Epidemiology and clinical outcome of common multi drug resistant gram negative bacterial infection in a network of hospitals in India (IMPRES): a multicenter, Intensive care unit-based, prospective clinical study.

Background:

Anti-biotic resistance(AMR) has emerged as leading public health threat and it is growing in alarmingrate. It has been estimated that in 2019, 1.2 million deaths were directlyattributed to AMR.1

India is leading consumer of antibiotics, and rateof antibiotic resistance is exponential.  The Indian Council of Medical Research (ICMR)through the Antimicrobial Resistance Research & Surveillance Network(AMRSN) studied 65561 culture positive isolates in the year 2020. The studyfound that Imipenem susceptibility of E. Coli is 72% and that of Klebsiellapneumoniae is only 45%. A. baumannii with reduced susceptibility of 10-20% wasobserved against cephalosporins, carbapenems, monobactams andβ-lactam-β-lactamase inhibitors. In Pseudomonas aeruginosa, the leastsusceptibility of 40% was observed for fluoroquinolones; and 60-70% tocephalosporins, carbapenems, and aminoglycosides.2 A largeprospective study conducted in 26 network hospital reported 2622health-care-associated bloodstream infections and 737 health-care associatedUTIs from 89 intensive care units (ICUs) between May 1, 2017, and Oct 31, 2018.Carbapenem resistance was common in Gram-negative infections, occurring in 72%of bloodstream infections and 76% of UTIs caused by Klebsiella spp, 77% ofbloodstream infections and 76% of UTIs caused by Acinetobacter spp, and 64% ofbloodstream  infections and 72% of UTIscaused by Pseudomonas spp.3

These large surveillancedata mainly look at the organism and its susceptibility but not at the clinicaloutcomes patients who are infected with these resistant pathogen.

Between Aug 1, 2014, andJune 30, 2015, PANORAMA recruited 297 patients’ blood stream infection from 16sites in ten lower and middle income countries. Carbapenem resistance wasassociated with an increased length of hospital stay, increased probability ofin-hospital mortality, and decreased probability of discharge alive. 57patients with carbapenam resistance from four Indian hospital were included inthe study.4

We did literature searchof PubMed database to find out  studiespublished in last ten years observing demography and clinical outcome patientinfected with multi drug resistant ESKAPE pathogen. Our literature search usingthe following keywords†((Demography) AND (antibiotic resistance) AND (clinicaloutcome)) AND (India) “resulted eight studies. (Supplements)  Out of those three studies observed fungalinfection and four assessed infection only pediatric age group.

So, a large good qualitymulti centric study of network hospital assessing impact of growing antibioticresistance is need of an hour.  A networkapproach to evaluate clinical impact of anti-microbial (AMR)   thatuses standardized  methodology  and case definition across participating  centers can provide high quality data,although is difficult to implement.

ICMR reported that Escherichia coli*,* Klebsiella pneumoniae, Acinetobacter baumannii,Pseudomonas aeruginosa, (PEAK organism) weremost common gram negative isolates and constituted 65.5% of total isolates.2 We choose to evaluatethe impact of resistance to these commonly isolated bacteria in India.

India has more than 90,000beds in different intensive care unit.5 Intensive Care Units are theepicenters of AMR because of immunosuppression of ICU patients, highernumber of invasive monitoring devices, mechanicalventilation, frequent use broad spectrum antibiotics etc.

So, the present study hasbeen designed to observe demography and clinical outcome of patients infected withfour common gram negative bacteria in network hospitals in India.

 Methods:

Technical working group: Atechnical working group i.e. ISCCM AMR Network comprising infectious diseasespecialist, microbiologist and intensivist will be set up. The working groupwill develop case definition of community acquired infection, hospital acquiredinfection, risk of MDR infection, pneumonia, abdominal infection, blood streaminfection, urinary tract infection, soft tissue infection, Muti drugresistance, extended drug resistance and Pan drug resistance etc. The groupwill also define standardize methods and criteria of pathogen identification,culture sensitivity, mechanism of bacterial resistance. (Supplements)

Participatingcenters:

Public or private hospitalhaving microbiological laboratory to do culture sensitivity will be invited toparticipate in the study. The centers should follow the case definitions andstandardized of pathogen identification, culture sensitivity, mechanism ofbacterial resistance adopted by ISCCM AMR Network group.

  Studydesign: Aprospective multi centric observational study

InclusionCriteria:

Patientswho are admitted in ICU

Patientswho are clinically diagnosed to have infection

Patientswho have positive report of identification of one these organism:   Escherichia coli*,* Klebsiella pneumoniae,Acinetobacter baumannii and Pseudomonas aeruginosa. (PEAK organism)

Data Collection and quality control:

All data will be collected by an investigator or a researchassistant using a uniform form or electronically.  Following data will be collected  patient’s age, sex, co morbidity, diagnosis,disease severity score (APACHE II), site of infection, whether communityacquired or hospital acquired infection, risk of  MDR pathogen, antibiotic use in previousthree months, empirical antibiotics, pathogen, antibiotics that the pathogen isresistant, antibiotics that the pathogen is sensitive, mechanism of  resistance, antibiotic therapy after culturereport, anti fungal therapy, duration of anti microbial therapy,  number of organ dysfunction if present, totalventilators days, total ICU stay and  28thday mortality. The data  (except totalICU stay) will be collected  till thetime   when the patient is discharged from ICU, diesor till 28 days  from the of admission.

Outcomes:

Primary outcome of the study will be:

1.      28 days mortality of patients who haveconfirmed infection with “PEAK†organism.

Secondary outcomes will be:

1.      Length of ICU stay

2.      Need of organ support

3.      Total ventilator days

4.      Various pathogen and theirresistance pattern.

Sample Size:

This study aims to recruit more than 1000 critically illpatients who have confirmed infection and positive pathogen identificationreport.  These sample sizes ofthe patients and ICUs will allow capturing the variation in related toorganism, antimicrobial therapy among ICUs. The recruitment will be for 3months at each center.  Sampling andselection bias due to over-representation of some centers may skew the results.To avoid this type of bias, we will limit the data collection to less than10% of total patients per center.

Statistical Analysis:

The data will be tested for normality by using Kolmogorov–Smirnov or the Shapiro–Wilk test.Categorical variables will be presented as frequencies and percentages, andcontinuous variables will be presented as the means with the SD or medians withthe IQR. Primary and secondary outcome will be compared between patients afterdividing according to pathogen antimicrobial sensitivity usingindependent t-test for normally distributed data, Mann Whiney U-test fornon-normally distributed data, and Chi square test or Fisher’s exact test, asappropriate, for categorical variables. Forparametric data student unpaired test with be used.  Correlation between the variables will betested using logistic regression analysis. Subgroup analysis of the primaryoutcome will be done  for examplepatients admitted Community acquired vs Hospital acquired ICU, Appropriate vsinappropriate antibiotic therapy before culture report, Carbapenam resistantvs  carbapenam sensitive, Collistin sensitivevs Collistin resistant and mechanism of resistance .

Role of the funding source

The funder of the study will have no role in study design, datacollection, data analysis, data interpretation, or writing of the report. Theprincipal investigator  will have fullaccess to the data and had final responsibility for the decision to submit forpublication.

 Ethics and dissemination:

This study will be conducted in accordance withthe principles of Helsinki Declaration and Good Clinical Practice.  This study will be reported according toguidelines of strengthening the Reporting ofObservational studies in Epidemiology.6 The study willbe commenced after taking institutional ethical committee clearance andregistration of protocol with clinical trial registry of India (CTRI). Allcenters who will participate in the study will also take approval from theirrespective ethic committee.   The need for informed consent willbe waived due to the observational nature of the study.

The results of the study will be disseminated to theparticipating hospitals, submitted to peer-reviewed journals for publicationand presented at scientific congresses.

      Reference

1.       Antimicrobial Resistance Collaborators. Global burden ofbacterial antimicrobial resistance in 2019: a systematic analysis. Lancet. 2022Feb 12;399:629-655

2.       Antimicrobial Resistance Research and Surveillance Network.Annual Report January 2020 to December 2020. Accessed on 1.10.2020 from[https://main.icmr.nic.in/sites/default/files/guidelines/AMRSN_annual_report_2020.pdf]

3.       Mathur P, Malpiedi P, Walia K, et al. Indian HealthcareAssociated Infection Surveillance Network collaborators. Health-care-associatedbloodstream and urinary tract infections in a network of hospitals in India: amulticentre, hospital-based, prospective surveillance study. Lancet GlobHealth. 2022 ;10:e1317-e1325.

4.       Stewardson AJ, Marimuthu K, Sengupta S, et al. Effect ofcarbapenem resistance on outcomes of bloodstream infection caused byEnterobacteriaceae in low-income and middle-income countries (PANORAMA): amultinational prospective cohort study. Lancet Infect Dis. 2019;19:601-610.

5.       Kapoor G, Hauck S, Sriram A, et al.State-wise estimates of current hospitals beds, Intensive care unit (ICU) bedsand ventilators in India: Are we prepared for a surge in COVID-19

hospitalization? medRxiv2020.06.16.20132787

6.      TheStrengthening the Reporting of Observational Studies in Epidemiology(STROBE)statement: guidelines for reporting observational studies. J ClinEpidemiol. 2008;61:344-9.