• 50% of hospital use is misuse (overused)
• disturbs hospital microbial ecology
• Increased chance of opportunistic infections
• should not be used as prophylaxis (unless for surgery)
• average length of use 1-21 days
• guidelines not adhered to

1. Inhibition of cell wall synthesis
2. alteration of cell membrane permeability
3. inhibition of ribosomal protein synthesis
4. Suppression of DNA synthesis
5. Inhibition of Folic acid synthesis

• Beta-Lactam antibiotics competitively inhibit the incorporation of new peptidoglycan strands via PBPs 
• Internal osmotic pressure causes lysis due to weakened wall
• Penicillins (amoxicillin, penicillin V)
• Cephalosporins (Cephalexin)

• bacterial enzymes that catalyze the formation of the cell wall by incorporating new peptidoglycan strands
• strands are cross linked with amide linkages

contains a lipopolysaccharide component, which maintains membrane integrity

• antibiotics such as polymyxin B displace Ca++ and Mg++ from the cell membrane and disrupt the membrane
• causes cell (membrane or wall?) to rupture

• antibiotics bind to the 'P' site of the subunits and inhibit peptidyl transferase
• this inhibits binding of tRNA to mRNA
• 30S: Tetracyclines, Aminoglycosides
• 50S: Macrolides, Clindamycin

• supercoiling of DNA, DNA replication, Recombination and DNA repair occurs by DNA Gyrase and Topoisomerase enzymes 

• Fluroquinolones and Metronidazole inhibit DNA Gyrase and topoisomerase enzymes
• Results: Vacuoles, filamentation and cell lysis

• Humans do not produce folic acid
• Bacterial synthesize folic acid from PABA (para amino benzoic acid)
• PABA converts into Dihydrofolic acid by enzyme Dihydrofolate reductase

• Sulfonamides are structural analogues of PABA and block the conversion
• Sulfamethoxazole and Trimethoprim
• (bacteria can not use folic acid taken in by humans, only that which they produce)

1. Enzymatic inactivation (i.e. break down the beta lactam ring of antibiotics)
2. Modification of target site
3. Altered cell membrane permeability
4. Active drug efflux
5. failure to activate the antibiotic
6. use of alternative growth requirements
7. overproduction of target sites

• Beta-lactamases inhibit the beta lactam ring of some antibiotics 
• Staphylococci and enterococci produce this enzyme
• Cross transfer this gene for resistance 
• Penicillins and Cephalosporins

• Can be caused by:
• Bacteriophages
• Integrons
• Transposon
• Plasmid

•  Genetic elements that capture and disseminate genes through a 'Gene cassette'
• Vibrio cholerae (most common bacteria that use integrons)

Can occur through 3 mechanisms:

1. Plasmid transfer
2. Transfer by viral delivery 
3. Transfer of free DNA (from dead bacteria)

• 50 such systems exist
• Cytoplasmic membrane transport proteins also used for the excretion of bacterial metabolic substrates and products
• E. Coli, Pseudomonas, Staphylococci, Streptococci, Pasteurella

A new infection while patient is being treated for a primary infection

• more likely with broad spectrum antibiotics
• often difficult to treat
• drug resistant microbes usually involved
• i.e GI infection due to antibiotics killing good bacteria as well as infectious bacteria

• Empiric:
  • Begin treatment immediately usually with severe infection
  • Consider taking a sample for culture

Susceptibility testing

• disk-diffusion testing
• broth dilution

active against a single species or a limited group of pathogens

• Penicillin G, Penicillin V, Erythromycin, Clindamycin

activity greater than narrow spectrum but lesser than broad spectrum

• Amoxycillin

agents that are active against a wide range of pathogens

• Tetracyclines, Sulfamethoxazole

• Lowest [antibiotic] that prevents growth of a microorganism after an 18-24 hr incubation period after inoculation
• [Serum] of antibiotic should always exceed MIC by 2-8 times
• provides guideline to antibiotic use
• some drugs more effective if they have a very ↑ blood [ ]
• others need a long duration of serum [ ] 
• very ↑ doses do not mean more antibacterial effect (long time periods between MICs allows bacterial growth and resistance development)

• inhibit the growth of bacteria but does not kill them
• # of bacteria remains relatively constant in the presence of a bacteriostatic drug
• immunologic mechanisms are required to eliminate organisms during treatment of an infection with bacteriostatic durgs

• kills sensitive organisms 
• the # of viable organisms falls rapidly after exposure to the drug
• (ie penicillins and cephalosporins)

• Blood [ ] too low
• patient compliance
• impaired host immune system
• inappropriate drug choice
• Limited vascularity or blood flow tissue (abscess, inflammation)
• Emergence of bacterial resistance
• delay in diagnosis
• incorrect diagnosis
• antibiotic antagonism or interactions

• teratology
• Long QT syndrome (prolonged refractory period)
• Agranulocytosis
• Superinfection
• Diarrhea and pseudomembranous colitis
• reduced oral contraception efficacy
• Photosensitivity, allergy and toxicity

• FDA class B or C
• amoxicillin is the only relatively safe antibiotic during pregnancy

• Genetic or acquired by drug use: Fluroquinolones and Macrolides may cause sudden syncope and arrest
• other drugs that cause long QT syndrome:
  • antihistamines
  • local anesthetics

• reduced neutrophil counts with septicemia and shock
• May be caused by Sulfonamides and Penicillins

• general structure contains a beta-lactam ring, a thiazolidine ring, and an aryl side chain
• shares basic chemistry with Cephalosporins, Monobactams, Carbapenems, and beta lactamase inhibitors

• Bind penicillin binding proteins (PBPs)
  • Inhibit Transpeptidases
  • promote autolysins
  • most effect against growing and dividing cells (so not effective against abscess) 

• creates cross-linkages between the peptidoglycan polymer strands
• Inhibited by penicillins

• Breaks section of cell wall to permit bacteria cell growth and cell lysis
• Promoted by Penicillins

Can be due to:

1. inability of drug to bind with PBP
2. Production of Beta-lactamases (Penicillinase) 
3. Impaired penetration of drug to bacteria
4. Antimicrobial efflux

• Different penicillins have different activity against gram + or - bacteria
• depends on structural differences in their cell wall
  • amount of peptidoglycan
  • penicillin receptors (PBP)
  • autolytic enzymes

• Narrow spectrum
• bactericidal 
• susceptible to b-lactamase
• IM, IV, not oral
• IV for Ludwig angina

• narrow spectrum
• oral
  • more stable to effects of GI enzymes than penicillin G

allergy (anaphylaxis, rash)

Candidasis (oral and vaginal) = superinfections

Exfoliative dermatitis

GI: loss of taste and appetite

• All penicillins are cross-sensitizing and cross reacting although mainly nontoxic
• anaphylaxis: 
  • serum sickness type

• Probenecid ↓renal tubular secretion of penicillin, thus used therapeutically (can give smaller, less freq doses)
• Aminoglycosides (Gentamicin) - inactivation
• Oral contraceptives: Hepatic enzyme induction, can lead to failure of OC and resultant pregnancy
• antibiotic combinations: do not give in combination, instead stack one after another

• Ampicillin, amoxicillin, Bacampicillin
• effective against Gm + and -
• Extended spectrum
• Amoxicillin: better oral absorption, taken with food, less AEs than ampicillin

• Enzyme produced by some bacteria
  • Penicillin V and Amoxicillin are ineffective against these bacteria
  • enzyme destroys these antibiotics
  • 2 strategies to overcome these resistant bacteria:

1. use penicillins that are resistant to the enzyme (cloxcillin)
2. Use amoxicillin and clavulanic acid combination

• Amoxicillin + Clavulanate (Augmentin)
• Cluvalante inhibits B-lactamase

• similar structure to penicillins
• stable against b-lactamases
• 4 generations
• allergic reactions have penicillin cross sensitiity

2 types of hypersensitivity seen:

1. Type I: Immediate with IM or IV injections 
   • If seen with penicillin DO NOT give cephalosporin
2. Type IV: delayed, with oral doses 
   • 10% chance of cross sensitivity

• Broad spectrum antibiotics
• Greater affinity for microbial ribosomal subunits 30S, 50S, 70S
• protein synthesis occurs much faster in microbial cells, therefore antibacterial activity is strong
• Bacteriostatic

• Tertacyclines
  • Tertacycline, Doxycycline
• Macrolides
  • Erythromycin, Azithromycin, Clarithromycin
• Clindamycin
• Chloramphenicol
• Streptomycin

• Cations: Antacids (Al, Mg), Ca and Fe supplements, laxatives (Mg), milk. ↓ drug absorption
• Antibiotics: Protein synthesis inhibitors
• Oral Contraceptives: ↓ OC reliability and ↑ breakthrough bleeding
• Cholestryamine or Colestipol: Cholesterol lowering agents. ↓ Absorption. Separate administration by several hours

• Antibiotics
  • Clindamycin, Cephalosporins, Ampicillin, Erythromycin
• Elderly
• Females with genitourinary diseases

• Crampy abdominal pain
• lower quadrant abdominal tenderness
• Watery diarrhea
• Fever
• Leukocytosis

• Stop all antibiotics
• Hydration
• Vancomycin (oral 500 mg qid for 2 days)
• Metronidazole (500 mg TID, 7-14 days)

• Alcohol - Disulfiram like reactions: nausea, giddiness, flushing, abd cramps, accumulation of acetaldehyde (non conversion)
• Disulfiram: confusion, psychotic rxns, convulsions (2 week washout pd recomm)
• Anticoagulants: inhibit metabolism, ↑ plasma levels, monitor PTT
• Barbiturates: ↓↓ metronidazole effect

MRSA

VRE

VRSA

Methicillin resistant Staph aureus

• isolate pt and wash hands
• Rx: Vancoycin 1g IV q12h
• Resistant to all penicillins and cephalosporins

Vancomycin resistant enterococci

• Infects immunocompromised pts
• routine id procedures in critical care areas with isolation of colonized pts

Vancomycin resistant Staph. aureas

• appearance has been feared and predicted for the last 20 years
• has potential to set back medicine back 100 years
• 1st reported case in detroit, MI Sept. 2002