Pharmacokinetics Of Antimicrobial Agents Research Articles

Pharmacokinetics of anti-infectious reagents in silkworms

Silkworm microorganism infection models are useful for screening novel therapeutically effective antimicrobial agents. In this study, we used silkworms to investigate the pharmacokinetics and metabolism of antimicrobial agents, in which cytochrome P450 plays a major role. The pharmacokinetic parameters of the antimicrobial agents were determined based on their concentrations in the hemolymph after administration. The parameters, such as half-lives and distribution volumes, in silkworm were consistent with those in mammalian models. In addition, antifungal agents with reduced therapeutic effectiveness due to high protein-binding capacities in mammalian serum exhibited similar features in silkworm hemolymph. Cytochrome P450 enzymes, which metabolize exogenous compounds in mammalian liver, were distributed mainly in the silkworm midgut. Most of the compounds metabolized by cytochrome P450 in humans are also metabolized in the silkworm midgut. These findings suggest that the pharmacokinetics of antimicrobial agents are fundamentally similar between silkworms and mammals, and that therapeutic effects in the silkworm infection model reflect the pharmacokinetics of the test samples.

Pharmakokinetische und pharmakodynamische Aspekte bei der Antibiotikatherapie

Severe sepsis and septic shock have a high mortality and, therefore require fast and effective antibiotic treatment with low toxicity. Because of sepsis-induced pathophysiological changes, pharmacokinetics of antimicrobial agents can be altered. Particularly water-soluble drugs display an enhanced volume of distribution during early sepsis. Therefore high loading doses are necessary. Renal clearance can also be increased at this time. Later on, organ damage frequently occurs resulting in delayed drug elimination which requires further dose adjustment. The different classes of antibiotics differ in their relevant pharmacokinetic-pharmacodynamic target parameters. Thus, the efficacy of an antimicrobial agent can depend on its concentration, on the exposure time, and on the total exposure as expressed by the area under the time-concentration curve. During treatment with time-dependent antibiotics (e.g. β-lactams), their concentration should be maintained above the minimal inhibitory concentration (MIC) warranting more frequent administration or continuous infusion. For concentration dependent agents (e.g. aminoglycosides), the single dose is pivotal, whereas the dosage interval can be extended. Drug-drug interactions involving antibiotics are mainly caused by inhibition of their metabolism, particularly of cytochrome P 450 iso-enzymes, or by additive toxic effects. They can result in severe complications such as renal failure or ventricular arrhythmias. Conversely, enzyme induction may lead to subtherapeutic drug levels. When continuous renal replacement therapy is required, the dosage of antibiotics has to be adapted according to the results of respective pharmacokinetic studies.

A Liquid Chromatography Assay for the Simultaneous Quantification of Piperacillin and Ciprofloxacin in Human Plasma and Dialysate in Critically Ill Patients Undergoing Continuous Renal Replacement Therapy

Piperacillin/tazobactam and ciprofloxacin are often used in combination as initial empiric anti-biotic therapy in critical ill patients. Especially in patients undergoing continuous renal replacement therapy (CRRT) the pharmacokinetics of antimicrobial agents can be highly variable. In order to avoid under- or overdosage of antibiotics therapeutic drug monitoring (TDM) is highly re-commendable. Based on two known HPLC assays for piperacillin a new method in combination with solid phase extraction (SPE) for the simultaneous determination of piperacillin and ciprofloxacin was developed. Method validation was performed according to the EMA guideline on validation of bioanalytical methods. The HPLC column used was a Perfect Bond ODS-HD C18 analytical column (100 mm × 4.6 mm i.d., particle size 5 μm), equipped with a guard column (10 mm × 4.6 mm, particle size 5 μm) containing the same packing material. Detection wavelength was set at 228 nm for piperacillin and benzylpenicillin was used as internal standard (IS). Ciprofloxacin was determined at two wavelengths (280 nm, 315 nm). This newly developed HPLC method in combination with SPE-extraction allows an accurate, precise, specific and efficient determination of piperacillin and ciprofloxacin in biological matrices. Results allow the calculation of all relevant pharmacokinetic data for critically ill patients undergoing CRRT and the optimization of dosing and TDM.

Methods to Measure Target Site Penetration of Antibiotics in Critically Ill Patients

While several tools are necessary to repair a car, the engineer knows exactly which instrument he has to utilize at different parts of the broken machine. Likewise, depending on the information we are interested in, we have to choose different tools to investigate and consecutively understand the multiple aspects that are involved in pharmacokinetics of antimicrobial agents in critically ill patients. Some techniques, like blood sampling, microdialysis or positrons emission tomography (PET) will allow for obtaining continues concentration time profiles while others like bronchoalveolar lavage (BAL), biopsy or surgical tissue samples can only be used a limited number of times per subject. PET and methods based on tissue homogenization will deliver an average of the actual concentrations in intra - and extracellular compartments while investigations in isolated blood cells or microdialysis allow for more distinguished allocation of a concentration to a defined compartment. The present review aims at discussing the advantages and disadvantages of the various methods used for assessing pharmacokinetics in critically ill patients with regard to specific aspects of pharmacokinetic research and further reviews data of selected antibiotics as examples for applications of the individual techniques.

Plasma Pharmacokinetics of Antimicrobial Agents in Critically Ill Patients

Plasma Pharmacokinetics of Antimicrobial Agents in Critically Ill Patients

Chapter 3-5. Appendix: Pharmacokinetics of antimicrobial agents indicated for anaerobic infections

Chapter 3-5. Appendix: Pharmacokinetics of antimicrobial agents indicated for anaerobic infections

Ertapenem in critically ill patients with early-onset ventilator-associated pneumonia: pharmacokinetics with special consideration of free-drug concentration

Most information about pharmacokinetics of antimicrobial agents is obtained from studies in healthy volunteers. However, antibiotics are therapeutically used in infected patients with very different pharmacokinetic properties compared with healthy individuals. In a single-centre, prospective, open-label study, 17 adult critically ill patients with early-onset ventilator-associated pneumonia (VAP) were treated with 1 g of ertapenem infusion once a day. Blood and urine samples were collected before and at different time-points up to 24 h after medication on day 1. Concentrations of ertapenem in plasma were determined with a validated HPLC method. Free-drug concentrations were estimated using a two-class binding site equation. The overall clinical success rate of the assessable cases was 66.7% (12/16). Pharmacokinetic parameters of ertapenem in our critically ill patients were clearly different when compared to those reported in the literature for healthy volunteers. The enhanced V(z) (17 vs. 8 L) and CL(TOT) (43 vs. 20 mL/min) with resulting lower C(max) (90 vs. 253 mg/L) and AUC(0-infinity) (418 vs. 817 mg x h/L) values were mainly related to hypoalbuminaemia (range 9.2-25.6 g/L) in our patient population. A population pharmacokinetic analysis using the NONMEM program indicated creatinine clearance as a significant covariate for explaining the between-subject variability of ertapenem in the patient population. Estimated free plasma concentrations of ertapenem exceeded a MIC(90) of 2 mg/L only for 6 h (25%) after infusion. For an adequate dose adjustment of highly protein-bound drugs like ertapenem, knowledge of actual albumin concentrations is necessary. A shortening of the dosage interval or continuous infusion of ertapenem should be considered to ensure optimal free concentrations in critically ill patients with severe hypoalbuminaemia and normal renal function.

Antimicrobial Resistance in Bacteria of Animal Origin

Resistance to antimicrobial agents develops soon after these life-saving drugs are introduced into human and animal medicine. The role of veterinary and animal use of antimicrobial agents has been debated for years. Frank Aarestrup and colleagues attempt to summarize information concerning this topic in their new book, Antimicrobial Resistance in Bacteria of Animal Origin. This book has 51 contributors, who have written 25 chapters on the public health, clinical, and regulatory importance of antimicrobial drug resistance in bacteria of animal origin. The editor recognizes the complexity of this subject and makes no claims to cover all the issues but rather highlights what he and the contributors believe to be the most important topics. The first 6 chapters highlight modes of action and resistance, history of usage, susceptibility testing, antimicrobial-drug resistance for antimicrobial agents, detection methods, dosing schedules, and mechanisms that lead to the spread of bacterial resistance. These chapters provide the reader with very detailed molecular and genetic information on resistance mechanisms in bacteria of animal origin. Knowing the pharmacodynamics and pharmacokinetics of antimicrobial agents is essential for these drugs to be used correctly, and a good overview of these mechanisms is also provided in these beginning chapters. The book also stresses the urgent need for establishing veterinary-validated breakpoints for species-specific host-pathogen combinations that are clinically relevant. Some of the tables and diagrams in these chapters contain a large amount of material and need to be read carefully to understand the total wealth of information. The 12 middle chapters provide an in-depth review of the known resistance mechanisms found in most of the pathogenic bacteria and bacteria of public health importance in animals. Each chapter takes a closer look at a particular family, genus, or species of bacteria and, when possible, attempts to estimate the prevalence of resistance to key antimicrobial agents. The information provided in these chapters is useful to clinicians, researchers, public health officials, and regulators. For some zoonotic agents, the animal health consequences of resistance are not known. For future editions, expanding on this topic would be helpful. The last 7 chapters attempt to tie all of the previous information together by providing an overview of the licensing and approval procedures for veterinary antimicrobial agents, surveillance systems that monitor resistance and usage, and the use of risk assessments to guide industry and government in decision making. These chapters take a global approach. When possible, side-by-side comparisons of resistance data or surveillance systems are discussed. This book is the first of its kind to provide a comprehensive overview of resistance mechanism in bacteria of animal origin rather than concentrating solely on zoonotic or foodborne bacteria. All uses of antimicrobial agents contribute to resistance, and each use must be examined in an attempt to understand its part in encouraging further dissemination of resistance in bacteria, including bacteria of animal origin. This book will serve as a valuable reference for persons who treat, research, or monitor resistance in bacteria of animal origin.

Pharmacokinetics of three new β-lactams in the Yucatan micropig model administered by intravenous bolus injection and continuous infusion

The miniature pig is becoming a popular non-rodent animal model in biochemical research because of physiological similarities to humans. In addition, the micropig presents the advantages of large animal species for experimental pharmacokinetics. However, pharmacokinetics of antimicrobial agents are poorly documented in the pig and further work is needed to establish interspecies comparisons. This prompted us to investigate the disposition of three well documented β-lactams (cefepime, cefpirome and meropenem) in this model and also to evaluate the potential to use it for pharmacodynamic studies. Each drug was given following a single dose both by direct intravenous injection (or short infusion for meropenem) and continuous infusion. Six animals were enrolled in each group. Blood samples were obtained over a 0–12 h period, using a catheter placed in the external jugular vein. All β-lactams were assayed by high performance liquid chromatography (HPLC). Pharmacokinetics of cefepime and cefpirome given by bolus injection in the microswine were close to those in man receiving equivalent dosage (i.e. 2 g). The terminal half-lives are similar (human: 1.80 h, 1.80 h; pig: 1.46 h, 1.29 h) as is the case for clearance values (human: 1.82, 1.80; pig: 1.90, 1.74 ml/min per kg) for cefepime and cefpirome, respectively. The administration by continuous infusion does not influence the elimination rate of cefepime, cefpirome and meropenem. Meropenem kinetics in the micropig were also similar to those in man. The terminal half-lives are similar (human, 0.83 h; pig, 0.88 h) as in the case for clearance values (human, 4.0 h; pig, 4.90 ml/min per kg) after 30 min intravenous infusion of meropenem. We concluded that the micropig is an adequate model for the study of the pharmacokinetics and probably the pertinent model for ex-vivo pharmacodynamics investigations of cefepime, cefpirome and meropenem.

Pharmacokinetics of antimicrobial agents in anuric patients during continuous venovenous haemofiltration

The optimal drug dosing in anuric patients undergoing continuous haemofiltration is a difficult task. More pharmacokinetic data is needed to derive practical guidelines for dosage adjustments. Drug elimination of various antimicrobial agents (amikacin, amoxycillin, ceftazidime, ciprofloxacin, flucloxacillin, imipenem, netilmicin, penicillin G, piperacillin, sulphamethoxazole, tobramycin, vancomycin) was studied in 24 patients with acute renal failure treated by pump-assisted continuous venovenous haemofiltration (CVVH). Concentrations of serial blood and ultrafiltrate samples were determined by HPLC or by fluorescence polarization immunoassay. Total body clearance (CL) and haemofilter clearance (CLf) rates were determined by standard model-independent equations. Data from published literature on fractions not bound to proteins (fu), non-renal drug clearance fractions (Qo), and normal clearance values (CLn) were used to derive a pharmacokinetic model, taking into account drug removal by ultrafiltration and by non-renal clearance. A total of 37 treatment periods was studied. Blood flow through the haemofilters was 100 ml/min resulting in an average ultrafiltrate flow rate (UFR) of 13.2 +/- 4.6 (range 3.2-22.1) ml/min. Acceptable correlations of calculated and measured haemofilter clearances and total body clearances were obtained. Total body clearance in anuric patients during CVVH is predictable from drug properties, which are generally known. The individual dosage requirements may be calculated by multiplying Qo + fu.UFR/CLn with the dose considered appropriate in the absence of renal impairment.

Pharmacokinetics of antimicrobial agents in anuric patients during continuous venovenous haemofiltration

Pharmacokinetics of antimicrobial agents in anuric patients during continuous venovenous haemofiltration

ANTIBACTERIAL AGENTS IN RENAL FAILURE

This article provides background information on the pharmacokinetics of antimicrobial agents in patients with normal and impaired renal function. Tables are provided to allow quick determination of appropriate dosages for varying degrees of renal failure. Specific mention is made of aminoglycoside dosing, dosage adjustment in dialysis, and antibiotic toxicity in renal failure.

Pharmacokinetics of antibiotics in shallow and deep compartments.

This paper reviews the influence of the type of capillary bed, type of compartment, and the presence of active transport systems, on the pharmacokinetics of antimicrobial agents in tissues and fluids of the body. In the absence of active transport or local degradation, the mean concentration or 'area under the curve' of free (unbound) drug in ordinary extravascular sites over the dosing interval at equilibrium is equal to that in the serum. Because the latter is easily measured, there should be no need to measure tissue concentrations except in unusual circumstances. Among the factors that will alter the relationship described above are active transport, pH partition, and bulk flow. Antibiotics such as the macrolides, lincosamines and quinolones may accumulate in high concentrations in cells containing lysosomes. There is some evidence that the intracellular sites may serve as a reservoir from which these drugs may later be released into tissue fluids, a phenomenon not taken into account in the relationships described above. Although knowledge of the in-vitro activity and local concentrations of antibiotics is of use in predicting therapeutic activity, many factors which are difficult to quantify in a given instance make precise correlations impossible. The inability of antibiotics alone to sterilize abscesses is probably not due to a problem in antibiotic penetration but to insusceptibility of the organisms and inefficacy of the phagocytes in an abscess. Similar processes operate to reduce the efficacy of antibiotics when treatment is delayed.

Pharmacokinetics of antimicrobial agents in organ function impairment

The pharmacokinetics of antimicrobial drugs in various types of organ function impairment are reviewed. The influence of renal function impairment on antimicrobial agents is well-known, although less is known about the accumulation of metabolites during renal failure. Fewer data are available on liver function impairment and more information is needed on highly metabolized agents. Pharmacokinetic studies in severely ill patients are urgently needed to investigate the influence of disease states on pharmacokinetics and to study the possibility of oral administration to seriously ill patients.

Effect of mucin on the pharmacokinetics of antibiotics in the rat.

The intramuscular pharmacokinetics of ticarcillin and amikacin in rats receiving 1 ml of 5% mucin suspension (equivalent to 250 mg/kg) administered intraperitoneally were not altered compared with the control animals. However, it is important to investigate the effect of mucin on the pharmacokinetics of antimicrobial agents in animals which are used to evaluate the efficacy of the agents.

Pharmacokinetics of antimicrobial agents in the elderly.

Many elderly individuals are treated with antibiotics, but knowledge of the pharmacokinetic performance of the compounds in these patients is limited. Advanced age is accompanied by many physiologic alterations that may have secondary effects on absorption, distribution, metabolism, and excretion of drugs. Information on absorption and metabolism in the elderly is scarce and conflicting. Because renal excretion of penicillins and cephalosporins decreases with the physiologic signs of the kidneys, dose reduction is advisable in elderly patients. Monitoring of serum drug levels is recommended for the selection of correct dosages of renally eliminated antibiotics with a narrow therapeutic range--e.g., aminoglycosides and vancomycin. There is a considerable need for additional studies of the influence of age on the kinetics of antimicrobial agents.

Considerations about the relationship of inhibitory concentrations and the pharmacologic and toxic properties of antimicrobial agents

Too little attention has been given to the correlation of antimicrobial susceptibility tests and the pharmacokinetics of antimicrobial agents. Ability to perform and provide reproducible, rapid, minimal inhibitory concentration data, combined with the knowledge of serum levels, can be used to yield inhibitory quotients which will improve the chemotherapy of serious infections. Antimicrobial susceptibilities have to be provided rapidly for the life-threatening infections that occur in certain clinical settings. Antimicrobial susceptibilities also must be provided in a manner that demonstrates that one may not be able to achieve therapeutic concentrations with certain drugs. We have reached an era in which knowledge of an organism being susceptible or resistant is no longer adequate.

Principles of Antibiotic Therapy

Many host factors influence both the presentation and response to therapy of clinical infections. Since the selection of an appropriate antibiotic depends significantly upon results of in vitro susceptibility testing, great care should be taken to obtain suitable specimens for culture and susceptibility studies. The likelihood that antibiotic therapy will be successful depends upon whether the drug will reach the infected site at the desired concentration and for an optimal duration of time. Local factors such as pH, oxygen tension, and the presence of inactivating substances may affect antibiotic activity. At present, many of our recommendations for dose, dosage intervals, and duration of therapy are largely empiric. Enhanced understanding of the pharmacokinetics of antimicrobial agents should provide the basis for more rational therapy in the future. The remainder of this symposium will present the data from which such recommendations can be drawn.