Page 816 - Basic _ Clinical Pharmacology ( PDFDrive )

802 SECTION VIII Chemotherapeutic Drugs

■ CEPHALOSPORINS & O
CEPHAMYCINS C NH S
R 1
B A
N
O R 2
Cephalosporins are similar to penicillins but are more stable COO –
to many bacterial β-lactamases and, therefore, have a broader N N R 1 R 2
spectrum of activity. However, strains of E coli and Klebsiella sp Cefazolin N CH 2 S N N
expressing extended-spectrum β-lactamases that can hydrolyze N CH 2 S CH 3
most cephalosporins are a growing clinical concern. Cephalo- Cephalexin CH CH 3
sporins are not active against L monocytogenes, and of the avail- NH 2
able cephalosporins, only ceftaroline has some activity against Cefadroxil HO CH
enterococci. NH 2 CH 3
O
Cefoxitin
Chemistry S CH 2 CH 2 O C NH 2
The nucleus of the cephalosporins, 7-aminocephalosporanic acid Cefaclor CH Cl
(Figure 43–6), bears a close resemblance to 6-aminopenicillanic NH 2
acid (Figure 43–1). The intrinsic antimicrobial activity of HO
natural cephalosporins is low, but the attachment of various R Cefprozil CH CH CH 3
1
and R groups has yielded hundreds of potent compounds, many NH 2
2
with low toxicity. Cephalosporins have traditionally been classi- Cefuroxime O C O
fied into four major groups or generations, depending mainly O N OCH 3 CH 2 O N C N NH 2
on the spectrum of antimicrobial activity. Several cephalosporins 1 H 2 NC S CH 2 S N
developed more recently do not fit the traditional classification Cefotetan HOOC C C S C N
groups. Their unique characteristics and spectra of activity are N C O CH 3
outlined below. Cefotaxime H 2 N S N OCH 3 CH 2 O C CH 3

N C
Cefpodoxime 1 N CH 2 O CH 3
FIRST-GENERATION CEPHALOSPORINS H 2 N S OCH 3
O OH
C
First-generation cephalosporins include cefazolin, cefadroxil, Ceftibuten C H
cephalexin, cephalothin, cephapirin, and cephradine; cefazolin H 2 N N
and cephalexin are the only two available in the USA. These drugs H 2 N S OH
are very active against Gram-positive cocci, such as streptococci Cefdinir S N CH CH 2
and staphylococci. Traditional cephalosporins are not active N C H
against methicillin-resistant strains of staphylococci; however, Ceftriaxone N C N H 3 C N N O
new compounds have been developed that have activity against H 2 N S OCH 3 N
methicillin-resistant strains (see below). E coli, K pneumoniae, and N C CH 3 CH 2 S O
Proteus mirabilis are often sensitive to first-generation cephalo- Ceftazidime H 2 N S N O C COOH
sporins, but activity against P aeruginosa, indole-positive Proteus CH 3 CH 2 N
species, Enterobacter sp, S marcescens, Citrobacter sp, and Acineto- N C
bacter sp is poor. Anaerobic cocci (eg, peptococci, peptostrepto- Cefepime H 2 N S N CH 2 N +
cocci) are usually sensitive, but Bacteroides fragilis is not. OCH 3 CH 3
O
N N + CH 3
Pharmacokinetics & Dosage Ceftaroline S N S N
N S
A. Oral H 2 N
H 2 N S N
Cephalexin is the oral first generation agent widely used in
the USA. After oral doses of 500 mg, peak serum levels are N N O
15–20 mcg/mL. Urine concentration is usually very high, but in Ceftolozane R 1 O N NH
most tissues levels are variable and generally lower than in serum. H 3 C OH H 3 C N NH N
Cephalexin is typically given in oral dosages of 0.25–0.5 g four H 3 C O
times daily (15–30 mg/kg/d). Excretion is mainly by glomerular
filtration and tubular secretion into the urine. Drugs that block FIGURE 43–6 Structures of some cephalosporins. R 1 and R 2
tubular secretion, eg, probenecid, may increase serum levels sub- structures are substituents on the 7-aminocephalosporanic acid
stantially. In patients with impaired renal function, dosage must nucleus pictured at the top. Other structures (cefoxitin and below)
1
be reduced (Table 43–2). are complete in themselves. Additional substituents not shown.