PubMed Health⌕ Search

Biomedical subjects

C M Kirkpatrick

Publications and source records attributed to C M Kirkpatrick.

11 recordsLinked to original sources
PubMed2001

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.

Aged↗
PubMed2001

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.

Anti-Bacterial Agents↗
PubMed1999

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.

Adult↗
PubMed1999

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.

Aminoglycosides↗
PubMed1997

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.

Adolescent↗
PubMed1997

Comparison of two Bayesian approaches to dose-individualization for once-daily aminoglycoside regimens.

AIMS: Bayesian dose-individualization methods have been shown to have good predictive performance using minimal data points, and are now used widely in clinical practice. This study was designed to compare two computerised Bayesian dose-individualization methods, ABBOTTBASE and SeBA-GEN, in once-daily dosing of aminoglycosides. METHODS: ABBOTTBASE uses the maximum a posteriori estimator (MAP) algorithm which analyses all available serum drug concentration data for individual patients simultaneously, while the prior model remains unchanged. SeBA-GEN analyses each data set sequentially while continually modifying the individual patient's prior model, allowing within-patient variability to be modelled. One hundred consecutive patients who received once-daily dosing of aminoglycosides were prospectively dose-individualized using either of these methods. Retrospectively the alternative dosing method was used to provide comparative data. The ability of the methods to predict subsequent serum aminoglycoside concentration data was assessed in terms of their predictive performance, bias and precision. RESULTS: From the 100 patients, 277 serum aminoglycoside concentrations were available. Ninety-eight patients had serum concentrations available from the first dose and 55 from the second dose. Gentamicin was used in 96 patients. There was no significant bias when predicting peak concentrations from the prior model using either SeBA-GEN or ABBOTTBASE. The prior model used by ABBOTTBASE did, however, significantly underpredict the mid-dose concentration (mean bias = -0.79 mg l-1, 95% Confidence Interval [CI]: -1.3 to -0.3). When using the Bayesian algorithms for prediction of the second set of concentrations neither method was biased when predicting the peak concentration. ABBOTTBASE significantly overpredicted the mid-dose concentration (mean bias = 0.38 mg l-1, 95% CI: 0.03 to 0.74). The prior model used by SeBA-GEN was more precise at predicting both peak and mid-dose concentrations (P < 0.01), indicating better use of covariates. There was no difference between the methods in terms of estimation of the value of volume of distribution, but they differed significantly in the estimation of clearance (mean difference = 0.24 l h-1 for SeBA-GEN-ABBOTTBASE, 95% CI: 0.05 to 0.43). CONCLUSIONS: Bayesian techniques appear to work well with once-daily aminoglycoside dosing. The method of incorporation of individual patient information into the prior model appears to be important in the optimum choice of the first dose. SeBA-GEN has an advantage in this and in the lack of bias related to predicting low concentrations compared with ABBOTTBASE.

Algorithms↗
PubMed1980

Possible role of wild mammals in transmission of pseudorabies to swine.

Of 73 wild and domestic mammals tested from an area endemic for pseudorabies in swine, 16 showed natural pseudorabies virus infection, 8 from farms with no pseudorabies history. In transmission experiments with swine and raccoons (Procyon lotor), pseudorabies was not transmitted between raccoons but was transmitted reciprocally between raccoons and swine by contact and when either consumed infected carrion of the other. The fluorescent antibody tissue section test proved valuable in diagnosis of pseudorabies, especially when employed with the virus isolation test.

Animal Population Groups↗