Page 820 - Basic _ Clinical Pharmacology ( PDFDrive )

806 SECTION VIII Chemotherapeutic Drugs

β-lactamase producing Enterobacteriaceae. While neither agent is reactions; consequently, alcohol and alcohol-containing medica-
active against organisms producing metallo-β-lactamases, ceftazi- tions must be avoided.
dime-avibactam may be an option for carbapenemase-producing
organisms. Due to limited activity against anaerobic pathogens,
both should be combined with metronidazole when treating ■ OTHER BETA-LACTAM DRUGS
complicated intra-abdominal infections. Both agents have short
half-lives of 2–3 hours and are dosed every 8 hours. Both are MONOBACTAMS
primarily renally excreted and require dose adjustment in patients
with impaired renal clearance. Monobactams are drugs with a monocyclic β-lactam ring
(Figure 43–1). Their spectrum of activity is limited to aerobic
Gram-negative organisms (including P aeruginosa). Unlike other
ADVERSE EFFECTS OF β-lactam antibiotics, they have no activity against Gram-positive
CEPHALOSPORINS bacteria or anaerobes. Aztreonam is the only monobactam avail-
able in the USA. It has structural similarities to ceftazidime,
A. Allergy and its Gram-negative spectrum is similar to that of the third-
Like penicillins, cephalosporins may elicit a variety of hyper- generation cephalosporins. It is stable to many β-lactamases with
sensitivity reactions, including anaphylaxis, fever, skin rashes, notable exceptions being AmpC β-lactamases and extended-
nephritis, granulocytopenia, and hemolytic anemia. Patients spectrum β-lactamases. It penetrates well into the cerebrospinal
with documented penicillin anaphylaxis have an increased risk fluid. Aztreonam is given intravenously every 8 hours in a dose of
of reacting to cephalosporins compared with patients without a 1–2 g, providing peak serum levels of 100 mcg/mL. The half-life
history of penicillin allergy. However, the chemical nucleus of is 1–2 hours and is greatly prolonged in renal failure.
cephalosporins is sufficiently different from that of penicillins Penicillin-allergic patients tolerate aztreonam without reaction.
such that many individuals with a history of penicillin allergy tol- Notably, because of its structural similarity to ceftazidime, there is
erate cephalosporins. Overall, the frequency of cross-allergenicity potential for cross-reactivity; aztreonam should be used with caution
between the two groups of drugs is low (~1%). Cross-allergenicity in the case of documented severe allergies to ceftazidime. Occasional
appears to be most common among penicillin, aminopenicillins, skin rashes and elevations of serum aminotransferases occur during
and early-generation cephalosporins, which share similar R-1 side administration of aztreonam, but major toxicity is uncommon. In
chains. Patients with a history of anaphylaxis to penicillins should patients with a history of penicillin anaphylaxis, aztreonam may be
not receive first- or second-generation cephalosporins, while third- used to treat serious infections such as pneumonia, meningitis, and
and fourth-generation cephalosporins should be administered sepsis caused by susceptible Gram-negative pathogens.
with caution, preferably in a monitored setting.

B. Toxicity BETA-LACTAMASE INHIBITORS
Local irritation can produce pain after intramuscular injection (CLAVULANIC ACID, SULBACTAM,
and thrombophlebitis after intravenous injection. Renal toxicity, TAZOBACTAM, & AVIBACTAM)
including interstitial nephritis and tubular necrosis, may occur
uncommonly. Traditional β-lactamase inhibitors (clavulanic acid, sulbactam,
Cephalosporins that contain a methylthiotetrazole group may and tazobactam) resemble β-lactam molecules (Figure 43–7), but
cause hypoprothrombinemia and bleeding disorders. Historically, they have very weak antibacterial action. They are potent inhibi-
this group included cefamandole, cefmetazole, and cefoperazone; tors of many but not all bacterial β-lactamases and can protect
however, cefotetan is the only methylthiotetrazole-containing hydrolyzable penicillins from inactivation by these enzymes. The
agent used in the USA. Oral administration of vitamin K, 10 mg traditional β-lactamase inhibitors are most active against Ambler
twice weekly, can prevent this uncommon problem. Drugs with class A β-lactamases (plasmid-encoded transposable element
the methylthiotetrazole ring can also cause severe disulfiram-like [TEM] β-lactamases in particular), such as those produced by

O O – O
S C
H 2 C CH O H 2 C CH CH 3 H 2 N
CH 2 R
C N C C N N
O CH CH 2 OH O COOH R = N N C N
COOH R = H N O OSO – 3
Clavulanic acid Sulbactam Tazobactam Avibactam

FIGURE 43–7 Beta-lactamase inhibitors.