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TETRACYCLINES

Demeclocycline, lymecycline, doxycycline, minocycline, tigecycline,

tigecycline sarecycline,
omadacycline, oxytetracycline, tetracycline

Introduction
 Broad spectrum antibiotics
 Short-acting - introduced in 1950s with plasma t1/2 of 6–8 hrs
 chlortetracycline, tetracycline, oxytetracycline
 Intermediate acting in 1960s (demeclocycline and methacycline) – t1/2 12 hrs
 Long-acting with plasma t1/2 16–18 hrs
 doxycycline, minocycline – once daily
 Tigecycline - used IV to treat difficult infections in the hospital setting

Mechanism of action
 Enters bacterial cell by passive diffusion and by an active transport system
 Bind reversibly to 30S subunit of bacterial ribosome, blocking binding of aminoacyl-tRNA to
acceptor site on the mRNA-ribosome complex
 This prevents addition of new amino acids to the growing peptide and inhibit protein synthesis
 They are broad-spectrum bacteriostatic antibiotics

Resistance
 The main mechanisms of resistance to tetracyclines are:
 (1) impaired influx or increased efflux by an active transport protein pump
 (2) ribosome protection due to production of proteins that interfere with tetracycline binding to
the ribosome
 (3) enzymatic inactivation

Spectrum of activity
 Broad spectrum antibiotics, active against:
 Many aerobic and anaerobic Gram-positive and Gram-negative pathogenic bacteria
 Chlamydiae, mycoplasmas, rickettsiae, mycobacteria, spirochetes
 Some protozoa - amebas
 However, their use has diminished over time due to increasing resistance
 Majority of penicillinase staphylococci are now insensitive to tetracyclines
 Tetracycline-resistant strains may be susceptible to doxycycline and minocycline
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Pharmacokinetics
 Oral absorption - high bioavailability - 60-80%
 Doxycycline, minocycline – 95-100%
 Absorption is impaired by food (except doxycycline and minocycline); by divalent cations (Ca2+,
Mg2+, Fe2+) or Al3+; by dairy products, antacids and multivitamins which contain multivalent
cations; and by alkaline pH
 Food/milk reduces their absorption by 50% or more. They are given 1/2 hr before or 2 hr after food
 Plasma protein binding: 40-80%, distributed widely to tissues and body fluids, except CSF, cross
placenta and excreted in milk
 Excreted mainly in bile and urine

Adverse effects
 GIT: common, especially with high doses, and are mostly attributed to irritation of the mucosa
 Nausea, anorexia, vomiting, diarrhea – give with food
 Superinfection: modify normal flora → overgrowth of pseudomonas, proteus, staphylococci,
resistant coliforms, clostridia, and candida
 intestinal functional disturbances, anal pruritus, vaginal or oral candidiasis, or enterocolitis
with shock and death
 Discoloration of teeth and enamel hypoplasia (young children)
 When given during pregnancy, it can be deposited in fetal teeth, leading to fluorescence,
discoloration, and enamel dysplasia
 it can be deposited in bone, where it may cause deformity or growth inhibition
 Impair hepatic function, especially during pregnancy, in patients with preexisting hepatic
insufficiency and when high doses are given IV
 Hepatic necrosis - with daily doses of ≥ 4 g IV
 Photosensitivity – sunburn especially with demeclocycline
 Autoimmune reactions with minocycline – very rare
 systemic lupus erythematosus, autoimmune hepatitis, serum sickness and vasculitis
 Fever, malaise, loss of appetite, rash, arthralgia or myalgia
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Clinical indications
 Doxycycline and minocycline spectrum of antibacterial activity, pharmacokinetic and safety
profile make them preferred drugs when tetracyclines are indicated in urologic infections
 May be used to treat infections caused by:
 Chlamydiae, and mycoplasma which can cause urethritis, cystitis, pyelonephritis, epididymitis,
prostatitis, and pelvic inflammatory disease
 Acute non-specific urethritis – first-line zithromycin 1 g stat
 Second-line, 100 mg doxycycline orally twice a day for 7 days
 Pelvic inflammatory disease
 Ceftriaxone 250 mg IM stat and
 doxycycline 100 mg, twice daily, for two weeks and metronidazole 400 mg, twice daily, for
two weeks
 Epididiymo-orchitis: usually males < 35 years,
 Ceftriaxone 250 mg, IM stat and doxacycline 100 mg, twice daily for at least two weeks
 Alternative, for penicillin-allergic patients
 Other urological diseases – syphilis, and chancroid caused by different bacteria
 Brucella - can cause brucellosis, a systemic infection that may involve the kidneys, prostate, and
epididymis
 Treatment of gastric and duodenal ulcer disease caused by H. pylori – in combination
 Atypical pneumonia - amoxicillin 500 mg – 1 g/3 times daily, for 7 days plus erythromycin,
roxithromycin or doxycycline
 Plague, tularemia – with aminoglycosides
 Protozoal infections - E. histolytica or P. falciparum
 Other uses include
 treatment of acne, exacerbations of bronchitis,
 community-acquired pneumonia, Lyme disease,
 Relapsing fever and some nontuber-culous mycobacterial infections (eg, M. marinum)

Drug interactions
 Minerals - aluminum (in antacids), bismuth, calcium, iron, magnesium, and zinc, interfere with the
absorption of tetracycline
 Minerals and tetracycline attach to each other and form insoluble chemical complexes that simply
pass out of the digestive tract
 Penicillins
 Bactericidal with bacteriostatic antibiotic
 Citrate:
 K citrate, Na citrate, and K-Mg citrate are sometimes used to prevent kidney stones
 These supplements reduce urinary acidity → ↓ blood levels and effectiveness of tetracycline
 Dong quai , st. john's wort: herbs
 Tetracycline may cause increased sensitivity to sun, amplifying risk of sunburn or skin rash.
 Because St. John's wort and dong quai may also cause this problem, taking these herbal supplements
during tetracycline treatment might add to this risk
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Contraindications
 Hypersensitivity to tetracyclines
 Severe hepatic dysfunction - should be avoided or used with caution in patients with hepatic
impairment
 Children aged under 18 years - associated with impaired bone growth and permanent
discoloration of teeth and enamel hypoplasia
 Tetracyclines bind to calcium molecules and are deposited in calcifying areas in bones and
teeth
 Pregnancy and breast feeding

Tigecycline

 It is derivative of minocycline, designed to overcome some of tetracycline resistance mechanisms

and is effective against a wide range of bacteria
 Its spectrum of activity is broad and many tetracycline resistant strains are susceptible to
tigecycline
 Tigecycline is poorly absorbed from GIT, so it is given IV only with a t1/2 of 36 hrs
 It is excreted in bile.
 It is not affected by tetracycline-specific efflux pumps or by the ribosomal protection mechanism of
tetracycline resistance
 Its spectrum is very broad
 Coagulase-negative staphylococci and S. aureus, including MRSA and extended-spectrum
beta-lactamase (ESBL)-producing Enterobacteriaceae, vancomycin-resistant strains
 Streptococci – penicillin-susceptible/resistant; enterococci including vancomycin-
resistant strains
 Multidrug-resistant strains of Acinetobacter spp.
 Anaerobes, both Gram-positive and Gram-negative
 Atypical agents, rickettsiae, chlamydia, and legionella; and rapidly growing mycobacteria
 Proteus and P. aeruginosa are resistant

Clinical uses
 Tigecycline is not commonly used as a first-line antibiotic in urology
 Reserved for specific situations where other treatment options may be limited due to antibiotic
resistance or when dealing with complicated infections
 Intra-abdominal infections
 Skin and skin structure infections
 Community-acquired bacterial pneumonia
 Hospital-acquired and ventilator-associated pneumonia
 Dosage: initially 100 mg, then 50 mg/12 hrs, IV over 30 – 60 minutes
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Omadacycline

 Structurally similar to tigecycline

 exerts potent effects against infections caused by MDR bacteria and shortens patient’s
hospitalization time
 Compared with other tetracycline drugs, omadacycline is:
 more active against bacteria that possess efflux pumps and other drug-resistant
factors
 Has certain advantages in therapeutic effect and safety