated in the blood of immunocompromised patients. We report a case of C. subterminale septicemia in an immunocompetent patient who presented with acute mediastinitis following spontaneous esophageal rupture

Acute life-threatening cardiac tamponade in a mechanically ventilated patient with COVID-19 pneumonia

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has recently evolved as a pandemic disease. Although the respiratory system is predominantly affected, cardiovascular complications have been frequently identified, including acute myocarditis, myocardial infarction, acute heart failure, arrhythmias and venous thromboembolic events. Pericardial disease has been rarely reported. We present a case of acute life-threatening cardiac tamponade caused by a small pericardial effusion in a mechanically ventilated patient with severe COVID-19 associated pneumonia. The patient presented acute circulatory collapse with hemodynamic features of cardiogenic or obstructive shock. Bedside echocardiography permitted prompt diagnosis and life-saving pericardiocentesis. Further investigation revealed no other apparent cause of pericardial effusion except for SARS-CoV-2 infection. Cardiac tamponade may complicate COVID-19 and should be included in the differential diagnosis of acute hemodynamic deterioration in mechanically ventilated COVID-19 patients

Pharmacokinetic Characteristics of Nebulized Colistimethate Sodium Using Two Different Types of Nebulizers in Critically Ill Patients with Ventilator-Associated Respiratory Infections

Background: Rising antimicrobial resistance has led to a revived interest in inhaled colistin treatment in the critically ill patient with ventilator-associated respiratory infection (VARI). Nebulization via vibrating mesh nebulizers (VMNs) is considered the current standard-of-care, yet the use of generic jet nebulizers (JNs) is more widespread. Few data exist on the intrapulmonary pharmacokinetics of colistin when administered through VMNs, while there is a complete paucity regarding the use of JNs. Methods: In this study, 18 VARI patients who received 2 million international units of inhaled colistimethate sodium (CMS) through a VMN were pharmacokinetically compared with six VARI patients who received the same drug dose through a JN, in the absence of systemic CMS administration. Results: Surprisingly, VMN and JN led to comparable formed colistin exposures in the epithelial lining fluid (ELF) (median (IQR) AUC0&ndash;24: 86.2 (46.0&ndash;185.9) mg/L&#8729;h with VMN and 91.5 (78.1&ndash;110.3) mg/L&#8729;h with JN). The maximum ELF concentration was 10.4 (4.7&ndash;22.6) mg/L and 7.4 (6.2&ndash;10.3) mg/L, respectively. Conclusions: Based on our results, JN might be considered a viable alternative to the theoretically superior VMN. Therapeutic drug monitoring in the ELF can be advised due to the observed low exposure, high variability, and appreciable systemic absorption

Cutaneous Vasculopathy in a COVID-19 Critically Ill Patient: A Histologic, Immunohistochemical, and Electron Microscopy Study

We describe a critically ill, SARS-CoV-2 positive patient with respiratory failure and thrombotic/livedoid skin lesions, appearing during the course of the disease. The biopsy of the lesions revealed an occlusive, pauci-inflammatory vasculopathy of the cutaneous small vessels characterized by complement and fibrinogen deposition on vascular walls, pointing to a thrombotic vasculopathy. Transmission electron microscopy of the affected skin failed to reveal any viral inclusions. Clinical evaluation and laboratory findings ruled out systemic coagulopathies and disseminated intravascular coagulation, drug-induced skin reaction, and common viral rashes. Our hypothesis is that the, herein evidenced, microvascular occlusive injury might constitute a significant pathologic mechanism in COVID-19, being a common denominator between cutaneous and pulmonary manifestations

Nebulized Colistin in Ventilator-Associated Pneumonia and Tracheobronchitis: Historical Background, Pharmacokinetics and Perspectives.

Clinical evidence suggests that nebulized colistimethate sodium (CMS) has benefits for treating lower respiratory tract infections caused by multidrug-resistant Gram-negative bacteria (GNB). Colistin is positively charged, while CMS is negatively charged, and both have a high molecular mass and are hydrophilic. These physico-chemical characteristics impair crossing of the alveolo-capillary membrane but enable the disruption of the bacterial wall of GNB and the aggregation of the circulating lipopolysaccharide. Intravenous CMS is rapidly cleared by glomerular filtration and tubular excretion, and 20-25% is spontaneously hydrolyzed to colistin. Urine colistin is substantially reabsorbed by tubular cells and eliminated by biliary excretion. Colistin is a concentration-dependent antibiotic with post-antibiotic and inoculum effects. As CMS conversion to colistin is slower than its renal clearance, intravenous administration can lead to low plasma and lung colistin concentrations that risk treatment failure. Following nebulization of high doses, colistin (200,000 international units/24h) lung tissue concentrations are > five times minimum inhibitory concentration (MIC) of GNB in regions with multiple foci of bronchopneumonia and in the range of MIC breakpoints in regions with confluent pneumonia. Future research should include: (1) experimental studies using lung microdialysis to assess the PK/PD in the interstitial fluid of the lung following nebulization of high doses of colistin; (2) superiority multicenter randomized controlled trials comparing nebulized and intravenous CMS in patients with pandrug-resistant GNB ventilator-associated pneumonia and ventilator-associated tracheobronchitis; (3) non-inferiority multicenter randomized controlled trials comparing nebulized CMS to intravenous new cephalosporines/ß-lactamase inhibitors in patients with extensive drug-resistant GNB ventilator-associated pneumonia and ventilator-associated tracheobronchitis