Page 831 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 44 Tetracyclines, Macrolides, Clindamycin, Chloramphenicol, Streptogramins, & Oxazolidinones 817

doxycycline, and minocycline. They are susceptible, how- Tetracyclines are classified as short-acting (tetracycline, as well
ever, to tigecycline, which is not a substrate of these pumps. as the agricultural agents chlortetracycline and oxytetracycline),
Similarly, a different pump [Tet(K)] of staphylococci confers intermediate-acting (demeclocycline), or long-acting (doxycy-
resistance to tetracycline, but not to doxycycline, minocycline, cline and minocycline) based on serum half-lives of 6–8 hours,
or tigecycline, none of which are pump substrates. The Tet(M) 12 hours, and 16–18 hours, respectively. Tigecycline has a half-life
ribosomal protection protein expressed by Gram-positives of 36 hours. The almost complete absorption and slow excretion
produces resistance to tetracycline, doxycycline, and mino- of doxycycline and minocycline allow for once-daily dosing for
cycline, but not to tigecycline, which, because of its bulky certain indications, but, by convention, these two drugs are usu-
t-butylglycylamido substituent, has a steric hindrance effect on ally dosed twice daily.
Tet(M) binding to the ribosome. Tigecycline is a substrate of
the chromosomally encoded multidrug efflux pumps of Proteus
sp and Pseudomonas aeruginosa, accounting for their intrinsic Clinical Uses
resistance to all tetracyclines including tigecycline. A tetracycline is the drug of choice in the treatment of most
infections caused by rickettsiae and Borrelia sp, including Rocky
Pharmacokinetics Mountain spotted fever and Lyme disease. Tetracyclines are used
preferentially to treat Anaplasma phagocytophilum and Ehrlichia
Tetracyclines differ in their absorption after oral administration sp. Tetracyclines are also excellent drugs for the treatment of
and in their elimination. Absorption after oral administration is Mycoplasma pneumoniae, chlamydiae, and some spirochetes. They
approximately 60–70% for tetracycline and demeclocycline (not are used in combination regimens to treat gastric and duodenal
typically used as an antibiotic; see below); and 95–100% for doxy- ulcer disease caused by Helicobacter pylori. They may be used in
cycline and minocycline. Tigecycline is poorly absorbed orally and various Gram-positive and Gram-negative bacterial infections,
must be administered intravenously. A portion of an orally admin- including vibrio infections, provided the organism is not resistant.
istered dose of tetracycline remains in the gut lumen, alters intes- In cholera, tetracyclines rapidly stop the shedding of vibrios, but
tinal flora, and is excreted in the feces. Absorption occurs mainly tetracycline resistance is an increasing problem. Tetracyclines
in the upper small intestine and is impaired by multivalent cations remain effective in most chlamydial infections, including sexually
2+
3+
2+
2+
(Ca , Mg , Fe , Al ); by dairy products and antacids, which transmitted infections. Doxycycline is also an alternative agent
contain multivalent cations; and by alkaline pH. Tetracycline and recommended by the Centers for Disease Control and Preven-
demeclocycline should be administered on an empty stomach, tion for primary and secondary syphilis in patients with penicillin
while doxycycline and minocycline absorption is not impaired by allergy. A tetracycline—in combination with other antibiotics—is
food. Specially buffered doxycycline and minocycline solutions are indicated for plague, tularemia, and brucellosis. Tetracyclines are
formulated for intravenous administration. sometimes used in the treatment or prophylaxis of protozoal infec-
Tetracyclines are 40–80% bound by serum proteins. Oral tions, eg, those due to Plasmodium falciparum (see Chapter 52).
dosages of 500 mg every 6 hours of tetracycline hydrochlo- Other uses include treatment of acne, exacerbations of bronchitis,
ride produce peak blood levels of 4–6 mcg/mL. Peak levels of community-acquired pneumonia, leptospirosis, and some nontu-
2–4 mcg/mL are achieved with a 200-mg dose of doxycycline or berculous mycobacterial infections (eg, Mycobacterium marinum).
minocycline. Steady-state peak serum concentrations of tigecy- Tetracyclines formerly were used for a variety of common
cline are 0.6 mcg/mL at the standard dosage. Tetracyclines are dis- infections, including bacterial gastroenteritis and urinary tract
tributed widely to tissues and body fluids except for cerebrospinal infections. However, many strains of bacteria causing these infec-
fluid, where concentrations are 10–25% of those in serum. Tet- tions are now resistant, and other agents have largely supplanted
racyclines cross the placenta and are also excreted in breast milk. tetracyclines.
As a result of chelation with calcium, tetracyclines bind to—and Minocycline, 100 mg orally twice daily for 5 days, can eradi-
damage—growing bones and teeth. Carbamazepine, phenytoin, cate the meningococcal carrier state, but because of side effects
barbiturates, and chronic alcohol ingestion may shorten the half- and resistance of many meningococcal strains, ciprofloxacin or
life of tetracycline and doxycycline by 50% due to induction of rifampin is preferred. Demeclocycline is rarely used as an antibac-
hepatic enzymes that metabolize the drugs. terial, but it has been used off-label in the treatment of inappropri-
Tetracyclines are excreted mainly in bile and urine. Concen- ate secretion of antidiuretic hormone because of its inhibition of
trations in bile exceed those in serum tenfold. Some of the drug antidiuretic hormone in the renal tubule (see Chapter 15).
excreted in bile is reabsorbed from the intestine (enterohepatic Tigecycline, the first glycylcycline to reach clinical practice, has
circulation) and may contribute to maintenance of serum levels. several unique features that warrant its consideration apart from the
Ten to fifty percent of various tetracyclines is excreted into the older tetracyclines. Its spectrum is very broad, and many tetracy-
urine, mainly by glomerular filtration. Ten to forty percent of the cline-resistant strains are susceptible to tigecycline because it is not
drug is excreted in feces. Doxycycline and tigecycline, in contrast affected by the common resistance determinants. Susceptible organ-
to other tetracyclines, are eliminated by nonrenal mechanisms isms include coagulase-negative staphylococci and Staphylococcus
and do not accumulate significantly in renal failure, requiring no aureus, including methicillin-resistant, vancomycin-intermediate,
dosage adjustment. and vancomycin-resistant strains; streptococci, penicillin-susceptible