Phoenix—In recent years, there has been an explosion of FDA-approved rapid diagnostic testing methodologies for infectious diseases. During an education session at the 2017 annual meeting of the American College of Clinical Pharmacy, pharmacists discussed some of the excitement surrounding the recent advances in treating the most worrisome bugs.
“Rapid diagnostic tests represents one of the few bright spots in the changing world of escalating antimicrobial resistance and stewardship,” said Katherine Perez, PharmD, BCPS-AQ ID, an infectious disease clinical specialist at Houston Methodist.
Dr. Perez pointed out that rapid identification of microorganisms and resistance is critical for targeted treatment in serious infections caused by multidrug-resistant gram-negative bacteria (GNB). Research efforts have focused on pathogens associated with increased morbidity, mortality and excessive health care costs, including influenza virus, methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus species, Clostridium difficile, extended-spectrum beta-lactamase (ESBL)-producing Klebsiella species, carbapenemases, Mycobacterium tuberculosis and Candida species.
Current conventional culture-based methods to isolate and identify a pathogen, followed by susceptibility testing, can take 72 hours or more. This is concerning, Dr. Perez noted, because delaying administration of appropriate antimicrobials is associated with increased mortality rates for patients with gram-negative septicemia and septic shock (Clin Infect Dis 2013;57:S139-S170). Having the ability to detect the presence of resistant bacteria in a clinical sample in less than one hour, Dr. Perez noted, helps improve the effectiveness of antimicrobial stewardship programs.
In an ideal world, antimicrobial treatment would be prompt; appropriate; administered at an adequate dose and interval, guided by pharmacokinetic/pharmacodynamic principles; and discontinued appropriately, based on clinical response and microbiological data. All of this, Dr. Perez noted, is contingent on accurately determining a pathogen’s identification and antimicrobial susceptibility.
Emerging rapid detection methods of pathogens include a variety of technologies that vary greatly in complexity, price, speed and ability to identify single or multiple pathogens. Dr. Perez highlighted a number of rapid infectious disease diagnostics using different methodologies, including the polymerase chain reaction (PCR)-based FilmArray Blood Culture Identification panel (BioFire Diagnostics LLC). The panel tests for 24 pathogens and three antibiotic resistance genes associated with bloodstream infections. The test can accurately identify pathogens in more than nine of 10 positive blood cultures in about an hour, with only two minutes of hands-on time, she said (J Clin Microbiol 2016;54:687-698).
The advantages of PCR-based testing, she noted, include rapid results, low detection limits, specific organism detection and subtyping, not requiring growth on media, high throughput and, generally, short hands-on time for laboratory staff. Disadvantages include susceptibility to contamination, the need for dedicated laboratory space for instruments, and dependence on quality of products used, and most require initiation from positive cultures/single colonies. PCR cannot indicate viability of the pathogen detected and comes with practical limitations that can affect turnaround time.
Targeting Worrisome Bugs
Ryan Shields, PharmD, MS, associate professor of medicine in the Division of Infectious Diseases at the University of Pittsburgh, said carbapenem-resistant bugs top the list of most worrisome bugs. Carbapenem-resistant Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacteriaceae (CRE) are listed as critical priorities for research and development of new antibiotics by the World Health Organization. The CDC lists multidrug-resistant A. baumannii and P. aeruginosa as serious threats, and CRE as an urgent threat.
Carbapenem-resistant pathogens, Dr. Shields said, are associated with loss of our last line of defense against resistant pathogens and cross-resistance to other antibiotic classes. They are also associated with increased lengths of stay, health care expenditures and increased mortality rates among patients. “Carbapenem resistance is a major threat to public health,” he said.
A recent study concluded that antibiotic stewardship and infection prevention and control have been unable to prevent the rapid spread of resistant GNB, particularly carbapenem-resistant P. aeruginosa and other nonfermenting GNB, ESBL-producing and CRE (Intensive Care Med 2017 Jul 21. [Epub ahead of print]). Carbapenem-resistant Klebsiella pneumoniae, Dr. Perez said, is an emerging nosocomial pathogen associated with considerable mortality.
Rapid tests should detect all carbapenem-resistant organisms and distinguish carbapenemase-producing organisms from isolates that are resistant to carbapenems because of other mechanisms, Dr. Perez noted. The organisms have diverse enzyme types and considerable variation in levels of phenotypic carbapenem resistance (e.g., minimum inhibitory concentration evaluation). Non–carbapenemase-mediated carbapenem resistance complicates things.
The Rapidec Carba NP biochemical test (bioMérieux) detects any type of carbapenemase activity by monitoring the color change of a pH indicator according to hydrolysis of the substrate, imipenem. The tests are rapid, easy to read and handle, and cost-effective, and have a turnaround time of approximately one hour. They can be used for first-line screening in the absence of molecular typing, Dr. Perez said.
|Table. Integrating Rapid Diagnostics Into Practice|
|CTX-M (ESBL)||Enterobacteriaceae||Ertapenem (Invanz, Merck)|
|KPC||Klebsiella pneumoniae and other enteric gram-negative organisms||Colistin + tigecycline/aminoglycoside/carbapenem; ceftazidime-avibactam (Avycaz, Allergan)|
|NDM carbapenemases||K. pneumoniae and other enteric gram-negative organisms||Colistin + tigecycline; aztreonam (Azactam, Bristol-Myers Squibb) + ceftazidime-avibactam|
|VIM or IMP carbapenemase||Pseudomonas aeruginosa||Colistin + aztreonam/aminoglycoside/tigecycline|
|OXA beta-lactamases||P. aeruginosa||Colistin + high-dose carbapenem|
|Acinetobacter baumannii||Colistin + minocycline; high-dose carbapenem|
|ESBL, extended-spectrum beta-lactamase Source: Katherine Perez, PharmD, BCPS-AQ ID.|
Integrating Into Practice
Dr. Perez noted that the Infectious Diseases Society of America, CDC and National Quality Forum have recognized the emerging role of rapid diagnostics and biomarkers in antimicrobial stewardship programs. Molecular biology and testing can be used to improve antimicrobial stewardship interventions, assist in anti-infective escalation and de-escalation efforts, and improve clinical outcomes.
Implementation of rapid diagnostic tests may be cost-neutral or even constitute a cost savings when stewardship efforts streamline care. “Rapid diagnostic tests can reduce total hospital costs by decreasing length of stay,” Dr. Perez said.
Multiple stakeholders, including infectious disease physicians, microbiologists and laboratory pharmacists, need to create guidance for clinicians up front regarding the use of rapid infectious disease diagnostics, Dr. Perez noted. “There is a need to connect the dots among antimicrobial stewardship, rapid diagnostics and improved outcomes to make this case,” she said. “Who gets notified when an organism and a resistance marker are identified by rapid diagnostics?”
Stewardship pharmacists can provide guidance to clinicians to positively affect patient care. Some stewardship programs use automated alerts for positive blood cultures coupled with antimicrobial stewardship interventions, to ensure that a patient is prescribed effective antibiotics sooner, Dr. Perez said. Selective antibiogram reports for blood culture isolates are helpful for driving empirical choices and may be useful particularly for multidrug-resistant organisms.
“Advances in testing provide new opportunities for stewardship programs to streamline care for patients with serious infections,” she added. “Rapid diagnostic tests are game-changing for patient care moving forward.”