Clinical Implication of Candida Score in Multidrug-Resistant Pneumonia with Airway Candida Colonization.

BACKGROUND: The growth of Candida in respiratory secretions is usually considered colonization, and antifungal therapy is rarely required. The role of Candida colonization in the progression of bacterial pneumonia remains controversial. The aim of this study was to identify the clinical implication of Candida score by analyzinge the relationship with multidrug-resistant (MDR) pneumonia and prognosis in patients with airway Candida colonization.
MATERIALS AND METHODS: This study was a retrospective review of patients with airway Candida colonization by bronchial washing or bronchoalveolar lavage. The Candida score was calculated according to the four factors (severe sepsis, surgery at baseline, total parenteral nutrition, and multifocal Candida colonization). Pneumonia related mortality or hopeless discharge expecting death was defined as a poor outcome.
RESULTS: A total of 148 patients were enrolled in the study. In a multivariate analysis model, Candida score was identified as an independent predictor of poor outcomes (odds ratio 2.23; 95% confidential interval 1.57 - 3.17; P <0.001) in pneumonia patients with airway Candida colonization. With a Candida score of three or higher compared with low score group, it was associated with bacterial pneumonia, especially methicillin-resistant Staphylococcus aureus (MRSA) infection (0.0% vs. 15.2%, P = 0.004). In addition, patients with a high Candida score had a longer hospital stay (13 vs. 38 days, P <0.001), longer duration of intensive care (7 vs. 18 days, P <0.001), and higher pneumonia-related mortality (0.0% vs. 45.5%, P <0.001) as compared to the low Candida score group. The Candida score showed a positive correlation with other pneumonia severity scales such as CURB-65 (Confusion, Urea, Respiratory rate, Blood pressure, and age ≥65 years) (r = 0.461, P <0.001), Pneumonia Severity Index (r = 0.397, P <0.001), and predisposition, insult, response, and organ dysfunction (PIRO) score (r = 0.425, P <0.001).
CONCLUSION: This study revealed that Candida is no longer a bystander of airway colonization, and that it affects the progression of bacterial pneumonia, including multidrug-resistant pathogens, particularly MRSA infection. Also Candida score can be used to predict the prognosis of patients with pneumonia.

Introduction

Ventilator-associated pneumonia (VAP) is a serious complication of mechanical ventilation (MV) with high morbidity [12]. Despite intensive efforts to control known risk factors of VAP, such as semi-recumbent position, stress ulcer prophylaxis, empirical antimicrobial therapy, and early weaning attempts from ventilation, these infections are frequently accompanied by high mortality rates, long-term hospitalization, and increased medical costs [3]. As most causes of VAP are bacterial species, the role of fungal pathogens in immune-competent hosts is unclear [4]. Isolation of Candida species in bronchial washing or lavage samples is not unusual for patients in the intensive care unit. Candida is found in approximately 30% of patients with MV care for more than 48 hours and is found in more than 40% of critically ill patients with MV care [5], although progression to Candida-associated fungal pneumonia is rare [67]. Thus, the growth of Candida in respiratory secretions is usually considered colonization, and antifungal therapy is rarely required. Some data show that there is no clinical correlation between VAP and airway colonization with Candida species, suggesting that Candida colonization does not affect the progression of bacterial pneumonia [89].

However, according to recent studies, Candida may no longer be considered a bystander in the airways [10]. Candida colony formation affects bacterial pneumonia, and there are reports that it is particularly associated with VAP caused by multi-drug resistant (MDR) Pseudomonas aeruginosa or Acinetobacter baumannii [111213]. In a rat model with Candida albicans airway colonization, researchers observed the promotion of bacterial pneumonia, via elicited helper T cell immune responses and then inhibition of bacterial phagocytosis by alveolar macrophages [14].

When Candida infection is suspected, fungal cultures for diagnosis take considerable time, and clinicians struggle to decide about when to start the administration of antifungal agents to prevent or treat fungal infections. As mortality increases when prompt treatment is delayed, clinical prediction models have been developed. These prediction tools include the Candida colonization index and Candida score [15], which have been used to predict the prognosis of Candida infection in patients with Candida colonization.

We aimed to analyze whether these scales can help predict the progress of bacterial pneumonia, especially pneumonia associated with MDR pathogens. Therefore, the clinical implication of Candida score was identified by analyzinge the relationship with MDR pneumonia and prognosis in patients with airway Candida colonization.

Materials and methods

1. Study design and population

This study is a retrospective review of patients with airway Candida colonization at the Gangnam Severance Hospital, a tertiary center in Seoul, Korea, from January 2007 to April 2020. During this period, clinical data from the patients with Candida species isolated by bronchial washing or bronchoalveolar lavage were obtained. Patients with invasive candidiasis such as candidemia or esophageal candidiasis were excluded from this study.

2. Ethics statement

The protocol for this retrospective study was reviewed and approved by the Institutional Review Board of Gangnam Severance Hospital, Yonsei University College of Medicine in Seoul, Republic of Korea (Reg. No. 3-2020-0482). The board waived the requirement for informed consent. The study was conducted according to the guidelines of the Declaration of Helsinki.

3. Clinical variables and definition

Clinical information was reviewed retrospectively for demographic features, including age, sex, and comorbidities. The definition of pneumonia was determined according to the American Thoracic Society/Infectious Diseases Society of America guidelines. Three types of pneumonia were stratified, community-acquired pneumonia (CAP) is defined as pneumonia that develops in the community. In turn, hospital-acquired pneumonia (HAP) is pneumonia that occurs 48 hours or more after admission in a hospital setting and is not incubating at the time of hospital admission. The VAP is defined as pneumonia after 48 hours of endotracheal intubation and ventilator care [1617]. The distinction between favorable and poor outcome was determined according to the patients’ condition at the time of hospital discharge. If the patient died or was transferred to a long-term care facility and the prognosis was expected to death, the outcome was classified as poor outcome.

The Candida score and index were assessed based on the initial Candida isolation status. Colonization was defined as the presence of Candida species in non-sterile body parts or body fluids [18]. Bronchoscopy was performed in the early stages of pneumonia, and bronchoalveolar lavage and washing culture were carried out at the same time. Patients with airway Candida colonization were those with Candida species incubated in the respiratory tract determined via bronchoscopy, including bronchoalveolar lavage or bronchial washing culture. The Candida score was calculated cross-sectionally based on the time point at which bronchoscopy was conducted. The Candida colonization index is defined as the ratio of the number of Candida species cultured in body sites other than blood to the total number of cultured body sites [19]. The Candida score was calculated according to the presence of four components (range, 0 - 5 points): severe sepsis (2 points), surgery at baseline (1 point), total parenteral nutrition (TPN) (1 point), and multifocal Candida colonization (1 point). In the other previous studies, if the cutoff score was three or higher, there was a high risk of developing candidiasis, with a sensitivity of 61.0% and a specificity of 86.0%. Therefore, we divided patients into two groups, a high-grade Candida score group with a range of three to five points and a low-grade Candida score group with a range of zero through two points [1520].

Pneumonia severity scales such as CURB-65 (Confusion, Urea, Respiratory rate, Blood pressure, and age ≥65 years) [21], Pneumonia Severity Index (PSI) [22], and predisposition, insult, response, and organ dysfunction (PIRO) score [232425] were also calculated concurrently when assessing Candida score. The components of PSI were sex, cormobidities, vital signs, mental status, arterial blood gas analysis, and so on. The parameters of the PIRO score are predisposition (chronic illness, age, comorbidities), insult (injury, bacteremia, endotoxin), response (neutropenia, hypoxemia, hypotension), and organ dysfunction. Other clinical data- causative pathogen of pneumonia, antimicrobial susceptibility test, use of antifungal agent for Candida species, duration of hospitalization, and duration of intensive care unit (ICU) care were extracted.

Categories of Gram-positive and Gram-negative strains were determined by Gram staining. Antimicrobial susceptibility tests were confirmed according to the breakpoint of Clinical and Laboratory Standards Institute-guidelines [26]. We identified whether carbapenemase-producing Enterobacteriaceae (CPE), MDR A. baumannii (MRAB), MDR P. aeruginosa (MRPA), and methicillin-resistant Staphylococcus aureus (MRSA) were isolated from airway specimens. The identified strains were bacterial pathogens clinically considered to be the causative pathogen of pneumonia, and only strains grown in class IV (10 - 25 epithelial cells and >25 leukocytes per field) or V (≤10 epithelial cells and >25 leukocytes per field) of the Murray-Washington grouping system, and bronchoalveolar lavage or bronchial washing culture were included.

The data of using anti fungal agents were extracted, and since invasive candidiasis was excluded in this study, the use of antifungal agents was not used as definite therapy for fungal diseases. The criteria for use of antifungal drugs depended on the judgment of physicians, considering the patient’s medical history and rapid deterioration during treatment. These conditions include neutropenia, long-term ventilator treatment, and Candida growth at multiple sites, while high-risk patients in the ICU setting used fluconazole to prevent invasive candidiasis [1827]. All data were collected until death or patient discharge.

4. Statistical analysis

Categorical variables were compared using the Chi-square test or Fisher’s exact test and expressed as number (percent). Continuous variables were expressed as median with interquartile range (IQR). Continuous variables between two groups were compared using the non-parametric Mann–Whitney U test. Significant clinical variables in primary analysis (P-value ≤0.05) were reviewed by multivariate logistic regression. Clinical correlation among other scales such as CURB-65, PSI, PIRO and Candida score was evaluated by spearman correlation analysis. All two-tailed P-values or adjusted P-values of ≤0.05 were considered statistically significant. All statistical analyses were performed using SPSS V23 software (IBM Corp., Armonk, NY, USA).

Results

1. Candida species distribution in patients with airway Candida colonization

From January 2007 to April 2020, clinical data from 176 patients with Candida species isolated by bronchial washing or bronchoalveolar lavage were retrieved. Among them, only 163 patients were adults, six patients were excluded due to invasive candidiasis with candidemia, and nine patients were excluded because of insufficient clinical data. Finally, a total of 148 patients with Candida colonization in the respiratory tract confirmed by bronchoscopy were included in this study (Fig. 1).

Figure 1

Flow chart of study population.

BAL, broncho-alveolar lavage.

Of the 148 pneumonia patients who showed Candida colonies in the results of bronchoscopy, 91 patients eventually had favorable progression and 57 colonizers progressed to poor results. According to the distribution of Candida species, C. albicans was the predominant species (64.8% in the favorable outcome group and 57.9% in the poor outcome group), and C. tropicalis (14.3% and 14.0%, respectively) was the second most common pathogen, followed by C. glabrata (3.3% and 3.5%, respectively), in airway colonization between the two groups (Fig. 2).

Figure 2

Distribution of Candida species isolated from bronchial washing and bronchoalveolar lavage. (A) Favorable outcome group, (B) Poor outcome group.

2. Predictive factor of poor outcome in patients with airway Candida colonization

Comorbidity with hypertension (42.9% vs. 63.2%, P = 0.016), diabetes (26.4% vs. 42.1%, P = 0.047), and autoimmune disease (3.3% vs. 14.0%, P = 0.023) were significant risk factors for poor prognosis as compared to favorable prognosis. Immunocompromised factors such as end-stage renal disease with regular hemodialysis, lung cancer, and use of steroids (prednisolone ≥20 mg/day more than 2 weeks) did not affect the disease outcome of the airway Candida colonizer. There were no cases of solid organ transplant or hematopoietic stem cell transplant recipients among the subjects in this study. The median Candida score was higher in the poor outcome group than in the favorable outcome group (2.0 vs. 4.0 days, respectively, P <0.001), while the median Candida index showed no specific differences between the two groups (Table 1). Anaysis in each respective factor of Candida score, sepsis (48.3% vs. 96.5%, P <0.001) and TPN (50.5% vs. 100.0%, P <0.001) showed significant differences between favorable and poor groups. Other prognostic scales for pneumonia, CURB-65 (1.0 vs. 2.0 points, P <0.001), PSI (110.0 vs. 136.0 points, P <0.001), and PIRO (2.0 vs. 4.0 points, P <0.001), also demonstrated similar trend. The clinical variables that were significant in the primary analysis were reviewed in the multivariate analysis (Table 2). CURB-65, PSI or PIRO score were also significant variables, but they are excluded in multivariate analysis due to the multicollinearity. Finally, the Candida score was identified as an independent predictor of poor outcomes (odds ratio [OR], 2.23; 95% confidential Interval [CI], 1.57–3.17; P <0.001).

Table 1

Baseline characteristics of pneumonia patients with airway Candida colonization

Variables		Favorable outcome (n = 91)	Poor outcome (n = 57)	P-value
Age, years		70.0 [60.0 - 78.0]	74.0 [65.0 - 82.0]	0.098b
Sex, male		66 (72.5)	40 (70.2)	0.757c
Comorbidity
	Hypertension	39 (42.9)	36 (63.2)	0.016c
	Diabetes	24 (26.4)	24 (42.1)	0.047c
	Pulmonary tuberculosis	17 (18.7)	12 (21.1)	0.724c
	Hepatitis	1 (1.1)	2 (3.5)	0.559d
	CVA	10 (11.0)	2 (3.5)	0.130d
	ESRD on HD	9 (9.9)	3 (5.3)	0.372d
	COPD	5 (5.5)	6 (10.5)	0.337d
	Lung cancer	8 (8.8)	11 (19.3)	0.063c
	ILD	2 (2.2)	5 (8.8)	0.108d
	Autoimmune disease	3 (3.3)	8 (14.0)	0.023d
Steroid usea		12 (13.2)	6 (10.5)	0.630c
Candida score, points		2.0 [1.0 - 4.0]	4.0 [3.0 - 4.0]	<0.001b
	Sepsis, n (%)	44 (48.3)	55 (96.5)	<0.001c
	TPN, n (%)	46 (50.5)	57 (100)	<0.001c
	Surgery at baseline, n (%)	12 (13.1)	6 (10.5)	0.629c
	Multifocal Candida colonization, n (%)	59 (64.8)	42 (73.7)	0.260c
Candida index		0.5 [0.3 - 0.5]	0.5 [0.5 - 0.5]	0.115b
CURB-65, points		1.0 [1.0 - 2.0]	2.0 [2.0 - 3.0]	<0.001b
Pneumonia Severity Index, points		110.0 [88.0 - 133.0]	136.0 [108.5 - 164.5]	<0.001b
Pneumonia Severity Index, category				<0.001d
	I (<50 points)	2 (2.2)	0 (0)
	II (51 - 70 points)	10 (11.0)	0 (0)
	III (71 - 90 points)	12 (13.1)	4 (7.0)
	IV (91 - 130 points)	43 (47.3)	17 (29.8)
	V (131 - 395 points)	24 (26.4)	36 (63.2)
PIRO score, points		2.0 [2.0 - 4.0]	4.0 [3.0 - 5.0]	<0.001b

Data are expressed by number (%) and median [25% - 75% IQR].

aUse of prednisolone ≥ 20 mg/day more than 2 weeks.

bMann-Whitney U test.

cPearson’s chi-squared test.

dFisher’s exact test.

COPD, chronic obstructive pulmonary disease; CURB-65, confusion, urea, respiratory rate, blood pressure, age ≥65 years; CVA, cerebrovascular accident; ESRD, end-stage renal disease; HD, hemodialysis; ILD, interstitial lung disease; PIRO, predisposition, insult, response, and organ dysfunction; TPN, total parenteral nutrition.

Table 2

Prognostic factors for poor outcomes among pneumonia patients with airway Candida colonization using multivariate logistic regression

Variables	OR	95% CI	P-value
Hypertension	1.26	0.57 - 2.79	0.577
Diabetes	1.39	0.62 - 3.10	0.425
Autoimmune diseases	2.45	0.59 - 10.13	0.217
Candida score	2.23	1.57 - 3.17	<0.001

OR, odds ratio; CI, confidence interval.

3. Clinical implication of Candida score with cut-off value above three points

When the Candida score was divided into two different levels (high grade, 3 - 5 points; and low grade, 0 - 2 points), high Candida scores ≥3 was significantly correlated with bacterial identification (32.7% in the low Candida score group vs. 65.7% in the high Candida score group, P <0.001), especially with MDR pathogens (14.3% vs. 39.4%, P = 0.002) compared with low Candida scores. There were no clinical differences in age, sex, and types of pneumonia, such as CAP, HAP, and VAP, between the two groups. Among isolated MDR bacterial pathogens, MDR Gram-positive cocci were significantly dominant in the group with a high Candida score (0.0% vs. 17.2%, P = 0.002) as compared to the low Candida score group. In particular, MRSA was the dominant pathogen in the high Candida score group as compared to the low Candida score group (0.0% vs. 15.2%, P = 0.004), whereas MDR Gram-negative rods, including CPE, MRAB, and MRPA, showed no significant differences between the two groups.

Despite frequent use of antifungal agents such as fluconazole in the high Candida score group (14.3% vs. 34.3%, P = 0.010), the median length of hospitalization (13 vs. 38 days, P <0.001), duration of ICU stay (7 vs. 18 days, P <0.001), all-cause mortality (12.2% vs. 48.4%, P <0.001), pneumonia-related mortality (0.0% vs. 45.5%, P <0.001), and duration from admission until airway Candida colonization (6.0 vs. 7.5 days, P <0.001) were significantly higher in the high Candida score group than the low Candida score group (Table 3). The Candida score showed a positive correlation with other pneumonia severity scales such as CURB-65 (r = 0.461, 95% CI [0.333 - 0.582], P <0.001), PSI (r = 0.397 [0.251 - 0.525], P <0.001), and PIRO score (r = 0.425 [0.289 - 0.553], P <0.001) (Table 4).

Table 3

Clinical implication of Candida score among pneumonia patients with airway Candida colonization

Variables		Low CS ≤2 (n = 49)	High CS ≥3 (n = 99)	P-value
Age, years		70.0 [63.5 - 79.5]	72.0 [62.0 - 80.0]	0.721b
Sex, male		15 (30.6)	27 (27.3)	0.672c
Type of pneumonia				0.145c
	CAP	32 (65.3)	55 (55.6)
	HAP	16 (32.7)	33 (33.3)
	VAP	1 (2.0)	11 (11.1)
Isolated bacteriaa, n (%)		16 (32.7)	65 (65.7)	<0.001c
Isolated MDR bacteria, n (%)		7 (14.3)	39 (39.4)	0.002c
	MDR-Gram negative rods	7 (14.3)	24 (24.2)	0.161c
	MDR-Gram positive cocci	0 (0)	17 (17.2)	0.002c
	CPE	3 (6.1)	5 (5.1)	>0.786c
	MRAB	3 (6.1)	13 (13.1)	0.196c
	MRPA	1 (2.0)	6 (6.1)	0.426d
	MRSA	0 (0)	15 (15.2)	0.004d
Use of fluconazole, n (%)		7 (14.3)	34 (34.3)	0.010c
All cause of mortality, n (%)		6 (12.2)	46 (48.4)	<0.001c
Pneumonia-related mortality, n (%)		0 (0.0)	45 (45.5)	<0.001c
Duration, days, n (%)
	Hospital stay	13.0 (9.3 - 28.0)	38.0 (18.5 - 53.0)	<0.001b
	ICU stay	7.0 (0.8 - 8.3)	18.0 (10.3 - 36.8)	<0.001b
	From admission until airway Candida colonization	6.0 (3.3 - 9.8)	7.5 (3.0 - 16.0)	<0.001b
	From mechanical ventilation until airway Candida colonization	2.5 (−4.8 - 7.5)	2.0 (0 - 6.8)	0.921b

Data are expressed by number (%) and median [25% - 75% IQR].

aIsolated bacteria within the respiratory tract.

bMann-Whitney U test.

cPearson’s chi-squared test.

dFisher’s exact test.

CS, Candida score; CAP, community-acquired pneumonia; CPE, carbapenemase-producing Enterobacteriaceae; HAP, hospital-acquired pneumonia; MDR, multidrug-resistant; MRAB, multidrug-resistant Acinetobacter baumannii; MRPA, multidrug-resistant Pseudomonas aeruginosa; MRSA, methicillin-resistant Staphylococcus aureus; VAP, ventilator-associated pneumonia.

Table 4

Correlation analysis using spearman model between the pneumonia severity scale and Candida score

Variables	Candida score r (95% CI)	P-value
CURB-65	0.461 (0.333 – 0.582)	<0.001
Pneumonia severity index	0.397 (0.251 – 0.525)	<0.001
PIRO score	0.425 (0.289 – 0.553)	<0.001

CI, Confidence interval; CURB-65, confusion, urea, respiratory rate, blood pressure, age ≥65 years; PIRO, predisposition, insult, response, and organ dysfunction.

Discussion

In this study, we found that underlying comorbidities such as hypertension, diabetes, autoimmune disease, and high mean Candida score could be a risk factor for poor outcomes in patients with bacterial pneumonia and airway Candida colonization. In particular, the Candida score was an independent predictor of disease progression, with an OR of 2.23 in multivariate logistic regression. Previous studies have reported an increased risk of poor prognosis or invasive candidiasis in patients with a Candida score of three or higher [1520], and it has been demonstrated that airway Candida colonization affects mortality and disease severity in immunocompromised patients [28]. However, in these data, end-stage renal diseases, lung cancer, and steroid therapy did not clearly impact the disease course. There were no cases of obvious immunocompromised patients such as solid organ transplant or hematopoietic stem cell transplant recipients. Therefore, the impact may be more severe in these population, and further analysis of this subgroup is needed. As already demonstrated in other studies, there was no effect of antifungal prophylaxis on disease outcome regardless of Candida score [927].

The proportion of bacteria thought to be the causative pathogen of pneumonia was also predominant in the high Candida score group and mostly included MDR pathogens (MRSA, CPE, MRPA, and MRAB). In particular, MRSA was found to be significantly dominant. Although controversial, Candida-colonized pneumonia is known to be associated with VAP, especially MRPA or MRAB. Previous studies showed that Candida colonization is mostly associated with Gram-negative pathogen identification. These studies showed that Candida colonization is no longer a bystander, and that it increases bacterial virulence and decreases bacterial clearance [29]. In our analysis, the proportion of causative bacteria of MRPA or MRAB was high but was not significant. Rather, it was interesting to note that it mostly included MRSA.

The actual mechanism of how Candida colonies lead to more serious consequences of bacterial pneumonia remains unclear. Several previous in vitro or in vivo studies have confirmed the interaction between Candida and bacteria. Mixed bacterial–fungal colonies are common in patients with pneumonia, especially those who have received ventilator care, forming a mixed biofilm. These colonies interact directly or indirectly and affect each other's survival or virulence. Physical interactions can attach bacteria to the surface of fungal hyphae, change the pH of the environment, and create metabolites or chemicals for polymicrobial coexistence [2930]. Microscopy and immunoassay demonstrated that S. aureus binds to fungal biofilm, and in this process, agglutin-like sequence 3 (Als3p) of C. albicans plays a key role in adherence to S. aureus [31]. In a mouse model study, C. albicans enhanced the virulence of S. aureus strains. A minimum dose of C. albicans between 1.1 × 105 and 1.1 × 107 colony-forming units was necessary for the amplification for virulence of S. aureus [32].

Biofilms inhibit the penetration rate of antibiotic agents and reduce the efficacy of antibiotics. S. aureus can be coated with Candida matrix within the polymicrobial biofilm, and S. aureus resistance to vancomycin was increased after being coated with the isolated Candida matrix [3334].

And when CURB-65, pneumonia severity index, and PIRO score were analyzed as variables, there was a significant difference according to the prognosis of pneumonia. In addition, a comparative analysis of the correlation between various pneumonia severity scales and Candida score was performed as shown in Table 4, it was confirmed that the Candida score had a positive correlation with them, so that it can be used to predict the prognosis of pneumonia patients. Analysis by component of Candida score showed that sepsis and TPN use were significant, suggesting that these major factors may effect poor prognosis.

This study has several limitations. First, this research was a retrospective review that relied on electronic medical records and was conducted in a single center. It is believed that biofilm formation leads to lower antibiotic penetration, causing to an increase antimicrobial resistance. Therefore, further prospective studies using clinical samples should be conducted to validate our hypothesis.Second, the exclusion of invasive candidiasis was not confirmed by histopathology. There were no cases of serious invasive candidiasis requiring lung biopsy, and there was no evidence of invasive fungal infection on chest computed tomography scan images. Patients with bacterial pneumonia and candidemia were excluded from the study. Lastly, MRSA is also a strain that can be colonized in VAP patients, and further analysis should be performed on more large scale subjects with airway Candida colonization comparing with control group. The point of this study is to predict infection with the MDR pathogen based on Candida and provide clinical evidence for preemptive response through early intervention. In addition, it does not raise the risk of all MDR pathogens, and in the case of MDR-Gram negative rods, the P-value was insignificant, and MRSA showed especially dominant findings. This results are thought to be a clinical verification of experimental data that has demonstrated interactions between Candida with MRSA in many previous studies.

In conclusion, the Candida score may be a predictive prognostic factor in patients with pneumonia and airway Candida colonization. A Candida score of three or higher can be a risk factor for poor outcomes due to longer hospitalization, prolonged ICU stays, and high mortality associated with pneumonia. The clinical implicaion of a high Candida score is associated with bacterial pathogens of pneumonia, especially MRSA. This study revealed that Candida is no longer a bystander of airway colonization, and that it affects the progression of bacterial pneumonia, including that caused by MDR pathogens.