DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

1524 Oral doses of doxycycline and minocycline are well absorbed the antibacterial activity lost to the tetracyclines due to
resistance and can be used for a number of infections
due to gram-positive and gram-negative organisms.
SECTION VII
CHEMOTHERAPY OF MICROBIAL DISEASES
(90-100%) and have half-lives of 16-18 hours; they therefore can be
administered less frequently and at lower doses than tetracycline or
demeclocycline. After an oral dose of 200 mg of doxycycline, a maximum
plasma concentration of 3 μg/mL is achieved at 2 hours, and
the plasma concentration remains above 1 μg/mL for 8-12 hours.
Plasma concentrations are equivalent whether doxycycline is given
orally or parenterally.
Distribution. Tetracyclines distribute widely throughout the body and
into tissues and secretions, including urine and prostate. They accumulate
in reticuloendothelial cells of the liver, spleen, and bone marrow,
and in bone, dentine, and enamel of unerupted teeth. Tigecycline
distributes rapidly and extensively into tissues, with an estimated
apparent volume of 7-10 L/kg. Because of this extensive distribution,
peak serum levels of tigecycline are relatively low (~1 μg/mL).
Inflammation of the meninges is not required for the passage
of tetracyclines into the cerebrospinal fluid (CSF). Penetration of
these drugs into most other fluids and tissues is excellent.
Concentrations in synovial fluid and the mucosa of the maxillary
sinus approach that in plasma. Tetracyclines cross the placenta and
enter the fetal circulation and amniotic fluid. Relative to the maternal
circulation, tetracycline concentrations in umbilical cord plasma
and amniotic fluid are 60% and 20%, respectively. Relatively high
concentrations of these drugs also are found in breast milk.
Excretion. The primary route of elimination of most older tetracyclines
(e.g., demeclocycline, tetracycline) is the kidney, although
they also are concentrated in the liver and excreted in bile. After biliary
excretion, they are partially reabsorbed via enterohepatic recirculation.
Elimination via the intestinal tract occurs even when the
drugs are given parenterally. Comparable amounts of tetracycline
(i.e., 20-60%) are excreted in the urine within 24 hours following
oral or intravenous administration.
Doxycycline is largely excreted unchanged both in the bile
and urine, tigecycline is mostly excreted unchanged along with a
small amount of glucuronidated metabolites, and minocycline is
extensively metabolized by the liver before excretion. Doses of these
agents do not require adjustment in patients with renal dysfunction.
Decreased hepatic function or obstruction of the common bile duct
reduces the biliary excretion of these agents, resulting in longer halflives
and higher plasma concentrations. Specific dosage adjustment
recommendations in hepatic disease are available only for tigecycline.
Because of their enterohepatic circulation, these drugs may
remain in the body for a long time after cessation of therapy. There
is some evidence for drug interactions between doxycycline and
hepatic enzyme-inducing agents such as phenytoin and rifampin, but
not for minocycline or tigecycline.
Therapeutic Uses and Dosage. The tetracyclines have
been used extensively to treat infectious diseases and
as an additive to animal feeds to facilitate growth. These
uses have increased resistance to tetracyclines among
gram-positive and gram-negative organisms, limiting
their use for a number of common bacterial infections.
However, the drugs remain useful as first-line therapy
for infections caused by rickettsiae, mycoplasmas, and
chlamydiae. The glycylcyclines have restored much of
Children >8 years of age should receive 25-50 mg/kg daily in
four divided doses. The total daily dose of intravenous tetracycline
(no longer available in the U.S.) for most acute infections is 1 g
(or 2 g for severe infection), divided into equal doses and administered
at 6- or 12-hour intervals. The low pH of tetracycline, but not
doxycycline or minocycline, invariably causes phlebitis if infused into
a peripheral vein. The recommended dose of demeclocycline is
150 mg every 6 hours or 300 mg every 12 hours for adults and
6.6-13.2 mg/kg in two to four divided doses for children >8 years of
age. Demeclocycline is used rarely as an antimicrobial agent because
of its higher risks of photosensitivity reactions and nephrogenic diabetes
insipidus. The oral or intravenous dose of doxycycline for adults
is 100 mg every 12 hours on the first day and then 50 mg every
12 hours, 100 mg once a day, or 100 mg twice daily when severe
infection is present; for children >8 years of age, the dose is 4-5 mg/kg
per day in two divided doses the first day, then 2-2.5 mg/kg given once
or twice daily. The dose of minocycline for adults is 200 mg orally or
intravenously initially, followed by 100 mg every 12 hours; for children,
it is 4 mg/kg initially followed by 2 mg/kg every 12 hours.
Tigecycline is administered intravenously to adults as a 100-mg loading
dose, followed by 50 mg every 12 hours. For patients with severe
hepatic impairment, the loading dose should be followed by a reduced
maintenance dose of 25 mg every 12 hours. Dosage data are not available
for tigecycline in pediatrics.
Tetracyclines should not be administered intramuscularly
because of local irritation and poor absorption. GI distress, nausea,
and vomiting can be minimized by administration of tetracyclines
with food. Generally, oral administration of tetracyclines should
occur 2 hours before or 2 hours after co-administration with any of
the agents listed. Cholestyramine and colestipol also bind orally
administered tetracyclines and interfere with the absorption of the
antibiotic.
Respiratory Tract Infections. Doxycycline’s good activity against
S. pneumoniae and H. influenzae and excellent activity against atypical
pathogens such as Mycoplasma and Chlamydophilia pneumoniae
make it an effective single agent for empirical therapy of
community-acquired pneumonia in the outpatient setting or as an
adjunct to cephalosporin-based therapy for inpatients (Mandell
et al., 2007). Tigecycline has been demonstrated to be effective for
use as a single agent for adults hospitalized with communityacquired
bacterial pneumonia (Bergallo et al., 2009).
Skin and Soft-Tissue Infections. Community strains of methicillinresistant
S. aureus often are susceptible to tetracycline, doxycycline,
or minocycline, which appear to be effective for uncomplicated skin
and soft-tissue infections, although published data are limited
(Cenizal et al., 2007). Tigecycline is approved by the Food and Drug
Administration (FDA) for the treatment of complicated skin and
soft-tissue infections.
Tetracyclines have been used to treat acne. They may act by
inhibiting propionibacteria, which reside in sebaceous follicles and
metabolize lipids into irritating free fatty acids. The relatively low
doses of tetracycline used for acne (e.g., 250 mg orally twice a day)
are associated with few side effects.