Page 815 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 43 Beta-Lactam & Other Cell Wall- & Membrane-Active Antibiotics 801

because of increasing rates of methicillin resistance in staphylo- therapy, an antipseudomonal β-lactam is sometimes used in com-
cocci. However, for infections caused by methicillin-susceptible bination with an aminoglycoside or fluoroquinolone, particularly
and penicillin-resistant strains of staphylococci, these are consid- in infections outside the urinary tract, despite a lack of data sup-
ered drugs of choice. porting combination therapy over single-drug therapy.
An isoxazolyl penicillin such as dicloxacillin, 0.25–0.5 g orally Ampicillin, amoxicillin, piperacillin, and, historically, ticarcil-
every 4–6 hours (15–25 mg/kg/d for children), is suitable for lin, are available in combination with one of several β-lactamase
treatment of mild to moderate localized staphylococcal infections. inhibitors: clavulanic acid, sulbactam, or tazobactam. The
These drugs are relatively acid-stable and have reasonable bioavail- addition of a β-lactamase inhibitor extends the activity of these
ability. However, food interferes with absorption, and the drugs penicillins to include β-lactamase-producing strains of S aureus as
should be administered 1 hour before or after meals. well as some β-lactamase-producing Gram-negative bacteria (see
Methicillin, the first antistaphylococcal penicillin to be devel- Beta-Lactamase Inhibitors).
oped, is no longer used clinically due to high rates of adverse
effects. Oxacillin and nafcillin, 8–12 g/d, given by intermittent Adverse Reactions
intravenous infusion of 1–2 g every 4–6 hours (50–200 mg/kg/d
for children), are considered drugs of choice for serious staphylo- The penicillins are generally well tolerated, and, unfortunately,
coccal infections such as endocarditis. this may encourage inappropriate use. Most of the serious adverse
effects are due to hypersensitivity. The antigenic determinants are
degradation products of penicillins, particularly penicilloic acid
C. Extended-Spectrum Penicillins (Aminopenicillins, and products of alkaline hydrolysis bound to host protein. A his-
Carboxypenicillins, and Ureidopenicillins) tory of a penicillin reaction is not reliable. About 5–8% of people
These drugs have greater activity than penicillin against Gram- claim such a history, but only a small number of these will have
negative bacteria because of their enhanced ability to penetrate a serious reaction when given penicillin. Less than 1% of persons
the Gram-negative outer membrane. Like penicillin G, they are who previously received penicillin without incident will have an
inactivated by many β-lactamases. allergic reaction when given penicillin. Because of the potential
The aminopenicillins, ampicillin and amoxicillin, have very for anaphylaxis, however, penicillin should be administered with
similar spectrums of activity, but amoxicillin is better absorbed caution or a substitute drug given if the person has a history of
orally. Amoxicillin, 250–500 mg three times daily, is equivalent to serious penicillin allergy. Penicillin skin testing may also be used
the same amount of ampicillin given four times daily. Amoxicillin to evaluate Type I hypersensitivity. If skin testing is negative, most
is given orally to treat bacterial sinusitis, otitis, and lower respira- patients can safely receive penicillin.
tory tract infections. Ampicillin and amoxicillin are the most active Allergic reactions include anaphylactic shock (very rare—0.05%
of the oral β-lactam antibiotics against pneumococci with elevated of recipients); serum sickness–type reactions (now rare—urticaria,
MICs to penicillin and are the preferred β-lactam antibiotics for fever, joint swelling, angioedema, pruritus, and respiratory com-
treating infections suspected to be caused by these strains. Ampi- promise occurring 7–12 days after exposure); and a variety of skin
cillin (but not amoxicillin) is effective for shigellosis. Ampicillin, rashes. Oral lesions, fever, interstitial nephritis (an autoimmune
at dosages of 4–12 g/d intravenously, is useful for treating serious reaction to a penicillin-protein complex), eosinophilia, hemolytic
infections caused by susceptible organisms, including anaerobes, anemia and other hematologic disturbances, and vasculitis may
enterococci, L monocytogenes, and β-lactamase-negative strains of also occur. Most patients allergic to penicillins can be treated
Gram-negative cocci and bacilli such as E coli, and Salmonella sp. with alternative drugs. However, if necessary (eg, treatment of
Non-β-lactamase-producing strains of H influenzae are generally enterococcal endocarditis or neurosyphilis in a patient with seri-
susceptible, but strains that are resistant because of altered PBPs ous penicillin allergy), desensitization can be accomplished with
are emerging. Due to production of β-lactamases by Gram- gradually increasing doses of penicillin.
negative bacilli, ampicillin can no longer be used for empirical In patients with renal failure, penicillin in high doses can
therapy of urinary tract infections and typhoid fever. Ampicillin cause seizures. Nafcillin is associated with neutropenia and
is not active against Klebsiella sp, Enterobacter sp, P aeruginosa, interstitial nephritis; oxacillin can cause hepatitis; and methi-
Citrobacter sp, Serratia marcescens, indole-positive Proteus species, cillin commonly caused interstitial nephritis (and is no longer
and other Gram-negative aerobes that are commonly encountered used for this reason). Large doses of penicillins given orally may
in hospital-acquired infections. These organisms intrinsically pro- lead to gastrointestinal upset, particularly nausea, vomiting, and
duce β-lactamases that inactivate ampicillin. diarrhea. Ampicillin has been associated with pseudomembra-
The carboxypenicillins, carbenicillin and ticarcillin, were nous colitis. Secondary infections such as vaginal candidiasis
developed to broaden the spectrum of penicillins against Gram- may occur. Ampicillin and amoxicillin can be associated with
negative pathogens, including P aeruginosa; however, neither skin rashes when prescribed in the setting of viral illnesses,
agent is available in the USA. The ureidopenicillin piperacillin is particularly noted during acute Epstein-Barr virus infection,
also active against many Gram-negative bacilli, such as Klebsiella but the incidence of rash may be lower than originally reported.
pneumoniae and P aeruginosa. Piperacillin is available only as a Piperacillin-tazobactam, when combined with vancomycin, has
co-formulation with the β-lactamase inhibitor tazobactam. Due been associated with greater incidence of acute kidney injury
to the propensity of P aeruginosa to develop resistance during compared to alternate β-lactam agents.