Pharmacokinetics and administration regimens of vancomycin in neonates, infants and children.

The increased use of vancomycin in neonatal and paediatric patients has prompted numerous pharmacokinetic studies and the development of many empirical administration methods. The majority of dosage guidelines use the relationship between pharmacokinetic parameters and patient variables such as chronological age, bodyweight, and/or measures of renal function. Currently, those dosage guidelines which are based upon postconceptional age and bodyweight seem to provide the best options for empirical administration in neonates and infants. In addition, serum creatinine may prove to be a useful guide to the empirical administration of vancomycin in neonates older than 7 to 14 days. Several investigators have reported the individualisation of dosage regimens based on pharmacokinetic-based administration methods. The most common techniques employed have been Sawchuk-Zaske method and Bayesian forecasting. However, only a limited number of studies have evaluated either empirical administration or individualised administration techniques in patient populations outside those of the original reports; this makes choosing between the methods difficult. Pharmacokinetic data and administration recommendations have gradually become available in special paediatric patient populations. The majority of studies have focused on patients requiring cardiopulmonary bypass surgery or with burns, cancer or central nervous system infections. However, a limited amount of information is available regarding vancomycin disposition in children older than 1 year of age with and without end-stage renal failure. The monitoring of serum vancomycin concentrations may be useful in selected neonatal and paediatric patient populations, especially where large interpatient variability occurs and administration guidelines are not clearly established. Similar to the literature on adults, the lack of conclusive evidence concerning the relationship between serum vancomycin concentrations and therapeutic responses leaves this topic open to debate.

Meropenem: a new carbapenem antimicrobial.

OBJECTIVE: To describe and then compare an investigational carbapenem antibiotic, meropenem, with the only currently available antibiotic in this class, imipenem/cilastatin. DATA IDENTIFICATION: An English language search using MEDLINE (1988-1993); Abstracts of the 31st Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), 1991; and Abstracts of the 32nd ICAAC, 1992. STUDY SELECTION: All current scientific publications were reviewed for study design and quality. Emphasis was placed on susceptibility and pharmacokinetic analysis. Phase 3 clinical trials are now being completed and have only been published in abstract form. Hence, conclusions derived regarding efficacy were tempered. RESULTS: Meropenem is active against a broad spectrum of gram-positive and -negative pathogens including beta-lactamase producers. Meropenem appears to be two- to fourfold less active than imipenem against gram-positive organisms. Meropenem is two- to fivefold more active against enterobacteriaceae. The two compounds appear to be equally active against Pseudomonas aeruginosa. Pharmacokinetic disposition is also similar for imipenem and meropenem. Meropenem may exhibit greater tissue penetration. Meropenem is not labile to renal hydrolysis and can be administered without a competitive antagonist of dihydropeptidase, such as cilastatin. In clinical trials, meropenem appears to be as safe and effective as imipenem/cilastatin or ceftazidime in the treatment of infections involving soft tissue, urinary tract, upper respiratory tract, abdominal processes, and febrile neutropenic episodes. CONCLUSIONS: Meropenem is comparable to imipenem in terms of in vitro susceptibility pattern and pharmacokinetic disposition. Overall, meropenem seems to offer promise as the second of the carbapenem class of antibiotics. Clinical data are preliminary, and further data are needed.

Effects of cardiopulmonary bypass surgery on intravenous ciprofloxacin disposition.

The pharmacokinetic parameters of intravenous ciprofloxacin were examined in five adult male patients on three separate occasions of open heart surgery: the 24 h before cardiopulmonary bypass (CPB) surgery, (PRE), during surgery (SURG), and 48 to 72 h after surgery (POST). Serial blood (n = 16), urine, and SURG tissue samples were collected after intravenous administration of a single 300-mg dose of ciprofloxacin during each study period. All samples were assayed for ciprofloxacin by a specific high-performance liquid chromatographic method. Serum ciprofloxacin concentrations remained constant or continued to decline during the course of CPB surgery. A significant (P < 0.05) decrease in total body clearance was observed during the SURG and POST phases (298 and 306 ml/min/1.73 m2, respectively) compared with that during the PRE phase (364 ml/min/1.73 m2). Renal clearances and elimination half-lives were similar during all three study phases. A nonsignificant decline occurred in the apparent volume of distribution, from mean values of 2.1 and 2.0 liters/kg during the PRE and POST phases, respectively, to 1.7 liters/kg during the SURG phase. The mediastinal fat tissue ciprofloxacin concentrations ranged from 0.45 to 2.89 micrograms/g. Overall, little significant difference was noted in the disposition of intravenous ciprofloxacin during CPB surgery compared with that before and after surgery.

An updated comparison of drug dosing methods. Part IV: Vancomycin.

The resurgence of the use of and interest in vancomycin, in conjunction with the high degree of interpatient variability in its pharmacokinetic profile, has prompted the development of many and varied dosing methods. Several dosing nomograms have been proposed and evaluated, methods which are useful for initial dosing but do not allow for individualisation of dosage. Given these constraints, several investigators have attempted to apply conventional least-squares regression techniques and, more recently, Bayesian methodologies using either 1- or 2-compartment pharmacokinetic models. Comparative information evaluating algorithmic methods demonstrates that those of Moellering and Lake offer the least biased and most precise predictions of vancomycin dosage. Patient individualisation using conventional least-squares methodology offers some improvement over nomogram-based methods, both in predictive performance and in dosage adjustment once serum concentration data are available. Overall, the latest data indicate that regimens which incorporate Bayesian principles tend to give better results than nomogram-based or conventional least-squares dosing methods for this drug. Despite the advances in methods for dosing vancomycin, several questions remain to be answered. A lack of convincing evidence of a correlation between serum concentrations and therapeutic outcome has prompted debate over the need for serum concentration monitoring and, if it is needed, over which patient population would most benefit. Secondly, little comparative information is currently available as to the dosing of vancomycin in paediatric and neonatal patient populations. Several nomograms for initial dosing have been proposed, but only 2 have been subject to subsequent testing. Finally, information regarding cost-effectiveness and the quality of patient outcome is lacking from the current literature.

An updated comparison of drug dosing methods. Part III: Aminoglycoside antibiotics.

Aminoglycoside antibiotics continue to be useful for the treatment of Gram-negative infections. Available dosing methods include predictive algorithms and nomograms, pharmacokinetics-based dosing methods, and methods that incorporate Bayesian forecasting. The individualised Sawchuk-Zaske and Bayesian methods have been extensively evaluated since the previous review in the Journal. Both methods continue to be rapid and accurate means of individualising dosage requirements for patients with diverse pharmacokinetic profiles. The predictive performance of the Bayesian method can be further enhanced when population-based parameters reflect the patient population being monitored. There are now several cost-effectiveness studies that demonstrate that pharmacokinetic dosing services for aminoglycosides result in cost savings, better therapeutic concentrations, fewer toxic serum concentrations, and shorter mean durations of hospital stay and aminoglycoside therapy. Further studies are needed for cost-effectiveness and comparison of various dosing methods in paediatric and neonatal patients.

An updated comparison of drug dosing methods. Part II: Theophylline.

This article updates the previous review in the Journal regarding theophylline dosing methods. Among the predictive algorithms evaluated, the dose-titration scheme of Weinberger and Hendeles was extensively tested in 1073 asthmatic patients. When the scheme was followed appropriately, 78% of initial serum concentrations and 66% of repeat serum concentrations were within the therapeutic range of 10 to 20 mg/L. Several authors have also demonstrated that the 'condition correction factor' method for estimating theophylline clearance is of limited value. The individualised methods of Chiou, Koup and Vozeh have been evaluated in over 300 patients. In addition, numerous authors have reported the relative predictive performance of Bayesian dosing programs for theophylline. All methods continue to be a rapid and accurate means of individualizing dosing requirements for patients with a diverse range of theophylline disposition characteristics. Overall, the Bayesian predictions have been less biased and slightly more precise than the pharmacokinetics-based dosing methods. The most recent cost-effectiveness data has shown that a pharmacokinetic dosing program resulted in fewer toxic serum concentrations (18.9% vs 37.8%), a shorter mean duration of hospital stay (6.3 vs 8.7 days) and more therapeutic concentrations with subsequent oral therapy (71.1% vs 44.4%) than among control patients receiving dosages prescribed by physicians.

An updated comparison of drug dosing methods. Part I: Phenytoin.

The relationship between a dose of phenytoin and the resultant serum concentration is difficult to predict, and numerous dosing methods have been developed to quantify the dose required to achieve a specific concentration. This review brings up to date the earlier article in the Journal regarding predictive algorithms, various pharmacokinetics-based dosing techniques and Bayesian feedback methods for phenytoin dosing. The latest data support the original conclusions that dosing methods for phenytoin which incorporate an individualised approach or Bayesian principles tend to offer results superior to those from predictive algorithms. Bayesian methods have the additional advantage of using only 1 serum concentration, obtained under either steady-state or non-steady-state conditions. There is still a need for future investigations that include prospective evaluations of predictive performance and cost-effectiveness data.

Bayesian forecasting of serum gentamicin concentrations in intensive care patients.

This study retrospectively evaluated the predictive performance of a 1-compartment Bayesian forecasting program in adult intensive care unit (ICU) patients with stable renal function. A comparison was made of the reliability of 3 sets of population-based parameter estimates and 2 serum concentration monitoring strategies. A larger mean error for prediction of peak gentamicin concentrations was seen with literature-derived parameters than when ICU population-based parameter estimates were used. Bias and precision improved when non-steady-state peak and trough concentrations were used to predict those at steady-state; the addition of steady-state values did not provide additional information for predictions once non-steady-state feedback concentrations were incorporated. The addition of 4 serial gentamicin concentrations obtained at both non-steady-state and steady-state did not noticeably improve the predictive performance. The results demonstrate that initial ICU pharmacokinetic parameter estimates for a 1-compartment Bayesian model provide accurate prediction of steady-state gentamicin concentrations. Prediction bias and precision showed the greatest improvement when non-steady-state gentamicin concentrations were used to determine individualised pharmacokinetic parameters.

Clinical pharmacokinetics of daptomycin.

Daptomycin is a new lipopeptide antibiotic for which preliminary pharmacokinetic data in adults have been limited to normal healthy volunteers and patients with renal insufficiency. We report the clinical pharmacokinetics of the first and fifth doses of iv daptomycin 150 mg (2 mg/kg) q24h in a 29-year-old man being treated for a gram-positive cellulitis and thrombophlebitis. Individual pharmacokinetic parameters yielded similar results during doses one and five. The pharmacokinetic profile observed in our patient did not markedly differ from data obtained from healthy volunteers.

Individualizing vancomycin dosage regimens: one- versus two-compartment Bayesian models.

The absolute and relative predictive performances of one- and two-compartment Bayesian forecasting models were evaluated and compared. Initial population parameters were derived from 25 adult patients with stable renal function and who were being treated for presumed or documented gram-positive infections. The performance of each model was compared using these population parameters with and without steady-state or non-steady-state feedback concentrations to predict future peak and trough concentrations in an additional 20 patients. Both models tended to underpredict vancomycin peak and trough concentrations obtained at steady state. The use of a two-compartment model resulted in statistically less bias and more precise predictions of vancomycin peak concentrations when either population parameters or non-steady-state concentrations were used for future predictions. No difference in model performance was observed when steady-state concentrations were used to predict future steady-state concentrations. The results of this evaluation demonstrate that the two-compartment Bayesian model is less biased and more precise in determining future vancomycin serum concentrations given only population parameters or non-steady-state feedback information. No difference in model performance could be discerned when steady-state concentrations were used as feedback information.

Evaluation of a two-compartment Bayesian forecasting program for predicting vancomycin concentrations.

The application of a two-compartment Bayesian forecasting program for vancomycin was tested retrospectively in 45 adult patients with stable renal function. Serial blood samples from 25 of these patients were used to determine population-based parameter estimates. The predictive performance of the Bayesian program was assessed by using both non-steady-state and steady-state vancomycin concentrations as feedback information. Overall, the program tended to underpredict peak and trough steady-state vancomycin serum concentrations. A larger mean prediction error (ME) was seen when non-steady-state feedback serum concentrations were used compared with using population-based parameter estimates (no feedback). In contrast, a marked improvement in ME (peaks: -1.03 versus -2.61; troughs: -1.60 versus -2.07) was seen when steady-state feedback serum concentrations were used compared with no feedback data. Precision improved when either feedback serum concentrations were used to predict steady-state peak and trough vancomycin concentrations. The results from this clinical evaluation demonstrate that the initial pharmacokinetic parameter estimates for a two-compartment Bayesian model provided accurate prediction of steady-state vancomycin concentrations. Prediction bias and precision were improved when steady-state vancomycin concentrations were used to determine individualized pharmacokinetic parameters.

Teicoplanin: an investigational glycopeptide antibiotic.

The chemistry, mechanism of action, antimicrobial spectrum, pharmacokinetics, adverse effects, and clinical uses of teicoplanin are reviewed. Teicoplanin, a novel glycopeptide that is similar to vancomycin, was isolated in the mid-1970s. A fermentation product of Actinoplanes teicomyceticus, teicoplanin is a structurally complex compound made up of six fatty-acid components attached to a common aglycone. Teicoplanin's mechanism of action, like that of vancomycin, is inhibition of cell-wall biosynthesis. In vitro activity is comparable to that of vancomycin and includes staphylococci, streptococci, corynebacterium, listeria, and anaerobic cocci. Resistance to teicoplanin has been reported with coagulase-negative staphylococci. Teicoplanin is 50 to 100 times more lipophilic than vancomycin. Teicoplanin is poorly absorbed after oral administration but is 90% bioavailable when administered intramuscularly. The drug distributes widely into body tissue and is eliminated primarily renally. Optimal dosing regimens and therapeutic serum drug concentrations have not been well established. Reported adverse effects have included irreversible ototoxicity, allergic reactions with maculopapular rash and eosinophilia, pain at intramuscular injection site, and elevation of aminotransferases. Initial clinical trials have yielded conflicting results in gram-positive bacteremia, endocarditis, osteomyelitis, and soft-tissue infections. Teicoplanin has shown promise in surgical and dental prophylaxis. Comparative trials with vancomycin and other antimicrobial agents must be completed before teicoplanin's role as a therapeutic agent in the treatment of systemic gram-positive infections is defined.