• 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 affinitypathogen 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

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 antibiotics 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 all the 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

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 Adverse effects
  • Contraindications
    • Lactating 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]

Aminoglycosides

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

Tetracyclines

References:[1][7]

Glycylcyclines

  • Drugs: tigecycline
  • Mechanism of action
  • CNS penetration: poor
  • Route of elimination: mostly biliary
  • Clinical use
  • Adverse effects
    • Gastrointestinal side effects
    • 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:[8][9][10]

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

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:[8][11]

Isoniazid (INH)

  • Mechanism of action
  • CNS penetration: variable (20–100% of serum concentration)
  • Route of elimination: renal elimination after hepatic metabolism
  • Clinical use: treatment and prophylaxis of M. tuberculosis: ; first-line for monotherapy of latent TB
  • Adverse effects:
  • Contraindications
    • Hepatic failure (relative contraindication)
    • Pregnancy (relative contraindication)

INH Injures Neurons and Hepatocytes!

Neurotoxicity and lupus may be prevented by supplementing with pyridoxine (vitamin B6)!

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:[12]

Dapsone

Contraindications

Patient group Contraindicated antibiotics
Age Infants
< 8 years
< 18 years
Pregnant women
Lactating women