Particulate Matter Contamination of Intravenous Antibiotics Aggravates Loss of Functional Capillary Density in Postischemic Striated Muscle

Abstract

Through the increased use of less expensive and counterfeit medicines, the contamination of parenteral fluids and drugs by particulate matter poses an increasing health hazard worldwide. However, the mechanism of action of such contamination has never been conclusively demonstrated. We have systemically injected the particles contained in three different 1-g preparations of the antibiotic cefotaxime into hamsters and visualized the functional capillary density in striated skin muscle, using intravital fluorescence microscopy. Injection of particles from either of the three preparations did not affect capillary perfusion in normal muscle (n = 3 hamsters, each). However, injection of particles from two generic drug preparations, but not the original preparation or the saline control, significantly reduced capillary perfusion in muscle tissue that had previously been exposed to 4 h of pressure-induced ischemia and 2 h of reperfusion (n = 9 hamsters per group). Histological sections demonstrated birefringent particles mechanically obliterating the microcirculation of the striated muscle. The loss of capillary perfusion due to particle injection or injection of standardized microspheres was dependent on the extent of ischemia/reperfusion-induced muscle injury, with more capillaries lost in the more severely compromised muscle areas. These findings suggest that particle contaminants may not pose a major threat in intact tissue, but may severely compromise tissue perfusion in patients with prior microvascular compromise of vital organs (i.e., after trauma, major surgery, or sepsis) and thus predispose to complications such as acute respiratory distress syndrome or multiple organ failure.

Factores de riesgo asociados a mortalidad en infecciones relacionadas con la atención en salud en un hospital universitario de tercer nivel en Colombia

“…Además, en la literatura científica no se registra ningún antibiótico genérico de los empleados en nuestro país que haya sido probado por medio de ensayos clínicos controlados para establecer su eficacia clínica y seguridad, y, sin embargo, se ha asumido que son las mismas del producto innovador. La eficacia clínica no solo depende del principio activo sino de la tecnología farmacéutica (definida como los procesos de manufactura del antibiótico), la cual puede ser responsable de reducir o eliminar propiedades del fármaco, alterando su mecanismo de acción (39).…”

Particulate Matter in Injectable Drugs: Evaluation of Risks to Patients

“…In hospital, IV fluids are not usually administered to healthy patients, but rather to ill patients (polytrauma, major surgery, microvascular blood affections, etc.). Lehr et al [105] investigated whether particulate contamination could affect the microvascular bed, using different IV solutions of cefotaxime. Functional capillary density (FCD) was analysed in non-ischemic and ischemic-reperfused muscle tissues; it was found that loss of FCD induced by particles was particularly significant in the post-ischemic tissue.…”

Non-Equivalence of Antibiotic Generic Drugs and Risk for Intensive Care Patients

“…Whilst no view will be expressed on risks associated with oral medication with generics, we will focus exclusively on the intravenous administration route in severely ill patients [21]. Former work from our laboratory involved a detailed study of generics of the antibiotic cefotaxime, in which the innovator product, Claforan ® , was compared with some of its generics [21].…”

“…Whilst no view will be expressed on risks associated with oral medication with generics, we will focus exclusively on the intravenous administration route in severely ill patients [21]. Former work from our laboratory involved a detailed study of generics of the antibiotic cefotaxime, in which the innovator product, Claforan ® , was compared with some of its generics [21]. This in vivo study was designed to test the possible functional significance of particulate contaminants, and aimed at simulating the state of the microcirculation in a typical patient in the intensive care unit (ICU), that is, generally with some degree of multiple organ dysfunction syndrome (MODS), in the form of microcirculatory dysfunction [22][23][24][25].…”

“…Microcirculatory dysfunction was induced by ischemia and reperfusion (I/R) injury, and the state monitored by the functional capillary density (FCD), that is the percentage of the capillary system in the observed microcirculation being actively perfused, as quantitatively determined from images taken randomly from video microscopy. The study using cefotaxime generics demonstrated in a membrane filter technique that many generics were contaminated by foreign particulate matter, and that intravenous injection of these particles in the rodent model caused further shut-down of the compromised microcirculation [21]. Detailed histological analysis of the skin window tissue revealed particulates in the lumen of capillary branches.…”