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Tackling the invisible pandemic
before it becomes
the invincible pandemic
Prof. Ashok Rattan,
MD, MAMS,
Common Wealth Fellow, INSA DFG Fellow , ex SEARO Temporary Advisor,
ex WHO Lab Director (CAREC/PAHO)
Chairman Medical Committee & Quality, Redcliffe Labs
31st Dec 2019 WHO is informed regarding an outbreak of Pneumonia
caused by a novel Corona Virus in Wuhan
10 Jan 2020 one full sequence of this RNA virus is available in public
domain , 5 more next day
30 Jan 2020 WHO declares
Covid-19 outbreak a Public Health Emergency of International Concern
11 March 2020 WHO declares Covid 19 a PANDEMIC
Infected: 640 million cases; 6.6.million deaths
Chinese new year 25 Jan 2020
5 Feb : Italian residents hug Chinese
people to encourage them in corona
virus fight
Diagnosis is essential for control of any disease
Infected: 640 million cases; 6.6.million deaths
ICMR Ramps up Labs able to test for Covid-19
Jan 2020: 1 lab (NIV Pune)
September 2020: 2234 Labs doing RT PCR; Now 3020
Covid-19 A very visible Pandemic
took a great toll in life & economy
Addressing Antimicrobial Resistance
An invisible Pandemic
Before it becomes
The invincible pandemic
Consumption of systemic antibiotics in India in 2019
lancet.com Vol 4 Month September, 2022
Consumption of systemic antibiotics in India in 2019
lancet.com Vol 4 Month September, 2022
• The total DDDs consumed in 2019 was 5071
million (10.4 DDD/1000/day).
• Watch contributed 54.9% (2783 million) DDDs,
• Access contributed 27.0% (1370 million).
• Formulations listed in the NLEM contributed
49.0% (2486 million DDDs);
• FDCs contributed 34.0% (1722 million), and
• unapproved formulations contributed 47.1%
(2408 million DDDs).
• Watch antibiotics constituted 72.7% (1750
million DDDs) of unapproved products and
combinations discouraged by the WHO
constituted 48.7% (836 million DDDs) of FDCs.
I
N
D
I
A
Susceptible bacteria
Resistant bacteria
Current Crisis of MDR Infections
• Act of GOD (nature)
• Spread of resistant gene
from antibiotic producing
bacteria to pathogens
• Acquisition of resistance to
available drugs by
mutation
• Act of Man Kind
• Selection of resistant
mutants by use & over use
of antibiotics
• Spread of MDR strains
from one patient to
another by non application
of Infection Control
policies
Current use of antibiotics in USA
Unnecessary antimicrobial therapy
Consequences of antibiotic use
•Clinical cure
•Inhibition of non pathogenic bacteria
•Selection of resistant mutants
•Toxicity / side effects
Bacterial infections have frequently caused
pandemics in the past
Great plague of 1660s
Discovery & Development of
Anti-bacterials is one of the most
important discovery of the
20th Century
Power of antibiotics
Disease Pre Antibiotic era
deaths
Deaths with
antibiotics
Change in deaths due
to antibiotics
CAP (1) 35% 10% - 25%
HAP (2) 60% 30% - 30%
Heart Infection (3) 100% 25% - 75%
Brain Infections (4) > 80% < 20% - 60%
Skin Infection (5) 11% < 0.5% -10%
By comparison…. Treatment of heart attacks with aspirin or clot busting drugs (6) - 3%
Ref.: (1) IDSA Position Paper. Clin Infect Dis 2008; 47 (S3): S 249 – 65
(2) IDSA/ACCP/ATS/SCCM position paper. CID 2010; 51 (S1): 51 – 3
(3) Kerr AJ. SABE Lancet 1935; 226: 383 – 4
(4) Waring et al. Am J Med 1948; 5: 402 – 18
(5) Spellberg et al CID 2009; 49: 383 – 91
(6) Lancet 1998; 351 : 233 – 41.
1940 1950 1960 1970  2000 2002 2004 2006 2007 2008 2012 2022
Introductions of New Antibiotic Classes
Sulfas 1936
Penicillin 1940
Tetracycline 1949
Aminoglycosides 1950
Macrolides 1952
Glycopeptides 1958
Streptogramin 1962
Quinolones 1962
Oxazolidinone 2000
Daptomycin 2003
Tigecycline 2006
Telithromycin 2004
Doripenem 2007
Me too drugs
Different Generations
Ertapenem 2001
Ceftaroline 2010 Beta lactam +
Boronic beta lactam
inhibitors 2018
Before
Antibiotic
Era
After
Antibiotic
Era
We are overwhelmed as it is, with
an infinite abundance of vaunted
medicaments; and here they add a
new one…..
Thomas Sydenham, MD
(1624 - 1689)
“By the year 2000, nearly all experts
agree that bacterial and viral diseases
will have been virtually wiped out…”
The futurists: looking toward year 2000
(Time magazine, february 25, 1966)
US surgeon general William Stewart:
“The time has come to close the book on
infectious diseases” (1969)
Mankind has always had
the benefit of “good” advice
100
80
60
40
20
0
1980
1975 1985 1990 1995 2000
1997
VISA
VRE
PRSP
MRSA
MRSE
Percentage of
Pathogens
Resistant to
Antibiotics
Increasing Incidence of Resistance in the US
MRSE, MRSA, VRE, PRSP, GISA
1980-2006
VRSA
2006
Why Big Pharma has abandoned
Antibacterial drug discovery
We have a basic problem
Targets of existing antibiotics
New Antibacterial Targets identified & exploited from
Whole Genome sequencing of many Gram Negative Bacteria
Combitorial Chemistry & High Throughput screening
Understand
Disease & Identify
unmet needs
Select
Mechanism/
Target
Design
NCEs &
Screens
Virtual
Screening
Synthesize
NCEs
Convert
Lead-to-IND
Candidate
New Drug Discovery Road Map
Preclinical work-up
IND directed
regulatory studies
Convert
Hit-to-Lead
Screen/
Identify Hit
30000 compound synthesized
2000 enter preclinical development
200 enter Phase 1
40 enter Phase II
12 enter Phase III trials
8 are approved
1 makes satisfactory ROI
Years
0
2
3
5
10
12
NCE In vitro In vitro
Acute tox
DRUG
Insoluble
New Drug Discovery is like snakes and ladder
failure is the norm
Active
New Drug Discovery and Development
(Timelines)
DISCOVERY/SCREENING
SYNTHESIS
AND
PURIFICATION
ANIMAL
TESTING
PHASE II
PHASE I
SHORT-TERM
PHASE III
LONG-TERM
PHASE IV
ADVERSE
REACTION
SURVEILLANCE
PRODUCT DEFECT
REPORTING
PRE-CLINICAL
RESEARCH CLINICAL STUDIES NDA REVIEW POST-MARKETING
24 + 18 months. AVG: 5 YEARS AVG: 12 MOS.
IND NDA APPROVAL
Vancomycin
Borneo 1953 ; Edmund Kornfeld 1956
Streptomyces orientalis 05865
(Nocardia, Amycolatopsis)
Active against Gram Positive
No development of resistance even after many in vitro passages
Named Vancomycin after vanquish
FDA gave Fast Track Approval
Mississippi Mud by Eli Lilly scientists
(due to presence of impurities)
Not much used in 1960s due to Oto and Nephro toxicities
Mol Wt 1546
Antibiotic from Nature
Vancomycin &
Teicoplanin
Linezolid
Daptomycin
Ceftaroline
MRSA  VISA  VRSA
Since 2007 USA FDA approved the following drugs for MRSA treatment:
1. Delafloxacin; 2. Omadacycline; 3. Tedizolid;
4. Dalbavancin; 5. Oritavancin; 6. Televancin
Vancomycin &
Teicoplanin
Linezolid
Daptomycin
Tigecycline
&Ceftaroline
Gram +ve problem
Nailed down
Tigecycline
& Colistin
Gram –ve infections may leave us exposed
Since 2007 USA FDA approved the following drugs for MRSA treatment:
1. Delafloxacin; 2. Omadacycline; 3. Tedizolid;
4. Dalbavancin; 5. Oritavancin; 6. Televancin
Bad bugs, no drugs: No ESKAPE
CID 2009; 48: 1 - 12
• Enterococcus faecium
• Staphylococcus aureus
• Klebseilla pneumoniae
• Acinetobacter baumanii
• Pseudomonas aeruginosa
• Enterobacter species
Clostridium difficile & E. coli
Targeted Therapeutic Options
Regulatory Status
Extinction of MDR Bacteria is not an achievable Goal
• Bacteria have inhabited the Earth longer than humans and in far
greater number
• In our body, bacteria outnumber our cells 10 : 1
• Humans have capability of causing extinction of other species, mostly
unintentional (Dodo, ? Tiger)
• However, Extinction of MDR bacteria is not an achievable goal by
Man Kind
Need for Antimicrobial Stewardship
• Antimicrobial stewardship is a coordinated program that
promotes the appropriate use of antimicrobials (including
antibiotics), improves patient outcomes, reduces microbial
resistance, and decreases the spread of infections caused by
multidrug-resistant organisms.
• Objective are: Right drug for the right patients at the right dose
by the right route for the right duration
ESCMID generic competencies in antimicrobial prescribing and
stewardship
• Section 1: core concepts in microbiology, pathogenesis and diagnosing infections
• 1 Every independent prescriber must understand:
• 1.1 The nature and classification of microorganisms that commonly cause infections in humans
• 1.2 The common microbiological aetiology of human infections, and the ways in which
microorganisms are commonly acquired in community and hospital settings
• 1.3 The differences between colonization (e.g. isolation of bacteria from a venous leg ulcer with
no signs of inflammation) and infection
• 1.4 That an inflammatory response can be due to both infectious and non-infectious causes
(e.g. acute pancreatitis)
• 2 Every independent prescriber must know how to:
• 2.1 Take a thorough history and perform a physical examination to diagnose common infections
and to assess their severity
• 2.2 Use and interpret investigations that can help in informing diagnosis of an infection and in
monitoring the response to treatment (e.g. microbiological investigations, biomarkers, point-of-
care tests)
ESCMID generic competencies in antimicrobial prescribing and
stewardship
• Section 2: antimicrobial prescribing
• 1 Every independent prescriber must understand:
• 1.1 How and where to access relevant guidance on antimicrobial prescribing and stewardship
• 1.2 When not to prescribe antimicrobials (e.g. antibiotics for viral infections, or when there is bacterial colonization)
• 1.3 That best practices for some infections may not include antimicrobial treatment (e.g. incision and drainage of abscesses,
removal of foreign material)
• 2 Every independent prescriber must understand how to
• select the appropriate antimicrobial, using relevant guidance when possible, as well as the key elements of initiating
prescribing an antimicrobial: Obtaining relevant microbiological cultures or relevant tests before commencing treatment
• The timing of antimicrobial administration in different situations (e.g. as soon as possible for life-threatening infections, less
urgently for chronic bone infections)
• The choice and dose of agent, and the route of administration
• The duration of treatment, review dates and stop dates
• 3 Every independent prescriber must understand the key elements of continuing and rationalizing
antimicrobial therapy:
• Monitoring antimicrobial levels when indicated, and adjusting doses (e.g. for patients with renal impairment)
• Changing antibiotics according to microbiology results and clinical condition, ideally to a narrower spectrum (de-escalation),
or if needed to a broader spectrum (escalation)
• Reviewing antibiotic therapy at 48e72 hours and regularly thereafter in hospitalized patients, and in appropriate situations in
the community
• Switching antibiotics from intravenous to oral administration as soon as possible when indicated (according to guidelines)
• Stopping antimicrobials if there is no evidence of infection based on clinical findings and investigations (e.g. negative
microbial cultures, imaging reports)
ESCMID generic competencies in antimicrobial prescribing and
stewardship
• 4 Every independent prescriber must understand the need to document the important details of the
antimicrobial treatment plan (e.g. agent, dosing, administration route, clinical indication, duration and review
dates) in the prescription chart, medical records and transfer notes to other healthcare institutions
• 5 Every independent prescriber must understand:
• 5.1 That empirical treatment should be guided by local antimicrobial susceptibility patterns
• 5.2 The clinically relevant spectrum of activity for commonly prescribed antimicrobials
• 5.3 The basic principles of pharmacokinetics and pharmacodynamics
• 6 When prescribing an antimicrobial, every independent prescriber must know:
• 6.1 The antimicrobial class that the agent belongs to, and the contraindications to its use
• 6.2 The name and class of antimicrobial being prescribed, if prescribing by trade name
• 7 Every independent prescriber must understand single prophylactic dosing for surgical and other procedures
for which prophylaxis has been shown to be effective, and that additional prophylactic antimicrobial doses can
occasionally be needed (e.g. when the duration of the operation/procedure is prolonged)
• 8 Every independent prescriber must know:
• 8.1 Common antimicrobial and drug/food interactions
• 8.2 Common side-effects of antimicrobials, including allergy, how to monitor for them, and what to do when they are suspected
(e.g. documenting allergic reactions in patient records, reporting side-effects)
• 9 Every independent prescriber must understand any legal requirements for prescribing antimicrobials in their
country, and comply with these when prescribing
ESCMID generic competencies in antimicrobial prescribing and
stewardship
• Section 3: antimicrobial stewardship
• 1 Every independent prescriber must understand that:
• 1.1 Antimicrobials need to be used responsibly to prevent the emergence and spread of antimicrobial resistance
• 1.2 Optimizing antimicrobial use can limit the common side-effects and collateral damage related to treatment (e.g. their
disruptive effects on the normal host flora, which may lead to Clostridium difficile infection, super-infection with Candida
spp.)
• 1.3 It is important to avoid unnecessary uses of antimicrobials, especially those with a broad spectrum
• 1.4 Transmission of microorganisms in community and hospital settings can significantly amplify antimicrobial resistance
• 2 Every independent prescriber must understand local stewardship policies based on national (or
international where these do not exist) evidence-based guidelines
• 3 Every independent prescriber must understand and engage with any locally or nationally agreed quality
measures for assessing antimicrobial prescriptions (e.g. compliance with guidance, adverse events, reviews of
antibiotic therapy at 48e72 hours in hospitalized patients)
• 4 Every independent prescriber must know how to communicate with patients and their careers, nurses,
pharmacists and other healthcare professionals about:
• 4.1 When antimicrobials are not needed
• 4.2 Complying with the duration and frequency of administration of their prescribed antimicrobials
• 5 Every independent prescriber must recognize that it is a duty of care to co-operate with others more expert
than oneself, such as the antimicrobial stewardship team, when such expertise is needed
Nurses
Patient
ID
MS
Surgeons
NS
Micro
IPC
Pharma
Underutilization of Pharmacists & Nurses in AMS
Lack of Leadership, expertise & human resources
in AMS
Limited involvement of Surgeons in AMS teams
Lack of appreciation of its importance by
health administrators
Antibiotic Stewardship
• The right antibiotic
• For the right patient
• At the right dose
• And the right time
• By the right route
• For the right duration
• It is essential for patient safety and delivery of high quality care
Diagnostic Stewardship
Considerations when selecting a diagnostic tests
Diagnostics tests can help combat AMR
• 1. Rapid & definitive Diagnosis of bacterial infection which would help
reduce the overuse of antibiotics in clinical medicine
• 2. Screening for presence of resistant bacteria on admission and
during stay in the hospital subsequently to prevent spread of infection
in health care setting.
• 3. Diagnostic tests is the only way to gather data on resistant trends
and to be altered to outbreaks and to assess effectiveness of AMR
measures.
• 4. AMR surveillance data is needed for development of treatment
guidelines and AMR control strategies.
Antibiotic Use Bundle
• Before starting antibiotics, document (Initiation Bundle)
• 1. What is the evidence that this is a bacterial infection
• 2. Collect & submit appropriate cultures
• 3. Remove any foreign body or I & D any collection of pus
• 4. Select and Plan the antibiotic based on local antibiogram
• Which antibiotic (Empiric therapy)
• What dose
• Which route
• How frequently
Results of individual’s sample
Circulation of cumulative antibiogram
Microbiologists spend all their time doing half the necessary work
Antibiotic use decisions are made at two phases
Continuation Bundle
72 hours or so
• 1. Condition of the patient
• 2. Review microbiology results
• 3. Was an initial bundle documented
• 4. Consider step down from IV to oral
Does you lab only do the following ?
If Robert Koch
Was to visit your
Microbiology Lab
Would he have a
Feeling of
Deja vu ?
1843 - 1910
Is your laboratory up to the task ?
Are the results quality assured ?
Are the services available 24 x 7 ?
Aerobic bottles grow aerobic bacteria & Yeasts
Anaerobic bottles grow facultative bacteria
& anaerobic bacteria
Phoenix M 50
identification and susceptibility of isolates
Detection & Classification of Carbapenemase
NMIC / ID: 136 wells containing dried reagents, AST is determined using an optimized redox indicator
51 wells for ID & 85 wells for AST; panels only for ID & only AST are also available
CPO Detect : uses 9 wells with to 1. Detect presence of Carbapenemase & 2. Ambler classification A, B & D
Meropenem; Doripenem; Temocillin & Cloxacin both alone & in combination with chelators & various β lactamase
inhibitors
Development & widespread use of Gene Xpert (a.k.a. CBNAAT in India)
was a significant step towards improving the diagnosis of Tuberculosis &
detection of Rifampicin Resistance in the world
But has its widespread use led to increase in MDR TB ?
Initiation of Treatment based on CBNAAT
Fact or Assumption based ?
• 1. Fact: Rif S  Assumption INH also S
• But if IMR  for 4 months patient will receive
(INH Mono Resistant) only Rif mono treatment  MDR TB
• 2. Fact: Rif R  Assumption Treat as MDR TB
• But if INH Sensitive  Benefit of INH denied to patient
 Toxicity of MDR TB regimen  non-adherence
Evolution of Extensively Drug-Resistant Tuberculosis over Four Decades: Whole Genome
Sequencing and Dating Analysis of Mycobacterium tuberculosis Isolates from KwaZulu-Natal
Keira A. Cohen et al. PLOS Medicine | DOI:10.1371/journal.pmed.1001880 September 29, 2015
In resistant Mtb, INH
resistance was the initial
resistant mutation to be
acquired
editorial
• Mutations conferring resistance to INH occur before resistance to other
drugs and then goes on to develop MDR-TB
• INH Resistance predates Rifampicin resistance
• Phenotype of IMR is a precursor for MDR-TB and requires intensified
diagnosis and therapeutic intervention
• Detection of MDR-TB by Gene Xpert, may potentially lead to further
selection for IMR and emergence of MDR-TB
• Routine testing of Mtb for all relevant drugs shoulnot be regarded as costly
extra, but, rather, as critical steps for overall drug resistant TB control and
elimination
• Reviewed 19 cohort studies and 33 clinical trials involving
19012 DS-TB and 3744 IMR-TB patients
• Pooled rate of treatment failure or relapse or both was
• MDR TB  15%; IMR TB  4 % and DS-TB  0.6 %
• Of pts with initial IMR 96% became MDR-TB
• Treatment of IMR-TB with first line drugs :
• T/t failure 11%; Relapse 10% and MDR TB 8%
• DS TB 1% 5% 0.3%
• Conclusion: Treatment of IMR-TB with first line anti TB drugs resulted in
suboptimal outcomes and could contribute to development of MDR-TB
Treatment of isoniazid-resistant tuberculosis with first-line drugs: a systematic
review and meta-analysis Medea Gegia et al. Lancet Infect Dis 2017; 17: 223–34
TB Burden in India
India TB Report 2022
• Year 2021 witnessed a 19% increase from the
previous year in TB patients' notification
• The total number of incident TB patients (new
and relapse) notified (2021)- 19,33,381
• % of Drug Sensitive TB Patients ~ 86 %
• % Isoniazid monoresistance ~7%
• % MDR TB cases ~ 7.5%
2nd generation molecular tests
Moderate Complex Automated NAAT
• 1. Abbott Molecular test
• A. Detection of MTB
• B. Detection of MTB and INH & Rif Resistance
• 2. BD Max for MTB and INH & Rif Resistance
• 3. Bruker Hain Diagnostics
• A. Fluorotype MTB
• B. Fluorotype MTBDR for INH & Rif Resistance
• 4. Roche Diagnostics
• A. MTB
• B. MTB DR for INH & Rif Resistance
All these four WHO approved tests are high throughput
A POCT being reviewed by WHO & ICMR
SD Biosensor
Advantage
•All-in-one cartridge (NA extraction +
amplification)
•Simultaneous detection of M. tuberculosis
complex and INH & Rif Resistance
•Fast result in 77 minutes
•Simple sputum pretreatment process
•Room temperature storage
3. All patients with PTB should be treated with an
appropriate regimen as recommended by the WHO and/or
national guidelines (Standard 3)
• Each patient with diagnosis of drug-susceptible PTB should be treated with a regimen
recommended by WHO and national guidelines
• Adults:
6-month regimen (2HRZE/4HR)
4-month regimen (2HPZMfx/2PMfx) for children aged 12 years and adults
• Children:
6-month regimen (2HRZ(E)*/4HR), with higher R and H dosing
(see WHO-recommended dosages)
•
SHINE regimen (2HRZ(E)*/2HR) for age , 16 years with non-severe TB
(SHINE : Shorter treatment for Minimal Tuberculosis in children)
For optimum diagnosis of tuberculosis beyond MDR TB
OR
For optimum & rapid initial diagnosis of pre XDR & XDR TB
NGS
WRD = WHO Recommended Diagnostic Tests ; DST = Drug Susceptibility Testing
For follow up of already diagnosed TB cases
It is now possible to
initiate the appropriate anti TB treatment at
the first patient contact thus benefiting the
patient in getting early relief
and benefiting the society by decreasing
transmission of infection after one test.
1882 2022
1882 2022
Circulation of cumulative antibiogram
Microbiologists must influence antibiotic selection in Empirical phase
Cumulative Antibiogram (CLSI 39 A)
• Analyze and present CASR at least annually
• Include only final, verified results Include only species with results for 30 isolates
• Include only diagnostic (not surveillance) isolates
• Eliminate duplicate isolates by including only first species’ isolate/patient/period of
analysis
• Include only routinely tested agents
• Report % S and exclude % I
• For Streptococcus pneumoniae, report data for both meningitis and non meningitis
breakpoints
• For viridans group streptococci, report both % S and % I
• For S. aureus, report % S for all isolates and MRSA subset
Essential, achievable, and aspirational antimicrobial stewardship activities for the
microbiology laboratory
Must provide round the clock service
• Provide timely, reliable, and reproducible identification and antimicrobial
susceptibility results
• Actively participate in antimicrobial stewardship committee or work group
• Collaborate in educating local health care workers on microbiology issues that
impact treatment and microbial resistance
• Promptly report unusual patterns of resistance, test supplementary agents, and
provide advice on therapy for patients awaiting results
• Optimize communication of critical test result values and alert systems
• Provide, revise, and publicize annual CASR consistent with CLSI standards
• Provide guidance for adequate collection of microbiology specimens
• Develop alert systems for specific multidrug-resistant organisms
• Use cascade or selective reporting
• Collaborate with ID physicians and pharmacists on updating methods for
susceptibility testing
Linking Diagnostics to Antibiotic Stewardship
Right test for the right patient at the right time
Is it a bacterial
infection ?
What is the
cause ?
Overuse of antibiotics in Respiratory Tract Infections
Levin M et al CMI 2018; 24: 1158
Is it Bacterial or Viral Infection ?
What is Procalcitonin (PCT) ?
Schuetz P et al. BMJ Medicine 2011; 9: 107
• 116 amino acid precursor of calcitonin produced by Thyroid C cells &
Neuroendocrine cells of the lungs
• Calcitonin is involved in calcium homostasis, while procalcitonin is not
• Many other cells can produce PCT after specific stimulation but lack
enzyme to convert PCT  calcitonin
• Excessive production of PCT by many cells  rapid increase in blood
levels
PCT in Bacterial Infection
Linscheid P et al. Endocrinology 2003; 144; 5578
1. Bacterial Infection (LPS) stimulates production of PCT from many somatic cells
2. These cells lack the enzymes to cleave PCT  calcitonin
3. PCT produced by these cells is rapidly released into blood stream
4. Cytokines produced during viral infection inhibit PCT production
Kinetics of PCT makes it a better biomarker of
bacterial infection
Simon J et al. Clin Infect Dis 2004; 19: 206
Serial measurement of PCT every 24 hours
Guidelines for Initiating antibiotics
PCT value (ng/mL)
PCT in ng/mL < 0.25 0.25 – 0.50 0.5 -- < 1 > 1
Antibiotic
initiation
Strongly
discouraged
Discouraged Encouraged Strongly
Encouraged
Guidelines for Stopping, continuing or
changing antibiotics
PCT value (ng/mL)
PCT in ng/mL < 0.25 > 0.25 – <0.50
Or
Decline of
>80% of peak
value
> 0.5
Or
Decline < 80%
of peak value
> 0.5
Or
Increase above
PCT Value
Antibiotic continuing
Strongly
discouraged
continuing
Discouraged
continuing
Encouraged
Changing or
Strongly
Encouraged
Economic evaluation of procalcitonin-guided antibiotic
therapy in acute respiratory infections: a US health system
perspective Schuetz P et al Clin Chem Lab Med 2015; 53(4): 583–592
Unfortunately & Paradoxically this test
is NOT USED in India
Reason cited by some is
1. PCT is Too Costly
2. It is a sent out test & not POCT
POCT Procalcitonin
Quantitative
Iquant analyser by J Mitra SD Biosensor F 200 Manesar
Minividas Wondfo Finecare
Procalcitonin
> 0.5 ng/ml < 0.25 ng/ml
Multicentre evaluation of two multiplex PCR platforms for the rapid
microbiological investigation of nosocomial pneumonia in UK ICUs: the INHALE
WP1 study Enne VE et al Thorax 2021
Syndromic Testing: One sample, multiple results
Pathogen-specific performance of RM and multiplex PCR tests
Conclusions: Film Array Pneumonia Panel (FA-PP) is a simple and rapid molecular test that could complement routine
conventional methods for improvement of diagnosis accuracy of pneumonia. Nabil Gastli et al
90.1% of detected bacteria with 106 DNA copies/mL grew significantly in culture
Fast multiplex bacterial PCR of bronchoalveolar lavage for antibiotic stewardship in
hospitalised patients with pneumonia at risk of Gram-negative bacterial infection
(Flagship II): a multicentre, randomised controlled trial Dhare et al. Lancet Resp Med 2022; Sept
• 208 patients were randomized to PCR group (n=100) and conventional
microbiology (n=108); followed up after 30 days
• Duration of inappropriate antibiotic treatment was significantly shorter by 38.6
hours in PCR group (47.1 vs 85.7 hours)
• Which translates into a decrease in duration of inappropriate antibiotics by 45%
A multiplex bacterial
PCR detects more
bacteria in BAL fluid
than conventional
diagnostic methods;
however, without a
specific antibiotic
stewardship approach,
PCR results do not
influence clinical
outcomes
63% of cases of AMR infections are associated with
health care = 72 % of AMR attributable deaths
Four bacteria mostly acquired in health care are
estimated to cause 68% of burden of antibiotic
resistance (disability and premature mortality)
www.thelancet.com/lancetgh Vol 9 August 2021
Tackling the invisible pandemic
Factors influencing race against
AMR
Tackling the invincible pandemic ?
National
Policy
Vaccination
Awareness
in Public
Surveillance
&
Monitoring
Global Fund
Infrastructure
Develeopment
National,
Regional &
International
collaboration
Developing
new
antibiotics
Public
Private
Partnership
Antimicrobial
stewardship
Ban on
growth
promoter
Infection
Prevention
& control
Ban on OTC
sale of
antibiotics
I
Thank you
For your attention
&
Action

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  • 1. Tackling the invisible pandemic before it becomes the invincible pandemic Prof. Ashok Rattan, MD, MAMS, Common Wealth Fellow, INSA DFG Fellow , ex SEARO Temporary Advisor, ex WHO Lab Director (CAREC/PAHO) Chairman Medical Committee & Quality, Redcliffe Labs
  • 2. 31st Dec 2019 WHO is informed regarding an outbreak of Pneumonia caused by a novel Corona Virus in Wuhan 10 Jan 2020 one full sequence of this RNA virus is available in public domain , 5 more next day
  • 3. 30 Jan 2020 WHO declares Covid-19 outbreak a Public Health Emergency of International Concern 11 March 2020 WHO declares Covid 19 a PANDEMIC Infected: 640 million cases; 6.6.million deaths Chinese new year 25 Jan 2020 5 Feb : Italian residents hug Chinese people to encourage them in corona virus fight
  • 4. Diagnosis is essential for control of any disease Infected: 640 million cases; 6.6.million deaths
  • 5. ICMR Ramps up Labs able to test for Covid-19 Jan 2020: 1 lab (NIV Pune) September 2020: 2234 Labs doing RT PCR; Now 3020
  • 6.
  • 7.
  • 8. Covid-19 A very visible Pandemic took a great toll in life & economy Addressing Antimicrobial Resistance An invisible Pandemic Before it becomes The invincible pandemic
  • 9.
  • 10. Consumption of systemic antibiotics in India in 2019 lancet.com Vol 4 Month September, 2022
  • 11. Consumption of systemic antibiotics in India in 2019 lancet.com Vol 4 Month September, 2022 • The total DDDs consumed in 2019 was 5071 million (10.4 DDD/1000/day). • Watch contributed 54.9% (2783 million) DDDs, • Access contributed 27.0% (1370 million). • Formulations listed in the NLEM contributed 49.0% (2486 million DDDs); • FDCs contributed 34.0% (1722 million), and • unapproved formulations contributed 47.1% (2408 million DDDs). • Watch antibiotics constituted 72.7% (1750 million DDDs) of unapproved products and combinations discouraged by the WHO constituted 48.7% (836 million DDDs) of FDCs.
  • 14. Current Crisis of MDR Infections • Act of GOD (nature) • Spread of resistant gene from antibiotic producing bacteria to pathogens • Acquisition of resistance to available drugs by mutation • Act of Man Kind • Selection of resistant mutants by use & over use of antibiotics • Spread of MDR strains from one patient to another by non application of Infection Control policies
  • 15. Current use of antibiotics in USA
  • 17. Consequences of antibiotic use •Clinical cure •Inhibition of non pathogenic bacteria •Selection of resistant mutants •Toxicity / side effects
  • 18.
  • 19. Bacterial infections have frequently caused pandemics in the past Great plague of 1660s
  • 20. Discovery & Development of Anti-bacterials is one of the most important discovery of the 20th Century
  • 21. Power of antibiotics Disease Pre Antibiotic era deaths Deaths with antibiotics Change in deaths due to antibiotics CAP (1) 35% 10% - 25% HAP (2) 60% 30% - 30% Heart Infection (3) 100% 25% - 75% Brain Infections (4) > 80% < 20% - 60% Skin Infection (5) 11% < 0.5% -10% By comparison…. Treatment of heart attacks with aspirin or clot busting drugs (6) - 3% Ref.: (1) IDSA Position Paper. Clin Infect Dis 2008; 47 (S3): S 249 – 65 (2) IDSA/ACCP/ATS/SCCM position paper. CID 2010; 51 (S1): 51 – 3 (3) Kerr AJ. SABE Lancet 1935; 226: 383 – 4 (4) Waring et al. Am J Med 1948; 5: 402 – 18 (5) Spellberg et al CID 2009; 49: 383 – 91 (6) Lancet 1998; 351 : 233 – 41.
  • 22. 1940 1950 1960 1970  2000 2002 2004 2006 2007 2008 2012 2022 Introductions of New Antibiotic Classes Sulfas 1936 Penicillin 1940 Tetracycline 1949 Aminoglycosides 1950 Macrolides 1952 Glycopeptides 1958 Streptogramin 1962 Quinolones 1962 Oxazolidinone 2000 Daptomycin 2003 Tigecycline 2006 Telithromycin 2004 Doripenem 2007 Me too drugs Different Generations Ertapenem 2001 Ceftaroline 2010 Beta lactam + Boronic beta lactam inhibitors 2018 Before Antibiotic Era After Antibiotic Era
  • 23. We are overwhelmed as it is, with an infinite abundance of vaunted medicaments; and here they add a new one….. Thomas Sydenham, MD (1624 - 1689)
  • 24. “By the year 2000, nearly all experts agree that bacterial and viral diseases will have been virtually wiped out…” The futurists: looking toward year 2000 (Time magazine, february 25, 1966) US surgeon general William Stewart: “The time has come to close the book on infectious diseases” (1969) Mankind has always had the benefit of “good” advice
  • 25. 100 80 60 40 20 0 1980 1975 1985 1990 1995 2000 1997 VISA VRE PRSP MRSA MRSE Percentage of Pathogens Resistant to Antibiotics Increasing Incidence of Resistance in the US MRSE, MRSA, VRE, PRSP, GISA 1980-2006 VRSA 2006
  • 26. Why Big Pharma has abandoned Antibacterial drug discovery
  • 27. We have a basic problem
  • 28. Targets of existing antibiotics
  • 29. New Antibacterial Targets identified & exploited from Whole Genome sequencing of many Gram Negative Bacteria Combitorial Chemistry & High Throughput screening
  • 30. Understand Disease & Identify unmet needs Select Mechanism/ Target Design NCEs & Screens Virtual Screening Synthesize NCEs Convert Lead-to-IND Candidate New Drug Discovery Road Map Preclinical work-up IND directed regulatory studies Convert Hit-to-Lead Screen/ Identify Hit
  • 31. 30000 compound synthesized 2000 enter preclinical development 200 enter Phase 1 40 enter Phase II 12 enter Phase III trials 8 are approved 1 makes satisfactory ROI Years 0 2 3 5 10 12
  • 32. NCE In vitro In vitro Acute tox DRUG Insoluble New Drug Discovery is like snakes and ladder failure is the norm Active
  • 33. New Drug Discovery and Development (Timelines) DISCOVERY/SCREENING SYNTHESIS AND PURIFICATION ANIMAL TESTING PHASE II PHASE I SHORT-TERM PHASE III LONG-TERM PHASE IV ADVERSE REACTION SURVEILLANCE PRODUCT DEFECT REPORTING PRE-CLINICAL RESEARCH CLINICAL STUDIES NDA REVIEW POST-MARKETING 24 + 18 months. AVG: 5 YEARS AVG: 12 MOS. IND NDA APPROVAL
  • 34. Vancomycin Borneo 1953 ; Edmund Kornfeld 1956 Streptomyces orientalis 05865 (Nocardia, Amycolatopsis) Active against Gram Positive No development of resistance even after many in vitro passages Named Vancomycin after vanquish FDA gave Fast Track Approval Mississippi Mud by Eli Lilly scientists (due to presence of impurities) Not much used in 1960s due to Oto and Nephro toxicities Mol Wt 1546 Antibiotic from Nature
  • 35. Vancomycin & Teicoplanin Linezolid Daptomycin Ceftaroline MRSA  VISA  VRSA Since 2007 USA FDA approved the following drugs for MRSA treatment: 1. Delafloxacin; 2. Omadacycline; 3. Tedizolid; 4. Dalbavancin; 5. Oritavancin; 6. Televancin
  • 36. Vancomycin & Teicoplanin Linezolid Daptomycin Tigecycline &Ceftaroline Gram +ve problem Nailed down Tigecycline & Colistin Gram –ve infections may leave us exposed Since 2007 USA FDA approved the following drugs for MRSA treatment: 1. Delafloxacin; 2. Omadacycline; 3. Tedizolid; 4. Dalbavancin; 5. Oritavancin; 6. Televancin
  • 37. Bad bugs, no drugs: No ESKAPE CID 2009; 48: 1 - 12 • Enterococcus faecium • Staphylococcus aureus • Klebseilla pneumoniae • Acinetobacter baumanii • Pseudomonas aeruginosa • Enterobacter species Clostridium difficile & E. coli
  • 39. Extinction of MDR Bacteria is not an achievable Goal • Bacteria have inhabited the Earth longer than humans and in far greater number • In our body, bacteria outnumber our cells 10 : 1 • Humans have capability of causing extinction of other species, mostly unintentional (Dodo, ? Tiger) • However, Extinction of MDR bacteria is not an achievable goal by Man Kind
  • 40. Need for Antimicrobial Stewardship • Antimicrobial stewardship is a coordinated program that promotes the appropriate use of antimicrobials (including antibiotics), improves patient outcomes, reduces microbial resistance, and decreases the spread of infections caused by multidrug-resistant organisms. • Objective are: Right drug for the right patients at the right dose by the right route for the right duration
  • 41.
  • 42. ESCMID generic competencies in antimicrobial prescribing and stewardship • Section 1: core concepts in microbiology, pathogenesis and diagnosing infections • 1 Every independent prescriber must understand: • 1.1 The nature and classification of microorganisms that commonly cause infections in humans • 1.2 The common microbiological aetiology of human infections, and the ways in which microorganisms are commonly acquired in community and hospital settings • 1.3 The differences between colonization (e.g. isolation of bacteria from a venous leg ulcer with no signs of inflammation) and infection • 1.4 That an inflammatory response can be due to both infectious and non-infectious causes (e.g. acute pancreatitis) • 2 Every independent prescriber must know how to: • 2.1 Take a thorough history and perform a physical examination to diagnose common infections and to assess their severity • 2.2 Use and interpret investigations that can help in informing diagnosis of an infection and in monitoring the response to treatment (e.g. microbiological investigations, biomarkers, point-of- care tests)
  • 43. ESCMID generic competencies in antimicrobial prescribing and stewardship • Section 2: antimicrobial prescribing • 1 Every independent prescriber must understand: • 1.1 How and where to access relevant guidance on antimicrobial prescribing and stewardship • 1.2 When not to prescribe antimicrobials (e.g. antibiotics for viral infections, or when there is bacterial colonization) • 1.3 That best practices for some infections may not include antimicrobial treatment (e.g. incision and drainage of abscesses, removal of foreign material) • 2 Every independent prescriber must understand how to • select the appropriate antimicrobial, using relevant guidance when possible, as well as the key elements of initiating prescribing an antimicrobial: Obtaining relevant microbiological cultures or relevant tests before commencing treatment • The timing of antimicrobial administration in different situations (e.g. as soon as possible for life-threatening infections, less urgently for chronic bone infections) • The choice and dose of agent, and the route of administration • The duration of treatment, review dates and stop dates • 3 Every independent prescriber must understand the key elements of continuing and rationalizing antimicrobial therapy: • Monitoring antimicrobial levels when indicated, and adjusting doses (e.g. for patients with renal impairment) • Changing antibiotics according to microbiology results and clinical condition, ideally to a narrower spectrum (de-escalation), or if needed to a broader spectrum (escalation) • Reviewing antibiotic therapy at 48e72 hours and regularly thereafter in hospitalized patients, and in appropriate situations in the community • Switching antibiotics from intravenous to oral administration as soon as possible when indicated (according to guidelines) • Stopping antimicrobials if there is no evidence of infection based on clinical findings and investigations (e.g. negative microbial cultures, imaging reports)
  • 44. ESCMID generic competencies in antimicrobial prescribing and stewardship • 4 Every independent prescriber must understand the need to document the important details of the antimicrobial treatment plan (e.g. agent, dosing, administration route, clinical indication, duration and review dates) in the prescription chart, medical records and transfer notes to other healthcare institutions • 5 Every independent prescriber must understand: • 5.1 That empirical treatment should be guided by local antimicrobial susceptibility patterns • 5.2 The clinically relevant spectrum of activity for commonly prescribed antimicrobials • 5.3 The basic principles of pharmacokinetics and pharmacodynamics • 6 When prescribing an antimicrobial, every independent prescriber must know: • 6.1 The antimicrobial class that the agent belongs to, and the contraindications to its use • 6.2 The name and class of antimicrobial being prescribed, if prescribing by trade name • 7 Every independent prescriber must understand single prophylactic dosing for surgical and other procedures for which prophylaxis has been shown to be effective, and that additional prophylactic antimicrobial doses can occasionally be needed (e.g. when the duration of the operation/procedure is prolonged) • 8 Every independent prescriber must know: • 8.1 Common antimicrobial and drug/food interactions • 8.2 Common side-effects of antimicrobials, including allergy, how to monitor for them, and what to do when they are suspected (e.g. documenting allergic reactions in patient records, reporting side-effects) • 9 Every independent prescriber must understand any legal requirements for prescribing antimicrobials in their country, and comply with these when prescribing
  • 45. ESCMID generic competencies in antimicrobial prescribing and stewardship • Section 3: antimicrobial stewardship • 1 Every independent prescriber must understand that: • 1.1 Antimicrobials need to be used responsibly to prevent the emergence and spread of antimicrobial resistance • 1.2 Optimizing antimicrobial use can limit the common side-effects and collateral damage related to treatment (e.g. their disruptive effects on the normal host flora, which may lead to Clostridium difficile infection, super-infection with Candida spp.) • 1.3 It is important to avoid unnecessary uses of antimicrobials, especially those with a broad spectrum • 1.4 Transmission of microorganisms in community and hospital settings can significantly amplify antimicrobial resistance • 2 Every independent prescriber must understand local stewardship policies based on national (or international where these do not exist) evidence-based guidelines • 3 Every independent prescriber must understand and engage with any locally or nationally agreed quality measures for assessing antimicrobial prescriptions (e.g. compliance with guidance, adverse events, reviews of antibiotic therapy at 48e72 hours in hospitalized patients) • 4 Every independent prescriber must know how to communicate with patients and their careers, nurses, pharmacists and other healthcare professionals about: • 4.1 When antimicrobials are not needed • 4.2 Complying with the duration and frequency of administration of their prescribed antimicrobials • 5 Every independent prescriber must recognize that it is a duty of care to co-operate with others more expert than oneself, such as the antimicrobial stewardship team, when such expertise is needed
  • 47.
  • 48.
  • 49.
  • 50.
  • 51. Underutilization of Pharmacists & Nurses in AMS Lack of Leadership, expertise & human resources in AMS Limited involvement of Surgeons in AMS teams Lack of appreciation of its importance by health administrators
  • 52. Antibiotic Stewardship • The right antibiotic • For the right patient • At the right dose • And the right time • By the right route • For the right duration • It is essential for patient safety and delivery of high quality care
  • 53. Diagnostic Stewardship Considerations when selecting a diagnostic tests
  • 54. Diagnostics tests can help combat AMR • 1. Rapid & definitive Diagnosis of bacterial infection which would help reduce the overuse of antibiotics in clinical medicine • 2. Screening for presence of resistant bacteria on admission and during stay in the hospital subsequently to prevent spread of infection in health care setting. • 3. Diagnostic tests is the only way to gather data on resistant trends and to be altered to outbreaks and to assess effectiveness of AMR measures. • 4. AMR surveillance data is needed for development of treatment guidelines and AMR control strategies.
  • 55.
  • 56. Antibiotic Use Bundle • Before starting antibiotics, document (Initiation Bundle) • 1. What is the evidence that this is a bacterial infection • 2. Collect & submit appropriate cultures • 3. Remove any foreign body or I & D any collection of pus • 4. Select and Plan the antibiotic based on local antibiogram • Which antibiotic (Empiric therapy) • What dose • Which route • How frequently
  • 57. Results of individual’s sample Circulation of cumulative antibiogram Microbiologists spend all their time doing half the necessary work Antibiotic use decisions are made at two phases
  • 58.
  • 59. Continuation Bundle 72 hours or so • 1. Condition of the patient • 2. Review microbiology results • 3. Was an initial bundle documented • 4. Consider step down from IV to oral
  • 60. Does you lab only do the following ?
  • 61. If Robert Koch Was to visit your Microbiology Lab Would he have a Feeling of Deja vu ? 1843 - 1910 Is your laboratory up to the task ? Are the results quality assured ? Are the services available 24 x 7 ?
  • 62. Aerobic bottles grow aerobic bacteria & Yeasts Anaerobic bottles grow facultative bacteria & anaerobic bacteria
  • 63.
  • 64.
  • 65.
  • 66. Phoenix M 50 identification and susceptibility of isolates Detection & Classification of Carbapenemase NMIC / ID: 136 wells containing dried reagents, AST is determined using an optimized redox indicator 51 wells for ID & 85 wells for AST; panels only for ID & only AST are also available CPO Detect : uses 9 wells with to 1. Detect presence of Carbapenemase & 2. Ambler classification A, B & D Meropenem; Doripenem; Temocillin & Cloxacin both alone & in combination with chelators & various β lactamase inhibitors
  • 67.
  • 68.
  • 69. Development & widespread use of Gene Xpert (a.k.a. CBNAAT in India) was a significant step towards improving the diagnosis of Tuberculosis & detection of Rifampicin Resistance in the world But has its widespread use led to increase in MDR TB ?
  • 70. Initiation of Treatment based on CBNAAT Fact or Assumption based ? • 1. Fact: Rif S  Assumption INH also S • But if IMR  for 4 months patient will receive (INH Mono Resistant) only Rif mono treatment  MDR TB • 2. Fact: Rif R  Assumption Treat as MDR TB • But if INH Sensitive  Benefit of INH denied to patient  Toxicity of MDR TB regimen  non-adherence
  • 71. Evolution of Extensively Drug-Resistant Tuberculosis over Four Decades: Whole Genome Sequencing and Dating Analysis of Mycobacterium tuberculosis Isolates from KwaZulu-Natal Keira A. Cohen et al. PLOS Medicine | DOI:10.1371/journal.pmed.1001880 September 29, 2015 In resistant Mtb, INH resistance was the initial resistant mutation to be acquired
  • 72. editorial • Mutations conferring resistance to INH occur before resistance to other drugs and then goes on to develop MDR-TB • INH Resistance predates Rifampicin resistance • Phenotype of IMR is a precursor for MDR-TB and requires intensified diagnosis and therapeutic intervention • Detection of MDR-TB by Gene Xpert, may potentially lead to further selection for IMR and emergence of MDR-TB • Routine testing of Mtb for all relevant drugs shoulnot be regarded as costly extra, but, rather, as critical steps for overall drug resistant TB control and elimination
  • 73. • Reviewed 19 cohort studies and 33 clinical trials involving 19012 DS-TB and 3744 IMR-TB patients • Pooled rate of treatment failure or relapse or both was • MDR TB  15%; IMR TB  4 % and DS-TB  0.6 % • Of pts with initial IMR 96% became MDR-TB • Treatment of IMR-TB with first line drugs : • T/t failure 11%; Relapse 10% and MDR TB 8% • DS TB 1% 5% 0.3% • Conclusion: Treatment of IMR-TB with first line anti TB drugs resulted in suboptimal outcomes and could contribute to development of MDR-TB Treatment of isoniazid-resistant tuberculosis with first-line drugs: a systematic review and meta-analysis Medea Gegia et al. Lancet Infect Dis 2017; 17: 223–34
  • 74. TB Burden in India India TB Report 2022 • Year 2021 witnessed a 19% increase from the previous year in TB patients' notification • The total number of incident TB patients (new and relapse) notified (2021)- 19,33,381 • % of Drug Sensitive TB Patients ~ 86 % • % Isoniazid monoresistance ~7% • % MDR TB cases ~ 7.5%
  • 75. 2nd generation molecular tests Moderate Complex Automated NAAT • 1. Abbott Molecular test • A. Detection of MTB • B. Detection of MTB and INH & Rif Resistance • 2. BD Max for MTB and INH & Rif Resistance • 3. Bruker Hain Diagnostics • A. Fluorotype MTB • B. Fluorotype MTBDR for INH & Rif Resistance • 4. Roche Diagnostics • A. MTB • B. MTB DR for INH & Rif Resistance
  • 76.
  • 77.
  • 78. All these four WHO approved tests are high throughput A POCT being reviewed by WHO & ICMR SD Biosensor Advantage •All-in-one cartridge (NA extraction + amplification) •Simultaneous detection of M. tuberculosis complex and INH & Rif Resistance •Fast result in 77 minutes •Simple sputum pretreatment process •Room temperature storage
  • 79.
  • 80. 3. All patients with PTB should be treated with an appropriate regimen as recommended by the WHO and/or national guidelines (Standard 3) • Each patient with diagnosis of drug-susceptible PTB should be treated with a regimen recommended by WHO and national guidelines • Adults: 6-month regimen (2HRZE/4HR) 4-month regimen (2HPZMfx/2PMfx) for children aged 12 years and adults • Children: 6-month regimen (2HRZ(E)*/4HR), with higher R and H dosing (see WHO-recommended dosages) • SHINE regimen (2HRZ(E)*/2HR) for age , 16 years with non-severe TB (SHINE : Shorter treatment for Minimal Tuberculosis in children)
  • 81. For optimum diagnosis of tuberculosis beyond MDR TB OR
  • 82. For optimum & rapid initial diagnosis of pre XDR & XDR TB NGS
  • 83. WRD = WHO Recommended Diagnostic Tests ; DST = Drug Susceptibility Testing For follow up of already diagnosed TB cases
  • 84. It is now possible to initiate the appropriate anti TB treatment at the first patient contact thus benefiting the patient in getting early relief and benefiting the society by decreasing transmission of infection after one test. 1882 2022 1882 2022
  • 85. Circulation of cumulative antibiogram Microbiologists must influence antibiotic selection in Empirical phase
  • 86. Cumulative Antibiogram (CLSI 39 A) • Analyze and present CASR at least annually • Include only final, verified results Include only species with results for 30 isolates • Include only diagnostic (not surveillance) isolates • Eliminate duplicate isolates by including only first species’ isolate/patient/period of analysis • Include only routinely tested agents • Report % S and exclude % I • For Streptococcus pneumoniae, report data for both meningitis and non meningitis breakpoints • For viridans group streptococci, report both % S and % I • For S. aureus, report % S for all isolates and MRSA subset
  • 87.
  • 88. Essential, achievable, and aspirational antimicrobial stewardship activities for the microbiology laboratory Must provide round the clock service • Provide timely, reliable, and reproducible identification and antimicrobial susceptibility results • Actively participate in antimicrobial stewardship committee or work group • Collaborate in educating local health care workers on microbiology issues that impact treatment and microbial resistance • Promptly report unusual patterns of resistance, test supplementary agents, and provide advice on therapy for patients awaiting results • Optimize communication of critical test result values and alert systems • Provide, revise, and publicize annual CASR consistent with CLSI standards • Provide guidance for adequate collection of microbiology specimens • Develop alert systems for specific multidrug-resistant organisms • Use cascade or selective reporting • Collaborate with ID physicians and pharmacists on updating methods for susceptibility testing
  • 89. Linking Diagnostics to Antibiotic Stewardship Right test for the right patient at the right time
  • 90. Is it a bacterial infection ? What is the cause ?
  • 91. Overuse of antibiotics in Respiratory Tract Infections
  • 92. Levin M et al CMI 2018; 24: 1158
  • 93. Is it Bacterial or Viral Infection ?
  • 94. What is Procalcitonin (PCT) ? Schuetz P et al. BMJ Medicine 2011; 9: 107 • 116 amino acid precursor of calcitonin produced by Thyroid C cells & Neuroendocrine cells of the lungs • Calcitonin is involved in calcium homostasis, while procalcitonin is not • Many other cells can produce PCT after specific stimulation but lack enzyme to convert PCT  calcitonin • Excessive production of PCT by many cells  rapid increase in blood levels
  • 95.
  • 96. PCT in Bacterial Infection Linscheid P et al. Endocrinology 2003; 144; 5578 1. Bacterial Infection (LPS) stimulates production of PCT from many somatic cells 2. These cells lack the enzymes to cleave PCT  calcitonin 3. PCT produced by these cells is rapidly released into blood stream 4. Cytokines produced during viral infection inhibit PCT production
  • 97. Kinetics of PCT makes it a better biomarker of bacterial infection Simon J et al. Clin Infect Dis 2004; 19: 206
  • 98.
  • 99. Serial measurement of PCT every 24 hours
  • 100. Guidelines for Initiating antibiotics PCT value (ng/mL) PCT in ng/mL < 0.25 0.25 – 0.50 0.5 -- < 1 > 1 Antibiotic initiation Strongly discouraged Discouraged Encouraged Strongly Encouraged
  • 101. Guidelines for Stopping, continuing or changing antibiotics PCT value (ng/mL) PCT in ng/mL < 0.25 > 0.25 – <0.50 Or Decline of >80% of peak value > 0.5 Or Decline < 80% of peak value > 0.5 Or Increase above PCT Value Antibiotic continuing Strongly discouraged continuing Discouraged continuing Encouraged Changing or Strongly Encouraged
  • 102. Economic evaluation of procalcitonin-guided antibiotic therapy in acute respiratory infections: a US health system perspective Schuetz P et al Clin Chem Lab Med 2015; 53(4): 583–592 Unfortunately & Paradoxically this test is NOT USED in India Reason cited by some is 1. PCT is Too Costly 2. It is a sent out test & not POCT
  • 103. POCT Procalcitonin Quantitative Iquant analyser by J Mitra SD Biosensor F 200 Manesar Minividas Wondfo Finecare
  • 104. Procalcitonin > 0.5 ng/ml < 0.25 ng/ml
  • 105. Multicentre evaluation of two multiplex PCR platforms for the rapid microbiological investigation of nosocomial pneumonia in UK ICUs: the INHALE WP1 study Enne VE et al Thorax 2021 Syndromic Testing: One sample, multiple results
  • 106. Pathogen-specific performance of RM and multiplex PCR tests
  • 107. Conclusions: Film Array Pneumonia Panel (FA-PP) is a simple and rapid molecular test that could complement routine conventional methods for improvement of diagnosis accuracy of pneumonia. Nabil Gastli et al 90.1% of detected bacteria with 106 DNA copies/mL grew significantly in culture
  • 108. Fast multiplex bacterial PCR of bronchoalveolar lavage for antibiotic stewardship in hospitalised patients with pneumonia at risk of Gram-negative bacterial infection (Flagship II): a multicentre, randomised controlled trial Dhare et al. Lancet Resp Med 2022; Sept • 208 patients were randomized to PCR group (n=100) and conventional microbiology (n=108); followed up after 30 days • Duration of inappropriate antibiotic treatment was significantly shorter by 38.6 hours in PCR group (47.1 vs 85.7 hours) • Which translates into a decrease in duration of inappropriate antibiotics by 45%
  • 109. A multiplex bacterial PCR detects more bacteria in BAL fluid than conventional diagnostic methods; however, without a specific antibiotic stewardship approach, PCR results do not influence clinical outcomes
  • 110.
  • 111.
  • 112.
  • 113. 63% of cases of AMR infections are associated with health care = 72 % of AMR attributable deaths
  • 114. Four bacteria mostly acquired in health care are estimated to cause 68% of burden of antibiotic resistance (disability and premature mortality)
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  • 134. Tackling the invisible pandemic Factors influencing race against AMR Tackling the invincible pandemic ? National Policy Vaccination Awareness in Public Surveillance & Monitoring Global Fund Infrastructure Develeopment National, Regional & International collaboration Developing new antibiotics Public Private Partnership Antimicrobial stewardship Ban on growth promoter Infection Prevention & control Ban on OTC sale of antibiotics
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  • 137. I Thank you For your attention & Action