Practical Strategies to Minimize Antimicrobial Resistance in Critically Ill Patients

EP: 1.Looking at Mortality Rates Comparing Treatments for Gram-Negative Resistant Pseudomonas aeruginosa Infections

EP: 2.Determining Resistance Patterns in Difficult-to-Treat Resistant Pseudomonas Infections

EP: 3.Statistical Weighting Helps Reduce Bias in Observational Studies

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EP: 4.Practical Strategies to Minimize Antimicrobial Resistance in Critically Ill Patients

In this short series with Pranita Tamma, MD, MHS, associate professor of pediatrics in the Division of Pediatric Infectious Diseases at The Johns Hopkins University School of Medicine, she has a discussion about ceftolozane-tazobactam vs ceftazidime-avibactam for gram-negative resistant Pseudomonas aeruginosa infections and the latest data supporting these decisions.

In one retrospective observational study, which compared ceftolozane-tazobactam and ceftazidime-avibactam and was funded by the National Institutes of Health, the findings showed similar 30-day mortality rates but higher resistance emergence in the ceftolozane-tazobactam group (38% vs 25%). Tamma was the senior investigator in this trial.

Below is a response from a conversation with her about resistance development.

Contagion: How do treatment duration and CRRT influence resistance development, and what steps can clinicians take to mitigate these risks?

Pranita Tamma, MD, MHS: I think that as clinicians, it’s reasonable for us to comment on how likely resistance is to develop. But what’s really important is identifying the factors we can actually modify. We can’t change a patient’s age, their immune status, or the fact that they’re in the ICU—at least not meaningfully. But we can focus on strategies that may help reduce the risk of resistance emerging.

In this study, and in a prior study we conducted, we tried to identify modifiable risk factors. For example, with ceftolozane–tazobactam, we recommend always using the higher dose—three grams every eight hours—for seriously ill patients, rather than the lower dose that’s often used for non-pneumonia infections. These patients are very sick, mortality is high, and the stakes are high, so we advocate for maximizing therapy.

The package insert recommends a one-hour infusion, but both we and the IDSA antimicrobial resistance guidance recommend extending the infusion to three hours. By prolonging the infusion, you’re more likely to maintain sustained drug concentrations, avoiding sharp drops that can increase the risk of resistance. In our earlier study, patients who received one-hour infusions, rather than three hours, were significantly more likely to have subsequent isolates with resistance. So high-dose therapy with appropriate infusion strategies is critical.

Another important factor is limiting the duration of treatment to what’s truly necessary. For example, the evidence supports seven days of therapy for bacteremia. Adding a few extra days “just in case” is usually not beneficial, and every additional day increases the risk of resistance.

Source control is also key. If infected catheters aren’t removed or abscesses aren’t drained, bacteria such as Pseudomonas have more opportunity to persist and develop resistance mechanisms. So ensuring source control is one of the most impactful steps we can take.

Finally, with continuous renal replacement therapy (CRRT), there’s no clear guidance on dosing for these agents. Some clinicians maintain the full dose, while others lower it. In our observational study, patients whose doses were reduced on CRRT had a higher risk of developing resistance. We suspect this is because CRRT makes drug levels unpredictable, and lowering the dose increases the chance of subtherapeutic concentrations. Since there isn’t strong evidence of “overdosing” risk with these agents, we believe it’s safer not to reduce the dose, thereby increasing the likelihood of maintaining adequate drug concentrations in both the bloodstream and the infection site.

The conversation was edited for grammar and clarity.