Guidelines on resistant gram-negatives

Those on the front lines against antimicrobial-resistant gram-negative infections don't get much time to rest.

Earlier this year, experts convened by the Infectious Diseases Society of America (IDSA) released the latest edition of their guidance on these infections, and they're already working on the next revision.

The recommendations, which were published in Clinical Infectious Diseases and on the IDSA's website, offer general guidance as well as treatments for six specific bugs/resistance mechanisms. The intended audience is all clinicians who treat these resistant infections, from subspecialists to generalists.

ACP Hospitalist recently talked to the guidance statement's lead author, Pranita Tamma, MD, MHS. Dr. Tamma is an associate professor of pediatrics in the division of infectious diseases and director of the pediatric antimicrobial stewardship program at the Johns Hopkins University School of Medicine in Baltimore.

Q: What motivated this update?

A: Antibiotic resistance is continuing to be a public health epidemic. By 2050, it's actually expected that more people will die from antibiotic-resistant infections than from all cancers together, which is obviously really concerning. In clinical practice, everyone is dealing with resistance much more than we used to. There are a lot of new types of resistance mechanisms, and fortunately, there are also new drugs coming to market. So, what we've elected to do is update the guidance document annually, because there are a fair amount of changes in the resistance landscape, the treatment landscape, [and] even just the evidence base that can help better inform how we select among different antibiotics.

Q: How much change will these annual updates likely entail?

A: We'll probably stick with the six organisms or resistance groups—the ESBLs [extended-spectrum beta-lactamase producing Enterobacterales], AmpCs [beta-lactamase-producing Enterobacterales], carbapenem-resistant Enterobacterales, Pseudomonas with difficult-to-treat resistance, carbapenem-resistant Acinetobacter baumannii (CRAB), and Stenotrophomonas maltophilia. We were thinking we could add more gram-negative organisms, for example, Achromobacter or Burkholderia, but they are quite rare, and there's just so little evidence on how best to treat them.

Q: What were the most substantial changes this year?

A: We actually updated the full document pretty extensively. I don't think there's a single question that has not had some change. There had been a lot of really great feedback from the clinician community through social media, emails, letters to the editor. We definitely take all of those very seriously. … For Acinetobacter, for example, where we were suggesting high-dose ampicillin-sulbactam, we gave a little more leeway—after reviewing the literature—on what we would consider high-dose, as we've heard from some really smart pharmacists about what's logistically feasible.

In this update, Table 1 is dosing, and there were some adjustments made. We also added a Table 2, which includes antibiotic breakpoints, because sometimes it's hard for clinicians to figure out how best to access that information. We added supplemental material which gives our justification for the dosing we selected. It's more transparent; previously, we would just have [recommended] dosing, and people weren't sure why, especially if it's in conflict with an FDA label.

Q: Do you think this many changes will be required in every annual update?

A: With the availability of new drugs, my guess is that there probably will be pretty significant updates on an annual basis. Even since the current guidance document was published, we have a drug called sulbactam-durlobactam, which is a new beta-lactam that is labeled to treat A. baumannii, although we would prefer it to be reserved for CRAB, because obviously, we don't want to overuse it for fully susceptible Acinetobacter infections if we have other options. The preclinical and the available clinical data on that drug do look quite good, so we are currently updating the CRAB section, and we'll probably be posting it online before the full document is out, because that section will change quite drastically with the availability of this new drug. Possibly by the end of this year, and likely by next year, we're expecting there to be at least one or two other new drugs that would be active against drug-resistant Pseudomonas [and] carbapenem-resistant Enterobacterales. I am very excited about this because these new drugs would likely be able to treat Pseudomonas and Enterobacterales infections that are resistant to several or even all of the antibiotics that became newly available in the past few years.

Q: What do you see as the biggest current challenges in treating drug-resistant gram-negative infections?

A: Academic medical centers often have the luxury of infectious disease pharmacists and microbiology labs that are actually able to test in relatively real time the new drugs against bacteria. A challenge is smaller hospitals that have to send isolates out to an outside lab to see if any of these new drugs are options, and by the time they get the results back, if they don't have the drugs on their hospital formulary, it could mean several days without effective treatment for a patient.

Also, despite the availability of new drugs, it is critical to continue to be judicious about their use. Only use them when absolutely necessary, transition to oral therapy whenever possible, keep your durations short, avoid unnecessary combination therapy. Those same principles apply even if it's a drug-resistant infection. We still want to be as careful as possible because every additional day a patient receives a drug they don't need, there's the possibility of resistance emerging. Patients with really drug-resistant infections can't afford to keep having increasingly resistant bacteria. There's a challenge to making it clear that it's great we have new drugs, but it doesn't mean that meropenem is suddenly the new amoxicillin. Sometimes I worry the more new drugs we get, the more there's this perception it's not that big of a concern if resistance develops to the antibiotics that have been around for some time.

Q: What's your advice for hospitalists?

A: I'm always impressed with hospitalists. I feel like they're probably the best stewards of antibiotic use. I am embarrassed to admit [that] in the infectious disease world, we're often more likely to overprescribe antibiotics than hospitalists. So I am very excited that this guidance document is not just limited to the infectious disease community and that other groups who really are very much involved in taking care of patients with drug-resistant infections are also using it in clinical practice.

Q: The guidance mentions consulting with infectious disease specialists or pharmacists. How do hospitalists decide when it's time for a consult?

A: Obviously, the authors of the guidance are all infectious disease specialists, so it is a little self-serving to write that—I say with a smile. I would say of course, for a patient with an ESBL infection who is relatively well-appearing, I don't think infectious disease specialists need to be involved routinely. For patients infected with carbapenem-resistant organisms, it might be helpful to have an infectious diseases specialist involved just to make sure there's not any new information that should be considered in antibiotic decision making. The infectious diseases specialist is often a conduit to discussions with the microbiology laboratory and pharmacy and can assist with expediting antibiotic susceptibility testing, resistance mechanism determination, adverse event profiles and drug interactions to consider, and more nuanced issues such as does this new drug penetrate the cerebrospinal fluid?

Q: Do you have any other takeaways on the guidance for hospitalists?

A: If there's parts of it that are not as user-friendly or confusing, we're hoping to get as much feedback as possible. The point was really to make this practical and understandable to your average clinician, even if they don't consider themselves as a gram-negative resistance expert. Hospitalists see patients day in and day out [and can help] to make sure that this document is actually user-friendly and feasible and [clarify] some of the nuances with patient care, like if a patient's getting valproic acid, is this drug safe? In the future, a hospitalist addition to the guidance document would be really nice.

Q: How does the panel operate?

A: We just did a rotation, so three of the members have transitioned off, and we have three new members who joined. It's good to have diversity of thought, because so much of this document is expert opinion. We definitely do a thorough literature review. Unfortunately, in this field, there are just so few clinical trials that are really robust, high-quality evidence that we are often left deciding, what management approaches do we feel comfortable with, with the available evidence we have? There's a fair amount of difference of opinions, but usually what we've been doing is having multiple virtual meetings where we talk about a topic. If there are lingering issues, we meet again, and we keep meeting until we come to a consensus. Sometimes it just means that we make sure the language is flexible and softened so that everyone's viewpoint is captured. It's definitely really enjoyable, but it is humbling because sometimes you decide upon a suggested treatment approach, and then the evidence comes out, and it's totally the opposite of what you were suggesting.