Novel Ovine Model of Methicillin-Resistant Staphylococcus Aureus-Induced Pneumonia and Sepsis

Abstract

Methicillin-resistant Staphylococcus aureus (MRSA)-related pneumonia and/or sepsis are a frequent serious menace. The aim of the study was to establish a standardized and reproducible model of MRSA-induced septic pneumonia to evaluate new therapies. Sheep were operatively prepared for chronic study. After 5 days' recovery, tracheostomy was performed under anesthesia, and smoke injury was induced by inhalation of cotton smoke (48 breaths, <40 degrees C). Methicillin-resistant S. aureus (AW6) (approximately 2.5x10(11) colony-forming units) was instilled into the airway by a bronchoscope. After the injury, animals were awakened and maintained on mechanical ventilation by 100% oxygen for first 3 h, and thereafter, oxygen concentration was adjusted according to blood gases. The sheep were resuscitated by lactated Ringer solution with an initial rate of 2 mL kg(-1) h(-1) that was further adjusted according to hematocrit. Study groups include (1) sham (noninjured, nontreated; n=6), (2) S+MRSA (exposed to smoke inhalation and MRSA, nontreated; n=6), and (3) smoke (exposed to smoke inhalation alone; n=6). Injured (S+MRSA) animals showed the signs of severe sepsis-related multiple organ failure 3 h after insult. Cardiovascular morbidity was evidenced by severe hypotension, with increased heart rate, cardiac output, left atrial pressure and severely decreased systemic vascular resistance index, and left ventricle stroke work index. Pulmonary dysfunction was characterized by deteriorated gas exchange (PaO2/FIO2 and pulmonary shunt) and increased ventilatory pressures. The S+MRSA group showed significantly greater lung tissue water content, myeloperoxidase activity, and cytokine production compared with uninjured sham animals. Microvascular hyperpermeability was evidenced by marked fluid retention (fluid net balance), decreased plasma protein with decreased plasma oncotic pressure, and increased pulmonary microvascular pressure. All these changes were accompanied by 6- to 7-fold increase in plasma nitrite/nitrate and increased production of reactive nitrogen species in lung. The smoke inhalation alone had a little or no effect on these variables. This model closely mimics hyperdynamic human sepsis. The excessive production of NO may be extensively involved in the pathogenic process.

The Selective Vasopressin Type 1a Receptor Agonist Selepressin (FE 202158) Blocks Vascular Leak in Ovine Severe Sepsis*

“…This model is characterized by a more severe vascular leak syndrome than the P. aeruginosa pneumonia-induced severe sepsis model studied here (46). Consistent with the observations that we reporting here, we showed that POV was superior to AVP at stabilizing MAP and SVRI and at reducing vascular leak, as shown by a reduction in fluid requirements, cumulative fluid balance, and thoracic cavity and abdominal cavity fluid accumulation, as well as by an attenuation of the decrease in plasma total protein concentration and plasma oncotic pressure.…”

Selective V1aagonism attenuates vascular dysfunction and fluid accumulation in ovine severe sepsis

“…The ovine model of methicillin resistant staphylococcus aureus pneumonia-induced sepsis has been described in detail by Enkhbaatar and colleagues (11). In brief, 24 female sheep were fasted for 24 h before the experiment began, but had free access to water.…”

“…Therefore, the present study was designed as a prospective, randomized, controlled laboratory experiment to elucidate the effects of these treatment strategies on neutrophil activation, nitrosative stress, and markers of vascular dysfunction, namely angiopoietin-2 and VEGF, as well as on cardiovascular and pulmonary function. The study hypothesis was tested in an established ovine two-hit model of severe sepsis resulting from methicillin resistant staphyloccocus aureus-induced pneumonia after smoke inhalation injury (11,15). …”

What lessons have been learnt from animal models of MRSA in the lung?: Table 1—

“…However, if there have been few experimental studies on the development of small animal models of MRSA-induced pneumonia, there have been even fewer using large animal models of MRSA. Nevertheless, it is important to point out the relevance of the study of ENKHBAATAR et al [22], using an ovine model of MRSA-induced pneumonia and sepsis that closely mimics hyperdynamic human sepsis. Authors established a standardised and reproducible model of MRSA-induced septic pneumonia by instillation of S. aureus, with and without smoke injury induced by inhalation of cotton smoke.…”