Antibiotics: Common Toxicities Antibiotics: Common Toxicities

1. superinfection1. superinfection• broad spectrum agents most likely to disrupt balance of broad spectrum agents most likely to disrupt balance of

normal flora and allow a single microorganism to normal flora and allow a single microorganism to predominate and cause pathologypredominate and cause pathology

The human-microbe balancing actThe human-microbe balancing act

The majority of cells in our The majority of cells in our bodies are microbialbodies are microbial non pathogenic non pathogenic

bacteria,viruses, eukaryotic bacteria,viruses, eukaryotic microorganismsmicroorganisms

Symbiotic relationshipSymbiotic relationship protects against pathogensprotects against pathogens improves feed efficiencyimproves feed efficiency synthesis of vitaminssynthesis of vitamins modulates immune responsemodulates immune response

DilemmaDilemma Recent study (1529 office-based physicians; 28,787 Recent study (1529 office-based physicians; 28,787

visits) reported that antibiotics were prescribed for:visits) reported that antibiotics were prescribed for: 51% of patients diagnosed with colds51% of patients diagnosed with colds 52% of patients diagnosed with URIs52% of patients diagnosed with URIs 66% of patients diagnosed with bronchitis66% of patients diagnosed with bronchitis

Gonzales R, Steiner JF, Sande M. Antibiotic prescribing for adults Gonzales R, Steiner JF, Sande M. Antibiotic prescribing for adults with colds, upper respiratory tract infections, and bronchitis by with colds, upper respiratory tract infections, and bronchitis by ambulatory care physicians. JAMA 1997; 278:901-904.ambulatory care physicians. JAMA 1997; 278:901-904.

from Conrad Liles

Antibiotics: Common Toxicities Antibiotics: Common Toxicities

1. superinfection1. superinfection• broad spectrum agents most likely to disrupt balance of normal flora broad spectrum agents most likely to disrupt balance of normal flora

and allow a single microorganism to predominate and cause and allow a single microorganism to predominate and cause pathologypathology

low risk: narrow spectrum agents (e.g. penicillin G)low risk: narrow spectrum agents (e.g. penicillin G) high: e.g. (chloramphenicol, tetracyclines high: e.g. (chloramphenicol, tetracyclines

clindamycin)clindamycin) highest: broad spectrum cephalosporins, fluoroquinoloneshighest: broad spectrum cephalosporins, fluoroquinolones

2. allergic reactions2. allergic reactions• most common with penicillins, cephalosporinsmost common with penicillins, cephalosporins• also seen with many others e.g. sulfonamides, tetracyclines, also seen with many others e.g. sulfonamides, tetracyclines, aminoglycosidesaminoglycosides

Drug specific toxicity: HighlightsDrug specific toxicity: Highlights

AminoglycosidesAminoglycosides multiple toxicities multiple toxicities

• ototoxic, nephrotoxic, neurotoxicototoxic, nephrotoxic, neurotoxic• low therapeutic indexlow therapeutic index

how to minimizehow to minimize• recognize initial symptoms recognize initial symptoms • monitor dose/blood levels and adjust if patient hasmonitor dose/blood levels and adjust if patient has

a) reduced kidney function?a) reduced kidney function? b) hepatic disease?b) hepatic disease?

YESYES

NOT NecessaryNOT Necessary

Main

ten

an

ce

Main

ten

an

ce

dose

dose

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tam

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of

gen

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Adjusting for renal failureAdjusting for renal failurein gentamicin therapyin gentamicin therapy

OtotoxicityOtotoxicity

affects both hearing and balanceaffects both hearing and balance incidence? not well documentedincidence? not well documented

3-14% auditory high freq. affected first (8-20K Hz)3-14% auditory high freq. affected first (8-20K Hz) 4-6% vestibular4-6% vestibular

• gentamicin--more vestibulargentamicin--more vestibular• amikacin--more auditoryamikacin--more auditory• tobramycin--bothtobramycin--both

Aminoglycosides concentrate to very high levelsAminoglycosides concentrate to very high levelsin the perilymphatic fluid of the inner earin the perilymphatic fluid of the inner earA

G c

once

ntra

tion

AG

con

cent

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on

PlasmaPlasma

PerilymphPerilymph

Drug infusionDrug infusion

half life =2-3hr

neomycinneomycin

controlcontrol

Acute inhibition of hearing by high concentration of aminoglycosideAcute inhibition of hearing by high concentration of aminoglycoside

Possible mechanism of aminoglycoside Possible mechanism of aminoglycoside toxicity involving binding to phospholipidstoxicity involving binding to phospholipids

Possible mechanism of aminoglycoside Possible mechanism of aminoglycoside toxicity involving binding to phospholipidstoxicity involving binding to phospholipids

CaCa2+2+CaCa2+2+

neomycinneomycinneomycinneomycin

Genetic component to AG toxicityGenetic component to AG toxicity

Mutation in the 12S mitochondrial rRNA increases sensitivityMutation in the 12S mitochondrial rRNA increases sensitivityto aminoglycoside toxicityto aminoglycoside toxicity

G1555 mutation

Rate of mitochondrial protein Rate of mitochondrial protein synthesis (no aminoglycoside)synthesis (no aminoglycoside)

Rate plus aminoglycosideRate plus aminoglycoside

Percent inhibitionPercent inhibition

Mitochondrial protein synthesis is more Mitochondrial protein synthesis is more sensitive to aminoglycoside in individuals sensitive to aminoglycoside in individuals carrying a mutation in the 12S mito rRNAcarrying a mutation in the 12S mito rRNA

Note: AS=asymptomaticNote: AS=asymptomaticS=some hearing lossS=some hearing lossC=controlC=control

CC ASAS SS

Other 12S rRNA mutations confer sensitivityOther 12S rRNA mutations confer sensitivity

Role of protein synthesis inhibition in mechanism ofRole of protein synthesis inhibition in mechanism ofaminoglycoside toxicity?aminoglycoside toxicity?

--Mitochondrial protein synthesis is essential for assembly of --Mitochondrial protein synthesis is essential for assembly of oxidative phosphorylation apparatusoxidative phosphorylation apparatus

--Cochlear hair cells have high ox/phos demands--Cochlear hair cells have high ox/phos demands

--Genetic mutations in 12S rRNA make an individual more --Genetic mutations in 12S rRNA make an individual more sensitive to ototoxic effects/they also develop spontaneous sensitive to ototoxic effects/they also develop spontaneous deafness in absence of drugdeafness in absence of drug

• High Frequency Hearing Loss

Nephrotoxicity of aminoglycosidesNephrotoxicity of aminoglycosides

increased concentration of drug in proximal increased concentration of drug in proximal renal tubulerenal tubule

altered phospholipid metabolismaltered phospholipid metabolism myeloid bodies formmyeloid bodies form decreased GFR-can lead to vicious cycledecreased GFR-can lead to vicious cycle reversible if drug dose decreased early--reversible if drug dose decreased early--

permanent damage laterpermanent damage later

NeurotoxicityNeurotoxicity

acute muscular paralysis, apnea, deathacute muscular paralysis, apnea, death non-depolarizing block at NMJnon-depolarizing block at NMJ rare: during high dose therapy in pts undergoing surgeryrare: during high dose therapy in pts undergoing surgery increased risk: with anesthetics or other NMJ blockers, increased risk: with anesthetics or other NMJ blockers,

myasthenia gravismyasthenia gravis cause: blocks acetylcholine release by interfering with cause: blocks acetylcholine release by interfering with

calcium binding calcium binding treatment: reversible by calcium gluconatetreatment: reversible by calcium gluconate

• also Acetylcholinesterase inhibitors can helpalso Acetylcholinesterase inhibitors can help which one would you recommend if you want a short acting, non covalent which one would you recommend if you want a short acting, non covalent

block?block?

Advantage of giving Advantage of giving aminoglycosides only once/dayaminoglycosides only once/day

time spent over threshold concentrationfor toxicity is less

allows drug level to decline in long t 1/2 compartments like the inner ear

Chloroamphenicol ToxicityChloroamphenicol Toxicity

Gray baby syndrome: Gray baby syndrome: (abdominal distention, vomiting, (abdominal distention, vomiting, cyanosis, hypothermia, death-40% after ~ 4d)cyanosis, hypothermia, death-40% after ~ 4d)

usually in premature/neonate with limited hepatic usually in premature/neonate with limited hepatic functionfunction

can also occur in adults with severe hepatic can also occur in adults with severe hepatic dysfunctiondysfunction

Two types of toxic bone marrow depressionTwo types of toxic bone marrow depression

Chloramphenicol toxicity to bone marrowChloramphenicol toxicity to bone marrow

1. Toxic bone marrow depression--anemia, leukopenia, 1. Toxic bone marrow depression--anemia, leukopenia, thrombocytopeniathrombocytopenia

• reversible, dose related, caused by decr. in mito. prot. synthesis reversible, dose related, caused by decr. in mito. prot. synthesis suppression of ferrochelatase required to uptake Fe++ into suppression of ferrochelatase required to uptake Fe++ into hemeheme

2. Aplastic anemia2. Aplastic anemia• recognized ~1950 after 3 years of userecognized ~1950 after 3 years of use• complete bone marrow depressioncomplete bone marrow depression• incidence 1/25,000-1/40,000incidence 1/25,000-1/40,000• irreversible, not dose-related, may appear months after drug dc’edirreversible, not dose-related, may appear months after drug dc’ed• frequently fatal--if not, high incidence of leukemia in survivorsfrequently fatal--if not, high incidence of leukemia in survivors

Inappropriate use of chloramphenicol from 1953-1964Inappropriate use of chloramphenicol from 1953-1964

Erythromycin:Erythromycin:Erythromycin estolate can cause Erythromycin estolate can cause

cholestatic hepatitis-rare (fever, jaundice,cholestatic hepatitis-rare (fever, jaundice,decreased liver function (hypersensitivity rx)decreased liver function (hypersensitivity rx)

epigastric distress (20-25% of pts) cramps, diarrheaepigastric distress (20-25% of pts) cramps, diarrhea-acts as motilin receptor agonist-acts as motilin receptor agonist

Drug specific Toxicity-1Drug specific Toxicity-1

Tetracyclines:Tetracyclines:incorp.into bones & teeth (complex w/Caincorp.into bones & teeth (complex w/Ca2+2+))phototoxicity ~1.5% with doxycyclinephototoxicity ~1.5% with doxycyclineGI irritation (nausea, vomiting, diarrhea)GI irritation (nausea, vomiting, diarrhea)

must distinguish from superinfectionmust distinguish from superinfection

ClindamycinClindamycinsuperinfection w/Clostridium difficilesuperinfection w/Clostridium difficile

(1-10%) treat w/ oral vancomycin or(1-10%) treat w/ oral vancomycin or metronidazolemetronidazole

Drug specific Toxicity-2Drug specific Toxicity-2

Sulfonamides (5% incidence of side effects)Sulfonamides (5% incidence of side effects)crystallization in urinecrystallization in urinedisplaces bilirubin -->kernicterus (esp. in newborns)displaces bilirubin -->kernicterus (esp. in newborns)acute hemolytic anemiaacute hemolytic anemia

a) Type II immune reactiona) Type II immune reactionb) G6PD deficiency (genetic)b) G6PD deficiency (genetic)

Mutations in G6PD increase sensitivity of Mutations in G6PD increase sensitivity of RBCs to oxidizing agentsRBCs to oxidizing agents

Drug specific Toxicity-3Drug specific Toxicity-3

VancomycinVancomycinmild nephrotoxicity- reversiblemild nephrotoxicity- reversiblered neck syndrome (may be due to histamine release)red neck syndrome (may be due to histamine release)

flushing, tachycardia, hypotensionflushing, tachycardia, hypotensionCiprofloxacinCiprofloxacin

mild GI complaints most common (2-5%)mild GI complaints most common (2-5%)not usually recommended for pre-pubertal children due to not usually recommended for pre-pubertal children due to

joint swelling, arthropathyjoint swelling, arthropathyAchilles and other tendon ruptures seen rarely Achilles and other tendon ruptures seen rarely

rare CNS effects: psychosis, seizures, lethargy, confusion,rare CNS effects: psychosis, seizures, lethargy, confusion, depression, paresthesiadepression, paresthesia

inhibits theophylline and caffeine metabolism inhibits theophylline and caffeine metabolism LinezolidLinezolid

thrombocytopenia in ~2.4% pts. monitor platlets if otherthrombocytopenia in ~2.4% pts. monitor platlets if otherrisk factors present or if long duration of treatmentrisk factors present or if long duration of treatment

Quinupristin/DalfopristinQuinupristin/Dalfopristininfusion related events--phlebitisinfusion related events--phlebitisinhibitor of CYP3A4--may prolong t1/2 of other drugsinhibitor of CYP3A4--may prolong t1/2 of other drugs