RESUMO
Introducción: la piomiositis (PMS) es una infección bacteriana aguda o subaguda del músculo esquelético. Entidad rara en pediatría, suele acompañarse de la formación de abscesos. Se presenta más frecuentemente en preescolares de sexo masculino, afectando mayoritariamente a extremidades y región pélvica. La manifestación multifocal es frecuente. El principal agente etiológico es Staphylococcus aureus. Caso clínico: 3 años, sexo masculino, sano. Consulta por fiebre continua de hasta 39 ºC de seis días de evolución, dolor de ambos miembros inferiores a predominio izquierdo, cojera y repercusión general. Examen físico: tumoración en muslo izquierdo de límites difusos de 13 x 5 cm, lisa, firme, impresiona adherida a planos musculares, dolorosa. Sin elementos fluxivos en la piel. Ecografía de partes blandas: aumento de tejidos blandos de la extremidad. Resonancia magnética (RM): abscesos que comprometen logia de los aductores del miembro izquierdo, el vasto externo del muslo derecho, musculatura paravertebral lumbar izquierda y cérvico-torácica izquierda. Tratamiento: drenaje, requiere de múltiples limpiezas quirúrgicas y antibioticoterapia prolongada. Cultivo de la lesión: Staphylococcus aureus meticilino resistente (SAMR). Buena evolución clínica e imagenológica. Discusión: la PMS ha presentado una incidencia creciente con la aparición del SAMR. La ecografía es un método adecuado para realizar diagnóstico local. La experiencia en la interpretación de la RM permite pesquisar el compromiso multifocal, identificando focos sin traducción clínica. La antibioticoterapia y el drenaje quirúrgico son los pilares del tratamiento. El pronóstico es bueno en la mayoría de los casos.
Introduction: pyomyositis (PMS) is an acute or subacute bacterial infection of the skeletal muscle. It is a rare infection in pediatrics, and it is usually accompanied by abscess formation. It occurs more frequently in male preschoolers, mostly affecting the extremities and pelvic region. The multifocal manifestation is frequent. The main etiological agent is Staphylococcus aureus. Clinical case: 3 year-old, male, healthy patient. He consulted for continuous fever of up to 39ºC of 6 days of evolution, pain in both lower limbs predominantly on the left, lameness and general repercussions. Physical examination: a 13 x 5 cm tumor in the left thigh with diffuse limits, smooth, firm, adhered to muscle layers, painful. Without fluxive elements on the skin. Soft tissue ultrasound: enlargement of the soft tissues of the extremity. Magnetic resonance imaging (MRI): abscesses involving the adductor lodge of the left limb, the vastus lateralis of the right thigh, left lumbar paravertebral musculature and left cervical-thoracic musculature. Treatment: drainage, requires multiple surgical cleanings and prolonged antibiotic therapy. Culture of the lesion: methicillin-resistant Staphylococcus Aureus (MRSA). Good clinical and imaging evolution. Discussion: PMS has had an increasing incidence with the appearance of MRSA. Ultrasound is a suitable method for local diagnosis. Experience in the interpretation of MRI has enabled us to research multifocal involvement, identifying unobserved foci during clinical check-up. Antibiotic therapy and surgical drainage are the main treatments. The prognosis is good in most cases.
Introdução: Ia Piomiosite (TPM) é uma infecção bacteriana aguda ou subaguda do músculo esquelético. É uma entidade rara em pediatria, costuma vir acompanhada de formação de abscessos. Ocorre com maior frequência em pré-escolares do sexo masculino, afetando principalmente as extremidades e a região pélvica. A manifestação multifocal é comum. O principal agente etiológico é o Staphylococcus aureus. Caso clínico: paciente 3 anos, sexo masculino, hígido. Consulta por febre contínua de até 39ºC há 6 dias, dor em ambos os membros inferiores predominantemente esquerdo, claudicação e repercussão geral. Exame físico: tumor na coxa esquerda com limites difusos de 13 x 5 cm, liso, firme, aparentemente aderido aos planos musculares, doloroso. Sem elementos fluidos na pele. Ultrassonografia de tecidos moles: aumento dos tecidos moles da extremidade. Ressonância magnética (RM): abscessos envolvendo o alojamento adutor do membro esquerdo, vasto lateral da coxa direita, músculos paravertebrais lombares esquerdos e cérvico-torácicos esquerdos. Tratamento: drenagem, requer múltiplas limpezas cirúrgicas e antibioticoterapia prolongada. Cultura da lesão: Staphylococcus aureus resistente à meticilina (MRSA). Boa evolução clínica e imagiológica. Discussão: a TPM tem tido uma incidência crescente com o aparecimento do MRSA. A ultrassonografia é um método adequado para diagnóstico local. A experiência na interpretação de ressonância magnética permite-nos investigar o envolvimento multifocal, identificando focos sem tradução clínica. A antibioticoterapia e a drenagem cirúrgica são os pilares do tratamento. O prognóstico é bom na maioria dos casos.
Assuntos
Humanos , Masculino , Pré-Escolar , Infecções Estafilocócicas/diagnóstico , Infecções Estafilocócicas/tratamento farmacológico , Coxa da Perna/microbiologia , Drenagem , Piomiosite/terapia , Piomiosite/diagnóstico por imagem , Músculos Paraespinais/microbiologia , Clindamicina/administração & dosagem , Combinação Trimetoprima e Sulfametoxazol/administração & dosagem , Antibacterianos/administração & dosagemRESUMO
Several studies with animal models have demonstrated that bioequivalence of generic products of antibiotics like vancomycin, as currently defined, do not guarantee therapeutic equivalence. However, the amounts and characteristics of impurities and degradation products in these formulations do not violate the requirements of the U.S. Pharmacopeia (USP). Here, we provide experimental data with three generic products of meropenem that help in understanding how these apparently insignificant chemical differences affect the in vivo efficacy. Meropenem generics were compared with the innovator in vitro by microbiological assay, susceptibility testing, and liquid chromatography/mass spectrometry (LC/MS) analysis and in vivo with the neutropenic guinea pig soleus infection model (Pseudomonas aeruginosa) and the neutropenic mouse thigh (P. aeruginosa), brain (P. aeruginosa), and lung (Klebisella pneumoniae) infection models, adding the dihydropeptidase I (DHP-I) inhibitor cilastatin in different proportions to the carbapenem. We found that the concentration and potency of the active pharmaceutical ingredient, in vitro susceptibility testing, and mouse pharmacokinetics were identical for all products; however, two generics differed significantly from the innovator in the guinea pig and mouse models, while the third generic was therapeutically equivalent under all conditions. Trisodium adducts in a bioequivalent generic made it more susceptible to DHP-I hydrolysis and less stable at room temperature, explaining its therapeutic nonequivalence. We conclude that the therapeutic nonequivalence of generic products of meropenem is due to greater susceptibility to DHP-I hydrolysis. These failing generics are compliant with USP requirements and would remain undetectable under current regulations.
Assuntos
Antibacterianos/farmacocinética , Dipeptidases/metabolismo , Medicamentos Genéricos/farmacocinética , Infecções por Klebsiella/tratamento farmacológico , Infecções por Pseudomonas/tratamento farmacológico , Tienamicinas/farmacocinética , Animais , Antibacterianos/metabolismo , Biotransformação , Encéfalo/efeitos dos fármacos , Encéfalo/microbiologia , Cilastatina/farmacologia , Dipeptidases/antagonistas & inibidores , Estabilidade de Medicamentos , Medicamentos Genéricos/metabolismo , Proteínas Ligadas por GPI/antagonistas & inibidores , Proteínas Ligadas por GPI/metabolismo , Cobaias , Infecções por Klebsiella/microbiologia , Klebsiella pneumoniae/efeitos dos fármacos , Klebsiella pneumoniae/fisiologia , Pulmão/efeitos dos fármacos , Pulmão/microbiologia , Meropeném , Camundongos , Testes de Sensibilidade Microbiana , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/microbiologia , Inibidores de Proteases/farmacologia , Infecções por Pseudomonas/microbiologia , Pseudomonas aeruginosa/efeitos dos fármacos , Pseudomonas aeruginosa/fisiologia , Equivalência Terapêutica , Tienamicinas/metabolismo , Coxa da Perna/microbiologia , Resultado do TratamentoRESUMO
Estudio de caso: Paciente de sexo masculino, de 38 años de edad,con tumor ación indolor a en muslo izquierdo de 3 años de evolución. Esta neoplasia corresponde típicamente a nódulos compuestos por células epiteloides poligonales, claras, que recuerdan a las de la notocorda y una segunda población de células e osinofílicas organizadas en cordones y nidos separados por estroma mixoide, con fenómenos de vacuolización citoplasmática similar a las del cordoma (células tipo fisalíferas).
Case Study: Male patient, 38 years old, with painless swelling in left thigh 3 years evolution. This neoplasm typicall y corresponds tonodules composed of polygonal epithelioid cells, clear, reminiscent of the notochord and a second population of eosinophilic cells arranged incords and nests separated by myxoid stroma with phenomena similar to cytoplasmic vacuolization the chordoma (physaliphorous type cells).
Assuntos
Humanos , Feminino , Adulto , Adulto , Mioepitelioma , Mioepitelioma/microbiologia , Coxa da Perna/anormalidades , Coxa da Perna/microbiologia , Coxa da Perna/patologiaRESUMO
Animal 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 vitro susceptibility testing, single-dose serum pharmacokinetics (PK) in infected mice, and in vivo pharmacodynamics (PD) against Bacteroides fragilis ATCC 25825 in synergy with Escherichia coli SIG-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 primary and secondary PD parameters. The generic and the innovator products were identical in terms of the concentration and potency of the API, chromatographic and spectrographic profiles, MIC and minimal bactericidal concentrations (MBC) (2.0 mg/liter), and mouse PK. We found no differences between products in bacteriostatic doses (BD) (15 to 22 mg/kg of body weight per day) or the doses needed to kill 1 log (1LKD) (21 to 29 mg/kg per day) or 2 logs (2LKD) (28 to 54 mg/kg per day) of B. fragilis under dosing schedules of every 12 h (q12h), q8h, or q6h. The area under the concentration-time curve over 24 h in the steady state divided by the MIC (AUC/MIC ratio) was the best PD index to predict the antibacterial efficacy of metronidazole (adjusted coefficient of determination [AdjR(2)] = 84.6%), and its magnitude to reach bacteriostasis in vivo (56.6 ± 5.17 h) or to kill the first (90.8 ± 9.78 h) and second (155.5 ± 22.2 h) logs was the same for both products. Animal models of infection allow a thorough demonstration of the therapeutic equivalence of generic antimicrobials.
Assuntos
Antibacterianos/farmacocinética , Bacteroides fragilis/efeitos dos fármacos , Medicamentos Genéricos/farmacocinética , Metronidazol/farmacocinética , Staphylococcus aureus/efeitos dos fármacos , Animais , Antibacterianos/farmacologia , Área Sob a Curva , Infecções por Bacteroides/tratamento farmacológico , Infecções por Bacteroides/microbiologia , Bacteroides fragilis/fisiologia , Cromatografia Líquida , Medicamentos Genéricos/farmacologia , Feminino , Injeções Intravenosas , Espectrometria de Massas , Metronidazol/farmacologia , Camundongos , Testes de Sensibilidade Microbiana , Neutropenia/complicações , Neutropenia/tratamento farmacológico , Neutropenia/microbiologia , Infecções Estafilocócicas/complicações , Infecções Estafilocócicas/tratamento farmacológico , Infecções Estafilocócicas/microbiologia , Staphylococcus aureus/fisiologia , Equivalência Terapêutica , Coxa da Perna/microbiologiaRESUMO
Previous studies have shown that "bioequivalent" generic products of vancomycin are less effective in vivo against Staphylococcus aureus than the innovator compound. Considering that suboptimal bactericidal effect has been associated with emergence of resistance, we aimed to assess in vivo the impact of exposure to innovator and generic products of vancomycin on S. aureus susceptibility. A clinical methicillin-resistant S. aureus (MRSA) strain from a liver transplant patient with persistent bacteremia was used for which MIC, minimum bactericidal concentration (MBC), and autolytic properties were determined. Susceptibility was also assessed by determining a population analysis profile (PAP) with vancomycin concentrations from 0 to 5 mg/liter. ICR neutropenic mice were inoculated in each thigh with â¼7.0 log(10) CFU. Treatment with the different vancomycin products (innovator and three generics; 1,200 mg/kg of body weight/day every 3 h) started 2 h later while the control group received sterile saline. After 24 h, mice were euthanized, and the thigh homogenates were plated. Recovered colonies were reinoculated to new groups of animals, and the exposure-recovery process was repeated until 12 cycles were completed. The evolution of resistance was assessed by PAP after cycles 5, 10, 11, and 12. The initial isolate displayed reduced autolysis and higher resistance frequencies than S. aureus ATCC 29213 but without vancomycin-intermediate S. aureus (VISA) subpopulations. After 12 cycles, innovator vancomycin had significantly reduced resistant subpopulations at 1, 2, and 3 mg/liter, while the generic products had enriched them progressively by orders of magnitude. The great capacity of generic vancomycin to select for less susceptible organisms raises concerns about the role of therapeutic inequivalence of any antimicrobial on the epidemiology of resistance worldwide.
Assuntos
Medicamentos Genéricos , Resistência a Meticilina/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Neutropenia/microbiologia , Infecções Estafilocócicas/tratamento farmacológico , Coxa da Perna/microbiologia , Vancomicina , Animais , Antibacterianos/administração & dosagem , Antibacterianos/efeitos adversos , Antibacterianos/farmacocinética , Contagem de Colônia Microbiana , Modelos Animais de Doenças , Esquema de Medicação , Medicamentos Genéricos/administração & dosagem , Medicamentos Genéricos/efeitos adversos , Medicamentos Genéricos/farmacocinética , Feminino , Humanos , Staphylococcus aureus Resistente à Meticilina/crescimento & desenvolvimento , Camundongos , Camundongos Endogâmicos ICR , Testes de Sensibilidade Microbiana , Infecções Estafilocócicas/microbiologia , Equivalência Terapêutica , Extratos de Tecidos , Vancomicina/administração & dosagem , Vancomicina/efeitos adversos , Vancomicina/farmacocinéticaRESUMO
Generic versions of intravenous antibiotics are not required to demonstrate therapeutic equivalence with the innovator because therapeutic equivalence is assumed from pharmaceutical equivalence. To test such assumptions, we studied three generic versions of vancomycin in simultaneous experiments with the innovator and determined the concentration and potency of the active pharmaceutical ingredient by microbiological assay, single-dose pharmacokinetics in infected mice, antibacterial effect by broth microdilution and time-kill curves (TKC), and pharmacodynamics against two wild-type strains of Staphylococcus aureus by using the neutropenic mouse thigh infection model. The main outcome measure was the comparison of magnitudes and patterns of in vivo efficacy between generic products and the innovator. Except for one product exhibiting slightly greater concentration, vancomycin generics were undistinguishable from the innovator based on concentration and potency, protein binding, in vitro antibacterial effect determined by minimal inhibitory or bactericidal concentrations and TKC, and serum pharmacokinetics. Despite such similarities, all generic products failed in vivo to kill S. aureus, while the innovator displayed the expected bactericidal efficacy: maximum antibacterial effect (Emax) (95% confidence interval [CI]) was 2.04 (1.89 to 2.19), 2.59 (2.21 to 2.98), and 3.48 (2.92 to 4.04) versus 5.65 (5.52 to 5.78) log10 CFU/g for three generics and the innovator product, respectively (P<0.0001, any comparison). Nonlinear regression analysis suggests that generic versions of vancomycin contain inhibitory and stimulatory principles within their formulations that cause agonistic-antagonistic actions responsible for in vivo failure. In conclusion, pharmaceutical equivalence does not imply therapeutic equivalence for vancomycin.
Assuntos
Medicamentos Genéricos/farmacocinética , Medicamentos Genéricos/uso terapêutico , Infecções Estafilocócicas/tratamento farmacológico , Staphylococcus aureus/efeitos dos fármacos , Vancomicina/farmacocinética , Vancomicina/uso terapêutico , Animais , Antibacterianos/farmacocinética , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Modelos Animais de Doenças , Medicamentos Genéricos/farmacologia , Humanos , Camundongos , Testes de Sensibilidade Microbiana , Neutropenia/complicações , Infecções Estafilocócicas/complicações , Infecções Estafilocócicas/microbiologia , Equivalência Terapêutica , Coxa da Perna/microbiologia , Falha de Tratamento , Vancomicina/farmacologiaRESUMO
BACKGROUND: Drug regulatory agencies (DRA) support prescription of generic products of intravenous antibiotics assuming therapeutic equivalence from pharmaceutical equivalence. Recent reports of deaths associated with generic heparin and metoprolol have raised concerns about the efficacy and safety of DRA-approved drugs. METHODOLOGY/PRINCIPAL FINDINGS: To challenge the assumption that pharmaceutical equivalence predicts therapeutic equivalence, we determined in vitro and in vivo the efficacy of the innovator product and 20 pharmaceutically equivalent generics of gentamicin. The data showed that, while only 1 generic product failed in vitro (MIC = 45.3 vs. 0.7 mg/L, P<0.05), 10 products (including gentamicin reference powder) failed in vivo against E. coli due to significantly inferior efficacy (E(max) = 4.81 to 5.32 vs. 5.99 log(10) CFU/g, PAssuntos
Infecções Bacterianas/complicações
, Medicamentos Genéricos/farmacocinética
, Medicamentos Genéricos/uso terapêutico
, Gentamicinas/farmacocinética
, Gentamicinas/uso terapêutico
, Neutropenia/tratamento farmacológico
, Coxa da Perna/patologia
, Animais
, Anti-Infecciosos/farmacologia
, Modelos Animais de Doenças
, Medicamentos Genéricos/farmacologia
, Gentamicinas/farmacologia
, Camundongos
, Testes de Sensibilidade Microbiana
, Neutropenia/complicações
, Neutropenia/microbiologia
, Especificidade de Órgãos/efeitos dos fármacos
, Reprodutibilidade dos Testes
, Análise de Sobrevida
, Equivalência Terapêutica
, Coxa da Perna/microbiologia