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Optimizing Therapy for GN HAP and VAP
Expert Answers to FAQs: Improving Time to Early Effective Therapy for Resistant Gram-Negative HAP/VAP

Released: May 31, 2023

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Key Takeaways
  • Risk stratification tools are important to implement locally to identify patients at highest risk of multidrug-resistant gram-negative hospital-acquired and ventilator-associated pneumonia.
  • Antimicrobial agent selection and the decision to use combination therapy should be guided by local resistance patterns and patient-specific factors.
  • Tools such as rapid molecular diagnostics, advanced antibiograms, and clinical decision support tools should be leveraged to improve time to effective therapy.

In this commentary, Kayla Stover, PharmD, BCIDP, BCPS, FCCP, FIDSA, and Trevor Van Schooneveld, MD, FSHEA, FACP, answer learner questions related to the program titled, “Optimizing Antimicrobial Management and Tackling Resistance in Gram-Negative HAP/VAP Infections.” 

Do you have a clinical guideline for hospital-acquired pneumonia (HAP)/ventilator-associated pneumonia (VAP) at your institution? If so, do you use risk factor–based criteria to stratify empiric regimen selection? 

Kayla Stover, PharmD, BCIDP, BCPS, FCCP, FIDSA: 
We have a HAP/VAP clinical guideline that walks through suggested diagnostic tests, initial therapy, and adjustments to therapy (eg, addition of double antipseudomonal coverage) based on high risk of mortality (new ventilator requirement, septic shock, anticipated mortality >25%) or risks of drug resistance (using the criteria from the 2016 IDSA guidelines).

Trevor Van Schooneveld, MD, FSHEA, FACP: 
Similarly, we have a guideline and we created a simple infographic with all the key recommendations on one page. We use the risk factors for resistance espoused in the guidelines. We also built order sets with the recommended antibiotic regimens, doses, and “second agent” options ready to order.

For patients who have septic shock because of HAP/VAP, we suggest considering the addition of an aminoglycoside. When there is no septic shock, we recommend a second agent if there is concern for resistant Pseudomonas. In addition, if the patient has a history of extended-spectrum β-lactamase (ESBL) colonization or resistance to our recommended agents (eg, cefepime or piperacillin/tazobactam), we recommend meropenem.

How much DTR-P. aeruginosa do you see at your site? Do you observe it more often in certain patient populations or care areas? What is your approach to combination therapy? What novel agents do you preferentially use? 

Kayla Stover, PharmD, BCIDP, BCPS, FCCP, FIDSA: 
Although we do see a lot of resistant Pseudomonas, it is not all DTR-Pseudomonas by technical definition. When we do have these infections, they are primarily in patients with significant healthcare exposure who end up in our medical intensive care units.

If we use combination therapy, we usually choose an aminoglycoside to be paired with our first-line β-lactams. The last update to the HAP/VAP guidelines predated the availability of novel β-lactam/β-lactamase inhibitors, and although data are emerging, much of the current evidence is retrospective in design or not in the patient populations or organism of interest. Therefore, institutions must often make these decisions locally. We preferentially use meropenem-vaborbactam as our novel agent hospitalwide but have ceftolozane-tazobactam, ceftazidime-avibactam, and imipenem-relebactam available for difficult or resistant cases. 

Trevor Van Schooneveld, MD, FSHEA, FACP: 
DTR-Pseudomonas is the most common resistant pathogen we see, and it is much more common than carbapenemase-producing Enterobacterales (CRE) at our site. We see it most often in patients with prolonged stays who have been on multiple antibiotic regimens, particularly in those who were previously colonized with Pseudomonas. 

We do not routinely use combination therapy, although it is certainly suggested in patients who have septic shock. Combination therapy is also recommended when there is a concern for multidrug-resistant (MDR) Pseudomonas, such as previous colonization with resistant strains or recent treatment with broad-spectrum antibiotics.

Our preferred novel agent is ceftolozane-tazobactam and we routinely report susceptibility to this for Pseudomonas only. Our second-line choice would be either ceftazidime-avibactam or imipenem-relebactam. Ceftazidime-avibactam is available on formulary mostly for CRE, but we do use imipenem-relebactam as it often retains activity against DTR-P. aeruginosa strains resistant to many antipseudomonal β-lactams.

How do you decide what to use as the second agent for combination therapy: a fluoroquinolone or aminoglycoside? Will the recent CLSI breakpoint changes for aminoglycosides affect their usefulness for HAP/VAP? 

Kayla Stover, PharmD, BCIDP, BCPS, FCCP, FIDSA: 
Our decision for which agent to pick is based on our local susceptibilities from our antibiogram. At our institution, fluoroquinolone resistance is fairly high, so we typically choose tobramycin. Although we have not yet incorporated aminoglycoside breakpoint changes into our microbiology processes, I do think it will affect their usefulness, especially for MDR HAP/VAP.

Trevor Van Schooneveld, MD, FSHEA, FACP: 
We created a combination antibiogram to help decide what agents to add to the antipseudomonal β-lactam. Our preferred combination agent is tobramycin for Pseudomonas, as we found quinolones add almost no activity at our institution. I suspect the CLSI breakpoint changes will have an impact, but owing to limitations with our current susceptibility panels, it will be challenging to implement. We are still working with our microbiology lab on how to interpret and implement these changes. 

What types of antibiograms do you use at your site? What have been the biggest barriers to implementation of novel antibiograms, such as combination or weighted incidence syndromic antibiograms? Any advice on how to overcome these barriers? 

Kayla Stover, PharmD, BCIDP, BCPS, FCCP, FIDSA: 
We have a traditional, whole-hospital yearly antibiogram. We have looked at adding unit-specific and source-specific antibiograms, but our biggest barrier has been inadequate number of samples in various units and inappropriately drawn, less helpful cultures from specific floors (especially respiratory cultures from our medicine floor). Although small numbers may be overcome by using a longer sample period, overuse of specific cultures may require institutional procedures or guidance documents to help reduce use in select units.    

Trevor Van Schooneveld, MD, FSHEA, FACP: 
We have an overall antibiogram, a urine specific antibiogram (which we use particularly for our emergency department), a blood antibiogram (which we use for our rapid blood panel identification system), and a respiratory tract antibiogram (which we use to help guide empiric therapy for pneumonia and to streamline definitive therapy for pathogens found on the rapid pneumonia panel). Creating these antibiograms can be a bit of a challenge in our electronic medical records. The primary issue I have run into is the lack of isolates for many pathogens, so we need to combine multiple years’ worth of data.

Are you using any rapid molecular diagnostic technologies to improve the time to effective therapy for patients with HAP/VAP? Have you implemented any panels specifically for pneumonia? What is on your wish list? 

Trevor Van Schooneveld, MD, FSHEA, FACP: 
We currently use the BioFire FilmArray Pneumonia Panel. Our local data suggest that healthcare professionals de-escalate antibiotics faster using this technology. I think it is a great tool to help rapidly get people off vancomycin, which is usually not needed. It can also be helpful in identifying highly drug–resistant pathogens such as carbapenemase and ESBL producers.

It does not provide much information on Pseudomonas resistance as this is usually multifactorial, but the lack of detection of Pseudomonas can be helpful in recommending de-escalation particularly if our antibiogram supports that this single agent is highly active.

Kayla Stover, PharmD, BCIDP, BCPS, FCCP, FIDSA: 
We have the BioFire FilmArray as well, but we have not yet implemented the Pneumonia Panel. We routinely use a limited viral-only rapid PCR screening panel (with influenza A and B, RSV, COVID-19), and we have access to the more complete respiratory viral panel, which we generally discourage because of routine overuse and limited impact on antimicrobial therapy.  

What is the role of procalcitonin and other biomarkers in improving time to effective therapy for HAP/VAP? 

Trevor Van Schooneveld, MD, FSHEA, FACP: 
Procalcitonin is a useful tool in 2 areas.

First, it can be helpful in areas of diagnostic uncertainty. HAP/VAP are overdiagnosed, and procalcitonin can be a useful tool in sorting out who really needs antibiotics and where can they be safely withheld.

Second, it can also be helpful in identifying patients who qualify for antibiotic discontinuation. We have learned from the community-acquired pneumonia literature that 5 days of antibiotics is not needed for all patients; some can be safely treated with 3-day courses. The current guidelines for HAP/VAP recommend all patients be treated with 7-day courses, but procalcitonin may help us to identify patients for whom antibiotics can be discontinued earlier.

Kayla Stover, PharmD, BCIDP, BCPS, FCCP, FIDSA: 
I agree. Procalcitonin seems to be particularly helpful in decisions regarding discontinuation of therapy, but this is most helpful when you have at least 2 procalcitonin values to compare progress (ideally one earlier in the infection and one on potential discontinuation days).

Use at my institution is inconsistent, which makes the practical use of procalcitonin a little more difficult. C-reactive protein, IL-6, and other potential biomarkers like TREM-1 have been evaluated for use in pneumonia, but use has been confounded by other comorbidities or circumstances related to the hospital stay. As a result, the uptake on general use of these alternative biomarkers for pneumonia has been slow.     

Your Thoughts?
What strategies do you use to improve time to effective therapy for resistant gram-negative HAP/VAP at your institution? Join the conversation by adding a comment in the discussion section.