Differences in length of stay for Hospital in the Home patients: comparing simple clinical coding with medical record review.

AIM: To determine whether the apparently longer length of stay (LOS) reported for patients with cellulitis managed in Hospital in the Home (HITH) compared with those managed as inpatients was correct. METHODS: Data, including LOS, from the Victorian In-patient Minimum Database (VIMD) of all patients with cellulitis managed between July 1998 and June 1999 at a large metropolitan teaching hospital were analysed and compared with a retrospective medical record review of the same patients. RESULTS: In the VIMD data, there were 266 episodes of cellulitis during the study period. However, the medical record review found that six episodes were not separate, but rather a continuation of treatment for the same episode of cellulitis, and that 18 were not episodes of cellulitis, but were pilonidal sinus infections. In the VIMD data set, the mean LOS for patients treated in HITH was generally longer than that for inpatients (7.2 days vs 5.1 days, respectively, P = 0.002). However, in the retrospective medical record review, the LOS for patients treated in HITH was similar to inpatients (7.3 days versus 7.0 days, respectively, P = 0.68). CONCLUSIONS: In contrast to the VIMD data, the medical record review demonstrated that, overall, patients with cellulitis had a similar LOS irrespective of whether they were managed at home or in hospital. This study confirms that caution is required in interpreting the VIMD data, highlights the importance of carefully monitoring the introduction of new treatment modalities and indicates areas for further research.

Cephalosporin clinical concentration-time profile modelling and in-vitro bactericidal effects on Escherichia coli.

We assessed the cephalosporin concentration-time curve area (AUC), peak concentration, maintained concentration and duration of exposure on in-vitro bactericidal effects on Escherichia coli NCTC 10418, using exposures modelling cephazolin clinical profiles after 1 g and 2 g i.m. injection, equal AUC exposures (288 mg x h/L, 576 mg x h/L; 48 h) and constant exposures to 6, 12 and 24 mg/L. Cephalosporin dosage exposures based on maintenance of concentrations at multiples (6-24 times) of the MIC were not as effective in early or sustained (24 h) bactericidal effect as exposures modelling im injection profiles with equal or lower AUC (P<0.05, ANOVA). Similar results applied to i.m. comparisons with equal AUC exposures modelling extremes of concentration and time exposures. These results indicate a need for intermittent dosage to produce optimally effective profiles, and raise the possibility that these optimum dosing profiles may allow an extension of minimum interdose intervals beyond 8 h.

Changes in MIC alter responses of Pseudomonas aeruginosa to tobramycin exposure.

The pharmacokinetic parameters determining antibiotic efficacy are peak concentrations (Cmax), minimum (trough) concentrations (Cmin), and area under the concentration-time curve (AUC). There is general agreement about the importance of Cmax and AUC for aminoglycosides, but this is not so for maintenance of Cmin. With in vitro exposures modelling in vivo administration, Pseudomonas aeruginosa reference strain ATCC 27853 (MIC, 1 mg/liter) and a higher-MIC (relatively resistant) clinical isolate (MIC, 4 mg/liter) were used to explore bacteriostatic and bactericidal outcomes. With P. aeruginosa ATCC 27853, kill followed a complete bolus profile with a 30-min postdistribution peak (Cpeak30) of 10 mg/liter. The clinical isolate required a Cpeak30 bolus profile of 20 mg/liter for kill, and there was no difference between the efficacies of the bolus and infusion exposures. Bolus profiles that were truncated at 8.5 h and producing sublethal effects were then combined with a wide range of Cmins. With a Cpeak30 profile of 8 mg/liter, P. aeruginosa ATCC 27853 showed a graded bacteriostatic response until a Cmin of > or = 0.8 mg/liter, when complete kill resulted. In contrast, bactericidal effects on the clinical isolate required a Cpeak30 profile of 18 mg/liter with a Cmin of > or = 1.0 mg/liter. Therefore, Cmin also contributes to the bactericidal effect of tobramycin, with requirements showing minor variation with change in MIC. Dosing principles for relatively resistant (higher-MIC) organisms are suggested from the data. Relatively higher aminoglycoside doses via infusion regimens are likely to be needed to generate higher peak concentrations and higher AUC values necessary for bactericidal effect in resistant organisms. Maintenance of trough concentrations on the order of 1.0 mg/liter during the interdose interval will tend to guard against the possibility of inadequate peak and AUC exposures for kill.

Initial concentration-time profile of gentamicin determines efficacy against Enterobacter cloacae ATCC 13047.

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.

Dosing implications of a clinical interaction between grapefruit juice and cyclosporine and metabolite concentrations in patients with autoimmune diseases.

OBJECTIVE: To determine the effect of chronic grapefruit juice administration on steady state blood concentrations of cyclosporine and metabolites in patients with autoimmune diseases. METHODS: 9 patients stabilized on administration of cyclosporine (range 0.7-6.7 mg/kg/day) were given either grapefruit juice or water using randomized crossover design. Whole blood samples were collected before the morning cyclosporine dose and during the 12 h interdose interval. Cyclosporine concentrations were measured using a relatively specific assay (Emit) and total metabolite concentrations were estimated using a nonspecific assay (polyclonal Abbott-TDx). RESULTS: Exposure to grapefruit juice produced significant increases in predose cyclosporine concentrations (p < 0.01) and total metabolite concentrations (p = 0.03) and the area under the cyclosporine and metabolite blood concentration-time curves (p = 0.005, p = 0.001, respectively). One patient developed significant neurological side effects associated with a 68.9 and 214% increase in predose cyclosporine and metabolite concentrations, respectively, during grapefruit juice co-administration. CONCLUSION: Grapefruit juice causes an increase in both parent and metabolite profiles, indicating an alteration in the disposition of cyclosporine and metabolites. This interaction is of potential clinical importance in terms of mechanism, side effects, and dosing.

Kill kinetics and regrowth patterns of Pseudomonas aeruginosa exposed to concentration-time profiles of tobramycin simulating in vivo infusion and bolus dosing.

Pseudomonas aeruginosa ATCC 27853 was exposed to tobramycin concentration-time profiles modelling in vivo bolus and infusion dosing. Dependence of bactericidal and bacteriostatic activity on the initial profile of peak concentration (bolus effect > infusion) and area under the antibiotic concentration-time curve was observed at peak concentration/MIC ratios of 10 or below.

Minimisation of aminoglycoside toxicity in patients with cystic fibrosis.

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.

Aminoglycoside dosing: one, two or three times a day?

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.

A prospective audit of total parenteral nutrition at a major teaching hospital.

OBJECTIVE: To examine patterns of use and clinical outcomes of total parenteral nutrition (TPN). DESIGN: A prospective six-month audit (December 1992-June 1993). PATIENTS AND SETTING: All inpatients administered TPN at a metropolitan teaching hospital during the audit period. MAIN STUDY MEASURES: Process measures included data about TPN initiation (bodyweight, period not receiving oral/nasogastric feeding, serum albumin level, compliance with hospital guidelines), TPN delivery data (kilojoules, and nutrient and electrolyte content), and bases for cessation or changes of TPN (biochemistry data, gastric and intestinal function). Outcome measures included body mass change, infection rate, detection of biochemical abnormalities, and death. RESULTS: During the audit 168 consecutive patients received 175 TPN courses. These patients were followed until discharge or death; 49 patients (29%) died. Intensive care units accounted for 57.7% of TPN use. Deviations from approved hospital guidelines for initiation of TPN were common. Only a minority of patients were malnourished on objective audit criteria; 18% of men and 13% of women were underweight by body mass index criteria and 36% were malnourished when serum albumin level (< 30 g/L) was considered. Early initiation of TPN outside accepted guidelines was common. Complications included bacteraemia (9.1% of patients tested) and catheter-tip sepsis (55.2% of 87 catheters tested). Four patients died; line sepsis caused one death and probably a further two. The incidence of glucose intolerance was 36.5%, and 25% had markers of abnormal liver function. CONCLUSIONS: TPN use is associated with a high risk of morbidity, and a 1.7% mortality. We recommend better patient selection for TPN, more appropriate use of enteral feeding, better infection control procedures, avoidance of substrate overload (particularly glucose), and earlier change to enteral nutrition.

Absence of toxicity in patients with malignant otitis externa following long-term treatment with high dosage tobramycin.

An in-vitro model of aminoglycoside dosing was used to demonstrate that the bactericidal activity of tobramycin against Pseudomonas aeruginosa is directly related to the peak concentration of the drug. In addition, six patients who were being treated for malignant otitis externa with long-term, high dosage tobramycin were monitored for oto- and nephro-toxicity; the only adverse effects were transient increases in the serum creatinine concentration in two patients.

Bactericidal effect of gentamicin trough concentration provides a rationale for administration of bolus doses and maintenance of trough levels.

An in-vitro study was made of the influence of trough gentamicin concentrations (Cmin) on the bactericidal effect of gentamicin against Escherichia coli NCTC 10418. Lag phase bacterial cells were exposed in vitro to gentamicin concentration versus time profiles which modelled profiles in patients up to 30 min after either an 80 mg iv bolus over 1 min or a 30 min infusion. The gentamicin was removed 30 min post-dose and the cultures were reconstituted in broth containing a constant trough gentamicin concentration in the range of 0-3 mg/L. Bacterial cfu counts and gentamicin concentrations were measured before and during antibiotic exposure. It was found that antibacterial activity was not determined by AUC, but rather there was a threshold trough concentration producing a bactericidal effect which differed between bolus and infusion profiles. With the bolus profile trough concentrations required for a bactericidal effect were 0.5-1.0 mg/L, while with the infusion profile generating an identical post-distribution peak concentration, trough concentrations required for a sustained bactericidal effect were 2.5-3.0 mg/L. These findings favour bolus iv gentamicin dosing over infusion dosing, provided appropriate attention is paid to any potential toxicity associated with high peak concentrations. Trough data indicate the likely need to maintain critical trough concentrations by choice of appropriate intervals between doses.

Kill kinetics and regrowth patterns of Escherichia coli exposed to gentamicin concentration-time profiles simulating in vivo bolus and infusion dosing.

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.

Prospective audit of an aminoglycoside consultative service in a general hospital.

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Pharmacoeconomic consequences of measurement and modification of hospital drug use.

Patterns of drug usage affect hospital-based delivery of healthcare in a variety of ways. Adverse reactions to drugs (ADR) precipitate some 5% of admissions and prejudice the care of some 20% of patients who are in hospital, while inadequate drug therapy prejudices outcomes and prolongs hospital stay. Conversely, appropriate application of drugs can promote recovery and increase the quality of care. Well documented examples include prevention of deep vein thrombosis and postoperative wound infections. Accordingly, optimisation of drug use represents a major quality assurance issue in addition to determining cost-efficiency of healthcare delivery. Drug utilisation review (DUR) requires all elements of the quality assurance process. In practice, therapeutically meaningful and cost-efficient exercises can only be mounted if there is knowledge of the linkage between patterns of drug use and clinical outcomes. These processes of measurement are currently rate-limiting in quality assurance. There are various ways that hospital drug usage can be measured. These range from readily available and relatively cheap quantitative methods to methods requiring the availability of expert staff. There is a sequence of methods involving increasing costs and increasing resource demands yielding increasing detail of information obtained. This sequence commences with pharmacy purchases, followed by pharmacy issues to particular clinical areas, prescription or treatment sheet survey, clinical record review, and finally the reports of trained investigators working in the clinical area. The simpler methods can provide useful information and an efficient basis for choosing and planning definitive studies. Once a category of drug use is appropriately targeted for intervention, drug use can be modified by planned intervention with improvement in clinical outcomes and reduced economic costs in many instances. The intervention strategies to modify drug usage may be classed as re-educative, persuasive, facilitative and power strategies. Other models for implementing behavioural change have been considered, including the impact of trained investigators and the use of online computer prescribing with interactive software with appropriate guidelines. The challenge is to achieve sustained change when interventions are implemented. Cost-efficient quality assurance of drug use is possible with modest resources if outcome-orientated activities are prioritised.

Dosage adjustment and clinical outcomes of long-term use of high-dose tobramycin in adult cystic fibrosis patients.

A two-phase study was undertaken designed to investigate the impact of computer-aided drug monitoring on tobramycin concentrations and clinical outcomes in adult patients with cystic fibrosis. In phase one, a baseline (historical control) study of drug use patterns was performed. During the second phase, patients admitted for intravenous treatment with tobramycin for acute exacerbations of pseudomonal pulmonary infections were randomly allocated to one of two schedules. Group A patients had tobramycin dosage regimens decided by clinicians based on pre-existing protocols using serum tobramycin assay data determined three times weekly. Group B patients had dosage regimens determined by a computerized pharmacokinetic predictive program using both population-based pharmacokinetic parameter estimation and fitting of serum concentration-time data using Bayesian regression. The agreed therapeutic target was a peak serum tobramycin concentration of 8-10 mg/L and a trough concentration of 1-2 mg/L. There was a major difference between the two groups comparing the number of paired trough and peak concentrations within the target concentration ranges (group A-14%; group B-34.7%, chi 2 test, P less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)