Antimicrobial drugs: Tetracyclines

Amphenicols, Aminoglycosides

Aleksandar Jovanović
Professor of Clinical Pharmacology and Therapeutics
Learning objectives

This lecture cover LOBs 1-5 (parts)

 Classification of anti-bacterial
drugs
1) Sulfonamides
2) -lactams (penicillines and cephalosporines)
3) Tetracyclines
4) Amphenicols
5) Aminoglycosides
6) Macrolides
7) Drugs acting on topoisomerase
8) Anti-mycobacterium
9) Miscellaneous and less common anti-bacterial drugs
Reminder (I)
Reminder (II)
Reminder (III)
 Tetracyclines
Tetracyclines are broad-spectrum antibiotics. The group
includes tetracycline, oxytetracycline, demeclocycline,
lymecycline, doxycycline and minocycline. Tigelcycline is
structurally related to the tetracycline family and has similar
therapeutic and unwanted effects.
Tetracyclines-mechanisms of
action
Tetracyclines inhibit
the 30S ribosomal
subunit, hindering
the binding of the
aminoacyl-tRNA to
the acceptor site on
the mRNA-
ribosome complex.
 Tetracyclines-pharmacokinetics
1) Orally absorbed (60 to ≥ 90%).
2) Absorption is decreased by metallic cations (eg, aluminium, Ca 2+, Mg2+, iron).
Tetracyclines are not to be taken with preparations containing these substances (eg,
antacids, many vitamin and mineral supplements).
3) Food decreases absorption of tetracycline but not of doxycycline or minocycline.
4) Tetracyclines penetrate into most body tissues and fluids.
5) CSF levels are not reliably therapeutic. Minocycline is the only tetracycline that reaches
high concentrations in tears and saliva. Tetracycline and minocycline are excreted
primarily in urine. Doxycycline is excreted primarily in the intestinal tract.
 Tetracyclines-indications (I)
Infections caused by Rickettsiae, Spirochetes (eg, Treponema
pallidum, Borrelia burgdorferi), Helicobacter pylori, Vibrio sp,
Yersinia pestis, Francisella tularensis, Brucella sp, Bacillus anthracis,
Plasmodium vivax, Plasmodium falciparum, Mycoplasma sp,
Chlamydia and Chlamydophila sp, Some methicillin-
resistant Staphylococcus aureus.

Tetracyclines are interchangeable for most indications,

although minocycline has been most studied for methicillin-
resistant S. aureus infections.
 Tetracyclines-indications (II)

• Acute exacerbations of chronic bronchitis, Lyme disease,

Brucellosis, Anthrax, Plague, Tularemia, Granuloma inguinale,
Syphilis, Prophylaxis of malaria caused by chloroquine-resistant P.
falciparum.

• Because of its high concentration in tears and saliva, minocycline is

the only tetracycline that can eradicate meningococci in carriers and
is an alternate to rifampin for this indication.
 Tetracyclines-adverse effects (I)

1) GI disturbances, Clostridium difficile–induced diarrhea

2) Candidiasis, photosensitivity, bone and dental effects in children, Fatty liver, Vestibular
dysfunction (with minocycline). Bone and dental effects include staining of teeth,
hypoplasia of dental enamel, and abnormal bone growth in children < 8 yr and in fetuses. In
infants, tetracyclines may cause idiopathic intracranial hypertension and bulging fontanelles.
3) If not swallowed with water, tetracyclines can cause esophageal erosions.
4) Excessive blood levels due to use of high doses or renal insufficiency may lead to fatal acute
fatty degeneration of the liver, especially during pregnancy.
 Tetracyclines-adverse effects (II)
1) Minocycline commonly causes vestibular dysfunction.
2) Minocycline has been associated with development of autoimmune disorders such as SLE and
polyarteritis nodosa.
3) Minocycline may also cause drug reaction with eosinophilia and systemic symptoms (DRESS), which
is characterized by fever, rash, lymphadenopathy, hepatitis, atypical lymphocytosis, eosinophilia, and
thrombocytopenia.
4) Tetracycline can exacerbate azotemia in patients with renal insufficiency.
5) Expired tetracycline pills can degenerate and, if ingested, cause Fanconi syndrome. Patients should be
instructed to discard the drugs when they expire.
 Tetracyclines-contraindications
Tetracyclines are contraindicated in patients who have had an

1)Allergic reaction to them

2)Patients with renal insufficiency (except for doxycycline, which has no dosage adjustment for renal
insufficiency)

3)Children < 8 yr (except sometimes for inhalational anthrax or other severe illnesses when the benefit
outweighs the potential risk of tooth staining).
Tetracyclines-dosing considerations
Doxycycline, excreted primarily in the intestinal tract,
requires no dose reduction in renal insufficiency.

Tetracyclines may decrease the effectiveness of oral

contraceptives and potentiate the effects of oral
anticoagulants.
 Tetracyclines Tetracycline, doxycycline,
minocycline
Mechanism Bacteriostatic; bind to 30S and prevent
attachment of aminoacyl-tRNA; limited
CNS penetration. Doxycycline is fecally
eliminated and can be used in patients
with renal failure. Do not take
tetracyclines with milk (Ca2+), antacids
(Ca2+ or Mg2+), or iron-containing
preparations because divalent cations
inhibit drugs’ absorption in the gut.
Clinical use Borrelia burgdorferi, M pneumoniae.
Drugs’ ability to accumulate
intracellularly makes them very
effective against Rickettsia and
Chlamydia. Also used to treat acne.
Adverse effects GI distress, discoloration of teeth and
inhibition of bone growth in children,
photosensitivity. Contraindicated in
pregnancy.
Mechanism of resistance Decreased uptake or increased efflux.
 Amphenicols

Chloramphenicol is prototype.
 Chloramphenicol-mechanisms of
action

Chloramphenicol binds to the bacterial 50S ribosomal subunit

and the binding interferes with peptidyl transferase activity,
thereby prevents transfer of amino acids to the growing peptide
chains and blocks peptide bond formation.
 Chloramphenicol-pharmacokinetics

Chloramphenicol is well absorbed orally. Parenteral therapy should

be IV. Chloramphenicol is distributed widely in body fluids,
including CSF, and is excreted in urine. Because of hepatic
metabolism, active chloramphenicol does not accumulate when renal
insufficiency is present. Chloramphenicol enters breast milk. Safety
during breastfeeding has not been determined.
 Chloramphenicol-indications
Chloramphenicol has a wide spectrum of activity against Gram-positive and gram-negative
cocci and bacilli (including anaerobes) Rickettsia, Mycoplasma, Chlamydia,
and Chlamydophila spp

Because of bone marrow toxicity, the availability of alternative antibiotics, and the
emergence of resistance, chloramphenicol is no longer a drug of choice for any infection,
except for serious infections due to a few multidrug-resistant bacteria that remain
susceptible to this antibiotic
 Chloramphenicol-adverse effects (I)
• Adverse effects include Bone marrow depression (most serious), Nausea, vomiting, and diarrhea, Gray
baby syndrome (in neonates)

• There are 2 types of bone marrow depression:

• Reversible dose-related interference with iron metabolism: This effect is most likely with high doses or
prolonged treatment or in patients with a severe liver disorder.
• Irreversible idiosyncratic aplastic anemia: This anemia occurs in < 1/25,000 treated patients. It may not
develop until after therapy is stopped. Chloramphenicol should not be used topically because small
amounts may be absorbed and, rarely, cause aplastic anemia.
 Chloramphenicol-adverse effects (II)
• Hypersensitivity reactions are uncommon. Optic and peripheral neuritis may occur
with prolonged use.

• The neonatal grey baby syndrome, which involves hypothermia, cyanosis, flaccidity,
and circulatory collapse, is often fatal. The cause is high blood levels, which occur
because the immature liver cannot metabolize and excrete chloramphenicol. To avoid
the syndrome, clinicians should not give infants ≤ 1 mo > 25 mg/kg/day initially, and
doses should be adjusted based on blood levels of the drug.
Chloramphenicol-contraindications
Chloramphenicol is contraindicated if another drug
can be used instead.
 Amphenicols
Amphenicols Chloramphenicol

Blocks peptidyltransferase at 50S ribosomal

Mechanism subunit. Bacteriostatic.

Meningitis (Haemophilus influenzae,

Clinical use Neisseria meningitidis, Streptococcus
pneumoniae) and Rocky Mountain spotted
fever (Rickettsia rickettsii). Limited use
owing to toxicities but often still used in
developing countries because of low cost.
Anemia (dose dependent), aplastic anemia
Adverse effects (dose independent), gray baby syndrome (in
premature infants because they lack liver
UDP-glucuronyl transferase).

Plasmid-encoded acetyltransferase inactivates

Mechanism of resistance the drug.
 Aminoglycosides

The aminoglycosides are a group of antibiotics of complex

chemical structure, resembling each other in antimicrobial
activity, pharmacokinetic characteristics and toxicity. The
main agents are gentamicin, streptomycin, amikacin,
tobramycin and neomycin.
Aminoglycosides -mechanisms
of action
Aminoglycosides work by
binding to the bacterial 30S
ribosomal subunit to inhibit the
translocation of the peptidyl-
tRNA from the A-site to the P-
site and also causing
misreading of mRNA,
Aminoglycosides-pharmacokinetics
1) Aminoglycosides are poorly absorbed orally but are well absorbed from the peritoneum,
pleural cavity, and joints and from denuded skin.
2) Aminoglycosides are usually given IV.
3) Aminoglycosides are distributed well into ECF except for vitreous humor, CSF, respiratory
secretions, and bile (particularly in patients with biliary obstruction). Intravitreous injection
is required to treat endophthalmitis. Intraventricular injection is often required to reach
intraventricular levels high enough to treat meningitis. Aminoglycosides are excreted by
glomerular filtration and have a serum half-life of 2 to 3 h; the half-life increases
exponentially as the GFR falls (eg, in renal insufficiency, in the elderly).
 Aminoglycosides-indications (I)

Serious gram-negative bacillary infections (especially those due to Pseudomonas

aeruginosa). Aminoglycosides are active against most gram-negative aerobic and
facultative anaerobic bacilli but lack activity against anaerobes and most gram-
positive bacteria, except for most staphylococci; however, some gram-negative
bacilli and methicillin-resistant staphylococci are resistant.
 Aminoglycosides-indications (II)

Aminoglycosides that are active against P.

aeruginosa include tobramycin (particularly), gentamicin,
and amikacin. Streptomycin, neomycin, and kanamycin are not
active against P. aeruginosa. Gentamicin and tobramycin have
similar antimicrobial spectra against gram-negative bacilli,
but tobramycin is more active against P. aeruginosa,
and gentamicin is more active against Serratia marcescens.
 Aminoglycosides-indications (III)
Amikacin is frequently active against gentamicin- and tobramycin-
resistant pathogens.

Aminoglycosides are infrequently used alone, except when used for

plague and tularemia. They are usually used with a broad-
spectrum β-lactam for severe infection suspected to be due to a
gram-negative bacillary species. However, because of increasing
aminoglycoside resistance, a fluoroquinolone can be substituted for
the aminoglycoside in initial empiric regimens.
 Aminoglycosides-indications (IV)
Gentamicin or, less commonly, streptomycin may be used with
other antibiotics to treat endocarditis due to streptococci or
enterococci.

Treatment of enterococcal endocarditis requires prolonged use of a

potentially nephrotoxic and ototoxic aminoglycoside plus a
bacterial cell wall–active drug (eg, penicillin, vancomycin). If the
strain is susceptible to high levels
of gentamicin and streptomycin, gentamicin is preferred because
serum levels can be readily determined and toxicity is less.
 Aminoglycosides-indications (V)

In case of endocarditis due to enterococci that are resistant to high

levels of gentamicin and streptomycin,
ampicillin and ceftriaxone combination to be used.

Because of toxicity, neomycin and kanamycin are limited to

topical use in small amounts. Neomycin is available for eye, ear,
oral, and rectal use and as a bladder irrigant. Oral neomycin is used
topically against intestinal flora to prepare the bowel before
surgery and to treat hepatic coma.
 Aminoglycosides-adverse effects (I)

All aminoglycosides cause:

Renal toxicity (often reversible).
Vestibular and auditory toxicity (often irreversible; vertigo
and ataxia)
Prolongation of effects of neuromuscular blockers
Aminoglycosides-adverse effects (II)
Risk factors for renal, vestibular, and auditory toxicity are 1)
frequent or very high doses, 2) very high blood levels of the
drug, 3) long duration of therapy (particularly > 3 days), 4)
older age, 5) Pre-existing renal disorder, 6) co-administration
of vancomycin, cyclosporine, or amphotericin B.

For renal toxicity alone, co-administration of contrast agents.

For auditory toxicity alone, a genetic predisposition, pre-

existing hearing problems, and co-administration of loop
diuretics.
 Aminoglycosides-adverse effects
(III)

Hypersensitivity reactions are uncommon except for contact

dermatitis due to topical neomycin. High oral doses
of neomycin can cause malabsorption.
 Aminoglycosides-contraindications

Aminoglycosides are contraindicated in patients

who are allergic to them.
Aminoglycosides-dosing considerations (I)

Because toxicity depends more on duration of therapeutic levels than

on peak levels and because efficacy is concentration-dependent
rather than time-dependent, frequent doses are avoided. Once/day IV
dosing is preferred for most indications except enterococcal
endocarditis. IV aminoglycosides are given slowly (30 min for
divided daily dosing or 30 to 45 min for once/day dosing).
 Aminoglycosides-dosing considerations
(II)
In critically ill patients, peak serum levels should be determined after the first
dose. In all patients, peak and trough levels are measured after the 2nd or 3rd
dose (when the daily dose is divided) or when therapy lasts > 3 days, as well as
after the dose is changed. Serum creatinine is measured every 2 to 3 days, and if
it is stable, serum aminoglycoside levels need not be measured again. Peak
concentration is the level 60 min after an IM injection or 30 min after the end of a
30-min IV infusion. Trough levels are measured during the 30 min before the
next dose.
 Aminoglycosides-dosing considerations
(III)

Peak levels in serum of at least 10 times the MIC are desirable.

Dosing is adjusted to ensure a therapeutic peak serum level (to
facilitate concentration-dependent activity) and non-toxic trough
levels.
 Aminoglycosides-dosing considerations
(IV)

For patients with renal insufficiency, the loading dose is the same as
that for patients with normal renal function; usually, the dosing
interval is increased rather than the dose decreased. Guidelines for
maintenance doses based on serum creatinine or creatinine clearance
values are available, but they are not precise, and measurement of
blood levels is preferred.
 Aminoglycosides
Aminoglycosides Gentamicin, Neomycin, Amikacin,
Tobramycin, Streptomycin.

Mechanism Bactericidal; irreversible inhibition of

initiation complex through binding of
the 30S subunit. Can cause misreading
of mRNA. Also block translocation.
Require O2 for uptake; therefore
ineffective against anaerobes.
Clinical use Severe gram ⊝ rod infections.
Synergistic with β-lactam antibiotics.
Neomycin for bowel surgery.
Adverse effects Nephrotoxicity, Neuromuscular
blockade, Ototoxicity (especially when
used with loop diuretics). Teratogen.
Mechanism of resistance Bacterial transferase enzymes inactivate
the drug by acetylation,
phosphorylation, or adenylation.
 Sources

• Rang and Dale's pharmacology 9th ed.

(Chapter 52)
• First Aid for the USML Step 1. 2016.