Multiple Daily Dosing Regimens Research Articles

Aminoglycosides: single- or multiple-daily dosing? An updated qualitative systematic review of randomized trials on toxicity and efficacy.

Aminoglycosides are among the first-choice antibiotics for routine clinical use. However, dose-limiting factors such as ototoxicity and nephrotoxicity are considered as serious complications of aminoglycosides. In this systematic review, the main goal was to investigate the efficacy and incidence of nephrotoxicity and ototoxicity of once-daily dosing (ODD) and multiple daily dosing (MDD) regimens of aminoglycosides through available randomized controlled trials (RCTs). We performed a literature-based research in relevant databases, including EMBASE, MEDLINE, and SCOPUS published between 1987 and 2023 using the keywords "aminoglycosides", "pharmacokinetics", "ODD", "MDD", "once daily", "multiple daily", "dosing regimen", "nephrotoxicity", "ototoxicity", "efficacy", "safety", and "toxicity". As so told, the results of this article were limited to papers available in English. Our initial search yielded 1124 results. After a review of the titles and abstracts of the articles, 803 articles were excluded from this study because they did not address the toxicity and effectiveness of ODD versus MDD of aminoglycosides. A total number of 21 studies on gentamicin, tobramycin, netilmicin, and amikacin met the inclusion criteria for the efficacy of aminoglycosides and their role in ototoxicity and nephrotoxicity were included in this review. Studies recruited different age classes, and the age of relevant cohorts varied from only a few days to more than 70 years. The most common clinical condition in the included studies was cystic fibrosis. In most studies, there were no significant differences between the two regimens regarding ototoxicity. In addition, the ODD regimens were safer than MDD concerning nephrotoxicity.

Gentamicin Vestibulotoxicity: Further Insights From a Large Clinical Series.

To review insights gained from a 21-year experience with gentamicin-induced vestibulotoxicity including differences in vestibulotoxicity between single daily dosing (SDD) and multiple daily dosing (MDD) regimens. Retrospective case series. Tertiary care center. Patients with gentamicin vestibulotoxicity referred to the Hertz Multidisciplinary Neurotology Clinic between January 1993 and September 2014. None. Spectrum of vestibular dysfunction measured using videonystagmography, vestibular evoked myogenic potentials, video head impulse testing, and magnetic scleral search coil testing. Of 53 patients with gentamicin-induced vestibulotoxicity, 24 received SDD and 29 received MDD treatment. The most common indications for treatment were sepsis, endocarditis, and osteomyelitis. Angular acceleration receptor function (semicircular canals) was more commonly affected than linear acceleration receptor function (otolithic organ of the saccule; 100% vs. 62%). A significant proportion of patients (53%) developed vestibulotoxicity in the absence of nephrotoxicity and 40% experienced vestibulotoxicity in a delayed fashion up to 10 days posttreatment cessation (mean 3.9 ± 0.7). Therapeutic monitoring did not necessarily prevent delayed vestibulotoxicity. Nephrotoxicity was less common for SDD compared with MDD (60% vs. 35%, p = 0.01). However, the SDD group experienced vestibulotoxicity at a lower cumulative dose (6.3 vs. 7.0 g, p = 0.04) and shorter duration of therapy (20.7 vs 29.4 d, p = 0.02). Our study further highlights important insights regarding gentamicin-induced vestibulotoxicity. While SDD is associated with decreased risk for nephrotoxicity compared with MDD, it confers a higher risk for vestibulotoxicity.

DEVELOPMENT OF A ONCE DAILY GENTAMICIN REGIMEN FOR PAEDIATRIC SURGERY PATIENTS

AimIntravenous gentamicin is given as a 5 day course to paediatric patients who have undergone abdominal surgery. There was an impression that the multiple daily dosing regimen in use at...

New Generation of Orally Disintegrating Tablets for Sustained Drug Release: A Propitious Outlook.

Orally disintegrating tablets (ODTs) or orodispersible tablets are solid dosage forms that disintegrate within 3 minutes in the mouth into a paste that can be easily swallowed. ODTs have improved over the past years, in an attempt to produce a safe and efficient substitute to the conventional oral dosage forms, particularly for dysphagia patients. Since its introduction in the market in the 1980s, ODTs expanded rapidly and achieved revenues over $3 billion in 2006 and sustaining 20% annual growth. It is therefore evident that ODTs carry good commercial value, however there is potential for improvement. Current sustained-release technologies may be exploited and incorporated into an ODT to provide greater therapeutic value by reducing the need for multiple daily dosing regimens and improving patient adherence. A number of technologies such as polymer coated nanoparticles, stimuli-responsive polymers and ion-exchange resins have emerged to produce robust, sustained release orally disintegrating tablets (SR-ODT). The purpose of this review is to highlight these various approaches and techniques and how they have been utilised in an ODT formulation to extend differentiated line, market exclusivity and patent life. The review also explores future perspective and the potential challenges that SR-ODTs will face.

ABSTRACT 723

Background and aims: Once daily dosing (ODD) of aminoglycosides has been shown to be less toxic and as efficacious as multiple daily dosing regimens. There is a lack of pharmacokinetic (PK), safety, and efficacy data for aminoglycoside ODD in critically ill paediatric patients. Aims: To evaluate the proposed exclusion criteria for use of ODD gentamicin by examining gentamicin PK disposition in patients excluded from ODD therapy, and to adapt the criteria as appropriate. Methods: A retrospective chart review (approved by Research and Ethics Board) of 176 critically ill paediatric patients excluded from ODD therapy was done. PK parameters were calculated based on available therapeutic drug monitoring (TDM) levels. Extrapolated serum gentamicin levels achieved using a dose of 9 mg/kg were calculated and used to determine whether an excluded patient would have adequately cleared ODD gentamicin. Exploratory analyses were done to assess other characteristics that may predict if a patient will adequately clear ODD gentamicin despite prior exclusion. Results: The majority of patients (56%) were excluded from ODD therapy based on having a weight of ≤5 kg. Thirty-nine percent of patients excluded due to weight may have been able to adequately clear ODD gentamicin based on extrapolated PK parameters. Of these patients, 53% were estimated to achieve target Cmax, and 97% were estimated to achieve target drug-free interval. Conclusions: Patients with a weight of ≤5 kg can potentially be considered a conditional exclusion criterion, whereupon critically ill pediatric patients started on gentamicin for non-cardiac indications can be subsequently switched to gentamicin ODD if TDM levels show adequate clearance.

Electronic Monitoring of Medication Adherence in a 1-year Clinical Study of 2 Dosing Regimens of Mesalazine for Adults in Remission with Ulcerative Colitis

Adherence to medication is an issue of great importance for patients with ulcerative colitis. Once daily mesalazine seems to be no worse than divided doses in preventing relapse in remitting patients. Although this has been attributed to improved adherence, detailed measures of adherence have been lacking from previous studies. A 1-year substudy was conducted alongside a trial that compared 2 different dosing regimens (once daily versus three times daily) of mesalazine for patients in remission with ulcerative colitis. Participants in the substudy had their adherence monitored electronically using the medication event monitoring system, self-report, and tablet counts. We compared measures, determined factors associated with adherence and associations between adherence and relapse, modeled adherence over time, and explored behavioral aspects. We included 58 participants. Adherence was high across all measures (89.3% self-report, 96.7% tablet counts, and 89.2% medication event monitoring system). Agreement between the measures was poor at times. Adherence according to the medication event monitoring system best distinguished between the participants who relapsed (71.4%) and those who remained in remission (93.4%), although this difference was not statistically discernible at the 5% level. Adherence deteriorated over the study period, with three times daily participants generally less adherent than once-daily participants (odds ratio, 0.03; 95% confidence interval, 0.01-0.08). Adherence was higher on weekdays (odds ratio, 1.47; 95% confidence interval, 1.31-1.65) and around clinic visit dates (odds ratio, 1.43; 95% confidence interval, 1.18-1.72). Simple dosing regimens are preferable to multiple daily dosing regimens. Electronic monitoring of adherence should be used more often in clinical studies. Self-reported adherence and tablet counts may underestimate adherence. Adherence declined over time, and adherence was generally lower and more varied for those allocated to the three times daily regimen.

Maintaining remission in ulcerative colitis – role of once daily extended-release mesalamine

The aminosalicylates (5-ASA; also referred to as mesalamine-based agents) are considered as first-line in the maintenance of remission of mild to moderate ulcerative colitis (UC). Traditionally these agents have required a large pill burden and multiple daily dosing regimens which may account for the low adherence rates, especially in patients in remission. Extended-release mesalamine is the first once daily mesalamine product approved by the Food and Drug Administration for the maintenance of UC remission. This review will examine the pharmacokinetics, dosing, efficacy, and safety data of extended-release mesalamine, and discuss the potential role of improving medication compliance and decreasing costs in UC maintenance.

Once versus individualized multiple daily dosing of aminoglycosides in critically ill patients

Background and objective The purpose of this study was to evaluate the once daily dosing (ODD) program in critically ill Egyptian patients compared to individualized multiple daily dosing (MDD) in terms of clinical and bacteriological efficacy. In addition, the incidence of nephrotoxicity associated with both regimens in this specific group of patients was assessed. Methods Fifty-two patients with suspected or confirmed bacterial infections admitted to the Critical Care Medicine Department, Kasr El-Aini-Cairo University Hospitals comprised the study population. The amikacin group (30 patients) was sub-divided into 14 patients receiving amikacin ODD (1 g i.v.) and 16 patients receiving amikacin in MDD (500 mg i.v./dose). The gentamicin group (22 patients) was sub-divided into 10 patients receiving the drug ODD (240 mg i.v.) and 12 patients receiving gentamicin MDD (80 mg i.v./dose). Amikacin or gentamicin serum levels were determined by the enzyme multiplied immunoassay technique using Emit 2000. MDD regimen was adjusted based on the individual pharmacokinetic parameters using the Sawchuk–Zaske method. Results There was no significant difference between the two dosing regimens with regard to clinical and antibacterial efficacy or incidence of nephrotoxicity of both gentamicin and amikacin groups. In the ODD regimen, duration of treatment had no effect on increasing incidence of nephrotoxicity unlike the individualized MDD regimen. No dose adjustments were needed in the once daily dosing regimen since trough concentrations have never been above toxic level. Conclusions The study showed that the ODD regimen is preferred in critically ill patients to individualized MDD as shown by comparable efficacy, nephrotoxicity and lesser need for therapeutic drug monitoring and frequent dose adjustments required in the individualized MDD regimen.

Once‐Daily Gentamicin Dosing in Pediatric Patients Without Cystic Fibrosis

To estimate an appropriate once-daily gentamicin dose and dosing interval for non-critical care pediatric patients older than 3 months of age without cystic fibrosis. Pharmacokinetic analysis of data from a retrospective medical record review. Large academic children's hospital. One hundred fourteen non-critical care pediatric patients older than 3 months of age without cystic fibrosis who received multiple-daily dosing regimens of gentamicin between September 2007 and April 2008. Patient-specific pharmacokinetic parameters were calculated using drug concentrations obtained at steady state. Once-daily doses were extrapolated for each patient to achieve goal peak and trough concentrations. Using the average of these doses and the patient-specific pharmacokinetic parameters, theoretical once-daily peak and trough concentrations were calculated for each patient. Patient characteristics were analyzed to determine differences between patients who did and those who did not achieve adequate peak concentrations. Mean +/- SD pharmacokinetic parameters were as follows: elimination rate constant 0.32 +/- 0.06 hour(-1), half-life 2.28 +/- 0.54 hours, and volume of distribution 0.24 +/- 0.08 L/kg. The only patient demographic characteristic found to have a significant effect on the extrapolated peak concentration was age. The following age-specific once-daily doses were calculated: 3 months to less than 2 years, 9.5 mg/kg; 2 years to less than 8 years, 8.5 mg/kg; and 8-18 years, 7 mg/kg. Age was the primary factor in determining the once-daily dose of gentamicin in our pediatric population. Further prospective research is necessary to determine the safety and efficacy of these age-based, once-daily doses for gentamicin.

Comparación de dos pautas de dosificación de gentamicina en el recién nacido

Gentamicin is widely used in full-term neonates as empirical therapy for early-onset suspected or proven sepsis. Several dosing schedules for gentamicin have been recommended for this neonatal population.To compare gentamicin serum levels, efficacy and toxicity of two dosing schedules in term and preterm newborns.The study included 200 newborns who were started on gentamicin therapy. Group A (N=100) was prescribed a multiple-daily dosing regimen and Group B (N=100) on a once-daily dosing regimen. Newborns in Group A received gentamicin at 2.5-3.5 mg/kg/dose q12-18 h depending on postnatal age and serum creatinine levels, and newborns in Group B received 4-5 mg/kg/dose q24-48 h depending on postconceptional and postnatal age. All peak and trough serum drug levels, demographic data, and markers of potential nephrotoxicity and ototoxicity were compared.Peak serum gentamicin levels were significantly higher (8.2+/-0.22 microg/ml vs. 5.9+/-0.13 microg/ml; p <or= 0.001) and trough levels were significantly lower (0.9+/-0.06 microg/ml vs. 1.7+/-0.08 microg/ml; p <or= 0.001) in Group B than in Group A. There was no significant difference between the groups either in the clinical failure rate or in the nephrotoxicity or ototoxicity outcomes.Once-daily dosing regimen of gentamicin in preterm and term newborns is safe and effective, with a reduced risk of serum drug concentrations falling outside the therapeutic range.

Extended-Interval Aminoglycosides in Children: More Guidance Is Needed

To the Editor .— We read with interest the article by Contopoulos-Ioannidis et al in the July 2004 issue of Pediatrics .1 We welcome this collation of pediatric data on the efficacy and safety of extended-interval aminoglycoside dosing (EIAD), given the lack of clear consensus about whether the existing evidence justifies a change in standard practice.2 This meta-analysis of the available evidence demonstrates that efficacy, and probably nephrotoxicity, is at least equivalent between EIAD and multiple daily-dosing regimens. More importantly, however, it identifies gaps in our knowledge about (1) the incidence of ototoxicity, (2) the appropriate dose …

Aminoglucósidos

Aminoglycosides remain as a efficacious class of antimicrobials, commonly used in the clinical practice. In spite of the existence of several mechanisms of resistance, they continue being active against most of the aerobic Gram-negative bacilli. Currently, although aminoglycosides may be used as monotherapy in the urinary tract infections, they are mainly used in combination with b-lactam antibiotics in severe infections caused by Gram-negative bacilli. The knowledge about the pharmacokinetic and pharmacodynamic parameters of aminoglycosides has suggested their use in an once-daily dosing regimen. This dosing has shown as efficacious as multiple-daily dosing regimen in several studies, which also have shown a trend toward a lower toxicity. Among the adverse events, nephrotoxicity and ototoxicity require a careful evaluation during its administration.

Relationship between daily dose frequency and adherence to antihypertensive pharmacotherapy: Evidence from a meta-analysis

Background: Rates of patient adherence (compliance) to pharmacotherapy range from <5% to >90%. Negative determinants include multiple daily dosing (MDD), chronic duration, and asymptomatic disease. Reports suggest that once-daily (QD) dosing may improve adherence, but their findings are inconclusive. Objective: The purpose of this study was to compare the rates of adherence with QD, twice-daily (BID), and MDD antihypertensive drug regimens. Methods: MEDLINE, Embase, and International Pharmaceutical Abstracts databases were searched to identify comparative trials of patient adherence to antihypertensive medication in solid, oral formulations. Data were combined using a random-effects meta-analytic model. Results: Eight studies involving a total of 11,485 observations were included (1830 for QD dosing, 4405 for BID dosing, 4147 for dosing >2 times daily [>BID], and 9655 for MDD), in which the primary objective was to assess adherence. The average adherence rate for QD dosing (91.4%, SD = 2.2%) was significantly higher (Z = 4.46, P < 0.001) than for MDD (83.2%, SD = 3.5%). This rate was also significantly higher (Z = 2.22, P = 0.026) than for BID dosing (92.7% [SD = 2.3%] vs 87.1% [SD = 2.9%]). The difference in adherence rates between BID dosing (90.8%, SD = 4.7%) and >BID dosing (86.3%, SD = 6.7%) was not significant (Z = 1.82, P = 0.069). Conclusions: The results of this meta-analysis demonstrate that with antihypertensive medications, QD dosing regimens are associated with higher rates of adherence than either BID or MDD regimens.

PHARMACOKINETICS AND PHARMACODYNAMICS OF ANTIBIOTICS IN MENINGITIS

The penetration of antimicrobials into the CSF is dependent on lipid solubility, molecular size, capillary and choroid plexus efflux pumps, protein binding, and the degree of inflammation. Penicillins, certain cephalosporins, carbapenems, fluoroquinolones, vancomycin, and rifampin provide the highest ratios of CSF levels to the MBC for common infecting organisms. For beta-lactam antibiotics, it is the duration of time that CSF concentrations exceed the MBC that determines the rate of bactericidal activity. It appears that levels should exceed the MBC for more than 50% of the dosing interval. The peak/MBC and AUC/MBC ratios are important determinants of efficacy for aminoglycosides and fluoroquinolones. Once-daily dosing of aminoglycosides is as effective as multiple-daily dosing regimens in experimental meningitis, probably because of drug-induced prolonged persistent effects. Fluoroquinolones do not produce as prolonged persistent effects and are slightly less effective when administered once daily. Although steroid use can reduce the penetration and decrease the bactericidal activity of some antimicrobials, such as vancomycin, in experimental meningitis, the clinical impact of steroid use in human meningitis is still unclear.

A randomised, multicentre study of ceftriaxone versus standard therapy in the treatment of lower respiratory tract infections

In this study the efficacy and cost-effectiveness of i.v. ceftriaxone 1 g once daily (CTX) was compared with standard i.v. antibiotic treatment (STD) for lower respiratory tract infections (LRTI). STD was given according to the guidelines of the American Thoracic Society and consisted of either cefuroxime 1500 mg three times daily (q8h), amoxicillin/clavulanic acid 1200 mg q8h or ceftriaxone 2 g once daily; each with or without a macrolide. After a minimum of 5 days i.v. therapy, patients could be switched to oral therapy. One hundred patients were enrolled in the study; 52 patients received CTX and 48 STD. Groups were comparable with respect to demographic and baseline characteristics. Seventy patients had a confirmed diagnosis of pneumonia. Twenty-nine patients had a severe type I exacerbation of chronic bronchitis. In one patient the diagnosis of LRTI could not be confirmed. In approximately 50% of the patients a microbiological diagnosis could be made. The most important isolated pathogens from sputum and blood were (positive blood cultures in brackets): Streptococcus pneumoniae 14 (9) and Haemophilus influenzae 16. Mean duration of i.v. therapy was 7.4 days in both groups. Average duration of hospitalisation was 15.0 days for CTX patients and 15.9 days for STD patients. Overall cure and improvement rate at the end of treatment was 47 (90%) for patients receiving ceftriaxone 1 g compared to 37 (77%) for patients receiving standard therapy. Pathogens were eradicated or presumed to be eradicated in 84% of the CTX patients and in 76% of the STD patients. Mean total costs per treatment were lower for CTX than for STD treatment: NLG 169 versus 458. These results show, that i.v. ceftriaxone 1 g once daily is as effective as standard therapy in the treatment of LRTI and that its use reduces treatment costs, in view of the multiple daily dosing regimens of most standard therapies.

Risk factors for antihypertensive medication refill failure by patients under Medicaid managed care

Antihypertensive medication noncompliance is common and leads to substantial morbidity for patients and increased health care costs for managed-care organizations. A retrospective cohort study using pharmacy prescription profiles to estimate noncompliance was conducted to determine important risk factors for patient noncompliance with antihypertensive therapy for Medicaid enrollees participating in a managed-care plan. The pharmacy and claims data for 1395 patients with uncomplicated hypertension who were enrollees of Tennessee's Medicaid managed-care program were analyzed to determine the frequency of the enrollee's failure to obtain timely antihypertensive medication refills (hereafter referred to as refill failure) and to identify the predictors of refill failure. Overall, refill failure occurred in 33% of 7413 refill opportunities studied, whereas refill failure occurred in 32% of the cases in which medication was dosed once daily and in 35% of the cases in which medication was dosed more than once daily. For patients taking alpha-blockers, there was a significantly lower rate of refill failure (11.0%) than for patients taking angiotensin-converting enzyme inhibitors, direct vasodilators, and thiazide diuretics. Patients taking calcium channel blockers, had a significantly lower rate of refill failure (38.5%) than for patients taking thiazide diuretics (45.5%). Younger age, medication class, multiple-daily dosing regimen, and fewer provider visits were all found to be significant independent predictors of refill failure, whereas gender and regimen complexity were not significant predictors in this population. Health care systems planning pharmacy-based interventions to improve patient compliance with antihypertensive medication for patients in a Medicaid managed-care program can expect to encounter high levels of refill failure and may want to target enrollee subgroups by age, medication class, or dosing regimen for intensive intervention efforts.

Once-daily dosing of aminoglycosides

Since their introduction one or more decades ago, aminoglycosides have generally been administered in multiple daily (i.e. twice- or thrice-daily) dosing regimens. However, nephrotoxicity can be reduced in animal models by administering the same total daily dose as one large dose instead of as multiple small doses. In addition, in vitro and in vivo studies that considered the impact of dosing regimens on efficacy suggest that once-daily dosing is equally or more effective compared to multiple daily dosing. Once-daily versus multiple daily dosing regimens have been compared for amikacin, netilmicin, and gentamicin in 24 randomized, clinical trials including a total of 3,181 patients. An analysis of these studies revealed superior results for once-daily regimens with respect to clinical efficacy (89.5% vs. 84.7%, p < 0.001) as well as bacteriological efficacy (88.6% vs. 83.4%, p < 0.01). No statistically significant differences were noted for toxicity. Nevertheless, both nephrotoxicity and ototoxicity occurred less frequently during once-daily dosing (4.5% vs. 5.5% and 4.2% vs. 5.8%, respectively). Finally, once-daily dosing is more economical, since less nursing time and infusion material are required and the efforts for drug monitoring can be reduced. In conclusion, amikacin, netilmicin, and gentamicin can be administered once a day.

Multicenter Quality Control Study of Amikacin Assay for Monitoring Once-Daily Dosing Regimens

During once-daily dosing regimens of aminoglycosides, administration of large single doses results in high peak levels and low 24-h trough levels. However, commercial assays for monitoring aminoglycoside levels are designed to cover the smaller range of serum concentrations usually observed during multiple daily dosing regimens. The study assessed (a) the range of serum concentrations during once-daily dosing of amikacin and (b) the performance of a widely used assay system for measuring concentrations within this range. A total of 42 dosing intervals from eight patients receiving a once-daily regimen of amikacin (20 mg/kg) were monitored. Median (and range) of peak, 8- and 24-h trough levels were 61 (25-89), 5.9 (2.2-19), and 1.3 (< 0.8-6.2) mg/L, respectively. The accuracy of a fluorescence polarization immunoassay for measuring concentrations of amikacin during once-daily dosing regimens was assessed in an international multicenter study. The performance of the assay was excellent for peak and 8-h concentrations; median deviations from the target concentrations were < 5%. The majority of the trough levels (26 of 42) measured in patients during once-daily treatment were within the range of 1-2 mg/L and could also be determined with an accuracy sufficient for clinical monitoring (median deviations 14%).

Once-daily dosing regimen for aminoglycoside plus betalactam combination therapy of serious lower respiratory tract infections.

Aminoglycosides are important antibacterial agents for treatment of serious gram-negative bacillary infections including lower respiratory tract infection. Once-daily aminoglycosides result in higher peak and lower trough plasma concentrations than conventional multiple daily dosing regimens; once-daily aminoglycoside therapy is equally effective, generally less toxic and much less expensive and therefore this regimen is more and more frequently used for treatment of suspected or confirmed gram-negative bacillary infections and of febrile episodes in neutropenic patients, in particular in combination with an appropriate betalactam antibiotic. Despite the lack of studies on this topic, once-daily aminoglycosides in combination with a betalactam agent can be used in subjects with lower respiratory tract infection, including patients with cystic fibrosis, in which tobramycin appears to be the aminoglycoside antibiotic of choice.

Monitoring serum concentrations for once-daily netilmicin dosing regimens.

A once-daily dosing regimen for aminoglycosides is less expensive, at least as effective and possibly less toxic than multiple-daily dosing regimens. Once-daily dosing might also allow the frequency of measuring the serum concentrations of these antibiotics to be reduced since two of the major objectives of monitoring, high peak and low trough concentrations, are more likely to be achieved with this regimen. A novel strategy for monitoring serum concentrations which relies on a single sample obtained 8 h after a dose, as opposed to both trough and peak samples, is evaluated here. Serum kinetics of netilmicin were studied prospectively in 51 adult patients with initial serum creatinine concentrations of < 130 mumol/L who were treated with a median daily dosage of 400 mg. Concentrations measured 8 h after administration were within the target range of 1.5-6 mg/L in 113 of 134 dosing intervals studied. Concentrations above and below this range correlated significantly with higher and lower 24-h trough concentrations and areas under the curve respectively. There was also a significant correlation between 8-h netilmicin concentrations and nephrotoxicity (P < 0.05); a relative increase of > or = 25% in the serum creatinine concentration or an absolute increase of > 25 mumol/L was detected in 0 of 7 patients with an 8-h concentration of < 1.5 mg/L, in 3 of 33 patients (9.1%) with an 8-h concentration of 1.5-6 mg/L and in 4 of 11 patients (36%) with an 8-h concentration of > 6 mg/L.(ABSTRACT TRUNCATED AT 250 WORDS)