33
Pharmacology of Specific Drug
Groups: Antibiotic Therapy*
K E Y I N F O R M AT I O N
• The major mechanisms by which antibacterial drugs act are the
following:
• Inhibition of cell wall synthesis
• Alteration of cell membrane function
• Inhibition of ribosomal protein synthesis
• Inhibition of DNA or RNA synthesis or function
• Inhibition of folic acid synthesis
• Mechanisms by which bacteria become resistant to antimicrobial
drugs include these:
• Enzymatic inactivation of the drug
• Change in the target of the drug
• Reducing permeability of the bacterial cell
• Active drug efflux from the cell
• Changing growth requirements, bypassing the mechanism of
the drug
• Overproduction of the drug target(s)
CASE STUDY
A 20-year-old female college sophomore presents with a complaint of
“extremely painful gums” (see Fig. 33-1). The patient also complains of chills
for the past two days. You record her temperature at 102 °F. Clinical exam-
ination reveals punched-out interdental papillae, gingival bleeding, abun-
dant plaque, and a fetid odor. What is the most likely diagnosis? How would
you treat this patient? Would you use systemic medications for treatment?
Describe potential and typical adverse effects of your prescription(s).
INTRODUCTION
The modern era of infectious disease began with the first visualization
of microbes by Anton van Leeuwenhoek in 1683, the “animicules”
of dental plaque scraped from his upper gingiva and killed with salt
(the first periodontal chemotherapy). In 1776, Edward Jenner admin-
istered the first smallpox vaccination. In 1848, Ignaz Semmelweiss
introduced clean surgical operating technique (“gentlemen, wash your
hands”). In 1854, John Snow showed the link between cholera and
drinking water.
In the 1860s, Louis Pasteur first used the word germ for living
entities that produced disease, and Joseph Lister used carbolic acid
*The author wishes to recognize Dr. Thomas J. Pallasch for his past contribu-
tions to this chapter.
Purnima Kumar
• Horizontal gene transfer (one microorganism acquiring DNA
from another microorganism) can take place by the following:
• Transduction
• Transformation
• Conjugation
• Adverse antibiotic effects vary from class to class. Some common
ones for certain classes include these:
• Allergies
• Superinfections, such as pseudomembranous colitis
• Gastrointestinal adverse effects
• Renal toxicity
• Ototoxicity
to disinfect wounds. In the 1870s, Robert Koch proved the bacterial
causation of anthrax and tuberculosis, and in the 1880s, Pasteur
developed anthrax and rabies vaccines. In 1891, Paul Ehrlich
showed that antibodies were responsible for immunity. In 1897,
Ivanowski and Beiternick discovered viruses. The mosquito vector
for yellow fever was described in 1900, Treponema pallidum was
found to be the cause of syphilis in 1905, human immunodeficiency
virus (HIV) was identified in 1983, Helicobacter pylori was discov-
ered as a cause of peptic ulcer in 1984, and the West Nile virus was
identified in 1999.
In the early 1900s, Paul Ehrlich used the term magic bullet for
his predicted chemical that would affect only microbial cells and
have no effect on mammalian cells. He later used fuchsin and mer-
cury (Salvarsan) to treat syphilis. In 1928, Alexander Fleming ser-
endipitously discovered that a mold, Penicillium chrysogenum, lysed
staphylococci; this was later developed to its full potential by the
isolation of penicillin from Penicillium notatum by Florey and col-
leagues at Oxford in the late 1930s and early 1940s. The first use of
penicillin was in 1941 on an English police constable with strepto-
coccal and staphylococcal skin abscesses. In the United States, pen-
icillin was first used in 1942 on Anne Miller, who had streptococcal
toxemia of pregnancy. Another ground-breaking event in medical
advances was the demonstration in 1935 by Gerhard Domagk that
sulfanilamide could be safely used systemically to treat infectious
disease. Thus was born the era of antibiotics and anti-microbials,
arguably one of the most revolutionary events in the history of
mankind.
457
458 CHAPTER 33  Pharmacology of Specific Drug Groups: Antibiotic Therapy
MECHANISMS OF ACTION
By strict definition, antibiotics are chemicals that are derived from
microorganisms (commonly yeasts and fungi) and are used to inhibit
other microorganisms. Almost all clinically antibacterial drugs are
derived from naturally occurring entities, with only few that are
entirely synthetically produced (sulfonamides, fluoroquinolones, and
oxazolidinones). These drugs are not antibiotics by the narrow defini-
tion but are included in the discussion of antibiotics.
Antimicrobials affect the viability of microorganisms by five known
processes: (1) inhibition of cell wall synthesis, (2) alteration of cell
membrane integrity, (3) inhibition of ribosomal protein synthe-
sis, (4) suppression of deoxyribonucleic acid (DNA) synthesis, and
(5) inhibition of folic acid synthesis (Fig. 33-2). Microbial cell wall
synthesis inhibition and membrane effects are extra-cytoplasmic, and
inhibition of nucleic acid, protein, and folic acid synthesis are intra-cy-
toplasmic. Drugs that affect bacterial cell wall or membrane integrity
and DNA synthesis are usually, but not always, bactericidal (inducing
cell death), and protein and folic acid synthesis inhibitors are usually
bacteriostatic (preventing cell growth or replication).
Whether an antimicrobial agent is bactericidal (cidal) or bacte-
riostatic (static) can also depend on its concentration at the infected
site and the particular offending organism because some static drugs
FIG 33-1  Photograph of patient in the case study.
Inhibitors of
metabolism
{Sulfonamides}
THF DNA
A Ribosomes
mRNA
PAB
A
Inhibitors of cell
wall synthesis
{β-Lactams}
Inhibitors of cell
membrane function
{Amphotericin B}
{Isoniazid}
FIG 33-2  Mechanisms of action of antimicrobial drugs and representative drugs.
become cidal at high concentrations. The previous preference for cidal
drugs over static antibiotics (cidal drugs allegedly do not rely on host
defenses) has become less distinct because of the appreciation of the
long post-antibiotic effects (continued antibiotic activity when the
drug blood levels have declined) of bacteriostatic drugs.
Inhibition of Cell Wall Synthesis
The principal cell wall inhibitors are β-lactam antibiotics and gly-
copeptides. Bacterial cell walls are rigid and composed of alternat-
ing peptidoglycan (murein) units of N-acetyl-d-glucosamine and
N-acetylmuramic acid (NAM). These are cross-linked via short pep-
tides by amide linkages to a d-alanyl group on NAM. Various bacte-
rial enzymes (transglycosylases, transpeptidases, carboxypeptidases,
endopeptidases) catalyze the formation of the rigid cell wall by incor-
porating new peptidoglycan into existing peptidoglycan and then
cross-linking to form a rigid cell wall. The internal osmotic pressure
of the bacterium causes lysis of the bacterial cell because the wall is no
longer an effective barrier (see Fig. 33-2).
In addition, in some organisms, an antibiotic may inhibit the
inhibitor of an endogenous bacterial autolysin (N-acetyl-muramyl-
l-alanine amidase). The autolysin causes the lysis of the bacterial cell
wall.
Alteration in Cell Membrane Integrity
A drug may disrupt the integrity of the cell membrane by displacing
Ca2+ and Mg++ from membrane lipid phosphate groups. Cationic
antimicrobial peptides are part of humans’ natural skin and mucosal
defense system and act by disrupting cell wall or membrane integ-
rity by an effect on the gram-negative lipopolysaccharide compo-
nent that literally puts holes in the wall or membrane (see Fig. 33-2).
Inhibition of Ribosomal Protein Synthesis
Antibiotics may inhibit at either the 30S or 50S ribosomal subunit.
This can result in inhibition of initiation of protein synthesis, inhi-
bition of peptidyl transferase, and inhibition of the extrusion of the
peptide chain from the ribosome, causing misreading of the mRNA
message and other mechanisms (see Fig. 33-2).
Inhibition of Nucleic Acid Synthesis
Mechanisms associated with either RNA or DNA include inhibition
of DNA gyrase and topoisomerase IV, inhibition of DNA-dependent
RNA polymerase, and damage to DNA (see Fig. 33-2).
Inhibitors of
protein synthesis
{Tetracyclines}
{Aminoglycosides}
{Mactrolides}
Inhibitors of nucleic
acid function or
synthesis
{Fluoroquinolones}
 CHAPTER 33  Pharmacology of Specific Drug Groups: Antibiotic Therapy
Inhibition of Folic Acid Synthesis
Sulfonamides and trimethoprim are anti-metabolites that inhibit
sequential steps in the bacterial synthesis of folic acid essential for
one-carbon transfers in nucleic acid synthesis (see Fig. 33-2).
MICROBIAL RESISTANCE TO ANTIBIOTICS
(FIG. 33-3)
Microbial resistance to antibiotics has become a major factor in deter-
mining when and which antibiotic is used and dosages and length of
administration. It also has spurred renewed interest in antibiotic phar-
macokinetics and pharmacodynamics.
Procedures designed to reduce antibiotic-resistant pathogenic
microorganisms have been developed, including education of health
care providers and the general public, improved handwashing tech-
niques, better hospital infection control, isolation of patients with
highly resistant bacteria, control of antibiotic use in hospitals through
formularies and pharmacist oversight, and the removal of antibiotics
for growth promotion in agricultural animals.
All microbial resistance is local; the patterns and extent of this resis-
tance are determined by the use of antibiotics in a particular commu-
nity. What is true in Miami may not be true in Los Angeles or in Paris,
London, Rome, or New Delhi. If tetracyclines are used widely in the
community for acne or Lyme disease, a high resistance level to the drug
is likely to be present in that locale. If not, the microbial resistance level
is likely to be low. If an antibiotic or its analogue has been used widely in
agriculture, this may strongly influence resistance patterns, to the point
of rendering a new antibiotic far less useful. In Taiwan, virginiamycin
(a streptogramin) has been used for more than 2 decades as a growth
promoter in food animals. When quinupristin-dalfopristin, a new strep-
togramin, was tested on human bacterial isolates before its clinical intro-
duction, more than 50% of some pathogens were already resistant to
the drug. Antibiotics are truly societal drugs that cumulatively affect the
individual receiving the drug and many others as well.
Microorganisms have developed six known mechanisms to evade
the bactericidal or bacteriostatic actions of antimicrobials, as follows:
(1) enzymatic inactivation, (2) modification/protection of the target
site, (3) limited access of antibiotic (altered cell membrane permea-
bility), (4) active drug efflux, (5) use of alternative growth require-
ments, and (6) overproduction of target sites (see Fig. 33-3).
Alteration of target sites
Alternate growth requirements
Enzymatic inactivation
Overproduction of target sites
Efflux pumps
Decrease in cell permeability
FIG 33-3  Mechanisms by which bacteria can become resistant to anti-
microbial drugs.
459
Enzymatic inactivation is one of the more common methods and
is typified by β-lactamase hydrolysis of penicillins and cephalosporins
and acetyltransferases that inactivate chloramphenicol, aminoglyco-
sides, and tetracyclines. Altered target sites include ribosomal point
mutations for tetracyclines, macrolides, and clindamycin; altered
DNA gyrase and topoisomerase for fluoroquinolones; and modified
penicillin-binding proteins (PBPs) for viridans group streptococci
(VGS) and pneumococci. Most microorganisms have developed
ways to alter their cell wall or membrane permeability to limit access
of the antibiotic to its receptor by deleting outer membrane proteins
or closing membrane pore channels. Altering antibiotic access to
the cell interior usually does not confer a high level of resistance on
the organism and must be combined with another mechanism for
significant resistance potential. Several hundred efflux proteins are
available that extrude waste products from the microbial cell but that
now have been adapted over time to eliminate antibiotics specifically
from the cell interior virtually as fast as they can enter. Enterococci can
evade destruction by developing alternative metabolic growth require-
ments (auxotrophs). Sulfonamide resistance may occur from the
overproduction of para-aminobenzoic acid (PABA), and some enteric
organisms evade β-lactam antibiotics by overproducing β-lactamase
(hyper–β-lactamase producers).
Antibiotic tolerance occurs when the antibiotic no longer kills
the microorganism, but it merely inhibits its growth or multiplica-
tion. Tolerant microorganisms start to grow after the antibiotic is
removed, whereas resistant microorganisms multiply in the presence
of the antibiotic. Tolerance is usually caused by the loss of autolysin
activity through a failure to create or mobilize the autolytic enzymes.
Vancomycin tolerance in Streptococcus pneumoniae is unique; a muta-
tion in the sensor-response system controls the bactericidal autolysin
activity.
A major factor in the development and maintenance of antibiotic
resistance in microbes is that sensitive microorganisms are inhibited,
allowing resistant ones to multiply and dominate. Microbial resistance
is most likely to occur when subtherapeutic antibiotic doses are used;
these are doses that do not kill or inhibit the microorganism, but rather
allow it to perceive the chemical as a threat to its survival and to react
by mutation to resistance, acquisition, or transfer of resistance genes/
virulence factors or induction (expression) of latent resistance genes.
The gastrointestinal tract is a massive reservoir for resistance genes
readily transferred within and between enteric microbial species, a
process greatly enhanced by antibiotics that readily induce the expres-
sion or transfer of resistance genes.
SPECIFIC RESISTANCE MECHANISMS
β-Lactamases
The most important acquired mechanism for β-lactam resistance,
particularly in gram-negative microorganisms, is the production of
various β-lactamases that hydrolyze the β-lactam ring to form a linear
metabolite incapable of binding to PBPs.
β-Lactamases have been variously classified by Richmond-Sykes
(I to V), Ambler (A to D), and Bush (1 to 4). β-Lactamase enzymes
can be chromosomally mediated or easily transferred by transpos-
able elements. The most pressing difficulties with β-lactamases are
their widespread dissemination throughout the microbial environ-
ment, ability to move between widely disparate organisms, tendency
to inhibit new antibiotic agents rapidly, and increasing resistance
to β-lactamase inhibitors (clavulanic acid, sulbactam, tazobactam,
and avibactam). β-Lactamases have been observed in numerous
gram-positive and gram-negative pathogens. The cohabitation of
staphylococci and enterococci on human skin in hospitals has likely
460 CHAPTER 33  Pharmacology of Specific Drug Groups: Antibiotic Therapy

led to the incorporation of β-lactamases genes into enterococci after

TABLE 33-1  Antibiotic Resistance Patterns
the latter organisms had successfully avoided this transfer for billions
of years. Antimicrobial Drugs and Examples of
Point mutations have appeared more recently in certain β-lac- Mechanisms Mechanisms
tamases, resulting in extended-spectrum β-lactamases in Klebsiella Enzymatic ­antibiotic β-Lactams by β-lactamases
pneumoniae that hydrolyze the latest cephalosporins. Certain enteric inactivation Aminoglycosides by aminoglycoside-modifying enzymes
microorganisms (Escherichia coli, Citrobacter freundii, K. pneumoniae, Chloramphenicol by acetyltransferases
Proteus mirabilis) can produce massive amounts of TEM-1 ­β-lactamase Streptogramins by acetyltransferases
(hyper–β-lactamase producers) that can overwhelm β-lactamase Tetracyclines by enzymatic oxidation
inhibitors. Metallo-β-lactamases possess the broadest spectrum of Modification/­ β-Lactams: altered PBPs
inhibitory activity and hydrolyze all β-lactam antibiotics except mono- protection of Fluoroquinolones: altered DNA gyrase or topoisomerases
bactams (aztreonam) and are not inhibited by any of the β-lactamase target site Rifampin: altered RNA polymerase
inhibitors currently available. Sulfonamides: altered dihydropteroate synthase
The first plasmid-encoded β-lactamases with the ability to hydro- Trimethoprim: altered dihydrofolate reductase
lyze cephalosporins were termed the extended-spectrum β-lactamases Macrolide-lincosamide-streptogramin B aggregate
(ESBLs). These ESBL microbes were also resistant to aminoglycosides, gene (MLSb): methylation of adenine on 23S rRNA
tetracyclines, and trimethoprim/sulfonamides. ESBLs cause resistance Glycopeptides: change of d-Ala-d-Ala to d-Ala-­d-
to third-generation cephalosporins (cefotaxime, ceftriaxone, ceftazi- lactate in cell wall
dime) and monobactams (aztreonam) but are sensitive to cephamy- Tetracyclines: ribosomal protection
cins (cefoxitin, cefotetan) and carbapenems (imipenem, meropenem, Limiting access of β-Lactams, fluoroquinolones, most antibiotics: altered
ertapenem). These ESBL microbes are horizontally transmitted by antibiotic outer membrane porins
mobile genetic elements from food, animals, or family members and Most antibiotics: reduced membrane transport
induce greater mortality than enteric bacilli without these ESBLs. Active antibiotic Tetracyclines: TET genes
efflux Fluoroquinolones: Nor A genes
Multidrug Antibiotic Efflux Pumps Failure to activate Metronidazole: decreased flavodoxin production
Certain bacteria can move an antibiotic out of the cell as soon as it antibiotic
enters. Currently, more than 50 such systems have been described, Use of alternative Enterococcal auxotrophs
and these cytoplasmic membrane transport proteins (multidrug efflux growth requirements
pumps) have likely evolved to protect the cell from foreign chemi- Overproduction of Sulfonamides: overproduction of PABA
cal invasion and allow its secretion of cell metabolic products. Efflux target sites Enteric bacilli: overproduction of β-lactamase
pumps operate in E. coli, Pseudomonas aeruginosa, staphylococci,
Streptococcus pyogenes, S. pneumoniae, Bacillus subtilis, Pasteurella mul­ PABA, p-Aminobenzoic acid; PBPs, penicillin-binding proteins.
tocida, Neisseria gonorrhoeae, mycobacteria, and enterococci. For tet- From Polk R: Optimal use of modern antibiotics: emerging trends, Clin
Infect Dis 29:264-274, 1999; Smith H: Host factors that influence the
racyclines, these efflux pumps are the major mechanism for resistance
behavior of bacteria pathogens in vivo, Int J Med Microbiol 290:207-
and are becoming increasingly so for the fluoroquinolones. 213, 2000.
Chromosomal and plasmid-mediated efflux transporter proteins
may be quite specific for antibiotics and metabolic product substrates
and are regulated by numerous genes and gene products. Repressors transformations are uncommon and require unique circumstances
are also present and are highly regulated to prevent the accidental over- involving genes, binding, uptake, and integration.
production of efflux pumps. Tetracyclines can derepress this system, Transduction is the movement of DNA from one bacterium to
leading to an overproduction of efflux proteins and increasing resis- another by a bacteriophage (bacterial virus) intermediary. Conjugation
tance to themselves and any other antibiotics carried by these proteins. is the self-transfer of genetic information by plasmids or transposons
to other microorganisms, generally by physical contact with a sex pilus
Genetic Variations in Bacteria in gram-negative organisms and stimulated by various pheromones
Microorganisms possess three mechanisms for genetic variation: (1) (small peptides).
local nucleotide changes in the genome, (2) rearrangement of genomic A summary or bacterial resistance mechanism by class of antimi-
sequences, and (3) horizontal acquisition of DNA from other microor- crobial drugs is given in Table 33-1.
ganisms (horizontal gene transfer).
Horizontal gene transfer between organisms occurs by three
mechanisms—transformation, transduction, and conjugation—and
ADVERSE REACTIONS TO ANTIBIOTICS
use numerous transposable elements that involve mobile genetic ele- This section discusses adverse drug reactions, some of which are
ments that are passed from one bacterium to another. These mobile unique to antibiotics; others are not exclusive to antimicrobials, but
genetic elements include naked DNA, plasmids, bacteriophages, trans- they are clinically significant for some antimicrobial drugs.
posons, and integrons.
Plasmids are circular, double-stranded DNA outside the chromo- Allergies
somes. Bacteriophages are viruses that infect bacteria and can medi- The penicillins are an example of antibiotics associated with a signifi-
ate genetic transfer. Transposons are DNA segments that cannot cant number of allergies among the population. These can range from
self-­replicate, but they can self-transfer between plasmids, bacterio- a mild rash to acute anaphylaxis.
phages, and chromosomes. Integrons capture and disseminate genes
by site-specific integration of DNA (gene cassettes). Antibiotic Resistance
During transformation, bacteria acquire “naked” DNA from An inevitable effect of the use of antibiotics is the development of resis-
their environment to incorporate into their genome. Such genetic tance on the part of bacteria. On balance, the evidence is substantial
 CHAPTER 33  Pharmacology of Specific Drug Groups: Antibiotic Therapy
that antimicrobial agents at any dose or concentration for virtually any
length of time do select for resistance and promote the acquisition and
transfer of drug-resistant genes. Many of these species exhibit extraor-
dinary resistance patterns: 50% to 100% of Salmonella, staphylococci,
and enteric bacilli are resistant to tetracycline, and 32% to 47% are
resistant to β-lactams, with 49.7% exhibiting polyantibiotic resistance;
30% of Staphylococcus aureus are resistant to ciprofloxacin and 47% to
tetracycline; 72% of Campylobacter in humans and 99% in chickens
and pigs are resistant to ciprofloxacin; and E. coli exhibits 70% to 94%
resistance to amoxicillin and 62% to 98% resistance to tetracycline.
Very low (nanogram/nanomolar) concentrations of antibiotics found
in the food chain used in nature to control bacterial ecologic niches
induce resistance patterns; subtherapeutic dosages in humans are suf-
ficient to challenge microorganisms and lead to resistance.
The mere presence of a β-lactam antibiotic produces a hundred-
fold to a thousandfold increase in induction of β-lactamase in micro-
organisms producing extended-spectrum β-lactamases. E. coli carries
resistance genes that are not expressed until tetracycline is present.
Concentrations of tetracyclines at 0.1 to 1 μg/mL/ per gram in meat
cause the dissemination of resistance genes in the human gastrointesti-
nal tract, and 1 μg/mL of tetracycline in drinking water results in a ten-
fold increase in the transfer of conjugative plasmids from Enterococcus
faecalis to Listeria monocytogenes.
The use of antibiotics can also promote the transfer of resistance
genes from one species to another. In oral plaque biofilm, tetracycline
resistance genes can be transferred from Bacillus subtilis to strepto-
cocci, illustrating that non-oral bacteria have the potential to trans-
fer genes to opportunistic oral microorganisms. The self-transfer of
Bacteroides conjugative transposons can be increased a hundredfold to
a thousandfold by the presence of low levels of tetracycline (1 μg/mL).
Oral streptococci can harbor tetracycline resistance genes in dental
plaque and disseminate such genes by mobile elements to other micro-
flora: Enterococcus faecalis, Veillonella, and other streptococci. Salyers
and colleagues stated that “the fact that tetracycline acts as an inducer
of transfer gene expression illustrates how the use of an antibiotic
could accelerate the spread of antibiotic resistance genes not only by
selecting for their acquisition but also by stimulating their transfer.”
Exposure to antibiotic doses at the low concentrations seen in agri-
culture and aquaculture, as therapy for inflammatory or other diseases,
or for growth effects is a major concern for public health. These antibi-
otics can make their way into the food and water supply and alter body
flora or promote emergence of resistant microbes or the transfer of
resistance genes. Perhaps more importantly, the wide use of antibiotics
in farm animals leads to organisms that are resistant to one or multiple
antibiotics.
Superinfection
A significant and unappreciated adverse effect of antibiotics is the
potential to decrease colonization resistance of indigenous anaer-
obic flora in the digestive tract and other anatomic areas (skin, oral
mucosa). The role of colonization resistance is to limit the concentra-
tion of potentially pathogenic flora of either an exogenous or endog-
enous nature in a given body part. Removal of indigenous flora by
antibiotics can promote growth of microorganisms not sensitive to the
drug (superinfection). Many superinfections result from a reduction
in the endogenous microorganisms important for colonization resis-
tance, with the most notable example being antibiotic-induced diar-
rhea and colitis.
Adverse colonic effects of antibiotics range from simple diarrhea
(antibiotic-associated diarrhea) to mucosal inflammatory diarrhea/­
colitis (antibiotic-associated colitis), with or without associated Clos­
tridium difficile (C. difficile–associated colitis [CDAC]), to potentially
461
fatal pseudomembranous colitis (PMC). Of the 25 million people
affected by serious diarrhea annually in the United States, approx-
imately 10% of these cases are the result of antibiotics, particularly
broad-spectrum agents. Most of these cases of antibiotic-associated
diarrhea are not clinically significant and respond to drug discontinu-
ance and rehydration if necessary.
Any antibiotic is capable of inducing diarrhea, colitis, or PMC,
but the most common agent involved is amoxicillin, followed by
third-generation cephalosporins and clindamycin. When the colonic
flora are disturbed by antibiotics or disease, the colonization resistance
of the gastrointestinal tract is reduced by the suppression of natural
antagonists of C. difficile such as Bacteroides, Lactobacillus, pseudo-
monads, staphylococci, streptococci, peptostreptococci, enterococci,
and E. coli.
The fear of inducing a potentially fatal case of PMC has led to a
reluctance to use clindamycin because early and faulty preliminary
data reported a 10% association of PMC with the drug. More recent
data indicate that incidence of antibiotic-associated diarrhea and
CDAC associated with clindamycin in community use of the drug is
very low. The overall risk rate for community-acquired C. difficile–
associated PMC from retrospective data may be 1 per 10,000 antibiotic
prescriptions, and the risk of hospitalization may be 0.5 to 1 per 100,000
patient years. The incidence rate was calculated to be 1.6 per 100,000
persons exposed to ampicillin, 2.9 per 100,000 persons exposed to
dicloxacillin, and 2.6 per 100,000 persons exposed to tetracycline, with
no antibiotic-associated diarrhea seen in the 1509 patients receiving
oral or topical clindamycin.
Statistically, PMC is more likely to occur with amoxicillin than
clindamycin. Clinicians should refrain from unnecessary antibiotic
therapy in patients within the first 2 months after the elimination of
CDAD. Any elective dental procedure requiring antibiotic treatment
or prophylaxis would best be postponed for this 2-month period. If
antibiotic therapy is required, the use of antibiotics far less commonly
associated with CDAD (penicillin V, macrolides) is appropriate.
An example of superinfection in the mouth is the growth of Candida
albicans as a result of treatment with an antibiotic, especially one with a
broad or extended spectrum or metronidazole.
Nephrotoxicity
The kidney is sensitive to the effects of some antibiotics, especially
aminoglycoside and peptide antibiotics. Combining two drugs with
overlapping toxicity compounds the problem. Mechanisms of renal
toxicity involve concentration of the drug in renal tubule cells, leading
to the lack of ability to concentrate urine and eventual reduced glomer-
ular filtration rate.
Ototoxicity
Aminoglycosides and peptide antibiotics also are associated with dam-
age and other effects on the eighth cranial nerve leading to vestibu-
lar and cochlear dysfunction. Hearing loss, especially high frequency,
occurs and can be irreversible due to the concentration of the drugs in
the endolymph and perilymph and damage to the cochlea.
Antibiotic-Induced Photosensitivity, Photoallergy, and
Phototoxicity
Some antibiotics (along with phenothiazine antipsychotics) are among
the most common drugs inducing skin reactions on exposure to sun-
light. Photosensitivity may occur in one of two forms: (1) phototoxicity,
in which chemicals (drugs) are deposited in the skin, absorb ultraviolet
light, and transfer the energy to local tissue, resulting in inflamma-
tory responses, or (2) photoallergy, in which sunlight causes a hapten
to become a complete antigen in the skin, eliciting an immediate or
462 CHAPTER 33  Pharmacology of Specific Drug Groups: Antibiotic Therapy
a delayed allergic reaction. The signs and symptoms (erythema, urti-
caria, eczema, lichenoid dermatitis, bullous lesions) may be the same,
but the mechanisms are different (photoallergy may need a sensitizing
dose unless the drug is continually taken for ≥5 to 10 days). The most
common antibiotics that induce photosensitivity are sulfonamides,
tetracyclines, and fluoroquinolones. Photosensitivity is managed by
discontinuing the drug, avoiding sunlight, and wearing protective
clothing.
Long QT Interval Syndrome
Long QT interval syndrome is a cardiac disorder caused by ion channel
abnormalities that prolong the time interval between the beginning of
the QRS complex and the end of the T wave on the electrocardiogram
(see Chapter 19). Antibiotics that have been implicated in the cause of
torsades de pointes include fluoroquinolones (gatifloxacin, levofloxa-
cin, moxifloxacin, sparfloxacin), macrolides (erythromycin, clarithro-
mycin), and clindamycin.
The Food and Drug Administration (FDA) Adverse Event Reporting
System has found that 77% were caused by macrolides and 23% by fluo-
roquinolones; 89% to 95% were in older patients; 9% to 13% were fatal;
the mean time to the adverse event was 4 to 5 days; and 42% to 62% had
cardiac disease, 7% to 11% had renal disease, and 17% had low blood
K+ or Mg++ levels. The risk rate has been estimated to be 1 per 1 million
exposures to ciprofloxacin, 3 per 1 million exposures to clarithromycin,
and 14.5 per 1 million exposures to sparfloxacin (withdrawn from the
market in the United States).
Antibiotics and Oral Contraceptives
In response to a few case reports, in the 1980s the FDA issued a warn-
ing that antibiotics may interfere with the action of oral contracep-
tives, potentially resulting in unwanted pregnancies. The proposed
mechanisms of reduced contraceptive blood concentrations leading
to decreased efficacy include (1) increased urinary/fecal excretion
from antibiotic-induced diarrhea, (2) increased microsomal liver
metabolism, (3) receptor displacement, (4) reduced gastrointestinal
absorption, and (5) reduced enterohepatic circulation. The antibiotic
rifampin stimulates the liver metabolism of the oral contraceptives,
reducing blood levels. No other experimental data or controlled clin-
ical studies have documented the interference of any other antibiotics
with the activity of oral contraceptives.
The reasoning is that some antibiotics, especially broad- or extend-
ed-spectrum antibiotics, reduce enteric bacteria that metabolize the
conjugated forms of the estrogens and progestins that make up the
contraceptive. As a result, less regenerated form of the hormones
would be available for reabsorption from the gut, resulting in less
effect from the contraceptive. However, several studies document no
effect of antibiotics on the blood levels of ethinyl estradiol, norethin-
drone, and progesterone in patients taking doxycycline (100 mg/day
for 7 days), tetracycline (500 mg every 6 hours for 10 days), and cipro-
floxacin (500 mg three times/day for 7 days). No effort has been made
to determine whether the failure rate of oral contraceptives in women
taking antibiotics is greater than the normal failure rate of oral con-
traceptives in women not taking antibiotics. No official authoritative
body has ever examined this alleged drug interaction to investigate the
evidence and make a recommendation.
From a purely scientific point of view, no reason exists to believe
that any antibiotics other than rifampin interfere with the action of
oral contraceptives. From a medicolegal point of view, the dentist may
wish to advise a patient taking oral contraceptives and receiving antibi-
otics to use an additional contraceptive method or practice abstinence
during the time the antibiotic is present and for several days after its
termination to allow for complete antibiotic excretion (usually five
times the half-life of the drug). The oral contraceptive should never
be stopped during antibiotic therapy because it is the most effective
means of contraception with the exception of abstinence.
The one antibiotic that has been shown to reduce the effect of oral
contraceptives is rifampin. In this case the mechanism is an induction
of hepatic metabolism by rifampin. Women taking an oral contracep-
tive and then prescribed rifampin must use a means of birth control
other than an oral contraceptive.
NEW ANTIMICROBIAL APPROACHES
Pharmaceutical companies see new antibiotic development as prob-
lematic for economic, regulatory, and scientific reasons. As a result, 10
of the 15 largest drug companies have reduced or eliminated antibiotic
research since 1999.
The scientific difficulty with developing new antibiotics is that all the
easy targets in bacteria have already been discovered with possibly only
a few remaining. Formulating “new” antibiotics that are merely deriv-
atives of existing antibiotics will not solve all the problems of microbial
resistance. Entirely new approaches to unique mechanisms of antibiotic
action attacking heretofore unknown microbial metabolic processes
require a much better basic understanding of microbial life and consid-
erable risk-taking on the part of the pharmaceutical industry.
ANTIBACTERIAL ANTIMICROBIAL DRUGS
Antibacterial drugs are primarily classified according to their chemical
class and mechanism of action. They also can be distinguished based
on spectrum and adverse effects. In addition to these aspects of anti-
microbial drugs, the therapeutic uses, including dental applications, of
each class of drugs are discussed.
β-Lactam Antibiotics
Penicillin belongs to the β-lactam family of antibiotics, which remain
the most widely used antibiotics in the world. β-lactams are composed
of five different groups of antibiotics, with the β-lactam nucleus as the
common feature: penicillins, cephalosporins, carbapenems, mono-
bactams, and carbacephems. Penicillins and cephalosporins are the
most important with carbapenems (imipenem, meropenem, ertape-
nem), monobactams (aztreonam), and carbacephems (loracarbef)
reserved for serious infections such as nosocomial (hospital-acquired)
infections. β-lactams vary greatly from one another in their spectrum
of antimicrobial activity, ranging from an extremely narrow spectrum
(e.g., β-lactamase–resistant penicillins) to a very wide spectrum (e.g.,
imipenem and some cephalosporins).
Penicillins
Penicillin is a generic term for a group of antibiotics that share the
β-lactam ring nucleus, similar adverse drug reactions, and similar
mechanism of action, but differ in their antibacterial spectrum, phar-
macokinetics, and resistance to β-lactamase enzymes.
Classification. Penicillin is a cyclic dipeptide consisting of two
amino acids (d-valine, l-lysine), a particular molecular configuration
unknown in higher life forms. The synthesis in 1958 of the basic structure
of penicillins (6-aminopenicillanic acid) allowed for its manipulation
by the addition of various side chains to the β-lactam and thiazolidine
rings (Fig. 33-4). Different salts (Na+, K+, procaine, benzathine)
were also created for pharmacokinetic purposes. On the basis of
these modifications, penicillins can be divided into four groups: (1)
penicillin G and penicillin V, (2) antistaphylococcal penicillins that
are resistant to β-lactamase produced by staphylococci, (3) amino-
penicillins with an extended-spectrum, and (4) extended-spectrum
 CHAPTER 33  Pharmacology of Specific Drug Groups: Antibiotic Therapy 463

penicillins with added activity against gram-negative organisms like and dicloxacillin are examples. (Although similar to penicillin V in
Pseudomonas aeruginosa (Table 33-2). Some penicillins are combined other ways, penicillin G is acid labile and is not often used orally.)
with a separate β-lactamase inhibitor to protect the penicillin from the Penicillinase-resistant penicillins are resistant to some β-lactamases.
enzyme. Bacteria, particularly staphylococci, develop resistance to penicillins
Acid-stable penicillins are resistant to break down in stomach acid, chiefly through the elaboration of β-lactamase enzymes (penicilli-
indicating their usefulness as oral drugs. Penicillin V, amoxicillin, nases) that inactivate the penicillins by cleavage of the 6-aminopeni-
cillanic acid nucleus to yield penicilloic acid derivatives (see Fig. 33-4).
The production of staphylococcal penicillinase is encoded in a plasmid
R Group and may be transferred to other bacteria. Methicillin was the first semi-
synthetic derivative to be introduced that was stable in the presence
O of β-lactamase. Subsequently, nafcillin and three isoxazolyl derivatives
H (oxacillin, cloxacillin, and dicloxacillin) were marketed.
HN S
CH3 Extended-spectrum penicillins are represented by two groups of
CH3
penicillin derivatives. One group is the aminopenicillin group: ampi-
Penicillin G N
O cillin, amoxicillin and bacampicillin. The latter is a drug that is rap-
R Groups
OH idly hydrolyzed in vivo to yield ampicillin. The second group contains
O ticarcillin and piperacillin that exhibit activity against Pseudomonas
Penicillinase and indole-positive Proteus species.
O Mechanism of action. Early in the discovery of penicillin, it was
Penicillin V noted that the drug acted only on rapidly dividing organisms, and it was
Cl O later determined that bacterial cell wall precursors (the Park nucleotides)
N CH3 O accumulated in sensitive bacteria exposed to the penicillins. Penicillin
H
was determined to be a structural analogue of d-alanine; the final step
HN S
CH3 in the formation of the bacterial rigid cell wall was a transpeptidation
Cl HN CH3 reaction involving the enzymatic removal of a terminal d-alanine to
Dicloxacillin O allow for the formation of the cross-linked peptidoglycan cell wall
OH
NH2
Benzylpenicilloic acid OH (Fig. 33-5). β-Lactams are competitive inhibitors of various enzymes
O (transpeptidases, carboxypeptidases), collectively termed penicillin-
sensitive enzymes, or more commonly PBPs. β-lactams promote the
HO formation of cell wall–deficient microorganisms of different shapes
(oval, oblong, spherical) depending on the particular PBP affected,
Amoxicillin
which cannot maintain their internal osmotic pressure and eventually
S burst. The mechanism of action of β-lactams is a classic example of
Ehrlich’s goal of the “magic bullet,” or more specifically a chemical
that inhibits a cellular activity present only in bacteria (a rigid cell wall)
HO O and not found in mammalian cells.
Ticarcillin In some bacterial species, β-lactams have an additional mechanism
FIG 33-4  Structure of penicillin G and structures of penicillin V, dicloxa- of action as they activate an enzyme, muramyl synthetase, responsible
cillin, amoxicillin, and ticarcillin, as shown by replacement of the R group for the separation of daughter cells after cell division. Activation of this
of penicilloic G. Also shown is the effect of penicillinase in producing the enzyme in the absence of cell division produces lysis of the cell wall
penicilloic acid metabolite, which is inactive as an antimicrobial drug. (autolysis) and results in bacterial “suicide.”

TABLE 33-2  Penicillin Groups

Group Examples Acid Stable Spectrum Penicillinase Resistant
Penicillin G and congener Penicillin G No Narrow No
Penicillin V Yes Narrow No
Anti-staphylococcal Methicillin* No Narrow Yes‡
Nafcillin Somewhat|| Narrow† Yes‡
Oxacillin Yes Narrow† Yes‡
Cloxacillin Yes Narrow† Yes‡
Dicloxacillin Yes Narrow† Yes‡
Amino-penicillins, extended-spectrum Ampicillin Yes Extended No
Amoxicillin Yes Extended No
Extended-spectrum§ Ticarcillin* No Extended§ No
Piperacillin No Extended§ No
*No longer used clinically.
†Limited to use against staphylococcal organisms.
‡Resistant to penicillinase from Staphylococcus aureus.
§Spectrum includes other gram-negative bacteria (e.g., Pseudomonas aeruginosa and indole-positive Proteus).
||Although nafcillin is somewhat acid stable, it is used parenterally.
464 CHAPTER 33  Pharmacology of Specific Drug Groups: Antibiotic Therapy

FIG 33-5  Bacterial cell wall synthesis. Details are discussed in the text. The sites of action of various drugs are
shown. The lipid carrier that is inhibited by bacitracin is shown as a wavy line. (From Cohen J, et al.: Infectious
diseases, ed 3, St Louis, 2010, Mosby.)

Considering these mechanisms, it is apparent why consistently
high blood levels of β-lactams are required for optimal success (not
all bacteria divide at the same time) and why penicillins do not kill
rapidly (it takes time for enzyme inhibition and eventual microor-
ganism rupture). This realization that β-lactams kill slowly has raised
questions about the mechanism of action in endocarditis prophy-
laxis: whether they act only (or at all) by microbial killing or rather
by cell wall alteration to retard attachment of the bacteria to damaged
cardiac valves.
Antibacterial spectrum. Penicillin G and penicillin V are narrow-
spectrum antibiotics, showing activity against mostly gram-positive
cocci and gram-positive bacilli and gram-negative cocci. Other
penicillins have an extended spectrum and greater activity against
some gram-negative bacilli.
Penicillin G or penicillin V are drugs of choice against the VGS, S.
pneumoniae, S. Pyogenes, Peptostreptococcus, E. faecalis, Fusobacterium
nucleatum, Actinomyces israelii, Clostridium tetani, Clostridium per­
fringens, Leptotrichia buccalis, N. meningitidis, and non-β-lactamase–
producing Prevotella and Porphyromonas. Amoxicillin alone or with
clavulanate has activity against the same organisms but also Eikenella
corrodens, K. pneumoniae, Enterobacter, Moraxella (Branhamella)
catarrhalis, Bacteroides fragilis, non–methicillin-resistant and (with
clavulanate) β-lactamase-producing Prevotella and Porphyromonas E.
coli, Haemophilus influenzae, H. pylori, and P. mirabilis (Table 33-3).
 CHAPTER 33  Pharmacology of Specific Drug Groups: Antibiotic Therapy
TABLE 33-3  Penicillins as Drugs of Choice
or Alternative Agents (Penicillin G, Penicillin
V, Ampicillin, or Amoxicillin Unless Otherwise
Indicated)
Acinetobacter*
Actinomyces israelii
Bacillus anthracis
Bacteroides*
Campylobacter fetus*
Capnocytophaga canimorsus
Citrobacter freundii*
Clostridium perfringens
Clostridium tetani
Eikenella corrodens
Enterobacter*
Erysipelothrix rhusiopathiae
Fusobacterium nucleatum
Group A, B, C, and G streptococci
Listeria monocytogenes
Neisseria meningitidis
Pasteurella multocida
Peptostreptococcus micros
Serratia marcescens*
Proteus mirabilis
Spirillum minus
Streptobacillus moniliformis
Staphylococcus aureus/Staphylococcus epidermidis†
Streptococcus bovis
Treponema pallidum
VGS
VGS, Viridans group streptococci.
*Imipenem/meropenem.
†β-Lactamase-resistant penicillins if methicillin susceptible.
From Handbook of antimicrobial therapy. Choice of antibacterial drugs.
Med Lett Drugs Ther 20:69-88, 2015; Facts and comparisons, St Louis,
2015, Facts and Comparisons.
Amoxicillin and penicillin V are the initial drugs of choice in oro-
facial infections in nonallergic patients, but they are ineffective against
streptococci (VGS) with altered PBPs. The clinical impact of antibiotic
failures against these resistant streptococci and gram-negative β-lact-
amase–producing oral anaerobes is likely to be significant but has yet
to be determined by clinical studies. On the basis of the antimicrobial
spectrum of penicillin G and V and other clinical characteristics, the
drugs are useful in the treatment of numerous diseases (Table 33-4).
Bacterial resistance. Bacteria evade the killing effects of β-lactams
by three mechanisms: reduced drug binding to PBPs (altered target
sites), hydrolysis by β-lactamase enzymes (enzymatic inactivation),
or development of tolerance by the loss of the autolysis mechanism
(penicillin becomes bacteriostatic instead of bactericidal). In most
species, the principal mechanism is β-lactamase production.
Absorption, fate, and excretion. Penicillin G (benzylpenicillin)
is rarely used orally because of its poor gastric absorption rate.
Penicillin V and amoxicillin are well absorbed orally, with amoxicillin
considerably longer in its half-life (∼1 hour vs ∼30 minutes). Better oral
absorption argues for the use of amoxicillin over penicillin V, but both
drugs are effective in microorganism-sensitive orofacial infections and
are equally inactive against VGS with altered PBPs.
Procaine penicillin G and benzathine penicillin G are repository
forms prepared for intramuscular injection with slow release from the
injection site. These preparations extend the plasma level profiles of
465
TABLE 33-4  Disease Entities for Which
Penicillin G, Penicillin V, and Amoxicillin Are
of Major Use
Abscesses, including orodental
Bacteremia (gram-positive)
Endocarditis
Gas gangrene
Mastoiditis
Meningitis
Orodental infections
Osteomyelitis
Pericarditis
Periodontal infections
Pharyngitis
Pneumonia
Rat-bite fever
Scarlet fever
Suppurative arthritis
Syphilis
Vincent’s stomatitis
Weil’s disease
Wound infections
These diseases are caused by various gram-positive cocci and bacilli
and some gram-negative organisms, spirochetes, and anaerobic
microorganisms. Susceptibility testing may be essential for some to
determine therapeutic mean inhibitory concentrations.
penicillin (Fig. 33-6). The route of excretion is primarily by the kid-
neys, with limited liver metabolism. Rapid kidney excretion accounts
for the short half-lives of most penicillins, 90% of which is due to
active proximal tubular secretion, while the remaining 10% is due to
glomerular filtration. This is the basis for occasionally extending the
half-lives of some penicillins by combining the penicillin with probe-
necid, which inhibits active tubular transport.
The distribution of the penicillins includes most body fluids but
not the humors of the eye or the brain. Penicillin does not pass through
the blood–brain barrier unless the meninges are inflamed, such as in
meningitis.
β-lactam antibiotics produce time-dependent killing of bacte-
ria, and frequent dosing is required to maintain relatively constant
blood levels with as little fluctuation as possible. The killing power of
β-lactams is maximum at three to four times the minimum inhibi-
tory concentration (MIC) of susceptible microorganisms. The prime
determinant of the efficacy of β-lactams is the length of time the con-
centration of the drug in the infected area is greater than the MIC of
the infecting organism.
To be maximally effective, the serum and tissue concentrations
of β-lactams should be greater than the MIC for 50% to 70% of the
dosing interval. The current package insert recommends dosing inter-
vals of 6 hours for penicillin V. Penicillin V and penicillin G have an
elimination half-life of approximately 30 minutes, and consequently,
6-hour dosing intervals may result in very low serum levels in the last
2 or 3 hours. Continuous intravenous penicillin is receiving greater
attention as a way to circumvent this problem.
β-lactamase inhibitors. Currently, four agents are available to
bind irreversibly to the catalytic site of susceptible β-lactamases to
prevent hydrolysis of β-lactam antibiotics: clavulanic acid, sulbactam,
tazobactam, and avibactam. Clavulanic acid is derived from
Streptomyces clavuligerus, sulbactam is a semisynthetic penicillinate
sulfone, tazobactam is chemically related to sulbactam, and avibactam
is a non-β-lactam inhibitor with broader activity against β-lactamases.
466 CHAPTER 33  Pharmacology of Specific Drug Groups: Antibiotic Therapy
7 300,000 units
Plasma concentration (units/mL)
6 300,000 units
5 1,200,000 units
3
2
1
2 3 1 6
Hours after IM injection
(compressed scale)
FIG 33-6  Comparative plasma concentrations of penicillin G obtained from soluble versus repository intra-
muscular (IM) dosage forms.
All β-lactamase inhibitors have the same mechanism of action, which
is to bind to the active site of β-lactamases, where they are converted
to an inactive product by β-lactamase (“suicide inhibition”). Only
clavulanic acid is orally absorbed. Clavulanic acid is combined with
amoxicillin, sulbactam with ampicillin, tazobactam with piperacillin,
and ceftazidime (see later) with avibactam.
The sole therapeutic use of β-lactamase inhibitors is to prevent the
hydrolysis of β-lactam antibiotics in the management of β-­lactamase–
producing microorganisms responsible for otitis media and sinusitis
(S. pneumoniae, H. influenzae, M. catarrhalis), nosocomial pneumo-
nia (methicillin-sensitive S. aureus (MSSA) or K. pneumoniae), intra-­
abdominal abscesses from β-lactamase–producing anaerobes and
other microorganisms, and some upper respiratory tract infections.
β-Lactamase inhibitor combinations offer no advantage against non-β-
lactamase–­producing microorganisms and are ineffective against methi-
cillin-resistant S. aureus (MRSA), many coagulase negative staphylococci
(CoNS) and enterococci, and the inducible β-lactamases produced by
P. aeruginosa, Serratia marcescens, Enterobacter cloacae, C. freundii, and
Morganella morganii. These β-­lactamase inhibitor combinations can
often be useful as alternative antibiotics against Bacteroides, M. catarrha­
lis, E. coli, K. pneumoniae, indole-positive Proteus and others (see Tables
33-3 and 33-5).
Therapeutic uses in dentistry. Because the oral route is the safest,
most convenient, and least expensive mode of drug administration,
it is favored in the treatment of dental patients. Currently, penicillin
V and amoxicillin are the most frequently prescribed antibiotics for
chemotherapy of infections of dental origin.
In some instances, penicillins G and V and amoxicillin are unsuit-
able for treating oral infections. Some dental infections are caused by
β-lactamase (penicillinase)–producing organisms, and in such cases
the appropriate antibiotic is a penicillinase-resistant penicillin deriv-
ative, erythromycin, or clindamycin. Patients who have been receiv-
ing extended prophylactic therapy with penicillin for the prevention
of rheumatic fever generally require another antibiotic if they acquire
an infection or require endocarditis prophylaxis. Certain periodontal
Aqueous crystalline penicillin G
Procaine penicillin G
Benzathine penicillin G
0.4
0.3
0.2
0.1
9 12 29 1 15 30
Days after IM injection
infections are associated with gram-positive and gram-negative aero-
bic and anaerobic microorganisms, for which an antimicrobial agent
with a more extended antibacterial spectrum, such as amoxicillin or
more commonly a β-lactam/β-lactamase agent combined with metro-
nidazole, may be the agent of choice.
Adverse effects. The adverse effects of penicillins are allergic and
nonallergic in nature.
Allergic reactions to penicillins are common, while allergic fatal-
ities are far less common. Allergy to penicillins ranges from 0.7% to
8% in various studies, with a 0.7% to 4% chance of an allergic reaction
(average of 2%) during any given course of penicillin therapy. Most
allergic manifestations are maculopapular or urticarial skin reactions.
Penicillin may be the most common cause of anaphylactic death
in the United States, accounting for 75% of all cases and 400 to 800
annual deaths. Estimates of severe penicillin anaphylaxis range from
0.004% to 0.015% of individuals exposed and, from the point of view
of number of exposures, possibly 1 in 1200 to 1 in 2500 penicillin
exposures.
Eventually, 1% to 10% of the general population exposed to thera-
peutic penicillin has an allergic reaction, with a higher positive history
with increased age. The incidence of allergy varies with the route of
administration: oral (0.3%), intravenous (2.5%), and intramuscu-
lar (5%); the lower incidence by the oral route has been questioned
because of limited data.
It is probable that an acute penicillin-allergic reaction is less com-
mon in children and elderly patients, but fatal reactions may be more
likely in elderly patients because of their compromised cardiopulmo-
nary function. Whether certain individuals are predisposed to peni-
cillin allergy remains unsettled. Risk factors for penicillin allergies
include multiple allergies to other drugs, particularly other antibiot-
ics (“multiple allergy syndrome”), or atopic disease (asthma, allergic
rhinitis, nasal polyps). Cross-allergenicity exists for all penicillins and,
even to a certain extent, other β-lactam antibiotics.
In individuals with a positive history of penicillin allergy, 15% to
40% exhibit allergy on re-exposure to penicillin, and individuals with
 CHAPTER 33  Pharmacology of Specific Drug Groups: Antibiotic Therapy
TABLE 33-5  Drugs Used to Treat Infections Caused by Specific Microorganisms
Microorganism
Gram-Positive Cocci
Staphylococcus species
Methicillin-sensitive
Methicillin-resistant
Streptococcus pyogenes
Streptococcus viridans group
Oral infections
Bacteremia or endocarditis
Streptococci, anaerobic (Peptost-
reptococcus)
Streptococcus ­pneumoniae
Enterococcus faecalis
Enterococcus faecium (vancomycin
resistant)
Gram-Negative Cocci
Neisseria gonorrhoeae
Neisseria meningitidis
Moraxella (Branhamella)
catarrhalis
Gram-Positive Bacilli
Bacillus anthracis
Clostridium difficile
Clostridium perfringens
Clostridium tetani
Corynebacterium ­diphtheriae
Corynebacterium jeikeium
Gram-Negative Bacilli
Bacteroides (oropharyngeal
strains)
Capnocytophaga ­canimorsus
Eikenella corrodens
Escherichia coli
Fusobacterium species
Haemophilus influenzae
Klebsiella pneumoniae
Drug of First Choice
Penicillinase-resistant penicillin
(e.g., dicloxacillin)
Vancomycin ± rifampin
Penicillin G or V
Penicillin G or V
Penicillin G with or without gentamicin
Penicillin G or V
Penicillin G or V, amoxicillin
Ampicillin, amoxicillin, penicillin
G + gentamicin or ceftriaxone
Daptomycin (+gentamicin or ampicillin)
Ceftriaxone
Ceftriaxone, cefotaxime, penicillin G
A fluoroquinolone, cefuroxime
Ciprofloxacin, doxycycline
Metronidazole, vancomycin
Penicillin G
Metronidazole
Erythromycin
Vancomycin
Penicillin G
Amoxicillin/clavulanic acid
Ampicillin ± sulbactam, amoxicillin ± clavulanate
Cefotaxime, ceftriaxone, ceftazidime, cefepime
Penicillin G, penicillin V, metronidazole
Cefotaxime, ceftriaxone, trimethoprim-
sulfamethoxazole
Cefotaxime, ceftriaxone, cefepime
467
Alternative Drugs*
A cephalosporin, vancomycin, imipenem, meropenem, clindamycin, a
fluoroquinolone, linezolid, tedizolid, daptomycin, telavancin
Daptomycin, quinupristin/dalfopristin, linezolid, a fluoroquinolone,
doxycycline, trimethoprim-sulfamethoxazole, telavancin, dalbavancin,
oritavancin
A cephalosporin, erythromycin, clindamycin, vancomycin, clarithro-
mycin, azithromycin, linezolid, tedizolid, daptomycin, telavancin,
dalbavancin, oritavancin
Erythromycin, clindamycin, a cephalosporin
Ceftriaxone, vancomycin
A cephalosporin, clindamycin, vancomycin, daptomycin, telavancin
A cephalosporin, trimethoprim/sulfamethoxazole, erythromycin,
clarithromycin, azithromycin, clindamycin, levofloxacin, gemifloxa-
cin, moxifloxacin, meropenem, imipenem, ertapenem, doripenem,
vancomycin, telavancin, a tetracycline
Vancomycin with gentamicin, daptomycin ± gentamicin, linezolid, ampi-
cillin with imipenem (nitrofurantoin or fosfomycin, urinary tract only)
Ampicillin + gentamicin, linezolid in combination with other active
drug, quinupristin/dalfopristin ± ampicillin (nitrofurantoin or fosfomy-
cin, urinary tract only)
Ceftizoxime, cefoxitin + probenecid, cefixime, cefpodoxime
A fluoroquinolone, meropenem, chloramphenicol
Trimethoprim-sulfamethoxazole, amoxicillin/clavulanate, erythromycin,
clarithromycin, azithromycin, doxycycline, cefotaxime, ceftizoxime,
ceftriaxone, cefpodoxime
Penicillin G, amoxicillin, erythromycin, imipenem, clindamycin, levofloxacin
Fidaxomicin
Clindamycin, imipenem, meropenem, ertapenem, doripenem, metroni-
dazole, chloramphenicol
Penicillin G, doxycycline
Penicillin G
Daptomycin
Cefotetan, cefoxitin, clindamycin, metronidazole, ampicillin-sulbactam,
amoxicillin-clavulanate
Cefotaxime, ceftriaxone, ceftizoxime, clindamycin, a fluoroquinolone,
imipenem, meropenem, vancomycin, doxycycline
Azithromycin, clarithromycin, ceftriaxone, doxycycline,
Ampicillin ± (gentamicin, tobramycin, or amikacin), aztreonam, ampicil-
lin/sulbactam, amoxicillin/clavulanic acid, piperacillin/tazobactam,
trimethoprim/sulfamethoxazole, imipenem, meropenem, doripenem,
ertapenem, a fluoroquinolone, tigecycline
Clindamycin, cefoxitin, imipenem, meropenem
Cefaclor, cefuroxime, cefotaxime, cefpodoxime, ceftizoxime, ceftri-
axone, cefixime, a fluoroquinolone, doxycycline, clarithromycin,
azithromycin, ampicillin or amoxicillin ± penicillinase inhibitor
An aminoglycoside, aztreonam, a fluoroquinolone, imipenem,
meropenem, ertapenem, doripenem, amoxicillin/clavulanic acid,
ampicillin/sulbactam, piperacillin/tazobactam, ticarcillin/clavula-
nate, tigecycline, trimethoprim/sulfamethoxazole
Continued
468 CHAPTER 33  Pharmacology of Specific Drug Groups: Antibiotic Therapy

TABLE 33-5  Drugs Used to Treat Infections Caused by Specific Microorganisms—cont’d

Microorganism Drug of First Choice Alternative Drugs*
Legionella pneumophila Azithromycin or ciprofloxacin or other fluoroquinolone Erythromycin, doxycycline
Leptotrichia buccalis Penicillin G, penicillin V Clindamycin, doxycycline, erythromycin
Proteus mirabilis Ampicillin An aminoglycoside, a cephalosporin, a fluoroquinolone, ticarcillin/­
clavulanate, piperacillin/tazobactam, aztreonam, imipenem, mero-
penem, ertapenem, doripenem, trimethoprim-sulfamethoxazole
Pseudomonas aeruginosa Ticarcillin/clavulanate or piperacillin/ (Aztreonam, ceftazidime, cefepime, meropenem, doripenem, or
tazobactam ± an aminoglycoside, ciprofloxacin ­imipenem) + an aminoglycoside, levofloxacin
Salmonella typhi Ceftriaxone, ciprofloxacin, levofloxacin Amoxicillin, ampicillin, azithromycin, trimethoprim-sulfamethoxazole,
chloramphenicol
Shigella species A fluoroquinolone Trimethoprim-sulfamethoxazole, azithromycin, ceftriaxone
Other Microorganisms
Mycobacterium ­tuberculosis Isoniazid + rifampin + pyrazinamide ± ethambutol or Amikacin, kanamycin, cycloserine, moxifloxacin, levofloxacin,
streptomycin ­ciprofloxacin, ofloxacin, capreomycin, kanamycin, ethionamide,
para-aminosalicylic acid, bedaquiline (all in combinations)
Actinomyces israelii Penicillin G, penicillin V Doxycycline, erythromycin, clindamycin
Nocardia asteroides Trimethoprim/sulfamethoxazole ± amikacin +  A tetracycline, sulfisoxazole, amikacin, imipenem, meropenem,
imipenem or meropenem ­ceftriaxone, linezolid, cycloserine
Treponema pallidum Penicillin G Ceftriaxone, doxycycline
Chlamydia psittaci A tetracycline Azithromycin, a fluoroquinolone
Rickettsiae Doxycycline Azithromycin, clarithromycin, chloramphenicol
Candida albicans†
Oral lesions Clotrimazole, nystatin, miconazole Itraconazole, fluconazole, posaconazole, caspofungin (all for more
serious infections)
Systemic infections Fluconazole, itraconazole, caspofungin, anidulafungin, Posaconazole, amphotericin B
micafungin
Viruses†
Herpes simplex
Orolabial Acyclovir, famciclovir, valacyclovir Penciclovir, docosanol
Keratitis Trifluridine, ganciclovir
Genital infection Acyclovir, famciclovir, valacyclovir
Encephalitis Acyclovir
Human immunodeficiency virus Non-nucleoside reverse transcriptase
(preferred regimens) inhibitor-based regimen
Efavirenz + tenofovir disoproxil fumarate + emtricitabine
Protease inhibitor-based regimen
Atazanavir or darunavir + ritonavir + abacavir + 
tenofovir disoproxil fumarate + emtricitabine
Integrase strand transfer inhibitor-based
regimen
1. Raltegravir or elvitegravir/cobicistat + tenofovir
disoproxil fumarate + emtricitabine
2. Dolutegravir + either abacavir + lamivudine or
­tenofovir DF + emtricitabine
Influenza A and B Oseltamivir, zanamivir
*Listing does not include all alternative drugs.
†See Chapter 34 for discussion of antifungal and antiviral drugs.

Adapted from the following: Treatment guidelines: Antiviral drugs, The Medical Letter 127:19-30, 2013; Abramowicz M, Zuccotti G, editors: Hand-
book of antimicrobial drugs: drugs for bacterial infections, The Medical Letter ed 20, 2015, New Rochelle, NY;
Treatment guidelines: drugs for HIV infection, The Medical Letter vol. 12, issue 138:7-16, 2014.

a positive history of penicillin allergy have a four to six times greater
likelihood of a subsequent reaction than individuals with a negative
history. The serum half-life of penicillin IgE antibodies ranges from 10
to more than 1000 days; the risk of recurrent penicillin allergy is higher
in individuals with antibodies with long half-lives or repeated peni-
cillin exposures. Few data are available regarding whether the 60% to
85% not exhibiting allergy on re-exposure reacquire the IgE antibodies
to penicillin and then have an allergic reaction to the drug on the next
(third) exposure by resensitization.
Allergy Testing
Because IgE antibody levels to penicillin are variable, skin testing for
penicillin allergy becomes problematic. The incidence of positive skin
tests in individuals with a history of penicillin allergy ranges from 4%
 CHAPTER 33  Pharmacology of Specific Drug Groups: Antibiotic Therapy
to 91% depending on the accuracy of the patient history, the haptens
in the test solution, and the time elapsed between the allergic reaction
and the skin test.
Penicillin skin testing can be considerably valuable in determining
who might have a severe anaphylactic reaction. Approximately 95%
of penicillin-allergic individuals form the penicilloyl-protein conju-
gate (the major antigenic determinant), and approximately 5% form
the 6-aminopenicillanic acid and other minor antigenic determinants.
Penicillin skin tests with the major and minor antigenic determinants
eliciting a negative skin test virtually eliminate the risk for a serious
IgE-mediated reaction. A positive skin reaction to the minor determi-
nant mixture indicates a high risk for anaphylaxis.
Penicillins are primarily associated with IgE-mediated (Gell and
Coombs type I) allergic reactions, but they may also induce cytotoxic
(type II) or immune complex (type III) reactions. Type I signs and
symptoms include skin erythema, itching, angioedema, urticaria,
wheezing, hypotension, and bronchospasm resulting from mast cell/
basophil release of histamine along with other tissue allergic mediators.
Type II reactions are caused by circulating IgM or IgG antibodies that
attach to blood cells and induce blood dyscrasias, including hemolytic
anemia, leukopenia, thrombocytopenia, and aplastic anemia. Type III
reactions result from the deposition of soluble immune complexes on
blood vessels and basement membranes resulting in serum sickness,
vasculitis, and glomerulonephritis. Type IV, delayed-type hypersensi-
tivity reactions are mediated by T lymphocytes. (See figure 3-4.)
Allergic reactions to penicillins can also be classified according to
their time of onset. Immediate IgE reactions begin within seconds to
1 hour after drug exposure and are the most life-threatening (it is an
allergy truism that the more rapid the onset of the allergic reaction,
the more serious the consequences). Accelerated reactions begin 1 to
72 hours after antigen exposure and usually manifest as urticaria or
angioedema. Late reactions occur after 72 hours and are characterized
by type II and type IV (eczema-like) Gell and Coombs reactions. Of all
fatal anaphylactic reactions, 96% occur within the first 60 minutes after
penicillin exposure.
Other adverse reactions to penicillins are likely to be autoimmune
in origin and have an obscure etiology, including maculopapular
rashes, eosinophilia, Stevens-Johnson syndrome, and exfoliative der-
matitis. A maculopapular rash is seen in 2% to 3% of patients late in
penicillin therapy.
Nonallergic adverse effects. Piperacillin may cause abnormal
coagulation times and may produce abnormal liver function test
results. Large intravenous doses of penicillins, especially in patients
with compromised renal function, may induce hyperexcitability, sei-
zures, and hallucinations. This is due to sufficient drug getting across
the blood–brain barrier under these conditions. Amoxicillin is the
most common cause of antibiotic-induced diarrhea/colitis because of
its spectrum and widespread use. Penicillins are FDA pregnancy cate-
gory B drugs.
Approximately 5% to 10% of individuals receiving ampicillin or
amoxicillin may have a mild pruritic rash, usually beginning on the
trunk and extending to the face, extremities, and extensor portions of the
knees and elbows. This nonallergic “ampicillin/amoxicillin rash” is not
associated with antibody formation and is of unknown cause. It does not
seem to increase the risk of true penicillin allergy. The rash may begin
24 hours to 28 days after the drug is begun and may last 90 minutes to
7 days. The incidence of ampicillin/amoxicillin rash is 95% to 100% in
individuals with cytomegalovirus infection/mononucleosis and 22% in
individuals given ampicillin or amoxicillin with allopurinol.
Rare and reversible disorders reportedly associated with penicillins
include acute pancreatitis, neutropenia, aseptic meningitis, hepatotox-
icity, and increased prothrombin time/international normalized ratio
469
(INR) in patients taking oral anticoagulants either through impaired
platelet function or altered gastrointestinal microbial flora. Untoward
bleeding may also occur, even in patients not taking coumarin anti-
coagulants, and is dose-dependent, with a maximum effect 3 to 7 days
after penicillin is begun, with a return to a normal bleeding time in 72
to 96 hours; this bleeding has been reported after a dental extraction.
The mechanism is likely due to an altered adenosine 5’-diphosphate–
mediated platelet aggregation response and is seen most commonly in
patients with underlying chronic illnesses associated with hypoalbu-
minemia and uremia.
Drug interactions. Oral penicillins (penicillin G, penicillin
V, amoxicillin) may be antagonized by bacteriostatic antibiotics
(tetracycline, erythromycin, clindamycin). NSAIDs and probenecid
may increase the serum half-lives of penicillins by decreasing their renal
excretion. Individuals taking β-adrenergic blocking drugs, especially
nonselective ones, may cause a diminished or nonexistent response to
a β-adrenergic receptor agonist given for the treatment of penicillin-
induced anaphylactic bronchospasm. Ampicillin or amoxicillin, when
taken with allopurinol, can be associated with a non-urticarial rash.
Contraindications. Penicillins are generally contraindicated in
individuals allergic to the drugs, but it is well documented that some
individuals with a previous allergic history may subsequently tolerate
penicillins without allergic manifestations. The best policy is to refrain
if possible from penicillin administration to anyone with a positive
history. Penicillins may be contraindicated in some individuals taking
coumarin anticoagulants because untoward bleeding may occur, but
this seems to be highly unpredictable and rare in occurrence. Avoid the
concurrent use of amoxicillin or ampicillin with allopurinol.
Cephalosporins
The isolation of the fungus Cephalosporium acremonium (now
Acremonium chrysogenum) in 1948 by Brotzu from the harbor sew-
age of Sardinia and the subsequent isolation of the active nucleus
of cephalosporin C (7-amino-cephalosporinic acid) by Florey and
Abraham at Oxford University contributed in large measure to a
golden age in antimicrobial chemotherapy. The widespread use of
cephalosporins because of their broad antibacterial spectra and low
toxicity and allergenicity has resulted in widespread microbial resis-
tance to these agents.
Chemistry and classification (Table 33-6). Cephalosporins are
closely related to penicillins, with a six-membered dihydrothiazine
ring replacing the five-membered thiazolidine ring of penicillin
(Fig. 33-7). Both contain the β-lactam ring, as do the monobactams
and carbapenems discussed later. Side chain modification of the 7-APA
nucleus has led to differences in antibacterial spectrum, pharmacoki-
netics, susceptibility to various β-lactamase, affinity for different PBPs,
and occasionally adverse reactions.
Cephalosporins are most commonly classified according to their
“generations”: first generation (introduced in the 1960s), second gen-
eration (introduced in the 1970s), third generation (introduced in the
1980s), fourth generation (cefepime introduced in 1997), and fifth
generation (advanced generation) (ceftaroline, introduced in 2010).
Cephalosporins evolved from early agents primarily active against
gram-positive microorganisms (first generation) to agents with a greater
gram-negative spectrum (second generation) to agents with greater
activity against various nosocomial pathogens, including P. aeruginosa,
B. fragilis, and organisms producing extended-­spectrum and ampi-
cillin C (ampC) β-lactamases. The broad spectrum of cephalosporins
and their wide use have been major factors in microbial resistance to
these agents. Technically, second-generation agents include true ceph-
alosporins and cephamycins (cefoxitin, cefotetan, cefmetazole), which
are derived from Streptomyces rather than Cephalosporium.
470 CHAPTER 33  Pharmacology of Specific Drug Groups: Antibiotic Therapy

TABLE 33-6  Classification and Indications of Cephalosporins by Generations and Other β-Lac-
tam Antibiotics
Cephalosporins Major Indications
First Generation
Cefadroxil (Duricef)* Gram-positive cocci, (but not enterococci or methicillin-resistant Staphylococcus aureus)
Cefazolin (Ancef, Kefzol, Zolicef)† Klebsiella pneumoniae, Proteus mirabilis, Escherichia coli, dental prophylaxis (cephalexin,
Cephalexin (Biocef, Keflex, Keftab)* cefazolin)
Cephalothin (Keflin)†
Cephapirin (Cefadyl)†
Cephradine (Velosef)‡
Second Generation
Cefaclor (Ceclor)* Greater effect against some gram-negative organisms than first-generation drugs; cefotetan
Cefamandole (Mandol)† and cefoxitin have activity against anaerobes
Cefonicid (Monocid)†
Cefotetan (Cefotan)†
Cefoxitin (Mefoxin)†
Cefprozil (Cefzil)*
Cefuroxime (Ceftin, Kefurox, Zinacef)‡
Loracarbef (Lorabid)*
Third Generation
Cefdinir (Omnicef)* Penicillin-resistant S. pneumoniae, VGS, multidrug-resistant S. pneumoniae, ­enterococci, and
Cefixime (Suprax)* some β-lactamase–producing organisms
Cefoperazone (Cefobid)† Ceftazidime/avibactam is effective against Enterobacteriaceae, Pseudomonas ­aeruginosa,
Cefotaxime (Claforan)† and organisms producing extended-spectrum β-lactamases
Cefpodoxime (Vantin)*
Ceftazidime (Ceptaz, Fortaz, Tazicef, Tazidime)†
Ceftazidime/avibactam (Avycaz)†
Ceftibuten (Cedax)*
Cefditoren (Spectracef)*
Ceftizoxime (Cefizox)†
Ceftriaxone (Rocephin)†
Fourth Generation
Cefepime (Maxipime)† Gram-negative bacteria, cefepime is more resistant to many β-lactamases
Fifth Generation
Ceftolozane/tazobactam (Zerbaxa) Similar to third generation drugs, but extended-spectrum β-lactamases; effective vs
Ceftaroline (Teflaro)† Enterobacteriaceae, P. aeruginosa, other gram-negative bacteria and methicillin-
resistant S. aureus
Other Lactam Antibiotics
 Carbapenems
Imipenem (with cilastatin in Primaxin)† Highly resistant gram-negative bacilli, including some anaerobes, P. aeruginosa, Campylobacter
Meropenem (Meronem)† fetus, Citrobacter freundii, Enterobacter, Acinetobacter, Serratia marcescens, and Rhodococ-
Ertapenem (Invanz)† cus equi, MSSA, non-penicillin-resistant S. pneumoniae, Bacillus subtilis, Bacillus cereus,
Doripenem (Doribax)† Clostridium perfringens, Bacteroides, E. coli, K. pneumoniae, P. mirabilis, indole-positive
Proteus, Providencia stuartii, Capnocytophaga canimorsus, Haemophilus influenzae
Monobactams
Aztreonam (Azactam)† Aerobic gram-negative bacteria, Enterobacteriaceae, K. pneumoniae, P. mirabilis, C. freundii,
Yersinia enterocolitica, Pasteurella multocida, Salmonella, Shigella, Providencia, Neisseria,
Haemophilus, and P. aeruginosa
*Oral.
†Parenteral.
‡Oral and parenteral.

Adapted from Asbel LE, Levison M, Cephalosporins, carbapenems, and monobactams, Infect Dis Clin N Am 14:435-447, 2000; Facts and compar-
isons, St Louis, 2002, Facts and Comparisons; Karchmer AW, Cephalosporins, In Mandell GL, Bennett JF, Dolin R, editors: Principles and practice
of infectious diseases, ed 5, New York, 2000, Churchill Livingstone; Marshall WF, Blair JE, The cephalosporins, Mayo Clin Proc 74:187-195,
1999; Abramowicz M, Zuccotti G, editors: Handbook of antimicrobial drugs: drugs for bacterial infections, The Medical Letter ed 20, 2015,
New Rochelle, NY.
 CHAPTER 33  Pharmacology of Specific Drug Groups: Antibiotic Therapy 471

O General therapeutic uses. Cephalosporins have wide applications

H in the treatment of infections. The utility of these drugs depends on the
HN S generation. Table 33-6 lists indications for the cephalosporins. First-
generation drugs are used to treat infections caused by staphylococci
NH2 N
CH3
and streptococci. They also are useful in surgical and endocarditis
O prophylaxis. Some gram-negative bacilli, such as P. mirabilis and K.
HO O pneumoniae, may be sensitive. A subset of second generation drugs
Cephalexin represented by cefoxitin has good activity against many gram-negative
HO
O
anaerobes.
O
Third-generation drugs have become prominent in the treatment
N
of serious gram-negative coccal and bacillary infections. They are
S very useful in treating meningitis, pneumonia, gonorrhea, and sepsis
H3C
from sensitive organisms. Cephalosporins are often given with ami-
H H noglycosides for gram-negative bacilli infections. There are significant
HN
HO individual differences between members of the third-generation drugs,
NH and not all indications apply to each member. Cefepime is resistant
Imipenem
to many β-lactamases and is effective in treating some gram-nega-
H 2N S tive bacilli that produce β-lactamases. Ceftaroline has activity against
methicillin-resistant staphylococci as well as several gram-negative
N O CH3
O
organisms (see Table 33-6).
Therapeutic uses in dentistry. Cephalosporins have good
N HN N S OH
activity against many orofacial pathogens but limited activity against
O
H 3C O oral anaerobes. These β-lactam antibiotics are also time-dependent
O agents without significant post-antibiotic effects, and the serum and
H3C OH
tissue concentrations of cephalosporins should remain greater than
O the organism’s MIC for at least 60% of the dosing interval to retard
Aztreonam organism regrowth as much as possible. Presently, some cephalosporins
FIG 33-7 Structural formulas for cephalexin, imipenem, and the are choices for prophylaxis during dental procedures; however, these
monobactam aztreonam. Notice the lack of a second ring fused to the drugs are not indicated in acute dental infections unless culture and
­β-lactam ring in aztreonam. sensitivity testing indicate otherwise.
Adverse effects. Serious adverse reactions associated with
cephalosporins are rare, with the major concern being the potential
Mechanism of action. Cephalosporins possess a mechanism for cross-allergy with penicillins. Less common adverse reactions
of action identical to penicillins: inhibition of bacterial cell wall include transient increases in liver enzymes, nephrotoxicity, reversible
peptidoglycan synthesis by inhibition of penicillin-sensitive enzymes neutropenia, eosinophilia and thrombocytopenia, aseptic meningitis,
(transpeptidases, carboxypeptidases) that are responsible for the and disulfiram-like reactions associated with cephalosporins with the
final three-dimensional structure of the rigid bacterial cell wall. methylthiotetrazole side chain (e.g., cefotetan).
Each bacterial species may have different PBPs, and the affinity of The inherent allergic potential of cephalosporins along with their
cephalosporins for these PBPs can vary greatly. Most cephalosporins cross-allergenicity with penicillins is of major concern. Cutaneous
bind to PBP1 and PBP3 of gram-negative organisms, and depending allergic reactions to cephalosporins (rash, pruritus, urticaria) are com-
on which PBPs are inhibited, the resulting bacterial cells may take monly reported to occur in 1% to 3% of patients. Serum sickness or a
different shapes: oval, round, or filamentous. morbilliform rash may be seen in children receiving cefaclor. Stevens-
Bacterial resistance. The major mechanism of resistance to Johnson syndrome and toxic dermal necrolysis have been reported.
cephalosporins is the microbial elaboration of various β-lactamases Anaphylactic reactions to cephalosporins seem to be rare, with
(cephalosporinases). First-generation agents are very sensitive to an incidence ranging from 0.0001% to 0.1% of individuals exposed.
β-lactamase hydrolysis, with the second to fifth generations more In 9388 patients without a history of penicillin allergy given cepha-
resistant to β-lactamases. losporins, two anaphylactic reactions were reported (0.2%). In a ret-
Absorption, fate, and excretion. Oral cephalosporins are gen- rospective study of 350,000 adverse drug reactions, six fatal cases of
erally well absorbed, with all except cefadroxil and cefprozil having cephalosporin-induced anaphylaxis were reported, with three of the
their absorption delayed, but not reduced, by food. Cephalosporins six cases in patients with a history of penicillin allergy.
are hydrophilic and widely distributed in extracellular fluid, but they The issue of cross-sensitivity between the cephalosporins and pen-
do not enter the cells of the immune system (macrophages, polymor- icillins has never been satisfactorily resolved. Estimates range from
phonuclear leukocytes), as do lipophilic macrolides, tetracyclines, 1.1% (the same as the allergy incidence to cephalosporins in the gen-
and lincosamides. Plasma protein binding is 10% for cephalexin, eral population) to 18% in the earliest studies. Penicillin-allergic indi-
25% for cefaclor, 8% to 17% for cephradine, and 80% to 90% for viduals may have a fourfold greater risk of allergy to cephalosporins
cefazolin and cefoxitin. Excretion of most cephalosporins takes place than individuals not allergic to penicillins; however, penicillin-allergic
mainly by glomerular filtration and active tubular secretion in the individuals have a three to four times greater risk of allergy to any drug.
kidney. The serum half-life is 50 to 80 minutes for cephalexin, 48 No skin test is available to detect cephalosporin allergy, and experience
to 80 minutes for cephradine, and 35 to 54 minutes for cefaclor. In with desensitization is limited and not standardized.
patients with end-stage renal disease, these half-lives may increase to Cephalosporins are generally contraindicated in patients with a
19 to 22 hours for cephalexin, 8 to 15 hours for cephradine, and 2 to positive penicillin skin test to the minor determinant mixture or a
3 hours for cefaclor. history of local or systemic penicillin anaphylaxis (severe urticaria,
472 CHAPTER 33  Pharmacology of Specific Drug Groups: Antibiotic Therapy

bronchospasm, hypotension, exfoliative dermatitis), unless cephalo-

TABLE 33-7  Macrolide Preparations
sporins are mandated in the management of a life-threatening infec-
tion, and anaphylaxis antidotal therapy is readily available.
­Available in the United States
Drug interactions. Antacids, H2 histamine receptor antagonists, Nonproprietary (Generic) Name Proprietary (Trade) Name
proton pump inhibitors, as well as iron supplements may reduce Erythromycin base (film-coated) Erythromycin Filmtabs
the oral absorption of some cephalosporins. Food decreases the oral Erythromycin (enteric-coated) E-Base, E-Mycin, Ery-Tab, Eryc
absorption of cefuroxime and cefpodoxime. Some cephalosporins Erythromycin stearate Erythrocin stearate
such as cefotetan may induce a disulfiram reaction with ethanol and Erythromycin ethylsuccinate E.E.S., EryPed
may cause hypoprothrombinemia. Nephrotoxicity may be seen with Erythromycin lactobionate —
the combination of cephalosporins with aminoglycosides or loop Clarithromycin Biaxin
diuretics. Azithromycin Zithromax
Contraindications. Cephalosporins are contraindicated in patients Dirithromycin Dynabac
allergic to these drugs and in individuals with a history of severe Troleandomycin TAO
penicillin reactions or a positive skin test reaction to the penicillin
minor determinant mixture.
O
Other β-lactam antibiotics
H3C CH3
Carbapenems. Carbapenems are derivatives of thienamycin (from
Streptomyces cattleya) and differ from penicillins by the replacement OH OH H3C
H3C CH3 HO
of the sulfur by a methylene group in the five-membered ring of the N CH3
OH
β-lactams (see Fig. 33-7). Currently, four carbapenems are available
H 3C
for parenteral use in the United States: imipenem, meropenem, O O
ertapenem, and doripenem. Imipenem is combined with cilastatin to O
CH3
reduce the hydrolysis of imipenem by renal dehydropeptidase. O O O CH3 CH
3
Carbapenems have a very wide antibacterial spectrum, have a high CH3
specificity for PBP2 of gram-positive and gram-negative microorgan-
OH
isms (resulting in ovoid organisms), and are not hydrolyzed by most
H 3C O CH3
β-lactamases. Their indications are listed in Table 33-6.
Microbial resistance to carbapenems is via the loss of an outer
membrane protein, resulting in retarding cell wall penetration of the Erythromycin
drugs, altered PBPs in Enterococcus faecium and MRSA, and hydrolysis FIG 33-8  Structure of erythromycin.
by metallo β-lactamases and other β-lactamases.
Carbapenems are classified as FDA pregnancy category B or C erythromycin A and a 14-membered macrolide with a 3-keto group
drugs, are cross-allergenic with other β-lactams, may increase the level substitution.
of serum liver transaminases, may induce PMC, and are associated
with a 3% to 4% incidence of skin rash. Imipenem, meropenem, and Mechanism of action and antibacterial spectrum
ertapenem are associated with increased central nervous system (CNS) The mechanism of action of macrolides is to bind reversibly to the P
toxicity and seizures. Doripenem has a lower risk of CNS toxicity. site of the 50S ribosomal subunit and inhibit RNA-dependent pro-
Monobactams. Aztreonam is a monocyclic β-lactam (monobac- tein synthesis by stimulating the dissociation of peptidyl transfer
tam) lacking the thiazolidine ring of penicillin (see Fig. 33-7). It is RNA (tRNA) from the ribosome (Fig. 33-9). Erythromycin is active
available only parenterally. It does not bind to the PBPs of gram-pos- against gram-positive aerobic/facultative staphylococci and strepto-
itive or anaerobic microorganisms; its spectrum is limited to aerobic cocci, gram-negative anaerobes (M. catarrhalis, Bordetella pertussis,
gram-negative species. Specific organisms are listed in Table 33-6. Legionella pneumophila), and Mycoplasma pneumoniae. It is also active
Aztreonam is not the initial drug of choice for any infection. It is not against organisms listed in Table 33-8 (see also Table 33-5).
indicated in dental infections. Microorganisms generally resistant to macrolides include H. influ­
Aztreonam is an FDA pregnancy category B drug and lacks cross-al- enzae, Peptostreptococcus, Aggregatibacter actinomycetemcomitans,
lergenicity with β-lactams. Aztreonam induces β-lactamase produc- Pasteurella, Fusobacterium, Mycobacterium tuberculosis, MRSA, and
tion and may be synergistic with the renal toxicity and ototoxicity of Enterobacteriaceae. Marginally affected organisms include Prevotella
aminoglycosides. and Porphyromonas.
Clarithromycin and azithromycin have special indications because
Macrolide and Ketolide Antibiotics they are more active against some organisms than is erythromycin, or
Chemistry and classification (Table 33-7; Fig. 33-8) in some cases in which erythromycin is not active. (See Table 33-5.)
Macrolide antibiotics are characterized by large 14-membered,
15-membered, or 16-membered lactone rings. Erythromycin, as Bacterial resistance
derived from Streptomyces erythreus, was introduced in 1952, and The major mechanism for microbial resistance is demethylation of the
azithromycin and clarithromycin were introduced in 1991 and 1992, 2058 residue of the gene coding for the 23S ribosomal RNA peptidyl
respectively. Azithromycin is a 15-membered macrolide with an transferase region, resulting in reduced macrolide binding (ribosomal
added nitrogen and N-methylation (making it technically an azalide), protection). The erm (erythromycin-resistant methylase) gene respon-
whereas clarithromycin is formed by the alkylation of a hydroxyl group sible for the ribosomal protection is often associated with tetracycline
of erythromycin (a 14-membered ring). Troleandomycin is a synthetic resistance genes and is frequently combined with the resistance genes
derivative of oleandomycin, dirithromycin is a prodrug yielding eryth- for lincosamides (clindamycin) and streptogramins (quinupristin-dal-
romycylamine in the intestine, and telithromycin is a derivative of fopristin) to form the macrolide-lincosamide-streptogramin B (MLSB)
 CHAPTER 33  Pharmacology of Specific Drug Groups: Antibiotic Therapy 473

Growing polypeptide

Chloramphenicol
binds to 50S portion inhibiting
formation of peptide bond

50S
portion

Tetracycline
interferes with attachment of
tRNA to mRNA-ribosome complex

Macrolides
Linezolid bind to 50S portion preventing
Binds to 50S portion translocation movement of
and inhibits initiation ribosome along mRNA
of protein synthesis

mRNA

Direction of
30S ribosome travel
portion
Aminoglycosides
bind to 30S portion inhibiting
translation and causing code
on mRNA to be read incorrectly
70S bacterial
ribosome
FIG 33-9  Sites of inhibition of bacterial ribosomal protein synthesis by various drugs.

TABLE 33-8  Macrolides as Agents of Absorption, fate, and excretion

Choice or Alternative Drugs* Erythromycin and azithromycin are available for oral and intravenous
use, whereas the remaining agents are used only orally. Bioavailability
Drugs of Choice Alternative Agents
ranges from 10% for dirithromycin to 40% to 50% for azithromycin,
Bartonella henselae Actinomyces israelii clarithromycin, and erythromycin. Food in the stomach may increase
Bartonella quintana Bacillus anthracis or have no effect on the absorption of azithromycin, but the remain-
Bordetella pertussis Borrelia burgdorferi ing macrolides should be taken 1 hour before or 2 hours after a meal,
Campylobacter jejuni Capnocytophaga canimorsus except for estolate and ethylsuccinate salts of erythromycin, which may
Chlamydia trachomatis Chlamydia pneumoniae be taken without regard to meals. (Note, however, that the estolate
Corynebacterium diphtheriae Eikenella corrodens form of the drug has a higher risk of hepatic toxicity.)
Corynebacterium jeikeium Erysipelothrix rhusiopathiae Erythromycin base is poorly resistant to gastric acid and is
Haemophilus ducreyi Leptotrichia buccalis prepared with enteric coating or as various salts (stearate), esters
Helicobacter pylori Mycobacterium leprae (ethylsuccinate), or salts of esters (estolate), which protect against
Legionella pneumophila Streptococcus pneumoniae gastric acid degradation. Macrolides are best absorbed in the small
Mycobacterium avium Streptococcus pyogenes intestine, and when given orally in standard doses, generally pro-
Mycobacterium kansasii duce adequate tissue MIC concentrations. Erythromycin may have
Mycobacterium marinum a variable absorption rate. The time to maximum blood concentra-
Mycoplasma pneumoniae tions of the macrolides after oral administration is about 2 hours.
Ureaplasma urealyticum Impaired renal function may reduce the excretion of the macrolides,
*Specific macrolide(s) for most indications are listed in Table 33-5.
with the elimination half-life of erythromycin increasing from 1.6
Drug combinations are used in some cases. to 5-6 hours in anuric patients. Clarithromycin and erythromycin
Abramowicz M, Zuccotti G, editors: Handbook of antimicrobial drugs: are primarily eliminated in the urine, and azithromycin is primar-
drugs for bacterial infections, The Medical Letter ed 20, 2015, New ily eliminated in the bile, although erythromycin may also undergo
Rochelle, NY. significant biliary excretion. The average serum half-lives are
∼68 hours for azithromycin, 3 to 7 hours for clarithromycin, and
aggregate, which confers resistance to all three antibiotic groups simul- ∼1.6 hours for erythromycin.
taneously. Other macrolide resistance mechanisms include active A remarkable property of macrolides and highly fat-soluble tetracy-
efflux genes encoding for transport efflux proteins and an esterification clines and clindamycin is selective uptake by phagocytic cells and fibro-
gene that codes for inactivation of the macrolides by phosphorylation blasts, which function as repository drug depots and as a drug delivery
and glycosylation. system to areas of inflammation and infection. These cells concentrate
474 CHAPTER 33  Pharmacology of Specific Drug Groups: Antibiotic Therapy
the macrolides and then transport them to areas of tissue pathology
where they are released for their antiinfective and antiinflammatory
properties. The tissue concentrations of azithromycin may reach 100
to 1000 times that of blood and persist long after blood levels have
declined because of their significant post-antibiotic effects. The tissue
concentration of azithromycin may exceed the microorganism’s MIC
for 2 to 10 days, and the elimination half-life in abscesses may be 4 days.
General therapeutic uses
Macrolides are often indicated for treating community-acquired bac-
terial pneumonia because of their action against numerous causative
organisms. Microbial resistance is becoming increasingly common,
however. They are useful against various chlamydial infections and
numerous gram-positive coccal infections, and they are also active
against Corynebacterium (see Table 33-8). The 14-membered macro-
lides possess antiinflammatory effects distinct from their antimicrobial
actions by decreasing proinflammatory cytokine release from phago-
cytes, which may prove useful in management of rheumatoid arthritis,
cystic fibrosis, asthma, and chronic sinusitis.
Therapeutic uses in dentistry
Erythromycin has a long and successful history of use against acute
orofacial infections, particularly in β-lactam–allergic patients. Its
spectrum of activity is good to excellent against gram-positive aero-
bic/facultative cocci (streptococci, some staphylococci). Its spectrum
is not generally favorable against gram-negative anaerobes associ-
ated with orofacial infections, including Prevotella, Porphyromonas,
Fusobacterium, and Veillonella. Azithromycin has been observed to
be effective against oral spirochetes and pigmented anaerobes. In the
management of acute periapical abscesses, azithromycin, 500 mg/day
for 3 days, has shown comparable efficacy to amoxicillin/clavulanic
acid, 625 mg three times daily for 5 to 10 days. Macrolides are also use-
ful for endocarditis prophylaxis. Due to its associated hepatic toxicity,
there is no reason for using the estolate form of erythromycin in dental
applications.
Clarithromycin is most active against gram-positive anaerobes
(Actinomyces, Propionibacterium, Lactobacillus), whereas erythromycin
is more active than azithromycin for these organisms. Azithromycin
has the best activity against gram-negative anaerobes (Fusobacterium,
Prevotella, Porphyromonas, Wolinella, Selenomonas, and A. actinomyce­
temcomitans). Azithromycin may be more active against streptococci
and staphylococci than erythromycin and clarithromycin and has
much less propensity for drug interactions. Prolonged use of erythro-
mycin and possibly other macrolides may lead to superinfection with
gram-negative enteric bacilli.
Adverse effects
Serious toxicity with macrolides is rare but occasionally significant.
The most important adverse effects include epigastric pain, ototoxicity
(deafness), ventricular arrhythmias (torsades de pointes), acute pan-
creatitis, mania, cholestatic hepatitis, hypersensitivity syndrome, and
certain drug interactions.
Cholestatic hepatitis is much more common with the estolate
form of erythromycin than with other forms of erythromycin or
other macrolides. This reaction can be misdiagnosed as viral hepatitis.
Symptoms usually appear after approximately 10 days of erythromycin
use, disappear 2 to 4 weeks after drug discontinuance with no residual
effects, and readily reappear with drug readministration. This reaction
is less common in children.
The most common serious adverse reaction associated with mac-
rolides, particularly erythromycin, is potentially severe epigastric
pain resulting from stimulation of the gastric smooth muscle motilin
receptor. Motilin is a regulatory peptide of the gastrointestinal tract
that stimulates enzyme secretions by the stomach and pancreas and
induces strong phasic contractions of the stomach. The most sig-
nificant agonists of the motilin receptor are the 14-membered mac-
rolides (erythromycin); azithromycin and clarithromycin are lesser
stimulants.
Approximately 30 cases have been reported of macrolide-induced
hearing loss, with at least two cases judged to be irreversible. Most
seem to be associated with erythromycin doses exceeding 4 g/day or
from accumulation of lesser doses in patients with impaired renal or
hepatic function. In patients with renal impairment, the dose of eryth-
romycin should be no greater than 1.5 g/day. Ototoxicity is particularly
common in patients with HIV/AIDS because of the use of macrolides
as prophylaxis for Mycobacterium avium infections. All macrolides
induce ototoxicity, possibly by an effect on the auditory nerve path-
ways, and tinnitus has been observed even with therapeutic doses of
azithromycin.
Long QT syndrome is characterized by delayed ventricular repo-
larization that triggers ventricular tachyarrhythmias, most notably
torsades de pointes, resulting in syncope, seizures, or sudden death.
Long QT syndrome may be either congenital or acquired, and the
list of drugs, diseases, and metabolic disorders inducing torsades de
pointes is long and impressive. Susceptible patients are at greater risk
of drug-induced torsades.
At least four cases of acute pancreatitis associated with erythromy-
cin have been reported, and several cases of mania have been asso-
ciated with clarithromycin in patients with and without HIV/AIDS.
Stevens-Johnson syndrome (erythema multiforme) may occur with
erythromycin along with a hypersensitivity syndrome associated with
azithromycin and clarithromycin consisting of fever, rash, hepatitis,
interstitial nephritis, oliguria, and xerostomia. Azithromycin and
erythromycin are classified as FDA pregnancy category B drugs, and
clarithromycin is classified as an FDA pregnancy category C drug.
Drug interactions
Erythromycin and clarithromycin, primarily through their inhibition
of the liver microsomal enzyme drug metabolizing and secondarily
through their effect on gastrointestinal microbial flora, increase serum
levels of fluconazole, ranitidine, alfentanil, benzodiazepines, tacrolimus,
theophylline, vinblastine, bromocriptine, buspirone, carbamazepine,
cyclosporine, digoxin, disopyramide, ergot alkaloids, felodipine, oral
anticoagulants, methylprednisolone, and omeprazole. Azithromycin has
much less effect on the liver microsomes. Macrolide blood levels may
be increased by fluconazole and decreased by theophylline. Antacids
reduce the rate, but not the total amount, of macrolide absorption, and
the combination of macrolides and oral contraceptives may result in
cholestasis. Bacteriostatic macrolides may interfere with the bactericidal
effect of cell wall inhibitors. Concomitant administration with a fluoro-
quinolone, or pimozide, may lead to torsades de pointes.
After only 3 days of administration, macrolides may seriously
reduce digoxin metabolism in the gastrointestinal tract by Eubacterium
lentum, resulting in digitalis toxicity because the microorganism may
metabolize 30% to 40% of the drug. Macrolides may potentiate the
anticoagulant effect of oral anticoagulants. Concomitant use of mac-
rolides may increase the myopathy and rhabdomyolysis seen with the
“statin” anti-cholesterol agents.
Contraindications
Macrolides are contraindicated in patients with allergy to the drugs
in patients with a history of previous allergic cholestatic hepatitis.
Macrolides are also contraindicated in combinations with other drugs
with which they interact, such as those that induce torsades de pointes.
 CHAPTER 33  Pharmacology of Specific Drug Groups: Antibiotic Therapy
The maximum daily dose should be 4 g in adults with normal renal
function and 1.5 g/day in patients with impaired renal function.
Ketolides
Ketolides (telithromycin) are derivatives of erythromycin A specifically
designed for activity against bacteria responsible for community-acquired
respiratory tract infections. Telithromycin is a 14-membered macrolide
with a 3-keto group substitution. The oral bioavailability of telithromy-
cin is approximately 55%, with maximum serum concentrations at 1 to
3 hours. The elimination half-life is about 13 hours; the drug has a long
post-antibiotic effect and is highly concentrated in white blood cells and
pulmonary tissue. It is primarily metabolized in the liver. Telithromycin
inhibits bacterial protein synthesis by binding to the 50S ribosomal sub-
unit to inhibit translation at the peptidyl transferase site. The drug also
inhibits formation of the bacterial 50 and 30S ribosomal subunits.
Telithromycin is active against a wide spectrum of respiratory
pathogens, including S. pneumoniae, H. influenzae, M. catarrhalis, C.
pneumoniae, M. pneumoniae, L. pneumophila, group A and B strepto-
cocci (S. pyogenes and Streptococcus agalactiae).
The most frequent adverse reactions associated with telithromycin
are diarrhea (12% to 20%), nausea (2% to 12%), dizziness (2% to 5%),
and headache (2.5% to 5%). A major concern is the drug’s association
with liver toxicity. Telithromycin is an inhibitor of the liver microsomal
enzyme cytochrome P450 system and would be expected to increase blood
levels of many drugs. Similar to macrolides, telithromycin may prolong
the QT interval. It is classified as an FDA pregnancy category B drug.
Telithromycin has no place in the management of acute or chronic
orofacial infections unless dictated by sensitivity testing. Its use is lim-
ited in the United States to community-acquired bacterial pneumonia.
Lincosamides
Clindamycin and lincomycin are the only lincosamide antibiotics.
Lincomycin was isolated from Streptomyces lincolnensis in 1962, and
clindamycin (7-chloro-7-deoxy-lincomycin) was introduced in 1966.
Clindamycin (Fig. 33-10) is used almost exclusively because of its
greater efficacy and superior pharmacokinetics.
Mechanism of action and antibacterial spectrum
The receptor site for lincosamides is identical to that of macrolides,
chloramphenicol, and streptogramins: the 23S subunit of the 50S bac-
terial ribosome, resulting in bacteriostatic inhibition of microbial
protein synthesis. Clindamycin has significant activity against many
gram-positive and gram-negative anaerobic and facultative/aero-
bic microorganisms. The major indications are listed in Table 33-9.
Clindamycin has indications for some oral infections.
Bacterial resistance
Resistance to clindamycin occurs by three mechanisms: (1) alteration
of 23S ribosomal RNA of the 50S ribosomal subunit by adenine meth-
ylation (ribosomal protection), (2) an altered single 50S ribosomal
protein at the receptor site (receptor alteration), or (3) inactivation in
Cl
CH3 O H CH3
N Actinomyces israelii
N
O CH3
H Fusobacterium species
HO S
H3C
HO OH
Clindamycin
FIG 33-10  Structure of clindamycin.
475
some staphylococcal strains by a nucleotidyl transferase (drug inacti-
vation). Adenine methylation is plasmid mediated and confers MLSB
resistance. The M phenotype macrolide resistance in S. pneumoniae
does not confer resistance to clindamycin. If erythromycin resistance
in staphylococci is inducible and not constitutive, the microorganisms
are resistant only to the 14-membered and 15-membered macrolides
and remain sensitive to lincosamides, streptogramins, and 16-mem-
bered macrolides. Constitutive resistance in staphylococci of the MLSB
type confers resistance to all these antibiotics simultaneously.
Absorption, fate, and excretion
Clindamycin is well absorbed orally with a 90% bioavailability not
appreciably reduced by food. The time to oral peak serum levels is 45
to 60 minutes, with an elimination half-life of 2.4 to 3 hours. With renal
failure the elimination half-life increases to 6 hours, with a doubling of
the serum level. The drug penetrates well into bone but not cerebro-
spinal fluid; is metabolized primarily in the liver (>90%); and is highly
concentrated in the bile, where it may alter colonic flora for 2 weeks
after it is discontinued. In a manner similar to macrolides, clindamy-
cin is concentrated preferentially in polymorphonuclear cells, alveolar
macrophages, and abscess tissue.
General therapeutic uses
Clindamycin is used in the treatment of certain infections caused by
susceptible strains of streptococci, staphylococci, pneumococci, or
anaerobes such as Bacteroides. Clindamycin may be indicated in the
treatment of refractory bone infections. Clindamycin is also useful in
treating certain conditions involving anaerobes, such as infections of
the female genital tract, pelvic infections, and abdominal penetrat-
ing wounds (see Table 33-5). It can also be used in combination for
Pneumocystis carinii and for toxoplasmosis.
Therapeutic uses in dentistry
Although amoxicillin and penicillin V remain drugs of choice for acute
orofacial infections, a resurgence in clindamycin use may be appropri-
ate as the oral microbial resistance to β-lactams continues to increase.
It is anticipated that oral microbial resistance to clindamycin will also
increase proportionately along with the specter of MLSB resistance
shared with macrolides and streptogramins.
Adverse effects
Minor adverse reactions associated with clindamycin include nau-
sea and vomiting, abdominal pain, esophagitis, glossitis, stomatitis,
TABLE 33-9  Indications for Clindamycin*
Methicillin-sensitive Staphylococcus aureus
Streptococcus pyogenes
Streptococcus pneumoniae
VGS
Peptostreptococcus
Bacillus anthracis
Clostridium perfringens
Leptotrichia buccalis
Capnocytophaga canimorsus
Bacteroides (oropharyngeal strains)
*Abramowicz M, Zuccotti G, editors: Handbook of antimicrobial drugs:
drugs for bacterial infections, The Medical Letter ed 20, 2015, New
Rochelle, NY.
476 CHAPTER 33  Pharmacology of Specific Drug Groups: Antibiotic Therapy
allergy, reversible increase in serum transaminase levels, reversible
myelosuppression, metallic taste, maculopapular rash (3% to 10%),
and diarrhea (2% to 20%, average of 8%). High intravenous doses of
clindamycin may result in a neuromuscular blockade similar to that of
aminoglycosides.
The major concern with clindamycin has been its purported pro-
pensity to cause antibiotic-induced diarrhea and colitis, most nota-
bly PMC, based on early reports of incidences reaching 10%. It is now
apparent that the association of clindamycin with these colonic disor-
ders in outpatient use is less than previously reported, although none-
theless real. Although antibiotic-associated diarrhea is common in the
outpatient environment and readily managed by drug discontinuance,
serious antibiotic-induced colitis and potentially lethal PMC is more
rare.
Care should be taken with patients who have recently recovered
from C. difficile–associated diarrhea or colitis for 2 months after
the cessation of the disease. Any elective dental procedure requiring
antibiotic therapy or prophylaxis is best postponed for this 2-month
period. If antibiotic therapy is required, antibiotics far less associated
with antibiotic-induced diarrhea (e.g., penicillin V, macrolides) are
appropriate.
Drug interactions
Clindamycin acts synergistically with nondepolarizing (curare-like)
neuromuscular blocking drugs in blocking neurotransmission at skel-
etal muscle. Oral absorption of clindamycin is slowed by kaolin-pectin
antidiarrheal drugs.
Contraindications
Clindamycin is contraindicated in patients allergic to the drug and in
combination with curare-like neuromuscular blocking drugs. All anti-
biotics should be avoided if possible for 2 months after antibiotic-in-
duced colitis.
Metronidazole
Metronidazole (Fig. 33-11) is a synthetic nitroimidazole patterned
after a naturally occurring antiparasitic substance that was isolated
from a Streptomyces species in 1955. The drug was introduced into
medicine in 1959 and was quickly found to possess strong tricho-
monacidal activity. Since then, metronidazole has become the drug
of choice for various protozoal infections. A chance observation
that the symptoms of acute necrotizing ulcerative gingivitis were
relieved in a woman receiving metronidazole for the treatment of
vaginal trichomoniasis stimulated research on the drug’s antibac-
terial effects, culminating in its approval in 1981 for the treatment
of anaerobic bacterial infections. Its extensive use in treating para-
sitic diseases worldwide has led to significant resistance to the drug
where parasites are a major problem. It was soon discovered that
the drug possessed exceptional activity against obligate anaerobic
and microaerophilic microorganisms, including microorganisms
OH
O
N
N+ CH3
–O
N are commonly resistant to metronidazole. The combination of metro-
Metronidazole
FIG 33-11  Structure of metronidazole.
involved in acute orofacial infections, periodontitis, and acute nec-
rotizing ulcerative gingivitis.
Mechanism of action and antibacterial spectrum
The antimicrobial activity of metronidazole requires entry into the cell
and reduction of its nitro group to produce metabolites that damage
DNA, eventually inducing cell death. Metronidazole is active only
against bacteria that are obligate anaerobes. It is a concentration-
dependent rather than time-dependent antibiotic. Because metroni-
dazole metabolites interfere with nucleic acid synthesis, concerns have
been raised regarding its potential for mutagenicity, carcinogenicity,
and teratogenicity.
Metronidazole penetrates all bacterial cells equally well. In sensitive
anaerobes, the nitro moiety of the drug is enzymatically reduced, how-
ever, and this metabolite is the active form of the drug. Metronidazole
is almost always bactericidal. The drug reacts with bacterial DNA,
causing inhibition of DNA replication, fragmentation of existing DNA,
and in low doses, mutation of the bacterial genome.
Bacterial resistance
Microbial resistance to metronidazole is limited probably because
of its limited clinical use, except in developing countries, where it is
widely used to manage parasitic diseases. A notable exception to this
generalization is the high level of resistance in H. pylori in developed
countries. Resistance to metronidazole is chromosomally mediated
and plasmid-mediated by a reduction in activity or expression of sev-
eral genes (rdxA, nimA, nimB) that control nitroreductase activity,
which reduces the concentration of active metronidazole metabolites
within the microbial cell.
Subinhibitory concentrations of metronidazole may increase resis-
tance rates in various periodontal pathogens, including Fusobacterium,
Prevotella, Porphyromonas, and Peptostreptococcus. Bacteroides strains
resistant to metronidazole also acquire enhanced virulence properties.
Absorption, fate, and excretion
Metronidazole is almost completely absorbed from the gastrointestinal
tract (oral bioavailability approaches 100%) so that serum levels are
essentially the same whether the drug is administered orally or intra-
venously. Food may delay peak serum levels of metronidazole but not
the total amount absorbed. Metronidazole attains a peak blood level
orally in 1 to 2 hours, has a wide volume of distribution, has excellent
CNS penetration, has an elimination half-life of 8 hours, and is bio-
transformed into five metabolic products, all of which have anti-an-
aerobic activity. The pharmacokinetics of metronidazole are the same
in pregnant and nonpregnant women, its metabolism is reduced in the
presence of severe hepatic dysfunction, and its pharmacokinetics are
not significantly altered with renal impairment.
General therapeutic uses
The principal medical indications for metronidazole are anaerobic
abdominal and CNS infections, bacterial vaginosis, protozoan and H.
pylori infections, and the management of C. difficile–associated diar-
rhea and colitis. Metronidazole is very active against obligate anaer-
obes (e.g., Bacteroides, Porphyromonas, Prevotella, Fusobacterium,
Peptostreptococcus, Clostridium), many of which are associated with
periodontitis, and various human parasites (e.g., Trichomonas vaginalis,
Gardnerella vaginalis, Entamoeba histolytica, Balantidium coli). A. acti­
nomycetemcomitans, E. corrodens, Actinomyces, and Propionibacterium
nidazole with amoxicillin may significantly enhance its activity against
A. actinomycetemcomitans, apparently by increasing cellular uptake of
metronidazole.
 CHAPTER 33  Pharmacology of Specific Drug Groups: Antibiotic Therapy
Therapeutic uses in dentistry
Metronidazole is highly effective against gram-negative anaerobic
pathogens responsible for acute orofacial infections and chronic peri-
odontitis. Combination of metronidazole with a β-lactam antibiotic
for oral infections may be indicated for serious acute orofacial infec-
tions and in the management of aggressive periodontitis.
Metronidazole is a concentration-dependent, not time-dependent,
antibiotic. The promiscuous use of metronidazole for classic chronic
periodontitis is a misuse of the drug and may contribute to the increas-
ing resistance of metronidazole seen with parasites, H. pylori, and other
microorganisms.
Adverse effects
Minor adverse reactions associated with metronidazole include revers-
ible neutropenia, metallic taste, dark or red-brown urine, skin rash,
urethral or vaginal burning sensation, gynecomastia, and nausea and
vomiting. Rare major adverse reactions include pancreatitis; PMC;
peripheral neuropathy; disulfiram reaction when combined with
ethanol; and CNS toxicity consisting of seizures, encephalopathy, cer-
ebellar dysfunction, paresthesias, mental confusion, and depression.
These neurologic reactions generally occur only with high, prolonged,
cumulative doses.
Because metronidazole affects DNA synthesis, numerous studies
have addressed its potential to cause birth defects. Its use in pregnancy
does not seem to be associated with any congenital abnormalities,
preterm delivery, or low birth weight in newborns, and the drug has an
FDA pregnancy category B classification.
Drug interactions
Barbiturates may reduce the efficacy of metronidazole, and cimeti-
dine may reduce its liver metabolism. The concurrent use of metroni-
dazole and ethanol may result in acute psychosis and the disulfiram
reaction (flushing, tachycardia, nausea and vomiting), although for
most individuals the risk is minor. Metronidazole may increase lith-
ium blood levels, decrease the body clearance of phenytoin, and signifi-
cantly increase blood warfarin levels by decreasing its liver metabolism.
Tetracyclines and Glycylcyclines
Tetracyclines (Fig. 33-12) are a group of broad-spectrum, bacterio-
static antibiotics that have been extensively used in the treatment of
numerous and varied infections. Their widespread use, and often
misuse, has resulted in the appearance of many bacterial strains that
are resistant to these drugs, which has curtailed their clinical useful-
ness. Paradoxically, the clinical use of tetracyclines has had a recent
resurgence of interest with the growing realization that the drugs may
be lifesaving in the treatment of serious nosocomial infections from
highly and multiply antibiotic-resistant methicillin-resistant staphy-
lococci. This renewed effectiveness of tetracyclines may be related to
the almost complete lack of use of the drugs in hospitals for several
decades, possibly leading to the loss of tetracycline resistance genes in
this environment. Because of the advent of widespread resistance of
OH O OH O O
OH
2 NH2
7 6 5 Demeclocycline hydrochloride
OH
H H
CH3 OH N Minocycline hydrochloride
H3C CH3
Doxycycline
FIG 33-12  Structure of doxycycline.
477
H. pylori to metronidazole and macrolides, tetracyclines have gained
importance in the treatment and prevention of peptic ulcers and gas-
tric cancer and have emerged as a prophylactic agent in the prevention
of multidrug-resistant malaria in travelers and the management of
community-acquired pneumonia, particularly in penicillin-resistant
and macrolide-resistant strains.
Tetracyclines comprise a group of antibiotics with a similar anti-
bacterial spectrum but differing pharmacokinetic properties created by
various chemical substitutions on the hydro-naphthacene four-ringed
nucleus. Chlortetracycline, oxytetracycline, tetracycline, and demeclo-
cycline constitute the first-generation tetracyclines. Second-generation
agents introduced from 1965 to 1972 include minocycline, methacy-
cline, and doxycycline. Glycylcyclines are third-generation agents. The
first microorganism clinically detected to be resistant to tetracyclines
was a Shigella dysenteriae strain in 1953. Today, doxycycline is the
most commonly used tetracycline (Table 33-10).
Mechanism of action
Tetracyclines inhibit bacterial protein synthesis by preventing the
association of aminoacyl-tRNA with the bacterial ribosome. The
drugs must transverse the gram-negative microbial outer membrane
via porin channels or through the gram-positive cell wall in its electro-
negative hydrophobic form and attach to a single high-affinity binding
site on the ribosomal 30S subunit and protein 7 on the 16S rRNA base.
Bacterial resistance
Microbial resistance to tetracyclines is widespread, transposable,
inducible, and commonly permanent because their resistance genes
are almost always combined in transposable elements with the genes
for resistance to other antibiotics (multidrug resistance gene cassettes).
Of the three mechanisms for tetracycline resistance (drug efflux, ribo-
somal protection, and enzymatic inactivation), drug efflux is the most
important, with at least 300 different active efflux proteins capable of
extruding tetracycline from the bacterial cell.
Tetracyclines are one of the most active chemical inducers of micro-
bial resistance gene expression and downregulate a repressor gene that
controls efflux activity for not only tetracyclines but also possibly other
antibiotics. Only nanomolar amounts of tetracycline are necessary to
de-repress this system and greatly increase antibiotic efflux from bac-
terial cells. Tetracyclines also promote the mobility of resistance deter-
minants (transfer of resistance genes between bacteria) by stimulating
the frequency of bacterial conjugation. Considering these extraordi-
nary properties of tetracyclines to induce and promote microbial resis-
tance not only to themselves but also other antibiotics, it would seem
prudent to restrict their use to serious medical infections and restrict
their use in most cases of periodontitis, where they may have limited or
even undocumented value.
TABLE 33-10  Commercially Available
­Tetracycline and Glycylcycline Preparations
Nonproprietary (Generic) Name Proprietary (Trade) Name
Tetracycline hydrochloride Tetralen, Panmycin, Sumycin,
Tetracyn, Tetracap
Oxytetracycline hydrochloride Terramycin
Declomycin
Doxycycline hyclate Vibramycin, Doxy Caps
Minocin, Vectrin, Dynacin
Glycylcycline
Tigecycline Tygacil
478 CHAPTER 33  Pharmacology of Specific Drug Groups: Antibiotic Therapy
Absorption, fate, and excretion
Tetracyclines are adequately but variably absorbed from the gastroin-
testinal tract with significant differences in bioavailability, as follows:
chlortetracycline, 30%; demeclocycline, tetracycline, and oxytetracy-
cline, 60% to 80%; and minocycline or doxycycline, 95% to 100%.
Dairy products, Ca2+, Mg++ and aluminum compounds, and Na+ bicar-
bonate significantly impair tetracycline absorption either by chelation
or by altered gastric pH. Their serum protein binding ranges from 20%
to 40% for oxytetracycline to 80% to 95% for doxycycline, and the per-
cent excreted unchanged in the urine ranges from 70% for oxytetracy-
cline to 30% to 42% for doxycycline and 12% to 16% for minocycline.
With renal impairment, only doxycycline and minocycline do not have
increased half-lives and can be administered with reasonable safety.
Other tetracyclines may accumulate in conditions of renal impairment,
resulting in high blood levels and possible liver necrosis and death.
Tetracyclines are metabolized in the liver to a varying degree
depending on the individual drug and are highly concentrated in the
bile at levels three to five times higher than serum. More recent tetracy-
clines are more lipid-soluble with greater tissue distribution than ear-
lier tetracyclines. Enterohepatic circulation and incomplete absorption
may lead to high drug concentrations in the feces, particularly with
older agents. Doxycycline may be found to some degree in the feces
as an inactive form, and it is as yet unknown if this metabolic product
is as capable of inducing resistance gene expression or transfer as the
parent compound. The serum half-lives of the various agents are 12
to 16 hours for oxytetracycline, tetracycline, and demeclocycline; 14 to
16 hours for methacycline; 11 to 18 hours for minocycline; and 15 to
25 hours for doxycycline. Peak serum concentrations are reached in
2 hours after the usual therapeutic doses.
General therapeutic uses (Table 33-11 and also see Table 33-5)
Tetracyclines are broad-spectrum antibiotics. Table 33-11 lists some sen-
sitive organisms against which they are used in therapy. Tetracyclines are
TABLE 33-11  Indications for Tetracyclines
and Tigecycline
Brucella
Borrelia burgdorferi*
Borrelia recurrentis
Chlamydia pneumoniae
Chlamydia psittaci
Chlamydia trachomatis
Ehrlichia chaffeensis*
Ehrlichia ewingii*
Mycobacterium marinum†
Mycoplasma pneumoniae
Rickettsiae*
Vibrio cholerae
Vibrio vulnificus
Yersinia pestis
Indications for Tigecycline
Community-acquired pneumonia caused by Streptoccocus pneumoniae,
Hemophilus influenza, and Legionella pneumophila
Intraabdominal and skin infections due to gram-negative rods, streptococcal
and staphylococcal bacteria, Kebsiella, Bacterioides, and others
*Specifically doxycycline.
†Specifically minocycline.
From Abramowicz M, Zuccotti G, editors: Handbook of antimicrobial
drugs: drugs for bacterial infections, The Medical Letter ed 20, 2015,
New Rochelle, NY.
major drugs in treating rickettsial diseases, Mycoplasma, Chlamydia
(treatment of community-acquired pneumonia), H. pylori, and Borrelia.
(Borrelia burgdorferi is the causative agent of Lyme disease.)
Many other bacteria nominally within their range of activity should
not be treated, at least initially, with a tetracycline because of the
numerous resistant strains.
Tetracyclines have been used in the treatment of acne using oral and
topical preparations. Tetracyclines are concentrated in the skin and are
effective against Propionibacterium acnes and may have an antisebor-
rheic action to reduce skin lipids. Because tetracyclines are deposited
in bone, they can be used to measure the rate of bone growth. Other
indications include plague, tularemia, cholera, brucellosis, and certain
protozoal infections.
Therapeutic uses in dentistry
The use of tetracyclines in the management of acute orofacial infec-
tions is widely considered inappropriate because of their bacteriostatic
activity and extensive microbial resistance. Evidence does not support
the use of tetracyclines in the management of chronic periodontitis.
Data showing clinical efficacy are lacking, and there is a propensity to
induce microbial resistance gene expression and stimulation of drug
efflux mechanisms and common association with multiple resistance
genes to other antibiotics in transposable elements. Tetracyclines may
be of use in the management of localized aggressive periodontitis and
its associated organism, Aggregatibacter (formerly Actinobacillus) acti­
nomycetemcomitans. Tetracyclines also seem to inhibit inflammatory
matrix metalloproteinase activity. Tetracyclines may also be used sub-
gingivally. The degree of benefit of the use of tetracyclines in periodon-
tal disease has to be weighed against the risk of developing resistant
strains of microorganisms.
Adverse effects
Numerous adverse drug reactions are associated with tetracyclines.
Tetracyclines may induce photosensitivity; nephrogenic diabetes
insipidus (demeclocycline); blood dyscrasias; liver dysfunction (high
doses and especially during pregnancy); pseudotumor cerebri and
bulging fontanelles (adults and infants); C. albicans overgrowth; gas-
trointestinal difficulties (nausea, vomiting, diarrhea, pancreatitis); and
various allergic manifestations, including urticaria, serum sickness,
angioneurotic edema, and anaphylaxis.
Minocycline in conventional doses is associated with skin, nail,
and hair pigmentation and a systemic lupus erythematosus–like syn-
drome, mainly in adolescents taking the drug for acne. This syndrome
is usually reversible but may require corticosteroid therapy; however,
the absolute risk seems to be low (52.8 per 100,000 uses). Sixteen cases
of autoimmune hepatitis have been described.
Minocycline is the only tetracycline that induces vestibular tox-
icity (ataxia, loss of balance), possibly because of its high concentra-
tion in the lipid-rich cells of the inner ear. Tetracyclines in general are
one of the few groups of drugs that are toxic if ingested beyond their
expiration date, inducing a Fanconi-like syndrome (azotemia, kidney
damage). Tetracycline-induced acute interstitial nephritis may result
in acute renal failure. Hepatotoxicity is rare except at high doses and is
most likely to occur during pregnancy, leading to an absolute contra-
indication to the drugs in pregnancy.
The chelation properties of tetracyclines are responsible for their
deposition in calcifying teeth, bone, and cartilage, and these drugs have
been used as vital stains to determine bone growth. Tetracycline stain-
ing is not permanent in tissues that are remodeled (bone, cartilage), but
it is permanent in tissues that are not remodeled (teeth). Tetracyclines
should not be used in children younger than 8 years unless other anti-
biotics are unlikely to be effective or are contraindicated. Tetracyclines
 CHAPTER 33  Pharmacology of Specific Drug Groups: Antibiotic Therapy
most likely to stain the dentition severely are tetracycline and deme-
clocycline with oxytetracycline, chlortetracycline, and doxycycline (the
least likely), but the magnitude of the staining may depend more on
dose and duration than the drug itself. Deposition of tetracyclines in
bone and teeth eliminates their antimicrobial activity. Because of the
deleterious staining effects on the teeth and the liver, tetracyclines are
classified by the FDA as pregnancy category D drugs. Tetracyclines
should not be used in pregnancy because of staining of teeth and
potential hepatotoxicity.
Minocycline is also able to impart a grayish discoloration of
teeth, even after tooth formation and eruption. This could at least in
part be an extrinsic stain; however, the exact mechanism(s) has/have
not been established. This type of staining does not occur with other
tetracyclines.
Drug interactions
Tetracyclines and all other antimicrobial ribosomal protein synthesis
inhibitors may reduce the efficacy of antibiotic cell wall inhibitors,
which rely on cell wall division for their action. Polyvalent cations
(aluminum, Ca2+, zinc, iron, magnesium, bismuth) may decrease gas-
tric tetracycline absorption by chelation. Na+ bicarbonate alters the
gastric pH and reduces absorption of tetracyclines.
Serum levels of tetracyclines may be reduced from increased
hepatic metabolism induced by barbiturates, carbamazepine, and
hydantoins. The addition of tetracyclines to coumarin anticoagulants
(e.g., warfarin) may greatly increase the latter’s effect on the INR and
lead to serious bleeding episodes. The effect is partially due to the
inhibitory effect of tetracyclines on the intestinal flora that produce
vitamin K.
Contraindications
Tetracyclines are contraindicated in children younger than 8 years, in
cases of allergy, during pregnancy, and during lactation.
Glycylcyclines
Glycylcyclines are synthetic derivatives of minocycline. Tigecycline is
the glycylcycline used in the United States. It is effective against some
tetracycline-resistant bacteria and other organisms listed in Table
33-11. The resistance gene for glycylcyclines is carried on the same
transposon as the resistance genes for the macrolides and tetracycline,
making the use of glycylcyclines potentially limited.
Fluoroquinolones
Fluoroquinolones were introduced in the 1980s and are C6 fluorine
derivatives of nalidixic acid. The terms fluoroquinolone and quinolone
are often used interchangeably; however, this is technically incorrect
because nalidixic acid is not a fluoroquinolone, being devoid of the
fluorine substitution.
The first fluoroquinolone (norfloxacin) was synthesized in 1978
as a 6-fluorinated derivative of nalidixic acid with a piperazine ring
at position 7 (Fig. 33-13). Ciprofloxacin was synthesized in 1981 and
HN
N N
OH
F Organisms that are sensitive to fluoroquinolones in general include
O O
Ciprofloxacin
FIG 33-13  Structure of ciprofloxacin.
479
marketed in 1986. Newer fluoroquinolones have improved activity
against S. pneumoniae, S. aureus, gram-positive cocci, anaerobes, P.
aeruginosa, and various other organisms.
Mechanism of action and antibacterial spectrum (Table 33-12)
DNA gyrase and topoisomerases are enzymes involved in the cru-
cial processes of DNA replication, transcription, and recombination.
DNA gyrase has two subunits (A and B) regulated by two genes (gyrA
and gyrB), with topoisomerase IV encoded by parC and parE genes.
Both enzymes are responsible for supercoiling DNA, forming dou-
ble-stranded DNA, and maintaining DNA in its physiologically stable
and biologically active state. Topoisomerase IV nicks double-stranded
DNA and seals the nicked DNA, whereas DNA gyrase guides the pas-
sage of the DNA through the interior of the enzyme complex. Both
enzymes are responsible for supercoiling DNA, allowing for its fit into
the bacterial cell. Fluoroquinolones stabilize the enzyme complex after
strand breakage and before resealing, preventing DNA supercoiling.
Table 33-12 indicates their antibacterial spectra and indications,
listing organisms that are sensitive to some or all fluoroquinolones.
Bacterial resistance
Three mechanisms account for microbial resistance to fluoroquino-
lones: mutations in DNA gyrase and topoisomerase IV, drug efflux
pumps, and reduction in microbial outer membrane permeability. The
target alterations are accomplished by simple point mutations in DNA
gyrase (gyrA) and topoisomerase IV (parC) and by efflux mechanisms.
TABLE 33-12  Classification of Fluoro-
quinolones Based on Antibacterial Spectrum
Indications Based on Advantage of
Group Individual Drug
Group I (Urinary Tract Infections)
Norfloxacin (Noroxin) Gram negatives, e.g., K. pneumoniae, E. coli, P.
mirabilis, P. vulgaris, Providencia
Group II (Broad Spectrum)
Ciprofloxacin (Cipro) Pseudomonas aeruginosa, Mycobacterium tuber-
culosis, Salmonella typhi, infectious diarrhea,
inhalation anthrax
Levofloxacin (Levaquin) Pneumonia, bronchitis, urinary tract infections,
inhalation anthrax, M. tuberculosis
Lomefloxacin (Maxaquin) Haemophilus influenzae or Moraxella catarrh-
alis respiratory tract infection, urinary tract
infections
Ofloxacin (Floxin) Pneumonia, urinary tract infections,
M. tuberculosis
Group III (Greater Gram-Positive Activity)
Gemifloxacin (Factive) Streptococci and other organisms causing
­pneumonia and bronchitis
Sparfloxacin (Zagam) Streptococci and other organisms causing
­pneumonia and bronchitis
Group IV (Greater Gram-Positive/Anti-Anaerobic Activity)
Moxifloxacin (Avelox) Anaerobes including Bacteroides, ­intraabdominal
infections, pneumonia, skin infections, M.
tuberculosis
Mycoplasma pneumoniae, Legionella pneumophila, Chlamydia spe-
cies, Escherichia coli, Haemophilus influenza, Klebsiella pneumoniae,
Neisseria gonorrhoeae, Shigella, Proteus mirabilis, and Staphylococcus
aureus. Added indications for specific drugs are listed.
480 CHAPTER 33  Pharmacology of Specific Drug Groups: Antibiotic Therapy
Absorption, fate, and excretion
Fluoroquinolones are well absorbed orally with a 70% and 90% bio-
availability for ciprofloxacin and levofloxacin. Food generally delays
the peak concentration of ciprofloxacin and levofloxacin, but it has
no effect on moxifloxacin. The percent excreted by the kidneys ranges
from 27% to 73%, and protein binding ranges from 15% to 35%.
Fluoroquinolone half-lives vary, approximately 4 hours for ciproflox-
acin and norfloxacin, 7 to 8 hours for lomefloxacin and sparfloxacin,
and ∼14 hours for moxifloxacin. Pharmacokinetic improvements have
included longer half-lives to allow for once-daily dosing and greater
volumes of distribution for better tissue penetration. The post-antibi-
otic effects of fluoroquinolones vary from 1 to 4 hours.
General therapeutic uses
Table 33-12 identifies differences in indications based on groups of
fluoroquinolones. Fluoroquinolones are used to treat urinary tract
infections and bacterial diarrhea (e.g., traveler’s diarrhea) because of
their activity against many of the causative organisms. Because fluoro-
quinolones vary in their pharmacokinetics and in their spectra, some,
but not all, fluoroquinolones are employed for upper and lower respi-
ratory tract infections, P. aeruginosa infections, genital diseases caused
by gonococci and Chlamydia, legionnaires disease, and tuberculosis.
Therapeutic uses in dentistry
Fluoroquinolones are not indicated for any acute orofacial infections
unless dictated by culture and sensitivity tests. Drugs with better anti-
microbial spectra are readily available.
Adverse effects
The major adverse effects associated with fluoroquinolones occur in
the gastrointestinal tract, CNS, skin, and cartilage. Less common sys-
tems involved are the cardiovascular, hepatic, and renal systems. The
incidence of each adverse effect may vary among the different drugs
because of chemical substitutions on the quinolone nucleus.
Gastrointestinal adverse reactions include nausea and vomiting,
dyspepsia and heartburn, and abdominal pain. The heavy use of flu-
oroquinolones has been associated with PMC and diarrhea owing to
overgrowth of C. difficile. CNS effects include mild neuropathy (head-
ache, dizziness, malaise, restlessness, bad dreams) possibly caused by
central γ-aminobutyric acid inhibition or activity at the N-methyl-
d-aspartate receptor. Dermatologic toxicity includes rash, pruritus,
exfoliative dermatitis, Stevens-Johnson syndrome, and phototoxicity
likely caused by dose-related ultraviolet light activation of reactive oxy-
gen from the fluoroquinolones in the skin.
Chondrotoxicity includes arthralgia, joint swelling, tendinitis, and
tendon rupture (primarily the Achilles tendon). These disorders are
more likely to occur in men, elderly patients, and patients with con-
comitant corticosteroid therapy, diabetes mellitus, renal failure, other
musculoskeletal disorders, or involvement in sports activity. These
agents are not approved for children younger than 18 years except for
ciprofloxacin.
Other possible adverse effects include induction of a prolonged
QT interval leading to torsades de pointes, especially with levofloxa-
cin, gemifloxacin, and moxifloxacin. Fluoroquinolones are associated
with transient increase in liver enzymes, neutropenia, serum sick-
ness, allergic vasculitis, and renal crystalluria. Because these antibiot-
ics affect DNA, they have been investigated as possible teratogens. At
extremely high in vitro doses, fluoroquinolones have induced genotox-
icity in the chromosomal aberration test; however, a clinical study of
200 women exposed to ciprofloxacin and norfloxacin during gestation
showed no increase in fetal malformations or musculoskeletal defects.
Exacerbation of myasthenia gravis has been reported.
Drug interactions
An important drug interaction with fluoroquinolones is the potential
increase in CNS toxicity with the concomitant use of NSAIDs and
methylxanthines. The combination of a fluoroquinolone with tricyclic
antidepressants, erythromycin, phenothiazines, and antiarrhythmic
agents (quinidine, procainamide, disopyramide) may increase the risk
of torsades de pointes. Fluoroquinolones may reduce the liver clear-
ance of warfarin and procainamide and increase the toxicity of cyclo-
sporine. Omeprazole may increase fluoroquinolone blood levels, and
antacids, sucralfate, and calcium, iron, or zinc supplements may reduce
gastric absorption of fluoroquinolones.
Contraindications
Ciprofloxacin should be used with caution during pregnancy and in
children. For children younger than 18 years, other fluoroquinolones
are contraindicated. Phototoxicity may occur on skin areas exposed to
sunlight, and sunscreens are not always effective.
Aminoglycosides
The era of the aminoglycosides began in 1943 with the isolation of
streptomycin by Waksman and the subsequent development of kana-
mycin (1957), gentamicin (1963), tobramycin (1968), amikacin
(1972), and netilmicin (1975).
Chemistry
Streptomycin is produced by Streptomyces griseus. Other amino-
glycosides are elaborated by various species of Streptomyces and
Micromonospora or, in the case of amikacin and netilmicin, are
semisynthetic derivatives of naturally occurring aminoglycosides. As
the name implies, these agents consist of a highly polar amino base
attached by glycosidic linkage to one or more sugars (Fig. 33-14).
Mechanism of action and antibacterial spectrum
Aminoglycosides bind irreversibly to the 30S ribosome to interfere
with the reading of the microbial genetic code and to inhibit protein
synthesis. Aminoglycosides are generally bactericidal, and their efficacy
in several cases can be greatly enhanced by the concomitant use of cell
wall–inhibiting β-lactams and glycopeptides.
The activity of aminoglycosides is primarily directed toward
gram-negative bacilli and mycobacteria (see Table 33-5). The spec-
trum includes gram-negative enteric bacilli and some other gram-neg-
ative bacilli (e.g., P. aeruginosa and Proteus). There are, however, some
differences among aminoglycosides regarding their efficacy toward
specific microorganisms. Gentamicin is the most commonly used ami-
noglycoside, often acting synergistically with ampicillin, penicillin G,
CH3
H3C
NH
O
NH2
H2N NH2
O
O
HO
O CH3
HO
HN
OH
CH3
Gentamicin
FIG 33-14  Structure of gentamicin.
 CHAPTER 33  Pharmacology of Specific Drug Groups: Antibiotic Therapy
ceftriaxone, vancomycin, and rifampin. Some original indications for
aminoglycosides have been supplanted by safer extended-spectrum
β-lactams and fluoroquinolones.
Bacterial resistance
Three resistance mechanisms presently exist for aminoglycosides:
ribosomal mutations (less affinity for the 30S ribosome), reduced
intracellular transport (primarily in staphylococci and pseudo-
monads), and, most commonly, plasmid-mediated aminoglyco-
side-modifying enzymes (acetyltransferases, adenyltransferases,
and phosphotransferases).
Absorption, fate, and excretion
Aminoglycosides are poorly absorbed orally and do not penetrate
well into the CNS, bronchial secretions, or certain microbial cells
(e.g., Rickettsiae, Chlamydiae), but they are effective intracellularly
in the treatment of tuberculosis, plague, brucellosis, and tularemia.
Aminoglycosides are classic concentration-dependent antibiotics com-
monly administered in high parenteral doses repeated after the blood
levels have decreased to a low concentration (peak and trough dos-
ing). Single daily dosing is becoming more common, taking advantage
of the long post-antibiotic effect of aminoglycosides, a reduction in
cost, and lessening of renal toxicity. The normal elimination half-life
of aminoglycosides is 2 to 3 hours, which can be extended to 24 to
100 hours in end-stage renal disease. Aminoglycosides are excreted pri-
marily by glomerular filtration.
General therapeutic uses
Parenteral aminoglycosides currently available include amikacin,
gentamicin, kanamycin, netilmicin, streptomycin, and tobramycin.
Kanamycin and neomycin are available for oral use (poorly absorbed)
for gastrointestinal infections. Aminoglycosides are primarily indicated
for infections caused by gram-negative aerobic bacteria, including
P. aeruginosa, Serratia, Klebsiella, Enterobacter, and Proteus. Anaerobic
bacteria are insensitive. Aminoglycosides are often combined with a
penicillin or cephalosporin for various infections.
Therapeutic uses in dentistry
Aminoglycosides have no uses in orofacial infections unless dictated by
culture and sensitivity tests.
Adverse effects
The major adverse effects of aminoglycosides are renal toxicity and
eighth cranial nerve toxicity (auditory and vestibular ototoxicity).
Nephrotoxicity is caused by inhibition of an intracellular lysosomal
phospholipase in the renal proximal tubules, resulting in aminogly-
coside accumulation and subsequent reduced glomerular filtration,
reduced water and Na+ transport, reduced mitochondrial respiration,
and reduced renal protein synthesis resulting in renal necrosis. The
incidence of some degree of nephrotoxicity can be 10% to 20%.
A primary target for toxicity of aminoglycosides is the hair cells of
the inner ear where the initial loss of the outer hair cells eventually
damages the inner ear cochlear hair cells (type II). Further damage may
occur to the cochlear sensory epithelium and the spiral ganglion cells
required for cochlear implants. Vestibular (type I) hair cell damage
occurs at the apex of the macula and often earlier than the cochlear hair
cell damage. Initial signs and symptoms are hearing loss at the higher
frequencies, which increases with dose, duration, and noise exposure.
The incidence of cochlear damage may be 15%. Other adverse reac-
tions associated with aminoglycosides include neuromuscular block-
ade of the curare type, rare blood dyscrasias, headache, dizziness, and
urticarial and peripheral neuropathy.
481
Drug interactions
The nephrotoxicity of aminoglycosides is increased by vancomycin and
cephalosporins. Loop diuretics increase auditory toxicity from amino-
glycosides. Aminoglycosides increase the neuromuscular blocking
effect of curare-type drugs.
Vancomycin
Vancomycin is a glycopeptide antibiotic, originally isolated from
Streptomyces orientalis in Borneo in 1956 and introduced into medi-
cine in 1958. Vancomycin is a seven-membered peptide chain with two
sugars, vancosamine and glucose. The drug is poorly absorbed from
the gastrointestinal tract and causes severe pain when given intramus-
cularly. It is administered intravenously to treat systemic infections or
orally to treat PMC. Its elimination half-life is ∼6 hours, and it has a
post-antibiotic effect of 1.5 to 3 hours.
Mechanism of action and antibacterial spectrum
Vancomycin inhibits gram-positive bacterial cell wall synthesis by
complexing with the d-alanyl-d-alanine portion of the peptide pre-
cursor units to inhibit the transglycosylase reaction in peptidoglycan
synthesis. This inhibition is at the second stage of bacterial cell wall
synthesis before the action of the penicillins at the third stage (see Fig.
33-5). Vancomycin may also affect cytoplasmic membrane permeabil-
ity and RNA synthesis and, as with the β-lactams, it requires active
cell replication. Because of its large molecular size, vancomycin cannot
traverse the outer cell membrane of gram-negative bacteria.
The activity of vancomycin is almost exclusively against aerobic
and anaerobic gram-positive species. Table 33-13 lists several impor­
tant pathogens that are inhibited by the drug.
Bacterial resistance
Vancomycin resistance is caused by an altered peptidoglycan terminus
(d-ala-d-lac instead of the usual d-ala-d-ala), resulting in reduced van-
comycin binding and failure to prevent cell wall synthesis. Resistance
in vancomycin-intermediate S. aureus and glycopeptide-intermediate
S. aureus may be due to the production of abnormal peptides (“false
binding sites”) in the cell wall that bind vancomycin and prevent its
attachment to its receptor or possibly to an increase of peptidoglycan
resulting in thickened cell walls. A form of resistance is seen in S. pneu­
moniae by a unique mutation in the sensor-response system that con-
trols autolysin activity necessary to kill certain bacteria.
TABLE 33-13  Antimicrobial Spectra of
Systemic Peptide-Containing Antibiotics
Class Representative Spectrum
Glycopeptide
Vancomycin Staphylococcus including MRSA, enterococci, Streptococ-
cus pneumoniae, Streptococcus pyogenes, Peptostrep-
tococcus, VGS, Clostridium difficile, Corynebacterium
jeikeium, Bacillus cereus, Bacillus subtilis
Lipopeptide
Daptomycin MRSA, enterococci, S. Pyogenes, Peptostreptococcus
Lipoglycopeptides
Telavancin MRSA, enterococci, S. Pyogenes, VGS, Peptostreptococ-
Dalbavancin cus, S. pneumoniae
Oritavancin
MRSA, Methicillin-resistant Staphylococcus aureus; VGS, viridans
group streptococci.
482 CHAPTER 33  Pharmacology of Specific Drug Groups: Antibiotic Therapy
General therapeutic uses
Vancomycin is used for serious gram-positive infections caused by
such organisms as methicillin-resistant staphylococci and S. pneu­
moniae. It is also useful for non-vancomycin-resistant enterococcal
infections. It is effective in treating enterocolitis caused by C. difficile;
however, metronidazole should be used for this situation if possible
because of the significant risk of promoting vancomycin enterococcal
resistance. Vancomycin may also be useful in treating multiple antibi-
otic-resistant VGS infections (see Table 33-13).
Therapeutic uses in dentistry
Vancomycin has no use in the management of acute or chronic orofacial
infections unless dictated by laboratory culture and sensitivity tests.
Adverse effects
Major adverse drug reactions associated with vancomycin include
transient or permanent ototoxicity, hypotension, reversible neutrope-
nia, renal toxicity, skin rash, and red man syndrome. The auditory
toxicity of vancomycin is dose-dependent and can be exacerbated by
the combination with aminoglycosides. Red man syndrome results
from the direct histamine release from mast cells manifesting as pru-
ritus; erythematous rash of the head, neck, face, and upper torso; and
hypotension mimicking anaphylactic shock. Rapid infusion makes it
worse. This glycopeptide-induced anaphylactoid reaction may occur
with the first drug exposure, is tachyphylactic in nature, and can be
reduced significantly by the slow infusion of vancomycin over a 1-hour
period and premedication with antihistamine drugs. To reduce the
development of resistant bacteria, vancomycin use is contraindicated
or discouraged for routine surgical prophylaxis.
Drug interactions
Vancomycin-induced nephrotoxicity or ototoxicity is increased with
the concomitant use of aminoglycosides, and neuromuscular blockade
with curare-like agents is enhanced by vancomycin.
Fidaxomicin
Fidaxomicin is a macrolide antibiotic whose spectrum is narrow and
limited to gram-positive aerobes and anaerobes. It inhibits RNA poly-
merase and is bactericidal against C. difficile. It is given orally to treat
colitis due to C. difficile. Systemic absorption is minimal when given
orally.
Daptomycin
Daptomycin is a cyclic lipopeptide bacteriocidal antibiotic. Its causes
depolarization of sensitive gram-positive bacteria after binding to
their cell membranes. Its spectrum includes MRSA, enterococci, S.
Pyogenes, and Peptostreptococcus (see Table 33-13). It is adminis-
tered intravenously and is excreted unchanged by the kidneys. Adverse
effects include skeletal muscle damage and peripheral neuropathy.
Lipoglycopeptides
Telavancin, dalbavancin, and oritavancin are intravenous drugs that
inhibit cell wall synthesis in gram-positive cocci, similar to vanco-
mycin. In addition, telavancin has the additional effect of causing
cell depolarization by acting on the cell membrane. The spectrum
of these drugs includes MRSA, enterococci, S. Pyogenes, VGS,
Peptostreptococcus, and S. pneumoniae (see Table 33-13). The half-
lives are telavancin, ∼8 hours; dalbavancin, ∼6 to 11 days; and orita-
vancin, ∼10 days. Telavancin causes taste disturbances and is linked to
QT prolongation and nephrotoxicity. Dalbavancin and oritavancin are
associated with GI disturbances and hepatotoxicity. The drugs are used
to treat complicated skin and soft tissue infections.
Streptogramins
Quinupristin-dalfopristin, a 30/70 mixture of streptogramins A and
B, is approved for intravenous use in the United States.
Mechanism of action and antibacterial spectrum
Quinupristin and dalfopristin bind sequentially to different sites of the
50S subunit of the 70S ribosome to prevent newly synthesized pep-
tide chains from extruding from the ribosome, resulting in cell death.
Quinupristin-dalfopristin is used to treat life-threatening vanco-
mycin-resistant E. faecium (E. faecalis is resistant) and skin or skin
structure infections from S. aureus and S. pyogenes. The drug is addi-
tionally approved in the United Kingdom for nosocomial pneumonia.
Its spectrum closely resembles that of vancomycin and linezolid.
Bacterial resistance
Microbial resistance occurs by three mechanisms: decreased ribo-
somal binding by methylation of an adenine residue, drug efflux,
and enzymatic inactivation. This resistance belongs to the MLSB
(Macrolide-Lincosamide-Streptogramin B) type, potentially confer-
ring cross-resistance to all these antibiotics.
General therapeutic uses
Quinupristin-dalfopristin should be reserved for life-threatening and
multiple antibiotic-resistant infections from E. faecium, staphylococci,
and some streptococci encountered primarily in the hospital.
Adverse effects
Adverse effects associated with streptogramins include possible severe
arthralgias and myalgias, elevation in conjugated serum bilirubin, and
significant inhibition of the liver microsomal CYP3A4 drug metabo-
lizing system.
Drug interactions
Streptogramins decrease the liver metabolism of Ca2+ channel block-
ers, immunosuppressant drugs, corticosteroids, several anticancer
agents, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors
(statins), HIV protease inhibitors, quinidine, nonsedating antihista-
mines, sildenafil, opioids, and benzodiazepines.
Oxazolidinones
Two oxazolidinones, linezolid and tedizolid, are totally synthetic anti-
microbial drugs.
Mechanism of action and antibacterial spectrum
The oxazolidinones have a unique mechanism of action by binding
to the 50S ribosome subunit near the interface with the 30S subunit
to prevent the initiation complex required for bacterial translation.
This unique mechanism may possibly limit cross-resistance with other
antibiotics. Linezolid is approved in the United States for the manage-
ment of vancomycin-resistant E. faecium; nosocomial and commu-
nity-acquired pneumonia from S. aureus and penicillin-sensitive S.
pneumoniae; and complicated skin and skin structure infections from
MRSA, MSSA, methicillin-resistant CoNS, S. pyogenes, and S. agalac­
tiae. Tedizolid has similar indications.
Bacterial resistance
Microbial resistance to linezolid has been detected in isolated cultures
of vancomycin-resistant enterococci, E. coli, and laboratory strains of
S. aureus. More recent reports of clinical isolates of E. faecium and S.
aureus resistant to linezolid are disconcerting because the drug has
been available only for a short time. The mechanism of resistance
seems to be a 62,576T mutation in the gene encoding the central loop
 CHAPTER 33  Pharmacology of Specific Drug Groups: Antibiotic Therapy 483

domain of 23S rRNA. Tedizolid may be active against certain strains of
bacteria resistant to linezolid.
Absorption, fate, and excretion
Linezolid, with a near 100% oral bioavailability, produces peak blood
levels at 1 to 2 hours and can be administered parenterally as well. It
has an elimination half-life of 4.4 to 5.5 hours and a post-antibiotic
effect of 0.6 to 1.4 hours. Tedizolid has a half-life of ∼12 hours.
Adverse effects
Approximately 2% to 3% of patients receiving linezolid experience
nausea and vomiting, diarrhea, headache, tongue discoloration, taste
alteration, fungal superinfections, or very rarely PMC. The most seri-
ous adverse reaction is myelosuppression (anemia, leukopenia, pan-
cytopenia, thrombocytopenia), which may occur in an average of 2.4%
of patients. Linezolid requires weekly blood monitoring tests. The
safety of the drug has not been established beyond 28 days of use. It
is classified as an FDA pregnancy category C drug. Adverse effects of
tedizolid are similar to those of linezolid.
Drug interactions
Linezolid is a weak monoamine oxidase inhibitor and should be
used with caution with drugs that release catecholamines and foods
containing tyramine. Linezolid may precipitate serotonin syndrome
(confusion, agitation, seizures, hypertension, tachycardia, sweat-
ing, myoclonus, muscle rigidity, trismus, death), but the clinical
Dihydropteroate synthase
PABA + pteridine Dihydropteroic acid
Sulfonamides
Dihydrofolate reductase
Dihydrofolic acid
Tetrahydrofolic acid Trimethoprim
Purine and pyrimidine synthesis
FIG 33-15 Sites of inhibition of folic acid synthesis by sulfonamides
and trimethoprim. Note the effect of the two drugs on this common
pathway and the effect on purine and pyrimidine synthesis. PABA,
p-Aminobenzoic acid.
significance of this drug effect is as yet unknown. GI disturbances,
tachycardia, and hypertension are among the adverse effects associated
with tedizolid.
Sulfonamides
The era of effective and safe systemic antimicrobial therapy began in
1932 with the discovery by Domagk that a dye (Prontosil) protected
laboratory animals from streptococcal infections. Domagk deter-
mined that the active antibacterial portion of Prontosil was sulfanil-
amide, which was subsequently first used in the United States in 1935.
Trimethoprim was introduced in 1968 as a synergistic agent with
sulfonamides, and the combination of sulfamethoxazole/trimetho-
prim is the most commonly used sulfonamide preparation today.
The discovery of Prontosil by Domagk ranks with the discovery of the
anesthetic properties of nitrous oxide by Wells, the work on penicillin
by the Oxford group, and the discovery by Jenner of vaccinations as
among the greatest of all medical discoveries.
Chemistry
All the sulfonamides are derivatives of p-aminobenzenesulfonamide.
Sulfonamides are weak acids with limited water solubility, particularly
in solutions of low pH. This property may present problems for the
excretion of these drugs in acidic urine.
Mechanism of action and antibacterial spectrum
Sulfonamides and trimethoprim interfere with the microbial synthe-
sis of folic acid necessary for life in some microorganisms (Fig. 33-15).
Mammals acquire folic acid from their diet. Sulfonamides competi-
tively inhibit the incorporation of PABA into dihydropteroic acid, a
precursor of dihydrofolate, because the sulfas have a greater affinity
for dihydropteroate synthetase than PABA. Trimethoprim inhibits
bacterial dihydrofolate reductase with 50,000 to 100,000 times greater
affinity for the bacterial than the human enzyme; this blocks the con-
version of dihydrofolic acid to tetrahydrofolic acid, which is important
in the synthesis of purines, and DNA. Sulfonamides and trimethoprim
inhibit successive steps in the synthesis of folic acid and eventually bac-
terial nucleotides and DNA.
The trimethoprim/sulfamethoxazole combination is commonly
used for respiratory, urinary, and gastrointestinal infections. This
combination is used for indications indicated in Table 33-14.
Bacterial resistance
Transferable microbial resistance to sulfonamides and trimethoprim
occurs by three principal mechanisms: increased cell permeability bar-
riers and efflux proteins, decreased sensitivity or alterations in target
enzymes (dihydropteroate synthase and dihydrofolate reductase), and
the acquisition of new target enzymes. Resistance genes for trimetho-
prim-sulfamethoxazole are carried on transposable elements along
with the resistance genes for other antibacterial drugs.

TABLE 33-14  Characteristics of Representative Sulfonamides*

Drug Half-Life (hrs) Route Spectrum
Sulfisoxazole ∼6 Oral Escherichia coli, Shigella, Yersinia enterocolitica, Burkholderia cepacia, Stenotrophomonas maltophilia, Nocar-
Trimethoprim/­ ∼11/∼11 Oral dia, Moraxella catarrhalis, MRSA, Streptococcus pneumoniae, Listeria monocytogenes, Bartonella henselae,
sulfamethoxazole Brucella, Vibrio cholerae, Mycobacterium marinum, Burkholderia pseudomallei
Mafenide — Topical (burns) —
Silver sulfadiazine — Topical (burns) —
Nocardia is an indication for sulfisoxazole alone.
*Antimicrobial spectrum corresponds to trimethoprim/sulfamethoxazole, except where noted.
484 CHAPTER 33  Pharmacology of Specific Drug Groups: Antibiotic Therapy
Absorption, fate, and excretion
Sulfonamides are classified as short-acting, medium-acting, or long-
acting. Short-acting to medium-acting agents include sulfisoxazole, sul-
famethoxazole, sulfamethizole, and sulfadiazine. Sulfadoxine is a long-
acting agent with an elimination half-life of 100 to 230 hours (it is
used in combination with pyrimethamine to treat malaria caused by
Plasmodium falciparum). Various other sulfonamide preparations
include preparations used topically for burns (silver sulfadiazine,
mafenide), vaginal preparations, ophthalmic preparations (sulfacet-
amide), and drugs for the management of ulcerative colitis (salicylazo-
sulfapyridine or sulfasalazine) given orally for local gastrointestinal
effects. Oral sulfonamides are 70% to 100% bioavailable (except for
sulfasalazine) with a large volume of distribution and ready penetra-
tion into all fluids and tissues in the body including the CNS. The
drugs are metabolized by acetylation and conjugation in the liver and
excreted by glomerular filtration.
General therapeutic uses
The primary clinical uses of a sulfonamide alone or trimethoprim/sul-
famethoxazole are genitourinary tract infections, otitis media, acute
bronchitis, community-acquired pneumonia, and traveler’s diar-
rhea from enterotoxigenic bacteria. Two topical sulfonamides, silver
sulfadiazine and mafenide, are also used to treat burns. Other sulfon-
amides are used for ophthalmic and local gastrointestinal indications.
There are no indications for sulfonamides and trimethoprim in the
management of orofacial infections.
Adverse effects
Approximately 8% of individuals receiving sulfonamides and tri-
methoprim have some form of adverse reaction, such as nausea and
vomiting, blood dyscrasias, and crystalluria (precipitation in the
urine more likely with less soluble preparations such as sulfadiazine).
Three to five percent of patients experience allergy in any of its forms
from skin rash and pruritus to major skin eruptions (Stevens-Johnson
syndrome, epidermal necrolysis, exfoliative dermatitis, photosensitiv-
ity) to anaphylaxis. Stevens-Johnson syndrome is much more likely to
occur with long-acting sulfonamides, which are not available in the
United States. Of patients with AIDS, 70% have some form of skin rash
and fever from sulfonamides and trimethoprim.
Drug interactions
Trimethoprim and sulfamethoxazole work together synergistically in their
antimicrobial effect, increasing the activity and spectrum of the other.
Trimethoprim/sulfamethoxazole increases the clinical activity of oral anti-
coagulants, thiopental, methotrexate, hydantoins, and sulfonylureas, and
it decreases the activity of cyclosporine. Sulfonamides are displaced from
plasma protein by aspirin, other NSAIDs, and probenecid. PABA (present
in some health foods) competes against the effect of sulfonamides.
Contraindications
Contraindications for the use of sulfonamides include allergy to sul-
fonamides and other related drugs, such as sulfonylureas and thia-
zide, loop, and carbonic anhydrase inhibitor diuretics. Health foods
and possibly sunscreens containing PABA are contraindicated because
PABA competes against the sulfonamide.
Chloramphenicol
Chloramphenicol (Chloromycetin) is a broad-spectrum antibiotic
isolated in 1949 from Streptomyces venezuelae. It is bacteriostatic and
inhibits bacterial protein synthesis by reversible binding to the pepti-
dyl transferase component of the 50S ribosomal subunit.
Chloramphenicol is a broad-spectrum antibiotic whose spectrum
includes several gram-positive and gram-negative bacteria, spirochetes,
and Rickettsiae. Common pathogens sensitive to chloramphenicol
include Salmonella typhi, other Salmonella species, S. pneumoniae, H.
influenzae, and N. meningitidis. The drug is an alternate drug for seri-
ous infections such as bacterial meningitis and rickettsial diseases such
as Rocky Mountain spotted fever.
The most significant adverse reactions associated with chloramphen-
icol are reversible and irreversible bone marrow depression seen with
oral, parenteral, and even topical use. (The drug is absorbed well by any
route.) The reversible type is dose-related and possibly caused by inhi-
bition of mitochondrial protein synthesis resulting in anemia, leukope-
nia, or thrombocytopenia. “Idiosyncratic” bone marrow aplasia is not
dose-related; may begin weeks or months after the drug is stopped; and
is manifested by an often fatal aplastic anemia, the incidence of which
seems to be 1 in 24,500 to 1 in 40,800 patients receiving chloramphenicol
by any route of administration. This incidence is 13 times greater than
the spontaneous random occurrence of aplastic anemia in the general
population. Topical use is associated with a risk of 3 cases in 440,000
uses. The cause of this idiosyncratic aplastic anemia is unknown, but it
may be due to a genetically determined liver metabolite.
The “gray baby syndrome” associated with chloramphenicol is
caused by toxicity resulting from the inability of the immature liver of
neonates to detoxify the drug by conjugation. The signs and symptoms
include abdominal distress, cyanosis, vomiting, circulatory collapse,
and possibly death. There are no indications for chloramphenicol
in the management of orofacial infections. The drug is rarely used
because of its major adverse effects, especially bone marrow aplasia.
Urinary Antiseptics
Nitrofurantoin
Nitrofurantoin is prepared in various suspension forms and, as
with all urinary antiseptics, has limited bioavailability, low volumes
of distribution, and high urinary excretion rates. Its mechanism of
action is unknown but may involve inhibition of DNA and pro-
tein synthesis after its enzymatic activation in the bacterial cell. Its
antibacterial spectrum includes E. coli, Citrobacter, Staphylococcus
saprophyticus, E. faecalis, group B streptococci, K. pneumoniae,
and Enterobacter, with inherent resistance in Proteus, Providencia,
Morganella, Serratia, Acinetobacter, and P. aeruginosa. Adverse drug
reactions include severe gastrointestinal upset (nausea and vomiting,
anorexia, cramping), hepatitis, pneumonitis, peripheral neuropa-
thy, and bone marrow suppression. Pulmonary pneumonitis may
be acute, subacute, or chronic with an incidence for the acute form
of 1 in 100,000 users. Hemolytic anemia may occur in individuals
deficient in glucose-6-phosphate dehydrogenase. Nitrofurantoin and
the other agents mentioned subsequently are indicated for uncompli-
cated urinary tract infections and cystitis.
Fosfomycin
Fosfomycin is a broad-spectrum bactericidal drug that is converted in
the blood to the free acid form of fosfomycin. Its mechanism of action
is to inactivate enolpyruvyl transferase responsible for the conden-
sation of uridine diphosphate-N-acetylglucosamine with p-enolpyru-
vate, one of the initial steps in microbial cell wall synthesis (see Fig.
33-5). The antimicrobial spectrum for fosfomycin includes E. coli, E.
faecalis, Citrobacter, Enterobacter, K. pneumoniae, P. mirabilis, and S.
marcescens. Adverse reactions are mild and include diarrhea, vaginitis,
rash, and headache. Use of fosfomycin is commonly restricted to only
a single dose because of rapid microbial resistance.
Methenamine
The hydrolysis of methenamine, below pH 5.5, results in the liberation
of formaldehyde as its component. This results in the denaturation of
proteins. Methenamine, as the hippurate or mandelate salt to acidify
 CHAPTER 33  Pharmacology of Specific Drug Groups: Antibiotic Therapy
the urine, has a broad spectrum of activity against E. coli, staphylo-
cocci, and enterococci, with significant resistance in P. vulgaris and P.
aeruginosa. It is used as suppressive or prophylactic therapy in chronic
urinary tract infections. Adverse reactions include pruritus, urticaria,
nausea and vomiting, cramping, headache, dizziness, proteinuria,
hematuria, and precipitation of urate crystals in the urine.
Nalidixic acid
This quinolone antibiotic is used exclusively for the management
of urinary tract infections from gram-negative microorganisms.
(See Table 33-12.) Its mechanism of action is the same as the fluo-
roquinolones: inhibition of DNA gyrase and topoisomerase IV. The
major adverse effects are CNS toxicity (dizziness, weakness, headache,
papilledema, and rare seizures and psychosis), blood dyscrasias, pho-
tosensitivity, and hemolytic anemia in glucose-6-phosphate dehydro-
genase–deficient individuals.
Drugs Used to Treat Tuberculosis
Successful treatment of tuberculosis caused by M. tuberculosis became
possible only with the advent of chemotherapeutic agents. Multidrug-
resistant strains of M. tuberculosis have arisen, especially among
patients with HIV/AIDS. Because of the rapid development of antimi-
crobial resistance in strains of M. tuberculosis, a combination of agents
is always employed for treatment. The primary (first-line) antituber-
culosis drugs are isoniazid, rifampin, pyrazinamide, ethambutol,
and streptomycin. (Rifabutin or rifapentine can be used to substitute
for rifampin if needed.) (Depending on the reference, streptomycin is
classified either as a first-line of second-line drug.) For recurrent infec-
tions or cases that exhibit microbial resistance, second-line drugs are
available, including ethionamide, cycloserine, amikacin, kanamycin,
capreomycin, levofloxacin, moxifloxacin, para-aminosalicylic acid,
and bedaquiline. These agents are generally less active and often more
toxic than the primary drugs. These drugs are used in combination for
active tuberculosis that is drug-resistant.
Until the results of sensitivity tests dictate the regimen, tuber-
culosis therapy should begin with four drugs: isoniazid, rifampin,
pyrazinamide, and ethambutol (or streptomycin) for 2 months, fol-
lowed by 4 (or 7) months of isoniazid and rifampin. After test results,
typical therapy consists of isoniazid, rifampin, and pyrazinamide for
2 months followed by isoniazid and rifampin for 4 months, or isoniazid
and rifampin for 7 months, the length depending on whether there is
a pulmonary cavity on the chest X-ray at presentation and/or a posi-
tive sputum culture observed after 2 months of therapy. Other treat-
ment times are recommended for TB meningitis and TB osteomyelitis.
Other drug options listed in Table 33-5 are available in multidrug-
resistant tuberculosis. The pharmacologic features of isoniazid, rifam-
pin, pyrazinamide, and ethambutol are described here. Streptomycin
and other aminoglycoside antibiotics have been previously discussed.
Isoniazid
Isoniazid, the name of which derives from its chemical designation
of isonicotinic acid hydrazide, is the most important drug for the
treatment and prophylaxis of tuberculosis. Its spectrum of activity is
limited, however, to M. tuberculosis and one species of atypical myco-
bacteria, Mycobacterium kansasii.
Isoniazid inhibits the synthesis of mycolic acids, unique and nec-
essary components of the cell wall of mycobacteria. The drug is bacteri-
cidal to actively growing tubercle bacilli but not to dormant organisms.
Resistance to isoniazid occurs by spontaneous mutation of the bac-
terial chromosome at a rate of ∼1 in 106 divisions. Most established
infections can be expected to harbor at least several resistant bacteria.
There is no cross-resistance between isoniazid and other antitubercu-
losis drugs except ethionamide.
485
Isoniazid is well absorbed after either oral or parenteral adminis-
tration, but the oral route is preferred for reasons of convenience and
maximum therapeutic effect. The drug is well distributed into all body
fluids, including the caseous material of the tubercle-infected foci.
Isoniazid is mainly metabolized in the liver and excreted in the urine
as metabolites. Genetic differences in the rate of biotransformation are
seen, but these seem to have little effect on therapeutic efficacy. The
plasma half-life is prolonged in patients with hepatic dysfunction.
One important adverse reaction with isoniazid is peripheral neu-
ritis caused by an isoniazid-induced increase in the excretion of pyr-
idoxine. This adverse effect is more common in slow acetylators.
This reaction and other symptoms of pyridoxine deficiency can be
prevented by prophylactic administration of vitamin B6 (15 to 50 mg
daily). Other adverse effects include allergic reactions (fever, rashes,
hepatitis), fatal hepatic necrosis (rarely), xerostomia, epigastric dis-
tress, hematologic reactions, and convulsions in seizure-prone patients
(although administration of isoniazid to patients taking phenytoin
has not been problematic except for the potential of pharmacokinetic
effects on phenytoin metabolism). A nonallergic hepatitis of some
severity has also been reported, and subsequent studies have shown
that the incidence of hepatic damage increases with age and in individ-
uals who regularly drink alcohol.
Isoniazid is also effective prophylaxis against tuberculosis and
approved for single-drug therapy for prophylaxis. It is also the most
important drug used in tuberculosis therapy for reasons of effective-
ness, expense, convenience of administration, and relative safety.
Rifampin
Rifampin is a semisynthetic derivative of one of the rifamycins, a group
of macrocyclic antibiotics produced by Streptomyces mediterranei.
Rifampin is effective against numerous gram-positive and gram-neg-
ative bacteria in addition to M. tuberculosis and most other species of
Mycobacterium. Its mechanism of action involves inhibition of DNA-
dependent RNA polymerase. Mammalian RNA polymerase does not
bind the drug, and RNA synthesis in host cells is unaffected. Resistance
can develop rapidly to rifampin, frequently in a single step, by alter-
ation of the target enzyme.
Rifampin is generally well absorbed from the gastrointestinal tract
after oral administration. The drug is distributed throughout the body
and imparts an orange-red color to the urine, saliva, sweat, tears, spu-
tum, and feces. It is secreted in the bile and undergoes enterohepatic
recirculation, prolonging its half-life. Elimination occurs by hepatic
deacetylation and excretion in the urine and feces.
Rifampin may be useful in prophylaxis of tuberculosis in contacts
of patients infected with isoniazid-resistant organisms. The drug has
proven effective in certain diseases refractory to conventional therapy,
such as rifampin in combination as an option in treating resistant S.
pneumoniae and methicillin-resistant staphylococci.
The incidence of adverse reactions to rifampin is low (4%), and
the most common is liver toxicity. Gastrointestinal disturbances, sup-
pression of T-lymphocyte function, neurologic disorders, and various
allergic reactions, including soreness of the mouth and tongue, have
been reported. Decreased effectiveness of oral anticoagulants, oral
contraceptives, estrogens, and glucocorticoids have occurred with
concomitant administration of rifampin because rifampin induces
liver microsomal enzymes. Oral contraceptives are not likely to be
effective in a patient taking rifampin.
If rifampin is used sporadically, a flulike syndrome (possibly
immune related) may develop, sometimes leading to renal failure,
hepatorenal syndrome, hemolysis, and thrombocytopenia. The drug
should be taken according to a prescribed regimen. Because rifampin
can cause a reddish-orange color in body fluids, staining of soft contact
lenses may occur.
486 CHAPTER 33  Pharmacology of Specific Drug Groups: Antibiotic Therapy
Rifabutin
Rifabutin is chemically similar to rifampin and acts by a similar mecha-
nism. Rifabutin is not as potent an inducer of cytochrome P450 enzymes
as rifampin and offers the advantage of not interacting with other drugs
to the extent that rifampin does. It is useful in treating patients who have
HIV/AIDS because it has less interaction with protease inhibitors and
non-nucleosidase reverse transcriptase inhibitors. Adverse effects include
uveitis and neutropenia but are otherwise similar to those of rifampin.
Rifapentine
Rifapentine is a long-acting rifampin-type drug that has a similar
mechanism of action and similar adverse effects. It can be used twice
weekly for initial treatment and once weekly during the continuation
phase of treatment.
Pyrazinamide
Pyrazinamide is the pyrazine analogue of nicotinamide. It is converted
to pyrazinoic acid by bacterial pyrazinamidase. Pyrazinoic acid inhib-
its mycolic acid synthesis, and it disrupts cell wall function. It had
widespread use in the 1960s but proved to be hepatotoxic in the doses
used and was relegated to secondary status after the development of
isoniazid and rifampin. More recently, pyrazinamide in reduced dos-
age has reemerged as the third most important anti-tuberculosis agent.
Resistance to the drug in M. tuberculosis infection is associated with the
loss of pyrazinamidase activity.
Pyrazinamide is well absorbed after oral administration and is dis-
tributed throughout the body. It is metabolized primarily in the liver
and excreted largely in the urine.
Pyrazinamide is administered with other anti-tuberculosis drugs to
decrease the duration of therapy required to effect a cure of uncom-
plicated tuberculosis. Hepatotoxicity is the most common adverse
effect, but this has been less evident with the lower dosages currently
used. Other toxic effects associated with current regimens are relatively
benign or infrequent. Gastrointestinal disturbances, arthralgias, fever,
and rash have been noted. Pyrazinamide may cause hyperuricemia,
and the drug represents a risk in patients with gout.
Ethambutol
Ethambutol is a synthetic agent that inhibits arabinosyl transferases,
which are important in cell wall synthesis of sensitive mycobacteria. It is
active against M. tuberculosis and some other mycobacteria such as M.
kansasii. Other bacteria are not affected by the drug. Ethambutol is tuber-
culostatic, and resistance develops, although slowly, if it is used alone.
Ethambutol is given orally because of good absorption from the
gastrointestinal tract. Distribution into various body compartments
is adequate. The major route of excretion of ethambutol is by renal
tubular secretion and glomerular filtration, with the drug appearing
in the urine mostly as unchanged drug and as two metabolites. Dosage
adjustment is required in the presence of renal impairment.
Adverse reactions to ethambutol are infrequent, the most notable
being optic neuritis, with symptoms of decreased visual acuity and loss of
the ability to perceive the color green. Other adverse effects include gastro-
intestinal upset; peripheral neuritis; allergic reactions, usually appearing as
skin rashes or drug fever; and increased retention of uric acid.
Second-line drugs
A number of second-line drugs are used to treat tuberculosis. These
are useful in cases of resistance to first-line drugs and include ethion-
amide, capreomycin, kanamycin, amikacin, para-aminosalicylic acid
(whose mechanism is similar to that of the sulfonamides), cycloserine
(which inhibits cell wall synthesis), levofloxacin, moxifloxacin, and
other fluoroquinolones.
Drugs Used to Treat Leprosy
Although leprosy is rarely seen in the United States, the World Health
Organization estimates that 12 million cases exist throughout the
world. Leprosy is a bacterial disease caused by the tubercle bacil-
lus Mycobacterium leprae. Treatment may be 2 to 4 years or extend
throughout the patient’s life, depending on the severity and type of
disease.
Dapsone is the major drug used in the treatment of leprosy. It
belongs to a group of drugs called sulfones, which are chemical rela-
tives of sulfonamides. Dapsone is bacteriostatic against M. leprae, with
a mechanism of action similar to that of sulfonamides. Dapsone is used
orally. Other drugs, normally used in combination with dapsone, are
rifampin and clofazimine. Clarithromycin, minocycline, and ofloxacin
may also be effective.
Topical Antibiotics
Bacitracin
Bacitracin is a polypeptide antibiotic derived from B. subtilis that
functions to block cell wall formation by interfering with the dephos-
phorylation of the lipid compound that carries peptidoglycans to the
growing microbial cell wall (see Fig. 33-5). The antibacterial spectrum
of bacitracin is gram positive and includes staphylococci, streptococci,
Corynebacterium, and Clostridium, with rare resistance seen in staphy-
lococci. Bacitracin is too toxic to be used parenterally but is well toler-
ated topically. Bacitracin is commonly combined with neomycin and
polymyxin B in over-the-counter topical antibiotic preparations, but
evidence for efficacy is limited.
Neomycin
Neomycin is an aminoglycoside derived from Streptomyces fradiae
and binds to the 30S ribosomal subunit to inactivate bacterial DNA
polymerase and causes misreading of the genetic code to produce
lethal proteins. Neomycin has a wide antibacterial spectrum against
gram-positive and gram-negative bacteria, but it is ineffective against
streptococci and P. aeruginosa.
Polymyxin B
Polymyxin B was isolated from Bacillus polymyxa and functions as a
cationic detergent to disrupt the microbial cell membrane, causing a
leak in cell constituents. Its spectrum is gram negative, and it is par-
ticularly useful against P. aeruginosa. The drug is not used parenterally
because it commonly induces paresthesias, ataxia, and slurred speech.
Mupirocin
Mupirocin has a unique chemical structure composed of a short fatty
acid chain linked to monic acid; it inhibits bacterial RNA and protein
synthesis by binding to isoleucyl-tRNA synthetase to prevent incorpo-
ration of isoleucine into bacterial proteins. The antimicrobial spectrum
for mupirocin includes staphylococci (MRSA, MSSA), streptococci,
anaerobes, and Enterobacteriaceae. The primary use of mupirocin is
as a topical application for skin infections, such as impetigo due to S.
aureus or S. pyogenes. Mupirocin is also used to reduce or eliminate
nasal carriage of staphylococci, particularly MRSA. Its widespread use
is associated with an increase in the reinfection rate due to resistance
development or reinfection from other body areas.
Retapamulin
Retapamulin belongs to a group of drugs called the pleuromutilins.
The drug inhibits protein synthesis by binding to the 50S ribosomal
subunit. Retapamulin inhibits S. pyogenes and S. aureus (methicillin
susceptible). It also has activity against some gram-negative bacteria
and many anaerobes. It is used to treat impetigo.
 CHAPTER 33  Pharmacology of Specific Drug Groups: Antibiotic Therapy 487

ANTIBACTERIAL ANTIBIOTICS* CASE DISCUSSION

Nonproprietary (Generic) Name Proprietary (Trade) Name The most likely diagnosis based on the age and circumstances of the patient is
Aminoglycosides acute necrotizing ulcerative gingivitis (ANUG). The patient’s chills and temperature
Amikacin Amikin indicate that she has signs of a systemic infection, most likely due to the spread of
Gentamicin Garamycin, Jenamicin the oral infection. You do two things at the first appointment: (1) debridement and
Kanamycin Kantrex (2) prescribe amoxicillin 500 mg t.i.d. for 7 to 10 days. Although ANUG should be
Neomycin Mycifradin treated by local debridement, you reason that the antibacterial drug is needed to
Netilmicin Netromycin reduce the systemic involvement. Amoxicillin is an extended-spectrum penicillin.
Paromomycin Humatin When you begin debridement, the patient may complain of pain. As a result
Streptomycin — you may use mild ultrasonic scaling to remove some of the supragingival
Tobramycin Nebcin plaque in the first appointment. Before dismissing the patient, you give her
instructions on good oral hygiene, proper diet, and, if the patient is a smoker,
Antituberculosis Drugs (Not Included Elsewhere in This List) to enter a smoking cessation program. You instruct the patient to call in three
Aminosalicylate sodium Tubasal days to check on progress. You find that the patient is much better in three
Bedaquiline Sirturo days and then schedule a second appointment to complete the scaling and
Capreomycin Capastat Sulfate removal of plaque.
Cycloserine Seromycin Adverse effects of amoxicillin or other penicillins include allergies that can
Ethambutol Myambutol range from mild to anaphylactic reactions. Amoxicillin is an extended-spectrum
Ethionamide Trecator antibiotic. This could lead to a superinfection if given for several days. Amoxi-
Isoniazid Nydrazid cillin is usually well tolerated.
Pyrazinamide —
Rifabutin Mycobutin
Rifampin Rifadin, Rimactane
Rifapentine Priftin
GENERAL REFERENCES
1. Abramowicz M, Zuccotti G, editors: Handbook of antimicrobial drugs:
Topical Antibiotics
drugs for bacterial infections. The Medical Letter, ed 20, New Rochelle,
Bacitracin Baciguent NY, 2015.
Mupirocin Bactroban 2. Albert RK, Schuller JL: Macrolide antibiotics and the risk of cardiac
Neomycin Myciguent arrhythmias, Am J Respir Crit Care Med 189:1173–1180, 2014.
Polymyxin B Aerosporin 3. Bennett PM: Plasmid encoded antibiotic resistance: acquisition and transfer
Retapamulin Altabax of antibiotic resistance genes in bacteria, Br J Pharmacol 153:S347–S357, 2008.
Bacitracin with neomycin and polymyxin B Neosporin 4. Bennett JE, Dolin R, Blaser MJ, editors: Mandell, Douglas, and Bennett’s
principles and practice of infectious diseases, ed 8, New York, Saunders,
Miscellaneous Agents 2015, Elsevier.
Chloramphenicol Chloromycetin 5. Cho H, Uehara T, Bernhardt TG: Beta-lactam antibiotics induce a lethal
Clofazimine Lamprene malfunctioning of the bacterial cell wall, Cell 159:1300–1311, 2014.
Colistimethate Coly-Mycin M 6. Drugs for bacterial infections, Med Letter 11(131):65–74, 2013.
Colistin In Coly-Mycin S 7. Drugs for tuberculosis, Med Letter 10(116):29–36, 2012.
Dalbavancin Dalvance 8. Leffler DA, Lamont JT: Clostridium difficile infection, N Engl J Med
372:1539–1548, 2015.
Dapsone —
9. Macy E: Penicillin and beta-lactam allergy: epidemiology and diagnosis,
Daptomycin Cubicin
Curr Allergy Asthma Rep 14:476, 2014 (published online).
Fidaxomicin Dificid 10. Salyers AA, Whitt DD: Bacterial pathogenesis: a molecular approach, ed 2,
Fosfomycin Monurol Washington, DC, 2002, ASM Press.
Lincomycin Lincocin
Linezolid Zyvox
Methenamine Hiprex, Mandelamine, Urex
Metronidazole Flagyl
Nitrofurantoin Furadantin, Macrodantin
Oritavancin Orbactiv
Quinupristin/dalfopristin Synercid
Tedizolid Sivextro
Telavancin Vibativ
Telithromycin Ketek
Tigecycline Tygacil
Troleandomycin TAO
Vancomycin Vancocin

*Agents not shown here are listed in various tables throughout this
chapter.