Relationship of fluconazole prophylaxis with fungal microbiology in hospitalized intra-abdominal surgery patients: a descriptive cohort study

With crude mortality approaching 40%, candidemia continues to take a high toll among certain groups of hospitalized patients [1]-[5]. In the past, the species most frequently responsible for candidemia and invasive Candida infections was Candida albicans[1]. Over time, however, there has been a shift in the epidemiology of invasive Candida infection, with an increasing proportion being due to species other than C. albicans[2],[3].

Invasive Candida is of particular concern in specific populations. Intra-abdominal surgery is a well-recognized risk factor for invasive fungal infection [6],[7]. The initial choice of an antifungal is critical in the setting of suspected candidemia, as it is strongly associated with the outcomes. Although well-established evidence-based clinical guidelines help in making correct choices, efforts to ensure appropriate and timely initial antifungal therapy have been complicated by the shifting microbiology and antifungal susceptibility patterns. To address this uncertainty, the guidelines recommend empiric therapy with an echinocandin to treat suspected candidemia in the setting of critical illness, as well as in neutropenia with fluconazole prophylaxis, where non-C. albicans isolates are more likely [8]. Unfortunately, candidal microbiology and thus initial coverage decisions are less clear in the setting of intra-abdominal surgery. One factor that may be driving shifts in candidal populations and antifungal susceptibility among these patients is fluconazole prophylaxis, which although controversial is used nevertheless. The concern stems from several studies in nonsurgical cohorts that have detected an association between fluconazole prophylaxis and increased infection with Candida glabrata and Candida krusei, reflecting the impact of selection pressure with fluconazole prophylaxis [3],[9]-[12]. However, it is unclear whether such selection pressure with a drift toward azole-resistant species is a factor among patients undergoing intra-abdominal surgery who develop candidemia.

Our study has confirmed that C. albicans was the most common species isolate among patients with intra-abdominal surgery and candidemia (39.6%), followed closely by C. glabrata (35.7%). Overall, non-C. albicans species accounted for more than one-half of all isolates and three-quarters of isolates among those who had fluconazole prophylaxis. Most alarmingly, based on timing and selection of empiric coverage, 63% of candidemia patients received treatment categorized as inappropriate based on conservative criteria.

There are several implications to the distribution of non-C. albicans species found among patients with prophylaxis. Admittedly, patients with prophylaxis who developed non-C. albicans candidemia were more severely ill than those without prophylaxis, as evidenced by their need for vasopressors and mechanical ventilation, as well as by their higher likelihood of having bacteremia. One could hypothesize that such patients are more likely to have had prior treatment, and not just prophylaxis, with fluconazole, which may have served as the stimulus for development of resistant species. Our data did not allow us to explore their prior exposure to fluconazole as treatment, an important question to address in future studies. However, the increase in resistant species among patients with prophylaxis also probably points to the selection pressures inherent in antimicrobial prophylaxis in this surgical cohort of patients with intra-abdominal infections, which is not well documented in prior studies. The risks and benefits of fluconazole prophylaxis in this group, although controversial, thus need to continue to be evaluated carefully, given its propensity to drive a switch to resistant species in this deadly disease. Importantly, when faced with a patient who has received prophylaxis, a clinician must consider that such a patient’s risk for a resistant candidemia may be considerably elevated and factor this information into his/her empiric treatment decisions.

Controversy remains regarding antifungal prophylaxis among intra-abdominal surgery patients. Research efforts to resolve these questions are impeded by the need for large sample sizes to demonstrate adjusted differences in clinical outcomes. Changing Candida epidemiology further complicates research and renders some prior studies obsolete. While shown effectively to decrease the incidence of fungal infection in high-risk, critically ill surgical patients [9],[14]-[16], fluconazole prophylaxis does not appear to improve their survival [9],[16]. These studies indicate that the benefit to the patient of the decision to use prophylaxis may not exceed the risk of driving the escalation of resistance to existing antifungal treatments. Our data indicate that although only a small proportion of this surgical population received prophylaxis, their risk of a resistant candidal species was high.

While earlier studies reported that non-C. albicans species accounted for one-half or fewer of isolated organisms [17],[18], later research uncovered an increase in cases of candidemia involving non-C. albicans[2],[3]. We observed a similarly increased proportion of non-C. albicans isolates, most pronounced among patients receiving prophylaxis with fluconazole. This switch in species is concerning, since non-C. albicans species, and in particular C. glabrata, exhibit greater resistance to fluconazole and are associated with worse outcomes when compared with C. albicans[19].

The association of increasingly resistant candidal species causing candidemia and their associated worsened outcomes may be explained by the difficulty of targeting initial empiric therapy amidst the shifting landscape of antifungal susceptibility. Many studies in both candidemia and other serious infections have noted a significant and clinically important rise in the risk of death when the patient does not receive prompt empiric treatment with an agent that covers the culprit pathogen [20]-[22]. Guidelines for patients with complicated intra-abdominal infections [23] recommend antifungal prophylaxis for healthcare-associated infection and those with severe community-acquired infection, leading with fluconazole. An echinocandin is recommended as initial therapy for critically ill patients, although no guidance is provided with respect to recent fluconazole prophylaxis. The Infectious Disease Society of America Expert Panel favors echinocandins for treating suspected invasive candidiasis in non-neutropenic patients who are moderately or severely ill or had recent azole exposure [8]. Guidelines recommend antifungal agents based on the Candida isolate or suspected isolate, but delaying appropriate selection until culture results are available or until the patient is critically ill may be too late [8],[23].

More than 60% of our study population failed to receive appropriate empiric therapy based on timing and coverage (the latter in those whose BCx grew non-C. albicans species). We chose not to evaluate adjusted mortality based on the appropriateness of treatment due to sample size considerations in the context of the low percentage of patients with evidence of appropriate treatment. The challenges that are leading to inappropriate treatment suggest the need for additional improvements to rapidly recognize and characterize candidemia. Risk stratification algorithms and emerging diagnostics such as β-D-glucan may play a role in the future [24]-[26].

Our data may be particularly prone to misclassification of several factors. For example, we used a relatively stringent definition for fluconazole prophylaxis. This was done in order to increase the specificity of the definition. As a consequence, we probably misclassified some patients who did not fit this definition and yet received prophylaxis as not receiving prophylaxis. We chose specificity over sensitivity in order to avoid inflating the magnitude of the differences in the candidal species between the two groups. As a result, the actual differences in the prevalence of potentially azole-resistant species between the groups on and off prophylaxis are probably even greater than what we have observed. On the other hand, it remains possible that at least some of the cases identified as prophylaxis in reality received treatment. However, the stringent nature of our definition of prophylaxis should have minimized such misclassification. The appropriateness of empiric antifungal therapy could not be determined reliably in nearly 25% of the study population based on data elements that were available. However, even in the unlikely event that all of these patients could have been ultimately assigned to the appropriate group, this would not detract from the finding that 63% did not receive appropriate therapy.

A distinct strength of our study, as compared with prior single-center reports, is its multicenter nature, which lends generalizability to our findings.

In summary, our study provides further evidence of the microbiologic shifts in candidemia among a population of patients who are at particular risk for this infection. To the best of our knowledge, this is the first study to examine the association of fluconazole prophylaxis with the candidal species distribution among intra-abdominal surgery patients. The result of this examination points to a likely role for selection pressures in such prophylaxis patients. In turn, the high prevalence of inappropriate treatment detected in our study is an important reminder for clinicians to consider candidemia in a fitting clinical setting, and to be aware of the factors that drive antifungal resistance. Most importantly, in the era of a widening gap between evolving microbial defenses and our abilities to address them, antifungal prophylaxis practices among intra-abdominal surgical patients require a measured re-evaluation.