Transcript AB_tox_07ho
Antibiotics: Common Toxicities
1.
superinfection
• broad spectrum agents most likely to disrupt balance of
normal flora and allow a single microorganism to
predominate and cause pathology
The human-microbe balancing act
The majority of cells in our
bodies are microbial
non pathogenic
bacteria,viruses, eukaryotic
microorganisms
Symbiotic relationship
protects against pathogens
improves feed efficiency
synthesis of vitamins
modulates immune response
Dilemma
Recent study (1529 office-based physicians; 28,787
visits) reported that antibiotics were prescribed for:
51% of patients diagnosed with colds
52% of patients diagnosed with URIs
66% of patients diagnosed with bronchitis
Gonzales R, Steiner JF, Sande M. Antibiotic prescribing for adults
with colds, upper respiratory tract infections, and bronchitis by
ambulatory care physicians. JAMA 1997; 278:901-904.
from Conrad Liles
Antibiotics: Common Toxicities
1. superinfection
• broad spectrum agents most likely to disrupt balance of normal flora
and allow a single microorganism to predominate and cause pathology
2.
low risk: narrow spectrum agents (e.g. penicillin G)
high: e.g. (chloramphenicol, tetracyclines
clindamycin)
highest: broad spectrum cephalosporins, fluoroquinolones
allergic reactions
• most common with penicillins, cephalosporins
• also seen with many others e.g. sulfonamides, tetracyclines,
aminoglycosides
Drug specific toxicity: Highlights
Aminoglycosides
multiple toxicities
• ototoxic, nephrotoxic, neurotoxic
• low therapeutic index
how to minimize
• recognize initial symptoms
• monitor dose/blood levels and adjust if patient has
a) reduced kidney function? YES
b) hepatic disease? NOT Necessary
Maintenance dose
of gentamicin
Adjusting for renal failure
in gentamicin therapy
Ototoxicity
affects
both hearing and balance
incidence? not well documented
3-14% auditory high freq. affected first (8-20K Hz)
4-6% vestibular
• gentamicin--more vestibular
• amikacin--more auditory
• tobramycin--both
AG concentration
Aminoglycosides concentrate to very high levels
in the perilymphatic fluid of the inner ear
Perilymph
Plasma
half life =2-3hr
Drug infusion
Acute inhibition of hearing by high concentration of aminoglycoside
control
neomycin
Possible mechanism of aminoglycoside
toxicity involving binding to phospholipids
Ca2+
neomycin
Genetic component to AG toxicity
Mutation in the 12S mitochondrial rRNA increases sensitivity
to aminoglycoside toxicity
G1555 mutation
Mitochondrial protein synthesis is more
sensitive to aminoglycoside in individuals
carrying a mutation in the 12S mito rRNA
Rate of mitochondrial protein
synthesis (no aminoglycoside)
Rate plus aminoglycoside
Note: AS=asymptomatic
S=some hearing loss
C=control
Percent inhibition
C AS S
Other 12S rRNA mutations confer sensitivity
Role of protein synthesis inhibition in mechanism of
aminoglycoside toxicity?
--Mitochondrial protein synthesis is essential for assembly of
oxidative phosphorylation apparatus
--Cochlear hair cells have high ox/phos demands
--Genetic mutations in 12S rRNA make an individual more
sensitive to ototoxic effects/they also develop spontaneous
deafness in absence of drug
• High Frequency
Hearing Loss
Nephrotoxicity of aminoglycosides
increased
concentration of drug in proximal
renal tubule
altered phospholipid metabolism
myeloid bodies form
decreased GFR-can lead to vicious cycle
reversible if drug dose decreased early-permanent damage later
Neurotoxicity
acute muscular paralysis, apnea, death
non-depolarizing block at NMJ
rare: during high dose therapy in pts undergoing surgery
increased risk: with anesthetics or other NMJ blockers,
myasthenia gravis
cause: blocks acetylcholine release by interfering with
calcium binding
treatment: reversible by calcium gluconate
• also Acetylcholinesterase inhibitors can help
which one would you recommend if you want a short acting, non covalent
block?
Advantage of giving
aminoglycosides only once/day
time spent over
threshold concentration
for toxicity is less
allows drug level to
decline in long t 1/2
compartments like the
inner ear
Chloroamphenicol Toxicity
Gray
baby syndrome: (abdominal distention, vomiting,
cyanosis, hypothermia, death-40% after ~ 4d)
usually in premature/neonate with limited hepatic
function
can also occur in adults with severe hepatic
dysfunction
Two
types of toxic bone marrow depression
Chloramphenicol toxicity to bone marrow
1. Toxic bone marrow depression--anemia, leukopenia,
thrombocytopenia
• reversible, dose related, caused by decr. in mito. prot. synthesis
suppression of ferrochelatase required to uptake Fe++ into
heme
2. Aplastic anemia
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recognized ~1950 after 3 years of use
complete bone marrow depression
incidence 1/25,000-1/40,000
irreversible, not dose-related, may appear months after drug dc’ed
frequently fatal--if not, high incidence of leukemia in survivors
Inappropriate use of chloramphenicol from 1953-1964
Drug specific Toxicity-1
Tetracyclines:
incorp.into bones & teeth (complex w/Ca2+)
phototoxicity ~1.5% with doxycycline
GI irritation (nausea, vomiting, diarrhea)
must distinguish from superinfection
Erythromycin:
Erythromycin estolate can cause
cholestatic hepatitis-rare (fever, jaundice,
decreased liver function (hypersensitivity rx)
epigastric distress (20-25% of pts) cramps, diarrhea
-acts as motilin receptor agonist
Clindamycin
superinfection w/Clostridium difficile
(1-10%) treat w/ oral vancomycin or
metronidazole
Drug specific Toxicity-2
Sulfonamides (5% incidence of side effects)
crystallization in urine
displaces bilirubin -->kernicterus (esp. in newborns)
acute hemolytic anemia
a) Type II immune reaction
b) G6PD deficiency (genetic)
Mutations in G6PD increase sensitivity of
RBCs to oxidizing agents
Drug specific Toxicity-3
Vancomycin
mild nephrotoxicity- reversible
red neck syndrome (may be due to histamine release)
flushing, tachycardia, hypotension
Ciprofloxacin
mild GI complaints most common (2-5%)
not usually recommended for pre-pubertal children due to
joint swelling, arthropathy
Achilles and other tendon ruptures seen rarely
rare CNS effects: psychosis, seizures, lethargy, confusion,
depression, paresthesia
inhibits theophylline and caffeine metabolism
Linezolid
thrombocytopenia in ~2.4% pts. monitor platlets if other
risk factors present or if long duration of treatment
Quinupristin/Dalfopristin
infusion related events--phlebitis
inhibitor of CYP3A4--may prolong t1/2 of other drugs