Antibiotic in The Butterfield

11/13/2019
Antibiotics on the Battlefield

‫ طارق المقطري‬.‫د‬
Dr. Tareq Al-Maqtari, PhD
IUST
Antibiotic vs antibacterial
Antibiotic
 Chemicals against microorganism but
obtained from microorganisms.
Antibacterial
 Chemicals against bacteria.
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Applications
- Penicillin
- Amphotericin B
- Sulfonamides
- Actinomycin D (Dactinomycin)
Antibiotic vs antibacterial
Currently:
Antibiotic
 Chemicals against bacteria causing diseases.
Antibacterial
 in external preparations like soaps.
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Selective Toxicity
= killing micro-organisms without

killing human cells
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Classification of Antibiotics
1) ↓ cell wall synthesis:
 Penicillins
2) ↓ cell membrane:
 Polymixin B (& Polymixin E = colistin)
3) ↓ protein synthesis:
 Aminoglycosides
4) ↓ Folic acid function:
  folic acid synthesis  Sulfonamides
  folic acid reduction  Trimethoprim
5) ↓ DNA synthesis or function  Quinolones
Classification of antibiotics
1) Narrow spectrum:
 Isoniazid
2) Extended spectrum:
 Amoxicillin
3) Broad Spectrum:
 Fluoroquinolones
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Another Classification
1) Bacteriostatic
 Tetracyclines
2) Bacteriocidal at high doses

 Macrolides
3) Bacteriocidal
 Penicillins
Inhibitors of cell wall synthesis
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1) Inhibitors of cell wall synthesis

Structure:
- Polymers of glycan units
- Polymers attached together by peptide cross-links.

 So the wall is called “Peptidoglycan cell wall”
The glycan units include:

- NAG = N-Acetyl Glucose-amine
- NAM = N-Acetyl Muramic acid
Dr. Tareq Al-Maqtari, PhD Lippincott 2015
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1) Penicillins
Historical Overview:
- The 1st antibiotics
- Discovered in 1928 & used in 1942
- Alexander Fleming isolated them from "Penicillium".
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Fleming receiving Nobel Prize from king

20 Gustaf V of Sweden Dr. Tareq Al-Maqtari, PhD
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Lippincott
2015
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M.O.A for penicillins
 Penicillins bind to transpeptidase (= PBPs)

  transpeptidase
  cell wall synthesis.
 Cell rupture (& lysis) occurs

by  osmotic pressure or
 activation of autolysins
Main advantages:
 Efficacy.
 Safety.
Penicillins are only effective against:
 Rapidly growing organisms.
 Bacteria with “peptidoglycan” cell wall.
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(1) Natural Penicillins

Source:
Penicillium Chrysogenum
Classification:
 Short
Penicillin G  Strong but IV
Penicillin V  Oral but weak
 Intermediate (12-24 hr): Procaine Penicillin G  (IM)
 Long (21 days): Benzathine Penicillin G  (IM).
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(A) Natural Penicillins

 Disadvantages of Natural Penicillin G:
1) Short.
2) Narrow spectrum.
3) HCL-sensitive.
4) Penicillinase-sensitive.
Antimicrobial Spectrum:
Mainly G+.
 G+ cocci  Streptococci
 Staphylococci
 G+ bacilli  Corynebacterium diphtheriae

 Bacillus anthracis
 G- cocci  Neisseria
 G- bacilli  None!
 Atypical  Treponema pallidum (A spirochete)

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Strep & Staph infections
Strep: Staph:
1) Resp. tract 1) Skin, abscess.
2) Pneumonia 2) Pneumonia
3) Endocarditis 3) Endocarditis
4) Osteo-myelitis 4) Osteo-myelitis
5) Meningitis 5) Meningitis
6) Rheumatic fever 6) Food poisoning

Diphtheria
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Anthrax
Uses
1) Penicillin G (IV)
Rapid, short & i.v.  So used in severe cases:
 Acute & subacute (infective) endocarditis
 Acute rheumatic fever
 Diphtheria
 Anthrax
 Meningitis (esp in babies)
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2) Penicillin V (oral)
Weaker than penicillin G  So used for :
 Prophylaxis of rheumatic fever
 Also 1st choice for tonsilitis
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3) Procaine Penicillin G (IM)

Usually used for moderate diseases such as:
 Syphilis
 Gonorrhea
 Prophylaxis against subacute endocarditis

before some dental procedures in patients
with some heart diseases.
4) Benzathine Penicillin G (IM)

Very slow and long-acting, So used for:
 Prophylaxis of rheumatic fever (/3-4 wks)
 Syphilis
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Dr. Tareq Al-Maqtari, PhD Lippincott 2015
Preparations:
Penicillin G  vials 1, 2, 3, 4, 5 million Units.
Penicillin V  tab, syr 250-500 mg.
Procaine P.  vials 600000 Units
Benzathin P. vials 1.2, 2.4 million Unit
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Buzzy®
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(B) Semi-synthetic Penicillins
a- Extended- b- Penicillinase- c- Anti-

spectrum resistant pseudomonal
penicillins penicillins penicillins
- Amoxicillin - Methicillin
- Ampicillin - Piperacillin
- Cloxacillin
(a) Penicillinase-resistant Penicillins

 Resist “pencillinase”
 Narrow spectrum (mainly for staph).
Drugs:
1) Parenteral
 Methicillin, nafcillin
2) Oral
 Cloxacillin, Dicloxacillin, Flucloxacillin
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Katzung 2015
Therapeutic use:
Effective only on Staph. aureus, so:
 Not used alone
 Used for penicillinase-producing staph
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A better solution for penicillinase

 Suicidal substrates
 Ampicillin + Sulbactam (Unasyn®)
 Amoxicillin + Clavulenic acid (Augmentin®)
 Piperacillin + Tazobactam
Katzung 2015
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51 Lippincott 2015
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(b) Extended-Spectrum Penicillins

Ampicillin & Amoxicillin
*Amoxicillin is better due to:

 Less frequently used
 Absorption not affected by food
*Ampicillin is better for:

 Enteritis
 Listeriosis
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Spectrum:
Like natural Penicillins plus:
G+  Listeria
G-  H. pylori, H. influenza,
Salmonella, Shigella
E. coli
Uses
1) RTIs (popular)
2) Skin, soft tissue infections, cellulitis, abscess,
impetigo
cellulitis Skin abscess impetigo

(boil)
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Uses
1) RTIs (popular)
2) Skin, soft tissue infections, cellulitis, abscess,
impetigo
3) Peptic ulcer
4) Shigellosis
5) Typhoid
6) Listeriosis
7) Prophylaxis against endocarditis before dental
procedures in pts with heart valve diseases
Typhoid fever
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To avoid effect of Ampicillin on normal flora:

1) Tal-ampicillin
2) Bac-ampicillin
3) Piv-ampicillin
The advantages:
 Better absorbed than ampicillin
 Do not affect the normal flora  less diarrhea
(c) Anti-pseudomonal Penicillins

Agents:
- Piperacillin
- Ticarcillin, carbinicillin
- Mezlocillin, Azlocillin.
Spectrum: (broad)
-  effect on G- (like pseudomonas).
-  effect on G+

Pseudomonas
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Antipseudomonal Penicillins
Use: (Expensive)
- Pseudomonal hospital (nosocomial) infections.
- Neutropenic sepsis
SEs of Penicillins
Very safe in general. Penicillin may cause:
 Hyper-sensitivity.
 Diarrhea.
 Local pain when injected.
 Nephrotoxicity (methicillin)
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Drug Interactions of Penicillins:
1) With bacteriostatic drugs
2) With gentamicin in the same syringe
Dr. Tareq Al-Maqtari, PhD Katzung 2015
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((Cephalosporins))
 Similar to penicillins:
- Chemical structure
- M.O.A
- Origin
- Spectrum (only 1st generation)
- Safety in pregnancy, lactation
- Destruction by β-lactamase
- Anaphylactic shock may occur
5 generations:
- 1st : narrow spectrum
- 2nd : intermediate
- 3, 4, 5th : broad spectrum
Origin:
- Ceph  natural (from acremonium)
- Cef  semisynthetic
- Moxilactam  synthetic
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All Cephalosporins are NOT effective against:

(MALEC)
 MRSA (except 5th generation)
How we treat “staphylo-coccus aureus”:
1) Penicillin-sensitive SA  give penicillins
2) PRSA  give methicillin
3) MRSA  give vancomycin Used for resistant G+!

4) VRSA  give Linezolid or quinupristin/dalfopristin
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All Cephalosporins are NOT effective against:

(MALEC)
 MRSA (except 5th generation)
 Atypical bacteria (chlamydia & mycoplasma)
 Listeria
 Enterococci (Streptococci faecalis)
 Clostridium Difficile
Pseudomembranous colitis caused by C. difficile
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1st generation
 Oral:
- Cephalexin, Cephradin, Cefadroxil.
 Parenteral (i.v. or i.m.):
- Cefazolin
1st generation
Spectrum:
Similar to Penicillins
 G+
 Some G-
 Not against most anaerobes
 Do not pass BBB
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1st generation
Uses:
Rarely 1st choice
1) A substitute for penicillins in case of:
 Allergy Or  Resistance
2) Surgical antimicrobial prophylaxis.
- Cefazolin is 1st choice.
3) Skin infections
- Cephalexin
2nd generation
 Oral:
Cefuroxime axetil, Cefaclor, cefprozil
 Parenteral (i.v. or i.m.):

Cefuroxime, cefamandole, cefoxitin,
cefotetan, cefonicid
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2nd generation (intermediate spectrum)

Spectrum:
 ↓ effect on G+
 ↑ effect on G- (even proteus but not pseudomonas)
 ↑ effect on anaerobes (esp. cefotetan & cefoxitin)
 Do not pass BBB (except cefuroxime).
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Notes on anaerobic bacteria:

- Predominate in the normal flora.
Bacteroid Fragilis (below the diaphragm)
Fuso- Pepto-
Clostridium Actinmyces
bacterium streptococci
1. C. difficile  Pseudo-membranous colitis
2. C. tetani  Tetanus
3. C. perfringens  Gas gangrene
Common anaerobic Infections:

- Sometimes cause “anaerobic infections” [1-species infection]
- Pseudo-membranous colitis
- Tetanus
- Gas gangrene
- Often cause “mixed anaerobic infections” with G- or G+ bacteria:

1. Brain abscess, lung abscess
2. Necrotizing gingivitis, chronic sinsusitis, chronic otitis media
3. Abdomen infections (peritonitis & diverticulitis)
4. Female (bacterial vaginosis & pelvic inflammatory disease)
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Best treatment for anaerobic infections:
1) If above the diaphragm (bacteroid fragilis is not involved)

 penicillin G (resistance increased)
2) Metronidazol
3) Clindamycin
4) Cefoxitin
5) β-lactam + β-lactamase inhibitor
2nd generation (intermediate spectrum)

Clinical Uses:
 Respiratory tract infections
 Esp. Cefuroxime
 because of its strong effect on H. influenzae & Klebsiella
 Mixed anaerobic infection

 use other parenteral 2nd generation cephalosporins for:
- brain & lung abscess
- chronic sinusitis, chronic necrotizing gingivitis
- peritonitis & diverticulitis
- pelvic inflammatory disease
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Other uses:
3) Skin infections (e.g. impetigo….)
4) UTIs (non-complicated)
5) Gonorrhea
www.medicinenet.com
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3rd generation
 Oral:
Cefixime, Cefpodoxime, Cefdinir, Ceftibuten
 Parenteral (IV or IM):

Ceftriaxone, Cefotaxime,
Cefoperazone, Ceftazidime,
Moxalactam (= latmoxef)
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3rd generation (broad spectrum)

Spectrum:
 ↓ effect on G+
 ↑ effect on G- (even proteus & pseudomonas)
 ↑ effect on anaerobes (moderate effect)
 Pass BBB ( best for meningitis!)
3rd generation (broad spectrum)
Clinical Uses:
 Meningitis.
 UTIs (even pseudomonal).
 Lower RTIs.
 Anaerobic Infections.
 Typhoid
 Gonorrhea.
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4th generation
 Parenteral (IV):
Cefepime (IV 1X3), Cefpirome (IV 1X2)
5th generation:
Ceftobiprole & Ceftaroline
4th generation
Similar to 3rd gen. but more effective against G+.
Use:
Reserved for resistant cases!
5th generation
Similar to 4th gen but effective on MRSA
Use:
Reserved for resistant cases.
* Cephamycins are structurally related to cephalosporins and include

cefotetan and cefoxitin (2nd gen). They are the only cephalosporins that affect
G- anaerobes.
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Side Effects of Cephalosporins:

 Allergy.
 Super-infections. (opportunistic infections)
 Nephrotoxic.
 Painful i.m. (so mixed with procaine or lidocaine)
 Ceftriaxone may cause biliary stone.
 Inhibit intestinal flora   vit K  hemorrhage.
Notes:
 Cefuroxime =(Zinnat®),  Cefotaxime =(Claforan®)
 Cefoperazone =(Cefobid®),  Ceftriaxone= (Rocephen®)
 Ceftazidime = (Fortum®),  Cefepime = (Maxipime®)
Cell wall inhibitors
β-lactam Non-β-lactam
1) Penicillins 1) Vancomycin
2) Cephalosporins 2) Fosfomycin
3) Carbapenems 3) Bacitracin
4) Monobactams 4) Cycloserin
5) Teicoplanin
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((Vancomycin))
Source:
A “glyco-peptide” from "Streptococcus Orientalis".
Importance:
It's effective against resistant G+ bacteria like:
 MRSA.
 Clostridium difficile.
 Enterococci.
 So it must not be used unless necessary
(to avoid bacterial resistance)
M.O.A:
Inhibits bacterial cell wall synthesis  bacteriocidal.
Spectrum  G+.
Therapeutic Uses:
1) Serious infections caused by MRSA
(severe endocarditis, severe pneumonia, severe meningitis)
2) Serious infections caused by Clostridium difficile

(e.g. severe pseudomembranous colitis [orally])
3) Other serious infections by G+ bacteria

(If other drugs fail).
Excellent Synergism  Vancomycin + Gentamycin.
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Side effects:
 Flushing (Red man syndrome!).
 Nephrotoxic & Ototoxic.
Dose:
IV  1 gr / 12 hrs (infusion), not absorbed orally.
Oral  250 mg / 6 hrs (local action)
* For Vancomycin resistant Staph. Aureus Quinupristin + Dalfopristine (IV).

* For Vancomycin resistant enterococci  Linezolid (oral or IV).
Red man syndrome
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(Carbapenems & Monobactams)
Carba-penems Mono-bactams
(Carbapenems & Monobactams)
Carba-penems Mono-bactams
Both synthetic
 Broadest spectrum  Narrow (G-)

Reserved for resistant Rarely used
cases (narrow, ↑ cost)
1. Imipenem/cilastatin Aztreonam
2. Meropenem
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((Carbapenems))
 Synthetic (relatively resistant to β-lactamase)
 β-lactam drugs but the S atom in the non-β-lactam

ring is replaced by a C atom.
 The broadest spectrum among β-lactam Antibiotics.
Spectrum: (wide)
 G+ (even β-lactamase producing).
 G- (even pseudomonas).
 Anaerobes.
Lippincott 2015
((Carbapenems))
Agents:
Emipenem (1X3)
Meropenem (1X3)
Doripenem (1X3)
Ertapenem (1X1 IM, IV)
Lippincott 2015
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Therapeutic Use:
 Serious nosocomial Infections by pseudomonas.
(If other antibacterials failed)
* Should be reserved for resistant cases.
(to prevent bacterial resistance)
Dose:
250-500 mg / 6-8 hrs (IV).
Note:
* Emipenem is metabolized in renal tubules by “dehydropeptidase”
into a nephrotoxic metabolite. So cilastatin is added to imipenem to inhibit
dehydropeptidase.
* Among carbapenems, only meropenemo is category B in pregnancy.
((Monobactams))
“β-lactam” is not fused with another ring.
Agents:
Aztreonam
Lippincott 2015
Spectrum (narrow)
G- bacilli (including pseudomonas aurigonosa)
 similar to aminoglycosides.
Therapeutic Uses:
Rarely used because of its narrow spectrum.
1-2 gr / 8 hours (IV).
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((Fosfomycin)) (oral)
Fosfomycin (= phosphomycin or phosphonomycin)
Produced by “streptomyces fradiae” (Also synthesized)
 Broad-spectrum (G+ & G-)
 Cell wall inhibitor  bacteriocidal
 1 single oral mega-dose is sufficient for simple UTIs
 Well-tolerated
 Not recommended for children or elderly (> 75 yrs)
 Not effective against pseudomonas
Use:
Uncomplicated UTIs mainly in women
(non-pseudomonal)
(effective in G- bacteria; more effective in acidic pH)

(1 sachet containing granules dissolved in water & used orally)
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((Bacitracin)) (topical)
Source:
A mix of polypeptides produced by "Bacillus subtilis".
Spectrum:  G+
Therapeutic Use: (Nephrotoxic  not used systemically)
With polymixin (G-) or Neomycin (G-) in ointments for:
Skin/mucous membranes/wounds infected by:

 staph. aureus.
Other cell wall inhibitors

Teicoplanin:
 Similar to Vancomycin except being used IV or IM only (1 X 1)
Cycloserin (oral)
 Only used for TB as a 2nd choice.
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Cell membrane Inhibitors
Cell membrane inhibitors
Polymixin B Polymixin E (Colistin)
Topical Reserved for

with neomycin & severe resistant G-
bacitracin infections (e.g. ESBL)
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Cell membrane inhibitors (Polymixins)
Spectrum:  G-
1) Polymixin B:
(Nephrotoxic  not used systemically)
With Bacitracin (G+) or Neomycin (G-) in ointments for:
Skin/mucous membranes/wounds.
2) Polymixin E (colistin):
Nephrotoxic  withdrawn in the past
But currently used for resistant G- bacteria. (injection)
Protein Synthesis Inhibitors
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M.O.A of Drugs
 30 S  50 S
ribosomal ribosomal
subunit subunit
- Aminoglycosides Others:
- Tetracyclines - Macrolides
- Lincosamides
- Chloramphenicol
- Fusidic acid
- ………….etc
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1) Aminoglycosidesβ-Blockers
1) Aminoglycosides
Source:
1) From bacteria “streptomyces” (..-mycin)
From bacteria “micromonospora” (..-micin)
2) Semisynthetic: Amikacin
Q) Why are these drugs put in the same family if they

have different sources?
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Lippincott 2015
M.O.A of aminoglycosides
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Aminoglycosides
1) Narrow spectrum (G- even pseudomonas).

2) Polar   absorption (IV or IM)
  distribution.
 Enter bacteria by active pumps
 rapidly excreted by kidneys
 
Good for UTIs. Nephrotoxic
Toxic
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Aminoglycosides
3) Toxic  only for serious cases.
 only for < 5 days.
 replaced by other drugs
 Not in pregnancy
Lippincott 2015
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Spectrum: (narrow)
• G- bacilli (even pseudomonas)
• Some G+ cocci (enterococci, Staph)
• Mycobacterium TB.
Drugs:
- Gentamicin - Streptomycin
- Tobramycin - Neomycin & kanamycin
- Amikacin - Paromomycin
- Gentamicin - Streptomycin
- Tobramycin - Neomycin & kanamycin
- Amikacin - Paromomycin
 G- & some G+ - G- mainly or ameba
 Less toxic
More used less used
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Gentamicin Tobramycin Amikacin

1. Endocarditis Eye infections Gentamicin
resistance
2. Pneumonia Pseudomonas
3. Septicemia
4. Complicated
UTIs
5. Local: skin, eye
Streptomycin Neomycin Paromomycin

Kanamycin
1st aminoglycoside Toxic Luminal
 ↑ resistance  local only amebicide
1) TB 1) Skin:
+ bacitracin/polymixin B
2) Plague 2) Lozenges
3) Eye drop
4) Tabs
 Intestinal antiseptic
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Indications:
*Gentamicin* IM or IV
In severe infections: (with cell wall inhibitors)
1) Endocarditis (acute or subacute)
2) Pneumonia
3) Septicemia
4) UTIs (complicated or pseudomonal)
5) Topical (skin & eye)
*Streptomycin* (IM)
The 1st aminoglycoside.
   resistance  rarely used
1) TB (2nd line)
 isoniazid + rifampicin
+ streptomycin + pyrazinamide
2) Plague (Yersinia pestis)

(doxycycline maybe better)
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A flea
*Tobramycin* IM, IV, eye drop

Similar to gentamicin but:
 Safer
 Better for pseudomonas and for eye infections
 But more expensive
 Used mainly as an eye drop (conjunctivitis)
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*Amikacin* IM
Used in gentamicin-resistant infections.
(resist any bacterial enzymes that inactivate Gentamycin &
Tobramycin)
 Amikacin is semisynthetic of Kanamycin but less toxic.
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*Neomycin & Kanamycin

 Very toxic
- Kanamycin  almost obsolete
- Neomycin  locally only
Uses of neomycin: (Local only)

1) Oral  before intestinal surgery.
2) Lozenges
3) Skin or eye ointment
(neomycin + polymixin + bacitracin)
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*Paromomycin* (oral)
As amebicide (luminal)
Aminoglycosides in pregnancy & lactation:

1) NOT used in pregnancy
2) May be used in lactation (gentamicin & streptomycin)
Why?
2) Macrolides
Source:
1) Erythromycin: from "Streptomyces erythreus"
2) Clarithromycin  Semisynthetic.
3) Azithromycin  Semisynthetic.
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General characteristics:
1) ↓ protein synthesis.
2) Bacterio-static (bacteriocidal at higher doses)
3) Spectrum: similar to penicillins (but not identical).

- G+
- Some G-
- ATYPICAL bacteria 
Chlamydia Mycoplasma Legionella
 Macrolides are effective against ATYPICAL bacteria
Chlamydia Mycoplasma Legionella
1) Atypical pneumonia
2) Genital infection
(STD)
3) Neonate
conjunctivitis
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1) Bacteriostatic at small doses & bacteriocidal at higher doses.
3) Spectrum: similar to penicillin G (but not identical).
- G+
- Some G-
- ATYPICAL bacteria
4) Irritant  not IM or IV (oral mainly)

- IV  thrombo-phlebitis
- IM  sterile abscess
- oral  GIT side effect
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1) Bacteriostatic at small doses & bacteriocidal at higher doses.
3) Spectrum  similar to penicillin G (but not identical).
4) Irritant  oral mainly
5) Safe in pregnancy
(except clarithromycin & erythromycin estolate)
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Erythromycin Clarithromycin Azithromycin

  
1x4 1x2 1x1
↑ ↑↑ ↑↑↑
distribution distribution distribution
Long treatment (5-10 days) Short (3 days)
GIT SEs Less GIT SEs
↓ CYP450 No effect
G+, some G- Better on H. Better on G- &

atypical pylori atypical
Lippincot 2015
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 Do not give these drugs together:

- Macrolides
- Chloramphenicol
- Lincosamides
- Fucidic acid
Mutual
antagonism
Lippincot 2015
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Spectrum
1) Erythromycin
2) Clarithromycin
more effective on G- (esp. H. Pylori)
3) Azithromycin
more effective on G- & atypical bacteria
4) Telithromycin (a Ketolide; similar to macrolides):

Similar to Azithromycin.
Effective against macrolide-resistant organisms.
**Notes**
* Spiramycin:
- Not a macrolide
- Similar in action to Azithromycin.
- Usually used in:

1) Oral cavity infections
2) Toxoplasmosis in pregnancy
* Erythromycin resistance in some streptococci and pneumcocci has made

macrolides less attractive as first-line agents for pharyngitis and pneumonia.
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Uses
1) 1st choice in many RTIs esp.:
a) Atypical pneumonia
b) G+ diphtheria
c) G- whooping cough (bordetella pertussis)
2) Atypical infections
3) A substitute for penicillins (in case of allergy or resistance)
4) Peptic ulcer (esp. Clarithromycin)
5) Some diarrheas
(campylobacter, cholera, shigella in children)
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Side effects
1) GIT distress
2) Liver toxicity (chole-static jaundice)
3) QT prolongation (use with caution in pts with arrhythmia)
4) Pyloric stenosis (in babies < 7 weeks of age)
* Macrolides can be given to nursing mothers unless their baby is

less than 7 weeks of age.
Adverse Effects of Macrolides Lippincott 2015
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3) Tetracyclines
β-Blockers
Katzung-Basic and Clinical Pharmacology, 9th edition
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Tetracyclines
General Characteristics:
  protein synthesis  bacteriostatic.
 Wide spectrum.
 Overused in the past   resistance.
(still wide spectrum)
 Irritant  oral mainly.
- IV  thrombo-phlebitis
- IM  sterile abscess
- oral  GIT side effect
Tetracyclines
 Bind minerals (Ca, Mg, Al, Fe) so:
  absorption with food, antacids, multivitamins
  bone & teeth
 Contra-indicated in pregnancy
 Contra-indicated in children < 8 yrs
(Tetracycline & doxycycline can be given for < 10 days

to nursing mothers)
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Source:
 Natural: “streptomyces aureofaciens"
1) Chlor-tetracycline
30% absorption
2) Oxy-tetracycline
3) Tetracycline
60% absorption
4) Demeclocycline
 Semisynthetic:
1) Minocycline
95-99% absorption
2) Doxycycline
(also methacycline, meclocycline, lymecycline,

rolitetracycline, tigecycline)
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 Doxycycline 
 Doxycycline is preferred:
 fat-soluble  99-100% absorption.
 Excellent distribution.
 Highest efficacy.
 absorption is only slightly affected by food.
 1X1.
 Safe in renal failure.
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Lippincot 2015
Spectrum of tetracyclines
Broad spectrum!
 Many G+ bacilli
 Many G- bacilli
 Anaerobes.
 Atypical bacteria (mycoplasma, chlamydia, rickettsiae)
 Some protozoa (ameba, plasmodium).
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Lippincot 2015
Clinical Uses
Doxycycline is the “tetracycline of choice”.
4 main uses:
1) Acne (propioni-bacterium).
2) Atypical bacteria infections:
Mycoplasma ( pneumonia)
Chlamydia ( pneumonia, genital, eye infections)
Rickettsiae ( typhus, spotted fever)
3) Peptic ulcer. ( + metronidazole + bismuth + H2 blocker or PPI)
4) Cholera & brucellosis.
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Typhus
Rocky mountain spotted fever
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4 other uses:
1) Resistant malaria or amebiasis
2) Plague
3) Lyme disease & relapsing fever (by borellia)
4) Leptospirosis & tularemia

(multiorgan failure!!)
* Tetracycline is also used as an eye ointment
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Ticks:
4 Side Effects
1) GIT discomfort.
(minocycline/doxycycline can be given with food to  GIT distress)
(Take doxycycline with plenty of H2O to avoid esophagus irritation)
2)  Bones & teeth.

3) Photo-sensitivity
4) Vestibulo-cochlear nerve toxicity
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Tetracyclines affect teeth
Doxycycline photo-sensitivity
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4) Chloramphenicol (oral)

 Toxic  bone marrow depression
 Grey baby syndrome
  Toxicity of co-administered drugs
 Overused   bacterial resistance

(still wide spectrum)
M.O.A:
- Binds 50S ribosomal subunit
 trans-peptidation step of protein synthesis.
Spectrum:
Broad spectrum!
- Some G+ bacteri.
- Many G- bacteria
- Atypical bacteria.
- Anaerobes.
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Lippincott 2015
Clinical uses:
- Not The best choice for any disease
- Only in life threatening infections.
1) Typhoid and paratyphoid fever.
2) Meningitis.
3) Serious Rickettsial infections.
4) Topical (eye and ear)
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5) Lincosamides
2 Drugs
Source:
1) Lincomycin (Lincocin®):
 natural (from streptomyces lincolnensis)
2) Clindamycin (Dalacin C®):
 semisynthetic (+ Cl)
 more active on anareobes
 Safer in pregnancy & lactation
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Side effects (2):

Currently less used (due to toxicity)
1) Pseudo-membranous colitis.
2) Hepato-toxic.
Spectrum (2): (narrow)

G+ & anaerobes
M.O.A:
Like macrolides
Uses:
Act on anaerobes:
1) Primarily for *Severe anaerobic infections*
- e.g. Bacteroid fragilis
Act on G+
2) Bone marrow infection
3) Alternatives to penicillins:
(Oral infections, skin, cellulitis & soft tissue infections)
4) Alternatives to macrolides in G+ bacilli infections like:

 diphtheria & anthrax.
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Other protein synthesis inhibitors

* Spiramycin: (related to macrolides)
1) Alone  for toxoplasmosis
2) With metronidazole  for oral cavity infections
* Fusidic acid:
 Locally: skin cream for staph infections
Newer Agents
Quinupristin/
Linezolid
Dalfopristin
IV Oral
New  Expensive
For vancomycin-
resistant bacteria
(VRSA, VRE)
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Lippincott 2015
A drug used to kill MDR G-

bacteria like ESBL bacteria?
 COLISTIN (POLYMIXIN E)
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4) DNA inhibitors:
β-Blockers
Quinolones
Quinolones
● Synthetic
●  DNA transcription & replication )bacterio-cidal(
● Wide spectrum (but particularly effective on G-)
● 1st gen.  quinolones (narrow-spectrum)

2nd, 3rd, 4th gen.  fluoro-quinolones. (wide-spectrum)
Fluoroquinolones vs. quinolones

 60 times more potent.
 wider spectrum (more effect on G+ & anaerobes).
 Safer.
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- Fluoro-quinolones  similar to tetracyclines:

A- SEs (photo-sensitivity & ↓ skeleton)
B- Bind minerals (absorption is affected by food)
C- Contra-indications (in pregnancy & children)
D- Some can be used in nursing mothers
Lippincott 2015
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M.O.A:
helicase DNA Gyrase
DNA polymerase
M.O.A:
1) ↓ DNA gyrase:
→ ↓ relaxation of supercoiled DNA
→ ↓ DNA transcription & replication (bacteriocidal)
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1st 2nd, 3rd, 4th

- Nalidixic acid ------floxacin
 Low systemic levels  ↑↑ systemic levels
 G-  G-, some G+,

atypical, anaerobic
1) UTIs
2) GITIs
Can be used in children
1st 2nd, 3rd, 4th
1) UTIs
2) GITIs
3) Typhoid
4) STDs (not syphilis)
5) Osteomyelitis
6) Peptic ulcer
7) RTIs (& pneumonia)
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What are
“Respiratory Quinolones”?
Levofloxacin Moxifloxacin
kill G+  Good for RTIs
- Both may be used in peptic ulcer

- Moxifloxacin is not used for UTIs (levo- can)
- Moxifloxacin can be used in renal failure
Classification
1st gen:
Nalidixic acid, cinoxacin
 Low systemic levels
 Narrow spectrum (G-)
2nd gen:
Ciprofloxacin, norfloxacin, ofloxacin
 high systemic levels
 ↑ G- + some G+ & atypical activity
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3rd gen:
Levofloxacin, sparfloxacin
 ↑ G+ & atypical activity (still active on G-)
1X1
4th gen
Moxifloxacin, Trovafloxacin, Gatifloxacin, Clinafloxacin,
 ↑ anaerobe activity (still active on G-, G+, atypical)
1X1
The most commonly used

quinolones
Levofloxacin Moxifloxacin
Ciprofloxacin
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Clinical Uses
Quinolones: (G- only & low systemic level)
 lower UTIs.
 Fluoroquinolones: (mainly for G-)
1) UTIs (even pseudomonal).

2) GIT infections
3) STDs except syphilis.
4) Typhoid
5) Osteomyelitis
6) Peptic ulcer (esp. levofloxacin & moxifloxacin)
7) Resp. infections (esp. levofloxacin & moxifloxacin)
Notes:
• 3rd & 4th generations are increasingly used in atypical
pneumonia (chlamydia, mycoplasma, legionella).
• Ciprofloxacin, levofloxacin & moxifloxacin

 popular drugs 
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Side Effects
Well tolerated!
1) Photo-sensitivity
2)  joints (chondrolytic)
3) ↑ CNS (insomnia, convulsions)
4) Not for: - pregnancy
- Lactation (except Ciprofloxacin & ofloxacin)
- < 18 yrs (unless necessary)
Trovafloxacin is hepatotoxic, so it is only used in:

• Life-threatening cases
• Only in hospitals & for < 14 days.
5) Folic Acid antagonists:
Sulfonamides
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Sulfonamides
• Synthetic (analogues of PABA)
•  folic acid synthesis  bacteriostatic.
• Old  overused   resistance  not used alone
• Differ in pharmacological properties.
• Start with “Sulfa”
M.O.A:
Katzung 2012
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Chemical Structure
Lippincott 2015
DHFR inhibitors:
- Trimethoprim : ↓ DHFR in bacteria  Anti-bacterial
- Pyremethamin : ↓ DHFR in plasmodium  Antimalarial
- Methotrexate : ↓ DHFR in humans  Anticancer
 “Sulfonamides + DHFR inhibitors” 

1) Sulfamethoxazole + Trimethoprim  for bacteria
(co-trimoxazole)
2) Sulfadoxin + Pyrimethamine  for malaria

(Fansidar®)
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Spectrum:
♦ Some G+ bacteria (Nocardia)
♦ Some G-
♦ Some protozoa (plasmodium)
♦ Some fungi (pneumocystis carinii)
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Lippincott 2015
Classification of Sulfonamides
1) Oral absorbable
2) Oral non-absorbable
3) Topical
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1) Oral absorbable:
- Short  Sulfasoxazole, Sulfamethizole = 6 hrs
- Medium  Sulfamethoxazole, Sulfadiazine = 12 hrs
- Long  Sulfadoxin = 7 day
• Sulfisoxazole = also known as “sulfafurazole”
Clinical uses
1) Co-trimoxazole:
☺ G.I.T infections
☺ UTIs
 Cholera & typhoid
☺ Nocardiosis (causes pneumonia).
☺ “Pneumcystis carinii” pneumonia.
2) Sulfadoxin + Pyremethamin (Fansidar®) :

☺ Malaria.
2) Sulfadiazine + Pyremethamine:
☺ Toxoplasmosis (in non-pregnant women)
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2) Oral Non-absorbable:
♥ Sulfa-salazine  Ulcerative colitis
Sulfa-pyridine 5-ASA
Anti-bacteria ↓ inflammation
↓ Immunity
* 5-ASA = mesalazine = mesalmine can also be used

* 5-ASA –- 5-ASA = olsalazine (can also ne used).
3) Topical:
♥ Sulfa-cetamide → conjunctivitis (eye drops).
♥ Silver sulfa-diazine → for burns.
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Side effects
1) Allergy:
- Stevenes-Johnson syndrome
2) Urinary tract disturbances:
- Crystal-urea, hemato-urea.
3) Blood:
- Hemolytic anemia (in patients deficient in G6PD).
- ↓ bone marrow  ↓ RBCs, ↓ WBCs, ↓ platelets.
4) Kernicterus
- Contraindicated in neonates < 1.5 mths
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Kernicterus in the brain
Kernicterus may lead to cerebral palsy
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Pick = Parents of Infants & Children with Kernicterus
Urinary tract Antiseptics

- UT infections in women are very common.
- For UTIs, the most common pathogens are:
* Eschericia coli (80%).
* Klebsiella pneumonia, Proteus, Staphylococcus.
Drugs:
1) Methenamine (hexamine)
2) Nitrofurantoin.
3) Nalidixic acid
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Lippincott 2015
Metronidazole
Excellent on protozoa:
1) Ameba & giardia
2) Trichomonas (that cause vaginal infections)
Excellent on anaerobic bacteria:

3) Oral cavity infections (with spiramycin)
4) Mixed anaerobic infections
5) Pseudo-membranous colitis
6) Peptic ulcer
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What is
Empirical Therapy?
Treating diseases
based on our previous experiences.
We usually use empirical therapy to treat

bacteria, without even knowing the exact
bacterial pathogen
To find me:
1. Facebook: Dr Tareq Al-Maqtari.
2. Youtube channel: Dr Tareq Al-Maqtari
3. Telegram )Pharma-Fun(
4. Pharma-Fun books
222
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Thanks!
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Antibiotic in The Butterfield

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Antibiotic in The Butterfield

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11/13/2019

Antibiotics on the Battlefield

Dr. Tareq Al-Maqtari, PhD

Dr. Tareq Al-Maqtari, PhD

Dr. Tareq Al-Maqtari, PhD

= killing micro-organisms without

Dr. Tareq Al-Maqtari, PhD

Dr. Tareq Al-Maqtari, PhD

2) Bacteriocidal at high doses

Dr. Tareq Al-Maqtari, PhD

Inhibitors of cell wall synthesis

1) Inhibitors of cell wall synthesis

- Polymers attached together by peptide cross-links.

The glycan units include:

Dr. Tareq Al-Maqtari, PhD

Dr. Tareq Al-Maqtari, PhD Lippincott 2015

- Discovered in 1928 & used in 1942

- Alexander Fleming isolated them from "Penicillium".

Dr. Tareq Al-Maqtari, PhD

Fleming receiving Nobel Prize from king

M.O.A for penicillins

 Penicillins bind to transpeptidase (= PBPs)

 Cell rupture (& lysis) occurs

Dr. Tareq Al-Maqtari, PhD

(1) Natural Penicillins

Dr. Tareq Al-Maqtari, PhD

Dr. Tareq Al-Maqtari, PhD

(A) Natural Penicillins

Dr. Tareq Al-Maqtari, PhD

 G+ bacilli  Corynebacterium diphtheriae

 Atypical  Treponema pallidum (A spirochete)

Strep & Staph infections

6) Rheumatic fever 6) Food poisoning

 Acute & subacute (infective) endocarditis

 Acute rheumatic fever

 Meningitis (esp in babies)

Dr. Tareq Al-Maqtari, PhD

Dr. Tareq Al-Maqtari, PhD

3) Procaine Penicillin G (IM)

 Prophylaxis against subacute endocarditis

Dr. Tareq Al-Maqtari, PhD

4) Benzathine Penicillin G (IM)

Dr. Tareq Al-Maqtari, PhD

Dr. Tareq Al-Maqtari, PhD Lippincott 2015

Penicillin V  tab, syr 250-500 mg.

Procaine P.  vials 600000 Units

Benzathin P. vials 1.2, 2.4 million Unit

Dr. Tareq Al-Maqtari, PhD

(B) Semi-synthetic Penicillins

a- Extended- b- Penicillinase- c- Anti-

Dr. Tareq Al-Maqtari, PhD

(a) Penicillinase-resistant Penicillins

 Narrow spectrum (mainly for staph).

Dr. Tareq Al-Maqtari, PhD

 Used for penicillinase-producing staph

Dr. Tareq Al-Maqtari, PhD

Dr. Tareq Al-Maqtari, PhD

Dr. Tareq Al-Maqtari, PhD

A better solution for penicillinase

 Amoxicillin + Clavulenic acid (Augmentin®)

Dr. Tareq Al-Maqtari, PhD

Dr. Tareq Al-Maqtari, PhD

(b) Extended-Spectrum Penicillins