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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

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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
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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)
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
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
•
•
•
•
•
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