Evaluation of a pharmacist-led penicillin allergy de-labelling ward round: a novel antimicrobial stewardship intervention.

BACKGROUND: Antibiotic allergy labels (AALs), reported by up to 25% of hospitalized patients, are a significant barrier to appropriate prescribing and a focus of antimicrobial stewardship (AMS) programmes. METHODS: A prospective audit of a pharmacist-led AMS penicillin allergy de-labelling ward round at Austin Health (Melbourne, Australia) was evaluated. Eligible inpatients with a documented penicillin allergy receiving an antibiotic were identified via an electronic medical report and then reviewed by a pharmacist-led AMS team. The audit outcomes evaluated were: (i) AMS post-prescription review recommendations; (ii) direct de-labelling; (iii) inpatient oral rechallenge referral; (iv) skin prick testing/intradermal testing referral; and (v) outpatient antibiotic allergy clinic assessment. RESULTS: Across a 5 month period, 106 patients were identified from a real-time electronic prescribing antibiotic allergy report. The highest rate of penicillin allergy de-labelling was demonstrated in patients who were referred for an inpatient oral rechallenge with 95.2% (n = 21) successfully having their penicillin AAL removed. From the 22 patients with Type A reactions, 63.6% had their penicillin AAL removed. We demonstrated a significant decrease in the prescribing of restricted antibiotics (defined as third- or fourth-generation cephalosporins, fluoroquinolones, glycopeptides, carbapenems, piperacillin/tazobactam, lincosamides, linezolid or daptomycin) in patients reviewed (pre 42.5% versus post 17.9%, P = 0.0002). CONCLUSIONS: A pharmacist-led AMS penicillin allergy de-labelling ward round reduced penicillin AALs and the prescribing of restricted antibiotics. This model could be implemented at other hospitals with existing AMS programmes.

Cost-utility analysis of antiviral use under pandemic influenza using a novel approach - linking pharmacology, epidemiology and heath economics.

Simulation models are used widely in pharmacology, epidemiology and health economics (HEs). However, there have been no attempts to incorporate models from these disciplines into a single integrated model. Accordingly, we explored this linkage to evaluate the epidemiological and economic impact of oseltamivir dose optimisation in supporting pandemic influenza planning in the USA. An HE decision analytic model was linked to a pharmacokinetic/pharmacodynamics (PK/PD) - dynamic transmission model simulating the impact of pandemic influenza with low virulence and low transmissibility and, high virulence and high transmissibility. The cost-utility analysis was from the payer and societal perspectives, comparing oseltamivir 75 and 150 mg twice daily (BID) to no treatment over a 1-year time horizon. Model parameters were derived from published studies. Outcomes were measured as cost per quality-adjusted life year (QALY) gained. Sensitivity analyses were performed to examine the integrated model's robustness. Under both pandemic scenarios, compared to no treatment, the use of oseltamivir 75 or 150 mg BID led to a significant reduction of influenza episodes and influenza-related deaths, translating to substantial savings of QALYs. Overall drug costs were offset by the reduction of both direct and indirect costs, making these two interventions cost-saving from both perspectives. The results were sensitive to the proportion of inpatient presentation at the emergency visit and patients' quality of life. Integrating PK/PD-EPI/HE models is achievable. Whilst further refinement of this novel linkage model to more closely mimic the reality is needed, the current study has generated useful insights to support influenza pandemic planning.

A dosing algorithm for metformin based on the relationships between exposure and renal clearance of metformin in patients with varying degrees of kidney function.

PURPOSE: The aims of this study were to investigate the relationship between metformin exposure, renal clearance (CLR), and apparent non-renal clearance of metformin (CLNR/F) in patients with varying degrees of kidney function and to develop dosing recommendations. METHODS: Plasma and urine samples were collected from three studies consisting of patients with varying degrees of kidney function (creatinine clearance, CLCR; range, 14-112 mL/min). A population pharmacokinetic model was built (NONMEM) in which the oral availability (F) was fixed to 0.55 with an estimated inter-individual variability (IIV). Simulations were performed to estimate AUC0-τ, CLR, and CLNR/F. RESULTS: The data (66 patients, 327 observations) were best described by a two-compartment model, and CLCR was a covariate for CLR. Mean CLR was 17 L/h (CV 22%) and mean CLNR/F was 1.6 L/h (69%).The median recovery of metformin in urine was 49% (range 19-75%) over a dosage interval. When CLR increased due to improved renal function, AUC0-τ decreased proportionally, while CLNR/F did not change with kidney function. Target doses (mg/day) of metformin can be reached using CLCR/3 × 100 to obtain median AUC0-12 of 18-26 mg/L/h for metformin IR and AUC0-24 of 38-51 mg/L/h for metformin XR, with Cmax < 5 mg/L. CONCLUSIONS: The proposed dosing algorithm can be used to dose metformin in patients with various degrees of kidney function to maintain consistent drug exposure. However, there is still marked IIV and therapeutic drug monitoring of metformin plasma concentrations is recommended.

Metformin therapy in patients with chronic kidney disease.

Metformin therapy is limited in patients with chronic kidney disease (CKD) due to the potential risk of lactic acidosis. This open-label observational study investigated metformin and lactate concentrations in patients with CKD (n = 22; creatinine clearances 15-40 ml/min) and in two dialysed patients. Patients were prescribed a range of metformin doses (250-2000 mg daily) and metformin concentrations were compared with data from healthy subjects (scaled to 1500 mg twice daily). A subset of patients (n = 7) was controlled on low doses of metformin (250 or 500 mg daily). No correlation between metformin and lactate concentrations was observed. Three patients had high lactate concentrations (>2.7 mmol/l) and two had high metformin concentrations (3-5 mg/l), but none had any symptoms of lactic acidosis. Reducing metformin dosage and monitoring metformin concentrations will allow the safe use of metformin in CKD, provided that renal function is stable.

Estimation of lean body weight in older women with hip fracture.

OBJECTIVE: Lean body weight (LBW) decreases with age while total body fat increases, resulting in altered drug pharmacokinetics. A semi-mechanistic equation estimating LBW using height, weight and sex has been developed for potential use across a wide range of body compositions. The aim of this study was to determine the ability of the LBW equation to estimate dual energy x-ray absorptiometry-derived fat free mass (FFM(DXA)) in a population of older women with recent hip fracture. METHODS: Baseline, four and 12 month data obtained from 23 women enrolled in the Sarcopenia and Hip Fracture study were pooled to give 58 measurements. LBW was estimated using the equation: LBW (kg) = (9270 x Wt) / (8780 + (244 x BMI)). Body composition was classified as: 'normal' (BMI <25kg/m(2) and not sarcopenic), 'overweight-obese' (BMI >25kg/m(2) and not sarcopenic), 'sarcopenic' (sarcopenic and BMI <25kg/m(2)), or 'sarcopenic-obese' (sarcopenic and BMI >25kg/m(2)). The ability of the LBW equation to predict FFMDXA was determined graphically using Bland-Altman plots and quantitatively using the method of Sheiner and Beal. RESULTS: The mean ± SD age of female participants women was 83±7 years (n=23). Sarcopenia was frequently observed (65.2%). Bland-Altman plots demonstrated an underestimation by the LBW equation compared to FFMDXA. The bias (95% CI) and precision (95% CI) calculated using the method of Sheiner and Beal was 0.5kg (-0.7, 1.66kg) and 4.4kg (-3.7, 12.4kg) respectively for pooled data. CONCLUSION: This equation can be used to easily calculate LBW. When compared to FFMDXA, the LBW equation resulted in a small underestimation on average in this population of women with recent hip fracture. The degree of bias may not be clinically important although further studies of larger heterogeneous cohorts are needed to investigate and potentially improve the accuracy of this predictive equation in larger clinical cohorts.

Comparative pharmacokinetics and pharmacodynamics of urocortins 1, 2 and 3 in healthy sheep.

BACKGROUND AND PURPOSE The urocortin (Ucn) peptides are emerging as potential therapeutic targets for heart disease. However, pharmacokinetic (PK) and pharmacodynamic (PD) data are lacking. Therefore, we investigated the PK/PD for all three Ucns. EXPERIMENTAL APPROACH Seven sheep received 1 µg·kg(-1) boluses of Ucn1, Ucn2 and Ucn3. Population PK/PD models were developed to describe the time course of the haemodynamic effects. RESULTS The population estimate for Ucn1 clearance (0.486 L·h(-1)) was lower than that for Ucn2 (21.7 L·h(-1)) and Ucn3 (220 L·h(-1)), while steady-state volumes of distribution were similar for Ucn1 and Ucn2 (∼8 L) but substantially larger for Ucn3 (23.5 L). Ucn1 disposition was adequately described by a two-compartment model, with a one-compartment model required for Ucn2 and Ucn3. The half-life for Ucn1 was 2.9 h (α phase) and 8.3 h (ß phase), and 15.7 and 4.4 min for Ucn2 and Ucn3 respectively. All Ucns produced significant increases in heart rate, cardiac output and left ventricular systolic and mean arterial pressures, and decreases in left atrial pressure and peripheral resistance. Delayed-effect pharmacodynamic models best described the time course of haemodynamic responses, with effects more rapid and less prolonged for Ucn2 and Ucn3 than Ucn1. Similar and physiologically plausible estimated baseline (E(0)) effects were exhibited by all Ucns, whereas EC(50) values were generally greater for Ucn1. CONCLUSIONS AND IMPLICATIONS Relative to Ucn1, both the PK and haemodynamic responses to Ucn2 and Ucn3 occurred more rapidly. Our data provide important comparative information, useful to the rational design of future clinical studies.

Continuous infusion vs. bolus dosing: implications for beta-lactam antibiotics.

Beta-lactam antibiotics display time-dependant pharmacodynamics whereby constant antibiotic concentrations rather than high peak concentrations are most likely to result in effective treatment of infections caused by susceptible bacteria. Continuous administration has been suggested as an alternative strategy, to conventional intermittent dosing, to optimise beta-lactam pharmacokinetic/pharmacodynamic (PK/PD) properties. With the availability of emerging data, we elected to systematically investigate the published literature describing the comparative PK/PD and clinical outcomes of beta-lactam antibiotics administered by continuous or intermittent infusion. We found that the studies have been performed in various patient populations including critically ill, cancer and cystic fibrosis patients. Available in vitro PK/PD data conclusively support the administration of beta-lactams via continuous infusion for maximizing bacterial killing from consistent attainment of pharmacodynamic end-points. In addition, clinical outcome data supports equivalence, even with the use of a lower dose by continuous infusion. However, the present clinical data is limited with small sample sizes common with insufficient power to detect advantages in favour of either dosing strategy. With abundant positive pre-clinical data as well as document in vivo PK/PD advantages, large multi-centre trials are needed to describe whether continuous administration of beta-lactams is truly more effective than intermittent dosing.

A model for venom-induced consumptive coagulopathy in snake bite.

Many snake venoms contain procoagulant toxins that activate the coagulation cascade and cause venom-induced consumptive coagulopathy (VICC). We developed a semi-mechanistic model of the clotting cascade in order to explore the effects of the procoagulant toxin from taipan venom on this system as well as the effects of antivenom. Simulations of the time course in the change of clotting factors were compared to data collected from taipan envenomed patients. The model accurately predicted the observed concentration of clotting factors over time following taipan envenomation. Investigations from the model indicated that the upper limit of the half-life of the procoagulant toxin was 1h. Simulations from the model also suggest that antivenom for Australasian elapids has negligible effect on reducing the recovery time of the coagulation profile unless administered almost immediately after envenomation. The model has generality to be expanded to describe the effects of other venoms and drugs on the clotting cascade.

Dosing in obesity: a simple solution to a big problem.

The global epidemic of obesity has led to an increased prevalence of chronic diseases and need for pharmacological intervention. However, little is known about the influence of obesity on the drug exposure profile, resulting in few clear dosing guidelines for the obese. Here we present a semi-mechanistic model for lean body weight (LBW) that we believe is sufficiently robust to quantify the influence of body composition on drug clearance, and is therefore an ideal metric for adjusting chronic dosing in the obese.

Drug-induced QT prolongation and torsades de pointes: evaluation of a QT nomogram.

BACKGROUND: Although QT prolongation is associated with increased risk of torsade de pointes (TdP), the precise relationship is not well defined. AIM: To evaluate the performance of a QT nomogram in assessing the risk of TdP from QT-RR combinations. DESIGN: Systematic review. METHODS: We systematically searched MEDLINE/EMBASE for cases of drug-induced TdP. Controls were patients taking non-cardiotoxic drugs in overdose. Inclusion criteria were definite TdP, normal ECG before or after the event, association with a drug/toxin and QT-RR measurements available. The upper bound of a QT-RR cloud diagram developed from human preclinical studies was converted into a QT nomogram [QT vs. heart rate (HR)]. QT-HR combinations for TdP cases and controls were plotted with the QT nomogram, and curves corresponding to a QTc = 440 ms and QTc = 500 ms for comparison (Bazett's correction). RESULTS: We identified 129 cases of TdP. TdP cases occurred at lower HR values with longer QT intervals, with most cases occurring at HR 30-90 bpm. Controls were more evenly distributed, with HR 40-160 bpm. The sensitivity and specificity of the QT nomogram were 96.9% (95%CI 93.9-99.9) and 98.7% (95%CI 96.8-100), respectively. For Bazett QTc = 440 ms, sensitivity and specificity were 98.5% (95%CI 96.3-100) and 66.7% (95%CI 58.6-74.7), respectively, whereas for Bazett QTc =500 ms they were 93.8% (95%CI 89.6-98.0) and 97.2% (95%CI 94.3-100), respectively. DISCUSSION: The QT nomogram is a clinically relevant risk assessment tool that accurately predicts arrhythmogenic risk for drug-induced QT prolongation. Further prospective evaluation of the nomogram is needed.

Pilot study to determine the ability of health-care professionals to undertake drug dose calculations.

BACKGROUND: It is essential for health-care professionals to calculate drug doses accurately. Previous studies have demonstrated that many hospital doctors were unable to accurately convert dilutions (e.g. 1:1000) or percentages (e.g. percentage w/v) of drug concentrations into mass concentrations (e.g. mg/mL). AIMS: The aims of the present study were to evaluate the ability of health-care professionals to perform drug dose calculations accurately and to determine their preferred concentration convention when calculating drug doses. METHODS: A selection of nurses, medical students, house surgeons, registrars and pharmacists undertook a written survey to assess their ability to perform five drug dose calculations. Participants were also asked which concentration convention they preferred when calculating drug doses. The surveys were marked then analysed for health-care professionals as a whole and then by subgroup analysis to assess the performance of each health-care-professional group. RESULTS: Overall, less than 14% of the surveyed health-care professionals could answer all five questions correctly. Subgroup analysis revealed that health-care professionals' ability to calculate drug doses were ranked in the following order: registrars approximately equal to pharmacists > house surgeons > medical students >> nurses. Ninety per cent of health-care professionals preferred to calculate drug doses using the mass concentration convention. CONCLUSIONS: Overall, drug dose calculations were performed poorly. Mass concentration was clearly indicated as the preferred convention for calculating drug doses.

An extended interval dosing method for gentamicin in neonates.

Traditional gentamicin dosing every 8-24 h depending on age and weight in neonates does not provide the ideal concentration-time profile to both optimize the concentration-dependent killing by aminoglycosides and minimize toxicity. Fifty-three neonates were audited prospectively while receiving gentamicin 2.5 mg/kg every 8-24 h, aiming for peak concentrations (Cmax) of 6-10 mg/L and trough concentrations (Cmin) <2 mg/L. After the first dose, the mean (+/- s.d.) Cmax was 5.5 +/- 0.7 mg/L with sub-therapeutic concentrations (<6 mg/L) in 62% of patients, while the mean Cmin was >2 mg/L in 15% of the neonates. After the third dose the Cmax was 7.5 +/- 1.5 mg/L, with 17% <6 mg/L, whereas the mean Cmin was 2.2 +/- 1.1 mg/L with 49% of values >2 mg/L. An extended interval dosing method (24, 36 and 48 h) for infant weights of 0.75-5 kg was developed by simulation, and audited prospectively in 51 neonates. Prospective analysis of the extended interval dosing method showed a mean Cmax after the first dose of 13.1 +/- 3.6 mg/L, while the mean Cmin was 0.7 +/- 0.6 mg/L. Seventy-eight per cent had Cmax of >10 mg/L after the first dose. The mean area under the concentration versus time curve AUC0-24 was 93 mg*h/L (target = 100 mg*h/L). The extended interval dosing achieved higher Cmax values while ensuring that overall exposure per 24 h was acceptable. Prospective testing of the method demonstrated good predictive ability.

The therapeutic monitoring of antimicrobial agents.

AIMS: To review the basis and optimal use of therapeutic drug monitoring of antimicrobial agents. METHODS: Antimicrobial agents for which a reasonable case exists for therapeutic drug monitoring are reviewed under the following headings: pharmacokinetics, why monitor, therapeutic range, individualization of therapy, sampling times, methods of analysis, interpretative problems and cost-effectiveness of monitoring. RESULTS: There is a strong historical case for monitoring aminoglycosides. The recent move to once-daily dosing means that criteria for therapeutic drug monitoring need to be redefined. Vancomycin has been monitored routinely but many questions remain about the most appropriate approach to this. A case can be made for monitoring teicoplanin, flucytosine and itraconazole in certain circumstances. CONCLUSIONS: The approach to monitoring aminoglycosides is being redefined in the light of once daily dosing. It may be that less stringent monitoring is required in some circumstances but toxicity, especially ototoxicity, remains a problem with these drugs. Monitoring to avoid high AUCs (areas under the concentration-time curve) is recommended. The ideal method for monitoring vancomycin remains to be defined although a reasonable case exists for measuring trough concentrations, mainly to ensure efficacy. Teicoplanin is sometimes monitored to ensure efficacy while flucytosine may be monitored to avoid high concentrations associated with toxicity. Itraconazole has various pharmacokinetic problems and monitoring has been suggested to ensure that adequate concentrations are achieved.

Pharmacokinetics of gentamicin in 957 patients with varying renal function dosed once daily.

AIMS: 1. To determine the population pharmacokinetics of gentamicin in 957 patients with varying renal function dosed once daily. 2. To see if current starting doses for once daily aminoglycoside dosing are appropriate. 3. To test whether calculating creatinine clearance using an adjusted Cockcroft and Gault method (CLCr,adjusted ) was a better predictor of gentamicin clearance than the standard Cockcroft and Gault method (CLCr,unadjusted ). METHODS: Nine hundred and fifty-seven patients were dose-individualized for gentamicin using SeBA-GEN, a Bayesian dosing method. This method returns estimates of the values of gentamicin CL and V d from which the 24 h AUC can be estimated. The goal of therapy was to attain an AUC of 70-100 mg l-1 h depending on the severity of the infection. The population was divided into four groups of differing renal function. Linear regression analysis was performed to determine the relationship between V d and various indices of weight, and gentamicin CL and either CLCr,adjusted or CLCr,unadjusted. RESULTS: The mean V d (+/-s. d.) and CL (+/-s.d.) of gentamicin in our total population were 17.4 (+/-4.1) l and 4.0 (+/-1.8) l h-1, respectively. There was a decrease in V d with reducing renal function when comparing patients with normal renal function and patients with poor renal function. The lower of total body weight (TBW) and lean body weight (LBW), termed dosing weight (DWT), was a slightly better predictor of V d (r2=0.28) than either TBW (r2=0.21) or LBW (r2=0.21). CLCr,adjusted (r2=0.80) was a better predictor of gentamicin CL than CLCr, unadjusted (r2=0.57). CONCLUSIONS: The mean population values of V d and CL of gentamicin dosed once daily are similar to those described by others in relation to multiple daily dosing. Given that previous methods have been based on population values of V d and CL from multiple daily dosing, the currently recommended starting doses for once daily aminoglycoside dosing would seem appropriate. The V d reduced with decreasing renal function, with a maximum of 23% difference between patients with normal and poor renal function. The Cockcroft and Gault method of calculating creatinine clearance does not appear to perform well at low values of serum creatinine concentration. An adjustment of the Cockcroft and Gault method is proposed to allow for this.

Once daily aminoglycoside therapy. Is it less toxic than multiple daily doses and how should it be monitored?

After 50 years of clinical experience with the aminoglycoside agents, there is continuing debate over the most appropriate administration regimen for these drugs. In recent years, once daily administration has been used increasingly, in the hope of both improving efficacy and reducing toxicity. At least 30 controlled clinical trials have compared once versus conventional multiple daily administration. Efficacy was assessed in some, but not all, studies using clinical and/or bacteriological cure. Toxicity was generally determined using rather nonsensitive end-points such as measurement of serum creatinine for nephrotoxicity and clinically detectable hearing loss for ototoxicity. The results of individual clinical trials and subsequent meta-analyses have been variable. However, 5 of 9 meta-analyses found clinical efficacy to be significantly better with once daily administration, and in 3 of the 9 there were significantly less nephrotoxicity with once daily administration. The results were not significant for ototoxicity in any of the meta-analyses. There is debate about how therapeutic drug monitoring should be performed, and whether it is still required with once daily administration. Previous experience with the aminoglycosides, especially in patients with impaired drug clearance caused by renal impairment, suggests that monitoring is still prudent. Results from the once daily administration trials appear to support this. Various methods of monitoring and dose adjustment have been proposed. The most common is to measure a 24-hour trough concentration and to adjust the dose to maintain the trough concentration below a value of 2, 1 or 0.5 mg/L. However, this method allows for greater total aminoglycoside exposure than has been permitted with conventional dosages, increasing the likelihood of toxicity in patients with impaired aminoglycoside clearance. Other methods measure drug concentrations at a time-point or points within the dose interval (when the concentration is still measurable), and adjust the dose according to concentration-time curve nomograms or to a target area under the concentration-time curve. This allows the use of higher doses in those with high drug clearance. Furthermore, in patients with impaired clearance, drug exposure is limited to the same extent as, or less than, that with conventional multiple daily administration. To date no controlled trials have compared methods of dose-individualisation. In summary, in addition to a slight overall improvement in efficacy, once daily administration has resulted in a small reduction in nephrotoxicity. In the studies using more sensitive measures of toxicity, the differences in toxicity were greater, strengthening the case for once daily administration. Therapeutic drug monitoring is probably required with once daily administration. Methods which use mid-dosage interval concentrations to gauge drug exposure would seem to be preferable over trough concentration measurement.

Measurement of total phospholipids in urine of patients treated with gentamicin.

AIMS: The excretion of phospholipids in urine may be a marker of the early renal toxicity of the aminoglycoside antibiotics. Urinary phospholipids are formed in myeloid bodies which develop in the lysosomes of proximal tubules during treatment with the aminoglycosides, and overflow into the urine. METHODS: Published assays were modified in order to measure the total phospholipid concentrations in human urine. Phospholipids were extracted from freeze-dried urine samples, digested in concentrated sulphuric acid, and the inorganic phosphorus content determined by complexing with ammonium molybdate and measuring the absorbance at 820 nm. Ten septicaemic patients treated with gentamicin for 5-7 days had significantly higher urine phospholipid concentrations than 10 healthy untreated control subjects (P < 0.0001). There was a negative linear relationship between phospholipid excretion and creatinine clearance (r2 = 0.71). RESULTS: In 34 patients with acute pyelonephritis, increased phospholipid concentrations were observed prior to treatment compared with healthy controls (P < 0.001) and did not alter during treatment with gentamicin. However, the phospholipid concentrations decreased significantly after treatment was completed (P < 0.03). CONCLUSIONS: These studies suggest that urinary phospholipids may indicate early aminoglycoside toxicity but with poor specificity, as many of the infections being treated may themselves be associated with phospholipiduria.