Abstract
The response rate among 58 patients with cancer and candidemia or deep-seated candidiasis treated with micafungin monotherapy was 81%. Intensive care unit (ICU) stay, concomitant nonfungal infections, and acute kidney injury were significantly associated with the 30-day crude mortality rate. Severe neutropenia was an independent predictor of micafungin failure. The efficacy and safety of micafungin in cancer patients with invasive candidiasis were comparable to those reported for patients without malignancy and for cancer patients treated with caspofungin.
TEXT
The shift to non-albicans Candida species over the past 2 decades is a worrisome trend, as these species frequently exhibit decreased susceptibility to azoles, justifying the use of echinocandins in first-line empirical treatment of invasive candidiasis (1–3). Micafungin is a well-tolerated echinocandin that met noninferiority criteria in two randomized trials in comparison with liposomal amphotericin B (4) and caspofungin (5). In a subgroup analysis of candidiasis in cancer patients, response rates for treatment with micafungin were lower in neutropenic patients than in nonneutropenic patients, but the majority of patients experienced successful treatment of their infections (6).
Patients enrolled in controlled studies make up only a small proportion of those seen in routine clinical practice in individual institutions, especially cancer hospitals (7). Therefore, assessing the real-world safety and efficacy of antifungals in populations of immunosuppressed patients with malignancies is important. To that end, we retrospectively studied the efficacy and tolerability of monotherapy with micafungin for candidemia and deep-seated candidiasis at a single tertiary cancer center, and we identified predictors of responses to micafungin treatment and all-cause-related death.
Pharmacy databases were searched for adult patients (≥18 years of age) with the indication of candidemia or invasive candidiasis who received at least three consecutive doses of micafungin between January 2006 and August 2013. Invasive or deep-seated candidiasis was defined as the isolation of Candida from a sterile body site, including intraabdominal samples collected at the time of drainage and samples of peritoneal fluid, pleural fluid, intra-articular fluid, or cerebrospinal fluid (1, 3, 7). Patients with mixed fungal infections and those who received combination antifungal treatment or another systemically administered antifungal agent for treatment of that episode, prior to micafungin treatment, for more than 5 days were excluded. Patients receiving another antifungal agent as prophylaxis were included in the study. The patients' medical records were reviewed for demographic, clinical, and laboratory characteristics (Table 1), as described previously (8, 9).
TABLE 1.
Basic demographic, clinical, and laboratory characteristics of the 58 study patients at the time of positive cultures for Candida spp.
| Characteristica | Value |
|---|---|
| Age (mean ± SD [range]) (yr) | 59.3 ± 13.46 (24–84) |
| Male (n [%]) | 30 (52) |
| Hematological malignancy (n [%]) | 25 (43) |
| AML | 8 (14) |
| ALL | 4 (7) |
| Lymphoma | 6 (11) |
| Multiple myeloma | 3 (5) |
| Myelodysplastic syndrome | 2 (3) |
| Myelofibrosis | 2 (3) |
| Solid tumor (n [%])b | 33 (57) |
| Hematopoietic stem cell transplantation (n [%]) | 4 (7) |
| Diabetes mellitus (n [%]) | 10 (17) |
| Recent abdominal surgery (within 1 mo) (n [%]) | 13 (22) |
| Malnutrition (albumin level of <3.0 g/dl) (n [%]) | 31 (53) |
| Total parenteral nutrition (n [%]) | 12 (21) |
| Clinical disease (n [%]) | |
| Deep-seated candidiasisc | 23 (40) |
| Fever (temp > 38°C) | 33 (57) |
| Pneumonia | 9 (16) |
| Concomitant bacterial or viral infection | 28 (48) |
| Breakthrough Candida infection while receiving antifungals | 10 (17) |
| ICU stay (n [%]) | 17 (29) |
| APACHE II score (mean ± SD) | 15.48 ± 6.72 |
| APACHE II score of >20 (n [%]) | 13 (22) |
| CVC present (n [%]) | 38 (66) |
| CLABSI (n [%]) | 22 (38) |
| Candida species (n [%]) | |
| C. glabrata | 21 (36) |
| C. albicans | 14 (24) |
| C. tropicalis | 9 (16) |
| C. parapsilosis | 7 (12) |
| C. krusei | 6 (10) |
| C. guilliermondii | 1 (2) |
| Recent exposures (within 1 mo) (n [%]) | |
| Antibiotics | 49 (84) |
| High-dose steroids (≥0.3 mg/kg prednisolone equivalent for ≥3 wk) | 5 (9) |
| Azoles | 17 (29) |
| Echinocandins | 13 (22) |
| Laboratory findings | |
| Neutropenia (<1,000 cells/μl) (n [%]) | 18 (31) |
| ANC of 500–1,000 cells/μl | 1 (2) |
| ANC of 100–500 cells/μl | 3 (5) |
| ANC of <100 cells/μl | 14 (24) |
| Lymphopenia (ALC of <500 cells/μl) (n [%]) | 33 (57) |
| Monocytopenia (AMC of <100 cells/μl) (n [%]) | 17 (29) |
| Initial creatinine level (median [25th to 75th percentile]) (mg/dl) | 1.00 (0.69–1.50) |
| Creatinine level at end of treatment (median [25th to 75th percentile]) (mg/dl) | 0.90 (0.60–1.31) |
| AKI or ARF (≥50% or 100% decrease in eGFR from baseline or hemodialysis, respectively) (n [%]) | 10 (17) |
| Initial ALT level (median [25th to 75th percentile]) (IU/liter) | 35.00 (20.25–69.50) |
| ALT level at end of treatment (median [25th to 75th percentile]) (IU/liter) | 33.50 (19.25–65.75) |
| Acute liver injury (3-fold increase in ALT level) (n [%]) | 4 (7) |
| Treatment | |
| Micafungin dose given once daily (median [range]) (mg) | 100 (50–150) |
| Duration of treatment with micafungin (median [25th to 75th percentile]) (days) | 10 (6–15) |
Data are presented as absolute numbers and percentages, as mean ± standard deviation values for normally distributed variables, or as median values with 25th to 75th percentile ranges for variables with skewed distributions. AML, acute myeloid leukemia; ALL, acute lymphoblastic leukemia; ALC, absolute lymphocyte count; AMC, absolute monocyte count; APACHE, acute physiology and chronic health evaluation; CVC, central venous catheter; CLABSI, central line-associated bloodstream infection (defined as a case with a colony count from blood obtained through the catheter hub that was at least 5-fold greater than the colony count from blood obtained from a peripheral vein or Candida-positive catheter tip culture or a case of persistent fungemia that did not meet the colony count criterion but resolved after removal of a central line and was documented by clinical staff members as a possible CLABSI); ALT, alanine aminotransferase; eGFR, estimated glomerular filtration rate.
Gastrointestinal, n = 14 (4 biliary tract tumors, 3 pancreatic adenocarcinomas, 3 gastric cancers, 2 colorectal cancers, 1 singlet cell tumor of the appendix, and 1 duodenal adenocarcinoma); genitourinary, n = 5 (2 renal tumors, 2 prostate tumors, and 1 metastatic testicular tumor); gynecological, n = 4; mesothelioma, n = 2; head and neck cancer, n = 3; melanoma, n = 1; metastasis of an unknown primary tumor, n = 1; sarcoma, n = 1; multiple malignancies, n = 2.
Pericarditis, n = 1; neck deep-space infection, n = 2; perinephric abscess, n = 1; pelvic abscess, n = 2; ascites, n = 3; other intra-abdominal collections (cultures drawn during drainage), n = 7; candidemia with Candida-positive cultures from other sterile sites, n = 7 (pleura, n = 1; urine, n = 2; joint, n = 2 [1 prosthetic]; ascites, n = 1; bile, n = 1).
The isolation and identification of Candida species were performed using standard microbiological procedures, and in vitro susceptibility of isolates to antifungals was defined according to the recently updated Clinical and Laboratory Standards Institute/European Committee on Antimicrobial Susceptibility Testing combined clinical breakpoints (10). Treatment failure was defined as either death with evidence of persistent candidiasis or modification of antifungal treatment owing to medication intolerance, clinical progression of the infection, or persistent culture positivity for Candida spp. (8, 9).
Categorical variables were compared using a χ2 test or the Fisher exact test, whereas continuous variables were compared using the Student t test or the Mann-Whitney U criterion for nonnormally distributed variables. Logistic regression analysis was performed to identify variables independently associated with treatment failure. Patient survival was assessed by Cox regression analysis. Clinically relevant variables in univariate analyses (P < 0.1) were entered in the model and were retained if the P value was ≤0.05. All calculations were performed using SPSS version 21. This study was approved by the University of Texas M. D. Anderson Cancer Center Institutional Review Board.
Fifty-eight episodes of candidemia (42 episodes [72%]) or candidiasis at sterile sites (16 episodes [28%]) were studied. Twenty-five patients (43%) had hematological malignancies. Most of the episodes (76%) were caused by non-albicans Candida spp. (Table 1). Nineteen Candida isolates (33%) exhibited intermediate/dose-dependent susceptibility to fluconazole in vitro, whereas 11 additional isolates (19%) were classified as resistant to fluconazole. Four isolates (7%) were not susceptible to caspofungin; three of those isolates were also fluconazole resistant.
Over 756 doses, micafungin was well tolerated in all patients. No significant differences in serum creatinine or transaminase levels before and after micafungin-based treatment were observed (Table 1). Also, treatment with micafungin was not discontinued owing to drug intolerance or toxicity.
The overall mortality rates were 2% (1/58 patients) on day 7, 9% (5/58 patients) on day 14, and 29% (95% confidence interval [CI], 17.59 to 41.01%) (17/58 patients) on day 30. Acute kidney injury (AKI) or acute renal failure (ARF), concomitant nonfungal infection, and intensive care unit (ICU) stay at the time of the Candida-positive culture were associated with the 30-day all-cause mortality rate. In a multivariate survival analysis, ICU stay and concomitant nonfungal infection were independent predictors of all-cause 30-day mortality (Table 2).
TABLE 2.
Predictors of all-cause-related deaths
| Predictor | Univariate analysis results |
Multivariate analysis results |
||
|---|---|---|---|---|
| HRa (95% CI) | P value | HRa (95% CI) | P value | |
| ICU stay | 4.651 (1.757–12.307) | 0.002 | 2.099 (1.267–3.476) | 0.004 |
| Concomitant nonfungal infection | 4.184 (1.364–12.844) | 0.012 | 2.247 (1.017–4.966) | 0.003 |
| AKI or ARFb | 2.963 (1.094–8.026) | 0.033 | 2.758 (0.951–7.998) | 0.062 |
HR, hazard ratio.
AKI, acute kidney injury; ARF, acute renal failure.
The clinical and mycological (blood culture sterilization for patients with candidemia) success rates for monotherapy with micafungin at day 14 were 81% (95% CI, 71 to 91%) (47/58 patients) and 79% (95% CI, 66 to 91%) (33/42 patients), respectively. Hematological malignancy, cytopenias, and recent echinocandin exposure were associated with lack of response (Table 3). Severe neutropenia (absolute neutrophil count [ANC] of <500 cells/μl) was the only independent predictor of treatment failure (odds ratio, 11.259 [95% CI, 2.48 to 51.11]) (Table 3). Three of the four patients with caspofungin-resistant Candida isolates had responses to treatment with micafungin and clearance of their blood cultures. All four patients were neutropenic, their ANCs recovered, and their central lines were removed.
TABLE 3.
Predictors of treatment failure
| Predictora | No. (%) of patients with treatment: |
P value (χ2 test) | ORb (95% CI) | P value | |
|---|---|---|---|---|---|
| Response (n = 47) | Failure (n = 11) | ||||
| Hematological malignancy | 17 (36) | 8 (73) | 0.028 | ||
| ANC of <500 cells/μl | 9 (19) | 8 (73) | 0.001 | 11.259 (2.480–51.111) | 0.002 |
| ALC of <500 cells/μl | 24 (51) | 9 (82) | 0.064 | ||
| AMC of <100 cells/μl | 10 (21) | 7 (64) | 0.010 | ||
| Echinocandin exposure within 1 mo of positive culture for Candida | 8 (17) | 5 (45) | 0.042 | ||
ALC, absolute lymphocyte count; AMC, absolute monocyte count.
OR, odds ratio.
The median duration of treatment with micafungin was 10 days (range, 3 to 52 days; 25th to 75th percentile, 6 to 15 days). Three patients (5%) received 50 mg of micafungin daily, 49 (85%) received 100 mg daily, and 6 (10%) received 150 mg daily. The 14-day clinical response rates for these three groups were 67% (2/3 patients), 82% (40/49 patients), and 83% (5/6 patients), respectively. Among patients with candidemia, the 14-day mycological response rates for those who received 50, 100, and 150 mg of micafungin were 67% (2/3 patients), 81% (29/36 patients), and 67% (2/3 patients), respectively. The overall 30-day mortality rates were 33% (1/3 patients), 33% (16/49 patients), and 0%, respectively. No significant correlations between doses and mycological response rates or all-cause 30-day mortality rates were observed (P > 0.1). We did not find any association between all-cause mortality rates or responses to micafungin and early (within 48 h after sample collection) removal of a central line, for all patients, those with a central line in place, or those with a central line-associated bloodstream infection (CLABSI) with Candida.
We studied the efficacy and tolerability of micafungin in cancer patients with candidemia or deep-seated candidiasis. The overall clinical response rate (81% [95% CI, 71 to 91%]) was comparable to those in two previous randomized controlled trials (74.0% and 71.2%) (4, 5), a contemporary study of micafungin treatment of patients with hematological malignancies (79%) (11), and previously published data on caspofungin (70.4% and 83.1%) (7, 8). Notably, we did not find significant effects of high micafungin doses on response rates or 30-day mortality rates, which agrees with previous results (6).
Our population appeared to be more immunocompromised than that in a previous study at our institution, in which we reviewed our clinical experience with caspofungin monotherapy for candidemia (8). Specifically, in the present study, we had relatively greater proportions of patients with hematological malignancies (43% versus 32%), neutropenia (31% versus 16%), and previous antibiotic exposure (85% versus 79%). We also observed a greater prevalence of non-albicans Candida infections (76% versus 62% [8]), as well as greater intermediate/dose-dependent or complete resistance to fluconazole (52% versus only 19% [8]), than in the previous study. However, our clinical (81%) and mycological (79%) success rates and crude mortality rate (29%) were comparable to those we reported previously for caspofungin (78%, 77%, and 21%, respectively) (8).
In addition, four Candida isolates (7%), as opposed to only one (2%) in our previous study (8), exhibited in vitro resistance to caspofungin; three of them were multidrug resistant (12). The majority of studies of Candida infections reported before 2010 used breakpoints higher than the currently recommended value to define caspofungin nonsusceptibility in vitro (>2 μg/ml [8] versus ≥1 μg/ml and 0.5 μg/ml for Candida glabrata [10, 12]). However, the prevalence of echinocandin- and multidrug-resistant Candida strains is increasing (3, 12), and antifungal resistance may therefore become an important problem of clinical significance in the management of severe candidiasis.
Data regarding the efficacy of micafungin in the treatment of severe Candida infections caused by caspofungin-resistant isolates are scarce. In animal models, other echinocandins have exhibited activity against caspofungin-resistant Candida isolates (13). In the present study, three of the four patients with caspofungin-resistant Candida isolates had responses to micafungin with catheter removal and neutrophil count recovery. However, our patient number was small, and infections with echinocandin-resistant Candida strains have been associated with treatment failure and poor clinical outcomes (12, 14). Nevertheless, in those previous studies, adjustments for malignancy, immunosuppression, neutrophil count recovery, and source control were limited. In the current era of emerging resistance of Candida species to antifungals, larger-scale prospective studies to elucidate the complex interplay between clinical outcomes and appropriate antifungal therapy based on in vitro susceptibilities are warranted.
Our negative results with regard to early central line removal might be due to the small number of patients with CLABSI. However, echinocandins have superior cidal activity in biofilms, compared with azoles (15). Therefore, the effect of catheter removal in our study could have been blunted because all patients received effective treatment with an echinocandin.
In agreement with previous reports (4–6), we observed that administration of micafungin, even at the highest dose, was not associated with organ toxicity or significant side effects among our patients, who were at high risk for multiorgan failure as well as drug interactions. Furthermore, in both the present study (Table 2) and previous studies of invasive candidiasis (12, 16), renal failure was a strong predictor of death. These findings underscore the importance of avoiding the use of potential nephrotoxins, such as amphotericin B, in the care of patients with malignancies, who often have multiple risk factors for kidney injury, such as advanced age, tumor lysis syndrome, sepsis-related hypoperfusion, and concurrent administration of other nephrotoxic agents.
The present single-institution noncomparative study was limited by the small sample size and retrospective data collection for patients with advanced malignancies. It is also possible that micafungin monotherapy was selected for patients with less-severe Candida infections. Therefore, the response rates and predictors of death or treatment failure with micafungin monotherapy may not be similar in different clinical settings and for patient groups at risk for invasive candidiasis (2, 3). In conclusion, micafungin was an effective, safe option for monotherapy for serious Candida infections in this population of adults with cancer, which included several significantly immunocompromised patients with hematological malignancies and severe neutropenia.
Footnotes
Published ahead of print 17 March 2014
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