Critically Ill Immunosuppressed Host

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53

Critically Ill Immunosuppressed Host

Patients often become immunosuppressed due to congenital or acquired disease. Additional patients become immunosuppressed because of the therapies that are being used to manage an expanding number of serious underlying conditions. Immunosuppressed patients present special management issues because (1) opportunistic infections often require special diagnostic tests; (2) opportunistic infections can be fulminant but can present without the usual expected signs and symptoms; and (3) patients are often receiving multiple unfamiliar drugs, which can have complex interactions that can lead to reduced drug efficacy or increased toxicity for the drugs related to the immunosuppressive illness or for drugs used for the management of critical care complications.

This chapter emphasizes the important ways in which immunosuppressed patients differ from immunologically normal individuals in terms of infectious complications. The noninfectious complications of immunosuppression are reviewed in Chapter 80.

Host Defense Mechanisms

The microbial complications that any patient develops in the ICU are determined by general, nonspecific barriers; innate immunity; acquired specific immunity; and environmental exposures. Nonspecific barriers include anatomic barriers such as intact skin and mucous membranes; chemical barriers, such as gastric acidity or urine pH; and flushing mechanisms, such as urinary flow or mucociliary transport in the lungs. Organisms that breach these barriers encounter nonspecific and innate host factors termed the acute phase response. Acute phase responses trigger a cascade of acquired specific immune responses including mononuclear phagocytes and antibodies, which also trigger a cascade of effector molecules and nonspecific inflammatory responses.1

Infections result from normal flora that colonize mucosal or cutaneous surfaces or from abnormal flora that are introduced by surface-to-surface contact, inhalation, ingestion, trauma, or medical procedures. Table 53.1 lists organisms that cause disease when specific anatomic defenses are disrupted in individuals with normal microbial flora. Patients with abnormal flora will develop disease that reflects unique, disease-specific characteristics of the host, the abnormal environment, and modifying factors such as drugs. Infections that result from common defects in the inflammatory or immunologic systems are detailed in Table 53.2.

Table 53.1

Normal Flora That Can Cause Disease When Anatomic Barriers Are Disrupted

Compromised Host Defense: Anatomic Disruption Bacteria Fungi
Oral cavity, esophagus α-Hemolytic streptococci, oral anaerobes Candida species
Lower gastrointestinal tract Enterococci
Enteric organisms
Anaerobes
Candida species
Skin Gram-positive bacilli
Staphylococci, streptococci
Corynebacterium, Bacillus species
Mycobacterium fortuitum, Mycobacterium chelonei
Candida species
Aspergillus
Urinary tract Enterococci
Enteric organisms
Candida species

Immunosuppressed patients are complicated because they generally have multiple factors that change the causes and manifestations of their infectious complications. Patients with hematologic malignancies, for instance, may be predisposed to infection because their leukemia or lymphoma has eliminated functional cells from their bone marrow. In addition, however, ablative chemotherapy may have eroded their mucosal surfaces and may have also altered their cellular immune responses or their neutrophil function.

Because of these host defense defects, organisms may cause local tissue destruction due to primary infection or reactivation and may gain access to the capillaries and lymphatics with unusual facility. Microbes that usually do not cause disease, such as BK virus, Cytomegalovirus (CMV), Aspergillus, and Mucor, can cause devastating organ damage or systemic inflammatory syndromes.

Recognition of which host defense mechanisms are disrupted enables the clinician to focus diagnostic, therapeutic, and prophylactic management and optimize patient outcome. For instance, if a patient presents with severe hypoxemia and diffuse pulmonary infiltrates, a health care provider who recognizes a prior splenectomy as the major predisposition to infection would focus the diagnostic evaluation and the empiric therapy on Streptococcus pneumoniae and Haemophilus influenzae.2,3 By contrast, if the patient’s major predisposition to infection was human immunodeficiency virus (HIV) infection with a CD4+ T lymphocyte count below 50 cells/µL, the health care provider would focus on Pneumocystis jiroveci and S. pneumoniae.4,5 However, additional history is also necessary: if the pneumonia occurs during an influenza outbreak, after exposure to a water aerosol (Legionella), or after a seizure (aspiration), the likely cause is plausibly linked to the precipitating event.

Immune competence should ideally be measurable by objective laboratory parameters. In fact, the risk for opportunistic infection in patients with HIV infection can be assessed by clinical laboratories with a high degree of accuracy by measuring the number of circulating CD4+ T lymphocytes. The susceptibility of cancer patients to opportunistic bacterial and Candida infections can be assessed by measuring the number of circulating neutrophils (Fig. 53.1), and treatment algorithms have been established for managing fever in such patients (Figs. 53.2 to 53.4) and Table 53.3).6 The predisposition of patients with certain congenital immunodeficiencies can be assessed by measuring serum immunoglobulin levels.7 Unfortunately, however, for a large number of immunodeficiencies, such as those associated with antilymphocyte monoclonal antibodies or corticosteroids, no objective laboratory measures have been validated as predicting the risk of infection. Moreover, each parameter must be validated for each specific disease entity: for instance, although CD4+ T-cell counts are excellent predictors of opportunistic infection predisposition for patients with HIV/AIDS (acquired immunodeficiency syndrome) (Fig. 53.5), they are not clinically useful for other immunosuppressive disorders.

Table 53.3

Modification of Standard Empiric Therapy in Patients with Neutropenia

Clinical Event Possible Modifications of Standard Empiric Therapy
Breakthrough bacteremia For gram-positive isolate (e.g., Staphylococcus aureus): Add vancomycin or daptomycin or linezolid until susceptibility pattern of isolate is known.
For gram-negative isolate: Add two new agents likely to have activity until susceptibility pattern of pathogen is known.
Cellulitis or catheter-associated infection Add vancomycin or daptomycin.
Severe necrotizing mucositis or gingivitis Add specific antianaerobic agent (e.g., metronidazole, meropenem, imipenem, piperacillin-tazobactam) plus agent with activity against streptococci; consider acyclovir.
Ulcerative mucositis or gingivitis Add acyclovir and anaerobic coverage.
Esophagitis Add fluconazole or caspofungin; consider adding acyclovir.
Pneumonitis, diffuse or interstitial Add trimethoprim-sulfamethoxazole and azithromycin or levofloxacin or moxifloxacin (plus broad-spectrum antibiotics if the patient is granulocytopenic).
Perianal tenderness Include anaerobic agents such as metronidazole, imipenem, meropenem, or piperacillin-tazobactam.
Abdominal involvement Add antianaerobic agent (e.g., metronidazole, meropenem, imipenem, piperacillin-tazobactam).

Clinical series that document the frequency, the timing, and the causative organisms associated with infectious complications are extremely valuable for managing specific populations of immunosuppressed patients. Timelines that depict the time periods of vulnerability following stem cell transplantation (Figs. 53.6 and 53.7) and solid organ transplants (Fig. 53.8) are very useful for clinicians in terms of guiding diagnostic evaluations and for guiding empiric therapy. However, a specific microbial diagnosis should be established for each syndrome that presents in an immunosuppressed patient because the range of possible pathogens is quite broad, and the timelines and laboratory parameters cannot take into account all of the individual patient variables that influence the infectious complications that develop. Although it is useful to narrow the list of likely pathogens by analyzing risk factors, identifying the true causative agents allows therapy to be focused, avoiding unnecessary toxicity and allowing specific therapy to be optimized for efficacy and safety.

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Figure 53.6 Approximate immune cell counts (expressed as percentage of normal counts) peri- and post-MA HCT. Nadirs are higher and occur later after NMA than MA transplantation, as recipient cells persist after NMA transplant for several weeks to months (in the presence of GVHD) or longer (in the absence of GVHD). The orange line represents the innate immune cells (e.g., neutrophils, monocytes, and NK cells), the recovery of which is influenced by the graft type (fastest with filgrastim-mobilized blood stem cells, intermediate with marrow, and slowest with UCB). The green line represents the recovery of CD8+ T cells and B cells, the counts of which may transiently become supranormal. B cell recovery is influenced by graft type (fastest after CB transplant), and is delayed by GVHD and its treatment. The blue line represents the recovery of relatively radiotherapy/chemotherapy-resistant cells such as plasma cells, tissue dendritic cells (e.g., Langerhans cells) and, perhaps, tissue macrophages/microglia. The nadir of these cells may be lower in patients with aGVHD because of graft-versus-host plasma cell/Langerhans cell effect. The red line represents CD4+ T cells, the recovery of which is influenced primarily by T cell content of the graft and patient age (faster in children than adults). aGVHD, acute graft-versus-host disease; GVHD, graft-versus-host disease; HCT, hematopoietic cell transplantation; MA, myeloablative; NK, natural killer; NMA, nonmyeloablative; UBC, umbilical cord blood. (From Storek J: Immunological reconstitution after hematopoietic cell transplantation—its relation to the contents of the graft. Expert Opin Biol Ther (Informa) 2008;8:583-597. Reproduced with permission of Informa Healthcare [Storek J: Immunological reconstitution after hematopoietic cell transplantation—its relation to the contents of the graft. Expert Opin Biol Ther (Informa) 2008;8:583-597], and Elsevier [Tomblyn M, Chiller T, Einsele H, et al: Guidelines for preventing infectious complications among hematopoietic cell transplantation recipients: A global perspective. Biol Blood Marrow Transplant 2009;15:1143-1238.])

General Approach to Management

With regard to infectious complications, effective management of immunosuppressed patients requires an understanding of several basic tenets of care.

1. Life-threatening complications often present with subtle symptoms and signs that can easily be overlooked.

    Because immunocompromised patients may lack inflammatory and immunologic mediators, the clinical manifestations of infections are often less prominent and less impressive than in immunocompetent patients with similar complications. Thus, clinicians must recognize that even subtle changes in temperature, skin color, tenderness, catheter site appearance, chest radiograph, or abdominal examination may warrant an aggressive diagnostic evaluation and early institution of broad-spectrum empiric therapy.

2. Fever is not invariably present when patients are infected.

    Fever and infection are often seen as equivalent. However, most clinicians recognize that in any patient population there are many noninfectious causes of fever. Conversely, many patients with infection do not have fever: some infected patients may in fact be hypothermic. Corticosteroids and blunted neutropenia are often implicated in the suppression of fever. When dealing with immunosuppressed patients, clinicians need to keep these concepts in mind so that patients do not get unnecessary antibiotics when there is a likely noninfectious cause of the fever. Similarly, afebrile patients with syndromes that could be infectious need consideration for prompt antimicrobial therapy even if there is no measurable temperature elevation.

    For immunosuppressed patients, it is invariably preferable to assume that fever is due to infection and to treat empirically until the situation is fully evaluated. Although many cases of fever and neutropenia may well be noninfectious, the consequences of late treatment are so dire that prompt and broad-spectrum initiation of antimicrobial therapy should almost always be the default management approach.

3. Patients are predisposed to deteriorate precipitously.

    Although all ICU patients demand prompt attention and vigorous diagnostic and therapeutic management, many types of immunosuppression can be associated with especially precipitous clinical deterioration despite their innocuous presentation. Thus, infected patients who are neutropenic or who have undergone splenectomy, for example, are especially likely to have a fulminant course.

4. Diagnostic evaluation needs to be prompt and definitive.

    As indicated earlier, patients with life-threatening infection may present with subtle symptoms and signs that progress rapidly to become florid: these early manifestations merit aggressive attempts to define the anatomy of the lesion and the causative microbial pathogen. Because the spectrum of potential pathogens in such patients usually includes a wide array of microorganisms (e.g., viruses, fungi, protozoa, and bacteria), clinicians must be certain that appropriate specimens are obtained and the appropriate microbiologic and histologic tests are ordered to identify common, as well as uncommon or unusual, pathogens. This choice requires knowledge of the patient’s underlying immunosuppressive disorder. Invasive diagnostic techniques such as bronchoalveolar lavage or tissue biopsies should be performed with less hesitancy than in immunologically normal patients. Patients often have enhanced risk factors for invasive procedures, such as thrombocytopenia, coagulation factor deficiencies, or compromised organ function. However, the benefit of definitive diagnosis often outweighs these risks when the procedures are performed by experienced operators. It is also important to recognize that timing is important: delay in scheduling diagnostic procedures may result in the patient being too hypoxic for bronchoscopy, too unstable for computed tomography (CT) scan or magnetic resonance imaging (MRI), or too coagulopathic for a lumbar puncture or needle aspirate of a fluid collection.

5. Infections may be community acquired, nosocomial, or latent, emphasizing the need for a thorough history of the patient’s prior infections and exposures in order to assure the proper diagnostic tests and the optimal empiric therapeutic regimens.

6. Not all infections are related to the underlying disease or immunosuppression.

    Immunosuppressed patients may be admitted to the ICU with an infection related to their immunosuppression. However, they may also develop infections that occur in normal hosts. Thus, aspiration pneumonia, catheter-related infections, influenza, mycoplasma infection, syphilis, or malaria may occur in relation to activities of daily living, substance abuse, travel, or community exposures.

7. Empiric therapy should be started promptly.

    Time to appropriate antibiotics is an important correlate of successful outcome in any patient outcome, but time is especially important in these patients, who are prone to deteriorate rapidly. Thus, the clinician must assure that the drugs are received by the patient and that there are no delaying factors related to pharmacy preparation, team communication, vascular access, or other factors.

    Intensivists are more and more aware of the importance for all patients of “time to antibiotics,” that is, the importance of starting antibiotics sooner rather than later, and including a drug that is active against the pathogen that is ultimately shown to be the causative organism.8,9

8. Empiric therapy should be broad spectrum.

    Antimicrobial stewardship is an important principle for preserving antibiotic efficacy on a population basis and for reducing unnecessary drug toxicities. However, given the breadth of pathogens that can cause the disease, and the often precipitous and sometimes irreversible clinical decline in this patient population, empiric regimens should be rational but very broad spectrum, with rapid narrowing of the regimen as further diagnostic information becomes available.

9. Antibiotic therapy should be narrowed when the causative organism is known, and monotherapy is usually adequate.

    The development of potent β-lactam and quinolone drugs in the 1980s and 1990s provided single agents that appear to be as effective as combination therapy for the treatment of gram-negative bacillary infections.10-15

    For aerobic gram-positive cocci, drugs such as oxacillin, vancomycin, and daptomycin appear to be as active as any combination regimen, except for endocarditis and infections involving prosthetic devices. Similarly, for most fungal and viral diseases, no combination therapy is documented to be more potent than the appropriate single-drug therapy.

    Exceptions may occur when pathogens are not highly susceptible to any available agent. However, both the microbial environment and the patient usually benefit from narrowing of the antibiotic regimen so that unnecessary toxicity and unneeded microbial resistance are not facilitated.

10. Foreign bodies and infectious foci should be assessed promptly for drainage or removal.

    When immunosuppressed patients are infected or septic, prompt consideration should be given to replacing all intravascular catheters and to assessing the patient for drainable foci of infection. Antimicrobial therapy may not be effective until such foci are drained or removed. Because some intravascular lines are not easy to replace or drainage procedures in some complicated patients may entail considerable potential morbidity, such decisions require considerable judgment.

11. Consideration should be given to reducing the level of immunosuppression.

    There is no proven survival benefit to interventions meant to augment or improve the immune or inflammatory response such as granulocyte colony-stimulating factor, neutrophil transfusions, or cytokines. It is plausible to reduce immunosuppression by reducing the dose of corticosteroid or other immunosuppressive agent if that is clinically feasible. Some institutions administer granulocyte infusions or colony-stimulating factors for patients with established infections. There is no documentation that such interventions improve survival, and deleterious effects, especially from granulocyte transfusions, can be life-threatening.16,17

12. The effectiveness and safety of antimicrobial therapy should be monitored regularly.

    ICU patients characteristically require attentive monitoring to assure the adequacy and safety of therapy. Immunocompromised patients often have multiple prior and concurrent insults to their renal and hepatic function, and they often receive multiple drugs that can produce drug-drug interactions. Further, their volume of distributions may change dramatically from day to day. Thus, monitoring the pharmacokinetics and assessing potential toxicities are especially important in these patient populations. Moreover, because response to therapy may be less robust than in immunocompetent patients, serial antigen titers or polymerase chain reaction (PCR) titers, as well as serial imaging studies, can be important to assure the adequacy of the management plan. Therapy must often be continued longer than in immunologically normal patients while awaiting return of immunologic or inflammatory host response, or awaiting a sluggish therapeutic response in the face of ongoing immunosuppression.

13. Noninfectious syndromes can masquerade as infections and can be life-threatening.

    Clinicians dealing with specific populations must be familiar with the noninfectious syndromes that occur, such as graft-versus-host disease, immune reconstitution syndrome, bronchiolitis obliterans, cardiomyopathy/pulmonary edema, and veno-occlusive disease of the liver. Failure to recognize these entities deprives patients of appropriate therapy, and exposes them to the toxicities and expense of unnecessary antimicrobial therapy.

Management of Specific Patient Populations

Cancer Patients with Neutropenia

General Principles

Cytotoxic therapy–induced neutropenia is a major predisposition to infection.6 Neutrophil counts below 1000 cells/µL (the total absolute number of polymorphonuclear neutrophils plus bands) increase susceptibility to infection in a linear fashion (i.e., the lower the neutrophil count, the greater the degree of susceptibility)18 (see Fig. 53.1). Although most research studies use 500 cells/µL as an arbitrary definition of neutropenia, intensivists must recognize that susceptibility increases as the neutrophil count declines below 500 to 1000 cells/µL. A patient with a neutrophil count of 100 cells/µL is much more vulnerable to infection than a patient with 500 or 1000 cells/µL, and a patient with zero neutrophils is at much higher risk for fulminant infection than a patient with 50 or 100 cells/µL. The trajectory of the neutrophil count is also important: a patient with a neutrophil count of 1500 cells/µL whose counts are dropping precipitously should best be treated like a patient with absolute neutropenia. Similarly, a patient with 500 neutrophils/µL whose counts are rising quickly is not nearly as vulnerable to a poor outcome as a patient with a count of 500 neutrophils/µL that is stable.

Patients with neutropenia are generally divided into high-risk and low-risk patients based on their likelihood of developing severe infectious complications. Markers for high risk include neutropenia for more than 7 days’ duration and neutrophil count less than 100 cells/µL, as well as obvious signs of a life-threatening process such as hypotension, obtundation, pneumonia, or severe abdominal pain. As Figures 53.2 to 53.4 outline, this risk assessment is used in designating empiric regimens.

Thus, although the absolute neutrophil count is an essential factor to follow, the duration of neutropenia, the functional capability of neutrophils, the integrity of physical barriers such as the skin and gastrointestinal mucosa, the patient’s microbiologic environment (endogenous and exogenous flora), and the status of other immune mechanisms also contribute to the infectious syndromes that will develop.

In the 1960s and 1970s, aerobic gram-negative bacilli such as Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa predominated as pathogens in neutropenic patients. In the 1990s the spectrum of causative pathogens in neutropenic patients shifted from a predominance of gram-negative bacilli to a majority of gram-positive cocci including streptococci, staphylococci (including oxacillin-resistant Staphylococcus aureus), and enterococci (including vancomycin-resistant enterococci).10,1215,1921 Candida species have also become more frequent as pathogens, especially as patients are on broad-spectrum antibacterials and have long-term venous access devices in place.

More recently, highly resistant gram-negative bacilli have become major threats for nosocomial transmission. Clinicians must consider the possibility that a patient may be colonized and then infected with a Stenotrophomonas, a Burkholderia, or a carbapenemase-producing gram-negative Enterobacteriaceae such as a Klebsiella, an Enterobacter, or an E. coli that has developed mechanisms that evade currently marketed drugs.22-26

The management of febrile, neutropenic fever is reviewed in a guideline that is widely used to direct care in North America.6 Figures 53.2 to 53.4 summarize important aspects of management. Table 53.3 also provides a summary of useful management information. Table 53.4 outlines common prevention strategies that will modify the spectrum of causative pathogens. Box 53.1 summarizes the organisms that most often cause disease in neutropenic patients.

Table 53.4

Prevention of Infectious Complications in Compromised Patients

Method/Agent to Prevent Acquisition of, Suppress, or Eliminate Microbial Flora Description/Example
Isolation Total protective isolation with high-efficiency particulate air filters and absorbable or nonabsorbable antibiotics for bone marrow transplant recipient
Prophylactic antibacterial drugs  
 Ciprofloxacin Reduce bacterial infections in neutropenic patients
 Trimethoprim-sulfamethoxazole Suppress flora in patients with chronic bronchitis
 Penicillin Reduce frequency of streptococcal infections after splenectomy or in rheumatic valvular disease or graft-versus-host disease
 Clarithromycin Prevention of Mycobacterium avium complex infection in patients with advanced HIV disease
 Isoniazid Prevention of tuberculosis in PPD-positive individuals
 Nonabsorbable broad-spectrum agents (i.e., aminoglycoside, plus bacitracin) Gut decontamination for neutropenic patients
Prophylactic antiviral drugs  
 Oral acyclovir or valganciclovir, or IV ganciclovir Reduce frequency of CMV disease after transplantation
 Rimantadine, oseltamivir Prevent influenza
Prophylactic antifungal drugs  
 Fluconazole Prevent recurrent candidiasis
 Liposomal amphotericin B or voriconazole or caspofungin Prevent Candida or mold infections
 Trimethoprim-sulfamethoxazole Prevent Pneumocystis pneumonia
Prophylactic antiprotozoal/anthelmintic drugs  
 Albendazole or ivermectin Prevent disseminated strongyloidiasis in high-risk patients
Augmentation of host defenses  
 Immunization Pneumococcal and Haemophilus vaccine for patients before splenectomy
 Immune serum globulin Augment levels in deficient patients (e.g., common variable immunodeficiency)
 Fresh frozen plasma Augment complement levels in deficient patients
 Neutrophil transfusions Augment inflammatory response in neutropenic patients or patients with chronic functional neutrophil disorders
 Lymphocyte or other mononuclear cell transfusions Experimental therapies for tumors, various immunodeficiencies
 Bone marrow or stem cell transplantion Reconstitute patients with congenital immunodeficiencies or certain acquired cytopenias
 Bone marrow human stem cell stimulation G-CSF or GM-CSF to increase neutrophil or mononuclear cell quantity and function
 Gene therapy Replace genes to allow normal function

AIDS, acquired immunodeficiency syndrome; CMV, cytomegalovirus; G-CSF, granulocyte colony-stimulating factor; GM-CSF, granulocyte-monocyte colony-stimulating factor; HIV, human immunodeficiency virus; PPD, purified protein derivative.

Patients with neutropenia are generally suspected of being infected if the clinical syndrome is consistent with infection, or if the temperature is at least 38.3° C on one occasion or 38.1° C on two separate occasions. An elevated temperature alone should trigger the institution of broad-spectrum antimicrobials in almost all situations. Given this emphasis of using temperature as an indicator for starting antimicrobial therapy, using a validated technique to measure temperature is important. Although pulmonary artery or urinary catheter thermistors appear to provide the most accurate measurement, most experienced ICUs use tympanic membrane thermistors. Rectal probes are avoided in order to reduce the induction of perirectal infections in neutropenic patients, and to reduce the potential for fecal pathogen transmission. As noted earlier, although fever is almost always a reason to start antimicrobial therapy in this patient population, the absence of fever should not be the grounds for avoiding antimicrobials if a patient has other symptoms or signs suggesting infection. The threshold for starting antimicrobials should be very low, i.e., if there is a suspicion of infection, a broad-spectrum regimen should be started.

As noted earlier, the initial regimen should not be parsimonious in terms of spectrum. Because this population of patients is susceptible to a wide variety of bacterial and fungal pathogens, a very wide broad-spectrum regimen should be used. There are many potential regimens, each of which must be tailored to the local experience with the patient population and the hospital, specific patient factors such as evidence of prior colonization or recent antimicrobial therapy, and clinical manifestations suggesting infection. Popular regimens would include (1) meropenem or cefepime or piperacillin-tazobactam for broad-spectrum antibacterial activity plus (2) vancomycin or daptomycin for staphylococcal infections27,28 plus (3) ciprofloxacin or moxifloxacin or aztreonam for broader gram-negative bacillus coverage. Many experienced clinicians would add an echinocandin for anti-Candida activity given the frequency of intravascular catheter-associated infections due to Candida species.2933 Intensivists need to work closely with their infectious disease consultants, microbiology laboratories, and referring teams to develop regimens that are optimal for their hospital environment, for the patient population involved, and for the specific, unique patient who is being managed.

Empiric antiviral therapy is not usually initiated unless there is a specific reason to suspect a viral process. Antiviral agents would generally be added only if a specific viral process such as CMV colitis or disseminated herpes simplex were suspected.

For the duration of neutropenia (when the neutropenia is expected to be time-limited), broad-spectrum therapy must be continued. When a specific causative organism is identified, antimicrobial therapy should be optimized for that organism. However, unlike other immunologically normal patients, the broad-spectrum “background” (i.e., meropenem or piperacillin-tazobactam or cefepime or ceftazidime) must be continued until the neutropenia resolves, on the assumption that a patient who develops one infection is likely to develop or manifest another infectious process while the neutropenia persists.

Coverage for methicillin-resistant Staphylococcus aureus (MRSA) does not necessarily need to be continued if no MRSA is identified. There are environmental advantages to reducing vancomycin exposure.

As noted previously, there is no documented reason, even in this population, to use combination therapy to treat a specific pathogen in most situations, although combination therapy is needed for the empiric approach for the duration of neutropenia (Box 53.2). In rare situations, if the causative organism is not susceptible to agents with well-documented efficacy, combination therapy may be an appropriate strategy out of desperation. As an example, for treating enteric carbapenemase-producing organisms, a combination of tigecycline plus colistin plus an aminoglycoside might be desirable given the high minimum inhibitory concentrations for all antibiotics for these organisms and the dreadful clinical results with any therapeutic intervention.3438

For patients with fever and neutropenia, the cause of the fever is historically documented in only 50% to 60% of patients. The duration of therapy once empiric antimicrobials are started depends on the evolution of the neutrophil count, the patient’s clinical status, and the results of diagnostic tests. If the patient defervesces and looks clinically well, however, the broad-spectrum regimen should not be stopped until the neutrophil count is above 500 to 750 cells/µL, preferably on two occasions, and the patient has received at least 10 to 14 days of therapy.

If a neutropenic patient is started on antibacterial therapy without fungal therapy, and defervescence has not occurred by days 3 to 5, an antifungal agent should be added (Figs. 53.3 and 53.4). The choice of antifungal agent depends on the patient population and the patient’s specific history. In the current era many patients have been receiving short- or long-term prophylaxis with fluconazole, voriconazole, or posaconazole. Although in general clinicians could add fluconazole, an echinocandin (e.g., caspofungin or micafungin or anidulofungin) or liposomal amphotericin B can also be used. An echinocandin is often a preferred choice if the patient has been on long-term azole prophylaxis and if a mold infection is not suspected.3942

As patients receive chemoprophylaxis with quinolones or azoles during periods of intense neutropenia or immunosuppression, breakthrough pathogens are more and more likely to be resistant to the prophylactic agents.40,42 Thus empiric regimens must be chosen with keen attention to the drugs that patients have received in the recent past, as well as pathogens they have previously been colonized or infected with.

Diagnostic Approach

Patients with fever and neutropenia require aggressive diagnostic efforts to identify the cause of fever so that the appropriate antimicrobial agent is used and appropriate procedures (e.g., surgical drainage, removal of a foreign body such as a catheter) can be performed. All febrile neutropenic patients should at a minimum have two blood cultures drawn, with one drawn peripherally and one drawn through the lumen of the indwelling catheter that has either been in the longest or is most suspicious for being infected. Other sites should be cultured as clinically indicated.

Regular physical examination is necessary to identify sites that merit more focused investigation. With impaired inflammatory response, findings on examination may be subtle. Knowledge of the specific immunologic defect is important so that when cultures of blood, sputum, urine, or other appropriate body fluids or body sites are performed, special microbiologic approaches can be used to detect viruses, fungi, helminths, protozoa, and bacteria as indicated by the clinical situation. Imaging studies are also important because intra-abdominal, intrathoracic, intracerebral, and musculoskeletal processes can be clinically subtle and may not be associated with identifiable organisms in the bloodstream. A growing array of antigen detection systems and molecular and high-performance chromatographic tests are being investigated to facilitate diagnosis.

Some of these approaches, despite their promising initial reports, are not yet clinically practical because of their level of sensitivity, specificity, or the cost or expertise required to perform them adequately. For instance, the PCR test for Pneumocystis is so sensitive that there is no clear separation of patients who are colonized with Pneumocystis (and whose pulmonary dysfunction is due to another process), and the serum β-glucan antigen detection system is so nonspecific that some clinicians are not confidant that the test provides useful information.43-45 Similarly, the PCR test for respiratory syncytial virus (RSV) or influenza or parainfluenza is so sensitive that immunosuppressed patients may shed small quantities of virus for many weeks after acute infection, confusing the diagnosis of the new pulmonary processes that occur after the acute viral infection is over, and at a time when another process is causing fever or pulmonary manifestations. Thus, these new tests must be interpreted with caution.

Empiric and Specific Antimicrobial Therapy

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