Antibacterials: tetracyclins
Mechanism
• enter bacteria via active uptake mechanism
– Mechanism not in human cells so we don’t get high uptake into human cells
• bind to 30S subunit of ribosomes so this inhibits protein synthesis necessary for survival
• bacteriostatic – inhibit replication. After bacteria has gone through it’s usual process it does
not regenerate or replicate others
• Common examples
– doxycycline
– minocycline
Tetracyclin kinetics
• Incomplete gut absorption and this can be worsened as the tetracycline can chelate in gut
with Ca 2+ (avoid milk) – so told to take on empty stomach so as to avoid interaction with
milk and cheese
• If it does get absorbed it diffuses quite well including into sputum (good for respiratory
infections) and urine (good for UTI)
– do not cross blood brain barrier (not in CSF) so would not use for meningitis
• Long T1/2
– once daily administration
• Biliary secretion so can also be used for gall bladder infections
– Partial reabsorption
• Renal elimination – may need to modify dose for renal impairment
– Mainly unchanged
Tetracyclin activity/indications
• Broad spectrum
– Gram positive & gram negative bacteria (but remember it is bacteriostatic and not
bacteriocidal
• Rickettsiae (infectious organism that is half way between fungus and bacterium) and
tetracyclins are used to treat them
• Atypical organisms
– Chlamydia
– Mycoplasma
Tetracyclin resistance
• increased pumping of drug out of bacteria. There is little channels that pump out certain
substances and may take out tetracyclins
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transferred by plasmids (bits of nucleic acid that can be transferred between
bacteria)
decreased binding of drug to 30S ribosomes – any change of the structure of the ribosomes
makes it harder for the drug to bind
develops slowly (tetracyclins are about half a century old) so resistance is fairly widespread
cross resistance between tetracyclines (if bacteria is resistant to one it will be resistant to
the other)
Porin pump is responsible for exclusion of drug from inside of the drug
Resistance can be intrinsic (natural feature of the bacteria usually from changes in
chromosomes) or acquired (by plasmid transmission)
Tetracyclin side-effects
• nausea, vomiting as with all antibiotics
• that can progress to abdominal discomfort / diarrhoea
• brown teeth (children – while teeth are developing)
– chelation of Ca 2+ (calcium is in teeth and when the tetracylcins bind they are then
taken up by teeth and stain teeth)
– avoid in ages < 12 years (& pregnancy)
• benign intracranial hypertension – meaning an increased pressure within the CSF but is
called benign because it doesn’t cause serious symptoms more just small headaches
Fluoroquinolones : mechanism
• inhibit replication of bacterial DNA and therefore the bacteria cant multiply
• does this by blocking activity of 2 enzymes:
– DNA gyrase (involved in the folding of DNA)
– DNA topoisomerase
• these enzymes essential for
– DNA replication & DNA repair
• Bactericidal – they attack the DNA and inhibit replication
• Examples
– Ciprofloxacin, norfloxacin, moxifloxacin, gatifloxacin
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Gyrase involved in winding up the nucleic acid
Topoisomerase works at the fork in the DNA
Fluoroquinolones activity
• broad spectrum
• ciprofloxacin
– Gram positive i.e. staphylococcus
– Gram negative i.e. pseudomonas – people with cystic fibrosis get colonizations of
pseudomonas
• norfloxacin
– Urinary tract infections as it is excreted quite high concentrations in the urine
• moxifloxacin / gatifloxacin
– pneumonia
– moxifloxacin is also used for treatment resistant tuberculosis
Resistance
• relatively uncommon as it is a relatively young class of drug (been around for about 5-10
years. In about another 10 years there will be more resistant based on the usual trends for
antibiotics )
• mechanisms of the resistance that has developed at the moment
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mutations of DNA gyrase – drug cant bind as well
increased drug efflux – bacteria starts to pump the drug out before it gets to the
gyrase
Fluoroquinolone kinetics
• oral formulations well absorbed
• widely distributed in body tissues so achieves significant concentrations in different types of
infections
• mainly renal excretion. may need to modify dose in renal impairment
• Range of T1/2
– moxifloxacin > norfloxacin > ciprofloxacin
– moxifloxacin once daily
Why kill bacteria fast?
• Rapid reduction of bacterial load in the host which means there is less harmful products
being released by the bacteria
• Decrease in the toxicity
• Decrease in immunologic “switch-on” (= allergy) i.e. if the bacteria is there for a long time it
can initiate an immune response such as allergic response and next time the person gets the
bacteria they can suffer a pretty significant reaction
• Faster relief of signs and symptoms
• Reduction of the potential for resistance development – bacteria there in a long time in the
presence of the antibiotic could lead to the production of resistant bacteria
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The streptococcus pneumonia are resistant to penicillin
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Vertical axis is colony forming units – means this experiment was done in vitro
Control was done in saline solution and the colonies obviously replicated
Levofloxacin is inhibiting the profileration of colonies
Gatifloxacin works for around 10 hours
Moxifloxacin continues inhibition in comparison to the control
So this all shows the fluroquinolones are effective in treating penicillin resistant strept
pneumonia
Optimal Pharmacokinetic (PK) /pharmacodynamic (PD) parameters associated with :
• high clinical and bacteriologic cure rates
• low propensity for emergence of resistance
Pharmacokinetic (PK) & pharmacodynamic (PD) parameters
• AUC = Area under the curve
• MIC90 = minimum concentration necessary to inhibit 90% of isolates
• Cmax = Peak serum concentration
• AUIC = Area under the inhibitory curve
Optimal PK & PD parameters: to minimise emergence of resistance
• AUIC = AUC/MIC90 ( Optimally >125)
• Cmax/MIC90 (Optimally > 8-10)
• The maximum concentration should be 8-10 times higher than the minimum
inhibitory concentration for 90% of the isolates
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Vertical axis is the concentration (mg/L)
Can see the Cmax is about 8 times higher
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Just read off the slide for the left side and said looks like everything meets the necessary
criteria i.e. Cmax/MIC90 is between 8 and 10
AUIC is lower than what we want though
Black circles is the concentration with oral doses
But if we want a to get control of an infection we do IV
He said we need to be aware of what MIC90 is and also the Cmax/MIC90 ratio as well as
AUIC
After 18 hours we would need to give another dose to stay above MIC90 but to be safe we
would do q12h
Side effects
• nausea, vomiting, abdo pain, diarrhoea – as with all antibiotics
• CNS effects
– Caution with epilepsy
• tendon rupture (esp in the ankle)
– Mainly ciprofloxacin. Was noticed with cystic fibrosis patients
• prolongation of QT interval (ECG)
– moxifloxacin. If patient has history of arrhythmias we would do ECG before giving
drug or if person was on another drug that increases QT we would look for another
antibiotic
– moxifloxacin is used in clinical trials as the ‘gold standard’ for QT prolongation. They
use it as a control to see if the other drug increases QT proloongation
• inhibition of P450s
– drug interactions
Aminoglycosides mechanism
• inhibit protein synthesis
– bind irreversibly to 30s ribosomal subunit
– inhibits translation from messenger RNA (mRNA) to protein – the amino acids do not
add on
– increases the frequency of misreading of genetic code – dysfunctional proteins are
created
• bactericidal even though tetracyclins which work in the same area are bacteriostatic. They
are more potent than tetracyclins
• Examples
– gentamicin, tobramicin, amikacin, netilmicin
Activity
• Gram negative bacteria
– Including Pseudomonas species
• also some gram positives
• inactive against anaerobic organisms
– unable to take up aminoglycosides so they don’t get into the bacteria
• Used in combination with cell wall inhibitors
– penicillins & aminoglycosides “synergistic”. This was noticed in vitro that together
you get a better effect than just them on their own. Theory is that penicillin
increases the access of the aminoglycosides to their sites of action
Resistance
• relatively common as they have been around for a while
• mechanisms (transferred by plasmids)
– enzymes acetylate, phosphorylate or adenylate aminoglycoside in periplasmic
membrane. In the membrane of the bacteria these enzymes add things to the
antibiotic and the drugs can no longer bind to the ribosomes
– modified drug does not access ribosomes
– also, changes in ribosomes may reduce drug binding
• May be overcome by combining with drugs that disrupt bacterial wall (e.g. penicillins) as
they can affect the enzymes in the periplasmic membrane
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So can have changes in the 30S ribosome or cell wall
There may be new enzymes such acetylases which can hinder the drugs
Kinetics
• poor oral absorption (give IV) – they stay in the bowel so are good for bowel infection. Good
for people who need bowel surgery to sterilize the bowel
• widely distributed in body tissues
– Not CSF so not for meningitis ; crosses placenta
• rapid renal excretion (unchanged drug) so may need to decrease dose in renal impairment
as drug has narrow therapeutic window
• short T1/2
– but given once daily as they have a “post antibiotic effect” – this was discovered in
animal models
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in these animal models there is a tissue infection
after a bolus dose the concentration goes up and then down like usual
but if you continue to sample the tissue after this the bacteria is still inhibited
so antibiotic is cleared from plasma but still has an effect in the body
Side effects
• ototoxicity
– prolonged high plasma [C] - accumulation in inner ear
– increased risk with loop diuretics. Frusemide with aminoglycosides seems to double
the risk of ototoxicity
• renal damage
– accumulation in proximal tubules and can interfere with kidney function. Need to
monitor kidney function during dosing
– reversible if detected early
• neuromuscular blockage
– inhibits acetyl choline release in neuromuscular junctions
– seen if co-administered with other neuromuscular blockers (e.g. during anaesthesia)
– so issue if someone is about to have general anesthetics as there is prolonged
neuromsuclar blockade and the person will need to stay on a ventilator