Outcomes with micafungin in patients with candidaemia or invasive candidiasis due to Candida glabrata and Candida krusei

J Antimicrob Chemother 211; 66: 375 3 doi:1.193/jac/dkq446 Advance Access publication 8 December 21 Outcomes with micafungin in patients with candidaemia or invasive candidiasis due to Candida glabrata and Candida krusei Andrew F. Shorr 1 *, Chunzhang Wu 2 and Smita Kothari 3 1 Pulmonary and Critical Care, Washington Hospital Center, 11 Irving St NW, Washington, DC 21, USA; 2 Astellas Pharma Global Development, 3 Parkway North, Deerfield, IL 15, USA; 3 Astellas Pharma US Inc., 3 Parkway North, Deerfield, IL 15, USA *Corresponding author. Tel: +1-22-877-7856; Fax: +1-22-291-386; E-mail: afshorr@dnamail.com Received 12 September 21; returned 24 October 21; revised 27 October 21; accepted 29 October 21 Objectives: Infection with Candida glabrata and Candida krusei represents a major challenge. We sought to describe outcomes for patients with candidaemia/invasive candidiasis (C/IC) due to these pathogens who were treated with micafungin. Methods: We pooled two randomized trials of micafungin versus comparator. We identified patients infected with either C. glabrata or C. krusei. One trial compared micafungin (1 mg/day with option for dose escalation) with liposomal amphotericin B, while the other compared micafungin (either 1 or 15 mg/day) and caspofungin (NCT16288 and NCT15144). Clinical cure was our primary endpoint while 28 day mortality represented a secondary endpoint. Results: Among 17 subjects with C/IC, 183 were infected with either C. glabrata (n¼144) or C. krusei (n¼39). One hundred and seventeen received micafungin. Clinical cure rates in those receiving micafungin were similar to those randomized to comparator [73.5% (86/117) versus 62.1% (41/66), P¼not significant]. Mortality at 28 days was also similar [29.1% (34/117) with micafungin versus 34.8% (23/66) with comparator, P¼not significant]. In logistic regression, treatment agent correlated with neither cure nor mortality. Factors independently linked with lower cure rates included: IC neutropenia; higher severity of illness; and medical admission. Higher severity of illness and failure to remove a central venous catheter were associated with 28 day mortality. Crude and adjusted outcomes were comparable irrespective of micafungin dose administered. Conclusions: Micafungin results in similar outcomes to comparators for C/IC due to C. glabrata and C. krusei. The 1 mg/day dose represents an acceptable option in this setting. Patient characteristics and catheter management appear to be more important factors affecting clinical outcomes. Keywords: mortality, C. glabrata, C. krusei Introduction Candida remains a major challenge in the care of seriously ill patients. Candida species represent the fourth most common organism in hospital-acquired bloodstream infections (BSIs). 1,2 They are also now implicated as a cause of infection in patients presenting to hospital. In addition, BSIs due to yeast result in significant morbidity and mortality. Crude mortality rates associated with candidaemia exceed % in some case series, while recent estimates suggest that the attributable costs associated with treating candidaemia exceed $2/case. 2,3 Efforts to prevent nosocomial BSIs, generally, appear to have successfully decreased the incidence of these infections, particularly those due to Gram-positive organisms. Prevention appears to have had less of an impact on candidaemia. This suggests that in the future, yeast will begin to account disproportionally for more cases of BSI. In turn, clinicians may be increasingly called upon to treat patients suffering from candidaemia. 3 Accompanying this evolution in the epidemiology of candidaemia has been a shift in the microbiology of the specific pathogens implicated in candidaemia. 4 Historically, Candida albicans accounted for the vast majority of BSIs due to yeast. At present, however, 5% of such infections are now caused by non-albicans Candida. 1 4 This trend is concerning since now organisms such as Candida krusei and Candida glabrata are often isolated as a cause of BSI. 4 Although C. glabrata remains more common than C. krusei, there remain geographical differences in the prevalence of both candidaemia and these specific pathogens across the globe. These two yeasts are either inherently resistant or presumptively resistant to even # The Author 21. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com 375

Shorr et al. high doses of fluconazole. This complicates efforts to ensure that a patient receives initially appropriate therapy, an important predictor of outcomes in candidaemia. 5,6 Because of these changes in the species responsible for candidaemia along with the need to ensure that a patient with candidaemia promptly receives therapy with an agent active in vitro against the pathogen, clinicians have increasingly relied upon echinocandins. These agents, unlike fluconazole, are active against C. krusei and C. glabrata. Reflecting this, recent guidelines from the Infectious Diseases Society of America (IDSA) recommend echinocandins as first-line therapy in this syndrome. 2 Micafungin represents a novel echinocandin requiring neither an initial loading dose nor a dose reduction in subjects with liver disease. Multiple clinical trials have documented the efficacy of micafungin in candidaemia. 7,8 Each individual trial, though, has been limited, as the number of patients with either C. krusei or C. glabrata in these studies has been small. We hypothesized that micafungin would be effective in the treatment of C. krusei and C. glabrata. To evaluate this theory we conducted a pooled analysis of two large randomized trials evaluating micafungin in candidaemia and invasive candidiasis. Methods Overview We pooled data across two double-blind, randomized trials to compare outcomes in subjects with infection due to either C. krusei or C. glabrata (NCT16288 and NCT15144). The methods and results of these trials have been described in detail previously. Briefly, in the first trial, patients were randomized to either micafungin 1 mg daily or liposomal amphotericin (LAMB). 7 The dose of LAMB in this trial was 3 mg/kg/day. For patients with infection persistence, the investigator had the option to increase the dose of study drug (i.e. micafungin) to 2 mg/day. In the second trial, patients were randomized to 1 mg/day micafungin, 15 mg/day micafungin or caspofungin (7 mg load followed by 5 mg/ day); 8 in this study, dose adjustments of micafungin were not permitted. The intended duration of therapy in the two trials was at least 14 days beyond clearance of blood cultures. Both trials were registered at www.clinicaltrials.gov and local institutional review boards approved the original studies. All participants, or their surrogates, provided informed consent. In the first trial, utilizing LAMB, 29 patients with C. glabrata received micafungin and 2 were treated with LAMB. Of the 19 subjects in this study with C. krusei infection, 1 and 9 were given micafungin and LAMB, respectively. In the second trial, 33 subjects with C. glabrata were randomized to caspofungin while 28 were given the 1 mg dose of micafungin and 34 were treated with the 15 mg dose. Of the 2 subjects in this study with C. krusei, 4 were randomized to caspofungin and the remaining 16 subjects were evenly divided between the 1 and 15 mg micafungin arms. All randomized patients are included in our pooled evaluation. An analysis, distinct from the present study, that focuses on results with micafungin and susceptibility testing in all non-albicans Candida (e.g. beyond just C. glabrata and C. krusei) derived from a similar clinical dataset has been presented elsewhere. 9 Subjects and endpoints We only included patients with either candidaemia or invasive candidiasis due to C. glabrata or C. krusei. Clinical cure at the end of intravenous therapy represented our primary endpoint for this analysis. In both trials, clinical cure as an endpoint was defined similarly and required resolution of signs and symptoms of infection along with microbiological evidence of pathogen eradication. In each of the two trials comprising the dataset for our analysis, clinical cure was determined by the original site investigator in a blinded fashion. For this pooled analysis, mortality at 28 days after enrolment represented a secondary endpoint. Co-variates In order to adjust for potential confounders in addition to treatment assignment, we extracted information regarding subject demographics, co-morbidities and severity of acute illness. Specifically, we noted age, gender and race. We further recorded the presence of co-morbid illnesses such as diabetes, end-stage renal disease, malignancy, and recent solid organ or haematopoietic stem cell transplantation. The presence of neutropenia, corticosteroid exposure and a history of recent surgery were also determined. Severity of illness was calculated based on the Acute Physiology and Chronic Health Evaluation (APACHE) II score. In the original trials, clinicians were encouraged to remove indwelling central venous catheters (CVCs). We recorded whether a CVC was present; and, if so, whether it was removed during the study or retained. Finally, we assessed whether a patient begun on 1 mg of micafungin had his/ her dose escalated during the course of therapy. Statistics Univariate comparisons were completed with either the Wilcoxon rank sum test or Fisher s exact test, as appropriate. All tests were two tailed; P,.5 was assumed to represent statistical significance. We utilized logistic regression to determine independent factors associated with both clinical cure and mortality, and variables significant at the P.2 level, in univariate analysis, were entered into the initial logistic regression. A step-wise backward elimination approach was applied. To remain in the model, variables had to have a P value of.2. The Wald statistic was applied both to test effects and to determine the odds ratios in the model. The final Wald adjusted odds ratios (AORs) and 95% confidence intervals (CIs) are presented. Model goodness of fit was determined via the Hosmer Lemeshow c-statistic. Results The two original trials enrolled a total of 119 subjects with 17 with candidaemia or invasive candidiasis. Our final study cohort included 183 patients with either candidaemia or invasive candidiasis. One hundred and forty-four suffered from C. glabrata while the remainder were infected with C. krusei. Approximately 64% (n¼117) were treated with micafungin. Baseline characteristics of the populations are shown in Tables 1 and 2. In general, when either comparing across the four possible treatment arms or contrasting micafungin-treated patients with those given comparator therapy, the populations were similar. Overall unadjusted cure rates among the four potential treatment arms ranged from 55.2% (16/29) to 83.3% (35/42) and were comparable (Figure 1a). The pooled cure rate with micafungin was 73.5% (86/117) versus 62.1% (41/66) with comparators [P¼not significant (NS)] (Figure 1b). Figure 2 demonstrates crude 28 day mortality rates. Mortality rates were numerically lower with the 1 and 15 mg/day doses of micafungin [3.7% (23/ 75) and 26.2% (11/42), respectively] than the mortality rates with either LAMB or caspofungin [34.5% (1/29) and 45.9% (17/37), respectively] (Figure 2a). These differences, however, were not statistically significant (Figure 2b). Logistic regression indicated that four variables were independently associated with clinical cure. Patients with invasive 376

Micafungin for C. glabrata and C. krusei JAC Table 1. Patient characteristics: separate treatment groups Characteristic Micafungin 1 mg (n¼75) Micafungin 15 mg (n¼42) Caspofungin (n¼37) LAMB (n¼29) Demographics age, years, mean+sd 55.4+16.6 57.3+18.1 56.8+18.1 55.6+18.1 male, % 56. 35.7 51.4 55.2 Caucasian, % 73.3 66.7 81.1 79.3 Co-morbidities diabetes, % 2. 47.6 21.6 6.9 renal failure, % 13.3 33.3.5. liver failure, % 1.3 4.8 8.1. neutropenia, % 21.3 14.3 5.4 17.2 concurrent corticosteroids, % 16. 26.2 27. 13.8 organ transplant, % 2.7 7.1 2.7 6.9 recent surgery, % 14.7 31. 51.4. Infection factors candidaemia, % 81.3 92.9 78.4 82.8 invasive candidiasis, % 18.7 7.1 21.6 17.2 Catheter management removed, % 53.3 71.4 56.8 44.8 retained, % 37.3 21.4 29.7 27.6 no catheter, % 9.3 7.1 13.5 27.6 Severity of illness APACHE II, mean+sd 14.9+7.8 14.6+7. 14.6+8.3 17.+1.4 candidiasis were less likely to be cured [AOR (95% CI).314 (.124.796)] as were patients with neutropenia at enrolment [AOR (95% CI).347 (.1.863)]. Higher severity of illness as indicated by an increasing APACHE II score [AOR (95% CI).936 (.89.983) for each 1 point increase] also correlated with a lower probability of cure. Surgical (versus medical) patients were more likely to be cured [AOR (95% CI) 3.61 (1. 9.37)]. The model had good fit with a c-statistic of.2. Two factors independently correlated with 28 day mortality. As was seen in the analysis of cure, those with a higher severity of illness had worse outcomes. As the APACHE II score increased, the likelihood of survival diminished [AOR (95% CI).886 (.839.935)]. CVC management was the only other factor related to survival. Patients who had their CVC removed during therapy as opposed to having the CVC retained were nearly four times more likely to survive [AOR (95% CI) 3.72 (1.52 9.9), c-statistic.71]. Randomization to any dose of micafungin resulted in similar adjusted outcomes (i.e. cure and survival) to those noted with subjects treated with either caspofungin or LAMB. Whether treatment assignment was entered into the model exploring all four possible treatment options or as a bivariate variable (micafungin versus comparator), study drug was never associated with outcome. Only two patients (1.7%) treated with micafungin had their dose increased from 1 to 2 mg/day. Discussion This pooled analysis of patients with candidaemia due to either C. glabrata or C. krusei confirms that micafungin represents an acceptable alternative for therapy. More importantly, the 1 mg/day dose of micafungin results in similar cure and mortality rates in these subjects to either the 15 mg/day dose of micafungin or other potential alternatives. Factors related to outcomes in these infections appear to reflect either patient characteristics such as severity of illness or underlying neutropenia or CVC management. Two other echinocandins are commercially available caspofungin and anidulafungin. Formal experience in randomized trials in treating C. glabrata and C. krusei with either of these agents is limited. In the original prospective study with caspofungin,, patients treated with caspofungin suffered from infection with either C. glabrata or C. krusei. 1 Additionally, the original randomized study examining anidulafungin, only included 5 patients with candidaemia due to C. glabrata. 11 By design, since the comparator agent was fluconazole, persons with candidaemia or invasive candidiasis due to C. krusei were excluded. Hence, our analysis represents one of the largest experiences exploring treatment of C. glabrata and C. krusei that derives from prospective clinical trial data. Much attention has been focused on the significance of C. glabrata and C. krusei. Multiple recent epidemiological analyses document that these organisms account for up to 25% of all cases of candidaemia and invasive candidiasis. 1 4 These reports reveal that mortality rates in candidaemia remain high, with some investigators observing that,5 infected with candidaemia caused by C. glabrata and C. krusei survive to hospital discharge. 2 4 The overall 28 day mortality rate we note is generally similar to what has been described previously, but is, nonetheless, somewhat lower than that found in 377

Shorr et al. most reports. This somewhat lower mortality rate probably reflects selection bias in that our patients were all, by definition, eligible to participate in a randomized study for regulatory approval. The specific exclusion and inclusion criteria of the two original trials we relied upon probably artificially reduced the severity of illness of patients in our analysis. Table 2. Patient characteristics: pooled treatment groups Characteristic Micafungin (n¼117) Comparator (n¼66) Demographics age, years, mean+sd 56.1+17.1 56.3+18..9722 male, % 48.7 53..6449 Caucasian, % 7.9.3.2173 Co-morbidities diabetes, % 29.9 15.2.317 renal failure, % 2.5 22.7.7119 liver failure, % 2.6 4.5.6688 neutropenia, % 18.8 1.6.254 concurrent corticosteroids, % 19.7 21.2.849 organ transplant, % 4.3 4.5..999 recent surgery, % 2.5 28.8.21 Infection factors.81 candidaemia, % 85.5.3 invasive candidiasis, % 14.5 19.7 Catheter management.117 removed, % 59.8 51.5 retained, % 31.6 28.8 no catheter, % 8.5 19.7 Severity of illness.8365 APACHE II, mean+sd 14.8+7.5 15.6+9.2 a Fisher s exact test for discrete variables and Wilcoxon rank-sum test for continuous variables. P a In terms of predictors of outcome in candidaemia/invasive candidiasis, controversy exists regarding the significance of initially appropriate therapy. Initially appropriate therapy describes the administration of an anti-infective, in a timely manner, which is active in vitro against the culprit pathogen. Morrell et al. 5 in a study of 134 patients with candidaemia concluded that even a short delay in antifungal treatment independently doubled a subject s risk of death. More specifically, if therapy was begun.12 h after the eventually positive blood cultures were drawn, the risk of death increased significantly. In a subsequent report that further took into account in vitro yeast susceptibilities, Labelle et al. 6 observed that utilization of fluconazole in candidaemia due to C. glabrata and C. krusei also correlated with lower cure and survival rates. Marriott et al., 12 on the other hand, concluded that inappropriate therapy for fungaemia did not impact outcomes. After controlling for multiple confounders in a multicentre Australian study, these researchers determined that timing of administration of antifungals, pathogen type and in vitro fluconazole susceptibility were not related to survival. The dichotomous findings from these analyses probably reflect differences in both study methodology and the criteria used to determine appropriateness of initial therapy. Our results cannot help to clarify the confusion surrounding this issue. Again, reflecting the design of the original clinical trials utilized, all patients we studied received therapy at nearly similar timepoints after the suspicion and/or confirmation of candidaemia and/or invasive candidiasis. In other words, to be included in our pooled populations, subjects essentially had to receive timely, appropriate antifungal therapy. Nonetheless, we confirm and add to the observations of others by documenting the importance of select factors associated with cure and survival in fungaemia caused by either C. glabrata or C. krusei. In nearly all prior work on this topic, patients with neutropenia are considered separately from subjects without neutropenia. Through pooling these populations we confirm that neutropenia adversely affects cure rates. We further document the crucial importance of severity of illness as it relates to outcomes. Some prior analyses of predictors of survival in candidaemia, whether due to any yeast species or specifically caused by C. glabrata and C. krusei, have not (a) 1 n = 42 (b) 1 P = NS n = 75 n = 37 n = 29 n = 117 n = 66 2 2 Micafungin 1 mg Micafungin 15 mg Caspofungin LAMB Micafungin Comparator Figure 1. Clinical cure rates. 378

Micafungin for C. glabrata and C. krusei JAC (a) 1 (b) 1 2 n = 75 n = 42 n = 37 P = NS n = 29 n = 117 n = 66 2 Micafungin 1 mg Micafungin 15 mg Caspofungin LAMB Micafungin Comparator Figure 2. Twenty-eight day mortality. considered or controlled for severity of illness at the time of infection onset. 13,14 Either these reports have failed to adjust for severity of illness or only describe severity of illness at the time a patient is admitted to the intensive care unit rather than when the subject is actually first suspected of suffering from candidaemia. 13,14 Needless to say, either of these approaches is insufficient for capturing the true effect of disease severity. We, however, had information regarding severity of illness at time of enrolment into the original two randomized trials, which allows us to more precisely estimate the significance of severity of illness. Perhaps the most important observation arising from our analysis relates to the nexus between CVC management and survival. We estimated that failure to remove a CVC in candidaemia due to either C. glabrata or C. krusei nearly quadrupled a patient s risk of death. Currently the IDSA guidelines recommend CVC removal in candidaemia if feasible. This recommendation is considered to reflect only moderate quality evidence. 2 In fact, some researchers have found that leaving a CVC in place does not adversely alter survival. 15,16 Specifically, the guidelines note that many prior studies of CVC management in candidaemia that have reported an association between failure to remove a CVC and mortality have suffered from substantial flaws. For example, some reports have not controlled for either severity of illness or underlying co-morbidities. The connection we found between CVC management and mortality, though, underscores the potential consequences of failing to remove such catheters in these infections. Unlike earlier analyses, which have been criticized for the reasons noted above, we were able to adjust for multiple potential co-variates and, because of the sample size, had sufficient statistical power to examine this question. Two recent reports that also expressly modelled the impact of disease severity and appropriateness of therapy determined that CVC management represented a factor that affected survival. Although Labelle et al. 6 and Marriot et al. 12 reached different conclusions regarding the implications of appropriate initial therapy, both sets of researchers determined that failure to remove a CVC in a subject suffering from candidaemia heightened the risk of death. Our study has several important limitations. First, the analysis is technically retrospective. However, the data we examined were all prospectively collected. Thus, although our study may be exposed to certain forms of bias it is unlikely to be confounded by factors such as either coding or recall bias. Second, as mentioned earlier, randomized controlled studies are constrained by their inclusion and exclusion criteria. Therefore, our findings may have limited generalizability. This is particularly true when the epidemiology of candidaemia can vary from institution to institution and from nation to nation. Third, our findings should not necessarily be interpreted as reflecting causation. In other words, the results of logistic regression can only suggest association. Finally, and most importantly, the sample size was limited. This suggests that our study was underpowered to potentially detect other factors associated with outcomes in this setting. In conclusion, our analysis reveals that micafungin represents an effective treatment for candidaemia and invasive candidiasis due to C. glabrata and C. krusei. Furthermore, those treated with the 1 mg dose of micafungin have similar clinical outcomes to patients given the higher, 15 mg dose. Variables such as catheter management also affect outcomes. Funding This work was supported by Astellas Pharma US. Transparency declarations A. F. S. has served as a speaker for, consultant to and investigator for Astellas Pharma US. C. W. and S. K. are employees of Astellas Pharma US, and have equity interests in Astellas Pharma US. Author contributions A. F. S. developed the hypothesis, designed the analysis plan, facilitated data interpretation, prepared the manuscript and had access to all the data. C. W. assembled the dataset and conducted statistical analyses. He revised the manuscript. S. K. secured access to the data, helped in developing the hypothesis and the data interpretation, and revised the manuscript. 379

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