passenger attempted to ignite his shoes with either
matches or a cigarette lighter, already prohibited. Unless I am terribly
mistaken, one's flora are being mixed with that of several hundreds of
thousand of passengers who have passed through the same lines. The floors
are rarely cleaned (evidently) and never disinfected. Has
simple hygiene been forfeited in the US in the name
of "security?" When the TSA finally answered a query, they told me that
OSHA had approved the cross contamination of hundreds of thousands of feet.
The CDC, NIH, WHO, or state or local health departments were not consulted.
National Security indeed. Though a disgusting and unaesthetic procedure,
the people at highest risk must obviously be airport security staff. Studies
documenting increased risk of dermatophytes and/or tinea pedis, and increased
risk of respiratory tract symptoms like asthma or allergic alveolitis,
is clearly highly needed
Invasive fungal infections (IFIs) are continuing
threats to patients with hematologic malignancies. Factors associated
with greater susceptibility for IFIs include:
-
prolonged neutropenia
-
graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell
transplantation (HSCT)
-
the use of antineoplastic therapies that cause intense and prolonged deficiency
of T cell immune responses
Candida and Aspergillus are the major fungal pathogens that cause
infection. New antifungal agents have been developed and new fungal diagnostics
are now licensed. It is hoped that incorporation of these new tools into
antifungal strategies will result in improved outcomes.
-
Candida infections : for years, the mainstay of treatment for Candida
infections has been the use of amphotericin B, a polyene that binds to
ergosterol in the fungal cell membrane, given in a dose of 0.6–1.0 mg/kg/day.
Alternatively, fluconazole, an azole that inhibits ergosterol biosynthesis,
given in a dose of 400–800 mg/day intravenously or orally, is also acceptable.
Amphotericin B is active against most Candida species. Exceptions include
variable susceptibility by C lusitaniae and C guillermondi strains
and rare resistant C albicans strains. Fluconazole is also active
against many Candida species, with the notable exceptions of C
krusei, C dubliniensis, and some strains of C glabrata.
Many strains of C glabrata are susceptible dose-dependent, meaning
that the agent is clinically useful for infections due to such strains
but higher doses (e.g., 800 mg/day rather than the usual 400 mg/day) are
needed; approximately 15% of C glabrata isolates are fully resistant
to fluconazole even at higher doses. The lower sensitivity of C glabrata
to fluconazole and the widespread use of fluconazole in critical care and
oncology units have been associated with a rise in the proportion of
C glabrata in numerous hospital fungal surveys (especially of colonizing
isolates) in recent years. Notwithstanding, worldwide surveys have been
consistent in showing no rise in rates of resistance to fluconazole of
Candida bloodstream isolates over timeref.
Randomized trials in patients with systemic candidiasis comparing amphotericin
B and fluconazole have shown comparable response rates and less toxicity
with fluconazole. Amphotericin B in lipid complex has been compared to
amphotericin B deoxycholate and found to have comparable response and survival
rates, but the lipid formulation was associated with less nephrotoxicity
(Anaissie EJ, White M, Ozun O, et al. Amphotericin B lipid complex versus
amphotericin B for treatment of invasive candidiasis: a prospective, randomized,
multicenter trial. (Poster Session). In: Program and abstracts of the 35th
Interscience Conference on Antimicrobial Agents and Chemotherapy. Washington,
DC: ASM Press. 1995: Abstract #330). It is important to note that most
trials that have evaluated fluconazole were conducted in non-neutropenic
patients, and some experts believe that its use in neutropenic patients
is not yet firmly establishedref.
Since susceptibility to fluconazole is well predicted by species, some
experts suggest use of fluconazole can be guided by knowledge of the species
of infecting pathogenref.
Susceptibility testing can also be used to guide therapy, but it is not
widely available. While both the azoles and polyenes exert their antifungal
activity through actions on ergosterol in the fungal cell membrane, a new
class of drugs, the echinocandins, acts on the fungal cell wall through
inhibition of biosynthesis of ß-1,3-glucan, a major constituent of
the cell wall. This action is exerted by inhibition of ß-1,3-glucan
synthase. The echinocandins have potent in vitro activity against all of
the Candida species. The first licensed member of this family was
caspofungin. Other members of the echinocandin class in clinical trials
include anidulofungin and micafungin. Caspofungin’s half-life is 12–16
hours, permitting once daily dosing. Bioavailability is poor, necessitating
administration by intravenous route. In adults, a loading dose of 70 mg
on the first day is given, followed by a once daily dose of 50 mg. No dose
adjustment is needed for renal impairment; however, the maintenance dose
should be reduced to 35 mg/day for patients with moderate hepatic impairment
(Child-Pugh score 7–9) and there are no published data in patients with
severe hepatic insufficiency. Data on dosing for children younger than
12 years of age are under evaluation. When caspofungin was given to volunteers
concomitantly with cyclosporine, a rise in hepatic transaminases was seen,
which raises a concern about a potential deleterious interaction; however,
two recent series suggest that patients treated with the two drugs concomitantly
have not suffered ill effects (Marr K, Hachem R, Papanicolaou G, et al.
Retrospective study of concomitant use of caspofungin with cyclosporine
A in patients treated during marketed use [abstract]. Blood. 2003;102:471a)
ref.
Caspofungin’s clinical activity was noted in case series of systemic Candida
infections, in a randomized comparative trial (compared with fluconazole)
of esophageal candidiasis in human immunodeficiency virus (HIV)–infected
patients, and more recently in a randomized comparison with amphotericin
B for systemic candidiasisref.
In this latter study, caspofungin had comparable response and survival
rates to amphotericin B. In secondary analyses, in evaluable patients,
the response rate in those given caspofungin was significantly higher.
Response rates were comparable across different Candida species. This trial
was mostly in non-neutropenic patients, but in the small subset of neutropenic
patients, response rates were lower but comparable. Caspofungin was well
tolerated and considerably less toxic than amphotericin B. Anidulafungin
has been evaluated for treatment of candidiasis in a case seriesref.
A randomized trial comparing voriconazole, an extended spectrum azole,
with amphotericin B has been completed and is being analyzed. Practical
use of current anti-Candida agents : For patients with serious Candida
infections, caspofungin or one of the amphotericin B formulations is most
appropriate, providing proven efficacy against practically all Candida
species. Safety considerations give an edge to caspofungin over amphotericin
B, including the lipid formulations (Walsh TJ, Sable C, DePauw B, et al.
A randomized, double-blind, multicenter trial of caspofungin vs liposomal
amphotericin B for empirical antifungal therapy of persistently febrile
neutropenic patients [Abstract M1761]. In: Program and abstracts of the
43rd Interscience Conference on Antimicrobial Agents and Chemotherapy (Chicago).
Washington, DC: American Society for Microbiology, 2003). Once the infection
is stabilized, then fluconazole can be substituted for continued therapy,
provided the Candida species is a fluconazole susceptible species. For
less serious Candida infections due to fluconazole-susceptible species,
fluconazole is appropriate, especially in non-neutropenic patients.
-
Aspergillus infections : amphotericin B administered in a dose of
at least 1.0 mg/kg/day has been the treatment of choice for decades. Unfortunately,
prolonged courses of amphotericin B in this dose schedule are poorly tolerated
in many patients, especially those with antecedent renal impairment or
those receiving concomitant nephrotoxins. Lipid formulations are much better
tolerated even when given in higher doses and are more advantageous as
salvage therapy, but no trial has convincingly shown them to produce significant
improvements in response or survival rates as primary therapyref.
Although one trialref
suggested that 1 mg/kg/day of liposomal amphotericin B was as effective
as 4 mg/kg/day, it was so underpowered as to make its conclusions moot,
and most experts believe higher doses of the lipid formulations are optimal
(4–6 mg/kg/day). Nephrotoxicity rates are substantially less with the lipid
formulations, and that consideration alone makes them the only reasonable
choice for a polyene therapy for most patients with aspergillosis. The
extended spectrum azoles, including itraconazole, voriconazole, posaconazole,
and ravuconazole, have excellent activity against Aspergillus in vitro
and case series demonstrate clinical utility for all of them. Only one,
voriconazole, has been tested in a randomized trial (compared with amphotericin
B) for first line therapy for aspergillosisref.
Patients included in the study were immunocompromised patients who were
documented to have proven or probable acute invasive aspergillosis. Both
response and survival rates were significantly better for voriconazole
in comparison with amphotericin B. Voriconazole was better tolerated than
amphotericin B with less nephrotoxicity and fewer switches to alternative
therapies due to toxicity. Voriconazole’s half-life is 6 hours and is administered
every 12 hours. It is available in both intravenous and oral formulations.
The
oral formulation is well absorbed with a 96% bioavailability, generally
better absorbed and more palatable than itraconazole. The intravenous formulations
of both voriconazole and itraconazole have cyclodextrin excipients. Although
the azole is not excreted renally, the excipient is; thus, use of the intravenous
formulation of both of these azoles should be avoided in patients with
severe renal impairment to avoid potential accumulation of the cyclodextrin.
This is not a concern with the oral formulation. The kinetics are nonlinear
for individuals over the age of 12: doubling of the dose leads to a 4-fold
increase in the blood area under the curve (AUC). In contrast, in children
under the age of 12, the kinetics are linear: doubling of dose results
in doubling of exposure. In children younger than 12, the clearance is
higher, and higher doses are necessary. For example, exposure is comparable
for a child given a dose of 4 mg/kg and an adult given a dose of 3 mg/kg.
For Aspergillus infections in adults, 2 loading doses of 6 mg/kg are given
intravenously on the first day and, subsequently, a dose of 4 mg/kg is
given twice daily. When the patient stabilizes, the drug can be switched
from intravenous to the oral formulation and dosed at 200 mg twice daily.
In clinical studies, voriconazole has been associated with infrequent hepatotoxicity
and nephrotoxicity. However, two unique toxicities are notable: visual
disturbances occur in approximately 30%; these tend to be self-limited
and not associated with severe or enduring sequelae and rarely require
discontinuation of the drug. Dermatologic reactions occur in 6%, often
in sun-exposed areas. These are mostly mild to moderate and generally do
not necessitate alteration of the treatment course. Both itraconazole and
voriconazole are metabolized by cytochrome P450 enzymes. The interaction
with cytochrome P450 isoenzymes results in alteration of the metabolism
of other drugs metabolized by this enzyme. Multiple important drug interactions
can occur. Two interactions of particular relevance to hematologists include
(1) an increase of cyclophosphamide toxic metabolites (thus, clinicians
should avoid concomitant use of these azoles when high doses of cyclophosphamide
are used) and (2) a predictable increase in blood concentrations of calcineurin
inhibitors (thus, clinicians should reduce the dose of cyclosporine by
about 50% and reduce the dose of tacrolimus by about 65% when these azoles
are instituted and adjust the calcineurin inhibitor doses based on blood
level monitoring). Caspofungin has been evaluated in patients intolerant
of first-line therapy or where the infection progressed on first-line therapy.
As "salvage" therapy, responses were seen in approximately 40% (Maertens
J, Raad I, Sable CA, et al. Multicenter, noncomparative study to evaluate
safety and efficacy of caspofungin in adults with invasive aspergillosis
refractory or intolerant to amphotericin B, AMB lipid formulations or azole.
In: Program and abstracts of the 40th Interscience Conference on Antimicrobial
Agents and Chemotherapy. Washington, DC: ASM Press. Abstract #1103. 2000).
This is comparable to response rates seen with lipid formulations of amphotericin
B and voriconazole used in the salvage setting. To date there are no published
data as to caspofungin’s efficacy as first-line therapy for aspergillosis.
Practical use of current anti-Aspergillus agents : voriconazole is currently
the drug of choice for first line therapy. For allergic, intolerant, or
non-responsive patients, one of the lipid formulations of amphotericin
B is an excellent alternative. Caspofungin is yet another option for salvage
therapy.
Combination therapy : few controlled trials
of combination therapy have been performed, despite this approach being
evaluated in numerous in vitro and animal model studies. Combination antifungal
therapy (amphotericin B + flucytosine) is well established for cryptococcal
meningitis. In a recent trial, the combination of fluconazole and amphotericin
B was compared to fluconazole in high doses (800 mg/day) as therapy for
candidemia
ref:
overall, the response rate was higher and time to bloodstream clearance
was shorter in the group receiving the combination. This advantage was
offset by greater nephrotoxicity in the combination arm. Despite considerable
interest in this concept, there are no controlled trials for aspergillosis.
Although several case series suggest benefit
ref1,
ref2,
the majority of Aspergillus cases in which combination therapy was evaluated
were only "possible" infections. There are pitfalls with the use of combination
therapy including potential antagonism, greater toxicity, and cost
ref1,
ref2.
Thus, controlled trials are clearly needed.
Adjunctive measures : for catheter-related
candidemia, removal of a central venous catheter, if possible, should be
strongly considered
ref.
More rapid clearance of fungemia with catheter removal has been seen in
several studies. For Aspergillus infections, consideration should be given
for surgical excision of infarcted tissue, especially if the patient faces
additional antineoplastic therapy. The role of cytokines such as myeloid
growth factors and interferon gamma are supported by preclinical data,
but there is a paucity of clinical trial data. Similarly, the use of granulocyte
transfusions for neutropenic patients not responding to antimicrobial therapy
is intuitively sensible, but this strategy is not without complications,
is difficult to implement, and lacks convincing clinical data.
Duration of therapy : the duration of therapy has not been defined
in clinical trials but generally lasts for several weeks to months.
-
In general, treatment of Candida infections should continue for
at least 2 weeks beyond the time when cultures become negative, signs and
symptoms of infection have improved, and preferably host defenses have
improvedref
-
For Aspergillus infections, treatment should continue until resolution
of symptoms and signs, clearance of cultures at previously culture-positive
sites, improvement and stabilization of radiological findings, and improvement
of underlying host defenses and control of the hematologic malignancy.
In the largest trial to date, the planned course of therapy was 12 weeksref
Prophylaxis : fluconazole, itraconazole, and low doses of amphotericin
B have been shown in randomized trials to be effective as prophylaxis.
More recently, micafungin has also been shown to be effective as prophylaxis
(Van Burik J-A, Ratanatharathorn V, Lipton J, et al. Randomized, double-blind
trial of micafungin versus fluconazole for prophylaxis of invasive fungal
infections in patients undergoing hematopoietic stem cell transplant. In:
Program and abstracts of the 43rd Interscience Conference on Antimicrobial
Agents and Chemotherapy (San Diego). [Abstract M1238]. Washington, DC:
American Society for Microbiology, 2002). In general, from meta-analyses
of randomized trial data, the benefit appears to be meaningful when the
risk of IFI is at least 15% in the patient group treated
ref.
Most of the antifungal benefit seen in clinical trials has been in the
prevention of
Candida infection. Trials of itraconazole during neutropenia
have been mostly conducted in patient groups at low risk for aspergillosis,
and thus no clear benefit against aspergillosis has been shown. A recent
meta-analysis
ref
showed that itraconazole given in oral solution at adequate doses (at least
400 mg/day) was associated with fewer Aspergillus infections. 2 randomized
trials of prolonged prophylaxis comparing itraconazole to fluconazole after
allogeneic HSCT provide an unclear message: although an anti-Aspergillus
benefit for itraconazole was suggested (but not definitely shown), issues
of excess toxicity were also raised
ref1,
ref2.
High rates of recurrence of IFI occur if the once-infected patient is subjected
to subsequent antineoplastic treatment cycles or undergoes hematopoietic
stem cell transplantation, and thus "secondary" prophylaxis or chronic
maintenance is necessary until the underlying disease is controlled and
the full treatment course is completed. Several published case series indicate
that hematopoietic stem cell transplantation can be successfully performed
in patients given secondary prophylaxis
ref.
After completion of therapy the patient should be observed to monitor for
possible exacerbation.
Empirical therapy for neutropenic patients with
persistent fever : early trials demonstrated that rates of IFIs
were 15–30% in neutropenic patients with fever persisting 4–7 days despite
antibiotics; fungal morbidity could be reduced by empirical amphotericin
B. Subsequent trials with lipid formulations of amphotericin B, itraconazole,
voriconazole and caspofungin have been performed. In each study, the test
agent was compared with either amphotericin B or liposomal amphotericin
B. Since all patients had an active agent, the rates of IFIs in both groups
were anticipated to be small and thus a surrogate endpoint of "success"
was used as the primary endpoint. Success was judged by defervescence,
resolution of an IFI if found at baseline, absence of breakthrough IFI,
survival to neutrophil recovery, and no toxicity that necessitated withdrawal
of study drug. None of these agents were found to be superior to amphotericin
B in the primary endpoint and, in one case, voriconazole failed to meet
its protocol-specified non-inferiority bounds. However, a strong trend
in favor of itraconazole was noted for the primary endpoint of success
(P = 0.055), and differences in secondary endpoints, in terms of rates
of breakthrough IFIs (in favor of voriconazole over liposomal amphotericin
B) and response of baseline IFIs (in favor of caspofungin over liposomal
amphotericin B), were noted in these various trials
ref.
Considerable differences in toxicity were demonstrated with the various
agents. Indeed, tolerability should be considered in the choice of a specific
agent for a given patient.
What the future holds : several studies indicate early treatment is
key in determining the outcome of IFI treatment. Conventional diagnostic
methods are either too slow or fraught with considerable imprecision, and
use of invasive procedures is not practical for many patients with aspergillosis.
Two rapid diagnostic tests using serum have been licensed. The serum galactomannan
assay, testing for a constituent of Aspergillus cell wall released into
blood early during the course of invasive Aspergillus infection, has been
found to have sensitivity and specificity both exceeding 80% (US Food and
Drug Administration [FDA] package insert). This assay used twice weekly
detected two-thirds of Aspergillus infections in advance of conventional
diagnostic testing
ref.
This assay clearly has promise. However, concerns as to its performance
in children, non-neutropenic patients, patients receiving anti-mould antifungal
prophylaxis, and in patients with antibody have been raised
ref.
Recent reports indicate that false-positive test results can often occur
in patients receiving piperacillin-tazobactam
ref.
More recently, another serum assay, the glucan assay, detecting a cell
wall constituent in a wide range of fungal pathogens (rather than limited
to only
Aspergillus), has received FDA approval. It was found to
have high levels of sensitivity and specificity
ref.
The development of PCR assays also appears promising, and one trial showed
that sampling of serum twice weekly accurately identified patients with
IFI
ref,
often earlier than known using conventional diagnostic criteria. It is
hoped that such assays can assist the clinician to better distinguish febrile
patients with fungal infections from those who are febrile but not infected.
Further experience is needed for all of these assays to determine if and
how these assays can assist us in making diagnoses more accurately, earlier,
and allow the targeting of antifungal therapy to replace empirical trials
in patients suspected of infection. Ultimately, successful resolution of
any IFI is dependent on restoration of the compromised host defenses that
led to susceptibility for infection in the first place. Indeed, it can
be argued that without immune recovery no IFI can be adequately or durably
controlled. There has been substantial progress in our understanding of
how host immune responses interact with fungal pathogens
ref.
These insights are leading to new therapeutic strategies. Cytokines such
as IL-12 show promise as adjunctive therapy in preclinical studies. Efforts
to enhance T
h1 immune responses (or decrease polarization to
T
h2 responses) also offer promise from preclinical studies.
Infusions of common myeloid progenitors provide protection against lethal
infection in animal models
ref.
New fungal molecular structures are being identified that may prove to
be novel targets for antifungal drugs or can elucidate crucial cellular
receptors, such as the TLRs, that can be exploited. Vaccine strategies
using dendritic cells pulsed with fungal antigens are also under development
ref1,
ref2.
Copyright © 2001-2005 Daniele Focosi.
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