Beta-Lactamase Inhibitors
• Clavulanic acid, Tazobactam, Sulbactam
• Drug Class: inhibitors of beta-lactamase
• Trade Names:
– Augmentin ® (Amoxicillin + Clavulanate)
– Zosyn ® (Piperacillin + Tazobactam)
– Timentin ® (Ticarcillin + Clavulanate)
• Mechanism of Action:
– these three substances resemble β-lactam molecules & are potent
inhibitors of “most” plasmid-mediated beta-lactamases.
– Sulbactam has intrinsic activity against Acinetobacter & may be used against
MDR strains.
• Indications:
– used in fixed combination with specific penicillins: ampicillin, amoxicillin or
ticarcillin
– penicillin-β-lactamase inhibitor combinations are used for empirical therapy
against a wide range of potential pathogens including treatment of aerobic &
anaerobic infections (e.g. intra-abdominal infections).
– The β-lactam inhibitor merely extends the activity of the combined penicillin
Penicillins Resistant to Staph Beta-Lactamase
Extended Spectrum Penicillins
• Ampicillin (po, im, iv)
• Drug Class: Semisynthetic Penicillin
• Mechanism of Action:
– Same as Pen G, but greater activity against gram negative
bacteria due to enhanced ability to penetrate the gram
negative outer membrane.
• Side Effects:
– skin rash, esp. if patient has mononucleosis.
– Diarrhea & Superinfections are common.
• Pharmacokinetics:
– oral, i.m. or i.v. administration
– acid resistant & well absorbed afer oral administration.
– Significant biliary excretion (hence effective against Salmonella
infections in the biliary tract). Half-life is 1.3 hours.
Amoxicillin
• Drug Class: Semisynthetic Penicillin
• Mechanism of Action:
– Same as Pen G, but greater activity against gram
negative bacteria due to enhanced ability to penetrate
the gram negative outer membrane.
• Side Effects:
– hypersensitivity (like other penicillins)
• Pharmacokinetics:
– absorbed better than ampicillin upon oral
administration.
Ticarcillin - Clavulanic Acid Combo
• Trade Names: Timentin ®
• Drug Class: Semisynthetic Penicillin
• Mechanism of Action:
– Same as Penicillin G, but greater activity against gram
negative bacteria due to enhanced ability to penetrate
the gram negative outer membrane.
– Almost always given as a combined medication with
clavulanic acid (Timentin ®) for inhibition of betalactamases.
• Pharmacokinetics:
– parental (i.m. or i.v.) use. Acid unstable.
Piperacillin - Tazobactam Combo
• Drug Class: Semisynthetic Penicillins
• Mechanism of Action:
– Same as Penicillin G, but greater activity against
gram negative bacteria due to enhanced ability to
penetrate the gram negative outer membrane.
– Piperacillin is combined with tazobactam to
provide protection against beta-lactamase
inactivation.
• Pharmacokinetics:
– given parentally
Cephalosporins
• Cephalosporin discovery credited to Brotzu in
1945 in sewer water off coast of Sardinina
• Several compounds isolated from
mold Acremonium chrysogenum with
cephalosporin C as basic nucleus for future drugs
• First introduced into clinical use in 1964
(cephalothin)
• Cephalosporins are the second major group of
beta-lactam antibiotics.
Cephalosporins
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Cephalosporins are a family of antibiotics originally isolated in 1948 from the
fungus Cephalosporium,
their -lactam structure very similar to that of the penicillins
, cephalosporins resemble penicillins in inhibiting the transpeptidation reaction during
• peptidoglycan synthesis.
• They are broad-spectrum drugs frequently given to patients with penicillin
allergies.
• Many cephalosporins are in use
• First-generation cephalosporins are more effective against gram-positive than
gram-negative pathogens.
• Secondgeneration drugs act against many gram-negative as well as grampositive
• pathogens.
• Third-generation drugs are particularly effective against gram-negative pathogens,
and often also reach the central nervous system.
Cephalosporins
• Bicyclic ring structure
– beta-lactam ring (in common with penicillins)
– 6 membered sulfur containing dihidrothiaizine
ring
• Changes in side chain R groups gives changes
in spectrum of activity, pharmacokinetics, etc.
• Mechanism of action: binds to penicillin binding proteins and
inhibition of formation of cell wall
• Mechanisms of resistance:
– Changes in drug target of penicillin binding proteins - methicillinresistantStaphyloccocus aureus
• Efflux pumps – MexAB-OprM efflux pump in Pseudomonas aeruginosa
• Decreased permeability of cell wall – less common for cephalosporins
– Alteration of drug itself by hydrolysis by beta-lactamases
• Numbers and types of beta-lactamases increasing
• Can be chromosomally or extra-chromosomally (more easily transmitted to
other organisms) mediated
• Resistance to one cephalosporin can result in resistance others
depending on mechanism
• Resistance to cephalosporins can confer resistance to other betalactam drugs like penicillins as well
Different classes
• Divided into “generations” for convenience but
many drugs in same “generation” not chemically
related and different spectrum of activity
• Currently four generations of cephalosporins but
which generation a particular drug belongs often
a matter of debate
• Generalization that with increasing “generation”
activity in vitro against Gram positive organisms
decreases while activity against Gram negatives
increases (but an oversimplification)
Diff classes
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1st Generation - Narrow Spectrum
Cephalexin, Cefazolin
2nd Generation - Intermediate Spectrum
Cefaclor, Cefotetan, Cefoxitin, Cefuroxime
3rd Generation - Broad Spectrum
Cefotaxime, Ceftriaxone
Cefixime
4th Generation - Broad Spectrum
Cefepime
Cephalosporins
• First generation
– Oral and intravenous forumlations
– Activity against E. coli, Klebsiella, Proteus
– In general, FDA approved for skin and soft tissue
infections, urinary tract infections, respiratory tract
infections
• Second generation
– Oral and intravenous - cefuroxime axetil
– Anti-anaerobic activity (cephamycins) - cefoxitin
• Third generation
– Non-anti-pseudomonal – ceftriaxone, cefotaxime
– Anti-pseudomonal – ceftazidime
• Fourth generation – cefepime
Glycopeptide antibiotics are a class of antibiotic drugs.
• The class is composed of glycosylated cyclic or
polycyclic nonribosomal peptides.
• Significant glycopeptide antibiotics
include vancomycin, teicoplanin,
Vancomycin
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Vancomycin is a glycopeptide antibiotic produced by Streptomyces orientalis.
It is a cup-shaped molecule composed of a peptide linked to a disaccharide.
The antibiotic blocks peptidoglycan synthesis by inhibiting the transpeptidation
step that cross-links adjacent peptidoglycan strands.
The resulting peptidoglycan is mechanically weak and the cells osmotically lyse.
Vancomycin’s peptide portion binds specifically to the D-alanine-D-alanine
terminal sequence on the pentapeptide portion of peptidoglycan.
This complex blocks transpeptidase action.
The antibiotic is bactericidal for Staphylococcus and some
members of the genera Clostridium, Bacillus, Streptococcus, and
Enterococcus.
It is given both orally and intravenously, and has
been particularly important in the treatment of antibiotic resistant staphylococcal
and enterococcal infections.
Vancomycin-resistant strains of Enterococcus have become widespread and
recently a few cases of resistant Staphylococcus aureus have appeared.
Teicoplanin
• Teicoplanin is a glycopeptide antibiotic from
Actinoplanes teichomyceticus
• is similar in structure and mechanism of actionto
vancomycin.
• It is active against staphylococci, enterococci,
streptococci, clostridia, Listeria, and many other
grampositive pathogens.
This antibiotic presently is used in Europe
and elsewhere, but not in the United States.
Bacitracin
• is a polypeptide antibiotic produced by Bacillus species.
• It prevents cell wall growth by inhibiting the release of the
subunits of peptidoglycan from the lipid carrier molecule
that carries the subunit to the outside of the membrane
• Teichoic acid synthesis, which requires the same carrier, is
also inhibited.
• Bacitracin has a high toxicity which precludes its systemic
use.
• It is present in many topical antibiotic preparations, and
since it is not absorbed by the gut, it is given to "sterilize"
the bowel prior to surgery