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Selecting Regimens for MDROs
Practical Insights on Antimicrobial Selection for MDR Gram-Negative Infections

Released: November 10, 2023

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Key Takeaways
  • Empiric and definitive treatment of complex clinical infections involving gram-negative resistance should be individualized and take into consideration patient-related and infection-related factors such as previous culture history and relevant PK/PD parameters (eg, drug penetration at infection site, optimization of synergistic regimens).

The following is a recap of the most commonly asked questions from a program moderated byTrevor Van Schooneveld, MD, FSHEA, FACP, and his colleagues Emily Heil, PharmD, MS, BCIDP, AAHIVP, and Laila Woc-Colburn, MD, discussing strategies to optimize antimicrobial regimens for patients with complex clinical infections involving gram-negative resistance.

When considering empiric antimicrobial therapy for your patients, how far back do you review past culture data?

Emily Heil, PharmD, MS, BCIDP, AAHIVP:
Using previous culture results to guide empiric therapy is essential. Unfortunately, there is not a lot of data on how far back to review. The past 6-12 months of culture data have been found to be a predictor of subsequent antimicrobial resistance. Rarely do we see a 3-year-old carbapenem-resistant Enterobacterales in the urine coming back to haunt us.

My current rule of thumb is to review the past year of culture data when determining empiric regimens. For antimicrobial stewardship purposes, it would be great to tighten up this timeframe and only go back 6 months, but we need more data to do this.

Laila Woc-Colburn, MD:
Most medical centers use infection prevention flags in their electronic medical record (EMR). These flags identify patients who have had a resistant organism—either as a cause of infection or from colonization—and may stay on the patient’s profile for a prolonged period.

Healthcare professionals (HCPs) do not need to go back 10 years. Reviewing culture history from the past year is more appropriate. This aligns with data we have from travelers from highly endemic regions with antimicrobial resistance; carriage of antimicrobial resistance can persist for up to a year after travel.

At your institution, how do you approach reporting susceptibility results for novel β-lactams? Have you included novel β-lactams on your susceptibility panels, or does your laboratory use a send-out laboratory for susceptibility results?

Laila Woc-Colburn, MD:
We have a centralized microbiology laboratory that performs in-house susceptibility testing. Our microbiology and hospital epidemiology colleagues have worked closely with our antimicrobial stewardship team to create a cascading system for our EMR to strategically display susceptibility results.

Susceptibility results for the novel β-lactams are hidden from HCPs and only reported when certain antibiotics return resistant. This is to encourage use of narrow spectrum antibiotics and avoid antimicrobial misuse. Also, we use this opportunity to direct HCPs when to consider an infectious diseases consultation, such as when a carbapenemase (eg, KPC) is detected.

Emily Heil, PharmD, MS, BCIDP, AAHIVP:
There is always a lag with updating automated susceptibility platforms after an antimicrobial is approved by the FDA. Ceftolozane/tazobactam was approved by the FDA in 2014, and we are finally seeing this agent added to susceptibility cards for commercial instruments, which is a big relief.

At our institution, we have a reflex testing protocol that our antimicrobial stewardship team created with our microbiology laboratory. For example, for Pseudomonas aeruginosa isolates, our microbiology laboratory will automatically test for ceftolozane/tazobactam, ceftazidime/avibactam, and potentially cefiderocol based on the susceptibilities of the initial isolate without requiring a call to request them. This allows for results a day or so sooner.

When considering empiric therapy for P. aeruginosa with difficult-to-treat resistance (DTR), how do you decide between novel β-lactams monotherapy vs traditional β-lactams in combination with aminoglycosides?

Emily Heil, PharmD, MS, BCIDP, AAHIVP:
Without the ability to use molecular diagnostic testing to give us clues on which resistance mechanisms are present, often we find out the patient has a DTR-P. aeruginosa 3-4 days into their care. What we should be using empirically is a big question that is not simple to answer.

HCPs need to weigh the pros and cons. If DTR-P. aeruginosa makes up a minority of your pathogens, then you don’t want to bring these broad-spectrum, novel β-lactams out as first-line therapy for everyone.

Without molecular diagnostic testing to identify the different resistance mechanisms for P. aeruginosa, we need to balance risks and benefits while using risk predictors as best we can.

At our site, we are in the process of building clinical decision support within our EMR based on an internal risk scoring system to predict a patient’s risk for DTR-P. aeruginosa. Our risk scoring system includes 4 factors that are easily gleaned from the EMR, with the most important factor being previous isolation of DTR P. aeruginosa, because we know history repeats itself. With this approach, we hope HCPs can better identify which patients would benefit the most from using these novel β-lactams empirically.

Trevor Van Schooneveld, MD, FSHEA, FACP:
I agree. When deciding to use these novel β-lactams empirically, we need to make individualized decisions based on the specific patient in front of us.

Which of the novel β-lactams can be used to treat DTR-P. aeruginosa?

Trevor Van Schooneveld, MD, FSHEA, FACP:
Based on the Infectious Diseases Society of America guidance, there are 3 preferred treatment options for DTR-P. aeruginosa: ceftolozane/tazobactam, ceftazidime/avibactam, and imipenem/relebactam. Cefiderocol is an alternative option, particularly if it is a metallo-β-lactamase-producing isolate (eg, NDM, IMP, VIP), in which case it would be the preferred option.

Determining which of these novel β-lactams should be preferred at your institution should be based on your local antibiogram. If this data is not available, it is worth evaluating a set of DTR-P. aeruginosa isolates to determine which agent is most active.

What are therapies that are not recommended? Meropenem/vaborbactam is not recommended because vaborbactam does not provide additional activity against DTR-P. aeruginosa compared with meropenem alone. In addition, use of combination therapy (eg, traditional β-lactam with either an aminoglycoside or fluoroquinolone) when susceptibility to preferred β-lactams is demonstrated is not recommended.

What if your laboratory does not report minimum inhibitory concentration (MIC) results, would you still consider using tetracyclines for carbapenem-resistant Acinetobacter baumannii (CRAB) treatment?

Emily Heil, PharmD, MS, BCIDP, AAHIVP:
This is such a tough question to answer. The current Clinical and Laboratory Standards Institute MIC for tetracyclines like minocycline and tigecycline is 4 µg/mL, but with this cutoff we are unlikely to reach the desired ratio of free drug under the concentration-time curve to MIC with standard dosing regimens.

In the absence of MIC data, you really need to think about drug penetration to the site of infection. If I were going blind and did not have MIC data, I would not use a tetracycline for high inoculum infections such as ventilator-associated pneumonia or in a situation where we did not have source control. I would be more likely to use a tetracycline without MIC data if the patient were stable and had a low inoculum infection where tetracyclines achieve higher concentrations (eg, skin and soft tissue infection or intra-abdominal infections with source control).

I struggle with this at my own institution because we still routinely use disk diffusion testing for A. baumannii isolates, so in most cases, I do not have actual MIC results available. If I am hanging my hat on using a tetracycline (eg, minocycline or tigecycline) as part of my combination regimen for CRAB, I request an E-test to be performed.

When treating metallo-β-lactamase–producing Enterobacterales, how do you administer ceftazidime/avibactam 2.5 g every 8 hours and aztreonam 2 g every 6 hours simultaneously when they are dosed at different frequencies?

Emily Heil, PharmD, MS, BCIDP, AAHIVP:
At my practice site, to optimize synergistic activity of ceftazidime/avibactam and aztreonam, we infuse ceftazidime/avibactam over 4 hours instead of 3 hours, and aztreonam over 3 hours to maintain a good overlap in administration. It is not perfect, and administration becomes a little staggered, but this strategy increases the amount of time these 2 antibiotics are administered simultaneously.

Your Thoughts?
What factors do you consider when selecting empiric therapy for your patients with complex clinical infections involving gram-negative resistance? Join the discussion by posting a comment.