Antibacterial drugs (Nucleic acid synthesis inhibitors)

Question 1

What removes DNA supercoils?

Answer 1

Topoisomerase IV. It also separates the replicated DNA into respective daughter cells during replication

Question 2

What is the group of synthetic antibiotics called?

Answer 2

Fluoroquinolones

Question 3

What some of the Fluoroquinolones?

Answer 3

ciprofloxacin, levofloxacin, gemifloxacin, moxifloxacin, ofloxacin,
norfloxacin,

Question 4

What are the uses for ciprofloxacin and ofloxacin?

Answer 4

-Potent activity → gram-negative aerobic organisms
Enterobacteriaceae: (enteric bacilli), Pseudomonas aeruginosa (not ofloxacin), Haemophilus, Neisseria and
Legionelle species
– Gram-positive organisms (streptococci and
pneumococci) no useful activity
– Mycobacteria (ofloxacin only)
– Lack activity against anaerobic bacteria
– Drug of choice for typhoid fever (ciprofloxacin)
– Used for cystitis (ciprofloxacin)
– Not recommended for gonorrhea
– Meningococcal prophylaxis (ciprofloxacin)

Question 5

What are the uses for Moxifloxacin, Gemifloxacin & Levofloxacin?

Answer 5

– More active against Gram pos. bacteria
– No useful activity against Pseudomonas
– Lower respiratory tract infections, acute
sinusitis, skin infections
– UTI, soft tissue infections (levofloxacin)
– M. tuberculosis (moxifloxacin and
levofloxacin)
– Note: use in respiratory infections could cause
delay of diagnosis & resistance in
undiagnosed TB
– Thus for respiratory infections mostly reserved
in cases of β-lactam allergy

Question 6

What is the use of Norfloxacin?

Answer 6

Only used for UTI. Structurally related to nalidixic acid but has a wider spectrum

Question 7

What is the use of Nalidixic acid?

Answer 7

– Gram-negative bacteria → acute & chronic
urinary tract infections
– Does not achieve systemic antibacterial levels
(lower urinary tract infections only)
– Use can result in quinolone resistance

Question 8

What is the MOA of Fluoroquinolones?

Answer 8

1. Inhibit topoisomerase II (DNA Gyrase)
   – Prevent the relaxation of positively
   supercoiled DNA required for normal
   transcription and replication
   – Inhibit the cutting and joining action of the
   enzyme on the DNA double helix
2. Inhibit topoisomerase IV
   – Prevent the removal of supercoils by the
   enzyme
   – Interfere with the separation of replicated
   chromosomal DNA into the respective
   daughter cells during cell division
   * Bactericidal

Question 9

Are Fluoroquinolones bacteriostatic?

Answer 9

No. They are bacteriocidal

Question 10

What causes resistance to quinolones?

Answer 10

Resistant organism especially among
– staphylococci, pseudomonas & serratia
Resistance
1. One or more point mutations in quinolone
binding region of target enzyme
2. Change in permeability

Question 11

T or F - Fluoroquinolones should be taken after eating?

Answer 11

False- must be taken on empty stomach

Question 12

What impairs the absorption of fluoroqinolones?

Answer 12

Divalent cations (including antacids)

Question 13

T or F - Adequate fluid intake is required with fluoroqinolones?

Answer 13

True

Question 14

T or F - Fluoroqinolones are metabolised by the kidneys ?

Answer 14

False. Metabolised via the liver cytochrome P450
enzyme system (inhibits liver enzymes)
± 40 - 50% excreted unaltered in the urine

Question 15

What are the side effects of Fluoroqinolones?

Answer 15

1. GIT disturbances and skin rashes
2. Could cause seizures
3. Hallucinations (rare)
4. QT- interval prolongation (levofloxacin, moxifloxacin)
5. Hyperglycemia in diabetic patients
6. Hypoglycemia in patients receiving oral hypoglycemic
   agents
7. May damage growing cartilage & cause arthropathy %
   arthralgia
8. Increased risk of tendinitis and tendon rupture
9. Peripheral neuropathy with increased time of exposure
10. Photosensitivity
11. Rarely aortic aneurysm

Question 16

What are the side effects of Nalidixic Acid?

Answer 16

1. Neurotoxic → caution in elderly
2. Cause photosensitivity
3. Could cause seizures

Question 17

What are the drug interactions of Fluoroqinolones?

Answer 17

1. Ciprofloxacin and theophylline → ciprofloxacin
   inhibits the cytochrome P450 enzyme system
   * Theophylline toxicity → in asthma patients
2. Warfarin (monitor INR)
3. NSAIDs
4. Oral hypoglycemic agents (glibenclamide)
5. Some may interfere with agents that prolong QTc
   interval
6. Antacids/minerals
7. Probenecid

Question 18

What are the CI of Fluoroqinolones?

Answer 18

1. Epilepsy (NB nalidixic acid C/I)
2. Hepatic failure
3. Pregnancy/lactation
4. Babies/children (<18 years)
5. Renal failure (NB nalidixic acid)
6. Porphyria (NB nalidixic acid C/I)
7. Elderly patients
8. Allergy
9. G6PD deficiency

Question 19

What are the uses of metronidazole?

Answer 19

• Powerful antibacterial action against anaerobic
  organisms (bacteria growing in the absence of
  O2) (excl. actinomycosis)
• Bactericidal
• Antiprotozoal action on trophozoites of:
  – Entamoeba histolytica
• Protozoa causing colon inflammation,
  amoebic dysentery and liver abscesses
  – Trichomonas vaginalis
• Protozoa that cause vaginitis and uretritis
• Helicobacter pylori → peptic ulcers
  (PPI+amoxicillin+metronidazole)
• Giardiasis
• Acute necrotising ulcerative gingivitis
• Pseudomembranous colitis
• Topical for rosacea & bacterial vaginosis

Question 20

What is the MOA of metronidazole?

Answer 20

Selectively toxic against anaerobic organisms
because:
* Activated → the nitro group receives electrons
from the electron transport protein, ferredoxine
* Four electron reduction of the nitro group →
hydroxylamine, chemical reactive intermediate
molecules are formed (e.g. the nitro radical anion)
* Reactions between reactive intermediates and
macromolecules like DNA cause:
– Alterations in the DNA helix
– Breaking of the DNA chain

Question 21

What are the resistance mechanisms of metronidazole?

Answer 21

Resistance mechanisms:
* Decreased uptake
* Increased removal
* Decreased activation in bacteria
* Altered enzymes that convert active metronidazole
to non-toxic derivatives

Question 22

Where is metronidazole metabolised?

Answer 22

• Metabolism in the liver and 10-20% are excreted
  unaltered in the urine
• Plasma clearance decreased with impaired liver
  function
• Dose adjustment with severe liver and renal
  disease

Question 23

What are the side effects of metronidazole?

Answer 23

Few side-effects at therapeutic dosages
1. Nausea, headache, dry mouth
2. Metallic taste
3. Mild GIT discomfort
4. Inhibits alcohol metabolism → acetaldehyde
levels ↑ → disulfiram-like effect
5. CNS effects
6. Possible dark coloured urine

Question 24

What are the drug interactions of metronidazole?

Answer 24

1. Cimetidine (metronidazole metabolism ↓)
2. Phenobarbitone (metronidazole metabolism ↑)
3. Phenytoin (plasma levels ↑)
4. Warfarin (anticoagulant effect ↑)
5. Alcohol
6. Lithium (plasma levels ↑)
7. Disulfiram

Question 25

What are the CI of metronidazole?

Answer 25

1. C/I with alcohol use
2. Caution in patients with epilepsy, porphyria
3. Caution with CNS disease
4. Caution with impaired hepatic function
5. Avoid if possible during 1st trimester of
   pregnancy and breastfeeding

Question 26

Do self study