Antimicrobial stewardship in immunocompromised hosts

Goals of stewardship in immunocompromised hosts

The basic goals of antimicrobial stewardship in immunocompromised hosts are the same as in other children: to maximize therapeutic success by optimizing choice, dose, route, and duration of therapy while limiting unintended consequences such as adverse events and cost. Stewardship can, however, be challenging in immunocompromised hosts, particularly in the transplant population. Because of multiple previous rounds of antimicrobial therapy, which may include prophylaxis, transplant recipients are more likely to be colonized with multidrug-resistant organisms, complicating empiric antibiotic choices. And even when the conditions of these patients improve with empiric therapy, their often profound immune deficiency and comorbid conditions, some of which mimic infection, may make de-escalation difficult as well.

It is crucial that stewardship teams develop expertise in immunocompromised hosts. This requires knowledge not only of the wide array of infectious diseases affecting these patients but also the mechanisms and impact of various immunosuppressive regimens to understand the specific arm(s) of the immune system rendered vulnerable and the opportunistic infectious diseases that exploit these deficiencies. Furthermore, stewardship teams should partner with immunocompromised patient care teams, including oncology, solid organ transplant, and bone marrow transplant services, to develop a working knowledge of protocols and approach to the antimicrobial prescribing by these services. Ideally, stewardship teams should collaborate with immunocompromised patient teams to optimize antimicrobial use in these populations, not dictate unilaterally.

Conducting stewardship requires a complete assessment of the risks and benefits of antimicrobial prescribing. On the one hand, these patients are at high risk of invasive infection and should be treated aggressively. On the other hand, use of broad-spectrum agents will further drive resistance, already present at a higher rate in this population, and may contribute to development of graft-versus-host-disease and Clostridium difficile infection (CDI). To further complicate the issue, clinicians may have different thresholds of risk. For example, the primary team may focus on the potential value of aggressive antimicrobial therapy (i.e., broader therapy for a longer duration), whereas the stewardship team may focus more on acute (e.g., organ toxicity, drug-drug interactions) and chronic (e.g., antimicrobial resistance, microbiome disruption) adverse events.

The role of antibacterial prophylaxis is a prime example of the challenges in this population. In adult hematopoietic stem cell (HSCT) recipients, the use of fluoroquinolone prophylaxis is common. The evidence is less clear in children. A recently published randomized placebo-controlled trial of levofloxacin prophylaxis administered during the first 2 cycles of chemotherapy found a significant decrease in the incidence of bacteremia for children with acute myeloid acute and relapsed lymphoblastic leukemia. A smaller, nonsignificant decrease in the incidence of bacteremia was seen in the subgroup of children after HSCT. Therefore implementing prophylaxis in this population depends on how the risks of antibacterial exposure are considered compared with a potential, albeit not statistically significant, decrease in bacteremia.

Although most pediatric stewardship efforts have focused on antibacterial agents, immunocompromised hosts are at high risk for complications from fungal and viral infections. Therefore strategies for antifungal and antiviral stewardship need to be considered in this population. The significant variability in use of these medications across institutions for both prophylaxis and treatment further highlights this need. A review of 2015 data from the Pediatric Health Information System database examined antifungal and antiviral use at 47 freestanding children’s hospitals. Although high-risk patients accounted for less than 5% of all hospital discharges, they accounted for nearly half of the antiviral and antifungal use. Specifically, HSCT recipients accounted for 20% of all antifungal use and 24% of all antiviral use. Although this cohort was limited to high-risk patients, there was still significant variation in prescribing, demonstrating the need for stewardship of these agents. Antivirals and antifungals are ideal targets for stewardship interventions because they are often inappropriately prescribed, have narrow therapeutic windows, and are costly. Although the most important strategies for antifungal and antiviral stewardship remain to be elucidated, therapeutic drug monitoring and development of protocols for fungal prophylaxis are examples.

Diagnostic stewardship is another important consideration. In otherwise healthy children, the use of rapid diagnostics has decreased time to optimal therapy, leading to better patient outcomes. Several studies have documented that having a stewardship pharmacist to act on results of these tests is more effective than the mere availability of the results. In addition to helping interpret these test results, stewardship teams can have an active role in determining criteria for laboratory test ordering. Unnecessary testing can lead to increased costs as well as to treatment of organisms that are normal colonizers and not true pathogens.

Other stewardship goals include the reduction of redundant antimicrobial coverage, promotion of the oral route of antibiotics over the intravenous route, and prevention of CDI.

Barriers to antimicrobial stewardship programs in immunocompromised children

Understanding barriers and challenges to effective antimicrobial stewardship, especially those that differ between targets and populations, is important to planning, implementing, modifying, and evaluating a stewardship program. Barriers to antimicrobial stewardship in immunocompromised pediatric patients may be similar to those in other populations, but there are some unique aspects. Issues particularly challenging to stewardship efforts in the immunocompromised population include the lack of evidence or consensus for optimal prevention and treatment of infection, diagnostic uncertainty, medical complexity and risk of severe or life-threatening infections, and the relatively high risk of antimicrobial-resistant infections.