Page 835 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 44 Tetracyclines, Macrolides, Clindamycin, Chloramphenicol, Streptogramins, & Oxazolidinones 821

renders them poor substrates for efflux pump–mediated resis- with aminoacyl translocation reactions. The binding site for
tance, and they bind to ribosomes of some bacterial species with clindamycin on the 50S subunit of the bacterial ribosome is
higher affinity than macrolides. identical with that for erythromycin. Streptococci, staphy-
Oral bioavailability of telithromycin is 57%, and tissue and lococci, and pneumococci are inhibited by clindamycin at
intracellular penetration is generally good. Telithromycin is a concentration of 0.5–5 mcg/mL. Enterococci and Gram-
metabolized in the liver and eliminated by a combination of negative aerobic organisms are resistant. Bacteroides sp and
biliary and urinary routes of excretion. It is administered as a other anaerobes are often susceptible, though resistance may
once-daily dose of 800 mg, which results in peak serum concen- be increasing, particularly in Gram-negative anaerobes. Resis-
trations of approximately 2 mcg/mL. It is a reversible inhibitor of tance to clindamycin, which generally confers cross-resistance
the CYP3A4 enzyme system and may slightly prolong the QT to macrolides, is due to (1) mutation of the ribosomal recep-
c
interval. In the USA, telithromycin is now indicated only for tor site; (2) modification of the receptor by a constitutively
treatment of community-acquired bacterial pneumonia. Other expressed methylase (see section on erythromycin resistance,
respiratory tract infections were removed as indications when it above); and (3) enzymatic inactivation of clindamycin. Gram-
was recognized that use of telithromycin can result in hepatitis negative aerobic species are intrinsically resistant because of
and liver failure. Telithromycin is also contraindicated in patients poor permeability of the outer membrane.
with myasthenia gravis because it may exacerbate this condition.
Due to its potential for serious toxicity, an FDA-approved patient Pharmacokinetics
medication guide detailing these risks must be dispensed to any
patient receiving the medication. Oral dosages of clindamycin, 0.15–0.3 g every 8 hours
Solithromycin is a novel fluoroketolide that is pending FDA (10–20 mg/kg/d for children), yield serum levels of 2–3 mcg/mL.
approval after two phase 3 clinical trials showed noninferior- When administered intravenously, 600 mg of clindamycin every
ity when compared with moxifloxacin in the treatment of 8 hours gives levels of 5–15 mcg/mL. The drug is about 90%
community-acquired pneumonia. Although not yet marketed, protein-bound. Clindamycin penetrates well into most tissues,
the dose used in clinical trials was a loading dose of 800 mg with brain and cerebrospinal fluid being important exceptions.
orally or intravenously, followed by 400 mg daily for a total of It penetrates well into abscesses and is actively taken up and con-
5 days. The intravenous formulation was associated with higher centrated by phagocytic cells. Clindamycin is metabolized by the
rates of infusion-related reactions compared with moxifloxacin. liver, and both active drug and active metabolites are excreted in
Similar to telithromycin, solithromycin maintains in vitro activ- bile and urine. The half-life is about 2.5 hours in normal indi-
ity against macrolide-resistant bacteria, including S pneumoniae, viduals, increasing to 6 hours in patients with anuria. No dosage
staphylococci, enterococci, Chlamydia trachomatis, and Neisseria adjustment is required for renal failure.
gonorrhoeae. Its chemical structure lacks the pyridine-imidazole
side chain group, which is thought to contribute to telithromy- Clinical Use
cin’s hepatotoxicity; severe toxicity has not been demonstrated in
Phase II or III clinical trials. Clindamycin is indicated for the treatment of skin and soft-
tissue infections caused by streptococci and staphylococci. It
may be active against community-acquired strains of methi-
■ CLINDAMYCIN cillin-resistant S aureus, though resistance has been increasing.
It is commonly used in conjunction with penicillin G to treat
Clindamycin is a chlorine-substituted derivative of lincomycin, toxic shock syndrome or necrotizing fasciitis caused by Group
an antibiotic that is elaborated by Streptomyces lincolnensis. A Streptococcus. In this setting, its use is typically limited to the
initial 48 to 72 hours of treatment with the goal of inhibiting
CH 3
CH 3 toxin production. Clindamycin is also indicated for treatment
N of infections caused by susceptible Bacteroides sp and other
CI CH
C H anaerobes. Clindamycin, sometimes in combination with an
3 7
C NH CH aminoglycoside or cephalosporin, is used to treat penetrating
O
O HO wounds of the abdomen and the gut; infections originating in
the female genital tract, eg, septic abortion, pelvic abscesses, or
OH
S CH 3 pelvic inflammatory disease; and lung and periodontal abscesses.
Clindamycin is recommended for prophylaxis of endocarditis in
OH
Clindamycin patients with specific valvular heart disease who are undergoing
certain dental procedures and have significant penicillin aller-
Mechanism of Action & Antibacterial gies. Clindamycin plus primaquine is an effective alternative
Activity to trimethoprim-sulfamethoxazole for moderate to moderately
severe Pneumocystis jiroveci pneumonia in AIDS patients. It is
Clindamycin, like erythromycin, inhibits protein synthesis also used in combination with pyrimethamine for AIDS-related
by interfering with the formation of initiation complexes and toxoplasmosis of the brain.