Management of Infections in Patients With Acute Leukemia

The article by Sarkodee-Adoo and colleagues on the management of infections in patients with acute leukemia provides an authoritative review of approaches to the prevention and treatment of infections in this high-risk population. Indeed, among the different populations of patients with neoplastic diseases, those with acute leukemia, particularly acute myelogenous leukemia (AML), are at very high risk for the development of severe infectious complications.[1,2]

The reasons for this high risk of infections include severe mucositis and protracted durations of profound neutropenia. These events are most commonly due to the potentially curative, dose-intensive anthracycline and cytarabine-based chemotherapy regimens. Corticosteroids used in acute lymphoblastic leukemia (ALL) induce profound immunodysregulation and directly impair phagocytic function of tissue macrophages and monocytes. The development of fever or a focus of possible infection in a neutropenic patient with acute leukemia constitutes a medical emergency, for which empiric antibacterial therapy should be instituted as promptly as possible.

Empiric Antibacterial Therapy

The initial empiric antibacterial therapy depends on the institutional patterns of antimicrobial resistance among the bacterial pathogens likely to infect and cause serious morbidity in this patient population. The Enterobacteriaceae and Pseudomonas species are potentially lethal pathogens in neutropenic patients with acute leukemia.

Options for initial empiric treatment include single-agent therapy with ceftazidime [Fortaz], cefepime (Maxi-pime), imipenem-cilastatin (Primaxin), or meropenem (Merrem). Alternatively, combination therapy with an anti-pseudomonal penicillin plus an aminoglycoside may be appropriate. Vancomycin is not routinely recommended as part of the initial antibacterial regimen, unless there is a high frequency of beta-lactam–resistant Staphylococcus aureus or viridans streptococci (eg, Streptococcus mitis) complicating the use of a particular cytotoxic regimen.

Modifications of the initial empiric therapy may be necessary, particularly in patients with a more protracted course of neutropenia. Such modifications may include the administration of vancomycin for the treatment of bacteremia or soft-tissue infections due to beta-lactam–resistant, gram-positive organisms. Anaerobic infections (eg, marginal gingivitis, typhlitis, or perirectal infections) may require clindamycin, metronidazole, or a change from cephalosporin to a carbapenem.

For the treatment of breakthrough fungal infections, such as acute disseminated candidiasis and pulmonary or disseminated aspergillosis, in patients who cannot tolerate or are refractory to conventional amphotericin B, a lipid formulation of amphotericin B (Abelcet, Amphotec), is recommended.

Among profoundly neutropenic patients who remain persistently febrile despite broad-spectrum antibacterial antibiotics, the risk of invasive fungal infections increases in direct relationship to the duration of persistent fever. Thus, empiric antifungal therapy with either conventional amphotericin B or liposomal amphotericin B (AmBisome), depending on the risk of nephrotoxicity, is used to reduce the frequency of proven invasive fungal infections and support the patient through recovery from neutropenia.

Pneumocystis carinii pneumonia is a common complication of ALL, particularly upon recovery from neutropenia. By comparison, P carinii pneumonia is relatively uncommon in patients with AML. Hence, trimeth-oprim-sulfamethoxazole prophylaxis is used in patients with ALL but usually not in those with AML.

Viral Infections

Among the viral infections that may ensue during the period of profound neutropenia of acute leukemia, herpes simplex virus infections commonly cause painful mucositis of the oral cavity, esophagus, and perineal region. Varicella virus may cause dermatomal or disseminated infection. Infections due to herpes simplex and varicella are treated with intravenous acyclovir (Zovirax). Cytomegalovirus infection is relatively uncommon during acute leukemic neutropenia.

In the setting of profound immunosuppression (eg, after stem-cell transplantation), primary infection and cytomegalovirus reactivation are commonly associated with life-threatening dissemination. Ganciclovir (Cytovene) and foscarnet (Foscavir) are effective agents for managing pulmonary and disseminated cytomegalovirus. Respiratory syncytial virus and other community respiratory viruses, including parainfluenza, influenza, and adenovirus, are frequently associated with pneumonia and/or dissemination in children and adults with leukemia.[3]

Progression from upper respiratory infection to pneumonia may be rapid and fatal. Although commonly seasonal in occurrence, respiratory viral infections can occur throughout the year; therefore, strict compliance with infection control measures is crucial to prevent nosocomial spread. Aggressive surveillance, including nasopharyngeal washes for viral culture and rapid immunoassays, should be performed in patients with leukemia who develop symptoms of upper respiratory tract infection.

If upper respiratory infection due to respiratory syncytial virus is documented, cytotoxic chemotherapy should be delayed (if possible), and preemptive therapy begun with aerosolized ribavirin (Rebetron, Virazole) and/or high-dose intravenous immunoglobulin or high-titered anti–respiratory syncytial virus intravenous immunoglobulin.

Novel Agents and Approaches

As emerging bacterial, fungal, and viral pathogens present new challenges to our existing antimicrobial strategies, novel compounds are expanding our armamentarium for the treatment and prevention of infections in patients with acute leukemia. New agents against multidrug-resistant, gram-positive bacteria include oxazolidinones (eg, linezolid), everninomicins, streptogramins (eg, quinupristin-dalfopristin [Synercid]), and ketolides. These new agents warrant careful investigation in patients with acute leukemia.[4-8]

New antifungal agents include echinocandins and second-generation triazoles (voriconazole [UK 109,496], posaconazole [Sch 56592], and ravuconazole [BMS 207147]).[9] Among the new antiviral agents are the neuraminidase inhibitors (zanamivir and oseltamivir) for the prevention and treatment of influenza, and oral agents (eg, valacyclovir [Valtrex] and famciclovir [Famvir]) with extended plasma half-lives for the management of infections with herpes simplex virus or varicella virus.[10]

Fundamental to the management of immunocompromised patients is the augmentation or restoration of host immune defenses. Strategies to do so include cytokine-activated granulocyte transfusions, adaptive immunotherapy, cytokine activation of host-tissue macrophages, and cytokine enhancement of early recovery from neutropenia. Acute leukemia patients with persistent neutropenia and proven bacterial or fungal infections refractory to conventional antimicrobial chemotherapy may benefit from granulocyte transfusions.[11]

Granulocyte colony-stimulating factor (G-CSF [Neupogen]) with or without dexamethasone is being used increasingly for mobilization of peripheral blood granulocytes. Administration of G-CSF (600 µg subcutaneously) and dexamethasone (8 mg orally) 12 hours before standard leukapheresis in adult donors routinely results in the collection of ³ 5 × 10¹⁰ granulocytes. Transfusion of this number of granulocytes may increase the absolute neutrophil count of a severely neutropenic patient to ³ 1,000 for 1 or more days, stabilizing or improving infections refractory to antimicrobial therapy. These benefits should be weighed against the potential complications of allogeneic immunization and infusion-related respiratory distress in prospective clinical trials.

Other approaches to augmenting host defenses may be available to leukemic patients who require allogeneic bone marrow or stem-cell transplantation. Nonmyeloablative preparative regimens have recently been shown to reduce the duration of neutropenia associated with allogeneic stem-cell transplantation.[12] However, this approach is still associated with graft-vs-host disease and profound immunosuppression, leading to a high incidence of opportunistic infection.

New strategies to improve specific antimicrobial immunity include pretransplant donor immunization to decrease the risk of bacterial infection[13] and post-transplant donor lymphocyte infusions[14] or adoptive immuno-therapy using donor-derived cytotoxic T-lymphocyte clones[15] to treat viral-associated infections, including infections with Epstein-Barr virus, cytomegalovirus, and adenovirus.

Other approaches targeting the mucosal surfaces, using such cytokines as keratinocyte growth factor, may restore disrupted mucosal integrity and, in combination with topical oral antimicrobial peptides, may improve mucosal host defenses. New cytokines to reduce thrombocytopenia may help reduce pulmonary injury in patients with fungal and bacterial pneumonias.

Thus, as we enter the 21st century, emerging bacterial, fungal, and viral pathogens pose new challenges in patients receiving treatment for acute leukemia. We are meeting these challenges with novel compounds and new approaches aimed at improving the supportive care of these patients.

References:

1. Jones GR, Konsler GK, Dunaway RP, et al: Infection risk factors in febrile, neutropenic children and adolescents. Pediatr Hematol Oncol 13:217-229, 1996.

2. Walsh TJ, Hiemenz J, Pizzo PA: Evolving risk factors for invasive fungal infections: All neutropenic patients are not the same (editorial). Clin Infect Dis 18:793-798; 1994.

3. Whimbey E, Couch RB, Englund JA: Respiratory syncytial virus pneumonia in adult patients with leukemia. Clin Infect Dis 21:376-379, 1995.

4. Moellering RC Jr: Antibiotic resistance: Lessons for the future. Clin Infect Dis 27(suppl 1):S135-140, 1998.

5. Dresser LD, Rybak MJ: The pharmacologic and bacteriologic properties of oxazolidinones, a new class of synthetic antimicrobials. Pharmacotherapy 19:456-462, 1998.

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7. Moellering RC, Linden PK, Reinhardt J, et al: The efficacy and safety of quinupristin/dalfopristin for the treatment of infections caused by vancomycin-resistant Enterococcus faecium. J Antimicrob Chemother 44:251-261, 1999.

8. Nichols RS, Graham DR, Barriere SL, et al: Treatment of hospitalized patients with complicated gram-positive and skin structure infections: Two randomized, multicentre studies of quinupristin/dalfopristin, cefazolin, oxacillin, or vancomycin. J Antimicrob Chemother 44:263-273, 1999.

9. Groll A, Piscitelli S, Walsh TJ: Clinical pharmacology of systemic antifungal agents: A comprehensive review of agents in clinical use, current investigational compounds, and putative targets for antifungal drug development. Adv Pharmacol 44:343-500; 1998.

10. Balfour HH Jr: Antiviral drugs. N Engl J Med 340:1255-1268, 1999.

11. Dale DC, Liles WC: Return of granulocyte transfusions. Curr Opin Pediatr 12:18-22, 2000.

12. Childs R, Clave E, Contentin N, et al: Engraftment kinetics after nonmyeloablative allogeneic peripheral blood stem cell transplantation: Full donor T-cell chimerism precedes alloimmune responses. Blood 94:3234-3241, 1999.

13. Molrine DC, Guinan AC, Antin JH, et al: Donor immunization with Haemophilus influenzae type b (HIB)-conjugate vaccine in allogeneic bone marrow transplantation. Blood 87:3012-3018, 1996.

14. Rooney CM, Smith CA, Ng CY, et al: Infusion of cytotoxic T cells for the prevention and treatment of Epstein-Barr virus-induced lymphoma in allogeneic transplant recipients. Blood 92:1549-1555, 1998.

15. Walter EA, Greenberg PD, Gilbert MJ, et al: Reconstitution of cellular immunity against cytomegalovirus in recipients of allogeneic bone marrow by transfer of T-cell clones from the donor. N Engl J Med 333:1038-1044, 1995.