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Animal models of Aspergillus infection in preclinical trials

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					Medical Mycology September 2006, 44, S119 ÁS126



Animal models of Aspergillus infection in preclinical trials,
diagnostics and pharmacodynamics: What can we learn
from them?
KARL V. CLEMONS & DAVID A. STEVENS
California Institute for Medical Research, San Jose, Department of Medicine, Division of Infectious Diseases, Santa Clara Valley
Medical Center, San Jose, and Department of Medicine, Division of Infectious Diseases and Geographic Medicine, Stanford
University, Stanford, California, USA

                                 Animal models of aspergillosis, particularly those studied in rodents, are an
                                 integral part of antifungal drug development. The capacity to control different
                                 variables is beneficial, allowing a well defined model system to be used to address
                                 various issues of efficacy with monotherapy, combinations, or immunotherapy.
                                 One beneficial aspect of the use of animal models is that they enable us to
                                 investigate novel indications of drugs prior to a clinical trial or where a clinical trial
                                 is impractical. Included in these types of studies is the testing of potentially
                                 preventative vaccines. Animal models also are useful for studying diagnostic assays,
                                 as well as pharmacology and toxicity. Thus, because of the ability of the best
                                 models to mimic human diseases, and our ability to infect genetically identical
                                 cohorts of the same age, sex, co-morbidities and risk factors, with an identical
                                 challenge inoculum at the same time, we are able to address issues in vivo that
                                 cannot be answered by in vitro tests. We also can have sufficient numbers of
                                 subjects for statistical analyses, can vary the severity of infection at will and can
                                 choose to terminate the experiments to enable using survival or clearance of
                                 residual infection as the efficacy end-point. Are these animal models predictive of
                                 clinical efficacy, pharmacology and toxicity of an antifungal drug? No single model
                                 should be relied upon, as different models of aspergillosis in mice or other animals
                                 sometimes show somewhat different results. However, the accumulated wealth of
                                 experience has demonstrated the utility of these models in predicting clinical
                                 efficacy, pharmacology and toxicity.
                                 Keywords         aspergillosis, animal models



Introduction                                                         the immune status of the host, what duration is desired
                                                                     for the course of disease and what outcome and end-
Animal models, particularly those studied in rodents,
                                                                     points will be examined. Thus, the model must be well-
are an integral part of antifungal drug development.
                                                                     defined, and the characteristics of a good model have
Various questions have to be addressed prior to the use
                                                                     been detailed previously [1 Á4].
of any single model for studies of antifungal drugs.
                                                                        Animal models have both strengths and weaknesses
These include the type of disease being mimicked, such
                                                                     that are taken into consideration. Murine models can
as invasive pulmonary aspergillosis or systemic disease,
                                                                     be done affordably with sufficient numbers of animals
                                                                     included to obtain statistically relevant data, and there
                                                                     are numerous genetically defined strains available. Mice
Correspondence: Karl V. Clemons, Division of Infectious Diseases,
Santa Clara Valley Medical Center, 751 South Bascom Avenue, San
                                                                     require less specialized animal care and support facil-
Jose, CA 95128, USA. Tel: '/1 408 998 4557. Fax: '/1 408 998-2723.   ities and personnel. However, most murine models of
E-mail: clemons@cimr.org                                             aspergillosis have the drawback of rapid and fulminant
– 2006 ISHAM                                                                                    DOI: 10.1080/13693780600871174
S120     Clemons & Stevens


disease progression, involvement of organs such as the           each showing good histopathologic correlation with
kidneys, which is often not seen clinically, and are             human disease [20,21].
difficult to use when repeated samplings of blood, for              Two primary parameters of efficacy are followed,
example, is desired from the same animal. In contrast,           survival and fungal burden in the tissues. Survival
rabbits are more expensive and require greater efforts           studies result in clear data sets, but ask much of a
from support and animal care personnel. Rabbit                   potential therapeutic. In addition, ethical questions
models do have the benefits of multiple sampling                 arise concerning the humane care and use of animals
from the same animals, better clinical evaluations and           for survival studies with most institutional committees
opportunity to obtain body fluids such as CSF that are           requiring euthanasia of the animals prior to death. The
not readily obtained from mice in sufficient quantity.           criteria for euthanasia must be evaluated carefully for
Thus, the choice of animal model will greatly depend             each animal, since subjective judgments made by the
on the types of studies needed.                                  investigators can skew the data by euthanizing animals
   The capacity to control different variables is bene-          too soon. These criteria need to be as quantitative as
ficial. Among the variables are strain of Aspergillus            possible, applied objectively from study to study to
fumigatus used, or the use of another species of                 ensure the accuracy of the data obtained from the
Aspergillus, inoculum size, immunosuppressive regi-              model, and the judgements on individual animals made
men, strain of mouse or other animal species, route              without knowledge of their study group, wherever
of infection, and route and duration of therapy. This            possible.
control allows a well defined model system to be used               Reduction of infectious burden can be a sensitive
to address various issues of efficacy with monotherapy,          parameter of efficacy, but the best method of determi-
combinations, immunotherapy, as well as investigate              nation for Aspergillus burdens in the tissues is con-
novel indications, and potentially preventative vaccines.        troversial. Some investigators choose a qPCR
In general, a great benefit of animal models of                  methodology or chitin assay, while others use CFU
aspergillosis is that therapeutics can be tried in a             determinations [7,22Á25]. Each method has benefits
variety of scenarios prior to a clinical trial or where a        and drawbacks. The assay of chitin in the tissues can be
clinical trial is impractical. Animal models also are            used as an indicator of fungal burden [24]. However,
useful for studying diagnostic assays, as well as                this is a tedious assay and does not indicate whether the
pharmacology and toxicity. Thus, we are able to                  organisms present were viable. More recently a qPCR
address issues in vivo that cannot be answered by in             assay has been developed and applied to the determi-
vitro tests. In addition to their use in the development         nation of Aspergillus burden in the tissues [22]. The
and testing of therapeutics, diagnostics and pharma-             need for specialized equipment and reagents for sample
cology, animal models of aspergillosis are used in               preparation are drawbacks for many laboratories and
studies of host-response and virulence. However, these           sending tissues samples to a commercial enterprise for
subjects are outside of the purview of this short review         the assay is cost-prohibitive in most cases. In compara-
and have been addressed elsewhere [1,5 Á8].                      tive studies, we demonstrated that drug efficacy of
                                                                 caspofungin and amphotericin B against CNS asper-
                                                                 gillosis could be demonstrated at a single time point
Animal models and evaluation parameters
                                                                 using either the qPCR or the CFU method [23]. The
Because no single model of aspergillosis can be relied           CFU method has the advantages of indicating viable
on to answer the many questions one asks in preclinical          organisms and is an assay that can be performed
studies or mimic the various disease progressions seen           readily by most laboratories. However, its level of
in all clinical cases of aspergillosis, it is necessary to use   sensitivity is less than that of the qPCR assay.
multiple models. In our laboratory we have standar-
dized three murine models of aspergillosis: systemic
                                                                 Surrogate and diagnostic markers
infection in noncompromised mice, cerebral infection
in pancytopenic mice and pulmonary infection in                  Surrogate markers of infection are much sought after
steroid-suppressed mice [9 Á11]. We use each of these            and have included radiographic imaging techniques
models to address specific questions. Other laboratories         applicable to pulmonary models in rabbits [1,7,8,16], as
have used inhalational murine models, and pulmonary              well as Aspergillus metabolites [26] and other clinical
or systemic models in rabbits and guinea pigs, as well as        parameters such as body weight and temperature. In
birds and insects [1 Á3,7,8,12 Á21]. More recently, two          addition, PCR methods for detection of Aspergillus
groups have reported the development of inhalational             DNA and assays for antigenemia (galactomannan and
models of invasive pulmonary aspergillosis in mice,              glucan) have been used to study disease progression, as
                                                                               – 2006 ISHAM, Medical Mycology, 44, S119 ÁS126
                                                                                   Animal models of Aspergillus infection   S121

well as for diagnostic purposes [26 Á31]. Rabbit studies     Aspergillus fumigatus have also proven to correlate
have shown that galactomannan assays were useful for         well with the clinical efficacy of the echinocandins,
diagnostic purposes and gave results similar to those        azoles and amphotericin B preparations [13,18,25,40 Á
from humans [7,27,29,32,33]. In each example men-            52]. In addition, a rat model of pulmonary aspergillosis
tioned, the utility of a particular assay is based on the    in granulocytopenic animals has demonstrated excel-
eventual correlation of animal data with clinical results.   lent efficacy of amphotericin B preparations when
Currently there are two commercial antigen assays            administered by inhalation of aerosolized drug
available, a glucan and a galactomannan assay kit, and       [53,54], while aerosolized itraconazole has proven
both show promise as useful diagnostic aids. However,        effective in a pulmonary murine model [55].
continued studies are needed on the clinical use of these       Although a vast majority of animal model studies use
tests to better determine standardized interpretive          A. fumigatus, one must be aware of the clinical
values and how the diagnostic results are best used [33].    epidemiology of all the causative agents. Possibly related
                                                             to more intensive immunosuppression and/or pro-
                                                             longed survival, though in the immunosuppressed state,
Preclinical therapeutic studies
                                                             and concurrent with the advent of new therapeutics,
A primary use of animal models of aspergillosis is           voriconazole and the echinocandins, there has been a
related to efficacy, safety and pharmacologic studies of     rise in the number of cases of aspergillosis due to other
antifungals, both new and licensed. The major question       species, particularly Aspergillus terreus [56 Á58]. Fatality
remains, ‘Are animal models predictive of how an             due to disease caused by A. terreus is high, and while
antifungal drug will work in humans with respect to          amphotericin B has been a mainstay of therapy for
clinical efficacy and safety?’. We have found the            aspergillosis until recently, this organism is frequently
systemic murine model using immunocompetent mice             resistant to amphotericin B in vitro. Little data is
has been predictive of clinical efficacy for azoles,         available for models of disease due to A. terreus [58].
echinocandins and amphotericin B preparations                In studies done several years ago we demonstrated that
[1,2,10,34 Á36].                                             saperconazole was superior to conventional amphoter-
   However, a single model cannot answer all efficacy        icin B for treatment in a murine model of systemic
questions and different models can give different            disease due to A. terreus [36]. More recently, a murine
results. As an example we found micafungin to be             model of systemic disease and a rabbit model of
highly efficacious in murine systemic and cerebral           pulmonary disease demonstrated the resistance of the
models of aspergillosis [34,37]. Using the systemic          organism in vivo to either conventional or liposomal
model a combination of micafungin and nikkomycin             amphotericin B treatment [59,60]; in the rabbit posaco-
Z had enhanced efficacy whereas the combination of           nazole and itraconazole were effective [60]; studies done
micafungin and conventional amphotericin B or itra-          in mice have shown the efficacy of micafungin versus
conazole showed no enhanced activity, but were not           A. terreus [61]. In addition, studies with Aspergillus
antagonistic. Similarly, in a cerebral model of aspergil-    flavus demonstrated a lack of correlation for in vitro
losis, we found the combination of micafungin or             susceptibility to itraconazole or amphotericin B and in
caspofungin and AmBisome to have no significantly            vivo efficacy [62]; similar results were obtained by this
enhanced activity [34,37]. The combination of Abelcet        group for A. fumigatus, while A. terreus resistance to
and caspofungin gave similar results in the CNS              amphotericin did correlate to in vivo results [63].
aspergillosis model [38]. In contrast, micafungin had           These types of data will be important in clinical
reduced activity and possible enhanced drug toxicity         decision-making in disease caused by this species, as it
with triamcinolone against pulmonary disease in ster-        is highly unlikely that a sufficiently large prospective
oid-suppressed mice [11]. Furthermore, in the pulmon-        clinical trial can be done. Thus, the species of Asper-
ary model the significantly enhanced activity of a           gillus causing disease is an important consideration
combination of micafungin and nikkomycin Z shown             and the results of studies with A. fumigatus may not
in the systemic model was not observed, and the              reflect drug efficacy against other species. This makes a
combination of micafungin and itraconazole showed            strong case for the development of additional models
antagonistic effects, with a reduction in efficacy by the    using other species of Aspergillus, which are relevant
combination [11]. Others have also found that what           clinically, albeit to a lesser extent currently, but also
works in one model may well not work in another when         require effective therapy [56 Á58,64 Á67].
testing the same drugs in different murine models [39].         A benefit of using models is the ability to examine
   Efficacy studies done in rabbit and guinea pig models     various antifungal combinations for potential enhance-
of invasive and pulmonary aspergillosis caused by            ment of efficacy or antagonisms [4]. We, and others,
– 2006 ISHAM, Medical Mycology, 44, S119 ÁS126
S122    Clemons & Stevens


have found conventional amphotericin B and itracona-        shown in selected preclinical data. Other studies have
zole or ketoconazole to show some antagonism in vivo        examined the drug interactions of itraconazole and
[3,68,69]. In a murine study, treatment with itracona-      cyclosporine [52], which are relevant clinically [78], as
zole prior to treatment with amphotericin B reduced         are interactions with phenytoin and rifampin [79]. The
efficacy [70]. In clinical practice, the effectiveness of   antifungal activity shown by several of the immuno-
combination therapy is not well established and             suppressants presents the interesting possibility of
combinations of amphotericin B and itraconazole             combining these with conventional therapy, and the
have primarily shown indifference, although sequential      use of animal models will further delineate this
therapy depends on the order of drug use. Amphoter-         potential [80].
icin B followed by itraconazole has been successful, but       The advent of immunomodulatory therapy, using
not when the drugs are given in the converse order [66].    cytokines such as interferon-g and colony stimulating
The correlation of results between animal studies and       factors in combination with conventional therapy, is
clinical observation in this instance are similar, yet      also of great interest. Relatively few model studies have
there may be differences in the result of the drug          been done, but results are encouraging [1,5,65,77,81 Á
interactions in vivo.                                       88]. However, the results of clinical trials on use of
   More recently, murine CNS and guinea pig pulmon-         CSFs have proven difficult to interpret.
ary disease studies have been published on the use of
voriconazole and liposomal amphotericin B [37,71]. In
                                                            The search for novel indications
both, the combination of voriconazole with liposomal
amphotericin B proved superior to monotherapy, and,         A true strength in the availability of different animal
in addition, sequential therapy of liposomal amphoter-      models of aspergillosis or any infectious disease is that
icin B followed by voriconazole also proved highly          of allowing therapeutic investigations into novel in-
effective [37,71].                                          dications or disease processes. For aspergillosis the
   An early echinocandin, cilofungin, showed antagon-       most common site of infection is pulmonary, with
ism with amphotericin B in a murine model of systemic       dissemination to other organs also occurring; other
aspergillosis [10]. However, micafungin and amphoter-       primary sites include keratitis and sinusitis. A very
icin B in combination showed positive interaction in        important site of infection for aspergillosis is the
our systemic aspergillosis studies [34]; trends toward      central nervous system, which is difficult to treat, and
significant enhancement of efficacy of micafungin or        in spite of therapy results in 90% fatality [89]. Effective
caspofungin in combination with AmBisome or ABLC            treatment is badly needed, whereas it would be
were found in murine CNS disease [37,38]. This is in        impractical to do a clinical trial. To address this, our
contrast to the results of Graybill et al . [39], who       laboratory has developed a murine model of central
reported liposomal amphotericin B and micafungin            nervous system [CNS] aspergillosis in pancytopenic
combinations effective in a systemic model of aspergil-     mice that allows us to examine new and different
losis, but ineffective in a model of pulmonary disease in   possible therapies.
steroid-suppressed mice.                                       We have used our model of CNS aspergillosis for
   Recently, the combination of micafungin and am-          monotherapy and combination therapy studies
photericin B were found to be superior to either drug       [23,37,38,90,91]. Among the azoles tested, posacona-
alone in a model of pulmonary infection done in             zole was highly effective resulting in significant en-
p47phox-/- chronic granulomatous disease mice [72].         hancement of efficacy by both survival and reduction
Also encouraging are the results of significantly           of infectious burden. Both itraconazole and voricona-
enhanced efficacy by low dose combination therapy           zole are effective at higher doses, but possibly less so
of Abelcet and caspofungin in a rat model of systemic       than posaconazole. Both micafungin and caspofungin
aspergillosis [73]. Similarly, combinations of an echi-     are highly effective in prolonging survival, but neither
nocandin and an azole have shown promise, as has the        results in cure. Of particular interest to us has been the
addition of G-CSF to conventional therapy [74 Á77].         examination of whether intravenous amphotericin B or
   Clinically, the use of combination therapy for           a lipid-carried amphotericin B formulation (AmBisome
aspergillosis was historically amphotericin B plus          or Abelcet) would be efficacious against CNS disease
5-flucytosine or rifampin with about 60% of patients        when administered intravenously. Our results indicate
showing improvement [66]. Even with the availability of     that lipid-carried amphotericin B is efficacious, but that
voriconazole and its improved therapeutic effects           even very high doses were not curative, with efficacy
against aspergillosis, combination therapy, with the        being reduced at doses above 15 mg/kg for AmBisome
addition of an echinocandin, may be desirable [32], as      [37,38]. Combinations of suboptimal dosages of AmBi-
                                                                          – 2006 ISHAM, Medical Mycology, 44, S119 ÁS126
                                                                                    Animal models of Aspergillus infection   S123

some or Abelcet and voriconazole proved highly              Conclusions
effective but again were not curative, whereas AmBi-
some or Abelcet in combination with an echinocandin         Overall, the use of animal models for various studies
showed nonsignificant improvements in efficacy and          provides us with useful information that has historically
were not antagonistic [37,38]. However, these enhanced      been shown to reflect what happens clinically. Their
efficacies again did not carry-over to the pulmonary        utility in pharmacologic and safety studies remains a
model of invasive aspergillosis in steroid-suppressed       primary function, for the results are predictive of
mice. Furthermore, we found that combination therapy        human responses. As our use of animal models of
in the CNS model using optimal dosages of each drug         aspergillosis becomes more sophisticated, our ability to
did not result in cure or any demonstrable improvement      improve patient care and clinical response will be
in efficacy. This latter point may be quite relevant        enhanced.
clinically as the costs associated with the new anti-
fungal agents are formidable and the ability to reduce      References
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