J Microbiol Immunol Infect Invasive fungal infections guidelines

2006;39:523-525

Guidelines for the use of antifungal agents in patients with

invasive fungal infections in Taiwan
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 Vaccine

Invasive fungal infections are associated with significant hemato-oncology, neurology and surgery. A consensus
morbidity and mortality despite advances in medical conference was held on March 11, 2006 in conjunction
care. Facing the transition to the era of managed care, with the Infectious Diseases Society of Taiwan, the
requiring both cost containment and quality assurance, Medical Foundation in Memory of Dr. Deh-Lin
there is an increasing need of better management of Cheng, Foundation of Professor Wei-Chuan Hsieh for
patients with invasive fungal infections. An aggressive Infectious Diseases Research and Education, and CY
diagnostic approach in patients at risk and prompt Lee’s Research Foundation for Pediatric Infectious
institution of antifungal therapy may be essential Diseases and Vaccine. Participants included board
for patient survival. Early intervention is strongly members of the Infectious Disease Society of Taiwan
recommended rather than waiting for microbiological and aforementioned experts*. These guidelines are
or histopathological confirmation, especially with limited to the most common invasive fungal infections
the availability of relatively safe options. Conventional including candidiasis, aspergillosis, zygomycosis and
amphotericin B has been the main therapeutic agent cryptococcosis. The aim of the guidelines is to provide
for the treatment of most invasive fungal infections national guidance to improve the use of antifungal
for four decades due to its broad spectrum of activity. agents. Three principles were maintained in establishing
However, such use must be accompanied by strategies these guidelines:
to reduce amphotericin B-related toxicity. Drug-related 1. Guidelines were based on academic principles
adverse effects are associated with a significantly rather than the regulations of the Bureau of National
prolonged length of stay, increased economic burden, Health Insurance on antifungal usage. The majority
and increased risk of death. Thus, the total cost of anti- of recommendations were evidence-based,
fungal treatment should not be limited to drug costs considering randomized controlled clinical trials
alone and the overall cost of health care must be taken and other study results, case reports and expert
into consideration in the era of global cost-containment. opinions. Guidelines follow the main structure
Selection of antifungal agents is not just a choice of the Infectious Diseases Society of America’s
between old versus new agents, but depends on the guidelines.
clinical status of the patient, the physician’s knowledge 2. Guidelines are based on local epidemiology and
of the species and/or antifungal susceptibility of the susceptibility patterns of pathogens.
infecting isolate, the relative drug toxicity, the presence 3. Antifungal agents recommended in the guidelines
of organ dysfunction that would affect drug clearance are agents already marketed in Taiwan.
as well as available knowledge of use of the drug in These guidelines are approved by the board of
the given patient population, and the patient’s prior the Infectious Diseases Society of Taiwan, and a copy
exposure to antifungal agents. In addition, antifungal will be sent to physicians in hospitals. The guide-
agents should be used rationally to avoid or prevent the lines are published in the Journal of Immunology,
selection of antifungal resistance and unnecessary use Microbiology and Infection and also available at the
of medical resources. Journal’s website (www.jmii.org). These guidelines
A series of symposia was held over the last two will be updated and revised yearly as necessary to serve
years in order to develop these guidelines. Participants as an easily accessible reference to all physicians
included experts in the field of infectious diseases, in Taiwan.

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Guidelines for the use of antifungal agents in patients with invasive fungal infections

Diagnosis Drugs of choice Alternative

1. Candidiasis
Candidemia Remove all intravascular catheters, if possible
Non-neutropenia AmB 0.6-1.0 mg/kg/d iv; Casp 50 mg/d iva;
Flu 400-800 mg/d iv or po for 14 days after Vor 4 mg/kg bid iv or pob;
last positive blood culture AmB 0.7 mg/kg/d iv plus Flu 800 mg/d iv or
po for 4-7 days, then Flu 800 mg/d po
Neutropenia AmB 0.7-1.0 mg/kg/d iv for 14 days after Flu 400-800 mg/d iv or po;
last positive blood culture L-AmB 3-6 mg/kg/d iv;
Casp 50 mg/d iv;
Vor 4 mg/kg bid iv or po
Neonates AmB 1.0 mg/kg/d iv; L-AmB 3-6 mg/kg/d iv;
Flu 8-12 mg/kg/d iv for 14-21 days after Casp 50 mg/m2 BSA/d iv
negative repeat blood culture
Chronic invasive candidiasis AmB 0.6-1.0 mg/kg/d iv; L-AmB 3-5 mg/kg/d iv;
Flu 400-800 mg/d iv or po for total 3-6 months Casp 50 mg/d iv
and resolution or calcification of radiologic lesions
Intra-abdominal Remove catheters, if possible
AmB 0.6-1.0 mg/kg/d iv; Casp 50 mg/d iv;
Flu 400-800 mg/d iv or po for 14-21 days Vor 4 mg/kg bid iv or po
Urinary Remove or replace urinary instruments
None for asymptomatic candiduria
Flu 100-400 mg iv or po; Casp 50 mg/d iv;
AmB 0.3-1.0 mg/kg/d iv for 7-14 days Vor 4 mg/kg bid iv or po
Oropharyngeal Nys 200,000-400,000 U 5 times/d; Itr 200 mg/d poc;
Flu 100-200 mg/d po for 1-7 days (children) or AmB 0.3-0.6 mg/kg/d iv for refractory casesd
7-14 days (adults) after clinical improvement
Esophageal Flu 200-400 mg/d iv or po; Casp 50 mg/d iv;
Itr 200 mg/d poc; Vor 4 mg/kg bid iv or po
AmB 0.3-0.7 mg/kg/d iv for 14-21 days after
clinical improvement

2. Empirical antifungal treatment of neutropenic patients with prolonged fever despite antibacterial therapy
AmB 0.5-1.0 mg/kg/d iv; Casp 50 mg/d iv;
Flu 400-800 mg/d iv or po (in selected patients)e Vor 4 mg/kg bid iv or po (in selected patients)f;
until resolution of neutropenia L-AmB 3-5 mg/kg/d iv

3. Aspergillosis
Pulmonary Surgical resection, if feasible
Vor 4 mg/kg bid iv po; L-AmB 3-5 mg/kg/d iv;
AmB 1-1.5 mg/kg/d iv in good partial response and Casp 50 mg/d iv;
neutrophil recovery, then change to Vor 4 mg/kg Itr 400 mg/d pog;
bid po or Itr 400 mg/d pog
ENT Surgical debridement, if possible
Same as pulmonary
Disseminated Surgical debridement, if possible
(excluding cerebral) Same as pulmonary
Cerebral Surgical debridement, if possible
Vor 4 mg/kg bid iv or po; AmB 1-1.5 mg/kg/d iv
L-AmB 3-5 mg/kg/d iv for 4-6 weeks, then change
to Vor 4 mg/kg bid po

4. Zygomycosis
Rhino-cerebral Aggressive eradicating surgery, if possible
L-AmB 3-10 mg/kg/d iv;

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AmB 1-1.5 mg/kg/d iv

Disseminated (excluding CNS) Aggressive eradicating surgery, if possible
Same as rhino-cerebral
Pulmonary Aggressive eradicating surgery, if possible
AmB 1-1.5 mg/kg/d iv L-AmB 3-10 mg/kg/d iv

5. Cryptococcosis
Pulmonary
Cryptococcoma and Close observation, if negative serum antigen;
immunocompetent Flu 200-400 mg/d po, if positive serum antigen
Pneumonia AmB 0.5-1.0 mg/kg/d iv for total 1000-2000 mg; Flu 400 mg/d iv or po plus
Flu 200-40 mg/d iv or po for 6-12 months 5-FC 100-150 mg/kg/d po for 10 weeks;
For AIDS, Flu 200-400 mg/d lifelong, discontinues Itr 200-400 mg/d for 6-12 months
if CD4 >200/mm3 post-HAART therapy
CNS, disseminated AmB 0.7-1.0 mg/kg/d iv plus 5-FC 100- L-AmB 3-6 mg/kg/d iv for 6-10 weeks;
150 mg/kg/d po for 2 weeks, then Flu 10-15 mg/kg/d iv or po plus 5-FC 100-
Flu 400 mg/d po for 10 weeks; 150 mg/kg/d po for 6 weeks;
AmB 0.7-1.0 mg/kg/d iv plus 5-FC 100- Itr 400 mg/pog for 10-12 weeks
150 mg/kg/d po for 6-10 weeks;
AmB 0.7-1.0 mg/kg/d iv for 6-10 weeks;
Flu 10-15 mg/kg/d (max. 800 mg/day) iv or
po for 10-12 weeks
For AIDS, Flu 400 mg/d lifelong, discontinues
if CD4 >200/mm3 post-HAART therapy

Management of elevated intracranial pressure

Keep initial CSF opening pressure <200 mm H2O
1. If CSF opening pressure >250 mm H2O, serial lumbar drainage to achieve closing pressure <200 mm H2O or 50% of initial
opening pressure
2. If CSF opening pressure <200 mm H2O, initiate medical therapy and follow-up lumbar puncture at second week or earlier as
clinically indicated
Follow-up for elevated pressure, if elevated pressure persists
1. Repeat drainage until opening pressure is stable
2. Ventriculoperitoneal shunt

Abbreviations: AmB = conventional deoxycholate amphotericin B; Flu = fluconazole; Casp = caspofungin; Vor = voriconazole;
L-AmB = lipid formulation of amphotericin B; BSA = body surface area; Nys = nystatin; Itr = itraconazole; bid = twice a day;
ENT = ear, nose and throat area; CNS = central nervous system; 5-FC = 5-flucytosine; AIDS = acquired immunodeficiency syndrome;
HAART = highly active antiretroviral therapy; CSF = cerebrospinal fluid; iv = intravenously; po = orally
aCaspofungin dosing in adults consists of 70 mg loading dose followed by 50 mg per day.

bVoriconazole dosing consists of 6 mg/kg bid on day 1 (loading dose) followed by 4 mg/kg bid.

cThe formulation of itraconazole is tablet.

dOnly in azole-refractory infections.

ePatients at low risk for invasive aspergillosis, who have not received an azole antifungal agent as prophylaxis; change to an

antifungal agent if there is no response after 3 days of treatment.

fAllogeneic bone marrow transplant recipients and individuals with relapse of leukemia.

gThe formulation of itraconazole is solution.

* Consensus conference participants (in alphabetical order):

Yu-Jiun Chan, Shan-Chwen Chang, Feng-Yee Chang, Yao-Shen Chen, Po-Yen Chen, Yee-Chun Chen, Yin-Ching
Chuang, Wei-Chuan Hsieh, Po-Ren Hsueh, Yhu-Chering Huang, Fu-Yuan Huang, Yung- Feng Huang, Li-Min Huang,
Kao-Pin Hwang, Yeu-Jun Lau, Chin-Yun Lee, Chun-Ming Lee, Hsieh-Shong Leu, Hsi-Hsun Lin, Tzou-Yien Lin,
Ching-Chuan Liu, Yung-Ching Liu, Cheng-Yi Liu, Cheng-Hsien Lu, Kwen-Tay Luh, Hung-Chin Tsai, Fu-Der Wang,
Lih-Shinn Wang, Ning-Chi Wang, Shue-Ren Wann, Wing-Wai Wong, Muh-Yong Yen

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