Antimicrobial Chemotherapy Flashcards
What are antibiotics active against
Only bacteria
Define bactericidal
Antimicrobial that kills bacteria
e.g. penicillins
Define bacteriostatic
Antimicrobial that inhibits growth of bacteria
e.g. erythromycin
Define sensitive
Organism is sensitive if it is inhibited or killed by the antimicrobial available at the site of infection
Define resistant
Organism is resistant if it is not killed or inhibited by the antimicrobial available at the site of infection
Define MBC
Minimal bactericidal concentration
Minimum concentration of antimicrobial needed to kill a given organism
Define MIC
Minimal inhibitory concentration
Minimum concentration of antimicrobial needed to inhibit growth of a given organism
How can antimicrobials be administered
Topically
Systemically
Parenterally
What is topical administration
Applied to a surface (skin or to mucous membranes
e.g. conjunctiva)
What is systemic administration
Taken internally (orally or parenterally)
What is parenteral administration
Administered intra-venously (iv) or intra-muscularly (im), occassionally subcutaneously
What are the three different areas of metabolic activity that antibiotics can use as their mechanism of action
Inhibition of cell wall synthesis (e.g. penicillins & cephalosporins)
Inhibition of nucleic acid synthesis (e.g. trimethoprim & ciprofloxacin)
Inhibition of protein synthesis (e.g. gentamicin & erythromycin)
Why can humans use antibiotics which inhibit cell wall synthesis
Humans don’t have a cell wall
What are penicillins and cephalosporins
β-lactams
How do β-lactams work
They disrupt peptidoglycan synthesis by inhibiting the enzymes (penicillin-binding proteins, PBPs)
responsible for cross-linking the carbohydrate chains
What types of antibiotics inhibit cell wall synthesis
β-lactams
Glycopeptides
What type of cell walls can glycopeptides penetrate
Gram positive
How must glycopeptides be administered
Parenterally (except in special circumstances)
as it cannot be absorbed from the GI tract
What is the mechanism of action for glycopeptides
They act on cell wall synthesis at a stage prior to β-lactams so inhibit assembly of a peptidoglycan precursor
Give examples of glycopeptides
Vancomycin
Teicoplanin
How is vancomycin administered to avoid the common toxicity
Careful I.V. infusion to avoid local tissue damage
Important to monitor levels of vancomycin
serum drug concentration is high enough to be therapeutic but not toxic
What are the advantages of teicoplanin
Its less toxic than vancomycin and has the advantage of single daily dosing
What types of antibiotics inhibit protein synthesis
Aminoglycosides Macrolides Tetracyclines Oxazolidinones Cyclic Lipopeptide
What is protein synthesis
The translation of messenger RNA at the ribosome
The differences between the bacterial ribosome and the mammalian ribosome allow selective action on bacterial protein synthesis
What are aminoglycosides useful for
Treatment of serious Gram negative infection (e.g. coliform)
Give an example on an aminoglycosides
Gentamicin which is toxic and requires a careful dosing regime and monitoring of levels
What are macrolides useful for
Useful as alternatives to penicillins in treatment of gram positive infections in patients who are penicillin allergic
Give an example of macrolides
Erythromycin
Give an example of oxazolidinones
Linezolid which can be given orally
Tends to be held in reserve for the treatment of serious infection
Give an example of a cyclic lipopeptide
Daptomycin has activity against Gram positives in general and MRSA in particular
Used in serious infections on specialist advice
How can nucleic acid synthesis be inhibited
Directly or indirectly by interrupting the supply of precursors for DNA synthesis
What types of antibiotics can be used to inhibit nucleic acid synthesis
Trimethroprim
Sulphoamindes
Combined form of co-trimoxazole could be used
Fluoroquinolones
What do sulphonamides do
Inhibit dihydropteroate synthase to stop purine formation
What does trimethoprim do
Inhibit dihydrofolate reductase to stop purine formation
Commonly used for UTIs
Describe fluoroquinolones
Used orally as well as parenterally
Particularly effective against gram negative organisms
Cannot be used in children (interference with cartilage growth)
Newer quinolones (e.g. levofloxacin) may have more activity against gram positives
What is the clinical definition of resistance
An organism is considered resistant to a given drug when it is unlikely to respond to attainable levels of that drug in tissues
Why have antibiotic sensitivity tests been developed
To predict whether an infection will respond to treatment with that antibiotic
What types of resistance are there
Inherent
Intrinsic
Acquired
What are gram negative organisms always resistant to
Gram negative organisms always resistant to vancomycin
What is streptococci always resistant to
Aminoglycosides
What is resistance normally due to
Inability of the drug to penetrate
the bacterial cell wall to exert its action
How can resistance be acquired
Spontaneous mutation
Spread of resistance
What does a spontaneous mutation cause (in regards to resistance)
A change in structure or function which no longer allows the antibiotic to act
(target may have changed)
How spread of resistance occur
Gene/s that code for resistance can spread from organism to organism or from species to species
Genes can be carried on plasmids (extra chromosomal packages of DNA) or on transposons (packets of DNA which insert themselves into the chromosome)
What does the widespread use of antibiotics cause
Selective pressure
Encourages new resistant organisms to outgrow sensitive strains
What is a current issue in antibiotic resistance
β-lactamase production
Alteration of penicillin binding protein (PBP) target site
What does β-lactamase production cause
They are bacterial enzymes which cleave the β–lactam ring of the antibiotic
and thus render it inactive
Where are β-lactamases common
Gram negative bacilli
How can β-lactamase be combated
Introduce a second component to the antibiotic (β-lactamase inhibitor) protecting the antibiotic from enzymatic degradation
Modify the antibiotic side chain producing new antibiotic resistant to the actions of β-lactamase
What are ESBLs
Extended spectrum β–lactamases
Produced by some Gram negative organisms
How do ESBLs work
Break down of third generation cephalosporins and penicillins then are
resistant to all β–lactam antibiotics is developed
What is CPE and CRE
Carbapenemase Producing Enterobacteriaceae
Carbapenem Resistant Enterobacteriaciae
How can some microorganisms develop resistance to to β–lactams
By changing the structure of their PBPs (enzymes involved in peptidoglycan synthesis inhibited by binding of penicillins and cephalosporins)
Mutations in PBP genes result in a modified target site to which β–lactams will no longer bind
What occurs in vancomycin resistant enterococci (VRE)
The peptidoglycan precursor to which vancomycin normally binds has an altered structure
Name some commonly used β-lactams: penicillins
Benzyl penicillin (Penicillin G) Flucloxacillin Amoxicillin, ampicillin Co-amoxiclav Flucloxacillin Piperacillin Imipenem, meropenem
Describe benzyl penicillin
Works against Gram positive organisms
Intravenous treatment of pneumococcal, meningococcal and Strep pyogenes infection
Describe flucloxacillin
Resistant to staphylococcal β-lactamase action.
First choice treatment for
staphylococcal infections
Describe amoxicillin, ampicillin
Has Gram negative activity (20-30% of coliform now resistant)
Oral absorption
It covers streptococci and some coliforms
Describe co-amoxiclav
Combination of amoxicillin and β-lactamase enzyme inhibitor clavulanic acid
Extended spectrum to cover β-lactamase producing coliforms
Describe piperacillin
Has extended gram negative cover
Activity against Enterococcus faecalis and Pseudomonas
Anti-anaerobic activity,
(for intra-abdominal infection)
Combination with the β-lactamase inhibitor tazobactam
Describe imipenem, meropenem
Are close relatives of the penicillins (carbapenems)
All active against most bacteria, including anaerobes
What do β-lactams: Cephalosporins act against
Activity against Gram negative organisms increases through generations
Activity against Gram positive organisms decreases through generations
How many generations of cephalosporins are there
3
Name some cephalosporins
First generation: cephradine
Second generation: cefuroxime
Third generation: ceftriaxone, ceftazidime
How are aminoglycosides administered
Parenteral use only
What are aminoglycosides active against
Gram negative organisms including pseudomonas,
with very little resistance seen in the UK
Most staphylococci are sensitive
Give an example of aminoglycosides
Gentamicin (cheapest)
What must be monitiored when using aminoglycosides
Serum levels
because of potential toxicity
How should glycopeptides be administered
Parenteral use only
What are glycopeptides active against
Gram positive organisms only
Aerobic and anaerobic
Give examples of glycopeptides
Vancomycin (levels must be monitored because of potential toxicity)
Teicoplanin
Give examples of macrolides
Clarithromycin or Erythromycin
Activity is mainly against gram positive organisms
When is clarithromycin or erythromycin used
As an alternative to penicillin in patients with penicillin hypersensitivity
Whats is clarithromycin or erythromycin effective against
Organisms causing ‘atypical pneumonia’ Chlamydia psittacci, Coxiella burnetti and Mycoplasma pneumoniae)
First choice therapy against Legionella pneumophila
When is azithromycin (a macrolides) used
Newer macrolide which is useful for single dose
treatment of Chlamydia infection
What are first and second generation quinolones active against
They have a wide spectrum of action and are active against nearly all gram negative organisms including pseudomonas
What are third generation quinolones active against
Active against pneumococci and the organisms causing atypical pneumonia
Activity against streptococci is generally poor
Which group of antibiotics provide the only form of oral therapy against pseudomonas infections
Quinolones
Name some quinolones
First generation: nalidixic acid
Second generation: ciprofloxacin
Third generation: levofloxacin
When is metronidazole effective
Against anaerobes, both gram positive
(e.g., Clostridia) and gram negative (e.g. Bacteroides spp.)
Used in any situation which may involved anaerobic infection
(intra-abdominal sepsis)
What is fusidic acid used as
Anti-staphylococcal drug
Should always be used in combination with other anti-staphylococcal drugs such as flucloxacillin
What is trimethoprim used for
UTIs
What is co-trimoxazole used for
A few specialised conditions and sometimes for treatment of chest infections on
the grounds that it does not predispose to Clostridium difficile infection
What are tetracyclines
Broad spectrum agents which inhibit bacterial protein synthesis and have a few limited applications nowadays
When should tetracyclines be used
For some genital tract (chlamydia) and respiratory tract infection (e.g. psittacosis, Mycoplasma pneumoniae)
Why should pregnant women and children under 12 not be given tetracyclines
They are deposited in teeth and bone
What does clindamycin
have good activity against
Gram positive organisms such as staphylococci and streptococci
Anaerobes
What are the advantages and disadvantages of clindamycin
Advantages: clindamycin has very good tissue penetration – e.g. into bone – and can be taken orally
Disadvantages: common cause of
pseudo-membranous colitis
What is linezolid active against
MRSA
Can cause bone marrow suppression
What is daptomycin active against
Gram positive organisms only
May be useful for the treatment of serious MRSA infections
Which agents are used only in treating lower UTIs (cystitis)
Nalidixic acid
Nitrofurantoin
What is nalidixic acid
A urinary antiseptic with activity only against gram-negative aerobes (coliform) organisms
Completely excreted in urine
What is nitrofurantoin effective against
Most gram negative organisms except of Proteus and Pseudomonas spp
Also effective against some gram positive organisms
What is the incidence of adverse reactions dependent upon
The dose and duration of therapy
When will allergic reactions from an antimicrobial occur
Following administration of any antimicrobial
Normally commonly associated with the β-lactam (penicillins and cephalosporins)
When will immediate hypersensitivity from an antimicrobial occur
Follows parenteral administration of the antibiotic
This is IgE mediated occurs within minutes of administration
What characterises immediate hypersensitivity
Itching, urticaria, nausea, vomiting, wheezing and shock
Laryngeal oedema may prove fatal unless the airway is cleared
When will delayed hypersensitivity from an antimicrobial occur
May take hours or days to develop
can have an immune complex or cell mediated mechanism
What characterises delayed hypersensitivity
Rashes are common, fever, serum sickness and erythema nodosum may occur
What is the Stevens-Johnson syndrome
A severe and sometimes fatal form
associated with the sulphonamides (skin and mucous membranes are involved)
What type of allergic reactions can occur
Immediate
Delayed
What are common GI side effects
Nausea and vomiting
Diarrhoea associated with toxin production
by Clostridium difficile
How are the toxins produced by C. dificile from the antimicrobal treatment treated
Diagnosis done by detection of toxin in the stool by enzyme immunoassay (EIA)
Treatment with oral metronidazole or oral vancomycin
How can antimicrobials cause thrush
Broad spectrum antimicrobials suppress normal flora in other parts of the body result in overgrowth of resistant organisms
Which drugs have been associated with hepatoxicity
Tetracycline and the
anti-tuberculous drugs isoniazid (INH)
and rifampicin
When is hepatoxicity common
In patients with pre-existing
liver disease and in pregnancy
When is nephrotoxicity (renal toxicity) common
Dose related
Common in patients with pre-existing renal disease
When is ototoxicity seen
Mostly seen following aminoglycoside or vancomycin use
What is optic neuropathy associated with
Ethambutol (an anti-tuberculous drug) associated with dose related optic nerve damage
Regular monitoring of optic nerve function during therapy is recommended
When are encephalopathy and convulsions seen
With high doses of penicillin and cephalosporin or aciclovir
What can cause peripheral neuropathy
Metronidazole and nitrofurantoin
produce reversible peripheral neuropathy of uncertain mechanism
What is haematological toxicity
Toxic effect on the bone marrow resulting in selective depression of one cell line (e.g. neutropenia)
or unselective depression of all bone marrow elements (i.e. pancytopenia)
How can adverse reactions be prevented
Antimicrobials should be used only when indicated and in the minimum dose and duration necessary to achieve efficacy
Care should be exercised in administering antimicrobials
to susceptible groups
Antimicrobials with a low therapeutic margin
should be monitored to ensure maximal efficacy and minimal toxicity
What should be thought of for the clinical usage of antimicrobials
Antibiotics should not be prescribed unless absolutely necessary and narrow spectrum antibiotics targeted at the likely infecting organism are less likely to encourage resistance
What patient characteristics should be considered when choosing antimicrobals
Age
Renal Function
Liver Function
Pregnancy
What are the indications for antimicrobials
Prophylaxis
Therapy
How can antibiotics be used for prophylaxis
To prevent the future occurrence of infection
How can antibiotics be used for therapy
When the organism(s) causing infection is not known
State some drug related considerations
Spectrum of antimicrobial agent
Monotherapy vs combination
What is Monotherapy vs combination
Monotherapy: the simplest approach
Combination: cover mixed infection by more than one organism, two antimicrobials sometimes have an enhanced effect together, minimises the development of resistant strains to any one agent
What is the spectrum of antimicrobial agent
Antibiotic chosen should normally be effective against the known or likely causative organism(s)
What are the possible outcomes of combination antimicrobal thearpies
Their effects are additive
They are antagonistic and their combined effect is less than the
sum of their individual contributions
They are synergistic and their combined effect is greater than
the sum of their individual contributions
What is the combination of two cidal drugs or two static drugs
Additive or synergistic
What is the combination of one cidal drugs and one static drugs
Antagonism
What else should be considered when choosing antibiotics
Penetration to site of infection
Monitoring
Dose and duration of therapy
What is the role of the laboratory on antimicrobials
Advice on choice of antimicrobials
Why should serum levels of an antimicrobal be monitored
To ensure that therapeutic levels have been achieved
To ensure that levels are not so high as to be toxic
How can the MIC of an antibiotic against one organism be measured
Using E-test
What is an E-test
A paper strip which has a gradient of antibiotic concentration absorbed into it. The MIC of the organism can be read directly from the point where organism growth intersects the strip
How does automated testing work
Growth of individual isolates is measured in the presence of different concentrations of each antibiotic and MIC calculated
What factors can influence the outcome of an antibiotic in practice
Route of administration
Dosing schedule
Penetration of antibiotic to the target site
Interactions with other drugs
