1

Infectious Disease Emergencies: Cleveland Clinic

http://www.clevelandclinicmeded.com/medicalpubs/diseasemanagement/infectious-disease/infectious-disease-
emergencies/

Infectious disease emergencies are conditions that have potential for significant harm to the patient if not
recognized and treated promptly. Timely and appropriate intervention may significantly improve outcomes. The
following is a discussion of important infectious disease emergencies.
Acute Bacterial Meningitis
Definition, Etiology, and Incidence
Bacterial meningitis is an inflammation of the meninges caused by bacterial infection. 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 Table 1.
Table 1. Important Causes of Bacterial Meningitis*
In Adults
In Children
After Neurosurgery
Streptococcus pneumoniae
Neisseria meningitidis
Listeria monocytogenes
Streptococcus pneumoniae
Neisseria meningitidis
Haemophilus influenzae
Streptococcus agalactiae
(in neonates)
Escherichia coli (in neonates)
Staphylococcus aureus
Pseudomonas aeruginosa
Enteric gram-negative bacteria
*Mycobacterium tuberculosis is also a bacterium and can cause meningitis, but it is usually discussed separately
as tuberculous meningitis.
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 meningitis was
predominantly a disease of children, the most common offending pathogen being Haemophilus influenzae. The
introduction of routine immunization of children against H. influenzae type B in the late 1980s dramatically
reduced the incidence of infection with this microorganism. As a consequence, the overall incidence of bacterial
meningitisand particularly of meningitis caused by H. influenzaedecreased, 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 inflammatory response occurs in the
subarachnoid space, but this response is inadequate to control the infection. This inflammatory response results
in increased permeability of the blood-brain barrier. This is responsible for the increased cerebrospinal fluid
(CSF) protein content seen in patients with meningitis. Progression of meningitis leads to the development of
cerebral edema, resulting in increased CSF pressure. Inflammation of blood vessels traversing the subarachnoid
space may lead to their thrombosis. This can result in ischemia and infarction of the underlying brain.
2
Clinical Presentation
Patients with acute bacterial meningitis usually present with headache, neck stiffness, fever, projectile vomiting,
and photophobia. In more advanced disease, there is progressive clouding of consciousness. On examination,
neck rigidity may be seen and Kernigs and Brudzinskis signs may be elicited. Cranial nerve palsies or focal
neurologic 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 difficult, 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 severe headache 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 deficits.
5
The CSF should be sent for cell count, protein and glucose
levels, and Gram staining and culture. Typical CSF findings in acute bacterial meningitis include an elevated
opening pressure, increased CSF white blood cell (WBC) count (100-10,000 cells/mcL), 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 confirm a diagnosis of viral meningitis is by specific
polymerase chain reaction (PCR) testing, if available.
Treatment
The management of bacterial meningitis includes appropriate antibiotic therapy and adjunctive
corticosteroids.
7,8
Ideally, the lumbar puncture should be done before the administration of antibiotics.
However, antibiotic administration should not be delayed for any reason if the lumbar puncture cannot be
immediately performed. 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 definite causal diagnosis, and its value in
guiding subsequent therapy and managing possible complications, are fully worth the effort. Empiric 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 dexamethasone 10 mg IV every 6 hours for 4 days with
the first dose of antibiotics. This has been shown to improve outcomes in patients with bacterial meningitis.
7

Antibiotic selection and dosing should also take into consideration the agents ability to cross the blood-brain
barrier and achieve an effective concentration in the CSF. In adults, initial empiric 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
3
empiric antibiotic therapy with a regimen consisting of vancomycin and ceftriaxone.
6
If Listeria monocytogenes
is a possibility (eg, in older adults, pregnant women, and those with cellular immune deficits), ampicillin should
be added. If Pseudomonas aeruginosa is a possibility, as after neurosurgical procedures, ceftazidime should be
used instead of ceftriaxone. Antibiotic therapy should be adjusted once the causative microorganism has been
identified. Duration of therapy for bacterial meningitis has not been adequately defined. 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

Summary
The differential diagnosis of acute bacterial meningitis includes viral meningitis and meningoencephalitis,
tuberculous meningitis, primary amebic meningoencephalitis, and subarachnoid hemorrhage.
Lumbar puncture should be performed as soon as possible.
Dexamethasone plus empiric antibiotics should be started without delay.
Antibiotics should be adjusted subsequently, based on culture and susceptibility data.
Back to Top
Acute Meningococcemia
Definition, Etiology, and Incidence
Acute meningococcemia is a disseminated infection caused by Neisseria 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 nasopharyngeal colonization. About 10% of the
population has asymptomatic 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 invasive disease include agent factors,
such as virulence, and transmissibility and host factors.
Patients with deficiencies of the late components of the complement pathway are at markedly increased risk of
developing recurrent episodes of meningococcal infections.12 Genetic variants of mannose-binding lectin
(MBL), a plasma opsonin that initiates the MBL pathway of complement activation, may also make patients
more susceptible to meningococcal infections.
13

Clinical Presentation
Meningococcal infection can manifest in a variety of forms: bacteremia without sepsis, meningitis (with or
without meningococcemia), acute meningococcemia (with or without meningitis), a meningoencephalitic
picture, or chronic meningococcemia. The most fulminant form is acute meningococcemia, in which death may
ensue within hours of the onset of symptoms.
4

Figure 1: Click to Enlarge
The most common manifestation of acute meningococcemia is fever with rash. The rash usually begins with
petechiae, initially with a few discrete lesions 1 to 2 mm in diameter that often progress and coalesce to form
larger ecchymotic lesions (Figure 1). In cases of 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 intravascular coagulation (DIC). Meningococcemia can lead to complications such as massive
adrenal hemorrhage; DIC; arthritis; heart problems such as pericarditis and myocarditis; neurologic problems
such as deafness and peripheral neuropathy; and peripheral gangrene.
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 might 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 characteristic ecchymotic rash, the diagnosis is not
difficult to make. Early infection could be missed if a careful physical examination is not carried out in a patient
with an acute febrile illness. Definitive diagnosis requires isolation of the microorganism from a normally
sterile site. Samples for blood cultures should be obtained before the administration of antibiotics, if possible.
Antibiotic therapy rapidly sterilizes the blood and CSF in patients with meningococcal infection.
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 identified in the biopsy of petechial skin lesions.
Treatment
The treatment of acute meningococcemia involves appropriate antibiotic 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 meningococcal disease.
18
The recommended treatment for severe
meningococcal 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 efficacious
alternatives. Patients who are allergic to cephalosporins may be treated with chloramphenicol, 100 mg/kg, in 4
divided doses. The maximum total dosage is 4 g/day.
20
High doses of penicillin G should also usually be
adequate; however, small numbers of resistant N. meningitidis have been reported, and therefore penicillin G is
not ordinarily the first-choice antibiotic in the absence of susceptibility data. The shock state is a dominant part
of the clinical picture of meningococcemia and supportive management is important. The use of steroids for
5
meningococcemia is controversial, and a recommendation for the routine use of steroids for treatment of this
condition cannot be made.
Prophylaxis
Household contacts are at significantly higher risk of infection.
21
Chemoprophylaxis is recommended for
household contacts, daycare center staff and clients, and anyone exposed to the patients oral secretions. Among
health care workers, this includes people who intubated the patient and who provided suction to clear secretions.
Effective prophylactic treatments include a single 1-g dose of ceftriaxone intravenously or intramuscularly, a
single 500-mg dose of ciprofloxacin, a single 500-mg dose of azithromycin, and 600 mg of rifampin every 12
hours for 2 days.
18

Summary
The classic presentation of meningococcemia is fever and rash.
Prompt antibiotic therapy can be lifesaving.
Shock is a dominant clinical finding and supportive management is important.
People who have come in close contact with the patient should receive chemoprophylaxis.
Back to Top
Cranial Subdural Empyema
Definition, Etiology, and Incidence
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 anaerobic infections in varying proportions of infections. However a high proportion of patients
have had anaerobic microorganisms recovered.
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

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 proportion of cases, subdural empyema may occur
by metastatic spread, usually from a pulmonary infection, for an unexplained reason.
Clinical Presentation
Patients with this condition usually present acutely, with headache and vomiting. Most patients have an altered
mental status at presentation and the level of consciousness deteriorates rapidly. Patients may have neurologic
deficits and complications such as local cerebritis, cerebral abscesses, and septic dural venous thromboses may
occur.
Diagnosis
6
The diagnosis should be considered in any patient who presents with features suggestive of meningitis and a
focal neurologic deficit 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 findings would be nonspecific, with
an elevated opening pressure, neutrophilic or mixed 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 combined surgical and medical approach. Empiric
antibiotic therapy should be broad spectrum and include coverage for gram-positive pyogenic bacteria and
anaerobes. Vancomycin is a reasonable choice. Cultures obtained at the time of surgery will help tailor
antibiotic treatment. 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 collection 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.
Summary
MRI or CT scanning should be performed promptly when cranial subdural empyema is suspected.
Treatment requires a combined medical and surgical approach.
Empiric broad-spectrum antibiotic therapy should be started promptly.
Cultures obtained at the time of surgery will help tailor antibiotic therapy.
Multiple operations may be necessary.
Back to Top
Necrotizing Soft Tissue Infections
Definition, Etiology, and Incidence
This term encompasses several specific clinical entities characterized by disease processes that produce necrosis
of subcutaneous tissue, muscle, or both, and that progress rapidly and require a combined emergent surgical and
medical approach for optimal outcomes. These entities include necrotizing fasciitis, streptococcal necrotizing
myositis, clostridial myonecrosis (gas gangrene), and nonclostridial crepitant myositis.
Type I necrotizing fasciitis is a mixed infection caused by an anaerobic bacterium (usually Bacteroides or
Clostridium) in association with a facultative anaerobic microorganism, such as a streptococcus or a member of
the Enterobacteriaceae. Type II necrotizing fasciitis, hemolytic streptococcal gangrene, is caused by group A,
B, C, or G 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 beta hemolytic streptococci, respectively.
Nonclostridial crepitant myositis encompasses several clinical entities that may result from mixed infection
caused by: anaerobic streptococci, along with group A streptococci or S. aureus (anaerobic streptococcal
7
myonecrosis); a mixture of anaerobic and facultatively anaerobic microorganisms (synergistic nonclostridial
anaerobic myonecrosis, or Meleneys bacterial synergistic gangrene); Proteus spp., Bacteroides spp., and
anaerobic streptococci in devitalized limbs (infected vascular gangrene); Vibrio vulnificus; and Aeromonas
hydrophila.
As a group, these illnesses are uncommon but not rare, and prompt recognition and appropriate management
can significantly improve outcomes.
Pathophysiology
Necrotizing fasciitis usually begins with the introduction of the offending microorganism into 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
Clostridium, 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 fish 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 development of necrotizing soft tissue infections.
28

Other risk factors include alcoholism, corticosteroid use, and parenteral drug use.
Clinical Presentation
Necrotizing fasciitis is usually an acute process, with severe infection of the superficial and deep fascia. It most
commonly occurs in the extremities. The affected area becomes erythematous, swollen, warm, and painful. The
infection 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 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 findings 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 findings. 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 associated with the toxic shock syndrome. Acute
vascular compromise from trauma or embolic occlusion leads to tissue infarction and may progress to infected
vascular gangrene if the appropriate microorganisms gain access to the devitalized tissues.
Diagnosis
8
Clinical suspicion is important in order to make an early diagnosis of a necrotizing soft tissue infection. 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 fluid in muscle compartments, but may not be apparent early in
the disease process. 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 one. When considered a
possibility, aggressive management is important. Clinical features cannot accurately predict the causative
microorganism. 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 until the etiologic
diagnosis has been established. The antibiotics of choice for initial empiric therapy are clindamycin plus
ampicillin-sulbactam plus ciprofloxacin.
29
If there is reason to suspect MRSA infection, vancomycin should be
added. Antibiotic therapy should be modified 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 debridement 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.
Summary
Clinical suspicion will facilitate the early diagnosis of necrotizing soft tissue infections.
Skin surface findings may be minimal.
Prompt and aggressive surgical debridement is the most important aspect of treatment.
Empiric antibiotic therapy should consist of clindamycin plus ampicillin-sulbactam plus ciprofloxacin.
Antibiotic therapy should be modified once culture data become available.
Back to Top
Toxic Shock Syndrome
Definition, Etiology, and Incidence
Toxic shock syndrome (TSS) is a severe toxin-mediated bacterial disease characterized by shock resulting from
an excess of inflammatory cytokines. Two important syndromes, staphylococcal TSS and streptococcal TSS,
are recognized to be caused by S. aureus and Streptococcus pyogenes, respectively. Both are uncommon
diseases. The incidence rate 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 rate 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 exotoxins 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 streptococcal pyrogenic exotoxins A, B, and C (SPEA, SPEB, SPEC) of S. pyogenes. These toxins
are capable of binding both major histocompatibility complex (MHC) class II molecules of antigen-presenting
9
cells and the V region of T cell receptors, leading to broad-range induction of T cell proliferation. The
resulting excessive production of inflammatory 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
The production of TSST-1 by colonizing S. aureus is
stimulated in such an environment. Nonmenstrual TSS can be 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.
Clinical Presentation
Toxic shock syndrome manifests as a multisystem illness, with shock being a prominent feature.
31
Clinical
features include high fever, hypotension, 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 streptococcal 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 nonmenstrual TSS, the site of infection may
show minimal inflammation 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 arthritis, peritonitis, and other deep infections.
33

Patients are usually very ill and may develop acute respiratory distress syndrome (ARDS) or DIC. The mortality
of adequately treated staphylococcal TSS is about 5%. The mortality of streptococcal TSS is about 50%.
Diagnosis
The diagnostic criteria for TSS are outlined in Tables 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 confirmation by additional
laboratory testing to look for abnormalities that indicate damage to the organ systems expected to be involved
by the process. CT or MRI helps in defining 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 findings do not
appear impressive when clinical features are suggestive of the disease.
Table 2. Diagnostic Criteria for Staphylococcal Toxic Shock Syndrome*
Diagnostic criteria include:
Fever: Temperature 102 F (38.9 C)
Rash: Diffuse macular erythroderma
Overt or orthostatic hypotension
Plus multisystem involvement ( 3 of the following):
Gastrointestinal: Vomiting or diarrhea at the onset of illness
Muscular: Severe myalgia or creatine kinase level 2 the upper limit of normal
Mucous membranes: Vaginal, oropharyngeal, or conjunctival hyperemia
10
Renal: Blood urea nitrogen or creatinine level 2 the upper limit of normal
or
urinary sediment with pyuria ( 5 leukocytes per high-power field) in the absence of urinary tract infection
Hepatic: Total bilirubin, aspartate transaminase, or alanine aminotransaminase level 2 the upper limit of
normal
Hematologic: Platelet count 100,000/mcL
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:
Blood, throat, or cerebrospinal cultures (blood cultures may be positive for Staphylococcus aureus)
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
*All 6 criteria have to be satisfied to make a definite diagnosis. Fulfillment of the first 5 criteria makes a
probable diagnosis.
Table 3. Diagnostic Criteria for Streptococcal Toxic Shock Syndrome*
Diagnostic criteria include 1 of the following:
Isolation of Streptococcus pyogenes
or
Hypotension
Plus 2 or more of the following:
Renal impairment: Creatinine level 2.0 mg/dL or 2 the upper limit of normal for age
Thrombocytopenia (platelet count 100,000/mcL) or disseminated intravascular coagulation
Liver involvement: Aspartate transaminase, alanine aminotransaminase, or total bilirubin level 2 the upper
limit of normal
Acute respiratory distress syndrome
Generalized macular erythrodermic rash that may desquamate
Necrotizing soft tissue infection
*All 3 criteria must be met. If S. pyogenes is isolated from a normally sterile site, the diagnosis is definite; if
isolated from a nonsterile site, the diagnosis is probable.
Treatment
Management of TSS includes eradication of the focus of infection plus supportive care, which includes fluid
resuscitation and vasopressors, as necessary.
36
Large volumes of crystalloids may be required 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 infection is identified in staphylococcal
TSS, it is important to drain abscesses and treat with appropriate antibiotics. If a hyperabsorbent tampon is in
place, it should be removed. Patients who have streptococcal TSS do better with combinations of clindamycin
and cell-wall active agents compared to patients who receive 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 effective in these patients. Thus, in both
staphylococcal and streptococcal toxic shock syndrome, clindamycin should be included initially.
11
Staphylococcal TSS should also initially be treated with vancomycin. Antibiotic therapy can be modified once
susceptibility data become available. MRSA infections should be treated with vancomycin; MSSA infections
with oxacillin; and penicillin-susceptible S. aureus should be treated with penicillin G. Treatment of
streptococcal TSS usually includes aggressive surgical debridement, with antibiotic therapy and supportive care.
The antibiotic of choice is penicillin G.
Summary
The toxic shock syndromes are toxin-mediated diseases of S. aureus and S. pyogenes.
The site of infection may not be readily apparent, especially in staphylococcal TSS.
Streptococcal TSS is often associated with necrotizing soft tissue infections.
Surgical debridement of the focus of infection may be necessary.
Early antibiotic therapy should include clindamycin in addition to cell-wall active agents.
Back to Top
Neutropenic Fever
Definition, Etiology, and Incidence
Fever in a neutropenic patient is defined as a single oral temperature > 101F (38.3C) or a temperature >100.4
(38.0C) sustained over a 1-hour period.
38
Neutropenia is defined as an absolute neutrophil count (ANC) < 500
cells/mcL and/or ANC that is expected to decrease to <500 cells/mcL over the next 48 hours.
38
More than 50%
of neutropenic patients who develop a fever have an obvious or occult infection. The risk of invasive infection
increases with the degree of neutropenia. At least 20% of patients with an absolute neutrophil count < 100
cells/mcL 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 inflammatory 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 infiltrates. The most likely sources of bacterial invasion in
such patients are the skin, because of the breaching of skin integrity by invasive vascular catheters, and the
gastrointestinal tract, because of mucosal damage from chemotherapeutic agents. The most common bacterial
pathogens causing fever in patients with neutropenia are listed in Table 4.
Table 4. Most Common Bacterial Causes of Infection in Patients with Neutropenic Fever
Gram-Positive Bacteria Gram-Negative Bacteria
Staphylococcus spp.
Streptococcus spp.
Enterococcus spp.
Viridans group streptococci
Streptococcus pneumoniae
Streptococcus pyogenes
Escherichia coli
Klebsiella spp.
Enterobacter spp.
Citrobacter spp.
Pseudomonas aeruginosa
Acinetobacter spp.
Stenotrophomonas maltophilia
12
Adapted from Freifeld AG, Bow EJ, Sepkowitz KA, et al: Clinical practice guideline for the use of
antimicrobial agents in neutropenic patients with cancer: 2010 update by the Infectious Diseases Society of
America. Clin Infect Dis 2011;52:e56-e93. Copyright 2011 Infectious Disease Society of America, with
permission from Oxford University Press.
Clinical Presentation
Patients may present with fever only. The clinical presentation may appear to be relatively mild, especially to
the inexperienced observer. Furthermore, many patients with chemotherapy-induced neutropenia may be taking
corticosteroids, which may actually mask fever. In neutropenic patients who are taking corticosteroids,
hypothermia, hypotension, 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. The clinician
should obtain 2 or 3 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 significantly more sensitive for
detecting pulmonary processes. Other investigations should be carried out if there are any localizing symptoms
or signs. Meningitis is uncommon and lumbar puncture should only be considered if there is strong evidence of
meningitis.
Treatment
For patients with neutropenic fever, empiric therapy should provide adequate coverage against enteric gram-
negative bacteria and P. aeruginosa. 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 bloodstream infections it is usually necessary to remove the catheter.
39

Several antibiotic regimens are effective for the empiric treatment of neutropenic fever, but no specific regimen
is recommended for all patients. Criteria have been defined to identify those patients considered to be at high-
risk for progression to severe illness.
40
Patients deemed to be low-risk may be treated with oral ciprofloxacin
plus oral amoxicillin-clavulanate. Those deemed to be high-riskall patients with an ANC of <100 cells/mcL,
duration of neutropenia exceeding 7 days, peak temperature 102.2 F (39 C) or higher, active malignancy, lack
of early evidence of marrow recovery, and any obvious focus of infectionshould be hospitalized and treated
with IV antibiotic therapy consisting of monotherapy with an anti-pseudomonal -lactam agent such as
cefepime or ceftazidime, a carbapenem (meropenem or imipenem), or piperacillin-tazobactam.
38
Other
antimicrobials may be added based on clinical circumstances. Recent infection or colonization, or treatment in a
hospital with high rates of endemicity, may necessitate addition of antimicrobial agents that would specifically
treat MRSA, vancomycin-resistant Enterococcus (VRE), extended-spectrum -lactamase (ESBL)-producing
gram-negative bacteria, and carbapenem-resistant Klebsiella pneumoniae (CRKP).
38

Antibiotic therapy should be modified if cultures identify a causative microorganism. If a gram-positive
infection is not identified by day 3, an empirically started gram-positive bacterial agent such as vancomycin or
daptomycin may be stopped. If there is worsening after 3 days, a change in the antibiotic regimen should be
considered. If the fever persists after 4-7 days, empiric 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, who have had graft-versus-host disease, severe mucosal erosive disease, extensive prior
13
antibiotic treatment, or prolonged hospitalization are at higher risk of subsequent infectious complications.
41

Patients who are neutropenic for fewer 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/mcL for at least 48 hours. Antibiotic therapy can be stopped at 5 to 7 days after the resolution of fever in
low-risk patients if the ANC is 500 cells/mcL, but should be continued for at least 2 weeks in high-risk
patients with an ANC 500 cells/mcL. If the fever persists beyond 5 days, but there is no obvious identified
infection, antibiotics may be stopped 4 to 5 days after the ANC recovers above 500 cells/mcL, but should be
continued for at least 2 weeks if the ANC remains below 500 cells/mcL.
Summary
Neutropenic fever is defined as an oral temperature >101 F (38.3 C), or >100.4 F (38.0 C) for more than 1
hour in a neutropenic patient (actual or predicted ANC <500 cells/mcL).
Signs of inflammation may be minimal.
There is potential for progression to death within hours.
Empiric broad-spectrum antibiotic therapy should be instituted immediately and adjusted later.
Back to Top
Sepsis in Patients with Prior Splenectomy or Functional Hyposplenism
Definition, Etiology, and Incidence
The importance of sepsis in these patients is the potential for progression 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 sepsis following splenectomy has been estimated to be approximately 5%.
43
The risk of infection persists
throughout life and is highest in the first 2 years after splenectomy.
42

The microorganisms that cause deadly infections in patients with prior splenectomy or functional hyposplenism
are S. pneumoniae, H. influenzae, N. meningitidis, Capnocytophaga canimorsus, and Babesia microti or B.
divergens. The most common responsible microorganism 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 producing specific
antibodies. However, the antigenic priming process for this response takes time, and makes this mechanism
protective in subsequent infections, not in initial infections. B1-a B cells are a subset of B lymphocytes that
produce antibodies without prior specific exposure.
45,46
These are natural antibodies of the immunoglobulin 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. influenzae, and N.
meningitidis.
The spleen is also responsible for the clearance of erythrocytes with abnormal inclusions from the circulation.
Such abnormal inclusions include intra-erythrocytic parasites such as Babesia species. Most cases of infection
14
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.
Clinical Presentation
The initial presentation, if patients present early, may be no different from that of a febrile illness in an
otherwise healthy patient. Typical symptoms 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 sepsis following splenectomy 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
sepsis. The clinician should obtain 2 to 3 sets of blood samples for culture. Other investigations should be
performed if there are any localizing symptoms 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 sepsis following splenectomy is to recognize the condition and the
potential for its occurrence in any patient who has had a splenectomy and who presents with a febrile illness.
Antibiotics should be started immediately. Antibiotic therapy should not be withheld for completion of blood
cultures. Empiric antibiotic therapy should consist of vancomycin and ceftriaxone. This empiric regimen will
adequately treat all the pathogens definitely associated with sepsis in these patients, except Babesia.
Vancomycin may be stopped if resistant pneumococci are not isolated. In those rare cases in which Babesia is
the causative agent, treatment is with quinine plus clindamycin.
Prophylaxis
All patients should receive the 23-covalent bond, unconjugated, capsular pneumococcal polysaccharide vaccine
(PPV23) at least 2 weeks before elective splenectomy.
50
If the splenectomy is an emergent procedure, the
vaccine should still be given as soon as possible. Revaccination once after 5 years is also recommended.
51

Although there are fewer data on the protective efficacy of the H. influenzae 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 first 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.
Summary
Patients with sepsis following splenectomy can progress from a healthy state to death within 24 hours.
The most important responsible microorganisms are S. pneumoniae and H. influenzae.
The degree of bacteremia is very high, and bacteria may be seen in the buffy coat or on a peripheral smear.
Vancomycin plus ceftriaxone will provide adequate antibiotic coverage in most cases.
15
Back to Top
Plasmodium Falciparum Malaria
Definition, Etiology, and Incidence
Malaria in humans is caused by 5 species of Plasmodium: P. falciparum, P. vivax, P. malariae, P. knowlesi, and
P. ovale. Malaria should always be considered 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. In 2009, there were an estimated 225 million cases
of malaria worldwide.
52
Globally, more than 1 million deaths occur from malaria each year.
53
The vast majority
are caused by P. falciparum. P. knowlesi is a newly recognized human malarial parasite that is capable of
causing severe malaria.
54
The following discussion 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 merozoites in the liver cells, and are released into the
bloodstream after several days. P. vivax and P. ovale, in addition to undergoing immediate 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 effective 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 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 2 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 must be ingested by
an appropriate mosquito. 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 find their way to the mosquitos salivary glands, where they
are poised to be transmitted 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 erythrocytes. 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 endothelial 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
erythrocytes in the cerebral, renal, hepatic, and other microcirculations, leading to the complications of P.
falciparum malaria.
16
Clinical Presentation
The most important symptom of malaria is fever. Classic descriptions 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. In our current perspective, 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
cerebral malaria.
P. falciparum malaria is far more likely to lead to complications than is the nonP. falciparum malarias. The
most important complications of P. falciparum malaria are severe anemia, hypoglycemia, cerebral malaria,
acute renal failure, ARDS, acute hepatocellular failure, and DIC.
Several clinical features indicate specific end-organ damage in P. falciparum malaria; these include headache,
seizures, and loss of consciousness (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 ARDS).
Diagnosis

Figure 1: Click to Enlarge
Malaria must be considered in the differential diagnosis of any febrile illness in a patient living in or having
recently traveled to an area in which malaria is endemic. The most important diagnostic and most practical test
is the Wrights- (or Wrights-Giemsa) stained peripheral blood smear (thick and thin), which should be
examined immediately if malaria is suspected. 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 finding in patients with P. falciparum malaria are ring-shaped trophozoites within red blood cells (Figure
2). Antigen-based tests and serologic tests also exist for the diagnosis of malaria. While these tests do not
require much expertise to read, they are unlikely to be available in areas in which malaria is not endemic.
Treatment
All patients with P. falciparum malaria should be hospitalized, at least for the first 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 antimalarials depends on the geographic area in which the
infection was acquired. Treatment regimens effective against P. falciparum are outlined in Table 5. 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 significant 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 Prevention (CDC) has published guidelines for the treatment of malaria in the
United States (available at http://www.cdc.gov/malaria/).
17
All patients should be closely monitored for the possibility of hypoglycemia, which can occur either as a result
of the infection itself or as an adverse effect of antimalarials, and is very common. Patients who are unable to
eat should receive glucose-containing fluids as a continuous infusion. Patients treated with quinine should be
monitored for findings suggestive of cinchonism, indicated by tinnitus and hearing loss which, if detected,
should prompt dose reduction or change in therapy.
Table 5. Effective Regimens for Treatment of P. falciparum Malaria
Pharmacologic
Agent(s)
Dosing Regimen
Quinine plus
doxycycline
Quinine 10 mg/kg PO or IV q8hr for 7 days; doxycycline 100 mg PO q8hr for 7 days
Atovaquone-
chloroguanide
Four adult tablets per day for 3 days (each adult tablet contains 250 mg atovaquone and 100 mg
chloroguanide)
Artemether-
lumefantrine
Four tablets initially, followed by 4 tablets 8 hr later, followed by 4 tablets twice daily on days 2
and 3 (each fixed-dose tablet contains 20 mg artemether and 120 mg lumefantrine)
Pyrimethamine-
sulfadoxine
Two or 3 tablets PO once (each fixed-dose tablet contains 25 mg pyrimethamine and 500 mg
sulfadoxine)
Artesunate plus
mefloquine
Artesunate 4 mg/kg/d for 3 days plus mefloquine 1250-mg single dose or 750 mg followed
by 500 mg after 12 hr

OR

Artesunate 2.4 mg/kg IV, first dose, followed by 1.2 mg/kg after 12 hr, followed by 1.2
mg/kg/d for 3 days plus mefloquine 1250-mg single dose or 750 mg followed by 500 mg
after 12 hr
Artemether plus
mefloquine
Artemether 3.2 mg/kg IM, first dose followed by 1.6 mg/kg after 12 hr, followed by 1.2 mg/kg/d
for 3 days plus mefloquine 1250-mg single dose or 750 mg followed by 500 mg after 12 hr

Summary
Most deaths from malaria are caused by P. falciparum infection.
P. falciparum causes sequestration of erythrocytes in the deep microvasculature, resulting in most of the
complications of the infection.
P. falciparum must be considered in the differential diagnosis of any patient with fever who has recently been in
a malaria-endemic area.
The diagnostic test of choice is the peripheral blood smear.
Quinine and artemisinin derivatives are the most commonly used treatments.
Back to Top
Cholera
18
Definition, Etiology, and Incidence
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 epidemics or pandemics
periodically. An outbreak of cholera in Haiti in October 2010 resulted in more than 470,000 cases and 6,631
deaths over the next year.
57

Pathophysiology
Of the more than 200 serogroups of V. cholerae, only 2O1 and O139cause clinical cholera. 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
intestinal tract of the host through ingestion of contaminated food or water. People who have decreased gastric
acidity have a greater likelihood of becoming infected. Bacteria that survive the gastric environment and gain
access to the small intestine cause disease by secreting an enterotoxin that stimulates the secretion of fluid and
electrolytes into the lumen by the cells lining the small intestine.
58
Excessive secretion leads to dehydration, 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.
Clinical Presentation
Cholera manifests with an abrupt onset of watery diarrhea, soon followed by dehydration. Stools are thin and
white, referred to as rice water stools. Vomiting is also common, and usually follows diarrhea. The severity of
diarrhea and dehydration is variable, and it is important to realize that dehydration from cholera could be so
severe that a previously healthy person 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 fluid 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 recognized in an
outbreak in Peru in 1991.
59

Diagnosis
It is not difficult to diagnose a patient with cholera. Patients present with diarrhea and 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 fluid resuscitation. Patients with mild dehydration can be treated with oral
fluids. Patients who are more severely dehydrated, or those with moderate dehydration who are unable to
tolerate oral fluids will require IV therapy. Rehydration should be provided in 2 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
rehydration solution (WHO ORS) has been recommended as the best choice for the management of diarrheal
illnesses, including cholera.
60
ORS is a sodium and glucose solution prepared by diluting 1 sachet of ORS in 1
L of safe drinking water. Effective and timely management will result is mortality rates < 1%. If ORS packets
are not available, homemade solutions consisting of half a teaspoon of salt and 6 level teaspoons of sugar
dissolved in 1 L of safe drinking water can be used.
61
For IV rehydration, normal saline or Ringers lactate
solution may be used. It must be noted that these fluids have low potassium content, and supplemental
potassium may be required.
19
Antibiotics have been shown to reduce the duration of diarrhea and volume of stools.
62
However, the use is of
antibiotics in malaria patients is of secondary importance to hydration. A single 100-mg dose of doxycycline
has been shown to be adequate antibiotic therapy.
63
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.
The WHO ORS solution is hyperosmolar relative to plasma and concern has been raised that this solution may
induce the development of an osmotically driven increase in stool output and resulting hypernatremia.
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 primary principle
of cholera treatment remains adequate rehydration.
Summary
Cholera is a diarrheal disease transmitted by contaminated drinking water.
It causes the most severe form of diarrhea of any infectious agent.
Rehydration with repletion of electrolytes is the mainstay of therapy.
Antibiotic therapy is of secondary importance.
Back to Top
Suggested Readings
Holdsworth RJ, Irving AD, Cuschieri A: Postsplenectomy sepsis and its mortality rate: Actual versus perceived
risks. Br J Surg 1991;78:1031-1038.
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 bacterial meningitis. Clin
Infect Dis 2004;39:1267-1284.
Tunkel AR, Scheld WM: Pathogenesis and pathophysiology of bacterial meningitis. Clin Microbiol Rev
1993;6:118-136.
Wong CH, Chang HC, Pasupathy S, et al: Necrotizing fasciitis: Clinical presentation, microbiology, and
determinants of mortality. J Bone Joint Surg Am 2003;85A:1454-1460.
Back to Top
References
1. Schlech WF 3rd, Ward JI, Band JD, et al: Bacterial meningitis in the United States, 1978 through 1981. The
National Bacterial Meningitis Surveillance Study. JAMA 1985;253:1749-1754.
2. Thingpen MC, Whitney CG, Messonnier NE, et al: Bacterial meningitis in the United States in 1998-2007. N Engl J
Med 2011;364:2016-25.
20
3. Stephens DS, Farley MM: Pathogenic events during infection of the human nasopharynx with Neisseria
meningitidis and Haemophilus influenzae. Rev Infect Dis 1991;13:22-33.
4. Tunkel AR, Scheld WM: Pathogenesis and pathophysiology of bacterial meningitis. Clin Microbiol Rev
1993;6:118-136.
5. Hasbun R, Abrahams J, Jekel J, Quagliarello VJ: Computed tomography of the head before lumbar puncture in
adults with suspected meningitis. N Engl J Med 2001;345:1727-1733.
6. van de Beek D, de Gans J, Tunkel AR, Wijdicks EF: Community-acquired bacterial meningitis in adults. N Engl J
Med 2006;354:44-53.
7. de Gans J, van de Beek D: Dexamethasone in adults with bacterial meningitis. N Engl J Med 2002;347:1549-1556.
8. Tunkel AR, Hartman BJ, Kaplan SL, et al: Practice guidelines for the management of bacterial meningitis. Clin
Infect Dis 2004;39:1267-1284.
9. Mylonakis E, Hohmann EL, Calderwood SB: Central nervous system infection with Listeria monocytogenes. 33
years experience at a general hospital and review of 776 episodes from the literature. Medicine (Baltimore)
1998;77:313-336.
10. Harrison LH, Jolley KA, Shutt KA, et al: Antigenic shift and increased incidence of meningococcal disease. J Infect
Dis 2006;193:1266-1274.
11. Edwards EA, Devine LF, Sengbusch GH, Ward HW: Immunological investigations of meningococcal disease. III.
Brevity of group C acquisition prior to disease occurrence. Scand J Infect Dis 1977;9:105-110.
12. Figueroa JE, Densen P: Infectious diseases associated with complement deficiencies. Clin Microbiol Rev
1991;4:359-395.
13. Hibberd ML, Sumiya M, Summerfield JA, et al: Association of variants of the gene for mannose-binding lectin
with susceptibility to meningococcal disease. Meningococcal Research Group. Lancet 1999;353:1049-1053.
14. Salzman MB, Rubin LG: Meningococcemia. Infect Dis Clin North Am 1996;10:709-725.
15. Bohr V, Rasmussen N, Hansen B, et al: 875 cases of bacterial meningitis: Diagnostic procedures and the impact
of preadmission antibiotic therapy. Part III of a three-part series. J Infect 1983;7:193-202.
16. Kanegaye JT, Soliemanzadeh P, Bradley JS: Lumbar puncture in pediatric bacterial meningitis: Defining the time
interval for recovery of cerebrospinal fluid pathogens after parenteral antibiotic pretreatment. Pediatrics
2001;108:1169-1174.
17. Levin S, Painter MB: The treatment of acute meningococcal infection in adults. A reappraisal. Ann Intern Med
1966;64:1049-1056.
18. Barquet N, Domingo P, Cayla JA, et al: Prognostic factors in meningococcal disease. Development of a bedside
predictive model and scoring system. Barcelona Meningococcal Disease Surveillance Group. JAMA
1997;278:491-496.
19. Neu HC: Cephalosporins in the treatment of meningitis. Drugs 1987;34(Suppl 2):135-153.
20. McCrumb CF, Hall HE, Merideth AM, et al: Chloramphenicol in the treatment of meningococcal meningitis. Am J
Med 1951;10:696-703.
21. Analysis of endemic meningococcal disease by serogroup and evaluation of chemoprophylaxis. J Infect Dis
1976;134:201-204.
22. Yoshikawa TT, Chow AW, Guze LB: Role of anaerobic bacteria in subdural empyema. Report of four cases and
review of 327 cases from the English literature. Am J Med 1975;58:99-104.
23. 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.
24. Brook I: Aerobic and anaerobic bacteriology of intracranial abscesses. Pediatr Neurol 1992;8:210-214.
25. Dill SR, Cobbs CG, McDonald CK: Subdural empyema: Analysis of 32 cases and review. Clin Infect Dis
1995;20:372-386.
26. Mauser HW, Van Houwelingen HC, Tulleken CA: Factors affecting the outcome in subdural empyema. J Neurol
Neurosurg Psychiatry 1987;50: 1136-1141.
27. Miller LG, Perdreau-Remington F, Rieg G, et al: Necrotizing fasciitis caused by community-associated methicillin-
resistant Staphylococcus aureus in Los Angeles. N Engl J Med 2005;352:1445-1453.
28. Wong CH, Chang HC, Pasupathy S, et al: Necrotizing fasciitis: Clinical presentation, microbiology, and
determinants of mortality. J Bone Joint Surg Am 2003;85A:1454-1460.
21
29. 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.
30. Gaventa S, Reingold AL, Hightower AW, et al: Active surveillance for toxic shock syndrome in the United States,
1986. Rev Infect Dis 1989;11(Suppl 1):S28-S34.
31. Lappin E, Ferguson AJ: Gram-positive toxic shock syndromes. Lancet Infect Dis 2009;9:281-90.
32. Fisher RF, Goodpasture HC, Peterie JD, Voth DW: Toxic shock syndrome in menstruating women. Ann Intern Med
1981;94:156-163.
33. Stevens DL, Tanner MH, Winship J, et al: Severe group A streptococcal infections associated with a toxic shock-
like syndrome and scarlet fever toxin A. N Engl J Med 1989;321:1-7.
34. Reingold AL, Hargrett NT, Shands KN, et al: Toxic shock syndrome surveillance in the United States, 1980 to
1981. Ann Intern Med 1982;96(6 Pt 2):875-880.
35. The Working Group on Severe Streptococcal Infections: Defining the group A streptococcal toxic shock
syndrome. Rationale and consensus definition. JAMA 1993;269:390-391.
36. Stevens DL: The toxic shock syndromes. Infect Dis Clin North Am 1996;10:727-746.
37. Zimbelman J, Palmer A, Todd J: Improved outcome of clindamycin compared with beta-lactam antibiotic
treatment for invasive Streptococcus pyogenes infection. Pediatr Infect Dis J 1999;18:1096-1100.
38. Freifeld AG, Bow EJ, Sepkowitz KA, et al: Clinical practice guideline for the use of antimicrobial agents in
neutropenic patients with cancer: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis
2011;52:e56-e93.
39. Mermel LA, Allon M, Bouza E, et al: Guidelines for the diagnosis and management of intravascular catheter-
related infection: 2009 update by the Infectious Diseases Society of America. Clin Infect Dis 2009;49:1-45.
40. Klastersky J, Paesmans M, Rubenstein EB, et al: The Multinational Association for Supportive Care in Cancer risk
index: A multinational scoring system for identifying low-risk febrile neutropenic cancer patients. J Clin Oncol
2000;18:3038-3051.
41. Chanock SJ, Pizzo PA: Fever in the neutropenic host. Infect Dis Clin North Am 1996;10:777-796.
42. Holdsworth RJ, Irving AD, Cuschieri A: Postsplenectomy sepsis and its mortality rate: Actual versus perceived
risks. Br J Surg 1991;78:1031-1038.
43. Lynch AM, Kapila R: Overwhelming postsplenectomy infection. Infect Dis Clin North Am 1996;10:693-707.
44. Styrt B: Infection associated with asplenia: Risks, mechanisms, and prevention. Am J Med 1990;88:33N-42N.
45. Ochsenbein AF, Fehr T, Lutz C, et al: Control of early viral and bacterial distribution and disease by natural
antibodies. Science 1999;286:2156-2159.
46. Hayakawa K, Hardy RR: Development and function of B-1 cells. Curr Opin Immunol 2000;12:346-353.
47. Casali P, Schettino EW: Structure and function of natural antibodies. Curr Top Microbiol Immunol 1996;210:167-
179.
48. Wardemann H, Boehm T, Dear N, Carsetti R: B-1a B cells that link the innate and adaptive immune responses are
lacking in the absence of the spleen. J Exp Med 2002;195:771-780.
49. Gorenflot A, Moubri K, Precigout E, et al: Human babesiosis. Ann Trop Med Parasitol 1998;92:489-501.
50. Davies JM, Lewis MPN, Wimperis J, et al: Review of guidelines for the prevention and treatment of infection in
patients with an absent or dysfunctional spleen: prepared on behalf of the British committee for standards in
Haematology by a working party of the Haematoo-Oncology task force.. Br J Haematol 2011;155:308-317.
51. Centers for Disease Control and Prevention: Recommended adult immunization scheduleUnited States, 2012:
MMWR Morbid Mortal Wkly Rep 2012;61:1-7.
52. Cibulskis RE, Aregawi M, Williams R, et al. Worldwide incidence of malaria in 2009: estimates, time trends, and a
critique of methods: Plos Med 2011;8:1-12.
53. Murray CJL, Rosenfeld AB, Lim SS, et al: Global malaria mortality between 1980 and 2010: a systematic analysis.
Lancet 2012;379:413-431.
54. Cox-Singh J, Davis TME, Lee K-S, et al: Plasmodium knowlesi malaria in humans is widely distributed and
potentially life threatening. Clin Infect Dis 2008; 46:165-71.
55. Craig A, Scherf A: Molecules on the surface of the Plasmodium falciparum infected erythrocyte and their role in
malaria pathogenesis and immune evasion. Mol Biochem Parasitol 2001;115:129-143.
56. Chen Q, Barragan A, Fernandez V, et al: Identification of Plasmodium falciparum erythrocyte membrane protein
1 (PfEMP1) as the rosetting ligand of the malaria parasite P. falciparum. J Exp Med 1998;187:15-23.
22
57. CDC: Cholera in Haiti: one year later. Available at
http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6117a4.htm. Accessed October 23, 2012
58. Dutta NK, Panse MV, Kulkarni DR: Role of cholera a toxin in experimental cholera. J Bacteriol 1959;78:594-595.
59. Gotuzzo E, Cieza J, Estremadoyro L, Seas C: Cholera. Lessons from the epidemic in Peru. Infect Dis Clin North Am
1994;8:183-205.
60. Avery ME, Snyder JD: Oral therapy for acute diarrhea. The underused simple solution. N Engl J Med
1990;323(13):891-894.
61. World Health Organization: WHO position paper on oral rehydration salts to reduce mortality from cholera.
http://www.who.int/cholera/technical/ORSRecommendationsForUseAtHomeDec2008.pdf. Accessed October
23, 2012.
62. Greenough WB 3rd, Gordon RS Jr, Rosenberg IS, et al: Tetracycline in the treatment of cholera. Lancet
1964;41:355-367.
63. Alam AN, Alam NH, Ahmed T, Sack DA: Randomised double-blind trial of single dose doxycycline for treating
cholera in adults. BMJ 1990; 300:1619-1621.
64. Fayad IM, Hirschhorn N, Abu-Zikry M, Kamel M: Hypernatraemia surveillance during a national diarrhoeal
diseases control project in Egypt. Lancet 1992;339:389-393.
65. Mahalanabis D, Sack RB, Jacobs B, et al: Use of an oral glucose-electrolyte solution in the treatment of paediatric
choleraa controlled study. J Trop Pediatr Environ Child Health 1974;20:82-87.
66. Alam NH, Yunus M, Faruque AS, et al: Symptomatic hyponatremia during treatment of dehydrating diarrheal
disease with reduced osmolarity oral rehydration solution. JAMA 2006;296:567-573.
67. Hahn S, Kim Y, Garner PL: Reduced osmolarity oral rehydration solution for treating dehydration due to
diarrhoea in children: Systematic review. BMJ 2001;323:81-85.