Overview of antibiotic therapy

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).

Definitions

• Antibiotics: antimicrobial drugs effective against bacteria
• Bactericidal drug: a substance that kills bacteria (e.g., β-lactams, glycopeptides, epoxides)
  • Some antibiotics are only effective if used:
    • In combination (e.g., sulfonamides combined with diaminopyrimidine; streptogramin A combined with streptogramin B
    • Against certain pathogens (e.g., oxazolidinones are only bactericidal against Streptococci)
    • In higher concentrations (e.g., amphenicols)
• Bacteriostatic drug: a substance that slows bacterial growth or stops bacterial reproduction (e.g., tetracyclines, glycylcyclines, macrolides)
  • Some antibiotics are bacteriostatic only against certain pathogens (e.g., glycopeptides against C. difficile).
  • Some antibiotics can be both bactericidal and bacteriostatic (e.g., dapsone ).
  • Antibiotics that are interfering with bacterial protein synthesis target the subunits (30S and 50S) of bacterial ribosomes (70S) and do not affect human ribosomes (80S).

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]

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-lactams

• Definition: : a group of antibiotics that contains beta-lactam ring in their molecular structure; and includes penicillins, carbapenems, monobactams, and cephalosporins
• Mechanism of action
  • Inhibit cell wall synthesis by blocking peptidoglycan crosslinking
    • β-lactam mimics the D-ala-D-ala structure of bacterial peptidoglycan residue.
    • β-lactam irreversibly binds to penicillin-binding proteins (PBPs) which act as transpeptidases → stalled cross-linking of peptidoglycan in cell wall (β-lactam cannot be cleaved) → inability to synthesize new cell wall during replication → bacterial death (bactericidal effect)
  • Activate autolytic enzymes ^[9]
• CNS penetration
  • Only when meninges are inflamed
  • Exceptions: ceftriaxone and aztreonam always have good CNS penetration.
• Route of elimination
  • Primarily renal (via tubular secretion)
  • Exceptions
    • Primarily biliary: nafcillin
    • Both renal and biliary: other anti-staphylococcal penicillins (e.g., oxacillin, dicloxacillin), ceftriaxone
• General adverse effects
  • Jarisch-Herxheimer reaction (e.g., in treatment of syphilis)
  • Hypersensitivity reactions

Beta-lactamase inhibitors

• β-lactamases
  • Are usually produced by gram-negative and anaerobic organisms
  • Can split the β-lactam ring and render certain β-lactam antibiotics ineffective
• β-lactamase inhibitors
  • Prevent the destruction of β-lactam antibiotics by β-lactamases and increase the spectrum of the antibiotic activity.
  • Can be coadministered with β-lactamase-sensitive penicillins in order to treat β-lactamase-producing organisms
• Examples
  • Clavulanate (combined with amoxicillin)
  • Avibactam (combined with ceftazidime)
  • Sulbactam (combined with ampicillin)
  • Tazobactam (combined with piperacillin)

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

• Examples
  • Oral or IV vancomycin
  • Topical bacitracin
• Mechanism of action
  • Bind terminal D-ala-D-ala of cell-wall precursor peptides → inhibition of cell wall synthesis (peptidoglycan formation) → bacterial death (bactericidal effect against most gram-positive bacteria)
  • Bacteriostatic against C. difficile
• CNS penetration: only when there is increased permeability of the meningeal vessels (i.e., with meningeal inflammation)
• Route of elimination: renal (via glomerular filtration)
• Clinical use: especially effective against multidrug-resistant organisms
  • Is effective against a wide range of gram-positive bacteria only
  • MRSA
  • S. epidermidis
  • Enterococci (if not vancomycin resistant enterococci)
  • C. difficile (causing pseudomembranous colitis): administered orally
• Adverse effects
  • Intravenous administration
    • Nephrotoxicity
    • Ototoxicity/vestibular toxicity
    • Thrombophlebitis
    • Red man syndrome: an anaphylactoid reaction caused by rapid infusion of vancomycin
      • Nonspecific mast cell degranulation → rapid release of histamine
      • Symptoms
        • Diffuse flushing of the skin, pruritus mainly of the upper body
        • Muscle spasms and pain in the back and chest
        • Possible hypotension and dyspnea ^[18]
      • Red man syndrome can be prevented by slowing the rate of infusion and pretreating with antihistamines
    • DRESS syndrome ^[19]
    • Neutropenia ^[20]
    • Dysgeusia and gastrointestinal side effects (e.g., nausea, vomiting, abdominal pain)
  • Oral administration: predominantly dysgeusia and gastrointestinal side effects
• Contraindications: Consider use in pregnant women only if the benefits outweigh the risks. ^[21]
• Mechanisms of resistance
  • Modification of amino acid D-Ala-D-Ala to D-Ala-D-Lac: occurs mainly in Enterococcus (e.g., E. faecium, less in E. faecalis)
  • Beta-lactamase resistant

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).

• Examples: : oral and IV fosfomycin
• Mechanism of action: : inhibits enolpyruvate transferase (MurA) → no formation of N-acetylmuramic acid; (a component of bacterial cell wall) → inhibition of cell wall synthesis → cell death (bactericidal effect)
• Route of elimination: renal
• Clinical use: : women with uncomplicated urinary tract infections (e.g., cystitis due to E. coli or E. faecalis) ^[22][3]
• Adverse effects
  • Mild electrolyte imbalances (e.g., hypernatremia, hypokalemia)
  • Diarrhea ^[3]
• Contraindications: hypersensitivity
• Mechanisms of resistance: MurA mutations ^[23]

• Examples: daptomycin
• Mechanism of action: incorporate K⁺ channels into the cell membrane of gram-positive bacteria → rapid membrane depolarization; → loss of membrane potential → inhibition of synthesis of DNA, RNA, and proteins → cell death (bactericidal effect) ^[24]
• Route of elimination: renal
• Clinical use
  • Gram-positive bacteria
  • S. aureus, especially MRSA
  • Mainly used in skin and skin structure infections, bacteremia, and endocarditis
  • Vancomycin-resistant Enterococci (VRE)
  • Not used in pneumonia (daptomycin is bound and inactivated by surfactant) ^[24]
• Adverse effects
  • Reversible myopathy
  • Rhabdomyolysis
  • Allergic pneumonitis ^[25]
• Contraindications: hypersensitivity
• Mechanisms of resistance: repulsion of daptomycin molecules due to the change in the bacterial surface charge ^[26]

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

• Examples
  • IV or IM polymyxin B
  • IV or IM polymyxin E (colistin) ^[27]
• Mechanism of action
  • A cationic detergent (polypeptides) molecule that binds to phospholipids of the cytoplasmic membrane of gram-negative bacteria → increased membrane permeability→ leakage of cell contents → cell death (bactericidal effect)
  • Binds to and inactivates endotoxins
• CNS penetration: poor
• Route of elimination: mostly renal
• Clinical use: severe infections caused by multidrug-resistant gram-negative bacteria
  • Effective only against gram-negative bacteria including P. aeruginosa, K. pneumoniae, E. coli, Acinetobacter baumannii, and Enterobacteriaceae spp.
  • Not effective against gram-positive bacteria
  • Topical antibiotics: triple antibiotic ointment; (bacitracin, neomycin, and polymyxin B) for superficial skin infections
  • Oral polymyxin B may be used to disinfect the bowel to prevent ICU infections
• Adverse effects
  • Nephrotoxicity
  • Neurotoxicity; (e.g., paresthesias, weakness, speech disorders, neuromuscular blockage)
  • Urticaria, eosinophilia, and/or anaphylactoid reactions ^[28]
  • Respiratory failure
• Contraindications:
  • Hypersensitivity to polymyxins
  • Cautious use in patients with renal dysfunction

• Examples
  • IV or IM gentamicin
  • IV or IM amikacin
  • IV or IM tobramycin
  • IV or IM streptomycin
  • Oral neomycin
• Mechanism of action
  • Bind to 30S subunit of the bacterial ribosome → irreversible inhibition of initiation complex → inhibition of bacterial protein synthesis → cell death (bactericidal effect)
  • Misreading of mRNA
  • Blockage of translocation
  • Synergistic effect when combined with β-lactam antibiotics: β-lactams inhibit cell wall synthesis → facilitated entry of aminoglycoside drugs into the cytoplasm
• CNS penetration: poor
• Route of elimination: renal (via glomerular filtration)
• Clinical use ^[29]
  • Severe gram-negative rod infections
  • Not effective against anaerobes (aminoglycosides require oxygen to be absorbed by cells)
  • Neomycin, which is not absorbed systemically, is administered orally to prepare the gut for bowel surgery.
  • Streptomycin is used as a second-line treatment for Mycobacterium tuberculosis and M. avium-intracellulare
• Adverse effects
  • Nephrotoxicity
  • Ototoxicity and vestibulotoxicity (risk of ototoxicity is higher when used concurrently with loop diuretics) resulting in:
    • Tinnitus
    • Ataxia
    • Vertigo
  • Neuromuscular blockade
  • Teratogenicity
• Contraindications
  • Myasthenia gravis
  • Botulism
  • Pregnancy
  • Cautious use in patients with renal dysfunction
• Mechanisms of resistance: inactivation via acetylation, phosphorylation, and/or adenylation by secreted bacterial transferase enzymes

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.

• Examples
  • Oral or IV minocycline
  • Oral or IV tetracycline
  • Oral doxycycline
  • Oral demeclocycline
• Mechanism of action: bind 30S subunit → aminoacyl-tRNA is blocked from binding to ribosome