Prophylaxis And Therapy

Antibacterial prophylaxis is recommended in allogeneic HSCT recipients who develop chronic GVHD and should be targeted at encapsulated organisms, including Streptococcus pneumoniae, Hemophilus influenzae, and Neisseria meningitidis.2 Selection of a regimen should be guided by local pneumococcal susceptibility profiles. Prophylaxis against Pneumocystis carinii is indicated in allogeneic HSCT recipients and should commence with engraftment and extend through all periods of immunodeficiency and for at least 6 months.2 High-risk autol-ogous HSCT recipients are candidates for PCP prophylaxis, including those with underlying hematologic malignancies, recipients of intensive preparative regimens or graft manipulation, and recent recipients of fludarabine or 2-chlorodeoxyadenosine. Trimethoprim-sulfamethoxazole is the preferred agent. In allergic individuals, desensitization should be attempted. In those unable to tolerate trimethoprim-sulfamethoxazole, alternative agents include dapsone, atovaquone, and aerosolized pentamidine. The latter is least effective and should only be used in patients unable to tolerate other regimens.

Prophylaxis against I. gondii is recommended in allogeneic HSCT patients with active GVHD or with a prior history of Toxoplasma chorioretinitis.2 Trimethoprim-sulfamethoxazole is preferred, though rare break-through cases have occurred.52 In sulfa-intolerant patients, clindamycin, pyrimethamine, and leucovorin may be substituted.

Prophylaxis against yeast infections is not routinely recommended following engraftment. The utility of and optimal regimen for prophylaxis against aspergillo-sis in the early postengraftment period is unclear; many centers nevertheless choose to continue Aspergillus prophylaxis though this period, especially in high-risk individuals with GVHD.

All allogeneic HSCT recipients at-risk for CMV, including CMV seropositive recipients and seronegative recipients with seropositive donors, should either receive prophylaxis commencing at engraftment or should be monitored at least weekly for evidence of CMV viremia.2 Several tests may be used to detect CMV viremia, including the pp65 antigenemia assay, CMV-DNA PCR, or hybrid capture DNA detection. Routine and rapid shell vial cultures are less sensitive and more time-consuming. CMV-DNA PCR is extremely sensitive, but has a low positive predictive value.53 Patients with detectable antigenemia on 2 or more consecutive tests positive for CMV DNA should commence preemptive therapy. Ganciclovir given intravenously has been the agent of choice for prophylaxis and preemptive treatment. However, one recent multicenter, randomized study compared oral valacyclovir with intravenous ganciclovir from engraftment to day 100 in CMV seropositive allogeneic HSCT recipients and found oral valacyclovir comparably effective.53 Once commenced, ganciclovir should be continued through day 100 or at least for 3 weeks in those receiving preemptive therapy, whichever is longer. If tests are available to detect viremia, a negative test result should be confirmed prior to discontinuing ganciclovir. A prophylactic strategy is preferred in centers unable to perform CMV antigen detection or CMV DNA detection by PCR or hybrid capture. Some centers with these capabilities nevertheless prefer a prophylactic strategy, while others advocate preemptive therapy so as to limit unnecessary ganciclovir exposure, as ganciclovir prophylaxis has been associated with more neutrope-nia, delayed recovery of CMV-specific immune responses, and a higher incidence of invasive fungal and bacterial infections.2 49 54 Neutropenia arising on ganciclovir may be managed with G-CSF, or by holding the drug for several days. In those unable to tolerate ganciclovir, foscarnet may be used. The strategies of CMV prophylaxis and preventive therapy have reduced the incidence of CMV disease in the early postengraftment period. There is increasing evidence, however, of late CMV disease beyond day 100 in high-risk patients.51 Risk factors for late disease include the presence of chronic GVHD, corticosteroid use, delayed development of high avidity anti-CMV antibody, low CD4 count, and receipt of a matched unrelated or T-cell-depleted HSCT.2 The utility of extended prophylaxis in high-risk patients has not been proven; these individuals should be monitored for evidence of CMV viremia beyond day 100, especially during intensification of immunosuppression. If detected, 3 weeks of preemptive therapy is recommended.

Because CMV disease is rare following autologous HSCT, screening for viremia is not routinely recommended, except in high-risk patients with underlying hematologic malignancies, in those who have recently received fludarabine or 2-chlorodeoxyadenosine, or in recipients of particularly intensive preparative regi-mens.2 In such individuals, monitoring to day 60 has been suggested; viremic patients should receive 3 weeks of preemptive therapy.

Patients with tissue invasive CMV disease, such as pneumonia and enterocolitis, should receive 3 weeks of therapy.5 Ganciclovir-resistant CMV is rare and usually occurs in immunodeficient patients who have previously received multiple courses of ganciclovir. Sustained viremia through ganciclovir should suggest the presence of UL97 genotypic resistance mutations and prompt a switch to foscarnet.

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