mbbs lecture ppt

1. Expand…….
 AM -
 PM –
 OD –
 BID -
ante meridiem
post meridiem
omne in die (once in a day)
bis in die (twice in a day)

2. Case Scenario
 A 65 Year Old Cigarette Smoker with a h/o Hypertension and
mild congestive heart failure presents to the emergency
room with worsening cough, fever and dyspnea at rest. The
illness began 2 weeks ago with fever throat pain and non-
productive cough and rapidly becoming worse.

3. Atypical pneumonia
Sputum culture and PCR – Chlamydia pneumoniae
Reticulo nodular
interstitial shadows

4. 1st Drug of choice for Atypical organisms
 Legionella
 Mycoplasma
 Chlamydia
 MACROLIDE ANTIBIOTICS !!

5. Dr Anoosha P Bhandarkar
Consultant Diabetologist
Dept Of Pharmacology
SDM College of Medical Sciences & Hospital
Dharwad
MACROLIDE ANTIBIOTICS & Miscellaneous
drugs inhibiting protein synthesis

6.  Having macrocyclic lactone ring attached to sugars
 Erythromycin --- 1950s
 Others – Roxithromycin
Clarithromycin
Azithromycin
Spiramycin

7. Mechanism of action-
Bacterial protein synthesis inhibitors
1. Aminoglycosides – freeze initiation, misreading of mRNA
2. Tetracyclines –> ↓ t-rna attachment to “A” on 30S
3. Chloramphenicol – ↓ peptide bond formation
4.Macrolides – translocation from A  P

9. VIDEO..

10. Erythromycin
 Soil bacteria - “Streptomyces Erythreus” – 1952
 Used as alternative to penicillin
 Orally effective

11. Antibacterial Activity :
 Narrow spectrum
 Effective against most Gram +ve & few Gram –ve organisms
 Highly active: Strep.pyogenes, Strep.pneumoniae,
N.gonorrhoeae, Clostridia, C.diphtheriae, Listeria,
Campylobacter jejuni, Mycoplasma
 Moderate activity : H.influenzae, H.ducreyi, B.pertussis,
Chl.trochomatis, Strep.viridans, N.meningitidis & Rickettssiae

12. • H. Pylori
• Not useful against Enterobacteriaceae

13. Resistance
 capacity to pump out erythromycin
 Enterobacteriacea - Produce erythromycin esterase
 Alteration in ribosomal binding site
 Change in 50S ribosome by chromosomal mutation
 Bacteria resistant to erythromycin are CLASS RESISTANT &
CROSS RESISTANT (Clindamycin/Chloramphenicol)

14. Pharmacokinetics:
 Acid labile
 Inactivated by gastric acid – enteric coated tab
 Food delays absorption by ↓ gastric emptying
 Incompletely but adequately absorbed upper part of intestine
(alkaline medium)
 Distribution - wide, crosses serous membrane, placenta, but
not Blood-brain barrier
(not suitable for CNS infections)

15. Pk contd..
 Prostatic fluid – Rx concentration
 70-80% PP bound
 Partly metabolized & excreted in bile in active form
 2-5% excreted in urine (can give in renal failure)
 t ½ is 1½ hrs – but persists in tissues longer

16. Dosage: 250-500mg 6 hrly - QID (max 4g/day)
Preparation:
i. Erythromycin estolate: (Althrocin) - relatively acid stable
adult tab- 250, 500 mg, paed tab- 125 mg,
dry syrup – 125 mg/5ml, 250 mg/5ml,
paed drops – 100 mg/ml
ii. Erythromycin stearate:(Erythrocin)
iii. Erythromycin ethyl succinate: well absorbed orally
dry syrup – 100 mg/5ml
paed drops – 100 mg/ml
iv. 30% ointment – topical application for boils, carbuncles

17. Uses
1. As an Alternative for Penicillin-G
- Pharyngitis, tonsillitis, community acquired resp inf
- Alternative drug – prophylaxis of Rheumatic fever & SABE
- Diphtheria – acute stage, for carriers- 7 days Rx
- Tetanus - as adjuvant to anti-toxin & toxoid therapy
- Syphilis, gonorrohea, leptospirosis
- allergic to penicillin
2. First choice – atypical pneumonia, whooping cough,
chancroid
3. Second choice – Camp.enteritis, Legionnaires’ disease,
chlamydia trachomatis, penicillin resistant staphylococcal
infections

19. Adverse effects
1. GI : mild – severe epigastric pain, diarrhoea
(stimulates motilin receptors)
2. Hypersensitivity reactions : rashes & fever infrequent
Hepatitis with Cholestatic jaundice resembling viral
hepatitis- estolate ester after 1-3 weeks, disappears on
discontinuation
3. Reversible hearing loss – very high doses

20. Drug Interaction
 inhibits hepatic oxidation (CYP3A4 enzyme) – potentiates
effects of theophylline, carbamazepine & warfarin
 potential to prolong Q-T interval  fatal arrythmias
Limitations of Erythromycin :
- narrow spectrum of activity
- gastric intolerance, gastric acid lability, low oral BA
- short t½, lesser tissue penetration

21. Roxithromycin
 Long acting, acid-stable, semisynthetic
 ABA similar to erythromycin- more potent Branh.
catarrhalis, Gard. Vaginalis & Legionella
Ppn: Roxid- tab – 150, 300 mg;
kid tab – 50 mg, liquid – 50 mg/5ml
- Oral abs good, better tissue pent, t½-12 hrs (BID)
Uses:
 Alternative to erythromycin
- In resp, ENT, skin, soft tissue & genital tract infections

22. Clarithromycin
 ABA = erythromycin, more active-Mycoplasma pneumoniae,
H.pylori, MAC & atypical mycobacteria
 erythromycin resistant = clarithromycin resistant
 Ppn: Claribid: tab – 250, 500 mg, dry syrup – 250 mg/5ml

23. Pharmacokinetics :
 More acid stable  Rapidly abs orally
 Oral bioavailability is 50% -d/t First pass
metabolism
 Food delay absorption, distributed in tissues &
erythrocytes
 Metab – saturation kinetics
 t ½ 3-6 hrs – small dose  6-9 hrs – higher doses
 NO dose adjustment – liver disease, mild –
moderate renal insufficiency

24. Uses :
 Respiratory - URTI , LRTI, sinusitis, otitis media, whooping
cough, atypical pneumonia
 Skin & STIs
 First choice for MAC infection in AIDS pts
 Second choice – Atypical mycobacterial infection & Leprosy
 A component in “triple drug regimen” in H.pylori gastritis
Side effects :
 Similar to erythromycin ; Better GI tolerance
 Higher doses- reversible hearing loss,
pseudo-membranous colitis, hepatic dysfunction

25. Azithromycin
 Azalide congener of erythromycin
 Improved Pk properties, tolerability, drug interaction
 Good bioavailability
Broad spectrum of ABA :
 More active against – H.influenza, Less active - G+ve
cocci
 Highly – Mycoplasma, Chl.pneumoniae, Legionella,
Moraxella, H.ducreyi, N.gonorrhoeae
 Not against MRSA
 Not active against erythromycin resistant bacteria

26. Pharmacokinetics:
 Acid stable, rapid oral absorption
 Distribution in tissues, better intracellular penetration
 Conc in tissues > plasma
 High conc – macrophages & fibroblasts
 Slowly released from intracellular sites
 Long t ½ > 50hrs (post-antibiotic effect)
 Convenient once-daily dosing
 Excreted unchanged – bile
 Renal excretion < 10%
 Ppn: Azithral – caps – 250, 500 mg ; dry syrup, inj. 500 mg
 A/E : mild gastric upset, abd pain, headache & dizziness

27. Uses
1. First drug of choice in – legionnaires’ & chlamydial
pneumonia, chlamydia trachomatis, donovanosis,
chancroid and PPNG urethritis (pen.resistant)
2. Pharyngitis, tonsillitis, sinusitis, otitis media, acute
exacerbations of chronic bronchitis
3. Skin & soft tissue infections
4. Combination with other drug for prophylaxis &
treatment of MAC in AIDS pts
5. Other potential uses - typhoid, toxoplasmosis, malaria

28. Spiramycin
- Resembles erythromycin in ABA & other properties
- Limits transplacental risk of transmission of
Toxoplasma gondii  Drug of choice in pregnancy
- Use is very limited and sporadic
Uses: toxoplasmosis, recurrent abortion in pregnant
women; other uses similar to erythromycin
A/E : gastric irritation, nausea, diarrhoea & rashes

29. Lincosamide Antibiotics
- Lincomycin – forerunner; fatal diarrhea & colitis
- Clindamycin – Gram positive aerobes & Anaerobes
 similar MOA & spectrum of activity to erythromycin
 partial cross resistance with erythromycin
 High activity - G+ve cocci & variety of anaerobes
 Not affected : Aerobic Gram -ve bacilli, spirochetes,
chlamydia, mycoplasma & rickettsia

30. Pharmacokinetics
 Good oral absorption, penetrates into most skeletal &
soft tissues, but not in brain & CSF (not for CNS
infections)
 Accumulates in neutrophils & macrophages
 excreted in urine & bile, t ½ is 3hr, TDS dosing
Side effects
 Rash, urticaria, abdominal pain
 Diarrhoea & pseudomembraneous enterocolitis d/t
Clostridium difficile superinfection- fatal

31. Clindamycin - Uses
 Restricted to anaerobic & mixed infections - abdominal,
pelvic & lung abscesses
 Prophylaxis of endocarditis PRIOR to dental surgery
 to prevent surgical site infection in colorectal/ pelvic surgery
 In AIDS patients:
- combined with Pyrimethamine for Rx of toxoplasmosis
- with Primaquine for Rx of pneumocystis jiroveci
 Topical – Rx of Acne vulgaris

32. MISCELLANEOUS ANTIBIOTICS

33. MISCELLANEOUS ANTIBIOTICS
 G lycopeptides: Teicoplanin, Vancomycin
 O xazolidinones : Linezolid
 S treptogramins : quinupristin/dalfopristin
 Li popeptides : Daptomycin
 P olypeptides : Polymixins, Bacitracin
 Others : - Spectinomycin
- Mupirocin
- Fusidic acid

34. GLYCOPEPETIDES
 Vancomycin and Teicoplanin
 Rx of Serious infections by ONLY G+ve Pathogens
 Doesn’t penetrate the Outer membrane of Gram –ve
BACTERICIDAL (to G+ve cocci, MRSA, MR Enterococci,
clostridia, diphtheroids)

35. Binds to D-ala-D-ala sequence (transglycosylation)
& inhibit bacterial cell wall synthesis
Mechanism of Action – Vancomycin & Teicoplanin
VIDEO

36.  Resistance : - Altered binding to D-ala-D-ala sequence
(Enterococci- VRE; plasmid mediated)
- Mutation in enzymes of cell wall synthesis
(Staphylococci- VRSA)

37. GLYCOPEPETIDES
 Spectrum :
 Only GPB ( Both cocci and bacilli)
Pk features :
 A : not absorbed orally, ONLY I.V route
 D : Wide (cross BBB) – Inflammed meninges
t1/2: 6hrs , TWICE DAILY dosing
 E : Renal (unchanged) – accumulates in Renal dysfunction

38. GLYCOPEPETIDES - Vancomycin
 Uses :
 Serious Skin and soft tissue infections by MRSA
 Bone and Joint infections by GP-Bacteria & MRSA
 CNS infections of pneumococci (pen-resistant)
 Endocarditis : by Enterococci, MRSA & streptococci
 Pseudo-membranous enterocolitis : oral route

40. GLYCOPEPETIDES - Vancomycin
 Toxicity :
 Ototoxic : permanent nerve damage, high dose
 Nephrotoxic : At high doses
 Rashes and anaphylaxis
 Local : thrombophlebitis
 Red-neck/ Red-man syndrome : rapid i.v. injection
- Histamine release
- Chills, rashes, urticaria, intense flushing, hypotension

41. GLYCOPEPETIDES - Teicoplanin
Newer
G+ve bacteria only
MOA & ABA spectrum similar to vancomycin
More active against Enterococci
 VRE are sensitive, but not VRSA
 Less ADRs and rare Histamine reactions
 ROA: both IV & IM, Long t1/2 : 3-4 days, OD dosing
 Excreted - urine, dose reduction in kidney failure

42. Teicoplanin
 Uses : Serious infections by MRSA, VRE
1. Serious Skin and soft tissue infections - by MRSA
2. Bone and Joint infections - GP-Bacteria & MRSA
3. CNS infections - Pneumococci (pen-resistant)
4. Endocarditis - Enterococci (also VRE), MRSA & streptococci

43. OXAZOLIDINONES : LINEZOLID
 Synthetic
 For resistant GPB (aerobic and anaerobic), M.TB
 NOT FOR Gram Negative bacteria
 MOA : - primarily - Bacteriostatic
- Bacteriocidal- streptococci, pneumococci, B.fragilis
- Binds 23S fraction of 50S ribosome and
- Inhibits formation of t-RNAfMet-70S initiation complex
Resistance : Mutation in ribosome (Rare), No cross resistance

44. LINEZOLID : Pharmacokinetics
- Rapid and complete oral absorption
- t1/2 : 5h, BID dosing (600mg)
- Non-enzymatic metabolism (partly)
- Renal elimination ( no dose reduction required)

45. LINEZOLID
 Uses : “restricted” to serious hospital-acquired
pneumonias, bacteremias and MDR G+ve infections
 VRE infections - UTI, sepsis
 VRE, VRSA and MRSA infections of skin and soft tissue
 MRSA & multi-drug resistant Staph pneumonia
 Febrile neutropenia
 ORAL & I.V. routes --> similar - 83-94% cure rates

46. OXAZOLIDINONE : LINEZOLID
ADRs :
 BM suppression – neutropenia, thrombocytopenia
 GI disturbances
 Rash, pruritus
 Peripheral neuropathy, optic neuritis : long term use
 Drug interactions:
 Weak MAO-inhibitor  tyramine cheese reaction
 Interaction with SSRIs
 No effect on CYP enzymes

47. STREPTOGRAMINS -
Quinupristin/Dalfopristin
 Bacteriostatic
 Most G+ve cocci, MRSA, VRSA ,VRE and atypical organisms
 PK features : - IV route only
- t1/2 : 8hrs
- Hepatic metabolism biliary excretion
 Uses : similar to linezolid
 ADRs : - infusion related
- Arthralgia and myalgia (cumulative toxicity)
 DI : They are CYP inhibitor

48.  Mupirocin- Topically used, mainly against G+ve bacteria
- Strep.pyopgenes, Staph aureus, MRSA etc.
- inhibits bacterial protein synthesis
- No cross resistance
- In furunculosis, folliculitis, impetigo, infected insect bites
and small wounds
 Fusidic acid- steroidal antibiotic
- Topically used against penicillinase-producing Staph & few
other G+ve bacteria
- Used for boils, folliculitis, syncosis barbae (barber’s itch)etc.

49. LIPOPEPTIDES : Daptomycin
 Rx of systemic and life-threatening infections
 by Multi Drug-Resistant Gram-positive bacteria
 MRSA, VRSA, VRE

50. Daptomycin is bactericidal against Gram-positive
bacteria only
 VRE
 MRSA
 VRSA

51. POLYPEPTIDES
Powerful bactericidal agents
Source : Natural Bacillus species – 1940s
1. Polymixins : Polymixin-B & Colistin
2. Bacitracin
3. Tyrothricin

52. Polymixins : Polymixin-B & Colistin
 Spectrum : GNB only except Proteus, Serratia, Neisseria
 Colistin more potent than polymixin B on pseudomonas,
Salmonella, Shigella
 MOA : - Bind to LPS, phospholipids of cell membrane
- Disrupt cell membrane structure
(Detergent-like action)
- Form “pseudopores”  ions, amino acids leak
- bactericidal

53. Polymixins - Polymixin-B & Colistin
 Uses : - Topical : Skin, mucosa, eye, ear, burns, cornea
(Polymixin-B)
- Oral : GNB enteritis/diarrhea (Colistin>polymixin B)
- Parenteral (i.v.) : For MDR GN-Bacterial infections
 ADRs : Systemic toxicity:
- Histamine release : Flushing, Paraesthesiae
- Nephrotoxicity – marked; dose-calculators
- Neuromuscular blockade
- Neurotoxicity

54. POLYPEPTIDES - Bacitracin
 Bacitracin : from Bacillus subtilis
 Spectrum : GP-Bacteria (unlike polymixins)
 MOA : - inhibition of cell wall synthesis
- By interfering with peptidoglycan synthesis
- bactericidal
 Use : Only topical, toxic for systemic use
wounds, ulcers, eye infections - NEOSPORIN
Neomycin
+
Polymixin-B
+
Bacitracin

55. OTHERS
SPECTINOMYCIN :
 Binds to 30s
 Used in MDR gonorrhea (& patients allergic to penicillins)
 Given by IM route, eliminated unchanged in urine
 TYROTHRICIN – GP-Bacteria and few GNB
 Causes cell membrane leakage
 Only Topically
 Too toxic - systemic

56. DRUG CLASS MOA SPECTRUM RESULT
ERYTHROMYCIN MACROLIDES
Bacterial
protein
synthesis
inhibition
Gram +ve
Gram -ve
Static
AZITHROMYCIN MACROLIDES Gram +ve, Gram –ve &
Atypical
Static
CLINDAMYCIN LINCOSAMIDE Only Gram +ve &
Anaerobes
Static
LINEZOLID OXAZOLIDENONES Only Gram +ve
MRSA, VRSA, VRE
Static
VANCOMYCIN GLYCOPEPTIDE
Cell wall
synthesis
inhibition
Gram +ve & MRSA Cidal
TEICOPLANIN GLYCOPEPTIDE Gram +ve, MRSA, VRE Cidal
DAPTOMYCIN LIPOPEPTIDE Gram +ve, MRSA
VRSA, VRE
Cidal
BACITRACIN POLYPEPTIDES Gram +ve(only topical) Cidal
POLYMIXIN-B
COLISTIN
POLYPEPTIDES Cell
membrane
lysis with
Pseudopores
Only for
Gram –ve
MDR organisms
Cidal

57. TID -
HS -
qD –
NPO –
ter in die (thrice in a daily)
hora somni (bed time)
Quaque die (every day)
Nil Per Os (nil orally)

58. Thankyou