The host defense consists of innate, or nonspecific, immunity and adaptive immunity. Innate immunity is present at birth and has 4 components: mechanical barriers such as skin and mucous membranes, secretion of chemicals and enzymes, phagocytosis, and inflammation. Adaptive immunity is acquired immunity that recognizes antigens after exposure and generates pathogen-specific response pathways. The immune response can also be categorized in terms of neutrophil defense, cell-mediated immunity (CMI), and humoral immunity. Abnormalities in the immune system predispose individuals to different types of infections depending on the site of the immune defect. This chapter will discuss the mechanisms of primary neutrophil defense, cell-mediated immunity, humoral immunity, strategies for infection prevention, and the types of commonly seen infections.

Polymorphonuclear neutrophils (PMNs) are major phagocytes for host immune response. They make up the majority of circulating white blood cells but migrate into tissue in response to a pathogen. Neutrophils kill microbes by engulfing the organism and using reactive oxygen metabolites and digestive enzymes. Neutrophil dysfunction can be qualitative or quantitative. Qualitative dysfunction is usually seen in children and includes abnormalities in (1) diapedesis, the mechanism by which PMNs leave the intravascular space via endothelial channels; (2) chemotaxis, which is the movement of the PMN to the site of infection; (3) ingestion; and (4) intracellular killing (via oxygen-dependent or oxygen-independent).^1,2

Quantitative defects are categorized by the absolute neutrophil count (ANC), which is calculated by multiplying the percent of neutrophils by the total white blood cell (WBC) count. Neutropenia is defined as an ANC less than 1500 cells/µL,^3,4 while severe neutropenia is less than 500 cells/µL. Neutropenia may be due to benign ethnic neutropenia, which is rarely less than 1200 cells/µL, congenital neutropenias, and acquired neutropenia. Acquired neutropenia can be caused by hematologic conditions, including malignancy and myelodysplastic syndromes, medications, infections, autoimmune, dietary deficiencies, such as vitamin B₁₂, folic acid, or copper, or paroxysmal nocturnal hematuria.⁵ Neutropenic patients often present with fever, which is defined as single oral temperature greater than 38.3°C (101°F) or a temperature greater than 38°C (100.4°F) sustained over 1 hour.³ Rectal temperatures are generally avoided in neutropenic patients to prevent bacterial translocation into tissues. Patients with neutropenia are at increased risk of bacterial and fungal infections.³

Patients with prolonged (> 7 days) and profound neutropenia (ANC ≤ 100 cells/µL) are at high risk of infection and should be admitted to the hospital for work-up and empiric intravenous (IV) antibiotics when they present with signs and symptoms suggestive of infection. Lower-risk patients with brief (≤ 7 days) neutropenia who are clinically stable may be eligible for outpatient management and oral therapy.³ In cancer patients with neutropenic fever, risk stratification is determined via Multinational Association for Supportive Care in Cancer Risk-Index Score (MASCC score) using the patient’s burden of illness (clinical symptoms), comorbidities, outpatient status at the time of onset of neutropenic fever, and age. A MASCC score less than 21 is considered high risk and should have inpatient treatment.³ A MASCC score greater than 21 can be managed with outpatient treatment.³

The empirical antibiotics for neutropenic fever should include pseudomonal coverage and be bactericidal since patients do not have adequate neutrophils for host defense. High-risk patients who require hospitalization should receive monotherapy with an antipseudomonal β-lactam such as cefepime, carbapenem (imipenem or meropenem), or piperacillin-tazobactam. An additional agent such as an aminoglycoside can be considered in a patient who is unstable or for whom there is concern about resistant organisms.³ Low-risk patients can receive the oral combination of ciprofloxacin and amoxicillin-clavulanate. Aerobic Gram-positive cocci coverage with vancomycin is not recommended as part of initial empiric therapy. Vancomycin might be started early if there is concern for methicillin-resistant Staphylococcus aureus (MRSA) infection, catheter-related infection, skin and soft tissue infection, pulmonary infection, or clinical instability.³ Patients with mild penicillin allergies can be given cephalosporins, but patients with severe penicillin allergy, such as angioedema or anaphylaxis, should avoid β-lactams, including cephalosporins and carbapenems. Empirical antibiotics for neutropenic patients with unexplained fevers are often continued until ANC is greater than 500 cells/µL. The duration of antibiotics is determined by the duration for that specific infection as well as recovery of the marrow (ANC > 500 cells/µL). Antibiotic prophylaxis with an oral fluoroquinolone can be considered in patients whose signs and symptoms of infection have resolved but who have persistent neutropenia; fluoroquinolone prophylaxis is also considered in high-risk patients with prolonged and severe neutropenia (ANC ≤ 100 cells/µL for > 7 days).⁶

The addition of empirical antifungal therapy and evaluation for a possible invasive fungal infection (IFI) should be considered in patients with persistent or recurrent fever for more than 4 days who are anticipated to have neutropenia for more than 7 days.⁶ These patients should be assessed clinically and radiographically, usually with computed tomography (CT) of the chest or sinuses, for evidence of IFI. Galactomannan and (1-3)-β-D-glucan are polysaccharides in fungal cell walls and can be measured in serum assays. These serum markers should be used in conjunction with the clinical setting and other diagnostic data when evaluating for IFI. Galactomannan is found in Aspergillus and Penicillium species with cross-reactivity to Histoplasma capsulatum. The test has a sensitivity of 58% to 65% and a specificity of 65% to 95%.⁷ False positive results can occur with the use of β-lactam/β-lactamase inhibitor antibiotics, and false negatives may occur with the use of antifungals that have mold activity.⁸ The (1, 3)-β-D-glucan test detects Candida, Aspergillus, Pneumocystis, and Fusarium with a sensitivity of 63% to 90% and a specificity of greater than 95%.^9-11 Lipid formulations of amphotericin B, such as liposomal amphotericin, are as effective as amphotericin B deoxycholate, which has been used as empiric antifungal therapy for decades; the lipid formulations have significantly fewer toxicities than amphotericin B desoxycholate. Voriconazole is an azole with mold activity that was found to be superior and better tolerated compared to amphotericin B deoxycholate for invasive aspergillosis.¹² Voriconazole is associated with more visual disturbances. Echinocandins such as caspofungin have excellent activity against Candida, including the azole-resistant species, with fewer side effects than amphotericin and are recommended for initial therapy for candidemia.¹³ Antifungal prophylaxis is recommended for (1) high-risk for invasive candidiasis, such as allogeneic stem cell transplant recipients or patients with acute leukemia undergoing intensive remission-induction or salvage induction chemotherapy; (2) patients older than 13 years of age undergoing chemotherapy for acute myeloid leukemia (AML)/myelodysplastic syndrome (MDS); (3) prior invasive aspergillosis; or (4) neutropenia lasting more than 2 weeks in allogeneic or autologous transplant recipients.⁶

Antiviral therapy for herpes simplex virus (HSV) or varicella zoster virus (VZV) with acyclovir is indicated, if there is clinical or laboratory evidence of active viral disease. Acyclovir prophylaxis is indicated for HSV seropositive patients undergoing allogeneic hematopoietic stem cell transplant (HSCT) or leukemia induction therapy.⁶

Colony stimulating factors (CSF) are not generally recommended in patients with established febrile neutropenia. Although some studies show decreased duration of fevers, time on antibiotics, and length of hospitalization with the use of myeloid CSFs, there is no evidence of overall clinical or survival benefit.⁹ Myeloid CSF are more commonly used for prophylaxis in the following conditions: (1) during cycles of chemotherapy for which patients have a 20% or greater risk of febrile neutropenia based on patient-, disease-, and treatment-related factors; (2) for patients who have a prior neutropenic complication in which reduction dose or treatment delay of chemotherapy may compromise outcomes; (3) after autologous stem-cell transplantation; and (4) for diffuse aggressive lymphoma in patients 65 years and older treated with curative chemotherapy (cyclophosphamide, doxorubicin, vincristine, prednisone, and rituximab). Dosing regimen of CSF is seen in Table 20-1.¹⁴ Colony stimulating factors should be avoided in patients with concomitant chemotherapy and radiation therapy particularly in the mediastinum.

Adaptive immunity has cell-mediated and humoral mechanisms. Cell-mediated immunity generally involves phagocytosis and cytotoxins rather than antibodies, which are key components of the humor response. T lymphocytes are divided into the subsets of helper T cells, which express CD4 surface proteins, and cytotoxic T cells, which express CD8 surface proteins. Although the distinctions are not exact, these immune responses have been categorized based on subpopulations of the T-helper lymphocytes into T helper type 1 (Th1) or type 1 immunity, which is primary cell mediated, and T helper type 2 (Th2) or type 2 immunity, which primarily stimulates the humoral response.¹⁵ Naïve helper T cells are Th0 before being activated into either Th1 or Th2 cells. These subpopulations secrete distinct combinations of cytokines. Because of the overlap of secreted cytokines, the primary distinctions are between the secretion of interferon (IFN) γ, which is secreted by Th1 but not by Th2, and interleukin (IL)-4, which is secreted by Th2 but not by Th1. The Th1 cells secrete IFN-γ, IL-2, and lymphotoxin (LT)-α, which result in strong cell-mediated immunity and weak humoral immunity. The Th2 cells secrete IL-4, IL-5, IL-9, IL-10, and IL-13, which stimulate antibody production for a strong humoral response and suppress cell-mediated immunity.

Cell-Mediated Immunity

Cell-mediated immunity is driven by T lymphocytes in response to intracellular pathogens and abnormal cells such as cancer cells. T cells respond to antigen presenting cells (APCs) and signal an inflammatory cascade leading to activation of cytotoxic T cells and phagocytes and release of cytokines. Cell-mediated immunity plays an important role in fighting intracellular organisms such as viruses, mycobacteria, fungi, and certain other bacteria. It is also an important part of transplant immunology and autoimmune responses.

Aging and pregnancy both decrease the cellular immune response. Cell-mediated immunity deficiencies may also be caused by congenital deficiencies, thymic dysplasia, viral illnesses, medications, and T-cell malignancies. HIV infection leads to the destruction of T helper cells and ultimately leads to AIDS without antiretroviral (ART) therapy. Medications can lead to decreased CMI either by decreasing the number of T cells, as is the case with corticosteroids, or by decreasing lymphocyte function, in the case of cyclosporine.

Humoral Immunity

Humoral immunity is mediated by large extracellular molecules including immunoglobulins and complement proteins. The humoral response is driven by B lymphocytes, which secrete antibodies, but requires activation by T lymphocytes. B cells produce 5 immunoglobulin antibody subclasses with different functions (Table 20-2).¹⁶ Antibodies are made up of 4 polypeptide chains, with 2 light and 2 heavy chains, which have variable and constant regions. The region of the antibody that binds to the antigen is the Fab (antigen-binding) fragment, while the fragment of the antibody that interacts with cell surface receptors is the Fc (fragment crystallizable) region. Immunoglobulin M (IgM) and IgG form antigen-antibody complexes that activate the complement system and lead to opsonization, a process by which antigens are marked for phagocytosis.

The complement system assists with phagocytosis, pathogen lysis, and inflammation.^17,18 There are 3 pathways of the complement system: the classical, lectin, and alternative pathways. These pathways converge to assemble the membrane attack complex (MAC) for lysis and destruction of the pathogen (Fig. 20-1).¹⁷ The classical pathway is triggered by antigen-antibody complexes, while the lectin pathway is activated by lectins, proteins that bind carbohydrates on the bacteria. Both lead to assembly of C4b2a, which causes proteolytic cleavage of C3 to C3b and leads to opsonization.

Defects of humoral immunity include (1) quantitative or qualitative disorders of immunoglobulins; (2) functional or actual asplenia; (3) complement deficiencies; and (4) impaired neutralization of toxins. Antibody deficiencies include IgA deficiency, x-linked or autosomal agammaglobulinemias, common variable immunodeficiency, specific antibody deficiency, IgG subclass deficiency, selective IgM deficiency, and selective IgE deficiency.^19-26 Medications such as anti-inflammatory agents, rheumatologic agents such as methotrexate, anticonvulsants, and rituximab can cause hypogammaglobulinemia. Protein-losing conditions and severe malnutrition also increase risk of infection from hypogammaglobulinemia. Specific infectious complications depend on the specific disorder, but patients with humoral deficiencies often get recurrent respiratory infection from encapsulated bacteria, such as Streptococcus pneumoniae and Haemophilus, and respiratory and gastrointestinal (GI) viral infections.^19-26

Complement disorders can be caused by different points in the classical or alternative pathways and may be acquired or hereditary.¹⁸ The total hemolytic complement, or CH50, measures total complement activity and is the screening test for classical pathway deficiencies. Conditions associated with falsely low CH50 include laboratory error or cold activation via mixed cryoglobulin or cold-reacting complexes. C3 or C4 are usually normal. CH50, like C3 or C4, is an acute phase reactant and therefore would be increased in periods of stress. C3 (normal 80–160 mg/dL) and C4 (normal 16–48 mg/dL) can be low in autoimmune diseases such as systemic lupus erythematosus (SLE), antiphospholipid syndrome, cryoglobulinemia, Sjögren syndrome, and membranoproliferative glomerulonephritis. Low C4 can be seen in acquired C1 inhibitor deficiency and hereditary angioedema. AH50 measures for total activity of the alternative pathway. Complement disorders should be considered in people with recurrent bacterial infections, autoimmune processes, and angioedema. The most common bacterial infections in patients with deficiencies in the classical pathway are recurrent Neisseria meningitis and bacteremia and recurrent infections with encapsulated bacteremia such as pneumococcus, Haemophilus, and Neisseria.¹⁷

The spleen is a hematopoietic organ that makes up 25% of the body’s lymphoid tissue and has an active role in humoral and cellular immunity. Its functions include antibody production by B lymphocytes and removal of opsonin-coated organisms or damaged cells from circulation. Anatomic asplenia, functional asplenia, or hyposplenic states predispose patients to infection, particularly with encapsulated organisms.^20,21 Conditions that cause splenic infarction, such as sickle cell disease or splenic vein thrombosis, or splenic infiltration, such as autoimmune processes or hematologic disease, can cause hyposplenic states or functional asplenia. Pathogens associated with splenic dysfunction include encapsulated bacteria, such as S pneumoniae, H influenzae type b, and N meningitidis, and protozoa that infect red blood cells, such as malaria and Babesia microti.²² Patients who have had splenectomies are also more susceptible to severe infection from Capnocytophaga canimorsus, a Gram-negative bacteria associated with dog bites.

Infections in transplant recipients are common.²⁷ Development of immunosuppression after transplant has improved graft survival but has caused increased incidence of infections. Risk of infection after transplantation is dependent on exposure and overall immunosuppression of the patient.²⁸ Patients can be exposed to common community-acquired pathogens, such as influenza or S pneumoniae, or can have reactivation of latent infections, such as tuberculosis (TB), cytomegalovirus (CMV), or herpes zoster, either from the donor organ or from the recipient. The timing of these infections is divided into less than 1 month after transplant, 6 to 12 months after transplant, and greater than 12 months after transplant. The majority of infections occur within the first 6 months of organ transplant when immune suppression is higher.^29-32

Infections within the first 30 days after solid organ transplantation can be due to hospital-acquired infection, technical complications from surgery, donor-derived infections, or recipient-derived infections. Opportunistic infections are uncommon early after transplant. Donor-acquired infections during this early period include active infections that were not diagnosed in the donor prior to transplant or activation of a latent infection. Bacterial and fungal infections are more common during this time. Organ transplant recipients do not always present with typical signs and symptoms of infection, as they are immune suppressed. Patients should be evaluated for infection when they present with altered mental status, hypotension, and evidence of graft dysfunction. Surgical site infections are also extremely common during the early post-transplant period. In the intermediate period of 1 to 6 months after transplant, opportunistic pathogen and viral infections become more common. Transplant recipients are given prophylaxis for opportunistic infections such as pneumocystis, CMV, and toxoplasmosis during this period. Allograft rejection can also cause fevers during this intermediate post-transplant period. After 6 months, the risk and type of infections seen depend on the patient’s net immunosuppression. Most patients are on lower stable doses of immunosuppression and are more likely to present with community-acquired infections rather than opportunistic infections. Transplant recipient who require higher levels of immunosuppression in the late transplant period are at risk for opportunistic pathogens as well as community-acquired infections.

Vaccines have played a crucial role in preventing communicable infections in the general population and are also important in immunocompromised hosts. Patients who anticipate immune suppression can be given live vaccines 4 months prior to immunosuppression and inactivated vaccines within 2 weeks of immunosuppression. Live vaccines such as measles-mumps-rubella (MMR), varicella, oral polio, rotavirus, and intranasal influenza vaccines should not be given to immunocompromised hosts. The intradermal influenza vaccine is inactivated and should be given to immunocompromised patients. Vaccines for tetanus and diphtheria, pneumococcus, meningococcus, human papilloma virus (HPV), hepatitis B (HBV), and hepatitis A are inactive vaccines and can be given to immunocompromised patients.^33-36

The polysaccharide 23-valent pneumococcal vaccine (PPSV23 or Pneumovax) is recommended in smokers between ages 19 and 64 years, and adults of any age with chronic lung disease, chronic heart disease, chronic liver disease, diabetes mellitus, or alcoholism. Patients over 65 years of age or who are at higher risk of invasive pneumococcal disease should also receive the 13-valent pneumococcal conjugate vaccine (PCV13 or Prevnar); PCV13 should be given first, when possible, followed by PPSV23. Populations who should receive both pneumococcal vaccines include all individuals over 65 years of age, people with cochlear implants, persistent cerebrospinal fluid leaks, HIV infection, functional or anatomic asplenia, chronic renal disease, nephrotic syndrome, hematologic malignancies, organ transplant, or congenital or acquired immunodeficiencies. Revaccination with a single dose of PPSV23 is recommended for these high-risk groups or for people over 65 years of age who received their vaccine before the age of 65.

Patients who require splenectomy should receive pneumococcal, meningococcal, and H influenzae B vaccine at least 2 weeks before splenectomy. Meningococcal vaccine is also recommended for patients with terminal complement component deficiencies and functional asplenia.³⁷

Prophylactic antimicrobials are given to immunocompromised patients such as those with HIV. CD4 T helper cell levels are used to gauge which prophylactic antimicrobials are given (Table 20-3).^38,39

Streptococcus

This genus of bacteria is seen as Gram-positive cocci in pairs and chains on Gram stain and are facultative anaerobes. Streptococci, including nonpathogenic species, reside in the human nasopharynx, respiratory tract, intestines, and skin. Streptococci can be classified by their hemolytic properties on blood agar plates: α hemolysis is incomplete hemolysis leaving a green zone on the plate, β hemolysis is complete hemolysis with clearing of the red blood cells, and γ hemolysis is the absence of hemolysis. The most clinically important α hemolytic streptococci are S pneumoniae and viridans group streptococci. β hemolytic streptococci are further divided into their Lancefield groups and include group A strep (S pyogenes) and group B strep (S agalactiae).

S pneumoniae, or pneumococcus, is a common cause of otitis media, community-acquired bacterial pneumonia, and bacterial meningitis. It can cause serious invasive infections in patients with HIV and patients who have undergone splenectomy.⁴⁰ It contains several virulence factors. The polysaccharide capsule prevents iC3b and Fc of antibody from interacting with phagocytes, allowing pneumococcus to avoid phagocytosis.⁴¹ Pneumococcus produces pneumolysin, a cytotoxin that binds to cholesterol, creating pores in cell membranes, and activates the classical complement pathway. Pneumococcus has surface proteins such as hyaluronidase and neuraminidase, which cause inflammation and damage to the host. Diagnosis is by sputum and blood culture, although the yield is variable. Urinary pneumococcal antigen has a sensitivity of 70% to 90% and a specificity of 80% to 100% and can aid in the diagnosis.⁴² Antibiotic options for pneumonia due to S pneumoniae include oral (PO) or IV penicillin, macrolides, quinolones, or third-generation cephalosporins such as ceftriaxone or cefotaxime. Because the incidence of penicillin resistance is increasing, third-generation cephalosporins are often used empirically while awaiting culture data. Treatment is usually for 5 days but is extended to 10 to 14 days if associated with bacteremia. For suspected pneumococcal meningitis, the empiric antibiotic treatment consists of vancomycin (15–20 mL/kg IV every 8–12 hours) with ceftriaxone 2 g IV every 12 hours or cefotaxime (2 g IV every 4–6 hours) for 14 days.⁴³ Penicillin G 4 million units IV every 4 hours can be used instead of a third-generation cephalosporin if the isolate is penicillin sensitive (minimum inhibitory concentration [MIC] < 0.06 µg/mL). Dexamethasone is often added at the beginning of treatment for bacterial meningitis to reduce incidence of hearing loss and other neurologic sequelae.

Group A streptococcus (GAS) resides in the nasopharynx and skin. It can cause pharyngitis and skin and soft tissue infections such as cellulitis, impetigo, myositis, necrotizing fasciitis, and streptococcal toxic shock syndrome. Complications of GAS infection include acute poststreptococcal glomerulonephritis (PSGN), acute rheumatic fever (ARF), and rheumatic heart disease (RHD).⁴⁴ Group A streptococcus contains 3 types of virulence factors: M proteins, cytolysins, and pyrogenic exotoxins. M proteins, encoded by the emm gene, inhibit the binding of antibodies and opsonin and can protect the organism from phagocytosis by neutrophils. Group A streptococcus cytolysins include (1) streptolysin O, which creates cholesterol aggregates that facilitate cell lysis; (2) hyaluronidase, which hydrolyzes hyaluronic acid in deep tissues; (3) streptokinase, which converts plasminogen to plasmin and may contribute to the development of poststreptococcal glomerulonephritis; (4) nicotinamide-adenine dinucleotidase; and (5) deoxyribonucleases A, B, C, and D. Group A streptococcus exotoxins act as super antigens and can contribute to invasive disease and toxic shock syndrome.

Group A streptococcus is highly susceptible to penicillins and β-lactams. Acute pharyngitis can be treated with oral penicillin 2 to 4 times per day for 10 days; penicillin is the recommended first-line therapy, but other antibiotic options include a macrolide, such as azithromycin, or cephalosporin, such cefuroxime or cefpodoxime, for 5 days.⁴⁴ For impetigo, focal lesions can be managed with mupirocin or retapamulin ointments, but diffuse disease should be treated with oral or IV antibiotics with consideration for cross coverage for Staphylococcus, particularly MRSA.⁴⁴ In the event of necrotizing fasciitis, prompt surgical debridement is crucial. Antibiotics for necrotizing fasciitis due to GAS are penicillin G 3 to 4 million units IV every 4 hours and clindamycin 600 to 900 mg IV every 6 to 8 hours.^45,46 Clindamycin has antitoxin effects.⁴⁴

Acute rheumatic fever is a nonsuppurative complication that can occur 1 to 5 weeks after streptococcal pharyngitis. Diagnosis is based on the Jones criteria. There are 5 major manifestations, which include carditis and valvulitis, arthritis, central nervous system (CNS) involvement known as Sydenham chorea, subcutaneous nodules, and erythema marginatum.⁴⁷ There are 4 minor manifestations, which include arthralgia, fever, elevated acute phase reactants, and prolonged PR interval on electrocardiogram (ECG).⁴⁷ Two major or 1 major and 2 minor manifestations in a patient with prior GAS infection are required for diagnosis. Late complications of ARF include rheumatic heart disease and Jaccoud arthropathy. Treatment consists of antibiotics to eradicate GAS carriage, symptomatic treatment of arthritis with nonsteroidal anti-inflammatory drugs (NSAIDs), and management of heart failure.⁴⁸ Secondary antibiotic prophylaxis to prevent rheumatic heart disease may be given with 1.2 million units of benzathine penicillin G intramuscularly (IM) every 4 weeks or oral penicillin twice daily.⁴⁹ The duration of antibiotics depends on the degree of cardiac involvement and the age of the patient.

Poststreptococcal glomerulonephritis is due to glomerular immune complex deposition and can occur 1 to 6 weeks after infection with nephritogenic strains of GAS. Clinical presentation can range from hematuria to acute nephritic syndrome (edema, hypertension, acute kidney injury with red to brown urine, and proteinuria).⁵⁰ Diagnosis is dependent on findings of nephritis with documented evidence of GAS infection by a positive culture or via serologic streptozyme test, such as antistreptolysin (ASO), antihyaluronidase (AHase), antistreptokinase (ASKase), antinicotinamide-adenine dinucleotidase (anti-NAD), and anti-DNase B antibodies.^51,52 Treatment is largely supportive.

Haemophilus influenzae

This pleomorphic Gram-negative rod is a nonmotile facultative anaerobe that resides in the human respiratory tract.⁵³ It can cause otitis media, sinusitis, conjunctivitis, epiglottitis, pneumonia, and meningitis. It has 6 serotypes (A through F) that are associated with an outer capsule and a nontypeable serotype that is not associated with a capsule.⁵⁴ It has an outer membrane lipopolysaccharide that acts as an endotoxin and 3 types of IgA proteases. The currently available H influenza type B conjugate vaccine is active against the most common serotype B and induces bactericidal antibodies to capsular polysaccharides. The widespread use of the vaccine has reduced the incidence of invasive disease due to H influenza serotype B, but it has been suggested to have increased the incidence of infections due to nontypeable serotype.^53,54 Haemophilus is generally β-lactam susceptible. More serious infections such as meningitis should be treated with IV ceftriaxone or cefotaxime. Amoxicillin or an oral second- or third-generation cephalosporin can be used for pneumonia and less severe infections.⁵⁵

Neisseria

The most common pathogens in this genus of Gram-negative diplococci are N meningitides, which causes meningitis and/or meningococcemia, and N gonorrhoeae, which primarily causes sexually transmitted genitourinary infections but can also present with pharyngitis, conjunctivitis, or proctitis. N meningitides presents with meningitis, meningitis with accompanying meningococcemia, or meningococcemia without meningitis. Patients may have a petechial rash that evolves into a purpuric rash, predominantly on the trunk and lower extremities. Diagnosis is via culture and cerebrospinal fluid analysis. Blood culture is positive 50% of the time. Antibiotics should be given promptly and should not be delayed while awaiting lumbar puncture (LP).⁵⁶ Cerebrospinal fluid cultures are less likely to be positive after antibiotics, but the Gram stain can be helpful. Cerebrospinal fluid studies for meningococcal meningitis typically show a high white blood cell count, a high protein level, and a low glucose level. Third-generation cephalosporins such as ceftriaxone or cefotaxime should be used for treatment.^57,58 Droplet precautions should be continued for 24 hours after initiation of appropriate antibiotics. Chemoprophylaxis should be given to close contacts, such as household contacts and healthcare workers exposed to oral secretions, within 24 hours of exposure. Options for prophylaxis are ciprofloxacin, rifampin, or ceftriaxone.^59,60

Pseudomonas

This Gram-negative aerobic rod is found in the environment, particularly in water, and commonly causes infections in patients with decreased immune defenses and in the healthcare system. It has virulence factors, including the formation of biofilm, which is in part secondary to a mucoid phenotype; exotoxins A, S, and U; endotoxin lipopolysaccharides; elastase; alkaline protease; and phenazines.^61-66 Pseudomonas is a common colonizer in the respiratory tract and skin, which is why it frequently causes hospital- or ventilator-associated pneumonia and infections in patients with burns. A colony count of 10⁵ cells/µL or higher in the appropriate clinical setting can help distinguish colonization from true infection in burns.^65,67,68 Bacteremia is more common in immunocompromised hosts. Severe infections can be complicated by ecthyma gangrenosum, which are ulcerative lesions with violaceous margins, penetrating the dermis.⁶⁹ Pseudomonas is intrinsically resistant to many antibiotics and has several mechanisms of acquiring resistance. Although combination therapy with double coverage has previously been recommended, this is now reserved as empiric therapy for patients with serious infections and suspicion of Pseudomonas infections with possible drug resistance. Once susceptibility data is available, antibiotic therapy should be tailored appropriately. Antibiotics with good antipseudomonal activity include antipseudomonal β-lactams with β-lactamases (such as piperacillin/tazobactam and ticarcillin/clavulanate), antipseudomonal cephalosporins (ceftazidime and cefepime), aztreonam, fluoroquinolones, and carbapenems (with the exception of ertapenem, which does not cover Pseudomonas). Aminoglycosides have antipseudomonal activity but are not generally recommended for monotherapy.

Staphylococcus

This genus of Gram-positive cocci colonize the skin and upper respiratory tract and include the group known as coagulase-negative Staphylococcus, including S epidermidis, and S aureus, which is coagulase positive. They appear as clusters of Gram-positive cocci on Gram stain. Although coagulase-negative Staphylococcus is often a blood culture contaminant, it can cause bloodstream infections, particularly in the setting of catheters, endocarditis, and prosthetic joint infections. Virulence is associated with production of biofilm, protective exopolymer, and proinflammation properties of pathogen-associated molecular patterns (PAMPs). Coagulase-negative Staphylococcus has a higher resistance to methicillin compared to MRSA and appears to have acquired resistance to other antibiotics including rifamycin, fluoroquinolones, gentamicin, tetracycline, chloramphenicol, erythromycin, clindamycin, and sulfonamides.⁷⁰

Staphylococcus aureus, which include methicillin-susceptible S aureus (MSSA) MRSA, is a very common cause of skin and soft structure infections (SSTIs), septic arthritis, prosthetic joint infections, necrotizing pneumonia, osteomyelitis, bloodstream infections, device-related infections, and endocarditis. Virulence factors for S aureus include the Panton-Valentine leukocidin (PVL), which lyses leukocytes and causes necrotizing infections; α-hemolysin; and phenol-soluble modulins.^71,72 The presence of the mecA gene encodes for methicillin resistance. Although MRSA was previously seen more in hospitalized patients, it has emerged as a common infection in the community. The USA300 strain of community-acquired MRSA (CA-MRSA) is the most common strain, and CA-MRSA is more closely associated with PVL compared to healthcare-associated MRSA.^73-75 Staphylococcus aureus skin and soft structure infections are generally purulent, with the development of pustules, furuncles, or abscesses, as opposed to the confluent cellulitis seen with Streptococcal cellulitis. Antistaphylococcal penicillins such as oxacillin or nafcillin, or cefazolin are the treatment of choice for MSSA infections. Vancomycin is generally the treatment for MRSA, although trimethoprim-sulfamethoxazole, tetracyclines, and clindamycin may be options for MRSA SSTIs. Bloodstream infections with S aureus require IV antibiotics, generally for at least 4 weeks. Endocarditis requires 6 weeks of treatment. Because S aureus forms biofilms on medical devices, removal of infected devices such as central lines and cardiac devices is crucial for clearance of infection.

Listeria

Listeria monocytogenes is an aerobic and facultatively anaerobic Gram-positive rod with “tumbling motility” that can cause febrile gastroenteritis, meningoencephalitis, cerebritis, rhombencephalitis, pneumonia, skin infections, eye infections, septic joints, biliary tract infections, and cholangitis. It can lead to stillbirth and abortion in pregnancy.^76,77 In addition to pregnant women, people at the extremes of age and immunocompromised hosts are more susceptible to listeriosis. It is diagnosed via culture. The bacteria are ingested and travel to the bloodstream and into the liver and spleen. They grow intracellularly in the cytosol of infected cells. First-line therapy is with ampicillin with gentamicin for synergy.^78-82 Duration is 14 days in bacteremia and 2 to 4 weeks in central nervous system infections.

Legionella

Legionella pneumophila is the most common species of this genus of aerobic Gram-negative bacilli. Legionella requires buffered charcoal yeast extract (BCYE) media to grow in cultures.⁸³ Legionella is found in fresh water and in water systems, such as cooling towers and plumbing systems, and infection occurs with inhalation of water droplets. Its virulence is related to its ability to inhibit phagosome-lysosome fusion via defective organelle trafficking (dot) genes and intracellular multiplication (icm) genes.⁸⁴ Suspicion for Legionella should be higher in patients with pneumonia and the following: GI symptoms, neurologic symptoms, fever greater than 39°C, hyponatremia, hepatitis, hematuria, and failure to respond to β-lactam therapy.⁸⁵ Although diagnosis can be made by culture on a BYCE plate, the Legionella urine antigen is more commonly used and has a sensitivity of 80% and specificity 97% to 100%. The urine antigen test is only for Legionella serogroup 1, but this serogroup causes the majority of infections.^86-90 Effective antibiotics must be able to reach high intracellular concentrations; options include macrolides, fluoroquinolones, and tetracyclines, with the newer macrolides and fluoroquinolones being the recommended treatment.^91-93 Levofloxacin was found to be superior than erythromycin or clarithromycin in terms of clinical response via defervescence, length of stay, and complications.⁹¹ However, newer macrolides like azithromycin appear to have superior clinical response, with a 95% cure rate at 10 to 14 days and a 96% cure rate at 21 days.⁹² For transplant patients, fluoroquinolones are preferred due to the interactions of macrolides and the immunosuppressant agents via the cytochrome P450 3A4 (CYP3A) enzyme.^94-97 The duration of antibiotics is dependent on the type of infection, although it is typically 14 to 21 days.

Nocardia

Nocardia is a genus of filamentous, branching Gram-positive rods that can partially stain acid fast.⁹⁸ The majority of infections are seen in immunocompromised hosts, particularly with defects in CMI, but a third of the infections are seen in immunocompetent hosts.⁹⁹ Nocardia is found in the environment and is inhaled, so infections are primarily pulmonary and radiographically appear as focal consolidation, pulmonary nodules, cavitary lesions, and pleural effusions. Extrapulmonary manifestations are secondary to hematogenous or contiguous spread. The CNS is the most common site of extra-pulmonary disease, so neuroimaging is recommended.¹⁰⁰ Cutaneous infections can occur with traumatic injury with direct inoculation. Diagnosis is via Gram stain and culture. Antibiotics with activity against Nocardia include amikacin, imipenem, meropenem, ceftriaxone, cefotaxime, minocycline, moxifloxacin, levofloxacin, linezolid, and tigecycline, but resistance to these agents is variable. Trimethoprim-sulfamethoxazole is the recommended first-line antibiotic.⁹⁸

Actinomyces

Actinomyces is part of the flora in the oropharynx, GI tract, and urogenital tract; it is a filamentous, microaerophilic Gram-positive bacillus on Gram stain, often seen with sulfur granules.¹⁰¹ Culturing the organism can be challenging, but the organism can be seen on Gram stain and pathology.^101,102 Actinomyces can appear as masses with abscesses and fistulae in the neck and face, lungs, and abdomen. Treatment includes surgical resection and prolonged course of antibiotics. Actinomyces is very susceptible to β-lactams. Recommended treatment is high dose IV penicillin G for 2 to 6 weeks followed by oral penicillin V or amoxicillin for 6 to 12 months.

Rhodococcus equi

This is an aerobic Gram-positive intracellular coccobacillus, previously known as Corynebacterium equi, and usually causes infection in immunocompromised patients, particularly those with HIV.¹⁰³ It is found in soil and in herbivores, such as horses. Rhodococcus most commonly causes cavitary pneumonia with or without pleural effusions in the immunocompromised, making it difficult to distinguish from tuberculosis.¹⁰⁴ Its appearance on Gram stain with pleomorphic cocci and bacilli can make it difficult to distinguish from a contaminant, but Rhodococcus forms distinct salmon-colored colonies.¹⁰⁴ Recommended treatment is with 2 drugs, usually with a macrolide or fluoroquinolone in combination with rifampin; duration of antibiotics can be up to 6 months.

Corynebacterium

Corynebacterium is a genus of Gram-positive bacilli that are catalase positive, urease negative, cystinase positive, and pyrazinamidase negative.^105-107 Corynebacterium diphtheria is the most common species to cause infection by producing diphtheria toxin, leading to pseudomembrane formation and upper respiratory tract infection. Similar disease is less frequently caused by C ulcerans and C pseudotuberculosis. Symptoms of malaise, sore throat, lymphadenopathy, and low-grade fever usually starts 2 to 5 days after infection. Diagnosis is with culture, on Loeffler or Tinsdale medium, and toxin detection. Outbreaks of cutaneous infection have been seen. Dissemination of the diphtheria toxin can lead to systemic disease with involvement of the heart, nervous system, and kidneys. Antitoxin is effective if given before the toxin enters cells. Antibiotic treatment is with erythromycin or penicillin for 14 days.

Bartonella

This genus of Gram-negative intracellular bacteria include Bartonella henselae, which causes cat-scratch disease, and B quintana, which causes trench fever, bacillary angiomatosis, and culture-negative endocarditis.^108-110 Cat-scratch disease presents as cutaneous lesions with regional lymphadenopathy. Complications of B henselae infection include neuroretinitis, peliosis hepatis, Parinaud oculoglandular syndrome, osteomyelitis, encephalitis, or endocarditis.¹¹⁰ In HIV patients, both B henselae and B quintana can cause bacillary angiomatosis, which are vascular lesions mostly involving the skin but can involve other organs, bacillary peliosis of the liver, and splenitis. B quintana is spread through lice and can cause trench fever with cyclical fevers that classically recur every 5 days, severe headache, bone pain, splenomegaly, and sometimes rash.¹⁰⁹ Both species can also cause culture-negative endocarditis. Bartonella is a fastidious organism and challenging to grow in culture, so diagnosis often includes serologies, histopathology and polymerase chain reaction (PCR) of tissue or blood. Treatment for cat-scratch disease is azithromycin 500 mg PO daily and 250 mg PO daily for 4 days.^111,112 Longer durations of combination therapy are used for more complicated Bartonella infections. For Bartonella endocarditis, treatment is doxycycline plus rifampin for 6 to 8 weeks.

Brucella

Brucella is a small, nonmotile, aerobic, intracellular Gram-negative coccobacilli that lacks a capsule, spores, and flagella.^113,114 It is a zoonotic infection that occurs after contact with infected animals, such as sheep or cattle, or after ingestion of contaminated food from these animals, such as unpasteurized cheese or milk. The bacteria travel through the lymph nodes after being ingested by PMNs and macrophages, replicates intracellularly, and disseminates after cell lysis. Brucella has a smooth lipopolysaccharide and proteins that are involved in cell entry and likely help evade the immune response. Clinical manifestations are nonspecific and variable. Symptoms include fevers, night sweats, anorexia, weight loss, malaise, and arthralgias; complicated infections can lead to neurobrucellosis, endocarditis, and hepatic abscess. Brucella is associated with complications in pregnancy, including spontaneous abortion, premature delivery, and fetal death. Diagnosis is based on serologies and culture. Because of the risk of laboratory infection, the microbiology lab must be notified in advance if there is suspicion of brucellosis. Treatment is with the combination of either doxycycline and rifampin or doxycycline and streptomycin.¹¹³

Capnocytophaga canimorsus

Capnocytophaga is a facultative anaerobe and a long, slender Gram-negative rod found in the oral flora of dogs or cats. It can cause severe sepsis after a dog bite in immunocompromised patients, most often due to splenic abnormalities such as asplenia or splenectomy, cirrhosis, or alcohol abuse.^115-118 Diagnosis is via culture. Treatment is with β-lactams such as a β-lactam/β-lactamase combination, a cephalosporin, or a carbapenem, and duration is determined by clinical response.^115-118

Enterococcus

Enterococcus is a genus of bacteria previously classified as group D Streptococcus. They appear as Gram-positive cocci in pairs and chains and are facultative anaerobes. The most common species that cause infection are E faecalis and E faecium, both of which reside in the human intestine.^119,120 Their virulence factors include surface adhesins such as the Enterococcal surface protein, which leads to bacterial adherence to the bladder, and gelatinase, which contributes to the development of endocarditis in animal models.¹¹⁹ Enterococci are a common cause of nosocomial infections, including urinary tract infections, bloodstream infections, and endocarditis. Diagnosis is via culture. Enterococcus faecalis is usually susceptible to ampicillin, which is the antibiotic of choice, but E faecium is usually resistant to ampicillin and is often resistant to vancomycin. Antibiotic options for vancomycin-resistant Enterococci (VRE) include linezolid and daptomycin. Quinupristin-dalfopristin is the only active antibiotic against E faecium and is not active against E faecalis.

Escherichia coli

Escherichia coli is a Gram-negative rod that resides in the GI tract and a common cause of urinary tract infections and intestinal infections. Escherichia coli is a facultative anaerobe and lactose fermenter. Enterohemorrhagic E coli (EHEC), particularly the strain O157:H7, expresses Shiga toxin, can cause hemorrhagic colitis, and is associated with hemolytic uremic syndrome (HUS; hemolytic anemia, acute renal failure, and thrombocytopenia).^120,121 Diagnosis is based on culture using sorbitol-MacConkey agar for O157:H7, O104:H4, and Shiga toxins in stool. Antibiotics are associated with development of HUS and are not recommended for EHEC.^122,123 Enterotoxigenic E coli (ETEC) expresses either a heat labile or heat stable cholera-like toxin that causes excretion of chloride and inhibits sodium chloride reabsorption in the intestinal tract, causing watery diarrhea. Enteropathogenic E coli (EPEC) adheres to enterocytes and alters electrolyte and water secretions.^124-128 Enteroaggregative E coli (EAEC) has mitogen-activated protein kinase, which releases IL-8, cytotoxin, and adherence fimbriae; it can cause an acute diarrheal illness. Diagnosis is via tissue culture adherence assay.^129-132

Salmonella

This genus of enteric Gram-negative rods can further be classified into typhoidal Salmonella, which cause a systemic infection called typhoid fever with minimal diarrheal symptoms, and nontyphoidal Salmonella, which are common causes of diarrheal illnesses. Salmonella typhi and S paratyphi can cause typhoid fever. Symptoms of typhoid fever usually occur several days to weeks after ingestion of the bacteria and include high fevers, often with relative bradycardia, abdominal pain, and salmon-colored macules known as “rose spots.”^133,134 Unlike infection with nontyphoidal Salmonella, typhoid fever can be associated with constipation. Diagnosis is by culture, with bone marrow cultures being the most sensitive; serologic tests such as the Widal test are of limited use in endemic areas as they may represent previous infection. Treatment includes fluoroquinolones, cephalosporins, and azithromycin. Patients can be chronic carriers of S typhi, shedding the bacteria in the urine and stool for more than 12 months after acute infection. Chronic carrier state also predisposes patients to biliary cancer.

Treponema pallidum

Treponema pallidum is the spirochete that causes syphilis. It cannot be grown in culture, so it is diagnosed with serology with non-treponemal tests, such as rapid plasmid regain (RPR), Venereal Disease Research Laboratory (VDRL) test, or treponemal antibodies, such as the fluorescent treponemal antibody absorption test (FTA-ABS).^135,136 The spirochete can also be seen with darkfield microscopy when a specimen is taken from a lesion. Clinically, syphilis can be divided into early infection (less than 1 year), which includes primary syphilis, secondary syphilis, and latent syphilis, or late infection. Primary syphilis presents as a painless genital ulcer. Secondary syphilis occurs weeks to months after the primary lesions with a diffuse maculopapular rash involving the soles and palms, constitutional symptoms, and lymphadenopathy. Secondary syphilis can also present with hepatitis, nephritis or nephrotic syndrome, and ocular disease.¹³⁷ Latent syphilis is asymptomatic. Early latent syphilis is when serologic tests are newly positive within the past 12 months, while late latent syphilis has positive testing either after 12 months or of unknown timing. Late syphilis can present up to 30 years from initial inoculation and consists of tertiary syphilis with gummatous syphilis, general paresis, tabes dorsalis, and cardiovascular syphilis.¹³⁷ Neurologic involvement can occur at any stage of infection and is diagnosed with a positive VDRL in the cerebrospinal fluid; cerebrospinal fluid VDRL is specific, though not sensitive.^135,136 Penicillin is the antibiotic of choice for all stages of syphilis. For early syphilis, treatment is 1 dose of penicillin G benzathine 2.4 million units IM. For late syphilis, treatment is penicillin G benzathine 2.4 million units IM weekly for 3 weeks.¹³⁷ Neurosyphilis treatment consists of penicillin G 3 to 4 million units IV every 4 hours for 10 to 14 days. Doxycycline or ceftriaxone can be used in patients who are allergic to penicillin, but there is limited data on efficacy and higher rates of failure in neurosyphilis.¹³⁷

Mycobacterium tuberculosis

Mycobacterium is a genus of aerobic acid-fast bacteria. Mycobacterium tuberculosis is the most clinically significant species, as the cause of tuberculosis, which causes significant infectious mortality worldwide. Primary infection is pulmonary disease, but tuberculosis can cause latent and extrapulmonary infection. Infection is more complicated in immune-compromised hosts, such as patients with HIV. Patients who receive anti–tumor necrosis factor (TNF) therapy are also at increased risk of TB.¹³⁸ Primary tuberculosis occurs in patients not previously infected with tuberculosis and may be asymptomatic. Symptomatic patients can present with fevers and chest pain. Patients with intact immune systems can control further disease and will develop latent TB. The majority of TB cases seen are due to reactivated TB, which most often involve the upper lung lobes but can present as disseminated disease, particularly in patients with HIV. Symptoms of reactivated pulmonary TB include fever, night sweats, cough, dyspnea, hemoptysis, and weight loss. Miliary TB, which can be seen with primary or reactivated infection, is seen with hematogenous spread of TB and is more common in immunocompromised hosts. Extrapulmonary TB is distinguished as TB infection not involving the lungs and can involve the lymph nodes, GI tract, CNS, pericardium, and bones.

The diagnosis of latent TB infection (LTBI) is made by either the tuberculosis skin test (TST) or interferon gamma release assays (IGRAs) in patients with no clinical symptoms and no radiographic evidence of TB. A TST is read between 48 and 72 hours, and induration of 5 mm or more is positive in patients with direct TB exposure, patients with HIV, or patients on immunosuppressive therapy. A TST with induration of 10 mm or greater is positive in patients at increased risk of exposure, such as healthcare workers, immigrants from areas with high prevalence of TB, IV drug users, employees or residents of high-risk settings such as prisons or nursing homes, and children younger than 4 years old. A TST with induration of 15 mm or greater is positive in all other populations.¹³⁹

Radiographic findings in patients with tuberculosis include homogenous consolidation on any lobes, but particularly on the right middle or right lower lobe; unilateral adenopathy, particularly right paratracheal or right hilar; miliary disease; unilateral pleural effusion; or normal radiograph.^140-142 Ranke complex, the presence of Ghon complex and calcified hilar adenopathy suggests prior tuberculosis. If the lymph nodes are greater than 2 cm with or without areas of necrosis, it can suggest active disease.¹⁴⁰ Postprimary tuberculosis is a reactivation or reinfection and radiographically has upper lobe predilection, cavitation, and absence of lymphadenopathy. Coinfection with HIV tends to have atypical presentation of tuberculosis.

The diagnosis of active tuberculosis is based on clinical symptoms, risk factors, and isolation of M tuberculosis by culture. Patients with suspected active TB should be placed in airborne isolation. Sputum should be sent for acid-fast bacilli (AFB) smear and culture in patients with suspected TB; the sensitivity of sputum AFB smear increases with the number of specimens sent, so the recommendation is to send 3 specimens 8 hours apart. Molecular testing is also available for M tuberculosis, including nucleic acid amplification testing (NAAT); molecular diagnostics can lead to more rapid detection of TB, and depending on the specific test, can detect drug resistance.¹³⁹ Isolates of M tuberculosis are tested for antimicrobial susceptibility, and treatment is based on susceptibility results. All patients are started on empiric treatment with at least 4 agents.