1. Aminoglycosides & Spectinomycin

2. Part A Aminoglycosides

3. Overview
History and Source : the research made by Waksman and coworks within
Clinical Applications: for the treatment of aerobic G- bacterial infections and tuberculosis
Two classes: crude product and semisynthetic derivative

4. General properties 1. Antimicrobial activity:
i) rapidly bactericidal to resting bacterium
ii) broad-spectrum： G- bacilli and cocci，G+ organisms，TB
iii) more active at alkaline
iv) concentration-dependent activity
v) the duration of post antibiotic effect (PAE) is concentration- dependent (10 hours).
vi) first exposure effect (FEE)
Blood
Concentration
MIC
Peak Concentration
Time (h)
Bacterial growth is inhibited long after concentration below the MIC

5. General properties 2. Mechanism of action: inhibit protein synthesis
act as Ionic-absorbent, act directly on permeability of the cell membrane of bacterium.

6. Inhibiting protein synthesis: Aminoglycosides

7. 2.Mechanism of action - inhibit protein synthesis
i) Interfering with the initiation complex of peptide formation.
ii) Inducing misreading of mRNA, which causes the incorporation of incorrect amino acid into peptide, resulting nonfunctional or toxic protein.
iii) causing breakup of polysomes into nonfunctional monosomes.
iv) disrupt the normal cycle of ribosomal, make the ribosomal exhausted.

8. 3. Mechanism of resistance
produces enzymes
Changes of Porins
Altered ribosomal subunit

9. Mechanism of Resistance
i) The microorganism produces a transferase enzyme or enzymes that inactivate the aminoglycoside by adenylyation, acetylation, or phosphorylation.
ii) Impaired entry of aminoglycoside into the cell.
iii) The receptor protein on the 30S ribosomal subunit may be deleted or altered as a result of mutation.

10. General properties ADME
i) Absorption: not absorbed after po, but rapidly absorbed after IM.
ii) Distribution: Binding to plasma protein is minimal, do not enter cell, nor do they cross BBB,but they cross the placenta, reach high concentrations in secretions and body fluids. Tissue level is low expect in the cortex of kidney.
iii) Elimination: excreted mainly by glomerular filtration. If renal function is impaired, accumulation occurs with a increase in those toxic effects which are dose related.

11. General properties Clinical Uses
be mostly used against aerobic G- bacteria (bacilli, enteric) and in sepsis, be almost always used in combination with b-lactam antibiotic and fluoroqunolones
Tuberculosis

12. General properties Adverse reactions i) Ototoxicity
involves progressive damage to and destruction of the sensory cells in the cochlea and vestibular organ in the ear (irreversible!! Auditory and vestibular damage).
ii) Nephrotoxicity
consists of damage to the kidney tubules and be reversed if stop using.

13. General properties Adverse reactions
iii) Neuromuscular blockade (paralysis)
generally occurred after intra-pleural or intra-peritoneal instillation of large doses of an aminoglycosides
Calcium salt or inhibitor of cholinesterase (neostigmine) is the preferred treatment for this toxicity.
iv) Allergic reaction
skin rashes fever, eosinophiliay , anaphylactic shock, etc.

14. Aminoglycosides Streptomycin Gentamicin Tobramycin Amikacin Netilmicin
Neomycin
Kanamycin
Arbekacin
Dibekacin
Micronomicin
Sisomicin
Etilmicin
Isepamicin
Astromicin

15. Streptomycin 1. ADME i) Absorption: IM
ii) Distribution: mainly at extracellular fluid, crosses the BBB and achieves therapeutic concentrations with inflamed meninges.
iii) Excretion: 90%, kidney
2.Clinical uses
i) plague and tularemia: combination with an oral tetracycline.
ii) tuberculosis: as first-line agent
iii) bacterial endocarditis: (enterococcal, viridans streptococcal, etc.), streptomycin and penicillin produce a synergistic bactericidal.
3. Adverse reactions
i) Allergic reaction
skin rashes, fever, anaphylactic shock
ii) Ototoxicity: disturbance of vestibular function, deafness of newborn
iii) Nephrotoxicity
iv) Neuromuscular blockade (paralysis)：Myasthenia Gravis, anesthetics, scoline

16. Gentamicin 1. ADME Gentamicin can accumulate in cortex of the kidney .
2.Clinical use :
i) serious G- bacillary infections (sepsis, pneumonia, etc.).
ii) infection induced by enterococcal, viridans streptococcal, staphylococcal etc. (in combination with other antibiotics, e.g. b-lactams)
iii) prevent the infection induced by operation (e.g., gastrointestinal operation )
iv) local application or intrathecal administration (rarely use)
3. Adverse reactions
i) Nephrotoxicity (reversible and mild)
ii) Ototoxicity (irreversible!)
iii) Nausea and vomiting etc.

17. Tobramycin
1. antimicrobial activity & pharmacokinetics: very similar to those of gentamicin; has cross-resistance to gentamicin.
2. Adverse reactions: Ototoxicity and Nephrotoxicity (may be less than dose gentamicin).

18. Netilmicin
1. similar to gentamicin & tobramycin in its pharmacokinetic properties.
2. broad spectrum, against aerobic G- bacilli.
3. tolerance to many aminoglycosides (gentamicin, tobramycin) - inactivating enzymes.
4. less toxic
Like other aminoglycosides, netimicin also produce Ototoxicity and Nephrotoxicity, but some studies suggested that netimicin may be the less toxic.

19. Amikacin 1.Antibacterial activity: the broadest in the group.
2.Clinical uses :
Treatment of G-bacillary infections which resistance to gentamicin and tobramycin.
Most strains resistance to amikacin found is also resistance to other aminoglycosides.
combination with b-lactams, produce a synergistic bactericidal.
3. Adverse reactions
i) Ototoxicity
ii) Nephrotoxicity
iii) Neuromuscular blockade (paralysis)
iv) skin rashes, fever, nausea and vomiting etc.

20. Macrolides and lincomycin

21. Structure

22. Representative drugs Erythromycin Dirithromycin Meleumycin Josamycin
Acetylspiramycin
Midecamycin
Penicillin-resistant Staphylococcus
Penicillin-allergic patients
First generation
Rokitamycin
Roxithromycin
Clarithromycin
Azithromycin
Acetylmidecamycin
flurithromycin
Second generation
Penicillin-resistant Staphylococcus
Penicillin-allergic patients

23. Antibacterial spectrum
board bactericidal or bacteriostatic drugs
G+ and G- bacteria, cocci, Neisseria gonorrhea, gram-positive bacilli, and spirochetes, mycoplasma, rickettsiosis
2. Mechanisms
Inhibition of protein synthesis
(1) reversible binding to 50S subunit of
ribosome (23S rRNA)
(2) L22 protein binding in 50S subunit,
lead to disruption of ribosome

24. 3. Clinical Usage 4. Adverse reaction (1) GI
(1) Streptococci infection
(2) Legionella pneumophila
(3) infection from spirochetes, mycoplasma, rickettsiosis
4. Adverse reaction
(1) GI
(2) hepatic damage
(3) superinfection: infection that occurs while treating another infection.
e.g. oral fungal infection
(4) Ototoxicity
(5) allergic reaction

25. Lincomycin & Clindamycin
Antibacterial spectrum
(1) board bactericidal or bacteriostatic drugs, similar to the macrolides
(2) Anaerobic G+ and G- bacteria
2. Mechanisms
Inhibition of protein synthesis
L16 protein binding in 50S subunit,
lead to disruption of ribosome. Avoid to using with erythromycin
(same binding sites), antagonistic effects.

26. 3. Clinical Usage 4. Adverse reaction (1) GI (1) Aerobic bacteria
(2) anaerobic bactreria
(3) infection from staphylcoccus in bone tissues (osteomyelitis )
4. Adverse reaction
(1) GI
(2) hepatic damage
(3) allergic reaction

27. Tetracyclins and chloramphenicol

28. Natural products Semisynthesis Chlortetracycline Oxytetracycline
Doxycycline
Methacycline
minocycline
Semisynthesis

29. Antibacterial spectrum
board bacteriostatic drugs
G+ and G- bacteria, cocci, spirochetes, mycoplasma, rickettsiosis,
chlamydia.
2. Mechanisms
(1) Cell membrane transportation
(2) Inhibition of protein synthesis
30S subunit of ribosome
(3) permeability

30. 3. Clinical Usage 4. Adverse reaction (1) GI (1) spirochetes
(2) mycoplasma
(3) rickettsiosis,
(4) chlamydia
(5) bacteria
4. Adverse reaction
(1) GI
(2) hepatic damage
(3) superinfection: infection that occurs while treating another infection.
e.g. oral fungal infection
(4) teeth and bone
(5) renal toxicity
(6) photosensitized reaction
(7) ototoxicity

31. chloramphenicol

32. Antibacterial spectrum
board bacteriostatic bactericidal drugs
G+ and G- bacteria, spirochetes, mycoplasma, rickettsiosis,
2. Mechanisms
Inhibition of protein synthesis
70S ribosome complex, 50S
hematopoietic stromal cell in bone marrow,
mammary 70S is similar to baterial 70S, lead to bone marrow suppression

33. 3. Clinical Usage 4. Adverse reaction (1) GI
(1) bacterial meningitis, purulent Meningitis in Children
(2) Corynebacterium diphtheriae infection
(3) eye infection (bacteria)
(4) anaerobic infection
4. Adverse reaction
(1) GI
(2) Gray baby syndrome: disturb the ribosome function in mitochondria
ability of detoxication via glucuronic acid conjugation
ability of renal excretion
(3) bone marrow suppresion:
AA, anemia, granulocytopenia, thrombopenia

34. Vancomycins Antibacterial Mechanism
Inhibiting cell wall synthesis by binding to the D-Ala-D-Ala terminus of nascent peptidoglycan penta-peptide.
Resistance
occurred because of the alteration of D-Ala-D-Ala to the D-Ala-D-Ser.

35. Fig. Antibacterial Mechanism of Vancomycins

36. Vancomycins ADME Oral administration (poorly absorbed).
Intravenous administration, is excreted by glomerular filtration (accumulates when renal function is impaired).
Widely distributed in the body, including CSF when the meninges is inflamed.

37. Vancomycins Clinical Uses 1) severe infection caused by MRSA etc.
2) alternative for b-lactam
3) enterococcal or staphyococcal endocarditis (combination with gentamicin).
4) pseudomembranous colitis
***Overuse should be avoided, in view of limited options for treatment of resistant gram positive infections.

38. Vancomycins Adverse Reactions 1) Hypersensitive reaction
(e.g. red man syndrome)
2) Ototoxicity
3) Nephrotoxicity
4) Gl effects, Phlebitis etc.

39. Synthetic antimicrobial agents
Part B
Synthetic antimicrobial agents

40. Synthetic antimicrobial agents
Quinolones
Generation Example time
Nalidixic acid
Pipemidic acid
Norfloxacin ’s
Clinfloxacin ’s
Sulfonamides
Other Synthetic antimicrobial
Trimethoprim, Nitrofurans

41. From chloroquine to nalidixic acid

42. First generation fluoroquinolones4 1 2 3 5 6 7 ８

43. From ofloxacin to levofloxacin

44. Fluoroquinolones
Second generation fluoroquinolones: Activity against S.pneumoniae (treatment of pneumonia, sinusitis, and bronchitis)

45. General properties of Quinolones
Antimicrobial activity & spectrum:
(1) bactericidal and have significant PAE.
(2) aerobic G- bacteria, Pesudomonas, aerobic G+ bacteria, Chlamydia spp., Legionella pneumophila , anaerobic bacteria, mycobacteria, multiple-resistance strains.

46. Mechanism of action DNA gyrase Topoisomerase
Key enzymes in DNA replication: bacterial DNA is supercoiled.

47. Mechanism of action
Topo
isomerase
DNA gyrase
Gram (-)
Gram (+)
porin

48. Mechanism of action DNA gyrase Catalytic subunite Fluoroquinolones:
4 stacked molecules
DNA gyrase
Catalytic subunite
ATP binding subunite

49. Mechanism of resistance
Topo
isomerase
DNA gyrase
Gram (-)
Gram (+)
porin
mutation of
the enzymes
active efflux
system
decreased
permeability
Mutation of the gyrA gene that encoded the A subunit polypeptide can confer resistance to these drugs.
Mutation of the gene cfxB and nfxB that encoded the porin decreased permeability of cell membrance.
The high expression of norA gene (encoded active pump protein) increased drugs efflux by a active transport protein pump.

50. ADME of fluoroquinolones
Absorption: well absorbed; bound by divalent cations
Do not administer with iron, magnesium, calcium
Distribution: all distribute widely (even in CSF), and most concentrate in urine
Metabolism:
hepatic metabolism diminishes the activity of norfloxacin and ciprofloxacin
Several have predominately hepatic clearance (Grepafloxacin, Sparfloxacin, Trovafloxacin)
Excretion: urinary excretion predominates for the first generation fluoroquinolones

51. Clinical Uses Urinary tract infections. GI and abdominal infections.
Respiratory tract infections.
Bone, joint and soft tissues infections, Osteomyelitis.
Meningitis
STD: Neisseria gonorrhea and Chlamydia (Quinolone
resistance in gonorrhea increasing)
Adverse reactions
Gastrointestinal effects.
CNS side effects.
Allergic reaction.
Hepatotoxicity, nephrotoxicity.
Joint/cartilage toxicity, Tendinopathy
Achilles tendon rupture
Limited FDA approval for children (under 18)

52. Fluoroquinolones agents
Norfloxacin
Ciprofloxacin
Ofloxacin
Levofloxacin
Lomefloxacin
Fleroxacin
Sparfloxacin
Clinafloxacin
Gatifloxacin

53. Sulfonamides : Inhibitors of Folate Synthesis
Gerhard Domagk
Nobel Laureate 1939
2,4-Diaminoazobenzen-4’-sulfonamide
Prontosil
Antimicrobial activity:
A wide antimicrobial spectrum.
Exerting only bacteriostatic effect.

54. Mechanism of action Pteridine+PABA Dihydropteroic acid
Blocked by
sulfonamides
Dihydropteroic acid
Dihydrofolic acid
glutamate
Tetrahydrofolic acid
Blocked by trimethoprim
NADPH
Dihydropteroate
synthase
Dihydrofolate
reductase

55. Mechanism of Resistance
A lower affinity for sulfonamides by the dihydropteroate synthase
Decreased cell permeability or active efflux of the drug
An alternative pathway to synthesis the essential metabolites
An increased production of essential metabolites

56. Classification & Clinical uses :
Oral absorbable agents (Systemic infections)
Short-acting agents: Sulfafurazole (SIZ)
Medium-acting agents:
Sulfadiazine (SD) [Co: pyrimethamine → toxoplasmosis]
best in the CSF and brain → → meningitis
Sulfamethoxazole (SMZ) [Co: trimethoprim, named
trimoxazole / TMP-SMZ
Long-acting agents: Sulfadoxine (SDM) [Co: pyrimethamine → malaria]
Oral nonabsorbable agents (Intestinal infections) Sulfasalazine
Topical agents (Infections of burn and wound)
Mafenide (SML)
Sulfadiazine sliver
Sulfacetamide (SA)

57. ADME of sulfonamides
Approximately 70%-100% of an oral dose is absorbed.
Distributing throughout all tissues of the body, even in CSF ( sulfadiazine and sulfisoxazole, may be effective in meningeal infections) ;readily passing through the placenta.
Metabolized in the liver by acetylation.
Eliminated mainly in the urine as the unchanged drug and metabolic product. In acid urine, the eliminated may precipitate, thus induced renal disturbance.

58. Adverse reactions Drugs interactions Hypersensitivity reaction
Urinary tract disturbances: Sulfonamide crystalluria
Hematopoietic system disturbances
Kernicterus
Hepatitis
GI effects
Drugs interactions
All sulfonamides are bound in varying degree to plasma protein.
Kernicterus: occurs in newborns where sulfonamides displace bilirubin from its binding site on serum albumin, and the excess bilirubin penetrates into the CNS to cause brain damage.

59. Combination agents: Co-trimoxazole
1) Features
Trimethoprim in combination with Sulfamethoxazole (1:5,eg,160mg:800mg for p.o.) exerts a synergistic effects (bacteriocidal effect ).
Co-block essential enzymes of folate metabolism.
The ADME of the two agents is similar.

60. Pteridine+PABA Dihydropteroic acid Dihydrofolic acid
Blocked by
sulfonamides
Dihydropteroic acid
Dihydrofolic acid
glutamate
Tetrahydrofolic acid
Blocked by trimethoprim
NADPH
Dihydropteroate
synthase
Dihydrofolate
reductase

61. 2)Clinical Uses 3)Adverse reactions
Chronic and recurrent infections in the urinary tract
Bacterial respiratory infections
GI infections (e.g. induced by Salmonella)
pneumocystis carinii pneumonia
3)Adverse reactions
There is no evidence that co-trimoxazole, when given in recommended dose, induced folate deficiency in normal persons.
Trimethoprim(TMP): megaloblastic anemia
Sulfamethoxazole (SMZ): all adverse reactions mentioned
HIV patients (fever, rashes, leukopenia, diarrhea, hyperkalemia)
Drug interactions: warfarin, phenytoin, etc.