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 pathologybroad 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 non pathogenic bacteria,viruses, eukaryotic microorganisms  Symbiotic relationship protects against pathogens protects against pathogens improves feed efficiency improves feed efficiency synthesis of vitamins synthesis of vitamins modulates immune response 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 51% of patients diagnosed with colds 52% of patients diagnosed with URIs 52% of patients diagnosed with URIs 66% of patients diagnosed with bronchitis 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: 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 pathologybroad spectrum agents most likely to disrupt balance of normal flora and allow a single microorganism to predominate and cause pathology low risk: narrow spectrum agents (e.g. penicillin G) low risk: narrow spectrum agents (e.g. penicillin G) high: e.g. (chloramphenicol, tetracyclines clindamycin) high: e.g. (chloramphenicol, tetracyclines clindamycin) highest: broad spectrum cephalosporins, fluoroquinolones highest: broad spectrum cephalosporins, fluoroquinolones  2. allergic reactions most common with penicillins, cephalosporins most common with penicillins, cephalosporins also seen with many others e.g. sulfonamides, tetracyclines, aminoglycosides also seen with many others e.g. sulfonamides, tetracyclines, aminoglycosides

Drug specific toxicity: Highlights  Aminoglycosides multiple toxicities multiple toxicities ototoxic, nephrotoxic, neurotoxicototoxic, nephrotoxic, neurotoxic low therapeutic indexlow therapeutic index how to minimize how to minimize recognize initial symptomsrecognize 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? YES 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) 3-14% auditory high freq. affected first (8-20K Hz) 4-6% vestibular 4-6% vestibular gentamicin--more vestibulargentamicin--more vestibular amikacin--more auditoryamikacin--more auditory tobramycin--bothtobramycin--both

Aminoglycosides concentrate to very high levels in the perilymphatic fluid of the inner ear AG concentration Plasma Perilymph Drug infusion half life =2-3hr

neomycin control Acute inhibition of hearing by high concentration of aminoglycoside

Possible mechanism of aminoglycoside toxicity involving binding to phospholipids Ca 2+ neomycinneomycin

Genetic component to AG toxicity

Mutation in the 12S mitochondrial rRNA increases sensitivity to aminoglycoside toxicity G1555 mutation

Rate of mitochondrial protein synthesis (no aminoglycoside) Rate plus aminoglycoside Percent inhibition Mitochondrial protein synthesis is more sensitive to aminoglycoside in individuals carrying a mutation in the 12S mito rRNA Note: AS=asymptomatic S=some hearing loss C=controlCASS

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 non-depolarizing block at NMJ rare: during high dose therapy in pts undergoing surgery rare: during high dose therapy in pts undergoing surgery increased risk: with anesthetics or other NMJ blockers, myasthenia gravis increased risk: with anesthetics or other NMJ blockers, myasthenia gravis  cause: blocks acetylcholine release by interfering with calcium binding treatment: reversible by calcium gluconate treatment: 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 block? 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 usually in premature/neonate with limited hepatic function can also occur in adults with severe hepatic dysfunction 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 hemereversible, 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 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 Inappropriate use of chloramphenicol from

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 Drug specific Toxicity-1 Tetracyclines:  incorp.into bones & teeth (complex w/Ca 2+ )  phototoxicity ~1.5% with doxycycline  GI irritation (nausea, vomiting, diarrhea) must distinguish from superinfection Clindamycin  superinfection w/Clostridium difficile (1-10%) treat w/ oral vancomycin or metronidazole 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 âmild GI complaints most common (2-5%) ânot usually recommended for pre-pubertal children due to âjoint swelling, arthropathy âAchilles and other tendon ruptures seen rarely ârare CNS effects: psychosis, seizures, lethargy, confusion, depression, paresthesia depression, paresthesia âinhibits 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