Beta lactam ABs (penicillins, B-lactam inhibitors, cephalosporins, monobactams, carbapenems) Flashcards
What are Beta-lactam ABs and their effect
-Penicillins, Cephalosporins, Lactamase-inhibitors, Monobactams, Carbapenems
•Cell wall is only in bacteria, not mammals. Beta-lactams bind to cross-links in the bacterial cell wall -> cell wall cannot be renewed -> bacteria will expand and wall gets thinner -> ruptures = Bactericidal!
What are Beta-lactamases (enzymes) and which bacteria have them
- Produced by bacteria and provide multi-resistance to Beta-lactam ABs.
- Gram-
- E. coli
- Staphylococcus
- Pseudomonas
Penicillins: in general
•Fungus = Penicillium (Brush like spores)
•Structure: beta lactam ring + thiazolidine ring (5 memebered ring) + 2 side chains
o R1: antibacterial spectrum
o R2: COO-, pharmacokinetic properties:
COONa2K = water soluble, IV/IM, short duration 4-6 h.
COO-procaine = not water soluble, IM/SC, delayed abs., long lasting 12-24 h.
COO-benzathine = not water soluble, IM/SC, slowest abs. 72-96 h.
Penicillins: Mechanism of action
-Inhibition of cell wall synt. - mostly active against G+
•Bacterial cell wall: peptidoglycan = NAM + NAG amine chain bound by transpeptide bonds synt. by transpeptidase and carboxipeptidase
–> these enzymes are inhib. by penicillins = penicillin binding protein (PBP) –> no bonds, cell wall degenerated, no cell wall synt. (death of bacteria)
o Gr +: thick peptidoglycan, then cell membrane with PBP
o Gr -: thick LPS, then cell membrane with PBP (some have porin channels - let AB go through, BUT P. aeruginosa very resistant to penicillin, no porin channels, no penetration through the cell wall)
o ABs have to penetrate cell wall to reach PBP (Gr- is much more resistant, harder to penetrate LPS than peptidoglycan)
o Special ABs available to penetrate the porin channel within the LPS of Gr- bacteria = Amoxicillin
• Bacteriolysis: penicillin only active in dividing bacteria - do NOT combine bacteriostatic antibiotic w. penicillin
Penicillins: Mode of action
- Bactericidal: time dependent (4-5 days, increase dosage doesn’t increase killing rate), post-antibiotic effect - PAE (lasts 6-8hrs before drug is eliminated from the body, enough as b.i.d. and last longer afterwards).
- Increasing their dosage will not effect their efficacy.
Penicillins: Resistance
•Ab ovo resistance = bacteria was never and will never be resistant
o Bacteria without cell wall, or with acid stable or complex cell wall. F.e. mycoplasma (no cell wall), pseudomonas (no porins), mycobacterium (acid fast cell wall = resistant to ALL beta lactam AB), brucella and chlamydia (acid fast cell walls).
o Pineracillin and Cettaziom can penetrate pseudomonas cell walls - have few porin channels!
•Beta-lactamase production: resistant mechanism, found in staphylococci (70% of staph sp. Gr+) and all Gr- bacteria (E.coli and P. aurginosa) -> Methicillin is resistant to beta lactamase, beta lactamase inhibitors.
o PBP gene mutation (MRSA, MRSP strains): altered PBP structure and penicillin cannot bind, these bacteria will be resistant to ALL beta lactam ABs - even to methicillin = changes the binding site!
MRSA = methicillin resistant Staph aureus (problem in swine and cattle)
MRSP = methicillin resistant Staph pseudointermedius (v. big problem in dogs and cats) (Use: Vancomycin, Linozolide, Rifampicin)
•Also inactive against virus, protozoa and fungi.
Penicillins: Antibacterial spectrum
- Narrowed spectrum penicillins: primary act against Gr+, Gr- fastidious (Pasteurella, Hemophillus, Actinobacillus, Mannheimia = RT infections) + leptospira (dis. in swine) and Borrelia spp (lime dis.)
- Penicillinase (beta-lactamase) stable: Gr+, resistant to beta-lactamase (methicillin), against Staphylococci and Streptococci (mastitis, dermatitis, otitis)
- Broad spectrum: both Gr+/-. Also include E. coli, Salmonella, Proteus (UTI), Bacteroides, Fusobacterium (foot dis. - Ru, mouth dis. - small animals), but Pseudomonas is STILL resistant
(4. Penicillins acting against pseudomonas species)
Narrowed spectrum penicillins: active substances
-Many of these are obsolete, infreq. used due to high level resistance.
o Benzyl-penicillin (all release penicillin as an active substance) - Either:
- Na2K (fast abs/elim, 4-6 hrs, IV/IM, high plasma cc., quick pronounced short action!)
- procaine (slower abs/elim, IM/SC, lower plasma cc, DOA ~24 hrs)
- benzathine (v. slow abs/elim, v. low plasma cc, 72 hrs IM/SC)
*Good to combine procaine and benzathine + dihydro-streptomycin (amino-glycoside) = high plasma cc and long duration up to 3 days = all injections, parental
o Penethamat: penetrate BBB and B-milk-B, for IM treatment of mastitis (Staph, Strep, E. coli -> primary against strep as others resistant), IM
o Phenoxy-methyl-penicillin: only one given orally as it resists gastric juice. Approx. 70% abs. after oral adm. Very commonly used in humans (Strep-throat), narrow spectrum: will not affect the gut flora.
o Penamecillin: orally, poultry against necrotic enteritis (Clostridium)
Narrowed spectrum penicillins: distribution, metabolism, excretion, side effects, indication
- Distribution: Poor penetration, blood-brain, blood-milk, blood-prostate barriers, can’t enter cells - not active against IC pathogens
- Metabolism: minimal - don’t go to liver (no hepatotoxic effect at all), but to kidney
- Excretion: mainly tubular secretion in active form (quick t1/2, approx. 30min) -> high cc. in urine!
- Side effects: almost non-toxic, broad therapeutic index, very safe. Caution about allergy, dysbacteriosis (herbivore rodents sensitive - cause diarrhea and death), procaine-penicillin = more toxic, also release procaine (local anesthetic, NS signs - in piglets and foals = movement disorient, tremors), Angiedema (15%)— immune reaction, edema from inflamed vessels - give GCs, epinephrine.
- Indications: RT infection (fastidious Gr-), swine erysipelas (diamond skin dis), anthrax, tetanus, necrotic enteritis, metritis, mastitis in combination, Strep (f.e. Strangles)
Penicillinase (beta-lactamase) stable: active substances
o Acid sensitive: Methicillin (bad oral abs)
o Acid resistant: Oxacillin, Cloxacillin, Dicloxacillin, Flucloxacillin (can take orally, but oral abs. not appropriate), for mastitis - only staph and strep mastitis (NOT E. coli), dermatitis - rather use Cephalosporins
o Frequently combined with Ampicillin: also active against G- (except B-lactamase-prod. ones)
Penicillinase (beta-lactamase) stable: distribution, metabolism, excretion, side effects, indication
-Indications:
Mastitis! → intramammary infusion = only local effect.
Dermatitis: dog/cat: PO → abs. is poor, penetration into skin is poor = not primary choice.
Broad spectrum penicillins: active substances
- Amoxicillin and Ampicillin
- Ampicillin: moderate oral abs., feed reduce abs., usually as inj.
Ampicillin-Na (IV), Ampicillin -trihydrates (IM, SC, orally)
Combination w. sulbactam - Amoxicillin: good oral abs., no effects from feed (imp. for swine), better as oral but can also be injected
Amoxicillin-Na (IV), Amoxicillin-trihydrate (IM, SC, orally)
Combination w. clavulanic acid
o Na-salts: higher plasma conc., faster elimination. Trihydrate form: lower plasma conc., slower elimination.
o Amoxicillin-clavulonic acid (Synulox inj. etc.)
Clavulanate = inhibitor of B-lactamases (broadens the spectrum: B-lactamase producing Staph., E. coli, Proteus).
Very hygroscopic substance, clavulanic acid is seen as brownish precipitate in the bottle.
Horses, herbivore rodents: prohibited to use even orally and parenterally!
Broad spectrum penicillins: distribution, metabolism, excretion, side effects, indication
- Distribution:
- Horses: bad oral abs. of ampicillin and amoxicillin - NEVER give orally, give bacampicillin and pivampicillin = better oral abs.
- Indications: everything from narrowed spectrum + UTI (E. coli - prod. beta lactamase, amoxicillin accumulate in urine at very high cc. and not affected by beta lactamase Amoxicillin-clavulanate!, GI infections (amoxicillin clavulanic acid combination), dermatitis and soft tissue infection, lyme disease, osteomyelitis (combinations)
- Side effects: wide therapeutic margin. Horses, herbivore rodents: dysbacteriosis (even parenterally!). Allergic reactions.
Penicillins acting against pseudomonas species
- Piperacillin, Ticarcillin, Carbenicillin
- The best, expensive, most superior, active against ALL bacteria, outstanding activity against anaerobic bacteria - used in peritonitis
- Piperacillin: combine with taxobactam (best beta lactamase inhibitor) = best combo, IV/IM
- Ticarcillin: orally, combined with clavulenic acid
- Indications: life-threatening pseudomonas infection, peritonitis
Beta-lacatamase inhibitors: bacterias it work against, drugs, pharmacokinetics, side effects
-Bacteria:
• Gr+ - Staphylococci
• Gr- - E. coli, Salmonella, Klebsiella, Proteus, Pseudomonas, Bacteriodes, Bordatella, Haemophiuls
-Drugs:
• Clavulanic acid (+ Amoxicillin)
o “Suicide” inhibitors – sacrifice themselves on Beta-lactamase enzyme
o NO antibacterial action – only inhibit enzymes
o Pharmacokinetics: similar to the antibiotics (Amoxicillin): can move together
o Side effects: negligible (almost none) - Very safe
Clavulanic acid can cause mild stim. of GI tract – vomit & diarrhoea
• Sulbactam (+ Ampicillin)
• Tazobactam (+ Piperacillin) – against pseudomonas
Cephalosporins in general
- Much more stable than beta-lactamines
- Almost everything is the same as penicillin
- MOA: Bacteriocidal, time dependent
- Cephalosporium acremonium fungi sp.
Cephalosporins: Structure
- Similar beta-lactam ring + dehydrothiazine ring
- Carboxylic acid group will protect the beta-lactam ring (therefore more resistant than penicillin)
- 4 generations of cephalosporins: as we advance in generations, the beta-lactamase stability is going to be higher
Cephalosporins: Mechanism of effect, mode of action
-Mechanism of effect: Cell wall synthesis inhibition (look at penicillins)
-MOA:
• Bactericidal! – time dependent
• Have to apply the drugs for a minimum of 4-5 mins
• Post-antibiotic effect
Cephalosporins: Resistance
•Ab ovo (mycoplasma, mycobacterium, chlamydia, pseudomonas are resistant) - never resistant to cephalosporins, and never will be.
•4 generations of cephalosporins: the higher the generations, the better the beta-lactamase stability (Gr- prod. beta-lactamases) - the better the effect against Gr-
o 1st: minor activity against Gr-
o 2nd: most sensitive to Gr-
o 3rd & 4th: more sensitive
•Gr+ will decr. as the generations incr. in nr - however 4th generation has high activity against Gr+
•4th generation: Gr- & Gr+ are very sensitive!
•Beta-lactamase prod. (Gr+: Staph, all Gr- f.e.: E. coli)
• PBP mutation – binding site is changing
o The target of cephalosporins & penicillin are the same
o MRSA & MRSB are changing the PBP structure – drugs unable to bind: resistant to all beta-lactams (!)
•(Ceftazidime and cefoperazone: used against pseudomonas)
Cephalosporins: Antibacterial spectrum
•Differs according to the 4 generations:
1.GEN: Pronounced activity against Gr+ bacteria (Staph!) -> penicillinase stable
Similar to penicillins: used against streptococcus
Mastitis, skin infection - dermatitis, ear infections,
*Gr-: NOT against lactamase producers!
*Accum. in urine -> treatment of UTI (although caused by Gr- E.coli)
*Great majority of E. Coli, P. Mirabilis and Klebsiella spp. sensitive, but incr. in 2nd and 3rd gen.
2.GEN: Less pronounced activity against Gr+ ,
*Gr-: active against several lactamase producers! (E. coli, Salmonella spp., Klebsiella spp. etc.). Moderatly resist the B-lactamase enzymes.
*Against B. Frigilis only cefoxitin.
*Rarely used
3.GEN: Weak activity against Gr+
*Gr-: potent activity against most beta-lactamase producers!
*Gr+ activity decreased
*E.coli and Resp. causing Gr- are very sensitive +Pseudomonas aeruginosa
•EXAM Drugs active against pseudomonas: Cefoperazone, ceftazidime
*UTI, RT infections, intestinal infections
4.GEN: Good activity against Gr+ and Gr-. Best and most expensive group.
*Gr-: most lactamase producers
•+ more active MIC: minimum inhibitor conc: the lowest conc required to inhibit the bacteria.
-3/4 gen: critically imp. for human medicine: their use should be decr. in the future
Cephalosporins: Pharmacokinetics
•Absorption: oral/parenteral
•Distribution: varies bw generations
o Incr. w. generations: pharmacokinetics is more advanced: incr. ability to cross barriers.
o How the drug can penetrate cells/special membranes (BBB, blood-milk, blood-prostate): Drugs are given IV
o 3rd generation: usually cannot penetrate the special barriers except ceftriaxone & cefotaxime (used to treat meningitis etc.)
• Metabolism: minimal in liver (10-20% metabolised, remaining excreted in urine in the active form - excellent for UTI treatment)
•Excretion: kidney – treatment of UTI (bile excretion: cefoperazone and ceftriaxone = preferred in renal failure)
•Half-life usually short: usually given once or twice a day
*Cefovecin: 5 days (lasts for 2 weeks after 1 SC inj.) - licensed for dogs & cats only
*Ceftiofor: large animal drug: Ru and swine -RT & GI infections & foot rot - SC (long WP: 70 days)
Cephalosporins: Side effects
•Insignificant, mild toxicity
o Allergy (~5% cross allergy with penicillin)
o Dysbacteriosis – herbivore rodents & rabbit
*Safest = 1st generation cephalosporin group! – skin infection, abscess, purulent inflammation
•Given together with probiotics!
o Haematological - very infrequent, sometimes anaemia, leukocytopenia (v. rare)
o Mild tissue irritation (IM can be painful – most given SC or IV)
o Mild nephrotoxicity (very rare – usually occurs to animals already w. kidney failure)
*Aminoglycoside + cephalosporin = nephrotoxic!
Cephalosporins: Indications generally
- Mastitis (Gr+: 1st, Gr-: 3rd) – intra-mammary
- Dermatitis, soft tissue infections (1st / 3rd gen)
- Respiratory infections (3rd/4th)
- Urinary tract infections (2nd/3rd)
- Meningitis, encephalitis, Lyme disease (3rd) – IV
- Praeoperative, intraoperative prophylaxis (1st)
Cephalosporins: Indications 1st generation
- S. auerus, S. intermedius (also penicillinase-producing!) and other Gr+, fastidious Gr- and members of Enterobacteriaceae family (not lactamase-producing Gr-).
- Cephalexin: mastitis (intra-mammary infusion), dermatitis & otitis (orally) – IMPORTANT - Dose: 15-25mg
- Cephapirin, Cefacetril, Cephazoline: mastitis and metritis - intra-mammary infusion, not abs. orally
- Cephazoline: preoperative prophylaxis (wound inf.)– against Staph & Strep [given IV half an hour before surgery]
