Diagnostics for superbugs

In September 2013, the Centers for Disease Control and Prevention (CDC) released a report on antibiotic resistance threats in the United States, citing the danger these increasingly prevalent drug-resistant infections present. According to the report, more than two million people are sickened with antibiotic-resistant infections in the U.S. annually, and more than 20,000 people die as a result.¹ The economic burden in the U.S. for treating these infections exceeds $20 billion per year.¹

This ever-evolving threat of antibiotic resistance is driven by both appropriate and inappropriate antibiotic usage. In fact, nearly 50% of all antibiotics prescribed in the U.S. are either inappropriate or unnecessary.¹ This contributes significantly to the problem as antibiotic resistance occurs when bacteria evolve to overcome threats to their survival. The more antibiotics we administer, the shorter the effective lifespan of available therapeutics. As the number of antibiotics with activity against multi-drug resistant bacteria dwindles, it becomes more critical than ever for healthcare providers to preserve the utility of available antibiotics.

Carbapenem-resistant Enterobacteriaceae (CRE) is one of the three types of antibiotic-resistant gram-negative bacteria the CDC has characterized as an “urgent” threat. An estimated 140,000 healthcare-associated Enterobacteriaceae infections occur annually in the U.S., 9,000 of which are caused by CRE.¹ These numbers are only expected to rise in the coming years as CRE spreads to the U.S. from other regions of the world. The primary cause of CRE in the U.S. remains organisms that produce Klebsiella pneumoniae carbapenemase (KPC). Other carbapenemases in Enterobacteriaceae, such as New Delhi metallo-β-lacatamases (NDM), are also becoming a threat in the U.S.

Bloodstream infections with CRE are associated with high mortality rates, due in part to the limited antibiotics available to treat these infections, including polymyxins, tigecycline and aminoglycosides.² These “drugs of last resort” are severely hampered by side-effect profiles and limited efficacy. Use of aminoglycosides and polymyxins is associated with nephrotoxicity and, in many instances, increased hospital length of stay.³ Tigecycline use has been linked to increased mortality, increased resistance, and low blood pressure levels.²

There is no consensus on optimal therapy for CRE bloodstream infections, but combination therapy is gaining traction. A recent study showed significantly reduced mortality using a triple-drug combination of colistin, tigecycline, and meropenem.⁴ While additional optimization of available antibiotics with activity against CRE is still necessary, additional research devoted to the development of novel antibiotics with activity against CRE is critical.

Equally important to limiting unnecessary antibiotic usage and decreasing the spread of antibiotic-resistant bacteria like CRE is development and adoption of new diagnostic tests for earlier detection of these “superbugs.” Traditional culture-based phenotypic identification of carbapenem resistance in Enterobacteriaceae is a slow and sometimes difficult process. Solutions such as molecular diagnostic tests provide hospitals rapid and accurate tools to identify these multi-drug resistant infections two to three days earlier than conventional culture-based techniques. Rapid identification of the infection-causing bacteria and drug resistance markers allows healthcare providers to treat patients with targeted antibiotic therapies faster, thereby minimizing patient exposure to unnecessary and sometimes toxic antibiotics.

Several studies have already demonstrated the value of rapid molecular diagnostics for gram-positive bloodstream infections. Recently, a study in PLOS Medicine demonstrated that a rapid molecular diagnostic test identified methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococci (VRE) 41.8 hours and 42.4 hours faster, respectively, than conventional culture-based techniques.⁵ Another recent publication evaluating the same molecular diagnostic test showed that rapid detection of VRE and vancomycin-susceptible enterococcal (VSE) infections led to a 21.7 day length-of-stay reduction as a result of earlier, targeted treatment. The corresponding reduction in mean healthcare costs was $60,729 per patient.⁶ In this study, patients with VSE were treated appropriately as a result of specific species level identification of E. faecalis and E. faecium, enabling clinicians to use a beta-lactam antibiotic when indicated to control the use of vancomycin.⁶

New molecular diagnostic tests that identify gram-negative bacteria and carbapenem resistance are expected to have a similar positive impact on clinical and economic outcomes as their gram-positive counterparts. One rapid molecular test in development identifies six Enterobacteriaceae members (Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca, Proteus spp., Citrobacter spp., Enterobacter spp.), two gram-negative non-fermenters (Acinetobacter spp., Pseudomonas aeruginosa), the CTX extended spectrum beta-lactamase (ESBL) genetic resistance marker, and the KPC, NDM, VIM, IMP, and OXA carbapenemase resistance genes from a positive blood culture in two hours.

There are many different mechanisms of acquired and intrinsic antibiotic resistance in gram-negative bacteria. While rapid detection of the genes that encode production of carbapenemase enzymes does not completely rule out other forms of resistance in gram-negative bacteria, a two- to three-day reduction in time to detecting carbapenemases over culture-based techniques would truly offer healthcare providers a significant advantage in managing CRE infections. This time saving would help minimize the spread of infection within a hospital by isolating infected patients with these carbapenem resistance genes and adjusting patient therapy two to three days earlier, potentially resulting in improved patient outcomes and reduced healthcare costs.

CREs have become a global health threat that will continue to increase among the U.S. population as bacteria containing new resistance genes spread from other parts of the world. Rapid molecular diagnostic tests that identify CRE much earlier than conventional culture-based techniques are one effective method healthcare providers can employ to improve infection control and antibiotic stewardship. However, addressing this problem on a global scale will require public health measures and effective action throughout the world to improve awareness and coordinate prevention efforts to minimize future spread and maintain the efficacy of our remaining antibiotics for as long as possible.

References

1. Centers for Disease Control and Prevention, U.S. Department of Health and Human Services. Antibiotic Resistance Threats in the United States, 2013. http://www.cdc.gov/drugresistance/threat-report-2013/pdf/ar-threats-2013-508.pdf. Accessed October 29, 2013.
2. van Dui D, Kaye KS, Neuner EA, Bonomo RA. Carbapenem-resistant Enterobacteriaceae: a review of treatment and outcomes. Diagn Microbiol Infect Dis. 2013;75(2):115-120.
3. Bauer KA, West JE, O’Brien JM, Goff DA. Extended-infusion cefepime reduces mortality in patients with Pseudomonas aeruginosa infections. Antimicrob Agents Chemother. 2013;57(7):2907-12.
4. Tumbarello M, Viale P, Viscoli C, et al. Predictors of mortality in bloodstream Infections caused by Klebsiella pneumoniae carbapenemase-producing K. pneumoniae: importance of combination therapy. Clin Infect Dis. 2012;55(7):943-950.
5. Buchan BW, Ginocchio CC, Manii R, et al. Multiplex identification of gram-positive bacteria and resistance determinants directly from positive blood culture broths: evaluation of an automated microarray-based nucleic acid test. PLoS Med. 2013;10(7):e1001478.
6. Sango A, McCarter YS, Johnson D, Ferreira J, Guzman N, Jankowski CA. A stewardship approach to optimize antimicrobial therapy through use of a rapid microarray assay on blood cultures positive with Enterococcus species. J. Clin. Microbiol. 2013 Sept 25. [Epub ahead of print]