• Clinical science

Overview of antibiotic therapy

Summary

Antibiotics are a class of drugs employed mainly against bacterial infections. Some antibiotics are also used against parasitic infections. Antibiotics can have bacteriostatic (i.e., stopping bacterial reproduction), bactericidal (i.e., killing bacteria), or both mechanisms of action. Antibiotics are effective against either 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 certain enzymes (e.g., THF, RNA-polymerase) in bacteria. Common side effects of antibiotic treatment include hypersensitivity reactions, as well as nephrotoxic and hepatotoxic effects. Many antibiotics are contraindicated in certain patient groups (e.g., children, pregnant and/or breastfeeding women). In the case of severe infection, one or more antibiotics may be initiated without waiting for a microbiological confirmation (empirical antibiotic therapy) to target the most likely pathogens.Antibiotics are widely used because they are instrumental in the management of infectious diseases; however, use of antibiotics without valid indications and with inappropriate dosages and timing has led to the emergence of antibiotic-resistant pathogens (e.g., MRSA, Pseudomonas).

Overview

Definitions

As a general rule, agents that inhibit cell wall synthesis are bactericidal (except ethambutol), while those that inhibit protein synthesis are bacteriostatic (except tigecycline, rifamycins, and aminoglycosides).

Overview of antibiotics [1][2]

Antibacterial classes Examples Mechanism of action Bacteriostatic/bactericidal Mechanisms of resistance
Inhibition of cell wall synthesis

β-lactams

Penicillins
Cephalosporins
Carbapenems
Monobactams
  • Cleavage by β-lactamases (less suceptible than other ß-lactams)

Glycopeptides

  • Reduced penetration in gram-negative bacteria
  • Change in peptidoglycan precursor structure

Epoxides

  • Reduced penetration
  • Enzyme gene overexpression
  • Enzymatic inactivation
Disruption of cell membrane integrity
Lipopeptides
Polymyxins
Inhibition of protein synthesis - 30S ribosomal subunit
Aminoglycosides
  • Inhibit initiation complex → protein mistranslation
Tetracyclines
  • Reduced cell wall penetration
  • Removal by efflux pumps (plasmid-encoded)
  • Production of a protein that protects ribosome
Glycylcylines (tetracyclin derivative)
Inhibition of protein synthesis - 50S ribosomal subunit
Macrolides and ketolides
  • Bind to 23S rRNA inhibition of transpeptidation, translocation, and chain elongation → ↓ protein synthesis
Lincosamides
  • Impair transpeptidation → inhibition of chain elongation → ↓ protein synthesis
  • Increase opsonization and phagocytosis
  • Inhibit alpha toxin expression
  • Reduced penetration
  • Mutation of bacterial ribosome binding site
Streptogramins
Oxazolidinones
Amphenicols
  • Reduced penetration
  • Enzymatic inactivation by acetyltransferase (plasmid-encoded)
DNA gyrase inhibition
Fluoroquinolones
Disruption of DNA integrity
Nitroimidazoles
  • Prodrug [6]
  • Free radical formation → single-strand breaks in DNA molecules
  • Reduced activation due to decreased enzymatic activity
Inhibition of folic acid synthesis and reduction
Sulfonamides and diaminopyrimidines
  • Overproduction of para-aminobenzoate (PABA)
  • Decreased uptake
  • Structural changes on target enzymes (e.g., dihydropteroate synthase)
  • Efflux pumps
Antimycobacterial drugs
Rifamycins
Hydrazides

Nicotinamides

  • Prodrug
  • Not completely understood
Ethylenediamine derivates
Sulfones
  • Mutations in folP1 gene coding for dihydropteroate synthase ↓ expression of dihydropteroate synthase
Others
Nitrofurans
  • Enzyme-mediated reduction
  • Efflux pumps

AcTions at 30, CELebrationS at 50: Aminoglycosides and Tetracyclines are 30S inhibitors; Chloramphenicol/Clindamycin, macrolides (e.g., Erythromycin), Linezolid, and Streptogramin are 50S inhibitors.

All protein synthesis inhibitors are bacteriostatic, except aminoglycosides (bactericidal) and linezolid (can be either bactericidal or bacteriostatic depending on concentration).

Beta-lactam antibiotics

Beta-lactams

Beta-lactamase inhibitors

CATS: Clavulanate, Avibactam, Tazobactam, Sulbactam are β-lactamase inhibitors.

Penicillins

Natural penicillins (prototype beta-lactam antibiotics)

Penicillinase-resistant penicillins

Use NAF (nafcillin) for STAPH (S. aureus).

Aminopenicillins (penicillinase-sensitive penicillins)

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

Aminopenicillin therapy HHEELPSSS against H. influenzae, H. pylori, E. coli, Enterococci, Listeria monocytogenes, Proteus mirabilis, Salmonella, Shigella, Spirochetes.

Antipseudomonal penicillins

The PIPER in his CAR full of TICks ran over Pseudomonas: PIPERacillin, CARbenicillin, and TICarcillin are antipseudomonals.

Carbapenems

Get a kill that is lastin' with imipenem plus cilastatin.

don't DIe on ME: Doripenem, lmipenem, Meropenem, and Ertapenem are carbapenems and used in life-threatening infections.

Monobactams

Cephalosporins

Clinical use of cephalosporins
1st generation cephalosporins 2nd generation cephalosporins 3rd generation cephalosporins 4th generation cephalosporins 5th generation cephalosporins
Examples
Microbial coverage
Activity against gram-positive bacteria
  • Highly active
  • Less active than 1st generation
  • Highly active
  • Highly active
Gram-negative bacteria coverage
  • Extended-spectrum
  • Extended-spectrum
  • Extended-spectrum
MRSA
  • No
  • No
  • No
  • No
  • Yes
Listeria
  • No
  • No
  • No
  • No
  • Yes
Pseudomonas
  • No
  • No
  • Yes
  • No
Enterococcus
  • No
  • No
  • No
  • No
Atypicals (Chlamydia, Mycoplasma, Legionella)
  • No
  • No
  • No
  • No
  • No
Special clinical considerations
  • N/A
  • Used for severe life-threatening infections (including nosocomial)
  • N/A

1 PEcK: 1st generation cephalosporins cover Proteus mirabilis, E. coli, Klebsiella pneumoniae.
2 HENS PEcK: 2nd generation cephalosporins cover H. influenzae, Enterobacter aerogenes (now Klebsiella aerogenes), Neisseria,
Serratia marcescens, Proteus mirabilis, E. coli, Klebsiella pneumoniae.

2nd graders wear fake fox fur to tea parties: 2nd generation cephalosporins include cefaclor, cefoxitin, cefuroxime, and cefotetan.

Cephalosporins are LAME: 1st–4th generation cephalosporins do not act against Listeria, Atypical organisms (e.g., Chlamydia, Mycoplasma), MRSA, and Enterococci (with the exception of ceftaroline, which does act against MRSA).

Glycopeptides

The vancomycin van carries a TON of red DRESSes: the side effects of vancomycin are Thrombophlebitis, Ototoxicity, Nephrotoxicity, red man syndrome, and DRESS syndrome.

The fine for VANdalism is one DALlAr in LACjac: VANcomycin resistance is caused by amino acid modification (D-Ala-D-Ala to D-Ala-D-Lac).

Epoxides

Lipopeptides

Dap-to-my-cin is good to my skin: daptomycin is used to treat skin infections.

Polymyxins

Aminoglycosides

Me and my NEw AMIgA are taking GENeral STEPs to AMeliorate our TOBacco intake but are still unsuccessful: NEomycin, AMIkAcin, GENtamicin, STrEPtomycin AMinoglycosides, and TOBramycin are unsuccessful in killing anaerobes.

Ah, MI(y) NEPHew's OTter keeps TERrorizing our block: the side effects of AMInoglycosides include NEPHrotoxicity, OTotoxicity, TERtogenicity, and neuromuscular blockade.

Tetracyclines