Rao MD


Fleming and Penicillin

Dr.T.V.Rao MD


Self Medication
• The greatest possibility of evil in selfmedication is the use of too small doses so that instead of clearing up infection, the microbes are educated to resist penicillin and a host of penicillin-fast organisms is bread out which can be passed to other individuals and from them to other until they reach someone who gets a septicemia or a pneumonia which penicillin cannot save.
Sir AlexanderFlemming Dr.T.V.Rao MD

Antibiotic brands
• • • • • • 50 penicillin's 71 cephalosporins 12 tetracycline's 8 aminoglycosides 1 monobactam 5 Carbapenems • 9 macrolides • 2 streptogramins • 3 dihydrofolate reductase inhibitors • 1 oxazolidinone • 5.5 quinolones

Dr.T.V.Rao MD

Evolution of b-Lactamase Plasmid-Mediated TEM and SHV Enzymes
Ampicillin 1965 1970s Third-Generation Cephalosporins 1980s





TEM-1 E coli S paratyphi

TEM-1 Reported in 28 GramNegative Species
Dr.T.V.Rao MD

ESBL in Europe

ESBL >120 ESBLs in Worldwide United States

Development of anti-microbials
The development
ertapenem tigecyclin daptomicin linezolid telithromicin quinup./dalfop. cefepime ciprofloxacin aztreonam norfloxacin imipenem cefotaxime clavulanic ac. cefuroxime gentamicin cefalotina nalidíxico ac. ampicillin methicilin vancomicin rifampin chlortetracyclin streptomycin pencillin G

of anti-infectives …





1950 Dr.T.V.Rao1960 MD






1962 and 2000, no major classes of

antibiotics were introduced

Fischbach MA and Walsh CT Science 2009
Dr.T.V.Rao MD 7

A Changing Landscape for Numbers of Approved Antibacterial Agents
18 16

Number of agents approved

14 12 10 8 6 4 2 0


1983-87 1988-92 1993-97 1998-02 2003-05 2008

Bars represent number of new antimicrobial agents approved by the FDA during the period listed.
Infectious Diseases Society of America. Bad Bugs, No Drugs. July 2004; Spellberg B et al. Clin Infect Dis. 2004;38:1279-1286; New antimicrobial agents. Antimicrob Agents Chemother. 2006;50:1912

Dr.T.V.Rao MD


• Biology and Society

About 50% of the antibiotics produced today are used in the livestock industry. What impact does this have on the treatment of human diseases?

Dr.T.V.Rao MD


ANTIMICROBIAL RESISTANCE: The role of animal feed antibiotic additives

• 48% of all antibiotics by weight is added to animal feeds to promote growth. Results in low, sub therapeutic levels which are thought to promote resistance. • Farm families who own chickens feed tetracycline have an increased incidence of tetracycline resistant fecal flora

Dr.T.V.Rao MD


Prescribing an antibiotic
 Is an antibiotic necessary ?  What is the most appropriate antibiotic ?  What dose, frequency, route and duration ?

 Is the treatment effective ?
Dr.T.V.Rao MD 12

How are antibiotics overused or Misused?
• Seven out of ten Americans receive antibiotics when they seek treatment for a common cold! Only one-third of patients use antibiotics the way doctors tell them. • This allows bacteria to become resistant by not killing them completely.
Dr.T.V.Rao MD


Antibiotic Prescribing Children are real Concern
• Antibiotics were prescribed in 68% of acute respiratory tract visits – and of those, 80% were unnecessary according to CDC guidelines • Children are of particular concern because they have the highest rates of Dr.T.V.Rao MD antibiotic use.


We too Contribute for Creating Drug Resistance
• Every time a person takes antibiotics, sensitive bacteria are killed, but resistant microbes may be left to grow and multiply. Repeated and improper uses of antibiotics are primary causes of the increase in drugresistant bacteria.
Dr.T.V.Rao MD 15

The consequences of antibiotic resistance
• Increased morbidity & mortality
– “best-guess” therapy may fail with the patient’s condition deteriorating before susceptibility results are available – no antibiotics left to treat certain infections

• Greater health care costs
– more investigations – more expensive, toxic antimicrobials required – expensive barrier nursing, isolation, procedures, etc.

• Therapy priced out of the reach of some third-world countries
16 Dr.T.V.Rao MD

• ↑Treatment failures • ↑Morbidity and mortality • ↑Risk of hospitalization • ↑Length of hospital stays • ↑Need for expensive and broad spectrum antibiotics
Dr.T.V.Rao MD 17

Costs Associated with Increased Bacterial Resistance

Social factors fuelling resistance
• Poverty encourages the development of resistance through under use of drugs
– Patients unable to afford the full course of the medicines – Sub-standard & counterfeit drugs lack


• Globalization, increased travel and trade ensure that resistant strains quickly travel elsewhere. So does excessive


Dr.T.V.Rao MD

Developed countries Overuse
• In wealthy countries, resistance is emerging for the opposite reason – the overuse of drugs. • Unnecessary demands for drugs by patients are often eagerly met by health services and stimulated by pharmaceutical promotion • Overuse of antimicrobials in food production is also contributing to increased drug resistance.
Dr.T.V.Rao MD 19

Classification of Pencillins
• Natural Benzyl penicillin Phenoxymethyl penicillin Penicillin v Semi synthetic and pencillase resistant

1 Methicillin 2 Nafcillin 3 Cloxacillin 4 Oxacillin 5 Floxacillin

Dr.T.V.Rao MD


• Contain macro cyclic lactone ring Erythromycin. Is popularly used drug • Other drugs Roxithromycin,Azithromy cin • Inhibits the protein synthesis. • Used as alternative to pencillin allergy patients.
Dr.T.V.Rao MD 21

Dr.T.V.Rao MD


• Like penicillin acts similar • Products of the molds of genus Cephalosporium except cefoxilin • Divided into 4 generation of Cephalosporins depending on the spectrum of activity. Dr.T.V.Rao MD


Major generations of Cephalosporins
• Cephalosporins are divided into 3 generations: • 1st generation: Cephalexin, cefadroxil, cephradine

• 2nd generation: Cefuroxime, cofactor
• 3rd generation: cefotaxime, Ceftazidime, cefepime - these give the best CNS penetration

• 4th generation Cephalosporins are already
Dr.T.V.Rao MD 24

Different Generations of Cephalosporins
• Cephalosporins are grouped into "generations" based on their spectrum of antimicrobial activity. The first Cephalosporins were designated first generation while later, more extended spectrum Cephalosporins were classified as second generation Cephalosporins.
Dr.T.V.Rao MD 25

5th Generation Cephalosporins
• Ceftaroline is a new intravenous (IV) cephalosporin that was FDA-approved October 2010. It is labelled for the treatment of adults with infections caused by susceptible bacteria, specifically skin and skin structure infections (SSSIs) caused by methicillinsensitive
Dr.T.V.Rao MD 26

5th Generation Cephalosporins
• Staphylococcus aureus (MSSA), methicillinresistant S aureus (MRSA), Streptococcus pyogenes, Streptococcus agalactiae, Escherichia coli, Klebsiella pneumoniae, or Klebsiella oxytoca; and community acquired pneumonia (CAP) caused by Streptococcus pneumoniae (with or without concurrent bacteraemia), MSSA, E coli, Haemophilus influenza, K.pneumoniae, or K oxytoca
Dr.T.V.Rao MD 27

Ceftaroline is effective …
• Ceftaroline is a fifth generation cephalosporin with excellent activity against GPCs including MRSA & DRSP Affinity for all PBPs including PBP 2’ and PBP 2X Not ESBL stable, Not active against Non fermenters
Dr.T.V.Rao MD 28

Irrational Use of Third Generation Cephalosporins
• Several studies have demonstrated that patterns of antibiotic usage greatly affect the number of resistant organisms which develop. Overuse of broadspectrum antibiotics, such as second- and thirdgeneration Cephalosporins, generate resistant strains.

Dr.T.V.Rao MD


Advantages with Newer generations
• Each newer generation of cephalosporins has significantly greater gram-negative antimicrobial properties than the preceding generation, in most cases with decreased activity against gram-positive organisms. Fourth generation cephalosporins, however, have true broad spectrum activity
Dr.T.V.Rao MD 30

Other Beta-lactams include
• Other beta-lactams include: • Aztreonam: a monocytic betalactam, with an antibacterial spectrum which is active only against Gram negative aerobes, including Pseudomonas aeruginosa, Neisseria meningitides and N. gonorrhoea.
Dr.T.V.Rao MD 31

How are Carbapenems Used?
Uses by Clinical Syndrome • Bacterial meningitis • Hospital-associated sinusitis • Sepsis of unknown origin • Hospital-associated pneumonia
Use by Clinical Isolate  Acinetobacter spp.  Pseudomonas aeruginosa  Alcaligenes spp.  Enterobacteriaceae
    

Mogenella spp. Serratia spp. Enterobacter spp. Citrobacter spp. ESBL or AmpC + E. coli and Klebsiella spp.

Reference: Sanford Guide Dr.T.V.Rao MD


Spectrum of Activity
Strep spp. & MSSA Enterobacteriaeae Nonfermentors



+ + + +

+ + + +

+ +
Limited activity

+ + + +





Emerging Carbapenem Resistance in Gram-Negative Bacilli
• Significantly limits treatment options for life-threatening infections • No new drugs for gram-negative bacilli • Emerging resistance mechanisms, carbapenemases are mobile,
• Detection of carbapenemases and implementation of infection control practices are necessary to limit spread
Dr.T.V.Rao MD 34


® (Cubicin )

• New drug class (lipopeptide) • Rapidly bactericidal • New mechanism of action: acts by binding to cell membrane and disrupting the cell membrane potential • No cross resistance • Dose: 4-6 mg/kg once daily

Other drugs
• Imipenem: a carbapenem with a broader spectrum of activity against Gram positive and negative aerobes and anaerobes. Needs to be given with cilastatin to prevent inactivation by the kidney.
Dr.T.V.Rao MD 36

• Quinolones are the first wholly synthetic antimicrobials. The commonly used Quinolones. • Act on the DNA gyrase which prevents DNA polymerase from proceeding at the replication fork and consequently stopping synthesis.
Dr.T.V.Rao MD 37

• Aminoglycosides are group of antibiotics in which amino sugars liked by glycoside bonds • Eg Streptomycin, • Act at the level of Ribosome's and inhibits protein synthesis • Other Aminoglycosides –

neomycins,paromomycins,tobr amycins Kanamycins and


Dr.T.V.Rao MD


Dr.T.V.Rao MD


• Broad spectrum antibiotic produced by Streptomyces species • 1. Oxytetracycle, chlortetracycle and tetracycline • Tetracyclnes are bacteriostatic drugs inhibits rapidly multiplying organisms • Resistance develops slowly and attributed to alterations in cell membrane permeability to enzymatic inactivation of the drug
Dr.T.V.Rao MD 40

Other Antimicrobial agents
• Lincomycins Clindamycin resembles Macrolides in biting site and antimicrobial activity. Streptogramins Quinpristin / dalfopristin useful in gram positive bacteria
Dr.T.V.Rao MD 41

Antibiotics in Anaerobes
• Major anaerobes – Anaerobic cocci, clostridia and Bactericides are susceptible to Benzyl pencillin • Bact.fragilis as well as many other anaerobes are treatable with Erythromycin,Lincomycin, tetracycline and Chloramphenicol • Clindamycin is effective against many strains of Dr.T.V.Rao MD Bacteroides


Metronidazole in Anaerobic Infections
• Since the discovery of Metronidazole in 1973 since then it was identified as leading agent anaerobes. • But also useful in treating parasitic infections Trichomonas, Amoebiasis and other protozoan infections.

Dr.T.V.Rao MD


Treatment of N. gonorrhoea
• Only current CDC-recommended options for treating N. gonorrhoea infections are from a single class of antibiotics, the cephalosporins.
– Ceftriaxone, available only as an injection, is the recommended treatment for all types of gonorrhea infections (i.e., urogenital, rectal, and pharyngeal). – Cefixime is the only oral agent recommended for treatment of uncomplicated urogenital or rectal gonorrhea Reduced susceptibility to cefixime being described in Japan and other countries

Drug Resistance
• In spite discovery of several antibiotics several microorganisms attained resistance. • The major factor contributing to persistence of infectious disease has been the tremendous capacity of microorganisms for circumventing the action of inhibitory drugs. • The drug resistance continues to be a threat for usefulness of the chemotherapeutic agents.
Dr.T.V.Rao MD 45

Inappropriate Antibiotic Use

Use of antibiotics with no clinical indication (eg, for viral infections)

Use of broad spectrum antibiotics when not indicated Inappropriate choice of empiric antibiotics

Dr.T.V.Rao MD


Multi Drug resistant pathogens
• If a bacterium carries several resistance genes, it is called multiresistant or, informally, a superbug. The term antimicrobial resistance is sometimes use to explicitly encompass organisms other than Dr.T.V.Rao MD bacteria


Extended-Spectrum β-Lactamases
• β-lactamases capable of conferring bacterial resistance to

– the penicillins – first-, second-, and third-generation cephalosporins – aztreonam – (but not the cephamycins or carbapenems)
• These enzymes are derived from group 2b β-lactamases (TEM-1, TEM-2, and SHV-1)

– differ from their progenitors by as few as one AA
Dr.T.V.Rao MD


Antibiotic Resistance Threat to Humans and Animals
• Antibiotic resistance has become a serious problem in both developed and underdeveloped nations. By 1984 half of those with active tuberculosis in the United States had a strain that resisted at least one antibiotic. In certain settings, such as hospitals and some childcare location
Dr.T.V.Rao MD 49

• Ability to hydrolyze penicillins, cephalosporins, monobactams, and carbapenems • Resilient against inhibition by all commercially viable ßlactamase inhibitors
– Subgroup 2df: OXA (23 and 48) carbapenemases – Subgroup 2f : serine carbapenemases from molecular class A: GES and KPC – Subgroup 3b contains a smaller group of MBLs that preferentially hydrolyze carbapenems
• IMP and VIM enzymes that have appeared globally, most frequently in non-fermentative bacteria but also in Enterobacteriaceae
Dr.T.V.Rao MD 50

K. pneumonia carbapenemases)
• KPCs are the most prevalent of this group of enzymes, found mostly on transferable plasmids in K. pneumonia • Substrate hydrolysis spectrum includes cephalosporins and carbapenems
Dr.T.V.Rao MD 51

Consequences of Antibiotic drug Resistance
• People infected with drug-resistant organisms are more likely to have longer and more expensive hospital stays, and may be more likely to die as a result of the infection. They require treatment with second- or thirdchoice drugs that may be less effective, more toxic, and more expensive. This means that patients with an antimicrobial-resistant infection may suffer more and pay more for treatment. (Issues with Insurance)
Dr.T.V.Rao MD


Emerging Trends in Antibiotic Resistance
• Reports of methicillin-resistant Staphylococcus aureus (MRSA)—a potentially dangerous type of staph bacteria that is resistant to certain antibiotics and may cause skin and other infections—in persons with no links to healthcare systems have been observed with increasing frequency in the United States and elsewhere around the globe.
Dr.T.V.Rao MD 53

Gram negative bacteria a great threat
• Multi-drug resistant Klebsiella species and Escherichia coli have been isolated in hospitals throughout the United States. • It is a Universal phenomenon
Dr.T.V.Rao MD 54

• Indian hospitals have reported very high Gram-negative resistance rates, with very high prevalence of ESBL (Extended Spectrum Beta Lactamases) producers and also high carbapenem resistance rates. Increasing carbapenem resistance will invariably result in increased usage of colistin, currently the last line of defence, with a potential for colistinresistant and Pan Drug Resistant bacterial infections.
Dr.T.V.Rao MD


Fungi too becoming resistant
• Antimicrobial resistance is emerging among some fungi, particularly those fungi that cause infections in transplant patients with weakened immune systems.

Dr.T.V.Rao MD


Resistance in Virus
• Antimicrobial resistance has also been noted with some of the drugs used to treat human immunodeficiency virus (HIV) infections and influenza.
Dr.T.V.Rao MD 57

Parasites too are Problematic
• The development of antimicrobial resistance to the drugs used to treat malaria infections has been a continuing problem in many parts of the world for decades. Antimicrobial resistance has developed to a variety of other parasites that cause infection. •
Dr.T.V.Rao MD 58

 Laboratory diagnosis  Interpretation of the report  What is isolated is not necessarily the pathogen
 Was the specimen properly collected ?

Identification of The Etiological Agent

 Is it a contaminant or colonizer ?  Sensitivity reports are at best a guide
Dr.T.V.Rao MD 59

Limitations of combination of antibiotics
• The role of combination antimicrobial therapy for the prevention of resistance is limited to those situations in which there is  A high organism load  A high frequency of mutational resistance during therapy. • Classic examples are tuberculosis or HIV infection.

Dr.T.V.Rao MD


Problems With Improper Use of Antibiotics
• They don’t help the patient at all • Expense: 75% of outpatient antibiotics are used for respiratory infections • Patient expectations: why no better? • Side effects: diarrhea, rash, allergy

• Development of resistance: the antibiotic
won’t work when you really DO need it for a bacterial infection
Dr.T.V.Rao MD 61

WHO global strategy on reducing the
antibiotic resistance

• The WHO Global Strategy for Containment of Antimicrobial Resistance identifies the establishment and support of microbiology laboratories as a fundamental priority in guiding and assessing intervention efforts.
Dr.T.V.Rao MD


Importance of local antibiotic Resistance data
 Resistance patterns vary
 From country to country  From hospital to hospital in the same country  From unit to unit in the same hospital

 Regional/Country data useful only for looking at trends NOT guide empirical therapy
Dr.T.V.Rao MD 63

Streamlining or De-Escalation of Therapy
– On the basis of culture and sensitivity reports we can more effectively target the causative pathogens, by elimination of redundant combination therapy – Resulting in decreased Ab exposure and substantial cost savings
Dr.T.V.Rao MD 64

Continuous Medical Education a Must .. Training and educating
health care professionals on the appropriate use of antibiotics must include appropriate selection, dosing, route, and duration of antibiotic therapy. To ensure that training and education is working, there should be extensive collaboration between the antibiotic stewardship and hospital infection prevention and control teams.
Dr.T.V.Rao MD 65

Antibiotic Pressure and Resistance in Bacteria
What factors promote their development and spread ?

 Alteration of normal flora

 Practices contributing to misuse of antibiotics  Settings that foster drug resistance  Failure to follow infection control principles
Dr.T.V.Rao MD 66

Practices Contributing to Misuse of Antibiotics
 
 
Inappropriate specimen selection and

Inappropriate clinical tests
Failure to use stains/smears Failure to use cultures and susceptibility tests
Dr.T.V.Rao MD 67

Settings that Foster Drug Resistance

     


Intensive care units
Oncology units Dialysis units Rehab units Transplant units Burn units
Dr.T.V.Rao MD 68

What Is Antimicrobial Stewardship?
• A combination of infection control and antimicrobial

management • Mandatory infection control compliance • Selection of antimicrobials from each class of drugs that does the least collateral damage • Collateral damage issues include – MRSA – ESBLs – C difficile – Stable derepression – MBLs and other carbapenemases – VRE • Appropriate de-escalation when culture results are available Dellit TH, et al. Clin Infect Dis. 2007;44:159-177.
Dr.T.V.Rao MD 69

IDSA Guidelines – Definition of Antimicrobial Stewardship
• Antimicrobial

stewardship is an activity that

promotes – The appropriate selection of antimicrobials – The appropriate dosing of antimicrobials

– The appropriate route and duration of antimicrobial therapy
Dr.T.V.Rao MD 70

The Primary Goal of Antimicrobial Stewardship
• The primary goal of antimicrobial stewardship is to – Optimize clinical outcomes while minimizing unintended consequences of antimicrobial use • Unintended consequences include the following – Toxicity – The selection of pathogenic organisms, such as C difficile – The emergence of resistant pathogens

Dr.T.V.Rao MD


Practices Contributing to Misuse of Antibiotics

  
Inappropriate specimen selection and collection
Inappropriate clinical tests Failure to use stains/smears Failure to use cultures and susceptibility tests

Dr.T.V.Rao MD


 Laboratory diagnosis  Interpretation of the report  What is isolated is not necessarily the pathogen
 Was the specimen properly collected ?

Identification of The Etiological Agent

 Is it a contaminant or colonizer ?  Sensitivity reports are at best a guide

• Legacy computer systems, quality improvement teams, and strategies for optimizing antibiotic use have the potential to stabilize resistance and reduce costs by encouraging heterogeneous prescribing patterns and use of local susceptibility patterns to inform empiric treatment.
Dr.T.V.Rao MD 74

Growing importance of

• World over antimicrobial resistance is a major public health problem. The WHONET software program puts each laboratory data into a common code and file format, which can be merged for national or global collaboration of antimicrobial resistance surveillance
Dr.T.V.Rao MD 75

Whonet helps us in ……
• The understanding of the local epidemiology of microbial populations; the selection of antimicrobial agents; the identification of hospital and community outbreaks; and the recognition of quality assurance problems in laboratory testing.
Dr.T.V.Rao MD 76

Drugs Under Development
• Lipopetides (Daptomycin: narrow therapeutic index) • Glycyclines • Glycopeptides (Vancomycin analogues) • Fluoroquinolones • Macrolides/Ketolides • Evernimicin (trials on hold)
Dr.T.V.Rao MD 77

Physicians Can Impact
Other clinicians

Optimize patient evaluation Adopt judicious antibiotic prescribing practices Immunize patients

Optimize consultations with other clinicians Use infection control measures Educate others about judicious use of antibiotics

Dr.T.V.Rao MD

A good clinical practice saves antibiotics
• Treatment should be limited to bacterial infections, using antibiotics directed against the causative agent, given in optimal dosage, interval and length of treatment, with steps taken to ensure maximum patient compliance with the treatment regimen and only when the benefit of treatment outweighs the Dr.T.V.Rao MD


Continuous Medical Education a Must ..
• Training and educating health care professionals on the appropriate use of antibiotics must include appropriate selection, dosing, route, and duration of antibiotic therapy. To ensure that training and education is working, there should be extensive collaboration between the antibiotic stewardship and hospital infection prevention and control teams

Dr.T.V.Rao MD


Chennai Declaration
• The Chennai Declaration wants India to take urgent initiatives to formulate an effective national policy to control the rising trend of antimicrobial resistance and to ban on over-thecounter sale of antibiotics. • Chennai: ‘The Chennai Declaration: A roadmap to tackle the challenge of antimicrobial resistance’ published in the latest edition of Indian Journal of Cancer has recommended to make it mandatory to set up an Infection Control Team (ICT) in all hospitals.
Dr.T.V.Rao MD 81

Educating the Educated
• The recommendations include offering PostMD/DNB (internal medicine) sub-specialisation in Infectious Diseases at all post-graduate centres that offer sub-speciality training, compulsory training in infection control and infectious diseases training in under-graduate and post graduate curriculum in all specialities. The Medical Council of India should introduce oneweek antibiotic stewardship and infection control training in the third, fourth and final year of MBBS and two-week training at the PG level.
Dr.T.V.Rao MD 82

Creating a Task force
• Recommending the setting up of a National Task Force to guide and supervise the regional and State infection control committees, the paper suggests that the National Accreditation Board for Hospitals & Healthcare Providers (NABH) insist on strict implementation of hospital antibiotic and infection control policy, during hospital accreditation and reaccreditation processes.
Dr.T.V.Rao MD 83

Are we overusing Antibiotics

Dr.T.V.Rao MD


Good hand washing practices still reduces antibiotic resistance and spread

Dr.T.V.Rao MD


 Antibiotic resistance is a major problem world-wide  Resistance is inevitable with use  No new class of antibiotic introduced over the last two decades  Appropriate use is the only way of prolonging the useful life of an antibiotic
Dr.T.V.Rao MD 86

Antibiotics save Lives Save Antibiotics from Misuse

Dr.T.V.Rao MD


Dr.T.V.Rao MD


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