Evaluation of a novel therapeutic approach to treating severe pneumococcal infection using a mouse model.
P4, a 28-amino-acid peptide, is a eukaryotic cellular activator that enhances specific in vitro opsonophagocytic killing of multiple bacterial pathogens. In a previous study, we successfully recreated this phenomenon in mice in vivo by using a two-dose regimen of P4 and pathogen-specific antibodies, which significantly reduced moribundity in mice. For the present study, we hypothesized that the inclusion of a low-dose antibiotic would make it possible to treat the infected mice with a single dose containing a mixture of P4 and a pathogen-specific antibody. A single dose consisting of P4, intravenous immunoglobulin (IVIG), and ceftriaxone effectively reduced moribundity compared to that of untreated controls (n = 10) by 75% (P < 0.05) and rescued all (10 of 10) infected animals (P < 0.05). If rescued animals were reinfected with Streptococcus pneumoniae and treated with a single dose containing P4, IVIG, and ceftriaxone, they could be rerescued. This observation of the repeated successful use of P4 combination therapy demonstrates a low risk of tolerance development. Additionally, we examined the polymorphonuclear leukocytes (PMN) derived from infected mice and observed that P4 enhanced in vitro opsonophagocytic killing (by >80% over the control level; P < 0.05). This finding supports our hypothesis that PMN are activated by P4 during opsonophagocytosis and the recovery of mice from pneumococcal infection. P4 peptide-based combination therapy may offer an alternative and rapid immunotherapy to treat fulminant pneumococcal infection.
Melnick
Nikkol
N
Division of Bacterial Diseases, Centers for Disease Control and Prevention, Atlanta, GA 30333, USA.
Rajam
Gowrisankar
G
Carlone
George M
GM
Sampson
Jacquelyn S
JS
Ades
Edwin W
EW
D000818:Animals; D000900:Anti-Bacterial Agents / Q000627:therapeutic use; D000907:Antibodies, Bacterial / Q000627:therapeutic use; D001426:Bacterial Proteins / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use; D002443:Ceftriaxone / Q000627:therapeutic use; D004359:Drug Therapy, Combination; D005260:Female; D007116:Immunization, Passive / Q000379:methods*; D016756:Immunoglobulins, Intravenous / Q000627:therapeutic use; D007155:Immunologic Factors / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology; D010455:Peptides / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use*; D010587:Phagocytosis / Q000187:drug effects; D011008:Pneumococcal Infections / Q000628:therapy*; D013296:Streptococcus pneumoniae / Q000737:chemistry / Q000276:immunology*; D016019:Survival Analysis
D000900:Anti-Bacterial Agents; D000907:Antibodies, Bacterial; D001426:Bacterial Proteins; D016756:Immunoglobulins, Intravenous; D007155:Immunologic Factors; D010455:Peptides; D002443:Ceftriaxone