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Common Problems in Infectious Diseases & Antimicrobial Therapy Peter V. Chin-Hong, MD B. Joseph Guglielmo, PharmD
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Common Problems in Infectious Diseases FEVER OF UNKNOWN ORIGIN (FUO)
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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. ``
with at least 2 days for cultures to incubate (see Chapter 31). 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 Chapter 2.
A. 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 disease or familial Mediterranean fever.
B. Age of Patient
``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) Hospital-associated 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 Health care-associated Infections below). (2) Neutropenic FUO includes patients with fever of 38.3°C or higher on several occasions with < 500 neutrophils per microliter in whom initial cultures are negative and the diagnosis remains uncertain after 3 days (see Chapter 2 and Infections in the Immunocompromised Patient, below). (3) HIVassociated 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
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, granulomatosis with polyangiitis (formerly Wegener granulomatosis), and polyarteritis nodosa are more common in adults. Still 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 granulomatosis with polyangiitis (formerly Wegener granulomatosis) account for 25–30% of all FUOs.
C. 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 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
Problems in Infectious Diseases & Antimicrobial Therapy 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 disease, familial Mediterranean fever, allergic alveolitis) account for another 25%. Approximately 50% of cases remain undiagnosed but have a benign course with eventual resolution of symptoms.
D. 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 P carinii) pneumonia, and mycobacterial infections.
E. Classification of Causes of FUO Most patients with FUO will fit into one of five categories. 1. 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 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 abscesses may be difficult to detect. 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. 2. Neoplasms—Many cancers can present as FUO. The most common are lymphoma (both Hodgkin and nonHodgkin) and leukemia. Posttransplant lymphoproliferative disorders may also present with fever. Other diseases of lymph nodes, such as angioimmunoblastic lymphoma and Castleman 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. 3. Autoimmune disorders—Still disease, systemic lupus erythematosus, cryoglobulinemia, and polyarteritis nodosa are the most common causes of autoimmune-associated FUO. Giant cell arteritis and polymyalgia rheumatica are seen almost exclusively in patients over 50 years of age and
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are nearly always associated with an elevated erythrocyte sedimentation rate (> 40 mm/h). 4. Miscellaneous causes—Many other conditions have been associated with FUO but less commonly than the foregoing types of illness. Examples include thyroiditis, sarcoidosis, Whipple disease, familial Mediterranean fever, recurrent pulmonary emboli, alcoholic hepatitis, drug fever, and factitious fever. 5. Undiagnosed FUO—Despite extensive evaluation, the diagnosis remains elusive in 15% or more of patients. Of these patients, the fever abates spontaneously in about 75% with no diagnosis; in the remainder, more classic manifestations of the underlying disease appear over time.
``Clinical Findings Because the evaluation of a patient with FUO is costly and time-consuming, it is imperative to first document the presence of fever. This is done by observing the patient while the temperature is being taken to ascertain that 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.
A. 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 possible pathogens. “Screening tests” with immunologic or microbiologic serologies (“febrile agglutinins”) are of low yield and should not be done. If the history or physical examination suggests a specific diagnosis, specific serologic tests with an associated fourfold rise or fall in titer may be useful. 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).
B. Imaging All patients with FUO should have a chest radiograph. Studies such as sinus films, upper gastrointestinal series with small bowel follow-through, barium enema, proctosigmoidoscopy, and evaluation of gallbladder function are reserved for patients who have symptoms, signs, or a history that suggest disease in these body regions. CT scan of the abdomen and pelvis is also frequently performed and is particularly useful for looking at the liver, spleen, and retroperitoneum. When the CT scan is abnormal, the findings often lead to a specific diagnosis. A normal CT scan is not
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quite as useful; more invasive procedures such as biopsy or exploratory laparotomy may be needed. The role of MRI in the investigation of FUO has not been evaluated. In general, however, MRI is better than CT for detecting lesions of the nervous system and is useful in diagnosing various vasculitides. Ultrasound is sensitive for detecting lesions of the kidney, pancreas, and biliary tree. Echocardiography should be used if one is considering endocarditis 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. Some experts use positron emission tomography (PET) in conjunction with CT scans early in the investigation of FUO. However, more studies are needed before this practice can be more fully integrated into clinical practice. Theoretically, a gallium or PET scan would be more helpful than an indium-labeled white blood cell scan because gallium and fluorodeoxyglucose may be useful for detecting infection, inflammation, and neoplasm whereas the indium scan is useful only for detecting infection. Indiumlabeled 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.
C. Biopsy Invasive procedures are often required for diagnosis. Any abnormal finding should be aggressively evaluated: Headache calls for lumbar puncture to rule out meningitis; skin rash should be biopsied for cutaneous manifestations of collagen vascular disease or infection; and enlarged lymph nodes should be aspirated or biopsied for neoplasm and sent for culture. Bone marrow aspiration with biopsy is a relatively low-yield procedure (15–25%; except in HIVpositive 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, particularly in persons with hematologic abnormalities. 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. CT scanning and MRI have decreased the need for exploratory laparotomy; however, surgical visualization and biopsies should be considered when there is continued deterioration or lack of diagnosis.
``Treatment An empiric course of antimicrobials for possible cystitis (eg, ciprofloxacin, 500 mg orally twice daily for 3 days) should be considered if an infectious diagnosis is strongly suspected. However, if there is no clinical response, it is
imperative to stop therapy and reevaluate. Once definitive culture results return, streamlining therapy to the most narrow-spectrum antimicrobial should take place. Empiric administration of corticosteroids should be discouraged because they can suppress fever and exacerbate many infections.
``When to Refer • Any patient with FUO and progressive weight loss and other constitutional signs. • Any immunocompromised patient (eg, transplant recipients and HIV-infected patients). • Infectious diseases specialists may also be able to coordinate and interpret specialized testing (eg, Q fever serologies) with outside agencies, such as the US Centers for Disease Control and Prevention.
``When to Admit • Any patient who is rapidly declining with weight loss where hospital admission may expedite work-up. • If FUO is present in immunocompromised patients, such as those who are neutropenic from recent chemotherapy or those who have undergone transplantation (particularly in the previous 6 months). Ben-Baruch S et al. Predictive parameters for a diagnostic bone marrow biopsy specimen in the work-up of Fever of unknown origin. Mayo Clin Proc. 2012 Feb;87(2):136–42. [PMID: 22226833] Cunha BA. Fever of unknown origin: clinical overview of classic and current concepts. Infect Dis Clin North Am. 2007;21 (4):867–915. [PMID: 18061081] Hot A et al. Yield of bone marrow examination in diagnosing the source of fever of unknown origin. Arch Intern Med. 2009 Nov 23;169(21):2018–23. [PMID: 19933965] Pedersen TI et al. Fever of unknown origin: a retrospective study of 52 cases with evaluation of the diagnostic utility of FDGPET/CT. Scand J Infect Dis. 2012 Jan;44(1):18–23. [PMID: 21888563]
INFECTIONS IN THE IMMUNOCOMPROMISED PATIENT
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Fever and other symptoms may be blunted because of immunosuppression. `` 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. ``
Problems in Infectious Diseases & Antimicrobial Therapy
``General Considerations Immunocompromised patients have defects in their natural defense mechanisms resulting in an increased risk for infection. In addition, infection is often severe, rapidly progressive, and life threatening. Organisms that are not usually problematic in the immunocompetent person may be important pathogens 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.
A. 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.
B. Granulocytopenia (Neutropenia) Granulocytopenia is common following hematopoietic cell transplantation (“stem cell 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 with a rapid rate of decline of neutrophils and 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 the mucormycoses.
C. Impaired Cellular Immunity Patients with cellular immune deficiency encompass a large and heterogeneous group, including patients with HIV infection (see Chapter 31); patients with lymphoreticular malignancies, such as Hodgkin 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 solid organ transplantation, many patients receiving therapy for solid tumors, and patients receiving prolonged high-dose corticosteroid treatment (eg, for asthma, temporal arteritis, systemic lupus). Patients taking
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tumor necrosis factor (TNF) inhibitors, such as etanercept and infliximab, are also included in this category. 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. Patients taking TNF inhibitors have specific defects that increase risk of bacterial, mycobacterial (particularly tuberculosis), and fungal infections (primary and reactivation).
D. 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), patients will become severely neutropenic for 7–21 days. 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 fungal infections. In contrast to solid organ transplant recipients, the source of fever is unknown 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 is possible, particularly in patients who receive additional immunosuppression for treatment of graft-versus-host disease. 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 graft-versus-host disease. Varicella-zoster is common, and Aspergillus and CMV infections are increasingly seen in this period as well.
E. 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 kidney 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. In rare instances, donor derived infections (eg, West Nile virus, tuberculosis) may present during this time period. Infections that occur between the first and sixth months are often related to immunosuppression. During this period, reactivation of viruses, such as herpes simplex, varicella-zoster, and CMV is quite common. Opportunistic infections with fungi
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(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 would be expected in any population occur. Patients with poorly functioning allografts receiving long-term immunosuppression therapy continue to be at risk for opportunistic infections.
F. Other Immunocompromised States A large group of patients who are not specifically immunodeficient are at increased risk for infection due to debilitating injury (eg, burns or severe trauma), invasive procedures (eg, chronic central intravenous catheters, 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, resulting in mucormycosis, emphysematous pyelonephritis, and foot infections.
``Clinical Findings A. Laboratory Findings Routine evaluation includes complete blood count with differential, chest radiograph, and blood cultures; urine and respiratory 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 (serum CMV antigen test or polymerase chain reaction), abscesses (which usually occur near previous operative sites), candidiasis involving the liver or spleen, or aspergillosis. Serologic evaluation may be helpful if toxoplasmosis or an endemic fungal infection (coccidioidomycosis, histoplasmosis) is a possible cause. Antigen based assays may be useful for the diagnosis of aspergillosis (detected by galactomannan level in serum or bronchoalveolar lavage fluid), or other invasive fungal disease, including Pneumocystis infection (serum (1→-β-d-glucan level).
B. 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, open lung biopsy). 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 lympho proliferative 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 hospital-associated infections, especially in the compromised patient. Invasive devices such as central and peripheral lines and Foley catheters are potential sources of infection. Some centers use laminar airflow isolation or high-efficiency particulate air (HEPA) filtering in hematopoietic cell transplant patients. Rates of infection and episodes of febrile neutropenia, but not mortality, are decreased if colonystimulating factors are used during chemotherapy or during stem-cell transplantation.
A. Pneumocystis & Herpes Simplex Infections Trimethoprim-sulfamethoxazole (TMP-SMZ), one double-strength tablet orally three times a week, one doublestrength 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. In patients allergic to TMP-SMZ, dapsone, 50 mg orally daily or 100 mg three times weekly, is recommended. 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).
B. CMV No uniformly accepted approach has been adopted for prevention of CMV. 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 oral valganciclovir, 900 mg daily for 3–6 months (longer in lung transplant recipients). Other solid organ transplant recipients (seropositive recipients) are at lower risk for developing CMV disease but still usually receive oral valganciclovir for 3 months. The lowest risk group for the development of CMV disease is in seronegative patients who receive organs from seronegative donors. Typically, no CMV prophylaxis is used in this group. Ganciclovir and valganciclovir also prevent herpes virus reactivation. Because immunosuppression is increased during periods of rejection, patients treated for rejection usually receive CMV prophylaxis 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 (usually CMV reactivation), and thus usually receive more aggressive prophylaxis. Two approaches have been used: universal prophylaxis or preemptive therapy.
Problems in Infectious Diseases & Antimicrobial Therapy In the former, all high-risk patients (seropositive patients who receive allogeneic transplants) may receive oral valganciclovir, 900 mg daily to day 100. This method is costly and associated with significant bone marrow toxicity. Alternatively, patients can be monitored without specific prophylaxis and have blood sampled weekly for the presence of CMV. If CMV is detected by an antigenemia assay or by polymerase chain reaction, preemptive therapy is instituted with oral valganciclovir, 900 mg twice daily for a minimum of 2–3 weeks followed by oral valganciclovir at 900 mg daily until day 100. This preemptive approach is effective but does miss a small number of patients in whom CMV disease would have been prevented had prophylaxis been used. Other preventive strategies include use of CMVnegative or leukocyte-depleted blood products for CMVseronegative recipients.
C. Other Organisms Routine decontamination of the gastrointestinal tract to prevent bacteremia in the neutropenic patient is 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 risk. 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. Lipid-based preparations of amphotericin B, aerosolized amphotericin B, intravenous and oral fluconazole or voriconazole, and oral posaconazole solution are all prophylactic options in the neutropenic patient. Because voriconazole is superior to amphotericin for documented Aspergillus infections and because posaconazole prophylaxis (compared with fluconazole) has been shown to result in fewer cases of invasive aspergillosis among allogeneic stem cell transplant recipients with graft-versus-host disease, 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) or oral posaconazole (200 mg solution three times daily) for those at high risk (allogeneic transplants, graft-versus-host disease) 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 fluconazole-resistant Candida and molds (Fusarium, Aspergillus, Mucor) has raised concerns about its routine use as a prophylactic agent. Given the high risk of reactivation of tuberculosis in patients taking TNF inhibitors, all patients should be
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screened for latent tuberculosis infection (LTBI) with a tuberculin skin test or an interferon-gamma release assay prior to the start of therapy. If LTBI is diagnosed, treatment with the TNF inhibitors should be delayed until treatment for LTBI is completed. There is also a marked risk of reactivation of hepatitis B and hepatitis C in patients taking TNF inhibitors; patients should also be screened for these viruses when TNF inhibitor treatment is being considered.
``Treatment A. General Measures Because infections in the immunocompromised patient can be rapidly progressive and life-threatening, diagnostic procedures must be performed promptly, and empiric therapy is usually instituted. While reduction or discontinuation of immunosuppressive medication may jeopardize the viability of the transplanted organ, this measure may be necessary if the infection is life-threatening. 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 reduction in infection.
B. Specific Measures Antimicrobial drug therapy ultimately should be tailored to culture results. While combinations of antimicrobials may be used to provide synergy or to prevent resistance, the primary reason for empiric combination therapy is 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 degree of immune compromise and the site of infection. For example, in the febrile neutropenic patient, an algorithmic approach to therapy is often used. Febrile neutropenic patients should be empirically treated with broad-spectrum agents active against gram-positive organisms, Pseudomonas aeruginosa, and other gram-negative bacilli (such as cefepime 2 g every 8 hours intravenously). The addition of vancomycin, 10–15 mg/kg/dose intravenously every 12 hours, should be considered in those patients with suspected infection due to methicillin-resistant Staphylococcus aureus (MRSA), S epidermidis, and enterococcus. Continued neutropenic fever necessitates broadening of antibacterial coverage from cefepime to agents such as imipenem 500 mg every 6 hours or meropenem 1 g every 8 hours intravenously with or without tobramycin 5 mg/kg intravenously every 24 hours. Antifungal agents (such as voriconazole, 200 mg intravenously or orally every 12 hours, or caspofungin, 50 mg daily intravenously) should be added if fevers continue after 5–7 days of broad-spectrum antibacterial therapy. Regardless of whether the patient becomes afebrile, therapy is continued until resolution of neutropenia. Failure to continue antibiotics through the period of neutropenia has been associated with increased morbidity and mortality.
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Patients with fever and low-risk neutropenia (neutropenia expected to persist for < 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 amoxicillinclavulanic acid, 500 mg every 8 hours. Antibiotics are continued as long as the patient is neutropenic even if a source is not identified. 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 (or fluoroquinolone) and TMP-SMZ, 15 mg/kg/d orally or intravenously (based on trimethoprim component) would be reasonable in those patients not receiving TMP-SMZ prophylaxis. 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 definite diagnosis, therapy can be specific, thereby reducing selection pressure for resistance and superinfection.
``When to Refer • Any immunocompromised patient with an opportunistic infection. • Patients with potential drug toxicities and drug interactions related to antimicrobials where alternative agents are sought. • Patients with LTBI in whom therapy with TNF inhibitors is planned.
``When to Admit Immunocompromised patients who are febrile, or those without fevers in whom an infection is suspected, particularly in the following groups: solid-organ or hematopoietic stem cell transplant recipient (particularly in the first 6 months), neutropenic patients, patients receiving TNF inhibitors, transplant recipients who have had recent rejection episodes (including graft-versus-host disease). Fishman JA. Infection in solid-organ transplant recipients. N Engl J Med. 2007;357(25):2601–14. [PMID: 18094380] Freifeld AG et al. Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis. 2011 Feb 15;52(4):e56–93. [PMID: 21258094] Grijalva CG et al. Initiation of tumor necrosis factor-alpha antagonists and the risk of hospitalization for infection in patients with autoimmune diseases. JAMA. 2011 Dec 7; 306(21):2331–9. [PMID: 22056398] Morris MI et al. Infections transmitted by transplantation. Infect Dis Clin North Am. 2010 Jun;24(2):497–514. [PMID: 20466280] Neofytos D et al. Epidemiology and outcome of invasive fungal infection in adult hematopoietic stem cell transplant recipients: analysis of Multicenter Prospective Antifungal Therapy (PATH) Alliance registry. Clin Infect Dis. 2009 Feb 1; 48(3):265–73. [PMID: 19115967] Palmer SM et al. Extended valganciclovir prophylaxis to prevent cytomegalovirus after lung transplantation: a randomized, controlled trial. Ann Intern Med. 2010 Jun 15;152(12):761–9. [PMID: 20547904]
Sax PE et al; AIDS Clinical Trials Group Study A5164 Team. Blood (1→3)-beta-D-glucan as a diagnostic test for HIVrelated Pneumocystis jirovecii pneumonia. Clin Infect Dis. 2011 Jul 15;53(2):197–202. [PMID: 21690628] Walsh TJ et al. Treatment of aspergillosis: clinical practice guidelines of the Infectious Diseases Society of America. Clin Infect Dis. 2008 Feb 1;46(3):327–60. [PMID: 18177225] Winthrop KL et al. Mycobacterial and other serious infections in patients receiving anti-tumor necrosis factor and other newly approved biologic therapies: case finding through the Emerging Infections Network. Clin Infect Dis. 2008 Jun 1;46(11): 1738–40. [PMID: 18419421]
HEALTH CARE–ASSOCIATED INFECTIONS
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Health care–associated infections are acquired during the course of receiving health care treatment for other conditions. `` Hospital-associated infections are a subset of health care–associated infections defined as those not present or incubating at the time of hospital admission and developing 48 hours or more after admission. `` Most health care–associated infections are preventable. `` Hand washing is the most effective means of preventing health care–associated infections and should be done routinely even when gloves are worn. ``
``General Considerations In the United States, approximately 5% of patients acquire a health care–associated infection, resulting in prolongation of the hospital stay, increase in cost of care, significant morbidity, and a 5% mortality rate. The most common infections are urinary tract infections, usually associated with Foley catheters or urologic procedures; bloodstream infections, most commonly from indwelling catheters but also from secondary sites, such as surgical wounds, abscesses, pneumonia, the genitourinary tract, and the gastrointestinal tract; pneumonia in intubated patients or those with altered levels of consciousness; surgical wound infections; MRSA infections; and Clostridium difficile colitis. Some general principles are helpful in preventing, diagnosing, and treating health care–associated 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 health care–associated infections develop are often critically ill, have been hospitalized for extended periods, and have received several courses
Problems in Infectious Diseases & Antimicrobial Therapy of broad-spectrum antibiotic therapy. As a result, health care–associated infections are often due to multidrug resistant pathogens and are different from those encountered in community-acquired infections. For example, S aureus and S epidermidis (a frequent cause of prosthetic device infection) are often 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 resistant to most antibacterials. When choosing antibiotics to treat the seriously ill patient with a health care–associated infection, antimicrobial history and the “local ecology” must be considered. In the most seriously ill patients, broadspectrum coverage with vancomycin and a carbapenem with or without an aminoglycoside is recommended. Once a pathogen is isolated and susceptibilities are known, the most narrow spectrum, least toxic, most cost-effective drug should be used. Widespread use of antimicrobial drugs contributes to the selection of drug-resistant organisms, thus every effort should be made to limit the spectrum of coverage and unnecessary duration. 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 radiograph, 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 A. 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. 1. 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 Chapter 9), 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,
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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. 2. 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. A. 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 and is characterized by extreme hyperthermia, muscle rigidity, rhabdomyolysis, electrolyte abnormalities, and hypotension. Aggressive cooling and dantrolene are the mainstays of therapy. Aspiration of acidic gastric contents during surgery can cause a chemical pneumonitis (Mendelson syndrome) that rapidly develops but is transient and does not require antibiotics. 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. B. Acute fever (within 1 week of surgery)—Acute fever is usually due to common causes of hospital-associated 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. Atelectasis following surgery is commonly invoked as a cause of postoperative fever but there is no good evidence to support a causal association between the presence or degree of atelectasis and fever. C. 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 predicts 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.
B. Laboratory Findings Blood cultures are universally recommended, and chest radiographs are frequently obtained. A properly prepared sputum Gram stain and semi-quantitative sputum cultures may be useful in selected patients where there is a high pretest probability of pneumonia but multiple exclusion criteria probably limit generalizability in most patients, such as immunocompromised patients and those with drug resistance. Other diagnostic strategies will be dictated by the clinical context (eg, transesophageal echocardiogram in a patient with S aureus bacteremia).
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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, resulting in the inappropriate use of vancomycin. Unless two separate venipuncture cultures are obtained— not through catheters—interpretation of results is impossible and unnecessary therapy may be given. Every such “pseudobacteremia” increases laboratory costs, antibiotic use, and length of stay. Microbiologic evaluation of the removed catheter can sometimes be helpful, but only in addition to (not instead of) blood cultures drawn from peripheral sites. 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 fever 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, and 4–6 weeks of antibiotics may be needed. In the case of septic thrombophlebitis, anticoagulation with heparin is also recommended if there are no contraindications.
``Differential Diagnosis Although most fevers are due to infections, about 25% of patients will have fever of noninfectious origin, including drug fever, nonspecific postoperative fevers (tissue damage or necrosis), hematoma, pancreatitis, pulmonary embolism, myocardial infarction, and ischemic bowel disease.
``Prevention The concept of universal precautions emphasizes that all patients are treated as though they have a potential bloodborne transmissible disease, and thus all body secretions are handled with care to prevent spread of disease. Body substance isolation requires use of gloves whenever a health care worker anticipates contact with blood or other body secretions. Even though gloves are worn, health care workers should routinely wash their hands, since it is the easiest and most effective means of preventing hospitalassociated infections. Application of a rapid drying, alcohol-based antiseptic is simple, takes less time than traditional hand washing with soap and water, is more effective at reducing hand colonization, and promotes compliance with hand decontamination. Peripheral intravenous lines should be replaced every 3 days. Arterial lines and 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. Using sterile barrier precautions (including cap, mask, gown, gloves, and drape) is recommended while inserting central venous catheters. 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. Silver-coated endotracheal tubes may reduce the incidence of ventilator-associated pneumonia. Whether the increased cost of these devices justifies their routine use should be determined by individual institutions. Catheter-related urinary tract infections and intravenous catheter-associated infections are not Medicare-reimbursable conditions. Preoperative skin preparation with chlorhexidine and alcohol (versus povidone-iodine) has been shown to reduce the incidence of infection following surgery. Another strategy that can prevent surgical-site infections is the identification and treatment of S aureus nasal carriers with 2% mupirocin nasal ointment and chlorhexidine soap. Daily bathing of ICU patients with chlorhexidine-impregnated washcloths versus soap and water may result in lower risk of catheterassociated bloodstream infections. Selective decontamination of the digestive tract with nonabsorbable or parenteral antibiotics, or both, may prevent hospital-acquired pneumonia and decrease mortality. Attentive nursing care (positioning to prevent decubitus ulcers, wound care, elevating the head during tube feedings to prevent aspiration) is critical in preventing hospital-associated infections. In addition, monitoring of high-risk areas by hospital epidemiologists is critical in the prevention of infection. Some guidelines advocate rapid screening for MRSA on admission to acute care facilities among certain subpopulations of patients (eg, those recently hospitalized, admission to the intensive care unit, patients undergoing hemodialysis). However, it is not clear whether this strategy decreases the incidence of hospitalassociated MRSA infections. Vaccines, including hepatitis A, hepatitis B, and the varicella, pneumococcal, and influenza vaccinations, are important adjuncts. (See section below on Immunization against Infectious Diseases.)
``Treatment A. 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 (see Table 30–5) are recommended for neutropenic and other immuno compromised patients and in patients who are clinically unstable.
B. Catheter-Associated Infections Factors that inform treatment decisions include the type of catheter, the causative pathogen, the availability of alternate catheter access sites, the need for ongoing intravascular access, and the severity of disease.
Problems in Infectious Diseases & Antimicrobial Therapy In general, catheters should be removed if there is purulence at the exit site; if the organism is S aureus, gramnegative rods, or Candida species; if there is persistent bacteremia (> 48 hours while receiving antibiotics); or if complications, such as septic thrombophlebitis, endocarditis, or other metastatic disease exist. Central venous catheters may be exchanged over a guidewire provided there is no erythema or purulence at the exit site and the patient does not appear to be septic. Methicillin-resistant, coagulase-negative staphylococci are the most common pathogens; thus, empiric therapy with vancomycin, 15 mg/kg intravenously twice daily, should be given assuming normal kidney function. Empiric gram-negative coverage may be considered in patients who are immunocompromised or who are critically ill (see Table 30–5). Antibiotic treatment duration depends on the pathogen and the extent of disease. For uncomplicated bacteremia, 5–7 days of therapy is usually sufficient for coagulasenegative staphylococci, even if the original catheter is retained. Fourteen days of therapy is generally recommended for uncomplicated bacteremia caused by gramnegative rods, Candida species, and S aureus. Antibiotic lock therapy involves the instillation of supratherapeutic concentrations of antibiotics with heparin in the lumen of catheters. The purpose is to achieve adequate concentrations of antibiotics to kill microbes in the biofilm. Antibiotic lock therapy can be used for catheter-related bloodstream infections caused by coagulase-negative staphylococci or enterococci and when the catheter is being retained in a salvage situation.
``When to Refer • • • •
Any patient with multidrug-resistant infection. Any patient with fungemia or persistent bacteremia. Patients with multisite infections. Patients with impaired or fluctuating kidney function for assistance with dosing of antimicrobials. • Patients with refractory or recurrent C difficile colitis. Bode LG et al. Preventing surgical-site infections in nasal carriers of Staphylococcus aureus. N Engl J Med. 2010 Jan 7;362(1):9–17. [PMID: 20054045] Climo MW et al. The effect of daily bathing with chlorhexidine on the acquisition of methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus, and healthcareassociated bloodstream infections: results of a quasiexperimental multicenter trial. Crit Care Med. 2009 Jun;37(6): 1858–65. [PMID: 19384220] Darouiche RO et al. Chlorhexidine-alcohol versus povidoneiodine for surgical-site antisepsis. N Engl J Med. 2010 Jan 7;362(1):18–26. [PMID: 20054046] Harbarth S et al. Universal screening for methicillin-resistant Staphylococcus aureus at hospital admission and nosocomial infection in surgical patients. JAMA. 2008 Mar 12;299(10): 1149–57. [PMID: 18334690] Kollef MH et al. Silver-coated endotracheal tubes and incidence of ventilator-associated pneumonia: the NASCENT randomized trial. JAMA. 2008 Aug 20;300(7):805–13. [PMID: 18714060] Louie TJ et al. Fidaxomicin versus vancomycin for Clostridium difficile infection. N Engl J Med. 2011 Feb 3;364(5):422–31. [PMID: 21288078]
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Mermel LA et al. Clinical practice guidelines for the diagnosis and management of intravascular catheter-related infection: 2009 update by the Infectious Diseases Society of America. Clin Infect Dis. 2009 Jul 1;49(1):1–45. [PMID: 19489710] Peleg AY et al. Hospital-acquired infections due to gramnegative bacteria. N Engl J Med. 2010 May 13;362(19):1804–13. [PMID: 20463340] Yokoe DS et al. A compendium of strategies to prevent healthcare-associated infections in acute care hospitals. Infect Control Hosp Epidemiol. 2008 Oct;29(Suppl 1):S12–21. [PMID: 18840084]
INFECTIONS OF THE CENTRAL NERVOUS SYSTEM
``
E s s e n t i a l s o f di a g n o s i s
Central nervous system infection is a medical emergency. `` Symptoms and signs common to all central nervous system infections 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.
``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).
A. 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%) of the cerebrospinal fluid.
B. 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).
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Table 30–1. Typical cerebrospinal fluid findings in various central nervous system diseases. Diagnosis
Cells/mcL
Normal
Glucose (mg/dL)
Opening Pressure 70–180 mm H2O
Low (< 45)
High (> 50)
Markedly elevated
100–1000, mostly lymphocytes3
Low (< 45)
High (> 50)
Moderately elevated
100–1000, mostly lymphocytes3
Normal
Moderately high (> 50)
Normal to slightly elevated
Normal or low
High (> 50)
Slightly elevated
Normal
Normal or high
Variable
45–85
200–20,000 polymorphonuclear neutrophils
Granulomatous meningitis (mycobacterial, fungal)3 Spirochetal meningitis
Purulent meningitis (bacterial) community-acquired
Protein (mg/dL) 15–45
0–5 lymphocytes 2
1
Aseptic meningitis, viral or meningoencephalitis4
25–2000, mostly lymphocytes
“Neighborhood reaction”5
Variably increased
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.
C. Aseptic Meningitis
D. Encephalitis
Aseptic meningitis—a much more benign and self-limited syndrome than purulent meningitis—is caused principally by viruses, especially herpes simplex 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. Prior to the routine administration of measles-mumps-rubella (MMR) vaccines, mumps was the most common cause of viral meningitis. Drug-induced aseptic meningitis has been reported with nonsteroidal anti-inflammatory drugs, sulfonamides and certain solid organ transplant agents, including muromonab-CD3 (OKT3).
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. Influenza has been associated with encephalitis, but the relationship is not clear.
E. 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% of the cerebrospinal fluid but will have little effect on cell count, protein, or glucose.
Table 30–2. Initial antimicrobial therapy for purulent meningitis of unknown cause. Population
1
Common Microorganisms
Standard Therapy
18–50 years
Streptococcus pneumoniae, Neisseria meningitidis
Vancomycin1 plus cefotaxime or ceftriaxone2
Over 50 years
S pneumoniae, N meningitidis, Listeria monocytogenes, gram-negative bacilli
Vancomycin1 plus ampicillin,3 plus cefotaxime or ceftriaxone2
Impaired cellular immunity
L monocytogenes, gram-negative bacilli, S pneumoniae
Vancomycin1 plus ampicillin3 plus cefepime4
Postsurgical or posttraumatic
Staphylococcus aureus, S pneumoniae, gram-negative bacilli
Vancomycin1 plus cefepime4
The dose of vancomycin is 10–15 mg/kg/dose intravenously every 6 hours. The usual dose of cefotaxime is 2 g intravenously every 6 hours and that of ceftriaxone is 2 g intravenously every 12 hours. If the organism is sensitive to penicillin, 3–4 million units intravenously every 4 hours is given. 3 The dose of ampicillin is usually 2 g intravenously every 4 hours. 4 Cefepime is given in a dose of 50–100 mg/kg intravenously every 8 hours. 2
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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.
to chronic, but unlike Acanthamoeba both immunocompromised and immunocompetent persons can be affected.
F. Neighborhood Reaction
This infection may arise as a result of invasive neurosurgical procedures (eg, craniotomy, internal or external ventricular catheters, external lumbar catheters), complicated head trauma, or from hospital-acquired bloodstream infections. In general, the microbiology is distinct from community-acquired meningitis, with gram-negative organisms (eg, Pseudomonas), S aureus, and coagulasenegative staphylococci playing a larger role.
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.
G. Noninfectious Meningeal Irritation Carcinomatous meningitis, sarcoidosis, systemic lupus erythematosus, chemical meningitis, and certain drugs— nonsteroidal anti-inflammatory drugs, 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.
H. 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).
I. Amebic Meningoencephalitis These infections are caused by free-living amebas and present as two distinct syndromes. The diagnosis is confirmed by culture (Acanthamoeba species 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
J. Health Care–Associated Meningitis
``Clinical Findings A. Symptoms and Signs 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.
B. Laboratory Tests Evaluation of a patient with suspected meningitis includes a 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 varicellazoster, 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.
C. 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 spaceoccupying 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
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antibiotics and corticosteroids administered even before cerebrospinal fluid is obtained for culture to avoid delay in treatment (Table 30–1). Antibiotics given within 4 hours before obtaining cerebrospinal fluid probably do not affect culture results.
``Treatment Although it is difficult to prove with existing clinical data that early antibiotic therapy improves outcome in bacterial meningitis, prompt therapy is still recommended. In purulent meningitis, the identity of the causative micro organism 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. Patients most likely to benefit from corticosteroids are those infected with gram-positive organisms (Streptococcus pneumoniae or S suis), and those who are HIV negative. It is unknown whether patients with meningitis due to N meningitidis and other bacterial pathogens benefit from the use of adjunctive corticosteroids. 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. Therapy of brain abscess consists of drainage (excision or aspiration) in addition to 3–4 weeks of systemic antibiotics directed against organisms isolated. An empiric regimen often includes metronidazole, 500 mg intravenously or orally every 8 hours, plus ceftriaxone, 2 g intravenously every 12 hours, with or without vancomycin, 10–15 mg/kg/ dose intravenously every 12 hours. In cases where abscesses are < 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. In addition to antibiotics, in cases of health care– associated meningitis associated with an external ventricular catheter, the probability of cure is increased if the catheter is removed. In infections associated with internal ventricular catheters, removal of the internal components and insertion of an external drain is recommended. Therapy of other types of meningitis is discussed elsewhere in this book (fungal meningitis, Chapter 36; syphilis and Lyme borreliosis, Chapter 34; tuberculous meningitis, Chapter 33; herpes encephalitis, Chapter 32).
``When to Refer • Patients with acute meningitis, particularly if culture negative or atypical (eg, fungi, syphilis, Lyme disease, M tuberculosis), or if the patient is immunosuppressed. • Patients with chronic meningitis. • All patients with brain abscesses and encephalitis. • Patients with suspected hospital-acquired meningitis (eg, in patients who have undergone recent neurosurgery). • Patients with recurrent meningitis.
``When to Admit • Patients with suspected acute meningitis, encephalitis, and brain abscess should be admitted for urgent evaluation and treatment. • There is less urgency to admit patients with chronic meningitis; these patients may be admitted to expedite diagnostic procedures and coordinate care, particularly if no diagnosis has been made in the outpatient setting. Glaser CA et al. Beyond viruses: clinical profiles and etiologies associated with encephalitis. Clin Infect Dis. 2006 Dec 15;43(12):1565–77. [PMID: 17109290] Granerod J et al; UK Health Protection Agency (HPA) Aetiology of Encephalitis Study Group. Causes of encephalitis and differences in their clinical presentations in England: a multicentre, population-based prospective study. Lancet Infect Dis. 2010 Dec;10(12):835–44. [PMID: 20952256] Honda H et al. Central nervous system infections: meningitis and brain abscess. Infect Dis Clin North Am. 2009 Sep;23 (3): 609–23. [PMID: 19665086] Logan SA et al. Viral meningitis. BMJ. 2008 Jan 5;336(7634):36–40. [PMID: 18174598] Thigpen MC et al; Emerging Infections Programs Network. Bacterial meningitis in the United States, 1998–2007. N Engl J Med. 2011 May 26;364(21):2016–25. [PMID: 21612470] van de Beek D et al. Nosocomial bacterial meningitis. N Engl J Med. 2010 Jan 14;362(2):146–54. [PMID: 20071704]
ANIMAL & HUMAN BITE WOUNDS ``
E s s e n t i a l s o f di a g n o s i s
Cat and human bites have higher rates of infection than dog bites. `` Hand bites are particularly concerning for 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
Problems in Infectious Diseases & Antimicrobial Therapy 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. Bites 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%). Streptococci and S aureus are the most common aerobes. Eikenella corrodens (found in up to 30% of patients), Prevotella and Fusobacterium are the most common anaerobes. Although the organisms noted are the most common, innumerable others have been isolated—including Capnocytophaga (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 A. 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, joint space penetration) is critical to appropriate care.
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B. Suturing 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.
C. Prophylactic Antibiotics Prophylaxis is indicated in high-risk bites and in high-risk patients. Cat bites in any location and hand bites by any animal, including humans, should receive prophylaxis. Individuals with certain comorbidities (diabetes, liver disease) are at increased risk for severe complications and should receive prophylaxis even for low-risk bites, as should patients without functional spleens who are at increased risk for overwhelming sepsis (primarily with Capnocytophaga species). Amoxicillin-clavulanate (Augmentin) 500 mg orally three times daily for 5–7 days is the regimen of choice. For patients with serious allergy to penicillin, a combination of clindamycin 300 mg orally three times daily plus doxycycline 100 mg orally twice daily, or double-strength TMP-SMZ orally twice daily, or a fluoroquinolone (ciprofloxacin 500 mg orally twice daily or levofloxacin 500–750 mg orally once daily) is recommended for 5–7 days. Moxifloxacin, a fluoroquinolone with good aerobic and anaerobic activity, may be suitable as monotherapy at 400 mg orally once daily for 5–7 days. Agents such as dicloxacillin, cephalexin, erythromycin, and clindamycin should not be used alone because they lack activity against Pasteurella species. Doxycycline and TMPSMZ have poor activity against anaerobes and should only be used in combination with clindamycin. 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.
D. Antibiotics for Documented Infection 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. The most commonly encountered pathogens require treatment with either a combination of a β-lactam plus a β-lactamase inhibitor (ampicillin-sulbactam [Unasyn], 1.5–3.0 g intravenously every 6–8 hours; piperacillintazobactam [Zosyn], 3.375 g intravenously every 6–8 hours; or amoxicillin-clavulanate [Augmentin], 500 mg orally three times daily) or with a carbapenem (ertapenem, 1 g intravenously daily; imipenem, 500 mg intravenously every 6–8 hours; meropenem, 1 g intravenously every 8 hours). For the patient with severe penicillin allergy, a combination of clindamycin 600–900 mg intravenously every 8 hours plus a fluoroquinolone (ciprofloxacin, 400 mg intravenously every 12 hours; levofloxacin, 500–750 mg intravenously once daily) or TMP-SMZ (10 mg/kg of trimethoprim daily in two or three divided doses) is indicated. Duration of therapy is usually 2–3 weeks unless
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complications such as septic arthritis or osteomyelitis are present; if these complications are present, therapy should be extended to 4 and 6 weeks, respectively.
E. Tetanus and Rabies All patients must be evaluated for the need for tetanus (see Chapter 33) and rabies (see Chapter 32) prophylaxis.
``When to Refer • If septic arthritis or osteomyelitis is suspected. • For exposure to bites by dogs, cats, reptiles, amphibians, and rodents. • When rabies is a possibility.
``When to Admit • Patients with infected hand bites. • Deep bites, particularly if over joints. Oehler RL et al. Bite-related and septic syndromes caused by cats and dogs. Lancet Infect Dis. 2009 Jul;9(7):439–47. [PMID: 19555903] Stevens DL et al; Infectious Diseases Society of America. Practice guidelines for the diagnosis and management of skin and soft-tissue infections. Clin Infect Dis. 2005 Nov 15;41(10): 1373–406. [PMID: 16231249] Warrell MJ. Emerging aspects of rabies infection: with a special emphasis on children. Curr Opin Infect Dis. 2008 Jun;21(3): 251–7. [PMID: 18448969]
SEXUALLY TRANSMITTED DISEASES
``
E s s e n t i a l s o f di a g n o s i s
All sexually transmitted diseases (STDs) have subclinical or latent periods, and patients may be asymptomatic. `` Simultaneous infection with several organisms is common. `` All patients who seek STD testing should be screened for syphilis and HIV. `` Partner notification and treatment are important to prevent further transmission and reinfection in the index case. ``
``General Considerations The most common STDs are gonorrhea,∗ syphilis,∗ human papillomavirus (HPV)-associated condyloma acuminatum, chlamydial genital infections,∗ herpesvirus genital infections, trichomonas vaginitis, chancroid,∗ granuloma inguinale, scabies, louse infestation, and bacterial vaginosis (among women who have sex with women). However, ∗
Reportable to public health authorities.
shigellosis∗; hepatitis A, B, and C∗; amebiasis; giardiasis∗; cryptosporidiosis∗; salmonellosis∗; and campylobacteriosis may also be transmitted by sexual (oral-anal) contact, especially in men who have sex with men. Both homosexual and heterosexual contact are risk factors for the transmission of HIV (see Chapter 31). All STDs 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. Simultaneous infection by several different agents is common. Infections typically present in one of several ways, each of which has a defined differential diagnosis, which should prompt appropriate diagnostic tests.
A. Genital Ulcers Common etiologies include herpes simplex virus, primary syphilis, and chancroid. Other possibilities include lymphogranuloma venerum (see Chapter 33), granuloma inguinale caused by Klebsiella granulomatis (see Chapter 33), as well as lesions caused by infection with Epstein-Barr virus and HIV. Noninfectious causes are Behçet disease (see Chapter 20), neoplasm, trauma, drugs, and irritants.
B. Urethritis with or without Urethral Discharge The most common infections causing urethral discharge are Neisseria gonorrhoeae and Chlamydia trachomatis. N gonorrhoeae and C trachomatis are also frequent causes of prostatitis among sexually active men. Other sexually transmitted infections that can cause urethritis include Mycoplasma genitalium, Ureaplasma urealyticum, and Trichomonas vaginalis. Noninfectious causes of urethritis includes reactive arthritis with associated urethritis (Reiter syndrome).
C. Vaginal Discharge Common causes of vaginitis are bacterial vaginosis (caused by overgrowth of anaerobes such as Gardnerella vaginalis), candidiasis, and T vaginalis (see Chapter 18). Less common infectious causes of vaginitis include HPV-associated condyloma acuminata and group A streptococcus. Noninfectious causes are physiologic changes related to the menstrual cycle, irritants, and lichen planus. Even though N gonorrhoeae and C trachomatis are frequent causes of cervicitis, they rarely produce vaginal discharge.
``Screening & Prevention All persons who seek STD testing should undergo routine screening for HIV infection, using rapid HIV-testing (if patients may not follow-up for results obtained by standard methods) or nucleic acid amplification followed by confirmatory serology (if primary HIV infection may be a possibility) as indicated. Patients in whom STDs have been diagnosed and treated (in particular, chlamydia or gonorrhea) are at a high risk for reinfection and should be encouraged to be rescreened for STDs at 3 months following the initial STD diagnosis.
Problems in Infectious Diseases & Antimicrobial Therapy Asymptomatic patients often request STD screening at the time of initiating a new sexual relationship. Routine HIV testing and hepatitis B serology testing should be offered to all such patients. In sexually active women who have not been recently screened, cervical Papanicolaou testing and nucleic acid amplification testing of a urine specimen for gonorrhea and chlamydia are recommended. Among men who have sex with men, additional screening is recommended for syphilis; hepatitis A; urethral, pharyngeal, and rectal gonorrhea; as well as urethral and rectal chlamydia. Nucleic acid amplification testing is FDAapproved for testing urine for gonorrhea or chlamydia. However, the use of nucleic acid amplification testing of secretions in the rectum and pharynx has not been validated in many laboratories. There are no recommendations to screen heterosexual men for urethral chlamydia but this could be considered in STD clinics, adolescent clinics, or in correctional facilities. The periodicity of screening thereafter depends on sexual risk, but most screening should be offered at least annually to sexually active adults (particularly to those 25-years-old and under). If not immune, hepatitis B vaccination is recommended for all sexually active adults, and hepatitis A vaccination in men who have sex with men. Persons between the ages of 9 and 26 may be offered vaccination against HPV. The risk of developing an STD following a sexual assault is difficult to accurately ascertain given high rates of baseline infections and poor follow-up. Victims of assault have a high baseline rate of infection (N gonorrhoeae, 6%; C trachomatis, 10%; T 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 nucleic acid amplification tests for N gonorrhoeae and C trachomatis should be performed. Vaginal secretions are obtained for Trichomonas wet mount and culture, or point-of-care testing. 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 STD should be repeated within 1–2 weeks, since concentrations of infecting organisms may not have been sufficient to produce a positive test at the time of initial examination. If prophylactic treatment was given (may include postexposure hepatitis B vaccination without hepatitis B immune globulin; treatment for chlamydial, gonorrheal, or trichomonal infection; and emergency contraception), 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.
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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 anti retroviral 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. In addition to screening asymptomatic patients with STDs, other strategies for preventing further transmission include evaluating sex partners and administering preexposure vaccination of preventable STDs to individuals at risk; other strategies include the consistent use of male and female condoms. 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 to all sexual contacts (patientdelivered therapy) is an important strategy for preventing further transmission and to prevent reinfection in the index case. Note that vaginal spermicides and condoms containing nonoxynol-9 provide no additional protection against STDs. Male circumcision has been demonstrated to protect against HIV and HPV acquisition in heterosexual men with HIV-infected partners. Early initiation of anti retroviral therapy in HIV-infected individuals can prevent HIV acquisition in an uninfected sex partner. Also, preexposure prophylaxis with a once-daily pill containing tenofovir plus emtricitabine has been shown to be effective in preventing HIV infection among high-risk men who have sex with men.
``When to Refer • Patients with a new diagnosis of HIV. • Patients with persistent, refractory or recurrent STDs, particularly when drug resistance is suspected. Cohen MS et al; HPTN 052 Study Team. Prevention of HIV-1 infection with early antiretroviral therapy. N Engl J Med. 2011 Aug 11;365(6):493–505. [PMID: 21767103] Grant RM et al; iPrEx Study Team. Preexposure chemoprophylaxis for HIV prevention in men who have sex with men. N Engl J Med. 2010 Dec 30;363(27):2587–99. [PMID: 21091279] Jena AB et al. Sexually transmitted diseases among users of erectile dysfunction drugs: analysis of claims data. Ann Intern Med. 2010 Jul 6;153(1):1–7. [PMID: 20621899] Ohnishi M et al. Is Neisseria gonorrhoeae initiating a future era of untreatable gonorrhea?: detailed characterization of the first strain with high-level resistance to ceftriaxone. Antimicrob Agents Chemother. 2011 Jul;55(7):3538–45. [PMID: 21576437] 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 Jan 21;54(RR-2):1–20. [PMID: 15660015]
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Tobian AA et al. Male circumcision for the prevention of HSV-2 and HPV infections and syphilis. N Engl J Med. 2009 Mar 26;360(13):1298–309. [PMID: 19321868] Workowski KA et al; Centers for Disease Control and Prevention (CDC). Sexually transmitted diseases treatment guidelines, 2010. MMWR Recomm Rep. 2010 Dec 17;59(RR-12):1–110. Erratum in: MMWR Recomm Rep. 2011 Jan 14;60(1):18. [PMID: 21160459]
INFECTIONS IN DRUG USERS
``
E s s e n t i a l s o f di a g n o s i s
Common infections that occur with greater frequency in drug users include: `` Skin infections, aspiration pneumonia, tuberculosis. `` Hepatitis A, B, C, D; STDs; AIDS. `` Pulmonary septic emboli, infective endocarditis. `` Osteomyelitis and septic arthritis.
``General Considerations There is a high incidence of infection among drug users, particularly those who inject drugs. Increased risk of infection is likely associated with poor hygiene and colonization with potentially pathogenic organisms, contamination of drugs and equipment, increased sexual risk behaviors, and impaired immune defenses. 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. Skin infections are associated with poor hygiene and use of nonsterile technique when injecting drugs. S aureus (including community-acquired methicillin-resistant strains) and oral flora (streptococci, Eikenella, Fusobacterium, Peptostreptococcus) are the most common organisms, with enteric gram-negatives generally more likely 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. 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.
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. Pulmonary septic emboli may originate from venous thrombi or right-sided endocarditis. STDs are not directly related to drug use, but the practice of exchanging sex for drugs has resulted in an increased frequency of STDs. 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 Chapter 31). Infective endocarditis in persons who use drugs intravenously is most commonly caused by S aureus, Candida (usually C albicans or C parapsilosis), Enterococcus faecalis, other streptococci, and gram-negative bacteria (especially Pseudomonas and Serratia marcescens). See Chapter 33. 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 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 (often not C albicans), and other pathogens rarely encountered in spontaneous bone or joint disease are found in injection drug users.
``Treatment 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 g intravenously every 24 hours, plus azithromycin, 500 mg orally or intravenously every 24 hours, or doxycycline, 100 mg orally or intravenously twice daily. If the chest radiograph is suggestive of septic emboli (nodular infiltrates), therapy for presumed endocarditis is initiated, usually with vancomycin 15 mg/kg/dose every 12 hours intravenously (due to the high prevalence of MRSA and the possibility of enterococcus). 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 is started. If blood cultures are positive for organisms that frequently cause endocarditis in drug users (see above), endocarditis is presumed to be present
Problems in Infectious Diseases & Antimicrobial Therapy 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.
``When to Refer • Any patient with suspected or proven infective endocarditis. • Patients with persistent bacteremia.
``When to Admit • Injection drug users with fever. • Patients with abscesses or progressive skin and soft tissue infection that require debridement. Deiss RG et al. Tuberculosis and illicit drug use: review and update. Clin Infect Dis. 2009 Jan 1;48(1):72–82. [PMID: 19046064] Gordon RJ et al. Bacterial infections in drug users. N Engl J Med. 2005 Nov 3;353(18):1945–54. [PMID: 16267325] Paintsil E et al. Survival of hepatitis C virus in syringes: implication for transmission among injection drug users. J Infect Dis. 2010 Oct 1;202(7):984–90. [PMID: 20726768] Jain V et al. Infective endocarditis in an urban medical center: association of individual drugs with valvular involvement. J Infect. 2008 Aug;57(2):132–8. [PMID: 18597851]
ACUTE INFECTIOUS DIARRHEA
``
E s s e n t i a l s o f di a g n o s i s
Acute diarrhea: lasts < 2 weeks Chronic diarrhea: lasts > 2 weeks. `` Mild diarrhea: ≤ 3 stools per day. `` Moderate diarrhea: ≥ 4 stools per day with local symptoms (abdominal cramps, nausea, tenesmus). `` Severe diarrhea: ≥ 4 stools per day with systemic symptoms (fever, 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) (Table 30–3). 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
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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 and other Shiga-toxin– producing strains of E coli (STEC), 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, norovirus, astrovirus, enteric adenoviruses), vibriones (Vibrio cholerae, Vibrio parahaemolyticus), enterotoxin-producing E coli, Giardia lamblia, cryptosporidia, and agents that can cause food-borne gastroenteritis. In developed countries, viruses (particularly norovirus) are an important cause of hospitalizations due to acute gastroenteritis among adults. 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; outbreak in long-term care facility, school, or cruise ship suggests norovirus; 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.
``Treatment A. General Measures In general, most cases of acute gastroenteritis are selflimited and do not require therapy other than supportive
Organism
Incubation Period
Vomiting
Diarrhea
Fever
Associated Foods
Diagnosis
Clinical Features and Treatment
+++
±
±
Staphylococci grow in meats, dairy, and bakery products and produce enterotoxin.
Clinical. Food and stool can be tested for toxin.
Abrupt onset, intense nausea and vomiting for up to 24 hours, recovery in 24–48 hours. Supportive care.
Bacillus cereus (preformed toxin)
1–8 hours
+++
±
–
Reheated fried rice causes vomiting or diarrhea.
Clinical. Food and stool can be tested for toxin.
Acute onset, severe nausea and vomiting lasting 24 hours. Supportive care.
B cereus (diarrheal toxin)
10–16 hours
±
+++
–
Toxin in meats, 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
8–16 hours
±
+++
–
Clostridia grow 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
12–72 hours
±
–
–
Clostridia grow 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.
–
+++
++
Associated with antimicrobial drugs; clindamycin and β-lactams most commonly implicated. Fluoroquinolones associated with hypervirulent strains.
Stool tested for toxin.
Abrupt onset of diarrhea that may be bloody; fever. Oral metronidazole for mild to moderate cases. Oral vancomycin for more severe disease.
Enterohemorrhagic Escherichia coli, including E coli O157:H7 and other Shiga-toxin producing strains (STEC)
1–8 days
+
+++
–
Undercooked beef, especially hamburger; 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. Plasma exchange may help patients with STEC-associated HUS.
Enterotoxigenic E coli (ETEC)
1–3 days
±
+++
±
Water, food 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.
Vibrio parahaemolyticus
2–48 hours
+
+
±
Undercooked or raw seafood.
Stool culture on special medium.
Abrupt onset of watery diarrhea, abdominal cramps, nausea and vomiting. Recovery is usually complete in 2–5 days.
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1–8 hours
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Staphylococcus (preformed toxin)
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Table 30–3. Acute bacterial diarrheas and “food poisoning.”
+
+++
–
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 and azithromycin shorten excretion of vibrios.
Campylobacter jejuni
2–5 days
±
+++
+
Raw or undercooked poultry, unpasteurized milk, water.
Stool culture on special medium.
Fever, diarrhea that can be bloody, cramps. Usually self-limited in 2–10 days. Treat with azithromycin or fluoroquinolones for severe disease. May be associated with Guillain-Barré syndrome.
Shigella species (mild cases)
24–48 hours
±
+
+
Food or water contaminated with human feces. Person to person spread.
Routine stool culture.
Abrupt onset of diarrhea, often with blood and pus in stools, cramps, tenesmus, and lethargy. Stool cultures are positive. Therapy depends on sensitivity testing, but the fluoroquinolones are most effective. Do not give opioids. Often mild and self-limited.
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
24–48 hours
±
+
+
Undercooked 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, self-limited in 1–3 weeks.
Rotavirus
1–3 days
++
+++
+
Fecally 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
12–48 hours
++
+++
+
Shell fish and 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.
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Vibrio cholerae
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measures. 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).
B. Specific Measures When symptoms persist beyond 3–4 days, initial presentation is accompanied by fever or bloody diarrhea, or if 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, and Campylobacter infections (early therapy, within 4 days of onset of symptoms, shortens the course of disease). Conversely, antibiotic therapy for infections with E coli O157:H7 does not ameliorate symptoms and may increase the risk of developing hemolytic-uremic syndrome. 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 orally 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 are useful 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.
ASGE Standards of Practice Committee; Shen B et al. The role of endoscopy in the management of patients with diarrhea. Gastrointest Endosc. 2010 May;71(6):887–92. [PMID: 20346452] Colic E et al. Management of an acute outbreak of diarrhoeaassociated haemolytic uraemic syndrome with early plasma exchange in adults from southern Denmark: an observational study. Lancet. 2011 Sep 17;378(9796):1089–93. [PMID: 21871657] DuPont HL. Clinical practice. Bacterial diarrhea. N Engl J Med. 2009 Oct 15;361(16):1560–9. [PMID: 19828533] Frank C et al; HUS Investigation Team. Epidemic profile of Shiga-toxin-producing Escherichia coli O104:H4 outbreak in Germany. N Engl J Med. 2011 Nov 10;365(19):1771–80. [PMID: 21696328] Lopman BA et al. Increasing rates of gastroenteritis hospital discharges in US adults and the contribution of norovirus, 1996–2007. Clin Infect Dis. 2011 Feb 15;52(4):466–74. [PMID: 21258098] Prince Christopher RH et al. Antibiotic therapy for Shigella dysentery. Cochrane Database Syst Rev. 2010 Jan 10;(1): CD006784. [PMID: 20091606]
INFECTIOUS DISEASES IN THE RETURNING TRAVELER
``
E s s e n t i a l s o f di a g n o s i s
Most infections are common and self-limited. Identify patients 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; > 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 lifethreatening 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.
``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 Chapter 35), diarrhea (see next section), and dengue (see Chapter 32). Others include respiratory infections, including seasonal influenza, influenza A/H1N1 ‘swine’ influenza, and influenza A/H5N1
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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, Strongyloides). Bone marrow biopsy to diagnose typhoid fever could be helpful in the appropriate patient.
‘avian’ influenza (see Chapter 32); leptospirosis (see Chapter 34); typhoid fever (see Chapter 33); and rickettsial infections (see Chapter 32). Foreign travel is increasingly recognized as a risk factor for colonization and disease with resistant pathogens, such as extended-spectrum β-lactamases (ESBL)–producing gram-negative organisms. Systemic febrile illnesses without a diagnosis also occurs commonly, particularly in travelers returning from subSaharan Africa or Southeast Asia.
``When to Refer
A. Fever and Rash
Travelers with fever, particularly if immunocompromised.
Potential etiologies include dengue, Chikungunya, viral hemorrhagic fever, leptospirosis, meningococcemia, yellow fever, typhus, Salmonella typhi, and acute HIV infection.
``When to Admit Any evidence of hemorrhage, respiratory distress, hemodynamic instability, and neurologic deficits.
B. Pulmonary Infiltrates Tuberculosis, ascaris, Paragonimus, and Strongyloides can all cause pulmonary infiltrates.
C. Meningoencephalitis Etiologies include N meningitidis, leptospirosis, arboviruses, rabies, and (cerebral) malaria.
D. Jaundice Consider hepatitis A, yellow fever, hemorrhagic fever, leptospirosis, and malaria.
E. Fever without Localizing Symptoms or Signs Malaria, typhoid fever, acute HIV infection, rickettsial illness, visceral leishmaniasis, trypanosomiasis, and dengue are possible etiologies.
F. Traveler’s Diarrhea See next section.
``Clinical Findings Fever and rash in the returning traveler should prompt blood cultures and serologic tests based on the exposure history. The work-up of a pulmonary infiltrate should include the placement of a PPD, examination of sputum for acid-fast bacilli and possibly for ova and parasites. Patients with evidence of meningoencephalitis should receive lumbar puncture, blood cultures, thick/thin smears of peripheral blood, history-guided serologies, and a nape biopsy (if rabies is suspected). Jaundice in a returning traveler should be evaluated for hemolysis (for malaria), and the following tests should be performed: liver function tests, thick/thin smears of peripheral blood, and directed 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, urinalysis, 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.
Centers for Disease Control and Prevention (CDC). Detection of Enterobacteriaceae isolates carrying metallo-beta-lactamase— United States, 2010. MMWR Morb Mortal Wkly Rep. 2010 Jun 25;59(24):750. [PMID: 20577157] Gregory CJ et al. Clinical and laboratory features that differentiate dengue from other febrile illnesses in an endemic area— Puerto Rico, 2007–2008. Am J Trop Med Hyg. 2010 May;82(5): 922–9. [PMID: 20439977] Griffith KS et al. Treatment of malaria in the United States: a systematic review. JAMA. 2007 May 23;297(20):2264–77. [PMID: 17519416] Hochedez P et al. Management of travelers with fever and exanthema, notably dengue and chikungunya infections. Am J Trop Med Hyg. 2008 May;78(5):710–3. [PMID: 18458301] Monsel G et al. Recent developments in dermatological syndromes in returning travelers. Curr Opin Infect Dis. 2008 Oct;21(5):495–9. [PMID: 18725799] Mukherjee P et al. Epidemiology of travel-associated pandemic (H1N1) 2009 infection in 116 patients, Singapore. Emerg Infect Dis. 2010 Jan;16(1):21–6. [PMID: 20031038] Taylor WR et al. Avian influenza—a review for doctors in travel medicine. Travel Med Infect Dis. 2010 Jan;8(1):1–12. [PMID: 20188299]
TRAVELER’S DIARRHEA
``
E s s e n t i a l s o f di a g n o s i s
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 significant 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 may 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
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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 A. 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 are usually watery and not associated with fever when caused by enterotoxigenic E coli. With invasive bacterial pathogens (Shigella, Campylobacter, Salmonella) stools can be bloody and fever may be present. 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%. Traveler’s diarrhea is also a significant risk factor for developing irritable bowel syndrome.
B. Laboratory Findings In patients with fever and bloody diarrhea, stool culture is indicated, but in most cases, cultures are reserved for those who do not respond to antibiotics.
``Prevention A. General Measures Avoidance of fresh foods and water sources that are likely to be contaminated is recommended for travelers to developing countries, where infectious diarrheal illnesses are endemic.
B. Specific Measures Because not all travelers will have diarrhea and because most episodes are brief and self-limited, the currently recommended approach is to provide the traveler with a supply of antimicrobials to be taken if significant diarrhea occurs during the trip. In areas where toxin-producing bacteria are the major cause of diarrhea (Latin America and Africa), 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), or ofloxacin (200 mg), cures most cases of traveler’s diarrhea. If diarrhea is associated with bloody stools or persists despite a single dose of a fluoroquinolone, 1000 mg of azithromycin should be taken. In pregnant women and in areas where invasive bacteria more commonly cause diarrhea (Indian subcontinent, Asia, especially Thailand where fluoroquinolone-resistant Campylobacter is prevalent), azithromycin is the drug of choice. Rifaximin, a nonabsorbable agent, 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 levels are insufficient, it should not be used in situations where there is a high likelihood of invasive disease (eg, fever, systemic toxicity, or bloody stools). Prophylaxis is recommended for those with
significant underlying disease (inflammatory bowel disease, AIDS, diabetes, heart disease in the elderly, conditions requiring immunosuppressive medications) and for those whose full activity status during the trip is so essential that even short periods of diarrhea would be unacceptable. 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, numerous oral antimicrobial once-daily regimens are effective, such as norfloxacin, 400 mg; ciprofloxacin, 500 mg; or rifaximin, 200 mg. 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.
``Treatment For most individuals, the affliction is short-lived, and symptomatic therapy with loperamide is all that is required, provided the patient is not systemically ill (fever ≥ 39°C) and does not have dysentery (bloody stools), in which case antimotility agents should be avoided. Packages of oral rehydration salts to treat dehydration are available over the counter in the United States (Infalyte, Pedialyte, others) and in many foreign countries.
``When to Refer • Cases refractory to treatment. • Persistent infection. • Immunocompromised patient.
``When to Admit Patients who are severely dehydrated or hemodynamically unstable should be admitted to the hospital. Hill DR et al. Management of travellers’ diarrhoea. BMJ. 2008 Oct 6;337:a1746. [PMID: 18838421] Hill DR et al. The practice of travel medicine: guidelines by the Infectious Disease Society of America. Clin Infect Dis. 2006 Dec 15;43(12):1499–539. [PMID: 17109284] Mohamed JA et al. Single nucleotide polymorphisms in the promoter of the gene encoding the lipopolysaccharide receptor CD14 are associated with bacterial diarrhea in US and Canadian travelers to Mexico. Clin Infect Dis. 2011 Jun;52(11):1332–41. [PMID: 21596674] Tuteja AK et al. Development of functional diarrhea, constipation, irritable bowel syndrome, and dyspepsia during and after traveling outside the USA. Dig Dis Sci. 2008 Jan;53(1):271–6. [PMID: 17549631]
cc
Antimicrobial therapy
Selected Principles of Antimicrobial Therapy Specific steps (outlined below) are required when considering antibiotic therapy for patients. Drugs within classes, drugs of first choice, and alternative drugs are presented in Table 30–4.
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Table 30–4. Drugs of choice for suspected or proved microbial pathogens, 2012.1 Suspected or Proved Etiologic Agent
Drug(s) of First Choice
Alternative Drug(s)
Gram-negative cocci Moraxella catarrhalis
Cefuroxime, a fluoroquinolone2
Cefotaxime, ceftriaxone, cefuroxime axetil, an erythromycin,3 a tetracycline,4 azithromycin, amoxicillin-clavulanic acid, clarithromycin, TMP-SMZ5
Neisseria gonorrhoeae (gonococcus)
Cefixime, ceftriaxone
Cefpodoxime proxetil
Neisseria meningitidis (meningococcus)
6
Penicillin
Cefotaxime, ceftriaxone, ampicillin
Streptococcus pneumoniae7 (pneumococcus)
Penicillin6
An erythromycin,3 a cephalosporin,8 vancomycin, clindamycin, azithromycin, clarithromycin, a tetracycline,4 respiratory fluoroquinolones2
Streptococcus, hemolytic, groups A, B, C, G
Penicillin6
An erythromycin,3 a cephalosporin,8 vancomycin, clindamycin, azithromycin, clarithromycin
Viridans streptococci
Penicillin6 ± gentamicin
Cephalosporin,8 vancomycin
Staphylococcus, methicillin-resistant
Vancomycin
TMP-SMZ,5 doxycycline, minocycline, linezolid, daptomycin, quinupristin-dalfopristin, tigecycline, televancin
Staphylococcus, non-penicillinase-producing
Penicillin6
A cephalosporin,8 clindamycin
Staphylococcus, penicillinase-producing
Penicillinase-resistant penicillin9
Vancomycin, a cephalosporin,8 clindamycin, amoxicillin-clavulanic acid, ampicillin-sulbactam, piperacillin-tazobactam, TMP-SMZ5
Enterococcus faecalis
Ampicillin ± gentamicin10
Gram-positive cocci
Enterococcus faecium
Vancomycin ± gentamicin
Vancomycin ± gentamicin 10
Linezolid,11 quinupristin-dalfopristin,11 daptomycin,11 tigecycline11
Gram-negative rods Acinetobacter
Imipenem, meropenem
Tigecycline, ertapenem, minocycline, doxycycline, aminoglycosides,12 colistin
Prevotella, oropharyngeal strains
Clindamycin
Metronidazole
Bacteroides, gastrointestinal strains
Metronidazole
Ticarcillin-clavulanate, ampicillin-sulbactam, piperacillintazobactam, carbapenem
Brucella
Doxycycline + rifampin4
TMP-SMZ5 ± gentamicin; ciprofloxacin + rifampin
Campylobacter jejuni
Erythromycin3 or azithromycin
Tetracycline,4 a fluoroquinolone2
Enterobacter
Ertapenem, imipenem, meropenem, cefepime
Aminoglycoside, a fluoroquinolone,2 TMP-SMZ5
Escherichia coli (sepsis)13
Cefotaxime, ceftriaxone
Imipenem13 or meropenem,13 aminoglycosides,12 a fluoroquinolone,2 aztreonam, ticarcillin-clavulanate, ampicillin-sulbactam, piperacillin-tazobactam
Escherichia coli (uncomplicated outpatient urinary infection)
Fluoroquinolones,2 nitrofurantoin
TMP-SMZ,5 oral cephalosporin
Haemophilus (meningitis and other serious infections)
Cefotaxime, ceftriaxone
Aztreonam
Haemophilus (respiratory infections, otitis)
TMP-SMZ5
Doxycycline, azithromycin, clarithromycin, cefotaxime, ceftriaxone, cefuroxime, cefuroxime axetil, ampicillin-clavulanate
Helicobacter pylori
Amoxicillin + clarithromycin + proton pump inhibitor (PPI)
Bismuth subsalicylate + tetracycline + metronidazole + PPI
Klebsiella13
A cephalosporin
TMP-SMZ,5 aminoglycoside,12 imipenem13 or meropenem,13 a fluoroquinolone,2 aztreonam, ticarcillin-clavulanate, ampicillin-sulbactam, piperacillin-tazobactam
Legionella species (pneumonia)
Azithromycin, or fluoroquinolones2 ± rifampin
Doxycycline ± rifampin (continued )
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Table 30–4. Drugs of choice for suspected or proved microbial pathogens, 2012.1 (continued) Suspected or Proved Etiologic Agent
Drug(s) of First Choice
Alternative Drug(s) 12
Proteus mirabilis
Ampicillin
An aminoglycoside, TMP-SMZ,5 a fluoroquinolone,2 a cephalosporin8
Proteus vulgaris and other species (Morganella, Providencia)
Cefotaxime, ceftriaxone
Aminoglycoside,12 imipenem, TMP-SMZ,5 a fluoroquinolone2
Pseudomonas aeruginosa
Piperacillin-tazobactam or Ciprofloxacin (or levofloxacin) ± piperacillin-tazobactam; ceftazidime or cefepime, or ciprofloxacin (or levofloxacin) ± ceftazidime; ciprofloxacin (or imipenem or meropenem or levofloxacin) ± cefepime; piperacillin-tazobactam + tobramycin; doripenem ceftazidime + tobramycin; cefepime + tobramycin; ± aminoglycoside12 meropenem (imipenem, doripenem) + tobramycin
Burkholderia pseudomallei (melioidosis)
Ceftazidime
Tetracycline,4 TMP-SMZ,5 amoxicillin-clavulanic acid, imipenem or meropenem
Burkholderia mallei (glanders)
Streptomycin + tetracycline4
Chloramphenicol + streptomycin
Salmonella (bacteremia)
Ceftriaxone
A fluoroquinolone2
Serratia
Carbapenem
TMP-SMZ,5 aminoglycosides,12 a fluoroquinolone,2 cefotaxime, ceftriaxone
Shigella
A fluoroquinolone2
Azithromycin, ampicillin, TMP-SMZ,5 ceftriaxone
Vibrio (cholera, sepsis)
A tetracycline4
TMP-SMZ,5 a fluoroquinolone2
Yersinia pestis (plague)
Streptomycin ± a tetracycline4
Chloramphenicol, TMP-SMZ5
Actinomyces
Penicillin6
Tetracycline,4 clindamycin
Bacillus (including anthrax)
Penicillin6 (ciprofloxacin or doxycycline for anthrax; see Table 33–2)
Erythromycin,3 a fluoroquinolone2
Clostridium (eg, gas gangrene, tetanus)
Penicillin6
Metronidazole, clindamycin, imipenem or meropenem
Gram-positive rods
3
Corynebacterium diphtheriae
Erythromycin
Corynebacterium jeikeium
Vancomycin
Listeria
Ampicillin ± aminoglycoside
Penicillin6 A fluoroquinolone 12
TMP-SMZ5
Acid-fast rods Mycobacterium tuberculosis14
Isoniazid (INH) + rifampin + pyrazinamide ± ethambutol
Other antituberculous drugs (see Tables 9–17 and 9–18)
Mycobacterium leprae
Dapsone + rifampin ± clofazimine
Minocycline, ofloxacin, clarithromycin
Mycobacterium kansasii
INH + rifampin ± ethambutol
Clarithromycin, azithromycin, ethionamide, cycloserine
Mycobacterium avium complex
Clarithromycin or azithromycin + Amikacin, ciprofloxacin ethambutol, ± rifabutin
Mycobacterium fortuitum-chelonei
Cefoxitin + clarithromycin
Nocardia
TMP-SMZ
5
Amikacin, rifampin, sulfonamide, doxycycline, linezolid Minocycline, imipenem or meropenem, linezolid
Spirochetes Borrelia burgdorferi (Lyme disease)
Doxycycline, amoxicillin, cefuroxime axetil
Ceftriaxone, cefotaxime, penicillin, azithromycin, clarithromycin
Borrelia recurrentis (relapsing fever)
Doxycycline4
Penicillin6
Leptospira
Penicillin6
Doxycycline,4 ceftriaxone
Treponema pallidum (syphilis)
Penicillin6
Doxycycline, ceftriaxone
Treponema pertenue (yaws)
Penicillin6
Doxycycline (continued )
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Table 30–4. Drugs of choice for suspected or proved microbial pathogens, 2012.1 (continued) Suspected or Proved Etiologic Agent
Drug(s) of First Choice
Alternative Drug(s)
Clarithromycin or azithromycin or doxycycline
A fluoroquinolone,2 erythromycin3
C psittaci
Doxycycline
Chloramphenicol
C trachomatis (urethritis or pelvic inflammatory disease)
Doxycycline or azithromycin
Levofloxacin, ofloxacin
C pneumoniae
Doxycycline4
Erythromycin,3 clarithromycin, azithromycin, a fluoroquinolone2,15
Rickettsiae
Doxycycline4
Chloramphenicol, a fluoroquinolone2
Mycoplasmas Chlamydiae
1
Adapted, with permission, from Treat Guide Med Lett. 2010 June;6(94):43–52. Fluoroquinolones include ciprofloxacin, ofloxacin, levofloxacin, moxifloxacin, and others (see text). Gemifloxacin, levofloxacin, and moxifloxacin have the best activity against gram-positive organisms, including penicillin-resistant S pneumoniae and methicillinsensitive S aureus. Activity against enterococci and S epidermidis is variable. 3 Erythromycin estolate is best absorbed orally but carries the highest risk of hepatitis; erythromycin stearate and erythromycin ethylsuccinate are also available. 4 All tetracyclines have similar activity against most microorganisms. Minocycline (most likely to have S aureus activity), doxycycline, tetracycline have increased activity against S aureus. 5 TMP-SMZ is a mixture of 1 part trimethoprim and 5 parts sulfamethoxazole. 6 Penicillin G is preferred for parenteral injection; penicillin V for oral administration—to be used only in treating infections due to highly sensitive organisms. 7 Infections caused by isolates with intermediate resistance may respond to high doses of penicillin, cefotaxime, or ceftriaxone. Infections caused by highly resistant strains should be treated with vancomycin. Many strains of penicillin-resistant pneumococci are resistant to macrolides, cephalosporins, tetracyclines, and TMP-SMZ. 8 Most intravenous cephalosporins (with the exception of ceftazidime) have good activity against gram-positive cocci. 9 Parenteral nafcillin or oxacillin; oral dicloxacillin, cloxacillin, or oxacillin. 10 Addition of gentamicin indicated only for severe enterococcal infections (eg, endocarditis, meningitis). 11 Linezolid, daptomycin, tigecycline, quinupristin-dalfopristin should be reserved for the treatment of vancomycin resistant isolates or in patients intolerant of vancomycin. 12 Aminoglycosides—gentamicin, tobramycin, amikacin, netilmicin—should be chosen on the basis of local patterns of susceptibility. 13 Extended β-lactamase–producing isolates should be treated with a carbapenem. 14 Resistance is common and susceptibility testing should be done. 15 Ciprofloxacin has inferior antichlamydial activity compared with levofloxacin or ofloxacin. Key: ±, alone or combined with. 2
A. Etiologic Diagnosis Based on the organ system involved, the organism causing infection can often be predicted. See Tables 30–5 and 30–6.
B. “Best Guess” Select an empiric regimen that is likely to be effective against the suspected pathogens.
C. Laboratory Control Specimens for laboratory examination should be obtained before institution of therapy to determine susceptibility.
D. Clinical Response Based on clinical response and other data, the laboratory reports are evaluated and then the desirability of changing the regimen is considered. If the specimen was obtained from a normally sterile site (eg, blood, cerebrospinal fluid, pleural fluid, joint fluid), the recovery of a microorganism in significant amounts is meaningful even if the organism recovered is different from the clinically suspected agent,
and this may force a change in treatment. Isolation of unexpected microorganisms from the respiratory tract, gastrointestinal tract, or surface lesions (sites that have a complex flora) may represent colonization or contamination, and cultures must be critically evaluated before drugs are abandoned that were judiciously selected on a “best guess” basis.
E. Drug Susceptibility Tests Some microorganisms are predictably inhibited by certain drugs; if such organisms are isolated, they need not be tested for drug susceptibility. For example, all group A hemolytic streptococci are inhibited by penicillin. Other organisms (eg, enteric gram-negative rods) are variably susceptible and generally require susceptibility testing whenever they are isolated. Organisms that once had predictable susceptibility patterns have now become resistant and require testing. Examples include the pneumococci, which may be resistant to multiple drugs (including penicillin, macrolides, and TMP-SMZ); the enterococci, which may be resistant to penicillin, aminoglycosides,
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Table 30–5. Examples of initial antimicrobial therapy for acutely ill, hospitalized adults pending identification of causative organism. Suspected Clinical Diagnosis
1
Likely Etiologic Diagnosis 1
Drugs of Choice 2
Meningitis, bacterial, communityacquired
Pneumococcus, meningococcus
Cefotaxime, 2–3 g intravenously every 6 hours; or ceftriaxone, 2 g intravenously every 12 hours plus vancomycin, 10 mg/kg intravenously every 8 hours
Meningitis, bacterial, age > 50, community-acquired
Pneumococcus, meningococcus, Listeria monocytogenes,3 gram-negative bacilli
Ampicillin, 2 g intravenously every 4 hours, plus cefotaxime, 2–3 g intravenously every 6 hours; or ceftriaxone, 2 g intravenously every 12 hours plus vancomycin, 10 mg/kg intravenously every 8 hours
Meningitis, postoperative (or posttraumatic)
S aureus, gram-negative bacilli (pneumococcus, in posttraumatic)
Vancomycin, 10 mg/kg intravenously every 8 hours, plus cefepime, 3 g intravenously every 8 hours
Brain abscess
Mixed anaerobes, pneumococci, streptococci
Penicillin G, 4 million units intravenously every 4 hours, plus metronidazole, 500 mg orally every 8 hours; or cefotaxime, 2–3 g intravenously every 6 hours or ceftriaxone, 2 g intravenously every 12 hours plus metronidazole, 500 mg orally every 8 hours
Pneumonia, acute, communityacquired, non-ICU hospital admission
Pneumococci, M pneumoniae, Legionella, C pneumoniae
Cefotaxime, 2 g intravenously every 8 hours (or ceftriaxone, 1 g intravenously every 24 hours or ampicillin 2 g intravenously every 6 hours) plus azithromycin 500 mg intravenously every 24 hours; or a fluoroquinolone5 alone
Pneumonia, postoperative or nosocomial
S aureus, mixed anaerobes, gramnegative bacilli
Cefepime, 1 g intravenously every 8 hours; or ceftazidime, 2 g intravenously every 8 hours; or piperacillin-tazobactam, 4.5 g intravenously every 6 hours; or imipenem, 500 mg intravenously every 6 hours; or meropenem, 1 g intravenously every 8 hours plus tobramycin, 5 mg/kg intravenously every 24 hours; or ciprofloxacin, 400 mg intravenously every 12 hours; or levofloxacin, 500 mg intravenously every 24 hours plus vancomycin, 15 mg/kg intravenously every 12 hours
Endocarditis, acute (including injection drug user)
S aureus, E faecalis, gram-negative aerobic bacteria, viridans streptococci
Vancomycin, 15 mg/kg intravenously every 12 hours, plus gentamicin, 1 mg/kg every 8 hours
Septic thrombophlebitis (eg, IV tubing, IV shunts)
S aureus, gram-negative aerobic bacteria
Vancomycin, 15 mg/kg intravenously every 12 hours plus ceftriaxone, 1 g intravenously every 24 hours
Osteomyelitis
S aureus
Nafcillin, 2 g intravenously every 4 hours; or cefazolin, 2 g intravenously every 8 hours
Septic arthritis
S aureus, N gonorrhoeae
Ceftriaxone, 1–2 g intravenously every 24 hours
Pyelonephritis with flank pain and fever (recurrent urinary tract infection)
E coli, Klebsiella, Enterobacter, Pseudomonas
Ceftriaxone, 1 g intravenously every 24 hours; or ciprofloxacin, 400 mg intravenously every 12 hours (500 mg orally); or levofloxacin, 500 mg once daily ( intravenously/orally)
Fever in neutropenic patient receiving cancer chemotherapy
S aureus, Pseudomonas, Klebsiella, E coli
Ceftazidime, 2 g intravenously every 8 hours; or cefepime, 2 g intravenously every 8 hours
Intra-abdominal sepsis (eg, postoperative, peritonitis, cholecystitis)
Gram-negative bacteria, Bacteroides, anaerobic bacteria, streptococci, clostridia
Piperacillin-tazobactam, 4.5 g intravenously every 6 hours, or ertapenem, 1 g every 24 hours
Some strains may be resistant to penicillin. Most studies on meningitis have been with cefotaxime or ceftriaxone (see text). 3 TMP-SMZ can be used to treat Listeria monocytogenes in patients allergic to penicillin in a dosage of 15–20 mg/kg/d of TMP in three or four divided doses. 4 Depending on local drug susceptibility pattern, use tobramycin, 5 mg/kg/d, or amikacin, 15 mg/kg/d, in place of gentamicin. 5 Levofloxacin 750 mg/d, moxifloxacin 400 mg/d. 2
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Table 30–6. Examples of empiric choices of antimicrobials for adult outpatient infections. Suspected Clinical Diagnosis
Likely Etiologic Agents
Drugs of Choice
Alternative Drugs
Erysipelas, impetigo, cellulitis, ascending lymphangitis
Group A streptococcus
Phenoxymethyl penicillin, 0.5 g orally four times daily for 7–10 days
Cephalexin, 0.5 g orally four times daily for 7–10 days; or azithromycin, 500 mg on day 1 and 250 mg on days 2–5
Furuncle with surrounding cellulites
Staphylococcus aureus
Dicloxacillin, 0.5 g orally four times daily for 7–10 days (If high-risk for MRSA, clindamycin 0.3 g orally four times daily for 7–10 days)
Cephalexin, 0.5 g orally four times daily for 7–10 days. (If high-risk for MRSA, TMP-SMZ two double strength tablets twice daily for 7–10 days)
Pharyngitis
Group A streptococcus
Phenoxymethyl penicillin, 0.5 g orally four times daily for 10 days
Clindamycin, 300 mg orally four times daily for 10 days; or erythromycin, 0.5 g orally four times daily for 10 days; or azithromycin, 500 mg on day 1 and 250 mg on days 2–5; or clarithromycin, 500 mg twice daily for 10 days
Otitis media
Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis
Amoxicillin, 0.5–1 g orally three times daily for 10 days
Augmentin,2 0.875 g orally twice daily; or cefuroxime, 0.5 g orally twice daily; or cefpodoxime, 0.2–0.4 g daily; or doxycycline, 100 mg twice daily; or TMP-SMZ,1 one double-strength tablet twice daily (all regimens for 10 days).
Acute sinusitis
S pneumoniae, H influenzae, M catarrhalis
Amoxicillin, 0.5–1 g orally three times daily; or TMP-SMZ, one double-strength tablet twice daily for 10 days
Augmentin,2 0.875 g orally twice daily; or cefuroxime, 0.5 g orally twice daily; or cefpodoxime, 0.2–0.4 g daily; or doxycycline, 100 mg twice daily (all regimens for 10 days)
Aspiration pneumonia
Mixed oropharyngeal flora, including anaerobes
Clindamycin, 0.3 g orally four times daily for 10–14 days
Phenoxymethyl penicillin, 0.5 g orally four times daily for 10–14 days
Pneumonia
S pneumoniae, Mycoplasma pneumoniae, Legionella pneumophila, Chlamydophila pneumoniae
Doxycycline, 100 mg orally twice daily; or clarithromycin, 0.5 g orally twice daily, for 10–14 days; or azithromycin, 0.5 g orally on day 1 and 0.25 g on days 2–5
Amoxicillin, 0.5–1.0 g orally four times daily; or a fluoroquinolone5 for 10–14 days
Cystitis
Escherichia coli, Klebsiella pneumoniae, Proteus species, Staphylococcus saprophyticus
Fluoroquinolones,4 3 days for uncom- TMP-SMZ,1 one double-strength tablet plicated cystitis, nitrofurantoin twice daily for 3 days; or cephalexin, macrocrystals, 100 mg orally four 0.5 g orally four times daily for 7 days times daily for 7 days; nitrofurantoin monohydrate macrocrystals, 100 mg twice daily for 7 days
Pyelonephritis
E coli, K pneumoniae, Proteus species, S saprophyticus
Fluoroquinolones4 for 7–14 days
Gastroenteritis
Salmonella, Shigella, Campylobacter, Entamoeba histolytica
See Note 3
Urethritis, epididymitis
Neisseria gonorrhoeae, Chlamydia trachomatis
Ceftriaxone, 250 mg intramuscularly once or cefixime 400 mg orally once or cefpodoxime 200–400 mg orally once, for N gonorrhoeae; plus doxycycline, 100 mg orally twice daily for 10 days, for C trachomatis
TMP-SMZ,1 one double-strength tablet twice daily for 7–14 days
Ciprofloxacin, 500 mg orally once, for N gonorrhoeae; plus doxycycline, 100 mg orally twice daily for 10 days, or ofloxacin, 300 mg orally twice daily for 10 days
(continued )
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Table 30–6. Examples of empiric choices of antimicrobials for adult outpatient infections. (continued) Suspected Clinical Diagnosis
Likely Etiologic Agents
Drugs of Choice
N gonorrhoeae, C trachomatis, anaerobes, gram-negative rods
Levofloxacin 500 mg orally daily, or ofloxacin, 400 mg orally twice daily, for 14 days, plus metronidazole, 500 mg orally twice daily, for 14 days
Cefoxitin, 2 g intramuscularly, with probenecid, 1 g orally, followed by doxycycline, 100 mg orally twice daily for 14 days; or ceftriaxone, 250 mg intramuscularly once, followed by doxycycline, 100 mg orally twice daily for 14 days
Early syphilis (primary, secondary, or latent of < 1 year’s duration)
Treponema pallidum
Benzathine penicillin G, 2.4 million units intramuscularly once
Doxycycline, 100 mg orally twice daily for 2 weeks
Latent syphilis of > 1 year’s duration or cardiovascular syphilis
T pallidum
Benzathine penicillin G, 2.4 million units intramuscularly once a week for 3 weeks (total: 7.2 million units)
Doxycycline, 100 mg orally twice daily, for 4 weeks
Neurosyphilis
T pallidum
Aqueous penicillin G, 12–24 million units/d intravenously for 10–14 days
Pelvic inflammatory disease
Alternative Drugs
Syphilis
1 TMP-SMZ is a fixed combination of 1 part trimethoprim and 5 parts sulfamethoxazole. Single-strength tablets: 80 mg TMP, 400 mg SMZ; double-strength tablets: 160 mg TMP, 800 mg SMZ. 2 Augmentin is a combination of amoxicillin, 250 mg, 500 mg, or 875 mg, plus 125 mg of clavulanic acid. Augmentin XR is a combination of amoxicillin 1 g and clavulanic acid 62.5 mg. 3 The diagnosis should be confirmed by culture before therapy. Salmonella gastroenteritis does not require therapy. For susceptible Shigella isolates, give ciprofloxacin, 0.5 g orally twice daily for 5 days; or TMP-SMZ double-strength tablets twice daily for 5 days; or ampicillin, 0.5 g orally four times daily for 5 days. For Campylobacter infection, give azithromycin, 1 g orally times one dose, or ciprofloxacin, 0.5 g orally twice daily for 5 days. For E histolytica infection, give metronidazole, 750 mg orally three times daily for 5–10 days, followed by diiodohydroxyquin, 600 mg orally three times daily for 3 weeks. 4 Fluoroquinolones and dosages include ciprofloxacin, 500 mg orally twice daily; ofloxacin, 400 mg orally twice daily; levofloxacin, 500 mg orally daily. 5 Fluoroquinolones with activity against S pneumoniae, including penicillin-resistant isolates, include levofloxacin (500-750 mg orally once daily) and moxifloxacin (400 mg orally once daily). Use fluoroquinolones as drug of choice if recent antibiotic use within 3 months or comorbidities present. MRSA, methicillin-resistant Staphylococcus aureus; TMP-SMZ, trimethoprim-sulfamethoxazole.
and vancomycin; and extended-spectrum β-lactamase producing–E coli resistant to third-generation cephalosporins and fluoroquinolones. Over the past several years, pharmaceutical companies have shifted away from developing and producing antibacterial medications, particularly those active against gramnegative pathogens. The lack of new drugs and increasing bacterial resistance reinforce the need to use these drugs judiciously. When culture and susceptibility results have been finalized, it is important to utilize the most narrow spectrum agent possible to decrease the selection pressure for antibacterial resistance. Antimicrobial drug susceptibility tests may be performed on solid media as disk diffusion tests, in broth, in tubes, in wells of microdilution plates, or as E-tests (strips with increasing concentration of antibiotic). The latter three methods yield results expressed as MIC (minimal inhibitory concentration). In most infections, the MIC is the appropriate in vitro test to guide selection of an antibacterial agent. When there appear to be marked discrepancies
between susceptibility testing and clinical response, the following possibilities must be considered: 1. Selection of an inappropriate drug, drug dosage, or route of administration. 2. Failure to drain a collection of pus or to remove a foreign body. 3. Failure of a poorly diffusing drug to reach the site of infection (eg, central nervous system) or to reach intracellular phagocytosed bacteria. 4. Superinfection in the course of prolonged chemotherapy. 5. Emergence of drug-resistant organisms. 6. Participation of two or more microorganisms in the infectious process, of which only one was originally detected and used for drug selection. 7. Inadequate host defenses, including immunodeficiencies and diabetes. 8. Noninfectious causes, including drug fever, malignancy, and autoimmune disease.
Problems in Infectious Diseases & Antimicrobial Therapy F. Promptness of Response Response depends on a number of factors, including the patient (immunocompromised patients respond slower than immunocompetent patients), the site of infection (deep-seated infections such as osteomyelitis and endocarditis respond more slowly than superficial infections such as cystitis or cellulitis), the pathogen (virulent organisms such as S aureus respond more slowly than viridans streptococci; mycobacterial and fungal infections respond slower than bacterial infections), and the duration of illness (in general, the longer the symptoms are present, the longer it takes to respond). Thus, depending on the clinical situation, persistent fever and leukocytosis several days after initiation of therapy may not indicate improper choice of antibiotics but may be due to the natural history of the disease being treated. In most infections, either a bacteriostatic or a bactericidal agent can be used. In some infections (eg, infective endocarditis and meningitis), a bactericidal agent should be used. When potentially toxic drugs (eg, aminoglycosides, flucytosine) are used, serum levels of the drug are measured to minimize toxicity and ensure appropriate dosage. In patients with altered renal or hepatic clearance of drugs, the dosage or frequency of administration must be adjusted; it is best to measure levels in the elderly, morbidly obese patients, or those with altered kidney function when possible and adjust therapy accordingly.
G. Duration of Antimicrobial Therapy Generally, effective antimicrobial treatment results in reversal of the clinical and laboratory parameters of active infection and marked clinical improvement. However, varying periods of treatment may be required for cure. Key factors include (1) the type of infecting organism (bacterial infections generally can be cured more rapidly than fungal or mycobacterial ones), (2) the location of the process (eg, endocarditis and osteomyelitis require prolonged therapy), and (3) the immunocompetence of the patient. Recommendations about duration of therapy are often given based on clinical experience, not prospective controlled studies of large numbers of patients.
H. Adverse Reactions and Toxicity These include hypersensitivity reactions, direct toxicity, superinfection by drug-resistant microorganisms, and drug interactions. If the infection is life threatening and treatment cannot be stopped, the reactions are managed symptomatically or another drug is chosen that does not cross-react with the offending one (Table 30–4). If the infection is less serious, it may be possible to stop all antimicrobials and monitor the patient closely.
I. Route of Administration Intravenous therapy is preferred for acutely ill patients with serious infections (eg, endocarditis, meningitis, sepsis, severe pneumonia) when dependable levels of antibiotics are required for successful therapy. Certain drugs (eg, fluconazole, voriconazole, rifampin, metronidazole,
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TMP-SMZ, and fluoroquinolones) are so well absorbed that they generally can be administered orally in seriously ill—but not hemodynamically unstable—patients. Food does not significantly influence the bioavailability of most oral antimicrobial agents. However, the tetracyclines and the quinolones chelate multivalent cations resulting in decreased antibacterial absorption. Azithromycin capsules are associated with decreased bioavailability when taken with food and should be given 1 hour before or 2 hours after meals. Posaconazole solution should always be administered with food. A major complication of intravenous antibiotic therapy is catheter infections. Peripheral catheters are changed every 48–72 hours to prevent phlebitis, and antimicrobialcoated central venous catheters (minocycline and rifampin, chlorhexidine and sulfadiazine) have been associated with a decreased incidence of catheter-related infections. Most of these infections present with local signs of infection (erythema, tenderness) at the insertion site. In a patient with fever who is receiving intravenous therapy, the catheter must always be considered a potential source. Small-gauge (20–23F) peripherally inserted silicone or polyurethane catheters (Per Q Cath, A-Cath, Ven-A-Cath, and others) are associated with a low infection rate and can be maintained for 3–6 months without replacement. Such catheters are ideal for long-term outpatient antibiotic therapy.
J. Cost of Antibiotics The cost of these agents can be substantial. In addition to acquisition cost, monitoring costs, (drug levels, liver function tests, electrolytes, etc), the cost of treating adverse reactions, the cost of treatment failure, and the costs associated with drug administration must be considered. Boucher HW et al. Bad bugs, no drugs: no ESKAPE! An update from the Infectious Diseases Society of America. Clin Infect Dis. 2009 Jan 1;48(1):1–12. [PMID: 19035777] Drusano GL. Antimicrobial pharmacodynamics: critical interactions of ‘bug and drug’. Nat Rev Microbiol. 2004 Apr;2(4): 289–300. [PMID: 15031728]
HYPERSENSITIVITY TESTS & DESENSITIZATION ``Penicillin Allergy All penicillins are cross-sensitizing and cross-reacting. The responsible antigenic determinants appear to be degradation products of penicillins, particularly penicilloic acid and products of alkaline hydrolysis (minor antigenic determinants) bound to host protein. Skin tests with penicilloylpolylysine, with minor antigenic determinants, and with undegraded penicillin can identify most individuals with IgE-mediated reactions (hives, bronchospasm). Among positive reactors to skin tests, the incidence of subsequent immediate severe penicillin reactions is high. Although IgG antibodies to antigenic determinants of penicillin develop in many persons, the presence of such antibodies is not correlated with allergic reactivity (except for rare instances of
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hemolytic anemia), and serologic tests have little predictive value. A history of a penicillin reaction in the past is often not reliable. Only 15–20% of patients with a history of penicillin allergy have an adverse reaction when challenged with the drug. The decision to administer penicillin or related drugs (other β-lactams) to patients with an allergic history depends on the severity of the reported reaction, the severity of the infection being treated, and the availability of alternative drugs. For patients with a history of severe reaction (anaphylaxis), alternative drugs should be used. In the rare situations when there is a strong indication for using penicillin (eg, syphilis in pregnancy) in allergic patients, desensitization can be performed. If the reaction is mild (nonurticarial rash), the patient may be rechallenged with penicillin or may be given another β-lactam antibiotic. Allergic reactions include anaphylaxis, serum sickness (urticaria, fever, joint swelling, angioedema 7–12 days after exposure), skin rashes, fever, interstitial nephritis, eosinophilia, hemolytic anemia, other hematologic disturbances, and vasculitis. The incidence of hypersensitivity to penicillin is estimated to be 1–5% among adults in the United States. Life-threatening anaphylactic reactions are very rare (0.05%). Ampicillin produces maculopapular skin rashes more frequently than other penicillins, but many ampicillin (and other β-lactam) rashes are not allergic in origin. The non-allergic ampicillin rash usually occurs after 3–4 days of therapy, is maculopapular, is more common in patients with coexisting viral illness (especially EpsteinBarr infection), and resolves with continued therapy. The maculopapular rash may or may not reappear with rechallenge. Rarely, penicillins can induce nephritis with primary tubular lesions associated with anti-basement membrane antibodies. If the intradermal test described below is negative, desensitization is not necessary, and a full dose of the material may be given. If the test is positive, alternative drugs should be strongly considered. If that is not feasible, desensitization is necessary. Patients with a history of allergy to penicillin are also at an increased risk for having a reaction to cephalosporins or carbapenems. Skin testing with carbapenems has been recommended in patients with confirmed accelerated reaction to penicillins. A common approach to these patients is to assess the severity of the reaction. If an IgE-mediated reaction to penicillin can be excluded by history, a cephalosporin can be administered. When the history justifies concern about an immediate-type reaction, penicillin skin testing should be performed. If the test is negative, the cephalosporin or carbapenem can be given. If the test is positive, there is a 5–10% chance of cross reactivity with cephalosporins, and the decision whether to use cephalosporins depends on the availability of alternative agents and the severity of the infection. While carbapenems historically have been considered highly cross reactive with penicillins, the cross reactivity appears to be minimal (1–5%).
history of penicillin allergy has a positive predictive value of only 15%. IgG-mediated delayed reactions such as erythematous or maculopapular skin rash or serum sickness should be distinguished from immediate-type IgE-mediated reactions, such as urticaria, angioedema, and anaphylaxis. Penicillin skin testing traditionally was used to identify those patients with an accelerated reaction to penicillin. This process involves the introduction of penicillin breakdown products by intradermal or prick application to detect a localized allergic reaction. At the present time, no products are available for penicillin allergy skin testing. In 2004, the only commercially available product (Pre-Pen; HollisterStier Laboratories; Spokane, Washington) was voluntarily withdrawn by the manufacturer from US and Canadian markets due to product irregularities. However, AllerQuest (West Hartford, Connecticut) is pursuing approval from the US Food and Drug Administration to manufacture and market Pre-Pen.
``Desensitization A. Precautions 1. The desensitization procedure is not innocuous— deaths from anaphylaxis have been reported. If extreme hypersensitivity is suspected, it is advisable to use an alternative structurally unrelated drug and to reserve desensitization for situations when treatment cannot be withheld and no alternative drug is available. 2. An antihistaminic drug (25–50 mg of hydroxyzine or diphenhydramine intramuscularly or orally) should be administered before desensitization is begun in order to lessen any reaction that occurs. 3. Desensitization should be conducted in an intensive care unit where cardiac monitoring and emergency endotracheal intubation can be performed. 4. Epinephrine, 1 mL of 1:1000 solution, must be ready for immediate administration.
B. Desensitization Method Several methods of desensitization have been described for penicillin, including use of both oral and intravenous preparations. All methods start with very small doses of drug and gradually increase the dose until therapeutic doses are achieved. For penicillin, 1 unit of drug is given intravenously and the patient observed for 15–30 minutes. If there is no reaction, some recommend doubling the dose while others recommend increasing it tenfold every 15–30 minutes until a dosage of 2 million units is reached; then give the remainder of the desired dose. For recommendations on skin testing and desensitization for other preparations (eg, botulism antitoxin and diphtheria antitoxin), the manufacturer’s package inserts should be consulted.
``Treatment of Reactions ``Intradermal Test for Hypersensitivity
A. Mild Reactions
Penicillin is the drug that most frequently serves as an indication for sensitivity testing and desensitization. A clinical
If a mild reaction occurs, drop back to the next lower dose and continue with desensitization. If a severe reaction
Problems in Infectious Diseases & Antimicrobial Therapy occurs, administer epinephrine (see below) and discontinue the drug unless treatment is urgently needed. If desensitization is imperative, continue slowly, increasing the dosage of the drug more gradually.
B. Severe Reactions If bronchospasm occurs, epinephrine, 0.3–0.5 mL of 1:1000 dilution, should be given subcutaneously every 10–20 minutes, followed by corticosteroids (250 mg of hydrocortisone or 50 mg of methylprednisolone intravenously every 6 hours for two to four doses), if needed. Hypotension should be treated with intravenous fluids (saline or colloid), epinephrine (1 mL of 1:1000 dilution in 500 mL of D5W intravenously at a rate of 0.5–5 mcg/min), and antihistamines (25–50 mg of hydroxyzine or diphenhydramine intramuscularly or orally every 6–8 hours as needed). Cutaneous reactions, manifested as urticaria or angioedema, respond to epinephrine subcutaneously and antihistamines in the doses set forth above. Arroliga ME et al. Penicillin allergy: consider trying penicillin again. Cleve Clin J Med. 2003 Apr;70(4):313–4, 317–8, 320–1 passim. [PMID: 12701985] Gruchalla RS et al. Clinical practice. Antibiotic allergy. N Engl J Med. 2006 Feb 9;354(6):601–9. [PMID: 16467547]
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IMMUNIZATION AGAINST INFECTIOUS DISEASES 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 can be accessed at www.cdc.gov/vaccines/recs/schedules. 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 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, to obtain HPV vaccine if not given previously, and to receive immunizations (influenza and pneumococcal vaccines) that may be indicated for certain high-risk individuals.
RECOMMENDED IMMUNIZATION FOR ADULTS Immunization is one of the most important tools (along with sanitation) used to prevent morbidity and mortality from infectious diseases. In general, the administration of most vaccinations induces a durable antibody response (active immunity). In contrast, passive immunization occurs when preformed antibodies are given (eg, immune globulin from pooled serum), resulting in temporary protection which is a less durable response. The two variants of active immunization are live attenuated vaccines (which
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are believed to result in an immunologic response more like natural infection), and inactivated or killed vaccines. The schedule of vaccinations varies based on the risk of the disease being prevented by vaccination, whether a vaccine has been given previously, the immune status of the patient (probability of responding to vaccine) and safety of the vaccine (live versus killed product, as well implications for the fetus in pregnant women). Recommendations for healthy adults as well as special populations based on medical conditions are summarized in Table 30–7, which can be accessed online at www.cdc.gov/vaccines/ recs/schedules.
1. Healthy Adults Vaccination recommendations are made by the Advisory Committee on Immunization Practices (ACIP) of the US Centers for Disease Control and Prevention (Table 30–7). In general, all adults should be immune to diphtheria, tetanus, varicella, measles, mumps and rubella, and vaccinated if not immune. Pertussis (via Tdap) boosters should be given once to all adults younger than 65 years, including pregnant women but after the end of the second trimester. A pertussis booster should be administered to persons aged 65 years and older if there is close child contact. The following vaccines are recommended for certain adult subgroups: HPV (women and men up to age 26), herpes zoster (adults aged 60 years and older), hepatitis A (men who have sex with men, injection drug users, patients with chronic liver disease), hepatitis B (sexually active adults, injection drug users, health care workers, patients with chronic kidney and liver disease, and patients with diabetes mellitus under the age of 60 years), and meningococcal vaccination (college freshmen, military recruits, patients with asplenia and terminal complement deficiencies). Pneumococcal polysaccharide vaccination (PPSV23) should be offered to persons 65 years and older, any adult with chronic medical comorbidities, and all cigarette smokers. Influenza vaccination should be offered annually to all persons aged 6 months and older.
2. Pregnant Women Given the uncertainty of risks to the fetus, vaccination during pregnancy is generally avoided with the following exceptions: tetanus (transfer of maternal antibodies across the placenta important to prevent neonatal tetanus), diphtheria, and influenza. Live vaccines are avoided during pregnancy. If the woman is pregnant and > 10 years has elapsed since tetanus and diphtheria toxoid vaccine (Td), then a Td booster vaccination should be given during the second or third trimester. ACIP also recommends prevention of pertussis in pregnant women (given the repercussions of transmission to the infant) since immunity wanes by adulthood. Women should therefore receive the combined tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine (Tdap) if possible. Tdap can be administered prior to conception, late in second trimester (> 20 weeks gestation), or in the immediate postpartum period if the mother has not previously received Tdap or if she only received Td during pregnancy.
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Table 30–7. Recommended adult immunization schedule—United States, 2012.
Recommended Adult Immunization Schedule—United States - 2012 Note: These recommendations must be read with the footnotes that follow containing number of doses, intervals between doses, and other important information.
VACCINE
AGE GROUP
19-21 years
22-26 years
27-49 years
50-59 years
60-64 years
≥ 65 years
1 dose annually
Influenza2 Tetanus, diphtheria, pertussis (Td/Tdap)3,*
Td/Tdap3
Substitute 1-time dose of Tdap for Td booster; then boost with Td every 10 yrs
Varicella4,*
CMDT 2013
Recommended adult immunization schedule, by vaccine and age group1
2 Doses 3 doses
Human papillomavirus (HPV) Male5,*
3 doses
Zoster 6
Chapter 30
Human papillomavirus (HPV) Female5,*
1 dose
Measles, mumps, rubella (MMR)7,*
1 or 2 doses
Pneumococcal (polysaccharide)8,9
1 dose 1 or 2 doses
1 dose
1 or more doses
Meningococcal10,* Hepatitis A11,*
2 doses
Hepatitis B12,*
3 doses
*Covered by the Vaccine Injury Compensation Program For all persons in this category who meet the age requirements and who lack documentation of vaccination or have no evidence of previous infection
Recommended if some other risk factor is present (e.g., on the basis of medical, occupational, lifestyle, or other indications)
Tdap recommended for ≥65 if contact with <12 month old child. Either Td or Tdap can be used if no infant contact
No recommendation
Report all clinically significant postvaccination reactions to the Vaccine Adverse Event Reporting System (VAERS). Reporting forms and instructions on filing a VAERS report are available at www.vaers.hhs.gov or by telephone, 800-822-7967. Information on how to file a Vaccine Injury Compensation Program claim is available at www.hrsa.gov/vaccinecompensation or by telephone, 800-338-2382. To file a claim for vaccine injury, contact the U.S. Court of Federal Claims, 717 Madison Place, N.W., Washington, D.C. 20005; telephone, 202-357-6400. Additional information about the vaccines in this schedule, extent of available data, and contraindications for vaccination is also available at www.cdc.gov/vaccines or from the CDC-INFO Contact Center at 800-CDC-INFO (800-232-4636) in English and Spanish, 8:00 a.m. - 8:00 p.m. Eastern Time, Monday - Friday, excluding holidays. Use of trade names and commercial sources is for identification only and does not imply endorsement by the U.S. Department of Health and Human Services.
VACCINE
INDICATION
Pregnancy
Immunocompromising conditions (excluding human immunodeficiency virus [HIV])
HIV infection CD4+ T lymphocyte count <200 cells/ µL
>200 cells/µL
1 dose TIV or LAIV annually
1 dose TIV annually
Influenza2 Tetanus, diphtheria, pertussis (Td/Tdap)3,*
Men who have sex with men (MSM)
Heart disease, chronic lung disease, chronic alcoholism
Asplenia (including elective splenectomy and persistent complement component deficiencies)
Chronic liver disease
Diabetes, kidney failure, end-stage renal disease, receipt of hemodialysis
1 dose TIV annually
Health-care personnel
1 dose TIV or LAIV annually
Substitute 1-time dose of Tdap for Td booster; then boost with Td every 10 yrs Contraindicated
Varicella4,*
2 doses 3 doses through age 26 yrs
3 doses through age 26 yrs
5,
Human papillomavirus (HPV) Female * Human papillomavirus (HPV) Male5,*
3 doses through age 21 yrs
3 doses through age 26 yrs Contraindicated
Zoster 6
1 dose
Contraindicated
7,
Measles, mumps, rubella (MMR) *
1 or 2 doses 1 or 2 doses 1 dose TIV annually
Pneumococcal (polysaccharide)8,9
1 or more doses
10,
Meningococcal * Hepatitis A11,*
2 doses
Hepatitis B12,*
3 doses
Problems in Infectious Diseases & Antimicrobial Therapy
Vaccines that might be indicated for adults based on medical and other indications1
*Covered by the Vaccine Injury Compensation Program For all persons in this category who meet the age requirements and who lack documentation of vaccination or have no evidence of previous infection
Recommended if some other risk factor is present (e.g., on the basis of medical, occupational, lifestyle, or other indications)
Contraindicated
No recommendation
CMDT 2013
The recommendations in this schedule were approved by the Centers for Disease Control and Prevention’s (CDC) Advisory Committee on Immunization Practices (ACIP), the American Academy of Family Physicians (AAFP), the American College of Physicians (ACP), American College of Obstetricians and Gynecologists (ACOG) and American College of Nurse-Midwives (ACNM).
These schedules indicate the recommended age groups and medical indications for which administration of currently licensed vaccines is commonly indicated for adults ages 19 years and older, as of January 1, 2012. For all vaccines being recommended on the Adult Immunization Schedule: a vaccine series does not need to be restarted, regardless of the time that has elapsed between doses. Licensed combination vaccines may be used whenever any components of the combination are indicated and when the vaccine’s other components are not contraindicated. For detailed recommendations on all vaccines, including those used primarily for travelers or that are issued during the year, consult the manufacturers’ package inserts and the complete statements from the Advisory Committee on Immunization Practices (www.cdc.gov/vaccines/pubs/acip-list.htm). Use of trade names and commercial sources is for identification only and does not imply endorsement by the U.S. Department of Health and Human Services.
(continued )
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U.S. Department of Health and Human Services Centers for Disease Control and Prevention
Footnotes — Recommended Adult Immunization Schedule—United States - 2012
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1. Additional information • Advisory Committee on Immunization Practices (ACIP) vaccine recommendations and additional information are available at: http://www.cdc.gov/vaccines/pubs/acip-list.htm. • Information on travel vaccine requirements and recommendations (e.g., for hepatitis A and B, meningococcal, and other vaccines) available at http://wwwnc.cdc.gov/ travel/page/vaccinations.htm. 2. Influenza vaccination • Annual vaccination against influenza is recommended for all persons 6 months of age and older. • Persons 6 months of age and older, including pregnant women, can receive the trivalent inactivated vaccine (TIV). • Healthy, nonpregnant adults younger than age 50 years without high-risk medical conditions can receive either intranasally administered live, attenuated influenza vaccine (LAIV) (FluMist), or TIV. Health-care personnel who care for severely immunocompromised persons (i.e., those who require care in a protected environment) should receive TIV rather than LAIV. Other persons should receive TIV. • The intramuscular or intradermal administered TIV are options for adults aged 18–64 years. • Adults aged 65 years and older can receive the standard dose TIV or the high-dose TIV (Fluzone High-Dose). 3. Tetanus, diphtheria, and acellular pertussis (Td/Tdap) vaccination • Administer a one-time dose of Tdap to adults younger than age 65 years who have not received Tdap previously or for whom vaccine status is unknown to replace one of the 10-year Td boosters. • Tdap is specifically recommended for the following persons: — pregnant women more than 20 weeks’ gestation, — adults, regardless of age, who are close contacts of infants younger than age 12 months (e.g., parents, grandparents, or child care providers), and — health-care personnel. • Tdap can be administered regardless of interval since the most recent tetanus or diphtheria-containing vaccine. • Pregnant women not vaccinated during pregnancy should receive Tdap immediately postpartum. • Adults 65 years and older may receive Tdap. • Adults with unknown or incomplete history of completing a 3-dose primary vaccination series with Td-containing vaccines should begin or complete a primary vaccination series. Tdap should be substituted for a single dose of Td in the vaccination series with Tdap preferred as the first dose. • For unvaccinated adults, administer the first 2 doses at least 4 weeks apart and the third dose 6–12 months after the second. • If incompletely vaccinated (i.e., less than 3 doses), administer remaining doses. Refer to the ACIP statement for recommendations for administering Td/Tdap as prophylaxis in wound management (See footnote 1). 4. Varicella vaccination • All adults without evidence of immunity to varicella (as defined below) should receive 2 doses of single-antigen varicella vaccine or a second dose if they have received only 1 dose. • Special consideration for vaccination should be given to those who — have close contact with persons at high risk for severe disease (e.g., health-care personnel and family contacts of persons with immunocompromising conditions) or — are at high risk for exposure or transmission (e.g., teachers; child care employees; residents and staff members of institutional settings, including correctional institutions; college students; military personnel; adolescents and adults living in households with children; nonpregnant women of childbearing age; and international travelers). • Pregnant women should be assessed for evidence of varicella immunity. Women who do not have evidence of immunity should receive the first dose of varicella vaccine upon completion or termination of pregnancy and before discharge from the health-care facility. The second dose should be administered 4–8 weeks after the first dose. • Evidence of immunity to varicella in adults includes any of the following: — documentation of 2 doses of varicella vaccine at least 4 weeks apart; — U.S.-born before 1980 (although for health-care personnel and pregnant women, birth before 1980 should not be considered evidence of immunity); — history of varicella based on diagnosis or verification of varicella by a health-care provider (for a patient reporting a history of or having an atypical case, a mild case, or both, health-care providers should seek either an epidemiologic link to a typical varicella case or to a — laboratory-confirmed case or evidence of laboratory confirmation, if it was performed at the time of acute disease); — history of herpes zoster based on diagnosis or verification of herpes zoster by a health-care provider; or — laboratory evidence of immunity or laboratory confirmation of disease.
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Table 30–7. Recommended adult immunization schedule—United States, 2012. (continued)
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5. Human papillomavirus (HPV) vaccination • Two vaccines are licensed for use in females, bivalent HPV vaccine (HPV2) and quadrivalent HPV vaccine (HPV4), and one HPV vaccine for use in males (HPV4). • For females, either HPV4 or HPV2 is recommended in a 3-dose series for routine vaccination at 11 or 12 years of age, and for those 13 through 26 years of age, if not previously vaccinated. • For males, HPV4 is recommended in a 3-dose series for routine vaccination at 11 or 12 years of age, and for those 13 through 21 years of age, if not previously vaccinated. Males 22 through 26 years of age may be vaccinated. • HPV vaccines are not live vaccines and can be administered to persons who are immunocompromised as a result of infection (including HIV infection), disease, or medications. Vaccine is recommended for immunocompromised persons through age 26 years who did not get any or all dosed when they were younger. The immune response and vaccine efficacy might be less than that in immunocompetent persons. • Men who have sex with men (MSM) might especially benefit from vaccination to prevent condyloma and anal cancer. HPV4 is recommended for MSM through age 26 years who did not get any or all doses when they were younger. • Ideally, vaccine should be administered before potential exposure to HPV through sexual activity; however, persons who are sexually active should still be vaccinated consistent with age-based recommendations. HPV vaccine can be administered to persons with a history of genital warts, abnormal Papanicolaou test, or positive HPV DNA test. • A complete series for either HPV4 or HPV2 consists of 3 doses. The second dose should be administered 1–2 months after the first dose; the third dose should be administered 6 months after the first dose (at least 24 weeks after the first dose). • Although HPV vaccination is not specifically recommended for health-care personnel (HCP) based on their occupation, HCP should receive the HPV vaccine if they are in the recommended age group. 6. Zoster vaccination • A single dose of zoster vaccine is recommended for adults 60 years of age and older regardless of whether they report a prior episode of herpes zoster. Although the vaccine is licensed by the Food and Drug Administration (FDA) for use among and can be administered to persons 50 years and older, ACIP recommends that vaccination begins at 60 years of age. • Persons with chronic medical conditions may be vaccinated unless their condition constitutes a contraindication, such as pregnancy or severe immunodeficiency. • Although zoster vaccination is not specifically recommended for health-care personnel (HCP), HCP should receive the vaccine if they are in the recommended age group. 7. Measles, mumps, rubella (MMR) vaccination • Adults born before 1957 generally are considered immune to measles and mumps. All adults born in 1957 or later should have documentation of 1 or more doses of MMR vaccine unless they have a medical contraindication to the vaccine, laboratory evidence of immunity to each of the three diseases, or documentation of provider-diagnosed measles or mumps disease. For rubella, documentation of provider-diagnosed disease is not considered acceptable evidence of immunity. Measles component: • A routine second dose of MMR vaccine, administered a minimum of 28 days after the first dose, is recommended for adults who — are students in postsecondary educational institutions; — work in a health-care facility; or — plan to travel internationally. • Persons who received inactivated (killed) measles vaccine or measles vaccine of unknown type from 1963 to 1967 should be revaccinated with 2 doses of MMR vaccine. Mumps component: • A routine second dose of MMR vaccine, administered a minimum of 28 days after the first dose, is recommended for adults who — are students in postsecondary educational institutions; — work in a health-care facility; or — plan to travel internationally. • Persons vaccinated before 1979 with either killed mumps vaccine or mumps vaccine of unknown type who are at high risk for mumps infection (e.g., persons who are working in a health-care facility) should be considered for revaccination with 2 doses of MMR vaccine. Rubella component: • For women of childbearing age, regardless of birth year, rubella immunity should be determined. If there is no evidence of immunity, women who are not pregnant should be vaccinated. Pregnant women who do not have evidence of immunity should receive MMR vaccine upon completion or termination of pregnancy and before discharge from the health-care facility. Health-care personnel born before 1957: • For unvaccinated health-care personnel born before 1957 who lack laboratory evidence of measles, mumps, and/or rubella immunity or laboratory confirmation of disease, health-care facilities should consider routinely vaccinating personnel with 2 doses of MMR vaccine at the appropriate interval for measles and mumps or 1 dose of MMR vaccine for rubella.
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8. Pneumococcal polysaccharide (PPSV) vaccination • Vaccinate all persons with the following indications: — age 65 years and older without a history of PPSV vaccination; — adults younger than 65 years with chronic lung disease (including chronic obstructive pulmonary disease, emphysema, and asthma); chronic cardiovascular diseases; diabetes mellitus; chronic liver disease (including cirrhosis); alcoholism; cochlear implants; cerebrospinal fluid leaks; immunocompromising conditions; and functional or anatomic asplenia (e.g., sickle cell disease and other hemoglobinopathies, congenital or acquired asplenia, splenic dysfunction, or splenectomy [if elective splenectomy is planned, vaccinate at least 2 weeks before surgery]); — residents of nursing homes or long-term care facilities; and — adults who smoke cigarettes. • Persons with asymptomatic or symptomatic HIV infection should be vaccinated as soon as possible after their diagnosis. • When cancer chemotherapy or other immunosuppressive therapy is being considered, the interval between vaccination and initiation of immunosuppressive therapy should be at least 2 weeks. Vaccination during chemotherapy or radiation therapy should be avoided. • Routine use of PPSV is not recommended for American Indians/Alaska Natives or other persons younger than 65 years of age unless they have underlying medical conditions that are PPSV indications. However, public health authorities may consider recommending PPSV for American Indians/Alaska Natives who are living in areas where the risk for invasive pneumococcal disease is increased. 9. Revaccination with PPSV • One-time revaccination 5 years after the first dose is recommended for persons 19 through 64 years of age with chronic renal failure or nephrotic syndrome; functional or anatomic asplenia (e.g., sickle cell disease or splenectomy); and for persons with immunocompromising conditions. • Persons who received PPSV before age 65 years for any indication should receive another dose of the vaccine at age 65 years or later if at least 5 years have passed since their previous dose. • No further doses are needed for persons vaccinated with PPSV at or after age 65 years. 10. Meningococcal vaccination • Administer 2 doses of meningococcal conjugate vaccine quadrivalent (MCV4) at least 2 months apart to adults with functional asplenia or persistent complement component deficiencies. • HIV-infected persons who are vaccinated should also receive 2 doses. • Administer a single dose of meningococcal vaccine to microbiologists routinely exposed to isolates of Neisseria meningitidis, military recruits, and persons who travel to or live in countries in which meningococcal disease is hyperendemic or epidemic. • First-year college students up through age 21 years who are living in residence halls should be vaccinated if they have not received a dose on or after their 16th birthday. • MCV4 is preferred for adults with any of the preceding indications who are 55 years old and younger; meningococcal polysaccharide vaccine (MPSV4) is preferred for adults 56 years and older. • Revaccination with MCV4 every 5 years is recommended for adults previously vaccinated with MCV4 or MPSV4 who remain at increased risk for infection (e.g., adults with anatomic or functional asplenia or persistent complement component deficiencies). 11. Hepatitis A vaccination • Vaccinate any person seeking protection from hepatitis A virus (HAV) infection and persons with any of the following indications: — men who have sex with men and persons who use injection drugs; — persons working with HAV-infected primates or with HAV in a research laboratory setting; — persons with chronic liver disease and persons who receive clotting factor concentrates; — persons traveling to or working in countries that have high or intermediate endemicity of hepatitis A; and — unvaccinated persons who anticipate close personal contact (e.g., household or regular babysitting) with an international adoptee during the first 60 days after arrival in the United States from a country with high or intermediate endemicity. (See footnote 1 for more information on travel recommendations). The first dose of the 2-dose hepatitis A vaccine series should be administered as soon as adoption is planned, ideally 2 or more weeks before the arrival of the adoptee. • Single-antigen vaccine formulations should be administered in a 2-dose schedule at either 0 and 6–12 months (Havrix), or 0 and 6–18 months (Vaqta). If the combined hepatitis A and hepatitis B vaccine (Twinrix) is used, administer 3 doses at 0, 1, and 6 months; alternatively, a 4-dose schedule may be used, administered on days 0, 7, and 21–30 followed by a booster dose at month 12.
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Table 30–7. Recommended adult immunization schedule—United States, 2012. (continued)
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12. Hepatitis B vaccination • Vaccinate persons with any of the following indications and any person seeking protection from hepatitis B virus (HBV) infection: — sexually active persons who are not in a long-term, mutually monogamous relationship (e.g., persons with more than one sex partner during the previous 6 months); persons seeking evaluation or treatment for a sexually transmitted disease (STD); current or recent injection-drug users; and men who have sex with men; — health-care personnel and public-safety workers who are exposed to blood or other potentially infectious body fluids; — persons with diabetes younger than 60 years as soon as feasible after diagnosis; persons with diabetes who are 60 years or older at the discretion of the treating clinician based on increased need for assisted blood glucose monitoring in long-term care facilities, likelihood of acquiring hepatitis B infection, its complications or chronic sequelae, and likelihood of immune response to vaccination; — persons with end-stage renal disease, including patients receiving hemodialysis; persons with HIV infection; and persons with chronic liver disease; — household contacts and sex partners of persons with chronic HBV infection; clients and staff members of institutions for persons with developmental disabilities; and international travelers to countries with high or intermediate prevalence of chronic HBV infection; and — all adults in the following settings: STD treatment facilities; HIV testing and treatment facilities; facilities providing drug-abuse treatment and prevention services; health-care settings targeting services to injection-drug users or men who have sex with men; correctional facilities; end-stage renal disease programs and facilities for chronic hemodialysis patients; and institutions and nonresidential daycare facilities for persons with developmental disabilities. • Administer missing doses to complete a 3-dose series of hepatitis B vaccine to those persons not vaccinated or not completely vaccinated. The second dose should be administered 1 month after the first dose; the third dose should be given at least 2 months after the second dose (and at least 4 months after the first dose). If the combined hepatitis A and hepatitis B vaccine (Twinrix) is used, give 3 doses at 0, 1, and 6 months; alternatively, a 4-dose Twinrix schedule, administered on days 0, 7, and 21–30 followed by a booster dose at month 12 may be used. • Adult patients receiving hemodialysis or with other immunocompromising conditions should receive 1 dose of 40 µg/mL (Recombivax HB) administered on a 3-dose schedule or 2 doses of 20 µg/mL (Engerix-B) administered simultaneously on a 4-dose schedule at 0, 1, 2, and 6 months. 13. Selected conditions for which Haemophilus influenzae type b (Hib) vaccine may be used • 1 dose of Hib vaccine should be considered for persons who have sickle cell disease, leukemia, or HIV infection, or who have anatomic or functional asplenia if they have not previously received Hib vaccine. 14. Immunocompromising conditions • Inactivated vaccines generally are acceptable (e.g., pneumococcal, meningococcal, and influenza [inactivated influenza vaccine]), and live vaccines generally are avoided in persons with immune deficiencies or immunocompromising conditions. Information on specific conditions is available at http://www.cdc.gov/vaccines/pubs/acip-list.htm.
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Influenza can be a serious infection if acquired in pregnancy, and all pregnant women should be offered influenza (inactivated) vaccination. The live attenuated (intranasal) influenza vaccine is not recommended during pregnancy.
3. HIV-Infected Adults HIV-infected patients have impaired cellular and B cell responses. Inactivated or killed vaccinations can generally be given without any consequence, but the recipient may not be able to mount an adequate antibody response. Live or attenuated vaccines are generally avoided with some exceptions (ie, in patients with CD4+ T lymphocytes > 200 cells/mcL). Guidelines for vaccinating HIV-infected patients have been issued jointly by the Centers for Disease Control and Prevention, the US National Institutes of Health, and the HIV Medical Association of the Infectious Diseases Society of America. The following non-live vaccines are recommended for all HIV-infected patients: tetanus and diphtheria toxoid (Tdap as a booster once, followed by Td boosters every 10 years), HPV (in women and men until age 26), inactivated influenza, pneumococcal polysaccharide (PPSV23), hepatitis A (for HIV-infected men who have sex with men, injection drug users, patients with chronic liver disease), hepatitis B, and meningococcal vaccines (two doses for those at risk). Several live vaccines are now recommended for eligible HIV-infected patients with CD4+ T cells > 200 cells/mcL: measles, mumps, and rubella (MMR); varicella; and zoster. Timing of vaccination is important to optimize response. If possible, vaccination should be given early in the course of HIV-disease, or following immune reconstitution.
4. Hematopoietic Cell Transplant Recipients Hematopoietic cell transplant (HCT) recipients have varying rates of immune reconstitution following transplantation, depending on (1) the type of chemotherapy or radiotherapy used pretransplant (in autologous HCT), (2) the preparative regimen used for the transplant (3) whether graft-versus-host disease is present, and (4) the type of immunosuppression used posttransplantation (in allogeneic HCT). Vaccines may not work immediately in the posttransplant period. B cells may take 3–12 months to return to normal posttransplant, and naïve T cells that can respond to new antigens only appear 6–12 months posttransplant. B cells of posttransplant patients treated with rituximab may take up to 6 months to fully recover after the last dose of the drug. Vaccines are therefore administered 6–12 months following transplantation with a minimum of 1 month between doses to maximize the probability of response. The following vaccines are recommended for HCT recipients: tetanus, diphtheria and pertussis (three doses of Tdap, although full-dose DTaP currently given to children < 7 years may be more immunogenic), inactivated polio (three doses), H influenzae (three doses), pneumococcal vaccine (can start at 3 months posttransplant; use three doses of pneumococcal conjugate vaccine [PCV; more immunogenic but covers only 7 strains of pneumococcus], followed by the polysaccharide vaccine [PPSV23, covers 23 strains]), and inactivated influenza (annually). Patients
may receive the live vaccines of MMR and varicella if at least 24 months have passed since the transplant and if they do not have graft-versus-host disease and are not receiving immunosuppressive medications. However, data supporting these recommendations are limited.
5. Solid Organ Transplant Recipients Solid organ transplant recipients demonstrate a broad spectrum of immunosuppression, depending on the reason for and type of organ transplanted and the nature of the immunosuppression (including T-cell depleting agents during treatment of organ rejection). These factors affect the propensity for infection posttransplantation and the ability to develop antibody responses to vaccination. In many cases, the time between placing a patient on a transplant list and undergoing the transplantation takes months or years. Providers should take this opportunity to ensure that indicated vaccines are given during this pretransplant period to optimize antibody responses. If this is not possible, most experts give vaccines 3–6 months following transplantation. Live vaccines are contraindicated in the posttransplant period. The American Society of Transplantation Infectious Diseases Community of Practice last issued vaccination guidelines in 2009. The following inactivated vaccines are recommended for patients posttransplantation if not given before transplantation: tetanus and diphtheria toxoid (Tdap as a booster once if no tetanus booster in the past 10 years, followed by Td boosters every 10 years), inactivated polio, HPV (until age 26), inactivated influenza, pneumococcal polysaccharide (PPSV23), hepatitis A (for HIV-infected men who have sex with men, injection drug users, patients with chronic liver disease), hepatitis B, and meningococcal vaccines (for those at risk).
RECOMMENDED IMMUNIZATIONS FOR TRAVELERS Individuals traveling to other countries frequently require immunizations in addition to those routinely recommended and may benefit from chemoprophylaxis against various diseases. Vaccinations against yellow fever and meningococcus are the only ones required by certain countries. These and other travel-specific vaccines are listed http://wwwnc.cdc.gov/travel/page/vaccinations.htm. Various vaccines can be given simultaneously at different sites. Some, such as cholera, plague, and typhoid vaccine, cause significant discomfort and are best given at different times. In general, live attenuated vaccines (measles, mumps, rubella, yellow fever, and oral typhoid vaccine) should not be given to immunosuppressed individuals or household members of immunosuppressed people or to pregnant women. Immunoglobulin should not be given for 3 months before or at least 2 weeks after live virus vaccines, because it may attenuate the antibody response. Chemoprophylaxis of malaria is discussed in Chapter 35.
``Cholera Because cholera among travelers is rare and the vaccine marginally effective, the World Health Organization (WHO) does not require immunization for persons traveling
Problems in Infectious Diseases & Antimicrobial Therapy to endemic areas or to areas with recent outbreaks (eg, Haiti). No country requires vaccination for entry, but some local authorities may require documentation for entry. In such cases, a medical waiver will suffice or a single dose of the oral vaccine is usually sufficient.
``Hepatitis B The risk of hepatitis B infection for most international travelers is low. Hepatitis B vaccination should be considered for those traveling to areas with high (≥ 8%) or intermediate (2–7%) rates of endemic hepatitis B infection if the individual will have contact with blood or secretions, have unprotected sex, or will be using illicit drugs. Examples of high and intermediate risk areas include all of Africa and most of South Asia and the Middle East. Vaccination should begin at least 6 months before travel to allow for completion of the series.
``Hepatitis A Protection is recommended for susceptible persons traveling to areas where sanitation is poor and the risk of exposure to hepatitis A high because of contaminated food and water supplies and contact with infected persons (eg, anywhere except Canada, western Europe, Japan, Australia, and New Zealand). Either hepatitis A vaccine or immunoglobulin can be used, although vaccination is preferred. The first dose of vaccine should be given as soon as travel is considered. In healthy individuals, a single dose of vaccine administered any time prior to travel will provide adequate protection. In older patients, those who are immunocompromised, and those with chronic liver disease or other chronic medical problems who are planning to travel in 2 weeks or less should receive hepatitis A vaccine and immunoglobulin 0.02 mL/kg simultaneously at different anatomic sites. Those who choose not to receive vaccine should receive immunoglobulin.
``Meningococcal Meningitis If travel is contemplated to an area where meningococcal meningitis is epidemic (Nepal, sub-Saharan Africa, the “meningitis belt” from Senegal in the west to Ethiopia in the east, northern India) or highly endemic, vaccination with MCV4 is indicated for those 2–55 years of age, otherwise MPSV should be used. (Saudi Arabia requires immunization for pilgrims to Mecca.)
``Plague The risk of plague is so small to travelers that vaccine is no longer commercially available and vaccination is not required for entry into any country. Travelers at unavoidable high risk of exposure to rodents should consider chemoprophylaxis with doxycycline or TMP-SMZ.
``Poliomyelitis Polio remains endemic in five countries (Afghanistan, India, Pakistan, Nigeria, and Niger), and sporadic outbreaks from reinfection continues to occur in Somalia, Ethiopia, Angola, and Bangladesh. Adults traveling to
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endemic or epidemic areas who have not previously been immunized against poliomyelitis should receive a primary series of three doses of inactivated enhanced-potency poliovaccine (IPV). Travelers who have previously been fully immunized with oral polio vaccine (OPV) or inactivated polio vaccine (IPV) should receive a one-time booster dose with IPV. Live attenuated poliovaccine is no longer recommended because of the risk of vaccine-associated disease and is no longer available in the United States, although it continues to be used in many other countries.
``Rabies For travelers to areas where rabies is common in domestic animals (eg, India, Asia, Mexico, Africa, areas of Central and South America), with extensive outdoor activities or certain professional activities (veterinarians, animal handlers, field biologists), preexposure prophylaxis with human diploid cell vaccine (HDCV), rabies vaccine adsorbed (RVA), or purified chick embryo cell culture (PCEC) vaccine should be considered. Chloroquine can blunt the immunologic response to rabies vaccine. If malaria prophylaxis with chloroquine (or mefloquine) is required, vaccination should be given intramuscularly (not intradermally) to ensure adequate antibody response.
``Typhoid Typhoid vaccination is recommended for travelers to developing countries (especially the Indian subcontinent, Asia, Africa, Central and South America, and the Caribbean) who will have prolonged exposure to contaminated food and water. Two preparations of approximately equal efficacy (50–75% effective) are available in the United States: (1) an oral live attenuated Ty21a vaccine supplied as enteric-coated capsules, and (2) a Vi capsular polysaccharide (Vi CPS) vaccine for parenteral use. The Ty21a vaccine is given as one capsule every other day for four doses. The capsules must be refrigerated and taken with cool liquids (37°C or less) at least 1 hour before meals. All four doses must be taken for maximum protection and should be completed 1 week before travel. It is not recommended for infants or children younger than 6 years. The Vi CPS vaccine is given as a single intramuscular injection at least 2 weeks prior to travel. It is not recommended for infants younger than 2 years. If continued or repeated exposures are anticipated, boosters are recommended every 2 years for the Vi CPS and every 5 years for the Ty21a. The live attenuated vaccine should not be used in immunosuppressed patients, including those with HIV infection.
``Yellow Fever The live attenuated yellow fever virus vaccine is administered once subcutaneously. Although the risk of yellow fever is low for most travelers, a number of countries require vaccination for all visitors and others require it for travelers to or from endemic areas (mainly equatorial Africa and parts of South and Central America). The WHO certificate requires registration of the manufacturer and the batch number of the vaccine. Vaccination is available in the United States only at approved centers; the local health
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department should be contacted for available resources. Reimmunization is recommended at 10-year intervals if continued risk exists. Because it is a live attenuated vaccine prepared in embryonated eggs, the yellow fever vaccine should not be given to immunosuppressed individuals or those with a history of anaphylaxis to eggs. Pregnancy is a relative contraindication to vaccination. Two very severe adverse reactions have been associated with yellow fever vaccination. Viscerotropic disease presents with fever, jaundice, and multiple organ system failure within 30 days of yellow fever vaccination. Clinically and histopathologically, the illness is identical to yellow fever and is associated with a high mortality rate. The other adverse reaction is neurotropic disease and presents as encephalitis, encephalomyelitis, and Guillain-Barré syndrome.
``Japanese B Encephalitis Japanese B encephalitis is a mosquito-borne viral encephalitis that affects primarily children and older adults (65 years and older) and usually occurs from May to September. It is the leading cause of encephalitis in Asia. Because the risk of infection is low and because adverse effects of the vaccine can be serious, not all travelers to Asia
should be vaccinated. Vaccine should be given to travelers to endemic areas who will be staying at least 30 days and who are traveling during the transmission season, particularly if they are visiting rural areas. Travelers who spend < 30 days in the region should be considered for vaccination if they intend to visit areas of epidemic transmission or if extensive outdoor activities are planned in rural ricegrowing areas. Of the two vaccines currently available in the United States, only one is for adults (inactivated Vero cell derived vaccine, IXIARO) aged 17 and older. The schedule is 0.5 mL intramuscularly at 0 and 28 days. Only children are eligible to receive the other vaccine (inactivated mouse brain derived vaccine, JE-VAX) given its limited supply in the United States.
VACCINE SAFETY Most vaccines are safe to administer. In general, it is recommended that the use of live vaccines be avoided in immunocompromised patients, including pregnant women. Vaccines are generally not contraindicated in the following situations: mild, acute illness with low-grade fevers (< 40.5°C); concurrent antibiotic therapy; soreness or redness at the site; family history of adverse reactions to vaccinations. Absolute contraindications to vaccines are rare (Table 30–8).
Table 30–8. Adverse effects and contraindications to vaccinations. Vaccine
Adverse Effects
Contraindications
Hepatitis A
Minimal Consist mainly of pain at the injection site
Hepatitis B
Minimal Consist mainly of pain at the injection site
Hypersensitivity to yeast Severe reaction to a previous dose
Human papillomavirus
Minimal Consists mainly of mild to moderate localized pain, erythema, swelling Systemic reactions, mainly fever, seen in 4% of recipients
History of hypersensitivity to yeast or to any vaccine component
Influenza (intramuscular inactivated and intranasal live attenuated vaccines)
Intramuscular, inactivated vaccine: Local reactions (erythema and tenderness) at the site of injection common, but fevers, chills, and malaise (which last in any case only 2–3 days) rare. Either inactivated or live attenuated vaccine: The risk of Guillain-Barré syndrome is not increased following vaccination. Influenza vaccination may be associated with multiple false-positive serologic tests to HIV, HTLV-1, and hepatitis C, but it is self-limited, lasting 2–5 months.
Intranasal, live attenuated vaccine [FluMist] should not be used in: People 50 years of age and over Household members of immunosuppressed individuals Health care workers, or others with close contact with immunosuppressed persons Presence of reactive airway disease; chronic underlying metabolic, pulmonary, or cardiovascular diseases (use intramuscular inactivated vaccine) Long-term aspirin therapy in children or adolescents (because of the risk of Reye syndrome) Pregnancy1 Contraindication to both inactivated and live attenuated vaccine: History of Guillain-Barré syndrome, especially within 6 weeks of receiving a previous influenza vaccine History of egg allergy2 (continued )
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Table 30–8. Adverse effects and contraindications to vaccinations. (continued) Vaccine
Adverse Effects
Contraindications 4
Measles, mumps, and rubella (MMR)3
Fever will develop in about 5–15% of unimmunized individuals, and a mild rash will develop in about 5% 5–12 days after vaccination. Fever and rash are self-limiting, lasting only 2–3 days. Local swelling and induration are particularly common in individuals previously vaccinated with inactivated vaccine.
Pregnancy Immunosuppressed persons should not be vaccinated (with the exception of asymptomatic HIV-infected individuals whose CD4 count is > 200/mcL). History of anaphylaxis to neomycin or to related agents such as streptomycin
Meningococcal
Minor reactions (fever, redness, swelling, erythema, pain) occur slightly more commonly with MCV4. Major reactions are rare. A potential association between Guillain-Barré syndrome and vaccination with MCV4 has been reported, but current recommendations favor continued use of MCV4, since the benefits of preventing the serious consequences of meningococcal infection outweigh the theoretical risk of Guillain-Barré syndrome.
Persons with history of adverse reaction to diphtheria toxoid should not receive MCV4 since the protein conjugate used in MCV4 is diphtheria toxoid
Pneumococcal (polysaccharide)
Mild local reactions (erythema and tenderness) occur in up to 50% of recipients, but systemic reactions are uncommon. Similarly, revaccination at least 5 years after initial vaccination is associated with mild self-limited local but not systemic reactions.
Revaccination is not recommended for those who had a severe reaction (anaphylaxis or Arthus reaction) to the initial vaccination.
Tetanus, diphtheria, and pertussis
Minimal Consist mainly of pain at the injection site
Any history of anaphylaxis to vaccine components or if there is a history of unexplained encephalitis within 7 days of administration of a pertussis-containing vaccine.
Varicella
Can occur as late as 4–6 weeks after vaccination. Tenderness and erythema at the injection site are seen in 25%, fever in 10–15%, and a localized maculopapular or vesicular rash in 5%; a diffuse rash, usually with five or fewer vesicular lesions, develops in a smaller percentage. Spread of virus from vaccinees to susceptible individuals is possible, but the risk of such transmission even to immunocompromised patients is small and disease, when it develops, is mild and treatable with acyclovir.
Allergy to neomycin Avoid in immunocompromised individuals, including HIV-positive children and adults, or pregnant women. For theoretic reasons, it is recommended that salicylates should be avoided for 6 weeks following vaccination (to prevent Reye syndrome).
Zoster
Mild and limited to local reactions Although it is theoretically possible to transmit the virus to susceptible contacts, no such cases have been reported.
Presence of primary or acquired immunodeficiency state (leukemia, lymphoma, any malignant neoplasm affecting the bone marrow, HIV infection) Therapy with immunosuppressive medications (including high-dose corticosteroids) Pregnancy Persons with an anaphylactic type reaction to gelatin or neomycin should not receive the vaccine.
1
The inactivated influenza vaccine can be given during any trimester. The vaccine is prepared using embryonated chicken eggs. 3 MMR vaccine can be safely given to patients with a history of egg allergy even when severe. 4 Although vaccination of pregnant women is not recommended, with the currently available RA27/3 vaccine strain the congenital rubella syndrome does not occur in the offspring of those inadvertently vaccinated during pregnancy or within 3 months before conception. 2
Advisory Committee on Immunization Practices. Recommended adult immunization schedule: United States, 2012. Ann Intern Med. 2012 Feb 7;156(3):211–7. [PMID: 22298576] Centers for Disease Control and Prevention (CDC). Health Information for International Travel 2012. http://wwwnc.cdc. gov/travel/page/yellowbook-2012-home.htm
Centers for Disease Control and Prevention (CDC). Vaccine safety. http://www.cdc.gov/vaccinesafety/ Danzinger-Isakov L et al; Infectious Diseases Community of Practice. Guidelines for vaccination of solid organ transplant candidates and recipients. Am J Transplant. 2009 Dec; 9(Suppl 4): S258–62. [PMID: 20070687]
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Deer B. Wakefield’s “autistic enterocolitis” under the microscope. BMJ. 2010 Apr 15;340:c1127. [PMID: 20395277] Kaplan JE et al. Guidelines for prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. MMWR Recomm Rep. 2009 Apr 10;58(RR-4):1–207. [PMID: 19357635] Palefsky JM et al. HPV vaccine against anal HPV infection and anal intraepithelial neoplasia. N Engl J Med. 2011 Oct 27; 365(17):1576–85. [PMID: 22029979]
Shefer A et al. Updated recommendations of the Advisory Committee on Immunization Practices for healthcare personnel vaccination: a necessary foundation for the essential work that remains to build successful programs. Infect Control Hosp Epidemiol. 2012 Jan;33(1):71–4. [PMID: 22173525] Tomblyn M et al. Guidelines for preventing infectious complications among hematopoietic cell transplant recipients: a global perspective. Preface. Bone Marrow Transplant. 2009 Oct;44(8):453–5. [PMID: 19861977]