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1.  The impact of triclosan on the spread of antibiotic resistance in the environment 
Triclosan (TCS) is a commonly used antimicrobial agent that enters wastewater treatment plants (WWTPs) and the environment. An estimated 1.1 × 105 to 4.2 × 105 kg of TCS are discharged from these WWTPs per year in the United States. The abundance of TCS along with its antimicrobial properties have given rise to concern regarding its impact on antibiotic resistance in the environment. The objective of this review is to assess the state of knowledge regarding the impact of TCS on multidrug resistance in environmental settings, including engineered environments such as anaerobic digesters. Pure culture studies are reviewed in this paper to gain insight into the substantially smaller body of research surrounding the impacts of TCS on environmental microbial communities. Pure culture studies, mainly on pathogenic strains of bacteria, demonstrate that TCS is often associated with multidrug resistance. Research is lacking to quantify the current impacts of TCS discharge to the environment, but it is known that resistance to TCS and multidrug resistance can increase in environmental microbial communities exposed to TCS. Research plans are proposed to quantitatively define the conditions under which TCS selects for multidrug resistance in the environment.
PMCID: PMC4295542  PMID: 25642217
triclosan; antimicrobial resistance; antibiotic resistance; biosolids; wastewater
2.  Low Cardiac Output Secondary to a Malpositioned Umbilical Venous Catheter: Value of Targeted Neonatal Echocardiography 
AJP Reports  2014;4(1):23-28.
Systemic hypotension is common in very low birthweight preterm infants but the nature of the precipitating cause may be unclear. Targeted neonatal echocardiography (TnEcho) is being increasingly used to support hemodynamic decisions in the neonatal intensive care unit (NICU), including identifying impairments in the transitional circulation of preterm infants, providing timely re-evaluation after institution of therapies and evaluating the placement of indwelling catheters. We present a case of a preterm infant with systemic hypotension and low cardiac output secondary to a large transatrial shunt induced by a malpositioned umbilical venous catheter. Repositioning of the line led to resolution of the hemodynamic disturbance and clinical instability, highlighting the utility of TnEcho in the NICU.
PMCID: PMC4078164  PMID: 25032055
targeted neonatal echocardiography; umbilical venous catheter; low cardiac output; atrial septal defect
3.  Patent Ductus Arteriosus Ligation and Adverse Outcomes: Causality or Bias? 
Observational studies have associated patent ductus arteriosus (PDA) ligation in preterm infants with increased chronic lung disease (CLD), retinopathy of prematurity, and neurodevelopmental impairment at long-term follow-up. Although the biological rationale for this association is incompletely understood, there is an emerging secular trend toward a permissive approach to the PDA. However, insufficient adjustment for postnatal, pre-ligation confounders, such as intraventricular hemorrhage and the duration and intensity of mechanical ventilation, suggests the presence of residual bias due to confounding by indication, and obliges caution in interpreting the ligation-morbidity relationship. A period of conservative management after failure of medical PDA closure may be considered to reduce the number of infants treated with surgery. Increased mortality and CLD in infants with persistent symptomatic PDA suggests that surgical ligation remains an important treatment modality for preterm infants.
PMCID: PMC4089132  PMID: 25024972
Chronic lung disease; confounding by indication; conservative; mortality; neurodevelopmental impairment; neurosensory impairment; preterm; retinopathy of prematurity
4.  Should TED Talks Be Teaching Us Something? 
PMCID: PMC4140479  PMID: 25147385
5.  Towards rational management of the patent ductus arteriosus: the need for disease staging 
Perspective on the review by Bose and Laughon (see page 498)
PMCID: PMC2675381  PMID: 17951547
ductal ligation; indometacin; patent ductus arteriosus; staging
6.  GF120918 as a chemical Abcg2 knockout model to study nitrofurantoin transfer into milk 
Genetic knockout mice studies suggested ABCG2/Abcg2 translocates nitrofurantoin at the mammary – blood barrier resulting in drug accumulation in milk. The purpose of this study was to establish the role of Abcg2 in nitrofurantoin accumulation in rat milk using GF120918 as a “chemical knockout” equivalent. The inhibitory effect of GF120918 was verified in MDCKII cells stably expressing rat Abcg2 with Hoechst 33342 and nitrofurantoin flux in transwells. Nitrofurantoin was infused (0.5mg/h) in the absence and presence GF120918 (10mg/kg in DMSO) to Sprague Dawley lactating female rats using a balanced crossover design. Administration of GF120918 increased nitrofurantoin concentration in serum (from 443±51 to 650±120ng/ml) and decreased concentration in milk (from 18.1±0.9 to 1.9±1.2μg/ml), resulting in corresponding mean values for M/S of 41.4±19.1 vs. 3.04±2.27 in the absence and presence of GF120918 (p<0.05), respectively. There was a decrease in systemic clearance with GF120918 (2.8±0.5 L/h/kg) compared to vehicle controls (4.1±0.5L/h/kg; p<0.05). Western blot analysis revealed good expression of Abcg2 and no P-gp expression in mammary gland while immunohistochemistry confirmed the apical expression of Abcg2 in lactating mammary gland epithelia. Nitrofurantoin active transport into rat milk can be inhibited by GF120918 resulting in a 10-fold lower M/S. Although GF120918 inhibits both Abcg2 and P-gp, the high expression of Abcg2 and the absence of detectable P-gp expression in lactating mammary gland validates an important role for Abcg2 in nitrofurantoin accumulation in rat milk. GF120918 is particularly useful as a rat “chemical knockout” model to establish ABCG2’s role in drug transfer into milk during breastfeeding.
PMCID: PMC2837273  PMID: 18799806
7.  Localization and Functional Characterization of the Rat Oatp4c1 Transporter in an In Vitro Cell System and Rat Tissues 
PLoS ONE  2012;7(6):e39641.
The organic anion transporting polypeptide 4c1 (Oatp4c1) was previously identified as a novel uptake transporter predominantly expressed at the basolateral membrane in the rat kidney proximal tubules. Its functional role was suggested to be a vectorial transport partner of an apically-expressed efflux transporter for the efficient translocation of physiological substrates into urine, some of which were suggested to be uremic toxins. However, our in vitro studies with MDCKII cells showed that upon transfection rat Oatp4c1 polarizes to the apical membrane. In this report, we validated the trafficking and function of Oatp4c1 in polarized cell systems as well as its subcellular localization in rat kidney. Using several complementary biochemical, molecular and proteomic methods as well as antibodies amenable to immunohistochemistry, immunofluorescence, and immunobloting we investigated the expression pattern of Oatp4c1 in polarized cell systems and in the rat kidney. Collectively, these data demonstrate that rat Oatp4c1 traffics to the apical cell surface of polarized epithelium and localizes primarily in the proximal straight tubules, the S3 fraction of the nephron. Drug uptake studies in Oatp4c1-overexpressing cells demonstrated that Oatp4c1-mediated estrone-3-sulfate (E3S) uptake was pH-dependent and ATP-independent. These data definitively demonstrate the subcellular localization and histological location of Oatp4c1 and provide additional functional evidence that reconciles expression-function reports found in the literature.
PMCID: PMC3387246  PMID: 22768102
8.  Lessons learned during implementation of therapeutic hypothermia for neonatal hypoxic ischemic encephalopathy in a regional transport program in Ontario 
Paediatrics & Child Health  2011;16(3):153-156.
Therapeutic hypothermia (TH) is the first intervention to consistently show improved neurological outcomes in neonates with hypoxic ischemic encephalopathy (HIE). Since the recent introduction of TH for HIE in many centres, reviews of practices during the implementation of TH in Canada have not been published.
To determine if eligible neonates are being offered TH and to identify any barriers to the effective implementation of TH.
A retrospective review of neonates referred to a regional tertiary centre at a gestational age of 35 weeks or more with HIE was conducted.
Among 41 neonates referred, 29 (71%) were eligible for TH; among eligible patients, five were moribund and excluded, and TH was initiated in 16 (67%) of the remaining 24. Reasons for not cooling in eight eligible patients included a delay in referral (n=5, median age at referral was 14 h) and a failure to recognize the severity of HIE (n=3). Among cooled patients, median times were the following: 116 min for age at referral; 80 min for time from referral to transport team arrival; and 358 min for age at initiation of cooling. Seven (44%) patients had cooling initiated after 6 h of age.
A significant proportion of eligible patients were not offered TH, and in many cooled patients, initiation of cooling was delayed beyond the recommended 6 h. For eligible patients to benefit from TH, it is imperative that all birthing centres be made aware that TH is now widely available as an important treatment option, but also that TH is a time-sensitive therapy requiring rapid identification and referral. In the region studied, for eligible patients, referring hospitals should initiate passive cooling before arrival of the transport team. Referring hospitals should be prepared to provide early, yet safe initiation of passive cooling by having the appropriate equipment, and having staff trained in the use and monitoring of rectal temperatures.
PMCID: PMC3077305  PMID: 22379379
Hypoxic ischemic encephalopathy; Infant; Newborn; Therapeutic hypothermia
9.  Expanding the Utility of the Biphasic Alcohol Effects Scale (BAES) and Initial Psychometric Support for the Brief-BAES (B-BAES) 
The utility of one of the most widely used subjective alcohol assessment tools, the Biphasic Alcohol Effects Scale (BAES) has been somewhat limited based on lack of psychometric studies in large and diverse samples, a range of alcohol doses, the length of the measure, and the original instructional set which precluded baseline measurement and disclosed to subjects that they received alcohol.
The current study investigated the factor structure of the BAES with a modified instructional set at pre-drink baseline and after consumption of various doses of alcohol, in a sample of 190 men and women heavy and light social drinkers. This study also tested the psychometric properties of a brief BAES (B-BAES).
Results demonstrated robust support of the stimulant and sedative constructs across all conditions, and demonstrated strong psychometric support for a six-item B-BAES.
This is the first comprehensive study to expand the utility of the BAES by instructional set, baseline measurement, at various alcohol doses, and by drinking history and sex. In addition, the introduction of the B-BAES may further increase the utility of this scale, particularly in paradigms with repeated measurement or time constraints.
PMCID: PMC2856649  PMID: 19320625
Biphasic Alcohol Effects Scale (BAES); Brief-BAES (B-BAES); alcohol stimulation; subjective effects; psychometric properties
10.  Mechanism-Based Pharmacodynamic Models of Fluoroquinolone Resistance in Staphylococcus aureus 
Pharmacodynamic modeling from earlier experiments in which two ciprofloxacin-susceptible Staphylococcus aureus strains and their corresponding resistant grlA mutants were exposed to a series of ciprofloxacin (J. J. Campion, P. J. McNamara, and M. E. Evans, Antimicrob. Agents Chemother. 49:209-219, 2005) and levofloxacin (J. J. Campion et al., Antimicrob. Agents Chemother. 49:2189-2199, 2005) pharmacokinetic profiles in an in vitro system indicated that the subpopulation-specific estimated maximal killing rate constants were similar for both agents, suggesting a common mechanism of action. We propose two novel pharmacodynamic models that assign mechanisms of action to fluoroquinolones (growth inhibition or death stimulation) and compare the abilities of these models and two other maximum effect models (net effect and MIC based) to describe and predict the changes in the population dynamics observed during our previous in vitro system experiments with ciprofloxacin. A high correlation between predicted and observed viable counts was observed for all models, but the best fits, as assessed by diagnostic tests, and the most precise parameter estimates were obtained with the growth inhibition and net effect models. All models, except the death stimulation model, correctly predicted that resistant subpopulations would not emerge when a high-density culture was exposed to a high initial concentration designed to rapidly eradicate low-level-resistant grlA mutants. Additional experiments are necessary to elucidate which of the proposed mechanistic models best characterizes the antibacterial effects of fluoroquinolone antimicrobial agents.
PMCID: PMC1563538  PMID: 16940088
11.  Pharmacodynamic Modeling of the Evolution of Levofloxacin Resistance in Staphylococcus aureus 
Previously, we demonstrated the importance of low-level-resistant variants to the evolution of resistance in Staphylococcus aureus exposed to ciprofloxacin in an in vitro system and developed a pharmacodynamic model which predicted the emergence of resistance. Here, we examine and model the evolution of resistance to levofloxacin in S. aureus exposed to simulated levofloxacin pharmacokinetic profiles. Enrichment of subpopulations with mutations in grlA and low-level resistance varied with levofloxacin exposure. A regimen producing average steady-state concentrations (Cavg ss) just above the MIC selected grlA mutants with up to 16-fold increases in the MIC and often additional mutations in grlA/grlB and gyrA. A regimen providing Cavg ss between the MIC and the mutant prevention concentration (MPC) suppressed bacterial numbers to the limit of detection and prevented the appearance of bacteria with additional mutations or high-level resistance. Regimens producing Cavg ss above the MPC appeared to eradicate low-level-resistant variants in the cultures and prevent the emergence of resistance. There was no relationship between the time concentrations remained between the MIC and the MPC and the degree of resistance or the presence or type of mutations that appeared in grlA/B or gyrA. Our pharmacodynamic model described the growth and levofloxacin killing of the parent strains and the most resistant grlA mutants in the starting cultures and correctly predicted conditions that enrich subpopulations with low-level resistance. These findings suggest that the pharmacodynamic model has general applicability for describing fluoroquinolone resistance in S. aureus and further demonstrate the importance of low-level-resistant variants to the evolution of resistance.
PMCID: PMC1140504  PMID: 15917512
12.  Role of P-Glycoprotein in Distribution of Nelfinavir across the Blood-Mammary Tissue Barrier and Blood-Brain Barrier 
As a first approach in understanding the possible efficacy and toxicity of human immunodeficiency virus protease inhibitors during breast feeding, the milk-to-plasma ratio of nelfinavir was determined in lactating rats. The milk-to-plasma ratio of nelfinavir was determined to be 0.56 ± 0.10 (means ± standard deviations). Western blotting indicated that P-glycoprotein is expressed in rat mammary and brain tissue; however, the multidrug-resistant modulator GF120918 showed a significant effect only at the blood-brain barrier and not at the mammary-epithelial tissue barrier.
PMCID: PMC1068594  PMID: 15793156
13.  Pharmacodynamic Modeling of Ciprofloxacin Resistance in Staphylococcus aureus 
Three pharmacodynamic models of increasing complexity, designed for two subpopulations of bacteria with different susceptibilities, were developed to describe and predict the evolution of resistance to ciprofloxacin in Staphylococcus aureus by using pharmacokinetic, viable count, subpopulation, and resistance mechanism data obtained from in vitro system experiments. A two-population model with unique growth and killing rate constants for the ciprofloxacin-susceptible and -resistant subpopulations best described the initial killing and subsequent regrowth patterns observed. The model correctly described the enrichment of subpopulations with low-level resistance in the parent cultures but did not identify a relationship between the time ciprofloxacin concentrations were in the mutant selection window (the interval between the MIC and the mutant prevention concentration) and the enrichment of these subpopulations. The model confirmed the importance of resistant variants to the emergence of resistance by successfully predicting that resistant subpopulations would not emerge when a low-density culture, with a low probability of mutants, was exposed to a clinical dosing regimen or when a high-density culture, with a higher probability of mutants, was exposed to a transient high initial concentration designed to rapidly eradicate low-level resistant grlA mutants. The model, however, did not predict or explain the origin of variants with higher levels of resistance that appeared and became the predominant subpopulation during some experiments or the persistence of susceptible bacteria in other experiments where resistance did not emerge. Continued evaluation of the present two-population pharmacodynamic model and development of alternative models is warranted.
PMCID: PMC538881  PMID: 15616298
14.  Evolution of Ciprofloxacin-Resistant Staphylococcus aureus in In Vitro Pharmacokinetic Environments 
Antimicrobial Agents and Chemotherapy  2004;48(12):4733-4744.
The development of novel antibacterial agents is decreasing despite increasing resistance to presently available agents among common pathogens. Insights into relationships between pharmacodynamics and resistance may provide ways to optimize the use of existing agents. The evolution of resistance was examined in two ciprofloxacin-susceptible Staphylococcus aureus strains exposed to in vitro-simulated clinical and experimental ciprofloxacin pharmacokinetic profiles for 96 h. As the average steady-state concentration (Cavg ss) increased, the rate of killing approached a maximum, and the rate of regrowth decreased. The enrichment of subpopulations with mutations in grlA and low-level ciprofloxacin resistance also varied depending on the pharmacokinetic environment. A regimen producing values for Cavg ss slightly above the MIC selected resistant variants with grlA mutations that did not evolve to higher levels of resistance. Clinical regimens which provided values for Cavg ss intermediate to the MIC and mutant prevention concentration (MPC) resulted in the emergence of subpopulations with gyrA mutations and higher levels of resistance. A regimen producing values for Cavg ss close to the MPC selected grlA mutants, but the appearance of subpopulations with higher levels of resistance was diminished. A regimen designed to maintain ciprofloxacin concentrations entirely above the MPC appeared to eradicate low-level resistant variants in the inoculum and prevent the emergence of higher levels of resistance. There was no relationship between the time that ciprofloxacin concentrations remained between the MIC and the MPC and the degree of resistance or the presence or type of ciprofloxacin-resistance mutations that appeared in grlA or gyrA. Regimens designed to eradicate low-level resistant variants in S. aureus populations may prevent the emergence of higher levels of fluoroquinolone resistance.
PMCID: PMC529206  PMID: 15561851
15.  Acyclovir, Ganciclovir, and Zidovudine Transfer into Rat Milk 
Treatment with antiviral agents that accumulate in breast milk may offer a novel approach to reduce the rates of vertical transmission of important viruses and the risk of clinical illness in suckling neonates. The present study evaluated the extent and mechanism of transfer of three antiviral nucleoside analogues into milk in a lactating rat model system. Acyclovir (0.26 mg/h), ganciclovir (0.13 mg/h), and zidovudine (0.5 mg/h) were each infused to steady-state concentrations in six rats 15 to 16 days postpartum. The observed ratios of the concentrations in milk to the concentrations in serum (observed milk-to-serum ratio), calculated from the ratio of the steady-state concentration in serum to the steady-state concentration in milk, determined the extent of drug transfer into milk. To identify the mechanism of transfer into milk, the observed milk-to-serum ratio was compared to a predicted milk-to-serum ratio estimated from an in vitro passive diffusion model of transfer of each drug into milk. High-pressure liquid chromatography methods determined milk and serum drug concentrations. Mean ± standard deviation observed milk-to-serum ratios for acyclovir, ganciclovir, and zidovudine were 5.1 ± 1.4, 1.6 ± 0.33, and 1.0 ± 0.29, respectively, compared with their corresponding predicted ratios of 1.1, 0.85, and 0.71. These results suggest that acyclovir accumulates in milk due to active transport mechanisms, while passive diffusion processes govern the transfer of both ganciclovir and zidovudine into milk. The presence of all three antiviral drugs in milk and the potential for active drug transfer into milk warrants further investigation of the accumulation of other antiviral drugs in milk and their therapeutic benefits in reducing the vertical transmission of viruses and clinical sequelae in the breast-feeding infant.
PMCID: PMC127258  PMID: 12019097
16.  GF120918, a P-Glycoprotein Modulator, Increases the Concentration of Unbound Amprenavir in the Central Nervous System in Rats 
The goal of this study was to determine the distribution of unbound amprenavir in the central nervous system (CNS) of rats. The concentration of unbound amprenavir in the extracellular fluid of the brain and the blood was examined in the presence and absence of the MDR modulator GF120918 by microdialysis. The brain-to-blood ratio of amprenavir in the absence and presence of GF120918 was found to be significantly different (P < 0.003; 0.076 and 0.617, respectively). The use of the MDR modulator GF120918 could potentially increase the penetration of human immunodeficiency virus protease inhibitors into the CNS.
PMCID: PMC127290  PMID: 12069991
17.  Protein binding predictions in infants 
AAPS PharmSci  2002;4(1):19-26.
Plasma binding protein levels are lower in the newborn than in the adult and gradually increase with age. At birth, human serum albumin (HSA) concentrations are close to adult levels (75%–80%), while alpha 1-acid glycoprotein (AAG) is initially half the adult concentration. As a result, the extent of drug binding to HSA is closer to that of the adult than are those drugs bound largely to AAG. A model that incorporates the fraction unbound in adults and the ratio of the binding protein concentration between infants and adults successfully predicted the fraction unbound in infants and children.
PMCID: PMC2751289  PMID: 12049488
plasma protein binding; fraction unbound; infants; children; newborn; albumin; alpha 1-acid glycoprotein

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