Technology Also Helps Determine Most-Effective Antibiotics
By Brenda L. Mooney
The DoD’s involvement with the development of new technology to rapidly identify pathogens and appropriate antibiotic therapy has its roots in the Iraq and Afghanistan wars. Transporting wounded warriors increased survival rates but also raised the likelihood that those servicemembers received inappropriate antibiotics.
DENVER—U.S. warfighters injured in combat in Iraq and Afghanistan had a remarkable 90% or more rate of survival, with much of that success credited to a medical evacuation system that quickly transported them to locations such as Landstuhl Regional Medical Center in Germany or to Brooke Army Medical Center in Texas.
The unexpected consequence, however, was the dramatic increase in opportunities for those wounded warriors, who traveled thousands of miles during days of being treated, to acquire opportunistic infections. Study after study documents how those patients, often suffering from polytrauma, were then prescribed antibiotics—sometimes inappropriate—based on the best guess of a physician they might see once. The result: Greater antibiotic resistance.
Although there weren’t many other options at the time, the history helps explain why the need for rapid identification of pathogens is so important to the U. S. military, which also faces the risk of bioterrorism or biological weaponry in future conflicts.
“Wounded warriors (WW) have a high rate of combat-associated infections that, because of their debilitated state, can become life- or limb-threatening if not treated appropriately within a few hours of symptom onset,” wrote Connie Price, MD, of the Denver Health and Hospital Authority in a technical abstract seeking funding from the Congressionally Directed Medical Research Programs (CDMRP). “Conventional laboratory cultures require 2-3 days to produce results that can guide antibiotic selection, which is too late to affect outcomes. Adverse events (AEs), such as drug toxicity and/or Clostridium difficile infection, from use of overly broad-spectrum antimicrobial agents while awaiting cultures adds to the associated morbidity and mortality.”
Price’s research focuses on more rapid technologies to accurately diagnose the specific cause of an infection and to allow better targeted antibiotic treatment. “This would result in more effective early treatment of infection, decrease unnecessary exposure to excess antibiotics, and could slow the development of antibiotic resistance,” she added.
The technology she proposed—multiplexed automated digital microscopy (MADM)—has shown success in preclinical research in identifying and quantifying multiple pathogens within two hours. The effect of selected antibiotics on the bacteria, including multidrug-resistant pathogens, allows clinicians to determine within six hours from specimen collection what agent to employ.
The equation is fairly straightforward, as Price told U.S. Medicine, “More rapid identification of antimicrobial resistance equals earlier appropriate therapy and/or de-escalation to more narrow spectrum therapy to avoid development of antimicrobial resistance.”
Since the 2012 funding of the grant, she and her study team have validated and identified within an hour a number of bacterial species including S. aureus, Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca, Enterobacter aerogenes, Enterobacter cloacae, Acinetobacter baumannii and Pseudomonas aeruginosa with sensitivity and specificity of at least 97% in blood cultures, according to CDMRP.
Also performed, the agency noted, was “antibiotic susceptibility testing with specific minimum inhibitory concentration within 5 hours for methicillin vs. S. aureus, ciprofloxacin, imipenem, amikacin and minocycline vs. A. baumanii and ciprofloxacin and amikacin vs. P. aeruginosa.”
Price has been working with an industry partner, Accelerate Diagnostics Inc., which received approval from the Food and Drug Administration in February to allow marketing of the PhenoTest BC Kit, performed on the Pheno System.
“The digital microscopy platform we studied in our DoD work ultimately became the FDA-approved Pheno system,” Price pointed out.
In a press release, the FDA explained the value of the technology. “By identifying organisms and knowing earlier which antibiotics the organism is likely to respond to, health care professionals can treat patients with bloodstream infections more appropriately,” said Alberto Gutierrez, PhD, director of the FDA’s Office of In Vitro Diagnostics and Radiological Health at the FDA’s Center for Devices and Radiological Health.
The FDA press release also discussed benefits outside of the military setting, noting, “bacterial or yeast blood infections can occur in patients of all ages, but are particularly severe in infants, the elderly and those with weakened immune systems. If not treated rapidly, such bloodstream infections can lead to severe complications, such as septic shock and death.”
The agency pointed out that, as opposed to most currently used identification and antibiotic susceptibility tests that can take a day or two to return results after a positive blood culture, the PhenoTest BC Kit identifies bacteria or yeast from a positive blood culture in about 90 minutes.
“For certain organisms, the test also provides important information to guide treatment recommendations in approximately 6.5 hours after the organisms are detected from blood cultures,” the FDA wrote.
The PhenoTest BC Kit, which works by measuring the similarity of the infection-causing organism’s genetic material to DNA known to be unique to specific bacteria or yeast, can identify 14 different species of bacteria and two species of yeast that cause bloodstream infections.
It also provides antibiotic sensitivity information on 18 selected antibiotics for a subset of the identified organisms as appropriate. Also pinpointed are the presence of two indicators of antibiotic resistance.
Targeted organisms are mixed with antibiotics and the growth of the bacteria is measured by time-lapse images to adjudge its effectiveness.
While the product has been well-received, Price said getting used to the “new paradigm” has been difficult for some infectious disease specialist. And, even though it identifies a myriad of pathogens, some of the feedback has request that be broadened.
The PhenoTest BC Kit was reviewed by the FDA through the de novo premarket review pathway, a regulatory pathway for devices of a new type with low to moderate-risk that are not substantially equivalent to an already legally marketed device and for which special controls can be developed, in addition to general controls, to provide a reasonable assurance of safety and effectiveness of the devices.
The decision to allow marketing was based on Accelerate Diagnostic’s primary clinical study of 1,850 positive blood cultures. The trial included more than 39,000 tests conducted on 1,850 samples across 13 trial sites.
It showed overall sensitivity of 97.4% and specificity of 99.3% for identification. For susceptibility, overall essential and categorical agreement vs. standard broth microdilution was 96.3% and 96.4%, respectively.
The Accelerate PhenoTest BC kit includes 140 assays for both identification and susceptibility testing, of which 116 were submitted to the FDA, and also includes what Accelerate refers to as a “definitive” monomicrobial test indicating when a patient’s positive blood culture sample has only one targeted pathogen.
In the Accelerate clinical trial the monomicrobial result had a 99.6% positive predictive value (PPV) when evaluated in combination with the Gram stain. The monomicrobial result, matched with a Gram stain, allows microbiologists to report results without additional laboratory workup, the company said.
Improved identification of pathogens and antibiotic selection will continue to be important to the DoD, especially with complex problems with resistance.
The military reported that, in 2013, the methicillin-resistant Staphylococcus aureus (MRSA) incidence rates were 58.7 and 73.0 per 100,000 persons per year in the DoD and Navy beneficiary populations, a 59% decrease since 2005.1
Most of the MRSA were outpatient, community-associated and involved skin and soft tissue infections (SSTIs).
In the DoD from 2005—2013, MRSA isolates showed decreased susceptibility to cefazolin, but increased susceptibility to erythromycin and cefotaxime in both the DoD and Navy and to gentamicin in the Navy only.
Furthermore, according to the document, the proportion of MRSA cases with inducible clindamycin resistance is increasing, with a 31.3% increase in the DoD and a 65.3% increase in the Navy from 2005 to 2013.
- Spencer J, Chukwuma U. Methicillin-Resistant Staphylococcus aureus (MRSA) Infections in the Department of Defense (DOD): Annual Summary 2013. Navy and Marine Corps Public Health Center. Portsmouth, VA.
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