6. Miscallaenous antibiotics Flashcards
1
Q
Glycopeptides
- structure and mechanism of action
A
- it has structures containing either glycosylated cyclic or polycyclic nonribosomal peptide
- these antibiotics inhibit the cell wall structure Gram + cocci by inhibiting peptidoglycan synthesis
2
Q
Glycopeptides
- first and second generation
A
First generation glycopeptide:
- Vancomycin (Amycolatopsis /f. Streptomyces)
- Teicoplanin
- Ramoplanin
Second generation semisynthetic glycopeptide:
- Oritavancin/Orbactive
- Dalbavancin/Dalvance
- Telavancin
3
Q
How does Vancomycin and Teicoplanin inhibit cell wall synthesis
A
They interrupt cell wall synthesis by binding tightly to the D-Ala-D-Ala terminus of the murein monomer unit, inhibit transglycosidase and thereby blocking the addition of murein units to the growing polymer chain.
4
Q
Oral vancomycin is used to treat?
A
antibiotica associated enterocolitis, especially if it is caused by C. difficile
5
Q
When is Glycopeptides used?
A
due to their toxicity, their use is restricted to those patients who are critically ill (eg. nosocomial infections) or who have a demonstrated hyperensitivity to the B-lactams
6
Q
Glycopeptides
- spectrum of action
A
they have a narrow spectrum of action
- principally effective against Gram + rods and cocci
- gram - rods are resistant to the action of these drugs
- they are bactericidal aganist most species
- they are only bacteriostatic against the enterococci
- some tissues are not penetrated very well by glycopeptides, and they dont penetrate into the CSF
7
Q
Treatment of MRSA
A
- Glycopeptide is the last effective
- Linezolid of the oxazolidinone class and daptomycin of the lipopeptide class have proven to have activity against MRSA
8
Q
Glycopeptides
Teicoplanin vs Vancomycin
A
- Teicoplanin is more lipophilic than vancomycin, as it has more fatty acid chains.
- it is considered to be 50-100 times more lipophilic than vancomycin
- Teicoplanin has an increased half life compared to vancomycin, as well as having better tissue penetration.
- it can be 2-4 times more active than vancomycin, but it does depend upon the organism.
- Teicoplanin is more acidic, forming water soluble salts, so it can be given IM
- Teicoplanin is much better at penetrating into leucocytes and phagocytes than Vancomycin
9
Q
Glycopeptides
- Side effects
A
- Vancomycin:
- can cause tissue necrosis and phlebitis at the injection site if given too rapidly IV
- nephrotoxicity including renal failure and interstitial nephritis, and blood disorders (reversible once therapy is stopped)
- pain at site of injection
- Idiosynchratic reaction to bolus, caused by Histamine release
- risk of accumulation in patiens with renal impairment because 90% of the dose is excreted in the urine. Therapeutic drug monitoring (TDM) is recommended!
10
Q
Glycopeptides:
Route of administration
A
- Vancomycin is usually given IV as an infusion
- oral preparations are available (eg. solution powder)
- however, they arent absorbed from the lumen of the gut, so are on no use in treatment of systemic infections
- but they are formulated for the treatment of infection in the GI tract, eg: C. difficile
11
Q
Glycopeptides
- What is “VISA”?
A
- Vancomycin and Teicoplanin are used to treat MRSA infections.
- They must be given IV or IM (because of low oral absorption) (Vancomycin only IV)
- Several newly discovered strains of MRSA show antibiotic resistance to Vancomycin and Teicoplanin.
- these new evolutions of the MRSA bacterium are called Vancomycin intermediate-resistant Spaohylococcus aureus (VISA)
- VISA has a thicker murein layer in which increased amounts of free D-Ala-D-Ala act as decoy target for vancomycin
12
Q
Glycopeptides
- what confers vancomycin resistance?
A
- the VanA gene
13
Q
Glycopeptides
- Vancomycin compared to Second generation glycopeptides
A
- Several derivatives of vancomycin are being developed (second generation), including: Oritavancin, Dalbavancin, Telavancin
- they process longer half-lives than vancomycin, and demonstrate improvements over vancomycin due to less frequent dosing and activity against vancomycin-resistant bacteria.
- they are las resort antibiotics, used for treatment of:
- Acute bacterial skin and skin structure infections caused by Staphylo - and Streptococci
- IV, SID for 7-10 days
14
Q
Rifamycins
- structure and use
A
- Rifampicin and its structural relative, Rifabutin, are two semisynthetic derivatives of the naturally occuring antibiotic Rifamycin B.
- Rifampin and Rifabutin inhibit bacterial DNA-dependent RNA polymerase
- Rifampin can be used for:
- prophylaxis of meningococcal disease and treatment of some bacterial infections
- its major use is treatment of Tuberculosis and other Mycobacterial infections
- particularly effective agianst phagosome-dwelling mycobacteria because it is bactericidal for intracellular as well as extracellular bacteria
15
Q
Rifamycins
- Rifampin mode of action
A
- Rifampin inhibits bacterial DNA-dependent RNA polymerase by binding to the beta-subunit of the polymerase
- Rifampin exerts its bactericidal activity by forming a stable complex with bacterial DNA-dependent RNA polymerase, thereby inhibiting RNA synthesis
- Rifampin displays high selectivity for bacteria, as mammalian polymerases (even those of mitochondria) are inhibited by rifampin only at far higher concentrations
- Hence, Rifampin is well tolerated, ant he incidence of adverse effects (typically: rash, fever, nausea, vomitting and jaundice) is low
16
Q
Rifamycins
- spectrum
A
- Rifampin is widely distributed, including CSF
- Active against most Gram + organisms
- R. equi, Neisseria spp., Mycobacteria (incl. M. tuerculosis)
- Rifampin is also used prophylactically for meningitis
17
Q
Mupirocin (Bactroban)
- mechanism of action, mode of action, usage
A
- category A: prohibited in food producing animals
- Fermentation product of Pseudomonas fluorescens (pseudomonic acid A)
- Bacteriostatic (in eight-times higher dose bactericidal)
- Reversibly inhibits the isoleucyl tRNA synthetase enzyme, the protein synhtesis decreases in the sensitive bacteria (G+ cocci)
- Usage only topically against S. aureus infections
- Other indication of use: intranasal use against MRSA strains (eg. after operations)
18
Q
Polymixins
- mechanism and mode of action
A
- Polymyxins (Bacillus polymyxa) are cationic basic polypeptides that acts as a detergent to disrupt the cell membrane functions of Gram - bacteria
- They are positively charged molecules attracted to negatively charged bacteria (LPS)
- they act like a cationic detergent: rapid killing, but effect all membranes similarly –> toxicity
- little or no effect on Gram + as PG cell wall is too thick
- they neutralize LPS, preventing its pathological action
- They are concentration dependent bactericidal
- they interact strongly with phospholipids in bacterial cell membranes and radically disrupt their permeability and function
- they are poorly absorbed and are poorly distributed to tissues
19
Q
Polymyxins
- route of admin,
A
of this group of polypeptide antibiotics:
- Polymyxin B, polymyxin E = colistin
- Polymyxin M = mattacin
- –> they are most commonly used topically and PO
- Colistimethate is a form of colistin intended for parenteral administration
20
Q
Polymyxins
- spectrum
A
- more effective against Gram - than Gram +
- their narrow spectrum includes:
- Enterobacter, klebsiella, salmonella, pasteurella, bordetella, shigella spp., E. coli and Pseudomonas spp. (incl resistant strains)
- higher levels (topical formulation) S. aureus
- most Proteus spp. are not susceptible
21
Q
Polymyxins
- indications and combinations
A
- Polymyxin B is often applied as a topical ointment in mixture with bacitracin or neomycin, or both
- Polymyxins acts synergistically when combined with:
- potentiated sulfonamides, tetracyclines and som other antibacterials (penicillins, fluoroquinolones and aminoglycosides)
- they reduce the activity of endotoxins in body fluids and can be benefitial for endotoxaemia
22
Q
Polymyxins
- resistance
A
- resistance is uncommon (<5%) and is chromosome-dependent mainly
- plasmid mediated: mcr-1 gene (2-9) obilized colistin resistance
23
Q
Polymyxins
- their action is inhibited by?
A
- divalent cations, unsaturated fatty acids and quaternary ammonium compounds
24
Q
Polymyxins
- absorbtion
A
- they are not absorbed after PO or topical administration
- plasma levels peak 2hr after parenteral administration
- blood levels are usually low because polymyxins bind to cell membranes as well as tissue debris and purulent exudates
25
Q
Polymyxins
- elimination
A
- they undergo renal elimination motly as degradation products, and their plasma half-lives are 3-6 hr
26
Q
Polymyxins
- side effects
A
- nephrotoxic (tubular necrosis) and neurotoxic
- B < E < M
- therefore mainly for oral, opthammic, otic or topical use
- neuromuscular blockade (breathing difficulties) at higher conc.
- pain at injection site and hypersensitivity reactions
- Polymyxin B is a potent histamine releaser
27
Q
Polymyxins
- indications
A
- the main indication: for parenteral use in life-threatening infection due to gram - bacilli or Pseudomonas spp. that are resistant to other drugs.
- PO against intstinal infections
- topical application: pyoderma, otitis externa
- intramammary in combinations
PS: IV admin is potentially toxic!
28
Q
Bacitracin-Zn
- mechanism of action
A
- It is a mixture of cyclic peptides, product of Bacillus subtilis*
- Inhibition of bacterial cell wall synthesis
- Bacitracin interferes with the dephosphorylation of C55-isoprenyl pyrophosphate
29
Q
Bacitracin-Zn
- antibacterial spectrum
A
- most active against Gram+ bacteria, including Staphylo (producing B-lactamase) and Streptococci, Clostridia and Haemophilus spp.
30
Q
Bacitracin-Zn
- clinical use
A
- not used systematically (nephrotoxicity)
- topical and local infections of mouth, nose, eye, skin and mammary gland
- in topical formulations often combined with polymyxins or neomycin, for suppression of mixed bacterial flora in skin, wounds or mucous membranes
- oral premixes for prevention of necrotic enteritis (Cl. perfringens) in rabbits
31
Q
Sulphonamides
- usage
A
- widely used in food producing animals because of their relatively low cost and ease of administration
- their use in vet.med are widespread, particularly as mass medicants for the control of diseases in food producing animals
- they are marketed either alone (rare) or formulated in combination with other diaminopyrimidines and/or antibiotics
- they are presented as feed additives, or oral, topical, intrauterine pessaries and injectable preparations
32
Q
Sulphonamides
- mode of action, spectrum
A
- bacteriostatic
- affecting Gram +, Gram - and many protozoan organisms
- bacteristaatic diaminopyrimidines are currently used in vet.med only in combination with Sulphonamdides (alone resistance develops rapidly)
- when diaminopyrimidines combined with sulphonamides, a sequential blockade of microbial enzyme systems occurs with bactericidal consequences
33
Q
Sulphonamides
- structure
A
- Prodrug of Sulphonamides: Prontosil
- 2,4 diaminopyrimidnes (DAPs) eg: trimethoprim:
- weak base, poorly soluble in water
- Sulphonamides (SUAs)
- bad solubility in acidic environment
- Na-salts is used highly alkaline (sulfacetamide)
34
Q
Sulphonamides (SUAs)
- active substances
A
Local:
- Sulfacetamide
- Mafenide
- Silver sulfadiazine
- Sulfathiazine
- “Intestinal disinfectant”: Sulfaguanidine
Systemic:
- Short acting:
- Sulfadimidine
- Sulfachlorpyridazine
- Sulpadoxine
- Sulfadiazine
- Sulfamethoxasole
- Sulfaquinoxaline
- Sulfachlorpyrazine
- Sulfasalazine (salazopyrin) IBD
- Long acting:
- Sulfadimethoxine, sulfamethoxypyrazine
35
Q
2,4 Diaminopyrimidines (DAPs)
- active substances
A
Short acting?
- Trimethoprim
- Diaveridine
- Pirimethamin
- Ormethoprim
Long acting:
- Aditoprim
- Baquiloprim
36
Q
Sulphonamides
- mechanism of action
A
Sulphonamides:
- compete with PABA for the enzyme dihydropteroate synthetase, preventing incorporation PABA into the folic acid (pteroylglutamate)
- susceptible microorganisms must synthesize folic acid, whereas mammalian cells use performed folic acid. Selective action.
Diaminopyrimidines:
- inhibit THF synthesis from DHF by combining with the enzyme dihydrofolate reductase
37
Q
Sulphonamides
- toxicity, mode of action
A
Selective toxicity
- greater affinity for the bacterial enzyme than the mammalian
Mode of action
- bacteriostatic on their own
- bacteriocidal administered together
38
Q
Antimicrobial activity of SUAs
A
Wide antibacterial spectrum:
- Gram + and Gram - bacteria
- aerobic and several anaerobiv bacteria
- some Chlamydophila spp.
Anti-protozoal effect:
- coccidia (Eimeria spp., Isospora spp.)
- toxoplasma spp
39
Q
Sulphonamides
- resistance
A
- very frequent among sulphonamides
- chromosomal mutation (develops slowly and gradually)
- plasmid - and integron-mediated resistance
- cross resistance among the SUAs is complete
- Mechanisms:
- decreased penetration
- PABA-specific dihydropteroate-synthetase enzyme
- 3- overproducing of PABA (purulent tissue debris)
40
Q
Antimicrobial activity of DAPs
A
Wide antibacterial spectrum:
- Gram + aerobic bacteria
- Gram - aerobic bacteria
- susceptible bacteria with an MIC < 1ug/ml
Negligible activity against:
- anaerobes, chlamydophila spp., mycobacterium spp., mycoplasma spp
Anti-protozoal effect
41
Q
resistance to Diaminopyrimidines
A
- plasmid - and integronn-mediated resistance (at least 20 different resistance genes)
- plasmid or chromosomal synthesis of a resistant dihydrofolate reductase enzyme
- commonly multiple resistances, including sulphonamide resistance
42
Q
sulphonamides
- Antimicrobial activity of combinations
A
Mode of action: bactericidal
Wide antibacterial spectrum
- gram + aerobic bacteria
- gram - aerobic bacteria
- anti-protozoal effect (toxoplasma, coccidia)
- further sensitive parasites: pneumocystis carinii, some Malarias
They are not active aganist:
- mycoplasmas, mycobacteria,
- rickettsias, spirochates
- leptospira spp., pesudomonas aeruginosa
- in vivo they are not active against anaerobes (high levels of PABA antagonize their effect in necrotic tissues)
43
Q
Sulfonamides
- Advantages of the combination:
A
synergistic interactions - potentiated SUAs
- two bacteriostatic agents –> bactericidal effect
- 10-fold increased activity of the DAPs component, 100-fold of the SUAs
- broadened spectrum
- resistance less frequent
- more than 40% of SUA-resistant strains are susceptible to the combination (practically they are sensitive to the DAPs)
44
Q
SUAs
- absorption, distribution
A
Absorption:
- good absorption after PO administration (except sulfaguanidine)
Distribution:
- good in tissues and extracellular fluid
- inhibited by purulent material, tissue debris
- meningitis: good penetration across BBB
45
Q
SUAs
- metabolism, elimination
A
Metabolism
- acetylation.
- Badly soluble metabolites (acetyl-sulpha crystals –> dog lower acetylation), precipitation
- Glucoronic acid conjugation, soluble molecules, quick excretion
Elimination:
- kidney (active + metabolites)
- acidic ph, bad solutbility (acetyl-sulpha crystals –> dog lower acetylation)
Free access to driniking water! (acetyl-sulpha crystals –> dog lower acetylation)
46
Q
DAPs
- absorpion, distribution, metabolism and elimination
A
Absorption
- well absorbed PO
Distribution:
- excellet, high Vd
- good penetration thorugh special barriers, therapeutic drug level in liquor, prostate and milk
Metabolism and elimination:
- partly metabolised in liver
- eliminated via kidney (60% humans), mainly in an active form
- TMP half-life: notable difference, in humans longer
47
Q
SUAs, DAPs
Pharmacokinetic properties of combinations
A
Sulphonamides
- worse penetration to tissues
Diaminopyrimidines
- quick enters to tissues
- shorter half life of TMP (except humans)
- Ormetropri, aditoprim, baquiloprim: longer half-life, less frequent dosing
SC admin of combination is not preferred in cows (TMP deposit –> low concentration) maybe in other species as well.
48
Q
SUAs
- side effects
A
wide therapeutic margin
- crystalluria
- in acidic urine due to acetyl metabolite
- haematuria and crystal nephrosis
- frequent in cats, rare in dogs
- rarely idiosyncratic drug reactions (immune mediated toxicity)
- idiosyncratic hepatotoxicity (K9 and humans)
- allergy (in dobberman more frequent)
- KCS
- frequent in smaller dog breeds
- too large doses/and or long term use? irreversible!
- dysbiosis vitamin-K deficiency in poultry
- haematological deviations
- sylphmethaemogobinaemia (swine)
- sulfaquinoxaline: vit-k antagonism in different species leads to haemorrhagic diathesis
- hypothyroidism
49
Q
DAPs
- side effects
A
- they are relatively non-toxic drugs
- folic acid deficiency at high doses (cf. methotrexate - cytostatic agent)
- aditoprim and baquiloprim are hepatotoxic
50
Q
SUAs and DAPs
- side effects of combinations
A
- in horses minor tissue damage, and pain after IM injection
- in horses fatal adverse reaction after IV administration (possible respiratory failure)
- the concurrent intravenous use of potentiated sulphonamides with alpha-2 agonists has been reported to cause cardiac arrhytmias in horses and cattle, which may be fatal
- diarrhea after PO application (alteration in GI microbiota, is not significantly different from that observed in horses recieving other antibiotics orally)
51
Q
SUAs
- clinical usage
A
- systemic infections
- infections of organs
- Respiratory infections (B. bronchiseptica, A. pleuropneumoniae)
- GI bacterial infections (E. coli, salmonella) + idiopathic colitis: sulphasalazine
- urinary infections
- metritis, MMA
- foot rot
- prostatitis
- menigitis (strept., Listeria)
- eye treatment: sulphacetamide
- special diseases:
- nocardia infection
- toxoplasmosis (in sheep prevetion abortion)
- coccidiosis
- sarcocystosis
- crytposporidiosis
- chlamydiosis
- plasmodium gallinaceum malaria
