1,721,244 research outputs found
[Mutant Prevention Concentration: is it significant in the clinical practice?]
No full textFluoroquinolones therapeutic efficacy is closely related to the achievement of the highest concentration (concentration-dependent drugs). However, following exposure to antibiotics, along with a decrease in the overall bacterial population, a selection of resistant bacterial population can also occur. In such a scenario, the Mutant Prevention Concentration (MPC) has to be considered, the antibiotic concentration that approximatively allows to obtain inhibition of fully susceptible as well as low resistant strains. In the range between MPC and MIC values, the Mutant Selection Window (MSW) is delineated, a range of antibiotic concentrations within a selection of mutant strains could possibly take place. The clinical impact of these microbiological observations can be found in the importance that the drug concentration a patient will be exposed to, consequently assumes: a concentration that doesn't reach MIC, although doesn't alter the resistance pattern, will not guarantee the recovery; increasing concentration up to values comprised within the MSW, leads to killing of susceptible bacteria and to a successful clinical response; on the other hand, the possibility does exist that less susceptible microorganisms are selected. Finally, a third higher concentration profile subsists, corresponding to the MPC, above the MSW, which permits to obtain both the results. Such an approach has been extensively studied with fluoroquinolones. A number of studies suggests that different fluoroquinolones are contradistinguished by a diverse MPC value. Multiple factors can influence the risk of selecting bacterial resistance: mutagenicity of the fluoroquinolone utilized, size of microbial population to treat, antibiotic concentration attainable at the site infection, pathophysiologic features of the patient, and lastly the prescribing behaviour, not always appropriate
PK/PD profile and post-marketing surveillance of levofloxacin | Il profilo PK/PD e la post-marketing surveillance della levofloxacina
No full textTen years after introduction in therapeutic handbook, levofloxacin still plays a main role in treating bacterial infections. In particular, the deeper knowledge of kinetic-dynamic characteristics has allowed to highlight that high dosage approach in short term therapy might reveal as extremely interesting in a setting of critical patients. In addition, the good tissue diffusion, documented by pharmacokinetic studies performed in different districts, including the ones protected by anatomic barriers, lets to assume a good efficacy in the treatment of infection localized in deep tissues, as observed in different animal models, and successively confirmed by clinical studies. Use of levofloxacin for infections localized at particular body sites, such as bones and joints, has allowed to evidence a good tolerability profile in the long term tolerability, as well
Intracellular Pharmacokinetics of Antibacterials and Their Clinical Implications
No full textThe intracellular pharmacokinetics of the different classes of antimicrobials into surrogate markers of tissue accumulation (alveolar macrophages and/or total alveolar cells collected by means of bronchoalveolar lavage or peripheral white blood cells) was reviewed. The aim of this review was to discuss the clinical implications of the intracellular pharmacokinetics of antibacterials, either from the therapeutic or toxicological perspective. The different pharmacokinetic behaviour of antimicrobials within cells is mainly related to their physicochemical properties (hydrophilicity and lipophilicity), and may have several clinical implications. Therapeutic efficacy against intracellular pathogens has been correlated mainly with the intracellular concentrations achieved by the different antimicrobial agents. This is relevant especially for macrolides, tetracyclines, fluoroquinolones and rifampicin in the treatment of bacterial infections such as Legionella pneumophila pneumonia, Mycoplasma pneumoniae pneumonia, non-gonococcal urethritis and chronic staphylococcal infections. Additionally, intracellular accumulation of antibacterials was correlated with the possibility of causing organ-specific toxicity, as in the case of aminoglycosides in regard to the risk of nephrotoxicity. Finally, it should be kept in mind that intracellular accumulation may also represent a drug reservoir in the case of lipophilic antimicrobials. This may become extremely relevant from the clinical standpoint when treating critically ill patients with sepsis with antibacterials. The pathophysiology of sepsis may explain why it is necessary to start therapy with an increased loading dose of hydrophilic antimicrobials to promptly achieve therapeutically effective concentrations
Jumping into the future: overcoming pharmacokinetic/pharmacodynamic hurdles to optimize the treatment of severe difficult to treat-Gram-negative infections with novel beta-lactams
No full textIntroduction: The choice of best therapeutic strategy for difficult-to-treat resistance (DTR) Gram-negative infections currently represents an unmet clinical need. Areas covered: This review provides a critical reappraisal of real-world evidence supporting the role of pharmacokinetic/pharmacodynamic (PK/PD) optimization of novel beta-lactams in the management of DTR Gram-negative infections. The aim was to focus on prolonged and/or continuous infusion administration, penetration rates into deep-seated infections, and maximization of PK/PD targets in special renal patient populations. Retrieved findings were applied to the three most critical clinical scenarios of Gram-negative resistance phenotypes (i.e. carbapenem-resistant Enterobacterales; difficult-to-treat resistant Pseudomonas aeruginosa, and carbapenem-resistant Acinetobacter baumannii). Expert opinion: Several studies supported the role of PK/PD optimization of beta-lactams in the management of DTR Gram-negative infections for both maximizing clinical efficacy and preventing resistance emergence. Optimizing antimicrobial therapy with novel beta-lactams based on the so called 'antimicrobial therapy puzzle' PK/PD concepts may represent a definitive jump into the future toward a personalized patient management of DTR Gram negative infections. Establishing a dedicated and coordinated multidisciplinary team and implementing a real-time TDM-guided personalized antimicrobial exposure optimization of novel beta-lactams based on expert clinical pharmacological interpretation, could represent crucial cornerstones for the proper management of DTR Gram-negative infections
Antimicrobial treatment of bacterial infections in frail elderly patients: The difficult balance between efficacy, safety and tolerability
No full textThe elderly population is increasing worldwide and shows an increasing prevalence of frailty. Frailty is recognized as an important factor for inappropriate drug prescribing in elderly patients. Appropriate drug prescription, either in terms of drug choice or in terms of drug dosage, is of paramount importance among the frail elderly patients, this requiring the need of a difficult balance between efficacy, safety and tolerability. Bacterial infections are quite frequent among the elderly, and use of antimicrobials may be associated with severe adverse events in this population, especially when in presence of co-medications and/or of co-morbidities. The aim of this paper is to argue about the most recent published evidences on how to prevent major adverse events whenever antimicrobials should be co-prescribed in frail elderly patients
Should the Clinical Pharmacologist Play a Role in the Multidisciplinary Team Managing Severe Necrotizing Soft-Tissue Infections?
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Plasma pharmacokinetics of antimicrobial agents in critically Ill patients
No full textPrompt optimal antimicrobial treatment in critically ill patients is mandatory and must be achieved not only in terms of spectrum of activity, but also in terms of exposure at the infection site. Plasma profile of antimicrobial agents may represent a valid surrogate marker of drug exposure and allow to identify the correct dosage for a given drug. However, in the critically ill patients the pharmacokinetic behavior of antimicrobials may be altered by some very peculiar pathophysiological conditions, so that dosages significantly different from those used in clinically stable patients or from those originally studied in healthy volunteers for regulatory purposes may often be needed in order to ensure optimal plasma drug exposure in such population. This is especially true for hydrophilic antimicrobials (aminoglycosides, beta-lactams, glycopeptides, lipopeptides, echinocandins, fluconazole, acyclovir, ganciclovir) whose volume of distribution and clearance may be significantly altered by these conditions. These aspects are particularly relevant in patients with severe sepsis or with septic shock for whom the time for being considered as a special population to be studied apart from the general population has probably come. From the healthcare system perspective, this means that individualization of antimicrobial therapy by means of a real time therapeutic drug monitoring coupled with clinical pharmacological advice should be considered an invaluable tool for optimizing antimicrobial therapy and for the containment of microbial resistance in this setting
The Cytokine Release Syndrome and/or the Proinflammatory Cytokines as Underlying Mechanisms of Downregulation of Drug Metabolism and Drug Transport: A Systematic Review of the Clinical Pharmacokinetics of Victim Drugs of this Drug–Disease Interaction Under Different Clinical Conditions
Full text linkBACKGROUND AND OBJECTIVE: An ever-growing body of evidence supports the impact of cytokine modulation on the patient’s phenotypic drug response. The aim of this systematic review was to analyze the clinical studies that assessed the pharmacokinetics of victim drugs of this drug–disease interaction in the presence of different scenarios of cytokine modulation in comparison with baseline conditions. METHODS: We conducted a systematic review by searching the PubMed-MEDLINE database from inception until February 2022 to retrieve prospective and/or retrospective observational studies, population pharmacokinetic studies, phase I studies, and/or case series/reports that investigated the impact of cytokine modulation on the pharmacokinetic behavior of victim drugs. Only studies providing quantitative pharmacokinetic data of victim drugs by comparing normal status versus clinical conditions with documented cytokine modulation or by assessing the influence of anti-inflammatory biological agents on metabolism and/or transport of victim drugs were included. RESULTS: Overall, 26 studies were included. Rheumatoid arthritis (6/26; 23.1%) and sepsis (5/26; 19.2%) were the two most frequently investigated pro-inflammatory clinical scenarios. The victim drug most frequently assessed was midazolam (14/26; 53.8%; as a probe for cytochrome P450 [CYP] 3A4). Cytokine modulation showed a moderate inhibitory effect on CYP3A4-mediated metabolism (area under the concentration–time curve increase and/or clearance decrease between 1.98-fold and 2.59-fold) and a weak-to-moderate inhibitory effect on CYP1A2, CYP2C9, and CYP2C19-mediated metabolism (in the area under the concentration–time curve increase or clearance decrease between 1.29-fold and 1.97-fold). Anti-interleukin-6 agents showed remarkable activity in counteracting downregulation of CYP3A4-mediated activity (increase in the area under the concentration–time curve between 1.75-fold and 2.56-fold). CONCLUSIONS: Cytokine modulation may cause moderate or weak-to-moderate downregulation of metabolism/transport of victim drugs, and this may theoretically have relevant clinical consequences. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40262-022-01173-8
Is a high baseline inflammatory burden the major driver in causing daptomycin-induced eosinophilic pneumonia and muscular toxicity?
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