This chapter reviews the basic pharmacology of commonly prescribed antimicrobial
agents used in the ED. Topics discussed are mechanisms of action,
indications for use in the ED, contraindications, adverse drug reactions,
dosage adjustments for renal or hepatic insufficiency, use in pregnancy,
and important drug interactions. Additional information regarding
the treatment of specific infections are found in other chapters of
this text, and principles of drug interactions are discussed in Chapter e170.1, Principles of Drug Interactions.
Effective antibacterial drugs have the ability to either inhibit
the growth of (bacteriostatic effect) or kill (bactericidal effect) bacteria.
Antibacterial effects result from a variety of mechanisms, including
the inhibition of cell wall synthesis, inhibition of intrabacterial
protein synthesis, alteration in nucleic acid metabolism, or intrabacterial
enzyme inhibition (Table 158-1). A drug’s
mechanism of action does not necessarily correlate with bacteriostatic
or bactericidal effects, as these effects are also highly dependent
on the concentration of antibiotic to which bacteria are exposed.
Drugs of choice for most infections are not based on a bacteriostatic
or bactericidal effect of an agent but rather on whether the drug
reaches the site of infection in adequate quantities, the spectrum
of the agent, its safety, and cost.
158-1 Mechanisms of Action of Antibacterial Drugs
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β-lactam (penicillins, cephalosporins) and glycopeptide
antibiotics (vancomycin, teicoplanin) must bind to receptors
in the bacterial cell wall to cause an antibacterial effect. The
target receptors (there are at least seven) for penicillins and
cephalosporins are collectively called penicillin-binding
proteins. Autolytic enzymes within the cell wall bind to
penicillin-binding proteins, and the enzymes are activated, resulting
in the deterioration of the peptidoglycan component of the cell
wall, cell wall weakening, and eventual cell lysis. Glycopeptide antibiotics
bind to a terminal dipeptide (alanine-alanine) in the cell wall peptidoglycan,
and then, by steric hindrance, prevent the necessary cross-linking
for a competent cell wall structure. At usual doses, β-lactam
and glycopeptide antibiotics are bactericidal. Resistance can arise
to these antibiotics due to mutations in the penicillin-binding
proteins, leading to markedly reduced β-lactam
binding (e.g., in oxacillin-resistant Staphylococcus aureus or
penicillin-resistant Streptococcus pneumoniae),
or when the terminal dipeptide mutates to a lactate-alanine (e.g.,
vancomycin-resistant Enterococcus faecium) that
markedly reduces the level of vancomycin binding. Daptomycin inserts
a lipophilic part of the molecule into the cell wall of gram-positive
bacteria, depolarizing the cell wall, which causes the leakage of
intracellular content, and a bactericidal effect.
Several classes of antibacterial drugs bind to ribosomes within
bacteria, thereby blocking necessary protein synthesis. Aminoglycosides and tetracyclines bind
to the 30S ribosomal subunit, whereas macrolide antibiotics and clindamycin bind
to the 50S subunit. Ribosomal binding inhibits transfer RNA function,
thereby decreasing the amount of protein synthesis. For ribosomal-binding
drugs to work, they must enter the cell through the cell wall and
bind in adequate concentrations to reversibly inhibit protein synthesis.
Resistance mechanisms arise when there is reduced cell wall permeability,
an active efflux pump that removes the antibiotic from the cell,
or ribosomal-binding site mutations that decrease antibiotic affinity.
All these mechanisms may result in resistance to each of the drug
classes listed above.
Fluoroquinolone antibiotics inhibit DNA gyrase, the enzyme responsible
for DNA unwinding for transcription and then recoiling during bacterial
replication. Fluoroquinolones must reach the nucleus of the bacterial
cell to provoke these effects; hence, resistance can arise when
cell wall permeability is reduced, active efflux occurs, or a DNA
gyrase mutation has arisen that reduces fluoroquinolone binding. Rifampin is
a broad-spectrum antimicrobial agent active against many gram-positive and
gram-negative bacteria and mycobacteria. Rifampin (or rifampicin) inhibits
RNA synthesis by binding to DNA-dependent RNA polymerase, thereby
blocking the initiation of RNA chain formation. Nitrofurantoin is modified
by bacterial metabolism to a compound that damages DNA. Susceptible
bacteria rarely become resistant to nitrofurantoin.
Sulfonamides and trimethoprim block sequential steps
in the formation of folic acid. Sulfonamides inhibit dihydropteroate
synthase, the enzyme that converts p-aminobenzoic
acid to dihydrofolic acid; then trimethoprim inhibits dihydrofolate
reductase, the enzyme that converts dihydrofolic to tetrahydrofolic
acid. Resistance to these drugs can arise by enzyme mutations that
reduce the affinity of the sulfonamide or trimethoprim to their
respective enzyme targets.1 These antibacterial
drug mechanisms of action are summarized in Figure
158-1. Table 158-2 summarizes the classification
and names of most antibiotics within each antibiotic class referred
to above. Available routes of administration are also listed.1
Mechanisms of action of antibacterial drugs. The peptidoglycan
layer in the bacterial cell wall is a crystal lattice structure formed
from linear chains of two alternating amino sugars, namely N-acetylglucosamine
(GlcNAc or NAG) and N-acetylmuramic acid (MurNAc
or NAM). Penicillins, cephalosporins, and vancomycin are cell wall active
agents, preventing the necessary cross-linking within the peptidoglycan
layer, rendering it incompetent. Other listed antibiotics exert their
actions on cellular mechanisms within the bacteria as shown. AA = amino
acids; DHO = dihydropteroate; FH2 = dihydrofolate,
FH4 = tetrahydrofolate; (G)2 = glucose;
K+ = potassium; PA = peptide
donor-acceptor site; PABA = p-aminobenzoic
acid; + = enhance; – = inhibit.
Table 158-2 Classification of Antibacterial Drugs with Common Trade Names
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