ANTIFUNGAL AND

ANTIPARASITIC AGENTS

n a "parasite" i n cl u d es all of the known infectious agenrs

the m os t ge n e r al sciencific sense,

I suc has viruses, b acte ria, fu n gi, pro[Qzoa (single-celled eukaryotes of the an imal kingdom),
and helminths (worms) that live in or on host tis s u e, gen e ra lly at the expense of the host.
Certain species of pa t'as i tes cause human i nfecrio n s . Some i nfections , esp ecially fungal, are com­
m on in bo th industrialized and u n d er de veloped nations and cause varying degrees of ill nes s
and d ebi li ty. Diseases caused by prorozoan and helminchic p a ras i tes are among the leadin g
causes of diseas e and death in tropic a l and subtropical regions. Many of t he s e infections are

incensifted by inadequate water sanitation and hygiene , and their management is h a mpered by
difficulty in con t roll i ng the vector (e . g ., mos quito, in the case of malaria). T his chapter describes
the most commonly used d r u gs to treat fu n ga l , protozoan, and helminthic i n fections .

ANTIFUNGAL AGENTS

Most hu m an mycoses-diseases caused by fungal infections-are m i n o r or superficial. However,

the i n cidence and sevetity of human fungal infect i o n s have increased d ta m a t i ca l ly over the last
few decades. This shift re fl ec ts the enormous number of immunocompromised patiencs (sec­
ondary to HIV and immunosuppressive d r u gs) who are at increased risk fo r i nv a sive fu n g al
in fe c t ion s , as well as the wi d esp r e a d use of b r oa d-spectrum ancimicrobials, w h ic h eliminate
com pe t itiv e n o np at ho ge ni c bacteria. In addition, fung i (especially Candida species) may be
i n tro d uce d into tissues that are norm ally resistant to invasion by, for e xa m p l e , central intravas­
cu l ar devices or hemodialysis.
Fungal infections are difficult to ueat for several reasons. First, selective roxiciry against
fu n gal cells (and not the human host's cells) is mo re difficult to achieve than for bacteria. Sec­
ond, many an cifungal agencs suffer from problems with solubility, sta bility, and a bs o rp t io n .
Third, fun g i read i l y develop resistance.
Fm yea rs, the mainstay of pharmacotherapy a ga ins t systemic fu n ga l infecrions has been the
polyene class of dru gs, especially amphotericin B. These drugs are roxic and azole agents (a different
chemical class) have been developed as al tern a tive antifu n gal drugs. However, owing [Q widesp read
use, azole-resistant o rganisms are becoming more wid espread . Recently, the n ew est class of anci­
fun g a J s- the echinocandins-has demonstrated improved safety, effi cacy, and [Qlerability.
Antifungals are generally classified on rhe basis of th ei r target site of action. The major
classes of a nt i funga l agenrs-azoles, polyenes, echinocandins, and terbinafine-kill fungi by
disrupting th e synthesis or function of fungal cellular m e mbr a n es . In co n t ras t, the fung ic i da l

421
422 CHEMOTHERAPEUTICS

Drugs acting on fungi

Alter cell Block nucleic Disrupt

membrane permeability acid synthesis microtubule functions

Azoles
I
Polyenes Terbinafine Flucytosine Griseofulvin

Figure 29-1. Fungal infections are difficult to treat, particularly in the immunocompromised patient. Most fungi are
resistant to conventional antimicrobial agents, and only a few drugs are available for the treatment of systemic fun­
gal diseases. Amphotericin B (a polyene) and the azoles are the primary drugs used in systemic infections. They are
selectively toxic to fungi because they interact with or inhibit the synthesis of ergosterol, a sterol unique to fungal cell
membranes. Echinocandins (not shown) Interfere with cell wall function.

ac( i ons of ( h e less i m portanc a gen cs, flucytosine an d p are n tera l) fo r system i c i n fect i ons, o ra l d ru gs for
griseofulvin, a re d u e [0 i ncer ference wi t h i n crace ll u l ar mucocutaneous i n fect i ons ( muco u s mem b ra nes and
fu ncr i ons (Figure 29-1 a n d 29-2). Cli n i ca lly, a n c i ­ s ki n ) , a n d [O pi c al d rugs fo r mucocu taneous i n fecri ons
fung a l d ru gs fa ll i nco severa l careg or i es: d ru gs (o r a l o r (Ta bl e 29-1).

Cytoplasmic membrane

������������
m
��� �
� Blocked by azoles Blocked by terbinafine

f£
0=- ... Ergosterol ...
I Lanosterol ",
I Squalene

Polyenes form
artificial pores
��
��
Nucleic
acids
Purines

Blocked by
flucytosine
�� Precursors

Figure 29-2. Sites of action of some antifungal drugs. The cell cytoplasmic membrane shown is that of a typ­
ical fungus. Because ergosterol is not a component of mammalian membranes, significant selective toxicity
IS achieved with the azole drugs. Echinocandins (not shown) cause disruption of the cell wall.
 Antifungal and Antiparasitic Agents 423

Table 29-1. Some important antifungal drugs

Class Drug Indications Toxicities

Allylamines Terbinafine, Tinea cruris, tinea corporis
(topical) naftifine,
butenafine
hydrochloride
Allylamines Terbinafine Onychomycosis Rash, gastrointestinal irritation,
(oral) taste disturbances, rare cases of
hepatic failure
Azoles FI uconazole Treatment and prophylaxis Gastrointestinal disturbances,
for cryptococcal meningitis rash, varyi ng degree of hepatic
Itraconazole Blastomyces and damage, drug interactions, visual
Sporothrix infections, disturbances (voriconazole)
subcutaneous
chromoblastomycosis
Voriconazole Invasive aspergi Ilosis,
candidemia
Posaconazole Prophylaxis of invasive
aspergi Ilosis, treatment
of oropharyngeal
candidiasis
Azoles Clotrimazole, Tinea pedis, tinea cruris,
(topical) miconazole, tinea corpons, vaginal
ketoconazole yeast infections, oral
candidal infections
Echinocandin Caspofungin, Candida infections,
micafungin, life-threaten i ng fungal
anidulafungin infections that are
resistant to amphotericin
and azoles
Flucytosine Cryptococcus neoformans Bone marrow impairment
and some Candida (anemia, leukopenia,
species thrombocytopenia)
Griseofulvin Dermatophytoses Skin rash, hives, gastrointestinal
irritation, photosensitivity,
drug interactions
Polyenes Amphotericin B Almost all life-threatening 1. Infusion-related: fever, chills,
(primarily systemic fungal functions muscle spasms, hypotension
parenteral) 2. Slower: renal damage
Polyenes Nystatin Localized candidal
(topical) infections in oropharynx,
vagina, and areas where
opposing skin rub together
424 CHEMOTHERAPEUTICS
Drugs for Systemic Fungal Infections
Amphotericin B
CHEMISTRY AND PHARMACOKINETICS. Ampho­
ter i cin B is a polyene agenr and one of the most impor­
tant d ru gs for the treatment of s yste mi c mycoses . It is
a v a i la b l e in oral, top ical , a nd p ar en te r al forms. Because
it is poorly absorbed , oral amp h ote ricin B is onl y effec­
tive aga i n s t fungi in th e lumen of the gas tro int es tinal
mICt. To p i cal forms are used for oral or cutaneous can­
didiasis. Am p h oter i c i n B is gener all y ad m i n i s t ered
in t ra ven o u sly as a non lipid colloi d al s us pe n sion , as a
lip id co mp l e x, or in a l i po s omal formulation. Devel­
opm ent of the laner fo rm has red u ced its nep h rotox i c­
i ty by d e c reasi ng no n s p eci fic bind i ng to human cell
mem b ranes, p e r m i tting the use oflarger doses. Ampho­
t e ric in B is wide l y distributed to al l tissues exce pt the
central nervous system (CNS). Th e re fore, treatmenr of
CNS fungal infec t i o ns ma y n eces s i tate i n r r a t h ecal
a dmin is tra tion . Am ph oter ic in B is p rima rily eliminated
by h e pa ti c m eta b o l ism . Hep atic impairment, renal
impairmenr, and d ial ys is have l i t tle effect on drug con­
centrations.
MECHANISM OF ACTION AND CLINICAL
USES. A m p h oter i c i n B kil l s fungi by b i n d i ng to
e rgo sterol (a m aj o r sterol co ns tit u e nr unique to fun ­
gal cell m e m b r a n e s) a n d for m i n g pores, which
results i n leakage o f ce l l u l ar contents and cell d eath
( Fi gu r e 29-2). Some b i n d ing to human cellular
m e m branes occurs, probably accou n t i n g for a m p h o ­
teri c i n 8's serious to x i ci ty .
Amph ote ri c in B h as the wid e st anrifungal s pec­
trum of any agent. It is cons i d ered the d rug (or co­
drug) of choice for t re a ting al mos t al l l ife-threatening
sy ste m i c infec tions caused by AspergilLus, BLastomyces,
Candida afbicans, Cryptococcus, Histoplasma, and
Mucor. It is ofte n used as the initial agen t within a
treatment reg i me n for serious fu ngal i nfec ti o ns , and is
then r e pl a ced by an azole for c h ro ni c ueatment o r
relapse p r eve n ti on . Amp h oter ic in B i s typically ad m i n­
iste red by slow i n t ra v e nou s i n fu s i o n continued to a
defined t o ta l d ose rather t han a d efined t i m e span .
Doses vary d epending on the pa r ticula r infection, but
it is no t uncom mon for p at i en r s to rece i ve d ai l y IV
t r e at m e nt for 6 to 12 weeks .
TOXlCITY. Toxic side effem of a m ph ote r i ci n 8 are
d ivid ed in to two cat egori es : imm ediate r e a ct i o n s
rel a ted to drug in fus i on and reac t i o n s tha t occur mo re
s l owly. Infusion-related adverse e ffects o f amphotericin
B are ex t r e m e l y com mOil. These in cl u de fever, chi l l s,
vomit ing, muscle spas m s, headach e, and s ign i ficant
h y p ote nsion oc c u r r i ng d u r ing i n fusion of rhe d r u g.
Slow i ng the in fu s i o n rare or decreasing the daily dose
may reduce these effects. In addition, pre m edicati on
with a n t i py retics , antiemetics, antihistam ines, meperi­
d i n e (an o p i oid analges ic) , or g l u coco r tico id s may be
prov ided ro partially ov ercom e infusion-related effeC[s.
The most s i gn i fi c a n t s l ower roxic i ty associated
with amphote rici n B is renal d am age . Nea r ly all pati ents
e x pe r i e nce some renal impairment, w i th reversible and
irrevers i ble co m p onen rs . The irrevers i b l e form of
nephroto x i c i ty usually results from p rolonged ad min­
istration. Srr ateg ie s to d ec re as e ne p h roto x i city incl u d e
concom itanr saline infusio n, dose reduc tion (m ade
pos s ibl e by ad d i ng ano t h er anrifu n ga l age nt), and the
u s e of l i p oso m a l formulations of a m p h o te r i c in 8.
Anemia may also result because of decreased renal pro­
duC[ion of erythro p o i e t in. Intrathecal administration
may caus e seizures and n euro l ogic damage.
Azoles
CHEMISTRY AND PHARMACOKINETICS. The
azoles are a class of an t i fu ngals named after the flve­
membered car bo n - n i t roge n ring in their structure. The
azoles used for s ys tem ic fu ng al infections include keto­
conazole, fluconazole, itraconawle, posaconazole,
and voriconazole. Fluconazole, pos a conazole, and
voriconazole are more reliably absorbed ora ll y than rhe
other azoles . The az ol es are dis t ri bu ted to m os t body
tissues, b u t drug levels a c h i ev ed in rl1 e CNS are very
low (w i t h the e x ce pt i on of fluconazole and poss i b l y
posaconazo le) . The liver m e tab ol iz e s ke toco nazole,
itraconazole, posaconazo l e, and voricona20le, and the
ki d n eys eliminate flucon azo l e .
MECHANISM O F ACT I O N . T h e azol es disrupt
membran e function of fu n ga l cells by i n te r fer i ng with
the s ynrhe s is of ergos te rol (F i g ure
29-2), a process uti­
lizing c y t oc h rome P450 e n zy m e s s i m i lar to human
P450 iso forms. Resista nce to azo les is becom i ng m ore
widesp r e ad owing to increased use of this class of dru gs

for lo n g- t erm prophylaxis of systemic mycoses in
i m m un oco m p ro m ised and neutropenic patients.
TOXICITY. As a group, the azoles are relatively non­
toxic. The most common adverse effects include minor
gast rointes tinal disturbances and rash. Varying degrees
of hepatotox i ci ty may occur, especia.lly in patiems with
impaired liver function. All azoles inhibit human hepatic
cytochrome P450s to some extent because of their sim­
ilarity to tbe fungal target enzymes . T hus, patients tak­
ing azoles (especially ketoconazole) in combination with
other drugs may have higher plasma concentrations of
d r u gs that are primarily metabolized by the cytochrome
P450 system. In addition, inhibition of human
cytochrome P450 ( espec i al ly by keroconazole) interferes
with sy nr hesis of ad renal an d other steroids, which may
lead to gy neco m astia, menstrual irregularities, or infer­
tility. Because it cau se s more adverse effects than the
other azoles, ketocon azole is rarely used for systemic fun­
gal infections, and is now m os cl y used for chronic muco­
ClICaneous and de r m arologic fungal infections.
Specific Azoles
FLUCONAZOLE. Because of its high oral bioavail­
ability, re / ative ly good gastroinrestinal tolerance, and
fewer effects on hepatic enzymes, fluconazole has the
highest therapeutic index of all the azoles. Fluconazole
is the t r ea t ment of choice for initial treatment and sec­
ondary prophylaxis for c r yprococcal meningitis, and
is also used in treating acrive infection due ro Crypto­
coccus neoformans. It is effective against esophageal and
oropharyngeal candidiasis, vaginal candidiasis, can­
didemia, and most infections caused by Coccidioides.
ITRACONAZOLE. I t r aconazole is effective against
many s ys tem i c fungal infections caused by Blastomyces
and Sporothrix and for subcutaneous chromoblasto­
mycosis (chronic, localized skin and subcutaneous tis­
sue i n fectio n that follows traumatic implantation of
one of several different fu n gal species). It can be used
as t he p r i m ar y or alternative drug for treating infec­
tions caused by Aspergillus, Coccidioides, Cryptococcus,
and Histoplasma. It is also used extensively in the treat­
m e n t of dermarophytoses and onychomycosis.
POSACONAZOLE. This newest azole has been rec­
ommended for prophyLu,is of invasive aspergillosis in
Antifungal and Antiparasitic Agents 425
h igh -risk immunocompromised patients and for treat­
menr of oropharyngeal candidiasis, including cases
refractory to irraconazole and fluconazole. The full
clinical usefulness and toxic potential of posaconazole
are not yet established.
VORICONAZOLE. Voriconazole is well absorbed
orally and has an even wider spectrum of antifungal
activity than itraconawle. It is replacing amphotericin B
for the treatment of invasive aspergillosis because of
greater efficacy with less toxicity. Voriconazole has also
been used as an alternative drug in candidemia and in
AIDS patiems for the treatmenr of candidal esophagi­
tis and stomatitis. In addition to the adverse effects
common to the azoles, voriconazole has been reported
to cause transient visual disturbances in more than
30% of patients.
Flucytosine
CHEMISTRY AND PHARMACOKINETICS. Flucy­
tosine (5-fluorocytosine, 5-FC) is related to the anti­
cancer drug fluorouraciL Unlike amphotericin B, it is
effective orally and is distributed to most body tissues,
including the CNS. To avoid toxic accumulation,
serum concentrations are monitored regularly and
dose reductions are made for patients with renal
impairment.
MECHANISM OF ACTION AND CLINICAL USES.
Flucytosine is preferentially taken up by fungal cells,
where it is enzymatically converted to a compound
that inhibits deoxyribonucleic acid (DNA) and
(RNA) synthesis, thus preventing for­
ribonucleic acid
mation of fungal proteins (Figure 29-2). When used
as a single-drug therapy, resistance to flucytosine
emerges rapidly. Co-treatment with amphotericin B
decreases the likelihood of resistance and produces syn­
ergistic fungicidal effects.
The antifungal spectrum of flucyrosine is fairly
narrow; it is active against yeasts such as Cryptococ­
cus neofo rmans and some Candida species. To pro­
vide optimal fungicidal effects and reduce resistance,
flucytosine is given in combination with ampho­
tericin B or fluconazole. T hese drug combinations
may be used to treat susceptible candidal septicemia,
endocarditis and urinary tract infections, cryptococcal
426 CHEMOTHERAPEUTICS
meningitis (one of the most common oppo[[unistic
CNS infections in AIDS patienrs), and pulmonary
infections.
TOXIClTY. The most common adverse effects result
from the metabolism of flucytosine ro the anticancet
drug fluorouracil. Reversible impairment of bone mar­
row function results in anemia, leukopenia, and
thrombocytopenia. Less commonly, flucyrosine causes
liver dysfunction. Patients' blood concentrations and
renal function are monirored during drug therapy to
avoid toxic accumulation.
Echinocandins
CHEMISTRY AND PHARMACOKlNETICS. Echino­
candins represent the newest class of anrifungal agents,
wirh a novel mechanism of action. Currently, three
agents are available in this category: caspofungin,
micafungin, and anidulafungin. Because these drugs
are not well absorbed orally, they are only administered
intravenously. Caspofungin distribmes widely to most
tissues except the cerebrospinal fluid (CSF). However,
despite low CSF concentrations, positive results have
been reported with caspofungin in the treatment of
cerebral aspergillosis. Doses are decreased in patients
with severe hepatic impairment.
MECHANISM OF ACTION AND CLINICAL USES.
The echinocandins inhibit an enzyme present in fun­
gal, but not mammalian cells. The result is impaired
synthesis of �(l-3) glucan, an essential component of
fungal cell walls. The echinocandins are used for the
treatment of patients with candidemia and other forms
of Candida infections (esophageal candidiasis, peri­
tonitis, and intra-abdominal abscess). Early studies
suggest that the potential for development of resist­
ance to the echinocandins is low, suggesting that this
class of ant ifungal agents may be used as therapy in
life-threatening fungal infections (e.g., invasive
aspergillosis) with strains that are no longer susceptible
to conventional antifungals such as amphotericin B
and the azoles.
TOXICITY. To date, excelle"nt tolerability and safety
have been reponed with the echinocandins. Compared
with the other systemic antifungal agents, very few drug
interactions have been reported with caspofungin.
Systemic Drugs Used in Mucocutaneous
Fungal Infections
Mucocutaneous fungal infections include the superfi­
cial infections of skin, mucous membranes (including
the oropharynx and vagina), and the nails. These dis­
orders are confined to the cutaneous surFace, with lit­
tle likelihood for systemic proliFeration. Commonly,
these include infections with Candida organisms, usu­
ally C albicans. The severity of diseases may range from
relatively minor cosmetic inconveniences such as ony­
chomycosis (chronic fungal infection that affects toe­
nails more commonly than fingernails) to oral thrush,
which is a painful candidal infection that is often the
first manifestation of local or systemic immunosup­
pression. AJthough mucocucaneous fungal infections
are superficial, topical drug application alone is often
ineffective because of insufficient penetration into
;:tffected tissues. This is especially true with ony­
chomycosis, in which rapical antifungal agents are
unlikely to penetrate through all nail layers.
Griseofolvin
Griseofulvin is used to treat dermatophytoses-fungal
infections of the skin, hair, and nails. Griseofulvin's oral
absorption is variable, but can be optimized when
patients take ultramicrosize formulations with a high-fat
meal. Griseofulvin interferes with microtubule forma­
tion in dermatophytes (Figure 29-2). It is deposited in
keratin precursor cells, which are gradually exfoliated and
replaced with noninfected tissue. Griseofulvin remains
bound ra new keratin, protecting the skin hom new
infection. To allow for replacement of infected keratin
by newly resistanr keratin, griseofulvin must be admin­
istered for long periods of tinle: 2 to 6 weeks for skin and
hair infeccions ,md for at least 6 months for toenail infec­
tions. However, the use of griseofulvin is plagued by high
relapse rates, especially for onychomycosis. Tile most
common adverse reactions include skin r;:tshes and
urticaria (hives). Other side effects include gastrointesti­
na.l irrit;:ttion, mental confusion. headache, and photo­
sensitivity. Drug interactions occur with warfarin,
phenobarbital, and alcohol. In addition, griseofulvin may
increase the rate at which hepatic enzymes metabolize
estrogens, possibly decreasing effectiveness of conuacep­
tives and producing menstrual irregularities.

Terbinafine
Terbinaflne has generally replaced griseofulvin in the
treatment of onychomycosis. Terbinafine inhibits a
fungal enzyme and results in accumulation of a sub­
stance toxic to the fungus. Terbinafine offers a shorrer
treatment regimen, higher cure rate, lower relapse rate,
and fewer adverse effects than griseofulvin. Daily oral
treatment for 12 weeks may result in a clinical cure
rate as high as 60 to 75%. Adverse reactions include
gastrointestinal upset, headache, rash, and taste dis­
tutbances. Rare cases of hepatic failure have been
reponed with the use of terbinaflne in individuals with
and without preexisting liver disease. Consequently,
liver enzyme levels and a complete blood count are
obtained before terbinafine is initiated and repeated
every 4 to 6 weeks during treatment.
Topical Antifungal Drugs
A number of dermatologic fungal infections such as
ringworm, jock itch, and athlete's foot as well as some
localized (oral, vaginal) candidal infections may be suc­
cessfully treated with topical antifungal agents. Topical
agents can be divided into three major categories: poly­
enes, azoles, and allylamines.
Nystatin is a polyene agent similar to ampho­
tericin B. It acts by disrupting fungal cell membrane
permeability, resulting in cell death. Because its toxic­
ity precludes systemic use, nystatin is only used topi­
cally; tbe drug is not significantly absorbed from skin
or mucous membranes. Nystatin (as powder, cream,
ointment, or vaginal tablet) is commonly used to treat
localized candidal infections in the oropharynx, in the
vagina, and in areas where opposing skin surfaces may
rub together, such as around tbe perineum or under
the breasts. Localized infections can be cured tapidly,
often within 24 to 72 hours after treatment initiation.
T he most common ropical azole agents are clotri­
mazole and miconazole. Both are available with a pre­
scription as well as over-the-counter (OTC) as creams,
powders, sprays, or vaginal suppositories. Clorrimazole
and miconazole creams are used for the effective treat­
ment of tinea pedis (athlete's foot), tinea cruris (jock
itch), and ti nea corporis (ringworm). Vaginal clotrima­
zole suppositories are used in the rreatment of vaginal
yeast infections. Oral c1otrimazole lozenges (called
Antifungal and Antiparasitic Agents 427
troches) are used to treat oral candidiasis infections
that commonly occur in immunocompromised indi­
viduals. Systemic absorption is minimal and adverse
effects are rare.
Topical allylamine creams are available by pre­
scription for the rreatment of dermatologic fungal
infections such as tinea cruris and tinea corporis.
These include terbinafine, naftifine, and butenafine
hydrochloride.
ANTIPARASITIC AGENTS
A large number of protozoa and helminths are capable
of infecting humans. Drugs designed to kill these par­
asites must tal<e into account their complex life cycles
and the differences berween their metabolic pathways
and those of the host. Thus, drugs acting against pro­
tozoa are usually inactive against helminths and vice
versa. Because protozoa and helminths are eukaryotes,
they are metabolically more similar to humans than are
bacteria. Although some antibacterial agents have
antiprotozoal activity (e.g., metronidazole and doxycy­
cline), most are ineffective against eukaryotic parasites.
Rational approaches to antiparasitic chemotherapy
use the principle of selective toxicity, which exploits the
biochemical and physiologic differences berween para­
site and human host cells. Many antiparasitic agents act
on targets (usually enzymes) that are either unique to
the parasite, or that possess sufficient differences
berween host and parasite to allow safe drug activity.
Despite differences berween host and parasite, man)' of
the more effective amiparasitic drugs have significant
toxicity and their use has to balance benefit against risk.
Climatic changes and imernational travel have
facilitated the spread of many parasitic diseases, while
starvarion and poor sanitation that accompany poverty
and war have promoted the reemergence of others.
Drug resistance has also dramatically influenced rhe
ability [Q treat and control many parasitic diseases.
Antiprotozoal Drugs
Protozoa are unicellular eukaryotic organisms. The para­
sitic protozoa that cause disease in humans either require
the invasion of a suitable host to complete alJ or part of
their life cycle, or they present as feee-living protozoa that
428 CHEMOTHERAPEUTICS

within RBCs (e.g., chloroquine, quinine) can cure most

of these infections if tne parasite is not drug resistant.
On the other hand, P ovate and P viVa:< can remain
Antimalarial Drugs for Drugs used dormant in tne liver for months or years. Subsequent
agents amebiasis for
malaria relapses can occur after successful pharma­
I I I cotherapy directed against the erythrocytic parasites.
Chloroquine Metronidazole Pneumocystosis
M e fl oqu i n e Diloxanide Toxoplasmosis To cure these infections, an antimalarial agent tnat
Primaquine Emetine Leishmaniasis eliminates liver parasites must be used in conjunction
Quinine lodoquinol T rypanosomiasis with agents that eliminate erythrocytic parasites. No
Antifolates
Others single available antimalarial agent can reliably bring
about a radical cute; that is, eliminate both hepatic and
Figure 29-3. Diseases caused by protozoans constitute a
erythrocytic stages.
worldwide health problem. Antlprotozoal drugs are used to
combat malaria, amebiasis, toxoplasmosis, pneumocystosis, T he major drugs used in malarial prophylaxis and
trypanosomiasis, and leishmaniasis. rreatment are snown in Table 29-2. For many agenrs,
antimalarial activit), is due to either inrracellular accu­
mulation of a compound roxic to the parasite (e.g.,
may become pathogenic in immunocompromised indi­
chloroquine), interference with parasitic DNA replica­
viduals. Condirions caused by prorowa include malaria,
rion (e.g., quinine), or inhibition of critical enzymes
amebiasis, roxoplasmosis, pneumocystosis, trypanoso­
involved in folic acid synrhesis (e.g., pyrimethamine,
miasis, and leishmaniasis (Figure 29-3).
proguanil, sulfadoxine). For other drugs, tne antimalar­
ial mechanism of action is not clear (e.g., halofantrine
Drugs for Malaria
and doxycycline). Since parasites are increasingly resistanr
In rerms of annual mortality, malaria remains the
to multiple drugs, no chemoprophylactic regimen is fuUy
most imporrant tropical parasitic disease. T he World
protective, and treatmenr for malaria depends on knowl­
Health Organization esrimates that malaria kills over
edge of changing resistance patterns.
2.5 million people yearly, wirh the majoriry of deaths
The first line of defense against malaria is limiting
occurring in children under the age of 5 years in sub­
contact with mosquitoes by using mosquito repellent,
Saharan Africa. AI rho ugh four Plasmodium species
keeping arms and legs covered, st aying indoors during
infect humans (Pfo!ciparum, P rnalariae, P ovale, P vivax) ,

mosquitoes' feeding hours (dusk and rhroughout the

P folciparum is responsible for the most serious life­
night), and sleeping under mosquito netting. Physical
threarening complications and death. Transmission
therapists involved in the Peace Corps, Health Volun­
most commonly occurs when an infected mosquiro
teers Overseas, or other inrernationaJ organizations are
injects the infectious form of the parasite, the sporo­
likely ro practice in malaria endemic areas. Prior to
zoite, into the individual's blood. Sporozoites circu­
leaving home, individuals should consult the Centers
late ro rhe liver and infect liver cells. Here, they
for Disease Control and Prevention (CDC) (http://
reproduce to form merozoites, which eventually leave
www.cdc.gov/travel!destinat.htm; or telephone 877-
the liver, reenter the bloodstream, and invade red
FYI-TRIP) for current recommendations regarding
blood cells (RBCs). Parasites mature within RBCs, are
specific antimalarial chemoprophylaxis, resistance pat­
released, and continue infecting more RBCs. Ar this
terns, and treatmenr if malaria is contracted.
stage of infection, clinical disease is manifested by
recurrent flu-like attacks, fever, severe anemia, and, in CHLOROQUINE, MEFLOQUINE, AND ANTlfO­

some cases, cerebral malaria and death. LATE AGENTS (PYRIMETHAMINE/SULFADOX­

In P falciparum and P ma lariae infections, only lNE). Chloroquine, long considered the drug of
one cycle of liver cell invasion and multiplication choice for prophylaxis and treatment of malaria, is no
occurs. Liver infection ceases spontaneously in less longer considered the first-line antimalarial agent in

than 4 weeks. In this case, dtugs that eliminate parasites many counrries owing to worldwide prevalence of
 Antifungal and Antiparasitic Agents 429

Table 29-2. Drugs used in malaria

Use for Eradication

Drug Use in Acute Attacks? of Liver Stages? Use for Prophylaxis?
Chloroquine Yes No Yes, except in regions where
P falciparum is resistant
Quinine, Yes, in resistant No Yes, mefloquinel is used in regions
mefloquine P falciparum with chloroquine-resistant
P falciparum
Primaquine No Yes Yes, if exposed to P vivax or P ovale

Antifols Yes, but only in No Not usually advised as si ngle agents

resistant P falciparum
Artemisinins Yes No No

lOoxycycline or atovaquone-proguanil (Malarone) are also recommended for chemoprophylaxis in regions where chloroquine­
resistant P fafciparurn are endemic,

chloroquine-resisranr parasites, In regions where P
Jdciptlrum is not resistanr, chloroquine is used for
chemoprophylaxis and for acute attacks of falciparum
and nonfalciparum malaria, Chloroquine is generally
well rolerated, even with prolonged use, The most
common adverse effects are gastrointestinal upset, skin
rash or itching, and headaches, Consumption of calcium­
and magnesium-conraining anracids should be avoided
because they significantly decrease oral chloroquine
absorption, Dosing after meals may reduce some
adverse effects, Long-term ad ministration of high
doses may cause sevete skin lesions, peripheral neu­
l'Oparhies, myocardial depression, retinaJ damage, audi­
[Ory impairment, and roxic psychosis,
Common alternatives for treating chloroquine­
resIstant strains include m e A oqune
i ,
include gastroinrestinal d istress and rash, Mefloq uine
causes headache and d izziness, Severe neuropsychiatric
disturbances such as depression, confusion, acute psy­
chosis, or seizures have aJso been reported with meflo­
quine, Toxicities for rhe antifolate compound s include
hemolysis and kidney damage, The toxicity of malarone
iIlclud es gasrroimestinaJ disturbances, headache, and rash,
QUININE. Quinine is the original antimalarial drug
that is derived from the bark of the native South Amer­
ican cinchona tree, Quinine (emains rhe drug of choice
for life-rhreatening malaria. Quinine acts rapidly
against all four species of human malaria parasites in
erythrocytes, Irs main use is in treating chloroquine­
resistant falciparum malaria, However, quinine is often
used in combination with a second d rug (doxycycline
combined
or c 1 indamyc i n ) to limir toxicity by shortening its d ura­

pyrimethamine/sulfadoxine (antifolate agents), and

tion of use (generally to 3 days), Quinine is generally
atovaquone/proguanil (Malarone), but resistance is
not used in chemoprophylaxis because of toxicity and
emerging [0 mdloquine in some regions (parts of South­
potential increases in parasitic resistance to these
east Asia), and significant resistance to the antifolate
agents, Therapeutic d oses of quinine commonly cause
agenrs is now common for P folciptlntm and less com­
cinchonism, Milder symptoms of cinchonism such as
mon for P vivtlx, Malarone is becoming the preferred gastrointestinal distress, headache, vertigo, blurred
prophylactic agenr for travelers [0 Africa and has shown vision, and tinnitus do nor warrant discontinuation of
efficacy for treatmenr of active maJaria, Common adverse the drug. Higher doses of quinine result in cardiac
effects of mefloquine and rhe antifolate compounds conduction disrurbances, In some individuals wirh
430 C H E M OT H E RAPEUTICS

h y p e rs e ns i tivi ry, severe blood d i so rd e rs can occu r.
Therapy is d i sco n t i n ued inhypersensitive p a r i e n ts a n d
r h o s e w i rh severe cinchonism.
PRI MAQU INE. Pri maq u i n e i s r h e o n ly drug avai lable
ro e ra d i ca te l i ve r s tage p a r asi t e s o f P vivax a n d P ovale
a n d s h o u l d be used i n co nj un c t i o n w i th an a n t i mala r­
ial e ffective aga i n s t parasi tes w i thi n R B C s . I t is gener­
all y w e ll rol era ted , b u r s o m e t i mes causes n a u s e a ,
headache, and epigas tric pai n . Because i t can produce
severe hem o l ys i s i n p a t ie n ts w i th g l ucose- 6-phos phate
d e hy d rogenase ( G 6 P D ) deficiency, pers o n s fo r whom
th is age n t is b e i n g cons i d e red m u s t be eva l u a red fo r
G6PD e nzyme l eve l s a n d the d r ug s h o u l d n o t be used
in those who are G6PD deficient.
A RTEMI S I N IN . The m o s t i mp o r ta n t newe r an t i ­
ma larial co m p o u n d s a re derivati ves o f a r tem i s i n i n (an
extracr o f the Chinese herbal remedy q u i nghaos u) .
T h ese agents co m b i n e rapid a n t i m a l a r i al a cti v i ry with
a n a bsence o f c l i n i c a l l y i m porta n t res is rance: they are
r h e o n l y d r u gs re l i a b l y effective a ga i n s t q u i n i ne ­
res i s ca n t s t ra i n s . B e c a u s e of their s h o r t h a l f- l i v e s ,
arre m i s i n i n a nd i ts a n a l ogs arres u na te a n d artemerher
a re ge n e ral ly used wirh a n o ther a n t i m a larial age n t a n d
a re n o t usefu l i n chemo prop hylax i s . Al t h o u g h the y
a p p ea r ro be b e t te r rolera ted t h a n most anti mala rials,
the attemisin ins a re cu rre n tly ava il a b le in the Uni ted
Sta tes a n d Ca n a da o n l y on s p ec i a l req u e s t , b u t a re
widely available i n Afr i ca and Asi�1 .
Drugs for Amebiasis
Ame b i a s i s i s i n fection w i t h Entamoeba histolytica.
Although ameb iasis occu rs worldwide, ir is most preva­
l e n t in tropical and s u b trop ical a reas , especia l l y in
crowd ed an d u nsani ta ry l i v i ng condi tions. The orga n­
ism Jives and rep rod u ces o n the mucosal su rface of the
latge i n tes ti ne. En cys ted forms period i cal ly pass Out in
t h e feces, and c a n s u rv i ve i n the external e nv i ro n m e n t
and a c t as i n fective fo r m s . I n fection w i th E histolytica
occu rs as a res ult o f i n adequa te s a n i tati o n , o r when food
or d ri n k i s co n ta m i n a ted by i n fected food h a n d l e rs .
Ingested cysts a d h e re to i n te s t i n al e p i thel ial ce l ls and
invade the mu cosal l in i ng. E histolytita can ca use asymp­
ro m a t i c i n tes tinal i n fec r i o n , m i l d to moderate coli ris,
m i l d diarrhea, severe i n tesrinal i n fection ( a mebic dysen­
rery ) , l iv e r a bscess, and orher exrra i n resr i na l i n fecrions.
D r u gs fo r a m e b i a s i s Crable 29-3) i n cl u d e tiss ue
a m e b i cides (ch l oroquine , e m etines, metronidazo l e) ,

Ta ble 29-3 . Drugs used in the treatment of protozoa l i nfections other than ma laria

Drugs of C h o i c e P r i m a ry I n d i ca t i o n s
D i l oxa n i d e f u r o at e Asym pto m a t i c intestinal amebiasis
M e l a r sop r ol Drug of c h o i c e in Afri c a n sleepi n g s i c k n ess ( l a te , e N S stage of
trypanosom iasis) ; a lso used i n m u c o c u t a n e o u s f o r m s of t h e d i seas e
M etronidazole plus diloxan ide M i ld to severe i ntest i n a l ame b i asis
or iodoq uin o l
Metron i d a zole plus diloxa n i d e , H e pa t i c a bscess f o r m of a mebia s i s
fo llowed by p a romomy cin
N i f u rt i mox Try panosom i asis ca used by Trypanosoma cruzi
Pen t a m i d i ne H e m oly m p h at i c stage of t ryp a no s o m ias i s ; a l so used In Pneumocystis
jiro veci pne u mo n ia
Pyrimetha mine plus sulfad i a z i ne D r u g c om b i n a tio n of c h oi c e i n toxo pla smos i s
S o d i u m st i bog l u c on a t e D r u g o f c h oi ce f o r lei s h m a n i as i s ( all s pec i es)
S u r a mi n Drug of choice for h e mo l y m phat i c stage of trypanosom i a s i s (T brucel
gambiense, T rhodesiense)
Trimethopri m-su I f a met hoxazo l e D r u g com bina t i on of cho i ce i n P jiro veci i n fe c t i o n s

w h i c h J c t o n o r gan i s m s i n t h e bowel w a l l a n d t h e
liver; a n d l u m i n a l a m e b i c i d es ( d iloxanide furo a re,
iodoqu i n o l , p a romo mycin) , w h i c h act only i n the
l u men o f the bowe l . D r ug c h o ice depends o n the ty pe
of amebic infectio n .
D I LOXA N I D E F U ROAT E . For as y m p r o m a t i c d i s ­
ease ( ca r r i e rs w i t h n o s y m p ro m s i n n o n e n d e m i c
a re a s ) , d i l oxa n ide fu roare is t h e fi rs t cho i ce . T h i s d r u g
i s we l l to l e rated . w i th u s u a l l y m i l d gas t ro i n ce s t i n a l
s y m p to m s .
M ET RO N I D A ZO L E . F o r m i l d t o severe i n tes t i n a l
i n fe ct i o n , l i ve r a b s ces s , a n d other extra i n ce s t i n aJ a m e ­
b i c d isease, m e t ro n i d azo le i s ge nerally u s e d i n c o n ­
j u nG i o n with a l u m i n a l a me b i c i d e . Adverse e ffects o f
metro n idazo l e i n c l u d e ga s t ro i n cesti n a l i r r i ta t i o n ,
headache. a n d , l e s s freq uendy, l e u kopen i a , dizzi n ess,
; Hld a tax i a . (See C h a p te r 3 0 fo r fu rther d iscussi o n of
metro n i dazole.)
E M E T I N E A N D D E H Y D RO E M ETIN E . E m e t i n e
and de h y d r oe m e t i n e m a y sti l l be used a s back- u p drugs
fo r rreatmen t of severe i n testinal or hepatic ameb iasis
in h o s p i ta l i zed
p a r i en ts . Howeve r, because t hey may
ca u s e severe tox i c i lY (i n c l u d i ng gast roi n tes tinaJ dis tress,
muscle w e a k n.ess, a n d card i ovasc u l a r dysfu n c t i o n ) ,
they have b ee n m os tly re p l a ced by metro n i d azo le.
Drugs for Pneumocystosis and Toxoplasmosis
Pn eumocystis jiroveci ( fo r m e r l y caJ led P carinil)
cause of h u m a n p n e u mocys tos i s . Al though n ow rec­
o gn ized as a fu ngus, Pji ro veci is res ponsive to a n t i p ro­
towal d r ugs , n o t a n t i fu n ga l s . Co m m o n ly fo u n d i n
normal h u ma ns, t h e fu n gu s causes sympromatic d is­
ease o n l y in i m m u ne-deficient i n d ividuals. Th u s , the re
is a high i n cidence o f P jiroveci pneumon i a in patie n ts
rec e i v i ng i m m u n o s u p p ress i v e t h e rapy a n d in patie n ts
wi th A I D S .
TRl M ET H O P R1 M P L U S S U LFAtvl E T H OXAZOLE.
Tr i m e t h o p ri m p l us s u l fa m e thoxazo l e (TMP-SMZ)
i s [he fi rs t - l i n e therapy fo r P jiroveci p n e u m o n i a .
TMP- S M Z i s a l so used a s a chemop rophylac tic d rug
co m b i n a t i o n fo r p r e ven t i o n o f P jiroveci i n fec tio n i n
i m m u n oco m p rom i s e d i n d i v i d uals. While che m o p ro­
p hy l a cr i c doses a re genera Ll y m u c h bett e r to lerated
than trea tme n t fo r active i n fectio n , h i gh-dose therapy
A n t i fu n ga l and A n t i p a r a s i t i c A ge n ts 43 1
e n tails s i g n i fi c a n t rox i c i ty i n up to 5 0 % o f AI D S
p a t i e n ts . I m portant toxici ties i nc l u d e gas tro i n testi nal
d i s t ress, ras h , fever, n e u trope n i a , and thrombocytope­
nia. These adverse effects may be severe enough to war­
r a n t d is co n t i n u a n ce of T M P - S M Z . Because o f t h e
high prevaJence o f serious adverse e ffects w i t h TM P­
S M Z , several d r ugs h ave b e e n used a s a l te r n a t i ve
agen ts aga i n s t P jiroveci i n fectio n . Nota bly, n o n e is as
effective as TM P - S M Z .
PENTAM I D INE. Pen ta m i d i n e i s a we l l -esta blished
alternative d r u g fo r P jiroveci i n fe c ti o n . Fo r pro p h y­
laxis, p e n ta m i d i n e is a d m i n i s tered as an i n h a l ed
aeros o l . Al t h o ugh wel l tolera ted in this fo rm, i t is n o t
as e ffec t ive as d a i ly T M P - S M Z . Fo r trea t m e n t o f
active P jiroveci i n fecti o n , p e n ra m i d i n e m u s t be
ad m i n i s te red p a r e n r e ra l l y. S e r i o u s a d ve rs e e ffects
res u l t fro m p a re n te ra l ad m in is trati o n , i n cl u d i n g res­
p i ra to ry s t i m u l ation fo llowed by res p i ra to ry dep res­
s i o n , severe hypo t e ns i o n , hypoglyce m i a , a n e m i a ,
n e u tro p e n i a , hepatitis, a n d p a ncrea ti tis .
ATO VA QUO NE. Atovaquone is an o ral drug i n i ti al l y
develo ped a s an a n t i malarial, b u t i t h a s also been
approved for the treatment o f m i ld ( Q modera te Pjiroveci
p n e u m o n ia. Al t h o ugh l ess effective than TMP-SMZ
or penram idine, i t is better tolerated. Adverse effects
i ncl ude fever, ras h , co u g h , n a usea, vom i ti n g, d ia r r h e a ,
a nd ab normal l i ve r fun c t i o n tests.
is the
Drugs for Toxoplasmosis
Toxop l a s m o s i s is i n fection w i t h ToxopLasma gondii.
I n fect i o n occu rs by i nges t i ng oocysts released i n t h e
feces o f i n fected cats ( p r i m a r y hosts) o r by e a t i n g raw
meat contai n i n g tiss u e cys ts. I n fection with this p ro ­
tozoan is w i d espre a d , b u t i s n o t s e r i o u s u n less i t i s
acqu i red (or reactivated) in i m m u n os u p p ressed
p a t i e n ts o r acq u i red d u r i n g p regn a n cy, when the
o rga n ism i nvades aJl fe tal tissues, especia l ly t h e CNS.
Damage to the eye i s the most common consequence,
al t h o u gh the b rai n may also be affected .
The a n t i fo l a te age n ts pyrimethamine w i t h sulfa­
di azi ne (or w i th clindamycin in patients allergic to sul­
fo n a m i d es) a re used fo r treatm e n t o f co nge n i tal
toxo plasmosis a n d a c u t e i n fec t i o n i n i m m u noco m ­
p r o m ised i n d ivi d u a l s . I n AI D S - re l a ted Toxoplasma
e n cep h a l i tis, h igh-dose trea t m e n t m u s t be given fo r
432 C H E M O T H ERAP E U T l CS
m a ny weeks a n d is a ss o ci a te d w i t h ga s t r i c i rr i tatio n ,
n e u rologi c sym p r o ms (headaches, i ns o mn i a , tre m o rs,
seizu res) and se ri o u s blood a b n o rma l i ties. Spi ramycin
is an a n t i b i o t i c t h a t is u sed ro treat r oxo p l a s m o s i s
a c q u i re d d u r i n g pregn ancy. Treatmen t lowers the risk
of deve l o p me n t o f conge n i ta l ro x o pla s m o s i s .
Drugs For Trypanosomiasis
T h e p ro tozo a n g e n u s Trypanosoma co nta i ns th r e e
s p ec i e s t h a t c a u s e h u m a n d i s e a s e . I n fe c t i o n s w i t h
T ga m biense a n d T rhodesiense cause Afri ca n t ry
p a n o s o m i as i s ( A fr i c a n s l ee p i n g sickness) , a n d T cruzi
i n fe c t i o n causes Am e r i c a n t typ a n o s o m i a s i s ( Chagas
d i sea s e ) . Trypanosom i as i s is t ra n s m i t te d by the b i te of
i nfe c t e d i n s e c t vec tors, which a re the t sets e fl y fo r
African t r y pa n oso m i as i s a n d red uviid b u gs fo r Am e r
i c a n trypa n oso m i a s i s . Curre n r l y ava i l a b l e d r ugs fo r al l
fo r m s of rr yp an oso m i a s is are seriously defici e n t i n both
e ffi c acy a n d s a fe ty. Avail a b i l i ty of these d rugs is also a
co nce r n : t h e CDC c l a ss i fies several of these dr ugs as
i n ve s t i g a t i o n al a ge n t s , s u p p l y i n g them o n l y u p o n
req u e s t . So me of t h ese d r u gs i n c l u d e bithiono l , dehy­
droemetine, diethylcarbamazine, melarsoprol, ni fu r­
timox, sod ium stibogluconate, a n d suramin.
SURAMIN AN D PENTAM l D I NE. After a b i te by an
i n fe cted tsetse fly, wi des p read lym ph node e n l a rgement
occurs a n d the o r ga n i s m esta bl ishes i n t h e blood and
r ap i d l y m u l t i p l ies . S u r a m i n is t h e fi r st - l i n e th e ra py fo r
t h i s acu te h e m o l y m p h a t ic s tage of Afr ica n trypanoso­
m i asis. B ec a u s e s u ra m in does nor e n ter the CN S , i t is
n o t effe c t i v e ag ai n s t ad vanced d isease when the CNS
beco mes i n v o lv ed . S u ra m i n i s a d m i n istered i n t r a ­
v e n o u s ly a n d c a u s e s adverse e ffects i n c l u d i n g s k i n
r as he s , ga s t r o i n testi n al d i s rress , a n d n e urologic co m ­
p l i c a t i o ns . Pen ta m i d i ne may b e used a s a n al t e r n a t i v e
ro s u ra m i n o r in c o m b i n a t i o n with s u r a m i n fo r the
ea r l y h e molym p h a t ic s tage. Adverse e ffects (described
a bo ve fo r its use a ga i n s t p n e u m o cys rosis) are n o ted i n
h a l f o f pat ienrs receiving thera p e u r ic doses .
M ELARSO P R O L AN D E F LO R N IT H I N E . O n ce
African rr y pan o s o m i a s is has infec ted the CNS, d r ugs
r h a r cross t h e b l oo d - brain b a r r i e r m u s r be a d m i n is­
tere d . Even t h o ugh melarsopro l is ex tre m el y t o xi c ( it i s
an a r s e n i c d e r i va t i ve) , it is s ti l l co n s id ered the d rug of
choice because o f th e severity o f African trypanos o m i ­
asis at t h is s tage. Im m ed i a te tOxi c i ty i n c l u des fever,
v om i ri n g , a bdo m i n a l p a i n , a n d a rr h r a l g i as . The d r u g
may a l so cause a re act ive en ce p h al o p ath y that can be
fata l . To avo i d t h e tOx i c i ty o f m e l a rs o p r o l as well as
i n c reas i ng trea t m e n t fa i l u re s tha r may be d u e ro d r u g
res i s r a nce, eflorni t h i n e has been i n r ro du c e d as a sec­
o n d o p r i o n fo r trea r i n g advan ced d i s e a se . It i s ava i l ­
a b l e o ra l l y a n d i n t r av e n o u s l y, a n d i s effective ag a i ns t
s o m e fo rms o f A fr i ca n t ryp a noso m iasis . Tox i c i ry i s
­ markedl y l e s s t h a n that fro m m ela r so p r o l , b u t adverse
e ffe cts s ri l l i nc l u d e gas tro i n tesri na l d i s rress , b l oo d
abnormal i ries, a n d seizu res .
N I FURTI M OX AN D B EN Z N I DAZO LE. Chagas dis­
ease, caused by T cruzi i n fec tio n , is one o f t h e ma in
c a uses o f death d u e to heart fai l u re in Lati n Am e r ic a n
­
co u n tries. T cruzi prim a r i l y i nvades card i ac muscle ceLls
and macrophages. I n i t ial i n feni o n u s u al l y res u l ts i n a
transient fe b r i le i l l ness. After i n v as i o n of host cells, the
d isease p u rs u es a very slow cou rse. The two maj o r
sym pw m s of Chagas d i sease, myoc a rd i t i s a nd in tesri n a l
(fan d i la t i o n , ca n rake y e a rs t o de ve l o p . Two d r u gs a re
ava i l able to trea t Chagas d i sease: n i fu r t i mox a n d benz­
n i dazo l e . Both d r u gs a re c o m m onl y used to treat the
acute i n fect i o n , but a re o fte n u nsu ccessfu l at com p l ete
e ra d i c a ri o n of rhe protozoan , t h u s al lowing p r o g ress i o n
to the ca rdi a c and gastro i n testi n al s y n d r o m es . T h e tox­
icities of b o t h d ru gs , i n c l u d i n g gasrro i n r est i n a l i r rita ­
tion and severe CNS effects, are a m a j o r drawback i n
t h e i r use, freque n t l y fo r c i n g d i sco n tin u a t i on o f the
t rea t men r . Benzn i d azole is n o t co m m e r ci a l l y ava i l ab l e
i n t h e Un i ted St a tes a nd Ca nada .
Drugs for Leishmaniasis
L eishmania p a ras i te s a re trans m i tted b y r h e b i te of
i n fected sand flies. I n fe c ti o n resu l rs i n cu taneo us (skin) ,
m u cocu taneous ( s ki n , nose, m o u t h ) , or v iscera l ( l iver
and s p l een) l e i s h m a n i a s i s . M o re th an 12 m i l l i o n peo­
ple are k n ow n to be i n fected with l e i s h maniasis, w i rh
the cu ta n e o us a n d m ll CO Cutaneo u s fo r ms b ei n g m u c h
m o re pr ev a le n t t han rhe l i fe- th rea te n i n g v i scera l d i s­
ease. The c u ta neO ll S d isease is pa rt icu l a r ly p revalent i n
Afg h a n i s t a n , A l ge r i a , Brazi l , i ra q , i r a n , Pe r u , Sa u d i
Arabia, a n d S y r i a . M o re tha n 90% o f t h e world's cases
o f visceral l e i s h m a n i a s i s a re i n I n d i a , B a n g l a d esh ,
 A n t i fu n g a l a n d An t i p a r a s i t i c Age n t s 433

Nepal, S u d a n , a n d B razi l . The d isease is o Ec e n known
by m a n y l ocal n a m es ( e . g . , O r i e n t a l sore, e s p u n d i a ,
Bag h dad b o i l , D e l h i so r e , a n d kala-azar) . Those a t
i n creased risk o f leish m a niasis ( pa r t i c u la r l y c u ta neous
l ei s h m a n iasis) i n c l u d e Peace C o rps vol u n teers , peo p l e
who do rese a r ch o u tdoors at n ight , and soldiers . The
cutaneous and m u cocutaneous leis h m a n i a i n fections
range fro m local ized sel f- heal i n g u l cers to d isse m i n a ted
l esions that give rise ro chro n i c d isfi g u ri n g co n d i t i o ns .
L e s io ns may eve n tu a l l y heal w i th s i g n i fica n t sca r r i n g ,
b u t w i l l l eave the i nd i v i d u al relatively i m m u ne to rei n ­
fect io n . I n con trast, visceral i n fect io n develo ps slowly
and is ch aracterized by h ep a tom egal y and splenomegaly.
Left u n t r e a t ed , v i s ceral l e i s h m a n i as i s a l m o s t a l ways
res u l cs in d e a t h .
t e ratoge n ici ry, m i l tefos i n e s h o u l d n o t b e given to p reg­
na n t wo me n . M i l tefosine is c u r ren t l y n o t a p p roved fo r
u se in the U n i ted S ta tes .
Anthelmintic D rugs
T h e h e l mi n t h s i nc l u d e a l l g ro u p s of pa ras I t i c
wo rms. Three m a i n g r o u p s p a r a s i t i ze h u m a n o rga ns,
mo s t o ft e n t h e gas tro i n te s t i n a l tra c r : tapewo rms
( Cestodil) , fl u kes ( Tremiltodtz o r Digeneil) , a nd ro u n d ­
worms (Nemiltodil) . Ta p e w o r m s a n d fl u kes a re rela­
tive! y fl a t a n d h a ve s p e c i a l ize d s t r u c t u tes ro se c u re
a t tachm e n t to the h o s t's i n te s t i n e o r b l o o d vess e l s .
Ro u n d w o r m s h ave l o n g c yl i n d r i ca l b o d ies a n d gen­
era ll y l a ck s p e c i a l i z e d a t tach m e n t s t ru c t ures. Tra n s ­
m i s s i o n m a y b e d i rect by sw a l l o w i n g i n fe c t i ve s ta ges

S O D I U M S T I B O G LUCONAT E. Th is d r u g , based o n o r by l a rvae act ive l y p e netr a t i n g t he s ki n or i n d i rect by

t h e h eavy metal a IH i m o n y, h a s been t h e m a ins tay o f i nj e c t i o n fro m i n fec ted i n s e c t vecto rs . S o m e of t h e

trea t m e n t fo r leish m a n iasis. The d ru g m u s t be admi n­ d ru gs used i n hel m i n t h i c i n fec t i o n s a r e o u t l i n e d I n

i s te red p a ren t e rally ( i n traven o u s o r i n t ra m uscu lar) , Fi g u r e 2 9-4 , a n d l i s ted i n Ta b l e 29-4 .

a n d i n t r a m u sc u l a r i nj e c t i o n s can be very p ai n fu l . Drugs Thilt Act Agilinst Nemiltodes (Roundworms)
Al t h o u g h few adverse e ffects occur i n i t i a l ly, t h e toxic­
It is es t i m a ted t h a t m o re t h a n 1 b i l li o n people world­
i ry of s o d i u m s t i bogl uco n a te i n c reases over the co u rse
w i d e a re i n fe c t ed b y i n te s t i n a l n e m a t o d es , w i t h
o f th e r a p y. The most co m m o n l y e n co u n te red adve rse
m u c h h i g h e r p rev a l e n ce i n m o i s t s u b t r o p i c a l a n d
effects i n cl u de ga s t ro i n te s t i n a l sym p to m s , fever,
t ro p i ca l c l i m a t e s . M e d i c a l l y i m p o r t a n t i n te s t i n a l
headache, myal gi as , a r th r al gias , and ras h . It is po t e n ­
n e m a todes res p o n s ive t o an th e l mi n t i c d r u gs i n cl u d e
tia l l y ca rdiotox i c ( QT p rolo nga tion) , b u t t hese effects
are ge n eral l y revers i b l e . C u re rates fo r the cu t a n eo u s
and m ucoc u ta n eo us fo rms a re generally good w i t h sev­
Antihelminthic Drugs
eral weeks o f t h e ra py. H owever, treatment fo r the v i s ­
c e r a l d i sease ( ka l a - aza t) is i n e ffective a t times, has
s hown i n c reas i n g resi s t a n c e , and i s assoc i a ted w i th D rugs active
I
D rugs active D rugs active
trea tmen t-related deaths i n a smal l percen tage of cases . against against against
n ematodes trematodes cestodes
Al ternative d r ugs such as pentam idine and mil tefosine
I I I
( for visceral leis h m a n iasis) , fluconarole o r metronida­ Al bendazole Praziquantel Niclosamide
ro le ( fo r c u taneous l es i o ns) , a n d amphotericin B ( fo r Diethylcarbamazine Bit h i onol Praziquantel
Ivermectin Metrifonate Albendazole
m u cocutaneous leis h m a n iasis) h ave been used when
Mebendazole Oxamniquine M ebendazole
therapy is i ne ffective. Pyrantel pamoate

M I LTEFOS I N E . T h i s drug, o rigi nal ly de v e l o p ed as
a n t i neo p l as t i c d r ug, is the fi rs t effective o ral d r u g used
in the t reatmen t o f c u ta neous and visce ral l e i s h m a n i ­
a s i s . The c u re rate o f m i l tefosi ne , especially fo r t h e vis­
ce ral d isease, i s very p ro m i s i n g, and the drug i s
ge nerally we l l role rated . Adverse e ffec ts include nau­
s e a a n d v o m i t i ng. Because the d r u g has de mo n s tra ted
an Figure 29-4. A n thelmintic drugs have diverse mecha n isms of
action a nd prope rties. M a ny act against specific parasites , a n d
few a r e devoid of toxicity t o h ost ce lls . Reactions to d e a d a nd
d ying pa rasites may cause se rious toxic i t y in patie nts
A n thelmintic d r ugs a re d ivid ed i nto three groups o n the ba S I S
of the type of worm primarily affected-nematodes, trematodes,
and c estodes. The drugs of choice and a lte r n a tive age nts for
some importa n t helmi nthic infections a re listed i n Table 29-4 .
434 C H EM OTH ERAP EUTICS

Table 29-4. Major hel m i nthic i nfections and the drugs used to treat them

Infect i ng Orga n i s m Drugs of Choice Alternative Dr ugs

Nem atodes
A scaris lumbricoides A l b e n d a zo l e , m e b e n d az ole Pyra n t e l p a moate , p i p e r a z i n e
( ro u n dwor m )
Necator american us, A l be n da zo l e , m e b e n d a zo l e Pyra n t e l p a m oate
A n cylostoma duodena Ie
Trich uris trichiura A l b e n d az o l e M e b e n d a zo l e , pyra n te l p a m oate
( w h i pwo r m )
Strongyloides stercoralis I v e rm ect i n T h i a be n d a zo l e , a l b e n d a zo l e
( t h rea d wo r m )
Enterobius vermicularis A l b e n d az o l e o r m e be n d azole Pyra n t e l pamoate
( p i n wo r m )
C u t a n e o u s l a rva m i g r a n s I ve r m e c t i n A l b e n d a zo l e , d i e t h y l c a r b a m a z i n e
Wucherena bancrofti, I ve r m e c t i n + a l b e n d a zo l e D i et h y l c a r b a m a z i ne
Brugia malayi
Onchocerca volvulus I ve rmec t i n S u ra m i n
Trematodes (flukes)
Schistosoma haema tobium Praz i q u a n t e l M et r i f o n at e
Schistosoma mansoni Praz i q u a nte l Oxa m n i q u i n e
Schis tosoma Japonicum Pra z i q u a n te l None
Paragonimus westermani P ra z i q u a n t e l B ithionol
Fasciola hepatica B it h i o n o l Pra z i q u a n t e l , e m et i n e , d e h yd roe m et i n e
Cestodes (ta pewor m s )
Taenia sagina ta N i closam ide or p raz i q u a n te l M e b e n d azo l e
Taenia solium N iclosam i d e or p r a zi q u a nt e l
Diphyllobothrium latum N i c l osa m i d e o r p ra z i q u a n t e l
Cyst i c e rc o s i s A l bendazole Pra z i q u a nte l
Echinococcus gran ulosus A I bendazole M e b e n d a zo l e
( h yda t i d d i sease)

Entero bius vermicuLaris ( p i n wo r m ) , Trichuris trichium rural a r eas o f rhe s o u t h e a s t e r n s r a re s and [he
( wh i p w o r m) , Asca ris Lu m b ri co i des
( ro u n dwo rm) , Appalachi a n regi o n . N o t as com mon as i n tes t i n a l
A n cylosto ma and Necato r s pecies (hookwo rms) , and n ematodes, tiss ue nem a to des s till i n fect over a h a l f
Stro ngyloides stercoralis ( threadworm) . P i n w o rm s a re b i l l i o n people w o r l d w i de Tiss u e n e ma t o des respon­
.

the m o s t co m m o n i n tes r i n al n e matod e in de v el o ped sive to a n t h el m i n r i c r h e r a p y i ncl u d e A n cylostoma,

co u n tries a n d are also the leasr p a r h o genic. Eggs that Dracunculus, Onchocerca, and Toxoca ra sp e cies and
are l a i d o n r h e pe r i anal skin c a us e i rchi ng, a n d r ra n s ­ Wu cheraia bancrofi i .
m i s s i o n generally o cc u rs fr o m con tam inated fi n gers . ALB ENDAZOLE. T h i s is a n o ra l d r u g with a wid e
Wh i l e h o o kw o r m (A n cylosto ma and Necator species) a n the l m i n t ic specuu m . It is the d r u g of c h o i c e fo r
i n fect i o n s are rare i n the U n i ted S t a te s , ri1read wo r m ro u n d worm ( ascariasis ) , hookwo r m , p i n w o r m and ,

( Stro ngyio ide,· s te rco ra lis ) i n fe c t i o n s a re e n d e m i c i n w h ipw o rm i n fectio n s . It i s an a l re rn a t ive dru g fo r


th read worm J n d fI lariasis ( e n d e m i c i n s o m e tropical
a reas a l1d r es p ons i b l e for elephantias is when t h e lym­
D os i n g of a l bend azo le
p h a t ics a re i n fected) i l1 fecti o n s .
varies d e p e n d i n g on the p a r a s i t i c i n fec t i o n b e i n g
t rea ted . D u r i n g s h o r r co u rses o f t h e ra p y, a l be n d a zo l e
h a s re l a t i ve l y few adve rse effects .
M EB E N D AZO L E . T h i s is a n o t h e r pri m a ry d rug fo r
ascarias i s , p i n wo r m , a n d w h i pworm i n fections, w i th
c u re ta tes o f 90 ro J 0 0 % . I t h a s a l ow i n c i dence o f
advers e e ffects, p r i m a r i l y l i m i ted t o gas tro i mesti n a l
i rr i ta t i o n . I ts u s e is co n t ra i n d icated i n p regn a n cy, a s i t
may be e m b ryoro x i c .
I V E RM ECT I N . T h i s is t h e d r u g o f c h o i c e fo r
o n c h o c e rc i a s i s , a c h ro n i c d i sease e n d e m i c i n Wes t
and s u b-Sa h a ra l1 A fr i c a , as we l l S a u d i Ar a b i a a n d
Yemen . Ch ro n ic i n fection often res u l ts i n serious oph ­
t h a l m o l o g i c co m p l ica t i o n s , i n cl u d i ng b l i n d ness. lver­
mecti n i m mo b i l i zes sens i t i ve parasites by i n h ib i t i n g
n e u ro t r an s m i tter fUDC[i o n i n paras i tes. I t d o es n o t
cross t h e b l o o d - b tai n b a r r i e r, a n d does n o t i n terfere
w i t h h u m a n n e u ro r ra n s m issio n . ]ve r m ec t i n i s gener­
a l l y g i ve n as a s i ngle-dose o ra l therapy. Adverse effects
i n c l u d e fe ve r, h e a d a c h e , d i zz i n ess, rash , p r u r i t u s ,
ta c hycard i a , h ypote n s i o n , a n d p a i n i n j o i ms , m us c l e s ,
al1d lym p h glands. T h e s e sy m p toms a te ofte n o f s h o r r
d u r a t io n a n d m a n agea b l e w i th a n t i hi s ta m i nes a n d
n o n s tero i d a l a n ti-i n fl a m m arory d r ugs (NSAI Ds) .
Drugs That Act Agaimt Trematodes (Flukes)
The m ed i ca l l y i m p o r ra m t rema todes i n c l u de several
p a r as i t e s t h a t h ave a n e n o r mo ll s i m pa c t o n h u m a n
po p u l a t i o n s , s u c h <I S Clono rchis sinensis ( h u m a n l i ver
fl u ke, e n d e m i c in S o u t h e a s t Asia) , Schistosoma s pecies
( b lood fl u kes , es t i m a ted ro affect m o re t h a n 200 mil­
l i o n pers o n s wo rldwide) , a n d Paragon imus westemwni
( l u n g fl u ke , e n d e m ic in A s i a and I n d i a ) .
P RAZIQUANTEL. T h i s d rug has a wide a n thel m i n t i c
s p e c tr u m . I t k i l l s s u s c e p t i b l e w o r m s by i n c reas i n g
ce l l m e m b r a n e p e r m ea b i l i ty, res u l t i n g i n p a ra ly s i s o f
t h e i r m u s c u l a t u re , a n d e ve n t u a l p h a g o c y tos i s b y
h u m a n i m m u n e ce l ls a n d d ea t h . P raziq u a n te \ i s t h e
s a fest a n d m o s t e ffe c t i ve d ru g fo r trea t i n g sch istoso­
m iasis ( a l l s p e c i e s ) and mos t o th e r t r e m a t o d e a n d
ces ro d e i n fec t i o n s . J r i s e ffe c tive a ga i ns t a d u l t w o r m s
A n t i fu n g a l a n d A n t i p a r a s i t i c A ge n t s 435
a n d i m m a t u re s tages . C o m m o n m i l d a nd t r a n s i e nt
adverse e ffe c t s i n c l u d e h e a d a ch e , d izz i n es s , a n d
m a l a i s e . T h e s e g e n e r a l l y d o n o t re q u i re trea t m e n t ,
b u t may be m o re freq u e n t o r s e r i o lls i n p a t i e n ts w i t h
h e avy w o r m b u rd e n s .
Drugs That Act Against Cestodes (Tapeworms)
Cestode eggs are passed i n to so i l from a pri m a ry h o s t
( h u mans i n most ces tode i n festat i o n s ) , a n d i n ges ted by
a n d h a tched in an i n te r m ed i a te host (e. g . , cow, p ig) i n
wh ich they emer tissue a n d e ncys t. Pri m a ry h o s rs [hen
i n gest cysts in t h e flesh of [he i n te r m ed i a re h o s t . In
s o m e ces todes (Echinococcus and Spirom etra species) ,
h u m a n s a re the i n te r m e d i a t e h o s ts a n d larvae l i ve
w i th i n tissues a n d m i grate th ro u g h d i ffe re n t o rga n sys­
tems. The fo ur medical ly i m portan t cestodes are Taenia
saginata ( b e e f rapewo rm) , T so/tum ( p o r k tapewo r m ,
w h ic h c a n c a u se larval fo rms i n the b ra i n a n d eyes) ,
Diphyllo bothriu m Iatum ( fi s h tapewo r m ) , and
Echinococcus granulosus (dog tapeworm, w h i c h i s
e n d e m i c i n S o u th Am e r i c a , Icel a n d , Australia, New
Zea l an d , a n d s o u t h e r n parts of Africa a n d can cause
cysts i n the l iver, l u ngs, a n d b ra i n) . The p r i ma ry d r ugs
fo r trea tment of cestode i n fections are praziquanre\ (see
above) and niclosamide. Nicl osa m i d e is used to trea t
i n fections caused by beef, pork, a n d fish tapewo rms. I t
is n o t effective i n cysticercosis, a n i n fe c t i o n caused by
the p o r k ta pewo r m T .fOlium (albendazole o r p ra z i ­
q u a n te l i s u s e d ) o r disease caused b y E granu/osus
(a1bendawle is used) . Tox i c e ffects are m i l d , b u t i n c l u de
gastro i n test i nal d i s t ress , headache, rash, a n d feve r.
REHABILITATI O N FOCUS
T h i s chapter i n c l udes a n e x t re m ely b road spectr u m o f
a n t i p a r as i t i c agen ts-fro m a n t i fu n ga l d r u gs to a n t i ­
m a l a r i a l a n d a m h e l m i n ti c d r u gs . Most p h y s i ca l thera­
p i s ts w i l l trea t p a t i e n ts t ak i n g a n t i fu n ga l age n ts ,
whethe r i t is the a t h l ete usi n g a t o p i ca l a n ti fu n ga l for
a t h l e te's fo o t or the A I D S p a t i e n t re c e i v i n g an i n tra­
venous a ge n t to rre a t a syste m i c m ycos i s . Less com­
monly, physical therap ists will enco u n ter infecrions such
as malaria a n d leish ma n i as i s tha t a re endemic in t ro p ­
i c a l regi o n s th ro u g h o u t the worl d . H owever, t hera p i s t s
trave l i n g to these regions or cari ng for retu r n i ng m il i tary
436 C H E M O T H E RA P E U T I C S

perso n nel wi l l o fte n be i nvolved i n the m a nagem e n t o Anemia and rhrom bocyro p e n i a m ay res u l t in
o f i n fected i n d iv i d ua l s . Fo r example, m a ny i n d ividuals decreased capaci ty to exercise a n d t o co n t r o l b l eed ­
in m al a r i a l ende m i c regi o n s will be receiving chemo­ i n g a fter i nj u ry, res pecri vely.
p ro p h y l ax i s o r t reat m e n t fo r a c t i v e malaria whi l e par­ o I n h i b i t i o n of cytoch ro m e P 4 5 0 s can cause h i g h e r
ricipa t i n g in re h a b i l i ration p rograms . An u n d ersranding p l a s m a co ncentrarions o f o rher d r u gs res u l r i n g i n a
,

o f rhe m e d i c a t i o ns' potential adverse e ffeces al lows r h e p o te n cial i n crease or p ro l o n garion of therapeuric o r
therapisr ro o p t i m i ze t h e delivery (e.g. , in te ns i ty and adverse effects .
ri m i n g) o f t h e r a py sessio ns. I n some cases , ind i v i d u al s o Tr a n s i e n r v i s u a l d i s r u r b a nces ca n i n ter fere w i t h
s u fferi n g fro m adva n ced s tages of these d iseases a r e n o t fu n c t i o n a l perfo r m a nce o f p a r i e n r s p a r r i c i pa r i n g i n
a p p ro p r i a te re h a b i l i ra t i o n cand i d a tes . However, the reh a b i l i ta r i o n .
p hys ical r h e r a p i s t s t i l l se rves as a val u a b l e member of
the hea l t h - care ream i n prov i d i n g ed u c a ti o n regard i n g Antiparasitic drugs

l i m i r i n g rhe s p read of i n fec t i o n . o The severi ty o f m a n y pa ra s i ri c i n fecri o n s , as well as

CLINICAL RELEVANCE
F O R REHABILITATION
Adverse Drug Reacrions
Systemic drugs used for fungal infrctions
o Am p h o re r i ci n
B a l m o s r always p ro d u ces infus i o n ­
rdared adverse effecrs i n clud ing fever, c h i l l s, vom i r i ng,
muscle spasms, head ache, and signi ficant hypo tension.
o Am pho te r i c i n B may cause a n e m i a .
o Flucy rosine may cause reversi ble a n e m i a a n d r h ro m ­
bocyropen i a .
o Al l azo le agents i n h i b i r h e p a t i c d r u g- m e ra b o l izing
enzy m es (cy roch ro me P4 5 0s) ro s o m e exte n t .
o Vo rico n azo le m a y ca use transien t visual d isru rbances .
An tiparasitic drugs
o A t thera p e u ric doses , m a n y a n t i p a ras i tic agents pro­
d u ce s k i n rashes, varyi ng d egrees o f gastrointes tinal
dis tress, and neu ro logic co mplica r i o ns rangi n g fro m
head aches a n d t re m o rs ro c o n fu s i o n , a c u te p s y­
ch osis, a n d seizu res .
a dverse e ffects of the d r u gs used to trear them, ca n
i n te r fe re w i r h fu ncrional perfo r m a nce of pariell rs .
Anthelmintic drugs
o Many a n rh e l m i n r i cs cause d i zzi ness , r 3 chyc a rd i a ,
hyporens i o n , j o i n r a n d m uscle p a i n , a n d m a l a ise.
Possi ble Thera py So l u tions
Systemic drugs usedfor fungal infrctio ns
o If a p a t i e n r is recei v i n g i n rraven o u s amphore r i c i n S ,
reh a b i l i ra r i o n s e r v i ces s h o u l d be s c h ed u l e d away
fro m t h is r i m e .
o I f decreased exercise tol e ra nce o r excessive b r u i s i ng
i s n o red w i t h p a t i e n rs rec e i v i n g a m p h o re r i c i n B
o r A u cyros i n e , co n tact the refe r r i n g hea l th -care
p rovi d e r.
o I f a patient taki ng a n y azo l e agem d e mons t rates new
symptoms or if a patient is conside r i n g (or cu rren dy)
taking a n OTe d rug or herbal s u p p lement, con tacr
the referring heal th-care p rovi der fo r con cerns regard ­
ing d r u g i n teract i o n s .
o Visu a l d is tu rba n ces sho u l d b e repo rred r o the re fer­
r i n g healrh-care p rovider.

Anthelmintic drugs An tiparasitic drugs

o M a n y a n the l m i n tics c a u s e d i zzi n ess, tachyca rd i a , o Therapy may n eed ro be postponed u m i l p a ra s i t i c

h y p o re n s i o n , j o i n t and m u scle pain, a n d m a l a ise. i n fectio n has been b ro u gh t u n der CO n t ro l .

Anthelmintic drugs
Effects Interfering with Rehab i l i tation
o D u ri n g s h o r r co u rses o f rhera py, adverse e ffeces of
Systemic drugs used for fu ngal infrctions m a n y a n the l m i n tic d r u gs are usu a l l y s h o r t i n d u ra­
o Infusion-rela ted effects of ampho re r i c i n B ca n l i m i r t i o n . Reh a b i l i tatio n can b e pos rpo ned u n ti l adverse
p a t i e n ts' a b i l i ty t o parricipare i n re h a b i l i ta r i o n . e ffecrs cease or i m p rove.
 An t i fu n ga l a n d An t i p aras i t i c Ag e n t s 43 7

P RO B LE M - O RI E N TED PAT I E N T STUDY

Brief History: The p a ti e n t i s a 2 2 -yea r-old male twice s e c o n d a r y ro d i z z i n ess . He complains o f

who re t u r n e d fro m a m i l i t a r y ro ta t i o n i n I ra q severe h i p a n d knee p a i n , a s well as g l u t e a l ,
2 months ago. He was ad m i r red ro a m i l i tary q u adriceps , a n d b ac k m uscle soreness. Al rhough
rehab i l i ta t i o n h o s p i tal 4 days ago fo r a n a m p u tee some o f the pat i e n t s complai nts may b e due ro
'

re habi l i ta t i o n p r o g r a m . He s us t a i n e d a be l ow the his v i gorous participatio n i n re h a b i l i tatio n , the

knee am putation (B KA) of the righ t l owe r extremity therap i s t n o tes that some sym p r o m s may be
1 week ago , se c o n d a r y to a traumatic i nj u r y that adverse effects o f the drug t he r a p y fo r cu ta n eo u s
occu rred during a m i l i ta ry op e r a t i on . Prior ro his leishmaniasis. The therap i s t enco u r a g e s the
i n j u r y, he was fu n c t i o n a l l y i n depen den t a n d a n patient that these sym ptoms are l i k e l y to d i ss i pate
a v i d baske t b a l l p l a yer. o n ce the fu ll course of d r ug t h er apy has ended.
The p a ti e n t s tates that the d r u g treatment " h as
Current Medical Status and Drugs: At admission,
been fa r w o r se than these l i ttle sores . " He states
the p a t i e n t was n o ted ro h ave several c ru s ted
his i n te n t i o n ro tell the docror that he is n o
ra i s ed les i o n s that w e r e up ro I i n c h i n d i a meter
l o nger go i ng r o take t h e p rescri bed medicati o n ,
on his fa ce, neck, and left fo rearm . The pa ti e n t
so that h e c a n "get o n w i t h re h a b . "

re p o r ted t h a t the les i o n s were much l a r ge r a n d

p a i n fu l several weeks a g o . A n i n fe c t i o u s d i sease
Problem/Clinical Options: The physici a n should
p hysician s a m pled skin scrapings o f the lesi on and
be notified o f the patien t's sympto m s , as well as
d i a g n osed t h e con d i t i o n as c u t a n eo u s leishmania­
thei r l i m i ti ng i m p ac t o n phys i c a l rehab i li ta t i o n
sis, co m m o n l y known as " B a g h d ad b o i l . " The
goal s . O v e r half o f patie n t s rece i v i n g I V sod i u m
p a tient was s t a r ted on a 2 0 d ay i n traveno us course
-

s t i b o gl u co n a t e e x per i e nce fa t i g u e , a r t h r a l g i a s ,
o f sod i u m s t i bogl uconate, wh i c h he receives o n ce
a n d m yalgias . Wh ile sym ptoms n e c e s s i t a te i n ter­
per day, i m m e d i ately p r i o r ro a fte r noo n phys i cal
r u p ti o n of treatm en t in only a s m a l l percen tage
therapy sess ions. Reh a b i l i t a t i o n p recautions include
o f c as e s these s i de effects are generally reversible.
,

n o n -weigh t - b ea r i n g o n the righ t s t u m p . T h e

First, the patient s h o u l d be e d u cated a b o u t the
patiem's r
c u re n t drugs i n clude p ai n medication as
cos t ro benefit ratio of co n t i n u i ng drug therapy.
needed .
U n treated cutaneous leis h m a n iasis l es i o n s can
Rehabilitation Setting: The p a t ie n t is very m o t i ­ leave large, u n s ightly scars . I n some cases, local­
va ted ro re t u rn to h i s p r i o r level o f fu n c t i o n a n d ized skin i n fections can s p re ad to the m o u th or
l1:1s been p a r ti c i p a t i n g i n reh a b i l i ta t i o n th e ra py nose ( m ucosal l e i s h m a n i asis) a n d cause poten­
twice per day s i nce the first day of a dm is s i o n . D ur­ tially d i s fi gu ring scars . Seco n d , ar r e m p t s s h o u l d
i ng t he fi rs t week of reha b i l i ta t i o n , the patien t be m ade to schedule therapy sessions as far a p art
met each therapy goal regard i n g edema contro l , fro m I V d r ug sessions as poss i b l e to determ i n e
s t u m p m a i n te n a n c e , s t re t c h i n g , s t rengthen i n g, w h e t h e r adverse e ffects a r e a t t e n u a te d d u r i n g
a n d p rega i t activi t i es . He was m a ki n g rem arka b l e t h e r a p y sess i o n s . F i n al ly, the t h e rap i s t can
gai n s i n thera p y, un ti l 5 d a y s a ft e r he s t a r t e d I V encou rage and r e assu r e t h e patient t h a t the drug
s o d i u m s t i bogl u co n a t e . H i s e n e r gy l evel b e g an therapy i s l i m i t e d to a m ax i m u m o f 2 0 days , a n d
decl i n i ng, a n d h e has been unable ro com p le t e a n t h a t the d i s tressing sym p to m s w i ll likely n o t per­
h o u rl y p h ys i c a l t h e r a p y sess i o n . To day, w h i l e s i s t or i n t e r fere w i t h l o ng t e r m re hab i l i t a t i o n
-

exerc i s i n g i n t h e p a r a l l e l b a r s , h e h a d ro s i t down goals .

438 C H E M OT H E RA P E U T I CS

P R E P A R AT I O N S A VA I L A B L E
. ::.,

Antifunga l Age nts Ketoconazole (generic, Nizora/)

O ra l : 2 0 0 - m g ta b l ets
Amphotericin B
To p i c a l : 2% crea m , s h a m poo
Parentera I :
C o n ve n t i o n a l form u l a t i o n ( A m p h ot e r i c i n B, Miconazole (Mica tin, others)
F u n g i zo n e ) : 5 0 - m g powd e r for i n j e ct i o n To p i c a l : 2 % c re a m , powd e r , s p ra y ; 1 0 0 - , 2 0 0 - m g

L i p i d form u l at i o n s : va g i n a l s u p p o s i t o r i e s

( A b e l c et ) : 1 00 m g/ 2 0 mL suspension for Naftifine (Naftin)

i njection To p i c a l : 1 % c re a m , ge l
( A m B i so m e ) : S O - m g p ow d e r f o r i n j e c t i o n
Natamycin (Natacyn)
( A m p h ot ec ) : S O - , 1 0 0 - m g powd e r f o r i n j e c t i o n
To p i c a l : S% o p h t h a l m i c s u s p e n s i o n
To p i c a l : 3 % c re a m , l ot i o n , o i n t m e n t
Nystatin (generic, Mycostatin)
Butaconazole (Femstat, Mycelex-3)
O ra l : S O O , O O O - u n i t ta b l et s
To p i c a l : 2 % vagi n a l c re a m
To p i c a l : 1 00 , 000 u n i t s/g crea m , oi ntment,
Butenafine (Mentax) powd e r ; 1 0 0 , 0 0 0 u n i t s v a g i n a l ta b l ets
To p i ca l : 1 % c re a m
Oxiconazole (Oxistat)
Caspofungin (Cancidas) To p i c a l : 1 % c re a m , l o t i o n
P a r e n te r a l : S O - , 7 0- m g powd e r for i n j e c t i o n
Sulconazole (Exelderm)
Clotrimazole (L otrimin, others) To p i c a l : 1 % c re a m , l ot i o n
To p i c a l : 1 % c re a m , sol uti o n , lotion ; 1 00-,
Terbinafine (Lamisi/)
2 0 0- m g v a g i n a l s u p p o s i to r i e s
O ra l : 2 5 0 - m g t a b l ets
Econazole (Spectazole) To p i c a l : 1 % c re a m , ge l
To p i c a l : 1 % c r e a m
Terconazole (Terazol 3, Terazol 7)
Fluconazole (Diflucan) To p i c a l : 0 . 4 % , 0 . 8 % vag i n a l c r ea m ; 8 0 - m g vag i n a l
O ra l : S O - , 1 0 0 - , l S 0 - , 2 0 0 - m g t a b l ets ; pow d e r s u p po s i t o r i e s
f o r 1 0 , 4 0 m g/ m L s u s p e n s i o n
Tioconazole (Vagistat- l)
P a r e n te r a l : 2 m gl m L i n 1 00- and 200-m L
To p i c a l : 6 . S % v a g i n a l o i n t m e n t
vials
Tolnaftate (generic, Aftate, Tinactin)
Flucytosine (Ancobon)
To p i ca l : 1 % c rea m , ge l , so l u t i o n , a e roso l powd e r
O ra l : 2 S 0 - , S O O - m g c a p s u l e s
Voriconazole (Vfend)
Griseofulvin (Grifulvin, Grisactin, Fulvicin PIG)
O ra l : S O - , 2 0 0 - m g ta b l ets
Ora l m i c ro s i z e : 1 2 5-, 2 50-mg c a ps u l e s ;
Paren tera l : 200-mg vials, reco n s t i t uted to a
2 S 0 - m g t a b l et s , 1 2 S mg/S m L s u s pe n s i o n
S m g/ m L so l u t i o n
Ora l u l t r a m i c ro s i ze L 1 2 5- , 1 6 S- , 2 S0-,
3 3 0 - m g t a b l e ts
Ant i p a ra s i t i c Agents
Itraconazole (Sporanox)
O ra l : 1 0 0 - m g c a p s u l e s ; 1 0 m g/ m L so l u t i o n A lbendazole (A lbenza)
P a re n t e r a l : 1 0 m g/ m L f o r I V i n f u s i o n O ra l : 2 0 0 - m g ta b l ets
 A n t i fu n gal a n d A n t i p a ra s i ti c A g e n ts 4 3 9

Ato vaquone (Mepron) Pentamidine (Pentam 300-, Pentacarinat, pentami­

Ora l : 7 5 0 m g! 5 m L s u s p e n s i o n dine isethionate)
Pare n t e ra l : 3 0 0 - m g powd e r fo r i n j ec t i o n
Ato vaquone-proguanil (Malarone)
O ra l : 2 5 0 mg a tovaq u o n e + 1 0 0 mg p rogu a n i l Primaquine (generic)
ta b l et s ; ped i a t r i c 6 2 . 5 m g atova q u o n e + 2 5 mg O ra l : 2 6 . 3 mg ( e q u i va l e n t to 1 5 mg b a s e ) ta b l e t
p rog u a n i l t a b l ets
Pyrimethamine (Daraprim)
Chloroquine (generic, Aralen) O ra l : 2 5 - m g ta b l ets
O ra l : 2 5 0 - , 5 0 0 - m g ta b l ets ( e q u i va l e n t to 1 5 0 ,
Quinidine gluconate (generic)
3 0 0 m g base , respect i v e l y )
P a re n t e ra l : 80 mg/ m L ( e q u i v a l e n t to 5 0 mg/m L
P a re n te r a l : 5 0 m g!m L ( e q u i va l e n t to 40 m g! m L
base ) for i n j ect i o n
base) fo r i n j e c t i o n
Quinine (generic)
Clindamycin (generic, Cleocin)
Ora l : 2 60-mg ta b l ets; 2 0 0 - , 2 6 0 - , 3 2 5-mg c a ps u l es
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
Sodium stibogluconate2
suspension
P a re n tera l : 1 5 0 m g!m L f o r i n j ec t i o n Sulfadoxine and pyrimethamine (Fansidar)
O ra l : 500 mg su lfadox i ne p l u s 2 5 mg pyr i m etha m i n e
Dehydroemetine2
t a b l e ts
Doxycycline (generic, Vibramycin)
S u ra m i n 2
O ra l : 2 0 - , 50- , 1 0 0-mg c a p s u l es ; 5 0 - , 1 0 0 - m g
ta b l et s ; 2 5 m g! 5 m L s u s p e n s i o n ; 50 m g! 5 m L
Anth e l m i ntic Age nts
syr u p
P a r e n tera l : 1 0 0 , 2 0 0 m g for i n j e c t i o n A lbendazole (Albenza, Zentel)3

Eflornithine (Ornidy/) O ra l : 2 0 0 - m g ta b l et s ; 1 0 0 m g! 5 m L s u s pe n s i o n

P a r e n t e ra l : 2 0 0 m g!m L for i n j e c t i o n Bithionol (Bitin)4

Halotantrine (Halfan) O ra l : 2 0 0 - m g ta b l ets

O ra l : 2 5 0- m g ta b l e ts Diethylcarbamazine (Hetrazan)4

lodoquinol (Yodoxin) O ra l : 5 0 - m g t a b l et s

O r a l : 2 1 0 - , 6 5 0 - m g ta b l et s Ivermectin (Mectizan, Stromectol)S

Mefloquine (generic, Lariam) O ra l : 3 - , 6 - m g t a b l e t s

O ra l : 2 5 0 - m g ta b l e ts Levamisole (Decaris, Ethnor, Ketrax, Sola ski/)

O ra l : 5 0 - , 1 5 0 - m g t a b l e t s a n d sy r u p
Melarsoprol ( M e l 8)2
Mebendazole (generic, Vermox)
Metronidazole (generic, Flagy/)
O ra l : 1 00 - m g c h ewa b l e ta b l et s ; o u t s i d e t h e U n i ted
O ra l : 2 5 0 - , 5 0 0 - m g ta b l e t s ; 3 7 5 - m g c a p s u l e s ;
State s , 1 0 0 m g!5 m L s u s p e n s i o n
e x te n d e d - re l ease 7 5 0 - m g ta b l ets
Metritonate (trichlorton, BilarcilJ6
P a re n te ra l : 5 m g!m L
O ra l : 1 0 0 - m g ta b l e t s
N ifurti m o x2
Niclosamide (NiclocideJ6
Nitazoxanide (A linia)
O ra l : 5 0 0 - m g c h ewa b l e ta b l ets
O r a l : powd e r for 1 0 0 mg/5 m L ora l so l u t i o n
Oxamniquine (Vansil, Mansi/)
Paromomycin (Humatin) O ra l : 2 5 0 - m g c a p s u l e s ; o u ts i d e t h e U n i t e d States ,
O r a l : 2 5 0 - m g c a p s u l es 5 0 m g/m L sy r u p
440 C H E M OT H ERA P E U T I C S

Oxantel pamoate (Quantre/}6; oxantellpyrantel Pyrantel pamoate (A ntiminth, Combantrin,

pamoate (Telopar)6 Pin-rid, Pin-X)
O ra l : t a b l ets c o n ta i n i n g 1 0 0 mg ( base) of e a c h Ora l : 5 0 mg ( base)/m L s u s pe n s i o n ; 6 2 , 5 mg ( base)
d r u g ; s u s pe n s i o n s c o n ta i n i ng 2 0 or 5 0 mg ( base) c a p s u l e s ( a va i l a b l e w i t h o u t p resc r i p t i o n i n t h e
per m L U n i t e d States)

Piperazine (generic, Vermizine)

Suramin (Bayer 205, others)4
O ra l : p i p e r a z i n e c i t r a t e t a b l e ts e q u i va l e n t to
P a r e n t e ra l : a m p u l e s c o n ta i n i n g 0 , 5 - or l -g powd e r
2 5 0 m g of t h e h exa h y d ra t e ; p i pe r a z i n e c i trate
to be r e c o n st i t u t e d a s a 1 0 % so l u t i o n a n d u s e d
syru p e q u i va l e n t to 5 0 0 mg of t h e h e x a h y d rate
i m m ed i a t e l y
per 5 m L

Praziquantel (Biltricide; others outside the United Thiabendazole (Mintezo/)

States)
O ra l : 500-mg c h ewa b l e ta b l e t s ; suspension ,
O ra l : 6 0 0 - m g ta b l ets ( o t h e r stre n gt h s o u ts i d e
500 m g/m L
t h e U n i t e d States)

I U I t r a m i c ro s i ze f o r m u l a t i o n s of griseof u l v i n a re a p p ro x i m a te l y 1 . 5 ti mes m or e pote n t , m i l l igra m f o r m i l l i g ra m , t h a n

t h e m i c r o s i ze p r e p a ra t i o n s ,
2Ava i l a b l e i n t h e U n i t e d S t a t e s o n l y from t h e D r u g S e rv i c e , C D C , At l a n t a ( 4 0 4 - 6 3 9 - 3 6 7 0 ) ,
3A l b e n d a zo l e i s a p p roved i n t h e U n ited States f o r t h e t r e a t m e n t of cys t i c e r c os i s a n d h y d a t i d d i sease ,
4 N ot m a r keted i n t h e U n i t e d States b u t is a va i l a b l e f r o m t h e P a r as i t i c D i sease D r u g S e rv i c e , C e n ters for D i sease
C o n t r o l and Preve n t i o n , A t l a n t a : 404-6 3 9 -3 6 7 0 ,
5A p p roved f o r u s e i n t h e U n i t e d States f o r t h e trea t m e n t o f o n c h o c e rc i a s i s a n d s t r o n gy l o i d i a s i s , See C h a pt e r 1 for
c o m m e n t o n the u n l a b e l ed u s e of d r u g s ,
6 N ot ava i l a b l e i n t h e U n i ted S t a t e s ,

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An a d o l D , e r al: Trea r m e n t o f hydarid disease. Paediatr Drugs 94 : 20 5 .
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MISCELLANEOUS ANTIMICROBIAL
AGENTS: DISINFECTANTS, ANTISEPTICS,
STERILANTS, AND PRESERVATIVES

T
he agenrs d i scussed in th i s chapter includemis cel laneous ami m i crobials, i n clud i ng those
specific for urinary i nfec tio ns, and disinfectams a n d amiseptics (Figure 30-1). Because
phys ical the ra p i sts often [feat pati ems with in fecti o ns a n d use equipmenr that can
p o temi ally tra nsfer pat hoge n s , the use of amisept i cs and disinfec tams discussed in the latter
half of the c hap te r is particularly releva n t to rehab ili tation practice.

MISCELLANEOUS ANTIMICROBIAL AGENTS

Metronidazole

Chemistry and Pharmacokinetics

Merronidazole is a nitroimid azo l e drug used pri mari l y in treating in fect i ons caused by anaero­
bic bacteri a and p ro rozoa . Metronidazole can be adm iniste red orally, intrav enously, or by rec­
tal supposirory. The drug pene trates readily imo almo s t all tissues, i n cl udi ng the cerebrospinal
Auid, a ch ie vi ng levels similar ro plasma.

Mechanism ofAction and Clinical Uses

Metronidazole kills am oe b ae , bacteria, and sensi tive prorozoans . The drug is readily taken up b y
a n a e ro b i c organ i sms and cells, where i t ac ts by di sru p ting DNA and i nh ib i ti n g nucleic ac i d syn­

thesis. Metro nidazole is the trea tmem of choice for anaero bic or mixed imra-abdo m i nal infec­
(lOllS, pseudomembranolls colitis, and brain abscess involvin g susc ept ib le organisms .
Metronidazole may be used in treating anaerob i c infections sllch as m i ght be presem in empyema,
lung abscess, b o ne a n d j o i n r infections, and diabetic foot ulcers. In th e treatmem of diabetic
10weL" extremiry infections in older males, o nce-daily use of metronidazole combined with another
ami bi o t i c has been s h own to be as effective as the tradi ti onal ami b i otic regime n given eve r y
6 hours with significan tly less associated cos t. Metro nidazole is also used ro treat i nfec ti o ns
caused by Clostridium difficile, a gra m -pos iti ve bacillus that can p recipi tate ps eudo memb ran ous
colitis, which is clinically manifested as severe diarrhea (C diffieile-associa ted diarrhea, COAD) .
C diffieile is one of the most rapidly i n cre as ing communicable i nfections, poss i b ly e xce e d i ng
methici l l in-resis tanr Staphylococcus aureus (MRSA) and o ther drug-resis tanr m i croorga n is m s .
Metro nidazole h as many other uses. A s a n oral tabler o r topical vag i n al gel , i t effectively
bacterial vag i n os i s . As pan of a mulridrug regimen, merronidazole is co m m o n ly used i n
[I'ea ts
the eradication of Helicobacter pylori i n peptic ulcer d isease. A s a n amipr orozo al drug , metron­
idazole is t h e drug of choice for treati n g giardiasi s (traveler's diarrhea) and the c om mon sexually
443
444 CHEMOTHERAPEUTICS

Miscellaneous antimicrobial agents membrane potential, and results in rapid b a cte r i al cell
& '"lP' ' death. Daptomycin is administered by slow intra­
venous infusion fo r the treatment of complicated skin
and sofe tissue infections due t o aer obic g r am- p osi tive
organisms. Since daptomycin is primarily excre te d by
Miscellaneous U ri n ary Disinfectants the kidneys, dose reductions are required in patienrs
antimicrobials antiseptics & antiseptics
with renal impairment.

Clinical Uses
Metronidazole Nitrofurantoin Alcohols, aldehydes,
Daptomycin Methenamine heavy metals, halogens,
Daptomycin is effective aga ins t most clinicaJly relevant
Mupirocin chlorhexidine, phenolics, gram-positive bacteria, including infections due to
Polymyxins peroxygen compounds, MRSA, vancomycin-resistant S aureus (VRSA), and
quatemary ammonium
vancomycin-resistant enterococcus (VRE). Dapro­
compo unds , sterilants
and preservatives mycin has also proven effective for S aureus ba c tere m i a
and endocarditis.
Figure 30-1. These agents are divided into miscellaneous
antimicrobials, those specific for urinary infections and disin­ Toxicity
fectants and antiseptics. Subsequent divisions are based on Mild adverse effects i n clud e nausea and vom i t i n g , con­
chemical class or clinical use. stipation, diarrhea, headache, dizziness, and injection
site reactions. During d aprom yci n t rea t menr , a s m al l but
s igni fi can r percen tage of p a ti ents develo p myopathies
transmitted disease trichomoniasis. Metronidazole is (generalized muscle pain, cramps, or weakness) associ­
also used as a tOpical ami biotic for the chronic derma­ ated with elevations in creatine kinase. Tl1us, patien rs
tologic condition rosacea . given daptomycin should be monirored for skeleta l
Toxicity
muscle dysfunction and creatine ki n ase elevation and
coadminis tra t ion with 3-hydroxy-3-methylglmalyl coen­
The most common adverse effects include nausea or
zyme A (HMG-CoA) reductase i nh ibitors ("statins")
vomiting, gastroinrestinal discomfort, cliarrhea, headache,
should be avoided. In addition, tra ns ito ry paresthesias
dizziness, dry mouth, and altered taste sensation (es pe ­
and peripheral neuropathies have been reported.
cially the perception of a sharp metallic taste). Because
metronidazole has a disulfiram-like effec t, drinking
Mupirocin
alcoholic beverages while taking metronidazole can
cause stomach pain, nausea, vomiting, heada che, and Mechanism ofAction and Clinical Uses
flushing of the face. Patients should be inst(llcted to Mupirocin (pseudomollic acid A) is an anribiotic orig­
avoid alcohol (includ i ng alcohol-containing cough inally isolated from the gram-negative bacterium
syrups) while ta ki n g this drug and for at least 3 days Pseudomonas fluorescens. By binding to banerial
afeer discontinuing treatment. isoleucyl transfer-Rl\IA synthetase, mupirocin prevents
isoleucine incorporation into banerial proteins, rhus
Da p tomycin
inhibiting bacterial protein synthesis.
Chemisfr)l Mechanism ofAction, and Pharmacokinetics Mupirocin is formulated as a topical ointment
D ap t o m ycin is a member of one of the newer classes and indicated for the treatment of secondarily infected
of antibiotics called cyclic lipopeptides. Daptomycin's traumatic skill lesions and minor skin infections slich as
structure promotes r apid bactericidal effects via a im pe rigo caused by gram-positive bacteria (e.g., Sat/reus,
unique mechanism. By insertion of its l ipophi lic tail bera-hemolytic streptococci and Streptococcus pyogenes).
into the bacterial cell mem brane , daptomycin causes loss Wirh direct application of mupiroci n ro the skin or
of imracellular potassium, depolarizes the b act e r ial mucous membranes, high local concentrarions are
 Miscellaneous Antimicrobial Agents: Disinfectants. Antiseptics. Sterilants and Preservatives 445
achieved. Use of an occlusive dressing following appli­
cation increases penetration 5- ro 10-fold. bur the
absorbed amounr has been estimated ro be <0.24% of
the applied amount. Systemic absorption of mupirocin
through inract skin is minimal; however. any drug
reaching the systemic circulation is rapidly metabo­
lized ro an inactive metabolite that is eliminated by
renal excretion. Most drug elimination is via desqua­
mation of skin cells rather than metabolism.
Nasal carriage of S aureus (both methicillin­
susceptible and methiciUin-resistant strains) is a weJI­
defined risk factOr for subsequenr nosocomial infection
in hospitalized patienrs. Thus. intranasal application
of mupirocin has been used for the elimination of
S aureus in patienrs and health-care workers. However.
prolonged and widespread mupirocin use is associated
with the developmenr of mupirocin resistance. Judi­
cious use of ropical mupirocin. including limiting
treatment ro carriers and considering other treatmenr
regimens. should be emphasized.
Adverse Efficts
The most common adverse side efFects are local
erythema. rash. stinging. and itching. In addition. pro­
longed usage may result in overgrowth of nonsuscepti­
ble organisms. including fungi.
Polymyxins
Mechanism ofAction and Clinical Uses
The polymyxins are a group of cationic detergent
antibiotics that kill gram-negative bacteria by disrupt­
ing the bacterial cell membrane. Owing ro signiflcanr
tOxicity associated with systemic administration. the
polymyxins are primarily used tOpically, but have also
been used for irrigation of wounds and the urinary
bladder. Ointments or drops conraining polymyxin B
in combination with neomycin and hydrocortisone are
often used for eye or ear infections. Over-the-counter
ropical formulations including polymyxin B with
neomycin andlor bacitracin are commonly used for
infected superficial skin lesions.
Toxicity
If systemic absorption occurs. serious adverse effects
include neuroroxiciry (dizziness, ataxia, paresthesias)
and nephrotOxiciry (acute renal tubular necrosis).
URINARY TRACT ANTISEPTI CS
The urinary tract is one of most common sites of bac­
terial infection. especially among women. Urinary tract
antiseptics such as nitrofurantOin and methenamine are
oral drugs that lack systemic antibacterial effects because
of their rapid metabolism. Because these drugs are
excreted into (he urine in high enough concentrarions to
inhibit urinary pathogens. they are useful drugs for the
treatment of acute lower urinary tract infections (UTIs)
as well as prevention of recurrent UTls. Urine pH is
monitored before starring and throughout therapy
because the agents' effectiveness is increased at low pH
«5.5), and low pH i s an independent inhibiror of bac­
terial growth i n urine. Thus, these drugs are often
administered with urine-acidifying agents such as a
protein-rich diet with cranberry juice. In addition,
patienrs are instructed to avoid eating most fruits (espe­
cially citrus fruits and juices) and dairy products.
which tend ro alkalinize the urine. NitrofurantOin and
methenamine are bactericidal for many gram-positive
and gram-negative bacteria. although they have no activ­
ity against urea-splitting gram-negative bacteria (Proteus
or Pseudomonas species), because these organisms
increase urinary pH and thereby decrease the drugs'
effectiveness. Both nitrofurantoin and methenamine
have the advantage that resistance rarely or slowly devel­
ops in susceptible bacterial populations.
Nitrofurantoin
When used to treat uncomplicated acute UTI, the
normal adult daily dose of nitrofurantoin is 50 ro
100 mg taken four times daily for at least I week.
For prevention of chronic UTls. a single 100-mg
daily dose may be taken.
Nitrofuranroin should be taken with food ro
improve drug absorption and to decrease adverse gas­
trointestinal effects such as vomiting, nausea. and
anorexia. In addition to gastrointestinal irritation. skin
rashes and phorosensitivity are common side effects.
Patients should also be informed that nitrofurantoin
colors the urine dark yellowish orange or brown, which
is a normal and harmless side effect.
Nitrofuranroin may cause hemolytic anemia in
patienrs with glucose-G-phosphate dehydrogenase
446 CHEMOTHERAPEUTICS

(G6PD) deficiencies. This deficiency is me most com­
mon human enzymopathy; it is found in roughly
10% of African Americans and 60% of Kurdish Jews.
Hemolytic anemia may also occur in neonates with
immature enzyme systems within the red blood cells.
For this reason, niuofuranroin is contraindicated in
women in the last month of pregnancy (38 to 42 weeks'
gestation) , in nursing mothers, and in neonates less
than 1 month of age.
Peripheral neuropathies have been reported, and
may be more likely in patients with renal impairment,
diabetes mellitus, and vitamin B deficiency. Progres­
sive pulmonary interstitial pneumonitis and fibrosis
have been reported when nitrofurantoin has been given
over longer periods of time (<!6 months). Because nitro­
furantoin is primarily excreted by the kidneys, urinary
concentrations in patients with renal impairmem may
be subtherapeutic. In patients with severe renal insuffi­
ciency, nitrofurantoin is comraindicated because high
blood levels may cause toxicity. Finally, in patiems with
diabetes mellitus, nitrofuramoin may cause inaccurate
results with some urine glucose tests.
Methenamine
Methenamine mandelate and methenamine hippurate
are methenamine salts. When combined with urine
acidification, methenamine acts as a weak base that
hydrolyzes in acidic urine to form ammonia and
formaldehyde. Urinary formaldehyde may be bacteri­
cidal or bacteriostatic depending on urinary pH, vol­
ume, and flow. Methenamines may be used in the
ueatmem of UTIs in patiems with intermittent
catheterization, but they are not effective in patiems
with indwelling urinary carheters. Both methenamine
salts are commonly used for the prevention of UTIs,
although evidence regarding their effectiveness in UTI
prophylaxis is mixed and may be dependent on patient
population. The methenamines should not be taken
concurrenrly with sulfonamide antibacterials because
insoluble precipitates may form and increase the like­
lihood of crystalluria.
DISINFECTANTS, ANTISEPTICS,
STERILANTS, AND PRESERVATIVES
Although the terms are often used interchangeably,
disinfectants and antiseptics have specific definitions
(Table 30-1) . Disinfectams are chemical agents that
inhibit or kill various microorganisms on nonliving
objects in the environment (Table 30-2). They should
not be used on living tissue. Antiseptics inhibit
microorganism growth and reproduction on inanimate
objects, but they are also safe enough to be used on tile
surfaces of living tissue, such as skin. Notably, disin­
fectants and antiseptics do not have selective toxicity;
each agent displays a different microbicidal profile that
must be considered for appropriate and effective use.
Sterilization refers to the use of physical or chemical
means to desrroy all microbial life, including highly
resistant bacterial endospores.
Disinfection involves the destruction of infective
organisms by physical or chemical means (Table 30-2),

Table 30-1. Commonly used terms related to chemical and physical k i lling of microorganisms

Antisepsis Application of an agent to living tissue for the purpose of preventing infection
Decontamination Destruction or marked reduction in number or activity of microorganisms
Disinfection Chemical or physical treatment that destroys most vegetative microbes or
viruses, but not spores, in or on inanimate surfaces
Sanitization Reduction of microbial load on an inanimate surface to a level considered
acceptable for public health purposes
Sterilization A process intended to kill or remove all types of microorganisms, including spores,
and usually including viruses with an acceptable low probability of survival
Pasteurization A process that kills nonsporulating microorganisms by hot water or steam at 65-100°C
 Table 30-2. Activities of disinfectants

Bacteria Viruses Other

Gram- Gram- Amebic

positive negative Acid-fast Spores Lipophilic Hydrophilic Fungi cysts Prions
Alcohols HS HS S R S V R
(isopropanol,
ethanol)
Aldehydes HS HS MS S (slow) S MS S R
(glutaraldehyde,
formaldehyde)
Chlorhexidine HS MS R R V R R
gluconate
Sodium hypochlorite, HS HS MS S(pH 7.6) S S (at high MS S MS (at
chlorine dioxide cone) high cone)
Hexachlorophene S (slow) R R R R R R R R
Povidone, iodine HS HS S S(at high S R S S R
cone)
Phenols, quaternary HS HS MS R S R R
ammonium
compounds
Strong oxidizing HS MS to R R R S R R R R
agents, cresols

HS = highly s usce ptibl e ; S = susceptible; MS = moderately susceptible; R = resistant; V = variable; - = no data.

�
�
'..J
448 CHEMOTHERAPEUTICS

reducing the number of potentially infective organisms
either by kiLling, removing, or diluting them. Disin­
fection is often accomplished by ionizing radiation or
dry or moist heal
The ideal be able to kill all
number of microorganisms present (microbial load),
mixed populations of organisms, amount of organic
material present (e.g., blood, feces, tissue), stability and
agent, time and temperarlllf'
hydration and binding of 1

pathogenic harming healthy

nfectant does not nfectants, antiseptics,
exist, a combi often used (e.g., toxicity. Every agenr
addition of a detergent), and the
choice of which on the particular
51 tuatlon. Interfere with wound healing. Thus, both the patient
Washing, which dilutes and partially removes and health-care professionals must consider the short­
potentially infectious organisms, and the use of barri­ term and long-term toxicity of each agent. The Envi­
ers (e.g., gloves, condom, respirator), which prevent ronmental Protection Agency (EPA) regulates
pathogens from gaining entry into the host, are fore­ disinfectants and sterilants and the Food and Drug
Illost in infection prevenrion and control. Administration (FDA) regulates anriseptics. Major
Hand washing is the single most important way classes of antiseptics, disinfectants, and sterilants are
to prevent transmission of pathogens from person to described below.
person or from microbial load (e.g.,
mouth, nose, sites of infection.
Although hand and water effec-
tively removes 111 ff:ctious agents, skin used akohols for tre:Jtmenr

disinfectants are for preoperative ethanol

skin antisepsis are

surgical cleansing hands and the (isopropanol). Alcohols

patient's surgical minimize IrrItation, Alycobacterium tuberculo.'!s,
dryness, and skin sensitization, regular hand washing fungI. Alcohol's bIOcidal effects are due to its abiltty to

should be done without disinfectants. In addition, for dehydrate cells, disrupt membranes, and coagulate

regular hand washing, it may be preferable to create proteins. Exposure to 70 to 80% ethanol or iso­

conditions that are inhospitable to bacterial reproduc­ propanol (by volume in water) for at least 5 minutes is
tion rather than to kill bacteria with disinfectanrs. the best practice for optimal surface and skin disinfec­

Because of their rapid reproduction rate, it is possible tion. These high-concentration alcohol mixtures also

that survival of bacteria following an antiseptic chal­ quickly and effectively inactivate HIV and hepatitis B

lenge Illay result in increased propagation of strains of and C viruses on surfaces. Alcohols are nor considered

antiseptic-resisun [ lhis reason, the wis­ [hey do not inactivate

dom of the currene antibacterial agents containing organic material,

to regular hand cloths and fab- In addition, rapid evaporaflon

rics may be having a lasting residl1al

Appropriate Disinfectant,
Antiseptic, or Sterilant
The choice of anriseptic, disinfectant, or sterilant (or
combination) depends on several factors including, but
not I imited to, risk of infection associated with the use
of each agent, intrinsic resistance of the microorganism,
in situations in which
is limited (e.g., home
skin-drying effect, emollienLI
added to hand-use antiseptic formulations. Because of
alcohols' flammability, they should be used and stored
in cool and well-ventilated areas. Their complere evap­
oration must be allowed before use of any flame,
cautery, or lasers.
 Miscellaneous An t i m i c rob ial Agents: Disinfectants, A n ti s e p t ic s , Sterilants and Preservatives
Aldehydes
Formaldehyde and glutaraldehyde (sometimes called
cold sterilants) are used for high-level disinfection or
sterilization of medical instruments that cannot toler­
ate exposure to the hig h temperatures required for
steam sterilization (autoclaving). Thus, they are used
for sterilizing plastic and rubber and equipment that
cannot be autoclaved. By cross-linking proteins and
nucleic acids, aldehydes inactivate a broad spectrum
of rganisms and viruses. Aldehyde disinfection
m ic ro o
or sterilization may fail i f
dilutions are below effective
concentrations, if organic material is presenr, or if the
liquid formulation is unable to penetrate into crevices
in medical insuuments. For this last reason, circulating
baths can be used to increase penetration of aldehyde
solutions, while decreasing exposure of the operator to
irritating fumes.
Formaldehyde is available as a 40% weight/volume
solution in water (100% formalin). At a concentration
or 8%, rormaldehyde exhibits a broad spectrum of
acrivity against bacteria, bacterial toxins, spores,
viruses, and fungi. Destruction of spores may take up
to 18 hours, but the speed of aerion may be increased
by so l ution in 70% alcohol. Alcohol probably strips
protective lipids, allowing formaldehyde better access
to the pathogen. Formalin is used for high-level disin­
feerion of hemodialyzers, preparation of vaccines, and
embalming of tissues.
A 2% glutaraldehyde solurion is activated by
alkali for use as a broad-spectrum disinfectant. Specific
applications for its use include disinfeering respiratory
therapy equipmenr, physical therapy whirlpool tubs,
and dialysis treatment equipment. Glutaraldehyde is
round in commonly used produers such as Cidex,
Hospex, and Sonacide. While glutaraldehyde has
greater sporicidal ae rivity than formaldehyde, it may
nor be as effective at kiHing M tuberculosis. Once acti­
vated by alkali, glutaraldehyde begins to polymerize.
Thus, its activated shelf life is about 2 weeks. Test strips
are available to measure aerivity.
Formaldehyde and glutaraldehyde are highly irri­
tat i ng to the skin, eye, and respiratory traer even at low
levels for shorr periods. Formaldehyde gas has a dis­
tinctive, pungent, and irritating odor that is deteerable
even at extremely low concentrations (<1 ppm). The
449
Occupational Safety and Health Administration
(OSHA) has declared that formaldehyde is a potential
carcinogen and has established an exposure standard
that limits the 8-hour time-weighted exposure of
employees to0.75 ppm (permissible exposure limit
[PEL]). However, for sensitized individuals, odor may
not be an adequate indicator of the presence of
formaldehyde and may not provide a reliable warning
of hazardous concenrracions. Because it is slightly heav­
ier than air, vapors can result in asphyxiation in poorly
venrilated, enclosed, or low-lying areas. Glutaraldehyde
solutions are pale yellow liquids with a rotten-apple
odor. Although OSHA does not currently have a
required PEL for glutaraldehyde, the National Institute
for Occupational Safety and Health (NIOSH) has
established a recommended exposure limit of 0.2 ppm.
There are several ways to minimize or limit occupa­
tional exposure to the aldehydes, including ensuring
the agents are used in fume hoods with exhaust venti­
lation, using only enough to perform requi red disin­
fecting procedure, avoiding skin contaer by use of
personal protective equipmenr (PPE) such as gloves,
goggles, face shields, and respirators. Gloves should be
made of nitrile or butyl rubber because latex gloves do
not provide adequate protection.
Heavy Metals
For many years, heavy metal salts were used as anti­
septics and disinfectants because of their ability ro
denature proteins. Most heavy metal ion preparations
are now considered to be too toxic for routine use.
However, mercury and silver still have a limited num­
ber of applications.
Mercury is an environmental hazard, and many
strains of bacteria have developed resistance to mercu­
rials. While the use of mercury-containing preserva­
tives has declined in recent years because of an
increasing awareness of the theoretic potential for neu­
rotoxicity, thimerosal is still used as a preservative
(0.001 to 0.004%) in numerous biologic and drug
products, including immune sera, antitoxins, and cer­
tain vaccines. Notably, thimerosal was removed from
or reduced to trace amounts in all vaccines rourinely
recommended for children :::.6 years of age except for
inAuenza vaccines. Mercuroch.rome, generically known
450 CHEMOTHERAPEUTICS
as merbromin, was a po p ula r ropical antise ptic for
years. In 1998, erIe FDA declared merbromin "not
generally recognized as safe and effective" because of
conc e rns about its merc u r y contenL Although disrri­
bution has effectively been discontinued in the United
States, it is still available in most other countries.
Inorga nic silver salts are strongly bactericidal. Bac­
terial (and proba b l y fungal) silver sensitivity relates ro
silve r's ability ro ir rev ersi b ly denature key enzyme sys­
tems. Silver exhibits low roxicity in hu m a n s, with
minimal expected risk from clinical exposure by der­
mal applications or through urologic and hematoge­
nous routes. Silver sulfadiazine (l %) is a widely used
safe and effective ropical cream used ro hel p preve n t
gra m -positive and gra m -negative bacterial colonization
of burned skin and tissues. Ph ysical thera p ists should
be aware that a blue-black pseudoeschar forms over the
wound surface that must be removed before more
cream is applied or wound h ea l i n g will be hindered.
Over the past 5 years, silver has undergone a ren­
aissance as a topicaJ antibacterial agent in wound heal­
ing. It is inc o rporated into v irtuall y all classes of
wound dressings. The popularity of silver-based
antimicrobial dressings may be due to new formula­
tions all owin g slow and sustained release of silver,
newer research indicating that colonized wounds dis­
play delayed wound heali ng, and aggressive manufac­
turer marketing. The major i t y of in vivo studies
indicate that silver dressings decrease wound biobur­
den and may be effectiv e against antibiotic-resistant
Staphylococcus, Pseudomonas, Entero­
organisms (e.g.,
coccus); however, bacterial resistance may occur.
Although some evidence suggests that silver retards
wound epithelialization, the majority of in vivo evi­
dence suggests that silver is not cytoroxic ro viable cells.
Ha10gens ( I o d ine , Iodo phors, Chlorine)
Iodine and lodophors
Iodine antiseptics have a wide spectrum of antimicro­
bial and antiviral activity. Thus far, microorganisms
appear unable ro develop resistant srrains to iodine .
Iodine in a I :20,000 solution is bactericidal within one
minute and s por icid al within 15 minutes. It is usuall y
used in an alcohol solution called tincture of iodine as
a preoperative antiseptic for intact skin. Although
iodine pre parations are ef fecti ve bactericidals, many
studies have demonstrated some degree of cyroroxicity,
impaired wound healing, and reduced wound strength.
In addition, iodine use is decreasing because of serious
hypersensitivity reactions and its p ro pensity ro stain
clothi ng and dressings.
Iodophors are mixtures of iodine with solubilizing
agents such as surfactants or povidone. Iodophor top­
ical solutions release free iodine, but are more gentle to
the skin, less likely ro provoke hypersensitivity reac­
tions, and less likely ro stain fabric than tincture of
iodine. Although they maintain g er m ici d al action, the
effectiveness of any iodo phor depends on the percent­
age of released free iodine. They may be used as anti­
se ptics or disinfectants, with the latter co nta i n i n g more
free iodine. The most common iodophor is povido n e­
iodine (polyvinylpyrolidone [PVP]); m a r k e ted as Beta­
dine. Povidone itself has no germicidal acrion; it
co n trols the release of the inorga n ic io d ine. Pov idone­
iodine is widely used for cleaning dirty wounds, scrub­
bing surgeons' hands, and patients' int ac r preoperative
surgical site. Povidone iodine has not been proven to
be effective for decontaminating medical equipment.
Chlorine
When chlo ri n e dissolves in warer, h y pochlo ro u s acid is
produced. Chlorine is a fairl y universal and inexpen­
sivedisinfectant. IE is foun d mosr commonly as a
5.25% sodium hypochlori te solution in rhe form of
common household bleach. D e pend ing on the con­
centration, sodium hypochlorite is effective against
most common pa thogens , including H IV, tuberculo­
sis, hepatitis Band C, fungi, antibiotic-resistant mains
of staphylococci, and enterococci. The Centers for
Disease Control and Prevention (CDC) recommends
a 1: 1 0 dilution of 5.25% household bleach (5000 ppm
of available chlorine) for disinfecting blood sp i l ls. At
this concentration, most pathogens and spores are
killed or inactivated. The exception is that a concen­
tration range of 1,000 to 10,000 pplll is required ro
kill mycobacte r ia. In a recent review of 33 studies,
sodium hypochlorite was effective for sterilization at
a co n centratio n of 5000 ppm for 5 minutes and for
disinfection at 1000 ppm for 10 m i n ute s . Dilutions of
 Miscellaneous Antimicrobial Agents: Disinfectants, Antiseptics, Sterilants and Preservatives
sodium hypochlorite in water (pH 7.5 to 8.0) will
rerain antimicrobial activity for months if kept in
tightly closed opaque containers. However, frequent
opening and closing markedly reduces its efficacy.
Because chlorine is inactivated by blood, serum,
feces, and protein-containing materials, organic mate­
rial must be removed from the surface to be disinfected
prior to use of sodium hypoch.lorite. Th.us, bleach is an
excellent disinfectant, but a poor cleaner. After clean­
ing, a l: I 0 solution is effective simply by being wiped on
and left to dry. Extreme caution must be taken not to
combine sodium hypocl110rite with either ammonia or
with any acid because irritating chlorine gas evolves. If
sodium hypochlorite solution contacts a product con­
taining formaldehyde, a carcinogenic compound results.
The best practice is not to add anything to sodium
hypochlorite except warel·. Sodium hypochlorite
solutions are caustic to the skin and eyes, so users
should wear rubber gloves and-if venrilation is not
ideal-goggles. Sodium hypochlorite solutions are
corrosive to aluminum, silver, and stainless steel.
Chlorhexidine
Chlorhexidine gluconate is a water-soluble antisep­
tic whose bacteriostatic and bactericidal properries
arise from its ability to disrupt bacterial membranes.
It is more effective against gram-positive cocci and
mycobacteria and less effective against gram-negative
rods. It also has moderate activity against fungi and
viruses. Chlorhexidine inhibits spore germination
(unlike alcohol-based antiseptics), and is effective in
the presence of blood and organic materials (unlike
sodium hypochlorite).
One of the primary uses of chlorhexidine is as an
oral mouthwash used in [he prevention and treatment
of gingivitis. This application may be appropriate in
patients who cannot independently or adequately brush
their teeth because it provides up to 24 hours of antimi­
crobial activity. Nondental uses for chlorhexidine
include preoperative skin preparation and antiseptic
hand wash (Hibiclens: 4% chlorhexidine gluconare)
against MRSA. Chlorhexidine is inactivated by anionic
and nonionic compounds found in many mouth­
washes, toothpastes, soaps, and moisturizers. Chlorhex­
idine mouth rinses should be used approximately
451
2 hours after use of other dental products. Likewise,
hand moisturizers or soaps should nor be used after
hand washing wirh chlorhexidine immediately prior ro
parient care. Because chlorhexidine binels strongly ro
the skin and mucosa, it has significant residual activ­
ity; it inhibitS the proliferation or survival of microor­
ganisms after application. Often, low concentrarions
(0.5% ro 1.0%) of chlorhexidine are added ro alcohol­
based hand-washing preparations ro increase the resid­
ual activity of alcohol alone. Chlorhexidine is safe for"
cleansing the skin of adults and infanrs, and has a low
potential for eliciting skin sensitivity. Although uncom­
mon, skin irritation is concentration dependent, so
products containing 4% chlorhexidine are the most
likely to cause skin reactions with frequent use. Eye
contact should be avoided because it can cause corneal
damage.
Phenolics
Phenol was the first disinfectant ro be used in clinical
medical practice. Although effective, it is highly cor­
rosive, roxic upon absorption, and carcinogenic. Many
less roxic derivarives of phenol have been developed.
Among the mosr popular are hexachlorophene and
chlorhexidine (discussed above).
Phenolic disinfectants are commonly used for
hard surface decontamination in hospitals (e.g., floors,
counters, beds). Phenolics are bactericidal (including
mycobacteria), fungicidal, and capable of inactivating
many viruses such as HIV and herpes simplex types
land 2. Phenolics do not destroy spores.
Because of irs bacteriostatic properties (especially
against 5 aureus) , hexachlorophene was widely used as
an antiseptic hand wash in hospitals. It has residual
activity for several hours after use and gradually
reduces bacrerial counts on hands after repetitive use.
However, with repeared use, hexachlorophene is
absorbed through the skin. In 1972, the FDA warned
rhat hexachlorophene should not be used routinely ro
bathe infants because of its potential neurotoxic effects.
Hexachlorophene should nOt be used ro batlle patients
with burns or extensive areas of sensitive skin. Soaps
containing 3% hexachlorophene are available by pre­
scription only, and routine use of hexachlorophene is
generally not recommended for hand antisepsis.
4 5 2 CH E M OTHERAPE U TICS
Peroxygen Compounds
When used dr appro p r i a re concentrarions, rhe perox­
ygen co m p o u n ds , hyd rogen p eroxide and peracetic
acid, are usefu l as d is i n fecran ts and s [eri l a n ts. Thei r
advan rages i n clude effec[iveness aga i nsr a w i d e vari e ry
o f organ i s m s ( bacreria, yeas r, fu ngi, v iruses, and
s p o res) and rhe facr rhar the i r decom posi r i o n p rod­
ucrs (oxygen and wa rer) are n o n toxic. The p ri ma ry d is­
advan tage is a rarher shorr-l ived a nt i m icro b i a l effect.
Hyd rogen peroxide's ki l l i n g abiliry is d u e ro rhe
hyd roxyl rad ica l, which i s o n e o f rhe strongest oxida n rs
k n o w n . It is a n effective d i s i n fecra n t w h e n used fo r
i n a n i ma te o bj ects w i th low water co n t e n t . Anaerobes
a re most sensi rive beca use they do nor produce cata­
lase, wh ich breaks d own peroxide. In the home, h yd ro­
gen perox i d e c a n be fo u n d in d i l u ted fo rm (3% ro
1 0 % ) , whereas i n d u s t r i a l uses i n vo lve concentra ted
so l u ri o n s (30% o r g rea rer) . Hydroge n peroxide is n O [
s ta b l e; ir rnust be pro rected from l i g h t and kep t in a
coo l place because l ight a n d heat ex pos u re cause degra­
d a ti o n . Hydroge n perox ide is used ro d is i n fecr s u rfaces
s uch as res p i ra tors , plas tic ea ring u rens i l s , and so ft co n­
tacr lenses. To be a n effective s poricidal, co ncentrations
o f 1 0 ro 2 5 % a re req u i re d . D i lute hyd rogen perox i d e
is u s e d as a m o u thwas h ro h e l p c o n trol plaque,
a l t h o ugh i r has n o t been p roven ro be effective i n c r i t­
i caJ l y i l l parien ts . Final ly, hydrogen peroxide was pre­
viously used in 11m aid ki rs to disinfecr and debride
wounds. When appl ied to a wo u n d , hyd rogen perox­
ide co m b ines wi rh caralase p roduced in tiss ues, decom­
posi n g i n to oxygen and water a n d prod u c i n g
effe rvesce nce. I [ w a s r a r i o n a lized [ h a c r h i s p rocess
h e l ped loosen n ecro ric or i norga n i c rn a [erial [hat
m ig h r inh i b i r wound heal i ng. However, hyd rogen per­
oxide damages hea l r h y ce l l s ( ke rati nocyres and II b ro­
b l as rs) req u i red fo r wo u n d heal i ng. T h u s , hydrogen
perox ide is no lo nger reco m me n d ed fo r wo u n d care.
Peraceric acid is a mixrure of hydrogen peroxide and
aceric acid i n a wareLY so]u rion. Si nce i[ is explosive i n
pure form , i r i s used i n dilu[e solurion and transpo ned in
ven ted containers ro prevenr increased pressure as oxygen
is released . As wirh hydrogen peroxide, rhe hydroxyl rad­
ical released fro m peraceric acid is the ierhal species. Per­
aceric acid is a monger bacrericidal and sporicidal agen r
rhan hyd rogen peroxide. Ar room rem peraru re, 250 to
5 0 0 ppm peracric acid is effecrive againsr most bacteria
when applied to con tam i n a ted surfaces fo r 5 m i n u res.
Destruction of spores is i ncreased with both a rise in tem­
pera ture and an i ncrease in co n ce n t ration (500 to
300,000 ppm) . Effecriveness is sl ighdy decreased by the
presence of organ ic matrer, bu r ca n be mai n ra i ned by an
increase in concen tration . Peraceric acid may be form u­
l a ted as a l iquid spray or mop-on sol u tion. Automaric
sterilization sysrems using low concen trations o f peraceric
acid (0. 1 % to 0 . 5%) have been designed to sterilize med­
ical and dental i nsrru menrs .
Quaternary Ammonium Compounds
Qu arernary a m m o n i u m com p o u n d s ("quats") a re
catio n i c surface-active deterge n ts widely used i n hospi­
rals fo r disi n fection of noncri tical hard surfaces such as
bench rops and fl oo rs . They a re mosr l i kely to be
enco u n tered by hea l th-care wo rkers i n cenrral s u p ply,
housekeepi ng, and patien t and surgica.l servi ces areas.
Benzalkonium chloride is the mosr wid e l y used quar
a n risepric. Orher quats used as amisep tics are cetrimide .
ce rylpyridium chloride, and benzethonium chlori de.
Qua re r n a r y a m m o n i u m co m po u n ds a re mosrly
bacteriosta r i c. sporisraric, and fu ngisra t ic. alrhougfl
rhey a re m icro b i ci d a l aga i n s t certa i n pa thogens ar
higher co n ce n trati o n s . A n t i m icro b i a l act i v i ty p roba­
b ly invo lves ce l l mem brane disruption . They a re i nef­
fective aga i ns t m ycobacteria a n d gra m - n ega rive
bacreri a . In add i t i o n , t h e i r a n t i m i cro b i a l acriviry is
an tago n ized by the p resence o f orga n ic ma terial, soaps,
many non i o n i c de tergenrs, and calci u m , m agnes i u m ,
fe rric, a nd al u m i n u m i o n s . Several s r ra i ns o f 5 aureus
h ave recen tly been described w i t h generic res is ta nce ro
quaternary a m m o n i u m compounds. Because con tam­
i nation of s rock solu tions w i t fl gram-negarive rod s ca n
be a p roblem , rhe CDC h as reco m men ded that ben­
za l ko n i u m c h l o r i d e and other s i m i l a r q u a te r n a ry
a m m o n i u m compo u n d s nor be used as a n tiseprics.
Sterilants
When a1l microbial l i fe, i ncludi ng h ighly resista n r bac­
rerial endospores, m u s t be destroyed, s r e r i l iza r i o n is
req u i re d . S reri l i ry is a n abso l u te rerm mean i n g there
a re no rela rive d egrees of s ter i l i ry. Steri l iza tion can be
performed by phys ical or c h e m i c a l m ea n s . Du ring
 M i s c e l l a n e o u s A n t i m i c ro b i a l A ge n t s : D i s i n fe c t a n t s , A n t i s e p t i c s , S t e r il a n t s a n d P r e s e rva t i v e s
chemical steri l iza t i o n , s te r i l a n rs a re appl ied ro m a teri­
als fo r appropriate times and tem pera t u res .
The recom mended s teriliza t i o n fo r biohazardous
material is au roclaving-the use o f pressu rized steam a t
a temperature o f 1 20°C for a m i n i m u m of 30 m in u tes.
Au roclaving medical and s u rgical i nstruments can
be done when these materials do not contain plas tic or
rubber. In the la tter case, gas steri l ization may be per­
fo rmed . Al though few gases are able to kill m icrobes ,
ethylene oxide gas is a h igh ly effective disinfectan t, and
kil l s spores rapid ly. Wides pread use of ethylene oxide is
l i m i ted by i ts ext reme fl am mabil i ty, i ts cost, and i ts c l as­
si fication as a m u tagen and carci nogen . O S HA's per­
missible exposure level fo r ethylene oxide is 1 p pm as a
t i me-weigh ted meas u re . Al ternative sterilan ts
increasi ngly being employed, such as vapor phase hyd ro­
gen peroxide, peracetic acid, ozone, gas plasma, chlo­
rine d i oxide, fo rmaldehyde, and p ropylene oxide.
Preservatives
Preservatives are required to p reve n t m i cro b i al grow t h
a n d co n tam ination i n m a n y pharmaceu t i cal , cosmetic,
and therapy- re la ted p roducts i n m u l t i ple-use con tai n ­
ers s u c h a s u l traso und gel o r fri c t i o n m assage crea m .
The ideal p reserva tive m u s t b e effective aga inst a broad
spectrum of m icroorganisms, sol u b l e, s t a b le, and n o n ­
i r r i tati ng to tissues r o which t h ey a r e applied.
Commonly used p reserva t i ves include benzoic
acid and sal ts , parabens, sorbic acid and sal ts, p ropy­
lene glycol , p h e n o l i c compounds, q u a ternary ammo­
nium sal ts, al co hols, and mercu rial s such as thimerosal .
To i n h i b i t S aurem and Escherichia coLi, the concen­
tra t i o n o f p ropylene glycol m U S t exceed 1 0% . At this
conce n tra t i o n , propylene glyc o l i s a sk i n sensitizer.
Al tho ugh rare, cases of con tact derma titis from p reser­
va t i ves in u l tras o n i c gels h ave been reponed . Health­
care profess i o n a l s should i nves tiga te the type a n d
concen tra t i o n o f p reserva tive i n a n y pro d u c t prior t o
patient appl i c a t i o n .
REHABILITAT I O N F O CUS
Phys ical thera p i s ts, l i ke al l health-care wo rkers , s h o u l d
fo l low sta ndard preca u ti o ns w i th all p a t i e n ts rega rd­
less o f the i r i n fection status. These practices i nclude
45 3
rou r i n e hand was h ing. befo re a n d afte r co nract with
each patient and hand dry i n g with clean one-use rowels,
wearing appro priate PPE (e. g . , gloves, gown, eyewear)
when trea ting p a t i e n ts with whom there is p o t e n t i a l
c o n tac t w i th b l o o d , m u c o u s m e m b ra n e s , o r o t he r
only body fl u i d s . I f a speci fi c d i ag n o s i s o f a trans m i ss i ble
i n fecti o n has been m a d e , t h e ra p i s ts sho u l d fo l low
fac i l i ty g u i d e l i nes regard i n g a d d i t i onal p reca u t i o n s
t h a t need c o be taken b ased o n h o w t h e i nfec t i o n is
trans m i t ted.
S i nce physical therap i s ts treat m u l ti p l e p a t i e n ts
w i t h thera py-related e q u i p m e n t , ens u r i ng t h a t th i s
equ i pmen t is no t a n infection reservo i r o r r r a n s p o r c
vehicle is of the utmost impona n ce. Thera p i s ts m u s t
a re eval u a te all e q u i p m e n t a n d ask how e a c h i tem can be
s a fely d i s i n fected between each p a t i e n t .
Al t h o u g h fol lowi n g prod u c t reco m m e n d a t i o n s
fo r d i s i n fe c ti o n o f e q u i p m e n t i s a s tr a i g h t fo rward
policy, the type o f d i s i n fe c ta n r chosen i s o fte n fac i l ­
i ty dependen t , a n d d i s i n fec t i o n p ro cedu res a re ch o ­
s e n b a s e d u p o n the freq u e n cy o f e n c o u n ce r i n g
s pecific p a thogens. I n o u rp a t ie n r cl i n i c s , i nd iv i d u a l
trea tmen t tables a n d m a ts c a n be p ro tected with clean
s i n g l e - u s e s h e e t s . B e tween p a t i e n ts , these s u rfaces
s h o u ld t h e n be w i ped down w i t h a broad-spec t r u m
sp ray d i s i n fecta n t a c t ive aga i n s t m a n y fun g i , viruses,
a n d strains o f Strep tococcus a nd Staphylococcus (e . g . ,
M a t e-Kle e n , Whiner) . I n h o s p i tal set tings , m u l t i p l e
p a ci e n t u s e t h e ra py eq u i p m e n t s u ch as w a l kers,
c r u tches, and ca n es m u s t a l s o b e d i s i n fe c t e d , w i t h
careful a t te n t i o n b e i n g p a i d [0 h a n d -grippi n g s u r faces
a n d , if poss i b l e , a b r o a d e r-s pectru m d i s i n fe c ta n t
s h o u l d b e used .
The e p i d e m i ol o gy o f C difficile i n fec t i o n p r o ­
v i d e s a n imp o rtan t e x a m p l e . I t h a s been shown that
p a tien ts recei v i n g reha b il i ta t i o n servi ces i n a h o s p i tal
s e t ting have a 2 . 6- fold h i gher chance of deve l o p i ng
C difJici le- assoc ia ted d i a rrhea (CDAD ) , a p o te n t i al l y
fa t a l i n fec ti o n , c o m p a red to p a ti e n ts no t rece i v i ng
such services. H owever, a p p ro p ri a te i n fec t i o n c o n ­
trol measu res can decrease the i n c i d ence o f CDAD
by 5 0 % . Preve n t i n g the s p read o f C difficiLe s p o res
a m o n g patie nts in i ns t i t u t i o n a l s e t t i n gs req u i res i s o ­
l a t i o n o f the C difJicile- i n fec ted p a t i e n t , use o f b a r ­
rier p reca u t i o n s , a p p ro p riate h a n d hygie n e , a n d use
454 C H E M O T H E RA P E U T I C S
o f a p p ro p r i a te s p o r i c i d a l age n ts o n e n v i ro n m e n t a l
s u r faces . Phys ical the r a p i s ts should red u c e the
i n c reased i n c i d e n c e o f CDAD associ ated with reh a ­
b i l i t a t i o n by h a n d was h i n g wi th s o a p a n d wa t e r
s i n ce alco h o l - b a s e d h a n d c l e a n e rs d o n o t e r a d i cate
C difficile. In a d d i t i o n , t herapy-re l a ted e q u i p m e n t
a nd o t h e t h a rd e n vi ro n m e n tal s u r faces t h a t h ave
co m e in c o n t a c t wi th C difficife- i n fected p a tien ts
s h o u l d be d i s i n fected wi t h b l each fo r approx i m a te l y
10 ro 1 5 mi n u tes r o i n ac tivate s p o re s .
I n s i t ua t i o n s i n wh ich patients h a v e b e e n i d e n t i ­
fied as h a v i n g a read i l y transm issi ble pathoge n , t he r ­
a p i sts m u s t fo l l ow i s o l a t i o n p reca u t i o n s . I d e a l l y,
thera py e q u i p m e n t sho u l d be ded i c a ted ro that p a r­
t i c u l a r patien t . If eq u i p m e n t m us t be used with othet
p a t i e n ts (e . g . , wh i r l p o o l , u l t raso u n d) , co n s u l t fac i l ity
i n fection co ntrol p o l ic ies regard i ng what type of d is­
i n fe c t a n t m u s t be used ro eradicate the p a r t ic u l a r
p a t ho gen . I f a p pro p r i a te d i s i n fec t i o n c a n n o t take
place i ns i d e t h e p a tien t's roo m , d i scuss wi t h i n fection
c o n trol s p ec i a l i s ts a t the faci l i ty rega rd i n g the safest
way ro t ra n sport e q u i p m e n t ro the locatio n where it
can b e cleaned ro decrease t he potential o f tra n s m i t ­
t i n g i n fe c t i o n e n ro u te .
Hea l t h-care p r o fessionals s h o u l d u n derstand the
advan tages and d isadvantages of each a n tiseptic or d is­
i n fectant i n orde r ro choose the most appropriate age n t
fo r a given a p p l icati o n . I t i s cri t i cal that health -care
p ro fessionals a lways ask pa tients a b o u t pote n tial sen­
s i t i v i ties ro age nts , and that therapists reco g nize signs
and sym p r o m s o f alle rgy o r se nsitivities ro a ge n ts .
I n h i b iti n g o r des troying p athogens m u s t b e performed
w h i le p rovi d i n g adeq u a te p ro tec t i o n fo r the p a t i e n t
a n d t h e heal th-care pro fess i o naL Whe n wo und care is
a c o m p o ne n t of a p a t ie n t's t re a t m e n t , the therap ist
m u s t a p p l y knowledge rega rd i n g the pote n tial (e . g . , i n
v i tro) o r d e m o n s t r a ted e ffect o f a n t isep t i cs o n the
wo u n d - healing p rocess.
Befo re selecting an a n tisep ti c o r d is i n fecta n t o r
work ing i n a n e n v i ron me n t where these age n ts a re
used , the thera p i s t s h o u ld answer several questions: (J)
Wha t a re t he a c t i ve i n g red i e n ts i n the a ge n ts used
i n t h e reh a b il i tation e n v i ro n me n t ( e . g . , q u a te r n a r y
a m m o n i u m com po u nd s , phenolics, chlorine bleach,
iod i ne prod ucts) ? (2) Aga i ns t wh ich microorga nisms
is the age n t effective? (3) Is i t safe fo r d a i l y use) (4)
Sho u l d PPE be wo rn and what type? (5) Are perm iss i­
ble expos u re levels set by O S HA or N I OS H ? (6) What
co nditions m ust be met fo r the age n t to be the most
(7) Will it d a m a ge s u r faces
effe c t i ve a n t i m i c ro b i a l ?
cleaned with it?(8) Is it safe ro m ix with another agent
ro maxim ize anti bacter ial e ffectiveness ? (9) Is i t a "o ne­
step" d i s i n fec tant-cleaner or a d i s i n fectant? ( e . g . ,
chlorhexidine vs sod i u m hypoch l o r i te) ? ( 10) What is
the cost of the p ro d u c t )
F i n a l ly, product i n s t r u c t i o n s fo r d i l u t i o n r a t i o
m us t always b e followed carefu l l y fo r safe ty a n d effec­
tive ness . I nap propriate choice, conce n tratio n , o r appli­
cation o f a n y d i s i n fecta n t or a n tisep t ic age n t may
res u l t in u ns u ccessfu l a n t i m icro b i al e fficacy, co m p ro­
mised safety, o r both.
CLINICAL R ELEVANCE FOR
REHABILITATION
Adverse Drug Reactions
S o m e of the a n t i m i c r o b i a l d r u gs descri bed in t h is
cha p ter have pote n ti al adverse effects tha t may nega­
tively i m pact a patien t's reha b i l i tation progress . Each of
the d i s i n fectan ts and a n t i se p t i cs discussed also h as
u n iq u e d i sadvan tages. Adverse or poten tially rox ic
reactions or sensitivi t ies ro t hese age n ts may a ffect the
p a t ie n t , and also the physi cal therapist using o r co m­
ing i n ro con tact wi th the m .
Miscellaneous antim icrobial agents
• D izzi ness is a co m m o n adverse effect o f metro n ida­
zole a n d d a p romyc i n .
• Myo p a th ies m a y occ u r wi t h dapromyc i n .
• Peripheral neu ropathies may o cc u r wi th d ap romycin
and n i tro fu ra n to i n .
• N i trofu ra n ro i n may produce i n a ccu ra te res u l ts i n
s o m e u r i ne glucose tests .
Disinfectants, antiseptics, sterilants, and preservatives
• Alcohols a n d c h l o rhexid i n e can produce excessive
d rying of the s ki n , especiaJ ly when used frequen t ly.
Alcohols a re ve ry fla mmable.
• Silve r allergy is a co ntraindication for using any si lver­
impregnated o r si lver-based wo u nd - ca re p roduct.
 M i s c e l l a n e o u s A n t i m i cro b i a l Age n t s : D i s i n fe c t a n t s , A n t i s e p t i c s , S t e r i i a n t s a n d Pre s e r v a t i v e s
I o d i n e a n d i o d o p h o r s h a v e va r y i n g d e g r ee s o f
c y to t o x i c i t y d e p e n d i n g o n the c o n c e n t r a t i o n o f
fr e e i o d i n e . S o m e p a t i e n t s h a v e a l l e r g i c r e a c ­
t i o n s t o i o d i n e ; t h e y o ften rep o r t t h i s a s " sea fo o d
a l l e r gy. "
• So d i u m h ypodtlo r i t e (bleach) is inactivated b y o rganic
ma te rial . In a dd i tio n , b leach em i ts u n pl easa n t odors
and reacrs with o th e r chemicaJ s ro create toxic gases.
• Hy d r o ge n p e r o xi d e da m a ge s hea l rhy k e ra t i no c y t es
and fi b roblas ts .
• Som e p r e s e r vat ves
i have t h e po te n t i a l t o act as ski n
sensi t izers.
Effects Interferin g with Rehabilitation
Miscellaneous antimicrobial agents
• D i zzi n e s s m a y li m it p a t i e n t s ' a b i l i t y to c h a nge
po s i t i o n s and thei r ab i l i t y to p a r tic i p a te in aero­
bic exe r c i s e .
• Myo p a t h i es m a y p r ese n t a s m uscle pain o r decreased
m u s c l e s t r e n g t h . S y mp to ms d e pe n d on the seve r i ty
of the m y o p a r hy as well as wh i c h m u s c l e gro ups are
i n volved . Diffic u l ty r is i n g from chai rs, c l i m b i n g or
d es c e n d i ng s ta i rs, ge t ti n g o u t o f the b a t h r u b, shav­
i ng, a n d b r u s h i n g ha i r s u ggests p rox i m a l m uscle
wea kness . D i fficul t i es with h a n d w r i t i n g a n d grasp
i n d i cate d istal m us c l e weakness .
• Per i p he r a l neu ropa thies m ay b e p u rely s e n s o ry or
m i xed se nso r i m o to r, m a n i fested by n u m bness, ti n­
gl i n g, p i n p r i c k sensa ti o n ( p ares t h es i a s ) in fm g e rs
and to es , J n d p o s s i b l y m u s c l e weakness.
• Som e g l u cos e u ri n e tes ts (e . g . , C l i n i test) cannot be
u sed as a ma rker fo r gl ucose u rine concentra t i o n fo r
p a t i e n ts t a k i n g ni t ro fu ra n to i n .
Disirifectants, an tiseptics, sterilants, and preservatives
• E xc ess i v e ski n d r y n ess due to h a b i tual use of alco­
hols or c h l o r h e x id i n e can lead ro skin i rri ta ti o n or
b reakdow n .
• The fl a m mability o f alcoho l - based h a n d a n t i se p t ics
l im i ts t h e i r use to cool, wel l-ve n t i la ted a re as free o f
spa rks or fla m es . This m a y p reve n t t h e i r use du r i n g
certain home-based re habil itation trea tments.
• Use of s i lver- i m p regna ted w o u n d -care p ro d u c ts
s ho u l d be avo i d ed in individuals with an al lergy o r
sens i tivity r o s i lve r.
455
Iod i n e a n d i o d o p h o rs i m p a i r wo u n d h e a l i n g a n d
re d u c e wo u n d s tren g t h and may cause serious
h y p erse n s i t i vi ty react i o n s .
• To d i s i n fec t a su rface e ffectively, b o d y fl u i d s m u s t be
re moved p rior ro the use of sod i u m h y p o c h l o r i te , cre­
ati n g rwice the work for the heal th-care professional
res p o ns i b le for cleaning and d i s i n fecti ng biologic s p il l s .
Pri o r to choosing bleach for disinfect i o n , the the ra p i s t
m u s t also d e t e r m i n e whether the c h e m i cal u s e d (0
clean the area is safe [Q u s e w i th sodi um h y p ochlo ri te .
• Hyd ro ge n p e ro x i d e i n h i b i ts wo u n d h e a li n g .
• Qu a t e r n a ry am m o n i u m c o m po u nd s a n d c h l o rhex­
i d i n e a re rendered i n e ffe c t i ve in the p rese n ce o f
soaps a n d many n o n io n i c deterge n ts .
• Many p rod u c ts co m m o n ly used i n the re h a b il i ta t i o n
set t i n g s u c h as u l traso und gel an d friction m a ssa g e
cream c o n tai n p re serva t ives that have the pote n t ial to
cause all e rg ic skin reactions such as contact dermariris .
Possible Therapy Solutions
Miscellaneous antimicrobial agents
• To p reve n t loss of bal an ce , patients should be advised
not to change pos i ti o ns a bru p tly, and thera pis tS s h o ul d
pro v i de more assis tance in t ransfers and gai t as needed.
• Patient complaintS of p a res thes i as or weakness s h o u l d
be tho r o u gh l y eval ua ted and s y m p ro m s a n d signs
re p o r ted ro the attendi n g physician . T h e ra pis ts s h o u l d
b e alen r o the greate r l i ke lihood of perip heral neu­
ro pathies i n patientS with renal im p ai r m e n t o r d i a be tes
me l l i tus. Any pa tien t rakin g d a p to m yc i n who co m ­
plai ns of muscle p ai n or presen ts w i th muscle wealrness
should be reponed ro the p h ys ic i an fo r po s s i b l e assess­
ment of eleva ted cre ati n e p ho s p h oki n as e l e vels .
• Diabetic pa t i e n t s ta ki n g n i tro fu ra n t o i n s h o u l d be
a d v i s ed to use blood glucose m o n i t o r i ng to m e as u re
blood g l u cose levels . If u ri n e m o n i ro r i n g is neces­
sary, urine tests that are n o t affected by n i t ro fu ra n ­
toin (e. g. , C l i n i s t i x o r Tes-Tape) s h o u l d be used .
Disinfectants, antiseptics, sterilants, and p reservatives
• Avoid hand m o i s tu r izers a fter was h i n g h a n ds w i th
chlorhex i d i n e be c a u s e m o is tu r i zin g age n ts an tago­
n ize chlorhexi d i ne's a n t i m ic ro b i a l p r o p e r t i es . For
t h e r a p i s ts who c o nsistently use a l c o h o l - b ased hand
a. n r i se p t i cs , c hoo se p rod uc ts wi t h ad d ed em o l l iell t s
456 C H E M OTH ERA P E U T I C S
rather t h a n s e p a rate h a nd creams to ameliora te the
s ki n -d r y i n g e ffecr. H a n d c r e a m scan o ften act as vec­
tors fo r p at h o g e n s .
• W h e n u s i n g a l c o h ol - b a s e d a n t i s e p ti cs or d i s i n fe c­
ta n ts , t h e r a p i sts s h o u l d ensure t hat the a ge n t has
com pl etely eva p o ra ted befo re t h e use o f a ny e q u i p ­
m e n t t h a t co u l d p o te n r i a J ly create a s p a rk .
• In pat i e n ts with c h ron ic w o u n d s , t h e rap i s ts s h o u l d
i nq u i re a b o u t a n y known a l l ergi e s o r s e n s i t i v i r i es [0
s i lver p r io r to the u se of s i l ver- i m p regnated wound­
ca te p ro d uc t s o r silver sulfadiazine crea m . I n addi­
ti o n , t h e ra p i s t s s h o u l d re co g n i z e a nd r e po r t a n y
a d v e r s e r ea c t io n [ 0 t h e a t te n d i n g phy s i c i a n a n d
e n s ure t h a t the patient's med i c a l record r efl ects the
si lver a l l e rgy or s e n s i t ivi ry s i nce m a ny wo u n d care
a n d med ical p ro d uc ts c o n r a i n s i lv e r.
P R O B L E M - O R I E N T E D PAT I ENT STUDY
BriefHistory: The p a t i en t is a 64-yea r-o l d female
wi t h type I d i a be te s mellitus since age 1 0 . She was
ad m i tted to t h e h o s p i tal 1 0 d ay s ago fo r w o u n d
care of a ne uro p a t h i c right foot u l c e r i n fecte d with
M RSA. Prior to ad m ission, she was i ndepende n t
w i t h a l l a c t i v i t i es o f daily l i v i n g (AD Ls) , transfers,
and a m b u l a t i oll w i t h o u t a n as s i s t i ve device.
LtO'1"ent Medical Status and Drugs: A t admission,
th e pat i e nt w a s treated wi t h vancomycin to t rea t
[ h e M RSA i n fectio n . After 3 days, the u l cer
appeared (0 be w o rse n i n g, a n d i t w a s a l s o deter­
m i n e d that the S tllIre w i n fec ti o n was re s i s ta n t (0
van c o m yc i n . On d ay 4 a ft e r admiss ion, van­
c o m y c i n was d i s c o n t i n ued and t h e p a t i e n t was
s t a r ted on daily intravenous daptomyc i n . Reha­
b ilita t i o n precautions i n c l u d e n o we igh t b ear i n g
( N W B) on the ri g h t lower extre m i ty. Patient's c u r­
rent drugs i n c l ud e i n s u l i n a n d d a p t o m yc i n .
Rehabilitation Setting: The patienr has been par­
ticif)at i n g in reha b i l itation therapy twice a day since
th e second day of h er ad m is,� ion. On ev a l u a t i o n , the
• I o d i n e , i o d o p h o rs , and hyd roge n perox i d e should
n o t b e used t o d i s i n fect o r d e b r i d e wo u n ds.
A lco h o l - b ased d i s i n fe c t a n r s a re reas o n a b l y i n ex ­
p ens i v e and safe and c a n b e used if t h e co r ros ive
e ffects o f b l e a c h a re to b e a vo i d e d . T hese a g e n ts
s h o u l d be u s ed [0 d i s i n fe c t trea t m e n t t a b l es a n d
rehabilitation equipmen r between every p at i e n t . In
t h e p re s e n ce of o rga n i c m a te r i a l , ch l o r h e x i d i n e i s
s t i l l a n e ffec ti v e d i s i n fecta n t . I f s p o r i c i d a l effe e rs
a re req u i re d , an ad d i t i o n a l d i s i n fec ta n t m u s t b e
c h o s e n since c h l o r h e x i d i n e i s o n ly s po r i s ta t i c .
• Phys i c a l th era p i sts must k n o w the i n gred i e n ts i n
prod ucts ap p l ied to pati e n rs' skin. T h ey m u s t i n qu i re
w h e t h e r pa t i ents have known s e n s i t i v i ties or allergies
to s pe c i fi c p re s e rv a t i v es , be a b l e to re c o gn ize s k i n
reactions, a n d d i sco n ti n ue use approp ria tely.
no te d d ecreased strength in b i lateral u pper
thera p ist
and The p at i e n t req u i red
lower extre m i t ies ( 4 / 5 ) .
m oderate assistance fo r transfer from bed to chair.
S h e was a b l e to a m b ul a te 20 fee t w i t h a fron t­
wheeled wa l ke r w i th moderate assis tance fo r bal­
ance and maintenance of N W B s t a t u s o n the righ t
lower extre m i ty. For the fi rst 7 days of t h era py, t h e
pa t i e n t m a d e c o n s i s t e n t ga i n s i n s t rength a n d
a m b u la t i o n . S h e was
able to transfer i n depende n tl y
a n d a m b u l a te ove r 2 0 0 feet with a fro n t-whee l ed
walker with s ta n d b y assista n ce . Yesterday, when the
t h erapist a rrived at the patien t's ro o m , t h e p a t ie n t
complai ned of m uscl e ac hes and pai ns a n d dec l i ned
therapy. Today, the p ati e n t requires m i nimal ass is­
tance to transfe r fr o m a chai r to s t a n d i n g in t h e
wal ker b e ca u se
of leg weakness. She dec l i nes fu r­
ther therapy today beca use of persi s t e n t m u scle
pai n a n d cra m p i ng.
Pl'oblemlClilliCtlI Options: Onset o f m uscle pain
and wea kness 7 d ay s i n to rehab i l i ta t i o n t h era p y
wi tho u t an abr u p t pr og ress i o n in exerc i s e progra m
s i g n a l s another poss i b l e source fo r the p a tien t's
 M i s c e l l a n e o u s A n t i m i c r o b i a l A g e n r s : D i s i n fe c r a n rs , A n r i s e p r i c s , S r e r i l a n r s and P r e s e r v a r i ves 457

P RO B LE M - O R I E N T E D PAT I E N T S T U D Y ( Co n tin ued )

com p l a i n ts . Thep a t i e n t s com plaints of muscle pa i n

' it is likely that she also has some re n a l i m pairment,
began 5 days after she began i n travenous daptomycin wh ich may i ncrease the l i ke l i ho o d fo r
adverse effects
for trea tm e n t of the i n fec ted foot u lcer. Al though not since daprom ycin is p rim a ri ly excreted by the kid­
co m m o n , the adverse effect p rofile for daptol1lyci n n eys . The therap ist should rep o r t t h ese m uscu lar
i ncludes reports o f myop a th y characterized b y gen­
, symptoms to the ph y sician i m m e d iatel y If the .

e ralized m uscle pai n , cra m ps, o r weakness. Because myo pa t h y was ind uced by daprom ycin, it s h o u ld
the p a t i e nt has had diabetes for more than 5 0 years , resolve after daptomyci n is d iSCOnti nued.

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

M i s c e l l a n e o u s Anti m i c ro b i a l Drugs Benzoyl peroxide (generic)

To p i c a l : 2 . 5% , 5%, 1 0% l iquid; 5%, 5. 5%,
Methenamine hippurate (Hiprex, Urex) 1 0 % l ot i o n ; 5 % , 1 0 % c rea m ; 2 . 5 % , 4 % , 5 % , 6 % ,
O ra l : 1 . 0-g ta b l ets 1 0 % , 2 0 % ge l

Methenamine mandelate (generic) Chlorhexidine glue onate (Hibiclens, Hibistat, others)

O ra l : 0 . 5 - , l og t a b l et s ; 0 . 5 g/ 5 m L To p i c a l : 2 % , 4 % c l e a n se r , s p o n g e ; 0 . 5 % r i n se i n
suspension 7 0 % a l co h o l
Ora l r i n s e ( Pe r i d e x , Per i oga r d ) : 0 . 1 2 %
Metronidazole (generic, F1agy/)
O ra l : 2 5 0 - , 5 0 0 - m g ta b l e ts ; 3 7 5 - m g Glutaraldehyde (Cidex)

c a p s u l e s ; 7 5 0 - m g exte n d e d - re l ea s e I n st r u m e n t s : 2 % , 3 . 2 % so l u t i o n

ta b l ets Hexachlorophene (pHisoHex)

P a r e n t e ra l : 5 m g/ m L ; 500 m g for i n j e c t i o n To p i c a l : 3% l i q u i d ; 0 . 2 3 % foa m

Mupirocin (Bactroban) Iodine aqueous (generic, L ugol's Solution)

To p i c a l : 2 % o i n t m e n t , c re a m To p i c a l : 2 - 5 % i n water w i t h 2 . 4% sod i u m i od i d e
o r 1 0 % potass i u m i o d i d e
Nitrofurantoin (Macro dantin, generic)
O ra l : 2 5- , 5 0 - , 1 0 0 - m g c a p s u l e s , 2 5 m g/ 5 m L Iodine tincture (generic)

suspension To p i c a l : 2 % i o d i n e o r 2 . 4 % s o d i u m i o d i d e i n
4 7 % a l c o h o l , i n 1 5 , 3 0 , 1 2 0 m L a n d i n l a rge r
Polymyxin B (Polymyxin B Sulfate) q u a nt i t i e s
P a re n tera l : 5 0 0 , 0 0 0 u n i t s p e r v i a l for
Nitrofurazone (generic, Furacin)
i n j ect i o n
To p i c a l : 0 . 2 % so l u t i o n , o i n t m e n t , a n d c re a m
Ophth a l m i c : 500,000 u n its per v i a l

Ortho-phthalaldehyde (Cidex OPA)

D i s i nfectants, Anti s e pt i C S , a n d S te r i l a nts I n stru m e n t s : 0 . 5 5 % so l u t i o n

Benzalkonium (generic, Zephiran) Oxychlorosene sodium (Clorpa ctin)

To p i c a l : 17% conce ntrate ; 50% so l u t i o n ; To p i c a l : 2 g powd e r f o r so l u t i o n f o r i r r i ga t i o n ,
1 : 7 5 0 so l ut i o n i n st i l l a t i o n , or r i n se
458 C H E M OT H E R A P E U T I C S

Povidone-iodine (generic, Betadine) Silver nitrate (generic)

To p i c a l : ava i l a b l e i n m a ny form s , i n c l u d i ng To p i c a l : 1 0 % , 2 5 % , 5 0 % so l u t i o n
a e roso l , o i n t m e n t , a n t i se p t i c ga uze pad s ,
Thimerosal (generic, MersoJ)
s k i n c l ea n ser ( l i q u i d o r foa m ) , so l u t i o n , a n d
To p i c a l : 1 : 1 000 t i n c t u re a n d s o l u t i o n
swa bst i c k s