Transcript General Outline for Antibiotics

General Outline for Antibiotics
• Chemistry –MIP
• Effect on microbes - MIP
• Spectrum of coverage
• Mechanism(s) of action
• Mechanism(s) of resistance
• Pharmacology of antibiotic class –
mostly new info
• Absorbance
• Fate after absorption
• Excretion
• Pharmacology of select agents –
mostly new info
• Therapeutic uses – somewhat new
info
• Toxicity/contraindications – mostly
new info
• Common (> 10%)
• Uncommon (1-9%)
• Rare (< 1%)
Sir Alexander Fleming
Sulfonamides
• Analogues of PABA
• Broad spectrum
• Competitive inhibitors of
dihydropteroate synthase –
needed for folic acid
synthesis
• Cidal in urine
• Mechanisms of resistance
• Altered affinity of enzyme for
drug
• Decreased permeability or
active efflux
• New pathway of folic acid
synthesis
Gerhard Domagk gets a
Nobel for Medicine, 1939.
Sulfonamides
• Mostly absorbed from GI
tract
• Binds variably to serum
albumin
• Wide tissue distribution,
including transplacentally
• Variably inactivated in liver
by acetylation and then
excreted in urine
• Some agents can precipitate
in acid urine
Rapidly Absorbed and
Eliminated Sulfonamides
• Sulfisoxazole,
sulfamethoxazole,
sulfadiazine
• Bind extensively to
plasma proteins
• Highly concentrated in
urine (cidal)
• Sulfamethoxazole
combined with
trimethoprim (Bactrim) is
widely used to treat a
variety of infections (esp.
UTI)
Poorly Absorbed Sulfonamides
• Sulfasalazine
• Poorly absorbed in GI
tract
• Used to treat ulcerative
colitis and irritable
bowel syndrome
• Gut flora metabolize
drug into 2
compounds, 1 toxic, 1
therapeutic (5aminosalicylate)
Ulcerative Colitis
Sulfonamides for Topical Use
• Sulfacetamide
• Good penetration in
eye
• Non-irritating
• Silver sulfadiazine
Bacterial corneal infection
• Prevention and
treatment of burn
wound infections
Long Acting Sulfonamide
• Sulfadoxine
• Serum half-life is
measured in days
rather than minutes
or hours
• Combined with
pyirethamine to
treat malaria
Plasmodium vivax
Therapeutic Uses
of Sulfonamides
• Urinary tract
infections
• Nocardiosis
• Toxoplasmosis
(avoid using in
pregnant women)
Nocardia asteroides
Toxicity/Contraindications
of Sulfonamides - UT
• Crystallization in
acid urine
• Common to
uncommon
depending on drug
• Alkalize urine or
increase hydration
Toxicity/Contraindications
of Sulfonamides - blood
• Acute hemolytic anemia
• Rare to extremely rare
• Associated with glucose-6-phosphate
dehydrogenase activity in RBC
• Agranulocytosis (extremely rare)
• Aplastic anemia (extremely rare)
Toxicity/Contraindications
of Sulfonamides - immune
• Hypersensitivity reactions (common to
uncommon)
• Skin and mucous membrane
manifestations (rashes)
• Serum sickness
• Focal or diffuse necrosis of the liver (rare)
Toxic Epidermal Necrolysis
(TEN)
Toxicity/Contraindications
of Sulfonamides - miscellaneous
• Nausea, anorexia, vomiting
(common)
• Kernicterus
• Displacement of bilirubin
from plasma albumin to
brain resulting in
encephalopathy
• Never give sulfa drugs to a
pregnant or lactating
woman
Bilirubin deposits in
neonatal brain
• Potentiation of oral
coagulants, sulfonylurea
hypoglycemic drugs, and
hydrantoin anticonvulsants
The Quinolones
• Naladixic acid was a
byproduct of chloroquine
synthesis
• Current drugs are
fluoridated 4-quinolones
• Broad coverage (some
broader than others)
• Targets DNA gyrase (G-)
and topoisomerase IV (G+)
• Resistance due to efflux and
mutations in targets
Quinolones
• Favorable pharmacological
attributes
• Orally administered, quickly absorbed,
even with a full stomach
• Excellent bioavailability in a wide
range of tissues and body fluids
(including inside cells)
• Mostly cleared by the
kidneys
• Exceptions are pefloxacin and
moxifloxacin which are metabolized by
liver
• Ciprofloxacin, ofloxacin, and
pefloxacin are excreted in
breast milk
“Got Cipro?”
Therapeutic Uses
of Quinolones
• Urinary tract
infections
• Prostatitis
• STD’s
• Chlamydia
• Chancroid
• Not syphilis or
gonorrhea (due to
increased resistance)
Therapeutic Uses
of Quinolones
• GI and abdominal
• Travelers diarrhea
• Shigellosis
• Typhoid fever
• Respiratory tract
• All work well
against atypicals
• New agents for
strep. pneumonia
Therapeutic Uses
of Quinolones
• Bone, joint, soft tissue
• Ideal for chronic
osteomylitis
• Resistance developing in S.
aureus, P. aeruginosa, and
S. marcesens
• Good against
polymicrobial
infections like diabetic
foot ulcers
Therapeutic Uses
of Quinolones
• Ciprofloxacin for
anthrax and
tuleremia
• Combined with
other drugs, useful
for atypical
Mycobacterium sp.
or for prophylaxis
in neutropenic
patients
Pulmonary Anthrax
Toxicity/Contraindications
of Quinolones
• Nausea, vomiting, abdominal discomfort (common)
• Diarrhea and antibiotic-associated colitis
(uncommon to rare)
• CNS side effects
• Mild headache and dizziness (common to rare)
• Hallucinations, delirium, and seizures (rare)
• Arthropy in immature animals (common)
• Quinolones not given to children unless benefits outweigh
the risks
• Leukopenia, eosinophila, heart arythmias (rare)
The Beta-Lactams
Penicillins
• Penicillium notatum
produces the only
naturally occuring agent –
penicillin G or
benzylpenicillin
• Dosage and potency
based on IU (1 IU = 0.6
micrograms pure
penicillin G)
• P. chrysogenum produces
6-aminopenicillanic acid,
raw material for semisynthetics
• Dosage and potency
based on weight
Penicillins
• Spectrum of activity based on R groups
added to 6-aminopenicillanic acid core
• All are bactericidal and inhibit
transpeptidases
• Mechanisms of resistance
•
•
•
•
Alter affinity of transpeptidase
Enzymatically cleave the beta-lactam ring
Efflux pumps
Poor penetration into cell
Penicillins
• Administered orally, intramuscularly, or
intravenously depending on agent
• After oral dose, widely distributed in tissues
and secretions (except CNS, prostatic fluid,
and the eye)
• Do not kill intracellular pathogens
• Food interferes with adsorption
• Rapid elimination through kidney, secreted
in breast milk
Penicillins G and V
• Effective against aerobic G+ organisms except Staphylococcus,
Pen G active against Neisseria and anaerobes
• 2/3 of oral Pen G destroyed by stomach acid, Pen V is more
resistant so more is delivered to serum
• Rapid elimination through kidney so probenecid, procaine, of
benzathine added to slow excretion
• Most drug is bound to serum albumin but significant amounts
show up in liver, bile, kidney, semen, joint fluid, lymph, etc.
• Cautious use in neonates and infants because renal function is
not fully established
• Patients with renal failure clear the drugs through liver
although at a slow pace
Penicillins G and V
Therapeutic Uses
• Streptococcus pneumoniae
infections
• S. pyogenes infections
• Viridans strep endocarditis
(also given
prophylactically)
• Anaerobes except
Bacteroides fragilis group
• Meningococcal infections
• Syphilis and other diseases
caused by spirochetes
Isoxazolyl Penicillins
• Oxacillin, cloxacillin, dicloxacillin, nafcillin
• Designed to resist staphylococcal betalactamases
• Like Pen V, stable in stomach acid but usually
given parentally for serious staph infections
• MRSA not covered
• Absorption and fate of drugs after absorption,
excretion similar to Pen G and Pen V
Aminopenicillins
• Ampicillin and amoxicillin
• Broad spectrum
• Not effective against beta-lactamase producers
• Beta-lactamase inhibitors extend spectrum
• Both are acid resistant but amoxicillin is
better absorbed, even with food
• Don’t bind plasma proteins as much as
predecessors
• Secreted through the kidney
Aminopenicillins
Therapeutic Uses
• Upper respiratory
tract infections
• Otitis media
• Uncomplicated UTI
• Acute bacterial
meningitis in kids
• Typhoid fever
A Carboxypenicillin and
a Ureidopenicillin
• Ticarcillin and
piperacillin
• Ticarcillin is antiPseudomonas drug
• Piperacillin +
tazobactam has the
broadest spectrum
• Give parentally
• Used for serious
infections
Toxicity/Contraindications
of Penicillins
• Hypersensitivity reactions (uncommon)
• Rash, fever, bronchospasm, vasculitis, serum
sickness, exfoliative dermatitis, SJS, anaphylaxis
• Drugs act as haptens when bound to serum
proteins
• Rashes will disappear when drug is withdrawn
or can treat with antihistamines
• For patients with allergies, switch to a different
class of antibiotics or try to desensitize
Toxicity/Contraindications
of Penicillins
• Pain and sterile
inflammatory reaction at
injection site (dose-related)
• Large doses given to
patients with renal failure
can cause lethargy,
confusion twitching and
seizures
• Sudden release of procaine
can cause dizziness,
tinnitus, headache and
hallucinations
• Pseudomembranous colitis
Cephalosporins
• Base molecule is 7aminocephalosporanic acid
produced by a Sardinian
sewer mold
• R groups determine
spectrum of activity and
pharmacological properties
• Mechanism of
action/resistance and class
pharmacology essentially the
same as penicillins
First Generation
Cephalosporins
• Cefazolin, cephalexin,
cephadroxil
• Excellent against
susceptible staph and strep
• Modest activity against G• Cefazolin given parentally,
others orally
• More than half of the drug
is bound to plasma proteins
• Excreted by kidneys
unmetabolized
• Good for staph and strep
skin and soft tissue
infections
Second Generation
Cephalosporins
• Cefaclor, cefuroxime, cefprozil
• Modest activity against G+, increased
activity against G-, works against anaerobes
• Cefaclor and cefprozil given orally
• Absorption and excretion same as first gen.
• Good for treating respiratory tract
infections, intra-abdominal infections,
pelvic inflammatory disease, diabetic foot
ulcers
Third Generation
Cephalosporins
• Ceftaxime, ceftriaxzone,
cefoperazone, cefpodoxime
• Broad spectrum killers
• Drugs of choice for serious
infections
• No effect against Listeria and
beta-lactamase producing
pneumococci
• Cefpodoxime given orally,
others parentally
• Most excreted by kidney
• Therapeutic uses
• Bacterial meningitis (2
exceptions)
• Lyme disease
• Life-threatening G- sepsis
Fourth Generation
Cephalosporin
•Cefepime
•Same antimicrobial spectrum as
third generation but resists more
beta-lactamases
•Given parentally, excellent
penetration into CSF
•Good for nosocomial infections
Toxicity/Contraindications
of Cephalosporins
• Hypersensitivity reactions (uncommon)
essentially same as for penicillins
• Cross-reaction between 2 classes
Carbapenems
•Beta-lactam ring is fused to a 5
member ring system
•Effect on microbes and
pharmacology of carbapenems
similar to penicillins
Select Carbapenems
• Imipenem
• Broad spectrum including anaerobes and
Pseudomonas aeruginosa
• Parentally administered
• Must be combined with cilastatin to be absorbed
• Excreted by kidneys
• Meropenem, ertapenem, and doripenem are
similar to imipenem but don’t need coadministration with cilastatin
Aztrenam – a monobactam
• Works only on G-, including
Pseudomonas aeruginosa
• Useful for treating G- infections that
require a beta-lactam because it does
not elicit hypersensitivity reactions
Toxicity/Contraindications
of Carbapenems
• Nausea and vomiting (common)
• Hypersensitivity reactions
(uncommon)
• Essentially the same as for penicillins,
exception is the monobactam
• Cross-reactivity is possible, exception is
the monobactam
The End?
Nope.