Journal Reading

2016 Guidelines for The Use of Antifungal Agents in Patients

with Invasive Fungal Diseases in Taiwan

Written by:

Sylvia Alicia Salim 1840312300

Yeni Novi Yanti 1840312277

Preceptor:
dr. Liliriawati Ananta Kahar, Sp.An, KIC

DEPARTEMENT OF ANESTHESIOLOGY
FACULTY OF MEDICINE ANDALAS UNIVERSITIY
RSUP DR. M. DJAMIL
PADANG
2018
Abstract The Infectious Diseases Society of Taiwan, Medical Foundation in Memory of Dr. Deh-Lin Cheng, Foundation
of Professor Wei-Chuan Hsieh for Infectious Diseases Research and Education, and CY Lee’s Research Foundation for
Pediatric Infectious Diseases and Vaccines have updated the guidelines for the use of antifungal agents in adult patients with
invasive fungal diseases in Taiwan. This guideline replaces the 2009 version. Recommendations are provided for Candida,
Cryptococcus, Aspergillus and Mucormycetes. The focus is based on up- to-date evidence on indications for treatment or
prophylaxis of the most common clinical problems. To support the recommendations in this guideline, the committee
considered the rationale, purpose, local epidemiology, and key clinical features of invasive fungal diseases to select the primary
and alternative antifungal agents. This is the first guideline that explicitly describes the quality and strength of the evidence to
support these recommendations. The strengths of the recommendations are the quality of the evidence, the balance between
benefits and harms, resource and cost. The guidelines are not intended nor recommended as a substitute for bedside judgment
in the management of individual patients, the advice of qualified health care professionals, and more recent evidence
concerning therapeutic efficacy and emergence of resistance. Practical considerations for individualized selection of antifungal
agents include patient factors, pathogen, site of infection and drug-related factors, such as drug-drug interaction, drug-food
intervention, cost and convenience. The guidelines are published in the Journal of Microbiology, Immunology and Infection
and are also available on the Society website.

Introduction
Rate of invasive fungal diseases (IFDs) increases and produce significant morbidity and
mortality, related to weaken host defense mechanisms due to medical care. This guideline aims
to identify opportunities to improve the management of adults with and at risk of developing
IFDs. The goals are to show the proven and optimal use of antifungal agents, and risk
assessment and management.
This guideline is intended for clinicians who are likely to diagnose and manage adult patients
with IFDs and those who are at risks (see Tables 1-4).
Clinical practice guidelines are considered to be the essence of evidence-based medicine. The
first and second versions were released in 2006 and 2009. This 2016 version updates the
previous recommendations based on more recent evidences, and were approved by the
Infectious Diseases Society of Taiwan (IDST).

Methods
The IDST coordinated the process of updating the guideline. All of the
recommendations, strength, and quality of the evidences were extensively reviewed and
discussed in series of multidisciplinary conferences and forums, consisted of development and
validation phases.
Framework principles used in this guideline; first, that this guideline based on
evidences and academic principles. Because high-quality evidence for antifungal is limited, in
vitro data, case reports and expert opinions were collected. Second, guideline was based on
local epidemiology and susceptibility patterns of invasive fungal pathogens. The heterogeneity
of the patient population and current clinical practice were also taken into consideration. Third,
antimicrobial agents recommended in the guidelines available in Taiwan.
Target populations, adult patients with IFDs of those at risk. The guideline
recommendations are restricted to Candida, Cryptococcus, Aspergillus, and Mucormycetes,
and focus on the most commonly encountered clinical problems. In the guideline, IFDs are
classified by certainty of the diagnosis, host factors, clinical findings including symptoms/signs
and imaging studies, into proven, probable, and possible IFDs. This is due to international
consensus recommendations for research purposes, for example, proven invasive aspergillosis
(IA) include microbiological of histopathological confirmation. Probable IA included relevant
clinical presentations (fever, cough, and high resolution CT Scans showing halo signs), and
positive biomarkers suggestive of IA such as serum galactomannan antigen assay in high-risk
patients. This guideline did not distinguish possible or suspect IFDs because therapeutic
decisions need to be individualized. Because not all infections in high-risk patients are caused
by fungal pathogens and can be difficult to distinguish presumes fungal from bacterial,
mycobacterial or viral infections.
Table 1 Summary of recommendations for the treatment of candidiasis
Table 1 (continued)
Table 1 (continued)
Table 1 (continued)
Table 1 (continued)

Each author contributed in this guideline, were assigned to review the recent literature
for a single topic, evaluate the evidence, determine the strength of the recommendations, and
prepare a written draft of recommendations. This guideline used literature published by
PubMed from 2009 to 2016, latest guidelines of Infectious Diseases Society of America
(IDSA), Infectious Diseases Working Party (AGIHO) of the German Society of Hematology
and Oncology (DGHO), the Third European Conference on Infections in Leukemia (ECIL-3),
the European Society of Clinical Microbiology and Infectious Diseases (ESCMID), as
evidences. They all were reviewed based on the GRADE method, that has been adopted by
IDSA. Includes a systematic method of grading both the quality of evidence (very low, low,
moderated, and high) and the strength of the recommendations (weak or strong). The strength
of recommendations are based on, but not limited to quality (certainty) of evidence. For these
reasons the Taiwan guidelines have included conventional amphotericin B. In the process of
making this guideline, a lot of considerations were taken for the balance between benefits
(treatment efficacy and benefit of early intervention) and harms (potential toxicity and drug-
drug interaction), the negative impact of delay intervention, burdens, resources and cost.

The recommendations and findings are summarized in the tables, ang designed to
achieve a balance between theoretical and practical applications for specialists, generalists,
house staff, and students. This guideline also emphasizes the limitation of current medical
knowledge and gaps between daily practice and research needs. The references provide
background information and key publications not included in the international guidelines, and
not intended nor recommended as a substitute for bedside judgment for the management of
individual patients, advice of qualified health care professional or search for updated evidence.
Th guidelines are published in the Journal of Microbiology, Immunology and Infection and are
also available on the Society website.

Invasive Candidiasis
Candidemia and other invasive candidiasis (IC) are important healthcare-associated
infections. The incidence increased significantly, worldwide. The Taiwan Nosocomial
Infection Surveillance data show that Candida sp. have become the second most common cause
of healthcare-associated bloodstream infection in intensive care units (ICU) and are the leading
pathogens that cause healthcare-associated urinary tract infections (UTIs). According to
researches, IC is associated with high mortality rate, increased length of hospital stays, and
excess medical costs for hospitalized patients. In Taiwan, there are four Candida species
account for more that 90% strains of IC. Candida albicans remains a major cause of IC (> 50%
of all cases), and the rest were non-albicans Candida; Candida tropicalis, Candida glabrata,
and Candida parapsilosis.
The emergence of each non-albicans Candida is particularly important for hemato-oncology
patients as well as for non-neutropenic crictically ill and non-critically ill patients.
C.tropicalis is more likely to be isolated from neutropenic patients receiving chemotherapy on
hemato-oncology services. Although most invasive Candida isolates were often susceptible to
fluconazole in the past, azole non-susceptibility (including susceptible-dose dependet [S-DD]
and resistant strains) have become a major concern. C.krusei is intrinsically resistant to
fluconazole, but is rarely isolated from hospitals in Taiwan.
Antifungal susceptibility testing and search for intravascular lesions or a metastatic focus are
ofthen helpful in guiding therapy for patients with breakthrough infection or who fail treatment.
 There are special efforts needed to prevent infection by reducing risk factors for
acquiring IC, due to the poor outcome and difficulty in making timely diagnosis.
Those factors include the use of antibiotics, central venous catheters, surgical procedures,
parentheral nutrition, sepsis, severity of illness, neutropenia, renal failure, mechanical
ventilations, use of. Immunosuppressive agents, and Candida colonization. Majority of
Candida blood isolates are similar or identical to prior colonization in patient’s urinary and
gastrointestinal tracts. Exogenous infections can also occur, from cross transmission, that is
why hand hygiene need to be implemented.
In critically ill and neutropenic patients with persistent fever despite bacterial therapy,
multiple risk factors, multiple and heavy colonization of Candida, and without an established
cause of fever, empiric therapy including fungicidal agent should be considered. Patient needed
re-evaluation after 48-72 h and fungal therapy can be deescalated after IC is ruled out by blood
cultures and other diagnostic measures.
In patients with asymptomatic candiduria, antifungal therapy is not indicated, because
it developed cadidemia in less than 5% of cases. Removal of an indwelling urinary catheter is
often sufficient to clear candiduria, without antifungal agents. Though in patients with
candiduria in the absence if urinary catheter may be a manifestation of disseminated candidiasis
in neutropenic patients with persistent unexplained fever, high-risk surgical patients, neonates,
and immunocompromised patients.

Cryptococcosis
There are 70 species in the genus Crytococcus, but only Cryptococcus gattii and
Cryptococcus neoformans are the predominant cause of infections in immunocompromised or
immunocompetent hosts. The disease spectrum includes meningoencephalitis, pneumonia,
cryptococcemia, sepsis and fever of unknown origin.
Treatment for cryptococcosis depends on immune status of the host site of infection,
access to health care facilities and availability of antifungal drugs. Treatment for central
nervous system (CNS) also depends on intracranial pressure. Treatment of disseminated
cryptococcosis and CNS diseases consists of induction, consolidation, and maintenance phases.
Induction therapy needs at least 2 weeks, and then followed by 8 weeks or more consolidation
therapy, and maintenance therapy to prevent recurrence in selected patiens.
Antifungal agents against Cryptococcus include polyenes (amphotericin B),
flucytosine, and azoles. Combination therapy with deoxycholate amphoterisin B (AmB-d) and
flucytosine is recommended as the first line induction treatment. For transplant recipients with
meningoencephalitis, lipid formulation amphotericin B such as liposomal amphotericin B (L-
AmB) is preferable as induction therapy in view of the high proportion patients with renal
insufficiency and concurrent use of nephrotoxic drugs. Treatment for localized infections of
mild-to-moderate severity, fluconazole is the drug of choice. For CNS diseases, therapeutic
lumbar punctures on survival have been shown to be independent of the initial ICP.

Table 2 Summary of recommendations for the treatment of cryptococcosis

Table 2 (continued)

Invasive Aspergillosis

Invasive aspergillosis (IA) has emerged as the most important fungal pathogen during
the past decade for both immune and structurally compromised patients. IA is associated with
significant morbidity and mortality. Aspergillus fumigates and Aspergillus flavus are the most
common species. A. Flavus tends to be less succeptible to antifungal drugs than A. Fumigates.
AmB-d remains as the therapeutic agent of choice in this guideline for the following
reasons. It has broad spectrum activity and preferred agent for pregnant women and neonates
and provides an alternative choice when confronting drug-drug interactions with azoles.
However up to 24% of patients receiving AmB-d developed nephrotoxicity in a multicenter
prospective observational. The ways to prevent aspergillosis is controlling environmental, that
is an essential strategy for IA.

Table 3 Summary of recommendations for the treatment of invasive aspergillosis (IA)

Table 3 (continued)

Table 3 (continued)
Mucormycosis

The majority of pathogens in the order Mucorales are Rhizopus, Mucor, Rhizomucor,
Lichtheimia, Cunninghamella, Apophysomyces and Saksenaea. It is less common than IA in
patients with haematological diseases, but the prognosis is remarkably poor. The predisposing
conditions associated with mucormycosis include granulocytopenia, immunosuppression,
diabetes, penetrating trauma, and iron overload.
AmB and posaconazole are the only active agents for these infections. AmB is currently
the recommended systemic antifungal agent. L-AmB is often preferred over AmB-d because it
is less nephrotoxic and allows the administration of higher doses. Posaconazole is an option
for salvage or maintenance therapy. Surgical debridement is recommended in addition to
antifungal therapy. Correction of underlying conditions is also crucial for successful
management.

Table 4 Summary of recommendations for the treatment of mucormycosis

Conclusion
The patient’s physician has the primary responsibility to provide care, request
consultations, and make decisions for specific procedures, choice of drug and dosage according
to the best available information. These decisions must be made after consideration of all the
relevant clinical findings and interests of the patient. Close collaboration is needed with the
pertinent hematologists, transplant experts, surgeons and critical care physicians. It is
particularly important that there be awareness of drug interactions particularly for critically ill
patients who are receiving multiple drugs. Emergence of resistance is a critical problem for all
antimicrobial drugs including antifungal agents. It is therefore important to avoid inappropriate
or excessive use of these agents when not indicated or no longer needed.