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Healio

Outbreak Tracker
Issue: February 2018
ByKimberly Boeser, PharmD, MPH, BCIDP
ByAshley Cubillos, PharmD, BCPS
February 16, 2018
6 min read
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Triple threat: Treatment challenges for emerging pathogens

Issue: February 2018
ByKimberly Boeser, PharmD, MPH, BCIDP
ByAshley Cubillos, PharmD, BCPS
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Health care-associated infections, or HAIs, and inappropriate antimicrobial use independently lead to worse patient outcomes, but together they can produce a double whammy. Add in the complexity of an “emerging pathogen” and the challenges they present, and we are faced with a triple threat. In the hospital setting, two pathogens fit this description: Candida auris and carbapenem-resistant Enterobacteriaceae, or CRE. Their propensity to spread is alarming, and difficulty with accurate and timely identification and nuanced treatment approaches make them a unique challenge for health care providers.

C. auris

Invasive Candida infections in the health care setting are widely variable, manifesting from mucocutaneous disease to health care-associated bloodstream infections. Some of the more severe invasive Candida infections, such as candidemia, are associated with up to 47% attributable mortality and are a major cause of morbidity. The most common Candida species that cause human disease include C. albicans, C. dubliniensis, C. parapsilosis, C. tropicalis, C. glabrata, and C. krusei; however, an emerging pathogen, C. auris, is of increasing clinical concern. As of Dec. 31, 2017, the CDC reported 228 clinical cases (200 confirmed, 28 probable) from 10 different states.

Kimberly Boeser
Ashley Cubillos

C. auris is a challenging pathogen for several reasons. It can be resistant to first-line antifungal agents (eg, triazoles); it can demonstrate elevated minimum inhibitory concentrations (MICs) to the three major classes of antifungals, severely limiting treatment options; and it can mount resistance quickly. Susceptibility testing in the United States has identified a high level of resistance (about 90%) to fluconazole, 30% resistance to amphotericin B and approximately 5% resistance to echinocandins. These susceptibilities are subject to change as more isolates are tested. An additional challenge is that C. auris can be misidentified by standard laboratory methods and has a high capacity to cause outbreaks in health care facilities. Matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) with specific reference databases are required to differentiate C. auris from other Candida species.

If there is high clinical suspicion for C. auris infection or if it has been identified in a patient, the treatment of choice is an echinocandin. Echinocandins are semisynthetic lipopeptides that inhibit the synthesis of 1,3 beta-D-glucan, a major component of the fungal cell wall. They are considered “fungicidal” against Candida species. Caspofungin, Mycamine (micafungin, Astellas) and Eraxis (anidulafungin, Pfizer) are the three available products in the U.S. The Infectious Diseases Society of America’s 2016 guideline for the management of candidiasis recommends echinocandins as first-line therapy for patients with candidemia.

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The dosing strategy for echinocandins includes:

  • l caspofungin 70 mg IV loading dose, followed by 50 mg IV daily;
  • l micafungin 100 mg IV daily; and
  • l anidulafungin 200 mg IV loading dose, followed by 100 mg IV daily.

Echinocandins have a high level of efficacy against invasive candidiasis; however, the elevated MICs of C. auris and the pathogen’s unique ability to develop resistance quickly makes this treatment strategy challenging. An alternative treatment recommendation in the setting of suspected echinocandin failure or persistent candidemia (> 5 days of positive blood cultures) would be amphotericin B liposomal at 5 mg/kg daily. Amphotericin products are generally less well-tolerated (eg, infusion-related fevers, rigors, injection site pain and hypotension) and can lead to acute kidney injury. Continued surveillance of C. auris will allow us to better characterize its pathogenicity, enhance our testing and identification methods and improve our treatment approach to this emerging pathogen.

CRE

CRE are among the few organisms to earn a place on the CDC’s Urgent Threat list, causing approximately 9,300 infections yearly, with reported mortality rates ranging from 24% to 70% in the literature. CRE are defined by the CDC as any Enterobacteriaceae demonstrating resistance to a carbapenem and/or documented to produce a carbapenemase. Klebsiella pneumoniae is the most common CRE pathogen nationwide, accounting for nearly 60% of infections, followed by Enterobacter species (~25%) and Escherichia coli (~15%). Carbapenemase-producing CRE express beta-lactamases that cleave and inactivate carbapenems. The most common carbapenemase expressed by CRE in the U.S. is K. pneumoniae carbapenemase (KPC), though organisms expressing OXA or metallo-beta-lactamases (eg, NDM, IMP and VIM) are becoming more commonly isolated. Enterobacteriaceae can also demonstrate resistance to carbapenems via noncarbapenemase mechanisms.

The selection of appropriate antimicrobial therapy for CRE infections is highly dependent on the individual organism’s susceptibility profile, the site of infection, and other patient-specific factors. Retrospective studies have shown a mortality benefit with combination therapy in severe CRE infections, and combination therapy with two or more agents should be strongly considered, especially in patients who are critically ill.

The backbone of therapy for CRE infections often remains a carbapenem. Carbapenem therapy can confer benefit, despite the organism’s susceptibility profile showing resistance to the agent, when MICs are moderately elevated (eg, meropenem 16 g/mL) and the carbapenem is dosed appropriately (eg, meropenem 2 g IV q8h or extended infusion). Patients with CRE displaying significantly elevated MICs (eg, meropenem > 16 g/mL) are less likely to benefit from carbapenem-based therapy.

Polymyxins, including colistin and polymyxin B, generally retain excellent activity against CRE, making them important additions in many CRE treatment regimens. The choice between colistin vs. polymyxin B should be patient-specific. Colistin is a prodrug that takes time to convert in vivo to the active agent, making it challenging to achieve therapeutic blood and tissue levels in a timely fashion. Colistin provides significantly higher urinary concentrations than polymyxin B, making colistin the preferred treatment for urinary tract infections. Dosing regimens of colistin must be calculated based on renal function, whereas polymyxin B does not require adjustment. Both agents have significant nephrotoxicity and neurotoxicity associated with their use, and patients must be closely monitored for adverse effects.

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Avycaz (ceftazidime-avibactam, Allergan), initially marketed in 2015, retains activity against organisms producing KPC and OXA-48 carbapenemases. However, ceftazidime-avibactam has no activity against the metallo-beta-lactamases and other OXA carbapenemases, making susceptibility testing critical for this agent when used for CRE. A recently published analysis of ceftazidime-avibactam vs. colistin for treatment of CRE found a lower mortality rate at 30 days with ceftazidime-avibactam than with colistin (9% vs. 32%; difference, 23%; 95% bootstrap confidence interval, 9%-35%; P = .001), though the study is limited by its retrospective nature. Ceftazidime-avibactam has often been used in combination with other agents in retrospective analyses of CRE treatment but its role in combination therapy has not been clearly defined.

Vabomere (meropenem-vaborbactam, Rempex Pharmaceuticals), approved in 2017, represents the newest treatment option for CRE. It retains activity against KPC-producing organisms but does not have activity against the metallo-beta-lactamases or OXA. A 4-g dose (2 g meropenem plus 2 g vaborbactam) is administered as a 3-hour infusion every 8 hours. A phase 3 trial of meropenem-vaborbactam vs. the “best available therapy” for CRE infections showed no difference between the two groups in overall mortality. However, when a subgroup of patients with bacteremia or hospital-acquired pneumonia (n = 43) was analyzed, a 28-day mortality benefit was seen in favor of meropenem-vaborbactam (25% vs. 44%; P value not calculated). Of note, commercial susceptibility tests are not yet available for this agent.

CRE infection treatment remains a clinical challenge, with little evidence supporting the use of the few antimicrobial agents that are available. Newer agents, including ceftazidime-avibactam and meropenem-vaborbactam, represent attractive treatment options but further clinical research and drug development in this area is imperative.

Pathogens have been emerging and re-emerging for centuries. Arguably, this natural history is what makes the practice of infectious diseases so intriguing. We have the triad effect in infectious diseases — the patient, the treatment (ie, antimicrobial agent) and the pathogen. Whether it be a virus, bacteria or fungus, emerging pathogens present challenging clinical conundrums. C. auris and CRE pathogens are no different. They continue to challenge our lab methodology for more rapid diagnostics, our advancements and research for the most effective, safest treatment strategies and our ability to prevent their rapid spread. Ultimately, emerging pathogens will continue to challenge us, and after all, this is the “art of medicine.”

  • For more information:
  • Kimberly D. Boeser, PharmD, MPH, BCPS AQ-ID, is an infectious diseases clinical pharmacist and antimicrobial stewardship coordinator at the University of Minnesota Medical Center-MHealth. She can be reached at kvarejc1@fairview.org.
  • Ashley Cubillos, PharmD, BCPS, is a PGY2 infectious diseases pharmacy resident at the University of Minnesota Medical Center-MHealth.

Disclosures: Boeser and Cubillos report no relevant financial disclosures.

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