Infectious Disease Emergencies

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Infectious disease emergencies are conditions that have potential for
signicant harm to the patient if not recognized and treated promptly,
and for which timely and appropriate intervention may signicantly
improve outcomes. The following is a discussion of important infec-
tious disease emergencies.
ACUTE BACTERIAL MENINGITIS
Denition, Etiology, and Incidence
Bacterial meningitis is an inammation of the meninges caused by
bacteria. Acute meningitis is characterized by the development of
meningeal signs over the course of a few hours to a few days. The
important causes of bacterial meningitis are outlined in Box 1.
A passive survey conducted in the United States between 1978 and
1981 revealed an annual incidence rate for bacterial meningitis of 3.0
cases per 100,000 population.
1
During this period, bacterial menin-
gitis was predominantly a disease of children, the most common
offending pathogen being Haemophilus inuenzae. The introduction
of routine immunization of children against H. inuenzae type B in
the late 1980s dramatically reduced the incidence of infection with
this microorganism. A consequence was a decrease in the overall
incidence of bacterial meningitis and particularly in meningitis
caused by H. inuenzae, so that bacterial meningitis is now a disease
predominantly of adults.
2
Pathophysiology
The initial event is usually nasopharyngeal colonization with a
pathogenic microorganism.
3
This is followed by mucosal invasion,
bacteremia, and meningeal invasion.
4
A marked inammatory
response occurs in the subarachnoid space, but this response is inad-
equate to control the infection. This inammatory response results
in increased permeability of the blood-brain barrier. This is respon-
sible for the increased cerebrospinal uid (CSF) protein content seen
in patients with meningitis. Progression of meningitis leads to the
development of cerebral edema, resulting in increased CSF pressure.
Inammation of blood vessels traversing the subarachnoid space may
lead to their thrombosis. This can result in ischemia and infarction
of the underlying brain.
Clinical Presentation
Patients with acute bacterial meningitis usually present with head-
ache, neck stiffness, fever, projectile vomiting, and photophobia. In
more advanced disease, there is progressive clouding of conscious-
ness. On examination, neck rigidity may be seen and Kernigs and
Brudzinskis signs may be elicited. Cranial nerve palsies or focal neu-
rologic signs may be seen in a minority of patients. The presence of
petechial skin lesions should raise suspicion for meningococcemia.
Diagnosis
The differential diagnosis includes viral and tuberculous meningitis,
viral meningoencephalitis, subarachnoid hemorrhage, and primary
amebic meningoencephalitis. Differentiation from viral meningitis
on clinical grounds is usually difcult, and requires laboratory
testing. Where tuberculosis is prevalent, it must be recognized that
tuberculous meningitis can sometimes manifest acutely and could be
mistaken for bacterial meningitis. Viral meningoencephalitis may
manifest somewhat similarly with headache and fever, but patients
would usually have more profound alteration in the sensorium early
in the illness and neck stiffness may not be prominent. The most
prominent symptom of subarachnoid hemorrhage is a severe head-
ache with a rapid onset. Primary amebic meningoencephalitis is a
rare condition with a presentation similar to that of acute bacterial
meningitis, but cultures are negative and amebae can be detected in
the CSF by careful microscopic examination. There is usually a recent
history of swimming in a warm freshwater lake or pond.
The most important diagnostic test is a lumbar puncture, which
should always be performed in all patients with suspected acute
meningitis. Imaging tests do not help in making the diagnosis or
identifying the cause of bacterial meningitis. It is not necessary to
obtain a computed tomography (CT) scan before performing a
lumbar puncture unless there are focal neurologic decits.
5
The CSF
should be sent for cell count, protein and glucose levels, and Gram
staining and culture. Typical CSF ndings in acute bacterial menin-
gitis are an elevated opening pressure, increased CSF white blood cell
(WBC) count (100-10,000 cells/L), usually with a predominance of
neutrophils, increased CSF protein level (>50 mg/dL) and decreased
CSF glucose level (<40% of simultaneously measured serum glucose
level).
6
Gram staining may reveal the presence of microorganisms
and, if so detected, would be helpful for guiding therapy. In viral
meningitis, the CSF WBC count is elevated, but the cells are usually
predominantly lymphocytes, and the CSF glucose level may be
normal or marginally decreased. The best way to conrm a diagnosis
of viral meningitis is by specic polymerase chain reaction (PCR)
testing, if available.
Treatment
The management of bacterial meningitis includes appropriate anti-
biotic therapy and adjunctive corticosteroids.
7,8
Ideally, the lumbar
puncture should be done before the administration of antibiotics.
However, if there is a delay in performing the lumbar puncture for
any reason, antibiotic administration should not be delayed. A
lumbar puncture should be performed as soon as possible, even if
antibiotics have already been administered; the possibility of being
able to make a denite causative diagnosis, and its value in guiding
subsequent therapy and managing possible complications, are fully
worth the effort. Empirical antibiotics should be selected based on
the expected pathogens. The patients age, presence or absence of risk
factors such as middle ear or sinus disease, or recent neurosurgery
provide clues about the cause and pathogenesis.
It is recommended that patients be started on adjunctive dexa-
methasone 10 mg IV every 6 hours for 4 days with the rst dose of
antibiotics, because this has been shown to improve outcomes in
bacterial meningitis.
7
Antibiotic selection and dosing should also take
into consideration the ability to cross the blood-brain barrier and
achieve an effective concentration in the CSF. In adults, initial empir-
ical treatment should provide adequate therapy for Streptococcus
pneumoniae and Neisseria meningitidis. Increasing resistance of S.
pneumoniae to beta-lactam antibiotics (including ceftriaxone) has
prompted recommendations to initiate empirical antibiotic therapy
with a regimen consisting of vancomycin and ceftriaxone.
6
If Listeria
monocytogenes is a possibility (e.g., in older adults, pregnant women,
705
Infectious Disease
Emergencies
Nabin K. Shrestha
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Deciencies of the late components of the complement pathway
place individuals at markedly increased risk of developing meningo-
coccal infections.
12
These patients have recurrent episodes of menin-
gococcal infection. Genetic variants of mannose-binding lectin
(MBL), a plasma opsonin that initiates the MBL pathway of comple-
ment activation, may also predispose to increased susceptibility to
meningococcal infections.
13
Meningococcal infection may manifest in different forms: bacteremia
without sepsis, meningitis (with or without meningococcemia),
acute meningococcemia (with or without meningitis), a meningoen-
cephalitic picture, or chronic meningococcemia. The most fulminant
form is acute meningococcemia, in which death may ensue within
hours of the onset of symptoms.
The most common manifestation of acute meningococcemia is
fever with rash. The rash usually begins as a petechial rash, initially
with a few discrete lesions 1 to 2 mm in diameter, which often prog-
ress and coalesce to form larger ecchymotic lesions (Fig. 1). If there
is associated meningitis, meningeal signs and symptoms may also be
present.
The shock state is a dominant feature in patients with acute
meningococcemia, and is often accompanied by disseminated intra-
vascular coagulation (DIC). Meningococcemia can lead to complica-
tions such as massive adrenal hemorrhage, DIC, arthritis, heart
problems such as pericarditis and myocarditis, neurologic problems
such as deafness and peripheral neuropathy, and peripheral gan-
grene.
14
In epidemic settings in third-world countries, case-fatality
rates as high as 70% have been recorded. In endemic settings in
industrialized countries, the mortality rate is approximately 8%, but
could be as high as 19%.
Meningococcemia does not always manifest in a fulminant
manner. An unusual manifestation of meningococcal infection is
chronic meningococcemia, which manifests with low-grade fever,
rash, and arthritis. This manifestation is identical to that of chronic
gonococcemia.
Diagnosis
When patients present with an acute febrile illness with the charac-
teristic ecchymotic rash, the diagnosis is not difcult to make. Early
infection could be missed if a careful physical examination is not
carried out in a patient with an acute febrile illness. Denitive diag-
nosis requires isolation of the microorganism from a normally sterile
site. Samples for blood cultures should always be obtained before the
administration of antibiotics, if possible. Antibiotic therapy rapidly
and those with cellular immune decits), ampicillin should be added.
If Pseudomonas aeruginosa is a possibility, as after neurosurgical
procedures, ceftazidime should be used instead of ceftriaxone. Anti-
biotic therapy should be adjusted once the causative microorganism
has been identied. Duration of therapy for bacterial meningitis has
not been adequately dened. For meningococcal meningitis, 7 days
of therapy is considered adequate. S. pneumoniae should be treated
for 10 to 14 days. L. monocytogenes should be treated for at least 21
days.
9
Figure 1 Classic rash of patient with meningococcemia.
*Mycobacterium tuberculosis is also a bacterium and can cause meningitis, but it
is usually discussed separately as tuberculous meningitis.
In Adults
Streptococcus pneumoniae
Neisseria meningitidis
Listeria monocytogenes
In Children
Streptococcus pneumoniae
Neisseria meningitidis
Haemophilus inuenzae
Streptococcus agalactiae (in neonates)
Escherichia coli (in neonates)
After Neurosurgery
Staphylococcus aureus
Pseudomonas aeruginosa
Enteric gram-negative bacteria
Box 1 Important Causes of Bacterial Meningitis*
l The differential diagnosis of acute bacterial meningitis
includes viral meningitis and meningoencephalitis,
tuberculous meningitis, primary amebic
meningoencephalitis, and subarachnoid hemorrhage.
l Lumbar puncture should be performed as soon as possible.
l Dexamethasone plus empirical antibiotics should be
started without delay.
l Antibiotics should be adjusted subsequently, based on
culture and susceptibility data.
Summary
ACUTE MENINGOCOCCEMIA
Acute meningococcemia is a disseminated infection caused by Neis-
seria meningitidis, with high mortality rates in those with fulminant
disease. Meningococcal infection occurs in an endemic pattern, with
periodic epidemics. There are substantial cyclic variations in disease
incidence. In the United States, epidemics account for less than 5%
of the reported cases. The incidence of meningococcal disease in the
United States peaked at 1.7 cases per 100,000 population in 1997.
10
Pathophysiology
The pathogenesis of meningococcal infection begins with nasopha-
ryngeal colonization. About 10% of the population has asymptom-
atic nasopharyngeal carriage of N. meningitidis during nonepidemic
periods. A small proportion of carriers go on to develop invasive
meningococcal disease. People who develop invasive disease generally
do so soon after acquisition of carriage.
11
Factors that facilitate inva-
sive disease include agent factors such as virulence and transmissibil-
ity and host factors.
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Pathophysiology
Cranial subdural empyema is usually a complication of infection
of the paranasal sinuses.
23
Less commonly, it results from spread
from the middle ear.
25
It may also occur as a complication of trauma
or neurosurgery. Infection spreads intracranially through the
emissary veins that communicate between the veins draining the
facial structures and intracranial venous channels. In a small pro-
portion of cases, subdural empyema may occur by metastatic
spread, usually from a pulmonary infection, for an unexplained
reason.
Patients with this condition usually present acutely, with headache
and vomiting. Most patients have an altered mental status at presen-
tation and the level of consciousness deteriorates rapidly. Patients
may have neurologic decits and complications such as local cereb-
ritis, cerebral abscesses, and septic dural venous thromboses may
occur.
Diagnosis
The diagnosis should be considered in any patient who presents with
features suggestive of meningitis and a focal neurologic decit or
rapid deterioration in the level of consciousness. If recognized,
lumbar puncture should not be performed because of the risk of
cerebral herniation.
23
CSF ndings would be nonspecic, with an
elevated opening pressure, neutrophilic pleocytosis, and elevated
protein level. Gram staining and culture of CSF are usually negative.
The diagnostic procedure of choice is magnetic resonance imaging
(MRI). If not available, CT scanning with contrast should be done.
CT is inferior to MRI in detecting empyemas at the base of the brain
and in the posterior fossa.
Treatment
Effective treatment for cranial subdural empyema requires a com-
bined surgical and medical approach. Empirical antibiotic therapy
should be broad spectrum and include coverage for gram-positive
pyogenic bacteria and anaerobes. Vancomycin is a reasonable choice
for empirical antibiotic therapy. Cultures obtained at the time of
surgery will help tailor antibiotic therapy. The goal of surgery is
complete evacuation of the purulent collection, which may be
accomplished by craniotomy or through burr holes, depending on
the circumstances of the case. It is important to evacuate the collec-
tion completely, and a craniotomy or multiple surgical procedures
may be necessary to accomplish this. Up to 50% of patients who are
treated with burr hole drainage require reoperation, compared with
20% of those treated with craniotomy.
26
The duration of antibiotic
therapy is usually 3 to 4 weeks after adequate drainage. If there is
associated osteomyelitis of the skull, treatment should be extended
to approximately 6 weeks.
sterilizes the blood and CSF in patients with meningococcal infec-
tion.
15,16
CSF cultures are often positive for microorganisms, even
in patients who do not have clinical evidence of meningitis,
17
and
should always be examined when meningococcemia is suspected.
Microorganisms may also be identied in the biopsy of petechial skin
lesions.
Treatment
The treatment of acute meningococcemia involves appropriate anti-
biotic therapy, along with supportive therapy for shock, heart failure,
DIC, and other complications. Early antibiotic therapy has been
conclusively shown to improve outcomes in patients with meningo-
coccal disease.
18
The recommended treatment for severe meningo-
coccal infection is a third-generation cephalosporin with good CSF
penetration. Ceftriaxone, 1 g every 12 hours, is the most commonly
used treatment.
19
Cefotaxime and ceftazidime should be equally ef-
cacious alternatives. Patients allergic to cephalosporins may be
treated with chloramphenicol, 100 mg/kg, in four divided doses, up
to a total dosage of 4 g/day.
20
High doses of penicillin G should also
usually be adequate; however, small numbers of resistant N. menin-
gitidis have been reported, and penicillin G should therefore not
ordinarily be the rst choice of antibiotic in the absence of suscepti-
bility data. The shock state is a dominant part of the clinical picture
of meningococcemia and supportive management is important. The
use of steroids for meningococcemia is controversial, and a recom-
mendation for its routine use for treatment of this condition cannot
be made.
Prophylaxis
Household contacts are at signicantly higher risk of infection.
21

Chemoprophylaxis is recommended for household contacts, daycare
center staff and clients, and anyone exposed to the patients oral
secretions. For health care workers, this would include persons who
intubated the patient and who provided suction to clear secretions.
Effective prophylactic treatments include a single 1-g dose of ceftri-
axone intravenously or intramuscularly, a single 500-mg dose of
ciprooxacin, a single 500-mg dose of azithromycin, and 600 mg of
rifampin every 12 hours for 2 days.
18
l The classic presentation of meningococcemia is fever and
rash.
l Prompt antibiotic therapy can be lifesaving.
l Shock is a dominant clinical nding and supportive
management is important.
l Close contacts should receive chemoprophylaxis.
Summary
CRANIAL SUBDURAL EMPYEMA
Subdural empyema is a condition in which there is collection of pus
in the region between the dura and the arachnoid. The most common
causes of subdural empyema are aerobic and anaerobic streptococci
(especially the S. milleri group), Staphylococcus aureus and, to a lesser
extent, aerobic gram-negative bacilli.
22,23
Studies have found anaero-
bic infections in varying proportions of infections, with high propor-
tion of patients having anaerobic microorganisms recovered in some
studies with careful culturing.
24
This raises the possibility that these
infections are usually polymicrobial, with anaerobic microorganisms
usually present. Subdural empyemas account for 15% to 20% of all
localized intracranial infections.
23
l MRI or CT scanning should be performed promptly when
cranial subdural empyema is suspected.
l Treatment requires a combined medical and surgical
approach.
l Empirical broad-spectrum antibiotic therapy should be
started promptly.
l Cultures obtained at the time of surgery will help tailor
antibiotic therapy.
l Multiple operations may be necessary.
Summary
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than cellulitis. Pain out of proportion to the skin changes also may
be an indicator of a more serious infection. On palpation, the affected
area has a woody hard feel. Increasing tissue edema may lead to the
development of compartment syndrome.
Necrotizing myositis or myonecrosis may occur without overt
ndings on the skin surface. The predominant symptom is intense
muscle pain, usually accompanied by fever. Patients usually appear
more ill than would be expected from the physical ndings. Gas
gangrene and other syndromes of necrotizing myositis caused by
anaerobic microorganisms will also have crepitations because of the
presence of subcutaneous gas.
At initial presentation, it may not be possible to make a clinical
distinction between necrotizing fasciitis and necrotizing myositis.
Indeed, both processes may occur simultaneously, especially with
streptococcal infection. Lack of involvement of the overlying skin
does not exclude the presence of an underlying necrotizing process.
Streptococcal necrotizing soft tissue infections are usually associ-
ated with the toxic shock syndrome. This is discussed separately (see
later). Acute vascular compromise from trauma or embolic occlusion
leads to tissue infarction and may progress to infected vascular gan-
grene if the appropriate microorganisms gain access to the devital-
ized tissues.
Diagnosis
Clinical suspicion is important if an early diagnosis of a necrotizing
soft tissue infection is to be made. A clue to the presence of a deep
necrotizing process is the presence of tenderness clearly beyond the
areas of apparent involvement in the skin. Leukocytosis is common.
The creatine kinase (CK) level is usually elevated, but may be normal
in cases of necrotizing fasciitis with minimal muscle involvement.
Ultrasonography, CT scanning, or MRI will usually reveal muscle
swelling and uid in muscle compartments, but may not be apparent
early in necrotizing fasciitis. Histopathologic examination will reveal
the presence of sheets of neutrophils in fascial planes. Gram staining
of tissue exudates will reveal the presence of microorganisms.
Treatment
It is not always obvious whether a skin or soft tissue infection is a
necrotizing infection. When considered a possibility, aggressive man-
agement is important. It is not always possible to predict the causative
microorganism from the clinical features accurately. A prudent
approach would be to treat with antibiotics that are effective against
group A streptococci, S. aureus, enteric gram-negative bacteria, and
anaerobic microorganisms. The antibiotics of choice for initial
empirical therapy are clindamycin plus ampicillin-sulbactam plus
ciprooxacin.
29
If there is reason to suspect MRSA infection, vanco-
mycin may be added. Antibiotic therapy should be modied when
culture and susceptibility data become available. A lack of response
to a reasonable trial of antibiotics should prompt emergent surgical
intervention. Prompt and aggressive fasciotomy and dbridement of
devitalized tissue are necessary to gain control of the infection. Early
surgical intervention reduces mortality.
28
If infection is advanced,
amputation may be necessary, and lifesaving.
NECROTIZING SOFT TISSUE INFECTIONS
This term encompasses several specic clinical entities characterized by
disease processes that produce necrosis of subcutaneous tissue, muscle,
or both that progress rapidly and require a combined emergent surgical
and medical approach for optimum outcomes. These entities include
necrotizing fasciitis, streptococcal necrotizing myositis, clostridial myo-
necrosis (gas gangrene), and nonclostridial crepitant myositis.
Type I necrotizing fasciitis is a mixed infection caused by an
anaerobic bacterium (usually Bacteroides or Propionibacterium) in
association with a facultative anaerobic microorganism, such as a
streptococcus or a member of the Enterobacteriaceae. Type II necro-
tizing fasciitis, hemolytic streptococcal gangrene, is caused by group
A streptococci. Other microorganisms may be present in the mix.
Community-associated methicillin-resistant S. aureus (CA-MRSA)
has recently been described as a cause of necrotizing fasciitis.
27
Clostridial myonecrosis, also commonly known as gas gangrene,
and streptococcal necrotizing myositis, as their names imply, are
caused by Clostridium spp. and by group A streptococci, respectively.
The latter can rarely be caused by groups B, C, or G streptococci.
Nonclostridial crepitant myositis encompasses several clinical
entities that may result from mixed infection caused by anaerobic
streptococci, along with the following: group A streptococci or S.
aureus (anaerobic streptococcal myonecrosis); a mixture of anaerobic
and facultatively anaerobic microorganisms (synergistic nonclos-
tridial anaerobic myonecrosis, or Meleneys bacterial synergistic gan-
grene); Proteus spp., Bacteroides spp., and anaerobic streptococci in
devitalized limbs (infected vascular gangrene); Vibrio vulnicus; and
Aeromonas hydrophila.
As a group, these illnesses are uncommon but not rare, and
prompt recognition and appropriate management will signicantly
affect outcomes.
Pathophysiology
Necrotizing fasciitis usually begins with the introduction of the
offending microorganism to the subcutaneous structures, usually as
a result of minor trauma. Gas gangrene occurs in situations in which
muscle injury is compounded by wound contamination with soil or
other foreign material harboring spores of a tissue-invasive Clos-
tridium, such as C. perfringens, C. novyi, and C. septicum. Such injuries
include war injuries, compound fractures, and septic abortion. Most
cases of streptococcal myositis appear to begin spontaneously. The
different forms of nonclostridial myonecrosis usually begin with the
introduction of the offending microorganisms at the time of usually
minor trauma. Aeromonas hydrophila myonecrosis occurs as a result
of inoculation of the microorganism at the time of penetrating injury
in a freshwater setting or in association with sh or other aquatic
animals. In all these conditions, there is rapid progression of disease,
often with gas formation in the muscles and subcutaneous tissues,
and in many cases associated with the development of gangrene.
Diabetes mellitus is the most important risk factor for the devel-
opment of necrotizing soft tissue infections.
28
Other risk factors
include alcoholism, corticosteroid use, and parenteral drug use.
Necrotizing fasciitis is usually an acute process, with severe infection
of the supercial and deep fascia. It most commonly occurs in the
extremities. The affected area becomes erythematous, swollen, warm,
and painful. It typically progresses rapidly, with the skin becoming
darker, and over a few days bullae and skin breakdown develop. In
the polymicrobial form, crepitations may be felt subcutaneously,
indicating the presence of gas. Development of anesthesia over an
erythematous area may precede development of skin breakdown and
may serve as a warning sign that the disease process is more serious
l A high index of suspicion will facilitate the early diagnosis
of necrotizing soft tissue infections.
l Skin surface ndings may be minimal.
l Prompt and aggressive surgical dbridement is the most
important aspect of treatment.
l Empirical antibiotic therapy should consist of clindamycin
plus ampicillin-sulbactam plus ciprooxacin.
l Antibiotical therapy should be modied once culture data
become available.
Summary
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Diagnosis
The diagnostic criteria for TSS are outlined in Boxes 2 and 3.
34,35
In
streptococcal TSS, streptococci can usually be detected in culture at
the affected site or in blood culture. In staphylococcal TSS, it is rare
to detect staphylococci, except if vaginal cultures are obtained from
patients with menstruation-associated TSS. Prompt diagnosis
requires recognition of the constellation of symptoms and signs, with
conrmation by additional laboratory testing to look for abnor-
malities that indicate damage to the organ systems expected to be
involved by the process. CT or MRI helps in dening the presence of
deep soft tissue infection in patients with streptococcal TSS. Gas is
not produced, but the diagnosis should not be excluded if imaging
ndings do not appear impressive when clinical features are sugges-
tive of the disease.
TOXIC SHOCK SYNDROME
Toxic shock syndrome (TSS) is a severe toxin-mediated bacterial
disease characterized by shock resulting from an excess of inamma-
tory cytokines. Two important syndromes, staphylococcal TSS and
streptococcal TSS, are recognized, caused by S. aureus and Streptococ-
cus pyogenes, respectively. Both are uncommon diseases. The inci-
dence of streptococcal TSS in the United States is 3.5 per 100,000
population per year. Staphylococcal TSS has an overall incidence of
about 1 per 100,000, with menstrual TSS about twice as common as
nonmenstrual TSS.
30
At the peak of the epidemic of menstrual TSS,
before the recognition of the association between the use of certain
tampons and TSS, the incidence of menstrual TSS was as high as 10
per 100,000 population per year, and accounted for over 90% of all
cases of staphylococcal TSS.
Pathophysiology
Toxic shock syndrome is a toxin-mediated disease.
31
Several exotox-
ins of S. aureus and S. pyogenes are capable of stimulating excessive
T cell responses, and are thus known as superantigens. These toxins
include toxic shock syndrome toxin 1 (TSST-1) and staphylococcal
exotoxins A, B, and C (SEA, SEB, SEC) of S. aureus, and strepto coccal
pyrogenic exotoxins A, B, and C (SPEA, SPEB, SPEC) of S. pyogenes.
These toxins are capable of binding both major histocompatibiliy
complex (MHC) class II molecules of antigen-presenting cells and
the V
region of T cell receptors, leading to broad-range induction

of T cell proliferation. The resulting excessive production of inam-
matory cytokines (interleukin-1 and -6 [IL-1, IL-6], tumor necrosis
factors and [TNF-, TNF-], interferon gamma [IFN-]) leads
to increased capillary permeability resulting in tissue damage to
various organs and shock.
Staphylococcal TSS is commonly associated with menstruation
(menstrual TSS).
32
The pathophysiology of menstrual TSS includes
a high local protein level and relatively high local pH (caused by the
presence of blood and blood products), high partial pressure of
carbon dioxide (caused by higher than atmospheric Pco
2
in blood),
and high Po
2
(introduced by high-absorbency tampons).
31
In such
an environment, the production of TSST-1 by colonizing S. aureus is
stimulated. Nonmenstrual TSS is caused by S. aureus infection at any
site in the body, including surgical wounds, the lungs, peritoneal
dialysis catheters, and skin and mucosal infections. The illness is
mediated by TSST-1 or SEA or SEB produced by the microorganisms
at the site of infection.
Toxic shock syndrome manifests as a multisystem illness, with shock
being a prominent feature. Clinical features include high fever, hypo-
tension, tachycardia, tachypnea, anasarca, and a morbilliform rash.
Many patients also have myalgias and gastrointestinal symptoms,
such as vomiting, abdominal pain, and diarrhea. Patients may develop
confusion. The disease progresses rapidly and, especially with strep-
tococcal TSS, can lead to death within 24 to 48 hours. Menstrual TSS
starts within 2 days of the beginning or end of menses in women
using high-absorbency tampons.
32
In many patients with nonmen-
strual TSS, the site of infection may show minimal inammation and
may not be readily apparent.
Streptococcal TSS is generally a more serious condition.
33
In this
condition, the site of infection with S. pyogenes may be obvious. It is
usually a necrotizing soft tissue infection, but streptococcal TSS has
been described in patients with pneumonia, meningitis, septic arthri-
tis, peritonitis, and other deep infections.
33
Patients are usually very
ill and may develop the adult respiratory distress syndrome or DIC.
The mortality of adequately treated staphylococcal TSS is about 5%.
The mortality of streptococcal TSS is about 50%.
*All six criteria have to be satised to make a denite diagnosis. Fulllment of the
rst ve criteria makes a probable diagnosis.
Fever: Temperature 102 F (38.9 C)
Rash: Diffuse macular erythroderma
Overt or orthostatic hypotension
Multisystem involvement (three or more of the following):
l Gastrointestinal: Vomiting or diarrhea at the onset of illness
l Muscular: Severe myalgias or creatine kinase level at least twice the
upper limit of normal
l Mucous membranes: Vaginal, oropharyngeal, or conjunctival hyper-
emia
l Renal: Blood urea nitrogen or creatinine level at least twice the upper
limit of normal or urinary sediment with pyuria (5 leukocytes er
high-power eld) in the absence of urinary tract infection
l Hepatic: Total bilirubin, aspartate transaminase, or alanine amino-
transaminase level at least twice the upper limit of normal
l Hematologic: Platelet count 100,000/L
l Central nervous system: Disorientation or alteration in consciousness
without focal neurologic signs when fever and hypotension are
absent
Negative results on the following tests, if performed:
l Blood, throat, or cerebrospinal cultures (blood cultures may be posi-
tive for Staphylococcus aureus)
l Rise in antibody titer to Rocky Mountain spotted fever, leptospirosis,
or rubeola
Desquamation 1-2 wk after onset of illness, particularly over palms and
soles
Box 2 Diagnostic Criteria for Staphylococcal Toxic
Shock Syndrome*
*All three criteria have to be met. If S. pyogenes is isolated from a normally sterile
site, the diagnosis is a denite diagnosis. If isolated from a nonsterile site, the
diagnosis is a probable diagnosis.
Isolation of Streptococcus pyogenes
Hypotension
Two or more of the following:
l Renal impairment: Creatinine level 2.0 mg/dL or twice the upper
limit of normal for age
l Thrombocytopenia (platelet count 100,000/L) or disseminated
intravascular coagulation
l Liver involvement: Aspartate transaminase, alanine aminotransami-
nase, or total bilirubin level twice the upper limit of normal
l Adult respiratory distress syndrome
l Generalized macular erythrodermic rash that may desquamate
l Necrotizing soft tissue infection
Box 3 Diagnostic Criteria for Streptococcal Toxic
Shock Syndrome*
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ing of skin integrity by invasive vascular catheters, and the gastroin-
testinal tract, because of mucosal damage from chemotherapeutic
agents. The most common bacterial pathogens causing fever in
patients with neutropenia are listed in Box 4.
Patients may present with little other than fever. The clinical presen-
tation may appear to be relatively mild, especially to the inexperienced
observer. Furthermore, many patients with chemotherapy-induced
neutropenia may be on corticosteroids, which may actually mask
fever. In neutropenic patients on corticosteroids, hypothermia, hypo-
tension, or other unexplained acute clinical deterioration should be
considered as a fever equivalent.
Diagnosis
A careful physical examination should be carried out to identify any
possible sources of infection. Two or three sets of blood cultures,
urinalysis and urine culture and, if the patient has productive cough,
sputum Gram staining and culture should be performed. Chest
radiographs should be obtained and there should be a low threshold
for obtaining a CT scan of the chest, because the latter is signicantly
more sensitive for detecting pulmonary processes. Other investiga-
tions should be carried out if there are any localizing symptoms or
signs. Meningitis is uncommon and lumbar puncture need not be
done routinely in all patients.
Treatment
For patients with neutropenic fever, empirical therapy should provide
adequate coverage against enteric gram-negative bacteria and P. aeru-
ginosa. If S. aureus infection is considered a possibility, as in patients
with indwelling vascular catheters, vancomycin should also be given
until culture data become available. For patients with catheter-related
infections, it is usually necessary to remove the catheter unless the
microorganism is a coagulase-negative staphylococcus and there is
no evidence of tunnel infection or catheter-associated deep venous
thrombophlebitis.
39
Several antibiotic regimens are effective for the empirical treat-
ment of neutropenic fever, but no specic regimen is recommended
for all patients. Criteria have been dened to identify those patients
considered to be at low risk for progression to severe illness.
40
Patients
deemed to be at low risk may be treated with oral ciprooxacin plus
oral amoxicillin-clavulanate. Patients deemed to be at high risk,
which would include all patients with an ANC of less than 100
cells/L, a duration of neutropenia exceeding 7 days, peak tempera-
ture 102.2 F (39 C) or higher, active malignancy, lack of early evi-
dence of marrow recovery, and any obvious focus of infection, should
receive IV antibiotics.
Treatment
Management of TSS includes eradication of the focus of infection as
well as supportive care, which includes uid resuscitation and vaso-
pressors, as necessary.
36
Large volumes of crystalloids may be neces-
sary because of the loss of intravascular volume caused by capillary
leak. Circulating bacterial hemolysins may lead to moderate to severe
anemia, necessitating blood transfusions. When the focus of infec-
tion is identied in staphylococcal TSS, it is important to drain
abscesses and treat with appropriate antibiotics. In women with
hyperabsorbent tampons, the tampons should be removed. Patients
with streptococcal TSS do better with combinations of clindamycin
and cell wall active agents compared with cell wall active agents
alone.
37
Because clindamycin is not affected by bacterial inoculum or
stage of growth, and because it inhibits synthesis of bacterial toxin,
there are theoretical reasons why it would also be useful for the treat-
ment of staphylococcal TSS. Thus, in both staphylococcal and strep-
tococcal toxic shock syndrome, clindamycin should also be added
initially. Staphylococcal TSS should also initially be treated with van-
comycin. Antibiotic therapy can be modied once susceptibility data
become available. MRSA infections should be treated with vancomy-
cin; MSSA infections should be treated with oxacillin. Penicillin-
susceptible S. aureus should be treated with penicillin G. Treatment
of streptococcal TSS usually includes aggressive surgical dbride-
ment, with antibiotic therapy and supportive care. The antibiotic of
choice is penicillin G.
l The toxic shock syndromes are toxin-mediated diseases of
S. aureus and S. pyogenes.
l The site of infection may not be readily apparent,
especially in staphylococcal TSS.
l Streptococcal TSS is often associated with necrotizing soft
tissue infections.
l Surgical dbridement of the focus of infection may be
necessary.
l Early antibiotic therapy should include clindamycin in
addition to cell wall active agents.
Summary
NEUTROPENIC FEVER
Fever in a neutropenic patient is dened as a single temperature
higher than 101.3 F (38.3 C) or a sustained temperature higher than
100.4 (38) for longer than 1 hour.
38
Neutropenia is usually dened
as an absolute neutrophil count (ANC) lower than 500 cells L or
less than 1000 cells/L. with a predicted nadir of less than 500
cells/L.
38
More than 50% of neutropenic patients who develop a
fever have an obvious or occult infection. The risk of invasive infec-
tion increases with the degree of neutropenia. At least 20% of patients
with an absolute neutrophil count below 100 cells/L will develop
bacteremia.
Pathophysiology and Natural History
Neutrophils and macrophages represent the cellular arm of innate
immunity. Neutrophils are recruited to the site of infection, where
their role is to ingest the offending microorganisms. Patients with
neutropenia have decreased neutrophil numbers, and their inam-
matory responses are blunted. These patients may therefore have skin
and skin structure infections, with minimal erythema or induration,
urinary tract infection without pyuria, and pulmonary infection
without chest radiographic inltrates. The most likely sources of
bacterial invasion in such patients are the skin, because of the breach-
Gram-Positive Bacteria
Staphylococcus spp.
Streptococcus spp.
Enterococcus faecalis or faecium
Corynebacterium spp.
Gram-Negative Bacteria
Escherichia coli
Klebsiella spp.
Pseudomonas aeruginosa
Box 4 Most Common Bacterial Causes of Infection in Patients
with Neutropenic Fever
Adapted from Hughes WT, Armstrong D, Bodey GP, et al: 2002 guidelines for the
use of antimicrobial agents in neutropenic patients with cancer. Clin Infect Dis
2002;34:730-751.
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inuenzae, N. meningitidis, Capnocytophaga canimorsus, and Babesia
microti or B. divergens. The most common responsible microorgan-
ism is S. pneumoniae, accounting for 50% to 90% of cases.
42,44
Pathophysiology
The innate immune system provides immediate protection against
invasion by microorganisms. The adaptive immune system provides
a more vigorous, targeted, and durable immune response by produc-
ing specic antibodies. However, the antigenic priming process for
this response takes time, and makes this mechanism protective in
subsequent infections, not in initial infections. B-1a B cells are a
subset of B lymphocytes that produce antibodies without prior spe-
cic exposure.
45,46
These are natural antibodies of the immunoglobu-
lin M (IgM) isotype that target polysaccharides of bacteria.
47
Thus,
they are part of the innate immune system and are responsible for
the early inhibition of encapsulated bacteria. Splenectomy results in
a marked reduction in the number of B-1a B cells.
48
This reduction
seriously compromises the ability of the body to mount an early
response to infection with encapsulated microorganisms such as S.
pneumoniae, H. inuenzae, and N. meningitidis.
The spleen is also responsible for the clearance of erythrocytes
with abnormal inclusions from the circulation. Such abnormal inclu-
sions include intraerythrocytic parasites such as Babesia species.
Most cases of infection with Babesia have occurred in splenectomized
individuals.
49
The removal of erythrocytes infected with malarial
parasites is also affected by splenectomy, but whether this increases
the severity of disease is unclear.
The initial presentation, if patients present early, may be no different
from a febrile illness in an otherwise healthy patient. Typical symp-
toms are fever, chills, sore throat, vomiting or diarrhea, and diffuse
muscle aches. In young children, meningitis is common. Rapid
progression within hours is the usual course. Shock, seizures, and
DIC often accompany the clinical deterioration. Purpura fulminans
and extremity gangrene can occur. With modern treatment, the
mortality rate for postsplenectomy sepsis is in the range of 50% to
70%.
42,44
Diagnosis
In the setting of prior splenectomy or functional hyposplenism, any
febrile illness must raise suspicion for postsplenectomy sepsis. Two
to three sets of samples for blood cultures should be obtained. Other
investigations should be performed if there are any localizing symp-
toms or signs. In children, the CSF should be examined. The degree
of bacteremia is usually several orders of magnitude greater than in
patients with a functional spleen, and blood cultures usually turn
positive within 12 to 24 hours. Because of the degree of bacteremia,
Gram staining of the buffy coat often reveals the presence of bacteria.
Bacteria may even be seen on a peripheral blood smear, which will
also show the presence of Babesia. Thus, a peripheral smear should
always be examined in any patient with postsplenectomy sepsis.
Treatment
The most important aspect of management of postsplenectomy
sepsis is to recognize the condition and the potential for its occur-
rence in any patient with a prior splenectomy presenting with a
febrile illness. Antibiotics should be started immediately. Antibiotic
therapy should not be withheld if blood cultures cannot be tested
immediately. Empirical antibiotic therapy should consist of vanco-
mycin and ceftriaxone. This empirical regimen will adequately
treat all the pathogens denitely associated with postsplenectomy
sepsis, except Babesia. Vancomycin may be stopped if resistance
pneumococci are not isolated. The treatment for Babesia is quinine
The decision for these patients will be whether to use vancomycin.
Unless such patients can be reasonably excluded from having a
serious gram-positive infection, these patients should all receive van-
comycin in addition to antibiotics to cover gram-negative bacteria.
Regimens for the coverage of gram-negative bacteria must include
coverage for P. aeruginosa. Effective monotherapy regimens for gram-
negative bacteria include imipenem-cilastatin, meropenem, cefepime,
and ceftazidime. Effective combination regimens for the empirical
treatment of gram-negative bacteria include an aminoglycoside
(e.g., gentamicin, tobramycin, amikacin) with an antipseudomonal
penicillin (e.g., piperacillin-tazobactam, ticarcillin-clavulanate), an
antipseudomonal cephalosporin (e.g., ceftazidime, cefepime), or a
carbapenem (e.g., imipenem, meropenem).
38
Antibiotic therapy should be modied if cultures identify a caus-
ative microorganism. If S. aureus or another gram-positive bacterium
requiring vancomycin is not identied by day 3, vancomycin may be
stopped. If there is worsening after 3 days, a change in the antibiotic
regimen should be considered. If the fever persists after 5 days,
empirical antifungal therapy should be initiated.
The duration of therapy must be based on the clinical response
and clinical status of the patient. It is clear that neutropenic patients
are a heterogeneous group. Patients who have undergone allogeneic
stem cell transplantation, graft-versus-host disease, severe mucosal
erosive disease, extensive prior antibiotic treatment, or prolonged
hospitalization are at higher risk of subsequent infectious complica-
tions.
41
Patients who are neutropenic for less than 7 to 10 days are at
low risk of infectious complications. If the fever resolves in 3 to 5
days, antibiotics may be stopped 2 days after the resolution of fever
if the ANC is 500 cells/L or higher for at least 48 hours, or 5 to 7
days after the resolution of fever in low-risk patients if the ANC is
500 cells/L or lower, but should be continued for at least 2 weeks in
high-risk patients with an ANC <500 cells/L or lower. If the fever
persists beyond 5 days, but there is no obvious identied infection,
antibiotics may be stopped 4 to 5 days after the ANC recovers above
500 cells/L, but should be continued for at least 2 weeks if the ANC
remains below 500 cells/L.
l Neutropenic fever is dened as temperature higher than
101.3 F (38.3 C), or higher than 100.4 F (38 C) for more
than 1 hour in a neutropenic patient (actual or predicted
ANC of less than 500 cells/L).
l Signs of inammation may be minimal.
l There is potential for progression to death within hours.
l Empirical broad-spectrum antibiotic therapy should be
instituted immediately and adjusted later.
Summary
SEPSIS IN PRIOR SPLENECTOMY OR FUNCTIONAL
HYPOSPLENISM PATIENTS
The importance of sepsis in these patients is the potential for pro-
gression from a healthy state to death within 24 hours when infected
with certain microorganisms. This situation is not common but,
when it does occur, the mortality rate is high. It is much more likely
to occur at younger ages, with infection rates of 15.7% in infants,
10.4% in children younger than 5 years, 4.4% in children younger
than 16, and 0.9% in adults.
42
The lifetime risk of postsplenectomy
sepsis has been estimated to be approximately 5%.
43
The risk of infec-
tion persists throughout life, but the risk is highest in the rst 2 years
after splenectomy.
42
The microorganisms that cause deadly infections in patients with
prior splenectomy or functional hyposplenism are S. pneumoniae, H.
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trophozoites that mature into schizonts, which then divide into
several merozoites. The merozoites are in turn released by lysis of the
infected cells; the process takes 48 hours in the case of P. falciparum.
Lysis of infected cells occurs in a coordinated fashion every 24 hours,
with two batches undergoing lysis on alternate days. It is at this time
that the patient experiences chills and rigors. The released merozoites
are capable of infecting other red blood cells, thus perpetuating
illness. Some schizonts mature into male or female gametocytes. For
transmission of malaria to occur, gametocytes have to be ingested
by an appropriate mosquito.
54
Fertilization occurs in the lumen of
the mosquito stomach; the resulting zygote penetrates the wall of the
stomach and develops into an ookinete on the outer surface of the
stomach wall. When the ookinete matures, it develops into an oocyst
that multiplies and ruptures to release many sporozoites into the
body cavity of the mosquito. The sporozoites then nd their way to
the mosquitos salivary glands, where they are poised to be transmit-
ted to another human host at the time of the mosquitos next blood
meal.
The most important aspect of the pathogenesis of disease caused
by P. falciparum is the ability of the parasite to sequester in the deep
microvasculature. P. falciparum erythrocyte membrane protein 1
(PfEMP-1) is a molecule expressed on the surface of infected eryth-
rocytes. This molecule is capable of adhering to various host cell
surface ligands, including CD36 on endothelium, monocytes, and
platelets and intercellular adhesion molecule-1 (ICAM-1) on endo-
thelial surfaces.
55
Furthermore, PfEMP-1 also mediates rosetting of
host erythrocytes.
56
This combination of endothelial binding and
rosette formation leads to massive sequestration of parasitized eryth-
rocytes in the cerebral, renal, hepatic, and other microcirculations,
leading to the complications of P. falciparum malaria.
The most important symptom of malaria is fever. Classic descrip-
tions of malaria include the occurrence of paroxysms that begin
with chills and rigors, followed by high fever and then by profuse
sweating and defervescence, with the entire paroxysm lasting a
few hours. These symptoms classically occurred every 24 hours in
patients with P. falciparum malaria. Nowadays, paroxysms may not
be very prominent, and patients may even have continuous fever.
Headache is common, and may be seen even in the absence of cere-
bral malaria.
P. falciparum malaria is far more likely to lead to complications
than the nonP. falciparum malarias. The most important complica-
tions of P. falciparum malaria are severe anemia, hypoglycemia, cere-
bral malaria, acute renal failure, acute respiratory distress syndrome,
acute hepatocellular failure, and DIC.
Several clinical features indicate specic end-organ damage in P.
falciparum malaria; these include headache, seizures, and loss of con-
sciousness (with cerebral malaria), decreased urine output or blood
in urine (blackwater fever), deep jaundice (algid malaria), bleeding
from multiple sites (caused by DIC), and respiratory failure (caused
by acute respiratory distress syndrome).
Diagnosis
The most important diagnostic and most practical test is the Wrights-
or Giemsa-stained peripheral blood smear (thick and thin), which
should be examined immediately if malaria is considered a likely
diagnosis. These tests can be performed in any laboratory but
the limitation in nonendemic areas may be the nonavailability of
personnel with experience in reading the slides. The most likely
nding in patients with P. falciparum malaria is the nding of ring-
shaped trophozoites within red blood cells (Fig. 2). Antigen-based
tests and serologic tests also exist for the diagnosis of malaria.
Although these tests do not require much expertise to read, they
are unlikely to be available in areas that are nonendemic for the
disease.
plus clindamycin in those rare cases in which it is the causative
agent.
Prophylaxis
All patients should receive the 23-covalent bond, unconjugated, cap-
sular pneumococcal polysaccharide vaccine (PPV23) at least 2 weeks
before elective splenectomy.
50
If the splenectomy is an emergent pro-
cedure, the vaccine should still be given as soon as possible. Revac-
cination once after 5 years is also recommended.
51
Although there are
fewer data on the protective efcacy of the H. inuenzae type B (Hib)
vaccine and meningococcal vaccine, both should be administered as
soon as possible, preferably before splenectomy.
Children are often given prophylactic penicillin V for the rst few
years after splenectomy, which may provide some protection. This
approach is not recommended for adults because of the uncertainty
of the magnitude of protection offered and the potential for selection
of resistant microorganisms.
l Postsplenectomy sepsis can progress from a healthy state
to death within 24 hours.
l The most important responsible microorganisms are
S. pneumoniae and H. inuenzae.
l The degree of bacteremia is very high, and bacteria may
be seen in the buffy coat or on a peripheral smear.
l Vancomycin plus ceftriaxone will provide adequate
antibiotic coverage in most cases.
Summary
PLASMODIUM FALCIPARUM MALARIA
Malaria in humans is caused by ve species of Plasmodium: P. falci-
parum, P. vivax, P. malariae, P. knowlesi, and P. ovale. Malaria should
always be considered a possibility in any person presenting with fever
who has recently been in a malaria-endemic region, even if malaria
prophylaxis was taken. Malaria occurs in most of the tropical and
subtropical regions of south and southeast Asia, sub-Saharan Africa,
and South America. P. falciparum malaria is far more dangerous than
the nonP. falciparum malarias. There are more than 500 million
cases of malaria yearly, mostly in sub-Saharan Africa, and millions of
deaths.
52
The vast majority of the deaths from malaria are caused by
P. falciparum. P. knowlesi is a newly recognized human malarial par-
asite and is capable of causing severe malaria. The following discus-
sion focuses on P. falciparum malaria, the most important cause of
malaria worldwide.
Pathophysiology
The life cycle of Plasmodium involves an asexual stage in a mosquito
belonging to the genus Anopheles and its sexual stage in humans.
Humans are infected by the bite of an infected mosquito. In humans,
the infective sporozoites initially invade the liver, develop into mero-
zoites in the liver cells, and are released into the bloodstream after
several days.
53
P. vivax and P. ovale, in addition to undergoing imme-
diate development in the liver, are also capable of remaining in liver
cells as latent infections for several months to years; the latent forms
are known as hypnozoites. These hypnozoites perpetuate what is
known as the exoerythrocytic cycle, its importance being that effec-
tive treatment for these infections must include medications active
against the liver stage of the parasite.
This cycle is not seen with P. falciparum. The merozoites released
from the liver cells invade red blood cells, where they develop into
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Figure 2 Peripheral blood smear showing numerous ring-shaped
trophozoites of Plasmodium falciparum. (Leishman stain, 1000
magnication).
Table 1 Regimens Effective for Treatment of P. falciparum Malaria
Pharmacologic Agent(s) Dosage Regimen
Quinine + doxycycline Quinine 10 mg/kg PO or IV q8hr for 7 days plus doxycycline 100 mg PO q8hr for 7 days
Atovaquone-chloroguanide Four adult tablets (each) daily for 3 days (each adult tablet contains 250 mg atovaquone and 100 mg
chloroguanide)
Artemether-lumefantrine
(Coartem)
Four tablets initially, followed by four tablets 8 hr later, followed by four tablets twice daily on days 2 and 3
(each xed-dose tablet contains 20 mg artemether and 120 mg lumefantrine)
Pyrimethamine-sulfadoxine Two or three tablets PO once (each xed-dose tablet contains 25 mg pyrimethamine and 500 mg sulfadoxine)
Artesunate + meoquine Artesunate 4 mg/kg PO daily for 3 days plus meoquine 1250-mg single dose or 750 mg followed by 500 mg
after 12 hr
or
Artesunate 2.4 mg/kg IV, rst dose, followed by 1.2 mg/kg after 12 hr, followed by 1.2 mg/kg q24h 3 days
plus meoquine 1250-mg single dose or 750 mg followed by 500 mg after 12 hr
Artemether + meoquine Artemether 3.2 mg/kg IM, rst dose followed by 1.6 mg/kg after 12 hr, followed by 1.2 mg/kg q24hr 3 days
plus meoquine 1250-mg single dose or 750 mg followed by 500 mg after 12 hr
Treatment
All patients with P. falciparum malaria should be hospitalized, at least
for the rst 48 hours after initiation of treatment, regardless of how
well they may appear at presentation. Patients with severe malaria
may require ICU admission. The effectiveness of different antima-
larials depends on the geographic area in which the infection was
acquired. Treatment regimens effective against P. falciparum are out-
lined in Table 1. The most commonly used drugs are quinine or
artemisinin derivatives, which should be effective for almost all cases
of malaria in most regions. In many endemic regions, there is sig-
nicant resistance to pyrimethamine-sulfadoxine, and this drug
should be used with caution; if used, patients should be closely
monitored for response. The Centers for Disease Control and Preven-
tion (CDC) has published guidelines for the treatment of malaria
in the United States (available at http://www.cdc.gov/malaria/pdf/
clinicalguidance.pdf).
All patients should be closely monitored for the possibility of
hypoglycemia, which occurs as a result of the infection itself and as
an adverse effect of antimalarials, and is very common. Patients
unable to eat should receive glucose-containing uids as a continu-
ous infusion. Patients treated with quinine should be monitored for
ndings suggestive of cinchonism, indicated by tinnitus and hearing
loss which, if detected, should prompt dose reduction or change in
therapy.
l Most deaths from malaria are caused by P. falciparum.
l P. falciparum causes sequestration of erythrocytes in the
deep microvasculature, resulting in most of the
complications from this infection.
l P. falciparum must be considered in the differential
diagnosis of any patient with fever who has recently been
in a malaria-endemic area.
l The diagnostic test of choice is the peripheral blood smear.
l Quinine and artemisinin derivatives are the most
commonly used treatments.
Summary
CHOLERA
Cholera is a diarrheal disease caused by Vibrio cholerae. The disease
is widely distributed in Asia, Africa, and South America. It occurs as
an endemic form and has the potential to cause pandemics periodi-
cally. Of the more than 200 serogroups of V. cholerae, only twoO1
and O139cause clinical cholera. In 2005, the number of reported
cases of cholera was 131,943, with 2,272 deaths from 52 countries.
57
Pathophysiology
The natural reservoir of V. cholerae is water, and the predominant
mode of spread is contamination of drinking water supplies. The
bacterium can survive in a free-living state in water when conditions
are favorable and reaches the hosts intestinal tract through con-
taminated food or water. Persons with decreased gastric acidity
because of disease or medications have a greater likelihood of becom-
ing infected. Bacteria that survive the gastric environment and gain
access to the small intestine cause disease by secreting an enterotoxin
that stimulates secretion of uid and electrolytes into the lumen by
the cells lining the small intestine.
58
Excessive secretion leads to dehy-
dration, and the dehydration resulting from cholera is the most
severe of any infectious disease. The bacterium does not invade the
wall of the small intestine.
Cholera manifests with an abrupt onset of watery diarrhea, soon
followed by dehydration. Stools are thin and white, referred to as rice
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Hughes WT, Armstrong D, Bodey GP, et al: 2002 guidelines for the use of antimicrobial
agents in neutropenic patients with cancer. Clin Infect Dis 2002;34:730-751.
Nathoo N, Nadvi SS, van Dellen JR, Gouws E: Intracranial subdural empyemas in the
era of computed tomography: A review of 699 cases. Neurosurgery 1999;44:529-535.
Salzman MB, Rubin LG: Meningococcemia. Infect Dis Clin North Am 1996;10:709-725.
Seas C, DuPont HL, Valdez LM, Gotuzzo E: Practical guidelines for the treatment of
cholera. Drugs 1996;51(6):966-973.
Stevens DL, Bisno AL, Chambers HF, et al: Practice guidelines for the diagnosis and
management of skin and soft-tissue infections. Clin Infect Dis 2005;41:1373-1406.
Stevens DL: The toxic shock syndromes. Infect Dis Clin North Am 1996;10:727-746.
Tunkel AR, Hartman BJ, Kaplan SL, et al: Practice guidelines for the management of
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Tunkel AR, Scheld WM: Pathogenesis and pathophysiology of bacterial meningitis. Clin
Microbiol Rev 1993;6:118-136.
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References
For a complete list of references, log onto www.expertconsult.com.
water stools. Vomiting is also common, and usually follows diarrhea.
The severity of diarrhea and dehydration is variable, and it is impor-
tant to realize that dehydration from cholera could be so severe that
previously healthy people could die of dehydration within hours of
the onset of symptoms. In a much smaller proportion of patients,
the presentation is abdominal distention rather than diarrhea because
of accumulation of uid within the intestinal lumen, a presentation
known as cholera sicca. The most important complication is prerenal
acute renal failure, and an incidence rate of 10.6 per 1000 was recog-
nized in an outbreak in Peru in 1991.
59
Diagnosis
It is not difcult to diagnose a patient with cholera. Patients present
with diarrhea, with surprising degrees of dehydration considering the
short duration of the illness. For routine clinical care, microbiologic
diagnosis cannot be made in a timely manner and is unnecessary.
Treatment
The mainstay of therapy is adequate uid resuscitation. Patients with
mild dehydration can be treated with oral rehydration. Patients with
severe dehydration or those with moderate dehydration and unable
to tolerate oral rehydration need IV rehydration. Rehydration should
be provided in two phases, a rapid rehydration phase lasting 2 to 4
hours and a maintenance phase lasting the duration of the diarrhea.
When possible, electrolytes should be monitored and abnormalities
corrected. Since 1978, the World Health Organization oral rehydra-
tion solution (WHO ORS) has been recommended as the oral rehy-
dration uid for the management of diarrheal illnesses, including
cholera.
60
For IV rehydration, normal saline or Ringers lactate solu-
tion may be used. It must be noted that these uids have low potas-
sium content, and supplemental potassium may be required.
Antibiotics have been shown to reduce the duration of diarrhea and
volume of stools;
61
however, their use is of secondary importance in
comparison with rehydration. A single 100-mg dose of doxycycline
has been shown to be adequate treatment.
62
Alternative agents are
trimethoprim-sulfamethoxazole, furazolidone or erythromycin for 3
days, or a single dose of azithromycin, all of which can also be used
in pregnant women and children. Practical guidelines for the man-
agement of cholera have been published.
63
The WHO ORS solution is hyperosmolar relative to plasma and
concern has been raised that this solution may induce the develop-
ment of an osmotically driven increase in stool output and hyperna-
tremia.
64
Indeed, the use of this solution does not reduce stool
volume or duration of diarrhea.
65
In recent years, the use of reduced
osmolarity ORS in areas endemic for cholera has gained favor,
66
and
this solution appears to be more effective than standard ORS.
67

Regardless of the nature of the rehydration solution used, the prin-
ciple of cholera treatment remains adequate rehydration.
l Cholera is a diarrheal disease transmitted by contaminated
drinking water.
l It causes the most severe form of diarrhea caused by any
infectious agent.
l Rehydration with repletion of electrolytes is the mainstay
of therapy.
l Antibiotic therapy is of secondary importance.
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region of T cell receptors, leading to broad-range induction

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