6. Miscallaenous antibiotics Flashcards
Glycopeptides
- structure and mechanism of action
- it has structures containing either glycosylated cyclic or polycyclic nonribosomal peptide
- these antibiotics inhibit the cell wall structure Gram + cocci by inhibiting peptidoglycan synthesis
Glycopeptides
- first and second generation
First generation glycopeptide:
- Vancomycin (Amycolatopsis /f. Streptomyces)
- Teicoplanin
- Ramoplanin
Second generation semisynthetic glycopeptide:
- Oritavancin/Orbactive
- Dalbavancin/Dalvance
- Telavancin
How does Vancomycin and Teicoplanin inhibit cell wall synthesis
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.
Oral vancomycin is used to treat?
antibiotica associated enterocolitis, especially if it is caused by C. difficile
When is Glycopeptides used?
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
Glycopeptides
- spectrum of action
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
Treatment of MRSA
- Glycopeptide is the last effective
- Linezolid of the oxazolidinone class and daptomycin of the lipopeptide class have proven to have activity against MRSA
Glycopeptides
Teicoplanin vs Vancomycin
- 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
Glycopeptides
- Side effects
- 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!
Glycopeptides:
Route of administration
- 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
Glycopeptides
- What is “VISA”?
- 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
Glycopeptides
- what confers vancomycin resistance?
- the VanA gene
Glycopeptides
- Vancomycin compared to Second generation glycopeptides
- 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
Rifamycins
- structure and use
- 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
Rifamycins
- Rifampin mode of action
- 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
Rifamycins
- spectrum
- 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
Mupirocin (Bactroban)
- mechanism of action, mode of action, usage
- 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)
Polymixins
- mechanism and mode of action
- 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
Polymyxins
- route of admin,
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
Polymyxins
- spectrum
- 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
Polymyxins
- indications and combinations
- 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
Polymyxins
- resistance
- resistance is uncommon (<5%) and is chromosome-dependent mainly
- plasmid mediated: mcr-1 gene (2-9) obilized colistin resistance
Polymyxins
- their action is inhibited by?
- divalent cations, unsaturated fatty acids and quaternary ammonium compounds
Polymyxins
- absorbtion
- 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
Polymyxins
- elimination
- they undergo renal elimination motly as degradation products, and their plasma half-lives are 3-6 hr
Polymyxins
- side effects
- 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
Polymyxins
- indications
- 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!
Bacitracin-Zn
- mechanism of action
- 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
Bacitracin-Zn
- antibacterial spectrum
- most active against Gram+ bacteria, including Staphylo (producing B-lactamase) and Streptococci, Clostridia and Haemophilus spp.
Bacitracin-Zn
- clinical use
- 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
Sulphonamides
- usage
- 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
Sulphonamides
- mode of action, spectrum
- 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
Sulphonamides
- structure
- 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)
Sulphonamides (SUAs)
- active substances
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
2,4 Diaminopyrimidines (DAPs)
- active substances
Short acting?
- Trimethoprim
- Diaveridine
- Pirimethamin
- Ormethoprim
Long acting:
- Aditoprim
- Baquiloprim
Sulphonamides
- mechanism of action
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
Sulphonamides
- toxicity, mode of action
Selective toxicity
- greater affinity for the bacterial enzyme than the mammalian
Mode of action
- bacteriostatic on their own
- bacteriocidal administered together
Antimicrobial activity of SUAs
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
Sulphonamides
- resistance
- 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)
Antimicrobial activity of DAPs
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
resistance to Diaminopyrimidines
- 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
sulphonamides
- Antimicrobial activity of combinations
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)
Sulfonamides
- Advantages of the combination:
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)
SUAs
- absorption, distribution
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
SUAs
- metabolism, elimination
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)
DAPs
- absorpion, distribution, metabolism and elimination
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
SUAs, DAPs
Pharmacokinetic properties of combinations
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.
SUAs
- side effects
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
DAPs
- side effects
- they are relatively non-toxic drugs
- folic acid deficiency at high doses (cf. methotrexate - cytostatic agent)
- aditoprim and baquiloprim are hepatotoxic
SUAs and DAPs
- side effects of combinations
- 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)
SUAs
- clinical usage
- 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