Awarenessof Antibiotics
BY
Dr Hussein Fatehy
Consultant pulmonologist
PhD-FCCP-MCTS
Abbassia Chest Hospital
Antibiotics

Definition
Antibiotics are substances that
kill or inhibit the growth of
micro-organisms.
Bacteriostatic (Tet...
History
Thanks to work by Alexander Fleming (1881-1955), Howard
Florey ( 1898-1968) and Ernst Chain (1906-1979), penicilli...
Why take antibiotics?




"The desire to take
medicine is perhaps the
greatest feature which
distinguishes man from
anim...
Indications for antibacterial therapy:
1. Definitive therapy
•This is for proven bacterial infections
•Attempts should be ...
2. Empirical therapy
• Empirical antibacterial therapy should be restricted
to critical cases, when time is inadequate for...
3. Prophylactic therapy
•

Certain clinical situations require the use of
antibiotics for the prevention rather than the
t...
Bacteria vs Host

Bacteria

Host

Pathogen Vs non pathogen

Host defence

Virulence

antibiotic

Disease
Selection of
antimicrobial agents
Factors should be considered before
prescribing antibacterial agent
1. Site of infection
2. Type of infection
3. Severity ...
1. Site of infection
Infection above the diaphragm:
•URTI eg pharyngitis, tonsilitis, sinusitis, otitis,
epiglottitis etc....
1. Site of infection…con’t
Lower respiratory tract infections:
Eg. Bronchitis, pneumonitis, pneumonia, lung abscess
etc
-g...
1. Site of infection …. con’t
Infection below the diaphragm:
•Eg UTI, intra-abdominal sepsis, pelvic infections etc --thes...
1. Site of infection …. con’t
• There are certain sites where the infection tends to be difficult for
treatment :
- mening...
2. Type of infection
Infections can be localised/extensive; mild/severe;
superficial/deep-seated; acute/sub acute/chronic ...
3. Severity of infections
• Bacteremia / sepsis syndrome / septic shock;
• abscess in lung / brain/ liver/ pelvis/ intra-a...
4. Isolate & sensitivity
• Ideal management of any significant bacterial
infection requires culture & sensitivity (C&S) st...
5. Source of infection
Community-acquired infections are
less likely to be resistant
whereas
Hospital-acquired infections ...
6. Patient factors
• Factors should be considered in choosing the
antibacterial agent:
- Age of the patient
- immune statu...
Patient factors…….con’t
Children

- Tetracycline are contraindicated < 8
years because they discolour the teeth
- < 18 yea...
Patient factors…….con’t
Patients with compromised immune status
• In patients with likelihood of
compromised immune status...
Patient factors…….in pregnancy
Contraindicated in all trimesters
• tetracylines

Contraindicated in the last trimesters
• ...
Patient factors…….in patients
with renal failure
Absolutely contraindicated
• tetracycline

Relatively contraindicated
•Am...
Patient factors…….in patients
with hepatic failure
No drugs are absolutely contraindicated.
Relatively contraindicated

Sa...
7. Drug factors

1. Hypersensitivity:
If the patient has prior history of hypersensitivity the
antibacterial agent should ...
7. Drug factors

3. Cost:
It should always be remembered that just because as
particular drug is expensive, it need not be...
7. Drug factors…….con’t
4. Interactions:

Interactions with food & other concomitant drugs should be
considered before ins...
Methods of administration of antimicrobials
Route of administration
The route of administration depends on the site, type ...
Route of administration…….con’t
- IV

route is the best for the management of severe &
deep-seated infections since it ens...
Switching from IV to
Oral

 Step-down

therapy:
Conversion of an IV antibiotic to another
oral
 Transitional therapy:
Co...
Dosage
- Dosage depends on patient’s age, weight, associated
conditions like pregnancy, renal & hepatic failure &
site, ty...
Frequency of administration
• The drug should be administered 4-5x the plasma
half-life to maintain adequate therapeutic
c...
Duration
• Duration of therapy depends on the site
1) Tonsilitis – 10 days
2) Bronchitis – 5-7 days
3) UTI – single shot t...
Combinations
1) For synergistic effect:
eg: combination of 2 bacteriostatic drugs such as

trimethoprim + sulfamethoxazole...
Combinations…….con’t
2) Treatment of infections with multiple
organisms:
Mixed infections in lung abcess, peritonitis, soi...
Combinations…….con’t
3) To prevent resistance:

Use of combination is a well known method of
preventing drug resistance. T...
The following combinations are irrational, not useful
or even harmful:
1) Bactericidal with bacteriostatic
eg. Penicillins...
Clinical failure of
antimicrobial
therapy
Failure of an antibiotic regimen (1)
Inadequate clinical or microbiological response to
antimicrobial therapy can result f...
Failure of an antibiotic regimen (2)
2) Host factors
•

poor host defense,

•

age

•

renal & liver function

•

pre-exis...
Antibiotic Resistance
“Penicillin Era”


1942-1950 available without a prescription
Public demand followed by production of throat
sprays, coug...
The Problem of Antibiotic
Resistance
 Penicillin

resistance first identified in 1940’s
 Since then, antibiotic resistan...
History
INTRODUCTION

APPEARANCE
OF RESISTANCE

Penicillin

1943

1946

Streptomycin

1945

1959

Tetracycline

1948

1953...
Antibiotic Resistance
 Relative

or complete lack of effect of
antimicrobial against a previously
susceptible microbe

• ...
What Factors Promote Antimicrobial
Resistance?
What causes the rapid occurrence of widespread
resistance?

(1) Incomplete ...
What Factors Promote Antimicrobial
Resistance?
(2) Mis-prescription:
- patients demand antibiotics
for cold
- widespread i...
Inappropriate Antibiotic Use
 Prescription

not taken correctly
 Antibiotics for viral infections
 Antibiotics sold wit...
Mechanisms of Antibiotic
Resistance (1)
•

The four main mechanisms by which microorganisms
exhibit resistance to antibiot...
Mechanisms of Antibiotic
Resistance (2)
(3) Alteration of metabolic pathway:
e.g. some sulfonamide-resistant bacteria do n...
Resistance: β-lactamase Enzymes
• β-Lactam
antibiotics act by
inhibiting the
synthesis of the
peptidoglycan
layer of bacte...
β-lactamases
 Enzymes

produced by bacteria which
destroy β-lactam antibiotics

 Many

different types

 Most

are plas...
Overcoming β-lactam Resistance
slow to
hydrolyze



As a response to bacterial resistance to β-lactam drugs, there are
dr...
Overcoming β-lactam Resistance
Amoxicillin (β-lactam antibiotic)
+ clavulanic acid (a β-lactamase inhibitor)
= Co-amoxicla...
Genetic alterations in drug
resistance


Acquired antibiotic resistance requires the
temporary or permanent gain or alter...
Spontaneous mutation of DNA






Stable and heritable genetic change
Not induced by antimicrobial agents
Resistance v...
DNA/Gene transfer of drug
resistant
conjugation

transformation

transduction




DNA Most resistance genes are plasmid ...
Measuring Antimicrobial
Sensitivity
Disk
E-

Diffusion

test

(antimicrobial
gradient method)

Serial

dilution
Measuring Antimicrobial
Sensitivity
MIC

increase in the
case of resistance

(Minimal inhibitory concentration)
- importa...
Consequences of Antimicrobial
Resistance
Infections

resistant to
available
antibiotics

Increased

cost
of treatment
Prevention of resistance
 Speed

development of new antibiotics
 Track resistance data nationwide
 Restrict antimicrobi...
Pathogen

Drug (s) of first choice

Alternative Drug (s)

Gram +ve cocci
Pneumococcus

Penicillin G, Ampicillin

Erythromy...
RECOMMENDATIONS
Don'ts about antibiotics







DO NOT...pressure your doctor to prescribe an
antibiotic .
DO NOT...ta...
RECOMMENDATIONS
Do's about antibiotics
 DO...ask your doctor whether your infection or your
family member's infection wil...
Awareness of antibiotics
Awareness of antibiotics
Awareness of antibiotics
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  • Accutely ill patients with infections of unknown origin – require immediate treatment.
  • Drug factors – penetration into CSF
    Local factors- Pus – phagocytes, fibrin, protein can bind drugs and alter activity.
    Hemoglobin can bind penicillins and teteracyclines
    pH: low ph reduces effetivesness of aminoglycosides, erythromycin, clindamycin
    Anaerobic conditions. Aminoglycosides require oxygen to transport into bacteria
    Foreign body(cardiac valves, prosthetic joint) attractphagocytes which may destroy drug
    Host- BMT patient with no neutrophils, fast and slow acetylaters with isoniazid
    Host – age, renal function, liver function, pre-existing dysfunctionof other organs
    CA-mRSA with Panton valentine leukocidin
  • Drug factors – penetration into CSF
    Local factors- Pus – phagocytes, fibrin, protein can bind drugs and alter activity.
    Hemoglobin can bind penicillins and teteracyclines
    pH: low ph reduces effetivesness of aminoglycosides, erythromycin, clindamycin
    Anaerobic conditions. Aminoglycosides require oxygen to transport into bacteria
    Foreign body(cardiac valves, prosthetic joint) attractphagocytes which may destroy drug
    Host- BMT patient with no neutrophils, fast and slow acetylaters with isoniazid
    Host – age, renal function, liver function, pre-existing dysfunctionof other organs
    CA-mRSA with Panton valentine leukocidin
  • MRSA deaths exceeds death rate for AIDS in US.
    Globally – TB resistance
    Institute of Medicine estimates 1998
    JAMA 2007 Klevens et al.
    Costs can be looked at patient, physician, provider, industry, public.
  • β-Lactam antibiotics act by inhibiting the synthesis of the peptidoglycan layer of bacterial cell walls.
  • If the cell survives, it can replicate and transmit its mutated properties to progeny cells.
  • MIC - the lowest concentration of an antimicrobial that will inhibit the visible growth of a microorganism after overnight incubation.
    Culture and Susceptibility Testing
    1) Disk diffusion (Kirby Bauer)
    2) Serial dilution (Macro and micro)
    Automated (Vitek, MicroScan)
    3) Antimicrobial gradient method (E test)
  • Awareness of antibiotics

    1. 1. Awarenessof Antibiotics BY Dr Hussein Fatehy Consultant pulmonologist PhD-FCCP-MCTS Abbassia Chest Hospital
    2. 2. Antibiotics Definition Antibiotics are substances that kill or inhibit the growth of micro-organisms. Bacteriostatic (Tetracycline, Chloramphenicol) Bactericidal (Beta lactams, Aminoglycosides) .
    3. 3. History Thanks to work by Alexander Fleming (1881-1955), Howard Florey ( 1898-1968) and Ernst Chain (1906-1979), penicillin was first produced on a large scale for human use in 1943. At this time, the development of a pill that could reliably kill bacteria was a remarkable development and many lives were saved during World War II because this medication was available. A. Fleming E. Chain H. Florey Yang BC
    4. 4. Why take antibiotics?   "The desire to take medicine is perhaps the greatest feature which distinguishes man from animals." "One of the first duties of the physician is to educate the masses not to take medicine" William Osler, MD (1849 - 1919) H. Cushing, Life of Sir William Osler (1925)
    5. 5. Indications for antibacterial therapy: 1. Definitive therapy •This is for proven bacterial infections •Attempts should be made to confirm the bacterial infection by means of staining of secretions/fluids/exudates, culture & sensitivity, serological tests & other tests •Based on the reports, a narrow spectrum, least toxic, easy to administer & cheap drug should be prescribed.
    6. 6. 2. Empirical therapy • Empirical antibacterial therapy should be restricted to critical cases, when time is inadequate for identification & isolation of the bacteria & reasonably strong doubt of bacterial infection exists: - septicemic shock/sepsis syndrome - immunocompromised patients with severe systemic infection - hectic temperature - neutropenic patient (reduction in neutrophils) In such situations, drugs that cover the most probable infective agent/s should be used. Empiric antibiotic is antibiotic therapy that is begun before a specific pathogen is identified
    7. 7. 3. Prophylactic therapy • Certain clinical situations require the use of antibiotics for the prevention rather than the treatment of infections. • In all these situations, only narrow spectrum & specific drugs are used • The duration of prophylaxis is dictated by the duration of the risk of infection. • eg. 1. Prevention for persons from non-malarious areas who visit areas endemic for malaria. 2. Treatment prior to certain surgical procedures to prevent infections
    8. 8. Bacteria vs Host Bacteria Host Pathogen Vs non pathogen Host defence Virulence antibiotic Disease
    9. 9. Selection of antimicrobial agents
    10. 10. Factors should be considered before prescribing antibacterial agent 1. Site of infection 2. Type of infection 3. Severity of infection 4. Isolate & its sensitivity 5. Source of infection 6. Patient factors 7. Drug-related factors
    11. 11. 1. Site of infection Infection above the diaphragm: •URTI eg pharyngitis, tonsilitis, sinusitis, otitis, epiglottitis etc. - commonly caused by organism like Strep. pyogenes, S. pneumoniae, Fusobacteria, Peptostreptococci (rarely Mycoplasma, H. influenzae) - Can be treated with drugs like penicillins macrolides cephalosporins
    12. 12. 1. Site of infection…con’t Lower respiratory tract infections: Eg. Bronchitis, pneumonitis, pneumonia, lung abscess etc -generally caused by the organisms Strep. pyogenes, S. pneumoniae, Fusobacteria, Peptostreptococci, Staph aureus (rarely Mycoplasma, H. influenzae, Moraxella, Klebsiella) etc. - can be treated penicillins, cephalosporins, macrolides & tetracylines
    13. 13. 1. Site of infection …. con’t Infection below the diaphragm: •Eg UTI, intra-abdominal sepsis, pelvic infections etc --these are caused by the organisms like E. coli, Klebsiella, Proteus, Pseudomonas, Bacteroides etc. • Quinolones, aminoglycosides, 3rd generation cephalosporins & metronidazole alone or in combination are useful in these infections. Rule of the thumb Infections above the diaphragm Cocci & Gram +ve organisms Infections below the diaphragm Bacilli & Gram -ve organisms
    14. 14. 1. Site of infection …. con’t • There are certain sites where the infection tends to be difficult for treatment : - meningitis (impenetrable BBB), - chronic prostatitis (non-fenestrated capillaris), - intra-ocular infections (non-fenestrated capillaries), - abscesses (thick wall, acidic pH, hydrolizing enzymes etc.), - cardiac & intravascular vegetations (poor reach & penetration), - osteomyelitis (avascular sequestrum) etc In such cases:Higher & more frequent dose Longer duration of therapy Combinations Lipophilic drugs may have to be used
    15. 15. 2. Type of infection Infections can be localised/extensive; mild/severe; superficial/deep-seated; acute/sub acute/chronic & extracellular/intracellular. For extensive, severe, deep-seated, chronic & intracellular infections – • Higher & more frequent dose • Longer duration of therapy • Combinations • Lipophilic drugs may have to be used
    16. 16. 3. Severity of infections • Bacteremia / sepsis syndrome / septic shock; • abscess in lung / brain/ liver/ pelvis/ intra-abdominal; • meningitis/ endocarditis/ pneumonias / pyelonephritis / puerperal sepsis; • Severe soft tissue infections / gangrene & hospital acquired infections For severe infections only IV route - to ensure adequate blood levels. only bacterial drugs - to ensure faster clearance of the infection. dose should be higher & more frequent. - If the site is unknown, attempt should be made to cover all possible organisms, including drug resistant Staphylococcus, Pseudomonas, & anaerobes. - A combinations of Penicillins / 3rd generation cephalosporins, aminoglycosides & metronidazole may be used.
    17. 17. 4. Isolate & sensitivity • Ideal management of any significant bacterial infection requires culture & sensitivity (C&S) study of the specimen. • If the situation permits, antibacterials can be started only after the sensitivity report is available. • Narrow spectrum, least toxic, easy to administer & cheapest of the effective drugs should be chosen. If the patient is responding to the drug that has already been started, it should not be changed even if the in vitro report says otherwise
    18. 18. 5. Source of infection Community-acquired infections are less likely to be resistant whereas Hospital-acquired infections are likely to be resistant & more difficult to treat (eg. Pseudomonas, MRSA etc)
    19. 19. 6. Patient factors • Factors should be considered in choosing the antibacterial agent: - Age of the patient - immune status - pregnancy & lactation - associated conditions like renal failure, hepatic failure, epilepsy etc. • In infants, chloramphenicol (can cause grey baby) & sulpha drugs (can cause kernicterus) are contraindicated
    20. 20. Patient factors…….con’t Children - Tetracycline are contraindicated < 8 years because they discolour the teeth - < 18 years ALL fluoroquinolones are contraindicated because they cause arthropathy by damaging the growing cartilage. Elderly • In the elderly, achlorhydria may affect absorption of anticbacterial agents; drug elimination is slower, requiring dose adjustments & ototoxicity of aminoglycosides may be increased.
    21. 21. Patient factors…….con’t Patients with compromised immune status • In patients with likelihood of compromised immune status, like extremes of age, HIV infection, diabetes mellitus, neutropenia, splenectomy, using corticosteroids or immunosuppresants, patients with cancers/blood dyscrasias, ONLY bactericidal drugs should be used.
    22. 22. Patient factors…….in pregnancy Contraindicated in all trimesters • tetracylines Contraindicated in the last trimesters • sulpha drug • quinolones • nitrofurantoin • streptomycin • chloramphenicol • clarithromycin Safe in pregnancy •penicillins •cephalosporins •erythromycin •isoniazid •ethambutol Contraindicated in lactating mothers • sulpha drug • tetracylines •nitrofurantoin • quinolones •metronidazole Drugs with limited data on safety like aminoglycoside, azithromycin, clindamycin, vancomycin, metronidazole, trimethoprim, rifampicin & pyrazinamide should be used with caution when benefits overweigh the risks
    23. 23. Patient factors…….in patients with renal failure Absolutely contraindicated • tetracycline Relatively contraindicated •Aminoglycoside •Cephalosporins •Fluoroquinolones Relatively safe •Sulpha drug •Penicillins •Macrolides •Vancomycin •Metronidazole •Isoniazid •Ethambutol •Rifampicin It is better to avoid combinations of cephalosporins & aminoglycosides in these patients because both classes can cause nephrotoxicity
    24. 24. Patient factors…….in patients with hepatic failure No drugs are absolutely contraindicated. Relatively contraindicated Safe •Chloramphenicol •Penicillins •Erythromycin estolate •Cephalosporins •Fluoroquinolones •Ethambutol •Pyrazinamide •Aminoglycosides •Rifampicin •Isoniazid •Metronidazole
    25. 25. 7. Drug factors 1. Hypersensitivity: If the patient has prior history of hypersensitivity the antibacterial agent should be avoided. It is therefore important to elicit this history in all patients (common with penicillin) 2. Adverse reactions: Certain ADRs warrant discontinuation of therapy & the doctor should adequately educate the patients on these adverse effects.
    26. 26. 7. Drug factors 3. Cost: It should always be remembered that just because as particular drug is expensive, it need not be superior than the cheaper ones. Eg. Cheaper drug like doxycycline or co-trimoxazole are as effective as the costlier clarithromycin or cephalosporins in the management of lower RTI.
    27. 27. 7. Drug factors…….con’t 4. Interactions: Interactions with food & other concomitant drugs should be considered before instituting antibacterial therapy so as to maximize efficacy & minimize toxicity. a) Interactions include enhanced nephrotoxicity or ototoxicity when aminoglycosides are given with loop diuretics, vancomycin or cisplatin. b) Rifampicin, a strong inducer of hepatic drug-metabolizing enzymes, decreases the effects of digoxin, ketoconazole, oral contraceptives, propranolol, quinidine & warfarin. c) Erythromycin inhibits the hepatic metabolism of a number of drugs, including phenytoin, terfenadine, theophylline & warfarin.
    28. 28. Methods of administration of antimicrobials Route of administration The route of administration depends on the site, type & severity of the infection & the availability of a suitable drug - Oral route is the most preferred, easy & cheap, but may not be reliable in all circumstances, esp. in patients with severe infections, non-compliant patients, in the presence of vomiting etc. Certain drugs like the aminoglycosides & most 3rd generations cephalosporins are not available for oral administration. - IM route should generally be restricted for the administration of procaine & benzathine penicillin. The absorption is not very reliable & it is painful & dislike by the patients.
    29. 29. Route of administration…….con’t - IV route is the best for the management of severe & deep-seated infections since it ensures adequate serum drug levels. Procaine penicillin & benzathine penicillin should never be given IV. •However, some drugs are not available for parental use (eg. Most macrolides, sulpha drugs, tetracyclines) • Chloramphenicol, the fluoroquinolones & trimethoprimsulphamethoxazole (TMP-SMZ) are also available orally. • Antibacterials are also used topically
    30. 30. Switching from IV to Oral  Step-down therapy: Conversion of an IV antibiotic to another oral  Transitional therapy: Conversion from same IV antibiotic to oral but not of same dosage or strength  Sequential therapy: Conversion from same IV antibiotic to oral of same dosage and strength
    31. 31. Dosage - Dosage depends on patient’s age, weight, associated conditions like pregnancy, renal & hepatic failure & site, type & severity of infection. - Generally the dose should be higher in cases of severe, deep-seated infections & lower in cases of renal-failure. - Unnecessary overdosage only adds to the cost & adverse effects.
    32. 32. Frequency of administration • The drug should be administered 4-5x the plasma half-life to maintain adequate therapeutic concentrations in the serum throughout the day. • Frequency can be:- increased in cases of severe, deep seated & sequestrated infections - reduced in cases of renal & hepatic failure.
    33. 33. Duration • Duration of therapy depends on the site 1) Tonsilitis – 10 days 2) Bronchitis – 5-7 days 3) UTI – single shot to 21 days 4) Lung abscess- 2-4 weeks 5) Tuberculosis – 6-24 months • Longer courses of therapy are usually required for infections due to fungi or mycobacteria • Endocarditis & osteomyelitis require longer duration of treatment
    34. 34. Combinations 1) For synergistic effect: eg: combination of 2 bacteriostatic drugs such as trimethoprim + sulfamethoxazole = Co-Trimoxazole (bacterim®) Therapeutic advantage of sulphonamide + trimethoprim 1) Synergistic effects 2) Bactericidal activity 3) Decrease resistance 4) Bigger spectrum of activity 5) Reduced toxicity
    35. 35. Combinations…….con’t 2) Treatment of infections with multiple organisms: Mixed infections in lung abcess, peritonitis, soiled wounds etc naturally require multiple antibiotics for complete clearance of the infection – penicillins (for Gram +ve & certain anaerobes) & aminoglycosides (for Gram –ve); metronidazole for bacteroides. penicillins + aminoglycosides + metronidazole
    36. 36. Combinations…….con’t 3) To prevent resistance: Use of combination is a well known method of preventing drug resistance. The classic example is the antiTB therapy, Eg isoniazid + ethambutol + rifampicin 4) To overcome resistance: Combination of specific drugs can be useful in overcoming that resistant infections, eg Penicillins + β-lactamase inhibitors (Co-amoxiclav/augmentin)
    37. 37. The following combinations are irrational, not useful or even harmful: 1) Bactericidal with bacteriostatic eg. Penicillins (bactericidal) with tetracyclines ( bacteriostatic) Bactericidal a/b (kill bacteria) – tend to be used in combination with one another Bateriostatic a/b (prevent bacteria’s reproduction) – tend to be used on its own 2) Combinations of drugs with similar toxicity eg. Chloramphenicol & sulpha drug 3) Combining drugs for non-existing “mixed infections” eg. Tablets of ciprofloxacin + metronidazole/tinidazole
    38. 38. Clinical failure of antimicrobial therapy
    39. 39. Failure of an antibiotic regimen (1) Inadequate clinical or microbiological response to antimicrobial therapy can result from multiple causes, including; 1) Drug factors • incorrect choice, • poor tissue penetration • inadequate dose • pH – low pH reduces effectiveness of aminoglycosides, erythromycin, clindamycin
    40. 40. Failure of an antibiotic regimen (2) 2) Host factors • poor host defense, • age • renal & liver function • pre-existing dysfunction of other organs 3) Pathogen factors  resistance  superinfection
    41. 41. Antibiotic Resistance
    42. 42. “Penicillin Era”  1942-1950 available without a prescription Public demand followed by production of throat sprays, cough lozenges, mouthwashes, soaps and other products containing penicillin  Alexander Fleming  Warned that excessive use could result in antimicrobial resistance  “the microbes are educated to resist penicillin and a host of penicillin-fast organisms is bred out which can be passed to other individuals and from them to others until they reach someone who gets a pneumonia or septicemia which penicillin cannot save.” The New York Times 1945  Fleming’s words proved to be correct....
    43. 43. The Problem of Antibiotic Resistance  Penicillin resistance first identified in 1940’s  Since then, antibiotic resistance has developed faster than new drugs  Estimated cost of infections: $4-5 million per year  Antibiotic resistance previously concentrated in hospitals, especially ICUs  MRSA recently estimated to kill 18,000 Americans yearly
    44. 44. History INTRODUCTION APPEARANCE OF RESISTANCE Penicillin 1943 1946 Streptomycin 1945 1959 Tetracycline 1948 1953 Erythromycin 1952 1988 Vancomycin 1956 1988 Methicillin 1960 1961 Ampicillin 1961 1973 Cephalosporins 1964 late 1960’s DRUG
    45. 45. Antibiotic Resistance  Relative or complete lack of effect of antimicrobial against a previously susceptible microbe • Bacteria are said to be resistant to an antibiotic if the maximal level of that antibiotic that can be tolerated by the host does not stop their growth.
    46. 46. What Factors Promote Antimicrobial Resistance? What causes the rapid occurrence of widespread resistance? (1) Incomplete treatment: - people fail to finish the full course of their medication - 25% of previously-treated tuberculosis patients relapsed with drug resistant strains; most had failed to complete their initial course
    47. 47. What Factors Promote Antimicrobial Resistance? (2) Mis-prescription: - patients demand antibiotics for cold - widespread inappropriate use: up to 50% of prescriptions in developing countries are for viral infections that cannot respond (3) Exposure to microbes carrying resistance genes
    48. 48. Inappropriate Antibiotic Use  Prescription not taken correctly  Antibiotics for viral infections  Antibiotics sold without medical supervision  Spread of resistant microbes in hospitals due to lack of hygiene   Lack of quality control in manufacture or outdated antimicrobial Use of broad-spectrum agents when a narrowspectrum drug would suffice  (eg, use of third-generation cephalosporins for communityacquired pneumonia)
    49. 49. Mechanisms of Antibiotic Resistance (1) • The four main mechanisms by which microorganisms exhibit resistance to antibiotics are: (1) Drug inactivation or modification: e.g. enzymatic deactivation of Penicillin G in some penicillin-resistant bacteria through the production of β-lactamases. (2) Alteration of target site: e.g. alteration of PBP—the binding target site of penicillins—in MRSA and other penicillin-resistant bacteria – resulting in decreased binding of the antibiotic to its target.
    50. 50. Mechanisms of Antibiotic Resistance (2) (3) Alteration of metabolic pathway: e.g. some sulfonamide-resistant bacteria do not require para-aminobenzoic acid (PABA), an important precursor for the synthesis of folic acid and nucleic acids in bacteria inhibited by sulfonamides. Instead, they turn to utilizing preformed folic acid. (4) Reduced drug accumulation: by decreasing drug permeability and/or increasing active efflux (pumping out) of the drugs across the cell surface.
    51. 51. Resistance: β-lactamase Enzymes • β-Lactam antibiotics act by inhibiting the synthesis of the peptidoglycan layer of bacterial cell walls. •Bacteria produce β-lactamase enzymes to hydrolyze the β-lactam ring before drugs can reach inner membrane where PG synthesis occurs •A cell may produce 100,000 β- lactamase enzymes, each of which can destroy 1,000 penicillins per second 100 million molecules of drug destroyed per second
    52. 52. β-lactamases  Enzymes produced by bacteria which destroy β-lactam antibiotics  Many different types  Most are plasmid mediated  Penicillinases, cephalosporinases, carbapenemases
    53. 53. Overcoming β-lactam Resistance slow to hydrolyze  As a response to bacterial resistance to β-lactam drugs, there are drugs, such as Augmentin, which are designed to disable the βlactamase enzyme.  Augmentin is made of amoxicillin, a β-lactam antibiotic, and clavulanic acid, a β-lactamase inhibitor.  The clavulanic acid is designed to overwhelm all β-lactamase enzymes, bind irreversibly to them, and effectively serve as an antagonist so that the amoxicillin is not affected by the βlactamase enzymes.
    54. 54. Overcoming β-lactam Resistance Amoxicillin (β-lactam antibiotic) + clavulanic acid (a β-lactamase inhibitor) = Co-amoxiclav (Augmentin®) Ampicillin (β-lactam antibiotic) + sulbactam (a β-lactamase inhibitor) = Unasyn®
    55. 55. Genetic alterations in drug resistance  Acquired antibiotic resistance requires the temporary or permanent gain or alteration of bacterial genetic information.  Resistance develops due to the ability of DNA:To undergo spontaneous mutation To move from one organism to another (DNA/gene transfer) 1. 2.
    56. 56. Spontaneous mutation of DNA     Stable and heritable genetic change Not induced by antimicrobial agents Resistance variant will proliferate Eg. The emergence of rifampicin-resistant M.tuberculosis when rifampicin is used as a single antibiotic
    57. 57. DNA/Gene transfer of drug resistant conjugation transformation transduction   DNA Most resistance genes are plasmid mediated Plasmid may enter cells by processes such as conjugation, transduction (phage mediated) & transformation
    58. 58. Measuring Antimicrobial Sensitivity Disk E- Diffusion test (antimicrobial gradient method) Serial dilution
    59. 59. Measuring Antimicrobial Sensitivity MIC increase in the case of resistance (Minimal inhibitory concentration) - important in diagnostic laboratories to confirm resistance of microorganisms to an antimicrobial agent
    60. 60. Consequences of Antimicrobial Resistance Infections resistant to available antibiotics Increased cost of treatment
    61. 61. Prevention of resistance  Speed development of new antibiotics  Track resistance data nationwide  Restrict antimicrobial use  Narrow spectrum Combination in long term use (TB)  Direct observed dosing (TB)  Appropriate dose and duration  Use more narrow spectrum antibiotics  Use antimicrobial cocktails
    62. 62. Pathogen Drug (s) of first choice Alternative Drug (s) Gram +ve cocci Pneumococcus Penicillin G, Ampicillin Erythromycin, Cephalosporin Streptococcus (common) Penicillin G Erythromycin, Cephalosporin Staphylococcus (penicillase-producing) Augmentin®, Unasyn®, Cloxacillin, Methicillin, Nafcillin, Timentin® Cephalosporin Staphylococcus (methicillin resistance) Vancomycin TMZ-SMZ Enterococcus Penicillin G plus gentamicin Vancomycin plus gentamicin Gonococcus Cetrriaxone Penicillin G, Ampicillin, Spectinomycin Meningococcus Penicillin G, Ampicillin Cefotaxime, Cefuroxime, Chloramphenicol E.coli, Proteus, Klebsiella E.coli, Aminoglycosides, 3rd generation cephalosporin TMZ-SMZ, Fluoroquinolone, extended spectrum penicillin Shigella Fluoroquinolone TMZ-SMZ, Ampicillin Enterobacter, Citrobacter, Serratia Imipenam, Fluoroquinolone TMZ-SMZ, extended spectrum penicillin Hemophilus spp Cefuroxime or 3rd generation cephalosporin TMZ-SMZ, Ampicillin, Chloramphenicol Pseudomonas aeruginosa Aminoglycosides plus extended spectrum penicillin Ceftazidime, Aztreonam, Imipenam Bacteroides fragillis Metronidazole, Clindamycin Imipenam, Chloramphenicol, Ampicillin/sulbactam Gram -ve cocci Gram -ve rods
    63. 63. RECOMMENDATIONS Don'ts about antibiotics     DO NOT...pressure your doctor to prescribe an antibiotic . DO NOT...take antibiotics that have been sitting around the house unless prescribed by your doctor for a current illness . DO NOT...give your antibiotics to other people. Their illness is probably different than yours, and so your antibiotics will not help them to get well. Also, they might even be harmed by your medicine. DO NOT...take antibiotics simply because you were exposed to someone with a disease. You are only increasing your chances of picking up a resistant infection. If you are exposed to an infectious disease, seek medical advice.
    64. 64. RECOMMENDATIONS Do's about antibiotics  DO...ask your doctor whether your infection or your family member's infection will respond to antibiotics.  DO...ask your doctor about antibiotic-resistant bacteria and what you can do to help prevent its occurrence. .  DO...follow the instructions for taking your antibiotic. Always take the exact amount specified on the label at a specified time. Take the medicine for the entire time that your doctor has prescribed. Even if you feel better, take all of the medicine!

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