Gail Itokazu, Pharm.D.
Spring 1998
Infections in Immunocompromised Hosts
Gail Itokazu, Pharm.D.
Spring 1998
Infections in Immunocompromised
Hosts
Required Readings:
1. Goodwin SD et al. Infections in Immunocompromised Patients. In: Pharmacotherapy: A Pathophysiologic Approach. DiPiro JT, et al. eds. Elsevier, NY 1997; Chapter 114, pp 2281-2303.
Optional Readings:
The following readings are not required, but may enhance your understanding of the material in this section.
Know the four broad categories of risk factors that predispose the compromised host to infection.
Granulocytopenia
1. be able to calculate the absolute neutrophil count (ANC)
example: if the total WBC count is 2.0 mm3 (2000 cells) with a differential of 45% segs, 5% bands, 35% lymmphs, 5% eos, 5% basos, 5% monos; the ANC is:
50% of 2000 cells = 1000 cells
2. at what ANC is the risk of bacteremia and death the greatest
Immune system defects
1. know what types of pathogens are most likely to occur in patients with defects in cell-mediated immunity and humoral immunity
Destruction of protective barriers
1. list the various ways in which medical interventions damage the skin and mucous membranes, thus predisposing patients to infection.
2. list the common pathogens associated with disruption of protective integumental barriers.
Environmental contamination/alteration of microbial flora
Patients become infected with microbes which colonize them, therefore knowledge of the ways in which patients become colonized with bacteria can lead to infection control measures that prevent colonization (and subsequent infection) of patients.
1. discuss the ways in which the hospital environment leads to colonization of patients with potentially pathogenic microbes.
2. discuss the impact that broad-spectrum antibiotics has on the flora of immunocompromised hosts.
3. discuss the concept of "colonization resistance."
INFECTIONS IN NEUTROPENIC CANCER PATIENTS
Febrile neutropenic patients are typically classified into one of three categories of infection:
a. microbiologically defined infection - isolation of an organism which is identified as the source of infection.
b. clinically defined infection - identification of a site of infection e.g., pneumonia, cellulitis, etc.; but a specific organism cannot be cultured. For example, a patient may have clinical evidence of pneumonia (cough, shortness of breath) but no organism is identified.
c. unexplained fever - fever not accompanied by either clinical or microbiologic evidence of infection.
Etiology
1. list the common gram-positive bacteria seen in febrile neutropenic patients.
2. list the major risk factor which predispose patients to infection with staphylococci.
3. list the major gram-negative bacteria seen in febrile neutropenic patients.
4. list the risk factors for invasive fungal infections.
5. list the major fungal pathogen seen in febrile neutropenic patients.
Clinical presentation
Because of their neutropenia, many of the usual clinical signs and symptoms of infection will be absent or altered in these patients. For example, there may be no white blood cells in the urine of a patient with a urinary tract infection, or no pus may be evident at the site of a catheter infection.
Management of febrile episodes in neutropenic cancer patients
1. list the major goal of empiric antibiotic therapy.
The optimal antibiotic regimen for empiric therapy in the febrile neutropenic patient is controversial. The regimen employed at each institution is based in part upon the susceptibility patterns of microbes identified in febrile neutropenic patients within the specific institution and the degree to which certain pathogens are problematic within the institution.
2. Discuss the pros and cons of the five different types of empiric antibiotic regimens: 1) aminoglycoside plus antipseudomonal beta-lactam, 2) beta-lactam monotherapy, 3) empiric regimens containing vancomycin, 4) double-beta lactam therapy, and 5) fluoroquinolone plus aminoglycoside, beta-lactam, or vancomycin.
Note: The emergence of vancomycin-resistant Enterococci has lead to the recommendation that vancomycin not be routinely included in the initial, empiric therapy for febrile neutropenic patients, unless there is a clear indication for vancomycin therapy or in hospitals where methicillin-resistant Staphylococci is a significant pathogen in these patients.
Note: Low-risk febrile and neutropenic patients (e.g., patients not expected to be neutropenic for more than 7-10 days, patients whose malignancy in remission, patients who are clinically stable without serious infection) may possibly be empirically treated as an outpatient with oral (ofloxacin; ciprofloxacin plus either clindamycin or amoxicillin/clavulanate) or intravenous antimicrobial therapies. Studies to date have reported a wide response rate of 53-95%, which in part may be related to the types of paients enrolled. Patient factors that favored a better response were solid tumors, durtion of neutropenia <7days (For additonal details, see optional reading, Rolston et al. Early empiric antibiotic theray for febrile neutropenia pateints at low risk. Infect Dis Clin NA 1996; 10(2): 223-37.
Management of antimicrobial therapy after initiation of empiric therapy.
1. Although the duration of treatment is controversial, guidelines are available.
Develop a plan (duration of antimicrobial therapy) for the following situations:
- afebrile after 72 hours, resolution of neutropenia.
- afebrile after 72 hours, ANC <500/mm3, clinically stable.
- persistently febrile after 72 hours, clinically stable.
- persistently febrile after 72 hours, evidence of disease progression.
2. Understand the rationale for empiric amphotericin B therapy. Be able to discuss at what point empiric amphotericin B should be initiated.
3. List 4 reasons for persistent fever of unknown origin.
4. Discuss the rationale of Pizzo et al. regarding their recommendation that "patients with ANCs of less than 500/mm3 be maintained on antimicrobial therapy until resolution of granulocytopenia, even if they become afebrile on antibiotic therapy."
Granulocytopenia is an important cause for infectious complications in the compromised host. Thus, the availability of colony stimulating factors (G-CSF and GM-CSF) are important advances in therapy aimed at decreasing the morbidity associated with infection. These agents stimulate the proliferation of neutrophil precursors thus lessening the duration of neutropenia, however; they have not been found to improve survival.
PROPHYLAXIS OF INFECTIONS IN NEUTROPENIC CANCER PATIENTS
1. Discuss the rationale for prophlactic antibiotics in the cancer patient.
Since the primary source (85%) of infection in the febrile neutropenic patient is their own endogenous flora (particularly the gastrointestinal tract) attempts have been made to eradicate organisms in the gastrointestinal tract. One of the concerns with the empiric use of prophylactic antimicrobials is the emergence of resistance to these antimicrobials, some of which are used for the treatment of infections, e.g., aminoglycosides, quinolones, azoles. Thus, when initiating empiric antimicrobial therapy in the febrile neutropenic patient, selection of empiric antimicrobials should take into consideration the prophylactic antimicrobials used.
The use of quinolones (ciprofloxacin, norfloxacin) may predispose patients to serious gram-positive infection with streptococci. In addition, widespread use of prophylactic quinolones has been found to contribute to the emergence of resistant organisms (e.g., aerobic gram-negative bacilli). As a result, routine use of quinolone prophylyaxis is not recommened, though may be considered in cases of profound and prolonged neutropenia, keeping in mind the potential for the emergence of resistant organisms (Hughes et al. 1997 Guidelines for the use of antimicrobial agents in neutropenic patients with unexplained fever. Clin Infect Dis 1997; 25:551-73). In addition, no effect on infection-related morbidity and mortality has been demonstrated (Clin Infect Dis 1997; pg 346).
The use of fluconazole may predispose patients to colonization with fluconazole resistant candida (C. krusei, some C. glabrata). Routine use of prophylactic antifungals is not recommended, though some clinicians may elect to use prophylaxis in settings where systemic C. albicans infection is high while infection due to other Candida species is low (Hughes et al. 1997 Guidelines for the use of antimicrobial agents in neutropenic patients with unexplained fever. Clin Infect Dis 1997; 25:551-73).
CC: fever, chills for 24 hours
HPI: DD is a 50 year old female with a history of breast cancer who was last hospitalized 2 weeks ago for her first round of chemotherapy. She had been doing well until she presented with the above complaints. She took some acetaminophen for the fever which provided only temporary relief.
PHM: breast cancer diagnosed 1 month ago
PE: temp 104 degrees farenheit, pulse 125, respiratory rate 30/minute, BP 100/60
Remainer of physical exam is unremarkable.
Labs: WBC 0.6 cells/mm3 with the following differential 40% segs, 10% bands, 20% lymphs, 20% monos, 5% eos, 5% basos; Bun 10, serum creatinine 0.7
1. Is empiric therapy warrented in this patient? Why?
Yes. The major goal of empiric antimicrobial therapy is to prevent death due to infection (Review page 2285; section on "Management of Febrile Episoldes in neutropenic Cancer Patients"). The absolute neutrophil count is <500/mm3 (i.e., = 300/mm3).
2. What are the likely bacterial pathogens in this patient and what empiric antimicrobial(s) would you recommend?
A variety of gram-negative organisms (including P. aeruginosa, E. coli, Klebsiella sp.) may cause fever in the neutropenic patient. Thus, an empiric regimen could be monotherapy (ceftazidime or imipenem) or a combination regimen having anti-pseudomonal activity (aminoglycoside plus an anti-pseudomonal beta-lactam such as ceftazidime, ticarcillin, mezlocillin, piperacillin, aztreonam, or imipenem).
3. What regimen would you recommend if DD had a serious penicillin allergy?
Aztreonam is an alternative anti-pseudomonal agent for penicillin-allergic patients, however; because it lacks activity against gram-positive bacteria, an agent such as clindamycin vancomycin should be also be.
4. What empiric antimicrobial regimen would you recommend if DD is expected to have profound (ANC <100/mm3) and persistent (beyond 7-10 days) neutropenia?
Synergistic combinations (beta-lactam plus aminoglycoside) appear benefical in these patients.
5. Within 72 hours of initiating empiric therapy, DD has defervesed, her ANC is >500/mm3, and no focus infection has been identified. When might therapy be discontinued?
Seven days of therapy would be reasonable with careful reevaluation of her clinical status.
6. If DD does not respond in 3-4 days, what would you recommend? Why?
Consider adding vancomycin for gram-positive infection.
7. When would you add empiric amphotericin B therapy?
After 7 days with no response to broad-spectrum antibacterial therapy, some clinicians may add amphotericin B sooner.
8. What would the role of G-CSF have been in the management of this patient?
If G-CSF had been administered no earlier than 24 hours after the last dose of chemotherapy, it may have minimized the duration of neutropenia, thus decreasing the risk of infection.
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