Background:

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

India is leading consumer of antibiotics, and rate of 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 study found that Imipenem susceptibility of E. Coli is 72% and that of Klebsiella pneumoniae is only 45%. A. baumannii with reduced susceptibility of 10-20% was observed against cephalosporins, carbapenems, monobactams and β-lactam-β-lactamase inhibitors. In Pseudomonas aeruginosa, the least susceptibility of 40% was observed for fluoroquinolones; and 60-70% to cephalosporins, carbapenems, and aminoglycosides.² A large prospective study conducted in 26 network hospital reported 2622 health-care-associated bloodstream infections and 737 health-care associated UTIs 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% of bloodstream infections and 76% of UTIs caused by Acinetobacter spp, and 64% of bloodstream  infections and 72% of UTIs caused by Pseudomonas spp.³   

These large surveillance data mainly look at the organism and its susceptibility but not at the clinical outcomes patients who are infected with these resistant pathogen.

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

We did literature search of PubMed database to find out  studies published in last ten years observing demography and clinical outcome patient infected with multi drug resistant ESKAPE pathogen. Our literature search using the following keywords” ((Demography) AND (antibiotic resistance) AND (clinical outcome)) AND (India) “resulted eight studies. (Supplements)  Out of those three studies observed fungal infection and four assessed infection only pediatric age group.  

So, a large good quality multi centric study of network hospital assessing impact of growing antibiotic resistance is need of an hour.  A network approach to evaluate clinical impact of anti-microbial (AMR)   that uses 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) were most common gram negative isolates and constituted 65.5% of total isolates.² We choose to evaluate the impact of resistance to these commonly  isolated bacteria in India.

India has more than 90,000 beds in different intensive care unit.⁵ Intensive Care Units are the epicenters of AMR because of immunosuppression of ICU patients, higher number of invasive monitoring devices, mechanical ventilation, frequent use broad spectrum antibiotics etc.

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

 Methods:

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

Participating centers:

Public or private hospital having microbiological laboratory to do culture sensitivity will be invited to participate in the study. The centers should follow the case definitions and standardized of pathogen identification, culture sensitivity, mechanism of bacterial resistance adopted by ISCCM AMR Network group.

Study design: A prospective multi centric observational study

Inclusion Criteria:

Patients who are admitted in ICU

Patients who are clinically diagnosed to have infection

Patients who 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 research assistant 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 community acquired or hospital acquired infection, risk of  MDR pathogen, antibiotic use in previous three months, empirical antibiotics, pathogen, antibiotics that the pathogen is resistant, antibiotics that the pathogen is sensitive, mechanism of  resistance, antibiotic therapy after culture report, anti fungal therapy, duration of anti microbial therapy,  number of organ dysfunction if present, total ventilators days, total ICU stay and  28^th day mortality. The data  (except total ICU stay) will be collected  till the time   when the patient is discharged from ICU, dies or till 28 days  from the of admission.

Outcomes:

Primary outcome of the study will be:

1.      28 days mortality of patients who have confirmed 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 their resistance pattern.

Sample Size:

This study aims to recruit more than 1000 critically ill patients who have confirmed infection and positive pathogen identification report.  These sample sizes of the patients and ICUs will allow capturing the variation in related to organism, antimicrobial therapy among ICUs. The recruitment will be for 3 months at each center.  Sampling and selection 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 than 10% 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, and continuous variables will be presented as the means with the SD or medians with the IQR. Primary and secondary outcome will be compared between patients after dividing according to pathogen antimicrobial sensitivity using independent t-test for normally distributed data, Mann Whiney U-test for non-normally distributed data, and Chi square test or Fisher’s exact test, as appropriate, for categorical variables. For parametric data student unpaired test with be used.  Correlation between the variables will be tested using logistic regression analysis. Subgroup analysis of the primary outcome will be done  for example patients admitted Community acquired vs Hospital acquired ICU, Appropriate vs inappropriate antibiotic therapy before culture report, Carbapenam resistant vs  carbapenam sensitive, Collistin sensitive vs Collistin resistant and mechanism of resistance .

Role of the funding source

The funder of the study will have no role in study design, data collection, data analysis, data interpretation, or writing of the report. The principal investigator  will have full access to the data and had final responsibility for the decision to submit for publication.

Ethics and dissemination:

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

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

                                                          Reference

1.       Antimicrobial Resistance Collaborators. Global burden of bacterial antimicrobial resistance in 2019: a systematic analysis. Lancet. 2022 Feb 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 Healthcare Associated Infection Surveillance Network collaborators. Health-care-associated bloodstream and urinary tract infections in a network of hospitals in India: a multicentre, hospital-based, prospective surveillance study. Lancet Glob Health. 2022 ;10:e1317-e1325.

4.       Stewardson AJ, Marimuthu K, Sengupta S, et al. Effect of carbapenem resistance on outcomes of bloodstream infection caused by Enterobacteriaceae in low-income and middle-income countries (PANORAMA): a multinational 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) beds and ventilators in India: Are we prepared for a surge in COVID-19

hospitalization? medRxiv 2020.06.16.20132787

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