Chemical structure of tetracycline. Note the 4-ring central pharmacophore that gives the drug class its name.

| Class | 1st Gen (Natural):

• Tetracycline (1953)
• Oxytetracycline (1951)

2nd Gen Semisynthetic:

• Demeclocycline (1957)
• Doxycycline (1967)
• Minocycline (1972)

3rd Gen (these will be covered separately) Glycylcyclines

• Tigecycline (2005)

Aminomethylcycline

• Eravacycline
• Omadacycline
• Sarecycline | | --- | --- | | Mechanism of action | Main: Reversibly binds 30S subunit of rRNA —> prevents tRNA binding to Ribosome-mRNA complex —> impairs protein synthesis

Tetracyclines bind at 1 major binding site (Tet-1) and 5 minor binding sites of 16S rRNA (significance of minor binding sites unclear).

Other:

• Bind 50S subunit, impairing function
• Alter Cytoplasmic membrane —> cell content leak

To get into cells, drug complexes with Mg and transports through OmpF & OmpC, then dissociates from Mg to move through the inner membrane.

(NB: Tetracyclines re-complex with Mg in cytoplasm before binding their target site) | | Origin | Natural: From Streptomyces spp.

Semisynthetic: 2nd & 3rd gen

Through variation of groups (Chloro, methyl, hydroxyl) attached to the tetracycline pharmacophore (NB: have no effect on spectrum of activity, but change PK/PD). | | Route | Oral; some IV IM: Only Tetracycline & Oxytetracycline | | Other uses | Antiinflammatory:

• Presumably by MMP inhibition —> decreased inflammation.
• Decrease production of TNFa, IL-6, IL-1b

Hyponatraemia:

• Demeclocycline only has anti-ADH activity in the kidney; blocks V2 vasopressor receptor —> diuresis —> Na concentrated. This is demeclocycline’s main use case. |

Indications

| Syndromic (From BNF) | Sinusitis LRTI Bronchiectasis/COPD flare SSTI Mild DFI/leg ulcer Human/animal bites Non-gonococcal Urethritis PID UTI | | --- | --- | | Bacterial | Gram positive: • Staphylococci • Pneumococci • Beta haemolytic Streptococci • Actinomyces

Atypical LRTI: • Mycoplasma • Chlamydophila • Legionella

Resp Gm negs: • Haemophilus influenzae • Moraxella catarrhalis

Gm Negs • GNBs ◦ ESBL E.coli UTI ◦ Pseudomonas UTI (controversial! see here) ◦ Burkholderia pseudomallei • Vibrio • H.pylori

STIs • Syphilis • Chlamydia • Gonorrhoea

Animal vector: • Brucella • Bartonella • Coxiella burnetii • Franciscella tularensis • Leptospira • Streptobacillus • Yersinia pestis

Tick vector • Borrelioses (Lyme, Relapsing fever) • Rickettsiales (RMSF, Typhus, Scrub typhus, Anaplasma, Erlichia)

Other • Whipple’s • Anthrax (Rx & PEP) | | Parasitic | Malaria (PEP, Rx [with Quinine]) Filarial infections (by killing Wolbachia endosymbionts) | | Other (as antiinflammatory) | Acne vulgaris Rosacea Periodontitis Bullous pemphigoid Hydradenitis suppuritiva |

Pharmacokinetics

PD

ADRs

• Ataxia
• Dizzy/lightheaded
• Auditory: tinnitus, hearing loss
• Visual disturbance | | | Teeth & bone (NB: dose & duration related) | | | Yellow —> gray-brown permanent discoloration, Enamel hypoplasia Demineralization Skeletal growth retardation | For advice on subtleties in pregnancy/breastfeeding see episode 56. | | Hepatic | | | Cholestasis Jaundice Rare: fulminant failure with acidosis, shock | | | Renal | | | High PO4 Acidosis Polyuria, polydipsia | |

Doxycycline Hyclate vs Monohydrate?

• Hyclate in UK. More water-soluble —> more GI ADRs

Doxy vs Mino

• ADRs:

  • Doxy: More GI
  • Mino: More allergy, autoimmune, hepatic, dizziness (9%) - slightly higher incidence of ADRs overall.

• Penetrance: CNS Mino > Doxy

  Tissue (Tissue:Serum concentration ratio)	Doxycycline	Minocycline
  CNS		0.5 (i.e. 50% penetrance)
  Liver/Bile	10-25	10
  Duodenum		5-10
  Gallbladder		5-10
  Thyroid		5-10
  Colon, bladder, prostate, uterus, breast, skin, lymph nodes and veins		<2
  Urine		5-12% of initial dose
  Sputum	8 - 28%
  Kidney, GI tract	High

EUCAST Breakpoints

Resistance Mechanisms

3 main mechanisms (All are easily transportable on MGEs):