Page 819 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 43 Beta-Lactam & Other Cell Wall- & Membrane-Active Antibiotics 805

proxetil are oral agents possessing similar activity except that cefix- FOURTH-GENERATION
ime and ceftibuten are much less active against pneumococci and CEPHALOSPORINS
have poor activity against S aureus.
Cefepime is the only available fourth-generation cephalosporin.
Pharmacokinetics & Dosage It is more resistant to hydrolysis by chromosomal β-lactamases
(eg, those produced by Enterobacter). However, like the third-
Intravenous infusion of 1 g of a parenteral cephalosporin produces generation compounds, it is hydrolyzed by extended-spectrum
serum levels of 60–140 mcg/mL. Third-generation cephalosporins β-lactamases. Cefepime has good activity against P aeruginosa,
penetrate body fluids and tissues well and intravenous cephalospo- Enterobacteriaceae, methicillin-susceptible S aureus, and S pneu-
rins achieve levels in the cerebrospinal fluid sufficient to inhibit moniae. It is highly active against Haemophilus and Neisseria sp. It
most susceptible pathogens. penetrates well into cerebrospinal fluid. It is cleared by the kidneys
The half-lives of these drugs and the necessary dosing and has a half-life of 2 hours, and its pharmacokinetic proper-
intervals vary greatly: ceftriaxone (half-life 7–8 hours) can be ties are very similar to those of ceftazidime. Unlike ceftazidime,
injected once every 24 hours at a dosage of 15–50 mg/kg/d. A however, cefepime has good activity against most penicillin-non-
single daily 1-g dose is sufficient for most serious infections, susceptible strains of streptococci, and it is useful in treatment of
with 2 g every 12 hours recommended for treatment of men- Enterobacter infections. The standard dose for cefepime is 1–2 g
ingitis and 2 g every 24 hours recommended for endocarditis. infused every 12 hours; however, when treating more complicated
The remaining drugs in the group (half-life 1–1.7 hours) can infections due to P aeruginosa or in the setting of immunocom-
be infused every 6–8 hours in dosages between 2 and 12 g/d, promise, doses are typically increased to 2 g every 8 hours. Because
depending on the severity of infection. Cefixime can be given of its broad-spectrum activity, cefepime is commonly used empiri-
orally (200 mg twice daily or 400 mg once daily) for urinary cally in patients presenting with febrile neutropenia, in combina-
tract infections. Due to increasing resistance, cefixime is no tion with other agents.
longer recommended for the treatment of uncomplicated
gonococcal urethritis and cervicitis. Intramuscular ceftriaxone Cephalosporins Active against Methicillin-
in combination with azithromycin is the regimen of choice
for treating most gonococcal infections. The adult dose for Resistant Staphylococci
cefpodoxime proxetil or cefditoren pivoxil is 200–400 mg Beta-lactam antibiotics with activity against methicillin-resistant
twice daily; for ceftibuten, 400 mg once daily; and for cefdinir, staphylococci are currently under development. Ceftaroline
300 mg/12 h. Ceftriaxone excretion is mainly through the fosamil, the prodrug of the active metabolite ceftaroline, is the
biliary tract, and no dosage adjustment is required in renal first such drug to be approved for clinical use in the USA. Cef-
insufficiency. The other third-generation cephalosporins are taroline has increased binding to penicillin-binding protein 2a,
excreted by the kidney and therefore require dosage adjustment which mediates methicillin resistance in staphylococci, resulting
in renal insufficiency. in bactericidal activity against these strains. It has some in vitro
activity against enterococci and a broad Gram-negative spectrum
Clinical Uses similar to ceftriaxone. It is not active against AmpC or extended-
spectrum β-lactamase-producing organisms. Ceftaroline is cur-
Third-generation cephalosporins are used to treat a wide variety of rently approved for the treatment of skin and soft tissue infections
serious infections caused by organisms that are resistant to most and community-acquired pneumonia at a dose of 600 mg infused
other drugs. Strains expressing extended-spectrum β-lactamases, every 12 hours. It has been used off-label to treat complicated
however, are not susceptible. Third-generation cephalosporins infections such as bacteremia, endocarditis, and osteomyelitis,
should be avoided in treatment of Enterobacter infections—even sometimes in combination with other agents and often at an
if the clinical isolate appears susceptible in vitro—because of increased dose of 600 mg every 8 hours. The normal half-life
emergence of resistance. Ceftriaxone and cefotaxime are approved is about 2.7 hours; ceftaroline is primarily excreted renally and
for treatment of meningitis, including meningitis caused by pneu- requires dose adjustment in renal impairment.
mococci, meningococci, H influenzae, and susceptible enteric
Gram-negative rods, but not by L monocytogenes. Ceftriaxone and Cephalosporins Combined with
cefotaxime are the most active cephalosporins against penicillin-
non-susceptible strains of pneumococci and are recommended a-lactamase Inhibitors
for empirical therapy of serious infections that may be caused Novel cephalosporin-β-lactamase inhibitor combinations have
by these strains. Meningitis caused by strains of pneumococci been developed to combat resistant Gram-negative infections;
with penicillin MICs >1 mcg/mL may not respond even to these see the subsequent section for more information on β-lactamase
agents, and addition of vancomycin is recommended. Other inhibitors. Ceftolozane-tazobactam and ceftazidime-avibactam
potential indications include empirical therapy of sepsis in both were both FDA-approved for the treatment of complicated
the immunocompetent and the immunocompromised patient intra-abdominal infections and urinary tract infections. Both
and treatment of infections for which a cephalosporin is the least agents have potent in vitro activity against Gram-negative organ-
toxic drug available. isms, including P aeruginosa and AmpC and extended-spectrum