The response to antimicrobial therapy in patients with pneumonia was assessed by using a previous... more The response to antimicrobial therapy in patients with pneumonia was assessed by using a previously developed pneumonia scoring system. Patients from two different clinical trials were evaluated. The first group (n = 22) was treated with cefmenoxime. For these patients, doses were adjusted to achieve an area under the plasma concentration-versus-time curve (AUC) above the MIC of 140 microg x h/ml and pneumonia response scores were evaluated retrospectively. The second group (n = 21) were treated with either ciprofloxacin (CIP) or ceftazidime (TAZ) in a randomized clinical trial. Here, doses were adjusted to achieve AUC from 0 to 24 h/MIC values that were > 250 SIT(-1) x h (estimate of the area under the curve of inverse serum inhibitory titer versus time) and pneumonia response scoring was concurrent. In both studies eradication of the pathogen was determined by serial endotracheal cultures and clinical parameters were scored daily. A decrease in total score was indicative of an ...
Antimicrobial agents and chemotherapy, Jul 11, 2016
Infections caused by multidrug-resistantAcinetobacter baumanniiare a major public health problem ... more Infections caused by multidrug-resistantAcinetobacter baumanniiare a major public health problem and polymyxins are often the last line of therapy for recalcitrant infections by such isolates. The pharmacokinetics of the two clinically-used polymyxins, polymyxin B and colistin, differ considerably, since colistin is administered as an inactive prodrug that undergoes slow conversion to colistin. However, the impact of these substantial pharmacokinetic differences on bacterial killing and resistance emergence is poorly understood. We assessed clinically relevant polymyxin B and colistin dosage regimens against one reference and three clinicalA. baumanniistrains in a dynamic one-compartmentin vitromodel. A new mechanism-based pharmacodynamic model was developed to describe and predict the drug concentrations and viable counts of the total and resistant populations. Rapid attainment of target concentrations was shown to be critical for polymyxin-induced bacterial killing. All polymyxin ...
In human liver, the two-electron reduction of quinone compounds such as menadione is catalyzed by... more In human liver, the two-electron reduction of quinone compounds such as menadione is catalyzed by cytosolic carbonyl reductase (CBR) and NAD(P)H:quinone oxidoreductase (NQO1) activities. We assessed the relative contributions of CBR and NQO1 activities to the total menadione reducing capacity in liver cytosols from black (n = 31) and white donors (n = 63). Maximal menadione reductase activities did not differ between black (13.0 ± 5.0 nmol/min.mg), and white donors (11.4 ± 6.6 nmol/min.mg; p = 0.208). In addition, both groups presented similar levels of CBR activities (CBR blacks = 10.9 ± 4.1 nmol/min.mg versus CBR whites = 10.5 ± 5.8 nmol/min.mg; p = 0.708). In contrast, blacks showed higher NQO1 activities (two-fold) than whites (NQO1 blacks = 2.1 ± 3.0 nmol/min.mg versus NQO1 whites =0.9 ± 1.6 nmol/min.mg, p < 0.01). To further explore this disparity, we tested whether NQO1 activity was associated with the common NQO1*2 genetic polymorphism by using paired DNA samples for genotyping. Cytosolic NQO1 activities differed significantly by NQO1 genotype status in whites (NQO1 whites[NQO1*1/*1] = 1.3 ± 1.7 nmol/min.mg versus NQO1 whites[NQO1*1/*2 + NQO1*2/*2] = 0.5 ± 0.7 nmol/min.mg, p < 0.01), but not in blacks (NQO1 blacks[NQO1*1/*1] = 2.6 ± 3.4 nmol/min.mg versus NQO1 blacks[NQO1*1/*2] = 1.1 ± 1.2 nmol/min.mg, p = 0.134). Our findings pinpoint the presence of significant interethnic differences in polymorphic hepatic NQO1 activity.
Proceedings of the Royal Society B: Biological Sciences, 2010
The plantSilene latifoliahas separate sexes and sex chromosomes, and is of interest for studying ... more The plantSilene latifoliahas separate sexes and sex chromosomes, and is of interest for studying the early stages of sex chromosome evolution, especially the evolution of non-recombining regions on the Y chromosome. Hitch-hiking processes associated with ongoing genetic degeneration of the non-recombining Y chromosome are predicted to reduce Y-linked genes' effective population sizes, andS. latifoliaY-linked genes indeed have lower diversity than X-linked ones. We tested whether this represents a true diversity reduction on the Y, versus the alternative possibility, elevated diversity at X-linked genes, by collecting new data on nucleotide diversity for autosomal genes, which had previously been little studied. We find clear evidence that Y-linked genes have reduced diversity. However, another alternative explanation for a low Y effective size is a high variance in male reproductive success. Autosomal genes should then also have lower diversity than expected, relative to the X, ...
In the plant genus Silene, separate sexes and sex chromosomes are believed to have evolved twice.... more In the plant genus Silene, separate sexes and sex chromosomes are believed to have evolved twice. Silene species that are wholly or largely hermaphroditic are assumed to represent the ancestral state from which dioecy evolved. This assumption is important for choice of outgroup species for inferring the genetic and chromosomal changes involved in the evolution of dioecy, but is mainly based on data from a single locus (ITS). To establish the order of events more clearly, and inform outgroup choice, we therefore carried out (i) multi-nuclear-gene phylogenetic analyses of 14 Silene species (including 7 hermaphrodite or gynodioecious species), representing species from both Silene clades with dioecious members, plus a more distantly related outgroup, and (ii) a BayesTraits character analysis of the evolution of dioecy. We confirm two origins of dioecy within this genus in agreement with recent work on comparing sex chromosomes from both clades with dioecious species. We conclude that sex chromosomes evolved after the origin of Silene and within a clade that includes only S. latifolia and its closest relatives. We estimate that sex chromosomes emerged soon after the split with the ancestor of S. viscosa, the probable closest non-dioecious S. latifolia relative among the species included in our study.
We attempted to find a relationship between the microbiological properties of bloodstream isolate... more We attempted to find a relationship between the microbiological properties of bloodstream isolates of methicillin-resistant Staphylococcus aureus (MRSA) and the efficacy of vancomycin in the treatment of bacteremia. Vancomycin susceptibility testing was performed, and bactericidal activity was determined for 30 isolates from 30 different patients with MRSA bacteremia for whom clinical and microbiological outcome data were available. The majority of these patients had been previously enrolled in multicenter prospective studies of MRSA bacteremia refractory to conventional vancomycin therapy. Logistic regression found a statistically significant relationship between treatment success with vancomycin and decreases in both vancomycin MICs (≤0.5 μg/ml versus 1.0 to 2.0 μg/ml; P = 0.02) and degree of killing (reduction in 1og 10 CFU/milliliter) by vancomycin over 72 h of incubation in vitro ( P = 0.03). For MRSA isolates with vancomycin MICs ≤ 0.5 μg/ml, vancomycin was 55.6% successful in...
Despite its recent evolutionary origin, the sex chromosome system of the plant Silene latifolia s... more Despite its recent evolutionary origin, the sex chromosome system of the plant Silene latifolia shows signs of progressive suppression of recombination having created evolutionary strata of different X–Y divergence on sex chromosomes. However, even after 8 years of effort, this result is based on analyses of five sex-linked gene sequences, and the maximum divergence (and thus the age of this plant's sex chromosome system) has remained uncertain. More genes are therefore needed. Here, by segregation analysis of intron size variants (ISVS) and single nucleotide polymorphisms (SNPs), we identify three new Y-linked genes, one being duplicated on the Y chromosome, and test for evolutionary strata. All the new genes have homologs on the X and Y chromosomes. Synonymous divergence estimated between the X and Y homolog pairs is within the range of those already reported. Genetic mapping of the new X-linked loci shows that the map is the same in all three families that have been studied s...
Given a $\mathbb{Z}^d$ homeomorphic action, $\alpha$, on the Cantor set, $X$, we consider the hig... more Given a $\mathbb{Z}^d$ homeomorphic action, $\alpha$, on the Cantor set, $X$, we consider the higher order continuous integer valued dynamical cohomology, $H^*(X,\alpha)$. We also consider the dynamical $K$-theory of the action, the $K$-theory of the crossed product $C^*$-algebra $C(X)\times_{\alpha}\mathbb{Z}^d$. We show that these two invariants are essentially equivalent. We also show that they only take torsion free values. Our work links the two invariants via a third invariant which is based on topological complex $K$-theory evaluated on an associated mapping torus.
Clinical trials show that the area under the inhibitory curve (AUIC) is predictive of antibacteri... more Clinical trials show that the area under the inhibitory curve (AUIC) is predictive of antibacterial killing rates in patients with nosocomial pneumonia and is useful for predicting clinical or microbiological outcomes and making dosage adjustments with b-lactams, quinolones, aminoglycosides, and vancomycin. The AUIC values of two antibiotics are additive, and since antibiotics are often given in combination, determining the AUIC for antibiotic combinations could potentially predict the microbiological outcomes for patients given these combinations. To further address this question, mathematical modeling was used to study in vitro pharmacokinetic and pharmacodynamic interactions of the antimicrobials piperacillin and ciprofloxacin. These agents were also studied in vivo in healthy volunteers. Blood samples were obtained for analysis of serum drug concentrations, and serum inhibitory titers were determined against eight common bacterial pathogens, chosen to reflect the range of MIC values to ciprofloxacin and piperacillin. Additive AUIC relationships predictive of bacterial killing rates were typical in patients given these antibiotics in combination. This article is part of a series of papers presented at a symposium entitled PK/PD relationships to clinical or microbiological outcomes. ''Pharmacodynamics of Antimicrobials'' that was held on 21-23 July 1995 in Québec City, Québec, Canada. This symposium was organized by the Inter-The relationships between AUIC and bacterial eradication national Society for Antiinfective Pharmacology. rate in vivo have been determined for several antibiotics. In Financial support: Bayer Corp. and Lederle Laboratories.
Thrombocytopenia is a common side effect of linezolid, an oxazolidinone antibiotic often used to ... more Thrombocytopenia is a common side effect of linezolid, an oxazolidinone antibiotic often used to treat multidrug-resistant Gram-positive bacterial infections. Various risk factors have been suggested, including linezolid dose and duration of therapy, baseline platelet counts, and renal dysfunction; still, the mechanisms behind this potentially treatment-limiting toxicity are largely unknown. A clinical study was conducted to investigate the relationship between linezolid pharmacokinetics and toxicodynamics and inform strategies to prevent and manage linezolid-associated toxicity. Forty-one patients received 42 separate treatment courses of linezolid (600 mg every 12 h). A new mechanism-based, population pharmacokinetic/toxicodynamic model was developed to describe the time course of plasma linezolid concentrations and platelets. A linezolid concentration of 8.06 mg/liter (101% between-patient variability) inhibited the synthesis of platelet precursor cells by 50%. Simulations predic...
Increasing evidence suggests that colistin monotherapy is suboptimal at currently recommended dos... more Increasing evidence suggests that colistin monotherapy is suboptimal at currently recommended doses. We hypothesized that front-loading provides an improved dosing strategy for polymyxin antibiotics to maximize killing and minimize total exposure. Here, we utilized an in vitro pharmacodynamic model to examine the impact of front-loaded colistin regimens against a high bacterial density (10 8 CFU/ml) of Pseudomonas aeruginosa . The pharmacokinetics were simulated for patients with hepatic (half-life [ t 1/2 ] of 3.2 h) or renal ( t 1/2 of 14.8 h) disease. Front-loaded regimens ( n = 5) demonstrated improvement in bacterial killing, with reduced overall free drug areas under the concentration-time curve ( f AUC) compared to those with traditional dosing regimens ( n = 14) with various dosing frequencies (every 12 h [q12h] and q24h). In the renal failure simulations, front-loaded regimens at lower exposures ( f AUC of 143 mg · h/liter) obtained killing activity similar to that of tradi...
In order to identify patients likely to be infected with resistant bacterial pathogens, analytic ... more In order to identify patients likely to be infected with resistant bacterial pathogens, analytic methods such as standard regression (SR) may be applied to surveillance data to determine patient- and institution-specific factors predictive of an increased MIC. However, the censored nature of MIC data (e.g., MIC ≤ 0.5 mg/liter or MIC > 8 mg/liter) imposes certain limitations on the use of SR. In order to investigate the nature of these limitations, simulations were performed to compare a regression tailored for censored data (censored regression [CR]) and one tailored for an SR. By using a model relating piperacillin-tazobactam MICs against Enterobacter spp. to patient age and hospital bed capacity, 200 simulations of 500 isolates were performed. Various MIC censoring patterns were imposed by using 26 left- or right-censored ( L , R ) pairs (i.e., MICs ≤ 2 mg/liter L [2 L ] or MICs > 2 mg/liter R [2 R ], respectively). Data were fit by CR and SR for which censored MICs were eit...
In an era of rapidly emerging antimicrobial-resistant bacteria, it is critical to understand the ... more In an era of rapidly emerging antimicrobial-resistant bacteria, it is critical to understand the importance of the relationships among drug exposure, duration of therapy, and selection of drug resistance. Herein we describe the results of studies designed to determine the ceftolozane-tazobactam exposure necessary to prevent the amplification of drug-resistant bacterial subpopulations in a hollow-fiber infection model. The challenge isolate was a CTX-M-15-producing Escherichia coli isolate genetically engineered to transcribe a moderate level of bla CTX-M-15 . This organism's bla CTX-M-15 transcription level was confirmed by relative quantitative reverse transcription-PCR (qRT-PCR), β-lactamase hydrolytic assays, and a ceftolozane MIC value of 16 mg/liter. In these studies, the experimental duration (10 days), ceftolozane-tazobactam dose ratio (2:1), and dosing interval (every 8 h) were selected to approximate those expected to be used clinically. The ceftolozane-tazobactam doses...
The pharmacokinetics of an extended-release (XR) formulation of ciprofloxacin has been compared t... more The pharmacokinetics of an extended-release (XR) formulation of ciprofloxacin has been compared to that of the immediate-release (IR) product in healthy volunteers. The only significant difference in pharmacokinetic parameters between the two formulations was seen in the rate constant of absorption, which was approximately 50% greater with the IR formulation. The geometric mean plasma ciprofloxacin concentrations were applied to an in vitro pharmacokinetic-pharmacodynamic model exposing three different clinical strains of Escherichia coli (MICs, 0.03, 0.5, and 2.0 mg/liter) to 24 h of simulated concentrations in plasma. A novel mathematical model was derived to describe the time course of bacterial CFU, including capacity-limited replication and first-order rate of bacterial clearance, and to model the effects of ciprofloxacin concentrations on these processes. A “mixture model” was employed which allowed as many as three bacterial subpopulations to describe the total bacterial load...
Little is known regarding killing activity of vancomycin against methicillin (meticillin)-resista... more Little is known regarding killing activity of vancomycin against methicillin (meticillin)-resistant Staphylococcus aureus (MRSA) in pneumonia since the extent of vancomycin penetration into epithelial lining fluid (ELF) has not been definitively established. We evaluated the impact of the extent of ELF penetration on bacterial killing and resistance by simulating a range of vancomycin exposures (24-h free drug area under the concentration-time curve [ƒAUC 24 ]/MIC) using an in vitro pharmacodynamic model and population-based mathematical modeling. A high-dose, 1.5-g-every-12-h vancomycin regimen according to American Thoracic Society/Infectious Diseases Society of America guidelines (trough concentration, 15 mg/liter) with simulated ELF/plasma penetration of 0, 20, 40, 60, 80, or 100% (ƒAUC 24 /MIC of 0, 70, 140, 210, 280, or 350) was evaluated against two agr -functional, group II MRSA clinical isolates obtained from patients with a bloodstream infection (MIC = 1.0 mg/liter) at a h...
Pharmacokinetic studies were conducted with human immunodeficiency virus-infected patients receiv... more Pharmacokinetic studies were conducted with human immunodeficiency virus-infected patients receiving efavirenz, nelfinavir, or both agents at weeks 4 and 32. Reductions of 25% and 45% were observed in the mean nelfinavir area under the concentration-time curve and minimum concentration of the drug in serum, and there was a 31% more rapid half-life for patients receiving both drugs compared to patients receiving nelfinavir alone. There were no significant differences in efavirenz pharmacokinetics.
Oritavancin is a novel glycopeptide antimicrobial agent with potent in vitro activity against a w... more Oritavancin is a novel glycopeptide antimicrobial agent with potent in vitro activity against a wide variety of gram-positive bacteria, including multidrug-resistant strains of staphylococci and enterococci. A population pharmacokinetic model was developed to describe the disposition of oritavancin with data from a pooled population of phase 1 healthy subjects and phase 2 and 3 patients with complicated skin and skin structure infections or Staphylococcus aureus bacteremia. In addition, the potential influence of factors such as the subject's age, gender, and clinical laboratory measures on oritavancin disposition was evaluated. Oritavancin was administered as both single- and multiple-dose intravenous (i.v.) infusions in fixed doses ranging from 100 to 800 mg or weight-based doses ranging from 0.02 to 10 mg/kg of body weight, with infusion durations ranging from 0.13 to 6.5 h across all studies. The most robust fit to the data ( n = 6,290 oritavancin plasma concentrations from ...
The response to antimicrobial therapy in patients with pneumonia was assessed by using a previous... more The response to antimicrobial therapy in patients with pneumonia was assessed by using a previously developed pneumonia scoring system. Patients from two different clinical trials were evaluated. The first group (n = 22) was treated with cefmenoxime. For these patients, doses were adjusted to achieve an area under the plasma concentration-versus-time curve (AUC) above the MIC of 140 microg x h/ml and pneumonia response scores were evaluated retrospectively. The second group (n = 21) were treated with either ciprofloxacin (CIP) or ceftazidime (TAZ) in a randomized clinical trial. Here, doses were adjusted to achieve AUC from 0 to 24 h/MIC values that were > 250 SIT(-1) x h (estimate of the area under the curve of inverse serum inhibitory titer versus time) and pneumonia response scoring was concurrent. In both studies eradication of the pathogen was determined by serial endotracheal cultures and clinical parameters were scored daily. A decrease in total score was indicative of an ...
Antimicrobial agents and chemotherapy, Jul 11, 2016
Infections caused by multidrug-resistantAcinetobacter baumanniiare a major public health problem ... more Infections caused by multidrug-resistantAcinetobacter baumanniiare a major public health problem and polymyxins are often the last line of therapy for recalcitrant infections by such isolates. The pharmacokinetics of the two clinically-used polymyxins, polymyxin B and colistin, differ considerably, since colistin is administered as an inactive prodrug that undergoes slow conversion to colistin. However, the impact of these substantial pharmacokinetic differences on bacterial killing and resistance emergence is poorly understood. We assessed clinically relevant polymyxin B and colistin dosage regimens against one reference and three clinicalA. baumanniistrains in a dynamic one-compartmentin vitromodel. A new mechanism-based pharmacodynamic model was developed to describe and predict the drug concentrations and viable counts of the total and resistant populations. Rapid attainment of target concentrations was shown to be critical for polymyxin-induced bacterial killing. All polymyxin ...
In human liver, the two-electron reduction of quinone compounds such as menadione is catalyzed by... more In human liver, the two-electron reduction of quinone compounds such as menadione is catalyzed by cytosolic carbonyl reductase (CBR) and NAD(P)H:quinone oxidoreductase (NQO1) activities. We assessed the relative contributions of CBR and NQO1 activities to the total menadione reducing capacity in liver cytosols from black (n = 31) and white donors (n = 63). Maximal menadione reductase activities did not differ between black (13.0 ± 5.0 nmol/min.mg), and white donors (11.4 ± 6.6 nmol/min.mg; p = 0.208). In addition, both groups presented similar levels of CBR activities (CBR blacks = 10.9 ± 4.1 nmol/min.mg versus CBR whites = 10.5 ± 5.8 nmol/min.mg; p = 0.708). In contrast, blacks showed higher NQO1 activities (two-fold) than whites (NQO1 blacks = 2.1 ± 3.0 nmol/min.mg versus NQO1 whites =0.9 ± 1.6 nmol/min.mg, p < 0.01). To further explore this disparity, we tested whether NQO1 activity was associated with the common NQO1*2 genetic polymorphism by using paired DNA samples for genotyping. Cytosolic NQO1 activities differed significantly by NQO1 genotype status in whites (NQO1 whites[NQO1*1/*1] = 1.3 ± 1.7 nmol/min.mg versus NQO1 whites[NQO1*1/*2 + NQO1*2/*2] = 0.5 ± 0.7 nmol/min.mg, p < 0.01), but not in blacks (NQO1 blacks[NQO1*1/*1] = 2.6 ± 3.4 nmol/min.mg versus NQO1 blacks[NQO1*1/*2] = 1.1 ± 1.2 nmol/min.mg, p = 0.134). Our findings pinpoint the presence of significant interethnic differences in polymorphic hepatic NQO1 activity.
Proceedings of the Royal Society B: Biological Sciences, 2010
The plantSilene latifoliahas separate sexes and sex chromosomes, and is of interest for studying ... more The plantSilene latifoliahas separate sexes and sex chromosomes, and is of interest for studying the early stages of sex chromosome evolution, especially the evolution of non-recombining regions on the Y chromosome. Hitch-hiking processes associated with ongoing genetic degeneration of the non-recombining Y chromosome are predicted to reduce Y-linked genes' effective population sizes, andS. latifoliaY-linked genes indeed have lower diversity than X-linked ones. We tested whether this represents a true diversity reduction on the Y, versus the alternative possibility, elevated diversity at X-linked genes, by collecting new data on nucleotide diversity for autosomal genes, which had previously been little studied. We find clear evidence that Y-linked genes have reduced diversity. However, another alternative explanation for a low Y effective size is a high variance in male reproductive success. Autosomal genes should then also have lower diversity than expected, relative to the X, ...
In the plant genus Silene, separate sexes and sex chromosomes are believed to have evolved twice.... more In the plant genus Silene, separate sexes and sex chromosomes are believed to have evolved twice. Silene species that are wholly or largely hermaphroditic are assumed to represent the ancestral state from which dioecy evolved. This assumption is important for choice of outgroup species for inferring the genetic and chromosomal changes involved in the evolution of dioecy, but is mainly based on data from a single locus (ITS). To establish the order of events more clearly, and inform outgroup choice, we therefore carried out (i) multi-nuclear-gene phylogenetic analyses of 14 Silene species (including 7 hermaphrodite or gynodioecious species), representing species from both Silene clades with dioecious members, plus a more distantly related outgroup, and (ii) a BayesTraits character analysis of the evolution of dioecy. We confirm two origins of dioecy within this genus in agreement with recent work on comparing sex chromosomes from both clades with dioecious species. We conclude that sex chromosomes evolved after the origin of Silene and within a clade that includes only S. latifolia and its closest relatives. We estimate that sex chromosomes emerged soon after the split with the ancestor of S. viscosa, the probable closest non-dioecious S. latifolia relative among the species included in our study.
We attempted to find a relationship between the microbiological properties of bloodstream isolate... more We attempted to find a relationship between the microbiological properties of bloodstream isolates of methicillin-resistant Staphylococcus aureus (MRSA) and the efficacy of vancomycin in the treatment of bacteremia. Vancomycin susceptibility testing was performed, and bactericidal activity was determined for 30 isolates from 30 different patients with MRSA bacteremia for whom clinical and microbiological outcome data were available. The majority of these patients had been previously enrolled in multicenter prospective studies of MRSA bacteremia refractory to conventional vancomycin therapy. Logistic regression found a statistically significant relationship between treatment success with vancomycin and decreases in both vancomycin MICs (≤0.5 μg/ml versus 1.0 to 2.0 μg/ml; P = 0.02) and degree of killing (reduction in 1og 10 CFU/milliliter) by vancomycin over 72 h of incubation in vitro ( P = 0.03). For MRSA isolates with vancomycin MICs ≤ 0.5 μg/ml, vancomycin was 55.6% successful in...
Despite its recent evolutionary origin, the sex chromosome system of the plant Silene latifolia s... more Despite its recent evolutionary origin, the sex chromosome system of the plant Silene latifolia shows signs of progressive suppression of recombination having created evolutionary strata of different X–Y divergence on sex chromosomes. However, even after 8 years of effort, this result is based on analyses of five sex-linked gene sequences, and the maximum divergence (and thus the age of this plant's sex chromosome system) has remained uncertain. More genes are therefore needed. Here, by segregation analysis of intron size variants (ISVS) and single nucleotide polymorphisms (SNPs), we identify three new Y-linked genes, one being duplicated on the Y chromosome, and test for evolutionary strata. All the new genes have homologs on the X and Y chromosomes. Synonymous divergence estimated between the X and Y homolog pairs is within the range of those already reported. Genetic mapping of the new X-linked loci shows that the map is the same in all three families that have been studied s...
Given a $\mathbb{Z}^d$ homeomorphic action, $\alpha$, on the Cantor set, $X$, we consider the hig... more Given a $\mathbb{Z}^d$ homeomorphic action, $\alpha$, on the Cantor set, $X$, we consider the higher order continuous integer valued dynamical cohomology, $H^*(X,\alpha)$. We also consider the dynamical $K$-theory of the action, the $K$-theory of the crossed product $C^*$-algebra $C(X)\times_{\alpha}\mathbb{Z}^d$. We show that these two invariants are essentially equivalent. We also show that they only take torsion free values. Our work links the two invariants via a third invariant which is based on topological complex $K$-theory evaluated on an associated mapping torus.
Clinical trials show that the area under the inhibitory curve (AUIC) is predictive of antibacteri... more Clinical trials show that the area under the inhibitory curve (AUIC) is predictive of antibacterial killing rates in patients with nosocomial pneumonia and is useful for predicting clinical or microbiological outcomes and making dosage adjustments with b-lactams, quinolones, aminoglycosides, and vancomycin. The AUIC values of two antibiotics are additive, and since antibiotics are often given in combination, determining the AUIC for antibiotic combinations could potentially predict the microbiological outcomes for patients given these combinations. To further address this question, mathematical modeling was used to study in vitro pharmacokinetic and pharmacodynamic interactions of the antimicrobials piperacillin and ciprofloxacin. These agents were also studied in vivo in healthy volunteers. Blood samples were obtained for analysis of serum drug concentrations, and serum inhibitory titers were determined against eight common bacterial pathogens, chosen to reflect the range of MIC values to ciprofloxacin and piperacillin. Additive AUIC relationships predictive of bacterial killing rates were typical in patients given these antibiotics in combination. This article is part of a series of papers presented at a symposium entitled PK/PD relationships to clinical or microbiological outcomes. ''Pharmacodynamics of Antimicrobials'' that was held on 21-23 July 1995 in Québec City, Québec, Canada. This symposium was organized by the Inter-The relationships between AUIC and bacterial eradication national Society for Antiinfective Pharmacology. rate in vivo have been determined for several antibiotics. In Financial support: Bayer Corp. and Lederle Laboratories.
Thrombocytopenia is a common side effect of linezolid, an oxazolidinone antibiotic often used to ... more Thrombocytopenia is a common side effect of linezolid, an oxazolidinone antibiotic often used to treat multidrug-resistant Gram-positive bacterial infections. Various risk factors have been suggested, including linezolid dose and duration of therapy, baseline platelet counts, and renal dysfunction; still, the mechanisms behind this potentially treatment-limiting toxicity are largely unknown. A clinical study was conducted to investigate the relationship between linezolid pharmacokinetics and toxicodynamics and inform strategies to prevent and manage linezolid-associated toxicity. Forty-one patients received 42 separate treatment courses of linezolid (600 mg every 12 h). A new mechanism-based, population pharmacokinetic/toxicodynamic model was developed to describe the time course of plasma linezolid concentrations and platelets. A linezolid concentration of 8.06 mg/liter (101% between-patient variability) inhibited the synthesis of platelet precursor cells by 50%. Simulations predic...
Increasing evidence suggests that colistin monotherapy is suboptimal at currently recommended dos... more Increasing evidence suggests that colistin monotherapy is suboptimal at currently recommended doses. We hypothesized that front-loading provides an improved dosing strategy for polymyxin antibiotics to maximize killing and minimize total exposure. Here, we utilized an in vitro pharmacodynamic model to examine the impact of front-loaded colistin regimens against a high bacterial density (10 8 CFU/ml) of Pseudomonas aeruginosa . The pharmacokinetics were simulated for patients with hepatic (half-life [ t 1/2 ] of 3.2 h) or renal ( t 1/2 of 14.8 h) disease. Front-loaded regimens ( n = 5) demonstrated improvement in bacterial killing, with reduced overall free drug areas under the concentration-time curve ( f AUC) compared to those with traditional dosing regimens ( n = 14) with various dosing frequencies (every 12 h [q12h] and q24h). In the renal failure simulations, front-loaded regimens at lower exposures ( f AUC of 143 mg · h/liter) obtained killing activity similar to that of tradi...
In order to identify patients likely to be infected with resistant bacterial pathogens, analytic ... more In order to identify patients likely to be infected with resistant bacterial pathogens, analytic methods such as standard regression (SR) may be applied to surveillance data to determine patient- and institution-specific factors predictive of an increased MIC. However, the censored nature of MIC data (e.g., MIC ≤ 0.5 mg/liter or MIC > 8 mg/liter) imposes certain limitations on the use of SR. In order to investigate the nature of these limitations, simulations were performed to compare a regression tailored for censored data (censored regression [CR]) and one tailored for an SR. By using a model relating piperacillin-tazobactam MICs against Enterobacter spp. to patient age and hospital bed capacity, 200 simulations of 500 isolates were performed. Various MIC censoring patterns were imposed by using 26 left- or right-censored ( L , R ) pairs (i.e., MICs ≤ 2 mg/liter L [2 L ] or MICs > 2 mg/liter R [2 R ], respectively). Data were fit by CR and SR for which censored MICs were eit...
In an era of rapidly emerging antimicrobial-resistant bacteria, it is critical to understand the ... more In an era of rapidly emerging antimicrobial-resistant bacteria, it is critical to understand the importance of the relationships among drug exposure, duration of therapy, and selection of drug resistance. Herein we describe the results of studies designed to determine the ceftolozane-tazobactam exposure necessary to prevent the amplification of drug-resistant bacterial subpopulations in a hollow-fiber infection model. The challenge isolate was a CTX-M-15-producing Escherichia coli isolate genetically engineered to transcribe a moderate level of bla CTX-M-15 . This organism's bla CTX-M-15 transcription level was confirmed by relative quantitative reverse transcription-PCR (qRT-PCR), β-lactamase hydrolytic assays, and a ceftolozane MIC value of 16 mg/liter. In these studies, the experimental duration (10 days), ceftolozane-tazobactam dose ratio (2:1), and dosing interval (every 8 h) were selected to approximate those expected to be used clinically. The ceftolozane-tazobactam doses...
The pharmacokinetics of an extended-release (XR) formulation of ciprofloxacin has been compared t... more The pharmacokinetics of an extended-release (XR) formulation of ciprofloxacin has been compared to that of the immediate-release (IR) product in healthy volunteers. The only significant difference in pharmacokinetic parameters between the two formulations was seen in the rate constant of absorption, which was approximately 50% greater with the IR formulation. The geometric mean plasma ciprofloxacin concentrations were applied to an in vitro pharmacokinetic-pharmacodynamic model exposing three different clinical strains of Escherichia coli (MICs, 0.03, 0.5, and 2.0 mg/liter) to 24 h of simulated concentrations in plasma. A novel mathematical model was derived to describe the time course of bacterial CFU, including capacity-limited replication and first-order rate of bacterial clearance, and to model the effects of ciprofloxacin concentrations on these processes. A “mixture model” was employed which allowed as many as three bacterial subpopulations to describe the total bacterial load...
Little is known regarding killing activity of vancomycin against methicillin (meticillin)-resista... more Little is known regarding killing activity of vancomycin against methicillin (meticillin)-resistant Staphylococcus aureus (MRSA) in pneumonia since the extent of vancomycin penetration into epithelial lining fluid (ELF) has not been definitively established. We evaluated the impact of the extent of ELF penetration on bacterial killing and resistance by simulating a range of vancomycin exposures (24-h free drug area under the concentration-time curve [ƒAUC 24 ]/MIC) using an in vitro pharmacodynamic model and population-based mathematical modeling. A high-dose, 1.5-g-every-12-h vancomycin regimen according to American Thoracic Society/Infectious Diseases Society of America guidelines (trough concentration, 15 mg/liter) with simulated ELF/plasma penetration of 0, 20, 40, 60, 80, or 100% (ƒAUC 24 /MIC of 0, 70, 140, 210, 280, or 350) was evaluated against two agr -functional, group II MRSA clinical isolates obtained from patients with a bloodstream infection (MIC = 1.0 mg/liter) at a h...
Pharmacokinetic studies were conducted with human immunodeficiency virus-infected patients receiv... more Pharmacokinetic studies were conducted with human immunodeficiency virus-infected patients receiving efavirenz, nelfinavir, or both agents at weeks 4 and 32. Reductions of 25% and 45% were observed in the mean nelfinavir area under the concentration-time curve and minimum concentration of the drug in serum, and there was a 31% more rapid half-life for patients receiving both drugs compared to patients receiving nelfinavir alone. There were no significant differences in efavirenz pharmacokinetics.
Oritavancin is a novel glycopeptide antimicrobial agent with potent in vitro activity against a w... more Oritavancin is a novel glycopeptide antimicrobial agent with potent in vitro activity against a wide variety of gram-positive bacteria, including multidrug-resistant strains of staphylococci and enterococci. A population pharmacokinetic model was developed to describe the disposition of oritavancin with data from a pooled population of phase 1 healthy subjects and phase 2 and 3 patients with complicated skin and skin structure infections or Staphylococcus aureus bacteremia. In addition, the potential influence of factors such as the subject's age, gender, and clinical laboratory measures on oritavancin disposition was evaluated. Oritavancin was administered as both single- and multiple-dose intravenous (i.v.) infusions in fixed doses ranging from 100 to 800 mg or weight-based doses ranging from 0.02 to 10 mg/kg of body weight, with infusion durations ranging from 0.13 to 6.5 h across all studies. The most robust fit to the data ( n = 6,290 oritavancin plasma concentrations from ...
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Papers by Alan Forrest