Risk factor for infection
Risk category
Low
High
General condition including organ function
Performance status
Good
Poor
Renal failure
No
Yes
Liver failure
No
Yes
Lung disease
No
Yes
Diabetes mellitus
No
Yes
Nutritional status
Normal
Impaired
Iron stores
Normal or decreased
Increased
Age
Younger (<40 years)
Older (>65 years)
Smoking
No
Yes
Underlying disease and its treatment
Tumor burden
None
Large
Likelihood of obtaining control of the underlying diseasea
High
Low
Disease-related immunosuppressionb
Absent
Present
Prior chemotherapy
None or minimal
Extensive
Receipt of purine analogues (fludarabine, cladribine, clofarabine) or monoclonal antibodies (rituximab, alemtuzumab)
No
Yes
Exposure to pathogens
Prior history of infectionc
No
Yes
Colonization with pathogens (bacteria, fungi)
No
Yes
Nosocomial exposure to potential pathogens (water and airborne pathogens such as Legionella, Aspergillus spp., and other molds, resistant bacteria, respiratory viruses)
No
Yes
Community-acquired infections, especially respiratory viruses
No
Yes
History of living or visiting areas of endemic infections
Immunogenetics
Deficiency of MBL
No
Yes
Polymorphism of TLR
Absent
Present
Duration of neutropenia
Short (<7 days)
Long (>10 days)
Severity of oral and gastrointestinal mucositis
Absent or mild
Severe
Chemotherapy regimen
Less intensive
Intensive
Polymorphisms of genes associated with metabolism of chemotherapeutic agents (pharmacogenetics)
Absent
Present
Renal failured
Absent
Present
T-cell immune reconstitution after HCT
Fast
Delayed
Prior chemotherapy
Minimal
Extensive
CMV serostatus
Negative
Positive
Need for additional chemotherapy to control the underlying diseasee
No
Yes
In vitro manipulation of stem cellsf
No
Yes
Graft versus host disease and its treatment (in allogeneic HCT)
No
Yes
Table 51.2
Pathogens likely to cause infection in patients with hematological malignancies according to the predominant type of immunodeficiency
Skin and mucous membrane disruption | Hypogammaglobulinemia | T-cell mediated immunodeficiency | Neutropenia and neutrophil dysfunction | |
|---|---|---|---|---|
Bacteria | ||||
Gram-positive cocci | ||||
Coagulase-negative staphylococci | +++ | – | – | ++ |
Staphylococcus aureus | +++ | – | – | ++ |
Viridans streptococci | +++ | – | – | ++ |
Enterococci | ++ | – | – | ++ |
Streptococcus pneumoniae | – | +++ | – | – |
Gram-positive bacilli | ||||
Bacillus spp. | ++ | – | + | ++ |
Corynebacterium jeikeium | ++ | – | + | ++ |
Listeria monocytogenes | – | – | +++ | – |
Gram-negative bacilli | ||||
Enterobacteriaa | ++ | – | – | +++ |
Pseudomonas aeruginosa | ++ | – | – | +++ |
Other non-fermentative bacteriab | ++ | – | – | +++ |
Salmonella spp. | + | + | ++ | + |
Legionella spp. | – | ++ | ++ | – |
Anaerobes | ||||
Clostridium difficile | ++ | – | – | ++ |
Clostridium septicum | ++ | – | – | ++ |
Fungi | ||||
Yeasts | ||||
Candida spp.,c mucosal disease | + | – | +++ | – |
Candida spp.,c invasive disease | ++ | – | – | +++ |
Cryptococcus neoformans | – | – | +++ | – |
Trichosporon spp. | ++ | – | + | ++ |
Molds | ||||
Aspergillus spp.d | – | – | ++ | +++ |
Fusarium spp. | –/+ | – | ++ | +++ |
Zygomycetes | – | – | ++ | +++ |
Scedosporium spp. | – | – | ++ | +++ |
Agents of phaeohyphomycosis | – | – | + | + |
Other | ||||
Pneumocystis jirovecii | – | – | +++ | – |
Histoplasma capsulatum | – | – | +++ | – |
Viruses | ||||
Herpes simplex | ++ | – | +++ | ++ |
Varicella-zoster | – | – | +++ | – |
Cytomegalovirus | – | – | +++ | – |
Epstein–Barr virus | – | + | +++ | – |
Respiratory virusese | + | + | ++ | – |
Hepatitis A, B and C | – | + | + | – |
Parvovirus | – | ++ | ++ | – |
Parasites | ||||
Strongyloides stercoralis | – | – | ++ | – |
Toxoplasma gondii | – | – | ++ | – |
Cryptosporidium parvum | – | + | ++ | – |
Mycobacteria | ||||
Mycobacterium tuberculosis | – | – | +++ | – |
Rapid growing mycobacteria | ++ | – | + | – |
Mycobacterium avium complex | – | – | +++ | – |
Infection Control Measures
Patients and healthcare workers should be educated about the risk of and methods to prevent acquisition of pathogens. These methods are discussed in this section.
Personal Hygiene
Handwashing
Handwashing remains the simplest and most effective measure to prevent the acquisition of organisms by patients [1]. Patients and healthcare workers (HCW) should wash their hands before eating, smoking, or inserting or removing contact lenses, and after using the restroom, blowing their nose, coughing, sneezing, handling dirty items such as soiled gausses, or garbage and after touching an animal. In addition, healthcare workers should also wash their hands between patients. All surfaces should be thoroughly cleaned, including wrists, palms, back of hands, fingers and under the fingernails, preferably with an alcohol-based hand rub [2]. However, if hands are visibly dirty or soiled with blood or body fluids, soap and water are best for cleaning hands [3]. Additional recommendations include the removal of rings prior to handwashing, keeping nails short and clean, and avoiding the use of artificial nails as they may carry pathogens [4].
Skin and Mucosal Care
The skin flora could potentially be a source of infections. Patients should keep their skin clean with daily baths using an antiseptic solution with special attention to potential portals of infection such as the perineum, and catheter sites.
The oral flora can lead to infection especially in the setting of severe mucositis, after radiotherapy, or in patients with graft vs. host disease (GVHD). Recommendations to maintain a good oral and dental hygiene include (a) oral rinses 4–6 times a day with sterile water, normal saline, or sodium bicarbonate; (b) tooth brushing at least twice a day with a soft or ultrasoft toothbrush. Swabs are less effective, but should be used if the patient cannot tolerate brushings.
Handling Pets
Pet owners should follow the following recommendations [3, 5]: (a) avoid contact with young animals as pets (higher risk of shedding Salmonella spp. and Campylobacter spp. because of a higher incidence of diarrhea); (b) obtain veterinarian consultation when a new pet is adopted and yearly thereafter; (c) keep pet’s vaccinations current; (d) keep pet’s feeding areas clean and its litter box away from kitchen and eating areas; (e) feed pets only with high-quality commercial pet foods, cooked egg, poultry and meat products, and pasteurized dairy products, and avoid access to bowl toilettes and garbage; (f) supervise pets when they are outdoors to prevent contact with other pet’s feces; (g) prevent animals from roaming through tick-infested woods; (h) wash hands after handling pets and avoid contact with pet’s feces and bird droppings; (i) avoid contact with animals with diarrhea, dogs exposed to shows or kennels, wild birds (especially pigeons), birds with avian tuberculosis, reptiles (high carriage and shedding of Salmonella spp.), and swine (source of B. bronchiseptica); (j) keep pets away from face and wounds; (k) trim pet’s nail short; (l) notify physician immediately if patient is bitten or injured by a pet; (m) instruct kids not to share kisses with the classroom pet; and (n) when cleaning cages, wear a particulate mask and avoid shaking cages.
Other Personal Hygiene Items including Food Handling
High risk patients should follow additional precautions to prevent serious infections as summarized in Table 51.3.
Table 51.3
Instructions to give to patients with hematological malignancies
Apply during periods of severe immunosuppression: maintain precautions for up to 3 months after last dose of chemotherapy or discontinuation of immunosuppression |
Personal hygiene |
Bathe regularly using a mild soap and shampoo and rinse well |
Don’t share razors (electric or blade) as they may retain particles of blood |
Wash hands frequently, preferably with liquid soap before eating and after contact with contaminated materials. If not washed, keep hands away from eyes nose and mouth |
Maintain good dental hygiene, by brushing teeth with soft bristle toothbrush, after meals and floss daily. Do not share toothbrushes and change toothbrush every 3 months |
Use disposable vaginal douches, and when menstruating, avoid tampons change sanitary napkins frequently |
Use sitz baths or soothing lotion for irritations of the rectum or vagina |
Prevent skin dryness (use moisturizing creams) |
Keep nails short and clean and avoid nail clippers used by others |
Clip toenails straight across to prevent them from becoming ingrown |
Try to avoid trauma to and irritation to the nails |
Wear cotton gloves for chores that don’t involve water and rubber gloves for chores involving water |
Avoid unprotected sexual exposure (HIV, Human papillomavirus, Herpes simplex, Hepatitis B) |
Environment |
Discourage visits by individuals with respiratory infections |
Avoid crowded places |
Don’t share towels with others |
Keep house and rooms well ventilated and change air-filters regularly |
Encourage household members to get influenza vaccine |
Avoid swimming (particularly in stagnant water) |
Ask your doctor for preventive measures before travel |
Avoid exploring caves, cleaning chicken coops (histoplasmosis) |
Other patients |
Avoid close contact with infected patients (tuberculosis, herpes zoster, herpes simplex, other) |
Medication/Vaccination |
Before traveling, consult your physician and take all medications |
Have vaccines according to recommendation of your clinician |
Food/Water |
Precautions for food handling |
Cook food thoroughly, wash fruits/vegetables before eating |
Wash dishes and silverware in hot soapy water and dry then very well |
Keep uncooked meats separate from vegetables, fruits and wash hands, knives, and cutting boards after handling uncooked foods & clean kitchen surfaces that have come in contact with raw meat |
Avoid using tap water for drinking or making juices, other food items |
Refrain from skinning animals or cleaning seafood |
Use plastic bags in all trash cans for proper disposal |
At the supermarket, pick up perishables last and take them home promptly |
Defrost meat, turkey, chicken in the refrigerator |
Wash the meat before cooking |
Cook thoroughly eggs and meat (use thermometers) |
Clean your refrigerator regularly discarding food of >3–4 days age, especially salad dressings, sauces, milk and egg products, condiments, processed meats, bacon |
Never use canned foods if the can is swollen dented, or rusted |
Toss out any cheese or food that’s moldy. Cut up fresh cheeses into small portions and store separately in the freezer, taking out only what can be used up quickly |
Keep cold foods cold (<40 °F) and hot foods hot (>140 °F) |
When preparing foods, the hands should be kept away from the hair, mouth and nose. If possible, rings and jewelry should be removed, because they may harbor germs. Try to limit touching food with the hands at all; use tongs or a fork if possible. After cutting up raw meats, soak the cutting board and all utensils for 30–40 min in solution of one part bleach and eight or nine parts water. One ounce of bleach to a cup of water. All foods that are not going to be cooked should be prepared first; only after those are out of the way, can any raw meat and poultry be prepared |
Wash all fruits and vegetables well |
Keep food preparation surfaces clean, and use a good dishwashing detergent on the work surface often, especially while handling raw meat, chicken or fish |
Never let cats or other animals up on the work surface |
Do not prepare food if you have diarrhea or vomiting, or have an open infected sore |
Put leftover foods into the fridge right away and divide large leftovers into individual containers (to avoid repeated warming) |
Food restrictions |
Raw eggs (sometimes used in restaurant-prepared Caesar salad dressing or homemade mayonnaise, eggnog) |
Dried, uncooked or undercooked meats, seafood and poultry (to include medium or rare steaks, game, pickled fish or oysters), or food from delis such as cold cuts, hot dogs, tofu, sausage, bacon, cold smoked fish and lox |
Unpasteurized commercial fruit and vegetable juices |
Unpasteurized milk or cheese products |
Soft and aged cheeses such as Feta, Brie, Camembert, blue-veined; Mexican-style cheese, refrigerated cheese-based salad dressings (e.g., blue cheese). Cream cheese, cottage cheese or yogurt (provided they do not contain Lactobacillus.spp) are ok to eat |
Unwashed raw vegetables and fruits end those with visible mold |
Unpasteurized honey or beer or raw, uncooked brewers yeast |
All miso products (e.g., miso soup); tempe (tempeh); mate’tea |
All moldy and outdated food products |
Herbal preparations and nutrient supplements |
Environmental Precautions
Hospital Environment
Air Precautions
Air quality is important to prevent infections in high-risk patients by airborne organisms such as molds (Aspergillus spp or other filamentous fungi), Legionella spp. and Mycobacterium tuberculosis. Patients at very high risk for invasive aspergillosis (IA) should be placed in sealed rooms with HEPA filters (central or point-in-use) and positive pressure. Air flow should be direct (air intake at one side of the room and air exhaust at the opposite side), and the system should be able to make ≥12 air exchanges per hour [6]. This group is represented mostly by patients receiving induction chemotherapy for acute myeloid leukemia (AML) and in the pre-engraftment period post-allogeneic hematopoietic cell transplantation (HCT).
The conidia levels in outdoor air vary widely, from 1–5 cfu/m3 [7] to 2,400 in winter and fall in certain areas [8]. The safe concentration of airborne fungi is not established and probably depends on the patient’s immune status. The efficacy of HEPA filters in preventing the entry of contaminated outside air into the hospital was confirmed after the demolition of a building. Despite the increase in the number of conidia of filamentous fungi, no conidia were found in most HEPA-filter equipped areas [9]. Because construction and renovation may increase the concentration of airborne fungi, guidelines have been developed when such activities are taking place close to areas were high-risk patients are cared for [10].
Portable HEPA filters decrease the concentration of airborne fungal spores [11] and their use has successfully prevented the occurrence of fungal infections during building construction [12]. However, it is generally agreed that they are less efficient than central or point-in-use HEPA filters [3].
Airborne fungi have been shown to secondarily aerosolize from a water source [13]. Therefore, preventive measures to limit exposure to water can decrease the airborne concentration of fungal pathogens (see the section on “Antifungal Prophylaxis”).
Diet
Although no data exist to support a role for sterile or low-level microbial-content (<1,000 CFU/ml of non-pathogenic organisms) diets for patients with hematological malignancy, this practice is generally recommended [3]. A recently published randomized study compared cooked and uncooked diet for patients undergoing induction remission for AML. There were no differences in the rates of episodes of major infection and death [14].
Water
The hospital water system can be a reservoir for Legionella spp [15], bacteria [16–18], and the opportunistic molds, especially Aspergillus spp [13, 19–21], Fusarium spp [22, 23], and Exophiala jeanselmei [24]. Potential modes of acquisition of infection include contamination of intravenous solutions, direct contact with skin breakdowns, and aerosolization of fungal spores. Measures to prevent the occurrence of infection depend on the mode of acquisition. It is generally recommended that patients at risk for such infections should avoid direct exposure to contaminated water. In addition, specific measures have been tested, including the use of point-in-use water filters for Legionella spp [25] and cleaning water-related structures to prevent aerosolization of fungi [26].
Healthcare Workers
Infections can be transmitted from the HCW to the patient. The risk of transmission is high for Varicella zoster (VZV), viral conjunctivitis, measles, and tuberculosis, and intermediate for influenza, mumps, Parvovirus B19, pertussis, respiratory syncytial virus (RSV), rotavirus, and rubella. Therefore, HCW with any of the previously mentioned infections or with Herpes Simplex Virus (HSV) lesions in lips or fingers should not be in contact with patients [3].
HCW who care for patients with hematological cancer should be immunized against rubella, measles, mumps, influenza, and chickenpox, in addition to the already recommended tetanus and hepatitis B immunization [3].
Household Exposure
The recommendations for immunization and precautions that apply to the HCW also apply to close contacts of patients with hematological cancer [3]. Immunization against hepatitis A and B is highly recommended for sexual contacts of patients. In addition, immunization against hepatitis A should be considered for all households of patients with chronic liver disease or living in endemic areas. Oral polio vaccine is contraindicated for all households of patients with hematological cancer since live polioviruses can be transmitted to and cause disease in immunocompromised patients, especially during the first month after vaccination [27]. Patients with hematological cancer should also avoid exposure to individuals with vesicular rash secondary to chickenpox immunization to prevent VZV disease [3].
Sexual Partners
Sexually active patients should avoid unprotected sex during the periods of significant immunosuppression to reduce the risk of exposure to CMV, HSV, HIV, HPV, HBV, HBC, and other sexually transmitted infections [3].
Invasive Procedures
Procedures that break the integrity of natural barriers such as skin and mucosa should be avoided when possible. Fixed orthodontic appliances and space maintainers should not be worn during any period of neutropenia to avoid oral trauma and infection. Enemas, suppositories, rectal temperature check or/and rectal examination are contraindicated. Necessary dental procedures should be performed prior to chemotherapy to allow proper healing before neutropenia and mucositis develop [28]. Bone marrow biopsies should be done aseptically to avoid cellulitis and osteomyelitis.
Recommendations for the insertion of indwelling devices include careful cleaning and sterilization of instruments and devices (particularly reusable ones) and guidelines for the prevention of intravascular device-related infections [29]. However, solid evidence to support some of the guidelines for the prevention of intravascular device-related infections is lacking.
Antimicrobial Prophylaxis
Antimicrobial prophylaxis may be primary, when prevention targets an individual that has not been infected in the past, and secondary, when prevention is used to avoid recurrence of infection in an individual who has been previously infected.
Antibacterial Prophylaxis
Bacterial infections occur frequently in two settings: neutropenia and hypogammaglobulinemia. As shown in Table 51.2, common bacterial infections in patients with neutropenia include staphylococci, enterococci and viridans streptococci among the Gram-positive bacteria, and enterobacteria and non-fermentative bacteria (especially Pseudomonas aeruginosa, Acinetobacter spp. and Stenotrophomonas spp. among the Gram-negative bacteria.
Because Gram-negative bacteremia may be associated with high mortality rates, strategies of antibacterial prophylaxis during neutropenia have been focused mostly to prevent the occurrence of Gram-negative bacteremia, and the quinolones have been extensively studied. A meta-analysis pooling data from 95 trials showed that quinolones reduced the incidence of fever, documented infections, and mortality associated with infection [30]. A major concern is the development of resistance. Another meta-analysis examined the effect of quinolone prophylaxis on microbial resistance. There was no difference in the incidence of colonization by resistant organisms, or in the rates of infection caused by resistant pathogens [31]. These data, however, must be interpreted with caution, because rates of resistance are very different among different institutions, cities, and countries. As a general rule, once the clinician decides to give prophylaxis with a quinolone for neutropenic patients, a careful attention to the development of resistance is advised.
Another concern when using quinolone prophylaxis is the increase in the incidence of infections caused by Gram-positive organism, notably viridans streptococci [32, 33]. A great concern related to such infections is that they may occasionally evolve to shock and respiratory failure [34]. Although most of such infections may be prevented by penicillin or macrolides [35], some strains are resistant to these agents [36]. The use of glycopeptides is not generally recommended for prophylaxis [3]. Table 51.4 shows the usual doses of quinolones in the prophylaxis of bacterial infections in neutropenic patients.
Table 51.4
Dosage schedule of antimicrobial agents used in the prophylaxis of infection in patients with hematological malignancies
Disease | Prophylaxis |
|---|---|
Bacterial infections | |
Neutropenic | Quinolonea |
Non-neutropenic | TMP–SMX—800 mg/160 mg PO daily or daily quinolone |
C. difficile diarrhea | Consider metronidazole prophylaxis (500 mg PO TID) if prior history of CDAD |
Tuberculosis | Isoniazid—300 mg PO daily |
Fungal infections | |
Invasive candidiasis | Fluconazole—200–400 mg PO daily |
Invasive aspergillosis | Posaconazole—200 mg TID |
Oral and/or esophageal candidiasis | Clotrimazole troches (10 mg, ×5 per day) or fluconazole—100–200 mg PO daily |
Pneumocystis jirovecii pneumonia | TMP–SMX—800 mg/160 mg PO daily or ×2 per week, pentamidine—300 mg aerosol monthly, dapsone—100 mg PO daily, atovaquone 1,500 mg PO daily |
Viral infections | |
Herpes simplex | Acyclovir—200–400 mg PO BID or TID, valacyclovir—500 mg PO TID or famciclovir—500 mg PO TID |
Herpes zoster | Acyclovir—400 mg PO BID or TID, valacyclovir—500 mg PO TID or famciclovir—500 mg PO TID |
Cytomegalovirus | Ganciclovir—5 mg/kg IV BID or valganciclovir—900 mg/d PO or foscarnet—60 mg/kg IV BID |
Influenza virus | Oseltamivir—75 mg PO daily for the duration of the Influenza season. Zanamivir is more appropriate in the presence of viral resistance |
Hypogammaglobulinemia is frequent in chronic lymphocytic leukemia (CLL), multiple myeloma, and in allogeneic HCT recipients who develop GVHD. These patients are at greater risk of developing bacterial infections, particularly by encapsulated bacteria. Intravenous immunoglobulin (400 mg/kg) every 4 weeks may be effective for the prevention of bacterial infections, and this recommendation is supported by randomized controlled studies [37–39]. However, since its use is costly, intravenous immunoglobulin should be reserved to a selected population of patients with repeated episodes of severe infections. A cheaper alternative to immunoglobulin is to give quinolone prophylaxis with levofloxacin (500 mg/day), moxifloxacin (400 mg/day) or sulfamethoxazole–trimethoprim (TMP–SMX) (Table 51.4) [40].
Antifungal Prophylaxis
Primary prophylaxis against invasive candidiasis is not indicated in all neutropenic patients. In allogeneic HCT recipients, two randomized clinical trials (RCTs) showed that fluconazole reduced the frequency of superficial and systemic candidiasis, as well as infection-related mortality [41, 42]. In one of these trials, fluconazole was given until day +75 post-transplant, and a post hoc analysis of the trial has shown that fluconazole was associated with prolonged protection against invasive candidiasis, even beyond the period of prophylaxis [43].
The benefit of prophylaxis against invasive candidiasis was not as apparent in other settings, such as in patients with acute leukemia [44]. However, the ineffectiveness of fluconazole in non-HSCT neutropenic patients is probably related to the heterogeneity of the populations of neutropenic patients studied (with different incidences of invasive candidiasis) rather than an absence of efficacy. In general, the higher is the risk for the patient to develop severe mucositis during neutropenia, the higher is the risk for invasive candidiasis.
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