Tufts OpenCourseware
Author: Michael Thompson, Ph.D.
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1. 1. Antibiotics, Antifungals, Antivirals

1.1. Definitions

1.1.1. Spectrum of activity

Narrow, extended or broad, based on range of susceptible organisms:

  1. Narrow: penicillin, macrolides, clindamycin, metronidazole
  2. Extended: amoxicillin, ampicillin, cephalosporins
  3. Broad: tetracyclines

1.1.2. Selective toxicity

Drug targets structures or cellular processes sufficiently unique to invading organisms that toxicity to host (us!) is minimal. Antibiotics are toxic to bacteria and not to us to the extent that they target a process or structure that we either don’t have or that is dissimilar enough that the drug targets the bacterial process or structure better.

  • Cell wall synthesis inhibitors: we don’t have cell walls
  • Protein synthesis inhibitors:
    • Target 30S or 50S ribosomal structures that bacteria have that we don’t have
    • Target bacterial protein synthesis that is occurring at a much faster rate than in mammalian cells
    • Actively taken up into bacteria cells-not ours
  • Antifungals: Target ergosterol synthesis or bind to ergosterol – we have cholesterol rather than ergosterol in our cell membranes
  • Sulfonamides: Target folic acid synthesis – we get folic acid from our diet, thus don’t have to synthesize it as do bacteria

1.1.3. Mechanism of action

  1. Is either bactericidal or bacteriostatic: cidal kills organism, static slows growth so immune system can kill
  2. Cidals should always be first choice; statics require functioning immune system, cidals don’t
  3. Cidal vs. static:
    1. Advantages/disadvantages:
      1. Cidal doesn’t require functioning immune system, static does
      2. Cidal has time dependent action, whereas static drugs are concentration dependent
      3. Cidal agents produce a “postantibiotic effect”:
        1. Binding to enzymes continues to kill bacteria even though the drugs are largely eliminated within 2 hours but can be dosed at 6 hr intervals
  4. Cidal mechanisms:
    1. Examples of agents with cidal activity (drug kills the bacteria, not immune system)
      1. Penicillins, cephalosporins, metronidazole, aminoglycosides, vancomycin, quinolones, clindamycin (at high doses)
    2. Cell wall synthesis inhibition: penicillins, cephalosporins, vancomycin
    3. Inhibition of DNA synthesis: metronidazole
    4. Inhibition of DNA gyrase: quinolones
    5. Inhibition of protein synthesis: aminoglycosides
  5. Static mechanisms:
    1. Protein synthesis inhibition: stops population from rapidly dividing so immune system can kill the bacteria
    2. Agents with static activity
      1. Macrolides, tetracyclines, clindamycin (at normal doses), sulfonamides

1.1.4. Superinfection/opportunistic infections

  1. When balance of normal flora is disturbed by antibiotic treatment allows resistant bacteria or fungi to flourish to the extent that they become problematic, requiring treatment. Superinfection is more likely when broad-spectrum antibiotics are used, but may occur anytime that prolonged treatment is used.
  2. Examples:
    1. Candida albicans
      1. Management: nystatin or clotrimazole: swish or pastilles
    2. Clostridium dificile: “Pseudomembranous colitis”
      1. Usually associated with clindamycin, but may occur with other antibiotics as well
      2. Severe, life-threatening diarrhea, fluid loss
      3. Management: stop antibiotic, administer metronidazole

1.1.5. Resistance

  1. Invading organisms are either inherently resistant or develop/acquire resistance to the effects of the drug:
    1. Cell wall structure
      1. Gm- bacteria are inherently resistant to penicillins because of their multilayered cell wall structure, which penicillins can’t penetrate readily.
    2. Manufacture of destructive enzymes
      1. Beta-lactamases: penicillinases and cephalosporinases break apart beta lactam ring structure, rendering the penicillins or cephalosporins inactive. Staph aureus is resistant to penicillin for this reason.
    3. Alteration of target site
      1. Penicillin: bacteria alter the structure of the penicillin binding protein in the cell wall, thus penicillin doesn’t bind very well anymore and can’t inhibit cell wall synthesis
      2. Protein synthesis inhibitors (macrolides, tetracyclines, clindamycin): alteration of ribosomal binding sites such that the antibiotics can’t bind enough to inhibit protein synthesis
    4. Decreased penetration/uptake
      1. Many bacteria actively take up antibiotics such as tetracyclines such that they achieve higher concentrations in bacterial cells than in mammalian cells. They develop resistance by reducing this active uptake, such that the antibiotic doesn’t penetrate very well.

1.2. Uses in Dentistry

1.2.1. Patients requiring prophylaxis against subacute bacterial endocarditis (SBE)

  1. Patients with rheumatic fever, prosthetic heart valves, septal defects or patent ductus arteriosis, etc
  2. Regimens:
    1. 1st choice: Amoxicillin: 2 g (4 X 500 mg), PO 1 hr before treatment
    2. For PCN allergic: Clindamycin: 600 mg (4 X 150 mg) PO 1 hr before treatment
    3. Non-oral: ampicillin IV/IM 2 g, 30 min before or clindamycin 600 mg IV 1/2 hr prior
    4. For PCN-allergic unable to take oral meds: clindamycin, 600 mg IV within 30 min of procedure

1.2.2. Acute infection

  1. Check for signs of infection: redness, swelling, presence of fever
  2. Identify source of infection
  3. Incise and drain
  4. Pick and administer antibiotic
    1. Pen VK: 250-500 mg PO, q6H, 7 days
    2. Clindamycin: 150-300 mg PO, q8H 5-7 days

1.2.3. Prophy for immunosuppressed ( e.g., diabetics) patient

1.3. Selection Issues

1.3.1. Appropriate spectrum of activity

  1. Use an antibiotic that will have activity against the organism(s) causing the infection, but has as narrow a spectrum as possible
  2. Bacteria found in dental infections:
    1. Generally caused by various gram-positive aerobes, a few gram-negative aerobes, and a variety of gram-positive and gram-negative anaerobes
    2. Infections characterized by cellulitus tends to be mostly aerobic bacteria
      1. Most commonly isolated aerobes are usually alpha-hemolytic streptococci
    3. Abscesses involve predominantly anaerobic bacteria
      1. Most commonly isolated anaerobes are bacteroides

1.3.2. Factors affecting patient compliance

  1. Cost: use the cheapest drug that will cover the infection. Patient may not have insurance coverage to pay for the most expensive drugs
  2. Regimen: drugs which can be taken the fewest number of times per day are easier for patients to take
  3. Preparation form: children should usually be given suspension/solution forms rather than pills
  4. Tolerability of adverse side effects: patient may stop taking the drug if the side effects (GI upset from erythromycin for example) become too unpleasant

1.3.3. Medical status

  1. Status of immune system
    1. Static agents should not be used in immunocompromised patients, since they only slow the growth of the bacterial population and it is the immune system that does the actual killing
  2. Organ function/dysfunction
    1. Renal dysfunction: avoid or reduce dose of penicillins, cephalosporins, clarithromycin, clindamycin (ESRD)
    2. Liver dysfunction: avoid or reduce dose of erythromycin, tetracycline, metronidazole, clindamycin
    3. Intestinal problems: avoid clindamycin
  3. Allergic status:
    1. Is the patient allergic to the medication you would like to prescribe?
    2. Asthmatics show higher incidence of allergies to penicillins
  4. Potential for problematic drug:drug interactions:
    1. Be aware of interactions involving erythromycin/clarithromycin
    2. Warn patient of the increased risk of pregnancy if patient is taking oral contraceptives
    3. If prescribing metronidazole, warn patient not to drink alcohol

1.4. Classes

1.4.1. Penicillins

  1. Narrow spectrum, bactericidal: cell wall synthesis inhibitor via prevention of cross-linking of peptidoglycan layers of cell wall
  2. Selective toxicity: targets cell wall structure of bacteria, human cells lack cell walls
  3. Typically 1st choice for dental infections due to safety, spectrum of activity and cost unless specific contraindications such as allergies, renal disease
    1. Useful for early stages in an infection, when the infection is predominated by aerobic bacteria
    2. Pen VK: 500 mg Q6h, 7 days
  4. Renal clearance: avoid/reduce dose in renally compromised patients. With pen VK, potassium buildup due to reduced excretion might lead to cardiac arrythmias. Switch to clindamycin
  5. Amoxicillin: 1st choice for prophylaxis
    1. 2 g: 500 mg, take 4 tabs PO 1 hr prior to treatment
    2. Not 1st choice for treating infections due to cost and increased incidence of nausea vs. pen VK
  6. Ampicillin: 1st choice for prophylaxis for patients that can’t take oral meds:
    1. 2 g, IV or IM 30 min prior to procedure
  7. Side effects: penicillins as a class are very safe except for allergenic reactions, can cause nausea

1.4.2. Clindamycin

  1. Narrow spectrum, more gm negative and better anaerobic coverage than Pen VK, and more useful in later stages of infection when bacterial population causing infection has become primarily anaerobic.
  2. Also, it is prescribed for patients with dental abscesses in bone and soft tissue that don't respond adequately to penicillin VK or macrolide-type drugs. It is a popular drug among oral surgeons and endodontists for chronic infections in bone.
  3. Bacteriostatic (usual oral doses, can be cidal at higher oral doses or when injected): inhibits 50 S ribosomal subunits
  4. Selective toxicity: targets 50S ribosomal subunit present in bacteria, not humans. Also bacterial protein synthesis occurs at much faster rate than in human cells
  5. 1st choice for patients that can’t take PCN due to allergy or renal dysfunction (except in end stage renal disease cases) or infection that has become more anaerobic in late stages
    1. Prophylaxis: 600 mg 1 hr prior (150 mg, take 4 tabs PO 1 hr prior to procedure)
      1. For patients that are PCN allergic and can’t take oral meds:
        1. 600 mg IV 30 min prior to procedure
    2. Infection: 150-300 mg q8h for 5-7 days
  6. Associated with pseudomembranous colitis

1.4.3. Cephalosporins

  1. Narrow spectrum, bactericidal: cell wall synthesis inhibition
    1. Available in 4 generations, shifting in spectrum of activity from
  2. Selective toxicity: targets cell wall structure – human cells lack cell wall
  3. Cross-allergenicity with PCNs; absolutely contraindicated in the pen allergic patient who has anaphylactoid type of reaction to pen
  4. Useful for staph and strep infections. In dentistry for surgical prophylaxis when cutting through skin
    1. Agents of choice for prophylaxis for patients with complete prosthetic joint replacements
  5. Better bone penetration than PCN
  6. Examples used in dentistry:
    1. 1st gen: cephalexin, 250mg, 2 capsules initially, 1 capsule every 6 hrs until gone, dispense 30
    2. 2nd gen.: Cefaclor
  7. DDIs: can potentiate warfarin effects due to interference with vitamin K synthesis

1.4.4. Macrolides

  1. Erythromycin, clarithromycin, azithromycin
  2. Bacteriostatic: inhibit 50 S ribosomal subunits
  3. Selective toxicity: targets bacterial ribosomal subunit that is absent in human cells
  4. Side effects:
    1. Dental use of erythromycin has decreased due to resistance, GI upset reducing patient compliance (erythromycin only), and problems with drug: drug interactions.
    2. Macrolides are useful for PCN allergic patients or patients with renal disease that can’t take PCN or clindamycin
  5. Erythromycin and biaxin inhibit drug metabolism by blocking cytochrome P4503A4, azithromycin is much less potent in this regard
  6. Clarithromycin and Azithromycin vs. erythromycin:
    1. Clarithromycin and azithromycin are more expensive but better tolerated alternatives offering somewhat extended coverage
    2. Do not cause GI upset
    3. Expanded activity against anaerobes and gm-
    4. While clarithromycin has similar inhibitory effects on drug metabolism, azithromycin does not
    5. Azithromycin taken 1 X day for 4 days
    6. Clarithromycin is not safe in pregnancy
    7. Clarithromycin contraindicated in renal disease
    8. Clarithromycin: adults: 500mg twice a day for 7 days

1.4.5. Metronidazole

  1. Narrow spectrum, anaerobes such as Bacteroides only: they possess the enzymatic machinery to convert metronidazole to its active metabolite; aerobes can’t do this
  2. Bactericidal: DNA synthesis inhibitor
  3. Selective toxicity: human cells are not anaerobic, thus can’t convert to active form
  4. Dental indication:
    1. Amoxicillin (250 mg) and metronidazole (250 mg), extends coverage to anaerobes
    2. Agent of choice for treating pseudomembranous colitis
  5. DDIs: warn patient to avoid alcohol due to disulfiram like effect
  6. Side effects: metallic taste

1.4.6. Tetracyclines

  1. Broad spectrum
  2. Bacteriostatic: inhibits 30S ribosome
  3. Selective toxicity: targets bacterial ribosomal subunit lacking in human cells; bacteria actively transport tetracyclines into the cell – mammalian cells don’t
  4. Primarily perio use, usually topically applied, also used locally in impregnated dressings to prevent dry socket following 3rd molar extractions
  5. Wide spread resistance due to increased efflux from cell limits use
  6. Side effects: potential to stain enamel in developing teeth – avoid use during pregnancy and in children under 8
  7. DDIs:
    1. reduced effectiveness due to chelation in GI tract in presence of metal ions in antacid preparations
    2. Can potentiate the effects of warfarin

1.5. Review of Adverse Side Effects

1.5.1. Penicillins: nausea, allergic reactions: skin rash to anaphylactoid

1.5.2. Clindamycin: pseudomembranous colitis (treat with metronidazole)

1.5.3. Erythromycin: GI upset, inhibition of drug metabolism (cyt. P4503A4)

1.5.4. Cephalosporins: cross allergenicity with PCN, increased warfarin effect

1.5.5. Metronidazole: metallic taste, interaction with alcohol (disulfiram effect)

1.5.6. Tetracyclines: staining of enamel in developing teeth, photosensitivity

1.6. Review of Drugs: Drug Interactions

1.6.1. Cidal: static

Cidal agents require actively growing bacteria synthesizing cell walls when dividing – bacteriostatic protein synthesis inhibitors stop cell division via protein synthesis inhibition, thus cell wall synthesis inhibitors will be greatly reduced in effectiveness when used in combination with a bacteriostatic agent.

1.6.2. Amoxicillin: clavulanic acid

Penicillins like amoxicillin are subject to enzymatic inactivation by beta-lactamases produced by certain bacteria. Clavulanic acid can be combined with amoxicillin to serve as a substrate for the enzymes, thus the enzymes get used up attacking the beta-lactam structure of clavulanic acid, leaving more of the amoxicillin unmetabolized and thus effective.

1.6.3. Antibiotics and oral contraceptives

Oral contraceptives are subject to metabolic inactivation via passing through the liver. Bacteria in the GI tract normally reactivate the hormones in the birth control medication, enabling proper plasma concentrations for effective birth control to be achieved. Antibiotics can reduce the bacteria flora in the GI tract, thus reducing the capacity to reactivate the birth control medication. Thus more remains inactive and gets excreted, proper plasma levels for birth control are not achieved.

1.6.4. Macrolides (erythromycin, clarithromycin)

  1. Seldane
    1. Conversion of seldane to active metabolite by cyt. P4503A4 liver enzyme is blocked by erythromycin. Unmetabolized Seldane causes dangerous cardiac arrhythmias.
  2. Warfarin
    1. Warfarin metabolism is reduced by erythromycin – patient can become over anticoagulated

1.6.5. Metronidazole: alcohol

Disulfiram-type reaction: metronidazole interferes with the normal metabolism of alcohol, leading to the buildup of alcohol acetaldehydes. These alcohol metabolites can result in nausea and vomiting similar to the type of reaction observed with the combination of disulfiram and alcohol.

2. Antifungals: Used for Candidiasis Opportunistic Infections

2.1. Polyenes: Nystatin (Topical)

  1. Bind to ergosterol, a cholesterol-like structural component of cell membrane - causes leaky cell membrane and eventual collapse
  2. Side effects
    1. Amphotericin
    2. Renal toxicity

2.2. Azoles

  1. Topical: clotrimazole
  2. Systemic: fluconazole
  3. Prevent ergosterol synthesis by blocking enzymatic conversion from lanosterol

2.3. Selective Toxicity of Antifungals

  1. Humans have cholesterol rather than ergosterol as structural component of their cell membranes
  2. Antifungals don’t affect cholesterol synthesis or bind to it with same affinity as they do to ergosterol
  3. Fluconazole sees extensive use in the management of opportunistic fungal infections in HIV patients
    1. Potent inhibitor of cyt. P4503A4, thus erythromycin type- DDIs

3. Antivirals

3.1. Herpes Drugs

  1. Oral herpetic infections usually are self-limiting and antiviral treatment is not necessary. In patients with compromised immune function, especially HIV patients, HSV infections can become severe and may require treatment (either topical or systemic) with antiviral agents such as acyclovir
  2. Acyclovir
    1. Metabolized by virally infected cells by thymidine kinase to triphosphate form that inhibits DNA polymerase
      1. Selective toxicity: non-infected cells don’t convert acyclovir to triphosphate form anywhere near as much and thus are less affected
      2. Uptake is 40-100 times greater in infected cells than in uninfected cells
    2. Systemic acyclovir is nephrotoxic