Page 837 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 44 Tetracyclines, Macrolides, Clindamycin, Chloramphenicol, Streptogramins, & Oxazolidinones 823

Newborns less than a week old and premature infants also clear Linezolid inhibits protein synthesis by preventing formation of the
chloramphenicol less well, and the dosage should be reduced to ribosome complex that initiates protein synthesis. Its unique binding
25 mg/kg/d. site, located on 23S ribosomal RNA of the 50S subunit, results in no
cross-resistance with other drug classes. Resistance is caused by muta-
Clinical Uses tion of the linezolid binding site on 23S ribosomal RNA.
Because of potential toxicity, bacterial resistance, and the availabil-
ity of many other effective alternatives, chloramphenicol is rarely Pharmacokinetics
used in the United States. It may be considered for treatment of Linezolid is 100% bioavailable after oral administration and has a
serious rickettsial infections such as typhus and Rocky Mountain half-life of 4–6 hours. It is metabolized by oxidative metabolism,
spotted fever. It is an alternative to a β-lactam antibiotic for treat- yielding two inactive metabolites. It is neither an inducer nor an
ment of bacterial meningitis occurring in patients who have major inhibitor of cytochrome P450 enzymes. Peak serum concentra-
hypersensitivity reactions to penicillin. tions average 18 mcg/mL following a 600-mg oral dose; cerebro-
spinal fluid (CSF) concentrations reach approximately 60–70% of
Adverse Reactions the serum level. The recommended dosage for most indications is
Adults occasionally develop gastrointestinal disturbances, includ- 600 mg twice daily, either orally or intravenously.
ing nausea, vomiting, and diarrhea. These symptoms are rare
in children. Oral or vaginal candidiasis may occur as a result of Clinical Uses
alteration of normal microbial flora. Linezolid is approved for vancomycin-resistant E faecium infec-
Chloramphenicol commonly causes a dose-related revers- tions, health care–associated pneumonia, community-acquired
ible suppression of red cell production at dosages exceeding pneumonia, and both complicated and uncomplicated skin and
50 mg/kg/d after 1–2 weeks. Aplastic anemia, a rare consequence soft tissue infections caused by susceptible Gram-positive bacte-
(1 in 24,000 to 40,000 courses of therapy) of chloramphenicol ria. Off-label uses of linezolid include treatment of multidrug-
administration by any route, is an idiosyncratic reaction unrelated resistant tuberculosis and Nocardia infections.
to dose, although it occurs more frequently with prolonged use.
Aplastic anemia tends to be irreversible and can be fatal, although Adverse Effects
it may respond to bone marrow transplantation or immunosup-
pressive therapy. Due to the severity of this reaction, a boxed The principal toxicity of linezolid is hematologic; the effects are
warning has been added to its U.S. labeling. reversible and generally mild. Thrombocytopenia is the most
Newborn infants lack an effective glucuronic acid conjugation common manifestation (seen in approximately 3% of treatment
mechanism for the degradation and detoxification of chloram- courses), particularly when the drug is administered for longer
phenicol. Consequently, when infants are given dosages above than 2 weeks. Anemia and neutropenia may also occur, most
50 mg/kg/d, the drug may accumulate, resulting in the gray baby commonly in patients with a predisposition to or underlying bone
syndrome, with vomiting, flaccidity, hypothermia, gray color, marrow suppression. Cases of optic and peripheral neuropathy
shock, and vascular collapse. To avoid this toxic effect, chloram- and lactic acidosis have been reported with prolonged courses of
phenicol should be used with caution in infants and the dosage linezolid. These side effects are thought to be related to linezolid-
limited to 50 mg/kg/d (or less during the first week of life) in full- induced inhibition of mitochondrial protein synthesis. There are
term infants and 25 mg/kg/d in premature infants. case reports of serotonin syndrome (see Chapter 16) occurring
Chloramphenicol inhibits hepatic microsomal enzymes that when linezolid is co-administered with serotonergic drugs, most
metabolize several drugs. Half-lives of these drugs are prolonged, frequently selective serotonin reuptake inhibitor antidepressants.
and the serum concentrations of phenytoin, tolbutamide, chlor- The FDA has issued a warning regarding the use of the drug with
propamide, and warfarin are increased. serotonergic agents.
Tedizolid is the active moiety of the prodrug tedizolid phos-
■ OXAZOLIDINONES phate, a next-generation oxazolidinone, with high potency against
Gram-positive bacteria, including methicillin-resistant S aureus.
It is FDA-approved at a dose of 200 mg orally or intravenously
MECHANISM OF ACTION & once daily for 6 days for the treatment of skin and soft tissue
ANTIMICROBIAL ACTIVITY infection. Potential advantages over linezolid include increased
potency against staphylococci and a longer half-life of 12 hours,
Linezolid is a member of the oxazolidinone class of synthetic allowing once-daily dosing. It may be associated with a decreased
antimicrobials. It is active against Gram-positive organisms risk of marrow suppression; however, it has not been studied over
including staphylococci, streptococci, enterococci, Gram-positive a prolonged duration of therapy. It is thought to have a lower risk
anaerobic cocci, and Gram-positive rods such as corynebacteria, of serotonergic toxicity, but concomitant use with serotonin reup-
Nocardia sp, and L monocytogenes. It is primarily a bacteriostatic take inhibitors has not been formally evaluated. Tedizolid is more
agent but is bactericidal against streptococci. It is also active highly protein-bound (70–90%) than linezolid (31%); there are
against Mycobacterium tuberculosis. no data on CSF penetration of tedizolid.