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1. Antibiotic
By Safaa Abdulwahab Andijani

2. Antibiotic classification

3. Cell Wall synthesis
B – lactam Cell Wall synthesis
Non B – lactam Cell Wall synthesis

4. Cell Wall synthesis
Are classified into 2 type :
• B – lactam Cell Wall synthesis :
1. Penicillin
2. Cephalosporin
3. Carbapenems
4. Monobactams
• Non B – lactam Cell Wall synthesis :
1. Vancomycin
2. Daptomycin
3. Bacitracin

5. Bacterial cell wall inhibitor
All β-lactam antibiotics interfere with the
synthesis of the bacterial cell wall peptidoglycan
(provides rigidity to the cell wall).

6. Penicillin

7. Penicillin
The penicillins are among the most widely effective and
the least toxic drugs known, but increased resistance has
limited their use.
This cell wall is unique to the bacteria so penicillin is non-
toxic to human.
Drugs in this group are bactericidal & posses time
dependent killing.

8. Mechanism of action
1. Penicillin-binding proteins :
Penicillin also inactivate numerous proteins on the bacterial cell membrane.
These penicillin-binding proteins (PBPs) are bacterial enzymes involved in the
synthesis of the cell wall and in the maintenance of the morphologic features
of the bacterium. Exposure these antibiotics can therefore not only prevent
cell wall synthesis but also lead to morphologic changes
Alterations in some of these PBPs provide the organism with
resistance to the penicillin's. [Note: Methicillin resistant
Staphylococcus aureus (MRSA) arose because of such an
alteration.]

9. Mechanism of action
2. Inhibition of transpeptidase:
Some PBPs catalyze formation of the cross-linkages between peptidoglycan
chains. Penicillins inhibit this transpeptidase-catalyzed reaction, thus
hindering the formation of cross - links essential for cell wall integrity.
3. Production of autolysins:
Many bacteria, particularly the gram- positive cocci, produce degradative
enzymes (autolysins) that participate in the normal remodeling of the
bacterial cell wall. In the presence of a penicillin, the degradative action of the
autolysins proceeds in the absence of cell wall synthesis.
Thus, the antibacterial effect of a penicillin is the result of both inhibition of
cell wall synthesis and destruction of the existing cell wall by autolysins.

10. Natural penicillin: (narrow spectrum) :
1. Benzyl penicillin (Pen G)
Highly water soluble, freshly prepared, acid-labile, given IV
poor oral absorption.
Spectrum :
Highly active against gram-positive cocci,
Treatment :
drug of choice for the treatment of gas gangrene (Clostridium
perfringens) and syphilis (Treponema pallidum).
2. Penicillin V
Penicillin V is more acid stable than penicillin G and is often employed
orally in the treatment of infections.
has a similar spectrum to that of penicillin G .

11. Natural penicillin: (narrow spectrum) :

12. Resistance of penecillin
• Penicillin G and V are susceptible to inactivated by penicillinases: is
β lactamases enzyme that are produced by the resistant bacteria.
• Penicillinases mainaly produced by S. aureus

13. Anti staphylococcal penicillin's:
Methicillin, nafcillin, oxacillin, and dicloxacillin are β lactamase
resistant penicillins.
Their use is restricted to the treatment of infections caused by
penicillinase- producing staphylococci, including methicillin sensitive
Staphylococcus aureus (MSSA).
MRSA is currently a source of serious community and nosocomial
(hospital-acquired) infections and is resistant to most the
commercially available β-lactam antibiotics.
The penicillinase- resistant penicillin's have minimal to no activity
against gram-negative infections.

14. Extended-spectrum penicillins:
• Ampicillin and amoxicillin have an antibacterial
spectrum similar to that of penicillin G but are more
effective against gram negative bacilli.
• Ampicillin (with or without the addition of gentamicin)
is the drug of choice for the gram-positive bacillus
Listeria monocytogenes and susceptible enterococcal
species.
• These extended-spectrum agents are also widely used in
the treatment of respiratory infections, and amoxicillin is
employed prophylactically by dentists in high risk
patients for the prevention of bacterial endocarditis.

15. Extended-spectrum penicillins:
Resistance to these antibiotics is now a major clinical problem because of
inactivation by plasmid-mediated penicillinases.
[Note: Escherichia coli and Hemophilus influenzae are frequently resistant.]
Formulation with a β-lactamase inhibitor, such as clavulanic acid
or sulbactam, protects amoxicillin or ampicillin, respectively, from
enzymatic hydrolysis and extends their antimicrobial spectra. For example,
without the β-lactamase inhibitor, MSSA is resistant to ampicillin and
amoxicillin.

16. β-LACTAMASE INHIBITORS
Hydrolysis of the β-lactam ring, either by enzymatic cleavage with a β-
lactamase or by acid, destroys the antimicrobial activity of a β-lactam
antibiotic.
Β Lactamase inhibitors, such as clavulanic acid, sulbactam, and
tazobactam, contain a β-lactam ring but, by themselves, do not have
significant antibacterial activity or cause any significant adverse
effects.
Instead, they bind to and inactivate β-lactamases, thereby protecting
the antibiotics that are normally substrates for these enzymes.
The β lactamase inhibitors are therefore formulated in combination
with β- lactamase–sensitive antibiotics.

17. Antipseudomonal penicillins:
Piperacillin and ticarcillin are called antipseudomonal penicillins because
of their activity against Pseudomonas aeruginosa.
These agents are available in parenteral formulations only.
Piperacillin is the most potent of these antibiotics.
They are effective against many gram-negative bacilli, but not against Klebsiella
because of its constitutive penicillinase.

18. Pharmacokinetics
1. Administration:
The route of administration of a β-lactam antibiotic is determined by the stability
of the drug to gastric acid and by the severity of the infection.
a. Routes of administration:
The combination of ampicillin with sulbactam, ticarcillin with clavulanic acid,
piperacillin with tazobactam,
antistaphylococcal penicillins nafcillin and oxacillin
must be administered intravenously (IV) or intramuscularly (IM).
Penicillin V, amoxicillin, and dicloxacillin are available only as oral preparations.
Others are effective by the oral, IV, or IM routes.
b. Depot forms:
Procaine penicillin G and benzathine penicillin G are administered IM and serve as
depot forms. They are slowly absorbed into the circulation and persist at low levels
over a long time period.

19. Pharmacokinetics
2. Absorption:
Most of the penicillin's are incompletely absorbed after oral administration,
and they reach the intestine in sufficient amounts to affect the composition of
the intestinal flora. Food decreases the absorption of all the penicillinase-
resistant penicillins because as gastric emptying time increases, the drugs are
destroyed by stomach acid. Therefore, they should be taken on an
empty stomach.

20. Pharmacokinetics
3. Distribution:
The β-lactam antibiotics distribute well throughout the body. All the
penicillin's cross the placental barrier, but none have been shown to
have teratogenic effects. However, penetration into bone or
cerebrospinal fluid (CSF) is insufficient for therapy unless these sites
are inflamed.
[Note: Inflamed meninges are more permeable to the penicillin's,
resulting in an increased ratio of the drug in the CSF
compared to the serum.] Penicillin levels in the prostate are
insufficient to be effective against infections.

21. Pharmacokinetics
4. Metabolism:
Host metabolism of the β-lactam antibiotics is usually insignificant,
but some metabolism of penicillin G may occur in patients with
impaired renal function.
5. Excretion:
The primary route of excretion is through the organic acid (tubular)
secretory system of the kidney as well as by glomerular filtration.
Patients with impaired renal function must have dosage regimens
adjusted. Nafcillin and oxacillin are exceptions to the rule. They are
primarily metabolized in the liver and do not require dose adjustment
for renal insufficiency. Probenecid inhibits the secretion of penicillins
by competing for active tubular secretion via the organic acid
transporter and, thus, can increase blood levels. The penicillins are
also excreted in breast milk.

22. Adverse effect :

23. cephalosporins

24. cephalosporins
The cephalosporins are β-lactam antibiotics that are closely related
both structurally and functionally to the penicillins.
Most cephalosporins are produced semi synthetically by the chemical
attachment of side chains to 7-aminocephalosporanic acid.
Antibacterial spectrum Cephalosporins have been classified as first,
second, third, fourth, and advanced generation, based largely on their
bacterial susceptibility patterns and resistance to β-lactamases.

27. Pharmacokinetics
1. Administration:
Many of the cephalosporins must be administered IV or IM because of their
poor oral absorption.
2. Distribution:
All cephalosporins distribute very well into body fluids. Cefazolin is commonly
used as a single prophylaxis dose prior to surgery because of its 1.8-hour half-
life and its activity against penicillinase-producing S. aureus. Cefazolin is
effective for most surgical procedures, including orthopedic surgery because of
its ability to penetrate bone. All cephalosporins cross the placenta.
3. Elimination:
Cephalosporins are eliminated through tubular secretion
and/or glomerular filtration.

29. FOSFOMYCIN
Fosfomycin is a bactericidal synthetic derivative of phosphonic acid. It blocks
cell wall synthesis by inhibiting the enzyme UDP-N acetylglucosamine
enolpyruvyl transferase, which catalyzes the first step in peptidoglycan
synthesis.
It is indicated for urinary tract infections caused by E. coli or E. faecalis.
The most commonly reported adverse effects include diarrhea, vaginitis,
nausea, and headache.

30. POLYMYXINS
The polymyxins are cation polypeptides that bind to phospholipids on the
bacterial cell membrane of gram-negative bacteria.
They have a detergent-like effect that disrupts cell membrane integrity,
leading to leakage of cellular components and ultimately cell death.
Polymyxins are concentration-dependent bactericidal agents with activity
against most clinically important gram-negative bacteria, including
P.aeruginosa, E. coli, K. pneumoniae, Acinetobacter species, and Enterobacter
species.

31. POLYMYXINS
Only two forms of polymyxin are in clinical use today, polymyxin B
and colistin (polymyxin E).
Polymyxin B is available in parenteral, ophthalmic, otic, and topical
preparations.
Colistin is only available as a prodrug, colistimethate sodium, which is
administered IV or inhaled via a nebulizer.
The use of these drugs has been limited for a long time, due to the
increased risk of nephrotoxicity and neurotoxicity (for example,
slurred speech, muscle weakness) when used systemically.

32. Protein Synthesis Inhibitors
By Safaa Abdulwahab Andijani

33. OVERVIEW
• A number of antibiotics exert their antimicrobial effects by targeting
bacterial ribosomes and inhibiting bacterial protein synthesis.
• Bacterial ribosomes differ structurally from mammalian cytoplasmic
ribosomes and are composed of 30S and 50S subunits (mammalian
ribosomes have 40S and 60S subunits).
• In general, selectivity for bacterial ribosomes minimizes potential
adverse consequences encountered with the disruption of protein
synthesis in mammalian host cells.
• However, high concentrations of drugs such as chloramphenicol or
the tetracyclines may cause toxic effects as a result of interaction with
mitochondrial mammalian ribosomes, since the structure of
mitochondrial ribosomes more closely resembles bacterial ribosomes.

34. Classification Protein
Synthesis Inhibitors

35. TETRACYCLINES bacteriostatic

36. Adverse effects:
Tetracycline should be taken on an empty
Stomach.
The use of tetracyclines is limited in pediatrics.
Patients should be advised to wear adequate sun
protection.
Pseudotumor cerebri: Benign, intracranial
hypertension characterized by headache and
blurred vision may occur rarely in adults.
Contraindications: The tetracyclines should not
be used in pregnant or breast-feeding women or in
children less than 8 years of age.

37. GLYCYLCYCLINES bacteriostatic
1. Antibacterial spectrum :
Tigecycline exhibits broad-spectrum activity that includes
methicillinresistant staphylococci (MRSA), multidrug-resistant streptococci,
vancomycin-resistant enterococci (VRE), extended-spectrum β-lactamase–
producing gram-negative bacteria, Acinetobacter baumannii, and many
anaerobic organisms.
However, tigecycline is not active against Morganella, Proteus, Providencia,
or Pseudomonas species.

38. Adverse effects
SAME TETRACYCLINE ALSO:
nausea and vomiting. Acute pancreatitis Elevations in liver
enzymes and serum creatinine decrease the clearance of
warfarin and increase prothrombin time.

39. AMINOGLYCOSIDES bacteriostatic

40. AMINOGLYCOSIDES bacteriostatic
1-Therapeutic drug monitoring of gentamicin, tobramycin, and
amikacin plasma levels is imperative to ensure adequacy of dosing and
to minimize dose-related toxicities.
The elderly are particularly susceptible to nephrotoxicity and
ototoxicity.
2-Deafness may be irreversible and has been known to affect
developing fetuses.
3-Allergic reactions: Contact dermatitis is a common reaction to
topically applied neomycin.

41. Adverse effect :

42. MACROLIDES AND KETOLIDES bacteriostatic
they may be bactericidal at higher doses for clindamycin and
chloramphenicol.

43. MACROLIDES AND KETOLIDES bacteriostatic
Contraindications:
- Patients with hepatic dysfunction should be treated cautiously with
erythromycin, telithromycin, or azithromycin.
- Severe hepatotoxicity with telithromycin has limited its use, given
the availability of alternative therapies.
- May prolong the QTc interval and should be used with caution in
those patients with proarrhythmic conditions or concomitant use of
proarrhythmic agents.

44. Fidaxomicin
Fidaxomicin has a very narrow spectrum of activity
limited to gram-positive aerobes and anaerobes.
While it possesses activity against staphylococci and
enterococci, it is used primarily for its bactericidal
activity against Clostridium difficile.
Due to the unique target site, cross-resistance with
other antibiotic classes has not been documented .
adverse effects include nausea, vomiting, and
abdominal pain. Hypersensitivity reactions including
angioedema, dyspnea, and pruritus have occurred.

45. CHLORAMPHENICOL bacteriostatic
1. Antibacterial spectrum
Chloramphenicol is active against many types of microorganisms
including chlamydiae, rickettsiae, spirochetes, and anaerobes.
The drug is primarily bacteriostatic, but depending on the dose and
organism, it may be bactericidal.
2. Adverse effects
1. Anemias: Patients may experience dose-related anemia, hemolytic
anemia (seen in patients with glucose-6-phosphate dehydrogenase
deficiency), and aplastic anemia. [Note: Aplastic anemia is independent
of dose and may occur after therapy has ceased.]
2. Gray baby syndrome
3. Drug interactions
blocks the metabolism of drugs such as warfarin and phenytoin

46. CLINDAMYCIN SAME ERYTHROMYCIN
Clindamycin is used primarily in the treatment of infections caused by
gram-positive organisms, including MRSA and streptococcus, and
anaerobic bacteria. Resistance mechanisms are the same as those for
erythromycin, and cross-resistance has been described.
C. difficile is always resistant to clindamycin, and the utility of
clindamycin for gram-negative anaerobes.
the most common adverse effect is diarrhea.
Oral administration of either metronidazole or vancomycin is usually
effective in the treatment of C. difficile.

47. QUINUPRISTIN/DALFOPRISTIN bactericidaL
the drug is normally reserved for the treatment of severe vancomycin-
resistant Enterococcus faecium (VRE) in the absence of other
therapeutic options.
1. Antibacterial spectrum
The combination drug is active primarily against gram-positive cocci,
including those resistant to other antibiotics. Its primary use is in the
treatment of E. faecium infections, including VRE strains, for which it
is bacteriostatic.
The drug is not effective against E. faecalis.
Resistance Enzymatic processes commonly account for resistance to
these agents.
can change the action from bactericidal to bacteriostatic

48. Adverse effects
1. Venous irritation commonly occurs when
quinupristin/dalfopristin is administered through a peripheral
rather than a central line.
2. Hyperbilirubinemia
3. Arthralgia and myalgia
4. Quinupristin/ dalfopristin inhibits the cytochrome P450
(CYP3A4) isoenzyme, and concomitant administration with drugs
that are metabolized by this pathway may lead to toxicities

49. LINEZOLID

50. LINEZOLID
Adverse effects IMPORTANT
The most common adverse effects are gastrointestinal upset, nausea,
diarrhea, headache, and rash.
Thrombocytopenia has been reported, mainly in patients taking the drug for longer than 10
days.
Linezolid possesses nonselective monoamine oxidase activity and may lead to serotonin
syndrome if given concomitantly with large quantities of tyramine-containing foods,
selective serotonin reuptake inhibitors, or monoamine oxidase inhibitors.
The condition is reversible when the drug is discontinued.
Irreversible peripheral neuropathies and optic neuritis (causing blindness) have been
associated with greater than 28 days of use, limiting utility for extended-duration
treatments.

51. Quinolones, Folic Acid Antagonists,
and Urinary Tract Antiseptics
By Safaa Abdulwahab Andijani

52. FLUOROQUINOLONES bactericidal agents
MOA (inhibit DNA topoisomerase )
In gram-negative organisms (for example, Pseudomonas aeruginosa)
the inhibition of DNA gyrase is more significant than that of
topoisomerase IV in gram-positive organisms (for example,
Streptococcus pneumoniae), the opposite is true.

53. FLUOROQUINOLONES bactericidal agents

54. FOLATE ANTAGONISTS bactericidal agent
The sulfonamides (sulfa drugs) are a family of antibiotics that inhibit
de novo synthesis of folate. A second type of folate antagonist
trimethoprim—prevents microorganisms from converting dihydrofolic
acid to tetrahydrofolic acid, with minimal effect on the ability of
human cells to make this conversion

55. SULFONAMIDES
Sulfa drugs are active against select Enterobacteriaceae in the urinary
tract and Nocardia infections.
Sulfadoxine in combination with pyrimethamine: Preferred treatment
for toxoplasmosis is used as an antimalarial drug.
Adverse reactions and drug interactions
Drug potentiation: Transient potentiation of the anticoagulant effect
of warfarin results from the displacement from binding sites on serum
albumin.
Serum methotrexate levels may also rise through its displacement.

56. SULFONAMIDES
Contraindications:
Due to the danger of kernicterus, sulfa drugs should be avoided in
newborns and infants less than 2 months of age, as well as in pregnant
women at term.
Sulfonamides should not be given to patients receiving methenamine,
since they can crystallize in the presence of formaldehyde produced by
this agent.

57. TRIMETHOPRIM
MOA:
The active form of folate is the tetrahydro derivative that is formed
through reduction of dihydrofolic acid by dihydrofolate reductase.
This enzymatic reaction is inhibited by trimethoprim, leading to a
decreased availability of the tetrahydrofolate cofactors required for
purine, pyrimidine, and amino acid synthesis.
The bacterial reductase has a much stronger affinity for trimethoprim
than does the mammalian enzyme, which accounts for the selective
toxicity of the drug.

58. TRIMETHOPRIM
1. Antibacterial spectrum
The antibacterial spectrum of trimethoprim is similar to that of
sulfamethoxazole.
However, trimethoprim is 20- to 50- fold more potent than the
sulfonamides.
Trimethoprim may be used alone in the treatment of UTIs and in the
treatment of bacterial prostatitis (although fluoroquinolones are
preferred).

59. TRIMETHOPRIM
2. Adverse effects
Trimethoprim can produce the effects of folic acid
deficiency. These effects include:
1-Megaloblastic anemia.
2-Leukopenia .
3-granulocytopenia, especially in pregnant patients
and those having very poor diets.
These blood disorders may be reversed by the
simultaneous
administration of folinic acid, which does not enter
bacteria.

60. COTRIMOXAZOLE The combination of trimethoprim
with sulfamethoxazole, called cotrimoxazole.
Mechanism of action:
The synergistic antimicrobial activity of cotrimoxazole results from its
inhibition of two sequential steps in the synthesis of tetrahydrofolic
acid.
Sulfamethoxazole inhibits the incorporation of PABA into dihydrofolic
acid precursors, and trimethoprim prevents reduction of dihydrofolate
to tetrahydrofolate

61. COTRIMOXAZOLE The combination of
trimethoprim

62. URINARY TRACT ANTISEPTICS/ANTIMICROBIALS
UTIs are prevalent in women of child-bearing age and in the elderly
population. E.coli is the most common pathogen, causing about 80%
of uncomplicated upper and lower UTIs.
Staphylococcus saprophyticus is the second most common bacterial
pathogen causing UTIs.
In addition to cotrimoxazole and the quinolones previously
mentioned, UTIs may be treated with any one of a group of agents
called urinary tract antiseptics including methenamine,
nitrofurantoin, and the quinolone nalidixic acid (not available in the
United States).
These drugs do not achieve antibacterial levels in the circulation, but
because they are concentrated in the urine, microorganisms at that
site can be effectively eradicated.

63. Methenamine
1. Mechanism of action:
Methenamine decomposes at an acidic pH of 5.5 or less in the urine,
thus producing formaldehyde, which acts locally and is toxic to most
bacteria . Bacteria do not develop resistance to formaldehyde, which is
an advantage of this drug.
[Note: Methenamine is frequently formulated with a weak acid (for
example, mandelic acid or hippuric acid) to keep the urine acidic. The
urinary pH should be maintained below 6. Antacids, such as sodium
bicarbonate, should be avoided.]

64. Methenamine
2. Antibacterial spectrum:
Methenamine is primarily used for chronic suppressive therapy to
reduce the frequency of UTIs.
Routine use in patients with chronic urinary catheterization to reduce
catheter associated bacteriuria or catheter-associated UTI is not
generally recommended.
Methenamine should not be used to treat upper UTIs (for example,
pyelonephritis).
Urea-splitting bacteria that alkalinize the urine, such as Proteus
species, are usually resistant to the action of methenamine.

65. Methenamine
2. Adverse effects:
The major side effect of methenamine is gastrointestinal distress,
although at higher doses, albuminuria, hematuria, and rashes may
develop.
Methenamine mandelate is contraindicated in patients with renal
insufficiency, because mandelic acid may precipitate.
[Note: Sulfonamides, such as cotrimoxazole, react with formaldehyde
and must not be used concomitantly with methenamine. The
combination increases the risk of crystalluria and mutual
antagonism.]

66. Nitrofurantoin
sensitive bacteria reduce the drug to a highly active intermediate that inhibits
various enzymes and damages bacterial DNA. It is useful against E. coli, but
other common urinary tract gram-negative bacteria may be resistant.
Grampositive cocci (for example, S. saprophyticus) are typically susceptible.
Hemolytic anemia may occur with nitrofurantoin use in patients with G6PD
deficiency.
Other adverse effects include gastrointestinal disturbances, acute
pneumonitis, and neurologic problems. Interstitial pulmonary fibrosis has
occurred in patients who take nitrofurantoin chronically.
The drug should not be used in patients with significant renal impairment or
women who are 38 weeks or more pregnant

69. ‫الحمدهللا‬
By Safaa Abdulwahab Andijani