RESUMEN
Intrathecal baclofen (ITB) delivery via an implanted pump is frequently used for the treatment of spasticity. This is an effective and safe neurosurgical and pharmacological intervention associated with an improvement in patient quality of life. There is, however, a risk of device-related infection. We present a patient with pump-site infection and Escherichia coli meningitis secondary to transcolonic perforation of an intrathecal baclofen pump catheter. While this is rare, we review the intraoperative precautions and best practices that should be taken to prevent and manage this unusual complication.
Asunto(s)
Antibacterianos/uso terapéutico , Baclofeno/administración & dosificación , Cateterismo/efectos adversos , Catéteres de Permanencia/efectos adversos , Bombas de Infusión Implantables/efectos adversos , Perforación Intestinal/microbiología , Meningitis por Escherichia coli/microbiología , Esclerosis Múltiple/tratamiento farmacológico , Relajantes Musculares Centrales/administración & dosificación , Catéteres de Permanencia/microbiología , Remoción de Dispositivos , Personas con Discapacidad , Femenino , Humanos , Enfermedad Iatrogénica , Bombas de Infusión Implantables/microbiología , Infusión Espinal/efectos adversos , Perforación Intestinal/etiología , Meningitis por Escherichia coli/etiología , Pruebas de Sensibilidad Microbiana , Persona de Mediana Edad , Recurrencia , Resultado del TratamientoRESUMEN
The gene cluster responsible for synthesis of the unknown molecule "colibactin" has been identified in mutualistic and pathogenic Escherichia coli. The pathway endows its producer with a long-term persistence phenotype in the human bowel, a probiotic activity used in the treatment of ulcerative colitis, and a carcinogenic activity under host inflammatory conditions. To date, functional small molecules from this pathway have not been reported. Here we implemented a comparative metabolomics and targeted structural network analyses approach to identify a catalog of small molecules dependent on the colibactin pathway from the meningitis isolate E. coli IHE3034 and the probiotic E. coli Nissle 1917. The structures of 10 pathway-dependent small molecules are proposed based on structural characterizations and network relationships. The network will provide a roadmap for the structural and functional elucidation of a variety of other small molecules encoded by the pathway. From the characterized small molecule set, in vitro bacterial growth inhibitory and mammalian CNS receptor antagonist activities are presented.
Asunto(s)
Escherichia coli/metabolismo , Metabolómica/métodos , Péptidos/metabolismo , Policétidos/metabolismo , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/metabolismo , Algoritmos , Bacillus subtilis/efectos de los fármacos , Antagonistas de Dopamina/farmacología , Evaluación Preclínica de Medicamentos/métodos , Escherichia coli/aislamiento & purificación , Escherichia coli/patogenicidad , Células HeLa/efectos de los fármacos , Humanos , Espectroscopía de Resonancia Magnética , Meningitis por Escherichia coli/microbiología , Redes y Vías Metabólicas , Estructura Molecular , Péptidos/genética , Probióticos , Bibliotecas de Moléculas Pequeñas/farmacologíaRESUMEN
The ability to capture iron is a challenge for most bacteria. The neonatal meningitis Escherichia coli strain S88 possesses several iron uptake systems, notably including siderophores. Transcriptional analysis of the ColV plasmid pS88 has shown strong induction of a previously undescribed gene with low identity to three E. coli chromosomal genes encoding phospho-2-dehydro-3-deoxyheptonate aldolases involved in aromatic amino acid and catecholate/phenolate siderophore biosynthesis through the shikimate pathway. Here, we investigated the role of this gene, ssbLp (ssbL carried on the plasmid), in siderophore biosynthesis and, consequently, in S88 virulence. We constructed an S88 mutant designated S88 ΔssbLp, which exhibited reduced growth under low-iron conditions compared to the wild-type strain. Liquid chromatography-mass spectroscopy analysis of culture supernatants showed that the mutant secreted significantly smaller amounts of enterobactin, salmochelin SX, and yersiniabactin than the wild-type strain. The mutant was also less virulent in a neonatal rat sepsis model, with significantly lower bacteremia and mortality. Supplementation with chorismate, the final product of the shikimate pathway, restored the wild-type phenotype in vitro. In a collection of human extraintestinal E. coli isolates, we found that ssbL was present only in strains harboring the iro locus, encoding salmochelins, and was located either on the chromosome or on plasmids. Acquisition of the iro locus has been accompanied by acquisition of the auxiliary gene ssbL, which boosts the metabolic pathway essential for catecholate/phenolate siderophore biosynthesis and could represent potential therapeutic targets.
Asunto(s)
Aldehído-Liasas/metabolismo , Proteínas de Escherichia coli/metabolismo , Escherichia coli/metabolismo , Meningitis por Escherichia coli/microbiología , Plásmidos/genética , Ácido Shikímico/metabolismo , Sideróforos/biosíntesis , Factores de Virulencia/metabolismo , Aldehído-Liasas/genética , Animales , Escherichia coli/genética , Proteínas de Escherichia coli/genética , Humanos , Hierro/metabolismo , Redes y Vías Metabólicas , Plásmidos/metabolismo , Ratas , Ratas Sprague-Dawley , Factores de Virulencia/genéticaRESUMEN
Moxifloxacin, an 8-methoxyquinolone with broad-spectrum activity in vitro, was studied in the rabbit model of Escherichia coli meningitis. The purposes of this study were to evaluate the bactericidal effectiveness and the pharmacodynamic profile of moxifloxacin in cerebrospinal fluid (CSF) and to compare the bactericidal activity with that of ceftriaxone and meropenem therapy. After induction of meningitis, animals were given single doses of 10, 20, and 40 mg/kg or divided-dose regimens of 5, 10, and 20 mg/kg twice, separated by 6 h. After single doses, the penetration of moxifloxacin into purulent CSF, measured as percentage of the area under the concentration-time curve (AUC) in CSF relative to the AUC in plasma, was approximately 50%. After single doses of 10, 20, and 40 mg/kg, the maximum CSF concentration (C(max)) values were 1.8, 4.2, and 4.9 microg/ml, respectively; the AUC values (total drug) were 13.4, 25.4, and 27.1 microg/ml x h, respectively, and the half-life values (t(1/2)) were 6.7, 6.6, and 4.7 h, respectively. The bacterial killing in CSF for moxifloxacin, calculated as the Deltalog(10) CFU per milliliter per hour, at 3, 6, and 12 h after single doses of 10, 20, and 40 mg/kg were -5.70, -6.62, and -7.02; -7.37, -7.37, and -6.87; and -6.62, -6.62, and -6.62, respectively, whereas those of ceftriaxone and meropenem were -4.18, -5.24, and -4.43, and -3.64, -3.59, and -4.12, respectively. The CSF pharmacodynamic indices of AUC/MBC and C(max)/MBC were interrelated (r = 0.81); there was less correlation with T > MBC (r = 0.74). In this model, therapy with moxifloxacin appears to be at least as effective as ceftriaxone and more effective than meropenem therapy in eradicating E. coli from CSF.