Multiple-dose Therapy Research Articles

Comparison of effectiveness of continuous subcutaneous insulin infusion with daily insulin injection in a Chinese population of Type I diabetic patients

Purpose: To compare the clinical effectiveness of continuous subcutaneous insulin infusion therapy with that of multiple-dose insulin therapy in type 1 diabetic patients.
 Methods: A total of 1000 type 1 diabetic patients were assigned to two groups, with 500 patients per group. Patients in group I were treated with continuous subcutaneous infusion of insulin (CSII), while those in group II received multiple daily doses of insulin injection. Body mass index (BMI), insulin dose, HbA1c levels, and frequencies of hypoglycemia and diabetic-ketoacidosis (DKA) were determined in each patient at baseline, and at 4-week intervals for 4 years.
 Results: The HbA1c levels at baseline and at the end of 4th year in group I were 8.9 ± 1.1 and 8.2 ± 1.5 %, respectively, relative to corresponding values of 8.6 ± 1.2 and 9.1 ± 1.1 %, respectively in group II. The results revealed significant difference in HbA1c between the two groups (p < 0.05). After 4 years of therapy, insulin requirement was markedly higher in group II than at baseline (0.8 ± 0.1 vs 0.9 ± 0.2, p < 0.05) IU/kg/day. However, insulin requirement in group I decreased after 4 years, relative to that at baseline (0.65 ± 0.2 vs 0.8 ± 0.1 IU/kg/day; p < 0.05).
 Conclusion: CSII therapy seems to be an effective and safe gold standard method for managing type I diabetes mellitus patients.

Multiple low dose therapy as an effective strategy to treat EGFR inhibitor-resistant NSCLC tumours

Resistance to targeted cancer drugs is thought to result from selective pressure exerted by a high drug dose. Partial inhibition of multiple components in the same oncogenic signalling pathway may add up to complete pathway inhibition, while decreasing the selective pressure on each component to acquire a resistance mutation. We report here testing of this Multiple Low Dose (MLD) therapy model in EGFR mutant NSCLC. We show that as little as 20% of the individual effective drug doses is sufficient to completely block MAPK signalling and proliferation when used in 3D (RAF + MEK + ERK) or 4D (EGFR + RAF + MEK + ERK) inhibitor combinations. Importantly, EGFR mutant NSCLC cells treated with MLD therapy do not develop resistance. Using several animal models, we find durable responses to MLD therapy without associated toxicity. Our data support the notion that MLD therapy could deliver clinical benefit, even for those having acquired resistance to third generation EGFR inhibitor therapy.

Comparison of single- and multiple-dose cefazolin as prophylaxis for transurethral enucleation of prostate: A multicenter, prospective, randomized controlled trial by the Japanese Research Group for Urinary Tract Infection.

To compare the optimal administration period of antimicrobial prophylaxis in patients undergoing transurethral enucleation of the prostate for benign prostatic hyperplasia. We carried out a randomized controlled trial to compare the differences in incidence of perioperative genitourinary tract infection between single and multiple (3days) administrations of cefazolin for transurethral enucleation of the prostate in benign prostatic hyperplasia patients without pyuria or bacteriuria between January 2015 and December 2018. This multicenter randomized controlled trial included 203 patients who underwent a transurethral enucleation of the prostate procedure. All received antimicrobial prophylaxis, and were randomized into those who received single-dose (n=101) or multiple-dose (n=102) therapy. The rate of genitourinary tract infection after transurethral enucleation of the prostate for all patients was 1.5%, whereas that in the single-dose group was 1.0% and in the multiple-dose group was 2.0%, which were not significantly different (P=1.00). A single dose of antimicrobial prophylaxis as a prophylactic antibacterial drug is sufficient for patients undergoing transurethral enucleation of the prostate who do not have presurgical pyuria or bacteriuria.

DESIGN AND EVALUATION OF FLUTAMIDE-LOADED POLYCAPROLACTONE NANOPARTICLES BY 23 FACTORIAL DESIGN AND NANOPRECIPITATION METHOD

Objective: The present work was aimed to prepare and evaluate polymeric nanoparticles (NPs) of flutamide by nanoprecipitation method and factorial. The influences of various formulation components such as polymer, organic phase volume, and surfactant on the characteristics of NPs were investigated.Methods: The polycaprolactone (PCL) loaded with drug was evaluated for surface morphology, surface charge, particles size, encapsulation efficiency, drug content, and in vitro release studies. Fourier transform infrared studies were indicated no interaction between the drug and polymer.Results: The results of the drug release study of NPs may fit with different kinetic equations. The particle size varied from 128 to 317 nm and zeta potential was in negative and its value found to be - 46.4 mv. The content of flutamide was found in between 74%±0.72 to 92%±0.53 in flutamide loaded PCL NPs. The minimum and maximum entrapment efficiencies were found to be of 75%±0.66 and 92%±0.70. The percentage yields of all formulations were in the range of 46.05%±1.56–86.78%±1.32. The in vitro drug release followed zero order with sustained behavior for a period of 24 h. Results of accelerated storage conditions of optimized formulation revealed that no significant changes in formulation F2.Conclusion: The present investigation opens new frontiers in developing flutamide NPs for targeting delivery to the prostate for the prostate cancer treatment which also overcome the problems associated with conventional formulations such as multiple-dose therapy, poor patient compliance, and high treatment cost.

APPROACHES TO OVERCOME NSAID INDUCED ULCERATION IN ARTHRITIC PAIN MANAGEMENT: PERSPECTIVES AND PROSPECTS

Rheumatoid arthritis is an auto-immune joint disorder involving pain and inflammation. Various approaches are used for pain management and relief from arthritis with single and multiple dose therapy. In single dose therapy, use of non-steroidal anti-inflammatory drugs like diclofenac aceclofenac, celicoxib etc. reported many side effects mainly leading to decrease in production of prostaglandin and holding the ulcer. High dosing frequency of these drugs is also a major factor of risk. Recently developed novel formulations are especially suitable for achieving controlled and delayed release profile with low risk of dose dumping. These systems have received great attention of pharmaceutical industry as they deliver accurate amount of drug at the right time and location thus increasing patient compliance and economic feasibility and avoiding drug associated side effects. Present review mainly deals with the problem of ulceration in pain management, various approaches to overcome this and specifically explore the possibilities to apply novel drug delivery systems for this purpose. Keywords: Arthritis, Drug delivery systems, Gastroretentive, NSAIDs, Pain, Rheumatoid arthritis, Rheumatic pain management.

Copper-64 Dichloride as Theranostic Agent for Glioblastoma Multiforme: A Preclinical Study.

Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor in adults with a median survival time less than one year. To date, there are only a limited number of effective agents available for GBM therapy and this does not seem to add much survival advantage over the conventional approach based on surgery and radiotherapy. Therefore, the development of novel therapeutic approaches to GBM is essential and those based on radionuclide therapy could be of significant clinical impact. Experimental evidence has clearly demonstrated that cancer cells have a particularly high fractional content of copper inside the nucleus compared to normal cells. This behavior can be conveniently exploited both for diagnosis and for delivering therapeutic payloads (theranostic) of the radionuclide copper-64 into the nucleus of cancerous cells by intravenous administration of its simplest chemical form as dichloride salt [64Cu]CuCl2. To evaluate the potential theranostic role of [64Cu]CuCl2 in GBM, the present work reports results from a preclinical study carried out in a xenografted GBM tumor mouse model. Biodistribution data of this new agent were collected using a small-animal PET tomograph. Subsequently, groups of tumor implanted nude mice were treated with [64Cu]CuCl2 to simulate single- and multiple-dose therapy protocols, and results were analyzed to estimate therapeutic efficacy.

Artemisinin-naphthoquine versus Artemether-lumefantrine for treating uncomplicated <i>plasmodium falciparum</i> malaria in children: A randomized controlled trial of efficacy and safety

Introduction : Artemether-lumefantrine (AL), the most frequently prescribed ACTs for uncomplicated P. falciparum malaria, requires multiple doses which may militate against adherence. It is necessary to evaluate the efficacy and safety of single dose ACT like Artemisininnaphthoquine (ANQ) to enhance adherence. Methods : This was an open label randomized controlled clinical trial. Eligible children were assigned to receive either a single dose of ANQ or six doses of AL following parental consent. A total of 108 children aged 5 – 14 years with uncomplicated falciparum malaria were enrolled and assigned as follows: 58 (ANQ) and 50 (AL). Participants were observed for 28 days and clinical and parasitological assessments carried out. Outcomes were assessed based on World Health Organization protocol. Results : A total of 97 patients completed the study. Overall 28-day cure rate was 87.0% (47/54) and 81.4% (35/43) for ANQ and AL respectively. One patient (2.2%) in the AL group had Early Treatment Failure while seven (16.3%) had Late Parasitological Failure (LPF). LPF was also reported in seven (13.0%) patients in the ANQ group. There was no Late Clinical Failure. A mild selflimiting papular rash was noted in one child in ANQ group. There was no serious adverse event. Conclusions : The therapeutic efficacies of ANQ and AL were comparable. A more robust, adequately powered, dose optimization study with PCR-confirmed parasitological outcome measures is needed. Key words : Malaria, artemetherlume f a nt r ine , a r t emi s i nin - naphthoquine, adherence, single and multiple dose therapy

Multiple-dose therapy with bovine colostrum confers significant protection against diarrhea in a mouse model of human rotavirus-induced gastrointestinal disease

Rotavirus is the most important etiologic agent of severe gastroenteritis. Previously, we reported that skimmed and concentrated bovine late colostrum (SCBLC) obtained from normal unimmunized cows at 6 to 7d after parturition effectively prevented against human rotavirus (HRV)-induced severe gastroenteritis in vivo, when administered as a single dose 60min before viral inoculation. In the present study, we examined the efficacy of multiple administrations of SCBLC at smaller dosages after viral inoculation in vivo. We demonstrate that multiple administrations within 24h after virus inoculation resulted in earlier recovery from diarrheal symptoms, in an administration frequency-dependent manner. Furthermore, we investigated whether isolated IgG anti-HRV activity in SCBLC was equivalent to that of IgG isolated from bovine mature milk as measured by in vitro activity assays. We found that IgG-containing fractions from SCBLC and mature milk exhibited approximately the same level of anti-HRV activity. We concluded that the SCBLC contains a high level of IgG against HRV-induced severe gastroenteritis, which will be possible to use in protective effects in immunocompromised hosts, such as children and the elderly. Multiple doses of SCBLC during the early stages of infection or lower dosage of SCBLC given as a single dose both resulted in relief of diarrheal symptoms.

Comparison of Pretargeted and Conventional CC49 Radioimmunotherapy Using 149Pm, 166Ho, and 177Lu

The therapeutic efficacies of radiolabeled biotin, pretargeted by monoclonal antibody (mAb)-streptavidin fusion protein CC49 scFvSA, were compared to those of radiolabeled mAb CC49, using the three radiolanthanides in an animal model of human colon cancer. The purpose of the present study was to compare antibody pretargeting to conventional radioimmunotherapy using (149)Pm, (166)Ho, or (177)Lu. Nude mice bearing LS174T colon tumors were injected sequentially with CC49 scFvSA, the blood clearing agent biotin-GalNAc(16), and (149)Pm-, (166)Ho-, or (177)Lu-DOTA-biotin. Tumor-bearing mice were alternatively administered (149)Pm-, (166)Ho-, or (177)Lu-MeO-DOTA-CC49. Therapy with pretargeted (149)Pm-,(166)Ho-, and (177)Lu-DOTA-biotin increased the median time of progression to a 1 g tumor to 50, 41, and 50 days post-treatment, respectively. Therapy with (149)Pm-,(166)Ho-, and (177)Lu-MeO-DOTA-CC49 increased the median time to progression to 53, 24, and 67 days post-treatment, respectively. In contrast, saline controls showed a median time to progression of 13 days postinjection. Treatment with pretargeted (149)Pm-, (166)Ho-, and (177)Lu-biotin or (149)Pm-, (166)Ho-, and (177)Lu-CC49 increased tumor doubling time to 18-36 days, compared to 3 days for saline controls. Among treated mice, 23% survived >84 days post-therapy, and 11% survived 6 months, but controls survived <29 days. Long-term survivors showed tumor growth inhibition or partial regression, extensive necrosis in residual masses, and no evidence of nontarget tissue toxicity at necropsy. Both pretargeted and conventional RIT demonstrated considerable efficacy in an extremely aggressive animal model of cancer. Our results identified (177)Lu as an optimal radiolanthanide for future evaluation of these agents in toxicity and multiple-dose therapy studies.

Insulin pump therapy: closing the inequality gap

110 Nurse Prescribing 2011 Vol 9 No 3 adapted accordingly. Mimicking the natural production of insulin is complex, and the way insulin is delivered through insulin pump therapy is closer to this natural phenomenon than multiple-dose insulin injection therapy. Pumps can help when: regulation is not sufficient with multiple-dose insulin injection therapy; glucose levels are unpredictable; the patient experiences severe hypoglycaemia, or even fits. Experience has shown that the use of the pump in the latter case led to the patient no longer experiencing fits or severe hypoglycaemia.

Molecular Imaging and Pharmacokinetic Analysis of Carbon-11 Labeled Antisense Oligonucleotide LY2181308 in Cancer Patients

Antisense oligonucleotides (ASOs) have potential as anti-cancer agents by specifically modulating genes involved in tumorigenesis. However, little is known about ASO biodistribution and tissue pharmacokinetics (PKs) in humans, including whether sufficient delivery to target tumor tissue may be achieved. In this preliminary study in human subjects, we used combined positron emission and computed tomography (PET-CT) imaging and subsequent modeling analysis of acquired dynamic data, to examine the in vivo biodistribution and PK properties of LY2181308 - a second generation ASO which targets the apoptosis inhibitor protein survivin. Following radiolabeling of LY2181308 with methylated carbon-11 ([(11)C]methylated-LY2181308), micro-doses (<1mg) were administered to three patients with solid tumors enrolled in a phase I trial. Moderate uptake of [(11)C]methylated-LY2181308 was observed in tumors (mean=32.5ng*h /mL, per mg administered intravenously). Highest uptake was seen in kidney and liver and lowest uptake was seen in lung and muscle. One patient underwent repeat analysis on day 15 of multiple dose therapy, during administration of LY2181308 (750mg), when altered tissue PKs and a favorable change in biodistribution was seen. [(11)C]methylated-LY2181308 exposure increased in tumor, lung and muscle, whereas renal and hepatic exposure decreased. This suggests that biological barriers to ASO tumor uptake seen at micro-doses were overcome by therapeutic dosing. In addition, (18)F-labeled fluorodeoxyglucose (FDG) scans carried out in the same patient before and after treatment showed up to 40% decreased tumor metabolism. For the development of anti-cancer ASOs, the results provide evidence of LY2181308 tumor tissue delivery and add valuable in vivo pharmacological information. For the development of novel therapeutic agents in general, the study exemplifies the merits of applying PET imaging methodology early in clinical investigations.

Treatment of Bacterial Vaginosis: A Multicenter, Double-Blind, Double-Dummy, Randomised Phase III Study Comparing Secnidazole and Metronidazole

Objective. Multiple-dose metronidazole oral therapy is currently the reference treatment for bacterial vaginosis (BV). This double-blind, double-dummy, noninferiority study compared the efficacy of secnidazole, another nitroimidazole with pharmacokinetics allowing a single dose regimen, to this standard treatment. Methods. A total of 577 patients were randomized to receive metronidazole (500 mg, b.i.d for seven days) or secnidazole (2 g, once). Therapeutic cure at D28 was defined as the resolution of vaginal discharge, positive KOH whiff test, vaginal pH >4.5 and Nugent score >7 on Gram-stained vaginal fluid. Results. According to this primary endpoint, the single-dose secnidazole regimen was shown to be at least as effective as the multiple-dose metronidazole regimen (60.1 % cured women vs 59.5% , 95% confidence interval with a noninferiority margin of 10%: [−0.082; 0.0094]). Safety profiles were comparable in both groups. Conclusion. The secnidazole regimen studied represents an effective, convenient therapeutic alternative that clinicians should consider in routine practice.

A simple in vitro PK/PD model system to determine time–kill curves of drugs against Mycobacteria

In vivo tuberculosis is exposed to continually changing drug concentrations for which static minimum inhibitory concentration (MIC) testing may be a poor surrogate. While in vitro approaches to determine time-kill curves for antibiotics have been widely applied in assessing antimicrobial activity against fast growing microorganisms, their availability and application for slow-growing microorganisms including Mycobacterium tuberculosis has so far been scarce. Thus, we developed a novel simple in vitro pharmacokinetic/pharmacodynamic (PK/PD) model for establishing time-kill curves and applied it for evaluating the antimicrobial activity of different dosing regimens of isoniazid (INH) against Mycobacterium bovis BCG as a surrogate for virulent M. tuberculosis. In the in vitro model M. bovis BCG was exposed to INH concentration-time profiles as usually encountered during multiple dose therapy with 25, 100 and 300mg/day in humans who are fast or slow INH metabolizers. Bacterial killing was followed over time by determining viable counts and the resulting time-kill data was analyzed using a semi-mechanistic PK/PD model with an adaptive IC(50) function to describe the emergence of insensitive populations of bacteria over the course of treatment. In agreement with previous studies, the time-kill data suggest that AUC(0-24)/MIC is the PK/PD index that is the most explanatory of the antimicrobial effect of INH. The presented in vitro PK/PD model and associated modeling approach were able to characterize the time-kill kinetics of INH in M. bovis BCG, and may in general serve as a potentially valuable, low cost tool for the assessment of antibacterial activity in slow-growing organisms in drug development and applied pharmacotherapy.

Surfactant Therapy for Neonatal Respiratory Distress Syndrome: A Review of Korean Experiences over 17 Years

We undertook a multi-hospital collective study to evaluate outcomes of neonatal respiratory distress syndrome (RDS) patients treated with pulmonary surfactant (PS) over 17 yr in Korea (Group I; 1990/91, Group II; 1996, Group III; 2002, and Group IV; 2007). There were 60 neonates in Group I (16 hospitals), 1,179 in Group II (64), 1,595 in Group III (62), and 1,921 in Group IV (57). We adopted Bomsel's classification to evaluate initial chest radiographic findings, categorized RDS severities, and classified response types to PS therapy. Almost all cases were treated using a single dose in Groups I and II, but 19.5% received multiple-dose therapy in Group IV. In Group IV, Bomsel's stages III and IV composed 62.9% and initial severities of mild, moderate, and severe RDS were 23.0%, 42.0%, and 35.0%. More infants showed good response in Groups II, III, and IV than in Group I (71.7%, 66.8%, and 69.2% vs. 58.3%). Complications and mortality rate were lower in Group IV than in Groups I, II, and III (mortality rate: 14.3% vs. 40.0%, 30.0%, and 18.7%). We conclude that PS therapy in neonates with RDS had a remarkable impact on improving clinical course and outcomes over 17 yr in Korea.

Early hospital discharge with oral antimicrobial therapy in patients with hematologic malignancies and low-risk febrile neutropenia

Although consensus exists relating criteria for the identification of low-risk patients with febrile neutropenia, no clear indication on how to manage these patients has been so far provided particularly in outpatients affected by hematologic malignancies. The feasibility and safety of early discharge was prospectively evaluated in 100 outpatients with hematologic malignancies and febrile neutropenia. A strategy considering the risk-index of the Multinational Association of Supportive Care in Cancer (MASCC) was applied. High-risk patients were entirely managed at hospital. Low-risk patients were early discharged if they were afebrile since 48 h and not on supportive therapy requiring hospitalization. Out of 90 low-risk episodes, in 69 instances (76.7%), patients were discharged after a median of 4 days and continued home therapy with oral cefixime (78%) or other antibiotics. Only five outpatients (7.2%) had fever recurrence. Twenty-one low-risk patients were not early discharged due to worsening conditions (three deaths), need of multiple daily dose therapy, or discharge refuse. No clinical characteristic was able to predict the eligibility for early discharge. The MASCC risk-index is a useful aid in the identification of high-risk febrile neutropenia needing whole in-hospital treatment. As for low-risk patients, hospitalization at least in the first days of fever is required. Cefixime could be included among the oral antibacterial drugs to be used in the outpatient treatment of adult patients with febrile neutropenia.

Responses of &lt;i&gt;Plasmodium falciparum&lt;/i&gt; infections to antimalarial drugs in north eastern Nigeria – Part 1: 1988 - 1995.

The responses of Plasmodium falciparum strains to different antimalarial drugs were assessed in the north east of Nigeria, using a modified version of the World Health Organization (WHO) extended in vivo field test protocol from 1988 to 1995. The sensitivity of the strains to chloroquine phosphate varied from a delayed clearance of parasitaemia, through Type-RI resistance or recrudescence to asymptomatic Type-RII resistance. Chloroquine was still clinically efficacious against P. falciparum malaria and continued to play a major role in reducing malaria-related morbidity. However, parasitological failure rates were on the increase as demonstrated in Damboa, where a 1.3-fold increase occurred in D7 failure rate over a 7-year period, from 18.7% in 1988 to 24.5% in 1995. This highlighted the need for continued monitoring of the performance of the drug against the parasites, in addition to evaluating the efficacy and tolerability of new products. Second-line drugs, particularly the combinations of pyrimethamine and sulphadoxine (SD-Pyr, Fansidar®), and pyrimethamine and sulfalene (SL-Pyr, Metakelfin®) were clinically and parasitologically efficacious, producing 100% and 97.1% cure rates, respectively. Self-medication, non-compliance with treatment regimens (particularly for multiple dose therapy), sub-standard or even fake drugs/products, in addition to parasite resistance were identified as factors compounding the treatment of P. falciparum malaria. Key Words: Antimalarial drugs; Plasmodium falciparum ; North Eastern Nigeria; 1988 – 1995. Journal of Pharmacy and Bioresources Vol.1(1) 2004: 51-60

Severe hypoglycaemia in children and adolescents during multiple-dose insulin therapy.

Episodes of severe hypoglycaemia, resulting in coma and/or convulsions, were documented in an unselected, population-based group of 376 children and adolescents with Type 1 diabetes mellitus (Type 1 DM) treated at the Aurora Hospital, City of Helsinki. A prospective study in 1994-95 yielded 493 patient-years and a retrospective study in 1990-93, 904 patient-years of data. Of these patients, 77-85% received insulin in three or more daily doses. During 1990-95, 43 patients had a total of 48 severe hypoglycaemic episodes. For each episode (n = 48), one control Type 1 DM patient who had never experienced any severe hypoglycaemia, matched by age, diabetes duration and puberty, was sought from the study population. Incidence of severe hypoglycaemia was 3.1/100 patients years prospectively and 3.6/100 retrospectively. At the time of the episode, median age was 13.3 (range 2.2-21) years, and median diabetes duration 6.1 (0.5-14.6) years. Rates were similar in different age groups (< 6, 6-12.9 and > or = 13 years). A potential explanation for the hypoglycaemia was found in 79% of the episodes. Insulin dose was higher (p = 0.04) and HbA1c lower (p = 0.005) in patients with severe hypoglycaemia than in controls. In conclusion, multiple-dose insulin therapy in young patients with Type 1 DM can be associated with a low rate of severe hypoglycaemia. The majority of such episodes seem to be preventable.

Choleretic activity of Gentiana lutea ssp. symphyandra in rats

Effects of an ethanolic extract prepared from G. lutea ssp. symphyandra roots on the bile production and liver in rats were investigated. Bile flows of rats which were treated by a single i.p. dose of CCl(4) 24 h prior to experiments were measured after the cannulation of bile duct under urethane anaesthesia. After an equilibration period of 1 h, the lyophilized extract were administered intraduodenally (500 mg/kg i.p.), while control animals received physiological saline only. To monitor the effect of multiple dose therapy, rats received the same dose of G. lutea ssp. symphyandra extract for 3 days (2 days prior to CCl(4) administration) and their bile flows were measured after the cannulation. In all groups, bile samples were collected for 3 h with 15 min intervals. After the completion of bile flow experiment, rat livers were removed and put in neutral formaldehyde solution (10%) for the histological examination. According to results obtained, multiple dose treatment of rats with the plant extract normalized the decreased bile flow due CCl(4), whereas single dose therapy was ineffective on the impaired bile flow. These data indicate that the extract prepared from Gentiana lutea ssp. symphyandra roots has a hepatoprotective activity.

82. Comparison of multiple-dose and once-daily nitrate therapy in patients with stable angina pectoris: effects on quality of life indices

82. Comparison of multiple-dose and once-daily nitrate therapy in patients with stable angina pectoris: effects on quality of life indices

Once-daily gentamicin therapy for experimental Escherichia coli meningitis.

In vitro and in vivo studies have demonstrated that the bacteriologic efficacy of once-daily aminoglycoside therapy is equivalent to that achieved with conventional multiple daily dosing. The impact of once-daily dosing for meningitis has not been studied. Using the well-characterized rabbit meningitis model, we compared two regimens of the same daily dosage of gentamicin given either once or in three divided doses for 24 or 72 h. The initial 1 h mean cerebrospinal fluid (CSF) gentamicin concentration for animals receiving a single dose (2.9 +/- 1.7 micrograms/ml) was threefold higher than that for the animals receiving multiple doses. The rate of bacterial killing in the first 8 h of treatment was significantly greater for the animals with higher concentrations in their CSF (-0.21 +/- 0.19 versus -0.03 +/- 0.22 log10 CFU/ml/h), suggesting concentration-dependent killing. By 24h, the mean reduction in bacterial titers was similar for the two regimens. In animals treated for 72 h, no differences in bactericidal activity was noted for 24, 48, or 72 h. Gentamicin at two different dosages was administered intracisternally to a separate set of animals to achieve considerably higher CSF gentamicin concentrations. In these animals, the rate of bacterial clearance in the first 8 h (0.52 +/- 0.15 and 0.58 +/- 0.15 log10 CFU/ml/h for the lower and higher dosages, respectively) was significantly greater than that in animals treated intravenously. In conclusion, there is evidence of concentration-dependent killing with gentamicin early in treatment for experimental E. coli meningitis, and once-daily dosing therapy appears to be at least as effective as multiple-dose therapy in reducing bacterial counts in CSF.