Current Medical Diagnosis and Treatment 2007 – 46th Edition II pdf

Several additional categories of FUO have been added: 1 Nosocomial FUO refers to the hospitalized patient with fever of 38.3 °C or higher on several occasions, due to a process not pres

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Current Medical Dx & Tx > Infectious Diseases: General Problems >

Infectious Diseases: Introduction

Most infections are confined to specific organ systems, and many of the important infectious disease pathogens

are discussed in chapters dealing with the relevant anatomic areas This chapter discusses some important

general problems related to infectious diseases.

Fever of Unknown Origin (FUO)

Essentials of Diagnosis

● Illness of at least 3 weeks duration

● Fever over 38.3 °C on several occasions

● Diagnosis has not been made after three outpatient visits or 3 days of hospitalization.

General Considerations

The intervals specified in the criteria for the diagnosis of FUO are arbitrary ones intended to exclude patients with

protracted but self-limited viral illnesses and to allow time for the usual radiographic, serologic, and cultural studies

to be performed Because of costs of hospitalization and the availability of most screening tests on an outpatient

basis, the original criterion requiring 1 week of hospitalization has been modified to accept patients in whom a

diagnosis has not been made after three outpatient visits or 3 days of hospitalization.

Several additional categories of FUO have been added: (1) Nosocomial FUO refers to the hospitalized patient with

fever of 38.3 °C or higher on several occasions, due to a process not present or incubating at the time of admission,

in whom initial cultures are negative and the diagnosis remains unknown after 3 days of investigation (see

Nosocomial Infections, below) (2) Neutropenic FUO includes patients with fever of 38.3 °C or higher on several

occasions with less than 500 neutrophils per microliter in whom initial cultures are negative and the diagnosis

remains uncertain after 3 days (see Common Symptoms and Infections in the Immunocompromised Patient, below)

(3) HIV-associated FUO pertains to HIV-positive patients with fever of 38.3 °C or higher who have been febrile for 4

weeks or more as an outpatient or 3 days as an inpatient, in whom the diagnosis remains uncertain after 3 days of

investigation with at least 2 days for cultures to incubate (see Infectious Diseases: HIV) Although not usually

considered separately, FUO in solid organ transplant recipients is a common scenario with a unique differential

diagnosis and is discussed below.

For a general discussion of fever, see the section on fever and hyperthermia in Common Symptoms.

Common Causes

Most cases represent unusual manifestations of common diseases and not rare or exotic diseases—eg, tuberculosis,

endocarditis, gallbladder disease, and HIV (primary infection or opportunistic infection) are more common causes of

FUO than Whipple's disease or familial Mediterranean fever.

Age of Patient

In adults, infections (25–40% of cases) and cancer (25–40% of cases) account for the majority of FUOs In children,

infections are the most common cause of FUO (30–50% of cases) and cancer a rare cause (5–10% of cases)

Autoimmune disorders occur with equal frequency in adults and children (10–20% of cases), but the diseases differ Juvenile rheumatoid arthritis is particularly common in children, whereas systemic lupus erythematosus, Wegener's granulomatosis, and polyarteritis nodosa are more common in adults Adult Still's disease, giant cell arteritis, and polymyalgia rheumatica occur exclusively in adults In the elderly (over 65 years of age), multisystem immune- mediated diseases such as temporal arteritis, polymyalgia rheumatica, sarcoidosis, rheumatoid arthritis, and

Wegener's granulomatosis account for 25–30% of all FUOs.

Duration of Fever

The cause of FUO changes dramatically in patients who have been febrile for 6 months or longer Infection, cancer, and autoimmune disorders combined account for only 20% of FUOs in these patients Instead, other entities such as granulomatous diseases (granulomatous hepatitis, Crohn's disease, ulcerative colitis) and factitious fever become important causes One-fourth of patients who say they have been febrile for 6 months or longer actually have no true fever or underlying disease Instead, the usual normal circadian variation in temperature (temperature 0.5–1 °C higher in the afternoon than in the morning) is interpreted as abnormal Patients with episodic or recurrent fever (ie, those who meet the criteria for FUO but have fever-free periods of 2 weeks or longer) are similar to those with prolonged fever Infection, malignancy, and autoimmune disorders account for only 20–25% of such fevers, whereas various miscellaneous diseases (Crohn's disease, familial Mediterranean fever, allergic alveolitis) account for another 25% Approximately 50% remain undiagnosed but have a benign course with eventual resolution of symptoms.

Immunologic Status

In the neutropenic patient, fungal infections and occult bacterial infection are important causes of FUO In the patient taking immunosuppressive medications (particularly organ transplant patients), cytomegalovirus (CMV)

infections are a frequent cause of fever, as are fungal infections, nocardiosis, Pneumocystis jiroveci (formerly

Pneumocystis carinii) pneumonia, and mycobacterial infections.

Classification of Causes of FUO

Most patients with FUO will fit into one of five categories.

Infection

Both systemic and localized infections can cause FUO Tuberculosis and endocarditis are the most common systemic infections, but mycoses, viral diseases (particularly infection with Epstein-Barr virus and CMV), toxoplasmosis, brucellosis, Q fever, cat-scratch disease, salmonellosis, malaria, and many other less common infections have been implicated Primary infection with HIV or opportunistic infections associated with the AIDS—particularly

mycobacterial infections—can also present as FUO The most common form of localized infection causing FUO is an occult abscess Liver, spleen, kidney, brain, and bone are organs in which abscess may be difficult to find A

collection of pus may form in the peritoneal cavity or in the subdiaphragmatic, subhepatic, paracolic, or other areas Cholangitis, osteomyelitis, urinary tract infection, dental abscess, or paranasal sinusitis may cause prolonged fever.

Neoplasms

Many cancers can present as FUO The most common are lymphoma (both Hodgkin's and non-Hodgkin's) and

leukemia Other diseases of lymph nodes, such as angioimmunoblastic lymphoma and Castleman's disease, can also cause FUO Primary and metastatic tumors of the liver are frequently associated with fever, as are renal cell

carcinomas Atrial myxoma is an often forgotten neoplasm that can result in fever Chronic lymphocytic leukemia and multiple myeloma are rarely associated with fever, and the presence of fever in patients with these diseases should prompt a search for infection.

Autoimmune disorders

Still's disease, systemic lupus erythematosus, cryoglobulinemia, and polyarteritis nodosa are the most common

autoimmune causes of FUO Giant cell arteritis and polymyalgia rheumatica are seen almost exclusively in patients over 50 years of age and are nearly always associated with an elevated erythrocyte sedimentation rate (> 40 mm/h).

Miscellaneous causes

Many other conditions have been associated with FUO but less commonly than the foregoing types of illness

Examples include thyroiditis, sarcoidosis, Whipple's disease, familial Mediterranean fever, recurrent pulmonary emboli, alcoholic hepatitis, drug fever, and factitious fever.

is not factitious (self-induced) Associated findings that accompany fever include tachycardia, chills, and piloerection

A thorough history—including family, occupational, social (sexual practices, use of injection drugs), dietary

(unpasteurized products, raw meat), exposures (animals, chemicals), and travel—may give clues to the diagnosis Repeated physical examination may reveal subtle, evanescent clinical findings essential to diagnosis.

Laboratory Tests

In addition to routine laboratory studies, blood cultures should always be obtained, preferably when the patient has not taken antibiotics for several days, and should be held by the laboratory for 2 weeks to detect slow-growing

organisms Cultures on special media are requested if Legionella, Bartonella, or nutritionally deficient streptococci

are considered possible pathogens "Screening tests" with immunologic or microbiologic serologies ("febrile

agglutinins") are of low yield and should not be done Specific serologic tests are helpful if the history or physical examination suggests a specific diagnosis A single elevated titer rarely allows one to make a diagnosis of infection; instead, one must demonstrate a fourfold rise or fall in titer to confirm a specific infectious cause Because infection

is the most common cause of FUO, other body fluids are usually cultured, ie, urine, sputum, stool, cerebrospinal fluid, and morning gastric aspirates (if one suspects tuberculosis) Direct examination of blood smears may establish

a diagnosis of malaria or relapsing fever (Borrelia).

or atrial myxoma Transesophageal echocardiography is more sensitive than surface echocardiography for detecting valvular lesions, but even a negative transesophageal study does not exclude endocarditis (10% false-negative rate) The usefulness of radionuclide studies in diagnosing FUO is variable Theoretically, a gallium or positron- emission (PET) scan would be more helpful than an indium-labeled white blood cell scan, because gallium and

fluorodeoxy-glucose may be useful for detecting infection, inflammation, and neoplasm whereas the indium scan is useful only for detecting infection Indium-labeled immunoglobulin may prove to be useful in detecting infection and neoplasm and can be used in the neutropenic patient It is not sensitive for lesions of the liver, kidney, and heart because of high background activity In general, radionuclide scans are plagued by high rates of false-positive and false-negative results that are not useful when used as screening tests and, if done at all, are limited to those patients whose history or examination suggests local inflammation or infection.

Biopsy

Invasive procedures are often required for diagnosis Any abnormal finding should be aggressively evaluated:

Headache calls for lumbar puncture (see Figure: illustration) to rule out meningitis; skin from a rash should be biopsied to look for cutaneous manifestations of collagen vascular disease or infection; and enlarged lymph nodes should be aspirated or biopsied and examined for cytologic features to rule out neoplasm and sent for culture Bone marrow aspiration with biopsy is a relatively low-yield procedure (except in HIV-positive patients, in whom

mycobacterial infection is a common cause of FUO), but the risk is low and the procedure should be done if other less invasive tests have not yielded a diagnosis Liver biopsy will yield a specific diagnosis in 10–15% of patients with FUO and should be considered in any patient with abnormal liver function tests even if the liver is normal in size The role of exploratory laparotomy is debatable since the advent of CT scanning and MRI Laparotomy or laparoscopy should be considered when the patient continues to deteriorate and the diagnosis is elusive despite extensive evaluation.

Prepackaged disposable sterile tray for lumbar puncture (Reproduced, with permission, from Chesnutt MS et

al: Office & Bedside Procedures Originally published by Appleton & Lange Copyright © 1992 by The

McGraw-Hill Companies, Inc.)

Treatment

Therapeutic trials are indicated if a diagnosis is strongly suspected—eg, it is reasonable to give antituberculous drugs

if tuberculosis is suspected, or tetracycline if brucellosis is suspected However, if there is no clinical response in several weeks, it is imperative to stop therapy and reevaluate the patient In the seriously ill or rapidly deteriorating

patient, empiric therapy is often given Antituberculosis medications (particularly in the elderly or foreign-born) and broad-spectrum antibiotics are reasonable in this setting.

Empiric administration of corticosteroids should be discouraged; they can suppress fever if given in high enough

doses, but they can also exacerbate many infections, and infection remains a leading cause of FUO

Crispin JC et al: Adult-onset Still disease as the cause of fever of unknown origin Medicine (Baltimore) 2005;84:331 [PMID: 16267408]

Knockaert DC et al: Fever of unknown origin in adults: 40 years on J Intern Med 2003;253:263 [PMID: 12603493] Mourad O et al: A comprehensive evidence-based approach to fever of unknown origin Arch Intern Med

2003;163:545 [PMID: 12622601]

Ozaras R et al: Is laparotomy necessary in the diagnosis of fever of unknown origin? Acta Chir Belg 2005;105:89

[PMID: 15790210]

Tal S et al: Fever of unknown origin in the elderly J Intern Med 2002;242:295 [PMID: 12366602]

Vanderschueren S et al: From prolonged febrile illness to fever of unknown origin Arch Intern Med 2003;163:1033 [PMID: 12742800]

Woolery WA et al: Fever of unknown origin: keys to determining the etiology in older patients Geriatrics

2004;59:41 [PMID: 15508555]

Infections in the Immunocompromised Patient

Essentials of Diagnosis

● Fever and other symptoms may be blunted because of immunosuppression; early diagnosis may be difficult

● A contaminating organism in an immunocompetent individual may be a pathogen in an immunocompromised one

● The interval since transplantation and the degree of immunosuppression can narrow the differential diagnosis

● Empiric broad-spectrum antibiotics may be appropriate in high-risk patients whether or not symptoms are localized because of high infection-related morbidity and mortality.

General Considerations

Immunocompromised patients have one or more defects in their natural defense mechanisms that put them at

an increased risk for infections Not only is the risk of infection greater in these individuals, but once established it

is often severe, rapidly progressive, and life-threatening Organisms that are not usually pathogens in

the immunocompetent person may cause life-threatening infection in the compromised patient (eg,

Staphylococcus epidermidis, Corynebacterium jeikeium, Propionibacterium acnes, Bacillus species) Therefore,

culture results must be interpreted with caution, and isolates should not be disregarded as merely

contaminants Although the type of immunodeficiency is associated with specific infectious disease syndromes,

any pathogen can cause infection in any immunosuppressed patient at any time Thus, a systematic evaluation

is required to identify a specific organism.

Impaired Humoral Immunity

Defects in humoral immunity are often congenital, although hypogammaglobulinemia can occur in multiple

myeloma, chronic lymphocytic leukemia, and in patients who have undergone splenectomy Patients with

ineffective humoral immunity lack opsonizing antibodies and are at particular risk for infection with

encapsulated organisms, such as Haemophilus influenzae, Neisseria meningitidis and Streptococcus pneumoniae.

Granulocytopenia (Neutropenia)

Granulocytopenia is common following hematopoietic cell transplantation ("bone marrow transplantation") and among patients with solid tumors—as a result of myelosuppressive chemotherapy—and in acute leukemias The risk of infection begins to increase when the absolute granulocyte count falls below 1000/mcL, with a

dramatic increase in frequency and severity when the granulocyte count falls below 100/mcL The infection risk

is also increased when there is a rapid rate of decline of neutrophils and in those with a prolonged period

of neutropenia The granulocytopenic patient is particularly susceptible to infections with gram-negative

enteric organisms, Pseudomonas, gram-positive cocci (particularly Staphylococcus aureus, S epidermidis,

and viridans streptococci), Candida, Aspergillus, and other fungi that have recently emerged as pathogens such

as Trichosporon, Scedosporium, Fusarium, and Pseudallescheria The methods used for detection of deficiencies

in the immune system can be found in Allergy & Immunology.

Impaired Cellular Immunity

Patients with cellular immune deficiency encompass a large and heterogeneous group, including patients with HIV infection (see Infectious Diseases: HIV); patients with lymphoreticular malignancies, such as Hodgkin's

disease; and patients receiving immunosuppressive medications, such as corticosteroids, cyclosporine,

tacrolimus, and other cytotoxic drugs This latter group—those who are immunosuppressed as a result of

medications—includes patients who have undergone transplantation, many patients receiving therapy for

solid tumors, and patients receiving prolonged high-dose corticosteroid treatment (eg, for asthma, temporal arteritis, systemic lupus) Patients with cellular immune dysfunction are susceptible to infections by a large number

of organisms, particularly ones that replicate intracellularly Examples include bacteria, such as Listeria,

Legionella, Salmonella, and Mycobacterium; viruses, such as herpes simplex, varicella, and CMV; fungi, such

as Cryptococcus, Coccidioides, Histoplasma, and Pneumocystis; and protozoa, such as Toxoplasma.

Hematopoietic Cell Transplant Recipients

The length of time it takes for complications to occur in hematopoietic cell transplant recipients can be helpful

in determining the etiologic agent In the early (preengraftment) posttransplant period (day 1–21), almost

all patients will become severely neutropenic for 7–21 days depending on whether growth factors are used and the source of stem cells Patients are at risk for gram-positive (particularly catheter-related) and gram-

negative bacterial infections as well as herpes simplex virus, respiratory syncytial virus, and candidal

infections; mucositis is also a risk factor In contrast to solid organ transplant recipients, the source of fever during this period cannot be found in 60–70% of hematopoietic cell transplant patients Between 3 weeks and

3 months posttransplant, infections with CMV, adenovirus, Aspergillus, and Candida are most common P

jiroveci pneumonia can also be seen during this period, particularly in patients in whom graft-versus-host

disease (GVHD) has developed and require immunosuppression Patients continue to be at risk for

infectious complications beyond 3 months following transplantation, particularly those who have received

allogeneic transplantation and those who are taking immunosuppressive therapy for chronic GVHD Varicella-zoster

is common, and Aspergillus and CMV infections are increasingly seen in this period as well.

Solid Organ Transplant Recipients

The length of time it takes for infection to occur following solid organ transplantation can also be helpful

in determining the infectious origin Immediate postoperative infections often involve the transplanted

organ Following lung transplantation, pneumonia and mediastinitis are particularly common; following

liver transplantation, intra-abdominal abscess, cholangitis, and peritonitis may be seen; after renal

transplantation, urinary tract infections, perinephric abscesses, and infected lymphoceles can occur.

Most infections that occur in the first 2–4 weeks posttransplant are related to the operative procedure and

to hospitalization itself (wound infection, intravenous catheter infection, urinary tract infection from a Foley

catheter) or are related to the transplanted organ Infections that occur between the first and sixth months are often related to immunosuppression During this period, reactivation of viruses occurs, and herpes simplex,

varicella-zoster, and CMV infections are quite common Opportunistic infections with fungi (eg, Candida,

Aspergillus, Cryptococcus, Pneumocystis), Listeria monocytogenes, Nocardia, and Toxoplasma are also

common After 6 months, if immunosuppression has been reduced to maintenance levels, infections that are found

in any population occur Patients with poorly functioning allografts who receive long-term

immunosuppression therapy continue to be at risk for opportunistic infections.

Other Immunocompromised States

A large group of patients who are not specifically immunodeficient are at increased risk for infection because

of debilitating injury (eg, burns or severe trauma), invasive procedures (eg, hyperalimentation lines, Foley

catheters, dialysis catheters), central nervous system dysfunction (which predisposes patients to

aspiration pneumonia and decubitus ulcers), obstructing lesions (eg, pneumonia due to an obstructed

bronchus, pyelonephritis due to nephrolithiasis, cholangitis secondary to cholelithiasis), and use of

broad-spectrum antibiotics Patients with diabetes mellitus have alterations in cellular immunity that make

them disproportionately susceptible to some diseases (eg, mucormycosis, emphysematous pyelonephritis, and foot infections).

Clinical Findings

Laboratory Findings

Routine evaluation includes complete blood count with differential, chest radiograph, and blood cultures; urine and sputum cultures should be obtained if indicated clinically or radiographically Any focal complaints (localized pain, headache, rash) should prompt imaging and cultures appropriate to the site

Patients who remain febrile without an obvious source should be evaluated for viral infection (CMV blood cultures

or antigen test), abscesses (which usually occur near previous operative sites), candidiasis involving the liver

or spleen, or aspergillosis Serologic evaluation may be helpful if toxoplasmosis, aspergillosis (detected

by galactomannan level in serum), or an endemic fungal infection (coccidioidomycosis, histoplasmosis) is a

possible cause

Special Diagnostic Procedures

Special diagnostic procedures should also be considered The cause of pulmonary infiltrates can be easily

determined with simple techniques in some situations—eg, induced sputum yields a diagnosis of

Pneumocystis pneumonia in 50–80% of AIDS patients with this infection In other situations, more

invasive procedures may be required (bronchoalveolar lavage, transbronchial biopsy, or even open lung

biopsy) Other investigations such as skin, liver, or bone marrow biopsy may be helpful in establishing a diagnosis

Differential Diagnosis

Transplant rejection, organ ischemia and necrosis, thrombophlebitis, and lymphoma

(posttransplant lymphoproliferative disease) may all present as fever and must be considered in the

differential diagnosis

Prevention

There is great interest in preventing infection with prophylactic antimicrobial regimens but no uniformity of

opinion about optimal drugs or dosage regimens Hand washing is the simplest and most effective means

of decreasing nosocomial infections in all patients, especially the compromised patient Invasive devices such

as central and peripheral lines and Foley catheters are a potential source of infection Some centers use

laminar airflow isolation or high-efficiency particulate air (HEPA) filtering in hematopoietic cell transplant

patients during the neutropenic phase.

Pneumocystis & Herpes Simplex Infections

Trimethoprim-sulfamethoxazole (TMP-SMZ), one double-strength tablet orally three times a week, one

double-strength tablet twice daily on weekends, or one single-strength tablet daily for 3–6 months, is frequently

used to prevent Pneumocystis infections in transplant patients It may also decrease the incidence of

bacterial pneumonia, urinary tract infections, Nocardia infections, and toxoplasmosis In patients allergic to

TMP-SMZ, aerosolized pentamidine is used in a dosage of 300 mg once a month, as is dapsone, 50 mg orally daily or

100 mg three times weekly (Glucose-6-phosphate dehydrogenase (G6PD) levels should be determined

before therapy when the latter is instituted.) Acyclovir prevents herpes simplex infections in bone marrow and solid organ transplant recipients and is given to seropositive patients who are not receiving acyclovir or ganciclovir for CMV prophylaxis The usual dose is 200 mg orally three times daily for 4 weeks (hematopoietic cell transplants)

to 12 weeks (other solid organ transplants).

CMV

Prevention of CMV is more difficult, and no uniformly accepted approach has been adopted Prevention

strategies often depend on the serologic status of the donor and recipient and the organ transplanted,

which determines the level of immunosuppression after transplant In solid organ transplants (liver, kidney,

heart, lung), the greatest risk of developing CMV disease is in seronegative patients who receive organs

from seropositive donors These high-risk patients usually receive ganciclovir, 2.5–5 mg/kg intravenously twice daily, during hospitalization (usually about 10 days) and then are given oral valganciclovir, 900 mg twice daily,

or oral ganciclovir, 1 g three times daily, for 3 months; of note, oral ganciclovir is not absorbed as well as

oral valganciclovir Other solid organ transplant recipients (seropositive recipients) are at lower risk for

developing CMV disease and usually receive intravenous ganciclovir while in the hospital followed by either dose oral acyclovir at a dosage of 800 mg four times daily or oral ganciclovir for 3 months Ganciclovir,

high-valganciclovir, and acyclovir prevent herpes virus reactivation Because immunosuppression is increased

during periods of rejection, patients treated for rejection usually receive intravenous ganciclovir during

rejection therapy.

Recipients of hematopoietic cell transplants are more severely immunosuppressed than recipients of solid

organ transplants, are at greater risk for developing serious CMV infection, and thus usually receive more

aggressive prophylaxis Two approaches have been used: universal prophylaxis or preemptive therapy In the former, all high-risk patients (seropositive patients who receive allogeneic transplants) receive 5 mg/kg

of intravenous ganciclovir every 12 hours for a week, followed by oral valganciclovir, 900 mg twice daily, or

oral ganciclovir (which is not absorbed as well as valganciclovir), 1 g three times daily to day 100 This method

is costly and associated with significant toxicity and is therefore being used less frequently Alternatively, patients can be monitored without specific therapy and have blood sampled weekly for the presence of CMV If CMV

is detected by an antigenemia assay, preemptive therapy with ganciclovir is given (5 mg/kg intravenously twice daily for 7–14 days, followed by oral valganciclovir, 900 mg twice daily for a minimum of 3 weeks or until day

100, whichever is longer) This approach is effective but does miss a small number of patients in whom CMV disease subsequently develops Other preventive strategies include use of CMV-negative or leukocyte-depleted blood products for CMV-seronegative recipients.

Other Organisms

not recommended Prophylactic administration of antibiotics in the afebrile, asymptomatic neutropenic patient

is controversial, although many centers have adopted this strategy Rates of bacteremia are decreased, but overall mortality is not affected and emergence of resistant organisms is a common problem Use of

intravenous immunoglobulin is reserved for the small number of patients with severe

hypogammaglobulinemia following bone marrow transplantation and should not be routinely administered to all transplant patients.

Prophylaxis with antifungal agents to prevent invasive mold (primarily Aspergillus) and yeast (primarily

Candida) infections is routinely used, but the optimal agent, dose, and duration have not been

standardized Moderate-dose (0.5 mg/kg/d) and low-dose (0.1–0.25 mg/kg/d) amphotericin B,

lipid-based preparations of amphotericin B, aerosolized amphotericin B, and itraconazole (capsules and solution) have all been used with varying success in the neutropenic patient Because voriconazole appears to be more

effective than amphotericin for documented Aspergillus infections, one approach to prophylaxis is to use

oral fluconazole (400 mg/d) for patients at low risk for developing fungal infections (those who receive

autologous bone marrow transplants) and oral voriconazole (200 mg twice daily) for those at high risk

(allogeneic transplants) at least until engraftment (usually 30 days) In solid organ transplant recipients, the risk

of invasive fungal infection varies considerably (1–2% in liver, pancreas, and kidney transplants and 6–8% in heart and lung transplants) Whether universal prophylaxis or observation with preemptive therapy is the

best approach has not been determined Although fluconazole is effective in preventing yeast infections,

emergence of resistant strains of Candida krusei, other Candida species, and molds (Fusarium, Aspergillus,

Mucor) has raised concerns about its routine use as a prophylactic agent.

Treatment

General Measures

Because infections in the immunocompromised patient can be rapidly progressive and life-threatening,

diagnostic procedures must be done promptly, and empiric therapy is usually instituted before a specific

pathogenic organism has been isolated.

Reduction or discontinuation of immunosuppressive medication may jeopardize the viability of the

transplanted organ, but in life-threatening infections, it is necessary as an adjunct to effective antimicrobial therapy Hematopoietic growth factors (granulocyte and granulocyte-macrophage colony-stimulating

factors) stimulate proliferation of bone marrow stem cells, resulting in an increase in peripheral leukocytes

These agents shorten the period of neutropenia and have been associated with fewer infections Use of

growth factors in patients with prolonged neutropenia (> 7 days) is an effective means of

reversing immunosuppression.

Specific Measures

Antimicrobial drug therapy is rationally based on culture results (see Infectious Disease: Antimicrobial

Therapy) Therapy should be specific for isolated pathogens, and bactericidal agents should be used Combinations

of antimicrobials are often required to provide synergy, to prevent resistance, or to serve as

broad-spectrum coverage of multiple pathogens (since infections in these patients are often polymicrobial).

Empiric therapy is often instituted at the earliest sign of infection in the immunosuppressed patient because prompt therapy favorably affects outcome The antibiotic or combination of antibiotics used depends on the type

of immunocompromise and the site of infection For example, in the febrile neutropenic patient, the primary concern is bacterial and fungal infections In this patient population, an algorithmic approach to therapy is often used, with initial treatment directed at gram-positive and gram-negative organisms If the patient does not

respond, broader-spectrum antibiotics and antifungal drugs are added Although a number of different agents can

be used, choices should be based on local microbiologic trends One example would be to initiate therapy with

a fluoroquinolone active against gram-positive organisms (such as levofloxacin, gatifloxacin, or moxifloxacin)

when the absolute neutrophil count falls below 500/mcL If fever develops, cultures are obtained, and

vancomycin, 10–15 mg/kg intravenously every 12 hours, is given to cover methicillin-resistant S aureus,

S epidermidis, and enterococcus If fever continues after 48–72 hours, antifungal coverage can be increased

by changing to either caspofungin, 50 mg daily intravenously, or voriconazole, 200 mg intravenously or orally twice daily (if the patient was receiving fluconazole prophylaxis); broader-spectrum antibiotics can be

added sequentially For example, to better cover Acinetobacter, Citrobacter, and Pseudomonas, the

fluoroquinolone may be switched to cefepime, 2 g every 8 hours intravenously; with continued fever, imipenem,

500 mg intravenously every 6 hours (or meropenem, 1 g intravenously every 8 hours), with or without

tobramycin, 1.8 mg/kg intravenously every 8 hours, may be used in place of cefepime If fevers persist, TMP-SMZ

at 10 mg/kg/d (of trimethoprim) intravenously in three divided doses can be added to cover

Stenotrophomonas Regardless of whether the patient becomes afebrile, therapy is continued until resolution

of neutropenia Failure to continue antibiotics through the period of neutropenia is associated with a high incidence

of relapse that can be associated with septic shock.

Patients with fever and neutropenia who are at low risk for developing complications (neutropenia expected to persist for less than 10 days, no comorbid complications requiring hospitalization, and cancer adequately treated) can be treated with oral antibiotic regimens, such as ciprofloxacin, 750 mg every 12 hours, plus amoxicillin-

clavulanic acid, 500 mg every 8 hours In the organ transplant patient with interstitial infiltrates, the main concern

is infection with Pneumocystis or Legionella species, so that empiric treatment with a macrolide and TMP-SMZ

would be reasonable If the patient does not respond to empiric treatment, a decision must be made to add

more antimicrobial agents or perform invasive procedures (see above) to make a specific diagnosis By making

a specific diagnosis, therapy can be specific and polypharmacy with multiple potentially toxic agents can be avoided Bucaneve G et al: Levofloxacin to prevent bacterial infection in patients with cancer and neutropenia N Engl J Med 2005;353:977 [PMID: 16148283]

Kalil AC et al: Meta-analysis: the efficacy of strategies to prevent organ disease by cytomegalovirus in solid

organ transplant recipients Ann Intern Med 2005;143:870 [PMID: 16365468]

Rubin RH: The direct and indirect effects of infection in liver transplantation: pathogenesis, impact, and

clinical management Curr Clin Top Infect Dis 2002;22:125 [PMID: 12520651]

Viscoli C et al: Treatment of febrile neutropenia: what is new? Curr Opin Infect Dis 2002;15:377 [PMID: 12130933] Walsh TJ et al: Caspofungin versus liposomal amphotericin B for empirical antifungal therapy in patients

with persistent fever and neutropenia N Engl J Med 2004;351:1391 [PMID: 15459300]

pneumonia in intubated patients or those with altered levels of consciousness; surgical wound infections; and

Clostridium difficile colitis.

Some general principles are helpful in preventing, diagnosing, and treating nosocomial infections:

1 Many infections are a direct result of the use of invasive devices for monitoring or therapy such as intravenous catheters, Foley catheters, shunts, surgical drains, catheters placed by interventional radiology for drainage,

nasogastric tubes and orotracheal or nasotracheal tubes for ventilatory support Early removal of such devices reduces the possibility of infection

2 Patients in whom nosocomial infections develop are often critically ill, have been hospitalized for extended periods, and have received several courses of broad-spectrum antibiotic therapy As a result, nosocomial infections are often caused by organisms that are multidrug resistant and are different from those encountered in community-acquired

infections Examples are S aureus and S epidermidis (a frequent cause of prosthetic device infection) that may be resistant to nafcillin and cephalosporins and require vancomycin for therapy; Enterococcus faecium resistant to ampicillin and vancomycin; gram-negative infections caused by Pseudomonas, Citrobacter, Enterobacter,

Acinetobacter, and Stenotrophomonas, which may be sensitive only to fluoroquinolones, carbapenems,

aminoglycosides, or TMP-SMZ When choosing antibiotics to treat the seriously ill patient with a nosocomial infection, the previous antimicrobial the patient has received as well as the "local ecology" must be considered It is often necessary to institute therapy with vancomycin and a carbapenem or aminoglycoside until a specific agent is isolated and sensitivities are known, at which time the least toxic and most cost-effective drug can be used.

One promising approach to preventing the development of multidrug-resistant organisms is antibiotic cycling By changing the class of antibiotic primarily used every 6–12 months (eg, a cephalosporin, then fluoroquinolones, then carbapenems), selection pressure is decreased and less resistance emerges

Because widespread use of antimicrobial drugs contributes to the selection of drug-resistant organisms that cause nosocomial infections, every effort should be made to limit the use of antibiotics to treat documented infections All too often, unreliable or uninterpretable specimens are obtained for culture that result in unnecessary use of

antibiotics The best example of this principle is the diagnosis of line-related or bloodstream infection in the febrile patient (see below) To avoid unnecessary use of antibiotics, thoughtful consideration of culture results is mandatory

A positive wound culture without signs of inflammation or infection, a positive sputum culture without pulmonary infiltrates on chest x-ray, or a positive urine culture in a catheterized patient without symptoms or signs of

pyelonephritis are all likely to represent colonization, not infection.

Clinical Findings

Symptoms and Signs

Catheter-associated infections have a variable presentation, depending on the type of catheter used (peripheral or central venous catheters, nontunneled or tunneled) Local signs of infection may be present at the insertion site, with pain, erythema, and purulence Fever is often absent in uncomplicated infections and if present, may indicate more disseminated disease such as bacteremia, cellulitis and septic thrombophlebitis Often signs of infection at the

insertion site are absent.

Fever in an intensive care unit patient

Fever complicates up to 70% of patients in intensive care units, and the etiology of the fever may be infectious or noninfectious Common infectious causes include catheter-associated infections, hospital-acquired and ventilator- associated pneumonia (see Pulmonology), surgical site infections, urinary tract infections, and sepsis Clinically relevant sinusitis is relatively uncommon in the patient in the intensive care unit.

An important noninfectious cause is thromboembolic disease Fever in conjunction with refractory hypotension and shock may suggest sepsis; however, adrenal insufficiency, thyroid storm, and transfusion reaction may have a similar clinical presentation Drug fever is difficult to diagnose and is usually a diagnosis of exclusion unless there are other signs of hypersensitivity, such as a typical maculopapular rash.

Fever in the postoperative patient

Postoperative fever is very common and in many cases resolves spontaneously Etiologies are both infectious and noninfectious Timing of the fever in relation to the surgery and the nature of the surgical procedure may help diagnostically.

Immediate fever (in the first few hours after surgery)

Immediate fever can be due to medications that were given perioperatively, to the trauma of surgery itself, or to infections that were present before surgery Necrotizing fasciitis due to group A streptococci or mixed organisms may present in this period Malignant hyperthermia is rare and presents 30 minutes to several hours following inhalational anesthesia (succinylcholine or halothane commonly) and is characterized by extreme hyperthermia, muscle rigidity, rhabdomyolysis, electrolyte abnormalities, and hypotension Aggressive cooling and dantrolene are the mainstays of therapy Fever due to the trauma of surgery itself usually resolves in 2–3 days, longer in more complicated operative cases and in patients with head trauma.

Acute fever (within 1 week of surgery)

Acute fever is usually due to common causes of nosocomial infections, such as ventilator-associated pneumonia (including aspiration pneumonia in patients with decreased gag reflex) and line infections Noninfectious causes include alcohol withdrawal, gout, pulmonary embolism, and pancreatitis.

Subacute fever (at least 1 week after surgery)

Surgical site infections commonly present at least 1 week after surgery The type of surgery that was performed may

be related to specific infectious etiologies Patients undergoing cardiothoracic surgery may be at higher risk for pneumonia and deep and superficial sternal wound infections Meningitis without typical signs of meningismus may complicate neurosurgical procedures Abdominal surgery may result in deep abdominal abscesses that require drainage

in a patient with S aureus bacteremia).

Any fever in a patient with a central venous catheter should prompt the collection of blood The best method to evaluate bacteremia is to gather at least two peripherally obtained blood cultures Blood cultures from unidentified

sites, a single blood culture from any site, or a blood culture through an existing line will often be positive for S

epidermidis and may lead to therapy with vancomycin Yet, the likelihood that such a culture represents a true

bacteremia is 10–20% Unless two separate venipuncture cultures are obtained—not through catheters—

interpretation of results is impossible and unnecessary therapy is given Every such "pseudobacteremia" increases laboratory costs, antibiotic use, and length of stay, increasing costs of hospitalization by about $4500 Microbiologic evaluation of the removed catheter can sometimes be helpful, but only in addition to (not instead of) blood cultures drawn from peripheral sites Semiquantitative cultures of the catheter is performed by rolling the distal 2 cm tip of the catheter on an agar plate The presence of > 15 colony-forming units (CFU) of organisms on the catheter tip together with identical organisms on peripherally drawn blood cultures establishes the diagnosis of a catheter-

associated bloodstream infection Other methods may permit catheters to remain in place while infection is being ruled out The differential time to positivity measures the difference in time that cultures simultaneously drawn through a catheter and a peripheral site become positive A positive test (about 120 minutes difference in time) supports a catheter-related bloodstream infection, and a negative test may permit catheters to be retained

Complications

Patients who have persistent bacteremia and continue to be febrile despite removal of the infected catheter may

have complications such as septic thrombophlebitis, endocarditis, or metastatic foci of infection (particularly with S

aureus) Additional studies such as venous Doppler studies, transesophageal echocardiogram, and chest radiographs

may be indicated Duration of therapy is longer, usually 4–6 weeks In the case of septic thrombophlebitis,

anticoagulation with heparin is also recommended if there are no contraindications.

Peripheral intravenous lines should be replaced every 3 days, and arterial lines should be replaced every 4 days Lines in the central venous circulation (including those placed peripherally) can be left in place indefinitely and are changed or removed when they are clinically suspected of being infected, when they are nonfunctional, or when they are no longer needed Silver alloy–impregnated Foley catheters reduce the incidence of catheter-associated

bacteriuria, and antibiotic-impregnated (minocycline plus rifampin or chlorhexidine plus silver sulfadiazine) venous catheters reduce line infections and bacteremia Whether the increased cost of these devices justifies their routine use should be determined by individual institutions based on local infection rates Selective decontamination of the digestive tract with nonabsorbable antibiotics to prevent nosocomial pneumonia is widely used in Europe, but the therapeutic efficacy of this expensive intervention is controversial

Attentive nursing care (positioning to prevent decubitus ulcers, wound care, elevating the head during tube feedings

to prevent aspiration) is critical in preventing nosocomial infections In addition, monitoring of high-risk areas by hospital epidemiologists detects increases in infection rates early and is a key factor in prevention of these types of infections

Several highly effective vaccines have been approved by the US Food and Drug Administration (FDA) that add to the armamentarium for preventing certain nosocomial infections Hepatitis A, hepatitis B, and the varicella vaccine should be considered in the appropriate setting (See section below on Immunization Against Infectious Diseases.)

Treatment

Fever in an Intensive Care Unit patient

Unless the patient has a central neurologic injury with elevated intracranial pressure or has a temperature > 41 °C, there is less physiologic need to maintain euthermia Empiric broad-spectrum antibiotics (as noted above) are recommended for neutropenic and other immunocompromised patients and in patients who are clinically unstable.

Catheter-Associated Infections

Factors that inform treatment decisions include the type of catheter that is affected, the type of organism, the availability of alternate catheter access sites, the need for ongoing intravascular access, and the extent of disease involved.

In general, catheters should be removed if there is purulence at the exit site; if the organism is S aureus, negative rods, or Candida species; if there is persistent bacteremia (> 48 hours while receiving antibiotics); or if

gram-complications, such as septic thrombophlebitis, endocarditis, or other metastatic disease exist Central venous catheters may be exchanged over a guidewire and the tip sent for semiquantitative cultures if a catheter infection is suspected, provided there is no erythema or purulence at the exit site and the patient does not appear to be septic

If the catheter tip cultures return with > 15 CFU, replacement of the catheter at a new site is recommended Given that coagulase-negative staphylococci are the most common organisms isolated and most are resistant to nafcillin, empiric therapy with vancomycin, 15 mg/kg IV twice daily, should be given to patients in whom a bloodstream infection is suspected and who have normal renal function Empiric gram-negative coverage may be considered in patients who are immunocompromised or who are critically ill.

Antibiotic treatment duration depends on the organism identified and the extent of disease For uncomplicated bacteremia, 5–7 days of therapy is usually sufficient for coagulase-negative staphylococci, even if the original catheter is retained Fourteen days of therapy is generally recommended for uncomplicated bacteremia caused by

gram-negative rods, Candida species, and S aureus.

Kollef MH: Prevention of hospital-associated pneumonia and ventilator-associated pneumonia Crit Care Med

2004;32:1396 [PMID: 15187525]

Lorente C et al: Prevention of infection in the intensive care unit: current advances and opportunities for the future Curr Opin Crit Care 2002;8:461 [PMID: 12357116]

Raad I et al: Differential time to positivity: a useful method for diagnosing catheter-related bloodstream infections

Ann Intern Med 2004;140:18 [PMID: 14706968]

Vermeulen H et al: Diagnostic accuracy of routine postoperative body temperature measurements Clin Infect Dis

2005;40:1404 [PMID: 15844061]

Vincent JL: Nosocomial infections in adult intensive-care units Lancet 2003;361:2068 [PMID: 12814731]

Infections of the Central Nervous System

Essentials of Diagnosis

● Central nervous system infection is a medical emergency

● Symptoms and signs common to all types of central nervous system infection include headache, fever, sensorial disturbances, neck and back stiffness, positive Kernig and Brudzinski signs, and cerebrospinal fluid abnormalities.

General Considerations

Infections of the central nervous system can be caused by almost any infectious agent, including

bacteria, mycobacteria, fungi, spirochetes, protozoa, helminths, and viruses The classic triad of fever, stiff neck

and altered mental status has a low sensitivity (44%) for bacterial meningitis However, nearly all patients

with bacterial meningitis have at least two of the following symptoms—fever, headache, stiff neck, or altered

mental status.

Etiologic Classification

Central nervous system infections can be divided into several categories that usually can be readily

distinguished from each other by cerebrospinal fluid examination as the first step toward etiologic diagnosis

(Table 30–1 and Figure: illustration).

Table 30–1 Typical cerebrospinal fluid findings in various central nervous

system diseases.

(mg/dL) Protein (mg/ dL) Opening Pressure

Purulent meningitis (bacterial) 2

community-acquired

200–20,000 polymorphonuclear neutrophils

Granulomatous meningitis

(mycobacterial, fungal) 3

100–1000, mostly lymphocytes 3

Aseptic meningitis, viral or

meningoencephalitis 4

25–2000, mostly lymphocytes 3

1 Cerebrospinal fluid glucose must be considered in relation to blood glucose level Normally, cerebrospinal

fluid glucose is 20–30 mg/dL lower than blood glucose, or 50–70% of the normal value of blood glucose.

2 Organisms in smear or culture of cerebrospinal fluid; counterimmunoelectrophoresis or latex agglutination may

be diagnostic.

3 Polymorphonuclear neutrophils may predominate early.

4 Viral isolation from cerebrospinal fluid early; antibody titer rise in paired specimens of serum; polymerase

chain reaction for herpesvirus.

5 May occur in mastoiditis, brain abscess, epidural abscess, sinusitis, septic thrombus, brain tumor Cerebrospinal

fluid culture results usually negative.

Collection of cerebrospinal fluid (Reproduced, with permission, from Chesnutt MS et al: Office & Bedside

Procedures Originally published by Appleton & Lange Copyright © 1992 by The McGraw-Hill Companies, Inc.)

Purulent Meningitis

Patients with bacterial meningitis usually seek medical attention within hours or 1–2 days after onset of

symptoms The organisms responsible depend primarily on the age of the patient as summarized in Table 30–2

The diagnosis is usually based on the Gram-stained smear (positive in 60–90%) or culture (positive in over 90%).

Table 30–2 Initial antimicrobial therapy for purulent meningitis of unknown cause.

Population Common Microorganisms Standard Therapy

Neisseria meningitidis

Vancomycin 1plus cefotaxime or ceftriaxone2

Listeria monocytogenes,

Postsurgical or

posttraumatic

Staphylococcus aureus, S pneumoniae, gram-negative bacilli

Vancomycin 1plus ceftazidime4

1 The dose of vancomycin is 10–15 mg/kg IV every 6 hours

2 The usual dose of cefotaxime is 2 g IV every 6 hours and that of ceftriaxone is 2 g IV every 12 hours If

the organism is sensitive to penicillin, 3–4 million units IV every 4 hours is given.

3 The dose of ampicillin is usually 2 g IV every 4 hours.

4 Ceftazidime is given in a dose of 50–100 mg/kg IV every 8 hours up to 2 g every 8 hours.

Chronic Meningitis

The presentation of chronic meningitis is less acute than purulent meningitis Patients with chronic meningitis usually have a history of symptoms lasting weeks to months The most common pathogens are

Mycobacterium tuberculosis, atypical mycobacteria, fungi (Cryptococcus, Coccidioides, Histoplasma), and

spirochetes (Treponema pallidum and Borrelia burgdorferi, the cause of Lyme disease) The diagnosis is made

by culture or in some cases by serologic tests (cryptococcosis, coccidioidomycosis, syphilis, Lyme disease).

Aseptic Meningitis

Aseptic meningitis—a much more benign and self-limited syndrome than purulent meningitis—is caused principally

by viruses, especially mumps virus and the enterovirus group (including coxsackieviruses and

echoviruses) Infectious mononucleosis may be accompanied by aseptic meningitis Leptospiral infection is

also usually placed in the aseptic group because of the lymphocytic cellular response and its relatively benign course This type of meningitis also occurs during secondary syphilis and disseminated Lyme disease.

Encephalitis

Encephalitis (due to herpesviruses, arboviruses, rabies virus, flaviviruses [West Nile encephalitis,

Japanese encephalitis], and many others) produces disturbances of the sensorium, seizures, and many

other manifestations Patients are more ill than those with aseptic meningitis Cerebrospinal fluid may be

entirely normal or may show some lymphocytes and in some instances (eg, herpes simplex) red cells as well.

Partially Treated Bacterial Meningitis

Previous effective antibiotic therapy given for 12–24 hours will decrease the rate of positive Gram stain results

by 20% and culture by 30–40% but will have little effect on cell count, protein, or glucose Occasionally,

previous antibiotic therapy will change a predominantly polymorphonuclear response to a lymphocytic

pleocytosis, and some of the cerebrospinal fluid findings may be similar to those seen in aseptic meningitis.

Neighborhood Reaction

As noted in Table 30–1, this term denotes a purulent infectious process in close proximity to the central

nervous system that spills some of the products of the inflammatory process—white blood cells or protein—into the cerebrospinal fluid Such an infection might be a brain abscess, osteomyelitis of the vertebrae, epidural abscess, subdural empyema, or bacterial sinusitis or mastoiditis.

Noninfectious Meningeal Irritation

Carcinomatous meningitis, sarcoidosis, systemic lupus erythematosus, chemical meningitis, and certain drugs

—nonsteroidal anti-inflammatory drugs, muromonab-CD3 (OKT3), TMP-SMZ, and others—can also

produce symptoms and signs of meningeal irritation with associated cerebrospinal fluid pleocytosis, increased protein, and low or normal glucose Meningismus with normal cerebrospinal fluid findings occurs in the presence

of other infections such as pneumonia and shigellosis

Brain Abscess

Brain abscess presents as a space-occupying lesion; symptoms may include vomiting, fever, change of mental status, or focal neurologic manifestations When brain abscess is suspected, a CT scan should be performed

If positive, lumbar puncture should not be performed since results rarely provide clinically useful information and herniation can occur The bacteriology of brain abscess is usually polymicrobial and includes S aureus,

gram-negative bacilli, streptococci, and anaerobes (including anaerobic streptococci and Prevotella species).

Amebic Meningoencephalitis

These infections are caused by free-living amebas and present as two distinct syndromes The diagnosis is

confirmed by culture (Acanthamoeba spp and Balamuthia mandrillaris) or identification of the organism in a wet mount of cerebrospinal fluid (Naegleria fowleri) or on biopsy specimens No effective therapy is available Primary amebic meningoencephalitis is caused by N fowleri and is an acute fulminant disease, usually seen in

children and young adults with recent fresh water exposure, and is characterized by signs of meningeal irritation that rapidly progresses to encephalitis and death Rare cures have been reported with intravenous

and intraventricular administration of amphotericin B.

Granulomatous amebic encephalitis is caused by Acanthamoeba species It is an indolent disease, frequently seen

in immunocompromised patients and associated with cutaneous lesions Central nervous system disease

is characterized by headache, nausea, vomiting, cranial neuropathies, seizures, and hemiparesis Infections

with Balamuthia are similar to Acanthamoeba in that the course is subacute to chronic, but unlike

Acanthamoeba both immunocompromised and immunocompetent persons can be affected.

Clinical Findings

Laboratory Tests

Evaluation of a patient with suspected meningitis includes a history, physical examination, blood count, blood culture, lumbar puncture followed by careful study and culture of the cerebrospinal fluid, and a chest film The fluid must be examined for cell count, glucose, and protein, and a smear stained for bacteria (and acid-

fast organisms when appropriate) and cultured for pyogenic organisms and for mycobacteria and fungi

when indicated Latex agglutination tests can detect antigens of encapsulated organisms (S pneumoniae,

H influenzae, N meningitidis, and Cryptococcus neoformans) but are rarely used except for detection of

Cryptococcus or in partially treated patients Polymerase chain reaction (PCR) testing of cerebrospinal fluid has

been used to detect bacteria (S pneumoniae, H influenzae, N meningitidis, M tuberculosis, B burgdorferi,

and Tropheryma whippelii) and viruses (herpes simplex, varicella-zoster, CMV, Epstein-Barr virus, and

enteroviruses) in patients with meningitis The greatest experience is with PCR for herpes simplex and

varicella-zoster, and the tests are very sensitive (> 95%) and specific Tests to detect the other organisms may not be any more sensitive than culture, but the real value is the rapidity with which results are available, ie, hours compared with days or weeks At present, with the exception of PCR for herpes simplex, these tests

are performed only in reference laboratories Although it is difficult to prove with existing clinical data that

early antibiotic therapy improves outcome in bacterial meningitis, prompt therapy is still recommended.

Lumbar Puncture and Imaging

Since performing a lumbar puncture in the presence of a space-occupying lesion (brain abscess, subdural

hematoma, subdural empyema, necrotic temporal lobe from herpes encephalitis) may result in brainstem

herniation, a CT scan is performed prior to lumbar puncture if a space-occupying lesion is suspected on the basis

of papilledema, seizures, or focal neurologic findings Other indications for CT scan are an

immunocompromised patient or moderate to severely impaired level of consciousness If delays are encountered

in obtaining a CT scan and bacterial meningitis is suspected, blood cultures should be drawn and antibiotics

and corticosteroids administered even before cerebrospinal fluid is obtained for culture to avoid delay in

treatment (Table 30–2) Antibiotics given within 4 hours before obtaining cerebrospinal fluid probably do not

affect culture results.

Treatment

Increased intracranial pressure due to brain edema often requires therapeutic attention Hyperventilation,

mannitol (25–50 g as a bolus intravenous infusion), and even drainage of cerebrospinal fluid by repeated

lumbar punctures or by placement of ventricular catheters have been used to control cerebral edema and

increased intracranial pressure Dexamethasone (4 mg intravenously every 4–6 hours) may also decrease

cerebral edema In purulent meningitis, the identity of the causative microorganism may remain unknown or

doubtful for a few days and initial antibiotic treatment as set forth in Table 30–2 should be directed against

the microorganisms most common for each age group.

The duration of therapy for bacterial meningitis varies depending on the etiologic agent: H influenzae, 7 days;

N meningitidis, 3–7 days; S pneumoniae, 10–14 days; L monocytogenes, 14–21 days; and gram-negative bacilli,

21 days.

Dexamethasone therapy is recommended for adults with pneumococcal meningitis Ten milligrams of

dexamethasone administered intravenously 15–20 minutes before or simultaneously with the first dose of

antibiotics and continued every 6 hours for 4 days decreases morbidity and mortality The number of patients

with meningitis due to N meningitidis and other bacterial pathogens studied does not support similar

conclusions However, because adverse effects of dexamethasone for short periods are few and because

potential benefits are great, many clinicians would advocate dexamethasone even if N meningitidis is the

causative agent.

Therapy of brain abscess consists of drainage (excision or aspiration) in addition to 3–4 weeks of systemic

antibiotics directed against organisms isolated A regimen often used includes metronidazole, 500 mg

intravenously or orally every 8 hours, plus ceftizoxime, 2 g intravenously every 8 hours, or ceftriaxone, 2 g every

12 hours In cases where abscesses are less than 2 cm in size, where there are multiple abscesses that cannot

be drained, or if an abscess is located in an area where significant neurologic sequelae would result from

drainage, antibiotics for 6–8 weeks without drainage can be used.

Therapy of other types of meningitis is discussed elsewhere in this book (fungal meningitis, Infectious

Diseases: Mycotic; syphilis and Lyme borreliosis, Infectious Diseases: Bacterial & Chlamydial; tuberculous

meningitis, Infectious Diseases: Sprirochetal; herpes encephalitis, Infectious Diseases: Viral & Rickettsial).

Bernardini GL: Diagnosis and management of brain abscess and subdural empyema Curr Neurol Neurosci

Animal & Human Bite Wounds

Essentials of Diagnosis

● Cat and human bites are more likely to become infected than dog bites

● Bites to the hand are of special concern because of the possibility of closed-space infection

● Antibiotic prophylaxis indicated for noninfected bites of the hand and hospitalization required for infected hand bites

● All infected wounds need to be cultured to direct therapy.

General Considerations

About 1000 dog bite injuries require emergency department attention each day, most often in urban areas Dog

bites occur most commonly in the summer months Biting animals are usually known by their victims, and

most biting incidents are provoked (ie, bites occur while playing with the animal or after surprising the animal

or waking it abruptly from sleep) Failure to elicit a history of provocation is important, because an unprovoked

attack raises the possibility of rabies Human bites are usually inflicted by children while playing or fighting; in

adults, bites are associated with alcohol use and closed-fist injuries that occur during fights.

The animal inflicting the bite, the location of the bite, and the type of injury inflicted are all important determinants

of whether they become infected Cat bites are more likely to become infected than human bites—between 30%

and 50% of all cat bites become infected Infections following human bites are variable: Those inflicted by

children rarely become infected because they are superficial, and bites by adults become infected in 15–30%

of cases, with a particularly high rate of infection in closed-fist injuries "Through and through" bites (eg involving

the mucosa and the skin) have an infection rate similar to closed-fist injuries Dog bites, for unclear reasons,

become infected only 5% of the time Bites of the head, face, and neck are less likely to become infected than

bites on the extremities Puncture wounds become infected more frequently than lacerations, probably because

the latter are easier to irrigate and debride.

The bacteriology of bite infections is polymicrobial Following dog and cat bites, over 50% of infections are caused

by aerobes and anaerobes and 36% are due to aerobes alone Pure anaerobic infections are rare Pasteurella

species are the single most common isolate (75% of cat bites and 50% of dog bites) Other common aerobic

isolates include streptococci, staphylococci, Moraxella, and Neisseria; the most common anaerobes

are Fusobacterium, Bacteroides, Porphyromonas, and Prevotella The median number of isolates following

human bites is four (three aerobes and one anaerobe) Like dog and cat bites, most human bites are a mixture

of aerobes and anaerobes (54%) or are due to aerobes alone (44%) Streptococcus, Staphylococcus, and

Eikenella corrodens (found in 30% of patients) are the most common aerobes Prevotella and Fusobacterium are

the most common anaerobes Although the organisms noted are the most common, innumerable others have

been isolated—including Capnocytophagia (dog and cats), Pseudomonas, and Haemophilus—emphasizing the

point that all infected bites should be cultured to define the microbiology.

HIV can be transmitted from bites (either from biting or receiving a bite from an HIV-infected patient) but has

rarely been reported.

Treatment

Local Care

Vigorous cleansing and irrigation of the wound as well as debridement of necrotic material are the most

important factors in decreasing the incidence of infections Radiographs should be obtained to look for fractures

and the presence of foreign bodies Careful examination to assess the extent of the injury (tendon laceration,

If wounds require closure for cosmetic or mechanical reasons, suturing can be done However, one should

never suture an infected wound, and wounds of the hand should generally not be sutured since a

closed-space infection of the hand can result in loss of function.

Prophylactic Antibiotics

Prophylaxis is indicated in high-risk bites, eg, cat bites in any location (dicloxacillin, 0.5 g orally four times a day for 3–5 days) and hand bites by any animal or by humans (penicillin V, 0.5 g orally four times a day for 3–5 days) Although dicloxacillin and penicillin have been specifically studied, there is concern about their use because

of their narrow spectrum of activity Based on the microbiology of bite wounds, other agents less adequately studied but that have broader spectrums of activity may be better as prophylactic agents Examples

include cefuroxime, amoxicillin-clavulanic acid and, in the penicillin-allergic patient, clindamycin plus

a fluoroquinolone Immunocompromised patients and especially individuals without functional spleens are at risk

for developing overwhelming bacteremia (primarily with Capnocytophagia spp.) and sepsis following animal bites

and should also receive prophylaxis, even for low-risk bites.

Because the risk of HIV transmission is so low following a bite, routine postexposure prophylaxis is

not recommended Each case should be evaluated individually and consideration for prophylaxis should be given

to those who present within 72 hours of the incident, the source is known to be HIV infected, and the exposure

is high risk.

Antibiotics

For wounds that are infected, antibiotics are clearly indicated How they are given (orally or intravenously) and

the need for hospitalization are individualized clinical decisions In general, Pasteurella multocida is best treated

with penicillin or a tetracycline Other active agents include second- and third-generation

cephalosporins, fluoroquinolones, or azithromycin and clarithromycin Response to therapy is slow, and

therapy should be continued for at least 2–3 weeks Human bites frequently require intravenous therapy with a -lactam plus a -lactamase inhibitor combination (Unasyn, Timentin, Zosyn), a second-generation

cephalosporin with anaerobic activity (cefoxitin, cefotetan, cefmetazole) or, in the penicillin-allergic

patient, clindamycin plus a fluoroquinolone Because the bacteriology of these infections is so variable,

infected woulds should always be cultured.

Tetanus and Rabies

All patients must be evaluated for the need for tetanus (see Infectious Diseases: Bacterial & Chlamydial) and rabies (see Infectious Diseases: Viral & Rickettsial) prophylaxis.

Brook I: Microbiology and management of human and animal bite wound infections Prim Care 2003;30:25 [PMID: 12825249]

Talan DA et al: Clinical presentation and bacteriologic analysis of infected human bites in patients presenting

to emergency departments Clin Infect Dis 2003;37:1481 [PMID: 14614671]

Taplitz RA: Managing bite wounds Currently recommended antibiotics for treatment and prophylaxis Postgrad Med 2004;116:49 [PMID: 15323154]

Sexually Transmitted Diseases

Some infectious diseases are transmitted most commonly—or most efficiently—by sexual contact Most of the infectious agents that cause sexually transmitted diseases are fairly easily inactivated when exposed to a harsh environment They are thus particularly suited to transmission by contact with mucous membranes They may be bacteria, spirochetes, chlamydiae, viruses, or protozoa In most infections caused by these agents, early lesions occur on genitalia or other sexually exposed mucous membranes; however, wide dissemination may occur, and involvement of nongenital tissues and organs may mimic many noninfectious disorders All sexually transmitted diseases have subclinical or latent phases that play an important role in long-term persistence of the infection or in its transmission from infected (but largely asymptomatic) persons to other contacts Laboratory examinations are

of particular importance in the diagnosis of such asymptomatic patients Simultaneous infection by several

different agents is common, and any person with a sexually transmitted disease should be tested for syphilis; a repeat study should be done in 3 months if negative, since seroconversion is delayed after primary infection For each patient, there are one or more sexual contacts who require diagnosis and treatment Prompt treatment of contacts by giving antibiotics to the index case to distribute all sexual contacts is an important strategy for

preventing further transmission The most common sexually transmitted diseases are gonorrhea,* syphilis,* condyloma acuminatum, chlamydial genital infections*, herpesvirus genital infections, trichomonas vaginitis, chancroid,* granuloma inguinale, scabies, louse infestation, and bacterial vaginosis (among lesbians) However, shigellosis,* hepatitis A, B, and C,* amebiasis, giardiasis*, cryptosporidiosis*, salmonellosis,* and

campylobacteriosis may also be transmitted by sexual (oral-anal) contact, especially in homosexual males

Homosexual contact is a typical method of transmission of HIV, although bidirectional heterosexual transmission is occurring more commonly (see Infectious Diseases: HIV).

*Reportable to public health authorities

The risk of developing a sexually transmitted disease following a sexual assault has not been established Victims

of assault have a high baseline rate of infection (Neisseria gonorrhoeae, 6%; Chlamydia trachomatis, 10%;

Trichomonas vaginalis, 15%; and bacterial vaginosis, 34%), and the risk of acquiring infection as a result of the

assault is significant but is often lower than the preexisting rate (N gonorrhoeae, 6–12%; C trachomatis, 4–17%;

T vaginalis, 12%; syphilis, 0.5–3%; and bacterial vaginosis, 19%) Victims should be evaluated within 24 hours

after the assault, and cultures for N gonorrhoeae and C trachomatis should be obtained (If culture is not

available, nonculture tests, such as nucleic acid amplification tests, are acceptable If the test is positive, it must

be confirmed with a second test using a different target sequence.) Vaginal secretions are cultured and examined

for Trichomonas If a discharge is present, if there is itching, or if secretions are malodorous, a wet mount should

be examined for Candida and bacterial vaginosis In addition, a blood sample should be obtained for immediate

serologic testing for syphilis, hepatitis B, and HIV Follow-up examination for sexually transmitted disease should

be repeated within 1–2 weeks, since concentrations of infecting organisms may not have been sufficient to

produce a positive culture at the time of initial examination If prophylactic treatment was given (see below), tests should be repeated only if the victim has symptoms If prophylaxis was not administered, the individual should be seen in 1 week so that any positive tests can be treated Follow-up serologic testing for syphilis and HIV infection should be performed in 6, 12, and 24 weeks if the initial tests are negative The usefulness of presumptive therapy

is controversial, some feeling that all patients should receive it and others that it should be limited to those in whom follow-up cannot be ensured or to patients who request it If therapy is given, a reasonable regimen would

be hepatitis B vaccination (without hepatitis B immune globulin, the first dose given at the initial evaluation and follow-up doses at 1–2 months and 4–6 months) and one dose of ceftriaxone, 125 mg intramuscularly, plus

metronidazole, 2 g orally as a single dose, plus doxycycline, 100 mg orally twice daily for 7 days, or azithromycin,

1 g orally as a single dose, instead of doxycycline In premenopausal women, azithromycin should be used instead

of doxycycline until the pregnancy status is determined; if the pregnancy test is positive, metronidazole should be given only after the first trimester.

Although seroconversion to HIV has been reported following sexual assault when this was the only known risk, this risk is believed to be low The likelihood of HIV transmission from vaginal or anal receptive intercourse when the

source is known to be HIV positive is 1 per 1000 and 5 per 1000, respectively Although prophylactic antiretroviral therapy has not been studied in this setting, the Department of Health and Human Services recommends the

prompt institution of postexposure prophylaxis with highly active antiretroviral therapy if the person seeks care

within 72 hours of the assault, the source is known to be HIV positive, and the exposure presents a substantial

risk of transmission.

Golden MR et al: Effect of expedited treatment of sex partners on recurrent or persistent gonorrhea or chlamydial infection N Engl J Med 2005;352:676 [PMID: 15716561]

Sexually transmitted diseases treatment guidelines 2002 Centers for Disease Control and Prevention MMWR

Recomm Rep 2002;51(RR-6):1 [PMID: 12184549]

Smith DK et al: Antiretroviral postexposure prophylaxis after sexual, injection-drug use, or other nonoccupational exposure to HIV in the United States: recommendations from the U.S Department of Health and Human Services MMWR Recomm Rep 2005;54(RR-2):1 [PMID: 15660015]

Infections in Drug Users

Essentials of Diagnosis

● Common infections that occur with greater frequency in drug users include the following: skin infections; hepatitis

A, B, C, D; aspiration pneumonia; tuberculosis; pulmonary septic emboli; sexually transmitted diseases; AIDS; infective endocarditis; osteomyelitis; and septic arthritis

● Rare infections in the United States include tetanus, malaria, and melioidosis.

General Considerations

The use of parenterally administered recreational drugs has increased enormously in recent years There are now

an estimated 300,000 or more injection drug users in the United States.

Common Infections That Occur with Greater Frequency in Drug Users

Skin infections are associated with poor hygiene and use of nonsterile technique when injecting drugs S

aureus (including methicillin-resistant strains) and oral flora (streptococci, Eikenella,

Fusobacterium, Peptostreptococcus) are the most common organisms, with enteric gram-negatives less common

and seen in those who inject into the groin Cellulitis and subcutaneous abscesses occur most commonly,

particularly in association with subcutaneous ("skin-popping") or intramuscular injections and the use of cocaine

and heroin mixtures (probably due to ischemia) Myositis, clostridial myonecrosis, and necrotizing fasciitis

occur infrequently but are life-threatening Wound botulism in association with black tar heroin occurs

sporadically but often in clusters.

Hepatitis is very common among habitual drug users and is transmissible both by the parenteral (hepatitis B, C,

and D) and by the fecal-oral route (hepatitis A) Multiple episodes of hepatitis with different agents can occur.

Aspiration pneumonia and its complications (lung abscess, empyema, brain abscess) result from

altered consciousness associated with drug use Mixed aerobic and anaerobic mouth flora are usually involved.

Tuberculosis also occurs in drug users, and infection with HIV has fostered the spread of tuberculosis in

this population Morbidity and mortality rates are increased in HIV-infected individuals with tuberculosis

Classic radiographic findings are often absent; tuberculosis is suspected in any patient with infiltrates who does not respond to antibiotics.

Pulmonary septic emboli may originate from venous thrombi or right-sided endocarditis.

Sexually transmitted diseases are not directly related to drug use, but the practice of exchanging sex for

drugs has resulted in an increased frequency of sexually transmitted diseases Syphilis, gonorrhea, and chancroid are the most common.

AIDS has a high incidence among injection drug users and their sexual contacts and among the offspring of

infected women (see Infectious Diseases: HIV).

Infective endocarditis The organisms that cause infective endocarditis in those who use drugs intravenously

are most commonly S aureus, Candida (especially Candida parapsilosis), Enterococcus faecalis, other

streptococci, and gram-negative bacteria (especially Pseudomonas and Serratia marcescens) A number

of complications of endocarditis can occur, including splenic abscesses, central nervous system infections

(meningitis, brain abscess, subdural empyema, epidural abscess), and endophthalmitis Involvement of the right side of the heart is common, and infection of more than one valve is not infrequent Right-sided

involvement, especially in the absence of murmurs, is often suggested by the presence of septic pulmonary

emboli The diagnosis must be established by blood culture Therapy, including empiric treatment, is discussed

in Infectious Diseases: Bacterial & Chlamydial.

Other vascular infections include septic thrombophlebitis and mycotic aneurysms Mycotic aneurysms

resulting from direct trauma to a vessel with secondary infection most commonly occur in femoral arteries and less commonly in arteries of the neck Aneurysms resulting from hematogenous spread of organisms

frequently involve intracerebral vessels and thus are seen in association with endocarditis.

Osteomyelitis and septic arthritis Osteomyelitis involving vertebral bodies, sternoclavicular joints, the

pubic symphysis, the sacroiliac joints, and other sites usually results from hematogenous distribution of

injected organisms or septic venous thrombi Pain and fever precede radiographic changes, sometimes by

several weeks While staphylococci—often methicillin-resistant—are common organisms, Serratia,

Pseudomonas, Candida (usually not Candida albicans), and other pathogens rarely encountered in spontaneous

bone or joint disease are found in injection drug users.

Infections Rare in United States

Tetanus

In the 1950s and 1960s, tetanus was commonly seen in drug users, especially in unimmunized women who

injected drugs subcutaneously ("skin-popping") Increased tetanus immunization among drug users has resulted in

a decline in this disease, although cases are still reported.

Malaria

Needle transmission occurs from intravenous drug users who acquired the infection in malaria-endemic areas outside the United States.

Melioidosis

This chronic pulmonary infection caused by Burkholderia pseudomallei occurs occasionally in debilitated drug

users, but most cases are reported in Asia and Australia.

A common and difficult clinical problem is management of the parenteral drug user who presents with fever

In general, after obtaining appropriate cultures (blood, urine, and sputum if the chest radiograph is

abnormal), empiric therapy is begun If the chest radiograph is suggestive of a community-acquired

pneumonia (consolidation), therapy for outpatient pneumonia is begun with a third-generation cephalosporin, such

as ceftriaxone, 1–2 g intravenously every 24 hours (many clinicians would add azithromycin, 500 mg orally

or intravenously every 24 hours, or doxycycline, 100 mg orally or intravenously twice daily, to this regimen) If

the chest radiograph is suggestive of septic emboli (nodular infiltrates), therapy for presumed endocarditis

is initiated, usually with a combination of vancomycin 15 mg/kg every 12 hours intravenously (due to the

high prevalence of methicillin-resistant S aureus and the possibility of enterococcus) and gentamicin, 1 mg/kg

every 8 hours intravenously If the chest radiograph is normal and no focal site of infection can be found,

endocarditis is presumed While awaiting the results of blood cultures, empiric treatment with vancomycin

and gentamicin is started If blood cultures are positive for organisms that frequently cause endocarditis in

drug users (see above), endocarditis is presumed to be present and treated accordingly If blood cultures are

positive for an organism that is an unusual cause of endocarditis, evaluation for an occult source of infection

should go forward In this setting, a transesophageal echocardiogram may be quite helpful since it is 90% sensitive

in detecting vegetations and a negative study is strong evidence against endocarditis If blood cultures are

negative and the patient responds to antibiotics, therapy should be continued for 7–14 days (oral therapy can

be given once an initial response has occurred) In every patient, careful examination for an occult source of

infection (eg, genitourinary, dental, sinus, gallbladder) should be done

Gordon RJ et al: Bacterial infections in drug users N Engl J Med 2005;353:1945 [PMID: 16267325]

Infections in injection drug users (entire issue) Infect Dis Clin North Am 2002;16:3

Acute Infectious Diarrhea

Essentials of Diagnosis

● Arbitrarily divided into acute and chronic and mild, moderate, and severe

● Diarrhea is acute if lasts < 2 weeks and chronic if lasts > 2 weeks

● Disease is mild if there are three or fewer stools per day, moderate if there are four or more stools in association with local symptoms (abdominal cramps, nausea, tenesmus), and severe if there are four or more stools per day with systemic symptoms (fevers, chills, dehydration).

General Considerations

Acute diarrhea can be caused by a number of different factors, including emotional stress, food intolerance,

inorganic agents (eg, sodium nitrite), organic substances (eg, mushrooms, shellfish), drugs, and infectious

agents (including viruses, bacteria, and protozoa) From a diagnostic and therapeutic standpoint, it is helpful

to classify infectious diarrhea into syndromes that produce inflammatory or bloody diarrhea and those that

are noninflammatory, nonbloody, or watery In general, the term "inflammatory diarrhea" suggests

colonic involvement by invasive bacteria or parasites or by toxin production Patients complain of frequent

bloody, small-volume stools, often associated with fever, abdominal cramps, tenesmus, and fecal urgency

Common causes of this syndrome include Shigella, Salmonella, Campylobacter, Yersinia, invasive strains

of Escherichia coli, E coli O157:H7, Entamoeba histolytica, and C difficile Tests for fecal leukocytes or the

neutrophil marker lactoferrin are frequently positive, and definitive etiologic diagnosis requires stool

culture Noninflammatory diarrhea is generally milder and is caused by viruses or toxins that affect the

small intestine and interfere with salt and water balance, resulting in large-volume watery diarrhea, often

with nausea, vomiting, and cramps Common causes of this syndrome include viruses (eg, rotavirus, Norwalk

virus, enteric adenoviruses, astrovirus, coronavirus), vibriones (Vibrio cholerae, Vibrio

parahaemolyticus), enterotoxin-producing E coli, Giardia lamblia, cryptosporidia, and agents that can cause

food-borne gastroenteritis.

The term "food poisoning" denotes diseases caused by toxins present in consumed foods When the incubation

period is short (1–6 hours after consumption), the toxin is usually preformed Vomiting is usually a major

complaint, and fever is usually absent Examples include intoxication from S aureus or Bacillus cereus, and toxin

can be detected in the food When the incubation period is longer—between 8 hours and 16 hours—the organism

is present in the food and produces toxin after being ingested Vomiting is less prominent, abdominal cramping

is frequent, and fever is often absent The best example of this disease is that due to Clostridium perfringens

Toxin can be detected in food or stool specimens.

The inflammatory and noninflammatory diarrheas discussed above can also be transmitted by food and water

and usually have incubation periods between 12 and 72 hours Cyclospora, cryptosporidia, and Isospora

are protozoans capable of causing disease in both immunocompetent and immunocompromised

patients Characteristics of disease include profuse watery diarrhea that is prolonged but usually self-limited (1–

2 weeks) in the immunocompetent patient but can be chronic in the compromised host Epidemiologic features

may be helpful in determining etiology Recent hospitalization or antibiotic use suggests C difficile; recent

foreign travel suggests Salmonella, Shigella, Campylobacter, E coli, or V cholerae; undercooked hamburger

suggests E coli, especially O157:H7; and fried rice consumption is associated with B cereus toxin Prominent

features of some of these causes of diarrhea are listed in Table 30–3.

Table 30–3 Acute bacterial diarrheas and "food poisoning."

Clinical Food and stool can

be tested for toxin.

Abrupt onset, intense nausea and vomiting for

up to 24 hours, recovery in 24–

Clinical Food and stool can

be tested for toxin.

Acute onset, severe nausea and vomiting lasting 24 hours Supportive care.

B cereus (diarrheal

toxin)

stews, and gravy.

Clinical Food and stool can

be tested for toxin.

Abdominal cramps, watery diarrhea, and nausea lasting 24–48 hours Supportive care.

Clostridium

perfringens

in rewarmed meat and poultry dishes and produce

an enterotoxin.

Stools can be tested for enterotoxin or cultured.

Abrupt onset of profuse diarrhea, abdominal cramps, nausea; vomiting

occasionally Recovery usual without

treatment in 24–

48 hours

Supportive care; antibiotics not needed.

Clostridium

botulinum

in anaerobic acidic environment

eg, canned foods, fermented fish, foods held warm for extended periods

Stool, serum, and food can

be tested for toxin Stool and food can

be cultured.

Diplopia, dysphagia, dysphonia, respiratory embarrassment Treatment requires clear airway, ventilation, and intravenous polyvalent antitoxin (see text) Symptoms can last for days

to months.

Clostridium difficile Usually occurs

after 7–10 days of antibiotics

Can occur after a single dose or several weeks after

completion of antibiotics.

with antimicrobial drugs;

clindamycin and

cephalosporins most

commonly implicated.

Stool tested for toxin.

Abrupt onset of diarrhea that may be bloody; fever Oral metronidazole first-line therapy If no response, oral vancomycin can

be given

unpasteurized milk and juice;

raw fruits and vegetables.

E coli O157:

H7 can be cultured on special medium

Other toxins can be detected in stool

Usually abrupt onset of diarrhea, often bloody;

abdominal pain

In adults, it is usually self- limited to 5–10 days In children, it is associated with hemolytic- uremic syndrome (HUS) Antibiotic therapy may increase risk of HUS

Enterotoxigenic E

coli (ETEC)

contaminated with feces.

Stool culture

Special tests required to identify toxin- producing strains.

Watery diarrhea and abdominal cramps, usually lasting 3–7 days

In travelers, fluoroquinolones shorten disease.

Abrupt onset of watery diarrhea, abdominal cramps, nausea and vomiting Recovery is usually complete

in 2–5 days

Vibrio cholerae 24–72 hours + +++ – Contaminated

water, fish, shellfish, street vendor food.

Stool culture

on special medium.

Abrupt onset of liquid diarrhea in endemic area Needs prompt intravenous or oral replacement

of fluids and electrolytes Tetracyclines shorten excretion of vibrios

Campylobacter

jejuni

undercooked poultry, unpasteurized milk, water.

Stool culture

on special medium.

Fever, diarrhea that can be bloody, cramps Usually self- limited in 2–10 days Early treatment (erythromycin) shortens course May be

associated with Guillain-Barré syndrome.

Shigella species

(mild cases)

contaminated with human feces Person

to person spread.

Routine stool culture.

Abrupt onset of diarrhea, often with blood cramps, tenesmus, and lethargy

Therapy depends

on sensitivity testing, but the fluoroquinolones are most active Often mild and self-limited, resolving in 4–7 days.

Salmonella species 1–3 days – ++ + Eggs, poultry,

unpasteurized milk, cheese, juices, raw fruits and vegetables.

Routine stool culture.

Gradual or abrupt onset of diarrhea and low- grade fever No antimicrobials unless high risk (see text) or systemic dissemination is suspected, in which case give

a fluoroquinolone Prolonged carriage can occur.

Yersinia

enterocolitica

pork, contaminated water, unpasteurized milk, tofu.

Stool culture

on special medium.

Severe abdominal pain, (appendicitis-like symptoms) diarrhea, fever Polyarthritis, erythema nodosum in children If severe, give tetracycline or fluoroquinolone Without

treatment, limited in 1–3 weeks.

contaminated foods touched

by infected food handlers.

Immunoassay

on stool.

Acute onset, vomiting, watery diarrhea that lasts 4–8 days Supportive care Noroviruses and

other caliciviruses

fecally contaminated foods touched

by infected food handlers.

Clinical diagnosis with negative stool cultures PCR available on stool.

Nausea, vomiting (more common in children) diarrhea (more common in adults), fever, myalgias, abdominal cramps Lasts 12–60 hours Supportive care PCR = polymerase chain reaction.

Treatment

Treatment usually consists of replacement of fluids and electrolytes and, very rarely, management of

hypovolemic shock and respiratory compromise In mild diarrhea, increasing ingestion of juices and clear soups

is adequate In more severe cases of dehydration (postural lightheadedness, decreased urination), oral

glucose-based rehydration solutions can be used (Ceralyte, Pedialyte) In general, most cases of acute gastroenteritis are

self-limited and do not require therapy other than supportive measures When symptoms persist beyond 3–4

days, initial presentation is accompanied by fever or bloody diarrhea, or the patient is immunocompromised,

cultures of stool are usually obtained Symptoms have often resolved by the time cultures are completed In

this case, even if a pathogen is isolated, therapy is not needed (except for Shigella, since the infecting dose is

so small that therapy to eradicate organisms from the stool is indicated for epidemiologic reasons) If

symptoms persist and a pathogen is isolated, it is reasonable to institute specific treatment even though therapy

has not been conclusively shown to alter the natural history of disease for most pathogens Exceptions

include infection with Shigella where antibiotic therapy has been shown to shorten the duration of symptoms by 2–

3 days, infections with E coli O157:H7 (antibiotic therapy does not ameliorate symptoms and may increase the risk

of developing hemolytic-uremic syndrome), and Campylobacter infections (early therapy, within 4 days of onset

of symptoms, shortens the course of disease) Uncomplicated gastroenteritis due to Salmonella does not

require therapy because the disease is usually self-limited and therapy may prolong carriage and perhaps

increase relapses Because bacteremia with complications can occur in high-risk patients, some experts

have recommended therapy for Salmonella in patients over the age of 50, in organ transplant recipients, in

those with HIV, in patients taking corticosteroids, in those with lymphoproliferative diseases, and in those

with vascular grafts Ciprofloxacin, 500 mg every 12 hours for 5 days, is effective in shortening the course of illness compared with placebo in patients presenting with diarrhea, whether a pathogen is isolated or not

However, because of concerns about selecting for resistant organisms (especially Campylobacter, where

increasing resistance to fluoroquinolones has been documented and erythromycin is the drug of choice) coupled with the fact that most infectious diarrhea is self-limited, routine use of antibiotics for all patients with diarrhea is not recommended Antibiotics should be considered in patients with evidence of invasive disease (white cells in stool, dysentery), with symptoms 3–4 days or more in duration, with multiple stools (eight to ten or more per day), and in those with impaired immune responses Antimotility drugs may relieve cramping and decrease

diarrhea in mild cases Their use should be limited to patients without fever and without dysentery (bloody

stools), and they should be used in low doses because of the risk of producing toxic megacolon.

Therapeutic recommendations for specific agents can be found elsewhere in this book.

Diagnosis and management of foodborne illnesses: a primer for physicians and other health care

professionals MMWR Recomm Rep 2004;53(RR-4):1 [PMID: 15123984]

Musher DM et al: Contagious acute gastrointestinal infections N Engl J Med 2004;351:2417 [PMID: 15575058] Thielman NM et al: Clinical practice Acute infectious diarrhea N Engl J Med 2004;350:38 [PMID: 14702426]

Infectious Diseases in the Returning Traveler

Essentials of Diagnosis

● Identify patients with acute, potentially life-threatening and treatable diseases, or those with transmissible diseases that require isolation

● The incubation period may be helpful in diagnosis

● Less than 3 weeks following exposure may suggest dengue, leptospirosis and yellow fever; greater than 3 weeks suggest typhoid fever, malaria, and tuberculosis

General Considerations

The differential diagnosis of fever in the returning traveler is broad, ranging from self-limited viral infections to threatening illness The evaluation is best done by identifying whether a particular syndrome is present, then refining the differential diagnosis based on an exposure history The travel history should include directed questions regarding geography (rural versus urban), animal or arthropod contact, unprotected sexual intercourse, ingestion of untreated water or raw foods, historical or pretravel immunizations, and adherence to malaria prophylaxis.

life-Etiologies

The most common infectious causes of fever—excluding simple causes such as upper respiratory infections,

bacterial pneumonia and urinary tract infections—in returning travelers are malaria (see Infectious Diseases: Protozoal & Helminthic), diarrhea (see next section), and dengue (see Infectious Diseases: Viral & Rickettsial)

Others include respiratory infections, leptospirosis (see Infectious Diseases: Spirochetal), typhoid fever (see

Infectious Diseases: Bacterial & Chlamydial), and rickettsial infections (see Infectious Diseases: Viral & Rickettsial) Systemic febrile illnesses without a diagnosis also occurs commonly, particularly in travelers returning from sub- Saharan Africa or Southeast Asia.

Fever and Rash

Potential etiologies include dengue, viral hemorrhagic fever, leptospirosis, meningococcemia, yellow fever, typhus,

Salmonella typhi, and acute HIV infection.

Consider hepatitis A, yellow fever, hemorrhagic fever, leptospirosis, and malaria.

Fever Without Localizing Symptoms or Signs

Malaria, typhoid fever, acute HIV infection, rickettsial illness, visceral leishmaniasis, trypanosomiasis, and dengue are possible etiologies.

serologic testing The work-up of traveler's diarrhea is presented in the following section Finally, patients with fever but no localizing signs or symptoms should have blood cultures performed Routine laboratory studies usually include complete blood count with differential, electrolytes, liver function tests, urine analysis, and blood cultures Thick and thin peripheral blood smears should be done (and repeated in 12–24 hours if clinical suspicion remains high) for malaria if there has been travel to endemic areas Other studies are directed by the results of history, physical examination, and initial laboratory tests They may include stool for ova and parasites, chest radiograph, HIV test, and specific serologies (eg, dengue, leptospirosis, rickettsial disease, schistosomiasis) Bone marrow biopsy to diagnose typhoid fever could be helpful in the appropriate patient.

Freedman DO et al; GeoSentinel Surveillance Network: Spectrum of disease and relation to place of exposure among ill returned travelers N Engl J Med 2006;354:119 [PMID: 16407507]

Ryan ET et al: Illness after international travel N Engl J Med 2002;347:505 [PMID: 12181406]

Stienlauf S et al: Epidemiology of travel-related hospitalization J Travel Med 2005;12:136 [PMID: 15996442]

Traveler's Diarrhea

Essentials of Diagnosis

● Usually a benign, self-limited disease occurring about 1 week into travel

● Prophylaxis not recommended unless there is a comorbid disease (inflammatory bowel syndrome, HIV, immunosuppressive medication)

● Single-dose therapy of a fluoroquinolone usually effective if symptoms develop

General Considerations

Whenever a person travels from one country to another—particularly if the change involves a marked difference in climate, social conditions, or sanitation standards and facilities—diarrhea is likely to develop within 2–10 days

Bacteria cause 80% of cases of traveler's diarrhea, with enterotoxigenic E coli, Shigella species, and

Campylobacter jejuni being the most common pathogens Less common are Aeromonas, Salmonella, noncholera

vibriones, E histolytica, and G lamblia Contributory causes include unusual food and drink, change in living habits,

occasional viral infections (adenoviruses or rotaviruses), and change in bowel flora Chronic watery diarrhea may

be due to amebiasis or giardiasis or, rarely, tropical sprue.

Clinical Findings

Symptoms and Signs

There may be up to ten or even more loose stools per day, often accompanied by abdominal cramps and nausea, occasionally by vomiting, and rarely by fever The stools do not usually contain mucus or blood, and aside from weakness and dehydration, there are no systemic manifestations of infection The illness usually subsides

spontaneously within 1–5 days, although 10% remain symptomatic for 1 week or longer, and symptoms persist for longer than 1 month in 2%.

Prophylaxis is started upon entry into the destination country and is continued for 1 or 2 days after leaving For stays of more than 3 weeks, prophylaxis is not recommended because of the cost and increased toxicity For prophylaxis, bismuth subsalicylate is effective but turns the tongue and the stools black and can interfere with doxycycline absorption, which may be needed for malaria prophylaxis; it is rarely used Numerous antimicrobial regimens for once-daily oral prophylaxis are effective, such as norfloxacin, 400 mg, ciprofloxacin, 500 mg,

ofloxacin, 300 mg, or TMP-SMZ, 160/800 mg Because not all travelers will have diarrhea and because most episodes are brief and self-limited, an alternative approach currently recommended is to provide the traveler with

a supply of antimicrobials to be taken if significant diarrhea occurs during the trip Loperamide (4 mg oral loading dose, then 2 mg after each loose stool to a maximum of 16 mg/d) with a single oral dose of ciprofloxacin (750

mg), levofloxacin (500 mg), ofloxacin (300 mg), or azithromycin (1000 mg) cures most cases of traveler's

diarrhea In pregnant women and in areas with a high prevalence of fluoroquinolone-resistant Campylobacter

(such as Thailand), azithromycin is the drug of choice If diarrhea is severe, associated with fever or bloody stools,

or persists despite single-dose ciprofloxacin treatment, then 3–5 days of ciprofloxacin, 500 mg orally twice daily; levofloxacin, 500 mg orally once daily; norfloxacin, 400 mg orally twice daily; ofloxacin, 300 mg orally twice daily;

or azithromycin, 500 mg orally once daily (for pregnant women) can be given TMP-SMZ, 160/800 mg orally twice daily, can be used as an alternative, but resistance is common in many areas Rifaximin, a nonabsorbable,

rifampin-like drug, is also approved for therapy of traveler's diarrhea at a dose of 200 mg orally three times per day or 400 mg twice a day for 3 days Because luminal concentrations are high, but tissue level are quite low, it should not be used in situations where there is a high likelihood of invasive disease (eg, fever, systemic toxicity, or bloody stools).

Ramzan NN: Traveler's diarrhea Gastroenterol Clin North Am 2001;30:665 [PMID: 11586551]

Rendi-Wagner P et al: Drug prophylaxis for travelers' diarrhea Clin Infect Dis 2002;34:628 [PMID: 11803509] Thielman NM et al: Clinical practice Acute infectious diarrhea N Engl J Med 2004;350:38 [PMID: 14702426]

Recommended Immunization of Infants, Children, & Adolescents

The recommended schedules and dosages of vaccination change often, so the manufacturer's package inserts should always be consulted.

The schedule for active immunizations in children is presented in Table 30–4 (see also http://www.cdc.gov/nip) All adolescents should see a health care provider to ensure vaccination of those who have not received varicella or hepatitis B vaccine, to make certain that a second dose of measles-mumps-rubella (MMR) has been given, to receive a booster of tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine (Tdap adolescent preparation), to receive meningococcal vaccine conjugate vaccine, and to receive immunizations (influenza and pneumococcal vaccines) that may be indicated for certain high-risk individuals.

MMWR Jan 6, 2006/vol54/Nos 51 & 52: http://www.cdc.gov/mmwr/index2005.htm

1 Indicates the recommended ages for routine administration of currently licensed childhood vaccines, as of

January 6, 2006, for children through age 18 years Any dose not given at the recommended age should be given

at any subsequent visit when indicated and feasible Gray areas with diagonal rules indicate age groups that warrant special effort to administer those vaccines not given previously Additional vaccines may be licensed and recommended during the year Licensed combination vaccines may be used whenever any components of the combination are indicated and the vaccine's other components are not contraindicated Providers should consult the manufacturers' package inserts for detailed recommendations.

2 Hepatitis B vaccine (Hep B) All infants should receive the first dose of HepB vaccine soon after birth and

before hospital discharge; the first dose also may be given by age 2 months if the infant's mother is

HBsAg-negative Only monovalent HepB vaccine can be used for the birth dose Monovalent or combination vaccine containing HepB may be used to complete the series; four doses of vaccine may be administered when a birth dose

is given The second dose should be given at least 4 weeks after the first dose except for combination vaccines, which cannot be administered before age 6 weeks The third dose should be given at least 16 weeks after the first dose and at least 8 weeks after the second dose The last dose in the vaccination series (third or fourth dose)

should not be administered before age 6 months Infants born to HBsAg-positive mothers should receive HepB

vaccine and 0.5 mL hepatitis B immune globulin (HBIG) within 12 hours of birth at separate sites The second dose

is recommended at age 1–2 months The last dose in the vaccination series should not be administered before age

6 months These infants should be tested for HBsAg and anti-HBs at 9–15 months of age Infants born to mothers

whose HBsAg status is unknown should receive the first dose of the HepB vaccine series within 12 hours of birth

Maternal blood should be drawn as soon as possible to determine the mother's HBsAg status; if the HBsAg test is positive, the infant should receive HBIG as soon as possible (no later than age 1 week) The second dose is

recommended at age 1–2 months The last dose in the vaccination series should not be administered before age 6 months.

3 Diphtheria and tetanus toxoids and acellular pertussis vaccine (DTaP) The fourth dose of DTaP may be

administered at age 12 months provided that 6 months have elapsed since the third dose and the child is unlikely

to return at age 15–18 months Tetanus and diphtheria toxoids (Td) are recommended at age 11–12 years if

at least 5 years have elapsed since the last dose of the Td-containing vaccine Subsequent routine Td boosters are recommended every 10 years.

4 Haemophilus influenzae type b (Hib) conjugate vaccine Three Hib conjugate vaccines are licensed for

infant use If PRP-OMP (PedvaxHIB® or ComVax® [Merck]) is administered at age 2 and 4 months, a dose at age

6 months is not required DTaP/Hib combination products should not be used for primary vaccination in infants at age 2, 4, or 6 months but can be used as boosters following any Hib vaccine.

5 Measles, mumps, and rubella vaccine (MMR) The second dose of MMR is recommended routinely at age 4–

6 years but may be administered during any visit provided that at least 4 weeks have elapsed since the first dose and that both doses are administered beginning at or after age 12 months Those who have not received the second dose previously should complete the schedule by the visit at age 11–12 years.

6 Meningococcal (Groups A, C, Y and W-135) conjugate vaccine (MCV-4) In 2005, the Advisory

Committee on Immunization Practices (ACIP) recommended routine vaccination of young adolescents with

meningococcal (Groups A, C, Y and W-135) conjugate vaccine (MCV-4) at the preadolescent visit (11- and old) For those who have not previously received MCV-4, the ACIP recommends vaccination before high school entry (~ 15-years-old) as the most effective strategy toward reducing the incidence of meningococcal disease in adolescence and young adulthood College freshmen who live in dormitories are at higher risk for meningococcal disease compared with other people of the same age Because of the feasibility constraints in targeting freshmen in dormitories, colleges may elect to target their vaccination campaigns to all matriculating freshmen The risk for meningococcal disease among non-freshmen college students is similar to that for the general population of similar age (18–24 years) However, the vaccines are safe and immunogenic and therefore can be provided to non-

12-year-freshmen college students who want to reduce their risk for meningococcal disease The vaccine is highly effective but it does not protect people against meningococcal disease caused by "type B" bacteria The new meningococcal vaccine was licensed by the US Food and Drug Administration (FDA) in January 2005 for use in people aged 11–55 years It is manufactured by Sanofi Pasteur and is marketed as Menactra.

7 Varicella vaccine Varicella vaccine is recommended at any visit at or after age 12 months for susceptible

children (ie, those who lack a reliable history of chickenpox) Susceptible persons aged 13 years should receive two doses given at least 4 weeks apart.

8 Pneumococcal vaccine The heptavalent pneumococcal conjugate vaccine (PCV) is recommended for all

children aged 2–23 months and for certain children aged 24–59 months Pneumococcal polysaccharide vaccine

(PPV) is recommended in addition to PCV for certain high-risk groups See MMWR 2000;49(No RR-9):1–37.

9 Hepatitis A vaccine Hepatitis A vaccine is recommended for children and adolescents in selected states and

regions, and for certain high-risk groups Consult local public health authority Children and adolescents in these states, regions, and high-risk groups who have not been immunized against hepatitis A can begin the hepatitis A vaccination series during any visit The two doses in the series should be administered at least 6 months apart.

10 Influenza vaccine Influenza vaccine is recommended annually for children aged 6 months with certain risk

factors (including but not limited to asthma, cardiac disease, sickle cell disease, HIV, and diabetes, and household members of persons in groups at high risk, and can be administered to all others wishing to obtain immunity In addition, healthy children age 6–23 months are encouraged to receive influenza vaccine if feasible because children

in this age group are at substantially increased risk for influenza-related hospitalizations

Additional information about vaccines, including precautions and contraindications for vaccine and vaccine

shortages, is available at http://www.cdc.gov/nip or at the National Immunization hotline, 800-232-2522 (English)

or 800-232-0233 (Spanish) Copies of the schedule can be obtained at http://www.cdc.gov/nip/recs/child-schedule htm Approved by the Advisory Committee on Immunization Practices (http://www.cdc.gov/nip/acip), the American

Recommended Immunization of Adults

Several vaccines are recommended for adults depending on the individual's previous vaccination status and the risks of exposure to certain diseases Recommendations are summarized in Table 30–5.

Table 30–5 Recommended adult immunization schedule—United States, 2006.*

Covered by the Vaccine Injury Compensation Program.

Centers for Disease Control and Prevention Recommended adult immunization schedule—United States,

October 2005–September 2006 MMWR 2005;54:Q1–Q4.

1 Tetanus and diphtheria (Td)—Adults including pregnant women with uncertain histories of a complete

primary vaccination series should receive a primary series of Td A primary series for adults is 3 doses: the first two doses given at least 4 weeks apart and the third dose, 6–12 months after the second Administer one dose if the person had received the primary series and the last vaccination was 10 years ago or longer Consult

MMWR 1991;40 (RR-10):1-21 for administering Td as prophylaxis in wound management The ACP Task Force

on Adult Immunization supports a second option for Td use in adults: a single Td booster at age 50 years for persons who have completed the full pediatric series, including the teenage/young adult booster.

2 Influenza vaccination—Medical indications: chronic disorders of the cardiovascular or pulmonary

systems including asthma; chronic metabolic diseases including diabetes mellitus, renal

dysfunction, hemoglobinopathies, or immunosuppression (including immunosuppression caused by medications or

by human immunodeficiency virus [HIV]), requiring regular medical follow-up or hospitalization during the

preceding year; women who will be in the second or third trimester of pregnancy during the influenza

season Occupational indications: health-care workers Other indications: residents of nursing homes and other long-term care facilities; persons likely to transmit influenza to persons at high risk (in-home care givers to

persons with medical indications, household contacts and out-of-home caregivers of children birth to 23 months

of age, or children with asthma or other indicator conditions for influenza vaccination, household members and care givers of elderly and adults with high-risk conditions); and anyone who wishes to be vaccinated For

healthy persons aged 5–49 years without high risk conditions, either the inactivated vaccine or the

intranasally administered influenza vaccine (Flumist) may be given MMWR 2004;53 (RR-6) NOTE: Modifications

in influenza vaccine recommendations were made because of the vaccine shortage in 2004, and then

subsequently further modified in December 2004 This schedule reflects those changes (MMWR 2004;53:1183).

3 Pneumococcal polysaccharide vaccination—Medical indications: chronic disorders of the pulmonary

system (excluding asthma), cardiovascular diseases, diabetes mellitus, chronic liver diseases including liver

disease as a result of alcohol abuse (eg, cirrhosis), chronic renal failure or nephrotic syndrome, functional

or anatomic asplenia (eg, sickle cell disease or splenectomy), immunosuppressive conditions (eg,

congenital immunodeficiency, HIV infection, leukemia, lymphoma, multiple myeloma, Hodgkin's disease,

generalized malignancy, organ or bone marrow transplantation), chemotherapy with alkylating

agents, antimetabolites, or long-term systemic corticosteroids Geographic/other indications: Alaskan Natives and certain American Indian populations Other indications: residents of nursing homes and other long-term care facilities.

4 Revaccination with pneumococcal polysaccharide vaccine—One-time revaccination after 5 years for

persons with chronic renal failure or nephrotic syndrome, functional or anatomic asplenia (eg, sickle cell disease

or splenectomy), immunosuppressive conditions (eg, congenital immunodeficiency, HIV infection,

leukemia, lymphoma, multiple myeloma, Hodgkin's disease, generalized malignancy, organ or bone

marrow transplantation), chemotherapy with alkylating agents, antimetabolites, or long-term

systemic corticosteroids For persons 65 and older, one-time revaccination if they were vaccinated 5 or more years previously and were aged less than 65 years at the time of primary vaccination.

5 Hepatitis B vaccination—Medical indications: hemodialysis patients, patients who receive

clotting-factor concentrates Occupational indications: health-care workers and public-safety workers who have exposure

to blood in the workplace, persons in training in schools of medicine, dentistry, nursing, laboratory technology, and other allied health professions Behavioral indications: injection drug users, persons with more than one sex partner in the previous 6 months, persons with recently acquired sexually transmitted disease (STD), all clients

in STD clinics, men who have had sex with men Other indications: household contacts and sex partners of

persons with chronic hepatitis B virus (HBV) infection, clients and staff of institutions for the

developmentally disabled, international travelers who will be in countries with high or intermediate prevalence

of chronic HBV infection for more than 6 months, inmates of correctional facilities.

6 Hepatitis A vaccination—For the combined HepA-HepB vaccine use three doses at 0, 1, 6 months

Medical indications: persons with clotting-factor disorders or chronic liver disease Behavorial indications: men who have sex with men, users of injection and noninjection illegal drugs Occupational indications: persons

working with HAV-infected primates or with HAV in a research laboratory setting Other indications: persons traveling to or working in countries that have high or intermediate endemicity of hepatitis A.

7 Measles, Mumps, Rubella vaccination (MMR)—Measles component: Adults born before 1957 may

be considered immune to measles Adults born in or after 1957 should receive at least one dose of MMR unless they have a medical contraindication, documentation of at least one dose, or other acceptable evidence of

immunity A second dose of MMR is recommended for adults who:

Are recently exposed to measles or in an outbreak setting

Were previously vaccinated with killed measles vaccine

Were vaccinated with an unknown vaccine between 1963 and 1967

Are students in post-secondary educational institutions

Work in health care facilities

Plan to travel internationally

Mumps component: one dose of MMR should be adequate for protection Rubella component: Give one dose of MMR to women whose rubella vaccination history is unreliable and counsel women to avoid becoming pregnant for

4 weeks after vaccination For women of childbearing age, regardless of birth year, routinely determine

rubella immunity and counsel women regarding congenital rubella syndrome Do not vaccinate pregnant women

or those planning to become pregnant in the next 4 weeks If pregnant and susceptible, vaccinate as early

in postpartum period as possible MMWR 1998;47 (RR-8):1–57; MMWR 2001;50:1117.

8 Varicella vaccination—Recommended for all persons who did not have reliable clinical history of

varicella infection, or serologic evidence of varicella zoster virus (VZV) infection who may be at high risk for exposure or transmission This includes health-care workers and family contacts of immunocompromised

persons, those who live or work in environments where transmission is likely (eg, teachers of young children, day care employees, and residents and staff members in institutional settings), persons who live or work

in environments were VZV transmission can occur (eg, college students, inmates and staff members of

correctional institutions, and military personnel), adolescents and adults living in households with children,

women who are not pregnant but who may become pregnant in the future, international travelers who are

not immune to infection Note: Greater than 95% of U.S born adults are immune to VZV Do not vaccinate

pregnant women or those planning to become pregnant in the next 4 weeks If pregnant and susceptible,

vaccinate as early in postpartum period as possible MMWR 1996;45 (RR-11):1–36; MMWR 1999;44 (RR-6):1–5.

9 Meningococcal vaccine (quadrivalent polysaccharide for serogroups A,C,Y and W-135)—

Consider vaccination for persons with medical indications: adults with terminal complement component

deficiencies, with anatomic or functional asplenia Other indications: travelers to countries in which disease

is hyperendemic or epidemic ("meningitis belt" of sub-Saharan Africa, Mecca, Saudi Arabia for Hajj) Revaccination

at 3–5 years may be indicated for persons at high risk for infection (eg, persons residing in areas in which disease

is epidemic) In 2005, the Advisory Committee on Immunization Practices (ACIP) recommended routine

vaccination of young adolescents with meningococcal (Groups A, C, Y and W-135) conjugate vaccine (MCV-4) at the preadolescent visit (11- and 12-year-old) For those who have not previously received MCV-4, the

ACIP recommends vaccination before high school entry (~ 15-years-old) as the most effective strategy

toward reducing the incidence of meningococcal disease in adolescence and young adulthood College freshmen