Brainscape's Knowledge GenomeTM

Browse over 1 million classes created by top students, professors, publishers, and experts.


See full index

Phase 2A > Antibiotics > Flashcards

Antibiotics Flashcards

1
Q

what is the bacterial resistome?

A

pool of genes that determines resistance

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

why did the bacterial resistome originally ecolve?

A
  • to counteract naturally occurring bactericidal compounds encountered in their natural habitats
  • changed to meet challenges posed by modern antibiotic drugs used in the clinic
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

what are the types of antibiotic resistance? what are the basic mechanisms by which resistance is spread?

A
  • innate or acquired
  1. by transfer of resistant bacteria between people
  2. by transfer of resistance genes between bacteria (usually on plasmids)
  3. by transfer of resistance genes between genetic elements within bacteria, on transposons
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

what is the aim of antibiotic stewardship?

A

sensible clinical use of existing medicines and the design of new antibacterial drugs

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

what are some genetic determinants of antibiotic resistance?

A
  • chromosomal determinants: mutations
  • gene amplification
  • extrachromosomal determinants: plasmids
  • transfer of resistance genes between genetic elements within the bacterium
  • transfer of resistance genes between bacteria
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

how can gene amplification lead to antibiotic resistance?

A
  • gene duplication and amplification are important
  • treatment with antibiotics can induce an increased number of copies for pre-existing resistance genes e.g. antibiotic destroying enzymes and efflux pumps
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

what are plasmids?

A
  • extrachromosomal genetic elements that can replicate independently
  • closed loops of DNA that may comprise a single gene or as many as 500 or more
  • often multiple copies are present, and there may be more than one type of plasmid in each bacterial cell
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

what are R plasmids?

A
  • plasmids that carry genes for resistance to antibiotics (r genes)
  • much of drug resistance is plasmid determined
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

what are transposons? how do they work?

A
  • some stretches of DNA are readily transferred (transposed) from one plasmid to another and also from plasmid to chromosome or vice versa
  • integration of segments of DNA (transposons) into the acceptor DNA can occur independently of normal mechanism of homologous genetic recombination
  • not able to replicate independently
  • may carry some resistance genes and hitch hike on a plasmid to a new species of bacterium
  • can integrate into the new host’s chromosome or into its indigenous plasmids
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

what is a gene cassette? what can happen to it?

A
  • resistance gene attached to a small recognition site
  • mobile element
  • multiple cassettes can be packaged together in a multicassette array
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

what is a multicassette array? what can happen to it?

A
  • multiple gene cassettes that are packaged together

- can be integrated into a larger mobile DNA unit called an integron

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

what is an integron? what does it do?

A
  • large mobile DNA unit
  • may be located on a transposon
  • contains a gene for an enzyme, integrase (recombinase)
  • integrase inserts gene cassette at unique sites on the integron
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

what does the transposon/integron/multiresistance cassette array allow?

A
  • rapid and efficient transfer of MDR between genetic elements within and between bacteria
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

what are mechanisms involved in the transfer of resistance genes between bacteria?

A
  • conjugation
  • transduction
  • transformation
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

how can conjugation contribute to antibiotic resistance?

A
  • involves cell-to-cell contact where chromosomal/extrachromosomal DNA is transferred from one bacterium to another
  • main mechanism for spread of resistance
  • ability to conjugate is encoded in conjugative plasmids
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

what are conjugative plasmids? what do they do?

A
  • have the ability to conjugate encoded in them
  • contain transfer genes that, in coliform bacteria, code for production by the host bacterium of proteinaceous surface tubules (sex pili) which connect the two cells
  • conjugative plasmid passes across from one bacterial cell to another
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
17
Q

what are promiscuous plasmids?

A
  • some can cross the species barrier, accepting one host as readily as another
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
18
Q

how can non-conjugative plasmids pass between bacteria?

A

by hitchhiking with conjugative plasmids

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
19
Q

what is transduction? how is it involved in antibiotic resistance?

A
  • process by which plasmid DNA is enclosed in a bacterial virus (phage) and transferred to another bacterium of the same species
  • ineffective means of transfer of genetic material
  • important in the transmission of resistance genes between strains of staphylococci and streptococci
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
20
Q

what is transformation? how does it relate to antibiotic resistance?

A
  • some bacteria can, under natural conditions, undergo transformation by taking up DNA from the environment and incorporating it into the genome by normal homologous recombination
  • probably not of clinical importance
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
21
Q

what are biochemical mechanisms of resistance to antibiotics?

A
  • production of an enzyme that inactivates the drug
  • alteration of drug-sensitive or drug-binding site
  • decreased drug accumulation in the bacterium
  • alteration of enzyme pathways
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
22
Q

what are examples of production of an enzyme inactivating an antibiotic drug?

A
  • inactivation of beta-lactam antibiotics
  • inactivation of chloramphenicol
  • inactivation of aminoglycosides
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
23
Q

how can beta-lactam antibiotics be inactivated?

A
  • beta-lactamases cleave the beta-lactam ring of penicillins and cephalosporins
  • cross resistance between two classes of antibiotic is not complete, as beta-lactamses have preferences for different drugs
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
24
Q

what are the main organisms that produce beta-lactimase?

A

staphylococci

  • transduction of plasmids
  • enzyme is inducible and minute, sub-inhibitory conc. of antibiotics de-repress the gene and lead to 50-80 x increase in expression

Gram-negative organisms

  • coded for by chromosomal or plasmid genes
  • enzyme may remain attached to the cell wall, preventing access of drug to membrane-associated target sites
  • transposons
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
25
Q

what is the action of beta-lactamse?

A
  • passes through the bacterial envelope

- inactivates antibiotic molecules in the surrounding medium

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
26
Q

how was the problem of resistant staphylococci secreting beta-lactamase tackled?

A

developing semisynthetic penicillins (e.g. meticillin) and new beta-lactam antibiotics (monobactams and carbapenems) and cephalosporins (e.g. cephamandole) that are less susceptible to inactivation

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
27
Q

what is MRSA?

A

meticillin-resistance Staphylococcus aureus

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
28
Q

how is chloramphenicol inactivated? how does this lead to antibiotic resistance?

A
  • inactivated by chloramphenicol acetyl-transferase
  • enzyme produced by Gram-positive and negative organisms, the resistant gene being plasmid borne
  • in Gram-negative bacteria, the enzyme is produced constitutively, resulting in levels of resistance 5 x higher than in Gram-positives, where the enzyme is inducible
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
29
Q

how are aminoglycosides inactivated? how does this lead to antibiotic resistance?

A
  • inactivated by phosphorylation, adenylation or acetylation, and enzymes are found in Gram-positive and negative organisms
  • resistance genes are carried on plasmids, and some found on transposons
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
30
Q

what are examples of alteration of drug-sensitive or drug-binding sites leading to antibiotic resistance?

A
  • aminoglycoside binding site on the 30S subunit of the ribosome may be altered by chromosomal mutation
  • plasmid-mediated alteration of the binding site protein on the 50S subunit of a ribosome underlies resistance to erythromycin
  • decreased binding of fluoroquinolones due to point mutation in DNA gyrase A
  • rifampicin resistance due to an altered DNA-dependent RNA polymerise determined by a chromosomal mutation
  • strains of S. aureus resistant to antibiotics that aren’t inactivated by beta-lactamase because they express an additional beta-lactam-binding protein coded for by mutated chromosomal gene
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
31
Q

what are examples of decreased drug accumulation in the bacterium leading to antibiotic resistance?

A
  • plasmid-mediated resistance to tetracyclines in bacteria
  • resistance genes in the plasmid code for inducible proteins in the bacterial membrane, which promote energy-dependent efflux of the tetracyclines, and resistance
  • resistance of S. aureus to erythromycin and other macrolides, and to fluoroquinolones, is by energy dependent efflux
  • plasmin-determined inhibition of porin synthesis can affect hydrophilic antibiotics that enter through proins
  • altered permeability due to chromosomal mutations involving polysaccharide components of the outer membrane of Gram negative bacteria may confer resistance to ampicillin
  • mutations affecting envelope components affect accumulation of aminoglycosides, beta-lactams, chloramphenicol, peptide antibiotics and tetracycline
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
32
Q

what are examples of alteration of enzyme pathways leading to antibiotic resistance? how is trimethoprim and sulfonamide resistance caused?

A
  • resistance to trimethoprim is due to plasmid-directed synthesis of a dihydrofolate reductase with low or zero affinity for trimethoprim; transferred by transduction, may be spread by transposons
  • sulfonamide resistance is plasmid-mediated and is due to dihydropteroate synthetase with low affinity for sulfonamides with no change in affinity for PABA
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
33
Q

what drugs does alteration of drug-binding sites affect?

A
  • aminoglycosides
  • erythromycin
  • penicillin
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
34
Q

what drug does reduction of drug uptake by the bacterium affect?

A

tetracyclines

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
35
Q

how can S. aureus manifest resistance to antibiotics? what is the mechanism for each?

A
  • to beta-lactams (production of beta-lactamase and additional beta-lactam-binding protein that renders them resistant to meticillin)
  • to streptomycin (chromosomally determined alterations of target site)
  • to aminoglycosides (altered target site and plasmid-determined inactivating enzymes)
  • to chloramphenicol and macrolides (plasmid-determined enzymes)
  • to trimethoprim (transposon-encoded drug-resistant dihydrofolate reductase)
  • to sulfonamides (chromosomally determined increased production of PABA)
  • to rifampicin (chromosomally and plasmid determined increases in drug efflux)
  • to fusidic acid (chromosomally determined decreased affinity of target site or plasmid-encoded decreased permeability to drug)
  • to quinolones (chromosomally determined reduced uptake)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
36
Q

how have enterococci developed resistance to vancomycin?

A
  • substitution of D-Ala-D-Ala with D-Ala-D-lactate in the peptide chain attached to N-acetylglucosamine-N-acetylmuramic acid (G-M) during first steps of peptidoglycan synthesis
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
37
Q

what pathogens have developed or are developing resistance to commonly used drugs?

A
  • S. aureus
  • enterococci
  • Psudomonas aeruginosa
  • Streptococcus pyogenes
  • S. pneumoniae
  • N. meningitidis
  • N. gonorrhoeae
  • Haemophilius influenzae
  • H. ducreyi
  • Mycobacterium, Campylobacter and Bacteroides species
  • M. tuberculosis
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
38
Q

what does the cell wall of Gram-negative organisms consist of from the plasma membrane outwards?

A
  • periplasmic space; contains enzymes and other components
  • peptidoglycan layer 2nm thick, linked to outwardly projecting lipoprotein molecules
  • outer membrane consisting of a lipid bilayer, containing protein molecules and lipoproteins linked to the peptidoglycan, and porins
  • complex polysaccharides on outer surface; differ between strains of bacteria and are main determinants of their antigenicity; source of endotoxins, which, when shed in vivo, triggers aspects of the inflammatory reaction by activating complement and cytokines
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
39
Q

why are some antibiotics less active against Gram-negative than Gram-positive bacteria?

A
  • difficulty in penetrating the complex outer layer

- Pseudomonas aeruginosa: can cause life threatening infections in neutropenic patients and those with burns/wounds

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
40
Q

what are examples of antibiotics that Gram-negative cell wall lipopolysaccharide is a barrier to?

A
  • benzylpenicillin
  • meticillin
  • macrolides
  • rifampicin
  • fusidic acid
  • vancomycin
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
41
Q

what are antibacterial agents that interfere with folate synthesis or action?

A

sulfonamides

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
42
Q

what are sulfonamide drugs that are still commonly used as systemic antibacterials? what are their uses?

A
  • sulfamethoxazole (usually combined with trimethoprim as co-trimoxazole
  • sulfasalazine (poorly absorbed in GI tract; used for UC and Crohns, IBD)
  • silver sulfadiazine (used topically for burns)
  • prasugrel (antiplatelet
  • acetazolamide (carbonic anhydrase inhibitor)
  • combined with pyrimethamine for drug-resistant malaria and toxoplasmosis
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
43
Q

what are the typical target organisms of sulfonamides?

A

T. gondii, P. jirovecii

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
44
Q

what is the mechanism of action of sulfonamides?

A
  • sulfanilamide is a structural analogue of p-aminobenzoic acid (PABA), which is an essential precursor in the synthesis of folic acid, required for synthesis of DNA and RNA in bacteria
  • sulfonamides compete with PABA for the enzyme dihydropteroate synthetase, and the effect of sulfonamide can be overcome by adding excess PABA
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
45
Q

what is PABA? what is its function?

A

p-aminobenzoic acid

- essential precursor in synthesis of folic acid, which is required for DNA and RNA synthesis in bacteria

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
46
Q

what do sulfanilamides and sulfonamides compete for?

A
  • competet with PABA for the enzyme dihydropteroate synthetase
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
47
Q

how can the effect of sulfonamide be overcome?

A
  • by adding excess PABA

- some local anaesthetics which are PABA esters can antagonise the antibacterial effect of these agents

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
48
Q

what are examples of bactericidal drugs? what do they do?

A
  • antibiotics that interfere with bacterial cell wall synthesis (e.g. penicillins)
  • antibiotics that inhibit crucial enzymes (e.g. quinolones)

generally kill bacteria

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
49
Q

what are examples of bacteriostatic drugs? what do they do?

A
  • antibiotics that inhibit protein synthesis (e.g. tetracyclines)
  • sulfonamides

prevent growth and replication

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
50
Q

when is sulfonamide action vitiated? what is resistance mediated by?

A
  • in presence of pus or products of tissue breakdown, because these contain thymidine and purines, which bacteria utilise directly
  • this bypasses the requirement for folic acid
  • resistance is plasmid mediated and results from synthesis of bacterial enzyme insensitive to the drugs
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
51
Q

what are pharmacokinetic aspects of sulfonamide?

A
  • given orally
  • well absorbed and widely distributed in the body
  • risk of sensitisation or allergic reactions when drugs are given topically
  • drugs pass into inflammatory exudates and cross placental and BBB
  • metabolised in the liver
  • major product is an acetylated derivative that lacks antibacterial action
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
52
Q

what are unwanted effects of sulfonamides?

A
  • hepatitis
  • hypersensitivity reactions
  • bone marrow depression
  • acute renal failure due to interstitial nephritis or crystalluria
  • cyanosis caused by methaemoglobinaemia
  • nausea, vomiting, headache and mental depression
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
53
Q

what are the components of folic acid?

A
  • pteridine ring
  • PABA
  • glutamic acid
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
54
Q

what is co-trimoxazole?

A

mixture of sulfamethoxazole and trimethoprim

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
55
Q

what is the pathway of DNA synthesis in bacteria from PABA?

A
  1. PABA -> folate (by dihydropteroate synthetase)
  2. folate -> tetrahydrofolate (by dihydrofolate reductase)
  3. tetrahydrofolate -> synthesis of thymidylate etc.
  4. thymidilate -> DNA
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
56
Q

what are the actions of sulfonamides and trimethoprim on bacterial folate/DNA synthesis?

A

sulfonamides: inhibit action of dihydropteroate synthetase (catalyses PABA -> folate)
trimethoprim: inhibit action of dihydrofolate reductase (catalyses folate -> tetrahydrofolate)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
57
Q

what is the mechanism of action of trimethoprim?

A
  • bacteriostatic
  • folate antagonist: resemble pteridine moiety of folate
  • used to treat various urinary, pulmonary and other infections
  • may be given as a mixture with sulamethoxazole as co-trimoxazole
  • sulfonamides can potentiate the action of trimethoprim
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
58
Q

what is the use of co-trimoxazole restricted to in the UK?

A
  • Pneumocystis carinii (P. jirovecii)
  • pneumonia (fungal)
  • toxoplasmosis (protozoan)
  • nocardiasis (bacterial)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
59
Q

what are the pharmacokinetic aspects of trimethaprim?

A
  • well absorbed orally
  • widely distributed throughout the tissues and body fluids
  • reaches high conc. in lungs and kidneys, and CSF
  • when given as co-trimoxazole, half the dose of each is excreted within 24h
  • weak base; elimination by the kidney increases with decreasing urinary pH
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
60
Q

what are unwanted effects of trimethaprim?

A
  • folate deficiency with megaloblastic anaemia due to long-term administration
  • nausea, vomiting, blood disorders and rashes
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
61
Q

what are pyrimethamine and proguanil used for?

A

antimalarial agents

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
62
Q

what are penicillins? what can they be destroyed by?

A
  • beta-lactam antibiotics

- can be destroyed by bacterial amidases and beta-lactamases

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
63
Q

what is the mechanism of action of penicillins?

A
  • interfere with synthesis of the bacterial cell wall peptidoglycan
  • after attachment to penicillin-binding proteins on bacteria, they inhibit the transpeptidation enzyme that crosslinks the peptide chains attached to the backbone of peptidoglycan
  • inactivation of an inhibitor of autolytic enzymes in the cell wall, leading to lysis of the bacterium
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
64
Q

what are some uses of penicillins?

A
  • bacterial meningitis; benzylpenicillin, high doses IV
  • bone and joint infections; flucoxacillin
  • skin and soft tissue infections; benzylpenicillin, flucloxacillin; animal bites; coamoxiclav
  • pharyngitis; phenoxylmethylpenicillin
  • otitis media; amoxicillin
  • UTIs; amoxicillin
  • gonorrhea; amoxicillin and probenecid
  • syphillis; procaine benzylpenicillin
  • endocarditis; high dose IV benzylpenicillin
  • serious Pseudomonas aeuginosa infections; ticarcillin, piperacillin
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
65
Q

what are the types of penicillin?

A
  • naturally occuring
  • semisynthetic penicillins: beta-lactamase-resistant penicillins and broad spectrum penicillins
  • extended spectrum penicillins
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
66
Q

what are features of benzylpenicillin?

A
  • active against a wide range of organisms and is drug of first choice for many infections
  • main drawbacks are poor absorption in the GI tract and its susceptibility to bacterial beta-lactamases
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
67
Q

what are examples of beta-lactamase-resistant penicillins? what is their administration and spectrum?

A

meticillin, flucoxacillin, temocillin

  • action: given orally
  • spectrum: Gram positive and Gram negative cocci and some Gram-negative bacteria
  • many staphylococci are now resistant
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
68
Q

what are examples of broad spectrum penicillins? what is their administration and spectrum?

A

ampicillin and amoxicillin

  • administration: given orally, destroyed by beta-lactamases
  • spectrum: Gram positive and Gram negative cocci and some Gram-negative bacteria and active against Gram-negative bacteria
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
69
Q

what are examples of extended spectrum penicillins? what are their actions and spectrum?

A
  • ticarcillin
  • piperacillin
    given orally; susceptible to beta-lactamases
    spectrum: Gram positive and Gram negative cocci and some Gram-negative bacteria and active against Gram-negative bacteria; also active against pseudomonads
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
70
Q

what are amoxicillin and ticarcillin sometimes given in combination with?

A
  • beta-lactamase inhibitor clavulanic acid (e.g. co-amoxiclav)
  • effective against many beta-lactamase-producing organisms
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
71
Q

what is pivmecillinam?

A

prodrug of mecillinam, which has a wide spectrum of action

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
72
Q

what are pharmacokinetic aspects of penicillin?

A
  • oral absorption of penicillins varies, depending on stability in acid and their adsorption to foodstuffs in the gut
  • can be given by IV injection
  • intramuscular injection
  • slow release preparations e.g. benzathine benzylpenicillin for syphillis as Treponema pallidum is a slowly dividing organism
  • penicillins are widely distributed in body fluids, passing into joints, pleural and pericardial cavities, into bile, saliva and milk and across the placenta
  • lipid insoluble; do not enter mammalian cells and cross BBB only if meninges are inflamed
  • elimination of most penicillins occurs rapidly and is mainly renal; 90% through tubular secretion
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
73
Q

what are some unwanted effects of penicillins?

A
  • free from direct toxic effects (other than proconvulsant effect when given intrathecally)
  • hypersensitivity reactions caused by degradation products which combine with host protein and become antigenic
  • skin rashes and fever
  • delayed type of serum sickness occurs infrequently
  • anaphylactic shock
  • alter bacterial flora in the gut; associated with GI disturbances and suprainfection
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
74
Q

what are cephalosporins and cephamycins?

A
  • beta-lactam antibiotics
  • first isolated from fungi
  • same mechanism of action as penicillins
  • second choice for many infections
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
75
Q

what are semisynthetic broad-spectrum cephalosporins? how are they produced? what are features of them?

A
  • by addition to the cephalosporin C nucleus, of different side chains at R1 and/or R2
  • water soluble and relatively acid stable
  • vary in susceptibility to beta-lactamases
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
76
Q

why has resistance to cephalosporins and cephamycins increased?

A

due to plasmid-encoded or chromosomal beta-lactamase

  • chromosomal beta-lactamase is present in nearly all Gram-negative bacteria and is more active in hydrolysing cephalosporins than penicillins
  • in several organisms a single mutation can result in high-level constitutive production of this enzyme
  • resistance occurs when there is decreased penetration of the drug due to alteration of outer membrane proteins, or mutations of binding-site proteins
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
77
Q

what are clinical uses of cephalosporins?

A

used to treat infections caused by sensitive organisms; patterns of sensitivity vary geographically and treatment is started empirically

  • septicaemia (e.g. cefuroxime, cefotaxime)
  • pneumonia caused by susceptible organisms
  • meningitis (e.g. ceftriaxone, cefotaxime)
  • biliary tract infection
  • UTI
  • sinusitis (e.g. cefadroxil)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
78
Q

what are pharmacokinetic aspects of cephalosporins and cephamycins?

A
  • some cephalosporins are given orally
  • most given parenterally, intramuscularly or IV
  • after absorption, they’re widely distributed in the body and some cross the BBB
  • excretion is mostly via the kidney, largely by tubular secretion
  • 40% of ceftriaxone is eliminated in the bile
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
79
Q

what are examples of cephalosporins that cross the BBB?

A

cefotaxime, cefuroxime and ceftriaxone

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
80
Q

what are some unwanted effects of cephalosporins and cephamycins?

A
  • hypersensitivity reactions and cross sensitivity
  • nephrotoxicity
  • drug-induced alcohol intolerance
  • diarrhoea is common; can be due to C. difficile
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
81
Q

a lady has streptococcal pharyngitis. what should be prescribed?

A

penicillin 500mg QDS, 10 days

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
82
Q

what is an antimicrobial?

A
  • agents produced by microorganisms that kill or inhibit the growth of other microorganisms in high dilution
  • produced by microorganism
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
83
Q

what are target points on a bacteria?

A

points of biochemical reaction crucial to the survival of the bacterium

  • penicillin-binding proteins in cell wall
  • cell membrane
  • DNA
  • ribosomes
  • topoisomerase IV or DNA gyrase
  • crucial binding site will vary with antibiotic class
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
84
Q

what is an antibiotic?

A
  • agents produced by microorganisms that kill oro inhibit the growth of other microorganisms in high dilution
  • molecules that work by binding a target site on a bacteria
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
85
Q

what are different mechanisms of antibiotic action?

A
  • cell wall synthesis
  • nucleic acid synthesis
  • protein synthesis
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
86
Q

what are examples of other beta-lactam antibiotics? what are they used for?

A
  • cabapenems and monobactams

- used to deal with beta-lactamase-producing Gram-negative organisms resistant to penicillins

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
87
Q

what are carbeapenems?

A
  • e.g. imipenem
  • used for beta-lactamase-producing Gram-negative organisms resistant to penicillins
  • broad spectrum of antimicrobial activity, being active against many aerobic and anaerobic Gram-positive and Gram-negative organisms
  • resistance to imipenem was low, and is increasing as some organisms have chromosomal genes that code for imipenem-hydrolysing beta-lactamases
  • e.g. meropenem (not metabolised by the kidney) and ertapenem
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
88
Q

what are unwanted effects of carbapenems?

A
  • nausea and vomiting

- neurotoxicity

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
89
Q

what are monobactams?

A
  • used for beta-lactamase-producing Gram-negative organisms resistant to penicillins
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
90
Q

what is an example of monobactams? what do they act on?

A
  • aztreonam
  • resistant to most beta-lactamses
  • given by injection and has a plasma half-life of 2 hours
  • unusual spectrum of activity and is effective only against Gram-negative aerobic bacilli e.g. pseudomonas species, Neisseria meningitidis and Haemophilus influenzae
  • no action against Gram-positive organisms or anaerobes
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
91
Q

what are some unwanted effects of monobactams?

A
  • similar to those of other beta-lactam antibiotics
  • doesn’t necessarily cross-react immunologically with penicillin and its products so does not usually cause allergic reactions in penicillin sensitive individuals
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
92
Q

what are examples of glycopeptides?

A
  • vancomycin (glycopeptide antibiotic)

- teicoplanin (longer lasting)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
93
Q

what is the mechanism of action of glycopeptides?

A
  • beta-lactam antibiotics: interfere with the synthesis of the bacterial cell wall peptidoglycan
  • vancomycin inhibits cell wall synthesis
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
94
Q

what does vancomycin work against? what are pharmacokinetic aspects?

A
  • inhibits cell wall synthesis
  • effective mainly against Gram-positive bacteria
  • not absorbed from the gut and is only given by oral route for treatment of GI infection with C. difficile
  • for systemic use, it’s given IV and has a plasma half life of 8 h
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
95
Q

what are some clinical uses of vancomycin?

A
  • treatment of MRSA (often last resort) and other serious infections
  • used in severe staphylococcal infections in patients allergic to penicillins and cephalosporins
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
96
Q

what are some unwanted effects of glycopeptides?

A
  • fever, rashes and local phlebitis at the site of injection

- ototoxicity, nephrotoxicity and hypersensitivity reactions may occur

97
Q

what is daptomycin?

A

a new lipopeptide antibacterial (glycopeptide) with similar spectrum of actions to vancomycin
- usually used, with other drugs, to treat MRSA

98
Q

what are antimicrobial agents affecting bacterial protein synthesis?

A
  • tetracyclines
  • chloramphenicol
  • aminoglycosides
  • macrolides
99
Q

what are examples of tetracyclines?

A
  • tetracycline
  • oxytetracycline
  • democlocycline
  • lymecycline
  • doxycycline
  • minocycline
  • tigecycline
100
Q

what is the action of beta-lactam antibiotics?

A

bactericidal because they inhibit peptidoglycan synthesis

101
Q

what are examples of beta-lactam antibiotics?

A
  • penicillins
  • cephalosporins and cephamycins
  • carbapenems
  • monobactams
  • benzylpenicillin
  • flucloxacillin
  • amoxicillin
  • amoxicillin-clavulanate
  • piperacillin-tazobactam
  • merepenem
  • cephalexin
  • cefuroxime
  • ceftriaxone
  • cefotaxime
102
Q

what are administration types of cephalosporins and cephamycins?

A
  • oral drugs (e.g. cefaclor) used in urinary infections

- parenteral drugs (e.g. cefuroxime, which is active against S. aureus, H. influenzae, enterobacteriaceae)

103
Q

what can imipenem be used with?

A

cilastin, which prevents its breakdown in the kidney

104
Q

what are polymixins? what is an example?

A
  • micellaneous antibacterial agents that prevent cell wall or membrane synthesis
  • e.g. colistimethate
  • bactericidal, act by disrupting bacterial cell membranes
  • highly neurotoxic and nephrotoxic, only used topically
105
Q

what is the mechanism of action of tetracycline?

A
  • following uptake into susceptible organisms by active transport, tetracyclines act by inhibiting protein synthesis
  • regarded as bacteriostatic, not bactericidal
106
Q

what is the antibacterial spectrum of tetracyclines?

A
  • very wide
  • includes Gram-positive and Gram-negative bacteria, Mycoplasma, Rickettsia, Chlamydia spp., spirochaetes and some protozoa
107
Q

what is the use of minocycline?

A
  • effective against N. meningitidis
  • used to eradicate this organism from the nasopharynx
  • widespread resistance to these agents has decreased their usefulness
108
Q

how is resistance transmitted in tetracyclines?

A
  • by plasmids

- organisms may develop resistance to other antibiotics simultaneously

109
Q

what are clinical uses of tetracyclines?

A
  • doxycycline is given once daily and may be used in renal impairment
  • rickettsial and chlamydial infections, brucellosis, anthrax and Lyme disease
  • second choice for patients with allergies, for infections including mycoplasma and leptospira
  • respiratory tract infections
  • acne
  • inappropriate secretion of ADH causing hyponatraemia
110
Q

what is the effect of demeclocycline?

A

inhibits the action of ADH by an entirely distinct action from its antibacterial effect

111
Q

what are pharmacokinetic aspects of tetracyclines?

A
  • generally given orally; can be given parenterally
  • minocycline and doxycycline are well absorbed orally
  • absorption of most other tetracyclines is irregular and incomplete but is improved in absence of food
  • tetracyclines chelate metal ions (calcium, magnesium, iron, aluminum), forming non-absorbable complexes; absorption is decreased in milk, antacids and iron preparations
112
Q

what are unwanted effects of tetracyclines?

A
  • GI disturbances caused by direct irritation and later by modification of gut flora
  • vitamin B complex deficiency
  • suprainfection
  • deposited in growing bones and teeth, causing staining and dental hypoplasia/bone deformities (because they chelate Ca2+)
  • hepatoxicity
  • phototoxicity (demeclocycline)
  • vestibular disturbances (minocycline)
  • decreased protein synthesis in host cells (antianabolic effect that may cause renal damage)
  • long term therapy can cause disturbances of the bone marrow
113
Q

what is the action of chloramphenicol? what was it isolated from?

A
  • isolated from cultures of Streptomyces

- inhibits bacterial protein synthesis by binding to the 50S ribosomal subunit

114
Q

what is the antibacterial spectrum for chloramphenicol?

A
  • wide spectrum of antimicrobial activity
  • Gram-negative and Gram-positive organisms and richettsiae
  • bacteriostatic for most organisms but kills H. influenzae
115
Q

what is resistance to chloramphenicol caused by?

A
  • production of chloramphenicol acetyltransferase

- plasma-mediated

116
Q

what are the clinical uses of chloramphenicol?

A

systemic use should be reserved for serious infections where the benefit of the drug outweighs its uncommon but serious haematological toxicity:

  • infections caused by Haemophilus influenzae resistant to other drugs
  • meningitis in patients in whom penicillin cannot be used
  • typhoid fever

topical use safe and effective in bacterial conjunctivitis

117
Q

what are pharmacokinetic aspects of chloramphenicol?

A
  • given orally, it’s rapidly and completely absorbed and reaches its maximum conc. in plasma within 2hrs
  • parenterally
  • widely distributed through tissues and bodily fluids including CSF
  • half life is 2 hours
  • 10% is excreted unchanged in the urine, and remainder is inactivated in the liver
118
Q

what are unwanted effects of chloramphenicol?

A
  • severe, idiosyncratic depression of bone marrow, resulting in pancytopenia (rare, but can occur with low doses)
  • used with care with newborns, with monitoring of plasma concentrations
  • inadequate inactivation and excretion can cause grey baby syndrome - vomiting, diarrhoea, flaccidity, low temp, ashen grey colour (40% mortality)
  • hypersensitivity reactions
  • GI disturbances secondary to alteration of the intestinal microbial flora
119
Q

what is pancytopenia?

A

decrease in all blood cell elements

120
Q

what are the main aminoglycosides?

A
  • gentamicin
  • streptomycin
  • amikacin
  • tobramycin
  • neomycin
121
Q

what is the mechanism of action of aminoglycosides?

A
  • inhibit bacterial protein synthesis
  • several sites of action
  • penetration through cell membrane depends on oxygen-dependent active transport by a polyamine carrier system (blocked by chloramphenicol)
  • minimal action against anaerobic organisms
  • bactericidal
  • enhanced by agents that interfere with cell wall synthesis
122
Q

what is the resistance to aminoglycosides? how can it be overcome?

A
  • occurs through several mechanisms
  • e.g. inactivation by microbial enzymes (9 or more are known)
  • amikacin was designed as a poor substrate for these enzymes, but some organisms can inactivate this agent too
  • resistance due to failure of penetration can be overcome by concomitant use of penicillin/vancomycin, at cost of increased risk of ADRs
123
Q

what is the antibacterial spectrum of aminoglycosides?

A
  • effective against aerobic Gram-negative and some Gram-positive organisms
  • widely used against Gram-negative enteric organisms and in sepsis
  • given together with penicillin in streptococcal infections and those caused by Listeria spp. and P. aeruginosa
  • gentamicin most commonly used
  • tobramycin is preferred for P. aeruginosa infections
  • amikacin has widest antimicrobial spectrum
124
Q

what are pharmacokinetic aspects of aminoglycosides?

A
  • polycations; highly polar
  • not absorbed from GI tract
  • given IM or IV
  • cross placenta, not BBB
  • high concs. in joint and pleural fluids
  • plasma half life is 2-3hrs
  • eliminaion is entirely by glomerular filtration in kidney; 50-60% is excreted unchanged within 24hrs
  • imparied renal function -> rapid accumulation -> increased toxic effects
125
Q

what are some unwanted effects of aminoglycosides?

A
  • serious dose-related toxic effects (ototoxicity and nephrotoxicity)
  • paralysis caused by neuromuscular blockade; usually only seen if the agents are given concurrently with neuromuscular blocking agents; results from inhibition of Ca2+ uptake necessary for exocytic release of acetylcholine
126
Q

what are features of ototoxicity caused by aminoglycosides?

A
  • ototoxicity: progressive damage to and eventually destruction of sensory cells in the cochlea and vestibular organ of the ear
  • ototoxicity is usually irreversible; manifests as vertigo, ataxia, loss of balance and auditory disturbances or deafness in cochlear damage
  • potentiated by concomitant use of other ototoxic drugs
  • susceptibility genetically determined by mitochondrial DNA
127
Q

what aminoglycosides are most likely to interfere with vestibular function?

A

streptomycin and gentamycin

128
Q

what aminoglycosides are most likely to interfere with hearing function?

A

neomycin and amikacin

129
Q

what are features of nephrotoxicity caused by aminoglycosides?

A
  • damage to kidney tubules
  • may necessitate dialysis; function usually recovers when administration ceases
  • more likely to occur in patients with preexisting renal disease or in conditions where urine volume is reduced
  • concomitant use of other nephrotoxic agents increases the risk
  • elimination of these drugs i almost entirely renal; nephrotoxic action can impair their own excretion and vicious cycle may develop
130
Q

what are macrolides? what is the main macrolide and related antibiotics?

A

a many-membered lactone ring to which one or more deoxy sugars are attached

  • erythromycin
  • clarithromycin
  • azithromycin
  • spiramcyin
  • telithromycin
131
Q

what is the mechanism of action of macrolides?

A
  • inhibit bacterial protein synthesis by an effect on ribosomal translocation
  • drugs bind to same 50S subunit of bacterial ribosome as chloramphenicol and clindamycin; any of these drugs may compete if given concurrently
132
Q

what is the antimicrobial spectrum of erythromycin?

A
  • erythromycin: similar to penicillin; safe and effective alternative for penicillin sensitive patients
  • erythromycin is effective against Gram-positive bacteria and spirochaetes, not against most Gram-negative organisms except N. gonorrhoeae and H. influenzae
  • Mycoplasma pneumoniae , Legionella spp. and chlamydial organisms are susceptible
133
Q

what is resistance to erythromycin caused by?

A

plasmid-controlled alteration of the binding site for erythromycin on the bacterial ribosome

134
Q

what is the antimicrobial spectrum of azithromycin?

A
  • less active than erythromycin against Gram-positive bacteria
  • more effective against H. influenzae and may be more active against Legionella
  • used to treat Toxoplasma gondii; kills the cysts
  • Lyme disease
135
Q

what is the antimicrobial spectrum of larithromycin?

A
  • as active, and its metabolite is twice as active, against H. influenzae as erythromycin
  • effective against Mycobacterium avium-intracellulare
  • may affect leprosy and Helicobacter pylori
  • effective in Lyme disease
136
Q

what are pharmacokinetic aspects of macrolides?

A
  • administered orally or parentally, or IV injections
  • diffuse readily into most tissues
  • don’t cross the BBB, poor penetration into synovial fluid
  • plasma half life of erythromycin is 90 min; clarithromycin’s is 3 x longer; azithromycin is 8-16 times longer
  • enter and are concentrated within phagocytes
  • enhance intracellular killing of bacteria by phagocytes
  • erythromycin is partly inactivated in the liver; azithromycin is more resistant to inactivation; clarithromycin is converted to an active metabolite
  • inhibition of the P450 cytochrome system by these agents can affect bioavailability of other drugs
  • main route of excretion is in the bile
137
Q

what are some unwanted effects of macrolides?

A
  • GI disturbances
  • erythromycin: hypersensitivity reactions, transient hearing disturbances and cholestatic jaundice
  • opportunistic infections of the GI tract or vagina can occur
138
Q

what are some antimicrobial agents that affect topoisomerase?

A
  • quinolones
139
Q

what are quinolones? what is their mechanism of actions? what are some examples?

A
  • most are fluorinated
  • inhibit topoisomerase II (bacterial DNA gyrase), which produces a negative supercoil in DNA and thus permits transcription or replication
  • e.g. ciprofloxacin, levofloxacin, ofloxacin, norfolxacin and moxifloxacin and nalidixic acid
140
Q

what is the antibacterial spectrum of quinolones (e.g. cirpofloxacin)?

A

ciprofloxacin

  • broad-spectrum
  • effective against Gram-positive and Gram-negative organisms, including Enterobacteriacae
  • effective against organisms resistant to penicillins, cephalosporins and aminoglycosides, H. influenzae, penicillinase-producing N. gonorrhoeae, Campylobacter spp and pseudomonads
  • weakly inhibits streptococci and pneumococci
141
Q

when should ciprofloxacin use be avoided?

A

in MRSA infections

142
Q

what are clinical uses of fluoroquinolones?

A
  • best reserved for infections with facultative and aerobic Gram-negative bacilli and cocci
  • resistant strains of S. aureus and P. aeruginosa have emerged
  • complicated UTIs (norfloxacin, oxflacin)
  • P. aeruginosa respiratory infections in patients with CF
  • invasive external otitis caused by P. aeurginosa
  • chronic Gram-negative bacillary osteomyelitis
  • eradication of Salmonella typhi in carriers
  • gonorrhoea (norfloxacin, ofloxacin)
  • bacterial prostatitis (norfloxacon)
  • cervicitis (ofloxacin)
  • anthrax
143
Q

what are lincosamides?

A
  • antimicrobial agent affecting bacterial protein synthesis
  • e.g. clindamycin
  • can be given orally and parenterally
  • can cause pseudomembranous colitis
144
Q

what are streptogramins?

A
  • antimicrobial agent affecting bacterial protein synthesis
  • e.g. quinupristin/dalfopristin
  • given by IV infusion as a combination
  • less active when administered separately
  • active against several strains of drug-resistant bacteria
145
Q

what is fusidic acid?

A
  • antimicrobial agent affecting bacterial protein synthesis
  • narrow-spectrum antibiotic that acts by inhibiting protein synthesis
  • penetrates bone
  • unwanted effects including GI disorders
146
Q

what is linezolid?

A
  • antimicrobial agent affecting bacterial protein synthesis
  • given orally or by IV injection
  • active against several strains of drug resistant bacteria
147
Q

what is the action of DNA gyrase (topoisomerase II)?

A
  • unwinds the RNA-induced positive supercoil and introduces a negative supercoil
148
Q

what are pharmacokinetic aspects of quinolones?

A
  • fluoroquinolones are wel absorbed orally
  • accumulate in several tissues, esp. the kidney, prostate and lung
  • all concentrated in phagocytes
  • most fail to cross the BBB, but ofloxacin can
  • aluminium and magnesium antacids interfere with their absorption
  • elimination of ciprofloxacin and norfloxacin is by hepatic P450 enzymes and renal excretion
  • ofloxacin is excreted in the urine
149
Q

what are some unwanted effects of quinolones?

A
  • infection with C. difficile
  • GI disorders and skin rashes
  • arthropathy in young people
  • CNS symptoms/disturbances
  • moxifloxacin prolongs the QT interval and is used extensively
150
Q

what is a clinically important interaction of ciprofloxacin?

A
  • with theophylline
  • through inhibition of P450 enzymes
  • leads to theophylline toxicity in asthmatics treated with fluoroquinolones
151
Q

what are some examples of miscellaneous and less common antibacterial agents?

A
  • metronidazole
  • streptogramins
  • clindamycin
  • oxazolidinones
  • fusidic acid
  • nitrofurantoin
  • polymixins
152
Q

what are features of metonidazole?

A
  • indroduced as an antiprotozoal agent
  • active against anaeobic bacteria e.g. Bacteroides, Clostridia spp. and some streptococci
  • effective in therapy for pseudomembranous colitis and in treatment of serious anaerobic infections
  • disulfiram-like action, so patients must avoid alcohol
153
Q

what are features of streptogramins? what is their mechanism of action, antibacterial spectrum, uses, pharmacokinetic aspects and unwanted effects?

A
  • e.g. quinupristin and dalfopristin
  • cyclic peptides, which inhibit bacterial protein synthesis by binding to the 50S subunit of the bacterial ribosome
  • dalfopristin changes the structure of the ribosome to promote binding of quinupristin
  • bacteriostatic activity
  • combined together as an IV injection, they’re active against Gram-positive bacteria
  • serious infections, where other antibiotics are unsuitable
  • extensive first-pass hepatic metabolism
  • half life is 1-2 hrs
  • unwanted effects: inflammation and pain at infusion site, athralgia, myalgia and nausea, vomiting and diarrhoea
  • resistance not a major problem
154
Q

what is clindamycin? what is it used for? what are some unwanted effects?

A
  • lincosamide
  • active against Gram-positive cocci, including penicillin-resistant staphylococci and anaerobic bacteria e.g. Bacteroides
  • acts in same way as macrolides and chloramphenicol
  • used to treat Bacteroides and staphylococcal infections
  • given topically as eye drops for staphylococcal conjunctivitis
  • used as an anti-protozoal drug
  • unwanted effects: GI disturbances, caused by C. difficile; ranging from diarrhoea to lethal pseudomembranous colitis
155
Q

what are oxazolidinones? what is their mechanism of action?

A
  • inhibit bacterial protein synthesis by inhibition of N-formylmethionyl-tRNA binding to the 70S ribosome
  • e.g. linezolid
156
Q

what is the antibacterial spectrum of oxazolidinones?

A
  • active against a wide variety of Gram-positive bacteria
  • used for treatment of drug resistant MRSA, penicillin resistant S. pneumoniae adn VREs
  • anaerobes e.g. C. difficile
  • most common Gram-negative organisms are not susceptible to the drug
  • linezolid can be used to treat pneumonia, septicaemia and skin/soft tissue infections
157
Q

what is oxazolidinone use restricted to?

A
  • serious bacterial infections where other antibiotics have failed
  • few reports of resistance
158
Q

what are unwanted effects of oxazolidinones?

A
  • thrombocytopenia
  • diarrhoea
  • nausea
  • rash and dizziness
    linezolid is a non-selective inhibitor of monoamine oxidase; precautions should be observed
159
Q

what is fusidic acid? what is its mechanism of action?

A
  • narrow-spectrum steroid antibiotic
  • active mainly against Gram-positive bacteria
  • acts by inhibiting bacterial protein synthesis
160
Q

what are pharmacokinetic aspects of fusidic acid? what are its uses?

A
  • well absorbed from the gut
  • distributed widely in the tissues
  • some excreted in the bile and some metabolised
  • used in combination with other antistaphylococcal agents in staphylococcal sepsis, widely used topically for staphylococcal infections
161
Q

what are unwanted effects of fusidic acid?

A
  • GI disturbances
  • skin eruptions and jaundice
  • resistance occurs if used systemically as a single agent so it’s always combined with other antibacterial drugs when used systemically
162
Q

what is nitrofurantoin? what is its mechanism of action?

A
  • synthetic compound active against a range of Gram-positive and Gram-negative organisms
  • developement of resistance in susceptible organisms is rare, and there is no cross-resistance
  • mechanism of action is probably related to its ability to damage bacterial DNA
163
Q

what are the pharmacokinetic aspects of nitrofurantoin?

A
  • given orally
  • rapidly and totally absorbed from the GI tract
  • rapidly excreted by the kidney
164
Q

what is the use of nitrofurantoin restricted to?

A

UTIs

165
Q

what are some unwanted effects of nitrofurantoin?

A
  • GI disturbances
  • hypersensitivity reactions involving the skin and the bone marrow
  • hepatotoxicity and peripheral neuropathy
166
Q

what are polymixins? what is their mechanism of action? what are their pharmacokinetic aspects and uses? what are some unwanted effects?

A
  • antibiotics
  • e.g. polymixin B and colistimethate
  • cationic detergent properties; disrupt the bacterial outer cell membrane
  • selective, rapidly bactericidal action on Gram-negative bacilli, esp. pseudomonads and coliform organisms
  • not absorbed from the GI tract
  • unwanted effects: neurotoxicity and nephrotoxicity
167
Q

what is clinical use of polymixins restricted to?

A
  • limited by their toxicity

- confined to gut sterilisation and topical treatment of ear, eye or skin infections caused by susceptible organisms

168
Q

what are first-line drugs against TB?

A
  • isoniazid
  • rifampicin
  • rifabutin
  • ethambutol
  • pyrazinamide
169
Q

what are second-line drugs against TB?

A
  • capreomycin
  • cycloserine
  • streptomycin
  • clarithromycin
  • ciprofloxacin
170
Q

what does combination drug therapy for TB involve?

A
  • initial phase of treatment (about 2 months) with a combination of isoniazid, rifampicin and pyrazinamide (and ethambutol if organism may be resistant)
  • second continuation phase (about 4 months) of therapy, with isoniazid and rifampicin; longer term treatment needed for patients with meningitis, bone/joint involvement or drug-resistant infection
171
Q

what is isoniazid? what is its mechanism of action?

A
  • its antibacterial activity is limited to mycobacteria
  • bacteriostatic, but can kill dividing bacteria
  • passes freely into mammalian cells and is effective against intracellular organimss
  • prodrug that must be activated by bacterial enzymes before it can exert its inhibitory activity on the synthesis of mycolic acids
  • resistance may be present, but cross-resistance doesn’t occur
172
Q

what are pharmacokinetic aspects of isoniazid?

A
  • readily absorbed into GI tract
  • widely distributed throughout tissues and body fluids, including CSF
  • penetrates well into caseous tuberculous lesions
  • metabolism depends on genetic factors determining if the person is a slow or rapid acetylator of the drug
  • half-life in slow inactivators is 3hrs and in rapid inactivators, 1h
  • excreted in the urine partly as unchanged drug and partly in acetylated/inactivated form
173
Q

what are some unwanted effects of isoniazid?

A
  • depend on dosage and occur in 5%, commonest being allergic skin eruption
  • fever, hepatotoxicity, haematological changes, arthritic symptoms and vasculitis
  • adverse reactions involving central or peripheral nervous systems are due to pyridoxine deficiency and are common in malnourished patients
  • haemolytic anaemia in people with glucose-6-phosphate dehydrogenase deficiency
  • decreases metabolism of antiepileptic agents phenytoin, ethosuximide and carbamazepine
174
Q

what is rifampicin? what is its mechanism of action? what can cause resistance?

A
  • antibiotic used to treat TB
  • acts by binding to and inhibiting DNA-dependent RNA polymerase in prokaryotic but not eukaryotic cells
  • effective against leprosy and most Gram-positive bacteria and Gram-negative species
  • enters phagocytic cells and can kill intracellular microogranisms including tubercle bacillus
  • resistance can be due to a chromosomal mutation changing its target site on microbial DNA-dependent RNA polymerase
175
Q

what are the pharmacokinetic aspects of rifampicin?

A
  • given orally
  • widely distributed in the tissues and body fluids (including CSF)
  • gives an orange tinge to saliva, sputum, tears and sweat
  • excreted partly in urine and in bile, some of it undergoing enterohepatic cycling
  • metabolite retains antibacterial activity but is less well absorbed from the GI tract
  • half life is 1-5hrs
176
Q

what are unwanted effects of rifampicin?

A
  • skin eruptions, fever and GI disturbances
  • liver damage with jaundice has been reported in a small proportion of patients
  • induction of hepatic metabolising enzymes, leading to increase in degradation of warfarin, glucocorticoids, narcotic analgesics, oral antidiabetic drugs, dapsone and oestrogens
177
Q

what is the mechanism of action of ethambutol? how does resistance arise?

A
  • no effect on organisms other than mycobacteria
  • taken up by bacteria and exerts a bacteriostatic effect after 24hrs
  • inhibits mycobacterial cell wall synthesis
  • resistance emerges rapidly if drug is used alone
178
Q

what are pharmacokinetic aspects of ethambutol?

A
  • given orally
  • well absorbed
  • can reach therapeutic concentrations in the CSF in TB meningitis
  • in blood, it’s taken up by erythrocytes and slowly released
  • ethambutol is partly metabolised and excreted in the urine
179
Q

what are unwanted effects of ethambutol?

A
  • uncommon
  • optic neuritis: dose-related and more likely to occur if renal function is decreased
  • results in visual disturbances manifesting initially as red-green colour blindness, progressing to decreased visual acuity
180
Q

what is pyrazinamide? what is its mechanism of action? how does resistance occur?

A
  • inactive at neutral pH but tuberculostatic at acid pH
  • first line drug for TB
  • effective against intracellular organisms in macrophages because they’re contained in phagolysosomes where pH is low
  • inhibits bacterial fatty acid synthesis
  • resistance develops readily, but cross resistance with isoniazid doesn’t occur
181
Q

what are pharmacokinetic aspects of pyrazinamide?

A
  • gout; associated with high conc. of plasma urates
  • GI upsets, malaise and fever
  • serious hepatic damage due to high doses
182
Q

what are features of capreomycin?

A
  • peptide antibiotic
  • second line drug for TB
  • given by IM injection
  • unwanted effects: kidney damage and injury to auditory nerve, with consequent deafness and ataxia
  • shouldn’t be given at same time as streptomycin or other drugs that may cause deafness
183
Q

what are features of cycloserine?

A
  • broad spectrum antibiotic that inhibits growth of many bacteria, including coliforms and mycobacteria
  • water soluble and destroyed at acid pH
  • competetively inhibits bacterial cell wall synthesis: prevents formation of D-alanine and the D-Ala-D-Ala dipeptide that’s added to the initial tripeptide side chain on N-acetylmuramic acid
  • absorbed orally and distributed throughout tissues and body fluids, including CSF
  • most of the drug is eliminated in active form in the urine, 35% is metabolised
  • unwanted effects: CNS disturbances; limited to TB that’s resistant to other drugs
184
Q

what drugs are given to treat tuberculoid leprosy?

A

dapsone and rifampicin

185
Q

what is dapsone? what is its mechanism of action? how does resistance occur?

A
  • used to treat TB leprosy
  • chemically related to sulfonamides
  • action is antagonised by PABA
  • acts through inhibition of bacterial folate synthesis
  • resistance has increased, and treatment in combination to other drugs is recommended
186
Q

what are pharmacokinetic aspects of dapsone?

A
  • given orally
  • well absorbed and widely distributed through body water and tissues
  • plasma half life is 24-48hrs
  • some drug persists in liver and kidneys
  • enterohepatic recycling
  • some is acetylated and excreted in the urine
187
Q

what are unwanted effects of dapsone?

A
  • frequent
  • haemolysis of red cells, methaemoglobinaemia, anorexia, nausea and vomiting, fever, allergic dermatitis and neuropathy
  • Lepra reactions (exacerbation of lepromatous lesions)
  • potentially fatal syndrome resembling infectious mononucleosis has been seen
188
Q

what is clofazimine? what is its mechanism of action?

A
  • drug to treat lepromatous leprosy
  • dye of complex action
  • mechanism of action against leprosy bacilli may involve action on the DNA
  • anti-inflammatory activity and is useful in patients in whom dapsone causes inflammatory side effects
189
Q

what are the pharmacokinetic aspects of clofazimine?

A
  • given orally
  • accumulates in body
  • sequesters in the mononuclear phagocyte system
  • plasma half life may be as long as 8 weeks
  • anti-leprotic effect is delayed and usually not evident for 6-7 weejs
190
Q

what are some unwanted effects of clofazimine?

A
  • may be because it’s a dye
  • skin and urine can develop a reddish colour
  • lesions develop a blue-black discolouration
  • dose-related nausea, giddiness, headache and GI disturbances
191
Q

what is used in streptococcal pharyngitis infection?

A

penicillin V 500mg QDS 10 days

192
Q

what are target sites on a bacteria?

A

points of biochemical reaction crucial to the survival of the bacterium

193
Q

what are examples of target sites on a bacteria that are targeted by antimicrobials?

A 
penicillin binding proteins in cell wall
cell membrane
DNA
ribosomes
topoisomerase IV or DNA gyrase
194
Q

what are mechanisms of antibiotic action?

A
  • binding to cell wall and inhibition of cell wall synthesis (PBP)
  • interference of nucleic acid synthesis or function
195
Q

what are examples of antibiotics that act on the cell wall?

A
  • beta lactams (penicillins and cephalosporins)
  • glycopeptides
  • inhibition of DNA gyrase
  • inhibition of ribosomal activity and protein synthesis
  • inhibition of folate synthesis and carbon unit metabolism
196
Q

what are examples of antibiotics that interfere with nucleic acid synthesis or function?

A

metronidazole, rifampicin

197
Q

what are examples of antibiotics that inhibit DNA gyrase?

A

fluoroquinolones

198
Q

what are examples of antibiotics that inhibit ribosomal activity and protein synthesis?

A

aminoglycosides, tetracyclines, macrolides, chloramphenicol

199
Q

what are examples of antibiotics that inhibit folate synthesis and carbon unit metabolism?

A

sulphonamides and trimethoprim

200
Q

what are characteristics and mechanisms of action of bacteriostatic drugs?

A
  • prevent growth of bacteria
  • kills >90% in 18-24 hrs
  • ratio of MBC to MIC of >4
  • antimicrobials that inhibit protein synthesis, DNA replication or metabolism
  • reduce toxin production (STSS), endotoxin surge is less likely (GNB), reduced bacterial component release (Ply)
201
Q

what are characteristics and mechanisms of action of bactericidal drugs?

A
  • kills the bacteria
  • kills >99.9% in 18-24 hrs
  • generally inhibit cell wall synthesis
  • useful if poor penetration (endocarditis), difficult to treat infections or need to eradicate infection quickly (meningitis)
202
Q

what is endocarditis?

A
  • bacteria within cardiac vegetations are at high concentration, and have lower rates of metabolism and cell division or are dormant
  • surrounded by fibrin, platelets, and possibly calcified material
  • high levels of bactericidal agents are required for a prolonged period
203
Q

what is required for an antimicrobial to work effectively?

A
  • drug must not only attach to its binding target but also occupy an adequate number of binding sites; related to its concentration within the microorganism
  • should remain at the binding site for a sufficient period of time in order for the metabolic processes of the bacteria to be sufficiently inhibited
204
Q

what are the two major determinants of anti bacterial effects of antimicrobials?

A
  • concentration

- time that the antimicrobial remains on these binding sites

205
Q

what are characteristics of concentration-dependent killing by antibiotics?

A
  • key parameter is how high the concentration is above MIC
  • peak concentration/MIC ratio
  • e.g. aminoglycosides, quinolones
206
Q

what does MIC stand for?

A

minimum inhibitory concentration

207
Q

what are characteristics of time dependent killing?

A
  • key parameter is the time that serum concentrations remain above the MIC during the dosing interval
  • t>MIC
  • e.g. beta lactams, clindamycin, macrolides, oxazolidinones
208
Q

what are pharmacokinetics?

A

movement of a drug from its administration site to the place of its pharmacological activity and its elimination from the body

209
Q

what are considerations to make about the site of infection?

A

which antimicrobials will penetrate that site?
what is the pH of the site?
is the antimicrobial lipid soluble?

what is the appropriate or available route of administration? (and dosage interval/duration)

210
Q

why may antimicrobials be unsafe for patients?

A
  • intolerance, allergy and anaphylaxis
  • side effects
  • age
  • renal function
  • liver function
  • pregnancy and breastfeeding
  • drug interaction
  • risk of Clostridium difficile
211
Q

how do bacteria resist antimicrobials?

A
  • change antimicrobial target
  • destroy antimicrobial
  • prevent antimicrobial access
  • remove antimicrobial from bacteria
212
Q

what are examples of target site mutation of antibiotics?

A
  • flucloxacillin (or methicillin) is no longer able to bind PBP of staphylococci - MRSA
  • wall components change in enterococci and reduce vancomycin binding - VRE
  • rifampicin activity reduced by changes to RNA polymerase in MTB - MDRTB
213
Q

what are examples of destruction of antimicrobials by bacteria?

A
  • beta lactam ring of penicillins and cephalosporins hydrolysed by bacterial enzyme ‘beta lactamase’ now unable to bind PBP
  • staphylococci produce penicillinase so penicillin but not flucloxacillin inactivated
  • Gram negative bacteria phosphorylate and acetlyate aminoglycosides (gentamycin)
214
Q

what are examples of prevention of antimicrobial entry by bacteria?

A

modify the bacterial membrane porin channel size, numbers and selectivity

  • pseudomonas aeruginosa against imipenem
  • Gram negative bacteria against aminoglycosides
215
Q

what are examples of bacteria removing antimicrobials from the bacterium?

A
  • proteins in bacterial membranes can act as an export or efflux pumps
  • level of antimicrobial is reduced
  • S. aureus or S. pneumoniae resistance to fluoroquinolones
  • enterobacteriacae resistance to tetracyclines
216
Q

how does resistance develop?

A

intrinsic
- naturally resistant

acquired

  • spontaneous gene mutation
  • horizontal gene transfer: conjugation, transduction, transformation
217
Q

what are examples of intrinsic resistance?

A

all subpopulations of a species will be equally resistant

  • aerobic bacteria are unable to reduce metronidazole to its active form
  • anaerobic bacteria lack oxidative metabolism required to uptake aminoglycosides
  • vancomycin is not taken up by gram negative bacteria; it cannot penetrate outer membrane
  • the PBP in enterococci are not effectively bound by the cephalosporins
218
Q

what is the process of spontaneous gene mutation? what is an example?

A
  • new nucleotide base pair
  • change in amino acid sequence
  • change to enzyme or cell structure
  • reduced affinity or activity of antimicrobial

MTB - point mutations in the rifampin-binding region of rpoB

219
Q

what is the process of horizontal gene transfer?

A

conjugation: sharing of extra chromosomal DNA plasmids (bacteria sex), e.g. MRSA - acquisition of mecA genes which is on a mobile genetic element called staphylococcal cassette chromosome
transduction: insertion of DNA by bacteriophages
transformation: picking up naked DNA

220
Q

what are clinically important resistances of gram positive and negative bacteria?

A

Gram positive

  • MRSA
  • VRE

Gram negative

  • beta lactamases
  • ESBL
  • carbapenemases
  • AmpC
221
Q

what is MRSA?

A

methicillin resistant Staphylococcus aureus

  • staphylococcal cassette chromosome mec (SCCmec) contains resistance gene mecA
  • encodes penicillin-binding protein 2a (PBP2a)
  • confers resistance to all beta-lactam antimicrobials in addition to methicillin
222
Q

what is VRE?

A

vancomycin-resistant enterococci

  • plasmid mediated acquisition of gene encoding altered amino acid on peptide chain preventing vancomycin binding
  • promoted by cephalosporin use
223
Q

what are beta-lactamases? what are some examles?

A
  • enzymes hydrolysing penicillins
  • TEM-1 in E. coli, H. influenzae and N. gonorrhoea
  • SHV-1 in K. pneumoniae
  • strains typically remained sensitive to beta-lactamase inhibitors
224
Q

what is ESBL? what are characteristics of it?

A

beta lactamase with an extended spectrum

  • further mutation at active site
  • can destroy more than just penicillin or amoxycillin

can inactivate:

  • cephalosporins
  • combination antibiotics
  • associated with clinical failure

genes may move to other organisms and are also present encoding resistance to other antibiotics

  • quinolones
  • aminoglycosides

may be difficult to detect and multi-resistance is increasing

225
Q

what are CTX-M ESBLs?

A

plasmid mediated

  • unrelated to TEM and SHV
  • mainly E. coli

CTX-M ESBLs
- mobilised on plasmid and transferred to E.coli

treatment

  • carbapenems
  • temocillin
226
Q

what are carbapenemases?

A
  • meropenam MIC >4mg/ml
  • metallo-beta-lactamases
  • IMP or VIM: pseudomonas aeruginosa, acetinobacter spp.
  • NDM-1: E. coli, klebsiella pneumoniae
  • OXA (oxacillinases - acetinobacter baumanii)
  • KPC (klebsiella pneumoniae)
227
Q

what are treatment options for carbapenemases?

A
  • colistin, a polymyxin
  • combo therapy may be better
  • tigecycline (not monotherapy for bacteremia or respiratory infection as bacteriostatic)
  • fosfomycin or aminoglycosides in combo with other agents
  • meropenam 2g tid (high dose, prolonged 3hr infusion if MIC 4-8mg/ml) with colistin/aminoglycoside
228
Q

what is NDM-1?

A

new Dehli metallo beta lactamase

  • first isolated 2008
  • HPA reports 60 cases since 2008 most with India/Pakistan travel
  • highly resistance, typically only sensitive to colistin (old and toxic), tigecylcine (new and not always appropriate), colistin and tige resistant strains reported
  • like CTX-M, a chance mobilisation of a gene onto a plasmid then promoted by antibiotic use
229
Q

what is AmpC beta-lactamse resistance? what are its characteristics and treatments?

A
  • broad spectrum penicillin, cephalosporine and monobactam resistance
  • beta lactamase inhibitor resistant as well as in vitro and in vivo
  • encoded on the chromosome in bacteria e.g. citrobacter spp., serratia marcescens, enterobacter spp.
  • inducible expression
  • may be carried on plasmids on E. coli where not inducible
  • can be treated with quinolones or trimethoprim
  • may require carbapenem treatment or agents e.g. fosfomycin or temocillin
230
Q

how can resistance be detected and sensitivity be tested?

A

antimicrobial sensitivity testing

  • dilutional liquid culture MIC and MBC
  • antimicrobial discs
  • e tests
  • breakpoint plates

chromogenic plates

mechanism specific tests e.g. detection of beta-lactamases

genotypic methods such as PCR for known resistance conferring genes e.g. rifampicin resistance probe

231
Q

what are uses of vancomycin and teicoplanin?

A

glycopeptides - cell wall weapon

  • gram positive only
  • MRSA
  • penicillin allergy
232
Q

what are antibiotics that act on the 50S subunit to inhibit protein synthesis?

A
  • macrolides
  • clindamycin
  • linezolid
  • chloramphenicol
  • streptogramins
233
Q

what are antibiotics that act on the 30S subunit to inhibit protein synthesis?

A

tetracyclines and aminoglycosides

234
Q

what are clarithromycin and erythromycin used as?

A

macrolides - protein synthesis

- gram positives and atypical pneumonia pathogens

235
Q

what is clindamycin used for?

A

lincosamides - protein synthesis

  • gram positives e.g. S. aureus, GAS, anaerobes
  • cellulitis, necrotising fascitis
  • turns off toxins made by gram positive bugs
236
Q

what is doxycline (oral) used for?

A

tetracyclines - protein synthesis

  • broad spectrum but mainly Gram positive
  • cellulitis (if penicillin allergy), chest infections
237
Q

what is ciprofloxacin used for?

A
  • IV and oral
  • gram negative&raquo_space;> gram positive
  • UTIs, gallbladder infections, abdominal infections
238
Q

what is trimethoprim used for?

A
  • folate antagonist
  • broad spectrum but mainly used for gram negatives
  • UTIs
239
Q

what is nitrofurantoin used for?

A
  • gram negatives

- UTIs

Phase 2A (28 decks)

Brainscape helps you reach your goals faster, through stronger study habits.
© 2024 Bold Learning Solutions. Terms and Conditions