Page 821 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 43 Beta-Lactam & Other Cell Wall- & Membrane-Active Antibiotics 807

staphylococci, H influenzae, N gonorrhoeae, Salmonella, Shigella, dosage of doripenem is 0.5 g administered as a 1- or 4-hour infu-
E coli, and K pneumoniae. They are not good inhibitors of class sion every 8 hours. Ertapenem has the longest half-life (4 hours)
C β-lactamases, which typically are chromosomally encoded and is administered as a once-daily dose of 1 g intravenously or
and inducible, produced by Enterobacter sp, Citrobacter sp, intramuscularly. Intramuscular ertapenem is irritating, and the drug
S marcescens, and P aeruginosa, but they do inhibit chromosomal is formulated with 1% lidocaine for administration by this route.
β-lactamases of B fragilis and M catarrhalis. The novel non-β- A carbapenem is indicated for infections caused by suscep-
lactam β-lactamase inhibitor avibactam is active against Ambler tible organisms that are resistant to other available drugs, eg,
class A β-lactamases but also active against Ambler class C and P aeruginosa, and for treatment of mixed aerobic and anaerobic
some Ambler class D β-lactamases. infections. Carbapenems are active against many penicillin-non-
Beta-lactamase inhibitors are available only in fixed combi- susceptible strains of pneumococci. Carbapenems are highly
nations with specific penicillins and cephalosporins. (The fixed active in the treatment of Enterobacter infections because they
combinations available in the USA are listed in Preparations are resistant to destruction by the β-lactamase produced by these
Available.) An inhibitor extends the spectrum of its compan- organisms. Clinical experience suggests that carbapenems are also
ion β-lactam provided that the inactivity against a particular the treatment of choice for serious infections caused by extended-
organism is due to destruction by a β-lactamase and that the spectrum β-lactamase-producing Gram-negative bacteria. Ertape-
inhibitor is active against the β-lactamase that is produced. Thus, nem is insufficiently active against P aeruginosa and should not
ampicillin-sulbactam is active against β-lactamase-producing be used to treat infections caused by this organism. Imipenem,
S aureus and H influenzae but not against Serratia, which produces meropenem, or doripenem, with or without an aminoglycoside,
a β-lactamase that is not inhibited by sulbactam. Similarly, if a may be effective treatment for febrile neutropenic patients.
strain of P aeruginosa is resistant to piperacillin, it is also resistant The most common adverse effects of carbapenems—which
to piperacillin-tazobactam because tazobactam does not inhibit tend to be more common with imipenem—are nausea, vomiting,
the chromosomal β-lactamase produced by P aeruginosa. diarrhea, skin rashes, and reactions at the infusion sites. Exces-
Beta-lactam–β-lactamase inhibitor combinations are fre- sive levels of imipenem in patients with renal failure may lead
quently used as empirical therapy for infections caused by a wide to seizures. Meropenem, doripenem, and ertapenem are much
range of potential pathogens in both immunocompromised and less likely to cause seizures than imipenem. Patients allergic to
immunocompetent patients. Adjustments for renal insufficiency penicillins may be allergic to carbapenems, but the incidence of
are made based on the β-lactam component. cross-reactivity is thought to be less than 1%.

CARBAPENEMS ■ GLYCOPEPTIDE ANTIBIOTICS

The carbapenems are structurally related to other β-lactam anti- VANCOMYCIN
biotics (Figure 43–1). Doripenem, ertapenem, imipenem, and
meropenem are licensed for use in the USA. Imipenem, the first Vancomycin is an antibiotic isolated from the bacterium now
drug of this class, has a wide spectrum with good activity against known as Amycolatopsis orientalis. It is active primarily against
most Gram-negative rods, including P aeruginosa, Gram-positive Gram-positive bacteria due to its large molecular weight and
organisms, and anaerobes. It is resistant to most β-lactamases but lack of penetration through Gram-negative cell membranes. The
not carbapenemases or metallo-β-lactamases. Enterococcus faecium, intravenous product is water soluble and stable for 14 days in the
methicillin-resistant strains of staphylococci, Clostridium difficile, refrigerator following reconstitution.
Burkholderia cepacia, and Stenotrophomonas maltophilia are resistant.
Imipenem is inactivated by dehydropeptidases in renal tubules, Mechanisms of Action & Basis of
resulting in low urinary concentrations. Consequently, it is admin- Resistance
istered together with an inhibitor of renal dehydropeptidase, cilas-
tatin, for clinical use. Doripenem and meropenem are similar to Vancomycin inhibits cell wall synthesis by binding firmly to the
imipenem but have slightly greater activity against Gram-negative d-Ala-d-Ala terminus of nascent peptidoglycan pentapeptide
aerobes and slightly less activity against Gram-positives. They are (Figure 43–8). This inhibits the transglycosylase, preventing
not significantly degraded by renal dehydropeptidase and do not further elongation of peptidoglycan and cross-linking. The pep-
require an inhibitor. Unlike the other carbapenems, ertapenem does tidoglycan is thus weakened, and the cell becomes susceptible to
not have appreciable activity against P aeruginosa and Acinetobacter lysis. The cell membrane is also damaged, which contributes to
species. It is not degraded by renal dehydropeptidase. the antibacterial effect.
Carbapenems penetrate body tissues and fluids well, including Resistance to vancomycin in enterococci is due to modifica-
the cerebrospinal fluid for all but ertapenem. All are cleared renally, tion of the d-Ala-d-Ala binding site of the peptidoglycan building
and the dose must be reduced in patients with renal insufficiency. block in which the terminal d-Ala is replaced by d-lactate. This
The usual dosage of imipenem is 0.25–0.5 g given intravenously results in the loss of a critical hydrogen bond that facilitates high-
every 6–8 hours (half-life 1 hour). The usual adult dosage of affinity binding of vancomycin to its target and loss of activity.
meropenem is 0.5–1 g intravenously every 8 hours. The usual adult This mechanism is also present in vancomycin-resistant S aureus