Antibiotics Targeting Bacterial Ribosomal Subunits

Macrolides

Bacteriostatic

Macrolides:

  • Erythromycin

Azalides:

  • Clarithromycin
  • Azithromycin

Ketolides:

  • Telithromycin & Cethromycin
Mechanism of Action:
  • Bind reversibly to 50s ribosomal subunit decreasing protein synthesis
  • Also has inherent anti-inflammatory effect: decrease leucocyte chemotaxis; decrease cytokines; decrease matrix metalloproteinases
Adverse Effects:
  • Hypersensitivity reactions including urticaria, angioedema, anaphylaxis, acute generalized pustular dermatosis (AGEP), Drug Rash with Eosinophilia and Systemic Symptoms (DRESS), Steven Johnson/toxic epidermal necrolysis (SJS/TEN), Henoch-Schönlein purpura (HSP); also, can cause photosensitivity
  • Hepatic: cholestatic hepatitis (increase LFTs especially with clarithromycin, liver impairment mostly with azithromycin)
  • Cardiac: QT prolongation, torsade de pointes (erythromycin) so caution with medications that prolong QT
  • Other: ototoxicity (mainly if high doses or known hepatic/renal failure); can exacerbate myasthenia gravis
Drug interactions / Pregnancy and Lactation
  • erythromycin > clarithromycin inhibits CYP 3A4 causing many drug interactions (↑ levels of cyclosporine, statins, CCBs, dapsone, warfarin, colchicine, amiodarone, antidepressants and antipsychotics)
  • excreted in breast milk; infant exposure during lactation is a risk factor for hypertrophic pyloric stenosis

Medication

Erythromycin

  • Category B
Spectrum of Activity
  • Gram positives (except MRSA and Enterococcus) AND gram negatives
Indications
  • Erythrasma, anthrax, erysipeloid, chancroid, LGV, early Lyme disease in < 8 years of age; Pityriasis lichenoides et varioliformis acuta (PLEVA) and Pityriasis lichenoides chronica (PLC)
Contraindications, Adverse Effects and Other
  • Contraindications: patient taking dihydroergotamine, ergotamine, pimozide
  • Adverse effects: nausea, abdominal pain, diarrhea in 15-20% of patients
  • Dose must be adjusted in renal disease

Medication

Clarithromycin

  • Category C
Spectrum of Activity
  • Gram positives (except MRSA and Enterococcus) AND gram negatives; 
  • Most active macrolide against M. leprae, toxoplasmosis, Treponema, Borrelia burgdorfi
Indications
  • Pyodermas, abscesses, infected wounds, infected ulcers erysipelas, leprosy, atypical mycobacterial skin infections, acne, rosacea, perioral dermatitis, PLEVA and PLC
Contraindications, Adverse Effects and Other
  • Contraindications: cholestatic jaundice with previous treatment, history of QTc prolongation/Torsade de pointes; patient taking dihydroergotamine, ergotamine, pimozide; also risk in patient with heart disease 
  • Adverse effects: metallic/bitter taste, fixed drug eruption, leukocytoclastic vasculitis
  • Dose must be adjusted in renal disease

Medication

Azithromycin

  • Category B
Spectrum of Activity
  • Gram positives (except MRSA and Enterococcus) AND gram negatives
  • E. Coli, Neisseria spp., H. ducreyi, Chlamydia, Toxoplasmosis, Treponema, Borrelia burgdorfi
Indications
  • Pyodermas, abscesses, infected wounds, infected ulcers erysipelas, donovanosis, cat scratch disease, toxoplasmosis, gonorrhea, chlamydia, Mediterranean spotted fever, animal bites, human bites (Eikenella), acne, rosacea, confluent and reticulated papillomatosis, PLEVA and PLC
Contraindications, Adverse Effects and Other
  • Contraindications: liver dysfunction
  • Adverse effects: irreversible deafness (rare), angioedema, photosensitivity
  • Azithromycin should be taken 1-2 hours before meal for better absorption

Generic Name

Clindamycin

  • Pregnancy Category B
Dosing and Formulations
  • 150-300mg BID
Mechanism of Action
  • Binds the 50S ribosomal subunit decreasing protein synthesis 
  • Gram positive cocci, anaerobes (MRSA also covered)
  • also inhibits production of superantigen toxins in toxic shock syndrome and exfoliatin in SSSS
Indications
  • Cellulitis, folliculitis, furunculosis, carbuncles, impetigo, ecthyma, hidradenitis suppurativa, infected diabetic foot, SSSS (toxin mediated)
Adverse Effects
  • Gastrointestinal: diarrhea in 20% of patients, nausea, vomiting, transaminitis
  • Hypersensitivity reactions: morbilliform, SJS/TEN, AGEP, erythema multiforme, DRESS, Sweet syndrome, urticaria, SDRIFE
  • May increase effect of neurotoxin / neuromuscular blockers
Other
  • Contraindications: allergy, previous C. difficile infection; caution with patients with severe liver disease

Generic Name

Oxazolidinones (Linezolid)

  • Pregnancy Category C
Dosing and Formulations

  • Linezolid 400 mg BID

Mechanism of Action
  • 23S portion of the 50S subunit decreasing protein synthesis
Indications
  • Broad spectrum: MRSA, VRSA, VRE, toxin-mediated;
  • used for skin infections caused by Staph. that have failed all other agents
Adverse Effects
  • Reversible thrombocytopenia, pancytopenia, serotonin syndrome (when used with SSRI’s, MOAI, TCAs), optic and peripheral neuropathy
Other
  • Use limited in dermatology due to high cost.
  • Platelets / CBC need to be monitored (especially if baseline low platelets/ hematologic abnormality)

Generic Name

Tetracyclines

(tetracycline, minocycline, doxycycline, demeclocycline)

  • Pregnancy Category D
Dosing and Formulations
  • Short acting (6-12h):
    • Tetracycline 250-1500mg / day (daily-BID), 
  • Intermediate (16hrs)
    • Doxycycline 50-200 mg/ day (daily-BID), Minocycline IR 50-200 mg/day (daily-BID), Demeclocycline
  • Long-acting – not to be used for infections (18-22hrs)
    • Doxycycline MR 40mg qd
    • Minocycline ER 1mg/kg/d
Mechanism of Action

Binds 30S subunit of bacterial ribosome decreasing protein synthesis 

gram positive > gram negative, Mycoplasma, rickettsia, spirochetes, some parasites

Anti-inflammatory effects

  1. Decrease neutrophil chemoattractants (peptide chemotactic factor, lipase) production by C. acnes which decrease neutrophil migration 
  2. Inhibits granuloma formation (inhibits Protein kinase C)
  3. Inhibits matrix metalloproteinases
  4. Downregulates cytokines involved in innate response
  5. Scavenger effect against reactive oxygen species

Lipophilic: accumulates in the pilosebaceous unit

Pharmacokinetics:

  • Food and high pH agents (e.g., antacids) decrease tetracycline absorption; therefore, should take 2 hours after food, others tetracyclines can be taken with food
  • Absorption decreased if taking polyvalent cations (laxatives, antacids, dietary supplements, dairy) causing chelation, mainly with tetracycline > doxycycline > minocycline 
  • Renal failure prolongs half-life (except doxycycline as it is excreted mostly in bile)
Indications
  • Acne (see discussion below)
  • Rosacea (doxycycline MR 40 only one that is FDA approved)
  • ocular rosacea, perioral dermatitis
  • immuno-bullous diseases (Bullous pemphigoid, linear IgA bullous dermatosis, Pemphigus vulgaris and foliaceus),
  • Granulomatous diseases (sarcoidosis)
  • Other: confluent and reticulated papillomatosis (minocycline), PLEVA, Lyme, ehrlichiosis (1st line for rickettsial diseases)
  • Also indicated for community-acquired MRSA, Mycobacterium avium complex, sexually transmitted and blood-borne infections, bartonellosis, etc

Systemic antibiotics in acne:

  • moderate/severe inflammatory acne resistant to topicals
  • doxycycline and minocycline are equal and superior to tetracycline
  • treatment for 3-4 months
  • combine with topicals
  • if patient cannot take tetracyclines, give: azithromycin, erythromycin or trimethoprim sulfamethoxazole (but these are 2nd line)

Contraindications:

  • Pregnancy (teeth staining, and hypoplastic bone development)
  • Children < 8 years old
  •  Renal disease (except doxycycline which can be used)
    Liver disease: caution with doxycyline
Adverse Effects
  • Gastrointestinal: nausea, pill esophagitis (especially doxycycline), hepatitis, pancreatitis
  • Vestibular: dizziness, tinnitus, vertigo (these ones mainly with minocycline), pseudotumor cerebri (if persistent, can lead to permanent vision loss)
  • hematologic: thrombocytopenia, neutropenia
  • pregnancy: affects fetal teeth, bones (but rare with doxycycline); children <9 years of age 🡪 yellowish staining of teeth and bone developmental abnormalities

Cutaneous side effect

  • Hypersensitivity: urticaria, fixed drug eruption, Sweets, Serum sickness-like reaction (minocycline mainly, especially if HIV), SJS/TEN, DRESS (minocycline)
  • Autoimmune (minocycline >> others): autoimmune hepatitis, SLE-like reaction (typically anti-dsDNA positive > anti-histone Ab), ANCA vasculitis (PAN); can have delayed onset x years
  • Photosensitivity (demeclocycline > doxycycline >> others), also photo-onycholysis
  • Infections (gram negative folliculitis)
  • dyspigmentation of skin, nails, teeth, bones, mucosa, sclera (minocycline)
    • Type I: blue-black in scars (iron)
    • Type II: blue-gray shins (melanin + iron)
    • Type III: diffuse muddy brown on sun exposed (melanin)

Drug interactions

  • Increase effects of warfarin, lithium, theophylline, digoxin, methotrexate, insulin
  • Increase likelihood pseudotumor cerebri if taken with retinoids
Other
  • Most common antibiotic used in dermatology
  • To reduce gastrointestinal symptoms, instruct patients to take with glass of water and no reclining for 1 hour 
  • ANA positivity during treatment does not correlate with autoimmune disease, most of these patients do not develop clinical disease
  • For acne, you see improvement after 3 weeks, and maximum benefit at 3-6 months 
  • New studies show efficacy of doxycycline 20 mg BID is similar to 100 mg BID in clearing inflammatory acne
  • Resistance to tetracyclines can be seen (~20% acne patients), and occurs due to ribosomal protection (point mutation in genes encoding 16S ribosomal RNA) and drug efflux
  • If a tetracycline must be given in pregnancy or in children (e.g. to treat early RMSF), use doxycline

Generic Name

Glycylcyclines (Tigecycline)

  • Pregnancy Category D
Dosing and Formulations

  • Tigecycline (IV)

Mechanism of Action
  • 30S ribosomal
Indications
  • Complicated skin infections, resistant organisms like MRSA
Adverse Effects
  •  nausea, vomiting, diarrhea
  • infusion site reaction
  • tooth discoloration <8 years old 
  • photosensitivity, pancreatitis, liver dysfunction
Other
  • Black box warning for all-cause mortality (last resort as antibiotic choice)

Generic Name

Aminoglycosides

Dosing and Formulations
  • Neomycin
  • Tobramycin
  • Gentamicin
Mechanism of Action
  • 30S ribosoma
  • Bacteriostatic and bactericidal
Indications
  • Systemic aminoglycosides not often used in dermatology
Adverse Effects

* For further reading/details: refer to a pharmacology book

Other

* For further reading/details: refer to a pharmacology book