CLINICAL PRACTICE
Expert Panel Recommendations on the Clinical Practice Guidelines for the Diagnosis and Management of Invasive Candidiasis in Indonesia Anna Rozaliyani 1-3* .
Erni Juwita Nelwan 4,5 .
Mardiastuti Wahid 6 .
Dita Aditianingsih 7 .
Mulya Rahma Karyanti 8 .
Siti Pratiekauri 9 .
Adityo Susilo4,5.
Fathiyah Isbaniah1,3.
Heidy Agustin1,3.
Yulia Rosa Saharman6.
Robiatul Adaw iyah 2,3,9 .
Findra Setianing rum 2,3 .
Vera Irawany 7 .
Rudyanto Sedono7.
Debbie Latupeirissa8.
Nina Dwi Putri8.
Winda Sofvina3,9.
Mulyati Tugiran2,3 The Indonesian Society of Respirology (Perhimpunan Dokter Paru Indonesia.
PDPI).
Jakarta.
Indonesia.
The Department of Parasitology.
Faculty of Medicine Universitas Indonesia.
Jakarta.
Indonesia.
The Indonesian Pulmonary Mycoses Centre (IPMC).
Jakarta.
Indonesia.
The Indonesian Society of Tropical Medicine and Infectious Diseases (Perhimpunan Kedokteran Tropis dan Penyakit Infeksi Indonesia.
PETRI).
Jakarta.
Indonesia.
The Indonesian Internist Association (Perhimpunan Dokter Spesialis Penyakit Dalam Indonesia.
PAPDI).
Indonesia.
The Indonesian Society for Clinical Microbiology (Perhimpunan Dokter Spesialis Mikrobiologi Klinik Indonesia.
PAMKI).
Jakarta.
Indonesia.
The Indonesian Society of Anaesthesiology and Intensive Therapy (Perhimpunan Dokter Anesthesiology dan Terapi Intensif Indonesia.
PERDATIN).
Jakarta.
Indonesia.
The Indonesian Pediatrics Society (Ikatan Dokter Anak Indonesia.
IDAI).
Jakarta.
Indonesia.
The Indonesian Society for Medical Specialist in Clinical Parasitology (Perhimpunan Dokter Spesialis Parasitologi Klinik Indonesia.
PDS ParK).
Jakarta.
Indonesia.
*Corresponding Author:
Anna Rozaliyani.
MD.
PhD.
The Department of Parasitology.
Faculty of Medicine Universitas Indonesia.
Jl.
Salemba Raya 6.
Jakarta 10430.
Indonesia.
Email: anna.
rozaliyani@ui.
ABSTRACT
Invasive candidiasis (IC) ranks among the primary causes of deadly fungal infections.
The frequency of IC rises alongside increasing number of patients with altered immune systems, critically ill, chronic diseases, and various medical procedures.
The disease causes high morbidity and mortality, as well as prolonged stay and increases hospital costs.
The diagnosis and management of IC in Indonesia is still a challenge.
Laboratory facilities in identifying pathogenic fungi and susceptibility tests to antifungals are still limited.
Clinical awareness and financial support from health policymakers are also insufficient.
Early diagnosis is essential for proper treatment to reduce morbidity and mortality rates.
Initiated by the Indonesian Pulmonary Mycoses Centre (IPMC), several expert representatives from six medical professional organizations in Indonesia have agreed to set up a meeting series to prepare a joint draft on the diagnosis and management of IC.
The expert panel aimed to achieve a consensus on the clinical practice guidelines for diagnosing and treating IC in Indonesia.
Keywords: diagnosis, expert panel, invasive candidiasis, management.
Acta Med Indones - Indones J Intern Med A Vol 56 A Number 2 A April 2024 Vol 56 A Number 2 A April 2024 Expert Panel Recommendations on the Clinical Practice Guidelines INTRODUCTION Fungal infection or mycosis is an important infection that can be life-threatening.
The serious and dangerous clinical spectrum of mycosis is known as invasive mycosis.
Invasive candidiasis (IC) is a type of invasive mycosis due to Candida It is frequently found in patients with certain predisposing factors and altered immune systems, including critically ill patients treated in the Intensive Care Unit (ICU).
The incidence of IC is estimated to reach 700,000 cases worldwide, with a mortality rate of 40-98%.
1Ae3 The World Health Organization (WHO) released a list of fungal priority pathogens (FPPL) in October 2022 to increase awareness of mycoses, including its link to problems related to fungal resistance to antifungal The list of priority pathogens should be encouraged by policymakers at national and global levels to provide better access to diagnosis and management for mycosis patients.
The fungi are divided into 3 groups: namely critical priority, high priority, and medium Candida auris and Candida albicans are included in the critical priority group, while Candida glabrata.
Candida parapsilosis, and Candida tropicalis are included in the highpriority group.
Meanwhile.
Candida krusei is included in the medium priority group.
The diagnosis and management of IC in Indonesia is still a challenge.
Morbidity and mortality also become crucial issues and a major burden of public health menace.
Diagnostic facilities for IC are very limited in Indonesia, including clinical awareness, access to antifungal agents, and health financing support.
Some expert representatives from six medical professional organizations in Indonesia have agreed to set up a meeting series to prepare a joint draft on the diagnosis and management of IC.
The expert panel aimed to achieve a consensus on the clinical practice guidelines for diagnosing and treating IC in Indonesia.
METHODS
Expert Panel The expert panel held a meeting series from August 2022 to February 2023, initiated by the Indonesian Pulmonary Mycoses Centre.
The meetings invited a panel of experts from six professional organizations in Indonesia: The Indonesian Society of Respirology (Perhimpunan Dokter Paru Indonesia.
PDPI).
The Indonesian Internist Association (Perhimpunan Dokter Spesialis Penyakit Dalam Indonesia.
PAPDI)/The Indonesian Society of Tropical Medicine and Infectious Diseases (Perhimpunan Kedokteran Tropis dan Penyakit Infeksi Indonesia.
PETRI).
The Indonesian Society of Anaesthesiology and Intensive Therapy (Perhimpunan Dokter Anesthesiology dan Terapi Intensif Indonesia.
PERDATIN).
The Indonesian Pediatrics Society (Ikatan Dokter Anak Indonesia.
IDAI).
The Indonesian Society for Clinical Microbiology (Perhimpunan Dokter Spesialis Mikrobiologi Klinik Indonesia.
PAMKI).
The Indonesian Society for Medical Specialist in Clinical Parasitology (Perhimpunan Dokter Spesialis Parasitology Klinik Indonesia.
PDS Par.
, and the expert from the Department of Parasitology.
Faculty of Medicine Universitas Indonesia.
The expert panel agreed to achieve a consensus on the clinical practice guidelines to aid the diagnosis and treatment of IC in Indonesia.
Evidence Evaluation The expert panel carefully discussed and analyzed some international guidelines and the latest literature on the diagnosis and management of IC.
The draft was prepared based on the critical review and adhered to the principles of evidence-based medicine.
The sources of evidence were the European Organization for Research and Treatment of Cancer and the Mycoses Study Group Education and Research Consortium (EORTC/ MSG) Consensus Group .
8, 2020, 2.
,6Ae8 the Infectious Diseases Society of America guideline .
,9 the Australasian Antifungal Guidelines Steering Committee .
,10 the European Society of Clinical Microbiology and Infectious Diseases .
2, 2.
,11,12 the European Conference on Infection in Leukemia .
7, 2.
13,14 The epidemiology data, clinical relevance, and applicability of the evidence for invasive Candida infections in Indonesia were also explored and discussed.
The review process was carried out in stages on Anna Rozaliyani Acta Med Indones-Indones J Intern Med the initial draft, followed by group discussions, until an agreement was reached in the form of a consensus regarding IC.
Levels of Recommendation The recommendations were constructed based on the quality of evidence, the diagnostic options that can be implemented considering the limited facilities in Indonesia, the affordability of treatment access, etc.
The task force followed the GRADE (Grading of Recommendations Assessment.
Development, and Evaluatio.
scheme of levels of evidence and recommendation grades (Table .
GRADE has four levels of strength of recommendation: high, moderate, low, and very low.
Furthermore, the panel also recommended a three-tier quality of evidence:
Level I.
II, and i.
Guideline Development The discussions were recorded at the meeting and written up as a manuscript draft.
The working group writing committee drafted the first version of the manuscript, which was sent to the other group members for their critical review.
The draft was reviewed, edited, and commented on the outline and manuscript drafts until a final version was reached and approved by all members.
The panel agreed on several recommendations based on the best scientific evidence.
EPIDEMIOLOGY OF INVASIVE CANDIDIASIS
Incidence Invasive candidiasis frequently occurs in hospitals, including a Candida bloodstream infection .
as the most common form of IC.
Various studies in many countries have reported an increased incidence of IC1,2 The incidence of candidemia in Europe was estimated at 79 cases per day, 3.
88 per 100,000 population, with a mortality rate of 37%.
3 The incidence of IC in Australia increased from 1.
41 cases per 100,000 population in 2001 and 16 Increased incidence of candidemia in Switzerland was reported from 2.
96 per 100,000 cases in 2009Ae2013 to 4.
20 in 2014Ae2018.
17 The incidence of candidemia also increased from 0.
33 cases per 1,000 hospitalizations between 2013-2018 in Korea.
Candidemia is a major cause of invasive mycoses in hospitalized children.
The highest incidence was reported in neonates and infants <1 year old.
19 In 2015, the incidence of candidemia in neonates in the United States reached 11.
8 per 100,000 births, while in infants was 17.
5 cases per 100,000 in 2015.
The incidence of IC in the pediatric population was 0.
8 cases per 100,000 in 20 The overall IC mortality rate in pediatric patients ranges from 10Ae14.
4%, while it was 22% in neonates.
Table 1.
Definition of the recommendationAos strength and evidence quality15 The strength of The quality of Grade Definition Strongly recommended for use Moderately support a recommendation for use Marginally support a recommendation for use Not recommended to use Level i Evidence from > 1 well-designed randomized controlled trial Evidence from > 1 well-designed clinical trial.
from cohort or case-control analytical from multiple case series Evidence from the opinion of respected authorities, based on clinical experience, descriptive case studies, or expert committee reports Table 2.
Invasive candidiasis/candidemia in Indonesia Population Critically ill patients Sepsis patients Critically ill children Sepsis neonates Location Cipto Mangunkusumo Hospital.
Jakarta Cipto Mangunkusumo Hospital Jakarta Hasan Sadikin Hospital.
Bandung National Brain Center Hospital.
Jakarta Cipto Mangunkusumo Hospital.
Jakarta Cipto Mangunkusumo Hospital.
Jakarta Year Incidence (%) 117 cases References Vol 56 A Number 2 A April 2024 Expert Panel Recommendations on the Clinical Practice Guidelines Epidemiological data on IC and candidemia are still lacking in Indonesia, both in adults and children because the data is only reported from the referral hospitals in Jakarta and Bandung (Table .
The incidence of candidemia in Indonesia was estimated at 10 cases per 100,000 population yearly, while in adultsAo data vary widely depending on the patient population.
The Etiology The primary pathogen responsible for IC is albicans, but in recent decades, nonCandida-albicans Candida (NCAC) species have emerged as causes of candidemia.
The total proportion of IC due to C.
has decreased from 57.
4% to 46.
4% during the 1997-2016 surveillance period based on SENTRY program data.
29 The distribution of NCAC species can be differentiated based on patient characteristics.
Candida parapsilosis is associated with candidemia in neonates and young adults.
Candida glabrata.
and C.
krusei were isolated from blood cultures of elderly patients (>65 year.
with risk factors, for example, abdominal surgery, solid tumors, hematological malignancies, organ transplantation, and long-term corticosteroid 28 Candida glabrata and C.
krusei were reported to be the most common causative agents of candidemia in patients with hematological 30 Studies at Cipto Mangunkusomo Hospital.
Jakarta showed that C.
albicans is the predominant species of IC .
72%), followed by tropicalis .
%), and C.
%).
Another study in the neonatal population showed that the most common cause of candidemia was tropicalis .
5%).
Risk Factors Candida spp.
is a typical microorganism in the human body, e.
in the mouth, gastrointestinal tract, and vagina.
However.
Candida spp.
cause superficial infections to deadly systemic infections in certain conditions.
32 The degree of IC severity depends on the presence or absence of risk factors or predispositions to IC, including prolonged use of broad-spectrum antibacterial therapy, length of ICU stays, use of central venous catheters, receipt of parenteral nutrition, neutropenia, use of immunosuppressive agents, implantable prosthetic devices, and renal replacement therapy.
Underlying diseases or comorbidities should also be carefully evaluated, as well as drugs, and host genetic factors.
33Ae36 Underlying Diseases or Comorbidities Several diseases might become the risk factors for IC, including malignancy, kidney failure, diabetes mellitus, neutropenia, and 36 Acute leukemia, lymphoma, and myelodysplastic syndrome are the most common conditions associated with candidemia.
Hematological malignancies and aplastic anemia also increase the risk of Candida infection .
%).
Invasive candidiasis is also associated with immunodeficiency conditions, e.
g, sepsis, stroke, cancer, chemotherapy recipients, patients living with HIV/AIDS, stem cell/organ transplant recipients, graft versus host disease (GVHD) patients, as well as neonates.
37,38
Nosocomial Infections The increasing cases of IC in hospitalized patients is associated and in line with the use of broad-spectrum antibiotics, immunosuppressant drugs, and long-term care, including in the ICU, as in critically ill patients.
The main risk factors for IC in ICU patients include the use of broadspectrum antibiotics.
Candida colonization, use of central venous catheters, and administration of total parenteral nutrition.
The risk of IC also increases in hemodialysis patients.
34,39,40
Critically ill patients in the ICU are more susceptible to Candida infections through contamination from the hospital environment, health workers, invasive medical equipment .
enous or urinary catheters, endotracheal tubes, drain tubes, etc.
), or the potential for biofilm formation on those devices.
35,41,42
Biofilm can trigger Candida resistance to antifungal agents by reducing the ability of drug penetration, as well as facilitating the development of persister cells which have various resistance mechanisms to reduce the effectiveness of antifungal agents.
The incidence of C.
infection in hospitals should specifically consider relevant risk factors, including travel history from endemic countries.
41,43,44
Anna Rozaliyani Medications Prolonged usage of systemic, broad-spectrum antibiotics, immunosuppressants, corticosteroids, and chemotherapy might increase the risk for IC.
34,36 Long-term antibiotic therapy can increase Candida colonization, change the composition of the microbiota in the body, and increase the risk of Candida resistance to antifungal agents.
35,44
Genetics Host genetic risk factors also influence, particularly the Dectin-1 receptor, a CD82 variant associated with the risk of candidemia and reduced cytokine production.
Mutations in CARD9 are associated with autosomal recessive inheritance of host susceptibility to invasive infections by Candida spp.
PATHOGENESIS
Candida is a commensal organism in the gastrointestinal tract, the skin, and the urinary Candida is detected in 50-70% of healthy human mucosa.
In patients with certain risk factors and/or altered immune systems.
Candida colonization may occur as an initial consequence of microbiota dysbiosis (Figure .
Candida colonization induces a resistance immune In cellular immunity, the production of T-helper cells increases.
Monocytes activate the Acta Med Indones-Indones J Intern Med inflammatory response through the phagocytosis and cytokine production.
Polymorphonuclear cells, including neutrophils, destroy fungi through opsonization processes, oxidative and nonoxidative mechanisms.
The immune response dysregulation will increase fungal growth, thereby increasing the risk of candidemia and IC.
Deepseated candidiasis is most often associated with intra-abdominal invasion.
Gastrointestinal or hepatobiliary surgery becomes the risk factor, as the intestinal mucosal barrier damage leads Candida to spread directly to the abdominal cavity and enter the bloodstream.
39,45Ae47 T h e b a s i c m e c h a n i s m o f C a n d9i d a pathogenicity is its ability to adapt to the host environment and physiological barriers.
Fungi are typically thermophilic, thriving best at room temperature.
Candida albicans is capable of forming hyphae at temperatures over 35AC and surviving at 40AC, establishing this fungi as a leading cause of candidiasis.
The ability to survive at high temperatures is used as a basis for distinguishing C.
albicans from other species (NCAC).
2,39
External and internal protective factors, including gut self-regulation, are necessary for maintaining Candida commensalism.
The internal factors, including the intestinal mucosal barrier, are composed of goblet cells .
roducers Figure 1.
Various risk factors or underlying diseases play an important role in developing invasive candidiasis.
Changes in the microbiota due to certain risk factors result in the overgrowth of Candida species and colonization.
The altered immune system, especially neutropenia, as well as invasive procedures that damage the natural barrier of the skin or mucosa, such as intravascular catheters, gastrointestinal surgery, and chemotherapy-associated mucositis, facilitate local invasion, candidemia, and invasive candidiasis .
dapted from Lass Florl, et al.
)48
Vol 56 A Number 2 A April 2024 Expert Panel Recommendations on the Clinical Practice Guidelines of mucu.
, paneth cells .
roducers of antimicrobial peptides/AMP.
, and gastrointestinal The mucus layer and intestinal epithelial cells control the translocation and composition of Candida yeast cells .
onpathogenic for.
External factors, including a healthy diet that supports the growth of intestinal microbiota, chemical conditions, nutrition, and physiological factors, also influence the balance of microbiota.
If hyphae are dominant.
Candida can cause mucosal infections and kill epithelial cells, activating c-Fos and the release of inflammatory mediators/cytokines.
This can be triggered by irrational use of antibiotics, unhealthy diet, cytostatic therapy, decreased intestinal mucus secretion, dysbiosis of the gastrointestinal microbiota, and others.
49Ae51
DIAGNOSIS OF INVASIVE CANDIDIASIS
Rapid and accurate diagnosis of IC is important to support the appropriate antifungal Early diagnosis can be challenging because fungal cultures have low sensitivity, often leading to delays in definitive treatment.
The gold standard for IC diagnosis is the fungal culture or histopathological examination from the sterile site.
The diagnosis of IC is intricate.
therefore, relying solely on laboratory findings is insufficient to establish the diagnosis.
For this reason, the terms proven, probable, or possible IC were introduced.
52,53
Probable IC is based on the assessment of specific host factors .
neutropenia, organ transplantation, immunosuppressive therapy, et.
, clinical manifestations, and mycological evidence that comprises culture and microscopic analysis, and also non-culture-based tests, e.
antigen detection.
Possible invasive candidiasis is no longer defined.
52,53 The expert panel agreed to use the recent definition of IC from the EORTC/MSG 2020 7 as part of the standard definition (Table .
Table 3.
Definition of proven and probable invasive candidiasis7
Diagnosis PROVEN
PROBABLE
Criteria Microscopic analysis or culture from sterile materials - Blood culture positive .
ield yeas.
OR - Histopathologic, cytopathologic, or direct microscopic examination of a specimen obtained by needle aspiration or biopsy from a normally sterile site .
ther than mucous membrane.
showing yeast cells of Candida OR - Recovery of a yeast by culture of a sample obtained by a sterile procedure .
ncluding a freshly placed [<24 hours ag.
from a normally sterile site AND clinical or radiological abnormality consistent with an infectious disease process Host factors - Recent history of neutropenia <0.
5 y 109 neutrophils/L (<500 neutrophils/ mm3 for >10 day.
temporally related to the onset of invasive fungal disease - Hematologic malignancy - Receipt of an allogeneic stem cell transplant - Solid organ transplant recipient - Prolonged use of corticosteroids .
xcluding among patients with allergic bronchopulmonary aspergillosi.
at a therapeutic dose of Ou0.
3 mg/kg corticosteroids for Ou3 weeks in the past 60 days - Treatment with other recognized T-cell immunosuppressants, such as calcineurin inhibitors, tumor necrosis factor-a blockers, lymphocyte- specific monoclonal antibodies, immunosuppressive nucleoside analogues during the past 90 day - Inherited severe immunodeficiency .
uch as chronic granulomatous disease.
STAT 3 deficiency.
CARD9 deficiency.
STAT-1 gain of function, or severe combined immunodeficienc.
- Acute graft-versus-host disease grade i or IV involving the gut, lungs, or liver that is refractory to first-line treatment with steroids Clinical features At least 1 of the following 2 entities after an episode of candidemia within the previous 2 weeks:
- Small, target-like abscesses in liver or spleen .
ullAos-eye lesion.
or in the brain, or meningeal - Progressive retinal exudates or vitreal opacities on ophthalmologic exam ination Mycological evidence y-D-glucan (Fungitel.
Ou80 ng/L .
g/mL) detected in at least 2 consecutive serum samples provided that other etiologies have been excluded Anna Rozaliyani Acta Med Indones-Indones J Intern Med Clinical Manifestations Figure 2 documented the culture of Candida on Sabouraud Dextrose Agar media and histopathological preparations.
The development and validation of diagnostic tests other than non-culture is the most important need in the diagnosis of IC and candidemia.
Laboratory tests other than non-culture-based are more sensitive and faster than blood culture, but cannot determine the identification to the species level or antifungal susceptibility testing.
The Candida PCR test has not been standardized yet.
The most important task in increasing laboratory capacity to diagnose IC is to incorporate tests other than non-culture into an effective and cost-effective management strategy so that the quality of IC management can be improved.
56Ae58 Laboratory Tests The possibility of IC can be predicted by using the Candida score.
Ostrosky-Zeichner clinical prediction rule, or other scoring systems.
60 The Candida score study at Cipto Mangunkusumo Hospital was developed based on risk factors in ICU patients.
The results of the study showed that the predictor factors for candidemia were:
length of stay 8-14 days .
, length of stay >14 days .
, severe sepsis .
, and Candidiasis is the most common fungal infection, both superficial and invasive.
Many organs and body systems are at risk of developing IC through bloodstream infections.
In the cardiovascular system, infective endocarditis possibly occurs.
The source of infection might be intracardiac or intravascular implants that cause The gastrointestinal, hepatosplenic, and genitourinary tract organs are also susceptible to IC, with symptoms in the form of abscesses.
The nervous system and osteoarticular .
he most common form is vertebral osteomyeliti.
, respiratory system .
Candida lung absces.
, and visual system .
are also not clear from the threat of Candida infection.
39,54,55
Species identification can be established after examining cultures on certain media, semiautomatic or automatic methods, and molecular Specimen handling is very important as an initial part of the diagnosis of IC (Table .
Identifying Candida spp.
from clinical material takes 24-96 hours.
This has an impact on delays in the initiation of early treatment.
56Ae58 Table 4.
Specimen type, clinical material, optimal volume, and delivery need to be considered in making a diagnosis of invasive Clinical material Optimal volume Blood .
20-30 mL Blood .
hildren, neonate.
Based on body weight - < 1 kg: 2mL - 1,1-2 kg: 4 mL - 2,1-12,7 kg: 6 mL - 12,8-36,3 kg: 20 mL - >36,3 kg: 40-60 mL Sterile body fluid .
spirates/ fluid from liver, peritoneal, pleural, cerebrospinal, pericardial, etc.
Tissue Swab Sufficient Clinical material from endophtalmitis patient Abses/purulent aspirates Sufficient Cases of aneurysm vascular infection and vascular graft Tissue biopsy/ resected 10-50 mL Sufficient Shipping .
ontainer, time, temperatur.
- Inoculated culture bottles .
sually in Bacte.
- Lysis-centrifugation blood culture tubes or aerobic blood culture bottles - Blood syringe/tube without preservatives - Stored for 2 hours at room temperature - Inoculated culture bottles .
sually in Bacte.
- Stored for 2 hours at room temperature Sterile container, stored for 2 hours at room temperature or if > 2 hours, stored at 4AC .
or 2-24 hour.
- Sterile container, keep the tissue moist .
dd a few drops of 0.
9% NaC.
, avoid formalin.
- Stored for 1 hour at room temperature, or at 4AC if >1 - Swab kit/ equipment - Stored for 2 hours at room temperature - Sterile container - Stored for 2 hours at room temperature - Sterile container - Stored for 2 hours at room temperature - Sterile container - Stored for 2 hours at room temperature Vol 56 A Number 2 A April 2024 Expert Panel Recommendations on the Clinical Practice Guidelines Figure 2.
Candida isolated from blood culture in Sabouraud Dextrose Agar.
Candida sub-culture in Sabouraud Dextrose Agar plate.
Histopathology of Candida from the organ tissue (Courtesy of Parasitology Laboratory.
Faculty of Medicine Universitas Indonesi.
, with a cut-off score of 3.
This Candida score can be used as a guide for starting empirical therapy at Cipto Mangunkusumo Hospital.
61 However, the role of the Candida score as a diagnostic method for IC in pediatric patients is still limited.
In critically ill patients, delaying antifungal therapy due to waiting for culture results is associated with a poor prognosis.
58 In ICU patients, the BDG test shows a sensitivity and specificity of 81% and 61%.
The assay has been used to guide pre-emptive antifungal therapy, with a positive predictive value of 63 The PCR test is the main component of molecular methods, used to amplify DNA from clinical material.
The use of PCR is still limited for research purposes due to the lack of standardization in various countries.
56Ae58 Fungal susceptibility testing uses methods based on the Clinical Laboratory Standards Institute (CLSI) and the European Committee on Antimicrobial Susceptibility Testing (EUCAST).
43,56 In Indonesia, the commonly used device to identify and conduct the susceptibility test is Vitek which is CLSI and EUCAST-based.
Recommendation:
Isolation and identification of Candida spp.
from clinical material culture should be performed using Sabouraud dextrose agar medium with the addition of antibiotics.
blood volume of 20-30 mL is recommended if the diagnosis suggests possible candidemia.
Blood cultures should be repeated if candidemia is present.
The aim is to monitor disease progression and determine the duration of therapy .
trong recommendation, level II evidenc.
Direct microscopic examination of sterile samples should be performed, in addition to fungal culture to diagnose IC .
trong recommendation, level II evidenc.
Susceptibility testing should be carried out routinely on clinically significant isolates grown from sterile samples, and for which clinicians and mycologists have been consulted, particularly if there has been previous use of antifungal drugs, or when there are species intrinsically associated with resistance, e.
Candida glabrata isolated in The susceptibility testing of invasive isolates should be reviewed periodically, to anticipate whether there are changes in the susceptibility profile and clinical .
trong recommendation, level II evidenc.
The expert panel agreed that there must be national guidelines approved by various medical professionals in Indonesia for an adequate diagnosis of IC.
The guideline should be applied wherever possible based on clinical and laboratory data, by optimal use of local resources and expert advice.
The panel also realized that the availability of diagnostic facilities in Indonesia is still limited for fungal infections.
However, every effort should be optimized to diagnose infections at the species level.
The local laboratory should be empowered and collaborate with reference laboratories to improve IC diagnostic quality.
Anna Rozaliyani Acta Med Indones-Indones J Intern Med
TREATMENT OF INVASIVE CANDIDIASIS
Once a diagnosis of IC has been made, providing adequate treatment is very crucial, considering that delayed treatment is associated with increased mortality.
Excessive or insufficient administration of antifungal therapy has the potential to cause drug toxicity and fungal To overcome these challenges, an initial treatment strategy was developed using the following scheme: prophylactic, empiric, pre-emptive, and targeted therapy (Table .
35,64,65
Principles for Selection of Antifungal Therapy The serious illnesses and problems of IC patients need careful consideration in choosing antifungal therapy.
The patientAos clinical condition, previous exposure to antifungal, risk of fungal colonization, local epidemiology, infection sites, organ dysfunction, accompanying therapy, and the need for therapeutic drug monitoring (TDM) are factors that should be considered in selecting appropriate treatment.
The antifungal group is divided based on its mechanism of action: echinocandins, triazoles, amphotericin B, and the new group.
Echinocandins have fungicidal activity against almost all Candida species by changing the structure of the fungal cell membrane.
Echinocandins inhibit the biosynthesis of 1,3--D-glucan, a component of Candida cell Echinocandins are recommended therapy of IC in critically ill or unstable patients, who have been previously exposed to antifungal agents and have proven resistance to azoles, for almost all Candida species.
Drugs included in this group are caspofungin, anidulafungin, and 2,9,39 Table 5.
Strategy for administering antifungal therapy in invasive candidiasis35 Strategy of Prophylaxis Empirical Pre-emptive Targeted Definition Antifungal prescription to prevent infection in risks patient Antifungal prescription in response to the signs and symptoms in ICU or critically ill patients with risk factors .
ossible diagnosi.
Antifungal prescription in response to positive non-culture or radiology-based tests .
robable diagnosi.
Antifungal prescription in response to microbiology test evidence in proven invasive candidiasis Table 6.
Risk factors associated with candidemia and antifungal treatment65 Patients at risk/ risk factors All patients Candida Candida Therapy Echinocandins .
Fluconazole, 800 mg then 400 mg .
Liposomal amphotericin B, 3Ae5 mg/kg/day .
Echinocandins .
Fluconazole, 800 mg then 400 mg .
ICU patients Candida Neonates Vascular catheter Older age Candida Fluconazole and voriconazole are not recommended for frequent azole Diabetes Cancer - Echinocandins .
Hematological malignancies - Liposomal amphotericin B, 3Ae5 mg/kg/day .
Stem cell transplantation Azole prophylaxis Corticosteroid therapy Candida - Echinocandins .
Hematological malignancies - Fluconazole, 800 mg then 400 mg .
Stem cell transplantation - Liposomal amphotericin B, 3Ae5 mg/kg/day .
Corticosteroid therapy Candida Fluconazole is not recommended for frequent azole resistance Hematological malignancy - Echinocandins .
Stem cell transplantation - Liposomal amphotericin B, 3Ae5 mg/kg/day .
Azole prophylaxis - Voriconazole .
Diabetes Candida - Echinocandins .
Cancer Hematological malignancy ICU/invasive procedure Notes: .
anidulafungin: loading dose 200 mg, then 100 mg daily, micafungin: 100 mg daily.
In stable patients without previous exposure to azoles.
If isolates are not susceptible to azoles and echinocandins or in the presence of organ involvement.
6 mg/kg q12h y 2 doses .
then 3Ae4 mg/kg q12h.
Vol 56 A Number 2 A April 2024 Expert Panel Recommendations on the Clinical Practice Guidelines Fluconazole, itraconazole, voriconazole.
Posaconazole .
ot available in Indonesi.
, and isavuconazole belong to the triazole group.
These drugs are fungistatic by inhibiting the biosynthesis of ergosterol, a component of the fungal cell wall, and inhibiting the cytochrome P450 enzyme.
The azole group can be used as an alternative to IC initial therapy.
Because all azole groups have decreased activity against C.
glabrata and C.
krusei, for these two species, the amphotericin B group is used as an alternative to echinocandins.
The mechanism of action of amphotericin B is that it binds to the ergosterol component in the fungal cell wall, resulting in leakage and disruption of the balance of the composition of the fungal cell wall which causes the death of the fungus .
ungicidal 2,39,65 A new and quite promising antifungal drug group has now passed phase 2 and 3 clinical trials for the treatment of invasive candidiasis, namely rezafungin.
It has a structure similar to an echinocandin with a longer half-life, so the interval between doses is longer .
Other drugs such as Ibrexafungerp oral is a glucan synthase inhibitors, while Fosmanogepix is a guanosine monophosphate inhibitor and has activity against all pathogenic Candida species, except C.
A new drug.
ATI-2307 works by inhibiting mitochondria and is expected to provide an alternative to antifungal drugs amidst the emergence of resistance to echinocandins.
The choice of antifungal therapy for candidemia must consider various factors, as summarized in Table 6.
35,65
Optimal IC management still affords many challenges, including the high cost of treatment, fungal resistance to antifungal therapy, the timing of starting and stopping antifungal therapy, etc.
Critically ill patients in the ICU might suffer from severe sepsis and unstable hemodynamic conditions, the use of organ support devices including mechanical ventilation, renal replacement therapy(RRT), extracorporeal membrane oxygenation (ECMO), etc.
35,65
antifungal therapy may be considered in patients with septic shock, multi-organ failure, and Candida colonization in at least 2 extra-intestinal organs .
oderate recommendation, level i evidenc.
Prophylaxis with fluconazole is recommended for very low birth weight infants admitted to units with a high incidence of IC .
trong recommendation, level II evidenc.
If there are cases of C.
auris in the hematology/ oncology or ICU population, infection control and prevention are necessary, including isolation, screening of close contacts, and environmental cleaning .
oderate recommendation, level i evidenc.
CONCLUSION
The expert panel has developed and approved national guidelines on diagnosing and managing invasive candidiasis for medical professionals in Indonesia.
The guidelines should be implemented based on sufficient clinical and laboratory Local laboratories must be empowered and collaborate with reference laboratories to improve the quality of IC diagnostics.
Early diagnosis is very important for adequate management so that morbidity and mortality rates can be reduced.
Direct microscopic examination of sterile samples should be conducted, including histopathological examination and fungal culture from sterile sites as the gold standard for IC The choice of antifungal treatment is performed by considering clinical condition, previous exposure to antifungal, risk of fungal colonization, local epidemiology, infection sites, organ dysfunction, accompanying therapy, and the need for therapeutic drug monitoring (TDM).
ACKNOWLEDGMENTS
The expert panel would like to thank all colleagues who has supported this joint activity, from the initial step to completion, including heads of medical professional organizations, research assistants, and all related partners.
Recommendation CONFLICTS OF INTEREST The authors declare that there are no conflicts of interest relevant to the content of the article.
Prophylactic and pre-emptive therapy is not recommended for ICU patients.
Empirical Anna Rozaliyani CONTRIBUTORS All authors contributed to the design and interpretation of the data and to further drafts.
REFERENCES