The safety and efficacy of conventional aminoglycoside dosing regimens have been proven in clinical trials. Higher doses at longer intervals may be more effective if they result in higher peak serum levels of the drug, but few trials of “once-a-day” dosing have shown improved clinical outcome. The clinical safety of allowing trough serum levels to fall below the minimum inhibitory concentration is not established. Literal “once-a-day” dosing will result in drug accumulation and toxicity in patients with reduced renal clearance, and in potential lack of efficacy and the emergence of antibiotic-resistant organisms in those with increased renal clearance. However, modified “once-a-day” dosing, with the interval determined by the individual's renal clearance rate (hence avoiding subtherapeutic trough levels), will avoid these problems.
Objective: To determine the extent of pharmacy services and drug usage for Hospital‐in‐the‐Home (HITH) programs in Victoria. Method: In 1997, 42 Victorian hospital pharmacies with HITH services were surveyed by a questionnaire on services and drug usage over the previous six months. Results: Of the 29 hospital pharmacies which responded, 5 were not providing services, 16 provided 6‐month drug usage data and 15 provided drug expenditure data. Pharmacy staffing varied from a dedicated HITH pharmacist actively involved in patient management to no pharmacy involvement beyond drug dispensing. The range of pharmacy services provided included: preparation of intravenous additives; development of drug and administration protocols; care plans (including allergy and anaphylaxis procedures); supply of information regarding drug stability, storage and appliances, and consumer medicine information; patient counselling; therapeutic drug monitoring; and dosing advice. The data on drug usage and pharmaceutical expenditure was compromised by the inability of some pharmacies to identify HITH patients and inconsistent inclusion of non‐drug items. The range of drugs dispensed to HITH patients was broad, reflecting concurrent medical conditions and individual hospital practices. The most commonly dispensed parenteral drugs were ceftriaxone, cephazolin, dalteparin, flucloxacillin and vancomycin — reflecting the most common indications for HITH. Conclusion: HITH is an emerging alternative to inhospital patient management resulting in more patients being managed in the community. This creates an opportunity for hospital‐based health professional services to go beyond the hospital boundaries. Unlike the US, pharmacy services in HITH in Victoria are still evolving.
Some of the medications used for weight loss in the management of obesity have been associated with unacceptable morbidity and mortality. Safety concerns have led to the withdrawal of aminorex, followed by the fenfluramines in 1997, and phenylpropanolamine (norephedrine) in 2000. Aminorex was associated with an increased prevalence of primary pulmonary hypertension (PPH), fenfluramines with an increased prevalence of PPH and valvulopathy, and phenylpropanolamine with an increased risk of haemorrhagic stroke. Several studies have investigated the safety of the fenfluramines, yet the benefit-risk profile has not been conclusively quantified. This is due to several deficiencies in the published studies, including a lack of data on the baseline prevalences of comorbid conditions in obese subjects, and potential confounders and biases in the study designs. Although several studies and systematic reviews support an increased risk of PPH and valvulopathy in patients who have taken fenfluramines, without knowledge of the background prevalence it is not possible to determine if the exposure preceded the outcome. The population at higher risk of these adverse effects includes those taking higher doses or with a longer duration of exposure to fenfluramines and those with pre-existing cardiac disease or a genetic predisposition. Patients exposed to fenfluramines continue to be monitored, with some follow-up studies indicating no overall worsening in valvulopathy over time. There are limited efficacy and safety data for amfepramone (diethylpropion) and phentermine and their approval for the management of obesity is limited to short-term use. Orlistat and sibutramine are the only currently approved medications for long-term management of obesity. Although the benefit-risk profiles of sibutramine and orlistat appear positive, sibutramine continues to be monitored because of long-term safety concerns. The safety and efficacy of currently approved drug therapies have not been evaluated in children and elderly patient populations and there is limited information in adolescents, whilst the long-term safety of current and potential new drug therapies in adults will require several years of postmarketing surveillance to fully elucidate their adverse effect profiles.
In vitro studies were designed to investigate the influence of peak drug concentration (Cmax), the area under the concentration-time curve (AUC), and, consequently, the trough concentration on the bactericidal effects of gentamicin against Enterobacter cloacae (MIC, 0.5 mg/liter) by simulating bolus versus infusion administration and bolus dosing with altered drug clearance. Bacteria in the lag phase were exposed to gentamicin concentration-time profiles modelling either bolus or infusion dosing (AUC constant, Cmax changing) with 30-min postdose peak concentrations (Cpeak30) of 4, 6, 8, and 10 mg/liter or bolus dosing with normal and double drug clearance (Cmax constant, AUC changing) corresponding to normal clearance profiles with Cpeak30 of 6 and 8 mg/liter. Exposure to gentamicin caused early bactericidal effects apparent by 2 h, followed by variable bacteriostatic and recovery phases. Exposure to bolus profiles resulted in greater bactericidal activity than the corresponding infusion profile up to a Cpeak30 of 8 mg/liter. At a Cpeak30 of 10 mg/liter, there were no differences in bactericidal effect. Double clearance profiles had a reduced bactericidal effect at 6 mg/liter compared to the corresponding normal clearance profile, but no differences in bactericidal effect were observed for 8-mg/liter double and normal clearance profiles. These results suggest that the initial exposure (i.e., 0 to 30 min) is a more important determinant for bacterial killing than the AUC or trough concentration for this bacterium. Subject to confirmation of these findings with other gram-negative bacteria, to optimize aminoglycoside efficacy the initial exposure (Cmax) should be maximized by giving higher doses or bolus administration at intervals which may not produce detectable trough concentrations. Clinical trials with a broad range of patients, especially those with higher clearance, would confirm these in vitro observations and define optimal dosing recommendations.
The relative influence of peak concentration (Cmax) versus the area under the antibiotic concentration-time curve (AUC) on the bactericidal effect of gentamicin against Escherichia coli NCTC 10418 was studied. Bacteria in the lag phase were exposed to an in vitro gentamicin concentration series which mirrored the concentrations determined in patients after 80-mg intravenous bolus (1 min) and 80-mg intravenous infusion (30 min) doses. Bacterial viable cell counts and gentamicin concentrations were measured before and during antibiotic exposure. Both the Cmax and AUC were shown to be factors determining antibacterial activity; however, the Cmax was an independent determinant of effect. These findings indicate that bolus intravenous dosing with gentamicin could maximize bactericidal activity. Increased efficacy could result at any given daily antibiotic dose if delivered via bolus with long intervals (12 to 24 h) between doses if appropriate precautions to avoid toxicity are taken.
Theophylline clearance was studied in normal healthy volunteers before and after chronic oral dosing. Oral theophylline clearance showed a significant decrease (P less than 0.001) from 59.3 +/‐ 6.48 ml/min (mean +/‐ s.e. mean, n = 10) to 48.0 +/‐ 6.4 ml/min. Steady‐state intravenous clearance decreased by 26 +/‐ 2% from 55.1 +/‐ 7.7 ml/min to 41.0 +/‐ 5.96 ml/min (mean +/‐ s.e. mean, n = 6; P less than 0.001) at constant steady‐state intravenous test concentrations (mean 15.0 +/‐ 1.6 micrograms/ml after chronic oral dosing), excluding significant concentration dependence. Extrapolation of acute clearance findings to maintenance requirement may not be valid even in the same individual, with theophylline therapy requiring on‐going review beyond acute stabilisation.
To investigate the impact of the introduction of a consultative service on the use, efficiency of dosing and clinical toxicology of the aminoglycoside antibiotics, gentamicin and tobramycin, in a general hospital.Two audits were conducted six months and 18 months after the introduction of the consultative service. The audits reviewed the use of drug assay services, the adequacy of drug administration (as measured by serum antibiotic concentrations), indications for prescription, adverse outcomes (by noting markers of nephrotoxicity) and the antibiotic sensitivity of Gram-negative pathogens. The results were compared with the results of an audit conducted before the consultative service was instituted.There was a significant (P < 0.001 by chi 2 test) increase in the use of assays, with drug assays performed in 67% (first audit) and 77% (second audit) of aminoglycoside courses compared with 48.2% in the pre-intervention audit. Sample timing was greatly improved, with more than 70% of the samples collected at the appropriate times. Assay wastage in terms of uninterpretable assay results decreased significantly (P < 0.001) from 42.9% of total assays to 6.3% at the first audit and 3.8% at the second audit. The percentage of assay results in the desirable range increased significantly (P < 0.001) from 39.1% to 71.9% (first audit) and 75.4% (second audit). Pharmacokinetic recommendations were made in 39.1% and 64% of all aminoglycoside courses during the first and second audits respectively, with clinician acceptance of dosage recommendations at 83.1% and 82.8% respectively. For aminoglycoside courses prescribed for therapeutic reasons, 97.9% (first audit, n = 325) and 98.6% (second audit, n = 280) of indications for use were judged as clinically appropriate. The incidence of suspected aminoglycoside-induced nephrotoxicity was reduced from 8.9% of patients to 1.6% (first audit, P < 0.001) and 2.4% (second audit). Bacterial sensitivity audits showed that the great majority of clinical isolates of target organisms (n = 3523, Year 1 and n = 3385, Year 2) were sensitive to gentamicin (92.2% and 91.5% respectively) and tobramycin (98.1% and 98.8% respectively); these aminoglycosides exceeded all alternative agents in effectiveness, including first and third generation cephalosporins.The overall results indicate that introduction of the consultative service had a positive impact on the effective use of aminoglycosides, with a marked decrease in clinical toxicity. These influences were shown to persist for at least 18 months. The availability of reliable predictive techniques to reduce toxicity allows active promotion of aminoglycosides as the agents of choice on grounds of efficacy and economy.
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