Evaluation of amoxicillin, metronidazole and gentamicin dosage regimens for use in antibiotic prophylaxis in colorectal surgery.

OBJECTIVES: To evaluate amoxicillin, metronidazole and gentamicin dosage regimens for antibiotic prophylaxis in colorectal surgery. METHODS: The study was conducted in 20 patients undergoing colorectal surgery. Patients received one or two doses of amoxicillin 1000 mg, metronidazole 500 mg and gentamicin 3 mg/kg ideal body weight, banded by height. Antibiotic concentrations were measured up to 7 h post dose. Population pharmacokinetic (PopPK) analysis with NONMEM followed by Monte Carlo simulation of different dosage regimens was used to estimate the PTA for potential organisms associated with surgical site infections (SSIs). RESULTS: A median of 5 (range 3-6) concentrations were available per patient. CL and V of all antibiotics were related to weight; gentamicin CL was also related to CLCR. The administered doses maintained the desired PTA up to 8 h for the Streptococcus anginosus group but not for enterococci, Bacteroides fragilis group, MSSA, and Escherichia coli. An additional 500 mg amoxicillin every 4 h was sufficient to achieve the PTA for most relevant organisms but 2 hourly dosing was required for patients at risk of infective endocarditis. A metronidazole dose of 1000 mg was required for patients >85 kg. In patients with CLCR >50 mL/min, 5 mg/kg gentamicin (with an additional 2.5 mg/kg in prolonged surgery at 6 h) maintained PTA targets for >10 h. CONCLUSIONS: PopPK analysis with Monte Carlo simulation identified prophylactic antibiotic regimens that would maintain the PTA for organisms associated with SSIs during short- and long-duration colorectal surgery.

Pharmacokinetic/pharmacodynamic analysis of weight- and height-scaled tobramycin dosage regimens for patients with cystic fibrosis.

OBJECTIVES: To determine the outcomes of weight- and height-based tobramycin dosing regimens for patients with cystic fibrosis (CF). METHODS: A simulated dataset of 5000 patients based on 331 patients with CF was created using NONMEM. Pharmacokinetic (PK) parameters were derived for each patient from a published model using Monte Carlo simulation. The abilities of 10 and 12 mg/kg/day and 3 and 4 mg/cm/day to achieve standard and extended Cmax (20-30 and 20-40 mg/L) and AUC0-24 (80-120 and 80-150 mg·h/L) targets were evaluated. PK/pharmacodynamic (PK/PD) indices were a Cmax/MIC ratio ≥10 and an AUC0-24/MIC ratio ≥110. For these indices and a range of MICs, cumulative fractions of response (CFRs) for Pseudomonas aeruginosa were also determined. RESULTS: More patients achieved standard Cmax and AUC0-24 targets with 3 mg/cm/day (64% and 62%, respectively) than with 10 mg/kg/day (43% and 48%, respectively). AUC0-24 estimates >120 mg·h/L were more common with weight-based dosing. With higher doses, 72% achieved high target peaks with 4 mg/cm/day and 65% with 12 mg/kg/day. For the Cmax/MIC index, the maximal MIC for the target microorganism was 2 mg/L with lower doses, 2.5 mg/L with higher doses and 0.5 mg/L for AUC0-24/MIC-based regimens. The CFR for all regimens was >90% for Cmax targets and 66% to 79% for AUC0-24 targets. CONCLUSIONS: A tobramycin dose of 3 mg/cm/day rather than 10 mg/kg/day achieved similar PK/PD outcomes but dose and AUC0-24 ranges were narrower and the incidence of high AUC0-24 values was lower. Height-based doses should therefore be considered for patients with CF.

Changing molecular profile of brain metastases compared with matched breast primary cancers and impact on clinical outcomes.

BACKGROUND: Breast cancer commonly metastasises to the brain, but little is known about changes in the molecular profile of the brain secondaries and impact on clinical outcomes. METHODS: Patients with samples from brain metastases and matched breast cancers were included. Immunohistochemical analysis for oestrogen receptor, progesterone receptor, p27kip1, cyclin D1, epidermal growth factor receptor, insulin like growth factor 1, insulin like growth factor 1 receptor, vascular endothelial growth factor A, transforming growth factor-ß and HER2 receptor was performed. Borderline HER2 results were analysed by fluorescent in situ hybridisation. Levels of expression were compared, with review of effect on clinical outcomes. RESULTS: A total of 41 patients were included. Of the patients, 20% had a change in oestrogen receptor or HER2 in their brain metastasis that could affect therapeutic decisions. There were statistically significant rises in brain metastases for p27kip1 (P=0.023) and cyclin D1 (P=0.030) and a fall in vascular endothelial growth factor A (P=0.012). Overall survival from the time of metastasis increased significantly with oestrogen receptor-positive (P=0.005) and progesterone receptor-positive (P=0.013) brain lesions and with a longer duration from diagnosis of the breast primary (P<0.001). CONCLUSIONS: In this cohort there were phenotypic differences in metastatic brain tumours compared with matched primary breast tumours. These could be relevant for aetiology, and have an impact on prognostication, current and future therapies.

Development and evaluation of vancomycin dosage guidelines designed to achieve new target concentrations.

OBJECTIVES: The aims of this study were to develop a population pharmacokinetic model of vancomycin in adult patients, to use this model to develop dosage guidelines targeting vancomycin trough concentrations of 10-15 mg/L and to evaluate the performance of these new guidelines. METHODS: All data analyses were performed using NONMEM. A population pharmacokinetic model was first developed from vancomycin dosage and concentration data collected during routine therapeutic drug monitoring in 398 patients, then new vancomycin dosage guidelines were devised by using the model to predict vancomycin trough concentrations in a simulated dataset. Individual estimates of CL and V1 were then obtained in an independent group of 100 patients using the population model and the POSTHOC option. These individual estimates were used to predict vancomycin trough concentrations and steady-state AUC(24)/MIC ratios using the current and new dosage guidelines. RESULTS: The population analysis found that the vancomycin data were best described using a bi-exponential elimination model with a typical CL of 3.0 L/h that changed by 15.4% for every 10 mL/min difference from a CL(CR) of 66 mL/min. V(ss) was 1.4 L/kg. The proposed dosage guidelines were predicted to achieve 55% of vancomycin troughs within 10-15 mg/L and 71% within 10-20 mg/L, which is significantly higher than current guidelines (19% and 22%, respectively). The proportion of AUC(24)/MIC ratios above 400 was also higher, 87% compared with 58%. CONCLUSIONS: New vancomycin dosage guidelines have been developed that achieve trough concentrations of 10-15 mg/L earlier and more consistently than current guidelines.

'Losing my touch': decline in self-reported confidence in performing practical procedures in consultant oncologists.

This study aimed to compare the confidence of oncology consultants and specialist registrars (SpRs) in the performance of practical procedures, to contrast this with confidence in other areas of practice and to determine at what grade they felt most confident. Questionnaires were sent to all 57 oncology consultants and SpRs in the South-West region. Respondents scored confidence on a five-point Likert scale. The response rate was 70%. SpRs were significantly more confident in cardiopulmonary resuscitation (p = 0.003) and central line insertion (p = 0.006). Consultants were significantly more confident in developing management plans (p = 0.001) and performing committee work (p = 0.002). Only 6% of consultants felt most confident performing practical procedures as a consultant, and were less confident about these than other tasks (p = 0.001). Some 86% of SpRs considered they were more confident performing practical procedures as senior house officers (SHOs). In conclusion, self-reported confidence in performing practical procedures declines during career progression in oncology. This raises questions about the teaching and supervision of these procedures. If there is a greater emphasis on a consultant-provided service, their educational needs will need to be recognized and retraining or outsourcing of these procedures to other specialties may be necessary.

Medical management of parapneumonic pleural disease.

Considerable heterogeneity exists in the management of parapneumonic pleural disease. A randomized controlled trial (RCT) demonstrated the effectiveness of small-catheter drainage with fibrinolysis, but surgical devotees suggest this may only be applicable to "early" cases. We examined evidence-based medical management in "all-comers." We performed a retrospective database analysis of the management of all children with complex pleural effusion admitted to the John Radcliffe Hospital over the 7-year period 1996-2003. One hundred and ten children were admitted. Ten were excluded as they were part of a multicenter RCT and had received intrapleural saline instead of urokinase. Of the remaining 100, 51 were female and 49 male. Median age on admission was 5.8 years (range, 0.3-16.5). Symptoms preadmission averaged 11 days, with December the most common month for presentation. Ninety-six underwent chest ultrasound, confirming an effusion in all, described as loculated/septated (68) or echogenic (11). In 17 cases, no specific comment was made regarding the nature of the fluid seen on ultrasound. Ninety-five had subsequent chest tube drainage and then received intrapleural fibrinolysis with urokinase. An etiological organism was identified in 21 cases (21%) (Streptococcus pneumoniae in 10, group A Streptococcus in 5, Staphylococcus aureus in 4, Haemophilus influenzae in 1, and coliform in 1). In a further 9 cases (9%), Gram-positive organisms were seen on pleural fluid microscopy, but did not grow on culture. Two (2%) required surgery due to the persistence of symptoms and an inadequate response to medical management. Median duration of admission was 7 days (range, 2-21 days); median duration of stay from intervention was 5 days (range, 2-19 days). At median follow-up of 8 weeks (range, 3-20 weeks), all children were symptom-free, with minimal pleural thickening on chest X-ray. In conclusion, antibiotic therapy with chest drain insertion and intrapleural urokinase is effective in treating complex parapneumonic effusion and is associated with a good long-term outcome.

Phase I clinical and pharmacokinetic study of PK1 [N-(2-hydroxypropyl)methacrylamide copolymer doxorubicin]: first member of a new class of chemotherapeutic agents-drug-polymer conjugates. Cancer Research Campaign Phase I/II Committee.

PK1 comprises doxorubicin covalently bound to N-(2-hydroxypropyl)methacrylamide copolymer by a peptidyl linker. Following cellular uptake via pinocytosis, the linker is cleaved by lysosomal enzymes, allowing intratumoral drug release. Radically altered plasma and tumor pharmacokinetics, compared to free doxorubicin, and significant activity in animal tumors have been demonstrated preclinically. We aimed to determine the maximum tolerated dose, toxicity profile, and pharmacokinetics of PK1 as an i.v. infusion every 3 weeks to patients with refractory or resistant cancers. Altogether, 100 cycles were administered (range, 20-320 mg/m2 doxorubicin-equivalent) to 36 patients (20 males and 16 females) with a mean age of 58.3 years (age range, 34-72 years). The maximum tolerated dose was 320 mg/m2, and the dose-limiting toxicities were febrile neutropenia and mucositis. No congestive cardiac failure was seen despite individual cumulative doses up to 1680 mg/m2. Other anthracycline-like toxicities were attenuated. Pharmacokinetically, PK1 has a distribution t(1/2) of 1.8 h and an elimination t(1/2) averaging 93 h. 131I-labeled PK1 imaging suggests PK1 is taken up by some tumors. Responses (two partial and two minor responses) were seen in four patients with NSCLC, colorectal cancer, and anthracycline-resistant breast cancer. PK1 demonstrated antitumor activity in refractory cancers, no polymer-related toxicity, and proof of principle that polymer-drug conjugation decreases doxorubicin dose-limiting toxicities. The recommended Phase II dose is 280 mg/m2 every 3 weeks. Studies are planned in colorectal, NSCLC, and breast cancer patients.

Pharmacokinetic optimisation of anticonvulsant therapy.

Changing attitudes towards the use of antiepileptic drugs have led to an emphasis on monotherapy with serum concentration measurement coupled with standard, weight-adjusted starting and maintenance regimens to guide initial therapy and subsequent dosage titration. Currently, the established anticonvulsants are carbamazepine, valproic acid (sodium valproate) and phenytoin. Phenobarbital is now less commonly prescribed due to its propensity to produce sedation and impair cognitive function. The value of pharmacokinetic optimisation with valproic acid is limited by its wide therapeutic index, large fluctuations in the concentration-time profile and concentration-dependent protein binding. Thus, although serum concentrations are often measured, they are rarely subjected to pharmacokinetic interpretation. Carbamazepine has a flatter concentration-time profile than valproic acid. Its target range is more clearly defined and it undergoes autoinduction of metabolism and interacts with other drugs. Pharmacokinetic principles can, therefore, be more readily applied to carbamazepine, although, in general, a simple clinical approach to its use is usually satisfactory. Phenytoin has required the greatest pharmacokinetic input due to its nonlinear pharmacokinetics and narrow target range. Many different graphical methods, equations and computer programs have been reported, some of which demand 2 steady-state, dose-concentration pairs; others function satisfactorily with only 1. Recent attempts have been made to interpret non-steady-state data. In addition, a number of workers have demonstrated the value of altering the population parameter estimates to account for ethnic differences. A pharmacokinetic approach can also be used to tailor the use of phenytoin in the treatment of status epilepticus. Dosage alterations may be needed for specific patient groups. In particular, children generally require higher dosages on a weight-for-weight basis than adults, while equivalently lower dosages should be given to neonates. Most anticonvulsants are principally cleared by hepatic mechanisms, so dosage adjustment is not usually required in renal disease, although care must be taken in interpreting serum concentrations because of changes in protein binding. Close monitoring is required in the elderly and patients with hepatic impairment, while increased dosages may be needed in critically ill patients and during pregnancy. Pharmacokinetic principles can be used in the treatment of treat self-poisoning with anticonvulsants. There are few data available on the pharmacokinetics of vigabatrin, lamotrigine, oxcarbazepine and gabapentin in patients. Due to its mode of action in binding irreversibly to its target enzyme, serum concentration monitoring of vigabatrin plays no role in optimising therapy. The value of applying pharmacokinetic principles with the other 3 drugs remains to be investigated.(ABSTRACT TRUNCATED AT 400 WORDS)

Bayesian parameter estimation and population pharmacokinetics.

The widespread application of Bayesian parameter estimation in the area of therapeutic drug monitoring (TDM) has prompted the need for well conducted population studies to obtain relevant prior pharmacokinetic parameter estimates. In many cases the population has consisted of a relatively small number of subjects. This may be unavoidable for drugs used in cancer chemotherapy or in small, specific populations of patients. In contrast, information about drugs which are used extensively, such as the aminoglycosides, can be obtained by population studies which involve a large number of individuals. Indeed, this technique has proved particularly useful for determining parameter estimates which can be employed in neonatal TDM. Bayesian parameter estimation has been most frequently used for drugs with narrow therapeutic ranges such as the aminoglycosides, cyclosporin, digoxin, anticonvulsants (especially phenytoin), lithium and theophylline. However, the technique has now been extended to cytotoxic drugs, Factor VIII and warfarin. Bayesian methods have also been used to limit the number of samples required in more conventional pharmacokinetic studies with new drugs. Further advances in the use of these methods are likely to include measures of drug response and toxicity requiring population studies which also include relevant pharmacodynamic information.

Expiratory airflow patterns in children and adults with cystic fibrosis.

STUDY OBJECTIVE: To determine whether tidal expiratory airflow patterns change with increasing airways obstruction in patients with cystic fibrosis. DESIGN: An observational study. SETTING: Lung function laboratory. PATIENTS: Sixty-four children and young adults with cystic fibrosis. MEASUREMENTS: After measuring FEV(1) and airways resistance using body plethysmography, each subject was seated and asked to mouth breathe through a pneumotachograph for 2 min. The collected data were analyzed, and three expiratory airflow pattern-sensitive indexes were computed. The first index was derived from the ratio of the time to reach peak expiratory flow to the total expiratory time (tPTEF/tE). The second index, Trs, was an estimate of the time constant of the passive portion of expiration. The third index, f1.gif" BORDER="0">, describes the slope of the whole post-peak expiratory flow pattern after scaling. RESULTS: Compared with FEV(1), the index tPTEF/tE was a poor indicator of airways obstruction (r(2) = 0.15, p = 0.002). Trs showed a strong relationship with the severity of airways obstruction (r(2) = 0.46, p < 0.001). Using f1.gif" BORDER="0">, the postexpiratory profile could be categorized into three shapes, and provided a good indicator of airways obstruction when linear and concave-shaped profiles occurred (r(2) = 0.42, p < 0.001). Convex-shaped flow profiles had to be treated separately and were indicative of normal lung function. CONCLUSIONS: In a cross-sectional study of patients with cystic fibrosis, increase in airways resistance above normal is reflected by quantifiable changes in the expiratory airflow pattern.

Methotrexate removal during haemodialysis in a patient with advanced laryngeal carcinoma.

A 62-year-old patient on long-term haemodialysis who developed an inoperable T2N3Mo squamous-cell carcinoma of the larynx was treated with weekly low-dose methotrexate (MTX) after failing to respond to radiotherapy. The patient was initially given one dose of 10 mg MTX (6 mg/m2) as a 1-h infusion, then he received three further i.v. doses of 20 mg (12 mg/m2). Haemodialysis was performed 15-18 h after each dose and the patient received folinic acid (30 mg i.v.q 6 h) until the MTX concentration was < 0.1 mumol/l. The MTX concentration was measured regularly until it reached < 0.1 mumol/l, and additional samples were withdrawn pre- and post-dialysis. The MTX elimination rate constant and half-life were estimated with the patient on and off dialysis. The patient failed to respond to treatment but did not experience MTX-related toxicity. The elimination half-life ranged from 22 to 42 h when he was off dialysis but fell to a median of 5.5 h during dialysis. Low-dose MTX was given to a patient on regular haemodialysis without evidence of toxicity. The rate of MTX elimination was increased during haemodialysis, although high MTX concentrations persisted for several days and prolonged rescue with folinic acid was required.

Cough flow-volume relationships in normal and asthmatic children.

The flow-volume profile of a maximum voluntary cough resembles that of a maximum expiratory flow-volume (MEFV) curve with superimposed transient peak flows at the onset of each cough effort and portions of zero flow corresponding to periods of glottis closure. A straight line (the cough slope) can be drawn through the transient peak flows, and the ratio of MEFV-equivalent flow to the cough peak flow can be calculated. This cough ratio has been shown to fall during adult life and may be related to changes in airway compliance and cross-sectional area with age. The present study investigated the cough ratio, cough slope, and maximum flows measured from the cough flow-volume curve in a group of normal children aged 7 to 16 years. Maximum flows and the cough slope increased with height, but the cough ratio did not change with growth or age. In a similar group of asthmatic children, baseline measurements of cough showed a reduction in cough peak flow rates, MEFV-equivalent flow, and the cough ratio. These changes are related to alterations in airway compliance and cross-sectional area and are partly reversed following inhalation of a bronchodilator.

Pharmacokinetics and dose requirements of vancomycin in neonates.

AIMS: To design and evaluate dosing guidelines for vancomycin based on data collected during routine use of the drug. METHODS: Following the observation that 66% of neonatal vancomycin trough concentrations were outside the target range, new dose guidelines were developed using a population pharmacokinetic approach. NONMEM (non-linear mixed effects model) was used to analyse dose histories and 347 concentration measurements collected during routine therapeutic drug monitoring in 59 neonates. RESULTS: Postconceptual ages in the patient group ranged from 26-45 weeks, weights from 0. 57-4.23 kg, and creatinine concentrations from 18-172 micromol/l. The population estimate of vancomycin clearance (l/h/kg) was 3. 56/creatinine concentration (micromol/l) with an interpatient coefficient of variation (CV) of 22% and volume of distribution 0.67 l/kg with a CV of 18%. Residual error was 4.5 mg/l. When the new recommendations on dosing were used prospectively in a separate group of neonates the proportion of acceptable troughs increased from 33% to 72%. CONCLUSIONS: The pharmacokinetics of vancomycin in neonates and young infants depend on weight and serum creatinine. Preliminary results from the new guidelines indicate an improvement on previous practice, but also an ongoing need to monitor concentrations.

Evaluation of nonlinear regression with extended least squares: simulation study.

A new approach to nonlinear least-squares regression analysis using extended least squares (ELS) was compared with three conventional methods: ordinary least squares (OLS); weighted least squares 1/C (WLS-1) and weighted least squares 1/C2 (WLS-2). With Monte Carlo simulation techniques, 3 X 200 data sets were constructed with constant proportional error (5, 10, and 15% error) and 3 X 200 with constant additive error (0.05, 0.10, and 0.15 g/mL) from an initial (perfect) data set based on known parameters. Two sampling strategies were employed: one with 17 time points and one with 10 time points. All data sets were fitted by each of the four methods, and parameter estimation bias was assessed by comparing the mean parameter estimate with the known value. The relative precision of each method was investigated by examination of the absolute deviations of each individual parameter estimate from the known value. ELS performed as well as the appropriate weighting scheme (WLS-2 for constant proportional error sets and OLS for constant additive error sets) and was superior with regard to both bias and precision to less appropriate methods.

A survey of extraction techniques for drugs of abuse in urine.

Sixty nine participants in the United Kingdom national external quality assessment scheme for drugs of abuse in urine reported details of their sample extraction technique by questionnaire. Laboratories were categorised by differences in technique and their analytical test results compared for samples containing D-amfetamine 0.4 (4) and 0.8 (3) mg/l, morphine 0.4 (4) and 0.8 (4)mg/l, and benzoylecgonine 0.15/0.2 (2) and 0.45/0.5 (4) mg/l. Values in parentheses are numbers of samples. For amfetamine, there was no significant difference in the frequency of true positive results between liquid-liquid or solid phase extraction and the Toxi-Lab A system at 0.8 mg/l. Toxi-Lab A gave significantly fewer positives when operating below its specified threshold at 0.4 mg/l. Paradoxically, laboratories using >5 ml urine volume performed less well. Acidification of the extract before volume reduction gave significantly more true positives. For extraction of morphine, solid phase systems significantly outperformed both liquid-liquid and the Toxi-Lab A system at both 0.8 and 0.4 mg/l. No significant differences between extraction techniques were demonstrated for analysis of benzoylecgonine.

External quality assessment of laboratory performance in analysis of toxicological cases.

A mean of 44 members of the United Kingdom national external quality assessment scheme (UKNEQAS) for toxicology reported analytical findings on 10 toxicological cases circulated between December 1995 and February 2000. Material distributed usually consisted of a 5ml blood and a 20ml urine sample simulated by quantitative addition of drugs and their metabolites to material donated by volunteers and patients. The samples were accompanied by a brief outline of the circumstances surrounding the case. Laboratories were requested to report their analytical findings, list methods of analysis, and provide interpretation of their findings. The mean overall success rate for identification of drugs or their pharmacological group was 76%, failure being largely by laboratories providing an immunoassay-based screening service for a fixed range of drug groups. The latter laboratories indicated that cases would be referred to regional toxicology centres for further investigation or confirmation. The coefficient of variation of measurements was <7% for routine analytes, such as ethanol and paracetamol, but 26-44% for tricyclics and opiates. There were 3% false positive reports. The quantity and content of interpretative comment provided by the laboratories was very variable. A number provide nothing in addition to the analytical result.

The efficacy of aerosol treatment with non-ionic surfactant vesicles containing amphotericin B in rodent models of leishmaniasis and pulmonary aspergillosis infection.

Amphotericin B (AMB) is used to treat both fungal and leishmanial infections, which are of major significance to human health. Clinical use of free AMB is limited by its nephrotoxicity, whereas liposomal AMB is costly and requires parenteral administration, thus development of novel formulations with enhanced efficacy, minimal toxicity and that can be applied via non-invasive routes is required. In this study we analysed the potential of non-ionic surfactant vesicles (NIV) given by nebulisation to deliver AMB to the lungs, liver and skin. Treatment with AMB-NIV resulted in significantly higher drug levels in the lungs and skin (p<0.05) compared to similar treatment with AMB solution but significantly lower plasma levels (p<0.05). Treatment with AMB-NIV resulted in a significant reduction in fungal lung burdens in a rat model of invasive pulmonary aspergillosis (p<0.05) compared to treatment with the carrier alone. Treatment with AMB-NIV but not AMB solution significantly suppressed Leishmania donovani liver parasite burdens (p<0.05) but could not inhibit the growth of cutaneous Leishmania major lesions. The results of this study indicate that aerosolised NIV enhanced pulmonary and hepatic delivery whilst minimising systemic exposure and toxicity.