ANTIBIOTIC ANTIBIOTIC RESISTANCERESISTANCE

Dr. Sachin Verma MD, FICM, FCCS, ICFCDr. Sachin Verma MD, FICM, FCCS, ICFC

Fellowship in Intensive Care MedicineFellowship in Intensive Care Medicine

Infection Control Fellows Course Infection Control Fellows Course

Consultant Internal Medicine and Critical CareConsultant Internal Medicine and Critical Care

Web:- Web:- http://www.medicinedoctorinchandigarh.com

Mob:- +91-7508677495Mob:- +91-7508677495

Lecture overviewLecture overview

Definition of multidrug resistance Definition of multidrug resistance History of antibioticsHistory of antibiotics How does resistance develop?How does resistance develop? Why is it important?Why is it important? Multidrug resistance organisms Multidrug resistance organisms

(MDROs)(MDROs) ControlControl

Multidrug-Resistant Multidrug-Resistant Organisms( MDROs)Organisms( MDROs)

Microorganisms that are resistant to one Microorganisms that are resistant to one or more classes of antimicrobial agents. or more classes of antimicrobial agents. MDRSP refers to isolates resistant to 2 or MDRSP refers to isolates resistant to 2 or more of the following antibiotics: penicillin, more of the following antibiotics: penicillin, second-generation cephalosporins, second-generation cephalosporins, macrolides, tetracycline, and macrolides, tetracycline, and trimethoprim/sulfamethoxazoletrimethoprim/sulfamethoxazole

CDC: Management of Multidrug-Resistant Organisms in Healthcare Settings, Healthcare Infection Control Advisory Committee, Jane D. Siegel et. al. pg 7-12

History of antibioticsHistory of antibiotics 1928: Penicillin first discovered by 1928: Penicillin first discovered by

Alexander Fleming Alexander Fleming Chain and Florey, helped develop penicillin Chain and Florey, helped develop penicillin

into a widely available medical productinto a widely available medical product

History of antibioticsHistory of antibiotics 1943- Drug companies begin mass 1943- Drug companies begin mass

production of penicillinproduction of penicillin 1944 – U.S. Military takes Penicillin to 1944 – U.S. Military takes Penicillin to

the battlefieldthe battlefield

History of antibioticsHistory of antibiotics

1945, Fleming, Chain and Florey awarded 1945, Fleming, Chain and Florey awarded the Nobel Prize in Physiology and Medicinethe Nobel Prize in Physiology and Medicine

After 2nd World War many more After 2nd World War many more antibiotics were developedantibiotics were developed

Today about 150 types Today about 150 types

History of antibioticsHistory of antibiotics

Many experts were confident the tide Many experts were confident the tide had turned in the war against had turned in the war against bacterial infectionsbacterial infections

1969, the then US Surgeon General, 1969, the then US Surgeon General, William Stewart, boldly told the US William Stewart, boldly told the US Congress it was time to "…close the Congress it was time to "…close the books on infectious diseases."books on infectious diseases."

March 1942

A 33 year-old lady lay dying of streptococcal sepsis in Connecticut, USA

Best efforts of doctors fail to clear the bloodstream infection

Doctors manage to obtain small amount of newly discovered penicillin which when injected cautiously, clears the streptococci from the blood

The patient miraculously survives. And lives up to 90 years

November 2011

A 16 year-old girl is being treated for pneumonia caused by Klebsiella pneumonia in Ivy Hospital Mohali

Despite best medical care – ALL antibiotics available for klebsiella , treating physicians unable to clear the patient’s blood

The patient dies, still with bloodstream infection

We have come almost full circle and arrived at a point as frightening as the pre-antibiotic era

Dr.T.V.Rao MD 12

How does resistance How does resistance develop?develop?

A variety of mutations can lead to antibiotic resistance

Mechanisms of antibiotic resistance

1. Enzymatic destruction of drug

2. Prevention of penetration of drug

3. Alteration of drug's target site

4. Rapid ejection of the drug

Resistance genes are often on plasmids or transposons that can be transferred between bacteria

BACTERIA MUTATE TO PROTECT THEMSELVES FROM ANTIBIOTIC

THE MUTATED BACTERIA SURVIVE AFTER THE ANTIBIOTICS ARE GONE

EVENTUALLY THERE ARE MORE ANTIBIOTIC-RESISTANT BACTERIA THAN NON-RESISTANT

Why is Resistance a Concern?

Resistant organisms are becoming commonplace

Bacterial resistance often results in treatment failure and increased mortality and cost

The problem is no longer confined to the hospital setting

Bacterial resistance will continue to worsen if not addressed

There are no antibiotics on the immediate horizon with activity against these multi-drug resistant pathogens

Number of New Molecular Entity (NME) Systemic Antibiotics Approved by the US FDA Per Five-year Period, Through 3/11.

Clin Infect Dis. 2011;52:S397-S428

Risk factors for acquisition Risk factors for acquisition of MDROsof MDROs

ICU stay ICU stay Previous exposure to antimicrobial agents Previous exposure to antimicrobial agents Underlying diseases Underlying diseases Dialysis Dialysis Invasive devices Invasive devices Recurrent admissions to hospitalRecurrent admissions to hospital Nursing home Nursing home Previous colonization of a multidrug-Previous colonization of a multidrug-

resistant organism resistant organism Advanced ageAdvanced age

How do patients acquire How do patients acquire MDRO’s?MDRO’s?

Select out the resistant strains due to Select out the resistant strains due to repeated courses of antibioticsrepeated courses of antibiotics

Spread from person to personSpread from person to person environmentenvironment hands of HCWhands of HCW patient equipmentpatient equipment contact with patientcontact with patient

Resistance is accelerated through inappropriate use of antimicrobials

–Standard treatment guidelines not provided–Provided but not adhered to

50 % prescriptions are inappropriate–Drugs not accessible

50% populations in developing countries do not have access

–Accessible but poor quality or expensive–Inadequate monitoring

50% of patients do not adhere to recommended regimen

–Irrational self-administration or prescription–Extensive use for therapeutic and growth promotion in animals

50% of national antibiotic consumption is for non-therapeutic purposes in animals

Multi-drug resistant Multi-drug resistant organismsorganisms

Gram positive organismsGram positive organisms MRSAMRSA VREVRE

Gram negative organismsGram negative organisms ESBLsESBLs CRECRE

MRSAMRSA NNIS (2004) – 60% of NNIS (2004) – 60% of S. aureusS. aureus are methicillin are methicillin

resistantresistant NosocomialNosocomial

mecAmecA gene encodes low affinity for PBP resulting in gene encodes low affinity for PBP resulting in resistance to all beta-lactamsresistance to all beta-lactams

Usually multi-drug resistantUsually multi-drug resistant Community-acquiredCommunity-acquired

More virulent – Panton-Valentine leukocidinMore virulent – Panton-Valentine leukocidin Skin and soft tissue infections in children and young Skin and soft tissue infections in children and young

adultsadults Usually susceptible to non beta-lactam drugsUsually susceptible to non beta-lactam drugs

VREVRE Non-existent as recently as 1989Non-existent as recently as 1989 NNIS report (2004) – 30% of all enterococcal NNIS report (2004) – 30% of all enterococcal

isolates are resistantisolates are resistant Mediated by vanA and vanB genes resulting in Mediated by vanA and vanB genes resulting in

alteration of target sitealteration of target site Clonal spread via poor infection controlClonal spread via poor infection control

Resistance in Gram Resistance in Gram negativesnegatives

AcinetobacterAcinetobacter Uncommon in most U.S. medical centersUncommon in most U.S. medical centers Incidence as high as 10% in some Incidence as high as 10% in some

geographic locationsgeographic locations Carbapenems are drug of choice Carbapenems are drug of choice

Pseudomonas aeruginosaPseudomonas aeruginosa Multi-drug resistance increasing nationwideMulti-drug resistance increasing nationwide

Fluoroquinolones: 29% resistance (NNIS 2004)Fluoroquinolones: 29% resistance (NNIS 2004) Beta-lactams: metallo-beta-lactamase producing Beta-lactams: metallo-beta-lactamase producing

strains have been reportedstrains have been reported

ESBLs a growing concern

Resistant to all penicillins, cephalosporins, and aztreonamCarbapenems are the drug of choice

Fluoroquinolone resistanceNNIS 2004 report: 8% E.coli resistantChromosomal and plasmid mediated alterations in target site or decreased access to target

Carbapenem resistanceKlebsiella pneumoniae carbapenemaseMetallo-beta-lactamasesampC beta-lactamase + loss of outer membrane channels

IVY HOSPITAL ANTIBIOGRAM (DEC 2010 - MAR 2011)

LACTOSE FERMENTING GNB (E. coli, Klebsiella spp., Citrobacter spp., Enterobacter spp., etc.)

TOTAL= 112 isolates

Percentage break up OF LFGNB( n= 112)

NON LACTOSE FERMENTING GNB (Acinetobacter spp, Pseudomonas spp. etc)

TOTAL = 55 ISOLATES

Staphylococcus aureus

(Total 21 isolates)

Prevention of antimicrobial Prevention of antimicrobial resistanceresistance

Prevent InfectionPrevent Infection VaccinateVaccinate Remove catheters Remove catheters

Diagnose and Treat Infection EffectivelyDiagnose and Treat Infection Effectively

Isolate the pathogen Isolate the pathogen

Target the pathogenTarget the pathogen

Access the expertsAccess the experts

Prevention of antimicrobial Prevention of antimicrobial resistanceresistance

Appropriate prescribing of antibioticsAppropriate prescribing of antibiotics Only prescribe antibiotics when Only prescribe antibiotics when

necessarynecessary Use local dataUse local data Treat infection, not contaminationTreat infection, not contamination Treat infection, not colonisation Treat infection, not colonisation Stop treatment when infection is cured Stop treatment when infection is cured

or unlikelyor unlikely

Prevention of antimicrobial Prevention of antimicrobial resistanceresistance

Surveillance:Surveillance: Moniters trends in resistance patterns, Moniters trends in resistance patterns,

incidence of MDROs, emerging MDROsincidence of MDROs, emerging MDROs

Locally, regionally, nationally, Locally, regionally, nationally, internationallyinternationally

Moniters effectiveness of interventionsMoniters effectiveness of interventions

Prevention of transmission to Prevention of transmission to other patientsother patients

Spread from person to personSpread from person to person Environment, hands of HCW, patient Environment, hands of HCW, patient

equipment, contact with patientequipment, contact with patient

Hand hygieneHand hygiene

Environmental cleaningEnvironmental cleaning

Antibiotic Stewardship Antibiotic Stewardship ProgramProgram

Optimal selection, dosage, and duration of Optimal selection, dosage, and duration of antimicrobial treatment thatantimicrobial treatment that Results in the best clinical outcome for the Results in the best clinical outcome for the

treatment or prevention of infectiontreatment or prevention of infection With minimal toxicity to the patient and With minimal toxicity to the patient and With minimal impact on subsequent resistanceWith minimal impact on subsequent resistance

Antibiotic Stewardship Antibiotic Stewardship ProgramProgram

InvolvesInvolves Prescribing antimicrobial therapy only Prescribing antimicrobial therapy only

when it is beneficial to the patientwhen it is beneficial to the patient Targeting therapy to the desired Targeting therapy to the desired

pathogenspathogens Using the appropriate drug, dose, and Using the appropriate drug, dose, and

durationduration

Antibiotic Policy : To Antibiotic Policy : To Minimise Antibiotic Minimise Antibiotic

ResistanceResistance Appropriate Use of Antibiotics and specific Appropriate Use of Antibiotics and specific

guidelines e.g. Therapy Recommendationsguidelines e.g. Therapy Recommendations

In serious infections; start with ultra-broad In serious infections; start with ultra-broad antibiotic then de-escalate to narrow spectrum antibiotic then de-escalate to narrow spectrum depending on culture reportdepending on culture report

Limit use of Broad Spectrum Antibiotics where Limit use of Broad Spectrum Antibiotics where possiblepossible

Antibiotic cycling/rotationAntibiotic cycling/rotation