Download Lecture 06 Antibiotics I 2013 [Kompatibilitási mód]

Resistance:
Antibiotics
Principle: inhibit growth of bacteria without harming the host
– Drug must penetrate body tissue to reach bacteria
(exception: GI infection)
– Bacteria targeted must be within the spectrum of the AB
– Drug can be bactericidal or bacteriostatic
– Different agents can be combined for synergistic effect
Identification of the invasive microorganism necessary for
optimal treatment
General side effect: Alteration in normal body flora
– GI tract harbors symbiotic bacteria which are killed by AB =>
resistant bacteria repopulate the niche = secondary or
superinfection (most common: overgrowth of Clostridium
difficile)
Resistance avoided/delayed by:
Using AB only when absolutely needed and indicated:
AB often abused for viral infections (diarrhea, flusymptoms, etc.)
Starting with narrow-spectrum drugs
Limiting use of newer drugs
Minimizing giving antibiotics to livestock
Identifying the infecting organism
Defining the drug sensitivity of the infecting organism
Considering all host factors: site of infection, inability
of drug of choice to penetrate the site of infection, etc.
Using AB combinations only when indicated: Severe or
mixed infections, prevention of resistance (tuberculosis)
Cell wall inhibitors
beta-lactams, glycopeptides,
cycloserine, bacitracin
Protein synthesis
inhibitors
erythromycins, clindamycin,
aminoglycosides, tetracyclins,
chloramphenicol, linezolid,
streptogramins
Nucleic acid
synthesis inhibitors
quinolones, sulfonamides,
trimethoprim, rifampin
Alteration of cell
membrane function
Polymyxins, lipopetides
Miscellaneous
metronidazole, isoniazid,
ethambutol
loss of efficacy of a given AB against a particular strain
– Frequently: Staphylococcus aureus, Pseudomonas
aeruginosa, Mycobacterium tuberculosis
Acquisition:
– Spontaneous mutation
– Adaption: drug metabolism (β-lactamase); alternative
metabolic pathways
– Gene transfer: plasmids (via conjugation and
transduction); transposons
The more ABs are used, the greater the chance of
resistance !!!
•RANGE OF ANTIBACTERIAL ACTIVITY
broad spectrum – narrow spectrum
Major groups of pathogenic bacteria used for
characterization of antibacterial spectrum
non-fermentative
Gram– rods
fermentative
Gram– bacteria
Gram+ bacteria
obligate intracellular
& cell wall defective
Mycobacteria
e.g. Pseudomonas
e.g.
E. coli
Salmonella
e.g.
Staphylococcus
e.g.
Chlamydia
Mycoplasma
e.g. causative
agents of
tuberculosis
Inhibitors of Cell Wall Synthesis
Beta–
Beta–lactam antibiotics
-Penicillin and derivates
-Cephalosporins
-Monobactams
-Carbapenems
Glycopeptides
Other Cell Wall- or Membrane-Active Agents
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Beta lactam antibiotics
In 1928, Alexander Fleming was researching
vaccines and noticed a culture of staphlococci had
undergone lysis from contamination with a mold
Fleming finally isolated the mold, Penicillium notatum,
notatum,
and found that the fluid beneath it possessed
antibacterial properties
Basic structure consists of thiazolidine ring connected
to β-lactam ring, to which is attached a side chain
Dosing: 22-4 times per day
Combination with aminoglycosides is useful
(Synergy)
Mechanism of Action
Interferes with last step of bacterial cell wall
synthesis, causing cell lysis
Bactericidal
Only effective against rapidly growing
organisms that synthesize a peptidoglycan
cell wall
Inactive against Chlamydia, Mycoplasma,
mycobacteria, fungi, viruses
β-lactamase resistant β-lactam antibiotics
Semisynthetic
Methicillin (1958),
(1958), Nafcillin, Oxacillin,
Oxacillin,
Dicloxacillin
All are penicillinasepenicillinase-resistant penicillins used
in penicillinasepenicillinase-producing staphylococci;
narrow spectrum
Methicillin--resistant Staphylococcus
Methicillin
Staphylococcus
aureus=MRSA (PBP change) (1961)
Mechanism of action way of being bactericide
Penicillin binding proteins:
proteins: Enzymes involved in forming
cross linkages between peptidoglycan chains inactivated
by penicillin
Inhibition of transpeptidase
transpeptidase:: Hinders last step in
formation of cross links needed for cell wall integrity
Autolysins:: Normally degrade cell wall, but penicillin
Autolysins
prevents new synthesis
Natural Penicillins (basic penicillin)
Penicillin G (Benzylpenicillin)
Gram +/+/- cocci, Gram + bacilli, spirochetes,
anaerobes (Narrow
Narrow--spectrum
spectrum))
Susceptible to inactivation by β -lactamase (i.e.
Staphylococcus aureus)
aureus)
Penicillin V
More acid stable than Pen G
For the treatment of meningitis caused by
susceptible organism
Aminopenicillins
(ampicillin and amoxicillin)
Broader spectrum against GramGram-negatives
(plus as in case of basic penicillin
penicillin))
Klebsiella species show primarily resistance
to aminopenicillins
Resistance due to plasmid mediated
penicillinase
May use clavulanic acid or sulbactam to
extend/maintain the antibacterial activity
Reach therapeutic concentration in the CSF
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Ureidopenicillins
Piperacillin
Carbenicillin, Ticarcillin
Azlocillin,, Mezlocillin
Azlocillin
Effective against Pseudomonas
Pseudomonas aeruginosa
Reach therapeutic concentration in the CSF
Allergic Reactions
Acute (< 30 min)
Urticaria, angioedema, bronchoconstriction, GI, shock
Accelerated (30 minmin-48 hrs)
Urticaria, pruritis, wheezing, mild laryngeal edema,
local inflammatory reactions
Delayed (> 2 days)
Skin rash
Oral glossitis, flurred tongue, black and brown tongue,
cheilosis, severe stomatitis with loss buccal mucosa
Cephalosporins
Cephalosporium
acremonium, first
source, isolated in
1948
β-lactam antibiotics
Related to penicillins
structurally and
functionally
More resistant to βlactamases
Beta-lactamase inhibitors
Irreversible inhibitor of β-lactamase
Clavulanic acid
Sulbactam
Tazobactam
Large molecules, do not penetrate into the CSF
Ampicillin+sulbactam=Unazyn (for newborn babies)
Amoxicillin+ Clavulanic acid=Augmentin
Piperacillin+tazobactam=Tazocin (against P. aeruginosa),
iv.
All combinations are effective against G+ and G- negative anaerobes
Carbapenems
Meropenem (Meronem): penetrates well into the CSF
Imipenem (Tienam), Doripenem;
Ertapenem (Invanz): No activity against P. aeruginosa
Synthetic β-lactam antibiotics
sulfur atom in the thiazolidine ring
Resists β -lactamase hydrolysis
Good efficacy against facultative anaerob GramGram-negatives,
Pseudomonas, Gram+ and Gram – anaerobes
Effective against ESBL producing GrGr-negatives
They are ineffective: MRSA, Stenotrophomonas maltophilia,
E. faecium, B. cepacia (for the second written test)
Antibacterial Spectrum
Five generations
Increased generation number:
number:
-increased gram negative bacterial
susceptibility
-increased β-lactamase resistance
-decreased efficacy against gram +
No effect against: MRSA, Enterococci,
Listeria, anaerobic bacteria (except:
cefoxitin),, Rickettsia, L. pneumophila,
cefoxitin)
Chlamydia, Mycoplasma (for the second
written test)
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First Generation
Cefazolin, Cephalexin, Cefadroxil,
Gram + cocci, some gram – bacilli (E. coli),
coli),
They are effective for treating Staphylococcal
(Meticillin sensitive =MSSA) and Streptococcal
infections
Do not penetrate into the CSF
Second generation
Cefaclor (Ceclor),
Cefuroxime axetil (Zinnat)(iv.
(Zinnat)(iv. and oral
oral))
Cefoxitin (Mefoxin) is effective against
against::
-anaerobes
-ESBL producing GramGram-negatives
Their antibacterial spectrum is broader than that of 1st generation
cephalosporins and includes some gram -ve pathogens (H.
influenzae, Neisseria)
Neisseria)
They are also more resistant to beta-lactamase
They are useful agents for treating upper and lower respiratory tract
infections and sinusitis
Do not penetrate into the CSF
Third Generation
Cefixime (Oral) (Suprax)
Cebtibuten (oral) (Cedax)
Cefotaxime (Claforane)
Ceftriaxone (Rocephine)
Ceftazidime (Fortum)
Cefoperazone (Cefobid)
Cefotaxime and cefriaxone are used for the blind
treatment of meningitis
Fourth Generation
Cefepime (Maxipime), Cefpirome (Cefir)
They have a greater resistance to betalactamases than the third generation
cephalosporins.
Many can cross blood brain barrier and are
effective in meningitis.
Active against P. aeruginosa.
Only for severe infections
Third Generation
They have an extended spectrum of action
against Gram -ve organisms (i.e. Haemophylus influenza,
Neisseria meningitidis, E.coli, Neisseria gonorrhea,
Enterobacter spp., most Klebsiella)
P. aeruginosae,
Resistant to most beta-lactamases
Ceftriaxone and cefotaxime have excellent activity
against Streptococcus pneumoniae, but never
effective against Pseudomonas aeruginosa
Ceftazidime is effective against Pseudomonas
Ceftriaxone, cefotaxime and ceftazidime reach
therapeutic concentration in the CSF
Cephalosporins Active Against MethicillinResistant Staphylococci (fifth generation)
Ceftaroline fosamil (Teflaro)
Ceftobiprole medocaril (Zeftera)
strong affinity for the PBP2a and PBP2x,
responsible for resistance in staphylococci
and pneumococci, respectively
Look effective against MRSA, S.
pneumoniae, Pseudomonas
Enter into the CSF
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Bacterial Resistance to β-lactams
Monobactams
Narrow spectrumspectrum- enterobacteriaceae,
pseudomonas; no gram + or anaerobic
activity
Resistant to β-lactamase
Aztreonam IV or IM
β-lactamase activity
1.
•
•
2.
3.
Hydrolyzes cyclic amide bond of β -lactam
ring
Usually acquired by transfer of plasmids
Decreased permeability to drug
Altered penicillin binding proteins (MRSA, S.
pneumoniae)
4.
Active efflux
efflux
Staphylococcus resistance to beta lactams
1.beta-lactamase
penicillinase only
Resistant to
-penicillin-G,
-aminopenicillins,
-ureidopenicillins
Susceptible:
- beta-lactamase resistant
penicillins (methicillin),
-First and second gen.
cephalosporins,
Augmentin, Unazyn
-carbapenems
Alternative cell wall synthesis
altered PBP
e.g. MRSA !
Because of the new, PBP2a is
produced, this strains are
resistant to practically all betalactams !
Susceptible: fifth gen.
cephalosp (clinically looks
effective).
Extended-Spectrum β-Lactamases
(ESBL)
β-lactamases capable of conferring
bacterial resistance to
All beta-lactams, but not the cephamycins
(cefoxitime) or carbapenems
Only in cases of Gram-negatives (i.e. E. coli, Klebsiella
pneumoniae)
Alteration of PBPs
Mosaic gene structure develops (PBP2x)
Recombination between Streptococcus
pneumoniae and other α-hemolytic Streptococci
Penicillin MIC will be increased and other β-lactam
MICs also will be increased
This resistance is not inhibited by β-lactam
inhibitors
Glycopeptides
(Vancomycine, teicoplanine)
It binds firmly to the DD-Ala
Ala--D-Ala terminus and inhibits
transglycosylase.
No effect against GrGr-negatives
Narrow--spectrum, against MRSA, penicillin resistant Streptoccus
Narrow
pneumoniae,, Corynebacterium jeikeium,
pneumoniae
jeikeium, pseudomembranous colitis
caused by Clostridium difficile
i. v., oral
ral route only for C. difficile
Synergy with aminoglycosides
Toxic to the ears and to the kidneys
Once per day
Side effects: red man syndrome or
red neck syndrome.
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Primary resistance
against some,
lesser important species:
-Leuconostoc
-Pediococcus
-Lactobacillus species
Acquired resistance
-S. aureus
-Enterococci
-Clostridium difficile
NAM/NAG-peptide subunits, normally
D-alanyl-D-alanine, which
vancomycin binds to
D-alanyl-D-lactate and D-alanyl-Dserine result in resistance
agricultural use of avoparcin , another
similar glycopeptide antibiotic, has
contributed to the emergence of
vancomycin-resistant organisms.
Newer glycopeptide antibiotics
Dalbavancin
Derived from teicoplanin
Effective on methicillin-resistant and vancomycinintermediate S aureus
Telavancin
Derived from vancomycin
active versus gram-positive bacteria
including strains with reduced susceptibility to
vancomycin
Other Cell Wall- or Membrane-Active Agents
Daptomycin
Novel cyclic lipopeptide
Similar to that of vancomycin
Active against vancomycin-resistant strains of enterococci
and S aureus
Fosfomycin
Analog of phosphoenolpyruvate
Active against both gram-positive and gram-negative
Cycloserine
Bacitracin:
-inhibits cell wall synthesis
-Effective against Gram positive microorganisms
-Topical application due to nephrotoxicity
-Often used for traumatic abrasions
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