Pharmacokinetics of ciprofloxacin in patients with chronic obstructive pulmonary disease exacerbation in the intensive care unit

Chronic Obstructive Pulmonary Disease (COPD) is the fourth leading cause of death worldwide and a major cause of chronic morbidity. COPD patients experience frequent and debilitating exacerbations of their disease, mainly of infectious origin. In some patients, mostly those with severe airflow obstruction, respiratory failure may occur and mechanical ventilation is sometimes necessary. Gram-negative enteric bacilli and mainly Pseudomonas spp. seem to have a prominent role in these severe exacerbations. Ciprofloxacin is considered to be one of the antibiotics of choice for the treatment of the respiratory infections, which are the cause of these severe exacerbations of COPD. Optimizing antimicrobial therapy in patients hospitalized in an Intensive Care Unit (ICU) can be difficult due to various pathophysiological changes that lead to altered and highly variable drug pharmacokinetics. In these critically ill patients and in the era of increasing antibiotic resistance, antibiotic therapy based on pharmacokinetics - pharmacodynamics becomes crucial. Regarding ciprofloxacin, the previously recommended dose of 800 mg per day has been increased to 1200 mg per day in critically ill patients because of inadequate serum levels and suboptimal pharmacodynamic exposure. Furthermore, antibiotic penetration into the site of infection is critical in order to achieve a favorable clinical outcome. Since in COPD patients the infection develops within the airway lumen, it is important to know the drug concentrations that are achieved in bronchial secretions. The purpose of this study is to investigate the pharmacokinetic profile of ciprofloxacin in critically ill patients with COPD exacerbation, to evaluate its penetration into their bronchial secretions and to calculate the pharmacodynamic parameters at various MIC of Gram-negative pathogens. Twenty-five mechanically ventilated patients were included in this prospective, open-label study. They were all suffering from an acute, infectious exacerbation of COPD and had risk factors for P. aeruginosa. All subjects received a 1-hour intravenous infusion of 400 mg ciprofloxacin q8h. Serial blood and bronchial secretions samples were obtained at steady state and concentrations were determined using high-performance liquid chromatography (HPLC). Plasma ciprofloxacin concentrations were plotted against time and the pharmacokinetic parameters were estimated by compartmental analysis using the WinNonlin software program. The penetration ratio for each patient was obtained by dividing the area under the curve from 0 to 24 h (AUC0→24) for bronchial secretions by the AUC0→24 for plasma. There was a large variability in the pharmacokinetic data. The mean peak and trough levels in plasma were 5.37 ± 1.57 and 1 ± 0.53 mg/L respectively. Mean values for volume of distribution, clearance, half-life and AUC0→24 were 169.9 ± 84.1 L, 27 ± 8.9 L/h, 5.35 ± 2.21 h and 47.41 ± 17.02 hrmg/L, respectively. In bronchial secretions, a mean Cmax of 3.08 ± 1.21 mg/L was observed in 3.12 ± 1.01 hours, while mean Cmin was found to be 0.88 ± 0.43 mg/L. The antibiotic penetrated well into bronchial secretions, achieving maximum concentrations that were 60 ± 25% of those in plasma and a penetration ratio of 1.16 ± 0.59. Moreover, in almost all patients the concentrations in bronchial secretions remained above 0.25 mg/L for the whole dosing interval, while in twenty or them they were ≥ 0.5 mg/L. As far as the pharmacodynamic parameters are concerned, the target of AUC0→24/MIC ≥ 125 was attained in all patients, in the majority of them (76%) and in none at MIC of 0.125, 0.25 and 1 μg/ml, respectively. Slightly better results were obtained for the target Cmax /MIC ≥ 10. Based on the microbiological data of our hospital, only 42% of P. aeruginosa strains had MIC ≤ 0.25 μg/ml, so the pharmacodynamics target of AUC0→24/MIC that is more frequently used, would be attained in less than half of the strains. In conclusion, ciprofloxacin demonstrates excellent penetration into bronchial secretions of critically ill COPD patients. There is wide interindividual variability in its pharmacokinetic parameters in this population and inadequate pharmacodynamic exposure against bacteria with MIC ≥ 0.5 μg/ml. Therefore, combination therapy is probably the best choice for the treatment of resistant pathogens, such as P. aeruginosa. The institution of therapeutic drug monitoring and the evaluation of the pharmacokinetics – pharmacodynamics of antibiotics, appear to be necessary for individualizing antimicrobial dosing in the ICU, in order to optimize efficacy and to prevent the development of resistance.Η Χρόνια Αποφρακτική Πνευμονοπάθεια (ΧΑΠ) είναι η τέταρτη αιτία θανάτου παγκοσμίως και ένας σημαντικός λόγος χρόνιας νοσηρότητας. Οι ασθενείς με ΧΑΠ εμφανίζουν συχνά και επιβαρυντικά επεισόδια παρόξυνσης της νόσου, κυρίως λοιμώδους αιτιολογίας. Σε ορισμένους αρρώστους και ιδιαιτέρως σε αυτούς που παρουσιάζουν σημαντική απόφραξη αεραγωγών, μπορεί να εμφανιστεί αναπνευστική ανεπάρκεια και να απαιτηθεί μηχανικός αερισμός. Έχει αποδειχθεί ότι τα Gram-αρνητικά μικρόβια και κυρίως στελέχη ψευδομονάδας, παίζουν σημαντικό ρόλο σε αυτές τις σοβαρές παροξύνσεις. Ένα από τα αντιβιοτικά εκλογής για την αντιμετώπιση των λοιμώξεων του αναπνευστικού, που ευθύνονται για αυτές τις σοβαρές παροξύνσεις της ΧΑΠ, θεωρείται η σιπροφλοξασίνη. Η βελτιστοποίηση της αντιβιοτικής αγωγής στους ασθενείς, οι οποίοι νοσηλεύονται σε Μονάδα Εντατικής Θεραπείας (ΜΕΘ), μπορεί να είναι δύσκολη, λόγω των διαφόρων παθοφυσιολογικών αλλαγών που παρουσιάζουν και οι οποίες οδηγούν σε μεταβαλλόμενη και διακυμαινόμενη φαρμακοκινητική των αντιβιοτικών. Έτσι, στους βαρέως πάσχοντες ασθενείς και μάλιστα στην εποχή της συνεχώς αυξανόμενης αντοχής των μικροβίων στα διάφορα αντιβιοτικά, η αντιμικροβιακή αγωγή, που βασίζεται στη φαρμακοκινητική -φαρμακοδυναμική, γίνεται ιδιαίτερα σημαντική και αναγκαία. Σχετικά με τη σιπροφλοξασίνη, η παλαιότερα συνιστώμενη δόση των 800 mg ημερησίως έχει αυξηθεί σε 1200 mg ημερησίως στους βαρέως πάσχοντες ασθενείς, λόγω των ανεπαρκών επιπέδων στον ορό και της μη-βέλτιστης φαρμακοδυναμικής έκθεσης. Επιπλέον, η διεισδυτικότητα ενός αντιβιοτικού στο σημείο της λοίμωξης, είναι καθοριστικής σημασίας για την επίτευξη ενός ευνοϊκού κλινικού αποτελέσματος. Είναι σημαντικό, λοιπόν, να γνωρίζουμε τις συγκεντρώσεις των φαρμάκων, που επιτυγχάνονται στις βρογχικές εκκρίσεις των ασθενών με ΧΑΠ, αφού η λοίμωξη αναπτύσσεται μέσα στον αυλό των αεραγωγών. Σκοπός της παρούσας μελέτης είναι η διερεύνηση του φαρμακοκινητικού προφίλ της σιπροφλοξασίνης στους βαρέως πάσχοντες ασθενείς με παρόξυνση ΧΑΠ, η εκτίμηση της διεισδυτικότητάς της στις βρογχικές εκκρίσεις τους, καθώς και η αποτίμηση των φαρμακοδυναμικών δεικτών της σε διάφορες MIC των Gram-αρνητικών μικροβίων. Συμπεριλήφθηκαν 25 ασθενείς υπό μηχανικό αερισμό σε αυτή την προοπτική, ανοιχτή στους ερευνητές μελέτη. Όλοι εμφάνιζαν οξεία, λοιμώδη παρόξυνση ΧΑΠ και παρουσίαζαν παράγοντες κινδύνου για P. aeruginosa. Οι άρρωστοι έλαβαν 400 mg σιπροφλοξασίνης ενδοφλεβίως ανά 8 ώρες, σε έγχυση 1 ώρας. Ελήφθησαν διαδοχικά δείγματα αίματος και βρογχικών εκκρίσεων σε σταθερή κατάσταση και οι συγκεντρώσεις προσδιορίστηκαν με τη μέθοδο της Υγρής Χρωματογραφίας Υψηλής Απόδοσης (HPLC). Κατασκευάστηκαν οι γραφικές παραστάσεις της συγκέντρωσης του αντιβιοτικού στο πλάσμα σε συνάρτηση με το χρόνο και υπολογίστηκαν οι διάφορες φαρμακοκινητικές παράμετροι με διαμερισματική ανάλυση, χρησιμοποιώντας το λογισμικό πρόγραμμα WinNonlin. Ο βαθμός διεισδυτικότητας της σιπροφλοξασίνης στις βρογχικές εκκρίσεις για κάθε ασθενή, υπολογίστηκε διαιρώντας την περιοχή κάτω από την καμπύλη που περιγράφει τη συγκέντρωση ως προς το χρόνο για 24 ώρες (AUC0→24) των βρογχικών εκκρίσεων με την αντίστοιχη του πλάσματος. Παρατηρήθηκε σημαντική διακύμανση στα φαρμακοκινητικά δεδομένα. Τα μέγιστα (peak) και ελάχιστα (trough) επίπεδα της σιπροφλοξασίνης στο πλάσμα ήταν 5.37 ± 1.57 και 1 ± 0.53 mg/L, αντιστοίχως. Οι μέσες τιμές για τον όγκο κατανομής, την κάθαρση, το χρόνο ημίσειας ζωής και την AUC0→24 ήταν 169.9 ± 84.1 L, 27 ± 8.9 L/h, 5.35 ± 2.21 h και47.41 ± 17.02 hrmg/L, αντιστοίχως. Στις βρογχικές εκκρίσεις, η συγκέντρωση της σιπροφλοξασίνης έφτασε μια μέση μέγιστη τιμή Cmax 3.08 ± 1.21 mg/L σε 3.12 ± 1.01 ώρες, ενώ η μέση ελάχιστη τιμή Cmin βρέθηκε να είναι 0.88 ± 0.43 mg/L. Το αντιβιοτικό παρουσίασε ικανοποιητική διεισδυτικότητα στις βρογχικές εκκρίσεις, επιτυγχάνοντας μέγιστες συγκεντρώσεις που ήταν 60 ± 25% των αντιστοίχων του πλάσματος και βαθμό διεισδυτικότητας 1.16 ± 0.59. Επίσης, τα επίπεδα της σιπροφλοξασίνης στις βρογχικές εκκρίσεις παρέμειναν ≥ 0.25 mg/L σε όλο το μεσοδιάστημα μεταξύ των δύο δόσεων σχεδόν σε όλους τους ασθενείς της μελέτης, ενώ στους 20 από αυτούς παρέμειναν ≥ 0.5 mg/L. Όσον αφορά τις φαρμακοδυναμικές παραμέτρους, ο στόχος AUC0→24/MIC ≥ 125 επιτεύχθηκε σε όλους τους ασθενείς, στην πλειοψηφία τους (76%) και σε κανέναν σε MIC 0.125, 0.25 και 1 μg/ml, αντίστοιχα. Λίγο καλύτερα αποτελέσματα είχαμε για το στόχο Cmax/MIC ≥ 10. Σύμφωνα με τα μικροβιολογικά δεδομένα του Νοσοκομείου μας, μόνο το 42% των στελεχών P. aeruginosa είχαν MIC ≤ 0.25 μg/ml, οπότε προκύπτει ότι ο φαρμακοδυναμικός στόχος AUC0→24/MIC που χρησιμοποιείται περισσότερο, θα επιτυγχανόταν σε λιγότερο από τα μισά στελέχη. Συμπερασματικά, η σιπροφλοξασίνη επιδεικνύει εξαιρετική διεισδυτικότητα στις βρογχικές εκκρίσεις των βαρέως πασχόντων ασθενών με ΧΑΠ. Παρατηρείται ευρεία διακύμανση στις φαρμακοκινητικές παραμέτρους στον πληθυσμό αυτό και ανεπαρκής φαρμακοδυναμική έκθεση έναντι μικροβίων με MIC ≥ 0.5 μg/ml. Έτσι, ο συνδυασμός αντιβιοτικών είναι πιθανόν η καλύτερη επιλογή για τη θεραπεία των ανθεκτικών παθογόνων, όπως η P. aeruginosa. Τέλος, απαραίτητη φαίνεται να είναι η εφαρμογή της παρακολούθησης των επιπέδων των αντιβιοτικών στο αίμα και η αξιολόγηση της φαρμακοκινητικής - φαρμακοδυναμικής τους, ώστε να εξατομικεύεται η αντιμικροβιακή αγωγή στη ΜΕΘ, με στόχο τη βελτιστοποίηση της αποτελεσματικότητας και την παρεμπόδιση ανάπτυξης αντοχής

A case of pulmonary veno-occlusive disease: diagnostic dilemmas and therapeutic challenges

Pulmonary veno-occlusive disease (PVOD) is a rare cause of pulmonary hypertension (PH). Misdiagnosis of the disease is common since PVOD presents with clinical and radiographic features mimicking idiopathic pulmonary arterial hypertension or even PH due to interstitial lung disease. Vasodilators may not be efficacious in PVOD and may in fact worsen hemodynamic status with the development of pulmonary edema. Lung transplantation represents the best treatment option. In the present report we describe the challenging diagnosis of PVOD in a patient with PH referred to our department. Final diagnosis was established by surgical lung biopsy. The patient was offered sequential combination therapy under close monitoring and maintained remarkable clinical stabilization while being on the waiting list for lung transplantation

Tigecycline Pharmacokinetic and Pharmacodynamic Profile in Patients with Chronic Obstructive Pulmonary Disease Exacerbation

Background: We aimed to evaluate the pharmacokinetic profile of tigecycline in plasma and its penetration to sputum in moderately ill patients with an infectious acute exacerbation of chronic obstructive pulmonary disease (COPD). Methods: Eleven patients hospitalized with acute respiratory failure due to an acute COPD exacerbation with clinical evidence of an infectious cause received tigecycline 50 mg twice daily after an initial loading dose of 100 mg. Blood and sputum samples were collected at steady state after dose seven. Results: In plasma, mean Cmax pl was 975.95 ± 490.36 ng/mL and mean Cmin pl was 214.48 ±140.62 ng/mL. In sputum, mean Cmax sp was 641.91 ± 253.07 ng/mL and mean Cmin sp was 308.06 ± 61.7 ng/mL. In plasma, mean AUC 0–12 pl was 3765.89 ± 1862.23 ng*h/mL, while in sputum mean AUC 0–12 sp was 4023.27 ± 793.37 ng*h/mL. The mean penetration ratio for the 10/11 patients was 1.65 ± 1.35. The mean Free AUC0–24 pl/MIC ratio for Streptococcus pneumoniae and Haemophilus influenzae was 25.10 ± 12.42 and 6.02 ± 2.97, respectively. Conclusions: Our findings support the clinical effectiveness of tigecycline against commonly causative bacteria in COPD exacerbations and highlight its sufficient lung penetration in pulmonary infections of moderate severity

Pharmacokinetics of Ciprofloxacin and Its Penetration into Bronchial Secretions of Mechanically Ventilated Patients with Chronic Obstructive Pulmonary Disease▿

We evaluated the pharmacokinetic profile of ciprofloxacin and its penetration into bronchial secretions of critically ill patients with chronic obstructive pulmonary disease (COPD). Twenty-five mechanically ventilated patients with severe COPD who were suffering from an acute, infectious exacerbation were included in this prospective, open-label study. All subjects received a 1-hour intravenous infusion of 400 mg ciprofloxacin every 8 h. Serial blood and bronchial secretion samples were obtained at steady state, and concentrations were determined using high-performance liquid chromatography. The pharmacodynamic parameters that are associated with the efficacy of fluoroquinolones against Gram-negative pathogens were also calculated. The mean peak (maximum) concentration (Cmax) and trough (minimum) concentration in plasma were 5.37 ± 1.57 and 1 ± 0.53 mg/liter, respectively. Mean values for volume of distribution, clearance, half-life, and area under the curve from 0 to 24 h (AUC0–24) were 169.87 ± 84.11 liters, 26.96 ± 8.86 liters/h, 5.35 ± 2.21 h, and 47.41 ± 17.02 mg · h/liter, respectively. In bronchial secretions, a mean Cmax of 3.08 ± 1.21 mg/liter was achieved in 3.12 ± 1.01 h, and the penetration ratio was 1.16 ± 0.59. The target of AUC0–24/MIC of ≥125 was attained in all patients, in the majority of them (76%), and in none at MICs of 0.125, 0.25, and 1 μg/ml, respectively. Slightly better results were obtained for the ratio Cmax/MIC of ≥10. In conclusion, ciprofloxacin demonstrates excellent penetration into bronchial secretions. There is wide interindividual variability in its pharmacokinetic parameters in critically ill COPD patients and inadequate pharmacodynamic exposure against bacteria with MICs of ≥0.5 μg/ml

Poor timing and failure of source control are risk factors for mortality in critically ill patients with secondary peritonitis

Purpose: To describe data on epidemiology, microbiology, clinical characteristics and outcome of adult patients admitted in the intensive care unit (ICU) with secondary peritonitis, with special emphasis on antimicrobial therapy and source control. Methods: Post hoc analysis of a multicenter observational study (Abdominal Sepsis Study, AbSeS) including 2621 adult ICU patients with intra-abdominal infection in 306 ICUs from 42 countries. Time-till-source control intervention was calculated as from time of diagnosis and classified into 'emergency' (< 2 h), 'urgent' (2-6 h), and 'delayed' (> 6 h). Relationships were assessed by logistic regression analysis and reported as odds ratios (OR) and 95% confidence interval (CI). Results: The cohort included 1077 cases of microbiologically confirmed secondary peritonitis. Mortality was 29.7%. The rate of appropriate empiric therapy showed no difference between survivors and non-survivors (66.4% vs. 61.3%, p = 0.1). A stepwise increase in mortality was observed with increasing Sequential Organ Failure Assessment (SOFA) scores (19.6% for a value ≤ 4-55.4% for a value > 12, p < 0.001). The highest odds of death were associated with septic shock (OR 3.08 [1.42-7.00]), late-onset hospital-acquired peritonitis (OR 1.71 [1.16-2.52]) and failed source control evidenced by persistent inflammation at day 7 (OR 5.71 [3.99-8.18]). Compared with 'emergency' source control intervention (< 2 h of diagnosis), 'urgent' source control was the only modifiable covariate associated with lower odds of mortality (OR 0.50 [0.34-0.73]). Conclusion: 'Urgent' and successful source control was associated with improved odds of survival. Appropriateness of empirical antimicrobial treatment did not significantly affect survival suggesting that source control is more determinative for outcome

Epidemiology of intra-abdominal infection and sepsis in critically ill patients: "AbSeS", a multinational observational cohort study and ESICM Trials Group Project

Purpose To describe the epidemiology of intra-abdominal infection in an international cohort of ICU patients according to a new system that classifies cases according to setting of infection acquisition (community-acquired, early onset hospital-acquired, and late-onset hospital-acquired), anatomical disruption (absent or present with localized or diffuse peritonitis), and severity of disease expression (infection, sepsis, and septic shock). Methods We performed a multicenter (n = 309), observational, epidemiological study including adult ICU patients diagnosed with intra-abdominal infection. Risk factors for mortality were assessed by logistic regression analysis. Results The cohort included 2621 patients. Setting of infection acquisition was community-acquired in 31.6%, early onset hospital-acquired in 25%, and late-onset hospital-acquired in 43.4% of patients. Overall prevalence of antimicrobial resistance was 26.3% and difficult-to-treat resistant Gram-negative bacteria 4.3%, with great variation according to geographic region. No difference in prevalence of antimicrobial resistance was observed according to setting of infection acquisition. Overall mortality was 29.1%. Independent risk factors for mortality included late-onset hospital-acquired infection, diffuse peritonitis, sepsis, septic shock, older age, malnutrition, liver failure, congestive heart failure, antimicrobial resistance (either methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci, extended-spectrum beta-lactamase-producing Gram-negative bacteria, or carbapenem-resistant Gram-negative bacteria) and source control failure evidenced by either the need for surgical revision or persistent inflammation. Conclusion This multinational, heterogeneous cohort of ICU patients with intra-abdominal infection revealed that setting of infection acquisition, anatomical disruption, and severity of disease expression are disease-specific phenotypic characteristics associated with outcome, irrespective of the type of infection. Antimicrobial resistance is equally common in community-acquired as in hospital-acquired infection

Antimicrobial Lessons From a Large Observational Cohort on Intra-abdominal Infections in Intensive Care Units

evere intra-abdominal infection commonly requires intensive care. Mortality is high and is mainly determined by disease-specific characteristics, i.e. setting of infection onset, anatomical barrier disruption, and severity of disease expression. Recent observations revealed that antimicrobial resistance appears equally common in community-acquired and late-onset hospital-acquired infection. This challenges basic principles in anti-infective therapy guidelines, including the paradigm that pathogens involved in community-acquired infection are covered by standard empiric antimicrobial regimens, and second, the concept of nosocomial acquisition as the main driver for resistance involvement. In this study, we report on resistance profiles of Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Enterococcus faecalis and Enterococcus faecium in distinct European geographic regions based on an observational cohort study on intra-abdominal infections in intensive care unit (ICU) patients. Resistance against aminopenicillins, fluoroquinolones, and third-generation cephalosporins in E. coli, K. pneumoniae and P. aeruginosa is problematic, as is carbapenem-resistance in the latter pathogen. For E. coli and K. pneumoniae, resistance is mainly an issue in Central Europe, Eastern and South-East Europe, and Southern Europe, while resistance in P. aeruginosa is additionally problematic in Western Europe. Vancomycin-resistance in E. faecalis is of lesser concern but requires vigilance in E. faecium in Central and Eastern and South-East Europe. In the subcohort of patients with secondary peritonitis presenting with either sepsis or septic shock, the appropriateness of empiric antimicrobial therapy was not associated with mortality. In contrast, failure of source control was strongly associated with mortality. The relevance of these new insights for future recommendations regarding empiric antimicrobial therapy in intra-abdominal infections is discussed.Severe intra-abdominal infection commonly requires intensive care. Mortality is high and is mainly determined by diseasespecific characteristics, i.e. setting of infection onset, anatomical barrier disruption, and severity of disease expression. Recent observations revealed that antimicrobial resistance appears equally common in community-acquired and late-onset hospital-acquired infection. This challenges basic principles in anti-infective therapy guidelines, including the paradigm that pathogens involved in community-acquired infection are covered by standard empiric antimicrobial regimens, and second, the concept of nosocomial acquisition as the main driver for resistance involvement. In this study, we report on resistance profiles of Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Enterococcus faecalis and Enterococcus faecium in distinct European geographic regions based on an observational cohort study on intra-abdominal infections in intensive care unit (ICU) patients. Resistance against aminopenicillins, fluoroquinolones, and third-generation cephalosporins in E. coli, K. pneumoniae and P. aeruginosa is problematic, as is carbapenem-resistance in the latter pathogen. For E. coli and K. pneumoniae, resistance is mainly an issue in Central Europe, Eastern and South-East Europe, and Southern Europe, while resistance in P. aeruginosa is additionally problematic in Western Europe. Vancomycin-resistance in E. faecalis is of lesser concern but requires vigilance in E. faecium in Central and Eastern and South-East Europe. In the subcohort of patients with secondary peritonitis presenting with either sepsis or septic shock, the appropriateness of empiric antimicrobial therapy was not associated with mortality. In contrast, failure of source control was strongly associated with mortality. The relevance of these new insights for future recommendations regarding empiric antimicrobial therapy in intra-abdominal infections is discussed