Unit:
Faculty of MedicineLibrary of the School of Health Sciences
Dissertation committee:
Ιωσήφ Μελετιάδης, Επίκουρος Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Λουκία Ζέρβα, Αναπληρώτρια Καθηγήτρια, Ιατρική Σχολή, ΕΚΠΑ
Παρασκευή Μιριαγκού, Ερευνήτρια Α, Ινστιτούτο Παστέρ
Αναστασία Αντωνιάδου, Αναπληρώτρια Καθηγήτρια, Ιατρική Σχολή, ΕΚΠΑ
Σπυρίδων Πουρνάρας, Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Νικόλαος Σιαφάκας, Επίκουρος Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Παναγιώτης Τσιριγώτης, Αναπληρωτής Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Original Title:
Αντιβακτηριακή δράση τιγεκυκλίνης, μεροπενέμης και κολιστίνης σε συνδυασμό εναντίον κλινικών στελεχών Klebsiella pneumoniae σε ένα επικυρωμένο in vitro φαρμακοκινητικό /φαρμακοδυναμικό μοντέλο
Translated title:
Antibacterial activity of tigecygline, meropenem and colistin triple combination therapy against Klebsiella pneumoniae isolates using an in vitro pharmacokinetic/pharmacodynamic simulation model
Summary:
Klebsiella pneumoniae is associated with a wide range of infections including urinary tract infections, pneumonia, surgical site infections and soft-tissue infections. Carbapenems can be used to treat these infections particularly against ESBL producing strains, although their efficacy is limited against carbapenemase producing strains. The clinically important carbapenamases belong to three classes; the class A enzymes of KPC type, the class B enzymes which are zinc dependent and they are represented by VIM, IMP and NDM types and the class D enzymes of the OXA-48 type. These infections are associated with high mortality, whereas the emergence of multidrug resistance phenotypes limits further the therapeutic options. Accurate and validated in vitro PK/PD models may serve as useful tools in order to quantitatively assess the efficacy of combination therapy, while they can be used to perform more comprehensive experiments compared to animal models and clinical trials.
In Chapter 2, the in vitro and in vivo antibacterial activity of meropenem was investigated against VIM-1 producing clinical isolates of K. pneumoniae exhibiting various levels of resistance to meropenem in a closed dialysis/diffusion pharmacokinetic/pharmacodynamic model and a neutropenic thigh infection animal model. Also, the probability of pharmacodynamic target attainment was calculated for different dosing regimens and the required trough levels were estimated for the standard dosing regimen. Using a 3-stage pharmacodynamic approach (extensive in vitro experiments -limited animal experimentation-bridging with human pharmacokinetics), clinically valuable pharmacodynamic data were obtained. The exposure index associated with bactericidal action was 40% fT>MIC for VIM producing K. pneumoniae isolates. Simulation analysis indicated that high doses up to 2 g and prolonged infusion up to 4h q8 or 3-12g continuous infusion regimens are required in order to attain the latter pharmacodynamic target. Furthermore, the human pharmacokinetics of meropenem were simulated after 0.5-hour and 3-hour infusion regimen of the standard dose of 1gr and studied the pharmacodynamics against VP-Kp, using an in vitro pharmacokinetic-pharmacodynamic model. Furthermore, the target attainment rates in different patient groups treated with these two regimens were calculated for isolates with different MICs.
After having optimized and validated the in vitro PK/PD model, as it reliably simulated meropenem PK in human serum and correlated with in vivo outcomes observed in animal models and clinical trials, it was adapted to accommodate upt ot three drugs with different half-lives, thus enabling the study of drug monotherapy as well as drug combinations. Particularly, in Chapter 3, the activity of colistin was investigated against K. pneumoniae in an in vitro PK/PD model simulating different dosing regimens. Three clinical isolates of K. pneumoniae with MIC 0.5, 1 and 4 mg/L were tested in an vitro PK/PD model following a dose-fractionation design over a period of 24h. A high and low inoculum of 107cfu/mL and 104 cfu/mL with and without a hetero-resistant subpopulation, respectively were used. PK/PD indices associated with colistin activity were explored and bactericidal activity (2-log kill) and Monte Carlo analysis was performed in order to determine the probability of target attainment.
Main subject category:
Health Sciences
Keywords:
Klebsiella pneumoniae (K. pneumoniae), In vitro PK/PD model, Meropenem, Tigecycline, Colistin, Combination Therapy
Number of references:
200
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Tsala Marilena PhD.pdf
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