Neutropenic Fever (Clinical)

Overview

Definition^[1,6]

Neutropenic fever Neutropenic fever Neutropenic fever is a medical emergency defined as a fever > 38.3°C (100.9°F) or higher than 38.0°C (100.4°F) for more than 1 hour in neutropenic patients. Neutropenic fever is a common life-threatening complication of hematologic malignancies and in patients undergoing chemotherapy. Neutropenic Fever is defined as a single oral temperature > 38.3 ℃ (101 ℉) or a temperature > 38.0℃ (100.4℉) for at least 1 hour with an absolute neutrophil count Absolute neutrophil count The number of neutrophils (as opposed to the percentage of WBCs) circulating per µL of blood . Neutropenia (ANC) of < 1,500 cells/µL or an ANC that is expected to decrease to < 500 cells/µL during the next 48 hours.

Epidemiology^[1,2,6]

• Febrile neutropenia Febrile neutropenia Fever accompanied by a significant reduction in the number of neutrophils. Neutropenic Fever develops in:
  • 10%–50% of patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with solid tumors
  • 80% of patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with hematologic malignancies
• 50% of patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship will develop an infection.
• Source of infection evident in only 20%–30% of cases
• Examination/culture fail to detect infectious focus/pathogen in 30%–60% of cases.
• 80% of infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease arise from an individual’s normally benign Benign Fibroadenoma or commensal bacterial flora.
• Common sites of infection include:
  • Lung
  • Skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions
  • Blood
  • GI tract

Etiology^[1,2]

In most cases, the source of infection is unknown (referred to as fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever of unknown origin (FUO)). The majority of documented infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease are bacterial.

The common sources of bacteremia Bacteremia The presence of viable bacteria circulating in the blood. Fever, chills, tachycardia, and tachypnea are common acute manifestations of bacteremia. The majority of cases are seen in already hospitalized patients, most of whom have underlying diseases or procedures which render their bloodstreams susceptible to invasion. Glycopeptides are:

• Translocation of enteric bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology into the bloodstream (e.g., from mucositis Mucositis Stomatitis is a general term referring to inflammation of the mucous membranes of the mouth, which may include sores. Stomatitis can be caused by infections, autoimmune disorders, allergic reactions, or exposure to irritants. The typical presentation may be either solitary or a group of painful oral lesions. Stomatitis)
• Catheter-related bloodstream infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease

Common bacterial pathogens:

• Gram-positive Gram-Positive Penicillins (make up over ½ of the cases):
  • Coagulase-negative staphylococci Coagulase-negative staphylococci Staphylococcus (most common)
    • Staphylococcus epidermidis Staphylococcus epidermidis A species of staphylococcus that is a spherical, non-motile, gram-positive, chemoorganotrophic, facultative anaerobe. Mainly found on the skin and mucous membrane of warm-blooded animals, it can be primary pathogen or secondary invader. Staphylococcus 
    • Staphylococcus Staphylococcus Staphylococcus is a medically important genera of Gram-positive, aerobic cocci. These bacteria form clusters resembling grapes on culture plates. Staphylococci are ubiquitous for humans, and many strains compose the normal skin flora. Staphylococcus haemolyticus
  • Staphylococcus aureus Staphylococcus aureus Potentially pathogenic bacteria found in nasal membranes, skin, hair follicles, and perineum of warm-blooded animals. They may cause a wide range of infections and intoxications. Brain Abscess (including MRSA MRSA A strain of Staphylococcus aureus that is non-susceptible to the action of methicillin. The mechanism of resistance usually involves modification of normal or the presence of acquired penicillin binding proteins. Staphylococcus)
  • Enterococci (including vancomycin-resistant)
  • Viridans group streptococci
  • Streptococcus Streptococcus Streptococcus is one of the two medically important genera of gram-positive cocci, the other being Staphylococcus. Streptococci are identified as different species on blood agar on the basis of their hemolytic pattern and sensitivity to optochin and bacitracin. There are many pathogenic species of streptococci, including S. pyogenes, S. agalactiae, S. pneumoniae, and the viridans streptococci. Streptococcus pyogenes
  • Streptococcus Streptococcus Streptococcus is one of the two medically important genera of gram-positive cocci, the other being Staphylococcus. Streptococci are identified as different species on blood agar on the basis of their hemolytic pattern and sensitivity to optochin and bacitracin. There are many pathogenic species of streptococci, including S. pyogenes, S. agalactiae, S. pneumoniae, and the viridans streptococci. Streptococcus pneumoniae
  • Bacillus Bacillus Bacillus are aerobic, spore-forming, gram-positive bacilli. Two pathogenic species are Bacillus anthracis (B. anthracis) and B. cereus. Bacillus species
• Gram-negative:
  • Escherichia coli Escherichia coli The gram-negative bacterium Escherichia coli is a key component of the human gut microbiota. Most strains of E. coli are avirulent, but occasionally they escape the GI tract, infecting the urinary tract and other sites. Less common strains of E. coli are able to cause disease within the GI tract, most commonly presenting as abdominal pain and diarrhea. Escherichia coli
  • Pseudomonas aeruginosa Pseudomonas aeruginosa A species of gram-negative, aerobic, rod-shaped bacteria commonly isolated from clinical specimens (wound, burn, and urinary tract infections). It is also found widely distributed in soil and water. P. Aeruginosa is a major agent of nosocomial infection. Pseudomonas
  • Klebsiella Klebsiella Klebsiella are encapsulated gram-negative, lactose-fermenting bacilli. They form pink colonies on MacConkey agar due to lactose fermentation. The main virulence factor is a polysaccharide capsule. Klebsiella pneumoniae is the most important pathogenic species. Klebsiella species
  • Enterobacter Enterobacter Multidrug-resistant Organisms and Nosocomial Infections
  • Fusobacterium Fusobacterium A genus of gram-negative, anaerobic, rod-shaped bacteria found in cavities of humans and other animals. No endospores are formed. Some species are pathogenic and occur in various purulent or gangrenous infections. Dog and Cat Bites
  • Acinetobacter Acinetobacter Multidrug-resistant Organisms and Nosocomial Infections species
  • Stenotrophomonas maltophilia

Common fungal pathogens:

• Aspergillus Aspergillus A genus of mitosporic fungi containing about 100 species and eleven different teleomorphs in the family trichocomaceae. Echinocandins species
• Candida Candida Candida is a genus of dimorphic, opportunistic fungi. Candida albicans is part of the normal human flora and is the most common cause of candidiasis. The clinical presentation varies and can include localized mucocutaneous infections (e.g., oropharyngeal, esophageal, intertriginous, and vulvovaginal candidiasis) and invasive disease (e.g., candidemia, intraabdominal abscess, pericarditis, and meningitis). Candida/Candidiasis species
• Fusarium species
• Endemic fungi Fungi A kingdom of eukaryotic, heterotrophic organisms that live parasitically as saprobes, including mushrooms; yeasts; smuts, molds, etc. They reproduce either sexually or asexually, and have life cycles that range from simple to complex. Filamentous fungi, commonly known as molds, refer to those that grow as multicellular colonies. Mycology

Common viral pathogens:

• Herpes simplex Herpes Simplex A group of acute infections caused by herpes simplex virus type 1 or type 2 that is characterized by the development of one or more small fluid-filled vesicles with a raised erythematous base on the skin or mucous membrane. It occurs as a primary infection or recurs due to a reactivation of a latent infection. Congenital TORCH Infections virus Virus Viruses are infectious, obligate intracellular parasites composed of a nucleic acid core surrounded by a protein capsid. Viruses can be either naked (non-enveloped) or enveloped. The classification of viruses is complex and based on many factors, including type and structure of the nucleoid and capsid, the presence of an envelope, the replication cycle, and the host range. Virology ( reactivation Reactivation Herpes Simplex Virus 1 and 2)
• CMV
• Influenza Influenza Influenza viruses are members of the Orthomyxoviridae family and the causative organisms of influenza, a highly contagious febrile respiratory disease. There are 3 primary influenza viruses (A, B, and C) and various subtypes, which are classified based on their virulent surface antigens, hemagglutinin (HA) and neuraminidase (NA). Influenza typically presents with a fever, myalgia, headache, and symptoms of an upper respiratory infection. Influenza Viruses/Influenza virus Virus Viruses are infectious, obligate intracellular parasites composed of a nucleic acid core surrounded by a protein capsid. Viruses can be either naked (non-enveloped) or enveloped. The classification of viruses is complex and based on many factors, including type and structure of the nucleoid and capsid, the presence of an envelope, the replication cycle, and the host range. Virology
• Parainfluenza virus Parainfluenza virus Human parainfluenza viruses (HPIVs) are single-stranded, linear, negative-sense RNA viruses of the family Paramyxoviridae and the genus Paramyxovirus. Human parainfluenza viruses are the 2nd most common cause of lower respiratory disease in children, after the respiratory syncytial virus. Parainfluenza Virus
• Adenovirus Adenovirus Adenovirus (member of the family Adenoviridae) is a nonenveloped, double-stranded DNA virus. Adenovirus is transmitted in a variety of ways, and it can have various presentations based on the site of entry. Presentation can include febrile pharyngitis, conjunctivitis, acute respiratory disease, atypical pneumonia, and gastroenteritis. Adenovirus
• Respiratory syncytial virus Respiratory Syncytial Virus Respiratory syncytial virus (RSV) is an enveloped, single-stranded, linear, negative-sense RNA virus of the family Paramyxoviridae and the genus Orthopneumovirus. Two subtypes (A and B) are present in outbreaks, but type A causes more severe disease. Respiratory syncytial virus causes infections of the lungs and respiratory tract. Respiratory Syncytial Virus
• Norovirus Norovirus Norovirus is a nonenveloped, single-stranded, positive-sense RNA virus belonging to the Caliciviridae family. Norovirus infections are transmitted via the fecal-oral route or by aerosols from vomiting. The virus is one of the most common causes of nonbacterial gastroenteritis epidemic worldwide. Symptoms include watery and nonbloody diarrhea, nausea, vomiting, and low-grade fever. Norovirus
• Rhinovirus Rhinovirus Rhinovirus is an acid-labile, positive-sense RNA virus of the Picornavirus family. The virus, which causes the common cold, is most often acquired through the airway via the inhalation of aerosols containing rhinovirus and fomites. Rhinovirus
• Enterovirus Enterovirus A genus of the family picornaviridae whose members preferentially inhabit the intestinal tract of a variety of hosts. The genus contains many species. Newly described members of human enteroviruses are assigned continuous numbers with the species designated ‘human enterovirus’. Coxsackievirus
• Hepatitis B Hepatitis B Hepatitis B virus (HBV) is a partially double-stranded DNA virus, which belongs to the Orthohepadnavirus genus and the Hepadnaviridae family. Most individuals with acute HBV infection are asymptomatic or have mild, self-limiting symptoms. Chronic infection can be asymptomatic or create hepatic inflammation, leading to liver cirrhosis and hepatocellular carcinoma (HCC). Hepatitis B Virus and C ( reactivation Reactivation Herpes Simplex Virus 1 and 2)
• Metapneumovirus
• Coronaviruses

Other common pathogens:

• Strongyloides stercoralis Strongyloides stercoralis A species of parasitic nematode widely distributed in tropical and subtropical countries. The females and their larvae inhabit the mucosa of the intestinal tract, where they cause ulceration and diarrhea. Strongyloidiasis
• Leishmania Leishmania Leishmania species are obligate intracellular parasites that are transmitted by an infected sandfly. The disease is endemic to Asia, the Middle East, Africa, the Mediterranean, and South and Central America. Clinical presentation varies, dependent on the pathogenicity of the species and the host’s immune response. Leishmania/Leishmaniasis species
• Trypanosoma species

Pathophysiology^[1,2,4]

The combination of the following factors contribute to the development of neutropenic fever Neutropenic fever Neutropenic fever is a medical emergency defined as a fever > 38.3°C (100.9°F) or higher than 38.0°C (100.4°F) for more than 1 hour in neutropenic patients. Neutropenic fever is a common life-threatening complication of hematologic malignancies and in patients undergoing chemotherapy. Neutropenic Fever:

• Chemotherapy-induced bone marrow Bone marrow The soft tissue filling the cavities of bones. Bone marrow exists in two types, yellow and red. Yellow marrow is found in the large cavities of large bones and consists mostly of fat cells and a few primitive blood cells. Red marrow is a hematopoietic tissue and is the site of production of erythrocytes and granular leukocytes. Bone marrow is made up of a framework of connective tissue containing branching fibers with the frame being filled with marrow cells. Bone Marrow: Composition and Hematopoiesis suppression Suppression Defense Mechanisms 
• Metastatic replacement of bone marrow Metastatic Replacement of Bone Marrow Neutropenic Fever
• Abnormal antibody production/clearance in antibody-producing cancers (e.g., multiple myeloma, chronic lymphocytic leukemia Chronic Lymphocytic Leukemia Chronic lymphocytic leukemia (CLL) is a hematologic malignancy characterized by excess production of monoclonal B lymphocytes in the peripheral blood. When the involvement is primarily nodal, the condition is called small lymphocytic lymphoma (SLL). The disease usually presents in older adults, with a median age of 70 years. Chronic Lymphocytic Leukemia), resulting in functional asplenia Functional Asplenia Asplenia
• Abnormal production and function of T cells T cells Lymphocytes responsible for cell-mediated immunity. Two types have been identified – cytotoxic (t-lymphocytes, cytotoxic) and helper T-lymphocytes (t-lymphocytes, helper-inducer). They are formed when lymphocytes circulate through the thymus gland and differentiate to thymocytes. When exposed to an antigen, they divide rapidly and produce large numbers of new T cells sensitized to that antigen. T cells: Types and Functions ( lymphoma Lymphoma A general term for various neoplastic diseases of the lymphoid tissue. Imaging of the Mediastinum)
• Chemotherapy-induced mucosal injury Chemotherapy-Induced Mucosal Injury Neutropenic Fever
• Presence of infection sources ( indwelling catheters Indwelling catheters Catheters designed to be left within an organ or passage for an extended period of time. Pseudomonas)

Clinical Presentation

Neutropenia Neutropenia Neutrophils are an important component of the immune system and play a significant role in the eradication of infections. Low numbers of circulating neutrophils, referred to as neutropenia, predispose the body to recurrent infections or sepsis, though patients can also be asymptomatic. Neutropenia may minimize symptoms and signs of infection:^[2,6,9]

• Neutrophil activation Neutrophil activation The process in which the neutrophil is stimulated by diverse substances, resulting in degranulation and/or generation of reactive oxygen products, and culminating in the destruction of invading pathogens. The stimulatory substances, including opsonized particles, immune complexes, and chemotactic factors, bind to specific cell-surface receptors on the neutrophil. Ehrlichiosis and Anaplasmosis responsible for many inflammatory symptoms of infection
• Neutropenia Neutropenia Neutrophils are an important component of the immune system and play a significant role in the eradication of infections. Low numbers of circulating neutrophils, referred to as neutropenia, predispose the body to recurrent infections or sepsis, though patients can also be asymptomatic. Neutropenia → ↓ neutrophil activation Neutrophil activation The process in which the neutrophil is stimulated by diverse substances, resulting in degranulation and/or generation of reactive oxygen products, and culminating in the destruction of invading pathogens. The stimulatory substances, including opsonized particles, immune complexes, and chemotactic factors, bind to specific cell-surface receptors on the neutrophil. Ehrlichiosis and Anaplasmosis → ↓ cytokine release → ↓ inflammatory symptoms

The presence of fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever may be the only sign of an infection.

Common symptoms of febrile neutropenia Febrile neutropenia Fever accompanied by a significant reduction in the number of neutrophils. Neutropenic Fever are:^[2,6,9]

• Odynophagia Odynophagia Epiglottitis
• Sore mouth
• Skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions ulcers
• Cough
• Dyspnea Dyspnea Dyspnea is the subjective sensation of breathing discomfort. Dyspnea is a normal manifestation of heavy physical or psychological exertion, but also may be caused by underlying conditions (both pulmonary and extrapulmonary). Dyspnea
• Dysuria Dysuria Painful urination. It is often associated with infections of the lower urinary tract. Urinary Tract Infections (UTIs)
• Urinary frequency and urgency
• Redness Redness Inflammation and tenderness at the catheter site

Diagnosis

Measuring the temperature accurately is important, but clinical judgment Judgment The process of discovering or asserting an objective or intrinsic relation between two objects or concepts; a faculty or power that enables a person to make judgments; the process of bringing to light and asserting the implicit meaning of a concept; a critical evaluation of a person or situation. Psychiatric Assessment is crucial since fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever may not be present in all cases of infection.^[12]

• Oral thermometry Thermometry Measurement of the temperature of a material, or of the body or an organ by various temperature sensing devices which measure changes in properties of the material that vary with temperature, such as elasticity; magnetic fields; or luminescence. Body Temperature Regulation is the most common method, but may be painful and/or overestimate the body temperature Body Temperature The measure of the level of heat of a human or animal. Heatstroke if there is oral mucositis Mucositis Stomatitis is a general term referring to inflammation of the mucous membranes of the mouth, which may include sores. Stomatitis can be caused by infections, autoimmune disorders, allergic reactions, or exposure to irritants. The typical presentation may be either solitary or a group of painful oral lesions. Stomatitis.
• Infrared tympanic membrane Tympanic membrane An oval semitransparent membrane separating the external ear canal from the tympanic cavity. It contains three layers: the skin of the external ear canal; the core of radially and circularly arranged collagen fibers; and the mucosa of the middle ear. Ear: Anatomy thermometry Thermometry Measurement of the temperature of a material, or of the body or an organ by various temperature sensing devices which measure changes in properties of the material that vary with temperature, such as elasticity; magnetic fields; or luminescence. Body Temperature Regulation
  • Advantage: noninvasive and convenient
  • Disadvantages
    • Operator-dependent
    • Falsely high readings possible if performed on the dependent ear.
    • Falsely low readings may occur if cerumen Cerumen The yellow or brown waxy secretions produced by vestigial apocrine sweat glands in the external ear canal. Otitis Externa is in the external auditory canal External Auditory Canal Otitis Externa.
• Axillary thermometry Thermometry Measurement of the temperature of a material, or of the body or an organ by various temperature sensing devices which measure changes in properties of the material that vary with temperature, such as elasticity; magnetic fields; or luminescence. Body Temperature Regulation is also operator-dependent and may also result in falsely low or falsely high measurements.
• Rectal measurements are NOT recommended in neutropenic or thrombocytopenic patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship because it increases the risk for local mucosal trauma-induced bacteremia Bacteremia The presence of viable bacteria circulating in the blood. Fever, chills, tachycardia, and tachypnea are common acute manifestations of bacteremia. The majority of cases are seen in already hospitalized patients, most of whom have underlying diseases or procedures which render their bloodstreams susceptible to invasion. Glycopeptides and bleeding.

All patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with febrile neutropenia Febrile neutropenia Fever accompanied by a significant reduction in the number of neutrophils. Neutropenic Fever should undergo a detailed history and physical examination, and diagnostic studies should be performed.

History^[1,2,6,8,9]

A detailed history should include:

• Review of systems to locate an infection focus
• Current medications
• Type of cancer
• Current chemotherapy Chemotherapy Osteosarcoma regimen
• Review any recent lab testing, particularly hematological studies.
• Presence of allergies Allergies A medical specialty concerned with the hypersensitivity of the individual to foreign substances and protection from the resultant infection or disorder. Selective IgA Deficiency
• Steroid use
• Comorbidities Comorbidities The presence of co-existing or additional diseases with reference to an initial diagnosis or with reference to the index condition that is the subject of study. Comorbidity may affect the ability of affected individuals to function and also their survival; it may be used as a prognostic indicator for length of hospital stay, cost factors, and outcome or survival. St. Louis Encephalitis Virus
• Prior history of infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease
• Recent prophylaxis Prophylaxis Cephalosporins with antibiotics 
• Recent administration of hematopoietic growth factors Hematopoietic growth factors Hematopoietic growth factors are a family of glycoproteins responsible for the proliferation and differentiation of hematopoietic progenitor cells in the bone marrow. Pharmacologic erythropoietin, thrombopoietin, granulocyte colony-stimulating factor (G-CSF), and granulocyte macrophage colony-stimulating factor (GM-CSF) are used in certain cases in which normal hematopoiesis is impaired owing to treatment (e.g., chemotherapy) or underlying disease (e.g., aplastic anemia). Hematopoietic Growth Factors
• History of transplantation

Physical exam^[2,6,8,9]

A thorough physical examination should include an evaluation of:

• Skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions:
  • Erythema Erythema Redness of the skin produced by congestion of the capillaries. This condition may result from a variety of disease processes. Chalazion 
  • Tenderness
  • Ulcers
  • Abscesses
  • Central catheter insertion sites
  • Ecthyma gangrenosum Ecthyma gangrenosum Pseudomonas (seen in P. aeruginosa P. aeruginosa A species of gram-negative, aerobic, rod-shaped bacteria commonly isolated from clinical specimens (wound, burn, and urinary tract infections). It is also found widely distributed in soil and water. P. Aeruginosa is a major agent of nosocomial infection. Pseudomonas infection)
• Optic fundi: signs of septic emboli
• Sinuses:
  • Tenderness
  • “Boggy” appearance (bluish, pale, swollen)
• Mouth:
  • Ulcers
  • Periodontal disease
  • Leukoplakia Leukoplakia Leukoplakia is a potentially malignant lesion affecting the squamous epithelium usually within the oral cavity. Leukoplakia can be associated with a history of chronic tobacco and alcohol use, both of which can synergistically damage the epithelium. Leukoplakia
• Lungs Lungs Lungs are the main organs of the respiratory system. Lungs are paired viscera located in the thoracic cavity and are composed of spongy tissue. The primary function of the lungs is to oxygenate blood and eliminate CO2. Lungs: Anatomy
• Abdomen:
  • Visceral mucosal examination
  • Do not perform rectal exam in neutropenic patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship.
• Perineal area:
  • Pilonidal cyst
  • Perirectal abscess Abscess Accumulation of purulent material in tissues, organs, or circumscribed spaces, usually associated with signs of infection. Chronic Granulomatous Disease
  • Vaginal/vulvar infection
• Neurologic system:
  • Meningismus Meningismus Subarachnoid Hemorrhage
  • Focal neurologic deficit Focal Neurologic Deficit Intracerebral Hemorrhage
  • Altered mental status Altered Mental Status Sepsis in Children
• Catheter sites:
  • Erythema Erythema Redness of the skin produced by congestion of the capillaries. This condition may result from a variety of disease processes. Chalazion
  • Fluctuance Fluctuance Examination of the Breast
  • Tenderness
  • Palpable cord along the vein

Diagnostic testing

Laboratory studies:^{[1,2,6–8,10]}

• CBC with differential:^[1]
  • ANC calculator
  • Neutropenia Neutropenia Neutrophils are an important component of the immune system and play a significant role in the eradication of infections. Low numbers of circulating neutrophils, referred to as neutropenia, predispose the body to recurrent infections or sepsis, though patients can also be asymptomatic. Neutropenia: ANC < 1,000 cells/µL (may vary depending on institution: some use ANC < 1,500 cells/µL)
  • Severe neutropenia Severe Neutropenia Neutropenia: ANC < 500 cells/µL
  • Profound neutropenia Neutropenia Neutrophils are an important component of the immune system and play a significant role in the eradication of infections. Low numbers of circulating neutrophils, referred to as neutropenia, predispose the body to recurrent infections or sepsis, though patients can also be asymptomatic. Neutropenia: ANC < 100 cells/µL
• Blood type
• Coagulation studies Coagulation studies Coagulation studies are a group of hematologic laboratory studies that reflect the function of blood vessels, platelets, and coagulation factors, which all interact with one another to achieve hemostasis. Coagulation studies are usually ordered to evaluate patients with bleeding or hypercoagulation disorders. Coagulation Studies
• Chemistry panel:
  • Renal function
  • Hepatic function
  • Electrolytes Electrolytes Electrolytes are mineral salts that dissolve in water and dissociate into charged particles called ions, which can be either be positively (cations) or negatively (anions) charged. Electrolytes are distributed in the extracellular and intracellular compartments in different concentrations. Electrolytes are essential for various basic life-sustaining functions. Electrolytes
• Lactate: Increased levels suggest sepsis Sepsis Systemic inflammatory response syndrome with a proven or suspected infectious etiology. When sepsis is associated with organ dysfunction distant from the site of infection, it is called severe sepsis. When sepsis is accompanied by hypotension despite adequate fluid infusion, it is called septic shock. Sepsis and Septic Shock.
• Urinalysis Urinalysis Examination of urine by chemical, physical, or microscopic means. Routine urinalysis usually includes performing chemical screening tests, determining specific gravity, observing any unusual color or odor, screening for bacteriuria, and examining the sediment microscopically. Urinary Tract Infections (UTIs) in Children 
• CRP
• ESR ESR Soft Tissue Abscess
• Procalcitonin Procalcitonin Neutropenic Fever ( PCT PCT The renal tubule portion that extends from the bowman capsule in the kidney cortex into the kidney medulla. The proximal tubule consists of a convoluted proximal segment in the cortex, and a distal straight segment descending into the medulla where it forms the u-shaped loop of henle. Osmotic Diuretics):^[5]
  • Prohormone of calcitonin Calcitonin A peptide hormone that lowers calcium concentration in the blood. In humans, it is released by thyroid cells and acts to decrease the formation and absorptive activity of osteoclasts. Its role in regulating plasma calcium is much greater in children and in certain diseases than in normal adults. Other Antiresorptive Drugs, produced during systemic infection in response to microbial toxins and host inflammatory mediators
  • May help differentiate infectious from noninfectious etiology of fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever:
    • Elevated in bacterial infection
    • Elevated in fungal infection
  • May help guide selection Selection Lymphocyte activation by a specific antigen thus triggering clonal expansion of lymphocytes already capable of mounting an immune response to the antigen. B cells: Types and Functions and duration of antibiotic therapy:
    • Strengthens decision for antibiotic initiation if elevated
    • Strengthens decision to withhold/withdraw antibiotics if not elevated
  • May help prevent unnecessary/prolonged antibiotic therapy

Culture:^{[1,2,6–8,10]}

• Blood culture:
  • 2 sets of blood cultures should be obtained from 2 separate peripheral venipuncture sites and from any indwelling venous catheter.
  • 1 set consists of 2 bottles (aerobic and anaerobic).
• Urine culture Urine culture Urinary Tract Infections (UTIs) should be obtained if:
  • Patient is symptomatic
  • Patient has a history of urinary tract Urinary tract The urinary tract is located in the abdomen and pelvis and consists of the kidneys, ureters, urinary bladder, and urethra. The structures permit the excretion of urine from the body. Urine flows from the kidneys through the ureters to the urinary bladder and out through the urethra. Urinary Tract: Anatomy infection
  • Catheter is present
• Site-specific cultures/tests:
  • Stool microscopy Stool Microscopy Giardia/Giardiasis and culture if diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea is present (Clostridioides difficile)
  • Sputum microscopy and culture if signs of respiratory infection are present
  • Skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions/wound swab
  • Viral diagnostics:
    • PCR PCR Polymerase chain reaction (PCR) is a technique that amplifies DNA fragments exponentially for analysis. The process is highly specific, allowing for the targeting of specific genomic sequences, even with minuscule sample amounts. The PCR cycles multiple times through 3 phases: denaturation of the template DNA, annealing of a specific primer to the individual DNA strands, and synthesis/elongation of new DNA molecules. Polymerase Chain Reaction (PCR)/direct fluorescence antibody (DFA) for vesicular or ulcerated skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions or mucosal lesions 
    • Throat Throat The pharynx is a component of the digestive system that lies posterior to the nasal cavity, oral cavity, and larynx. The pharynx can be divided into the oropharynx, nasopharynx, and laryngopharynx. Pharyngeal muscles play an integral role in vital processes such as breathing, swallowing, and speaking. Pharynx: Anatomy or nasopharynx Nasopharynx The top portion of the pharynx situated posterior to the nose and superior to the soft palate. The nasopharynx is the posterior extension of the nasal cavities and has a respiratory function. Pharynx: Anatomy swab for respiratory virus Virus Viruses are infectious, obligate intracellular parasites composed of a nucleic acid core surrounded by a protein capsid. Viruses can be either naked (non-enveloped) or enveloped. The classification of viruses is complex and based on many factors, including type and structure of the nucleoid and capsid, the presence of an envelope, the replication cycle, and the host range. Virology symptoms

Imaging:^[1,2,6–8]

• A chest X-ray X-ray Penetrating electromagnetic radiation emitted when the inner orbital electrons of an atom are excited and release radiant energy. X-ray wavelengths range from 1 pm to 10 nm. Hard x-rays are the higher energy, shorter wavelength x-rays. Soft x-rays or grenz rays are less energetic and longer in wavelength. The short wavelength end of the x-ray spectrum overlaps the gamma rays wavelength range. The distinction between gamma rays and x-rays is based on their radiation source. Pulmonary Function Tests or CT scan should be obtained (UK guidelines discourage this unless clinically indicated).^[10] 
• Further imaging should be performed when clinically indicated.

Management

The following information is based on current US, UK, and European literature and guidelines for adult patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship. Exact management protocols may vary based on location and institution. 

Risk assessment Risk assessment The qualitative or quantitative estimation of the likelihood of adverse effects that may result from exposure to specified health hazards or from the absence of beneficial influences. Preoperative Care

Considerations:^{[1,2,6–8,10]}

• Risk stratification tools:
  • Multinational Association for Supportive Care in Cancer (MASCC) score
  • Clinical Index of Stable Febrile Neutropenia (CISNE)
  • Talcott’s rules of1992 formed the basis for the two subsequent risk stratification models listed above.^[13]
  • As noted by Talcott himself: “Mathematical models used correctly assist decision making; they do not replace it.”^[14]
• Evaluate if a patient is appropriate for:
  • Outpatient versus inpatient management
  • Oral versus IV antibiotics
• Anticipated duration of therapy
• Caregiver availability

Low-risk criteria:^[2,6,7]

• Outpatient status at time of development of fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever
• Neutropenia Neutropenia Neutrophils are an important component of the immune system and play a significant role in the eradication of infections. Low numbers of circulating neutrophils, referred to as neutropenia, predispose the body to recurrent infections or sepsis, though patients can also be asymptomatic. Neutropenia duration < 7 days
• No comorbidities Comorbidities The presence of co-existing or additional diseases with reference to an initial diagnosis or with reference to the index condition that is the subject of study. Comorbidity may affect the ability of affected individuals to function and also their survival; it may be used as a prognostic indicator for length of hospital stay, cost factors, and outcome or survival. St. Louis Encephalitis Virus
• Normal hepatic and renal functions
• Good performance status
• Hemodynamically stable
• Able to follow closely with a clinician Clinician A physician, nurse practitioner, physician assistant, or another health professional who is directly involved in patient care and has a professional relationship with patients. Clinician–Patient Relationship
• Not on fluoroquinolone prophylaxis Prophylaxis Cephalosporins
• MASCC score ≥ 21 or CISNE < 3

High-risk criteria:^[1,2,6–8]

• Inpatient status at time of development of fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever
• Profound neutropenia Neutropenia Neutrophils are an important component of the immune system and play a significant role in the eradication of infections. Low numbers of circulating neutrophils, referred to as neutropenia, predispose the body to recurrent infections or sepsis, though patients can also be asymptomatic. Neutropenia (ANC ≤ 100 cells/µL)
• Prolonged neutropenia Neutropenia Neutrophils are an important component of the immune system and play a significant role in the eradication of infections. Low numbers of circulating neutrophils, referred to as neutropenia, predispose the body to recurrent infections or sepsis, though patients can also be asymptomatic. Neutropenia (≥ 7 days)
• Current fluoroquinolone prophylaxis Prophylaxis Cephalosporins
• MASCC score < 21 or CISNE ≥ 3
• Allogeneic hematopoietic stem cell transplantation Hematopoietic stem cell transplantation Transfer of hematopoietic stem cells from bone marrow or blood between individuals within the same species (homologous transplantation) or transfer within the same individual (autologous transplantation). Hematopoietic stem cell transplantation has been used as an alternative to bone marrow transplantation in the treatment of a variety of neoplasms. Organ Transplantation (HSCT)
• Hepatic insufficiency (5 times upper limit Limit A value (e.g., pressure or time) that should not be exceeded and which is specified by the operator to protect the lung Invasive Mechanical Ventilation of normal for
• aminotransferases)
• Renal insufficiency ( creatinine clearance Creatinine clearance Kidney Function Tests of < 30 mL/min)
• Uncontrolled or progressive malignancy Malignancy Hemothorax
• Significant mucositis Mucositis Stomatitis is a general term referring to inflammation of the mucous membranes of the mouth, which may include sores. Stomatitis can be caused by infections, autoimmune disorders, allergic reactions, or exposure to irritants. The typical presentation may be either solitary or a group of painful oral lesions. Stomatitis
• Multidrug-resistant organism (MDRO) colonization Colonization Bacteriology
• Comorbid conditions:
  • New-onset abdominal pain Abdominal Pain Acute Abdomen
  • Hypotension Hypotension Hypotension is defined as low blood pressure, specifically < 90/60 mm Hg, and is most commonly a physiologic response. Hypotension may be mild, serious, or life threatening, depending on the cause. Hypotension 
  • Pneumonia Pneumonia Pneumonia or pulmonary inflammation is an acute or chronic inflammation of lung tissue. Causes include infection with bacteria, viruses, or fungi. In more rare cases, pneumonia can also be caused through toxic triggers through inhalation of toxic substances, immunological processes, or in the course of radiotherapy. Pneumonia
  • Neurologic changes
  • Laboratory evidence of organ dysfunction
  • Hemodynamic instability

General approach to management

Empiric antibiotic therapy:^[1,2,6,8,10]

• Empiric therapy Empiric Therapy Meningitis in Children should be administered within 1 hour after admission.
• Antibiotic selection Selection Lymphocyte activation by a specific antigen thus triggering clonal expansion of lymphocytes already capable of mounting an immune response to the antigen. B cells: Types and Functions:
  • Should be broad-spectrum Broad-Spectrum Fluoroquinolones and include antipseudomonal activity
  • Keep in mind:
    • Prior infection with MDROs
    • Colonization Colonization Bacteriology with MDROs
  • Consider infectious disease (ID) consultation if source is unknown.
  • If no change in 4–5 days (3–7 days in European guidelines), consider:
    • Escalating antibiotics 
    • Additional imaging (e.g., chest CT to rule out fungal/ mold Mold Mycology infection)
    • Adding antifungal Antifungal Azoles therapy
    • ID consultation
  • If the patient deteriorates or becomes unstable → broaden coverage to include resistant organisms
• If infection becomes known:
  • Tailor therapy (if possible).
  • Remove catheter if implicated in infection.

Repeat cultures if:^[1] 

• Fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever does not defervesce after 2–3 days
• New fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever develops
• Initial cultures are positive

Low-risk management^[1,6,7,10]

Low-risk patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship are treated as outpatients or initially as inpatients and then transferred to outpatient with close follow-up (oral antibiotic therapy).

• Antibiotics:
  • No penicillin Penicillin Rheumatic Fever allergy Allergy An abnormal adaptive immune response that may or may not involve antigen-specific IgE Type I Hypersensitivity Reaction: levofloxacin Levofloxacin The l-isomer of ofloxacin. Fluoroquinolones/ ciprofloxacin Ciprofloxacin A broad-spectrum antimicrobial carboxyfluoroquinoline. Fluoroquinolones plus amoxicillin Amoxicillin A broad-spectrum semisynthetic antibiotic similar to ampicillin except that its resistance to gastric acid permits higher serum levels with oral administration. Penicillins–clavulanate
  • Penicillin Penicillin Rheumatic Fever allergy Allergy An abnormal adaptive immune response that may or may not involve antigen-specific IgE Type I Hypersensitivity Reaction: clindamycin Clindamycin An antibacterial agent that is a semisynthetic analog of lincomycin. Lincosamides plus levofloxacin Levofloxacin The l-isomer of ofloxacin. Fluoroquinolones/ ciprofloxacin Ciprofloxacin A broad-spectrum antimicrobial carboxyfluoroquinoline. Fluoroquinolones
  • Other: moxifloxacin Moxifloxacin A fluoroquinolone that acts as an inhibitor of DNA topoisomerase II and is used as a broad-spectrum antibacterial agent. Fluoroquinolones monotherapy
• Antifungal Antifungal Azoles therapy:
  • No antifungal Antifungal Azoles treatment is recommended initially.
  • Broad-spectrum Broad-Spectrum Fluoroquinolones antifungals should be administered if fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever persists ≥ 4–7 days.
• If assessing in the emergency department, observe for ≥ 4 hours before discharge home.^[8]
• Follow up with patient within 12–24 hours after initiating therapy and daily being given IV antibiotic therapy.
• Reevaluation and potential hospitalization Hospitalization The confinement of a patient in a hospital. Delirium is indicated if:
  • New fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever develops
  • Failure to improve after 3–5 days of treatment (2–3 days, per ASCO and IDSA)^[1,6,8]
  • Blood cultures become positive
  • Unable to tolerate oral antimicrobial therapy
  • Clinical deterioration

High-risk patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship

High-risk patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship must be treated as inpatients (IV antibiotic therapy).

• No penicillin Penicillin Rheumatic Fever allergy Allergy An abnormal adaptive immune response that may or may not involve antigen-specific IgE Type I Hypersensitivity Reaction:^[2,6,8,10]
  • Cefepime Cefepime A fourth-generation cephalosporin antibacterial agent that is used in the treatment of infections, including those of the abdomen, urinary tract, respiratory tract, and skin. It is effective against pseudomonas aeruginosa and may also be used in the empiric treatment of febrile neutropenia. Cephalosporins
  • Piperacillin Piperacillin Semisynthetic, broad-spectrum, ampicillin derived ureidopenicillin antibiotic proposed for pseudomonas infections. It is also used in combination with other antibiotics. Penicillins– tazobactam Tazobactam A penicillanic acid and sulfone derivative and potent beta-lactamase inhibitor that enhances the activity of other anti-bacterial agents against beta-lactamase producing bacteria. Cephalosporins (preferred in the UK)^[10]
  • Meropenem Meropenem A thienamycin derivative antibacterial agent that is more stable to renal dehydropeptidase I than imipenem, but does not need to be given with an enzyme inhibitor such as cilastatin. It is used in the treatment of bacterial infections, including infections in immunocompromised patients. Carbapenems and Aztreonam
  • Imipenem Imipenem Semisynthetic thienamycin that has a wide spectrum of antibacterial activity against gram-negative and gram-positive aerobic and anaerobic bacteria, including many multiresistant strains. It is stable to beta-lactamases. Clinical studies have demonstrated high efficacy in the treatment of infections of various body systems. Its effectiveness is enhanced when it is administered in combination with cilastatin, a renal dipeptidase inhibitor. Carbapenems and Aztreonam– cilastatin Cilastatin A renal dehydropeptidase-i and leukotriene d4 dipeptidase inhibitor. Since the antibiotic, imipenem, is hydrolyzed by dehydropeptidase-i, which resides in the brush border of the renal tubule, cilastatin is administered with imipenem to increase its effectiveness. The drug also inhibits the metabolism of leukotriene d4 to leukotriene e4. Carbapenems and Aztreonam
  • Ceftazidime Ceftazidime Semisynthetic, broad-spectrum antibacterial derived from cephaloridine and used especially for pseudomonas and other gram-negative infections in debilitated patients. Cephalosporins
• Complicated case or antibiotic resistance Resistance Physiologically, the opposition to flow of air caused by the forces of friction. As a part of pulmonary function testing, it is the ratio of driving pressure to the rate of air flow. Ventilation: Mechanics of Breathing: Aminoglycosides Aminoglycosides Aminoglycosides are a class of antibiotics including gentamicin, tobramycin, amikacin, neomycin, plazomicin, and streptomycin. The class binds the 30S ribosomal subunit to inhibit bacterial protein synthesis. Unlike other medications with a similar mechanism of action, aminoglycosides are bactericidal. Aminoglycosides should be added to the above regimens (not recommended in the UK unless absolutely necessary).^[2,6,8,10]
  • Gentamicin Gentamicin Aminoglycosides
  • Amikacin
  • Tobramycin
• Penicillin Penicillin Rheumatic Fever allergy Allergy An abnormal adaptive immune response that may or may not involve antigen-specific IgE Type I Hypersensitivity Reaction (and intolerance to cephalosporins Cephalosporins Cephalosporins are a group of bactericidal beta-lactam antibiotics (similar to penicillins) that exert their effects by preventing bacteria from producing their cell walls, ultimately leading to cell death. Cephalosporins are categorized by generation and all drug names begin with “cef-” or “ceph-.” Cephalosporins):^[2,6,8]
  • Not on fluoroquinolone prophylaxis Prophylaxis Cephalosporins: ciprofloxacin Ciprofloxacin A broad-spectrum antimicrobial carboxyfluoroquinoline. Fluoroquinolones plus clindamycin Clindamycin An antibacterial agent that is a semisynthetic analog of lincomycin. Lincosamides
  • On fluoroquinolone prophylaxis Prophylaxis Cephalosporins: aztreonam Aztreonam The carbapenems and aztreonam are both members of the bactericidal beta-lactam family of antibiotics (similar to penicillins). They work by preventing bacteria from producing their cell wall, ultimately leading to bacterial cell death. Carbapenems and Aztreonam plus vancomycin Vancomycin Antibacterial obtained from streptomyces orientalis. It is a glycopeptide related to ristocetin that inhibits bacterial cell wall assembly and is toxic to kidneys and the inner ear. Glycopeptides
• Patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with neutropenic enterocolitis Enterocolitis Inflammation of the mucosa of both the small intestine and the large intestine. Etiology includes ischemia, infections, allergic, and immune responses. Yersinia spp./Yersiniosis:^[6,8]
  • Piperacillin Piperacillin Semisynthetic, broad-spectrum, ampicillin derived ureidopenicillin antibiotic proposed for pseudomonas infections. It is also used in combination with other antibiotics. Penicillins– tazobactam Tazobactam A penicillanic acid and sulfone derivative and potent beta-lactamase inhibitor that enhances the activity of other anti-bacterial agents against beta-lactamase producing bacteria. Cephalosporins
  • Carbapenem Carbapenem The carbapenems and aztreonam are both members of the bactericidal beta-lactam family of antibiotics (similar to penicillins). They work by preventing bacteria from producing their cell wall, ultimately leading to bacterial cell death. Carbapenems and Aztreonam
  • Antipseudomonal cephalosporin Cephalosporin Multidrug-resistant Organisms and Nosocomial Infections plus metronidazole Metronidazole A nitroimidazole used to treat amebiasis; vaginitis; trichomonas infections; giardiasis; anaerobic bacteria; and treponemal infections. Pyogenic Liver Abscess
• Drug-resistant organisms:^[2,6,8,10]
  • Methicillin-resistant S. aureus S. aureus Potentially pathogenic bacteria found in nasal membranes, skin, hair follicles, and perineum of warm-blooded animals. They may cause a wide range of infections and intoxications. Staphylococcus:
    • Daptomycin Daptomycin A cyclic lipopeptide antibiotic that inhibits gram-positive bacteria. Lipopeptides and Lipoglycopeptides
    • Linezolid Linezolid An oxazolidinone and acetamide derived anti-bacterial agent and protein synthesis inhibitor that is used in the treatment of gram-positive bacterial infections of the skin and respiratory tract. Oxazolidinones
    • Vancomycin Vancomycin Antibacterial obtained from streptomyces orientalis. It is a glycopeptide related to ristocetin that inhibits bacterial cell wall assembly and is toxic to kidneys and the inner ear. Glycopeptides
  • Vancomycin-resistant enterococci Vancomycin-Resistant Enterococci Multidrug-resistant Organisms and Nosocomial Infections (VRE):
    • Daptomycin Daptomycin A cyclic lipopeptide antibiotic that inhibits gram-positive bacteria. Lipopeptides and Lipoglycopeptides
    • Linezolid Linezolid An oxazolidinone and acetamide derived anti-bacterial agent and protein synthesis inhibitor that is used in the treatment of gram-positive bacterial infections of the skin and respiratory tract. Oxazolidinones
  • Extended-spectrum beta-lactamase Beta-Lactamase Penicillins ( ESBL ESBL Klebsiella):
    • Carbapenems Carbapenems A group of beta-lactam antibiotics in which the sulfur atom in the thiazolidine ring of the penicillin molecule is replaced by a carbon atom. Thienamycins are a subgroup of carbapenems which have a sulfur atom as the first constituent of the side chain. Carbapenems and Aztreonam
  • Klebsiella pneumoniae Klebsiella Pneumoniae Gram-negative, non-motile, capsulated, gas-producing rods found widely in nature and associated with urinary and respiratory infections in humans. Aminoglycosides carbapenemase (KPC):
    • Polymyxin B– colistin Colistin Cyclic polypeptide antibiotic from Bacillus colistinus. It is composed of polymyxins e1 and e2 (or colistins a, b, and c) which act as detergents on cell membranes. Colistin is less toxic than polymyxin b, but otherwise similar; the methanesulfonate is used orally. Burkholderia
    • Tigecycline Tigecycline A tetracycline derivative that acts as a protein synthesis inhibitor. It is used as an antibacterial agent for the systemic treatment of complicated skin and intra-abdominal infections. It is also used for the treatment of community-acquired pneumonia. Tetracyclines
• Indications of vancomycin Vancomycin Antibacterial obtained from streptomyces orientalis. It is a glycopeptide related to ristocetin that inhibits bacterial cell wall assembly and is toxic to kidneys and the inner ear. Glycopeptides addition:^[6–8,10]
  • Hemodynamic instability
  • Pneumonia Pneumonia Pneumonia or pulmonary inflammation is an acute or chronic inflammation of lung tissue. Causes include infection with bacteria, viruses, or fungi. In more rare cases, pneumonia can also be caused through toxic triggers through inhalation of toxic substances, immunological processes, or in the course of radiotherapy. Pneumonia
  • Blood cultures positive for gram-positive Gram-Positive Penicillins bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology
  • Skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions or soft tissue Soft Tissue Soft Tissue Abscess infection
  • Catheter-related infection
  • Colonization Colonization Bacteriology with MRSA MRSA A strain of Staphylococcus aureus that is non-susceptible to the action of methicillin. The mechanism of resistance usually involves modification of normal or the presence of acquired penicillin binding proteins. Staphylococcus, penicillin-resistant Streptococcus Streptococcus Streptococcus is one of the two medically important genera of gram-positive cocci, the other being Staphylococcus. Streptococci are identified as different species on blood agar on the basis of their hemolytic pattern and sensitivity to optochin and bacitracin. There are many pathogenic species of streptococci, including S. pyogenes, S. agalactiae, S. pneumoniae, and the viridans streptococci. Streptococcus
• Antifungal Antifungal Azoles therapy:^[6,8]
  • Indications:
    • The patient is unstable and 
    • Fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever persists > 4–7 days
  • Medications:
    • Amphotericin B Amphotericin B Macrolide antifungal antibiotic produced by streptomyces nodosus obtained from soil of the orinoco river region of venezuela. Polyenes ( invasive aspergillosis Invasive aspergillosis Lung infections with the invasive forms of aspergillus, usually after surgery, transplantation, prolonged neutropenia or treatment with high-doses of corticosteroids. Invasive pulmonary aspergillosis can progress to chronic necrotizing pulmonary aspergillosis or hematogenous spread to other organs. Aspergillus/Aspergillosis)
    • Voriconazole Voriconazole A triazole antifungal agent that specifically inhibits sterol 14-alpha-demethylase and cytochrome p-450 cyp3a. Azoles ( invasive aspergillosis Invasive aspergillosis Lung infections with the invasive forms of aspergillus, usually after surgery, transplantation, prolonged neutropenia or treatment with high-doses of corticosteroids. Invasive pulmonary aspergillosis can progress to chronic necrotizing pulmonary aspergillosis or hematogenous spread to other organs. Aspergillus/Aspergillosis)
    • Itraconazole Itraconazole A triazole antifungal agent that inhibits cytochrome p-450-dependent enzymes required for ergosterol synthesis. Azoles
    • Posaconazole Posaconazole Azoles
    • Caspofungin Caspofungin A cyclic lipopeptide echinocandin and beta-(1, 3)-d-glucan synthase inhibitor that is used to treat internal or systemic mycoses. Echinocandins ( candidiasis Candidiasis Candida is a genus of dimorphic, opportunistic fungi. Candida albicans is part of the normal human flora and is the most common cause of candidiasis. The clinical presentation varies and can include localized mucocutaneous infections (e.g., oropharyngeal, esophageal, intertriginous, and vulvovaginal candidiasis) and invasive disease (e.g., candidemia, intraabdominal abscess, pericarditis, and meningitis). Candida/Candidiasis)
    • Micafungin Micafungin A cyclic lipo-hexapeptide echinocandin antifungal agent that is used for the treatment and prevention of candidiasis. Echinocandins
• Antiviral Antiviral Antivirals for Hepatitis B therapy:^[2,6,9]
  • Indications:
    • Active viral disease with herpes simplex Herpes Simplex A group of acute infections caused by herpes simplex virus type 1 or type 2 that is characterized by the development of one or more small fluid-filled vesicles with a raised erythematous base on the skin or mucous membrane. It occurs as a primary infection or recurs due to a reactivation of a latent infection. Congenital TORCH Infections/varicella zoster
    • Recent/current hematopoietic stem cell transplant (HSCT)
    • Active or suspected case of influenza Influenza Influenza viruses are members of the Orthomyxoviridae family and the causative organisms of influenza, a highly contagious febrile respiratory disease. There are 3 primary influenza viruses (A, B, and C) and various subtypes, which are classified based on their virulent surface antigens, hemagglutinin (HA) and neuraminidase (NA). Influenza typically presents with a fever, myalgia, headache, and symptoms of an upper respiratory infection. Influenza Viruses/Influenza
  • Medications
    • Acyclovir Acyclovir A guanosine analog that acts as an antimetabolite. Viruses are especially susceptible. Used especially against herpes. Herpes Zoster (Shingles) for herpes simplex Herpes Simplex A group of acute infections caused by herpes simplex virus type 1 or type 2 that is characterized by the development of one or more small fluid-filled vesicles with a raised erythematous base on the skin or mucous membrane. It occurs as a primary infection or recurs due to a reactivation of a latent infection. Congenital TORCH Infections
    • Acyclovir Acyclovir A guanosine analog that acts as an antimetabolite. Viruses are especially susceptible. Used especially against herpes. Herpes Zoster (Shingles) for varicella zoster 
    • Neuraminidase inhibitors Neuraminidase Inhibitors Antivirals for Influenza for suspected/confirmed influenza Influenza Influenza viruses are members of the Orthomyxoviridae family and the causative organisms of influenza, a highly contagious febrile respiratory disease. There are 3 primary influenza viruses (A, B, and C) and various subtypes, which are classified based on their virulent surface antigens, hemagglutinin (HA) and neuraminidase (NA). Influenza typically presents with a fever, myalgia, headache, and symptoms of an upper respiratory infection. Influenza Viruses/Influenza
  • The following should be considered (in conjunction with infectious disease specialist recommendations):
    • If HIV-positive → ensure adequate antiretroviral therapy Antiretroviral therapy Antiretroviral therapy (ART) targets the replication cycle of the human immunodeficiency virus (HIV) and is classified based on the viral enzyme or mechanism that is inhibited. The goal of therapy is to suppress viral replication to reach the outcome of undetected viral load. Anti-HIV Drugs
    • If hepatitis B Hepatitis B Hepatitis B virus (HBV) is a partially double-stranded DNA virus, which belongs to the Orthohepadnavirus genus and the Hepadnaviridae family. Most individuals with acute HBV infection are asymptomatic or have mild, self-limiting symptoms. Chronic infection can be asymptomatic or create hepatic inflammation, leading to liver cirrhosis and hepatocellular carcinoma (HCC). Hepatitis B Virus– or C–positive → appropriate antiviral Antiviral Antivirals for Hepatitis B treatment

Duration of therapy

Source of infection is identified:^[1,2,6,7]

• Appropriate treatment duration for that particular infection and
• ANC ≥ 500 cells/µL
• Switch to prophylactic therapy until neutropenia Neutropenia Neutrophils are an important component of the immune system and play a significant role in the eradication of infections. Low numbers of circulating neutrophils, referred to as neutropenia, predispose the body to recurrent infections or sepsis, though patients can also be asymptomatic. Neutropenia resolves.
• Minimum duration of treatment:^[6]
  • Adjust duration based on patient needs.

Source of infection unknown:^[1,2,7]

• Resolved fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever ≥ 48 hours and
• ANC ≥ 500 cells/µL

Supportive care

• IV fluids IV fluids Intravenous fluids are one of the most common interventions administered in medicine to approximate physiologic bodily fluids. Intravenous fluids are divided into 2 categories: crystalloid and colloid solutions. Intravenous fluids have a wide variety of indications, including intravascular volume expansion, electrolyte manipulation, and maintenance fluids. Intravenous Fluids
• Granulocyte colony-stimulating factor Granulocyte colony-stimulating factor A glycoprotein of mw 25 kda containing internal disulfide bonds. It induces the survival, proliferation, and differentiation of neutrophilic granulocyte precursor cells and functionally activates mature blood neutrophils. Among the family of colony-stimulating factors, G-CSF is the most potent inducer of terminal differentiation to granulocytes and macrophages of leukemic myeloid cell lines. White Myeloid Cells: Histology (G-CSF):[1]
  • Controversial
  • Administration is generally not recommended.
  • Does not reduce risk of neutropenia Neutropenia Neutrophils are an important component of the immune system and play a significant role in the eradication of infections. Low numbers of circulating neutrophils, referred to as neutropenia, predispose the body to recurrent infections or sepsis, though patients can also be asymptomatic. Neutropenia or mortality Mortality All deaths reported in a given population. Measures of Health Status
  • Use should be guided by a specialist (e.g., oncology).
• Indications for indwelling catheter Indwelling catheter Catheters designed to be left within an organ or passage for an extended period of time. Urinary Tract Infections (UTIs) removal:^[6,7]
  • Catheter tunnel or port pocket infection
  • Sepsis Sepsis Systemic inflammatory response syndrome with a proven or suspected infectious etiology. When sepsis is associated with organ dysfunction distant from the site of infection, it is called severe sepsis. When sepsis is accompanied by hypotension despite adequate fluid infusion, it is called septic shock. Sepsis and Septic Shock (if infectious source unknown)
  • Endocarditis Endocarditis Endocarditis is an inflammatory disease involving the inner lining (endometrium) of the heart, most commonly affecting the cardiac valves. Both infectious and noninfectious etiologies lead to vegetations on the valve leaflets. Patients may present with nonspecific symptoms such as fever and fatigue. Endocarditis
  • Septic emboli
  • Infection that persists > 72 hours despite antibiotic therapy
  • Infection caused by:
    • S. aureus S. aureus Potentially pathogenic bacteria found in nasal membranes, skin, hair follicles, and perineum of warm-blooded animals. They may cause a wide range of infections and intoxications. Staphylococcus
    • Streptococcus Streptococcus Streptococcus is one of the two medically important genera of gram-positive cocci, the other being Staphylococcus. Streptococci are identified as different species on blood agar on the basis of their hemolytic pattern and sensitivity to optochin and bacitracin. There are many pathogenic species of streptococci, including S. pyogenes, S. agalactiae, S. pneumoniae, and the viridans streptococci. Streptococcus
    • Fungi Fungi A kingdom of eukaryotic, heterotrophic organisms that live parasitically as saprobes, including mushrooms; yeasts; smuts, molds, etc. They reproduce either sexually or asexually, and have life cycles that range from simple to complex. Filamentous fungi, commonly known as molds, refer to those that grow as multicellular colonies. Mycology
    • Nontuberculous mycobacteria Mycobacteria Mycobacterium is a genus of the family Mycobacteriaceae in the phylum Actinobacteria. Mycobacteria comprise more than 150 species of facultative intracellular bacilli that are mostly obligate aerobes. Mycobacteria are responsible for multiple human infections including serious diseases, such as tuberculosis (M. tuberculosis), leprosy (M. leprae), and M. avium complex infections. Mycobacterium

Differential Diagnosis

• Transfusion reaction: complication of transfusion therapies (blood products/whole blood). Transfusion reaction presents with fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever, chills Chills The sudden sensation of being cold. It may be accompanied by shivering. Fever, urticaria Urticaria Urticaria is raised, well-circumscribed areas (wheals) of edema (swelling) and erythema (redness) involving the dermis and epidermis with associated pruritus (itch). Urticaria is not a single disease but rather is a reaction pattern representing cutaneous mast cell degranulation. Urticaria (Hives), itching, dyspnea Dyspnea Dyspnea is the subjective sensation of breathing discomfort. Dyspnea is a normal manifestation of heavy physical or psychological exertion, but also may be caused by underlying conditions (both pulmonary and extrapulmonary). Dyspnea, hypotension Hypotension Hypotension is defined as low blood pressure, specifically < 90/60 mm Hg, and is most commonly a physiologic response. Hypotension may be mild, serious, or life threatening, depending on the cause. Hypotension, and respiratory distress. Diagnosis is based on emergence of symptoms during or after the transfusion. Management includes stopping the transfusion, administration of IV fluids IV fluids Intravenous fluids are one of the most common interventions administered in medicine to approximate physiologic bodily fluids. Intravenous fluids are divided into 2 categories: crystalloid and colloid solutions. Intravenous fluids have a wide variety of indications, including intravascular volume expansion, electrolyte manipulation, and maintenance fluids. Intravenous Fluids, antihistamines Antihistamines Antihistamines are drugs that target histamine receptors, particularly H1 and H2 receptors. H1 antagonists are competitive and reversible inhibitors of H1 receptors. First-generation antihistamines cross the blood-brain barrier and can cause sedation. Antihistamines, and antipyretics.
• Neoplastic fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever: paraneoplastic syndrome caused by certain malignancies (mostly hematologic). The only presenting symptom is fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever, without signs of an infection or drug reaction. Neoplastic fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever is a diagnosis of exclusion. Naproxen Naproxen An anti-inflammatory agent with analgesic and antipyretic properties. Both the acid and its sodium salt are used in the treatment of rheumatoid arthritis and other rheumatic or musculoskeletal disorders, dysmenorrhea, and acute gout. Nonsteroidal Antiinflammatory Drugs (NSAIDs) administration may suppress the temperature. Management includes treatment of the underlying malignancy Malignancy Hemothorax and symptom control with NSAIDs NSAIDS Primary vs Secondary Headaches, acetaminophen Acetaminophen Acetaminophen is an over-the-counter nonopioid analgesic and antipyretic medication and the most commonly used analgesic worldwide. Despite the widespread use of acetaminophen, its mechanism of action is not entirely understood. Acetaminophen, and corticosteroids Corticosteroids Chorioretinitis.
• Other causes of fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever to consider:^[1]
  • Graft-versus-host disease Graft-versus-host disease The clinical entity characterized by anorexia, diarrhea, loss of hair, leukopenia, thrombocytopenia, growth retardation, and eventual death brought about by the graft vs host reaction. Transfusion Reactions
  • Drug fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever
  • Myeloid reconstitution syndrome
  • Engraftment syndrome
  • Radiation-related fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever
  • Mucositis Mucositis Stomatitis is a general term referring to inflammation of the mucous membranes of the mouth, which may include sores. Stomatitis can be caused by infections, autoimmune disorders, allergic reactions, or exposure to irritants. The typical presentation may be either solitary or a group of painful oral lesions. Stomatitis
  • Thromboembolism Thromboembolism Obstruction of a blood vessel (embolism) by a blood clot (thrombus) in the blood stream. Systemic Lupus Erythematosus