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Targeting GN Resistance
Expert Answers to FAQs on Approaches for Improving Time to Early Effective Therapy for Resistant Gram-Negative Infections

Released: March 20, 2023

Expiration: March 18, 2024

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Key Takeaways
  • As the prevalence of multidrug-resistant and extensively drug‒resistant organisms continues to rise, antimicrobial stewardship programs need to facilitate timely initiation of effective antibiotics.
  • Consider thorough history of patient factors, prior cultures, and laboratory data when selecting the optimal agent.
  • Several tools are available to improve time to effective therapy, including novel antibiograms, rapid diagnostics, and clinical decision support tools.

In this commentary, Elias B. Chahine, PharmD, FCCP, FASCP, FFSHP, BCPS, BCIDP, and Jaclyn Cusumano, PharmD, BCIDP, answer learner questions related to the webcast titled, “Targeting Antimicrobial Resistance in Complex Gram-Negative Infections: Approaches for Improving Early Effective Therapy.” 

When is it appropriate to use a novel β-lactam/β-lactamase inhibitor combination vs dual coverage with a traditional β-lactam plus a fluoroquinolone or aminoglycoside for empiric coverage of resistant gram-negative organisms? 
 
Jaclyn Cusumano, PharmD, BCIDP:  
I would use combination therapy in the empiric period when there is uncertainty of the efficacy of 1 agent alone. For example, if your local Pseudomonas aeruginosa susceptibility is 85% for cefepime, I would add on a second agent to improve the probability of a susceptible agent being used empirically. Combination antibiograms are very helpful in this setting to select the appropriate second agent, as 1 agent may better cover in the setting of cefepime resistance, for example. Additional data are needed to inform the role of novel β-lactam/β-lactamase inhibitor combinations as empiric therapy for suspected resistant gram-negative infections, as they often were not studied in patients with multidrug-resistant (MDR) and extensively drug‒resistant (XDR) infections in the FDA registration trials. However, empiric use may be considered in patients with a known history of MDR or XDR pathogens that are resistant to traditional β-lactams, or in patients with sepsis or septic shock with risk factors for MDR or XDR pathogens who may not tolerate the addition of a second agent because of the adverse event profile. More studies using tools to improve time to effective therapy will be helpful to determine when they may provide the most benefit in high-risk patients while preserving their use for the most resistant cases, where limited options are available.
 
Elias B. Chahine, PharmD, FCCP, FASCP, FFSHP, BCPS, BCIDP: 
The Infectious Diseases Society of America (IDSA) guidelines for the treatment of hospital-acquired pneumonia (HAP) recommend double covering for P. aeruginosa empirically using an antipseudomonal β-lactam plus either a fluoroquinolone or an aminoglycoside if the patient is at high risk of mortality (defined as need for mechanical ventilation because of HAP or septic shock), has received parenteral antibiotics in the past 90 days, or has structural lung disease (ie, bronchiectasis or cystic fibrosis). The same guidelines for the treatment of ventilator-associated pneumonia (VAP) recommend double covering for P. aeruginosa empirically if the patient has a risk factor for MDR pathogens (previous receipt of IV antibiotics in the past 90 days, septic shock, acute respiratory distress syndrome, ≥5 days of hospitalization, or acute renal replacement therapy prior to VAP onset), the antipseudomonal antibiotic has <90% local susceptibility, or the patient has structural lung disease. These guidelines were published in 2016 before the availability of many novel β-lactam/β-lactamase inhibitor combinations, which largely were studied as monotherapy.
 
What is your approach to treatment of P. aeruginosa with difficult-to-treat resistance (DTR)? How do you decide which of the novel agents to use (eg, ceftolozane/tazobactam, imipenem/cilastatin/relebactam, or ceftazidime/avibactam)? How did you manage this while ceftolozane/tazobactam was unavailable? 
 
Jaclyn Cusumano, PharmD, BCIDP:  
My general approach to DTR-P. aeruginosa infections is to use ceftolozane/tazobactam. Fortunately, at my institution I have not encountered ceftolozane/tazobactam resistance, but if this were to occur, my choice would be imipenem/cilastatin/relebactam, as it may retain activity against isolates resistant to ceftolozane/tazobactam. Imipenem/cilastatin/relebactam is unaffected by porin channel‒mediated resistance due to OprD loss or efflux pump‒mediated resistance. Another important consideration is dose optimization. The pharmacodynamics of these β-lactam agents is time above the minimum inhibitory concentration, so for ceftolozane/tazobactam we give higher doses (ie, 3 g) over a 3- to 4-hour infusion to maximize this parameter. There also are data supporting its administration as a continuous infusion. During the ceftolozane/tazobactam shortage, we used imipenem/cilastatin/relebactam.
 
Elias B. Chahine, PharmD, FCCP, FASCP, FFSHP, BCPS, BCIDP:  
I agree with your approach, and I would add that we used ceftazidime/avibactam for DTR-P. aeruginosa at my institution when ceftolozane/tazobactam was not available. Note that ceftazidime/avibactam would be helpful for the treatment of this pathogen if expressing Ambler class A, C, or D (eg, OXA-48) β-lactamases. Efflux pump and porin channel‒mediated resistance can confer resistance to this agent. Resistance to P. aeruginosa is complex and typically includes multiple mechanisms. Remember that we cannot use meropenem/vaborbactam for DTR-P. aeruginosa because vaborbactam does not restore the activity of meropenem against Pseudomonas.  
 
What factors do you take into consideration when deciding how to manage your formulary with the influx of new antimicrobial approvals targeted toward resistant gram-negative pathogens? 
 
Elias B. Chahine, PharmD, FCCP, FASCP, FFSHP, BCPS, BCIDP: 
Several factors must be taken into consideration when deciding which new antibiotics should be added to your formulary. One of the most important factors is the type and prevalence of MDR gram-negative organisms at your institution. If you see a lot of DTR-P. aeruginosa, I recommend that you prioritize the addition of ceftolozane/tazobactam and/or imipenem/cilastatin/relebactam. Remember, however, that some strains of DTR-P. aeruginosa are resistant to these agents, and ceftolozane/tazobactam does not cover carbapenem-resistant Enterobacterales (CRE). Local susceptibility patterns are important. Klebsiella pneumoniae carbapenemase (KPC) is the most common carbapenemase in the United States. If you see a significant amount of KPC-mediated CRE, I recommend that you prioritize the addition of meropenem/vaborbactam. If you see a lot of OXA-48 type, I recommend that you prioritize the addition of ceftazidime/avibactam. If you see a lot of metallo-β-lactamase‒producing CRE (IMP, VIM, NDM), I recommend that you prioritize the addition of cefiderocol, or if you already have ceftazidime/avibactam on formulary, you can use the latter in combination with aztreonam. Remember that time to effective therapy has a crucial effect on optimal patient outcomes, so it may be prudent to carry multiple options for individual patient circumstances that are readily available to avoid delays with shipping of a nonformulary agent when needed. Like with the use of any antibiotics, emergence of resistance is a concern, and you may need to have several agents on formulary. I recommend that you develop criteria for use of these agents and that you restrict their use to infectious disease healthcare professionals or stewardship programs to ensure optimal use. Talk to key stakeholders to come to a consensus on which agents to add to your formulary. 
 
Jaclyn Cusumano, PharmD, BCIDP:  
I absolutely agree with your approach. When determining which type of resistance is present at your institution, it will be so important to work closely with your microbiology lab. Have a discussion with them about building syndromic antibiograms, because there may be certain settings where having these newer agents on formulary may be most important. For example, your ICU may have a really high rate of DTR-P. aeruginosa that your traditional antibiogram misses, and that is therefore a missed opportunity to add a drug such as ceftolozane/tazobactam to the formulary. I think one other factor that goes in to determining addition to the formulary is cost. This often can deter hospitals from adding these important drugs to the formulary, so justifying their usage through sharing cost-effectiveness studies and building appropriate criteria for usage should assist with obtaining formulary approval. 
 
What dosing and/or administration strategies do you have in place to optimize pharmacodynamics against multidrug-resistant Acinetobacter baumannii? 
 
Elias B. Chahine, PharmD, FCCP, FASCP, FFSHP, BCPS, BCIDP: 
In general, it is recommended to use the higher end of the recommended dose for the treatment of systemic infections caused by MDR gram-negative organisms. Doses that should be used in practice often are higher than what is labeled in the prescribing information. It is also recommended to optimize pharmacokinetic/pharmacodynamic parameters by using extended infusion for β-lactams. The IDSA guidance for gram-negative resistance recommends combination therapy for moderate to severe infections. For ampicillin/sulbactam, the recommended dosage is 9 g every 8 hours, infused over 4 hours, or 27 g every 24 hours as a continuous infusion. A dosage of 3 g every 4 hours is reasonable for mild infections. The recommended dosage of minocycline is 200 mg IV/PO every 12 hours, and the recommended dosage of tigecycline is 200 mg x 1, then 100 mg every 12 hours. The recommended dosage of meropenem is 2 g every 8 hours, infused over 3 hours. Although the recommended dosage of cefiderocol is 3 g every 8 hours, infused over 3 hours, the prescribing information recommends a higher dose for patients with augmented renal clearance. For polymyxins, please refer to the international consensus guidelines for the optimal use of polymyxins.
 
Jaclyn Cusumano, PharmD, BCIDP:  
Cusumano: In treating MDR A. baumannii, one thing I found really important is educating all physicians, advanced practice providers, staff pharmacists, and nurses on the higher doses of ampicillin/sulbactam, as this is something that is likely outside their comfort zones. For many of us, ampicillin/sulbactam 3 g every 6 hours may be the highest dose we have ever given, so sharing why these higher doses are so important for treatment success will improve time to effective therapy in the future.  
 
What rapid diagnostic technologies are available at your practice site, and what would you recommend to maximize success with implementation of these tools? Any tips for pharmacists at smaller facilities with fewer resources to implement these technologies? 
 
Elias B. Chahine, PharmD, FCCP, FASCP, FFSHP, BCPS, BCIDP: 
I practice at a community teaching hospital with fewer resources, and we are going to implement BioFire BCID2. This does not necessarily mean that it is the best platform—it simply means that we think this platform will work best for us. My recommendations are to engage microbiology personnel, infectious disease physicians, and clinical pharmacists. Start with a platform for bloodstream infections, followed perhaps by respiratory infections. You will need the antimicrobial stewardship team, an infectious disease physician, or a clinical pharmacist to act on the results as soon as possible; otherwise, the impact of “rapid” diagnostics cannot be fully realized. Most of the studies on molecular rapid diagnostics demonstrated positive outcomes in bloodstream infections when combined with an active antimicrobial stewardship program.
 
Jaclyn Cusumano, PharmD, BCIDP:  
As someone who also practices at a community hospital but in a nonteaching setting, I can appreciate the challenges that come with implementing these tools. One thing I find so important, again, is education. At a smaller institution, we do not have the same number of staff as a large academic center, so it is important that everyone is trained in each area so we can cover one another. We recently rolled out ePlex blood culture rapid diagnostics, but without proper response, the impact of the results is significantly diminished. We are working to educate all healthcare professionals and develop guidance documents to assist with appropriate antimicrobial selection based on the ePlex results. Our microbiology lab also has developed text in the culture results that provides general recommendations for treatment or infectious disease consultation.  
 
What is the role of nonblood rapid diagnostic technologies, such as those available for respiratory specimens? 
 
Jaclyn Cusumano, PharmD, BCIDP:  
Respiratory rapid diagnostics unfortunately do not have as much data supporting use compared with blood culture rapid diagnostics. However, rapid respiratory diagnostics have a lot of potential in clinical practice, as traditional respiratory cultures can take up to 5 days to obtain final results. This is particularly problematic if the causative pathogen is resistant to the selected empiric antimicrobial, thus increasing patient risk of mortality. Syndromic antibiograms can improve empiric antimicrobial selection, but these may not always be available, especially in the outpatient setting. Therefore, rapid respiratory diagnostics are a vital tool, and I am looking forward to reviewing emerging clinical data. 
 
Elias B. Chahine, PharmD, FCCP, FASCP, FFSHP, BCPS, BCIDP:  
I agree, and I would add that the molecular rapid diagnostics for respiratory specimens can detect viruses. If we know that we are dealing with a viral infection, we can withhold antibiotics, and that can be a powerful stewardship strategy.  
 
What clinical decision support systems do you use to improve time to effective therapy? Is there anything you would like to implement in the future? 
 
Jaclyn Cusumano, PharmD, BCIDP:  
Several commercially available clinical decision support systems may be integrated with your electronic health record system or accessed separately to assist with improving time to effective therapy (eg, TheraDoc, Sentri7, VigiLanz, Epic). Presently, at my institution we do not use any clinical decision support systems, but we do use a few other tools to assist with antimicrobial stewardship. First, we run a positive blood culture report to ensure that all patients’ antimicrobials are optimized. However, as discussed, time to effective therapy is essential to improving patient outcomes. Our reports alone are not updated in real time and are unable to incorporate genotypic rapid diagnostic results. We also use traditional antibiograms to select appropriate empiric therapy. Traditional antibiograms may underpredict resistance in certain settings, such as the ICU, which is where syndromic antibiograms are an important tool. There is a new clinical decision support tool developed by bioMérieux called CLARION, which can build antibiograms that are patient specific. This platform also can optimize and integrate lab-based data with patient data to improve antimicrobial stewardship practice, as well as surveillance data to improve infection control practices. 
 
Your Thoughts?
What strategies do you use to improve time to effective therapy for resistant gram-negative infections at your institution? Join the conversation by adding a comment in the discussion section.