Antimicrobial chemotherapy IA % +

Question 1

Bactericidal and bacteriostatic definition

Answer 1

Bactericidal: antimicrobial that kills bacteria (penicillins)

Bacteriostatic: antimicrobial that inhibits growth of bacteria (erythromycin)

Question 2

Sensitive and resistant definition

Answer 2

Resistant: organism is resistant if it is not killed or inhibited by the antimicrobial available at the site of infection.

Sensitive: organism is sensitive if it is inhibited or killed by the antimicrobial available at the site of infection

Question 3

MBC & MIC definition

Answer 3

Minimal Bactericidal Concentration: minimum concentration of antimicrobial needed to kill a given organism.

Minimal Inhibitory Concentration: minimum concentration of antimicrobial needed to inhibit growth of a given organism.

Question 4

3 routes of administration

Answer 4

Topical

Applied to a surface (skin or to mucous membranes e.g. conjunctiva

Systemic

Taken internally, orally or parenterally

Parenteral

Administered intra-venously (iv) or intra-muscularly (im), occasionally subcutaneously.

Question 5

Antibiotic mechanism pic

Answer 5

Question 6

Inhibition of cell wall synthesis

Answer 6

Human cells do not have cell walls, so they are not affected by antibiotics that inhibit cell wall synthesis.

Some drugs may disrupt peptidoglycan synthesis by inhibiting the enzymes (penicillin-binding proteins, PBPs) responsible for cross-linking the carbohydrate chains.

Glycopeptides antibiotic mechanism:

• They act on cell wall synthesis at a stage prior to β-lactams, inhibiting assembly of a peptidoglycan precursor.
• are unable to penetrate the gram negative cell wall,they act only on gram positive organisms
• They are not absorbed from the GI tract and are only given parenterally

Question 7

Inhibtion of protein synthesis

Answer 7

• Protein synthesis involves translation of messenger RNA at the ribosome and differences between the bacterial ribosome and the mammalian ribosome allow selective action on bacterial protein synthesis.
• Useful in the treatment of serious Gram negative infection (e.g. coliform).
• Gentamicin is toxic and requires a careful dosing regime and monitoring of levels.

Question 8

Inhibitors of nucleic acid synthesis

Answer 8

• A wide range of antibiotics inhibit DNA synthesis either directly,or indirectly by interrupting the supply of precursors for DNA synthesis.
• Used orally as well as parenterally
• Particularly effective against gram negative organisms, including Pseudomonas
• Cannot be used in children (interference with cartilage growth)

Question 9

Mechanisms of bacterial resistance

Answer 9

• An organism is considered resistant to a given drug when it is unlikely to respond to attainable levels of that drug in tissues
• Measurement of the antibiotic sensitivity of an organism in the laboratory is designed to predict whether an infection will respond to treatment with that antibiotic.

Question 10

2 types of resistance

Answer 10

• Inherent or intrinsic resistance
• In some cases, all strains of a given species are naturally resistant to an antibiotic.
• Streptococci always resistant to aminoglycosides.
• Gram negative organisms always resistant to vancomycin
• This is usually due to inability of the drug to penetrate the bacterial cell wall to exert its action

Question 11

Acquired resistance

Answer 11

Spontaneous mutation

• change in structure or function which no longer allows the antibiotic to act (target may have changed)

Spread of resistance

• The gene(s) that code for resistance can spread from organism to organism or from species to species. Genes can be carried on plasmids or on transposons (packets of DNA which insert themselves into the chromosome).

Question 12

Natural selection

Answer 12

.The widespread use of antibiotics causes selective pressure and encourages new resistant organisms to outgrow sensitive strains.

Question 13

β-lactamase production

Answer 13

β−lactamases are bacterial enzymes which cleave the β–lactam ring of the antibiotic and thus render it inactive.

There are two ways to combat β-lactamase:

• To introduce a second component to the antibiotic -β-lactamase inhibitor
• To modify the antibiotic side chain producing new antibiotic that is resistant to the actions of β-lactamase.

Question 14

Issues in antibiotic resistance

Answer 14

• Resistance to vancomycin among gram positive organisms was virtually unknown
• Glycopeptides could be relied on for the treatment of serious gram positive infection
• Recently vancomycin resistant enterococci (Enterococcus faecalis and Enterococcus faecium) have emerged.
• In vancomycin resistant enterococci (VRE),the peptidoglycan precursor to which vancomycin normally binds has an altered structure
• VRE a major problem in infection control in some hospitals in the South of England. This mechanism of resistance might spread from enterococci to Staph. aureus, producing vancomycin resistant Staph aureus
• .

Question 15

Side effects and toxicity

Answer 15

• Most antimicrobials are associated with adverse reactions.
• The incidence of those is often dependent upon the dose and duration of therapy.
• Approximately 5% of hospitalised patients will develop adverse reaction(s) to prescribed antimicrobials.
• Fortunately, most are trivial and reversible upon withdrawal of the antimicrobial.However, some are severe or even fatal.

Question 16

Immediate hypersensitivity

Answer 16

• Anaphylactic shock usually follows parenteral administration of the antibiotic.
• This is IgE mediated occurs within minutes of administration.
• Characterised by itching, urticaria, nausea, vomiting, wheezing and shock.
• Laryngeal oedema may prove fatal unless the airway is cleared.

Question 17

Delayed hypersensitivity

Answer 17

• Hours or days to develop. can have an immune complex or cell mediated mechanism.
• Rashes, fever, serum sickness and erythema nodosum may also occur.
• Rashes are usually maculopapular (Redish) and restricted to the skin.
• The Stevens-Johnson syndrome, is a severe and sometimes fatal form associated with the sulphonamides, (skin and mucous membranes are involved).

Question 18

Toxicity examples

Answer 18

• Haematological (bone marrow) Toxicity
• Renal (kidney) toxicity
• Liver toxicity
• Thrush (oral/vaginal candidiasis)

Neurological toxicity

• -Ototoxicity (ear)
• -Optic Neuropathy (optic nerve)
• -Peripheral neuropathy (nerves)
• -Encephalopathy (brain) and convulsions

Question 19

Prevention of Adverse reactions

Answer 19

• 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 vulnerable groups such as extremes of age, pregnant women and patients with liver or renal insufficiency
• Antimicrobials with a low therapeutic margin should be monitored to ensure maximal efficacy and minimal toxicity

Question 20

Patient characteristics

Answer 20

Age

• Certain drugs contraindicated in children (eg, Ciprofloxacin, thought to affect developing cartilage)

Renal Function

• Many antimicrobials are excreted by the kidneys.
• Tend to accumulate in the body in cases of renal failure.
• Doses will need to be decreased proportional to the degree of renal insufficiency (eg, aminoglycoside antibiotics, aciclovir).

Liver Function

• Antimicrobials may be metabolised by the liver and excreted in bile
• Doses should be decreased in hepatic insufficiency or alternate drug should be chosen if possible.

Pregnancy

• Some antimicrobials contraindicated in pregnancy
• mutagenic, (induce mutation in foetal chromosomes)
• teratogenic (associated with congenital abnormalities) (eg, metronidazole and trimethoprim).
• Others are contraindicated because effects on unborn foetus not known.
• Safe in pregnancy: penicillins, cephalosporins and the urinary antiseptic nitrofurantoin.

Question 21

Prophylaxis

Answer 21

• Administration of antimicrobials to prevent the future occurrence of infection.
• Patient exposed to other patients with highly communicable disease or shortly about to be subjected to surgical procedures with high post-operative infection rates.
• Most abdominal operations (bowel is opened and organisms potentially released).Dosage should cover the period of risk only (usually one dose pre-operatively)
• Not be extended to avoid selecting out resistant organisms.

Question 22

Monotherapy vs combination

Answer 22

• The simplest approach i.e. monotherapy, is generally best, but sometimes it is necessary to use antimicrobials in combination:
• To cover mixed infection by more than one organism.
• Because two antimicrobials sometimes have an enhanced effect together
• To minimise the development of resistant strains to any one agent (especially in the treatment of TB or HIV).

Question 23

Antimicrobial combination

Answer 23

3 possible outcomes

• 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

General rule

• The combination of 2 cidal (kills microbes) drugs or of 2 static (prevents microbial replication) drugs is additive or synergistic.
• The combination of one static and one cidal drug may result in antagonism.

Question 24

Monitoring

Answer 24

• Gentamicin and Vancomycin have a low therapeutic index.The difference between a therapeutic and a toxic dose is small.
• Serum levels should be monitored, the decision to use them influenced by availability or facility to measure the drug.

Question 25

Doses and duration

Answer 25

• Patients with serious infections often require much higher doses,the use of drug combinations may further influence dosage.
• Standard course of therapy (many infections) 7 days

Question 26

2 main reasons for monitoring serum levels

Answer 26

1. To ensure that therapeutic levels have been achieved.Blood or serum levels may not be the same as tissue levels depending upon the ability of the antibiotic to penetrate.
2. To ensure that levels are not so high as to be toxic.

Question 27

Susceptibility testing

Answer 27

Strip test

The simplest way to measure the MIC (Minimum Inhibitory Concentration) of one antibiotic against one organism is with E-test.

A commercially available 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.

Automated methods

Most diagnostic labs use automated methodology

The growth of individual isolates is measured in the presence of different concentrations of each antibiotic and MIC calculated.

Nationally agreed “cut-offs” for MIC values below which an organism is considered “sensitive” and above which it is “resistant”.

In vitro laboratory test gives only a prediction whether the infection is likely to be cured by the antibiotic in question.

Factors influencing the outcome in practice include:

• route of administration, dosing schedule, penetration of antibiotic to
• the target site and interactions with other drugs.
• E test

Question 28

Antifungal drugs

Answer 28

• The majority of antibiotics have no action on fungi and fungal infections
• Fungi may be subdivided into: yeasts and filamentous fungi (moulds)

Question 29

Polyenes

Answer 29

Polyene drugs bind to ergosterol, present in the fungal cell wall but not in the bacterial cell wall, and this results in an increase in the permeability of the cell wall. Active against both yeasts and filamentous fungi.

Question 30

Azoles

Answer 30

• Inhibition of ergosterol synthesis
• Active against both yeasts and filamentous fungi, including Aspergillus spp. and dermatophytes.

Question 31

Allylamines

Answer 31

Suppress ergosterol synthesis, but act at a different stage of the synthetic pathway from azoles

Question 32

Echinocandins

Answer 32

Inhibit the synthesis of glucan polysaccharide in several types of fungi

Question 33

Antiviral drugs

Answer 33

• Antibiotics have no action against virus
• Few viral diseases are treatable
• More serious, potentially fatal, illnesses rather than those that are common and self limiting
• There are no virucidal agents (i.e. those that will kill the virus) but that they are all virustatic (ie, inhibit growth and/or replication)
• Many anti-viral drugs are nucleoside analogues which interfere with nucleic acid synthesis
• A fast changing field and drugs with other mechanisms of action are increasingly available.

Question 34

Anti-herpes virus drugs

Answer 34

• Herpes viruses are a clinically important group
• They are not all equally sensitive to anti-viral agents
• Treatment is most effective if started early, but does not eradicate any of these viruses.

Question 35

Antiviral resistance

Answer 35

Testing viruses for resistance is in its infancy is only available for a few drugs in specialist centres.

Genotypic analysis (i.e., sequencing of part of the viral genome) may help in choosing rational treatment in selected patients (e.g. in HIV infection, where the viral load is rising despite adherence to treatment, or for HSV, VZV or CMV not responding clinically to apparently adequate dosage

Question 36

Antiviral drug levels

Answer 36

This is available for only a few drugs (e.g. some anti-HIV drugs and aciclovir).

Drug monitoring is done to ensure therapeutic,but not toxic, serum levels are achieved.

Question 37

Alteration of penicillin binding protein (PBP) target site

Answer 37

• Micro-organisms develop resistance to β–lactams by changing the structure of their PBPs.
• Mutations in PBP genes result in a modified target site to which β–lactams will no longer bind.
• The best known example of this mechanism is found in Staph. aureus,known as meticillin resistant: Staph. aureus or MRSA.