Pharmacology Consult

The good, bad and unnecessary prescribing of oral vancomycin prophylaxis in immunosuppressed patients

Jennifer Ross
Kimberly D. Boeser

Clostridioides difficile infection, or CDI, continues to be a significant pathogen in both hospitals and community-based settings. The associated morbidity, mortality and health care costs have prompted many to strengthen infection prevention and antimicrobial stewardship strategies to minimize transmission and recurrence. Optimizing these efforts is a tough task because of the broad array of CDI risk factors. Recent antibiotic exposure — especially to fluoroquinolones, clindamycin, carbapenems and third- and fourth-generation cephalosporins — along with chemotherapy, proton-pump inhibitors, immunosuppression, advanced age, comorbidities such as renal dysfunction and hospitalization duration are known CDI risk factors. The frequent exposure to antimicrobials and health care settings, along with higher rates of C. difficile colonization in the immunosuppressed population, poses an appreciable conundrum to clinicians who are trying to reduce CDI risk.

In a recent review article by Revolinski and Munoz-Price, CDI rates ranged from 6% to 33% in the hematology-oncology population, with most cases occurring within 30 days after transplantation, and up to 19% and 23% in liver and lung transplant recipients, respectively. CDI recurrence is also prevalent in hematology- oncology and solid organ transplant patients, with rates nearing 40%. The 2017 Infectious Diseases Society of America CDI treatment guidelines make no specific treatment recommendations for immunosuppressed patients, only that oral vancomycin and fidaxomicin should be prescribed for initial CDI episodes. Despite the scarcity of literature in primary and secondary CDI prophylaxis regimens, there has been an alarming trend in prescribing these regimens. This has resulted in controversial use of prophylactic oral vancomycin, particularly in the immunosuppressed patient population.

The good ... maybe

In the limited literature available, enteral vancomycin is the most studied agent for primary or secondary CDI prophylaxis. Not only is this medication cost- effective in comparison to fidaxomicin, but it has a relatively benign adverse effect profile due to its lack of systemic absorption. A retrospective cohort study by Ganetsky and colleagues examined the efficacy of CDI prophylaxis with oral vancomycin (125 mg twice daily starting on admission and continued until discharge) compared with no prophylaxis in 145 adult allogeneic hematopoietic cell transplant (HCT) recipients. There were no cases of CDI in patients who received prophylaxis (0/90), whereas 20% (11/55) of patients who did not receive prophylaxis developed CDI (P < .001). Interestingly, the two cohorts did not differ significantly in terms of hospital lengths of stay, graft- versus host-disease rates, and survival outcomes. However, the study’s small sample size, along with unaccounted confounding factors such as other antibiotic prophylaxis, empiric antimicrobial therapy in the setting of neutropenic fever and clinical symptoms that prompted diagnostic testing, limit the study’s utility in similar practice settings.

Another retrospective study by Splinter and colleagues showed no cases of CDI recurrence among eight adult kidney transplant recipients who received broad-spectrum antibiotics in the vancomycin prophylaxis (125 mg twice daily) group compared with 8% (2/24) of patients who did not receive prophylaxis (P = .54). A significant limitation was the small sample size, resulting in insufficient power. Oral vancomycin prophylaxis was administered during specific CDI outbreak periods on the transplant unit at the discretion of the attending provider, increasing the likelihood of selection bias. Although the data are promising, more prospective studies are needed in this population.

Despite the above-mentioned studies, the data for using oral vancomycin are conflicting. A retrospective abstract by Pereiras and colleagues examined oral vancomycin prophylaxis vs. no prophylaxis in 180 allogeneic HCT patients with and without a documented CDI history. The rates of CDI occurrence were similar between the cohorts but, notably, 18 patients developed vancomycin-resistant Enterococcus (VRE) bacteremia.

The bad

The updated CDI treatment guidelines made a new, weakly designated recommendation for prescribing an oral vancomycin taper or pulsed regimen for second or subsequent CDI recurrences. The downstream effects this type of regimen has on the development of resistance and the promotion of VRE colonization is largely unknown. This same concern must carefully be evaluated before recommendations can be made regarding oral vancomycin prophylaxis in both immunosuppressed and immunocompetent populations.

Can other medications take the role of oral vancomycin prophylaxis? Metronidazole, a first-line treatment option for nearly 30 years, is shied away from because of short- and long-term adverse effects that include nausea, vomiting and peripheral and central neuropathies. There are some data, albeit limited, from immunocompetent patients, supporting the use of metronidazole as secondary prophylaxis in those with recurrent CDI.

Fidaxomicin is a narrow-spectrum macrolide antibiotic that is more selective for C. difficile compared with vancomycin, which may result in less gut microbiome alteration and selection of VRE. DEFLECT-1, a randomized, double-blind, placebo-controlled study, is the first trial to investigate fidaxomicin prophylaxis in 600 autologous and allogeneic HCT adults receiving fluoroquinolones during neutropenic periods. Fidaxomicin 200 mg daily was initiated within 2 days of the conditioning regimen or fluoroquinolone start and continued for 7 days after engraftment or completion of fluoroquinolone therapy. Rates of prophylaxis failure 30 days after treatment were similar in the fidaxomicin and placebo groups (28.6% vs. 30.8%; P = .278). However, many of the prophylaxis failures in the fidaxomicin group were attributed to non-CDI events, such as receipt of metronidazole and discontinuation because of adverse events. In the CDI-only analysis, CDI incidence was significantly lower in the fidaxomicin group than in the placebo group (4.3% vs. 10.7%; P = .0014).

Several articles have examined probiotics for the prevention of CDI, but most have not included immunosuppressed patients. Cohen and colleagues investigated the incidence and outcomes of bloodstream infections (BSIs) among HCT recipients receiving probiotic supplementation. According to the findings, 0.5% patients within 1 year of HCT developed a BSI caused by a common probiotic species, with Lactobacillus species being isolated in all but one case. Riquelme and colleagues described two Saccharomycescerevisiae fungemia cases in immunosuppressed patients (one kidney-pancreas transplant patient and one patient newly diagnosed with HIV) who were started on Saccaromyces boulardii capsules in the setting of persistent diarrhea after CDI diagnosis. Although the risk for probiotic-derived BSIs appears low in immunosuppression, more data are needed to further evaluate the efficacy of probiotics in preventing CDI and CDI recurrence in this population.

The unnecessary

The morbidity, mortality and financial implications of CDI and CDI recurrence for patients, health systems and communities remain prominent. As reporting and tracking of hospital-acquired CDI becomes a requirement for health systems, more pressure will mount to implement measures to reduce initial CDI episodes and recurrence. The current literature has many limitations and, at best, is conflicting in immunosuppressed patients. The retrospective nature, small sample sizes and heterogeneity across the studies make generalizability difficult and leave many lingering questions. Strong consideration has to be given to future implications because the potential for resistance and selection of VRE is largely unknown. The added costs associated with primary and secondary prophylactic vancomycin regimens not only contribute increased health care costs but may be without the added benefits of preventing CDI and CDI recurrence. For these reasons, continued efforts in optimizing infection prevention and inpatient and outpatient antimicrobial stewardship is critical. Immunosuppressed patients are clearly at greater risk of CDI and CDI recurrence. Risk stratification within this population based on donor source, conditioning regimen and CDI history is imperative to ensure proper use of oral vancomycin prophylaxis without more, prospective data. In the interim, use of oral vancomycin prophylaxis is unnecessary because the risks continue to outweigh the benefits.

Disclosures: Boeser and Ross report no relevant financial disclosures.

Jennifer Ross
Kimberly D. Boeser

Clostridioides difficile infection, or CDI, continues to be a significant pathogen in both hospitals and community-based settings. The associated morbidity, mortality and health care costs have prompted many to strengthen infection prevention and antimicrobial stewardship strategies to minimize transmission and recurrence. Optimizing these efforts is a tough task because of the broad array of CDI risk factors. Recent antibiotic exposure — especially to fluoroquinolones, clindamycin, carbapenems and third- and fourth-generation cephalosporins — along with chemotherapy, proton-pump inhibitors, immunosuppression, advanced age, comorbidities such as renal dysfunction and hospitalization duration are known CDI risk factors. The frequent exposure to antimicrobials and health care settings, along with higher rates of C. difficile colonization in the immunosuppressed population, poses an appreciable conundrum to clinicians who are trying to reduce CDI risk.

In a recent review article by Revolinski and Munoz-Price, CDI rates ranged from 6% to 33% in the hematology-oncology population, with most cases occurring within 30 days after transplantation, and up to 19% and 23% in liver and lung transplant recipients, respectively. CDI recurrence is also prevalent in hematology- oncology and solid organ transplant patients, with rates nearing 40%. The 2017 Infectious Diseases Society of America CDI treatment guidelines make no specific treatment recommendations for immunosuppressed patients, only that oral vancomycin and fidaxomicin should be prescribed for initial CDI episodes. Despite the scarcity of literature in primary and secondary CDI prophylaxis regimens, there has been an alarming trend in prescribing these regimens. This has resulted in controversial use of prophylactic oral vancomycin, particularly in the immunosuppressed patient population.

The good ... maybe

In the limited literature available, enteral vancomycin is the most studied agent for primary or secondary CDI prophylaxis. Not only is this medication cost- effective in comparison to fidaxomicin, but it has a relatively benign adverse effect profile due to its lack of systemic absorption. A retrospective cohort study by Ganetsky and colleagues examined the efficacy of CDI prophylaxis with oral vancomycin (125 mg twice daily starting on admission and continued until discharge) compared with no prophylaxis in 145 adult allogeneic hematopoietic cell transplant (HCT) recipients. There were no cases of CDI in patients who received prophylaxis (0/90), whereas 20% (11/55) of patients who did not receive prophylaxis developed CDI (P < .001). Interestingly, the two cohorts did not differ significantly in terms of hospital lengths of stay, graft- versus host-disease rates, and survival outcomes. However, the study’s small sample size, along with unaccounted confounding factors such as other antibiotic prophylaxis, empiric antimicrobial therapy in the setting of neutropenic fever and clinical symptoms that prompted diagnostic testing, limit the study’s utility in similar practice settings.

Another retrospective study by Splinter and colleagues showed no cases of CDI recurrence among eight adult kidney transplant recipients who received broad-spectrum antibiotics in the vancomycin prophylaxis (125 mg twice daily) group compared with 8% (2/24) of patients who did not receive prophylaxis (P = .54). A significant limitation was the small sample size, resulting in insufficient power. Oral vancomycin prophylaxis was administered during specific CDI outbreak periods on the transplant unit at the discretion of the attending provider, increasing the likelihood of selection bias. Although the data are promising, more prospective studies are needed in this population.

Despite the above-mentioned studies, the data for using oral vancomycin are conflicting. A retrospective abstract by Pereiras and colleagues examined oral vancomycin prophylaxis vs. no prophylaxis in 180 allogeneic HCT patients with and without a documented CDI history. The rates of CDI occurrence were similar between the cohorts but, notably, 18 patients developed vancomycin-resistant Enterococcus (VRE) bacteremia.

PAGE BREAK

The bad

The updated CDI treatment guidelines made a new, weakly designated recommendation for prescribing an oral vancomycin taper or pulsed regimen for second or subsequent CDI recurrences. The downstream effects this type of regimen has on the development of resistance and the promotion of VRE colonization is largely unknown. This same concern must carefully be evaluated before recommendations can be made regarding oral vancomycin prophylaxis in both immunosuppressed and immunocompetent populations.

Can other medications take the role of oral vancomycin prophylaxis? Metronidazole, a first-line treatment option for nearly 30 years, is shied away from because of short- and long-term adverse effects that include nausea, vomiting and peripheral and central neuropathies. There are some data, albeit limited, from immunocompetent patients, supporting the use of metronidazole as secondary prophylaxis in those with recurrent CDI.

Fidaxomicin is a narrow-spectrum macrolide antibiotic that is more selective for C. difficile compared with vancomycin, which may result in less gut microbiome alteration and selection of VRE. DEFLECT-1, a randomized, double-blind, placebo-controlled study, is the first trial to investigate fidaxomicin prophylaxis in 600 autologous and allogeneic HCT adults receiving fluoroquinolones during neutropenic periods. Fidaxomicin 200 mg daily was initiated within 2 days of the conditioning regimen or fluoroquinolone start and continued for 7 days after engraftment or completion of fluoroquinolone therapy. Rates of prophylaxis failure 30 days after treatment were similar in the fidaxomicin and placebo groups (28.6% vs. 30.8%; P = .278). However, many of the prophylaxis failures in the fidaxomicin group were attributed to non-CDI events, such as receipt of metronidazole and discontinuation because of adverse events. In the CDI-only analysis, CDI incidence was significantly lower in the fidaxomicin group than in the placebo group (4.3% vs. 10.7%; P = .0014).

Several articles have examined probiotics for the prevention of CDI, but most have not included immunosuppressed patients. Cohen and colleagues investigated the incidence and outcomes of bloodstream infections (BSIs) among HCT recipients receiving probiotic supplementation. According to the findings, 0.5% patients within 1 year of HCT developed a BSI caused by a common probiotic species, with Lactobacillus species being isolated in all but one case. Riquelme and colleagues described two Saccharomycescerevisiae fungemia cases in immunosuppressed patients (one kidney-pancreas transplant patient and one patient newly diagnosed with HIV) who were started on Saccaromyces boulardii capsules in the setting of persistent diarrhea after CDI diagnosis. Although the risk for probiotic-derived BSIs appears low in immunosuppression, more data are needed to further evaluate the efficacy of probiotics in preventing CDI and CDI recurrence in this population.

PAGE BREAK

The unnecessary

The morbidity, mortality and financial implications of CDI and CDI recurrence for patients, health systems and communities remain prominent. As reporting and tracking of hospital-acquired CDI becomes a requirement for health systems, more pressure will mount to implement measures to reduce initial CDI episodes and recurrence. The current literature has many limitations and, at best, is conflicting in immunosuppressed patients. The retrospective nature, small sample sizes and heterogeneity across the studies make generalizability difficult and leave many lingering questions. Strong consideration has to be given to future implications because the potential for resistance and selection of VRE is largely unknown. The added costs associated with primary and secondary prophylactic vancomycin regimens not only contribute increased health care costs but may be without the added benefits of preventing CDI and CDI recurrence. For these reasons, continued efforts in optimizing infection prevention and inpatient and outpatient antimicrobial stewardship is critical. Immunosuppressed patients are clearly at greater risk of CDI and CDI recurrence. Risk stratification within this population based on donor source, conditioning regimen and CDI history is imperative to ensure proper use of oral vancomycin prophylaxis without more, prospective data. In the interim, use of oral vancomycin prophylaxis is unnecessary because the risks continue to outweigh the benefits.

Disclosures: Boeser and Ross report no relevant financial disclosures.