5. Tetracyclines, macrolides, lincosamines Flashcards
(42 cards)
1
Q
Inhibitors of protein synhtesis
A
- Aminoglycosides
- tetracyclines
- macrolides
- lincosamides
- pleuromutilins
- phenicols
2
Q
Classification of tetracyclines
A
Naturally occuring tetracyclines:
- Streptomyces spp.
- oxytetracycline
- chlortetracycline
Semisynthetically derived tetracyclines:
- deoxycycline, minocycline
Short acting:
- tetracycline
- oxytetracycline
- chlortetracycline
Intermediate-acting:
- demeclocycline
Long acting:
- doxyxycline, minocycline
3
Q
Classification of tetracyclines
- structure, properties
A
- Lipophilic, pharmacokinetic: excellent
- penetrate BBB, penetrate intra-cellularly
- Will cause yellowish discolouration of the teeths in growin animals
- especially the Short acting
4
Q
Tetracyclines
- mechanism of action, mode of action
A
Mechanism of action:
- safe drugs
- inhibition of protein synthesis (30S subunit)
- At high concentrations (-cidal effect) loss of cuntional integrity of cytoplasmic membrane
- concentrated in the urine. in the urine they become bactericical. High conc = destroy the cell membrane
Mode of action:
- Generally Bacteristatic (but urine!)
5
Q
Tetracyclines
- antimicrobial spectrum
A
all tetracyclines are similar
- Bacteria
- both aerobic and aneaerobic
- gram + and gram -
- Broad spectrum = resistance
- Very sensitive: Mycoplasma, Rickettsiae, Chlamydophilae, Wolbachia spp.
- Borrelia: 1st choice Doxicyclin
- Anaplasma: 1st choice doxicyclin
- Bordetella: 2st choice doxicyclin
6
Q
Tetracyclines
- chlamydophilae
A
- tetracyclines are 1st choice
- cats + Ru
- zoonotic respiratory infection
7
Q
Tetracyclines
- mycoplasma haemofelis
A
- Surface of erythrocytes of cats –> anemia + icterus
- tetracyclines (doxiyclin?) 1st choice
8
Q
Tetracyclines
- anaplasma phagocytophilum
A
- lives in the WBC
- mainly in dogs –> fever, lameness
- 1st coice: doxicyclin
9
Q
Tetracyclines
- Wolbachia spp.
A
- unique bacteria
- bacterium of Diophilaria (heaertworm of dogs)
- 1st choice doxycillin
- If you destroy the heartworm this will lead to relase of Wolbachia, which will kill the animal
- therefore always treat wolbachia first with doxicillin, and then kill the heartworm
10
Q
Tetracyclines
- protozoa
A
- work moderate in these cases
- Plasmodium spp., Entamoeba histolytica (not so common), Babesia spp., Theileria spp.
11
Q
Tetracyclines
- mechanism of resistance
A
- Impared uptake into bacteria
- the bacteria dont let the AB penetrate the wall
- Active efflux
- Decomposition
- destroy the AB
- Altering of binding site
- the 30S binding site
12
Q
Tetracyclines
- resistance
A
- frequently resistant
- Ab ovo
- Pesuedomonas aeruginaosa: not sensitive to tetracyclines
Acquired resistance: because of the widepread use
- pathogenic E-coli
- salmonella spp.
- Pasteuralle multocida, mannheimia haemoltytica (30-40% resistance, so can work)
- Staph. aureus, streptococci: 50% resistance,
13
Q
Tetracyclines
- pharmacokinetic features
A
- Classic TTC
- less lipophiliv, short acting
- Oxy-chlorotetracyclines: 15% abosorbed in pigs, 80% eliminated
- excretion: 50% active and inactive, therefore not used for UTI
- Long acting TTC:
- more lipophilic
- Excretion in dog (morsly inactive): 20% in urine, 5% in bile, 75% in large intestine –> can be given to anmals with kidney and liver failure
14
Q
Tetracyclines
- indications
A
General infections:
- bronchopneumonia
- reisitance not more than 20%. 1st choice is tetracyclines
- Foot diseases
- sheep+ cattle
- TTC have moderate activity
- UTI: not used! we have better drugs
- Metritis, mastitis
Specific conditions: - only treated with TTC
- lyme disease and ehrlichiosis (especially doxyxycline)
- 10mg/kg TID, duration 6-8 weeks
- chlamydophilosis
- feline mycoplasmosis (formerly haemobartonellosis)
- infectious keratoconjunctivitis in cattle (moraxella bovis): injectable TTC
- proliferative enteropathy in horses (lawsonia intracellularis)
- Doxycycline only drug that can be used in horse, lethal if not treated!
- nocardiosis
- heartwater
- anaplasmosis
- heartworm (dirofilarosis)
- Doxycycline 10mg/kg BID for 30 days
15
Q
Tetracyclines
- side effects and toxicity
A
- oral application (Fe!):
- Tissue irritant –> irritation of esophagus.
- GI disturbances
- Dysbacteriosis
- Rapid IV injection: collapse
- Because TTC bind to calcium in blood and cause hypocalcemia –> increase contractility of the heart
- Tissue necrosis: IV or simultaniously
- yellow discoloration of teeth
- hepatotoxiciy
- infrequent, 1-2% but in that case it can be severe!
- eg in case of Lyme disease you give hepatoprotective aswell
- nephrotoxicity: mild, not severe
- photosensitivity:
- very sensitive to direct sunlight, 50SPF topical application is needed
16
Q
Phenicols
- source and chemistry
A
- produced by: Streptomyces venezuelae
- lipophilic, small molecules
- elimination in bile is excellent
- Chloramphenicol, tiamphenicol, florfenicol
- Chlorampenicol: see structure in ppt.
17
Q
Phenicols
- mechanism of action and mode of action
A
- inhibition of protein synthesis (50S)
- not to be combined with other 50S inhibitors
- bacteristatic
18
Q
Phenicols
- mechanism of resistance
A
- Acetyl transferases
- most important.
- enzymes that will put an acetyl group on the AB
- impared utake into bacteria
- active efflux
19
Q
Phenicols
- antimicrobial spectrum
A
- very borad
- gram + and gram -
- anaerobic and aerobic
- resistant against P. aeruginosa
- very sensitive: mycoplasma, chlamidophila, rickettsia
- Aeromonas salmonicida, Vibrio anguillarum (florfenicol: only AB for fish!)
20
Q
Phenicols
- pharmacokinetics
A
- Absorption:
- Excellent (80-100%) –> Oral almost the same as IM and SC
- Eye: 5% absorption –> therefore it can have all the side effects, but not frequent!
- Distribution:
- Excellent (bones, placenta, prostate)
- Special barriers
- Intracellular
- Metabolism and excretion:
- extensive in the liver (liver disease!)
- urine (mainly inactive, can not be used for UTI) + bile elimination
- Half life:
- Ruminants (longer, every 2nd day) > swine (Shorter. Every day) > cat (Shorter. BID) > dog (Shortest. SID)
- –> therefore not used in cats and dogs
21
Q
Phenicols
- Side effects
A
- Anemia
- Dose dependent (7-10 days, liver) –> all the phenicols. because of the protein synthesis inhibition
- Dose independent –> only chloramphenicol. Lethal - one molecule can cause it
- Ho 50000:1 –> low chance, but severe consequences.
- Excellent absorption (skin, eyes) NB always use gloves
- Prohibited in food producers
- Long term use also effects WBC
- Immunosuppression
- Do not give during vaccination program
- Pain at injection site
22
Q
Phenicols
- indications
A
Primary food producing animals (florfenicol)
- Respiratory diseade (BRD, SRD)
- Mycoplasma + fastidious organisms
- Foot diseases
- infectious keratoconjunctivitis
- Fish Aeromonas infection
Small animals
- (Short half-life, needs many doses: not convenient, very infrequent use)
- Eye infections
- prostatitis
- meningitis
- MRSP, MRSA infections
23
Q
Macrolides
- source and chemistry
A
- streptomyces soil-borne bacteria
- macrolytic lactone ring (lipophilicity) attached to sugar moieties
- weak bases
Summary:
- high intracellular concentrations
- broad distribution in tissues
- especially in resp. tract –> used against resp. infections (mycoplasma, mannheimia etc)
- prolonged half-lives
- stays in tissues, organs and eliminated by the blood very slowly
24
Q
Macrolides
- mechanism of action, mode of action and resistance
A
- inhibition of protein synthesis (50S)
- Bacteristatic
- in higher conc –> bacteriocidal (primarily in the lungs - resp. infections)
Resistance:
- decreased permability
- degrading enzymes
- modified binding site (50S) –> cross resistance (Lincosamides, phenicols)
- The modified binding side (50S) will not bind the macrolides –> causing cross resistance to other bacterial classes –> multidrug resistance!
25
Macrolides
- most important macrolides
Veterinary - newer
* Tulathromycin - semisynthetic - **trilamilide**
* gamithromycin - semisynthetic - **azalide** (has two N-groups --\> increased ion trapping --\> long duration of action)
Human medicine, companion animals
* azithromycin - semisynthetic - **azalide**
26
Macrolides
- antimicrobial spectrum
_Gram positive_
_Few Gram negative (anaerobic!)_
- Fastidious bacteria (Pasteurella, mannheimia etc)
- Capylobacter spp.: Azithro, clarithro, erythro
* enteritis in dogs, cats, humans. from raw chicken meat
- Brachyspira hyodysenteriae: Tylosin (always resistant, out of date now), Tylvalosin (excellent choice)
- Lawsiona intracellularis: Tylosin (swine), Tylvalosin (swine), Toxicyclin (horse)
* proliferative enteropathy - swine, horse
* 1st choice: macrolides
- Bordetella spp.
* Kennel cough in dog, atrophic rhinitis in igs
- Mycoplasma, Chlamydia spp.
- Borrelia spp.
* 2nd choice: macrolides. (1st choice: deoxycycline9
- Rhodococcus equi: Azithro, clarithro, erythro
* fatal pneumonia
27
Macrolides
- Pharmacokinetics
_- Absorption:_
oral absorption: variable
Exceptions:
* **Erythromycin:** acid sensitive. Capsules to prevent breakdown. Esters (synthesised and gets resistant to the gastric juice) --\> good for poultry, pigs
* **Tylosin** phosphate: low absorption =15%. Good in intesintal infections
* **Tartarate**: 30% absorption. Good in resp. infections
Im, SC absorption is good (very irritant!)
* Never IV! not water soluble
* Painfull, therefore never given to small animals by injection, only PO!
* Large animals can tolerate injection
_- Distribution:_
* Good (bones, placenta, prostate) --\> **but can not penetrate BBB**
* Respiratory tract --\>Lung conc. can be 100times higher than in the blood
* Intracellular
_- Metabolism:_
* extensive in the liver --\> contraindicated in liver disease
* 90% of the drug is excreted with bile: In both active and inacive form = can give serious bacteriosis, therefore very toxic in horse, rabbits and herbivore rodents, BUT not in foal!
* CYP450 enzyme inhibitor --\> interactions (toxicity increase!)
* - Ionophor antibiotids (coccidiosis)
28
Macrolides
- Side effects
- GI irritation --\> vomitting, diarrhea (also motilin agonists, especially erythromycin --\> enhance gastric emptying)
- Dysbacteriosis
* fatal enterocolitis in adult horses
* but foals (R. equi) tolerates the medication
- Tissue irritation!
29
Macrolides
- Erythromycin
Similar spectrum as Penicillins --\> in humans it is used for Penicillin allergic patients
Rare usage:
- Small animals: capylobacteriosis
- Food producing animals:
* resp. tract infection (incl. mycoplasmosis)
* diamond skin disease etc.
- Horses: more frequently used
* R. equi (+rifampicin): drug against TB in humans. 6 weeks duration of treatment, every day orally = expensive
30
Macrolides
- Spiramycin
- higher tissue levels
- frequent use in oral cavity infections (small animals): stomatitis
- Large animals: infrequent (mastitis)
31
Macrolides
- Tylosin
Frequent resistance - in swine dysentery 95%!
- Pigs:
* Never used against swine dysentery (was used before)
* usefull: Lawsiona intracellularis (proliferative enterophathy)
- Pigs, ruminants, poultry:
* respiratory tract infections, necrotic enteritis (clostridium) very sensitive to Tylosin
- Small animals:
* ARD = Antibiotic Responsive Diarrhea: affects large dogs, causes chronic diarrhea. Idiopathic
32
Macrolides
- Tilmicosin
Ruminants + pigs, poultry (ØGOAT!) only! highly toxic in other species!
- Most toxic macrolide (cardiotoxic - lethal) --\> horses, goats, humans!
- Cattle SC (Only! can dive from IV)
- Pigs + poultry PO
- excellent levels in the lungs (60:1 to plasma) --\> 3 days!
- Fastidious bacteria + mycoplasma very sensitive!
33
Macrolides
- Tylvalosin
- Oral application, new drug
- pigs, poultry
- outstanding against:
* B. hyodysenteriae
* L. intracellularis
* Mycoplasma + fastidoius bacteria (not so much)
34
Macrolides
- Tulathromycin, gamithromycin
- injectable application, new drugs (ruminants, pigs)
- **Triamilide** and **Azilide** antibiotics --\> excellent distribution
- outstanding against:
* fastidious organisms + mycoplasma
* Gram + coverage decreases
- several 100x higher concentation in the lungs --\> respiratory tract infections!
- ONLY injectable! can not be given in drinking water
35
Macrolides
- Tildipirosin
- The longest acting: 1 month
- No activity against Mycoplasma
- Injectable application, new drugs (ruminants, pigs)
- excellent distribution
- Outstanding against:
* Fastidious organisms + NO mycoplasma
- several 100x higher conc. in the lungs --\> respiratory tract infections!
36
Macrolides
- Azithromycin, clarithromycin
- **Azalite:** long action and better distribution
- **clarithro:** normal macrolide
- Oral application, ew drugs (small animals, humans)
* excellent absorption and distribution (half life is long)
- outstanding against:
* Gram + (1st choice is penicillin...)
* Fastidious Gram negatives
* Borrelia (small animals), Mycoplasmae (small animals), Capyloacter (small animals), R. equi (horse)
- good lung concentrations (Azithro \<-\> clarithro)
- Indications:
- Side effects: vomitting (always give together with food)
37
Lincosamides
- mechanism of action, mode of action, resistance, phamacokinetics
- Inhibition of protein synthesis (50S)
* Never combine them with other 50S! they are antagonists
- Bacteristatic
- cross resistance with **macrolides** and **phenicols**
- similar pharmacokinetics
* good absorption
* excellent distribution (bones, IC etc, but not BBB)
* these drugs are 1st choice in osteomyelitis (primary bact strept. aureus), eg after bone surgery
* metabolism in the liver
* excreted via bile and urine: not sensitive for UTI, and causes dysbacteriosis
* These are the most toxic AB in the intestinal flora --\> prohibited in Eq, rabbit, herbivore rodents!
38
Lincosamides
- toxicity, spectrum
Toxicity:
* very severe tissue irritation
* dysbacteriosis (life threatening entercolitis)
Spectrum:
- gram + and anaerobic!!
- but not for fastidious
- B. hyodysenteria, L. intracellulars
- Mycoplasma
- Campylobacter
39
Lincosamides
- Lincomycin
Lincomycin + spectinomycin = frequent synergism = Lincospectin (excellent choice for resp. inf.)
- mainly in food producing animals
Indications:
- foot rot, wounds, mastitis, metritis (gram +)
- swine dysentery, proliferative enteropathy
- mycoplasmosis (synergy)
40
Lincosamides
- clindamycin
- often used by dentists
- more active, mainly in companion animals
- dermatitis, abscesses, oral cavity
- anal sacculitis
- osteoyelitis
- orally
- side effects: vomitting and dysbacteriosis (give probiotics!)
41
Pleuromutilins
- mechanism of action, mode of action, resistance, pharmacokinetics
- very similar compounds as the others
- only large food producing animals!
- **Tiamulin, valnemulin:** much safer than Lincosamine, never cause dysbacteriosis!
- inhibition of protein syntehsis (50S)
- bacteriostatic
- cross resistance with **macrolides** and **phenicols**
**-** similar pharmacokinetics:
* good absrotpion
* excellent distribution
* metabolism in the liver: enzyme inhibitors (therefore icreased metabolism of other drugs which will increase toxicity) --\> interactions, inophore anticoccidials
* excreted via bile and urine
42
Pleuromutilins
- toxicity, spectrum, indications
Low toxicity, very safe drug!
- skin erythema, vulvar edema
* caused by inactive metabolites excreted by the urine
Similar spectrum to macrolides
- gram +
- fastidious
- B. hyodysenteriae, L. intracellularis, Mycoplasmae
Indications:
- Swine dysentery, Proliferative enteropathy, Mycoplasmosis + respiratory (pigs, poultry)
Drugs:
- **Tiamulin:** orally + inj.
- **Valnemulin:** orally
