Antibacterial drugs (Nucleic acid synthesis inhibitors) Flashcards
What removes DNA supercoils?
Topoisomerase IV. It also separates the replicated DNA into respective daughter cells during replication
What is the group of synthetic antibiotics called?
Fluoroquinolones
What some of the Fluoroquinolones?
ciprofloxacin, levofloxacin, gemifloxacin, moxifloxacin, ofloxacin,
norfloxacin,
What are the uses for ciprofloxacin and ofloxacin?
-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)
What are the uses for Moxifloxacin, Gemifloxacin & Levofloxacin?
– 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
What is the use of Norfloxacin?
Only used for UTI. Structurally related to nalidixic acid but has a wider spectrum
What is the use of Nalidixic acid?
– 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
What is the MOA of Fluoroquinolones?
- 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 - 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
Are Fluoroquinolones bacteriostatic?
No. They are bacteriocidal
What causes resistance to quinolones?
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
T or F - Fluoroquinolones should be taken after eating?
False- must be taken on empty stomach
What impairs the absorption of fluoroqinolones?
Divalent cations (including antacids)
T or F - Adequate fluid intake is required with fluoroqinolones?
True
T or F - Fluoroqinolones are metabolised by the kidneys ?
False. Metabolised via the liver cytochrome P450
enzyme system (inhibits liver enzymes)
± 40 - 50% excreted unaltered in the urine
What are the side effects of Fluoroqinolones?
- GIT disturbances and skin rashes
- Could cause seizures
- Hallucinations (rare)
- QT- interval prolongation (levofloxacin, moxifloxacin)
- Hyperglycemia in diabetic patients
- Hypoglycemia in patients receiving oral hypoglycemic
agents - May damage growing cartilage & cause arthropathy %
arthralgia - Increased risk of tendinitis and tendon rupture
- Peripheral neuropathy with increased time of exposure
- Photosensitivity
- Rarely aortic aneurysm
What are the side effects of Nalidixic Acid?
- Neurotoxic → caution in elderly
- Cause photosensitivity
- Could cause seizures
What are the drug interactions of Fluoroqinolones?
- Ciprofloxacin and theophylline → ciprofloxacin
inhibits the cytochrome P450 enzyme system
* Theophylline toxicity → in asthma patients - Warfarin (monitor INR)
- NSAIDs
- Oral hypoglycemic agents (glibenclamide)
- Some may interfere with agents that prolong QTc
interval - Antacids/minerals
- Probenecid
What are the CI of Fluoroqinolones?
- Epilepsy (NB nalidixic acid C/I)
- Hepatic failure
- Pregnancy/lactation
- Babies/children (<18 years)
- Renal failure (NB nalidixic acid)
- Porphyria (NB nalidixic acid C/I)
- Elderly patients
- Allergy
- G6PD deficiency
What are the uses of metronidazole?
- 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
What is the MOA of metronidazole?
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
What are the resistance mechanisms of metronidazole?
Resistance mechanisms:
* Decreased uptake
* Increased removal
* Decreased activation in bacteria
* Altered enzymes that convert active metronidazole
to non-toxic derivatives
Where is metronidazole metabolised?
- 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
What are the side effects of metronidazole?
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
What are the drug interactions of metronidazole?
- Cimetidine (metronidazole metabolism ↓)
- Phenobarbitone (metronidazole metabolism ↑)
- Phenytoin (plasma levels ↑)
- Warfarin (anticoagulant effect ↑)
- Alcohol
- Lithium (plasma levels ↑)
- Disulfiram
What are the CI of metronidazole?
- C/I with alcohol use
- Caution in patients with epilepsy, porphyria
- Caution with CNS disease
- Caution with impaired hepatic function
- Avoid if possible during 1st trimester of
pregnancy and breastfeeding
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