Poster #: 399 Address: Dr. Atul K.Patel, Infectious disease clinic, 3rd floor, ‘VEDANTA’, Navrangpura, Ahmedabad-380 009, INDIA. Email: atulpatel65@gmail.com Telefax: 91 79 2644 0816

Multi-centre observational study on epidemiology, treatment and outcome of Mucormycosis in India1,2 3 4 5 6 3 7 8 9 10 11 12 13 3Atul Patel, MD, FIDSA , Harsimran Kaur, MD , Immaculata Xess, MD , Joy S Michael, MD, , Jayanthi Savio, MD , Shivaprakash Rudramurthy, MD , Rakesh Singh, MD , Prakash Shastri, MD , Pamidimukkala Umabala, MD , Raman Sardana, MD , Anupma Kindo, MD , Malini R. Capoor, MD , Sangeetha Mohan, MD and Arunaloke Chakrabarti, MD, FIDSAFRCPath

1. Department of Infectious Diseases, Sterling hospital, Ahmedabad, India, 2. Department of Internal Medicine, University of South Florida, Tampa, FL, 3. Department of Microbiology, PGIMER, Chandigarh, India, 4. Department of Microbiology, All India Institute of Medical Sciences, New Delhi, India, 5. , 6. St. John's Medical College Hospital, , India, 7. Department of Microbiology, JIPMER, Pondicherry, India, Medical Dept of Microbiology, Christian Medical College, Vellore, India Benagaluru8. Intensive Care Medicine, Sir Gangaram Hospital, New Delhi, India, 9. Department of Microbiology, Nizam Institute of Medical Sciences, Hyderabad, India, 10. Department of Microbiology, Indraprastha Apollo Hospital, New Delhi, India, 11. Department of Microbiology, Chennai, India, 12. Department of Microbiology, Safdarjung Hospital, New Delhi, India, 13. Department of Microbiology, Christian Medical College, Ludhiana, India, Sri Ramachandra Medical College & RI,

Background

Mucormycosis is a life-threatening invasive fungal infection with high mortality

The rise in mucormycosis cases has been reported globally, but the rise in India is alarming especially in

uncontrolled diabetics

India needs a country specific guideline for mucormycosis management

Before going for it, we conducted this observational study to know how the clinicians manage the patients

and what was the outcome of such management

Methods

Study design: A single arm, multicenter prospective observational study Figure 1: Study sites

from April 2016 to September 2017 Study Sites are shown in figure 1

à 17 tertiary care centers were chosen on the basis of

1. At least managing 20 cases of mucormycosis every year

2. Willing to participate in the study

à Only 12 sites actively participated in the study

Study is registered at Clinical Trial Registry of India: Reg No.

CTRI/2016/02/006644

Primary objective was to describe treatment practice and outcome of

mucormycosis

Secondary objectives were to describe epidemiology & modes of diagnosis

Inclusion criteria:

à All consecutive patients regardless of age with a confirmed and probable

diagnosis mucormycosis through HPE & /or culture were enrolled in study

à In suspected cases on histopathology, molecular technique of extraction of DNA from tissue & sequencing

to identify the pathogen, used to confirm the diagnosiswas

Exclusion criteria: Any subject not fulfilling inclusion criteria was excluded

Primary outcome: Overall survival at 45 & 90 days

Clinical data including risk factors, investigations and treatment were collected in case report form (CRF)

All isolates and histopathological specimens were sent to Mycology Reference Laboratory at Chandigarh for

final identification (phenotypic and sequencing) and drug susceptibility testing

Statistical Methods

à The study data were analysed using SPSS 17.0 (SPSS Inc, Chicago, IL)

à The descriptive statistics is presented as frequencies, confidence interval, mean with standard deviation, median and interquartile range, as appropriate

à The categorical variables were compared by Pearson's chi square test or Fischer's exact test

à Student t test, ANOVA, Mann–Whitney or Kruskal–Wallis tests were performed for continuous data

à Logistic regression was performed for identifying factors predicting mortality

à Kaplan–Meier statistics [Log-Rank (Mantel-Cox)] was used for survival analysis

à Two tailed p values ≤0.05 were taken as significant

Results

465 cases were enrolled during the study period included in final analysis

9 cases were removed from final analysis as they did not inclusion criteriameet

Presented at ID WEEK 2018, San Francisco CA, October 3-7, 2018.

Treatment ModalitiesSurgical & medical treatmentSurgical treatment onlyMedical treatment onlyNo treatment

256 (56.9%)25 (5.4%)130 (27.9%)

Surgical treatmentRadical surgeryEndoscopic debridementRepeat surgery

17210539

Medical treatmentAmphotericin B

LiposomalConventionalLiposomal & conventional

PosaconazoleVoriconazoleFluconazole

382 (82%)2391271656 (12%)17 (3.6%)5 (1.1%)

Adjuvant therapyHyperberic oxgenDeferasiroxLuekocyte transfusionInterlukin

6711

Duration of Antifungal treatmentmean + SDmedian (range)

26.68 + 42.0515 (5-30.25)

Hospital stay in daysmean + SDmedian (range)

27.92 + 40.9616 (6-32)

OutcomeSurvivedDiedDAMA

224 (48.1%)130 (27.9%)112 (24%)

Table 1: Baseline demographic characteristics

Figure 2: Clinical presentations

Table 2: f risk factors: Diabetes, Characteristics oMalignancy & Transplant patients

Table 3: Treatment & Outcome

Figure 3: Modes of diagnosis (n=465) Microscopy: 406, Culture: 295; Histopathology (HPE): 343

Parameters n= (%)

DiabetesUncontrolled diabetesControlled diabetesDiabetic ketoacidosis

n=342279 (81.58%)55 (16.08%)50 (14.62%)

MalignanacyHematologic malignancy (HM)Solid organ malignancy (SOM)HM & SOM both

n=4134 (82. %)936 (14.63%)1 (2.44%)

TransplantHemopoietic stem cell transplantSolid Organ transplant

KidneyLiverKidney & liver bothHeart

n=366 (16.67%)30 (83.33%)24 (80.0%)4 (13.33%)1 (3.33%)1 (3.33%)

Kaplan-Meier curves showing parameters influencing outcomes, Comparison of the survival curve was performed by Log-rank (Mantel–Cox) test

*ITR: Itraconazole; ISV: Isavuconazole; CAS: Caspofungin

Parameters n=465 (%)

Age in yearsmean + SDmedian (range)

45.67 + 16.5248 (35-58)

SexMaleFemale

323 (69.53%)142 (30.47%)

Adult/PediatricAdultPediatric

438 (94.42%)27 (5.58%)

Risk FactorsNo Risk FactorsRisk Factor

DiabetesSteroidsMalignancyTransplantImmunosuppressantTraumaChemotherapyNeutropeniaMalnutritionHIVBurns Unsafe injection practice

54 (11.6%)411 (88.4%)342 (73.5%)55 (11.8%)41 (10.07%)36 (7.7%)34 (7.3%)32 (6.9 %)22 (4.7%)12 (2.6%)12 (2.6%)07 (1.5%)03 (0.6%)02 (0.4%)

Comorbidities*RenalCardiovascularPulmonaryHepaticNeurologic

n=17593 (53.14%)67 (38.28%)30 (17.14%)24 (13.71%)18 (10.28%)

Duration of symptoms in daysmean + SDmedian (range)

24 + 38.2712.50 (7-30)

Source of mucormycosisCommunity acquiredNosocomial

433 (6.9%)32 (93.1%)

Time to diagnosis in daysmean + SDmedian (range)

5.1 + 9.761 (1-

*Patients had multiple co-morbidities

(37.6%)

1a. Patients who received both medical and surgical therapy (1) had significantly better survival than those who either received medical or surgical or no therapy (0) (p=0.001)

1b. Patients who received combination of AmB and posaconazole (1) had significantly better survival than those who received AmB alone (0) (p=0.017)

1c. Patients exhibiting any associated comorbidity (1) had significantly poor survival than those who did not have any comorbidity (0) (p=0.004)

1d. Patients with shorter duration of illness (7 or less days) (1) at presentation had a poorer survival as compare to those who had been symptomatic for a longer duration (> 7 days) (0) (p=0.003)

1e. No significant survival difference in patients with (1) or without (0) voriconazole prophylaxis (1e) (p=0.788)

Table 4: Antifungal treatment

Discussion

The study confirms uncontrolled diabetes is the most common risk factor for mucormycosis in India, in contrast 1,2,3,4to hematological malignancy or solid organ transplant patients of western world

Though diagnosis of pulmonary mucomycosis has improved compared to earlier publications, rhino-cerebral

type remains most common form of mucormycosis

are emerging species in IndiaRhizopus microsporus, and Rhizopus homothallicus

Isolated renal mucormycosis in a patient without risk factors is unique presentation of mucormycosis in this part 2,5of the world, also described in previous studies

2Mortality and left against medical advice (LAMA) are higher in current study and also previous study

Possible explanation for LAMA is cost involved in treatment and associated prognosis

Lesser duration of symptoms before presentation and presence of any comorbidity are predictors of mortality

Lesser duration of symptoms probably represents aggressive disease with angioinvasion

Summary

Uncontrolled Diabetes is the most important risk factor for mucormycosis in India

Medical therapy with surgical debridement and combination antifungal therapy (AmB with Posaconazole)

are associated with better survival

Providing treatment to all patients leaving hospital against medical advice can improve outcome of

mucormycosis and is a major challenge

.References

1.Chakrabarti A, Chatterjee SS, Das A, et al. Invasive zygomycosis in India: experience in a tertiary care hospital. Postgrad Med J. 2009;85:573-581.2. Patel AK, Patel KK, Patel K, Gohel S, Chakrabarti A. Mucormycosis at a tertiary care centre in Gujarat, India. Mycoses. 2017 Jun;60(6):407-411. 3. Chakrabarti A, Dhaliwal M. Epidemiology of mucormycosis in India. Curr Fungal Infect Rep. 2013;7:287-292.4. Petrikkos G, Skiada A, Drogari-Apiranthitou M. Epidemiology of mucormycosis in Europe. Clin Microbiol Infect. 2014;20(Suppl 6):67-73.5. Dhaliwal HS, Singh A, Sinha SK, et al. Diagnosed only if considered: isolated renal mucormycosis. Lancet. 2015;385:2322.

1a 1b

1c

1d 1e

p=0.003

Figure 4: Spectrum of agents causing mucormycosisCulture Positive n=295

Rhizopus Species

Results contd. Results contd.

Logistic regression model showed patients with any comorbidities (p=0.018), duration of symptoms (p=0.002), PNS involvement (p=0.024) and PNS with brain involvement (p=0.038) is associated with poor outcome, while admission in the ward (p=0.063), surgicalsurgery performed (p=0.040), antifungal duration (p=0.0001) has favorable outcome

Amphotericin B Itraconazole Posaconazole

Range

(µg/ml)

MIC 50

(µg/ml)

MIC90

(µg/ml)

Range

(µg/ml)

MIC 50

(µg/ml)

MIC90

(µg/ml)

Range

(µg/ml)

MIC 50

(µg/ml)

MIC90

(µg/ml)

Rhizopus arrhizus

(n=69)0.03-2 0.12 0.5 0.03-16 0.25 1 0.06-16 1 1

Rhizopus

homothallicus (n=8)0.03-0.25 0.12 0.25 0.06-0.5 0.5 0.5 0.06-1 1 1

Rhizopus

microspores (n=7)0.03-0.5 0.5 0.5 0.12-1 0.12 0.5 0.06-1 0.12 1

Rhizopus species

(n=3)0.03-0.12 - - 0.12-0.5 - - 1 - -

Apophysomyces

variabilis(n=6)0.03-0.25 0.12 0.12 0.06-0.5 0.12 0.5 0.5-1 1 1

Mucor spp (n=4)0.03-0.25 - - 0.06-0.5 - - 0.5-1 - -

Antifungal Susceptibility Data (n=100)

MIC50 & MIC90 were determined by selecting the median & 90th percentile respectively.MIC: Minimum Inhibitory Concentration

1c

9.89

Parameters n= (%)

Treatment ModalitiesSurgical & medical treatmentSurgical treatment onlyMedical treatment only

n=419264 (56.8%)25 (5.4%)130 (28%)

Surgical treatment*

Endoscopic debridementRadicle syrgeryRepeat surgery

n=276172 (62.1%)104 (37.9%)39 (14.1%)

Days of Antifungal treatmentmean + SDmedian (range)

26.68 + 42.0515 (5-30.25)

Hospital stay in daysmean + SDmedian (range)

27.92 + 40.9616 (6-32)

OutcomeSurvivedDiedLAMA

n=465223 (48%)130 (28%)112 (24%)

* Surgical treatment detail unavailable in 4 patients

# Antifungal not specified in 6 patients

Antifungal treatment# n= (%)

Amphotericin B (AmB)Lipid formulation Conventional Lipid formulation & conventional both

381 (72%)238 (63%)127 (33%)16 (4%)

Voriconazol (VCZ) 5 (1.27%)

Fluconazole (FLU) 1 (0.25%)

Combination AmB+ POSAmB + VCZAmB + ITR*AmB+ FLUAmB + CAS*AmB + POS + ISV* AmB + POS + VCZAmB + POS + FLUVCZ+CASAmB + Deferasirox

80 (17.2%)53 (66.25%)10 (12.5%)8 (10.0%)3 (3.75%)2 (2.50%)1 (1.25%)1 (1.25%)1 (1.25%)1 (1.25%)6