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Biomedical subjects

Vincent H Tam

Publications and source records attributed to Vincent H Tam.

At least 19 recordsLinked to original sources
PubMed2006

Intraventricular or intrathecal use of polymyxins in patients with Gram-negative meningitis: a systematic review of the available evidence.

Several reports have described the use of polymyxins by the intraventricular or intrathecal route for multidrug-resistant Gram-negative meningitis. We reviewed the available clinical evidence regarding intraventricular/intrathecal administration of polymyxins in patients with meningitis, focusing on effectiveness and safety. Relevant studies were identified from PubMed (January 1950 to April 2006) as well as from the references of relevant articles. We identified 31 case reports/series that matched our inclusion criteria. Sixty-four episodes of Gram-negative meningitis (34 in adults) were reviewed. Monotherapy with polymyxins via the intraventricular or intrathecal route was used in 11 episodes and combination of systemic and local polymyxins was used in 25 episodes. In the remaining episodes, various combinations of local polymyxins with systemic and/or local antibiotics were administered. Cure was achieved in 51/64 episodes (80%); in 26/30 episodes (87%) due to Pseudomonas aeruginosa and in 10/11 episodes (91%) due to Acinetobacter spp. Toxicity related to local administration of polymyxins was noted in 17/60 (28%) patients. The most common toxicity was meningeal irritation (12 cases). Discontinuation of treatment was necessary in four episodes and dose reduction in four episodes; irreversible toxicity was not reported. The limited available evidence suggests that therapy with intraventricular/intrathecal polymyxins alone or in combination with systemic antimicrobial agents is effective against Gram-negative meningitis. Toxicity is not uncommon but it is dose-dependent and reversible. Further studies are needed to evaluate the criteria for initiation of local central nervous system treatment with polymyxins, the optimal dosages and the role of adjuvant systemic or local therapy.

Drug Resistance, Multiple, Bacterial↗
PubMed2006

The relationship between quinolone exposures and resistance amplification is characterized by an inverted U: a new paradigm for optimizing pharmacodynamics to counterselect resistance.

We determined the relationship between garenoxacin exposure and quinolone-resistant subpopulations for three bacterial isolates in an in vitro hollow-fiber infection model. An "inverted-U" relationship was identified wherein resistant subpopulations rose initially and then declined with increasing exposure, until reaching a threshold that prevented resistance amplifications. Different targets for the area under the concentration-time curve over 24 h/MIC ratio were required for different bacteria.

Anti-Bacterial Agents↗
PubMed2006

Impact of sample size on the performance of multiple-model pharmacokinetic simulations.

Monte Carlo simulations are increasingly used to predict pharmacokinetic variability of antimicrobials in a population. We investigated the sample size necessary to provide robust pharmacokinetic predictions. To obtain reasonably robust predictions, a nonparametric model derived from a sample population size of >/=50 appears to be necessary as the input information.

Anti-Bacterial Agents↗
PubMed2006

Comparative performance of different stochastic methods to simulate drug exposure and variability in a population.

Monte Carlo simulations (MCSs) are increasingly being used to predict the pharmacokinetic variability of antimicrobials in a population. However, various MCS approaches may differ in the accuracy of the predictions. We compared the performance of 3 different MCS approaches using a data set with known parameter values and dispersion. Ten concentration-time profiles were randomly generated and used to determine the best-fit parameter estimates. Three MCS methods were subsequently used to simulate the AUC(0-infinity) of the population, using the central tendency and dispersion of the following in the subject sample: 1) K and V; 2) clearance and V; 3) AUC(0-infinity). In each scenario, 10000 subject simulations were performed. Compared to true AUC(0-infinity) of the population, mean biases by various methods were 1) 58.4, 2) 380.7, and 3) 12.5 mg h L(-1), respectively. Our results suggest that the most realistic MCS approach appeared to be based on the variability of AUC(0-infinity) in the subject sample.

Area Under Curve↗
PubMed2006

Disposition of flavonoids via enteric recycling: structural effects and lack of correlations between in vitro and in situ metabolic properties.

The purpose of this study is to determine the importance of coupling of efflux transporters and metabolic enzymes in the intestinal disposition of six isoflavones (genistein, daidzein, formononetin, glycitein, biochanin A, and prunetin), and to determine how isoflavone structural differences affect the intestinal disposition. A rat intestinal perfusion model was used, together with rat intestinal and liver microsomes. In the intestinal perfusion model, significant absorption and excretion differences were found between isoflavones and their respective glucuronides (p <0.05), with prunetin being the most rapidly absorbed and formononetin glucuronides being the most excreted in the small intestine. In contrast, glucuronides were excreted very little in the colon. In an attempt to account for the differences, we measured the glucuronidation rates of six isoflavones in microsomes prepared from rat intestine and liver. Using multiple regression analysis, intrinsic clearance (CL(int)) and other enzyme kinetic parameters (V(max) and K(m)) were determined using appropriate kinetic models based on Akaike's information criterion. The kinetic parameters were dependent on the isoflavone used and the types of microsomes. To determine how metabolite excretion rates are controlled, we plotted excretion rates versus calculated microsomal rates (at 10 microM), CL(int) values, K(m) values, or V(max) values, and the results indicated that excretion rates were not controlled by any of the kinetic parameters. In conclusion, coupling of intestinal metabolic enzymes and efflux transporters affects the intestinal disposition of isoflavones, and structural differences of isoflavones, such as having methoxyl groups, significantly influenced their intestinal disposition.

Animals↗
PubMed2006

Mathematical formulation of additivity for antimicrobial agents.

The ability to describe and quantify pharmacodynamic interaction objectively is of paramount importance in the study of combination chemotherapy. Current methods based on Loewe additivity and Bliss independence are associated with implicit assumptions of the interacting system. We reviewed the hyperplane theorem that used a generalized equation for defining the isobols (surfaces of equal effect) for 2 noninteracting drugs. We showed that under certain conditions, the original equation might lead to nonintuitive results, which were inconsistent with the definition of additivity. To circumvent these limitations, an alternative model for defining additivity based on effect summation is proposed. This alternative definition for isobols deviates from the Loewe additivity, the null interaction criterion used as the foundation for Berenbaum's isobol equation. However, its results are simple, easily interpreted, and may be more applicable to a wide variety of clinical and experimental circumstances.

Anti-Infective Agents↗
PubMed2006

An integrated pharmacoeconomic approach to antimicrobial formulary decision-making.

PURPOSE: The utility of a novel interdisciplinary approach to antimicrobial formulary decision-making was studied. METHODS: Pseudomonas aeruginosa minimum inhibitory concentration (MIC) distribution data for cefepime and ceftazidime were retrieved from nonrepeat isolates obtained from November 2002 to October 2003. Unbound drug exposures were simulated for 5000 patients using the Monte Carlo method. Weighted target attainment rates (TARs) were calculated for cefepime and ceftazidime 1 g every 8 hours and 1 g every 12 hours (infused over 0.5, 2, and 4 hours), using three representative pharmacodynamic targets (percentage of time above the MIC of 67%, 100%, and 400%). RESULTS: MIC data for 1230 nonrepeat P. aeruginosa were analyzed. The MIC at which 90% of the P. aeruginosa isolates were inhibited was 16 and 32 mg/L for cefepime and ceftazidime, respectively. Drug acquisition cost was the highest with cefepime 1 g given every 8 hours (37.56 dollars/day), followed by cefepime 1 g every 12 hours (25.04 dollars/day) and ceftazidime 1 g every 8 hours (22.26 dollars/day). When infused over 0.5 hour, the highest TAR was achieved with cefepime 1 g every 8 hours (82%), followed by ceftazidime 1 g every 8 hours (77%) and cefepime 1 g every 12 hours (66%); ceftazidime 1 g every 8 hours was 70% more cost-effective than cefepime 1 g every 8 hours. Cefepime 1 g every 12 hours, infused over 4 hours, increased the TAR to 89% and was similar in cost-effectiveness to ceftazidime 1 g every 8 hours infused over 0.5 hour. CONCLUSION: An integrated pharmacoeconomic approach to antimicrobial formulary decision-making addressed local resistance patterns, population pharmacokinetics, pharmacodynamics, dosing regimens, and drug acquisition costs. This method appeared to be more realistic and objective than the conventional approach of considering only drug acquisition costs, especially for agents in a similar structural or functional class.

Anti-Infective Agents↗
PubMed2006

Pharmacodynamic profiling of cefepime in plasma and cerebrospinal fluid of hospitalized patients with external ventriculostomies.

Population pharmacokinetic (PK) modeling and Monte Carlo simulation (MCS) were used to describe the pharmacodynamic profile of cefepime in the both plasma and cerebrospinal fluid (CSF). Plasma and CSF cefepime data were obtained from a PK study of 7 hospitalized patients with external ventricular drains. Concentration-time profiles in plasma and CSF were modeled using a 3-compartment model with zero-order infusion and first-order elimination and transfer. Estimates of the PK parameters were identified in the Big Non Parametric Adaptive Grid with adaptive gamma (BigNPAG) program of Leary, Jelliffe, Schumitzky, and Van Guilder. MCS (10,000 subjects) was performed to estimate the probability of attaining the targets of free plasma concentration (20% protein binding) and total drug CSF concentration of 50-100% T>minimal inhibitory concentration (MIC) for MICs 0.06-8 mg/L for cefepime 2 g, iv, every 8 h (0.5-h infusion); cefepime 2 g, iv, every 12 h (0.5-h infusion); and cefepime 2 g (0.5-h infusion) once and 250 mg/h continuous infusion. After the Bayesian step, the observed-predicted regression and r(2) for plasma and CNS were as follows: plasma, observed=0.984 x predicted+2.570, r(2)=0.944; CSF, observed=0.785 x predicted+0.868, r(2)=0.821. The median penetration of cefepime as measured by AUC(CSF)/AUC(plasma) was 7.8%. In the MCS, the target attainment rates in plasma for 60-70% fT>MIC were high at each MIC value between 0.03 and 8 microg/mL for each regimen examined. In CSF, none of the regimens achieved 50-100% T>MIC for>80% of patients for MICs>0.5 mg/L.

Adult↗
PubMed2006

Comparative pharmacodynamics of gentamicin against Staphylococcus aureus and Pseudomonas aeruginosa.

Aminoglycosides are often used to treat severe infections with gram-positive organisms. Previous studies have shown concentration-dependent killing by aminoglycosides of gram-negative bacteria, but limited data are available for gram-positive bacteria. We compared the in vitro pharmacodynamics of gentamicin against Staphylococcus aureus and Pseudomonas aeruginosa. Five S. aureus strains were examined (ATCC 29213 and four clinical isolates). Time-kill studies (TKS) in duplicate (baseline inocula of 10(7) CFU/ml) were conducted to evaluate bacterial killing in relation to increasing gentamicin concentrations (0 to 16 times the MIC). Serial samples were obtained over 24 h to quantify bacterial burden. Similar TKS with P. aeruginosa ATCC 27853 were conducted, and the time courses of the all bacterial strains were mathematically modeled for quantitative comparison. A dose fractionation study (using identical daily doses of gentamicin) in an in vitro hollow-fiber infection model (HFIM) over 5 days was subsequently used for data validation for the two ATCC strains. Model fits to the data were satisfactory; r(2) values for the S. aureus and P. aeruginosa ATCC strains were 0.915 and 0.956, respectively. Gentamicin was found to have a partially concentration-dependent killing effect against S. aureus; concentrations beyond four to 8 times the MIC did not result in significantly faster bacterial killing. In contrast, a concentration-dependent profile was demonstrated in suppressing P. aeruginosa regrowth after initial decline in bacterial burden. In HFIM, thrice-daily gentamicin dosing appeared to be superior to once-daily dosing for S. aureus, but they were similar for P. aeruginosa. Different killing profiles of gentamicin were demonstrated against S. aureus and P. aeruginosa. These results may guide optimal dosing strategies of gentamicin in S. aureus infections and warrant further investigations.

Anti-Bacterial Agents↗
PubMed2006

Quinolone efflux pumps play a central role in emergence of fluoroquinolone resistance in Streptococcus pneumoniae.

The preferential use of older antimicrobial agents is, in general, sound public health policy and is meant to maintain susceptibility to newer agents. In the case of fluoroquinolones, however, this strategy is flawed and may actually hasten the spread of Streptococcus pneumoniae strains resistant to newer members of the class. In a mouse thigh infection model, we were unable to isolate clones of pneumococci resistant to the newer fluoroquinolone levofloxacin at 2 x or 4 x the baseline MIC. An initial exposure in vivo to the older agent, ciprofloxacin, allowed straightforward selection of clones resistant to levofloxacin in a subsequent experiment. The original ciprofloxacin exposure generated clones without changes in the parC/E and gyrA/B quinolone target sites almost exclusively but did allow overexpression of a reserpine-responsive pump. While this caused only minimal change in the levofloxacin MIC (0.6 mg/liter to 0.8 mg/liter), it allowed a major change in the mutational frequency to resistance for levofloxacin (<1/10(8.5) to approximately 1/10(4.5)), which allowed levofloxacin-resistant clones to be isolated in a subsequent in vivo experiment. The reason underlying ciprofloxacin's propensity to select for pump-overexpressed clones is likely related to its hydrophilicity. To preserve the susceptibility of Streptococcus pneumoniae to newer members of the class of quinolones, use of ciprofloxacin for community-acquired respiratory infections should be minimized.

Animals↗
PubMed2006

Pharmacodynamic activity of amphotericin B deoxycholate is associated with peak plasma concentrations in a neutropenic murine model of invasive pulmonary aspergillosis.

We conducted a dose fractionation study of neutropenic, corticosteroid-immunosuppressed mice to characterize the pharmacodynamic/pharmacokinetic (PK/PD) parameter most closely associated with amphotericin B (AMB) efficacy in the treatment of invasive pulmonary aspergillosis. Pharmacokinetic parameter estimates were determined by a nonparametric population pharmacokinetic analysis of plasma drug concentrations following single intraperitoneal doses (0.25, 1.0, and 3.0 mg/kg of body weight) of amphotericin B deoxycholate. Three dosage groups (0.5, 0.75, and 1.0 mg/kg) fractionated into three dosing intervals (every 8 h [q8h], q24h, or q72h) were tested to discriminate between the PK/PD parameters (the ratio of maximum concentration of drug in serum [Cmax]/MIC, the ratio of area under the concentration-time curve/MIC, and percentage of time above MIC) most closely associated with AMB efficacy over a range of clinically achievable exposures in humans. The efficacy of each regimen was determined by quantitative PCR and survival. Reductions in pulmonary fungal burden and improvements in survival were maximized at the highest peak plasma concentrations in each of the dosage groups. Reductions in pulmonary fungal burden and increased survival were most closely associated with Cmax/MIC, with maximal activity occurring as the Cmax/MIC approached 2.4. In our model, Cmax/MIC is the PK/PD parameter most closely associated with efficacy in the treatment of invasive pulmonary aspergillosis. These data predict that less frequently administered, higher dosages of AMB would optimize efficacy.

Amphotericin B↗
PubMed2005

A new modeling approach to the effect of antimicrobial agents on heterogeneous microbial populations.

We develop a mathematical framework to model the dynamics of the effect of antimicrobial agents on heterogeneous microbial populations of distributed antimicrobial resistance. Our framework uses the concept of cumulants of a distribution. Simplifications that result in easily usable approximation tools are presented. A case study on experimental data exemplifies shortcomings of standard methods and the usefulness of the proposed approach. Suggestions for future development are made.

Algorithms↗
PubMed2005

Disposition of flavonoids via recycling: comparison of intestinal versus hepatic disposition.

The purpose of this study was to compare intestinal versus hepatic disposition of six flavonoids to fully characterize their first-pass metabolism. The perfused rat intestinal model and microsomes prepared from rat liver, duodenum, jejunum, ileum, and colon were used. The results indicated that isoflavone (12.5 microM) glucuronidation was highly variable among different microsomes prepared from liver or intestine. Comparing to liver metabolism, the intestinal metabolism had higher K(m) values (>2-fold). Likewise, the hepatic intrinsic clearance (IC, or a ratio of V(max)/K(m)) values of isoflavones were generally higher than their intestinal IC values (200-2000% higher), except for prunetin, for which the jejunal IC value was 50% higher than its hepatic IC. When comparing intestinal metabolism, the results showed that intestinal metabolism rates and V(max) values of isoflavones were less when an additional A-ring electron-donating group was absent (i.e., daidzein and formononetin). In the rat perfusion model using the whole small intestine, genistein (10 microM) was well absorbed (77% or 352 nmol/120 min). The first-pass metabolism of genistein was extensive, with 40% of absorbed genistein excreted as conjugated metabolites into the intestinal lumen. In contrast, the bile excretion of genistein conjugates was much less (6.4% of absorbed genistein). In conclusion, intestinal glucuronidation is slower in isoflavones without an additional A-ring substitution. Perfusion studies suggest that intestine is the main organ for genistein glucuronide formation and excretion in rats and may serve as its main first-pass metabolism organ.

Animals↗
PubMed2005

Nebulized colistin in the treatment of pneumonia due to multidrug-resistant Acinetobacter baumannii and Pseudomonas aeruginosa.

Twenty-one patients with multidrug-resistant (MDR) Acinetobacter baumannii and Pseudomonas aeruginosa pneumonia were treated with nebulized polymyxin E (colistin). Overall clinical and microbiological response rates were 57.1% and 85.7%, respectively. Nebulized colistin may be reasonably efficacious and safe for treatment of MDR pneumonia. Its role in therapy warrants further investigation in comparative studies.

Acinetobacter Infections↗
PubMed2005

Bacterial-population responses to drug-selective pressure: examination of garenoxacin's effect on Pseudomonas aeruginosa.

The emergence of resistance to antibiotics is a serious problem often related to suboptimal drug dosing; such suboptimal dosing results in the preferential killing of drug-susceptible microbial subpopulations, allowing amplification of drug-resistant microbial subpopulations. We determined the effect that fluctuating concentrations of quinolone drugs have on both the total population and the resistant subpopulation of Pseudomonas aeruginosa, by employing, over a 48-h period, human pharmacokinetics and multiple regimens in an in vitro-infection model. All data were simultaneously modeled by use of 3 parallel inhomogeneous differential equations. Model parameters were used to derive the minimal, or breakpoint, drug exposure necessary to suppress amplification of the resistant subpopulation. In a prospective-validation study, we found that a drug exposure near to but below the calculated breakpoint amplified the resistant subpopulation, whereas a drug exposure at the breakpoint suppressed it. This approach allows delineation of target drug exposures (area under the concentration/time curve for 24 h : minimal inhibitory concentration [AUC(24) : MIC] = 190) that will suppress amplification of the antibiotic-resistant subpopulation, thereby preserving the susceptibility of target pathogens.

Area Under Curve↗
PubMed2005

Modelling time-kill studies to discern the pharmacodynamics of meropenem.

OBJECTIVES: Time-kill studies are commonly used in investigations of new antimicrobial agents. However, they typically provide descriptive information on pharmacodynamics. We developed a mathematical model to capture the relationship between microbial burden and antimicrobial agent concentrations. METHODS: Time-kill studies were performed with 10(8) cfu/mL of Pseudomonas aeruginosa at baseline. Meropenem at 0, 0.25, 1, 4, 16 and 64 x MIC was used (MIC = 1 mg/L). Serial samples were obtained to quantify bacterial burden over 24 h. The data were analysed by a population analysis using the non-parametric adaptive grid program. The rate of change of bacteria over time was expressed as the difference between linear bacterial growth rate and sigmoidal kill rate. Regrowth was attributed to adaptation, which was explicitly modelled as increase in C(50k) (concentration to achieve 50% maximal kill rate), using a saturable function of selective pressure (both meropenem concentration and time). RESULTS: The best-fit model consisted of eight parameters and the fit to the data was satisfactory. The r2 of maximum a-posteriori probability Bayesian predictions based on the mean parameter estimates was 0.984. Maximal killing rate at baseline was found to be 4.7 h(-1); C(90k) was achieved with meropenem at 5.0 mg/L. The model was validated by time-kill studies using 2x and 32x MIC of meropenem. CONCLUSIONS: Our model reasonably described and predicted the time course of P. aeruginosa in time-kill studies, and provided quantitative information on the pharmacodynamics of meropenem. The structural model appeared robust and could be used to provide a realistic expectation of the killing performance of antimicrobial agents.

Anti-Bacterial Agents↗
PubMed2005

Comparison of beta-lactams in counter-selecting resistance of Pseudomonas aeruginosa.

Suppression of resistance in a dense population of Pseudomonas aeruginosa has been shown with optimized quinolone exposures. However, relevance to the beta-lactams is questionable because of the unknown impact of the inoculum effect. We explored the bactericidal activity of various beta-lactams and their propensity to suppress spontaneous resistance. Minimal killing and resistance selection was seen with piperacillin, most likely due to the inoculum effect. Moderate and significant killing was seen at 24 h with ceftazidime and meropenem, respectively; however, regrowth and selective resistance amplification was apparent at 48 h. Our results suggest that different beta-lactam subclasses have a distinct killing profile and propensity to suppress resistance against a dense population of P. aeruginosa. The pharmacodynamics of each subclass of agent should be examined individually, and investigations longer than 24 h may be necessary to fully evaluate the relationship between drug exposures and the likelihood of resistance suppression.

Anti-Bacterial Agents↗