Complexity and diversity of Klebsiella pneumoniae strains with extended-spectrum beta-lactamases isolated in 1994 and 1996 at a teaching hospital in Durban, South Africa.

beta-Lactamase production was investigated in cultures of 25 Klebsiella pneumoniae isolates isolated at a hospital in Durban, South Africa, in 1994 and 1996. Twenty of these isolates gave ceftazidime MIC/ceftazidime plus clavulanate MIC ratios of >/=8, implying production of extended-spectrum beta-lactamases (ESBLs), and DNA sequencing identified an ESBL gene (bla(TEM-53)) in a further two isolates. Pulsed-field gel electrophoresis (PFGE) defined 4 distinct strains among the 12 isolates collected in 1994 and 9 distinct strains among the 13 isolates collected in 1996. In three cases, multiple isolates from single patients varied in their PFGE profiles and antibiograms, implying mixed colonization or infection. Isoelectric focusing and DNA hybridization found both TEM and SHV enzymes and their genes in all 25 isolates. Many isolates had multiple identical or different beta-lactamase gene variants, with at least 84 bla(SHV) and bla(TEM) gene copies among the 25 organisms. Sequencing identified the genes for the SHV-1, -2, and -5 enzymes and for four new SHV types (SHV-19, -20, -21, and -22). These new SHV variants had novel mutations remote from sites known to affect catalytic activity. Sequencing also found the genes for TEM-1, TEM-53, and one novel type, TEM-63. All the isolates had multiple and diverse plasmids. These complex and diverse patterns of ESBL production and strain epidemiology are far removed from the concept of an ESBL outbreak and suggest a situation in which ESBL production has become endemic and in which evolution is generating a wide range of enzyme combinations. This complexity and diversity complicates patient management and the design of antibiotic use policies.

Factors influencing phenytoin-induced gingival enlargement.

AIM: To ascertain the prevalence and severity of phenytoin-induced gingival enlargement (PIGE) as well as the relationship between PIGE and risk factors. METHOD: An outpatient population of patients on phenytoin treatment and attending the epilepsy clinic at Prince Mshiyeni Memorial Hospital (PMMH) in Durban, South Africa, was requested to participate. A structured questionnaire was used to collect data on patients' demographics, social habits (e.g., drinking and smoking), dental and oral hygiene practices and medication history. Gingival enlargement, dental plaque and gingival bleeding was also measured to assess gingival health. Venous blood was collected for serum folate and phenytoin serum levels measurements. A regression analyses was then undertaken to ascertain the association between PIGE and the risk factors. Factors tested for correlation were serum phenytoin and folate levels, age, bacterial plaque, gingival inflammation, toothbrushing, smoking and alcohol consumption. The association between PIGE and the risk factors was assessed either individually, i.e., as a single entity or in combination--multifactorially. RESULTS: Of the 134 patients studied, 62% had PIGE scores > or = 1, while 8% had a PIGE score of zero. With the exception of plaque, which showed a moderate association with PIGE (r=0.4), no other factor on its own was statistically significantly related to PIGE. In the multiple linear regression analysis, factors which on their own did not have a strong influence became more important. Bacterial plaque (p=0.0001), younger age (p=0.01) and higher free serum phenytoin levels (p= 0.03), were associated with PIGE. Although known to be associated with periodontal diseases, smoking and alcohol, (p=0.03 and p=0.04 respectively), appeared to give some protection against PIGE. CONCLUSION: Risk factors associated with PIGE may have a synergistic effect. Bacterial plaque, however, appears the most important determinant of PIGE severity. This latter finding emphasises the importance of instituting a preventive plaque-control programme, particularly in young patients on phenytoin therapy.

Validation of population pharmacokinetic parameters of phenytoin using the parallel Michaelis-Menten and first-order elimination model.

This study was conducted to assess whether the parallel Michaelis-Menten and first-order elimination (MM+FO) model fitted the data better than the Michaelis-Menten (MM) model, and to validate the MM+FO model and its parameter estimates. The models were fitted to 853 steady state dose: serum concentration pairs obtained in 332 adults with epilepsy using nonlinear mixed-effects modeling (NONMEM). The MM+FO model fitted the data better than the MM model. The validity of the pharmacokinetic models and the estimated population parameter values was tested using the naive prediction method. The estimation and validation of the pharmacokinetic parameters were undertaken in two separate patient groups (cross-validation) obtained by splitting the data set. Patients were randomly allocated to two equally matched groups (groups 1 and 2). The predictive performance was assessed using 770 paired predicted versus actual dose or measured serum concentrations. The population pharmacokinetic parameters estimated by NONMEM in group 1 were validated in group 2 and vice versa. When predicting steady state serum concentration, the MM+FO model was clearly superior to the MM model (mean bias of 0.91 and 8.13 mg/L, respectively).

The pharmacokinetics of theophylline in premature neonates during the first few days after birth.

The aims of the study were to estimate the pharmacokinetic parameters, clearance rate (CL), and volume of distribution (V) of theophylline in premature neonates during the first few days after birth, and to identify factors contributing to interindividual variability. The authors obtained 263 serum concentrations from 105 apneic premature neonates receiving intravenous (IV) theophylline. Mean (SD) birth weight and postnatal ages were 1.3 (0.3) kg and 1.1 (0.3) days, respectively. The data were analyzed using the nonlinear mixed effects model (NONMEM). A one-compartment model with first order elimination was used. The final models were: CL (L/h) = 0.006 * WGT 0.75 * P, V (L) = 0.63 * WGT, WGT = weight (kg) P = 1.47 with oxygen support and 1.0 without oxygen support. The CL in the study population was low, resulting in long half-lives. After inclusion of the above covariates, as well as interoccasion variability, the interindividual variability in CL was 56% and in V was 47%. Interoccasion variability in CL and V was 34% and 35% respectively. Theophylline pharmacokinetics are variable in the premature neonate during the first week of life, and this high variability makes it difficult to predict drug concentrations with the same degree of accuracy as in other populations.

Continuous infusion of intermediate-purity factor VIII in haemophilia A patients undergoing elective surgery.

An open, non-randomized trial of continuous infusion therapy was conducted involving five patients with severe haemophilia A who required factor VIII (FVIII) prophylaxis for elective surgery. This was preceded by a 24-h preoperative pharmacokinetic study to characterize the pharmacokinetic parameters of each individual patient following a bolus dose of the intermediate-purity product. A retrospective matched control group was identified to allow for comparisons of FVIII usage between bolus and continuous infusion administration. A loading dose of FVIII was administered preoperatively, and the continuous infusion was started at the end of surgery and continued for 5 days. The patients' FVIII levels, vital signs, and infusion sites were monitored on a daily basis. The clearance was re-calculated on a daily basis using the FVIII activity of that day to adjust the infusion rate to achieve the desired FVIII level. The mean (CV%) pharmacokinetic parameters estimated preoperatively by noncompartmental analysis were: clearance 3.2 mL kg-1 h-1 (35.5%), volume of distribution 52.1 mL kg-1 (40.2%), mean residence time 17.4 h (23.3%), and half-life 12.7 h (23.6%). A progressive decrease in the clearance of FVIII from a mean of 3.1 mL kg-1 h-1 to 2.0 mL kg-1 h-1 (P = 0.125) over the first 5 days was observed. A therapeutically acceptable level of FVIII was systematically achieved, with the only complication being frequent thrombophlebitis. On average the patients used 19% less FVIII when compared with matched historical controls (P = 0.25). This method was found to be safe and effective in haemophilia A patients undergoing elective surgery procedures.

Factors influencing the population pharmacokinetic parameters of phenytoin in adult epileptic patients in South Africa.

The influence of various covariates (including weight, race, smoking, gender, age, mild-to-moderate alcohol intake, and body surface area) on the population pharmacokinetic parameters of phenytoin in adult epileptic patients in South Africa was investigated. The parameters were the maximum metabolic rate (Vm) and the Michaelis-Menten (MM) constant (Km) of phenytoin. The study population comprised 332 black and colored epileptic patients (note: "black" refers to indigenous people of South Africa, who speak one of the Bantu languages as their native language; "colored" refers to people considered to be of mixed race, classified as such by the apartheid former government of South Africa). The influence of covariates on Vm and Km estimates was determined using nonlinear mixed-effects modeling (NONMEM). Parameter models describing the factors that could potentially influence Vm and Km were tested using the Michaelis-Menten parallel MM and first-order elimination models, to which 853 steady state dose-to-serum concentration pairs were fitted. The results indicated that body weight, smoking, race, and age (65 years or older), in descending order of importance, significantly influenced Vm (p < 0.05). Although a significant difference (p = 0.03) in Km was found between black and colored patients, incorporating the influence of race in Km in the final regression model did not improve the fit of the model to the data, which indicated that the variability in Km was accounted for by Vm. The scaling factors for smoking, colored patients and age (65 years or older) in Vm were 1.16, 1.10, and 0.88, respectively. These factors should be taken into account when adjusting phenytoin dose.

The effect of theophylline on apnoea and hypoxaemic episodes in the premature neonate during the 1st 3 days after birth.

Although the effect of theophylline on apnoea is well documented, its influence on hypoxaemic episodes in premature neonates is less well known. To investigate the influence of the drug on both parameters, 37 apnoeic neonates were monitored before and after theophylline treatment. Incidents and densities of pathological apnoea (cessation of nasal airflow > or = 20 seconds) were recorded. A fall of > or = 10% for > 10 seconds in peripheral oxygen saturation was classified as a hypoxaemic episode. Ethical constraints precluded the inclusion of a control group. Each infant served as its own control. Theophylline serum concentrations were 5.6 (3.4), 8 (7.1) and 8 (5.3) mg/l on days 1, 2 and 3, respectively. The apnoea incidents and densities decreased significantly (p = 0.0001) from baseline on all 3 days. The total number of hypoxaemic episodes, as well as those not associated with pathological apnoea, decreased, though not significantly. However, those hypoxaemic episodes associated with pathological apnoea and a fall in pulse rate of > or = 20% decreased significantly from baseline on day 2 only. Throughout the study period, over 80% of hypoxaemic episodes were not associated with apnoea. It is concluded that in the doses used, theophylline was more effective in reducing apnoea than hypoxaemic episodes in premature neonates.

A comparison of the standard approach and the NONMEM approach in the estimation of bioavailability in man.

There has recently been concern about confidence intervals calculated using the standard error of parameter estimates from NONMEM, a computer program that uses a non-linear mixed-effects model to calculate relative bioavailability (F), because of possible downward bias of these estimates. In this study an alternate approach, the log-likelihood procedure, was used to calculate the confidence intervals for F from NONMEM. These were then compared with those calculated using the standard error of the parameter estimates, the traditional NONMEM approach, and the standard model-independent method, to determine whether bias exists. By use of data from a single dose, open cross-over study of ibuprofen using 14 healthy male volunteers, NONMEM was shown to give results consistent with those obtained using the standard model-independent method of analysis and could be a useful tool in the determination of F where conditions for using the standard method of analysis are not optimum. The width of the confidence interval for F using the log-likelihood procedure was narrower and non-symmetrical when compared with that obtained using the traditional NONMEM approach. The width of the confidence interval obtained using the traditional NONMEM method was similar to that from the standard approach, however the parameter estimate for F was higher than that obtained from the standard method. This could have been because of an outlier in the data set to which the standard approach is more sensitive. No downward bias was found in the confidence intervals from NONMEM. The bioavailability data set was of relatively low variability and more research with highly variable data is necessary before it can be concluded that the confidence intervals calculated from NONMEM can be used for hypothesis testing.

Ketotifen pharmacokinetics in children with atopic perennial asthma.

OBJECTIVE: Published pharmacokinetic data on ketotifen are sparse, although it is a commonly used prophylactic agent in various allergic disorders in adults and children. The aim of this study was to assess the steady-state pharmacokinetics of ketotifen in children with atopic perennial asthma who were participating in a clinical trial. METHOD: The NONMEM population approach with sparse sampling was utilized. The data set consisted of 239 samples from 48 children who were randomized to receive either 1 mg or 2 mg oral ketotifen daily. Patients underwent a clinical examination and had a blood sample taken at 2-week intervals for 12 weeks. The ketotifen concentrations were measured by RIA. RESULTS: A one-compartment model with first-order absorption was fit to the data. Volume was estimated at 394 l and clearance (CL) at 97.4 l.h-1 (3.6 l.h-1.kg-1). Weight or body surface area were the most influential covariates for explaining interindividual variability in CL. The 2-mg dose appeared to have a relative bio-availability of 85% of the 1-mg dose. CONCLUSION: Children have a faster clearance of ketotifen than adults and would therefore require a higher dose per kilogram body weight to give comparable steady-state levels.

Carbamazepine and its metabolites in neuralgias: concentration-effect relations.

The aim of this study was to investigate the use of carbamazepine in the treatment of neuralgic pain and to determine a therapeutic plasma concentration range for carbamazepine in neuralgias. The relation between plasma concentration and the response to treatment (reduction in pain) was examined by logistic regression analysis of carbamazepine and its metabolites, the epoxide, the diol, and 2-hydroxycarbamazepine. The plasma concentrations of carbamazepine, the epoxide, and the diol were significantly related to the probability of a 25% reduction in pain. Only carbamazepine was significantly related to the probability of 50% and 75% pain reduction. However, multiple regression analysis with backward elimination of the data showed a significant correlation between both carbamazepine and the epoxide with regard to the probability of 50% and 75% reductions in pain. This confirms the previous finding that the epoxide has antineuralgic properties [Tomson and Bertilsson 1984]. The therapeutic plasma concentration range for carbamazepine in neuralgias, defined as the range of concentrations that would be expected to provide a 25-75% reduction in pain in 50% of patients, was 2-7 micrograms.ml-1 (HPLC) or 5-17 micrograms.ml-1 (EMIT).

Plasma noradrenaline and adrenaline levels in eclampsia. A preliminary study.

Plasma noradrenaline and adrenaline levels were measured in 18 women with eclampsia and 20 normotensive pregnant women matched for age and parity. While plasma noradrenaline concentrations were not statistically different in the two groups, plasma adrenaline values were higher in patients with eclampsia. The increases in adrenaline levels, although significantly elevated, were thought to be more related to stresses, such as muscular activity associated with convulsions. This study suggests that the aetiology of hypertension in pregnancy is not related to sympathetic overactivity.

The relevance of a First-World therapeutic drug monitoring service to the treatment of epilepsy in Third-World conditions.

In May 1988 a Therapeutic Drug Monitoring (TDM) service for anti-epileptic drugs was established at Prince Mshiyeni Memorial Hospital. This service was offered as a multidisciplinary team approach involving sisters, doctors, social workers and pharmacists at an epilepsy clinic. Statistics gathered over a 13-month period showed that: (i) epileptic patient numbers increased from 52 to 211 per 4-week cycle, while patients requiring TDM decreased from 40 to 20 per cycle; (ii) phenytoin was the most frequently prescribed anticonvulsant, followed by carbamazepine and phenobarbitone, throughout the period; (iii) TDM did not alter prescribing patterns--approximately 90% of patients were on monotherapy at the beginning and at the end of the assessment period; (iv) 471 serum levels were measured in 280 patients over 13 months. Phenytoin serum levels constituted the majority (53%) followed by carbamazepine (33%), phenobarbitone (12%) and valproate (2%); (v) of the levels measured in 24 patients taking phenytoin 300 mg/d who were experiencing neither seizures nor side-effects, 38% of levels were in the potentially toxic range; and (vi) well-controlled patients increased from 36% in the first cycle to 60% in the last cycle. A TDM service is very useful in a Third-World setting and can assist in conserving scarce sources provided it is utilised within a holistic treatment framework.

The pharmacokinetics of phenobarbitone in fasting and non-fasting dogs.

The pharmacokinetics of oral phenobarbitone was studied in 10 clinically healthy adult dogs. The drug was given once daily in tablet form, at a dose of 5 mg kg-1 of body mass. Serial venous blood samples (n = 9) were collected from each dog on Day 1 (the first day of drug dosing), on Day 22, and on Day 24 after continuous dosing. Trough serum concentrations were determined on Day 7, Day 14 and Day 21. The drug was administered to the dogs on an empty stomach, except on Day 24, when it was given with food, in order to assess the influence of food on its absorption. Drug serum concentrations were described by a one-compartmental open model with first order absorption and elimination. An average steady-state trough serum level of phenobarbitone of 52,96 +/- 8.40 mmol l-1 was achieved after 3 weeks of daily dosing. The mean elimination half-lives for Day 1 and Day 22 were 46.3 +/- 11.3 h and 29.3 +/- 4.6 h respectively. The area under the curve for Day 22 was 1,656.17 +/- 186.45 mumol h-1 l-1 and for Day 24 was 1,493.06 +/- 205.4 mumol h-1 l-1. The mean clearance value for Day 22 was 0.0133 +/- 0.0016 l h-1 kg-1. Side effects of polyphagia, polydipsia, sedation and ataxia were commonly observed in the first 2-9 d, but disappeared thereafter. It was concluded that a dose of 5 mg kg-1 would achieve an average serum concentration of 64.59 mumol l-1 in adult dogs.(ABSTRACT TRUNCATED AT 250 WORDS)

A comparative study of standard and slow-release oral lithium carbonate products.

Lithium serum levels were drawn over one steady-state dosing interval in 8 bipolar disorder patients receiving long-term lithium therapy: (i) after standard-release lithium (STD); and (ii) after changing to 2 weeks' continuous dosing of a slow-release (SR) preparation. Rate of absorption of the SR preparation was significantly slower than the STD preparation measured by the peak/trough difference, percentage peak/trough fluctuation and percentage swing. The extent of absorption measured by the area under the concentration time curve was not significantly different for the two preparations. Serum lithium levels drawn within 2 hours after administration of the SR preparation are likely to be within the range 0- -18% of the 12-hour standard serum lithium with a 95% limit of confidence. The STD preparation shows a deviation in the same period of -14.5-70%. These results suggest that if a patient taking the SR preparation presents within 2 hours after administration a serum lithium level would still be meaningful, whereas for a patient taking the STD preparation it is essential that blood be drawn 12 hours after administration for meaningful interpretation.

Effect of the H2-receptor antagonist ranitidine on depression and anxiety in duodenal ulcer patients.

Depression and anxiety were measured during the course of a double-blind, placebo-controlled trial of the histamine H2-receptor antagonist, ranitidine (150 mg twice daily), in patients suffering from duodenal ulcer but free of systemic disease. There were 25 patients in the ranitidine group (mean age: 33.2 years) and 28 in the placebo group (mean age: 37.2 years). In both groups there was a highly significant and progressive decrease in depression and anxiety scores over the 4 weeks of treatment. There were no instances of mental confusion. In our group of otherwise physically healthy patients, ranitidine appeared to be free of neuropsychiatric complications.

Pharmacokinetics of ranitidine in patients with chronic renal failure.

The pharmacokinetic behaviour of a single oral 150 mg ranitidine dose was studied in six patients with severe chronic renal failure (CRF) (creatinine clearance 2-18 ml/min) and compared to that in ten patients with duodenal ulceration but normal renal function (N) (creatinine clearance 69-125 ml/min). Although the maximum concentrations (Cmax) were significantly higher in CRF group when compared to N group (p less than 0.025) there was no difference in the time taken to reach Cmax (tmax). The area under the curve (AUC) was also significantly larger in the CRF group (p less than 0.001) than in the N group. Within the CRF group there was a large variation in Cmax (CV = 38%) and AUC (46%) which may reflect variable bioavailability of ranitidine. The terminal elimination rate constant (beta) was significantly smaller (p less than 0.001) in CRF group when compared with N group resulting in a median t1/2 for the CRF group of 7.3 h, 2.4 times that of N group. The recovery of unchanged ranitidine in the urine was significantly less in CRF group (p less than 0.001) despite a great interindividual variation in both groups. A significant linear relationship between beta and creatinine clearance was shown (r = 0.81 p less than 0.001). The results indicate that ranitidine elimination is appreciably reduced in renal failure. It is tentatively suggested that the standard 150 mg dose should be halved while keeping the dose interval unchanged at twelve hours in patients with severe renal failure (creatinine clearance less than 30 ml/min).

The pharmacokinetics of ranitidine in patients with chronic duodenal ulceration: a comparison of responders and non-responders.

The pharmacokinetics of orally administered ranitidine were studied in 17 male patients with chronic duodenal ulceration. The patients were divided into 2 groups, 10 responders and 7 nonresponders, on the basis of their endoscopic response to ranitidine treatment. The 10 responders were studied both after a single 150 mg dose (SD) and after multiple dosing (MD) with ranitidine 150 mg twice daily for 4 weeks. The area under the curve (AUC) and maximum concentration (Cmax) were significantly higher (p less than 0.01 and p less than 0.05, respectively) after MD than after SD, but the half-life (t1/2) and minimum concentration (Cmin) 12 h postdosing did not differ. The non-responders were studied after MD only and their pharmacokinetic characteristics were compared with those of responders. No differences between the 2 groups were found. However, 2 non-responders had particularly low plasma ranitidine levels and high acid output. Such patients may need larger doses of ranitidine for adequate suppression of gastric acid. Five patients (4 responders and 1 non-responder) received ranitidine 20 mg i.v. The drug followed a two-compartment model, with mean values for t1/2 beta, volume of distribution steady-state and total plasma clearance of 80 min, 701 and 680 ml/min, respectively. The oral bioavailability of ranitidine in these 5 patients showed wide variation (27-76%; mean 51%).