Antimicrobial Prophylaxis in Bone Marrow Transplantation

  1. Feroze Momin; and
  2. Pranatharthi H. Chandrasekar
  1. From Wayne State University, Detroit, Michigan. Requests for Reprints: Pranatharthi H. Chandrasekar, MD, Hematology-Oncology/Infectious Diseases Liaison Unit, Division of Infectious Diseases, Wayne State University School of Medicine, 4160 John R, Suite 2140, Detroit, MI 48201. Acknowledgment: The authors thank Ms. Eileen Surma for expert secretarial assistance.
     
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    Abstract

    Objective: To review the efficacy of antimicrobial prophylaxis in bone marrow transplantation.

    Data Sources: English-language articles identified through a MEDLINE search (1975 to 1994) and through the bibliographies of selected articles.

    Study Selection: Articles on the use of antimicrobial agents for the prevention of infections in bone marrow transplant recipients and neutropenic patients with cancer.

    Data Synthesis: Use of quinolones reduces the incidence of gram-negative bacillary infections but increases the frequency of infections caused by streptococci and staphylococci before marrow engraftment. Death associated with α-hemolytic streptococcal bacteremia is of concern and may justify the use of penicillin for prophylaxis. Conflicting data exist regarding prophylaxis with vancomycin. Although ganciclovir has diminished the incidence of infection and disease caused by cytomegalovirus in seropositive recipients, drug-induced myelotoxicity, emergence of resistant virus, and cost are major concerns. High-dose acyclovir may suppress reactivation of cytomegalovirus. Acyclovir prevents herpes simplex virus infection, but its prolonged use to prevent reactivation of varicella-zoster virus is not cost-effective and remains controversial. Fluconazole prevents colonization and infection with Candida species other than C. krusei and Torulopsis glabrata before marrow engraftment. Elevation of cyclosporine concentrations because of interaction between azoles and cyclosporine requires close monitoring of plasma drug levels. Optimal chemoprophylaxis is not available against aspergillus or fungal infections that develop after engraftment. Trimethoprim-sulfamethoxazole decreases the incidence of Pneumocystis carinii infection and “late” bacterial infections in recipients of allogeneic transplants who have chronic graft-versus-host disease.

    Conclusion: Available antimicrobial agents can prevent common bacterial, viral, and “early” fungal infections. However, the few studies that address antimicrobial prophylaxis in bone marrow transplantation have not always shown a survival benefit. Toxicity and cost-effectiveness of prophylactic strategies should be critically evaluated.

    Infections contribute significantly to illness and death in patients having allogeneic and autologous bone marrow transplantation [1]. High-dose myeloablative chemoradiotherapy used as a preparative regimen before transplantation results in granulocytopenia until engraftment of transplanted marrow and in a residual cellular and humoral immunodeficiency that recovers with time. Prolonged immunosuppressive therapy is used after allogeneic transplantation to prevent graft rejection and graft-versus-host disease. Immunosuppressive therapy after transplantation, T-cell depletion of donor marrow, and graft-versus-host disease significantly delay immune recovery in recipients of allogeneic grafts. In contrast, immune recovery after autologous transplantation is not hampered by immunosuppressive therapy or graft-versus-host disease.

    Risk for infection is not limited to the period of granulocytopenia that develops before marrow engraftment (defined as an absolute neutrophil count of 5.0 × 109/L) but persists until immune reconstitution occurs within 12 to 24 months of transplantation [2]. Chronic graft-versus-host disease and its treatment delay the recovery of immune function, further extending the risk period. The predictable timing of various infections after marrow transplantation (Figure 1) depends largely on the balance between the kinetics of granulocyte and lymphocyte recovery and the immunosuppressive influences of graft-versus-host disease and its treatment. Although granulocytopenia and defects in B- and T-lymphocyte functions result in a multifaceted humoral and cellular immunodeficiency, chemoradiotherapy-related mucositis, body sites of invasive procedures, and indwelling vascular devices serve as portals of entry for various microorganisms.

    Figure 1. GVHD = graft-versus-host disease. Adapted from: Meyers JD. Infections in marrow transplant recipients. In: Mandell GL, Douglas RG Jr, Bennett JE, eds. Principles and Practice of Infectious Diseases. 3d ed. New York: Churchill Livingstone; 1990:2291-4.
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    Figure 1. GVHD = graft-versus-host disease. Adapted from: Meyers JD. Infections in marrow transplant recipients. In: Mandell GL, Douglas RG Jr, Bennett JE, eds. Principles and Practice of Infectious Diseases. 3d ed. New York: Churchill Livingstone; 1990:2291-4. Commonly seen infections by time after bone marrow transplantation.

    Most bacterial and fungal infections in marrow recipients are caused by microorganisms colonizing the skin, mouth, gut, perianal area, and respiratory tract [3]. Viral infections usually result from the reactivation of latent virus or the acquisition of virus through transfusion of seropositive blood components or marrow to seronegative marrow recipients. Many methods of preventing infection in marrow recipients have been studied [4-7]. Strategies for infection prophylaxis include isolation of patients in laminar airflow rooms, barrier nursing, the use of sterile food, and the use of agents such as intravenous immunoglobulin, recombinant hematopoietic growth factors (granulocyte macrophage colony-stimulating factor and granulocyte colony-stimulating factor), and antimicrobial agents. We review the current literature on the often controversial and ever-changing area of prophylaxis with antimicrobial agents in bone marrow transplant recipients. Major concepts of antimicrobial prophylaxis are shown in Table 1.

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    Table 1. Concepts of Antimicrobial Prophylaxis
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    Methods

    We did a MEDLINE search (1975 to 1994) to identify English-language articles on antimicrobial prophylaxis in bone marrow transplant recipients. Because only a few large, well-controlled studies addressed bone marrow transplantation, we also included those on prophylaxis during chemotherapy-induced neutropenia in patients with cancer. We used the following Medical Subject Heading terms in our search: bone marrow transplantation, prophylaxis, antibacterial, antifungal, antiviral, and neutropenia. To locate additional relevant articles, we also examined the reference sections of the articles identified through the MEDLINE search. Study outcomes considered to be important were overall survival, incidence of infection or superinfection, toxicities and drug interactions of agents used for prophylaxis, and emergence of antibiotic-resistant microflora. We did not select studies of antimicrobial prophylaxis in other immunocompromised hosts, such as recipients of solid organ transplants and patients infected with human immunodeficiency virus (HIV).

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    Bacterial Infections

    Bone marrow transplant recipients have a prolonged period of granulocytopenia after myeloablative preparative chemoradiotherapy. Use of recombinant hematopoietic growth factors has shortened the duration of granulocytopenia and lessened the risk for infection [8]. However, there is conflicting evidence about the efficacy of these growth factors in preventing infection-related illness and death in bone marrow recipients [9-14].

    Life-threatening infections during this granulocytopenic period are primarily caused by aerobic gram-positive and gram-negative bacteria. These bacteria may colonize the skin, the oral cavity, or, most commonly, the gastrointestinal tract on admission to the hospital or during hospitalization. Eliminating potentially pathogenic endogenous gut flora has minimized the incidence of gram-negative bacterial infections in neutropenic patients [4-6]. Total gut decontamination eliminates both aerobic and anaerobic bacteria, whereas selective gut decontamination eradicates only the aerobic bacteria. The latter technique preserves the anaerobic flora, maintains “colonization resistance,” and prevents acquisition of infection with potentially pathogenic aerobic bacteria. Oral nonabsorbable and absorbable antibiotics have been used prophylactically to decontaminate the gut, with varying degrees of success in neutropenic patients with cancer [6, 7]. Patient compliance, cost, and emergence of resistant organisms limit the use of nonabsorbable oral antibiotics such as gentamicin, neomycin, colistin, framycetin, and vancomycin. Studies using absorbable antibiotics such as trimethoprim-sulfamethoxazole in patients with leukemia have had mixed results. Major drawbacks of trimethoprim-sulfamethoxazole include gastrointestinal intolerance, emergence of resistant gram-negative bacterial flora, poor activity against pseudomonas, and the risk for myelosuppression.

    Recent studies show that the oral fluoroquinolones (norfloxacin, ciprofloxacin, and ofloxacin) are well-tolerated, safe, and effective prophylactic agents during neutropenia in patients with cancer and in bone marrow recipients [15-24]. In randomized trials, norfloxacin (compared with placebo) and ciprofloxacin (compared with trimethoprim-sulfamethoxazole and colistin) have been shown to be safe and effective in reducing the incidence of gram-negative infection in neutropenic patients with leukemia [16-18]. Norfloxacin and ofloxacin were more effective and better tolerated than vancomycin and polymyxin [19, 20]. Few trials on prophylaxis with quinolones have been done in bone marrow recipients [20-23]. In a nonrandomized study [21], oral norfloxacin (400 mg/d) given to marrow recipients effectively prevented gram-negative infections; however, 18 episodes of gram-positive bacteremia developed. Schmeisser and colleagues [20] showed that significantly fewer febrile episodes occurred in patients receiving norfloxacin than in those receiving a combination of polymyxin, neomycin, amphotericin B, and trimethoprim-sulfamethoxazole. In a large randomized, multicenter trial comparing the efficacy of ciprofloxacin with that of norfloxacin in patients with hematologic malignancies (some of whom were bone marrow transplant recipients), patients receiving ciprofloxacin had fewer gram-negative infections (4% compared with 9%; P = 0.03) [23]. Notably, the efficacy of the two quinolones in the subset of marrow recipients did not differ. In our experience, prophylactically administered norfloxacin significantly reduced the incidence of gram-negative infections compared with matched historic controls [24]. None of the studies evaluating antibacterial prophylaxis in marrow recipients has shown a survival advantage.

    Although quinolone prophylaxis has reduced the frequency of gram-negative infections, it has been associated with a concomitant increase in the frequency of gram-positive infections. Bacteremia caused by streptococci and staphylococci of oral and cutaneous origin has been noted in neutropenic patients receiving quinolone prophylaxis [25-28]. Kern and colleagues [25] observed an increased frequency of α-hemolytic streptococcal bacteremia in patients receiving quinolone chemoprophylaxis. Mortality from streptococcal bacteremia was substantial (18%) and similar to that seen with gram-negative bacteremia. DePauw and colleagues [27] observed that gram-negative infections were nearly eliminated with ciprofloxacin but that Streptococcus viridans accounted for most of the bacteremic episodes. A similar phenomenon has also been noted during quinolone prophylaxis in bone marrow transplant recipients, and oral vancomycin appeared to eliminate the problem [28]. Not infrequently, streptococcal sepsis has been associated with the development of the acute respiratory distress syndrome [29]. The incidence of this pulmonary complication was lower in patients given prophylactic penicillin along with a quinolone than in historic controls. In a randomized study of 561 granulocytopenic patients with cancer (> 80% of whom were bone marrow recipients), the addition of oral penicillin to fluoroquinolone prophylaxis significantly reduced the frequency of febrile episodes and the incidence of streptococcal bacteremia [30]. A combination of ciprofloxacin and roxithromycin (a macrolide) was also shown to significantly reduce the incidence of gram-positive infections in granulocytopenic patients [31].

    Whether a glycopeptide antibiotic such as vancomycin should be used empirically or prophylactically against gram-positive bacteria is controversial. As many as 7 of every 10 cases of febrile neutropenia do not require empiric vancomycin therapy [32]. In a randomized trial of bone marrow transplant recipients, routine addition of intravenous vancomycin to a prophylactic regimen of total gut decontamination prevented gram-positive infections, decreased the number of febrile days, and reduced the need for empiric antibiotic therapy [33]. Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus viridans, and Bacillus species were the most common gram-positive pathogens among control patients. In another study, prophylaxis with vancomycin given before and after insertion of a Hickman vascular catheter did not reduce the incidence of gram-positive infections [34]. Despite the absence of compelling evidence, many centers include vancomycin in their empiric regimen for febrile neutropenia. It is of concern that widespread use of vancomycin may lead to the emergence of vancomycin-resistant, gram-positive flora and may be associated with an increased incidence of veno-occlusive disease [35, 36].

    In summary, the data on antibacterial prophylaxis suggest that the frequency of gram-negative infections can be markedly reduced by using oral quinolones during the neutropenic period. At the Detroit Medical Center, prophylaxis with norfloxacin (400 mg twice a day) is routinely used before marrow engraftment (Table 2). Gram-positive infections caused by staphylococci and streptococci are increasing, and fatal infections caused by gram-positive cocci, particularly α-hemolytic streptococci, are occasionally seen. In centers in which serious α-hemolytic streptococcal infections are frequent, empiric use of vancomycin or penicillin may be considered. Firm recommendations on the need for and the regimens of chemoprophylaxis against gram-positive organisms await the results of large randomized studies.

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    Table 2. Antimicrobial Prophylaxis in Recipients of Allogeneic Bone Marrow
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    Late Bacterial Infections

    In contrast to the early neutropenic period, occurrence of infections after engraftment depends on the kinetics of lymphopoietic reconstitution and the presence of graft-versus-host disease. Recipients of allogeneic bone marrow grafts are at risk for late bacterial infections because of their continued immunosuppression. Recipients of autologous grafts, however, do not develop graft-versus-host disease and have a faster immune recovery, and thus have a much lower risk for developing late bacterial infections than patients receiving allogeneic grafts. Chronic graft-versus-host disease involving the sinuses, oropharynx, and upper respiratory tract leads to increased bacterial adherence and mucosal colonization. In addition, graft-versus-host disease and its treatment delay the recovery of cellular and humoral immunity and predispose colonized bone marrow recipients to infection.

    Common pathogens include encapsulated bacteria, particularly pneumococci, and, less commonly, staphylococci and gram-negative bacteria, such as Pseudomonas species [37, 38]. Increased risk for pneumococcal infection is associated with impaired serum opsonizing activity, low serum antibody (IgG) levels for Streptococcus pneumoniae and impaired reticuloendothelial function of the liver and spleen, particularly in patients with chronic graft-versus-host disease [39, 40]. Immunization with 14-polyvalent pneumococcal vaccine has not been effective in bone marrow recipients [41]. Daily prophylaxis with oral penicillin or trimethoprim-sulfamethoxazole reduces the incidence of pneumococcal infection in patients with chronic graft-versus-host disease. Break-through pneumococcal infections have occurred during trimethoprim-sulfamethoxazole prophylaxis, and penicillin-resistant pneumococci have appeared during long-term penicillin prophylaxis [42]. Although no controlled studies have been done on the prophylactic use of antibacterial agents in patients with chronic graft-versus-host disease, it is prudent to provide prophylaxis against pneumococci, particularly after a pneumococcal infection is documented. At our bone marrow transplantation center, prophylaxis with oral penicillin is initiated after marrow engraftment and is continued throughout immunosuppressive therapy. Recipients of autologous bone marrow transplants do not require routine antipneumococcal prophylaxis.

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    Viral Infections

    As a result of impaired cellular immunity, all transplant recipients, especially recipients of allogeneic grafts who have graft-versus-host disease, are predisposed to various viral infections [43]. Herpesviruses (herpes simplex virus, varicella-zoster virus, cytomegalovirus, Epstein-Barr virus, and human herpesvirus 6) are frequent pathogens, and therapeutic and preventive strategies are available for dealing with some of these organisms [43-49]. Less commonly seen viral pathogens include adenovirus, respiratory syncytial virus, rotavirus, and BK/JC virus [50]. No effective prophylactic strategies are currently available against such infrequent infections.

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    Cytomegalovirus Infection

    Definitions of the terms infection and disease in the context of cytomegalovirus (CMV) should be emphasized. Cytomegalovirus infection is defined as CMV viremia or isolation of CMV from body fluids or body sites in an asymptomatic patient, whereas CMV disease is defined as CMV viremia, isolation of CMV from body fluids, or the presence of CMV in histologic sections of infected tissues in symptomatic patients. Recipients of allogeneic bone marrow transplants who are seropositive for CMV have a 70% risk for reactivation of latent infection [48, 49]. Although CMV also frequently reactivates in recipients of autologous transplants, these patients have a much lower risk (about 10%) for the development of symptomatic CMV. Thus, prophylactic strategies against CMV are aimed at recipients of allogeneic transplants rather than at patients receiving autologous transplants.

    Cytomegalovirus infection usually develops 1 to 4 months after transplantation; results of serologic testing done after transplantation are not reliable for diagnosis. Risk factors for CMV infection are seropositivity before transplantation, increasing age, and the presence of acute graft-versus-host disease [51]. T-lymphocyte depletion of donor marrow as a strategy to prevent the development of graft-versus-host disease also increases the risk for CMV reactivation. Although viral reactivation accounts for most infections, reinfection with new strains of CMV has been reported in seropositive recipients of solid organ transplants [52, 53]. The clinical spectrum of CMV in bone marrow recipients ranges in severity from asymptomatic infection to life-threatening interstitial pneumonia, which is the most common infectious cause of death in recipients of allogeneic transplants. Other manifestations of CMV infection include gastroenteritis, colitis, hepatitis, encephalitis, and even bone marrow failure. Cytomegalovirus retinitis, commonly seen in patients with the acquired immunodeficiency syndrome, is rare in bone marrow recipients.

    Cytomegalovirus disease may be caused by reactivation of endogenous latent virus or, less commonly, by primary infection through viral transmission from CMV-seropositive bone marrow or blood products to CMV-seronegative bone marrow recipients. Because the epidemiology of primary infection differs from that of reactivation of latent infection, the preventive strategies also differ. Use of CMV-seronegative blood products almost eliminates the risk for primary CMV infection in CMV-seronegative bone marrow recipients [54-57]. In CMV-seropositive recipients, however, the prophylactic approach relies on the use of antiviral drugs to prevent reactivation of latent virus. A nonrandomized study done in 1988 showed that prophylactic intravenous acyclovir (at 500 mg/m2 body surface area every 8 hours) administered to CMV-seropositive recipients of allogeneic bone marrow significantly reduced the rate of CMV infection and pneumonia, decreased the probability of CMV reactivation, and improved survival 100 days after transplantation [58]. The mortality rate in the first 100 days was 54% in the control group and 29% in the acyclovir group (P < 0.01). However, despite high doses of acyclovir, CMV infection developed in 59% and pneumonia developed in 19% of the treated group; the frequency of CMV viremia was similar in the control and treated groups.

    A recent randomized European study of 310 bone marrow recipients showed improved survival and delayed time to CMV infection with high-dose acyclovir used as prophylaxis for 6 months [59]. Ganciclovir (an acyclic nucleoside analog of acyclovir), which has an in vitro activity against CMV that is 50 times greater than that of acyclovir, has been studied in bone marrow transplant recipients [60-65]. Treatment with a combination of ganciclovir and intravenous immunoglobulin improved the survival of bone marrow recipients with CMV pneumonia [60]. For prophylaxis against CMV, two approaches have been studied: 1) early or preemptive treatment of recipients of allogeneic transplants with asymptomatic CMV infection [61, 62]; and 2) use of prophylaxis in all CMV-seropositive recipients of allogeneic transplants [63-65].

    With the first approach, isolation of CMV in culture from blood or body secretions is a strong predictor of CMV disease [66]. In a study using this approach, Schmidt and colleagues [62] identified 40 patients with asymptomatic pulmonary CMV infection by doing bronchoalveolar lavage 35 days after transplantation. They administered ganciclovir to patients whose lavage fluid was culture-positive for CMV. Twenty-five percent of ganciclovir recipients and 70% of culture-positive controls developed CMV pneumonia. In a related study, asymptomatic recipients of allogeneic transplants who had a CMV-positive culture from the throat, blood, urine, or lavage fluid were randomly assigned to receive placebo or ganciclovir for the first 100 days after transplantation [61]. Only 1 of 37 ganciclovir recipients developed CMV infection compared with 15 of 35 placebo recipients (P < 0.001). Survival 100 and 180 days after transplantation was significantly greater among ganciclovir recipients than among placebo recipients. A noteworthy finding was that 12% of patients with negative surveillance cultures developed CMV disease. Thus, administering ganciclovir only to patients with positive surveillance cultures would exclude many seropositive recipients who may benefit from antiviral prophylaxis.

    An example of the second treatment approach can be seen in a nonrandomized study in which CMV infection and disease were prevented with prophylactic ganciclovir given to all CMV-seropositive recipients of allogeneic transplants [63]. None of the 20 patients given ganciclovir developed infection compared with 23% of matched historical controls with CMV pneumonia. This observation was confirmed in two recent randomized, double-blind, placebo-controlled trials [64, 65]. Although the dosing schedules of ganciclovir differed, the incidence of CMV infection and disease was reduced in the ganciclovir groups in both trials (Table 3). The Seattle study [64] showed that ganciclovir significantly reduced both excretion of CMV (1 of 33 patients compared with 14 of 31 controls; P < 0.001) and CMV-associated disease 100 days (29% compared with 0%; P < 0.001) and 180 days (32% compared with 9%; P = 0.015) after bone marrow transplantation. The University of California, Los Angeles, study [65] also showed a reduction in the rates of CMV infection (8 of 40 patients compared with 25 of 45 patients; P < 0.001) and CMV disease (4 of 40 patients compared with 11 of 45 patients; P = 0.09). However, neither study confirmed the survival benefit reported in an earlier trial [63]. In addition, ganciclovir-related neutropenia was a significant problem in both studies. Expensive agents such as recombinant cytokines may be required to counter this adverse effect for continued ganciclovir administration. Furthermore, the emergence of drug-resistant strains during ganciclovir therapy has been documented in immunocompromised patients [67, 68]. Thus, administration of intravenous ganciclovir, an expensive and potentially myelotoxic agent, to all CMV-seropositive bone marrow recipients may not be the optimal form of prophylaxis. The efficacy of orally administered ganciclovir in transplant recipients awaits evaluation.

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    Table 3. Ganciclovir Prophylaxis for Cytomegalovirus-Seropositive Recipients of Allogeneic Bone Marrow

    Another antiviral agent, foscarnet (phosphonoformate) has been shown to be effective against ganciclovir-susceptible and -resistant CMV infections in patients with HIV infection. Limited data are available on the use of foscarnet in bone marrow recipients [69-72]. Although foscarnet is not myelosuppressive, it is nephrotoxic. In a phase I/II pilot study, prophylactic use of foscarnet prevented CMV infection in 19 seropositive recipients of autologous and allogeneic transplants. However, renal toxicity was particularly severe in those receiving cyclosporine and amphotericin B.

    At the Detroit Medical Center, we administer prophylactic ganciclovir therapy to all CMV-seropositive recipients of allogeneic grafts at a reduced frequency (Table 2) after engraftment. In addition, like many centers, we administer intravenous acyclovir during the neutropenic period. The efficacy of this regimen is currently being studied. Failure of ganciclovir given thrice weekly to prevent CMV reactivation in T-cell-depleted marrow recipients signals caution [73]. The key to a successful and cost-effective approach to the prevention of CMV is the reservation of prophylaxis for only those recipients of allogeneic transplants who are most likely to have reactivation of latent virus. Newer methods for the detection of CMV antigen in blood and plasma by the polymerase chain reaction [74-77] may help to identify patients at risk.

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    Herpes Simplex Virus Infection

    Herpes simplex virus type 1 accounts for most viral infections in patients receiving bone marrow transplants [78, 79]. Herpesvirus reactivates before marrow engraftment in 70% to 80% of seropositive recipients of allogeneic transplants. Herpes simplex virus infections cause hemorrhagic oral or genital mucocutaneous lesions, esophagitis, and, less commonly, pneumonia. The median time to onset of herpes simplex virus infection is 8 days after transplantation. Intravenous acyclovir at a dose of 125 to 250 mg/m2 given every 8 hours (from the day of marrow infusion until engraftment) prevents reactivation of herpes simplex virus in seropositive marrow recipients and patients with leukemia receiving chemotherapy [79-81]. When tolerated, oral acyclovir (400 mg five times a day) is equally effective and costs considerably less than the intravenous formulation [82]. Acyclovir-resistant herpes simplex virus causing clinically significant infections has been seen in marrow recipients receiving antiviral prophylaxis [83]. Herpes simplex hepatitis has been reported in patients receiving prophylactic acyclovir during transplantation [84]. Of the other antiviral agents available, foscarnet (not ganciclovir) is active against acyclovir-resistant herpes simplex virus. The efficacy of prophylaxis with foscarnet against herpes simplex virus is unknown.

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    Varicella-Zoster Virus Infection

    Varicella-zoster virus causes significant morbidity between 2 and 10 months (median, 5 months) after transplantation in about half of the patients receiving allogeneic transplants who have acute or chronic graft-versus-host disease [85]. In contrast to cytomegalovirus, varicella-zoster virus also commonly reactivates in recipients of autologous transplants. The disease usually presents as localized dermatomal involvement. Dissemination (cutaneous or visceral) occurs in about 30% of cases, and mortality is as high as 50%. Early treatment with high-dose intravenous acyclovir (500 mg/m2 three times daily) prevents dissemination and reduces mortality.

    Data on the use of acyclovir to prevent reactivation of varicella-zoster virus is limited. In a British study, intravenous acyclovir for the first 23 days after transplantation followed by oral acyclovir or placebo for 6 months significantly reduced infections caused by herpes simplex and varicella-zoster viruses [86]. After discontinuation of prophylaxis, the incidence of varicella-zoster virus infection was similar in the treatment and placebo groups. No control patients died of disseminated varicella-zoster virus infection, and the infection was effectively treated with intravenous acyclovir. Because varicella-zoster virus infection is usually seen well after engraftment and because effective prophylaxis must be given for several months, routine administration of long-term acyclovir is not cost-effective and remains controversial. The emergence of acyclovir-resistant varicella-zoster virus is also of concern. Nevertheless, few centers use prophylactic oral acyclovir for as long as 6 months after transplantation. Newer nucleoside analogs such as BV-ara-U, which have greater in vitro activity against varicella-zoster virus, are currently being studied and may prove to be superior to acyclovir [87]. The effect of live, attenuated varicella vaccine on the natural history of varicella-zoster virus infection in bone marrow recipients remains to be seen.

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    Fungal Infections

    Prolonged neutropenia, immunosuppressive therapy with cyclosporine or corticosteroids, use of broad-spectrum antibiotics, graft-versus-host disease, hyperalimentation, extended periods of hospitalization, and indwelling vascular catheters are key risk factors that have been identified as predisposing bone marrow recipients to fungal colonization and infection [88, 89]. Additional factors reported include age, underlying disease, conditioning regimen before transplantation, degree of donor mismatch, and T-cell depletion. About 40% of marrow recipients develop fungal infection when the granulocytopenic period extends beyond 3 weeks [90-93]. Mortality is about 40% in patients with candidemia alone and 90% for those who have tissue invasion with or without fungemia. Candida and Aspergillus species are the most common pathogens [94, 95]. Although Candida albicans has accounted for most candidal infections, C. parapsilosis, C. tropicalis, C. krusei, and Torulopsis glabrata have also emerged as important pathogens. Uncommon fungal pathogens have included Fusarium, Alternaria, and Trichosporon species. Sites of colonization for Candida species are the oral cavity, gastrointestinal tract, genital tract, and indwelling intravenous catheter sites, whereas Aspergillus species colonize the respiratory tract after the ubiquitous spores are inhaled. Denuded gut epithelium secondary to preparative regimens or graft-versus-host disease provides a portal of entry for Candida colonizing the gastrointestinal tract. Outbreaks of aspergillosis have been associated with nearby construction sites, contaminated airflow ventilation systems, and the care of patients on open wards.

    The lack of reliable serologic, microbiological, or other noninvasive tests and the hazards of obtaining a tissue biopsy sample from bone marrow recipients have been obstacles to the rapid and definitive diagnosis of invasive fungal infection. Fungal surveillance cultures do not reliably predict systemic infection. Furthermore, efficacy of amphotericin B against disseminated fungal infection is not consistent and depends on factors such as the susceptibility of the pathogen, the site of infection, and host status. Therefore, the concept of prophylaxis of fungal infections in transplant recipients, particularly before marrow engraftment, has been explored during the past decade. Meticulous personal hygiene, scrupulous care of intravenous catheters, and avoidance of uncooked food minimize candidal colonization, whereas the use of high-efficiency particulate air filters, air-controlled units, laminar airflow rooms, and avoidance of plants in patient rooms help prevent acquisition of aspergillus [96].

    Most studies of antifungal chemoprophylaxis have been done in patients at risk for early fungal infection. Neutropenic patients with cancer have been the participants in most studies [97-109]. Antifungal agents examined include polyenes, nystatin, amphotericin B, and azoles. Amphotericin B has been used orally, intravenously, and intranasally as prophylaxis against fungal infections. Oral amphotericin B is not absorbed from the gastrointestinal tract, and its prophylactic efficacy against candida remains controversial [97, 98]. In an uncontrolled study [100], prophylactic intravenous amphotericin B (20 mg/d) given to 186 consecutive recipients of allogeneic transplants from the initiation of therapy with the preparative regimen to the day of transplantation, followed by 20 mg every other day until marrow engraftment significantly reduced the incidence of invasive aspergillosis (P = 0.003) and mortality (P = 0.03). Using the same daily dose of intravenous amphotericin B for prophylaxis in recipients of autologous transplants, Perfect and colleagues [101] found no difference in the incidence of oral thrush or the empiric use of amphotericin B between treated and placebo groups [101]. Yeast colonization was significantly decreased (P = 0.01) in the treated group. In nonrandomized studies, use of inhalational amphotericin B significantly decreased the incidence of aspergillosis in neutropenic patients with cancer, including a few bone marrow recipients [102-104]. In an uncontrolled study of 303 bone marrow recipients, inhalational plus oral amphotericin B or fluconazole markedly reduced the incidence of invasive fungal infections, including aspergillosis [110]. The lack of convincing data and the toxicity of intravenous amphotericin preclude its routine use for prophylaxis. Less nephrotoxic lipid formulations of amphotericin B are being evaluated. A phase I study of amphotericin B colloidal dispersion in bone marrow recipients with invasive fungal infections found the drug to have an excellent renal-sparing profile and an efficacy similar to that of amphotericin B [111]. Interaction between the newer formulations of amphotericin B and cyclosporine must still be studied.

    Imidazoles and triazoles studied as antifungal agents for prophylaxis include clotrimazole, miconazole, ketoconazole, fluconazole, and itraconazole. Clotrimazole has been effective in reducing the frequency and severity of oropharyngeal candidiasis in patients with cancer [112, 113] and is widely used in many transplantation centers. However, compliance with clotrimazole troches is poor in patients with severe mucositis. Studies with ketoconazole in patients with cancer show conflicting results [95, 98, 105, 108]. Antagonism with amphotericin B, lack of activity against aspergillus, interactions with cyclosporine, emergence of resistance while patients are receiving therapy, and erratic absorption from the gastrointestinal tract limit the usefulness of ketoconazole in bone marrow recipients. Intravenous miconazole, when begun at the time of the first episode of neutropenic fever, significantly reduced the incidence of fungal sepsis in recipients of autologous and allogeneic marrow [109]. However, the toxicity profile of miconazole limits its consideration as a routine prophylactic agent. Recently, fluconazole, a triazole with excellent activity against many common fungal pathogens, has been evaluated for its prophylactic efficacy. Favorable pharmacokinetics, good safety profile, reliable absorption from the gastrointestinal tract, and availability in oral and parenteral formulations make fluconazole an attractive prophylactic agent. Two recent randomized, double-blind, placebo-controlled multicenter trials [114, 115] examined the efficacy of fluconazole in preventing fungal infections and colonization in bone marrow recipients and patients with leukemia. In the trial that involved 356 bone marrow recipients [114], prophylaxis with fluconazole at 400 mg/d during neutropenia and before marrow engraftment significantly reduced the incidence of both invasive and superficial infections caused by all strains of Candida except C. krusei. Systemic fungal infection was documented in 28 (16%) placebo recipients and in only 5 (3%) fluconazole recipients (P < 0.001). Although no difference in survival was seen between the two groups, only one death was attributable to fungal infection in the fluconazole-treated group; there were 10 fungus-related deaths in the placebo group (P < 0.001). Surveillance cultures from fluconazole recipients showed increased colonization with C. krusei. Some transplantation centers have reported increased colonization with fluconazole-resistant C. krusei in patients treated with fluconazole [116]. Others, however, have observed the presence of C. krusei even in patients not exposed to fluconazole [117]. In addition to C. krusei, increased colonization and infection with Torulopsis glabrata in fluconazole recipients have been reported [118]. The optimal dose of fluconazole is unknown, but most centers administer the drug at 400 mg/d on the basis of data from the multicenter trial [104]. We administer oral fluconazole at 100 mg/d to all bone marrow recipients until marrow engraftment (Table 2). At a decreased dose of 100 to 200 mg/d, fluconazole has been shown to significantly reduce the incidence of systemic and superficial fungal infections [119, 120]. At the lower dose, we have noted colonization and occasional fungemia caused by Torulopsis glabrata among fluconazole recipients. Prospective data are needed to validate our observations.

    Itraconazole has better activity against aspergillus than fluconazole. Nonrandomized studies have shown itraconazole to be superior to ketoconazole in the prevention of aspergillus infections in neutropenic patients [121]. Oral itraconazole is poorly soluble in water, and its erratic absorption from the gastrointestinal tract during neutropenia makes it an unreliable agent. A better-absorbed, liquid preparation of itraconazole is currently being evaluated. Parenteral formulation of itraconazole is not available. All three azoles (ketoconazole, fluconazole, and itraconazole) have caused increases in plasma cyclosporine concentrations, thereby requiring close monitoring of plasma drug levels [122-124].

    In summary, optimal chemoprophylaxis of fungal infections in bone marrow recipients during neutropenia and after marrow engraftment remains undefined. An ideal antifungal agent must be effective against candida and aspergillus, nontoxic, easily administered, well-tolerated, compatible with the immunosuppressive drugs that are used after transplantation, and inexpensive.

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    Protozoal Infections

    Pneumocystis carinii accounts for about 6% of nonbacterial pneumonias in recipients of allogeneic transplants within the first 6 months after transplantation. The mortality rate from this infection is about 60%, particularly in patients with graft-versus-host disease [125]. Although no controlled studies have been done in this area, the general consensus is that prophylaxis with trimethoprim-sulfamethoxazole is beneficial in recipients of allogeneic transplants. Oral trimethoprim-sulfamethoxazole is given in various dosing frequencies, ranging from twice weekly to daily from the time of marrow engraftment until 6 to 12 months after transplantation or longer in the presence of continued immunosuppression. Trimethoprim-sulfamethoxazole infrequently causes myelosuppression, which requires discontinuation of therapy. As an alternative, aerosolized pentamidine may be effective in bone marrow recipients, although few data support this practice [126].

    Several cases of toxoplasmosis have been reported worldwide in bone marrow recipients [127-132]. Toxoplasmosis usually occurs by reactivation of latent infection in patients who are seropositive for toxoplasma before transplantation. Encephalitis, myocarditis, and pneumonia are the common clinical manifestations. Most cases occur within 6 months after transplantation, with the highest incidence in the second and third months. Early diagnosis and treatment can prevent a potentially fatal outcome. Parasitemia and demonstration of toxoplasma in bone marrow smears or tissue sections have led to ante mortem diagnosis in a few patients, but in most cases, the diagnosis is made at autopsy. Serologic testing after transplantation is not helpful in diagnosis. In endemic areas such as France, chemoprophylaxis from the second to sixth month may be helpful in bone marrow recipients who are seropositive for toxoplasma. A recent trial in France with pyrimethamine-sulfadoxine (Fansidar) in 69 seropositive bone marrow recipients reported no break-through cases of toxoplasmosis [133]. Pyrimethamine-induced myelotoxicity warrants caution. The few effective drugs and potential toxicities preclude routine prophylaxis against toxoplasma in nonendemic areas. Routine prophylaxis is not recommended for rare protozoal infections such as cryptosporidiosis [134] and strongyloidiasis.

    Previous SectionNext Section

    Conclusion

    Successful treatment of established infections is complicated by difficulties in early diagnosis, defects in host immunity, and toxicities of antimicrobial drugs. Although chemoprophylaxis prevents the acquisition or reactivation of some infections, the prohibitive costs of many antimicrobial agents may not justify such strategies [135]. Cost-effectiveness and effect on overall survival have not been addressed in similar trials. With widespread use of multiple agents for chemoprophylaxis, emergence of resistant organisms is a significant concern. Ideally, chemoprophylaxis in bone marrow recipients should combine safe antimicrobial prophylaxis with improved strategies to prevent and treat graft-versus-host disease and accelerate immunohematopoietic recovery after bone marrow transplantation.

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