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Chapter 17 - General considerations in cardiothoracic critical care: importance of pharmacokinetics
No full textAntimicrobial agents in elective surgery: Prophylaxis or "early therapy"?
No full textA lack of a clear distinction between antimicrobial prophylaxis and therapy still exists in the surgical setting. Major concerns are: 1) Which surgical procedures are eligible for antimicrobial prophylaxis? 2) Which kind of antimicrobial agent should be used for surgical prophylaxis? 3) What is the optimal timing for administering antimicrobial prophylaxis and how long should administration be continued? In this paper we assess the rationales leading to the following answers: 1) Only clean-contaminated and prosthetic clean operations should be eligible for antimicrobial prophylaxis, whereas contaminated or dirty operations should be eligible for "early therapy". 2) First- or second-generation cephalosporins or aminopenicillin/beta-lactamase inhibitors are optimal choices for surgical prophylaxis, depending on location of the surgical wound. 3) The highest licensed dosage of the chosen antimicrobial agent should be administered at induction of anesthesia and redosing should be considered when the intervention lasts more than 2 antibiotic half-lives. This allows maintenance of optimal drug exposure against the potential pathogens in plasma and in the extracellular environment of the potentially contaminated tissues for the entire procedure and for some hours after wound closure. Post-surgical doses are not recommended in most cases whereas ultra-short prophylaxis is preferred
Chapter 219 - Principles of pharmacodynamics and pharmacokinetics of drugs used in extracorporeal therapies
No full textPharmacokinetic aspects of treating infections in the intensive care unit: focus on drug interactions
No full textPharmacokinetic interactions involving anti-infective drugs may be important in the intensive care unit (ICU). Although some interactions involve absorption or distribution, the most clinically relevant interactions during anti-infective treatment involve the elimination phase. Cytochrome P450 (CYP) 1A2, 2C9, 2C19, 2D6 and 3A4 are the major isoforms responsible for oxidative metabolism of drugs. Macrolides (especially troleandomycin and erythromycin versus CYP3A4), fluoroquinolones (especially enoxacin, ciprofloxacin and norfloxacin versus CYP1A2) and azole antifungals (especially fluconazole versus CYP2C9 and CYP2C19, and ketoconazole and itraconazole versus CYP3A4) are all inhibitors of CYP-mediated metabolism and may therefore be responsible for toxicity of other coadministered drugs by decreasing their clearance. On the other hand, rifampicin is a nonspecific inducer of CYP-mediated metabolism (especially of CYP2C9, CYP2C19 and CYP3A4) and may therefore cause therapeutic failure of other coadministered drugs by increasing their clearance. Drugs frequently used in the ICU that are at risk of clinically relevant pharrmacokinetic interactions with anti-infective agents include some benzodiazepines (especially midazolam and triazolam), immunosuppressive agents (cyclosporin, tacrolimus), antiasthmatic agents (theophylline), opioid analgesics (alfentanil), anticonvulsants (phenytoin, carbamazepine), calcium antagonists (verapamil, nifedipine, felodipine) and anticoagulants (warfarin). Some lipophilic anti-infective agents inhibit (clarithromycin, itraconazole) or induce (rifampicin) the transmembrane transporter P-glycoprotein, which promotes excretion from renal tubular and intestinal cells. This results in a decrease or increase, respectively, in the clearance of P-glycoprotein substrates at the renal level and an increase or decrease, respectively, of their oral bioavailability at the intestinal level. Hydrophilic anti-infective agents are often eliminated unchanged by renal glomerular filtration and tubular secretion, and are therefore involved in competition for excretion. Beta-lactams are known to compete with other drugs for renal tubular secretion mediated by the organic anion transport system, but this is frequently not of major concern, given their wide therapeutic index. However, there is a risk of nephrotoxicity and neurotoxicity with some cephalosporins and carbapenems. Therapeutic failure with these hydrophilic compounds may be due to haemodynamically active coadministered drugs, such as dopamine, dobutamine and furosemide, which increase their renal clearance by means of enhanced cardiac output and/or renal blood flow. Therefore, coadministration of some drugs should be avoided, or at least careful therapeutic drug monitoring should be performed when available. Monitoring may be especially helpful when there is some coexisting pathophysiological condition affecting drug disposition, for example malabsorption or marked instability of the systemic circulation or of renal or hepatic function
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No full textSystemic vancomycin overexposure in a patient with spinal cord injury who had staphylococcal sepsis and Clostridium difficile colitis
No full textIs antimicrobial underexposure due to glomerular hyperfiltration a possible cause of increased mortality rate from bacterial infections in critically ill patients?
No full textantimicrobial underexposure due to glomerular hyperfiltration may be associated to increased mortality rate from bacterial infections in critically ill patient
Clinical relevance of pharmacokinetics and pharmacodynamics in cardiac critical care patients
No full textPharmacokinetics is a discipline aimed at predicting the best dosage and dosing regimen for each single drug in order to ensure and maintain therapeutically effective concentrations at the action sites. In cardiac critical care patients, various pathophysiological conditions may significantly alter the pharmacokinetic behaviour of drugs. Gastrointestinal drug absorption may be erratic and unpredictable in the early postoperative period, and so patients may be unresponsive to oral therapy; thus the intravenous route should be preferred for life-saving drugs whenever feasible. Variations in the extracellular fluid content as a response to the trauma of surgery and the fluid load or significant drug loss through thoracic drainages may significantly lower plasma concentrations of extracellularly distributed hydrophilic antimicrobials (β-lactams, aminoglycosides and glycopeptides). Drug metabolism may be altered by the systemic inflammatory response and/or multiple organ failure and/or drug-drug pharmacokinetic interactions that can potentially occur during polytherapy, especially in immunosuppressed cardiac transplant patients. Instability of renal function may promote significant changes in body fluid concentrations of renally eliminated drugs, even in a brief period of hours. Finally, the application of extracorporeal circulation by means of cardiopulmonary bypass may significantly alter the disposition of several drugs during the operation because of acute haemodilution, hypoalbuminaemia, hypothermia and/or adsorption to the bypass equipment. Accordingly, to avoid either overexposure and the consequent increased risk of toxicity or underexposure and the consequent risk of therapeutic failure in critically ill cardiac patients, the dosing regimens of several drugs are expected to be significantly different from those suggested for clinically stable patients. Additionally, therapeutic drug monitoring may be helpful in the management of drug therapy and should be routinely used to guide individualized dose adjustments for (i) immunosuppressants whenever cytochrome P450 3A4 isoenzyme inhibitors (e.g. macrolide antibacterials, azole antifungals) or inducers (e.g. rifampicin [rifampin]) are added to or withdrawn from the regimen; and (ii) glycopeptide and aminoglycoside antibacterials whenever haemodynamically active agents (such as dopamine, dobutamine and furosemide [frusemide]) are added to or withdrawn from the regimen, and also whenever significant changes of haemodynamics and/or of renal function occur. © 2008 Adis Data Information BV. All rights reserved
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