Page 818 - Basic _ Clinical Pharmacology ( PDFDrive )

804 SECTION VIII Chemotherapeutic Drugs

B. Parenteral Pharmacokinetics & Dosage
Cefazolin is the only first-generation parenteral cephalosporin A. Oral
still in general use. After an intravenous infusion of 1 g, the Cefuroxime axetil is the most commonly used oral cephalosporin
peak level of cefazolin is approximately 185 mcg/mL. The usual in the USA. The usual dosage for adults is 250–500 mg orally
intravenous dosage of cefazolin for adults is 0.5–2 g intravenously twice daily; children should be given 20–40 mg/kg/d up to a
every 8 hours. Cefazolin can also be administered intramuscularly. maximum of 1 g/d. These drugs are not predictably active against
Excretion is via the kidney, and dose adjustments must be made penicillin-non-susceptible pneumococci.
for impaired renal function.
B. Parenteral
Clinical Uses
After a 1-g intravenous infusion, serum levels are 75–125 mcg/mL
Oral drugs may be used for the treatment of urinary tract infec- for most second-generation cephalosporins. Intramuscular admin-
tions and staphylococcal or streptococcal infections, including cel- istration is painful and should be avoided. Doses and dosing
lulitis or soft tissue abscess. However, oral cephalosporins should intervals vary depending on the specific agent (Table 43–2). There
not be relied on in serious systemic infections. are differences in half-life, protein binding, and interval between
Cefazolin penetrates well into most tissues. It is a drug of choice doses. All are renally cleared and require dosage adjustment in
for surgical prophylaxis and for many streptococcal and staphylo- renal failure.
coccal infections requiring intravenous therapy. Cefazolin may be
used for infections due to E coli or K pneumoniae when the organ- Clinical Uses
ism has been documented to be susceptible. Cefazolin does not
penetrate the central nervous system and cannot be used to treat The oral second-generation cephalosporins are active against
meningitis. Cefazolin is better tolerated than antistaphylococcal β-lactamase-producing H influenzae or Moraxella catarrhalis and
penicillins, and it has been shown to be effective for serious staphy- have been used primarily to treat sinusitis, otitis, and lower respi-
lococcal infections, eg, bacteremia. It can also be used in patients ratory tract infections. Because of their activity against anaerobes
with mild penicillin allergy other than immediate hypersensitivity. (including many B fragilis strains), cefoxitin and cefotetan can be
used to treat mixed anaerobic infections such as peritonitis, diver-
ticulitis, and pelvic inflammatory disease. Cefuroxime is some-
SECOND-GENERATION times used to treat community-acquired pneumonia because it is
CEPHALOSPORINS active against β-lactamase-producing H influenzae and also many
pneumococci. Although cefuroxime crosses the blood-brain bar-
rier, it is less effective in treatment of meningitis than ceftriaxone
Members of the second-generation cephalosporins include or cefotaxime and should not be used.
cefaclor, cefamandole, cefonicid, cefuroxime, cefprozil,
loracarbef, and ceforanide—of which cefaclor, cefuroxime,
and cefprozil are available in the USA—and the structurally THIRD-GENERATION CEPHALOSPORINS
related cephamycins cefoxitin and cefotetan, which have activity
against anaerobes. This is a heterogeneous group with individual Third-generation agents include cefoperazone, cefotaxime, ceftazi-
differences in activity, pharmacokinetics, and toxicity. In general, dime, ceftizoxime, ceftriaxone, cefixime, cefpodoxime proxetil,
second-generation cephalosporins are relatively active against cefdinir, cefditoren pivoxil, ceftibuten, and moxalactam. Cefo-
organisms inhibited by first-generation drugs, but, in addition, perazone, ceftizoxime, and moxalactam are no longer commer-
they have extended Gram-negative coverage. Klebsiella sp (includ- cially available in the USA.
ing those resistant to first-generation cephalosporins) are usually
sensitive. Cefuroxime and cefaclor are active against H influenzae Antimicrobial Activity
but not against Serratia or B fragilis. In contrast, cefoxitin and
cefotetan are active against B fragilis and some Serratia strains Compared with second-generation agents, these drugs have
but are less active against H influenzae. As with first-generation expanded Gram-negative coverage, and some are able to cross the
agents, no member of this group is active against enterococci or blood-brain barrier. Third-generation drugs may be active against
P aeruginosa. Compared with other cephalosporins, cefoxitin Citrobacter, S marcescens, and Providencia. They are also effective
shows improved stability in the presence of extended-spectrum against β-lactamase-producing strains of Haemophilus and Neis-
β-lactamases produced by E coli and Klebsiella sp. Clinical data seria. Ceftazidime is the only agent with useful activity against
are limited, but it may offer an alternative to carbapenems in P aeruginosa. Like the second-generation drugs, third-generation
treating certain infections due to these organisms. Second- cephalosporins are hydrolyzed by constitutively produced AmpC
generation cephalosporins may exhibit in vitro activity against β-lactamase, and they are not reliably active against Enterobacter
Enterobacter sp, but resistant mutants that constitutively express a species. Serratia, Providencia, Acinetobacter, and Citrobacter also
chromosomal β-lactamase that hydrolyzes these compounds (and produce a chromosomally encoded cephalosporinase that, when
third-generation cephalosporins) are readily selected, and they constitutively expressed, can confer resistance to third-generation
should not be used to treat Enterobacter infections. cephalosporins. Cefixime, cefdinir, ceftibuten, and cefpodoxime