General Outline for Antibiotics

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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 (gt 10)
• Uncommon (1-9)
• Rare (lt 1)

Sir Alexander Fleming
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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.
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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

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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)

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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 (5-aminosalicylate)

Ulcerative Colitis
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Sulfonamides for Topical Use

• Sulfacetamide
• Good penetration in eye
• Non-irritating
• Silver sulfadiazine
• Prevention and treatment of burn wound infections

Bacterial corneal infection
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Long Acting Sulfonamide

• Sulfadoxine
• Serum half-life is measured in days rather than
  minutes or hours
• Combined with pyirethamine to treat malaria

Plasmodium vivax
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Therapeutic Uses of Sulfonamides

• Urinary tract infections
• Nocardiosis
• Toxoplasmosis (avoid using in pregnant women)

Nocardia asteroides
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Toxicity/Contraindications of Sulfonamides - UT

• Crystallization in acid urine
• Common to uncommon depending on drug
• Alkalize urine or increase hydration

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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)

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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)

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Toxic Epidermal Necrolysis (TEN)
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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
• Potentiation of oral coagulants, sulfonylurea
  hypoglycemic drugs, and hydrantoin
  anticonvulsants

Bilirubin deposits in neonatal brain
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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

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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?
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Therapeutic Uses of Quinolones

• Urinary tract infections
• Prostatitis
• STDs
• Chlamydia
• Chancroid
• Not syphilis or gonorrhea (due to increased
  resistance)

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Therapeutic Uses of Quinolones

• GI and abdominal
• Travelers diarrhea
• Shigellosis
• Typhoid fever
• Respiratory tract
• All work well against atypicals
• New agents for strep. pneumonia

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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

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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
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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)

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The Beta-Lactams
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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 semi-synthetics
• Dosage and potency based on weight

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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

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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

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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

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Penicillins G and VTherapeutic 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

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Isoxazolyl Penicillins

• Oxacillin, cloxacillin, dicloxacillin, nafcillin
• Designed to resist staphylococcal beta-lactamases
• 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

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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
• Dont bind plasma proteins as much as
  predecessors
• Secreted through the kidney

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AminopenicillinsTherapeutic Uses

• Upper respiratory tract infections
• Otitis media
• Uncomplicated UTI
• Acute bacterial meningitis in kids
• Typhoid fever

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A Carboxypenicillin and a Ureidopenicillin

• Ticarcillin and piperacillin
• Ticarcillin is anti-Pseudomonas drug
• Piperacillin tazobactam has the broadest
  spectrum
• Give parentally
• Used for serious infections

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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

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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

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Cephalosporins

• Base molecule is 7-aminocephalosporanic 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

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First GenerationCephalosporins

• 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

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Second GenerationCephalosporins

• 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

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Third GenerationCephalosporins

• 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

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Fourth GenerationCephalosporin

• Cefepime
• Same antimicrobial spectrum as third generation
  but resists more beta-lactamases
• Given parentally, excellent penetration into CSF
• Good for nosocomial infections

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Toxicity/Contraindications of Cephalosporins

• Hypersensitivity reactions (uncommon) essentially
  same as for penicillins
• Cross-reaction between 2 classes

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Carbapenems

• Beta-lactam ring is fused to a 5 member ring
  system
• Effect on microbes and pharmacology of
  carbapenems similar to penicillins

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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 dont need co-administration with
  cilastatin

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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

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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

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The End? Nope.