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Immunotherapeutic advances in the treatment of gram-negative bacterial sepsis

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Abstract

Gram-negative bacterial sepsis with the frequent sequelae of shock, multi-system organ failure, and death represents one of the most severe infections that can occur in the surgical patient. Fatality in most series has paralleled the presence and severity of underlying host disease processes, polymicrobial bacteremia, shock, and lack of early appropriate antimicrobial therapy. Even patients with no underlying disease state have a significant mortality (10–20%). Therapy of gram-negative bacterial sepsis and shock at present consists of antimicrobial agents, hemodynamic monitoring, aggressive fluid resuscitation, and metabolic support. The use of these treatment modalities in concert has reduced, but not eliminated, the severe consequences that may ensue. Administration of antibody directed against the comon core lipopolysaccharide antigen of gramnegative microorganisms to patients with gram-negative sepsis represents a means by which the morbidity and mortality of this disease process may be further reduced. This is supported by a large body of experimental evidence, as well as several preliminary clinical studies. It is necessary to determine how the clinical efficacy of such antibody preparations can be maximized. This will entail rigorously controlled studies in which the timing of antibody administration and dose utilized can be correlated with clinical efficacy. Should such antibody preparations continue to prove efficacious as an additive form of therapy, it may be possible to identify high-risk groups of patients who would benefit from antibody prophylaxis.

Résumé

L'infection bactérienne à gram négatif et ses conséquences fréquentes: choc, défaillance multiviscérale, mort, représentent une des infections les plus graves susceptibles de survenir chez le malade chirurgical. La mortalité dans de nombreuses séries va de pair avec la présence et la sévérité du processus pathologique sous-jacent auquel est soumis le malade, avec l'infection polymicrobienne, le choc et l'absence d'une antibiothérapie précoce appropriée. Même les malades qui n'ont pas de maladie méconnue sont menacés d'une mortalité importante (10–20%). Le traitement de l'infection et du choc dûs à des germes gram négatif comporte plusieurs mesures: emploi d'agents anti-microbiens, monitorage hémodynamique, réanimation liquidienne importante, support nutritif. Leur emploi simultané a réduit mais n'a pas supprimé les conséquences de ce type d'infection. L'usage d'anticorps dirigé contre le noyau commun lipopolysaccharidique de l'antigène des micro-organismes à gram négatif représente chez ces malades un moyen susceptible de réduire la morbidité et la mortalité. Cette conception est soutenue par une vaste étude expérimentale et aussi par plusieurs études cliniques préliminaires. Il est nécessaire de déterminer comment l'efficacité clinique de cet anticorps peut être portée à son maximum. Ce dessein entraîne des études rigoureusement contrôlées au cours desquelles la posologie (temps et dose) utilisée peut être corrélée avec l'efficacité clinique. Si cette modalité thérapeutique par anticorps devait se montrer un agent adjuvant efficace, il serait possible d'identifier les malades à haut risque susceptibles de bénéficier de l'emploi prophylactique de l'anticorps.

Resumen

La sepsis por bacterias Gram negativas con sus frecuentes secuelas de shock, falla orgánica multisistémica, y muerte representa una de las más severas formas de infección que puede ocurrir en el paciente quirúrgico. La letalidad en la mayoría de las series ha sido paralela a la presencia y gravedad de la enfermedad de base, a la bacteremia polimicrobiana, al shock, y a la falla en iniciar terapia antimicrobiana apropiada y precoz. Aún pacientes libres de enfermedad de base exhiben una mortalidad significativa (10–20%). La terapia de la sepsis bacteriana y del shock Gram negativos actualmente consiste en el uso de agentes antimicrobianos, monitoría hemodinámica, resucitación agresiva con líquidos parenterales, y soporte metabólico. El uso concertado de estas modalidades terapéuticas ha reducido, aunque no eliminado, las severas complicaciones que pueden presentarse. La administración del anticuerpo contra el núcleo común del antígeno liposacárido de los microorganismos Gram negativos a pacientes con sepsis Gram negativa representa un método que puede lograr una reducción adicional de la morbilidad y mortalidad, a juzgar por un volumen considerable de evidencia experimental, así como de varios estudios clínicos preliminares. Es necesario determinar la manera como la eficacia de tales preparaciones de anticuerpos puede ser optimizada. Esto implica la realización de rigurosos estudios controlados en los cuales el momento de administración del anticuerpo y las dosis utilizadas puedan ser correlacionadas con la eficacia clínica. En el caso de que tales preparaciones de anticuerpos continuen demostrando su eficacia como terapia adyuvante, séria tal vez posible identificar los grupos de pacientes de alto riesgo que puedan beneficiarse de la profilaxis con anticuerpos.

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  1. Department of Surgery, University of Minnesota, Mayo Memorial Building, Box 242, 55455, Minneapolis, Minnesota, USA

    David L. Dunn M.D., Ph.D.

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Supported in part by grant GM 32414 from the National Institutes of Health.

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Dunn, D.L. Immunotherapeutic advances in the treatment of gram-negative bacterial sepsis. World J. Surg. 11, 233–240 (1987). https://doi.org/10.1007/BF01656407

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