Investigations over the past 20 years have demonstrated that antibacterials can vary markedly in the time course of antimicrobial activity. These differences in pharmacodynamic activity have implications for optimal dosage regimens. The results of more recent studies suggest that the magnitude of the pharmacokinetic/pharmacodynamic parameters required for efficacy are relatively similar in animal infection models and in human infections. However, there is still much to learn. Additional studies are needed to further correlate pharmacokinetic/pharmacodynamic parameters for many antibacterials with therapeutic efficacy in a variety of animal infection models and in human infections. The potential value of using pharmacokinetic/pharmacodynamic parameters as guides for establishing optimal dosing regimens for new and old drugs and for new emerging pathogens and resistant organisms, for setting susceptibility breakpoints, and for reducing the cost of drug development should make the continuing search for the therapeutic rationale of antibacterial dosing of mice and men worthwhile.

http://loyce2008.free.fr/Microbiologie/PK%20PD/Craig,%20PK-PD%20parameters,%20rationale%20for%20antibacterial%20dosing%20CID%201998.pdf

Pharmacokinetic/Pharmacodynamic Parameters: Rationale for Antibacterial Dosing of Mice and Men

Objective: To summarise quantitatively the association between moderate alcohol intake and biological markers of risk of coronary heart disease and to predict how these changes would lower the risk. Design: Meta-analysis of all experimental studies that assessed the effects of moderate alcohol intake on concentrations of high density lipoprotein cholesterol, apolipoprotein A I, fibrinogen, triglycerides, and other biological markers previously found to be associated with risk of coronary heart disease. Participants: Men and women free of previous chronic disease and who were not dependent on alcohol Studies were included in which biomarkers were assessed before and after participants consumed up to 100 g of alcohol a day. Interventions: Alcohol as ethanol, beer, wine, or spirits. Main outcome measures: Changes in concentrations of high density lipoprotein cholesterol, apolipoprotein A I, Lp(a) lipoprotein, triglycerides, tissue type plasminogen activator activity, tissue type plasminogen activator antigen, insulin, and glucose after consuming an experimental dose of alcohol for 1 to 9 weeks; a shorter period was accepted for studies of change in concentrations of fibrinogen, factor VII, von Willebrand factor, tissue type plasminogen activator activity, and tissue type plasminogen activator antigen. Results: 61 data records were abstracted from 42 eligible studies with information on change in biological markers of risk of coronary heart disease. An experimental dose of 30 g of ethanol a day increased concentrations of high density lipoprotein cholesterol by 3.99 mg/dl (95% confidence interval 3.25 to 4.73), apolipoprotein A I by 8.82 mg/dl (7.79 to 9.86), and triglyceride by 5.69 mg/dl (2.49 to 8.89). Several haemostatic factors related to a thrombolytic profile were modestly affected by alcohol On the basis of published associations between these biomarkers and risk of coronary heart disease 30 g of alcohol a day would cause an estimated reduction of 24.7% in risk of coronary heart disease. Conclusions: Alcohol intake is causally related to lower risk of coronary heart disease through changes in lipids and haemostatic factors. Key messages Results from observational studies provide strong evidence that moderate alcohol intake lowers risk of coronary heart disease Short term trials of alcohol intake show significant changes in concentrations of lipids and clotting factors The changes in concentrations of high density lipoprotein cholesterol, fibrinogen, and triglycerides associated with an intake of 30 g of alcohol a day should reduce risk of coronary disease by 24.7% Alcohol intake may be causally related to lower risk of coronary heart disease through changes in lipids and haemostatic factors

https://www.bmj.com/content/bmj/319/7224/1523.full.pdf

Moderate alcohol intake and lower risk of coronary heart disease: meta-analysis of effects on lipids and haemostatic factors.

In an examination of the relationships among plasma aminoglycoside concentrations, the minimal inhibitory concentration (MIC) for the infecting organism, and therapeutic outcome, data were analyzed from 236 patients with gram-negative bacterial infections who were participants in four clinical trials of gentamicin, tobramycin, and amikacin. Clinical response to therapy occurred in 188 (80%) patients. Elevated maximal and mean peak aminoglycoside concentration/MIC ratios were strongly associated with clinical response (P less than .00001 and P less than .0001, respectively). A graded dose-response effect was found between an increasing maximal peak concentration/MIC ratio and clinical response. By logistic regression the peak concentration/MIC ratios were associated significantly with clinical response after adjustment for underlying severity of illness and other factors correlated with response. These results demonstrate that a high peak concentration relative to the MIC for the infecting organism is a major determinant of the clinical response to aminoglycoside therapy.

Clinical Response to Aminoglycoside Therapy: Importance of the Ratio of Peak Concentration to Minimal Inhibitory Concentration

Aminoglycosides are highly potent, broad-spectrum antibiotics with many desirable properties for the treatment of life-threatening infections ([28][1]). Their history begins in 1944 with streptomycin and was thereafter marked by the successive introduction of a series of milestone compounds (

/pdf/aminoglycosides-activity-and-resistance-tw1debuc93.pdf

Aminoglycosides: Activity and Resistance

Infections in critically ill patients are associated with persistently poor clinical outcomes. These patients have severely altered and variable antibiotic pharmacokinetics and are infected by less susceptible pathogens. Antibiotic dosing that does not account for these features is likely to result in suboptimum outcomes. In this Review, we explore the challenges related to patients and pathogens that contribute to inadequate antibiotic dosing and discuss how to implement a process for individualised antibiotic therapy that increases the accuracy of dosing and optimises care for critically ill patients. To improve antibiotic dosing, any physiological changes in patients that could alter antibiotic concentrations should first be established; such changes include altered fluid status, changes in serum albumin concentrations and renal and hepatic function, and microvascular failure. Second, antibiotic susceptibility of pathogens should be confirmed with microbiological techniques. Data for bacterial susceptibility could then be combined with measured data for antibiotic concentrations (when available) in clinical dosing software, which uses pharmacokinetic/pharmacodynamic derived models from critically ill patients to predict accurately the dosing needs for individual patients. Individualisation of dosing could optimise antibiotic exposure and maximise effectiveness.

/pdf/individualised-antibiotic-dosing-for-patients-who-are-lhuvmfis7x.pdf

Individualised antibiotic dosing for patients who are critically ill: challenges and potential solutions

Cephalothin plus an aminoglycoside is more nephrotoxic than methicillin plus an aminoglycoside

High kidney concentrations of gentamicin or amikacin, measured by an enzymological assay, were found in 9 of 10 patients who died during therapy with these aminoglycosides. Renal cortical concentrations of gentamicin ranged from 140 to 540 μg/g of tissue, with medullary levels of 128 to 230 μg/g. Concentrations of amikacin ranged from 365 to 1,030 μg/g in the cortex and from 270 to 718 μg/g in the medulla. The only patient with low kidney concentrations was an infant who received a single dose of gentamicin. Tissue levels were high in patients with both normal and abnormal renal function. Our results indicate that gentamicin and amikacin are concentrated in renal cortical and medullary tissue.

Concentrations of Gentamicin and Amikacin in Human Kidneys

Effect of low-dose alcohol use versus abstention on apolipoproteins A-I and B.

We have reviewed our data from 391 patients entered into three prospective, double-blind studies of aminoglycosides and evaluated 127 cases to determine whether aminoglycoside-induced auditory toxicity and nephrotoxicity are independent events. The cases selected for evaluation included all patients treated for greater than 3 days (mean, 7.7 days) who had serial creatinine determinations and were able to cooperate with serial bedside audiograms (250 to 8,000 Hz). Patients received either gentamicin, tobramycin, or amikacin. Drug dosage was altered to keep serum levels 1 h after administration between 5 and 10 mug/ml (gentamicin or tobramycin) or 20 and 40 mug/ml (amikacin). The investigators evaluating auditory toxicity and nephrotoxicity were blind to the aminoglycoside being administered. The incidence of auditory toxicity in the nephrotoxic group (18.2%) was not significantly different from that in the nonnephrotoxic group (15.2%) (P = 0.75; Fisher exact test). There was no statistical difference between the nephrotoxic and auditory toxic groups in patient age, total dose of aminoglycoside, initial creatinine level, duration of therapy, or concurrent use of furosemide or cephalothin. We conclude that aminoglycoside-induced auditory toxicity and nephrotoxicity are independent events when the drug is administered for approximately 7 days and when aminoglycoside levels are maintained within a predefined range.

Craig R. Smith

Papers

Clinical Response to Aminoglycoside Therapy: Importance of the Ratio of Peak Concentration to Minimal Inhibitory Concentration

Cephalothin plus an aminoglycoside is more nephrotoxic than methicillin plus an aminoglycoside

Concentrations of Gentamicin and Amikacin in Human Kidneys

Effect of low-dose alcohol use versus abstention on apolipoproteins A-I and B.

Relationship between aminoglycoside-induced nephrotoxicity and auditory toxicity