General

• Selective Toxicity – destroy the microorganisms w/o harming the host
• Bactericidal -antibiotic causes cell death (Ex. Ags, penicillin, cephalosporins, vancomycin)
• Bacteriostatic – antibiotic inhibits bacterial growth ( Ex. Chloramphenicol, erythromycin, clinda, tetra
• -cidal vs. -static not hard and fast rule – Ex. Ampicillin -cidal against S. pneumonia and -static against Enterococcus
• Antagonism
• Synergy
• Indifference
• Mechanisms of Resistance

1)     Inactivation – destruction of the anti-biotic before it reaches its target

Ø  Enzymes

a.     b-lactamases ( Remember, Gram -‘s have periplasmic space)

b.     amino-glycoside modifying enzymes

c.      chloramphenicol acetyl transferase

Ø  chromosomal

Ø  plasmid-mediated

2)     Change in the targets

3)     Impermeability

Antibiotics That Inhibit Bacterial Protein Synthesis

Aminoglycosides

• all act at 30S site; leads to a “frozen” initiation complex or “nonsense” protein production

Ø  high doses – “frozen”

Ø  low doses or specific drugs (gentamicin)- leads to misreading and thus a “nonsense” protein

• all are bacteriocidal
• highly polar and use O₂ in an energy dependent mechanism to enter bacteria (so anaerobes are insensitive)
• Binding site – S12 (in streptomycin resistance a single a.a. substitution leads to prevention of binding)
• Resistance

Ø  inactivating enzymes – encoded on plasmids; can acetylate, phosphorylate, or adenylate

Ø  reduced uptake (Amikacin)

Ø  mutation of the 30S ribosomal subunit (streptomycin)

• Absorption

Ø  highly polar – IV or IM

Ø  if oral, work mainly in the gut lumen

• Excretion

Ø  entirely unchanged in the urine

• Distribution

Ø  low CSF penetration

Ø  usually in extracellular fluid

• Adverse Effects

Ø  Nephrotoxicity

-        parallels drug potency (Neomycin  > gentamicin, tobramycin > amikacin > streptomycin)

Ø  Ototoxicity – CONTRAINDICATED IN PREGNANCY

-        inversely related to drug potency (Streptomycin > amikacin > gentamicin > neomycin)

Ø  Neuromuscular blockade

-        high doses in accompaniment with anesthesia myasthenia gravis, or neuromuscular blockade

-        overcome via Ca salts

Indications for usage

• very wide spectrum against aerobic Gram (-) bacteria (penicillins or cephalosporins are usually used)
• organisms with acquired or innate resistance to other agents
• in combo with other drugs

Ø  intra-abdominal or pelvic infections – clindamycin + gentamicin

Ø  pyelonephritis – ampicillin + gentamicin

Ø  enterococcal endocarditis – ampicillin + gentamicin

Specific Drugs – Aminoglycosides

Streptomycin

• resistance via mutation of 30S complex

Gentamicin

Tobramycin

Amikacin

• structure resists modification with phosphorylating, adenylating, and some acetylation, so may remain active to bacteria resistant to other Ags.
• Resistance is via reduced uptake

Neomycin

• no longer used systemically
• used alone, or combined with bacitracin and polymixin, for minor soft tissue infections

Spectinomycin**

• aminocyclitol structure – similar to Ags
• ONLY ONE THAT IS NOT BACTERIOCIDAL
• Only use – penicillin-resistant gonorrhea

Tetracyclines

• These inhibit protein synthesis in BOTH prokaryotic and eukaryotic cells
• Selective toxicity – due to the active transport of tets into bacteria – we don’t do it
• Bind to the 30S; prevents binding of the aminoacyl-t-RNA at the A-site
• Resistance

Ø  plasmids which encode proteins which affect the transport of the drug into the bacteria

Ø  can be an “active export” system

Ø  cross resistance occurs (if resistant to one tetracycline, then resistant to all)

• Absorption

Ø  adequately absorbed via the GI tract

-        impaired by the ingestion of food, especially milk products and antacids

Ø  Minocycline and Doxycycline are highly lipophilic thus they are highly concentrated in the fatty tissue; they are easily absorbed and have long plasma t^1/2

• Distribution

Ø  entry into CSF (25%) of plasma level

Ø  good whole body penetration

Ø  bind to plasma proteins and tissues

• Excretion

Ø  most are eliminated via the kidney, but also passed in the feces

Ø  Exception: Doxy and Mino are hepatically metabolized.

Ø  All tets are conc. In liver and excreted in bile; so enterohepatic circulation can occur

• Adverse Effects

Ø  GI upset and diarrhea

Ø  Hepatotoxicity – especially in pregnancy; takes high doses (oxytetracycline and tetracycline are least hepatotoxic)

Ø  Phototoxicity

Ø  Can chelate calcium in growing calcified tissues. Perinatal exposure – discoloration of enamel of teeth.

Ø  Suprainfections

• Indications for Use

Ø  used to be wide spectrum but not now due to resistance

Ø  Main uses now: Chlamydia, Mycoplasma, Rickettsiae, Borrelia Burgdorferi, Leptospira, and certain parasites, acne treatment.

Specific Drugs – Tetracyclines

Doxycycline

Minocycline

Tetracycline

Oxytetracycline

Chloramphenicol

• binds to the 50S subunit to inhibit protein synthesis; prevents peptide bond formation
• Mammalian 80S chromosomes are insensitive, BUT mitochondrial synthesis (70S) is inhibited.
• Usually bacteriostatic but sometimes in high doses may be bacteriocidal.
• Resistance

Ø  inactivation by enzymes which reduce the NO group, hydrolyze the amide linkage, or acetylate the drug.

• Absorption

Ø  rapidly absorbed

• Distribution

Ø  lipophilic – crosses membranes easily

Ø  concentrated in brain

• Excretion

Ø  90% inactivated in liver by glucuronyl transferase

Ø  excretion via the kidney

• Adverse Effects

Ø  Hematological Toxicity – may be related to the inhibition of mito protein synthesis

Ø  Aplastic Anemia – same relation

Ø  Fatal toxicity in neonates (Gray Baby syndrome) – inadequate maturation of glucuronide conjugation system and underdeveloped liver and kidneys

• Indications for Use

Ø  potent wide spectrum antibiotic with good CSF penetration

Ø  activity against Gram(-) and Gram (+) aerobic and against virtually all anaerobic bacteria

Ø  like the Tets, active against rickettsia, chlymadia, mycoplasma

Ø  Niches:

1)     pediatric menigitis – ampicillim + Chloramphenicol

2)     Typhoid fever

3)     RMSF or other rickettsial diseases

4)     Brain abscess

5)     Intra-abdominal infections

6)     Penicillin-resistant strains of meningococcus and pneumococcus

Macrolide Antibiotics

• bind to the 50S subunit
• bacteriostatic
• Erythromycin, Azithromycin, and Clarithromycin are similar. Clindamycin has several differences
• Absorption

Ø  if oral – enterically coated because it is inactivated by a low pH in the stomach

Ø  IM injection very painful, so usually not done

Ø  Available IV

Ø  Good body tissue penetration; POOR CNS penetration

• Excretion

Ø  concentrated in the liver, excreted in the bile mostly in its active form

• Adverse Reactions

Ø  GI upset – nausea, vomiting, diarrhea

Ø  Allergic Reactions

Ø  Hepatitis – in high doses

Specific Drugs – Macrolide Antibiotics

Erythromycin

Azithromycin

• better absorbed than erythromycin
• fewer GI side effects
• concentrates in the tissues; low serum levels

Clarithromycin

• better absorbed than erythromycin
• fewer GI side effects

Clindamycin

• binds to the 50S subunit at or near to the site of chloramphenicol and erythromycin
• absorbed well; well distributed in tissues and bone, but not in CNS
• extensively metabolized to inactive products in the liver
• Adverse Effects

Ø  Stomach upset, “pill esophagitis”

Ø  Pseudomembrane colitis due to suprainfection with Clostridium difficile

• Therapeutic uses

1)     anaerobic abdominal, pelvic, or lung abscesses and bacteremia or pneumonia

2)     diabetic foot infections, Staph and Strep osteomyelitis

3)     Intrauterine infections, septic abortion, endometritis, pelvic abscesses

4)     Encephalitis caused by Toxoplasma gondii in AIDS patients – Clindamycin + pyrimethamine

5)     Pneumocystis Carinii – Clindamycin + Primaquine

• review bacterial Cell Wall and Membrane Structure on p. 103
• Gram (-)s have outer membrane

Ø  periplasmic space is where the b-lactamases reside in Gram (-) bacteria

• Gram (+)s secrete the b lactamase into the environment

The Penicillins – Penicillin, Penicillin V, ampicillin, amoxicillin, nafcillin, oxacillin, methicillin, cloxacillin, dicloxacillin, ticarcillin, piperacillin, sulbactam, clavulanic acid

General

• Basic Structure

Ø  two rings, b-lactam is the one responsible for the effect of penicillin antibiotics on bacteria

Ø  other side chains add various other characteristics

• Mechanisms

1)     inactivate transpeptidases – inhibit cell wall synthesis

2)     activate autolysins – unknown mech.

3)     the unchecked autolysis destroys the cell wall and the cell swells and undergoes osmotic rupture

The Plain Penicillins – Penicillin G, Penicillin V

·        not effective against enteric Gram (-) rods

Penicillin G

• Absrption – not well absorbed orally
• Distributed in body H₂O; ~1-5% CSF levels

Penicillin V

• Absorption – much better absorbed (especially the K salt)
• Distributed in body H₂O; ~1-5% CSF levels

Properties of both G and V

• very rapid glomerular filtration and tubular secretion

Ø  serum t^1/2 – 30 min

Ø  PROBENECID blocks tubular secretion – prolongs the t^1/2 of penicilins and cephalosporins

• Adverse Reactions

1)     Allergy – Anaphylaxis, “accelerated” reactions, late reactions, serum sickness

2)     Direct neurotoxicity – seizures at high doses or if applied directly to brain

3)     Na, K overload

4)     Platelet aggregation defect

Aminopenicillins – Ampicillin & Amoxicillin

Ampicillin

• like penicillin, covers Strept,
• Also covers Hemophilus, Enterococcus and many Gram (-) bacteria like E. coli
• Bactericidal against Streptococcus pneumoniae
• Bacteriostatic against Enterococcus

Amoxicillin

• much better absorbed than Ampicillin, low doses can be given
• less GI side effects than Ampicillin
• more expensive
• don’t use it to treat intestinal bacteria because it is absorbed before reaching the colon

Anti-Staphylococcal Penicillins -Nafcillin, Oxacillin, Methicillin

Nafcillin

• best anti-Staph penicillin
• irritating to veins
• dose-related neutropenia

Oxacillin

• used in susceptibility testing because of long shelf t^1/2
• suseptibility to oxacillin confirms susceptibility to all anti-staphylococcal penicillins
• less irritating to veins, more expensive

Methicillin – oral forms, cloxacillin, dicloxacillin

• weak activity against streptococci
• good for non-life threatening Staph and Strep infections

Extended Spectrum Penicillins – Ticarcillin, Piperacillin

• lower antimicrobial potency – must be given in high doses

Ø  watch out for NA and K overload and platelet function defects

• Used for: hospital acquired pneumonias, empiric therapy in neutropenic patients

b-Lactamase inhibitors – Clavulanic acid, Sulbactam

• these are b-lactam analogs without antibacterial activity
• act as suicide inhibitors of b-Lactamase

Augmentin – amoxicillin + clavulanic acid

• used for: H. influenza, gonococci, Pasteurella, Staph aureua, anaerobes, Moraxella

Unasyn – ampicillin + sulbactam

• used for hospital therapy of aspiration pneumonia, intra-abdominal infection

Timentin – Ticarcillin + clavulanic acid

• broad spectrum, Staph Aureus, Gram (-)s, anaerobes
• doesn’t cover MRSA, Strept viridians, Pseudomonas that are resistant to ticarcillin

Cephalosporins – Cephalothin, cefazolin, cephalexin, cefamandole, cefuroxime, cefaclor, cefoxitin, cefotetan, cefotaxime, ceftriaxone, ceftazidime, cefoperazone

• Mechanism

Ø  same as penicillins – inactivate transpeptidases

• Elimination

Ø  renal filtration and secretion

Ø  short t^1/2 – 0.5-1.8 hrs

Ø  Exception: Ceftriaxone, cefoperazone excreted via the bile and have long t^1/2

• Absorption

Ø  2^nd and 3^rd generations have sufficient activity and CNS penetration to be useful for bacterial meningitis

• Most common sdverse effects are allergic reactions – 5-10% of those allergic to penicillin will be allergic to 1^st generation, 3% to 3^rd generation
• Spectrum

Ø  streptococci, Staph Aureus, Gram (-)s (increased activity from 1^st to 3^rd generations),

Ø  NO CEPHALOSPORIN is effective against Enterococcus or Listeria

1^st generation Cephalosporins – Cefazolin, Cephalexin, cephalothin

Cefazolin

• used for surgical prophylaxis, post operative

Cephalexin

• used for penicillin substitution in selected penicillin-allergic patients
• Staph, skin infections

2^nd Generation Cephalosporins – Cefuroxime, Cefuroxime axetil, cefaclor, cefoxitin, cefotetan, cefomandole

Cefamandole

• used for peri-operative prophylaxis
• associated with

1)     coagulopathy with prolonged administration

2)     “Anatabuse” like reaction to alcohol

Cefuroxime

• pneumonias, skin & soft tissue infections (used to be for bacterial meningitis)

Cefuroxime axetil

• prodrug of cefuroxime
• newer agent for upper & lower respiratory infections (expensive)

Cefaclor

• otitis media, bacterial upper respiratory infections

Cefoxitin and Cefotetan

• good anti-anaerobic activity
• used for intra-abdominal infections, pelvic, infections, endometritis, spetic pelvic thrombophlebitis

3^rd Generation Cephalosporins – Cefotaxime, Ceftriaxone, Ceftazidime, Cefoperazone

Cefotaxime

• pneumonias, meningitis
• NOT effective against Pseudomonas

Ceftriaxone

• spectrum identical to cefotaxime
• excreted via the bile
• bacterial meningitis in children, adults; pneumonias, late Lyme disease
• DRUG OF CHOICE FOR – gonorrhea

Ceftazidime

• active against Pseudomonas
• weak against staphylococci

Cefoperazone

• similar spectrum to ceftazidime
• excreted in bile

Monobactams – Aztreonam

• has a “naked” b-lactam ring not fused to any other ring
• Absorption

Ø  not orally absorbed; must be given IM or IV

• Spectrum

Ø  ONLY COVERS aerobic Gram (-) rods

Ø  Does not cover gram (+) or anaerobes

Ø  If resistance exists to ceftazidime, will also be resistant to Aztreonam

Carbapenems – Imipenem

• has a carbon atom substituted at position 1 of the 5 membered ring instead of a sulfur like in penicillins
• Excretion

Ø  metabolized by an enzyme in the kidney – hihydropeptidase

1)     generates mildly nephrotoxic products

2)     causes the loss of anti-microbial activity

Ø  for this reason, Imipenem is combined with an inhibitor of the dehydropeptidase Cilastatin

• Adverse effects

Ø  N, V, and seizures if dose too high or rapidly given

• Spectrum

Ø  very broad because the carbapenem structure makes it resistant to many b-lactamases

Glycopeptides -Vancomycin

• tricyclic glycopeptide
• must be given IV
• Excretion

Ø  renal, not removed by dialysis

• Adverse reactions

1)     “Red Man” or “red neck” syndrome – flushing, headache, urticarial rash, hypoTN

Ø  mechanism is directly due to drug-induced histamine release

Ø  can be managed with anti-histamines and slow IV administration

2)     Nephrotoxicity

3)     Auditory toxicity – hearing more affected than vestibular system

4)     True allergy

5)     Irritation at injection site

• Used for

-        DRUG OF CHOICE for MRSA

-        Severe Strept or Staph in penicillin or cephalosporin allergic individuals

-        Gram (+) infections in patients on hemodialysis

-        Orally for Clostridium difficile – associated colitis

Inhibitors of Folic Acid Metabolism and Sulfonamides – trimethoprim, sulfisoxazole, sulfamethoxazole, sulfadoxine, topical sulfas

Sulfonamides in General

• usually bacteriostatic
• Mechanism

Ø  inhibits folic acid metabolism in bacterial cells

Ø  competitively inhibit production of tetrahydrofolate which is essential in the biosynthesis of 1) purines  2) thymidine   3) amino acid methionine

• Absorption

Ø  Good GI uptake except for those designed to stay in the gut.

Ø  Good CSF penetration for major analogues (30% to 80%)

• Excretion and Metabolism

Ø  liver enzymes acetylate to inactivate

Ø  high concentration achieved in the urine

• Adverse Reactions

1)     Allergic Reactions

2)     Bone marrow suppression

3)     Insoluble crystals in urinary tract – need to keep the urine alkaline so drink H₂O

4)     Kern icterus – in those with inadequate hepatic conjugation systems

-        do not use late in pregnancy or in newborns

• Resistance mechanisms

1)     impermeability

2)     overproduction of DHF reductase

3)     production of mutant DHFR enzyme

Sulfisoxazole

• UTI, upper respiratory infections

Sulfamethoxazole

• used in combo with Trimethoprim since it has a long t^1/2
• acute UTI

Sulfasalazine

• intra-GI tract agent – not systemically absorbed
• broken down by the gut to yield 5-ASA and sulfapyridine
• therapeutic for ulcerative colitis

Topical Agents – Sulfacetamide, Silver sulfadiazine

• eyes and burns

Sulfadoxine

• long acting
• used in combo with pryimethamine for treatment of chloroquine resistant malaria

Trimethoprim – Sulamethoxazole (Bactrim, Septra,)

• synergistic effect
• wide spectrum – Gram (+)s, Gram (-)s, and even some parasites

Quinolones – Ciprofloxacin, Norfloxacin, Ofloxacin, lomefloxacin, enoxacin

• Mechanism of Action

Ø  binds to A subunit of DNA gyrase (enzyme that unwinds supercoiled DNA)

-        inhibits the DNA gyrase so gene expression cannot take place

• Bacteriocidal against Gram (-)s
• Anaerobes are resistant to quinolones
• Absorption

Ø  good (Cipro) to fair (norfloxacin)

Ø  Divalent cations interfere with absorption (antacids, Tums, mineral supplements)

-        they can chelate the quinolones

> good penetration into most tissues (CSF is poor however ~10% of serum levels)

• Excretion and metabolism

Ø  moderate first pass metabolism in the liver

Ø  50% is passed unchanged in the urine

• Adverse effects

1)     CNS side effects – may interact with GABA receptors

2)     Photosensitivity

• Drug interactions

Ø  some quinolones interfere with caffeine and theophylline metabolism which leads to toxicity (esp. ciprofloxacin and enoxacin)

• Resistance Mechanisms

Ø  Quite rare in enteric bacteria

Ø  MRSA is usually

• Main uses

-        bacterial causes of diarrhea, thyphoid fever, prostatitis, bacillary osteomyelitis, complicates UTIs, Pseudomas, MDR TB, M. avium

Ciprofloxacin

• good absorption
• INTERACTS WITH CAFFEINE AND THEOPHYLLINE
• Uses: resp., skin, UTIs

Norfloxacin

• mediocre absorption
• less interaction with caffeine and theophylline
• used for UTIs and enteric infections

Ofloxacin

• good against Pseudomonas
• no interaction with caffeine or theophylline
• uses: resp, skin, GC, chlamydia, UTI

Lomefloxacin

• used for UTI, bronchitis due to H influenzae and Moraxella

Enoxacin

• INTERACTS WITH CAFFEINE AND THEOPHYLLINE
• Used for GC and UTIs only

RNA Polymerase Inhibitor – Rifampin

• Mechanism

Ø  inhibits bacterial RNA polymerase (remember Rifnmpia)

• Absorption

Ø  good oral, even goes into CNS well

• Metabolism

Ø  liver enzymes deacetylate – this product is also active

• Uses – Gram (+)s, Neiseria and Mycobacteria
• Prophylaxis of close contacts of Neisseria meningitidis or INH-resistant TB
• Adverse effects

1)     RED feces, urine, tears, sweat

2)     Hepatitis

3)     Fever and flu-like symptoms

Antibiotics for UTIs – nalidixic acid, Cinoxacin, Nitrofurantoin

Nalidixic Acid and Cinoxacin

• do not achieve therapeutic levels in the blood, but are concentrated in the urine
• Mechanism

Ø  inhibit DNA gryase

• rapid emergence of resistance

Nitrofurantoin (Macrodantin)

• unknown mechanism
• active against many Gram (-)s

Metronidazole (Flagyl)

• mechanism

Ø  ferredoxin in anaerobic bacteria and parasites reduce the NO₂ group to generate toxic byproducts

• Bacteriocidal against anaerobic organisms
• Absorption

Ø  good orally

Ø  good penetration including brain

• Excretion: mainly in the urine
• Adverse Effects

1)     Common: nausea, metallic taste in mouth, disulfiram-like effect

2)     Neurologic: tingling, numbness, dizziness, vertigo

3)     Rare: seizures, ataxia

• DO NOT GIVE DURING PREGNANCY OR NURSING or in prolonged courses in children
• Used for

1)     anaerobic infections – esp brain abscesses

2)     Giardia

3)     Invasive forms of amebiasis

4)     Vaginal Trichomonas

5)     Vaginal bacteriosis

Inhibitors of Cell Membrane Transport – Polymixins

• Mechanism

Ø  bind to the lipid A portion of lipopolysaccharide of Gram (-) outer membrane, and also to membranes high in PE and therefore disrupt transport mechanisms

• Used for:

1)     topical for wounds, burns, and areas infected with Pseudomonas

2)     can be inhaled for bronchial infections

• Adverse effects

1)     Topical: none

2)     IV: severe including dizziness, flushing, hypoTN, and nephrotoxicity

Tags: acetylation, adenylating, amikacin, Chloramphenicol, clinda, erythromycin, Nephrotoxicity, phosphorylating, Selective Toxicity, streptomycin

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