By David N. Leff
In the ding-dong war between infectious bacteria and antibacterial drugs, the bad guys seem to be winning. Infective pathogens are mounting resistance to long-established first-line antibiotics at an ever-faster rate, and so far the main counter-offensive is to throw new second-line antibiotics at the advancing microbial enemy.
Public enemy No. 1 is Staphylococcus aureus, one of the commonest perpetrators of nosocomial (hospital-acquired) infections. Because Staphylococcus is a common skin contaminant, it normally colonizes human body surfaces, including nasal passages.
In hospitalized patients, especially those undergoing surgery or catheterization — wherever there's a break in the skin, S. aureus sets up serious infections, such as internal abcesses. It's also one of the pathogens with the sharpest resistance to antibiotics — about 20 percent.
"And the big concern," observed applied microbiologist Spiros Jamas, "is that the only line of treatment left is the antibiotic vancomycin. So if a vancomycin-resistant strain of S. aureus emerges, that will obviously cause grave problems." Jamas is president and CEO of Alpha-Beta Technology Inc., of Worcester, Mass. His company's drug, Betafectin, is in both animal and human trials, and is designed to give antibiotics more firepower against infective microorganisms.
"Although new antibiotics are constantly being developed to treat nosocomial infections," Jamas observed, "it's always a race between the bacteria and the drugs. Bacteria are always adapting, mutating, and developing resistance over time."
Jamas made the point that antibiotic drugs are not self-sufficient pathogen-killing machines. "These agents only provide support," he said, "for the essential immunological functions of phagocytosis and intracellular killing."
It's there that Betafectin acts, by priming the functions of the immune system's neutrophils and monocytes. These white blood cells patrol the body's circulation, looking for pathogens to engulf and destroy.
A paper in the September 1998 issue of the journal Antimicrobial Agents and Chemotherapy (AAC) reports on a pivotal animal trial of Betafectin's ability to help a front-line antibiotic limit S. aureus infection. Its title is "Synergism between poly-(1-6)-ß-D-glucopyranosyl-(1-3)-ß-D-glucopyranose glucan and cefazolin [antibiotic] in prophylaxis of Staphylococcal wound infection in a guinea pig model."
This unabridged chemical formula reveals that Betafectin is a complex configuration of glucose, engineered in a triple helix, which finds receptors only on neutrophils and monocytes.
The AAC article's co-authors are infectious-disease specialists Aaron Kaiser and Douglas Kernodle, at Vanderbilt University, in Memphis, Tenn. They test guinea pigs in a special way.
"This is not a typical model where you measure survival and mortality, and count dead animals," Jamas said. "Rather, it gives a quantitative read-out."
Guinea Pigs Gauge Staphylococcus VirulenceIn Assorted Regimens
The Vanderbilt authors counted the number of Staphylococcus cells it took to create abcesses under the skins of 101 guinea pigs, inoculated with the virulent pathogens.
They acquired these fresh and hungry bacteria from wounds complicating cardiac surgery, and injected them under the shaved skins on the animals' backs in a grid of 12 sites, totaling 1,081 lesions.
One-fourth of the infected guinea pigs had received Betafectin infusions together with cefazolin. Two other equal cohorts got either the antibiotic or Betafectin alone, while placebos went to the remaining 25.
In one typical experiment, it took less than one Staphylococcus cell to infect the placebo contingent; 18 to raise abcesses on the Betafectin-only group; 315 germs to do in the cefazolin animals; and 2,468 bacteria to overcome the cocktail of Betafectin and cefazolin combined.
"Doctors Kaiser and Kernodle were surprised by the combination, which produced an almost multiplicative effect. It's not just purely additive, but truly synergistic," Jamas recalled. "Those Vanderbilt collaborators have published other papers where they've looked at combinations of various antibiotics, and seeing these resistant organisms. But they've never seen this level of synergy before between Betafectin and the antibiotic."
618 Post-Surgery Patients Testing Betafectin
Meanwhile, a large-scale, placebo-controlled Phase III clinical trial of Betafectin got under way last January. "This study," Jamas told BioWorld Today, "is designed to enroll 618 patients at 30 clinical sites in the U.S. (See BioWorld Today, Nov. 5, 1997, p. 1.)
"The trial is focusing on patients undergoing upper gastrointestinal surgery — stomach, esophageal, pancreatic procedures," he continued. "All of them are receiving a standardized antibiotic, mainly cefazolin, and being treated with one milligram per kilogram of Betafectin.
"The primary endpoint," Jamas went on, "is the number of patients who get a post-operative infection within 30 days of surgery."
Alpha-Beta has retained a clinical research organization to manage the study, together with a small clinical team within the company.
"We are about a month away from the midway point of this Phase III trial," Jamas observed, "getting close to 300 patients. We will then be doing an interim safety and efficacy analysis," he added, "so within about a month we will kick off that data collection."
On the company's drawing board is a project extending Betafectin use to other clinical indications. "As our next step," Jamas said, "we're going to evaluate it with vancomycin-resistant Staphylococcus isolates. We're beginning to plan a clinical development program directed at nosocomial pneumonia.
"The outcome with antibiotics for treating this pulmonary infection is not very good," he observed. "There's a fairly high mortality, and a lot of bacterial resistance developing to antibiotics. So, pneumonia is one area that we think could be very attractive — where we go in to a therapeutic study of hospitalized patients diagnosed with pneumonia, who would then be treated with Betafectin and a first-line antibiotic.
"The idea being," he concluded, "that you get a better outcome with that regimen, and don't have to switch to second-line antibiotics, which are much more expensive. And you have a resistant organism at that point, which becomes much more difficult to treat." *