2. Outline of the lecture
1)Indications for antibacterial therapy –
definitive, empiric & prophylaxis
2) Selection of antimicrobial agents
3) Methods of administration of antimicrobials
4) Antibiotics Resistance
5) Classification of antibacterial agents
3. 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.
4. 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
5. 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. 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
9. 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
10. 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
11. 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
12. 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
13. 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
14. 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.
15. 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
16. 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)
17. 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
18. • In the elderly, achlorhydria may affect absorption of
anticbacterial agents; drug elimination is slower, requiring
dose adjustments & ototoxicity of aminoglycosides may be
increased.
Patient factors…….con’t
Children
Elderly
- 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.
19. • 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.
Patient factors…….con’t
Patients with compromised immune status
20. Patient factors…….in pregnancy
Contraindicated in all trimesters Contraindicated in the last trimesters
Safe in pregnancy Contraindicated in lactating
mothers
• tetracylines
• quinolones
• streptomycin
• clarithromycin
• sulpha drug
• nitrofurantoin
• chloramphenicol
•penicillins
•cephalosporins
•erythromycin
•isoniazid
•ethambutol
• 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
21. Patient factors…….in patients
with renal failure
Absolutely contraindicated
Relatively contraindicated
Relatively safe
It is better to avoid combinations
of cephalosporins & aminoglycosides
in these patients because both
classes can cause nephrotoxicity
• tetracycline
•Penicillins
•Macrolides
•Vancomycin
•Metronidazole
•Isoniazid
•Ethambutol
•Rifampicin
•Aminoglycoside
•Cephalosporins
•Fluoroquinolones
•Sulpha drug
22. Patient factors…….in patients
with hepatic failure
No drugs are absolutely contraindicated.
Relatively contraindicated Safe
•Chloramphenicol
•Erythromycin estolate
•Fluoroquinolones
•Pyrazinamide
•Rifampicin
•Isoniazid
•Metronidazole
•Penicillins
•Cephalosporins
•Ethambutol
•Aminoglycosides
23. 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.
24. 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.
25. 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.
26. 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.
27. 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 & trimethoprim-
sulphamethoxazole (TMP-SMZ) are also available orally.
• Antibacterials are also used topically
28. 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.
29. 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.
30. 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
31. 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
32. 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
Combinations…….con’t
33. 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)
Combinations…….con’t
34. 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
36. Failure of an antibiotic regimen (1)
1) Drug factors
• incorrect choice,
• poor tissue penetration
• inadequate dose
• pH – low pH reduces effectiveness of
aminoglycosides, erythromycin, clindamycin
Inadequate clinical or microbiological response to
antimicrobial therapy can result from multiple
causes, including;
37. 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
39. “Penicillin Era”
1942-1950 available without a prescription1942-1950 available without a prescription
Public demand followed by production of throatPublic demand followed by production of throat
sprays, cough lozenges, mouthwashes, soaps and othersprays, cough lozenges, mouthwashes, soaps and other
products containing penicillinproducts containing penicillin
Alexander FlemingAlexander Fleming
Warned that excessive use could result inWarned that excessive use could result in
antimicrobial resistanceantimicrobial resistance
““the microbes are educated to resist penicillin andthe microbes are educated to resist penicillin and
a host of penicillin-fast organisms is bred outa host of penicillin-fast organisms is bred out
which can be passed to other individuals and fromwhich can be passed to other individuals and from
them to others until they reach someone who getsthem to others until they reach someone who gets
a pneumonia or septicemia which penicillin cannota pneumonia or septicemia which penicillin cannot
savesave.” The New York Times 1945.” The New York Times 1945
Fleming’s words proved to be correct....Fleming’s words proved to be correct....
40. The Problem of Antibiotic
Resistance
Penicillin resistance first identified in 1940’sPenicillin resistance first identified in 1940’s
Since then, antibiotic resistance hasSince then, antibiotic resistance has
developed faster than new drugsdeveloped faster than new drugs
Estimated cost of infections: $4-5 million perEstimated cost of infections: $4-5 million per
yearyear
Antibiotic resistance previously concentratedAntibiotic resistance previously concentrated
in hospitals, especially ICUsin hospitals, especially ICUs
MRSA recently estimated to kill 18,000MRSA recently estimated to kill 18,000
Americans yearlyAmericans yearly
41. History
APPEARANCE
DRUG INTRODUCTION 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
42. 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.
43. 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
What Factors Promote Antimicrobial
Resistance?
44. (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
What Factors Promote Antimicrobial
Resistance?
(3) Exposure to microbes carrying
resistance genes
45. Inappropriate Antibiotic Use
Prescription not taken correctlyPrescription not taken correctly
Antibiotics for viral infectionsAntibiotics for viral infections
Antibiotics sold without medical supervisionAntibiotics sold without medical supervision
Spread of resistant microbes in hospitals dueSpread of resistant microbes in hospitals due
to lack of hygieneto lack of hygiene
Lack of quality control in manufacture or outdatedLack of quality control in manufacture or outdated
antimicrobialantimicrobial
Use of broad-spectrum agents when a narrow-Use of broad-spectrum agents when a narrow-
spectrum drug would sufficespectrum drug would suffice
(eg, use of third-generation cephalosporins for community-(eg, use of third-generation cephalosporins for community-
acquired pneumonia)acquired pneumonia)
46. • The four main mechanisms by which microorganismsThe four main mechanisms by which microorganisms
exhibit resistance to antibiotics are: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.
Mechanisms of Antibiotic
Resistance (1)
47. (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.
Mechanisms of Antibiotic
Resistance (2)
48. Resistance: β-lactamase Enzymes
•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
• β-Lactam
antibiotics act by
inhibiting the
synthesis of the
peptidoglycan
layer of bacterial
cell walls.
49. β-lactamases
Enzymes produced by bacteria whichEnzymes produced by bacteria which
destroydestroy ββ-lactam antibiotics-lactam antibiotics
Many different typesMany different types
Penicillinases, cephalosporinases,Penicillinases, cephalosporinases,
carbapenemasescarbapenemases
Most are plasmid mediatedMost are plasmid mediated
50. 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 β-lactamase
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 β-lactamase enzymes.
52. Resistance in Simpler Terms…
BA
By-pass Altered
target
Efflux
Impermeability
Inactivation
(alteration of metabolic pathway)
(reduced drug accumulation)
(reduced drug accumulation)
53. Genetic alterations in drug
resistance
Acquired antibiotic resistance requires theAcquired antibiotic resistance requires the
temporary or permanent gain or alterationtemporary or permanent gain or alteration
of bacterial genetic information.of bacterial genetic information.
Resistance develops due to the ability ofResistance develops due to the ability of
DNA:-DNA:-
1.1. To undergo spontaneous mutationTo undergo spontaneous mutation
2.2. To move from one organism to anotherTo move from one organism to another
(DNA/gene transfer)(DNA/gene transfer)
54. 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
55. DNA/Gene transfer of drug
resistant
transduction
conjugation
transformation
DNA Most resistance genes are plasmid mediated
Plasmid may enter cells by processes such as conjugation,
transduction (phage mediated) & transformation
57. MIC increase in
the case of
resistance
(Minimal inhibitory concentration)
- important in diagnostic
laboratories to confirm resistance
of microorganisms to an
antimicrobial agent
Measuring Antimicrobial
Sensitivity
60. 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 antibioticsUse more narrow spectrum antibiotics
Use antimicrobial cocktailsUse antimicrobial cocktails
Prevention of resistance
62. Chemical structureChemical structure
Mechanism of actionMechanism of action
Spectrum of activitySpectrum of activity
Broad, extended, narrowBroad, extended, narrow
Types of actionsTypes of actions
Bactericidal, bacteriostaticBactericidal, bacteriostatic
Classification of antibacterial agents
64. TermsTerms DefinitionsDefinitions
Narrow-spectrumNarrow-spectrum
antibioticsantibiotics
Antibiotics acting only on a single or aAntibiotics acting only on a single or a
limited group of microorganismslimited group of microorganisms
Eg.-Eg.- isoniazid active only againstactive only against
mycobacteriamycobacteria
Extended-spectrumExtended-spectrum
antibioticsantibiotics
Antibiotics that are effective against gramAntibiotics that are effective against gram
+ve organisms & also against a significant+ve organisms & also against a significant
no. of gram -ve organisms.no. of gram -ve organisms.
Eg.-Eg.- ampicillin – acts against gram +ve– acts against gram +ve
organisms (Listeria monocytogenes) & someorganisms (Listeria monocytogenes) & some
gram -ve organisms (gram -ve organisms (E. coliE. coli).).
Broad-spectrumBroad-spectrum
antibioticsantibiotics
Antibiotics affect a wide variety ofAntibiotics affect a wide variety of
microbial speciesmicrobial species
Eg.-Eg.- tetracycline active against chlamydia,active against chlamydia,
mycoplasma, actinomyces, anaerobicmycoplasma, actinomyces, anaerobic
organisms, gram –ve rods (organisms, gram –ve rods (E. coliE. coli))
Spectrum of activity
68. Mechanism of actions
Mechanism of actionMechanism of action Antibacterial agentAntibacterial agent
Inhibition of cell wall synthesisInhibition of cell wall synthesis PenicillinPenicillin
CephalosporinsCephalosporins
MonobactamsMonobactams
VancomycinVancomycin
Inhibition of DNA gyrase,Inhibition of DNA gyrase,
RNA polymeraseRNA polymerase
QuinolonesQuinolones
RifampicinRifampicin
Inhibition of protein synthesisInhibition of protein synthesis AminoglycosidesAminoglycosides
TetracyclinesTetracyclines
ChloramphenicolChloramphenicol
MacrolidesMacrolides
Inhibition of folic acid metabolismInhibition of folic acid metabolism TrimethoprimTrimethoprim
SulfonamidesSulfonamides
69. 1. Beta-lactam antibiotics
1) Penicillin derivatives
2) Cephalosporins
3) Monobactams
4) Carbapenems
1) Penicillin 2) Cephalosporins
β-lactam ring in red
A. Cell wall Inhibitors
2. Glycopeptides
1) Vancomycin
3. Beta-lactamase inhibitors
1) Clavulanic acid
2) Sulbactam
72. A schematic of peptidoglycan’s structure. The NAM and NAG
sugars are shown as green and blue spheres respectively. The
tetrapeptides linked to NAM are cross-linked by a pentaglycine
peptide, shown as red lines linking the D-glutamine (L) to the D-
alanine (A).
β-lactam
antibiotics
inhibit
transpeptidases
enzymes that
form these
crosslinkages
Glycopeptides
bind D-alanine
and prevent
crosslinkage
78. Penicillins – adverse reaction
Relatively non-toxicRelatively non-toxic
Allergic reactionAllergic reaction
AnaphylaxisAnaphylaxis
- will occur in approximately in- will occur in approximately in
0.01% patients0.01% patients
A rash on the back of a
person with anaphylaxis
81. Cephalosporins – adverse reactions
Fairly safeFairly safe
Allergic reactionAllergic reaction
Cross reaction with penicillinCross reaction with penicillin
SuperinfectionSuperinfection
(an infection following a previous infection, esp. when caused by(an infection following a previous infection, esp. when caused by
microorganisms that have become resistant to the antibioticsmicroorganisms that have become resistant to the antibiotics
used earlier)used earlier)
82. Carbapenem
ExamplesExamples
ImipenemImipenem
MeropenemMeropenem
Wide spectrumWide spectrum
Resistant againstResistant against ββ-lactamase-lactamase
Good activity against both Gram +ve & -veGood activity against both Gram +ve & -ve
Active against pseudomonasActive against pseudomonas
Use in resistant organismsUse in resistant organisms
Hospital acquired infectionHospital acquired infection
83. Monobactam
Example
Aztreonam
Resistant against β-lactamase
Antipseudomonal activity
Inactive against Gram +ve
GIT side effects – diarrhea, nausea &
vomiting
IV – poorly absorbed when given via oral
route.
84. β- lactamase inhibitors
ResembleResemble ββ-lactam molecules-lactam molecules
No antibacterial activityNo antibacterial activity
Inhibits bacterialInhibits bacterial ββ -lactamase-lactamase
Use in combination with penicillinsUse in combination with penicillins
Ampicillin–sulbactamAmpicillin–sulbactam
Piperacillin-tazobactamPiperacillin-tazobactam
Amoxycillin-clavulanate (clavulanic acid)Amoxycillin-clavulanate (clavulanic acid)
85. Glycopeptides
Vancomycin, teicoplaninVancomycin, teicoplanin
Active against Gm +ve esp staphActive against Gm +ve esp staph
Not active against Gm –veNot active against Gm –ve
Use in MRSA infectionUse in MRSA infection
Nephrotoxicity, red man syndromeNephrotoxicity, red man syndrome
86. B. PROTEIN SYNTHESIS INHIBITOR
1) Aminoglycosides
2) Tetracyclines
3) Chloramphenicol
4) Macrolides
5) Fusidic Acid
87.
88. Aminoglycosides
BactericidalBactericidal
From variousFrom various StreptomycesStreptomyces speciesspecies
StreptomycinStreptomycin
NeomycinNeomycin
AmikacinAmikacin
GentamicinGentamicin
TobramycinTobramycin
NetilmicinNetilmicin
89. Aminoglycosides – physical
properties
Water soluble (polar)Water soluble (polar)
Poorly absorbed from gutPoorly absorbed from gut
Given parenterallyGiven parenterally
Less able to cross biologicalLess able to cross biological
barrierbarrier
More active at alkaline pHMore active at alkaline pH
90. Aminoglycosides - MOA
Irreversible inhibitor ofIrreversible inhibitor of
protein synthesisprotein synthesis
Passive diffusion via porinPassive diffusion via porin
channels of outerchannels of outer
membranemembrane
Actively transport intoActively transport into
cytoplasmcytoplasm
Bind to 30S subunitBind to 30S subunit
ribosomeribosome
Interfere with synthesisInterfere with synthesis
of proteinof protein
91. Use against Gram –ve infection
Usually combined with β-lactam
antibiotic
Better coverage
Synergistic effect
No activity against anaerobe
Aminoglycoside: clinical use
92. Aminoglycosides -
pharmacokinetic
Polar substancePolar substance
Given i.m. or i.v.Given i.m. or i.v.
Poorly penetrate CSF or eyePoorly penetrate CSF or eye
20% blood level in inflamed meninges20% blood level in inflamed meninges
May be given intrathecalMay be given intrathecal
t1/2 = 2-3 hours= 2-3 hours
Excreted unchanged by the kidneysExcreted unchanged by the kidneys
Adjust dosage with renal impairmentAdjust dosage with renal impairment
Can be calculated based on creatinine clearanceCan be calculated based on creatinine clearance
93. Aminoglycosides: PK-PD
Concentration dependent killingConcentration dependent killing
Rate of killing depend on concentrationRate of killing depend on concentration
Post antibiotic effectPost antibiotic effect
Antibacterial activity persist after theAntibacterial activity persist after the
level reduce to below MIClevel reduce to below MIC
Can be given single daily doseCan be given single daily dose
Same efficacySame efficacy
Reduce risk of toxicityReduce risk of toxicity
convenienceconvenience
94. Aminoglycosides: toxicity
OtotoxicOtotoxic
Auditory damageAuditory damage
Vestibular damageVestibular damage
NephrotoxicNephrotoxic
Potentiated by otherPotentiated by other
nephrotoxic drugsnephrotoxic drugs
Need to measureNeed to measure
level (TDM)level (TDM)
Peak and troughPeak and trough
High doseHigh dose
Block neuromuscularBlock neuromuscular
junctionjunction
95. Streptomycin
Mainly use in the treatment of TBMainly use in the treatment of TB
Combine with other anti TBCombine with other anti TB
Resistance easily developed withoutResistance easily developed without
combinationcombination
Side effectSide effect
Fever, rashesFever, rashes
Impair vestibular functionImpair vestibular function
Contraindicated in pregnancyContraindicated in pregnancy
Deafness in newbornDeafness in newborn
96. Gentamicin
Active both in Gram +ve & -veActive both in Gram +ve & -ve
StaphylococciStaphylococci
Resistance rapidly developedResistance rapidly developed
Pseudomonas, klebsiellaPseudomonas, klebsiella
No activity against streptococci andNo activity against streptococci and
enterococcienterococci
But can enhance the effect ofBut can enhance the effect of ββ-lactam or-lactam or
vancomycinvancomycin
97. Gentamicin – clinical uses
Combine with cell wall inhibitor in severeCombine with cell wall inhibitor in severe
infectioninfection
With penicillin G inWith penicillin G in Strept viridansStrept viridans
endocarditisendocarditis
Should not be used alone for pneumoniaShould not be used alone for pneumonia
Poor penetrationPoor penetration
Requires TDMRequires TDM
If use more than 5 daysIf use more than 5 days
Renal impairmentRenal impairment
98. Amikacin
Semi synthetic aminoglycosideSemi synthetic aminoglycoside
More resistant than genta towardsMore resistant than genta towards
inactivating enzymesinactivating enzymes
Active against MDRActive against MDR M. tuberculosisM. tuberculosis
Usually use as second line antibioticUsually use as second line antibiotic
99. Spectinomycin
Structure related to aminoglycoside but
lack of amino sugars
Given i.m.
Only use as an alternative to penicillin in
gonorrhoea therapy
Penicillin sensitivity
Resistant gonococcal
Rarely nephrotoxic
102. Macrolides
MOAMOA
Bind reversibly toBind reversibly to
the 50S subunitthe 50S subunit
Inhibit elongationInhibit elongation
of the proteinof the protein
• Streptomycin obtained fromStreptomycin obtained from StreptomycesStreptomyces
erythreuserythreus
• Clarythromycin & azithromycin are semisyntheticClarythromycin & azithromycin are semisynthetic
107. Clarithromycin
Improved acid stabilityImproved acid stability
Better absorptionBetter absorption
Longer tLonger t1/21/2
BD dosingBD dosing
Metabolised by liverMetabolised by liver
More active againstMore active against MycobacteriumMycobacterium
avianavian complexcomplex
More expensiveMore expensive
108. Azithromycin
More active againstMore active against
M avianM avian complexcomplex
Toxoplasma gondiiToxoplasma gondii
Penetrates well into tissuesPenetrates well into tissues
Concentration > 10 – 100 times serumConcentration > 10 – 100 times serum
Tissue tTissue t1/21/2 = 2-4 days= 2-4 days
Single daily doseSingle daily dose
Short coursesShort courses
111. Tetracyclines - MOA
Bind reversibly to
the 30S subunit
Misalignment of
anticodons of the
charged tRNAs with
the codons of the
mRNA.
Failure of protein
synthesis
113. Tetracyclines – P’kinetics
GI absorptionGI absorption
tetracycline (60-80%),tetracycline (60-80%),
doxycycline (95%),doxycycline (95%),
minocycline (100%)minocycline (100%)
Impaired by food (esp with MgImpaired by food (esp with Mg2+2+
,,
CaCa2+2+
))
Ditributed widely except intoDitributed widely except into
CSFCSF
Crosses placentaCrosses placenta
Excreted both thru bile andExcreted both thru bile and
urineurine
TT1/21/2
Short acting (6 hrs)Short acting (6 hrs)
TetracyclineTetracycline
Intermediate (12 hrs)Intermediate (12 hrs)
demeclocyclinedemeclocycline
Long (18 hrs)Long (18 hrs)
doxycycline, minocyclinedoxycycline, minocycline
114. Tetracyclines - uses
Drug of choice in atypical bacteria infectionDrug of choice in atypical bacteria infection
RicketsiaeRicketsiae
Used in combination to treat gastric orUsed in combination to treat gastric or
duodenal ulcerduodenal ulcer
To eradicateTo eradicate H. PyloriH. Pylori
CholeraCholera
AcneAcne
Lyme diseaseLyme disease ((Borelia burgdorferiBorelia burgdorferi))
115. Tetracyclines - ADR
GITGIT
Nausea, vomiting,Nausea, vomiting,
diarrhoeadiarrhoea
Damage growingDamage growing
bone & teethbone & teeth
Due to CaDue to Ca2+2+
chelatingchelating
propertyproperty
Yellow discolourationYellow discolouration
Contraindicated inContraindicated in
children < 8 years oldchildren < 8 years old
Hepatic injuryHepatic injury
Increased duringIncreased during
pregnancypregnancy
NephrotoxicityNephrotoxicity
PhotosensitizationPhotosensitization
Severe sunburn ;Severe sunburn ;
doxy/demeclocyclinedoxy/demeclocycline
116.
117. Chloramphenicol
Binds to 50 S ribosomalBinds to 50 S ribosomal
subunitsubunit
Mainly bacteriostaticMainly bacteriostatic
BactericidalBactericidal
H. influenzaH. influenza
N. meningitidisN. meningitidis
Broad spectrum (includingBroad spectrum (including
rickettsiae)rickettsiae)
118. Chloramphenicol – P’kinetics
IV (prodrug) or orallyIV (prodrug) or orally
Complete oral absorptionComplete oral absorption
Excretion depends on conversion in liverExcretion depends on conversion in liver
to glucuronide, then secretion in kidneyto glucuronide, then secretion in kidney
Slow excretion in liver impairmentSlow excretion in liver impairment
119. Chloramphenicol - uses
Staph brain abscess
Typhus
As an alternative in meningitis
Conjunctivitis – eye preparation
120. Chloramphenicol - ADR
Blood dyscrasias
Idiosyncratic aplastic anemia
Gray baby syndrome
Neonates if doses not adjusted
121. D. FOLIC ACID METABOLISM
INHIBITOR
1) Trimethoprim
2) Sulfonamides
122. Sulphonamide - MOA
Bacteria cannotBacteria cannot
transport folate intotransport folate into
cellscells
Tetrahydrofolate is aTetrahydrofolate is a
DNA precursorDNA precursor
p-aminobenzoic acidp-aminobenzoic acid
(PABA) is a precursor(PABA) is a precursor
for folate synthesisfor folate synthesis
Sulfonamides areSulfonamides are
structurally similar tostructurally similar to
PABAPABA
Inhibits synthesis ofInhibits synthesis of
dihydropteroatedihydropteroate
sythase (DHPS)sythase (DHPS)
DHPS & DHFR absent inDHPS & DHFR absent in
mammalian cellsmammalian cells
123. Sulfonamides - effect
Bacteriostatic
Active against
Both Gram +ve & -ve
E. coli, Klebsiella, Salmonella
Clamydia
Some protozoa –
Pneumocystis carinii
Not active against rickettsiae
124. Sulfonamides -
Pharmacokinetics
Preparation availablePreparation available
TopicalTopical
OralOral
Well absorbed from gutWell absorbed from gut
Distributed widely including CSFDistributed widely including CSF
Metabolized in liverMetabolized in liver
Excreted via kidneyExcreted via kidney
128. Trimethoprim + sulfamethoxazole
(TMP + SFX = co-trimoxazole)
TMPTMP
Inhibit DHFRInhibit DHFR
Synergistic whenSynergistic when
combined with SFXcombined with SFX
Combination isCombination is
bactericidalbactericidal
129. co-trimoxazole – p’kinetics
TMP:SFX = 1:5
Available in IV and oral
Oral
Well absorbed
T1/2 = 10 hrs (both)
Penetrates well into CSF, prostate
Excreted in urine
Usually given BD dose
138. Metronidazole - anaerobes
- It is used mainly in the treatment of infections caused by
susceptible organisms, particularly anaerobic bacteria and protozoa.
- It is used to treat ameobic dysentry, giardiasis, gangrene,
pseudomonas coitis & various abdominal infections, lung abscess &
dental sepsis.
Mechanism of actions
- The nitro group of metronidazole is chemically reduced by
ferredoxin (or a ferredoxin-linked metabolic process) and the
products are responsible for disrupting the DNA helical structure,
thus inhibiting nucleic acid synthesis.
139. Metronidazole - anaerobesanaerobes
Side Effects
PK
It is well absorbed after oral or rectal administration
•Nausea & vomiting
•Peripheral neuropathy
•Convulsions, headaches
•Hepatitis
140. Pathogen Drug (s) of first choice Alternative Drug (s)
Gram +ve cocci
PneumococcusPneumococcus Penicillin G, AmpicillinPenicillin G, Ampicillin Erythromycin, CephalosporinErythromycin, Cephalosporin
Streptococcus (common)Streptococcus (common) Penicillin GPenicillin G Erythromycin, CephalosporinErythromycin, Cephalosporin
StaphylococcusStaphylococcus
(penicillase-producing)(penicillase-producing)
AugmentinAugmentin®®
, Unasyn, Unasyn®®
, Cloxacillin,, Cloxacillin,
Methicillin, Nafcillin, TimentinMethicillin, Nafcillin, Timentin®®
CephalosporinCephalosporin
StaphylococcusStaphylococcus
(methicillin resistance)(methicillin resistance)
VancomycinVancomycin TMZ-SMZTMZ-SMZ
EnterococcusEnterococcus Penicillin G plus gentamicinPenicillin G plus gentamicin Vancomycin plus gentamicinVancomycin plus gentamicin
Gram -ve cocci
GonococcusGonococcus CetrriaxoneCetrriaxone Penicillin G, Ampicillin,Penicillin G, Ampicillin,
SpectinomycinSpectinomycin
MeningococcusMeningococcus Penicillin G, AmpicillinPenicillin G, Ampicillin Cefotaxime, Cefuroxime,Cefotaxime, Cefuroxime,
ChloramphenicolChloramphenicol
Gram -ve rods
E.coliE.coli, Proteus, Klebsiella, Proteus, Klebsiella Aminoglycosides, 3Aminoglycosides, 3rdrd
generationgeneration
cephalosporincephalosporin
TMZ-SMZ, Fluoroquinolone,TMZ-SMZ, Fluoroquinolone,
extended spectrum penicillinextended spectrum penicillin
ShigellaShigella FluoroquinoloneFluoroquinolone TMZ-SMZ, AmpicillinTMZ-SMZ, Ampicillin
Enterobacter, Citrobacter,Enterobacter, Citrobacter,
SerratiaSerratia
Imipenam, FluoroquinoloneImipenam, Fluoroquinolone TMZ-SMZ, extended spectrumTMZ-SMZ, extended spectrum
penicillinpenicillin
Hemophilus sppHemophilus spp Cefuroxime or 3Cefuroxime or 3rdrd
generationgeneration
cephalosporincephalosporin
TMZ-SMZ, Ampicillin,TMZ-SMZ, Ampicillin,
ChloramphenicolChloramphenicol
Pseudomonas aeruginosa Aminoglycosides plus extendedAminoglycosides plus extended
spectrum penicillinspectrum penicillin
Ceftazidime, Aztreonam, ImipenamCeftazidime, Aztreonam, Imipenam
Bacteroides fragillis Metronidazole, ClindamycinMetronidazole, Clindamycin Imipenam, Chloramphenicol,Imipenam, Chloramphenicol,
Ampicillin/sulbactamAmpicillin/sulbactam
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 .
Inactivation – Drug inactivation or modification alteration of target site – altered target Impermeability & Efflux – reduced drug accumulation By-pass – alteration of metabolic pathway
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)
The Gram positive cell wall is characterized by the presence of a very thick peptidoglycan layer the Gram negative cell wall contains a thin peptidoglycan layer Peptidoglycan layer in the bacterial cell wall is formed from linear chains of two alternating amino sugars , namely N - acetylglucosamine (GlcNAc or NAG) and N - acetylmuramic acid (MurNAc or NAM).
Probenecid is a uricosuric drug that increases uric acid excretion in the urine. It is primarily used in treating gout and hyperuricemia.