Assessment of the efficacy of polyclonal intravenous immunoglobulin G (IVIG) against the infectivity of clinical isolates of methicillin-resistant Staphylococcus aureus (MRSA) in vitro and in vivo

Abstract

The response to treatment of severe methicillin-resistant Staphylococcus aureus (MRSA) infections with the traditional antibiotics is sometimes unsatisfactory and multiple antibiotic resistance is common. Adjuvant therapy such as intravenous immunoglobulin G (IVIG) could possibly be helpful in the treatment of such infections. The effect of IVIG on the capacity of human neutrophils to phagocytose and kill MRSA was investigated in vitro using the MTT assay and measuring the production of reactive oxygen species (ROS) and nitric oxide (NO). The efficiency of IVIG in neutralizing α-hemolysin and coagulase of MRSA was also assessed. The capability of IVIG in the treatment and prevention of MRSA infections was also evaluated in a murine peritonitis model. IVIG significantly enhanced (p < 0.01) the killing of MRSA by neutrophils at all concentrations tested (0.1-5 mg/ml) by 30-80 % of control values. It significantly (p < 0.01) increased the level of NO production in a dose-dependent manner, giving up to 60 μM at 5 mg/ml. The ROS level significantly increased (p < 0.01) in the presence of IVIG. In addition, IVIG significantly reduced the hemolytic activity of MRSA 10-fold and its coagulation capabilities by 50 %. When tested in vivo, groups receiving IVIG via tail vein infusion showed no significant improvement in their survival. Only when delivered to the same site of infection did IVIG show an improvement in the survival of mice (n = 80). These results could pave the way for a better understanding of the mechanism of action of IVIG and suggest its clinical potential as an adjuvant preventive and therapeutic agent against life-threatening infections caused by MRSA and other bacteria.

Increased Neutrophil Extracellular Trap–Mediated Staphylococcus aureus Clearance Through Inhibition of Nuclease Activity by Clindamycin and Immunoglobulin

“…Both clindamycin and immunoglobulin are being used empirically in clinics [41, 42] to treat bacterial infections. In vitro antagonism of clindamycin and vancomycin against S. aureus has been described elsewhere [43, 44], but the clinical relevance of this in vitro antagonism has not yet been prospectively analyzed.…”

Targeted localized use of therapeutic antibodies: a review of non-systemic, topical and oral applications

“…Close to 100% survival for mice (n ¼ 15) was achieved when a single local post-burn dose of IgG (10 mg) was administered simultaneously or before the infection challenge (P. aeruginosa inoculation at the burn site) and prevented the spread of bacteria within the body (Felts et al, 1999). When local antibacterial IgG injections were combined with intravenous antibiotics, a synergistic effect was seen, which provided protection against various virulent antibiotic resistant strains of Gram-negative and Gram-positive bacteria (Barekzi et al, 2002;Farag et al, 2013;Felts et al, 2000). In contrast, no enhancement of test animal survival was reported when both the antibodies and antibiotic were systemically administered (Barekzi et al, 2002;Farag et al, 2013;Felts et al, 2000) again demonstrating the benefits of locally applied antibodies.…”

A novel combination approach of human polyclonal IVIG and antibiotics against multidrug-resistant Gram-positive bacteria

“…MRSA is the most common cause of septic shock and multiple organ failure. The outcomes of treatment of severe infections caused by MRSA with currently available antibiotics are often unsatisfactory 3,6…”

“…The broad-spectrum antimicrobial activity of IVIG is mediated through the immune modulation of the host humoral immunity and cellular immunity, particularly opsonization and phagocytic activation 6. Since the mechanisms of the antimicrobial action of the antibodies are different from those of the antibiotics, cross-resistance of antibiotic-resistant strains to IVIG never exists 11…”

“…The pool sizes of the IVIG guarantee wide spectrum of antibody specificities, including neutralizing antibodies for bacterial virulence factors such as streptococcal-super antigen, α-hemolysin, and coagulase of MRSA 6,15,16. It would be possible that IVIG contains neutralizing antibodies for bacterial virulence factors responsible for antibiotic resistance.…”