Antimicrobial chemotherapy booklet Flashcards
Bactericidal
An antimicrobial that kills bacteria (e.g. the penicillins)
Bacteriostatic
An antimicrobial that inhibits growth of bacteria (e.g. erythromycin)
Sensitive
An organism is considered sensitive if it is inhibited or killed by levels of the antimicrobial that are available at the site of infection.
Resistant
An organism is considered resistant if it is not killed or inhibited by levels of the antimicrobial that are available at the site of infection
Minimal inhibitory concentration (MIC)
minimum concentration of antimicrobial needed to inhibit visible growth of a given organism
Minimal bactericidal concentration (MBC)
minimum concentration of the antimicrobial needed to kill a given organism.
Routes of Administration:
Topical
Applied to a surface, usually skin or to mucous membranes e.g. conjunctiva.
Routes of Administration:
Systemic
Taken internally, either orally or parenterally.
Routes of Administration:
Parenteral
Administered either intra-venously (iv) or intra-muscularly (im), occassionally subcutaneously.
Sites of antibiotic action
- Inhibition of cell wall synthesis (eg, penicillins
& cephalosporins) - Inhibition of protein synthesis (eg, gentamicin
& erythromycin) - Inhibition of nucleic acid synthesis (eg, trimethoprim & ciprofloxacin)
gentamicin & erythromycin inhibit
protein synthesis
penicillins & cephalosporins inhibit
cell wall synthesis
- also known as b-lactams
trimethoprim & ciprofloxacin inhibit
nucleic acid synthesis
β-lactam antibiotics disrupt
peptidoglycan synthesis by inhibiting the enzymes which are responsible for cross-linking the carbohydrate chains.
human cells are not effected by antibiotics that
inhibit cell wall synthesis as human cells do not have cell walls.
Benzyl penicillin was
original naturally occurring β-lactam discovered by Fleming
Penicillins and cephalosporins are the two groups of
b-lactam antibiotics
b-lactams inhibit
cell wall synthesis
Vancomycin and teicoplanin are the two
glycopeptide antibiotics in common clinical usage.
Vancomycin and teicoplanin both act on
cell wall synthesis at a stage prior to β-lactams, inhibiting assembly of a peptidoglycan precursor.
- act only on gram positive organisms
penicillin-binding proteins (PBPs)
enzymes involved in the synthesis of Peptidoglycan.
Vancomycin and teicoplanin are not absorbed
from the GI tract and are only given parenterally, except in special circumstances.
common problem with vancomycin
Toxicity
- intravenous infusion must be given carefully to avoid local tissue damage if it leaks from the veins
- should be infused slowly over a period of hours
vancomycin side effects
ototoxicity - affects ears
nephrotoxicity - affects kidney
skin rashes
Protein synthesis involves
translation of messenger RNA at the ribosome.
Differences between the bacterial ribosome and the mammalian ribosome allow selective action on bacterial protein synthesis.
Aminoglycosides example
gentamicin
Aminoglycosides (e.g. gentamicin) are especially useful in
the treatment of serious Gram negative (e.g. coliform) infection.
primary use of aminoglycosides is to
treat gram negative infection and they are injectable rather than oral antibiotics.
problem with gentamicin
toxic and requires a careful dosing regime (follow local guidelines) and monitoring of levels.
antibiotics which act on protein synthesis
- Aminoglycosides
- macrolides
- tetracyclines
- Oxazolidinones
- Cyclic Lipopeptide
macrolides example
erythromycin
clarithromycin
Macrolide antibiotics are useful alternatives
to penicillins in treatment of gram positive infections in patients who are penicillin allergic
new class of protein synthesis inhibitors in common use
Linezolid
- has good activity against MRSA and can be given orally
Linezolid is generally held in reserve for
the treatment of serious infection. eg MRSA
Cyclic Lipopeptide example
Daptomycin
Oxazolidinones example
Linezolid
Daptomycin used against
Gram positives in general
- MRSA in particular
At present it is used in serious infections on specialist advice.
A wide range of antibiotics inhibit DNA synthesis
either directly, or indirectly by interrupting the supply of precursors for DNA synthesis.
Inhibitors of nucleic acid synthesis
- Trimethoprim and sulphamethoxazole
- Fluoroquinolones
Trimethoprim and sulphamethoxazole inhibit
different steps in purine synthesis, and are used in a combined form in the drug co-trimoxazole.
Trimethoprim is also used for
- chest infections
- urinary tract infections
Fluoroquinolones example
- ciprofloxacin
- levofloxacin
Ciprofloxacin is effective against
Gram negative organisms and can be taken orally and parenterally.
Ciprofloxacin cannot be used in
children as it could interfere with cartilage growth.
levofloxacin has more activity against
gram positive bacteria
sometimes used for chest infections
Types of Resistance:
- Inherent or intrinsic resistance
- Acquired resistance
Acquired resistance
may be present in some strain species but not in others.
this can happen through:
- spontaneous mutation
- genes coding for resistance may be passed on from organism to organism or species to species. (more common)
widespread use of antibiotics causes
selective pressure and encourages new resistant organisms to outgrow sensitive strains.
plasmids
extra chromosomal packages of DNA
transposons
packets of DNA which insert themselves into the chromosome
genes that have acquired resistance can be carried in
- transposons
- plasmids
Resistance to b–lactam antibiotics
two mechanisms:
- b-lactamase production
- Alteration of penicillin binding protein (PBP) target site
b−lactamases are
bacterial enzymes which cleave the b–lactam ring of the antibiotic and thus render it inactive.
ways to combat β-lactamase
- introduce a second component to the antibiotic which is a b-lactamase inhibitor and therefore protects the antibiotic from enzymic degradation
- modify the antibiotic side chain to produce an antibiotic which is resistant to the actions of b-lactamase
b-lactamase inhibitor example
clavulanic acid (in co-amoxiclav, antibiotic is amoxicillin)
Flucloxacillin is
b-lactamase resistant, and can be used to treat b-lactamase producing Staph. aureus.
Some organisms (eg, MRSA) have
genetically altered target sites (PBPs) to which b-lactams cannot bind.
MRSA are resistant to
all penicillins and cephalosporins.
ESBLs (extended spectrum β-lactamases) are
produced by some gram negative organisms and render them resistant to all β-lactam agents.
Vancomycin resistance is unusual in
Gram positive organisms.
Vancomycin resistant enterococci (VREs) have
appeared recently.
- the peptidoglycan precursor to which vancomycin normally binds has an altered structure - example of an altered target site
Antibacterial agents may be described as
broad spectrum or narrow spectrum, depending on the range of organisms against which they are active.
Benzyl penicillin (Penicillin G) is still the best choice for
intra- venous treatment of serious pneumococcal, meningococcal and Strep pyogenes (Group A) infection
Amoxicillin, ampicillin has much better
oral absorption orally than benzylpenicillin.
- covers streptococci (including enterococci) and some coliforms.
Flucloxacillin is resistant to the actions of
staphylococcal b-lactamase and is therefore first choice treatment for staphylococcal infections.
Piperacillin and spectrum
broad spectrum penicillin with extended gram negative cover.
carbapenems are
close relatives of the penicillins
- the widest spectrum of all and are active against most bacteria, including anaerobes.
parenteral use only drugs include
- Aminoglycosides
- Glycopeptides
Azithromycin
part of Macrolides
- useful for single dose treatment of Chlamydia infection.
Urinary tract agents
- Nalidixic Acid
- Nitrofurantoin
- used on gram negative bacteria
Miscellaneous antibiotics
- Metronidazole
- Fusidic acid
- Trimethoprim
- Tetracyclines
- Clindamycin
lincosamide antibiotic
Clindamycin
important side effect of antibiotic therapy
Clostridium difficile infection (CDI)
Allergic reaction types:
- Immediate hypersensitivity
- Delayed hypersensitivity
- Gastrointestinal side effects
Immediate hypersensitivity causes
Anaphylactic shock
- IgE mediated and occurs within minutes of administration
Delayed hypersensitivity
may take hours or days to develop and can have an immune complex or cell mediated mechanism.
- Drug rashes are the most common manifestation, but drug fever, serum sickness and erythema nodosum may also occur
Delayed hypersensitivity and Stevens-Johnson syndrome
severe and sometimes fatal form of delayed hypersensitivity associated with the sulphonamides, in which both skin and mucous membranes are involved.
Gastro-intestinal side effects are commonly encountered with
antimicrobial usage.
Nausea and vomiting are common, but diarrhoea associated with toxin production by Clostridium difficile has now become a major problem in healthcare acquired infection
Restricted prescribing of broad spectrum antibiotics according to local protocols
helps minimise Clostridium difficile infection (CDI) caused by antibiotic therapy.
Clostridium difficile infection (CDI) is treated with
oral metronidazole or oral vancomycin.
Other antibiotic treatment is discontinued if clinically appropriate and Infection Control measures put In place.
Therapy with broad spectrum penicillins or cephalosporins for example may be complicated by
overgrowth of the yeast Candida albicans, resulting in oral and/or vaginal candidiasis, also known as ‘thrush’.
liver is susceptible to a variety of side effects as
its an important organ of metabolism and excretion
Tetracycline and the anti-tuberculous drugs isoniazid (INH) and rifampicin have been associated
hepatotoxicity as has flucloxacillin.
- common in patients with pre-existing liver disease and in pregnancy.
The kidney is the most important
route of drug excretion
Nephrotoxicity (Renal toxicity) is dose related and is more common in patients with pre-existing renal disease
Renal toxicity is most commonly seen with
aminoglycoside group of antibiotics (e.g. gentamicin, netilmicin and amikacin) or with vancomycin.
- is reversiable but can may be permenant
Neurological toxicity
- Ototoxicity
- Optic Neuropathy
- Encephalopathy and convulsions
- Peripheral neuropathy
Ototoxicity is most commonly seen following
aminoglycoside or vancomycin use.
Ethambutol (an anti-tuberculous drug) is associated with
dose related optic nerve damage, and regular monitoring of optic nerve function during therapy is recommended.
Encephalopathy and convulsions may result from
high dose penicillin and cephalosporin use, or with aciclovir.
Metronidazole and nitrofurantoin may produce
reversible peripheral neuropathy of uncertain mechanism
Antimicrobials may have a toxic effect on the bone marrow resulting in
- selective depression of one cell line (eg, neutropenia)
- unselective depression of all bone marrow elements (ie, pancytopenia).
Patient Characteristics to look out for
- Age
- Renal Function
- Liver Function
- Pregnancy
Prophylaxis =
administration of antimicrobials to prevent the future occurrence of infection.
Prophylaxis given if
- patient has been exposed to other patients with highly communicable disease
- patient is subjected to surgical procedures associated with high post-operative infection rates.
Therapy is given when
the organism(s) causing infection is not known, empirical antimicrobial therapy may have to be commenced if urgent treatment is required
Drug Related Considerations
- Spectrum of antimicrobial agent
- Monotherapy (best) vs combination
- Penetration to site of infection
- Monitoring
- Dose and duration of therapy
When antimicrobials are used in combination, there are three possible outcomes:
- Their effects are additive.
- They are antagonistic
- They are synergistic
synergistic outcome =
their combined effect is greater than the sum of their individual contributions. The most common example of this is the combination of penicillin and gentamicin in the treatment of streptococcal infective endocarditis. Penicillin breaks down the streptococcal cell wall, and allows gentamicin access to the ribosome. Streptococci are normally impermeable to gentamicin.
antagonistic outcome =
their combined effect is less than the sum of their individual contributions.
Vancomycin and gentamicin levels should be monitored to
avoid toxicity as they have a low therapeutic index.
two main reasons for monitoring serum levels of an antimicrobial:
- To ensure that therapeutic levels have been achieved
- To ensure that levels are not so high as to be toxic.
Amphotericin B is used
intra-venously for serious yeast and other fungal infections.
it is also toxic as it can bind to cholesterol.
Nystatin is used
topically or in oral suspension and is not an intra-venous agent for serious fungal infection
Polyene drugs bind to
ergosterol, which is present in the fungal cell wall but not in the bacterial cell wall
This results in an increase in the permeability of the cell wall.
- they can also bind to other sterols like cholesterol
polyene examples
- Amphotericin B
- Nystatin
Azoles inhibit
ergosterol synthesis.
Fluconazole is used to treat
yeast (not filamentous fungal) infection.
Not all yeasts are sensitive to fluconazole.
Voriconazole and itraconazole are used to
treat aspergillosis.
Azoles example
- Fluconazole
- Voriconazole
- itraconazole
Allylamines inhibit
ergosterol synthesis.
- act at a different stage of the synthetic pathway from azoles.
Terbinafine is used for
fungal infection of skin and nails.
eg - athletes foot, ringworm and onychomycosis
Allylamines example
Terbinafine
Echinocandins example
Caspofungin, Mycafungin and Anidulafungin
Echinocandins are used for
serious Candida and Aspergillus infections
Aciclovir is active against
Herpes Simplex virus and Varicella zoster virus
Aciclovir is a
nucleoside analogue.
- Before it can work, it must first be converted into its active form by an enzyme (thymidine kinase) coded for by the virus genome
Famciclovir and valaciclovir are used for
treatment of HSV and shingles.
Ganciclovir, also a
nucleoside analogue, is active against CMV.
- restricted to treating life or sight threatening infections in the immunocompromised
Foscarnet can be used for
some HSV, VZV and CMV infections.
- highly nephrotoxic and can only be given intravenously.
Cidofovir is used for
CMV retinitis when other anti-viral drugs are inappropriate.
zidovudine
nucleoside analogue which interferes with the action of reverse transcriptase.
It slows the replication of the virus but does not kill it
- first treatment for HIV
Interferon-α is a protein that
forms part of the host immune response.
- subcutaneous injection
Lamivudine is used
mainly for HIV treatment
- unlike Interferon-α its given orally
Zanamavir and Oseltamivir used for
influenza A or B within 48 hours of the onset of symptoms
Ribavarin is another
nucleoside analogue.
- treatment of severe Respiratory Syncytial Virus (RSV) infections.
- is inhaled
Amphotericin B acts against a
narrow range of bacteria.
The differing ribosomes of mammalian and bacterial cells allow
selective toxicity.
Penicillin allergic patients may also be allergic to
cephalosporins
Piperacillin has an
extended spectrum and is active against
Pseudomonas species.
Metronidazole is widely used to treat
anaerobic infection.
Vancomycin is only active against
anaerobes.
Serum levels of gentamicin and vancomycin can be monitored in the laboratory to
minimise the risk of toxicity.
Inherent or intrinsic resistance:
streptococci is always resistant to
aminoglycosides
laboratory sensitive testing not required
Inherent or intrinsic resistance:
Gram-negative organisms always resistant to
Vancomycin.
laboratory sensitive testing not required
laboratory sensitive testing required for
Acquired resistance as some strains are resistant ut some arent.
MRSA is any strain of
S. aureusthat has developed, throughhorizontal gene transferandnatural selection,multiple drug resistancetoβ-lactam antibiotics
MRSA can be treated with
vancomyin - glycopeptide
linezolid - oxazoilidinone
Flucloxacillin is
β-lactamase resistant.
Can be used to treat β-lactamase producing S. aureus, but not MRSA.
β-lactams: Cephalosporins and gram negative bacteria
Gram-negative activity (increases through generations).
- better to use 3rd generation antibiotics
β-lactams: Cephalosporins and gram positive bacteria
Gram-positive activity
(decreases proportionately from first through to third generation drugs).
- better to use 1st generation drugs
High dose penicillin and cephalosporin or (if the dose is not reduced in the presence of renal impairment) can cause
Encephalopathy and convulsions
Anti MRSA agent linezolid toxicity
bone marrow suppression and may lower platelet counts.
Pregnancy:
mutagenic
induce mutation in foetal chromosomes
Pregnancy:
teratogenic
associated with congenital abnormalities
Safe in pregnancy
penicillins, cephalosporins
urinary antiseptic nitrofurantoin.
the combination of two cidal drugs or of two static drugs is
additive or synergistic.
combination of one static and one cidal drug may result in
antagonism.
Anti-Fungal Drugs:
- polyenes
- Azoles
- Allylamines
- Echinocandins
Antibiotics have no action against
virus
virucidal agents
those that will kill the virus
- only some
virustatic
inhibit growth and/or replication
- all are this
Many anti-viral drugs are
nucleoside analogues which interfere with nucleic acid synthesis.
Combination therapy with at least three drugs
is now normal practice in
HIV treatment.
- Two nucleoside analogue reverse transcriptase inhibitors, plus either a:
- non-nucleoside reverse transcriptase inhibitor (nevirapine)
- viral protease inhibitor (saquinavir).
