Omar Vesga - Academia.edu (original) (raw)
Papers by Omar Vesga
Antimicrobial Agents and Chemotherapy, Apr 1, 2000
The in vivo pharmacodynamic activities of two glycylcyclines (GAR-936 and WAY 152,288) were asses... more The in vivo pharmacodynamic activities of two glycylcyclines (GAR-936 and WAY 152,288) were assessed in an experimental murine thigh infection model in neutropenic mice. Mice were infected with one of several strains of Streptococcus pneumoniae, Staphylococcus aureus, Escherichia coli, or Klebsiella pneumoniae. Most infections were treated with a twice-daily dosing schedule, with administration of 0.75 to 192 mg of GAR-936 or WAY 152,288 per kg of body weight. A maximum-effect dose-response model was used to calculate the dose that produced a net bacteriostatic effect over 24 h of therapy. This dose was called the bacteriostatic dose. More extensive dosing studies were performed with S. pneumoniae 1199, E. coli ATCC 25922, and K. pneumoniae ATCC 43816, with doses being given as one, two, four, or eight equal doses over a period of 24 h. The dosing schedules were designed in order to minimize the interrelationship between the various pharmacokinetic and pharmacodynamic parameters studied. These parameters were time above 0.03 to 32 times the MIC, area under the concentration-time curve (AUC), and maximum concentration of drug in serum (C max). The bacteriostatic dose remained essentially the same, irrespective of the dosing frequency, for S. pneumoniae 1199 (0.3 to 0.9 mg/kg/day). For E. coli ATCC 25922 and K. pneumoniae ATCC 43816, however, more frequent dosing led to lower bacteriostatic doses. Pharmacokinetic studies demonstrated dose-dependent elimination half-lives of 1.05 to 2.34 and 1.65 to 3.36 h and serum protein bindings of 59 and 71% for GAR-936 and WAY 152,288, respectively. GAR-936 and WAY 152,288 were similarly effective against the microorganisms studied, with small differences in maximum effect and 50% effective dose. The glycylcyclines were also similarly effective against tetracycline-sensitive and tetracycline-resistant bacteria. Time above a certain factor (range, 0.5 to 4 times) of the MIC was a better predictor of in vivo efficacy than C max or AUC for most organism-drug combinations. The results demonstrate that in order to achieve 80% maximum efficacy, the concentration of unbound drug in serum should be maintained above the MIC for at least 50% of the time for GAR-936 and for at least 75% of the time for WAY 152,288. The results of these experiments will aid in the rational design of dose-finding studies for these glycylcyclines in humans.
The Journal of Infectious Diseases, Mar 1, 1996
Abstracts of the Interscience Conference on Antimicrobial Agents & Chemotherapy, Dec 6, 1996
Antimicrobial Agents and Chemotherapy, 2000
The in vivo pharmacodynamic activities of two glycylcyclines (GAR-936 and WAY 152,288) were asses... more The in vivo pharmacodynamic activities of two glycylcyclines (GAR-936 and WAY 152,288) were assessed in an experimental murine thigh infection model in neutropenic mice. Mice were infected with one of several strains of Streptococcus pneumoniae , Staphylococcus aureus , Escherichia coli , or Klebsiella pneumoniae . Most infections were treated with a twice-daily dosing schedule, with administration of 0.75 to 192 mg of GAR-936 or WAY 152,288 per kg of body weight. A maximum-effect dose-response model was used to calculate the dose that produced a net bacteriostatic effect over 24 h of therapy. This dose was called the bacteriostatic dose. More extensive dosing studies were performed with S. pneumoniae 1199, E. coli ATCC 25922, and K. pneumoniae ATCC 43816, with doses being given as one, two, four, or eight equal doses over a period of 24 h. The dosing schedules were designed in order to minimize the interrelationship between the various pharmacokinetic and pharmacodynamic parameters...
Antimicrobial Agents and Chemotherapy, 2001
One of the most challenging issues in the design of phase II/III clinical trials of antimicrobial... more One of the most challenging issues in the design of phase II/III clinical trials of antimicrobial agents is dose selection. The choice is often based on preclinical data from pharmacokinetic (PK) studies with animals and healthy volunteers but is rarely linked directly to the target organisms except by the MIC, an in vitro measure of antimicrobial activity with many limitations. It is the thesis of this paper that rational dose-selection decisions can be made on the basis of the pharmacodynamics (PDs) of the test agent predicted by a mathematical model which uses four data sets: (i) the distribution of MICs for clinical isolates, (ii) the distribution of the values of the PK parameters for the test drug in the population, (iii) the PD target(s) developed from animal models of infection, and (iv) the protein binding characteristics of the test drug. In performing this study with the new anti-infective agent evernimicin, we collected a large number ( n = 4,543) of recent clinical isol...
Antimicrobial Agents and Chemotherapy
Combination therapy with ampicillin plus ceftriaxone (AMP+CRO) is the first-line therapy for trea... more Combination therapy with ampicillin plus ceftriaxone (AMP+CRO) is the first-line therapy for treating severe infections due to Enterococcus faecalis . However, the pharmacokinetic/pharmacodynamic (PK/PD) index linked to the in vivo efficacy of the combination is not yet defined, hindering dose optimization in the clinic.
Revista Vitae, 2017
Antecedentes: Existen múltiples modelos animales de diabetes, pero todavía no se ha validado uno ... more Antecedentes: Existen múltiples modelos animales de diabetes, pero todavía no se ha validado uno útil para determinar la farmacodinamia de medicamentos. Objetivos. Usar el modelo de inducción de diabetes mediante estreptozotocina equilibrada en ratones no emparentados, para determinar de forma precisa y reproducible la farmacodinamia de insulina regular. Métodos. En ratones machos no emparentados de aproximadamente 37 g, se inyectó una dosis intraperitoneal de 150 mg/kg de una solución equilibrada de estreptozotocina. La glucemia (mg/dL) se midió a los 0, 7, 9, 14, 16, 17 y 18 días post-inducción. Una vez los ratones alcanzaron glucemias >300 mg/dL, se determinó la eficacia hipoglucemiante de insulina regular en tres experimentos independientes. El rango de dosis fue 0,25 UI/kg a 4 UI/kg. Una ecuación de decaimiento exponencial de dos parámetros se ajustó a los datos. Resultados. Al día 18, el modelo tuvo una efectividad del 80% para producir diabetes (glucemia 446 ± 59 mg/dL), con mortalidad de sólo 2%. El coeficiente de variación intra e interexperimento fue ≤13%. Los parámetros farmacodinámicos de insulina fueron indistinguibles después de tres experimentos (P=0,32). La magnitud del efecto máximo fue-374 ± 30,7 mg/dL y la dosis efectiva 50 fue 1,34 ± 0,2 UI/kg. Conclusión. El modelo de diabetes inducida por estreptozotocina equilibrada permitió determinar de manera reproducible la farmacodinamia de la insulina regular.
PLOS ONE, Sep 29, 2021
Timely and accurate diagnostics are essential to fight the COVID-19 pandemic, but no test satisfi... more Timely and accurate diagnostics are essential to fight the COVID-19 pandemic, but no test satisfies both conditions. Dogs can scent-identify the unique odors of volatile organic compounds generated during infection by interrogating specimens or, ideally, the body of a patient. After training 6 dogs to detect SARS-CoV-2 by scent in human respiratory secretions (in vitro diagnosis), we retrained 5 of them to search and find the infection by scenting the patient directly (in vivo screening). Then, efficacy trials were designed to compare the diagnostic performance of the dogs against that of the rRT-PCR in 848 human subjects: 269 hospitalized patients (COVID-19 prevalence 30.1%), 259 hospital staff (prevalence 2.7%), and 320 government employees (prevalence 1.25%). The limit of detection in vitro was lower than 10 −12 copies ssRNA/mL. During in vivo efficacy experiments, our 5 dogs detected 92 COVID-19 positive patients among the 848 study subjects. The alert (lying down) was immediate, with 95.2% accuracy and high sensitivity (95.9%; 95% C.I. 93.6-97.4), specificity (95.1%; 94.4-95.8), positive predictive value (69.7%; 65.9-73.2), and negative predictive value (99.5%; 99.2-99.7) in relation to rRT-PCR. Seventy-five days after finishing in vivo efficacy experiments, a real-life study (in vivo effectiveness) was executed among the riders of the Metro System of Medellin, deploying the human-canine teams without previous training or announcement. Three dogs were used to examine the scent of 550 volunteers who agreed to participate, both in test with canines and in rRT-PCR testing. Negative predictive value remained at 99.0% (95% C.I. 98.3-99.4), but positive predictive value dropped to 28.2% (95% C.I. 21.1-36.7). Canine scent-detection in vivo is a highly accurate screening test for COVID-19, and it detects more than 99% of infected individuals independent of key variables, such as disease prevalence, time post-exposure, or presence of symptoms. Additional training is required to teach the dogs to ignore odoriferous contamination under real-life conditions.
Background: FCZ continues to be one of the first choices for the treatment of systemic candidiasi... more Background: FCZ continues to be one of the first choices for the treatment of systemic candidiasis. Most generics of some antibacterials fail TE despite their pharmaceutical equivalence (PE), but there are no data with antifungals. We standardized a model of fungemia to test the TE of FCZ generics. Methods: the model of disseminated candidiasis by tail-vein inoculation in neutropenic MPF Udea:ICR(CD-2) male mice was standardized testing 4 clinical strains of C. albicans (blood isolates), incubation temperature (25°C vs. 37°C), inoculum (5 and 6 log CFU/ mL), target organ (kidneys, liver, spleen, blood), time to begin treatment (2h vs. 5h), and duration of therapy (24h vs. 48h). Two generics were compared with the innovator using doses from 1 to 64 mg/kg/d q6h SC. Effect was calculated by subtracting CFU of treated animals from untreated controls. Kidneys were homogenized and plated on SDA for CFU count. Data were fitted to Hill's model by nonlinear regression ands compared by cu...
Biomédica : revista del Instituto Nacional de Salud, 2005
The evolution and molecular mechanisms of vancomycin resistance in Staphylococcus aureus were rev... more The evolution and molecular mechanisms of vancomycin resistance in Staphylococcus aureus were reviewed. Case reports and research studies on biochemestry, electron microscopy and molecular biology of Staphylococcus aureus were selected from Medline database and summarized in the following review. After almost 40 years of successful treatment of S. aureus with vancomycin, several cases of clinical failures have been reported (since 1997). S. aureus strains have appeared with intermediate susceptibility (MIC 8-16 microg/ml), as well as strains with heterogeneous resistance (global MIC < or =4 microg/ml), but with subpopulations of intermediate susceptibility. In these cases, resistance is mediated by cell wall thickening with reduced cross linking. This traps the antibiotic before it reaches its major target, the murein monomers in the cell membrane. In 2002, a total vancomycin resistant strain (MIC…
Acta méd. colomb, 1994
Base de dados : LILACS. Pesquisa : 292816 [Identificador único]. Referências encontradas : 1 [ref... more Base de dados : LILACS. Pesquisa : 292816 [Identificador único]. Referências encontradas : 1 [refinar]. Mostrando: 1 .. 1 no formato [Detalhado]. página 1 de 1, 1 / 1, LILACS, seleciona. para imprimir. Fotocópia. experimental, Documentos relacionados. Id: 292816. ...
BMC Microbiology, 2013
Background Antibiotic therapy can select for small colony variants of Staphylococcus aureus that ... more Background Antibiotic therapy can select for small colony variants of Staphylococcus aureus that are more resistant to antibiotics and can result in persistent infections, necessitating the development of more effective antimicrobial strategies to combat small colony variant infections. Photodynamic therapy is an alternative treatment approach which utilises light in combination with a light-activated antimicrobial agent to kill bacteria via a non-specific mechanism of action. In this study, we investigated whether the combination of 665 nm laser light and the light-activated antimicrobial agent methylene blue was able to successfully kill S. aureus small colony variants. S. aureus and isogenic stable small colony variant were exposed to varying doses (1.93 to 9.65 J/cm2) of 665 nm laser light in the presence of varying concentrations (1 to 20 μM) of methylene blue. Results The combination of 665 nm laser light and methylene blue was found to be an effective strategy for the killing...
Antimicrobial Agents and Chemotherapy, 2012
ABSTRACTAnimal models of infection have been used to demonstrate the therapeutic failure of “bioe... more ABSTRACTAnimal models of infection have been used to demonstrate the therapeutic failure of “bioequivalent” generic products, but their applicability for this purpose requires the accurate identification of those products that are truly bioequivalent. Here, we present data comparing one intravenous generic product of metronidazole with the innovator product in a neutropenic mouse thigh anaerobic infection model. Simultaneous experiments allowed comparisons (generic versus innovator) of potency and the concentration of the active pharmaceutical ingredient (API), analytical chemistry (liquid chromatography/mass spectrometry [LC/MS]),in vitrosusceptibility testing, single-dose serum pharmacokinetics (PK) in infected mice, andin vivopharmacodynamics (PD) againstBacteroides fragilisATCC 25825 in synergy withEscherichia coliSIG-1 in the neutropenic mouse thigh anaerobic infection model. The Hill dose-response model followed by curve-fitting analysis was used to calculate and compare prima...
Application of microbiological assay to determine pharmaceutical equivalence of generic intraveno... more Application of microbiological assay to determine pharmaceutical equivalence of generic intravenous antibiotics
PLOS ONE, 2020
The combination of ampicillin (AMP) and ceftriaxone (CRO) is considered synergistic against Enter... more The combination of ampicillin (AMP) and ceftriaxone (CRO) is considered synergistic against Enterococcus faecalis based on in vitro tests and the rabbit endocarditis model, however, in vitro assays are limited by the use of fixed antibiotic concentrations and the rabbit model by poor bacterial growth, high variability, and the use of point dose-effect estimations, that may lead to inaccurate assessment of antibiotic combinations and hinder optimal translation. Here, we tested AMP+CRO against two strains of E. faecalis and one of E. faecium in an optimized mouse thigh infection model that yields high bacterial growth and allows to define the complete dose-response relationship. By fitting Hill’s sigmoid model and estimating the parameters maximal effect (Emax) and effective dose 50 (ED50), the following interactions were defined: synergism (Emax increase ≥2 log10 CFU/g), antagonism (Emax reduction ≥1 log10 CFU/g) and potentiation (ED50 reduction ≥50% without changes in Emax). AMP mon...
PLOS ONE, 2021
Timely and accurate diagnostics are essential to fight the COVID-19 pandemic, but no test satisfi... more Timely and accurate diagnostics are essential to fight the COVID-19 pandemic, but no test satisfies both conditions. Dogs can scent-identify the unique odors of volatile organic compounds generated during infection by interrogating specimens or, ideally, the body of a patient. After training 6 dogs to detect SARS-CoV-2 by scent in human respiratory secretions (in vitro diagnosis), we retrained 5 of them to search and find the infection by scenting the patient directly (in vivo screening). Then, efficacy trials were designed to compare the diagnostic performance of the dogs against that of the rRT-PCR in 848 human subjects: 269 hospitalized patients (COVID-19 prevalence 30.1%), 259 hospital staff (prevalence 2.7%), and 320 government employees (prevalence 1.25%). The limit of detection in vitro was lower than 10−12 copies ssRNA/mL. During in vivo efficacy experiments, our 5 dogs detected 92 COVID-19 positive patients among the 848 study subjects. The alert (lying down) was immediate,...
Molecular tests for viral diagnostics are essential to confront the COVID-19 pandemic, but their ... more Molecular tests for viral diagnostics are essential to confront the COVID-19 pandemic, but their production and distribution cannot satisfy the current high demand. Early identification of infected people and their contacts is the key to being able to isolate them and prevent the dissemination of the pathogen; unfortunately, most countries are unable to do this due to the lack of diagnostic tools. Dogs can identify, with a high rate of precision, unique odors of volatile organic compounds generated during an infection; as a result, dogs can diagnose infectious agents by smelling specimens and, sometimes, the body of an infected individual. We trained six dogs of three different breeds to detect SARS-CoV-2 in respiratory secretions of infected patients and evaluated their performance experimentally, comparing it against the gold standard (rRT-PCR). Here we show that viral detection takes one second per specimen. After scent-interrogating 9,200 samples, our six dogs achieved independe...
Antimicrobial Agents and Chemotherapy, Apr 1, 2000
The in vivo pharmacodynamic activities of two glycylcyclines (GAR-936 and WAY 152,288) were asses... more The in vivo pharmacodynamic activities of two glycylcyclines (GAR-936 and WAY 152,288) were assessed in an experimental murine thigh infection model in neutropenic mice. Mice were infected with one of several strains of Streptococcus pneumoniae, Staphylococcus aureus, Escherichia coli, or Klebsiella pneumoniae. Most infections were treated with a twice-daily dosing schedule, with administration of 0.75 to 192 mg of GAR-936 or WAY 152,288 per kg of body weight. A maximum-effect dose-response model was used to calculate the dose that produced a net bacteriostatic effect over 24 h of therapy. This dose was called the bacteriostatic dose. More extensive dosing studies were performed with S. pneumoniae 1199, E. coli ATCC 25922, and K. pneumoniae ATCC 43816, with doses being given as one, two, four, or eight equal doses over a period of 24 h. The dosing schedules were designed in order to minimize the interrelationship between the various pharmacokinetic and pharmacodynamic parameters studied. These parameters were time above 0.03 to 32 times the MIC, area under the concentration-time curve (AUC), and maximum concentration of drug in serum (C max). The bacteriostatic dose remained essentially the same, irrespective of the dosing frequency, for S. pneumoniae 1199 (0.3 to 0.9 mg/kg/day). For E. coli ATCC 25922 and K. pneumoniae ATCC 43816, however, more frequent dosing led to lower bacteriostatic doses. Pharmacokinetic studies demonstrated dose-dependent elimination half-lives of 1.05 to 2.34 and 1.65 to 3.36 h and serum protein bindings of 59 and 71% for GAR-936 and WAY 152,288, respectively. GAR-936 and WAY 152,288 were similarly effective against the microorganisms studied, with small differences in maximum effect and 50% effective dose. The glycylcyclines were also similarly effective against tetracycline-sensitive and tetracycline-resistant bacteria. Time above a certain factor (range, 0.5 to 4 times) of the MIC was a better predictor of in vivo efficacy than C max or AUC for most organism-drug combinations. The results demonstrate that in order to achieve 80% maximum efficacy, the concentration of unbound drug in serum should be maintained above the MIC for at least 50% of the time for GAR-936 and for at least 75% of the time for WAY 152,288. The results of these experiments will aid in the rational design of dose-finding studies for these glycylcyclines in humans.
The Journal of Infectious Diseases, Mar 1, 1996
Abstracts of the Interscience Conference on Antimicrobial Agents & Chemotherapy, Dec 6, 1996
Antimicrobial Agents and Chemotherapy, 2000
The in vivo pharmacodynamic activities of two glycylcyclines (GAR-936 and WAY 152,288) were asses... more The in vivo pharmacodynamic activities of two glycylcyclines (GAR-936 and WAY 152,288) were assessed in an experimental murine thigh infection model in neutropenic mice. Mice were infected with one of several strains of Streptococcus pneumoniae , Staphylococcus aureus , Escherichia coli , or Klebsiella pneumoniae . Most infections were treated with a twice-daily dosing schedule, with administration of 0.75 to 192 mg of GAR-936 or WAY 152,288 per kg of body weight. A maximum-effect dose-response model was used to calculate the dose that produced a net bacteriostatic effect over 24 h of therapy. This dose was called the bacteriostatic dose. More extensive dosing studies were performed with S. pneumoniae 1199, E. coli ATCC 25922, and K. pneumoniae ATCC 43816, with doses being given as one, two, four, or eight equal doses over a period of 24 h. The dosing schedules were designed in order to minimize the interrelationship between the various pharmacokinetic and pharmacodynamic parameters...
Antimicrobial Agents and Chemotherapy, 2001
One of the most challenging issues in the design of phase II/III clinical trials of antimicrobial... more One of the most challenging issues in the design of phase II/III clinical trials of antimicrobial agents is dose selection. The choice is often based on preclinical data from pharmacokinetic (PK) studies with animals and healthy volunteers but is rarely linked directly to the target organisms except by the MIC, an in vitro measure of antimicrobial activity with many limitations. It is the thesis of this paper that rational dose-selection decisions can be made on the basis of the pharmacodynamics (PDs) of the test agent predicted by a mathematical model which uses four data sets: (i) the distribution of MICs for clinical isolates, (ii) the distribution of the values of the PK parameters for the test drug in the population, (iii) the PD target(s) developed from animal models of infection, and (iv) the protein binding characteristics of the test drug. In performing this study with the new anti-infective agent evernimicin, we collected a large number ( n = 4,543) of recent clinical isol...
Antimicrobial Agents and Chemotherapy
Combination therapy with ampicillin plus ceftriaxone (AMP+CRO) is the first-line therapy for trea... more Combination therapy with ampicillin plus ceftriaxone (AMP+CRO) is the first-line therapy for treating severe infections due to Enterococcus faecalis . However, the pharmacokinetic/pharmacodynamic (PK/PD) index linked to the in vivo efficacy of the combination is not yet defined, hindering dose optimization in the clinic.
Revista Vitae, 2017
Antecedentes: Existen múltiples modelos animales de diabetes, pero todavía no se ha validado uno ... more Antecedentes: Existen múltiples modelos animales de diabetes, pero todavía no se ha validado uno útil para determinar la farmacodinamia de medicamentos. Objetivos. Usar el modelo de inducción de diabetes mediante estreptozotocina equilibrada en ratones no emparentados, para determinar de forma precisa y reproducible la farmacodinamia de insulina regular. Métodos. En ratones machos no emparentados de aproximadamente 37 g, se inyectó una dosis intraperitoneal de 150 mg/kg de una solución equilibrada de estreptozotocina. La glucemia (mg/dL) se midió a los 0, 7, 9, 14, 16, 17 y 18 días post-inducción. Una vez los ratones alcanzaron glucemias >300 mg/dL, se determinó la eficacia hipoglucemiante de insulina regular en tres experimentos independientes. El rango de dosis fue 0,25 UI/kg a 4 UI/kg. Una ecuación de decaimiento exponencial de dos parámetros se ajustó a los datos. Resultados. Al día 18, el modelo tuvo una efectividad del 80% para producir diabetes (glucemia 446 ± 59 mg/dL), con mortalidad de sólo 2%. El coeficiente de variación intra e interexperimento fue ≤13%. Los parámetros farmacodinámicos de insulina fueron indistinguibles después de tres experimentos (P=0,32). La magnitud del efecto máximo fue-374 ± 30,7 mg/dL y la dosis efectiva 50 fue 1,34 ± 0,2 UI/kg. Conclusión. El modelo de diabetes inducida por estreptozotocina equilibrada permitió determinar de manera reproducible la farmacodinamia de la insulina regular.
PLOS ONE, Sep 29, 2021
Timely and accurate diagnostics are essential to fight the COVID-19 pandemic, but no test satisfi... more Timely and accurate diagnostics are essential to fight the COVID-19 pandemic, but no test satisfies both conditions. Dogs can scent-identify the unique odors of volatile organic compounds generated during infection by interrogating specimens or, ideally, the body of a patient. After training 6 dogs to detect SARS-CoV-2 by scent in human respiratory secretions (in vitro diagnosis), we retrained 5 of them to search and find the infection by scenting the patient directly (in vivo screening). Then, efficacy trials were designed to compare the diagnostic performance of the dogs against that of the rRT-PCR in 848 human subjects: 269 hospitalized patients (COVID-19 prevalence 30.1%), 259 hospital staff (prevalence 2.7%), and 320 government employees (prevalence 1.25%). The limit of detection in vitro was lower than 10 −12 copies ssRNA/mL. During in vivo efficacy experiments, our 5 dogs detected 92 COVID-19 positive patients among the 848 study subjects. The alert (lying down) was immediate, with 95.2% accuracy and high sensitivity (95.9%; 95% C.I. 93.6-97.4), specificity (95.1%; 94.4-95.8), positive predictive value (69.7%; 65.9-73.2), and negative predictive value (99.5%; 99.2-99.7) in relation to rRT-PCR. Seventy-five days after finishing in vivo efficacy experiments, a real-life study (in vivo effectiveness) was executed among the riders of the Metro System of Medellin, deploying the human-canine teams without previous training or announcement. Three dogs were used to examine the scent of 550 volunteers who agreed to participate, both in test with canines and in rRT-PCR testing. Negative predictive value remained at 99.0% (95% C.I. 98.3-99.4), but positive predictive value dropped to 28.2% (95% C.I. 21.1-36.7). Canine scent-detection in vivo is a highly accurate screening test for COVID-19, and it detects more than 99% of infected individuals independent of key variables, such as disease prevalence, time post-exposure, or presence of symptoms. Additional training is required to teach the dogs to ignore odoriferous contamination under real-life conditions.
Background: FCZ continues to be one of the first choices for the treatment of systemic candidiasi... more Background: FCZ continues to be one of the first choices for the treatment of systemic candidiasis. Most generics of some antibacterials fail TE despite their pharmaceutical equivalence (PE), but there are no data with antifungals. We standardized a model of fungemia to test the TE of FCZ generics. Methods: the model of disseminated candidiasis by tail-vein inoculation in neutropenic MPF Udea:ICR(CD-2) male mice was standardized testing 4 clinical strains of C. albicans (blood isolates), incubation temperature (25°C vs. 37°C), inoculum (5 and 6 log CFU/ mL), target organ (kidneys, liver, spleen, blood), time to begin treatment (2h vs. 5h), and duration of therapy (24h vs. 48h). Two generics were compared with the innovator using doses from 1 to 64 mg/kg/d q6h SC. Effect was calculated by subtracting CFU of treated animals from untreated controls. Kidneys were homogenized and plated on SDA for CFU count. Data were fitted to Hill's model by nonlinear regression ands compared by cu...
Biomédica : revista del Instituto Nacional de Salud, 2005
The evolution and molecular mechanisms of vancomycin resistance in Staphylococcus aureus were rev... more The evolution and molecular mechanisms of vancomycin resistance in Staphylococcus aureus were reviewed. Case reports and research studies on biochemestry, electron microscopy and molecular biology of Staphylococcus aureus were selected from Medline database and summarized in the following review. After almost 40 years of successful treatment of S. aureus with vancomycin, several cases of clinical failures have been reported (since 1997). S. aureus strains have appeared with intermediate susceptibility (MIC 8-16 microg/ml), as well as strains with heterogeneous resistance (global MIC < or =4 microg/ml), but with subpopulations of intermediate susceptibility. In these cases, resistance is mediated by cell wall thickening with reduced cross linking. This traps the antibiotic before it reaches its major target, the murein monomers in the cell membrane. In 2002, a total vancomycin resistant strain (MIC…
Acta méd. colomb, 1994
Base de dados : LILACS. Pesquisa : 292816 [Identificador único]. Referências encontradas : 1 [ref... more Base de dados : LILACS. Pesquisa : 292816 [Identificador único]. Referências encontradas : 1 [refinar]. Mostrando: 1 .. 1 no formato [Detalhado]. página 1 de 1, 1 / 1, LILACS, seleciona. para imprimir. Fotocópia. experimental, Documentos relacionados. Id: 292816. ...
BMC Microbiology, 2013
Background Antibiotic therapy can select for small colony variants of Staphylococcus aureus that ... more Background Antibiotic therapy can select for small colony variants of Staphylococcus aureus that are more resistant to antibiotics and can result in persistent infections, necessitating the development of more effective antimicrobial strategies to combat small colony variant infections. Photodynamic therapy is an alternative treatment approach which utilises light in combination with a light-activated antimicrobial agent to kill bacteria via a non-specific mechanism of action. In this study, we investigated whether the combination of 665 nm laser light and the light-activated antimicrobial agent methylene blue was able to successfully kill S. aureus small colony variants. S. aureus and isogenic stable small colony variant were exposed to varying doses (1.93 to 9.65 J/cm2) of 665 nm laser light in the presence of varying concentrations (1 to 20 μM) of methylene blue. Results The combination of 665 nm laser light and methylene blue was found to be an effective strategy for the killing...
Antimicrobial Agents and Chemotherapy, 2012
ABSTRACTAnimal models of infection have been used to demonstrate the therapeutic failure of “bioe... more ABSTRACTAnimal models of infection have been used to demonstrate the therapeutic failure of “bioequivalent” generic products, but their applicability for this purpose requires the accurate identification of those products that are truly bioequivalent. Here, we present data comparing one intravenous generic product of metronidazole with the innovator product in a neutropenic mouse thigh anaerobic infection model. Simultaneous experiments allowed comparisons (generic versus innovator) of potency and the concentration of the active pharmaceutical ingredient (API), analytical chemistry (liquid chromatography/mass spectrometry [LC/MS]),in vitrosusceptibility testing, single-dose serum pharmacokinetics (PK) in infected mice, andin vivopharmacodynamics (PD) againstBacteroides fragilisATCC 25825 in synergy withEscherichia coliSIG-1 in the neutropenic mouse thigh anaerobic infection model. The Hill dose-response model followed by curve-fitting analysis was used to calculate and compare prima...
Application of microbiological assay to determine pharmaceutical equivalence of generic intraveno... more Application of microbiological assay to determine pharmaceutical equivalence of generic intravenous antibiotics
PLOS ONE, 2020
The combination of ampicillin (AMP) and ceftriaxone (CRO) is considered synergistic against Enter... more The combination of ampicillin (AMP) and ceftriaxone (CRO) is considered synergistic against Enterococcus faecalis based on in vitro tests and the rabbit endocarditis model, however, in vitro assays are limited by the use of fixed antibiotic concentrations and the rabbit model by poor bacterial growth, high variability, and the use of point dose-effect estimations, that may lead to inaccurate assessment of antibiotic combinations and hinder optimal translation. Here, we tested AMP+CRO against two strains of E. faecalis and one of E. faecium in an optimized mouse thigh infection model that yields high bacterial growth and allows to define the complete dose-response relationship. By fitting Hill’s sigmoid model and estimating the parameters maximal effect (Emax) and effective dose 50 (ED50), the following interactions were defined: synergism (Emax increase ≥2 log10 CFU/g), antagonism (Emax reduction ≥1 log10 CFU/g) and potentiation (ED50 reduction ≥50% without changes in Emax). AMP mon...
PLOS ONE, 2021
Timely and accurate diagnostics are essential to fight the COVID-19 pandemic, but no test satisfi... more Timely and accurate diagnostics are essential to fight the COVID-19 pandemic, but no test satisfies both conditions. Dogs can scent-identify the unique odors of volatile organic compounds generated during infection by interrogating specimens or, ideally, the body of a patient. After training 6 dogs to detect SARS-CoV-2 by scent in human respiratory secretions (in vitro diagnosis), we retrained 5 of them to search and find the infection by scenting the patient directly (in vivo screening). Then, efficacy trials were designed to compare the diagnostic performance of the dogs against that of the rRT-PCR in 848 human subjects: 269 hospitalized patients (COVID-19 prevalence 30.1%), 259 hospital staff (prevalence 2.7%), and 320 government employees (prevalence 1.25%). The limit of detection in vitro was lower than 10−12 copies ssRNA/mL. During in vivo efficacy experiments, our 5 dogs detected 92 COVID-19 positive patients among the 848 study subjects. The alert (lying down) was immediate,...
Molecular tests for viral diagnostics are essential to confront the COVID-19 pandemic, but their ... more Molecular tests for viral diagnostics are essential to confront the COVID-19 pandemic, but their production and distribution cannot satisfy the current high demand. Early identification of infected people and their contacts is the key to being able to isolate them and prevent the dissemination of the pathogen; unfortunately, most countries are unable to do this due to the lack of diagnostic tools. Dogs can identify, with a high rate of precision, unique odors of volatile organic compounds generated during an infection; as a result, dogs can diagnose infectious agents by smelling specimens and, sometimes, the body of an infected individual. We trained six dogs of three different breeds to detect SARS-CoV-2 in respiratory secretions of infected patients and evaluated their performance experimentally, comparing it against the gold standard (rRT-PCR). Here we show that viral detection takes one second per specimen. After scent-interrogating 9,200 samples, our six dogs achieved independe...