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1.  Individualization of Piperacillin Dosing for Critically Ill Patients: Dosing Software To Optimize Antimicrobial Therapy 
Piperacillin-tazobactam is frequently used for empirical and targeted therapy of infections in critically ill patients. Considerable pharmacokinetic (PK) variability is observed in critically ill patients. By estimating an individual's PK, dosage optimization Bayesian estimation techniques can be used to calculate the appropriate piperacillin regimen to achieve desired drug exposure targets. The aim of this study was to establish a population PK model for piperacillin in critically ill patients and then analyze the performance of the model in the dose optimization software program BestDose. Linear, with estimated creatinine clearance and weight as covariates, Michaelis-Menten (MM) and parallel linear/MM structural models were fitted to the data from 146 critically ill patients with nosocomial infection. Piperacillin concentrations measured in the first dosing interval, from each of 8 additional individuals, combined with the population model were embedded into the dose optimization software. The impact of the number of observations was assessed. Precision was assessed by (i) the predicted piperacillin dosage and by (ii) linear regression of the observed-versus-predicted piperacillin concentrations from the second 24 h of treatment. We found that a linear clearance model with creatinine clearance and weight as covariates for drug clearance and volume of distribution, respectively, best described the observed data. When there were at least two observed piperacillin concentrations, the dose optimization software predicted a mean piperacillin dosage of 4.02 g in the 8 patients administered piperacillin doses of 4.00 g. Linear regression of the observed-versus-predicted piperacillin concentrations for 8 individuals after 24 h of piperacillin dosing demonstrated an r2 of >0.89. In conclusion, for most critically ill patients, individualized piperacillin regimens delivering a target serum piperacillin concentration is achievable. Further validation of the dosage optimization software in a clinical trial is required.
PMCID: PMC4068511  PMID: 24798288
2.  Meropenem Dosing in Critically Ill Patients with Sepsis Receiving High-Volume Continuous Venovenous Hemofiltration ▿  
Use of high ultrafiltrate flow rates with continuous venovenous hemofiltration (CVVHF) in critically ill patients is an emerging setting, for which there are few data to guide drug dosing. The objectives of this study were, firstly, to investigate the pharmacokinetics of meropenem in critically ill patients with severe sepsis who are receiving high-volume CVVHF with high-volume exchanges (≥4 liters/h); secondly, to determine whether standard dosing regimens (1,000 mg intravenously [i.v.] every 8 h) are sufficient for treatment of less susceptible organisms such as Burkholderia pseudomallei (MIC, 4 mg/liter); and, finally, to compare the clearances observed in this study with data from previous studies using lower-volume exchanges (1 to 2 liters/h). We recruited 10 eligible patients and collected serial pre- and postfilter blood samples and ultrafiltrate and urine samples. A noncompartmental method was used to determine meropenem pharmacokinetics. The cohort had a median age of 56.6 years, a median weight of 70 kg, and a median APACHE II (acute physiology and chronic health evaluation) score of 25. The median (interquartile range) values for meropenem were as follows: terminal elimination half-life, 4.3 h (2.9 to 6.0); terminal volume of distribution, 0.2 liters/kg (0.2 to 0.3); trough concentration, 7.7 mg/liter (6.2 to 12.9); total clearance, 6.0 liters/h (5.2 to 6.2); hemofiltration clearance, 3.5 liters/h (3.4 to 3.9). In comparing the meropenem clearance here with those in previous studies, ultrafiltration flow rate was found to be the parameter that accounted for the differences in clearance of meropenem (R2 = 0.89). In conclusion, high-volume CVVHF causes significant clearance of meropenem, necessitating steady-state doses of 1,000 mg every 8 h to maintain sufficient concentrations to treat less susceptible organisms such as B. pseudomallei.
PMCID: PMC2897321  PMID: 20479205
3.  Development of Multiplex PCRs for Detection of Common Viral Pathogens and Agents of Congenital Infections 
Journal of Clinical Microbiology  2005;43(10):5102-5110.
Potential causes of congenital infection include Toxoplasma gondii and viruses such as cytomegalovirus (CMV), enterovirus, hepatitis C virus, herpes simplex virus types 1 and 2 (HSV-1 and -2), human herpesvirus types 6, 7, and 8, lymphocytic choriomeningitis virus, parvovirus, rubella virus, and varicella-zoster virus. Testing for each of these agents using nucleic acid tests is time consuming and the availability of clinical samples such as amniotic fluid or neonatal blood is often limited. The aim of this study was to develop multiplex PCRs (mPCRs) for detection of DNA and RNA agents in the investigation of congenital infection and an mPCR for the viruses most commonly requested in a diagnostic virology laboratory (CMV, Epstein-Barr virus, enterovirus, HSV-1, HSV-2, and varicella-zoster virus). The assays were assessed using known pathogen-positive tissues (cultures, placentae, plasma, and amniotic fluid) and limits of detection were determined for all the agents studied using serial dilutions of plasmid targets. Nested PCR was performed as the most sensitive assay currently available, and detection of the amplicons using hybridization to labeled probes and enzyme-linked immunosorbent assay detection was incorporated into three of the four assays. This allowed detection of 10 to 102 copies of each agent in the samples processed. In several patients, an unexpected infection was diagnosed, including a case of encephalitis where HSV was the initial clinical suspicion but CMV was detected. In the majority of these cases the alternative agent could be confirmed using reference culture, serology, or fluorescence methods and was of relevance to clinical care of the patient. The methods described here provide useful techniques for diagnosing congenital infections and a paradigm for assessment of new multiplex PCRs for use in the diagnostic laboratory.
PMCID: PMC1248455  PMID: 16207970
4.  Cost effectiveness of treating primary care patients in accident and emergency: a comparison between general practitioners, senior house officers, and registrars. 
BMJ : British Medical Journal  1996;312(7042):1340-1344.
OBJECTIVES--To compare outcome and costs of general practitioners, senior house officers, and registrars treating patients who attended accident and emergency department with problems assessed at triage as being of primary care type. DESIGN--Prospective intervention study which was later costed. SETTING--Inner city accident and emergency department in south east London. SUBJECTS--4641 patients presenting with primary care problems: 1702 were seen by general practitioners, 2382 by senior house officers, and 557 by registrars. MAIN OUTCOME MEASURES--Satisfaction and outcome assessed in subsample of 565 patients 7-10 days after hospital attendance and aggregate costs of hospital care provided. RESULTS--Most patients expressed high levels of satisfaction with clinical assessment (430/562 (77%)), treatment (418/557 (75%)), and consulting doctor's manner (434/492 (88%)). Patients' reported outcome and use of general practice in 7-10 days after attendance were similar: 206/241 (85%), 224/263 (85%), and 52/59 (88%) of those seen by general practitioners, senior house officers, and registrars respectively were fully recovered or improving (chi2 = 0.35, P = 0.840), while 48/240 (20%), 48/268 (18%), and 12/57 (21%) respectively consulted a general practitioner or practice nurse (chi2 = 0.51, P = 0.774). Excluding costs of admissions, the average costs per case were 19.30 pounds, 17.97 pounds, and 11.70 pounds for senior house officers, registrars, and general practitioners respectively. With cost of admissions included, these costs were 58.25 pounds, 44.68 pounds, and 32.30 pounds respectively. CONCLUSION--Management of patients with primary care needs in accident and emergency department by general practitioners reduced costs with no apparent detrimental effect on outcome. These results support new role for general practitioners.
PMCID: PMC2351016  PMID: 8646050
6.  Effects of drinking green tea. 
BMJ : British Medical Journal  1995;311(7003):513.
PMCID: PMC2550576  PMID: 7647675
7.  Travel prophylaxis. 
BMJ : British Medical Journal  1995;310(6978):533.
PMCID: PMC2548908  PMID: 7888915
8.  Is travel prophylaxis worth while? Economic appraisal of prophylactic measures against malaria, hepatitis A, and typhoid in travellers. 
BMJ : British Medical Journal  1994;309(6959):918-922.
OBJECTIVES--To estimate the costs and benefits of prophylaxis against travel acquired malaria, typhoid fever, and hepatitis A in United Kingdom residents during 1991. DESIGN--Retrospective analysis of national epidemiological and economic data. MAIN OUTCOME MEASURES--Incidence of travel associated infections in susceptible United Kingdom residents per visit; costs of prophylaxis provision from historical data; benefits to the health sector, community, and individuals in terms of avoided morbidity and mortality based on hospital and community costs of disease. RESULTS--The high incidence of imported malaria (0.70%) and the low costs of providing chemoprophylaxis resulted in a cost-benefit ratio of 0.19 for chloroquine and proguanil and 0.57 for a regimen containing mefloquine. Hepatitis A infection occurred in 0.05% of visits and the cost of prophylaxis invariably exceeded the benefits for immunoglobulin (cost-benefit ratio 5.8) and inactivated hepatitis A vaccine (cost-benefit ratio 15.8). Similarly, low incidence of typhoid (0.02%) and its high cost gave whole cell killed, polysaccharide Vi, and oral Ty 21a typhoid vaccines cost-benefit ratios of 18.1, 18.0, and 22.0 respectively. CONCLUSIONS--Fewer than one third of travellers receive vaccines but the total cost of providing typhoid and hepatitis A prophylaxis of 25.8m pounds is significantly higher than the treatment costs to the NHS (1.03m pounds) of cases avoided by prophylaxis. Neither hepatitis A prophylaxis nor typhoid prophylaxis is cost effective, but costs of treating malaria greatly exceed costs of chemoprophylaxis, which is therefore highly cost effective.
PMCID: PMC2541147  PMID: 7726905
10.  The social and economic impact of salmonellosis. A report of a national survey in England and Wales of laboratory-confirmed Salmonella infections. 
Epidemiology and Infection  1991;107(2):335-347.
This study presents the findings of a national survey of 1482 cases of salmonellosis reported to Environmental Health Departments in England and Wales between August 1988 and March 1989. A questionnaire survey of ill individuals and the environmental health officers who investigated them sought information about costs which were imposed upon public health authorities, the health sector, individuals and their families and the costs to the wider economy in terms of lost production. Costs of 996,339 pounds were identified. Over half (507,555 pounds) resulted from lost production due to sickness absence and more than a third (392,822 pounds) were costs to the public sector which resulted from health care and local authority investigation of cases. The remaining costs (95,962 pounds), although the smallest proportion of the total, indicated that salmonellosis can have a significant impact on affected individuals and their families.
PMCID: PMC2272060  PMID: 1936155
12.  The Bevan factor. 
BMJ : British Medical Journal  1992;304(6830):844.
PMCID: PMC1881667  PMID: 1392734
13.  Economic impact of a nationwide outbreak of salmonellosis: cost-benefit of early intervention. 
BMJ : British Medical Journal  1989;298(6682):1227-1230.
The recognition and investigation of an outbreak of food poisoning in 1982 due to chocolate contaminated with Salmonella napoli enabled the food that carried the salmonella to be identified and four fifths of the implicated consignment of chocolate to be withdrawn. The economic benefits of prompt intervention in the outbreak have been assessed. The cost of the outbreak was over 0.5 pounds m. It is estimated that five deaths were prevented by the intervention and that 185 admissions to hospital and 29,000 cases of S napoli enteritis were avoided. This successful investigation yielded a 3.5-fold rate of return to the public sector and a 23.3-fold return to society on an investment in public health surveillance. A methodology is described that can be used to estimate the benefits of early intervention in outbreaks of foodborne illness and topics for further research are suggested. It is concluded that public health authorities and industry have much to gain by collaborating in the research into the design of cost effective programmes to prevent foodborne infections.
PMCID: PMC1836236  PMID: 2502224
14.  Vocational training and recruitment into general practice 
A recent survey of doctors in the practice year of vocational training indicates a strong preference for group practice from purpose-built premises (health centre and other) with multidisciplinary staffing and attachments. While it might be assumed that the introduction of mandatory vocational training would provide a continuing supply of well trained recruits into general practice, it may well raise recruitment problems for those areas where practice facilities and opportunities do not meet with expectations. This possibility is of particular concern for those metropolitan regions encompassing inner city areas which have traditionally been highly dependent on hospital-based services, but where deficiencies in primary care provision, particularly in terms of practice structure and premises, have been identified repeatedly over the past 30 years. In view of the present policies for changing the balance of care away from the hospitals, there is an urgent need to develop primary care facilities which will accord with the expectations of vocationally trained general practitioners and their population of patients.
PMCID: PMC2159775  PMID: 7230105

Results 1-15 (15)