Clinical Approach to Infections in the Compromised Host

Published on 04/03/2015 by admin

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Chapter 40 Clinical Approach to Infections in the Compromised Host

Samuel A. Shelburne, Russell E. Lewis, Dimitrios P. Kontoyiannis

Figure 40-1 CONSTELLATION OF FACTORS CONTRIBUTING TO INCREASED RISK FOR INFECTION IN IMMUNOCOMPROMISED HOSTS.

Table 40-1 Malignant and Select Nonmalignant Hematologic Diseases and Their Associated Infection-Predisposing Host Defects

Hematologic Condition	Infection-Predisposing Host Defects
Acute myeloid leukemia	Neutropenia; therapies such as dose-intensive chemotherapy and hematopoietic stem cell transplant may result in additional anatomic disruptions, cell-mediated defects, and humoral defects
Acute lymphocytic leukemia	Neutropenia; therapy effects similar to acute myeloid leukemia
Hairy cell leukemia	Neutropenia (also monocytopenia); abnormal humoral immunity; T-cell suppressing therapy
Chronic lymphocytic leukemia	Hypogammaglobulinemia; abnormal cell-mediated immunity
Chronic myeloid leukemia	No prominent host defects unless aggressive therapy, advanced stage, or postsplenectomy
Multiple myeloma	Hypogammaglobulinemia; other host defects may occur with aggressive therapy or advanced stage
Hodgkin/non-Hodgkin lymphomas	Abnormal cell-mediated immunity, therapy-related neutropenia, splenic dysfunction (if splenectomy or radiation)
Myelodysplastic syndromes	Functional or absolute neutropenia
Aplastic anemia	Neutropenia; abnormal cell-mediated immunity from immunosuppressive therapies (e.g., steroids, antithymocyte globulin, cyclosporine, hematopoietic stem cell transplantation)
Paroxysmal nocturnal hemoglobinuria	Deficient Fc receptor may contribute to abnormal cell-mediated immunity
Hemolytic states (thalassemia)	Gallstones may serve as a nidus for infection; splenic dysfunction or splenectomy
Sickle cell disease	Can be neutropenic with aplastic crisis; bone infarcts may serve as a nidus for infection; splenic dysfunction with poor complement activation and opsonization from autosplenectomy

Table 40-2 Host Defense Impairments and Their Associated Infectious Pathogens

Figure 40-2 RELATIONSHIP OF SEVERITY AND DURATION OF NEUTROPENIA TO THE RISK FOR DEVELOPING A SERIOUS INFECTION.

(Courtesy GE Body.)

Figure 40-3 APPROACH TO PATIENT WITH FEVER AND NEUTROPENIA.

Approach to Pulmonary Infiltrates

Pulmonary infiltrates can be divided into three general categories: consolidative, interstitial, and nodular. A consolidative infiltrate may be bacterial, even polymicrobic, so sampling of the infiltrate through sputum or endotracheal tube suctioning for bacterial and fungal cultures is required. If either of these methods does not provide an adequate sample from a consolidative infiltrate, or if these methods do not lead to a diagnosis, “early” (within 72 hours) bronchoscopy is indicated. If interstitial or nodular infiltrates are not peripheral (i.e., within the range of the bronchoscope), they should also be evaluated with timely bronchoscopy. An advantage of bronchoscopy, in addition to the ability to obtain a deep specimen, is that the samples usually are sent for a broad range of diagnostic tests. These tests usually are ordered from preprinted order sheets, which reduce errors. Most preprinted order sheets for bronchoalveolar lavage fluid will test for the following:

• Cytology, with the attendant Fite and Gomori methenamine silver stains

• Bacterial (Gram) stain and aerobic culture

• Mycobacterial (acid-fast bacillus) stain and culture

• Fungal (potassium hydroxide or calcofluor) stain and culture

• Nocardia culture

• Legionella culture

• Viral cultures for herpes viruses and respiratory viruses

• Rapid test for cytomegalovirus (shell vial or polymerase chain reaction [PCR])

• Rapid test for respiratory viruses during respiratory virus season (pooled respiratory virus shell vial, respiratory syncytial virus antigen, influenza A/B antigen)

Optional tests that can be requested from bronchoalveolar lavage fluid, some at significant extra expense, include the following:

• Mycobacterial stain (requires separate 5-mL volume that cannot be used later for culture)

• Mycoplasma pneumoniae PCR

• Chlamydia pneumoniae PCR

• Human herpes virus type 6 PCR

• Human metapneumovirus PCR

• Aspergillus galactomannan antigen

• Any of the above first-tier tests that your institution does not send on a routine basis (e.g., Nocardia or Legionella)

Invasive sampling may be the only definitive means for making a diagnosis of peripheral nodules. The two main options are percutaneous fine-needle aspiration or open lung biopsy (usually obtained through video-assisted thoracoscopic surgical procedure). In toto sampling of a lung nodule permits enough material for the whole range of the above diagnostic tests as well as histopathology. Of note, fewer lobectomies of unilateral pulmonary nodular infiltrates have been reported in recent years, probably a result of the frequent use of a broad range of less toxic antifungal medications.

Table 40-3 Pulmonary Infiltrates and Their Association With Specific Infectious and Noninfectious Etiologies

Treatment of Drug-Resistant Gram-Negative Bacilli

The widespread use of antibiotic prophylaxis among immunocompromised patients has been associated with the development of antimicrobial drug-resistance, which is especially problematic among gram-negative bacilli. Drug-resistant organisms can colonize the GI tract for prolonged periods of time and emerge to cause serious infections during periods of neutropenia or other medical stress (e.g., following admission to the intensive care unit).

• Pseudomonas aeruginosa is the paradigm for drug resistance among gram-negative bacilli and often rapidly develops pan-resistance to antimicrobials. Serious pseudomonal infections are generally treated with two antimicrobial agents, although convincing data supporting this approach are lacking.

• Extended-spectrum β-lactamase (ESBL) production among Enterobacteriacae such as Escherichia coli and Klebsiella pneumoniae renders these organisms resistant to non-carbapenem β-lactam antibiotics. Treatment is generally with a carbapenem (e.g., meropenem), although a quinolone can sometimes be used.

• The presence of a Klebsiella pneumoniae carbapenemase (KPC) can occur among species other than K. pneumoniae and creates resistance to all β-lactam antibiotics including carbapenems. Resistance to quinolones is also typical, so therapy is limited to the polymyxins (e.g., colistin), or to tigecycline and the aminoglycosides depending on the organism’s antibiotic susceptibility pattern.

• Like P. aeruginosa, A. baumannii can develop resistance to all known antimicrobials via a variety of mechanisms. This generally occurs among critically ill patients following prolonged stays in the intensive care unit. Treatment options may include polymyxins and sulbactam, a β-lactamase inhibitor that possesses some activity against drug-resistant Acinetobacter.

• Enterobacter, Serratia, and Citrobacter species can elaborate an AmpC β-lactamase following initiation of β-lactam therapy, which can result in a relapsing infection following an initial response. Thus clinicians treating such infections with penicillins or cephalosporins should closely monitor patients for the emergence of resistance. If resistance does emerge, AmpC-producing organisms can be treated with a carbapenem.

• Patients with multidrug-resistant gram-negative infections should be cared for in such a manner as to minimize spread of these dangerous organisms to other patients. Compliance with infection control protocols is paramount.

• Knowledge of the local epidemiology and antibiogram are important for preemptive and empiric antibiotic choices, especially against gram-negative rods

• A carefully designed and executed antibiotic stewardship program could curtail unnecessary antibiotic use, thereby decreasing antibiotic selection pressure with a resulting decrease in bacterial resistance rates.

Use of Antifungal Agents in Combination

The development of new antifungal drugs gives the clinician more options for prophylaxis and therapy than in previous years. There is an overall level of simplicity to the drug choices once their mechanisms of action are understood. The polyenes, including amphotericin products and the topical agent nystatin, attach onto ergosterol in the fungal cell membrane and are considered fungicidal, because cytoplasm leaks out, and individual cells die. The azoles, including fluconazole, itraconazole, voriconazole, and posaconazole, prevent the formation of new ergosterol. Azoles are considered fungistatic, because removal of the drug permits cell regrowth. Theoretically, use of an azole together with a polyene may have an overall static effect for an established infection as the ergosterol target for the fungicidal polyene is depleted. However, this combination may have advantages in terms of enhanced spectrum of activity. The echinocandins, including caspofungin, micafungin, and anidulafungin, prevent interaction of the catalytic and regulatory subunits of the β-glucan synthesis enzyme, so less β-glucan is formed for the cell wall. The scaffolding for the fungal cell wall is not maintained, and a dividing cell may burst open when trying to extend the new cell wall over daughter cells. The echinocandins are considered fungicidal for yeasts but fungistatic for molds, because drug activity is concentrated at only the tips of the extending hyphae with little effect on less metabolically active subapical compartments of the fungus. Combination therapy may have the most effect when a cell wall agent (an echinocandin) is used together with a cell membrane agent (a polyene or an azole). There is no role for three-drug therapy (an echinocandin, a polyene, and an azole). Aside from cases of cryptococcal meningitis, in which the importance of combination therapy is well established, the benefits of frontline use of combination antifungal for molds remain controversial, although active investigation continues in clinical trials. The value of combination regimens as salvage therapy for refractory mold infections remains uncertain.

Figure 40-4 TIMING OF INFECTIONS FOLLOWING HEMATOPOIETIC STEM CELL TRANSPLANT.

GVHD, Graft-versus-host disease.

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