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Antimicrobial Resistance

A Case based Discussion

IAP is Proactive..

A Must read….

Case 1A 13 months previously healthy boy 9Kg (fully immunized) has high fever since 24 hours, intake down, A bit Fussy during fever

No Focus

Given Paracetamol

Clinical Exam – No Clue/Focus, Temp 1020F

His mother is crying, saying, "Do something! The fever will go in brain and my child will have brain damage!” (neighbor's son had Febrile Convulsion)

Case 1..…Unfortunately child gets a seizure on way back from the OPD and is brought back

Convulsion stopped without medication

CBC MP, CRP, NS1, Urine R sent

TC 16,400, N55 L42 E3, Plt 3.5L, MP Neg, Urine R - N, CRP Neg, CSF N

Treatment? Empirical antibiotics?

When? Why? Which? On D1/2 of Fever

Empiric antibiotics – When?High probability of bacterial infection while waiting for laboratory results

UTI, Enteric fever

High probability of bacterial infection where waiting is dangerous

Meningitis, Pneumonia, Osteomyelitis

High probability of bacterial infection in spite of absence of proof of infection

Otitis Media, Abscess

Suspected viral infection with atypical progress Varicella + Secondary Staph Sepsis, Measles + Pneumonia

Uncomplicated near-certain bacterial infections Dysentery, Suppurative adenitis

Fortunately….

Story unfolded the very next day (D3 of fever)

Sudden disappearance of fever and appearance of rash

Pink non pruritic morbilliform

Exanthem subitum/Roseola infantum

Case 2

1y 8m girl, admitted on 18/12

Fever x 12 days (since 7/12/18)

Documented up to 1030F,

3 to 4 spikes/d

Amoxiclav from 10/12 to 15/12

P/A L 2cms, S JP

10/12/18 15/12/18Hb 10 9.8WBC 7210 15,600N/L 37/45 45/52Platelets 3 L 4.4 LSGOT 50 53CRP 18.5

Case 2

1y 8m girl, admitted on 18/12

Fever x 12 days (since 7/12/18)

Documented up to 1030F, 3 to 4 spikes/d

Amoxiclav from 10/12 to 15/12

P/A L 2cms, S JP

Blood culture sent, poor oral intake and vomiting

Inj Ceftriaxone started

Day 3 of ceftriaxone - fever ++

10/12/18 15/12/18 18/12/18Hb 10 9.8 10.1WBC 7210 15,600 14,300N/L 37/45 45/52 58/39Platelets 3 L 4.4 L 5.41SGOT 50 53 70CRP 18.5 31

USG Abdomen

Hepatosplenomegaly

Case 2 summary

S. Typhi

Sensitive to Ceftriaxone

Sensitive to Azithromycin

Resistant to Nalidixic Acid (NARST)Sensitive to Ampicillin, Chloramphenicol, Cotrimoxazole

1y 8m girl with 15 days of fever

Mild HS megaly

Raised WBC

Platelets increasing

Rising CRP

Normal X ray chest

3 days of Ceftriaxone

Fever on day 5 of Ceftriaxone

Add Azithromycin ?

Evolution of drug resistance in S Typhi

• Ampicillin• Chloramphenicol• Cotrimoxazole

Before 1980

• Quinolones• 3rd gen

cephalosporins• Azithromycin

MDR• NARST• Increasing MIC in

3rd gen cephalosporins

Quinolone resistance

• 3rd gen cephalosporins

• Azithromycin

2 Antibiotics

1948 Chloramphenicol

Recent phylogenetic studies suggest the multidrug resistant clade H58 originated in India and subsequently expanded through Asia and Africa11

Evolution of drug resistance in S Typhi

• Ampicillin• Chloramphenicol• Cotrimoxazole

Before 1980

• Quinolones• 3rd gen

cephalosporins• Azithromycin

MDR• NARST• Increasing MIC in

3rd gen cephalosporins

Quinolone resistance

• Ceftriaxone resistant typhoid fever !

Pakistan

1948 Chloramphenicol

Only Azithromycin !

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Salmonella enterica serovar Typhi be added to the list of bacterial pathogens of public health importance that have become extensively drug resistant (XDR)

H58 haplotype is known for its ability to spread worldwide and

displace endemic S. Typhi 13

S Typhi - Major concerns

Antibiotic arsenal for typhoid treatment is receding

S. Typhi can transform from MDR to XDR in a single step by acquisition of a plasmid

XDR clones can spread globally

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The use of antibiotics is the single most important factor leading to antibiotic

resistance around the worldAmpicillin, Chloramphenicol and Cotrimoxazole use went down over the years lifting the antibiotic pressure leading to regaining of efficacy

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Learning points

Clinical suspicion of typhoid should be supported by Blood Culture

Send blood cultures even if the child has received antibiotics

In Typhoid,Fever defervescence can take 7 days

Avoid addition of Azithromycin in Ceftriaxone sensitive S . Typhi

Single Drug is enough for Enteric Fever

Judicious use of Azithromycin is required for a potential threat of XDR typhoid

Case 3

In the 1980s

Penicillin + Chloramphenicol

Beta lactamase by H Influenzae

PBP alteration by S pneumoniae

Beta lactamase BL+BLI or 3rd gen cephal

BL + BLI can’t cross the BBB

Ceftriaxone

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6m girl

Fever and irritability x 2 days

AF - full

WBC 18,600, N67, CRP 102

CSF – 302 cells, N 90, Sugar 40 (110)

Blood culture and CSF culture awaited

S pneumo., H influ b, N mening

Resistance in S. pneumoniae

Sensitive Intermediate Resistant

New (non CNS) < 2 4 8

New (CNS) < 0.06 None > 0.12

MIC of > 0.12 in about only 8% of isolates

For non CNS infections Standard dose of Amoxicillin is effective

Hence Ceftriaxone alone is recommended to treat CNS infection Routine Vancomycin not indicated

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Penicillin resistance of pneumococcal meningeal isolates increased from <10% in 2008 to over 40% by 2016

Non-susceptibility to cefotaxime amongst meningeal isolates increased from <5% in 2008 to over 25% in 2016

© 2017 Indian Journal of Medical Microbiology 19

Changing recommendation for the empiric treatment of Acute Bacterial Meningitis

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Penicillin Ceftriaxone Ceftriaxone + Vancomycin

Case 4

3 yr old F/ch

High fever for 3 days,NS1 Positive

Admitted for IVF

Kept In the hospital for 4 days

Discharged, Well and Afebrile

Came back with High Fever, Thrombophlebitis, Abscess, Pre gangrenous changes

Pus grew Gram positive cocci in clusters++

Sick, Rash, Hypotension

Toxic shock syndrome

Multiple IV Punctures with complications

Antibiotics ?

Clox/Cefazoline + Vancomycin

Clox/Cefazoline + Vancomycin + Clindamycin

Clox/Cefazoline + Clindamycin

Vancomycin + Linezolid

Resistance in S. aureus Infection : Indian scenario

AMR data from ICMR,10 centers: Jan-Dec 2017

9186 Staph Isolates; 6297 S. aureus and 899 from blood

Both Hospital and Community acquired

Overall MRSA around 30%

Clindamycin Resistance in MRSA 40%

NO VRSA

Occasional VISA and Linezolid Resistance

Culture - Staph aureus

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S aureus

MRSA

HA MRSA CA MRSA

MSSA

Culture - Staph aureus

Oxacillin Resistant

MRSA

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Culture - Staph Aureus

Oxacillin Resistant

MRSA

Cotrimoxazole Resistant

Vancomycin/Linezolid/Teicoplanin Sensitive

HA MRSA

Clindamycin Sensitive

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CA MRSASCC IV,V

SSTI, Necrotizing pneumonia

Doxy, Clinda, Quinolones, Cotrimoxazole sensitive

HA MRSAGenetically different

Disease Spectrum

Antibiotic susceptibility

Risk factor

SCC I, II, III

All

Invasive device, H/O MRSA, Surgery, dialysis, hospitalization in past 1y

Staphylococcal Infection: Treatment

MSSA : Cloxacillin/Cefazoline/Ceftriaxone - Vancomycin is inferior

MRSA: Vancomycin, Teicoplanin, Linezolid, Clindamycin, TMP-SMX

Daptomycin – not for Pneumonia – Consider for Endocarditis

Empirical therapy - Add MRSA cover if Hospital acquired/very sick patient

ADD Clindamycin for TSS

Definitive therapy

Prolonged IV especially if bacteremia, repeat blood cultures, search for new sites

Case 5

18 months old child with Bilteral Gr II VUR on TMP SMX prophylaxis

H/o UTI 1 month ago treated with Cefixime

T 1020F, Vomiting, poor oral intake

Tc 23,900 N 89%, Urine - Pus cells 60, Nitrite +ve

S. Creat 1.7

Vitals stable

Urine and Blood culture sent

Antibiotics?

Cefixime

Ceftriaxone

Ceftriaxone + Amikacin

Piperacillin Tazobactum

Meropenem

Resistance in Gram Negative organisms

Intrinsic and acquired

• Inactivating enzymes( Beta lactamase)• Reducing drug in cell( porin/efflux)• Target modification• Modification of metabolic pathway

Multiple mechanisms

Plasmid and chromosomal

Multiple mechanisms can co exist

ESBL- When to suspect and when not?

When?• Hospital acquired infections• Community acquired infections

• Neonatal sepsis• UTI• Intra abdominal sepsis

When not?• Meningitis beyond Newborn/RTI/SSTI/Bone and Joint infection beyond neonatal age• Typhoid, Shigella

TreatmentBL-BLI Pip Tazobactam

Cefoperazone sulbactumAmikacin

Carbapenems( 1st choice in very sick patients)

Clinical Response in UTI despite in vitro resistance is known

Pneumonia A case based approach

Mission Uday 2020

Learning Objectives

Review

Rational Antimicrobial Use in CAP in outpatient and inpatient setting

Microbiological diagnostics in pneumonia

Management of complicated pneumonia

Community Acquired Pneumonia

15% of deaths in children worldwide

1 in 500 children hospitalized for CAP

Viral causes more common than bacterial

Differentiating viral for bacterial is challenging - Antimicrobial overuse

Broad spectrum and less effective antibiotics are used in place of pharmacokinetically favorable narrow spectrum agents

What is CAP ?

Fever, cough and rapid and/or difficult breathing in a previously healthy child

Supporting evidence of parenchymal inflammationFindings on auscultation of chest

Focal opacity on x ray chest

Case 1

A 2 months old baby is brought with High fever, cough, fast breathing since 1 day

O/e RR 60 Lower chest indrawing

Which antibiotics would you use?

Bug : Gram negative/Strep/Chlamydia/Viruses

Drug: Cefotaxime/ Ceftriaxone +/- aminogly

Always hospitalize and give IV

2nd line - (Piperacillin+Tazobactum) - If resistant Gram negative organism

WHO revised classification of Pneumonia

Danger signs- Grunt, Not able to drink, persistent vomiting, convulsions, lethargic or unconscious, stridor in a calm child or severe malnutrition

Challenges in establishing etiologic diagnosis of pneumonia

Blood culture

Lung tapNP aspirateUrinary pneumococcal antigen

Insensitive methods underestimate the burden

Low sensitivityFurther lowered by Ab andinadequate labs

Do not differentiate NP carriage from pathogenicity

Finding one pathogen does not rule out other

Case 2• 3yr old with fever, cough and RR of 55/Min of 2 days duration,

feeding well• No lower chest indrawing, SpO2 96• Bronchial breathing + Right side infrascapular• Which antibiotics would you use?• Bug: Viruses (35%)

• S. pneumoniae• H. influenzae• Staphylococcus • Mycoplasma pneumoniae

Drugs

• PO Amoxycillin• 40mg/kg/day in 2/3 divided doses.• Co amoxyclav• Cefuroxime

WHO - Children age 2 - 59 months with fast breathing/chest indrawing pneumonia should be treated with oral amoxicillin: at least 40mg/kg/dose twice daily (80mg/kg/day) for five daysIn India 40mg/kg/day is enough for Pneumonia

Case 3• A 9 year old girl comes with cough ,fever 100F sore throat,

malaise, and headache since 3 days. Non specific erythematous rash on trunk. Went to school till a day ago on Amoxycillin with no response,

• Tachypneic, Chest scattered crepts, SPO2 95• X-ray : Patchy pneumonia• What antibiotics will you use?• Bug: Virus/ Mycoplasma• Drug: Amoxycillin plus Macrolide eg Azithromycin

Questions

When to consider Atypical Coverage in Community Acquired Pneumonia?

Is Azithromycin appropriate for the same?

What about Macrolide resitant Mycoplasma?

When do you use Fluoroquinolones in CAP in children?

BottomlineWhen Macrolides in CAP?

1) No Response to First Line Abx- No suppuration, Fully Immunized (especially in children> 4 years of age)

2) Clues to Atypical Pneumonia present clinically or radiologically

3) Extrapulmonary manifestations

3) Pertussis with CAP

Case 4

• A 3 yr old child presented with history of cough cold and fast breathing for 2 days. Child had a flu like illness 10 days back

• At admission he had fever of 102 0 F, RR of 50 per min with grunting. Saturation in room air was 90%, signs of respiratory distress present

• On examination of respiratory system bilateral air entry normal. Bilateral diffuse crepitations heard

Case 4…

• Within 4 hours of admission child’s respiratory status

deteriorated saturation dropped to 85% on 3 L O2, child was

drowsy and all signs of hypoxia were present

• What is the most likely cause of this child’s condition

• What is the most likely cause of this child’s pneumonia?

INTERACT

S. aureus infection American Family Physician

Volume 86, Number 7 , October 1, 2012

• In young children with CAP• severely ill, • have current or recent influenza, • whose symptoms do not improve

with beta-lactam or macrolide antibiotic therapy.

• In older children• Signs of pneumonia with preceding

skin lesions like abscess, or furuncles as in the first case

Radiologic findings of S. aureus Pneumonia

• Although not specific to S. aureus the following signs are very suggestive of a staphylococcal disease

• Pneumatoceles• Empyema / Loculated fluid• Air leaks - Pneumothorax, Hydropneumothorax, Pneumopericardium• Bilateral fluffy infiltrates

Management of Staph Pneumonia

• MSSA Cefazolin/Clox +/- aminoglycoside• MRSA Vancomycin /Clindamycin

• Second line – Linezolid

• Supportive measures – Drainage, etc

Clues to Etiology of Pneumonia

Predisposing factor Organism (apart from usual ones)Pyoderma, Measles StaphylococcusHIV PneumocystisNeutropenia Gram negative, AspergillusCystic fibrosis Pseudomonas, StaphylococcusSevere PEM Gram negative, staphAspiration pneumonia Anaerobes

Antibiotics (IV) for InpatientsAge First Line Second Line< 3 mths Cefotaxime/ Ceftriaxone +/- aminogly3 mths - 5 yrs Ampicillin/Amoxycillin/Coamox

yclav/ Cefuroxime/Ceftriaxone/ Cefotaxime

> 5 yrs Ampicillin/AmoxycillinMacrolide (if mycoplasma suspected)

Ceftriaxone/ Cefotaxime andMacrolides

Suspected staph

MSSA Cefazolin/Clox +/- AminoglycosideMRSA VancomycinClindamycin

Linezolid

When to admit - Age < 3 mths, Severe Pneumonia (WHO), suspected Staph Pneumonia

Non Response to Initial Empirical Therapy

• Complication• Empyema• Abscess

• Different pathogen• Tuberculosis, mycoplasma

• Drug resistance• Beta-lactamase produced Hib,• DRSP• Community acquired MRSA

Duration of

Treatment

• Uncomplicated pneumonia • Outpatient/Inpatient – 7-10days

• Complicated pneumonia –• Necrotizing infections, empyema and

lung abscess• Up to 4 weeks

Cough and Antibiotics

• Justified situations for considering antibiotic use,

• Pertussoid cough (any stage)• Paroxysms of intense coughing

lasting up to several minutes, occasionally followed by a loud whoop

• Post-tussive vomiting and turning red with coughing

• Azithromycin – 10mg/kg /day for 5 days.

Wake up call

No action Today, No Cure Tomorrow

At the moment the pace is

faster then that of development

of new abx

It is natural for microbes to become resistant to antibiotics

Stress on infection

control and antibiotic

stewardship

Need to reduce

antibiotic use

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Actions Preventing infections and preventing the spread of

resistance - Infection Control

Promoting the development of new

antibiotics

Tracking resistant bacteria

Improving the use of today’s antibiotics

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Question to the audience

• Are doctors by and large prescribing antibiotics unnecessarily in majority of instances in private practice?

• Yes/No

Possible reasons• Fever means bacterial – concept• Parental pressure• Fear of losing the client• Fear of secondary infection• Lack of time to think• Saturday evenings• Pressure from pharma industry• Lack of confidence

Possible reasons • Past bitter experience• Genuinely convinced it is right.• Past success• Impractical to withhold antibiotics• Parents are not convinced and happy• Every visit should be followed by a new

prescription with a new drug

Possible reasons

• Sheer economics• Peer pressure• Playing safe and feeling secure• Lack of Role Models• Lacunae in Medical Curriculum• Need for saving Antibiotics not felt• Western concept not acceptable to our country ie. Rural practice

Do you know ?

• Antibiotic resistant microbes are more dangerous than most human terrorists.

• Let us be Rational and Protect our children from these new age terrorists.

Thank You