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

3. Antibiotics
Definition
Antibiotics are substances that
kill or inhibit the growth of
micro-organisms.
Bacteriostatic (Tetracycline,
Chloramphenicol)
Bactericidal (Beta lactams,
Aminoglycosides)
.

4. 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

5. 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)

6. 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.

7. 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

8. 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

9. Bacteria vs Host
Bacteria
Host
Pathogen Vs non pathogen
Host defence
Virulence
antibiotic
Disease

10. Selection of
antimicrobial agents

11. 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

12. 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

13. 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

14. 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

15. 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

16. 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

17. 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.

18. 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

19. 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)

20. 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

21. 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.

22. 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.

23. 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

24. 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

25. 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

26. 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.

27. 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.

28. 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.

29. 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.

30. 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

31. 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

32. 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.

33. 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.

34. 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

35. 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

36. 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

37. 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)

38. 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

39. Clinical failure of
antimicrobial
therapy

40. 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

41. 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

42. Antibiotic Resistance

43. “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....

44. 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

45. 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

46. 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.

47. 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

48. 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

49. 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)

50. 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.

51. 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.

52. 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

53. β-lactamases
 Enzymes
produced by bacteria which
destroy β-lactam antibiotics
 Many
different types
 Most
are plasmid mediated
 Penicillinases,
cephalosporinases,
carbapenemases

54. 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.

55. 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®

56. 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.

57. 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

58. 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

59. Measuring Antimicrobial
Sensitivity
Disk
E-
Diffusion
test
(antimicrobial
gradient method)
Serial
dilution

60. 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

61. Consequences of Antimicrobial
Resistance
Infections
resistant to
available
antibiotics
Increased
cost
of treatment

63. 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

64. 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

65. 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.

66. 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!