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Teicoplanin is an investigational glycopeptide antibiotic that is structurally and microbiologically similar to vancomycin. Since teicoplanin possesses a very long elimination half-life, the manufacturer suggests that the drug be administered every 12 h for the first day of therapy and once daily thereafter. We studied the multiple-dose (6 mg/kg per dose) pharmacokinetics of teicoplanin in volunteers following intravenous administration every 12 h for 5 days and then every 24 h for 9 days in an attempt to identify the optimal duration of the every-12-h loading-dose regimen. Multiple serum samples were obtained throughout the study, including intensive sampling after the first and last doses; urine was collected during the entire study. A three-exponential equation was fitted to the serum concentration data. The mean terminal-phase half-life was 157 +/- 93 h. Concentrations of teicoplanin in serum similar to those observed after the administration of the last dose (day 14) were observed following the fourth or fifth dose given every 12 h. Therefore, it is suggested that for clinical dosing regimens for teicoplanin, dosing every 12 h for approximately 48 h should be used, followed by once-daily dosing thereafter.

In a study of intramuscular injection of quinine eight adults with moderately severe falciparum malaria resistant to chloroquine were treated with quinine dihydrochloride, being given a loading dose of 20 mg salt (16.7 mg base)/kg followed by three or four eight hourly maintenance doses of 10 mg salt (8.3 mg base)/kg injected into the anterior thigh. All patients responded to treatment. Fever and parasite clearance times (mean (SD) 60 (23) h and 53 (22) h respectively) were comparable with those obtained with intravenous quinine. The mean peak plasma quinine concentration of 11.0 mg/l (34.4 mu mol/l) [corrected] was reached a median of five hours after administration of the loading dose. In all patients plasma quinine concentrations exceeded the high minimum inhibitory concentration for Plasmodium falciparum malaria prevalent in Thailand within four hours of the start of treatment but did not cause toxicity other than mild cinchonism. When intravenous infusion is not possible an intramuscular quinine loading dose is an effective means of starting treatment in patients with moderately severe falciparum malaria who cannot swallow tablets.

The efficacy and toxicity of teicoplanin and vancomycin in the initial empirical antibiotic regimen in febrile, neutropenic patients with hematologic malignancies were compared in a prospective, randomized, unblinded, multicenter trial in the setting of 29 hematologic units in tertiary-care or university hospitals. A total of 635 consecutive febrile patients with hematologic malignancies and chemotherapy-induced neutropenia were randomly assigned to receive intravenously amikacin plus ceftazidime plus either teicoplanin at 6 mg/kg of body weight once daily or vancomycin at 1 g twice daily. An efficacy analysis was done for 527 evaluable patients: 275 treated with teicoplanin and 252 treated with vancomycin. Overall, successful outcomes were recorded for 78% of patients who received teicoplanin and 75% of those who were randomized to vancomycin (difference, 3%; 95% confidence interval [CI], -10 to 4%; P = 0.33). A total of 102 patients presented with primary, single-agent, gram-positive bacteremia. Coagulase-negative staphylococci accounted for 42%, Staphylococcus aureus accounted for 27%, and streptococci accounted for 21% of all gram-positive blood isolates. The overall responses to therapy of gram-positive bacteremias were 92 and 87% for teicoplanin and vancomycin, respectively (difference, 5%; CI, -17 to 6%; P = 0.22). Side effects, mainly represented by skin rash, occurred in 3.2 and 8% of teicoplanin- and vancomycin-treated patients, respectively (difference, -4.8%; CI, 0.7 to 8%; P = 0.03); the rate of nephrotoxicity was 1.4 and 0.8% for the teicoplanin and vancomycin groups, respectively (difference, 0.6%; CI, -2 to 1%; P = 0.68). Further infections were caused by gram-positive organisms in two patients (0.7%) treated with teicoplanin and one patient (0.4%) who received vancomycin (difference, 0.3%; CI, -0.9 to 1.0%; P = 0.53). Overall mortalities were 8.5 and 11% for teicoplanin- and vancomycin-treated patients, respectively (difference, -2.5%; CI, - 2 to 7%; P = 0.43); death was caused by primary gram-positive infections in three patients (1%) in each treatment group. When used for initial empirical antibiotic therapy in febrile, neutropenic patients, teicoplanin was at least as efficacious as vancomycin, but it was associated with fewer side effects.

Changes in plasma glucose and insulin concentrations were monitored over 24 hours in 28 African patients receiving quinine intravenously in an average dose of 8.5 mg base/kg over one hour eight hourly for severe malaria. The patients (nine children and 19 adults) were moderately undernourished; none was pregnant or had renal insufficiency. Plasma insulin concentrations rose during the infusion and then declined. Plasma glucose concentrations were decreased at two, three, and four hours after the start of the infusion. Insulin: glucose ratios were raised between half an hour and two hours after the start of the infusion. The three infusions of quinine increased plasma insulin concentrations in a similar way. In nine patients, including four children, plasma glucose concentrations fell below 2.8 mmol/l on one or two occasions. At the time of the hypoglycaemia plasma insulin concentrations were inappropriately high as shown by a consistent and often considerable increase in the insulin:glucose ratio. Hypoglycaemia that may pass unnoticed in comatose patients is thus a common complication of treating severe malaria with quinine, in particular in children. Its high incidence calls for attentive monitoring and preventive measures.

BACKGROUND: There is evidence that administration of higher doses of aminoglycosides given less frequently improves the bactericidal effect and reduces the potential to cause side effects. To investigate this, a prospectively randomised open label therapeutic trial was undertaken in stratified groups of patients with cystic fibrosis to examine the efficacy and toxic potential of an aminoglycoside dosing regimen designed to generate high peak drug concentrations at 12 hourly intervals compared with conventional dosing at eight hourly intervals. METHODS: Patients in group A received tobramycin eight hourly using a dose aimed at generating a peak concentration of 10 mg/l with trough concentrations below 2 mg/l, and those in group B received the total daily dose required to achieve eight hourly target concentrations administered as two equal 12 hourly doses. Clinical outcomes measured and assessed included vestibular symptoms, hearing and renal function, length of hospital stay, readmission rate, and mortality. RESULTS: Twenty nine patients were recruited during a six month period, 20 to group A and nine to group B. The average peak tobramycin level was higher in group B (12.5 (2.2) mg/l) than in group A (7.9 (1.9) mg/l), whilst the average trough level was higher in group A (0.8 (0.3) mg/l) than in group B (0.5 (0.2) mg/l). There was a difference in the number of ototoxic events between patients in group A (seven of 18, 38.9%) and group B (none of eight), but no difference was found in other outcome measures assessed. CONCLUSIONS: These results suggest that 12 hourly high peak aminoglycoside dosing may be less toxic than equivalent eight hourly dosing, without any apparent difference in efficacy.

The effect of protein binding on the activity of teicoplanin against Staphylococcus aureus was evaluated. Bactericidal rates of teicoplanin in cation-supplemented Mueller-Hinton broth (SMHB) and in a 1:1 mixture of pooled human serum and cation-supplemented Mueller-Hinton broth (PHS-SMHB) were compared with those of vancomycin. Eight concentrations of each drug ranging from 15 to 150 micrograms/ml were studied in two series which correspond to the concentrations in serum achieved with low- (6 mg/kg of body weight once daily) and high-dose (30 mg/kg once daily) teicoplanin. Overall, the bactericidal rate of teicoplanin was lower than that of vancomycin. In the presence of serum, the bactericidal rate of teicoplanin in PHS-SMHB was lower than that in SMHB, often resulting in only one log10 drop in CFU over a 24-h period. There was no statistical difference in the bactericidal rates of high- and low-concentration teicoplanin in either medium. Additionally, concentration-dependent killing in SMHB was not evident with either agent. The bactericidal rates of teicoplanin and vancomycin in a 1:1 mixture of serum ultrafiltrate and SMHB at 60 micrograms/ml were also studied. It was noted that the bactericidal rate of neither agent was affected by the presence of serum ultrafiltrate. This finding is consistent with teicoplanin's high degree of protein binding (reported to be greater than 90% in undiluted serum) and further substantiates the hypothesis that only the free drug is active against microorganisms. These data support protein binding as being a factor in teicoplanin activity against S. aureus.

Sustained release procainamide tablets were administered to 34 patients 48 hours after the onset of an acute myocardial infarct. Therapeutic blood levels of procainamide in the range of 4 to 8 mug/ml were consistently achieved using an 8-hourly maintenance dose of 1.5g after an initial loading dose of 2g. In contrast conventional procainamide capsules administered to 21 comparable patients repeatedly failed to produce plasma concentrations in the therapeutic range, despite the administration of a maintenance dose of 375 mg 3 hourly, after a loading dose of 1g. It is suggested that when the oral administration of procainamide is indicated for the management of ventricular arrhythmias after myocardial infarction, a sustained release preparation should be used.

We used an experimental rat model to compare the therapeutic efficacy of teicoplanin, linezolid, and quinupristin/dalfopristin with that of vancomycin as standard therapy for infective endocarditis.

Aortic endocarditis was induced in rats by insertion of a polyethylene catheter into the left ventricle, followed by intravenous inoculation of 106 colony-forming units of methicillin-resistant Staphylococcus aureus 24 hours later. Forty-eight hours after bacterial challenge, intravenous antibiotic therapies were initiated. There were 6 groups of 8 rats each: uninfected control; infected, untreated control; vancomycin-treated (40 mg/kg twice daily); teicoplanin-treated (20 mg/kg twice daily after a loading dose of 40 mg/kg); linezolid-treated (75 mg/kg 3 times daily for 1 day, then 75 mg/kg twice daily); and quinupristin/dalfopristin-treated (30 mg/kg twice daily and an additional 10 mg/kg dalfopristin infusion over 6 to 12 hr daily). At the end of therapy, the aortic valve vegetations in the drug-treated rats were evaluated microbiologically.

Compared with the infected, untreated group, all drug-treated groups had significantly reduced bacterial titers in the vegetations. Vancomycin, teicoplanin, and quinupristin/dalfopristin all effectively reduced the quantitative bacterial cultures of aortic valve vegetations. In addition, there was no significant difference in the comparative efficacy of teicoplanin, linezolid, and quinupristin/dalfopristin. Vancomycin significantly reduced bacterial counts in comparison with linezolid, which was nonetheless also effective.

Our experimental model showed that each of the investigated antimicrobial agents was effective in the treatment of infective endocarditis.

Twenty-five febrile patients with a history of intravenous drug use who were receiving either vancomycin (15 patients) or teicoplanin (10 patients) as part of a multicenter, double-blind, randomized, clinical efficacy trial were enrolled, upon receipt of their first dose of antibiotic, into a study to evaluate the effect of 1 g of vancomycin and high-dose teicoplanin (30 mg/kg of body weight) on histamine release and the occurrence of "red man syndrome" (RMS). In addition, 10 healthy volunteer subjects (HVS) were randomized to receive either 1 g of vancomycin intravenously or a saline infusion in a double-blind, crossover design study. Patients and HVS were observed for the presence of erythema, flushing, pruritus, and hypotension during and for up to 1 h postinfusion by a blinded investigator. Histamine concentrations in plasma were measured at baseline and during and after drug infusion. No significant differences were noted in baseline temperature between patients (vancomycin recipients, 102.3 degrees F [39.1 degrees C]; teicoplanin recipients, 102.4 degrees F [39.1 degrees C]) or incidence of bacteremia (7 of 15 vancomycin recipients; 5 of 10 teicoplanin recipients). There were no significant differences in peak vancomycin concentrations in the sera of patients (40.8 micrograms/ml) and HVS (49.9 micrograms/ml). There were no reactions consistent with RMS in any patient who received teicoplanin (0 of 10); there was a significant difference in the occurrence of RMS in patients in comparison with that in HVS (0 of 15 patients, 9 of 10 HVS; P less than 0.001) who received vancomycin. The predominant reaction was erythema and pruritus. Histamine concentrations in plasma and the area under the histamine plasma concentration-time curve were highly variable within groups and were not statistically different between patients and HVS. The incidence of RMS secondary to vancomycin or teicoplanin in our patient population appears to be low and consistent with clinical observations. Similar to previous investigations, RMS secondary to vancomycin in HVS was high (90%). However, we found no relationship between the histamine concentration in plasma or the area under the plasma histamine concentration-time curve and the severity of RMS in HVS. The reason for the discrepancy of RMS in patients versus that in HVS in unknown, but it may be related to a blunted effect of glycopeptides to produce the reaction in the presence of infection or it may be specific to our patient population.

This study evaluates the use of a multidrug resistance (MDR) modulator (verapamil) in combination with a standard dose of single-agent etoposide in relapsed or refractory paediatric malignancy. A total of 20 patients (median age 6.5 years) were treated with an infusion of verapamil (loading dose 0.1 mg kg-1, followed by continuous infusion 0.15 mg kg-1 h-1) for 72 h. Etoposide was given daily (150 mg m-2 day-1) for three doses (each over 1 h); the first dose was given 12 h into the verapamil infusion. Cardiovascular toxicity was monitored by ECG and 2 hourly blood pressure and pulse recordings. Verapamil and norverapamil plasma concentrations were measured daily. Disease response was assessed after two courses. A total of 29/35 treatment courses were given at the desired verapamil dose; five courses required a dose reduction owing to cardiovascular toxicity. No patient required intensive monitoring. All patients who developed cardiovascular toxicity were over 14 years old. There was no correlation between plasma verapamil or norverapamil concentrations and toxicity. There were six partial responses (three rhabdomyosarcoma, three neuroblastoma) after two courses, but because of variation in the dose and schedule of etoposide these cannot be unequivocally contributed to MDR reversal. In conclusion, a regimen using a continuous infusion of verapamil combined with divided-dose etoposide is tolerable in children, and this strategy may be effective in refractory neuroblastoma and rhabdomyosarcoma.

Because studies showed similar viral suppression with lower raltegravir doses and because Asians usually have high antiretroviral concentrations, we explored low-dose raltegravir therapy in Thais. Nineteen adults on raltegravir at 400 mg twice daily (BID) with HIV RNA loads of <50 copies/ml were randomized to receive 400 mg once daily (QD) or 800 mg QD for 2 weeks, followed by the other dosing for 2 weeks. Intensive pharmacokinetic analyses were performed, and HIV RNA was monitored. Two patients were excluded from the 400-mg QD analysis due to inevaluable pharmacokinetic data. The mean patient weight was 58 kg. Mean pharmacokinetic values were as follows: for raltegravir given at 400 mg BID, the area under the concentration-time curve from 0 to 12 h (AUC0-12) was 15.6 mg/liter-h and the minimum plasma drug concentration (Ctrough) was 0.22 mg/liter; for raltegravir given at 800 mg QD, the AUC0-24 was 33.6 mg/liter-h and the Ctrough was 0.06 mg/liter; and for raltegravir given at 400 mg QD, the AUC0-24 was 18.6 mg/liter-h and the Ctrough was 0.08 mg/liter. The HIV RNA load was <50 copies/ml at each dose level. Compared to the adjusted AUC0-24 for Westerners on raltegravir at 400 mg BID, Thais on the same dose had double the AUC0-24 and those on raltegravir at 400 mg QD had a similar AUC0-24. More patients had a Ctrough of <0.021 mg/liter on raltegravir at 400 mg QD (9/17 patients) than on raltegravir at 800 mg QD (1/19 patients) or 400 mg BID (0/19 patients). Seventeen patients used raltegravir at 400 mg QD for a median of 35 weeks; two had confirmed HIV RNA loads between 50 and 200 copies/ml, and both had low Ctrough values. Low-dose raltegravir could be a cost-saving option for maintenance therapy in Asians or persons with low body weight. However, raltegravir at 400 mg QD was associated with a low Ctrough and with a risk for HIV viremia. Raltegravir at 200 or 300 mg BID should be studied, but new raltegravir formulations will be needed.

The in vitro and in vivo therapeutic efficacies of teicoplanin-loaded calcium sulfate (TCS; 10% [wt] teicoplanin) were investigated in a rabbit model of chronic methicillin-resistant Staphylococcus aureus (MRSA) osteomyelitis. The in vitro elution characteristics of teicoplanin from TCS pellets were realized by carrying out an evaluation of the release kinetics, recovery rate, and antibacterial activity of the released teicoplanin. Chronic osteomyelitis was induced by inoculating 107 CFU of a MRSA strain into the tibial cavity of rabbits. After 3 weeks, the animals were treated by debridement followed by implantation of TCS pellets in group 1, calcium sulfate (CS) pellets alone in group 2, and intravenous (i.v.) teicoplanin (6 mg/kg of body weight every 12 h for three doses and then every 24 h up to 4 weeks) in group 3. Animals in group 4 were left untreated. After 6 weeks, the efficacy of the osteomyelitis treatment was evaluated by hematological, radiological, microbiological, and histological examinations. In vitro elution studies showed sustained release of teicoplanin at a therapeutic level over a time period of 3 weeks. The released teicoplanin maintained its antibacterial activity. In vivo, the best therapeutic effect was observed in animals treated with TCS pellets, resulting in significantly lower radiological and histological scores, lower positive rates of MRSA culture and bacterial load, and excellent bone regeneration compared with those treated by CS alone or i.v. teicoplanin, without any local or systemic adverse effects. TCS pellets are an effective alternative to i.v. teicoplanin for the treatment of chronic MRSA osteomyelitis, particularly because teicoplanin is delivered locally while the TCS pellets simultaneously promote bone defect repair.

Objective: To assess the knowledge of four groups of individuals regarding who is legally authorised to consent to health care or research involving older patients.

Design: A provincewide postal survey.

Setting: Province of Quebec, Canada.

Participants: Three hundred older adults, 434 informal caregivers of cognitively impaired individuals, 98 researchers in aging and 136 members of research ethics boards (REBs).

Measurements: Knowledge was assessed through a pretested postal questionnaire comprising five vignettes that describe hypothetical situations involving an older adult who requires medical care or is solicited for research. The respondent had to identify the person who is legally authorised to provide consent.

Results: Nearly 80% of all respondents provided the correct answer when the hypothetical scenario depicted a person who was competent to consent or incompetent but legally represented. Knowledge was worse (from 2% among older adults to 44% among REB members) for the scenario describing a research situation that involved an incompetent adult without a legal guardian.

Conclusion: The observed lack of knowledge raises doubts about the ability of current legislation to truly protect the rights of older adults with diminished decision making capacity. It points to the need for educational programmes aimed at increasing public awareness of the legislation put in place for those requiring special protection.

The pharmacokinetics of teicoplanin were studied in 15 adult patients in the acute phase of severe infections caused by gram-positive cocci. All the subjects were given a daily intravenous bolus dose of 6 mg of teicoplanin kg-1 (body weight). The pharmacokinetic study was performed over a 48-h period after injection 4. The subjects were categorized according to their mean creatinine clearances (ml.min-1.kg-1) during the study period: group 1 (n = 3), greater than 1.6; group 2 (n = 6), 0.8 to 1.6; and group 3 (n = 6), 0.15 to 0.8. Mean concentrations of teicoplanin in serum at 1, 24, and 48 h were 33 +/- 8, 9 +/- 3, and 6 +/- 2.5 micrograms.ml-1, respectively. The mean half-lives of the concentration-time curve from 12 to 48 h were 28 +/- 4, 44 +/- 24, and 48 +/- 14 h in groups 1, 2, and 3, respectively (group 3 versus group 1: P less than 0.05). The mean area under the serum concentration-time curve from time zero to 24 h was 344 +/- 92 mg.h.liter-1, and the mean hybrid volume of distribution was 1.09 +/- 0.46 liter.kg-1. These values were similar for the three groups, with a trend for larger areas under the curve in group 3. Creatinine clearance correlated directly with the total body clearance of teicoplanin (r = 0.70) and with the renal clearance of teicoplanin (r = 0.82). However, in critically ill patients, the wide interindividual variations in pharmacokinetic parameters are more relevant than those related to the variations in renal function when creatinine clearance is above 0.30 ml.min-1.kg-1. We concluded that, in such conditions, monitoring of concentrations of teicoplanin in serum is mandatory.

Background

The purpose of this study was investigate the dose proportionality of a novel, once-daily, controlled-release formulation of hydromorphone that utilizes the OROS® Push-Pull™ osmotic pump technology.

Methods

In an open-label, four-way, crossover study, 32 healthy volunteers were randomized to receive a single dose of OROS® hydromorphone 8, 16, 32, and 64 mg, with a 7-day washout period between treatments. Opioid antagonism was provided by three or four doses of naltrexone 50 mg, given at 12-hour intervals pre- and post-OROS® hydromorphone dosing. Plasma samples for pharmacokinetic analysis were collected pre-dose and at regular intervals up to 48 hours post-dose (72 hours for the 64-mg dose), and were assayed for hydromorphone concentration to determine peak plasma concentration (Cmax), time at which peak plasma concentration was observed (Tmax), terminal half-life (t1/2), and area under the concentration-time curve for zero to time t (AUC0-t) and zero to infinity (AUC0–∞). An analysis of variance (ANOVA) model on untransformed and dose-normalized data for AUC0-t, AUC0–∞, and Cmax was used to establish dose linearity and proportionality.

Results

The study was completed by 31 of 32 subjects. Median Tmax (12.0–16.0 hours) and mean t1/2 (10.6–11.0 hours) were found to be independent of dose. Regression analyses of Cmax, AUC0–48, and AUC0–∞ by dose indicated that the relationship was linear (slope, P ≤ 0.05) and that the intercept did not differ significantly from zero (P > 0.05). Similar analyses with dose-normalized parameters also indicated that the slope did not differ significantly from zero (P > 0.05).

Conclusion

The pharmacokinetics of OROS® hydromorphone are linear and dose proportional for the 8, 16, 32, and 64 mg doses.

Trial Registration

Clinical Trials.gov NCT00398957

The pharmacokinetics of teicoplanin were determined after multiple 30-min intravenous infusions of 10 to 15 mg/kg every 12 to 24 h in 11 intravenous drug abuse (IVDA) patients being treated for bacterial endocarditis. Multiple serum samples were obtained over 7 to 14 days. Twenty-four-hour urine collections were obtained on days 1 and 5. Serum concentration-time data were analyzed by using multiple-dose pharmacokinetic analysis (NONLIN84). Results were compared with pharmacokinetic parameters derived from previous studies in normal healthy volunteers following multiple intravenous infusions of teicoplanin (3 to 6 mg/kg/day). Total and renal clearances of teicoplanin in IVDA patients were found to be significantly greater and more highly variable than those observed previously in normal healthy volunteers. As a result, predicted steady-state trough concentrations in serum may vary up to fivefold. The mechanism responsible for this variation appears to be related to the glomerular filtration rate. In IVDA patients, individualized teicoplanin dosage may be required in the treatment of bacterial endocarditis.

Trough serum teicoplanin concentrations were compared in healthy adults following intravenous administration of one of two regimens: (i) 12 mg/kg of body weight every 12 h for 3 doses and then 15 mg/kg every 48 h for 4 doses (n = 16 subjects) or (ii) 6 mg/kg every 12 h for 2 doses and then 6 mg/kg every 24 h for 9 doses (n = 8 subjects). The mean ± standard deviation trough concentrations in serum on day 11 (24 and 48 h after administration of the last dose for the daily and alternate-day dosing schedules, respectively) were 16.0 ± 2.1 and 17.9 ± 3.5 mg/liter for subjects receiving the two regimens, respectively, by a fluorescence polarization immunoassay. The limits of the 95% confidence interval of the difference (−0.2, 3.6 mg/liter) determined by a nonparametric test were situated above the −1.3-mg/liter maximum set difference and indicated a noninferiority of the alternate-day dosing to the daily dosing. Throughout the study the individual trough concentrations in serum in the alternate-day dosing group constantly exceeded 10 mg/liter, the presently recommended target concentration for the treatment of severe infections. The trough concentrations in the sera of all subjects were bactericidal for six Staphylococcus aureus strains for which teicoplanin MICs are between 0.5 and 4 mg/liter. The bactericidal activity of serum was related to total teicoplanin (protein bound and unbound). In conclusion, an alternate-day dosing schedule (15 mg/kg on alternate days following administration of a 12-mg/kg loading dose three times every 12 h) could be considered for further efficacy and safety studies.

The prophylactic and therapeutic activities of teicoplanin were evaluated in two different experimental models of foreign body infections caused by methicillin-resistant Staphylococcus aureus (MRSA). In a guinea pig model of prophylaxis, subcutaneously implanted tissue cages were infected at a > 90% rate by 10(2) CFU of MRSA in control animals. A single dose of 30 mg of teicoplanin per kg of body weight administered intraperitoneally 6 h before bacterial challenge was as effective as vancomycin in preventing experimental infection in tissue cages injected with either 10(2), 10(3), or 10(4) CFU of MRSA. In a rat model evaluating the therapy of chronic tissue cage infection caused by MRSA, the efficacy of a 7-day high-dose (30 mg/kg once daily) regimen of teicoplanin was compared with that of vancomycin (50 mg/kg twice daily). Whereas high levels of teicoplanin were found in tissue cage fluid, continuously exceeding its MBC for MRSA by 8- to 16-fold, no significant reduction in the viable counts of MRSA occurred during therapy. In contrast, either vancomycin alone or a combined regimen of high-dose teicoplanin plus rifampin (25 mg/kg twice daily) could significantly decrease the viable counts in tissue cage fluids. Whereas the bacteria recovered from tissue cage fluids during therapy showed no evidence of teicoplanin resistance, they failed to be killed even by high levels of this antimicrobial agent. The altered susceptibility of in vivo growing bacteria to teicoplanin killing might in part explain the defective activity of this antimicrobial agent when used as monotherapy against chronic S. aureus infections. These data may indicate the need for a combined regimen of teicoplanin with other agents such as rifampin to optimize the therapy of severe staphylococcal infections.

Plasma sodium and osmolality were determined in 80 adult epileptic patients receiving chronic treatment with carbamazepine and in 50 control patients treated with other anticonvulsant drugs. Mean plasma osmolality was significantly lower in the carbamazepine-treated patients but mean plasma sodium did not differ in the two groups. Hyponatraemia was found in five of the carbamazine-treated patients and hypo-osmolality in six. None of the control patients had hyponatraemia and only one had a borderline low osmolality. Three of the 13 patients receiving carbamazepine alone were hyponatraemic. Plasma sodium concentration correlated negatively with both daily carbamazepine dose and serum carbamazepine level. Free water clearance after an oral water load was determined in six patients on carbamazepine alone and in six normal subjects not receiving drug therapy. The capacity of some of the patients to excrete the water load was found to be grossly impaired.

In this double-blind, randomized study, five healthy subjects per group received doses of 15, 20, or 25 mg of teicoplanin per kg of body weight, and one subject per group received a 0.9% NaCl placebo as single intravenous infusion over 30 min. Serial blood samples and urine were collected for 13 days postadministration, and concentrations of teicoplanin were determined by microbiological assay. The pharmacokinetic data were analyzed by noncompartmental and compartmental analyses. Laboratory safety tests, audiometry, and serum creatinine clearance measurements were done prior to day 1 and on days 2 and 14. In the three groups, peak levels at the end of the infusion averaged 194, 197, and 253 mg/liter, respectively. Mean concentrations in plasma 24 h after the administration were 10.5, 13.6, and 19.8 mg/liter, respectively. Mean values of volume of distribution at steady state were 0.80, 0.87, and 0.87 liters/kg, respectively. Terminal half-lives averaged 88, 83, and 92 h. Mean total clearance values were 10.9, 11.0, and 11.3 mg/h/kg, respectively, with renal clearance accounting for 75, 81, and 78%, respectively, of the total. The 13-day cumulative mean urinary recovery ranged from 71 to 78% of the dose within the groups. The pharmacokinetics of teicoplanin appears to be linear in the range of administered doses. Teicoplanin was generally well tolerated. Side effects, appearing in five subjects, were represented by fevers, chills, and skin reactions; these adverse reactions were mild, but one episode of rash necessitated the interruption of infusion, and one episode of chills necessitated treatment with corticosteroids. There was no indication of drug-related modifications of laboratory test results.

Thirteen patients in chronic atrial fibrillation with a normal resting heart rate but with exercise tachycardia and episodes of bradycardia were randomised to treatment periods of two weeks on xamoterol (200 mg twice daily), low dose digoxin, or placebo, in a blind crossover study. The results (mean SEM) of symptom scores, a treadmill exercise test, and 24 hour ambulatory electrocardiographic monitoring were obtained. Xamoterol improved symptom scores and controlled exercise heart rate better than digoxin. Xamoterol was better than digoxin or placebo in reducing the heart rate response to exercise and tended to improve exercise duration. Xamoterol, by reducing the daytime maximum hourly heart rate and increasing the night time minimum hourly heart rate, significantly reduced the difference between the two compared with placebo. In contrast, digoxin tended to reduce both the maximum and minimum hourly heart rates through day and night. Both the frequency and duration of ventricular pauses were reduced by xamoterol but tended to increase with digoxin. Xamoterol reduced both the circadian variation in ventricular response to atrial fibrillation and exercise tachycardia by modulating the heart rate according to the prevailing level of sympathetic activity. These changes were translated into symptomatic benefit for the patients studied.

ACKGROUND--Systemic absorption of inhaled corticosteroids may adversely influence the function of the hypothalamo-pituitary-adrenal axis, bone metabolism, and circulating leucocytes. These changes can be used to assess the safety of different types and modes of administration of these drugs. METHODS--The study was a randomised, double dummy, crossover design with nine healthy adults. It compared the effects of beclomethasone dipropionate and budesonide (given by metered dose aerosols with and without their respective large volume spacers (Volumatic and Nebuhaler) attached) on serum cortisol, 24 hour urinary free cortisol, and plasma osteocalcin concentrations, and circulating neutrophils and lymphocytes. Subjects inhaled the drug (1 mg) and matching placebo at 0900 and 2200 hours on each of six study days. Blood samples were taken hourly for six hours after the morning dose and at the end of the study period. RESULTS--All results were within the reference ranges. Both drugs caused similar reductions in serum cortisol four to six hours after inhalation. These changes were not affected by the use of a large spacer and did not persist at 24 hours. Use of spacers tended to increase the haematological effects of the steroids. Beclomethasone dipropionate inhaled through a Volumatic provoked a rise in circulating neutrophils compared with placebo although lymphocyte numbers were unaffected. Budesonide did not influence neutrophil numbers but did reduce circulating lymphocytes, numbers of which were further reduced when the Nebuhaler was used. There were no significant changes in plasma osteocalcin concentration or 24 hour urinary free cortisol excretion with budesonide, with or without a spacer. Beclomethasone dipropionate inhaled without a spacer reduced urinary cortisol and plasma osteocalcin at 24 hours; however, use of the Volumatic protected against these effects. CONCLUSIONS--Attaching a Volumatic reduces the systemic effects of 2 mg aerosol beclomethasone dipropionate on the hypothalamo-pituitary-adrenal axis and circulating osteocalcin concentrations. This study did not establish whether the Nebuhaler reduces the systemic effects of budesonide. When large spacers are used, 2 mg per day of beclomethasone dipropionate and budesonide seem to be equivalent in terms of unwanted effects.

Aims: To test the suitability of a simple once daily (OD) gentamicin regimen for use in young infants where routine therapeutic drug monitoring is not possible.

Methods: In an open, randomised, controlled trial, infants with suspected severe sepsis admitted to a Kenyan, rural district hospital received a novel, OD gentamicin regimen or routine multi-dose (MD) regimens.

Results: A total of 297 infants (over 40% ⩽7 days) were randomised per protocol; 292 contributed at least some data for analysis of pharmacological endpoints. One hour after the first dose, 5% (7/136) and 28% (35/123) of infants in OD and MD arms respectively had plasma gentamicin concentrations <4 µg/ml (a surrogate of treatment inadequacy). Geometric mean gentamicin concentrations at this time were 9.0 µg/ml (95% CI 8.3 to 9.9) and 4.7 µg/ml (95% CI 4.2 to 5.3) respectively. By the fourth day, pre-dose concentrations ⩾2 µg/ml (a surrogate of potential treatment toxicity) were found in 6% (5/89) and 24% (21/86) of infants respectively. Mortality was similar in both groups and clinically insignificant, although potential gentamicin induced renal toxicity was observed in <2% infants.

Conclusions: A "two, four, six, eight" OD gentamicin regime, appropriate for premature infants and those in the first days and weeks of life, seems a suitable, safe prescribing guide in resource poor settings.

BACKGROUND: Although the need for corticosteroids in acute severe asthma is well established the appropriate dose is not known. METHODS: The response to intravenous hydrocortisone 50 mg (low dose), 100 mg (medium dose), and 500 mg (high dose), administered every six hours for 48 hours and followed by oral prednisone, was compared in patients with acute asthma in a double blind randomised study. After initial emergency treatment with bronchodilators subjects received oral theophylline or intravenous aminophylline and nebulised salbutamol four hourly. Patients were given low, medium, or high doses of intravenous hydrocortisone and then 20, 40, or 60 mg/day respectively of oral prednisone with a reducing regimen over the following 12 days. Beclomethasone dipropionate, 400 micrograms twice daily by metered dose inhaler, was also started. Peak expiratory flow (PEF), forced expiratory volume in one second (FEV1), and visual analogue dyspnoea scores (VAS) were recorded daily in hospital and PEF and VAS twice daily after discharge for a total of 12 days. RESULTS: The 66 subjects (40 female) who completed the study had a mean (SD) age of 31(14) years. On presentation mean (SD) FEV1% predicted in the low (n = 22), medium (n = 20), and high dose (n = 24) groups was 17(13), 19(12), and 19(11) and after emergency bronchodilator treatment 32(20), 30(12), and 36(13). After 24 hours of treatment the respective post-bronchodilator FEV1% predicted values were 62(22), 62(23), and 65(28) compared with 71(24), 69(22), and 71(24) after 48 hours. No significant difference between the groups was detected. PEF and VAS improved with treatment over the 12 days but was not influenced by steroid dose. CONCLUSIONS: Hydrocortisone 50 mg intravenously four times a day for two days followed by low dose oral prednisone is as effective in resolving acute severe asthma as 200 or 500 mg of hydrocortisone followed by higher doses of prednisone.

Forty-five patients who had undergone major operations were given a slow intravenous injection of morphine sulphate (1 mg/ml saline) until their pain was relieved and were then randomly divided into three equal groups to receive different regimens of morphine sulphate over the next 72 hours. Patients in group A received 3.5 times the pain-relieving dose (28-63 mg, mean 36 mg) by continuous intravenous infusion; those in group B received the pain-relieving dose (90-160 mg, mean 110 mg) intramuscularly, four-hourly for the first 24 hours, six-hourly for the next 24 hours, and then eight and 20 hours later; and those in group C received the pain-relieving dose (80-280 mg, mean 140 mg) intramuscularly as required. Pain was assessed on a linear analogue scale and vital capacity and peak expiratory flow rate measured 12-hourly. The mean pain score was significantly lower and respiratory function significantly better in group A than in groups B and C. Only one patient (in group A) required extra morphine. Thus morphine administered by continuous intravenous infusion is superior to other regimens, giving better pain relief at a lower dosage.