BETA-LACTAM ANTIBIOTICS
Penicillins
Cephalosporins
Carbapenems - Not really a beta-lactam but
retains its ring structure
A. Penicillins
• Derivatives of 6-aminopenicillanic
acid
• Contains a beta-lactam ring essential
for antibacterial activity
• Have additional chemical
substituents which confer differences
(antimicrobial activity, susceptibility
to acid, enzymatic hydrolysis, and
biodisposition)
• Pharmacokinetics
o Vary in resistance to gastric
acid (and thus have variable
bioavailability)
o Not metabolized extensively
(in effect excreted
unchanged in the urine via
glomerular filtration and
tubular secretion)
o Tubular secretion is
inhibited by probenecid
o Nafcillin (excreted mainly in
bile)
o Ampicillin (undergoes
enterhepatic recycling)
o half-lives of mostly 30
minutes to 1 hour
o Procaine and Benzathine
have longer half-lives (given
IM à active drug has slow
release into the
bloodstream)
o Note:most penicillins are
able to cross the blood-brain
barrier only when meninges
are inflamed
• Mechanism of Action: bactericidal
- Inhibits cell wall synthesis by
the following steps:
• Drug binds to specific
enzymes (penicillinbinding proteins [PBPs]
located in the bacterial
cytoplasmic membrane
• Inhibition of the
transpeptidation reaction
•
that crosslinks the linear
peptidoglycan chain
constituents of the cell
wall
• Activation of autolytic
enzymes that cause
lesions in the bacterial cell
wall
Resistance:
o Enzymatic hydrolysis of the betalactam ring results in the loss of
antibacterial activity
o Formation of beta-lactamases
(penicillinases) by mostly
staphylococci and many gramnegative organisms is the major
cause of resistance
o To combat this development,
inhibitors of these bacterial enzymes
are often used in combination with
penicillins to prevent their
inactivation
1. Clavulanic acid
2. Tazobactam
3. Sulbactam
o In the case of MRSA structural
changes in the target PBPs (also in
resistance to penicillin G in
pneumococci)
o In some gram-negative rods
(pseudomonas), changes in porin
structures in the outer cell wall may
contribute resistance (it prevents
penicillins from accessing and
binding to the PBPs)
Clinical Uses
Narrow spectrum Penicillinase-susceptible agents
• Penicillin G
–
Prototype of a subclass of penicillins
with limited spectrum of antibacterial
activity (and susceptible to betalactamases)
–
Used against common streptococci,
meningococci, gram-positive bacilli,
and spirochetes
–
Many strains of pneumococci are now
resistant to penicillins (PRSP)
–
Most strains of S. aureus and N.
gonorrhea are resistant due to betalactamse production
–
No longer DOC for gonorrhea, but still
for syphilis
–
•
enhanced by co-administration of
aminoglycosides
Penicillin V
–
Used for oropharyngeal infections
(given orally)
Very Narrow Spectrum Penicillinase-Resistant
• Subclass of penicillins which includes:
–
Methicillin (prototype, but rarely used
due to its nephrotoxic potential)
–
Nafcillin
–
Oxacillin
• Primary use: staphylococcal infections
• Note: MRSA and MRSE (S. epidermidis) are
resistant to all penicillins, and often against
multiple antimicrobials
Wider Spectrum Penicillinase-Susceptible
• Ampicillin and Amoxicillin:
–
Subgroup that has wider spectrum of
antibacterial activity compared to
penicillin G (but still susceptible to
penicillinase)
–
Clinical use similar to penicillin G, as
well as against:
• Enterococci, L.
monocytogenes, E. coli, P.
mirabilis, H. influenzae, and M.
catarrhalis
(Some resistant strains have
developed)
–
Activity is enhanced when used with
penicillinase inhibitors (e.g. clavulanic
acid Co-Amoxiclav)
–
Synergistic with aminoglycosides in
enterococcal and listerial infections
(ampicillin)
•
Piperacillin and Ticarcillin:
–
Activity against some gram-negative
rods, including:
• Pseudomonas
• Enterobacter
• Klebsiella
–
Often used with penicillinase
inhibitors (tazobactam and clavulanic
acid) to enhance their activity
Penicillins
•
Toxicity:
–
Allergic reactions
o Urticaria, severe pruritus, fever,
joint swelling, hemolytic anemia,
nephritis, and anaphylaxis
o Allergic response occurs if given
penicillin again (in 5-10% of
persons)
o Maculopapular skin rash (but
mimics an allergic reaction)
ampicillin
–
Gastrointestinal disturbances
o Nausea and diarrhea (oral
penicillins)
o May be due to direct irritation or
by overgrowth of gram-positive
organisms or yeasts
o Pseudomembranous colitis
(ampicillin)
–
Miscellaneous:
o Neutropenia (nafcillin)
o Interstitial nephritis (methicillin)
B. Cephalosporins
• Derivatives of 7-aminocephalosporanic
acid and contain the beta-lactam ring
structure
• Many members are in clinical use
–
Vary in antimicrobial activity and
are designated according to their
generations (in order of their
introduction into clinical use)
• Pharmacokinetics:
–
Many are available for oral use
(mostly parenteral)
–
Those with sidechains may
undergo heptaic metabolism but
majority undergo renal excretion
via active tubular secretion
• Only Cefoperazone and
Ceftriaxone are excreted
mainly in the bile
–
Most cephalosporins do not enter
the cerebrospinal fluid even
when meninges are inflamed
•
Mechanism of Action
–
Bind to penicillin-binding proteins
to inhibit bacterial cell wall
synthesis (just like penicillins)
• bactericidal
–
Some structural differences make
them less susceptible to
penicillinase produced by
staphylococci
•
Resistance
–
Some bacteria are able to
produce beta-lactamases which
can inactivate cephalosporins
–
May occur from decreases in
membrane permeability to
cephalosporins or from changes
in PBPs
–
MRSA is resistant
1st Generation
• Cefazolin (parenteral) and Cephalexin (oral)
–
Active against gram-positive cocci
(staphylococcus and common
streptococci)
–
Effective against many strains of E. coli
and K. pneumoniae
–
Usually used as surgical prophylaxis
–
Minimal activity against:
• Gram-negative cocci
• Enterococci
• MRSA
• most gram-negative rods
2nd Generation
• Lesser activity against gram-positive microbes
versus 1st generation drugs
–
But have extended gram-negative
coverage
–
Marked differences between
usefulness between drugs in the
group
• Examples:
–
Bacteroides fragilis (cefotetan and
cefoxitin)
–
Sinus, ear, and respiratory infections
caused by H. influenzae or M.
catarrhalis (cefamandole, cefuroxime,
and cefaclor)
3rd Generation
• Increased activity against gram-negative
microbes resistant to other beta-lactam
medications
–
Plus the ability the penetrate the
blood-brain barrier (except for
cefoperazone and cefixime)
• Most active against:
–
Providencia, serratia marcescens, and
beta-lactamase-producing strains of H.
influenzae and Neiserria
• Less active against:
–
Enterobacter strains that produce
extended-spectrum beta-lactamases
• Most drugs in this class are reserved usually
for serious infections:
–
Pseudomonas à cefoperazone,
ceftazidime
–
B. fragilis àcetizoxime
• Except for: ceftriaxone (parenteral) and
cefixime (oral) àfor gonorrhea
4th Generation
• Cefepime àmore resistant to betalactamases produced by gram-negative
microorganisms:
–
Enterobacter, haemophilus, neisseria,
and some penicillinase-resistant
pneumococci
–
combines:
o Gram-positive activity of 1st
generation
o Wider gram-negative
spectrum of 3rd generation
th
5 Generation
• Indicated for treating bacteria which are
otherwise resistant to commonly used
antibiotics
• Ceftaroline – has broad spectrum activitiy
against MRSA (others: MRSE, VRE)
- Not effective against Pseudomonas
• Ceftobiprole – this drug has been called a 5th
gen cephalosporin, but the terminology is not
universally accepted.
- has powerful antipseudomonal activity,
and binds strongly to PBP 2a
- has activity against MRS, S. pneumonia,
enterococci
- newer medication used for healthcareassociated pneumonia (HCAP) or HAP
•
•
Cephalosporins Toxicity:
–
Allergies (skin rashes to anaphylactic
shock)
• Between cephalosporins is
complete (100%)
• Between a cephalosporin and
penicillin is incomplete (510%)
Other Adverse Effects:
–
May cause pain at IM injections (as
well as phlebitis if given IV)
–
May increase nephrotoxicity of
aminoglycosides (if given together)
–
Some may cause:
hypoprothrombinemia and disulfiramlike actions with ethanol
(cefamandole, cefoperazone, and
cefotetan)
• Due to their
methylthiotetrazole group
• Disulfuram-like action:
- reaction to alcohol
leading to nausea,
vomiting, flushing,
dizziness, throbbing
headache, chest and
abdominal discomfort,
and general hangoverlike symptoms among
others
Other Beta-Lactam Drugs
•
Aztreonam
•
Carbapenems (Imipenem, Meropenem, and
Ertapenem)
•
Beta-Lactamase Inhibitors (Clavulanic acid,
Sulbactam, and Tazobactam)
•
•
•
•
•
Aztreonam
monobactam resistant to beta-lactamases
produced by some gram-negative rods
(including Klebsiella, pseudomonas, and
serratia)
No activity against gram-positive bacteria or
anaerobes
Cell wall synthesis inhibitor (preferentially
binds with penicillin-binding protein (PBP3)
Synergistic with aminoglycosides
Given intravenously and is eliminated via
renal tubular secretion
•
•
Half-life is prolonged in renal failure
Adverse effects include GI upset with possible
superinfection, vertigo, headache, and rarely
hepatotoxicity
–
Skin rash may occur but there is no
cross-allergenicity with penicillins
Carbapenems
(Imipenem, Doripenem, Meropenem, Ertapenem)
•
Chemically different from penicillins but
retain the beta-lactam ring structure
•
Have low susceptibility to beta-lactamases
which makes them useful against:
– Gram-positive cocci
– Gram-negative rods
– anaerobes
All are active against P. aeruginosa and
acinetobacter spp, except for ertapenem
–
Often paired with an aminoglycoside if
used against pseudomonas
Given parenterally, are useful against
microbes resistant to other antibiotics
- But is not effective against MRSA
Co-drugs of choice for:
–
Enterobacter, citrobacter, and serratia
spp
•
•
•
Imipenem
•
•
Rapid inactivation by renal dehydropeptidase I
Administered in fixed combination with
cilastatin (an inhibitor of the enzyme above)
–
Increases its half-life and inhibits the
formation of a metabolite toxic to the
kidneys
Note: other carbapenems are not
significantly degraded by the kidneys
Imipenem-Cilastatin
•
Partial cross-allergenicity with penicillins
•
Adverse effects:
–
GI distress, and skin rash
–
CNS toxicity confusion,
encephalopathy, and seizures (at very
high plasma levels)
Meropenem
•
Similar to imipenem but not metabolized by
renal dehydropeptidases
•
Less likely to cause seizures
Ertapenem
•
Long half-life but less active against
enterococci and pseudomonas
•
Intramuscular route causes pain and irritation
•
•
•
Beta-Lactamase Inhibitors
(Clavulanic acid, Sulbactam, Tazobactam)
Used in fixed combinations with certain
hydrolyzable penicillins
Most active against plasmid-encoded betalactamases (produced by gonococci,
streptococci, E. coli, and H. influenzae)
Not useful against enterobacter,
pseudomonas, and serratia
–
Their type of beta-lactamase is
chromosomal (and not plasmidencoded)
OTHER CELL WALL OR MEMBRANE-ACTIVE AGENTS
(Vancomycin, Fosfomycin, Bacitracin, Cycloserine,
Daptomycin)
Vancomycin
•
Bactericidal glycoprotein which inhibits
transglycosylation
–
Prevents elongation of the
peptidoglycan chain and interferes
with cross-linking
–
Resistance à due to decreased
affinity for the binding site
•
Narrow spectrum of activity
–
Used for serious infections caused by
drug-resistant gram-positive
organisms
• Methicillin-resistant
staphylococci (MRSA)
• Penicillin-resistant
pneumococi (PRSP) in
combination with a 3rd
generation cephalosporin
(usually ceftriaxone)
–
Used for serious infections caused by
drug-resistant gram-positive
organisms
• Backup drug for Clostridium
difficile infection
•
Not absorbed in the GI tract (and may be
given orally for bacterial enterocolitis)
•
Given parenterally, it penetrates most tissues
and is eliminated unchanged in the urine
•
Dosage modification is mandatory in renal
failure patients
•
Toxicity:
–
Chills, fever, phlebitis, ototoxicity, and
nephrotoxicity
–
Rapid intravenous infusion Red Man
Syndrome (due to histamine release)
Fosfomycin
•
Antimetabolite inhibitor of cytosolic
enolpyruvate transferase
–
Prevents formation of Nacetylmuramic acid (an essential
precursor for peptidoglycan chain
formation)
–
Resistance decreased intracellular
accumulation of the drug
•
Excreted by the kidney in urinary levels higher
than minimum inhibitory concentrations
(MIC) àmakes it useful against UTIs
•
In multiple dosing, diarrhea is common
•
May be synergistic with beta-lactam and
quinolone antibiotics in some infections
Bacitracin
•
Peptide antibiotic which interferes with a late
stage in cell wall synthesis in gram-positive
organisms
•
Limited to topical use because of its marked
nephrotoxicity
Cycloserine
•
Antimetabolite that blocks incorporation of
amino acids into the side chain of the
peptidoglycan
•
Highly neurotoxic (tremors, seizures, and
psychosis)
–
Limited use to tuberculosis that is
resistant to first-line antituberculosis
drugs
Daptomycin
•
Novel cyclic lipopeptide with spectrum similar
to vancomycin (but active against
vancomycin-resistant strains of enterococci
and staphylococci)
•
Eliminated via the kidney
•
Monitor creatinine since it causes myopathy