ANTIBACTERIAL AGENTS

nfectious diseases are among the most common forms of illness. Thus, many patients under­

I going physical rehabilitation may be taking one or more antimicrob ial drugs. Most agents
(but not all) have little direct impact on the functional rehabilitation outcomes, but they will
certai nly have an impact on the overall health status of the patient.
The next fo u r chapters address agent s used to treat infections caused by various p a r a s i t e s
including bacteria, vir uses, fungi, protozoa, and helminths (worms). Once these pathogens
gain access inside the human body, they can cause illnesses ranging from minor infections to
life-threatening i l lnesses. Antimicrobia l drugs are among the most dramatic examples of
advances of modern medicine; many infectious diseases once considered incurable and lethal
are now amenable to treatment. Antimicrobial drugs are classified and identified according
to the p rimary type of infectio us organism they are used to treat (e.g., antibacterial, antivi­
ral, anti fungal).
The remarkably powerful and specific activity of antimicrobial dru gs is due to selective
toxicity--that is, drugs are designed to target structures selectively that are either u nique to
m icroorgan i s m s or much more important in them than in humans. Therefo re, a general under­

s tanding of mic ro b i al str ucture and function is necessary to understand me mechanisms of

action of antimicrobial agents. Notably, selective toxiciry is not perfect, and antimicrobials may
exert some adverse ef f ects in humans.

BACTERIAL PATHOGENI CITY

Bacterial infec t ions harm humans in several ways. Bacteria can direcdy damage or destroy
human cells by releasing toxins, and they can compete with human cells for vital nu trients. In
addition, in immunocompetent individuals, bacteria trigger a hos t immune response that may
damage not o n ly pathogenic bacteria b u t also human cells and tissues.
It is also important to unders tand that not all bacteria living in the human body are harm­
ful. In fact, some bacteria no rmally coexist within humans and acrually benefit their human
hos ts. For example, Escherichia coLi microorganisms n o rma ll y inhabit the gastrointes tinal tract
and are thus cons idered pan of the normal flora. E coLi assist in digestion of food, synthesize
essemial nutrients such as vitamin K, and inhibit the growth of o ther organisms. As an illus­
(['atio n of the latter function, antibiotic therapy often results in the eradication of normal gut
flora. After antibiotic treatment is completed, overgrowth of other microorganisms (e.g., yeasts)
often occurs.

369
370 CHEM O THERA P E UT I C S
BACTERIAL S TRUCTURE
AND NOMENCLATURE
The target site for antibacterial drugs, or antibiotics, is
either the cell wall o r structu res involved in bacterial
reproductio n.
Bacteria are single-celled prokaryotes (cells wimou t
a dis tin c t n u cleus) that have a characteristic cellular
organization. Fungi, prorowa, and multicellular organ­
isms have nuclei conta i n i ng their genetic material and
are called eukaryotes. Viruses, on the o ther hand, are not
strictly cel lular at all and comprise a very differen t form
of life. Bacterial deoxyribonucleic acid (DNA) forms a
long circular mo lecule called a nucleoid. In additio n,
genetic information may be presen t in DNA molecules
termed plasmids. Plasmids replicate independenrly of
chromosomal DNA and may carry genes that affect
resistance to an timicro bials (i. e., plasmid-mediated
resimnce). Bo th nucleoid DNA and plasmids are sub­
ject to mutations mat can be passed on to daughter cells.
In addition, bacteria can exchange genetic material by a
process called conjugation, mus allowing passage of drug
resistance genes witho ut mutation. Both nucleoid and
plasmid DNA are transcribed into messenger ribo nu­
cleic acid (RNA) by the enzyme RNA polymerase.
Ribosomal function is the same in prokaryotic and
eukaryotic cells-that is, ribosomes translate messen­
ger RNA in to a new protein chain, the final product of
the gene. However, ribosomal structure is characterized
as 70S in prokaryo tes and as 80S in eukaryotes. (The
"5" un i t refers ro how a molecule sedimen ts u nder cen­
trifugal force in an u l tracentrifuge.) The bacterial 70S
ribosome is specifically targeted by certain antibacteri­
als such as the aminoglycosides. Two major subunits
comprise the ribosome: 305 and 50S in prokaryo tes
and 405 and 60S in eukaryo tes.
In all bacteria except mycoplasmas, the cell is
completely s u rro u nded by a cell wall, a structure not
fo u nd in e ukatyo tes. The cell wall lies exte rnal to a
cytoplasmic membrane, which is simi lar to the cell
membranes of eukaryotic cells. The cell wall's rigidity
main tains cell integrity, pro tecting bacteria from lysis
due to high in ternal osmo tic pressure.
Bac teria are classified as gram positive or gram neg­
ative accotding to their cell wall structu re. The primary
structural component of the ceJl wall is a peptidoglycan,
a polymer of sugars and charged ami no acids, which
make the peptidoglycan highly polar. In gram-posi tive
bacteria, the peptidoglycan fo rms a very thick
hydrophilic layer external to the cell membrane. The
thick hydrophilic surface of gram-positive bacteria can
be digested by lysozyme, an enzyme present in body
secretions and in tracellular organelles, but provides pro­
tection against most other enzymes and bile in the
intestine. Pe n i cill i n and cephalospo rin antibiotics
inhibit bacterial cell wall synthesis by disrupting pepti­
doglycan formatio n. In gram-negative bacteria, the
peptidoglycan layer is thinner and anchored to an over­
lying o u ter membrane (Figu re 27-1). The ou ter mem­
brane is relatively hydrophobic. To enabl e hydrophil ic
n u trients to e nter the cell, gram-negative bacteria have
special pores fo rmed by proteins called porins.
The ceU wall is a primary determinant of the ulti­
mate shape of the bacterium, which is an important char­
acteristic for bacterial identification. In general, bacterial
shapes are categorized as spherical (cocci), rods (bacilli),
or helical (spirilla). Although each bacterium is named
according to its gen us and species (e.g., Staphylococcus
aureus), bacteria are otten categorized by common char­
acteristics such as hisrologic s taining properties and
shape. For example, gram-positive cocci i nclude bacteria
that stain in a certain manner (determined by the gram­
positive cell wall) and are spherical in shape (cocci). This
group includes S aureus and Streptococcus pneumoniae.
The most commo n way to classifY an tibio tics is
on the basis of their site of actio n: inhibitors of bacte­
rial cell wall synthesis, inhibitors of bacterial protein
synthesis, and inhibito rs of bacterial DNA synthesis.
Antimycobacterial drugs are discussed separately.
PRINCIPLES OF ANTIBIOTIC
THERAPY
Some an tibio tics are bactericidal (kill bacteria), while
o thers are bacteriostatic (inhibit bacterial growth). Bac­
teriostatic an tibio tics are successful in treating i nfec­
tions in patien ts with intact immune systems because
they preve n t the bacterial population from increasing,
and allow host defe nse mechanisms ro eradicate the
remaining pop u lation. For bacteriostatic drugs (e.g.,
 Antibacterial Agents 371

Outer
membrane

Cell
wall

} Periplasmic
space

Cytoplasmic
membrane

Figure 27-1. A simplified diagram of the cell envelope of a gram-negative bacterium. The outer mem brane,
a lipid bil ayer, is present in gram-negative but not gram-positive bacteria. It is penetrated by porins, pro­
teins that form channels providing hydrophilic access to the cytoplasmic mem brane. The peptidoglycan layer
is unique to bacteria and is much thicker in gram-positive bacteria than in gram-negative bacteria. Together,
the outer mem brane and the peptidoglycan l ayer constitute the cel l wal l. Penicillin- binding proteins (PBPs)
are mem brane proteins that cross-link peptidoglycan. B-Lactamases, if present, reside in the periplasm ic
space or on the outer surface of the cytoplasmic mem brane, where they may destroy B-Iactam antibiotics
that penetrate the outer mem brane.

clindamycin, macrolides, sulfonamides, tetracyclines), concentrations above the minimal inhibitory concentra­
th e concentrations that inhibit growth are much lower tion (MIC) for as long as possible, Howeve r, the in vivo
than those that kill bacteria. Bactericidal dr ugs (e.g., effectiveness o f some antibiotics (e.g., aminoglycosides)
aminoglycosides, �-lactams, fluoroquinolones, strep­ results from a concentration-dependent killing action. As
togramins, vancomycin, and most antimycobacterial the plas ma level is increased above the MIG these agents
agents) are preferred for treati n g infections in kill an i nc reasing proporrion of bacteria and do so at a
immunocompromised patien ts because they are able more r api d rate. Many other antibiotics (e.g., penicillins

to eradicate an infection even in the absence of nor­
mal host defense mechanisms. For bactericidal dr ugs,
there is l itt le difference berween concen trations that
inhibit grow t h and t h os e that kill bacteria.
Dosage regimens with an t ibioti cs have tra di t i on ­
ally llsed mul tip l e d ai l y doses to maintain serum
and ceph al osp orins) cause time-dependent ki l li ng of bac­
te ria , wherein th ei r in vivo efficacy is directly related to
time above MIC and becomes i n de pe n de n t of concen­
tr at i on once the MIC has been reached.
Some agents exert a postantibiotic effect in which
inhibition of bacterial growth continues after p l as ma
372 CHEMOTHERAPEUTICS

levels h a ve faJlen ro low levels. The mecha n isms of the
p o s t a n ribio ric e ffe c t a re u nc l e a r , but may refle c t
d e l ayed t i m e re q u i r e d b y b ac r e ri a r o s y n r h e s i ze new
enzymes and cellular componenrs, pers i s tenc e of
a n r i b io tic at targe t sites, o r e n h a n ce d su s cep t i bi l i ry of
bacteria ro host defe nse mechanisms. The postan ribi­
otic effect conrri b u tes ro the e ffi c a c y o f onc e - d a il y
ad m inis r ration of a min og l y co s i des , and may also con­
rri b u t e ro the efficacy of the fluoroquinolones.
ANT I B I O T I C RES ISTANCE
The e mergence of microbia! resistance poses an increas­
in g cha l l e n g e to the use of all a n t i microbial d r u gs . The
mec h anisms u n d erlying micro b ia l resistance to antibi­
oti cs i n cl u d e production of drug-inactivating enzymes,
c ha n ges in t h e s tr uct ur e of target receptors, i n creased
anribiotic efflux via d rug transporters, and decreases
in cell wall perm eabi lity to antibioti cs. S rra te gi es
designed to combat m i cro bial resis tance i n c l ude the
use of additional a ge n t s that protect against e nzy m atic
inacrivation, the use of anribiotic combinations, t he
introduction of new ( a n d often e x pe n s i v e ) ch emical
de r i va t i ve s of es t a b li shed a n tibio tics, a n d effortS to
avoid ind iscriminate use or misuse of a n tibiotics.
The most common cause of resis tance is the use of
inappropriate anti bio tics for viral or other nonsusceptible
infectio n s . This presen ts r e s i d e nr and enviro n m ental
orga n i s m s w i th selec tive pressu re to deve lop resistance
ro the d r u g bei n g used. A secondary cause of resistance
is t h e use of i n a de qu a te dosage or d uration of an
appro p r i ate d r ug. Such treatmenr eliminates onl y the
most susceptible o rga nisms, l eavi n g the m ore re sist anr
ones to p r o l ifera te.
INHI BITORS OF BACTERIAL CELL
WALL S YNTHES IS
The major a n r i b i o tics i n this class are penic i l l ins and
cephalosporins. These agenrs o nly kill bacterial cells that
a re a ct i ve l y growing a n d synrhesizing new cel l wal l s .
They are called �- lactams, o r �- lactam a n ti b i o tics,
because they sh are an unusual four-member ring struc­
ture called a �-lactam r i n g . The �- lactam an ti b iot i cs
include some of the most effective, widely used, and weU­
ro l e r a te d a n timicro bial agents. The sel ective toxiciry of
�-lactams and o ther cell wall synrh esis inhibitors is due
to specific actions on the synthesis of ceU walls-s- truct u res
that are unique to bacteria. More th a n 50 a n ribiotics
that act as cell wall synthes is inhibitors are curren tly avail­
ab le, w i th i ndividual spectra of a cti viry chat afford a wide
range of clinical a p plications. Figu re 27-2 o u rl i nes this
broad class of cell wall s y nt h es is inhi b i to rs, a n d
Ta b l e 27-1 lists the key d rugs i n this class.

Bacterial cell wall synthesis inhibitors

Penicillins Cephalosporins Miscellaneous

Narrow Wider
�
Narrow Wider Carbapenems
spectrum spectrum spectrum spectrum

Penicillinase
I
151 generation
I
2nd, 3rd, 41h
Aztreonam

generations
susceptible
Vancomycin

Penicillinase
resistant

Figure 27-2. Key classes of drugs that inhibit bacterial cell wall synthesis.
 Antibacterial Agents 3 7 3

Table 27-1. Key inhibitors of cell wall synthesis

Subclass Prototype Other Significant Agents

Penicillins
Limited spectrum Penicillin G Penicillin V
f3-lactamase-resistant Methicillin l\Jafci IIi n, oxaciII in
Wider spectrum Ampicillin Amoxicillin, piperacillin, ticarcillin
Cephalosporins
First-generation Cefazolin Cephradine
Second-generation Cefamandole Cefaclor, cefotetan, cefoxlti n
Th i rd-generation Cefoperazone Cefotaxime, ceftazidime, ceftriaxone
Fourth -generation Cefepime
Carbapenems Imipenem Ertapenem, meropenem
Monobactam Aztreonam
13-lactamase inhibitors Clavulanic acid Sulbactam, tazobactam
Other agents Vancomycin Bacitracin, cycloserine, fosfomycin

Penicillins Mechanisms ofAction and Resistance

All pen icillins are derivatives of 6-aminopenicillanic The �-lactams exert bactericidal effects by inhibiting

acid and contain a �-Iac[am ring structure that is cell wall synthesis. Inhibition of cell wall synthesis

essential (01- antibacterial activity_ Penicillin sub­ occurs as follows (Figure 27-1): (1) binding of the

classes have additional chemical modifications that �-lactam agent ro specific recepror p rotei ns called

confer differences in antimicrobial activiry, suscepti­ peniciJJin-binding proteins (PBPs) located in the baere­
bi li ty to acid and enzymatic hydrolysis, and biodis­ rial cyroplasmic membrane, enzymes that cross-link

position_ Penicillins vary in their I-esistance ro gastric linear peptidoglycan chains that form parr of the cell

acid a nd, ther e fo re, vary in their oral bioavailability_ wall; and (2) aerivation of autolytic enzymes that

Except for amoxicillin, oral p enic i l l ins should gen­ cause lesions in the bacterial cell wall.

erally not be g iven with food ro minimize binding Bacteria have developed several mechanisms ro

ro food proteins and acid inactivation. Thus, patients resist destruerion by �-lactam drugs. The most com­

should be advised ro take pen ici ll ins 1 ro 2 hours mon mechanism of resistance is the production of�­

before or after meals. Penicillins are not metabolized lacramases (peniciJlinases) by many bacteria (especially
extensively; they are usually excreted un changed in Staphylococcus species and many gram-negative organ­

the urine via glomerular filtration and [Ubular secre­ isms). 13-Lactamases hydrolyze the �-lactam ring of

tion.Ampicillin and nafcillin are excreted pardy in these antibiotics, resulting in the loss of antibacterial

the bile. The pl asma half-lives of most penici l li n s activity. To prevent the inactivation of the �-la((am
ri ng , pencillins are sometimes administered in combi­
vary from 30 [Q 60 minutes. Two forms of penicill i n G,
the prototype of a subclass of penicillins with a lim­ nation with inhibirors of bacterial �-laccamases (e.g.,

ited antibacterial spectrum, are administered intra­

clavulanic acid, sulbacram, tazobacram) . Another mech­
mu s c u la r l y and have long plasma half-lives because anism of resistance is structural change in target PBPs.

the aerive drug is released very slowly into the blood­ T his is an important mechanism because altered PBPs

s o ea m . Most peniciIlins cross the blood-brain barrier

·
are responsible for methicillin resiscance (in staphylo­

only when t h e meninges are inflamed (e.g., in cocci) and penicillin resistance (in pneumococci and

meningitis). enterococci). In some gram-negative bacteria, resistance

374 CHEMOTHERAPEUTICS
may be due to impaired penetration of antibiotics to
their target PBPs. To cross the outer membrane that
distinguishes gram-negative from gram-positive bac­
teria, p-lactams must enter gram-negative bacteria via
porins (Figure 27-1). Altered porin structures may
contribute to resistance by impeding p-Iactam access
to PBPs. Finally, some gram-negative bacteria may pro­
duce efflux pumps that effectively expel some p-lactam
agencs that get past the outer membrane.
Clinical Uses
Penicillins can be divided into very narrow, narrow,
and wider spectrum agents, with spectrum referring to
the number of organisms against which they provide
ancibacterial activity. T hey may also be classified by
whether the agents are susceptible to bacterial p-Iacta­
mase (penicillinase) (Figure 27-2).
Among the narrow-spectrum peniciUinase-susceptible
agents, penicillin G is the prorotype. Clinical uses
include treatment for infections caused by common
streprococci, meningococci, gram-positive bacilli, and
spirochetes. Many strains of pneumococci are now
resistant to penicillins. Most strains of Staphylococcus
aureus and a significant number of strains of Neisseria
gonorrhoeae are resistant via production of p-Iactamases.
Penicillin V, the oral equivalenc of penicillin G, is only
used in minor oropharyngeal infections.
The very narrow-spectrum penicillinase-resistant
subclass includes the prototype methicillin, nafcillin,
and oxacillin. Their primary use is in the treatment of
known or suspected staphylococcal infections. However,
methicillin-resistant Sta p hylococcus aureus (MRSA) and
methicillin-resistant Staphylococcus epidermidis (MRSE),
two strains important in many hospital-acquired infec­
tions, are resistant to other members of this subgroup
and are often resistant to multiple antimicrobial drugs.
Wider spectrum penicillinase-susceptible drugs
are among the most commonly used penicillins. Ampi­
cillin and amoxicillin are often used to treat urinary
tract infections (UTIs), otitis media, pneumonia, and
bacteremias resulting from infections with susceptible
bacterial species. Piperacillin and ticarcillin have activ­
ity against several gram-negative bacteria, including
Pseudomonas (e.g., UTI, pneumonia, bacteremia),
Enterobacter (e.g., UTI), and in some cases Klebsiella
species (e.g., UTI, pneumonia). For infections with
penicillinase-producing bacteria, inhibitors of penicil­
linases (e.g., c1avulanic acid) are co-administered to
enhance the antibacterial activity of this subclass. Most
drugs in this subclass have synergistic actions when
used with aminoglycosides, inhibitors of protein syn­
thesis discussed later in this chapter.
Adverse Efficts
T he penicillins are remarkably nontoxic. However, the
potential for allergic reactions is a concern and allergic
reactions account for most of the serious adverse effects.
All penicillins are cross-sensitizing and cross-reacting, so
cross-allergenicity among different penicillins is
assumed. About 5 ro 10% of individuals with a history
of penicillin reaction have an allergic response when
given a penicillin again. Allergic reactions include
u[[icaria, severe pruritus, fever, joint swelling, hemolytic
anemia, nephritis, and in rare cases anaphylaxis. Methi­
cillin causes nephritis more often than other penicillins,
and nafcillin is associated with neutropenia. Ampicillin
frequently causes maculopapular skin rash that does not
appear to be an allergic reaction.
Large oral doses of penicillins, especially ampi­
cillin, may lead to gastrointestinal upset (e.g., nausea,
vomiting, and diarrhea). Gastrointestinal upset may
be caused by direct irritation or by overgrowth of
gram-positive organisms or yeasts.
Problems Relating to the Use and Misuse ofPenicillins
Penicillins are among the most misused antibiotics,
having been used irrationally for nonsusceptible infec­
tions for over 50 years. As a result, 90% of all staphy­
lococcal strains both in the hospital and in the
community are p-Iactamase producers, and the preva­
lence of methicillin-resistant strains of S aureus
(MRSA) continues to increase. Broad-spectrum peni­
cillins also eradicate normal flora, thereby predisposing
the patient to colonization and superinfection with
opportunistic, drug-resistant species present within the
hospital environment.
Cephalosporins
The cephalosporins also contain the p-Iactam ring struc­
ture, and are tl1erefore classified as p-lactam antibiotics.

They vary in rheir amibacrerial acriviry and are desig­
nared hrsr-. second-. rhird-. or fourrh-generarion drugs
according ro rhe order of rheir inrroducrion inro c1ini­
cal use (Figure 27-2). Several cephalosporins are avail­
able for oral use (e.g.. cephalexin. ceflXime). but mosr
are adminisrered parenterally. Cephalosporins with
side chains may undergo heparic merabolism. but the
major eliminarion mechanism is renal excretion via
aC[ive rubular secrerion. Cefoperawne and ceftriaxone
are excrered mainly in rhe bile. Mosr first- and second­
generarion cephalosporins do not enter rhe cere­
brospinal Auid even when rhe meninges are inAamed.
Mechanisms ofAction
Cephalosporins have a broader specrrum of acriviry
rhan the penicillins because rhey are less susceprible ro
many bacrerial penicillinases. Cephalosporins' bacre­
ricidal acrivity resulrs from binding ro PBPs in bacre­
rial cell membranes and imerfering wirh bacrerial cell
wall synthesis.
Bacterial resisrance ro cephalosporins can resulr
from cerrain �-laC[amases. decreases in membrane per­
meabiliry to cephalosporins. and from altered PBP
srructures. Merhicillin-resisrant sraphylococci (i.e
MRSA) are also resisram ro cephalosporins.
Clinical Uses
Cefazolin (parenreral) and cephalexin (oral) are examples
of firsr-generarion cephalosporins. Alrhough rhey are
fairly broad-spectrum agenrs wirh very minimal toxici­
ties. first-generarion cephalosporins are rarely drugs of
choice for any infecrion. Clinical uses include rrearmenr
of infections caused by gram-positive cocci. including sus­
ceptible staphylococci and common srreptococci. Cefa­
wlin may be [he drug of choice in infections for which ir
is the least toxic drug (e.g.. Klebsie!1£l pneumoniae).
Second-generation agents include cefotetan, cefox­
irill. cefamandole. cefuroxime, and cefuclor. Members of
this subclass usually have less activity agains[ gram-posi[ive
organisms rhan firsr-generation drugs. bur have ex [ended
gram-negative coverage. Marked differences in acriviry.
pharmacokinerics, and toxiciry occLu" among second­
generarion agents. Examples of clinical uses include infec­
tions caused by Bacteroides fagilis (e.g peritoniris.
.•
diverticuliris) and Haemophifus influelZZae or Moraxefl£l
catarrhali.r (e.g.. sinusiris. oritis.lower respiratory infections).
Antibacrerial Agenrs 375
Characrerisric fearures of third-generarion drugs
(e.g .• ceftazidime, cefoperazone, ceforaxime) include
increased acriviry againsr gram-negarive organisms
resisranr to orher �-lacram drugs and abiliry ro pene­
rrare rhe blood-brain barrier (excepr cefopera20ne and
cefixime). Individual drugs have acriviry againsr
Pseudomonas (cefopera7.0ne. cefrazidime) and B fag­
ilis (ceftizoxime). Drugs in this subclass are usually
reserved for rrearmenr of serious infections (e.g .• bac­
terial meningiris). The exceptions are ceftriaxone (par­
enreral) and ceflXime (oral). which are currenrly drugs
of choice to ([eat gonorrhea. Likewise, in acute oriris
media. a single injecrion of cefrriaxone is usually as
effecrive as a lO-day rreatmem course wirh amoxicillin.
The fourrh-generarion agents have rhe w idest
anribacrerial spec([um of rhe cephalosporins. They are
more resistant ro �-lactamases produced by gram­
negative organisms. including Enterobacter, Haemophilus,
Neisseria, and some penicillin-resistanr pneumococci.
Cefe pime. rhe prororypic fourrh-generarion agent.
combines the gram-posirive acriviry of firsr-generarion
agenrs with [he wider gram-negative spectrum of
rhird-generation cephalosporins.
.•
Adverse Efficts
Cephalosporins may e1icir a variety ofhypersensiriviry
reacrions rhar are idenrical to rhose of penicillins.
including fever. skin rashes. nephriris. granulocytope­
nia. h emolytic anemia, and anaphylaxis. However.
rhe chemical nucleus of cephalosporins is sufficienrly
differenr from rhat of penicillins so rhar some individ­
uals wirh a history of penicillin allergy may somerimes
be rreared successfully wirh a cephalosporin. However.
parienrs wirh a hisrory of anaph ylaxis to penicillins
sh ould not receive cephalosporins. Complete cross­
hypersensirivity among differenr cephaJosporins should
be assumed.
Cephalosporins may cause pain at inrramuscu­
lar injecrion sires a nd phlebiris after inrravenous
adminisrrarion. They may increase the nephrotoxic­
ity of aminoglycosides when the (wo are adminisrned
rogether. Drugs conraining a merhylthiorerra7.0le
group (e.g., cefamandole. cefoperazone. cefoteran)
may cause hypopr orbrombinemia and disulfiram-like
reacrions wirh ernanoL
376 CHEMOTHERAPEUTICS

Other �-Lactam Drugs anribacterial action themselves. They are adminis­

rered in fixed combinarions wirh certain penicillins
Several other �-Iacram drugs are of clinical Impor­
co treat infecrions caused by bacteria that produce
rance. Aztreonam is neirher a penicillin nor a
�-Iactamases. Adverse effects of these drug combi­
cephalosporin. Ir is a monobacram, named for its
nations are caused primarily by the penicillin agent.
chemical structure rhat contains one �-lactam ring.
Aztreonam is resistanr to �-Iactamases produced by
certain gram-negative rods, but has no activity against
Other Inhibitors of Cell Wall Synthesis
gram-posirive bacteria or anaerobes. It inhibits cell waJl
Vancomycin is a glycopeptide antibiotic produced by
synrhesis by preferentially binding co a specific
penicillin-binding protein (PBP3). It is synergistic
a strain of Streptococcus. It binds to a unique set of
amino acids used in cross-linking the peptidoglycan
with aminoglycosides. Aztreonam is administered
cell wall. As a result, chains of the peptidoglycan can­
intravenously, and is eliminared via renal tubular secre­
not be cross-linked and the cell wall is disrupted,
tion. Penicillin-allergic patienrs rolerate azrreonam
making rhe bacrerial cell susceptible to lysis. Van­
without reaction. Adverse effects include gastroinresti­
comycin has a narrow spectrum of activity Jnd is used
nal upser with possible superinfection, vertigo, headache,
for serious infections caused by drug-resisrant gram­
and rare hepacotoxicity.
positive organisms, including MRSA, penicillin­
Imipenem, meropenem, and ertapenem are car­

bapenems and are chemically different from pencillins.

resistant pneumococci, Clostridium difficile.
and
Teicoplanin, another glycopeptide, has similar char­
While they retain the �-lactam ring structure, they have
acteristics.
low susceptibility to f3-lacramases. Carbapenems have
Some strains of enterococci and staphylococci have
wide acrivity against gram-positive cocci (including
become resistanr to vancomycin (i.e., vancomycin­
some penicillin-resistant pneumococci), gram-negative
resisrant enterococci [VRE] and vancomycin-resisrant
rods, and anaerobes. The carbapenems are administered
parenrerally, and are especially useful for infections
S au reus [VRSAJ). Resisrance to vancomycin is due to
a single amino acid change in rhe bacterial binding site
caused by organisms resistanr to other antibiotics.
for vancomycin, which significantly decreases its bind­
Because imipenem is inactivared by a renal
ing affinity. The prevalence of VRE is increasing and
enzyme, it is administered in combination with cilas­
poses a serious clinical problem because such organisms
ratin, an inhibitor of this enzyme. Adverse effects of
usually exhibir mulriple-drug resistance. Likewise,
imipenem-cilastatin include gasrroinrestinal distress,
strains of MRSA have been repotTed with inrerrnediate
skin rash, and, at very high plasma levels, central nerv­
resistance ro vancomycin, leading to treatment failures.
ous system (CNS) coxicity (confusion, encephalopa­
Vancomycin is not absorbed From the gastroin­
rhy, seizures). There is partial cross-allergenicity wirh
(estinal trac[, but may be given orally to rreat bacterial
rhe penicillins. Meropenem is similar co imipenem
enterocolitis . When given parenterally, vancomycin
except that ir is nor metabolized by renal enzymes and
penerrates mosr [issues and is eliminated unchanged
is less likely co cause seizures. Errapenem has a long
in the urine. Dosage modificarion is mandatory in
half-life, and irs inrramuscular injecrion causes pain
parienrs with renal impairment. Toxic eFfecrs of van­
and irritarion.
comycin include chills, Fever, phlebitis, ototoxicity, and
nephroroxicity. Rapid inrravenous inFusion may cause
�-Lactamase Inhibitors
diFfuse flushing Cred man syndrome").
An obvious problem with using �-Iactam antibiotics Daptomycin, a new lipopeptide agent, is chemically
such as pencillins and cephalosporins is that many differenr From vancomycin and has a diFferent mecha­
bacteria prod uce �-lactamases that inacrivate rhese nism of action, bur a similar spectrum of acriviry and
agenrs. Clavulanic acid, sulbactam, and tazobacram indications. It is active againsr several strains of VRE
are �-lactamase inhibirors rhar have little or no and VRSA. Daptomycin is described in Chapter 30.
 Antibacterial Agents 3 77

Other inhibitors of cell wall synthesis include
bacitracin and cycloserine. Bacitracin is a peptide
antibiotic that interferes with a late stage in cell wall
synthesis in gram-positive organisms. Because of its
marked nephrotoxicity, this antibiotic is limited to top­
ical use for skin lesions. Bacitracin solutions in saline
can also be used for irrigation of joints, wounds, or the
pleural cavity. Cycloserine prevents formation of a
functional bacterial peptidoglycan. Because of its
potential neurotoxicity (tremors, seizures, psychosis),
cycloserine is only used to treat srrains of Mycobac­
terium tuberculosis (the causative agent of tuberculosis)
that are resistant to first-line antituberculous drugs.
INHIBITORS OF BACTERIAL
PROTEIN SYNTHESIS
The basic process by which mammalian and bacterial
cells make proteins is similar. In both mammalian and
bacterial cells, the specific genetic information con­
tained within DNA is transcribed into messenger
RNA (mRNA). Next, mRNA is translated into a new
polypeptide or protein chain. The role of ribosomes in
this process is to move along the mRNA chain, recruit
transfer RNA (tRNA) molecules that carry different
amino acids, and join incoming amino acids to the
growing polypeptide chain. One critical difference
berween protein synthesis in mammalian and bacter­
ial cells is the structure of their ribosomes.
Differences in ribosomal subunits, chemical com­
position, and functional specificities of component
nucleic acids and proteins form the basis of selective
toxicity of certain antibiotics against bacterial protein
synthesis with much less effect on mammalian cells.
Although drugs in this class vary dramatically in
their structure and spectrum of antimicrobial efficacy
(Figure 27-3), each agent inhibits bacterial protein
synthesis by acting at the level of the bacterial ribo­
some. Chloramphenicol, tetracyclines, and amino­
glycosides were the first inhibitors of bacterial protein
synthesis to be discovered. Because they had a broad
spectrum of antibacterial activity and were thought to
have low toxicities, they were overused. As a result,
many once highly susceptible bacterial species have
become resistant, and these drugs are now only used
for more selected targets. Erythromycin, an older
macrolide a n ti bi o ti c , has a narrower spectrum of
action but continues to be active against several impor­
tant pathogens. Newer drugs (e.g., streptogramins,
linewlid, telithromycin) have activity against certain
gram-positive bacteria that have developed resistance
to older antibiotics.

Bacterial protein synthesis inhibitors

Broad spectrum Moderate spectrum Narrow spectrum

Chloramphenicol Macrolides Aminoglycosides Ketolide Lincosamides

(erythromycin, (gentamiCin, (telithromycin) (clindamycin)
azithromycin, streptomycin,
clarithromycin) neomycin, Streptogramins
tobramycin) (quinupristin­
Tetracyclines dalfopristin)
(tetracycline,
demeclocycline, Oxazolidinones
doxycycline, (Iinezolid)
minocycline)

Figure 27-3. Diagram classifying inhibitors of bacterial protein synthesis based on spectrum of antibacterial activily.
378 C H E MOTHERA P E U T I C S
Mechanisms o f Action
M o s t a n t i b i o t i cs i n t h is s u bclass are bacter iosta t i c .
Figu re 27-4 illusua tes the s pec i fi c b i n d i n g s it es on the
70S bacte rial ri boso mal complex fo r ch l o ram phen ico l ,
tet racycl i nes, and t h e macro l i d e s . With the excep tion
of te t racyclines a n d a m i nog lycos i d es, t h e b i n d i ng s i tes
for t h ese a n r ib iotics a re on t h e 5 0 S r i boso mal s u b u n i t .
C h l o ra m p h e n i col, cl i n da m yci n , a n d t h e m ac ro l i d es
p reve n t a s tep cal led t ra n s p e p ti d a t i o n , i n which the
nex t new am i no ac i d is added to the nascenr pepti d e
c h a i n . Te tracyc l i n es b i n d to th e 305 r i boso m a l s ubunit
at a s i te that blocks th e b i n d i n g of a m i n o aci d-ca rrying
tRNA ( cha rg ed tRN A) to the acce p tor si te of the
r i bosome- m RNA co m p l ex .
A m i no
acid
C h a rg ed
tRNA
Peptidyl
donor
U n charged
tRNA
Figure 27-4. Steps i n bacterial protein synthesis and ta rgets of
chlora m phenicol, the macrol ides, and tetracycl ine s . I ndivid­
ual am ino acids a re shown as n um bered c i rcles. The 70S bac­
terial ribosomal m R N A com plex is shown with its 50S and 30S
subunits . In step 1 , the charged t R N A carrying a mi n o acid 8
bi nds to the acce ptor site A on t h e 70S riboso m e . Transpe pti­
dation occ u rs w hen the p e ptidyl t R N A at the donor site (with
a mino acids 1 through 7l b i nds the growi ng am ino acid cha in
to a m ino acid 8 (step 2 ) . The u n c h arged t R N A l eft at the donor
site is released (step 3 ) , a nd the new 8-am ino acid cha in with
its t R N A shifts to the peptidyl site ( transpeptidation , step 4)
The anti biotic binding sites a re s h own sc ll ematica l l y as trian­
gles. Chlora m phenicol (C) a n d the m acrolides ( M ) b ind to t h e
50S subunit and bloc k transpeptidation (ste p 2 ) Tetracycl ines
(T) bind to the 30S su bun it and prev e n t binding of the incom­
ing charged t R N A unit (ste p 1)
The s t re p t o gr a m i ns a re b acte r i c id a l fo r most sus­
c e p t i b le orga n i s ms . They bind to the 50S r i b oso m al
s u b u n i t , and p reve n r extr usion of the nasce n r pol y pep ­
tid e chain . In addition , s tre p t og ra m i n s i n h i b i t the
act i v i ry of e n zy m es th a t syn rn es ize t RNA, lead i n g to a
decrease i n free tRNA w i t h i n the ce l l . L i n ezo l i d also
binds to th e 50S s u b u n i t . I t blocks fo r m a t i o n o f the
tRNA-ribosome- m RNA com p l e x . The a c t i o n of the
a m i n o g lycos i des is described be l ow.
Chloramphenicol
C h l o r a m ph en i co l h a s a s i m p l e and d is t inct i ve s t r uc­
t u re , a n d no o th e r a n r i mic rob i a l s have been d iscovered
in this chem ical c l ass . It is effective o ral ly as wel l as par­
en rerall y an d is d i s t r i b u ted t h r o u gh o u t al l t i s s u es . Ir
rea d i ly crosses the p l acen t a l and blood - b rain bar r i e rs .
The d r u g unde rgoes en terohcpatic cyc l i ng , and i s
m o st l y i n ac t i v a ted by the l ive r. C h lo ra m p h e n icol h.as
a wi de spew'um of antim icrobial a c tiv i ry a n d is u s u ally
bacte r i o s t a t i c . It is n o t ac t i ve ag a i n s t Chlamydia .
Al th o u g h c h l o ra m p h e n i col d o es not b i n d to ri boso­
m al RNA o f m a m m a l i a n cel l s , it can i n h i b i t t h e fu n c­
tions of m a m mal ian m i to ch o n d r ia l ri bosomes , which
are mo re s i m i lar t o bacterial ribosomes. C l i n ical ly s i g­
n i ficant res is tance to ch l ora m phe n i co l o cc u rs t h ro ugh
rhe fo r m a t i o n of pl a s m i d- enco d ed enzymes t h a t i n ac­
tivate the d r ug.
C L I N I CAL U S ES . B ecause of i ts tox ici ty and bacter­
ial res is rance, c h l o ram p henico l has very few uses as a
sys t e m i c d r u g . It is a back-up d r u g fo r severe i n fec ­
tions caused by Salmonell<z species and fo r the t rea tm ent
of penic i l l i n- res istam p n e u m ococcal or m en i ngococ­
cal m e n i ng i t i s , o r in p a tie n ts who have m aj o r h yper­
sens i tivi ry reactions to pe n i ci l l i n . C h l o r a m p h e n i co l is
co m mo n l y used as a c o p i cal age n t fo r eye i n fections
beca use o f its broad s p ec t r u m and a b i l i ry to pene tra te
ocu la r t i ssue .
ADVERSE EF FECTS . Patien t s ta k i n g ch loram pheni­
c o l occas i o n a l ly d evel o p n a use a , v o m i t i ng , and d i a r­
rhea . Oral o r vagi n a l ca n d i d i a s i s may occ u r as a res u l t
o f a l r e ra t i o n of n o r m a l m i c ro b i a l fl o ra. C h l o r a m ­
p h e n icol com m o n l y ca u se s dose-rela ted revers i b l e
s u p p ressio n o f r e d b loo d ce l l p rod ucti on. l d i o s yn ­
c fa t i c apla s t i c ane m ia, wh ich i n vol ves s u p p res s i o n o f

prod uction o f a l l blood ce l l s, can also occur, b u t is
ra re and u n rela ted to dose. Unfortunately, it occ u rs
m o re freq uently w i th p r o l o n ged use a n d is u s u a l l y
i r reversi b l e .
I f n ewbo rn i n fants are given h i gh dosages , chlo­
ra m p henicol may accu m u l ate because i n fa n ts l a ck
effective mechan isms for m etabolism of the drug. The
res u l ting gray baby syndrome i n cludes vo m i ting, flac­
cid i ty, hyp othermia, gray col o r, cyanosis, and card io­
vascular collapse.
Because ch loramphenicol i n h i b i ts hepa tic
enzymes that metabol ize several d rugs, i t has s ign i fi ­
can t i n terac tions w h e n taken w i t h o t h e r d rugs . Half­
l ives a re p r o l o n ged , and s e r u m conce n tra t i o n s o f
phenyto i n , to l b u tam ide, ch l o r p ropam ide, a n d war­
fa r i n are i ncreased. Like other bacteriostatic i n h i b i to rs
of m icrobial protein syn t hesis, chloramphenicol can
an tago n i ze bacte ricidal d r ugs such as pe n i c i l l ins or
ami noglycos ides.
Tetracycfines
Tetracyc l i nes ( tetracycl ine, doxycycline, minocycl ine,
demeclocyc l i ne) a re b road-spectrum bacterios tatic
anti b i o t i cs tha t i n h i b i t pro tein syn t hesis i n gra m ­
posi tive and gra m - negative bacteria, Rickettsia ( the
cause of Rocky M o u n ta i n spo tted fever and some
o t her d i fficu l t to t rea t i nfections), Chlamydia,
Mycoplasma, Borrelia (the cause o f Lym e d isease) , and
some p ro tozoa. Drugs i n this c lass have o n ly minor
d i fferences i n their activi ties agai nst specific organisms.
Susceptible organ isms accu m u l a te tetracycl ines i n rra­
ce l l u l a r l y via energy-dependen t transport sys tems i n
the i r cell membranes. Tetracycli nes have l i ttle e ffect on
mammalian p rotei n synthesis because a n active efflux
mecha n ism p revents their i n tracellu lar accu mulati o n .
O ra l absorp t i o n i s va r i a b l e , especi ally fo r t h e
o l d e r d r ugs , a n d m a y be i m p a i re d b y fo o d s a n d
m u l tiva l e n t cations (cal c i u m , i ro n , a l u m i n u m ) .
Te t racyc l i nes ha ve a w i d e t i s s u e d i s tr i b u t i o n a n d
cross t h e p l ace n ta l b a r r i e r. A l l o f t h e tetracycl ines
u n d ergo e n terohe p a t i c cycl i n g . Doxycyc l i n e is
exc reted ma i n ly in feces; the o ther tet racyc l i nes a re
el i m i n ated p r i m a r i l y i n the u r i n e . The h a l f- l ives o f
doxycyc l i n e a nd m i nocycl i n e a re l o nger t h a n those
o f other tetracyc l i n e s .
A n t i b a c t e r i a l A ge n t s 379
P l as m i d - m ediated · resista n ce ro tetracycl ines is
wi desp read . Res istance mechanisms i nclude decreased
activi ty o f the uptaJ(e sys tems and, most i m p ortan tly,
the developmen t of mecha n isms such as effl ux p u m p s
for active ex trusion of te tracycli nes. Plasm ids that
include genes i nvolved i n producing effl u x p u m p s fo r
tetracycl ines co m mo n ly i n clude res ista nce genes fo r
m u l ti p le antibio tics .
CLIN I CAL USES . A tetracycl ine is the d rug of choice
i n i n fec tions caused by Mycoplasma pneu m o n iae ( i n
a d u l ts) , Chlamydia, Rickettsia, and Vib rio (e.g. ,
ch olera) . S p ecifi c tetracycl i nes a re used in the t reat­
ment of gas tro i n testinal ulcers caused by Helicobacter
pylori ( tetracycl ine) , in Lyme disease (doxycycl i ne) , and
in the meningococcal ca rrier s ta te ( m i n ocyc l i ne) .
Doxycycline is also used fo r the p revention o f malaria
a n d i n the trea tmen t of amebiasis . Demecl ocyc l i n e
i n h i b i ts t h e re nal a c t i o n s o f a n t id i u re t i c h o r m o n e
(AD H) a n d is u s e d i n the manage m e n t o f p a t i e n ts
with ADH-secreting tum ors.
Te tracycl i nes a re a l ternative d ru gs i n the t reat­
ment o f syphi lis. They are aJso used in t he rreatment of
res p iratory infec tions caused by susceptible organisms,
fo r prophylaxis against i n fec tion in chro nic b ro n ch i­
tis, in the t reatment o f leptospirosis , and in the treat­
ment of acne.
ADVERSE EFF ECTS . Hypersensitivity reactions ( i . e . ,
fever, rashes) t o tetracyclines are unco m mon. Most o f the
adverse reactions are due to di rect toxici ty of the tetra­
cycline agent or due to aJ terations in m icrobiaJ flora.
Effects on the gastrointestinaJ sys tem ra nge fro m
m i ld na usea a n d d ia rr h ea to seve re, possi bly l i fe­
th reate n i ng col i tis. D i sturba n ces i n the normal fl o ra
a re d u e to s u p p ressi o n of tetracycli ne-susce p t i b l e
organ isms and overgrowth of res istant organ isms, es pe­
cially pseud o m o nas, staphylococci, and cand i d a . T h is
can res ult in i n testinaJ disturbances, anaJ p r u ri tus, vagi­
nal o r o ral cand id iasis, o r e n teroco l i tis.
Te tracycli n es b i nd to caJci u m deposi ted i n newly
fo rmed bo ne or teeth in yo u n g c h i l d re n . T h us, fe tal
expos u re to tetracyclines may lead to roo t h enamel dys­
p lasia and d iscoloration and i rreg u l a r i t ies in bone
grow th . Al though usually co n tr a i n dicated i n p reg­
n a n cy, there may be si tuations in which the bene fi t o f
380 CHEMOTHERAPEUTICS
ad m i nistering tetracycl i nes ou tweighs the risk. I f t aken
fo r l o n g p erio d s of time i n ch i l d re n under 8 years of
a g e , te trac y c l i n es may ca u se s i m i lar changes i n teeth
and bo ne .
High d oses of tetracyc l i nes, e s p ecial l y in p reg n a n t
patie nts a n d t h o s e with p ree x i s ti n g hep a t i c d isease,
may impair li ve r fu nctio n and lead to hepatic n ecros is.
Likewise, i n p a t i en ts w i th ki d n ey d isease, tet r a cyclines
may exacerbate renal dysfuncti o n .
S y s tem i c te t rac ycl i nes (especially dem ecl o cycl ine)
m ay en hance ski n se n s i t i vi ry to u l travi o l e t l ig h t , p a r
­ o r ganis m is res i st a n t t o o n e macrolide agent, i t w i ll be
tic u lar ly i n fa ir-s ki n ned i n d iv i d u a l s .
D o s e - d e p en d e n t rev ers i b l e d izz i n ess and vertigo
have been r ep o r te d with d oqc yc l i n e a n d m i nocyc l i n e .
MacroLides
The m ac rol ide a n t i b i o tics a re large cycl ic lacto ne r i ng
structures with attached sugars . The m acro l i des i ncl u d e
t h e p ro to ry p ic d r ugs e ryth rom ycin, azithromycin, a n d
c1arith rom ycin. T h e macrolides have g o o d oral
b i o a va i la b i l i ry, but azi thro mycin a bsorp ti o n i s i m ped ed
by fo od . Macrolides d i s t r i b u t e w mo st body tissues, b u t
azithromycin i s u n ique i n that the levels achi eve d i n tis­
s u e s a n d in p h a go cy t e s are co nsidera bly h ighe r t h a n
t hose i n t h e plas m a . T h e e l i m i nation of eryt hromyci n
(via b i l i a r y excretion) and c1ari th ro mycin (via hepatic
meta bolism and urinaty e x cre t i o n of i n tact d r ug) is
fa i r l y ra p i d (half- l i fe 2 t o 5 h o u rs ) . Azi t h romyc i n is
el i minated slowly (h al f-l i fe 2 w 4 days) , mainly in u r i n e
as u n c h anged drug.
CLI N I CAL U S ES . Erythro mycin has activiry ag a i n s t
many s pecies of Campylobacter, Chlamydia, j\1ycoplasma,
Legio nella, gra m - p o s i ti ve cocci ( i n cl u d i n g �-lactamase­
p r o d u ci ng s t a ph y l o c o cci) , a n d some gra m - n egative
o r ga n i sm s . The a n ti bacterial action may be bacterio­
static o r bactericidal; the l a t te r effeer o cc u r r i n g more
co m m o n l y at h i g he r conce n trations fo r s u s cep t i b l e
o r ga n i s m s . Er y th ro m yci n d o e s n o t h a v e activity
aga i nst pen icill i n - resistan t Streptococcus p neumo niae or
m e t h i c i ll i n-resista n t 5 aureus (M RSA) .
The s pectra o f act i v i ty of azi thro myc i n and clar­
i t h ro myc i n are similar to eryth romyc i n , but include
grea ter ac t i v i t y aga i ns t Chlamydia, Myco bacteriu m
aviurn complex, a n d Toxoplasma s p e c i es . Beca use of i ts
l o n g h a IJ- J i fe , a 4 - d a y course of treatmen t w i t h
azi thro mycin has b e e n effective i n c o m m u n i ry ­
ac q u i red pneu mon i a. Clari t h r omyc i n is a p p roved fo r
p rop hylaxis aga i ns t and trea tment o f M avium co m ­
pl e x and a s a com pon e n t o f d r u g r eg i m en s fo r ulce rs
ca us e d by Helico bacter pylori.
Res i s tance ro m ac r o l i d e antibiotics i n gra m­
p o s i t i v e org a n i s ms involves efflux pump mechan isms
a n d the production of a n enzyme ( m e t hy l a s e ) that
alters the dr u gs' ri boso mal bi nding site. Cross-re, istance
among individ ual macrol i d es is complete; t hat i s , i f a n
r e s i s ta n t to a l l o ther m ac ro l i d es . I n t h e c as e of
methyl ase- p ro d u c i n g b an e r i a l stra i ns, there is partial
c ross - res is ta n ce w i t h o ther d r u gs that bind to the s a m e
ri bosomal s i te as macrolides, i n c l u d i ng c l i n da m yci n
a n d s t rep w g ram i n s . Resistance i n Ente robacteriaceae is
d u e ro fo rmation of d ru g- m e ta bo l izi ng esterases.
ADVERSE E F F ECTS . G a s t ro i n tes t i n a l I IT l ta t J O n
(ano rexia, na u s ea , vomiting) is onen associated w i th oral
ad ministrati o n . Stim u lation of g U t m o ti l i ry is the m o st
comm on reason fo r d i s co n r i n u i n g e ry t h r o myci n and
cho o s i ng another a n t i b io t ic. This action is someti mes
exploi ted therapeutica l ly in pa tien rs with i n a d e q ua te
gas tro i n tes t i nal m o ti l i ry. A hypersensi tivity-based acu te
ch o l es tat i c h e pati r.i s (fever, j a u n d ice, impaired liver fu n c­
ti o n ) may occu r w i t h erythro myci n estoJate. T h is co n­
d i tion us uall y res olve s . Hep a t i t i s is rare i n children, b u t
there is an i ncreased risk wi t h erythromyc i n estolate i n
p regnant patients. Because e rythromyc i n i n hibits sev­
eral fo r m s of h e p at i c cytoch rome P450, i t increases the
pl a s m a l evels of a n ticoagu l a n ts, ca rbamazepine, cis­
ap r i d e , di go xi n , and rheophylli ne. S i m ilar d r u g i n te rac­
tions have a l s o occurred wi th c l a r i t h ro m yci n . Drug
i n re r a c t ion s are unco m m o n with az i t h ro myc i n beca use
this age n t does not i n h i b i t hepatic cyto ch ro m e P4 50.
Telithrornycin
Teli chromyc i n is a ketolide stru cturally rela ted to
macrolides. Ir has t h e same mechanism of act i o n as
erythromycin a n d a s i m i la r m o d e ra te s pectru m of
antimicrobial activity. However, some macrol ide-resistant
m icrobial srrains are s u sce pr i b le to tel i th ro myci n because
i t binds m o re t i gh dy w r i bo so mes and i s a poor su bs tra te
fo r bacterial efflux p u m ps rhat m e d i a te resisrance.
Clinical uses i n cl u d e co mm u n i ty-acq u i red b a c terial

p n e u m o nia a n d o r ner upper resp ira tory t r ac t i n fectio n s .
Telith to myc i n is given o rall y o n ce daily and is eli m i na ted
in the b i l e and tne u rine .
Clindamycin
C l i nd a m ycin i n n i b i ts ba cte r i al p r o tei n synt n esis v i a a
mecnani sm similar co that of the m3crol i des, al th o u gh
it is n o t ch e m i call y related. Mechanisms of res istan c e
i nclude altera t i o n of t h e d rug 's riboso m a l binding s i te
and enz yma tic i n ac t i v a t i o n o f t h e d ru g . Cross­
res i s ta nce between c 1 in d a m yci n a n d tne m a c ro l i des is
com m o n . G ood ti ssue penet r a t ion occ u rs after oral
absorp t i o n . C linda m ycin is el i m ina ted pardy by
metabolism and p a r t ly by b i lia r y a n d re n al ex c re t io n .
C L i N I CAL U S ES . T h e mai n use of c 1 i ndamycin is i n
t n e trea tme n t o f seve re infec t i o ns ca u sed by certa i n
anaerobes sllcn a s Bacteroides ( m os t co m mo n bac te ria
in t n e colon) tha t often p a r ricipa te in mixed infectio n s.
C1 i n d a m yci n (so m e t i m es in co m b in at i on w i th an
aminoglycosi d e o r cepnal osporin) is us ed to treat pene­
tra ti ng w o u nds o f the a bdomen and the gut, infections
origina t i n g i n t h e female ge n i tal tract ( e . g . , sep t i c abor­
tio n and pel vic a bscesse s) , or a s pira t i o n p neu m o nia .
Cl i ndamycin has been used as a back - u p drug against
gram -p os i tive cocc i , and is c u r re n t ly recommended fo r
p r ophylaxi s of endocarditis in patien cs with cardi ac valve
d isease who a re allergic ro p en i c i l li n . C l i nd amyc i n plus
p r i m aq u i ne is an effe cti ve alternative to t rime thop ri m ­
s u l fa methoxazole for moderate to m ode r a tely severe
Pneumocystis jiroveci pn e um oni a in A[DS pa tie n cs . It is
also used in co m b i n a t i o n w i t h pyr i m e thamine fo r
AI D S - re l a ted toxo p las mosis of t h e b r a in .
ADVERS E EHECTS . Adverse effects of c1inda m ycin
include gast rointestinal i rr ita tion, skin rashes , n e u ­
tropen i a , a n d n epa tic dysfu nc tion. Severe diarrhea and
enterocol itis have followed c li n da m yc in a d m i n is t ra­
tio n . An tib i o t ic -assoc ia ted colitis due co supe ri n fectio n
with C difficile i s a po te n c ially fa tal co m pl i c a tio n and
m ust be recogn i z ed p ro m pdy and treated .
Streptogramins
Quinupristin-dalfopristin is a com b ina t io n of rwo
s t rept og r am i n s . The co m b i n a t i o n has rap id bactericidal
act i v i ty t h a t lasts longe r tnan the half- l ives of the indi­
vidua l co m po u n ds . An t i b ac teri al ac tiv i ty i ncludes
An t i b a cteri a l A g e n t s 3 8 1
penicill in-resistant p n eumococc i , m e t h i c i l l i n -res i s ta n t
a n d v a n co m yc i n - res i s ta n t s t a p h y l oc o cci (M RSA and
VRSA, respectively) , and resis tan t Enterococcusfoecium.
Ad m i nistered i n t raveno ll sly, the co m b i nation p roduc t
may cause pa in ar t h e i n fusion site and an a r rh ralgia­
m yalgi a syndrome . S r rept og ram ins are potent inhibitors
of CYr3A4 a nd inc rease p lasma levels of many drugs,
i n c luding ci sa pride , cyclospor i ne, diazepam, nonnucle­
os ide reverse transcri p tase i n h i b i tors, and wa r far i n .
Linezolid
Linezolid is the fi rst of a new class of antibiotics called
oxazolidino n es . Li ne-£o l i d is mai n ly bacterios tatic, and is
active against gram -posi tive cocc i , i ncluding s trai ns resist­
ant to �-Iactams and vancomycin (e. g . , va n com yc in ­
resista n t Efoecium) . L ine-£ol id b i nds to a un i que s i te on
o ne of the riboso mal s u b u n i ts , and there is cu rren tly no
cross-resistance wi th o ther pro t ei n sy n thesis i n h ib i tors .
Al tho ugh ra l'e t o da te , res istance can occ u r wit h a
decreased affi n i ty of l i newlid fo r its binding s i te. Li ne­
w l id is available in both oral and pa ren teral form u la­
tions. The p rim a r y adverse effec t i s h e m a tOlogic;
th ro m bocy t Ope n ia a nd neutropenia occ u r, most co m­
m o n ly in i mmun os u ppressed patients .
Aminoglycosides
Am inoglycos ides exerr bactericidal activi ry and are u se ­
fu l ma i nl y aga i ns t aero b i c gra m - n ega tive m ic roo r ga n ­
isms. O n e of the prima ry ad v an tage s of aminoglycosides
is tnat t ney can often be used i n a o n ce- d a ily dosing pro­
roco l , wh ich can s ave t i m e and lends itself to o u tpa t ien t
therapy w i t h these agents. In addition , once-da ily dos­
ing can be more effec tive and less toxic tha n t r ad i t i o nal
dosing re g i me n s . Am inoglycosi des have greater effi cacy
when ad m i n iste red as a singl e la rge dose because their
bactericida l effectiveness is co n cen t r a tio n dependent.
Tha t i s , as the plasma level is i nc reased above the M I C ,
a mi noglyco s ides kj ll a n i ncreas i n g p ropor t ion of bacte­
ri a and do so m o re rapidly. Am i noglycos ides can also
exe rt a p os ta n tib io r ic effect, so t ha t that their killing
a c t i o n con t i n u es when plasma levels have d ec l i n ed
below me a surabl e levels. The s ingle la rge daily dose of
an a m i n oglyco s i d e ge ne ral l y res u l ts in fewe r adverse
effects because tox i c i ty depends both on a cri tical
p l as m a concent ra tio n and o n t h e t i me t h at such a level
is exceeded. Wit n s in gle l arge doses, tne t i m e a bove
382 C H E M O T H E RA P E U T I C S

such a th res hold i s s h or te r tha n with ad m i n istra tion o f s e l e c t i o n a n d adj u s t m e n t . Eve n wi th o nce- daily dos­
m u l ti p l e smal ler d oses. i n g , plasma l e v e l s m ay be m o n i to red , espe c i a l ly In

The am i noglycosides inc l u d e gentamicin, amikacin, fu nctio n .

neomycin, tob ramycin, and o th e r s . They a re struc­
t ur a l l y related a m i n o s u g a rs a t tached by glyc o s i d i c
l i n kages. All o f the a m i n o g l yc o s i d e s a r e p o l a r c o m ­
p o u nds, s o t h e y a re n o t a bs o r bed after o ral a d m i n is­
t r a t i o n . T h e re fo re , t hey m u s t b e gi ve n i n rram usc u l arly
or i n t r av e n o usly for s ys te m i c effect. They have l i m i ted
t iss u e p e n e t ra t i o n and do not read i ly cross the b l o od ­
b ra i n b a r r i e r. The maj o r mode o f exc re t i o n is via rile
kid n e y, a n d p l a s m a levels o f these d r u gs a re g re a t l y
a ffected by c h a nges in re n a l fu n c tio n . Wi th n o r m a l
ren a l fu n c t i o n , the e l i m i n a t i o n h alf- l i fe o f a m i n ogly­
cos ides i s 2 to 3 h o urs . Pa tien rs re c e i v i ng a m i n oglyco­
s i d es fo r m o re [ h a n I d a y m u s t have plasma l evels o f
t h e d r u g m o n i to red for s a fe a n d e ffective dosa g e
p a t i e n rs w i t h dec r e a s ed ki d ney
M E C HAN I S M O F ACTI O N . To ki l l suscep t i b l e bac­
teria, am i noglycosides m u s t penetra te the bacterial cel l
envelope . Th is p ro cess i s p a r r ly d e p e n d e n t on oxygen­
d e pend em active transpo rt; therefore, these age n ts have
m i n i mal activiry ag a i n s t st r i c t a n aerobes. To ass ist entry
of a m i n oglycosides i n ro bacterial cel is, am i n o glyco s i des
may b e co-ad m i n is te red w i t h a cell wa l l s y n t h e s i s
inhib i to r s u c h as a B - I a c t a m age n t . Once i n s i de the bac­
terial ce l l, a m i n o glyc o s i d es bind to t he 305 ri b o s o ma l
s u b u n i t a n d i nte r fere wi th p ro t e i n synrhesis in at l e a s t
th ree ways : ( 1 ) they b l ock formation of t h e i n i tiation
complex; (2) they cause m i s rea d i ng o f m RNA; a n d (3)
they i n h i b i t transloca ti o n (Figu re 27-5) .

Normal bacterial c e l l

I n i t i ation 50S s u bu n i t Nasce nt pept i d e c h a i n

3'

A m i n oglycosi de-treated bacteria l cell

Drug ( b l ock o f Drug ( m iscoded peptide c h a i n )

i n itiation complex)

D r u g ( b l o c k of trans location)

5\J
mRNA 3'

Figure 27-5 . Puta tive mech a n i s ms of action of t h e aminoglycosides. Normal protein synt h lCs i s is s h own in the
top panel . At least t h ree different a m inoglycoside effects have been descri bed ( bottom pane!) : block of forma tion
of the initiation com ple x ; miscoding of amino a c id s in t he emerging peptide chain due to m i srradi l l g of the m R N A;
and block of translocation on m R N A. Block of movement of the ribosome may occur a fter the fo rmation of a s i n ­
gle initiation com plex , resulting in a n m R N A chain with only a single ribosome on it, a so-called monosome.

CLIN ICAL U S E S . Am i noglycos ides a re mos t l y used
agai nst gra m - n egative e n te r i c ( i . e . , i n testinal) bacteria.
The main d i ffe re nces among the i n d i v i d u al a m inogly­
cos ides l i e i n t h e i r activi ties aga i n s t specific o rga nisms,
particularly gram-negative rods. Gen tamicin, tobramycin,
and a m i kaci n are i m po rtan t drugs fo r the trea tment of
serious i n fecrions caused by aero b i c gram- negative bac­
reria, i n c l u d ing E coli and Enterobacter, Klebsiella (espe­
cially importa n t in res p i ra tory i nfections and urinary
tract i n fections), Proteus, Providencia, Pseudomonas,
and Serratia ( i m po r ta n t in sept icem i a and pul mo nary
i n fections) species. T h ese a m i n oglycosi d es also have
activi ry aga i n s t o t h e r s p ecies ( e . g . , H influenzae,
Moraxella catarrhalis, Shigella) , al tho ugh they are n o t
d r ugs o f c h o i c e fo r i n fections caused by these o rgan­
isms. When used alo n e , aminoglycos i des a re not re l i ­
a b l y effective fo r trea r i n g i n fections c a u s e d by
gram-posi t ive cocc i . An tibacterial syn ergy may occur
when a m i noglycosi d es a re lIsed in co m b i nation w i t h
ce l l wall syn thesis i n h i b i tors. Fo r example, a m i nogly­
cos ides may be c o m b i ned with penicil l i n s to treat
pseudo m o n a l , l i s terial ( importa n t i n some cases of
meni ngi tis) , a n d e n terococcal i n fectio ns.
Streptomycin is an ami noglycoside that is often used
in the trea tment of tu berculosis, p l ague, and tulare m i a
(rabb i t fever) . Because o f the r i s k of irreversible o to tox­
ici ty, strepto myci n should not be used when other drugs
will serve. Ow i ng to i ts toxic potential , neomycin is only
used topically or l ocal ly (e. g . , i n [he gastroin testi nal tract
to elim inate bowe l Aora) . Newmi ci n is usually reserved
fo r trea tment of serious i n fections caused by orga n isms
resista n t to the other am i noglycosides.
ADVERSE EFFECTS . All am i noglycosides are o totoxic
and nephrotoxic. Aud i tory or ves t i b u l a r damage ( o r
bo th) m ay o c c u r and m a y be i rreve rs i b l e . Auditory
i m pairment, which may man i fes t as t i n n i tus and high­
frequency hearing l oss i n i t i al l y, is more likely w i th
amikacin and kanamyc i n . Ves tibular dysfunction , which
may man i fest as ver tigo, ataxia, and l oss of balance, is
m o re l i kely with gen tam icin and tob ramyc i n . These
toxic risks are p ro portio nate to plasma levels of the drug.
Precautions taken w reduce these risks i n c l u d e o nce­
d a i l y d o s i n g (versus tra d i t i o n a l d o s i n g regi m e ns) ,
m o n i to r i ng plasma leve ls of a m i noglycos i d es w i th
a p p ro p r i a t e dose m o d i fi c a t i o n , a n d avo i d i n g the
Antibacterial Agents 383
additive o w toxiciry of loop di u retics d u r i n g dosing.
Because ototoxicity has been reported after fetal exposure,
am i noglycosides are contraindicated in pregnancy u nless
their poten tial bene fi ts are j udged to outweigh risk.
Renal tox i c i ry u s ually takes the fo r m of acute
tubular necros is, wh ich i s often reversi ble. I t is more
c o m m o n i n elderly p a t i e n ts and in those co n c u rrendy
rece iving a m p h o ter i c i n B, ceph a l o s p o r i ns , o r van­
co m yci n . G e n ta m i c i n a n d tobramyc i n are the most
nephrotoxic aminogl ycosides.
Al lergic ski n reactions m ay occur i n patients , and
con tact dermatitis may occur in perso n n e l h a n d l i n g
these d r ugs. Neo mycin is t h e m o s t likely culprit.
Al though rare, respiratory paralysis may occur at
h i gh doses. It is usually reve rsible by prompt treatment
w i th calc i u m and neostigm ine, b u t ven tilatory su ppOrt
may be req u i red.
INHIBITO RS O F BACTERIAL
DNA SYNTHES IS
The sulfonamides, trimethoprim, and fluoro q uinolones
m ake u p the gro u p o f d r u gs t h a t exe rt a n t i b acterial
effects by i n terfe r i n g with bacterial DNA syn thesis
(Figure 27-6) . Individ ual key d r u gs in t h i s cl ass o f
d r ugs a r e lis ted i n Ta ble 27-2 .
Sulfonamides and Trimethoprim
Mechanism ofAction and Pharmacokinetics
S u l fonam ides a n d trimethoprim a re called an tifola(e
drugs because they i n terfere with folic a c id syn thesis.
Fol i c acid and fo l a(e a re the names of forms o f vitam i n
B 9 • Fol i c a c i d is the synthetic fo rm fou nd i n fo r t i fi e d
foods and s uppleme n ts , a n d folate is t h e a n i o n i c fo rm
fo und n a t u rally in foods. Folic acid i s necessa ry fo r
DNA rep lication; th us, i t is necessary fo r production
a n d m a i n te n a n ce of new cells. Wh ile m a m mals can
use exogenous ( i . e . , d i e tary) fo late, many bacteria ca n­
not and rely on e nzymes to syn thesize folate fro m i ts
precu rso r, para-am inobenzo ic acid (PABA) . An tifolate
d r u gs i n h i b i t fol i c a c i d synthesis at d i fferent s tages
(Figu re 27-7) . The selective toxiciry o f a n t i fo l a te d r u gs
res u l ts fro m the fac t t h a t m a m m a l i a n cells u ti l ize
dietary folic acid, so i n h i b i t i o n of fo l ic acid syn thesis
wi l l primarily affect bacteria .
384 C H E M OT H E RA P E U T I C S

Sulfonamides, tr i m et h opr i m , & f l uo roq u i n o l o n e s

I
A n timeta bolites

Su lfonamides
N a rrow s pect r u m Wide spectrum
Trimethoprim ( 1 st g e n e ra t i o n )

T r i m e t h o p ri m ­ 2nd g e n e ration
s u l fameth oxazole
3rd g e n e ration

4 th g e n e r a t i o n

Figure 27-6 . Classification of inhi bitors of bacterial D N A synthesis: sulfonamides , t rim ethoprim , and fluo­
roquinolones .

Used as s i n g l e agems, s u lJo n a mides a re b a c t e r i o ­ res i s t a n c e is co m m o n i f s u l fo n a m i d es a re u s e d as s i n­

s t a t i c i n h i b i to r s of fo l i c acid s ym h e s i s (Figure 27-7) . gle a m i m i c r o b i a l agems , a su l fo n a m i d e is freq u e n d y
T h ey co m p e t i tively i n h i b i t d ihyd ro p teroate syn thase u s e d i n c o m b i n a t i o n wi t h t r i m e t h op r i m , w i t h t h e
a nd c a n a lso a c t as s u b s tra t e s fo r t h i s e n zym e , tes u l t­ com b i na ti o n be i n g k n o w n as T M P - S M Z o r TMP­
i n g in the s y n thesis of n o n fu n c t i o n a l fo t m s of fo l i c S MX. This co m b i n a t i o n c a u ses a sequen tial blockade
aci d . Tr i m e th o p r i m s e lec ti vely i n h i b i ts bacterial di hy­ of fo l i c a c i d symhes i s i n w h i c h b o r h d r u gs i n h i b i t
d ro fo la te red u c tase, w h i c h p reven rs fo r m a t i o n o f the s e q u e m i a l s teps i n b ac t e r i a l m e ta b o l i s m . This res u lts
a c t ive fo rm of fo l i c a ci d . B a c t e r i a l d i h yd r o fo l a t e i n a synergi s t i c, o ft e n b a c t e r i c i d a l , a c t i o n a ga i ns t a
red u c tase is 4 to 5 o rd e rs of mag n i tu d e m o re s e n s i t i ve w i d e s p e c t r u m o f m i croo rga nisms. Res i s tance t o the
to r r i m e th o p r i m i n h i b i t i o n than the ma m m a l i a n co m b i n a t i o n o c c u rs but has been re l a t i ve l y s l o w in
fo r m o f d i h y d ro fo l a t e re d u c t as e . B e c a u s e m i c ro b i a l developmen r .

Ta b l e 2 7-2 . Key i n h i b itors of bacterial D N A synthesis

S u bc l a s s Prototype Oth e r S i gnificant Agents

S u lfona m i d e s
Ora l age n t s S u l f i soxazo l e
Loc a l age nts S u I faceta m i d e
C o m b i nation Tr i m et h o p r i m -
s u l f a m et h oxazo l e
( T M P-S M X )
F l u o ro q u i n o l o n es
F i rst g e n erat i o n N o rf l oxac i n
S e c o n d ge n e rat i o n C i p ro f l oxac i n Ofl oxac i n
Th i rd ge n e ra t i o n Levof l o xa c i n
Fo u rt h ge n e ra t i o n M o x i f l oxac i n

p-Aminobenzoic acid
Sulfonamid es
D i hydropteroate
synthase
--0-- (compete
with PABA)
D i hydrofolic acid
Dihydrofolate
--0-- Trimethoprim
reductase
Tetrahydrofolic acid
Purines
DNA
F i gure 27-7 . I nh i b i tory effects of s u l fo n a m i des and t r i m etho­
pri m on foli c acid syn thesis. I n h i bition of 2 successive steps in
the fo r m ati o n o f t e t rahyd rofoli c ac i d c o n st i t u tes seq u e nti a l
bloc kade a n d r e s u l t s in a n t i bacteria l syne rgy.
The s u l fo n amides a re we akJy acidic compo u n d s
thar have a chemical n ucleus resembl i ng PABA, the s u b ­
mate with which they compete. Members of th is group
d i ffer mainly i n their pharmacokinetic propenies and
clin ical uses . Shared pharmacokinetic features i nclude
modesr tissue penecratio n , hepatic metabolism , and
excretion of both inract drug and acetylated metabolites
in the u r i ne . They can be divided i n to th ree m ajor
groups: ( 1 ) oral a bso rb a bl e ; (2) oral nonabso r b a b l e ;
and ( 3 ) to p i c a l . T h e o ra l a bs o rb a b l e s u lfonami des
can be cl assi fied as shorr-acting (e.g. , su lfisoxazole) ,
i n termed iate-acting (e.g. , sulfamethoxazole) , or long­
acti ng (e.g., sulfadoxine) on the basis of their half-lives.
Sul fonamides bind co p lasma protei ns a t s i tes shared by
bilirubin and by o ther drugs.
Tri metho prim is s([uctu raHy similar to fo lic acid.
Ir is a weak base and is [('apped in acidic envi ro n ments,
reach ing high co n cen trations i n p rostatic and vagin al
fluids. A la rge fractio n of trim ethop r i m is excreted
u nchanged in the urine.
Antibacte r i a l A g e n t s 38 5
Clinical Uses
Among the oral absorbable sulfonamides , sulfisoxazole
and sulfamethoxazole a re used al most exclusively fo r
nea t i ng u ri nary tract i n fections . O ral s u l fadiazi ne p l u s
pyrimetha m i n e (a d i hyd rofolate red uctase i n h i b i tor)
wo rk synergistically as a fi rst-l ine treatmen r fo r coxo­
p las mosis. As top i ca l agenrs, several su l fonamides are
used co treat bacterial o p h th a l m i c and wo u n d i n fe c ­
tions. Sod ium sulfacetamide o p h t h a l m i c sol u t i o n o r
o i n tm e n t is effective for nea ting bacterial conj u n c tivi­
tis. I n the p reve n ri o n o f i n fectio n of burn wo u nd s ,
m afen i de acetate can be used t o treat topical i n fections.
However, silver s ulfadiazine is the p r e fe r re d agen t
because mafe n i d e acetate can cause metabo lic acidosis.
The combination of tri methoprim-sulfamethoxazole
is the drug regimen of choice for i n fections such as Pneu­
mocystis jiroveci pneumonia, toxoplasmosis, and nocar­
diosis (Chapter 29) . TMP-SMX is also a possible back-u p
dr u g for cholera, typhoid fever, and shigellosis, a n d h as
been used i n the treatmenr of infen ions caused b y MRSA
and Listeria monocytogenes.
Adverse Effects
Adverse effects o f the sulfo n a m i des i ncl ude h y p e rs e n ­
si tivi ty reactions, hepatotoxici ty, nep h ro toxiciry, a n d
gas tro i n testinal d isco m fort such as nausea, v o m i t i ng,
and d iarrhea. All e rgic reactions, i n c l u d i n g s k i n ras h es
and fever, a re common. Cross-allerge n i ci ry among the
individual s u l fonam i d es shou l d be ass umed and m ay
ra rely occ u r wi th c he m i cally related drugs ( e . g . , oral
hypoglycem i cs , thiazides) . Com mo n drug i nreractions
i ncl ude competi tion with war fa r i n a n d metho trexa te
fo r p l as m a p r o te i n b i n d i ng, which tra n s i e n t l y
i n c reases the p la s m a l evels of these d rugs . S u lfo n ­
a m i d es c a n d i s p l a c e b i l i r u b i n fro m p l a s m a p ro ­
t e i n s , with the risk o f severe n ewbo rn j a u nd i ce a n d
ker nicterus i f u s e d in the t h i rd tri mester o f p reg­
na ncy. Perso n s with glucose-6-phosphate dehyd roge­
nase (G6PD) deficiency may s u ffe r h e m o l ys i s i f
sulfonamides a re given .
Tri methoprim may cause the p red i cta b l e adverse
e ffects of an a n t i fol a te d rug, including mega l o b l astic
ane m i a , l e u kope n i a , and gran ulocyto penia . These
e ffects ar e u s u a ll y a meliorated by s u p p lemen tary
fo l i n i c a c i d . The co m b i n a t i o n o f TMP-SMX m a y
386 C H E M OT H E R A P E U T I C S
also ca use a n y o f t h e adverse e ffects asso c i a ted w i th
s u l fo n a m i des . A I D S p a t i en r s g i v en TM P-SMX have a
h i g h inc i d ence o f adverse e ffe c ts, i nc l u di n g fever,
rashes, l e u k ope n ia , a n d d i a r rhea .
F1uoroquinolones
Mechanism ofActio n and Pharmaco kinetics
F l u o roq u i n o l o nes selec t i vel y i n hi b i t [wo enzymes crit­
ica l for bacterial D N A syn r h e sis : topoisomerase l [
( D NA gyrase) a n d topoisomerase IV . I nh i b i t i o n of
D NA gy rase p reven rs re l ax a t i o n o f po s i t i v e l y super­
coiled DNA; unco i l ing is required fo r no rmal t ra n
sc r i p t i o n , whereas inh i b i ti o n of co p o i s o m e rase I V
i n terfe res w i t h t he sep a r a t i o n of repl ica ted chromo­
soma l DNA d u r i ng cell d ivis i o n .
F l u o roquinolones a re usually b a c t e ricidal a ga i nst
s us cep t i b l e o rg a n is m s . Li ke a m inoglycosi des, the fluo­
r o q u i n o l i n es also exllibi t p os t a n r i b i o t i c e ffects.
Re s i s t a nc e h a s e m e rge d co t h e older fl u o r o ­
quinolo nes, b u t has been offse t co some ex t en t by the
inrroduction o f newer g e n era t i o n s wi t h ex p a n ded
ac t i v i ty a g a ins t c o m m o n pa t h ogen ic organisms.
Al l of the fl u o roquinolones have go o d o r a l
b i o a va i l a b i l i ty ( al r h oug h so me anracids m ay inrer fere)
a n d penetrate most body t issues. Eli m i n a t i o n of most
fluo roquinolones is t h rough the kidneys; dosage reduc­
tio ns a re usually needed in rena l dys fun c t i on . Moxi­
fl oxaci n i s el i mi n a ted par tly by he p a t i c metabol i s m
a n d a l so by b i l i a r y excre tion. Hal f- l ives o f fl uo ro ­
q u inolones a re u su a l ly 3 co 8 h o u rs, but t h e agenrs
e l i mina ted by nonrenal ro utes have h a l f- l ives fro m
1 0 r o 2 0 hours .
F l u o ro q u i n o l i n e s a re cl a s si fi e d by "g e n e ra t i o n "
based o n th e i r a n timicro b i a l spec trum o f a ct i v ity
(Ta b l e 27-2) . Norfloxacin, a fi rs t-genera t ion age n r , is
the l east ac t i ve fl uo r o q ui n o lo n e a g a i n s t both g r a m ­
n e g a t i v e a n d gr a m - posit i v e o rg a n i sm s . Cip rofloxacin
and ofloxacin (second-gene ration fl uoroqu inolones)
have e xce l l e n r a ct i v i ty a g a i ns t g r a m - n ega t i v e bacteria
and m o d erate co goo d act i v i ty a g a i n st gram - p osi ti v e
cocc i . T h i r d - g e n e ra t io n fl u o r o q u i n o l ones ( e. g . , lev­
ofloxacin) a re sl i g h tl y less active aga inst gram - ne ga t i ve
bacte ri a , b u t h ave grea ter ac r i v i ty a gai ns t g r a m - p o s i ti v e
cocc i , i n c l u di n g 5 pneumoniae and some stra ins o f
e n rerococci and M RSA. The mo s t recently i n r ro du c e d
fo u r t h - g e n e r a t i o n d r u gs ( e. g . , moxiAoxaci n) a re t h e
b ro a de s t s p e ct r u m fl u o r o q u i n o lo n e s c o d a te, w i t h
en hanced a c t i v i ty a g a i n s t a n a e robe s .
Clinical Uses
F l uo roq u i n o l o nes a re effective i n t h e treat ment o f uro­
g eni t al and g a s tro i n t es t i n a l t ract in fections even when
caused by m u l t idrug-resista n r bacteria. F l u o ro ­
qu i n o l o n e s ( e xcep t n o rfloxac i n , w h i c h d o es no t
a ch i e ve a de q ua te syste m i c co n cenrra tions) have been
used w i dely for re sp i r a to ry tract, skin, bone, j o i n r , a n d
­ so ft tissue infections. However, their e ffectiveness m ay
be variable b ecause of the e m e rge nce of res istance.
C ip ro fl o xac i n and ofl o xacin a re al te rnati ves co rh i rd ­
g e n er a ti o n c ep h a l o s p o r i n s i n g o n o r r h e a , a nd a re
a d m i n i s t e r e d i n s i ngle o ral doses. O fl oxac i n wi l l erad­
i c a te acco m p a n yi n g o r g a n i sm s s u c h as Chlamydia.
Levo floxacin h as good a cti v i ty aga i nst o rga n ism s asso­
ciated w i t h co mmuni ty-acq u i red pneumonia. F l u o ro­
qui n olones h a ve also been used i n the m e n i n gococca l
carrier state, in the r rea t m enr of tubercu losis, and i n
p r op h yl a c t i c m a n agem e n r o f n e u tr o p eni c p a t i en rs .
Adverse Efficts
O v e r al l , fl u o roq u i n o l o ne s are very w e l l colerated . Gas­
tr oin r esti n al d istress is the m ost co m m o n s i d e effecr. In
addition, t h ey may cause skin rashes, headache, d izz i ­
ness, i nsomnia, abn ormal l i ver f u n c t i o n tes ts, and p h o ­
to tox ici ty. Al t houg h rare , tendo n i tis h as been re po r ted ,
w h ich may be serious because of t h e risk of tendo n r u p­
ture . Th ey a re not reco m mended for use i n c h i ldren or
i n p reg n ancy beca use they have ca u s ed c a r t i l a ge prob­
lems in d ev e lo p i n g animals. Fluo ro qu i n o lo n e s may
increase pl a sma levels o f t h eop h y l l i n e a n d o t h er
m eth y Lx a n thi nes, e n h a n c i n g rheir toxici ty.
ANTIMYCO BACTERlAL DRUGS
M),c o bacter i a a re slow-growi ng aerobic gra m- p osi ri v e
bacreria that are wid espread i n th e enviro n me n t and in
animals. T he p ep tidoglycan layer has a d i ffe re n t chemical
b asis than gram-positive or gram - negative b ac te ri a . The
outer envelope co n tai n s a variety of com plex l i p ids called
m ycolic acids, which crea te a waxy layer char pro v i des
 A n t i b a c t e r i a l Age n t s 387

res ista n ce co d ty i n g a n d o t her e n v i ro n memal faccors. Drugs Used in Tu berculosis

Thus, m yco b a cte r i a ca n sU lvi ve fo r p rolo n ged p e riods i n
The m aj o r d r u gs used in tu b e r c u l o s i s a re isoniazid
rhe environmem and are effec t i ve l y t ra n s m i l te d by air­
(IN H), rifampin, ethambutol, pyrazinamide, and strep­
borne d roplets . After enteri ng host cel l s , my co b act e ri a
tomyc i n ( Ta b l e 27-3) . Acti o n s of t h e s e agen ts o n
su rvive as i n t ra ce l l u lar parasi tes in macrophages .
M tuberculosis are bactericidal o r bac terios tatic, de p e n d ­
Major h u m a n pat h o ge ns i n cl u d e Mycobacterium
i ng on d r u g concentration an d s ttain s u s c e p ti b i l i ty. Treat­
tubercuLosis and iv/ leprae, the ca usative agents o f tu ber­
ment of pulmonary tu berculosis u s u al ly be g i n s w i t h a
culosis and lep rosy, res pec t i vel y. My cob a c t e r i a o t h e r
th ree- or fo ur-drug co m b i nation regim en de p e n d i n g o n
t h a n tu bercu l osis a re a s soc i a t ed w i t h s eve r al other co n ­
t h e known o r a n t i ci p a te d rate o f res i s t a n ce c o I N H .
d i tions, U S U ;) l ly i n i m m u n o co m p ro m ised i n d ivid uals.
D i rec r l y o bserved therapy (DOT) re g i m e n s , i n wh ich a
In A I DS p a t i e n ts i n t h e U n i t ed S tates, M aviu m co m ­
h eal th-care p rovi der wi t n esses i n ges t i o n of t h e a n t i tu ­
plex is a n i n c reas i n g l y im p o rta n t p a t h og e n .
bercu losis age n ts, a re teco m m ended in n o n c o m p l i a n t
Myco bacteria l i n fec t i o n s a te ge n e ra l l y slowly
pa t ien r s a n d in d r ug-resistanr tuberc u l os i s .
d e v el o p i n g chro n i c con d i t i o n s . Because mycobacterial
cel l waJ J c o m po n e n ts promote i mm u n o l o g i c teactions, Isoniazid
a s i g n i fi ca n t p ortion o f the p a t h o l o g is a t t r i b u ta bl e to
y Isoniazid is str u c t urall y s i m ilar to pyridoxi ne (vi tam i n BJ
the host i m m u ne resp onse rather than to direct bacte­ The d r ug is wel l absorbed oral l y and penetra tes ceUs to
rial co xi ci ty. Fo r a l l myco bacterial i n fections, social and a c t o n i n tracel l u l a r m ycob a c t e r i a. It is metabol i zed by
envi ro n m e n tal faccors as wel l as gen e tic p red i s po s i ti o n the l iver an d the rate of metabo l ism varies among ethnic
play a role. gro u ps. Fast meta bol izers m a y req u i re h igher d o sage th an
C h e m o t h erapy fo r tu betcu losis, leprosy, a n d o t h e r s l o w metabol izers for e q u i v ale n t the r apeu ti c effects.
a ty p ical m ycobacteria is co m pl i c a te d by n u m e r ous fac­
M E C HA N I S M OF ACT I O N . An t i tu be rc u l a r action
tors, i n c l u d i n g ( I ) l i m i t e d i n fo r m a t i o n ab o u t the
involves i n h i b i t i o n o f a n acyl c a rr i e r pro te i n red u c tase
mec h a n isms o f a n r i m yco bacte r i a l d r u g actions; (2) t he
i n vo l ved i n sy n t h e s i s of m yc o l i c a ci d r e q u i re d fo r the
rap i d d e vel o p m e n t of r es i sta n c e ; (3) the i n t r a ce l l u la r
outer enve l o p e o f t h e p ep t i d o gl y c a n l a ye r . Because
l oca tion of m y c o b a c t e t i a ; (4) t h e ch ro n i c n a t u re o f
tes i s t a n ce can emerge r a p i d ly i f the d r ug is used a l o n e ,
m ycobac te r i a l disease, wh i c h req u i res p r o t r a c ted d r u g
I N H is a l w a y s used toge t h e r w i t h o th e r a n t i t u bercu­
trea tm e n t a n d i s as s o c i a t e d w i t h d r u g tox ici ties; and
losis d r u gs i n ac tiv e i n fe c t i o n s .
(5) p a ti e n t c o m p l i a n ce . C h e m o th e r a p y of m ycobacte­
rial i n fections almos t a l way s i n volves prolo nged u s e of CLI N I CAL USE. I N H is the si n gJ e m os t i m p o r t a n t
d rug c o m b i n a t i o n s ro d el ay t h e e m e rgence of res ist­ d r u g used i n t u be r c u los i s a n d is a co m p one n t of mos t
a nce and to e n h a n ce a n r i m y co b acte r ia l e ffi c acy. d r u g co m b i n a t io n reg i m e n s fo r [his disease (Table 27-3) .

Table 27-3. Anti m i c robials used i n the treatment o f tu berc u losis and
recommended d u ration of therapy

Regi men (in a p p roxi mate order of prefe rence) D u ra t i o n ( m o nths)

I so n i a z i d , r i fa m p i n , pyraz i n a m i d e 6
I so n i a z i d , r i fa m p i n 9
R i fa m p i n , eth a m b u to l , pyra z i n a m i d e 6
R i f a m p i n , et h a m b uto l 12
I so n i a z i d , et h a m b uto l 18
A l l ot h e r 2: 2 4
388 C H E M OT H E RA P E U T I C S
INH i s gi ve n a s the sole drug i n the [[ea tmen r of latenr
i n fect i o n ( form e rl y known as prop hylaxis) i n c l u d i n g
p u r i fi e d p r o te i n derivative (PPD) s ki n test conveners,
a n d for i n d iv i d u a ls w ho have c l os e co n ra c t w i t h
p a ri e n rs w i t h a c r i v e d i s e ase .
ADVERSE EFFECTS . Ne u rotox i c e ffects a r e com mo n
a n d i n c l u d e p e r i p h e ral neuri ris, restlessness , m uscle
tw i rch i ng , and i nsom n i a . P yr ido x i n e can be given to
re d u ce r h is tox i c i ty w i th ou t i m p ai r i ng the a m i bacterial
action. l N H is h ep a to t oxic and may cause ab normal
liver function t es ts , j a u nd i ce , a nd h e pa t i t is. For r u n a tely,
h e p a totox i c i ty is r a re in child ren. I N H may inhibit t h e
h ep a r i c metabolism o f dr u gs ( e . g . , ph e n yto i n ) . Hemol­
ysi s and a l u p u s - l i ke sy n d ro m e h av e be en re p or t ed .
Rifa mpin
Ri fa m p i n is bacterici dal aga i n s t sus cep t i b l e M tuber­
cuLosis o rg a n i s ms . When given o rall y, it is well absorbed
a n d d ist ributed to mos t b od y t issu es , i n c l u d i n g
CNS. The d r ug u nd e r go e s e n te r ohe p a t i c cyc l i n g a n d
is p a r t i al l y m e ta b o l i zed i n t h e l i ve r. Both free dr u g and
m e tabo l i tes are e l i minated m a i n l y in the feces.
M ECHAN ISM OF ACTI O N . Ri farn pin inh i b i ts DNA­
d ep e n d e n t R N A p o l y m e r ase ( e n c o d e d by t h e
g e n e ) i n M tuberculosis a nd many o t h e r m i c r o o r gan
i s m s . I f r i fa m p i n is used a l o n e , c h a n g es i n d r u g se n ­
s i t iv i ty o f t h e polym erase e m e rges r a p i d l y, l e a d i n g to
re s Is t a n c e.
C LI N I CA L USE. In t u b erc u losis, r i fa m p in is al w ays
u s ed i n co m b i n a t ion w i t h other d r u gs (Ta b l e 27-3)
be cau s e r es i s ta n c e d e v elo p s ra p i d l y when it is used
a lone i n active i n fectio n s . Ri fa m p i n can b e used as th e
so le d rug in t r e a tm e m of l a te m tu berculosis i n INH­
i n tolerant p a t i e n t s or i n i n d i v i d ua ls w h o h a ve cl ose
contact w i t h p a t i e n ts ca r r y in g I N H - resis ta m s tr a i ns .
O th e r us e s o f r i fa m p i n i n cl u d e t h e m e n i n go c o c ca l
a n d s t a p llylococ ca l carrier s t a tes . I n l e p tosy, r i fa m p i n
given m o n t h l y d e l a ys th e emergence of res istance to
d a pso ne .
A D V E RS E E F F ECTS . R i fam p i n i m p ar ts a harmless
o ra n ge color to u ri n e , sw e a t , tears , and con tac t lenses
(soft l en s es m ay b e per m a n e n tl y s ta i ned) . Occasional
ad v e rse effe c ts i n e l u d e ras hes , thro m b o cy t o p e n i a ,
ne p h r i t is , and liver dysfuncrion.
Ri fa mp i n co m m o n l y causes l igh t- ch a i n p r o t e i n ­
u ria and may i m p a i r a n t i bod y res ponses . I f g i ve n l ess
often t ha n tw i ce wee kl y, ri fa m p i n may cause a fl u - l i k e
sy ndro m e (chill s , feve r, mya lg i as ) a nd a n e m i a .
Rifa m p i n stro n gl y ind uces l i ver d r u g-me tabo l iz i ng
e nzy m es and en h a n ces t h e e l i m i n a t ion rate of m a n y
d rugs, i n cl u d i n g a n t i co n v u l sa n ts , co n t ra cept i ve s tetoi d s ,
cycl o s po r in e , ketOconazole, me t h a d o n e , te r b i n a fi n e ,
and warfa ri n . Ri fabutin is l ess like l y to caus e dr u g
i n t e r a ct ions t h a n r i Fa m p i n a n d is e q u a l l y e ffective as
an a n t i m y c o b a c t e r i a l age n t . Ri fa b u t i n is u s u al l y p re­
fer t·ed over r i fa m pi n in tre a t i n g tu berc u l osis in AI D S
pa t i en ts .
Ethambutol
This a n ti t u berc u l o u s d r u g is well a bso r bed o ra l l y and
d is t r i b u t e d to most tissues, in c l ud i n g the C N S when
the m en i n ges are i n fla m ed . A l a rge fra c t i o n is e l i m i ­
n a ted u n c h a n ged i n t h e ur i n e . D o s e reduction i s nec­
the
essary in ren a l fa i l u re .
M E C HAN I S M O F ACT I O N . E t h a m b u to l i n te r fe res
wi t h m yco b a c te r i a l ce l l w a l l sy n t h es i s by i n h i b i t i n g
a r a b i n o s y l transferases involved i n t h e s y n r h es i s of ara­
b i n oga l a cta n , a componenr of t h e o rga n isms' c e l l wal ls.
rpo
R e s i s t a n ce o cc u rs ra p i d l y v i a m u ta t i o n s in t h e emb
­
g ene i f the d r u g is used a l o n e .
CLINICAL USF. The m a i n use of e th a m b u to l is i n
tu bercu losis, i n c l u d i n g r u b er c u l a r m e n i n gi ti s . To avoid
resis ta n ce , e th a m b u to l i s a l ways given in com b i n a tion
w i t h o t h e r an t i t u be rc u l ou s d r ugs (Ta b l e 27-3).
A D VERSE EFF E C TS . T h e most co m m o n a d verse
effects ar e d ose - d e pe n d e n t v i s u a l d i s r u r ba n ces , i nc l u d ­
i n g d e c reased vi s u a l a c u i ty, red-green c o lo r b l i n d n ess ,
o p t ic ne u r i tis, a nd possi b l e re r i n a l d a m a g e ( from p ro ­
l o n ged use a t h ig h doses) . Mos t o f rhese effecrs regress
if t h e d r u g is s tO p p ed p ro m p c l y. O t h e r n e u ro tox ic
e ffects i n c l u d e h e a d a c h e , co n fu s i o n , a n d peri p heral
n e ur i tis. Eth a m b u tol is r e l a t i ve l y c o n trai n d i c a red i n
c h i l d re n too yo u ng to perm i t assess m e n t o f v is u a l acu ­
i ty and re d - g re en co l o r d i scr i m i n a ti o n .
Pyrazinamide
Py r az i n am i d e is w e l l a bsorbed o r a l l y a n d p e n e r r a tes
most b o d y ti ss u es , i n c l u d i n g i n fl a m e d m e n i n ge s . The
drug is p a r t ly m eta bo l i ze d t o p y r a z i n o i c ac i d , a n d both

paren t molecu le and merabo l i re a re excreted in the
u ri n e . Plasma hal f- l i fe o f pyrazi namide is increased in
hepatic o r renal fa i l u re.
MECHAN I S M O F ACTI ON . The mecha n i s m of
action of pyrazinam ide is unknown; however, i ts bac­
terios tatic action appears to requ i re metabolic conver­
sion via pyrazinami dases (encoded by the pncA gene)
present in M tuberculosis. Resis ta nt myco bacteria l ack
these enzymes, a n d res istance develops rapidly if the
drug is used al one. Th ere i s m i n i m a l ctOss-resistance
wirh other anrimyco bacterial d r ugs.
CLINICAl. USE. Pyrazinam ide, when comb i ned with
other antitu berculous d r ugs (IN H and rifampin) , is
i m porra n t ftO n t-line drug used i n "short-co u rse" (i.e.,
G mont hs) treatmem regi mens as a "steril izing" agenr
active agai nst resid ual i n tracellular organisms that may
cause rela pse.
ADVE RSE E F FECTS . Approxi mately 40% of patients
develop nongoury polya rth ralgia ( i . e . , pain at m ulti­
p l e j o in ts) . Hyperuricem i a occurs com m o nly but is
usually asym ptOma tic. Other adverse effects i nclude
mya lgia, gas t roin testi nal i r r i ta r i o n , macu lopapular
ras h , hepatic dys function, porphyria , and p ho tosensi­
tiviry reactions.
Streptomycin
T h i s a m i n og lycos i d e is now used more freq u e n t l y
than befo re b e c a u s e o f the grow i n g p reva l e nce o f
strai ns o f M tuberculosis res i s t a n t r o o t h e r drugs.
Stre p ro myci n is used p r i n cipa l l y in d r u g com b i na­
tions fo r the trea t m e n r o f l i fe - t h reate n i n g t u b e r ­
c u lous d is ease, i n c l uding meningi t i s , miliary
dissemi n a tion ( m ycobacte r i a l i nvasion o f m u l ti p l e
organs v i a [ h e bloodstream) , a n d severe o rgan tuber­
culosis. The pharmacodyn amic and pharm acoki netic
proper ties of s t re ptomyc i n a re s i m i l a r to those of
other a m i no glyco s i d es .
Alternative Drugs
Several d ru gs w i t h a n t i m ycobacterial a c t i v i ty are
used in cases that a re res i s ta n t ro fi rs t - l i n e a ge n t s ;
they are considered seco nd-line d rugs because they are
no more effective, and the i r toxicities are often more
serious than [hose of the maj o r drugs. Second-line
agen ts i n c l u d e ami kacin, cip rofloxacin, ofloxacin,
A n t ibacterial Age n ts 3 8 9
ethionamide, para-aminosalicylic acid ( PAS) , capre­
omycin, a n d cycloseri ne. As w i th fi rs t-li n e agents,
these d rugs a re always used i n co m b i nations.
Drugs Used in Leprosy
Myco bacterium leprae is the causative agent of leprosy
(Hanse n's disease) . M leprae grows i n tracellularly, ryp­
ically w i thin ski n and endothel ial cel ls and Schwann
cel ls of peripheral nerves . Onser o f lep rosy is gradual
and the spectrum of disease is b road, depend i n g o n the
host's i m m u n e response. Lep rosy requ i res close and
prolo nged co n tact for transm iss i o n . Transm issi o n is
d i rectly relared to overcrowdi n g and poor hygiene, and
an
occurs by d i rect con tact a n d aerosol i n ha l a t i o n .
A1rho ugh rare i n rhe U n i red Srates, t h e worldwide
p revalence o f cases is esrimated at over 1 million, wirh
highest concentration bei ng i n Sou rheast Asia, Africa,
and Central and Somh America.
Several drugs closely related to the s u l fonam ides
h ave been used effectively in long-term treatment o f
leprosy. Dapsone (diaminod iphenyl s u l fone) remains
rhe most active drug against M leprae. Like the sul­
fonamides , i ts m echa nism of acti o n involves i n h i bi­
tion o f fo l i c acid syn thesis. Resistance can d evel op,
especially i f low doses are give n . Dapsone can be given
o rall y, penetrates tissues weJl, undergoes enterohepatic
cycli ng, and is eliminated i n the urine, partly as acery­
lated metabolites . It is usuaJly weJl tolerated. Com m o n
adverse effects include gastroi ntesti nal irritation, fever,
skin rashes , and methemoglob i ne m i a . Hemolys is may
occur, especial ly i n patienrs with G6PD deficiency.
Dapsone is rarely used alone in leprosy. Drug reg­
i mens usually include combinations of dapsone with
rifa m p i n (or rifabutin, see discussion above) with or
without clofazimine. Clofazi m i ne causes gastrointesti­
nal i rritation and pinkish b rown skin discoloratio n .
Acedapsone is a repository form of d apsone that
p rovides inhibito ry plasma concen trations for several
momhs. In addition to its use in lep rosy, dapsone is an
alternative drug for the treatment of P jiroved pneu­
monia i n AI D S patients.
Drugs for Atypical Myco bacterial Infections
I n fections res u l t i ng fro m arypical myco bacteria (e .g.,
M marin um, M avium - in traceffufare, M u/cerans) ,
390 C H E M OT H ERAP E U T I C S
a l t h o u g h s o m e t i m es asym p toma t i c, m a y b e t r ea t ed
w i t h the descri be d a n ti m yco bacte r i a l d r ugs (e . g . ,
etha m b u tol, r i fa m p i n l o r other a n ti b i o t i cs ( e . g . , e r yth­
ro m y cin , am i ka c i n l .
M avium com plex ( MAC) is a cause of d i ssemi­
n a ted i n fecrions i n AIDS p a t i e n ts . C u rren tly, c1a r­
i th ro m yci n or a z i t h r o m yc i n is reco m m ended fo r
p r i m a ry p rop h y l axi s i n p a t i e n t s with CD4 co u n ts l ess
tha n 5 0 / � L . Tre a t m e n t of MAC i n fections req u i res a
co m bi n a t i o n of d r ugs; o n e favored regi m e n consists of
a zi t h r o m y c i n o r c 1 a r i th ro m yc i n w i th e t h a m b u tol a n d
r i fa b u r i n .
REHABILITATI O N F O CUS
A l a r g e n u m b e r o f a n ti b a c te r i a l agenrs are c u r re n r l y
i n cl i n i ca l u s e . M a ny fa c r o rs are co n s i d ered i n t h e
c h o i c e o f a p a rt i c u l a r d r u g . T h ese i n c l u d e t h e
s p e c i es o f b a c te r i u m ( i f k n o w n ) , t h e b a c te r i u m's
d r u g s u sce p t i b i l i ty ( i f k n ow n ) , the loca tio n of t h e
i n fe c t i o n ( w h i c h o ft e n p o i n t s to t h e m o s t l i kely
o rgan i s m ) , t h e sever i ty o f i n fec t i o n , a nd t h e a d v e rs e
e ffe c ts o f t h e d r u g u n d e r co ns i d e r a t i o n i n a p a t i e n t
w i t h i m p a i re d e l i m i n a t i o n m echanisms ( e . g . , re n a l
o r l i v e r d y s fu n c t i o n ) .
O ne s e r i o u s p ro b lem of a n t i baccerial t h e r a p y i s
t h e p o te n tial fo r i n c re asi n g t h e p r ev a l e n ce o f res ista n t
s t ra i n s . The n um be r o f res i s tan t bac terial s t ra i n s co n ­
t i n ues to i n crease a n d mecha n i s ms fo r the deve l o p ­
m e n t o f bacterial res istance a re co m p lex. As h e al t h - care
p ro fess i o n a l s , p h ys i c a l th e r a p i s ts should e d u c a te
p a t i e n ts a b o u t the ro l e each i n d ivid u a l p l a ys in l i mi t ­
i n g t he d evelo p m e n t o f d r u g-res istam bacteria. Specif­
i ca l l y, pa t i e n ts ca n be rem i nded tha t ( 1 ) antibacterial
d r u g s s h o u ld be used c a u ti ousl y and n o t overused, a n d
(2) o n ce a d r ug reg i m e n has b e e n i n i t i a ted , it sho u l d
be com ple ted i n i t s e n tire ty.
P h ys i ca l t h e rap i s ts ro u ti nely treat p at i e n t s rece i v­
i n g a n t i bacterial a g e n ts fo r cond i tions e i t h e r d i r ect l y
o r i n d i rec t l y rel a t e d to t h e i r n e e d fo r re h a b i l i t a t i ve
i nt e rv e n t i o n . For ex a m p l e , th e r a p i s ts o fte n t r e a t
p a t i e n t s w i t h i n fec t i o ns d i re c d y r e l a t e d to reh a b i l ita­
t i o n , such as b urns, open w o u n d s , a n d s u rge ry. O th e r
i n fec t i o n s not d i rec dy re la ted ro re h a b i l i ta t i o n
i n c l u d e p n e u m o n i a a n d u r i n a r y tract i n fe c r i o n s .
These i n fe c t i o ns a re co m m o n i n b o t h h os p i ta l ized
p a t i e n t s and p a t i e n t s r ece i v i n g o u t p a t i e n t or h o m e
h e al t h c a re .
Beca u se s u c h a l a rg e p ro p o r t i o n o f p a t i e n ts rece i v­
ing reha b i l i t a t i o n servi ces w i l l be t a k i n g a n t i b acterial
age n ts, phys i cal t h e r a p i s ts sho u l d h ave a ge n er a l u n d er­
sta n d i ng of t h e v a r i o u s types of a n t i b ac terial agents,
t he i r type o f a c t i o n ( e . g . , bactericidal o r bacterios ta­
tic) , a n d thei r ad v ers e e ffec ts .
F i n a l l y, p h y s i c a l t h e ra p is ts m u s t u n d e rs ta n d the i r
ro l e i n p r e v e n t i n g t h e s p r ead o f i n fe c ti o n s . H a n d ­
w as h i n g b e tween p a t i e n ts, adeq u a tel y clea n i n g or s t e r ­
il izing r e h a bi l i t a t i o n eq u i p m e n t ( e . g. , wal kers,
w h i r l pools) between patien ts, and m a i n t ai n i n g a p p ro­
p r i a te s te r i le tec h n i q u e when w o rki n g wi t h open i n fec­
t ions can l i m i t t he r ap i s t s ' tr an s fe rr i n g i n fect i o n a m o ng
p a t i e n ts .
CLI N I CAL RELEVAN CE
FOR RE HABILITAT I O N
Adverse Drug Reactions
The m o s t c o m m o n a d v e r s e e ffe c ts assoc i a ted w i th
m a n y of the a n t i b a c te r i a l agen ts i n cl u d e hypersen­
s i t i v i ty and a l l e r g i c re a c t i o n s and g a s c r o i n t es t i n a l
d i s t u r b a nces .
• Hypersens i t i v i ty o r a l l e rgic reactions: s k i n r a s h e s ,
itc h i ng , wheez i n g , u l t rav i o l e t sens i tivi ty, fever, a n a ­
p h y l ax i s
• G a s t ro i n t e s t i n a l p ro b l e m s : nausea, vo m i t i n g ,
d ia r rhea, s u pe r i n fec t i o n w i t h res i s ta n r o r ga n i s m s ,
co l i t i s
• Many a n t i b i o r i cs (es p e c ia l l y c h l o ra m p h e n i co l ,
e r yr h ro m y c i n , c l a r i rh ro m y c i n , fl u o roq u i n o l o nes,
a n d ri fa m p i n ) h a ve s i gn i fi c a n t d r u g i n rerac t i o n s ,
i n cre asi n g o r d e c r eas i n g p l a s m a levels o f o t h e r
d r u gs .
• I V i n fu sio n s o f cep halospo r i ns and va nco myc i n may
cause p h l e b i ti s .
• S o m e a n t i b i o t i c s i n h i b i t p ro d u c t i o n of red b l ood
cel l s (e. g . , c h l o ra m p henico l ) , wh ire b lood cells ( e . g . ,
c l i n d a m y ci n , l i n ezo l id , t r i m e t h oprim) o r p l a t e i e rs
(e.g . , l i n ezo l i d ) .

• D oxycycl i ne and m inocycl ine m ay ca use dizziness
and vertigo.
• Vancomycin and am i noglycosi des are otoroxic.
• F l u o roq u i n o l o nes m ay cause tendonitis.
• An t i mycobacteri al drugs commonly cause neuroroxic
effects (e.g. , isoniaz i d, etha mburol) , v isual ch anges
(e.g. , etha m b urol, pyrazina m i de) , and nongouty
polyar rhralgia ( e . g. , p yrazina m ide) .
Effects I n te rfering with Re habilitation
• Hyp ersensitivi ty reactions and gastroi ntesti n al p rob ­
lems may hinder rehabil i tation intervention.
• If plasma levels of other d rugs increase, pati ents may
experience increased adverse effects. I f plasma levels of
other drugs decrease, their efficacy may be decreased.
• Phleb i t i s ca using p ai n , tenderness, and edema in the
a ffected extrem i ty may lim i t mob i l i ty.
• Ane m i a l i m its exercise rol erance . Leukocytopenia
i n c reases patients' susceptibi l i ty ro infection. Thro m­
bocyto p enia i ncreases p a t i e n ts' suscep tib i l i ty ro
b leed i n g and bruis i ng.
• Dizzi ness and vertigo m a y l i m it mob i l i ty and bal­
a nce, incre asi ng the risk of falling.
• H i g h - freq u e n cy hearing loss, more com mon with
a m i kacin and kanamyci n , may l i m it patients' abi l i ty
ro fo l low d i rections of therap i st. Vertigo, atax i a, and
loss of balance, mOre com mon with gen tam ici n a n d
robramyc in, may l i m i t mob i l ity and increase r i s k o f
falling.
• Tendonitis m ay l i m i t ran ge of motion and strength­
eni ng of i n volved joints.
• Neurorox ic and vi s ua l d i s t u rbances may h i nder par­
tici p a ti on in reh ab i l itation progra m s.
Poss i b l e The rapy Solutions
• A l ter therapy ti m es a round gastroin testi na l prob­
lems if sy m p roms occ ur routine ly with continued
therapy.
• Th e p hys i ca l therapist s h o u l d know all of the d r ugs
t h e p a t ient is ta king, be aware of the agents with
h igh p oten t ial ro cause signi ficant drug interactions,
and recognize adverse effects, or decreases i n dr ug
efficacy.
A n t i b a c t e r i a l A g e n ts 3 9 1
• P h l ebit i s after parenteral a n ti b iotic a d m i n i s t r a t i o n
s h o u l d be repo rted ro t h e p r i m a ry h ea l t h-care
provider. Weight bearing on the a ffected e x trem i ty
should be as rol erated, follow ing any restr ictions set
by the p r i m a ry health - ca re p rovider.
• Aerobic exercise goals should be lowered i n p a t i ents
with ane m i a . Oxygen saturation should be moni­
rored by p ulse o x i m e t ry d u r i n g exerci se ro e nsure
ad eq u ate oxygenation.
• P hysical therapists shou Id ta ke extra i n fect ion con­
trol p recautions when wo rking with p ati ents with
leukocytopen i a : sanitizing a l l eq u i p m en t pri o r to
patient use, treat i ng patient in h is/ h e r own room in
p reference ro a re as with larger p a tho genic exposures
(e.g. , therapy gym ) , a n d avoid ing pa.t i ent co n tact i f
the thera p ist i s i l l .
• In p atie n ts with thrombocyropen i a , sharp wo und
debr i d e m ent, deep ti ssue massage , and res i s ti ve
exercise t h a t p u ts sig n i fi cant p ressure on bony o r
s m a l l su r face a r e a s ( e . g . , resi stive tub ing a round
ankl e , resi sted seated knee extension) s h o u l d b e
avo i d e d .
• F o r dizzi ness, i n crease the assista nce p rov ided or the
stab i l i ty of the assistive device a nd ca u t i o n p a t i en ts
to move slowl y, especia l l y wh e n tra nsi tion i ng
between posi tions.
• If the p atie n t reports ( o r t h e thera p i st obse r ves)
decreased hearing acui ry or ves t i b u l a r fu n ction , these
symproms should be reported ro the pri m a ry health­
care prov i d e r i m mediately.
• Te n d o n i tis as a resu l t of fl u o toq u i n olo n es should be
repor ted to the p r i m ary health-care p rov i der.
Str ength ening exercises a round i n vo l ve d j oi n t s
should be avoided to avoid risk of tendon ru p tu r e .
• Neurotoxic and visual d i stu rbances consequen t to
anti mycobacterial drugs should be reported ro the
p ri m ary health-cate provide r. In the absence of seri­
ous tox ici ry, t he patient should be sttongl y encou r­
aged to con tin ue with the drug regi m e n beca use
com plia n ce i s req u i red for erad ication of t h e i nfec­
tious age n t . If symptoms are li m i t ing activi ry, re ha­
b i l itation goals may need to be postponed until the
drug reg i men has b een com p leted .
392 C H E M O T H E RA P E U T I C S

P RO B LEM - O RI ENTED PATIENT S T U DY

Brief History: The p a t i e n t is a 5 3 - yea r- o l d whi te taken p ri o r t o h e r M I . H owever, the wo u n d bed

fe m a l e with a 4 0 -year h i s to r y of i ns u l i n ­ appears to have a n i nc r e a s e d a m o u nt of n ecro t i c tis­
d e p e n d e n t type 1 d i a b e tes m e l l i t u s . Two weeks sue. The p hys i ci a n wo rki n g a t the wou nd cl i n i c
ago , she s u ffe red a m yo c ar d ia l infarction (MI) fo r wri tes a n o rder fo r wh i rl pool clea n s i n g a n d wet- to­
w h i c h s h e was h o s p i tal ized fo r seve ral days . I n dry d r es s i ngs fo r d e b r i d e m e n t . After d iscuss i o n
add i t i o n [ Q h e r i n s u l i n , s h e h as been t a k i ng the between t h e physician and t h e physical therapist o f
a n ticoagu l a n t warfa r i n s i nce her M I . P r i o r [Q her the proposed treatment p l a n , changes a re made to
M I , the patien t had been refe rred [Q a n o u t p at i en t t h e trea t m e n r p l an to i n c l ude enzymatic d eb r i de­
wo u n d c l i n i c fo r eval uation a n d creatmen t of neu­ ment i n s tead o f wet- to-dry d ress i n gs and mod i fi ca ­
ropat h i c u lcers o n both fee t . tion of orthotics [Q i n h i b i t wo u n d p rogressio n .

CU17"Cnt Medical Status a n d Drugs: The p a t i e n t

Problem/Clinical Options: T h e p a t i e n t was p re­
a t tends the wo u n d cl i n i c fo r h e r fi rs t trea t m e n t ,
s c r i b ed an a n t i coagu l a n t after her MI to lessen the
2 . 5 weeks after h er M I . W h e n the pat i e n t ta kes
Subseq uen tly,
l i kel i h o o d o f th ro m b u s fo rmat i o n .
o ff h e r shoes a n d socks, the p hys i cal t he r a p i s t
bacterial
s h e was g i ven ery t h ro m yc i n to treat t h e
n o tes t h a t the ulcer on h e r righ t foo t has i ncreased
i n fec ti o n i n h e r righ t l ower ex t re m i ty. Ery­
in s i ze s i nce the eval u a t i o n a n d t h a t the r i g h t
t h ro m yc i n i n h i b i ts several h e p a tic cyto c h r o m e
l ower extrem i ty i s edema[Q u s . The therap i s t co n ­
P45 0 isofo r m s , and therefore has significam d r u g
tacts t h e p r i m ary heal th-ca re p r o vi de r w i t h t h e
i n rerac t i o n s . Spec i fi c a l ly, e ryth ro myci n i ncrease s
p a t i e n t 's ch a nge i n status. The wo u n d is c u l t u red
the plasma leve l of an ricoagu l a n t s , l e a d i ng to a n
and is posi t i ve fo r S a u reus. The pa t i en t i s given
i n c reas ed risk o f b l e e d i n g . T h e proposed treat­
oral e r y t h r o m yci n t o t re a t the wo u n d i n fec t i o n
m e n t plan o f w e t - t o - d r y d re s s i ngs for wo u n d
a n d res u l ti n g p h le b i ti s .
debr i d e m e n t wou l d res u l t i n s i g n i fi c a n t t i ss ue
Rehabilitation Setting: After ano ther week, the te a r i n g , w i th res u l t a n t b l ee di n g r h a t m a y be
patient retu rns [Q the wo u n d clinic. The ph ysical i n creas ed w i t h the p a ti e n t 's c u r re n t medica tions.
therap i s t n o tes tha t the wo u n d circu mference o n I n c o n tras t , e n zy m a t i c d e b r i d e m e n t o f n e c ro t i c
the right foO [ i s back t o t h e basel ine measurements t i ssue wo uld m a ke b l eed i n g a l m o s t negl i g i b l e .

P R E P A R AT I O N S AV A I L A B L E

�-Lacta m Ant i b i ot i c s and Other Ce l l Wa l l pow d e r to rec o n st i t u te for 5 0 , 1 2 5 , 2 0 0 , 2 50 , 400

Synthesis I n h i bitors m g/ m L s o l u t i o n

Penicillin s
Amoxicillinlpotassium clavulanate (generic,
Amoxicillin (generic, Amoxil, others) A ugmentin) 1
O ra l : 1 2 5 - , 2 0 0 - , 2 50 - , 400-mg c h ewa b l e ta b l ets; O ra l : 2 5 0 - , 5 0 0 - , 8 7 5 - m g ta b l et s ; 1 2 5 - , 2 0 0 - ,
500-, 8 7 5-mg ta b l et s ; 2 50 - , 500-mg c a ps u l e s ; 250-, 400-mg c h e wa b l e t a b l et s ; 1 000-mg
 A n t i b a c t e r i a l Age n t s 393

exte n d ed - r e l ea se t a b l et powd e r to reco n s t i t u t e Piperacillin (Pipraci/)

for 1 2 5 , 2 0 0 , 2 5 0 m g/5 m L s u s p e n s i o n
Ampicillin (generic)
O r a l : 2 5 0 - , 5 0 0 - m g c a ps u l es ; powd e r to rec o n ­
st i t u te for 1 2 5 - , 2 5 0 - m g s u s p e n s i o n s
P a re n t e ra l : powd e r to r e c o n st i t u t e f o r i n j e c t i o n
( 2 , 3 , 4 g per vial)
Piperacillin and tazobactam sodium (Zosyn)3
P a r e n t e ra l : 2 - , 3 - , 4-g powd e r to rec o n s t i t u t e f o r

Pare n tera l : powd e r to reco n st i t u t e f o r i n j e c t i o n I V i n j ec t i o n

( 1 2 5 , 2 5 0 , 500 mg, 1 , 2 g per v i a l ) Ticarcillin (Ticar)

Ampicillinlsulbactam sodium (generic, UnasynF
P a re n te ra l : 1 , 2 g a m p i c i l l i n pow d e r to re c o n ­
st i t ute f o r I V o r I M i n j ect i o n
Carbenicillin (Geocillin)
O ra l : 3 8 2 - m g ta b l ets
P a r e n t e r a l : powd e r to r e c o n s t i t u t e f o r i n j e c t i o n
( 1 , 3, 6 g per via l)
Ticarcillinlcla vulanate potassium (Timentinr
P a re n te ra l : 3 g powd e r to rec o n s t i t u te for i n j e c t i o n
C e p h a l o s p o r i n s a n d Oth e r �-la cta m Drugs

N a rrow S p e ctru m (Fi rst- G e n e rat i o n ) C e p h a l o s p o r i n s

Dicloxacillin (generic)
O ra l : 2 5 0 - , 5 0 0 - m g c a ps u l e s Cefadroxil (generic, Duricef)
O ra l : 5 0 0 - m g c a p s u l e s ; 1 -g t a b l et s ; 1 2 5 , 2 5 0 ,
Mezlocillin (Mezlin)
5 0 0 m g/5 m L s u s pe n s i o n
P a r e n t e r a l : powd er to rec o n s t i t ute for i n ject i o n
( i n 1 - , 2 - , 3-, 4 - g v i a l s) Cefazolin (generic, Ancef, Kefzol)
P a re n t e ra l : powd e r to r e c o n s t i t u t e f o r i n j e c t i o n
Nafcillin (generic)
( 0 . 2 5 , 0 . 5 , 1 g p e r v i a l o r I V p i ggy b a c k u n i t )
O ra l : 2 5 0 - m g c a ps u l e s
Pare n tera l : 1 , 2 g p e r I V p i ggy bac k u n i t s Cephalexin (generic, Kef/ex, others)
O ra l : 2 5 0 - , 5 0 0 - m g c a p s u l e s a n d t a b l et s ; l -g
Oxacillin (generic)
t a b l et s ; 1 2 5 , 2 5 0 m g/ 5 m L s u s pe n s i o n
O ra l : 2 5 0 - , 5 0 0 - m g c a ps u l e s ; powd e r to re c o n ­
st i t u te f o r 2 5 0 m g/ 5 m L so l u t i o n Cephalothin (generic, KeflinP
Pa rentera l : powd e r t o reco n s t i t u te f o r i n j e c t i o n Parentera l : powd e r to reco n st i t u te for i n j ect i o n a n d
( 0 . 5 , 1 , 2 , 1 0 g per v i a l ) so l ut i o n for i n j e c t i o n ( 1 g p e r v i a l or i n f u s i o n pac k )

Penicillin G (generic, Pentids, Pfizerpen) Cephapirin (Cefadyl)

O ra l : 0 . 2 - , 0 . 2 5 - , 0 . 4 - , 0 . 5 - , 0 . 8- m i l l i o n u n i t P a r e n t e ra l : powd e r to re c o n st i t u t e f o r i n j e c t i o n
ta b l et s ; powd e r to rec o n s t i t u te 4 0 0 , 0 0 0 u n its/ ( 1 g p e r v i a l o r I V p i ggy b a c k u n i t )

5 m L s u s pe n s i o n Cephradine (generic, Velosef)

P a r e n t e r a l : powd e r t o rec o n st i tute for i n j e ct i o n O ra l : 2 5 0 - , 5 0 0 - m g c a p s u l e s ; 1 2 5 , 2 5 0 m g/ 5 m L
( 1 -, 2 - , 3-, 5-, 1 0-, 20-m i l l i on u n its) s u s pe n s i o n

Penicillin G benzathine (Permapen, Bicillin) P a re n t e r a l : powd e r t o re c o n st i t u t e f o r i n j e c t i o n

Pare n t e ra l : 0 . 6 - , 1 . 2 - , 2 . 4 -m i l l i o n u n its per dose (0 25, 0.5, 1 , 2 g per vial)

Penicillin G procaine (generic) I n t e r m e d iate S p e ctrum ( S e c o n d - G e n e rati o n )

P a r e n t e r a l : 0 . 6 - , 1 . 2 - m i l l i o n u n i t s/m L for 1 M Cephal osporins

i n j ec t i o n o n l y Cefaclor (generic, Ceclor)

Penicillin V (generic, V-Cillin, Pen- Vee K, others) O ra l : 2 50 - , 500-mg capsu les; 375-, 500-mg

O ra l : 2 5 0 - , 5 0 0 - m g ta b l et s ; powd e r to rec o n ­ exte n d ed-re l ease ta b l e ts; powd e r to rec o n st i t ute for

st i t u te for 1 2 5 , 2 5 0 m g/ 5 m L so l u t i o n 1 2 5 , 1 8 7 , 2 5 0 , 3 7 5 m g/ 5 mL s u s p e n s i o n
394 CH EMOTH ERAPEUTICS

Cefamandole (Mando/) Cefoperazone (Cefobid)

P a re n te ra l : 1 , 2 g ( i n v i a l s ) f o r 1 M , I V i n j ect i o n P a r e n t e ra l : powd e r to reco n st i t u te for i n j e c t i o n ( 1 ,
2 g per v i a l , 1 0 g b u l k )
Cefmetazole (Zefazone)
P a r e n t e ra l : 1 - , 2 -g powde r for I V i n j ect i o n Cefotaxime (Claforan)
P a r e n t e r a l : powd e r to rec o n st i t u te for i n j e c t i o n
Cefonicid (Monocid)
(0 5 , 1 , 2 g p e r v i a l )
P a r e n t e ra l : powd e r to rec o n st i t ute for i n j e c t i o n
( 1 , 1 0 g per vial) Cefpodoxime proxetil ( Vantin)
Ora l 1 00 - , 200-mg t a b l et s ; 50- , 1 00-mg
Cefotetan (Cefotan)
gra n u l es for s u s p e n s i o n i n 5 m L
Pare n t e ra l : powd e r to rec o n st i t u t e for i n j e c t i o n
( 1 , 2 , 10 g per v i a l ) Ceftazidime (generic, Fortaz, Tazidime)

Cefoxitin (Mefoxin) P a re n te r a l : powd e r to r e c o n st i t u te for i n j ec t i o n

P a re ntera l : p ow d e r to r e c o n s t i t u t e for i n j e c t i o n (0.5, 1 , 2 g per vial)

( 1 , 2 , 10 g per via l) Ceftibuten (Cedax)

Cefprozil (Cefzil)
O ra l : 2 5 0 - , 5 0 0 - m g t a b l et s ; p owd e r to rec o n ­
st i t ute 1 2 5 , 2 5 0 m g/ 5 m L s u s pe n s i o n
Cefuroxime (generic, Ceftin, Kefurox, Zinacef)
O ra l : 1 2 5 - , 2 5 0 - , 5 0 0 - m g t a b l e t s ; 1 2 5 , 2 5 0
m g/ 5 m L s u s pe n s i o n
P a r e n tera l : powd e r t o r e c o n st i t u te f o r i n j e c t i o n
Ora l : 4 0 0 - m g c a p s u l e s ; 9 0 , 1 8 0 mg/5 m L powd e r
f o r ora l s u s p e n s i o n
Ceftizoxime (Cefizox)
P a r e n t e ra l : powd e r to re c o n st i t u t e for i n j e ct i o n a n d
so l u t i o n f o r i n j e c t i o n ( 0 . 5 , 1 , 2 g p e r v i a l )
Ceftriaxone (Rocephin)

( 0 . 7 5 , 1 . 5, 7 . 5 g per v i a l or i nf u s i o n pack) P a re n te ra l : powd e r to re c o n st i t u t e for i n j e c t i o n

(0.25, 0.5, 1 , 2, 10 g per vial)
L oracarbef (Lorabid)
O ra l : 2 0 0 - , 4 0 0 - m g c a p s u l e s ; powd e r for 1 0 0 , Carba p e n e m s a n d M o n o b a c t a m

2 0 0 m g/ 5 m L s u s pe n s i o n Aztreonam (Azactam)
B r o a d - S p e c t r u m (Th i rd - a n d F o u rt h - G e n e rat i o n ) P a r e n t e r a l : powd e r to r e c o n st i t u te for i n j e c t i o n
Cephalosporins (0. 5, 1 , 2 g)

Cefdinir (Omnicef) Ertapenem (lnvanz)

Ora l : 300-mg capsu l e s ; 1 2 5 mg/5 m L suspe n s i o n P a r e n t e r a l : 1 g powd e r to re c o n st i t u t e for i n t r a ­
ve n o u s ( 0 . 9 % N a C I d i l u e n t ) o r i n t ra m u sc u l a r ( 1 %
Cefditoren (Spectracef)
l i d oc a i n e d i l u e n t ) i n j e c t i o n
O ra l : 2 0 0 - m g ta b l ets

Cefepime (Maxipime) Imipenemlcilastatin (Primaxin)

P a r e n te r a l : powder for i n j e c t i o n 0 . 5 , 1 , 2 g P a r e n te r a l : powd e r to r e c o n s t i t u t e f o r i n j e c t i o n

( 2 5 0 , 5 0 0 , 7 5 0 mg i m i p e n e m p e r v i a l )
Cefixime (Suprax)
O ra l : 2 0 0 - , 4 0 0 - m g ta b l et s ; powd e r for o r a l Meropenem (Merrem I V)

s u s pe n s i o n , 1 0 0 m g/5 m L Parentera l : powd e r for i n ject i o n ( 0 . 5 , 1 g per v i a l )

I C l av u l a n a te c o n te n t v a r i e s w i t h t h e form u l a t i o n ; see pac kage i n se r t .

2 S u l bactam conten t i s half the a m p i c i l I i n content.
3Ta zo ba cta m c o n t e n t is 1 2 . 5 % of t h e p i p e r ac i l l i n c o n t e n t .
'C l av u l a n a t e c o n t e n t 0 . 1 g .
5 N o t a va i l a b l e i n t h e U n i ted States.
 A n t i b a c terial A g e n t s 395

Oth e r D rugs D is c u ss e d i n T h i s C ha pter M a c ro l i d es

Cycloserine (Seromycin Pulvules) Azithromycin (Zithromax)

O ra l : 2 S 0 - m g c a p s u l e s
Fosfomycin (Monurol)
Ora l : 3-g pac ket
Vancomycin (generic, Vancocin, Vancoled)
Ora l : 1 2 S - , 2 S 0-mg P u l v u l es ; powd e r to recon­
st i t u te for 2 S 0 mg!S m L , SOO mg!6 mL so l u t i o n
P a r e n t e ra l : O . S - , 1 - , 5 - , l O -g powd e r to re c o n ­
st i t ute f o r I V i n j e c t i o n
Inhibitors o f Bacterial Protein Synthesis
C h l o ra m p h e n i c o l
Chloramphenicol (generic, Chloromycetin)
Ora l : 2 50-mg ca psu l es ; 1 50 mg!S m L suspe n s i o n
Paren tera l : 1 0 0 - m g powde r to rec o n st i t u te f o r
i n jection
Tetracyc l i nes
Demeclocycline (Declomycin)
O ra l : 1 5 0 - , 3 0 0 - m g t a b l ets; 1 5 0 - m g c a p s u l e s
O ra l : 2 50-mg capsules; powd e r for 1 00 ,
2 0 0 m g!5 m L ora l s u s p e n s i o n
Clarithromycin (Biaxin)
O ra l : 2 5 0 - , 5 0 0 - m g ta b l et s , 5 0 0 - m g exte n d e d ­
re l ease ta b l ets; g ra n u l e s f o r 1 2 5 , 2 5 0 m g/5 m L
ora l s u s p e n s i o n
Erythromycin (generic, lIotycin, lIosone, E-Mycin,
Erythrocin, others)
Ora l ( ba se ) : 2 S 0 - , 3 3 3 - , 5 0 0 - m g e n t e r i c -coated
ta b l ets
O ra l ( base) d e l ayed-re l e a s e : 3 3 3 - m g ta b l et s , 2 5 0 -
mg c a ps u l e s
O r a l ( esto l a te ) : 5 0 0 - m g ta b l ets; 2 50 - m g c a p s u l e s ;
1 2 5 , 2 5 0 mg!5 m L s u s p e n s i o n
O ra l ( e t h y l s u c c i n ate ) : 2 0 0 - , 400- m g f i l m -coated
ta b l ets; 2 0 0 , 4 0 0 m g! 5 mL s u s p e n s i o n
Ora l (stearate ) : 2 5 0 - , 500-mg f i l m -coated ta b l ets
Parentera l : lacto b i o n ate , 0 . 5- , l -g powd er to reco n ­
st i t u te f o r I V i n j e c t i o n
K e t o l ides

Telithromycin (Proteck)
Doxycycline (generic, Vibramycin, others)
O ra l : 8 0 0 - m g t a b l ets
Ora l : S O - , 1 0 0-mg t a b l ets a n d c a psu l e s ; powd e r
to rec o n st i t u te for 2 5 m g/S m L s u s p e n s i o n ;
l i n c omyc i n s
50 mg!S m L syru p
Clindamycin (generic, Cleocin)
Pare n t e ra l : 1 00 - , 2 0 0 - m g powd e r to rec o n st i ­
O ra l : 7 5 - , 1 5 0 - , 3 0 0 - m g c a p s u l e s ; 7 5 m g/5 m L
t u t e for i n j ec t i o n
gra n u l e s to re c o n s t i t ute for so l u t i o n

Methacycline (Rondomycin) P a r e n t e ra l : 1 50 m g!m L i n 2 - , 4 - , 6 - , 6 0 - m L v i a l s

O ra l : l S 0- , 3 0 0 - m g c a p s u l e s for i n ject i o n

Minocycline (Minocin) Stre ptogra m i n s

O ra l : 50-, 1 00-mg ta b l ets and capsu les; Quinupristin and dalfopristin (Synercid)
5 0 mg!5 m L s u s pe n s i o n Pare n t e ra l : 3 0 : 7 0 form u l a t i o n i n 500 mg v i a l for
reco n st i t u t i o n for I V i n j e c t i o n
Tetracycline (generic, Achromycin V, others)
O ra l : 1 00 - , 2 50-, 500-mg capsu les; 2 S 0-, Oxazo l i d i n o n e s

S O O - m g ta b l ets; 1 2 5 mg!5 m L s u s p e n s i o n Linezolid (Zyvox)

P a r e n tera l : 1 00 - , 2 50 - m g powd e r to reco n s t i ­ O ra l : 4 0 0 - , 6 0 0 - m g ta b l et s ; 1 00 - m g powd e r for
tute for 1 M i n je c t i o n ; 2 5 0- , 5 0 0 - m g powder to so l u t i o n
re c o n s t i t ute for I V i n j ec t i o n P a r e n t e ra l : 2 mg!m L for I V i n f u s i o n
396 C H EM OT H E RA P E U T I CS

A m i noglyc o s i d e s a nd S p e cti n o m y c i n Sulfisoxazole (generic, Gantrisin)

Ora l : 5 0 0 - m g ta b l et s ; 500 m gl 5 m L syr u p
Amikacin (generic, Amikin) O p h t h a l m i c : 4 % so l u t i o n
Pa r e n te ra l : 5 0 , 2 5 0 mg ( i n v i a l s ) for 1 M , I V
S u lfon a m i d e s for S p e c i a l A p p l i cat i o n s
i n j ec t i o n
Mafenide (Sulfamylon)
Gentamicin (generic, Garamycin)
To p i c a l : 85 m glg c re a m ; 5% so l u t i o n
P a r e n t e r a l : 1 0 , 40 m g/ m L v i a l s for 1 M , I V
i njection
Silver sulfadiazine (generic, Silvadene)
To p i c a l : 1 0 - m glg c r e a m
Kanamycin (Kantrex)
Sulfacetamide sodium (generic)
O ra l : 5 0 0 - m g c a p s u l e s
O p h t h a l m i c : 1 , 1 0 , 1 5 , 3 0 % so l u t i o n s ; 1 0 %
P a re n tera l : 5 0 0 , 1 0 0 0 mg for 1 M , I V i n j e c t i o n ;
o i ntment
7 5 m g for p e d i atr i c i n j ec t i o n
Tri m et h o p r i m
Neomycin (generic, Mycifradin)
O ra l : 5 0 0 - m g ta b l et s ; 1 2 5 m gl 5 m L so l u t i o n Trimethoprim (generic, Proloprim, Trimpex)
O ra l : 1 0 0 - , 2 0 0 - m g ta b l ets
Netilmicin (Netromycin)
P a r e n t e ra l : 1 0 0 m gl m L for 1 M , I V i n j e c t i o n Trimethoprim-sulfamethoxazole co-trimoxazole,

Paromomycin (Humatin) TMP-SMI (generic, Bactrim, Septra, others)

O ra l : 80 mg t r i m e t h o p r i m + 400 mg su l f a m et h oxa­
O ra l : 2 5 0 - m g c a ps u l e s
zo l e per s i ngl e-stre n gth ta b l et ; 1 6 0 mg tri metho pri m
Spectinomycin (Trohicin)
+ 8 0 0 mg s u l f a m e t h oxazo l e p e r d o u b l e-stre ngt h
P a r e n t e ra l : 2 g powd e r to rec o n s t i t ute f o r 1 M
ta b l e t ; 4 0 m g tri m e t h o p r i m + 2 0 0 m g s u l fa m e t h ox­
i njection
azo l e per 5 m L s u s p e n s i o n
Streptomycin (generic) P a r e n t e ra l : 80 m g t r i m et h o p r i m + 400 mg
P a re n t e ra l : 4 0 0 m gl m L fo r 1 M i n j e c t i o n s u l fa m e t h oxazo l e p e r 5 m L f o r i n f u s i o n ( i n 5 m L
a m p u l e s a n d 5 � , 1 0- , 2 0 - , 3 0 - , 5 0 - m L v i a l s )
Tohramycin (generic, Nehcin)
P a re nte r a l : 1 0 , 4 0 m glm L for 1 M , I V i n j e ct i o n ; Qu i n o l o n es a n d F l u o ro q u i n o l o n e s
powd e r t o reco n st i t u t e for i n j e c t i o n
Cinoxacin (generic, Cinohac)
O ra l : 2 5 0 - , 5 0 0 - m g c a p s u l e s

I n h i b ito rs o f B a cte r i a l D N A Synth e s i s Ciprofloxacin (Cipro, Cipro I . v. )

O ra l : 2 5 0 - , 5 0 0 - , 7 5 0 - m g ta b l ets; 5 0 , 1 00 m glm L
S u lfona m i d e s , Tr i m ethopri m , a n d F l u o roq u i n o l o n e s
suspension
G e n e ra l - P u r p o s e S u lfon a m i d es P a re n tera l : 2 , 1 0 m glm L f o r I V i n f u s i o n

Sulfadiazine (generic) O p h t h a l m i c ( C i l oxa n ) : 3 m g/m L so l u t i o n ; 3 . 3 mg/g

O ra l : 5 0 0 - m g ta b l ets oi ntment

Sulfamethizole (Thiosulfil Forte) Enoxacin (Penetrex)

O r a l : 5 0 0 - m g ta b l ets Ora l : 2 0 0 - , 4 0 0 - m g t a b l ets
Sulfamethoxazole (generic, Gantanol, others) Le vofloxacin (Le vaquin)
Ora l : 5 0 0 - m g ta b l ets ; 5 0 0 m g/5 m L s u s p e n s i o n O ra l : 2 5 0 , 5 0 0 , 7 5 0 mg for i n j e ct i o n
Sulfanilamide (A VC) P a re ntera l : 2 5 0 , 5 0 0 m g f o r I V i n j ec t i o n
Va g i n a l cre a m : 1 5 % O p h t h a l m i c ( Q u i x i n ) : 5 mg/m L so l u t i o n
 A n t i b a c t e r i a l Age n ts 3 9 7

Lomefloxacin (Maxaquin) Ethambutol (Myambuto/) .

Ora l : 4 0 0 - m g ta b l ets O ra l : 1 0 0 - , 4 0 0 - m g ta b l ets

Moxifloxacin (A velox, A velox I. v.)

Ethionamide (Trecator-SC)
Ora l : 4 0 0 - m g ta b l ets
O ra l : 2 5 0 - m g ta b l ets
Pare ntera l : 400 mg in IV bag

Nalidixic acid (NegGram) Isoniazid (generic)

Ora l : 250-, 500-, 1 000-mg caplets; 2 5 0 mg/5 m L Ora l : 50-, 1 00-, 300-mg tablets; syru p , 50 mg/5 m L
suspension Pare n t e ra l : 1 0 0 m g/ m L for i n j e c t i o n

Norfloxa cin (Noroxin)

Pyrazinamide (generic)
O ra l : 4 0 0 - m g t a b l e ts
O ra l : 5 0 0 - m g t a b l ets
Ofloxacin (F/oxin)
Rifabutin (Mycobutin)
O ra l : 2 0 0 - , 3 0 0 - , 4 0 0 - m g t a b l ets
O r a l : 1 5 0 - m g c a ps u l e s
P a r e n t e ra l : 2 0 0 m g in 5 0 mL 5 % D/W for I V
ad m i n i strat i o n ; 2 0 , 4 0 m g/ m L for I V i n j e ct i o n Rifampin (generic, Rifadin, Rimactane)

O p h t h a l m i c ( Oc u f l ox ) : 3 m g/m L so l u t i o n O ra l : 1 5 0 - , 3 0 0 - m g c a p s u l e s
P a re n te ra l : 6 0 0 - m g powder for I V i n j e c t i o n

Rifapentine (Priftin)
Anti mycobacte r i a l D rugs
Ora l : 1 5 0-mg t a b l ets

Drugs U s e d i n Tu berc u l o s i s Streptomycin (generic)

Aminosalicylate sodium (Paser) P a r e n te ra l : 1 g l y o p h i l i zed for 1 M i n j ect i o n

O ra l : 4 g d e l ayed-re l e ase gra n u l e s Drugs U s e d i n leprosy

Capreomycin (Capastat Sulfate) Clofazimine (Lamprene)

Parentera l : l -g powd er to reco nstitute for i n ject i o n O ra l : 5 0 - m g c a p s u l e s

Cycloserine (Seromycin Pulvules) Dapsone (generic)

O ra l : 2 5 0-mg c a ps u l e s O ra l : 2 5 - , 1 O O - m g ta b l ets

REFERENCES Davidson R, et al: Res i s t a n c e ro levo floxacin an d fa i l ur e o f

rrea t m e m o f p n e u mococcal pneu m o n ia . N Eng!] Med
Bain KT, Wittbrodt ET: Linezolid for the treatmem of res ist­ 2002;34 6:747.
a n r gram-pos i t ive cocc i . Ann Pharmacother 20 0 1 ; Diagnos is a n d t rea tme n r o f d i sease caused b y n o n r u b e rcu­
35: 566. lous myco b acteri a . A m ] Resp ir Crit Care Med
B londeau JM: E x p a n d e d a c t iv i ty a n d u t i l i ty o f t h e n ew 1 99 7; 1 5 6 { 2 Pan 2) :S I .
fl u o to q u i n o l o n e s : A revi ew. C!in Ther 1 9 9 9 ; F u l ro n B, Pe r r y CM: C e fo p o d ox i m e p roxe t i l : A
21 :3. rev i e w of i t s u s e i n t h e m a n a ge m e n t o f b a c te r i a l
Cemers fo r D isease Con trol a n d Preve m i o n : Va nco m yci n i n fe c t i o n s i n ped i a t r i c patienrs. Paediatr Drugs 2 0 0 1 ;
res i s t a m Staphylococcus aureus- Pen n s y l v a n i a , 2 0 0 2 . 3: 1 37.
]AMA 200 2 ; 2 8 8 : 2 1 1 6 . G e e T, e t a l : Pha rmacoki netics a n d tissue penetration of I i n e­
Cemers fo r D i sease C o n r rol and Preve n t i o n . Prevemion a n d zo l i d foJ l ow i ng m u l t i p l e o ral doses. A n tim icrob Agents
t re a t m e m o f ruberculosis i n p a t i e n rs i n fected w i r h Chemother 200 1 ;4 5 : 1 8 4 3 .
h u m a n i m m u nod e FIcie ncy v i rus: Prin c i p l es o f therapy Havl i r DV, Barnes P F : Tu bercu losis i n patie n ts w i th h u m a n
and rev ised reco m m e n d ations. MMWR Morb Mortal i m m u nod e fi c i e n cy v i rus i n fectio n . N Eng!] Med 1 9 9 9 ;
Wkly Rep 1 9 9 8 ; 4 7 { RR-20) : I . 3 4 0 : 367.
ANTIVIRAL AGENTS

VIRUSES

Viru ses are obligate intracellular paras i tes. That is, unlike bacteria, v i ruses d epend on living host
cells to rep l icate and function. S ince viruses rely on the synthetic machinery of host ce l ls , viruses
can be ex tre mel y small. In many cases, the entire viral particle, or virion, consists o n ly of nucleic
acids (deoxyribonucleic acid [DNA] or ribonucleic acid [RNA]) surrounded by a protein shell,
or capsid. Some viruses have an addicional glycoprotein coat called an envelope.
Viral infections range from common minor illnesses, such as t h e common cold and cold
sores, to life-threatening diseases, such as AIDS, Ebola, and severe acute respiratory syndrome
(SARS). In addition, some viruses can cause certain types of cancer. For example, hu m an p a pil­
lomavirus is the prim ary causative agent of cervical cancer.
Viral transmission can occur in many ways. The most co m m on ways that virions enter
the body are via i n h a led droplecs (e. g. , rhinovirus, che causative agent of che common cold),
contaminated food or water ( e . g. , hepatitis A), direct contact from infected hosts (e. g.,
HIV), or direct inoculacion by bites of infected vectors (e.g. , de n gue fever, transmit ted by
mosquitoes).

ANTIVIRAL AGENTS

Viruses are complicated chemotherapy targets for several reasons. Since viruses re l y on host
cells' machinery to funccion, the selective pharmacologic destru ction of a virus without destroy­
ing human cells is difficult. E arly treatment is critical, b u t frequently not possible because viral
replication o ften peaks before clinical symptoms develop. Many antiviral agents also rely on a
nor m a l immune system to destroy the virus. Thus, immune suppression often lengchens viral
illnesses. F i n al ly, mutations that cause changes in viral structLUe and enzymes o ften lead to the
emergence of dru g - r es is ta n t viral strains. Some viruses (influenza A and
B, hepatitis B virus
[HBV]) can be effecci vely controlled by vaccines (see section Vaccines and I m m u ne G l ob ulin s :
Active and Passive Immunizations below).
Antiviral drugs can pocentially exerc their actions at several stages of viral replication, includ­
ing (1) viral attach m ent and entry into the host cell; (2) uncoacing of viral nucleic acid; (3) syn­
thesis of early viral regulatory pro teins; (4) synthesis of RNA or DNA nucleic acids; (5) la te
procein sy nthesis and processing; (6) viral packaging and assembly, and (7) virion release
(Figure 28-1).

399
400 CHEMOTHERAPEUTICS

Blocked by Blocked by
enfuvirtide (HIV);
amantadine,
docosanol (HSV), rimantadine
(influenza)

p .? etration �

Blocked by
interferon-alfa
(HBV, HCV) Early protein
synthesis

�
Mammalian
cell Blocked by NATls
(HIV), NNATls (HIV),
Nucleic acid
�--t-I-I acyclovir(HSV),
synthesis
foscarnet (CMV),
entecavir (HBV)
Blocked by
neuraminidase
inhibitors
�
/\--"'? Late protein
(influenza) L..-I synthesis and
processing Blocked by
Viral protease inhibitors
(H I V)

. �:�::
' . .. . .
(.�:�: :
Figure 28-1. The major sites of drug action on viral replication. Diseases in parentheses, see text.

One of the most importanr trends in viral
chemotherapy, especially in the managemenr of HIV
infection, has been the inrroduction of combination
drug therapy, in which more than one stage of viral
replication is inhibited. The benefits of combination
anriviral therapy include greater clinical effectiveness
and the prevenrion or delay of drug resistance.
The anriviral agents covered in this chapter
include drugs against herpes, HIV, influenza, HBV,
and hepatitis C (HCY) (Figure 28-2) .
ANTI HERPES DRUGS
Second to Au (inAuenza) and common cold viruses,
herpes viruses are among the leading causes of human
viral disease. The term herpes is derived from the
Greek word herpein, which means to creep. This refers
to (he creeping or spreading qualiry of skin lesions
caused by many herpes viruses. Although eight types
of human herpes viruses have been idenrified, the
most common herpes viruses are herpes simplex virus
rype 1 (HSV-l) , herpes simplex virus rype 2 (HSV-2) ,
varicella-zoster virus (VZY), Epstein-Barr virus (EBV),
and cytOmegalovirus (CMV) .
Once infected by any herpes virus, the infection
remains for the life of the individual. Herpes infections
are well-known for remaining silenr-or latenr-for
months or even years. Then, in response to some trig­
ger (e.g., sun exposure, concurrenr viral illness,
immunosuppression), the virus is reactivared and the
patienr once again becomes sympromatic.
Most adult Americans harbor HSV-l, the HSV
strain primarily responsible for orofacial (e.g., cold
sores) and ocwar infections. It is estimated that one in
five Americans over the age of J 2 years carries HSV-2,
which generally causes genital infections. Notably,
HSV- J and HSV-2 can cause ourbreal(s at either body
site by direct conract wirh infectious secretions or

Antiviral agents
I
Drugs for Drugs for HIV
herpes
Acyclovir Fusion Protease
Ganciclovir inhibitor inhibitors
Foscarnet
Reverse transcriptase
inhibitors
Nucleosides Non-nucleosides
Figure 28-2. Drugs classes used in the treatment of viral infections and diseases
mucous membranes. During the primary infection,
HSV spreads from infected epithelial and mucosal cells
to nearby sensory nerve endings and is transported
along the axon to the cell body. The virus enters the
nucleus of a neuron, where it persists indefinitely in a
latent state. Recurrent HSV infection occurs as a resulr
of reactivation of the virus in the sensory ganglion. The
virus migrates down the nerve axon and produces vesic­
ular lesions, as well as intermirrent asymptomatic viral
shedding. Lesions usually heal within 2 weeks. Relaps­
i n g episodes are often physically and psychologically
distressing. Pregnant women who are shedding the
virus may transmit it during delivery, with severe and
potentially fatal consequences to the neonate.
In its primary infection, VZV causes chickenpox
(herpes varicella) in children and is rapidly spread
via airborne droplets and contact with lesions.
Herpes zoster, also known as shingles, is a reactivation
of a previolls infection with VZV. Roughly 2 to 3 days
before vesicular skin lesions appear, the patient often
experiences pain along affected dermatomes. The area
generally remains painful until lesions heal in 2 to 3
weeks. Herpes zoster cannot be contracted from some­
one who has herpes zoster because the infection always
comes from latem VZV infection in the patient's own
spinal cord ganglia. However, the primary infection--
Antiviral Agents 401
Drugs for Drugs for
influenza HBV and HeV
Amantadine IFN-a.
Zanamivir Lamivudine
Ribavirin
chickenpox can be transmiued from a person with her­
pes zoster to someone who has not already had chick­
enpox (or the chickenpox vaccine). Vaccines are
currently available for both chickenpox and shingles
(see section Vaccines and Immune Globulins: Active
and Passive Immunizations).
Cytomegalovirus (CMV ) may be acquired con­
genitally, perinatally, or postnatally. It is the most com­
mon congenital (presem at birth) infection in the
United States, and its incidence increases with age.
Indeed, CMV is estimated to infect the majority of
adulrs by 40 years of age. While multiple organs can be
affected , CMV is usually asymptomatic in healthy
adults. However, in immunocompromised individu­
als, especially those with AIDS, CMV infections cause
various illnesses. In individuals with AIDS, the most
common manifestation is an eye infection called CMV
retinitis.
Most drugs active against herpes viruses inhibit
viral DNA polymerases, enzymes that assist in viral
replication. Often, antiviral drugs are bioactivated by
virus-specific or host enzymes to active drug forms. It
is important to note that anti-herpes agents act against
the replicating virus by incorporating into the viral
DNA, and therefore are ineffective against latent (non­
replicating) virus. Three oral anti herpes drugs are
402 CHEMOTHERAPEUTICS

licensed for th e rreatment of HSV an d VZV i nfec­
tions: acyclovir, valacyclovir, and famciclovir. They
share similar mechani s ms of action and indicat ions for
c l inica l use, and a ll are fa i rl y well [Olerated .
Acyclovir
Mechanism ofAction and Pharmacokinetics
Acyclovir (acycloguanosine) is d eri ved from the nucle­
oside gua nos ine . Acyclovir is a cri v a r ed firsr by virus­
spe cifi c and rhen by h os r enz y m es [0 form acyc l ovi r
triphosphate, which comperes with d eoxyguanosine
t riphospha re for rhe viral DNA p olymerase . The d rug
rhe n becomes incorporated into rhe viral DNA, bur
because acycloguanos ine lacks rhe necessary posirion
for nuc l eoride attachment, rhe DNA chain rerminates.
Resisrance of H SV has been rep o n ed , mainly among
immunocompromised pa ri enrs . Resistance is ofren
associated wirh m utarion s in rhe vi ra l enzyme rhymi­
d i n e kinase, which is involved in the initial bioactivarion
of acyclovir. Srrains resistanr [0 acyc l ovi r are cross ­
resisranr w similar drugs such as gan cic l ovir, va l acy ­
c1ovir, and fa m c ic l ovi r. Resistant infections are ofren
managed by foscarnet, cidofovir, or trifluridine, whic h
use a d i ffe re nt mechanism of antiviral action, bur these
d rugs are significanrly more [Oxic than acyclovir.
Acyclovir is availab l e in ora l , wpical, and intra­
venous forms. Because of its short half-life, oral acy­
clovir must be r a k en several times per d ay. Pa rients
with renal imp airm en t req u ire reduced dosages
because rhe ki d n eys are pri mari ly resp ons i bl e for elim­
in a ring acycl ovir.
ClinicaL Uses and Toxicity
Oral acyclovir has mul t ip l e uses. Ir i s mosr co mmonly
u sed for the rre ar m ent of mucocutaneous and ge ni tal
herpes lesions (Table 28- 1 ) a n d pro p h ylax is in
immunocompromised pa t ie nts. O ral r h e r a py is the
most effective route of administrarion for rrea ti ng pri­
mary HSV infecrion and recurre n t gen i ral he rpes . In
inirial ep i so d es of genital h erpes , oral acyclovir short­
ens rhe durarion of sy mp [O m s , rhe time for l esions [0
heal, and rhe dura rion of viral s hedd ing . In recurrent
geni t al he rpes , rhe time course is also sh o rrened . D ail y
oral suppre s sive rherapy decreases the frequency of
sym p[Om atic genital herpes outbreaks and asympto­
ma ti c vi r a l she d ding . T his latter point is es p ecia l l y
imp ortan t in decreas ing the risk of rransmission [0 sex­
u al partners . Intravenous l
acyc ov ri is rhe t rear men t of
choice for serious HSV infections such as h erp es sim­
plex encephal iris and n eo naral HSV infections, serious
VSV infecrions, and VSV infections in immunocom­
promise d pati en ts .
Oral adminisrration of acycl ov i r is generally well
[Olerated, wirh headache and gas troin res ri nal d isrress
occasionally re po n ed . Toxic effects wirh in tr av en ous
administration include delirium, rremor, seizures,
hyporension, and n ephro[ Oxiciry.

Table 28-1. Clin ical uses of antiviral drugs

Virus Drug(s) of Choice Alternative or Adjunctive Drugs

CMV Ganc i c l over Cidofov i r, fosc a r n e t , fom i v i rsen
HSV, VZV Acyclov i r or s i mi l a rl Cidofov i r, fosca rnet, v i da rab i n e
HBV IFN-a or l a m i v u d i ne Adefov i r
HCV I FN-a R i bavir i n
I nf l u e n za A A m a n tadine or R i m a n t i di n e
ose l t a m iv i r
I n f l u e nza B Ose l ta m i v i r Za n a m i v i r

CMV = cytomegalovirus; HSV = herpes simplex virus; VZV = varicella-zoster vi ru s;

HBV = hepatitis B v irus; HCV = h e pa t i t i s C virus; IFN-a = interferon -a.

IAnti-HSV d rugs similar to acyclovir include famciclovir, penciclovir, and valacyclovir.

Acyclovir Congeners
Several anriherpes d ru g s, such as valacydovir, famci­
dovir, and pencidovir, are congeners-drugs t h a t
share s im ilar chemical s tr uct u res and characteristics­
of acyclovir. Consequenrly, acyclovir congeners sh a re
many of acyclovir's clinical uses. After oral adminis­
cration, valacyclovir is convened co acyclovir by the
liver. Greatec plasma levels can be achieved with vala­
c y c lov ir than with acyclovir; thus, the duration of
aerion is long e r. A lth oug h va la cydovir is as effe ctiv e
as acyclovir in the cutaneous healing rate for h e r pe s
zoster (shingles), valacyclovir has b een shown co be
a s s oci ated wirh a shorrer duration of zoster­
associated pain. Oral famciclovir is co n ver ted co pen­
cidovir by the liver. It is we ll colerated, and it is
s i m ila r co a cyclov i r in its pharmacokinetic proper­
ties and c l inical uses. Penciclovir is the active
metabolite of famc i d ov i r. Topical pencidovir is an
effeerive treatment for recurrenr genital herpes infec­
tion of the labia.
Ganciclovir
Mahanism ofAction and Pharmacokinetics
Gancicl ovir inhibits viral DNA poly m e rases of
cytomegalovirus (CMV) and HSV The first step in
bioactivation of ga n ciclovi r is a phosphorylation step
ca t a lyze d by virus-specific enzymes in both HSV­
infected and CMV-infected cells. Ganciclovir is usually
given intravenousl y and penetrates well inro tissues,
including the cen t ra l nervous system (CNS) and the
eye. It is also available as an inrraocular i m pla n t. Val­
gancicl ovir, a prod r ug of ganciclovir, has greater oral
bioavailability than ga ncic lovir. Thus, valganciclovir
has l arge ly replaced oral ganciclovir because patients
are required co take fewer piUs per day.
Clinical Uses and Toxicity
Ganciclovir's activity a ga inst CMV is abol\[ 100 times
greater than that of acyclovir. It is often used in
immunocompromised patients for the treatment and
prophylaxis of CMV infections, espec i all y CMV
retinitis, a vision-threatening infection of the eye. The
m ost common system i c toxic effect of gan ciclov ir (and
valganciclovir) is myelosuppression, a decrease in the
Antiviral Agents 403
ability of bone marrow to produce blood cells. R are
side effects include n e u rotox ici ty (confusion, seizures)
and nephrotoxicity.
Cidofovir
Mechanism ofAction and Pharmacokinetics
Cidofovir is b i oactiv at ed exclusi vely by h os t cell
enzymes. It i nh ibi ts the DNA polymeras es of HSV,
CMV, aden ovir us, and human papillomavirus. Cido­
fovir is act i ve against many acyclov ir and ganciclovir­
resistant strains because its bioactivation does n ot
require viral kinases. To d ate , clinical re si st an ce to cid­
ofovir is rare. Cidofovir is ge n er al ly administered top­
ically or intravenously. It h a s a long intracellular
half-I ife of 17 to 65 h o u r s, permitting l ong intervals
between doses.
Clinical Uses and Toxicity
Intravenous cidofovir is used to treat CMV retinitis
and mucocutaneous HSV in fect ion s, including strains
resistant co acyclovir. It is also effective in treati ng gen­
ital warts. Cidofovir is dose-dependently nephrotoxic.
Patients rece i vin g cidofovir will also receive a dr ug that
blocks aerive tubular secretion (probenecid) to decrease
its nephrotoxicity. Concurrent administration of other
potentially nephrotoxic drugs (e .g. , nonsteroidal anti­
inflammatory drugs [NSAIDsj) should be avoided.
Foscarnet
Mechanism ofAction and Pharmacokinetics
Foscarnet inhibits viral DNA polymerase, RNA poly­
merase, and HIV reve rse transcriptase . It is only
administered intravenously, and it p e n e t rates well inro
tissues, including the CNS.
Clinical Uses and Toxicity
Foscarnet is an alternative
drug for the prophylaxis and
t re a tm e nt of CMV infections , and it has acti vity
against ganciclovir- and cidofovir-resistant su'ains. It
is also effective aga inst acyclovir-resistant HSV and
VZV herpes strains, and may suppress resistant infec­
tions in AIDS pati e nts. Toxic effects can be severe.
These include nephrotoxicity, electrolyte imbalances
(especially hypocalcemia), gen it o uri n ary ulcerations,
and CNS effects (h eada c h e, hallucinations, seizures),
404 CHEMOTHERAPEUTICS
Idoxuridine, Trifluridine, and Vidarabine
ldoxu r i d i ne, trifluridine, and vidarabine a re frequently
used to pically in the treatmenr of herpes keratitis, an
ey e i nfectio n tha t can be recu rrent and may l e a d co
bli n dness. ldoxu ridine a n d triflurid ine are too cox. i c for
systemi c use. Despite marked cox i c pote n tia l, vid a ra­
b ine has been used i ntravenously for severe HSV i nfec­
tio ns, especiall y those resis ranr co acyclov i r. Toxic
syste mic effects i n clude gas t roin rest i n a l irrita tion,
hepat i c dysfunction, a n d CNS cox i ciry (paresthesias,
rremor, co nvulsions) .
ANTI-HIV DRUGS
Human i m munodeficiency virus (HIV) strikes the
immune system, specifically ta rge ting CD4 T l ym­
phocy tes. Depletion of CD4 ce lls ultimately leads
co profoun d immunosuppression. Acquired im mune
d eficie ncy sy nd rome (AIDS) is sympcom a tic disease,
characterized by the devel opment of a wide spectrum
of opportu nistic infections a n d malignancies e ither
acqui red o r react i vated as a resu lt of the i mmunosup­
p ression caused by HIV Worldwi de. HIV/AIDS is a
glo bal health prob lem, affecting over 40 m i l l ion peo­
ple, with over 70% of infected i n div i duals living in
su b-Saharan Africa. I n the Un ited States, it is esti m ated
that 1 million peop le a re cur re n t l y l iv i ng with
HIV/AIDS. While primary routes of i nfection in
d evel oped co u nr ries include m ale homosexual i nrer­
course and intravenous drug use, pr imary routes of
infecti o n in developing countries i nclude hete rosexuaJ
contact a n d ve rtical tra nsm ission from mother co
ch ild.
To understand tfle drugs used in tfle treatme n t of
HIV, the life cycle of HIV must be bri efly exam i ned
(F igure 28-3). HIV is a retrovirus, meaning tha t i t is
an enveloped virus w i t h a single-strand ed RNA, nor
DNA, genome. Before HIV can enter CD4 cells, viral
glyco p rotei ns i n t h e e n velope bind to CD4 and
chemokine recepco rs. Nex t, the virus fuses wi th the
host cell m em b rane and un coats as i t enters the host
cel l . After uncoari ng, viral repfica rion d epends on the
viral reverse transcriptase enzyme, which transcribes
the v i r a l geno me from RNA i nto DNA. T h is n ewly
formed dou ble-srra n ded DNA is i ntegrated i nro the
human h ost's genome by an integrase enzyme. I nte­
grated viral DNA is then transcr i bed by a host poly­
merase e nzyme inco messenger RNA, wh i ch is
translated i nro proteins that assemb le into i mmature
noninfectious vi rions tha t bud from the host cell mem­
b rane. Proteolytic cleavage a llows maturation i nto fully
infectious virio ns.
As we m a rk the completi o n of the first 25 yea rs of
the HIV/AIDS epidemic, there is no cure for HIV
i nfection or AIDS. However, ph armacologic t herapy
can d ra m ar i caJly i m p rove the length and qualiry of life
for i nfec ted ind iv i dua ls, a n d can delay the onset of
AIDS. Without phar m a cologic trea tment, most
patien ts d ie w i thin a few yea rs after rhe onset of sym p­
coms. Currently, the standard of care in trearing HTV
infection i nvo lves init i ating highly active anriretrovi­
ral therapy (HAART) t h at requires three co fou r anri­
rerroviral drugs. If possible, HAART is i nitiated before
sympcoms a p pear. The goaJ of co m b inat ion regi mens
is co inh i bit or scop v iral replication at a number of
d iffere n t ste ps (Figure 28-3). Com p a red wirh the
adm inistration of a single antiretrovi ral agent, com b i ­
natio n therapy i n c reases t h e efficacy o f d rug rhera py.
dec reases the risk of deve loping d rug resistance, and
reduces v i ral load. Six classes of anriretroviral agenrs
a re currenrly ava ilable: nucleoside reverse t ranscriptase
i n h i b icors (N RTls), non nucl eoside reverse transcrip­
tase inhibitors (NNRTTs), p rorease i nhi bitors (PIs). a
fusion i n hib icor, an integrase i nhibicor, a n d an entry
recepcor blocker (Table 28-2).
D rug combina tio ns are tailored to each patient
depending o n many variables, includ i ng potency and
susce ptibi l iry, patienr colerance, convenience, and
ad herence to drug reg i m en. With rhe exce p t ion of the
fusion inhib i to r, the anri-HIV agenrs are all ava i lable
as oral formulations. Drug management of HIVIAI OS
is subject to cha nge as newer agents become ava i l a b le.
New pharmacorherapies are being sought that offer rhe
advantages of once-dai l y dosing, smaller p ill size, lower
i n c i de n ce of adverse e f fects, new viral rargets, and
activiry aga insr vi rus rha t is resisra nt co other agen ts.
Nucleoside Reverse Transcriptase Inhibitors
The NRTls were rhe firsr group of d rugs used to trear
HIV infection . NRTTs se lective l y inhibi r rhe HIV viral
 Antiviral Agents 405

gp41
gp120

Host cell membrane

Chemokine receptors

Blocked by
uncoating
fusion inhibit ors

Blocked by
NRTls, NNRTls
�j
••••••••••
Reverse
transcription

�DNA
l
Integration

............. Blocked by integrase inhibitors

\.t
O
TranscriPtion Translation
.
J •

A
RN I
+
Virion
assembly

o
Budding and
maturation

Figure 28-3. Life cycle of H IV and the major target sites of antiretroviral agents.

reverse transcriptase (Figure 28-3). The reverse tran­ HIV, resistance emerges rapidly. However, resistance is
s c ri p tas e incorporates the phosphorylated NRTI rare incombination regimens. The NRTls include
(instead of a natural nucleotide) il1[o the g row i ng zidovudine, didanosine, zaJcitabine, lamivudine,
DNA chain, thus prevenring complete conversion of stavudine, and abacavir. Derails abolJ[ each of these
viral RNA il1[o DNA. If used as single agents to [real' drugs follow.
406 CHEMOTHERAPEUTICS
Antiretroviral drugs
Subclass Prototype
Nucleoside reverse Zidovudine
transcriptase inhibitors
Nonnucleoside reverse Delavirdine
transcriptase inhibitors
Protease inhibitors Indinavir
Fusion inhibitor Enfuvirtide
Integrase inhibitor Raltegravir
Entry receptor blocker Maraviroc
ITenofovir is a nucleotide reverse transcriptase inhibitor.
Severe toXIC effects are associated with most
NRTls, with the exception of lamivudine (3TC). All
of the NRTls have the potential to cause a rare, but
serious, lactic acidosis and severe hepatic steatosis,
likely due to mitochondrial damage in liver cells. Risk
factors include obesiry, prolonged treatment with
NRTls, and preexisting liver dysfunction. Symptoms
include severe nausea, vomiting, and persistent
abdominal pain. NRTI administration will often be
suspended in these cases.
Zidovudine (ZDV), formerly called azidothymi­
dine, or AZT, was the first antiretroviral drug approved
for HIV treatment. Zidovudine is still frequently used
in combination drug regimens. Ie is also used in pro­
phylaxis against HIV infection through accidental nee­
dle sticks and via vertical transmission from mother to
fetus. Zidovudine is active orally and is distributed to
most tissues, including the CNS. The primary adverse
effect is myelosuppression, which may be severe
enough to require transfusions. Gastrointestinal dis­
tress, headaches, myalgia, agitation, and insomnia may
also occur, but tend to decrease or resolve during
therapy.
Didanosine (ddI) should be taken on an empry
stomach to maximize bioavaiLi.biliry. The major clini­
cal toxiciry of didanosine (and to a lesser extent zal­
citabine and stavudine) is dose-dependent pancreatitis.
This occurs more frequently in alcoholic patients and
Other Significant Agents
Abacavir, didanosine, lamivudine,
stavudine, za lcitab i n e , tenofovir1
Efavirenz, nevirapine
Amprenavir, lopinavir, nelfinavir,
ritonavir, saquinavir
those with hypertriglyceridemia. Other adverse effects
include painful petipheral distal neutopathy, diarrhea,
and CNS toxicity (headache, irritability, insomnia).
Patients on didanosine also must have frequent retinal
examinations because of reports of retinal changes and
optic neuritis.
Zalcitabine (ddC) has relatively high oral
bioavailabiliry, bur plasma levels decrease significantly
when the drug is taken with food or antacids. The
major adverse effect is peripheral neuropathy, which
can be treatment limiting in 10 to 20% of patients.
The neuropathy appears to be slowly reversible if treat­
ment is discontinued promprly. Other major toxicities
include oral and esophageal ulcerations and pancreati­
tis. Headache, arthralgias, myalgias, nausea, and rash
may occur, but tend to resolve during therapy.
Unlike didanosine and zalcitabine, the bioavail­
ability of lamivudine (3TC) is high and not food­
dependent. It is commonly used as a component in
HAART, as well as in the treatment of hepatitis B
infections (see discussion below). Lamivudine is one
of the best-tolerated NRTls. Potential adverse effects
are generally mild and include headache, fatigue, and
gastrointestinal discomfort.
Sravudine (d4T) also has good oral bioavailabiliry
that is not food dependent. The major adverse effect of
stavudine is dose-related peripheral sensory neuropa­
thy. The incidence of these symptoms increases with

coadministration of other neuropathy-inducing
NRTls such as didanosine and zalcitabine. Symptoms
usually resolve completely if stavudine is discontinued.
Other potential adverse effects include pancreatitis and
arrhralgias. As discussed above, all NRTIs have the
potential ro cause lactic acidosis with hepatic stearo­
sis. However, these toxicities tend ro occur more fre­
quendy in patients receiving stavudine than in those
receiving other NRTIs.
Abacavir has good oral bioavailability that is unaf­
fected by food. In a smaJi percentage of patients taking
abacavir, potentially fatal hypersensitivity reactions can
occur. Symproms usually occur in the first 6 weeks of
therapy and include fever, malaise, vomiting, diarrhea,
and anorexia.
Ten ofovir (a nucleotide) inhibits the HIV reverse
transcriptase and becomes incorporated into the
DNA, causing chain termination. Its bioavailability
increases after ingestion of a high-fat meal, so patients
are advised ro ingest tenofovir with a meal. G asttoin­
testinal irritation is the most common adverse effect,
but this rarely requires discontinuation of therapy.
Nonnudeoside Reverse Transcriptase Inhibitors
The NNRTIs interrupt transcription of viral RNA
inro DNA by a different mechanism than the NRTls.
The NNRTls bind directly to the viral reverse tran­
scriptase (Figure 28-3), change the shape of the
enzyme, and inhibit DNA synthesis. Thus, unlike the
NRTls, which become incorporated into the viral
DNA, NNRTI agents inactivate the reverse tran­
scriptase to prevent DNA formation. Like the NRTIs,
resistance can occur rapidly if these drugs are used as
monotherapy. As a class, adverse effects associated
with NNRTI administration include varying levels of
gastrointestinal distress and skin rashes. NNRTI
agents are metabolized by the cy toch rome P450
(CYP450) system, which increases the likelihood
of drug-drug adverse interactions. Drugs in the
NNRTI class include nevi r apin e, delavirdi ne, and
efavirenz.
Oral bioavailability of nevirapine is good, and is
not affected by food intake. Nevirapine is typically
used as a component in HAART. It is also used pro­
phylactically as a single dose to HIV-infected mothers
Antiviral Agents 407
at the onset of labor and to the neonate. Nevirapine
can cause severe hypersensitivity reacrions such as
Stevens-Johnson syndrome and a life-threatening toxic
epidermal necrolysis.
Delavirdine's oral bioavailability is good, but it is
reduced by antacids. Delavirdine causes rash in
about 20% of patients, although the rash is not life­
threatening. Other adverse effects include headache,
nausea, fatigue, and diarrhea. Because it has been
shown to cause birrh defects in animals, women should
take precautions against pregnancy while taking
delavirdine.
Efavirenz is generally used in combination with
two NRTIs. The bioavailability of efavirem increases
after a high-fat meal. Adverse effects include CNS dys­
function (dizziness, drowsiness, headache, confusion,
agitation, delusions, nightmares), skin rash, and
increases in plasma cholesterol. Dosing at bedtime may
be helpful for decreasing perception of some of the
CNS effects. Pregnancy should also be avoided in
women taking efavirem because of fetal abnormalities
observed in animals.
Protease Inhibitors
Assembly of infectious HN virions depends on HIV-l
protease (Figure 28-3). Protease inhibitors (PIs) result
in production of immature, noninfectious virions. As
a class, the PIs in HAART drug combinations lead ro
the development of carbohydrate and lipid metabolic
dysregulation. This syndrome includes hyperglycemia,
insulin resistance, and hyperlipidemia. A lipodystro­
phy, or selective redistribution of fat, also occurs. Thus,
patients may acquire a cushingoid appearance: buffalo
hump, gynecomastia, abdominal obesity, and periph­
eral wasting. Incidence of the syndrome is about 30 to
50% of those patients on a HAART regimen contain­
ing PIs, with a median onset time of aboU( 1 year after
onset of treatment. Owing ro these side effects, AIDS
patients receiving PIs within a HAART regimen often
receive counseling about heart disease as a new com­
plication. Like the NNRTI agents, PIs are metabolized
by the CYP450 system, increasing the likelihood of
drug-drug adverse interactions. Six PIs are available for
HIV treatment, and these are used in combinations
with NRTIs and NNRTIs.
408 CHEMOTHERAPEUTICS
Indinavir m ust be raken on an empty stomach for
maximaJ absorption. To avoid renaJ damage (nephrolithi­
asis), patients should consume ar least 48 oz ofwarer daily.
Other adverse effecrs include nausea, diarrhea, and
th ro mb o cyto pen ia.
Bioavailability of ritonavir increases when given
with food. T he m os t common adverse effects are gas­
trointesrinal disturbances, pa resr hes ias (peripheral and
circumoral), alre r ed (bitter) rasre, and hy p e m ig lyc ­
eridemia. During rhe first weeks of t h erapy, nausea,
vomiring, and abdominal pain u sually occur and
parients should be warned to expecr rhese symptoms.
Saquinavir s h ou l d be raken wirh food to i m prove
its bioavailability and to decrease gastrointestinal dis­
tress. Orh e r adverse effecrs include rhinitis, headache,
a nd neur rope nia .
Nelfinavir has hig h e r ab sorpt ion when taken
with food. Irs primary advers e effecr is dose-l imiting
d ia r r h e a , a l t houg h this symptom ofren responds to
antidiarrheal medica ti o n s.
Amprenavir is rap idly absorbed from the gastroin­
tesrinaJ rract, and it can be taken wirh or without food;
however, high -fat meals may decrease absorption and
should be avoided. Com mo n side effects are gastroin­
restinaJ distress, perioraJ paresthesias, depression, and rash.
In a s maJ l percentage of cases, am prena vir has caused Iife­
threatening rashes, i nclud i n g S tevens-Johnson syndro m e ,
severe e no u gh for rhe drug to be discontinued.
Lopinavir is often administered wirh ri tona vir
because of enhanced ef fi c acy and improved toler abil­
ity.A bso r p tio n is e nhan ced with food. Adverse effects
include nausea, v omi tin g, diarrhea, panc re a titis, and
asthenia ( dec rease in streng t h).
Fusion Inhibitor
Enfuvirtide rep r esen ts a new class of antiretroviral
agents . The drug binds to a porrion of the viral enve­
lope and prevents conformational changes required for
fusion of the viral and human cellular membr a nes
(Figure 28-3). Unlike other anti-HIV drugs, enfuvir ­
tide is not available in oralformulations. It is admin­
isrered sub c ut ane ousl y in com b in at i o n with other
antiretrovirals in rreatment-experienced p atie n ts with
persistent HIV-J repl i c a rion despire current rherapy.
Inj e crion sire r e ac t io n s and h ype rs ens i tivi ty may occur.
Integrase Inhibitor
Raltegravir is an i n h ib i ro r of viral in tegrase , rhe
enzyme required for integ ratio n of rhe viraJ DNA wi t h
rhat of rhe h ost . Block of rhis step (Figure 28-3) pre­
vents rep licarion of the viral genome. Th e d r ug is
active by rhe oral route and is not affecred by food .
The drug is well tolerated bur h eadache and g a s t roi n­
testinal disturbances have been reported.
HIV Entry Receptor Blocker
Maraviroc combines with a c hemo kin e receptor on
lymphocytes and prevents the bi nd i n g of HIV to cell­
surface receptors, a step requi red for entry into hosr
cells (Figure 28-3). It is orally acrive and always used
with other anti-H1V drugs. Toxicity includes hyper­
sensitivity reactions and hepatotoxicity.
ANTI-INFLUENZA DRUGS
There are three types of in fl uen z a viruses: A, B, an d
C. Influenza A and B produce similar clinical infec­
ti ons , manifested by fever, chills, malaise, myalgia,
headach e, nasal congestion, nonp rodu ctive cough, and
sore t h r oat . Influenza C is usually a mi n or illness.
Influenza A and B i n fect i ons are typically sel f-l imiting,
and most patients recover withi n 7 days. Anti­
influenza agents can decrease the durarion and sever­
ity of fever an d systemic symptoms. They can also be
used for prop hylaxis of clinical infecrion. Complica­
tions of influenza, including p neu m on i a, occur more
frequently in o l d e r adults, residents of long-term
health-care facilities, and individ ual s wirh chronic ill­
nesses such as diabetes mellitus and pulmonary or car­
diovascular diseases. Available vaccines for the mosr
cu r r ent influenza A and B viral srrains are recom­
mended before rhe begi n ning of influenza season (typ­
ical ly fall or winter) for susceptible individu als as well
as health-care workers.
Amantadine and Rimantadine
Amantadine and rimantadine inhibir an early replica­
tion step of the i nfluenza A vi rus (not influenza B).
These agents prevent viraJ unco atin g wirhin infected
host cells (Figure 28-\). Both drugs are about 70 ro
 An t i v i r a l Age n ts 40 9

90% e ffe c r i v e i n p reve n ring cl i nical i l l ness. I f treat­ B o t h H BV a nd H CV a re b l o o d b o r n e vi r a l i n fecrio n s .

me n t begi ns a bo u t l ro 2 d a ys a fter the onset o f cli n i ­ S h a r i n g o f i n tra veno u s d r u g u s e e q u i p m e n t a n d sex­
ca l �u s y m p to m s , b o th d r ugs red u ce t h e d u ra t i o n of u a l con tact w i rh an i n fected pers o n a re rhe most rl'e­
fever a n d syste m i c co m pla ims by 1 ro 2 days . Rapid quent s o u rces of H BV rra ns m iss io n , whereas
d e ve l o p m e n t o f res i s ta n ce o cc u rs in up to 50% of i n trave n o u s d rug use i s the p r i m a r y means of H CV
treated i n d ivi d u al s , d n d trans m i s s i o n o f res i s t a n r v i r us t ra n s m i ss i o n . Trea t m e n r o f t hese i n fect i o n s i s c r i t ical
ro h o useh o l d m e m b e rs has been d o c u m e n red . beca u s e t h e re are m i l l i o n s o f c h r o n i c ca r r i e rs o f H BV
Al rhough t h e m ec h a n i s m o f a c t i o n is n o t c l e a r l y a n d H CV. U n t reated ca rri ers a re n o t o n ly i n fec t i o u s
d e fi n e d , a m a ruad i n e is a l so u s e d r o a l le v i a te m o r o , t o o t hers , b u t t h ey c a n a lso deve l o p l o n g- term co m ­
a b no r m al i ties i n Pa r ki nso n's d i sease (Chapte r 1 7) . T h e p l ications s u c h as ch ron i c h epa t i t i s , c i r r h o s i s o f t h e
m o s t co m m o n adverse e ffecrs i n c l u d e gas t ro i n res t i nal l iver, a n d hepa tOce l l u l a r carc i n o ma .
i r ri ta t i o n , d i zz i n ess, atax i a , a n d s l u r red s p eech . Al l c u r rently ava i l a b l e age n ts fo r u s e i n t h e treat­
m e n t of H BV a n d H CV a re s u p p ressive rather tha n
Oseltam ivir and Zanam ivir c ura tive. I n general, ant i he p a t i tis d r u gs a re more effec­

T h e s e d r u gs i n h i b i t neu ra m i n i d ases p ro d u ce d by t i ve at h i nderi n g d i sease p rogress i o n in H BV i n fec t i o n

i n fl uenza A a n d B . By c l ea v i n g a t tac h m e n ts b e tween t h a n i n H CV i n fec tion. C o m p l iance wi th d r u g treat­

v i ra l p ro t e i ns and s u r face p ro t e i n s o f i n fected ce l l s , m e n t is also p roblem a t i c . Adve rse effects may be i n to l ­
v i r a l n e u ra m i n i d ases p ro m o te v i r i o n release a n d p re­ e ra b l e, a n d d o s i n g reg i m e n s a re o ften r i go ro u s ,

v e n t c l u m p i ng o f n ew l y re l eased vi r i o n s . Th u s , neu­ req u i ri n g i nj ec ti o n s o n ce d a i ly o r th ree t i m es weekly

ra m i n i d ase i n h i b i rors h i nd e r v i ra l s p read . B o t h d r ugs fo r several m o n ths in rhe case o f i n terfero n s . D r u gs

are a p p ro v e d fo r t h e t re a t m e nr of a c u te u n c o m p l i ­ used fo r t rea tmen t of viral h epa t i t i s fa l l i n to two b road

cated i n fl u e nza i n fe c t i o n . U n l i ke a m a n ra d i n e a n d catego r i e s : i m m u n e mod ulators ( i n te r fero ns) a n d

r i m a n r i d i n e , oseltamivir a n d z a n a m ivir are a c t ive replication i nhibitors (l a m iv u d i ne, adefov i r, ri bavi ri n)

ag a i n s t both i n fl u e nza A a n d i n fl u e l12a B . W h e n a ( Ta ble 2 8- 1 ) . G iven the m o rbi d i ty and mo r ta l i ty asso­

5 -d ay d ru g cou rse is i n i t i a ted w i th i n 36 ro 48 h o u rs c i a ted w i th these i nfecti o n s , im proved chemorherapies

a fter the o n s e t o f sym p to m s , u s e o f e i ther d r u g s h o rt ­ a re c r i t i ca l l y need e d . Al th o u g h a vacc i n e is available

ens the severity a n d d u r a ti o n o f i l l n ess, a n d m a y a lso fo r H BV, n o n e is yet ava i l ab l e fo r H CV.

decrease the i n c i d e n ce o f res p i ra t o r y co m p l i c a t i o ns i n

c h i l d re n and a d u l ts . Oselta m ivir i s used o r a l ly, a n d Interferon-a and Pegylated Interferon-a
z a n a m i v i r is used i n r ranasal ly o r b y o ra l i n h al a t i o n
u s i n g t h e D i s kh a l e r dev ice p rovided . Ta ken p r o p h y­ Mechanism ofAction and Pharmacokinetics
l a c t i c a l l y ose l ta m i v i r s i g n ificantly decreases t h e i n c i ­
,
I n re r ferons a re endoge n o u s cytoki nes that a re parr o f

d e nce o f i n fl u e n z a . Gastro i n tes t i n a l sy m p toms m ay t h e body's i n n a te i m m u n e d e fenses . These p ro t e i n s act

o cc u r w i t h ose l ta m i v i r, w h i c h may be d ec reased by thro u gh host cell s u r face recep tors to i n crease the for­
a d m i n i s t ra t i o n w i t h fo o d . Za n a m i v i r m a y i n d u c e m a t i o n of a n t i v i ra l p ro te i n s . I n te r ferons a re class i fi e d
b ro n c h o s p a s m i n as t h m a t i c p a t i e n ts . accord i n g t o t b e cell type fro m w h ich t h e y were derived .
Each of the th ree d is ti nct m aj o r classes of human inter­
ANT I H E PATITIS DRUGS ferons (a, �, y) has u nique physicochemical properties,
b i ologic effects, a n d prod ucer cel l s . The a n t i v i ral acrion
Each o f t h e reco g n i zed h e p a ti t is v i r u ses (A ro E) of i n terfero n -a ( I FN-a) i s p r i m a uy due to activation o f
r

b e l o ngs ro a d i s t i n c t v i r us fa m i l y, b u t al l o f them h ave a host ce ll ribonuclease that d egrades v i r a l RN A. I n

a long i ncub a ti o n period between i n i tial i n fectio n and add i ti o n , IFN-a promo tes fo rmation o f n a t u ral ki l ler
o n s e t of s y m p t o m s . H epa t i t i s can e a s i l y be sp read cel l s that destroy v i ral ly i n fected l i ver cel l s .
b e fo re s y m p to ms a p p e a r, and ma ny cases a re l i kely T here a re s evera l prepara ti o n s o f I F N - a ava i l a b l e
u n re p o rt e d beca use i n i t i a l s y m p to m s may be m i l d . fo r treatme n t o f b o t h H BV a n d H CV. T h e i n te r ferons
410 C H E M OT H ERA P E U T I CS

a re available as subcuraneous or i n t ramuscul ar injec­ Lamivudine

tions, w h i c h a re given either daily or t h ree ti mes per
Lamivud i ne is a NRTI agen t used i n t rea tmen t of
week. The attac hmen t of polyethylene glycol to I F N
HIV (see d iscussion a bove) . At lower doses than those
-

0. ( ter med pegylated I F N-o.) ex tends i ts duration of

used for H I V, la m i vud i ne is used for trea tmen t of
actio n , a l l owi ng for l ess frequen t dosi ng.
c h ronic H BV i n fectio n . Al though l a m ivud i ne's use as

Clinical Uses and Toxicity a mono therapy ra pidly su pp resses H B V repl ica tion

I F N - o. is used in t h e trea tmen t of ch ron i c H BV as a and is rel a tively nontOx i c , res ista n ce emerges rap id l y. If

mo notherapy or i n co m bi n a tion w i t h l a mivud i ne . patien ts still h ave detec ta ble levels of H BV DN A t hey ,

I F N - o. used w i th r i b av i ri n for acute H eV infection a re often switched to I F N-o. or adefovir.

red uces prog ressio n to c h ro nic H e v. For chro n i c

HeV, pegyl a ted I F N -a wi th ribavir i n i s super ior to Ribavirin
non pegyla ted I F N- o. as monotherapy. I F N - o. is a lso
Mechanism ofAction and Pharmacokinetics
used i n t h e trea t m e n t of Ka pos i sarco m a , pa p i l lo­
R i b av i r i n i n h i b i ts the repl i ca t ion o f m a n y D N A
m a tos is, a n d top ical l y for gen i t a l w a r ts. I n terferon s
a n d RNA v i ruses, i n clud i n g i n fluenza A a n d B ,
a l so p reve n t d i ssem i n a t i o n o f herpes zoster in c a n cer
p a ra i n fluenza , H e V, a n d H I Y. T h e p recise mec h a ­
p a tien ts. Ty pica l ad verse effec ts of IFN-o. i n cl u d e a
n is m of a c t i o n i s not know n , b u t i t i n h i bits the for­
fl u -like sy n d rome wi t h i n G hours a frer dos i ng i n
m a tio n of v ir a l D N A , p reven t s c a p ping o f v i r a l
a bou t 3 0 % of patients, wh i c h tends t o resolve w i t h
m R N A , a n d b loc ks RNA- d ep enden t R N A po l y ­
con t i n ued a d m i n i stra r i o n . G as c roin testi n a l sym p ­
merases of so me v i ruses. R i b avi r i n is available orally,
tom s , p rofou n d far i gue, neu t ropenia, myalg i a , ras h ,
i n t ravenously, a n d as a n aeroso l . O r a l b ioav a i l a b i l­
a n d hypotension c a n a lso occur. Severe neurop sych i ­
i ty i n c reases w i th h ig h - fa t m eals a n d dec reases w i t h
a u i c sym p toms (severe dep ressio n , mental con fusion)
a n tacid co nsu m p t io n .
h ave been reponed .
Clinical Uses and Toxicity
Adefovi r Ri b avi r i n is used wi th I FN - o. to t rea t pa tien ts wi th
chro n i c HeV i n fec tion w i th liver d isease. Mono ther­
Mechanism ofAction, Pharmacokinetics,
apy with ribavi ri n alone is not effec tive. In vi ral hem­
and Clinical Use
o r r h agic fevers, ea rly i n travenous r i baviri n dec reases
Al rhough i n i ti a l ly d evel oped for trea tmen t of H I V,
mo rtality. Ri bavi r i n is also used in the rrea tmen t of res­
adefov i r is currentl y a p p roved for trea tmen t of HBY.
p i ra tory synci tial v i rus (RSV) in c h ild ren . System ic use
S im i la r to tenofovir (see section on anti-HTV d rugs) ,
may cause a dose-dependen t hemolytic anemia . Aeroso­
adefovir is a nuc l eotide a n a log . It co m peti tive l y
l i c formulations may cause conjuncti val a n d b ronch i al
i n hib i ts H B V D NA polymerase, caus i ng chain termi­
i r r i ta r ion . Ri bavi r i n is a bsolute l y co n tra i n d i ca ted i n
na tion a fter i n corpora t i o n i n to viral DNA. It sup ­
p regnancy because i t i s a human teratogen .
presses H BV rep l ica tion a n d imp roves l iver h istology
and fi b rosis at I yea r. However, a fter cessa tion of ther­
a p y, H BV DNA reappears. Oral b ioava i l a b i l i ty is VACCINES AND IMMUNE
good, and it is unaffec ted by m eals. GLO B ULINS : ACTIVE AND PASS IVE
IMMUNIZATIONS
Toxicity
The pri m a ry tox i c i ty is dose-depen den t nephrotoxi c ­ Va cci nes consist of whole virions o r v i rus fragmen ts
i ty, w h i c h is m o re l i kely in p a ti e n ts with ren al dys­ that are com pletely i nactivated (dead) or pa rtially inac­
function a n d t hose receivi ng t he d rug for more t h a n tivated (live attenua ted ) . Active i m mun ization consists
I yea r. A s w i t h t h e N RTls, adefovi r m a y cause lactic of inoc u l a tion w i th a vacc i n e that triggers the host
a cidosis a n d hepa tomegaly. im mune system to produce antibod ies and cell- media ted

i m m u n i ty ag a i n s t t h i s a n r i g e n . T h us , active immu­
n i za t i on p r ov i d es i mmu n i ty to subsequent exp osu re to
t h a t p a r t i c u la r v i r u s . T h e i d ea l va c c i n e p reve n ts t h e
v i ra l d i s e as e , p reven ts t h e v i l'U s c a r r i e r state, a n d p r o­
duces l on g- l as ti n g i m mun i ty w itl1 a minimum number
of i m m u n i za t i o n s , a b s e n ce of tox i c i ty, a n d co nve n ­
i ence for mass i mmun izations (e.g. , t n expe n s ive a n d
easy t o a d m i n i s ter) . Live a t te n u a ted p rod ucts s t i m u ­
l a te n a t u r a l res i s tance and i m pa rt l on g er l as ti n g immu­
n i ty th a n dead a n t i g e n s . However, the r i s k of
con t r a c t i n g the v i ral d i s ease is grea ter tha n wi t h com­
p l e te ly i n a c t iva te d a.n t i ge ns . Exa mp l es of l i ve a t t e n u ­
ated vaccines include those for m easles, m umps , and
rubella ( M M R) , p ol i ovi rus (the oral vacci n e) , and vari­
cella. Vaccines c on t ain i n g dead v i ra l a n t i gens i n cl u d e
t h ose fo r ra b i es, both h e p a t i t i s A a n d B v i r uses, a n d
pol i ov i r u s ( the p a re n te ral va cc i ne) . C urren tly, vaccin es
a re ava i l a b le fo r ma n y v iral i n fecti ons. Whereas some
va c c i n a t i o n s a re req u i red by law ( e . g. , measles,
p o l i o myel i tis) , o thers a r e o n l y admin istered to h i gh­
risk p op u l a t i o ns (e.g. , i n fl uenza) . Sel eered exam p l es of
co m m o n l y used m a t e r i a l fo r active i m m u n i za t i o n i n
t h e U n i ted S ta tes a re given i n Ta ble 28-3 .
Un l i ke aer ive i mm u n iza ti o n , w h i ch req u i res time
to d evel op beca use the i n d i v i d u al 's i m m u n e sys t em
m u s t p r od u ce i ts own a n tibod ies, passive immuniza­
tion a l l ows a n i n d i v i d ual to ga i n i m med i a t e i m m u n i ty
beca use i t c o n s i s ts of the transfer of p r efo r med
i m m u n oglobul i n s to an i n d ivid u a l . S i n ce th e rec i pi­
ent does n ot p r od uc e his/her own a n r i b od i es , passive
i m m u n i za t i on is te m p o r a ry. P a s sive i m m u n i z a ti on
p r od u c t s genera l l y con tain h i g h ti ters of a n t i bo d i es
e i ther d i rected ag a i n s t a s pec i fi c a n ti ge n , or may sim­
ply co n ta i n antibod ies found i n mo st of the p o p u l a­
t i o n . Passive i m m u n iza ti o n is used for ( l ) i n d iv i d u al s
w h o a re u n a b l e to fo r m a n r i b o d ies ( e . g . , co n g e n i t a l
aga m magl o b u l i n e m i a ) ; (2) p rev e n t i o n of d is e a se when
time d oes not per m i t aerive immu nization (e. g. , post­
exposu re); (3) r rea tme n r of c er ta i n d i s eases n ormal ly
p reven ted by i m m u n i za t i o n ( e . g . , teta n u s) ; a n d (4)
rrea t m e n r of condi tions for which active immuniza­
tion is u n ava i l a b l e or i mp r a c t i c a l (e . g. , s n akeb i te) .
A n t i bod ies can be d e r i ved fr om a n i m a l o r h u m a n
sources . I m m u n i za t i o ns derived from h uman anti­
b od i e s have t h e ad va n t a ges of avoi d i n g th e risk of
A n t ivi r a l Agents 41 1
hypersens i ti v i ty re ac t i o ns a n d h avi n g a l onge r h a l f- l i fe
than th os e from a n imal s o u rces. Selected materials for
p ass ive i m m u n iza tio n a re p r e s e n ted i n Ta ble 2 8 -4 .
REHABILITATI O N F O C U S
Al r h ough m a n y a n rivi ral age n ts l i m i t the exte n t of sys­
tem i c d a ma ge, es pec i a l l y when i n i ti a ted e a rl y in the
course of viral infection , very few comple tel y c u re v i ra l
i n fect i o n s . Pa t ie n ts taki ng a n tivi ral agents face pa r ri cu­
lar c h a l le n ges i n a d h er i n g to com p l i c a ted d r u g reg i ­
mens. HAART re g i me ns ge n er a l l y r eq u i re HIV/AIDS
pat i e n ts to tal<e more than a dozen pi l ls per d ay-some
on an empty s tomach, some w i th meals , and others with
l arge qua n ti t i es of wa ter. An ri h epa t i tis
interferon com­
pounds require i nj ec ti o ns o n e to t h ree times per week,
often fo r exte n d ed pe r i od s of t i m e . In a d d i ti o n , th e
adverse effects of s ys te m ic a n t i v i ra l agen ts may cause
patients t o a ban d o n a compl ete cou rse of t rea t m e n t .
P hys ica l th e r a p i s ts can ass i s t p a ti e n ts ' c omp l i a nce
w i t h drug reg ime n s . T h e ra p is ts can ar r a n ge d rugs i n a
s i n gle read ily a cc ess i b l e l oca t i on , te a c h pa t i e n t s to use
a t i mer to signal d os i ng times, develop a color-coded
s ys t em with p i ll boxes t o rem i nd pa t i e n ts which d r ugs
need to be ta ken s e p a r a t el y fro m o r w i t h fo o d , a n d
r em i n d a nd ed u ca t e p a ti e n ts a b o u t t h e i mpor ta n c e of
a d h e rence to the antivital r egim en .
I n arran g i n g t h era py sess i on s , t h e r a p i sts m u s t b e
sensi tive to t h e p r ofou n d i m p a c t that a n t i v i ra l d r ug s
h ave on pa t i en ts ' abi l i ty [0 p a r r i c i pa r e . Nausea , vom­
i t i n g , d i a r rh ea , or m a l a i s e m ay d e l ay trea t m e n r ses­
s i ons . In an i n pa tien t se t t i n g , fre quen t brief sess i o n s
may be mor e e ffective a n d to l e rab l e t h a n a s i n g l e
l on ge r sessi o n . P ai n d ue [0 pe r i ph e r al n e u ro p a th i es or
myal g i a may alter a trea t ment p l an toward pain allevi­
ation, i n which therapists can as s i s t b y adj un ct i v e use
of heat m od al i t ie s and tra nscutaneous electr ica l n e rve
s t i m u l a ti o n (TENS) . F l ex i b ly m an a gi n g t h e r a p y ses­
sions aro u n d pa ti en ts' best time op t i mizes their a b i l i ty
[0 te a ch teh a b i l i ta tion goa l s .
Because H I V d i rec tl y targets the i m m u ne sys tem ,
AI DS pat i e n ts a re am o n g th e mos t i mm u n oc o m p ro ­
m ised i n d iv i d u a l s . In a d d i t i o n to H AA RT, AI D S
patie n ts a r e often ta k i n g p r op h yl a c t i c med i c at i o ns [ 0
412 C H E M OTH ERAPEUTICS
Materials commonly used for active i m m un ization i n the U n ited Statesl
Vac c i n e
D i p h t h e r i a-teta n u s­
ace l l u l a r pert u ss i s
( DTa P )
Haemophilus
in fluenzae type b
c o n j u gate ( H i b)
H e pat i t i s A
H e pa t i t i s B
I nf l u e n z a ,
i n ac t i vated
I nf l u e n za , l ive
atte n u ated
Route of
Type of Agent Ad m i n istrat i o n I n d icati o n s
Toxo i d s a n d I ntra m u sc u l a r l . F o r a l l c h i I d re n
i n act i vated 2 . Booster every 1 0 years i n a d o l esce n ts
bacte r i a l a n d a d u lts
c o m p o n e nts
Bacte r i a l I ntra m u sc u l a r 1 . For a l l c h i l d ren
pol ysacc h a r i d e 2. Asp l e n i a and ot h e r at-r i s k
conj ugated conditions
to prote i n
I nactivated v i r u s I ntra m u sc u l a r 1 . Trave l ers t o h e pa t i t i s A e n d e m i c a reas
2. H o m osex u a l and b i se x u a l m e n
3 . I l l i c it drug u sers
4. C h ron i c l i ver d i sease or c l ott i n g factor
d i sorders
5 . Pe rso n s w i t h oc c u p at i o n a l r i s k for
i nfect i o n
6 . Pe rso n s l i v i n g i n , o r re locat i n g to ,
e n d e m i c a reas
7 . H o u se h o l d a n d sex u a l c o n tacts of
i nd i v i d u a l s w i t h ac ute hepat i t i s A
I n ac t i ve v i ra l I nt ra m usc u l a r l . For a l l i nfants
a n t i ge n , (su bc ut a n e o u s 2 . Prea d o l escents, a d o l esc e n t s , a n d
recom b i n a n t i nject i o n i s you n g a d u lts
ac c e pta b l e 3 . Pe rson s w i t h occ u pa t i o n a l , l i festy l e ,
i n i n d iv i d u a l s o r e n v i ro n m e n t a l r i s k
w i t h b l eed i n g 4 . H e m o p h i l iacs
d i sorders) 5 . H e m o d i a l ys i s pati ents
6. Postexpos u re pro p h y l a x i s
I nac t i vated I ntra m u sc u l a r l . Ad u lts ;?, 5 0 yea rs o f age
virus or viral 2. Perso n s w i t h h i g h r i s k cond i t i o n s
c o m p o n e nts ( e . g . , asth m a )
3 . H ea l th c a re workers a n d ot h e rs
i n c o n tact w i t h h ig h - r i s k gro u ps
4 . R e s i d e nts of n u rs i ng homes a n d
ot h e r res i d e n t i a l c h ro n i c c a re
fac i l i t i es
5 . A l l c h i l d ren aged 6-23 m o n t h s
L i ve v i r u s I ntra n a s a l H ea l t h y pe rson s aged 5-4 9 yea rs w h o
d es i re protec t i o n aga i n st i n f l u e n za
( continued )

Ta ble 28-3 . Materia ls commonly used for active i m m u n ization in the U n ited States 1
Va c c i n e
M ea s l es
M ea s l es-m u m ps­
r u be l l a ( M M R )
M e n i n gococ c a l
conj ugate
vacc i ne
M e n i ngococc a l
polysac c h a r i d e
vacc i ne
M u m ps
P n e u m ococ c a l
conj ugate vac c i n e
P n e u mococ c a l
p o l ysac c h a r i d e
vacc i n e
Po l i ov i rus vacc i n e ,
i nactivated ( I PV)
Antiviral Agents 413
( Continued )
Route of
Type of Agent Ad m i n i strat i o n I n d i cations
L i ve v i ru s S u bc uta n e o u s 1 . Ad u l t s and a d o l esc e n t s born after
1 9 5 6 w i t h o u t a h i sto ry of m e a s l e s or
l ive v i r u s vacc i n at i o n o n or after t h e i r
f i rst b i rt h d ay
2 . Postexpos u re pro p h y l a x i s i n
u n i m m u n i ze d perso n s
L i ve v i ru s S u bc ut a n e o u s F o r a l l c h i l d ren
Bacter i a l I ntra m u sc u l a r 1 . A l l a d o l escents
p o l ysac c h a r i d e s 2 . Preferred ove r p o l ysacc h a r i d e vacc i n e
c o n j u gated to i n perso n s aged 1 1 - 5 5 years
d i p h t h e r i a toxo i d
Bacte r i a l S u bc uta n e o u s 1 . M i l i t a ry rec r u its
polysacc h a r i des 2. Trave l e rs to a reas w i t h e p i d e m i c
of seroty pes m e n i ngococ c a l d i sease
A/CIY/W- 1 3 5 3. I n d i v i d u a l s w i t h a s p l e n i a ,
c o m p l e m e n t defi c i e n cy, o r p r o p e r d i n
defi c i e n cy
4. Control of o u t b r e a k s i n c l os e d or
se m i -c losed po p u l at i o n s
5 . Col l ege fres h m e n w h o l ive i n dorm itories
6. M ic robiologists who a re routinely ex posed
to isol ates of Neisseria meningitidis
L i ve v i ru s S u bcuta n eo u s A d u I ts born after 1 9 5 6 w i t h o u t h i story
of m u m ps or l ive v i r u s vacc i n a t i o n on o r
a fter t h e i r fi rst b i rt h d ay
Bacte r i a l I n t ra m u sc u l a r o r
polysac c h a r i des s u bc u ta n e o u s
conj ugated to
p rote i n
B acte r i a l I n t ra m u sc u l a r 1 . Ad u l ts � 6 5 yea rs of age
p o l ysacc h a ri des or s u bc ut a n e o u s 2. Pe rso n s a t i n c reased r i s k for
of 2 3 se roty pes p n e u mococ c a l d i sease or i t s
co m p l i c at i o n s
I n act ivate d v i r u ses S u bc u ta n e o u s 1 . F o r a l l c h i l d ren
of a l l t h ree 2 . Prev i o u s l y u n vacc i nated a d u l t s at
serotypes i n c reased r i s k for occ u pa t i o n a l o r
trave l exposure to pol i ov i r u ses
( continued )
414 C H E M O T H E RA P E U T I CS

Ta ble 28-3 . Materials commonly used for active i m m u nization in the U n ited States! ( Continued )

R o ute o f
Va c c i n e Ty p e of Age nt Ad m i n i strat i o n I n d i ca t i o n s
R a b i es I n a c t i vated v i rus I ntra m u sc u l a r l . Pre ex p osure p ro p h y l a x i s i n perso ns at
( 1 M) or r i s k for c o n ta c t w i t h ra b i e s v i ru s
i n tra d e r m a l ( I D) 2 . Postex p o s u re p r o p h y l a x i s ( a d m i n i st e r
w i t h ra b i es i m m u n e g l o b u l i n )
R u be l l a L i ve v i r u s S u b c u t a n eo u s Ad u l ts born a f t e r 1 9 56 w i t h o u t h i s t or y
of r u b e l l a or l i v e v i r u s v a c c i n at i o n on or
after t h e i r f i rst b i rt h d ay
Tet a n u s-d i p h t h e r i a To x o i d s I ntra m u sc u l a r l . A l l a d u l t s w h o h a ve n o t be e n
(Td o r DT) 2 i m m u n i z e d a s c h i l d re n
2 . Postex p o s u re p r o p h y l a x i s i f > 5 y e a r s
has p a ss ed s i n c e l a st d o s e
Ty p h o i d , Ty 2 1 a o r a l L i ve bacte r i a O ra l R i s k of e x p os u re to t y p h o i d fever
Va r i c e l l a L i ve v i r u s S u b c u ta n eo u s l . For a l l c h i l d re n
2 . Perso n s p a s t t h e i r 1 3 l h b i rt h d a y w i t h ­
o u t h i st o ry o f va r i c e l l a i n f e c t i o n
3 . Po st e xp os u r e prophy l a x i s i n su sc e pt i b l e
pe r s o n s
Ye l l ow Fever Live vi rus S u b c u ta n eous l . La b o r a t o r y p e rs o n n e l who may be
e x p os e d to ye l l ow fever v i r u s
2 . Tr a v e l e r s to a re a s w h e re y e l l o w fever
oc c u rs

I Dosage for t h e spec i f i c p r o d u c t , i n c l u d i n g va r i a t io n s for age , a re best obta i n e d from t h e m a n u fact u re r 's pac kage i n sert .
2Td = Teta n u s a n d d i p h t h e r i a tox o i d s for u s e i n perso n s ?, 7 years o f age ( c o n ta i n s l e ss d i p ht h e r i a toxo i d t h a n D PT a n d Dn
DT = Teta n u s a n d d i p h t h e r i a toxo i d s fo r u s e i n perso n s <7 years o f age ( c o n ta i n s t h e s a m e a m o u n t o f d i p h t h e r i a toxo i d
a s D PT) .

p reve n r op p o r t u n i s t i c i n fecr i ons from ot h er vi ruses, CLIN I CAL RELEVANCE

b acter i a , fu ngi, and m i s ce l l a n eous p a t h o gens . T h era­ F O R REHABILITATI ON
pists s ho u ld b e a le r t co new s i gns and s y m p co m s of
acute i n fect i o n s , an d re p ort th ese co th e p r i mar y Adverse D r u g Reactions
h ea l t h -ca re pr o v i d e r immedi ately to fac i l i tate a gg res­
Antiherpes drugs
sive trearme n r in ea rly i n fe ct i ou s stages. P hy s i cal t her­
• Ganci cl ov i r may cause myelosu ppression .
a p i sts m us t v i g i l an t ly p racr i ce s ta n d a r d p recaut i ons
• Cidofovir a n d foscarnet can cause nephro toxici ty.
w h e n wor ki n g wi t h HIV/AI D S p at i enrs . T h i s a l so
• Fos carnet (an d l ess commonly, g anci c l ov i r ) can
i n c lud es s ra yi ng home o r a vo id i n g patien t care w h e n
cause CN S cox i c i ry i nc l u d i ng
headache , ha.l l uci n a ­
i l l ness s r r i k e s the t h e r a p i s t r o p reve n r p at h o ge n
t i ons, an d se i z u res .
tra nSm iSS i o n .
 A n t i v i r a l Agen ts 415

Ta ble 2 � . Selected passive i m m u n izations l

I n d i cation Pro d u ct Dosage C o m m e n ts

Bone m a r row I m m u n e globu l i n 5 0 0 m g/kg I V o n d ays 7 Pro p h y l a x i s to d e c re a s e t h e r i s k of
t ra n s p l a n t a t i o n ( i ntrave n o u s ) 2 a n d 2 p r i o r to i n fec t i o n , i n terst i t i a l p n e u m o n i a ,
t ra n s p l a n tat i o n a n d a n d a c u te graft-vers u s - h ost
t h e n o n c e wee k l y d i sease i n a d u l t s u n d e rgo i n g b o n e
t h ro u g h d a y 90 afte r m a rrow t ra n s p l a n t a t i o n .
tra n s p l a n t at i o n .
C h ron i c l y m p h o c yt i c I mmune globu l i n 400 m g/kg I V every C l l p a t i e nts w i t h
l e u k e m i a ( C lL) ( i ntrave n o u s ) 2 3 - 4 wee ks . Dosage h y poga m m a g l o b u l i n e m i a a n d a
s h o u l d b e a d j u sted h i story of at l e ast o n e s e r i o u s
u pward i f bacte r i a l bacter i a l I n fec t i o n .
i n fec t i o n s occ u r.
Cyto m ega l ov i r u s Cytom ega l ov i r u s Co n s u l t t h e Pro p h y l a x i s of C M V
(CMV) i m m u ne globu l i n m a n u f a c t u rer's d o s i n g i n fect i o n i n b o n e m a rrow,
( i n t rave n o u s ) rec o m m e n d a t i o n s . k i d n ey, I i ve r, l u n g , p a n c re a s , h ea rt
t ra n s p l a n t rec i p i e n t s .
H I V- i nfected I m m u ne globu l i n 400 m g/kg I V e v e ry H I V- i nfected c h i I d re n w i t h
c h i l d re n ( i ntrave n o us ) 2 2 8 d a ys . rec u rr e n t s e r i o u s b a c t e r i a l i n f e c -
t i o n s o r h y p oga m m a g l o b u l i n e m i a .
I d iopath i c I m m une glob u l i n Consu I t the R es p o n se i n c h i l d re n w i t h ITP is
t h ro m bocyto pe n i c ( i n t rave n o u s ) 2 m a n u f a c t u rer's d os i n g greater t h a n i n a d u l t s .
p u r p u ra ( I TP) reco m m e n d a t i o n s f o r C o rt i c oste ro i d s a r e t h e treat m e n t
t h e s p e c i f i c prod u ct of c h O i c e i n a d u l t s , ex c e pt for
b e i ng u se d . severe pregn a n cy-assoc i a ted I T P.
P r i m a ry I mm u ne globu l i n Con s u l t the P r i m a ry i m m u n o d ef i c i e n c y
i m m u n odef i c i e n cy ( i n trave n o u s ) 2 m a n u fa c t u re r 's d o s i n g d i sord e rs i n c l u d e s p e c i f i c
d i so r d e rs recom m e n d a t i o n s f o r a n t i b o d y d ef i c i e n c i e s ( e . g . ,
t h e s pec i f i c prod u c t X - l i n ke d aga m m a g l o b u l i n e m i a )
be i n g u se d . a n d combi ned defi c i e n c ies
( e . g . , severe c o m b i ned i m m u n o-
d ef i c i e n c i es) .

l Passive i m m u n o t h erapy or i m m u n o p ro p h y l ax i s s h o u l d a l ways be ad m i n i ste red as soo n as poss i b l e after e x p os u r e . P r i o r to

t h e a d m i n i stra t i o n of a n i m a l s e r a , pat i e n ts s h o u l d be q u e st i o n e d a n d tested for h y p e rse n s i t i v i ty.
2 S e e t h e fo l l owi n g refere n c e s for an a n a l ys i s of a d d i t i o n a l u ses o f i n t rave n o u s l y a d m i n i stered i m m u n e g l o b u l i n : R a t k o TA ,
et a l : Recom m e n d a t i o n s for off- l a b e l u s e of i n trave n o u s l y a d m i n istered i m m u n o g l o b u l i n preparat i o n s . JAMA 1 99 5 ; 2 7 3 : 1 86 5 ;
a n d D a l a k a s M e : I n trave n o u s i m m u n e g l o b u l i n t h erapy for n e u ro l og i c d i seases. Ann In tern Med 1 99 7 ; 1 2 6 : 7 2 1 .

Anti-HI V drugs • The N N RTls a n d PIs a re m e t a b o l i zed by r h e

• M a n y a n r i - H IV d r u gs cause gas tro i nres r i n a l d i s t ress cytoch ro m e P450 sys re m , i ncreasing l i ke l i h o o d o f
( nausea, vo m i r i n g , d i a rrhea, a b d o m i n a l p a i n ) , d r u g-drug i n re racri o n s .
m a l a ise, fa t i g u e , a n d e N S d ys fu n c t i o n (h eadache, • F o o d decreases b i o avai l a b i l i ry o f s o m e N RTls
agi ra r i o n , d i zz i n ess, con fu s ion) . ( d id a n o s i n e , zaic i ta b i ne) a n d the PI i n d i navi r.
4 16 C H E M OT H E RA P E U T I CS

o An e m p ty s to mach decreases b i o avai l a b i l i ty o f s o m e o f breath ( d u e to a n e m i a ) , and easy b r u i s i n g or

N N RTls (efav i re nz) , a n d P I s ( r i to n a v i r, saqu i n a v i r, exce s s i ve b l eed i n g fro m m i n o r wo u n d s (due to
nelfl navir, l o p i n av i r) . rhrombocytopenia) .
o A nt a c i d s d ecrease b i oava i l a b i l i ty o f zalci t a b i n e , o C o n c u r re n t use o f N S A I D s fo r m u s c u l os k e l e r a l
d e la v i rd i n e , a n d a m p renavi r. p a i n a n d i n fl a m m a t i o n s h o u l d b e avo i d e d wh e n
p a r i e n ts a re t a ki n g neph rotox i c d r u gs ( e . g . , c i d o ­
NRTls
fovi r, foscarner) .
o Al l N RTls (es pecia l l y s tav u d i ne) h ave the pote n t i al
o Gasrro i n cesti n al a n d CNS e ffects can affect p a r t i c i ­
to cause s e r i o u s l a c t i c a c i d o s i s a n d severe h e p a t i c
p a r i o n a n d fu n c r i o n a ! perfo r m a nce o f p a ti e n cs i n
s reatos l s .
rehab i l i ta t i o n p rogra m s .
o Zidovud i n e can cause seve re myelosupp ress i o n .
o H I V/AI D S parien rs o n HAART who r a k e over- rhe­
o D i d a n o s i n e , zalci ra b i ne , a n d s ta v u d i n e c a n
co u n ce r d r u gs or s u p p l e m ents r i s k dec reased or
ca use dose-depen d e n t p a ncrea r i ti s .
i n creased blood d r u g levels, res u l r i n g i n e i r h e r
o D i d a n o s i n e , zalcitabine, a n d s tav u d i n e c a n
u n de r m ed i ca r i o n o r i ncreased ad verse effecrs assoc i ­
c a u s e periph eral neuropathy.
a red wirh overmed ica t i o n .
o D i d a nosine can p roduce retinal change s .
o S evere na usea, vom i ti ng, a b d o m in al pai n , rapid respi­
NNRTls rations o r shortness of b rearh in HIV/AlDS parienrs
o M o s r N N RTIs tend to p ro d u ce a ras h , w h i c h can receiving N RTls m ay i nd ica re o nset of l acric acidosis.
be l i fe - r h reaten i ng wirh nev i r a p i n e . o H IV/AIDS patients recei v i ng N RTls who co m p l a i n
PIs o f consta n r p a i n in t h e upper a b d o m e n wi th possi­

o T h e PIs o ften cause carbo hydrare and l i p i d m e ra- ble rad i a t i o n to the back m a y be ex perienci ng aeu re

bo l i c d ys regu lario n . p a ncreari t i s .

o I n d i n a v i r c a n cause ki d n ey d a m age. o Pa i n fu l p e r i p heral n e u ro p a t h i es ( d i d a n o s i n e , z a l ­

o Ri conavir and am prenavi r can cause paresthesias. c i t a b i ne, stav u d i n e) , p a resthesias ( r i to n avi r, a m p re­

o Amp re n av i r can cause l i fe- t h reare n i ng rashes. n av i r) , d i zz i n ess and a t ax i a (a m a n rad i ne) , a n d

o Lo p i n a v i r can cause asrhe n i a (weakness) . asthen ia ( lo p i navir) can affect m o b i l i ty a n d g a i r , and

l i m i r p a r t i c i pa tio n in reha b i l i ta r i o n .
Anti-influenza drugs
o Re t i nal c h a n ges ( d i d a n os i n e) c a n aEfecr v i s i o n , bal­
Am a n rad i n e a n d o s e l ra m i v i r can cause gas rro l J1 -
ance, a n d m o b i l i ty.
tes t i na! u pset.
o Pro tease i n h i b i to r - i n d u ced m e rabo!ic dys regu lation
o Ama n tad i ne can cause d i zzi ness a n d a t ax i a .
increases pacienrs' risk profile fo r card iovascular disease.
o Za n a m iv i r m ay i nd u c e b r o n chospasm i n asthma tic
o Pa t i e n rs taki ng za n a m iv i r or ribaviri n m ay h ave res­
p a t i e n ts .
piratory dysfu n c t i o n .

Anti-hepatitis drugs o Pa n i ci p a r i o n i n rherapies may be l i m i ted w i th i n rhe

o IFN-a can cause flu-l i ke symptoms wirh i n s i x ho u rs first h o u rs a fter I F N - a ad m i n is r ra t i o n .

a frer paren ce ral dos i ng.

o I F N - a ca n cause hypotension a n d severe n e u ro psy­ Possible Therapy Solu tions

c h i a r r i c sym p t o m s . o I f the patie n t has myelos u p p ress i o n , phys i cal rhera­

o Aeroso l i c ri b av i ri n c a n c a u s e co nj u ncriva! a n d p i s ts s h o u l d practice excel l e n r s ta n d a rd p reca u t i o n s

b r o n c h i a l i r r i tation. to p reve n r i n fection tra n s m iss i o n . Exe rcise i n re n s i ty

Effects Inte rfering wi th Rehabilitation
o Mye l osuppressi o n (gancic lovi r, zi dovu d i ne) can
i n d ecreased resis tance to nosoco m i al i n fe c t i o n s
( d u e t o l e u ko pe n i a ) , i ncreased fa tigue a n d sho rtness
a n d d u ra r i o n s h o u l d be red uced to acco u n r fo r
decreased oxyge n-carryi n g capacity of t h e blood. I n
res u l t addition, extreme ca u t i o n s ho u l d b e t a k e n c o avo i d
inadverte n t o r s u s ta i ned p ress u re o n any a rea o f r h e
p a t i e n t , d u e t o decreased c l o t t i n g a b i l i ty.
 A n t i v i r a l Age n t s 4 1 7

• If p a t i e ms ta king nep h ro wxi c d r u gs experience m us­ any d r u g , i n clu d i ng h e r b a l s u p ple m e n ts a n d c o l d

c u l o s ke l e ta l p a i n a fter exe rcise o r t h e r a pi e s d r u g , me d i c i n e s , w i n t e rfe re w i t h d r u g m e t a b o l i s m .
a l ternatives s u c h as h e a t o r i ce sh o u l d be used T he r a p i s ts s h o ul d s tro n gl y e ncou rage t h e p a t i e n t to
i n s tead of N SAI Ds. d iscuss all current d r u g use wi th th e re fe rring heal th­
• Th e r a p y s h o u l d be timed w o cc u r d u r i n g p e r i o d s cate provi der.
when a d ve r s e e ffe c t s a r e l o wes t . T h e ra p i s t s • S y m p to ms cons i s tem w i th l ac t ic acidosis or p a n c re­
s h o u l d d i s c u s s w i t h t h e r efe r r i n g h ea l t h - c a re a t i t i s s h o u l d be i m me d i a t e l y r e p o r r e d w re fe r r i n g
p ro v i d e r or p h a r m a c i s t w h e t h e r certa i n d r u gs can heal th-care pr ovid e r a n d t h e rapy d is co n t i n u ed u mi l
,

b e taken at ni g ht w dec rease pe rce p t i o n o f s o m e s y m pt o m s r e s o lve .

CNS e ffe c t s a n d m i n i m i ze th e i r i m p a c t o n • P a t i e n r r e p o rts of v i s i o n c h a n g e s peri p h eral n e u ­

,

p a t i e n ts' fu n c t i o n a l p e rfo r m a n ce a n d a b i l i ty w ro p a t h y and p a re s t h e s i a s sho u l d b e re p o r r e d

, [0

p a r t i c i pa t e in r h e ra py. re fe rrin g health-ca re p ro v i d e r w d e te r m i n e i f dose

• P h y s i c a l t h e r a p i s t s c a n a s s i s t w i t h r e i n fo rc i n g re d u c t i o n al leviates symp wms.
o p t i m a l d r ug d o s i ng sc hed u les fo r p a t i e n ts o n • Any rash o r p ro g r es s i o n o r s p re a d of a cu rren t rash
HAA RT. Fo r ex a m p l e t h e ra p i s ts c a n m a ke p i ctu re s
, s ho u ld be i m m e d i a t e ly r e p o r r e d w rhe p r i m a r y
or ta b les i n co n ve n i e n t loca tions, such as above the h e a l t h -ca r e p rovide r because of the a b i l i ty for m a n y
bed s i d e or in the ki tche n , w rem i n d pa t i e ms w h i c h a n tivi ral d r ugs to p ro d u ce l i fe- t h reate n i n g ras hes.
p i l ls s h o u l d be taken o n a n e m p ty s w m ach a n d • P a t i e n ts taki n g PIs should b e m o n i to re d fo r s i g n s of
w h i c h s h o u l d be ta ken w i t h meal s . Didanosine, zal­ ca rd i o v a scu l a r d i sease. I f w lera ted , exercise p re ­
c i t a b i n e a n d i n d i n a v i r s ho u ld be taken o n an e m p ty
, scriptions s h o u l d be m o d i fi ed w i ncrease p a r t i c i pa­
s r o ma c h Efa v i renz, te n o fo vi r rironavir, saqu in avir,
. , tion in aero b i c exercise .
n e l fl n a v i r, a n d l o pi n a v i r s ho u ld be take n w i th meals. • P hysical t he ra pis ts should carefu l ly m on i r o r res p i ra ­

A macids s ho u ld not be t a k e n w i th za l c i t a b i ne, w ry fu nction d u r i n g th era p y with p a t i e ms t a k i n g

cl e l a v i rd i ne, a n d a m p re n a v i r. za namivir o r r i baviri n , esp e c i a ll y i f p a t i e nts have
• Beca use of rhe la rge p o te n t i a l fo r d r ug d r u g i n ter­-
chronic obstructive p u l m o n a ry d i s e as e Wo r s e n i n g o f
.

actions w i th H IV/ A I D S p a t i e ms on HAART, phys­ symptoms s h o ul d be re p or te d ro the p rima r y health­

ical t hera p i s ts sh o u l d ta k e a c o m p l ete d ru g h iswry care provi der. S h o rr- acti n g b ro nchod i lawrs sho u l d be
and ed u c a t e the p a t i e n t regard i ng the p o t e m ial fo r i mme d ia te l y avai l able in the case of b ro nchos pas m .

P RO B LEM - O RIENTED PATIENT STUDY

Brief Histo ry: The p a t i e n t i s a 44-yea r- o l d male an d a p ro t eas e inhibi ror. Si nce the patient's H N intec­
w h o has b e e n H I V p o s i t i ve fo r 1 0 yea r s O n h i s . tion h a s respo nded very wel l ro this d rug regimen, his
mos t recent p h ysic i a n visit, i t was noted that h e was p hys ician is cu rren tl y reluctant ro switch ro a protease
h y p e rgl yce m i c and hyperl i p i de m i c . In a d d i t i o n , i nhibi ror-sparing regim e n. Instead, she has refe rred
a l thou g h h i s weigh t has n o t changed in the p a s t him to rehabil i tation ro assess the efficacy of a no n ­
yea r, he n o t es tha t h i s legs appea r t h i n ner and his pharmaco logical a pp roa ch ro the hyperglyce mia,
waist is defin itely la rger. hyperlipidemia, and l i podystrophy sy n d ro me .

Current Medical Status and Drugs: The patien t's Rehahilitatum Setting.· The ph ysical therapist p rescri bes
HAART regimen i ncludes t\vo NRTIs, one N N RTI, an exercise p ro g ra m for the patient that i n c l u d e s
(continued)
4 1 8 CH E M OT HER APE U T I CS

PROBLEM- O RIENTED PATIENT STUDY ( Co n tinued)

aero bic and progressive resistance trai ning. His exer­ the quality of li fe o f individuals with HIV i n fec t i o n .

cise program includes 40 min u tes of moderate aerobic As HIV/Al DS p a t ients live longer, other morbidities
activity and 20 m i n utes of resistance train in g three to have emerged including cardiovascular disease. Pro
,
­

four ti mes per week. Larger muscle groups, especially tease i nh i b i tors traditionally i ncl uded in HAART
the lower ex tremi t ies are targeted for strengthening.
, regimens are often associated with deve l op m e n t of
The th erapist monitors his vital signs and progresses, dys lip ide m ia insulin res istance, and l ipodystrophy.
,

exercises appropr i ately to his tolerance. The pati e nt Similar to the management of these conditions i n
has been stringe n tly followi n g his exercise program for H IV-uninfected i ndivi du a l s , exercise can be u sed to
4 months He is quite pleased with the results, as he
. hel p p reve nt p oten tial cardiovascular and metabolic
no tes that his belt fits better now and he is noting complications in HIV-infected people. Recommen­
more strength and mass in his legs . At his p hysician's dations incl ude smoking cessation, reductio n in
reassessment, his metabolic proftie has also i mproved dietary fat, and i n c re as i ng exercise. Specifically,
significantly: decreased lipidemia decreased fasting
, resistance a n d aerobic exercises have been shown to
blood glucose and decreased resting
, b lood pressure. help HIV-infected individuals gain lean body mass,
dec re ase truncal adipos i ty and decrease total cho­
,

Problem/Clinical Options: Without questi o n ,

lesterol and triglyce ride concentrations.

HAART h as i ncreased the l ifesp an and i m p roved

A baca vir (Ziagen) Cidofovir (Vis tide)

O ra l : 3 0 0 - m g tab l et s ; 20 m g/m L s o l u t i o n Pare n tera l : 3 7 5 m g/v i a l ( 7 5 m g/m L) for IV i n j ect i o n
Ora l (Tr i z i r ) : 300-mg tabl ets i n com b i n a t i o n w i t h
Delavirdine (Rescriptor)
1 5 0 m g l a m i v u d i n e a n d 3 0 0 m g z i d ov u d i n e
O ra l : 1 0 0 - , 2 0 0 - m g ta b l ets
Acyclovir (generic, Zovirax) Didanosine (dideoxyinosine, ddl)
O ra l : 2 0 0 - m g c a p s u l e s ; 4 0 0 - , 8 0 0 - m g t a b l e t s ; Ora l ( V i dex) : 2 5- , 50-, 1 00-, 1 5 0-, 200-mg
2 0 0 m g/ 5 m L s u s pe n s i o n ta b l et s ; 1 0 0 - , 1 6 7 - , 2 5 0 - m g pow d e r f o r ora l so l u ­
P a r e n t e ra l : 5 0 m g/ m L ; powd e r t o rec o n st i t u te t i o n ; 2 - , 4-g powd e r for ped i at r i c so l u t i o n
for i n j e ct i o n ( 5 0 0 , 1 0 0 0 m g/v i a l ) Ora l ( V i dex- E C ) : 1 2 5- , 200-, 250-, 400-mg
To p ica l : 5 % o i n t m e n t d e l ayed-re l ease c a p s u l e s

A defovir (Hepsera) Efa virenz (Sustiva)

O ra l : 1 0 - m g ta b l ets Ora l : 50- , 1 00 - , 2 0 0 - m g ca ps u l e s ; 6 0 0 - m g tabl ets

A mantadine (generic, Symmetrel) Enfuvirlide (Fuzeon)

O ra l : 1 00-mg c a ps u l es , ta b lets ; 50 mg/5 m L syr u p Pare ntera l : 90 m g/m L f o r i n j e c t i o n

Amprena vir (Agenerase) Famciclovir (Fam vir)

O ra l : 5 0 - , 1 5 0 - m g c a p s u l es ; 1 5 m g/m L so l u t i o n O ra l : 1 2 5 - , 2 5 0 - , 5 0 0 - m g t a b lets
 A n t i v i ral Age n t s 4 1 9

Fomivirsen (Vitra vene) Ne/finavir (Viracept)

I n tra v i trea l : 6 . 6 m g/m L for i n ject i o n O ra l : 2 5 0 - m g t a b l ets ; 50 m glg powd e r

Foscarnet (Fosca vir) Ne virapine (Viramune)

P a re n t e ra l : 2 4 m g/m L f o r I V i n j ec t i o n O ra l : 2 0 0- m g t a b l et s ; 50 m gl 5 m L s u s p e n s i o n

Ganciclovir (Cytovene)
Oseltamivir (Tamiflu)
O ra l : 2 5 0 - , 5 0 0 - m g c a p s u l e s
O ra l : 7 5 - m g c a p s u l e s ; powd e r to r e c o n st i t u t e a s
Pare n tera l : 5 0 0 m glv i a l for I V i n j ec t i o n
s u s pe n s i o n ( 1 2 m gl m L )
I n t r a oc u l a r i m p l ant ( V i t ra s e rt ) : 4.5 mg
ga n c i c l ov i r/ i m p l a n t Pegin terferon a/fa-2a (pegylated interferon-a/fa

Idoxuridine (Herplex) 2a, Pegasys)

P a re n te ra l : 1 80 m cg/m L
O p h t h a l m i c : 0 . 1 % so l u t i o n

Imiquimod (Aldera) Pegin terferon a/fa-2b (pegyla ted interferon -a /fa

To p i c a l : 5 % c re a m 2b, PEG-In tron)
Pare n te ra l : powd e r to re c o n st i t u te a s 1 0 0 , 1 6 0 ,
Indina vir (Crixivan)
2 4 0 , 3 0 0 mCglm L i n j e c t i o n
O ra l : 1 0 0 - , 2 0 0 - , 3 3 3 - , 4 0 0 - m g c a p s u l es

Interferon a/fa-2a (Roferon-A) Penciclovir {Dena vir)

Pare n te ra l : 3 - , 6 - , 9 - , 3 6 - m i l l i o n I U v i a l s To p i c a l : 1 % c rea m

Interferon a/fa-2b (/ntron-A) Raltegra vir (/sentress)

Parente ra l : 3 - , 5 - , 1 0- , 1 8- , 2 5 - , a n d 50- m i l l i o n O ra l : 4 0 0 - m g t a b l ets
I U vials
Riba virin
Interferon a/fa-2b (Rebetron)
Aerosol ( V i razo l e ) : powd e r to r e c o n st i t u t e for
Parentera l : 3 - m i l l i o n I U v i a l s ( s u p p l i e d w i t h o r a l
aeroso l ; 6 gl 1 0 0 m L v i a l
r i ba v i r i n , 2 0 0 - m g c a ps u l es )
O r a l ( R e b eto l ) : 2 0 0 - m g c a p s u l e s
Interferon a/fa-n3 (A/feron N) Ora l ( R e be t ro n ) : 2 0 0 m g i n c o m b i n a t i o n w i t h
P a re n tera l : 5 - m i l l i o n I U /v i a l 3 - m i l l i o n u n i t s i n t e rfe r o n a l f a - 2 b ( I n t ro n -A )

In terferon a/facon - l (/nfergen)

Rimantadine (Flumadine)
P a re n tera l : 9- a n d 1 5 - m c g v i a l s
O ra l : 1 0 0 - m g ta b l et s ; 50 m g/5 m L sy r u p
Lamivudine (Epivir)
Ritona vir (Norvir)
Ora l ( E p i v i r ) : 1 5 0 - , 3 0 0 - m g ta b l ets; 1 0 mglm L
O ra l : 1 0 0 - m g c a p s u l e s ; 80 m gl m L ora l so l u t i o n
ora I sol u t i o n
O ra l ( E p i v i r- H BV ) : 1 0 0 - m g ta b l et s ; 5 m g/ m L Sa quina vir
so l u t i o n O r a l ( I n v i rase ) : 2 0 0 - m g h a rd ge l c a p s u l es
O r a l ( C o m b i v i r ) : 1 5 0-mg ta b l ets i n c o m b i n at i o n O ra l ( Fo rtovase ) : 2 0 0 - m g soft ge l c a p s u l e s
w i t h 300 mg z i dovud i n e
Stavudine (Zerit)
Ora l (Tr i z i r) : 3 0 0 - m g ta b l ets i n c o m b i n a t i o n w i t h
O ra l : 1 5 - , 2 0 - , 3 0 - , 4 0 - m g c a p s u l e s ; powd e r f o r
1 50 m g l a m i v u d i n e a n d 3 0 0 m g z i d ov u d i n e
1 mglm L ora l so l u t i o n
Lopina vir/ritonavir (Kaletra)
O ra l : 1 3 3 . 3 m gl3 3 . 3 mg c a ps u l es ; 400 mgl 1 00 Tenofovir (Viread)
mg p e r 5 m L so l u t i o n O ra l : 3 0 0 - m g ta b l ets

Maraviroc (Selzentry) Trifluridine (Viroptic)

O ra l : 1 5 0 , 3 0 0 m g ta b l ets To p i c a l : 1 % o p h t h a l m i c so l u t i o n
420 C H E M OT H ERA P E U T I C S

Va/acyclovir (Valtrex) Zidovudine (azidothymidine, AZT) (Retrovir)

O ra l : 5 0 0 - , 1 0 0 0 - m g ta b l ets Ora l : 1 00-mg c a psu l es , 300-mg ta b l ets, 50 mg/5 m L
syr u p
Va/gancyc/ovir (Va/cyte)
O r a l ( C o m b i v i r ) : 3 0 0 - m g t a b l e ts i n c o m b i n a t i o n
O ra l : 4 5 0 - m g c a ps u l e s
w i t h 1 50 mg l a m ivud i n e
Za/citabine (dideoxycytidine, ddC) (Hivid)
O r a l ( Tr i z i r ) : 3 0 0 - m g t a b l ets i n c o m b i n a t i o n w i t h
O r a l : 0 . 3 7 5 - , O . 7 5 - m g t a b l ets
1 5 0 mg l a m i v u d i n e a n d 3 0 0 mg z i d o v u d i n e
Zanamivir (Re/enza) P a r e n te r a l : 1 0 m glm L
I n h a l a t i o n a l : 5 m gl ro t a d i s k

REFERENCES i n the U n i ted S t a t e s . Med Leu Drugs Ther 2 0 0 2 ;

5 1 ( RR- 1 8 ) : 1 .
S a k e r D E : Pegyla ted i me r ferons. Rev Castroenterol Disord Sexual ly Tran s m i tted D iseases Tre a t men r G u i d e l i nes-2002.
200 1 ; 1 : 8 7 . Med Lett Drugs Ther 2 0 0 2 ; 5 1 ( RR-6) : 1 .
Cocohoba J M , McNicho l 1 T R : Valga nciclov i r: A n ad v a n ce i n W h i tley RJ : Herpes s i m plex v i r u s i n fec t io n . Semin Pediatr
c yro m e g a l o v i r u s r h e r a p e u rics. Arm Pharmacother Infect Dis 2 0 0 2 ; 1 3 : 6 .
200 1 ;36:2075. Yen i PG , et a l : An ri retrovi ra l t re a r m e n t fo r ad u l t H I V i n fe c­
D r u gs fo r n o n - H I V v i ra l i n fe c r i o n s . Med Lett Drugs Ther t i o n i n 2 0 0 2 . U pd a t e d reco m me n d a t io n s of t h e I n t e r ­
2002;44: 9 . n a r i o n a l AI D S S o ci e ty- U S A P a n e l . ]AJvfA 2 0 0 2 ;
Gea r y RS , et a l : Fo m i v i rs e n : C l i n i ca l p h a r m ac o l o gy a n d 288 :222.
p o r e m i a l d r u g i m e ra c ( i o n s . Clin I'harmacokinet 2 0 0 2 ; Relevant Websites
4 1 :255
www . a i d s i n fo . n i h . gov
Jo h n so n MA, er a l : Cl i n i c a l p h a rmacokinetics o f l amivud i ne.
www. c dc . go v
Clin Pharmacokmet 1 9 9 9 ; 3 6 : 4 1 .
www. h i v i n s i re . c o m
K i m berl i n OW, e t a l : S a fe ry a n d effi cacy o f h igh - d o s e i n t ra­
ve n o u s acyc l ov i r in t h. e m a n a g e m e n t o f ne o na ta l her­ Rehabilitation
pes s i m p l ex virus i n fec t i o ns . Pediatrics 2 0 0 I ; I 0 8 : 2 3 0 . Fisher S O , et al: I mpact of HIV a n d h i g h l y acrive a n ti re t ro­
La u e r G M , Wa lker B D : Hepari r i s C i n fe cr io n . N Englj Med viral t h e r apy on l e u kocy re ad h es io n m o l e c u l es , a r te r i a l
200 1 ;345:4 1 . i n fl a mm a t i o n , d y s l i p i d e m i a , a n d a t h e rosc l e ros i s .
M a l i k A H , Lce W M : C h r o n i c h e p a r i (is B virus i n fecrio n : A therosclerosis 2 0 0 6 ; 1 8 5 : I .
Tre a r me n r s rra tegies fo r r h e n e x t m i l l en i u m. Ann Intern G o o d m a n C c , B o i s s o n n a u l t WG , Ful l e r KS : Pathology:
Med 2 0 0 0 ; 1 3 2 : 7 2 3 . Implications for the Physical The rap ist, 2 n d ed . P h i l a d e l ­
Ma rci n O F, er a l : A co n r ro l l ed trial of val ga n c i cl o v i r as i n d u c ­ p h i a : S a u n d e rs , 2 0 0 3 .
r i o n r h e rapy fo r cy to m ega l ovi rus re tin iris. N Eng!] Med J o n es S P, e t a l : S h o r t - te r m exercise t ra i n i n g i m p roves b o d y
2002;346: 1 1 1 9. compos i tion a n d h y p e r l i p i d a e m ia i n H 1 V-pos i t i ve indi­

P i sc i re l l i S C , G a l l i c a n o K D : I n t e racr i o n s a m o n g d rugs fo r v i d u a l s w i th l i po d YS trophy. AIDS 2 0 0 I ; 1 5 : 2 0 4 9 .

J-l I V a n d o p p o r t u n i s r i c i n fec r i o n s . N Eng! ] Med Ro ubenoff R, e t al : Feas i b i l i ry o f i n c re as i n g lea n body mass
200 1 ;344 :984 in H I V- i n fecred ad u l ts u s i n g p r o g r e ss i v e res i s t a n ce

Qaz i N A , er a l : Lo p i na v i rl r i to na v i r (A ST- 3 7 8 f r) . Expert (ra i n i ng. Med Sci Sports Exerc 1 9 9 8 ; 3 0 : S 1 8 3 .

Opin Pharmacother 2 0 0 2 ; 3 : 3 1 5 . Ro u b e n o ff R , e t a l : A p i l o r s tu d y o f exercise t ra i n i ng to
Reco m m e n d a t i o n s fo r use o f a n t i r e r r ov i ra l d r u gs i n p reg ­ reduce tru n k fa t in ad u l ts w i t h. H I V- assoc ia ted fa t re d i s ­
n a n r J-l I V- l -i n fected wo m e n fo r m a te r na l hea l r h and t r i b u t io n . A IDS 1 99 9 ; 1 3 : 1 373-5 .
i n te rven t i o n s to red uce p e r i na t a l H I V- l r ra n s m i ss i o n