• Clinical science

Overview of antibiotic therapy

Summary

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 antibiotic action

Beta-lactam antibiotics

Beta-lactamase inhibitors

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

Penicillins

Natural penicillins

Anti-staphylococcal penicillins

  • Drugs (oral or IV)
    • Nafcillin
    • Dicloxacillin
    • Oxacillin
    • Methicillin
  • 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
    • Secondary fungal infections
    • Can lower seizure threshold (especially imipenem)
    • Gastrointestinal upset
    • Rash
    • Thrombophlebitis

“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
  • Clinical use: especially effective against multidrug-resistant organisms
  • Adverse effects
    • Nephrotoxicity
    • Ototoxicity/vestibular toxicity
    • Rapid infusions are associated with anaphylactoid reactions ("red man syndrome" or "red neck syndrome")
    • Thrombophlebitis
    • Neutropenia
  • Contraindications

References:[1]

Epoxides

Lipopeptides

  • Drugs: daptomycin
  • Mechanism of action
    • Incorporation of potassium ion-channels into the cell membrane of pathogens, leading to rapid membrane depolarization
      • → Inhibition of intracellular synthesis of DNA, RNA, and proteins.
    • Bactericidal
  • CNS penetration: poor
  • Route of elimination: renal
  • Clinical use
  • Adverse effects
    • Reversible myopathy
    • Rhabdomyolysis
    • Allergic pneumonitis

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
  • Adverse effects (severe)
  • Contraindications
    • Renal failure (relative contraindication)

Aminoglycosides

Mean GNATScaNNOT kill anaerobes. (AMINoglycosides; Gentamycin, Neomycin, Amikacin, Tobramycin, Streptomycin; Nephrotoxicity, Neuromuscular blockade, Ototoxicity, Teratogenic)
References:[1][2]

Tetracyclines

  • Drugs
  • Mechanism of action
  • CNS penetration: poor
  • Route of 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][3]

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:[4][5][6]

Macrolides

References:[1]

Lincosamides

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

Oxazolidinones

Amphenicols

References:[1]

Fluoroquinolones

  • Mechanisms of resistance
    • Bacterial mutations can occur in genes that mediate:
      • DNA gyrase and topoisomerase IV enzymes
      • Cell wall permeability
      • Efflux pumps

References:[7][8]

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
  • 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][9][10]

Sulfonamides and trimethoprim

Trimethoprim (TMP) Treats Marrow Poorly.

References:[1][11][12]

Nitrofurans

  • Drugs: nitrofurantoin
  • Mechanism of action
    • Nonspecific binding to bacterial ribosomal proteins → impaired metabolism, impaired protein, DNA, and RNA synthesis
    • Bactericidal
  • Route of elimination: : mostly renal
  • Clinical use: : treatment of and/or prophylaxis against lower urinary tract infections (e.g., urethritis, cystitis)
  • Adverse effects
  • Contraindications
    • Renal injury
    • Breastfeeding women

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)
    • 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:[4][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
  • 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 synthesis of folic acid by acting as a competitive antagonist of para-aminobenzoic acid (PABA)
    • Bactericidal or bacteriostatic
  • Route of elimination: mostly renal
  • Clinical use
    • M. leprae
    • Alternative to TMP/SMX for the prophylaxis of P. jiroveci pneumonia
    • Alternative to sulfadiazine + pyrimethamine for toxoplasmosis
    • In combination with pyrimethamine as an alternative to standard therapy for chloroquine-resistant malaria
  • Adverse effects
  • Contraindications

Contraindications

Patient group Contraindicated antibiotics
Age Infants
< 8 years
< 18 years
Pregnant women
Breastfeeding women
Renal failure
Hepatic failure

We list the most important contraindications. The selection is not exhaustive.

Guidelines & therapy recommendations

Targeted antibiotic therapy

Antibio