The importance of diagnostics in responding to antibiotic resistance

We’ve all heard concerns about antibiotic resistance (AR). Messages coming from the doctor’s office and even the mainstream press point to an increasing number of infections that don’t respond to antibiotics because bacteria are becoming resistant. These infections are occurring in both outpatient and inpatient settings. Patients are cautioned that antibiotics may not be necessary for every infection, especially those that may be viral in origin, like ear infections or the common cold. Doctors are encouraged to hold off prescribing antibiotics to see if a minor infection resolves, or until diagnostics tests indicate that therapy is needed and, if so, which drugs are likely to be effective. Data from Centers for Disease Control and Prevention (CDC) indicate that as much as 50 percent of antibiotic prescriptions are inappropriate.¹

However, antibiotics are essential, life-saving drugs for many patients with bacterial infections. Efforts to use antibiotics appropriately—better known as antibiotic stewardship—aim to ensure patients who need antibiotics get the right drug, at the right time and the right dose. Another stewardship goal is to avoid overuse of antibiotics. This reduces the selective pressure that drives new resistance and preserves a patient’s natural microbiome, the healthy bacteria that populate a body and serve as protection from colonization with drug-resistant pathogenic bacteria. Antibiotic disruption of the microbiome is often a precursor to infections with resistant bacteria or with Clostridium difficile, a bacterium which is naturally resistant to many antibiotics and a cause of severe gastroenteritis.

While we have heard about AR, it is hard to understand what the threat is and how it might evolve in the future. The CDC AR Threats Report is an essential resource for understanding antibiotic resistance today.² This report ranks AR threats, reports national burden estimates for infections, and describes the epidemiology behind transmission. To understand how the threat of antibiotic resistance is likely to evolve, it is helpful to think about the evolution of antibiotic resistant Enterobacteriaceae over the past 30 years.

Enterobacteriaceae: A study in evolving resistance

Species of Enterobacteriaceae, like Escherichia coli and Klebsiella pneumoniae, are common causes of infections in outpatients and inpatients. Community-associated infections are usually urinary tract infections (UTIs). Healthcare associated infections (HAIs) include UTIs, respiratory infections and bloodstream infections. In the 1980s, extended-spectrum beta-lactamase (ESBL) producing Enterobacteriaceae emerged as a cause of drug resistant HAIs.³ ESBLs are plasmid-encoded enzymes that hydrolyze most beta-lactam drugs—including expanded-spectrum cephalosporins, the mainstay treatment for serious Enterobacteriaceae infections.

These bacteria are commonly resistant to other major classes of antibiotics as well. Carbapenems—broad-spectrum beta-lactam drugs—are recommended treatment for infections with ESBL-producing Enterobacteriaceae (ESBL infections). In the late 1990s, ESBL infections were uncommon causes of HAIs, but now there are nearly 200,000 infections per year in the U.S. and about 50 percent of these are community-associated. Doctors are faced with trying to treat an outpatient UTI infection without admitting a patient for IV antibiotics. Soon, oral carbapenems will also be available for treating outpatient UTIs.

Increased use of carbapenems is a likely consequence of an increasing number of ESBL infections. This is especially worrisome since it will now increase the selective pressure for carbapenem-resistant Enterobateriaceae (CRE) infections. CRE emerged in the late 1990s, and today are listed as an urgent threat by CDC.⁴ About 40 percent of the CRE in the United States produce a carbapenemase, a plasmid-mediated enzyme that hydrolyzes all beta-lactam drugs including carbapenems.⁵ It is easiest to think of these carbapenemases as a broad-spectrum version of ESBLs, and to think of ESBL-producing Enterobacteriaceae as pre-CRE.

In fact, many CRE harbor multiple resistance mechanisms including ESBLs. CRE infections in the U.S. occur in healthcare settings. Elsewhere in the world, CRE are an increasingly common cause of community-associated infections. The CDC reported a relatively flat trend for CRE infections. These numbers likely reflect efforts to prevent HAIs. If CRE follow the same trend as ESBLs, we can expect to see more community-associated infections in the U.S. in the future. Preventing community-associated infections is much harder than preventing HAIs.

New drugs for treating CRE infections are scarce. For serious infections, the only drugs recommended for monotherapy are three new beta-lactam/beta-lactamase inhibitor drugs: ceftazidime-avibactam, meropenem-vaborbactam and imipenem-relebactam. However, these drugs work for infections with some types of CRE and not others. For example, the three new drugs are most active for CRE infections with class A carbapenemases but not CRE with class B carbapenemases. Resistance to ceftazidime-avibactam is occurring in class A enzymes, limiting treatment options to two drugs, not three.

 Treatment of serious infections caused by CRE with class B carbapenemases requires a combination of ceftazidime-avibactam and aztreonam, essentially creating the drug aztreonam-avibactam which is still in phase 3 clinical trials.⁶ Aztreonam-avibactam and another drug in phase 3 clinical trials, cefepime-taniborbactam, offer some future relief for treating these infections. However, infections with class B carbapenemase CRE are likely to become more common and resistance to new drugs is likely to occur, resulting in hard-to-treat or untreatable Enterobacteriaceae infections for the foreseeable future.

CRE are challenging antimicrobial susceptibility testing (AST) systems. Normally, laboratories perform AST for drugs on the panel of their primary AST device first. If an isolate is resistant to these drugs, then off-line testing is performed of additional drugs. To treat a serious CRE infection without delay, initial susceptibility testing of an Enterobacteriaceae isolate should include extended-spectrum cephalosporins, carbapenems, ceftazidime-avibactam and either meropenem-vaborbactam or imipenem-relebactam.

 Delaying results for additional off-line testing can delay appropriate treatment of a potentially life-threatening infection. In one study, delayed appropriate treatment was associated with a 20 percent increase in the risk of in-hospital mortality/discharge to hospice, regardless of susceptibility status, and a 70 percent increase in length of stay.⁷ If a CRE isolate is resistant to all the new beta-lactam/beta-lactamase inhibitor drugs, then it likely carries a class B carbapenemase and needs susceptibility testing to aztreonam-avibactam. Because there are no FDA breakpoints for this drug combination, testing is not available on any commercial AST device. It is only available in regional laboratories of the AR Lab Network.⁸ When new drugs like this come to market, it is essential to add these to AST devices as quickly as possible to avoid delays in appropriate therapy.

Testing trends and challenges

Enterobacteriaceae are just an example. The other AR threats present similar challenges to the healthcare community despite differences in epidemiology. Common to all AR threats is the need for robust diagnostic testing and the impact these tests can have on antibiotic stewardship and prevention strategies. The diagnostic needs for antibiotic resistance generally fall into three categories:

1. Tests to determine if an antibiotic is needed. A test that can differentiate bacterial vs. viral vs. non-infectious diseases would fundamentally improve the way antibiotics are used, especially if the test can be used at the bedside and it worked across infectious syndromes. The quest for a biomarker test with these characteristics has been elusive. Advances are occurring in syndrome-specific markers of infection. This includes tests to more accurately diagnose sepsis from other causes of fever, and tests to more quickly identify an infectious agent from a positive blood culture or other clinical specimen.
2. Tests that determine which drug works best. Phenotypic antimicrobial susceptibility testing is still the gold standard diagnostic for therapy decisions. Molecular testing is fast and can provide important epidemiological data, but tests detect resistance and not susceptibility. Doctors need to know which drugs are most likely to be effective. Rapid AST from a positive blood culture is a reality today, but there is a need to make rapid testing more widely applicable to all AST needs. The challenge is to increase speed without sacrificing accuracy. No matter how AST data are generated, epidemiological tools are needed to collect and analyze data for better empiric treatment decisions and to identify new trends in resistance.
3. Tests for infection control decisions. The uptake of colonization testing for AR threats is slow in the U.S. This may reflect the lack of reimbursement for tests used in outbreak response rather than tests for individual patient care. New data showing that colonization in a patient proceeds infection with the same pathogen may help to overcome reimbursement issues. In addition, delays in availability of FDA-cleared colonization tests occur because the cost of test development is very high and the return on investment (ROI) is hard to predict early in an outbreak. The first FDA-cleared test for CRE colonization occurred in 2016, 15 years after the first report of CRE. There is still no colonization test for Candida auris, a fungus that is another urgent AR threat. Mitigating these risks will help with new test development.

 Antibiotic resistance is a health crisis that will be with us for a long time and continue to evolve. The forecast is that this problem will get worse before it gets better. Diagnostic laboratories need to be prepared.

References:

1. Centers for Disease Control and Prevention. Antibiotic Use in the United States. 2018 Update (https://www.cdc.gov/antibiotic-use/stewardship-report/pdf/stewardship-report-2018-508.pdf).
2. Centers for Disease Control and Prevention. Antibiotic Resistant Threats in the United States (https://www.cdc.gov/drugresistance/pdf/threats-report/2019-ar-threats-report-508.pdf).
3. Sanders CC and Sanders WE. Emerging Resistance to Cefamandole: Possible Role of Cefoxitin-Inducible Beta-Lactamases. Antimicrob. Agents & Chemother. 1979; 15(6):792-797.
4. Yigit H, Queenan AM, Anderson GJ, et al. Novel Carbapenem-Hydrolyzing β-Lactamase, KPC-1, from a Carbapenem-Resistant Strain of Klebsiella pneumoniae. Antimicro. Agents & Chemother. 2001; 45(4): 1151-1161.
5. Logan LK and Weinstein RA. The Epidemiology of Carbapenem-Resistant Enterobacteraiceae: The Impact and Evolution of a Global Menace. J of Infect Dis. 2017; 215(S1): S28-36.
6. The Pew Charitable Trusts. Antibiotics Currently in Global Clinical Development. Sept 2019 (https://www.pewtrusts.org/en/research-and-analysis/data-visualizations/2014/antibiotics-currently-in-clinical-development).
7. Bonine NG, Berger A, Altincatal A, et al. Impact of Delayed Appropriate Antibiotic Therapy on Patient Outcomes by Antibiotic Resistance Status from Serious Gram-negative Bacterial Infections. Am J Med Sci. 2019; 357(2):103-110.
8. Centers for Disease Control and Prevention. Expanded Antimicrobial Susceptibility Testing for Hard-to-Treat Infections (https://www.cdc.gov/drugresistance/pdf/drug-susceptibility-tests-508.pdf).