Editorial
Fecal concentration of intravenous vancomycin preparation after oral administration: Preclinical data supporting unmet clinical needs
Concentración fecal de la preparación de vancomicina intravenosa posterior a administración oral: datos preclínicos que sustentan necesidades clínicas no satisfechas
J. Asbun-Bojalil
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Juan.asbun@indice.org.mx
Corresponding author at. Investigación y Divulgación Científica de Excelencia INDICE S.C., Av. Paseo de la Reforma 300 Piso 16 Colonia Juárez, Alcaldía Cuauhtémoc C.P. 06600, Ciudad de México, México. Tel.: +52-5554511584.
Corresponding author at. Investigación y Divulgación Científica de Excelencia INDICE S.C., Av. Paseo de la Reforma 300 Piso 16 Colonia Juárez, Alcaldía Cuauhtémoc C.P. 06600, Ciudad de México, México. Tel.: +52-5554511584.
Investigación y Divulgación Científica de Excelencia INDICE S.C., Ciudad de México, México
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Red represents the 125 mg dose, blue represents the 500 mg dose, and yellow represents the placebo. MBC<span class="elsevierStyleInf">90</span> was only achieved with the 500 mg dose (depicted by the dotted line).</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "J. Ramos-García, F. Robles-Rivera, M. Chávez-Soto, M. Valdés, F. Calzada, N. Ortiz-Olvera" "autores" => array:6 [ 0 => array:2 [ "nombre" => "J." "apellidos" => "Ramos-García" ] 1 => array:2 [ "nombre" => "F." "apellidos" => "Robles-Rivera" ] 2 => array:2 [ "nombre" => "M." "apellidos" => "Chávez-Soto" ] 3 => array:2 [ "nombre" => "M." "apellidos" => "Valdés" ] 4 => array:2 [ "nombre" => "F." "apellidos" => "Calzada" ] 5 => array:2 [ "nombre" => "N." "apellidos" => "Ortiz-Olvera" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "es" => array:9 [ "pii" => "S0375090621001245" "doi" => "10.1016/j.rgmx.2021.05.007" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "es" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0375090621001245?idApp=UINPBA000046" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2255534X22000184?idApp=UINPBA000046" "url" => "/2255534X/0000008800000002/v1_202305280003/S2255534X22000184/v1_202305280003/en/main.assets" ] "en" => array:13 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Editorial</span>" "titulo" => "Fecal concentration of intravenous vancomycin preparation after oral administration: Preclinical data supporting unmet clinical needs" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "83" "paginaFinal" => "84" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "J. Asbun-Bojalil" "autores" => array:1 [ 0 => array:4 [ "nombre" => "J." "apellidos" => "Asbun-Bojalil" "email" => array:1 [ 0 => "Juan.asbun@indice.org.mx" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] ] "afiliaciones" => array:1 [ 0 => array:2 [ "entidad" => "Investigación y Divulgación Científica de Excelencia INDICE S.C., Ciudad de México, México" "identificador" => "aff0005" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author at. Investigación y Divulgación Científica de Excelencia INDICE S.C., Av. Paseo de la Reforma 300 Piso 16 Colonia Juárez, Alcaldía Cuauhtémoc C.P. 06600, Ciudad de México, México. Tel.: +52-5554511584." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Concentración fecal de la preparación de vancomicina intravenosa posterior a administración oral: datos preclínicos que sustentan necesidades clínicas no satisfechas" ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">Antimicrobial resistance is one of the biggest global health threats in our time, according to the World Health Organization. Therefore, efforts to optimize the use of antimicrobial medicines and develop sustainable innovation are part of the objectives of worldwide actions<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a>. In low and medium-income countries, such as those in Latin America, we may see the coexistence of insufficient access to antibiotics and excessive consumption, making distribution and regulation a difficult challenge<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a>. Thus, it is important to provide scientific evidence, at all levels, on the correct use of those drugs.</p><p id="par0010" class="elsevierStylePara elsevierViewall">One example is the oral administration of vancomycin (either by off-label use of the parenteral presentation or by specific oral formulations), given that its use has increased in the treatment and prevention of active <span class="elsevierStyleItalic">Clostridioides difficile</span> infection (CDI). Although typically used in severe forms of CDI, vancomycin usually supersedes metronidazole, especially for mild-to-moderate disease<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a>. A rationale behind said substitution is that almost 25% of patients have disease recurrence after initial treatment, and a second recurrence is reported in 35% of patients<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a>. In addition, metronidazole resistance in CDI has been reported from 0 to 18.3% and can be unstable, inducible, and heterogeneous<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a>. Moreover, vancomycin has good water solubility, protease stability, and lacks metabolism<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a>, and its poor absorption from the gastrointestinal tract results in high intracolonic drug levels<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a>. This is clearly an advantage when CDI is confined to the colon, long-term therapy is needed, and systemic adverse events may complicate baseline health conditions.</p><p id="par0015" class="elsevierStylePara elsevierViewall">A low-dose regimen of oral vancomycin, using the intravenous formulation (i.e., 125<span class="elsevierStyleHsp" style=""></span>mg every 6<span class="elsevierStyleHsp" style=""></span>h) has demonstrated no detectable drug in the serum of patients with different levels of renal function<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a>. Other reports suggest that higher doses (500<span class="elsevierStyleHsp" style=""></span>mg of vancomycin capsules), severe CDI (with increased intestinal permeability), and renal compromise (supportive dialysis) are risk factors for systemic vancomycin absorption after oral administration<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a>. Effects of assay detection limits, associated morbidities, concomitant drugs, and dosage regimens make the findings on the non-absorbable property of oral administration of vancomycin inconclusive. Nonetheless, the risk-benefit balance is positive, compared with the known systemic effects of intravenous vancomycin (ototoxicity, nephrotoxicity).</p><p id="par0020" class="elsevierStylePara elsevierViewall">It is important to remember that the most feared adverse event for vancomycin, the “red man syndrome”, has been reported with both intravenous and oral administration, given that it is not related to systemic drug concentration<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a>.</p><p id="par0025" class="elsevierStylePara elsevierViewall">Despite the available information, switching vancomycin to noninvasive administration routes to increase patient quality of life and reduce direct and indirect costs, as well as systemic adverse events, is still an incomplete task. In that context, the original article by Ramos-García et al. that is published in the current issue of the <span class="elsevierStyleItalic">Revista de Gastroenterología de México</span>, “Fecal concentration of intravenous vancomycin preparation after oral administration in an experimental model: preclinical assay” is an important contribution because it provides preclinical evidence that corroborates the important excretion of intravenously designed vancomycin in stools after oral dosing, using a murine model.</p><p id="par0030" class="elsevierStylePara elsevierViewall">Several significant messages can be highlighted: first, the confirmation that stool concentration is dose-dependent (mouse dosing equivalent to 125<span class="elsevierStyleHsp" style=""></span>mg and 500<span class="elsevierStyleHsp" style=""></span>mg in humans); second, that vancomycin showed important concentration as fast as 2<span class="elsevierStyleHsp" style=""></span>h post dose; and third, that at 6<span class="elsevierStyleHsp" style=""></span>h, the low-dose regimen showed a decrease in stool concentration of vancomycin (below the 2<span class="elsevierStyleHsp" style=""></span>h data), confirming the need for an administration schedule of every 6<span class="elsevierStyleHsp" style=""></span>h.</p><p id="par0035" class="elsevierStylePara elsevierViewall">Some of the concerns regarding the discussion presented in the manuscript should be addressed in future work. Alongside the ones identified by the authors, others are proposed. For example, the safety of the oral administration of vancomycin in their experimental study cannot be properly analyzed, because no specific details on mouse necropsy (if any) were provided. Moreover, the study design was meant for acute exposure only (single dosing). In the clinical setting, oral vancomycin can be needed for at least one week, and tapering is preferred to the traditional loading dose regimens. The fact that vancomycin is a concentration-independent antibiotic and that higher peak concentrations do not reflect clinical efficacy should be kept in mind<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a>.</p><p id="par0040" class="elsevierStylePara elsevierViewall">Further experiments must properly address systemic effects of long-term exposure. In addition, extrapolating vancomycin’s stool concentration to the minimum inhibitory concentration or to the minimum bactericidal concentration (MBC<span class="elsevierStyleInf">90</span>) is risky, given that there are other factors to consider. For example, the total quantity of water drunk, if different between groups, could have misrepresented the vancomycin concentration in stool, unless dry weight or other harmonization strategies were put in place. Furthermore, even though the doses tested resemble the current availability of vancomycin for humans, the suggestion to use the 500<span class="elsevierStyleHsp" style=""></span>mg dosing regimen as the starting dose in CDI is not in line with the current clinical recommendations. At present, tapering doses, instead of loading them, is recommended for mild CDI and moderate CDI.</p><p id="par0045" class="elsevierStylePara elsevierViewall">In conclusion, the study by Ramos-García et al. and the projects derived from it will contribute to further evaluating the oral administration of intravenous-intended vancomycin as a novel approach to improve CDI treatment in our clinical setting. Clinical efficacy, safety, costs, and quality of life in those patients are the main outcomes to be addressed in future projects.</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Financial disclosure</span><p id="par0050" class="elsevierStylePara elsevierViewall">No financial support was received in relation to this article.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Conflict of interest</span><p id="par0055" class="elsevierStylePara elsevierViewall">The author has been an academic and researcher at public and private institutions. He works for Takeda México S.A. de C. V. in the area of pharmacovigilance. The text solely and exclusively reflects his professional experience in the area of pharmacology and is not related to his current position.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0005" "titulo" => "Financial disclosure" ] 1 => array:2 [ "identificador" => "sec0010" "titulo" => "Conflict of interest" ] 2 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "NotaPie" => array:2 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Asbun-Bojalil J. Concentración fecal de la preparación de vancomicina intravenosa posterior a administración oral: datos preclínicos que sustentan necesidades clínicas no satisfechas. Rev Gastroenterol Méx. 2023;88:83–84.</p>" ] 1 => array:2 [ "etiqueta" => "☆☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0010">See related content at <span class="elsevierStyleInterRef" id="intr0005" href="https://doi.org/10.1016/j.rgmxen.2022.03.005">https://doi.org/10.1016/j.rgmxen.2022.03.005</span>, Ramos-García J, Robles-Rivera F, Chávez-Soto M, et Al. Fecal concentration of intravenous vancomycin preparation after oral administration in an experimental model: preclinical assay. Rev Gastroenterol Mex.2023;88:85-90.</p>" ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:8 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:1 [ "referenciaCompleta" => "The Comprehensive Review of the WHO Global Action Plan on Antimicrobial Resistance (volume 2: Annexes, September 2021). Available from: <a target="_blank" href="https://cdn.who.int/media/docs/default-source/documents/about-us/evaluation/gap-amr-final-annexes-v2.pdf?sfvrsn=d7c23fe7_1%26download=true">https://cdn.who.int/media/docs/default-source/documents/about-us/evaluation/gap-amr-final-annexes-v2.pdf?sfvrsn=d7c23fe7_1&download=true</a>." ] ] ] 1 => array:3 [ "identificador" => "bib0010" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Access, excess, and ethics-towards a sustainable distribution model for antibiotics" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:3 [ 0 => "G. Heyman" 1 => "O. Cars" 2 => "M.T. Bejarano" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.3109/03009734.2014.904958" "Revista" => array:5 [ "tituloSerie" => "Upsala J Med Sci." 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| 2024 February | 66 | 47 | 113 |
| 2024 January | 59 | 39 | 98 |
| 2023 December | 71 | 49 | 120 |
| 2023 November | 104 | 65 | 169 |
| 2023 October | 93 | 54 | 147 |
| 2023 September | 137 | 77 | 214 |
| 2023 August | 155 | 80 | 235 |
| 2023 July | 140 | 65 | 205 |
| 2023 June | 156 | 68 | 224 |
| 2023 May | 90 | 40 | 130 |
| 2023 April | 20 | 20 | 40 |
| 2023 March | 70 | 34 | 104 |
| 2023 February | 31 | 23 | 54 |
| 2023 January | 38 | 28 | 66 |
| 2022 December | 43 | 38 | 81 |
| 2022 November | 56 | 35 | 91 |
| 2022 October | 45 | 42 | 87 |
| 2022 September | 31 | 45 | 76 |
| 2022 August | 43 | 51 | 94 |
| 2022 July | 59 | 58 | 117 |
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