Shorter Dosing Intervals Research Articles

Dosage Regimens of Antibacterials

A prominent trend in optimising anti-infective therapy is to prescribe time-dependent antibacterials (e.g. β-lactams, glycopeptides) using short dosing intervals, but to prescribe concentration-dependent antibacterials (e.g. aminoglycosides, quinolones) using widely spaced intervals — even once daily. However, the currently prevailing notion that the clinical efficacy of concentration-dependent antibacterials can be improved by lengthening the dosing interval has not been well established. We integrated the differential equations of a pharmacokinetic/pharmacodynamic model describing the fate of a bacterial population in the presence of an antibacterial agent. We studied the variations of predicted efficacy, using a 1-compartment pharmacokinetic model with intravenous administration, according to the ratio between the dosing interval and the half-life of the drug, for a given daily dose. Simulations were performed using the published in vitro killing curve data of Pseudomonas aeruginosa obtained with tobramycin and ticarcillin. The results suggest that, independent of the time- or concentration-dependent nature of the antibacterial agent and the susceptibility of the pathogen, steady-state efficacy will decrease as the dosing interval increases, and therefore all antibacterials should ideally be administered at relatively short dosing intervals compared with their half-life, so that concentrations are below the minimum inhibitory concentration (MIC) as little as possible. Some arguments support the use of a large loading dose for concentration-dependent antibacterials, to rapidly reach steady-state at the infection site (this is also valid for time-dependent antibacterials), and to avoid the emergence of resistant mutants. Aminoglycosides are a special case within the class of concentration-dependent antibacterials, because of the possibility of adaptive resistance in terms of efficacy and of saturable target-organ uptake in terms of toxicity, both of which may support the concept of a long administration interval for these agents. Widely spaced administration of large doses of antibacterials with little dose-dependent toxicity may remain a valuable option, for reasons of cost and convenience, in the case of high susceptibility of the pathogen. However, in difficult situations (e.g. short drug half-life, high MIC of the pathogen, compromised host defences), optimising therapy using short dosing intervals should be most beneficial, especially when both the dose and the dose interval are adjusted for each patient (bodyweight, renal function, etc.) to achieve and maintain specific peak and trough concentrations selected according to the infecting organism and its susceptibility to the drug.

Continuous Spinal Anesthesia with Invasive Hemodynamic Monitoring for Surgical Repair of the Hip in Two Patients with Severe Aortic Stenosis

Continuous Spinal Anesthesia with Invasive Hemodynamic Monitoring for Surgical Repair of the Hip in Two Patients with Severe Aortic Stenosis

Continuous Spinal Anesthesia with Invasive Hemodynamic Monitoring for Surgical Repair of the Hip in Two Patients with Severe Aortic Stenosis

25%, severe global hypokinesis, and moderate mitral regurgitation. The patient also had a history of hypertension, atria1 fibrillation (AF), and noninsulin-dependent diabetes. His preoperative medications included digoxin, furosemide, enalapril, nitroglycerin patch, and glyburide. He had no known drug allergies. On physical examination, the patient was 180 cm in height and weighed 62 kg. Heart rate (HR) and blood pressure (BP) were 74 bpm and 120/70 mm Hg, respectively. Head and neck evaluation was significant for a Mallampati class II airway and decreased range of motion of the neck. The cardiac examination revealed an irregularly irregular heart beat with a grade 3/6 systolic murmur. The lungs were clear to auscultation. The electrocardiogram (ECG) revealed AF with a ventric

Antianginal and Anti-Ischemic Efficacy of Nicorandil in Comparison with Isosorbide-5-Mononitrate and Isosorbide Dinitrate

The purpose of the two double-blind studies summarized in this article was to compare the antianginal and anti-ischemic effects of nicorandil with those of two different nitrate preparations. A total of 129 patients with stable New York Heart Association functional class II or III coronary heart disease were enrolled in the studies. Ninety-five patients received nicorandil, 34 received isosorbide dinitrate (ISDN), and 63 received isosorbide-5-mononitrate (MN). In study 1, nicorandil was compared with MN in a crossover design with 54 protocols eligible for efficacy assessment of MN and 52 eligible for nicorandil, respectively. Twenty milligrams of nicorandil and 20 mg MN administered b.i.d. for 4 weeks were equally effective in the treatment of stress-induced angina. Both drugs prolonged bicycle exercise tolerance and reduced weekly anginal attack rates. In study 2, nicorandil and ISDN were administered to two parallel groups of patients at a dose of 10 mg t.i.d. for 2 weeks and then 20 mg t.i.d. for 4 weeks. Under the assumption that the repetitive administration of nitrates with short dosing intervals might induce the development of tolerance to the nitrate mechanism of action, the t.i.d.-dosing regimen had been chosen in this study. Thirty-two protocols from those receiving nicorandil and 34 protocols from those receiving ISDN were eligible for efficacy assessment. Both drugs increased exercise capacity and reduced ST-segment depression at identical work loads with no significant difference between groups (p > 0.05). For both drugs, the higher doses were more effective than the lower doses. tolerance to the nitrate mechanism of action did not develop with either drug.(ABSTRACT TRUNCATED AT 250 WORDS)

Usefulness of oral nisoldipine for stable angina pectoris

The duration and extent of antianginal effects of nisoldipine, a dihydropyridine calcium antagonist, were assessed in 178 patients with chronic stable angina pectoris. Using a placebo run-in, placebo-controlled, randomized, parallel study design, patients received placebo twice daily for 2 to 3 weeks and were then randomized to receive either placebo (n = 42), nisoldipine 10 mg once daily (n = 44), nisoldipine 10 mg twice daily (n = 47) or nisoldipine 20 mg once daily (n = 45) for 5 weeks. Frequency of angina and nitroglycerin consumption were assessed by weekly patient diaries. Exercise tolerance time was assessed at baseline and at weeks 1, 3 and 5 in the double-blind phase. Peak effects after 5 weeks of double-blind medication showed significant or nearly significant improvements with nisoldipine over placebo in time-to-termination of exercise, time to onset of angina, and time to onset of 1 mm ST-segment depression. There were no significant improvements in trough effects with nisoldipine. Also, placebo was not significantly different from nisoldipine in either the number of anginal attacks or nitroglycerin consumed. Although significantly more drug-related, adverse effects were observed with the nisoldipine regimen, 20 mg once daily, compared with placebo, nisoldipine appears to be an effective and well-tolerated antianginal drug. However, its duration of antianginal action, as measured by exercise stress testing, is relatively short. The drug needs to be examined using shorter dosing intervals and higher daily doses, or in a longer-acting sustained-release formulation.

Comparison of 6 and 8 hourly tobramycin dosing intervals in treatment of pulmonary exacerbations in cystic fibrosis patients

The efficacy and toxicity of a shortened tobramycin dosing interval in the treatment of exacerbations of Pseudomonas aeruginosa pulmonary infection in cystic fibrosis patients were evaluated prospectively. Patients ages 13 to 30 years received 34 treatment courses and were randomized by pairs to receive tobramycin administered either every 6 or 8 hours. Peak serum concentrations were adjusted to 8 to 10 micrograms/ml; thus a larger total daily dosage was administered to patients receiving tobramycin every 6 hours. The shorter dosing interval was associated with better pulmonary function at follow-up and significantly longer time before next hospital admission for a pulmonary exacerbation. During the study hospitalization there were no differences in pulmonary function tests, clinical score, sputum carriage of P. aeruginosa, toxicity or necessary length of hospitalization. A 6-hour tobramycin dosing interval was more efficacious than an 8-hour dosing interval in the treatment of cystic fibrosis patients.

Treatment of Patent Ductus Arteriosus With Indomethacin-Reply

In Reply .—Spritzer and Sauer report their experience with an indomethacin regimen that includes higher doses and a shorter dosing interval. The clinical response appears to be somewhat better than that achieved in our study. Because of our disappointing clinical results, we altered our indomethacin administration protocol to achieve therapeutic serum indomethacin levels greater than 500 ng/dL over a period of five to seven days. Indomethacin was administered daily using a dosage schedule adjusted according to the serum indomethacin level. Thus far, 21 premature infants weighing between 700 and 1200 g have been treated in this manner. The results are similar to those we reported with a more standard drug administration regimen. Initial constriction or closure occurred in 19 (90%) of 21 infants, but ductal reopening occurred frequently, and eventually nine (43%) of 21 infants required ductal ligation. Thus, it appears that long-term administration of indomethacin is no more efficacious than short-term

Effects of sucralfate or mild irritants on experimental gastritis and prostaglandin production

Rats pretreated with dilute ethanol, dilute hydrochloric acid, or dilute sodium hydroxide had significantly less gastric mucosal damage when they were exposed 15 or 30 minutes later to strong irritants. The dilute agents, known as mild irritants, also caused an increase in the production of gastric mucosal prostaglandin E 2 at the 15- and 30-minutes dosing intervals. This suggests that the mild irritants are only effective in providing gastric mucosal protection when they increase gastric production of prostaglandin E 2. Sucralfate treatment also caused an increase in gastric mucosal production of prostaglandin E 2 at only the 15- and 30-minute dosing intervals. In contrast, pretreatment with sucralfate protected against the damaging effects of the strong irritants for at least 480 minutes. Therefore, prostaglandin E 2 may play a role in sucralfate's protective effect at short dosing intervals, but at longer intervals, when prostaglandin E 2 changes were not observed, sucralfate was still found to be very effective in reducing the severity of gastritis. This suggests that sucralfate acts, at least in part, through some other mechanism(s) besides increasing gastric mucosal prostaglandin E 2 production.

Identification of children for whom routine monitoring of aminoglycoside serum concentrations is not cost effective

On the basis of our clinical impression that aminoglycoside serum concentration measurements did not result in dosage changes in many children with normal renal function, data collected during pharmacokinetic consultations were evaluated to identify pediatric patients for whom routine serum concentration monitoring would not be cost effective. The frequency of peak or trough concentrations outside the desired ranges was related to age and duration of therapy in 88 children with normal renal function who were given recommended doses of gentamicin or tobramycin. Trough concentrations were outside the target range (greater than 2 micrograms/ml) in five of 26 patients who had received more than 10 days of therapy or were older than 18 years of age. In contrast, troughs were less than 2 micrograms/ml and did not significantly increase over the course of therapy in all patients who were younger than 18 years of age and had received less than 10 days of therapy. This latter group represented 36% of all aminoglycoside pharmacokinetic consultation requests to our service. In addition, when infusion technique and sample time were meticulously controlled, peak concentrations were greater than or equal to 4 micrograms/ml in all patients who had received a dose of approximately 2.5 mg/kg. We conclude that routine peak and trough measurements are unnecessary in patients between 3 months and 18 years of age unless duration of therapy extends beyond 10 days, renal function is impaired, there is a clinical need for higher doses or shorter dosing intervals, or a potential nephrotoxin has been administered in the previous 3 months.

Diurnal variation in cyclosporine kinetics.

Venkataramanan, Raman*; Yang, Shuin†; Burckart, Gilbert J.*; Ptachcinski, Richard J.*; Van Thiel, David H.‡; Starzl, Thomas E.† Author Information

196 PROCAINAMIDE ELIMINATION KINETICS IN PEDIATRIC PATIENTS

Procainamide (PA) is a common antiarrhythmic used in pediatrics, yet little is known about its kinetics in children. We examined PA elimination kinetics following a single intravenous dose (range 4-30 mg/kg) in 5 patients (pts), ages 6-16 yrs, (ventricular tachycardia 3 pts, atrial flutter 2 pts). Serial blood samples were analysed for PA and N-acetyl procainamide (NAPA) by a gas chromatographic assay. PA concentration-time curves fit a two compartment model and the following pharmacokinetic parameters were calculated: distribution half-life, T½α = 0.16 ± 0.09 (mean ± S.D.) hr; elimination half-life, T½β = 1.99 ± 0.37 hr; apparent volume of distribution, VD = 2.34 ± 0.42 L/Kg; elimination rate constant, KE = 1.23 ± 0.54 hr−1 and plasma clearance, PCL = 14.97 ± 4.51 ml/min/kg. NAPA levels peaked 2.04 ± 1.21 hr after PA administration and the elimination half-life was 3.5 ± 1.1 hr. The elimination half-life for PA in our patients is significantly lower than that reported in healthy adult volunteers (1.99 ± 0.37 vs 2.80 ± 0.44 hr; p < 0.05) whereas, the volume of distribution is higher (2.34 ± 0.42 vs 1.98 ± 0.84 L/Kg, p < 0.05). The short PA elimination half-life appears to be related to a significantly higher plasma clearance in children (14.97 ± 4.51 vs 5.86 ± 1.26 ml/min/kg, p < 0.02). Thus, pediatric patients should require relatively higher doses and/or shorter dosing intervals, as compared to adults, to achieve therapeutically effective blood levels of PA.

Relationship of theophylline clearance to oral dosage in children with chronic asthma

Theophylline clearance was examined in 23 children with chronic asthma by administering constant intravenous infusions of theophylline until steady-state serum concentrations were documented. Clearance was subsequently related to peak and trough serum concentrations during a multiple-dose oral theophylline regimen. Although theophylline clearances tended to decrease with age, considerable interpatient variability was observed. Clearances correlated inversely with a standardized index of serum concentration response to oral dosage resulting in a wide range of dosage requirements to maintain therapeutic serum concentrations of 10 to 20 microgram/ml. Intrapatient variability over an interval up to seven months, however, was acceptably small, suggesting that dosage requirements, once established for an individual, should remain relatively stable under normal conditions. Differences in serum theophylline values during a 6-hour dosing interval among children who were receiving theophylline on a continuous basis correlated with clearance and averaged 9 +/- 3 microgram/ml (mean +/- SD), exceeding to 10 microgram/ml interval width of the therapeutic range among 40% of the children. This observation supports the clinical need for reliable sustained-release preparations of theophylline for children who are receiving continuous therapy in order to avoid unrealistically short dosing intervals.

Practical Pharmacokinetic Techniques for Drug Consultation and Evaluation IV: Gentamicin Blood Level Versus Time Profiles of Various Dosage Regimens Recommended for Renal Impairment

The gentamicin blood level vs. time profiles of various dosage regimens recommended for renal impairment were reassessed by applying pharmacokinetic techniques to the patient data in the clinical literature. Eight dosage regimen modifications were tested in eight prototype cases of renal impairment (serum creatinine range of 0.9-12.0 mg/100 ml and creatinine clearance range of 5-100 ml/min/1.73 m-2) using simulated blood level vs. time profiles generated from the known pharmacokinetic parameters for gentamicin. Employing a one-hour intravenous infusion at dosages and dosing intervals recommended by the various blood level vs. time profiles. Methods recommending shorter dosing intervals (every 24 hours and less) generally resulted in a greater percent duration of the dosing interval above the selected "effective response concentration" (ERC) of a 4mug/ml blood level and a markedly shorter duration of sub-ERC blood levels. Methods based on creatinine clearance as an index of renal function generally achieved greater percent duration of the dosing interval above the ERC and lesser duration of blood levels below this value than methods based on serum creatinine.