Page 832 - Basic _ Clinical Pharmacology ( PDFDrive )

818 SECTION VIII Chemotherapeutic Drugs

and resistant; enterococci, including vancomycin-resistant strains; Adverse Reactions
Gram-positive rods; Enterobacteriaceae; multidrug-resistant strains
of Acinetobacter sp; anaerobes, both Gram-positive and Gram- Hypersensitivity reactions (drug fever, skin rashes) to tetracyclines
negative; rickettsiae, Chlamydia sp, and Legionella pneumophila; are uncommon. Most adverse effects are due to direct toxicity of
and rapidly growing mycobacteria. Proteus and Providencia sp and the drug or to alteration of microbial flora.
P aeruginosa, however, are intrinsically resistant.
Tigecycline, formulated for intravenous administration only, A. Gastrointestinal Adverse Effects
is given as a 100-mg loading dose, then 50 mg every 12 hours. Nausea, vomiting, and diarrhea are the most common reasons for
As with all tetracyclines, tissue and intracellular penetration is discontinuing tetracyclines. These effects are attributable to direct
excellent; consequently, the volume of distribution is quite large local irritation of the intestinal tract. Oral tetracyclines can rarely
and peak serum concentrations are low. Elimination is primarily cause esophageal ulceration, so patients should be instructed to
biliary, and no dosage adjustment is needed for patients with renal take them with 8 ounces of water and remain upright for at least
insufficiency. In addition to the tetracycline class effects, the chief 30 minutes after each dose.
adverse effect of tigecycline is nausea, which occurs in up to one Tetracyclines alter the normal gastrointestinal flora, with sup-
third of patients, and occasionally vomiting. Neither nausea nor pression of susceptible coliform organisms and overgrowth of
vomiting usually requires discontinuation of the drug. Pseudomonas, Proteus, staphylococci, resistant coliforms, clostridia,
Tigecycline is approved for treatment of skin and skin- and Candida. This can result in intestinal functional disturbances,
structure infection, intra-abdominal infections, and community- anal pruritus, vaginal or oral candidiasis, or Clostridium difficile–
acquired pneumonia. However, in a meta-analysis of clinical trials, associated colitis. However, the risk of C difficile colitis may be
tigecycline was associated with a small but significant increase in lower with tetracyclines than with other antibiotics.
the risk of death compared with other antibiotics used to treat
these infections. The increased risk was most apparent in hospital- B. Bony Structures and Teeth
acquired and ventilator-associated pneumonia but was also seen in Tetracyclines are readily bound to calcium deposited in newly
other infections. This has led the U.S. Food and Drug Adminis- formed bone or teeth in young children. When a tetracycline
tration (FDA) to issue a black box warning that tigecycline should is given during pregnancy, it can be deposited in the fetal teeth,
be reserved for situations where alternative treatments are not suit- leading to fluorescence, discoloration, and enamel dysplasia. It
able. Because active drug concentrations in the urine and serum can also be deposited in bone, where it may cause deformity or
are relatively low, tigecycline may not be effective for urinary tract growth inhibition. Because of these effects, tetracyclines are gener-
infections or primary bacteremia. Tigecycline has in vitro activ- ally avoided in pregnancy. If the drug is given for long periods to
ity against a wide variety of multidrug-resistant pathogens (eg, children younger than 8 years, similar changes can result.
methicillin-resistant S aureus, extended-spectrum β-lactamase-
producing Gram-negatives, and Acinetobacter sp); however, its C. Other Toxicities
clinical efficacy in infections with multidrug-resistant organisms, Tetracyclines can impair hepatic function, especially during
compared with other agents, is unproven. pregnancy, in patients with preexisting liver disease, and when
high doses are given intravenously. Hepatic necrosis has been
A. Oral Dosage reported with daily doses of 4 g or more intravenously. Renal
The oral dosage for rapidly excreted tetracyclines, equivalent to tubular acidosis and Fanconi syndrome have been attributed to
tetracycline hydrochloride, is 0.25–0.5 g four times daily for the administration of outdated tetracycline preparations. Tetracy-
adults and 25–50 mg/kg/d for children (8 years of age and older). clines given along with diuretics may cause nephrotoxicity. Tetra-
For severe systemic infections, the higher dosage is indicated, at cycline and minocycline may accumulate to toxic levels in patients
least for the first few days. The dosage for doxycycline is 100 mg with impaired kidney function. Intravenous injection can lead
once or twice daily; the minocycline dose is 100 mg twice daily. to venous thrombosis. Intramuscular injection produces painful
Doxycycline is the oral tetracycline of choice for most indications local irritation and should be avoided. Systemically administered
because it is generally well tolerated, it can be given twice daily, tetracyclines commonly induce sensitivity to sunlight or ultravio-
and its absorption is not significantly affected by food. All tetracy- let light, particularly in fair-skinned persons. Dizziness, vertigo,
clines chelate with metals, and none should be orally administered and tinnitus have been noted, particularly with high doses or
with milk, antacids, or ferrous sulfate. To avoid deposition in prolonged administration of minocycline. These symptoms may
growing bones or teeth, tetracyclines should be avoided in preg- also occur with higher doses of doxycycline.
nant women and children younger than 8 years.
■ MACROLIDES
B. Parenteral Dosage
Doxycycline and minocycline are available for intravenous injec- The macrolides are a group of closely related compounds charac-
tion at the same doses as the oral formulations. Intramuscular terized by a macrocyclic lactone ring (usually containing 14 or 16
injection is not recommended because of pain and inflammation atoms) to which deoxy sugars are attached. The prototype drug,
at the injection site. erythromycin, which consists of two sugar moieties attached to