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Infection in the neutropenic patient
Infection in the Neutropenic Patient Alma C. Oniboni
NFECTION is a major cause of morbidity and
mortality in the neutropenic patient with Ileukemia. 1"9 Infection in this immunocompromised host results from the combined effects of the leukemia itself, treatment, and invasive procedures and hospitalization (see Fig 1). Infection is most often due to gram-negative bacteria, but grampositive and fungal infections are increasing. 6'7"m Typical signs and symptoms of infection are often absent in the neutropenic patient. Fever may be the only sign, and should be considered a medical emergency. It is imperative, then, that nurses caring for the patient with leukemia become thoroughly familiar with the etiology, causative organisms, diagnosis, and therapy of infection in the neutropenic patient. FACTORS CONTRIBUTING TO INFECTION
Leukemia Patients with leukemia have a higher infection rate than patients with solid tumors. In acute leukemia, the mature and immature neutrophils may be functionally abnormal. Other contributing factors vary with the type of leukemia and include abnormal immunoglobulins, impaired lymphocyte function, monocytopenia, and, after bone marrow transplantation, the increased activity of suppressor T lymphocytes.7's'H'13
Neutropenia Neutropenia is the single most important factor predisposing the patient with leukemia to infection.7'9'11'13 Neutropenia has commonly been defined as an absolute neutrophil count less than 1,000 cells per cubic millimeter. 14-16As the prime function of the neutrophil is phagocytosis, neutropenia eliminates one of the body's prime defenses. The risk of infection is related to the degree, duFrom the Mercy Hospital of Pittsburgh, Pittsburgh, PA. Alma C. Oniboni, RN, MSN, OCN: Oncology Clinical Nursing Specialist, The Mercy Hospital of Pittsburgh, Pittsburgh, PA. Address reprint requests to Alma C. Oniboni, RN, MSN, 325 Hamill Rd, Verona, PA 15147. © 1990 W.B. Saunders Company. 0749-2081190/0601-0008505.00/0 50
ration, and rate of change of neutropenia. The frequency of infection increases as the absolute neutrophil count decreases below 500lmm 3, and the longer the patient remains neutropenic. 7A3'17 A stable level of neutropenia is less likely to be associated with infection than rapidly progressing neutropenia, as seen in patients receiving induction or reinduction chemotherapy. ~4'16 Patients with profound, prolonged neutropenia are at the highest risk of dying, as recovery from most severe infections is related to the patient's ability to respond with an increased production of neutrophils. Fatal infection during chemotherapy-induced neutropenia is the major barrier to successful treatment of leukemia. If infection could be controlled, perhaps survival rates would improve.
Other Factors Contributing to Infection One risk factor is the breakdown of the body's first line of defense--the skin and mucous membranes. 1"9'11'12'16Openings in the skin or ulcerated mucosa occur through changes induced by chemotherapy, venipuncture, bone marrow aspirations, total body irradiation, use of central venous catheters, and other invasive procedures. Adrenal corticosteroids are often used as part of specific chemotherapeutic regimens or as supportive therapy. Alterations associated with the use of steroids include suppression Of acute and chronic inflammatory responses by decreasing vascular permeability and leukocyte infiltration, suppression of antibody production, reduced interferon synthesis, decreased delayed hypersensiti~,ity, impaired phagocytosis, and interference with the antigen-processing functions of macrophages.6'7'9 As a result, steroids predispose the patient to a variety of infectious complications. Antibiotic therapy alters the patient's normal flora by suppressing susceptible organisms and permitting colonization by resistant, opportunistic organisms. 9 Hospitalization may contribute to colonization of unique organisms as a result of contaminated intravenous (IV) fluid, blood products, respiratory equipment, and food. 6 Invasive procedures, such as urinary or IV catheters, create a pathway along which microorganisms can enter. Malnutrition and subsequent negative nitrogen balance also lead to immune deficiencies. In older Seminars in Oncology IVurs/ng, Vol 6, No 1 (February), 1990: pp 50-60
51
INFECTION IN THE NEUTROPENIC PATIENT LEUKE~RA
HOSPITAL
CATHETERS~
~
~
RADIATION
/
/
~MALNUTRC£1ON
IINFECTIONI ~
~AGU
,K., BREAKDOWN
"ANTI'RIOTIC$
Fig 1. Factors contributing to risk of infection. (Data from Pizzo and Young, s Carlson, s and Bodey.7)
adults, age-related changes in the immune system lead to an increased susceptibility to infectious diseases, is CLINICAL PRESENTATION OF INFECTION
Common Sites of Infection Most infections in neutropenic, patients arise from three major sites: the skin, the respiratory system, and the gastrointestinal tract. 6'8'1°J2 Chemotherapy-induced damage occurs, particularly to the mucosa of the respiratory and gastrointestinal (GI) tracts. Pneumonia and sinusitis are commonly seen. 12"t9Infection may arise from any point along the GI tract. Oral infections may result from ulcerations secondary to stomatotoxic chemotherapy and underlying periodontal disease. Drug-induced vomiting and stomach acid reflux may explain the frequency of infection in the distal third of the esophagus. 16,19 Perirectal cellulitis or abscess is more common in patients with leukemia than in those with solid tumors, and may even be seen as a presenting sign in acute leukemia. 1'2° Perirectal infections result from several compounding factors: pressure generated during defecation, frequent bowel movements associated with some chemotherapy regimens, preexisting hemorrhoids, constipation, and the skin and mucosal changes induced by chemotherapy or total body irradiation. Rectal abscesses may cause a life-threatening septicemia. Neutropenie enterocolitis, a fulminating, inflammatory process that involves the cecum, ascending colon, and surrounding tissue, occurs in patients with profound neutropenia and increases with the use of aggressive chemotherapy. 2°'2~ Neutropenic enterocolitis, which is found in 10% to 15% of leukemic patients atpostmortem exam-
ination, is characterized by necrosis of the bowel wall and extensive fungal or bacterial involvement. Less commonly, urinary tract infections and meningitis may be seen. ~°'12 The many blood products transfused in the support of these patients are associated with hepatitis.~2"16 And, at times the source of bacteremia is never found.4
Caustive Organisms of lnfection Acquisitionlshift of microbial flora. Microorganisms that do not ordinarily cause disease may, under certain circumstances such as immunosuppression, cause opportunistic infections in the neutropenic patient. Quite often, the causative organism is not part of the patient's original endogenous flora, but rather is acquired in the hospital. Any seriously ill individual, and, in particular, the compromised host, will undergo changes in the microbial flora in various areas of the body. 14 There is a redistribution of the patient's endogenous flora and colonization by exogenous organisms. The use of antibiotic therapy that suppresses the anaerobic flora of the GI tract alters colonization resistance, so that even small numbers of hospital-acquired organisms can rapidly colonize. 14.16 In the presence of mucosal damage, microorganisms can penetrate and cause local infection. Dissemination and bacteremia may then occur. Surveillance culturing has provided useful research data in defining the degree to which patients with acute leukemia become infected with organisms acquired during their hospitalization. Although surveillance cultures can be costly and unreliable, some investigators advocate their use for those patients at high risk. 14J6'22 By following the changing flora colonizing within the patient, the physician can more accurately choose empiric antibiotics should fever develop. 8'14'16J9"22 Normal flora in the mouth can rapidly change to gram-negative bacilli, Staphylococcus aureus, or yeasts. Later in the patient's illness, particularly after repeated use of antibiotics, gram-negative bacilli and fungi are found in the nose. The normal flora of the rectum is often replaced by Pseudomonas aeruginosa or Klebsiella pneumoniaefl 4 As a result, infections in these sites are often caused by these newly acquired opportunistic organisms, rather than by the more manageable communityacquired organisms. 8
ALMA C. ONIBONI
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Food is one of the most important sources of contamination with gram-negative bacilli and fungi, and may initiate colonization of exogenous organisms in the patient whose intestinal flora may have been suppressed by antibiotic therapy, t6 Plants, such as African violets and chrysanthemums, may also be a source of microorganisms. Stagnant water found in the vases of fresh flowers is of particular concern because it may contaminate the environment when the water is changed. 16 Tap water generally contains few viable bacteria. However, there is a danger of contamination by P aeruginosa in the presence of faucet aerators; therefore, this water should not be considered safe without sterilization. Ice machines or ice that has been contaminated by improper handling may also be a source of exogenous organisms.J4"16 Aspergillus sp, important airborne organisms, are second only to Candida sp in causing fungal infections in neutropenic patients. 14.16.23Aspergillus spores are found in large numbers in the outside air during autumn as leaves decompose, and in fireproofing material used in steel-frame constructed buildings. The Aspergillus spores persist and may enter the patient's environment, particularly during times of hospital remodeling and construction. Predominant pathogens. The microorganisms most commonly implicated in infections in the neutropenie patient are summarized in Table 1. Each hospital tends to be colonized by its own unique organisms, but some generalizations may
be made. Usually, bacterial infections due to gram-positive cocci and enteric gram-negative bacilli are seen in the neutropenic, febrile patient newly admitted to the hospital. After prolonged hospitalization and empiric broad-spectrum antibiotic therapy, infections due to resistant grampositive, gram-negative, and fungal organisms are s e e n . 5,13
Gram-negative bacilli, such as P aeruginosa, Escherichia coli, and Klebsiella sp are the most common cause of infection in the neutropenic patient and often account for the high mortality rate among neutropenic patients. 7 The incidence of infection caused by gram-positive organisms, such as Staphylococcus epidermidis, Streptococcus viridans, and JK diptheroids, has increased over the past several years. S epidermidis, once viewed as only a contaminant, has emerged as a significant pathogen, especially in patients with indwelling venous catheters. 5'9'19"22"24'25 Of particular concem is S epidermidis which is resistant to penicillins and cephalosporins. Fungi, such as Candida sp and Aspergillus sp, are major pathogens in the patient who has prolonged periods of neutropenia or in those who receive long courses o f antibacterial antibiotic therapy, s'~°'19 Infection with viruses such as herpes zoster, as well as protozoa such as Pneumocystis carinii, can also be quite problematic. 5'6 Compounding factors. Patients infected with cytomegalovirus have a higher incidence of bacterial superinfection. Interactions between two or
Table 1. Predominant Pathogens Causing Infection in the Neutropeni¢ Patient Gram-negative bacteria E coil P aeruginosa K pneumoniae Enterobacter species Serratia species Proteus species Haemophilus influenzae Acinetobacter species Legionella pneumophi/a
Gram-positive bacteria
A A, B
A, B B B
Fungi Aspergillus species Candida albicans Torulopsis glabrata Cryptococcus neoformans Ph¥comycetes Histoplasma capsulatum Fusarium
S aureus S epidermidis Enterococcus species Corynebacteria (group JK diptheroids) Streptococcus species Mycobacterium species Clostridium difficile Cl septicum
Protozoa A
A
Pneumocystis carinii Toxoplasma gondii Viruses Herpes simplex virus Varicella zoster virus Cytomagalovirus
Data from references 5, 7-9, 13, 14, 22-25. Abbreviations: A, most common organisms; B, most virulent organisms.
A A
INFECTION IN THE NEUTROPENIC PATIENT
more infecting organisms may potentiate infectious complications: Some organisms are more capable of colonizing the patient than others, and once colonized, are more likely to result in infection. This may be the result of some inherent virulence or pathogenicity of that organism. 5'~4 For example, only a small percentage of patients who became colonized with E coli develop infection. On the other hand, although P aeruginosa is not the most common organism, it is often the most virulent. Forty percent to 68% of patients who are colonized with P aeruginosa develop serious infection while neutropenic.5"14"26P aeruginosa rapidly invades in the presence of mucosal damage and neutropenia, whereas other species of pseudomonas are incapable of doing so) 4 These factors must be taken into account when choosing empiric antibiotic therapy.
Signs and Symptoms Patients with neutropenia are not able to produce an adequate inflammatory response to infection; therefore, typical signs and symptoms of infection are often absent. 5"s'~s Physical findings, such as exudate, ulceration, swelling, or adenopathy, are less prevalent. The patient with pneumonia often presents only with shortness of breath or nonproductive cough. Pulmonary infiltrates may not be seen on initial chest radiograph, but may take 2 to 3 days to appeal'. 5"7"12"27 Pain and fever may be the only indication of an infection of the skin, Rectal infections are often not clinically diagnosed, as the patient's only complaint may be pain on defecation) "6 Bacterial or fungal pharyngitis often presents with a sudden onset of severe pain, difficulty swallowing, fever, and chills. Fever. Fever is the single most important and often the only sign of infection in the neutropenic patient. 2s3° Thirty percent to 60% of fevers in this population are due to infection.4,s Other possible causes of fever in the neutropenic patient with leukemia include neoplasm, liver metastasis, drug hypersensitivity, transfusion reaction, phlebitis, and atelectasis. When infection is present, however, fever almost always occurs. Failure to develop fever in the presence of infection is a poor prognostic sign. Fever patterns may sometimes suggest the cause of the fever, if unrelated to administration of antipyretic medications. An intermittent fever pat-
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tern, characterized by temperature spikes and daily returns to normal, is commonly seen in patients with gram-negative septicemia. Routine use of antipyretic medications is not advocated by many, as the diagnostic fever patterns will be altered. 29'3° Fever of unknown origin is a continued problem in the care of the neutropenic patient. Diagnosis is often difficult, as cultures may be negative even in the presence of infection. One explanation offered is that organisms may have not yet entered the bloodstream. The use of prophylactic antibiotics may also be partially responsible for failure to isoI 2 outlines late the offending o r g a n i s m24T . , abe some possible causes of fever of unknown origin. Fever of unknown origin, particularly in the patient treated with empiric antibiotic therapy, is often due to fungal infection.7'9'26 The longer the period of neutropenia persists, the more likely leukemic patients will develop a potentially fatal fungal infection) ° Sepsis. Rapid progression from localized infection to sepsis results in a high fatality rate. Nurses must be attuned to the early signs and symptoms of septic shock, such as restlessness and confusion, as patient recovery depends on rapid assessment and treatment. TREATMENT OF INFECTION
Development of fever in a neutropenic patient represents a medical emergency, and prompt assessment, diagnosis, and initiation of antibiotic therapy are vital. The steps in evaluation of the febrile, neutropenic patient are summarized in Table 3. The value of invasive diagnostic procedures is debated. Many investigators feel that a proceTable 2. Fever of U n k n o w n Origin Resistant bacterial infection Bacterial infection associated with tissue necrosis Nonbacterial infection Superinfection with resistant bacteria or fungi Drug or transfusion fever Tumor fever caused by Hemorrhage Necrosis Tissue destruction Liberation of tissue pyrogens Liver damage affecting steroid conjugation Adrenal hyperplasia producing steroid pyrogen Immunologic reaction to tumor antigens Inflammatory response to tumor growth or necrosis Spontaneous production of an endogenous pyrogen Data from references 7, 24, 31.
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Table 3. Evaluation of Febrile, Neutropenic Patient Temperature of 101°F (38.5°C) lasting more than 2 h, unassociated with administration of pyrogenic substances, indicates presence of infection until proven otherwise. Thorough history and physical examination: Particular attention paid to oropharynx, axillae, groin, perianal area, sinuses, indwelling catheters, any suspected area of infection Characteristic signs and symptoms of infection may be absent Blood cultures: Two sets (at least 10-15 mL each) before antibiotics begun Culture both central line and peripheral site Repeat daily while febrile Cultures of nose, throat, urine, sputum, stool, rectum, axilla, obvious lesions, as a baseline and repeat as indicated. Urinalysis (looking for bacteriuria, not pyuria) Chest radiograph (may initially be negative; repeat). Reexamine patient on a regular basis until site of infection is documented. Data from references 6-9, 22, 25-29, 31-34.
dure such as open-lung biopsy is of little value, as it results in a low yield of specific diagnoses, seldom leads to changes in therapy, and has little influence on the patient's outcome. 9'26"32 Institutions should establish guidelines for initiating treatment for a fever. Some suggest that two or three low-grade elevations above 38°C or a single elevation above 38.5°C, in conjunction with neutropenia, are sufficient criteria to initiate therapy. 5"22 Therapy is not begun if the fever coincides with the administration of a pyrogenic agent, such as a blood product transfusion. 22 Bodey9"22'28 suggests that antibiotics be started immediately in the febrile patient who appears ill or has clinical signs of infection. Otherwise, Bodey suggests withholding antibiotic therapy and rechecking the temperature 1 to 2 hours later. If the patient remains febrile during this interval, blood cultures are repeated and antibiotic therapy started. This procedure eliminates the unnecessary administration of antibiotics to the patient with a single temperature elevation due to unknown reasons, yet does not delay initiation of antibiotics for those requiring immediate therapy.
Empiric Antibiotic Therapy The prompt initiation of empiric antibiotic therapy has markedly reduced the infection-related
morbidity and mortality for the neutropenic patient with leukemia. 17,22.24 Delays in the administration of antibiotic therapy can diminish its efficacy.7 Several factors influence the choice of antibiotics to be used in the neutropenic patient (see Table 4). Therapy should be given IV, with no delays or omissions from the prescribed schedule. The sodium load of each antibiotic may be of concern in some patients. For the anti-pseudomonal penicillins commonly used, ticarcillin contains 5.2 mEq of sodium per gram, whereas each gram of piperacillin contains only 1.85 mEq of sodium. 33 Potential toxic effects of antibiotic therapy must also be considered when choosing antibiotic therapy. 22 A major concern is nephrotoxicity associated with the use of aminoglycosides. Cumulative renal damage may occur with repeated antibiotic usage. The concurrent use of other nephrotoxic agents, such as cisplatin or amphotericin B, also increases the risk of toxicity.l°'22 "Ideally, an antibiotic should be selected that provides high serum concentrations for prolonged periods of time with minimal toxicity. ''9 Table 5 outlines the antibiotics most commonly prescribed in the treatment of the neutropenic patient. Combination therapy. Usually, initial therapy consists of a combination of two drugs directed at bacterial infections, including both gram-negative and gram-positive organisms, s'12 P aeruginosa is one of the most virulent infecting organisms; therefore, initial therapy usually includes an effective anti-pseudomonal antibiotic. 26 Although every two-drug combination has some gaps in its spectrum of coverage, the addition of a third drug has Table 4. Factors Influencing the Choice of Antibiotics Spectrum of activity Bactericidal activity Efficacy in neutropenia Pharmacokinetic properties Potential for synergy Rapidity of bactericidal activity MIC (minimal inhibitory concentration)/serum concentration Flora of individual hospital Individual hospital's susceptibility/resistance pattern Presence of intravascular devices Age and renal function of patient Previous exposure to aminoglycosides and cisplatin Sodium load Toxicities Cost Data from references 9, 22-24, 33.
INFECTION IN THE NEUTROPENIC PATIENT
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Table 5, Commonly Used Antibiotics in the Neutropenic Patient Antibiotic (trade name)
Comments
Broad-spectrum penicillins Azlocillin (Azlin) Carbenicillin (Geopen} Ticarcillin (Ticar) Mezlocillin (Mezlin) Piperacillin (Pipracil)
A, E A,E A, E B, E, Increased activity against E coil A, B, E, Increased activity against E coil Most activity of the broad-spectrum penicillins against P aeruginosa
Penicillinese-resistantpenicillins Methicillin (Staphcillin) Nafcillin (Unipen) Oxacillin (Prostaphin)
C, E C,E C, E
Aminoglycosides Amikacin (Amikin) Gentamicin (Garamycin) Tobramycin (Nebcin)
More toxic in elderly, patients with impaired renal function
Third-generation cephalosporins Cefotaxime (Claforan) Ceftizoxime (Cefizox) Moxalactam (Moxam) Cefoperazone (Cefobid) Ceftazidime (Fortaz)
B, E, No coverage of P aeruginosa B, E, No coverage of P aeruginosa A, B, D, E, Poor coverage against Staphylococcus and Streptococcus A, B, D, E, Active against many gram-positive and gram-negative organisms A, B, E, Poor gram-positive coverage
Antifungels Amphotercin B (Funglzone) Ketoconazole (Nizoral) Nystatin
Antivirals Acyclovir
Effective against herpes simplex and zoster; not effective against cytomegalovirus
Miscellaneous Clindamycin (Cleocin) Metrovidazole (Flagyl) Trimethoprim/sulfamethoxazole (Bactrim, Septra) Vancomycin Penicillin + beta-lactamase inhibitor Amoxicillin t- clavulanic acid (Augmentin) "l'icarcillin + clavulanic acid (Timentin) Carbapenems Imipenem/cilastin (Primaxin)
Anti-anaerobic Anti-anaerobic Effective against many gram-positive and gram-negative organisms; ineffective against P aeruginosa Anti-gram-positive, drug of choice for CI difficile E, Oral; activity against beta-lactamase-producing strains of Staphylococcus, H influenza E, Active against Staphylococcus
E, Active against most gram-positive, gram-negative, and anaerobes Not effective against methicillin-resistant S aureus
Monobactams Aztreonam (Azactam} Fluoroquinolones Norfloxacin (Noroxin) Ciprofloxacln (Cipro)
E, Active against aerobic gram-negative organisms Not effective against gram-positive organisms or anaerobes Available orally Effective against many gram-positive and gram-negative organisms
Abbreviations: A, antipseudomonal; B, anti-gram-negative; C, anti-staphylococcal; D, prolongs prothrombin time; E, beta-lactam antibiotic. Data from references 5, 7, 24, 28, 34.
not proven to increase efficacy for initial therapy, but may increase toxicity and cost. 5"7'22'24 The initial regimen may be altered to provide appropriate coverage as infecting organisms are identified.
Current recommendations for empiric antibiotic combination therapy include (1) an aminoglycoside plus a beta-lactam antibiotic, and (2) two betalactam antibiotics. 13'22"28 Most institutions use a
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two-drug combination of an aminoglycoside plus either an extended-spectrum penicillin (such as piperacillin) or an extended-spectrum cephalosporin (such as ceftazidime).5'1° Aminoglycoside antibiotics have been part of the standard empiric therapy for years. It is now felt that an aminoglycoside is not an essential component of combination therapy, but its inclusion may prevent the emergence of resistant organisms seen with the use of the beta-lactam antibiotics. 24 Drawbacks to the use of aminoglycosides include the potential for ototoxicity and nephrotoxicity, and the prevalence of bacteria that are resistant to some aminoglycosides.9"24'2s Therapeutic drug monitoring, often used initially and weekly with the use of aminoglycosides, can escalate the cost of therapy. However, used appropriately, therapeutic drug monitoring has the potential to confil-m suspected drug toxicity, subtherapeutic response to an otherwise adequate doge, drug interactions, and the presence of disease that can alter the body's ability to handle a drug. 35 This can lead to decreased costs and length of stay. Nurses play a vital role in the successful use of therapeutic drug monitoring. Proper collection and labeling of blood samples are essential. For results to be valid, consideration is given to the time of blood sampling in relation to the last dose, dose administered, and concurrent drug therapy which may affect the results. 3s Improper collection of a sample, such as drawing blood above an IV line or inaccurate timing of blood sampling, will waste personnel time, add considerably to an already costly procedure, and provide invalid, and potentially dangerous, results upon which therapeutic decisions are made. s'35 It is generally felt that the beta-lactam antibiotics are the foundation of all antibiotic regimens, and should be included in any two-drug regime. 2s Beta-lactam antibiotics, because of their chemical structure, resist inactivation by enzymes (called beta-lactamases) produced by gram-negative bacteria. Cephalosporins, penicillins, monobactams, and carbapenems are included in this class of drugs. Clavulanic acid, a beta-lactamase inhibitor, is added to some antibiotics, such as ticarcillin and amoxicillin to enhance their spectrum of activity. 17.33.34 Clavulanic acid is structurally similar to penicillin. By binding to and inactivating bacterial beta-lactamases, clavulanic acid protects
ALMA C. ONIBONI
the antibiotic from hydrolysis.34 Nurses should be aware that both the Augmentin (amoxicillin + elavulanic acid) " 2 5 0 " and " 5 0 0 " tablets contains the same amount of clavulanic acid (125 mg); therefore, two Augmentin " 2 5 0 " tablets do not equal one Augmentin " 5 0 0 " tablet, and should not be substituted. 36 As aminoglycoside toxicity remains a problem, many investigators recommend a double betalactam antibiotic combination, s'll This combination, unfortunately, has been associated with suppressed neutrophil recovery and the emergence of resistant organisms because of suppression of intestinal anaerobic organisms. 7'9"13'1739"34In recent years, considerable resistance has developed to the older antibiotics such as cephalothin and ticarcillin, which had been used in combination with aminoglycosides to cover gram-negative pathogens and S aureus. 17 Although use of the broadspectrum cephalosporins may avoid the necessity of an aminoglycoside, less activity is seen against gram-positive cocci, and another antibiotic, such as vancomycin, may then need to be added to provide appropriate coverage.9 Vancomycin is the only agent effective against some gram-positive organisms, such as enterococci, JK diptheroids, S epidermidis and S aureus, and is often added to empiric or continued therapy if the patient has a central IV line.~a'2s'28 Ceftazidime is currently the third-generation cephalosporin with the most activity against P aeruginosa. Resistant P aeruginosa is being seen as the usage of Ceftazidime increases. Many of the newer cephalosporins can induce synthesis of beta-lactamases, causing the bacteria to become significantly more resistant to a broad range of beta-lactam drugs. 34'37 Also of concern is the development of cross-resistance to the aminoglycoside antibiotics. Sanders 37 reports of two instances in which moxalactam alone provoked the development of resistance not only to itself, but also to gentamycin, tobramycin, and amikacin in P aeruginosa infections. The implication of this resistance is that both the beta-lactams and possibly the aminoglycosides may be compromised if the newer cephalosporins are widely and indiscriminately used. Also, if these newer cephalosporins become first-line therapy, antibiotic-resistant organisms will emerge rapidly and become part of the hospital's flora. Recommendations include avoiding use of the newer cephalosporins for pro-
INFECTION IN THE NEUTROPENIC PATIENT
phylactic or empiric therapy, and in situations where a first-generation cephalosporin or a penicillin would provide adequate therapy, a7 The beta-lactam, moxalactam, causes prolonged prothrombin times and increases the risk of bleeding. 9"1° One of the main reasons for not using double-beta-lactam antibiotics routinely for all patients is the cost. Initial therapy with doublebeta-lactam antibiotics is reserved for the patient with greatest risk of renal toxicity, m The fluoroquinolones are one of the newest groups of antimicrobial agents, as Norfloxacin and ciprofloxacin are active against many grampositive and gram-negative organisms. In neutropenic patients, the fluoroquinolones have great activity against enterobacteriaceae and P aeruginosa, making them successful in the decontamination of the intestinal tract. However, they have little activity against anaerobes, thereby maintaining the colonization-resistance of the intestinal tract. 39 Monotherapy. The recent development of new antimicrobial agents has again sparked interest in monotherapy. 24'4° Imipenem, a broad-spectrum beta-lactam antibiotic, is effective against most infecting organisms, even those resistant to other traditional antibiotics. 25 The fluoroquinolones also possess a broad spectrum of activity.24 Use of monotherapy may lead to the emergence of resistant organisms during the course of therapy. Most authors agree that monotherapy needs more evaluation before it can be recommended as standard therapy for neutropenic patients. 7'24 Pizzo et al, 4° however, feel that single-agent therapy with certain beta-lactam antibiotics is a safe alternative to standard combination antibiotic therapy, although patients with documented infection or protracted neutropenia are likely to require additional or modified treatment. Schedule and length of therapy. Traditional administration of antibiotics at 6- or 8-hour intervals results in prolonged periods of time between doses when the serum concentration is suboptimal, allowing proliferation of the infecting organism. 22 Several authors22'24'2s suggest that aminoglycosides be administered by continuous infusion to maintain high serum concentrations. Many physicians advocate continuing antibiotic therapy until neutropenia resolves. 9'24m Prolonged treatment, however, increases the patient's risk for toxicities and superinfection with resistant
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bacteria and fungi. Others treat patients for 4 days after all signs and symptoms of infection have resolved (minimum of 7 days). 9"24 The following guidelines may be helpful. For the persistently neutropenic patient who receives antibiotic therapy, has no other sign of infection, and becomes afebrile on therapy, consider stopping therapy after 7 days without fever. A new fever, or slightest clinical deterioration, warrants appropriate cultures and reinstitution of antibiotic therapy. Careful monitoring of these patients is mandatory. Anti-fungal: agents. Prolonged treatment with broad-spectrum antibiotics places the neutropenic patient at high risk for development of a superinfection with fungi. 7'I° Neutropenic patients with persistent fever that fails to respond to antibacterial antibiotics are candidates for empiric amphotericin B 7'9'26'42 (see Table 6). Patients with acute myelogenous leukemia who have had one episode of fungal pneumonia or sinusitis are at high risk for recurrence during subsequent neutropenic periods. 43 Empiric or prophylactic amphotericin B may be indicated for these patients. Toxicities of amphotericin B may includeacute febrile reactions, occasional anaphylaxis, renal insufficiency, hypokalemia, hypomagnesemia, renal tubular acidosis, and severe rigors, l° Premedication with steroids, acetaminophin, meperidine, and/ or dantrolene can reduce the incidence of rigors. 42 A prolonged course of treatment over many weeks or months is often necessary..~2 The most critical factor in recovery from fungal infection is remission of the underlying malignant disease. 7"9'2s Table 6. Indication for Empiric Amphotericin B Fever: 5-7 d duration, unresponsive to antibacterial antibiotics Neutropenia: over 7 d duration No other obvious cause forfever Progressive debilitation Prolonged adrenal corticosteroid therapy Fever that responds to adrenal corticosteroids, but recurs on discontinuation Parenteral hyperalimentation Prolonged intravascular catheterization Prolonged and poorly Controlled hyperglycemia Diffuse pulmonary infiltrates Progressive unexplained liver or renal failure Candida species cultured from multiple body orifices Aspergi//us species cultured from any site Data from references 7, 9, 11.
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INFECTION PROPHYLAXIS
It may not be possible to prevent infection in the neutropenic patient, but only to delay or reduce its incidence. Untd recently, 35% to 40% of patients with acute myelogenous leukemia died of infection before an adequate course of remission induction chemotherapy could be completed. 14 Prevention of int'ection includes measures to improve the patient's defense mechanisms, decrease the acquisition of new organisms, suppress organisms already colonizing the patient, and minimize potentially dangerous procedures. •
•
6
.
Protective Isolation One of the most highly debated methods of decreasing the transmission of microorganisms is the use of protective isolation.6'12"16 Many feel that standard reverse isolation is of little use, whereas others support its use in certain patients. 5'24 A1ttiough the cost may be prohibitive, rooms equipped with high-efficiency particulate air (HEPA) filtration, in combination with topical antiseptics and oral antibiotics, are often used for severely immunocompromised patients. 6'12"t4'44
Antibiotics Complete reverse isolation significantly reduces the colonization of new organisms. However, because endogenous flora, especially in the intestinal tract, can still cause infection, oral nonabsorbable antibiotics have been used to suppress the flora of the GI tract. 4'6'12'16 However, most authors do not recommend prophylactic systemic antibiotic therapy. 44 Prophylactic trimethoprim/sulfamethoxazole suppresses aerobic bacteria, but not anaerobes, so colonization resistance remains relatively intact. 45 In hospitals where the incidence of P carinii infection is high, prophylactic use of trimethoprim/ sulfamethoxazole should be considered. 14 Norfloxacin and ciprofloxacin have been proposed to be safe, effective, well-tolerated alternatives for preventing gram-negative infection in neutropenic patients with acute leukemia. 19'24
attempted. 5'24 Means of bolstering host defense mechanisms, such as the use of J5 antiserum and monoclonal antibodies, are being studied for use in neutropenic patients. 5"24 NURSING CARE
Many nursing care measures have been developed based on knowledge of the usual characterTable 7. Measures for Prevention and Early Detection of Infection Assessment
interventions
Daily examination of patient, with particular attention to rectum, axilla Assess vital signs every 4 h Assess respiratory function Inspect all IV sites and breaks in integument
Move patient to private room Limit clutter in patient's room Restrict number of visitors Screen visitors and staff for signs of infection Strict handwashing by anyone in contact with patient HEPA filtration in rooms Rooms should have positive air pressure (prevents airborne bacteria and spores from entering room from hallway) Patient to wear mask if leaving room Care for neutropenic patient first Disinfect all equipment used Avoid stagnant water Do not shake dirty linen Low microbial diet No uncooked fruits and vegetables No fresh flowers or live plants Sterile water and ice Aseptic technique for all procedures Avoid urinary catheterization Maintain normal bowel function: Avoid constipation, diarrhea, enemas, suppositories, rectal thermometers Use sitz baths if diarrhea occurs Cleanse perirectal area twice a day and after each bowel movement with soap or povidone-iodine, rinse with water, apply protective ointment Provide meticulous skin care: Chlorhexidrine bath Providone-iodine swabs to axilla Change IV tubing and bottles per hospital policy Use consistent mouth care protocol Turn, cough, deep breathe bed-fast patients Maintain adequate nutrition
Other Measures of Infection Prophylaxis Patient/family education
Several other measures have been proposed by various authors. The use of prophylactic leukocyte transfusions is a debatable issue. 6'7'44 Active immunization against P aeruginosa has been
All of the above interventions with emphasis on handwashing and keeping room free of clutter Data from references 1, 3, 4, 6, 14, 16, 19, 44.
59
INFECTION IN THE NEUTROPENIC PATIENT
istics o f infection in the neutropenic patient. T h e s e measures are s u m m a r i z e d in Table 7. SUMMARY
Infection is the m a j o r cause o f death in neutropenic patients. P r e v e n t i o n and therapy o f infection are an important, d y n a m i c c o m p o n e n t o f the care o f the neutropenic patient with leukemia. Nurses c a r i n g for t h e s e p a t i e n t s m u s t h a v e a c u r r e n t k n o w l e d g e o f i m m u n o s u p p r e s s i o n , the usual sites
and causative organisms, the clinical presentation, and the treatment o f infection. This k n o w l e d g e then needs to be applied clinically in the care o f the neutropenic patient. ACKNOWLEDGMENT
The author wishes to thank Judith Maloni, RN, PhD, Robert Lumish, MD, Adriarme Farley, RN, Darlene Petrelli, Sr Diane Matje, RN, MSN, Sr Lorraine Meskowski,-Veronica Harrison, and Simone Karp, RPh, for their assistance in the preparation of this manuscript.
REFERENCES
1. Yeomans AC: Rectal infections in acute leukemia. Cancer Nurs 9:295-300, 1986 2. Pizzo PA: Management of fever and infection in the patient with cancer. Mediguide Oncol 2:1-14, 1983 3. Bran& B: A nursing protocol for the client with neutropenia. Oncol Nurs Forum 1i:24-28, 1984 4. Young LS: Management of infections in leukemia and lymphoma, in Rubin RH, Young LS (eds): Clinical Approach to Infection in the Compromised Host. New York, NY, Plenum, 1981, pp 461-497 5. Pizzo PA. Young RC: Infections in the cancer patient, in DeVita VT, Hellman S, Rosenberg SA (eds): Cancer: Principles and Practice of Oncology (ed 2). Philadelphia, PA, Lippincott, 1985, pp 1963-1998 6. Carlson AC: Infection prophylaxis in the patient with cancer. Oncol Nut's Forum 12:56-64, 1985 7. Bodey GP: Infection in cancer patients: A continuing association. Am J Med 81:11-26, 1986 (suppl IA) 8. Schimpff SC: Diagnosis and treatment of infection in granulocytopenie patients. Mediguide Oncol 2:1-3,14-16, 1982 9. Bodey GP: Infections in the neutropenic cancer patient. Mediguide Oncol 2:1-5,9-12, 1985 (special issue) I0. Wade JC: Treatment of infections in cancer patients. Infec Med:13-16, 1985 (suppl) 11. Elliott GR, Quie PG: Infections in the compromised patient: A complex problem. Drug Ther 7:19-26, 1982 12. Schimpff SC: Infections in patients with acute leukemia, in Mandell GL, Douglas RG, Bennett JE (eds): Principles and Practice of Infectious Diseases. New York, NY, Wiley, 1979, pp 2263-2277 13. Brown AE: Neutropenia, fever, and infection. Am 3 Med 76:421-428, 1984 14. Schimpff SC: Infection prevention in patients with cancer and granulocyt0penia, in Grieco MH (ed): Infections in the Abnormal Host. New York, NY, Yorke, 1980, pp 926-950 15. Reheis CE: Neutropenia: Causes, complications, treatment, and resulting nursing care. Nurs Clin North Am 20:219225, 1985 16. Schimpff SC, Young VM: Epidemiology and prevention of infection in the compromised host, in Rubin RH, Young LS (eds): Clinical Approach to Infection in the Compromised Host. New York, NY, Plenum, 1981, pp 5-33
17. Klastersky J: Concept of empiric therapy with antibiotic combinations: Indications and limits. Am J Med 80:2-12, 1988 18. Weksler ME: The senescence of the immune system. Hosp Pract 16(10):53-64, 1981 19. Wade JC: Prevention of infection in the granulocytopenic patient. Immunocompr Host 4:1-23, 1987 20. Nadwomy HA, Greene WH: Surgical aspects of infection and supPortive care in neutropenic patients. Infect Surg 182-188, 1984 21. Farnell MB: Neutropenic enterocolitis: A surgical disease? Infect Surg:120-131, 1987 22. Bodey GP: Antibiotics in patients with neutropenia. Arch Intern Med 144:1845-1851, 1984 23. Bready BB: Treatment of fungal infections in cancer patients. Highlights Antineoplast Drug 5:2-5, 1987 24. Rolston K, Bode)' GP: Managing infections in the neutropenic patient: Antimicrobial therapy reviewed. Hosp Formul 22:710-719, 1987 25. Fainstein V: Initial antibiotic therapy: Old and new strategies for neutropenic patient. Prim Care Cancer 17-21, 1987 26. Cohen MS: Relationship between host defense and infectious diseases. Infect Med 182-187, 1986 27. Jocbelson MS; Altschuler J, Stomper PC: The yield of chest radiography in febrile and neutropenie patients. Ann Intern Med 105:708-709, 1986 28. Bodey GP: Infectious complications of leukemia-Seven principles of treatment. Prim Care Cancer 41-50, 1985 29. Henschel L: Fever patterns in the neutropenic patient. Cancer Nurs 8:301-305, 1985 30. Gurevich I: Fever: When to worry about it. RN 48:1419, 1985 31. Atkins E: The causes of fever in cancer patients. Mediguide Infect Dis 3:1-8, 1984 32. McCabe RE, Brooks RG, Mark JBD, et al: Open lung biopsy in patients with acute leukemia. Am J Med 78:609-616, 1985 33. Drug review: Antipseudomonal peniciUins. Pharm Update Univers Hosp Boston 2:2-4, 1987 34. Donowitz GR, Mandell GL: Beta-lactam antibiotics. N Engl J Med 318:419-426, 1988 35. Livengood B, Windisch RM: Two views of therapeutic drug monitoring. Lab Med Today Mercy Hosp Pittsburgh 1988, pp 1-2
60
36. Physicians' Desk Reference. Oradell, NJ, Medical Economics, 1989, pp 659-661 37. Sanders CC: Emerging problems of resistance to the newer cephalosporins: Clinical significance. Intern Med Specialist 5:1-5, 1984 38. Banaszak RS, Forbidussi D, Cobaugh D: New drugs. Pharmacy 3:1, 1988 39. Quintiliani R, Andriole V: The clinical role of the fluoroquinolones. Mediguide Infect Dis 8:1-4, 1988 40. Pizzo PA, Hathom JW, Hiemenz J, et al: A randomized trial comparing ceftazidime alone with combination antibiotic therapy in cancer patients with fever and neutropenia. N Engl J Med 315:552-558, 1986 41. Joshi JH, Schimpff SC, Termey JH, et al: Can antibac-
ALMA C. ONIBONI
terial therapy be discontinued in persistently febrile granulocytopenie cancer patients? Am J Ivied 76:450-457, 1984 42. Gross MH, Fulkerson WJ, Moore JO: Prevention of ampbotericin B-induced rigors by dantrolene. Arch Intern Med 146:1587-1588, 1986 43. Robertson MJ, Larson RA: Recurrent fungal pneumonias in patients with acute nonlymphocytic leukemia undergoing nmltiple courses of iatensive chemotherapy. Am J Med 84:233-239, 1988 44. Featherstone JH, Dale DC: Managing infections in immunosuppressed patients. Postgrad IVied 64:141-148, 1978 45. Schimpff SC: Infection prevention during profound granulocytopenia: New approaches to alimentary canal microbial suppression. Ann Intern Med 93:358-361, 1980
NFECTION is a major cause of morbidity and
mortality in the neutropenic patient with Ileukemia. 1"9 Infection in this immunocompromised host results from the combined effects of the leukemia itself, treatment, and invasive procedures and hospitalization (see Fig 1). Infection is most often due to gram-negative bacteria, but grampositive and fungal infections are increasing. 6'7"m Typical signs and symptoms of infection are often absent in the neutropenic patient. Fever may be the only sign, and should be considered a medical emergency. It is imperative, then, that nurses caring for the patient with leukemia become thoroughly familiar with the etiology, causative organisms, diagnosis, and therapy of infection in the neutropenic patient. FACTORS CONTRIBUTING TO INFECTION
Leukemia Patients with leukemia have a higher infection rate than patients with solid tumors. In acute leukemia, the mature and immature neutrophils may be functionally abnormal. Other contributing factors vary with the type of leukemia and include abnormal immunoglobulins, impaired lymphocyte function, monocytopenia, and, after bone marrow transplantation, the increased activity of suppressor T lymphocytes.7's'H'13
Neutropenia Neutropenia is the single most important factor predisposing the patient with leukemia to infection.7'9'11'13 Neutropenia has commonly been defined as an absolute neutrophil count less than 1,000 cells per cubic millimeter. 14-16As the prime function of the neutrophil is phagocytosis, neutropenia eliminates one of the body's prime defenses. The risk of infection is related to the degree, duFrom the Mercy Hospital of Pittsburgh, Pittsburgh, PA. Alma C. Oniboni, RN, MSN, OCN: Oncology Clinical Nursing Specialist, The Mercy Hospital of Pittsburgh, Pittsburgh, PA. Address reprint requests to Alma C. Oniboni, RN, MSN, 325 Hamill Rd, Verona, PA 15147. © 1990 W.B. Saunders Company. 0749-2081190/0601-0008505.00/0 50
ration, and rate of change of neutropenia. The frequency of infection increases as the absolute neutrophil count decreases below 500lmm 3, and the longer the patient remains neutropenic. 7A3'17 A stable level of neutropenia is less likely to be associated with infection than rapidly progressing neutropenia, as seen in patients receiving induction or reinduction chemotherapy. ~4'16 Patients with profound, prolonged neutropenia are at the highest risk of dying, as recovery from most severe infections is related to the patient's ability to respond with an increased production of neutrophils. Fatal infection during chemotherapy-induced neutropenia is the major barrier to successful treatment of leukemia. If infection could be controlled, perhaps survival rates would improve.
Other Factors Contributing to Infection One risk factor is the breakdown of the body's first line of defense--the skin and mucous membranes. 1"9'11'12'16Openings in the skin or ulcerated mucosa occur through changes induced by chemotherapy, venipuncture, bone marrow aspirations, total body irradiation, use of central venous catheters, and other invasive procedures. Adrenal corticosteroids are often used as part of specific chemotherapeutic regimens or as supportive therapy. Alterations associated with the use of steroids include suppression Of acute and chronic inflammatory responses by decreasing vascular permeability and leukocyte infiltration, suppression of antibody production, reduced interferon synthesis, decreased delayed hypersensiti~,ity, impaired phagocytosis, and interference with the antigen-processing functions of macrophages.6'7'9 As a result, steroids predispose the patient to a variety of infectious complications. Antibiotic therapy alters the patient's normal flora by suppressing susceptible organisms and permitting colonization by resistant, opportunistic organisms. 9 Hospitalization may contribute to colonization of unique organisms as a result of contaminated intravenous (IV) fluid, blood products, respiratory equipment, and food. 6 Invasive procedures, such as urinary or IV catheters, create a pathway along which microorganisms can enter. Malnutrition and subsequent negative nitrogen balance also lead to immune deficiencies. In older Seminars in Oncology IVurs/ng, Vol 6, No 1 (February), 1990: pp 50-60
51
INFECTION IN THE NEUTROPENIC PATIENT LEUKE~RA
HOSPITAL
CATHETERS~
~
~
RADIATION
/
/
~MALNUTRC£1ON
IINFECTIONI ~
~AGU
,K., BREAKDOWN
"ANTI'RIOTIC$
Fig 1. Factors contributing to risk of infection. (Data from Pizzo and Young, s Carlson, s and Bodey.7)
adults, age-related changes in the immune system lead to an increased susceptibility to infectious diseases, is CLINICAL PRESENTATION OF INFECTION
Common Sites of Infection Most infections in neutropenic, patients arise from three major sites: the skin, the respiratory system, and the gastrointestinal tract. 6'8'1°J2 Chemotherapy-induced damage occurs, particularly to the mucosa of the respiratory and gastrointestinal (GI) tracts. Pneumonia and sinusitis are commonly seen. 12"t9Infection may arise from any point along the GI tract. Oral infections may result from ulcerations secondary to stomatotoxic chemotherapy and underlying periodontal disease. Drug-induced vomiting and stomach acid reflux may explain the frequency of infection in the distal third of the esophagus. 16,19 Perirectal cellulitis or abscess is more common in patients with leukemia than in those with solid tumors, and may even be seen as a presenting sign in acute leukemia. 1'2° Perirectal infections result from several compounding factors: pressure generated during defecation, frequent bowel movements associated with some chemotherapy regimens, preexisting hemorrhoids, constipation, and the skin and mucosal changes induced by chemotherapy or total body irradiation. Rectal abscesses may cause a life-threatening septicemia. Neutropenie enterocolitis, a fulminating, inflammatory process that involves the cecum, ascending colon, and surrounding tissue, occurs in patients with profound neutropenia and increases with the use of aggressive chemotherapy. 2°'2~ Neutropenic enterocolitis, which is found in 10% to 15% of leukemic patients atpostmortem exam-
ination, is characterized by necrosis of the bowel wall and extensive fungal or bacterial involvement. Less commonly, urinary tract infections and meningitis may be seen. ~°'12 The many blood products transfused in the support of these patients are associated with hepatitis.~2"16 And, at times the source of bacteremia is never found.4
Caustive Organisms of lnfection Acquisitionlshift of microbial flora. Microorganisms that do not ordinarily cause disease may, under certain circumstances such as immunosuppression, cause opportunistic infections in the neutropenic patient. Quite often, the causative organism is not part of the patient's original endogenous flora, but rather is acquired in the hospital. Any seriously ill individual, and, in particular, the compromised host, will undergo changes in the microbial flora in various areas of the body. 14 There is a redistribution of the patient's endogenous flora and colonization by exogenous organisms. The use of antibiotic therapy that suppresses the anaerobic flora of the GI tract alters colonization resistance, so that even small numbers of hospital-acquired organisms can rapidly colonize. 14.16 In the presence of mucosal damage, microorganisms can penetrate and cause local infection. Dissemination and bacteremia may then occur. Surveillance culturing has provided useful research data in defining the degree to which patients with acute leukemia become infected with organisms acquired during their hospitalization. Although surveillance cultures can be costly and unreliable, some investigators advocate their use for those patients at high risk. 14J6'22 By following the changing flora colonizing within the patient, the physician can more accurately choose empiric antibiotics should fever develop. 8'14'16J9"22 Normal flora in the mouth can rapidly change to gram-negative bacilli, Staphylococcus aureus, or yeasts. Later in the patient's illness, particularly after repeated use of antibiotics, gram-negative bacilli and fungi are found in the nose. The normal flora of the rectum is often replaced by Pseudomonas aeruginosa or Klebsiella pneumoniaefl 4 As a result, infections in these sites are often caused by these newly acquired opportunistic organisms, rather than by the more manageable communityacquired organisms. 8
ALMA C. ONIBONI
52
Food is one of the most important sources of contamination with gram-negative bacilli and fungi, and may initiate colonization of exogenous organisms in the patient whose intestinal flora may have been suppressed by antibiotic therapy, t6 Plants, such as African violets and chrysanthemums, may also be a source of microorganisms. Stagnant water found in the vases of fresh flowers is of particular concern because it may contaminate the environment when the water is changed. 16 Tap water generally contains few viable bacteria. However, there is a danger of contamination by P aeruginosa in the presence of faucet aerators; therefore, this water should not be considered safe without sterilization. Ice machines or ice that has been contaminated by improper handling may also be a source of exogenous organisms.J4"16 Aspergillus sp, important airborne organisms, are second only to Candida sp in causing fungal infections in neutropenic patients. 14.16.23Aspergillus spores are found in large numbers in the outside air during autumn as leaves decompose, and in fireproofing material used in steel-frame constructed buildings. The Aspergillus spores persist and may enter the patient's environment, particularly during times of hospital remodeling and construction. Predominant pathogens. The microorganisms most commonly implicated in infections in the neutropenie patient are summarized in Table 1. Each hospital tends to be colonized by its own unique organisms, but some generalizations may
be made. Usually, bacterial infections due to gram-positive cocci and enteric gram-negative bacilli are seen in the neutropenic, febrile patient newly admitted to the hospital. After prolonged hospitalization and empiric broad-spectrum antibiotic therapy, infections due to resistant grampositive, gram-negative, and fungal organisms are s e e n . 5,13
Gram-negative bacilli, such as P aeruginosa, Escherichia coli, and Klebsiella sp are the most common cause of infection in the neutropenic patient and often account for the high mortality rate among neutropenic patients. 7 The incidence of infection caused by gram-positive organisms, such as Staphylococcus epidermidis, Streptococcus viridans, and JK diptheroids, has increased over the past several years. S epidermidis, once viewed as only a contaminant, has emerged as a significant pathogen, especially in patients with indwelling venous catheters. 5'9'19"22"24'25 Of particular concem is S epidermidis which is resistant to penicillins and cephalosporins. Fungi, such as Candida sp and Aspergillus sp, are major pathogens in the patient who has prolonged periods of neutropenia or in those who receive long courses o f antibacterial antibiotic therapy, s'~°'19 Infection with viruses such as herpes zoster, as well as protozoa such as Pneumocystis carinii, can also be quite problematic. 5'6 Compounding factors. Patients infected with cytomegalovirus have a higher incidence of bacterial superinfection. Interactions between two or
Table 1. Predominant Pathogens Causing Infection in the Neutropeni¢ Patient Gram-negative bacteria E coil P aeruginosa K pneumoniae Enterobacter species Serratia species Proteus species Haemophilus influenzae Acinetobacter species Legionella pneumophi/a
Gram-positive bacteria
A A, B
A, B B B
Fungi Aspergillus species Candida albicans Torulopsis glabrata Cryptococcus neoformans Ph¥comycetes Histoplasma capsulatum Fusarium
S aureus S epidermidis Enterococcus species Corynebacteria (group JK diptheroids) Streptococcus species Mycobacterium species Clostridium difficile Cl septicum
Protozoa A
A
Pneumocystis carinii Toxoplasma gondii Viruses Herpes simplex virus Varicella zoster virus Cytomagalovirus
Data from references 5, 7-9, 13, 14, 22-25. Abbreviations: A, most common organisms; B, most virulent organisms.
A A
INFECTION IN THE NEUTROPENIC PATIENT
more infecting organisms may potentiate infectious complications: Some organisms are more capable of colonizing the patient than others, and once colonized, are more likely to result in infection. This may be the result of some inherent virulence or pathogenicity of that organism. 5'~4 For example, only a small percentage of patients who became colonized with E coli develop infection. On the other hand, although P aeruginosa is not the most common organism, it is often the most virulent. Forty percent to 68% of patients who are colonized with P aeruginosa develop serious infection while neutropenic.5"14"26P aeruginosa rapidly invades in the presence of mucosal damage and neutropenia, whereas other species of pseudomonas are incapable of doing so) 4 These factors must be taken into account when choosing empiric antibiotic therapy.
Signs and Symptoms Patients with neutropenia are not able to produce an adequate inflammatory response to infection; therefore, typical signs and symptoms of infection are often absent. 5"s'~s Physical findings, such as exudate, ulceration, swelling, or adenopathy, are less prevalent. The patient with pneumonia often presents only with shortness of breath or nonproductive cough. Pulmonary infiltrates may not be seen on initial chest radiograph, but may take 2 to 3 days to appeal'. 5"7"12"27 Pain and fever may be the only indication of an infection of the skin, Rectal infections are often not clinically diagnosed, as the patient's only complaint may be pain on defecation) "6 Bacterial or fungal pharyngitis often presents with a sudden onset of severe pain, difficulty swallowing, fever, and chills. Fever. Fever is the single most important and often the only sign of infection in the neutropenic patient. 2s3° Thirty percent to 60% of fevers in this population are due to infection.4,s Other possible causes of fever in the neutropenic patient with leukemia include neoplasm, liver metastasis, drug hypersensitivity, transfusion reaction, phlebitis, and atelectasis. When infection is present, however, fever almost always occurs. Failure to develop fever in the presence of infection is a poor prognostic sign. Fever patterns may sometimes suggest the cause of the fever, if unrelated to administration of antipyretic medications. An intermittent fever pat-
53
tern, characterized by temperature spikes and daily returns to normal, is commonly seen in patients with gram-negative septicemia. Routine use of antipyretic medications is not advocated by many, as the diagnostic fever patterns will be altered. 29'3° Fever of unknown origin is a continued problem in the care of the neutropenic patient. Diagnosis is often difficult, as cultures may be negative even in the presence of infection. One explanation offered is that organisms may have not yet entered the bloodstream. The use of prophylactic antibiotics may also be partially responsible for failure to isoI 2 outlines late the offending o r g a n i s m24T . , abe some possible causes of fever of unknown origin. Fever of unknown origin, particularly in the patient treated with empiric antibiotic therapy, is often due to fungal infection.7'9'26 The longer the period of neutropenia persists, the more likely leukemic patients will develop a potentially fatal fungal infection) ° Sepsis. Rapid progression from localized infection to sepsis results in a high fatality rate. Nurses must be attuned to the early signs and symptoms of septic shock, such as restlessness and confusion, as patient recovery depends on rapid assessment and treatment. TREATMENT OF INFECTION
Development of fever in a neutropenic patient represents a medical emergency, and prompt assessment, diagnosis, and initiation of antibiotic therapy are vital. The steps in evaluation of the febrile, neutropenic patient are summarized in Table 3. The value of invasive diagnostic procedures is debated. Many investigators feel that a proceTable 2. Fever of U n k n o w n Origin Resistant bacterial infection Bacterial infection associated with tissue necrosis Nonbacterial infection Superinfection with resistant bacteria or fungi Drug or transfusion fever Tumor fever caused by Hemorrhage Necrosis Tissue destruction Liberation of tissue pyrogens Liver damage affecting steroid conjugation Adrenal hyperplasia producing steroid pyrogen Immunologic reaction to tumor antigens Inflammatory response to tumor growth or necrosis Spontaneous production of an endogenous pyrogen Data from references 7, 24, 31.
ALMA C. ONIBONI
54
Table 3. Evaluation of Febrile, Neutropenic Patient Temperature of 101°F (38.5°C) lasting more than 2 h, unassociated with administration of pyrogenic substances, indicates presence of infection until proven otherwise. Thorough history and physical examination: Particular attention paid to oropharynx, axillae, groin, perianal area, sinuses, indwelling catheters, any suspected area of infection Characteristic signs and symptoms of infection may be absent Blood cultures: Two sets (at least 10-15 mL each) before antibiotics begun Culture both central line and peripheral site Repeat daily while febrile Cultures of nose, throat, urine, sputum, stool, rectum, axilla, obvious lesions, as a baseline and repeat as indicated. Urinalysis (looking for bacteriuria, not pyuria) Chest radiograph (may initially be negative; repeat). Reexamine patient on a regular basis until site of infection is documented. Data from references 6-9, 22, 25-29, 31-34.
dure such as open-lung biopsy is of little value, as it results in a low yield of specific diagnoses, seldom leads to changes in therapy, and has little influence on the patient's outcome. 9'26"32 Institutions should establish guidelines for initiating treatment for a fever. Some suggest that two or three low-grade elevations above 38°C or a single elevation above 38.5°C, in conjunction with neutropenia, are sufficient criteria to initiate therapy. 5"22 Therapy is not begun if the fever coincides with the administration of a pyrogenic agent, such as a blood product transfusion. 22 Bodey9"22'28 suggests that antibiotics be started immediately in the febrile patient who appears ill or has clinical signs of infection. Otherwise, Bodey suggests withholding antibiotic therapy and rechecking the temperature 1 to 2 hours later. If the patient remains febrile during this interval, blood cultures are repeated and antibiotic therapy started. This procedure eliminates the unnecessary administration of antibiotics to the patient with a single temperature elevation due to unknown reasons, yet does not delay initiation of antibiotics for those requiring immediate therapy.
Empiric Antibiotic Therapy The prompt initiation of empiric antibiotic therapy has markedly reduced the infection-related
morbidity and mortality for the neutropenic patient with leukemia. 17,22.24 Delays in the administration of antibiotic therapy can diminish its efficacy.7 Several factors influence the choice of antibiotics to be used in the neutropenic patient (see Table 4). Therapy should be given IV, with no delays or omissions from the prescribed schedule. The sodium load of each antibiotic may be of concern in some patients. For the anti-pseudomonal penicillins commonly used, ticarcillin contains 5.2 mEq of sodium per gram, whereas each gram of piperacillin contains only 1.85 mEq of sodium. 33 Potential toxic effects of antibiotic therapy must also be considered when choosing antibiotic therapy. 22 A major concern is nephrotoxicity associated with the use of aminoglycosides. Cumulative renal damage may occur with repeated antibiotic usage. The concurrent use of other nephrotoxic agents, such as cisplatin or amphotericin B, also increases the risk of toxicity.l°'22 "Ideally, an antibiotic should be selected that provides high serum concentrations for prolonged periods of time with minimal toxicity. ''9 Table 5 outlines the antibiotics most commonly prescribed in the treatment of the neutropenic patient. Combination therapy. Usually, initial therapy consists of a combination of two drugs directed at bacterial infections, including both gram-negative and gram-positive organisms, s'12 P aeruginosa is one of the most virulent infecting organisms; therefore, initial therapy usually includes an effective anti-pseudomonal antibiotic. 26 Although every two-drug combination has some gaps in its spectrum of coverage, the addition of a third drug has Table 4. Factors Influencing the Choice of Antibiotics Spectrum of activity Bactericidal activity Efficacy in neutropenia Pharmacokinetic properties Potential for synergy Rapidity of bactericidal activity MIC (minimal inhibitory concentration)/serum concentration Flora of individual hospital Individual hospital's susceptibility/resistance pattern Presence of intravascular devices Age and renal function of patient Previous exposure to aminoglycosides and cisplatin Sodium load Toxicities Cost Data from references 9, 22-24, 33.
INFECTION IN THE NEUTROPENIC PATIENT
55
Table 5, Commonly Used Antibiotics in the Neutropenic Patient Antibiotic (trade name)
Comments
Broad-spectrum penicillins Azlocillin (Azlin) Carbenicillin (Geopen} Ticarcillin (Ticar) Mezlocillin (Mezlin) Piperacillin (Pipracil)
A, E A,E A, E B, E, Increased activity against E coil A, B, E, Increased activity against E coil Most activity of the broad-spectrum penicillins against P aeruginosa
Penicillinese-resistantpenicillins Methicillin (Staphcillin) Nafcillin (Unipen) Oxacillin (Prostaphin)
C, E C,E C, E
Aminoglycosides Amikacin (Amikin) Gentamicin (Garamycin) Tobramycin (Nebcin)
More toxic in elderly, patients with impaired renal function
Third-generation cephalosporins Cefotaxime (Claforan) Ceftizoxime (Cefizox) Moxalactam (Moxam) Cefoperazone (Cefobid) Ceftazidime (Fortaz)
B, E, No coverage of P aeruginosa B, E, No coverage of P aeruginosa A, B, D, E, Poor coverage against Staphylococcus and Streptococcus A, B, D, E, Active against many gram-positive and gram-negative organisms A, B, E, Poor gram-positive coverage
Antifungels Amphotercin B (Funglzone) Ketoconazole (Nizoral) Nystatin
Antivirals Acyclovir
Effective against herpes simplex and zoster; not effective against cytomegalovirus
Miscellaneous Clindamycin (Cleocin) Metrovidazole (Flagyl) Trimethoprim/sulfamethoxazole (Bactrim, Septra) Vancomycin Penicillin + beta-lactamase inhibitor Amoxicillin t- clavulanic acid (Augmentin) "l'icarcillin + clavulanic acid (Timentin) Carbapenems Imipenem/cilastin (Primaxin)
Anti-anaerobic Anti-anaerobic Effective against many gram-positive and gram-negative organisms; ineffective against P aeruginosa Anti-gram-positive, drug of choice for CI difficile E, Oral; activity against beta-lactamase-producing strains of Staphylococcus, H influenza E, Active against Staphylococcus
E, Active against most gram-positive, gram-negative, and anaerobes Not effective against methicillin-resistant S aureus
Monobactams Aztreonam (Azactam} Fluoroquinolones Norfloxacin (Noroxin) Ciprofloxacln (Cipro)
E, Active against aerobic gram-negative organisms Not effective against gram-positive organisms or anaerobes Available orally Effective against many gram-positive and gram-negative organisms
Abbreviations: A, antipseudomonal; B, anti-gram-negative; C, anti-staphylococcal; D, prolongs prothrombin time; E, beta-lactam antibiotic. Data from references 5, 7, 24, 28, 34.
not proven to increase efficacy for initial therapy, but may increase toxicity and cost. 5"7'22'24 The initial regimen may be altered to provide appropriate coverage as infecting organisms are identified.
Current recommendations for empiric antibiotic combination therapy include (1) an aminoglycoside plus a beta-lactam antibiotic, and (2) two betalactam antibiotics. 13'22"28 Most institutions use a
56
two-drug combination of an aminoglycoside plus either an extended-spectrum penicillin (such as piperacillin) or an extended-spectrum cephalosporin (such as ceftazidime).5'1° Aminoglycoside antibiotics have been part of the standard empiric therapy for years. It is now felt that an aminoglycoside is not an essential component of combination therapy, but its inclusion may prevent the emergence of resistant organisms seen with the use of the beta-lactam antibiotics. 24 Drawbacks to the use of aminoglycosides include the potential for ototoxicity and nephrotoxicity, and the prevalence of bacteria that are resistant to some aminoglycosides.9"24'2s Therapeutic drug monitoring, often used initially and weekly with the use of aminoglycosides, can escalate the cost of therapy. However, used appropriately, therapeutic drug monitoring has the potential to confil-m suspected drug toxicity, subtherapeutic response to an otherwise adequate doge, drug interactions, and the presence of disease that can alter the body's ability to handle a drug. 35 This can lead to decreased costs and length of stay. Nurses play a vital role in the successful use of therapeutic drug monitoring. Proper collection and labeling of blood samples are essential. For results to be valid, consideration is given to the time of blood sampling in relation to the last dose, dose administered, and concurrent drug therapy which may affect the results. 3s Improper collection of a sample, such as drawing blood above an IV line or inaccurate timing of blood sampling, will waste personnel time, add considerably to an already costly procedure, and provide invalid, and potentially dangerous, results upon which therapeutic decisions are made. s'35 It is generally felt that the beta-lactam antibiotics are the foundation of all antibiotic regimens, and should be included in any two-drug regime. 2s Beta-lactam antibiotics, because of their chemical structure, resist inactivation by enzymes (called beta-lactamases) produced by gram-negative bacteria. Cephalosporins, penicillins, monobactams, and carbapenems are included in this class of drugs. Clavulanic acid, a beta-lactamase inhibitor, is added to some antibiotics, such as ticarcillin and amoxicillin to enhance their spectrum of activity. 17.33.34 Clavulanic acid is structurally similar to penicillin. By binding to and inactivating bacterial beta-lactamases, clavulanic acid protects
ALMA C. ONIBONI
the antibiotic from hydrolysis.34 Nurses should be aware that both the Augmentin (amoxicillin + elavulanic acid) " 2 5 0 " and " 5 0 0 " tablets contains the same amount of clavulanic acid (125 mg); therefore, two Augmentin " 2 5 0 " tablets do not equal one Augmentin " 5 0 0 " tablet, and should not be substituted. 36 As aminoglycoside toxicity remains a problem, many investigators recommend a double betalactam antibiotic combination, s'll This combination, unfortunately, has been associated with suppressed neutrophil recovery and the emergence of resistant organisms because of suppression of intestinal anaerobic organisms. 7'9"13'1739"34In recent years, considerable resistance has developed to the older antibiotics such as cephalothin and ticarcillin, which had been used in combination with aminoglycosides to cover gram-negative pathogens and S aureus. 17 Although use of the broadspectrum cephalosporins may avoid the necessity of an aminoglycoside, less activity is seen against gram-positive cocci, and another antibiotic, such as vancomycin, may then need to be added to provide appropriate coverage.9 Vancomycin is the only agent effective against some gram-positive organisms, such as enterococci, JK diptheroids, S epidermidis and S aureus, and is often added to empiric or continued therapy if the patient has a central IV line.~a'2s'28 Ceftazidime is currently the third-generation cephalosporin with the most activity against P aeruginosa. Resistant P aeruginosa is being seen as the usage of Ceftazidime increases. Many of the newer cephalosporins can induce synthesis of beta-lactamases, causing the bacteria to become significantly more resistant to a broad range of beta-lactam drugs. 34'37 Also of concern is the development of cross-resistance to the aminoglycoside antibiotics. Sanders 37 reports of two instances in which moxalactam alone provoked the development of resistance not only to itself, but also to gentamycin, tobramycin, and amikacin in P aeruginosa infections. The implication of this resistance is that both the beta-lactams and possibly the aminoglycosides may be compromised if the newer cephalosporins are widely and indiscriminately used. Also, if these newer cephalosporins become first-line therapy, antibiotic-resistant organisms will emerge rapidly and become part of the hospital's flora. Recommendations include avoiding use of the newer cephalosporins for pro-
INFECTION IN THE NEUTROPENIC PATIENT
phylactic or empiric therapy, and in situations where a first-generation cephalosporin or a penicillin would provide adequate therapy, a7 The beta-lactam, moxalactam, causes prolonged prothrombin times and increases the risk of bleeding. 9"1° One of the main reasons for not using double-beta-lactam antibiotics routinely for all patients is the cost. Initial therapy with doublebeta-lactam antibiotics is reserved for the patient with greatest risk of renal toxicity, m The fluoroquinolones are one of the newest groups of antimicrobial agents, as Norfloxacin and ciprofloxacin are active against many grampositive and gram-negative organisms. In neutropenic patients, the fluoroquinolones have great activity against enterobacteriaceae and P aeruginosa, making them successful in the decontamination of the intestinal tract. However, they have little activity against anaerobes, thereby maintaining the colonization-resistance of the intestinal tract. 39 Monotherapy. The recent development of new antimicrobial agents has again sparked interest in monotherapy. 24'4° Imipenem, a broad-spectrum beta-lactam antibiotic, is effective against most infecting organisms, even those resistant to other traditional antibiotics. 25 The fluoroquinolones also possess a broad spectrum of activity.24 Use of monotherapy may lead to the emergence of resistant organisms during the course of therapy. Most authors agree that monotherapy needs more evaluation before it can be recommended as standard therapy for neutropenic patients. 7'24 Pizzo et al, 4° however, feel that single-agent therapy with certain beta-lactam antibiotics is a safe alternative to standard combination antibiotic therapy, although patients with documented infection or protracted neutropenia are likely to require additional or modified treatment. Schedule and length of therapy. Traditional administration of antibiotics at 6- or 8-hour intervals results in prolonged periods of time between doses when the serum concentration is suboptimal, allowing proliferation of the infecting organism. 22 Several authors22'24'2s suggest that aminoglycosides be administered by continuous infusion to maintain high serum concentrations. Many physicians advocate continuing antibiotic therapy until neutropenia resolves. 9'24m Prolonged treatment, however, increases the patient's risk for toxicities and superinfection with resistant
57
bacteria and fungi. Others treat patients for 4 days after all signs and symptoms of infection have resolved (minimum of 7 days). 9"24 The following guidelines may be helpful. For the persistently neutropenic patient who receives antibiotic therapy, has no other sign of infection, and becomes afebrile on therapy, consider stopping therapy after 7 days without fever. A new fever, or slightest clinical deterioration, warrants appropriate cultures and reinstitution of antibiotic therapy. Careful monitoring of these patients is mandatory. Anti-fungal: agents. Prolonged treatment with broad-spectrum antibiotics places the neutropenic patient at high risk for development of a superinfection with fungi. 7'I° Neutropenic patients with persistent fever that fails to respond to antibacterial antibiotics are candidates for empiric amphotericin B 7'9'26'42 (see Table 6). Patients with acute myelogenous leukemia who have had one episode of fungal pneumonia or sinusitis are at high risk for recurrence during subsequent neutropenic periods. 43 Empiric or prophylactic amphotericin B may be indicated for these patients. Toxicities of amphotericin B may includeacute febrile reactions, occasional anaphylaxis, renal insufficiency, hypokalemia, hypomagnesemia, renal tubular acidosis, and severe rigors, l° Premedication with steroids, acetaminophin, meperidine, and/ or dantrolene can reduce the incidence of rigors. 42 A prolonged course of treatment over many weeks or months is often necessary..~2 The most critical factor in recovery from fungal infection is remission of the underlying malignant disease. 7"9'2s Table 6. Indication for Empiric Amphotericin B Fever: 5-7 d duration, unresponsive to antibacterial antibiotics Neutropenia: over 7 d duration No other obvious cause forfever Progressive debilitation Prolonged adrenal corticosteroid therapy Fever that responds to adrenal corticosteroids, but recurs on discontinuation Parenteral hyperalimentation Prolonged intravascular catheterization Prolonged and poorly Controlled hyperglycemia Diffuse pulmonary infiltrates Progressive unexplained liver or renal failure Candida species cultured from multiple body orifices Aspergi//us species cultured from any site Data from references 7, 9, 11.
58
ALMA C. ONIBONI
INFECTION PROPHYLAXIS
It may not be possible to prevent infection in the neutropenic patient, but only to delay or reduce its incidence. Untd recently, 35% to 40% of patients with acute myelogenous leukemia died of infection before an adequate course of remission induction chemotherapy could be completed. 14 Prevention of int'ection includes measures to improve the patient's defense mechanisms, decrease the acquisition of new organisms, suppress organisms already colonizing the patient, and minimize potentially dangerous procedures. •
•
6
.
Protective Isolation One of the most highly debated methods of decreasing the transmission of microorganisms is the use of protective isolation.6'12"16 Many feel that standard reverse isolation is of little use, whereas others support its use in certain patients. 5'24 A1ttiough the cost may be prohibitive, rooms equipped with high-efficiency particulate air (HEPA) filtration, in combination with topical antiseptics and oral antibiotics, are often used for severely immunocompromised patients. 6'12"t4'44
Antibiotics Complete reverse isolation significantly reduces the colonization of new organisms. However, because endogenous flora, especially in the intestinal tract, can still cause infection, oral nonabsorbable antibiotics have been used to suppress the flora of the GI tract. 4'6'12'16 However, most authors do not recommend prophylactic systemic antibiotic therapy. 44 Prophylactic trimethoprim/sulfamethoxazole suppresses aerobic bacteria, but not anaerobes, so colonization resistance remains relatively intact. 45 In hospitals where the incidence of P carinii infection is high, prophylactic use of trimethoprim/ sulfamethoxazole should be considered. 14 Norfloxacin and ciprofloxacin have been proposed to be safe, effective, well-tolerated alternatives for preventing gram-negative infection in neutropenic patients with acute leukemia. 19'24
attempted. 5'24 Means of bolstering host defense mechanisms, such as the use of J5 antiserum and monoclonal antibodies, are being studied for use in neutropenic patients. 5"24 NURSING CARE
Many nursing care measures have been developed based on knowledge of the usual characterTable 7. Measures for Prevention and Early Detection of Infection Assessment
interventions
Daily examination of patient, with particular attention to rectum, axilla Assess vital signs every 4 h Assess respiratory function Inspect all IV sites and breaks in integument
Move patient to private room Limit clutter in patient's room Restrict number of visitors Screen visitors and staff for signs of infection Strict handwashing by anyone in contact with patient HEPA filtration in rooms Rooms should have positive air pressure (prevents airborne bacteria and spores from entering room from hallway) Patient to wear mask if leaving room Care for neutropenic patient first Disinfect all equipment used Avoid stagnant water Do not shake dirty linen Low microbial diet No uncooked fruits and vegetables No fresh flowers or live plants Sterile water and ice Aseptic technique for all procedures Avoid urinary catheterization Maintain normal bowel function: Avoid constipation, diarrhea, enemas, suppositories, rectal thermometers Use sitz baths if diarrhea occurs Cleanse perirectal area twice a day and after each bowel movement with soap or povidone-iodine, rinse with water, apply protective ointment Provide meticulous skin care: Chlorhexidrine bath Providone-iodine swabs to axilla Change IV tubing and bottles per hospital policy Use consistent mouth care protocol Turn, cough, deep breathe bed-fast patients Maintain adequate nutrition
Other Measures of Infection Prophylaxis Patient/family education
Several other measures have been proposed by various authors. The use of prophylactic leukocyte transfusions is a debatable issue. 6'7'44 Active immunization against P aeruginosa has been
All of the above interventions with emphasis on handwashing and keeping room free of clutter Data from references 1, 3, 4, 6, 14, 16, 19, 44.
59
INFECTION IN THE NEUTROPENIC PATIENT
istics o f infection in the neutropenic patient. T h e s e measures are s u m m a r i z e d in Table 7. SUMMARY
Infection is the m a j o r cause o f death in neutropenic patients. P r e v e n t i o n and therapy o f infection are an important, d y n a m i c c o m p o n e n t o f the care o f the neutropenic patient with leukemia. Nurses c a r i n g for t h e s e p a t i e n t s m u s t h a v e a c u r r e n t k n o w l e d g e o f i m m u n o s u p p r e s s i o n , the usual sites
and causative organisms, the clinical presentation, and the treatment o f infection. This k n o w l e d g e then needs to be applied clinically in the care o f the neutropenic patient. ACKNOWLEDGMENT
The author wishes to thank Judith Maloni, RN, PhD, Robert Lumish, MD, Adriarme Farley, RN, Darlene Petrelli, Sr Diane Matje, RN, MSN, Sr Lorraine Meskowski,-Veronica Harrison, and Simone Karp, RPh, for their assistance in the preparation of this manuscript.
REFERENCES
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36. Physicians' Desk Reference. Oradell, NJ, Medical Economics, 1989, pp 659-661 37. Sanders CC: Emerging problems of resistance to the newer cephalosporins: Clinical significance. Intern Med Specialist 5:1-5, 1984 38. Banaszak RS, Forbidussi D, Cobaugh D: New drugs. Pharmacy 3:1, 1988 39. Quintiliani R, Andriole V: The clinical role of the fluoroquinolones. Mediguide Infect Dis 8:1-4, 1988 40. Pizzo PA, Hathom JW, Hiemenz J, et al: A randomized trial comparing ceftazidime alone with combination antibiotic therapy in cancer patients with fever and neutropenia. N Engl J Med 315:552-558, 1986 41. Joshi JH, Schimpff SC, Termey JH, et al: Can antibac-
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terial therapy be discontinued in persistently febrile granulocytopenie cancer patients? Am J Ivied 76:450-457, 1984 42. Gross MH, Fulkerson WJ, Moore JO: Prevention of ampbotericin B-induced rigors by dantrolene. Arch Intern Med 146:1587-1588, 1986 43. Robertson MJ, Larson RA: Recurrent fungal pneumonias in patients with acute nonlymphocytic leukemia undergoing nmltiple courses of iatensive chemotherapy. Am J Med 84:233-239, 1988 44. Featherstone JH, Dale DC: Managing infections in immunosuppressed patients. Postgrad IVied 64:141-148, 1978 45. Schimpff SC: Infection prevention during profound granulocytopenia: New approaches to alimentary canal microbial suppression. Ann Intern Med 93:358-361, 1980