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1 ,3 Medicine1 and Community Medicine3 , UAE University Faculty of Medicine and Health Sciences, Al-Ain, Abu Dhabi, United Arab Emirates
2 ,5 Oncology and Haematology2 and Radiology5 , Tawam Hospital, Al-Ain, Abu Dhabi, United Arab Emirates
4 Pulmonary and Critical Care Division, UCSF Fresno School of Medicine, 445 S Cedar Ave., Fresno, CA 93702, USA
Correspondence
Michael Ellis
michael.ellis{at}uaeu.ac.ae
Received 5 December 2005
Accepted 12 May 2006
Abbreviations: ALL, acute lymphocytic leukaemia; AML, acute myeloid leukaemia; CT, computed tomography; IFI, invasive fungal infection; IPA, invasive pulmonary aspergillosis; NF, neutropenic fever unresponsive to broad-spectrum antibiotics.
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INTRODUCTION |
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 TOP INTRODUCTION METHODSRESULTSDISCUSSIONREFERENCES |
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Liposomal amphotericin B (AmBisome) is one of three lipid formulations of amphotericin B that has been advocated as the current gold-standard therapy for IFIs in view of its enhanced activity and reduced toxicity compared with conventional amphotericin B (Ostrosky-Zeichner et al., 2003). Issues of high drug-acquisition costs, notable, though reduced, systemic and renal toxicities, and the persistently high mortalities despite treatment, have driven the development of alternative antifungal drugs, particularly the echinocandin caspofungin. This drug is licensed for empirical therapy of neutropenic fever, candidaemia and for salvage treatment of invasive aspergillosis (Maertens et al., 2004; Mora-Duarte et al., 2002; Walsh et al., 2004).
Prior to 2002, liposomal amphotericin B was the major licensed approved antifungal drug available to treat neutropenic fever or an invasive fungal infection. Caspofungin was added to Tawam Hospital's formulary as an alternative treatment drug in 2002. Physicians had the option of using caspofungin or liposomal amphotericin B. This paper analyses the indications, responses, mortality and toxicity for each drug used in a real-time, non-trial setting since 2002.
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METHODS |
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TOPINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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Patients. Patients admitted to Tawam Hospital, the tertiary care oncology centre for the United Arab Emirates, with a diagnosis of acute haematological malignancy received standard induction or consolidation chemotherapy following international guidelines (Coiffier et al., 2002; Farag et al., 2005; Medical Research Council Working Party on Leukemia in Adults, 2006). Prophylactic antibiotics and antifungals were not used. Those patients with prolonged neutropenia or who developed an invasive fungal infection received haematopoietic growth factors. Patients who developed bacterial-culture-negative, target-organ-negative neutropenic fever unresponsive to broad-spectrum antibiotics (NF) or who had an IFI were given either caspofungin or liposomal amphotericin B at the discretion of the treating physician. In keeping with antimicrobial guidelines in use in Tawam Hospital, no patient received antifungal drug prophylaxis unless there was a previous episode of IFI.
Drug administration.
Caspofungin was given at an initial loading dose of 70 mg intravenously, followed by 50 mg daily. Liposomal amphotericin B was given at a dose of 3 mg kg–1 per day for NF or 5 mg kg–1 per day for invasive pulmonary aspergillosis (IPA), candidaemia or hepatosplenic candidiasis. The physician could dose-escalate AmBisome to up to 10 mg kg–1 per day for progressive fungal disease. Guidelines indicated that treatment was continued until neutropenia and fever had resolved and the drug had been administered for at least 10 days for NF. For IFI, treatment was given until there was a satisfactory response, recovery of neutropenia and at least 14 days of intravenous treatment had been given and the patient was considered fit for discharge. Orally administered voriconazole was given to patients with a satisfactory response for a further 14 days. Patients who developed progression of their IFI or whose NF did not respond had their initial antifungal drug changed to an alternative antifungal treatment. This was at the discretion of the treating physician. Generally, for patients receiving caspofungin, liposomal amphotericin B was substituted and vice versa. For patients who had cardiovascular instability or who were otherwise judged highly septic, combination therapy was given (see Table 6
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38 °C (Hughes et al., 2002) where there was neither clinical focal infection nor positive blood cultures for pathogenic bacterial organisms on two occasions. Invasive fungal infection. IFI was defined according to EORTC/MSG criteria (Ascioglu et al., 2002) with modification for IPA. A probable case of IPA was therefore diagnosed if a high-resolution computed tomography (CT) scan demonstrated a halo sign with one or more host factor criteria and two or more minor criteria. A halo sign is widely accepted as pathognomonic for IPA in this patient setting (Kami et al., 2002).
NF response. Both the unabridged five-point criteria as used by Walsh and others (Walsh et al., 2004) and a modification were used. The modification was to allow for resolution of fever outside the period of neutropenia but before the end of the study drug administration.
IPA or hepatosplenic candidiasis response.
This was based on previous literature citations (Maertens et al., 2004). A complete response was resolution of all clinical and radiological features (a). A partial response was meaningful improvement of clinical features and 50 to <100 % improvement of the radiographical score (b). Stable disease was neither improvement nor worsening of the clinical features and radiographical score (c). Progressive disease was worsening of the radiographical score and clinical features necessitating administering an alternative antifungal drug or resulting in death (d). (a) or (b) was considered to be a response to treatment; (c) or (d) was a failure. Outcome was measured at the time of discharge and again at a 1 month follow-up after hospital discharge (modified response).
Candidaemia response. This was resolution of all clinical signs with two or more consecutive negative blood cultures for Candida species. Failure was no improvement or worsening of clinical signs with persistence or relapse of positive blood cultures, resulting in a change in antifungal therapy or death.
Radiographical scores. It was hypothesized that each Aspergillus lesion had an ovoid shape. Each lesion was measured in the two longest axes at the CT section where the lesion was seen to be biggest. The measure of the lesion height, along the z axis, was obtained by using jointed CT sections. The calculated volume in cm3 of each lesion was obtained using the following formula: volume=[(heightxlengthxwidth)x3.1416]/6. For several Aspergillus lesions, the total volume was calculated by the addition of each volume (Calliot et al., 2001).
Toxicity. Toxicity due to, or possibly due to, the study drug was measured according to universal clinical toxicity criteria definitions for liver, creatinine, potassium and infusion-related chills/rigors. At least 1 day of drug toxicity was recorded as a toxic event.
Outcome measurements. The primary outcome measurements were: (i) all causes of mortality within 7 days of completing the antifungal drug treatment; (ii) response to treatment; and (iii) toxicity. This primary analysis was performed for patients receiving the drug for the first time during their hospital admission and who had not received an antifungal drug for at least 1 month previously. Secondary outcome measurements included all antifungal drug administrations during each hospital admission.
Statistical methods.
Standard descriptive statistics, including means, medians and frequencies, were used to describe the presentation and outcome features of the two treatment groups. Percentages were compared between the groups using a 
2 or Fisher's exact test as appropriate. Other variables were tested using independent t tests or the non-parametric Mann–Whitney U test. An exploratory multivariate analysis was used to determine whether any differences in mortality between therapies could be explained by differing prognostic profiles. The exploratory nature of this logistic regression analysis is emphasized, given that the number of events (eight deaths) was limited and that the true independence of the 73 episodes used may be questioned.
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RESULTS |
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TOPINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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The demographics and haematological characteristics of the 73 treatment episodes are detailed in Table 1. There were 24 episodes with caspofungin treatment and 49 with liposomal amphotericin B treatment. No significant differences between the two drug treatment groups were seen apart from the Karnovsky scale, which was significantly lower (P<0.01) in patients treated with caspofungin. There were also significantly more diagnoses (P=0.009) of haematological diseases other than acute myeloid leukaemia (AML) and acute lymphocytic leukaemia (ALL) in the episodes treated with caspofungin.
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. The 23 episodes of neutropenic fever, 40 episodes of IFI and 10 episodes of secondary prophylaxis were similarly distributed between the two drug treatments. However, there were more cases of IPA treated with liposomal amphotericin B and slightly more cases of candidal and other IFIs treated with caspofungin.
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) was similar for the two drug treatments, even when the five-point composite score was modified to allow for late defervescence. Reasons for the treatment failures in each group (Table 3) included three episodes of breakthrough IFI (one each of IPA, cryptococcosis and candidaemia), all of which occurred under caspofungin treatment (P=0.047). Two instances of severe drug toxicity were seen with liposomal amphotericin B and were due to hyperbilirubinaemia in both instances. One episode in each treatment group resulted in death due to underlying malignant disease. One episode treated with caspofungin and two receiving liposomal amphotericin B, respectively, failed to defervesce during neutropenia but did so after resolution of neutropenia.
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Mean C-reactive protein values documented at weekly intervals did not differ between the two treatment groups (data not shown).
IFI responses
Thirteen of the 40 episodes of IFI were treated with caspofungin and 27 were treated with liposomal amphotericin B (Table 3). The proportion of overall favourable responses was slightly higher in the liposomal amphotericin B treatment group (57.7 vs 33.3 %, respectively; P=0.16). The response rate for IPA was similar for caspofungin and liposomal amphotericin B (50.0 and 55.0 %, respectively). However, none of the four episodes of candidaemia and hepatosplenic candidiasis responded to treatment with caspofungin, whilst three of the four patients treated with liposomal amphotericin B for these conditions did respond to treatment (P=0.14).
Patients with IPA showed an increase in radiological scores at day 7 compared with the baseline value. However, the increase was more marked in patients treated with caspofungin (P=0.13). Radiological improvement was first documented at 14 days of treatment with liposomal amphotericin B, but not until day 21 of caspofungin treatment (Fig. 1).
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). Two of 24 episodes (8.3 %) treated with caspofungin were discontinued as a result of drug toxicity compared with 8/49 (16.3 %) on liposomal amphotericin B (P=0.48).
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). Of these, 6/24 (25.0 %) followed caspofungin treatment and 2/49 (4.1 %) followed liposomal amphotericin B treatment (P=0.013). The primary cause of death was an IFI in four episodes (16.7 %) of caspofungin treatment and one episode (2 %) of liposomal amphotericin B treatment (P=0.037). Bacterial and other causes accounted for the remaining three patients. The length of treatment was similar in the two treatment groups.
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The other candidaemic patient was infected with Candida tropicalis. Although treatment with caspofungin was started promptly and the organism was fully sensitive to fluconazole, amphotericin B and itraconazole (MICs of 0.19, 0.25 and 0.012 µg ml–1, respectively), and therefore probably to caspofungin (although not tested), and the patient received 6 days of treatment, death occurred from multiorgan failure.
The third IFI death under caspofungin treatment was due to fungal sinusitis, epicenter ethmoid and maxillary sinuses with perosseous intraorbital extension.
The final IFI death under caspofungin treatment had an IPA fungal volume of 59.03 cm3, which did not change despite 14 days of caspofungin treatment. The terminal 3 days were further complicated by meticillin-resistant Staphylococcus aureus bacteraemia.
Factors associated with mortality on univariate analysis were: severe sepsis/septic shock (P=0.03), a shorter duration of antifungal treatment (P=0.02), a longer duration of neutropenia of between 100 and 500 (P=0.008) and caspofungin drug treatment (P=0.01). When these were entered into a multivariate logistic regression model, antifungal treatment with caspofungin remained an independent predictor of mortality [odds ratio=7.6 (95 % confidence intervals 1.2–45.5)].
Salvage therapy
There were 15 episodes of treatment failures that survived and were available for treatment with alternative antifungal drugs (Table 6). Of the four failures on caspofungin, all were subsequently treated with liposomal amphotericin B (one as combination therapy) and the success rate was 2/4 (50 %). Of the 11 assessable failures with liposomal amphotericin B, 9/11 (81.8 %) were treated with caspofungin (two as combination therapy) and this resulted in a successful outcome in 4/9 episodes (44.4 %). Of the two remaining episodes on liposomal amphotericin B, one was treated with itraconazole and was not assessable, and the other with a high dose (10 mg kg–1 per day) of liposomal amphotericin B with voriconazole and was successful.
Overall assessment of the 97 treatment episodes
When all 97 episodes of treatment with caspofungin or liposomal amphotericin B monotherapy were analysed, the presentations and outcomes were similar to those documented for first-exposure drug therapy. There was an additional death in the caspofungin group when all episodes were considered.
Combination antifungal therapy
Five of the 24 episodes were not considered in the analyses above; these were managed with combination treatment of caspofungin plus liposomal amphotericin B because of the critical clinical condition of the patient (Table 7). Two episodes of Candida blood stream infection resulted in death. In one of these, the terminal event was Stenotrophomonas septicaemia co-infection. In the other, the dose of liposomal amphotericin B selected was not increased above 5 mg kg–1 per day. A third episode failed to respond to treatment because of drug toxicity. An episode of Candida inconspicua fungaemia did not result in death, despite the development of IPA soon after starting treatment. The recovery was further complicated by hepatosplenic candidiasis, despite combination therapy. This complication was successfully managed with prolonged caspofungin treatment. One episode of IPA was managed successfully.
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DISCUSSION |
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TOPINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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Episodes of NF and all episodes of IFI were generally treated equally with caspofungin or liposomal amphotericin B, but slightly more episodes of IPA were given liposomal amphotericin B treatment, reflecting the current guidelines that caspofungin should be used for salvage treatment of IPA (Maertens et al., 2004). Nevertheless, there are reports of its efficacy when used as the primary therapy for IPA (Candoni et al., 2005). The episodes of invasive candidal infections, extrapulmonary IFI and unspecified or mixed IFI were more often managed with caspofungin.
Response rates in NF were similar for both drug treatments, consistent with the findings of a large prospective comparative clinical trial (Walsh et al., 2004). The improvement in the favourable response rate when allowance was made for defervescence just after recovery from neutropenia (modified response) in caspofungin-treated episodes was interesting. This may suggest a slower antifungal response from caspofungin compared with AmBisome during ongoing neutropenia. The main reason for caspofungin failure was a significantly greater number of breakthrough IFIs (P=0.047). These included Cryptococcus species, against which caspofungin has no activity. In contrast, the study by Walsh et al. (2004) showed no difference in breakthrough IFIs between treatments. One explanation may be the use of azole prophylaxis in 56 % of each treatment group in that study, which could have given a sequential synergistic antifungal advantage (Mukherjee et al., 2005) for the caspofungin group, whereas no patient in our study received antifungal prophylaxis. IFIs other than Candida species and Aspergillus species are emerging as important causes of NF, many of which are resistant to caspofungin. In order that these fungi are therapeutically covered, the broader spectrum liposomal amphotericin B is preferred.
Favourable responses for IPA episodes were similar in frequency for both antifungal drugs in our study. This is encouraging and suggests that caspofungin can be used effectively as an initial treatment for IPA, as has been described recently (Candoni et al., 2005). All episodes in which at least a modified favourable response was observed on initial intravenous treatment with caspofungin or liposomal amphotericin B then received oral voriconazole or itraconazole to complete their treatment upon hospital discharge. No patient who was given oral treatment died from IPA within 3 months of hospital discharge. A longer-term follow-up of these patients was not carried out in this study.
Volume changes in IPA episodes assessed by weekly serial CT chest scans indicated a difference in this parameter of response between caspofungin and liposomal amphotericin B treatment. Volumes were similar on day 1 of treatment and both treatment groups showed a volume increase at 7 days, consistent with previous observations (Caillot et al., 2001). However, the increase was greater in caspofungin-treated episodes. Furthermore, radiological improvement was not seen before day 21 in the caspofungin-treated episodes but was apparent by day 14 with liposomal amphotericin B treatment (Fig. 1).
The lower favourable response seen for invasive candidal and other IFIs treated with caspofungin is of concern. No episode of candidaemia or hepatosplenic candidiasis responded to caspofungin, whereas three of the four episodes treated with liposomal amphotericin B responded. Previous studies using caspofungin to treat candidaemia had a low accrual of neutropenic patients (Mora-Duarte et al., 2002) and the outcome in that subgroup may not have been assessed distinctly.
The action of caspofungin may be predominantly fungistatic rather than fungicidal against mould infections, which may be of concern in persistently neutropenic patients (Denning, 2003). In contrast, amphotericin B is fungicidal. It has been demonstrated that viable Aspergillus hyphae persist in vitro (Bowman et al., 2002), and in animal models fungal clearance is incomplete with caspofungin compared with amphotericin B (Denning, 2003). Our findings of the slower radiological resolution, and the more frequent poorer responses with caspofungin in candidal and other IFIs that were documented, suggest that there may be clinically relevant translations of the in vitro and animal data. This may be clinically significant in patients at risk of rapid clinical deterioration, which is frequently observed in candidal infections, for example (Ellis et al., 2003). Patients with IPA, on the other hand, generally have a more stable course. The sequential use of voriconazole (a fungicidal drug) may be a factor resulting in the similar modified response rates and survival seen in our patients treated with either caspofungin or liposomal amphotericin B.
More of the episodes treated with caspofungin compared with liposomal amphotericin B resulted in fungus-related deaths. Two of these were associated with candidaemia. A delay in treatment may well have been a factor contributing to one death. The other candidaemic patient was infected with C. tropicalis. Literature evidence of the efficacy of caspofungin in candidaemia has not included large studies within neutropenic subgroups, particularly in critically septic patients (Hughes et al., 2002; Pappas et al., 2004). Response rates in neutropenic patients, however, are generally low (Denning, 2003). Although the fungus associated with sinusitis in the third death episode was not identified, the possibility of Mucorales should be considered and high-dose liposomal amphotericin B or posaconazole given rather than caspofungin, as these fungi are resistant to candins. This observation illustrates the need to use a broader-spectrum agent than caspofungin where there is a possibility of a non-Aspergillus mould infection. The fourth episode of IFI death had a substantial lung fungal burden, which proved impossible to clear. The suboptimal antifungal and static>cidal activity among the candins, resulting in failure to clear galactomannaemia or reduce tissue burden (Denning, 2003), is therefore relevant to this particular observation.
The severity of sepsis, the length of antifungal treatment and protracted neutropenia were additional factors in caspofungin treatment that were significantly associated with patient death. However, multiple logistic analysis confirmed that caspofungin therapy itself was an independent predictor of mortality, the excess mortality in this group of patients mainly being due to IFIs. In such a small sample size in a non-blind, non-randomized study of retrospective design, there is a strong possibility of prescribing and other biases, for example from analysing episodes, that may confound our treatment-related observations. Furthermore, inclusion of some cases of a diagnostic category that were not definite or probable IFIs could have influenced the outcome. However, such strict criteria, which are normally required in prospective clinical studies, often do not reflect the clinical reality and patient diversity present in a clinical setting. Therefore, the fact remains that our results reflect the current patterns for the use of and the outcome from using two antifungal drugs in a genuine clinical setting, with the objective end point of death as the primary response determinant. Therefore, our clinical experience is consistent with the lack of activity of caspofungin against certain fungi, the mooted concern over its use in neutropenic candidaemic patients and the persistence of viable fungal elements that have been found in vitro and in animal models.
Despite accumulating evidence that a combination of caspofungin and amphotericin B reduces MICs and tissue fungal burden and enhances survival in animal models, there is little or no evidence of such an effect from human studies (Kontoyiannis & Lewis, 2004). Our findings also do not suggest that there is an enhanced clinical benefit from combination therapy in patients with enhanced sepsis due to candidosis or IPA, with only one of the five patients (the patient with IPA) having a response and/or surviving for longer than 1 month.
In conclusion, broadly similar responses for caspofungin and liposomal amphotericin B were seen when treating IFIs or NF. However, the higher level of overall as well as fungal-related mortalities, the delays in clinical and radiological response and the increased number of breakthrough IFIs occurring with caspofungin suggest that there may be an antifungal-drug-dependent clinical difference in outcome. This observation requires further study.
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ACKNOWLEDGEMENTS |
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REFERENCES |
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TOPINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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