Antimicrobial prophylaxis in allogeneic bone marrow transplantation. Guidelines of the Infectious Diseases Working Party (AGIHO) of the German Society of Haematology and Oncology

W. H. Krüger1,*, J. Bohlius2, O. A. Cornely2, H. Einsele3, H. Hebart3, G. Massenkeil4, S. Schüttrumpf5, G. Silling6, A. J. Ullmann7, D. T. Waldschmidt8 and H.-H. Wolf9

1 Medizinische Klinik C, Greifswald, Germany; 2 Klinik I für Innere Medizin, Klinische Infektiologie, Klinikum der Universität zu Köln, Köln, Germany; 3 Medizinische Klinik II, Abt. Hämatologie/Onkologie/Immunologie, Eberhard-Karls-Universität, Tübingen, Germany; 4 Klinik für Hämatologie und Onkologie,Universitätsklinik Charité, Campus Virchow-Klinikum, Berlin, Germany; 5 Zentrum Innere Medizin, Abteilung für Hämatologie/Onkologie, Georg-August-Universität Göttingen, Göttingen, Germany; 6 Medizinische Klinik A – KMT-Zentrum, Westfälische-Wilhelms-Universität, Münster, Germany; 7 Medizinische Klinik und Poliklinik, Klinikum der Johannes Gutenberg-Universität, Mainz, Germany; 8 Klinik IV für Innere Medizin, Klinikum der Universität zu Köln, 9 Klinik für Innere Medizin IV, Martin-Luther-Universität Halle-Wittenberg, Halle (Saale), Germany

* Correspondence to: Dr W. H. Krüger, Medizinische Klinik C (Hämatologie und Onkologie, Transplantationszentrum), Ernst-Moritz-Arndt-Universität-Greifswald, Ferdinand-Sauerbruch-Straße, 17487 Greifswald, Germany. Tel: +49-3834-86-22 007/22 006; Fax: +49-3834-86-22 012. Email: william.krueger{at}uni-greifswald.de


    Abstract
 Top
 Abstract
 Introduction
 Conditioning therapy and...
 Immune-system recovery after...
 Bacterial infections
 Viral infections
 Fungal infections
 Toxoplasmosis
 Conclusions
 References
 
Patients undergoing allogeneic stem cell transplantation are at high risk for infection with a variety of pathogens during different phases of the procedure. Bacteria and fungi predominate the first phase until engraftment. During the second phase, from engraftment to about day 100, major infectious problems are caused by fungi and cytomegalovirus. Both pathogens remain important under continued immunosuppression, however, in the late post-transplantation period infections with encapsulated bacteria may become a problem. In this review the Infectious Diseases Working Party of the DGHO gives recommendations for prophylaxis of infections under allogeneic stem cell transplantation with drugs and other measures. The aim of the group was to do this on an evidence-based-medicine rating, if possible.


    Introduction
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 Abstract
 Introduction
 Conditioning therapy and...
 Immune-system recovery after...
 Bacterial infections
 Viral infections
 Fungal infections
 Toxoplasmosis
 Conclusions
 References
 
Patients undergoing allogeneic stem cell transplantation are highly susceptible for acquisition and reactivation of infectious diseases. A variety of bacteria, fungi, viruses and protozoa can induce potentially lethal disease during distinct phases of transplantation. The susceptibility of the host for infections is influenced by the underlying disease including preceding courses of antineoplastic therapy, the intensity and compound of conditioning therapy, and the degree of human leukocyte antigen (HLA)-conformity between stem cell donor and recipient. Furthermore, intensity and duration of GvHD-prophylaxis and the manifestation of graft-versus-host disease contribute substantially to susceptibility for severe infections.

Patients with long periods of chemotherapy-induced neutropenia during the course of disease and concomitant antibiotic therapy are at increased risk for colonisation with highly resistant organisms such as vancomycin-resistant Gram-positive cocci, Candida krusei, other non-albicans Candida spp. and Aspergillus spp. HLA-disparity between donor and recipient bears an increased risk for graft-versus-host disease demanding for an intensive and prolonged immunosuppressive therapy.

In this paper the Infectious Diseases Working Party of the German Society of Haematology and Oncology (AGIHO) provides a guideline for antimicrobial prophylaxis in allogeneic bone marrow transplantation based on evidence-based-medicine criteria. The recommendations should follow the ranking shown in Table 1. However, this approach is hampered by the following problems.

  1. A variety of clinical trials carried out during the 1990s were not restricted to patients receiving an allograft. It was common practice for a long period to include a mix of patients undergoing allogeneic or autologous stem cell transplantation into these investigations.
  2. Clinical trials comparing a prophylactic measure, e.g. prophylactic drug administration, versus placebo are very rare in this field. Most investigators compared an old with a new medication.
  3. Allogeneic stem cell transplantation has experienced a rapid development during the last 15 years. Data from patient cohorts receiving a bone marrow graft without growth factor stimulation after transplantation must not necessarily be valid for patients receiving a large-scale granulocyte colony-stimulating factor (G-CSF)-mobilised stem cell graft after dose-reduced conditioning therapy.


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Table 1. Evidence-based rating system used to determine strength of recommendations (top) and quality of evidence (bottom)

 
In conclusion, these evidence-based guidelines are sometimes no more than a description of the youngest history or even presence of reality, and the evidence-based-medicine rating does not always make the sense it should. A lot of recommendations are commonly followed; however, they are only quality-level III due to the lack of clinical trials.


    Conditioning therapy and neutropenia
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 Abstract
 Introduction
 Conditioning therapy and...
 Immune-system recovery after...
 Bacterial infections
 Viral infections
 Fungal infections
 Toxoplasmosis
 Conclusions
 References
 
The major risk factor during the early post-transplant phase is therapy-related severe neutropenia. Regimen-related toxicity of conditioning therapy contributes significantly to enhanced susceptibility for infections at this time. Therapy-associated mucositis is the breakdown of a physiological barrier allowing microbes to invade into the tissue and bloodstream [1Go]. Furthermore, methotrexate-injections for GvHD-prophylaxis can intensify oropharyngeal mucosa damage.

In general, duration of neutropenia and degree of organ toxicity depend on the conditioning protocol chosen. Classical myeloablative regimens consisting of high-dose busulphan or total body irradiation (TBI) and cyclophosphamide, with or without etoposide (VP-16), have the highest toxicity, whereas toxicity of modern reduced-intensity regimens can be very moderate without mucositis and only very short neutropenic episodes.


    Immune-system recovery after stem cell transplantation and opportunistic pathogens
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 Abstract
 Introduction
 Conditioning therapy and...
 Immune-system recovery after...
 Bacterial infections
 Viral infections
 Fungal infections
 Toxoplasmosis
 Conclusions
 References
 
The immune system of stem cell recipients follows a typical pattern of deficiency and recovery during the first year after transplantation. Host lymphocytes are usually eliminated by conditioning therapy and thus the immunological memory acquired during prior life is lost. Time and degree of transfer of donor immunity are not predictable, however, and up to 2 years may be necessary to regain humoral and cellular immunocompetence. During the early transplant period including neutropenia, the predominant pathogens are Gram-negative bacteria translocating from the gut and resident Gram-positive organisms. From day 10 of neutropenia, fungal infections become more prevalent. In central Europe Aspergillus spp. and Candida spp. are most important. After engraftment the recovery of the immune system can be prolonged when the patient experiences an acute graft-versus-host disease or a cytomegalovirus reactivation. The latter complication can contribute substantially to a delay of immune recovery. In addition, the immunosuppressive agents given for GvHD-prophylaxis and treatment make the patient more vulnerable to opportunistic pathogens. Infections due to encapsulated bacteria such as Streptococcus pneumoniae or Haemophilus influenzae occur in the late post-engraftment period. An overview of transplant phases and common pathogens is shown in Figure 1.



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Figure 1. Predominance of opportunistic infections after allogeneic bone marrow transplantation.

 

    Bacterial infections
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 Abstract
 Introduction
 Conditioning therapy and...
 Immune-system recovery after...
 Bacterial infections
 Viral infections
 Fungal infections
 Toxoplasmosis
 Conclusions
 References
 
The best measure to avoid carryover of resistant organisms from person to person is frequent and appropriate hand-disinfection. The other important reservoir is the patient itself, especially the gut and the skin during the early phase. Gram-negative organisms can translocate from the gut into the bloodstream after breakdown of physiological barriers and Gram-positive bacteria can invade through the damaged mucosa, skin lesions or follow intravascular catheters.

Antibacterial prophylaxis carried out with fluoroquinolones or trimethoprim-sulfamethoxazole is common in European transplant centres, although there are no trials comparing both drugs against placebo [2Go].

The major effect of fluoroquinolone prophylaxis is the reduction of infections with Gram-negative rods. Gluckman et al. in 1991 compared a combination of ofloxacin/amoxicillin to a non-absorbable combination and found a significantly reduced duration of fever [3Go]. The GIMEMA (Gruppo Italiano Malattie Ematologiche Maligne dell'Adulto) [4Go] compared norfloxacin with ciprofloxacin in 1991 in a randomised, large but mixed cohort and did not find any influence on mortality although the ciprofloxacin-treated patients had a lower rate of documented infection, of infections with Gram-negative rods and a longer time to the first febrile episode. Lew et al. [5Go] compared ciprofloxacin to trimethoprim/sulfamethoxazole in a randomised, blind study in transplant patients. Both drugs were equally safe and effective in the prevention of infections. However, trimethoprim/sulfamethoxazole was associated with a higher incidence of Clostridium difficile enterocolitis and Gram-negative infection, as well as a trend towards prolongation of neutropenia. Ciprofloxacin with colistin was compared with a classical non-absorbable regimen consisting of neomycin and colistin by Prentice et al. [6Go]. The authors described a significantly increased rate of infections with Staphylococcus aureus, Gram-positive and Gram-negative bacteria in general, and overall infection rate with non-absorbable prophylaxis. Furthermore, two out of 73 (2.7%) patients from the latter group died from infection compared with none in the ciprofloxacin group. The advantage of fluoroquinolones over trimethoprim/sulfamethoxazole prophylaxis was confirmed by two large meta-analyses [7Go, 8Go]. Here it should be mentioned that most studies were carried out with ciprofloxacin or ofloxacin. Newer fluoroquinolones were hardly investigated.

An additional Gram-positive prophylaxis has been suggested by some investigators [9Go]. However, it must be pointed out that the emergence of vancomycin-resistant cocci has become an important problem and that the mortality of Gram-positive infections is low, even after marrow transplantation [10Go, 11Go]. Cruciani et al. [12Go] published a meta-analysis on the addition of Gram-positive prophylaxis to quinolones and concluded that Gram-positive antibiotics should be added only in high-risk collectives.

In conclusion, the authors encourage transplant physicians to perform an antibacterial prophylaxis with fluoroquinolones (AI rating). An additional Gram-positive prophylaxis is generally not recommended (DIII rating) and should be restricted to single high-risk patients, e.g. as a secondary prophylaxis.

Late bacterial infections after allogeneic bone marrow transplantation are often caused by encapsulated bacteria such as Streptococcus pneumoniae, Haemophilus influenzae or Neisseria meningitidis. These infections contribute substantially to the mortality of patients with chronic graft-versus-host disease treated with additional immunosuppressive drugs [13Go, 14Go]. A pneumococcus prophylaxis is recommended for patients with active cfvHD and lifelong after splenectomy (BII) [15Go]. Patients under pneumocystis carinii pneumonia (PCP)-prophylaxis with trimethoprim/sulfamethoxazole will be protected sufficiently against pneumococci. Additional prophylaxis should be chosen considering local epidemiology and resistance patterns (BIII rating).

The use of intravenous immunoglobulins for anti-infectious prophylaxis is generally not recommended due to controversial results (DI rating) [16Go, 17Go].


    Viral infections
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 Introduction
 Conditioning therapy and...
 Immune-system recovery after...
 Bacterial infections
 Viral infections
 Fungal infections
 Toxoplasmosis
 Conclusions
 References
 
General considerations
Herpes viruses usually persist lifelong in the host after primary infection and can be reactivated under certain conditions, e.g. intensive immunosuppression. Reactivation of viruses from the herpes group after allogeneic stem cell transplantation can lead to severe illness with substantial morbidity and mortality. As a consequence, all candidates for allogeneic stem cell transplantation should undergo a test for immunoglobulin G (IgG) antibodies against the viruses listed in Table 2. All patients negative for IgG against the viruses listed in Table 2 should stay on strict prophylactic measures to avoid de novo infection prior to transplantation and afterwards.


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Table 2. Human herpes viruses with practical relevance in stem cell transplantation

 
Human cytomegalovirus
All candidates for allogeneic stem cell transplantation should be tested for anti-cytomegalovirus (CMV) IgG-antibodies to determine their risk for de novo infection or reactivation (AIII).

Preventing exposure
All CMV-negative recipients should be transplanted from a CMV-negative donor, if available [18Go, 19Go]. CMV-negative patients living in a monogamous relationship should ask their partners to be CMV-serotested since discordant results over long periods have been described. Patients with CMV-positive partners or patients without a monogamous relationship should always use latex-condoms during sexual contacts. CMV-negative candidates and patients should not share glasses, cups and eating utensils with others to reduce the risk of exposure to CMV (BIII).

CMV-seronegative recipients transplanted from a negative donor should only receive blood-products from negative donors upon availability. Blood banks without a sufficient pool of CMV-negative donors should deliver only leukocyte-depleted red cells and thrombocytes. It should be considered that irradiation to prevent transfusion-associated graft-versus-host disease does not destroy CMV (AI) [20Go–24Go].

Administration of human immunoglobulin preparations for prophylaxis of CMV-infection in negative patients is not recommended (DI) [25Go]. This statement refers to prophylaxis of infections in matched related donors; For unrelated donors information is sparse.

Preventing disease and reactivation
The choice of the appropriate donor for a CMV-positive patient has been controversial [18Go, 19Go]. Most transplant physicians prefer a CMV-positive donor considering the adoptive immune transfer by donor T-cells (BIII).

CMV-positive recipients and CMV-negative recipients grafted from a positive donor are at risk for CMV-disease after allogeneic stem cell transplantation. Additional risk factors are a T-cell depleted graft, HLA-mismatched transplantation, steroid treatment, and acute or chronic graft-versus-host disease [26Go, 27Go]. CMV-disease preferably manifests as marrow depression, pneumonia and gastroenteritis in stem cell recipients [28Go]. All patients at risk for CMV-disease should be screened for pp65 antigenaemia or nucleic acid detection by real-time PCR at least once a week from day 10 to day 100 after transplantation (AI). Other methods such as classic culture or pp72-detection by shell-vial culture can be used; however, these methods require much more time until the results become available [29Go, 30Go].

The current standard is the early initiation of a so-called pre-emptive therapy (AI) [31Go]. Pre-emptive therapy should start after one positive pp65 or two consecutive PCR results. Physicians without access to pp65- or PCR test should consider prophylactic strategies with antiviral therapy [32Go].

Drugs that are effective in therapy or prophylaxis of CMV disease are ganciclovir, foscarnet (AI) and cidofovir (BII) [33Go, 34Go] (AI). The broadest experiences have been with the intravenous formulation of ganciclovir. Recommendations about the oral formulation can not be made so far. The main side-effect of ganciclovir is neutropenia. G-CSF can be used to diminish myelosuppression, although it is not usually necessary (AIII) [35Go]. Foscarnet is the second virustatic drug that has been comprehensively investigated and is usually recommended as second-line therapy. Foscarnet does not have myelosuppressive side-effects and is nephrotoxic. Therapy with foscarnet requires sufficient hydration of patients and frequent monitoring of renal function. However, an evidence-based-medicine study has recently shown that both drugs have a similar effect in the pre-emptive setting (AI) [33Go].

Pre-emptive therapy should be given for 2 weeks and maintenance therapy should follow for a further 2 weeks (AI). If viraemia recurs during maintenance therapy, induction with ganciclovir should be restarted or, if a resistance against ganciclovir is presumed, physicians can switch to foscarnet despite there being less data available. Tests for pp65 or PCR should be negative when treatment is discontinued [36Go]. Earlier discontinuation of therapy may have less toxic side-effects but carries a considerable relapse-rate. Therefore, in the latter setting, continuation of weekly CMV-monitoring until day 100 is mandatory (AII) [32Go, 37Go].

Some investigators have published efficacy of high-dose acyclovir or its prodrug valacyclovir in the prevention of CMV disease [38Go, 39Go]. Acyclovir is not recommended because it failed to prevent CMV disease after autologous transplantation (EI) [40Go]. Recently, Winston et al. [39Go] and Ljungman et al. [41Go] compared valacyclovir against ganciclovir in two randomised studies and consistently found that CMV disease was prevented. However, due to the controversial results, valacyclovir is not recommended for CMV prophylaxis in this guideline. Administration of human immunoglobulins for prophylaxis or therapy of CMV disease is generally not recommended (EI) [17Go].

Herpes simplex virus (HSV)
Preventing exposure
The precautions to prevent de novo infection are similar to those described for CMV. A serum test for anti-HSV serostatus is also mandatory (AIII). In addition, all transplant candidates and patients after transplantation should avoid contact with persons with active disease (AIII) [42Go].

Preventing reactivation
The standard prophylaxis against reactivation of herpes simplex virus in IgG-positive patients is acyclovir. Acyclovir is usually initiated between the start of conditioning therapy and day 1 after transplantation and should be continued until day 30 after stem cell transplantation (AI). Chemotherapy-induced oral mucositis should be resolved prior to discontinuation of acyclovir. There is no evidence from the literature to recommend acyclovir prophylaxis to be increased to day 100 or longer (CI) [43Go–45Go]. Prolonged prophylaxis is only recommended for patients with repeated episodes of HSV reactivation of herpes simplex virus after day 30 (BIII).

Patients who are seronegative for HSV do not need acyclovir prophylaxis regardless of the serostatus of the stem cell donor. Acyclovir prophylaxis should be discontinued whenever CMV prophylaxis or therapy with ganciclovir or foscarnet is initiated, as both drugs are active against HSV in vitro (EIII) [46Go].

It is presumed that valacyclovir and famciclovir are effective in the prevention of HSV reactivation. However, there are no trials to support a recommendation (CIII).

Varicella–zoster virus
Immunosuppressed patients are highly susceptible for de novo infection with Varicella–zoster virus (VZV) and VZV reactivation. VZV disease is associated with substantial morbidity and mortality in these patients [47Go–49Go]. All stem cell transplant candidates who are negative for anti-VZV IgG should strictly avoid contact with anyone suspected to have an active VZV infection or reactivation of prior infection (AIII) [42Go]. Some authors suggest vaccination of all household members and other contact persons of transplant candidates prior to the transplant procedure (BIII). However, this approach should be completed 1 month, at the latest, before transplantation. Since VZV is highly contagious, patients with overt disease under transplantation should be isolated until all lesions are crusted to prevent nosocomial spreading of viruses (AIII) [42Go, 50Go]. All anti-VZV IgG-negative stem cell recipients should receive VZV immunoglobulin rapidly after contact with a potentially infected person. It should be pointed out that even a person developing a rash after vaccination should be regarded as infectious. VZV-IgG administration protects for 30 days. After this time period it needs to be renewed in the case of subsequent exposition (BIII) [51Go, 52Go].

Any transplant patient developing a VZV rash should be treated with acyclovir until 2 days after all lesions are crusted. Alternatively, foscarnet can be used. In this context it should be mentioned that acyclovir prophylaxis for HSV reactivation usually given for the first 30 days after transplantation, is also effective against VZV. Long-term acyclovir prophylaxis to prevent VZV disease is not generally recommended (CIII). However, it can be useful in subgroups with a high risk of reactivation of VZV disease [53Go, 45Go].

Vaccination of stem cell transplant recipients with live-attenuated virus is strictly contraindicated during the first 24 months after transplantation.

Epstein–Barr virus (EBV)
All candidates for stem cell transplantation who are seronegative for EBV should undergo the same hygienic measures as described for the prevention of CMV infection, to avoid de novo infection (AIII). Early EBV disease after transplantation is extremely rare. Acyclovir prophylaxis is not effective against EBV. EBV-associated lymphoproliferative disease will not be dealt within these guidelines [54Go].

Community respiratory viruses
The increasing number of reports about respiratory virus infections after allogeneic stem cell transplantation during the last few years is obviously, in part, a result of improved diagnostic tools and awareness. The most important virus is the respiratory syncytial virus (RSV) followed by influenza, parainfluenza and adenovirus [55Go]. These viruses can contribute to morbidity after transplantation; however, mortality seems to be low [56Go]. The critical point to avoid infections with these viruses is an adequate exposure prophylaxis (AIII) [57Go]. The admittance to transplant units should be forbidden for all visitors with respiratory infections. Furthermore, influenza vaccination is strongly recommended for all persons living with stem cell transplant candidates or patients and for personnel working on transplant units (BII). If vaccination was carried out during an influenca outbreak, a 2-week course of chemoprophylaxis with amantadine or rimantadine should follow until the immune response is effective (BIII) [57Go, 58Go]. Recently, a group from Brazil published their experience with newer virustatics in pre-emptive strategies. However, this approach needs investigation in randomised trials (AIII) [59Go].

No vaccination or sufficient drug prophylaxis against infections with the other respiratory viruses has been described so far.


    Fungal infections
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 Immune-system recovery after...
 Bacterial infections
 Viral infections
 Fungal infections
 Toxoplasmosis
 Conclusions
 References
 
Yeasts
Candida spp. and Aspergillus spp. are the most important fungal pathogens contributing to significant morbidity and mortality in immunocompromised patients in Europe. Yeast infections are mainly caused by fungi colonising the gastrointestinal tract, which overgrow under antibacterial treatment and subsequently invade tissue and blood vessels during neutropenia [60Go]. Thus exposure prophylaxis is limited here to food restrictions (CIII). However, to avoid carryover by personnel, appropriate hand-washing and disinfecting is important (AIII).

All allogeneic stem cell recipients should receive fluconazole to prevent systemic infection with susceptible yeasts during neutropenia (AI) [61Go, 62Go]. Short-term versus prolonged prophylaxis until day 75 have not been compared so far. The recommended dose is 400 mg/day, either orally or intravenously given (AI). Some groups prefer 200 mg/day; however, this dose was not superior to any comparator in randomised trials [63Go]. Winston et al. [64Go] recently published the superiority of itraconazole over fluconazole. However, oral administration of itraconazole is sometimes limited by gastrointestinal side-effects (BI). Itraconazole is not recommended under conditioning therapy due to interactions with metabolism of busulfan (EII) and cyclophosphamide (EI) [65Go, 66Go]. However, in this context it should be mentioned that azole-prophylaxes may lead to selection of non-albicans yeasts with significantly higher virulence such as Candida krusei [67Go]. Overall, antifungal prophylaxis is recommended at least until day +75. If immunosuppression is given after day +75, antifungal prophylaxis should be considered.

Moulds
Invasive or systemic mould infections in stem cell recipients most frequently result from inhaled spores colonising the nasal sinus and the respiratory tract. Risk factors for mould infections after stem cell transplantation are graft-versus-host disease, prolonged immunosuppression and a history of prolonged neutropenia under prior chemotherapy [68Go, 69Go]. Several outbreaks of aspergillosis related to construction or renovation have been published [70Go, 71Go]. Stem cell transplant candidates and patients should strictly avoid areas of construction, renovation or other exposure to dust (AII). Air conditioning on transplant units with high efficiency particulate air (HEPA) filtration or laminar air flow (LAF) technique significantly reduces mould spores contamination in the air, and fungus-related mortality even when neighbouring an area of construction (AII). [72Go] In the latter scenario, barriers such as sealed plastic are necessary to prevent transfer of dust [73Go, 74Go]. Transplant patients should wear well-fitting masks during transports or procedures outside the unit to reduce inhalation of spores (BIII) [75Go].

Early detection of aspergilli in the blood stream to facilitate pre-emptive strategies similar to CMV disease, is a promising approach but currently still the subject of research [76Go].

No drug can be recommended for primary prophylaxis of aspergillosis after bone marrow transplantation due to the lack of sufficient clinical trials. Potentially effective drugs such as itraconazole, intravenous amphotericin-B in conventional and lipid formulations and intranasal amphotericin-B were used in varying doses (BII) [77Go–80Go]. The results were not clear enough to allow any recommendation. Itraconazole capsules are of limited value due to low bioavailability (DII) [81Go]. Itraconazole solution was effective at reducing the incidence of invasive aspergillosis in patients with acute leukaemia when plasma levels were above 500 ng/ml (AI) [82Go]. Transplantation of patients with a history of invasive fungal infection has been described by several investigators. Systemic secondary prophylaxis and surgical resection of pulmonal manifestations of aspergillosis prior to transplantation reduce relapse rate and improve outcome. Despite the lack of substantial trials, the authors recommend secondary prophylaxis with a systemically effective drug that is active against moulds (AIII) [83Go–85Go].

Pneumocystis jiroveci
The former protozoon Pneumocystis carinii has been reclassified as a lower fungus and renamed as Pneumocystis jiroveci. It has been suggested to preserve the old abbreviation PCP for P. carinii pneumonia, which is now Pneumocystis pneumonia [86Go]. Pneumocystis jiroveci can cause severe, often lethal atypical pneumonia. Although the disease is mainly caused by organisms colonising the respiratory tract, a person-to-person transmission has been discussed [87Go, 88Go]. Therefore stem cell recipients should avoid contact with patients with PCP (BIII).

All allogeneic transplant patients should receive drug prophylaxis from engraftment until the end of immunosuppressive therapy or resolution of chronic GvHD. PCP prophylaxis should be given for at least 6 months. First choice is the administration of trimethoprim-sulfamethoxazole (AII). Alternatives, when TMP-SMZ is not tolerated or contraindicated, are dapsone or aerosolised pentacarinate; higher breakthrough rates have been reported for these drugs (AII) [89Go–91Go].


    Toxoplasmosis
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 Immune-system recovery after...
 Bacterial infections
 Viral infections
 Fungal infections
 Toxoplasmosis
 Conclusions
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Patients who plann to receive an allograft should be tested for antibodies against Toxoplasma gondii to determine their risk for reactivation. All patients should be instructed regarding exposure strategies (AIII). Contact with cats should be restricted after discharge and restrictions in nutrition regarding raw meat should be considered (AIII). Some investigators propose Toxoplasma prophylaxis during acute GvHD or a secondary prophylaxis after a history of toxoplasmosis (CIII). Proposed drugs are TMP-SMZ, clindamycine and pyrimethamine with leucovorine. However, the optimal regimen has not been determined so far. Overall, toxoplasmosis is a rare disease after bone marrow transplantation and mainly associated with severe GvHD [92Go].


    Conclusions
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 Conditioning therapy and...
 Immune-system recovery after...
 Bacterial infections
 Viral infections
 Fungal infections
 Toxoplasmosis
 Conclusions
 References
 
With regard to the cited clinical trials and other references, the panel recommends the antimicrobial prophylaxis after allogeneic bone marrow transplantation as given in Table 3.


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Table 3. Overview about antimicrobial drug prophylaxis in allogeneic stem cell transplantation

 
Food restrictions
Food can be contaminated by bacteria, fungi and other organisms. Thus, food restrictions during and after stem cell transplantation are common practice in the transplant scene. For example, nuts can be contaminated with Aspergillus spp. or other moulds, non-pasteurised milk and related products can contain Listeria spp., and eggs can be contaminated with Salmonella spp. Table 4 shows risk-bearing nutrients and recommended alternatives (BIII).


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Table 4. Risk-bearing food and better alternatives

 
Vaccination after stem cell transplantation
Immunity after transplantation is influenced by immunity prior to transplantation, by the donor's immunity, by the course of immune reconstitution after transplantation, and by other factors. Therefore, 1 year after allogeneic transplantation an analysis of immunity against distinct pathogens should be carried out and re-immunisation with inactivated vaccine or toxoids can be initiated (AIII). Recommendations are shown in Table 5. These recommendations are based on the presumption that the patients are immunologically reconstituted 24 months after stem cell transplantation, do not have active graft-versus-host disease and are not on immunosuppressive medication [58Go, 93Go, 94Go].


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Table 5. Recommended vaccinations after allogeneic stem cell transplantation

 

Received for publication February 9, 2005. Accepted for publication March 3, 2005.


    References
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 Abstract
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 Conditioning therapy and...
 Immune-system recovery after...
 Bacterial infections
 Viral infections
 Fungal infections
 Toxoplasmosis
 Conclusions
 References
 
1. Cornely OA, Schirmacher P. Clinical picture: bacterial translocation in neutropenic sepsis. Lancet 2001; 358: 1842.[CrossRef][ISI][Medline]

2. Kruger WH, Hornung RJ, Hertenstein B et al. Practices of infectious disease prevention and management during hematopoietic stem cell transplantation: a survey from the European group for blood and marrow transplantation. J Hematother Stem Cell Res 2001; 10: 895–903.[CrossRef][ISI][Medline]

3. Gluckman E, Roudet C, Hirsch I et al. Prophylaxis of bacterial infections after bone marrow transplantation. A randomized prospective study comparing oral broad-spectrum nonabsorbable antibiotics (vancomycin-tobramycin-colistin) to absorbable antibiotics (ofloxacin-amoxicillin). Chemotherapy 1991; 37 (Suppl 1): 33–8.

4. Gruppo Italiano Malattie Ematologiche Maligne dell'Adulto. Prevention of bacterial infection in neutropenic patients with hematologic malignancies. A randomized, multicenter trial comparing norfloxacin with ciprofloxacin. The GIMEMA Infection Program. Ann Intern Med 1991; 115: 7–12.[ISI][Medline]

5. Lew MA, Kehoe K, Ritz J et al. Ciprofloxacin versus trimethoprim/sulfamethoxazole for prophylaxis of bacterial infections in bone marrow transplant recipients: a randomized, controlled trial. J Clin Oncol 1995; 13: 239–250.[Abstract/Free Full Text]

6. Prentice HG, Hann IM, Nazareth B, Paterson P, Bhamra A, Kibbler CC. Oral ciprofloxacin plus colistin: prophylaxis against bacterial infection in neutropenic patients. A strategy for the prevention of emergence of antimicrobial resistance. Br J Haematol 2001; 115: 46–52.[CrossRef][ISI][Medline]

7. Engels EA, Lau J, Barza M. Efficacy of quinolone prophylaxis in neutropenic cancer patients: a meta-analysis. J Clin Oncol 1998; 16: 1179–1187.[Abstract/Free Full Text]

8. Cruciani M, Rampazzo R, Malena M et al. Prophylaxis with fluoroquinolones for bacterial infections in neutropenic patients: a meta-analysis. Clin Infect Dis 1996; 23: 795–805.[ISI][Medline]

9. Attal M, Schlaifer D, Rubie H et al. Prevention of gram-positive infections after bone marrow transplantation by systemic vancomycin: a prospective, randomized trial. J Clin Oncol 1991; 9: 865–870.[Abstract/Free Full Text]

10. Kolbe K, Domkin D, Derigs HG, Bhakdi S, Huber C, Aulitzky WE. Infectious complications during neutropenia subsequent to peripheral blood stem cell transplantation. Bone Marrow Transplant 1997; 19: 143–147.[CrossRef][ISI][Medline]

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