IVIG-mediated protection against necrotizing pneumonia caused by MRSA

Abstract

New therapeutic approaches are urgently needed to improve survival outcomes for patients with necrotizing pneumonia caused by Staphylococcus aureus One such approach is adjunctive treatment with intravenous immunoglobulin (IVIG), but clinical practice guidelines offer conflicting recommendations. In a preclinical rabbit model, prophylaxis with IVIG conferred protection against necrotizing pneumonia caused by five different epidemic strains of community-associated methicillin-resistant S. aureus (MRSA) as well as a widespread strain of hospital-associated MRSA. Treatment with IVIG, either alone or in combination with vancomycin or linezolid, improved survival outcomes in this rabbit model. Two specific IVIG antibodies that neutralized the toxic effects of α-hemolysin (Hla) and Panton-Valentine leukocidin (PVL) conferred protection against necrotizing pneumonia in the rabbit model. This mechanism of action of IVIG was uncovered by analyzing loss-of-function mutant bacterial strains containing deletions in 17 genes encoding staphylococcal exotoxins, which revealed only Hla and PVL as having an impact on necrotizing pneumonia. These results demonstrate the potential clinical utility of IVIG in the treatment of severe pneumonia induced by S. aureus.

Targeting Alpha Toxin To Mitigate Its Lethal Toxicity in Ferret and Rabbit Models of Staphylococcus aureus Necrotizing Pneumonia

“…MEDI4893* prophylaxis conferred greater protection against lethal pneumonia due to HA-MRSA USA100 compared to CA-MRSA USA300 (Fig. 3) in rabbits, likely because MEDI4893* does not neutralize PVL, which was also shown to play a role in the pathogenesis of USA300 necrotizing pneumonia (5,13). This hypothesis is supported by a recent publication demonstrating a MAb specific for alpha toxin, PVL, LukED, and gamma hemolysin provided greater protection in USA300 necrotizing pneumonia in rabbits than an anti-AT MAb alone (6).…”

“…Alpha toxin (AT), a pore-forming cytolytic toxin, has been shown to be a key virulence determinant in mouse and rabbit S. aureus pneumonia models (4,5). Consequently, it has been the focus of much research to better understand its role in pneumonia and its utility as a target for novel methods to treat or prevent S. aureus pneumonia (6)(7)(8)(9)(10).…”

Could Intravenous Immunoglobulin Collected from Recovered Coronavirus Patients Protect against COVID-19 and Strengthen the Immune System of New Patients?

“…IVIg is a pool of IgG from thousands of healthy donors, and exposure of individual donors to endemic infectious diseases, vaccines, and ubiquitous microorganisms participates in the production of IgG antibodies against different microorganisms and their products [13][14][15].…”

Effects of Tedizolid Phosphate on Survival Outcomes and Suppression of Production of Staphylococcal Toxins in a Rabbit Model of Methicillin-Resistant Staphylococcus aureus Necrotizing Pneumonia

“…The superior protective efficacy of tedizolid phosphate over that of vancomycin in the rabbit MRSA USA300 pneumonia model stands in contrast to the superior protective efficacy of vancomycin over that of tedizolid phosphate in the rabbit model of aortic valve endocarditis (20). One potential explanation for this discrepancy could be that the USA300/SF8300 clinical strain used in the rabbit pneumonia model is known to naturally hyperproduce alpha-toxin and PVL (21), which together play critical roles in the pathogenesis of necrotizing pneumonia (5,7). In contrast, although alpha-toxin is known to contribute to the pathogenesis of aortic valve endocarditis (22), the MRSA strain used for evaluating the protective efficacies of tedizolid phosphate and vancomycin in the rabbit aortic valve endocarditis model, strain COL, produces little alphatoxin and is largely nonhemolytic (23); COL also does not produce PVL because it lacks the horizontally acquired prophage encoding this toxin (24).…”

“…In a preclinical rabbit model of necrotizing pneumonia caused by MRSA strain USA300, linezolid was shown to be superior to vancomycin, a cell wall synthesis inhibitor, in improving survival outcomes by inhibiting the production of two key lung-damaging staphylococcal toxins, Panton-Valentine leukocidin (PVL) and alphatoxin (Hla) (5)(6)(7). MRSA strain USA300 is currently causing epidemic disease within communities and hospitals throughout the United States and other countries (8,9) and is an important cause of difficult-to-treat and potentially lethal community-associated and hospital-associated pneumonia (10,11).…”