Lysostaphin Effectively Kills S. Aureus

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        Promising Agent Emerging To Battle Mesh Infection

        Gabriel Miller
        Orlando, Fla.— Investigators have identified a novel antimicrobial against Staphylococcus aureus that can be embedded on hernia mesh, providing a possible solution to one of the most stubborn and expensive complications of tension-free hernia repair—mesh infection.

        Results of two studies of the antimicrobial were presented at the annual meeting of the American Hernia Society (AHS), where experts hailed the compound lysostaphin as a much-needed breakthrough in an area that has seen little progress over the past several decades.

        “Despite refinements in our operative technique, despite scrutiny in our antibiotic selection and the timing of our antibiotics, despite protocol-driven perioperative management plans that address oxygen and temperature, we have not made much headway in the incidence of mesh-related infections,” said Paul Montero, MD, a research fellow in general surgery at Carolinas Medical Center in Charlotte, N.C., who presented one of two studies at the AHS meeting.

        The reason so little headway has been made, according to investigators, is biofilm. A microbial biofilm develops when microorganisms adhere to an inert object, like a hernia mesh, and produce a structural matrix on the surface of the object, most often in the presence of necrotic tissue.

        Any number of bacteria can develop biofilms on indwelling medical devices, but one of the key aspects of all biofilms is that the microorganisms of a biofilm behave much differently from their free-bacteria counterparts. For one, a biofilm develops a protective shield of extracellular polymers that encases the bacterial cell adhering to the device. Infectious disease specialists at the Centers for Disease Control and Prevention (CDC) wrote that “biofilms are both tenacious and highly resistant to antimicrobial treatment” in a 2001 article in Emerging Infectious Diseases that pointed to biofilms as an emerging public health problem. Bacteria within a biofilm are more resistant to antimicrobial agents, which the CDC noted was “an area of great importance from a public health perspective.”

        “The problem with antibiotics is that they are great at managing bacteremia in soft tissue infections, but the problem is that bacterial biofilms can survive with an antibiotic concentration of about 1,000 to 1,500 times that of free bacteria,” said Terri Martin, MD, also a research fellow in general surgery at Carolinas Medical Center who presented at the AHS.

        For hernia surgeons, the most common pathogen in mesh-related infections is Staphylococcus aureus, which is increasingly found to be methicillin-resistant and now colonizes one-third of the world’s population.

        Thus, an S. aureus biofilm on hernia mesh “renders most of our antibiotics pretty much useless and enables foreign body-related infections to be nearly impossible to eradicate with antibiotics alone,” said Dr. Montero.

        Enter lysostaphin, a peptide developed by a competing Staphylococcus bacterium that specifically targets and destroys S. aureus. Lysostaphin attacks the cell walls of S. aureus and causes pores to develop, eventually killing the S. aureus cells. Critically, lysostaphin is bactericidal, meaning that it kills both active S. aureus as well as penetrates biofilm, killing encapsulated quiescent bacteria as well. “Its sole purpose is to kill Staph aureus,” Dr. Martin said.

        In a study presented by Dr. Martin, the Carolinas Medical Center group identified lysostaphin as the only effective protein in killing S. aureus from among a group of more than 29 potential candidates. The results were based on a number of measures, including cell colony counts, analyzed in an in vitro infection model of mesh embedded with lysostaphin.

        Taking the results one step further, the Carolinas group then studied lysostaphin in vivo using biologic mesh in a rat model of hernia repair.

        The study included two biologic meshes, an allograft (Alloderm) and a xenograft (Strattice), which were divided into groups of untreated, low-dose, and moderate-dose lysostaphin-embedded meshes.

        Rats also were divided into two groups—no infection or inoculation with 108 S. aureus.

        In general, the study was designed to answer two questions:

        1. Did lysostaphin effectively overcome S. aureus in vivo?
        2. Can lysostaphin-laced mesh potentially cause any harm?

        The effects of lysostaphin were stark. In the xenograft group, not a single untreated, infected rat survived to 28 days, whereas every single rat treated with moderate-dose lysostaphin survived.

        In uninfected rats whose xenograft mesh had been treated with lysostaphin, the addition of the antimicrobial agent had no deleterious effects. The two groups whose mesh was treated with lysostaphin showed a slightly decreased neutrophil count and increased fibroblast count, which investigators did not consider negative.

        In the allograft group, results were almost equally as stark. When meshes were extracted at 28 days, lysostaphin-treated meshes had significantly less bacterial colonies (P=0.003), neutrophils (P=0.036), plasma cells (P=0.0004) and lymphocytes (P=0.003). Antimicrobial treatment did not affect shear strength of the mesh (P=0.10) and, again, an increased fibroblast count was seen in treated mesh compared with untreated controls.

        In the allograft group, there also were no differences in mesh strength, lymphocytes, neutrophils, plasma cells or fibroblasts between uninfected controls and rats that were inoculated with S. aureus and repaired with lysostaphin-treated mesh.

        The same held true for meshes explanted at 60 days; however, only a portion of the untreated and infected rats survived compared with survival of all treated and infected rats.

        “In summation, the addition of lysostaphin to biologic mesh can help revert or avert the deleterious consequences of infection, and there are no negative consequences by adding lysostaphin to controls,” said Dr. Montero.

        The studies were immediately heralded as promising from a clinical point of view.

        “First of all, I’d like to congratulate [the Carolinas group] on a wonderful paper,” said John Murphy, MD, a general surgeon at William Beaumont Hospital in Troy, Mich., and the president of the AHS. “I predict that within the next two or three years, we’ll be using mesh that’s impregnated with lysostaphin.”

        “This is perfect, and a great study,” said Klaus-Joachim Conze,, consultant general surgeon in the Department of Surgery at the University Hospital in Aachen, Germany. “Maybe we don’t even need this in biologic meshes but we can use this great antimicrobial protein on synthetic meshes.”

        Studies currently are under way to test lysostaphin embedded on synthetic mesh, Dr. Montero said, but biologic mesh was chosen first because it is used most often in infected fields.

        One question raised by Dr. Murphy was whether the Carolinas group had developed any “secondary backups” if resistant strains emerged. But here, again, lysostaphin seemed to excel.

        According to Dr. Martin, lysostaphin resistance is extraordinarily rare and those very few strains that are lysostaphin-resistant are significantly less virulent and grow five times slower than other S. aureus strains. Furthermore, the very quality that makes rare strains resistant—changes in their cell wall—results in higher susceptibility to β-lactam antibiotics like cephalosporins.

        “Those Staph aureus species that are resistant to lysostaphin have a reduced fitness in terms of their ability to replicate or cause infection and are susceptible to first-generation cephalosporins, so it’s a very promising antimicrobial,” Dr. Montero said.

        Courtesy of General Surgery News. For access to this article, free registration is required, see

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