• Clinical science

Overview of antibiotic therapy

Abstract

Antibiotics are employed against bacterial as well as some parasitic infections. They have either a bacteriostatic or a bactericidal effect and can be effective against a small group of bacteria (narrow-spectrum) or a wide range of pathogens (broad-spectrum). Most antibiotics work by inhibiting cell wall synthesis, protein synthesis, or nucleic acid synthesis in bacteria. Common side effects include allergies and cross-reacting hypersensitivities, as well as nephrotoxic and hepatotoxic effects. Many antibiotics are contraindicated in certain patient groups (e.g., children, pregnant or lactating women). In the case of severe infections, early initiation of one or more antibiotics without waiting for a microbiological confirmation is indicated (empirical antibiotic therapy), with the aim of targeting the most likely pathogen(s). Because of widespread use of antibiotics (often misuse!), antibiotic-resistant pathogens have emerged (e.g., MRSA, Pseudomonas).

Basic mechanisms of antibiotics action

DNA destabilization

Bacterial DNA is damaged by free radicals, causing breaks in the DNA strands.

Inhibition of tetrahydrofolate synthesis and ribonucleic acid synthesis

Inhibition of replication

Inhibition of protein synthesis

Cell membrane destabilization

Inhibition of cell wall synthesis

Beta-lactam antibiotics

Beta-lactamase inhibitors

Beta-lactamase inhibitors (CAST): Clavulanic Acid, Sulbactam, Tazobactam

Penicillins

Classical penicillins

Anti-staphylococcal penicillins

  • Drugs (oral or IV)
  • Special characteristics: Intrinsically beta-lactamase resistant through the addition of bulky side chains (e.g., isoxazolyl)
  • Clinical use: gram-positive aerobes, especially S. aureus (non-MRSA)
  • Adverse effects: interstitial nephritis
  • Development of resistance: : due to alteration of binding site of penicillin-binding proteins; → reduced affinity → pathogen is not bound or inactivated by β-lactam (one of the main virulence factors in MRSA)

Aminopenicillins

Aminopenicillin therapy HHELPSSS destroy enterococci.

AMinoPenicillins are AMPed-up penicillins.

AmOxicillin is administered Orally, while amPicillin is administered via a Prick!

Ureidopenicillins

  • Drugs
  • Clinical use: extended spectrum
    • Gram-negative bacilli
      • Especially Pseudomonas
      • Also anaerobes, i.e., Bacteroides fragilis
    • Gram-positive aerobes

Carboxypenicillins

For antipseudomonals: A TICk kills Pseudomonas with a PIPE bomb in a CAR. (ticarcillin, piperacillin, carbenicillin)
References:[1]

Carbapenems

  • Drugs
  • Clinical use: broad-spectrum antib iotics with intrinsic beta-lactamase resistance
  • Adverse effects: considered a “last resort” drug because of its significant adverse effects

“I'm a pen” that crosses out allthe bacteria.

Monobactams

Cephalosporins

First generation cephalosporins

First generation cephalosporins: PEcK

Second generation cephalosporins

Second generation cephalosporins: HEN PEcKS

Third generation cephalosporins

Fourth generation cephalosporins

Fifth generation cephalosporins

Cephalosporins can be LAME because they don't act against Listeria, Atypical organisms (Chlamydia, Mycoplasma), MRSA , and Enterococci!

Adverse effects

References:[1]

Glycopeptides

  • Drugs: : Oral or IV vancomycin
  • Mechanism of action
    • Inhibits cell wall synthesis by binding the terminal D-ala-D-ala moiety of cell-wall precursor peptides, therefore only effective against gram-positive bacteria.
    • Vancomycin; is bactericidal.
  • CNS penetration: only when meninges are inflamed
  • Route of elimination: renal (via glomerular filtration)
  • Clinical use: especially effective against multidrug-resistant organisms
  • Adverse effects
  • Contraindications

References:[1]

Epoxides

Lipopeptides

Sulfonamides and trimethoprim

Trimethoprim (TMP) Treats Marrow Poorly.

References:[1][2][3]

Fluoroquinolones

  • Nalidixic acid
  • Moxifloxaci
  • Gemifloxacin
  • GatifloxacinBLI Should be anchored yes rlo: done Causes hypoglycemia/hyperglycemia and hence, has been withdrawn from use.fmn:really “banned”?master the boards 2015 step 2 CK
  • Mechanisms of resistance
    • Bacterial mutations can occur in genes that mediate:
      • DNA gyrase and topoisomerase IV enzymes
      • Cell wall permeability
      • Efflux pumps

References:[4][5]

Nitroimidazoles

  • Drugs
  • Mechanism of action
    • Creates free radicals within the cell, which leads to DNA-strand breaks
    • Bactericidal
  • CNS penetration: good
  • Route of elimination: renal elimination after hepatic metabolism
  • Clinical use
    • Certain protozoa (Entamoeba, Giardia histolytica, Trichomonas)
    • Anaerobes (e.g., Clostridium, Bacteroides)
    • Facultative anaerobes
    Adverse effects
  • Contraindications
    • Breastfeeding women
    • Hepatic failure (relative contraindication)

GET GAP on the Metro! (Giardia, Entamoeba, Trichomonas, Gardnerella, Anaerobes (Clostridium, Bacteroides), H. Pylori → Metronidazole)

Clindamycin is indicated for anaerobes above the diaphragm and metronidazole treats anaerobes below it!
References:[1][6][7]

Aminoglycosides

Mean GNATScaNNOT kill anaerobes. (AMINoglycosides; Gentamycin, Neomycin, Amikacin, Tobramycin, Streptomycin; Nephrotoxicity, Neuromuscular blockade, Ototoxicity, Teratogenic)
References:[1][8]

Tetracyclines

  • Drugs
  • Mechanism of action
  • CNS penetration: poor
  • Route of elimination
    • Renal elimination (via glomerular filtration)
    • Doxycycline: only GI elimination
  • Clinical use
  • Adverse effects
    • Hepatotoxicity
    • Deposition in bones and teeth → discoloration of teeth and inhibition of bone growth in children
    • Damage to mucous membranes (e.g., esophagitis)
    • Photosensitivity: UV light is absorbed by the drug, which releases energy to the surrounding area and damages exposed areas
    • Degraded tetracyclines associated with Fanconi syndrome
  • Contraindications
    • Children < 8 years
    • Pregnancy
    • Breastfeeding women
    • Renal failure (except doxycycline)
    • Hepatic failure (relative contraindication)

References:[1][9]

Glycylcyclines

  • Drugs: tigecycline
  • Mechanism of action
  • CNS penetration: poor
  • Route of elimination: mostly biliary
  • Clinical use
  • Adverse effects
    • GI upset
    • Hepatotoxicity
    • Deposition in bones and teeth
    • Damage to mucous membranes (these antibiotics should be taken with a lot of water)
    • Photosensitivity
  • Contraindications
    • Pregnancy
    • Hepatic failure (relative contraindication)
    • Should be used with caution for children < 8 years and lactating women

References:[10][11][12]

Lincosamides

Clindamycin is indicated for anaerobes above the diaphragm and metronidazole treats anaerobes below it!

Amphenicols

References:[1]

Oxazolidinones

Macrolides

References:[1]

Nitrofurans

Polymyxins

  • Drugs
  • Mechanism of action
    • A cationic detergent molecule the disrupts cell wall membranes
    • Binds to and inactivates endotoxins
    • Bactericidal
  • CNS penetration: poor
  • Route of elimination: mostly renal
  • Clinical use
    • Topical antibiotics
    • Systemically against severe gram-negative infections including Pseudomonas, Acinetobacter; , and species of Enterobacteriacea
    • Polymyxins are not effective against gram-positive organisms
    • Oral polymyxin B may be used to disinfect the bowel to prevent ICU infections
  • Adverse effects (severe)
  • Contraindications
    • Renal failure (relative contraindication)

Antimycobacterial drugs

Compare drugs below with tuberculosis therapy for an overview

The four drugs used as first-line treatment are “RIPE”: Rifampin, Isoniazid, Pyrazinamide, and Ethambutol.

Rifamycins

  • Drugs
  • Mechanism of action
  • CNS penetration: only when meninges are inflamed
  • Route of elimination: biliary
  • Clinical use
  • Adverse effects
    • Harmless orange discoloration of body fluids (e.g., urine, tears)
    • Flulike symptoms (fever, arthralgia and in severe cases hemolytic anemia, thrombocytopenia, renal failure) if administered less often than twice weekly
    • Hepatotoxicity
    • Resistance develops rapidly if used as monotherapy
    • CYP induction (CYP3A4, CYP2C9)
  • Contraindications
    • Hepatic failure (relative contraindication)
    • Pregnancy (relative contraindication)

The 4Rs' of rifampin: RNA polymerase inhibition, Ramping up of cytochrome P450 activity, Red or orange colored urine, and Rapid developement of resistance if used alone
References:[10][13]

Isoniazid (INH)

INH Injures Neurons and Hepatocytes!

Neurotoxicity and lupus may be prevented by supplementing with pyridoxine (vitamin B6)!References:[14]

Pyrazinamide

  • Mechanism of action
    • Not completely understood.
    • Bactericidal
  • CNS penetration: only when meninges are inflamed
  • Route of elimination: renal elimination after hepatic metabolism
  • Clinical use: M. tuberculosis
  • Adverse effects
  • Contraindications
    • Hepatic failure (relative contraindication)
    • Pregnancy (relative contraindication)

Ethambutol

  • Mechanism of action
    • Prevents cell wall synthesis by inhibiting arabinosyltransferase
    • Bacteriostatic
  • CNS penetration: only when meninges are inflamed
  • Route of elimination: primarily renal
  • Clinical use
  • Adverse effects
    • Optic neuritis, retrobulbar neuritis → ↓ visual acuity and red-green color-blindness→ can result in irreversible blindness
    • Resistance develops rapidly if used as a monotherapy.
  • Contraindications
    • Children (relative contraindication)

EYEthambutol causes optic neuropathy!
References:[15]

Dapsone

  • Mechanism of action
    • Prevents sythesis of folic acid by acting as a competitive antagonist of para-aminobenzoic acid (PABA)
    • Bactericidal or bacteriostatic
  • Route of elimination: mostly renal
  • Clinical use
  • Adverse effects
  • Contraindications